U.S. DEPARATMENT OF HEALTH, EDUCATION, AND WELFARE • Public Health Service • Alcohol, Drug Abuse, and Menial Health Administration
The International Challenge of

Drug Abuse

Editor:

Robert C. Petersen, Ph.D.

NIDA Research Monograph 19

DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE

Public Health Service

Alcohol, Drug Abuse, and Mental Health Administration

National Institute on Drug Abuse

Division of Research

5600 Fishers Lane

Rockville, Maryland 20857
The NIDA Research Monograph series is prepared by the Division of Research of

the National lnstitute on Drug Abuse. Its primary objective is to provide critical reviews of research problem areas and techniques, the content of state-of-the-art

conferences intergrative research reviews and significant original research. Its

dual publication emphasis is rapid and targeted dissemination to the scientific

and professional community.

Editorial Advisory Board

Avram Goldstein, M.D.

Addiction Research Foundation

Palo Alto, California

Jerome Jaffe, M.D.

College of Physicians and Surgeons

Columbia University, New York

Reese T. Jones, M.D.

Langley Porter Neuropsychiatric Institute

University of California

San Francisco, California

William McGlothlin, Ph.D.

Department of Psychology, UCLA

Los Angeles, California

Jack Mendelson, M.D.

Alcohol ond Drug Abuse Research Center

Harvard Medical School

McLean Hospital

Belmont. Massachusetts

Helen Nowlis, Ph.D.

Office of Drug Education. DHEW

Washington, D.C.

Lee Robins, Ph.D.

Washington University School of Medicine

St. Louis, Missouri

NIDA Research Monograph series

Robert DuPont, M.D.

DIRECTOR, NIDA

William Pollin, M.D.

DIRECTOR, DIVISION OF RESEARCH, NIDA

Robert C. Petersen, Ph.D.

EDITOR-IN-CHIEF

Eleanor W. Waldrop

MANAGING EDITOR

Parklawn Building, 5600 Fishers Lane, Rockville, Maryland 20857
The International Challenge of

Drug Abuse
ACKNOWLEDGMENTS

Thanks are due to the World Psychiatric Association,

sponsor; the American Psychiatric Association, host; the

staff of the VI World Congress of Psychiatry, held in

Honolulu, Hawaii, August 28-September 3, 1977; and

especially to each person who took part in the plenary

session and symposia of the Drug Dependence Section upon

which this monograph is based.

The National Institute on Drug Abuse has obtained

permission from the copyright holder to reproduce chapter

12. Further reproduction of chapter 12 is prohibited

without specific permission of the C. V. Mosby Co.

Library of Congress catalog card number 78-60498

DHEW publication number (ADM) 78-654

Printed 1978

NIDA Research Monographs are indexed in the Index

Medicus. They are selectively included in the coverage of

BioSciences Information Service, Chemical Abstracts,

Psychological Abstracts, and Psychopharmacology Abstracts.

iv
FOREWORD

All over the world, people use drugs outside of medical

supervision; this has been true throughout the ages. Such drug use is

as unchanging as human physiology and the desire to “feel good.”

It is as diverse as a ten-year-old street boy sniffing toluene in

Mexico City, college students drinking beer or smoking “pot” in

Chicago, a young woman “mainlining” heroin in Paris, or an

octogenarian smoking his bamboo opium pipe in Burma’s Naga

Hills. Which drugs and what circumstances of use will be legally and

socially acceptable varies widely in different times and places. In

the United States, for example, use of caffeine, alcohol, and

tobacco is so familiar that it is difficult to think of them as drugs at

all.

Often, however, drug use becomes drug abuse in terms of its

serious adverse consequences for the individual, such as family

disruption, and for the society, as in increases of narcotics-related

crime. When this happens, government agencies concerned with

public health and safety intervene to try to limit the abuses. Each

country directs its limited resources to what are perceived as its

own problems of highest priority, seeking to reduce both the supply

and demand for drugs.

Not only is the abuse of drugs a global problem and a serious

one, it is also growing. This can be understood as the result of such

worldwide developments as increased mobility of people and goods,

rapid communication of news, greater numbers of young persons

concentrated in large cities which provide profitable drug markets,

and a general weakening of traditional social controls.

Governments at all levels are recognizing the urgency of their

drug abuse problems. More and more there is an awareness that

these problems are interrelated. In the demand reduction area, there

is increasing recognition of the need to share knowledge about

drugs and their effects and about methods of treatment and

prevention of drug abuse. These combined efforts will improve the

effectiveness and coordination of actions to combat drug problems

within each country, between nations, and through international

organizations.

An important opportunity for interchange of knowledge about

drug abuse took place at the VI World Congress of Psychiatry,

v
FOREWORD

which met in Honolulu, Hawaii, from August 28 to September 3,

1977, bringing together some 4000 psychiatrists. In recognition of

the present importance and even greater potential role of psychiatrists in understanding and dealing with demand reduction

aspects of drug abuse, a Drug Dependence Section was developed

which sponsored a plenary session and several symposia at the

Congress. This monograph is comprised of the papers presented at

those meetings.

While the United States, Canada, and Western Europe had the

largest attendance at the Congress, about one-fourth of those

present represented countries of Asia, Africa, and South America.

Individuals with major responsibilities in health organizations in

their countries and representatives from the United Nations and

World Health Organization came together to share their knowledge

and their problems in sessions dealing with:

Drug abuse and actions to deal with it by various countries,

the UN, and WHO

Psychobiology of drug abuse and affective disorders, and

mechanisms common to both

Research on the biological bases of drug abuse

Treatment of drug abuse, including an overview and detailed

reviews on narcotic antagonist therapy and long-acting methadone.

This collection of papers will share the facts and the highly varied

perspectives they present with a larger group of professionals

around the world who work with various aspects of drug abuse

demand reduction. It is offered in the hope that in some small

measure it will further our progress and help us better coordinate

our efforts to deal with the myriad of problems known collectively

as “drug abuse.”

ROBERT L. DUPONT, M.D.

Director

National Institute on Drug Abuse

vi
CONTRIBUTORS

Awni E. Arif, M. D.

Senior Medical Officer in Charge

Drug Dependence Program

Division of Mental Health

World Health Organization

Geneva, SWITZERLAND

Tolani Asuni, M.D.

Professor and Head

Department of Psychiatry

University of Ibadan

Ibadan, NIGERIA

Guido Belsasso, M.D.

Director General

Instituto Nacional de

Estudio de1 Trabajo

Pisa, MEXICO

Jack D. Blaine, M.D.

Research Psychiatrist

Clinical and Behavioral Branch

Division of Research

National Institute on Drug Abuse

Rockville, Maryland U.S.A.

Robert Byck, M.D.

Departments of Psychiatry and

Pharmacology

Yale University School of

Medicine

New Haven, Connecticut U.S.A.

V. Charles Charuvastra, M.D.

Chief, Drug Dependence Treatment

Program

Veterans Administration Hospital,

Brentwood

Los Angeles, California U.S.A.

James M. N. Ch’ien, M.S.W.,

M.P.H.

Superintendent of Social Service

Society for the Aid and Rehabilitation of Drug Addicts

HONG KONG

Brian Cox, B. Sc., D.P.A.

Drug Dependence Program

Division of Mental Health

World Health Organization

Geneva, SWITZERLAND

Robert L. DuPont, M.D.

Director

National Institute on Drug Abuse

Alcohol, Drug Abuse, and Mental

Health Administration

Rockville, Maryland U.S.A.

Mark S. Gold, M.D.

Department of Psychiatry

Yale University School of

Medicine

New Haven, Connecticut U.S.A.

J. Gomez del Prado

Social Affairs Officer

Division of Narcotic Drugs

United Nations

Geneva, SWITZERLAND

Robert Greenstein, M.D.

Department of Psychiatry

University of Pennsylvania

Drug Dependence Treatment and

Research Center

Veterans Administration Hospital

Philadelphia, Pennsylvania U.S.A.

Patrick H. Hughes, M.D.

Drug Dependence Program

Division of Mental Health

World Health Organization

Geneva, SWITZERLAND

Demetrios A. Julius, M.D.

Director

Social Development Center

of Tehran

Tehran, IRAN

Richard S. Kestenbaum, Ph.D.

Division of Drug Abuse Research and

Treatment

New York Medical College

New York, New York U.S.A.

vii
Inayat Khan, M.B., B.S., Ph.D.

Senior Medical Officer

Drug Dependence Program

Division of Mental Health

World Health Organization

Geneva, SWITZERLAND

U Khant M.B.B.S., D.P.M.

Rangoon Psychiatric Hospital

Rangoon, BURMA

C. James Klett, Ph.D.

Chief, Cooperative Studies Program,

and

Chief, Central Neuropsychiatric

Laboratory, Support Center

Veterans Administration Hospital

Perry Point, Maryland U.S.A.

Gail L. Levine

John Whysner Associates

3217 K Street, N. W.

Washington, D.C. U.S.A.

George M. Ling, Ph.D.

Director

Division of Narcotic Drugs

United Nations

Geneva, SWITZERLAND

Walter Ling, M.D.

Chief, Drug Dependence Treatment

Program

Veterans Administration Hospital

Sepulveda, California U.S.A.

William R. Martin, M.D.

Director, Addiction Research

Center

National Institute on Drug Abuse

P.O. Box 13290

Lexington, Kentucky U.S.A.

Nancy K. Mello, Ph.D.

Associate Professor of Psychology

Associate Director of the Alcohol

and Drug Abuse Research Center

McLean Hospital—Harvard Medical

School 

Belmont, Massachusetts U.S.A.

CONTRIBUTORS

Jack H. Mendelson, M.D.

Professor of Psychiatry

Director, Alcohol and Drug Abuse

Research Center

McLean Hospital—Harvard Medical

School

Belmont, Massachusetts U.S.A.

M. R. Moharreri, M.D.

Associate Professor of Psychiatry

Pahlavi University

Regional Officer for Drug Addiction

and Rehabilitation Services

Ministry of Social Welfare

Shiraz, IRAN

Dennis Murphy, M.D.

Chief, Section of Clinical Neuropharmacology

National Institute of Mental Health

Bethesda, Maryland U.S.A.

Ne Win, M.B.B.S., D.P.M.,

MRC Psych.

Rangoon Psychiatric Hospital

Rangoon, BURMA

Nils D. Noya, M.D.

National Director of Control of

Dangerous Substances

Assistant Professor of Psychiatry

of the U.M.S.A.

Department of Medicine—Sociology

La Paz, BOLIVIA

Charles P. O’Brien, M.D., Ph.D.

Associate Professor of Psychiatry

Director, Drug Dependence Treatment

and Research Center

Veterans Administration Hospital

Philadelphia, Pennsylvania U.S.A.

Robert C. Petersen, Ph.D.

Assistant Director for Program

Integration and Coordination

Division of Research

National Institute on Drug Abuse

Rockville, Maryland U.S.A.

vii
CONTRIBUTORS

Pierre F. Renault, M.D.

Chief, Clinical and Behavioral

Branch

Division of Research

National Institute on Drug Abuse

Rockville, Maryland U.S.A.

Richard B. Resnick, M.D.

Director, Division of Drug Abuse

Research and Treatment

New York Medical College

New York, New York U.S.A.

R. Kusumanto Setyonegoro, M.D.

Professor of Psychiatry

University of Indonesia

Director of Mental Health

Ministry of Health

Jakarta, INDONESIA

Costas Stefanis, M.D.

Professor of Psychiatry

University of Athens School of

Medicine

Eginition Hospital

Athens, GREECE

Richard C. Stillman, M.D.

Research Psychiatrist

Division of Research

National Institute on Drug Abuse

Laboratory of Clinical Psychopharmacology

National Institute of Mental Health

Bethesda, Maryland U.S.A.

Muriel A. Thomas, R.N.

Division of Drug Abuse Research

and Treatment

New York Medical College

New York, New York U.S.A.

Arnold M. Washton, Ph.D.

Division of Drug Abuse Research

and Treatment

New York Medical College

New York, New York U.S.A.

Herbert Weingartner, Ph.D.

National Institute of Mental Health

Bethesda, Maryland U.S.A.

John A. Whysner, M. D., Ph.D.

President, John Whysner Associates

3217 K Street, N. W.

Washington, D.C. U.S.A.

Robert E. Willette, Ph.D.

Chief, Research Technology Branch

Division of Research

National Institute on Drug Abuse

Rockville, Maryland U.S.A.

George E. Woody, M.D.

Assistant Professor of Psychiatry

University of Pennsylvania

Assistant Chief, Drug Dependence

Treatment and Research Center

Veterans Administration Hospital

Philadelphia, Pennsylvania U.S.A.

Tomoji Yanagita, M.D.

Professor of Pharmacology

Preclinical Research Laboratories

Central Institute for Experimental

Animals

Kawasaki, JAPAN

ix

CONTENTS

Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v

Robert L. DuPont

Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii

I. The International Challenge of Drug Abuse

Robert L. DuPont and George M. Ling, Chairmen

1. International Challenge of Drug Abuse: A Perspective From

the United States

Robert L. DuPont . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

2. The Drug Abuse Scene in Nigeria

Tolani Asuni . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

3. The International Challenge of Drug Abuse: The Mexican

Experience

Guido Belsasso . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

4. WHO’s Programme in Drug Dependence, With Special

Emphasis on Developing Countries

Inayat Khan, Awni E. Arif, Patrick H. Hughes,

and Brian Cox . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

5. Drug Abuse in the Socialist Republic of the Union of Burma

U Khant and Ne Win.. . . . . . . . . . . . . . . . . . . . . . . . . 51

6. International Challenge of Drug Abuse: A Perspective From

the United Nations

George M. Ling and J. Gomez de1 Prado . . . . . . . . . . . . . 60

7. General View of Drug Abuse in Iran and a One-Year Report

of Outpatient Treatment of Opiate Addiction in the City of

Shiraz

M. R. Moharreri . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69

8. Coca and Cocaine: A Perspective from Bolivia

Nils D. Noya . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82

9. Drug Abuse in Indonesia

R. Kusumanto Setyonegoro . . . . . . . . . . . . . . . . . . . . . 91

xi
CONTENTS

II. Biological Aspects of Drug Dependence

Jack H. Mendelson, Chairman

10. Bio-Socio Approach in Drug Abuse Treatment and

Prevention

James M. N. Ch’ien.. . . . . . . . . . . . . . . . . . . . . . . . . .112

11. Behavioral Pharmacology of Narcotic Antagonists

Nancy K. Mello . . . . . . . . . . . . . . . . . . . . . . . . . . . . .126

12. Plasma Testosterone Levels During Chronic Heroin Use and

Protracted Abstinence: A Study of Hong Kong Addicts

Jack H. Mendelson and Nancy K. Mello . . . . . . . . . . . . . 142

13. Biological Aspects of Cannabis Use

Costas Stefanis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149

14. Drug Dependence Studies in Laboratory Animals

Tomoji Yanagita . . . . . . . . . . . . . . . . . . . . . . . . . . . .179

III. Psychobiology of Drug Abuse and Affect Disorders

Richard C. Stillman, Chairman

15. Endorphins, Lithium, and Naloxone: Their Relationship to

Pathological and Drug-Induced Manic-Euphoric States

Mark S. Gold and Robert Byck . . . . . . . . . . . . . . . . . . 192

16. Drug and Mood State-Specific Encoding and Retrieval of

Experience

Herbert Weingartner, Dennis Murphy, and

Richard C. Stillman . . . . . . . . . . . . . . . . . . . . . . . . . 210

IV. Treatment

17. Multimodality Treatment of Narcotic Addiction: An

Overview

George E. Woody, Charles P. O’Brien, and

Robert Greenstein . . . . . . . . . . . . . . . . . . . . . . . . .226

Treatment: LAAM

Walter Ling, Chairman

18. Levo-Alpha-Acetylmethadol: New Drug for Old Habits

Walter Ling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .242

19. Early Clinical Studies of Levo-Alpha Acetylmethadol

(LAAM): An Opiate Agonist for Use in the Medical Treatment

of Chronic Heroin Dependence

Jack D. Blaine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .249

xii
CONTENTS

20. A U.S. Veterans Administration Cooperative Study on

Methadyl Acetate

V. Charles Charuvastra . . . . . . . . . . . . . . . . . . . . . . . . 260

21. The SOADAP Cooperative Studies of LAAM: Unblinded

Comparison with Methadone

C. James Klett . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271

22. Phase III Clinical Study of LAAM: Report of Current

Status and Analysis of Early Terminations

John A. Whysner and Gail L. Levine . . . . . . . . . . . . . 277

23. The Future of LAAM

Pierre F. Renault . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291

Treatment: Naltrexone

Demetrios A. Julius, Chairman

24. A History of the Development of Narcotic Antagonists for

the Treatment of Narcotic Addiction

William R. Martin . . . . . . . . . . . . . . . . . . . . . . . . . . . .

25. Historical Trends in Naltrexone Research

Demetrios A. Julius . . . . . . . . . . . . . . . . . . . . . . . .

26. Naltrexone: The Clinical Investigator’s Dilemma

Walter Ling . . . . . . . . . . . . . . . . . . . . . . . . . . . .

27. Update on Naltrexone Treatment

Charles P. O'Brien, Robert Greenstein, and

George E. Woody . . . . . . . . . . . . . . . . . . . . . . . . .

28. Naltrexone in the Treatment of Opiate Dependence

Richard B. Resnick, Arnold M. Washton, Muriel A.

Thomas, and Richard S. Kestenbaum . . . . . . . . . .

29. The Development of Sustained Action Preparations of

Narcotic Antagonists

296

301

308

315

321

Robert E. Willette . . . . . . . . . . . . . . . . . . . . . . . . . . . .

30. The Future of Naltrexone

333

Pierre F. Renault . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340

List of Monographs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346

xiii
I.

The International Challenge

of Drug Abuse

Robert L. DuPont

George M. Ling

Chairmen

CHAPTER 1

International Challenge of Drug

Abuse: A Perspective From the

United States

Robert L. DuPont, M. D.

It is a great pleasure for me to welcome you to this important

meeting. With the leadership of my cochairman, Dr. Ling, and the

outstanding presentations by members of this panel, we are coming

to the end of a unique week-long panoramic view of drug abuse as a

key issue in modern psychiatry. The panel members have reflected

the global dimensions of this serious, growing problem. We owe all

of them our sincere thanks.

Some of the most valuable experiences I have had in the four

years since I joined the United States Government’s drug abuse

program have been my travels to many of the countries represented

at this Congress. These travels, plus the many international visitors

to the National Institute on Drug Abuse in Washington, have

convinced me that our responses to drug abuse problems can bring

us together to share our knowledge and thus build new bridges

between countries and cultures.

Psychiatry with its unique blend of scientific medicine, understanding of human behavior, and compassion for the human

condition must play a central role in helping our nations cope with

the vexing problems of drug abuse. Throughout the world, I have

been privileged to work with psychiatrists who have assumed

leadership roles in the drug abuse field. Our profession has much to

be proud of, but far more remains to be done.

In my presentation today, I will briefly summarize the U.S. drug

scene and highlight some of the common themes which have

emerged from the preceding presentations. Based on these presentations and current experience from the United States, we can learn

several lessons.

3
INTERNATIONAL CHALLENGE OF DRUG ABUSE

THE DRUG ABUSE SITUATION IN THE UNITED

STATES AND OUR RESPONSE TO IT

A major national response to drug abuse, involving all segments

of our population, has occurred in the United States during the last

six or seven years. Since about 1970, drug abuse has been an

important item on our national agenda. One important manifestation of this national experience is demonstrated by our new

President. When Jimmy Carter became Governor of Georgia in

1971, one of the first problems in which he took a personal interest

was drug abuse. While he was Governor, a system of drug abuse

clinics was established throughout the State of Georgia, not only in

the capital city of Atlanta, but also in the smaller communities. Mr.

Carter created a national model for statewide drug abuse services. In

1971 and in subsequent years, he has spent time visiting drug abuse

programs all over the country, talking personally to drug abuse

workers and to drug abusers. We now have a U. S. President who is

involved in our efforts.

Drug abuse is not only a political issue to Mr. Carter, it is a very

personal issue and one about which he is personally knowledgeable.

His special advisor on human needs, including drug abuse, is Dr.

Peter Bourne who was the psychiatrist who started the Carter drug

abuse program in Georgia in 1971. Peter Boume was one of the first

persons to grasp the important international dimensions of the drug

abuse problem outside the traditional law enforcement area. Peter is

close to the President, and he is now placed directly within the

White House. We can definitely count on a dedicated, high-level,

and continuing commitment to drug abuse prevention from the

U.S. Government.

As an expression of our current national response to drug abuse,

today there are about 250,000 people receiving drug treatment in

over 3,000 clinics and drug abuse programs in the United States.

These treatment centers, which employ over 30,000 fulltime

workers, are found not only on the coasts and big cities, but

throughout the country. Physicians make up 600 of the total drug

abuse workers. Paraprofessional counselors, numbering nearly

11,000, are the core staff members of these modern clinics. Nearly

40 percent of this large drug abuse treatment capacity is funded by

the Federal Government. State, local, and private sources provide

the remainder of the support for these programs.

Approximately 65 percent of the patients admitted to federally

funded drug abuse treatment programs in the United States are

treaded for heroin addiction. After heroin, the most often reported

4
DUPONT: A PERSPECTIVE FROM THE UNITED STATES

drug problems at admission are marihuana, barbiturates, and

amphetamines. Smaller percentages of U.S. patients report problems with cocaine, LSD, PCP, and volatile solvents.

Overall, about 30 percent of the U.S. treatment programs use

methadone as part of their treatment for heroin addicts. Looking

specifically at the persons treated for heroin abuse, we find slightly

more than half receiving methadone as part of their treatment. I

want to say an additional word about this because it is a

controversial area.

In the United States, methadone is one part of a comprehensive

response to heroin addiction; this treatment must also involve

counseling and other supportive services. Methadone, which has no

role in the treatment of drug problems other than opiate addiction,

is desirable as a substitute drug because it can be taken orally and

lasts for the whole day. Heroin, by contrast, has to be taken

intravenously four or five times a day. The individual who is taking

methadone can lead a relatively normal life with far fewer drug

administrations, and these by the oral route in a treatment context,

in contrast to his experience with heroin which is almost always

taken intravenously by the U. S. addicts. I hope that those of you

who have not yet seen a patient who is using methadone will visit a

good methadone clinic. It is a striking experience to see how normal

these patients appear. People who have never had this experience

have a hard time believing that they are talking with someone who

is taking a narcotic medication, when they first meet a methadone

maintenance patient.

It should be emphasized that most opiate users prefer detoxification, with gradually decreasing doses of methadone, to longterm

methadone maintenance. Outpatient methadone detoxification has

proven to be particularly attractive to American heroin addict

patients. Overall, about 33 percent of heroin addicts admitted to

federally funded treatment receive detoxification, 27 percent

receive maintenance, and the remainder, 40 percent, are treated in

drug-free programs.

When considering the use of methadone, it should be emphasized

that about two-thirds of all U.S. drug abuse treatment—for heroin

and other drugs—is now drug-free; that is, no opiate is used as part

of the treatment experience.

As we heard earlier this week, there are two promising new drugs

for the treatment of heroin addiction. The first is LAAM,

levo-alpha-acetylmethadol, an orally effective, synthetic opiate,

which needs to be taken only three times a week. In the same way

that methadone is better than heroin, so LAAM is better than

5
INTERNATIONAL CHALLENGE OF DRUG ABUSE

methadone: it lets the patient lead a more normal, less drug-centered

life. Perhaps I should also add that we see no practical reason to use

heroin as part of our U. S. treatment system, because heroin is not

effective by the oral route and its short duration of action requires

frequent administration and makes stabilization difficult to achieve.

The other new drug now being used successfully is naltrexone. It

is a safe and powerful, orally effective, narcotic antagonist.

Although both LAAM and naltrexone remain in research status,

we in the United States are optimistic that they will soon become

part of our anti-heroin effort. But, once again, neither should

detract from the important role of drug-free treatment.

Marihuana, like methadone, is a controversial issue. You will hear

it said that the United States is moving to legalize marihuana. This

statement is a distortion of reality. We in the United States are

trying to get the marihuana user and the person who has small

amounts of the drug for personal use out of prisons and out of the

criminal justice system, and to get the suppliers of drugs into the

prisons. The proposal that President Carter has made, and which I

strongly support, is the introduction of a fine or non-criminal

citation for marihuana possession offenses, instead of a prison

sentence. That is known as decriminalization. Prison sentences

remain and will remain for all marihuana traffickers in the United

States. There will be no legal supply of marihuana, except for

approved research studies.

OVERVIEW OF DRUG ABUSE: AN INTERNATIONAL

PROBLEM

The United States is different from much of the rest of the world

in that our heroin problem appears to have stabilized now after a

decade of growth. Use of barbiturates and LSD has fallen slightly in

recent years, but the use of marihuana and cocaine continues to rise

in the United States. Other areas of the world are now seeing the

same trends in heroin abuse that were evident in the United States

some time ago: an increase in heroin use with heroin becoming the

principal opiate of abuse, as well as the major source of drug-related

health and social problems. In Europe and Southeast Asia, increases

in heroin use appear to be particularly serious. Further, there is a

global concentration of heroin use in metropolitan areas and, to a

lesser extent, a spread of abuse into some rural areas.

Treatment approaches to heroin addiction also have spread

throughout the world. Methadone is used widely around the world,

6
DUPONT: A PERSPECTIVE FROM THE UNITED STATES

although—as in the United States—most countries do not rely on it

as the sole treatment approach. Outpatient and residential therapeutic community programs are now found in all parts of the

world. Although there are some communities in the world which

still do not have substantial heroin problems, they are becoming

fewer and fewer. There is increasing evidence all over the world of

growing problems with heroin addiction and other drug problems.

Many wonder why this is happening. The answer is so simple it

almost eludes us. Most drugs with psychoactive properties are what

psychiatrists and psychologists call reinforcing substances, They are

chemicals which, when taken into the body, produce feelings that

the user enjoys. It is as simple as that. The effects of drug abuse on

our countries and our communities are partly determined by the

biological action of the chemicals we call “drugs.” This biological

effect does not depend upon one’s age, sex, race, culture, or

national origin. This means that no person and no country is

immune from drug abuse. Drug abuse is not a unique characteristic

of any particular segment of society, any particular geographic

region, or any particular nation. It is a global human problem.

Certainly demographic, geographic, political, and social factors do

influence the levels of drug abuse throughout the world. However,

it is important to recognize that none of these factors eliminates

drug abuse problems and that epidemic spread of drug abuse is no

longer infrequent, even in areas once thought to be safe from drug

abuse. In fact, far more needs to be learned about how those

complex social and economic factors do, and do not, influence drug

use patterns.

In the past, the use of psychoactive drugs tended to be contained

in isolated geographic and cultural islands with social controls on

those who used them, how much they were used, when they were

used, and what was done with people who used too much.

Elaborately built-up cultural restraints on specific drug-taking

behaviors can be identified in countries all over the world. Good

examples of this are the traditional chewing of coca leaf in the

Andes region of South America, the traditional use of cannabis in

India and Mexico, and opium smoking in Iran or Laos. But, today,

these cultural constraints which characterized most cultures of the

world are dramatically breaking down.

The leading edge of this change has been the use of cannabis in

much of the world. The global levels of cannabis consumption are

truly remarkable. Heroin use, and other psychotropic drug use, has

shown a similar growth in many parts of the world. One of the most

fascinating questions is: What happened that suddenly brought

7
INTERNATIONAL CHALLENGE OF DRUG ABUSE

about a change in cannabis and other drug use in the last decade?

Most of these drugs have been around for a millenium, but suddenly

use has spread across the world in a dramatic fashion. How did this

happen? Why now?

WORLD SOCIAL CHANGES RELATED TO DRUG ABUSE

Some of the reasons for this global epidemic can be fairly easily

identified. Increased travel has brought us much more in contact

with each other. International travel is no longer only for the

privileged individual or the isolated sailor. Today, large numbers of

our populations are in contact with each other. This contact brings

tremendous benefits, but it also brings a contagion of behavior that

helps explain how drug abuse can spread rapidly over global areas.

Obviously, the increased travel has involved the traffickers too.

They now have the ability to move quickly large amounts of drugs

long distances.

Increased global communications have made a big impact in

recent years. An event reported in a newspaper in one part of the

world will be seen, experienced, and thought about by people all

over the world. Drug use and drug trafficking have been big news

during the last decade all over the world.

Some of the hallmarks of the modem world are increased

individual responsibility, decreased traditional cultural constraints,

and increased flexibility of behavior. These global cultural trends

bring many benefits, but they also create serious problems. One

example of this complex phenomenon comes from agriculture.

Many parts of the world produce low levels of food partly because

of the persistence of traditional, less effective, agricultural practices.

Many governments try to change these practices so that the farmers

will adopt new and more efficient techniques. But the same cultural

barriers that have kept people from adopting new farming techniques have kept people from adopting new social behaviors such as

drug taking. And the same relaxation of these barriers that produces

a good effect in one area produces a negative effect in another. It is

often the younger, better educated farmer who first adopts newer

techniques, just as it is often the younger, better educated people

who first adopt new drug-using behaviors. I do not suggest this as

criticism of any lifestyle, but merely to point out that these

conflicts between traditional practices and modem life affect all of

us in complex ways.

8
DUPONT: A PERSPECTIVE FROM THE UNITED STATES

Another important global social change relates to our attitudes

toward tobacco and alcohol. One of the effects of our heightened

awareness of drug abuse is the recognition by many of us that

alcohol and tobacco are drugs. Most of us were oblivious to the

effects of these substances in our own lives and in our cultures until

the drug abuse epidemic of the last decade. Today you will find in

the United States a widespread recognition of the fact that alcohol

and tobacco are drugs and have all the characteristics—the reinforcing properties and the negative health consequences—that we

associate with illegal drugs. The difference is that these common

and generally accepted drugs have already gone through the

extensive process of diffusion throughout most societies. We have

become accustomed to paying a staggering social price for the

privilege of individual choice in the use of alcohol and tobacco. In

the United States, we pay about $35 billion a year for alcohol-related health problems. All of our illegal drugs together cost us about

$10 billion a year in the United States in terms of health and social

costs.

One consequence of this pervasive spread of tobacco, alcohol,

and other commonly used drugs is that the practice of drug taking

is already deeply ingrained throughout the world. With the wide

availability and acceptance of these psychotropic drugs, it is but a

short step to the use of other new drugs, especially by young and

relatively affluent persons.

Drug abuse is not a fad. It will simply not go away, any more

than alcohol and tobacco use will simply go away. Drug abuse is a

characteristic of our lives and, judging from the social changes

occurring throughout the world, it is going to remain a very serious

problem. In addition to increased travel, faster communications,

conflicting traditional and modern values, and the wide acceptance

of alcohol and tobacco, important changes in the composition of

our population have taken place in the last decade. These changes

relate directly to drug-using patterns. A dramatic increase in the size

of the youthful population took place in the United States in the

decade of the 1960’s. The so-called baby boom following the

Second World War produced, 20 years later, a sudden upsurge in the

size of the adolescent population most vulnerable to drug abuse.

Given the other conditions outlined above, the change in the size

and nature of our population fostered drug abuse. While other

factors involved should not be minimized, the age-related changes in

our population were also necessary for the drug abuse epidemic.

Similar demographic conditions now exist in many other

countries. Reductions in infant mortality during the last decades

9
INTERNATIONAL CHALLENGE OF DRUG ABUSE

have increased the number of young people in the vulnerable age

range in many countries, particularly in developing nations. Perhaps

of even greater concern in many nations is the massive migration of

youth to cities, producing a greater concentration of young people

in urban areas, even in those nations where overall age patterns have

not changed substantially. Such an increase of often underemployed youth in cities raises a nation’s vulnerability to drug abuse. Many

drugs are readily available in most, if not all, regions of the world.

The widespread existence of heroin user groups; the decrease in

traditional cultural restraints on adopting new—and often deviant—

behaviors; increased affluence, travel, and communication; and the

tremendous increase in the capacity of the global illegal heroin and

other drug supply systems—all these factors bode ill for many

nations.

LESSONS LEARNED IN THE UNITED STATES

In our attempts to meet the drug abuse challenge, there are

several lessons we have learned in the United States. The first is that

the complete elimination of drug abuse is not a realistic objective.

The drug abuse problem has been with us a long time. In our

modern society, it is unlikely that the drug problem is going to go

away no matter how effective our approaches may be. The public is

eager to be told that we will solve the problem—that it will go away.

I suggest to you that this is not a realistic objective. On the other

hand, the drug abuse problem can be limited; we can achieve

realistic and important objectives, but elimination of the drug

problem is not, candidly speaking, one of these. In the United

States, recognition of this fact has encouraged us to place priorities

on our programs and to focus on achievable objectives in the drug

abuse prevention field.

The second lesson is the importance of balancing supply

reduction with demand reduction strategies, and of balancing

national and international efforts. At the same time that societies

are attempting to limit the availability of abusable substances, it is

also important to provide treatment, rehabilitation, and prevention

services to help drug users. In the United States, about 60 percent

of our national drug abuse expenditures are for demand reduction

or health-related activities, and about 40 percent of our resources

are now going to supply reduction or law enforcement efforts.

While treatment is provided, efforts to reduce access to illicit

substances must continue to be supported. Some restraint, consis10
DUPONT: A PERSPECTIVE FROM THE UNITED STATES

tent with each nation’s values, has to be exercised in terms of what

techniques are used to limit the access of the population to drugs.

In other words, we do not want to use techniques of reducing

access to drugs which produce more harm than the drugs

themselves. Effective techniques that reduce illicit drug supply

through law enforcement and pharmaceutical control are nevertheless necessary in all countries.

Just as efforts at reducing supply and demand should be

balanced, it is essential that national and cooperative international

programs be balanced as well. It is tempting to resort to a national

protectionism, a feeling that one has to seal one’s borders and keep

out drugs from other countries. However, there is simply too much

legitimate and economically necessary movement across national

boundaries for this approach to work. But if we work together, we

can produce realistic international strategies that will reduce the

supplies of illicit drugs. We need a sense of balance and a sense of

partnership. Both supply and demand reduction activities are

essential. In addition, a sense of balance and partnership of national

and international activities should be one of our main drug abuse

prevention goals.

A third lesson concerns treatment. In the United States, only 1

percent of our national drug abuse treatment capacity is in hospital

or institutional programs. We have learned the importance of

outpatient programs in treating drug abusers and the very limited

usefulness of hospital institutions for this purpose. This lesson is

consistent with treatment outcome research for most illnesses,

ranging from pneumonia to schizophrenia.

A fourth lesson, and this might be the most controversial of all, is

that general service programs, including integrated health care

approaches, do not, in general, respond to the unique needs of drug

abusers. We have not had good experience putting drug abusers into

general clinics, hoping that they would get their drug problems

dealt with. Medical problems related to the drug use may be taken

care of in a general health facility, but beyond this there seems to

be a need for a critical focus of attention around the drug problem

itself for programs to be effective. This can happen in a clinic or a

mental health program, but most often it does not. There needs to

be a specific focus on the drug-using behavior in order to get a

therapeutic benefit. Of course, specific drug abuse programs do

successfully operate as discrete parts of general health or mental

health centers. This approach often achieves the benefits of both

specific and general programs. But it has been our experience that

11
INTERNATIONAL CHALLENGE OF DRUG ABUSE

these benefits can be realized only when there is a specific focus on

drug abuse in the general health program.

The fifth lesson we have learned is the necessity of a firm

knowledge base in the drug abuse field. The assessment of drug

abuse in a country is the first step in drug abuse prevention. Most

countries have suffered by not having an accurate definition of their

problems and by not knowing who is using which drugs, how much

is being used, what the effects are, and what the trends are over

time. There are now some very good techniques for drug abuse

assessment.

A second example of the necessity of a knowledge base is the

development of new therapeutic tools for drug abuse treatment. At

the National Institute on Drug Abuse, we support both basic and

applied research to clarify the nature of the biochemical interactions between opiate receptors in the brain and opiate drugs. Out

of this work on the opiate receptors has come the discovery of

endorphins, which are endogenous morphine-like substances in the

normal mammalian brain. Endorphins appear to be peptides which

mimic at least some of the actions of opiates. It is not clear at this

time whether these substances are genuine transmitters in brain

pathways, or whether they are degradation products of more

powerful analgesic peptides. Biochemists in the United States and

abroad are searching for enzymes that may be involved in the

synthesis and deactivation of these peptides for clues to understand

the biological roles they play in addiction, pain, and other

physiological and pathological processes. The intensive research

now under way is extremely important as it seeks to clarify how

these substances are involved in the addictive process. Through

these studies, new treatment modalities or more effective prevention strategies may be developed. We should not overlook the

possibility that endorphins may be involved in more general

processes that control normal behavior and influence mental health.

Studies in the biochemistry of drug abuse are now in the forefront

of scientific research and may increase our basic understanding of

human behavior. The latest developments in this exciting area are

summarized in one of the presentations of our Drug Dependence

Section of the World Psychiatric Association.

The last example of the necessity of increasing our knowledge

base is in the field of prevention. Both common sense and research

findings on human behavior support the position that negative

factors, such as boredom, feelings of failure, and lack of self-worth

and community involvement, increase the probability of the

occurrence of a variety of personally and socially destructive

12
DUPONT: A PERSPECTIVE FROM THE UNITED STATES

behaviors. If drugs are available and if their use is valued by peers,

these negative factors may lead to harmful drug or alcohol use. To

prevent this, we support programs that reinforce positive behavior,

that provide constructive alternatives to drug taking, and that

intervene early in the process with minimal treatment to reduce the

number of persons who will later require costly treatment and

rehabilitation.

We must also be realistic in our prevention goals. Today about

two-tenths of 1 percent of the U.S. population is addicted to

heroin. Thus one could say, quite correctly, that 99.8 percent of

the population of the United States has been prevented from

becoming heroin addicts! Nevertheless, we consider 500,000 heroin

addicts, costing the Nation over $6 billion a year, to be a serious

social and public health problem. Stated this way, it becomes

clearer why it is so difficult to develop effective prevention

strategies, since the vulnerable population is such a small part of the

total. With nearly 15 million current marihuana users in the United

States, the prevention target is a bit larger if not more easily hit.

We at NIDA also support the development of the Resource Book

on Demand Reduction by the Division of Narcotic Drugs of the

United Nations. This practical guide to prevention, treatment, and

assessment will assist all of us in carrying out better programs.

The major need in the drug abuse prevention area in the United

States today is for additional evaluation studies directed at

measuring the impact of programs to reduce harmful drug use.

Available evidence indicates that the new prevention approaches,

including effective education and parent-oriented and peer-oriented

strategies, yield more positive results than the old approach of

simply providing information about drugs or of using factually

unsound scare tactics. We think effective approaches using peers

and parents and programs which concentrate specifically on the

most vulnerable youth are promising prevention measures worthy

of rigorous evaluation.

The presentations we have heard today indicate that drug abuse

is now endemic throughout the world, and that periodic epidemics

superimposed on this large and enduring problem are to be

expected. None of us individually, or even collectively, can solve all

of the problems related to drug abuse; we can, however, honestly

face them.

No area of the world, no social, religious, or political process will

completely immunize our countries against drug abuse. With a

search for new knowledge and a willingness to learn from each

other, as we have done at this Conference, we have a unique

13
INTERNATIONAL CHALLENGE OF DRUG ABUSE

opportunity to contribute to the welfare of our fellow human

beings. By working together and by collaborating with our

colleagues in the United Nations and the World Health Organization, we can do a much better job in the future.

In conclusion, I want to thank especially my colleagues who have

shared this panel with me today, and the others who did such an

outstanding job in the earlier sessions of our Section, for their fine

contributions.

Thank you.

14
CHAPTER 2

The Drug Abuse Scene in Nigeria

Tolani Asuni, M.D.

INTRODUCTION

It has often been stated that a number of communities in the

world use drugs to enhance the spirit of such occasions as social

gatherings, religious ceremonies, and the like. In some communities

individuals may use certain drugs regularly for various nonmedical

reasons. It has been observed in Nigeria that alcohol was used

mainly on ceremonial occasions and also during traditional religious

rituals. In the northern part of Nigeria, Kola nuts, which contain

much caffein, are chewed regularly, much more so than in the

southern part of the country, where they are mainly grown.*

Tobacco is smoked in clay pipes by some older men and women.

There is also a practice, mainly in some parts of the South, in which

shredded tobacco leaves are kept in the middle of the tongue all the

time and only taken out when the user wants to drink water, eat, or

sleep. A similar practice is the keeping of a small ball of tobacco

leaves or chewed Kola nuts in one cheek, again taken out only when

the user wants to eat or sleep.

In the South, especially among the Yoruba people, Kola nuts are

used as a symbol of peace and harmony on occasions of betrothal,

settling a quarrel, important visitations, etc. They are also used by

those who want to keep awake at night, like students and those

who have to keep vigil.

The above brief account of traditional nonmedical drug use in

Nigeria provides a basis for contrast with current use patterns.

*In the north, Cola nitida is the most commonly used of the various types of

Kola nuts.

15
INTERNATIONAL CHALLENGE OF DRUG ABUSE

DRUGS OF ABUSE IDENTIFIED

In the last two to three decades, new drugs have been introduced

for nonmedical purposes and used side by side with the more

traditional ones mentioned above.

The use of alcohol has become more widespread and extended to

nontraditional alcoholic beverages. There are now more than six

breweries in Nigeria and more are expected. The demand so far

outstrips the domestic supply that nearly 100 million Naira worth

of beer was imported in one year. (A Naira is approximately $1.50

USA.) Distilled alcoholic beverages are also bottled in the country.

In the past most people drank local alcoholic beverages, which

were sometimes distilled illegally, but the government has now

legalised the distillation of local alcoholic beverages in approved

situations. With affluence most people are now drinking bottled

beer brewed locally or imported, as well as spirits.

With this enormous use of alcohol, and with little or no control of

its sale, it is to be expected that a large number will become

dependent on it. Asuni (10) reviewed the number of patients with

psychiatric problems involving alcohol admitted to the Neuropsychiatric Hospital, Aro, Abeokuta, Nigeria, between 1964 and

1973. The number was not indicative of the size of the problem in

the country, for several reasons. Alcohol abuse and dependence are

still hardly regarded as a psychiatric problem, and there is no

recognised agency available for dealing with the problem of alcohol

dependence except some traditional healers. Psychiatric service in

the country is still very meagre and unevenly distributed. Even if

the problem of alcohol dependence is regarded as a psychiatric

problem, there are not enough treatment facilities available.

In Asuni’s (10) study of 60 cases, he also included other drugs

that were used in combination with alcohol: cannabis in 11 cases,

pethidine in one case, and amphetamine in one case.

Amphetamine and its Derivatives

In the past students took Kola nuts to stay awake at night to

study. Many still do, but some use amphetamine tablets, especially

before and during examinations. The fact that users get dependent

on amphetamines is not striking; rather it is the psychotic

breakdown some of them have that makes the situation disturbing.

Amphetamine psychosis has been well documented (Connell 14).

16
ASUNI: DRUG ABUSE SCENE IN NIGERIA

It has been observed by Oshodi (20) (personal communication)

and confirmed by others that in the northern parts of Nigeria

labourers take amphetamines. They are taken by the handful to

enable them to do sustained hard work. It is also suspected that

their employers provide these tablets in order to get the maximum

work output from them. Some Moslems also take the tablets to

Saudi Arabia on Pilgrimage both to use and to sell. The government

of Nigeria has taken steps to stop the importation of amphetamines

into the country.

In Ahmed and Akindele’s (2) report, amphetamines figured

prominently among the drugs of abuse seen in a University

Teaching Hospital in Kaduna, Northern Nigeria.

Phenoharbitone

It has become common knowledge that phenobarbitone is an

hypnotic, and it has been readily available at chemists’ shops. From

time to time one sees cases of dependence on phenobarbitone. It is

suspected that in view of the ready availability of these drugs, many

people are dependent on them but they have not been brought to

the notice of psychiatrists, and their physicians may not even be

aware that they have become dependent on the drugs.

Mandrax

Mandrax is a hypnotic which when taken with cola drinks gave a

“high” experience. It was abused by older school children. It has

since been withdrawn from the market and there is no evidence that

it is being smuggled into the country.

LSD

Anumonye (7) mentioned 2 cases of the use of LSD in his study.

LSD is not a common drug of dependence and it is certainly not

readily available in the country.

Pethidine (Meperidine)

This is perhaps the most significant drug of dependence in

Nigeria; significant because of the type of people who get involved.

17
INTERNATIONAL CHALLENGE OF DRUG ABUSE

They are usually highly trained people such as physicians, pharmacists, and nurses in a country which is short of such highly trained

manpower. Akindele (4) reported twenty-two cases of teaching

hospital personnel treated or followed up personally by him. Of

these, twenty were males and two females. Ten were physicians and

twelve were nurses. All the physicians used pethidine either alone or

in combination with other drugs. The twelve nurses were on

pethidine alone. These findings are in keeping with the observation

of some other psychiatrists working in psychiatric hospitals.

An interesting observation by the author is that those dependent

on pethidine who died, died as a result of what looked like tetanus.

It is questionable whether it was real tetanus or a toxic effect of

pethidine or of withdrawal. The reason for the doubt is that those

involved are persons of relatively high status who lived in

environments in which their needles were unlikely to be contaminated by tetanus bacillus. It would have been acceptable as tetanus if

it occurred only in one case, but for it to occur in 3 cases raises

doubt. This observation has not, to my knowledge, been confirmed

by others. It is worth further investigation.

Unlike amphetamines and barbiturates which are not necessarily

introduced to the user by a doctor’s prescription, pethidine is

usually initially prescribed by a physician, and then the user tries to

get it without a prescription. To this extent, physicians are

somewhat to blame for the initial introduction which later leads to

dependence.

Some of those dependent on pethidine start with the tablets and

later graduate to intramuscular injection of the drug. It is now

under very strict control by the Federal Government.

Heroin

Heroin is practically unknown in Nigeria as a drug of dependence. In Akindele’s (4) series, one doctor who was psychotic had

used morphine, pethidine, heroin, and barbiturates. It is not known,

however, if he was dependent on heroin or if he only used it on a

few occasions. A male patient who had lived in Britain for many

years and who used Cannabis told me that he had used heroin in

Nigeria and that he got it in a famous market in Onitsha. The truth

of this could not be ascertained, but he was not addicted to heroin

when seen.

18
ASUNI: DRUG ABUSE SCENE IN NIGERIA

Morphine

Morphine is also practically unknown in Nigeria as a drug of

dependence.

Cannabis

Cannabis is the most common drug of dependence used in

Nigeria. Since Asuni’s (8) first paper in Nigeria focused on the

subject of Cannabis in Nigeria, there have been a few others—

Lambo (16), Boroffka (12), Ahmed, M., and Akindele, M.O. (2),

Adelaja (l), Akindele (3), etc. It is significant that all are

psychiatrists. The reason for this is partly the fact that the

psychiatrists are most likely to observe the harmful effects of the

use of Cannabis.

As easily as Cannabis can grow in Nigeria, there is very strong

evidence that it is not native to Nigeria. Asuni (8) wrote:

Cannabis sativa is not indigenous to Nigeria, and evidence

indicates that it was introduced to the country, and most likely to

other parts of West Africa, during and after the Second World War

by soldiers returning from the Middle East, the Far East and North

Africa and also by sailors. There is less reliable indication that it

was first introduced to the country during the First World War, but

it did not gain a foothold, nor did it spread afterwards. It grows

profusely in this tropical climate with little or no care. Farms of

the plant, scattered over Southern Nigeria, have been reported by

the police.

The only purpose for which it is grown in Nigeria is for

smoking, since it is not used for fibre. It is neither chewed nor

brewed. It is not used in the herbal concoctions of traditional

healers or in home remedies, as confirmed by Oliver (19). . . .It is

significant that in his exhaustive collection of useful plants of West

Africa, Dalziel (15) does not mention Cannabis.

The picture of the use of Cannabis has changed in Nigeria over

the years. For instance, whereas it was earlier reported that it was

only smoked, Adelaja (1) found among his soldier psychiatric

patients that it is also ingested with alcohol—beer, palm wine, home

distilled gin; brewed as tea, and even chewed.

There are also more cases reported all over the country; this may

well be a factor of the increased number of psychiatrists and also

increased number of people at risk, e.g., the phenomenal rise in the

number of soldiers in the country as a result of the Nigerian Civil

War in 1967 to 1970. In addition to this apparent increase in

Cannabis use, there is some evidence that there is a real increase.

19
INTERNATIONAL CHALLENGE OF DRUG ABUSE

For instance, Asuni (8) reported 16 cases of Cannabis use, out of

380 cases discharged from Yaba Mental Hospital in 1962.

Anumonye (7) reported 116 out of 1,061 inpatients in the same

hospital in 1970, an increase from 4.2 percent to 10.9 percent.

There is also some controversy about the relationships between

psychosis and Cannabis use. Akindele (3) doubted if there was any

causal relationship between Cannabis use and psychosis. Adelaja (1)

from his study in Military Psychiatric Hospital concluded:

“. . .acute toxic psychosis often reported may be acute excitement

states reported among Africans or an onset of other major

psychotic illness.” Asuni (8) suggested a “schizophrenic propensity” in those who break down with psychosis after using Cannabis.

Boroffka (12) however distinguishes between those who smoke

Cannabis as a symptom of an incipient psychosis, by this action

escalating the psychotic process, and those who develop a psychosis

ab nouo in a previously well integrated personality, and whose

psychosis does not clear up in a few days as it would have done if it

were merely toxic. Paton (21) also notes that distinctions need to

be made between effects due simply to Cannabis, exacerbation of a

personality disorder, precipitation of psychosis, and exacerbation of

preexisting psychosis. A preliminary EEG study by Asuni, Schoenberg, and Oluwole (11) suggests that there may be a relationship

between the psychotic behaviour of some Cannabis users and

epileptogenic phenomena; that the use of Cannabis normalises

mildly abnormal EEGs in some and deranges normal EEGs in

others, and it is this derangement that is manifested in psychotic

behaviour. This observation is comparable with the different effect

of coffee on different people, While many need coffee to keep them

functioning for long hours, a few become disturbed, agitated, and

restless. The disorganisation is of course more severe with Cannabis

use.

TREATMENT

Treatment policy of drug dependence depends on social, economic, and scientific factors. The patient almost never comes for

treatment on his own initiative. He is referred from his place of

work because of a decline in work performance, deteriorating

habits, carelessness, indifference, sluggishness, dopiness, etc., and

the suspicion that he is on drugs. Often a condition for his

remaining employed is that he undergo treatment. Since he usually

has others such as his wife, parents, and older members of his

20
ASUNI: DRUG ABUSE SCENE IN NIGERIA

family financially and socially dependent on him, they often

encourage his having treatment, which in some cases they have

failed to persuade him to take. Sometimes relatives take the

initiative to bring the patient for treatment. As in psychiatric

treatment in general, relatives are actively involved in the treatment

programme.

Of course the drug-dependent patient usually denies being

“hooked” on drugs until he is presented with incontrovertible

evidence, e.g., many injection scars on the usual injection sites, or

unusual behaviour during the period when he is under the influence

of the drug.

The patient may appear to have good motivation, but it is usually

spurious. This motivation is, however, exploited to have the patient

admitted into the hospital; treatment is unlikely to be successful on

an outpatient basis except in those very rare situations in which the

patient can be kept under twenty-four hour surveillance by those

around him who have been educated about the problem.

The objective of treatment is not just detoxification, but

continued abstinence. While the patient may be voluntarily admitted, this may be converted into an involuntary admission if he goes

out to use the drug while in the hospital or even after discharge.

The rationale for involuntary admission is that drug behaviour

constitutes a danger to the patient himself and, by extension, to his

family, of which he is an integral part. The laws of Nigeria relating

to mental illness are out of date, and in any case are silent on this

matter of voluntary or involuntary admission and do not give any

guidance. The psychiatrists in charge of psychiatric hospitals with

facilities for involuntary admission, however, adopt this rationale.

For economic and scientific reasons the “cold turkey” method of

sudden withdrawal is practised. This is another reason for admission

into hospital. The patient is given the appropriate drugs to alleviate

withdrawal symptoms. During admission to the Neuropsychiatric

Hospital, Aro, Abeokuta, he is given individual psychotherapy by

the staff, mostly psychiatric nurses and psychiatrists; he is involved

in group psychotherapy with other patients, as well as in family

therapy.

While he is hospitalized, efforts are made to identify and unravel

the patient’s emotional, social and economic problems. If he has

any basic psychiatric problems such as anxiety state or depression,

these are treated. He is usually kept in the hospital for not less than

six weeks after complete abstinence and then discharged to the

surveillance of his relatives with some anxiolytic drugs.

21
INTERNATIONAL CHALLENGE OF DRUG ABUSE

In a developing country like Nigeria, drug substitution, such as

methadone maintenance, is not advocated. The reason is that where

drugs for treatment of life-threatening situations are not always

readily available everywhere, where antimalaria drugs cannot be

distributed freely, it is not rational to keep some people on

maintenance medication for drug problems at government expense.

The anxiolytic drugs prescribed do not provide the same subjective

experience, and therefore cannot be regarded as substitutes. They

are meant to allay anxiety and also to minimise the need for the

drugs of dependence.

FOLLOWUP

It is unfortunate that it has not been possible to do any

systematic followup of cases treated with the regime referred to

above. There are indications that those who have been weaned from

their drugs often relapse; yet they seldom come back to us. One of

the causes of this is that physicians and nurses dependent on

pethidine, for instance, have good incomes and have grown away

from their extended families. Because of their persistent behaviour

regarding drugs they have alienated themselves from their family of

orientation and extended family who can exert some influence on

them.

Those cases who have been brought to hospital with psychosis

related to Cannabis tend to comply better. It is as if they are

frightened by their psychotic experience, and the dependence on

Cannabis, if it can be termed dependence, is not as compelling and

overwhelming as with pethidine.

The Federal Government of Nigeria is proposing to set up drug

dependence units all over the country. Perhaps if these units are

established in such a way that patients will not have to travel very

far from their homes to use their services, and if the units are well

staffed with mobile personnel, it will be possible to follow up cases

which use the services.

THE ROLE OF TRADITIONAL HEALERS IN THE TREATMENT

OF DRUG DEPENDENCE

It can be argued that since the problem of drug dependence is a

new phenomenon, the traditional healers may not be equipped to

deal with it effectively. Yet it is necessary to mention their possible

22
ASUNI: DRUG ABUSE SCENE IN NIGERIA

role in view of the increasing advocacy for the incorporation and

integration of traditional healing practices in Africa into the health

delivery system.

The common explanation of maladaptive behaviour given by

traditional healers is curse, evil machination of others, violation of

taboos, heredity, etc. I have not heard of any effective treatment

based on this explanation. On the other hand I have heard of

effective treatment of alcoholism by some medicinal powder being

put on incisions made under the lower lip of the patient. It has not

been possible to confirm this. Even if it is true, one wonders how

this can be applied to the treatment of dependence on drugs taken

by injection and not orally. This whole area needs to be explored.

PREVENTION

In spite of the legitimate preoccupation of the Government of

Nigeria with malnutrition, infectious and contagious diseases, etc.,

consideration is being given to problems of drug dependence. In

1966 very severe penalties were prescribed for traffic in and use of

Cannabis. These have since been relaxed considerably, as the

penalties were considered too severe. Recently a drug unit has been

set up in the Federal Ministry of Health. The importation and sale

of such drugs as Mandrax, amphetamine, and pethidine have been

either stopped or restricted. The Inspectorate Unit of the Pharmacy

Division of the Ministry is being strengthened to provide better,

more vigilant control of the sale of dangerous drugs by pharmacists.

Education of the public against the use of drugs is also being

contemplated. A Unit has been established in the Pharmacy

Division of the Federal Ministry of Health charged with the duty of

controlling drugs of addiction and drug abuse generally. No action

has been proposed to reduce the risk of alcoholism which is likely

to increase with the vast increase in the importation and brewing of

beer in Nigeria.

CONCLUSION

In conclusion it can be noted from the above brief account that

drug dependence is not of the same magnitude in Nigeria as it is in

some other countries. There is, however, evidence that it will

increase with increasing affluence, disintegration of the family and

other cultural systems which have had a supportive and restraining

23
INTERNATIONAL CHALLENGE OF DRUG ABUSE

influence on the individual. This is therefore the time to take

rigorous steps to arrest the growth of drug dependence before it

gets out of hand.

Before appropriate and rational steps can be taken, more studies

need to be done to identify some of the causative factors. Some

studies have already indicated the role of peer pressure (Akindele

5), parental deprivation and parental influence (Odejide and Sanda

17), as contributory to abuse of drugs.

A study of drug taking among secondary school students by

Olatawura and Odejide (18) indicated among other findings the

reasons the students take drugs. These include: to keep awake for as

long as they wish; feeling at ease only after smoking Cannabis;

Cannabis providing courage to talk to superiors; to facilitate

reasoning; to facilitate enjoyment of social gatherings; and to feel

happier when unhappy or fed up. Some of these reasons, if

confirmed by further studies, will point to the examination of the

school system and the study habits of the students with a view to

minimising the need to take drugs to keep awake at night to study.

There is therefore a need for more studies of drug abuse and drug

dependence in Nigeria, since the findings in one country cannot be

directly applied to another, especially where there are important

social, cultural, economic, and other differences. The warning given

by the American Academy of Pediatrics Committee on Drugs (6)

that there are reasons for using caution in relating much of the

seemingly relevant information from developing nations to Western

populations also applies the other way around.

REFERENCES

1. Adelaja, O. “Some Aspects of Cannabis Users.” Proceedings of the 6th

Annual Scientific Conference of Association of Psychiatrists in Nigeria,

1975. (Mimeographed.)

2. Ahmed, M., and Akindele, M.O. “Drug Abuse as seen in the Psychiatric

Unit of Ahmadu Bello University Hospital, Kaduna.” Proceedings of the

1974 Workshop of the Association of Psychiatrists in Africa—Alcohol and

Drug Dependence, Lausanne, Switzerland: International Council on

Alcohol and Addiction, 1975.

3. Akindele, M. O. “Cannabis and Psychosis.” Report of 3rd Pan African

Psychiatric Workshop. Sandoz Nigeria, Limited, 1971.

4. Akindele, M. O. “Drug Dependence amongst Hospital Personnel.” Proceedings of the 1974 Workshop of the Association of Psychiatrists in

Africa—Alcohol and Drug Dependence. Lausanne, Switzerland: International Council on Alcohol and Addiction, 1975.

5. Akindele, M. O. “Student and Drug Habits.” Ghana Medical Journal, 15

(3), 1976.

24
ASUNI: DRUG ABUSE SCENE IN NIGERIA

6. American Academy of Pediatrics Committee on Drugs. Effects of marihuana on man. Pediatrics, 56(1) 1975.

7. Annumoye, A. “Drug Abuse Behaviour in Lagos Secondary Schools.”

Proceedings of the 6th Annual Scientific Conference of Association of

Psychiatrists in Nigeria, 1975. (Mimeographed.)

8. Asuni, T. Socio-psychiatric problems of Cannabis in Nigeria. Bulletin

Narcotic, 16:17,1964.

9. Asuni, T. Psychiatry in Nigeria over the years. Nigeria Medical Journal,

2(2), 1972.

10. Asuni, T. “Pattern of Alcohol Problem as seen in the Neuro-psychiatric

Hospital Aro, Abeokuta 1964-1973.” Proceedings of the 1974 Workshop

of the Association of Psychiatrists in Africa—Alcohol and Drug Dependence, Lausanne, Switzerland: International Council on Alcohol and

Addiction, 1975.

11. Asuni, T., Schoenberg, F.; and Oluwole, J.A. “Cannabis and EEG

changes.” Proceedings of the 6th Annual Scientific Conference of

Association of Psychiatrists in Nigeria, 1975. (Mimeographed.)

12. Boroffka, A. “Mental Illness and Indian Hemp in Lagos.” East African

Medical Journal, Vol. 43, 1966.

13. Boroffka, A. Psychiatry in Nigeria today and tomorrow. Journal Nigeria

Medical Association, 7:36, 1970.

14. Connell, P.H. “Amphetamine Psychosis.” Maudsley Monograph No. 5.

London: Institute of Psychiatry, 1958.

15. Dalziel, J. M. “The useful plants of West Tropical Africa.” London: Crown

Agents for Overseas Government and Administration, 1936.

16. Lambo, T. A. Medical and social problems of drug addiction in West Africa,

with special reference on psychiatric aspects. Bulletin Narcotic, 17(l),

1965.

17. Odejide, A. O., and Sanda, A. O. Observations on drug abuse in Western

Nigeria. The African Journal of Psychiatry, 2(2), 1976.

18. Olatawura, M. O., and Odejide, A. O. “Prevalence of Drug Taking Among

Secondary School Students: A pilot study.” Proceedings of the 1974

Workshop of the Association of Psychiatrists in Africa. Lausanne,

Switzerland: International Council on Alcohol and Addiction, 1975.

19. Oliver, B. “Medical Plants in Nigeria.” Private Edition by the Nigerian

College of Arts, Science and Technology, 1960.

20. Oshodi, C. O. Personal communication, 1971.

21. Paton, W.D.M. “Cannabis and Its Problems.” Proceedings of the Royal

Society of Medicine, 66(7), 1973.

25
CHAPTER 3

The International Challenge of Drug

Abuse: The Mexican Experience

Guido Belsasso, M.D.

INTRODUCTION

The extreme complexity of drug addiction and the implacable

organization of drug traffic are today, more than ever, a challenge

that demands solidary action from all the nations of the Earth. Few

other issues are so revealing of the close interrelationship between

countries and of the extent to which anything one of them achieves

or fails to achieve has a bearing on the others.

This paper undertakes the task of briefly weighing past actions,

analyzing the present situation, and predicting future trends in the

Mexican struggle against drug addiction and drug traffic, in terms

both of internal measures and international collaboration actions.

INTERNATIONAL COOPERATION

Participation in international meetings

Long before the problem reached large proportions internally,

Mexico chose the path of active participation in those international

forums which have stated the need for energetic action against the

traffic in drugs of abuse, Mexico first took part in the 1912 The

Hague Convention which established cooperation on narcotic

control as a matter of International Law. Our country thereafter

participated in the 1925, 1931 and 1936 Conferences held in

Geneva.

26
BELSASSO: THE MEXICAN EXPERIENCE

On February 16, 1946, the United Nations Economic and Social

Council adopted the resolution creating the Commission on

Narcotics. Mexico was one of the fifteen countries that composed

the Commission.

Subsequently, in Paris and New York City, the 1948 and 1953

Protocols respectively were agreed upon. In 1961 New York City

was host to the Sole Convention, and in 1971 the Convention on

Psychotropic Substances was signed in Vienna. Mexico has adhered

to all these instruments of international control (4).

COOPERATION WITH THE UNITED STATES

Parallel to its participation in international forums, Mexico has

reached bi-national cooperation agreements with other countries.

Owing to geographical proximity, joint actions with the United

States—dating back more than four decades—are outstanding.

Juan Barona-Lobato (l), a prominent scholar on the subject, has

divided the history of cooperation between Mexico and the United

States into several phases. Phase one began in 1930 with an

exchange of diplomatic notes through which both governments

reached an administrative agreement on mutual police aid to

prosecute those involved in drug traffic.

Phase two started around 1959. At the proposal of the United

States, where the number of drug addicts showed an alarming

upward trend, a series of informal and friendly talks were held

which tended to reinforce operations against international drug

traffic. In 1960, the U. S. Government for the first time provided at

low cost air and land equipment to be used in the search and

destruction of papaver somniferum and cannabis plantations.

Subsequently, in May 1969, Mexico City was host to a new series of

meetings which resulted in a report stressing the need for

cooperation between both countries. Three months later, however,

on September 21, 1969, American authorities ordered, on a

unilateral basis and without previous consultation, severe measures

of inspection of people, luggage, and vehicles crossing the border

and arriving at U.S. ports of entry, thus generating complaints and

inconveniences. These measures of inspection, known as “Operation

Intercept,” impaired relations between the two countries and

hindered daily transactions between border towns on both sides,

which initiated a so-called “Operation Dignity,” emphasizing

greater respect for the individual.

27
INTERNATIONAL CHALLENGE OF DRUG ABUSE

Diplomatic relations between Mexico and the United States

could have come to an end but for the swift negotiation Mexican

and American commissioners at the highest level carried out in

Washington, thanks to which the inefficient “Operation Intercept,”

launched with complete disregard for Mexico’s dignity, was

replaced by “Operation Cooperation.” This decision was made

public through the October 11, 1969, joint communique marking

the beginning of phase three.

Several meetings of the task forces presided by the Assistant

Attorneys General of Mexico and the United States were held

during the third phase of cooperation. Their duty was to submit a

report to the Attorneys General who, in turn, assembled to discuss

recommendations and dictate measures for their implementation.

Achievements within the framework of “Operation Cooperation”

have been highly rewarding.

Yet, in spite of efforts by both countries leading to a decline in

international drug traffic in 1972 and 1973, in the following

years—1974 and 1975—the United States registered a substantial

increase in confiscations of heroin produced from clandestine

cultivations of poppy in Mexico, and of cocaine finding its way

from South America through Mexico. Both drugs were designed to

meet the demands of more than a half million U.S. cocaine and

heroin addicts.

Under these circumstances, former President Gerald Ford asked

the Domestic Council Drug Abuse Task Force to undertake a study

to determine the extent of the problem and to offer recommendations. As a result, a report entitled White Paper on Drug Abuse was

issued. On the basis of data included in the above-mentioned report,

President Ford called an urgent meeting on December 22, 1975, to

discuss the drug traffic problem, with special emphasis on the

Mexican and Latin American situations.

In 1976, from January 6 through 18, Congressmen Lester L.

Wolff and Benjamin A. Gilman, with the purpose of gathering

information on international drug traffic, made a tour of Mexico,

Costa Rica, Panama and Colombia, exchanging views with their

respective Presidents and searching for adequate cooperation

formulas.

It was around that time that the fourth phase of cooperation

between Mexico and the United States against drug traffic and drug

addiction began to develop. The outstanding feature of this phase is

the high priority both governments have placed on such actions. It

has certainly been a period of fruitful achievements during which

vigorous pronouncements, exchange of friendly letters between

28
BELSASSO: THE MEXICAN EXPERIENCE

Presidents, and programs for collaboration have been followed by

effective and determined action (1).

FIGHT AGAINST PRODUCTION

The past few years have been witness to activities carried out by

Mexico which are virtually unprecedented in the history of the

battle against drug addiction and drug traffic.

Deterrent efforts against the supply of drugs have been paramount, especially in view of Mexico’s geographical, socioeconomic,

and political characteristics, and the fact that the world’s greatest

consumer market lies just north of its border. Figures describing

this effort are highly eloquent. Between 1970 and 1976, Mexico

destroyed more than 65,000 poppy plantations and more than

46,000 marihuana plantings, nearly two tons of opium, more than

1,000 kilograms of heroin, 35 kilograms of morphine, more than

1,000 kilograms of cocaine, 800 kilograms of hashish, 534 liters of

cannabis liquid extract, 412 kilograms of poppy seed, more than six

tons of cannabis seed, and more than 92 million tablets containing

psychotropic substances. In addition, more than 18,000 persons

were arrested, of whom some 2,000 were foreign citizens. More than

30 underground laboratories were dismantled, and many drug

traffic gangs were broken up (1).

FIGHT AGAINST CONSUMPTION

Epidemiology

But Mexico is not only a drug-exporting country. A number of

complexly interrelated factors have accounted for an alarming

increase in domestic consumption.

Estimates show that the problem is essentially an urban one. In

rural areas, although one can find certain towns where drugs still are

employed in religious rituals or simply as an element in the

subculture of the group, drug abuse as such is not considered a

problem that affects public health.

The majority of urban drug abusers range in age from 12 to 21

years. The younger set uses inhalants and solvents, while the older

group usually uses marihuana. It seems certain that the use of

barbiturates and amphetamines is on the increase. Barbiturates and

29
INTERNATIONAL CHALLENGE OF DRUG ABUSE

tranquilizers are preferred by young adults. At present there is a

problem of hard drugs such as opium and its derivatives among a

group along the northern border of the country, where an increase

has been observed in the number of Mexicans taking heroin (2, 3).

The highest percentage of drug experimentation and use appears

to be among preadolescent and adolescent males and young adult

females. In general, however, lower-class youths tend to use

industrial-type solvents, which are cheap and easily obtainable,

while middle- and upper-class teenagers and young adults favor

marihuana, barbiturates, and amphetamines (table 1).

Certain figures may give a more accurate image of the magnitude

of drug abuse in Mexico. Use of psychotropic drugs and opium

derivatives affects great numbers of people. In 1974, 87 percent of

the population 14 years and older then living in Mexico City had

TABLE 1

General Characteristics of Drug Abuse in Mexico

Geography: Urban (Heroin abuse in northern border.)

Age: Mainly between 12 and 21 years

Adolescents: inhalants

Adolescents and young adults: marihuana

Young adults: barbiturates and tranquilizers

Sex: Mainly male

Social class:

Lower: inhalants

Middle and upper: marihuana, barbiturates, and amphetamines

30
BELSASSO: THE MEXICAN EXPERIENCE

TABLE 2

Percentage of Drug Users, 14 Years and Older, in the Federal District

Drug Percent of Population

Psychotropic drugs and opium derivatives 87.00

Amphetamines 2.34

Barbiturates 4.20

Marihuana 1.31

Inhalants

Hallucinogens

Heroin

0.40

0.31

0.10

taken one or more of these drugs, and 35 percent were doing so on

a customary basis, that is, every day for a minimal period of one

week during at least six months (6). Obviously, medical prescriptions are responsible for a high proportion of these cases. Use of

amphetamines through prescriptions thus accounts for 90 percent

of all users, who, in turn, represent a total of 2.34 percent of the

Federal District population. For its part, barbiturate abuse affects

4.20 percent of the capital’s dwellers 14 years of age and older

(table 2).

Regarding marihuana, the estimates are that in the Federal

District alone 66,000 nonregular users can be found (4). After the

above-mentioned drugs, marihuana is the most favored drug among

the age group 14 and older, of which 1.31 percent have already

tried it. Furthermore, eight out of every thousand individuals

between 14 and 24 years of age—0.84 percent—use it on a regular,

customary basis (6).

Inhalant abuse constitutes one of the worst problems of drug

addiction in Mexico. It is estimated that 20,087 individuals

representing 0.40 percent of the Federal District population 14

years and older, have used this kind of drug. Three of every

thousand individuals between 14 and 24 years of age—0.31

31
INTERNATIONAL CHALLENGE OF DRUG ABUSE

percent—use it on a regular, customary basis (6). These figures,

however, do not include two high-risk groups: the home-lacking

population and the less-than-14 population, where inhalation is

quite common. Indeed, the average starting age of inhalating

patients at the Centers of Juvenile Integration—institutions which

we will deal with shortly—was 14 years. Nevertheless, several

community studies carried out in different areas of the Republic

show that starting ages are much earlier, even 5 or 6 years (7). In

fact, more than half of the patients treated at the Centers of

Juvenile Integration—52 percent—come there because of substance

inhalation problems (7). Figure 1 shows the annual incidence rate

for each Center. It can be observed that the highest incidence rate is

that of Ciudad Netzahualcóyotl, where 87 out of every 100

residents use inhaled substances. It is important to note that Ciudad

Netzahualcóyoti is part of Mexico City’s metropolitan area, and a

majority of its population is composed of rural immigrants who are

extremely marginal economically, socially, and culturally. Figure 2

shows the incidence curve representing the number of cases started

in different years. An increase beginning in 1968 and continuing

from 1970 through 1975 can be observed. One possible explanation

for this may be the fact that these Centers of Juvenile Integration,

only recently opened, are perhaps treating few cases which started

before 1970. We must not dismiss the possibility, however, that a

marked increase in the use of inhalants has actually taken place.

The 1976 decline is explained by the fact that the diagram was

done when only four months of that year had elapsed. This fact

might suggest that in 1976 there was really an increase in use (7),

although further epidemiological studies are required to give this

phenomenon an accurate definition. It must be noted, however,

that the growth rates of both inhalant and marihuana abuse,

estimated from information obtained at the treatment centers, are

far from encouraging: growth rates from 1970-1975 throughout the

country are 40 percent for marihuana and 45 percent for inhalants

(6).

Other relatively less used drugs are hallucinogens and heroin.

