Cocaine:

Pharmacology,

Effects, and

Treatment of Abuse

U. S. DEPARTMENT OF HEALTH AND HUMAN SERVICES • Public Health Service • Alcohol, Drug Abuse, and Mental Health Administration
Cocaine: Pharmacology,

Effects, and Treatment

of Abuse

Editor: John Grabowski, Ph.D.

Division of Clinical Research

National Institute on Drug Abuse

NIDA Research Monograph 50

1984

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service

Alcohol, Drug Abuse, and Mental Health Administration

National Institute on Drug Abuse

5600 Fishers Lane

Rockville, Maryland 20857

For sale by the Superintendent of Documents, U.S. Government Printing Office

Washington, D.C. 20402
NIDA Research Monographs are prepared by the research divisions of the

National Institute on Drug Abuse and published by its Office of Science The

primary objective of the series is to provide critical reviews of research problem

areas and techniques, the content of state-of-the-art conferences, and

integrative research reviews. Its dual publication emphasis is rapid and targeted

dissemination to the scientific and professional community.

Editorial Advisors

MARTIN W. ADLER, Ph.D. SIDNEY, COHEN M.D.

Temple University School of Medicine LosAngeles, California

Philadelphia, Pennsylvania

SYDNEY ARCHER, Ph.D. MARY L. JACOBSON

Rensselaer Polytechnic Institute National Federation of Parents for

Troy, New York Drug Free Youth

RICHARD BELLEVILLE, Ph.D. Omaha, Nebraska

NB Associates, Health Sciences

Rockville, Maryland REESE T. JONES, M.D.

KARST J. BESTMAN Langley Porter Neuropsychiatric Institute

Alcohol and Drug Problems Association San Francisco, California

of North America

Washington, D.C. DENISE KANDEL, Ph.D.

GILBERT J. BOVTIN, Ph.D. College of Physicians and Surgeons of

Cornell University Medical College Columbia University

New York, New York New York, New York

JOSEPH V. BRADY, Ph.D.

The John Hopkins University School of HERBERT KLEBER, M.D.

Medicine Yale University School of Medicine

Baltimore, Maryland New Haven, Connecticut

THEODORE J. CICERO, Ph.D.

Washington University School of RICHARD RUSSO

Medicine New Jersey State Department of Health

St. Louis, Missouri Trenton, New Jersey

NIDA Research Monograph Series

CHARLES R. SCHUSTER, Ph. D.

Director, NIDA

JEAN PAUL SMITH, Ph.D.

Acting Associate Director for Science, NIDA

Acting Editor

Parklawn Building, 5600 Fishers Lane, RockviIle, Maryland 20857
Cocaine: Pharmacology, Effects,

and Treatment of Abuse
Dr. John Grabowski, editor of this monograph, was on the staff

of the Clinical and Behavioral Pharmacology Branch, Division of

Clinical Research, NIDA. He is now affiliated with the Department of Psychiatry, School of Medicine, Tufts University,

Boston, MA 02111.

COPYRIGHT STATUS

All material in this volume except quoted passages from

copyrighted sources is in the public domain and may be used or

reproduced without permission from the Institute or the authors.

Citation of the source is appreciated.

Opinions expressed in this volume are those of the authors and do

not necessarily reflect the opinions or official policy of the

National Institute on Drug Abuse or any other part of the U.S.

Department of Health and Human Services.

Library of Congress catalog card number 84-601074

DHHS Publication No. (ADM)87-1326

Alcohol, Drug Abuse, and Mental Health Administration

Printed 1984 Reprinted 1987

NIDA Research Monographs are indexed in the Index Medicus. They

are selectively included in the coverage of American Statistics

Index, Biosciences Information Service, Chemical Abstracts,

Current Contents, Psychological Abstracts, and Psychopharmacology

Abstracts.

iv
Contents

Foreword . . . . . . . . . . . . . . . . . . .vii

Cocaine 1984: Introduction and Overview

John Grabowski. . . . . . , . . . . . . . . . . 1

Cocaine: A Growing Public Health Problem

Edgar H. Adams and Jack Durell . . . . . . . . . . . 9

Neural Mechanisms of the Reinforcing Action of Cocaine

Roy A. Wise. . . . . . . . . . . . . . . . . . 15

The Pharmacology of Cocaine

Reese T. Jones. . . . . . . . . . . . . . . . . 34

Assessment of the Dependence Potential of Cocaine in Animals

Chris E. Johanson. . . . . . . . . . . . . . . . 54

The Behavioral Pharmacology of Cocaine in Humans

Marian W. Fischman . . . . . . . . . . . . . . . 72

Changing Patterns of Cocaine Use: Longitudinal Observations,

Consequences, and Treatment

Ronald K. Siegel . . . . . . . . . . . . . . . . 92

Cocaine Abuse: A Review of Current and Experimental Treatments

Herbert D. Kleber and Frank H. Gawin . . . . . . . . .111

List of NIDA Research Monographs . . . . . . . . . . .130

v

Foreword

Cocaine is currently the drug of greatest national concern, from a

public health point of view, and of particularly high interest from

the research and scientific point of view.

The public health concern derives from the following sources: It

has shown the highest continuing rate of increase in DAWN mentions

(emergency room visits), overdose deaths, and serious clinical

problems, despite a leveling of national prevalence since 1980.

Animal studies show it to be one of the most potent reinforcers

available. It is the one drug most easily and universally accepted

in animal self-administration studies without prior induction

training, and is widely used to shape animal behavior for the

self-administration of other reinforcing drugs. It has one of the

highest reinforcing potentials as measured by breaking point

studies, and is the drug which animals, with unlimited access, are

most likely to select repeatedly in preference to food and water to

the point of death. These preclinical observations and related

clinical data lead to the conclusion that the prospect of

substantial increases in available supply and decreases in price

constitutes a major and growing public health danger.

We are still uncertain as to whether the leveling off in overall

national prevalence, which as shown by our two major national

surveys occurred for cocaine between 1979 and 1982, has continued

since then. If so, the increase in medical complications,

addiction, and clinical problems described above would represent a

higher percentage of a constant total pool of users running into

serious problems. This interpretation is consistent with studies

showing that an average of 4 to 5 years elapses between first use of

cocaine and the need for treatment, and other studies showing that

the best predictor of cocaine use is heavy, early marijuana use.

The current upsurge in public health related cocaine problems would

then be the predictable second stage of the peak of marijuana use

which we saw in this country in the late 1970s. An alternative

possibility is that greatly increased availability of this most

reinforcing illicit drug has broken through powerful cultural and

demographic barriers and begun to lead to a substantial increase in

the number of users and/or intensified patterns of use. Evidence

for this latter alternative may only become evident in future

national surveys.

vii
In any event, while we await further clarification of the exact

nature of current trends in cocaine use, there is an urgent need for

a rapid increase in information on mechanisms of brain action,

treatment methods, health consequences, and prevention strategies.

This monograph makes an important contribution towards planning

future research by reviewing our knowledge base.

Charles R. Schuster, Ph.D.

Director

National Institute on Drug Abuse

viii
Cocaine 1984: Introduction

and Overview

John Grabowski

INTRODUCTION

Diverse aspects of cocaine pharmacology, use, and effects

have been discussed at length in both the lay press and the

scientific literature. Research involving cocaine has a

long, interesting history which has been described at

intervals, and this volume provides a current review of

present knowledge concerning the drug. Dramatic increases

in use in the past decade, increasing evidence of untoward

consequences of use, and resultant public health concerns

also set the stage for a timely and thorough review of

scientific and clinical issues concerning cocaine.

Cocaine is an alkaloidal agent and is derived from the plant

Erythroxylon coca and other Erythroxylon species in South

America. Its multiple behavioral effects constitute those

of the prototypic "stimulant" (with all the caveats

pertaining to such loose categorizations). The drug is,

thus, viewed in the context of amphetamines, caffeine, khat,

and a variety of more recently developed synthetic agents.

Cocaine, in the leaf form or as the extracted substance, has

been used for different purposes, with varying restrictions,

in different cultures. Paralleling the accepted medical and

cultural uses has been a history of abuse of the drug.

There is, as a result, ample evidence that cocaine abuse can

have debilitating physical and behavioral-psychological

consequences. Since not all users exhibit these symptoms,

however, some have assumed that it is inherently safe. As

with all drugs, this is an unwarranted assumption, since

definable dose-related hazards exist. Thus, there is

considerable interest in delineating the drug's

characteristics in terms of abuse. Investigation of this

and related drugs is also extremely important because of

fundamental scientific issues concerning its neurochemical,

pharmacological, and behavioral spectra of action.

1
OVERVIEW OF MONOGRAPH

This monograph was developed with emphasis on major areas of

scientific and clinical interest. Thus, the topics range

from postulated neurochemical mechanisms of action, through

analysis of behavioral effects and patterns of use, to

review of therapeutic strategies.

There has been a dramatic resurgence of cocaine use in the

last decade. Adams and Durell address this issue and

provide a brief overview of the epidemiological sources by

which trends have been followed. In particular, they note

substantial increases in medical examiner and emergency room

"mentions" of cocaine use which strongly indicate a change

to patterns of use with more hazardous consequences. In the

past, cocaine use among so called "street" heroin users was

not common, but was observed. More publicity concerning use

has accrued to upper socioeconomic status users. However,

as Adams and Durell note, the drug is now used, and untoward

consequences of use have been observed in individuals across

all socioeconomic groups. It is in this context of a major

public health concern and important area of scientific and

therapeutic inquiry that the present monograph arises.

A cogent and timely review of one perspective on cocaine s

neurochemical mechanisms of action is provided by Wise. In

the last decade, inroads have been made in delineating

chemical and structural foci at which drugs have their

effects. Major breakthroughs were made in identifying the

mechanisms by which opiates act at specific "receptors."

This, in turn, led to the search for specific sites at which

benzodiazepines and other agents including cocaine act.

There was, and is, a need to identify integrated neuronal

pathways mediating the complex interacting events of

behavior, drug action, neural function itself, and

environmental conditions. Since drugs constitute but one of

many items serving to reinforce and strengthen behavior,

there is a further need to relate the mechanisms of their

reinforcing properties to those of other events and

conditions (food, water, etc.).

Wise and many other scientists have pursued this line of

inquiry, and these efforts are reviewed. Differing

viewpoints on the specifics of both the relative

contribution of various neurochemical systems and/or neural

pathways do exist in the scientific literature. Wise notes

the interactions in areas of scientific research which have

contributed to our enhanced understanding of brain function

and reinforcement, including that derived from reports over

several decades describing the effects of electrical brain

stimulation. This research, integrated with the work of

others on neurochemical functions, generated current efforts

to define the mechanisms of drug reinforcement. The

questions which must be pursued are those related to

2
examining commonalities and differences in the neural

substrates of reinforcement. As Wise notes, these data will

contribute to vastly improved understanding of behavior and

reinforcement generally, and drug abuse behavior in

particular. The great need for further research in this and

related areas is evident and advances will be forthcoming.

These, in turn, must be related to and integrated with the

data which have accumulated concerning complex

behavioral-psychological and clinical issues. The need for

substantial interdisciplinary research is apparent.

All chapters in this volume refer in one way or another to

the pharmacology of cocaine. Thus, the thrust of the

chapter entitled "The Pharmacology of Cocaine" simply refers

more specifically to issues of absorption, drug onset,

distribution of the drug in the body, metabolism, and

excretion. Jones has provided an overview of the cocaine

literature in the discipline of pharmacology, including

discussions of central nervous system (in this case, EEG)

effects and physiological function. The need to understand

fully how drugs alter physiological functions, are absorbed,

distributed, metabolized, and excreted by the body is

clear. Other important pharmacological issues are

addressed, including those concerning both theoretical and

practical questions on tolerance and dependence. Tolerance

has been clearly demonstrated and, as Jones notes,

dependence with respect to physiological systems may well be

related to dosing and duration of action. In any case,

presence or absence of physiological dependence is

irrelevant in terms of potential hazards of compulsive

administration. While the issue is of great scientific

interest, many of the discussions which have arisen involve

definitional problems rather than scientific questions.

From a scientific perspective, it is important to note that

many of the related questions are similar or identical to

those concerning other drugs. In addition to tolerance and

dependence, questions concerning toxicity and route of

administration can be discussed reasonably based on Jones'

review and presentation of data.

An important bridge between understanding the specific

neurochemical and general pharmacologic characteristics of

an abused agent and the observation of use in the "real

world" emanates from tightly controlled laboratory

experiments of behavioral effects. Without such efforts

linking the specifics of action within the body and

behavioral effects, it would be impossible to describe

accurately mechanisms of the therapeutic effects of a drug

or the basis for compulsive drug use. Depending on specific

scientific questions, the research may proceed with either

nonhuman or human subjects. The results of a decade or more

of research to determine precisely the behavioral

pharmacology of cocaine in the animal laboratory are

reviewed by Johanson. Attention is given to those questions

3
which can only be reasonably and objectively examined using

nonhuman subjects. The model described permits precise

specification of features of the reinforcing effectiveness

and inferred "abuse liability" of cocaine. The mechanisms

and character of behaviorally toxic effects are similarly

examined. Data on toxicity resulting from this model point

to an important distinction: Pharmacologic studies can

provide clear indications of physiologic effect as a

consequence of increasing doses. It has become apparent

through research on effects of drugs of abuse, however, that

collateral untoward behavioral consequences (or trends

suggesting their impending emergence) may appear long before

physiologic damage is evident. Indeed, behavioral

disruption may be evident at doses below those which would

lead to physiologic toxicity.

Based on the data reviewed by Johanson which describe the

nature and generality of cocaine administration across

species and disparate environmental conditions, general

statements can be made about likely patterns and

consequences of chronic human use, but always with

appropriate scientific caution and awareness of their

limitations. The dose-related toxic behavioral consequences

observed in research with nonhuman subjects are well

summarized, ranging from stereotypic behavior to anorexia

characteristic of stimulant drugs. Also reviewed are the

necessary comparisons with other drugs which are always

essential in placing in perspective the behavioral effects

of an agent.

Some scientific questions concerning behavioral-pharmacological issues are better resolved using human subjects in

laboratory settings. The complexities are numerous, but

these efforts provide unique information which would not

otherwise be obtained, They help to bridge the gaps between

studies founded in neurochemistry, pharmacology,

behavioral pharmacologic or clinical research, and

observations in the natural environment.

Fischman has reviewed the spectrum of available data on

cocaine administration in humans under controlled

conditions. In the human laboratory, the opportunity exists

to study the pharmacologic characteristics, physiologic

effects, basic behavioral indicants of reinforcing

effectiveness, and other drug response and related these to

both results of animal laboratory research and patterns of

use and abuse in the natural environment. Thus, as Fischman

notes, reports of cardiovascular responses to cocaine and

the evolution of tolerance are similar in nonhuman primates

and in humans. Such cross-validation and determinations of

generalizability of effects are important.

Measuring these responses in relation to subjective effects

is likewise important, In particular, specifically relating

4
these subjective effects to the route of administration in a

laboratory setting provides clearer understanding of the

effects which are likely to be observed in the natural

environment. Thus, this review of the work of numerous

Investigators permits reasonable statements about the

probability and character of abuse and the subjective

effects of cocaine as a consequence of different

administration routes. Precision can also be observed in

defining the character of tolerance and dependence.

Similarly, analysis of the effects of drugs on human

performance is clearly important. These effects depend on

complex interactions between dosage, environmental

conditions and the task at hand.

The relationship between effects of cocaine and other drugs

commonly self-administered by humans is likewise of

considerable interest. The similarities as well as

differences between a range of "stimulants" and other local

anesthetics are, thus, discussed. The significance of these

issues resides not only in the determination of behavioral

and pharmacologic mechanisms of action, but in the practical

public health issue that "substances" obtained illegally are

often composites of various drugs with differing actions.

An extensive laboratory literature on effects of cocaine is

evolving, as are epidemiological data bases and clinical

efforts. Siegel reviews an area in which limited data are

available and relates this to other issues surrounding

cocaine use. Reports of use obtained through careful

repeated interviews can be related to both specific

laboratory research as described by Jones, Johanson, and

Fischman, and clinical research reviewed by Kleber and

Gawin. Thus, Siegel cites the limited number of reports

concerning perceptions about cocaine and reported effects in

chronic, but moderate users. More important, Siegel

describes patterns of use, abuse, and abstinence by a group

of individuals over time. These unique data provide

important insights into the evolution of both problematic

use and cessation along with symptomatology that emerges at

different points among users in the natural environment. In

particular, the information supports laboratory-based

predictions concerning dosage and routes of administration.

These data also provide a basis from which the clinician can

retrospectively interpret or evaluate the patterns of use

resulting in a patient's entering treatment.

Of considerable importance are the data indicating that

differing dosages are likely to be self-administered via

different routes. Reports indicating that, over extended

periods, users might not only increase dosage but might have

periods of abstinence, point to the importance of long-term

followups when evaluating treatment. That is, cessation

during treatment may be temporary, just as it would be if

initiated independently of formal treatment. This

5
observation coincides with much that is known about other

drug use ranging from tobacco to opiates. That different

users explicitly use the drug for different purposes (e.g.,

social vs. work), suggests that when a cocaine user appears

for treatment, rather different stategies may be required in

reestablishing nondrug-oriented behavioral repertoires.

Data presented on both chronic effects and toxic responses

clearly enhance our understanding of these phenomena and, in

this case, do so in the context of regular users of the

drug. Equally important has been the fact that the review

suggests the possibility of predictively separating the

probability of dysfunction in relation to conditions

correlated with use.

One response of treatment of drug abuse, including cocaine

(Crowley 1983) and its correlated problems, has been

extensively discussed in another recent NIDA monograph

(Grabowski et al. 1983). In the present monograph, Kleber

and Gawin provide a thorough review of both the literature

and concepts underlying potential therapeutic approaches.

The authors provide important clinical background

information on both diagnostics and symptomatology. In

addition, they discuss, from a somewhat different

perspective, the severity of consequences of different forms

and patterns of use. Severity of problems is also viewed in

the extended framework ranging from neurochemical to

socioeconomic issues. The importance of this wide-ranging

perspective in drug abuse treatment is clear, and the

authors provide cogent indications of the need. Kleber and

Gawin note the long history of efforts to treat cocaine

abuse and, in so doing, provide a background for the diverse

strategies currently available. Again, the need for

integrated behavioral-psychiatric and pharmacological

strategies is emphasized. They note the importance of

emphasizing basic treatment components and, thereby, point

to the fact that cocaine abuse has elements in common with

other drug abuse. In particular, it is explicitly noted

that, as with other drugs, the user must, because of

behavioral environmental interactions, spend "drug-free"

time in the environment in which drug abuse occurs or

relapse is probable. They also point to the advantages and

disadvantages of various currently available treatment

approaches.

Perhaps most important in the review is attention to the

possibility of different generative conditions leading to

patterns of abuse. While attending to a range of social and

environmental features, reports are cited suggesting a

quasi-therapeutic, albeit ineffective, element which may be

inherent in some cases of escalating cocaine use. That is,

some users may be pursuing self-medication of depression

predating cocaine use which is, in turn, exacerbated by the

cycles of use. Plausible neurochemical bases for this view

are proffered. In addition, the authors provide salient

6
reviews of pertinent literature on pharmacological adjuncts

in the treatment of cocaine abuse. Again, the important

focus of this review is its emphasis on the need for

integrated therapeutic approaches and, of perhaps greater

importance, the need for integrated interdisciplinary

perspectives on clinical research in the area.

ISSUES AND QUESTIONS OF SPECIAL INTEREST

Two superordinate categories of questions arise concerning

cocaine. One is defined in terms of use, abuse, and

correlated social and clinical issues. The other involves

numerous scientific, theoretical and technical issues not

directly linked to the issue of abuse. Overlap necessarily

exists and, in some cases, it is simply the framing of the

question which contributes to an apparent difference. In

fact, the scientific issues concerning mechanisms of action

ultimately have relevance to the clinical concerns.

Similarly, the questions raised in the clinical environment

often contribute to the formulation of questions addressed

in laboratory research. Issues of both categories are

discussed in this volume, and it is apparent that there is a

wealth of knowledge concerning cocaine. There are,

nevertheless, numerous questions which remain to be

answered.

Dominant issues of public interest are addressed throughout

this volume and in the abundant scientific literature.