Hallucinogens have been used by 0.31 percent of the capital’s

population 14 years and older, and heroin by 0.10 percent (table

2). It must be noted, however, that the latter figure refers to heroin

use in the Federal District, whereas heroin abuse is alarmingly

increasing in towns along the northern border of the country. Thus,

40 percent of the patients treated in 1973 at the Tijuana, Baja

California, Center of Juvenile Integration used opium derivatives,

and in 1974 there was a 5 percent increase. In Nogales, Sonora,

32
FIGURE 1

Substance Inhalation Incidence Rate for Each Treatment Center in the Mexican Republic 1976
FIGURE 2
BELSASSO: THE MEXICAN EXPERIENCE

incidence of heroin abuse was twice as great in 1973 as in 1972, and

ten times greater than in 1971. Of the patients treated in 1975 and

1976 at the Nogales Center of Juvenile Integration, 75 percent

were heroin addicts (6).

In view of this situation, it has been necessary to design an action

strategy against drugs that is not limited to the repression of drug

traffic but also contemplates, in an integral fashion, the prevention

of drug addiction and the treatment and rehabilitation of affected

individuals.

Creation of CEMEF

With the purpose of creating an organization to coordinate and

promote different activities involved in the struggle against abused

drugs, the Mexican Center for Drug Abuse Studies (CEMEF) was

officially founded on August 4, 1972, by presidential instructions.

In February 1975, it achieved legal status as a decentralized agency

of the Federal Executive, with its own budget.

In accordance with its character as a coordinating and promoting

organization, CEMEF has had a governing structure whose top

authority is represented by the Board of Directors which, in turn, is

presided over by the Secretary of Health and Welfare. The

Secretaries of the Interior and Public Education, the Attorney

General of the Republic, the Attorney General of the Federal

District, and the Director General of the Center itself are also

members of the Board.

CEMEF has carried out the following activities: biomedical and

social research to determine the way in which the drug addict

population is affected; evaluation of the incidence and prevalence

of specific types of drug use and abuse; predicting the evolution of

the problem; training of personnel in diagnosis, treatment, rehabilitation, and primary prevention; provision of research elements for

those involved in the area, and technical advice for both public and

private organizations on related aspects; publication of its research

findings; and the conclusion of agreements with similar national and

foreign institutions on matters within its province (5).

The government’s solid commitment to the task of fighting drug

addiction was internationally acknowledged when CEMEF was

designated, in September 1976, as the World Health Organization’s

Regional Center for drug addiction research and higher instruction.

35
INTERNATIONAL CHALLENGE OF DRUG ABUSE

Centers of Juvenile Integration

The private sector and the community have played a major role

in the struggle against consumption. Centers of Juvenile Integration

created in March 1971 sprang from a pilot project initiated in 1970.

The Centers have a tripartite structure which includes the federal

government, the state governments, and the community. Currently

there are 30 Centers throughout the Mexican Republic, which

provide an infrastructure for treatment, rehabilitation and prevention work.

The Centers of Juvenile Integration are far-reaching institutions

of high standing in the treatment and rehabilitation of drug abusers.

Up to 1976, the total number of drug addicts treated at these

Centers was 6,630 (7). Their staff includes psychiatrists, psychologists, social workers, psychiatric nurses, and volunteers. A wide

range of treatment is provided at the Centers, including pharmacotherapy; individual, family and group therapy; occupational

therapy; and recreational therapy. Some Centers run employment

bureaus; one of them has a day center as well. In addition to

secondary and tertiary prevention tasks, the Centers of Juvenile

Integration perform community work leading to early case finding

and implementation of primary prevention measures.

Other institutions for drug addiction treatment are currently in

existence. Special emphasis must be placed upon the Community

Mental Health Centers, whose primary purpose is to give both the

family and the community the opportunity to learn to treat the

patient. The Centers are not limited to illicit drug problems, but

also deal with alcohol and other mental health problems. There are

six Centers and two hospitals offering this kind of service in key

locations throughout Mexico City. There is another in Veracruz,

and the northern border will soon see the opening of still one more.

Mexico also benefits from a foster home program for children

who inhale solvents. Under this program, ten adopted children are

supplied with a home, food, schooling, and affection. The treatment pattern is behaviorally oriented, and the child is encouraged

to abandon inhalation practices. The program has a year’s duration,

after which the child returns to its own home, if it had one, or is

provided with one, with followup studies being done. This program

is currently under experimentation at two Centers, one in Acapulco

and the other in the Federal District.

On the other hand, a program against alcoholism involves the

greater part of the rehabilitation budget. Under this program, an

Alcoholic Rehabilitation Center provides a Federal District area

36
BELSASSO: THE MEXICAN EXPERIENCE

with psychiatric, detoxification, and control services benefitting

approximately 300,000 residents. There are also aid centers for

alcoholics and their relatives which are run by Alcoholics Anonymous. A program against alcoholism in the rural areas is currently

under study.

Finally, one more effort in the struggle against drug addiction is

embodied in a heroin addiction treatment program sponsored by

the Ministry of Health and Welfare. Treatment is based on

substitution of morphine for heroin, and it reaches approximately

40 people. This is an old program, now under evaluation.

Methadone is not used in Mexico.

Mexico’s experience in fighting drug-related problems has therefore covered all fronts of action, with the participation of wide

sectors of society.

PRESENT POLICIES

With tile change of federal administration in December 1976,

certain structural modifications have been made which seem logical

in an ever-changing social and political environment. While it is still

too early to attempt an evaluation, at least four well-defined

policies can be singled out:

1. The campaign against drug traffic continues. The Attorney

General of the Republic’s Office and the Ministry of National

Defense are multiplying their efforts to reduce drug production as

well as domestic and international drug traffic.

2. Small consumers are granted ammesty. CEMEF has favored

this measure in the past. Only recently, however, have solid steps

been taken to treat individuals who obtain drugs for personal use as

sick people rather than as criminals. This is encouraging, since it

reveals a shift of emphasis from repression to prevention, treatment,

and rehabilitation, even if repressive action is still taken against

those who deserve it: drug traffic profiteers rather than consumers.

3. Official support for Juvenile Integration Centers is maintained. Another encouraging sign of the new policies is the fact that

both state and federal governments—the latter through CEMEF—

have maintained their support of the private sector participating in

the struggle against drug addiction. This is indicative of a continued

eagerness to have the national community join in this all-important

task.

4. A change in the political visibility of drug-combatting

programs has been brought about. This fact reveals an historical

37
INTERNATIONAL CHALLENGE OF DRUG ABUSE

trend which is not solely Mexican. When drug consumption became

a serious public health problem, because it was a relatively recent

problem towards which public opinion was not yet fully sensitized,

it was necessary to create an organization with a high degree of

political visibility, which would have its own budget and a wide

margin of action. This explains CEMEF’s birth as a decentralized

agency. Once the initial—and most difficult—steps have been taken

to face this complex problem and to create public awareness,

programs against drug addiction have been able to find their place

among general public health actions. This principle has been

implemented in practice through the new regime’s administrative

reform, by virture of which decentralized agencies are integrated

under a sector head represented by the corresponding ministry.

Thus CEMEF has been integrated into the general mental health

programs of the health sector. This need had already been

considered in the formulation of the National Health Plan in 1974.

The struggle against drug addiction is included in the Plan as a

subprogram within the National Mental Health Program. Now this

formulation has been carried into practice.

The time is past when it was politically necessary to emphasize

CEMEF’s actions; they have now been brought to their actual level

as part of a more general project contemplating integral improvement of mental health. CEMEF therefore no longer handles its

budget in an autonomous fashion, but follows instead the guidelines

of the health sector head: The Ministry of Health and Welfare.

There is nothing new in such a change. Other countries have

experienced similar changes. In the United States, for example, the

shift has been from a special agency reporting directly to the

President to the wider-reaching Alcohol, Drug Abuse, and Mental

Health Administration.

FUTURE TRENDS

Integral Strategy

Once the historical vision and an analysis of present policies

have been put forth, it becomes necessary to expound the short

term and long term trends that are likely to develop within the

context of drug addiction in Mexico.

Firstly, the problem will almost certainly increase, at least in

terms of absolute figures, as a function of population growth.

38
BELSASSO: THE MEXICAN EXPERIENCE

Secondly, a drug supply-combatting approach alone is unlikely to

be successful. This has been found to be true in other countries as

well as in Mexico. The time in which such an emphasis predominated is fortunately past. It is clear today that it is illegal demand

for drugs that encourages supply and not the opposite, as was long

believed. Supply and demand are dialectically interrelated factors,

the reduction of the latter requiring a concomitant struggle against

the former. The need for an integral strategy is therefore evident.

While such a stretegy may be difficult to implement during an

initial state, it is certainly the only one that will yield positive

long-range results.

Education and Employment

Two elements of increasing relevance to youth can be distinguished in the complex of factors that determine drug addiction: the

lack of educational opportunities and unemployment.

Estimates are that only 1,800,000 Mexicans between 14 and 25

years of age attend some type of school, while another 12 million

have completed their studies, cannot pursue them, or have never

attended a school. Furthermore, only 9.4 percent of those between

20 and 24 years of age have access to higher education (8).

Unemployment among young people is coming to represent a

source of social conflict in many nations of the world. In Mexico,

17 percent of total unemployment occurs among the young. This is

one of the major challenges the present administration has to

face—the generation of more than 600,000 jobs or spiraling

unemployment figures.

These two factors are closely linked with increased drug

addiction amongst the young. Great effort must be made in the

near future to improve educational and employment opportunities

for the young, while simultaneously slowing down population

growth and raising the general standards of living.

The answer to the complexity of drug addiction must be the

implementation of an integral strategy that contemplates education

and employment as first-line preventive measures, while pursuing

treatment and rehabilitation programs, intensifying the struggle

against drug traffic, and promoting international cooperation as an

act of solidarity and respect among all the peoples of the world.

Then, and only then, shall we be facing the challenge of drug abuse.

39
INTERNATIONAL CHALLENGE OF DRUG ABUSE

REFERENCES

1. Barona-Lobato, Juan. México ante el Reto de las Drogas. México, D.F.:

Procuraduría General de la Republica, 1976. 395 pp.

2. Belsasso, Guido. “Drug Use and Abuse in Mexico.” Staff document, Centro

Mexicano de Estudios en Farmacodependencia. 14 pp. (Xerox.)

3. Belsasso, Guido. Drug abuse and treatment in Mexico. Addictive Diseases:

An International Journal, 3(1):21-24, 1977.

4. Belsasso, Guido; Cueli, José; Dallal y Castillo, Eduardo; Grajales, Armando

A.; and Llanes, Jorge. Bases para un programa de salud mental en Mexico.

In: Instituto de Estudios Políticos, Económicos y Sociales, ed. Reunión

Nacional sobre el Sector de Organización y Desarrollo Social. Mexico, D.F.:

The Instituto, June, 1976. p. 3.3.

5. Centro Mexicano de Estudios en Farmacodependencia. Esto es el Centro

Mexicano de Estudios en Farmacodependencia. Memoria de un Organismo.

Mexico, D.F.: The Centro, 1976. 80 pp.

6. Medina-Mora, Maria Elena, and Chao, Zita V. “El Problema de la

Farmacodependencia en Mexico y la Importancia de la Recuperation de la

Informacion.” Centro Mexicano de Estudios en Farmacodependencia, 1976.

18 pp. (Xerox.)

7. Natera, Guillermina. “Estudio sobre Incidencia de1 Consumo de Disolventes

Volátiles, en 27 Centros de la Republica Mexicana.” Paper read at Primer

Simposio Internacional sobre la Inhalacion Deliberada de Disolventes

Industriales, 21-24 June, 1976, Mexico City. (Xerox.)

8. Soto-Izquierdo, Enrique; Flores, Felix G.; Ibarra, Javier H.; Leon, Leonardo

C.; Morales, Eduardo, C.; and Velazquez, Carlos H. La comunidad juvenil en

la organización social y su participación política. In: Instituto de Estudios

Politicos, Económicos y Sociales, ed. Reunion Nacional sobre el Sector de

Organización y Desarrollo Social. México, D.F.: The Instituto, June, 1976.

p. 2.6.

40
CHAPTER 4

WHO’s Programme in Drug

Dependence With Special

Emphasis on Developing Countries

Inayat Khan, M.B., B.S., Ph.D., Awni E. Arif, M.D., Patrick H.

Hughes, M.D., and Brian Cox, B.Sc., D.P.A.

I. WHO’S RESPONSIBILITIES

The World Health Organization’s programmes are dictated by

resolutions of the World Health Assembly, its governing body,

which meets once a year, usually in Geneva. All of its 150 Member

States are invited to this meeting. WHO’s responsibilities in the field

of drug abuse and dependence, according to the numerous

resolutions of the World Health Assembly and the international

drug control treaties are:

(i) to collaborate with countries in planning, managing, and

evaluating programmes concerned with the identification

and magnitude of the problem, prevention of drug

dependence, treatment and rehabilitation of those affected;

(ii) to collaborate with countries in the training of health,

social welfare, education, and other professionals involved

in the management of drug dependence;

(iii) to stimulate, coordinate, and promote research required

for more effective programmes;

(iv) to recommend to the United Nations Commission on

Narcotic Drugs whether a substance should be controlled

nationally or internationaliy and the level of such control,

based on the benefit and risk ratio;

41
INTERNATIONAL CHALLENGE OF DRUG ABUSE

(v) to give advice in the planning and implementation of drug

dependence programmes sponsored by UN agencies and

other intergovernmental and nongovernmental organizations.

The following is a description of the three different types of

activities within the Division of Mental Health relating to WHO’s

obligations on the subject.

II. COUNTRY, REGIONAL, AND INTER-REGIONAL

PROGRAMS

A major emphasis of current work is on the development of

effective treatment programmes in developing countries, using

operational research to optimize the use of resources. The objectives of these programmes are to develop, at national and local

levels, flexible and dynamic management systems that will assist in

the prevention and reduction of nonmedical use of drugs. The

approach involves (1) the training of key personnel through

fellowships; (2) epidemiological surveys in rural and urban target

communities; and (3) the introduction and systematic evaluation of

treatment programmes. In addition to the development of more

realistic and effective treatment approaches, these activities are

expected to contribute to knowledge about the aetiology and

nature of drug dependence problems.

It is essential that planning and implementing of programmes at

the national level be based on existing public health services, taking

into consideration existing social services. By utilizing personnel

with various types of training, treatment and rehabilitation programmes can be integrated into the basic health services. Priority is

now being given to developing countries with serious drug problems

where manpower and financial resources are limited. In such

settings it appears unwise to develop specialized institutions for

drug-dependent persons.

The treatment of drug dependence in such settings may require

the use of medical assistants, primary health care workers,

recovered addicts, and others to take up specific responsibilities

with the support of physicians.

To select from and adapt the experience of other countries is a

cardinal principle for the development of these programmes. There

is also a need to develop more than one model so that alternative

approaches may be developed to meet the needs for the specific

drug abuse problems in each country.

42
KHAN ET AL.: WHO’S PROGRAMME IN DRUG DEPENDENCE

A. Thailand

The first WHO/UN pilot treatment programme was implemented

in Thailand in 1974. Initial effort emphasized the strengthening of

existing services in Bangkok and the development of a hospitalbased treatment service in Chiang Mai, near the opium-producing

regions. During 1975, 1976, and 1977, the operational research

component of the programme was emphasized. This is being

achieved by assigning the in-country programme coordinating role

to the Health Research Institute, Chulalongkorn University, Bangkok, and by strengthening the Institute’s existing data management

and laboratory facilities. This programme has thus been structured

to (1) develop information on the extent and nature of drug

addiction in Thailand; (2) identify through evaluation studies,

effective low cost treatment and health delivery methods; and (3)

develop data and experience to assist the government in planning

and application of improved programmes throughout the country.

Community-based treatment services in Bangkok provide facilities for treatment evaluation studies and for intensive case-finding,

monitoring, and intervention projects in high drug use target

communities. In similar fashion, primary health care and drug

dependence treatment services are being introduced in opium-using

villages of the hill tribe region in conjunction with before-and-after

case-finding surveys to determine the impact of the programmes on

drug use. The initial village survey was carried out in October 1976.

Data collection and intervention programmes are underway in six

villages, and dependent persons from the hill tribe area are being

treated in the Chiang Mai Hospital.

Discussions have taken place with various existing treatment

programmes in Bangkok to undertake programme evaluations, and

planning has begun on establishing a treatment centre in slum areas.

Preliminary work has been completed on the treatment evaluation

of Wat Tham Krobak Temple treatment centre.

B. Burma

In May 1976, the Socialist Republic of the Union of Burma, the

UN Division of Narcotic Drugs, and the UN Fund for Drug Abuse

Control signed a five-year agreement to implement the UN/Burma

Programme for Drug Abuse Control. This is a multi-sectorial

programme involving agriculture, education, law enforcement,

health, and social welfare components.

43
INTERNATIONAL CHALLENGE OF DRUG ABUSE

The major drug problem in Burma is opium dependence, much of

this in the rural areas, particularly in provinces where the opium

poppy is cultivated. With the strengthening of international drug

enforcement activities, heroin laboratories have appeared in opiumproducing countries, including Burma. This has resulted in the

spread of heroin use in the major cities of Burma.

Early in 1977, the plan for implementation of the health sector

was reviewed, and a work plan for the first two years was drawn up.

During this period ambulatory and inpatient treatment services will

be expanded and improved in Rangoon, Mandalay, and Taunggyi.

The intent is to develop a flexible set of treatment facilities that

will permit the testing and evaluation of different treatment

approaches. An epidemiological data base will be developed through

a compulsory registration system, and field surveys of “at risk”

populations are planned to assist in determining the magnitude and

nature of the drug dependence problem and in evaluating the

impact of intervention programmes.

In addition, laboratory facilities will be expanded, and group and

inservice training programmes for medical and paramedical staff will

be developed.

C. Pakistan

An agreement has been reached with the Pakistan Narcotics

Control Board for the implementation of a pilot treatment

programme in urban and rural regions of Pakistan. The epidemiological component of this programme was initiated in 1976 with the

visit of a WHO consultant who worked with country experts to

carry out a one day prevalence count of visitors to all licensed

opium shops in two cities. A second WHO consultant visited

Pakistan in early 1977 to finalize the work plan for implementing

treatment research programmes in four cities and in opium-using

villages of the North West Frontier Province. Training activities have

already begun, and establishment of the treatment centres will

begin immediately after approval of the project some time this

summer.

D. Iran

This project is carried out in collaboration with the Iranian

Ministry of Health and Social Welfare; the United States Alcohol,

44
KHAN ET AL.: WHO’S PROGRAMME IN DRUG DEPENDENCE

Drug Abuse, and Mental Health Administration; and the International Committee Against Mental Illness; and it receives financial

support from the United Nations Fund for Drug Abuse Control

(UNFDAC). It is a treatment evaluation study comparing the

outcome of four groups of opium-dependent persons (50 in each

group) receiving either (1) methadone, (2) mutabon—an antidepressant, (3) placebo, or (4) no placebo. In mid-1976 one hundred

completed records (with 87 percent followup of admitted patients)

were analyzed; it is hoped that final data collection on 200 patients

will be completed by the end of 1977. A preliminary analysis of the

data suggests (1) approximately 70 percent of patients did not

relapse nine months after discharge, regardless of treatment

category; (2) level of emotional depression during the followup

period appears to be associated with relapse and with employment

status, regardless of treatment category; and (3) patients who

maintain contact with treatment staff tended not to relapse, while

those who departed from treatment did tend to relapse. Data

analysis and final interpretation will be carried out during 1978.

Other projects in Afghanistan, Egypt, and Vietnam, are at various

stages of the planning process.

E. Studies of the Long Term Effects of Cannabis Use

The objectives of this multi-phased study which began in 1972

are to determine the physical, mental, and social effects of the long

term use of cannabis and its preparations. These are retrospective

and partially prospective studies comparing groups of long term

cannabis users with matched controls. Investigations have been

carried out in Chandigarh, Varanasi, Lucknow, and Lahore. These

studies have assessed the incidence of bronchopulmonary and

cardiovascular diseases, and chromosomal abnormalities, as well as

dysfunctional behaviour and deficits in cognitive and other skills.

F. Seminar on Drug Dependence in Central America, Mexico and

Panama

A seminar on drug dependence for countries in the region of

Central America was held in November 1976. The objective was to

improve knowledge of health professionals of this region about the

prevention, epidemiology, causes, and treatment of drug abuse.

45
INTERNATIONAL CHALLENGE OF DRUG ABUSE

G. Working Group on Early Intervention Programmes in Drug

Abuse

In December 1976, the WHO Regional Office for the Western

Pacific convened a Working Group of participants from the region

to work out strategies for tackling the problem of drug abuse.

Emphasis was placed on the development of appropriate epidemiological instruments and practical programmes of action.

H. National Organizations

Further progress has been achieved in establishing WHO Collaborating Centres for Research and Training in Drug Dependence. The

Centro Mexicano de Estudios en Farmacodependencia, Mexico, and

the Addiction Research Foundation, Toronto, have been officially

designated as WHO Collaborating Centres, and other institutes will

be designated shortly.

III. EPIDEMIOLOGY AND TREATMENT EVALUATION

RESEARCH

A WHO project concerning Research and Reporting on the

Epidemiology of Drug Dependence became operational in February

1975 and is financed by the UNFDAC. The objective of the project

is to strengthen the planning of effective prevention and control

programmes through the international collection and exchange of

data on the epidemiology of drug dependence.

The framework for implementing this project includes an annual

meeting of collaborating investigators and consultants to review

progress, priorities, and future plans. Data collecting activities are

carried out by a network of collaborating institutions, the majority

in developing countries with serious drug dependence problems.

WHO staff and consultants coordinate and facilitate the work by

designing instruments and methods and by assuming responsibility

for cross-national analysis of data generated.

The initial activities have been organized around four study areas.

The first involves the testing of an epidemiological case reporting

form for collecting “minimum essential” data on drug users in

contact with treatment and other institutions. The form is being

tested on drug users in each of seven countries: Burma, Canada,

Indonesia, Malaysia, Mexico, Pakistan, and Thailand. The results

46
KHAN ET AL.: WHO’S PROGRAMME IN DRUG DEPENDENCE

will be reviewed by collaborating investigators in October 1977.

The objective of the second study is to develop a general

methodology for evaluation of drug dependence treatment. The

instruments and methods will be tested in evaluation studies of

treatment programmes in these same seven countries.

The third study involves the testing of self-administered drug use

survey instruments on students in nine countries (India, Nigeria,

and the United States of America, in addition to the majority of

countries previously identified). It is hoped that agreement can be

obtained by collaborating investigators on the essential data items

and methods to be made available for international application. The

use of these instruments will permit comparisons of data in this

important area of epidemiological research.

The fourth study involves the pilot testing of previously

developed WHO Guidelines for reporting available information on

nonmedical drug use. Investigators responsible for this study at the

Institute of Psychiatry in London have now selected experts to

review a wide range of types and sources of epidemiological data. It

is expected that a monograph will be produced to guide planners in

other countries to recognize and use the types of epidemiological

data that are either already existing or that can be generated.

In addition to the data and methodology being generated in these

studies, the Research and Reporting project provides a collaborative

mechanism for permitting investigators from developed and developing countries to work together, to learn from one another, and to

share in the development of a common technology.

IV. INTERNATIONAL DRUG CONTROL TREATIES

Nations have responded to the need to take collective action

against drugs which are liable to abuse. The first effort was that of

the Shanghai Conference, in 1909. This was followed by The Hague

Convention, in 1917. These efforts were aimed at the control of

opium, morphine, heroin, and cocaine. After the Second World

War, an additional need was recognized for the control of

synthesized drugs which were being abused. The 1948 Protocol of

Lake Success (New York), created a mechanism whereby the new

products as designated by WHO automatically came under international control, and thus the role of WHO was established in

evaluating drugs for international control.

The Single Convention on Narcotic Drugs of 1961 simplified and

unified the earlier treaties and continued to assign to WHO the role

47
INTERNATIONAL CHALLENGE OF DRUG ABUSE

of evaluating drugs and making recommendations to the UN

Commission on Narcotic Drugs, a 30-member body elected by the

Economic and Social Council. This Convention continued to

control drugs obtained principally from plant material, i.e., opium,

cannabis, and coca leaves, as well as morphine-type synthetic drugs.

The increasing availability in recent years of a large number of

synthetic psychotropic substances led to their widespread abuse in

many parts of the world. Concern about this problem led to the

Vienna Conference of 1971 which discussed international control

of psychotropic substances. After ratification by 40 countries, the

Convention on Psychotropic Substances came into force on 16

August 1976. This Convention requires WHO to recommend to the

UN Commission on Narcotic Drugs whether and how a psychotropic substance is to be controlled nationally and internationally.

The recommendations of WHO are determinative as far as medical

and scientific evidence is concerned. The UN Commission on

Narcotic Drugs has final authority in approving the scheduling of

individual drugs, taking into account the WHO recommendations

and economic, social, legal, and administrative factors.

Under the 1971 Convention on Psychotropic Substances, 32

substances were placed under four schedules. Schedule I contains

generally hallucinogens, subjected to strict control measures,

stricter than narcotics and substances in Schedule II (generally

amphetamines and similar stimulants), Schedule III (generally

shorter acting barbiturates and similar CNS depressants), and

Schedule IV (generally longer-acting barbiturates and similar CNS

depressants and minor tranquillizers), which are successively less

strictly controlled. The basis for recommending control of psychotropic substances is their dependence liability, abuse potential, and

actual abuse on the one hand, and their therapeutic usefulness on

the other.

The testing and evaluation of drugs in general and psychotropic

substances in particular is complex technical work and requires

considerable expertise. Nevertheless, the Convention provides a

mechanism for the international community to decide as early as

possible whether a substance creates a drug abuse problem, so that

remedial steps can be taken. As synthetic pharmaceutical products

are increasingly available in all parts of the world, this drug control

mechanism offers equal benefit to the developing and developed

countries. Universal ratification of this Convention is essential for

an effective combined effort on the part of the world community

to use psychotropic drugs only when needed and to avoid their

abuse. WHO plans to carry out this activity in close collaboration

48
KHAN ET AL.: WHO’S PROGRAMME IN DRUG DEPENDENCE

with experts in the Member States located within WHO Collaborating Centres and other institutions.

In October 1976 a meeting of advisers was convened to advise

WHO in the various fields related to the implementation of the

1971 Convention on Psychotropic Substances, and to review the

functions and responsibilities of WHO. Their advice formed the

basis of a WHO report (OMH/76.6) to the 27th Session of the UN

Commission on Narcotic Drugs which discussed the implementation

of the 1971 Convention.

In May 1977 the World Health Assembly discussed the functions

and responsibilities of WHO with respect to the Convention on

Psychotropic Substances and authorized the Director-General to

carry out the functions assigned to WHO. The World Health

Assembly also urged WHO Member States which were not yet party

to the Convention to accede to it. The Director-General has since

written to all Member States informing them of the decision of the

Assembly.

An Expert Committee on Drug Dependence is scheduled to meet

26 September to 1 October 1977, to review the instruments for

scheduling drugs under the Convention, and to consider necessary

notifications.

A circular letter has been sent to all Member States requesting

information on their experience relative to Articles 3 and 10 of the

Convention. A meeting is planned for later in 1977 to review and

suggest what WHO’s position should be on the subject. This

decision will be communicated to the UN Commission on Narcotic

Drugs.

A review of the existing literature on “The Biological Activity of

the Tetrahydrocannabinols,” which will result in specific recommendations, has been carried out with scientists from the University

of Utrecht.

Research on Dependence-liability of Drugs

Information is required on the dependence-liability of thebaine

and other products derived from papaver bracteatum, a form of

poppy believed not suitable for illicit heroin production. Studies to

develop this information are essential before a decision can be taken

to grow papaver bracteatum as a major source of codeine. A

consultation was held to advise WHO on the methodology for

implementing this project. Work has begun in seven centres to

examine the dependence-liability of thebaine and alpigenine.

49
INTERNATIONAL CHALLENGE OF DRUG ABUSE

Preliminary data from these studies has been presented to a meeting

in July 1977 in Boston. Planning is underway for a meeting of

experts in October 1977 which will review projects and determine

what further work is required.

V. CONCLUSION

The WHO programme on drug dependence will continue to be

reshaped as the Organization faces new challenges and as we learn

more about the special needs of developing countries.

50
CHAPTER 5

Drug Abuse in the Socialist

Republic of Union of Burma

U Khant, M.B.B.S., D.P.M., and Ne Win, M.B.B.S., D.P.M.,

M.R.C. Psych.

In the presentation of this paper, an attempt is made to outline

the nature and extent of drug abuse in the Socialist Republic of

Union of Burma and the problems faced in its management.

HISTORICAL REVIEW

It is not known when opium was first used in Burma. The earliest

recorded evidence we have of it is from Caesar Fredericke, a

Venetian who travelled in the East for many years and who

published an account of his travels in or about the year 1581. He

describes at some length two sea voyages to Burma from the west

coast of India carrying opium (1).

A memorandum of the Dutch East India Company also gives an

account of the trade of the company in the year 1613, in which it is

mentioned that 200 pounds of opium were sold annually in the

Malaccas, and that the drug was profitably sold in Siam and Burma

(1).

Under the Burmese kings, the use of opium was not encouraged.

King Mindon objected to the smoking of opium, and later, King

Thibaw, the last of the Burmese kings, prohibited it altogether. The

prohibition, however, was not wholly effective, since the Britishoccupied areas of Burma were selling opium under license and

because raw opium was available from Yunnan. Immediately after

annexation of the whole of Burma by the British, a noble society in

Rangoon submitted an appeal to the Secretary of the Government

of India urging that importation of opium into Burma be prohibited

totally or restricted as far as possible (4).

51
INTERNATIONAL CHALLENGE OF DRUG ABUSE

GEOGRAPHICAL AND SOCIAL CONSIDERATIONS

Poppy growing was introduced in the Frontier Areas from

Assam. Some missionaries coming down from Assam to Ava in

1837 noted in their writings that poppy cultivation in Hukawng and

Mogaung area was widespread.

The opium poppy is cultivated by various tribal groups in the

highlands of the Shan State and Kachin State of Northern Burma.

Previously, many tribal people in these areas depended upon the

opium poppy as their sole or major source of cash income (5).

In accordance with the recommendation of the Hague Conference, the sale of prepared opium ceased at Government opium

shops in Burma on 1 April 1921. This also led to the reduction of

poppy plantation acreage, and in 1942 there were only three small

areas where opium was grown. These were the Shan State territories

east of the Salween, including the Wa States; the small area known

as the triangle and the Hukawng Valley in the Kachin Hills; and

the Naga Hills (1).

Opium smoking, common in the above-mentioned areas, was

usually carried out by means of a bamboo piece. Its top is open,

and it has a slanting spout near its bottom. Thus, it serves as a pipe

(figure 1). It is filled with water to the level just above the base of

the spout. Raw opium is cooked until it reaches the consistency of

treacle. It is then mixed with finely shredded dried plantain leaf and

made into small balls. These small balls are placed in the tip of the

spout and burned by a lighted stick (4).

LEGISLATION

The Government of Burma had a complex body of opium laws

and regulations dating back to the Opium Act of 1878. This was

revised in 1909, and the Dangerous Drugs Act was passed in 1930.

Separate regulations were passed for Shan States in 1923 and the

Kachin Hill tracts in 1937.

After Burma gained its independence, the Government on 11

February 1948, prepared a plan to eradicate poppy cultivation and

opium addiction within five years. To a certain extent, this was an

overly ambitious opium policy. Subsequently, in 1953, the Union

Government formed an Opium Enquiry Committee, whose task was

to seek and recommend the ways and means to solve the poppy

growing and opium addiction problems in the country.

With the advent of the Revolutionary Council in 1962, definite

steps were taken to eradicate the scourge. They were:

52
KHANT AND WIN: DRUG ABUSE IN THE UNION OF BURMA

FIGURE 1

53
INTERNATIONAL CHALLENGE OF DRUG ABUSE

(1) Formation of an Opium Enquiry Commission in 1964 to

compile statistics showing the exact number of opium

addicts in the whole of the Union; to ascertain the main

causes of addiction; to advise on substitute crops; and to

revise the existing laws.

(2) Permission for a UN team to study the opium problem in

Burma.

(3) Prohibition of the sale of opium in the Shan States

beginning 1 October 1965.

(4) Formulation of the Kokang Development Project to improve economic and social conditions in the important

opium-producing areas.

In spite of such measures, the problem did not abate, and by

1973, evidence of the use of heroin in Rangoon was established.

In the autumn of 1973, the Government of the Socialist

Republic of the Union of Burma convened a meeting of administrators, agriculturists, agronomists, teachers, lawyers, drug manufacturers, doctors, psychiatrists, social workers, and representatives of

law enforcement agencies to advise it in drafting a new law on

narcotics and dangerous drugs. After a series of discussions and

meetings, the Narcotics and Dangerous Drugs Law of 1974 was

promulgated on 20 February 1974.

The reasons for passing the law are mentioned in its preamble:

the abuse of narcotics and dangerous drugs could lead to the

destruction of humanity; punitive action alone is inadequate;

schemes should be developed to enable persons earning their

livelihood by poppy growing to cultivate substitute crops; and

arrangements need to be made to enforce compulsory medical

treatment of all addicts (3).

Since registration of drug addicts precedes medical treatment, the

task of registration of all addicts has been carried out in all the

townships within the Union.

INCIDENCE OF DRUG ABUSE

At the end of February 1977, the total number of persons who

had registered in specified health departments in the whole of the

country was 20,269. These included 14,823 opium users, 1,106

heroin users and 4,340 using other drugs.

This figure does not represent the total number of persons who

abuse drugs, and many feel that there is under-registration. The

Government is using all means to get the correct figures. Some feel

54
KHANT AND WIN: DRUG ABUSE IN THE UNION OF BURMA

that only about 20 percent to 25 percent of those using drugs have

registered. Ignorance and fear of the law or of treatment are some

of the causes.

The number of patients who registered and received active

treatment at the Rangoon Psychiatric Hospital within the period

from February 1974 to May 1977 were as follows:—

Male Female

Opium users . . . . . . . . . 438 11

Heroin users . . . . . . . . .1,003 15

Cannabis users. . . . . . . . . 92 —

Other drugs . . . . . . . . . . 93 4

Total 1,626 30

An initial “rush” of applications took place in the first two

months after the 1974 law was passed. A similar occurrence was

reported by Lau in Hong Kong in 1967 (2). Thereafter, there was a

fairly steady rate of registration and treatment of between 20 and

40 patients per month.

Opium addiction was most common among older persons (40-59

age group), while heroin abuse occured mostly in the young (20-39

age group). Statistics have shown that the age of onset of heroin

abuse has fallen below 19 years.

Tables 1 through 5 give more detailed information concerning

drug abuse patients: the number admitted into the Rangoon Psychiatric hospital, 1974-1977, occupation and education, mode of drug

use, and distribution by age.

TABLE 1

Number of Patients Admitted into the Rangoon Psychiatric Hospital

1974 1975 1976

1977

(Till end of May)

Male

Opium ........ 179

Heroin ........ 119

Pethidine ...... 31

Marihuana ...... 5 4

Others ......... 1

Multiple drug ... 50

Total ........ 434

Female Male Female Male Female Male Female

— 124 11 6 6 — 42 —

2 225 — 382 11 276 2

— 2 3 — 7 — 9 —

— 1 5 — 1 4 — 3 —

2 1 — 3 2 1 —

— 2 5 — 2 8 — 1 6 —

4 413 11 500 1 3 347 2

55
INTERNATIONAL CHALLENGE OF DRUG ABUSE

TABLE 2

Distribution By Occupation

1974 1975 1976

Students . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Workers . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Farmers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Office workers . . . . . . . . . . . . . . . . . . . . . . .

Business men . . . . . . . . . . . . . . . . . . . . . .

No Job . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Others . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

% % %

21.37 28.1 31.25

4.78 — 0.82

9.6 7 4.08

10.7 8.9 4.10

7.5 13.70 15.42

24.77 19.6 25.78

21.28 22.7 18.55

TABLE 3

Distribution By Educational State of Students

1974 1975 1976

1. Primary education . . . . . . . . . . . . . . . . . . .

2. Middle school . . . . . . . . . . . . . . . . . . . .

3. High school . . . . . . . . . . . . . . . . . . . . . . .....

4. College students . . . . . . . . . . . . . . . . . . . . . .

5. Graduates . . . . . . . . . . . . . . . . . . . . . .

%

—

% %

— —

53.68 30.17 38.36

38.94 59.48 48.12

5.28 7.77 4.77

2.10 2.58 8.75

TABLE 4

Mode of Drug Use

Opium Heroin

Smokes Swallows Smokes Injects

% % % %

1973 .......... 70.6 29.4 —

1974 .......... 60.1 39.9 100 —

1975. ......... 52.5 47.5 84.4 15.6

1976 .......... 2 0 8 0 30.3 69.7

56
KHANT AND WIN: DRUG ABUSE IN THE UNION OF BURMA

TABLE 5

Distribution By Age

Years

Opium

%

Heroin Marihuana

% %

Others

%

11-20 ......... 5.5 54.9 21 28.6

21-30 ......... 2 0 39.3 16.4 24.3

31-40 ......... 6 2 18.8 6.2 1 3

41-50 ......... 93.4 3.4 — 3.2

51+. .......... 97.1 1.7 — 1.2

TREATMENT PROGRAMMES

In accordance with the law, all drug abusers after registration are

given suitable medical treatment. To meet this need, treatment

centres have been opened in various towns in the country. In these

centres, multi-modality programmes are being introduced. These include:

1. Compulsory hospitalization

2. Ambulatory treatment

3. Detoxification

4. Acupuncture

5. Day hospital

6. Crisis intervention services

7. Treatment by religion or spiritual inspiration

At the Rangoon Psychiatric Hospital, the following modes of

treatment are carried out:

I. Detoxification

(a) By use of Methadone in gradually decreasing doses

(b) By use of tranquillizers and other drugs

(c) “Cold Turkey” method

(d) Acupuncture

II. Rehabilitation

(a) Individual psychiatric counselling

(b) Group psychotherapy

(c) Family therapy

(d) Social counselling

(e) Locational rehabilitation

57
INTERNATIONAL CHALLENGE OF DRUG ABUSE

III. Ambulatory Drug Free Treatment

Withdrawal of drug of dependence is done through decreasing

doses of Methadone and monitored through urine analysis.

IV. Day Hospital

This facility combines the advantages of residential treatment

with those of ambulatory treatment. Patients live at the hospital during the day but are allowed to leave in the evening.

Inservice training of medical officers, nurses, and health educators is being organized by the Health Department. Priority is given

to those working in the Shan and Kachin States and in other parts

of the country where the incidence of drug abuse is high.

RESEARCH PROGRAMMES

Under WHO and Ministry of Health collaboration, research work

is being carried out, particularly for the at-risk groups. Programmes

in progress at present are:

1. Epidemiological Case Reporting of Drug Users

This research programme is to improve epidemiological information on drug use by field testing of a case reporting form for

collecting minimal essential data.

2. Evaluation of Drug Dependence Treatment Method

The objective of this project is to improve knowledge of the effectiveness of low cost treatment methods in the management of

drug dependence.

3. Drug Use Surveys of Young People

This project is developing a model survey instrument for use in

disease settings. Later, a full scale student survey is proposed.

CONCLUSION

The Government of the Socialist Republic of the Union of

Burma adopted a resolution in its first session and fourth meeting

of the Pyithu Hluttaw, held in October 1975, to combat drug abuse

on a national campaign level. In view of the present administrative

structure and functions of the Government, the resolution in practice amounts to an attempt to involve the entire population in combating this affliction. The civil, military, and legal branches of the

Government are all involved in different ways.

58
KHANT AND WIN: DRUG ABUSE IN THE UNION OF BURMA

Under guidance of the Burma Socialist Programme Party and

with close cooperation of the People’s Councils at different. levels,

this campaign is making good headway, and we shall work on until

we are rid of the scourge of drug abuse.

REFERENCES

1. Aubrey, D.O.B. A short history of opium and its consumption with particular reference to Burma. The Nation Daily, May 1952. pp. 2-4.

2. Lau, M.P. An Epidemiological Study of Narcotic Addiction in Hong-Kong.

1967. pp. 22.

3. Legislation. Inter-country Seminar on prevention and control of drug abuse.

Jakarta: World Health Organization, 7-12 October 1974.

4. Taung, Paline. Opium and Northern Burma, I & II. Working People’s Daily,

May 1966. pp. 2-4.

5. World Opium Survey 1972. Cabinet Committee on International Narcotics

Council.

59
CHAPTER 6

International Challenge of Drug

Abuse: A Perspective From the

United Nations

George M. Ling, Ph.D., and J. Gomez del Prado

International awareness and concern about the misuse and abuse

of dangerous drugs have grown substantially in recent years. The increasing use of psychoactive substances indicates that we are living

in a drug-oriented age. It is claimed that society has become more

responsive to promotional advertisements for mood-modifying

chemicals (alcohol, analgesics, sedatives, tranquillizers, etc.), but it

also is worthwhile to recall that throughout recorded history,

societies in all parts of the world have used a variety of substances

in various forms to alter mood and behaviour. The use of drugs in

earlier societies differed according to the region of the world, the

period of history, the nature of the drug, and the frequency and

consequences of use. Comparable variations in use and acceptability

remain today. On the other hand, while the use of mind-altering

substances in earlier times was limited largely to persons who had

attained the locally accepted age of responsibility, such substances

are now taken with increasing frequency and in greater amounts by

younger persons as well as in a larger number of regions of the

world.

Although the real extent of the problem emerges only partially,

like the tip of an iceberg, indicators show an upward trend in the

abuse of most substances. For instance, the total quantity of opium

seized worldwide, after falling for two consecutive years, rose by 19

percent in 1976. Of this quantity, 69 percent was seized in the Far

East and 27 percent in the Near and Middle East. A similar pattern

has been noted with respect to morphine seizures, which, after

decreasing for two consecutive years, rose by 129 percent.

60
LING AND DEL PRADO: A UNITED NATIONS PERSPECTIVE

In North America, the heroin problem appears to have stabilized

after a decade of growth. The use of amphetamines and LSD has

also decreased, while that of cannabis, cocaine, and phencylidine

continues to increase.

In contrast, other areas of the world are now witnessing some of

the patterns and characteristics of heroin use that were evident in

North America some time ago. This is reflected in an increase in

use, both orally by smoking and parenterally by injection, to the

extent that heroin in some areas is becoming the principal opiate of

abuse.

In Southeast Asia, there is an increasing interest in heroin use

rather than in opium and morphine. This pattern of use is concentrated primarily in metropolitan areas, but it continues to spread

to rural areas as well, and to younger age groups. As an example, in

one city in the region an anti-drug campaign against narcotic addicts

has resulted in the arrest of over 2,500 drug addicts of which 78

percent were between the ages of 16 and 25. In addition, the total

amount of heroin seized in Asia and the Far East region increased

from 417 kg in 1975 to 967 kg in 1976.

In Africa, heroin is at present little used as a drug of dependence,

but there is an increasing use of amphetamines, sedative-hypnotic

agents, hallucinogens, and synthetic opioid narcotics. In this connexion, the law enforcement authorities of Egypt have been increasingly effective in their seizure controls, and recently a smuggling group was arrested while trying to smuggle 6 million narcotic

tablets into that country.

In areas around the Red Sea, the use of the khat leaves of the

catha edulis plant as a stimulant, euphorant, and hallucinogen is on

the increase. This plant has nitrogen-containing components

(norpseudoephedrine, cathinone, etc.) with actions and effects

comparable to those of the amphetamines. Khat is at present not

under international control, but work is continuing in the UN

Narcotics Laboratory of the Division of Narcotic Drugs and the

World Health Organization to determine the degree of control

which might be required for this substance.

In Lebanon, reports indicate that approximately 2,500 acres of

opium poppies are now under cultivation in the Bekaa Valley, a

tribal area which for years has long been the source of illicit

hashish.

Moreover, in Europe, where in the past there has been a tendency

to believe that the drug problem is only of particular concern to

North America and the countries of the Far East, official sources as

well as the lay press have emphasized the alarming spread of drug

61
INTERNATIONAL CHALLENGE OF DRUG ABUSE

abuse in this region and have called attention to increasing seizures

in recent months of opiates, particularly heroin, at various Northern

European transit points. The increases had been observed mainly in

Denmark, Germany, Italy, the Netherlands, and Sweden, and

quantities seized during 1976 have increased more than 120 percent

over 1975. There are concerns also about the medical, social, and

economic problems associated with the compulsive use of other

types of drugs such as cocaine, cannabis and its preparations,

methaqualone, the barbiturates, the amphetamines, and even

trihexyphenidyl. In 1976, total worldwide seizures of central

nervous stimulants increased 52 percent over 1975. Of these

seizures, 72 percent were made in Europe and 27 percent in the

American region.

A further problem is that drugs are being used either in sequence

or simultaneously, and multiple drug abuse has become a common

pattern in many countries, with unpredictable and even fatal

consequences.

For many years, United Nations bodies, international organizations, and governments have given considerable attention to drug

abuse, to the identification of dependence-producing substances,

and to the control of their production and distribution, as well as to

the reduction of demand.

International efforts to control drug abuse have also been

focussed on the development of an international treaty system

which will assist national control policies. In the international

system, two categories of controlled drugs are recognized: narcotic

drugs and psychotropic substances. At present, control is exercized

over 86 narcotic drugs and 26 psychotropic substances. The

narcotic drugs include opium and its derivatives, morphine, codeine

and heroin, and other synthetic narcotics, as well as cannabis and

cocaine. These drugs are controlled under the provisions of the

Single Convention on Narcotic Drugs of 1961 as amended by the

1972 Protocol. The psychotropic substances comprise, broadly, the

hallucinogens, the stimulants, and the depressants. These are

controlled by the Convention on Psychotropic Substances of 1971.

Both instruments have already entered into force.

The three main organs of international control are the UN

Commission on Narcotic Drugs, the International Narcotics Control

Board, and the World Health Organization.

The Commission on Narcotic Drugs is a functional organ of the

Economic and Social Council of the United Nations and comprises

representatives from 30 governments, elected with due regard to the

adequate representation of:

62
LING AND DEL PRADO: A UNITED NATIONS PERSPECTIVE

1. countries which are important producers of opium or

coca leaves;

2. countries which are important in the manufacture of

narcotic drugs; and

3. countries in which drug addiction or the illicit traffic in

narcotic drugs constitutes an important problem.

The Commission assists the Council in the application of

international conventions and agreements dealing with drugs and

carries out such functions as the Council has found necessary to

assume and continue.

It advises the Council on all matters pertaining to the control of

drugs and prepares such draft international conventions as may be

necessary.

It further considers what changes may be required in the existing

machinery for the international control of drugs and submits

proposals to the Council.

The Commission has been operative for over thirty years. It sits

annually in regular or special session and provides a continuous

review of the global situation in regard to the international control

of drugs of abuse and by its decisions and resolutions takes

appropriate steps to remedy any weaknesses.

The World Health Organization has long been involved in

activities designed to prevent and reduce the seriousness and extent

of health care problems associated with the nonmedical use of

narcotic drugs and psychotropic substances. In this context, the

Organization’s responsibilities relate, inter alia, to two important

aspects of international control. These include, firstly, the assessment of those substances which may produce personal and public

health hazards, and, secondly, the Organization’s recommendations

to the UN Commission on Narcotic Drugs of substances to be listed

for control under appropriate schedules of the Single Convention

on Narcotic Drugs (opiates, cannabis, coca, cocaine) and the

Convention on Psychotropic Substances (e.g. hallucinogens, sedative-hypnotics and stimulants).

Another important international control organ is the International Narcotics Control Board, which comprises 13 specialists

selected by the UN Economic and Social Council on the basis of

their competence and impartiality. The Board’s objectives are to

ensure that the aims of the Conventions are not endangered by the

failure of any government to monitor the licit production,

manufacture, and trade in narcotic drugs and psychotropic substances required for medical and scientific purposes only, and to

63
INTERNATIONAL CHALLENGE OF DRUG ABUSE

ensure that there is no diversion of these compounds into illicit

channels.

Financial assistance for many of these programmes is provided,

where appropriate, by the United Nations Fund for Drug Abuse

Control (UNFDAC). The establishment of UNFDAC was announced by the Secretary-General on 26 March 1971. In doing so,

he was initiating action that had been called for by the General

Assembly of the United Nations in its resolution 2719(XXV), the

Economic and Social Council resolution 1559(XLIX) and the

Commission on Narcotic Drugs. Seventy-two countries and one

foundation are now actively supporting the Fund by voluntary

contributions.

The objective of UNFDAC is to furnish assistance to governments and international organizations, including in particular the

specialized agencies of the United Nations, in their efforts to:

Limit the supply of drugs to legitimate requirements by

putting an end to illegal or uncontrolled production,

processing and manufacture;

improve the administrative and technical capabilities of

existing bodies concerned with the elimination of the

illicit traffic in drugs;

develop measures to prevent drug abuse through programmes of education and special international campaigns;

provide facilities and develop methods for the treatment,

rehabilitation and social integration of drug-dependent

persons;

conduct chemical, pharmacological, medical, sociological

and operational research on drug abuse and its control.

The Division of Narcotic Drugs, in consultation with the

specialized agencies and international organizations, is instrumental

in developing the overall plan for drug abuse control and in

formulating those projects and programmes for which it is the

executing agency.

The operational aspect of the Division’s activities which has been

enlarged by the support of the Fund continues to expand in several

areas. These include, inter alia, analytical research and identification

of controlled substances by the UN Narcotics Laboratory, assistance to developing countries to enable them to reduce both the

supply of and the demand for illicit drugs, the reduction of illicit

traffic, and the continuous provision of fellowships and training

programmes to control drug abuse. As an example of the latter

activity, the Central Training Unit of the Division of Narcotic Drugs

64
LING AND DEL PRADO: A UNITED NATIONS PERSPECTIVE

has trained since 1972 over 1,000 enforcement officers from

approximately 88 developing countries. This training has stimulated

further interest in control measures and has not only improved the

effectiveness of national enforcement agencies but has fostered and

increased international cooperation. The Division is also assisting

the Government of Turkey to prevent the illegal conversion of

opium gum into illicit morphine and its congeners by the use of the

“straw process.” In this context, the poppy capsules are not lanced,

opium cannot be formed, and instead the dried capsules are

delivered to a government for legal processing. Multidisciplinary

country programmes with emphasis on the reduction of supply are

also being conducted in countries in the Far East, the Near and

Middle East and South America, where efforts are being made to

determine the mutually most acceptable income and crop substitution programmes needed to overcome the farmer’s reliance on the

cultivation of crops which yield narcotic substances.

The United Nations organs dealing with the international control

of drugs are convinced, however, that measures to reduce the illicit

supply of drugs cannot be effective in the long run unless measures

are taken concurrently to reduce the illicit demand for drugs. In

this context, the UN Economic and Social Council adopted in 1975

a resolution entitled “Measures to Reduce Illicit Demand for

Drugs,” whereby it recommended that Governments, inter alia,

should incorporate measures for the prevention and treatment of

drug abuse in their integrated public health programmes.

The Commission therefore entrusted the Division of Narcotic

Drugs to undertake a “study on measures to reduce illicit demand

for drugs” with the collaboration of the World Health Organization,

the United Nations Educational, Scientific and Cultural Organization, the International Labour Office, the International Narcotics

Control Board, the United Nations Division of Social Affairs, and

the International Council on Alcohol and Addictions. It is of

interest that this provision for adequate measures to respond to the

demand for illicit drugs was foreseen in both the Convention on

Psychotropic Substances, 1971, and the Single Convention on

Narcotic Drugs, 1961, as amended by the 1972 Protocol.

A preliminary report on the first phase of the Study was

prepared and considered by the Commission on Narcotic Drugs in

February 1977. The report examined major issues concerning

conceptual questions and policy alternatives which merit consideration for demand reduction activities. These include, inter alia, the

assessment of drug abuse problems, the design and implementation

of preventive, treatment, and rehabilitation measures, the evalua65
INTERNATIONAL CHALLENGE OF DRUG ABUSE

tion of the effectiveness of demand reduction programmes, and

plans to meet future challenges and needs as they arise. The report

also directed attention to the relationship between demand for

illicit drugs and the irrational and unintelligent use of licit

psychoactive substances. In this connexion, increased consideration

should be given to the availability and self-administration of

psychoactive substances as well as to the control of the manufacture, prescription, and dispensing of drugs considered to have an

abuse liability. Members of the health profession are therefore

urged to exercise continuing vigilance in preventing abuse of drugs

by developing realistic measures of control and by exercising

caution to prevent the overprescribing of psychoactive drugs with

dependence-producing liability.

As a second phase of the Study, the Commission also adopted a

decision requesting the Division, in collaboration with the specialised agencies concerned with illicit demand, to prepare a Resource

Book on Demand Reduction. It is anticipated that its content

would offer a practical guide for dealing with basic drug abuse

problems of a community, and in particular would meet the needs

of developing countries.

In a related area of demand reduction, governments are obliged

to furnish data to the Secretary-General of the United Nations on

different aspects of drug control, among which are the extent and

patterns of drug abuse. On the basis of the information received

from governments, the Division of Narcotic Drugs prepares a

document on the abuse of drugs by regions of the world for

consideration by the Commission. The sources of data collection

utilized differ from one country to another and comparability of

data is extremely difficult to achieve. To assist national authorities

in assessing the characteristics of drug abuse in their countries and

in structuring their annual reports, the Division, in collaboration

with the World Health Organization, has structured a Manual on

Drug Abuse Assessment. This Manual is now being tested in

Malaysia, Pakistan, the Philippines, and Thailand.

The Division and the Commission have a special relationship with

the International Criminal Police Organization (ICPO/Interpol)

which involves reciprocal attendance at meetings and constant

cooperation in all matters related to the international traffic in

narcotic drugs and psychotropic substances. The Division also

cooperates with the Arab Narcotics Bureau of the Social Defence

Organization of the League of Arab States, the Council of Europe,

the Colombo Plan Bureau, and the Customs Cooperation Council,

66
LING AND DEL PRADO: A UNITED NATIONS PERSPECTIVE

as well as with certain nongovernmental organizations and in

particular the International Council on Alcohol and Addictions.

Integration and coordination of the work of these various

organizations have fostered concerted international cooperation in

efforts to control drug abuse and its associated problems, and

developed industrialized societies must continue with their determination to assist the international effort both through declarations

of intent and through allocation of appropriate resources. In this

regard, it is worthwhile recalling United States President Carter’s

personal message to the 27th session of the Commission on

Narcotic Drugs in February 1977: “As I begin my administration, I

recognize that drug abuse, like so many problems that face us, is

global in nature and can be solved only through concerted

international cooperation. Drug addiction is the cause of untold

human suffering, afflicting both the rich and the poor. Of particular

concern to us, however, is the recent dramatic increase in addiction

and its destructive effect on the limited human and economic

resources of many of the less affluent nations of the world.”

BIBLIOGRAPHY

Cameron, D.C., and Ling, G.M. World Health. WHO, December 1975.

Cameron, D.C. Drug Dependence: Some Research Issues, Bull. Wld. Hlth. Org.

1970, 43.

Chauncy Leake, New York Academy: Interaction of Drugs Abuse, Ann. N.Y.

Acad. Sci, vol. 281, 1976.

Conwell, P.H., and Dorn, N. Cannabis and Man, London: Churchill Livingstone, 1975.

Dumont, M.P. Social Policy, July/August, 1972.

Final Report of the Commission of Inquiry into the Non-Medical Use of Drugs,

Ottawa: Information, Canada, 1973.

Guy Edwards, J. Addiction — The Practitioner, 212, 1974.

Johnson, B.D. Marihuana Users and Drug Subculture, New York: Wiley, 1973.

Josephson, Eric, and Carroll, Eleanor E. Drug Use: Epidemiological and

Sociological Approaches in Drug Use. New York: Wiley, 1974.

PACT/NADAP Report, June 1977, vol. 4, no 4.

Parish, P.A. J Roy Coll Gen Practit, suppl. no. 2, 23, 49, 1973.

Patterson, M.A. Addictions can be Cured: An interim Report, Herts, 1975.

Siam Roth Newspaper, Rangoon, Thailand, May 11, 1974.

The Vancouver Sun, Vancouver, Canada, August 3, 1977.

United Nations Economic and Social Council, Resolution 1934 (LVIII),

Measures to Reduce Illicit Demand for Drugs, E/5667.

United Nations Convention on Psychotropic Substances, 1971, Article 20:

Measures against the abuse of psychotropic substances.

United Nations Single Convention on Narcotic Drugs, 1961, as amended by the

1972 Protocol, Article 38: Measures against the abuse of drugs.

67
INTERNATIONAL CHALLENGE OF DRUG ABUSE

United Nations Economic and Social Council. Study on Measures to Reduce

Illicit Demand for Drugs, Preliminary Report by the Director of the

Division of Narcotic Drugs. E/CN.7/602.

United Nations Economic and Social Council, Commission on Narcotic Drugs.

Report on the 27th. session, E/5933.

United Nations Economic and Social Council. Drug Abuse: Extent, Patterns

and Trends. Note by the Secretary-General. E/CN.7/612.

United Nations Economic and Social Council. Review of the Illicit Traffic of

Narcotic Drugs and Psychotropic Substances during 1976. E.CN.7/613.

United Nations. Information letter. Division of Narcotic Drugs, October/

November 1976.

United Nations. The United Nations and Drug Abuse Control. New York,

1976.

Westermeyer, J. The pro-heroin effects of anti-opium laws in Asia. Arch Gen

Psych, 33(9):1135-1139, 1976.

Westermeyer, J., and Bourne, P.A heroin ‘epidemic’ in Asia. Amer J of Drug &

Alc Abuse, 4(1):1-11, 1977.

Westermeyer, J., and Peng, G. Brief communication. Opium and heroin addicts

in Laos. I.A comparative study. J New Ment Dis, 164(5):346-350,1977.

Westermeyer, J.; and Peng, G.Brief communication. Opium and heroin addicts

in Laos. II.A study of matched pairs. J New Ment Dis, 164(5):351-354,

1977.

Wld. Hlth. Org. Tech Rep. Ser., No. 551. Geneva, 1974.

68
CHAPTER 7

General View of Drug Abuse in Iran

and a One-Year Report of Outpatient

Treatment of Opiate Addiction in

the City of Shiraz

M. R. Moharreri, M.D.

Drug addiction has been a nationwide problem in Iran since the

17th Century. Opium is the most widely abused drug, but with

rapid industrialization and social change, Western patterns of drug

abuse, including the use of heroin, alcohol, hallucinogens, and

hypnotics are emerging.

In contrast to other countries, the addict population in Iran do

not represent any specific socioeconomic or religious segment of

the general population. For almost 14 years cultivation of opium

poppies was banned in Iran. However, in 1969, the Government of

Iran decided to permit limited and supervised cultivation.

In 1969 the Government initiated a nationwide opium maintenance program for individuals 60 years of age or older and for those

suffering from chronic diseases for whom detoxification was not

advisable.

In 1975 Government figures showed that 185,000 registered

addicts were participating in the maintenance program, but this

figure is believed to represent only one third of the actual number

of nonauthorized addicts.

The nonregistered addicts are able simply to obtain their

supplies from drug traffickers or registered addicts who sell a

fraction of their supply. Although the measures taken by the

Government against drug traffickers are quite severe, opium

continues to enter Iran.

69
INTERNATIONAL CHALLENGE OF DRUG ABUSE

With the exception of a few centers located in Tehran, the

treatment of addicts has been largely the responsibility of local

physicians. The usual method of detoxification employed has

been a gradual reduction in dosage of opium extract pills. Followup

was not commonly done. Results of this treatment regimen were

not satisfactory. Until 1974 in the large cities inpatient detoxification was the only treatment service offered to addicts. These

detoxification centers were often located far from those drug

abusers who live in small towns and villages.

From August 1973 to April 1975, the pilot project studied 533

addicts treated in an outpatient setting in Shiraz city. Outcome of

this study showed better results, greater convenience for patients

and staff, and much lower cost. In 1974, the National Iranian

Society for Rehabilitation of the Disabled (NISRD) accepted the

responsibility for treatment and rehabilitation of drug addicts. In

the summer of 1975, Ramsar Medical Congress devoted its entire

session to the problem of drug addiction. As a result of this

congress, outpatient detoxification and rehabilitation programs

received further impetus. The main resolutions of the Congress were

as follows:

1. All individuals below the age of 50 who are on opium

maintenance will be expelled from the program and immediately

detoxified.

2. The dosage of opium maintenance for those who are in the age

group from 50 to 60 will be reduced to 2.5. grams daily.

3. No new applicant below the age of 60 will be accepted into the

opium maintenance program and only after meeting certain

restricted criteria will a registration card be issued to new

applicants over 60 years of age.

4. The minimum age limit for entering the maintenance program

will be increased by one year annually.

5. Outpatient treatment was accepted as the most desirable and

practical method to be established in all local NISRD offices

throughout the country.

These resolutions were immediately accepted and put into operation by the Ministry of Health & Welfare. As a result, a drastic

reduction in the number of registered addicts has occurred. A

similarly increased demand for outpatient treatment and detoxification has been reported from various parts of the country.

In the tables that follow, I have tried to summarize the main

findings of a study of 643 patients seen in our outpatient drug

rehabilitation facility in Shiraz city from March 1975 to March

1976.

70
TABLE 1

Age and Educational Status Distribution of Drug Addicts Treated in Shiraz Rehabilitation Center

(N=643)
TABLE 2

Sex and Marital Status of Drug Addicts Treated in Shiraz Rehabilitation Center (N=643)
MOHARRERI: VIEW OF DRUG ABUSE IN IRAN

TABLE 3

Occupational Status of Drug Addicts Treated in

Shiraz Rehabilitation Center (N=643)

TABLE 4

Starting Age of Drug Addicts Treated in Shiraz Rehabilitation Center

(N=643)

73
INTERNATIONAL CHALLENGE OF DRUG ABUSE

TABLE 5

Type of Addictive Drug Used by the Addicts Treated in Shiraz

Rehabilitation Center (N=643)

TABLE 6

Duration of Addiction in the Addicts Treated in Shiraz Rehabilitation Center

(N=643)

TABLE 7

Mode of Drug Use by Addicts Treated in Shiraz Rehabilitation Center

(N=643)

74
TABLE 8

Drug Intake (Per Day) in Addicts Treated in Shiraz Rehabilitation Center

TABLE 9

Dose of Opium and Shireh Intake Per Day in Addicts Treated in Shiraz Rehabilitation Center
INTERNATIONAL CHALLENGE OF DRUG ABUSE

TABLE 10

Heroin Intake (Per Day) in Addicts Treated in Shiraz Rehabilitation Center

TABLE 11

Distribution of Addicts According to Daily Cost of Addiction

(in Rials*) During the First Six Months of 1975

(Before the Ramsar Congress)

TABLE 12

Distribution of Addicts According to Daily Cost of Addiction

(in Rials*) During the Second Six Months of 1975

(After the Ramsar Congress)

76
MOHARRERI: VIEW OF DRUG ABUSE IN IRAN

TABLE 13

Way of Obtaining Drugs in Addicts Treated in Shiraz Rehabilitation

Center in the First Six Months of 2535

(March 1976—September 1976)

TABLE 14

Way of Obtaining Drugs in Addicts Treated in Shiraz Rehabilitation Center

in the Second Six Months of 2535 (October 1976-March 1977)

TABLE 15

Treatment Situation of Addicts Treated in Shiraz

Rehabilitation Center (N=643)

77
TABLE 16

Frequency and Dose of Methadone Intake (Per Day) in Addicts Treated in Shiraz Rehabilitation Center

(N=643)

TABLE 17

Duration of Treatment in Addicts Treated in Shiraz Rehabilitation Center (N=643)
MOHARRERI: VIEW OF DRUG ABUSE IN IRAN

TABLE 18

Results of Treatment in Addicts Treated in Shiraz

Rehabilitation Center

79
TABLE 19

Causes of Addiction in Addicts Treated in Shiraz Rehabilitation Center (N=643)

From March 1976-March 1977
MOHARRERI: VIEW OF DRUG ABUSE IN IRAN

BIBLIOGRAPHY

1. Mehryar, A.H., and Moharreri, M.R. Some socio-characteristics of registered

opium addicts in Fars Province. Shiraz: Pahlavi Population Center, 1975.

(Accepted for publication in British Journal of Drug Addiction.)

2. Moharreri, M.R. Out-patient treatment of opium addicts: report of a pilot

project in Shiraz. Bulletin on Narcotics, 28(3):31—39, 1976.

3. Moharreri, M.R., and Mehryar, A.H. “Opium Addiction in Iran.” Shiraz:

Pahlavi Population Center, 1976. (Mimeographed.)

4. The report of Ramsar Iranian Medical Congress on Addiction to Her Majesty

the Queen. September 1976.

81
CHAPTER 8

Coca and Cocaine: A Perspective

from Bolivia

Nils D. Noya, M.D.

INTRODUCTION

We have been aware for several years, of youth’s consumption

and abuse of cocaine in different parts of the world. However, we

must say that this is a rebirth of an epidemic that had already begun

during the last part of the nineteenth century and extended to the

middle of the 1920’s, especially in Europe (12). This epidemic, like

any other infectious disease, involves a period of increasing

intensity, a maintenance period and than a gradual descent.

Nevertheless, as physicians and, specifically, as psychiatrists, we

should be concerned about a number of disorders produced by

cocaine, that sometimes an erroneously informed press tends to

minimize (17). We are, then, dealing with a powerful drug that,

although in a majority of cases does not produce physical

dependency, produces very clear psychic alterations when used

continuously. These occur apart from the paranoid type of

psychosis, already described, that is caused by a chronic use of this

drug.

HISTORY

Cocaine’s history begins with its discovery by Karl Scherzer, in

Cottingen, Germany, in 1859 (20). Initially, cocaine was utilized as

a local anaesthetic; later, it was used in laryngology but mainly,

according to Keller’s work in 1884, in surgical and opthalmologic

treatments (6). That same year, Dr. Sigmund Freud, the father of

psychoanalysis, began to use the drug on himself and also as a

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morphine substitute on one of his colleagues, who was a morphine

addict (9). These methods of using cocaine had already been

employed in the U.S.A. to treat morphine addicts (4), and in 1884,

German psychiatrists adopted cocaine as a therapeutic means to

reproduce their American colleagues’ experiments (4).

When Freud described a cocaine-derived “good humor, together

with a feeling of security, self-possession, increased strength, greater

working capacity,” he contributed to the possibly exaggerated

spread, at that time, of the use of cocaine. However, we must join

Jean Marie Gerbold when he says that, even when ill, Freud refused

to use drugs, whatever their medical significance, and if, in extremis

he resorted to drugs, it was in the final declination of his life, in

order to end his hopeless agony as soon as possible.

Dr. Aschenbrandt was another European physician who also used

cocaine as a tonic and as a stimulant. He was a German physician

who administered cocaine orally to the soldiers, claiming that he

had discovered it to have a refreshing and soothing effect (2). In

1887, Dr. Albrecht Erlenmeyer, referring to morphine addiction

treatment, described the physical and psychical collapse of cocaine

addicts, especially in those cases where morphine addiction had

clearly developed into cocaine addiction. He suggested this type of

treatment be given up as soon as possible (8). Later, in 1889, the

Frenchman Magnan specifically described the tactile hallucinations

— the feeling of small worms moving under his skin, or of being

assaulted by millions of fleas. (Today we know this as the “Magnan

syndrome.”) There were patients who even pulled off their skin or

cut themselves, trying to rid themselves of the imagined worms. By

that time, the psychiatric alterations began to be described,

especially paranoia or delusions of persecution or of reference (16).

It is interesting to point out that the real beginning of cocaine

mania took place in the U.S.A. between the years 1902 and 1903.

There are figures that indicate that in Cincinnati, Ohio, 10,000

people had already used cocaine by that time, and the states of

Ohio and Kentucky passed special laws forbidding the sale of

cocaine without a medical prescription (20).

It is interesting to speculate on the fact that in the critical prewar

periods, the increase in the use of cocaine was especially significant.

We can observe that before the First World War it had increased

greatly in the European countries. The same phenomenon happened

before the Second World War.

In 1924, the Paris police estimated the number of cocaine addicts

at 80,000; mainly students and even school children (7). Some

authors even mention cocaine as an important influence on the

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

development of some schools of art, i.e., cubism and dadaism. Color

diffraction and the unfolding of objects represent the effects of

disorders produced by this kind of drug (5). Jean Luis Brau in his

book, History of Drugs, mentions some of the dadaists that utilized

the drug.

In Germany, at the University Clinics, it was possible to observe

clearly that the cocaine influence in the prewar and postwar periods

created a really alarming situation. Of 1,000 patients admitted to

the University psychiatric clinics between 1915 and 1924, the

proportion of cocaine addicts increased from 0 in 1915, to 13

percent in 1924. The book, Phantastica, written by the Berlin

pharmacologist, Lewin (14), also tells us about the great quantity of

different preparations that can be made out of this drug, i.e.,

cocaine wine, cocaine champagne, cocaine cigarettes, etc. Later, a

new type of wine appeared: it had a great impact in Europe at that

time and was known as “Vin Mariani.” It was made from a coca-leaf

infusion (18).

In 1929, the first year that official data were available, the legal

production of cocaine was estimated as 5,700 kg; 4,600 kg in 1934;

2,593 kg in 1955; 1,563 kg in 1963 and 1,038 kg in 1968. We must

not forget that today, both legal and illegal cocaine production have

considerably increased, specifically in the countries that grow the

coca leaf. In these countries the proportion of increase in cocaine

production cannot even be measured, because of the geographic and

communication difficulties, lack of roads, and other factors. It is

clear that even with the best intention of the local governments to

control the cultivation of coca, the future appears extremely

unpredictable.

COCA

For centuries the natives in the Ecuadorian, Peruvian, and

Bolivian regions have been chewing coca. Coca, whose etymology

means plant, was used during the pre-Inca and Inca periods as a

divine drug that was exclusively meant for the royal Incas, supreme

priests, and members of the Inca’s royal family. Later, for reasons

still unknown, the habit of chewing coca spread to all social levels,

before the Spaniards reached America. In the books written by the

Inca Garcilaso de la Vega (10) and by Jose Acosta (l), written in

1609 and 1590 respectively, the chewing of coca by the Incas

(“coqueo”) is specifically mentioned, as is its subsequent use by the

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conquerors themselves. Years later, the Swiss naturalist J.J. Von

Tschudy, in his book, Croquis des Voyages, (1842) describes a

gloomy and highly harmful health situation among the natives who

chewed coca (21).

However, the experience in Bolivia that is described in the works

of Gutierrez Noriega and Ortiz Zapata is a different one (13). They

dealt with several subjects, trying above all to eradicate cultivation

of coca in their own country, Peru, as a way to prevent the chewing

of coca, and of course, to prevent its being transformed into

cocaine. These studies were highly valuable, as were those carried

on by the UN Commission on Narcotic Drugs in 1964 and 1966,

but they are not convincing from a medical point of view, when

they refer to the chewing of coca leaf as producing. important

damage or even any kind of disorder (19).

COCAINE

A different situation is seen with the chronic as distinct from the

sporadic use of cocaine.

Lately, Newsweek magazine, in its volume LXXX-IX-22, dated

May 30, 1977, describes the noxious effect of cocaine when used

by human beings (17), but again, it does not mention the quality

and quantity of this stimulant, that, at least in Bolivia, is used in a

state of 97 percent purity. We realize that the statements made by

the authorities in charge of drug abuse control, are a consequence

of their experience of cocaine abuse with extremely low drug purity

and where the regular dose is approximately 0.15 gr. Also, its value,

in that same proportion, is about $20. In Bolivia the cocaine used is

extremely pure, as already mentioned, and the usual dose is

between 4 gr. and 6 gr. As its effect is quite transient, it produces a

very strong psychological dependence that induces the addict to use

approximately 20 to 25 gr of cocaine chlorhydrate per dose. This

undoubtedly produces serious disorders in the psychic life of the

drug-dependent individual. We must also consider the cost of

cocaine in Bolivia, which is much lower than anywhere else in the

world. Because of this, there is a great temptation to come to

Bolivia to get cheap, high-quality cocaine. This is responsible for

filling the prisons with foreigners, who, in spite of the strict

Bolivian laws regarding drugs, come with the intention of doing

illegal business.

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

SYMPTOMATOLOGY

We can group the symptoms based on the three ways cocaine is

utilized in Bolivia today and in accord with our experience. This

experience has led us to agree with the research carried on by

Grinspoon and Bakalar in their latest book on cocaine (11).

When absorbed or inhaled, cocaine produces a feeling of

relaxation and an emotional release of inhibition similar to that

produced by the early effects of alcohol. There is a feeling of

self-sufficiency, and, as some patients describe it, the sensation of

being “the owner of the world.” However, we must point out that,

in the majority of patients treated, it was observed that the first

nasal absorptions or injection of cocaine chlorhydrate produces

almost no specific sensations. Symptoms appeared only after the

third or fourth use. Patients said that then they experienced a

general lulling sensation in the whole body and a feeling of

“unfolding.” We must not forget that when cocaine is used, it is

generally among a group of people and that the other participants

help the newcomer to inhale the cocaine. The cocaine is rolled

inside a $100 bill. The insufflation must be violent so that it can

reach the upper part of the nasal cavities, where the cocaine will be

easily absorbed into the olfactory bulbs. In this way the consumers

also avoid the possibility of cocaine being deposited on the nasal

septum, thus preventing vasoconstriction in the nasal fossa, its

necrosis and later perforation, as often happens to cocaine users.