Specific discussion of these issues can be found elsewhere

(e.g., Van Dyke and Byck 1982; Grabowski and Dworkin 1984).

It is, thus, sufficient to note here that the most commonly

raised questions of public interest are those concerning

routes of administration (e.g., nasal vs. inhalation),

dosage forms or related issues (e.g., cocaine base vs.

hydrochloride), dosage administered acutely and chronically,

risks, drug interactions (e.g., cocaine and heroin),

predisposition to use the drug, and treatment. One issue

not raised in the lay press, but of potential public health

interest, is that concerning coca paste. This product,

while not used in the United States, is widely used in South

American countries where coca is prevalent. Coca paste is a

contaminated intermediate product of the cocaine extraction

process which has specific health hazards associated with

its inhalation through smoking (Jeri 1980: Hawks, personal

communication).

A reasonable comparative perspective indicates that our

knowledge of cocaine and its effects is considerable. Some

questions raised in the past globally, the research issues

of significance with respect to cocaine specifically and

stimulants generally include: (1) analysis of relationships

between neurochemical mechanisms, behavioral mechanisms, and

interactions with environmental determinants of effects;

7
(2) delineation of subjective effects and human performance

with emphasis on interactions with other drugs;

development of optimal combined pharmacological-behavioral

treatment strategies; and, (4) developing epidemiological

techniques for examining drug use trends and patterns which

reside outside the current drug treatment and medical

networks. Finally, given that much is known about this

agent and much data will result from ongoing research,

cocaine is an important pharmacological tool and metric for

analysis of other complex psychopharmacologic and

sociopharmacologic phenomena.

REFERENCES

Crowley, T.J. Contingency Contracting Treatment of Drug

Abusing Physicians, Nurses and Dentists. In: Grabowski,

J.: Stitzer, M.L.; and Henningfield, J.E., eds.

Behavioral Intervention Techniques in Drug Abuse

Treatment. National Institute on Drug Abuse Research

Monograph 46. DHHS Pub. No. (ADM) 84-2382. Washington

D.C.: supt. of Docs., U.S. Govt. Print. Off., 1984.

Grabowski, J., and Oworkin, S. Cocaine: An overview of

current issues. Int. J. Addict., In preparation, 1984.

Grabowski, J.; Stitzer, M.L.; and Henningfield J. Therapeutic application of behavioral techniques: An

overview. In: Grabowski, J.; Stitzer, M.L.; and

Henningfield, J.E., eds. Behavioral Intervention

Techniques in Drug Abuse Treatment. National Institute on

Drug Abuse Research Monograph 46. DHHS Pub. No. (ADM)

84-2382. Washington D.C.: Supt. of DOCS., U.S. Govt.

Print. Off., 1984.

Hawks, R.L. Personal communcation, 1983.

Jeri, F.R., ed. Cocaine 1980. Pan American Health Office,

World Health Organization, Lima, Peru, 1980.

Petersen, R. Cocaine: An overview. In: Petersen, R., and

Stillman R., eds. Cocaine: 1977. National Institute on

Drug Abuse Research Monograph 13. DHHS Pub. NO. (ADM)

77-471. Washington D.C.: Supt. of Docs., U.S. Govt.

Print. Off., 1977.

Van Dyke, C., and Byck, R. Cocaine. Scientific American

246:128-141, 1982.

AUTHOR

John Grabowski, Ph.D.

Department of Psychiatry

Louisiana State University Medical Center

Shreveport, Louisiana 71130
Cocaine: A Growing Public

Health Problem

Edgar H. Adams and Jack Durell

This monograph, reviewing the pharmacology, behavioral effects, and

the treatment of cocaine abuse, appears at a time of intensifying

concern regarding what appears to be an epidemic of serious adverse

consequences. This chapter outlines some of the epidemiologic data

which describe the rise in cocaine use over the past several years.

These issues will be further elaborated in a future monograph which

will be based on a NIDA-sponsored scientific review held in July

1984.

Cocaine abuse has grown from a relatively minor problem 15 years ago

to a major public health threat today. Oral ingestion of cocaine

was widespread in the late 19th and early 20th centuries when it was

an ingredient in many patent medicines, tonics, and soft drinks.

Following the passage of the Harrison Narcotic Act in 1914 and the

Narcotic Drugs Import and Export Act in 1922, its use began to

decline; between the 1930s and the late 196Os, cocaine had all but

disappeared from the American scene. The second report from the

National Commission on Marihuana and Drug Abuse in 1973 stated that

little social cost related to cocaine had been verified in this

country (National Commission 1973). At the same time, the Strategy

Council on Drug Abuse stated that the morbidity associated with

cocaine use did not appear to be great. They further stated that

there virtually were no confirmed cocaine overdose deaths and that a

negligible number of users seek medical help or seek the kinds of

treatment offered by specialized drug treatment programs (Strategy

Council 1973).

Unfortunately, these low rates of actual abuse led the general

public, as well as many drug experts, to conclude that cocaine was a

safe drug. It was not generally recognized that cocaine has a high

abuse potential and that under conditions of greater accessibility

of cocaine, much more serious patterns of abuse would become

evident. This possibility was recognized by a few clinicians and

was clearly enunciated by Drs. Donald R. Wesson and David E. Smith

who in the 1977 NIDA monograph on cocaine concluded:

However, if the drug were more readily available at a

substantially lower cost, or if certain socio-cultural

rituals endorsed and supported the higher dose patterns,

more destructive patterns of abuse could develop. (p. 150)

Their conclusion was prophetic.

9
The situation now is vastly different. The adverse consequences of

cocaine abuse are abundantly evident, both as reflected in the

popular media and in those statistical data sets that are

available. Both the print media and television are replete with

reported cases of compulsive use which have resulted in wrecked

lives and fortunes. Many cocaine victims have been rich and

famous--many have not! The statistical data sets, on the other

hand, provide us with some aspect of the overall dimensions of the

problem. Unfortunately, there are gaps in our data which make it

impossible to make precise statements about the full extent of

cocaine abuse and dependence.

The data from the National Household Survey indicate that the

prevalence of cocaine use rose dramatically during the middle and

late seventies. This change is exemplified by the following:

1. The number of people who had tried cocaine at least once

had increased from 5.4 million in 1974 to 21.6 million in

1982 (NIDA 1983).

2. The number of current users of cocaine rose from 1.6

million in 1977 to 4.2 million in 1982 (Blanken et al. in

press).

While the most recent surveys of prevalence of use indicate that

trends have leveled off, at least among those under 26, the impact

of the dramatic increases of the late 1970s is becoming more and

more visible as both demand for treatment of dependence and medical

crises associated with cocaine use increase. For example, "There

was more than a threefold increase in the rate of cocaine-related

(medical) emergencies (from 0.7 to 2.3/10,000 emergencies) and the

rate of cocaine-related deaths per 10,000 medical examiner reports

(from 4.5 to 19.1/10,000 deaths) between 1976 and 1980-1981" (Kozel

et al. 1982). Over the same time period, the proportion of drug

treatment program admissions with cocaine as their primary drug

problem increased from 1.2 percent to 5.8 percent. More recent data

indicate that these increasing trends have continued unabated. For

example, cocaine accounted for almost 9 percent of the treatment

admissions reported to NIDA in 1983.

Data on adverse health consequences are reflected by hospital

emergency room visits and medical examiner cases as collected by

NIDA through the Drug Abuse Warning Network (DAWN). Data on

admissions to treatment were collected through the Client Oriented

Data Acquisition Process (CODAP) which was the national reporting

system through 1981 and during most of 1982.

Previous reports have indicated that emergency room admissions

associated with cocaine use increased approximately three and

one-half times between 1976 and 1981. More recent data, based on a

subset of DAWN emergency rooms that have reported consistently since

1981, indicate that this upward trend continues. Since 1981 through

the fourth quarter of 1983, emergency room mentions for cocaine have

increased by 75 percent. Early data for 1984 indicate that

approximately 2,000 cocaine mentions were recorded for the first

10
quarter of 1984. This is remarkable in that it equals the cocaine

mentions for the entire year of 1978.

Other changes that have occurred between 1978 and 1982 are

consistent with the aging of the abusing population. In 1978, 21

percent of the emergency room admissions were over 30, while in

1982, 41 percent were age 30 or over (Blanken et al. in press).

Perhaps indicating more chronic use, 52 percent of emergency room

admissions for cocaine in 1982 indicated dependence vs. 44 percent

in 1978. There has also been an increase in the intravenous use of

cocaine and the use of cocaine in combination with other drugs. For

example, in 1978, 57 percent of the cocaine mentions were in

combination with other drugs, while in 1982, 71 percent were in

combination (Blanken et al. in press). As cocaine has become more

available, the practice of speedballing, the combination of heroin

and cocaine, has increased. In 1979, speedballing mentions

accounted for approximately 17 percent of the cocaine mentions in

DAWN, whereas in 1983, speedballing accounted for more than 25

percent of the mentions.

Similar to the DAWN trends, CODAP admissions have also shown marked

increases over the past several years. In 1977, primary cocaine

admissions accounted for 1.8 percent of all admissions to CODAP.

while in 1981 they accounted for 5.8 percent (NIDA 1978,1982).

This further increased to 7 percent of admissions in 1982 and, as

previously mentioned, to 9 percent in 1983. The increase in cocaine

admissions is even more striking if admissions for other than for

primary use are included. For example, admissions for speedballing

generally record heroin as primary and cocaine as secondary. When

both primary and secondary admissions are included, cocaine was

abused by over 17 percent of all admissions in 1981. This

represents in excess of 42,000 people admitted for some problem with

cocaine. We know that this is an underestimate, since there are

many admissions of cocaine abusers to private drug treatment units

and to alcoholism treatment units that are not reflected in CODAP

data. Since cocaine is used extensively by the higher

socio-economic group, seriously undersampled in the CODAP data, the

extent of the underestimate may be quite large. The more recent

situation is even worse in estimating the demand for treatment in

that CODAP data are no longer collected on a national basis.

As with the DAWN statistics, CODAP admissions presented multiple

drug problems; 82 percent of all primary cocaine admissions in 1982

reported having at least a secondary drug problem. The order of

frequency in the secondary drug problems was marijuana, alcohol, and

heroin. This is the reverse of the order of the frequency of

combinations reported in DAWN, where heroin, alcohol, and marijuana

were the most cited combinations with cocaine. Of course, DAWN data

would be expected to reflect combinations that are more likely to

eventuate in acute medical crisis.

Of particular concern has been the tendency of users to shift from

snorting cocaine to other routes of administration. In several

reports, an increase in the intravenous administration of cocaine,

as well as free basing (smoking) has been noted (Kozel et al. 1982;

11
Adams 1982a; Blanken et al. in press). The 1982 CODAP data indicate

a dramatic increase in free basing of cocaine from 1 percent of

admissions in 1979 to almost 7 percent in 1982. These changes are

important because of the reports that either free basing or

intravenous injection of cocaine may lead more readily to intensive

use and compulsive drug-seeking behavior (Van Dyke and Byck 1982).

An analysis of CODAP data by frequency of use and route of

administration does, in fact, indicate that both intravenous

administration and free basing or smoking of cocaine more frequently

lead to daily use than does inhalation (Adams 1982b). In

recognizing this pattern, however, it should not be forgotten that

inhalation (snorting) still accounts for almost 60 percent of all

admissions for cocaine problems and that compulsive use has been

reported among those who limit their use to the intranasal route.

Furthermore, recent evidence suggests that intranasal administration

is not without its medical consequences. Recently, a case of

myocardial infarction in an otherwise healthy 21-year-old male was

reported after intranasal administration of 0.25 gram of cocaine

(Schachne et al. 1984). This raises the possibility that cocaine,

which has a direct effect on catecholamines, may in fact be a

cardiovascular risk factor in some individuals.

In May 1983, a private treatment unit opened a toll-free telephone

hotline offering advice to cocaine abusers. The number of callers

was a surprise. In the 18 months since the service began, over

450,000 calls, sometimes as many as 1,000 per day, have been

received. Hotline staff have conducted 20-40 minute telephone

interviews on several samples of the callers. Though there is much

uncertainty regarding the representativeness of the sample and the

validity of the telephone interview, the technique has provided a

rich data source regarding self-reported cocaine abusers. Several

findings (Gold and Washington 1984) are of particular interest:

(1) Sixty-one percent of callers used primarily the intranasal

route and they reported patterns and consequences of cocaine

use comparable to those free-basing (21%) and using IV (18%).

(2) From 66% to 83% reported addictive patterns of use including

loss of control over use (75%) and inability to stop using in

spite of repeated attempts (67%).

(3) Over 90% reported adverse physical, psychological and

consequences associated with its use.

In summary, a wealth of data based on mortality statistics,

emergency room admissions, treatment admissions, and calls to the

national toll-free cocaine hotline indicate that we are in the midst

of an epidemic of adverse consequences of cocaine abuse with no

indication of any abatement in the rising tide. Moreover, there is

evidence that the cost of cocaine is diminishing and the supply is

increasing. This was first seen at the wholesale level and is now

being seen on the retail level. Since the high cost of cocaine has

been a barrier that helped to prevent many users from compulsive,

uncontrolled use, the decrease in cost increases the possibility

12
that compulsive use will increase. Indeed, there is reason to be

concerned about the possibility of increased use by adolescents and

young adults, age groups that have not as yet developed a widespread

problem with cocaine.

One example of the spread of cocaine use in a population in which it

is not thought to be predominant is reflected by a study of arrestees in a police initiative aimed at drug-related offenses in East

Harlem (Wish et al. 1984). Urine samples, obtained from 84 percent

of a sample of arrestees, were 87 percent drug positive. Of the

positive urines, 79 percent were positive for cocaine vs. 58 percent

for opiates. In this street population, cocaine use was prevalent

over opiate use in all age groups. Furthermore, 46 percent of the

sample reported that they had been dependent on cocaine for some

time vs. 24 percent for heroin. These findings, while they are a

small sample, suggest that cocaine is prevalent among street drug

users and is not the sole preserve of the affluent.

Though previous upsurges in stimulant use have tended to be passing

fads, the current epidemic is unprecedented. Increased production

and profits have resulted in a growing illicit industry with a

vested interest in sustaining, and even increasing, cocaine use.

The one hopeful fact is that prevalence of use appears to have

leveled off. If that is so, the current continuing increase in

adverse consequences may be the result of the reported lag,

averaging about 4 years, between the onset of cocaine use and

entrance into treatment and also of an increase in the occurrence of

intensified patterns of use. Thus, the residual effects of the

epidemic and continuing effects of endemic levels of use may be seen

for some time. Perhaps increased public knowledge of cocaine's

dangers will contribute to a decrease in its use. For the moment,

however, if prices continue to decline, there is ample reason to

fear even more widespread use of cocaine.

REFERENCES

Adams, E.H. The epidemiology of cocaine abuse. Presented at the

Regent Progress Symposium, Cocaine Abuse: Recognition and

Treatment, Fair Oaks Hospital, Summit, New Jersey, May 8, 1982(a).

Adams, E.H. Abuse/availability trends of cocaine in the United

States. Drug Surveillance Reports, Vol. 1, No. 2, 1982.

Division of Epidemiology and Statistical Analysis, National

Institute on Drug Abuse. Rockville, MD: The Institute, 1982(b).

Blanken, A.J.; Adams, E.H.; and Durell. J. Drug abuse: Implications

and current trends. Psychiatric Medicine, in press.

Gold, M.S., and Washington, A.M. Cocaine abuse: Neurochemistry,

phenomenology, and treatment. Presented at the National Institute

on Drug Abuse technical review on cocaine, July 11-13, 1984.

Kozel, N.J.; Crider, R.A.; and Adams, E.H. National surveillance of

cocaine use and related health consequences. Centers for Disease

Control, Atlanta, GA. HHS publication No. (CDC) 82-8017.

Morbidity and Mortality Weekly Report 31, (20):265-273, 1982.

National Commission on Marihuana and Drug Abuse. Drug Use in

America: Problem in Perspective. Second Report of the National

Commission on Marihuana and Drug Abuse. Washington, D.C.:

National Institute on Drug Abuse, March 1973.

13
National Institute on Drug Abuse. SMSA Statistics 1977. Data from

the Client Oriented Data Acquisition Process (CODAP) NIDA

Statistical Series E, No. 9. DHHS Pub. No. (ADM)78-756.

Rockville, MD: the Institute, 1978.

National Institute on Drug Abuse. Annual Data 1981. Data from the

Client Oriented Data Acquisition Process (CODAP) NIDA Statistical

Series E, No. 25. DHHS Pub. No. (ADM)82-1223. Rockville, MD: the

Institute. 1982.

National Institute on Drug Abuse. Population Projections, Based on

the National Survey on Drug Abuse, 1982. DHHS Pub. No.

(ADM)83-1303. Washington, DC: Supt. of Docs., US Govt. Print.

Off.. 1983.

Schachne, J.S.; Roberts, B.H.; and Thompson, P.D. Coronary artery

spasm and myocardial infarction associated with cocaine use. New

England Journal of Medicine, 310(25): 1665-1666, 1984.

Strategy Council on Drug Abuse. Federal Strategy for Drug Abuse and

Drug Traffic Prevention 1973. Washington, D.C.: Supt. of DOCS.,

 U.S. Govt. Print. Off., 1973.

Van Dyke, C., and Byck, R. Cocaine. Scientific American,

246(3):128-141. 1982.

Wesson, D.R., and Smith, D.E. Cocaine: Its use for central nervous

system stimulation including recreational and medical uses. In:

Petersen, R.C.,, and Stillman, R.C., eds. Cocaine: 1977. National

Institute on Drug Abuse Research Monograph 13 Washington, D.C.:

Supt. of Docs., U.S. Govt. Print. Off., 1977. pp. 137-150.

Wish, E.D.; Anderson, K.; Miller, T.; and Johnson, B. Drug use and

abuse in arrestees: New findings from a study of arrestees in

Manhattan. Paper presented at the annual meeting of the Academy

of Criminal Justice Science, Chicago, March 1984.

AUTHORS

Edgar H. Adams, M.S.

Division of Epidemiology and Statistical Analysis

National Institute on Drug Abuse

Rockville, Maryland 20857

Jack Durell, M.D.

Office of Science

National Institute on Drug Abuse

Rockville, Maryland 10857

14
Neural Mechanisms of the

Reinforcing Action of Cocaine

Roy A. Wise

Cocaine shares with a number of drugs the property of strong abuse

potential. In attempting to understand abuse potential it is useful to consider the factors in common and the factors not in common

between cocaine and other abused drugs; every drug has multiple

effects, and only those effects shared by the variety of abused

drugs are likely to account for abuse liability. Cocaine is, over

most of its effective dose range, a psychomotor stimulant; it

shares this property with amphetamine but not, over most of their

effective dose ranges, with opiates, barbiturates, benzodiazepines,

or ethanol. Cocaine does not share the physical dependence-producing property of the sedative hypnotics. Cocaine has local anesthetic properties which are not shared with the other major classes

of drugs of abuse; other local anesthetics, while sometimes selfadministered, are not significantly or knowingly abused by man.

These drug actions, then, would not seem to provide likely explanations for the development of compulsive drug intake which can develop across the variety of abused agents.

What cocaine does share with opiates, barbiturates, benzodiazepines, and ethanol is a rewarding or "reinforcing" property. When

behavioral acts are regularly followed by intravenous, or, in some

cases, oral, administration of drugs in these classes, such behavioral acts become more and more frequently repeated. Of the habitforming drugs, cocaine and heroin stand out as perhaps the most

powerful reinforcers as defined by the rapidity of acquisition of

self-administration. Thus the property shared by cocaine, a stimulant, and other drugs of abuse, primarily depressants, is the

quality of reinforcement. In the attempt to understand the neural

mechanisms underlying the abuse liability of cocaine and other

drugs one important place to start is with brain structures implicated in the process of reinforcement.

For a number of reasons it is believed, first, that the brain has

specialized neural circuits that are activated by the various reinforcers capable of influencing behavior (Olds 1962), and, second,

that the activation of these circuits is necessary for natural re15
inforcers to be effective (Wise 1982). Just as it proved reasonable to assume that opiate receptors did not evolve only to serve

the need of modern man for synthetic analgesics, so is it reasonable to assume that the neural substrates of drugs of abuse did not

evolve only to serve our nonmedical impulses. Analgesics suppress

pain by centrally activating endogenous pain control circuits

(Mayer and Price 1976; Basbaum and Fields 1978); similarly, we

might expect drugs of abuse to be reinforcing by centrally activating endogenous reward circuits (Olds and Travis 1960; C.D. Wise

and Stein 1970; Belluzzi and Stein 1977). It is from this perspective that students of drug abuse might hope to benefit from the

study of reward circuits in the brain.

The notion that cocaine and amphetamine can centrally activate natural reward mechanisms and that they owe their reinforcing action

to such activation (C.D. Wise and Stein 1970) is consistent with

the fact that these agents have the traditional properties of conventional reinforcers (Johanson 1978). If animals are reinforced

with amphetamine or cocaine on fixed or variable ratio schedules or

fixed or variable interval schedules, the patterns of responding

seen are similar to those characteristic patterns which would be

established with the same reinforcement schedules in an operant

chamber delivering food or at a slot machine delivering silver

dollars. Amphetamine reinforcement also shares several of the

characteristics of reinforcement by electrical stimulation of the

brain (Pickens and Harris 1968). In both cases responding is sustained for long periods of time, with occasional periods of abstinence that are unpredictable as to onset and duration. In both cases

the rate of responding is regular, depending on the parameters of

reinforcement and on the response demands of the task, but not

depending on the length of preceding abstinence periods. In both

cases voluntary abstinence periods can be terminated by the experimenter if unearned reinforcement or "priming" is given. In both

cases the central reinforcer can be more powerful than more "natural"

reinforcers, even in cases of acute need; access to psychomotor

stimulant reinforcement (Pickens and Harris 1968) or to electrical

brain stimulation reinforcement (Routtenberg 1964) can cause selfstarvation to the point of severe weight loss.

Our present understanding of neural mechanisms of reinforcement

began with the discovery that rats would work for electrical stimulation of some but not all portions of their own brains (Olds and

Milner 1954). Early studies followed two major directions: anatomical mapping (Olds and Olds 1963) and pharmacological challenge

(Olds and Travis 1960). The mapping studies exploited the relative

anatomical selectivity of brain stimulation and generated hypotheses as to what anatomical circuitry might participate in reward

function (Olds 1962). The pharmacological studies soon implicated

catecholamine systems as likely links in reward circuitry, and the

study of psychomotor stimulant reward became a useful adjunct to

brain stimulation (Baxter et al. 1974; Yokel and Wise 1975; Davis

and Smith 1977), since stimulants activate catecholamine systems

with a degree of neurochemical selectivity that the anatomically

selective brain stimulation lacks. Recently it has proven pos16
sible to train animals to work for reasonably localized central

injections of drugs; with this approach it is possible to activate

reward circuits with useful degrees of both anatomical and neurochemical selectivity (Bozarth 1983). Current evidence from studies

involving these techniques suggests the view that different drugs

and even drugs of different classes may activate common reward

circuitry of the brain--reward circuitry essential for the rewarding

impact not only of drugs of abuse but also of food, water, and rewarding hypothalamic brain stimulation. This evidence on the mechanisms of cocaine and opiate reinforcement, evidence on their relation to the anatomical substrate of opiate physical dependence, and

the implications of this evidence for theories of drug abuse are

the subjects of the present chapter.

SUBSTRATE OF BRAIN STIMULATION REWARD

In the three decades of research on brain stimulation reward three

dozen or so distinct reward sites have been studied (German and

Bowden 1974) . Brain stimulation has been found to be rewarding at

all supra-spinal levels of the central nervous system, though not

in all portions of each level. A major goal of workers in the

field has been to find anatomical common denominators for the

diverse reward sites that have been identified. Olds’ early (1962)

theory of limbic and hypothalamic subsystems has been superseded by

the catecholamine theories of Stein and others (German and Bowden

1974; Fibiger 1978; Wise 1978), and Stein’s early (1962) noradrenergic hypothesis has been superseded by the various dopamine hypotheses (see Fibiger 1978; Wise 1980, 1981a). Current evidence

now rules out the view that either noradrenergic or dopaminergic

circuits are the primary (directly activated) fibers of brain

stimulation reward (Shizgal et al. 1980a; Gallistel et al. 1981),

and there is currently no viable theory of brain reward mechanisms

which ties together more than a few of the dozens of known reward

sites.

The most frequently studied brain stimulation reward site is the

lateral hypothalamic portion of the medial forebrain bundle. It

now seems clear that rewarding stimulation in this region depends

primarily on the direct activation of descending fibers of passage.

The refractory periods of the directly activated neurons of the

lateral hypothalamus can be estimated by stimulating with trains

of pulse pairs of different inter-pulse intervals. When the

intervals are shorter than the refractory periods of the directly

activated fibers, performance drops precipitously; the critical

interval at which this change occurs indicates the length of the

refractory period for that portion of the directly activated pop

ulation of neurons which plays a role in the behavior. In the case

of lateral hypothalamic self-stimulation, the refractory periods

are short (Yeomans 1979), suggesting that the directly activated

fibers are probably myelinated, and ruling out the possibility

that they are catecholaminergic (Gallistel et al. 1981).

The conduction velocities and direction of conduction of the

reward-relevant fibers of the medial forebrain bundle can also be

17
determined. In this case it is necessary to place two electrodes

at different points on the hypothesized path of the reward-relevant

fibers. Pulse pairs are again administered, with one member of

each pair going to each of the two electrodes. When the interpulse interval is long, both pulses are behaviorally effective and

performance is strong; this is usually true whether or not the two

electrodes activate the same fibers. When the second pulse loses

behavioral effectiveness as a result of decreasing the inter-pulse

interval, however, it can be concluded that the electrodes must

lie at different sites along the same continuous fibers (Shizgal

et al. 1980a). With short inter-pulse intervals, stimulation at the

more efferent electrode site effectively cancels the effects of

stimulation at the more afferent site; stimulation at the efferent

site elicits (along with the orthodromic or "normally" conducting

impulse) an antidromic or "backwards" conducting impulse. When

the inter-pulse interval is short, the antidromic impulse collides

with and inactivates the oncoming impulse from the other stimulation site.

When long inter-pulse intervals are used, on the other hand, the

first impulse bypasses the site of the second electrode before the

second pulse is administered, and, if sufficient extra time is

given for membrane recovery, a normal second impulse will be elicited and performance will reflect it. The critical time in this

case is equal to the sum of the time necessary for the first

impulse to travel from the tip of the first to the tip of the second electrode (conduction time) , plus the time necessary for the

membrane to recover from the first impulse (refractory period).

In the case of lateral hypothalamic self-stimulation, the critical

fibers extend to the ventral tegmental area, and the conduction

velocities are fast (Shizgal et al. 198Oa; Bielajew and Shizgal

1982), again suggesting that the fibers are probably myelinated

and again ruling out catecholaminergic fibers as the directly

activated substrate (Shizgal et al. 1980a; Bielajew and Shizgal

1982).

The two-electrode preparation used for conduction velocity tests

can also be used to determine the direction of conduction of the

reward-relevant fibers. If stimulation is given through one electrode and tissue is hyperpolarized at the other, stimulation will

be effective only when it is administered at a site efferent to

the hyperpolarization (Kuffler and Vaughan Williams 1953). In the

case of medial forebrain bundle self-stimulation, this test reveals

that at least the major portion of the directly activated reward

system projects caudally from the lateral hypothalamic area to the

ventral tegmental area (Shizgal et al. 1980b).

The descending reward fibers of the medial forebrain bundle terminate in a region sharing the precise dorsal, ventral and lateral,

and the approximate caudal boundaries of the dopaminergic cell

groups of the ventral tegmental area and substantia nigra (Corbett

and Wise 1980; Wise 1981b). Since pharmacological interference with

dopaminergic transmission attenuates the rewarding impact of lateral hypothalamic stimulation (Fouriezos and Wise 1976; Fouriezos

18
et al. 1978; Franklin 1978; Franklin and McCoy 1979; Gallistel et

al. 1982; Zarevics and Setler 1979), it seems likely that the descending fibers make synaptic contact with either the dopaminergic

cells or the terminals of their afferents (both the reward sites

and the terminals of any dopaminergic afferents share the anatomical dispersion of the dopaminergic cells). Opiates and psychomotor stimulants both appear to have their effect in this circuitry,

opiates at the level of the dopamine cell bodies and stimulants at

the terminals of the dopaminergic nerve fibers. It is not yet

known which of the efferents of the dopaminergic fiber projections

represent the next link in the reward circuitry, but cells of the

nucleus accumbens are most strongly implicated from studies of

psychomotor stimulant reinforcement.

MECHANISM OF REWARDING ACTION OF COCAINE AND AMPHETAMINE

Several lines of evidence suggest the dopaminergic synapse to be

the site of the rewarding actions of the psychomotor stimulants

cocaine and amphetamine. Amphetamine and cocaine share the ability to increase transmitter concentrations in both the noradrenergic and the dopaminergic synapse, cocaine by blocking the reuptake

mechanism (which usually terminates catecholamine synaptic action)

and amphetamine by blocking reuptake and also by directly causing

or augmenting synaptic catecholamine release (Axelrod 1970;

Carlsson 1970; Heikkila et al. 1975). The rewarding effects of

cocaine and amphetamine are attenuated by nonselective catecholamine synthesis and receptor blockade (Pickens et al. 1968; Wilson

and Schuster 1972), and whereas selective blockade of noradrenergic synapses alone does not have similar effects, selective

blockade of dopaminergic synapses does (Yokel and Wise 1975, 1976;

Risner and Jones 1976, 1980; deWit and Wise 1977). When low doses

of dopamine antagonists are given, stimulant self-administration

is maintained, but it is maintained at a higher than normal level

of hourly intake (Yokel and Wise 1975; Risner and Jones 1976, 1980;

deWit and Wise 1977). There is no question of response debilitation

from the dopamine antagonism; the animals actually respond more

under dopamine receptor blockade than they would under normal conditions. Rather, it seems clear that dopaminergic antagonism

attenuates the reinforcing effectiveness of the stimulants;

higher than normal concentrations of stimulants are earned before

the animal shows signs of drug satiety.

When higher doses of dopamine antagonists are given, the animals

cease responding for stimulants (Yokel and Wise 1975, 1976; deWit

and Wise 1977). Response cessation is not imnediate, however, and

in the case of the rat, at least, responding is accelerated for an

hour or two before it ceases (Yokel and Wise 1975, 1976; deWit and

Wise 1977). The response acceleration parallels what is seen when

nonrewarding saline is substituted for rewarding amphetamine. This

has been conceptualized as reflecting the "frustration" of responding in the absence of the expected rewarding payoff (Amsel and

Roussel 1952); descriptively and procedurally it is an extinctioninduced rate increase. The period of response acceleration makes

it clear that the animals are not critically incapacitated by the

19
dopaminergic antagonists (even at the time of peak antagonist action: Yokel and Wise 1976) and suggests that response cessation results from an absence or attenuation of the usual reinforcing

impact of the stimulant. With high doses of dopamine antagonists

it appears that the reinforcing efficacy of amphetamine and cocaine

is either eliminated or reduced to levels inadequate to sustain

responding.

That activation of some dopaminergic receptor population accounts

for psychomotor stimulant reinforcement is also consistent with the

fact that apomorphine and piribedil, direct dopamine receptor

agonists, have amphetamine-like rewarding actions in rats and dogs

(Baxter et al. 1974; Risner and Jones 1976; Wise et al. 1976;

Davis and Smith 1977; Yokel and Wise 1978). Clonidine, a noradrenergic receptor agonist, has reinforcing properties at very

low doses, though the behavioral side-effects are more like opiate

effects than like stimulant effects (Davis and Smith 1977). Clonidine and methoxamine, another noradrenergic agonist, do not have

amphetamine-like reinforcing properties, as reflected in a number

of tests (Risner and Jones 1976; Yokel and Wise 1978). The reinforcing action of apomorphine is not altered by dopamine synthesis

inhibition (Baxter et al. 1976), and thus it is post-synaptic dopamine receptors and not dopamine autoreceptors that mediate the

rewarding effect of dopamine agonists (normal dopamine function

would be needed to express effects of apomorphine that were mediated at the autoreceptor).

The conclusion derived from animal studies, that the reinforcing

effect of psychomotor stimulants is attenuated by dopamine antagonists, is confirmed by human studies. The subjectively rated euphoria produced by intravenous amphetamine is reduced by nonselective

catecholamine antagonists (Jonsson et al. 1971) or by the selective

dopamine antagonist pimozide (Gunne et al. 1972), but it is enhanced, if anything, by the selective noradrenaline antagonists

propranolol, phentolamine and phenoxybenzamine (Gunne et al. 1972).

It thus seems clear that of the shared pharmacological actions of

amphetamine and cocaine it is the action in the dopaminergic synapse that is critical to the phenomenon of reinforcement.

Which of the various dopaminergic pathways are implicated? There

are three major anatomical projections of the dopaminergic cells of

the ventral tegmentum: the striatum, the limbic system, and the

cortex. Of these the nucleus accumbens, most frequently treated as

a limbic structure, is most clearly implicated in psychomotor stimulant reinforcement. Neurotoxin-induced lesions of this structure

reduce or eliminate amphetamine and cocaine reinforcement (Roberts

et al. 1977, 1980; Lyness et al. 1979), as do local injections of

dopamine antagonists (Phillips and Broekkamp 1980). Direct injections of amphetamine into nucleus accumbens are rewarding in their

own right (Monaco et al. 1980). Injections of amphetamine into

the cortex of monkeys are also reported to be reinforcing (Phillips

et al. 1981) as are injections of cocaine into the cortex of rats

(Goeders and Smith 1983); thus there may be more than one dopaminergic projection that participates in brain reward circuitry.

20
The nucleus accumbens seems particularly important, however, at

least in the rat.

Thus the mechanism of psychomotor stimulant reinforcement and the

mechanism of lateral hypothalamic brain stimulation reinforcement

seem to share common elements. The brain stimulation reinforcement

seems to activate dopaminergic synapses indirectly, by stimulating

the fibers that make anatomical contact with the dopamine cells or

their afferents; the cocaine and amphetamine reinforcements activate the dopaminergic synapse directly, by increasing dopamine concentrations at the post-synaptic receptor.

DOPAMINE INVOLEVMENT IN FOOD AND WATER REINFORCEMENT

The dopaminergic synapse also seems involved in the mechanisms of

food and water reinforcement. If the dopaminergic synapse is

pharmacologically blocked, several findings suggest the reinforcing impact of food and water to be compromised (Wise et al. 1978a,

b; Wise 1982; Spiraki et al. 1982; Xenakis and Sclafani 1982).

Briefly, the effects of dopaminergic blockade are as follows: food

loses the ability to establish the lever-pressing habit in untrained hungry rats; food loses the ability to sustain such habits in

trained rats; rats with experience lever-pressing for food under

dopaminergic blockade initiate responding progressively less on

subsequent test days; and food continues to be a potent elicitor

of free-feeding responses but loses much of its ability to maintain free feeding after food is tasted (Wise 1982). Responding

also fails to be maintained by water reinforcement under dopamine

blockade (Gerber et al. 1981) .

Attenuation of the rewarding effects of food by neuroleptics can

also be demonstrated on the day after the neuroleptic treatment,

when the animal is no longer under the influence of the blocker;

hungry animals having received food previously under pimozide

treatment do not subsequently return, as do normal animals, to

the part of the environment where food was last found (Spiraki et

al. 1982). The effects of dopaminergic blockade do not always and

do not perfectly parallel the effects of withholding reinforcement;

thus it is clear that dopamine blockers do more than simply block

reinforcement (they probably produce motoric impairment as well)

and that they usually block reinforcement only partially, at least

in the dose range most frequently tested (Wise 1982). While

they do not block responding in all paradigms at equal doses,

dopaminergic blockers decrease responding in the same manner over

a wide enough range of paradigms to make it clear that, whatever

its side effects, dopamine blockade alters the reinforcing

efficacy of both food and water.

This evidence thus relates food and water reward to an anatomical

mechanism having a critical dopaminergic link, though it is not

yet known by which anatomical pathways the reward message reaches

the dopaminergic cells. While the dopaminergic link in the mechanism of food reward may not be identical to the dopaminergic link

in the mechanism of brain stimulation and psychomotor stimulant

21
reward, a common link does become one of the more attractive of

the obvious possibilities.

DOPAMINE INVOLVEMENT IN OPIATE REINFORCEMENT

Other drugs of abuse might be suspected to act through the same

reward mechanism, though there is no logical necessity that they

must do so. In the case of opiates, however, there is strong

recent evidence that a dopaminergic mechanism of rewarding action

is again involved. Whereas reward-relevant dopaminergic neurons

appear to be transsynaptically activated by brain stimulation

reward, they seem more likely to be directly activated by reinforcing injections of morphine. This is not so clear from pharmacological challenge of intravenous opiate self-administration; while

moderate doses of dopamine blockers cause response cessation in this

paradigm (G.J. Gerber, M.A. Bozarth, and R.A. Wise, unpublished

observations), they do not cause the low-dose response acceleration

(Ettenberg et al. 1982) which helps make their effects on psychomotor stimulant self-administration so clearly interpretable as a

reward deficit (Yokel and Wise 1975). It is not clear why animals

do not compensate for dopaminergic blockade by increasing their

opiate intake, particularly when they do increase intake to compensate for opiate receptor blockade (Ettenberg et al. 1982); however,

a similar lack of compensatory response acceleration is also seen

when apomorphine self-administration is challenged by dopamine

receptor blockade (Yokel and Wise 1978); thus the lack of compensatory response acceleration in response to low dose neuroleptics cannot be taken as reason to disregard the decreases in drug intake

caused by higher neuroleptic doses. Nor can the lack of accelerated

responding, before response cessation, following moderate doses of

neuroleptics (Ettenberg et al. 1982) be taken as reason to disregard

the response cessation. Responding for apomorphine also ceases

without response acceleration after moderate dose of neuroleptics

(Yokel and Wise 1978), and this does not rule out a role for dop

amine in apomorphine reinforcement. Additional paradigms are

needed, however, to make it clear (a) that reinforcing opiates do

activate dopaminergic neurons and (b) that such activation is

critical to their reinforcing action. Several are now available.

First, direct injections of morphine (Phillips and LePiane 1980;

Bozarth and Wise 1981a, 1982) and other opiates and opioid peptides

(van Ree and de Wied 1980; Phillips and LePiane 1982) are reinforcing when administered into the region of the dopaminergic cells of

the ventral tegmentum. This is seen in a conditioned place preference paradigm, where animals learn to return to the place where

they have experienced opiates in the past (Phillips and LePiane

1980, 1982; Bozarth and Wise 1982), and also in a lever-pressing

paradigm where responding is reinforced by direct brain injections

of morphine (Bozarth and Wise 1981a) or fentanyl (van Ree and de

Wied 1980). Injections dorsal (Phillips and LePiane 1980), anterior or posterior (Bozarth and Wise 1982) to the dopaminergic

cell group are not reinforcing. Injections of morphine in other

regions, particularly the lateral hypothalamus (Stein and Olds

1977; M.E. Olds 1979), have also been reported to be reinforcing, but

22
it seems most likely that such injections diffuse and have their

reinforcing action in the ventral tegmental area (Broekkamp 1975;

Wise and Bozarth 1981; Bozarth 1983). Intravenous heroin reinforcement is not altered by destruction of the cells of the lateral hypothalamus, as it would be if there were important rewardrelevant opiate receptors in this region (Britt and Wise 1981),

and rats do not learn to lever-press for hypothalamic injections

as rapidly or as reliably as they learn to lever-press for ventral

tegmental injections (Bozarth and Wise 1982).

On the other hand, ventral tegmental microinjections of opiate antagonists cause compensatory increases at low doses and extinguish

responding for intravenous opiates at high doses (Britt and Wise

1983). Ventral tegmental microinjections of the enkephalinase inhibitor thiorphan produce a reinforcing state, presumably mediated

by an endogenous opioid peptide transmitter, as shown by the place

preference test (Glimcher et al. 1983). Thus the reinforcing action of opiates seems localized to the region of the dopamine-containing cells that are implicated in psychomotor stimulant reward.