The intravenous shot of cocaine chlorhydrate produces illusions

or visual hallucinations, as well as auditory hallucinations of

paranoid character, with threatening screams and attempts at

self-damage, etc. Patients say that while the hallucinatory effect

lasts, the typical coca flavor persists in the mouth of the consumer.

Contrary to current belief, we have discovered that coca

produces a high degree of tolerance, apart from the possibility of a

situation that could result in physical dependence. This is based on

the following observation: among people who use cocaine by

inhalation or intravenous injection, after a time the usual dose fails

to produce the same state of intoxication as it did earlier. That is

why the dose of cocaine chlorhydrate is gradually increased in order

to produce the desired effect.

Regarding the experiences of our patients who consumed cocaine

to feel a greater sexual excitement, we have found that, except in a

few cases, there is no significant enhancement of sexual feeling. On

the contrary, in some cases where there existed some apparent

sexual excitement, mainly among men, the sexual act could not be

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NOYA: COCA AND COCAINE — PERSPECTIVE FROM BOLIVIA

performed because of lack of erection. The use of cocaine as a

topical anesthetic on the penis produces only anesthesia, with a

feeling of increased size, but not necessarily an improvement or

lengthening of the period of erection. Instead, it produces flaccidity.

Also, the use of cocaine, applied locally to the labia minora and

clitoris produces a sensation of anaesthesia. In one case, because of

its continuous use, it produced ischemia of the mucous membrane

of the labia minora and of the vagina. (It also produced a subjective

sensation that the partner’s penis size was increased.) We must add

that through our limited experience, we have seen no real cases of

sexual excitement with the usual doses (5 gr to 10 gr/day, with a

minimum degree of purity of 95 percent).

We have mainly described the inhalation and intravenous

methods, and we must describe another very peculiar form of

addiction that has led us to consider the possibility of the existence

of tolerance, and also what could be called a situation of physical

dependence.

The consumer of cocaine sulphate or cocaine base, mixed with

ordinary golden tobacco, presents a completely different symptomatology from that observed through our experience. After the first

inhalation of the “pitillo” (name given to the mixture of tobacco

with cocaine base sulphate), the subject feels an immediate

paranoid-like sensation, with delusions of persecution and potential

harm. We have treated patients who, after the first inhalation, closed

all doors and windows hermetically, “so that the police would not

get them” (sic). Immediately afterwards, the patient experienced a

compulsive need for continuous and exaggerated smoking: 60 to 80

“pitillos” in only one session, with the persistence of the paranoid

sensation, as long as the “gathering” lasts. These gatherings usually

take place among groups and only stop when both the cigarettes

and the base sulphate are finished. As it is possible to obtain great

quantities of cocaine base sulphate in our countries and because of

the greater damage caused by its lack of purity and the possibilities

of an intoxication by high doses of nicotine, we should focus our

attention on this problem, from a public health point of view.

Another evident reaction observed in each smoking session of

cigarettes made out of cocaine base sulphate, is an increase of

intestinal peristalsis, as well as the presence of abundant diarrhea

that appears as soon as the drug is inhaled.

The question is why, once the use of the cocaine base sulphate is

suspended, one frequently observes “flashback-type” problems.

This is how patients who have consumed this substance describe it.

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

They also mention the appearance of profuse perspiration, psychosomatic disorders, and even convulsions, that have a clear physiopathological explanation.

The appearance of deep depressions with suicidal ideas and

intentions, is very frequent, and they are again associated with

paranoid-type feelings.

It is also interesting from the point of view of our medical

experience, that when consumers feel that they have had an

overdose that could be dangerous, they can stop the state of

excitement by drinking a solution of only sugared water and lemon

juice. This simple measure controls the anxiety level, anguish, and

excitement that is reached by some cocaine dependents.

Among the important and unusual data, lies the possibility of

stopping the “bad LSD trips” with an inhalation of cocaine or the

smoking of a “pitillo.” Possibly in an entirely empirical way, this

notion could lead us to discover some of the pharmacological

properties of cocaine that are still unknown to us.

We also have been able to observe that the conjunctival injection,

peripheral vasodilatation with reddening of the skin, and metabolic

disorders appear only after a dose of more than 10 gr. of active

substance using either base sulphate or cocaine chlorhydrate.

We do not pretend, through these statements, to announce new

theories based on false hypothesis; rather, we want to introduce for

consideration and discussion some of the problems that we observe

through our experience. However, we must emphasize that the

possibility of using extremely pure cocaine in high doses produces

entirely different results from those observed in cases where doses

of less than 0.5 gr/day have been sporadically used. This is,

basically, the point at which we stand to sustain an approach to an

hypothesis about the damage produced by cocaine in the human

organism. We desire only that our experience be transmitted,

without any intention of causing panic or alarm, to show,

scientifically, how cocaine when consumed in high doses of high

purity, produces unsuspected problems.

Our research infrastructure is stiil highly deficient but we are

willing to accept suggestions and to receive help; and our medical

and scientific staff is ready to offer to any institution or interested

person, the possibility of a truly serious investigation, that can

definitively clarify the cocaine question.

If we minimize or try to diminish the importance of cocaine as a

powerful drug, we run the enormous risk that the future generations might have even more serious problems that those produced

by other drugs. I firmly believe that it is better to exaggerate our

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NOYA: COCA AND COCAINE — PERSPECTIVE FROM BOLIVIA

concern than to have an apathetic position or follow a weak policy

that could lead us, in the long run, to face a serious psychosocial

problem.

Those who have been able to see at first hand the physical and

mental deterioration of the real cocaine addicts, will justify our

concern and will understand the reason for the strict measures

Bolivia has taken (15). As an example of this situation we observe

that the deductive capacity in those individuals who can be

considered abusers of cocaine sulphate, is notably diminished, as is

their capacity for mathematical calculation, compared to the

normal scholastic efforts of other young people. The most evident

abuse that we have been capable of detecting is that found in

smokers of cocaine sulphate cigerattes.

Perhaps because of a lack of better communication between

countries of customary cocaine consumption in the form of

chewing dry coca leaves (“coqueo”), we do not yet have clearer and

more concrete information about the disorders that are produced.

Therefore, we cannot concisely speak about the harm that the

chronic chewing of coca leaf can eventually produce. This unknown

factor should be one more challenge for the investigations that will

be carried on in the future, in the countries involved. For this

reason I wish to invite all professionals and researchers from Peru,

Ecuador and Northern Argentina (where the habit of chewing

cocaine is frequent among several social groups), to coordinate their

actions toward investigation of specific pharmacologic and toxicologic action of the chewing of coca leaf. Our cooperation is

important: in our country coca usage is an ancient custom, with

deep social, cultural and anthropological roots, with no immediate

possibility of eradication, not even under the conditions of other

pharmaceuticals considered to be stupefacients. We have to establish, though, regarding use and abuse of cocaine, that only through

our experience have we been able to classify it as a powerful drug,

that easily leads to addiction, either exclusively psychological or,

merely as an hypothesis, of physical dependency. These conclusions

can evidently be discussed based on direct investigations of great

duration, under specific conditions, so that we can all be sure of the

kind of drug we are dealing with, and not adopt extremely rigid

attitudes or, on the contrary, an attitude of decided permissiveness.

The strict Bolivian control policy is inspired by the problems this

drug produces within our society and because we have had direct

experience with the damage cocaine causes among our youth. Its

final consequences we must deal with as physicians, in our primary

goal of saving lives, and as psychiatrists, within a basically social

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

setting, in order to enable youngsters to adapt to our life canons

and to be useful to society. It is, therefore, of enormous importance

for us, as psychiatrists, that we have complete understanding of

drug induced behavior, specifically of these drugs derived from

coca, so as to be able to establish more suitable control methods to

minimize the future short or long term implications for consumers.

REFERENCES

1. Acosta, Jose. Historia Natural y Moral de las Indias, Tanto Orientales como

Occidentales. Madrid, 1590.

2. Aschenbrandt. Deutche Mediz Wochenschr, 1883.

3. Bellanguer, J.L. La Stupefiante. Histoire de la Drogue dans le Monde. See:

(Science; Information), Union General d’Editions. Paris, 1963.

4. Bentley. 1878. Cited in Varenne, G. L’Abus des Drogues. Brussels: Charles

Dessart. 380 pp.

5. Brau, Jean Louis. Histoire de la Drogue. Paris: Claude Tchou, 1968.

6. Coller, K. Wiener Mediz Wochenschr, 1884.

7. Courtois-Suffit and Giroux, R. Ann de Med Leg, 3:294-299 and 391-398,

1923.

8. Erlenmeyer, A. Die Morphiumsucht und Ibre Behandlung. Berlin: Heuser,

1887.

9. Freud, S. Uber Coca Vermehrter S.A. aus dem Zentralbl fur Ther von

1884. Vienna: Perles, 1885.

10. Garcilaso de la Vega. Comentarios Reales, que Tratan del Origen de los

Incas, de sus Leyes, de su Gobierno. Lisbon: 1609-1616.

11. Grinspoon, L., and Bakalar, J. Cocaine. New York: Basic Books, 1976.

12. Guillain, Journ Med Franc, 15, VI, 1914.

13. Gutierrez Noriega Carlos y Ortiz — V. Zapata. Experimental cocainism:

General toxicologist, habituation and sensitization. Ref Med Exper, Lima,

3:279-306, 1944.

14. Lewin, L. Phantostica. Berlin, 1924. (English edition: Phantastica: Narcotic

and Stimulating Drugs. New York: E.P. Dutton & Co., 1964. 332 pp.)

15. Ley Nacional de Control de Substancias Peligrosas. Bolivia, 1975.

16. Magnan, V. Compt Rend Deseances de la Societe de Biol, p. 60, 1889.

17. Newsweek, volume LXXXIX-22. May 30, 1977.

18. Noya, N.

19. O.M.S. Serie des Raports Techniques, No. 76, 1954.

20. Varenne, G.L. L’Abus des Drogues. Brussels: Charles Dessart. 380 pp.

21. Von Tschudy, J.J. Peru Reiseskizzen aus den Jahren 1832-1842. Bd. 2,

Sankt Gallen, 1845.

90
CHAPTER 9

Drug Abuse in Indonesia

R. Kusumanto Setyonegoro, M.D.

INTRODUCTION

Drug abuse is a global problem. The phenomenon of opium

smoking in Indonesia was known long before World War II; the

Chinese segment of the population was especially known for this

habit. They obtained their opium through a special rationing system

under the colonial rule of the Dutch which ended abruptly with the

Japanese invasion in 1942.

For a better understanding of the Indonesian background a few

glimpses are given of its historical and cultural background.

Indonesia, Unity in Diversity

The land area of Indonesia—the world’s largest island country—is

scattered across a 3,500 mile span roughly comparable to an area

somewhat bigger than Europe. Indonesia has more than 15,000

islands. About 300 ethnic groups exist, each with its own identity,

and more than 250 languages are spoken; yet there is one universal

language. The major world religions are represented. Economic

activities range from stone age hunting in Irian Jaya (West New

Guinea) through a variety of agricultural pursuits to the sizeable

beginnings of a small but fast-growing modem industrial society,

primarily centered around big cities like Jakarta (estimated population 5 million) and Surabaya (estimated population 3 million).

The Indonesian population (now estimated at 130+ million, of

which roughly 60 percent live on the relatively small island of Java)

is one measure of the urbanization pressure that confronts this

country, if one compares with the recorded pre-World War II

populations: Indonesia, 80 million; Jakarta, less than 2 million.

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

Throughout the 350 year colonial period as a Dutch colony, the

Jakarta population grew slowly from 32,068 (1673) to 47,217

(1815), to 110,669 (1893). But according to the Indonesian Bureau

of Statistics the population reached 1,636,098 in 1930 and in the

subsequent 45 years it has more than tripled again. Today the total

stands at more than 5 million.

At the beginning of the Christian era, most Indonesians still lived

in communities which recognized no consistent political authority

above the village level. Their religion was animistic, the worship of

spirits and belief in a complicated multilevel world of the dead. No

written history is available in a systematic form.

In the beginning of the third or fourth century A.D. a strong

wave of Indian culture came to the Indonesian islands. Apparently

it was not the result of a definite migration of Indians from the

Indian continent to these southern islands. Rather, historians agree,

local Indonesian rulers adopted Hinduism (or in some cases

Buddhism) on their own initiative with the advice of wandering

Indian Brahmans. From them the islanders learned the concept of

divine kingship, a wide range of accompanying political techniques,

and the uses of royal rituals.

At the start of the 12th century, Islam came to Indonesia. It

entered the islands through the trading ports and got, footholds in

the harbors of Java and Sumatra. Gradually it penetrated inland and

was eventually accepted by the Hindu-Javanese ruling kings.

Historians speculate that Islamism was utilized as a militant

“religious force” capable of countering Christianity brought by the

Europeans who at about the same time began to discover the islands

of the Indonesian archipelago.

The Moslem sultans conquered Hindu kingdoms in Java, but were

unable to gain a foothold in Bali, which remained until today an

outpost of the pre-Moslem civilization. European influence was

brought to Indonesia when the Portuguese came, who later

established parts of their empire in the Far East. After the

Portuguese came the Spanish, the British, and the Dutch, who in

1619 founded an establishment in the Jakarta area, called Batavia,

through the well-known East India Company. Then the slow

process of colonialization started and finally the Dutch East Indies,

as the colony was known since, evolved.

The history of religion in Indonesia consists of successive layers

of Hinduism, Buddhism, Islam, and Christianity over animistic

beliefs that prevailed in the beginning. “Javanese religion” is

considered a syncretism of these influences. Religion in its various

forms is a fundamental integrating factor of the Indonesian

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SETYONEGORO: DRUG ABUSE IN INDONESIA

personality. The religious perspective is pervasive in almost every

aspect of life: birth, puberty, adolescence, engagement, marriage,

sickness, old age and death. Another basic integrating component in

sociopolitical life in Indonesia is the Pancasila (Five Principles)

which constitute the philosophy of the government in which belief

in one God, nationalism, internationalism (brotherhood with other

nations), representative government and social government are

incorporated. Through this approach it is attempted that sociopolitical and socioeconomic freedom should be interwoven with a

strong spiritual bond to build an authentic Indonesian community.

CONCEPT OF DRUG ABUSE AND RELATED TERMS

One of the basic difficulties confronting the medical and

psychiatric profession is the difficulty of translating the already

complicated term “drug abuse” in common language which is

acceptable and agreeable to the public. If other terms are presented,

the problem of translation is especially burdensome: addiction,

nonmedical use of drugs, drug dependence. The challenge is to be

informative to the interested public but at the same time not to be

sensational or seductive. Also the extent to which nonmedical

use of drugs is aimed at genuine self-medication is a problem which

is increasingly difficult to delineate or define.

We are now in agreement with nearly all professionals everywhere

that some sort of drug abuse does exist in every country. Once the

phenomenon of abuse, especially of opiate drugs, enters a society, it

is most likely to remain there for a considerable period of time.

Another observation is that when the country was faced with

grave external and internal threats the problem of drug abuse was

smaller or nonexistent. This was true during the Japanese occupation during World War II (1942-1945) and the following turbulent

period of guerilla warfare against former colonializers (1945-1950).

Thus certain segments of society feel that drug abuse perhaps

only emerges when people live in relative affluence, and when there

is a relative loss of purpose of life.

COPING WITH EMERGENCY AND CHRONICITY

The first adolescent drug abuser came to the attention of the

psychiatric profession in Jakarta in 1969. Since that early date an

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

increasing number of adolescent youth and young adults have come

to our reception centers for treatment.

After an initial “shock reaction,” the government responded by

providing modest treatment and rehabilitation facilities in the major

mental hospitals located in the urban centers. Government as well

as private mental hospitals were requested to participate in this

move. A small Drug Dependence Institute, Kebayoran, Jakarta,

was established in 1972. General hospitals were also requested to

admit drug abuse patients with acute intoxications for intensive

care treatments. The Directorate of Mental Health, Ministry of

Health, Jakarta, with its state mental hospital system, was assigned

to monitor the drug abuse problem and admit patients to its

facilities if they had problems of drug abuse. The Police Department in the Jakarta Metropolitan Area also established a facility

which functions as an adolescent detention home for adolescents

who are engaged in delinquent acts with or without concomitant

abuse of drugs. The Social Affairs Ministry also has a facility whose

main concern is the resocialization process of the drug abuser.

These centers cooperate and cross refer their patients or clients as

indicated.

Most drug abusers in Indonesia are multiple drug users. They

usually start with marihuana smoking, although sometimes morphine or heroin may be the first drug used. Generally marihuana

smokers become users of hard drugs if the smoking habit does not

prove satisfactory. Morphine is smoked or injected (intramuscularly

or intravenously). Packages of 4-6 mg (of dubious quality or purity)

used to cost about US $3.50; the price has now doubled because of

a scarcity arising from frequent police razzias or raids carried out in

the urban centers of Indonesia. They may be one reason that many

youngsters have now turned to alcohol, tranquilizers, barbiturates,

or, more often, to a combination of all these.

One retrospective study of the first 100 drug abusers admitted to

the Drug Dependence Institute, Kebayoran, Jakarta, Indonesia,

showed the following demographic characteristics: The average drug

dependent youth is between the ages of 16 and 26, and belongs to

one of the major racial groups of the country: Javanese, Sundanese,

Menangkabau (West Sumatra), Menado (North Sulawesi or Celebes),

Batak (North Sumatra), or Chinese. His/her religious affiliation also

reflects the major religions of Indonesia: Moslem, Christian, or

Buddhist. He or she is usually unmarried and is either still registered

as a high school student or is a dropout. He/she started his/her habit

6-24 months ago and prior to admission to the Institute was treated

by a private mental hospital in Jakarta. Relations to the parents are

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SETYONEGORO: DRUG ABUSE IN INDONESIA

generally considered good; most of these young people were

referred by their parents (3).

TREATMENT MODALITIES

Because of its short history, drug abuse treatment in Indonesia so

far has only involved the usual modalities. Treatment and rehabilitation centers are only available in large urban centers. Obviously

getting people off the drugs and keeping them off these compounds

are different matters.

“Cold turkey” (the so-called treatment without treatment) is

widely practiced. More popular, however, are detoxification

methods using medication to relieve withdrawal symptoms. This

method is especially popular with the helping professions of

medicine and psychiatry. Acupuncture, hypnosis, religious and

other meditative techniques, as well as other modalities are used,

but rather inconsistently. They universally aim at “strengthening

the inner forces” of the individual. Perhaps psychodynamically the

matter can be approached from an “ego strengthening” point of

view, and the psychological approaches are usually popular additional activities done in these treatment and rehabilitation centers.

Maintenance programs have not been used but discussions have

started to explore their feasibility. Therapeutic communities utilizing a religious framework have not been a major focus of interest.

Outpatient counseling is increasingly popular. What is felt as a need

are evaluative studies of these activities to determine if they

adequately meet existing needs.

CENTRAL CASE REGISTER

From the point of view of the Ministry of Health, a drug abuser

is basically an individual with a health and mental health problem.

Since 1971 the Directorate of Mental Health has had a Mental

Health Information System which utilizes a centralized recording

system processed by computer techniques. It uses a psychiatric

questionnaire (the GPPQ or General Purpose Psychiatric Questionnaire) as vehiculum to collect data on mental patients admitted to

all mental hospitals in Indonesia. The data contain administrative

information, demographic items, personal and family information,

and summary data about the patient’s previous illnesses. Thirty-four

psychiatric and mental health facilities reported their activities in

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

this way to the central agency, the Directorate of Mental Health in

Jakarta, in 1973. Of these, 13 hospitals reported having admitted

drug abusers. Unfortunately no detailed information is available

about the drug use, the amount used or routes of administration of

these drugs. For this purpose a special record has to be devised.

Numbers, figures, and other information in the section of this paper

en titled, “Statistics Based on the Central Register,” are based on

this information system (5).

There is also a need to link this information system with data

collected from other agencies active in the field of drug abuse, such

as the Social Welfare Ministry and the Police Department.

Certain administrative constraints have yet to be overcome, and

it is expected that through the restructuring of the Central

Coordinating Body for Drug Abuse in Indonesia a better coordination of agencies working in this field can be effected. It is expected

that eventually technical details such as a separate or unified

identification numbering system, problems of confidentiality, and

other matters can be approached more systematically.

AN “INDONESIAN” APPROACH

Since the problem of drug abuse is also determined by the local

socio-cultural situation, it is felt that the problem as it presented

itself in Indonesia should be approached in a more or less

specifically “Indonesian” way.

Involvement of Ministries

By Presidential Decree, in 1971, a number of Ministries of the

Indonesian Government were given the task of coordinating their

efforts in supply reduction, treatment and rehabilitation as well as

in the prevention of drug abuse. These Ministries are (1):

1. Ministry of Defense and Security

2. Ministry of Justice

3. Attorney General’s Office

4. The Ministry of Finance (c.q. Directorate General of

Customs and Excise)

5. Ministry of Health

6. Ministry of Information

7. Ministry of Foreign Affairs

8. Ministry of Social Affairs

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SETYONEGORO: DRUG ABUSE IN INDONESIA

9. Ministry of Education and Culture

10. Ministry of Home Affairs

11. Ministry of Religious Affairs

Another development was the adoption by the Parliament of a

new Narcotic Law in 1976 which replaced the outdated law of

1927 (6). Based on this law, preparatory committees have been

formed to formulate further implementations specifically for

treatment and rehabilitation, and organizational provisions (dealing

with matters on how coordination should be further improved).

More emphasis will now be given to medical, mental health or

psychiatric, social welfare, vocational, educational and other socalled “welfare” approaches (in contrast to “law enforcement”

approaches). In this way it is the hope of all parties involved that a

better balance can be achieved for demand and supply reduction

efforts as part of an overall strategy towards drug abuse.

Guidelines for Drug Abuse Rehabilitation

One of the results of rather intensive discussions is a program

outline for Guidelines for Drug Abuse Rehabilitation. This document will form the basic outline of drug abuse rehabilitation

processes and phases which must be carried out by a comprehensive

rehabilitation program. Every treatment and rehabilitation unit or

agency will be asked to identify more specifically its modality(ies),

so that a better-coordinated approach can be effected (see

appendix).

STATISTICS

This is one of the most difficult areas in drug abuse. Some of our

figures and numbers are estimates. Other statistics like those

collected at reception centers (mental hospitals and the Drug

Dependence Institute, Kebayoran, Jakarta) can be considered as

very reliable and “hard data” although more detailed information

may be desired (such as types of derivatives or types of drugs used,

quantity, frequency of use, duration of use, route of administration, circumstances of use, degree of severity of dependence, etc.).

Estimates

It is officially estimated that drug abuse in Indonesia shows the

following statistical trends (2):

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

1969 2 persons

1970 400 persons

1971 2,000-3,000 persons

1975 5,000-10,000 persons

In another survey it was shown that the majority of drug abusers

were adolescents in high school (junior and senior) or even students

in primary schools:

14.3% Students, Primary School (up to grade 7)

40.2% Students, Junior High School (up to grade 9-10)

38.75% Students, Senior High School (up to grade 12)

They use: ganja (marihuana), morphine and heroin, barbiturates

and their combinations. It is generally known that although they

are treated, a high relapse rate is likely, so that serious consideration

should be given to possible new avenues of treatment and

rehabilitation for these youngsters.

Statistics Based on the Central Register

(General Purpose Psychiatric Questionnaire as used by the

Directorate of Mental Health, Ministry of Health, Jakarta, Indonesia)

All Admissions in 1976*

The bulk of admissions were by the Drug Dependence Institute

in Jakarta (64 out of a total of 122). The other mental health

facilities which have admitted patients are all located within the

Jakarta Municipal Area (Sanatoria Dharmajaya, Dharmasakti, Ongkomulyo, and the Navy Hospital). This again emphasizes that drug

abuse in Indonesia is primarily a problem of large cities like Jakarta.

*Tables presenting full details of all drug dependence admissions to thirteen

institutions in Indonesia from 1972-1976 have not been printed here. For this

reason, some data from the tables, indicated by [ ], have been added to Dr.

Setyonegoro’s text by the editors. The institutions which contributed statistics

are: Bandung State Mental Hospital; St. Carolus Hospital, Jakarta; Sanatorium

Dharmasakti, Jakarta; Sanatorium Dharmawangsa, Jakarta; Jakarta State

Mental Hospital; Lawang State Mental Hospital; Semarang State Mental

Hospital; Department of Psychiatry, Indonesian Navy Hospital, Jakarta;

Sanatorium Dharmajaya, Jakarta; Drug Dependence Institute, Fatmawati

Hospital, Jakarta; Sanatorium Ongkomulyo, Jakarta; Palembang State Mental

Hospital; Banjarmasin State Mental Hospital.

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SETYONEGORO: DRUG ABUSE IN INDONESIA

There is a clear predominance of male patients (88.5 percent)

over female patients (10.7 percent).

The bulk of patients are within the age groups of 15-19 (36.1

percent), 20-24 (42.6 percent) and 25-29 (8.2 percent).

The source of referrals is predominatly the family (63.9 percent).

Doctors and psychiatrists are much less important referral sources,

referring respectively 9.8 percent and 13.1 percent.

The nominal religions reflect the demographic denominations in

the population at large, although there are proportionately fewer

Moslem patients (45.1 percent) compared to about 90 percent

Moslems in the general population. Catholics, other Christians and

Buddhists are relatively strongly represented in the patient population.

The family home is by far the primary developmental milieu

(90.2 percent).

The language spoken presents no problem; most patients speak

Indonesian, the dominant language (91.0 percent).

Again, “urbanity” is emphasized as place of upbringing in more

than 82.8 percent of the cases.

Most patients are single; a minority are married (21.3 percent);

others are separated, divorced or widowed.

Income level is very difficult to evaluate. Usually the salary

received from the government or employer is not the main means of

income. Figures in this area are therefore not very reliable.

The rapidity of onset of the present episode is generally not

known (45.1 percent). Some report that it happened within 24

hours; others indicate that the episode built up during weeks. The

same holds true for the duration of the present episode. We doubt

whether these data are very relevant to the matter of drug abuse,

which is one reason to adapt this questionnaire more adequately to

secure information on drug abuse.

The prognosis of the majority of cases is considered as guarded

(53.3 percent) or only fair (31.1 percent).

Finally, there is a wide variety of educational levels, with 7 to 12

years of schooling constituting the largest segment.

First Admissions in 1976

There were 80 first admissions in 1976 out of a total of 122

admissions. This may be an indication of the relative “virulency” of

the drug abuse problem, although in absolute terms the condition is

obviously a minor one (in comparison with neighboring countries

like Thailand). Other data seem to conform with the general trends

already indicated for “all admissions in 1976.”

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

All Admissions in 1972-1976

[These data are generally comparable to those for 1976 alone as

to sex and age distribution, marital status, nominal religion, and the

like.] There seems to be a relatively greater number of admissions

during 1973-1974 than is the case in the later years [198 in 1973

and 152 in 1974 compared with 130 in 1975 and 122 in 1976]. It is

also the impression in clinical practice that nowadays fewer cases

are seen of “clear cut” drug abuse compared to the situation in

1973-74. The exact reasons are not clearly known. Perhaps a supply

reduction was one of the causes, in view of the many police raids

that were conducted in 1976.

The age distribution remains basically the same [with 94-97

percent of admissions under age 30. In each year prior to 1976,

when 36.9 percent were 20 years old or younger, more than

half were in this youngest group]. In 1976 there was a further

“stretch” into the older age groups [with 8 admissions over 40

years old—4 over 60—where there had been no more than 1

before].

The family continues to be the main source of referral (50-65

percent); also, the medical doctor and psychiatrist are stable agents

of referral for drug abusers to mental health facilities for treatment

(3.0-9.8 percent for doctors; 7.5-22.3 percent for psychiatrists).

An interesting phenomenon is the fact that in 1976, in contrast

with earlier years, somewhat more people of lower educational level

appear to be abusing drugs. [There were 23 admissions with less than

6 years of education, while the highest number in any earlier year

was 11.]

Drug Dependence Institute, First Admissions 1972-1976

Generally data for first admissions over these years again

underscore the earlier conclusions. [Of 636 patients, 97 were

admitted twice, 42 were admitted 3 times, and 21 were admitted 4

times.] It is clear from these figures that a fairly high relapse rate

should be anticipated. Provisions to meet this challenge are being

contemplated but the impression is that mental health problems

and situational circumstances are very intimately associated with

the relapse rate and this may require more specific investigation.

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SETYONEGORO: DRUG ABUSE IN INDONESIA

CONCLUSION

In the course of our limited experiences in the field of drug abuse

we have come to know that these problems are not just “drug

problems.” We also have the feeling that the approaches based on

the “legal aspect” (that drug taking is a crime in itself), pharmacologic (that the study of the condition of acute and chronic

intoxication or “addiction” can reveal all causes) and medico- or

socio-psychiatric (that drug abuse is a priori a problem of mental

disorder), although useful, do not contain the full answer to the

drug abuse problem in Indonesia.

We now view more and more the “drug problem” as a problem of

people, or perhaps more specifically a problem of young people.

Based on this, a beginning has been made in involving as many

disciplines as possible in a more comprehensive approach to the

problem. In 1975 an International Seminar on the Non-Medical Use

of Drugs was held in Jakarta (4) and another Workshop on Drug

Abuse Prevention was held in Jakarta, 26 June-l July 1977, both in

cooperation with The Colombo Plan Bureau, Colombo, Sri Lanka.

In this way perhaps we may ask the question, as already asked by

the WHO Study on Youth and Drugs: “How can a community best

meet the adverse effects associated with a continuing or increasing

rate of drug taking among both the young and old?”

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APPENDIX

GENERAL GUIDELINES FOR DRUG ABUSE REHABILITATION
SETYONEGORO: DRUG ABUSE IN INDONESIA

APPENDIX

General Guidelines for Drug Abuse

Rehabilitation

I. Initial intake

(a) Basic Policy

Referrals of drug abuse “victims” (drug abusers) are received through

two channels:

(i) Chief, Provincial Health Service

(ii) Provincial Courts

and are based on articles 32 and 33 of the Law on Narcotics.

(b) Objectives

1. To establish a provisional diagnosis encompassing such data as:

personal medical history

patterns of drug use: experimental, casual or recreational,

situational, intensified, compulsive dependent.

level of dependence (on drugs)

medical complications

general physical condition

mental health condition

2. To decide on the most adequate referral

3. To decide on the (provisional) therapeutic strategy, emergency

therapy, etc.

(c) Course of Action

1. Special interview technique

2. Personal data and history of drug use

3. Clinical and physical diagnostic procedures:

(a) vital signs/symptoms

(b) skin

(c) eyes

(d) pupils

(e) nose

(f) chest

(g) abdomen

(h) central nervous system

(i) motoric functions

(j) pathologic reflexes

(k) brief psychiatric examination

4. Laboratory examinations/tests

5. Thin layer chromatography

6. If necessary also: EEG, EKG, and other examinations

(d) Personnel

1. Doctors and nurses with special training in drug abuse treatment

and rehabilitation

2. Laboratory technicians

3. Administrative personnel

(e) Other

Based on the provisional diagnosis, the drug abuser is now referred to

the next phase of the rehabilitation process, the Detoxification and

Treatment Facility for Medical Complications. Or he may be referred

to one of the following facilities:

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

(a) the General Hospital, Intensive Care Unit

(b) the Mental Hospital for treatment of an underlying

psychiatric condition

(c) an Ambulatory Treatment Facility which is authorized to

carry out this type of treatment

II. Detoxification and Treatment of Medical Complications

(a) Basic Policy

1. A drug abuser, especially a narcotic drug dependent, is a patient

suffering from a condition of chronic intoxication. For this

reason the first phase of treatment should be to withdraw the

intoxicating compound from his physical system.

2. A drug abuser rather frequently suffers from medical complications, and these should receive proper medical attention.

3. The withdrawal treatment is not without risk, especially if the

patient abuses a number of drugs combined, such as narcotic

drugs, alcohol, and barbiturates. Such conditions can be very

severe and even have fatal consequences.

4. If withdrawal is done at once (abrupt withdrawal), a frequent

mental condition can emerge, the so-called personality decompensation syndrome, in which the patient suffers from

intense confusion and even from massive painful sensations. A

medical clinical examination is therefore an absolute necessity

during withdrawal treatment.

(b) Objectives

1. To withdraw (to “free”) the abuser from a chronic intoxication

(opiates, barbiturates, alcohol etc.)

2. To give proper attention to possible medical complications

3. To avoid “personality decompensation”

(c) Course of Action

1. Continuous 24-hour observation of patient’s physical and mental

condition

2. Monitor all modalities used in the withdrawal treatment (abrupt

withdrawal, symptomatic treatment, substitution therapy, acupuncture, and other)

3. Treatment of emergency conditions

4. Avoid personality decompensation. Provide adequate treatment

for this condition if it occurs

5. Treatment for medical complications

(d) Personnel

1. Medical doctors and nurses with special training

2. Medical specialists for consultation

3. Laboratory technicians and paramedical personnel

(e) Other

1. Based on medical principles certain conditions must be fulfilled

in this area of medical care:

(i) the facility should be a special section of an existing

hospital or a special drug abuse hospital

(ii) medical instruments and medicines necessary for the

treatment of emergency conditions should be available

(iii) medical instruments and medicines necessary to treat

medical complications should be available

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SETYONEGORO: DRUG ABUSE IN INDONESIA

2. As soon as the general health condition of the patient has

sufficiently improved (physically and mentally) further processing of the intake procedure can be carried out. Data should

be compiled on areas of his mental and emotional background,

vocational skills, intelligence and education, legal status, etc. The

main objective of the processing of the intake procedure is to

establish a comprehensive diagnosis. If time does not allow a

complete workup, this can be further carried out during the next

phase of the rehabilitation process, the phase of stabilization.

III. Stabilization

(a) Basic Policy

1.

2.

The drug abuser (narcotic dependent) is an individual who because

of continuous use of the drug(s) has developed a physical and

psychic dependence on the drug(s)

Some direct unfavorable effects of this condition are:

(i) the general lowering of the condition of his health, physically

3.

4.

5.

6.

and mentally

(ii) failures in adjustment at a family level (in his home), socially

and professionally

(iii) economic and financial dependence

(iv) tendencies to commit unlawful acts or crimes

(v) if overdosage is the basic condition, even sudden death

Some of the known reasons to use drugs (narcotics) are:

(i) feelings of alienation

(ii) pain and feelings of discomfort

(iii) frustration and feelings of inadequacy

(iv) intense difficulties in work or academic performance

(v) anxiety and depression

(vi) feelings of being discriminated against

The drug abuser sometimes feels that he can perform or function

better when he is taking drugs, but this is usually a very subjective

statement

7.

8.

9 .

The stabilization phase aims at achieving a better general level of

physical and mental wellbeing

Social stabilization covers goals which are directed to the enhancement of social responsibility feelings for the drug abuser under

treatment and his family as well, so it can be considered a “social

group process”

Cultural and educational stabilization mechanisms aim at the

enhancement of the level of general knowledge, general skills, and

aesthetic feelings

The stabilization of skills aims at developing flexibility and

dexterity in carrying out household skills, adapting and adjusting to

changing environments, and willingness to work

Stabilization of religious feelings aims at enhancing religious

practices and religious harmony (understanding of other religions

than his own)

(b) Objectives

To achieve stabilization in the areas of health, intellectual performance,

emotion, education and culture, religious feelings, social adjustment,

and general skills in order that the adolescent drug abuser after his

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

rehabilitation can function better and more meaningfully without the

need to use drugs.

(c) Course of action

1. Religious stabilization

(a) to be more conscious about the place of man within the

framework of nature and universe

(b) to understand human weaknesses

(c) to understand the meaning of religion to man

(d) to stimulate feelings of optimism baaed on religion

(e) to engage in religious practices (pray, group reading of religious

books, etc.)

2. Stabilization of physical health

(a) diagnostic classification and evaluation of the individual’s

physical health condition

(b) symptomatic therapy

(c) physical therapy

(d) relaxation exercises

(e) physical exercises

3. Stabilization of mental health level

(a) diagnostic classification or evaluation of mental health status

(b) individual and group psychotherapy

(c) psychotropic medication

(d) medication to enhance cerebral metabolism or stimulative to

central nervous system

(e) family therapy

(f) alternative approaches

4. Social stabilization

(a) individual/social case work activities

(b) social group work activities

(c) family case work activities

(d) community guidance at the abuser’s residence or residential

area

(e) continuous information sessions for special groups of clients as

well as for people associated with such clients.

5. Stabilization in the areas of education and culture

To maintain and improve the level of general knowledge and skill

adapted to his level prior to entering the rehabilitation process.

Activities can be done in a number of ways:

(a) individual or group instruction

(b) evaluation studies of achieved results

(c) special instruction classes for those who are relatively slow

learners

(d) special instruction classes for those who wish to learn special

skills

(e) special classes to enhance aesthetic feelings in the fields of

poetry, writing, dancing, etc.

6. Stabilization of vocational skills

(a) to establish the individual’s capacity to acquire vocational skills

(b) aptitude testing

(c) to overcome barriers or constraints in placement of the

individual

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SETYONEGORO: DRUG ABUSE IN INDONESIA

(d) to enhance or improve the individual’s skills

(e) training of new skills

7. Other stabilization mechanisms as needed individually

(d) Personnel

1. Religious stabilization

(a) religious leaders who are interested in problems of adolescence

(b) religious leaders knowledgeable about the developmental problems of adolescent drug abusers and willing to associate with

them

2. Physical stabilization

(a) medical doctors and nurses with special training

(b) acupuncturists

(c) sports leaders/specialists in physical education

(d) other supportive specialists

(e) information and education specialists

3. Mental health stabilization

(a) medical doctors and nurses, adequately trained

(b) ex drug abusers who successfully terminated the rehabilitation

program with additional training in mental health

(c) other specialists with special knowledge in the area of “alternative approaches” or “meaningful alternatives”

4. Social stabilization

Social workers with special training in drug abuse rehabilitation

5. Stabilization in the areas of education and culture

(a) educators/teachers in special subjects

(b) other educational specialists

6. Stabilization of vocational skills

(a) special placement officers

(b) vocational guidance officers

(c) vocational training instructors

7. Other stabilization procedures

Specialist personnel as needed

(e) Other

This is a difficult phase with many complicating factors, and no

“standard” approach seems to be possible. Emphasis is laid on efforts

of integration and cooperation of all professionals and professional

institutions active in this field.

IV. Preparation for reentry info society

(a) Basic Policy

1. Those drug abusers who successfully terminated the previous phases

(detoxification, therapy of medical complications, and stabilization) can directly perform this “reentry into society” successfully if

their parents and their community can accept them back in a

positive way

2. A fairly large segment of drug abusers (although they have finished

the previous phases successfully) appear to have difficulties in this

phase of “reentry into society,” Most difficulties are associated

with their own personality, habits, family members, and the

community where they live

These adolescents need a special preparatory program before their

“reentry into society” can be performed reasonably successfully:

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

(a) through a trial phase

(b) through a special guidance program

3. If reentry is to be performed through a trial phase, a number of

special activities are to be performed during the stabilization phase.

These activities have limited goals and are specifically directed.

4. If reentry is to be performed through a special guidance program,

certain vocational skills will be studied. A number of problems will

be approached: economic or financial difficulties, problems in the

areas of social adjustment, cultural adaptation, and other.

(b) Objectives

To enhance feelings of social responsibility towards society at large, his

own community, and his family.

(c) Course of Action

1. Preparation for direct reentry into society involves a number of

special arrangements:

(i) to prepare this reentry in cooperation with his family, his direct

community as well as with the adolescent himself with regard

to challenges which will be faced in reality

(ii) to plan further consultations with the appropriate agency or

counselor with regard to problems which may arise not only in

the area of concrete difficulties but also in the “spiritual sense”

(e.g., social responsibilities towards his country’s philosophy,

Pancasila, etc.)

2. Preparation for reentry through special programs

(i) Day centers

(ii) Night hospitals

(iii) Trial discharges

which contain activities of a more limited nature compared to those

during the stabilization phase

3. Preparation for reentry through a special guidance program which

contains the following, among others:

(i) problem solving of economic and financial difficulties

(ii) difficulties of reacceptance by family or community

(iii) overcome difficulties of personal nature: disgrace, lack of self

confidence, etc.

(iv) difficulties at school, job placement, and other socio-cultural

difficulties

(d) Personnel

1. Reentry into society in a direct way will follow the general pattern

as described for the Stabilization Phase

2. Preparation through special programs in day centers, night hospitals

and trial discharges will need the same personnel as the stabilization

phase

3. Preparation through special guidance programs will need personnel

who have been trained as social workers with special abilities for

guidance of adolescents

(e) Other, As Needed

V. Resocialization (in Society)

(a) Basic Policy

The ex drug abuser should be able to conduct a meaningful life (with

due regard to the limitations set by the realistic situation), utilizing the

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SETYONEGORO: DRUG ABUSE IN INDONESIA

existing “societal infrastructures” and stable institutions such as school,

“pesantre” (religious boarding schools), jobs offered by employers, and

other agencies.

(b) Objectives

It is a reasonable expectation that those who have completed the

previous phases successfully will be able to establish themselves in

society in a more stable way, without the necessity of using drugs. If,

however, a relapse should occur, they would be able to benefit from

their past experiences so that they would be in better control of their

behavior.

(c) Course of activities

Long term followup guidance by

1. family members (especially parents)

2. teachers

3. social workers

4. special placement officers

5. medical doctors and psychiatrists

6. nurses

7. other concerned individuals

(d) Other

Followup guidance should be done continuously over a period of “one

thousand days” (about 3 years).

REFERENCES

1. BAKOLAK Inpres 6/1971. Coordinating Body for the Implementation of

Presidential Instructions, or in Indonesian: Badan Koordinasi Pelaksanaan

Instruksi Presiden (“Bakolak”).

2. BAKOLAK Inpres 6/1971. Report quoted by the Minister of National

Welfare, in a speech, Jakarta, November 1, 1975. Publication, Ministry of

National Welfare.

3. Kusumanto Setyonegoro, and Saifun Mansur, M. “Epidemiological data of

the first 100 patients admitted to the Drug Dependence Institute,

Kebayoran, Jakarta.” Presented, Kuala Lumpur, Malaysia, Meeting Malaysian Singapore College of Medicine, 1976. Jakarta: Ministry of Health,

Directorate of Mental Health, publication 1976.

4. Kusumanto Setyonegoro, ed., et al. Drug Abuse in Indonesia. Yayasan

Dharma Graha, 1977.198 pp.

5. Taintor, Z.; Salan, R.; and Sadono, B. Some developments on the

computerized recording system of mental patients in Indonesia. Proc 2nd

Ann Meeting, Indon Soc Neurol, Psychiatr, and Neurosurg. Surabaya,

Indonesia, 1972

Annual Reports, Directorate of Mental Health (Buku Laporan Statistik

Kesehatan Jiwa), 1971, 1972, 1973, 1974, 1975, 1976. Department

Kesehatan, R. I. (Ministry of Health), Jakarta.

6. Verdoouende Middelen Ordonnantie van 1927. (Regulated in the State

Gazette, 1927, no. 278, juncto no. 536, with its amendments and additions

which were promulgated in the State Gazette, 1949.)

109

II.

Biological Aspects of

Drug Dependence

Jack H. Mendelson

Chairman
CHAPTER 10

Bio-Socio Approach in Drug Abuse

Treatment and Prevention

James M.N. Ch’ien, M.S.W., M.P.H.

THE GENERIC CONCEPT OF BIO-SOCIO APPROACH

In dealing with drug abuse, especially the problem of hard-core

narcotic addiction, the different professions concerned have tended

to adopt in the past a singular or simplistic approach, be it legalistic,

medical, pharmacological, or sociological, none of which has

achieved much success individually. Considerable time and energy

have been wasted on the debate whether opiate dependents should

be dealt with by law-enforcing or social-medical agencies (20),

whether they should be treated by professionally trained rehabilitation personnel or nonprofessional exaddicts (12), and whether

supply suppression or demand reduction is more important (25).

After fifteen years of practice in the field and after studying the

programmes of many countries which have a serious drug abuse

problem, the writer wishes to propose a generic bio-socio approach

which calls for the integration of all pertinent biomedical sciences

and social sciences and the cooperation of all relevant professionals,

paraprofessionals, and nonprofessionals in the treatment and

prevention of drug abuse.

THE MYTH OF “OVERDOSE” AND MORTALITY

OF MAINLINING

In order to illustrate the danger of a singular approach and the

need to integrate the expertise of different disciplines concerned,

the writer would like to cite the common misunderstanding even by

professional people working with opiate dependents, of the term

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CH’IEN: BIO-SOCIO APPROACH

“overdose,” which is thought to be inevitably and closely associated

with the mainlining or intravenous injection of heroin, Actually,

deaths from such heroin abuse could be the result of acute reaction

toward the unknown quantity and quality of diluents of street

heroin (e.g., quinine, caffeine, sugar, etc.) or toward the bacteria,

allergens, and other foreign matter introduced through the unsterilized needles, and not necessarily the result of an excessive dosage

of heroin, far beyond the tolerance of the individual users.

A New York Medical Examiner reported not long ago that acute

fatal reaction of true pharmacological overdose of heroin occurs

approximately once in every 100,000 injections, yet “narcotic

abuse” was listed as the leading cause of death among the age group

of 15-35 of the city population in the late sixties (2). Obviously

infectious complications, including hepatitis, tetanus, bacterial and

mycotic endocarditis, etc., plus malnutrition, vitamin deficiency

and plain dehydration contribute much more to the high mortalities

among mainliners than direct overdose. The same report

registered more than 150 deaths in 1970 as a result of homicide,

suicide, and accidents among New York addicts — a fact apparently

reflecting their high-risk life styles (5).

It is ironic that coroners in many places tend to label all deaths

among heroin addicts as “overdose” when the exact cause cannot

be determined and that the pusher who was known among street

addicts as the supplier of a fatal bag is not shunned but rewarded

with better business after such an incident. It is obvious that efforts

by social workers or drug counsellors to warn their clients against

the danger of “overdose” are often futile and occasionally

counterproductive. More recent research indicates that sudden

deaths through pulmonary and cerebral edema following heroin

injection are more likely to be due to the combined effect of heroin

and quinine or heroin and alcohol/barbiturates (4).

In Hong Kong, until very recently, heroin injection was a minor

route of consumption by addicts, the majority of whom preferred

to smoke their heroin with cigarettes (“firing the ack-ack gun”) or

to inhale the fume from the heated mixture of heroin and barbiturates

(“chasing the dragon”). On account of rising prices in the black

market in the past three or four years, the writer has noticed an

increasing proportion of mainliners among the Society for Aid and

Rehabilitation of Drug Addicts (SARDA) intake of voluntary male

patients (rising from 25 percent in 1974 to 37.4 percent in the first

six months of 1977), and simultaneously a certain number of

reports of “overdose” deaths among its prospective clientele have

recently emerged. Preventive education in Southeast Asian cities,

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

emphasizing the danger of death through heroin injection does not

seem to stem the tide of “ack-ack gunners” and “dragon chasers”

converting to mainlining under economic pressure. The writer

suspects that many addicts in Hong Kong as well as neighboring cities

are now injecting the brown coloured No. 3 heroin, which is a mixture

prepared for smoking and which is proven to be much more lethal

than the purely white No. 4 heroin prepared for exports (1). Only

intensive interdisciplinary research could pinpoint the true causes of

heroin-related deaths and thus guide our preventive efforts. Such a

research project would require trained exaddicts to act as interviewers to elicit true information from active addicts as to the amount

and method of consumption of heroin, type and quantity of other

drugs including alcohol used and the life styles they lead. This is

indeed an example of the advantage of the Rio-Socio approach in

research over pure clinical or pharmacological studies.

BIO-SOCIO APPROACH IN HUMAN DEVELOPMENT

AND ADDICTIVE LIFE STYLES

The National Institute on Drug Abuse compiled in 1975 a life

style study of drug addicts in America which the writer finds to be

quite universally applicable in other countries as well (16). They are

summarized below:

1. Paranoid life could be rooted in the mistrust developed at neonatal

and early childhood (e.g., rejection by mother). The person who has

paranoid tendency is overly conscious of the impact of what he feels

to be hostile reality. S/he needs drugs to still the anxiety and rage

when considering his/her misfortune. S/he is suspicious, and therefore

lonely. Through the use of drugs, the hostile environment becomes

bearable.

2. The pseudo life feels like real life, but is counterfeit. It is lived out

most dramatically by the “con-man.” Rewards are received by

exploitation of others, and his/her sense of shame is gradually dulled

by the use of drugs. At length, the person can experience gratification

only from the mistakes he has caused others to make. Because s/he

continually lives on thin ice, s/he must continually be anxious. The

taking of drugs gives him/her a sense of reality in a fake life.

3. There are three variants of the passive life: indifferent, dependent,

and aggressive. The passive-indifferent person shows little initiative in

anything and is full of weariness or apathy. A sense of defeat precedes

every movement, even though one may not even have fought and lost.

They tend to age prematurely and seem to leap from a childhood

mentality to senility, bypassing an active adulthood.

4. The passive dependent person, faced with the complexity and

cruelty of reality, tries to find a strong figure to lean on in order to

make life easier. S/he lacks industry and feels inferior. S/he may

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CH’IEN: BIO-SOCIO APPROACH

appear polite and cooperative, projecting an image of the “model

patient” under treatment, but is seldom able to lead an independent

or productive life. Chemical or emotional crutches are needed to

sustain life,

5. The passive aggressive person despairs about his/her lack of

identity. Confused with roles, s/he suffers from impotence and

passivity, which turns his/her mood into irritation, with anger at those

around him. S/he will sometimes attack physically, if not narcoticized

or tranquilized.

6. The obsessional life is oriented around rituals and codes (e.g.,

secret society practices) and the practitioner is compulsively obedient

to both. Therefore s/he is unable to develop an intimate relationship

with nonpractitioners and isolated from the “square world.” The

obsessed individual seeks in drugs the way of extinguishing the need

for tender emotions.

7. The depressed person finds the present empty and boring and is

pessimistic about the future. Nothing generates any interest and

his/her life is full of stagnation. Drugs provide an exciting break in this

otherwise grey, colorless life.

8. The retreatist is filled with anxiety about the world; he/she

particularly fears that his/her ego is falling apart. S/he uses drugs to

provide a sense of illusory integration and to suppress despair.

To the above eight life styles, the writer wishes to add a ninth

one which is based on his observation of elderly opium smokers in

Chinatowns on the East and West Coasts of the United States, as

well as Chinese communities in Southeast Asia, as follows:

9. The waiting to die group. Having wasted one’s adult life on opiate

drugs yet managed to survive till a relatively old age, the elderly

person is afraid both to look back and to look ahead. Whatever family

wealth or prestige he once enjoyed has been squandered. Lonely and

fearing of death, he feels too far gone to try to salvage something out

of life. An opiate provides a little comfort while he is waiting to die.

According to Erikson, there are certain psychological and

emotional conflicts which have to be resolved at each stage of

human development (15) which the writer believes could be the

crucial determinants of one’s life style. Conversely, in order to

change a person’s life style, the unresolved conflicts and the

consequent retardation of his/her personality development must be

treated and bridged to enable him/her to catch up with his/her

bio-socio growth. Erikson’s “Eight Ages of Men,” based on

psychoanalytic theory, contributes much to our understanding of

personality formation (15), yet he failed to clarify or elaborate the

influence of education and socio-cultural conditioning. Piaget’s

child psychology (13) and his theory of “Moral Judgement Development” (17) could be used to fill the gap and complement Erikson’s

Epigenetic-gram to form both a biosexual and a sociocultural axis.

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

The Confucian School of Chinese philosophy teaches that education of our younger generation actually begins from the embryo

stage and forms a continuous process from cradle to grave. Prenatal

education depends on the mother’s inner peace and tranquility as

well as the environment she lives in and provides for her unborn

child, which in modern language could be called “maternal

characteristics” (26). After the child is born, both parents should be

responsible to serve as role models and to create a home

environment conducive to learning. Confucius said, “A man

should refine his learning skills at the age of 15, stand firmly on his

feet by 30, keep an open mind at 40, be aware of his life mission at

50, confident of truth at 60, and fulfill his destiny by 70” (10). He

also taught his disciples that if a man is confident of his destiny and

learned of TAO (the way and the truth) why should he be afraid to

die! Therefore, the writer has constructed a composite model

combining the thoughts of Erikson, Piaget and Confucius to form

a guideline for counselling and guidance of opiate abusers in Hong

Kong, many of whom seem to be middle-aged adolescents who have

not yet resolved their identity crisis. (See figure 1).

Naturally, a detoxified or a rehabilitated drug user also has

diversified biological and material needs which have to be met

under aftercare. With Bio-Socio approach, social work is not merely

a problem-solving process, but also a goal oriented developmental

process. Therefore the client system of SARDA is constantly

motivated and stimulated to develop self-help and mutual aid

activities which will be explained in the next section.

BIO-SOCIO ENVIRONMENT AND COMMUNITY SUPPORT

Urban ghettoes and physically depressed areas are often described as breeding grounds for crime, delinquency, and addiction.

Scientific studies however indicate that the causal factors of such

dysfunctioning or deviant behavior are mostly psychological and

social in nature (6, 7). Therefore environmental manipulation as

part of our rehabilitation service must aim to meet both the

physical needs for decent housing and the psychosocial needs of our

clients, who often require community support to cope with stress

and anxiety (9). In order to promote adjustment to his/her

environment of working and home life and to change his/her

undesirable life style to a more constructive one, a treated opiate

dependent requires as support information or action leading

him/her to believe that:

1. S/he is cared for and loved

2. S/he is esteemed and valued

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FIGURE 1

The Composite Model of Human Growth and Bio-Socio Conflicts as Determinants of Life Styles

(Based on the Constructs of Erikson, Piaget, and Confucius)

Possible life styles rooted in unresolved conflicts or retarded personality development:
INTERNATIONAL CHALLENGE OF DRUG ABUSE

3. S/he belongs to a network of communication and mutual

obligation.

Simple as it may appear, the writer’s experience in working with

drug dependents in Hong Kong and alcoholics in Denver, Colorado,

convinced him that such support cannot be organized by professional service alone. The client systems in total (individuals, families,

peer groups, and the functional community) must be involved for

self-help and mutual support. Therefore, using Alcoholics Anonymous as a reference model, the writer encouraged and motivated a

small group of fully rehabilitated exaddicts who had successfully

completed the three year followup service to form an Alumni

Association in 1968 to provide continued support to each other as

well as to new dischargees of SARDA’s treatment centers (23). The

name was chosen by its founding members to symbolize their bond

with the rehabilitation agency whose programme was considered an

educational experience to them and which coincidentally has the

same initials as Alcoholics Anonymous. The A.A. of Hong Kong

was registered as an independent nonprofit society and began to

recruit additional members as more men and women continued to

graduate from SARDA’s programmes. In the beginning, the

Association depended very much on the writer or his representative

for direction, and in the absence of such an “advisor,” their board

meetings would sometimes bog down in confusion over parliamentary procedures or rivalry for power and prestige. Gradually,

the indigenous leadership was stabilized and a workable structure

emerged. All members are required to pass a one-year probationary

period of drug and crime free life in the community before

qualifying for full voting status. Membership of those who relapsed

to drug abuse is suspended until drug free status is again proven by

urine tests. As membership expanded, the Association branched

into six district chapters which are located in different neighborhoods of Hong Kong and Kowloon. Annual elections are held both

at the chapter level and the central Board of Directors’ level; to

avoid excessive power concentration, their constitution stipulates

that no chapter chairman shall serve more than two years and no

board chairman shall serve more than three consecutive years. As

self-assumed roles, they took on the casefinding job of encouraging

active drug users to seek treatment and relapsed members to apply

for readmission into SARDA’s programme. The Association also

organized “vocational cooperatives” which included a “sanitation

and cleansing team” to serve the residents of housing projects, a

“tailor shop” to make, mend, and alter dresses for A.A. members/

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CH’IEN: BIO-SOCIO APPROACH

families as well as SARDA staff, and a “carpenter shop” to make

furniture and interior decorations. All of these activities provide

short or mid-term employment for former patients until better jobs

can be found in the open market (1). In the past three years, the

Association has built parks for senior citizens, beautified neighborhoods with plants and flowers, and established hostels or halfway

houses in different districts to offer transitory accommodation to

new “graduates” who do not have a suitable home to return to. So

far they have managed to open three hostels and kept all of them

clean and drug free. There are now approximdtely one thousand

members who each pay a membership fee of $10 per annum and

enjoy all the recreational and educational facilities provided in their

respective districts. The need of affiliation and mutual emotional

support is thus met, and by binding together, the members are

finding the pressure of social prejudice or injustice no longer so

difficult to bear and the temptation of drugs and crime no longer so

overwhelming to resist. Since 1970, the A.A. has, by invitation,

participated in each year’s anti-narcotic campaigns organized by the

Government-sponsored Action Committee Against Narcotics, and

on their own initiative, has sent out entertainment teams to various

neighborhoods, institutions, and schools to present variety shows

and musical programmes with a theme focused on preventive

education. This coming summer, the A.A. will celebrate its tenth

anniversary, and it is gratifying to see that the Association has

managed to change not only the values of its own members from

selfishness to altruism but also of the community from that of

reciprocal rejection and suspicion to that of mutual acceptance and

cooperation (8).

PURPOSIVE BEHAVIOR & RECIPROCAL ALTRUISM

Biologically speaking, all animal behaviors are purposive, although goal intended action does not always achieve its purpose

(28). When street addicts flock to a pusher whose previous supplies

are known to have caused “overdose” death, they are taking a

calculated risk based on the purpose of achieving the high benefits

of a “kick” at a reasonable cost. Many are, of course, disappointed

by the fact that a particular pusher’s supplies of heroin are not

purer or more potent, but they continue their search for the potent

stuff like ants scouting for food and bees hunting for nectar. Some

American users even cross the oceans to look for the pure No. 4

heroin in the East. Without understanding this “vocational drive”

and the values of heroin addicts, therapists and social workers often

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

waste their time as well as their clients’ time by lecturing them

about foolish actions or taking unnecessary risks. On the other

hand, when a client says that he is unable to change his behavior or

life style it is very often a refusal to change. Self-help and

self-programming groups can be effective to induce change if the

therapist helps to clarify group values and establish the group norms

in the beginning. Sid Simon, the founder of Identity Therapy,

advocates that each group member be asked to publicly affirm his

values and to act upon them (22). William Glasser underscores the

necessity for consistency and repeatedness in behavior until it is

indeed owned by the patient (23). If there is little progress or

change, either the involvement is insufficient or one has bitten off

more than one can chew in designing the working plan. The

Bio-Socio approach is congruent with the “Teleological Explanation” of life (3). Where there is life, there is always the possibility

of change and of catching up. The patient never fails; only the plan

fails, but the plan can be revised, and the involvement of both the

patient and therapist can be intensified. So, there is no giving up;

only more work to do.

The Bio-Socio approach is therefore also a philosophy to sustain

both the patients and the therapist. No chemical substitutes of

opiates alone, no antagonists and no neuro-endocrinal stimulation

(including acupuncture) can in themselves change behavior (21,24,

27). Only the motivated and determined individual can change

his/her behavior, but a wholesome reference group with which

he/she is identified can certainly help to motivate and strengthen

the determination of the individual to change. The writer’s belief in

such potentials is further strengthened by his recent experience

with a group of ex-heroin users maintained on naltrexone in New

Bedford, Mass. With the encouragement of the chairman of this

symposium who is directing research on antagonist therapy at the

McLean Hospital, Belmont, Massachusetts, the writer was able to

motivate those former patients who came from and returned to

New Bedford to form a mutual aid association there. In a short span

of six months the writer was gratified to see improved communication and interpersonal transactions along with better human

relationships among the group members. An experienced drug

counsellor is continuing to work with this group, whose goal has

now extended from wholesome recreation and fellowship to

reciprocal support.

Sociobiology is traditionally defined as the study and application

of biological sciences for the development of natural resources in

the service of the human race, to the improvement of environment

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CH’IEN: BIO-SOCIO APPROACH

quality, and to the clarification of fundamental truth underlying

human behavior (19). However, modern sociobiologists tend to

focus their attention on the genetic basis and bio-programming of

behavior. Altruism thus becomes genetic self-interest: maternal love

being genetic investment; friendship and sacrifice being rooted in

reciprocal obligation to propagate the same or similar set of genes

(18). However Bio-Socio approach is broader and more generic than

modern sociobiology and does not deny that there is an ultimate

purpose in creation nor downgrade the values of education and

socialization in human societies. Whatever the explanation, the

writer has seen altruism at play in groups of exaddicts. The A.A.

members in Hong Kong donate instead of selling blood to the Red

Cross, and they voluntarily offer time, money, and energy in

community development projects. Although they gain community

acceptance and social recognition in return, the writer does not

believe that they act with any ulterior motive in giving blood as well

as themselves to the service of the community.

In this respect, the writer would like to quote Dr. Robert

DuPont, who said at the recent National Conference on Drug

Abuse, in San Francisco (14):

NIDA’s highest priority during the next year will be on the

development of self-help programs for drug abusers which are

independent of both government funding and treatment professionals and paraprofessionals. The goal is not to eliminate the

Institute, but to complement our treatment programs the way

Alcoholics Anonymous complements alcoholism treatment programs. We need Weight Watchers, SmokEnders, and AA for drug

users.

The writer submits that every community which has a drug

problem should accept this challenge and support voluntary

programs to promote self-help and voluntary service of former

users, whose life styles can thus be changed through reciprocal

altruism demonstrated by the community as well as the AA

members.

EVALUATION OF MICRO AND MACRO INTERVENTION

For micro-intervention, we have already seen that an individual

should not be compartmentalized in treatment. A drug dependent’s

physical, psychological, and social problems must be dealt with in

total; otherwise the effort of medical treatment, no matter how

intensive, may very well be wasted. The many facets of an addictive

life style are interlocked but equally important; the use of drugs is

but one surface which attracts professional attention. Delong

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

cautioned against the dichotomy of assessment in the following

words (11):

After treatment, an addict might hold a job, support a family,

refrain from criminal activity, and still go on occasional benders of

drug use. Or, he might continue to commit crimes but fewer than

before. His physical health might be improved even if nothing else

was changed. It is also possible for a programme to have a reverse

effect. It might, for example, eliminate opiate addiction at the

price of alcoholism — a dubious gain . . In short there is a range

of possible benefits and adverse effects that can be produced . . . .

An objective examination of treatment programmes should ideally

use varying measures rather than only two categories — “success”

(total abstinence only) or “failure” (anything else).

In line with this thinking, the following major criteria of program

evaluation were formulated recently by the UN Fund for Drug

Abuse Control at a Geneva workshop participated in by the writer

(25):

reduction in drug abuse, such as drug-free periods following

each withdrawal treatment, the decrease of the amount of drug

taken or the change in the form of consumption, e.g., from

injection to smoking.

the improvement or lack of improvement in family relationships

and in reference peer-groups.

increasing or decreasing capacity to engage in occupational or

vocational activities.

involvement or lack of involvement with criminal or anti-social

sub-cultures.

As to macro-intervention, national and international policy

makers will do well to view the community or country as an organic

whole and not compartmentalize the drug problem as a single

segment’s dysfunction or a single government department’s responsibility. The same workshop submitted a set of recommendations to

the United Nations in 1976 which are summarized below for

convenient reference (25):

a. Drug abuse should be dealt with in the social context as a whole

and the control of drugs should be considered only as one element of

action, albeit a necessary one. It was considered important not to

limit society’s vigilance to those drugs placed under international

control, but to extend it to all drugs whether “controlled,” sold over

the counter, or otherwise available. International controls were

indispensable in the fields of regulating production, manufacture and

distribution of drugs, and international treaties established minimum

requirements which should be flexibly adapted to national situations.

b. Up to the present, principal attention has been given to the

reduction of supply and the suppression of illicit traffic. To restore

the balance, more effort should be directed to programmes for the

reduction of demand, to assist both the individual country which

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CH’IEN: BIO-SOCIO APPROACH

initiates the programme and other countries as well, by curtailing the

market for production and distribution. The international community

should support country studies, selecting both developed and developing countries, and provide assistance on an inter-agency basis with a

view toward producing model information systems and demonstrating

the integration of all pertinent data.

c. In order to be able to estimate future incidence of drug abuse,

more research has to be done to identify the nature and scope of the

problem. Simple standardized methods should be developed, capable

of application in both developed and developing countries for

monitoring drug abuse, at least its patterns and trends. It is possible to

do this within a reasonable time frame. Methodology for data

collection and analysis should provide means to measure not only the

extent of drug abuse but also the impact of intervention programmes.

Early action to identify new patterns of drug abuse is important,

especially in developing countries, to assist in designing effective and

integrated programmes.

d. In the national context there should be concentration on the social

environment, not just the individual, on the reactions and resources of

the whole society, not on any particular service. All community and

government services, public and private, should collaborate. Law

enforcement by itself is not enough. Parallel efforts for example in

education, treatment and rehabilitation are also necessary. Police

action is necessary however to apply pressure upon drug supplies and

traffic to reduce the levels to those which society would find tolerable

and directly upon drug dependents to seek treatment.

e. The rehabilitation of drug users should take place within the

community, not by long-term isolation or institutionalization of

individuals. Drug users should not be considered mere objects of

experiments but should be participants in a group process for their

own rehabilitation. Treatment should be directed not only at drug use

but also at changing life styles. Success should be measured by

realistic criteria of quantitative and qualitative improvement and

reintegration into family, gainful employment and a wholesome social

environment.

The above-recommended principles truly reflect the generic

concept of the Bio-Socio approach in dealing with drug abuse. The

planet Earth can be viewed as a spaceship for the human race to

travel in time; and in order to protect our external and internal

environments from drug pollution, reciprocal altruism must be

promoted regionally, nationally, and internationally.

REFERENCES

1. Action Committee Against Narcotics, Hong Kong Narcotics Report

1975-76. Hong Kong: Government Printer, 1976.

2. Baden, M. Narcotic abuse: A medical examiner’s view. New York State

Journal of Medicine, 72(7):834-840, April, 1972.

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

3. Beckner, M. The Biological Way of Thought. New York: Columbia

University Press, 1959.

4. Brecher, M. “Heroin Overdose” — mystery and other occupational hazards

of addiction. Consumer Reports, Licit and Illicit Drugs. Boston: Little

Brown and Company, 1972. pp. 101-114.

5. Catton, K., and Shain, M. Heroin users in the community: A review of the

drug use and life styles of addicts and users not in treatment: Addictive

Diseases: An International Journal, 3(l), 1977.

6. Chein, I. Gerard, D.; Lee, R.; and Rosenfeld, E. The Road to H. New York:

Basic Books, 1964. pp. 459-467.

7. Ch’ien, J. M.N. Behavioral approach in the rehabilitation of drug abusers.

Asian Journal of Medicine, Vol. 8, March 1972.

8. Voluntary treatment of drug abuse in Hong Kong. Addictive

Diseases: An International Journal, Vol. 3, No. 1, 1977.

9. Cobb, S. Social support as a moderator of life stress. Psychosomatic

Medicine, Vol. 38, No. 5 (September-October) 1976.

10. Confucius’ Dialect. Second Chapter on Public Administration, Section 4.

Hong Kong: The World Press, 1936. (Many Chinese editions have been

published since 206 B.C. and several versions of English translation

available since 1900.)

11. Delong, J. V., ed. Dealing with Drug Abuse. A Report to the Ford

Foundation. New York: Praeger Publishers, 1972, 396 pp. p. 179.

12. Delvin, J.J. The treatment of drug addicts by professionals and nonprofessionals. Toxicomanies, 8(4):341-342, 1975.

13. Elkind, D. Giant in the nursery — Jean Piaget. In: Connelly, R., ed.

Readings in Human Development. Guiffort, Ct: Dushkin Publishing Group,

1976. pp. 9-11.

14. DuPont, Robert L. Speech at the National Drug Abuse Conference, San

Francisco, May, 1977. National Drug Reporter, 7-6, June-July, 1977.

15. Erikson, E. Childhood and Society. New York: N.W. Norton and

Company, 1963. pp. 269-273.

16. Ferguson, P.; Lennox, T.; and Lettieri, D.J., eds. Drugs and Addict

Lifestyles. Research Issues 7. National Institute on Drug Abuse. DHEW

Pub. No. (ADM) 77-189. Washington, D.C.: Superintendent of Documents,

U.S. Government Printing Office, 1977.

17. Likona, T. Research on Piaget’s Theory of Moral Development. In: Moral

Development and Behavior, Theory, Research and Social Issues. New York:

Basic Books, 1976. pp. 219-240.

18. Jaroff, Leon, ed. Why You Do What You Do? Sociobiology: A new theory

of behavior, Time Magazine, August 1, 1977.

19. Neville-Rolfe, Sybil, and McLachlan, A.E.W. Social Biology and Welfare.

London: George Allen and Unwin Limited, p. 49.

20. Parsons, Richard D., et. al. White Paper on Drug Abuse: a report to the

President from the Domestic Council Drug Abuse Task Force. Washington

D.C.: Superintendent of Documents, U.S. Government Printing Office,

1975.

21. Parwatikar, S.; Crawford, J.; Nelkupa, J.; and DeGracia, C. Factors

Influencing Success in an Antagonist Treatment Program. In: Julius, D.,

and Renault, P., eds. Narcotic Antagonists: Naltrexone Progress Report.

NIDA Research Monograph 9. National Institute on Drug Abuse. DHEW

Pub. No. (ADM) 76-387. Washington, D.C.: Superintendent of Documents,

U.S. Government Printing Office, 1976.

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CH’IEN: BIO-SOCIO APPROACH

22. Silverstein, L.M., and Brett, J.E. Shaping the sounds of silence. Addictions,

23(3):1-21, 1976.

23. Society for the Aid and Rehabilitation of Drug Addicts and Its Alumni

Association. Annual Reports since 1967. Hong Kong: The Society,

1967—.

24. Tam, Y.K. The relaxation therapies — A review. Hong Kong Journal of

Mental Health, 6(1), June 1977.

25. UN Fund for Drug Abuse Control. Report on the Workshop on Future

Trends in Drug Use and Abuse. Geneva: Palais de Nations, Document No.

GE 76-1007, 1975.

26. Valadian, I. The characteristics of childhood illness and immunity. In:

Stuart and Prugh, eds. The Healthy Child, his physical, psychological and

social development. Cambridge, Massachusetts: Harvard University Press,

1960. pp. 30-32.

27. Wen, H.L. “Fast Detoxification of Drug Abuse by Acupuncture and

Electrical Stimulation (A.E.S.) in Combination with Naloxone.” Unpublished report for Society for the Aid and Rehabilitation of Drug Addicts,

Hong kong.

28. White, Robert W. Lives in Progress: A Study of the Natural Growth of

Personality. New York: The Dryden Press, 1955.

29. Wilson, Edward. Sociobiology: The New Synthesis. Cambridge: Harvard

University Press, 1975.

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CHAPTER 11

Behavioral Pharmacology of

Narcotic Antagonists

Nancy K. Mello, Ph.D.

Narcotic antagonists are currently the major pharmacological

alternative to methadone for the long-term treatment of narcotic

addiction. The clinical utility of antagonist treatment is undergoing

continuing evaluation (11, 43, 57, 58, 59, 67). Within the last five

years, there have been several comprehensive reviews of research on

narcotic antagonist drugs (3, 34, 35, 41). This review will focus

upon some recent behavioral studies of narcotic antagonist drugs in

man and in animals.

It is now apparent that antagonist drugs may have a number of

complex behavioral effects, in addition to antagonism of the

pharmacological effects of opiate drugs (86). Recent explorations

of the aversive properties of some antagonists (7, 8, 21, 26, 27, 75)

have been complemented by studies of the positive reinforcing

qualities of antagonist drugs. The finding that opiate dependent

monkeys will work to produce an infusion of a narcotic antagonist

under certain conditions (16, 86) suggests the complexity of the

process of drug-related reinforcement (52). Narcotic agonists and

antagonists each may maintain behavior that leads to their

administration.

Of the several compounds which have narcotic antagonist

properties (34, 42), only two appear to be relatively “pure”

antagonists with minimal agonistic activity. Consequently, naloxone

and more recently naltrexone have become the antagonists of

choice for most behavioral studies. The antagonists cyclazocine and

nalorphine have been found to be partial agonists. For example,

nalorphine may produce dysphoria and psychotomimetic effects in

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MELLO: BEHAVIORAL PHARMACOLOGY OF ANTAGONISTS

man, as well as autonomic effects similar to those produced by

morphine (34). Although some antagonists have analgesic potency,

adverse side effects have limited their clinical use for analgesia (34).