That rewarding ventral tegmental morphine injections pharmacologically activate the dopaminergic cells of this region is inferred

from the fact that they cause contralateral circling (Bozarth and

Wise 1982). Such circling is known to accompany activation of the

dopaminergic projection to the striatum (Ungerstedt 1971), and dopaminergic antagonists block the circling elicited by morphine in

this region (Holmes et al. 1983). The fact that the circling is

directed away from the side of morphine injection indicates that

the injections excite rather than inhibit the dopaminergic cells

in question (Ungerstedt 1971), and electrophysiological evidence

confirms that there is a population of dopaminergic cells in the

ventral tegmentum which is excited by morphine (Matthews and German

1982; Ostrowski et al. 1982). That this dopaminergic activation

plays a necessary role in opiate reinforcement is confirmed in the

conditioned place preference task; if morphine is given during dopaminergic receptor blockade, the animals do not show learned approach to the morphine-associated portion of the environment

(Bozarth and Wise 1981b; Spiraki et al. 1983).

The emerging picture is, then, one of a reward circuit involving a

descending myelinated fiber system in the medial forebrain bundle

(activated directly in the case of brain stimulation reward), communicating with dopaminergic cell bodies of the ventral tegmental area

(where morphine initiates its reinforcing action), and ultimately

resulting in synaptic release of dopamine at terminals where the

reinforcing effects of psychomotor stimulants are pharmacologically

initiated. Food and water reward are thought to depend on at least

the dopaminergic portion of this circuitry, but it is not known by

what input fibers the message arrives at the dopaminergic cells.

DOPAMINERGIC MECHANISMS AND OTHER HABIT-FORMING DRUGS

At least two other drugs with some degree of abuse liability appear

likely to have actions at the dopaminergic link of this same re23
inforcement system. Phencyclidine, which has amphetamine-like reinforcing properties (along with several non-amphetamine-like side

effects), shares amphetamine's approximate site of reinforcing action in nucleus accumbens; phencyclidine injections in this region

cause conditioned place preference (Giovino et al. 1983). It is not

known whether phencyclidine has presynaptic or postsynaptic effects

in the dopaminergic synapse, like cocaine or apomorphine, respectively, or whether it acts in other synaptic junctions to influence

the same output cells. Nicotine, which is self-administered intravenously in man (Henningfield et al. 1983) and in lower animals

(Dougherty et al. 1981), is also capable of activating dopaminergic

cells (Giorguieff-Chesselet et al. 1979; Lichtensteiger et al.

1982), although, again, the mechanism of interaction is not known

in any detail. Thus there is a good chance that future research

will link the reinforcing mechanisms of action of at least some

other drugs of abuse to the mechanism shared by food, water, lateral hypothalamic brain stimulation, amphetamine, cocaine, and op

iates. Other neurotransmitter systems are also likely to be linked

to the mechanisms under discussion; for example, neurotensin, an

endogenous peptide transmitter, is reinforcing when injected into

the ventral tegmental area, as shown in both place preference and

self-administration tests. The rewarding effects are dopaminedependent, as they are blocked by neuroleptics (Glimcher et al.

1983b).

RELATION OF DRUG DEPENDENCE TO DRUG REINFORCEMENT

In considering the mechanism of cocaine's abuse liability it has

been useful to consider cocaine actions that are shared with other

drugs of abuse. It is unlikely that the peripheral autonomic effects or local anesthetic effects of cocaine are critical, since

these are not effects common to other classes of abused drugs.

Similarly, it seems clear that actions other than physical dependence-producing actions such as those of opiates, ethanol, barbiturates, and benzodiazepines must explain the habit-forming consequences at least of cocaine; cocaine shares the habit-forming property but not the dependence-producing property of these drugs.

Based on this conclusion, it is tempting to accept the currently

popular notion that cocaine is less dangerous (less "addicting"

or less compulsively habit-forming) than so-called "hard drugs"

that do produce physical dependence syndromes. It is widely held

that cocaine is a much safer drug for recreational use than is

heroin, for example, because heroin "addicts" the user while cocaine does not. This unfortunate and erroneous belief is based on

two fallacies, one empirical and one logical. The empirical fallacy is that humans seem usually not to endanger their health by

taking cocaine to excess; the logical fallacy is that it is the

ability to produce physiological dependence that makes drugs most

dangerous. The first fallacy is refuted by direct evidence; the

second is refuted by the fact that even opiate self-administration

can be shown to derive from opiate actions unrelated to physical

dependence.

24
Studies in animals suggest that cocaine is a far more inherently

health-threatening pharmacological agent than heroin. Rats given

free access to intravenous cocaine or amphetamine take drug to the

exclusion of food. These animals lose weight and usually die in a

few weeks (Pickens and Harris 1968; Bozarth and Wise, unpublished

observations); rewarding brain stimulation can have similar effects

(Routtenberg 1964). Widespread human experience with cocaine suggests that cocaine does not have such compelling effects in man;

but it must be remembered that few humans have unlimited access to

cocaine, and among those that do, compulsive and potentially lethal

cocaine abuse are increasingly reported. The seeming safety of cocaine as used recreationally by man may be an illusion that depends

more on the intake-limiting effects of cocaine price and availability than on any inherent safety in the drug itself. In as much as

cocaine and amphetamine have very similar effects in the reward

circuitry of the brain, the lessons learned with intravenous amphetamine in both man and animals are very relevant: the psychomotor

stimulants do not impose reasonable limits on their own intake;

they have a dangerous tendency to be self-administered to the

detriment of health when they are freely available in unlimited

quantity. Positive reinforcing properties alone, as shared with

rewarding brain stimulation, are enough to produce this high degree

of health risk (Routtenberg 1964).

Whatever the safety factor we attribute to cocaine, it is clear

that its habit-forming property, and thus its abuse liability, is

independent of a classic physical dependence syndrome. In considering the degree to which cocaine shares common mechanisms of reinforcing action with other drugs, it is important to determine how

critical the physical dependence syndrome is for the reinforcing

effects of those drugs that do produce it. Recent evidence on the

nature of opiate reinforcement suggests that physical dependence

is not a necessary condition for reinforcement even in the case of

opiates. Thus the primary mechanisms of opiate and cocaine reinforcement do, indeed, seem shared.

There are two major principles of reinforcement as analyzed in the

literature of experimental psychology, and each has been suggested

to underlie opiate reinforcement (Beach 1957). The first is the

principle of "positive reinforcement," in which a positive state

caused by the drug--euphoria--is seen to account for the reinforcing effects of the drug. Although many of the subjective effects

are different, euphoria is a property that opiates share with cocaine and amphetamine; stimulant euphoria and opiate euphoria are

sufficiently similar to make it appropriate to rate them on the

same mood scale (Jasinski 1973). The second principle is the principle of "negative reinforcement," in which a negative state which

the drug reduces--withdrawal dysphoria--is seen to account for opiate reinforcement. Stimulants do not share with opiates the ability to block the opiate withdrawal syndrome, and there is no comp

arable withdrawal syndrome, in severity or quality, associated

with psychomotor stimulants; thus the negative reinforcement principle is not a satisfying explanation of cocaine self-administration

and is not a common denominator of drugs of abuse, despite the fact

25
that it is a principle widely held to explain compulsive intake of

opiates and other sedative-hypnotics.

There is now strong and direct evidence that the primary reinforcing effects of even opiates are positive and not negative reinforcement effects. First, no obvious signs of opiate dependence

develop in animals allowed to work for low doses of intravenous

opiates (Woods and Schuster 1968; Deneau et al. 1969) or for limited access to central (ventral tegmental) morphine injections

(Bozarth and Wise 1983). Thus opiates can be reinforcing, producing strong self-administration habits, when given in dose regimens

and by routes of administration that do not lead to obvious dependence signs.

It is always possible, however, that some degree of dependence

develops, but goes undetected, in any paradigm where drug is given

more than once; dependence signs need not be obvious to outside

observers in order to play a role in drug reinforcement. However,

opiate reinforcement can also be demonstrated in a place-preference

paradigm where drug is administered only once (Bozarth and Wise

1983); here there is never any opportunity for drug to relieve withdrawal distress. Thus opiate dependence is not a necessary condition for opiate reinforcement.

There is even clearer recent evidence, however, that morphine dependence and primary morphine reinforcement are not causally linked; opiate reinforcement and opiate dependence are now known to be

mediated by anatomically distinct neural mechanisms, each with its

own population of central opiate receptors. Even 72 hours of continuous infusion of morphine into the opiate reward site of the

ventral tegmental area fails to produce the opiate dependence syndrome as reflected in naloxone-precipitated withdrawal symptoms

(Bozarth and Wise 1983). When the same dose is infused into the

periaqueductal gray matter, on the other hand, strong dependence

signs develop (Wei and Loh 1976; Wei 1981; Bozarth and Wise 1983).

Drug-naive rats do not work for injections into this region, however (Bozarth and Wise 1981a) , nor do injections in this region

produce conditioned place preference (see the control group of

Phillips and LePiane 1980). Thus the primary reinforcing effect

of opiates involves a population of opiate receptors that interacts with reward circuitry of the ventral tegmental area and that

is not involved in dependence phenomena, whereas the dependenceproducing effect of opiates involves an anatomically distinct pop

ulation of opiate receptors that interacts with circuitry of the

periaqueductal gray matter and is not involved in positive reinforcement phenomena. Thus opiates, along with cocaine, have habitforming actions involving positive reinforcement mechanisms. It

remains possible that opiates can produce, in addition, negative

reinforcement; it is not yet known whether morphine-dependent animals will work for morphine injections into the periaqueductal gray;

it seems likely that in dependent subjects both factors may come

into play (Beach 1957).

The potent reinforcing actions of opiates and cocaine which are

26
common actions, however, would appear to be positive reinforcing

actions. Whatever the influence of withdrawal distress in dependent subjects, it would appear that the mood elevation associated

with cocaine and opiates in nondependent subjects is sufficiently

powerful to account for the initial acquisition of drug self-administration habits and is likely to account as well for the rapid

reacquisition of such habits in detoxified subjects. This positive

reinforcement property and the mood elevation that tends to accompany it appear to result from the activation of neural systems which

evolved to serve the control of behavior by conventional reinforcers

such as food and water. The fact that drugs and rewarding brain

stimulation can activate these endogenous reward systems powerfully

and centrally may account for the fact that these reinforcers which

do not offer obvious survival value to either the individual or the

species can sometimes exert more effective behavioral control than

substances or events that do.

SUMMARY AND CONCLUSIONS

Cocaine has multiple central and peripheral pharmacological actions.

The action responsible for the rewarding property, and hence the

abuse liability, of cocaine is an action in the dopaminergic synapse; in the rat the major set of critical dopaminergic synapses

appears to be in the nucleus accumbens. Cocaine prolongs the activity of dopamine in the synapse by blocking the dopamine reuptake

mechanism (which usually inactivates the transmitter by removing it

from the proximity of its synaptic targets). This is an action

shared with amphetamine; in addition to blocking the dopamine reuptake mechanism, amphetamine also augments dopaminergic function by

augmenting dopamine release directly into the synapse. While

amphetamine and cocaine have discriminable subjective effects,

perhaps due to differences in rate of onset and metabolism or perhaps due to different side effects, cocaine shares its rewarding

impact and abuse liability very closely with amphetamine. When

drug access is unlimited, cocaine and amphetamine have the same

ability to dominate behavior, reducing other behaviors such as

feeding and sleeping and, in the process, reducing stress resistance to life-threatening levels.

Opiates also owe their reinforcing properties to their ability to

activate dopaminergic synapses in brain reward circuitry, though

they activate the system at a different site and by a different

local mechanism than those of amphetamine and cocaine. Where

amphetamine and cocaine activate dopaminergic activity in the dop

aminergic synapse, opiates activate dopaminergic activity by activating (or disinhibiting) the dopaminergic cell bodies. The site

of rewarding action of opiates is the ventral tegmental area, where

the dopaminergic cells projecting to the nucleus accumbens (as

well as other targets) are located. Opiate actions that are restricted to this mechanism do not include opiate physical dependence; the dependence syndrome involves anatomically distinct systems in the brain, systems not activated by amphetamine or cocaine.

While opiate physical dependence may contribute to the motivation

for opiate intake in dependent subjects, it is not necessary for

27
opiates to be habit-forming.

The neural circuitry involved in the rewarding actions of cocaine,

amphetamine, and the opiates is circuitry thought to be specialized

for natural reward function. The circuit activated by these drugs

is also activated by some cases of rewarding brain stimulation.

While there may be more than one reward circuit in the brain, the

rewarding effects of food and water appear to depend, along with

those of cocaine, amphetamine, opiates and lateral hypothalamic

brain stimulation, on the integrity of a dopaminergic link in such

circuitry. The rewarding effects of cocaine, however, need not

be conveyed to the central nervous system over networks of sensory

nerves, as are those of food and water; cocaine can activate, powerfully and directly, the central circuits of goal-directed behavior.

Given this fact it should not be surprising that motivation for

cocaine can come to dominate motivation for more essential and

health-promoting substances. Survival value has resulted from the

fact that food, water, warmth, shelter, sex partners, and social and

parental interactions have been subserved by the central circuits

of reward and motivation. The refinement of substances such as

cocaine and methods such as rewarding brain stimulation which can

activate central reward circuitry directly, are unlikely to serve

the further evolution of man so long as they provide shortcuts to

the pleasures of reward and bypass the adaptive activities that

have led to these pleasures over most of our evolutionary history.

REFERENCES

Amsel, A., and Roussel, J. Motivational properties of frustration:

I. Effect on a running response of the addition of frustration

to the motivational complex. J Exper Psychol, 43: 363-368, 1952.

Axelrod, J. Amphetamine: Metabolism physiological disposition and

its effects on catecholamine storage. In: Costa, E., and

Garattini, S., eds. Amphetamines and Related Compounds. New

York: Raven Press, 1970. pp. 207-216.

Basbaum, A.I., and Fields, H.L. Endogenous pain control mechanisms: Review and hypothesis. Ann Neurol, 4:451-462, 1978.

Baxter, B.L., Gluckman, M. I., and Scerni, R.A. Apomorphine selfinjection is not affected by alpha-methylparatyrosine treatment:

Support for dopaminergic reward. Physiol Behav, 4:611-612, 1976.

Baxter, B.L., Gluckman, M.I., Stein, L., and Scerni, R.A. Selfinjection of apomorophine in the rat: Positive reinforcement bv a

dopamine receptor stimulant. Pharmacol Biochem Behav, 2:387-391,

1974.

Beach, H.D. Some effects of morphine on habit function. Canad J

Psychol, 11:193-198, 1957.

Belluzzi, J.D., and Stein, L. Enkephalin may mediate euphoria and

drive-reduction reward. Nature; 266:556-558, 1977.

Bielajew, C., and Shizgal, P. Behaviorally derived measures of

conduction velocity in the substrate for rewarding medial forebrain bundle stimulation. Brain Res, 237:107-119, 1982.

Bozarth, M.A. Opiate reward mechanisms mapped by intracranial

self-administration. In: Smith, J.E. and Lane, J.D., eds.

Neurobiology of Opiate Reward Mechanisms. New York: Raven Press,

28
1983. pp. 331-359.

Bozarth, M.A., and Wise, R.A. Intracranial self-administration of

morphine into the ventral tegmental area in rats. Life Sci, 28:

551-555, 1981a.

Bozarth, M.A., and Wise, R.A. Heroin reward is dependent on a

dopaminergic substrate. Life Sci, 29:1881-1886, 1981b.

Bozarth, M.A., and Wise, R.A. Localization of the reward-relevant

opiate receptors. In Harris, L.S., ed. Problems of Drug Dependence, 1981. National Institute on Drug Abuse Research Monograph

41. Rockville Maryland; The Institute, 1982. pp. 158-164.

Bozarth, M.A., and Wise, R.A. Dissociation of the rewarding and

physical dependence-producing properties of morphine. In Harris,

L.S., ed. Problems of Drug Dependence, 1982. National Institute

on Drug Abuse Research Monograph 43. DHEW Pub. No. (ADM) 83-1264.

Washington, D.C.: Supt. of Docs., U.S. Govt. Print. Off., 1983.

pp. 171-177.

Britt, M.D., and Wise, R.A. Opiate rewarding action: Independence

of the cells of the lateral hypothalamus. Brain Res, 222:213-

217, 1981.

Britt, M.D., and Wise, R.A. Ventral tegmental site of opiate

reward: Antagonism by a hydrophilic opiate receptor blocker.

Brain Res, 258:105-108, 1983.

Broekkamp, C.L.E. The modulation of rewarding systems in the

animal brain by amphetamine, morphine and apomorphine. Unpublished thesis, University of Nijmegen, 1975.

Carlsson, A. Amphetamine and brain catecholamines. In Costa, E.,

and Garattini, S., eds. Amphetamines and Related Compounds. New

York: Raven Press, 1970. pp. 289-300.

Corbett, D., and Wise, R.A. Intracranial self-stimulation in relation to the ascending dopaminergic systems of the midbrain: A

moveable electrode mapping study. Brain Res, 185:1-15, 1980.

Davis, W.M., and Smith, S.G. Catecholaminergic mechanisms of reinforcement: Direct assessment by drug self-administration. Life

Sci, 20:483-492, 1977.

Deneau, G., Yanagita, T., and Seevers, M.H. Self-administration of

psychoactive substances by the monkey. Psychopharmacologia,

16:30-48. 1969.

deWit, H., and Wise, R.A. Blockade of cocaine reinforcement in rats

with the dopamine receptor blocker pimozide but not with the noradrenergic blockers phentolamine OK phenoxybenzamine. Canad J

Psychol, 31:195-203, 1977.

Dougherty, J., Miller, D., Todd, G., and Kostenbauder, H.B. Reinforcing and other behavioral effects of nicotine. Neurosci

Biobehav Rev, 5:487-495, 1981.

Ettenberg, A., Pettit, H.O., Bloom, F.E., and Koob, G.F. Heroin

and cocaine intravenous self-administration in rats: Mediation by

separate neural systems. Psychopharmacology, 78:204-209, 1982.

Fibiger, H.C. Drugs and reinforcement mechanisms: A critical

review of the catecholamine theory. Ann Rev Pharmacol Toxicol,

18:37-56, 1978.

Fouriezos, G., and Wise, R.A. Pimozide-induced extinction of intracranial self-stimulation: Response patterns rule out motor or

performance deficits. Brain Res, 103:377-380, 1976.

Fouriezos, G., Hansson, P., and Wise, R.A. Neuroleptic-induced

29
attenuation of brain stimulation reward. J Comp Physiol Psychol,

92:659-669, 1978.

Franklin, K.B.J. Catecholamines and self-stimulation: Reward and

performance deficits dissociated. Pharmacol Biochem Behav,

9:813-820, 1978.

Franklin, K.B.J., and McCoy, S.N. Pimozide-induced extinction in

rats: Stimulus control of responding rules out motor deficit.

Pharmacol Biochem Behav, 11:71-75, 1979.

Gallistel, C.R., Boytim, M., Gomita, Y., and Klebanoff, L. Does

pimozide block the reinforcing effect of brain stimulation?

Pharmacol Biochem Behav, 17:769-781, 1982.

Gallistel, C.R., Shizgal, P., and Yeomans, J. A portrait of the

substrate for self-stimulation; Psychol Rev, 88:228-273, 1981.

Gerber, G.J., Sing, J., and Wise, R.A. Pimozide attenuates lever

pressing for water reinforcement in rats. Pharmacol Biochem

Behav, 14:201-205, 1981.

German, D.C., and Bowden, D.M. Catecholamine systems as the neural

substrate for intracranial self-stimulation: A hypothesis. Brain

Res, 73:381-419, 1974.

GiGuieff-Chesselet, M.F., Kemel, M.L., Wandscheer, D., and

Glowinski, J. Regulation of dopamine release by presynaptic

nicotinic receptors in rat striatal slices: Effect of nicotine in

a low concentration. Life Sci, 25:1257-1261, 1979.

Giovino, A.A., Glimcher, P.W., Mattei, C.A., and Hoebel, B.G. Phencyclidine (PCP) generates conditioned reinforcement in the nucleus

accumbens (ACC) but not in the ventral tegmnental area (VTA).

Soc Neurosci Abstr, 9:120, 1983.

Glimcher, P.D., Giovino, A.A., and Hoebel. B.G. Self-injection of

neurotensin into the ventral tegmental area (VTA). Soc Neurosci

Abstr, 9:120, 1983.