However, it is important to recognize that even the “purest”

antagonists may have some agonistic properties at sufficiently high

doses (1, 2).

Naloxone and naltrexone differ in potency and duration of

action. Naloxone is estimated to have a duration of action of

approximately four hours, which makes it especially useful for

behavioral studies. Naltrexone is estimated to be between two and

eight times more potent than naloxone, depending upon the test

system employed (1, 2, 76). In man, the antagonist actions of

naltrexone appear to persist beyond 24 hours (43), even though

analysis of urinary excretion patterns indicate that naltrexone is

cleared within 16 to 24 hours (32). Recent evidence suggests that

beta-naltrexol, the major urinary metabolite of naltrexone, may

contribute to its long duration of action in man (32). However,

chronic high doses of naltrexone (100 mg/day) do not result in the

accumulation of either naltrexone or beta-naltrexol (77). Although

beta-naltrexol is the predominant urinary metabolite in man, nearly

equal proportions of naltrexone and beta-naltrexol are excreted in

the urine of monkey (32). The implication of these findings for the

apparent difference in duration of naltrexone blockade in man and

monkey remains to be clarified (cf. 29, 53).

ANTAGONISM OF OPIATE EFFECTS

The primary effects of narcotic antagonists are to reverse or to

block the pharmacological effects of opiates. Pre-treatment with a

narcotic antagonist will prevent the physiological and behavioral

effects of acute opiate administration. Chronic administration of

narcotic antagonists also blocks the development of tolerance and

physical dependence upon opiates (6, 42, 69). Administration of

narcotic antagonists to an opiate dependent person or animal will

precipitate an opiate withdrawal syndrome (4, 69, 78, 79). The

severity of antagonist precipitated opiate withdrawal appears to be

antagonist-dose related (cf. 4, 53). The capacity of these compounds to reverse respiratory depression induced by opiates has

long been an effective tool for emergency ward treatment of

overdose.

There has been considerable progress towards understanding the

mechanism of action of narcotic antagonists within the past five

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

years. Several laboratories have found stereospecific opiate receptor

sites in brain which appear to be binding sites for endogenous

neural ligands termed endorphins (22, 66, 70, 71, 72). It has been

hypothesized that endorphins may act to inhibit or modulate

neural responses to painful stimuli (cf. 31). Opiate antagonists may

compete with exogenous morphine-like drugs for stereospecific

opiate receptor sites. However, Jaffe and Martin (34) suggest that

the notion of competitive antagonism at a single receptor site

cannot account for many of the interactions between opioids and

opioid antagonists. For example, although most antagonists do not

induce tolerance or physical dependence, antagonists of the

nalorphine type may produce a withdrawal syndrome which is

qualitatively different from the morphine withdrawal syndrome.

Moreover, partial agonists of the nalorphine type may substitute for

morphine at relatively low levels of physical dependence and

precipitate withdrawal at high levels of morphine dependence.

These and other observations have led to the hypothesis that

specific receptors or receptor configurations may exist for antagonists and for opiates (42).

SOME EFFECTS OF ANTAGONISTS ON FOOD

AND SHOCK MAINTAINED BEHAVIOR

Over the past decade, behavioral pharmacologists have studied a

variety of narcotic antagonists. There is little question that narcotic

antagonists will effectively block or reverse the behavioral effects of

opiates in nondependent animals, in a dose-related manner. Behavioral effects have been variously defined as rate of response for

food and efficiency of avoidance responding under a variety of

single and multiple schedules of reinforcement (9, 17, 25, 28, 29,

49, 50). The effects of narcotics and antagonists on multiple fixed

interval-fixed ratio schedules of food presentation have been

reviewed recently (48).

It is generally found that high doses of morphine decrease the

rate of operant responding for another reinforcer such as food.

However, very small doses of morphine may increase a pigeon’s rate

of response for food. Increases of about 50 percent have been

observed in the fixed interval component of a multiple fixed

ratio-fixed interval schedule. Certain antagonists have also been

shown to increase rates of responding in the fixed interval

component of the multiple schedule at low doses and decrease rates

at high doses (17, 48). Narcotic antagonists can block the rate

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MELLO: BEHAVIORAL PHARMACOLOGY OF ANTAGONISTS

decreasing effects of opiates at dose levels which do not produce

direct behavioral effects, For example, pretreatment with naloxone

(0.1 mg/kg) blocked both the rate increasing and the rate decreasing

effects of morphine on schedule-controlled performance for food

reinforcement. However, naloxone doses as high as 30 mg/kg did

not antagonize the rate decreasing effects of cyclazocine (48).

Naltrexone and diprenorphine (0.1 mg/kg) appear to have

comparable potency for blockade of the effects of an acute dose of

morphine (30 mg/kg) on food-maintained responding in pigeon (9).

Those antagonists appear to be as much as three times more potent

than naloxone (2, 9). Naltrexone can block the effects of morphine

administered as long as six hours after acute antagonist administration in pigeon (9).

Species-related differences in response to narcotic antagonists

have been reported (17). For example, nalorphine decreased rates

of food-maintained responding in squirrel monkeys and increased

response rates in pigeons under comparable schedule conditions and

across a comparable dose range, whereas high doses of naloxone

decreased response rates in both monkeys and pigeons and

produced gross tremors and vomiting (17). Naloxone did not

antagonize the rate decreasing effects of nalorphine at doses which

completely antagonized the effects of morphine. The interactions

between antagonists and consequent effects on behavior do not

appear to be reliably predicted from the behavioral effect of an

antagonist plus a narcotic drug.

EFFECTS OF ANTAGONISTS OF OPIATE

SELF-ADMINISTRATION

Clinical Studies

Since narcotic antagonists can block the effects of opiates,

proponents of narcotic antagonist maintenance for the treatment of

heroin addiction argue that pharmacological blockade will eventually eliminate opiate self-administration (cf. 83). However, recent

studies of the efficacy of naltrexone maintenance in modulating

heroin self-administration on a clinical research ward have shown

that some addicts may continue to sample heroin during antagonist

blockade (55, 59). The frequency of heroin self-administration

during antagonist blockade was influenced by a number of factors,

including whether or not the heroin addict was told that he was

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

given naltrexone. When subjects were not told who was receiving

naltrexone and who was receiving naltrexone placebo, seven of the

nine subjects maintained on naltrexone blockade (75 mg/day PO)

sampled heroin an average of 13 times (range: 2 – 46) over a

ten-day period of heroin availability. Assessments of temperature,

blood pressure, pulse, respiration and pupil diameter revealed no

physiological effect of heroin during naltrexone blockade. Although

all subjects took less heroin during naltrexone blockade than under

unblocked conditions (X occasions = 55.07; range: 32 – 78), the

frequency of heroin sampling after naltrexone appeared to be

related to the duration of addiction history. Addicts with a long

history of heroin addiction persisted longest in heroin self-administration under conditions of naltrexone blockade (59). Parallel

findings have been observed in animal models where consumption

of etonitazene during naloxone blockade persisted longest in rats

with the longest history of addiction (56).

When heroin addicts were given access to heroin during naltrexone blockade (50 mg/day PO) under double blind conditions, each

of 22 subjects studied sampled heroin occasionally. Eleven subjects

took heroin on an average of 15.9 occasions, whereas the other 11

subjects took heroin on an average of 4.3 occasions over a ten day

period. Unlike addicts in the first series of studies, six of the 11

subjects who sampled heroin most frequently showed respiratory

depression and pupillary constriction after the first few heroin

doses. Comparable physiological changes did not occur after later

heroin use. Meyer and Mirin (55) suggest that these autonomic

effects were not due to inadequate antagonist blockade, but rather

were classically conditioned responses which extinguished after

repeated blocked heroin injections. Insofar as subjects were aware

of these autonomic changes, these may have contributed to the

persistence of heroin self-administration as secondary reinforcing

discriminative stimuli (55).

Heroin addicts stabilized on either cyclazocine or naltrexone also

reported some sensation of rush, high, and taste when permitted to

self-inject an acute dose of hydromorphone or saline under double

blind conditions (65). Pupillary constriction was observed in some

instances. The pleasurable response to saline or to hydromorphone

under naltrexone blockade was less intense and prolonged than

under cyclazocine blockade. After repeated systematic extinction

trials, the self-injection procedure became neutral and then aversive.

The observation that saline could induce subjective and pupillary

change equivalent to hydromorphone, during antagonist blockade,

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MELLO: BEHAVIORAL PHARMACOLOGY OF ANTAGONISTS

suggests the importance of conditioning effects associated with the

ritual of self-injection (65).

Animal Models of Opiate Self-Administration

Stimuli associated with drug infusions can come to control

behavior leading to presentation of the stimulus, even in the

absence of drug infusion. Most recently it has been shown that

operant behavior can be maintained for periods as long as one hour

by intermittent presentation of a stimulus previously associated

with infusion of cocaine or morphine. A single drug reinforcement

is then delivered at the end of the hour upon completion of the

response requirement (18). Discriminative stimulus control of drug

reinforced behavior is an experimental analog of the complex

external situational stimuli alleged to contribute to the maintenance

of and relapse to drug abuse in man (83).

Stimulus control of opiate withdrawal signs has been observed in

several species under a variety of experimental conditions (14, 84).

Stimuli which are repeatedly associated with antagonist precipitated

opiate withdrawal can acquire the ability to produce withdrawal

signs and behavior changes (13). For example, a light associated

with nalorphine injections continued to suppress food maintained

responding and to decrease heart rate for two to four months after

morphine dependence was terminated (15). Conversely, stimuli

previously associated with opiate infusions can maintain responding

leading to presentation of those same stimuli plus saline, when

opiate dependent monkeys are in withdrawal (68). Consequently

opiate acquisition and the physiological and behavioral concomitants of opiate withdrawal can be modulated by external stimuli

associated with drug infusions or antagonist precipitated drug

withdrawal (cf. 12, 13, 86).

Acute administration of the antagonists naloxone, nalorphine or

naltrexone usually increases the rate of response for opiates in

opiate dependent animals (19, 20, 53, 81, 86, 87). However, high

doses of antagonists may also suppress morphine maintained

responding (20). As a function of repeated experience with low

doses of antagonists, morphine dependent monkeys may learn to

initiate morphine self-administration more rapidly following antagonist infusion (20, 53). Despite the early increases in opiate

maintained responding usually seen after antagonist administration,

the total daily morphine intake level may not change significantly

from the preantagonist baseline. During a 25 hour period following

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

high acute doses of naltrexone (0.035-0.065 mg/kg), opiate

dependent monkeys maintained a stable level of morphine selfadministration (53). Varying periods of morphine deprivation have

also been followed by no significant increases in the total amount

of morphine self-administered over a 24 hour period (87). Monkeys

appear to be exquisitely sensitive to any deviation from their

accustomed level of morphine intake and are able to adjust

morphine self-administration behavior with considerable precision

to maintain baseline morphine levels (53). The nature of the

discriminative stimuli which permit an opiate dependent monkey to

adjust morphine self-administration to maintain a stable daily level

of morphine dosage is unknown.

Chronic antagonist blockade with high doses of naloxone (200

mg) has been shown to inhibit relapse to morphine self-administration in postaddict rats (61). The effects of lower doses of naloxone

on relapse were variable, and some animals took enough morphine

to overcome blockade and reestablish dependence (61).

AVERSIVE EFFECTS OF ANTAGONISTS

Clinical studies indicate that administration of narcotic antagonists such as nalorphine and cyclazocine may produce dysphoria,

anxiety, and a spectrum of feelings of unreality, including hallucinosis in some individuals (23, 34). Comparable effects have not

been reported following acute administration of naloxone. Dysphoric and psychotomimetic side effects do not appear to be a

prominent feature of naltrexone administration.

Some morphine antagonists have negative reinforcing properties

in opiate naive monkeys (26). Monkeys worked to avoid or escape

nalorphine (10-500 mcg/kg/inj) and cyclazocine (2.5-10 mcg/kg/

inj); however, naloxone (5-100 mcg/kg/inj), pentazocine and

propiram (50 mcg/kg/inj) did not maintain escape or avoidance

behavior at rates higher than saline (26). These data suggest that the

aversive properties of certain antagonists are not solely a function

of opiate dependence.

Primates will work to avoid or to terminate infusions of narcotic

antagonists under a variety of conditions (7, 8, 21, 26, 27, 75).

Nalorphine. naloxone, pentazocine, and propiram have been shown

to maintain escape and avoidance behavior in morphine-dependent

monkeys. Primates will also work to terminate a discriminative

stimulus which was previously associated with the administration of

a narcotic antagonist (7, 8, 16, 21, 27, 75). However, a number of

132
MELLO: BEHAVIORAL PHARMACOLOGY OF ANTAGONISTS

compounds other than narcotic antagonists have also been shown to

maintain behavior leading to termination or postponement of

injections (cf. 27, 30).

ANTAGONIST SELF-ADMINISTRATION

Primate Studies

The behavioral effects of narcotic antagonists are usually

concordant with expected predictions of what the effects of these

agents should be. What is more intriguing and perplexing are the

recent findings that, under certain conditions, opiate dependent

monkeys will work to produce an infusion of a narcotic antagonist

(16, 86).

In 1972, Goldberg, Hoffmeister, and Schlichting (16) reviewed

their behavioral studies of the effects of morphine antagonist

administration to morphine dependent monkeys. When either saline

or nalorphine was substituted for morphine during a seven and

one-half hour session, it was found that responding which was

followed by nalorphine injections decreased less rapidly than

responding followed by saline injections. In fact, nalorphine

maintained responding occurred at a higher rate than either saline

maintained responding or morphine maintained responding (16).

These data indicate that response produced nalorphine injections

(100 mcg/kg/inj) can maintain responding when monkeys are

physiologically dependent on morphine.

In 1975, Woods, Downs, and Carney (86) reported that

morphine dependent monkeys, trained to avoid infusion of naloxone, will, under certain schedule conditions, work to produce

injections of the narcotic antagonist naloxone (.002 mg/kg) on a

second-order schedule. Every 30 responses produced a secondary

reinforcement stimulus (a 1.5 second flash of light), and every 300

responses produced an injection of naloxone followed by a one

minute time out and the same light signal. When the naloxone

infusion pump was disconnected, and the secondary reinforcing

visual stimuli and the basic schedule remained unchanged, monkeys

ceased to respond. When the naloxone pump was reconnected there

was a resumption of naloxone maintained responding and the

response requirement was reduced from 300 to 150 responses for

naloxone reinforcement. Under these conditions, morphine dependent monkeys could earn about 10 naloxone injections over the

course of an hour (86).

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

These data illustrate that the experimental history of the subject

and the behavioral schedule under which a stimulus event is

presented, rather than the type of event, may determine the effect

that an event will have upon behavior. The importance of the

schedule of drug injections in determining how drugs affect

behavior has been a general finding in behavioral pharmacology (36,

37, 39, 62, 63). The crucial point is that drug reinforcement, or the

maintenance of behavior by drug self-administration, is conjointly

determined by the pharmacological effects of the drug and the

schedule of drug presentation.

Implications for an Analysis of Drug Reinforcement

Response-produced antagonist infusion by opiate dependent

monkeys is a recent entry into the now considerable literature

which describes behavior maintained by the presentation of

“aversive” events. Response-produced antagonist self-administration

is a direct parallel of another behavioral phenomenon usually

termed response-produced shock. It has been found that the same

electric shock events that can maintain escape and avoidance

behavior, may under certain conditions, be self-administered by the

same monkey. Identification of this phenomenon evolved from the

observation of Kelleher and co-workers in 1963 that responding

increased during a pre-shock stimulus and decreased if the terminal

shock was removed (40). Response-produced shock has now been

observed in many laboratories, across several species and has been

shown to be a reliable and persistent phenomenon (5, 10, 38, 44,

45, 46, 62, 64, 73, 74). Under certain conditions, monkeys will

continue to self-administer electric shock for months and even for

years (62).

Electric shock has been the favorite “aversive” event of generations of psychologists. The effectiveness of electric shock for

maintaining escape and avoidance behavior and the punishing

effects of electric shock on ongoing response behavior for reinforcers such as food are general findings too familiar to require

documentation. However, the discovery that electric shock may be

a positive reinforcer challenges common-sense assumptions about

what constitutes a “positive” and “aversive” event and what classes

of events will be reinforcing.

The view that events do not have inherently reinforcing or

punishing properties, but rather should be defined in terms of

behavioral effects, has been most fully developed by Morse and

Kelleher (62, 63). There is now considerable evidence that the same

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MELLO: BEHAVIORAL PHARMACOLOGY OF ANTAGONISTS

stimulus may have either reinforcing or punishing effects, depending upon the conditions (or schedule) under which it is presented. A

schematic summary of this formulation appears below. If the

presentation or removal of a stimulus event increases the behavior

leading to that consequence, it can be defined as a reinforcer. If the

presentation or removal of a stimulus event decreases the behavior

leading to that consequence, it can be defined as a punisher (62,

63).

This conceptual framework can accommodate a number of

otherwise incongruous illustrations of behavior maintained by

“aversive” consequences, for example: (1) chronic opiate or alcohol

abuse may lead to profound anxiety, depression, and agitation

during intoxication rather than to the expected “euphoria” (24, 51,

55, 60); (2) monkeys will work to self-administer the same electric

shock they previously worked to avoid (62); (3) opiate dependent

monkeys will self-administer a narcotic antagonist that they

previously worked to avoid (16, 86).

The extent to which “aversive” consequences comprise an

important aspect of the complex process of drug reinforcement in

man is unknown. Clinical data indicate that both alcohol and

abused drugs may have aversive subjective consequences for the

naive or occasional user (33, 52, 80, 85) and for the addict (54, 55,

60). These findings challenge the assumption that persistent drug

abuse can be accounted for solely by its “rewarding” or “euphorogenic” consequences. The process by which an initial drug

experience, which may involve nausea, vomiting, and dysphoria

becomes translated into recurrent drug abuse or drug addiction is

unclear. The details of this transition are perhaps impossible to

study in man.

However, if drug abuse is examined in terms of its actual effects

on behavior, rather than in terms of time-honored a priori

assumptions, it may be possible to identify more accurately the

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

determinants of its reinforcing properties. A better understanding

of the process of drug reinforcement would be valuable for the

development of optimally effective techniques for modifying drug

abuse in man. Behavior which is maintained by events such as

antagonist self-administration by opiate addict monkeys may offer

one model for exploration of the complex determinants of drug

reinforcement. Over 25 years ago, Wikler (82) observed that partial

withdrawal may enhance the gratifying effects of morphine

injections in human addicts. The nature of the interactions between

narcotic agonists and antagonists, and the effects of these interactions on behavior remain to be determined in future research.

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43. Martin, W.R.; Jasinski, D.R.; and Mansky, P.A. Naltrexone, an antagonist

for the treatment of heroin dependence effects in man Arch Gen Psychiat,

28:784-791, 1973.

44. McKearney, J.W. Maintenance of responding under a fixed-interval schedule of electric shock presentation. Science, 160:1249-1251, 1968.

45. . Fixed-interval schedules of electric shock presentation: Extinction and recovery of performance under different shock intensities and

fixed interval durations. J Exp Anal Behav, 12:301-313, 1969.

46. . Maintenance and suppression of responding under schedules of

electric shock presentation. J Exp Anal Behav, 17:425-432, 1972.

47. . Effects of morphine, methadone, nalorphine and naloxone on

responding under fixed interval (FI) schedules in the squirrel monkey. Fed

Proc, 34:766, 1975.

48. McMillan, D.E. Effects of narcotics and narcotic antagonists on operant

behavior. In: Braude, M.C.; Harris, L.S.; May, E.L.; Smith, J.P.; and

Villarreal, J.E., eds. Narcotic Antagonists: Advances in Biochemical

Psychopharmacology, Vol 8. New York: Raven Press, 1973. pp. 345-359.

49. McMillan, D.E., and Morse, W.H. Some effects of morphine and morphine

antagonists on schedule-controlled behavior. J Pharmacol Exp Ther,

157:175-184, 1967.

50. McMillan, D.E.; Wolf, P.S.; and Carchman, R.A. Antagonism of the

behavioral effects of morphine and methadone by narcotic antagonists in

pigeon. J Pharmacol Exp Ther, 175:443-458, 1970.

51. McNamee, H.B.; Mello, N.K.; and Mendelson, J.H. Experimental analysis of

drinking patterns of alcoholics: Concurrent psychiatric observations. Am J

Psychiat, 124:1063-1069, 1968.

52. Mello, N.K. Stimulus self-administration: Some implications for the

prediction of drug abuse liability. In: Thompson, T., and Unna, K.R., eds.

Predicting Dependence Liability of Stimulant and Depressant Drugs.

Baltimore: University Park Press, 1977, pp. 243-260.

53. Mello, N.K., and Mendelson, J.H. The effects of naltrexone on patterns of

morphine and food self-administration in rhesus monkey. In: Problems of

Drug Dependence, Proceedings 38th Annual Meeting, Committee on

Problems of Drug Dependence. Washington, D.C.: National Academy of

Sciences—National Research Council, 1976. pp. 394-414.

54. Mello, N.K., and Mendelson, J.H. Alcohol and human behavior. In: Iversen,

L.L.; Iversen, S.D.; and Snyder, S.H., eds. Handbook of Psychopharmacology, Section III. Chemistry, Pharmacology and Human Use. New York:

Plenum Publishing Corp., forthcoming.

55. Meyer, R.E., and Mirin, S. The Heroin Stimulus. New York: Plenum Press,

forthcoming.

56. Meyer, R.E.; Marcus, R.; Carnathan, G.; and Cochin, J. Narcotic blockade,

length of addiction and persistence of etonitazene consumption in rats.

Psychopharmacologia, 47:273-279, 1976.

57. Meyer, R.E.; McNamee, H.B.; Mirin, S.M.; and Altman, J.L. Analysis and

modification of opiate reinforcement. Int J Addict, 11:467-484, 1976.

58. Meyer, R.E.; Mirin, S.M.; Altman, J.L.; and McNamee, H.B. A behavioral

paradigm for the evaluation of narcotic antagonists. Arch Gen Psychiat,

33:371-377, 1976.

59. Meyer, R.E.; Randall, M.; Mirin, S.M.; and Davies, M. Heroin self-administration: The effects of prior experience, environment and narcotic

blockade. J Psychiat Res, in press.

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60. Mirin, S.M.; McNamee, H.B.; and Meyer, R.E. Psychopathology, craving

and mood during heroin acquisition: An experimental study. Int J Addict,

11:525-543, 1976.

61. Moreton, J.E.; Young, G.A.; Meltzer, L.; and Khazan, N. Effects of

naloxone subcutaneous pellets on relapse to morphine self-administration

in post-addict rats. Res Com Chem Path Pharmacol, 11(2):209-219, 1975.

62. Morse, W.H., and Kelleher, R.T. Schedules as fundamental determinants of

behavior. In: Schoenfeld, R.N., ed. The Theory of Reinforcement

Schedules. New York: Appleton-Century-Crofts, 1970. pp. 139-185.

63. . Determinants of reinforcement and punishment. In: Honig,

W.K., and Staddon, J.E.R., eds. Handbook of Operant Behavior, volume 2.

Englewood Cliffs, N.J.: Prentice-Hall, 1977. pp. 174-200.

64. Morse, W.H.; Mead, R.N.; and Kelleher, R.T. Modulation of elicited

behavior by a fixed-interval schedule of electric shock presentation.

Science, 157:215-217, 1967.

65. O’Brien, C.P. Experimental analysis of conditioning factors in human

narcotic addiction. In: Kelleher, R.T.; Goldberg, S.R.; and Krasnegor, N.A.,

eds. Control of Drug Taking Behavior by Schedules of Reinforcement.

Baltimore: Williams & Wilkins Co., 1976. pp. 533-543.

66. Pert, C.B.. and Snyder, S.H. Opiate receptor: Demonstration in nervous

tissue. Science, 179:1011-1014, 1973.

67. Schecter, A. Clinical use of naltrexone (EN 1639 A). Part II: Experience

with the first 50 patients in a New York City Treatment Clinic. Amer J

Drug & Alc Abuse, 2(3-4):433-442, 1975.

68. Schuster, C.R., and Woods, J.H. The conditioned reinforcing effects of

stimuli associated with morphine reinforcement. Int J Addict, 3:223-230,

1968.

69. Seevers, M.H., and Deneau, G.A. Physiological aspects of tolerance and

physical dependence. In: Root, W.S., and Hofmann, F.G., eds. Physiological Pharmacology. New York: Academic Press, 1963. pp. 565-640.

70. Simon, E.J.; Hiller, J.M.; and Edelman, I. Stereospecific binding of the

potent narcotic analgesic (

3H) etorphine to rat-brain homogenate. Proc Nat

Acad Sci, 70:1947-1949, 1973.

71. . Solubilization of a stereospecific opiate-macromolecular complex from rat brain. Science, 190:339-390, 1975.

72. Snyder, S.H. Opiate receptor in normal and drug-altered brain function.

Nature, 257:185-189, 1975.

73. Stretch, R.; Orloff, E.R.; and Dalrymple, S.D. Maintenance of responding

by fixed-interval schedule of electric shock presentation in squirrel

monkeys. Science, 162:583-586, 1968.

74. Stretch, R.; Orloff, E.F.; and Gerber, G.J. Multiple interruption of

responding maintained by a fixed-interval schedule of electric-shock

presentation in squirrel monkeys. Can J Psychol, 24:117-125, 1970.

75. Tang, A.H.; and Morse, W.H. Termination of a schedule complex associated

with intravenous injections of nalorphine in morphine-dependent rhesus

monkeys. In: Kelleher, R.T.; Goldberg, S.R.; and Krasnegor, N.A., eds.

Control of Drug Taking Behavior by Schedules of Reinforcement.

Baltimore: Williams & Wilkins, 1976. pp. 407-418.

76. Verebely, K., and Mule, S.J. Naltrexone pharmacology, pharmacokinetics

and metabolism: Current status. Amer J Drug & Alc Abuse, 2:357-363,

1975.

140
MELLO: BEHAVIORAL PHARMACOLOGY OF ANTAGONISTS

77. Verebely, K.; Kojan, M.J.; Depace, A.; and Mule, S.J. Quantitative

determination of naltrexone and beta-naltrexol in human plasma using

electron capture detection. J Chromatography, in press.

78. Villarreal, J.E. The effects of morphine agonists and antagonists on

morphine-dependent rhesus monkeys. In: Kosterlitz, H.W.; Collier, H.O.J.;

and Villarreal, J.E., eds. Agonist and Antagonist Actions of Narcotic Drugs.

Baltimore: University Park Press, 1973. pp. 73-53.

79. Villarreal, J.E., and Karbowski, M.G. The actions of narcotic antagonists in

morphine-dependent rhesus monkeys. In: Braude, M.C.; Harris, L.S.; May,

E.L.; Smith, J.P.; and Villarreal, J.E., eds. Narcotic Antagonists. Advances

in Biochemical Pharmacology, Vol 8. New York: Raven Press, 1974. pp.

273-289.

80. Warren, G.H., and Raynes, A.E. Mood changes during three conditions of

alcohol intake. Q J Stud Alcohol, 33:979-989, 1972.

81. Weeks, J.R., and Collins, R.J. Factors affecting voluntary morphine intake

in self-maintained addicted rats. Psychopharmacologia, 6:267-279, 1964.

82. Wikler, A. A psychodynamic study of a patient during experimenta!

self-regulated re-addiction to morphine. Psychiat Q 26:270-293. 1952.

83. . Dynamics of drug dependence: Implications of a donditioning

theorv for research and treatment. Arch Gen Psychiat. 28:611-616. 1973.

84. Wikler, A., and Pescor, F.T. Classical conditioning of a morphine

abstinence phenomenon, reinforcement of opioid-drinking behavior and

“relapse” in morphine-addicted rats. Psychopharmacologia, 10:255-284,

1967.

85. Williams, A.F. Social drinking anxiety and depression. J Personality Soc

Psychol, 3:689-693, 1966.

86. Woods, J.H.; Downs, D.A.; and Carney, J. Behavioral functions of narcotic

antagonist: Response-drug contingencies. Fed Proc, 34:1777-1784, 1975.

87. Woods, J.H.; Downs, D.A.; and Villarreal, J.E. Changes in operant behavior

during deprivation- and antagonist-induced withdrawal states. In: Psychic

Dependence. (Bayer-Symposium IV) 1973. pp. 114-121.

ACKNOWLEDGEMENT

Preparation of this review was supported by grant No. DA 01676-01 from

the National Institute on Drug Abuse.

141
CHAPTER 12

Plasma Testosterone Levels During

Chronic Heroin Use and Protracted

Abstinence: A Study of Hong Kong

Addicts1

Jack H. Mendelson, M.D., and Nancy K. Mello, Ph.D.

According to clinical reports, heroin addicts experience both

diminished sexual drive and impairment of sexual function when

actively using narcotics (14). Diminished sexual drive has been

characterized as lack of desire for initiation of, and unreceptivity

to, sexual interaction. Impaired sexual function has been reported

as difficulty in initiating or sustaining penile erection and significant

prolongation of ejaculatory time. There is also evidence that plasma

testosterone levels in man may be correlated with sperm count and

sperm motility (7). The mechanisms by which narcotics use

produces suppression of sexual desire and function are unknown.

It has recently been shown that heroin (1, 11), high-dosage

methadone (1, 11), and alcohol (10) suppress plasma testosterone

levels in addicted subjects. The duration of the suppressive effects

of narcotics on testosterone is not known and the mechanism of

inhibition is unclear (11). It is not known if chronic use of heroin

for varying periods of time causes long-lasting or short-term

suppression of testosterone levels. This study was undertaken to

determine if chronic narcotic use produces permanent impairment

of androgen levels. No data have been reported previously on

testosterone levels following abrupt cessation of heroin use and

during protracted abstinence.

1

 Reprinted with permission from Clinical Pharmacology and Therapeutics

17:529-533, 1975; copyrighted 1975 by the C.V. Mosby Company, St. Louis,

Missouri, U.S.A.

142
MENDELSON AND MELLO: HEROIN AND PLASMA TESTOSTERONE

Attempts to relate plasma testosterone levels to heroin use or to

abstinence present several methodologic problems, First, it is

difficult to study heroin addicts for months or years following

initiation of abstinence because of the high frequency of recidivism.

Secondly, many narcotic addicts have polydrug abuse problems and

it is difficult to ascertain whether alterations in endocrine levels are

specifically associated with heroin or with use of other drugs alone

or in combination with heroin. For example, it has been shown that

many American heroin addicts, both in drug-free status and on

methadone maintenance, develop significant alcohol abuse problems (4). Alcohol abuse has been shown to be associated with a

suppression of plasma testosterone levels (10).

In order to examine the long-term effects of heroin on plasma

testosterone levels in an addict population where polydrug abuse

was uncommon and alcohol abuse was relatively rare, a study of

Hong Kong heroin addicts was undertaken. Hong Kong has

probably the largest number of heroin addicts per capita in the

world. There are estimated to be over 100,000 addicts in a

population of about 4.2 million (9). In Hong Kong, addicts have

access to a high-quality and relatively pure heroin that they can

obtain at low cost on the illicit drug market.

There are two types of heroin for sale on the illicit drug market

in Hong Kong. “Number 3 heroin” is sold primarily for smoking.

An average packet contains 300 mg of heroin and is 30% to 50%

pure. “Number 3 heroin” is sometimes mixed with a trace of

barbiturates to produce a slower burning mixture. In 1973, the

average cost of a packet of “Number 3 heroin” was 5 Hong Kong

dollars, which is equivalent to 0.4 or one U.S. dollar. “Number 4

heroin” is sold primarily for intravenous use. An average packet

contains 40 mg of heroin, which is 60% to 95% pure. A packet of

“Number 4 heroin” costs approximately 2 Hong Kong dollars,

which is equivalent to .17 new pence or 40 U.S. cents.

Until recently, the preferred mode of heroin use in Hong Kong

was by smoking the drug in cigarettes or by inhaling vapors of

volatilized heroin, a technique known locally as “chasing the

dragon,” which consists of placing heroin in a tinfoil cup, igniting

the heroin and deeply inhaling the smoke and vapors. During the

past two years an increasing number of addicts administered heroin

intravenously, and it is currently estimated that in 15% to 20% of

all addicts, intravenous heroin is the preferred mode of use (9).

This study was undertaken in an effort to determine if alterations

in plasma testosterone levels persist during early and late phases of

heroin abstinence.

143
INTERNATIONAL CHALLENGE OF DRUG ABUSE

SUBJECTS AND METHODS

The subjects were 31 male heroin addicts, between the ages of 15

and 43 (X = 30). All were Chinese residents of Hong kong who

reported a history of heroin addiction ranging from 2 to 20 years’

duration. Plasma testosterone samples were obtained from all

subjects between the hours of 10:30 and 12:30 each morning.

Plasma testosterone levels were determined by a commercially

available double-antibody radioimmunoassay modified from a

procedure used for protein hormones as described by Niswender

and associates (12).

In order to reconfirm the suppressive effects of chronic heroin

use on testosterone levels, and to examine the effects of varying

periods of abstinence, 4 groups were studied. The chronic heroin

group (6 subjects) had plasma testosterone levels determined on the

morning of their admission to a residential treatment center. The

recent abstinence group (12 subjects) was studied during the

course of their residential treatment program (1 to 3 months). The

long-term abstinence group consisted of “alumni” members of the

treatment program who had totally abstained from heroin use for

over 12 months. A fourth group of 7 subjects was studied during

the course of their methadone maintenance program at a clinical

facility on Kowloon.

All subjects had initiated heroin use by smoking and most

subsequently began to “chase the dragon,” Twelve subjects reported

total abstinence from heroin within the past 3 months after 2 to 20

years of chronic heroin use. Seven of these recently abstinent

subjects had routinely used the drug intravenously.

Three of the 7 subjects on methadone maintenance had either

used or were currently using intravenous heroin. Six subjects had

been abstinent for over one year, and 2 reported a history of

intravenous heroin. Thus, in all 4 groups, in one-third or more of

the subjects intravenous heroin was the preferred mode of

administration.

Arrangements for the study were made possible through the

assistance and cooperation of the Society for the Aid and

Rehabilitation of Drug Addicts, a nonprofit organization with

headquarters in Hong Kong. The study was carried out in three

facilities operated by the Society: The Acute Admissions Center,

Administrative Headquarters and Alumni Group Center on Hong

Kong Island; the residential treatment center on the island of Shek

Kwu Chau in the South China Sea; and the methadone maintenance

clinic on the peninsula of Kowloon.

144
MENDELSON AND MELLO: HEROIN AND PLASMA TESTOSTERONE

FIGURE 1

Plasma testosterone levels of heroin addicts during active heroin use, during

combined heroin use and methadone administration, and following initiation

of abstinence for periods of less than 1 month to over 12 months. Circled

points in Col. 2 represent subjects who stated that they were not concurrently

using heroin. All other subjects in this group report recurrent heroin use while

on methadone maintenance therapy.

RESULTS

Plasma testosterone levels for each group of subjects are shown in

figure 1. The 6 subjects sampled within 4 to 5 hr of acute use of

heroin had testosterone values that were below the normal average

for adult males observed in our laboratory (400 to 1,000 mμg/100

ml). There was, however, no correlation between the reported

duration of heroin use or the reported dose employed and degree of

suppression of plasma testosterone levels.

Comparable suppression of testosterone levels was found in 5 of

7 subjects maintained on methadone. These data are shown in

column 2 of figure 1. Methadone dosage ranged between 10 and

150 mg per day. All but 2 of these subjects reported concurrent use

of heroin.

One subject who reported using no heroin but received 60 mg of

methadone per day had normal testosterone levels (506 mμg/l00

ml). However, another subject who used only 10 mg of methadone

145
INTERNATIONAL CHALLENGE OF DRUG ABUSE

per day had quite low serum testosterone values (132 mμg/100 ml).

Because urine screening was carried out only occasionally for

patients on methadone maintenance, it is difficult to ascertain if

their reported use of abstinence from heroin was accurate.

Three subjects who abstained from heroin for less than 1 month

(13 to 18 days) had either borderline or low serum testosterone

levels (figure 1, column 3). The subject who had abstained for only

13 days had serum testosterone values that were consistent with the

very low values observed for active heroin users. Three subjects who

had abstained from heroin for approximately one month had

normal testosterone levels (figure 1, column 4) and 5 of the 6

subjects who abstained from heroin use for 2 to 3 months also had

normal plasma testosterone values (figure 1, column 5). The single

exception, a 15-year-old male, had very low plasma testosterone

values (118 mμg/100 ml). This subject was the youngest studied

and he reported initiation of heroin use when he was 12 years of

age. He began smoking heroin and after 4 months started “chasing

the dragon.” He was the only subject who initiated heroin use prior

to the onset of puberty, and his very low plasma testosterone levels

may reflect a persistent and severe impairment of sexual development.

Six subjects who abstained from heroin use for a period of 1 to 4

years had plasma testosterone levels that were within the normal

range for adult males. These data are shown at the far right of figure

1, column 6.

DISCUSSION

Data obtained in this study are in agreement with previous

findings that both heroin and methadone suppress plasma testosterone levels in male narcotic addicts (1, 11). Since polydrug abuse

problems were not encountered in the patients studied in Hong

Kong, it is likely that heroin per se has a direct suppressive effect on

plasma testosterone. The mechanism of action of heroin suppression of plasma testosterone is not known. It is possible that heroin

may inhibit secretion of gonadotrophins from the pituitary in

humans since this phenomenon has been demonstrated in experimental animals (5). Martin and his associates (8) found that

follicle-stimulating hormone and luteinizing hormone were decreased in a group of male patients studied during a cycle of

methadone maintenance and withdrawal. These patients also

reported a diminished sexual activity during the induction phase of

146
MENDELSON AND MELLO: HEROIN AND PLASMA TESTOSTERONE

methadone maintenance but tolerance to this effect developed as

methadone administration was continued (8).

Cicero and associates (2) found marked reduction in seminal

vesicle and prostate gland weights of rat following implantation of

morphine pellets. Associated with these changes was a significant

decrease in seminal vesicle secretory activity. In more recent studies

Cicero and associates (3) found no changes in seminal vesicle and

prostate weight and function in hypophysectomized rats given

morphine but maintained on human chorionic gonadotrophins (3).

These findings converge to suggest that heroin may inhibit secretion

of pituitary gonadotrophins and thereby decrease the level of

plasma testosterone. It is also of interest that spontaneous penile

erection and ejaculation has been observed in rat during abrupt

morphine withdrawal following induction of physical dependence

(13).

The role of plasma testosterone levels for regulation of sexual

behavior and function in males is complex. In Hong Kong, common

folklore reports that males often initiate heroin use with the

expectancy that the drug will enhance their sexual desire and

function. Clinical reports obtained from heroin addicts in the

United States suggest that impairment of sexual function and desire

is the usual concomitant of heroin use (14). However, the

relationships between plasma testosterone levels and sexual potency

are ambiguous, since low testosterone levels have not been found in

impotent but otherwise healthy males (6).

The finding of normal testosterone values in subjects who had

not used heroin for at least one month indicates that heroin

suppression of plasma testosterone levels is of relatively short

duration and that even protracted heroin use (e.g., up to 20 years)

does not appear to inhibit the recovery of plasma testosterone

following abstinence. The persistence of significant suppression of

plasma testosterone in a single young adult male who initiated

heroin use prior to or at the onset of puberty, suggests that chronic

heroin administration at a critical age may cause long-lasting sexual

impairment.

REFERENCES

1. Azizi, F.; Vagenakis, A. G.; Longcope, C.; Ingbar, S. H., and Braverman, L.

E. Decreased serum testosterone concentration in male heroin and

methadone addicts. Steroids, 22:467-472, 1973.

147
INTERNATIONAL CHALLENGE OF DRUG ABUSE

2. Cicero, T. J.; Meyer, E. R., Bell, R. D., and Wiest, W. G. Effects of

morphine on the secondary sex organs and plasma testosterone levels of

rats. Res Commun Chem Pathol Pharmacol, 7:17-24, 1974.

3. Cicero, T. J., Meyer, E. R., Wiest, W. G., Olney, J. W., and Bell, R. D.

Effects of chronic morphine administration on the reproductive system of

the male rat. J Pharmacol Exp Ther, 192(3):542-548, 1975.

4. Cushman, P. Plasma testosterone in narcotic addiction. Am J Med,

55:452-455, 1973.

5. George, R. Hypothalamus: Anterior pituitary gland, in Clouet, D. H.,

editor: Narcotic drugs, biochemical pharmacology, New York, 1971,

Plenum Press, pp. 283-300.

6. Hudson, B., and Coghlan, J. P. Abnormalities of testosterone secretion in

the male, in Astwood, E. B., and Cassidy, C. E., editors: Clinical

Endocrinology, New York: Grune & Stratton, Inc. 1968. pp. 562-568.

7. Kolodny, R.; Jacobs, L.; Masters, W.; Toro G.; and Daughaday, W. Plasma

gonadotrophins and prolactin in male homosexuals, Lancet 2:18-20: 1972.

8. Martin, W. R.; Jasinski, D. R.; Haertzen, C. A.; Kay, D. C.; Jones, B. E.;

Mansky, P. A.; and Carpenter, R. W. Methadone—a reevaluation, Arch Gen

Psychiatry, 28:286-295, 1973.

9. Mendelson, J. H. Personal communication from staff of Society for the Aid

and Rehabilitation of Drug Addicts, Hong Kong, 1973.

10. Mendelson, J. H., and Mello, N. K. Alcohol, aggression and androgens, in

Frazier, S., editor: Aggression, Baltimore, 1974, Williams & Wilkins Co.,

vol. 52, pp. 225-247.

11. Mendelson, J. H.: Mendelson, J. E.; and Patch, V. D. Plasma testosterone

levels in heroin addiction and during methadone maintenance, J Pharmacol

Exp Ther, 192:211-217, 1975.

12. Niswender, G. D.; Reichert, L. E.; Midgley, A. R.; and Nalbandov, A. V.

Radioimmunoassay for bovine and ovine luteinizing hormone, Endocrinology, 84:1166-1173, 1969.

13. Teiger, D. G. Induction of physical dependence on morphine, codeine and

meperidine in the rat by continuous infusion J Pharmacol Exp Ther,

190:408-415, 1974.

14. Wieland, W. E., and Younger, M.: Sexual effects and side effects of heroin

and methadone, Proceedings of the Third National Conference on

Methadone Treatment, Washington, D.C., 1970, pp. 50-53.

ACKNOWLEDGMENTS

We thank Mr. James M. N. Ch’ien, Dr. Tieu, Dr. M. Lehy, Dr. J.B.

Hollinrake, and Sir Albert Rodrigues of the Society for the Aid and

Rehabilitation of Drug Addicts, Hong Kong for their generous assistance and

cooperation, which made this study possible.

The work reported in this paper was supported in part by Grant No. DA

4RG010 from the Special Action Office for Drug Abuse Prevention, Executive

Office of the President, Washington, D.C.

148
CHAPTER 13

Biological Aspects of Cannabis Use

Costas Stefanis, M.D.

Cannabis research has flourished in recent years and publications

dealing with the biological, psychological and sociocultural aspects

of cannabis use have flooded the literature. Inspired by the public’s

concern over the worldwide cannabis epidemic that challenged

traditional values and disregarded barriers of culture, sex, age, and

class (52, 67), these studies yielded valuable information that

largely contributed to revising official and lay attitudes towards the

problem. Whereas in the past reports on cannabis use reflected only

horror and rejection, the majority of recent papers refute old myths

and project a more benevolent picture of this enigmatic plant. The

tide has reversed to the point that laws are being passed to

decriminalize its use and reports questioning its innocence are

currently the least popular.

From 1970 we have been engaged in a multidisciplinary and

long-term study of cannabis use. The first and major part of this

study was performed in our Department in collaboration with Drs.

M. Fink, R. Dornbush, and J. Volavka of the United States.

Findings from this part of the study appeared in several papers (7,

8, 21, 23, 24, 55, 86, 87, 88, 89, 90, 91) and in a recently

published monograph (84). The second part of the study, which is

still in progress and for which the same previously studied

experimental group (54) was used, is mainly directed towards the

elucidation of biological mechanisms of cannabis action in man and

involves a variety of approaches suitable for answering questions

left open from our previous work. Part of the results from the

histochemical investigation have already been reported elsewhere

(85).

It is the purpose of this paper (a) to present a critical review of

our previous and current work on cannabis with a particular

reference to findings pertaining to the biological aspects of its use;

149
INTERNATIONAL CHALLENGE OF DRUG ABUSE

(b) to emphasize the fact that despite recent advances in cannabis

research only a few of the vital questions regarding mechanisms of

its action and implication of its chronic use have been answered; and

(c) to urge further. investigation in order to avoid premature and

unwarranted conclusions with serious social repercussions.

MATERIALS AND METHODS

Findings to be reported in this paper were obtained from a

population of forty-seven chronic hashish users and forty control

subjects. The users were selected on the basis of a number of strict

criteria (among them maximum age of 58 years, no use of other

addictive substances except for occasional or moderate use of

alcohol, and a minimum duration of hashish smoking of ten years),

and they came largely from refugee families from Asia Minor

residing in a working class, low income, section of Athens. Controls

were nonusers but cigarette smokers, matched to our users for age,

refugee origin, upbringing, educational and socioeconomic characteristics.

The hashish data reported by the subjects are presented in table

1.

TABLE 1

Reported Hashish Data

A variety of clinical, neurophysiological, psychological, psychophysiological, histochemical and biochemical methods were used.

Whenever necessary, reference regarding methodology is given in

the appropriate section of the text. The reader may also consult

two of our previous publications (84, 85) for methods and

procedures pertaining to this presentation.

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STEFANIS: BIOLOGICAL ASPECTS OF CANNABIS USE

FIRST PART OF THE STUDY

The first part of the study proceeded in three phases:

1. Identification of chronic cannabis population and its comparison

by a variety of biological, behavioural, and social characteristics to

the control sample;

2. Experimental assessment of the effects of various strengths of

cannabis preparations; and

3. Assessment of possible withdrawal effects.

Comparison of Chronic Cannabis Users With a Control Sample

In an extensive medical examination associated with a diagnostic

laboratory investigation, chronic cannabis users were found not to

differ from nonusers with respect to incidence of any clinically

defined physical disability. A higher incidence of enlarged liver was

encountered in the group of users, but this correlated more closely

to alcohol use rather than to cannabis consumption. No clinically

evident toxic effects commonly identified with chronic alcoholism

or opiate addiction were detected (8, 84). Moreover, resting

electroencephalograms (EEGs), recorded from 46 of the 47 users

and from 40 nonusers failed to reveal abnormalities that would

distinguish users from nonusers. Normal, borderline, and abnormal

EEG records were almost evenly distributed in the two groups (23,

84, 89). These results signifying absence of brain disfunction

manifested in EEG are in agreement with some (14, 17, 73) but not

all (11) previous reports. Measurements of the third ventricle size

by echoencephalography (Echo-EG) in 14 users and 21 nonusers

have shown an average width of 6.6 mm for the users’ group and

6.3 mm for the nonusers’ group, a difference not statistically

significant. These results do not support Campbell et al.’s (10)

pneumoencephalographic findings of ventricular dilatation.

Chronic cannabis users and nonusers could not be distinguished

on the basis of their global IQs in both the WAIS and the RAVEN

tests (84). However, as shown in table 2, significant differences in

performance between the two groups were noted in a number of

subtests in the WAIS test. The impaired performance in the

Comprehension and Similarities subtests indicate possible defect in

the verbal sphere, i.e., in verbal comprehension, expression memory, associative thinking, and verbal abstraction. The low score in the

Digit Symbol Substitution subtests indicates possible defect in

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TABLE 2

Statistically Significant Differences Between Hashish Users

and Controls in W.A.I.S. Subtests

visual-motor coordination and memorizing capacity. It is reported

that cannabis consistently affects performance on this subtest

during the postsmoking period. Performance in the Picture Arrangement test that measures primarily logical sequential thought was

found to be inferior in the users’ group. This difference however did

not reach the level of statistical significance due to the high

dispersion index of the results (S.D.=3.10). It is at present not clear

whether the impairment manifested in the above subtests is a sign

of permanent deterioration related to hashish long term use, or

whether it is a transient. phenomenon due to persistence of an acute

drug effect at the time of testing.

The issue of long term effects of cannabis use on mental health is

still debated. In recent years an attempt has been made to

systematize research in this area by well designed controlled studies

on representative samples of population (73, 74). Although these

studies yielded essentially negative results regarding an association

between cannabis smoking and psychopathology, there are still

reports in the literature (12, 50) indicating that such an association

may exist which may not be revealed by small group assessment

methods but only by clinical follow-up of individual cases.

Different conclusions may be drawn by using traditional psychiatric

clinical approach and structured psychiatric assessments and this is

clearly reflected in the conclusions reached by the same author in

two different studies (3, 48).

In our investigation the psychiatric assessment of the two groups

included a psychiatric history and a mental status examination

based on a structured format. Information from the psychiatric

history revealed that 9 (19%) of the users had previous psychiatric

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TABLE 3

Incidence of Psychiatric Disorder

treatment, compared with 2 (5%) of the controls. The results

concerning incidence of psychopathology are shown in table 3. No

subject displayed signs or symptoms of an organic psychosis. Three

users were diagnosed as psychotics of schizophrenic type. Two of

these had had prior psychiatric and outpatient treatment. A positive

family history was also recorded for two of the three. The diagnosis

of personality disorder was defined in 25% of the users and in 7% of

the controls. The antisocial type of personality disorder was the

main diagnostic subcategory that distinguished users from controls.

In comparing incidence of mental abnormalities with those

aspects (7) discriminating users from controls it was found that

more mentally abnormal users were sentenced for offences not

related to cannabis (83%) than were mentally normal users (48%).

This finding is consistent with prevalence in our group of antisocial

type personality disorders.

It is clear from our results that no specific psychotic disability is

related to cannabis use. The three users with psychotic symptomatology were indistinguishable from typical schizophrenia cases, and

there were no clinical features suggesting their mental state was

related to drug-induced brain damage (174). The higher incidence

of personality disorders in our population of users has also been

noted in another recent controlled study (30) but needs to be

further investigated. It is most likely that it is more closely

associated with sociocultural and legal aspects of cannabis smoking

in a country in which cannabis use is proscribed, severely punished,

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and largely alien to its cultural tradition (88). It is thus reasonable

to assume that psychopathic personalities are more prone to

dissociate themselves from the prevailing sociocultural value system

by smoking illicit cannabis, rather than that the pharmacological

action of cannabis is instrumental in modifying personality structure. However, conclusive evidence for or against this assumption

can only be derived from well designed prospective studies.

Relevant to psychopathology is the question of the so-called

“amotivational” syndrome (60), which was claimed to be associated

with prolonged cannabis use (50). Several recent studies on

subchronic users, mainly derived from the student population of

North America (61), as well as on chronic users in Jamaica (73) and

Costa Rica (74) refuted this claim. In fact motivational rather than

amotivational properties were ascribed by some (15, 73) to

cannabis, in such areas as work efficiency and socially productive

activity. In our study no clear-cut evidence was obtained to support

an association of prolonged hashish use and an “amotivational”

syndrome. Indirect evidence may only derive from employment and

work records of the two groups, which show that significantly more

users were unemployed when seen and significantly more nonusers

were skilled workers (7, 84). Such differences may not be related to

hashish smoking but either to the higher incidence of psychopathy

in the group of users or to psychosocial factors linked to cultural

and legal aspects of cannabis use in Greece (88). Several of our

subjects reported that hashish improved their work performance.

Objective measurements are needed to confirm such subjective and

expectedly biased information deriving from subjects prone to

rationalizing and in great need of social acceptance. However, if this

is true, one should not hastily ascribe to cannabis motivational

properties before the alternative interpretation of a state of

dependence is adequately explored. In line with Wikler’s thinking

(101), once a drug-induced state-dependence is established, inclination to work may first require satisfaction of drug-dependency

needs. Also to be considered in evaluating drug effects on

motivation is a possible differential effect depending on the type of

work and the level of performance complexity associated with it.

As noted by Soueif (79), the lower the nondrug level of proficiency

on tests of cognitive and psychomotor performance, the smaller the

size of functional deficit associated with drug usage.

In summarising results obtained by comparing users and nonusers

with respect to their physical, mental, and social functioning we

may conclude that users are essentially indistinguishable from

nonusers for the investigated parameters. Our results in particular

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STEFANIS: BIOLOGICAL ASPECTS OF CANNABIS USE

failed to provide support for claims that an organic brain syndrome

may develop following prolonged cannabis use. Similar conclusions

derive from the Jamaican (7, 13) and Costa Rican (13, 74) studies.

It should, however, be emphasized that these two studies as well as

ours (a) were all retrospective and were based on reported and not

on controlled information; (b) were based on small samples, the

representativeness of which was not documented; (c) were subject

to sampling bias, since only subjects who could be reached and were

willing to participate were included in the study while others

possibly not equally resistant to cannabis’ ill-effects might have

been missed; (d) were limited by their investigative instrumentation

which may not be capable of revealing more than overt and gross

physical and mental pathology at a group level.

Acute Experiments

The acute experiments were designed to measure degree of

tolerance by long term users to various cannabis preparations and to

determine if in long term cannabis users the immediate subjective,

psychophysiological, and psychological test responses are altered

compared to the immediate responses observed in casual or short

term cannabis users. Twenty users from our original group

volunteered for the experiments in which various strengths of

cannabis (U.S. marihuana with THC- -9 content of 78 mg, low

potency hashish with THC- -9 content of 90 mg, high potency

hashish with THC- -9 content of 180 mg and pure THC- -9 of 100

mg) and placebo were inhaled and assessed in terms of their

psychological, behavioural, EEG and psychophysiological effects

(21, 23, 24, 55, 84, 89).

Regarding the question of tolerance, it was shown in these

experiments that our subjects tolerated in a single smoking session

and without any adverse reactions or discomfort cannabis preparations of a very high THC- -9 potency (up to 180 mg). Considering

the fact (20, 52) that the subjective feeling of “high” as well as a

variety of autonomic and adverse effects are produced in occasional

users by preparations equivalent in strength to 20 mg or less of

THC- -9, the amount inhaled by our subjects should be evaluated

as an indication of tolerance (84).

Subjective responses to acute cannabis inhalation in our subjects

were no different from those reported by less experienced users

(20). Although set and setting were noted to contribute to their

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subjective responses, all participants in the acute experiments easily

differentiated active preparations from placebo.

Psychological tests were adversely affected by THC and in a way

similar to that observed in naive subjects or short term users (21,

84, 100). The adverse effects on mental functioning were shortlived and died away 70 minutes after the cannabis inhalation.

The EEG recorded at fixed time intervals before and after

smoking and analysed quantitatively by hierarchical multiple

regression analysis was affected by all active but not by placebo

preparations. An increase in alpha activity, a decrease in alpha mean

frequency, and a decrease in fast beta activity was observed (21, 23,

84). The degree and the duration of cannabis effects on the EEG

parallelled the THC- -9 potency and were inversely related to the

cannabidiol (CBD) content of the smoked preparations. These

results are not essentially different from those obtained from naive

or occasional users (20,84) and they may indicate a sedative central

action of cannabis in both long term and short term users.

Visual evoked responses (VER) were only slightly changed by

cannabis inhalation. The change was confined to an increase in the

amplitude of the late VER component. Similar findings were

obtained in less experienced users by Tinklenberg, et al. (95) and

Tassinari et al. (94) and tend to support evidence from animal

experiments indicating cerebral association areas and their related

subcortical structures as the principal sites of THC- -9 action (9,

18). Since the increased late negative VER component has been

related to excitatory postsynaptic potentials, a stimulant action of

THC- -9 on cortical association areas may be postulated.

Of all the psychophysiological parameters, pulse rate of our

chronic users was found to be most closely and consistently

affected by acute cannabis inhalation (55, 84). As shown in figure

1, pulse rate significantly increased following administration of all

four active preparations at all time periods tested. Although a

dose-response relationship seems to exist, it is to be noted that

hashish inhalation produced pulse rate changes less pronounced

than expected on the basis of the preparation’s potency in THC- -9

content. Similar dissociation between potency and response was

found in the EEG and may be attributed to an antagonistic

interference of CBD to the THC- -9 effect as already suggested by

Karniol et al. (44). In addition to pulse rate, other psychophysiological parameters were affected. Finger Plethysmography showed a

decrease of blood flow 20-30 minutes after smoking, pupil size

measurements showed slight pupil dilation lasting up to 70 minutes

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STEFANIS: BIOLOGICAL ASPECTS OF CANNABIS USE

FIGURE 1

EFFECTS OF CANNABIS ON HEART RATE [N=20]

(FROM LIAKOS ET AL: 1976)

after smoking, and “basal” skin conductance measurements showed

a significant decrease after smoking (55, 84).

In summarising our results from the acute experiments we may

conclude that acute cannabis inhalation by chronic users, despite

their tolerance to high doses of the active material, evokes responses

which are not essentially different from those evoked by low doses

in casual smokers. The kind of responses indicate that in man both

a sympathetic arousal (manifested by changes in pulse rate, pupil

size and FPV) and a sedative effect (manifested by the reported

feelings of relaxation and changes in EEG and conductance) are

associated with the cannabis pharmacological action.

Withdrawal Studies

Although old reports in the literature indicated that tolerance

and physical dependence may develop in man following prolonged

cannabis use (102), most researchers until recently held the view,

explicitly voiced by the National Commission on Marihuana and

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Drug Abuse (67), that cannabis does not lead to physical

dependence. The issue resurged and is still in the center of current

cannabis research following publications documenting cannabis

dependence in animals (45) and either supporting (4, 42, 43) or

refuting (2, 24, 63, 72) such a dependence in man. In our study, 16

chronic hashish smokers from the original pool of experimental

subjects were used. They all volunteered to be hospitalized for six

consecutive days during which half of them smoked U.S. marihuana

ad lib twice a day during the first three days and were subsequently

switched to placebo for the following three days (order I) while the

other half followed the reverse order (order II), i.e., they smoked

placebo during the first three-day period and active substance

during the second three-day period. During the experiment subjects

were assessed on a double blind basis and at fixed post-smoking

periods by a variety of clinical, psychological, psychophysiological

and behavioural measures (84, 9 1).

Psychological testing provided no evidence for tolerance or

withdrawal (84). What could only be inferred from these studies

was that practice effect in the tests, although not abolished by the

consumption of marihuana, is lower than that observed under

placebo conditions.

Medical laboratory and behavioural assessments all failed to

provide definite evidence in support of an abstinence syndrome

(84). Subjects were scored higher in their adjustment in the ward

while smoking marihuana irrespective of the order of smoking.

Those who started with the sequence placebo-marihuana were more

irritable and less cooperative while on placebo than those who

started with the reverse order. It is to be noted that despite the lack

of objectively assessed differences between marihuana and placebo

periods, the “blind” personnel in the ward could easily tell which of

the subjects was on or off marihuana.

In most of the psychophysiological measurements including

quantitative EEG analysis, only small and insignificant differences

were found between drug and placebo periods (84, 91). Differences

were only found in temperature, blood pressure, and finger

plethysmography. Since these differences were observed two hours

after smoking and they were not seen immediately after smoking,

they may suggest a mild abstinence syndrome.

A rather interesting finding derived from measuring the ad

libitum amounts of marihuana consumed by the subjects. As shown

in figure 2, they smoked more marihuana cigarettes in order I

(placebo-marihuana) than in order II (marihuana-placebo), and in

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STEFANIS: BIOLOGICAL ASPECTS OF CANNABIS USE

FIGURE 2

each case they smoked more on the first smoking each day than on

the second. They also smoked increasingly smaller amounts of

marihuana in the three-day sequence of the drug period (84, 91)

whether this preceded or followed the placebo period. This might

indicate development of a “reverse tolerance” with regard to the

subjective effects of cannabis. The opposite was noted by Mendelson et al. (63) in their study in which experimental subjects were

less experienced, however, and less heavy users. Moreover their

experimental design was different from ours.

The observation that our subjects smoked more marihuana

cigarettes the first day of testing when the marihuana smoking

period followed the placebo period calls for some further comment.

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It has been reported (53) that the half life of THC- -9 is 28 hours in

the blood of chronic users and 57 hours in the blood of nonusers

and that the metabolism of THC- -9 is increased with repeated

administration. The increased consumption of marihuana following

the placebo period could thus be interpreted as representing the

need of the organism to replenish the tissue with the active material

that was depleted during the 3-day abstinence period. The

alternative, but not basically different, explanation would be that as

with other addictive substances, materials ordinarily blocked by

THC- -9 accumulate in its absence and by producing withdrawal

dysphoria motivate the user to rapidly replenish the tissue losses

and reconstitute the cellular homeostasis (84).

In closing this review of our withdrawal study we may conclude

that under the described experimental conditions no clear-cut

evidence of an abstinence syndrome has been obtained. However, in

view of the described suggestive findings the possibility of such a

syndrome cannot be excluded, particularly in areas not explored or

inadequately explored in our study. Withdrawal symptoms recently

obtained by Jones et al. (43) under conditions of long and

continuous cannabis ingestion suggest, as already proposed by

Wikler (101), that more rigorous criteria are needed in future

research, to define withdrawal states.

SECOND PART OF THE STUDY

Histochemical and Electron-Microscopic Investigation of

Blood Cells and Sperm

This study was instigated by our findings in the past few years

indicating an interaction of psychoactive drugs with metabolic

processes in the cell nucleus affecting its synthetic capacity. 1Such

a study is further justified by recent reports in the literature (37,

40, 65, 83) indicating that cannabis, and THC- -9 in particular,

interferes with cellular metabolism in animals and affects ribonucleic acid (RNA) and protein synthesis. Such effects are both

interesting and alarming since they may not only provide useful

information regarding the drug’s mode of action but they may also

be potentially harmful to physical and/or mental health. A rigorous

1

For review see “Short and long term effects of neuroleptics in relation to

their cellular mechanism of action,” C.N. Stefanis and M.S. Issidorides, in

Perspectives in Psychopharmacology, ed., F. Vartanian. Pergamon Press, 1977.

In press.

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STEFANIS: BIOLOGICAL ASPECTS OF CANNABIS USE

scrutiny of THC interaction with human cell systems under in vivo

conditions is therefore badly needed.

In our investigation easily accessible tissues were studied, i.e.,

blood cells and sperm. The subjects who were used in these

experiments (34 cannabis users and 18 nonusers) were recruited

from the same groups that were previously used for the first part of

our study.

Nuclear Morphology

Using the routine May-Grünwald-Giemsa staining method, smears

were made from peripheral capillary blood for the study of nuclear

morphology of neutrophils. It was found that 21 out of 34 chronic

hashish users (i.e., 61 percent) displayed in their neutrophils

drumstick-like appendages similar to those normally found only in

females and in about 1-7 percent of their granulocyte population

(5). In males they are rarely encountered (in only about 1 out of

500 males and in less than 1 percent of their neutrophil

population). It is to be noted that in about one fifth of the users

with “drumsticks” in their neutrophils sessile nodules were also

observed. These findings clearly indicate that chromatin is altered

under the effect of prolonged cannabis use.

Histochemistry of the Nucleus

Subsequent to the above morphological findings indicating an

interaction of cannabis with chromatin, an histochemical investigation was carried out mainly directed to chromosomal proteins.

Basic proteins mainly consist of histones (arginine and lysine-rich)

which are known to maintain chromatin structure and repress gene

expression (81). Non-histone acidic proteins, on the other hand, are

involved in selective template activity, acting mainly as activators

but in certain conditions as repressors of chromatin transcription

(99).

Histochemistry of Basic and Acidic Nuclear Proteins

By using the PTAH anionic metachromatic stain (see 85), the

basic proteins of leucocytes of 34 users and 18 control subjects

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were studied. It was found that all cells of all control subjects

displayed the expected metachromatic reaction indicative of a high

concentration of basic groups. Conversely in all cells of all users the

reagent failed to bind to the nuclei, indicating that binding sites are

not available. This may not necessarily signify absence of basic

proteins but their binding to DNA phosphates.

By using the carbocyanin cationic reagent (28) which stains

selectively nuclear acidic phosphoproteins it was found that while

the leucocyte nuclei in the control group did not show the dark

blue staining indicative of phosphoproteins the leucocyte nuclei in

the user group reacted intensely to the stain. This finding, in

addition to providing evidence of high concentration of acidic

proteins in the cell nuclei of the users, may partly explain the

nonbinding of the anionic PTAH reagent to some of the histones

since their reactive (positive) groups could be neutralized by the

phosphoproteins (103).

Electron Microscopy

In view of the histochemical findings an electron microscopic

(EM) study was carried out by using the EM adaptation (58) of the

Black and Ansley ammoniacal silver reaction technique for histones

(6). With this technique the integrity of the deoxyribonucleoprotein (DNP) complex is preserved and a parallel light microscope

(LM) study of the thick Epon section of the leucocyte pellet is

feasible. In the latter case arginine-rich histones appear in the LM

brownish black and the lysine-rich histones yellow. Blood cells and

spermatozoa were studied.

Blood Cell Studies

In the LM study of the thick sections of leucocyte pellets the

following observations were made. In the group of controls the

nuclei of about 55 percent of small lymphocytes were stained

black, while the rest of lymphocytes were stained brownish. The

remaining population of leucocytes (neutrophils and monocytes)

were stained yellow. In the group of chronic users the pattern of

histone reactivity differed from that of controls in all subjects and

in all cells except for the monocytes. The nuclei of 57 percent of

the lymphocytes appeared orange-brown with large black masses

while the nuclei of the remaining lymphocytes appeared yellow.

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STEFANIS: BIOLOGICAL ASPECTS OF CANNABIS USE

These results indicate a lower concentration of arginine-rich

histones in the lymphocytes of users. By contrast to lymphocytes

the nuclei of neutrophils in the same group of users appeared

brown, an indication of arginine-rich histone preponderance. We

would thus summarize these results by saying that cannabis affects

the nucleohistones differentially so that arginine-rich histones

decrease in lymphocytes and increase in neutrophils.

This differential effect is more clearly shown in studying in the

EM thin sections of the same blocks used for the LM study. The

ammoniacal silver reaction method (58), which was used for the EM

study is based on the specific interaction of silver with reactive

centers in the arginine content and it can thus be used for revealing

selectively arginine-rich histones (H3 and H4) and protamines.

In our study a consistently more intense reaction was found in

neutrophil nuclei of users compared to controls. This is illustrated

in figure 3. Conversely, a distinctly weaker reaction was noted in

the heterochromatin of roughly half of the lymphocytes of the

chronic users.

FIGURE 3

Electron micrographs of neutrophil nuclei from control subject (a) and user

(b). Ammoniacal silver reaction (From Stefanis and Issidorides 1976)

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

Sperm Studies

The cannabis effect on arginine-rich proteins was more strikingly

shown on spermatozoa. During maturation of the sperm in the

testis spermatozoa become increasingly elongated in shape (56) and

replace their somatic histones with arginine-rich protamines (26). It

is their content in this protein that renders the spermatozoa heads a

very useful cell system to study drug effects on arginine-rich

nucleoproteins. The results we obtained by using four controls and

four cannabis users have shown that the spermatozoan nuclei of all

four users although not different in shape compared to controls give

a spotty reaction to arginine, i.e., they have an appearance

indicating that replacement of somatic histones by protamines has

been impaired. This is illustrated in figure 4, which shows that

spermatozoa from controls give a dense black reaction on the entire

nuclear area, indicative of high arginine content, while spermatozoa

from users give a spotty punctate reaction with particulate

precipitates and unreactive areas in between (85).

Membrane Histochemistry

The lipophylic properties of THC are well established in animal

work (25). It is generally agreed that the affinity of THC molecules

for membrane lipids is an important factor accounting for its

biological action (7). In order to study the effect of cannabis on

membrane lipids in human users we applied the LFB-PAS technique

(47) after which phospholipids stain blue and glycolipids stain red.

Thirty-four users and 18 controls were investigated. The results

have shown that the two groups differ substantially in that the ratio

of phospholipids to glycolipids is altered in the neutrophils of users.

This change in ratio was found to be due to a loss of phospholipids

from the membrane of the cortical cytoplasm and an increase in

glycolipids in the cytoplasm. Such an action of cannabis on the

membrane structural constituents is to be considered in evaluating

its clinical effects.

In summary, results obtained from the morphological histochemical investigation of blood cells and sperm clearly demonstrate

that cannabis use in man leads to changes in nuclear metabolism,

indicative of an alteration in the state of chromatin. In our previous

publication (85) several suggestions were made regarding the

mechanism by which these changes are brought about. The

assumption of a direct inhibitory action of cannabis on the

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STEFANIS: BIOLOGICAL ASPECTS OF CANNABIS USE

FIGURE 4

Electron micrographs of spermatozoa from control subject (a) and two users (b

and c). Ammoniacal silver reaction (From Stefanis and Issidorides 1976)

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template either by interrelating with nucleic acids or by affecting

nucleohistone metabolism would be consistent with observations of

other investigators on tissue cultures that cannabis inhibits RNA

and protein synthesis (37, 40, 65, 83). However, the alternative

interpretation of an indirect action of cannabis on nuclear

metabolism by affecting hormonal levels has also to be considered

in view of the fact that hormones are known to be required for

inducing changes leading to maturation and differentiation of a

variety of all systems. Characteristically testosterone is required for

protamine synthesis during sperm maturation (82), a fact calling for

particular attention in view of the current controversy on the effect

of cannabis long-term use on gonadal function and testosterone

plasma levels (13, 31, 51, 61, 75). Our findings on membrane lipid

composition changes in chronic users may also raise the possibility

that the observed nuclear changes may be indirectly triggered by a

primary cannabis effect on the cell membrane.

What seems to be of significance is that regardless of the

mechanism of cannabis action in the nucleus, the necessary

cell-drug interaction to bring about the observed changes has to

take place at the level of the tissue of origin of the affected cells

and while they are still at their early stage of differentiation.

In fact the nuclear appendages observed in the neutrophils of

users can only be formed in the bone marrow since they are

associated with the reconstitution of the chromatin immediately

after mitotic division (5). Similarly, decrease in the arginine-rich

protamine in the sperm of users can only be explained by a drug

action during the spermatid stage, when replacement of somatic

histones by protamines is taking place. Finally, the observed

differential effect of cannabis on the arginine content of the blood

cells’ nuclei (increase in neutrophils and decrease in roughly half of

the lymphocytes) speaks for drug effect during haemopoiesis in the

bone marrow.

We may now discuss our histochemical findings with regard to

their functional significance and to the individual’s physical health.

The appendages in males are usually associated with pathological

conditions (5) but their presence may not be accompanied by any

known abnormality (77). This is also true for the acidic phosphoproteins. They are found increased in neoplastic and regenerative

conditions (80), but they may merely indicate induction of the

chromatin to altered template activity (98).

The fact that in our cases the increase of phosphoproteins

paralleled a decreased reactivity of basic groups signifying a

condensation of the nucleus may indicate that phosphoproteins are

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STEFANIS: BIOLOGICAL ASPECTS OF CANNABIS USE

increased in order to compensate for a primary repressing effect of

cannabis on the template. If so, this would be consistent with the

finding that -9-THC added in tissue culture results in condensation

of the nucleus (37, 38); it would further imply that prolonged

cannabis use may result in the development of compensatory

mechanisms to counteract functional repercussions arising from a

primary repressing effect on nucleohistones or from any other drug

effect deranging cellular homeostatic state. This would be consistent with our essentially negative results from the clinical and

diagnostically orientated laboratory investigation of our group of

users. In fact, despite the histochemical findings in their blood cells

no overt hematological abnormality was detected. Similarly, despite

the low protamine content the sperm head’s species specific shape

was not affected signifying normal condensation and unimpaired

reproductive capacity (57).

Lack of positive clinical findings should not, though, mislead us

to disregard the potential functional significance of changes in such

cell constituents as nucleohistones which are mainly responsible for

regulating gene expression and template activity (41). Compensatory mechanisms may develop in some cell systems and not in

others, and even when such compensatory mechanisms are established they may still steal away part of the organism’s initial

functional capacity, rendering it more liable to internal and external

stressors.

Biochemical Investigation of Cannabis Acute Effects on Chronic

Users and Controls

It is known that drugs causing euphoria and stimulatory effects

in man (opiates, amphetamine, ethanol) do affect central catecholaminergic, serotonergic and acetylcholinergic synaptic transmission

by a variety of mechanisms. It would thus be expected that

cannabis and Delta-9-tetrahydrocannabinol (THC) in particular

would affect central biogenic amine activity. Several studies in this

area conducted mainly in animals yielded results which are far from

clarifying the mode of THC action that brings about the wellknown central and peripheral effects. Ho et al. (32) reported a

biphasic effect of THC on biogenic amines: low doses caused an

increase in noradrenaline (NA) with a concomitant decrease in

serotonin (5-HT), while high doses caused the reverse effect.