Glimcher, P.D., Giovino, A.A., Margolin, D.H., and Hoebel, B.G.

Endogenous opiate reward induced by an enkephalinase inhibitor,

thiorphan, injected into the ventral midbrain. Behav Neurosci,

1984, in press.

Glimcher, P.D., Margolin, D.H., Giovino, A.A., and Hoebel, B.G.

Neurotensin: A new "reward peptide" Brain Res, 1983b in press.

Goeders, N.E., and Smith, J.E. Cortical dopaminergic involvement

in cocaine reinforcement. Science, 221:773-775, 1983.

Gunne, L.M., Anggard, E., and Jonsson, L.E. Clinical trials with

amphetamine-blocking drugs. Psychiatr Neurol Neurochir, 75:225-

226, 1972.

Heikkila, R.E., Orlansky, H., and Cohen, G. Studies on the distinction between uptake inhibition and release of (3H) dopamine in rat

brain tissue slices. Biochem Pharmacol, 24:847-852, 1975.

Henningfield, J.E., Miyasato, K., and Jasinski, D.R. Ciqarette

smokers self-administer intravenous nicotine. Pharmacol Biochem

Behav, 19:887-890, 1983.

Holmes, L.J., Bozarth, M.A., and Wise, R.A. Circling from intracranial morphine applied to the ventral tegmental area in rats.

Brain Res Bull, 11:295-298, 1983.

Jasinski, D.R. Assessment of the dependence liability of opiates

and sedative hypnotics. In: Goldberg, L., and Hoffmeister, F.,

eds. Psychic Dependence: Definition, Assessment in Animals and

Man, Theoretical and Clinical Implications. New York: Springer30
Verlag, 1973, pp. 39-53.

Johanson, C.E. Drugs as reinforcers. In Blackman, D.E., and

Sanger, D.J., eds. Contemporary Research in Behavioral Pharmacology. New York: Plenum, 1978. pp. 325-390.

Jonsson, L., Anggard, E., and Gunne, L. Blockade of intravenous

amphetamine euphoria in man. Clin Pharmacol Therap, 12:889-896,

1971.

Kuffler, S.W., and Vaughan Williams, E.M. Small-nerve junctional

potentials. The distribution of small motor nerves to frog

skeletal muscle, and the membrane characteristics of the fibers

they innervate. J Physiol, 121:289-317, 1953.

Lichtensteiger, W., Hefti, F., Felix, D., Huwyler, T., Melamed, E.,

and Schlumpf, M. Stimulation of nigrostriatal dopamine neurones

by nicotine. Neuropharmacol, 21:963-968, 1982.

Lyness, W.H., Friedle, N.M., and Moore, K.E. Destruction of

dopaminergic nerve terminals in nucleus accumbens: Effect on

d-amphetamine self-administration. Pharmacol Biochem Behav, 11:

553-556, 1979.

Matthews, R.T., and German, D.C. Electrophysiological evidence for

morphine excitation of ventral tegmental area dopamine neurons

Soc Neurosci Abstr, 8:777, 1982.

Mayer, D.J., and Price, D.D. Central nervous system mechanisms of

analgesia. Pain, 2:379-404, 1976.

Monaco, A.P., Hernandez, L., and Hoebel, B.G. Nucleus accumbens:

Site of amphetamine self-injection: comparison with the lateral

ventricle. In Chronister, R.B., and DeFrance, J.F., eds. The

Neurobiology of the Nucleus Accumbens. New Brunswick, Maine:

Haer Institute, 1980. pp. 338-342.

Olds, J., and Milner, P. Positive reinforcement produced by electrical stimulation of septal area and other regions of rat brain.

J Comp Physiol Psychol, 47:419-427, 1954.

Olds, J., and Travis, R.P. Effects of chlorpromazine, meprobamate,

pentobarbital and morphine on self-stimulation. J Pharmacol

Exper Therap, 128:397-404, 1960.

Olds, M.E., and Olds, J. Approach-avoidance analysis of rat diencephalon. J Comp Neurol, 120:259-295, 1963.

Ostrowski, N.L., Hatfield, C.B., and Caggiula, A.R. The effects of

low doses of morphine on the activity of dopamine-containing cells

and on behavior. Life Sci, 31:2347-2350, 1982.

Pickens, R., and Harris, W.C. Self-administration of d-amphetamine

by rats. Psychopharmacologia, 12:158-163, 1968.

Pickens, R., Meisch, R.A., and Dougherty, J.A. Chemical interactions

in methamphetamine reinforcement. Psychol Rep, 23:1267-1270,

1968.

Phillips, A.G., and Broekkamp, C.L.E. Inhibition of intravenous

cocaine self-administration by rats after microinjection of

spiroperidol into the nucleus accumbens. Soc Neurosci Abstr,

6:105, 1980.

Phillips, A.G., and LePiane, F.G. Reinforcing effects of morphine

microinjection into the ventral tegmental area. Pharmacol

Biochem Behav, 12:965-968, 1980.

Phillips, A.G., and LePiane, F.G. Reward produced by microinjection

of (d-Ala2),Met5-enkephalinamide into the ventral tegmental area.

Behav Brain Res, 5:225-229, 1982.

31
Phillips. A.G., Mora, F., and Rolls, E.T. Intracerebral self-administration of amphetamine by rhesus monkeys. Neurosci Lett, 24:

81-86, 1981.

Risner, M.E., and Jones, B.E. Role of noradrenergic and dopaminergic

processes in amphetamine self-administration. Pharmacol Biochem

Behav, 5: 477-482, 1976.

Risner, M.E., and Jones, B.E. Intravenous self-administration of

cocaine and norcocaine by dogs. Psychopharmacology, 71:83-93,

1980.

Roberts, D.C.S., Corcoran, M.E., and Fibiger, H.C. On the role of

ascending catecholaminergic systems in intravenous self-administration of cocaine. Pharmacol Biochem Behav, 6:615-620, 1977.

Roberts, D.C.S., Koob, G.F., Klonoff, P., and Fibiger, H.C. Extinction and recovery of cocaine self-administration following 6-OHDA

lesions of the nucleus accumbens. Pharmacol Biochem Behav, 12:

781-787, 1980.

Routtenberg, A. Self-starvation caused by "feeding center"

stimulation. Amer Psychol, 19:502-507, 1964.

Shizgal, P., Bielajew, C., Corbett, D., Skelton, R., and Yeomans, J.

Behavioral methods for inferring conduction velocity and anatomical linkage: I. Pathways connecting rewarding brain stimulation

sites. J Comp Physiol Psychol, 94:1227-237, 1980a.

Shizgal, P., Bielajew, C., and Kiss, I. Anodal hyperpolarization

block technique provides evidence for rostro-caudal conduction

of reward related signals in the medial forebrain bundle. Soc

Neurosci Abstr, 6:422, 1980b.

Spiraki, C., Fibiger, H.C., and Phillips, A.G. Attenuation by

haloperidol of place preference conditioning using food reinforcement. Psychopharmacology, 77:379-382, 1982.

Spiraki, C., Fibiger, H.C., and Phillips, A.G. Attenuation of

heroin reward in rats by disruption of the mesolimbic dopamine

system. Psychopharmacology, 79:278-283, 1983.

Stein, E.A., and Olds, J. Direct intracerebral Self-administration

of opiates in the rat. Soc Neurosci Abstr, 3:302, 1977.

Stein, L. Effects and interactions of imipramine, chlorpromazine,

reserpine and amphetamine on self-stimulation: Possible neurophysiological basis of depression. In Wortis, J., ed. Recent

Advances in Biological Psychiatry. New York: Plenum, 1962.

pp. 288-308.

Ungerstedt, U. Striatal dopamine release after amphetamine or nerve

degeneration revealed by rotational behavior. Acta Physiol Scand,

Suppl. 367:49-68, 1971.

van Ree, J.M., and de Weid, D. Involvement of neurohypophyseal

peptides in drug-mediated adaptive responses. Pharmacol Biochem

Behav, 13 (Suppl. 1):257-263, 1980.

Wei, T.T. Enkephalin analogs in physical dependence. J Pharmacol

Exper Therap, 216:12-18, 1981.

Wei, T.T., and Loh, H. Physical dependence on opiate-like peptides.

Science, 193:1262-1263, 1976.

Wilson, M.C., and Schuster, C.R. The effects of chlorpromazine on

psychomotor stimulant self-administration in the rhesus monkey.

Psychopharmacologia, 26:115-126, 1972.

Wise, C.D., and Stein, L. Amphetamine: Facilitation of behavior

by augmented release of norepinephrine from the medial forebrain

32
bundle. In Costa, E., and Garattini, S., eds. Amphetamine and

Related Compounds. New York: Raven Press, 1970. pp. 463-485.

Wise, R.A. Catecholamine theories of reward: A critical review.

Brain Res, 152:215-247, 1978.

Wise, R.A. Action of drugs of abuse on brain reward systems.

Pharmacol Biochem Behav, 13(Suppl.1):213-223, 1980.

Wise, R.A. Brain dopamine and reward. In Cooper, S.J., ed.

Progress in Psychopharmacology. New York: Academic Press,

1981a, pp. 165-196.

Wise, R.A. Intracranial self-stimulation: Mapping against the

lateral boundaries of the dopaminergic cells of the substantia

nigra. Brain Res, 213:190-194, 1981b.

Wise, R.A. Neuroleptics and operant behavior: The anhedonia hypothesis. Behav Brain Sci, 5:39-53, 1982.

Wise, R.A., and Bozarth, M.A. Brain substrates for reinforcement

and drug self-administration. Prog Neuropsychopharmacol, 5:467-

474, 1981.

Wise, R.A., Spindler, J., deWit, H., and Gerber, G.J. Neurolepticinduced "anhedonia" in rats: Pimozide blocks the reward quality

of food. Science, 201:262-264, 1978a.

Wise, R.A., Spindler, J., and Legault, L. Major attenuation Of food

reward with performance-sparinq doses of pimozide in the rat.

Canad J Psychol, 32:77-85, 1978b.

Wise, R.A., Yokel, R.A. and deWit, H. Both positive reinforcement

and conditioned taste aversion from amphetamine and apomorphine

in rats. Science, 191:1273-1275, 1976.

Woods, J.H., and Schuster, C.R. Reinforcing properties of morphine,

cocaine and SPA as a function of unit dose. Int J Addict,

3:231-246, 1968.

Xenakis, S., and Sclafani, A. The dopaminergic mediation of a sweet

reward in normal and VMH hyperphagic rats. Pharmacol Biochem

Behav, 16:293-302, 1982.

Yeomans, J.S. Absolute refractory periods of self-stimulation

neurons. Physiol Behav, 22:911-919, 1979.

Yokel, R.A., and Wise, R.A. Increased lever pressing for amphetamine after pimozide in rats: Implications for a dopamine theory

of reward. Science, 187:547-549, 1975.

Yokel, R.A., and Wise, R.A. Attenuation of intravenous amphetamine

reinforcement by central dopamine blockade in rats.

pharmacology

Psycho-

, 48:311-318, 1976.

Yokel, R.A., and Wise, R.A. Amphetamine-type reinforcement by

dopamine agonists in the rat. Psychopharmacology, 58: 289-296,

1978.

Zarevics, P., and Setler, P. Simultaneous rate-independent and

rate-dependent assessment of intracranial self-stimulation:

Evidence for the direct involvement of dopamine in brain reinforcement mechanisms. Brain Res, 169:499-512, 1979.

AUTHOR

Roy A. Wise, Ph.D.

Center for Studies in Behavioral Neurobiology

Department of Psychology

Concordia University, Montreal, Quebec

Canada

33
The Pharmacology of Cocaine

Reese T. Jones

As we approach the one hundredth anniversary of the use of cocaine

in medicine, the reader might assume that scientific knowledge of

cocaine is relatively complete. It is not. Much of what is known

about cocaine, its local anesthetic properties, central nervous

system stimulant actions, general subjective and cardiovascular

effects when ingested by a variety of routes -- oral, nasal, by

chewing, by injection -- was described 50 to 100 years ago. The

"new" facts regarding the pharmacology of cocaine have mostly been

collected and reported since 1975 when NIDA funded a series of

research contracts to study the pharmacology of cocaine in humans.

Those studies and ones evolving from them provide detailed descrip

tions of acute, short-term cocaine effects and are reviewed elsewhere in this volume. The studies provide better documented

information on relationship between dose and route of administration, blood levels of cocaine and limited physiologic or psychologic effects (Fischman et al. 1976,1983; Resnick et al. 1977; Van

Dyke et al. 1978,1982; Fischman and Schuster 1980,1981,1982).

However, many large gaps in what we should know about the pharmacology of cocaine remain. This chapter touches on some of the

issues where more should be known, speculates on assumptions about

what we do know, and suggests a few areas needing attention from

researchers and from those sources that should support good

research on the pharmacology of cocaine.

COCAINE AND BRAIN FUNCTION

Some of the most impressive and predictable consequences of

cocaine are effects on brain function and the sought-after consequences of altered brain function -- euphoria, relief of fatigue

and boredom, and other consequences of psychic stimulation. Hans

Berger, in one of the earliest reports describing the human electroencephalogram (Berger 1931), mentioned that a 24-year-old man

given a 30 mg dose of cocaine subcutaneously showed increased EEG;

alpha frequency and amplitude 20 minutes after injection. Cocaine

given during a second test session with this young man produced

less EEG; change. A second subject demonstrated a similar alpha

amplitude and frequency increase associated with the "stimulating

34
action of cocaine upon psychic processes." Berger gave a few more

volunteers cocaine (Berger 1937). His new recording equipment

allowed him also to measure EEG beta activity and he found increased beta activity along with the higher amplitude and higher

frequency alpha 30 minutes after a 20 mg subcutaneous injection of

cocaine. "We are confronted here with the graphic representation

of the stimulating action exerted by cocaine upon mental processes," Berger said. Keep in mind Berger's papers were the first

demonstrations of human EEGs and involved, among other things,

comparisons of caffeine and cocaine.

Now, almost 50 years after Berger's auspicious demonstrations of

cocaine effects on the electrical activity of the human brain, no

further publications describing the effects of cocaine on the

resting EEG in humans have appeared. One small study examined

cocaine-induced sleep EEG; changes in depressed patients. Modest

doses of cocaine (30 to 200 mg daily) given orally for ten days

suppressed rapid eye movement sleep. When cocaine was stopped, a

rebound of REM sleep quantity followed as it does after withdrawal

of amphetamines and many other psychoactive drugs given for a few

days (Post et al. 1974). The depressions did not improve.

In studies in our laboratories, we find substantial cocaineinduced changes in nonstimulated resting EEG and on the late

components of auditory event-related potentials thought to be

related to information processing. Intravenous doses of cocaine

similar to those commonly used outside of the laboratory setting

(0.2 mg/kg) produced increases in beta2 activity like those described by Berger 50 years ago. However, no differences between

cocaine and placebo on alpha activity have been found. Cocaine

decreases the amplitude of the so-called P300 component of an

auditory-evoked response recorded during a task that required the

subject to evaluate each stimulus as to its task relevance. That

the cocaine effect seems to be maximal at a 0.2 mg/kg dose with

higher doses producing no greater decreases in amplitude suggests

that even lower doses of cocaine may have measurable effects on

brain function. Other laboratories report stimulants like methylphenidate increase the P300 component amplitudes. It is generally

assumed that methylphenidate, amphetamine, and related stimulants

have actions and many mechanisms similar to cocaine. The different pattern of evoked potential changes suggests that there may

be some differences in actions or mechanisms as well.

Generalized convulsions were among the very earliest toxic effects

of cocaine noted in the late 19th century (Van Dyke and Byck 1976;

Eidelberg et al. 1963). The convulsions were generally considered

to reflect cocaine's CNS stimulant effects. Early studies noting

that at high doses the convulsive behavior was followed by death

generally associated with respiratory depression, assumed that

cocaine acted at the cortical level with "stimulation proceeding

from above downward." When more precise neurophysiologic recording techniques were developed in the 19606, it was obvious that

changes in limbic system function preceded the generalized motor

convulsions. It was suggested that cocaine seizures originating

in limbic structures might provide a useful model to investigate

35
temporal lobe epilepsy and psychoses that may be associated with

psychomotor seizures (Eidelberg et al, 1963). Worth noting is

that, in contrast to cocaine's propensity to induce seizures even

after a single dose, amphetamines generally induce seizures only

after repeated administration of high doses, suggesting possible

differences between amphetamines and cocaine.

Ihe relative lack of interest in the human electrophysiology of

cocaine is even more surprising since with animals one of the more

dramatic consequences of chronic cocaine administration is a phenomenon referred to as 'kindling," manifest by increased sensitivity and responsivity of various neural and other systems (Post

et al. 1976,1981; Stripling and Hendricks 1981; Ellinwood and

Kilbey 1980). Hypothesized mechanisms accounting for kindling

are related to enhanced propagation of electrical signals in the

nervous system. That the locus of activity seems to be in the

limbic system structures makes the phenomenon all the more interesting and clinically relevant because chronic cocaine and other

stimulant administration mimics certain aspects of a schizophreniclike process (Post 1975; Ellinwood and Kilbey 1980). It is plausible that the electrical and behavior changes seen in animals

given cocaine repeatedly and some of the behaviors of people taking

cocaine repeatedly could result frorm similar mechanisms. Such

EEG phenomena as kindling have not been reported to occur in longterm, frequent cocaine users. On the other hand, such populations

have not been studied systematically, if at all, in terms of this

phenomenon observed in the laboratory.

Cocaine has complex actions on the central nervous system. Many

effects on brain function are similar to those produced by other

stimulants, for example, amphetamines or caffeine. Other cocaine

effects are more similar to other local anesthetics, for example,

potent membrane stabilizing properties. Since most local anesthetics do not produce the mental stimulation and other psychological

effects of cocaine (Fischman et al. 1983), its local anesthetic

properties are probably neither necessary nor sufficient explanations for cocaine's sought-after effects but could account for

some of its untoward toxic effects. Cocaine alters the metabolism

of norepinephrine, dopamine, serotonin, and acetylcholine. It is

a potent convulsant, but under other circumstances has anticonvulsant properties. Some of the earliest studies with cocaine documented its delay in the inactivation of epinephrine and norepinephrine and blockade of norepinephrine reuptake. Subsequent

neurochemical studies on the actions of cocaine on the brain

focused on the catecholamine systems and generally reported

effects similar to the more extensively studied amphetamines.

However, some evidence has accumulated that cocaine also alters

serotoninergic mechanisms, for example, blocking the synaptosomal

uptake of tryptophan (Knapp and Mandell 19721. This would slow

the conversion of tryptophan to serotonin even though tryptophan

hydroxylase activity increases (Mandell and Knapp 1977). Turnover

of 5-hydroxy tryptophan is slowed, suggesting possible differences

in cocaine and amphetamine mechanisms (Friedman et al. 1975).

Cocaine also decreases acetylcholine uptake (Liang and Questel

1969). Assuming that lithium diminishes cocaine effects (Cronson

36
and Flemenbaum 1981) and that endorphinergic mechanisms may be

involved, then the whole story of cocaine mechanisms in the CNS

is still incompletely understood and is probably complex.

ABSORTION AND METABOLISM

The availability of biochemical assays sufficiently sensitive to

measure tissue levels of cocaine and its metabolites in humans now

enables researchers to better assess the significance of clinical

data and to more properly design research studies (Jatlow and

Bailey 1975; Chinn et al. 1980; Lindgren 1981; Ambre et al. 1982;

Miller et al. 1977; Johns et al. 1977; Hawks et al. 1974). In

recent years, many of the laboratory studies with cocaine reporting data from humans have measured plasma levels of cocaine. Some

rudimentary understanding has developed regarding relationships

between cocaine dose, route of administration, and effects, but

uncertainty remains.

Enzymes called esterases play an important role in the metabolism

of cocaine. In humans and other mammals, plasma and liver have

high levels of esterase activity. Moderate activity is present in

other organs including brain (Foldes 1978). Cholinesterases, also

referred to as plasma cholinesterase, serum cholinesterase, pseudocholinesterase, nonspecific cholinesterase, play an important role

in the metabolism of cocaine (Stewart et al. 1979; Inaba et al.

1978). Individuals with low cholinesterase activity may have

slower metabolism of cocaine and some of its metabolites (Jatlow

et al. 1979). In vitro activity of these enzymes becomes an

important consideration in cocaine assay procedures (and can make

for considerable in vitro losses of cocaine unless inhibited by

the addition of fluoride, physostigmine, or other esterase inhibitors) (Jatlow and Bailey 1975).

Plasma cholinesterase activity can vary greatly between individuals and between species. The genetics of plasma esterase

inheritance are relatively well understood (Neitlich 1966; Foldes

1978). The percent inhibition of the esterase activity by dibucaine, known as the dibucaine number, is one common clinical

measure used to screen for unusual sensitivity to the muscle

relaxant succinylcholine. People with low dibucaine numbers seem

to be not only slow metabolizers of succinylcholine but may also

be slow metabolizers of cocaine, at least as judged by in vitro

tests (Jatlow et al. 1979; Stewart et al. 1979). On the other

hand, some individuals may have genetically determined increased

cholinesterase activity and would be expected to metabolize

cocaine more rapidly. A number of disorders including liver

disease, the presence of carcinoma, and exposure to anticholinesterase drugs will lower cholinesterase activity (Foldes 1978).

Some inconsistencies in the cocaine literature, particularly in

issues of tolerance and dependence, may result from species variations in cholinesterase activity and resulting cocaine metabolism.

Cholinesterase activity is relatively high in humans, horses, and

certain species of monkeys (for example, chimpanzees) but not

others (for example, macaques). Cholinesterase activity is much

37
lower in other mammals (for example, dogs, cats, sheep, and rats)

and very low in cows. Fourfold differences in cholinesterase

activity can occur in various strains of mice. Cholinesterase

activity is much lower in the fetus, infants, and aged males, and

decreases to a lesser degree during pregnancy.

The pharmacologic significance of such variations in determining

cocaine metabolism or toxicity is not entirely clear. Most

cocaine studies in animals, particularly behavioral studies, have

rarely even measured cocaine or cocaine metabolite levels, let

alone determined kinetics. However, there is enough evidence from

in vitro assays to indicate that variations in cholinesterase

activity in the range commonly encountered clinically can have

significant effect on the in vitro metabolism of cocaine and

cocaine metabolites. Since there is both hepatic and nonhepatic

metabolism of cocaine, the functional impact of very low or much

higher than normal cholinesterase activity might depend on route

of administration -- for example, it might be more important when

the cocaine is given intravenously or perhaps smoked than with

oral, intraperitoneal, or subcutaneous administration Rate and

dose could interact as well.

METABOLITES

Cocaine is extensively metabolized in humans to water soluble

metabolites that are mainly excreted in urine. The two major

metabolites in urine are benzoylecgonine and ecgonine methyl ester

(Fish and Wilson 1969; Inaba et al. 1978; Kogan et al. 1977).

These hydrolysis products are generally assumed to result from the

action of esterases in liver and in serum, though benzoylecgonine

may be formed nonenzymatically in vivo (Stewart et al. 1979). The

N-demethylated metabolites of each of the above may occur. Norcocaine has been identified in rat, monkey, and human (Inaba

et al. 1978). Although the effects of norcocaine in humans are

yet to be determined, norcocaine is biologically active as judged

by inhibition of norepinephrine uptake in synaptosomes (Hawks

et al. 1974), local anesthetic actions (Just and Hoyer 1977), and

by effects on schedule controlled behavior (Spealman et al. 1979).

Since norcocaine may have very similar kinetics to the parent

compound, it may be less of a confounding variable than if its

kinetics differed (Misra et al. 1975)

Benzoylecgonine is generally assumed to be without significant

biological activity, though it occurs at substantial levels in

plasma (Johns et al. 1977; Kogan et al. 1977). Even though it

produces significantly less inhibition of norepinephrine uptake in

synaptosomes that does cocaine (Hawks et al. 1974), Misra has

speculated that benzoylecgonine could form molecular complexes

with calcium ion and thus participate in a number of membrane

level nerve functional changes (Misra 1976). Additional metabolites, hydroxycocaine and methylecgonidine, have been identified

in the bile of a person dying of cocaine overdose (Lowry 1979).

Cocaine blood levels in that case were substantial, 3700 ng/ml.

38
Assays of ecgonine methyl ester in urine (Ambre et al. 1982) or

benzoylecgonine are useful as markers of cocaine use, although the

pathways, particularly enzymatic versus nonenzymatic formation,

are not yet completely worked out (Stewart et al. 1979). When

considering the biological importance of cocaine metabolites,

attention to possible species differences is important. For

example, cocaine is a potent hepatotoxin in mice, probably due to

the hepatic tissue binding of a metabolite of N-hydroxy-norcocaine

(Rauckman et al. 1982; Smith et al. 1981). In humans and most

other species, liver damage does not seem to be specifically

associated with cocaine administration other than by speculative

comments in some human studies where the general consequences of

chronic intravenous drug use confound the issue. A relatively old

report (Yamamoto et al. 1953) suggested decreased cocaine metabolism by rabbit livers after chronic administration, but the study

did not specifically measure liver damage. Given some of the

variability already alluded to in discussing plasma cholinesterase

activity, it is particularly important when studying cocaine metabolites to keep in mind that there will be species selectivity and

probably dose- and route-dependent interactions.

COCAINE RECEPTORS

Although a cocaine receptor has not yet been identified, specific

binding characteristics have been suggested. In an appropriately

speculative report, three lines of evidence were cited supporting

the association of high affinity type cocaine binding in the

cerebral cortex with serotonergic nerve terminals (Reith et al.

1983). There was a correlation between cocaine binding inhibition

by various drugs and the inhibition of serotonin neuronal uptake

in mouse cerebral cortex. In mice treated with various serotonin

and catecholamine neurotoxins, only the serotonin neurotoxin

decreased the high affinity binding of tritiated cocaine in rat

cerebral cortex. Some reports have implicated serotonergic

systems as important, particularly in increases in cocaine-induced

locomotor activity that are not blocked by haloperidol or alpha

methyl paratyrosine. Reith et al. (1983) remind us that the-array

of effects produced by cocaine that include locomotor stimulation.

mood changes, stereopy, and hallucinations are not likely to be

due to a single mechanism. Thus, cocaine binding sites on serotonergic nerve terminals may mediate only some effects, but it is

the mood elevating effects that are perhaps involved with these

binding sites.

KINETICS

The pharmacokinetics of cocaine and its metabolites, that is, the

mechanisms of absorption, metabolism, and excretion, have yet to

be fully worked out. Some important parameters have not been

determined in humans: for example, renal excretion pattern,

protein binding, and blood/plasma partitioning. What has been

published on the kinetics of cocaine and its metabolites reflects

great unaccounted for variability, both within and between subjects in the same laboratory and between laboratories. For

example, estimates of elimination half-life after intravenous

39
doses range from approximately 19 minutes (mean 41.4) (Javaid

et al. 19831 to 168 minutes (Kogan et al, 1977). Some of the

earlier studies offering kinetic data probably did not sample

bloods long enough after cocaine administration to properly

define the terminal phase of clearance, and numbers of subjects

tested often were very small. Elimination half-life may be dose

related but not to the extent that would account for the reported

variability (Barnett et al. 1981). With a sample of 40

infrequent cocaine users, we found t-1/2 to range from a mean of

61 minutes at 0.2 mg/kg intravenously to 80 minutes at a dose of

0.6 mg/kg. However, at any given dose level there was great

variability in the range of half-lives and equally great variability when subjects were tested on more than one occasion a

week or two apart. Similar variability is evident even on such

basic pharmacokinetic parameters as plasma versus time area under

the curve, peak plasma levels, and times to peak plasma levels.

It seems that one attribute of cocaine uptake, distribution, and

metabolism is that it is variable.

ROUTE OF ADMINISTRATION

The availability of sensitive assays has led to a better understanding of the contribution of route of cocaine administration

in determining effects. Although cocaine now is rarely taken

orally, that is by swallowing or drinking, oral ingestion as an

elixir was common in the late 19th century. Why has the nasal

route become so popular? Relative bioavailability and intensity

of many cocaine effects were similar after oral or nasal doses

(Wilkinson et al. 1980; Van Dyke et al. 1978). we found similar

patterns of effects after nasal and oral doses in a large number

of subjects given oral, nasal, and intravenous cocaine. Bioavailability of both oral and nasal cocaine is about 30% to 40%

when compared to intravenous doses given to the same person. The

comparisons of oral, nasal, and intravenous routes suggest that

the rate of change in plasma and presumably in brain drug levels

and associated subjective effects may be very important considerations in determining preferred route of administration.

Similar oral and nasal cocaine doses produce similar peak blood

levels and times to peak blood level (about 60 minutes), yet the

onset and magnitude of both subjective effects and cardiovascular

changes such as heart rate and blood pressure increase are much

more rapid after intranasal administration. Effects begin within

a minute or so after spraying the dose in the nasopharynx with a

18% cocaine solution and within a few minutes of administration

of cocaine as a crystalline material. No one has done enough

early plasma sampling after administration to properly define the

earliest phase of uptake, but initial uptake appears to be faster

when cocaine is taken nasally than when taken orally. For

example, after 2 mg/kg doses; plasma levels at 15 minutes were

5.7 ng/ml with the oral route and 17.5 no/ml after nasal administration, yet the peak plasma levels at 1 hour were similar. It

is likely that plasma concentrations do not adequately reflect

brain levels of the drug, and that brain levels are important

determinants of the sought-after effects. Regional distribution

40
and cocaine levels in various organs are not well characterized.

In an autopsy case, brain cocaine levels were surprisingly high

as compared to blood levels (Chinn et al. 1980). Given the

vasculature of the nasopharnyx, it is plausible that cocaine

brain levels at the earliest phase of nasal administration may

exceed systemic plasma levels. Brain levels in rats given radiolabeled cocaine suggest cocaine is taken up rapidly by the brain

(Misra et al, 1975). Perhaps the best illustration of the importance of rate of uptake is the intense but very transient subjective effect after smoking cocaine (Paly et al. 1982; Perez-Reyes

et al. 1982; Siegel 1982). The initial effects after smoking seem

more intense and more rapid in onset than comparable intravenous

doses would produce.

NEUROCHEMICAL SUBSTRATES

As with most if not all psychoactive drugs, the neurochemical

substrates of action are not completely understood. More precisely, the substrates seem to become more complicated as their

interactions are better appreciated. It is important to consider

neurochemical substrates following acute administration separately from those that follow chronic administration of cocaine.

Single doses of cocaine (and other stimulants) may have quite

different consequences than does chronic repeated administration.

It traditionally has been said that the stimulating effects of

cocaine could be attributed to its ability to block the reuptake

of norepinephrine. This obviously is no longer considered to be

a sufficient explanation, since many psychoactive drugs (for

example, antidepressant drugs) in common use block the reuptake

of neurotransmitters but are not stimulants and do not produce

euphoria. Cocaine inhibits the reuptake of norepinephrine, and

also dopamine and serotonin. Cocaine alters tryptophan hydroxylase and, thus, the drug-sensitive regulatory processes in the

biosynthesis of serotonin. It may have direct effects on noradrenergic receptors. As do other stimulants, it interacts with

the cholinergic system as well; for example, physostigmine, an

acetylcholinesterase inhibitor, inhibits cocaine-induced hyperactivity and stereotypy in rats (Post et al. 1976). With

repeated doses, neurochemical mechanisms can interact with conditioning or learning mechanisms, electrophysiologic changes,

alterations in dopamine receptor binding sites, and possibly

pharmacokinetic mechanisms (Ellinwood and Kilbey 1980).

ABSORPTION

Cocaine, when taken as the salt, is water and fat soluble and

thus readily enters the body. When considering cocaine's pharmacology, particularly questions of absorption and metabolism,

broad generalizations become risky because of the varied routes of

administration available to the user or used by the scientist.

Cocaine can be taken orally, i.e., swallowed; it can be taken

nasally as a spray or a powder, much as tobacco snuff is taken; it

can be taken buccally, either by chewing coca leaves or by placing

it in the buccal pouch, much as one would do with tobacco snuff;

41
it can be smoked, injected intravenously or subcutaneously or

intramuscularly. Since it is readily absorbed through mucous

membranes or even abraded skin, those routes are available and

have been utilized. Intraperitoneal injection is commonly used in

studies with rodents.

Dose of any drug is, of course, of great importance in determining

both acute and chronic toxicity. With cocaine, route of administration may be of equal and perhaps at times greater importance

than dose, since metabolism and disposition are relatively rapid

and involve mechanisms both in blood and liver and perhaps elsewhere. Since cocaine is a potent vasoconstrictor, its rate of

absorption is altered by its effects on regional vasculature when

given subcutaneously and perhaps by other routes. Most acute

toxic reactions from cocaine are associated with the rapid onset

of high plasma levels, usually after rapid absorption. Estimates

of what is a lethal dose of cocaine vary greatly and depend very

much on route of administration. Other aspects of toxicity,

particularly chronic toxicity, may well vary with route of administration, possibly because of route-dependent metabolic differences.

ORAL INGESTION

Despite seemingly authoritative statements to the contrary,

cocaine is readily absorbed when taken orally (Van Dyke et al.

1978; Wilkinson et al. 1980). This should not be surprising,

since during the 19th century initial widespread use of cocaine

in Europe and the United States was in the form of oral elixirs

containing cocaine (Van Dyke and Byck 1982). The most common

route by which cocaine is taken is still, of course, by chewing

coca leaf or sucking on powdered coca leaves (Holmstedt et al.

1979; Paly et al. 1979; Holmstedt and Fredga 1981). When coca

leaves are chewed, probably there is a combination of cocaine

absorption from the mucous membranes of the mouth (and thus some

avoidance of first pass liver metabolism) and also swallowing and

absorption from the gastrointestinal tract. When coca leaves are

chewed OK sucked on, measurable amounts of cocaine appear in the

blood as soon as 5 minutes after chewing begins and, when

swallowed, cocaine is measurable in blood within 15 minutes and

perhaps earlier. The bioavailability of cocaine when taken

orally has been estimated at about 20% (Mayerson and Perrier

1978). Currently in our laboratory, where more precise comparisons can be made to intravenous doses (thus taking into account

metabolic processes other than hepatic metabolism), we find

systemic absorption between 30% and 40% after oral doses.

The relative lack of popularity for oral dosing on the current

drug-using scene is curious. Although peak subjective effects are

slower in onset, they are not greatly different from those following dosage by the more popular intranasal route (Van Dyke et al.

1982, 1978). It has been argued that the toxicity of cocaine might

be quite different, probably considerably less, if it were ingested

orally by chewing coca leaves rather than by currently popular

routes (Weil 1981). Most cocaine-using volunteers tested in our

42
San Francisco laboratories have never heard of or considered oral

administration. Those few who are familiar with the oral route

rarely have ever tried it. The precise sites of absorption,

stomach versus duodenum, etc., and possible differences in metabolic profiles when taken by the oral route should be determined.

NASAL ADMINISTRATION

Cocaine produces excellent anesthesia and vasoconstriction of

mucous membranes. For many years, cocaine was the anesthetic of

choice for nasal surgery for that reason. When compared to oral

administration, the absorption after nasal administration has a

more rapid onset with correspondingly more rapid appearance of

subjective effects. Even so, the peak plasma levels of cocaine,

the time of peak plasma levels, and the bioavailability are similar with both nasal and oral administration Wilkinson et al.

1980; Van Dyke et al. 1982, 1978). The preference for the nasal

route suggests that rate of increase in tissue levels is an important attribute to the cocaine user. The pattern and timing of

effects suggest that there may well be more rapid increases in

brain lwel of cocaine than in systemic levels reflected by venous

blood samples. The vasculature of the nasopharnyx would allow for

this possibility.

It should be kept in mind that plasma levels of cocaine do not

necessarily indicate organ levels -- for example, brain levels.

In an instance where cocaine blood levels were being measured in

surgical patients (Miller et al, 1977), one patient developed

restlessness, excitement, and bradycardia thought to represent

early toxic symptoms from the cocaine within 2 minutes after

cotton packs containing 5% cocaine solution were inserted in his

nose. Even though the packs were removed immediately, his peak

plasma cocaine levels 75 minutes later were 350 ng/ml, a threefold

higher level than seen in other patients at that dose. At 20

minutes after the pack was removed, levels were 100 ng/ml. This

single case illustrates that, for reasons not completely understood, the systemic uptake and perhaps more importantly the brain

uptake of cocaine after nasal administration can be extremely

rapid.

The factors determining rate of absorption of cocaine from nasal

administration are not completely understood, Differences between

the inhalation of crystals OK solution are small (Wilkinson et al.

1980). Variations in blood drug levels seem to be a function of

total dose and not of the concentration of cocaine solution used

(Cambell and Adriani 1958; Miller et al. 19771. Some of the

relatively rare acute toxic reactions when cocaine is used for

anesthesia may be due to the inhalation of cocaine mist which, if

containing particles small enough to diffuse into alveoli, might

be very quickly absorbed and, because of the very rapid uptake

into brain, produce CNS levels that would otherwise not be

attained through the slower absorption from nasal or pharyngeal

mucosa or trachea (Campbell and Adriana 19581.

43
When the cocaine is instilled into the nasopharynx either as

crystalline material or as a spray, surprisingly little of the

delivered dose appears in saliva, suggesting relatively complete

absorption from the nasopharynx rather than partial swallowing,

The cocaine is very slowly cleared from nasal mucous membranes

with measurable levels remaining 3 hours after administration

(Van Dyke et al. 1982), probably due to paralysis of the cilia

on the membranes of the nasal mucous blanket (Barton and Gray

1979). Since some studies reporting terminal half-lives for

nasally administered cocaine only sample bloods for 2 or 3 hours,

the validity of such kinetic measures must be considered in the

context that absorption is still going on throughout the period

when clearance is being measured.

PARENTERAL ADMINISTRATION

Cocaine can be injected subcutaneously or into muscle or vein.

The former routes give relatively slow onset of effects, probably

because of vasocontriction and thus relatively slowed absorption.

The effects following intravenous injection are related to both

dose and rate of administration (Javaid et al. 1978; Resnick

et al. 1977; Fischman et al. 1976; Barnett et al. 1981). When

injected rapidly, subjective and physiologic effects appear within

30 seconds, rapidly peak, and then decrease relatively rapidly

over the next 30 minutes. Absorption, of course, is 100%. Rate

of change, i.e., rapidity of injection, seems to be almost as

important in determining subjective and physiologic effects as

absolute blood levels. Rate and dose relationships have not been

studied nor are the dose effect functions for most effects well

worked out at cocaine dose levels much in excess of 0.6 mg/kg of

body weight. A dose of that level injected over 1 minute will

produce peak blood levels of between 300 and 400 ng/ml with brief

but intense subjective effects. In contrast, a volunteer subject

given four to five times that dose but distributing the injections

over 60 minutes demonstrated peak cocaine levels of 1100 ng/ml but

no greater subjective and cardiovascular measures than those produced by the much lower dose given over 1 minute (Fischman and

Schuster 1982). Although the precise relationships between dose

and rate of administration have not been investigated, one would

expect that with a rapidly metabolized and rapidly redistributed

drug like cocaine, rate might be as important as dose.

INHALATION: SMOKING

The very intense and relatively brief cocaine effects that follow

the smoking of cocaine probably reflect the fact that the smoking

of any drug is a very efficient way of delivering it in a very

concentrated bolus to the brain (Jeri et al. 1978; Paly et al.

1982; Siegel 1982). The alveoli of the lung offer an enormous

area for the absorption of the volatilized cocaine. More important perhaps in its appeal to certain users is that the circulation time from lungs to brain is about 8 seconds while from arm to

brain it is at least 16 seconds. Even then an intravenous injection in an arm vein must first pass through the left heart, lungs,

and right heart before reaching brain, with ample time for distri44
bution and metabolism by blood cholinesterases before brain is

reached. The probable efficiency of smoking varies with the

technique used (Jeri et al. 1978; Perez-Reyes et al. 1982). Most

smoking techniques do not allow for precise temperature control,

and variations from optimal pipe temperature may either make for

low delivery or destroy most of the available cocaine.