Schildkraut and Efron found that THC decreased the retention

of 3H-THC injected intracisternally and increased the O-methylated

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and deaminated metabolites of NA (76), while others found an

attenuation of the disappearance of radioactive NA from rat brain

(97), i.e., a slowdown of the turnover of the injected amine.

Presynaptically, THC was found to inhibit the depletion of 5-HT by

reserpine while the NA depletion was not affected (22). In

synaptosomal studies, THC was shown to inhibit the uptake of

5-HT (78). Another group has reported an inhibition of the

dopamine uptake and a small release of dopamine by THC (36). By

fluorescence methods it was shown in rats that administration of

cannabis sublimate increases the NA content of the terminal axonal

varicosities of the hypothalamus (16). In its presynaptic actions,

THC given chronically caused an induction in tyrosine hydroxylase,

while tryptophan hydroxylase remained unaffected (33). Daily

injections of 20 mg/kg THC in rats, a rather high dose, after seven

days caused a decrease in serum dopamine-ß-hydroxylase (DBH),

while in rats subjected daily to immobilization stress, THC

potentiated the stress-induced increase in the enzyme activity (69).

The effect of THC on brain acetylcholine appears only at high

doses. The drug causes an elevation of ACH content and a reduction

of its utilization (19). In this sense, THC acts like a sedative.

It has been proposed that THC acts by changing the balance at

the antagonistic dopaminergic-acetytcholinergic system in the striatum by reducing dopamine transmission (27), although the effects

of the drug on dopaminergic system are not established. It could be

expected that THC generally acts on the mechanisms of amine

depletion, releasing them from their storage. This has been shown

for 5-HT (34): THC causes a shift of 5-HT from the particulate

fraction to the supernatant, that is from the bound to the free

form. If THC releases 5-HT and at the same time has a slowdown

effect on the turnover of NA (32), then, depending on the predrug

state, the balance between NA and 5-HT could be affected and the

overall action of the drug could be either depressant or antidepressant.

Yet, all the above findings from animal experiments, however

informative they may be, cannot be extrapolated and used to

explain the experimental responses of man to cannabis. Since

studies on the effects of cannabis smoking on biogenic amine

metabolism in man are scarce (35) and fragmentary, our group has

recently attempted to systematically investigate biogenic amines in

chronic users and to correlate their changes with changes in a

variety of other clinical, behavioral and biological parameters. Work

in this area is still in progress, and only preliminary findings

168
STEFANIS: BIOLOGICAL ASPECTS OF CANNABIS USE

obtained by dopamine-b-hydroxylase (DbH) and cyclic AMP

determinations will be presented.

Serum DbH Studies

Dopamine-b-hydroxylase is an enzyme that is localized in

noradrenergic neurons and is responsible for the final step in NA

biosynthesis by converting dopamine to norepinephrine (1). It is

thus a logical target of cannabis investigation, since it may serve as

an index of the drug’s effect on the sympathetic system and its

activity can be linked to noradrenergic activation of reward centers

in the lateral hypothalamus.

Serum DbH activity was determined at fixed time intervals

before and after cannabis smoking in 11 chronic users and 5 naive

subjects. In their single smoking experiment users consumed an

amount, of cannabis oil equivalent to approximately 120 mg

THC- -9 while naives consumed less than l/5 of the same material.

The results obtained by this preliminary study are shown in figure

5. Despite the small number of subjects and the wide dispersion of

individual values, a progressive decrease of DbH activity is clear in

both groups after smoking. In the group of users the decrease has

reached levels of statistical significance at the 60 and 120 minutes

post-smoking testing intervals. These results indicate that THC

exerts a stress-relieving sedative effect on the sympathetic system

which is contrasted with its immediate stimulant effect on pulse

rate (55, 84). Similar effects on DbH have been observed with

antipsychotic drugs (59) and are consistent with experimental

findings (32) indicating that by slowing down the exocytosis

process THC slows the turnover of NA and increases slightly its

concentration in brain tissue.

Plasma Nucleotides Studies

Closely related to biogenic amine investigation and to our

histochemical findings on nucleoproteins (85) is our study on the

cannabis effect on the cyclic adenosine 3’, 5’-monophosphate

(CAMP) levels in the plasma of chronic users. It is known that levels

of CAMP are affected by catecholamines such as NA and dopamine

as well as by 5-HT, Ach and prostaglandins. It is also known that

dibutyryl CAMP increases the levels of a variety of enzymes

including those which are involved in metabolic pathways of

169
INTERNATIONAL CHALLENGE OF DRUG ABUSE

FIGURE 5

neurotransmitter synthesis (46). Moreover, cAMP levels in animal

brain homogenates were found to be affected by psychotropic

drugs which interfere with either adenylate cyclase or phosphodiasterase activity (29, 39, 49, 54, 70). In man, urine (68) and plasma

(93) cAMP levels were found to vary with mood states in affective

disorders (68). Plasma cAMP levels were also found to be decreased

following treatment with antipsychotic drugs (92).

With respect to cannabis effects in nucleotides, information

derives so far only from animal and tissue culture experiments.

Golby and Kleinsmith (see 34) studied the effect of THC on brain

levels of CAMP in mice. They found that THC- -9 in low doses

caused a significant increase whereas high doses caused a definite

decrease of cAMP concentrations. This diphasic effect was correlated with changes in biogenic amine concentrations. Askew and Ho

(see 34) failed to reveal a significant effect of THC- -9 on brain

nucleotide levels in the rat. A definite elevation of cAMP was only

found by these authors in response to THC- -8 administration.

Huot (37) in neuroblastoma cultures has noticed a significant

increase in cAMP due to stimulation of adenylate cyclase. This

170
STEFANIS: BIOLOGICAL ASPECTS OF CANNABIS USE

increase paralleled an inhibitory effect on ATPase activity. It was

postulated that a THC stimulating action on adenylate cyclase

activity may be involved in the cannabis psychodysleptic effects in

man.

By using the protein-binding assay method of Tovey et al. (96),

cAMP levels were investigated in the same material (11 chronic uses

and 5 naives) and under the same experimental conditions as for the

DbH study. The results which were obtained by this preliminary

investigation have shown that there is a slight and slowly progressive

rise of cAMP levels following hashish smoking by subjects of both

groups (users and nonusers). This rise in the group of users reached

statistical significance at the 30 minute post-smoking interval. The

results indicate that the effect of cannabis on cAMP plasma levels

simulate the effects that were observed in depressed patients treated

with tricyclic compounds (93). Whether this effect may be due to

phosphodiesterase inhibition or to adenylate cyclase stimulation is a

question that needs to be further investigated in conjunction with

determinations of biogenic amine conditions in body fluids.

SUMMARY

In this paper the results of a multidisciplinary long term and

controlled study on chronic cannabis use are critically reviewed.

The first part of the study consisted of: (a) standardization of

methods and identification of the experimental sample of chronic

cannabis users and matched controls; (b) comparison of the two

groups on a number of variables following administration of a

battery of medical, psychiatric, neurophysiologic, and psychologic

tests; (c) acute cannabis inhalation experiments during which the

effect of cannabis preparations of various strengths and of

THC-delta-9 were studied in relation to behavioral, psychologic,

neurophysiologic, and psychophysiologic responses; (d) identification of possible withdrawal symptoms during a 3-day abstinence

period and reintroduction of hashish use.

The second part of the study consisted of: (a) a controlled

histochemical and electron-microscopic investigation of blood cells

and sperm, aimed at revealing changes produced by cannabis at the

molecular level, particularly in the cell-nuclear area; (b) a biochemical investigation of changes in biogenic amines and substances

related to their metabolism and function during cannabis presmoking and postsmoking periods.

171
INTERNATIONAL CHALLENGE OF DRUG ABUSE

Our findings from the first part of the study failed to distinguish

users from nonusers on most of the investigated parameters.

However, they provided useful information on a variety of

controversial issues and revealed methodological limitations which

should guide future research. Our findings from the second part of

the study, although still preliminary, clearly indicate that

cannabis use affects cell-nuclear metabolism and produces changes

on the molecular level potentially significant for man’s biologic

functioning. Furthermore findings from this part of this study

indicated that cannabis’ acute effects in man are correlated with

changes in metabolism directly related to biogenic amine biosynthesis and function. It is concluded that despite advances in recent

years cannabis research has still a long way to go before providing

the definitive answers to the very important questions arising from

its habitual use by man.

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ACKNOWLEDGMENTS

The first part of this study was supported by NIH (Contract HSM-42-70-98)

through the International Association for Psychiatric Research. The second

part of the study was partly supported by the Hellenic Research Foundation

and the Embirikion Institute. Drs. M. Issidoridis, M. Markianos and E.

Lykouras are principally involved in this part of the study.

178
CHAPTER 14

Drug Dependence Studies in

Laboratory Animals

Tomoji Yanagita, M.D.

Drug dependence studies in laboratory animals are usually

conducted for such purposes as: (1) analysis of dependence-producing properties of a drug (dependence potential); (2) evaluation of

the possibility that a drug is likely to be abused by man (abuse

liability); (3) prediction of the possible harm that might be

produced by abuse of a drug; and (4) studies on dependence-producing mechanisms. In this paper the progress related to all of the

above problems with the exception of the last will be discussed.

DEPENDENCE-PRODUCING PROPERTIES

The dependence-producing properties of a drug can be divided

into psychological and physical aspects.

Psychological Dependence

In laboratory animals the psychological dependence-producing

property of a drug can be studied by observing their drug-seeking

and drug-taking behaviors when the drug is made available to them

(1, 11, 14). Behaviorally this effect of a drug will be called its

reinforcing effect (8). Most of the principal drugs of abuse in man,

except hallucinogens, were found to possess this reinforcing effect

in animals as studied by self-administration techniques (1, 8, 18).

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

Table 1 summarizes the results obtained by continuous selfadministration experiments with various types of drug in rhesus

monkeys. The monkeys were allowed to self-administer drugs by

pressing a lever switch around the clock for several weeks without

time or dose limitations. The animals self-administered these drugs

at high daily dose levels and manifested overt signs of drug effects

(1, 15, 16, 18). With such drugs as morphine, codeine, demerol,

pentazocine, pentobarbital, and alcohol, a gradual increase in

self-administration was observed in the first 4-5 weeks. Thereafter,

for most animals the daily doses reached a plateau. The gradual

increase appears to reflect tolerance development, since the severity

of the drug effects remained constant or even diminished in spite of

the dose increase. The drugs of this group are also known on the

basis of other evidence to be tolerance-producing. By contrast, lack

of increase in the self-administration of nicotine or benzodiazepines

may be attributable to rapid or weak tolerance development.

The daily intake pattern was erratic in self-administration of

some stimulants and volatile anesthetics (16). The reinforcing effect

could not be observed in the self-administration of LSD-25,

mescaline, STP, nor with nalorphine. While many studies of THC

were not successful in demonstrating its reinforcing effect, one

study found evidence of self-administration of THC in rhesus

monkeys following its substitution for cocaine (7). Reinforcing

effects can also be demonstrated by short term cross selfadministration experiments using a prototype reinforcing drug and

saline as reference agents (4, 13, 18).

In animals the evidence of a definite reinforcing effect and the

overt signs of drug effects at self-medicated dose levels are similar to

those known in man. Thus it can be said that psychological

dependence on certain types of drugs has been experimentally

reproduced in animals.

Physical Dependence

Physical dependence-producing properties of a drug can be

studied in laboratory animals by withdrawing the drug after

repeated administration for a fixed period. The major withdrawal

signs observable in morphine dependent monkeys are hyperirritability and aversive autonomic manifestations (table 2) (9). On

the other hand the withdrawal signs observable in barbital or

alcohol dependent monkeys are hyper-irritability, convulsive disorders, and occasional delirium-like behavior (table 3) (17).

180
YANAGITA: DEPENDENCE STUDIES IN LABORATORY ANIMALS

TABLE 1

Continuous self-administration in Rhesus monkeys (iv)

Self-administration positive

Stable daily intake Erratic

Gradual Frequent

increase No increase intake Infrequent Negative

Morphine

Meperidine

Codeine

Pentazocine

Pentobarbital a)

Alcohola)

Nicotine

Diazepam

Chlordiazepoxidea)

Cocaine

Amphetamines

Volatile

anesthetics b)

Caffeine LSD-25

Mescaline

STP(DOM)

THC?

Nalorphine

Saline

a) Both intravenous and intragastric

b) Inhalation

In the development of physical dependence on these drugs, dose

regimen is a crucial determinant. If the route of administration, the

size of each dose, and the time interval from one dose to the next

are sufficient to produce strong and continuous drug effects in the

animals, physical dependence can be developed in as short a period

as 2 weeks or even less. This has been confirmed in rhesus monkeys

with morphine, pentobarbital, or alcohol (17, 18). Some investigators have observed a rapid development of physical dependence on

morphine or alcohol within 24 hours in small animals by using a

continuous infusion or vapour exposure technique (2, 12). The

lower the dose level or the longer the dosing time interval is, the

slower the development of physical dependence.

Cross physical dependence as well as cross tolerance is a well

known phenomenon among certain drugs. These fall into two major

groups: a morphine group which includes natural, half-synthetic,

and synthetic narcotic analgesics (table 4) and a barbiturates group

which includes many sedative-hypnotics and alcohol (table 5) (19).

Within each group each drug mutually supports physical dependence on other drugs of the same group. Experimentally, cross

physical dependence can be demonstrated by substituting one drug

for a preexisting drug on which physical dependence has previously

been developed and maintained.

Some drugs which produce physical dependence by repeated

administration and are antagonized by naloxone, may, however, not

181
Grade Withdrawal signs

Mild

Intermediate

INTERNATIONAL CHALLENGE OF DRUG ABUSE

TABLE 2

Withdrawal signs in morphine dependent Rhesus monkeys

(M. H. Seevers 1936)

Apprehension, Continual yawning.

Rhinorrhea, Lacrimation,

Hiccup, Shivering, Perspiration on face,

Chattering, Quarrelling and fighting

Intention tremor. Anorexia,

Pilomotor activity,

Muscle twitchings and rigidity,

Holding the abdomen

Severe Extreme restlessness,

Assumption of peculiar attitudes.

Vomiting, Severe diarrhea,

Erection and continued masturbation,

Inflammation of the eyelids and conjunctiva,

Continual calling and crying,

Lying on the side with eyes closed.

Marked spasticity

Very severe Docility in the normal excitable animal,

Dyspnea, Pallor. Strabismus,

Dehydration, Weight loss,

Prostration, Circulatory collapse,

Death

TABLE 3

Withdrawal signs in barbital dependent Rhesus monkeys

(Yanagita and Takahashi 1970)

Grade

Mild

Withdrawal signs

Apprehension

Hyperirritability

Mild tremor

Anorexia

Piloerection

Intermediate Aggravated tremor

Muscle rigidity

Impaired motor activities

Retching or vomiting

Weight loss (10%)

Severe Convulsions

Delirium (Hallucinatory behavior, Nystagmus, Dissociation

from environment)

Hyperthermia (>1.5°C)

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TABLE 4
INTERNATIONAL CHALLENGE OF DRUG ABUSE

TABLE 5

Physical dependence potential of several sedative-hypnotics tested in

Rhesus monkeys (Yanagita 1973b)

Cross physical dependence*

Drugs

Suppression

of barbital

withdrawal

Physical depenComplete dence producing

suppression property

(mg/kg)

Barbital

Pentobarbital

Alcohol

Chloroform

Meprobamate

Diazepam

Chlordiazepoxide

Oxazolam

Chlorpromazine

Perlapine

+

+

+

+

+

+

+

+

+

+

75 po

>25 iv

4,000 po

>200 po

5 po

20 po

20 po —

—

+ +

++

++

untested

++

++

++

+—

—

* = Tested in monkeys dependent on barbital and withdrawn (75mg/kg x 2 per day po)

support morphine dependence because of their antagonistic properties. These drugs are called “partial antagonists.” Whether these

drugs support physical dependence on morphine or precipitate

withdrawal signs depends on the balance between the loss of the

agonistic effect of morphine and the gain of the agonistic effect of

the partial antagonist. In man and animals it has been demonstrated

that pentazocine will support physical dependence maintained by

low doses of morphine but will not support physical dependence

maintained by high doses of morphine, and it will precipitate

withdrawal (6,18).

EVALUATION OF THE ABUSE LIABILITY

The history of drug abuse demonstrates that not all drugs with

substantial dependence potential are necessarily abused by man.

While some drugs have continuously drawn abusers’ attention,

others have been of only transient interest. For example, while the

abuse of opiates and alcohol has been continuous and popular,

abuse of codeine and ether has been limited to either a small

population or to a relatively short period of time in their histories

(3, 5). Marihuana smoking and organic solvent inhalation are also

184
YANAGITA: DEPENDENCE STUDIES IN LABORATORY ANIMALS

worldwide epidemics of relatively recent onset, compared to the

long term availability of these agents. Thus, it is obvious that for

evaluation of the abuse liability of a drug, one has to consider not

only its dependence potential but also individual and social factors

related to susceptibility to the drug. Therefore the prediction of

human abuse potential is a comprehensive evaluation of the

interaction among the drug properties, individual differences, and

the social environment. However, there is no doubt that the

dependence potential of drugs plays an essential role in the onset,

maintenance, or exaggeration of abuse incidences. An important

property of a drug in evaluating its abuse liability is its reinforcing

effect. The mere fact that a drug has been self-administered by

animals, however, may not be sufficient evidence to predict a high

abuse liability for the drug. For prediction of high abuse liability, it

is necessary to demonstrate a potent reinforcing effect comparable

to those of the principal drugs of abuse.

Table 6 is the result of a progressive ratio test conducted by

intravenous self-administration of morphine, pentazocine, and

alcohol in rhesus monkeys for determination of the reinforcing

potencies of these agents. In this experiment the ratio of lever

presses versus drug injection progressively doubled after every 4

doses beginning from 100:1, and a breaking point at which

monkeys extinguished the drug-seeking behavior was observed. As a

result, substantial potencies of reinforcing effect have been demonstrated with these agents. If the reinforcing potency of a drug is

found to be equal to or even higher than those of other abused

agents, there is good reason to believe that the abuse liability of the

drug may be noteworthy.

Contrary to the long-held view, however, physical dependence

has only limited significance for the evaluation of abuse liability; it

is significant only when the withdrawal manifestation is very

aversive, since the drug-seeking behavior is then likely to be

intensified in an attempt to avoid the aversion. Under these

conditions, physical dependence becomes very important. In fact;

this appears true with many morphine-like drugs. Experimentally

this intensification has been demonstrated in the above mentioned

progressive ratio test (table 6). In the table, ratios of 3 subjects at

the breaking point for morphine were much higher when physical

dependence on the drug had already been developed prior to the

test (pretreated) than when had it had not (untreated). On the

other hand, this intensification was less marked with alcohol and

was not observed with pentazocine. It may be fair to say that the

185
TABLE 6
YANAGITA: DEPENDENCE STUDIES IN LABORATORY ANIMALS

physical dependence potential of pentazocine or alcohol does not

contribute as much to its abuse liability as does that of morphine.

PREDICTION OF THE POSSIBLE HARM CAUSED BY DRUG

ABUSE

The harm caused by drug abuse is the basic issue from which the

whole problem of drug abuse derived. The possible harm can be

classified roughly into two categories: the harm to the public and

that to individuals. The immediate causes of harm are mainly: (1)

drug-seeking behaviors, (2) drug-taking behaviors, (3) pharmacological effects, (4) physically toxic effects, and (5) withdrawal.

Compulsive drug-seeking behaviors may result in economic and legal

irresponsibility with regard to families and society. Drug-taking

behavior itself may also involve procedures possibly hazardous to

health. Pharmacological effects may result in psychotic and/or

antisocial behaviors in addition to death. The physically toxic

effects imply subacute and chronic toxicity which produces such

morphological and functional disturbances as the liver injury by

barbiturates and alcohol, gonadal atrophy by opium alkaloids, and

respiratory disturbance by glue sniffing. Withdrawal may also be

harmful to both society and the individual since it may involve

delirium and be life-threatening from dehydration or convulsions.

In predicting harm, animal studies can provide information about

the following, which may or may not relate to the dependenceproducing properties of drugs:

(1) Potency of the reinforcing effect of a drug to produce

compulsive drug-seeking behaviors.

(2) Potency of the pharmacological effects of a drug to

produce behavioral disorders on self-medicated dose

regimens.

(3) Potency of the physically toxic effects of a drug to

produce biohazardous changes on self-medicated dose

regimens.

(4) Severity of the withdrawal manifestations in terms of

aversiveness and mortality.

Laboratory procedures to assess the reinforcing potency have

been discussed previously, so will not be repeated here. With regard

to pharmacological effects, the basic information can be obtained

through general pharmacological studies in various animal species.

Crucial information, however, is obtainable only through continuous self-administration experiments as described in the first part of

187
INTERNATIONAL CHALLENGE OF DRUG ABUSE

this paper. These experiments will reveal to what extent the animals

seek a drug and its effects. Thus, it is known that monkeys may

seek and take pentobarbital, alcohol, and volatile anesthetics, up to

the point that they are self-anesthetized. They will take cocaine to

the point of convulsions; amphetamines to extreme excitation, and

morphine to severe depression. Death due to overdoses of cocaine

or morphine and by suffocation when self-anesthetized with

pentobarbital or volatile anesthetics is not uncommon. On the other

hand, animals will never self-administer nicotine or caffeine to the

point at which excitation is demonstrated.

Similarly, the basic information on physical toxicity can be

obtained through subacute or chronic toxicological studies in

various species of animals, but crucial information is dependent on

the continuous self-administration experiment, since toxicity at the

self-determined dose regimen is in question. For example, it has

been known for some time that some monkeys will take high doses

of alcohol daily, become emaciated, eventually develop severe liver

and renal injuries, and finally die several weeks after the initiation

of self-administration (19). In contrast to alcohol, monkeys selfadministering morphine for longer than 6 months at daily doses of

more than 60 mg/kg show no serious organ injury except for

gonadal atrophy. However, some infection and thrombosis attributable to long-term catheterization have been observed (1).

A rough idea of aversiveness and possible life threat of a drug can

be obtained through observing withdrawal. Among analgesics,

withdrawal appears to be most severe with morphine-like drugs, less

severe with some synthetic narcotics, and minimal with pentazocine. Withdrawal symptoms are substantially milder with barbiturates or alcohol than with morphine.

It is, however, known in man that the convulsions developed in

barbiturate withdrawal can be life-threatening, and the risks in

abrupt withdrawal are even higher with this class of drugs than with

opium alkaloids (5). In animals, regardless of species, convulsions

are one of the most characteristic signs observed in barbiturate or

alcohol withdrawal. It has also been found in some monkeys that

while maintaining physical dependence on morphine or demerol by

frequent self-administration of these drugs, an abrupt withdrawal

resulted in death (15). Such severe physical dependence on

narcotics, however, seems to be very rare in man.

188
YANAGITA: DEPENDENCE STUDIES IN LABORATORY ANIMALS

CONCLUSION

In any extrapolation of animal findings to man, it is necessary to

consider the problems of species differences. Major differences exist

in the pharmacodynamic and pharmacokinetic susceptibilities

among the various species of animals and man. Clinical pharmacological considerations such as the drug’s bioavailability (e.g.,

differences in the preparation forms) and the conditions under

which drugs are delivered to subjects are also important. Careful

consideration of al! these biological and situational differences

between the animals in laboratories and man in society makes

animal studies a valid approach of practical value for the prediction

of abuse liability of drugs and their potential harm.

REFERENCES

1. Deneau, G.; Yanagita, T.; and Seevers, M.H. Self-administration of

psychoactive substances by the monkey — A measure of psychological

dependence. Psychopharmacologia, 16:30-48, 1969.

2. Goldstein, D.B. and Pal, N. Alcohol dependence produced in mice by

inhalation of ethanol. Science, 172:288-290, 1971.

3. Hart, E. An address on ether-drinking; its prevalence and results. Brit Med

J, Oct 18, 1890. pp. 885-890.

4. Hoffmeister, F. and Goldberg, S.R. A comparison of chlorpromazine,

imipramine, morphine and d-amphetamine self-administration in cocainedependent rhesus monkeys. J Pharmacol Exptl Therap, 187:8-14, 1973.

5. Isbell, H. and White, W.M. Clinical characteristics of addictions. Am J

Medicine, 14:558-570, 1953.

6. Jasinski, D.R.; Martin, W.R.; and Hoeldtke, R.D. Effects of short- and

long-term administration of pentazocine in man. Clin Pharmacol Ther,

11(3):385-403, 1969.

7. Kaymakcalan, S. Tolerance to and dependence on cannabis, Bull Narcot,

25(4):39-48, 1973.

8. Schuster, C.R. and Thompson, T. Self-administration of and behavioral

dependence on drugs. Ann Rev Pharmacol. 9:483-502, 1969.

9. Seevers, M.H. Opiate addiction in the monkey. I. Methods of study. J

Pharmacol Exptl Therap, 56:147-156, 1936.

10. Slight, D. Codeine addiction. Canad Med Assoc J, 32:69-71, 1935.

11. Weeks, J.R. Experimental narcotic addiction. Scientific American, Mar.

1964. pp. 2-8.

12. Wld. Hlth. Org. techn. Rep. Ser., No. 577, 1975. “Evaluation of

dependence liability and dependence potential of drugs.”

13. Woods, J.H. and Schuster, C.R. Reinforcement properties of morphine,

cocaine, and SPA as a function of unit dose. Internat J Addict, 3:215-222,

1968.

189
INTERNATIONAL CHALLENGE OF DRUG ABUSE

14. Yanagita, T.; Deneau, G.A.; and Seevers, M.H. Evaluation of pharmacologic

agents in monkey by long term intravenous self or programmed administration. Excerpta Med Int Congr Ser, 87:453-457, 1965.

15. Yanagita, T. Self-administration studies on various dependence-producing

agents in monkeys. U of Mich Med Ctr J, 36(4):216-224, 1970a.

16. Yanagita, T.; Takahashi, S.; Ishida, K.; and Funamoto, H. Voluntary

inhalation of volatile anesthetics and organic solvents by monkeys. Jap J

Clin Pharmacol, 1:13-16, 1970b.

17. Yanagita, T. and Takahashi, S. Development of tolerance to and physical

dependence on barbiturates in rhesus monkeys. J Pharmacol Exptl Therap,

172:163-169, 1970c.

18. Yanagita, T. An experimental framework for evaluation of dependence

liability of various types of drugs in monkeys. Bull Narc, 25(4):57-64,

1973a.

19. Yanagita, T. and Takahashi, S. Dependence liability of several sedativehypnotic agents evaluated in monkeys. J Pharmacol Exptl Therap,

185:307-316, 1973b.

20. Yanagita, T. Some methodological problems in assessing dependenceproducing properties of drugs in animals. Pharnmcol Rev, 27(4):503-509,

1975.

190
III.

Psychobiology of

Drug Abuse and

Affect Disorders

Richard C. Stillman

Chairman
CHAPTER 15

Endorphins, Lithium, and Naloxone:

Their Relationship to Pathological

and Drug-Induced Manic-Euphoric

States

Mark S. Gold, M.D., and Robert Byck, M.D.

Cocaine and amphetamine induced states and naturally occurring

manias appear similar clinically and can be blocked by lithium (32,

69, 83, 98). Although it has become fashionable to think of acute

amphetamine induced states (19, 28) as a model for paranoid

schizophrenia, clinically these states bear a close resemblance to

spontaneously occurring mania (30, 65). Behavioral similarities and

lithium blockade link the drug induced and naturally occurring

euphoric states. Unfortunately, it is difficult to approach the

question of the neurochemical mechanism of euphoria by deductions from lithium’s presumed mode of action. Lithium is known to

influence many physiological systems (17, 20, 24, 35, 50, 60, 69,

86, 88, 89, 90, 99) and while there have been a number of

speculations (38), no specific mechanism has been identified for its

efficacy in treating either acute mania or manic-depressive illness

(86).

Although its mechanism of action remains elusive, lithium is an

effective therapeutic agent in the treatment of the manic phase of

manic-depressive illness and in prophylaxis of both mania and

depression (1, 3, 10, 14, 34, 38). It is an antagonist of the

hyperactivity, catatonia, increased pressure and production of

speech, sleeplessness, grandiosity, and euphoria characteristic of

naturally occurring manic episodes and some drug induced states

(32, 98). Lithium has been reported to ameliorate amphetamine

induced motoric effects in rats (36, 88). Lithium pretreatment has

also been found to reduce the jumping, fighting, stereotypes, and

192
GOLD AND BYCK: ENDORPHINS, LITHIUM, AND NALOXONE

hyperactivity induced by d-amphetamine (9). Lithium antagonizes

the amphetamine induced changes in the serotonergic (62) and

noradrenergic systems (4) in rodent and man, respectively. Supporting the suggestions of these data regarding lithium’s antagonistic

effect in amphetamine induced euphoria and hyperactivity in man

are a case study (32) and double blind placebo controlled study

(98) reporting that lithium attenuates the euphoriant and activating

effects of amphetamine. There then appears to be both research and

clinical data consistent with the notion that lithium attenuates

stimulant-response, euphoria and mania. Lithium also appears to be

effective in the treatment of naturally occurring pathological

euphoric manic states and catatonia associated with mania and

primary affective illness (1, 3, 10, 14, 34, 38). But how?

Mandell and Knapp (69) suggest a serotonergic mechanism for

the blockade of cocaine by lithium as lithium antagonizes behavioral effects of other drugs that, like cocaine, reduce the biosynthesis

of 5-HT in animals. On this basis they suggest a place for lithium in

the treatment of compulsive stimulant users as a subject for further

study. An alternative proposal attributing the blockade of stimulant

drug effects as well as mania to lithium’s cationic activity has been

suggested by Byck (13).

ENDORPHINS

The discovery of the endogenous substances with opioid activity,

the endorphins, in man and other species (45, 53, 66, 79) has

stimulated recent investigations attempting to delineate the role of

these substances in euphoria and human behavior (8, 12, 55, 64, 87,

93). Opiate receptors, through which opiate alkaloids and peptides

exert their pharmacological effects, have receptor density profiles in

brain (66, 77, 91) which make them prime candidate structures for

the mediation of emotionality, drive, motor behavior and pain

perception (45, 64). Since “pure” narcotic antagonists are known

to block and reverse the effects of opiates and displace endorphins

at opiate receptor sites in the brain (45), the administration of the

antagonist naloxone has recently been employed as a strategy for

investigating behavior and mood effects mediated by endorphins (2,

5, 49, 74, 78). The reversal or attenuation of behavior or mood

effects by the opiate antagonist naloxone, therefore, appears to

provide information about the pharmacological substrate of the

behavior or mood effects which can not be derived from data with

193
INTERNATIONAL CHALLENGE OF DRUG ABUSE

lithium pretreatment. Demonstration of an effect for naloxone

alone, as well as reversal and attenuation of opioid agonist effects,

would lend considerable support to the hypothesis that opiate

receptors are involved in a particular phenomenon. Naloxone has

recently been found to attenuate the amphetamine-induced increases in continuous avoidance responding and locomotor activity

in the rat (51) and reverse the effects of both morphine and

d-amphetamine on intracranial self-stimulation in the rat (52).

These data support the hypothesis that at least some of the effects

of stimulant drugs might be mediated by the endorphin system (13,

87).

We report a case of lithium carbonate blockade of cocaine and

amphetamine effects in the same person. This blockade occurred

only at high plasma lithium concentrations. This report adds to the

body of evidence that indicates that stimulant induced euphoria

may be impaired by pretreatment with lithium. This case provides

clinical evidence which lends support to hypotheses regarding the

neurochemical mechanism of drug-induced and naturally occurring

euphorias (13, 70, 57).

CASE REPORT

James, a forty-year-old former heroin addict maintained on

methadone (30 mg/day) for three years in the Yale Substance

Abuse Unit, is the subject of this report. The patient had been

referred repeatedly by the staff of the unit to the psychiatric

consultants for “hyperactivity” and episodes of “suspiciousness

associated with hyperactivity and grandiosity,” as well as for one

episode of depressed mood. It was suggested that the use of

amphetamine or cocaine could be responsible for these abrupt

changes in his behavior. Although he was frequently seen in the

company of known cocaine dealers and users, and fresh antecubital

scars were seen on occasion, he had only two urines positive for

cocaine metabolites during the three year period. No positive

amphetamine urines had been reported.

While James had no psychiatric hospitalizations unrelated to his

heroin addiction, an aunt and cousin were hospitalized for “acute

psycho tic episodes.” There was no personal or family history of

alcohol abuse. His developmental history was unremarkable.

In August of 1976 the patient presented with hyperactivity,

pressure of speech, and flight of ideas. A presumptive diagnosis of

manic-depressive illness was considered and treatment with lithium

194
GOLD AND BYCK: ENDORPHINS, LITHIUM, AND NALOXONE

carbonate was begun. Two months passed without a “hyperactiveeuphoric” episode.

Shortly afterwards the patient complained that he had “a blood

disease.” On further questioning, he gave a detailed history of four

unsuccessful attempts to “get off” on cocaine. He reported, “I’d

wait for a rush and I wouldn’t get a rush at all so I just kept bootin’

but I wouldn’t feel anything.” Four days prior to this presentation,

he stated, “I bought $20 worth of cocaine and didn’t get anything.

I went back and I got another $20 worth . . . he gave me another

spoon for nothing and I did that and I didn’t get anything . . . I

knew I had a hit . . . I got absolutely nothing; the other kids were

all getting speedy . . . getting off . . . they told me there’s something

wrong with you, J . . . I thought it might be because there were

little bubbles in my blood.” He then added that, “about a month

ago I tried to shoot it [cocaine] . . . and got absolutely nothing,”

but that over the “last week I tried to get off three separate times

. . . all I did was blow $150 bucks . , . I usually get off on $10 or at

the most a spoon ($20) [but I] didn’t get all speedy or get a rush

. . . as a matter of fact, the last time I got more depressed.”

The patient’s known lithium levels and account of successful and

abortive attempts to “get off” on intravenous cocaine and

amphetamine are presented in figure 1. The figure shows the weekly

serum lithium levels which resulted from the patient’s intermittent

compliance on a prescribed program of 1800 mg each day. It can be

seen that both cocaine and amphetamine produced euphoria at

lower lithium levels, but no effect was reported at lithium levels

above .6 mEq/1.

The patient was reassured that he did not have a blood disease

and informed that the lithium might be responsible for the change

in his response to cocaine. He was nonetheless encouraged to

continue taking his lithium regularly. He discontinued attempts to

“get off” on cocaine as “it was a waste of money.” Then, after an

unsuccessful attempt to obtain effects from amphetamine, he

stopped taking his lithium. He began taking his lithium regularly

only after his urine was found to be positive for amphetamine since

he wanted to “avoid a speed run” and remain in good standing in

the drug program. He was thus using the lithium as a self treatment

regime to prevent the consequences of his impulsivity.

195
INTERNATIONAL CHALLENGE OF DRUG ABUSE

FIGURE 1

The effect of serum lithium on subjective response to cocaine and amphetamine in P. over

time. Serum lithium levels above 0.6 mEq/1 were necessary to “block” the effects of

intravenous cocaine or amphetamine.

Key

Positive response to cocaine

No response to cocaine

Positive response to amphetamine

No response to amphetamine

RESPONSE TO COCAINE AND AMPHETAMINE IN A PATIENT ON LITHIUM

Discussion of Case Report

This case clearly demonstrates blockade of cocaine and

amphetamine euphoria by lithium carbonate treatment. Retrospcctively, it is probable that this patient did not have endogenous

manic-depressive illness. The patient later reported that the previous

episodes of euphoria and hyperactivity were all associated with

stimulant usage. The pharmacological demonstration of lithium

blockade may be confounded by the concurrent administration of

methadone, but there was no block of stimulant effects by

methadone alone. However, the interaction between chronic opiate

agonist and chronic lithium administration could be responsible for

the reported blockade. As with all street reports of drug usage, the

identity of the specific stimulant used in each instance must remain

in doubt. The patient’s account, confirmed by the positive urines

for benzoylecgonine (97), is assurance that cocaine was used in at

least two instances. The positive responses of his companions

196
GOLD AND BYCK: ENDORPHINS, LITHIUM, AND NALOXONE

suggest that an active compound was used. Double blind studies are

necessary to confirm this case report and determine whether the

euphoric effects of cocaine were truly blocked or modified to the

extent that J. did not experience the desired effects of the drug.

ENDORPHIN-EUPHORIA/MANIA: LITHIUM CONNECTION

The clinical similarity between cocaine and amphetamineinduced and naturally occurring manic states and their blockade by

lithium, link the drug-induced and naturally occurring euphorias.

Unfortunately, because of its actions on many physiological

systems, it is difficult to approach the neurochemical mechanism of

euphoria or pathological euphoric states by deductions from

lithium’s mechanism of action. Byck has proposed a hypothesis

(32) which suggests that endorphins are inextricably involved with

hedonic and anhedonic feelings. He suggested that endorphin

binding is modified in drug-induced and naturally occurring

euphoric states and may explain the action of lithium in preventing

and treating these states.

Opiate agonist and antagonist binding to receptors is markedly

influenced by sodium. Except for lithium, whose hydration radius

is similar to that of sodium, monovalent cations do not change this

affinity (93). Agonists and antagonists compete for the same

receptors, but the affinity of these receptors at the physiological

extracellular sodium concentration is greater for antagonists than

for agonists; increasing the sodium concentration enhances this

difference. While long term changes in sodium balance do not occur

in lithium-treated patients (probably because any alteration in

sodium excretion is rapidly corrected by homeostatic mechanism),

the therapeutic use of lithium may produce a long-term modification of total cationic concentration in various body compartments.

The effect of added lithium would thus be equivalent to increasing

the sodium concentration. If lithium administration produced an

increase in the cationic concentration which acted in a manner

consistent with opiate binding studies, we could expect increased

antagonistic binding and decreased binding of euphorigenic agonist

compounds. By this logic, lithium should be anti-euphorigenic in

endogenous pathological states as well as in exogenous drug-induced

states as a result of modification of peptide receptor systems. The

demonstrated actions of lithium in the treatment of manic states

and naloxone in reversing behavioral effects of both morphine and

d-amphetamine (51, 52) are consistent with this hypothesis. Data

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

using naloxone effects and opioid reversal or attenuation to link

affective and behavioral effects of amphetamine-induced and

naturally occurring catatonic and other pathological manic states to

actions at endogenous opiate receptor sites may be a more

promising strategy when employed in humans for separating the

relative contribution of endorphin and adrenergic systems to

euphoria and psychomotor activation and inhibition.

However, naloxone has been reported to be without effects of its

own in a variety of behavioral, neuroendocrine, and neurochemical

model systems in mammals (6, 7, 33, 45, 48, 63, 84). There are no

reports of physiological or behavioral effects of naloxone in

primates or humans (25, 29, 46, 47, 49). In addition, lithium

blockade of euphoria seems to be partial, and occurs with certain

exogenously or pathologically induced ego-dystonic feelings of

well-being. The involvement of other transmitter systems, particularly aminergic, in an interactive manner is likely in stimulant-induced and endogenous mood state changes. A full discussion of

aminergic theories of euphoria and mania (11, 69, 70) and possible

relation to the neuromodulatory influences of the endorphins (94)

is pertinent but beyond the scope of this paper. However, a brief

discussion of the suggestion that dopaminergic mechanisms might

play an important role in mania is required because of the clinical

effects of L-Dopa in manic-depressive patients (11, 75), known

actions of d-amphetamine and opioid agonists at dopaminergic

synapses (15, 23, 26, 27, 39, 40, 82, 92), and data that dopamine

receptor blocking antispsychotic agents are antimanic (37).

Haloperidol and pimozide action as antimanic and known

dopamine receptor blocking agents seemingly supports a dopamine

hypothesis (37). However, Creese et al. (21) have demonstrated the

substantial affinity of some butyrophenones for the opiate receptor

in brain. This observation provides a biochemical rationale for the

known influences of these drugs on opiate addiction in animals and

abstinence in man (59, 81, 96). In fact the butyrophenones used

clinically are analogues of the opiate meperidine (56). Some of the

more potent butyrophenones examined for opiate receptor binding

activity were found to have a greater affinity for the receptor than

opiates like meperidine and propoxyphene. Benperidol and

pimozide were the most active of these drugs and have a binding

profile similar to opiate antagonists (21, 80). Haloperidol produces

some behavioral effects (e.g., catelepsy) which mimic some of the

effects of opiate agonists. Haloperidol can potentiate analgesia and

the development of tolerance and dependence to morphine when

both drugs are given concurrently (27) and produces some degree of

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GOLD AND BYCK: ENDORPHINS, LITHIUM, AND NALOXONE

cross tolerance with morphine (27, 82). Haloperidol also antagonizes morphine-induced hyperactivity very effectively (15). These

data suggest that opiate receptor activity might be responsible for at

least part of the butyrophenones’ antimanic and antieuphoric

effects.

ENDORPHINS AND PSYCHOSIS

Opiate agonist receptor activity may contribute to antipsychotic

activity as well. Support for this hypothesis comes from data which

suggest that, like the traditional antipsychotic medications, morphine and other narcotic agonists interfere with the post-synaptic

action of dopamine (23, 26, 27, 39, 40). Opiate agonists, as does

haloperidol, increase dopamine metabolites HVA and DOPAC in rat

brain as well as inhibit the enzyme dopamine stimulated adenylate

cyclase (40). These actions of opiate agonists are consistent with

the prediction of antipsychotic efficacy (41) on the basis of current

theories of psychosis (92) and the antipsychotic action of the

neuroleptics (54, 92).

The involvement of dopamine in the tonic inhibition of prolactin

secretion (71) and the known action of the neuroleptics at

dopaminergic receptors (54, 92) have led to the suggestion that

antipsychotic medications can be identified by their stimulation of

prolactin secretion (16, 72, 73). Potent antipsychotic phenothiazines, butyrophenones, but not structurally-related drugs without antipsychotic potency, block dopamine receptors (54) and

stimulate prolactin secretion (16, 67, 72, 73). These and other data

have led to the hypothesis that tuberoinfundibular dopamine

blockade, as assessed by elevations in serum prolactin, might be the

best model system for screening new antipsychotic compounds (16,

72, 73). However, morphine, methadone, and endorphins have

recently been found to increase prolactin secretion through opiate

receptor stimulation as assessed by naloxone blockade (31, 68, 95).

Gold et al. (43-44) have recently found that 0.4 mg/kg of morphine

sulfate produces significant three-fold increases in basal serum

prolactin while 0.4 mg/kg of a synthetic d-alanine m-enkephalin

derivative (85) produces significant sevenfold increases in serum

prolactin in primates. These m-enkephalin-induced increases in

serum prolactin are similar to those produced by the potent

antipsychotic haloperidol in this species (42). These prolactin data

are consistent with animal data suggesting that opioid agonists

interfere with the post-synaptic action of dopamine (23, 26, 27, 31,

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

39, 40). Opiate agonists may, through opiate receptors, modify

dopaminergic impulse flow and release (41) to act as a neuromodulator of dopamine receptor activity. In this way, opiate neuromodulatory mechanisms could bias dopaminergic systems to be involved

in motor behavior and mood as well as in antipsychotic effects (18,

55, 76) and psychosis (8). But what about the “pure” opiate

antagonists? If endorphins function in the brain to modulate

dopaminergic impulse flow, then naloxone should have an opposite

effect on biological measurements which correlate with dopaminergic activity.

NALOXONE-PROLACTIN: A MARKER FOR CENTRAL

ENDORPHIN BLOCKADE?

Naloxone has generally been found to have no effects of its own

other than to block or reverse the effects of opioid agonists (6, 7,

25, 29, 33, 46-49, 63, 84). There are no reports of physiological

effects reported for naloxone in nonhuman primates or humans.

These and other negative data have been difficult to interpret due

to a lack of any central and measurable effect of naloxone which

could be measured concurrently and provide a marker or evidence

of a central effect of naloxone at a particular dose. However, these

negative data have led to the suggestion that the endorphins are

secreted episodically and do not have a tonic neuromodulatory role

in the brain. We have recently investigated and described an effect

of naloxone on serum prolactin which suggests at least one tonic

neuromodulatory function of endogenous opioid peptides (44).

Naloxone hydrochloride (0.25 mg/kg) administered intravenously caused significant and sustained decreases in serum

prolactin in five Macaca arctoides. Each experimental session lasted

5 h with the last 4 h involving blood-sample withdrawal and either

naloxone or saline administration by means of an intravenous

cannula without handling or confrontation. All samples were

prepared for radioimmunoassay as previously described (41, 42).

Naloxone produced a marked and significant fall in serum prolactin

from 23.0 ng/ml +/– 2.9 S.E.M. to 3.5 ng/ml +/– 0.9 S.E.M. at 60

minutes after drug infusion (p<0.01). Serum prolactin concentration was significantly decreased from baseline levels at each time

point from +30 to +180 minutes after naloxone. There were no

significant effects on serum prolactin after saline administration.

These naloxone-induced decreases in basal serum prolactin are

similar to those produced by the dopamine receptor stimulating

drug apomorphine.

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GOLD AND BYCK: ENDORPHINS, LITHIUM, AND NALOXONE

These data on naloxone and prolactin may be useful in studies

where naloxone is administered to investigate behavioral and other

effects of endorphins by allowing the administration of a dose of

naloxone which produces a measurable effect. With this central

marker data. negative data in naloxone studies may be more

meaningful and support an episodic rather than tonic role of

endorphins in a particular behavior or psychopathological state.

Alternatively, positive data in naloxone studies may be more likely

if higher, prolactin-lowering, doses of naloxone are employed.

These naloxone data indirectly support the hypothesis that

antipsychotic drugs can be identified by their stimulation of

prolactin secretion (16, 72, 73), since naloxone decreases serum

prolactin and has not been found to have antipsychotic activity in

psychotic humans (22). Higher doses of naloxone given in a chronic

treatment protocol may be necessary to support these data.

Exogenous and endogenous opioid agonists are potent stimulators

of prolactin secretion and may have antipsychotic activity in man

(41, 61, 76). The opioid agonist-induced increase in prolactin can

be blocked by concurrent or pretreatment with naloxone or the

dopamine receptor stimulating drug apomorphine (31, 68, 95).

These and other data reviewed above suggest that dopaminergic

neurotransmitter systems are involved in an interactive manner with

peptide neurotransmitters. This interaction may be involved in the

generation and pharmacological treatment of complex mood and

behavioral states.

CRITIQUE

There are several weak links in this chain of reasoning. For

example, the effects of lithium on opiate receptor binding have

been determined with this ion alone, and so results of adding small

amounts of lithium to sodium are as yet hypothetical. The ionic

environment of the receptor must be known before the magnitude

of the lithium and sodium effect can be measured. In addition there

is evidence for both opioid agonist and antagonist activities of

“specific” dopamine blocking agents. Whether prolonged opiate

agonist and antagonist activity contributes to antipsychotic and

antieuphoric effects, respectively, remains to be demonstrated.

Tuberoinfundibular dopamine blockade as assessed in vivo by

increases in serum prolactin may not be a viable model for the

antipsychotic locus of action of the neuroleptics. Naloxone may be

a more potent morphine and exogenous opiate than endorphin

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

antagonist. Finally, there is the suggestion that opiate agonist

activity may produce euphoria, provide the pathophysiological

substrate for acute mania, and also act as an antimanic agent. One

possible explanation for this apparent paradox is suggested in the

recent acute vs. chronic effects of heroin study of Mirin et al. (74).

In contrast to acute effects, chronic exogenous agonist administration (or chronic endorphin excess in mania) may, through modification of dopaminergic or other aminergic systems, cause the

opposite—dysphoric, antimanic—effects. A similar phenomenon

may explain the euphoria followed by depression in manic-depressive disease.

Our hypothesis, which attempts to provide a mechanism of

action for lithium and a neurohumoral substrate for euphoria, is

readily testable. Naloxone, or related but more potent endorphin

antagonists, should be found to be an effective antagonist to

drug-induced and naturally occurring euphoric states. These antagonists could be useful in the treatment of bipolar affective illness

and manic states associated with catatonia. A test of the lithium

effect on the postulated opiate-euphoria system is possible in a

number of physiological systems and in each instance the effect of

lithium should in part be similar to that of opiate antagonists.

Similarly, anti-euphoric antipsychotics might be expected to act

like lithium or naloxone in amphetamine- and cocaine-induced

states, naturally occurring euphoric states, and opiate receptor

binding systems. Finally, chronic administration of endorphins

should be antieuphoric and antipsychotic in man.

Recently lithium has been reported to have no effect on the

euphoriant action of large doses of morphine (57). This endorphin

hypothesis would predict only a partial antagonist action for

lithium against the effects of morphine and so the failure to block

large doses does not markedly affect the status of that hypothesis.

The same authors reported a dysphoric effect as well as a sensation

of sluggishness and tiredness in normal subjects treated with

lithium. These are, in effect, the opposite sensations to those

produced by the stimulant drugs. The effects of lithium can be

summarized as universally opposite to those of stimulants, i.e.,

dysphoria, tiredness and sluggishness (58). These are not dissimilar

to the effects of the antipsychotics given in acute doses to normals

or chronic heroin administration (74). Since all these are the

opposite to symptoms of mania, it may be that either a dopaminergic or peptidergic mechanism, or both, is involved in mania and the

action of stimulants.

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GOLD AND BYCK: ENDORPHINS, LITHIUM, AND NALOXONE

CONCLUSION

Biological psychiatrists have for the most part centered their

interest on the relationship of abnormalities in brain dopamine to

amphetamine psychosis and schizophrenia. It is probably more

appropriate to consider that acute administration of stimulants

provides a model for euphoria and mania. The hypothesis that

amphetamine psychosis is a model for mania with psychosis could

thus be investigated in humans by cumulative administration of

amphetamine after lithium pretreatment. Lithium pretreatment

would be expected to block or attenuate this experimental

amphetamine psychosis.

We have presented a case which represents a clear clinical

example of a specific lithium block of two stimulant drugs. This

case is compatible with an endorphin hypothesis for drug-induced

and naturally occurring euphoric states. We have also suggested the

possibility that an opioid peptide mechanism might have pathophysiological significance in manic-depressive disease. If this hypothesis is viable, naloxone should block the euphoria of drug and

naturally occurring manic states. We have also reviewed recent data

on the effects of exogenous and endogenous opioid agonists as well

as the opioid antagonist naloxone on serum prolactin levels. These

prolactin data offer theoretical support for clinical trials of

prolactin stimulating endorphins in psychosis and naloxone in

catatonia and possibly parkinsonism. These prolactin and other

animal data suggest that the endorphins are potent tonic modulators of dopaminergic activity in brain. It may be necessary to

invoke a peptidergic-aminergic mechanism to adequately explain

complex, drug-induced and pathological manic-euphoric states.

These prolactin data may be helpful in determining appropriate

doses of naloxone and opioid peptides for clinical trials.

Direct experimental investigations are necessary in most cases but

expecially in response to our speculative hypotheses.

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ACKNOWLEDGMENTS

We thank Herbert Kleber, M.D., Director of the Substance Abuse Unit at

Connecticut Mental Health Center, for his interest and support. We also thank

D.E. Redmond, Jr., M.D., J.W. Maas, M.D., R.K. Donahedian, M.D., and A.

Casswell for their help. This work was supported in part by the Biological

Sciences Training Program grant no. USPHS MH 14276, Burroughs-Wellcome

Scholarship in Clinical Pharmacology (R. Byck), National Institute on Drug

Abuse contract no. ADM 45-74-164, and in part by NIMH grant MH-24607.

Some material from this paper was presented at the VI World Congress of

Psychiatry as a paper by R. Byck entitled, “Endorphins: The Symptoms of

Affective Disorder and the Action of Lithium.”

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CHAPTER 16

Drug and Mood State-Specific

Encoding and Retrieval of

Experience

Herbert Weingartner, Ph.D., Dennis Murphy, M.D., and

Richard C. Stillman, M.D.

Many psychoactive drugs produce neurochemical changes which

are both discriminable from an undrugged state and are reinforcing

for the drug user. Such discriminable and reinforcing properties are

clearly pertinent in accounting for the subjective drug experience.

These two properties may also help to explain the potential of some

drugs for abuse and the interactive situational and personality-related factors that would determine idiosyncratic individual or group

drug effects. Dramatic alterations in mood such as seen in

depression or mania in bipolar and unipolar affective disorder

appear to share some of the behavioral and biological features that

characterize the response to abusable drugs.

In this report we contrast some of the cognitive changes that

occur in mood altered states with those seen in the drug intoxicated

state. We have observed that the changes in state and their cognitive

components such as those seen associated with depressed and/or

manic phases of unipolar or bipolar illness share much with

responses to drugs that induce euphoria, sedation, stimulation,

activation, or arousal. Likewise some of the neurochemical events

associated with disturbances in mood also appear to be relevant to

the understanding of the biology of the drug altered experience (7).

In our laboratory we have designed information processing

systems that might be particularly effective in exploring some of

the cognitive characteristics of state change in response to a variety

of psychoactive drugs. We have used similar methods of approach

for the study of cognition as it relates to disturbances in mood in

bipolar and unipolar affective illness. One major focus of this

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approach has been to use state dependent learning designs to

interrelate the storage and retrieval of experience (11, 13). The

major feature of this research has been to relate biological and

psychological processes that might be involved in experiencing and

encoding events in one state and retrieving experience in either the

same or some other state, as for example an altered mood, a drug

altered change in brain function, or a change in neurochemical

activity in the brain.

FEATURES OF STATE DEPENDENT LEARNING (SDL)

A growing number of studies have demonstrated that under some

learning and test conditions information acquired in some altered

state is most effectively retrieved in a similar altered state as

compared to retrieval in a different or disparate state. This

phenomenon was first studied in animals and then in man. In most

of these studies state change was accomplished through the use of a

drug manipulation either at the time of learning or at the time of

retrieval or at both times. We have studied this phenomenon not

only under drug altered conditions, such as in the alcohol or

marihuana intoxicated state but in patients who, over time,

manifest robust changes in mood state as in depressed and manic

phases of bipolar illness. The studies reported have suggested that

drug induced dissociations of learned information stored in one

state and recalled in a different state may share much in common

with similar effects seen in patients as they evidence changes in

mood state and attempt to recover experiences acquired in some

earlier but different mood state.

In an alcohol SDL study we had 10 normal subjects each

consume 3.5 ounces of 190 proof alcohol mixed in 3.5 ounces of

orange juice. Twenty minutes later we obtained Breathalyzer

measures as estimates of blood alcohol level (mean values were .081

mg%). Following this we asked these subjects to generate 20 verbal

free associations to each of 2 standard stimuli, a method previously

found useful for measuring cognitive responses to psychoactive

drugs (14). This same task was also accomplished, at another time,

in an unintoxicated state. Five hours later subjects were asked to

reproduce their self-generated associative responses. Reproduction

of associations was accomplished under two different conditions. In

one, subjects were sober at the time of recall. In the other condition

they accomplished this retrieval 20 minutes after consuming the

same quantity of alcohol, producing about the same state of

intoxication. The four conditions were then:

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Generate Retrieve

In formation In formation

(congruent)

conditions)

sober

intoxicated

(disparate sober

conditions) intoxicated

sober

intoxicated

intoxicated

sober

The findings from this study showed that when information is

generated and retrieved in the same state, the reproduction of

patterns of associations is more complete than when this occurs in

disparate generation-retrieval conditions (F(3,27) = 5.41; p<.01).

FIGURE 1

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WEINGARTNER ET AL.: ENCODING AND RETRIEVAL

This experiment was repeated in a different 10 subjects using the

same design and alcohol dose. Unlike the first study we required

subjects not merely to regenerate their associations but to do so in

the same order or sequence in which they were initially generated in

response to the same stimuli. The retrieval of episodic events (e.g.,

A occurred, then B, then C) was thought to better reflect how we in

fact experience, encode, and retrieve events than merely recapitulating what word events were thought to have previously been related

to some stimulus. Such episodic time-sequence tagged information

is also a closer match to how we store biographically relevant

events. Again, in this study, we saw a robust dissociation of

information when recall of episodic events is attempted in some

disparate retrieval state (F(3,27) = 11.84; p< .001).

Average

Displacement

within List

FIGURE 2

Reproduction of Episodic Associative Information in Congruent and

Disparate State Recall

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A similar strategy for examining SDL effects was used in a study

in which we systematically studied 8 patients with bipolar affective

illness over a period of many weeks. Patients would generate 20 free

verbal associations to different word stimuli and four days later

they would try to regenerate their responses. This was repeated for

different word stimuli over and over again. At the same time we had

trained clinical staff rate and measure the patient’s mood-clinical

state using previously designed and validated mood rating scales (6).

We then examined the relationship between reproducibility of

patterns of associations with the absolute change in mood-clinical

state. There emerged a consistent pattern of significant negative

correlations, each showing that reproduction of associative responses was dependent on the similarity between mood state at the

time these associations were generated and mood at the time of

reproduction of associations (retrieval). Analysis of data on all

patients as a group, and individual patient data both showed that

retrieval is most effective if mood state is similar at the time of

response generation and response regeneration. These findings are

summarized in figure 3, which describes the composite pattern of

relationships using all data generated from the 8 patients studied:

186 pairs of generated associative patterns and their reproduction

(r=–.45; df=185; p<.001).

ENCODING CHANGES THAT ACCOMPANY CHANGES IN

STATE AND THE SDL PHENOMENON

The studies described above illustrate that the SDL phenomenon

occurs in the context of states of alcohol intoxication and altered

mood. Three studies which we have completed also suggest that

states that are associated with SDL dissociations also induce

qualitatively unique strategies for processing input which would

cognitively differentiate such states from the “normal” state. In one

such study we have been able to demonstrate that the kind of

associative responses that are produced while manic are qualitatively different from the patterns of associations produced by these

same patients in the non-manic state (5). That is, as patients

become increasingly manic they produce an increased number of

rarer, more idiosyncratic associative responses at the expense of

more commonly elicited associations. The relationship between the

kinds of associations that come to mind in response to word stimuli

is an important determinant of how subjects think about events,

encode events, organize information, and remember information (2,

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WEINGARTNER ET AL.: ENCODING AND RETRIEVAL

FIGURE 3

10). Thus, changes in associative patterns that occur during mania

are, in part, responsible for changes in how events are interpreted

in a mood state specific manner. These changes ultimately affect

how a stimulus would also be used in reproducing associative word

responses in a same or different mood state.

Similarly, we have begun to explore the kinds of eye scan

strategies that subjects use in examining visual displays in an

undrugged state as compared to a marihuana intoxicated state. Our

preliminary data seems to indicate that subjects looking at pattern

information in a marihuana intoxicated state tend to exhibit scan

paths that focus on the fine detail of displays. Normally these same

subjects tend to “look” at fields of information using wholistic

processing strategies evidenced by eye fixations that sweep over

larger fields of visual information. This detailed scanning while

intoxicated as compared to gestalt processing in the unintoxicated

state may also have implications for brain lateralizing effects of

marihuana as perhaps reflected in such state specific differences in

visual scan strategies. Other recent findings from our laboratory are

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

consistent with such a notion. We noted consistent changes in the

speed of processing simple letters, displayed either in a block upper

case form or as a lower case letter display, when presented to the

left vs. right hemisphere, which would indicate that marihuana

produces somewhat different effects in the dominant vs. nondominant hemisphere (8). Thus, marihuana-induced shifts in the

cognitive strategies used to transform, process, and encode experience may reflect lateralizing effects of marihuana in the brain. As

such, it represents one kind of expression of qualitative differences

in state specific information processing strategies.

In another study we asked subjects to impose organization on

sets of pictures which were each random displays of texture, line,

and form. These displays were deliberately constructed, pretested,

and selected so as to make them difficult to encode with some

verbal label. Subjects while either marihuana intoxicated, having

smoked marihuana cigarettes assayed to contain 12 mg THC, or in

an undrugged state, examined equivalent sets of these stimuli and

imposed subjective organization by sequencing these 20 stimuli,

presented as 2” x 4” pictures, in some order which made sense to

the subject and which he felt he could reproduce at some later time.

Later, in either a congruent or disparate state, subjects attempted to

reorder these same stimuli. Under congruent conditions the

reordering of these stimuli was a significantly better match to the

original sequential ordering (encoding) than when ordering and later

reordering occurred in disparate state (see figure 4 below).

FIGURE 4

Reproduction of Pattern Sequencing in Congruent and Disparate State

Recall

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WEINGARTNER ET AL.: ENCODING AND RETRIEVAL

All of these studies seem to suggest that where SDL appears it

involves qualitatively different encodings or strategies for dealing

with experience or recovering experience from memory.

MECHANISMS OF SDL

Some of our recent research efforts have focused on the structure

and mechanisms of SDL, including defining the characteristics of

stimuli and conditions at the times of storage and retrieval that

might modulate SDL related dissociations. We have designed a

number of experiments in which the induction of SDL could be

assured, given a particular manipulation of storage and retrieval

state, and then have superimposed conditions which might attenuate or potentiate dissociations of memory. The purpose of these

studies was specifically focused on possible mechanisms and

determinants of SDL and their implication for understanding state

specific encoding and retrieval operations.

In one of these studies we had subjects listen to categorized lists

of words after either smoking placebo material or active marihuana

(containing 15 mg THC). Later, subjects tried to remember these

words in either a congruent or disparate state. As expected, recall in

a disparate retrieval state was significantly less complete than

congruent storage-retrieval state recall. Subjects who attempted

recall in the disparate state appeared to “lose” whole categories of

information. For example, they would forget that names of flowers,

vegetables, and cities were read to them. If a category name was

recalled, however, they were no less able to recall category

exemplars than when recall was attempted under congruent

storage-retrieval state conditions. That is, whole categories of

information dissociate rather than the fine detail within previously

experienced structured events. If subjects are provided with the

names of presented categories as cues or prompts at the time of

recall, then SDL dissociations are erased. Such external cueing

allows subjects to access information stored in some disparate state

which was previously available but inaccessable under free recall

retrieval conditions (4). This same effect of cueing at the time of

retrieval erasing dissociations of memory has also been seen using

physostigmine to induce state change (13).

The retrieval test conditions can also be altered by what the

subject does in attempting to remember information. If a subject

begins to recall previously stored words by starting with the

information which was presented first, then dissociations are less

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

likely to be evident than if the subject starts the process of

remembering with some event other than the first. The first recalled

response by the subject effectively acts as a cue or prompt for

recalling other information, and some cues, because of their learned

relationship to other events that follow, provide a kind of context

that can effectively surmount the state specific and disparate

retrieval condition (3).

Some characteristics of stimuli can also modulate the likelihood

of inducing dissociations in information processed in disparate

state. For example, if subjects are presented with a mix of words

some of which are more saliently encoded than others, then it

appears that the least effectively encodable events are most

susceptible to dissociation in a disparate state (12). Another way of

altering how well an event is encoded is merely to repeat that event

at the time of storage. That is, when events are presented just once,

encoding is shallow, and they are more vulnerable to dissociation

than when these same events are repeated, leaving a more salient,

deeply processed trace event (3).

It therefore appears that striking or saliently encoded events are

less vulnerable to dissociation. Regardless of encoding depth, if the

subject’s self-generated retrieval strategy for searching memory for

information stored in the disparate state is not used, but instead the

subject utilizes strong, effective search strategies provided by the

environment (e.g., the experimenter), then dissociations are not

evident. Dissociations involve the loss of subtle characteristics of

experience that tie episodic, biographical events together. The

recovery of such events requires that if the key to recall is lost, it

must be provided for effective access to such previous experience.

THE SUBJECTIVE EXPERIENCE OF STATE CHANGE

AS A NECESSARY CONDITION FOR SDL

We have noted in a number of studies that occasionally subjects

would rate themselves in some state as particularly high, even if that

state happened to follow placebo treatment. Recall might then

occur in a disparate state with respect to their rated high, even if

this occurs after again smoking placebo material but not experiencing an intoxicated state. These subjects show some of the same

kinds of dissociation in recall as can be seen when, for example,

learning takes place following marihuana treatment and retrieval

follows smoking of placebo material.

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WEINGARTNER ET AL.: ENCODING AND RETRIEVAL

We systematically explored this phenomenon by treating with

amphetamine a group of depressed patients similar to those who

had evidenced mood related dissociations of memory. Patients

learned a sequence of words one hour following treatment with

d-amphetamine, on another occasion following l-amphetamine

treatment, and after placebo treatment. These three conditions

were repeated after pretreating and maintaining patients on lithium.

We found that amphetamine does induce SDL dissociations of

information recalled in a disparate state. However, the most robust

finding was that the extent to which dissociations of previously

learned episodic events were evident was a function of the extent to

which mood was lifted following amphetamine treatment and the

disparity in mood that differentiated the storage state and retrieval

state (see figure 5). The drug treatment was a necessary condition

for the expression of SDL, but it also required a pronounced

subjective drug response, lifting of mood and then return to

baseline mood state (15). FIGURE 5

Amphetamine Mood State-Dependent Retrieval of Previously Learned

Responses

A similar finding was observed by behaviorally manipulating the

mood of depressed patients and normal controls. Here we manipulated success or failure on tasks preceding the acquisition of

information and/or just prior to the recall of information. We found

that the success-failure manipulation produced a much stronger

mood altering response in the depressed patients than in normal

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

controls. If mood as a result of the success-failure manipulation at

the time of storage was disparate with mood at the time of retrieval,

then SDL retrieval dissociations were evident. Normal controls, who

were less mood response sensitive to these same success-failure

manipulations, showed no evidence of a dissociation at the time of

recall. Again the state difference could not merely be defined by a

manipulation of state with drug or some behavioral context but

required the experience of a strong subjective response. This may,

in fact, merely reflect the larger phenomenon which defines a

response, be it to a drug or some other stimulus, in terms of a

behavioral and biological history which helps to induce the milieu

in which that stimulus is “read” and “interpreted.”

DISCUSSION AND CONCLUSIONS

It has been clear to us that one potentially rich research framework within which it appears possible to pursue some of these basic

issues which might relate the biology of altered brain states with its

psychology involves the use of information processing frameworks

to define and describe changes in how experiences are appreciated,

understood (encoded), stored (acquired, learned) and later retrieved

either in terms of performance which requires access to previous

learning or in remembering previous experience. Using the now

numerous models and related techniques that have emerged from

the study of how non-drug or mood-altered learning and memory

proceed, it has been possible to begin to define some of the

cognitive and other behavioral changes that characterize disturbances in mood as in depression and mania and similarly to use such

schemes to examine the drug altered states such as are produced by

alcohol, marihuana, and amphetamine. Most of the findings that

have emerged from these research efforts have been limited to issues

of the efficiency of cognition or behavior in some altered brain

state, rather than on the qualitative changes in information

processing that characterize how events are experienced and

retrieved differently, rather than less well, in one state vs. another.

Furthermore, almost none of such state specific information

processing changes have been related to concurrent biological

events. The studies reported here illustrate how one might

systematically explore this set of issues, namely the qualitative

changes in information processing that would differentiate one state

from another.

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WEINGARTNER ET AL.: ENCODING AND RETRIEVAL

Qualitative changes in how experiences are attended, stored, and

later retrieved should also be reflected in a pattern of biological

changes that would characterize brain as a unique context for the

occurrence of state specific cognition. To accomplish this we have

used and developed state dependent learning (SDL) paradigms as

research strategies for framing pertinent questions that would

differentiate cognition in one state from that in another state. The

most important concepts that are basic to our approach include the

following: Experienced events are those which have been selected

out from a larger field of information on the basis of stimulus

structural characteristics, as well as pertinent structured histories of

previously stored experience (information) in memory. These

structures define the strategies which are used to search fields of

information, e.g., as in scanning a field or visual display of

information. Some events are processed further, and are held in a

short term memory store for further analyses. The extent to which

events have been processed, and the elaborateness or depth of

processing will, to a large extent, determine the likelihood of later

recall (1). Events are also processed in some informational context

which determines how they will be encoded. The specific encoding

of events also determines the retrieval strategies which must be

generated and used to search memory store if some event is likely

to be recalled at a later point in time (9). Retrieval occurs in some

context, in much the same way as information acquisition and

encoding. An information context determines how information is

encoded or what retrieval strategies are generated to search

memory, and similarly a drug or mood-altered brain state can define

a unique context for searching an information field, interpreting,

organizing and encoding information, or inducing or biasing

strategies for searching and accessing previously experienced events.

Using such a framework, it is possible to ask, first, whether a

given state is discriminable from some other state, not only in terms

of whether it “feels” different, but whether it induces a unique

context for interpreting and storing events or for recapitulating past

experience. Is information experienced in one state effectively

recoverable in some different or disparate state? That is, are

experiences that have occurred in one state dissociated at the time

of recall when retrieval is attempted in some disparate state?

Second, what are the unique transformations of events that occur in

such an altered state? What is the unique context for processing

events in a given state? Third, what are the mechanisms that

determine, modify, and alter state specific strategies for encoding

and retrieving experience? Finally, what are the interrelated

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biological and psychological determinants that characterize such

state specific encodings and retrieval of experience? The research

accomplished to date has represented some of the bare beginnings

of an exploration of these issues, which we believe to be a powerful

vehicle for understanding the psychological and biological factors

that are necessary to appreciate drug- and mood-altered states in

man.

We would propose that a euphoriant, stimulant, or depressant

drug, or some altered mood state forms a kind of biological and

psychological context for processing and encoding events. Such a

context may uniquely determine how we understand the meaning

of events, how these are related to one another and to past events,

and their interrelated relevance to the stream of ongoing events that

precedes and follows some experience. Such a context also serves to

determine and limit how we search for previously experienced

biographical events in memory. The structures of these search

strategies are intimately linked to the structures that were used to

encode events. These contexts can be quite different from one

another, and some happen to feel good while others represent a

milieu for dealing with events which are dysphoric and to be

avoided. Part of our behavior is motivated so that we might find

effective contexts that permit events to be interpreted in a manner

that permits positive evaluations. When the events around us look

bleak we might seek out some alternative context for altering

experience, and one vehicle for accomplishing this is with drugs of

abuse.

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7. Murphy, D.L., and Redmond, D.E. The catecholamines: Possible role in

affect, mood and emotional behavior in man and animals. In: Friedhoff,

A.J., ed. Catecholamines and Behavior. New York: Plenum Press, 1975.

8. Stillman, R.C.; Wolkowitz, O.; DeLorenzo, E.; Weingartner, H., and Wyatt,

R.J. In preparation.

9. Tulving, E., and Thompson, D.M. Encoding specificity and retrieval

processes in episodic memory. Psychol Rev, 80:352-373, 1973.

10. Weingartner, H. The free recall of sets of associatively related words.

Journal of Verbal Learning and Verbal Behavior, 3:6-10, 1964.

11. Weingartner, H. Human state-dependent learning. In Chute, Ho, and

Richards, (eds.), Behavioral Biology. New York: Academic Press, forthcoming.

12. Weingartner, H., Martello, and Murphy, D.L. Mood state-dependent

learning following the experience of success or failure. J Consult Clin

Psychol in press.

13. Weingartner, H., and Murphy, D.L. Brain states and memory: Statedependent storage and retrieval of information. Psychopharmacol Bull, 13:

66-67, 1977.

14. Weingartner, H.; Snyder, S.; Faillace, L.A.; and Markley, H. Altered free

associations: Some cognitive effects of DOET (2, 5-dimethoxy-4-ethylamphetamine). Behav Sci, 15:296-303, 1970.

15. Weingartner, H., Van Kammen, D., and Murphy, D.L. Amphetamine statedependent learning in depressed patients. Journal of Abnormal Psychology,

in press.

223

IV.

Treatment
CHAPTER 17

Multimodality Treatment of Narcotic

Addiction: An Overview

George E. Woody, M.D., Charles P. O’Brien, M.D., Ph.D.,

and Robert Greenstein, M.D.

A major commitment of time and resources has been made in the

treatment of narcotic addiction during the last fifteen years. This

contrasts with addiction treatment prior to the 1960’s when

long-term therapy at Lexington, Kentucky, or Ft. Worth, Texas, or

detoxification in a local hospital were the only treatments available.

In those times, many hospitals excluded addicts, and there was little

interest from most of the medical community in applying its

expertise toward developing effective treatments for addiction. The

more recent efforts and the current high level of interest have

produced great changes, and many options are now available. As a

result, treatment is easier to obtain, and the outlook for this once

discouraging condition has been improved. Pharmacological treatments and therapeutic communities have provided the backbone of

the present-day therapeutic approaches, but interest is growing in

outpatient psychological therapies. This paper will discuss the

treatments being used now and will present an overview of the field.