The intense, pleasurable, and hence reinforcing, effects which

sometimes lead to surprisingly frequent, compulsively repeated use

should not be unexpected if similar patterns of tobacco use are

considered. Although taking tobacco orally by chewing or by snuff

will satisfy the nicotine craving of some tobacco-dependent individuals, most tobacco smokers would agree that the first few inhalations of the day are really quite different and are a special

way of delivering nicotine to the brain. There is at least a

partial analogy when comparing the various alternate routes of

administration of cocaine. For smoking, the conversion of cocaine

from its more common salt to the base is necessary because the

physical chemical characteristics of the base, stability particularly, are more desirable. The toxicity that develops with smoked

high-dose use is not well understood in terms of mechanisms

(Siegel 1982).

Given that both liver and blood contain enzymes that metabolize

cocaine, one might well expect differences in metabolism depending

on route of administration. The metabolic profiles, particularly

of benzoylecgonine and ecgonine methyl ester as they may differ by

route, have not yet been determined, mainly because suitable

plasma assays have only recently become available. The terminal

half-life of cocaine, that is, the amount it takes for half of the

material to be eliminated, is about 60 to 80 minutes no matter

what the route, though there is tremendous variability both within

and between subjects at any given route.

TOXICITY

Sometimes consideration of the acute and chronic toxicity of a

drug will give insights into its modes of action. When cocaine is

used for anesthesia, toxic reactions are not common. For example,

a survey of American plastic surgeons found only five fatalities

and 34 severe reactions out of a total of over 108,000 patients

given topical cocaine. However, even under the relatively controlled conditions of the operating room, the mechanism of toxic

reactions is still not well understood. Simple overdose does not

seem to be the most common determinant and factors leading to

rapid absorption may be more important (Campbell and Adriani 1958;

Pearman 1979). Various authorities have estimated maximum safe

doses of cocaine between 100 and 300 mg when administered topically (Pearman 1979). Doses in that range are in common use in

experimental situations with normal volunteers without untoward

effects, so those figures must be conservative ones.

The features of acute cocaine poisoning include profound central

nervous system stimulation progressing to preconvulsive movements,

then convulsions and cardiovascular and respiratory failure.

45
Although probably a more common sequelae after intravenous administration, deaths occur after cocaine taken by virtually any route

if the dose is large enough (Bar-Or and Wahby 1982; Bednarczyk

et al. 1980; Bettinger 1980; Dimaio and Garriott 1978; Fishbain

1982). Postmortem tissue levels, particularly blood levels, vary

greatly because of cocaine metabolism postmortem, so the establishment of precise toxic doses is difficult (Fletcher and Hancock

1981; Jatlow et al. 1979; Lowry et al. 1979). The sudden death

following cocaine administration may occur so rapidly that treatment is not available. In dogs (Catravas and Waters 1981) and in

primates Guinn et al. 1980) chlorpromazine, possibly because of

its antidopaminergic, antiadrenergic, sedative, and antihyperthermic effects, and diazepam, possibly because of anticonvulsant

and sedative effects, appear useful in the treatment of acute

cocaine intoxication. Symptomatic treatment of the respiratory

and cardiovascular depression, of course, is important as well.

Although beta blockers have been recommended in the treatment of

early cocaine toxicity (Rappolt et al. 1978) in the animal

studies, propranolol seemed to be of little use in modifying the

consequences of high doses.

Because of the potentiation of catecholamine effects by cocaine,

one might assume potentially toxic interactions with drugs or

conditions where adrenergic activity plays a role (Smith 1973;

Coleman et al. 1982). Curiously, although neuroleptics seem to

diminish or block cocaine effects (Colpaert et al. 1978; Catravas

and Waters 1981), tricyclic antidepressants, which might be

expected to potentiate the effects of cocaine, seem to diminish

some vasoconstrictor effects (Schecter et al. 1982), and diminish

acute cardiac toxicity in rats (Antelman et al. 1981).

TOLERANCE AND DEPENDENCE

It is often said and written that tolerance to cocaine does not

occur and that dependence as manifest by "physiologic" withdrawal

signs does not occur. Both these beliefs are firmly reinforced by

authoritative reviews and are probably incorrect. Discussions of

cocaine tolerance usually start by citing the extensive evidence

of seemingly increasing sensitivity to cocaine effects (Ellinwood

and Kilbey 1980; Post 1975; Post et al. 1976, 1981; Stripling and

Hendricks 1981; and many others). There has been less emphasis on

data consistent with the development of more traditional tolerance, i.e., diminished effects with repeated doses (Branch and

Dearing 1982; Teeters et al. 1963). Decreases in some cocaine

effects with repeated doses are not necessarily inconsistent with

the concomitant increased intensity in other effects, for example,

kindling, indicating a sensitization to cocaine.

Tolerance must involve a variety of adaptive mechanisms and

changes. It is reasonable to assume that some of these adaptive

changes to the presence of the drug OK its metabolites might

appear as increasing effects while at the same time other effects

are decreasing. Only in the very special case where tolerance to

a drug can be accounted for mainly by more rapid or complete

metabolism is the coexistence of disappearing acute effects and

46
the gradual enhancement of other consequent effects not plausible.

In the case of cocaine, dispositional changes or changes in the

metabolism of the drug do not seem to be sufficient explanations

for the phenomenon of tolerance when it appears.

Cocaine is a relatively short-acting drug. Optimal conditions to

produce tolerance require a Constant presence of the drug in the

body, particularly if the measures of tolerance are not sensitive

ones, as may be the case in some animal studies. It may be that

once daily or three times daily doses as have been used in animal

studies are not always sufficient to produce tolerance. From the

very earliest accounts of cocaine use in humans, in those instances where it was used frequently, diminished effects are

commonly reported and are now being observed in controlled laboratory situations (Fischman and Schuster 1981).

In humans the progressive increases in irritability, restlessness,

hypervigilance, paranoid and suspicious behavior associated with

prolonged high-dose cocaine use may be the human correlate of the

kindling phenomenon observed in some animal experiments. The

psychoses Seen after sustained amphetamine use and after cocaine

use are similar and thought to be a useful model in the study of

naturally occurring schizophrenic psychoses (Post et al. 1976).

such a state, i.e., Concurrent increasing and decreasing sensitivity to a drug, certainly does not fit the simplistic model of

what tolerance to a drug should represent, On the other hand, if

one conceives of tolerance as involving a number of mechanisms

adaptive in one sense and perhaps maladaptive in another sense (if

neurochemical changes produce a psychosis), then what is commonly

observed clinically fits. Whether people with a genetic predisposition for schizophrenia are at more risk to cocaine-induced

psychoses has not been determined. Whether metabolic explanations

are relevant, likewise has not been determined. Curious inconsistencies appear-for example, the sustained and, at least as

measured by plasma levels, relatively high dose yet relatively

nontoxic use of cocaine by the Quechua Indians. Animal studies

indicate that coca leaf contains constituents other than cocaine

that alter its pharmacology (Bedford et al. 1982,1981). Does the

whole leaf have something that serves as a protective device for

the Quechua? Is it bioavailability? Is it a matter of cultural

difference?

As clinical observations accumulate, the existence of a true

withdrawal syndrome following cocaine use seems compelling. The

depression, Social withdrawal, craving, tremor, muscle pain, eating disturbance, electroencephalographic changes, and changes in

Sleep patterns must be more than simply the consequence of what

traditionally has been termed "psychological dependence." When

listening to descriptions of this state by cocaine-using patients,

these dysphoric and often dramatic Symptoms must be viewed as

negative reinforcers. For many patients it appears that the

withdrawal symptoms are a major consideration that makes discontinuing cocaine almost impossible so long as the drug is available. Yet continuing the drug produces unacceptable irritability,

paranoid and delusional thinking, and other unpleasant effects.

47
This cocaine-induced state becomes of theoretical importance in

terms of model building as well as a practical consideration in

treatment. Many of the current models, particularly those involving explanations for stimulant drug administration, tend to consider mainly positive reinforcement with only minimal attention to

negative reinforcement because of what increasingly appears to be

the inappropriate belief that tolerance does not develop and

dependence does not follow the withdrawal of stimulant drugs. The

differences between so-called physical dependence and so-called

psychological dependence may be more a matter of semantics and

sensitivity of measures than of neurochemistry. Most investigators would concede that psychological dependence certainly is a

consequence of repeated cocaine use.

REFERENCES

Ambre, J.J.; Ruo, J.H.; Smith, G.L.; Backer, D.; and Smith, C.M.

Fcgonine methyl ester, a major metabolite of cocaine. J Analytical Toxicol, 6:26-29, 1982.

Antelman, S.M.; Kocan, D.; Rowland, N.; DeGiovanni, L.; and

Chiodo, L.A. Amitriptyline provides long-lasting immunization

against sudden cardiac death from cocaine. Eur J Pharmacol,

69(1):119-120, 1981.

Barnett, G.; Hawks, R.; and Resnick, R. Cocaine pharmacokinetics

in humans. J Ethnopharmacol, (3(2):353-366, 1981.

Bar-Or, D., and wahby, L. (Letter) Cocaine intoxication, delirium, death in body packer. Ann Emerg Med 11(7):389-390, 1982.

Barton, R.P.E., and Gray, R.F.E. Thetransportof crystalline

cocaine in the nasal mucous blanket. Ann Laryngol Otol,

93(12):1201-1204, 1979.

Bedford, J.A.; Turner.C.E.; and Elsohly. H.N. Comparative lethality of coca and cocaine. Pharmacol Biochem Behav, 17(5):

1087-1088. 1982.

Bedford, J.A; Wilson, M.C.; Elsohly, H.N.; Elliott, C.; Cottam,

G.; and Turner, C.E. The effects of cocaine free extracts of

the coca leaf on food consumption and locomotor activity.

Pharmacol Biocheem Behav, 14(5):725-728, 1981.

Bednarczyk, L.R.; Gressmann, E.A.; and Wymer, RL. Two cocaineinduced fatalities. J Anal Toxicol, 4(5):263-265, 1980.

Berger, H. Archiv Fur Psychiatrie Und Nervenkrankheiten, 94:16-

60, 1931. Translated in: Gloor, P., ed. Hans Berger on the

Electroencephalogram of Man. EEG Clin Nerophysiol, Supplement 

28:95-132, 1969.

Berger, H. Archiv Fur Psychiatrie Und Nervenkrankheiten, 106:

577-584, 1937. Translated in: Gloor, P., ed. Hans Berger on

the Electroencephalogram of Man. EEG Clin Neurophysiol,

Supplement 28:291-297, 1969.

Bettinger, J. Cocaine intoxication: Massive oral overdose. Ann

Emerg Med, 9(8):429-430, 1980.

Branch, M.N., and Dearing, M.E. Effects of acute and daily

cocaine administration on performance under a delayed-matchingto-sample procedure. Pharmacol Biochem Behav 16(5):713-718,

1982.

48
Campbell, D., and Adriani, J. Absorption of local anesthetics.

J Am Med Assn, 168(7):873-877, 1958.

Catravas, J.D., and Waters, I.W. Acute cocaine intoxication in

the conscious dog - Studies on the mechanism of lethality. J

Pharmacol Exp Ther, 217(2):350-356, 1981.

Chinn, D.M.; Crouch, D.J.; Peat, M.A.; Finkle, B.S.; and JenniSon, T.A. Gas chromatography-chemical ionization mass spectrometry of cocaine and its metabolites in biological fluids. J

Anal Toxicol, 4(1):37-42, 1980.

Coleman, D.L.; Ross, T.F.; and Naughton, J.L. Myocardial

ischemia and infarction related to recreational cocaine use.

West J Med 136(5):444-446, 1982.

Colpaert, F.C.; Niemegeers, C.J.E.; and Janssen, P.A.J. Neuroleptic interference with cocaine cue - Internal stimulus control of behavior and psychosis. Psychopharmacology, 58(3):247-

255, 1978.

Cronson, AJ., and Flemenbaum, A Antagonism of cocaine highs by

lithium. In: Schecter, AJ., ed. Drug Dependence and Alcoholism. Vol. I. New York: Plenum Publishing Corporation,

1981. pp.1139-1141.

Dimaio, V.J.M., and Garriott, J.C. Four deaths due to intravenous

injection of cocaine. Forensic Sci, 12(2):119-125, 1978.

Eidelberg, E.; Lesse, H.; and Grault, F.P. An experimental model

of temporal lobe epilepsy: Studies of the convulsant properties

of cocaine. In: Glasser, G.H., ed. EEG and Behavior. New

York: Basic Books, 1963. pp. 272-283.

Ellinwood, E.H., and Kilbey, M.M. Fundamental mechanisms underlying altered behavior following chronic administration of

psychomotor stimulants. Biol Psychiatry, 15(51:749-757, 1980.

Fischman, M.W., and Schuster, CR Acute tolerance to cocaine in

humans. In: Harris, L.S., ed. Problems of Drug Dependence

1980. National Institute on Drug Abuse, Research Monograph 34.

DHHS Pub. No. (ADM)81-1058. Washington, D.C.: Supt. of Docs.,

U.S. Govt. Print. Off., 1981. pp. 241-242.

Fischman, M.W., and Schuster, C.R. Cocaine self-administration in

humans. Fed Proc, 41:241-246, 1982.

Fischman, M.W., and Schuster, CR Cocaine effects in sleepdeprived humans. Psychopharmacology, 72(1):1-8, 1980.

Fischman, M.W.; Schuster, C.R.; and Hatano, Y. A comparison of

the subjective and cardiovascular effects of cocaine and lidocaine in humans. Pharmacol Biochem Behav, 18(1):123-127, 1983.

Fischman, M.W.; Schuster, C.R.; Resnekov, L.; Shick, J.F.E.;

Krasnegor, N.A.; Fennel,. W.; and Freedman, D.X. Cardiovascular

and subjective effects of intravenous cocaine administration in

humans. Arch Gen Psych, 33:983-989, 1976.

Fish, F., and Wilson, W.D.C. Excretion of cocaine and its metaboiites in man. J Pharm Pharmacol, 21:1355-1385, 1969.

Fishbain, D.A. (Letter) Cocaine intoxication, delirium, death in

body packer - Reply. Ann Emerg Med, 11(7):390, 1982.

Fletcher, S.M., and Hancock, V.S. Potential errors in benzyolecgonine and cocaine analysis. J Chromatogr, 206(1):193-195,

1981.

Foldes, F.F. Enzymes in anesthesiology. In: Foldes, F.F., ed.

Enzymes in Anesthesiology. New York: Springer-Verlag, 1978.

pp.91-168.

49
Friedman, E.; Gershon, S.; and Rotrosen, J. Effects of active

cocaine treatment on the turnover of 5-hydroxytryptamine in the

rat brain. Br J Pharmacol, 54:61-64, 1975.

Guinn, M.M.; Bedford, J.A.; and Wilson, M.C. Antagonism of intravenous cocaine lethality in nonhuman primates. Clin Toxicol,

16(4):499-508, 1980.

Hawks, R.L., Kopin, I.J., Colburn, RW., and Thoa, N.B. Norcocaine: A pharmacologically active metabolite of cocaine found

in brain. Life Sci, 15:2189-2195, 1974.

Holmstedt, B., and Fredga, A Sundry episodes in the history of

coca and cocaine. J Ethnopharmacol, 3(2-3):113-147, 1981.

Holmstedt, B.; Lindgren, J.E.; Rivier, L.; and Plowman, T.

Cocaine in blood of coca chewers. J Ethnopharmacol, 1:69-78,

1979.

Inaba, T.; Stewart, D.J.; and Kalow, W. Metabolism of cocaine in

man. Clin Pharmacol Ther, 23:547-552, 1978.

Jatlow, P., and Bailey, D. Gas chromatographic analysis for

cocaine in human plasma with use of a nitrogen detector. Clin

Chem, 21:1918-1921, 1975.

Jatlow, P.; Barash, P.G.; Van Dyke, C.; Radding, J.; and Byck, R.

Cocaine and succinylcholine sensitivity: A new caution. Anesth

Analg Curr Res, 58(3):235-238, 1979.

Javaid, J.I.; Fischman, M.W.; Schuster, C.R.; Dekirmenjiian, H.;

and Davis, J.M. Cocaine plasma concentrations: Relation to

physiological and subjective effects in humans. Science,

200:227-228, 1978.

Javaid, J.I.; Musa, M.N., Fischman, M.; Schuster, C.R.; and

Davis, J.M. Kinetics of cocaine in humans after intravenous

and intranasal administration. Biopharmaceutics and Drug Disposition, 4:9-18, 1983.

Jeri, F.R.; Sanchez, C.; Del Pozo, T.; and Fernandez, M. The

syndrome of coca paste. J Psychedelic Drugs 10(4):361-370,

1978.

Johns, M.E.; Berman, A.R.; Price, J.C.; Pillsbury, R.C.; and

Henderson, RL, Metabolism of intranasally applied cocaine.

Ann Otol, 86:342-347, 1977.

Just, W.W., and Hoyer, J. The local anesthetic potency of

norcocaine, a metabolite of cocaine. Experientia, 33:70-71,

1977.

Knapp, S., and Mandell, A.J. Narcotic drugs: Effects on the

serotonin biosynthetic systems of the brain. Science,

177:1209-1211, 1972.

Kogan, M.J.; Verebey, K.G.; dePace, A.C.; Resnick, R.B.; and

Mule', S.J. Quantitative determination of benzoylecgonine and

cocaine in human biofluids by gas liquid chromatography. Analyt

Chem, 49:1965-1969, 1977.

Liang, C.C., and Quastel, J.H. Effects of drugs on the uptake of

acetylcholine in rat brain cortex slices. Biochem Pharmacol

18:1187-1194, 1969.

Lindgren, J.-E. Guide to the analysis of cocaine and its metabolites in biological material, J Ethnopharmacol, 3(2-3):336-

351, 1981.

50
Lowry, W.T.; Lomonte, J.N.; Hatchett, D.; and Garriott, J.C.

Identification of two novel cocaine metabolites in bile by gas

chromatography and gas chromatography mass spectrometry in a

case of acute intravenous cocaine overdose. J Analy Toxicol,

3:91-95, 1979.

Mandell, AJ., and Knapp, S. Acute versus chronic effects of

psychotropic drugs: Adaptive responses in brain amine systems

and their clinical implications. Psychopharmacol Bull, 13:40-

42, 1977.

Mayersohn, M., and Perrier, D. Kinetics of pharmacologic response to cocaine. Res Commun Chem Pathol Pharmacol, 22:465-

Miller, S.H.; Dvorchik, B.; and Davis, T.S. Cocaine concentrations in the blood during rhinoplasty. Plastic and Reconstructive Surgery, 60:566-571, 1977.

Misra, A.L. Disposition and biotransformation of cocaine. In:

Mule', S.J., ed. Cocaine: Chemical, Biological, Clinical,

Social and Treatment Aspects. Cleveland: CRC Press, 1976.

pp. 73-90.

Misra, A.L.; Nayak, P.K.; Bloch, R.; and Mule, S.J. Estimation

and disposition of [3H]benzoylecgonine and pharmacological

activity of some cocaine metabolites. J Pharm Pharmac, 27:784-

786, 1975.

Neitlich, R.W. Increased plasma cholinesterase activity and

succinylcholine resistance: A genetic variant. J Clin Invest,

45:380-387, 1966.

Paly, D.; Jatlow, P.; Van Dyke, C.; Jeri, R.; and Byck, R.

Plasma cocaine concentrations during cocaine paste smoking.

Life Sci 30(9):731-738, 1982.

Paly, D.; Van Dyke, C.; Jatlow, P.; Cabieses, F.; and Byck, R.

Cocaine plasma concentrations in coca chewers. Clin Pharmacol

Ther, 25(21:240,1979.

Pearman, K. Cocaine. Ann Laryngology and Otology, 93:1191-1199,

1979.

Perez-Reyes, M.; Diguiseppi, S.; Ondrusek, G.; Jeffcoat, A.R.; and

Cook, C.E. Free-base cocaine smoking. Clin Pharmacol Ther,

32(4):459-465, 1982.

Post, R.M. Cocaine psychosis: A continuum model. Am J Psychiat,

132:225-231, 1975.

Post, R.M.; Kopanda, RT.; and Black, K.E. Progressive effects

of cocaine on behavior and central amine metabolism in rhesus

monkeys: Relationship to kindling and psychoses. Biol Psych,

11:403-419, 1976.