PHARMACOLOGIC THERAPIES

Narcotic substitution

The single therapy that has had the greatest impact on narcotic

addiction appears to be methadone maintenance. Unlike drug-free

approaches, it is acceptable to a large number of addicts (9). It is

medically safe, has minimal side effects and no toxicity when given

to tolerant individuals, even for long periods of time (29). Though

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WOODY ET AL.: MULTIMODALITY TREATMENT OF ADDICTION

the results of methadone treatment vary among programs, there is

strong evidence that it provides a way to control narcotic addiction.

Most patients who remain in methadone treatment have a marked

decrease in heroin use, an increase in employment rates, and

demonstrate improved personal adjustment (12). At present there

are approximately 80,000 people being treated with methadone in

the United States (45), but despite methadone’s wide applicability

and effectiveness, it leaves much to be desired. It has been

controversial since the beginning, and many aspects of methadone

programs have been criticized (7, 13).

One problem has been an inability to demonstrate that methadone treatment increases the long term cure rate for addiction.

This is a disappointment, as many had hoped that the social

rehabilitation obtained via methadone maintenance would lay the

groundwork for successful detoxification. In retrospect, this disappointment is probably natural and has precedents in other areas of

medicine where new treatments are accompained by hopes which

are not realized.

A second problem is the inability of methadone programs to

attract and retain more addicts in treatment. Early experiences led

to hopes that the majority of addicts within a given area could be

enrolled and retained in programs. This has not happened.

Enrollment usually includes much less than 50 percent of the

addicts in any immediate area, and dropout rates are usually high

(42). Program variables may account for many of these difficulties,

and improvements in program quality may produce better results. A

rapid evaluation and prompt initiation of treatment is one such

quality that may increase program retention (66).

Another problem with methadone is diversion. Unless programs

require daily attendance, “take home” doses must be given. A

portion of these are almost always diverted. This may result in

accidental ingestion of methadone by children or other nontolerant

individuals, or in the sale of legitimately-prescribed methadone to

other drug abusers (56, 61). On the other hand, the inconvenience

of the requirement for daily attendance may reduce the attractiveness of treatment. Unfortunately, this may be particularly true for

patients who are working and showing other indications of progress.

A fourth problem is that methadone is highly addicting, and

some patients have complained that it is harder to detoxify from

than heroin. This observation probably relates to dosage level and

not to the drug itself (38). Most street heroin is of low purity, and

thus physical dependence is low (2). Because of these differences,

many patients being treated with methadone may develop a greater

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

degree of physical dependence while receiving methadone than they

had prior to entering treatment. This may be necessary in order for

some addicts to benefit from methadone treatment, particularly in

cases where high levels of tolerance are desirable, but it should iead

to caution in prescribing high dosages.

In spite of these problems, however, it is probably accurate to

say that prior to the development of methadone maintenance there

was no outpatient treatment that could demonstrate positive results

for significant numbers of addicts. Methadone treatment, though

far from perfect, seems to have added an important and positive

element to the treatment of narcotic addiction.

The current development of methadyl acetate (LAAM), a

derivative of methadone that prevents withdrawal symptoms for

forty-eight to seventy-two hours, shows promise for correcting the

diversion problem. Currently this drug is in a developmental phase,

but it is undergoing widespread clinical trials. LAAM has effects

that are similar to methadone and appears to have no serious

toxicity when used properly. Its major advantage is that people

taking it need come to clinic only three times per week. This is

especially beneficial for patients who must travel long distances and

for those who have irregular schedules or who work long hours. It is

also desirable from a public health standpoint because its use almost

eliminates the need for take-home bottles. Some think that it also

tends to lessen dependency on the clinic and is a step toward

becoming drug free (15). Studies done to date show that results for

those who remain on LAAM compare favorably with those on

methadone (31). However, LAAM may be less acceptable to addicts

than methadone, as initial dropout rates are higher (3). This is

difficult to evaluate because it is a new drug, and anxiety or other

psychological factors related to its newness and investigative status

probably influence some patients to discontinue it. If LAAM meets

the safety and efficacy standards of the U.S. Food and Drug

Administration (FDA) and is approved for general use, all clinics

could use it, and most programs then would be in a position to

offer patients either LAAM treatment three times per week or daily

methadone. This system could lead to a marked reduction in

methadone diversion and would be much easier for patients than

coming to clinic for daily methadone treatments.

Propoxyphene napsylate, a drug with weak narcotic effects, has

been tried with an eye to developing a maintenance drug that will

produce less physical dependence than methadone. Propoxyphene

can suppress abstinence symptoms in patients who have low degrees

of physical dependence, and open clinical trials have shown that

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WOODY ET AL.: MULTIMODALITY TREATMENT OF ADDICTION

some addicts can be maintained on it (21, 58). However, double

blind studies comparing low doses of methadone (maximum

36mg/day) with high doses of propoxyphene (maximum 1200

mg/day in divided doses) have shown that propoxyphene is not as

well accepted as methadone. Preliminary data from these studies

show that dropout rates and frequency of street drug use are

considerably higher in patients maintained on propoxyphene. It

seems that propoxyphene, therefore, is not as effective as methadone for maintenance treatment (34). Since a few patients do well

on propoxyphene it might be useful as an alternative to methadone

for selected patients who have low levels of physical dependence,

who do not fulfill FDA requirements, or who want maintenance but

are opposed to taking methadone. Detoxification from propoxyphene produces less discomfort than detoxification from methadone and therefore it may be useful as a transitional drug that can

bridge the gap between a low dose of methadone and abstinence. At

the present time, however, propoxyphene does not have FDA

approval for the treatment of opiate addiction.

Detoxification

Detoxification has never resulted in very much social rehabilitation or long-term abstinence (8), as patients usually relapse within

the first two months after release from a detoxification program,

sometimes even on the day of discharge. Many patients leave against

medical advice before detoxification is finished (16). Most patients

in a three-week outpatient program relapse to illicit drug use before

they stop receiving methadone. Behavior problems are common

during detoxification, and patients can become very disruptive,

with adverse effects on other patients and staff. Several investigators have found recently that more addicts complete detoxification with fewer behavior problems if they are permitted to alter

their own dose within limits set by the treatment team (48, 49).

This method should increase the short-term success of detoxification. Its long-term results may be improved by following it with

narcotic antagonist treatment.

Narcotic antagonists

Antagonists have been used for many years to treat narcotic

overdoses. Nalorphine was the first in clinical use, but it was used

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

only with caution as it had agonistic as well as antagonistic effects.

It was replaced by naloxone, an excellent antagonist with essentially no agonistic effects. Neither of these drugs is useful for the

treatment of addiction per se, as they are short-acting and

ineffective when given orally unless used in very high doses (39).

However, two antagonists, cyclazocine and naltrexone, have been

developed recently for use in outpatient treatment programs. Both

appear to be safe and effective when administered to detoxified

addicts (50, 51). They are given orally and completely block or

markedly attenuate the effects of narcotics for twenty-four to

seventy-two hours (16). Naltrexone is the superior drug, as it

appears to have no agonistic effects other than occasional gastric

irritation, and it is considerably longer acting (up to 72 hours).

These drugs can be used as “insurance” against relapse, and they are

effective in well-motivated patients. On the basis of favorable

experience with antagonists in selected patients, some treatment

programs are recommending that they be used for two to six

months following detoxification.

Though antagonists are effective pharmacologically, their clinical

usefulness for the majority of patients is uncertain. Most addicts are

not interested in taking them, and most of those who start drop out

within the first month (16). Naltrexone produces no euphoria or

physiological dependence, so it does not have an immediate reward,

nor does it motivate patients to continue in order to prevent

withdrawal symptoms as methadone does. Depot forms lasting 2 to

4 weeks are being developed, and they may result in more

compliance with antagonist treatment. Some programs are experimenting with behavioral reinforcers that may encourage patients to

stay in antagonist treatment longer.

Pharmacologic Treatments for Concurrent

Psychiatric Problems.

Another area of current interest is the treatment of psychiatric

problems that often accompany addiction. Some believe that

psychiatric problems are a prerequisite for the development of

addiction (10, 14, 46, 68, 69). Others feel that narcotic addicts have

minimal inherent psychopathology and that much of the psychopathology noted is a consequence rather than a cause of addiction

(43, 44). Wherever the truth may lie, many studies and clinical

observations indicate that addicts have an assortment of psychiatric

disorders (17, 18, 19). The degree of psychopathology is probably

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WOODY ET AL.: MULTIMODALITY TREATMENT OF ADDICTION

related to the addict’s cultural background. Those individuals who

come from an environment where there are great social pressures

against drug abuse are more likely to have serious psychiatric

problems than are those coming from a background in which drug

abuse is viewed less negatively (22, 23).

One common problem is depression (59). There is considerable

evidence that addicts have a higher incidence of depression than

nonaddict peers. The depression, when present, is probably greatest

at admission (27), but it remains high even after stabilization on

methadone. Some studies have shown that 20 to 40 percent of

patients on methadone maintenance are depressed (52, 60). The

depression is typically mild to moderate, and not the severe,

psychomotor-retarded and delusional type seen on inpatient psychiatric units. If untreated, it may contribute to the severity of the

addiction, since self-medication for depression (or other psychiatric

problems) may be a reason that addicts relapse or continue to use

drugs while being treated with methadone (24). Effective antidepressant treatment may improve outcome, and two pilot studies

have shown that depressed, methadone-treated addicts will respond

to tricyclic antidepressants (53, 65). In one double blind study

comparing doxepin with placebo, patients treated with methadone

and doxepin had less anxiety, less depression, reported less drug

craving and less amphetamine use than patients treated with

methadone and placebo (65).

Many addicts have significant anxiety and may request tranquilizers, especially diazepam and sedative hypnotics. Though these

drugs are effective in reducing anxiety, there is considerable risk

that they will be abused. Addicts not infrequently take 30-80 mg

of diazepam in one dose and say that it creates a peaceful, euphoric

sensation which they describe as a “high.” Continuous use of high

doses of these drugs can produce physiological dependence; we have

observed several instances of this, including three patients who had

grand mal seizures after high dose diazepam was abruptly stopped

(63, 64). Because of its frequent abuse by patients in drug

treatment programs, diazepam should be prescribed with great

caution. It is probably more appropriate to prescribe small amounts

of oxazepam, chlordiazepoxide, doxepin, phenothiazines, or haloperidol for patients who request medication for anxiety. At least

one of these usually works, and none has been noted to be abused

by addicit patients to any significant degree.

Neuroleptics are useful for addicts with psychosis or borderline

personality disorders. Psychoses probably are seen more commonly

in patients who come from high socioeconomic groups (22).

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

Patients with these problems can be very disruptive to their

families, employers, and the treatment program when they are

overtly psychotic or when expressing intense affects such as anger

or acute depression with suicidal behavior. Often, they can be

treated by combining neuroleptics with methadone. Brief hospitalization may be necessary. We have been impressed by the ability of

low doses of haloperidol to attentuate the intense outbursts of

anger or aggression seen in paranoid schizophrenics and borderlines.

It has been noted by clinicians for a long time that methadone

aione appears to have some antipsychotic action (28), but this is

enhanced by adding haloperidol.

Another area of interest is the treatment of alcoholic narcotic

addicts. Alcoholism has been reported in 20 to 80 percent of

narcotic addicts (70), and is a problem among patients on

methadone maintenance. Some workers feel that methadone

treatment increases the severity of alcoholism (11). However, a

recent study has shown that methadone neither increases nor

decreases its severity (1). Some pilot work has shown that

disulfiram (Antabuse) can be used safely with methadone and may

improve treatment outcome (4, 30). At present the Veterans

Administration has started a collaborative project to study the

effectiveness of disulfiram when used as an adjunct to methadone in

the treatment of addicts who are also alcoholic.

Therapeutic Community

Some of the most intensive efforts to treat addiction have been

made by therapeutic communities. These are iong term residential

programs, some lasting for more than two years. They rely heavily

on group therapy and use intense confrontation techniques.

Selectivity in referral is essential in order to screen out those

patients who cannot tolerate the anxiety that is generated. Studies

have shown high rates of rehabilitation in patients who complete

treatment in therapeutic communities (47). Recent work has

demonstrated that positive changes occur in patients who complete

even a portion of the entire program and that those patients who

stay longest tend to improve the most (6). However, all studies of

therapeutic communities are difficult to interpret because there are

self-selection factors operating in those who enter and those who

graduate. Controlled studies are needed to differentiate what part

of outcome is due to treatment and what is due to patient factors.

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WOODY ET AL.: MULTIMODALITY TREATMENT OF ADDICTlON

The practical and ethical problems inherent, in random assignment

of patients to a therapeutic community or a methadone program

make controlled studies of therapeutic communities difficult. They

are four to five times more expensive per patient-year than

methadone programs, and consequently their cost-effectiveness

relative to methadone programs is an area that must be considered.

Outpatient, Psychotherapies Used

With Methadone Maintenance

There is growing interest in studying the effect of outpatient

psychotherapy when combined with methadone maintenance.

Some feel that psychotherapy is one aspect of treatment which, if

improved, wouid lead to better results (32). Family therapy as an

approach has been studied, and some preliminary results show that

it can have a positive effect. In a controlled study completed

recently in Philadelphia, a group receiving structural family therapy

plus methadone did significantly better than control groups

receiving only methadone and routine counselling. The family

therapy patients detoxified more frequently and successfully and

had higher rates of employment than controls (54, 55). At this time

no other controlled studies of family therapy in addiction have

been done, and more work in this area seems indicated.

Individual psychotherapy is another area to be explored. Traditional psychiatric and psychoanalytic teaching has indicated that

analytically oriented psychotherapy is not appropriate for addicts

(67). However, clinicans with experience working in maintenance

programs have expressed the belief that analytic psychotherapy or

a modification of it may be helpful if used in addition to

methadone. It is not clear what type of therapy is most applicable,

but participants in a recent NIDA conference suggested that it

should combine support, structure and self-expression (32). No

controlled studies on the effectiveness of psychotherapy have been

done at this time, and positive results from psychotherapy studies

could have a major impact on the organization and staffing patterns

of methadone treatment programs.

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BEHAVIORAL THERAPIES

Contingency Contracts

Contingency contracts are written agreements between a patient

and his therapist which stipulate that certain behaviors must be

produced within a specified time if the patient is to remain in good

standing. These contracts are used most often for patients who do

not respond to methadone and routine counselling. Some feel that

they may provide the extra push that is necessary to make

something happen (57) and may lead to positive results in as many

as 60 percent of cases (37). Initiating such a contract commits one

to suspending the patient if he does not respond, so it should be

done carefully and selectively.

Deconditioning

Deconditioning techniques aim to diminish the intensity of

drug-seeking behavior. Some patients have been observed to develop

signs and symptoms of narcotic withdrawal following detoxification

when they return to their old neighborhood (62). This has occurred

following months or years of abstinence, such as after release from

long-term incarceration. These withdrawal reactions appear to be

conditioned to environmental stimuli that were associated previously with drug use. Recently, signs and symptoms of conditioned

withdrawal have been reproduced under controlled laboratory

conditions in patients being treated in a methadone program (35).

Conditioning of euphoria and other agonistic effects has also been

observed (41). The significance of these phenomena under clinical

conditions is uncertain. They may account for only a small part of

the tendency to relapse to drug use. Nevertheless, a program to

locate and extinguish these responses in individual patients seems

feasible. A series of experiments is now underway to see whether

extinction of conditioned responses contributes to improved

treatment results (36, 40). In these studies, patients undergoing

treatment with naltrexone are exposed to drug-related stimuli and

gradually desensitized to their effects. Eventually they are permitted to self-inject narcotics while on naltrexone. The antagonist

blocks the rewarding effects of opiates, and the absence of this

reinforcement leads to extinction of the conditioned responses

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WOODY ET AL.: MULTIMODALITY TREATMENT OF ADDICTION

associated with drug injection. This procedure or variations of it

may decrease the intensity of drug-seeking impulses and improve

outcome.

Biofeedback

EMG biofeedback may be useful, especially for the reduction of

anxiety and depression associated with addiction. It has special

appeal because it is a nonpharmacological treatment which offers

the promise of teaching patients techniques which they can use

safely and independently. Several pilot studies have shown that

biofeedback may reduce anxiety and depression (26); however it is

not clear whether these results are treatment effects or nonspecific

(placebo) effects. A recently completed controlled study of

biofeedback has shown that both treatment and control groups

improved significantly and equally (25). More controlled studies are

necessary if actual treatment effects are to be demonstrated.

Milieu Therapy

Certain aspects of the treatment milieu, such as structure,

support, staff quality, doctor time per patient, physical facilities,

staff to patient ratio, and staff cooperation probably affect

outcome (33). Milieu qualities may influence who applies for

therapy, who stays, and how patients respond. Very little work has

been done in examining the treatment milieu of drug programs.

Moos has developed scales to measure environment in general

psychiatric treatment facilities, and his scales may be adapted for

use in addiction programs. It is not known what elements of milieu

are helpful, but structure and support are probably important

qualities. Studies in this area may identify aspects of programs that

influence outcome. This area is complex since the milieu itself is

most likely a result of interactions between the program and

patients enrolled in it. However, it may be possible to identify

qualities of the milieu and relate them to outcome in specific

groups of patients. For example, it may be found that psychopathic

personalities do best in settings that use intense and frequent

confrontation, whereas neurotic patients do poorly in such a setting

and have a better outcome in settings that are less intense and more

supportive.

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

ENDORPHINS

The recent and exciting discovery of endorphins (5, 20) may lead

to a significant breakthrough in understanding and treating addiction. Endorphins are naturally occuring peptides which have

narcotic-like effects. Important basic research is now going on

which may clarify a biological basis for opiate addiction. Interestingly, the hypothesis of such a biological basis for addiction

originally led Dole and Nyswander to propose methadone substitution therapy. The possibility that the strong drug-seeking behavior

of chronic opiate addicts may be influenced by biochemical

deficiencies in endorphins is one of many potential clinical

applications of this line of research.

SUMMARY

In closing, it seems important to add that, when viewed

longitudinally, addiction resembles a chronic medical disease.

Rehabilitation may take several years and improvement rather than

cure may be the most reasonable goal. Disappointment at the lack

of success in finding an effective cure is common, but a relapsing

and remitting course does not necessarily imply failure. Return to

treatment may signal continuing efforts and progression toward

abstinence. Improvement in current techniques may make remissions longer and relapses shorter. Current work on endogenous

opiates (endorphins) may lead to tests which will identify those

patients who can achieve drug-free status and those who can

function only when maintenance opiates are applied.

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program. In: Julius, D., and Renault, P., eds., Narcotic Antagonists:

Naltrexone Progress Report. National Institute on Drug Abuse Research

Monograph 9. DHEW Pub. No. (ADM)76-387. Washington, D.C.: Superintendent of Documents, U.S. Government Printing Office, 1976.

37. O’Brien, C.P.; Woody, G.E.; Khatami, M.; and Stockdale, D. Unpublished

data.

38. O’Brien, C.P. Comment on neonatal addiction. New Eng J Med, 291:311,

1974.

39. O’Brien, C.P., Greenstein, R., Ternes, J., Woody, G.E. Clinical pharmacology of narcotic antagonists. Ann NY Acad Sci, in press.

40. O’Brien, C.P.; Ternes, J.; and Greenstein, R. Unpublished data.

41. O’Brien, C.P. Experimental analysis of conditioning factors in human

narcotic addiction. Pharmacol Rev, 27:533-543, 1975.

42. O’Donnell, J.A.; Voss, H.L.; Clayton, R.R.; Slatin, G.T., and Room, G.W.

Young Men and Drugs–A Nationwide Survey. National Institute on Drug

Abuse Research Monograph 5. DHEW Pub. No. (ADM)76-311. Washington,

D.C.: Superintendent of Documents, U.S. Government Printing Office,

1976.

43. Pescor, M.J. A statistical analysis of the clinical records of hospitalized drug

addicts. Pub. Health Reports (suppl. 143) pp. l-30, 1943.

44. Pfeffer, A.Z., and Ruble, D.C. Chronic psychosis and addiction to

morphine. Arch Neurol Psych, 56:665-672, 1946.

45. Pollin, W. At NIDA Conference on Psychiatric Aspects of Opiate

Dependence, Arlington, Va., March 17-18, 1977.

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46. Rado, S. The psychoanalysis of pharmacothymia (drug addiction). In:

Psychoanalysis of Behavior. New York: Grune & Stratton, 1956.

47. Ramond, A.M.; Forrest, C.K.; and Kleber, H.D. Follow-up of participants

in a drug dependence therapeutic community. Arch Gen Psych,

32:369-374, 1975.

48. Raynes, A.E., and Patch, V.D. An improved detoxification technique for

heroin addicts Arch Gen Psych, 29:417-419, 1973.

49. Razani, J.; Chisholm, D.; Glasser, M.; and Kappeler, T. Self-regulated

methadone detoxification of heroin addicts: An improved technique in an

in-patient setting. Arch Gen Psych, 32:909-911, 1975.

50. Resnick, R.; Fink, M.; and Freedman, A.M. Cyclazocine therapy of opiate

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EN-1639A (Naltrexone): A new narcotic antagonist. Am J Psych,

131:646-650, 1974.

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53. Spensley, J. The adjunctive use of tricyclics in a methadone program. J

Psychedel Drugs 6. (4):421-423, 1974.

54. Stanton, M.D. Some outcome results and aspects of structural family

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Psych, 15:599-609, 1966.

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Clinical depression among narcotic addicts maintained on methadone in the

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Hargrove, E. Diazepam use by patients in methadone program—How

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

66. Woody, G.E.; O’Hare, K.; Mintz, J.; and O’Brien, C.P. Rapid intake: A

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ACKNOWLEDGMENT

The work reported in this paper was supported in part by Grants No.

DA00586 and DA01218 from the National Institute on Drug Abuse.

240
IV.

Treatment: LAAM

Walter Ling

Chairman
CHAPTER 18

Levo-Alpha-Acetylmethadol: New

Drug for Old Habits

Walter Ling, M.D.

INTRODUCTION

Welcome to the symposium on -alpha-acetylmethadol (LAAM).

This symposium deals with the clinical aspects of the development

of LAAM as a pharmacological therapeutic surrogate for the

treatment of chronic heroin addiction. It will review a group of

individual and cooperative studies completed in the past decade,

report on the progress of several ongoing studies, draw some

conclusions on the safety and efficacy of LAAM as a maintenance

treatment agent, and offer some perspective about the future

development of LAAM and its eventual role in the treatment of

narcotic addiction.

Perhaps a good place to begin the story of LAAM is with

methadone maintenance. The idea of a pharmacological approach

to heroin addiction is, of course, not new and has been used in

England for many years.

In the United States, however, for many years before the

introduction of methadone maintenance it was generally believed

that chronic heroin addicts were primarily mentally ill, and that

their craving for narcotics was an epiphenomenon which would

automatically disappear with successful psychological rehabilitation. Treatment was focused on long-term psychological intervention in institutions. The results of these therapeutic approaches

were generally disappointing, because of frequent relapses.

In 1965, Drs. Vincent Dole and Marie Nyswander of the

Rockefeller Institute, New York City, introduced the idea of

methadone maintenance. They believed that the craving for

narcotics exhibited by chronic heroin addicts was based on some

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LING: LAAM — NEW DRUG FOR OLD HABITS

physical, biochemical changes resulting from repeated exposure to

the narcotics and proposed that this aspect of the addict’s problem

can be treated independently and quite apart from other aspects of

social rehabilitation, much like treating diabetics with insulin. In

practice, addicts were maintained on a stabilizing dose of oral

methadone given once daily which relieved them of their everpresent narcotic hunger and thus enabled many of them to become

socially rehabilitated.

Over the next several years, methadone maintenance rapidly

gained popularity, and by the early 1970’s it had become one of the

most widely accepted treatments for heroin addicts in the United

States.

The widespread use of methadone maintenance, however, has not

been without problems. For although its 24-hour duration of action

may seem a vast improvement over the situations with heroin, this

is really too short for the purpose of social rehabilitation. Daily

clinic attendance often interferes with such rehabilitation efforts as

job training, school attendance, and actual employment. Allowing

addicts to take methadone home partially alleviated this situation

but created some serious problems of a different kind. Medications

taken home were sold on the street and became the major

commodity of a new black market for drugs. Reports of primary

street methadone addiction and deaths from accidental poisoning

soon began to appear. The need to find a longer acting methadonelike drug that will reduce this need for take-home medication in

particular and improve the maintenance treatment of heroin addicts

in general led to renewed interest in LAAM.

LAAM, a congener of methadone, was first synthesized in 1948

and underwent early clinical testing as an analgesic. However, the

delayed onset of action and its prolonged time course, leading to

culminative toxicity, limited its clinical usefulness as an analgesic

for acute pain. In the early 1950’s, Fraser and Isbell and their

colleagues (1) had demonstrated that a single oral dose of LAAM

could suppress the symptoms of narcotic withdrawal for up to 72

hours. However, they felt this was not an advantage over methadone, since at that time major medical interest was in detoxification

rather than in maintenance. In 1968, Jaffe and coworkers (2) first

used alpha-acetylmethadol in a narcotic addict treatment program

in Chicago, Illinois. They substituted d- -alpha-acetylmethadol

(DLAAM) three times weekly in a small group of patients

maintained on daily methadone and showed that these patients did

about equally well on acetylmethadol as they did on methadone.

Since the L-form of acetylmethadol was largely responsible for the

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observed clinical effects, subsequent investigations have been

focussed on LAAM.

Many investigators, individually and in collaboration, have

contributed to the clinical development of LAAM in the past

decade. Except for some early individual studies, various members

of this panel have been personally involved in one way or another in

much of this effort. Dr. Jack Blaine, who is the project officer for

LAAM at the National Institute on Drug Abuse (NIDA), will review

the early clinical studies which provided the first indications of

safety and efficacy for LAAM. Most of these were results of

investigations by individual investigators or several investigators

working together at a single site.

By 1972 sufficient data had become available for the safe

conduct of a multihospital large-scale trial. Dr. Jerome Jaffe, Head

of the Special Action Office for Drug Abuse Prevention (SAODAP).

Dr. Samuel Kaim, Chief of the Veterans Administration (VA)

Alcohol and Drug Dependency Service, and Dr. C. James Klett,

Chief of the VA Central Neuropsychiatric Research Laboratory, at

Perry Point, Maryland, were instrumental in the planning of this

12-hospital double blind cooperative study.

As a member of the Executive Committee for that study and as

one of the principal investigators, Dr. Charuvastra is intimately

knowledgeable of the study and will review for this audience the

results of this effort which has been from time to time called

pivotal in the development of LAAM.

Another large scale multicenter study, an open trial designed to

complement the VA study, was initiated in 1973 by SAODAP. Dr.

C. James Klett not only served as the principal investigator and

sponsor for the project but also coordinated the collections and

analysis of the research data, as he did in the VA study. The success

of the two multicenter studies owes much to the untiring effort on

Dr. Klett’s part, and his patience with the investigators and

coordinators has earned him the title “Shepherd of LAAM” among

some investigators. Dr. Klett will review the results of the SAODAP

study. I suspect in his usual relaxed manner he will make the

project sound simple and straightforward, whereas in fact it was

clinically and administratively most complex and complicated.

We believe that the VA and SAODAP cooperative projects, taken

in conjunction with some earlier studies, provide substantial

evidence of safety and efficacy for LAAM. However, at the

conclusion of these studies the number of investigators having

experience with LAAM remained relatively small. In an effort to

bring this experience to a larger number of clinicians and to gather

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LING: LAAM — NEW DRUG FOR OLD HABITS

further safety and efficacy data on this drug, several thousand

patients are being treated in some 60-70 clinics across the United

States under a common protocol sponsored and administered by

Whysner Associates under a contract from NIDA. Dr. John

Whysner, whose involvement in LAAM research dates back to the

earlier SAODAP study, having served as its first project officer at

SAODAP, is head of Whysner Associates and will report on

the progress of this most ambitious undertaking.

The development of LAAM is unique in one other important

respect. I have asked Dr. Pierre Renault to be the final speaker in

this presentation because of his present position as Chief of the

Clinical/Behavioral Branch at NIDA, within which resides the

responsibility for the current efforts on LAAM. Ordinarily, a

pharmaceutical company becomes interested in a certain drug and

undertakes to develop it through various phases of preclinical and

clinical trials until sufficient data on safety and efficacy have been

gathered. It then applies to the U.S. Food and Drug Administration

(FDA) for approval to market the product. In so doing, the

company commits its resources as a developer and hopes for a

return in profit through sales under a patent. The government has

only the role of a regulatory agency. Because LAAM has been in the

public domain for many years and therefore was not patentable,

there was no particular incentive for drug companies to become

interested in its development. The government was thus put in the

peculiar position of having to undertake the major effort to develop

the drug and at the same time to regulate its development. Through

the formation of an Interagency Pharmacological Task Force,

several government agencies have been able to work cooperatively

but maintain their separate and distinct responsibilities. The

eventual approval of LAAM for general use remains with the FDA.

NIDA has more or less assumed the task of assembling the scientific

data to satisfy the FDA’s requirements. Dr. Renault’s office is that

branch of NIDA directly charged with this latter responsibility. The

emphasis of his presentation will be on the current status and the

future perspective of LAAM.

There remain a few loose ends. Much of the clinical data on

LAAM have been gathered in adult male heroin addicts. Little

information is available in females. More work obviously will be

needed here. The pharmacokinetic data on LAAM remain somewhat incomplete. There may be time for us to report on some of

the ongoing work between Sepulveda VA Hospital and the Center

for Human Toxicology at the University of Utah, Salt Lake City.

Several investigators working as a consortium are examining several

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methods of induction and detoxification. For the purpose of this

introduction, I have chosen to share with you the relative

advantages of LAAM in comparison to methadone. Whereas the

bulk of this symposium is focused on how LAAM is being

developed, the examination of its relative merits in comparison to

methadone hopefully will provide some insight into why this work

is of clinical interest. I shall examine this from the standpoint of the

patients, the clinics, and the community at large.

As was alluded to earlier, the 24-hour duration of action of

methadone really is too short for purposes of social rehabilitation.

Many hours have to be spent in traveling to and from the clinics

daily to receive methadone. This interferes with school attendance,

job training, actual employment, and homemaking. Moreover, many

addicts actually feel enslaved by this rigid ritual; they feel tied

down and “hooked” in a new way.

This in turn leads to resentment and anger. Not infrequently,

harsh criticism and charges were made against methadone maintenance treatment as a result of these feelings. Given three times

weekly, LAAM allows the addict more time for other rehabilitative

efforts; it breaks the daily ritual of methadone ingestion, deemphasizes the issue of medication, and may also decrease the degree of

psychological dependence.

For some addicts, a moderate dose of methadone does not

suppress abstinence for the full 24 hours. Many patients arrive at

the clinic on the verge of suffering from withdrawal. They describe

themselves as feeling “icky,” and are irritable, impatient, and easily

provoked. Many confrontations occur between patients and clinic

personnel under these circumstances. On the other hand, at higher

doses, some patients become oversedated soon after receiving their

medication and are at times arrested for being under the influence

of drugs. The longer time course of LAAM eliminates or minimizes

this psychological seesaw phenomenon.

The major problems of street diversion and accidental poisoning

with take-home medication have already been noted. In addition,

patients are sometimes harassed because of their being in possession

of a narcotic even though it was dispensed by a clinic. Occasionally,

genuine loss or thefts of medication also occur, and this may lead to

the patient’s coming under suspicion of selling his methadone.

Usually the patient is unable to prove such losses, and clinics

generally refuse replacement of such medication. The result is that

the patient often feels that his efforts have been futile, that nobody

would trust him no matter how hard he tries.

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LING: LAAM — NEW DRUG FOR OLD HABITS

Many addicts, after being on methadone, find it very difficult or

impossible to discontinue treatment. There is some suggestion,

though hard data remain lacking, that it might be easier to detoxify

from LAAM than methadone. If this proves to be the case from

several ongoing studies, it alone would make LAAM a superior drug

to methadone as far as the patients are concerned.

Perhaps the biggest beneficiaries of LAAM are the clinics. A

three-time-per-week dispensing schedule simplifies the logistics of

drug handling, storage, and bookkeeping, and improves accountability. It gives the clinic staff more time to spend with their patients in

other therapeutic activities and may expand the clinic’s total

treatment capacity.

More importantly, a three-time-per-week dispensing at the clinic

with no take-homes will eliminate the dosage games altogether. In

methadone clinics where take-home medication is allowed, staff and

patients spend an enormous amount of time engaged in dosage

bargaining, because methadone is such a sellable commodity on the

street. It is often impossible to tell whether a complaining patient

genuinely needs more medication or whether he is trying to

convince his doctors to give him more methadone so that he can sell

part or all of it. Consequently, clinic staff try their best to hold the

dosages down, and patients through various means try to increase

them. All this takes time but has little therapeutic value. Moreover,

since take-home privileges often depend on the patient’s ability to

give a urine free of illicit drugs, urine games and tricks, including

bribery, are an integral part of the clinic’s daily routine. Eliminating

take-home medication would remove the incentive on the patient’s

part to obtain more drugs and give the physician more flexibility in

his dosage considerations.

The fact that LAAM has a slow onset of clinical effect makes it

much less likely to be abused by addicts, since there is no

immediate gratification, which is what most addicts are after when

they “fix.”

Predictably LAAM will not totally replace methadone, but its

availability with concurrent modification in clinic practice should

give clinics added flexibility and improve the general strategies of

the pharmacological approach to narcotic addiction.

Improvement in treatment strategies ultimately means cost saving

to the community as a whole. The risk of accidental poisoning will

be vastly reduced, and the methadone black market will hopefully

disappear.

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

REFERENCES

1. Fraser, H.F., and Isbell, H. Actions and addiction liabilities of alphaacetylmethadols in man, J Pharmacol Exp Ther, 105(4):458-465, 1952.

2. Jaffee, J.H.; Schuster, C.R.; Smith, B.B.; and Blachly, P.H. Comparison of

dl-alpha-acetylmethadol and methadone in the treatment of long-term

heroin users: A pilot study. JAMA, 211:1834-1836, 1970.

248
CHAPTER 19

Early Clinical Studies of Levo-Alpha

Acetylmethadol (LAAM): An Opiate

for Use in the Medical Treatment of

Chronic Heroin Dependence

Jack D. Blaine, M.D.

INTRODUCTION

For many years, heroin-dependent individuals were treated by

abrupt or gradual discontinuation of heroin, leading to abstinence.

Resulting withdrawal symptoms were often treated palliatively with

non-opiate medication. The failure of medically controlled heroin

detoxification alone to achieve the goal of long term continued

abstinence has been voluminously documented in the United States.

The reduction of human suffering and freedom from the compulsive search for and use of heroin do have value as a first step in

rehabilitation by permitting a shift to more constructive pursuits.

Efforts at treatment by maintenance of heroin-dependent individuals on legally dispensed heroin also appear to be an inadequate

and impractical treatment approach.

Methadone, a synthetic developed as an analgesic opiate, has a

pharmacological profile similar to morphine. Methadone retains its

activity when taken by mouth and is slowly inactivated (22). Thus,

one oral daily dose of methadone can substitute for several

intravenous doses of heroin.

Dole and Nyswander (9) demonstrated that heroin-dependent

persons could be “stabilized” for extended time periods on a single

daily oral dose of methadone. Dose is gradually increased as

tolerance develops, starting from the dose which relieves the

abstinence syndrome. As dose is raised, a level is reached which

relieves the individual’s craving or “hunger” for heroin but is not

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

intoxicating itself. As the dose level is increased, sufficient tolerance

is induced to block the euphoric effect of intravenous heroin. Thus,

stabilization on methadone frees the individual from heroinoriented hustling and allows participation in a comprehensive

treatment and rehabilitation program. Data generated by several

clinical researchers in the ensuing years indicated the safety and

efficacy of this form of treatment under good medical supervision

(13, 26).

While methadone was an effective agent, several investigators (4,

24, 25) realized in the late 1960’s that a longer-lasting medication

would offer several practical therapeutic advantages. Chemical (6,

38, 42, 10) and pharmacological (11, 12) data already available

suggested the potential clinical usefulness of levo-alpha acetylmethado1 (LAAM), a methadone derivative developed two decades earlier.

CLINICAL PHARMACOLOGY OF LAAM

Extensive investigations of the clinical pharmacology of LAAM

were carried out at the Addiction Research Center, Lexington,

Kentucky (11, 12, 22, 23), using subjects formerly dependent on

opiates and withdrawn. Single doses of LAAM produced morphinelike physiological and subjective effects.

However, Fraser and Isbell (11) commented that “the results

were very peculiar,” based on the time-effect curves by the

parenteral and oral routes of administration. When 10 to 30 mg of

LAAM was given by the subcutaneous and intravenous route, no

objective manifestations of opiate-like action were noted for four to

six hours after injection, after which time the opiate-like effects

slowly became apparent over 12 to 16 hours. The opiate effects

after a single dose were extremely long lasting compared to other

opiates. These effects were always detectable 24 hours after

injection, usually seen at 48 hours, and occasionally persisted for 72

hours. After oral administration of 30 to 40 mg of LAAM, definite,

more intense, morphine-like effects were observed much more

rapidly, within 90 minutes, reaching maximum effect in 4 hours,

and had similar persistent action to the parenteral route. Subcutaneous doses of LAAM given twice daily for several days resulted in

cumulative opiate toxicity including respiratory depression, mental

confusion, altered consciousness approaching coma, and severe

nausea and vomiting.

Fraser and Isbell (11) further demonstrated that single oral doses

of 30 to 60 mg of LAAM rapidly abolished all signs of abstinence in

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BLAINE: EARLY CLINICAL STUDIES OF LAAM

patients who had been stabilized on 400 mg of morphine daily and

abruptly withdrawn 28 hours previously.

Substitution of LAAM for morphine was completely adequate

when 1 mg daily of oral LAAM was substituted for each 6 to 8 mg

of parenteral morphine given four times a day. No withdrawal signs

appeared when the interval between LAAM doses was increased to

72 hours. Definite, but mild, abstinence symptoms developed in all

patients 84 hours after administration of the last oral dose of

LAAM. Following abrupt discontinuation of LAAM, a mild

abstinence syndrome appeared which was quite similar in time

course and intensity to methadone. Gradual reduction of LAAM

dose over a period of seven days did not appear to alter the course

or intensity of abstinence after the last dose.

Thus, LAAM was found to be approximately equally as

efficacious as 1-methadone in alleviating abstinence from morphine

by the oral route, but the drug was inconsistent by the parenteral

route of administration, due to the slow onset but persistent

activity.

Interestingly, Fraser and Isbell (11) suggested LAAM may possess

advantages over methadone and other narcotic analgesics if the

drug’s analgesic effect has as great a duration as the physical

dependence-supporting and miotic actions. They cautioned that “if

the drug is used clinically, it should be given orally in small dose

and at widely separated intervals in order to prevent cumulation of

the toxic effects.”

EVALUATION AS AN ANALGESIC

Early clinical investigation did focus on the usefulness of LAAM

as an analgesic in chronic pain. As predicted, LAAM was less

effective than morphine when administered subcutaneously, and

the onset of analgesic activity was delayed for about 90 minutes.

Delayed cumulative toxic effects of opiate overdose were noted

when larger doses of LAAM were given more than once daily to

nontolerant chronic pain patients (1, 35). Effective analgesia with

extended duration was noted with lower doses of orally administered racemic alpha acetylmethadol (7, 8). The LAAM metabolite,

nor-LAAM, was shown to be a more potent analgesic than

morphine or LAAM, and toxic side effects were less when taken by

mouth (16). Analgesic effects were equivalent with a similar time

course to morphine when nor-LAAM was given parenterally (18).

However, the delayed onset of action, prolonged time course, and

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

cumulative effect limited the clinical usefulness of LAAM and

nor-LAAM for analgesia, and its development was not undertaken

by the pharmaceutical industry.

CLINICAL PSYCHOPHARMACOLOGY OF LAAM

Irwin, Blachly and co-workers (20, 21) compared in double

blind, randomly controlled studies the psychopharmacological

profiles of 0.1 to 0.2 mg/kg doses of oral methadone and LAAM in

nontolerant subjects. Peak effects occurred after three to four hours

for both drugs. Durations of action were similar for both drugs at

lower doses, but at higher doses the action of methadone lasted less

than 12 hours, while LAAM persisted over 24 hours. The higher

dose of LAAM produced similar but somewhat less intense

subjective effects than the lower dose of methadone.

Biphasic effects were noted for both drugs, with early activation,

elevation of mood, and liking for the drug, followed by a later

depressant effect and dislike for the drug. The effects of LAAM

were primarily activating, including slightly increased capacity for

functioning; increased arousal, drives, energy, speed, and durations

of movement and expressiveness; and slightly improved mood. In

contrast, depressant effects predominated with methadone, including impaired arousal, focusing, and psychomotor activity; distorted

perceptions; and worsened mood. Methadone and LAAM were

quantitatively equipotent in many other effects characteristic of

opiates, including causing ataxia, unusual body sensations, distortion of sensations, impaired memory, reduced impulse control, mild

headaches, itching, nausea and vomiting, facial pallor, slowed

respiratory rate, and miosis.

EVALUATION OF CROSS TOLERANCE TO

INTRAVENOUS OPIATES

Several investigators have studied the development of cross

tolerance by LAAM to the effects of intravenous opiates. Irwin and

coworkers found that LAAM was usually effective in providing

blockade to 30 mg of morphine sulfate in subjects stabilized on a

variety of LAAM doses. Occasionally, a slight high was reported,

usually within 8 hours or after 48 hours of LAAM consumption.

Subjects could distinguish morphine from placebo and experience a

slight rush (20).

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BLAINE: EARLY CLINICAL STUDIES OF LAAM

In studies by Zaks and Fink (45), LAAM provided complete

blockade to 25 mg of intravenous heroin for 24 hours after last

dose in subjects rnaintained on low doses (30 to 40 mg twice

weekly and 50 mg on Friday), while 50 mg of heroin produced

mild, transient euphoria. LAAM provided complete blockade to 25

and 50 mg of heroin for 24 hours in subjects maintained on high

dose LAAM (80 mg Monday, Wednesday, and Friday) or methadone (100 mg daily).

In another study (37), a dose-response curve was established for

the dose of LAAM and blockade of 25 mgm of intravenous heroin

given 72 hours after the previous LAAM dose in maintenance

patients. At dose levels of 30 mg of LAAM given Monday,

Wednesday, and Friday, some effects of heroin were experienced.

At 50 mg levels, no effect of heroin was perceived by the subjects,

but slight pupillary constriction was detected. At dose levels of 70

mg and above, blockade was complete. Interestingly, this approximated the dose-response curve of LAAM to produce sustained

maximum pupillary constriction (miosis): 20 mg for 24 hours;

30-50 mg for 48 hours; 80-90 mg for 72 hours.

METABOLISM AND PHARMACOKINETICS

The recent development of methodologies for identifying and

quantitating levels of LAAM and its metabolites in human biofluids

(31) has stimulated interest in the metabolism and pharmacokinetics of LAAM. The delayed onset, long duration of action,

differences by oral and parenteral routes of administration, and

cumulative effects of LAAM have, in part, been attributed to the

biotransformation to two active metabolites, nor-LAAM and

dinor-LAAM by the n-demethylating enzymes in the liver (2).

Several studies indicate that the opiate-like effects of LAAM may

be determined primarily by these metabolites rather than the parent

compound (3, 14, 17, 30). Because of the potential clinical

usefulness of this information for clinical management, further

studies are currently going on in this area.

CLINICAL TRIALS AS A MAINTENANCE DRUG FOR

TREATMENT OF HEROIN DEPENDENCE

Jaffe and co-workers in Chicago (24, 25) initiated in the late

1960’s the first clinical trials of acetylmethadol based on the

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

indications of human safety and efficacy as a long-acting opiate

maintenance drug suggested by the earlier clinical pharmacological

studies at the Addiction Research Center. In a series of well-controlled, double-blind studies (24, 25, 27, 28, 29, 40), these researchers

investigated the safety and efficacy of LAAM and racemic

acetylmethadol compared to methadone in chronic heroindependent persons. Subjects already stabilized on methadone were

randomly assigned to LAAM or methadone. The experimental

groups received LAAM on Monday, Wednesday, and Friday, and

dextramethorphan placebo on alternate days, while the control

group received methadone daily.

Generally, these controlled clinical trials revealed few differences

between LAAM and methadone patients on outcome measures of

use of heroin and other illicit drugs, illegal activity and arrests,

employment, education, clinic attendance, patient acceptance, or

dosage changes. They confirmed earlier findings that LAAM can be

administered at 48 to 72-hour intervals without the development of

an opiate abstinence syndrome.

Few unusual reports of toxicity or side effects were noted. These

adverse reactions which did occur were particularly associated with

excessive dosage. Similar reactions were not uncommonly reported

with methadone and would be considered common to all opiates.

Results of hematology, blood chemistry, urinalysis, and physical

examinations revealed few differences between LAAM and methadone patients. Most results have been within normal limits, and

treatment commonly produced an improvement in some abnormal

pretreatment laboratory values. The isolated deaths which occurred

during the study were not related to LAAM or methadone.

Although there were several reports of anxiety and nervousness in

an earlier study with racemic acetylmethadol, these were not

present using LAAM. No occurrences of confusion, unpleasant

subjective states, or psychotic symptoms caused by LAAM were

reported. Several instances of nightmares and anxiety and one

report of a dissociative state with bizarre behavior were reported

(41).

In the years following the reports of the initial pilot studies,

several additional teams of investigators conducted clinical trials

with LAAM (4, 15, 19, 36, 39, 41, 45). Generally, these studies

confirmed the findings of comparable safety and effectiveness of

LAAM and methadone as maintenance drugs for use in the

treatment of chronic heroin-dependent persons. Approximately 750

patients were given LAAM in these studies. Dosages varied widely,

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BLAINE: EARLY CLINICAL STUDIES OF LAAM

with a mean LAAM dosage of 60 mg three times weekly and a range

of 20 to 90 mg.

Most of these investigators found that LAAM given Monday,

Wednesday, and Friday prevented the occurrence of withdrawal

symptoms equally to methadone given seven times a week. Some

reported that increasing the dosage either at each administration or

on Friday was necessary to completely prevent abstinence symptoms for 72 hours (36, 45). However, the results of a double-blind

controlled study by Goldstein (15) suggest that complaints of

LAAM not holding over the entire weekend were psychological

rather than pharmacological in origin and arose out of the patient’s

attitude and concern that the medication would not prevent

withdrawal for 72 hours. Great individual variation was noted in the

dosage that will prevent abstinence for 72 hours.

Treatment outcome measures were generally found not to show

significant differences between LAAM and methadone treatments.

The main differences between LAAM and methadone treatment

groups noted in all these studies is that a larger percentage of

LAAM patients than of methadone patients drop out of the study,

although the differences were often not statistically significant. The

dropouts tended to occur early in the studies during the stabilization phase. These early dropouts may be partially related to

psychological concerns about taking an “experimental” new drug.

Thus, any minor symptom experienced by the patient may be

attributed to the “experimental” drug and be perceived as proof

that it won’t work. As discussed previously, LAAM does have a

delayed onset because of the time required to metabolize LAAM to

its more active metabolites and build up pharmacologically active

blood levels. Thus, initial discomfort may occur in some patients

dependent on large doses of heroin or methadone who are not given

adequate starting doses of LAAM, or for patients who slowly

convert LAAM to its active metabolites.

Results of these studies confirmed the absence of significant

toxicity or adverse reactions for both LAAM and methadone.

Laboratory tests and physical examinations were generally normal

and unchanged by the drug. The few adverse experiences which did

occur were general opiate effects attributable to excessive dosage of

LAAM or administration more frequently than three times a week,

with resultant accumulation of active drug.

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

SUMMARY

Opiate maintenance with methadone has been demonstrated to

be an effective treatment modality for many chronic heroindependent individuals. However, the many clinical and societal

advantages of a longer-lasting medication prompted the development of LAAM, which could be administered three days a week

rather than daily. Early Phase II clinical trials of LAAM in about

750 patients have been reviewed and have demonstrated the safety

and effectiveness of this drug and confirmed its usefulness for

treatment of this chronic disease.

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narcotics in man. J Pharmacol Exp Ther, 108:158-167, 1953.

2. Billings, R.E.; McMahon, R.E.; and Blake, D.A. L-acetylmethadol (LAAM)

treatment of opiate dependence: plasma and urine levels of two pharmacologically active metabolites. Life Sci, 14:1437-1446, 1974.

3. . L-acetylmethadol treatment of opiate dependence: the crucial

role of active metabolities. Fed Proc, 33(3):473, 1974.

4. Blachly, P.H. L-alpha-acetylmethadol in the treatment of opiate addiction:

Progress Report, 1971. In: Blachly, P.H.. Ed. Methadone, 1971 Workshop

Proceedings. Corvallis, Oregon: ACEB Books, 1971. pp. 23-25.

5. Blachly, P.H.; David, N.A.; and Irwin, S. Alpha-acetylmethadol (LAM):

comparison of laboratory findings, electroencephalograms, and Cornell

Medical Index of patients stabilized on LAM with those on methadone.

Proc of Fourth Natl Conf on Methadone Treatment, San Francisco: Jan.

1972, pp. 203-205.

6. Chen, K.K. Pharmacology of methadone and related compounds. Ann NY

Acad Sci, 51:83-97, 1948.

7. David, N.A., and Semler, H.J. Clinical trial of alpha-acetylmethadol

(dl-6-dimethylamino-4, 4-diphenyl-3-acetoxy-heptane) as an analgesic. J

Pharmacol Exp Ther, 106: 380, 1952.

8. David, N.A.; Semler, H.J.; and Burgner, P.R. Control of chronic pain by

dl-alpha-acetylmethadol. JAMA, 161(7):599-603, 1956.

9. Dole, U.P., and Nyswander, M.A. A medical treatment for diacetylmorphine (heroin) addiction. JAMA, 193:646-650, 1965.

10. Eddy, N.B.; Touchberry, C.F.; Lieberman, J.E.; and Khazan, N. Synthetic

analgesics; methadone isomers and derivatives. J Pharmacol Exp Ther,

98:121-137, 1950.

11. Fraser, H.F., and Isbell, H. Actions and addiction liabilities of alphaacetylmethadols in man. J Pharmacol Exp Ther, 105(4):458-465, 1952.

12. Fraser, H.F.; Nash, T.L.; Vanhorn, G.D.; and Isbell, H. Use of miotic effect

in evaluating analgesic drugs in man. Arch Int Pharmacodyn Ther,

98:443-451, 1954.

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BLAINE: EARLY CLINICAL STUDIES OF LAAM

13. Goldstein, A. Heroin addiction and the role of methadone in its treatment.

Arch Gen Psychiatry, 26:291-297, 1972.

14. Goldstein, A. LAAM and LAAM metaholites: plasma levels in patients.

Summary progress report. Stanford, California: Stanford University, 1975.

(Unpublished.)

15. Goldstein, A., and Judson, B. Three critical issues in the management of

methadone programs: Critical Issue 3: Can the community be protected

against the hazards of take-home methadone? Addiction. Peter G. Bourne,

ed. New York: Academic Press, pp. 140-148, 1974.

16. Gruber, CM., Jr., and Babtisti, A., Jr. Estimating the acceptability of

morphine of noracetylmethadol in postpartum patients. Clin Pharmacol

Ther, 4(2):172-181, 1962.

17. Henderson, G.L. A two-year pharmacokinetic study of LAAM. Progress

report. Prepared under Contract HSM 42-73-211 at the University of

California at Davis. 1974-76. (Unpublished.)

18. Houde, R.W.; Murphy, T.W.; and Wallenstein, S.L. Clinical studies of

narcotics at Memorial Sloan-Kettering Cancer Center: A. Relative analgesic

potencies of (1) noracymethadol (d- -3-acetoxy-6-methylamino-4, 4-

diphenyltheptane) and morphine; (2) dextropropoxyphene and pethidine;

(3) Ro-4-1778/1 (1-[p-chlorophenethy]-6, 7-dimethoxy-2-methyl-1, 2, 3,

4-tetrahydroisoquinoline) and codeine; (4) oral codeine and morphine. B.

Relative respiratory depressant potencies of piminodine (ethyl 4-phenyll-[3-phenylamino-propyl]-4-piperadine carboxylate) and morphine. Committee on Drug Addiction and Narcotics and the Committee on Problems

of Drug Dependence, National Research Council, Division of Medical

Sciences. 24th Meet., App. 14, p. 2852. Sloan-Kettering Cancer Center,

New York, New York, 1962 (Unpublished.)

19. Irwin, S.; Blachly, P.H.; Marks, J.; Carlson, E.; Loewen, J.; and Reade, N.

The behavioral cognitive and physiologic effects of long-term methadone

and methadyl treatment. University of Oregon Medical School, Portland,

Oregon. 1973. (Unpublihsed.)

20. Irwin, S.; Blachly, P.; Marks, J.; and Carter, C. Preliminary observations

with acute and chronic methadone and 1-alpha-acetylmethadol administration in humans. University of Oregon Medical School, Portland, Oregon,

1973. (Unpublished.)

21. Irwin, S.; Kinohi, R.; Cooler, P.; and Bottomly, D. Acute time-doseresponse effects of cyclazocine, methadone, and methadyl in man.

Prepared under NIMH Contract ND-72-115 at University of Oregon

Medical School, Portland, Oregon, 1973. (Unpublished.)

22. Isbell, H.; Wickler, A.; Eisenman, A.J.; Daingerfield, M.; and Frank, E.

Liability of addiction to 6-dimethlamino-4-4-diphenyl-3-hepatone in man.

Arch Intern Med, 82:362-392, 1948.

23. Isbell, H.; and Fraser, H.F. Addictive properties of methadone derivatives. J

Pharmacol Exp Ther, 13:369-370, 1954.

24. Jaffe, J.H.; Schuster, C.R.; Smith, B.B.; and Blachly, P.H. Comparison of

acetylmethadol and methadone in the treatment of long-term heroin users:

A pilot study JAMA, 211:1834-1836, 1970.

25. Comparison of dl-alpha-acetylmethadol and methadone in the

treatment of narcotics addicts. Pharmacologist, 11(2):256, 1969.

26. Jaffe, J.H. The maintenance approach to the management of opioid

dependence. In: Zarafonetis, Chris J.D., Ed. Drug Abuse: Proceedings of

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

the International Conference. Philadelphia: Lea and Febiger, 1972. pp.

161-170.

27. Jaffe, J.H., and Senay, E.C. Methadone and -methadylacetate. Use in

management of narcotics addicts JAMA, 216:1303-1305, 1971.

28. Jaffe, J.H.; Senay, E.C.; and Renault, P.F. A six-month preliminary report

of the rehabilitative efficacy of -methadyl acetate compared to methadone. Proceedings of Fourth National Conference on Methadone Treatment, San Francisco: Jan. 1972. pp. 199-201.

29. Jaffe, J.H.; Senay, E.C.; Schuster, C.R.; Renault, P.F.; Smith, B.; and

DiMenza, S. Methadyl acetate vs methadone. A double-blind study in

heroin users JAMA, 222(4):437-442, 1972.

30. Kaiko, R.F.; Chatterjie, N.; and Inturrisi, C.E. Simultaneous determination

of acetyl-methadol and its active biotransformation products in human

biofluids. J Chromatogr, 109(2):847-858, 1975.

31. Kaiko, R.F., and Inturrisi, C.E. A gas-liquid chromatographic method for

the quantitative determination of acetylmethadol and its metabolites in

human urine. J Chromatogr, 82(2):315-321. 1973.

32. . Disposition of acetylmethadol in relation to the pharmacological activity. Clin Pharmacol Ther, 18(1):96-103. 1975.

33. . Identification of some biotransformation products of acetylmethadol in human urine. Fed Proc, 32:764Abs, 1973.

34. . Time course of plasma levels of acetylmethadol and biotransformation products in relation to pharmacological activity in man. Fed Proc,

33(3):473, 1914.

35. Keats, A.S., and Beecher, H.K. Analgesic activity and toxic effects of

acetylmethadol isomers in man. J Pharmacol Exp Ther, 105:210-215,

1952.

36. Lehmann, W.X. The use of z-alpha-acetylmethadol (LAAM) as compared to

methadone in the maintenance and detoxification of young heroin addicts.

Vitam Center, Norwalk, Connecticut, 1973. (Unpublished.)

37. Levine, R.; Zaks, A.; Fink, M.; and Freedman, A.M. Levomethadyl acetate.

Prolonged duration of opioid effects, including cross tolerance to heroin, in

man. JAMA, 226(3):316-318, 1973.

38. Pohland, A.; Marshall, F.J.; and Carney, T.P. Optically activity compounds

related to methadon. J Am Chem Soc, 71:460-462, 1949.

39. Savage, C.; Karp, E.; and Curran, S. A methadone/z-alpha-acetylmethadol

(LAAM) maintenance study. Compr Psychiatry, 17(3):6415-424, 1976.

40. Senay, E.C.; Jaffe, J.H.; diMenza, S.; and Renault, P.F. A 48-week study of

methadone, methadyl acetate, and minimal services. In: Fisher, S., and

Freedman, A.M., eds. Opiate Addiction: Origins and Treatment. Washington, D.C.: V.H. Winston & Sons, 1973.

41. Senay, E. C.; Renault, P.F.; diMenza, S.; Collier, W.E.; Daniels, S.J.; and

Dorus, W. Three times a week LAAM equals seven times a week

methadone: A preliminary report of a control study. Reported to the

Committee on Problems of Drug Dependence, May 19-21, 1975.

42. Speeter, M.E.; Byrd, W.M.; Cheney, L.C.; and Binkley, S.B. Analgesic

carbinols and esters related to amidone (methadon). J Am Chem Soc,

71:57-60, 1949.

43. Wilson, B.K. Research report of clinical effects of z-alpha-acetylmethadol

on man observed during pharmacokinetic studies. Yolo County Mental

Health Service, Broderick, California. (Unpublished.)

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BLAINE: EARLY CLINICAL STUDIES OF LAAM

44. Zaks, A.; Fink, M.; and Freedman, A.M. -alpha-acetylmethadol in

maintenance treatment of opiate dependence. Proc. of Fourth National

Conference on Methadone Treatment, San Francisco: Jan. 1972. pp.

207-210.

45. . Levomethadyl in maintenance treatment of opiate dependence.

JAMA, 226(6):811-813, 1972.

259
CHAPTER 20

A U.S. Veterans Administration

Cooperative Study on Methadyl

Acetate

V. Charles Charuvastra, M.D.

Street diversion and accidental poisoning are complications of

methadone maintenance, resulting directly from the drug’s short

duration of action. These problems might be avoided by employing

a longer acting, methadone-like drug that could be ingested by

patients at the clinic at less frequent intervals, without the need of

take-home medication. One such substance is levomethadyl acetate.

Methadyl acetate is a derivative of methadone. Early clinical studies

by Fraser and Isbell (2) demonstrated its ability to suppress

symptoms of opiate withdrawal and its long duration of action. A

pilot study comparing methadyl acetate with methadone maintenance of chronic heroin addicts observed that former addicts who

had made satisfactory social adjustments while receiving oral

treatment with methadone continued to do as well while taking

methadyl acetate three times weekly during a five week period of

observation (3).

In subsequent studies chronic heroin addicts were treated with

either methadone or methadyl acetate. No significant differences in

terms of patient acceptance, illicit drug use, employment, criminal

activities, frequency of clinic attendance, or medical safety were

noted (4, 5). In another study street heroin addicts were randomly

assigned, after detoxification with methadone, to a methadone or a

methadyl acetate group. No differences were noted in patient

acceptance, withdrawal symptoms, response to heroin challenges, or

positive urine tests between the methadone group and the high-dose

methadyl acetate group (6).

Laboratory findings in these early studies showed few differences

between methadyl acetate and methadone patients. In a comparison

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CHARUVASTRA: COOPERATIVE STUDY ON METHADYL ACETATE

study the only statistically significant finding was slight hyperglycemia in the methadyl acetate group (1). Adverse reactions to

methadyl acetate were rarely reported.

Although these early studies tend to substantiate the initial

observation of the clinical usefulness of methadyl acetate, the

number of patients studied was quite small. The present study

attempted to maximize subject availability by means of multihospital participation in a common protocol. The goals of the study

were to evaiuate the safety and toxicity of a fixed dose of methadyl

acetate (80 mg. three times weekly) and to compare its relative

efficacy with two doses of methadone hydrochloride, a high (100

mg.) and a low (50 mg.) daily dose. The present study was initiated

as a double blind, multihospital cooperative project in 12 U.S.

Veterans Administration Hospitals on April 16, 1973; the last

patient completed the study on March 21, 1975.

METHOD

Patients

Patients were male, military service veteran heroin addicts who

met all of the criteria for admission to methadone maintenance

programs as defined by the U.S. Food and Drug Administration

(FDA), were not currently enrolled in some other methadone

treatment program, and were between the ages of 18 and 60.

Patients were excluded for incapacitating or life-threatening conditions, disease requiring regular, repeated medication, frankly

psychotic states, epilepsy, current severe alcoholism, and pending

criminal charges. Eligible patients who signed an informed consent

for voluntary participation in the study were then given a general

physical examination, with neurologic and psychiatric evaluations.

Procedure

Patients were randomly assigned to levomethadyl acetate or one

of two dose levels of methadone. The two methadone groups

received active medication daily, but the methadyl acetate group

received active medication on Monday, Wednesday, and Friday,

with placebo on all other days. All doses were dispensed in a

masking-diluting liquid, such as orange drink or grapefruit juice.

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

The first dose in all three groups was 30 mg., which was increased

by 10 mg. on each succeeding Monday until the patient achieved his

target dose of 50 mg. of methadone hydrochloride (M-50), 100 mg.

of methadone hydrochloride (M-100), or 80 mg. of methadyl

acetate (L-80). All doses were dispensed double blind. Duration of

treatment was 40 weeks.

Patients’ conditions were evaluated immediately before and every

four weeks during their tenure in the study. The evaluation

included a brief history, a current status record of their employment activity, legal involvement, interpersonal relationships, and

drug use during the preceding four weeks, a supplementary

medication record, and a symptom-sign checklist. The complete

physical examination was repeated at the 12th week and at the end

of the study, with abbreviated physical examinations at all other

four-week evaluations. Each patient’s adherence to the clinic

schedule of visits and details of medication dispensed were

recorded. Whenever a patient concluded treatment, an attempt was

made to repeat all evaluations.

The first level of responsibility for the safety of patients in the

study was assumed by the principal investigator at each participating

hospital, who was in a position to make direct clinical observations

and who reviewed all laboratory and other data prior to their

submission to the data processing center. The second level of review

was performed by the study chairman, who was regularly provided

with an updated computer listing of laboratory values, vital signs,

and symptom-sign ratings of each patient. Every three to six

months, the data processing center performed extensive statistical

analyses for group differences on all safety variables and prepared

data displays to show changes in individual patients. During the

trial, emphasis was placed on the evaluation of safety-toxicity. In

the early months of the study there was great dependence on

clinical monitoring by the principal investigator and the study

chairman. However, several additional series of analyses incorporating the hospital as a factor were done to supplement the

convariance analyses and the trend analyses. Analysis of symptomsign data was initially evaluated by X (to the second power) during

the monitoring stage, but when sufficient data had accumulated to

make it meaningful, the items were factor analyzed.

Several indices of efficacy were monitored throughout the study.

In all of these analyses a probability less than .05 was accepted as

the level of statistical significance.

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CHARUVASTRA: COOPERATIVE STUDY ON METHADYL ACETATE

RESULTS

Characteristics of Sample

The sample consisted of 430 men whose median length of

addiction to opiates was 7.3 years. They were reasonably young and

reasonably well educated. Most had been married at one time, but

37 percent were still single. Racially, 46 percent were black, 39

percent white, and 11 percent had Spanish surnames. Employment

characteristics were consistent with expectation in an addict group.

The sample cannot be considered to be representative of all

addicts in the United States since it was limited to male veterans of

the armed forces. Additionally, the regional distribution of the

sample is vastly different from the addict population in this

country: 44% were admitted to four California clinics, while the

East accounted for only 26%.

Program Retention

Only 42 percent of the starting sample completed the full 40

weeks of the study: 69 percent terminated early from the L-80

group, 58 percent from the M-50 group, and 48 percent from the

M-100 group. This difference between the L-80 and M-100 group is

statistically significant. It has to be concluded that high-dose

methadone maintenance (M-100) was superior in retention to the

L-80 group. It does not necessarily follow that high-dose methadone is the superior maintenance drug, however, because there are

other dimensions of outcome that must be considered.

The average length of stay in the study before early termination

was remarkably similar for the three groups: 82 days for the two

methadone groups and 81 days for the L-80 group. To summarize,

most terminations occurred in the early weeks, and over all there

was a greater number of L-80 terminators than M-100 terminators,

but this difference is not concentrated in the early weeks. Broad

categories of termination were established and the only significant

differences between groups for these specific categories of dropout

were a greater number of terminations for side effects in the L-80

group than in the M-50 group, and a greater number of “no-shows”

in the L-80 group than the M-100 group.

Great variation among clinics is evident in the early termination

data. The percentage of terminators was quite low in two California

clinics (23 percent and 30 percent), but 75 percent or higher in

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

seven other clinics. Furthermore, the average time in the study for

terminators in these two California clinics was relatively long (151

days and 140 days) compared to most other clinics. As a final

contrast, one clinic had 85 percent early terminations, 82 percent

of which occurred in the first eight weeks (for an average length of

stay of 21 days), while the best record was 23 percent early

terminators, 15 percent of which dropped out in the first eight

weeks for an average length of stay of 151 days.

Safety

There were no deaths of study patients, nor were any serious

adverse reactions reported. There were 11 patients terminated

primarily for side effects: Four L-80 patients terminated because of

inability to ejaculate, and another L-80 patient who was terminated

because of swelling joints listed in addition decreased sexual interest

along with heartburn, nodding, and constipation. The other L-80

terminators were a patient who could not keep medication down

(nausea and vomiting) and dropped out after 16 days; another who

complained of being tired and dizzy with chest and arm pain, and

one who experienced jerking of extremities at bedtime as well as

some nausea. Of the three high-dose methadone patients who were

terminated, one developed a pruritic maculopapular rash on the

second day while the patient was still receiving 30 mg., one had

abnormally high liver function values, which were present before

treatment, but showed only minor trends towards stabilization at a

lower level, and the third was an apparent case of bone marrow

suppression.

As a general statement, reporting of any symptom-signs was

infrequent and those that were reported were not severe. In only

three instances was there a significant drug difference: aching bones

and joints, for which the M-50 group had a significantly higher

frequency of moderate to severe ratings than either of the other

groups; insomnia, for which the M-50 group had a significantly

higher frequency than the M-100 group, and anxiety, for which the

M-50 group significantly exceeded the L-80 group in terms of

moderate to severe ratings.

It is worth noting that the L-80 group was equal to or lower than

whichever methadone group had the greatest number of severe

ratings on 26 of the 31 symptom-signs. Each patient’s pattern of

symptom-sign ratings was reviewed together with his urine test

results, his clinic visit record, his laboratory data, and his record of

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CHARUVASTRA: COOPERATIVE STUDY ON METHADYL ACETATE

adjunct medication. This gave a much clearer idea of the patient’s

total experience in the study, but did not add to or substantially

change the results already presented.

The hematologic tests, blood chemistry studies, vital signs, and

weight provided 25 comparisons for each of the ten test periods.

Only six of these were statistically significant. Three of these

occurred on a single variable, weight. The others represented a

difference between groups at one period only: white blood count at

week 20, calcium at week 36, and alkaline phosphatase at week 16.

Two cohorts of patients were established, to permit investigators to

look specifically at changes over time rather than cross sectionally.

The 24-week cohort consisted of patients who had a complete set

of data on a variable at pretreatment and every test period for the

first 24 weeks. There was a single significant finding: the interaction

of drug and time on weight. In the analysis of the same variables

using the 40-week cohort, there was a significant interaction for

total WBC. total red blood count, hematocrit reading, hemoglobin

level, and weight. In addition, there was a significant difference

between groups for SGOT level when all values were collapsed

across time.

In another series of analyses, a cohort of 128 patients from three

hospitals who had a complete set of values over a 20-week period

were used to provide similar, but somewhat different, information.

In these analyses, the pretreatment value was included as a

covariate, and all subsequent values were adjusted for initial level.

Hospital was included as a factor in the design, which permitted a

comparison of hospitals and the various interactions of hospital

with drug and time. In these analyses, the only main effects of

treatment that reached significance were weight and pulse rate.

There were significant interactions between drug and time on

hematocrit reading, hemoglobin level, and SGOT level.

A final attempt to gain precision and extract information about

any drug group changes present in the data consisted of a series of

multivariate analyses of covariance. The following hematologic tests

were analyzed simultaneously: WBC, RBC, neutrophils, lymphocytes, hematocrit, and hemoglobin. There were no significant

differences involving treatment group in these analyses. The renal

tests (calcium, BUN, and uric acid) were analyzed in the same

manner and with the same result. In the analysis of liver function

tests there was a significant difference between groups at the 16th

week only. The multivariate test of vital signs and weight was

significant at the fourth week only.

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

Each of these different analyses supplies somewhat different

information and needs to be further examined and integrated. In

the hematologic tests, all means at all test points were within the

normal range. There is a suggestion that something might have been

happening with WBC in at least some patients during the middle

weeks, but it is difficult to give clinical meaning to it because it did

not persist; all means are comfortably in the normal range, and a

review of individual patients’ data did not identify anything

remarkable about this part of the treatment period. Red blood cell

count, hematocrit reading, and hemoglobin level surfaced as

possibly significant (in a clinical sense) on the cohort analyses only.

The evidence for RBC count is not convincing. There was some

initial decline in RBC count which then leveled off. Considering the

results of the multivariate tests that included all of these variables as

well, it seems reasonable to conclude that the occasional betweengroups differences that did emerge as statistically significant have

no clinical importance. In no case were the blood changes sufficient

to necessitate termination from the study.

The evaluation of renal and liver function tests was similarly

clinically reassuring. The level of SGOT was noteworthy for the fact

that the means of all three drug groups before and throughout

treatment were well above the usual normal range (from a low 56 to

107), and the pretreatment values for many individual patients were

high enough to be of serious concern in a nonaddict sample. All

three groups show essentially no change across time on SGOT level.

The analysis of vital signs and weight had a generally low yield,

except for weight, which is clearly affected by all three drug

regimens, particularly methadyl acetate. There is clearly an upward

trend in all groups, and somewhat more substantially so in the L-80

group. The average weight gain at week 12 was 1.02 kg for the M-50

group, 1.48 kg for M-100, and 2.86 kg for L-80; at week 24, it was

2.30 kg for M-50, 2.64 kg for M-100, and 5.12 kg for L-80; and at

week 32, it was 2.43 kg for M-50, 3.79 kg for M-100, and 5.63 kg

for L-80. No morbid obesity was reported. Nothing of interest

appeared in the data from routine urinalyses.

There is abundant evidence that both methadyl acetate and

methadone hydrochloride will maintain addicted individuals without their having to resort to supplementary (illicit) narcotic use to

avoid withdrawal. It seems reasonable to assume efficacy in this

sense and turn to the question of the relative efficacy of the three

drug regimens.

Urine drug testing data are considered to be the key to evaluation

of the results of this study. Not only is this considered the most

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CHARUVASTRA: COOPERATIVE STUDY ON METHADYL ACETATE

important outcome, but it provides a way of evaluating the

secondary or contingent variables. The amount of drug use is, of

course, important, but the pattern is probably even more so.

An index of illicit morphine use has been derived that takes into

account total use and pattern of use. This index was developed

completely independently of the study data and was therefore not

biased by a knowledge of drug group outcomes (Klett and Ling,

personal communication). Using this index to compare the three

drug regimens gave the following results: 110 M-50 patients had a

urine index of 33.3, 111 M-100 patients had an index of 22.6, and

96 L-80 patients had an index of 20.8. The “F” was 6.19 (p<.005).

The M-50 group was significantly higher on the urine index than

either M-100 (P<.05) or L-80 (P<.01).

Urine test data were analyzed in other ways as well. For each

patient, the number of urine tests positive for morphine was divided

by the number of specimens tested. A similar score was calculated

for barbiturate positive, amphetamine positive, and “something”

positive, the latter being the number of specimens positive for

either morphine, barbiturates, amphetamines, or cocaine. The

results of these analyses showed the L-80 group less likely to use

illicit barbiturates than the M-50 group (P=.014).

Another kind of outcome index is program conformity, which

was defined as each patient’s number of actual scheduled clinic

visits divided by his total number of expected scheduled visits for

however long he was in the study. The M-50 group had an average

of 92 percent attendance; M-100, 95 percent; and L-80, 90 percent

(F=5.34, P<.01). The difference between M-100 and L-80 on this

clinic visit index was significant at P<.01. However, since the

methadyl acetate patients only received active medication on

Mondays, Wednesdays, and Fridays, the analysis was redone,

comparing the three groups on percent attendance rate. The L-80

group (93.12) had lower attendance than M-50 (94.07) or M-100

(95.69), but the difference is not significant.

Another evaluation of relative efficacy was made, using the

global rating of outcome, which was a combined staff judgment

made shortly after a patient’s termination, taking into account all

known information about the patient.

The M-50 group was judged to be significantly less improved than

either the M-100 group (P<.01) or the L-80 group (P<.05).

Preliminary review of secondary (contingent) outcome variables,

such as number of arrests, hours of employment, income, and

others, has not yielded evidence of advantage of any one group over

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another, but a conclusive summary of these variables will have to be

deferred until more definitive analyses have been done.

DISCUSSION

This study was organized and initiated at a time when there was

relatively little clinical experience with methadyl acetate. With a

limited amount of information for guidance, some decisions had to

be made about the design of the study, which, if incorrectly made,

could jeopardize its outcome, or possibly increase the risk to the

participating patients. The dose schedule is an example. It was

decided to start methadyl acetate patients at 30 mg. three times

weekly and increase the dose 10 mg./week until they had stabilized

at 80 mg. three times weekly. The methadone patients were

inducted according to the same schedule. There is now reason to

believe that this was not an optimal induction schedule for either

group and that there probably is less patient discomfort and better

patient retention if, in the clinical use of methadyl acetate, this

schedule is accelerated, if the Friday dose is somewhat larger, or if

in the early weeks there is supplementary use of methadyl acetate

or methadone on days when the methadyl acetate is not regularly

dispensed.

This study also suffers from the same defect that all fixed-dose

studies do. Clinical experience tells us that dosage of many drugs

needs to be individualized not only during the induction phase but

also in the search for the optimal stabilization dose. Undoubtedly,

patients that were undermedicated or overmedicated were lost from

each group.

Another necessary element of conservatism in the planning led to

the decision to conduct laboratory tests every four weeks. This

increased the difficulty of acquiring the sample of volunteer

participants and led to the subsequent termination of many patients

who tired of the procedures involved in drawing blood, taking

urine, and the completion of other kinds of evaluation. Similarly,

the study had to be double blind to provide meaningful information

about efficacy in particular. At least a small group of patients had

second thoughts about being in a study where they did not know

what they were taking and chose the more familiar methadone

experience.

It was pointed out earlier that there was a great deal of variation

in clinic performance during the study, more than could be

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CHARUVASTRA: COOPERATIVE STUDY ON METHADYL ACETATE

accounted for by differences in geographical location or by chance.

Hence it is inferred that in part, this variation has to be related to

patient and staff attitudes towards the study and the three drug

regimens.

Additionally, there are differences in addict population that

contribute to geographic variation. The clinics’ performances are

probably a fair sampling of what might be expected of any 12

hospitals within the artificial constraints of the study.

In spite of all these shortcomings, the evidence supports the

conclusion that methadyl acetate is as safe a drug as methadone and

that it compares favorably with high-dose methadone in terms of

efficacy as previously defined. Both methadyl acetate and high-dose

methadone appear to be better maintenance regimens than low-dose

methadone under the conditions of this study.

Each of these conclusions needs to be qualified. It is conceivable

that sample attrition may have introduced bias in the direction of

apparent safety of both drugs or selectively for methadyl acetate.

Second, laboratory analysis was done locally rather than in a central

laboratory, and this, without question, contributed to the variability of measurement and decreased the sensitivity of the statistical

analysis.

Finally, the complete story on safety awaits truly large-scale

phase 3 testing. There were no deaths, serious adverse reactions, or

compelling trends in the laboratory or side effects data, but it is not

possible to anticipate what experiences might emerge when thousands of patients are exposed to this new drug or any new drug. The

statements about efficacy are obviously limited by the fixed-dose

design of the study and shaped by the philosophic position that was

taken about evaluating outcome. The conclusions with respect to

the high-dose vs. low-dose methadone comparison, if translated into

action, do not support a policy of giving all patient 100 mg. of

methadone hydrochloride daily, nor do they contradict the known

fact that many patients do very well receiving doses of 50 mg/day

or even less. It seems hardly necessary to stress the importance of

individualization of dosage in actual clinical practice. However,

strong advocates of low-dose methadone maintenance might reconsider their position in the light of these findings. Methadyl acetate

might be better or worse than it appears in this study if used with

other induction schedules or individualized doses.

However, it is believed that this study has established methadyl

acetate, used three times weekly, as a suitable alternative to

methadone as a maintenance treatment for heroin addicts. In the

judgment of the investigators and many of their associates, it is of

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

the utmost importance to complete the developmental work on

methadyl acetate so it can be made generally available for the

treatment of heroin addicts. The advantages of methadyl acetate (if

it continues to appear safe and effective) are socially important. As

an alternative to methadone, it offers a solution to the familiar

dilemma of either demanding daily clinic attendance, which

imposes hardships on patients and lowers program retention, or

permitting take-home doses of methadone with its associated

dangers of diversion or death for intolerant individuals. It would

seem to be enlightened policy to have methadyl acetate available on

a three times a week basis with no take-home privileges and at the

same time move in the direction of less take-home use of

methadone.

REFERENCES

1. Blachly, P.H.; David, N.A.; and Irwin, S. Alpha-acetylmethadol (LAM):

comparison of laboratory findings, electroencephalograms, and Cornell

Medical Index of patients stabilized on LAM with those on methadone. Proc

of Fourth Natl Conf on Methadone Treatment, San Francisco, Jan. 1972.

pp. 203-205.

2. Fraser, H.F., and Isbell, H. Actions and addiction liabilities of alphaacetylmethadols in man. J Pharmacol Exp Ther, 105(4):458-465, 1952.

3. Jaffe, J.H.; Schuster, C.R.; Smith, B.B.; and Blachly, P.H. Comparison of

acetylmethadol and methadone in the treatment of long-term heroin users:

A pilot study. JAMA, 211:1834-1836, 1970.

4. Jaffe, J.H., and Senay, E.C. Methadone and -methadylacetate. Use in

management of narcotics addicts. JAMA, 216:1303-1305, 1971.

5. Jaffe, J.H.; Senay, E.C.; Schuster, C.R.; Renault, P.F.; Smith, B.; and

DiMenza, S. Methadyl acetate vs methadone. A double-blind study in heroin

users. JAMA, 222(4):437-442, 1972.

6. Zaks, A.; Fink, M.; and Freedman, A.M. Levomethadol in maintenance

treatment of opiate dependence. JAMA, 220(6):811-813, 1972.

270
CHAPTER 21

The SAODAP Cooperative Studies

of LAAM: Unblinded Comparison with

Methadone

C. James Klett, Ph.D.

Two cooperative studies of -alpha-acetylmethadol (LAAM) were

conceptualized by the U.S. Special Action Office for Drug Abuse

Prevention (SAODAP) at about the same time as the U.S. Veterans

Administration (VA) study, but because of inevitable administrative delays involving the U.S. Food and Drug Administration, the

Drug Enforcement Administration, and institutional review clearances, the first patients did not begin treatment until almost nine

months after the VA study had started. The first of the SAODAP

studies was deliberately designed to be comparable to the VA study

in most important respects, e.g., duration of study was to be 40

weeks, and the evaluations were done at the same intervals with

essentially the same forms, laboratory tests, and other procedures.

There were, however, two important differences. The patient

sample in the SAODAP study consisted of patients currently being

maintained on methadone rather than patients newly applying for

maintenance. Second, although patients were randomly assigned to

either methadone or LAAM, it was decided to conduct the study as

an open clinical trial rather than using the double blind control.

There was another important difference between the two studies

that derived from the first two. Because of the difference between

patient types, i.e., street addicts requesting maintenance vs. patients

already on maintenance, the dosage problem in the SAODAP study

was one of determining the proper cross-over dosage ratio from

methadone to LAAM rather than determining an appropriate

induction schedule. The induction schedule and ultimate maintenance dose were fixed in the VA study, not simply to make the

logistics of double blind unit-dose administration less complex, but

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because conservative elements in the planning of this study

suggested that dose should be controlled. These constraints were

considered less important in the SAODAP study. Since the trial was

nonblind, clinicians could begin to adjust the dose beginning with

the second visit. In fact, they were encouraged to do so and

particularly to consider a higher Friday dose. It was, however,

believed to be necessary to standardize the crossover ratio, and after

much debate it was decided to use a one to one conversion.

Before presenting any results of the SAODAP study, a few

general comments about these two studies may be in order. The

goals and the design of both the VA and the SAODAP studies made

sense at the time they were planned. In retrospect they still do, but

both studies have their strengths and their weaknesses which ought

to be clearly recognized so they can be put in proper perspective

with the studies that preceded them and the studies that are now in

progress or that still remain to be done. Obviously, the double blind

control of the VA study has to be considered its main strength from

the standpoint of research design. However, it will never be known

for certain how well the double blind control worked. There were

patients who correctly identified their assigned drug as LAAM,

including one who dramatically poured his Tuesday placebo dose

on the clinic floor. No matter how imperfect this double blind

control was, it did provide greater protection from bias than the

open SAODAP trial, as we shall see when I give some comparative

results. The fixed induction-maintenance schedule of the VA study

was an asset in comparing three drug regimens, but in other ways it

restricted the amount of information we might have obtained about

LAAM. The first dose might have been too high or too low, dosage

was probably increased too slowly, and the fixed maintenance dose

of 80 mg TIW was certainly not optimal for all patients. However,

the apparent advantage of flexible dosage in the SAODAP study

was largely cancelled out either by the conservatism of many of the

clinicians in terms of adjusting dosage upwards or by their greater

willingness to terminate patients from the study who were known

to be on LAAM and who were having real or imagined difficulties

in adapting to the new drug.

Both studies suffer from conceptual problems when it comes to

evaluating efficacy and this issue has been discussed in the report of

both studies (1, 2). At one level, the efficacy of LAAM relates to its

ability to substitute for heroin and/or methadone in the prevention

of the abstinence syndrome. A somewhat, different question

involves the length of time an oral dose of LAAM is effective in this

regard either as a single dose or administered on some intermittent

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KLETT: SAODAP COOPERATIVE STUDY OF LAAM

schedule, i.e., every other day, three times a week, or whatever. If

this is the level at which the efficacy of LAAM is to be assessed,

then the appropriate criterion would seem to be the extent and

intensity of withdrawal symptoms reported by patients assigned to

LAAM. Unfortunately, this criterion has some defects associated

with ways of reliably and validly establishing degree of discomfort.

There are alternative ways of approaching this problem, each of

which has its own merit, but it is a certainty that whatever solution

is adopted, it must be conducted under double blind control. An

equally important consideration which limits the usefulness of

discomfort, as the criterion of effectiveness is that degree of

discomfort will be a function of the dosing pattern, and, until the

best induction/crossover schedules are known, there will be more

discomfort experienced than there would need to be.

If symptoms of withdrawal are not quickly and adequately

brought under control, the patient is likely to do one of two things:

drop out of the study or begin supplementing his maintenance

dosage with heroin. This suggests two additional criteria of

effectiveness: program retention and urine tests positive for

morphine. Although program retention would be expected to be

depressed if LAAM were ineffective in suppressing abstinence, it is a

most unsatisfactory criterion of effectiveness because it is related to

so many other factors. Some patients complete the study but

complain of withdrawal symptoms throughout and/or consistently

supplement with heroin, while other patients apparently do well on

LAAM until they terminate for some reason. Termination from the

study often has nothing whatsoever to do with the drug to which a

patient is assigned. There is good reason to believe that study

retention for both methadone and LAAM was reduced by the

demands imposed by participation in these studies. Finally, study

retention is absolutely worthless as a criterion of efficacy in an

unblinded trial. At any time that a patient assigned to LAAM in the

SAODAP study experienced real or imaginary distress of any kind,

the option was available to terminate him from LAAM and put him

on methadone. The reverse option was not available for the

methadone patients.

Urine tests positive for illicit drugs is a more attractive criterion

of effectiveness, particularly if it is appropriately weighted not only

for total use of drug but also for pattern of use. Thus, it might be

expected that illicit drug use might occur during induction or

following crossover, particularly if these induction/crossover schedules are not optimal. If illicit drug use continues much beyond this

period, however, it strongly suggests that maintenance is not

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effective. Since another goal of maintenance is to decrease or

eliminate illicit drug use by providing an acceptable substitute, the

use of urine tests positive for morphine as a criterion of efficacy

seems particularly appropriate.

Consumer acceptance may actually be the ultimate criterion of

LAAM as a maintenance drug. If the client doesn’t like the drug

because he is uncomfortable, or doesn’t experience his customary

high, is afraid of the drug because of something he has heard on the

street, or loses income because he has no take home dose to sell, he

will be likely to drop out or start supplementing his maintenance

drug with illicit heroin. On the other hand, if he likes the idea of

not taking drugs daily, feels more alert or less like a junkie, he is

likely to do well on LAAM. Unfortunately we haven’t measured

consumer satisfaction directly and can only infer it by inspecting

retention, discomfort, and illicit drug use.

There is another class of criteria that has been suggested as

bearing on the issue of effectiveness, and that is the extent to which

individual patients’ lives are modified in terms of employment,

illegal activity, interpersonal relationships, and the like. It seems to

me that such criteria are important socially and politically in

evaluating maintenance as a concept but are not the ones to use in

evaluating the value of a specific drug as a maintenance agent.

It should be clear at this point that the SAODAP study, because

of its design, could not provide definitive information about the

efficacy of LAAM. However, it did provide some suggestive

evidence. Thirteen clinics contributed 636 patients for randomization to either continued treatment on methadone or crossover to

LAAM. Of the 308 patients randomly assigned to methadone, 186

(60%) completed the full 40 weeks of the study. Of the 328

patients assigned to LAAM, however, only 128 (39%) completed

the full course. Patients assigned to LAAM not only dropped out in

greater numbers but dropped out significantly earlier-after an

average 72 days in the study compared to 122 days for the

methadone patients. Furthermore, there were 62 LAAM patients

who terminated because the medication was not warding off

abstinence symptoms, another 7 because they didn’t like the drug,

14 for psychiatric reasons, and 11 because of side effects. No

methadone patients terminated for any of these reasons. LAAM

patients also complained much more about symptoms of withdrawal. All of this would seem to be overwhelming evidence that

LAAM is not as good a maintenance drug as methadone, and if the

study had been conducted double blind, it would be difficult to

escape this conclusion. However, there are two additional pieces of

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KLETT: SAODAP COOPERATIVE STUDY OF LAAM

information that suggest otherwise. First, the two groups were

comparable in terms of illicit drug use. This evidence would also be

stronger if the study had been double blind, but it seems unlikely

that urines positive for heroin are subject to quite as much bias as

other criteria. Secondly, when the 128 patients who completed 40

weeks of LAAM maintenance were asked to volunteer for another

40 weeks of LAAM to provide a long-term safety profile, 112 (89%)

elected to do so (11 did not want to stay in the study at all, and

another 5 were willing to do so but asked to be switched to

methadone). This seemed to be fairly powerful consumer acceptance, especially when compared to the methadone experience: Only

66% (124 out of 186) of the methadone finishers agreed to stay in

the study, 29 declined, and 33 asked to be switched to LAAM. If

nothing else, this suggests that for at least some patients, LAAM is

an acceptable or even preferred alternative to methadone.

Additional evidence for the acceptability of LAAM as a

maintenance drug can be inferred from the second study organized

by SAODAP. This was a study at four clinics of 136 patients

randomly assigned to methadone or LAAM. The LAAM group

received methadone on Monday through Thursday but received

LAAM on Friday and no drug at all on Saturday and Sunday. This

would seem to be a rather rigorous test of LAAM as a maintenance

agent, but remarkably 35% of the LAAM starters completed 40

weeks of this regimen (compared to 52% of the straight methadone

controls).

The best justification for conducting these two SAODAP studies

was to accumulate more clinical experience with LAAM, particularly experience bearing on safety-toxicity issues. Relatively few

patients had been exposed to LAAM in earlier studies. Even in the

VA study, because the total sample was distributed among three

groups, only 142 patients received LAAM. In the two SAODAP

studies, another 393 were added. In this total of 535 patients who

collectively were treated with LAAM for almost 300 man years,

there were four deaths. Two of these were homicides, one was an

alcohol-related death, and the last was a result of (non-LAAM)

overdose. There were no serious adverse reactions, and the number

and kind of side effects were not very different from those

commonly associated with methadone. Extensive laboratory evaluation revealed a number of significant differences between groups in

the average amount of change over time, but these differences

tended to be either sporadic, i.e., at one or two time periods only,

or of such small magnitude that they did not seem to be clinically

meaningful. There was no evidence of systematic, progressive

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changes in value over time. It was concluded that LAAM and

methadone are comparable in terms of safety over extended periods

(up to 80 weeks).

In conclusion, these large studies (taking VA and SAODAP

together) suggest that LAAM is likely to be an acceptable

alternative to methadone as a maintenance drug. It is expected that

the two drugs will become even more comparable in terms of

reported discomfort, program retention, and illicit drug use as

clinicians learn to use the drug more effectively, i.e., to optimize

the induction/crossover schedules, and as both patients and staff

become more familiar with the drug and are more willing to accept

it as an alternative without the suspicion that might be associated

with any new agent. The continual accumulation of data strengthens the conviction that the drug is as safe as methadone, at least

used by healthy males who were included in these studies and

probably also in the less carefully screened patients now being

evaluated in the large Phase III trial. Females still remain to be

studied, and there are other questions which still need to be

answered. One of the most important of these is the relative ease or

difficulty of detoxification from LAAM vs. methadone. There were

a few LAAM patients in these studies that attempted and/or

completed detoxification, but information was not systematically

collected on their course. This is now being remedied in ongoing

studies. Also underway are double blind evaluations of alternative

induction schedules in patients newly applying for maintenance and

alternative crossover schedules for patients already on maintenance

who will be switched to LAAM. These studies will help to fill in

some of the remaining gaps in the total picture of this new

maintenance drug.

REFERENCES

1. Ling, W.; Charuvastra, V.C.; Kaim, S.C.; and Klett, C.J. Acetylmethadol and

methadone as maintenance treatments for heroin addicts. A Veterans

Administration Cooperative Study. Arch Gen Psychiatry, 1976.

2. Ling, W., and Klett. C.J. Clinical safety and efficacy of LAAM — the

collective VA and SAODAP-NIDA experience. Proceedings of the National

Drug Abuse Conference, New York, March 28, 1976.

276
CHAPTER 22

Phase III Clinical Study of LAAM:

Report of Current Status and

Analysis of Early Terminations

John A. Whysner, M.D., Ph.D., and Gail L. Levine

INTRODUCTION

Levo-alpha-acetylmethadol (LAAM) is under investigation for

maintenance therapy of persons addicted to opiate drugs. Jaffe et

al. (5, 6, 7) reported that LAAM was successful as a maintenance

drug when administered by a schedule of three times weekly.

Although LAAM is not very active as an opiate, its two major

metabolites by N-demethylation have potencies which approximate

methadone and morphine. Whereas the time course of the blood

concentration of LAAM is similar to that of methadone, the time

course of the metabolites shows a substantially longer profile (3, 4).

Two cooperative studies have been completed in which approximately 200 patients gained at least a 40-week experience with

LAAM; these studies have not shown significant safety problems for

LAAM when compared to methadone (8, 9). Clinical laboratory

tests throughout the 40-week period remained within the normal

range for the drug-abusing population and did not show any

significant clinical differences between LAAM and methadone.

Reports of side effects, of opiate type and others, are similar for

LAAM and methadone, and no unusual adverse reactions have been

reported. The only significant adverse safety findings are an

unknown contribution of LAAM in a few incidences of overdose

reactions–a problem which has been well described for methadone

and heroin.

Efficacy of LAAM maintenance therapy has been more difficult

to measure due to the problems in defining efficacy. In double

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

blind studies, Jaffe et al. (5, 6, 7), Ling et al. (8), and Savage et al.

(11) have all found LAAM to be a useful maintenance drug.

Although patient dropout rates are higher for LAAM than for

methadone, illicit heroin use during LAAM maintenance has been

found to be less than with methadone. A number of possible

reasons for the higher dropout rate for LAAM subjects may be

postulated. Because of the lack of a large amount of clinical

experience with LAAM, rigid design of experimental protocols

precluded flexible dosing of LAAM, especially during the early

induction phase. In open studies, anxiety over taking a new drug

which is still classed as experimental, the ready alternative of

methadone maintenance, and the lack of take-home methadone

which has an economic value may all be contributors to the higher

dropout rate observed in the LAAM groups.

METHODS

The current work is a large cooperative clinical trial aimed at

obtaining 40-week experience with 2000 LAAM patients and a

suitable methadone control group. This report provides a general

overview of progress in this Phase III study and specifically

examines the question of study dropouts, reasons for such

dropouts, and possible remedies to decrease such dropouts. All

patients in this study are males, 18 years of age or older, who meet

the criteria for methadone maintenance therapy. This is a progress

report, and the number of patients in the study depends upon the

date analyzed and is indicated in the results section.

Three separate protocols have been utilized in this study. In

Protocol I, all patients in the study are assigned to LAAM

maintenance. In Protocol II, 60 percent of the patients are

randomly assigned to LAAM and 40 percent to methadone on an

open basis. In these two protocols, for each 1 mg of daily

methadone the patient is given 1.2 mg of LAAM on a three times

weekly schedule. For new patients a 20 mg initial dose with 10 mg

increments is used. In Protocol III, current methadone maintenance

patients are randomly assigned to three different medication

schedules described in table 1.

Schedule A is an immediate 1.2 crossover ratio from methadone

to LAAM with methadone supplementation for the first two weeks.

Schedule B is a gradual crossover with LAAM dosage increasing

while methadone dosage decreases until the full 1.2 crossover dose

is achieved. Schedule C is a full dose 1.2 crossover ratio from

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WHYSNER AND LEVINE: PHASE III LAAM CLINICAL STUDY

TABLE 1

methadone to LAAM with smaller doses of LAAM supplements in

between the regular three times weekly medication.

For all patients in the Phase III study, an informed consent is

signed by the patient, a complete medical history, physical exam,

vital signs, SMA 12, CBC, urinalysis, background information, and

urine screen for drugs are obtained. There is regular reporting by

investigators of all maintenance medication, all adjunctive therapy,

weekly tests for morphine in the urine, and monthly tests for

amphetamines, barbiturates, and methadone. Measures of efficacy

for the three schedules in Protocol III include the administration of

a Medication Index and Symptom-Sign Checklist at pretreatment,

3, 10, 17, and 24 days of treatment. The Medication Index asks the

patient to evaluate drug effect on a continuum from extremely

undermedicated to extremely overmedicated. The Symptom-Sign

Checklist is identical to that used by Ling et al. (8). Since this is a

progress report, most of this data has not been completely analyzed

and will not be presented here.

The patients in the Phase III study are from approximately 50

methadone clinics across the United States. This paper especially

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

acknowledges the five investigators participating in Protocol III.

They are: Dr. Robert Duplis, St. Lukes Center, Miami; Dr. Henri

Moyal, Valle del Sol. Phoenix; Dr. Carl Oestermeyer, Cleveland

Treatment Center, Cleveland; Dr. John Renner, Boston City

Hospital, Boston; and Dr. Edward Senay, Substance Abuse Services,

Chicago.

RESULTS

The number of starting patients required to meet the goal of

2000 patients with 40-week experience will depend upon retention

rates in this study. By the most recent study census (7/20/77) a

total of 2019 patients have been initiated. Of the 1109 patients

inducted in Protocol I, 705 are currently in treatment and 404 have

terminated. In Protocol II, 910 patients have been started, 634 are

in treatment and 276 have terminated. For the patients initiated on

methadone 19 percent have terminated, while 37 percent have

terminated from LAAM. A more complete description of these

terminations follows.

LAAM Terminations

In figure 1 the number of LAAM patients remaining in treatment

over time is described by probability of retention. This method of

life table analysis computes the probability of survival in the study

for a given week (2). Projections from this calculation will give

estimates of retention even though very few patients have had the

opportunity to complete 40 weeks, Figure 1 shows that street

admissions and crossovers from methadone have similar retention

rates. Linear projections from the available data indicate that

40-week retention will be about 45 percent. The shape of the

probability curve shows an initial high termination rate, but

whether or not this curve decreases in slope in the last 10 weeks of

treatment remains to be seen.

Reasons for LAAM patients terminating are shown in table 2.

Most patients terminate For reasons clearly not related to the study

medication. As expected a higher percentage of “No Shows” are

from street admissions than from methadone crossover patients.

Patients who were already stabilized on methadone before LAAM

treatment terminated at higher rates (and presumably went back to

methadone) for side effects, abstinence, or overmedication. Overall

280
WHYSNER AND LEVINE: PHASE III LAAM CLINICAL STUDY

FIGURE 1

the differences between the two groups are predictable. Street and

methadone crossover initiates do not appear to differ in overall

dropout rates.

LAAM vs. Methadone

The probability of retention figures for LAAM and methadone

are shown in figure 2. These figures must be considered estimates

because of the small numbers; however, there is a distinct difference

between LAAM and methadone. Projected estimates show that the

40 week retention for methadone should be approximately 65

percent and for LAAM 45 percent. More data points are shown for

LAAM because there is a greater sample size for LAAM data due to

the random assignment which places 60 percent of patients on

LAAM and 40 percent on methadone. The assignment was designed

in this manner because a higher termination rate was predicted for

LAAM.

Reasons for termination are shown in table 3. Under “Clearly

Not Drug Related,” there appear to be differences between drugs,

but clinical investigators have determined that these terminations

are clearly not drug related. Further analysis of these differences

281
INTERNATIONAL CHALLENGE OF DRUG ABUSE

TABLE 2

Reasons for early termination: LAAM patients – Protocol I & II

Starters (N) 1031 236 1267

Early terminators (N) 296 77 373

Reasons for early termination (%)

No show 2.2 11.4 3.9

Clearly not drug related 8.3 4.2 8.6

Possibly drug related 10.7 7.2 10.1

Clearly drug related

Side effects

Adverse reaction

Med not holding

Feels overmedicated

No show

Other

TOTAL

1.8

0.5

3.5

1 .l

0.2

0.2

28.5

0.8

0.4

1.7

0.4

0.8

0.0

26.9

1.7

0.4

3.1

0.9

0.3

0.2

29.2

Crossover Street Total

will be performed with a greater sample size. Under “Possibly Drug

Related,” more patients drop out from the LAAM group in all

categories. The largest of these categories is possible opiate side

effects, which the patient notices more on LAAM (usually when

switched from methadone to LAAM). Results show that LAAM

patients have been terminated for excessive alcohol and drug use.

Methadone patients may be having the same difficulties but they

are not terminated because no other treatment is available. The

category “Does Not Like Study Medication” is a catch-all for any

drug-specific complaints which do not fit any other category. For

example, one patient terminated because he didn’t like the taste of

LAAM. Another patient said that he felt overmedicated on the day

on which he ingested medication and undermedicated on the days

between doses. This is possibly a variant in metabolism of the drug.

Other patients have missed the necessity of coming to the clinic

daily. The results also indicate that some patients appear to show

increased anxiety or may act out some impulsive behavior on

LAAM; these are termed psychiatric discharges.

In the “Clearly Drug Related” category, all dropouts are in the

LAAM group as would be expected since the methadone patients

have previously been through a stabilization period; the LAAM

282
WHYSNER AND LEVINE: PHASE III LAAM CLINICAL STUDY

FIGURE 2

patients have switched to a new drug, Opiate side effects such as

constipation, sexual dysfunction, insomnia, or gastrointestinal upset

are experienced by some LAAM patients.

All reported adverse reactions have been investigated thoroughly.

None are alarming and these will be reported in a later publication.

Dosing problems causing abstinence or overmedication have been

lower than expected. Only 3.8 percent of LAAM patients dropped

out because the medication was not holding.

Very Early Terminations

In previous studies terminations very early due to undermedication are prevalent (8, 9). In the Phase II study, 8.8 percent of

patients dropped out in the first month for undermedication. Table

4 shows the LAAM dropouts in the first month of treatment for the

present study and for the SAODAP Cooperative study. As shown,

21.4 percent in the SAODAP study had dropped out by the end of

the first month compared to 14.2 percent in the present study;

almost all of this difference can be accounted for in the category of

“Medication Not Holding.” None of the other categories appear to

show differences.

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WHYSNER AND LEVINE: PHASE III LAAM CLINICAL STUDY

TABLE 3

Phase III LAAM Study: Reasons for Early Termination

Protocol II-LAAM vs. Methadone 6/30/77

Starters (N)

Early Terminators (N)

Reasons for Early Termination (5%)

LAAM Meth

424 280

130 45

Clearly Not Drug Related

Jail

Moved

No Show

Disciplinary Discharge

Unrelated Psychiatric

Unrelated Medical

Completed Detox on Study Med

Does Not Like Study Med

Transferred to Another Clinic

Pregnancy

Eligible for 2-Day Pick-Up

Other

3.1 2.5

0.5 1.1

2.4 2.5

0.5 1.4

0.5 0.4

1.4 0

0.5 1.8

0.7 0

0.7 2.5

0 0

0.2 0

1.4 1.1

Possibly Drug Related

Possible Side Effects

No Show

Excessive Alcohol Use

Excessive Drug Abuse

Medical

Psychiatric

Requested Detox on Nonstudy Med

Does Not Like Study Med

Other

4.0 0

1.4 1.1

0.1 0

0.7 0

0.2 0

0.9 0

0.7 0.1

1.7 1.1

0 0

Side Effects

Adverse Reaction

Medication Not Holding

Feels Overmedicated

No Show

Other

Clearly Drug Related

1.4 0

0.9 0

3.8 0

1.9 0

0.5 0

0 0

Protocol III

This substudy was initiated to determine the most effective

means of crossing patients over from methadone to LAAM using

supplemental medication of either LAAM or methadone (table 1).

Where a “±” is indicated the clinical investigators were free to

adjust dosage up or down as the patient signs and symptoms

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WHYSNER AND LEVINE: PHASE III LAAM CLINICAL STUDY

TABLE 4

Comparisons of first month drop-outs: LAAM patients only

SAODAP vs. Phase III crossovers 7/18/77

Starts (N)

%Drop-outs

Reasons for early termination (%)

328 1031

21.4 14.2

Jail 1.5 0.5

No show 0 1.2

Moved 0.3 0.2

Side effects 2.1 2.4

Med not holding 8.8 2.2

Dose too high 0.9 0.9

Didn’t like study 1.5 0.7

Didn’t like med 0.6 1.3

Detoxification 0 0.1

Disciplinary discharge 0.3 0.2

Excessive drug use 0.6 0.5

Excessive alcohol use 0.3 0.1

Psychiatric 1.5 1.4

Unrelated med 0.6 0.5

Adverse reaction 0 0.6

Other 2.4 1.4

SAODAP Phase III

required. No conclusive results can be presented since the study

sample is not yet complete and all data have not been analyzed.

A profile of the demographic characteristics of the three

randomly assigned groups is shown in table 5. The unequal

distribution in cell size is due to misassignment of several patients;

these patients have been excluded from the analysis. The demographic profiles of each group show that Schedule A may have

contained a slightly older sample with more months in treatment.

The prestudy methadone dosage in the Schedule C group may have

been higher.

Preliminary results show that Schedule C, LAAM supplementation, has some advantages over A and B in two parameters. First,

there were fewer dosage adjustments required for this schedule. The

results show that the investigator did not need to change the basic

LAAM dose before the third week in this schedule. Second, in table

6 the Medication Index scores showed a superiority in that only 1

percent of patients in Schedule C were overmedicated and none

were extremely undermedicated. For all three schedules the number

of terminators was almost equal and was 10.8 percent of the

starting sample.

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

TABLE 5

Protocol III demographics

TABLE 6

Dosage schedule changes

Followed nominal schedule

Changed bld third week

Changed supplement

1 increase

2 increases

3 increases

1 decrease

2 decreases

Changed bld before third week

Wrong crossover schedule

Miscellaneous deviations

Not included–did not complete three weeks

in study

TOTAL

A B

6 (29%) 4 (22%)

4 (19%) 4 (22%)

7 (33%) 4 (22%)

1 0

1 1

3 2

2 1

0 0

3 (14%) 4 (22%)

1 (5%) 2 (11%)

1 (3%) 0

0 0

21 18

C

5 (31%)

1 (6%)

4 (25%)

0

1

3

0

0

0

2 (13%)

2 (13%)

2 (13%)

16

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WHYSNER AND LEVINE: PHASE III LAAM CLINICAL STUDY

DISCUSSION

The Phase III LAAM study is now well underway, and the

preliminary results show that the drug is achieving widespread use

and good patient acceptance. Currently the drug is being used in 50

methadone clinics and more than 1% of patients in maintenance

therapy are using LAAM.

The dropout rate for LAAM is much better than in the Phase II

studies, and a continued improvement in the rate is expected with

the development of further experience with the drug. Until the drug

is no longer classified as “experimental” any open study conducted

to determine the comparative efficacy of LAAM and methadone

will be prejudiced against LAAM as will be described below.

The reason for examining dropout rates during LAAM development is to determine whether there are specific problems with the

way the drug is used which contribute to dropout. The SAODAP

cooperative study had a significant number of dropouts from

undermedication. Individual investigators had indicated that the

low crossover ratio and restrictions concerning supplemental medication contributed to this problem.

The comparison of dropouts before one month has shown that

whereas there was an 8.8 percent dropout rate for undermedication

in the SAODAP study, in the current study only 2.2 percent of

patients terminated for undermedication. This one factor accounted

for almost all of the differences in the terminations before one

month between these two studies. In the SAODAP study the initial

crossover equivalence was 1 mg of LAAM TIW per 1 mg of

methadone daily. In the present study, 1.2 mg of LAAM was used

for each mg of methadone. Resnick et al. (10) has shown that after

the initial 1.0 crossover ratio patient doses equilibrated from 1.1 to

1.6 times the prestudy methadone dose.

In the Phase III study investigators were urged to treat patients

symptomatically for abstinence in the initial crossover period. Since

pharmacokinetic results indicated that a period of several weeks

may be required for some patients to achieve maximal blood levels

of the active metabolites, supplements of methadone were recommended in the present study. In the previous SAODAP study, no

provision was made for allowing methadone or LAAM to be used

on an as-needed basis. Also other psychoactive medications are

allowed in this study, in contrast to the SAODAP study.

The complete sample for Protocol III will be obtained in the

future. Preliminary analysis, however, shows that the LAAM

supplemental schedule may be superior. The probable mechanism

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

for such a finding is that the small LAAM supplements add to the

total amount of LAAM given in the first two weeks. Since there

appears to be a loading dose effect necessary, supplemental LAAM

may speed up this process. By the end of the second week,

Schedule C patients receive 1 l/4 extra basic LAAM doses. This

may be enough to help the crossover process. In distinction,

Schedule B patients receive two fewer basic LAAM doses. All of the

clinics in the Protocol III study appear to have a lesser dropout rate.

This indicates that a prescribed supplement of methadone or LAAM

during the first two weeks may be beneficial.

An examination of all other categories in which patients have

reported drug-related reasons for termination will be done in the

future. In some cases it may be possible to identify specific

difficulties with LAAM which can be changed by altering instructions to investigators. However, it is likely that other reasons may

be operative which will not change until the drug is no longer

experimental.

Most patients are crossovers from methadone or at least have had

extensive previous experience with methadone. Patients know those

things which methadone can and cannot do. In contrast, any

physical, social, or psychiatric problem which arises while a patient

is on LAAM is apt to be related to the new experimental drug. The

VA Cooperative study was double blind and the SAODAP study

was not. All symptoms and signs in the SAODAP study were

reported with greater frequency for LAAM, whereas in the VA

study only five out of 31 were significantly greater on LAAM (8,

9). This finding indicates that patients may blame the drug for any

personal or program failure.

In the early experience with methadone similar problems were

encountered. Adams et al. (1) found that 24 percent of patients

blamed side effects for their failure on methadone treatment. Yaffe

et al. (13) described a very high incidence of side effects from

methadone. These side effects are very similar to those of LAAM

patients and include constipation, excessive sweating, loss of

interest in sex, nausea, sleepiness, drowsiness, insomnia, and so

forth.

Another problem related to the open study is the existence of an

additional option for those patients randomly assigned to LAAM.

The patient who is randomly assigned to LAAM and experiences a

problem may choose to try methadone again before dropping out

of treatment. The patient. randomly assigned to methadone does

not have the option of trying LAAM before terminating from the

program.

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WHYSNER AND LEVINE: PHASE III LAAM CLINICAL STUDY

Patient motivations for entering a treatment program are varied.

At one end of the spectrum are patients who are in treatment

without having any desire to stop heroin use. These patients will

possibly find that a drug which has characteristics close to heroin

will have the greatest acceptability. These characteristics may

include euphoria, economic value from the sale of take-home doses,

and the ability to use heroin after blockade has diminished. For

these patients a drug like LAAM which has little euphoria,

eliminates take-home doses, and provides a prolonged blockade of

heroin will be less acceptable than methadone.

For those patients who look at a maintenance drug for its

therapeutic value, however, LAAM may offer advantages. Trueblood et al. (12) in a study of patients at the Addiction Research

Foundation (ARF) where only LAAM is provided found that

patients reported that LAAM was more acceptable than methadone.

Patients felt more comfortable and in better health. Heroin craving

was less and heroin blockade was better on LAAM compared to

methadone. ARF patients are probably more therapeutically

motivated since they are enrolled in a LAAM research clinic.

Higher dropout rates for LAAM will probably continue until the

drug can be used outside of a research protocol and until it is not

stigmatized by the label “experimental drug.” In the present study

a continuing effort will be made to examine specific reasons for

dropout so that changes in instructions to clinical investigators can

be made. However, the most important factor will probably remain

attitude toward the drug. Although not reported in the Results

section, there is a tremendous variability in dropout rates between

clinics. The clinics with high dropouts are always contacted and

usually visited. The problems usually include a negative initial staff

attitude towards LAAM, which is unfounded, a “bad rap” of

LAAM by a few patients, or an unavailable physician, so that

patients cannot adequately explore possible medication problems or

perceived side effects. Usually it is possible to change these

attitudes with the provision of knowledge and interest in the

patient’s problems.

REFERENCES

1. Adams, R.G.; Bloom, W.A.; Capel, W.C.; and Stewart, G.T. Heroin addicts

on methadone replacement: A study of drop-outs. Int J Addict,

6(2):269-277, June 1971.

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

2. Cutler, S.J., and Ederer, F. Maximum utilization of life table method in

analyzing survival. J Chronic Dis, 12:699-712, 1958.

3. Henderson, G.L.; Weinberg, A.; Hargreaves, W.; Lau, D.; Tyler, J.; and

Baker, B. Accumulation of LAAM and active metabolites in plasma

following chronic administration. J Analyt Toxicol, l(l):l-5, 1977.

4. Henderson, G.L.; Wilson, B.K.; and Lau, D. Plasma levels of LAAM

following acute and chronic administration. J Clin Pharmacol Ther,

21(1):16, 1977.

5. Jaffe, J.H.; Schuster, C.R.; Smith, B.B.; and Blachly, P. Comparison of

acetylmethadol and methadone in the treatment of long-term heroin users:

A pilot study. JAMA, 211:1834-1836, 1970.

6. Jaffe, J.H.; Senay, E.C.; and Renault, P.F. A six-month preliminary report

of the rehabilitative efficacy of -methadyl acetate compared to methadone. In: Proceedings of the Fourth National Conference on Methadone

Treatment. San Francisco, January 1972. pp. 199-201.

7. Jaffe, J.H.; Senay, E.C.; Schuster, C.R.; Renault, P.F.; Smith, B.; and

DiMenza, S. Methadyl acetate vs. methadone: A double-blind study in

heroin users. JAMA, 222(4):437-442, 1972.

8. Ling, W.; Charuvastra, C.; Kaim, S.; and Klett, C.J. Methadyl acetate and

methadone maintenance treatments for heroin addicts. Arch Gen Psychiatry, 33:709-720, 1976.

9. Ling, W.; Klett, J.C.; Gillis, R. A cooperative clinical study of methadyl

acetate I. Arch Gen Psychiatry, in press.

10. Resnick, R.B.; Orlin, L., Geyer, G.; Schuyten-Resnick, E.; Kestenbaum,

R.S.; and Freedman, A.M. L-alpha-acetylmethadol (LAAM): Prognostic

considerations. Am J Psychiatry, 133:7, July 1976.

11. Savage, C.; Karp, E.G.; Curran, S.F.; Hanlon, T.E.; and McCabe, O.L.

Methadone/LAAM maintenance: A comparative study. Compr Psychiatry,

17(3), May/June 1976.

12. Trueblood, B.; Judson, B.A.; and Goldstein, A. Acceptability of methadyl

acetate (LAAM) as compared with methadone in a treatment program for

heroin addicts. J Drug Alc Dependence, in press.

13. Yaffe, G.J.; Strelinger, R.W.; and Parwatikar, S. Physical symptom

complaints of patients on methadone maintenance. In: Proceedings of the

Fifth National Conference on Methadone Treatment. Washington, 1973,

pp. 507-514.

290
CHAPTER 23

The Future of LAAM

Pierre F. Renault, M.D.

Hopefully, in the not too distance future, LAAM will have a

major impact on opioid dependence replacement therapy and on

programs delivering that therapy. It is anticipated that LAAM will

gradually supersede methadone as the major opioid used to

maintain opioid-dependent individuals. The advantage of LAAM’s

longer duration of action should relegate methadone to a secondary

role in treating the symptoms of opiate withdrawal syndrome in

situations where the flexibility of a more rapidly acting preparation

is needed. Therefore, the future of LAAM is interrelated with the

future of replacement therapy, with all of its attendant controversy.

The concepts of maintenance or stabilization have been controversial from the time of their inception. Allowing or encouraging an

individual to remain physically dependent on a drug, even though

that drug is safer and less personally destructive than the drug of

abuse, is repugnant to many. Maintenance treatment, since it

represents continued physical dependence, appears to forego the

concept of “cure of heroin addiction.” Although the administration

of LAAM three times a week can give freedom from the hazardous

use of other drugs as well as from a dangerous and destructive

lifestyle to the heroin addict, he remains dependent on a clinic and

on those who control his maintenance drug. This apparent lack of

cure and the continued dependence on the clinic and the clinicians

have been seen by some as representing enslavement, economic

control, and cultural domination; yet, paradoxically, for some

nonaddicts methadone has symbolized “dogooderism” and the

coddling of criminals. For those who would take a hard line,

methadone has symbolized ineffectual humanitarianism which

flames the fires of social unrest instead of dealing directly with

them by decisive suppression.

These controversies surrounding replacement therapy have arisen

from an inappropriate expectation that a medication can resolve

291
INTERNATIONAL CHALLENGE OF DRUG ABUSE

major historical and social problems. These expectations have, in

turn, arisen from an oversimplification of the problems of drug

dependence. Replacement therapy has suffered from the naive

belief that all drug-dependent individuals have the same characteristics of personality and social background, and the equally naive

belief that one treatment method can be uniformly applied to all

drug-dependent individuals, thus putting an end to the demand for

drugs.

The future of LAAM and, therefore, the future of replacement

therapy itself depends on our ability to improve our selection of

patients for specific therapies and to increase and diversify the

types of therapies which can be made available to drug-dependent

individuals.

The development of LAAM should mark a turning point in our

thinking about treatment. LAAM is an ideal maintenance drug, and

it represents the epitome of our effort to develop innovative

pharmacotherapies for heroin dependence. LAAM is also the

product of our preoccupation with pharmacotherapies. Our preoccupation with pharmacotherapy and with pharmacological diagnosis has been the basis for the oversimplifications, in our view, of

addicts and treatment and some of the unrealistic expectations of

replacement therapy. The controversy over replacement therapy has

focused our attention on pharmacology in both diagnosis and

treatment. This controversy has made too great an issue of

pharmacology, allowing us to neglect the theory and implementation of psychotherapy and rehabilitation. Replacement therapy

would not be so controversial if it were not considered by so many

to be the basic treatment rather than what it is in reality, simply an

adjunct to treatment. Replacement medications like LAAM should

be conceived of as agents which can produce symptomatic relief

safely and effectively. This symptomatic relief in turn enables

individuals to participate in psychotherapy and to follow through

with rehabilitative plans. The purpose of psychotherapy should be

to help individuals achieve genuine control ever drug taking by

identifying and changing critical aspects of their personalities and

their environments.

The future of LAAM and the future of replacement therapy

depends on our ability to turn our focus once again to the needs of

the individual addict. We must develop more sophisticated ways of

diagnosing addicts and placing them into diagnostic subgroups,

which have genuine relevance for available psychiatric treatments

and rehabilitative measures. An excellent example of this important

new direction in replacement therapy has been those studies which

292
RENAULT: THE FUTURE OF LAAM

have shown that as many as a third of addicts coming for

replacement therapy are depressed. There is preliminary data which

indicates that psychiatric treatment of this depression not only

improves the addict’s depression, but also increases treatment

compliance and success in treatment for heroin dependence.

In summary, the future of LAAM is the future of replacement

therapy. Excellent pharmacologic agents have been developed for

replacement therapy, and LAAM is foremost among these. However, the future of replacement therapy depends primarily on our

ability to develop accurate diagnoses and specific treatment for

individuals who come to treatment over and above the pharmacologic problems which they present. It is time to use LAAM as an

adjunct to treatment. It is time to focus on the treatment and to

shift the focus away from the pharmacologic adjunct.

293

IV.

Treatment: Naltrexone

Demetrios A. Julius

Chairman
CHAPTER 24

A History of the Development of

Narcotic Antagonists for the

Treatment of Narcotic Addiction

William R. Martin, M.D.

The use of narcotic antagonists for therapy had an inauspicious

beginning. When I was appointed Director of the Addiction

Research Center in 1963, among my responsibilities was the

completion of the study of the abuse potentiality of cyclazocine

which had been initiated by Dr. H. Frank Fraser. As part of this

study, we attempted to make patients dependent on a larger dose of

cyclazocine. On the basis of single doses, we estimated that

cyclazocine was some 20 times more potent than morphine as an

agonist; consequently, we felt that if we addicted patients to

around 13 mg/70 kg/day of cyclazocine this would be roughly

equivalent to administering 240 mg/day of morphine, a level of

dependence which had been well characterized at the Addiction

Research Center.

During this study we learned that tolerance developed rapidly to

cyclazocine’s subjective effects, such as sedation, racing thoughts,

dysphoria, and hallucinations. However, with small increments in

dose, the subjective effects would reappear, and it was necessary to

stabilize some patients for several days before again advancing the

dose. When patients who had achieved the stabilization dose were

abruptly withdrawn, an atypical abstinence syndrome did become

manifest by the fourth day of withdrawal and achieved peak

intensity on the seventh day of withdrawal. This was the first

indication that cyclazocine had a very long duration of action (6).

Studies were then initiated to determine the duration of action

of cyclazocine, and to this end two studies were conducted to

determine the duration of (a) signs and symptoms, and (b) the

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MARTIN: DEVELOPMENT OF NARCOTIC ANTAGONISTS

morphine antagonistic effects produced by single doses of cyclazocine. It was found that signs and symptoms produced by cyclazocine persisted almost undiminished for over 12 hours, and its

morphine antagonistic effect was evident for from 12 to 24 hours

(8). These data confirmed our speculation that cyclazocine was a

very long-acting drug in man, a property not evident in experimental animals.

We had previously shown that chronically administered nalorphine also induces a cyclazocine type of tolerance and dependence,

and that when subjects were stabilized on nalorphine they were

refractory to the effects of morphine (7). Cyclazocine, administered

chronically by the oral route in a dose of 4 mg/70 kg/day, markedly

antagonized the effects of single doses of morphine and heroin. One

of the patients stabilized on cyclazocine was given 100 mg of heroin

intravenously and only minimal subjective effects were produced,

probably no greater than those that would have been seen had the

same subject received 5 or 10 mg intravenously in the absence of

cyclazocinc. We also attempted to make patients dependent on 240

mg of morphine daily while receiving cyclazocine chronically. In

this study we were able to escalate the dose of morphine very

rapidily. When the subjects were withdrawn from morphine, only

liminal signs of abstinence were seen, suggesting that cyclazocine

had also blocked physical dependence-producing properties of

morphine (8). We suggested that cyclazocine might have utility in

the treatment of narcotic addicts.

These studies clearly demonstrated that chronically administered

cyclazocine could antagonize both the euphorigenic (reinforcing)

and the physical dependence-producing properties of morphine.

Further, we knew that chronic cyclazocine would essentially

prevent an addict from overdosing himself. We thought it highly

unlikely that addicts would attempt to inject more than 100 mg of

heroin intravenously, and our studies had indicated that not only

was this dose not lethal but produced modest effects at best. We

suggested that cyclazocine

may be of value to therapists and social workers who are treating

addicts. If subjects under treatment use narcotics in sprees in an

effort to cope with transient stresses, they will not he forced to

continue the use of narcotics because they will have become

physically dependent. In addition, it would be almost impossible

for the nontolerant addict to die from heroin.

There may be other benefits. Wikler stated that two of the

important reasons for relapse of the abstinent narcotic addict

are conditioned abstinence which may be evoked hy stimuli that

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

have been associated with the addict’s hustling activity to acquire

drugs, and reinforcements of drug-seeking behavior through

repeated reductions of abstinence by drug. It is possible in subjects

who attempt to readdict themselves while receiving a narcotic

antagonist such as cyclazocine, there may be extinction of

conditioned physical dependence and drug-seeking behavior.

We further suggested “Cyclazocine could be used for the ambulatory

management of former addicts who are highly motivated” (8).

Dr. Abraham Wikler thought the idea that conditioned abstinence and drug-seeking behavior might be extinguished with a

narcotic antagonist could have clinical utility, and he communicated his enthusiasm to Dr. Alfred Freedman of New York Medical

College. Dr. Freedman and Dr. Sharoff visited the Addiction

Research Center where we shared with them our experiences with

cyclazocine. In addition, I told Dr. Jerome Jaffe, then in the

Department of Pharmacology and Psychiatry of the Albert Einstein

Medical College, of our results with cyclazocine and he initiated

studies. Dr. Freedman and Dr. Jaffe essentially confirmed our

original observations and showed that it was possible to maintain

addicts on narcotic antagonists and that the use of narcotics by

addicts so maintained was considerably decreased. However, in

these studies by Drs. Freedman and Jaffe it became apparent that

although tolerance developed to the dysphoric effects of cyclazocine, these effects still had a deterrent effect on acceptance of the

drug by addicts (3, 4). There were several reasons for this.

Considerable care had to be taken during the induction phase with

cyclazocine lest the dysphoric effects deter patients from continuing in therapy. Further, once patients had become stabilized and

had developed tolerance to cyclazocine, missing only one or two

doses would cause a sufficient reduction in tolerance that a

stabilization dose when reinitiated would again produce undesirable

and dysphoric subjective effects. Because of these dysphoric effects,

cyclazocine acquired a bad name among some addicts.

In 1965 we initiated studies with naloxone with the purpose of

determining if it had an abuse potential and whether the sedative,

dysphoric, and analgesic properties of this drug could be separated

from its antagonistic action in man. With Dr. Thomas K. McClane

we also initiated studies in the chronic spinal dog. It was soon

apparent that naloxone did not produce either sedation or

dysphoria in human subjects (5) nor depress the flexor reflex or

constrict pupils in the chronic spinal dog (11). As a matter of fact,

an enhancement of the amplitude of the flexor reflex with very

large doses of naloxone in the chronic spinal dog was observed. This

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MARTIN: DEVELOPMENT OF NARCOTIC ANTAGONISTS

enhancement was related at that time to naloxone’s convulsant

effects. Because naloxone was devoid of agonistic activity, we then

initiated studies to determine its duration of action when administered both subcutaneously and orally to determine if it might have

potential for maintenance therapy using techniques that we had

previously used for determining the duration of action of cyclazocine. We were unable to determine the duration of the blocking

effects of naloxone sharply in these studies; however, we did have

evidence that indicated that the blockade of naloxone was already

diminishing within 5 hours after naloxone had been administered.

We then attempted to make patients dependent on naloxone by

administering naloxone in dose levels of 15 mg administered six

times daily (q. 4 hr). The effects of morphine in patients receiving

the stabilization dose of naloxone were essentially blocked except

at the time immediately preceding the next dose of naloxone. This

further indicated that we had a high level of blockade. When

naloxone was abruptly withdrawn, no signs of abstinence emerged.

On the basis of these experiments, we concluded that naloxone was

devoid of agonistic activity; however, its duration of action seemed

too short for maintenance therapy (5).

Drs. Freedman and Fink were more enthusiastic about naloxone,

however, and a blockade of heroin of up to 24 hours was observed

in patients receiving large oral doses of naloxone (2).

We felt that the long duration of action of cyclazocine was

attributable to the methylcyclopropyl substitution on nitrogen,

that for some reason the presence of a 14-hydroxyl group markedly

reduced nalorphine-like agonistic activity, and raised the question

of whether N-allylnoroxymorphone or naltrexone might be a pure

antagonist with a long duration of action in man since it had

important structural similarities to both naloxone and cyclazocine.

Through the cooperation of Drs. Harold Blumberg, Ralph Jacobsen,

and Irwin Pachter of Endo Laboratories, they not only made the

compound available for clinical studies but conducted toxicity

studies. Dr. Blumberg (1) had already shown that naltrexone was a

potent narcotic antagonist in animals. Almost all of our expectations of this drug in man have been fulfilled. In the first studies

conducted in man, naltrexone proved to be several times more

potent than naloxone and to have a longer duration of action. It has

a high degree of oral effectiveness and when administered in dose

levels of 50 mg/day not only antagonizes the effects of large doses

of morphine but markedly attenuates morphine’s ability to produce

physical dependence (9, 10). Studies conducted under the auspices

of the National Research Council indicate that naltrexone is a safe

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

drug without untoward effects. Further, acute and chronic toxicity

studies conducted by the National Institute on Drug Abuse indicate

that naltrexone is an especially nontoxic drug.

REFERENCES

1. Blumberg, H.; Dayton, H.B.; George, M.; and Rapaport, D.N. N-allylnoroxymorphone: A potent narcotic antagonist. Fed Proc, 20:311, 1961.

2. Fink, M.; Zaks, A.; Sharoff, R.; Mora, A.; Bruner, A.; Levit, S.; and

Freedman, A.M. Naloxone in heroin dependence. Clin Pharmacol Ther,

9:568-577, 1968.

3. Freedman, A.M.; Fink, M.; Sharoff, R.; and Zaks, A. Cyclazocine and

methadone in narcotic addiction. JAMA, 202:191-194, 1967.

4. Jaffe, H.H., and Brill, L. Cyclazocine, a long acting narcotic antagonist: Its

voluntary acceptance as a treatment modality by narcotics abusers. Int J

Addict, 1:99-123, 1966.

5. Jasinski, D.R.; Martin, W.R.; and Haertzen, C.A. The human pharmacology

and abuse potential of N-allylnoroxymorphone (naloxone). J Pharmacol

Exp Ther, 157:420-426, 1967.

6. Martin, W.R.; Fraser, H.F.; Gorodetzky, C.W., and Rosenberg, D.E. Studies

of the dependence-producing potential of the narcotic antagonist 2-cyclopropylmethyl-2’-hydroxy-5,9-dimethyl-6,7-benzomorphan (cyclazocine,

WIN-20,740, ARC II-C-3). J Pharmacol Exp Ther, 150:426-436, 1965.

7. Martin, W.R., and Gorodetzky, C.W. Demonstration of tolerance to and

physical dependence on N-allylnormorphine (nalorphine). J Pharmacol Exp

Ther, 150:437-442, 1965.

8. Martin, W.R.; Gorodetzky, C.W.; and McClane, T.K. An experimental study

in the treatment of narcotic addicts with cyclazocine. Clin Pharmacol Ther,

7:455-465, 1966.

9. Martin, W.R.; Jasinski, D.R.; and Mansky, P.A. Characteristics of the

blocking effects of EN-1639A (N-cycloprophylmethyl-7,8-dihydro-14-hydroxynormorphinone HC1). Presented at 33rd meeting, Committee on Problems of Drug Dependence, Notional Research Council, Toronto,

Ontario, Canada, 1971.

10. Martin, W.R.; Jasinski, D.R.; and Mansky, P.A. Naltrexone, an antagonist

for the treatment of heroin dependence. Arch Gen Psychiatry, 28:784-791,

1973.

11. McClane, T.K., and Martin, W.R. Effects of morphine, nalorphine,

cyclazocine, and naloxone on the flexor reflex. Int J Neuropharmacology,

6:89-98, 1967.

300
CHAPTER 25

Historical Trends in Naltrexone

Research

Demetrios A. Julius, M.D.

The development of the narcotic antagonist, naltrexone, has

related to and reflected in a fascinating way various medical and

psychiatric research trends as well as an array of social and political

trends. It has involved innovative cooperation between the clinical

community, multiple research groups, various Federal Government

agencies, and private industry. Through this cooperative interest in

the project, and of course due to the pressing social need to devise

new treatment approaches to the problem of heroin abuse, the

research effort has yielded what seems to be a most promising and

safe chemotherapeutic addition to opiate dependence therapy.

The existence of narcotic antagonist agents has been known since

the early twentieth century. Initially, the primary interest in this

class of drugs focused on their ability to counteract the effects of

opiates in man and on their consequent use in the treatment of

acute opiate overdose. This application, of course, was of direct

medical life-saving use in hospital emergency rooms across the

country. The main agent used for this purpose has become

naloxone, which is a potent narcotic antagonist with a short

duration of action. However, concurrent laboratory research within

the drug industry was and has been constantly seeking out other

types of narcotic antagonists.

With the increase of heroin abuse in America during the

turbulent 1960’s, the interest in new therapeutic approaches also

increased. Up until then, heroin dependent individuals had not only

been shunned by society in general, but had also been passed along

like hot potatoes within the medical and therapeutic professions.

The problem was that no solid therapeutic approaches seemed to

have any lasting effect with most of these opiate abuses. There

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

were, of course, inpatient facilities like that in Lexington,

Kentucky, as well as other detoxification centers, but the relapse to

heroin dependence was a constant erosion of the therapeutic work

of these centers. It was during this upsurge in heroin abuse that the

classic work and publication by Dole and Nyswander (2) stimulated

widespread interest in their new treatment modality of methadone

maintenance. Concurrently, new treatment modalities were being

devised and explored at the Government’s Addiction Research

Center in Lexington, Kentucky.

One such treatment centered around the concepts of classical

conditioning theory. Building on earlier theoretical formulations,

Abraham Wikler elaborated in the mid-1960’s the theory that

operant conditioning plays an important role in initiating and

perpetuating heroin use. Initially, the euphorigenic properties of

narcotics probably act as strong reinforcers of what was called

“drug-seeking behavior” in the opiate dependent individual. After

this initial phase, tolerance to the narcotic develops and slowly

reduces the euphoric effects. Thus in addition to the pursuit of

pleasure (i.e., the euphoric effects), there is now a need to avoid

pain (i.e., the abstinence syndrome). Therefore, the avoidance of

the discomforting opiate abstinence syndrome also perpetuates the

“drug-seeking behavior.” In addition to this, a hypothesized

“conditioned abstinence syndrome” may apparently be precipitated

by environmental stimuli that have been associated with opiate

dependence in the past. This syndrome has occasionally been

reported merely after contact with a previous drug environment. It

is characterized by increased reactivity to stimuli, prolonged

autonomic responses, and often an intense “craving.”

The narcotic antagonist drugs fit in very neatly, of course, with

this line of thinking. Pharmacologically these substances have the

ability to block the euphorigenic and dependence-producing

properties of opiates. It is currently theorized that these drugs have

this ability because of their structural similarity to narcotics

themselves. Thus antagonists are able to occupy the same presumed

opiate receptor sites in the body and thereby produce competitive

inhibition of narcotics. It seemed logical, therefore, that a narcotic

antagonist could be used to control the above mentioned

determinants of drug-seeking behavior. Since the antagonist would

block the euphoria and the dependence produced by the opiates,

the reinforcement provided by these factors would gradually be

attenuated. Thus with the prolonged absence of these reinforcers

would come the gradual extinction of drug-seeking behavior.

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JULIUS: TRENDS IN NALTREXONE RESEARCH

Now by 1971, the heroin epidemic had reached panic

proportions. The number of opiate dependent individuals was

steadily rising along with an expansion into almost all sectors of

American society. One need only remember all the media reports

on heroin use and overdose in the high schools and grade schools to

be soberly reminded of the mood of the times. By this time, the

Federal Government began formulating action plans to attack this

ever-expanding problem. Through Public Law #92-255, a mandate

was given to establish within the Executive Office of the President a

consolidated agency called the Special Action Office for Drug

Abuse Prevention (SAODAP). Among other tasks, SAODAP

assumed the lead role in research aimed at the development of new

therapeutic techniques. Then SAODAP Director, Dr. Jerome Jaffee,

set the development of a safe, long-acting, and effective narcotic

antagonist as one of the top priorities for his new agency.

As coordinator for federal drug abuse programs, SAODAP had to

work with as many as fourteen different agencies within the Federal

Government that were dealing with drug abuse issues at that time.

One of the main collaborators with SAODAP was the Division of

Narcotic Addiction and Drug Abuse (DNADA) within the National

Institute of Mental Health. Conjointly, these two agencies drew up

a general development plan for narcotic antagonists. This plan

called for concurrent research in the laboratory, in research animals,

and in limited clinical use in man in order to develop perhaps more

than one usable narcotic antagonist. The criteria set forth by these

agencies for an optimal narcotic antagonist were as follows:

1.

2.

3.

4.

Ability to antagonize the euphoric high of opiates

Absent or low agonistic effects, especially unpleasant ones

Does not cause physical dependence

Does not exhibit increasing tolerance to its antagonistic

actions

5.

6.

7.

a.

9.

10.

Absence of serious side effects and toxicity even in chronic

use

Easily administered

Long-lasting or moderate duration of antagonist effects

Absent or low abuse potential

Reversible effects in case of medical emergency

High potency to allow administration of small amounts in a

biodegradable vehicle

11. Easily available and inexpensive

12. Therapeutic efficacy in treatment of narcotic addiction

By early 1972 there were several antagonists in existence at

various stages of development. The purest antagonist was naloxone.

It seemed to be a potent antagonist and showed almost no agonistic

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action of its own. Its main drawbacks as a therapeutic agent in

opioid dependence were its high cost, the difficulty in synthesizing

it, its very poor oral absorption rate, and especially its short

duration of action in the body. Naloxone had been approved by the

FDA for short-term use in humans for opiate overdose. In spite of

its drawbacks, naloxone had met with limited success as an adjunct

to treatment by several investigators. This seemed encouraging for

narcotic antagonist treatment in general.

Concurrently being developed was another promising and potent

antagonist called cyclazocine (3, 6, 7). This drug demonstrated a

longer duration of action of up to 24 hours with 4 milligrams of the

substance. However, its drawbacks were also recognized. These

consisted of strong agonist properties when administered rapidly to

individuals. These properties included quite unpleasant feelings

described as dysphoria and psychotomimetic effects. Despite the

tolerance that develops to these effects, cyclazocine was not well

received by the addict volunteers and soon acquired a bad street

reputation. However, it was successful in the treatment of some

individuals, and these individuals are still, in fact, being treated with

cyclazocine in certain clinics in New York City.

Additionally, three other compounds, designated as M-5050,

BC-2605, and EN-1639A, were in early animal and human testing at

the time. One of these, EN-1639A, seemed to be a potent

antagonist and also did not show the dysphoric and unpleasant side

effects of cyclazocine (1). It had a good duration, in that 50 mg

seemed able to block narcotic action for 24 hours. By late 1972,

there was a substantial supply available for testing of this drug,

which came to be known as naltrexone. By mid-1973 it became

evident that this drug fulfilled the criteria of an optimal narcotic

antagonist to a greater degree than any of the other available

substances (4, 5, 8, 9, 10).

Besides the research progress being made, there were also

administrative changes occurring within the Government. By 1973,

the Division on Narcotic Addiction and Drug Abuse was separated

from NIMH and expanded into the National Institute on Drug

Abuse (NIDA). Thus, from 1973 to 1974, NIDA and SAODAP

shared the responsibility for the ongoing development of the

narcotic antagonists in general and of naltrexone in particular. By

mid-1974, as SAODAP began to phase out of existence, the entire

direction and monitoring of the naltrexone research fell to the

Division of Research, NIDA.

Under the direction of NIDA Director Dr. Robert DuPont and

Division of Research Director Dr. William Pollin, the naltrexone

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JULIUS: TRENDS IN NALTREXONE RESEARCH

research project was accorded the same high priority it had enjoyed

at earlier times. Meanwhile, the day to day planning,

implementation, and monitoring were carried on through a

succession of project officers such as Dr. Alan Ramsey, Dr. Joe

Silvio, and Dr. Demetrios Julius.

It was NIDA’s goal to expedite the development and marketing

of naltrexone in the fastest, safest, and most effective way possible.

With this goal in mind, an effort was made to interest the National

Research Council of the National Academy of Sciences (NAS) in

undertaking this development process. The Council agreed to do

this in part by developing a well-controlled, double blind clinical

trial of naltrexone. A Committee on Clinical Evaluation of Narcotic

Antagonists was formed in order to design, organize, monitor, and

evaluate the planned research project on naltrexone. Five research

clinics were selected to participate in this cooperative study which

included among other things standardized and rigid protocols. The

Baltimore and New Haven clinics could use only “post-addicts” in

their research. The Detroit and Sepulveda clinics could use only

“methadone maintenance addicts,” while the St. Louis clinic could

use only “street addicts.” One of the papers to follow–that by Dr.

Ling–will deal with the experience of one of these N.A.S. research

clinics.

In addition to the controlled cooperative study, NIDA supported

from 1573 to 1974 21 other grants dealing with clinical and

preclinical research into narcotic antagonists. This support totalled

over five million dollars. Researchers in this group were free to use

different protocols, to use different treatment settings, to treat

different types of dependent individuals, and to pursue any variety

of different research questions. These “open” clinical studies added

much useful information on the safety, clinical use, and efficacy of

naltrexone. Another of the papers that follow–the one by Dr.

Resnick–will deal with his experiences in ten years of clinical

experience both with cyclazocine and later naltrexone.

A final category of naltrexone clinics dealt with the direct testing

out of the original behavioral formulations discussed earlier. The

clinic sites were at Camarillo Neuropsychiatric Institute in Ventura,

California; McLean Hospital in Belmont, Massachusetts; and the

Veterans’ Hospital in Philadelphia, Pennsylvania. The experience at

the latter clinic will be discussed by Dr. O’Brien as an example of

these group clinic studies.

The data from most of these studies has now been collected and

has been partially analyzed. The N.A.S. study report has been

pulled together and is set for public distribution. At the same time

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

the remaining data from the NIDA studies are being consolidated

for submission to the Food and Drug Administration in order to

proceed with Phase III of the drug’s development. This will be the

widespread and uncontrolled clinical testing of naltrexone.

As for the present, the analysis has shown that although

naltrexone has not been proven to be statistically more significant

than placebo in retaining subjects in the N.A.S. study and in

extinguishing their drug seeking behavior, there certainly is a trend

favoring its efficacy in a great number of subjects tested. This trend

is most evident in the “post-addict” group. This was the group who

were currently drug free following incarceration or participation in

a therapeutic program. Furthermore they were often under court

pressure in probationary or parole status. Therefore naltrexone

seems to be most effective in the externally or internally motivated

drug-dependent person.

Naltrexone has also proven to be safe in the population tested,

with only occasionally gastrointestinal symptoms of nausea, vomiting, and cramping being reported in some patients. It has also been

shown that naltrexone given in a dose of 50 mg per day completely

blocks the euphoria and dependence producing effects of narcotics.

And quite impressively, the feasibility of doing a well controlled,

double blind study of a new chemotherapeutic treatment has been

demonstrated even with such difficult groups as street addicts,

methadone maintenance addicts, and post addicts. In fact, the

naltrexone study, and especially the N.A.S. portion, stands as a

model for placebo controlled studies with drug-dependent

individuals.

It will be interesting to see what the future has in store for this

research. The final Phase III study plan has been formulated and has

been offered to Endo Laboratories who hold the patent on the

drug. They will be taking the lead on the final development and

eventual marketing of naltrexone.

Meanwhile interest in clinical testing of naltrexone continues

both in the United States as well as in the International community.

Both in Malasyia and in Iran there is strong desire to institute

clinical use of naltrexone in their respective opiate dependent

populations. With the existing legal pressures to cease the

dependence on opiates in these countries, it may well be that

naltrexone proves to be a most effective treatment there.

Naltrexone is, of course, not a cure-all for all opiate dependent

individuals. There probably is no such treatment, as we have learned

through the shortcomings of methadone maintenance. However,

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JULIUS: TRENDS IN NALTREXONE RESEARCH

naltrexone seems to be a safe, and in some small percentage of

individuals, a most effective new chemotherapeutic treatment.

REFERENCES

1. Blumberg, H., and Dayton, H.B. Naloxone, naltrexone, and related

noroxymorphones. In: Braude, M.C.; Harris, L.S.; May, E.L.; Smith, J.P.;

Villareal, J.E., eds. Narcotic Antagonists. New York: Raven Press, 1973.

pp. 33-44.

2 . Dole, V.P., and Nyswander, M.E. A medical treatment for

diacetyl-morphine (heroin) addiction. JAMA, 193(8):646-650, 1965.

3. Jaffe, J.H. Cyclazocine in the treatment of narcotic addiction. Curr

Psychiat Ther, 7:147-56, 1969.

4. Martin, W.R., and Jasinski, D.R. Characterization of EN-1639A. Clin

Pharm Therap, 14:142, 1973.

5. Martin, W.R., Jasinski, D.R.; and Mansky, P.A. Naltrexone, an antagonist

for the treatment of heroin dependence effects in man. Arch Gen Psychiat,

28:784-791, 1973.

6. Resnick, R.; Fink, M.; and Freedman, A.M. A cyclazocine typology of

opiate dependence. Am J Psychiatry, 126:1256-1260, 1970.

7. . Cyclazocine treatment of opiate dependence: a progress report.

Compr Psychiatry, 12:491-502, 1971.

8. Resnick, R.; Schuyten, E.; Kestenbaum, R.; Volavka, J.; and Freedman,

A.M. Narcotic antagonists and methadone maintenance: comparative

aspects of two treatment modalities. Presented to National Conference on

Drug Abuse, Chicago, March 1974.

9. Resnick, R.; Volavka, J.; Freedman, A.M.; and Thomas, M. Studies of

EN-1639A (naltrexone): a new narcotic antagonist.. Am J Psychiat,

131:646-650, 1974.

10. Resnick, R.; Volavka, J.; and Freedman, A.M. Short-term effects of

naltrexone: a progress report. Proceedings of the Committee on Problems

of Drug Dependence of the National Academy of Sciences, 1974. pp.

250-263.

307
CHAPTER 26

Naltrexone: The Clinical

Investigator’s Dilemma

Walter Ling, M.D.

In the summer of 1974 we became involved in a clinical

investigation using the narcotic antagonist naltrexone in the

treatment of heroin addicts. The study was organized by the

Committee on Clinical Evaluation of Narcotic Antagonists (CENA),

U.S. National Academy of Sciences National Research Council

(NAS/NRC), under contract to the U.S. National Institute on Drug

Abuse (NIDA), U.S. Department of Health, Education, and Welfare.

Naltrexone was chosen because of its high efficacy after oral

administration, its virtual lack of agonistic properties, and its

relatively long duration of action.

The goals of the study were to examine the acceptability of

naltrexone at the clinical level and to provide some preliminary

assessment of its toxicity and efficacy in this context. Under three

separate double blind protocols, three distinct populations of

addicts were studied: (1) “street addicts” (patients currently

addicted who either could not or would not enter methadone

maintenance programs), (2) “postaddicts” (former addicts, typically recently released from incarceration and more or less under

external pressure to remain in treatment), and (3) methadone

maintenance patients who wished to detoxify and become drug

free. Five clinics participated in the study, with St. Louis, Missouri,

treating “street addicts,” Baltimore, Maryland and New Haven,

Connecticut, treating “postaddicts,” and Sepulveda, California, and

Detroit, Michigan, treating those detoxified from methadone

maintenance.

All subjects were males, 18 years and older, free of serious

medical and/or psychiatric illnesses. They were randomly assigned,

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LING: NALTREXONE — CLINICAL INVESTIGATOR’S DILEMMA

within each clinic, to either naltrexone or placebo, dispensed as a

syrup with similar taste and appearance.

After induction, naltrnxone patients received naltrexone 100 mg.

on Mondays and Wednesdays and 150 mg. on Fridays, with no

medication for the other days. Placebo patients remained on

placebo throughout the study, which consisted of nine months of

active treatment with a six-month followup. All other auxiliary

services were offered to both groups of patients. Periodic physical

examinations and laboratory tests, as well as detailed analyses of

early terminations for medical reasons, provided indices of safety.

Efficacy was evaluated in terms of program retention, illicit drug

use, changes in psychosocial adjustment, and changes in the degree

of craving for heroin.

I will not attempt to give a detailed report on the results of the

study, since the committee has prepared its own report which will

soon appear in print. In general, the study confirmed the extreme

difficulties in assessing treatment results in the addict population.

Naltrexone appeared slightly better than placebo in terms of

retention and use of illicit drugs. Craving for heroin also seemed to

decrease with prolonged naltrexone administration. Clinical and

laboratory data tended to indicate that naltrexone is safe under the

conditions of this study. No serious medical complications or

adverse reactions were reported and only minor side effects had

occurred.

Undoubtedly the NAS/NRC Committee will draw certain

conclusions and make its recommendations to NIDA based on these

results. My reasons for describing the study are to provide some

background information and to use this study to illustrate some of

the difficulties which, as the result of my participation in the

project, I have become aware of both clinically and as an

investigator. From time to time I shall refer to certain observations

made in the NAS/NRC study to aid my discussion. However, the

interpretations of these findings are my own and do not represent

the view of the committee.

Obviously, the questions about any new drug of greatest interest

to clinicians are: (1) Does it work? (2) Is it safe? and (3) Will patients

take it? In the case of naltrexone, there are problems in answering

each of these questions, but the major problem has to do with

deciding what naltrexone is to do. In other words, how does one

define efficacy and measure it with some degree of certainty?

The pharmacological property of naltrexone, i.e., its ability to

block the euphorigenic effect of narcotics, is already known and is

not an issue requiring clinical investigation. The problem in defining

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

efficacy here is what the clinicians, and ultimately the patients,

wish to accomplish in naltrexone treatment. It is essential then first

to define the goals of naltrexone treatment in ways that may be

measured at baseline and at periodic intervals during and after

treatment with naltrexone. In the case of the NAS/NRC study,

these were: adherence to a recommended treatment regime

(program retention), decrease in the use of illicit drugs (urine test

records), less craving for heroin (craving scale), improvement in

social adjustment (status interview), and improvement as seen by

the clinic staff at termination or completion of treatment (global

assessment).

As a measurement of efficacy, adherence to treatment regimen as

reflected by program retention is problematic at least in two

respects, one having to do with the process of data acquisition and

the other with interpretation of the data acquired. With the possible

exception of methadone maintenance, retention in drug abuse

treatment programs has been generally poor. This undoubtedly

relates to the transient nature of the addict’s motivation for

treatment of any sort, but there are some additional problems

peculiar to treatment with naltrexone. For an addict to be started

on naltrexone, he must first become drug free. This requires time,

especially for patients who are on methadone maintenance. During

the course of detoxification, an addict may become disinterested

for a variety of reasons. Sometimes he becomes discouraged because

of the discomfort, which may be quite substantial for some

patients, experienced during withdrawal from methadone. Parenthetically , there is some evidence that successful detoxification

from methadone maintenance may require months rather than

weeks. The longer the period between the addict’s initial interest in

naltrexone and the actual dosage initiation, the more opportunity

for him to change his mind. Even for those who maintain an

interest in naltrexone, successful detoxification may prove impossible for a patient on methadone maintenance.

As for street addicts, since they generally require less time for

detoxification, one might expect to have greater success with this

group. In actual practice, they proved to be even more difficult

because of the tenuous nature of their motivation and the general

lack of stability in their lives.

Keeping patients on naltrexone after dosage initiation is also very

difficult. For one thing, naltrexone tastes bitter and tends to leave an

unpleasant aftertaste which many addicts dislike. Moreover, unlike

methadone, which allows patients to feel considerable narcotic

effect, naltrexone leaves the patient with no positive subjective

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LING: NALTREXONE — CLINICAL INVESTIGATOR’S DILEMMA

experience to induce him to continue ingesting the drug. Finally,

discontinuing naltrexone induces no subjective discomfort to

remind patients that they need their medication. All these factors

tend to lead to premature termination from naltrexone treatment.

The difficulties in acquiring sufficient program retention data are

well illustrated by the NAS/NRC study. Of the 276 methadone

maintenance patients who indicated an interest in naltrexone, less

than one in five actually received even one dose of naltrexone.

Eighteen subjects (less than 1/15) remained in treatment over 60

days, and only five subjects completed nine months of treatment.

To put this problem in another way: suppose an investigator is

interested in having as few as 50 patients complete a nine-month

study, and let us say optimistically that one half of all patients on

methadone maintenance are interested in becoming drug free and

taking naltrexone. Using the current experience as a guide, this

investigator will have to approach some 5,000 methadone maintenance patients in order to carry out his study successfully. This

means that each time he approaches a potential study subject his

changes of seeing that patient through the nine-month study are

only one in a hundred.

For street addicts he could do even worse. None of the 252 street

addicts completed the study. Only one out of every 18 street

addicts who expressed an interest in taking naltrexone and being

drug free remained in treatment for 60 days.

Another problem with using retention to measure treatment

effects with drug addicts has to do with interpreting the retention

data itself. Many addicts remain in treatment for reasons having

little or nothing to do with the treatment they receive. An addict

may choose to remain in treatment because the alternative would

be going to jail. This can hardly be attributed to any pharmacological efficacy of the drug he receives. For instance, most of the

subjects remaining in treatment after eight months belong to the

postaddict group (5/7 naltrexone—5/16 placebo) who, as indicated

earlier, are often under external pressure to remain in treatment.

A few subjects assigned to a placebo continued to believe they

were receiving naltrexone even after “testing.” A subject on placebo

who “fixed” with his friends but believed that he was protected on

naltrexone and therefore not expecting any drug effect, might

indeed not experience it if the quality of street heroin was poor.

Some subjects, however, having tested and discovered that they

were on a placebo, chose to remain in the study because they could

then use illicit drugs without the fear of disciplinary actions against

them to which they would be subject in a usual treatment program.

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

Furthermore, no outcome data are generally available on subjects

who dropped out of the study. We really do not know if these

people are doing any better or worse than those who remained in

the study.

The extent of illicit drug use (as reflected by urine testing) would

seem to be somewhat more objective, and elsewhere we have argued

that such is the case with LAAM and methadone treatment (1). In

the case of naltrexone, even here the situation is a little more

complicated. If the rationale for administering naltrexone is based

on the behavior theory of extinction, the subjects ought to be

encouraged to test it, and one would assume that the more they test

the more therapeutic it would be for them. It is at least

conceptually difficult to see how the magnitude of this therapeutic

effect (degree of testing) can at the same time indicate how poorly

they are doing. On the other hand, since there is no subjective

sensation that a patient can feel when he is on the medication, until

a subject has tested, all the changes may be due to a placebo effect.

In the NAS/NRC study, an attempt was made to measure the

extent of drug use after the subjects have tested and we did find the

naltrexone group using less illicit drugs subsequent to their first

positive urines.

Changing psychosocial adjustment is meaningful only if there is

concomitant improvement in drug-seeking behavior. If a patient is

doing better in terms of employment and other social adjustments

but continues to use illicit drugs regularly, his social changes may be

attributed to the total treatment program impact but can hardly be

a direct result of any specific drug action. On the other hand, can a

man be considered a failure as far as naltrexone is concerned if he

never uses heroin again but continues to be unemployed and makes

no other attempts to improve his lot?

One interesting observation from the NAS/NRC study was a

decrease in the degree of craving with continued naltrexone

treatment. It is not yet clear whether this relates directly to the

phenomenon of prolonged naltrexone treatment, or whether the

desire for drugs simply decreases with passage of time. As an

instrument for measurement of efficacy, it is too early to judge how

useful this index will be.

A global assessment on the part of the clinic staff is useful at the

end of treatment. However, since the impressions upon which the

assessments are made are based on knowledge of the patient during

his course of treatment, they cannot be accurately measured at

baseline.

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LING: NALTREXONE — CLINICAL INVESTIGATOR’S DILEMMA

Each measurement of efficacy is thus defective in its own way,

and efficacy must be measured in some integrated manner. How to

approach this depends on the investigator’s belief of what

naltrexone should do for the patient. Still, there are other ways to

consider what efficacy really means. We might, for instance, take

the position that since we already know naltrexone will block the

effect of narcotics, the major clinical problem is how to deliver

naltrexone to the target treatment population: in other words, how

to get patients to accept naltrexone. Thus we may reason that in

this instance patient acceptance and efficacy are one and the same.

Furthermore, knowing that an addict’s motivation for treatment is

transient, we might develop new means of drug delivery which

would make it difficult for an addict to stop taking medication

once he is on it. One such approach is the use of a sustained action

preparation.

Still another approach to the issue of efficacy of naltrexone is to

accept what takes place at the clinical level as a fact of life and

attempt to work within these limitations. We know that long-lasting

therapeutic effects rarely if ever result from single treatment

episodes but from repeated efforts to engage addicts in treatment.

(One problem with the NAS/NRC study protocol is the prohibition

of reentry once a patient drops out of the study.) It appears to us

that one way to look at the clinical effectiveness of naltrexone over

time is to allow and encourage patients to undergo treatrnent

repeatedly even though the duration of each treatment episode may

be shortlived. If naltrexone is beneficial, it should lengthen the time

interval between detoxification and the occurrence of physical

readdiction for those who receive treatment with naltrexone, as

compared to those who do not. This time interval may thus serve as

an index of clinical efficacy for naltrexone. And the survival time

from initiation of treatment to clinical relapse can be analyzed by

means of a life table method and compared to a nontreatment

group. This is the direction where our current thinking is leading us.

In summary, I hope this discussion has directed your attention to

some of the difficulties that a clinical investigator must consider in

studying addicts in general and in conducting clinical trials with

naltrexone in addicts in particular. I hope our suggestion of an

alternative method to measure the clinical effects of naltrexone will

prompt others to give further consideration to still other ways of

using naltrexone clinically.

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REFERENCE

1. Ling, W.; Charuvastra, V.C.; Kaim, S.C.; and Klett, C.J. Acetylmethadol and

methadone as maintenance treatments for heroin addicts. A Veterans

Administration Cooperative Study. Arch Gen Psychiatry, 1976.

314
CHAPTER 27

Update on Naltrexone Treatment

Charles P. O’Brien, M.D. Ph.D., Robert Greenstein, M.D.,

and George E. Woody, M.D.

Our group in Philadelphia has used naltrexone in the treatment

of 201 narcotic addicts in 258 separate treatment episodes as of 1

July 1977. The antagonist treatment program is an important part

of our overall multimodality program which includes methadone or

propoxyphene maintenance treatment, inpatient detoxification,

long-term therapeutic community, family, group, and individual

therapies, and a variety of behavioral treatments. Narcotic antagonist treatment, of course, appeals only to those patients who are

genuinely interested in becoming drug free. It is not nearly as

popular as methadone treatment, but it occupies an important

niche–amounting to 5-10 percent of our total patient population at

some time in their treatment careers.

Our narcotic antagonist patients are demographically similar to

our other patients: mean age 27, 60 percent black, more than 95

percent male, and more than 95 percent veterans of military service.

Our methods for detoxification from narcotics and institution of

antagonist therapy have been reported elsewhere (2, 4); they are

similar to those described by others. We use intravenous naloxone

prior to the first naltrexone dose to detect residual physical

dependence and thus reduce the incidence of precipitated withdrawal when the first dose of naltrexone is ingested.

RESULTS

Our results will be discussed in four categories.

1. Side Effects and Toxicity of Naltrexone.

Because naltrexone is such an effective antagonist, it will

precipitate acute withdrawal reactions in patients who have even

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small degrees of residual physical dependence on narcotics. Even in

addicts detoxified up to a week previously, some degree of

cramping and general aches and pains may occur with the first few

doses of naltrexone. Patients with a history of peptic ulcer disease

may have severe abdominal pain precipitated by naltrexone. We

now exclude such subjects from naltrexone treatment.

Other subjective complaints such as dizziness, nausea, insomnia,

or weakness may be related to protracted narcotic abstinence

symptoms rather than naltrexone effects. They diminish after the

first week and gradually disappear over the next several weeks of

treatment.

We found no significant and consistent blood pressure changes in

our 201. subjects. Inpatient blood pressure recordings tended to be

lower than outpatient measures. But outpatient blood pressure

prior to and during naltrexone therapy was not significantly

changed. In fact, we have identified hypertensive addicts during our

screening, treated their hypertension and then successfully placed

them on naltrexone with no adverse effects on their anti-hypertension program.

The only serious toxicity occurring in our series was a case of

idiopathic thrombocytopenic purpura while on naltrexone which

may have been drug-related and a case of allergic dermatitis or drug

rash. The relationship to the rash was established by resuming

treatment with naltrexone cautiously, and the rash reappeared.

Overall, we found naltrexone to be a safe drug with minimal side

effects–the same conclusion reached by Bradford and Kaim (1).

2. Naltrexone Blockading Effects

We evaluated the degree of protection from narcotic effects

afforded by naltrexone by conducting hydromorphone and saline

self-injections under double blind conditions. Hydromorphone

(Dilaudid) is a narcotic whose subjective effects could not be

distinguished from heroin by experienced addicts (3). A variety of

hydromorphone dose levels were used (1-4 mg) equivalent to 7-30

mg heroin, and a variety of dose levels of naltrexone (50-200 mg/70

kg) and a variety of time periods after naltrexone ingestion (2-72

hrs) were used. Our results were quite consistent. Naltrexone

reliably attenuated narcotic objective and subjective effects for up

to 72 hours. The degree of attenuation was proportional to dose of

naltrexone, dose of narcotic, and the time since naltrexone was

ingested. Thus, the narcotic effects were less than those produced

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O’BRIEN ET AL.: UPDATE ON NALTREXONE TREATMENT

by a similar dose in that subject prior to naltrexone but reliably

more than saline effects. These effects were seen in operant

responses, pupillary constriction, and subjective reporting of rush,

high, and street value of the injection.

3. Conditioned Responses Associated With Self-Injection

The availability of patients volunteering to take naltrexone

provides an opportunity to study some of the conditioning factors

associated with the self-injection ritual. The importance of conditioning in the addiction process was first recognized by Wikler (8),

and it has been extensively studied in experimental animals. We

have described several types of conditioning in human addicts (5,

6).

Conditioned abstinence occurs when the addict is exposed to

stimuli which, in the past, have consistently been associated with

opiate withdrawal and the obtaining of the next dose. Examples are

“copping” area, bags of heroin, “cook-up” rituals, and room in

which narcotics are usually injected. After repeated pairing, the

stimuli are able to elicit drug craving and withdrawal responses

(pupillary dilation, cooling of skin, tachycardia) even when the

addict is drug free.

The stimuli which elicited withdrawal responses were all preinjection stimuli. The act of self-injection usually relieved the

withdrawal and craving even if the injection actually consisted of

saline. Some addicts reported definite pleasure from the self-injection when saline was received in a double-blind design. This has

been described clinically as the “needle-freak” phenomenon.

The pleasure received from the injection itself (either saline or

narcotic in the presence of naltrexone) extinguished rapidly. After

several trials the pleasure turned to dislike and the patients reported

that the self-injection caused their craving to be intensified. Thus

some of the conditioned effects of self-injection were modified by

unreinforced self-injection in the laboratory. This did not have a

discernible effect on treatment outcome. Naltrexone patients who

had their self-injection responses extinguished had only a slightly

better outcome than those who received naltrexone with no

self-injections. Still, the changes in injection behavior were dramatic. It may be more clinically effective to begin by desensitizing the

patients to environmental stimuli related to drug procurement and

then systematically progress in steps to desensitization to the

self-injection procedure.

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

4. Clinical Outcome

The determination of relative effectiveness of a specific treatment is especially difficult when types of treatment differ radically.

In the treatment of narcotic addiction, therapeutic community,

methadone or other narcotic maintenance, and narcotic antagonist

therapy all appeal to different patients. Thus random assignment of

unselected patients to a given treatment is not possible. In our

program, all of the above treatment modalities are available, but

patients participate in the decision as to which treatment is used.

Often they are used sequentially at different stages in a patient’s

treatment. The result at followup then might be attributed to

several treatments rather than just the last one.

We have interviewed naltrexone patients at one month and six

months after stopping naltrexone treatment. Social and vocational

functioning, drug use, and urine tests were evaluated. We compared

naltrexone patients to patients treated in a maintenance study

comparing propoxyphene (a weak opiate) and low dose (up to 36

mg per day) methadone. The only differences at intake were that

the naltrexone patients reported more different types of drug abuse

in addition to opiate dependence, more alcohol abuse, and more

attempts at detoxification.

The results at followup showed that methadone patients remained in treatment longer, but there was no significant difference

in treatment duration between propoxyphene maintenance and

naltrexone. After termination from study treatment, naltrexone

patients were significantly less likely to return to methadone

maintenance. Nevertheless, naltrexone patients were more likely to

be located for followup at one and six months. Naltrexone patients

reported significantly more alcohol use at followup, but this

difference was present at intake. Naltrexone patients reported

significantly more benefits from treatment and more satisfaction

with the program than the two maintenance groups. Significantly

more naltrexone patients (40%) were opiate-free at one month, but

the difference became nonsignificant six months after stopping

treatment. Overall, there were remarkably few differences on any

outcome measure. These results will be reported in detail elsewhere

(7).

SUMMARY

To summarize, then, our work with naltrexone in a multimodality treatment program indicates that it appeals to about 5-10

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O’BRIEN ET AL.: UPDATE ON NALTREXONE TREATMENT

percent of narcotic addicts–those who consciously want to obtain

drug-free status. It does significantly attentuate the effects of

narcotics to the extent that they lose their reinforcing properties,

and it has minimal side effects. Although we treated a self-selected

population, it is noteworthy that about 40 percent of those who

remained on naltrexone for more than a week were still opiate free

6 months after cessation of treatment. For some it appeared to be a

turning point in their lives. It was the first time in years that they

could live in their neighborhood and not be either intoxicated or

occupied with the pursuit of narcotics. Our behavioral studies have

identified a number of conditioned psychophysiological responses

associated with the self-injection ritual. So far, although we have

succeeded in extinguishing some of these responses, this has not

resulted in an improved clinical outcome. We are currently working

on more comprehensive behavioral treatments, but the clinical

significance of these conditioned responses is uncertain at present.

REFERENCES

1. Bradford, H.A., and Kaim, S.C. Final Report, Double-Blind Placebo-Controlled Study, Administered by the National Academy of Sciences to

Evaluate the Safety and Efficacy of the Narcotic Antagonist, Naltrexone.

Washington, D.C.: Biometric Research Institute, Inc., 1977.

2. Greenstein, R.; O’Brien, C.P.; Mintz, J.; Woody, G.; and Hanna, N. Clinical

experience with naltrexone in a behavioral research study. In: Julius, D.,

and Renault, P., eds. Narcotic Antagonists: Naltrexone Progress Report,

NIDA Research Monograph 9. DHEW Pub No. (ADM 76-387). Washington,

D.C.: Superintendent of Documents, U.S. Government Printing Office,

1976. pp. 141-149.

3. Martin, W.R.; Jasinski, D.R.; Haertzen, C.A., et al. Methadone – a

reevaluation. Arch Gen Psychiatry, 28:286-295, 1973.

4. O’Brien, C.P.; Greenstein, R.A.; Mintz, J.; and Woody, G. Clinical

experience with naltrexone. Am J Drug Alcohol Abuse, 2(3-4):365-377,

1975.

5. O’Brien, C.P. Experimental analysis of conditioning factors in human

narcotic addiction. Pharmacological Reviews, 27:533-543, 1976.

6. O’Brien, C.P.; Testa, T.; O’Brien, T.J.; Brady, J.P.; and Wells, B. Conditioned narcotic withdrawal in humans. Science, 195:1000-1002, 1977.

7. O’Brien, C.P.; Mintz, J.; Greenstein, R.; and Woody, G. Follow-up studies of

addicts treated by maintenance and by antagonists. (Manuscript in

preparation, 1977).

8. Wikler, A. Dynamics of drug dependence, implication of a conditioning

theory for research and treatment. Arch Gen Psychiatry, 28:611-616, 1973.

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

ACKNOWLEDGMENT

The work reported in this paper was supported in part by Grants No. DA

00586 and DA 01218 from the National Institute on Drug Abuse.

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CHAPTER 28

Naltrexone in the Treatment of

Opiate Dependence

Richard B. Resnick, M.D., Arnold M. Washton, Ph.D.,

Muriel A. Thomas, R.N., and Richard S. Kestenbaum, Ph.D.

INTRODUCTION

At the Division of Drug Abuse Research and Treatment of New

York Medical College, we began using naltrexone early in 1973, and

studies are continuing at the present time. Over the past four years,

more than 400 opiate addicts have been detoxified and inducted

onto naltrexone by members of our staff. Our clinic is located in

the East Harlem section of New York City, where the incidence of

opiate addiction is exceptionally high. The clinic’s patient population is comprised of individuals from all levels of society, although

most are of low socioeconomic status and have a high incidence of

unemployment and use of public assistance. On the average, 38

percent are black, 38 percent are Puerto Rican, and 24 percent are

white. Heroin and/or illicit methadone are the drugs primarily

abused. Patients are referred to us by community service agencies,

by nearby ambulatory detoxification facilities, and by expatients or

those continuing in treatment. The clinic’s staff includes psychiatrists, internists, psychologists, nurses, social workers, vocational

and recreational therapists, students in the mental health professions, and paraprofessional counselors.

This report summarizes the results of four years’ clinical

experience with naltrexone, in both outpatient and inpatient study

groups, and covers the following topics: (a) safety, toxicity, side

effects, and duration of opiate blocking action of naltrexone; (b)

clinical efficacy of naltrexone in the treatment of opiate dependence; (c) methods for rapid induction onto naltrexone; and (d)

future directions.

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SAFETY, TOXICITY, SIDE EFFECTS, AND

OPIATE-BLOCKING ACTION

Our early work with naltrexone focused primarily on the

pharmacology of the drug as a prelude to exploring its clinical

efficacy in treating opiate dependence (3, 8, 9). To be clinically

useful, a narcotic antagonist should be orally effective, safe,

nonaddicting, have minimal side effects, and provide blockade to

opiates for at least 24 hours following a single dose. Results of the

above studies demonstrated that naltrexone met these criteria. For

example, in one study with 37 detoxified heroin addicts (3), daily

dosages of naltrexone ranging from 120 to 200 mg were found to

produce almost no untoward side effects except for epigastric pain

in some individuals, especially when taken on an empty stomach.

Basal heart rate and blood pressure as well as blood and urine

chemistry were not significantly altered, and no signs of toxicity

were detected. Unlike induction onto cyclazocine (1), induction

onto naltrexone was accomplished without dysphoric effects, and

abrupt cessation of daily naltrexone by placebo substitution

resulted in no withdrawal effects. Also, complete blockade of the

euphoric and miotic effects of 25 mg experimentally-administered

intravenous heroin was found 24 hours following a single

naltrexone dose of 50 mg or more, as assessed by subjective rating

scales and measures of pupillary diameter. Blockade was also found

up to 72 hours following administration of 200 mg naltrexone.

These findings were subsequently confirmed (9) in a larger patient

group (N=155), although an insignificant elevation of blood

pressure was found in some cases.

Since these studies indicated that naltrexone was safe, relatively

free of side effects, and acceptable to patients, we directed our

attention toward assessing its clinical efficacy in the treatment of

opiate dependence.

CLINICAL EFFICACY

Predictive Variables

Our evaluation of naltrexone’s clinical efficacy focused primarily

upon identifying opiate users most likely to benefit from

naltrexone treatment (5). This focus emerged from earlier work

with cyclazocine (1) which presented a typological classification of

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opiate users based upon patients’ self-ratings of the role opiates play

in their lives. Briefly, two major groups were identified and shown

to have a differential response to cyclazocine treatment. One group

appeared to use opiates as a form of “self-medication” to relieve

chronic emotional symptoms or stress. They indicated that the drug

reduced their inhibitions, anxieties, and painful affects, and

perceived themselves to function better with opiates in their system

as compared with periods when they were opiate-free. In general,

such individuals discontinued cyclazocine treatment prematurely.

By contrast, the other group seemed to use heroin as a result of

environmental influences: in these individuals disorders of feeling

and impaired capacity to function without opiates did not

predominate. In general, such individuals remained in cyclazocine

treatment for longer periods of time.

Based upon these earlier findings with cyclazocine we hypothesized that patients most likely to benefit from naltrexone would

be those with: (a) greater capacity for object relations; (b) higher

levels of psychosocial functioning; (c) longer histories of opiate

addiction; and, (d) longer opiate-free periods interspersed between

periods of addiction. In a group of 81 opiate-dependent individuals,

applying for naltrexone treatment over a 10-month period, an

extensive battery of information was obtained at intake and then

correlated with treatment outcome at 12 months (l-year followup).

After meeting all criteria for naltrexone treatment (i.e., male, at

least 18 years of age, and no serious medical or psychiatric

disturbance), patients were detoxified from opiates, kept opiatefree for 5-10 days, and then inducted onto naltrexone. Naltrexone

was dispensed, in the clinic, three times weekly (Monday, 100 mg;

Wednesday, 100 mg; Friday, 150 mg). No take-home doses were

provided. Each patient was assigned a primary therapist who

monitored the course of treatment and provided ancillary services.

At twelve months following the first naltrexone dose, patients were

categorized as opiate-free or opiate-dependent based upon urinalysis, Narcan Test, and clinical interview with the patient, family

members, or close friends.

Results showed that of these 81 patients, 33 percent were

opiate-free and 67 percent were opiate-dependent one year following their first naltrexone dose. Consistent with our hypotheses, the

opiate-free as compared with the opiate-dependent group, on the

average, had been addicted for a longer period of time prior to

naltrexone treatment, had longer opiate-free periods interspersed

between periods of addiction, had lower levels of opiate dependence at intake according to money spent for opiates during the

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INTERNATIONAL CHALLENGE OF’ DRUG ABUSE

preceeding 6 months, and a greater percentage had an ongoing

relationship, although none of these differences were statistically

significant. The number of weeks that patients stayed on naltrexone

did significantly differentiate the two outcome groups: opiate-free

patients had taken naltrexone for a mean of 12.1 weeks, whereas

opiate-dependent patients had taken it for only 6.8 weeks. Other

findings were that: (a) relapsing patients tended to return for

treatment and stay for increasingly longer periods of time with each

return, and, (b) the proportion of the 81 patients who were

opiate-free and opiate-dependent at various points in the study

varied greatly during the first 6 months of the study but stabilized

thereafter (i.e., the ratio of opiate-free to opiate-dependent patients

was approximately the same at 9, 12, and 15 months following the

first naltrexone dose).

All 81 patients discussed above stayed on naltrexone for at least

one week after receiving their first dose. Another 66 patients who

had entered treatment during the same 10-month period failed to

complete detoxification and thus received no naltrexone. A

comparison of these two groups revealed some striking differences:

(1) patients who failed to complete detoxification had used

significantly larger amounts of opiates during the 6 months prior to

intake; and (2) nearly twice the percentage of patients who stayed

on naltrexone for at least one week had been gainfully employed at

intake.

Although this study failed to uncover reliable predictors of

treatment outcome with naltrexone, an important finding was that

time on naltrexone significantly differentiated opiate-free from

opiate-dependent patients at 12 months. This finding suggests that

naltrexone contributes favorably to treatment outcome as time on

naltrexone increases.

Treatment Outcome

Table 1 presents treatment and followup data for 265 patients

who were inducted onto naltrexone and then discontinued it within

the 29-month period from February 1975 to June 1977. As shown

in the column headings, these 265 patients are categorized into

three groups, based upon the amount of time they stayed on

naltrexone: Group I consists of 62 patients (23 percent of the total

N) who stayed on naltrexone 7 days or less; Group II consists of

140 patients (59 percent) who stayed on naltrexone from 8 days to

3 months (mean of 4.8 weeks); and, Group III consists of 63

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RESNICK ET AL.: NALTREXONE IN TREATMENT

TABLE 1

Treatment Outcome as a Function of Time on Naltrexone (N=265)

TIME ON NALTREXONE

Group I Group II

(N=62) (N=140)

Group III

(N-63)

TREATMENT OUTCOME

7 days

or less

8 days to

3 months

3 to 24

months

Re-addicted:

within 1 month

within 2-6 months

total

Opiate-free:

6 months or more

less than 6 monthsa

Other:

left NYC opiate-freeb

lost to follow-up

82% (51) 63% (88) 24% (15)

2% (1) 15% (21) 27% (17)

84% (52) 78% (109) 51% (32)

2% (1) 2 % (3) 29% (18)

0% (0) 2% (3) 6% (4)

3% (4) 3 % (4) 2% (1)

13% (8) 19% (27) 13% (8)

a

currently opiate-free but discontinued naltrexone less than 6 months ago

b

left NYC opiate-free from 1 to 5 months after discontinuing naltrexone

patients (24 percent) who stayed on naltrexone from 3 to 24

months (mean of 26.8 weeks). Followup data show that with

increasing time on naltrexone the incidence of readdiction within 6

months after discontinuing naltrexone decreases. Note that the

overwhelming majority of patients in Group I (82 percent) became

readdicted within 1 month after their last naltrexone dose. It can

also be seen that there is a direct relationship between time on

naltrexone and the numbers of patients who have been opiate-free

for at least 6 months since their last naltrexone dose: only 2

percent of Groups I and II fall into this category, as contrasted with

29 percent of Group III. Fifty-two of the original 265 patients fall

into the category of “Other.” These fifty-two include: (a) patients

who left New York City opiate-free from 1 to 5 months after their

last naltrexone dose; and (b) patients who terminated naltrexone

treatment and were lost to followup.

Not included in the preceeding analysis are 20 patients who have

been receiving naltrexone, without interuption, from 1-20 months.

Consistent with our earlier results (5), the present findings

suggest that naltrexone’s clinical efficacy is a function of treatment

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duration. The longer patients stay on naltrexone, the better their

prognosis for remaining opiate-free. It would appear, therefore, that

a critical efficacy issue is to identify factors that help retain patients

in treatment for at least some minimum period of time. Present

findings suggest 6 months as a possible minimum: most patients

who became readdicted did so within the first 6 months of

treatment; Group III, who stayed on naltrexone for an average of 6

months, showed the most favorable treatment outcome.

What are some of the factors that affect patient retention in

treatment? From the outset, our clinical experience has strongly

suggested that individual counseling/therapy plays an important, if

not essential, role in patient retention and rehabilitation in

antagonist treatment (7).

Treatment Approaches

Narcotic antagonists do not pharmacologically alter the substrates of opiate-seeking behavior nor do they offer symptomatic

relief. Their clinical efficacy derives indirectly from blocking the

effects of potentially self-administered opiates. As long as patients

stay on the antagonist, opiate-seeking behavior is thwarted and

readdiction is virtually impossible. It would appear, therefore, that

models for evaluating the clinical efficacy of antagonists cannot be

the same as those used for pharmacologic therapies of other

illnesses, that directly influence underlying malfunctions and

alleviate symptoms. The efficacy of such therapies is readily

discernable, as when imiprimine is found to have an antidepressant

effect. By contrast, narcotic antagonists do not directly alter

underlying psychopathology or its behavioral manifestations. Unless

otherwise treated, intrapsychic and environmental factors which

contribute to opiate-seeking behavior will remain unaltered by

antagonist medication alone and predispose the individual to

terminate treatment and become readdicted. It is our contention

that psychotherapeutic intervention contributes positively to retaining patients in treatment and fosters overall rehabilitation. Accordingly, the efficacy of antagonist treatment is inseparable from the

overall therapeutic context within which it is provided. If the

efficacy of naltrexone depends upon other variables in an overall

treatment approach, it is unreasonable to evaluate it without

identification and control of these other variables.

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Some of the clinical techniques we employ and consider most

important will be discussed below. First, we must emphasize the

obvious: Good clinical judgment is never fully explainable from a

description of specific techniques.

When working with narcotic antagonists, it is important to

emphasize to patients that the medication alone is not the whole

treatment. Obviously, to do this, the staff themselves must know it,

understand it, and believe it!

The medication can, however, be used as a tool for engaging the

patient in therapy: It can be a way of enabling the patient to begin

to trust the therapist and to establish a therapeutic alliance.

Whatever therapeutic techniques are employed, the importance of

good rapport and positive transference between the patient and a

therapist cannot be overemphasized. This relationship can be

beneficial in many ways, ranging from providing support the patient

needs during the postwithdrawal period to substituting for

emotional resources that are lacking in the patient’s life, In early

work with antagonists, when we did not provide such therapy, our

results were poor; they improved subsequently when patients were

seen by trained and empathetic therapists for regularly-scheduled

counseling sessions.

With continued treatment, the patient can learn to look to the

therapist rather than to opiates for gratification of dependency

needs, relief of anxieties, and solutions to problems. Through this

relationship the patient is reinforced for decisions that foster a

more stable and socially acceptable lifestyle, which excludes

opiates.

One aspect of treatment that should be considered is the benefit

a patient may derive from having conditioning theory explained to

him, so that he may begin to look for signs of conditioned

responses within himself. The value for the patients who have this

understanding has been remarkable in some of our followup

interviews. When conditioning is explained to patients, it has the

additional benefit of alerting them to the possibility that they could

become readdicted at some time in the future, even after a long

period of successful antagonist treatment.

Discontinuing antagonist medication and resuming opiate use are

insufficient criteria for labeling the treatment a failure. Would you

say that digitalis is not clinically efficacious if a patient with

congestive heart failure stops taking it?

The model we use should be similar to the one we use in treating

chronic medical illnesses. Patients must be told that whenever

medication is discontinued, they can and should ask to be put back

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on the antagonist whenever they feel tempted, or have begun, to

use opiate drugs again. Imagine the positive effect it has on patients

and their families when they can view addiction as no worse than

other recurrent medical problems for which treatment is available.

The emotional impact on the patient is usually profound, since he

has previously experienced negative attitudes and rejection whenever he has become readdicted.

The primary focus of treatment should be for patients to change

their lifestyle rather than never to use drugs again. For some

individuals, a meaningful commitment to rehabilitation can be

made only after relapsing and becoming readdicted one or more

times. Others have to know their therapist long enough to trust that

the therapist cares and will help in times of need.

We have found that the most successfully rehabilitated patients

are those who learn to rely more and more on the therapist for

help, especially during the early phase of treatment. As this

relationship begins to become a trusted and consistent source of

satisfaction, these patients dwell less and less on the instant

gratification afforded by opiates.

Clinic attendance is a crucial issue. Methadone patients come

because they fear getting sick; antagonist patients don’t have that

worry. Their attendance must be based on a strong desire to remain

drug free, fear of family or other external pressure, or a good

relationship with their therapist. Few patients can be expected to

come to the clinic because of a commitment to their therapist,

initially. It becomes a very strong message to the patient, however,

if he skips one day of medication and is called by his therapist to

find out where he is. Our patients often express surprise and state

that they have never been “cared about in this way” by other

treatment programs. A few such calls, and soon many patients begin

to respond to that caring with a commitment to their therapist that

includes coming to pick up their medication.

Requiring daily medication is usually a good idea with antagonist

patients, at least in the initial months of treatment. It not only

provides some structure to their lives and puts them in frequent

contact with the staff, but also can serve to alert the staff to the

potential for readdiction whenever a patient skips a day of

medication. Many patients feel they can skip medication and use

opiates “once in a while.” We have found that antagonists become

useful in respect to this issue for two reasons. Since the patient

must make a conscious decision to skip medication, he cannot deny

responsibility for his impulsive drug use. Many good antagonist

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RESNICK ET AL.: NALTREXONE IN TREATMENT

candidates–those we believe have the best prognosis–are also those

whose drug use is impulsive.

By helping the patient understand these dynamics, the therapist

forces the patient to become aware of his choices, instead of

believing that he used drugs because he was “weak-minded” and

implying it was beyond his control. We often tell patients and their

families that refusal to take medication is analogous to stating an

intention to get “high.” A patient who is ambivalent about taking

medication on a particular day is less likely to act on his impulse to

skip it, if he knows that doing so is equivalent to announcing to his

family and staff: “Today I plan to shoot heroin.” We have found

that involving the family in this way places the patient in a situation

where he can rely on external pressures to help him through times

of ambivalence, until he can integrate his desire to remain drug free

on a new emotional level, under more conscious control.

METHODS FOR RAPID INDUCTION ONTO NALTREXONE

Irrespective of overall treatment approach, there is the initial

problem of induction onto the antagonist (in this case, naltrexone).

Opiate-dependent patients scheduled for antagonist treatment must

first be detoxified from opiates. Detoxification is usually accomplished by gradually decreasing doses of methadone. This must be

followed by an opiate-free period of 5-10 days duration before

naltrexone can be administered without precipitating severe abstinence symptoms (3). The final stages of detoxification (from 20 to

0 mg methadone) and the subsequently required opiate-free period

are the most difficult for patients to handle, as evidenced by high

dropout rates. Unless incarcerated, many patients return to illicit

opiate use before receiving an initial dose of naltrexone. It is

desirable, therefore, to have these high-risk periods be as short as

possible.

Recently, we explored naloxone-precipitated withdrawal as a

means for rapid opiate detoxification and induction onto

naltrexone (4). The rationale was that by precipitating withdrawal

directly we might reduce the total duration of the withdrawal

syndrome without increasing its severity to unacceptable levels.

Moreover, since naloxone is a short-acting antagonist, if precipitated

withdrawal became unacceptably severe it would subside within a

short period of time (i.e., within 1 hour). In patients dependent

upon 5 to 25 mg methadone, successive injections of naloxone (1.2

mg IM) were administered over a three-day period. On the first day,

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the initial naloxone injection precipitated acute withdrawal which

was at times severe, but subsided within 1 hour after the injection.

With subsequent injections, the severity of precipitation diminished,

so that by the end of the first day naloxone was precipitating little

or no acute withdrawal. On the second and third days, with

continued naloxone administration, withdrawal signs did not

emerge and all patients felt reasonably comfortable.

Patients found the procedure acceptable, and, as word spread

among the clinic’s population, it became increasingly common for

patients to request this procedure in lieu of the more gradual

detoxification procedures routinely employed. This high degree of

acceptance was somewhat surprising, and was thought to be due to

preference for a brief, albeit more concentrated, episode of

abstinence over the milder but more prolonged experience with

routine procedures. Moreover, naloxone-precipitated withdrawal

was found to be safe in that vital signs (heart rate, blood pressure,

and respiration rate) were only minimally altered, even at the peak

of withdrawal severity. This procedure did not, however, significantly reduce the number of opiate-free days prerequisite to

receiving an initial dose of naltrexone. We found that at least 5

opiate-free days were still required before naltrexone could be

administered without producing additional manifestations of withdrawal.

In a more recent study (6), we explored the possibility of

modifying the precipitated withdrawal procedure to see whether the

prerequisite opiate-free period might be shortened. The most rapid

procedure allowed induction onto naltrexone within 48 hours after

a final opiate dose (5 to 20 mg methadone). This procedure

consisted of 1.2 mg naloxone IM every 30 minutes for 3 to 6 hours,

followed by hourly increasing doses (from 5 to 50 mg, in 10 mg

increments) of oral naltrexone. Additional findings were: (a) that

peak severity ratings of naloxone-precipitated withdrawal (signs and

symptoms) were directly related to the patient’s level of opiate

dependence just prior to the start of the procedure; and, (b) that

premeditation with diazepam and atropine helped mitigate the

nervousness and gastrointestinal upset often experienced during

precipitated withdrawal. Moreover, the procedure was found to be

safe, and acceptable to patients.

FUTURE DIRECTIONS

Overall, our clinical experience indicates that naltrexone alone is

not a highly efficacious treatment for opiate dependence, except,

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RESNICK ET AL.: NALTREXONE IN TREATMENT

perhaps, in selected individuals highly motivated to become opiate

free, For the typical “hard-core” street addict, opiate dependence is

part of a lifestyle and thus deeply ingrained in the individual’s

behavioral and intrapsychic repertoire. It is difficult to imagine that

a medication which offers no immediate gratification or symptomatic relief would itself cure the “ill.” One might ask at this point

what is the “ill”? Although we would all agree that being opiate

dependent is itself a serious problem with numerous ramifications

for the opiate-dependent individual, the analysis must not end here.

Opiate-seeking behavior is merely symptomatic of a host of

underlying problems. We suggest, therefore, that treatment be

directed toward the individual, as by the use of psychotherapeutic

techniques. From this vantage point, antagonist medication is seen

as adjunctive to psychotherapy rather than vice versa.

It would appear that the relative contributions of psychotherapy

and antagonist medication to overall treatment efficacy need to be

assessed. Although our clinical impressions suggest that the combination of treatment modalities is more efficacious then either

alone, these impressions have not been assessed systematically.

Therefore, we are conducting a study of treatment outcome

wherein psychotherapy is the variable manipulated. Briefly, one

group of patients receives naltrexone in conjunction with individual

psychotherapy, whereas another receives naltrexone and concrete

services only. Information obtained from this study may help to

formulate the most appropriate clinical setting for naltrexone’s

application.

A factor which limits naltrexone’s efficacy is that it is easily

discontinued. Too often, patients discontinue naltrexone impulsively and fail to return to the clinic, before a therapeutic relationship

with the staff has had an opportunity to develop. Cyclazocine,

however, is more difficult to discontinue than naltrexone. Unlike

naltrexone, abrupt cessation of daily cyclazocine results in withdrawal symptoms that serve as a “reminder” to come in to the

clinic. This makes it more difficult for patients to miss clinic visits

impulsively. However, induction onto cyclazocine is often difficult

because of dysphoric side effects (1). These differences in ease of

induction and termination between cyclazocine and naltrexone

suggest the possibility of a combined regimen wherein patients are

first inducted onto naltrexone and then begin to receive cyclazocine. After a maintenance dosage of cyclazocine is reached,

naltrexone would be discontinued while cyclazocine remains. We

plan to assess the acceptability and efficacy of this combined

regimen in an upcoming study.

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

REFERENCES

1. Resnick, R.; Fink, M.; and Freedman, A.M. A cyclazocine typology of

opiate dependence. Am J Psychiatry, 126:1256-1260, 1970.

2. . Cyclazocine treatment, of opiate dependence: a progress report.

Compr Psychiatry, 12:491-502, 1971.

3. Resnick, R.; Volavka, J.; Freedman, A.M.; and Thomas, M. Studies of

EN-1639A (Naltrexone): a new narcotic antagonist. Am J Psychiatry,

131:646-650, 1974.

4. Resnick, R.; Kestenbaum, R.; Gaztanaga, P.; Volavka, J.; and Freedman,

A.M. EEG and behavioral effects of naltrexone in man. Electroencephalogr

Clin Neurophysiol, 38:107, 1975.

5. Resnick, R.; Aronoff, M.; Lonborg, G.; Kestenbaum, R.; Kauders, F.;

Washton, A., and Hough, G. Clinical efficacy of naltrexone: a one-year

follow-up. In, Julius, D., and Renault, P., eds. Narcotic Antagonists:

Naltrexone Progress Report. NIDA Research Monograph 9. DHEW Pub. No.

(ADM) 76-387. Washington, D.C.: Superintendent of Documents, U.S.

Government Printing Office, 1976.

6. Resnick, R.; Kestenbaum, R.; Washton, A.; and Poole, D. Naloxone-precipitated withdrawal: a new method for rapid induction onto naltrexone.

Clin Pharmacol Ther, 21(4):409-413, 1977.

7. Resnick, R., and Schuyten-Resnick, E. A point of view concerning

treatment approaches with narcotic antagonists. In, Julius, D., and Renault,

P., eds. Narcotic Antagonists: Naltrexone Progress Report. NIDA Research

Monograph 9. See reference 5 above.

8. Verebely, K.; Volavka, J.; Mule, S.J.; and Resnick, R. Naltrexone:

disposition, metabolism, and effects after acute and chronic dosing. Clin

Pharmacol Ther, 20:135-328, 1976.

9. Volavka, J.; Resnick, R.; Kestenbaum, R.; and Freedman, A.M. Short-term

effects of naltrexone in 155 heroin ex-addicts. Biol Psychiatry, 11:689-694,

1976.

ACKNOWLEDGMENT

This work was supported by contract No. HSM 42-73-258 with the National

Institute on Drug Abuse.

332
CHAPTER 29

The Development of Sustained

Action Preparations of Narcotic

Antagonists

Robert E. Willette, Ph.D.

INTRODUCTION

The use of narcotic antagonists in the treatment of opiate

addiction is based on the concept of a pharmaceutical agent capable

of blocking the reinforcing properties of a dose of opiate taken

during an addict’s rehabilitation. The rationale for use is that the

antagonist blocks the opiate “high,” making it pleasureless, thus

removing the addict’s incentive for continued use. Earlier successful

therapy with cyclazocine and naloxone prompted the full-scale

development of new and superior antagonists. Presently naltrexone

is the drug under the most intensive clinical evaluation and appears

to be a promising antagonist candidate.

It was felt from the outset that a most desirable component of

antagonist therapy would be a long-acting drug, so that the need for

an addict to repeatedly decide to take his medication would be

minimized. Naltrexone in oral doses of 70 mg. will provide

adequate blocking protection for at least 48 hours, or perhaps as

long as 72 hours in certain individuals. This is not felt to be a long

enough interval between dosages to aid the addict in becoming

dissociated from his drug-taking behavior.

It was recognized very early that in order to achieve the desired

one week, one month or longer duration between dosages, it would

be necessary to develop a long-acting drug delivery system or a

sustained-release preparation of an acceptable, but short-acting

antagonist. A “drug-delivery system” is the unwieldly but currently

favored expression describing any pharmaceutical preparation

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

capable of providing a sustained or long-acting antagonistic effect.

This effect may be achieved mechanically (e.g., by implanted discs

with timed release capacity) or chemically (e.g., microcapsules,

tubes, solid balls, gelatinous masses injected intramuscularly).

Distinct from the problem of finding an optimum antagonist is that

of inventing suitable carriers for the antagonist in order to release it

uniformly bit by bit over a period of time.

Efforts to achieve satisfactory drug delivery systems were

launched in the early 1970’s by the City of New York Public Health

Department and by the U.S. National Institute of Mental Health’s

Division of Narcotic Addiction and Drug Abuse, now the National

Institute on Drug Abuse (NIDA).

During this early period, the pioneering efforts of Dr. Seymour

Yolles, of the University of Delaware (U.S.), demonstrated for the

first time that sustained release of an antagonist could be obtained

from a biodegradable polymer, i.e., polylactic acid. This success

generated expanded and intensified efforts, which are summarized

in this article. At the present time, the program supported by NIDA

includes two contracts concerned with the development of new

delivery systems and three contracts with the responsibility of

evaluating them for potential clinical trials. The program is now

narrowing down on those candidates that appear to have the best

combination of essential properties to assure a successful clinical

trial.

SYSTEM DESIGN SPECIFICATIONS

There are several properties and features that are important

characteristics in the design and development of a clinically

acceptable and useful delivery system. Some of these are:

1. An adequate and smooth drug release rate

2. Ease of insertion or injection

3. Balancing the desirability of making removal by the patient

difficult versus the desirability of ease of removal by the

physician

4. Biocompatability or lack of adverse tissue reaction or pain

upon injection

5. Ease and low cost of manufacture

6. Stability when subjected to sterilization

7. Stability and storage characteristics

8. Patient and physician acceptability

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WILLETTE: SUSTAINED ACTION NARCOTIC ANTAGONISTS

Each of these considerations has a different relative importance,

and it is the task of the development team to select an optimal

compromise of specifications in order to bring a candidate

preparation into clinical trial. It is recognized that the first trial

preparation may not be the ideal system and that additional

refinement may be necessary before a system can be introduced

into wide clinical usage.

DEVELOPMENT PLAN

In the Spring of 1973, a new program for the development of a

long-acting narcotic antagonist was initiated. It consisted of two

contracts and two grants to design and prepare candidate delivery

systems. Each group was also responsible for carrying out the

preliminary screening of the systems by in vitro and in vivo tests to

select those with the most promising release properties. This

program included work on polylactide microcapsules, polylactidepolyglycolide beads, polyglyceride pellets, and an insoluble salt

complex, the latter three having been originated under an earlier

program supported by New York City.

In addition to these projects, three contracts were let to carry

out in centralized facilities the evaluation of all promising candidates emerging from the developers. This consisted of a multiple

level pharmacological and pharmacokinetic testing schedule as well

as a range of toxicological measures. The overall scheme was

designed in a pyramidal fashion with more rigorous criteria required

to pass from one level to the next.

At the heart of this plan was the recognition that an advisory

group composed of scientists from several relevant areas was

essential to assist in monitoring progress and in making the difficult

decisions about which leads to pursue. Their dedication and loyalty

to the program has played a critical role in its success. The group

has consisted of: Drs. Sidney Archer, William L. Dewey, James T.

Doluisio, Fred A. Kincl, Fred Leonard, and James L. Olsen. Others,

including Drs. Joseph Borzelleca, Douglas R. Flanagan, Stanley

Kurtz, Grant Wilkinson, and Ann Wolven, have also provided

important input. Valuable advice and sharing of information has

come from Drs. Gabrial Bialy and Henry Gablenick from the Center

of Population Research, U.S. National Institute of Child Health and

Human Development, where a similar program for long-acting

antifertility agents is being supported.

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

At the present time the program is concentrating on four systems

that have demonstrated the most promise. These will be described

next.

CANDIDATE DELIVERY SYSTEMS

Polypeptide Tubes and Rods

Arthur D. Little, Inc.

In order to minimize the amount of animal testing required to

receive the U.S. Food and Drug Administration’s approval for an

early clinical trial, it was desirable to select a system capable of

being removed at the end of a month, but which could eventually

be left permanently implanted. A preparation that meets these and

the other criteria is a tiny hollow tube of a synthetic polypeptide

composed of a 22/78 copolymer of glutamic acid and ethyl

glutamate. Slowly biodegradable, these 2 mm by 10 to 20 mm

tubes are filled with a solid core of naltrexone free base or

hydrochloride which diffuses out through the tube wall. Rates of

release may be adjusted by varying the thickness of the tube’s walls.

The tubes are manufactured in a fashion similar to candles, with

a fine glass mandrel being dipped at a controlled rate into a heated

solution of the polymer. The tubes are removed, filled with a little

saline, a solid rod of 90 percent naltrexone bound in polymer, and

sealed with a cap. Sterilization may then be achieved by autoclaving.

Originally polymers composed of glutamic acid and leucine were

prepared and evaluated. Early samples of these gave up to 60 days

of sustained release, releasing up to 30 micrograms of naltrexone

per hour. Unfortunately, improvements in the release rates and the

lack of significant biodegradation have forced the shift to the newer

glutamate/ethyl glutamate polymer. Early prototypes appear to give

good release rates and nearly complete biodegradation within 90

days. Further tests are underway.

This work is under the general supervision of Mr. Kenneth

Sidman.

Polylactic/glycolic Acid Beads

Dynatech Corporation

Potentially removable by a surgeon, these l/16 inch beads of

90/10 polylactic and glycolic acid copolymer offer flexibility in

336
WILLETTE: SUSTAINED ACTION NARCOTIC ANTAGONISTS

dose administration. Implantable by means of a trocar, the 70

percent naltrexone free base loaded beads have shown continuous

release for more than a month. Samples of beads have been

periodically removed from injection sites and examined for biodegradation. They gradually soften, grow smaller or crumble, and

eventually become undetectable.

On the basis of the series of tests described below, this candidate

system is currently undergoing toxicological testing to enable its

administration to humans. To date, the toxicity studies have shown

no adverse effects and it is expected that a clinical trial will be

possible by early in 1978.

This work has been directed by Dr. Donald Wise.

Earlier contracts that have provided potentially useful preparations are:

Polylactic Acid Microcapsules

Washington University

Two major advantages of a microcapsule approach to drug

delivery is their potential for zero-order release rates and injectability. To date microcapsules of less than 180 microns of micronized

particles of naltrexone pamoate coated with dl-polylactic acid have

shown sustained release for more than forty days. They have been

injected to date as a suspension in 2 percent aluminum monostearate gel in peanut oil. Other more acceptable vehicles are beihg

tried.

Additional work on perfecting capsules of naltrexone free base,

considered more desirable because higher payloads of drug may be

achieved, have not been very encouraging. A suitable sterilization

procedure is not yet possible.

Because of the apparent incomplete release of naltrexone and the

difficulty in removing traces of the solvents used to prepare the

microcapsules, work on this approach has been temporarily halted.

If such a preparation is judged to be more acceptable under clinical

conditions, it would then be pursued further.

These systems have been developed by Dr. Kurt Thies.

Naltrexone Aluminum Tannate

IITRI

Based on older formulation approaches, this insoluble aluminum

tannate complex of naltrexone, when injected intramuscularly in a

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

suspension of 2 percent aluminum monostcarate peanut oil gel,

gives a sustained release of over thirty days. The complex is both

readily prepared and easy to sterilize.

In preliminary studies on tissue compatibility, relatively little

reaction was seen. It is known, however, that peanut oil suspensions

cause occasional reactions. This preparation would require an

extensive amount of toxicological testing before undergoing human

trials and will await trials with other systems.

This preparation was developed by Dr. Allan Gray.

EVALUATION PROCEDURES

Preliminary Screening

Each developer was responsible for carrying out the screening of

trial preparations by in vivo and in vitro methods. The test used by

all groups was the mouse tail-flick method of Dewey and Harris.

Animals were injected or implanted with the preparation, and at

various intervals different groups were injected with morphine and

their analgetic response measured in order to determine whether

continued antagonism occurs.

Some variations in in vitro tests were used, with the primary

purpose being to establish a correlation with the animal tests.

Eventually, only the in vitro methods became necessary for general

screening. As a followup to the animal testing, injection sites were

examined for gross pathological reactions. If nothing is visibly

apparent, little is usually found upon histological examination.

Advanced Pharmacological Evaluation

At Ohio State University, under the direction of Dr. Richard

Reuning, all candidate systems selected from preliminary screening

were tested using the mouse tail-flick test under standard conditions. Those systems showing unusual promise were then tested in

rats using radiolabeled drug, and the pharmacokinetics of release

were studied.

In the course of developing suitable test procedures, considerable

work was done on the metabolism and pharmacokinetics of

naltrexone. This was essential for the calculation of actual release

rates of the systems themselves.

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WILLETTE: SUSTAINED ACTION NARCOTIC ANTAGONISTS

Advanced Toxicological Evaluation

As candidate systems passed on through the pharmacological

testing, they were evaluated in parallel at Industrial Bio-Test by Mr.

Carmen Mastri. Depending on the dosage form being tested, the

systems were implanted or injected into mice, rats, and intramuscularly in rabbits. The last is the classical U.S.P. irritation test.

When possible, suitable positive and negative control materials were

run concurrently.

Final Animal Evaluations

The most promising candidates eventually find their way into the

most rigorous evaluation. The pharmacological test is carried out in

monkeys trained to self-administer morphine. Developed at Parke,

Davis and Company by Dr. Duncan McCarthy, the suppression of

morphine administration is an indication of how long the system

delivers an effective level of naltrexone. At the same time, samples

of plasma are obtained at various intervals and analyzed by the

Ohio State group to determine the exact amount of drug released.

Correlation of this data with pharmacokinetic measures of

naltrexone in the same animals has thoroughly characterized the

candidate systems.

As indicated above, the Dynatech beads have also been started in

a detailed toxicological evaluation at Parke-Davis. This involves

three species at three dose levels. Periodic sacrifices are being made

to obtain a detailed pathological evaluation. The protocol is

designed so as to assure an early clinical trial based on the idea of

removing the test system at the end of one month.

SUMMARY

After several years of tedious and often frustrating efforts, a few

promising systems are now near final evaluation, with the intention

of conducting human trials in the near future.

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CHAPTER 30

The Future of Naltrexone

Pierre F. Renault, M.D.

The immediate future of naltrexone involves the initiation of the

final phase of clinical testing. In the United States, drug manufacturing is regulated by the Food and Drug Administration (FDA).

The regulations are quite specific and detailed when it comes to the

development of new drugs. For a drug to be marketed in the United

States, it must initially pass preclinical, animal toxicity tests, and

then a series of clinical trials in humans. The clinical trials in

humans are in three phases. The first phase usually involves the

determination of dosage and side effects. Phase two involves the

determination of safety and efficacy in a controlled environment on

selected patients. The third and final phase of clinical testing

involves using the drug as it is intended to be used clinically.

Naltrexone has completed phase two of clinical testing and has been

shown to be both safe and effective. This testing was conducted in

males who were healthy aside from their heroin addiction. Phase

three will involve both males and females and no one will be

excluded on the basis of health if he or she is otherwise appropriate

for naltrexone treatment. The purpose of phase three testing is to

determine therapeutic efficacy of the medication in the general

treatment population and to search for low incidence side effects

which may not have been detected in the selected phase two

treatment population.

An important issue in the determination of the clinical efficacy

of naltrexone is that of treatment compliance. Will addicts take

naltrexone? Clearly, it must be taken if it is to do any good. The

problem of compliance is common to all medications administered

to an asymptomatic group with a disease in a latent form. An

excellent example is the compliance of individuals taking antihypertensive medication. The basic question is whether the simple

efficacy of naltrexone in blocking the euphoria and the develop340
RENAULT: THE FUTURE OF NALTREXONE

ment of physical dependence will be sufficient for the drug to be

marketed or whether the FDA will insist on evidence of treatment

compliance as a further measure of efficacy.

There is also a series of more difficult questions surrounding the

clinical use of naltrexone. How should patients be selected for

naltrexone treatment? On what basis should the decision be made

to use the drug as a crisis intervention technique or as a

maintenance drug? Can it be used safely and effectively in

adolescents? How ethical and acceptable would it be to use

naltrexone in work release programs for addicts in prison?

The real future of naltrexone involves a series of unanswered

questions. Central and perhaps the most fascinating of all the

questions which are provoked by naltrexone is what effect it has on

the endogenous opioid or endorphine system. We know from

subhuman data that narcotic antagonists block the effects of

endorphines, and we can infer that the endorphine system is

important in the normal functioning of human mood, pain,

awareness of bodily processes, etc. As it now stands, we have very

little understanding of the effects that chronic opiate use has on

this endorphine system, although it is clear that it must have some

effect. In all likelihood, chronic opiate use will diminish endorphine

production. It is not clear, however, if in some or all individuals,

chronic opiate use causes an atrophy of the ability to produce

endorphine analogous to the inability of individuals to recover from

prolonged corticosteroid treatment. It also seems probable that

endogenous opioids produce a hypertrophy or a hyperactivity in

those physiologic systems which antagonize the effects of endorphine.

It is conceivable that antagonists could stimulate the production

of endorphine by blocking the natural feedback which presumably

regulates that production, and thereby have a healing effect on a

clinically suppressed endorphine system. The fact that naltrexone

diminished craving in the phase two double blind study argues for

this possibility. On the other hand, if naltrexone is reacted to by

the central nervous system as an opioid substance, it could cause a

decrease in endorphine production similar to the presumed effect of

agonistic opioid drugs. It seems unlikely antagonists would have any

effect on those physiologic systems which are antagonistic to the

effects of endogenous opioid substances, given the fact that they

produce the abstinence syndrome when administered to physically

dependent individuals.

Answering these questions is basic to naltrexone’s future. If

naltrexone does not heal the damage done to the endorphine

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system by chronic opiate use, then perhaps another antagonist

could be designed which would. This system is critical to human

functioning and, in particular, to a sense of well-being. In this way,

chronic heroin addiction conceivably could cause a degeneration of

the endorphine system which could, in turn, lead to a loss of sense

of well-being and thus to a vicious cycle of intensified craving for

opiates.

The issue of the effect of naltrexone on the endogenous opioid

system also has implications for the use of drugs by adolescent

patients. Such young patients have had a relatively short experience

with narcotic drugs. The use of methadone in such individuals has

not been acceptable, because they have had so little time to develop

physical dependency that the treatment itself might produce a

greater physical dependency than the initial “disease.” This

situation has left adolescents without a suitable pharmacologic

adjunct to their treatment. Given the well-known impulsiveness of

adolescents and the consequent difficulty in treating them, they are

especially vulnerable to progress from drug experimentation to

full-fledged, chronic heroin dependency. Then, only after years of

dependency, will they become eligible for pharmacologic supports

which have been shown to be so valuable in making it possible for

older individuals to participate in treatment. Naltrexone appears to

be an ideal agent for such an adolescent drug-using population. It

can be used to prevent the development of physical dependence,

and thus it can prevent an aspect of the disease without producing

that aspect, as would be the case with an agonistic drug. For

example, an adolescent who has fallen in with a group of drug users,

who feels social pressure to use drugs along with his friends, and yet

is concerned about this use and its ultimate consequences, could

come to a physician and be given naltrexone to protect him when

his resolve weakens and he feels compelled to use heroin.

On the other hand, the use of naltrexone to protect such

individuals depends on the absence of any bad effects of this drug.

And foremost among potentially bad effects would be a destructive

effect on the endorphine system. In order for naltrexone to be

widely used in an adolescent population, it will have to be

demonstrated that it does not damage the individual’s capacity to

produce endorphine.

This leads to the larger question of the acceptability of

naltrexone. Who will take this drug? How many will take it and for

how long? Drug abuse treatment is one of those rare instances

where a medication must not only be effective but must also carry

with it its own guarantee of compliance. We can clearly conclude

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RENAULT: THE FUTURE OF NALTREXONE

from the phase two studies with naltrexone that the drug does what

it is supposed to do; viz., it blocks euphoria, blocks the development of physical dependence, and blocks “readdiction” for as long

as the person takes it. If an individual at risk of becoming an addict

takes heroin in the presence of naltrexone, the phase two studies

have demonstrated that the probability that he will again take

heroin is diminished. In other words, when individuals who are

taking naltrexone were compared with individuals taking placebo,

those who actually used heroin after having taken naltrexone were

much less likely to take another injection of heroin during the

course of the study than were those who were on placebo. This

difference was statistically significant, and needless to say, it is

clinically significant as well. This finding leads one to conclude not

only that naltrexone is effective, but also that motivation on the

part of the patient is in itself not sufficient for treatment success.

Presumably, levels of motivation were equal between the naltrexone

and placebo groups, since they were randomly assigned and the

medication was administered under double blind conditions. Thus,

if an individual can be protected when his motivation falters, the

effect will be to preserve and amplify his motivation.

It can be argued, and should, that treatment compliance is

another matter. Compliance depends not only on the pharmacologic properties of a drug, although certain medications that taste

bad or have to be taken frequently or produce discomforting side

effects are associated with lowered compliance. However, the

factors which determine whether or not an individual will take a

drug when these factors are not operating are much more

complicated. It should be possible to create incentives within the

clinic, the social strata from which the addicts are recruited, and

even in the society as a whole, to encourage the use of an antagonist

drug by those who are at high risk of becoming readdicted. An

analogous situation would be smokers wishing to give up cigarette

smoking. Very often, the temptation is to take “just one cigarette,”

with the smoker finding that “just one cigarette” leads to a pattern

of readdiction. This is also the rationale behind the abstinence

imposed by Alcoholics Anonymous. A similar rationale underlies

antagonist treatment: that is, to protect the individual from that

chain of events by blocking effects of that “one fix of heroin.”

Compliance is a problem in all of medicine, but especially so with

medications administered to asymptomatic individuals who have a

latent form of a disease. Convenient analogies are to antihypertensive and antituberculous medications. It is humanly characteristic to

forget the pain, the symptoms which led us to treatment in the first

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

place, as soon as those symptoms are eliminated by the treatment.

Another apparent advantage of naltrexone maintenance treatment is that it satisfies one of the great objections to maintenance

treatment in general, which is that with methadone individuals are

maintained in a continued state of physical dependency. Since

naltrexone does not produce physical dependency, maintenance

with it is likely to be more acceptable both to clinicians and to

patients who object to maintenance with such agonist drugs as

methadone. This acceptability would be enhanced by a further

demonstration of a salutary effect on the endorphine system, a

correction of the defect which either preexisted the chronic opiate

use or has been caused by the chronic opiate use. In the United

States, opioid dependence is based on intravenous heroin use. It was

in this context that the concept of methadone maintenance

developed, because methadone, since it can be given orally and

since it lasts for an entire day, is safer and less disruptive than

heroin. In many parts of the world, however, opioid dependence is

based on smoked heroin and opium and orally ingested opium. In

that context, methadone maintenance is inappropriate except to

the extent that methadone produces less disruption to daily

functioning than a drug which produces intoxication. Naltrexone

should have value in individuals who are dependent on opioids

taken by less hazardous routes of administration than intravenously. Because it is a drug which does not produce physical

dependency, but simply blocks the effects of opiates, the validity of

this prediction will have to await the verdict of clinicians treating

those who are dependent on ingested or smoked opiates.

The future of naltrexone is also dependent on the future of other

forms of drug abuse treatment. In the United States, heroin addicts

often use other drugs when they are available. They smoke heavily

and a high percentage drink alcohol heavily. Thus, the future of

naltrexone is dependent on our ability to develop treatments that

are effective against these other forms of dependence. This also

emphasizes the fact that while we are often criticized for our

preoccupation with pharmacologic adjuncts to the treatment of

heroin-dependent individuals, those same adjuncts have made

heroin dependence one of the more treatable forms of drug

dependence, while our ability to treat other forms of drug

dependence lags behind.

Needless to say, it is our hope that the phase three testing of

naltrexone will further substantiate the safety and efficacy of this

drug. We are confident that problems with compliance can be

solved where the drug is used on a large scale. We also feel that the

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RENAULT: THE FUTURE OF NALTREXONE

evidence that naltrexone decreased craving argues for its salutary

effect on those systems responsible for the sense of well-being,

systems which are disrupted by chronic opioid use. The future of

naltrexone is the future of an important new addition to the

pharmacologic armamentarium of those of us who wish to help

individuals afflicted with chronic opioid dependency. Its further

development also entails fascinating new research into the factors

underlying that dependency.

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INTERNATIONAL CHALLENGE OF DRUG ABUSE

monograph series

Single copies of the monographs may be obtained free of charge from the

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publications of the National Institute on Drug Abuse relevant to drug abuse

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GPO NTIS

Superintentent of Documents National Technical Information Service

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Washington, D.C. 20402 Springfield, Virginia 22161

346
LIST OF MONOGRAPHS

1 FINDINGS OF DRUG ABUSE RESEARCH. An annotated bibliography of

NIMH- and NIDA-supported extramural grant research, 1964-74.

Volume 1, 384 pp., Volume 2, 377 pp.

Vol. 1: GPO out of stock NTIS PB #272 867/AS $14

Vol. 2: GPO Stock #017-024-0466-9 $5.05 NTIS PB #272 868/AS $13

2 OPERATIONAL DEFINITIONS IN SOCIO-BEHAVIORAL DRUG USE

RESEARCH 1975. Jack Elinson, Ph.D., and David Nurco, Ph.D., editors. Task

Force articles proposing consensual definitions of concepts and terms used in

psychosocial research to achieve operational comparability. 167 pp.

GPO out of stock NTIS PB #246 338/AS $8

3 AMINERGIC HYPOTHESES OF BEHAVIOR: REALITY OR CLICHE?

Bruce J. Bernard, Ph.D., editor. Articles examining the relation of the brain

monoamines to a range of animal and human behaviors. 149 pp.

GPO Stock #017-024-0048-6-3 $2.25 NTIS PB #246 687/AS $8

4 NARCOTIC ANTAGONISTS: THE SEARCH FOR LONG-ACTING PREPARATIONS. Robert Willette, Ph.D., editor. Articles reporting current alternative inserted sustained-release or long-acting drug devices. 45 pp.

GPO Stock #017-024-00488-0 $1.10 NTIS PB #247 096/AS $4.50

5 YOUNG MEN AND DRUGS: A NATIONWIDE SURVEY. John A. O’Donnell, Ph.D., et al. Report of a national survey of drug use by men 20-30 years

old in 1974-5. 144 pp.

GPO Stock t017-024-00511-8 $2.25 NTIS PB #247 446/AS $8

6 EFFECTS OF LABELING THE “DRUG ABUSER”: AN INQUIRY. Jay R.

Williams, Ph.D. Analysis and review of the literature examining effects of drug

use apprehension or arrest on the adolescent. 39 pp.

GPO Stock #017-024-00512-6 $1.05 NTIS PB #249 092/AS $4.50

7 CANNABINOID ASSAYS IN HUMANS. Robert Willette, Ph.D., editor.

Articles describing current developments in methods for measuring cannabinoid levels in the human body by immunoassay, liquid and dual column

chromatography and mass spectroscopy techniques. 120 pp.

GPO Stock #017-024-00510-0 $1.95 NTIS PB #251 905/AS $7.25

8 Rx:3 TIMES/WK LAAM – METHADONE ALTERNATIVE. Jack Blaine,

M.D., and Pierre Renault, M.D., editors. Comprehensive summary of development of LAAM (Levo-alpha-acetyl methadol), a new drug for treatment of

narcotic addiction. 127 pp.

Not available from GPO NTIS PB#253 763/AS $7.25

9 NARCOTIC ANTAGONISTS: NALTREXONE. Demetrios Julius, M.D., and

Pierre Renault, M.D., editors. Progress report of development, pre-clinical and

clinical studies of naltrexone, a new drug for treatment of narcotic addiction.

182 pp.

GPO Stock #017-024-00521-5 $2.55 NTIS PB #255 833/AS $9

347
LIST OF MONOGRAPHS

10 EPIDEMIOLOGY OF DRUG ABUSE: CURRENT ISSUES. Louise G.

Richards, Ph.D., and Louise B. Blevens, editors. Conference Proceedings.

Examination of methodological problems in surveys and data collection. 259

pp.

GPO Stock #017-024-00571-l $2.60 NTIS PB #266 691/AS $10.75

11 DRUGS AND DRIVING. Robert Willette, Ph.D., editor. State-of-the-art

review of current research on the effects of different drugs on performance

impairment, particularly on driving. 137 pp.

GPO Stock #017-024-00567-2 $1.70 NTIS PB #269 602/AS $8

12 PSYCHODYNAMICS OF DRUG DEPENDENCE. Jack D. Blaine, M.D.,

and Demetrios A. Julius, M.D., editors. A pioneering collection of papers to

discover the part played by individual psychodynamics in drug dependence.

GPO Stock #017-024-00642-4 $2.75 NTIS PB #276 084/AS $9

13 COCAINE: 1977. Robert C. Petersen, Ph.D., and Richard C. Stillman,

M.D., editors, A series of reports developing a picture of the extent and limits

of current knowledge of the drug, its use and misuse. 223 pp.

GPO Stock #017-024-00592-4 $3 NTIS PB #269 175/AS $9.25

14 MARIHUANA RESEARCH FINDINGS: 1976. Robert C. Petersen, Ph.D.,

editor. Technical papers on epidemiology, chemistry and metabolism, toxicological and pharmacological effects, learned and unlearned behavior, genetic

and immune system effects, and therapeutic aspects of marihuana use. 251 pp.

GPO Stock #017-024-00622-4 $3 NTIS PB #271 279/AS $10.75

15 REVIEW OF INHALANTS: EUPHORIA TO DYSFUNCTION. Charles

Wm. Sharp, Ph.D., and Mary Lee Brehm, Ph.D., editors. A broad review of

inhalant abuse, including sociocultural, behavioral, clinical, pharmacological,

and toxicological aspects. Extensive bibliography. 347 pp.

GPO Stock #017-024-00650-5 $4.25 NTIS PB #275 798/AS $12.50

16 THE EPIDEMIOLOGY OF HEROIN AND OTHER NARCOTICS. Joan

Dunne Rittenhouse, Ph.D., editor. Tash Force report on measurement of

heroin-narcotic use, gaps in knowledge and how to address them, improved

research technologies, and research implications, 249 pp.

GPO Stock #017-024-00690-4 $3.50 NTIS PB #276 357/AS $9.50

17 RESEARCH ON SMOKING BEHAVIOR. Murray E. Jarvik, M.D., Ph.D., et

al., editors. State-of-the-art of research on smoking behavior, including

epidemiology, etiology, socioeconomic and physical consequences of use, and

approaches to behavioral change. From a NIDA-supported UCLA conference.

383 pp.

GPO Stock #017-024-00694-7 $4.50 NTIS PB #276 353/AS $13

18 BEHAVIORAL TOLERANCE: RESEARCH AND TREATMENT IMPLICATIONS. Norman A. Krasnegor, Ph.D., editor. Conference papers discuss

theoretical and empirical studies of nonpharmacologic factors in development

of tolerance to a variety of drugs in animal and human subjects. 151 pp.

GPO Stock #017-024-00699-8 $2.75 NTIS PB #276 337/AS $8

348
LIST OF MONOGRAPHS

Prices of Government publications ordered from GPO

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349

U.S. GOVERNMENT PRINTING OFFICE: 1978 0-278-964
DHEW Publication No. (ADM) 78-654

Printed 1978