Post, R.M.; Kotin. J.; and Goodwin, F.K. The effects of cocaine

on depressed patients. Amer J Psych, 131:511-517, 1974.

Post, R.M.; Lockfeld, A.; Squillace. K.M.: and Contel, N.R.

Drug-environment interaction: Context dependency of cocaineinduced behavioral sensitization. Life Sci, 28(7):755-760,

1981.

Rappolt, T.R.; Gay, G.; Inaba, D.S.; Rapport, N.; and Rappolt,

R.T. Use of Inderal (propranolol-Ayerst) in l-a (early stimulative) and l-b (advanced stimulative) classification of

cocaine and other sympathomimetic reactions. Clin Toxicol,

13(2):325-332, 1978.

51
Rauckman, E.J.; Rosen, GM.; and Cavagnaro, J. Norcocaine nitroxide A potential hepatotoxic metabolic of cocaine. Mol Pharm

acol, 21(2):458-462, 1982.

Reith, M.E.A.; Sershen, A.; Allen, D.L.; and Lajtha, A. A

portion of (3H) cocaine binding in brain is associated with

serotonergic neurons. Molec Pharmacol, 23:600-606, 1983.

Resnick, R.B.;Kestenbaum, R.S.; and Schwartz, L.K. Acute

systemic effects of cocaine in man: A controlled study by intranasal and intravenous routes. Science, 195:696-698, 1977.

Schechter, G.L.; Brase,D.A.; and Powell, J. Adverse effects of

tricylic antidepressants during nasal surgery. Otolaryngol

Head Neck Surg, 90:233-236, 1982.

Siegel, R.K. Cocaine smoking. J Psychoact Drugs, 14:271-3259,

1982.

Smith, A.C.; Freeman, R.W.; and Harbison, R.D. Ethanol enhancement of cocaine induced hepatotoxicity. Biochem Pharmacol,

30(5):453-458, 1981.

Smith, R.R. Cocaine and catecholamine interaction. Arch Otolaryngol, 98:139-141, 1973.

Spealman, R.D.; Goldberg, S.R.; and Kelleher, RT. Effects of

norcocaine and some norcocaine derivatives on schedule-controlled behavior of pigeons and squirrel monkeys. J Pharmacol Exp

Ther, 210:196-205, 1979.

Stewart, D.J.; Inbaba, T.; Lucassen, M.; and Kalow, W. Cocaine

metabolism: Cocaine and norcocaine hydrolysis by liver and

serum esterases. Clin Pharmac Ther, 25:464-468, 1979.

Stripling, J.S., and Hendricks, C. Effect of cocaine and lidocaine on the expression of kindled seizures in the rat.

Pharmacol Biochem Behav, 14(3):397-403, 1981.

Teeters, W.R.; Koppanyi, T.; and Cowan, F.F. Cocaine tachyphylaxis. Life Sci, 7:509-518, 1963.

Van Dyke, C., and Byck, R. Cocaine. Sci Am, 246(3):128-134 and

139-142, 1982.

Van Dyke, C., and Byck, R. Cocaine 1884-1974. In: Ellinwcod,

E.H., and Kilbey, M., eds. Cocaine and Other Stimulants. New

York: Plenum Press, 1976. pp. 1-30.

Van Dyke, C.; Jatlow, P.; Barash, P.G.; and Byck, R. Oral

cocaine: Plasma concentrations and central effects. Science,

100:211-213, 1978.

Van Dyke, C.; Ungerer, J.; Jatlow, P.; Barash, P.; and Byck, R.

Intranasal cocaine: Dose relationships of psychological effects

and plasma levels. Int J Psychiatry Med, 12(1):1-13, 1982.

Weil, A.T. The therapeutic value of coca in contemporary medicine. J Ethnopharmacol, 3(2-3):367-376, 1981.

Wilkinson, P.; Van Dyke, C.; Jatlow, P.; Brash, P.; and Byck, R.

Intranasal and oral cocaine kinetics. Clin Pharmacol Ther,

27(3):386-394, 1980.

Yamamoto, I.; Mikauni, K.; and Kurogochi, Y. The enzymic breakdown of cocaine by the rabbit liver. Jap J Pharmacol, 3:39-49,

1953.

52
ACKNOWLEDGEMENTS

National Institute on Drug Abuse Grants DA00053, DA01696 and

DA02829 provided partial support for the preparation of this

paper.

AUTHOR

Reese T. Jones, M.D.

Drug Dependence Research Center

Langley Porter Psychiatric Institute

University of California, San Francisco

San Francisco, California 94143

53
Assessment of the Dependence

Potential of Cocaine in Animals

Chris E. Johanson

INTRODUCTION

The illicit use of cocaine has increased dramatically over the last decade.

The discussions, articles, and songs about cocaine in popular literature

and the media are excessive, and few would disagree that cocaine is

the most infamous drug of abuse in the United States today. Although

actual use of other illicit drugs such as marijuana may exceed the use

of cocaine, this is most likely due to cost and availability rather than

preference. A myriad of factors are responsible for the meteoric rise

in cocaine’s popularity. One factor often cited is the association of

cocaine with glamorous and highly successful segments of society such

as movie stars, recording artists, and the ultra-rich. While such an

association without a doubt contributes significantly to the popularity

of cocaine, the drug itself, in the absence of these influences, has high

dependence potential. In this paper, the experimental evaluation of

cocaine’s dependence potential will be reviewed, and it will be concluded

that there is strong evidence demonstrating that cocaine is a drug of

extremely high dependence potential. It is understandable that this

characteristic of the drug coupled with social factors arising from its

association with success and glamour would lead to the present disturbing

level of abuse.

Two components are essential in the experimental assessment of the

dependence potential of any drug. The first is the demonstration that

the drug will be voluntarily self-administered by the experimental subject

or, in the terminology of behavior analysis, that the drug has positive

reinforcing properties. An event such as drug self-administration is

considered a positive reinforcer if it increases behavior leading to its

delivery or decreases behavior resulting in its withdrawal. More generally

speaking, behavior is controlled by its consequences, including the

administration of a drug. A variety of studies have shown that most

drugs abused by humans also increase behavior leading to their selfadministration in an experimental situation (Johanson and Balster 1978;

Griffiths et al. 1980; Johanson and Schuster 1981). The reinforcing

properties possessed by a drug are not a static pharmacological

characteristic. They are the result of a dynamic interaction between

the event and the environmental context of its administration. The

dependence potential of a drug is directly related to the range of

54
conditions under which it functions as a reinforcer as well as the extent

to which it controls behavior compared to other drug or nondrug

reinforcers.

A second component in the assessment of the dependence potential of

a drug is the demonstration that at doses which are voluntarily

administered there are toxic consequences to the organism. This toxicity

could include changes in morphology, biochemistry, sensory processes,

or a vast array of behaviors, as well as the development of tolerance

or physical dependence. All drugs produce toxicity but the important

issue is the relationship and degree of overlap between reinforcing and

toxic doses. In conclusion, the dependence potential of a drug such as

cocaine can be assessed by measuring the range of conditions under

which it functions as a positive reinforcer and the strength of its

reinforcing properties relative to other drugs plus the degree of

deleterious consequences produced by the self-administered drug at both

individual and societal levels.

To assess these properties of a drug, it is essential to develop an

experimental model capable of analyzing the variables controlling both

excessive self-administration and its consequences in a simple enough

situation that functional relationships between independent and dependent

variables emerge clearly. Although more complex situations, which build

upon and combine these relationships, can then be studied in order to

understand their potential interactions, they can never reach the

complexity of nonlaboratory settings and still produce unambiguous

results. To a large degree, the experimental model which has been

most extensively developed uses animal subjects, such as rats and rhesus

monkeys, but it is desirable that the results are not species specific.

The organism selected for a model of drug abuse would not have to be

nonhuman. In fact, human self-administration studies in controlled

laboratory settings have been increasing in number and are important

for validating animal studies. However, using animals has several

advantages. The range of manipulations possible with animals allows

experiments to be done that would be impossible using human subjects.

In addition, using animals in the study of behavioral influences on drug

self-administration assists investigators in divesting themselves of

psychological preconceptions and in being less prone to use vaguely

defined hypothetical constructs as an explanation of drug selfadministration (Schuster et al. 1979).

The continued use of the animal model which has been developed over

the last 20 years is due to demonstrations of its validity (Johanson and

Schuster 1981). Most important, drugs which are self-administered by

animals in a laboratory situation are the same as those commonly abused

by humans (Johanson and Balster 1978). These include psychomotor

stimulants, opiates and opioids, sedative-hypnotics, alcohol, and some

but not all hallucinogens (e.g., phencyclidine). In addition, the effects

of environmental and pharmacological manipulations leading to changes

in the degree of self-administration are similar in infra-humans and

humans (Griffiths et al. 1980; Johanson and Schuster 1981). This

concordance has led to the acceptance of the animal model as a valid

predictor of dependence potential (Thompson and Unna 1977). In the

55
present paper, the use of this animal model to assess the dependence

potential of cocaine will be reviewed.

METHODOLOGY

Prior to reviewing the experimental studies on the reinforcing properties

and toxic consequences of cocaine in animals, a brief description of the

methods is necessary. Cocaine is taken by humans by a variety of

routes, including the oral, intranasal, and intravenous, as well as by

inhalation (smoked as the base). Although cocaine is self-administered

principally by the intranasal route in humans, the intravenous injection

of cocaine is not uncommon. For technical reasons, however, this route

has been more extensively utilized in experimental studies.

Techniques for the intravenous delivery of drugs to animals were

originally described for rats by Weeks (1962) and for rhesus monkeys by

Yanagita et al. (1965). Such systems have several fundamental aspects:

(1) the chronic implantation of a venous catheter into the organism to

allow immediate delivery of a drug; (2) an experimental arrangement

that allows the organism relatively unrestricted movement, yet still

protects the catheter; and (3) an automatic programming system for the

delivery of drug, contingent upon some response by the animal. The

salient feature of this type of system is that it is possible to deliver

a drug with minimal delay into a vein without disturbing the animal.

Several designs incorporating these features have been used. In our

laboratory, for instance, rhesus monkeys are fitted with a tubular steel

harness which is connected to the wall of a large chamber by a metal

spring. This arrangement allows the monkey to move relatively freely

within the confines of the chamber. The catheter runs through the

metal spring and is connected outside the chamber to a pump. The

chamber is also equipped with response levers and lights signalling drug

availability, all of which are controlled by electronic equipment.

THE REINFORCING PROPERTIES OF INTRAVENOUS COCAINE

In this section, the range of conditions under which cocaine has been

shown to function as a positive reinforcer, i.e., to maintain responding,

will be reviewed. The purpose of this review is to demonstrate that

the number of experimental contexts where cocaine is self-administered

is far ranging. It would be difficult to quantify the extent of this range

simply by counting studies, but it is generally believed by researchers

in the area that cocaine is one of the most reinforcing drugs. Although

rigorous experimental proof of this contention is not easy to demonstrate,

there is anecdotal evidence of cocaine’s strength. For instance, most

researchers use cocaine to train experimentally naive animals to selfadminister drugs. Further, in most substitution studies, regardless of

the drug(s) being evaluated, cocaine is used as the baseline drug because

responding is so readily maintained (Johanson and Balster 1978). Finally,

researchers embarking on a new area of behavioral research often select

cocaine as the first drug to evaluate. For instance, except for alcohol,

early studies on the effects of punishment on drug-taking behavior used

cocaine (e.g., Grove and Schuster 1974).

56
In addition to demonstrating the ubiquitous quality of cocaine’s

reinforcing properties, this review will also show that behavioral variables

such as schedule of presentation are exceedingly important in the way

cocaine controls performance. Responding leading to cocaine delivery

is controlled in much the same way as responding leading to the delivery

of nondrug reinforcers. This qualitative similarity has important

implications for understanding the behavioral mechanisms of action of

drug reinforcement.

One of the first studies to investigate cocaine as a reinforcer was

conducted by Wilson et al. (1971). Rhesus monkeys were given 4 hrs

of daily access to cocaine during which each lever press resulted in

drug delivery. Under these limited access conditions, animals regulated

their drug intake to a remarkable degree. After animals were trained,

they showed stability in their daily intake of cocaine over periods of

months. There were no indications of changes in sensitivity to cocaine’s

reinforcing effects as would be indicated by an increase (tolerance) or

a decrease (supersensitivity) in its rate of self-administration. Wilson

et al. (1971) also demonstated the constancy of cocaine intake by

changing the dose delivered for each lever press. As dose per delivery

was increased, the number of infusions taken by the animals decreased,

resulting in an almost constant intake of drug regardless of the dose

per infusion. Regulation was also evident in the pattern of cocaine

self-administration. Infusions were equally spaced throughout the session

almost as if the drug were being delivered under the control of a clock.

While most animals who administered cocaine showed clear signs of

stimulation (e.g., piloerection, agitation), convulsions rarely occurred

except in the beginning stages of training.

The results of this study by Wilson et al. (1971) have been replicated in

a number of ways. What is impressive is the generality of the

phenomenon. For instance, cocaine is self-administered by every species

of animal tested, including rats (Pickens and Thompson 1968), squirrel

monkeys (Goldberg 1973; Stretch 1977; Katz 1979), rhesus monkeys

(Woods and Schuster 1968), pigtail macaques (Young and Woods 1980),

and baboons (Griffiths et al. 1975), as well as dogs (Risner and Jones

1975; Risner and Silcox 1981; Risner and Goldberg 1983). This

concordance across species is one type of evidence of the robustness of

cocaine’s ability to function as a reinforcer. A second type of evidence

is that cocaine maintains responding regardless of its route of delivery.

Allthough the i.v. route has been used most commonly, cocaine also

maintains responding when delivered intragastrically (Altshuler and

Phillips 1978; Woolverton and Schuster 1983), by chewing or smoking

(Siegel et al. 1976), and even intramuscularly (Katz 1980; Goldberg et

al. 1976). The failure to demonstrate that animals will snort cocaine

is more likely a function of experimenter skills and absence of appropriate

technology than of any difference across species.

Cocaine self-administration not only occurs with a variety of species

and using several routes of administration but also under a variety of

environmental circumstances. In the terminology of behavior analysis,

this can be translated into schedule contingencies, i.e., the rule that

governs the relationship between behavior and the delivery of the

5 7
reinforcer. As will be shown, the nature of that rule can have an

overwhelming influence on the reinforcing properties of a drug. In the

simplest schedule, continuous reinforcement (CRF), every response is

followed by a reinforcer (e.g., Wilson et al. 1971). However, the

relationship between responding and reinforcer may be more complex.

A response may be reinforced on the basis of the number of responses

emitted since the termination of the previous reinforcer delivery (a ratio

schedule), or on the basis of the time elapsed since the last reinforcer

delivery (an interval schedule). A ratio or interval schedule may either

be fixed or vary in number or time. Four basic schedules, then, are

fixed ratio (FR), variable ratio (VR), fixed interval (FI) and variable

interval (VI). In addition to these, there exist numerous other possibilities

for relating responding and the delivery of the reinforcer, i.e., schedules

of reinforcement (Ferster and Skinner 1957).

Many studies have shown that cocaine maintains responding under fixed

ratio schedules (Downs and Woods 1974; Balster and Schuster 1973a).

The pattern of responding, typical of performance maintained by other

events such as food and water (Ferster and Skinner 1957), is characterized

by an initial pause followed by a high terminal rate of responding.

Although the pattern of ratio responding maintained by cocaine is similar

to that maintained by other events, the rates of responding typically

found in drug self-administration studies have been low compared to

rates maintained by food, and increases in dose/delivery further decrease

rates (Kelleher 1975). In many studies, however, rates are higher at

the beginning of the session (Downs and Woods 1974). This generally

low or decreasing rate is most likely due to the dual actions of the

drug (see Johanson and Schuster, 1981, p 233, for a complete discussion).

On the one hand, cocaine serves as a reinforcer which increases rates

of responding, but on the other hand the drug has the ability to

temporarily disrupt ongoing behavior (Wilson and Schuster 1975; Spealman

et al. 1977; Herling et al. 1979) and thus have a rate-decreasing effect.

Since increased responding under ratio schedules results in increased

rates of drug intake, the problem is particularly striking under this

schedule. Several techniques have been used to avoid these effects

while still using response-based, rather than time-based schedules.

Goldberg and Kelleher (1976), for instance, limited the number of

infusions available each session and, as well, imposed a time-out following

infusions. These modifications resulted in much higher rates of

responding.

Cocaine has also been demonstrated to maintain responding under fixed

interval schedules. An important feature of interval schedules is that

rates of responding can change considerably without affecting rate of

reinforcement. One of the first studies using an interval schedule of

drug delivery in monkeys was done by Balster and Schuster (1973b).

They used a fixed interval 9-min schedule with responding maintained

by cocaine infusions in one component and food delivery in the other.

In addition, there was a 15-min time-out following the delivery of each

reinforcer. Responding was well maintained and the pattern with cocaine

was similar to that maintained by food. In contrast to ratio schedules,

as dose per infusion increased, rate of responding increased. Similar

results were found in a study by Goldberg and Kelleher (1976) using a

58
fixed interval 5-min schedule of cocaine delivery. However, response

rates increased only up to a dose of 0.5 mg/kg and then decreased as

dose was further increased. This difference was most likely due to the

more frequent injections in the Goldberg and Kelleher (1976) study.

Again despite the powerful nature of the contingencies governing

reinforcer delivery in controlling responding, the nonspecific ratemodifying actions of cocaine also exerted an influence.

Several studies with cocaine as well as other drugs have used secondorder schedules as a way of minimizing the direct effects of drug

administration in order to get a less confounded estimate of a drug’s

reinforcing actions. In this type of schedule, responding specified by

one particular schedule is treated as a unitary response that is itself

reinforced by another schedule (Kelleher 1966). The responding treated

as a unitary response can also be followed by the presentation of a

brief stimulus paired with the delivery of the reinforcer. Goldberg,

(1973) using squirrel monkeys, studied responding maintained by cocaine

and d-amphetamine as well as food under a fixed ratio 30 schedule of

stimulus presentations (2-sec yellow light), which itself was maintained

under a fixed interval 5-min schedule of drug or food delivery. This

schedule was designated a second-order (FI 5-min (FR 30:s)). When

either drug was used to maintain responding, rates of responding were

extremely high and performance was ratio-like between stimulus

presentations. Furthermore, early in the interval, overall response rate

was relatively low but accelerated as the interval progressed, which is

the pattern of responding typical of fixed interval performance

maintained by diverse reinforcing events. For instance, in the same

study, responding maintained by food was virtually identical in both

pattern and rate. Several additional studies have been conducted with

this schedule using both squirrel and rhesus monkeys. Typical responding

has been maintained under FI (FR) schedules by intravenous and

intramuscular cocaine as well as with fixed ratio schedules of fixed

interval components (Goldberg et al. 1981; Kelleher and Goldberg 1977;

Goldberg and Kelleher 1977; Goldberg et al. 1975). Furthermore, in

many studies, high rates of responding were maintained even when only

one cocaine reinforcer was delivered at the end of the session (Goldberg

et al. 1976; Katz 1979,198O).

Kelleher and Goldberg (1977) demonstrated the importance of the brief

stimuli in maintaining responding under second-order schedules. When

these stimuli were removed following the FR components but the drug

was still delivered, rate declined and patterning was disrupted. If both

drug delivery and the brief stimuli were removed, responding declined

even further. However, when the brief stimuli were then reinstated

without the drug, responding increased. Similar results have been found

in other studies including ones with intramuscular cocaine (Katz 1979).

Whether such rates would be maintained over long periods of time is

not known. In order to determine whether the stimuli used in secondorder schedules derive their ability to maintain responding from their

association with drug, Goldberg et al. (1979) compared the response

maintenance properties of drug-paired and unpaired stimuli. In this

study both intravenous cocaine and morphine maintained typical

responding under FI (FR) schedules in squirrel monkeys. Removing the

59
stimuli decreased rates and disrupted the pattern of responding. When

new stimuli were presented at the completion of the FR components

but never in association with the terminal ratio when drug was injected,

response rate also declined. Therefore, it is not the presentation of a

stimulus per se that maintains responding in these second-order schedules

but rather the response-contingent presentation of a stimulus associated

with the drug delivery. However, although Katz (1979) also showed that

the substitution of unpaired stimuli decreased responding, the magnitude

of the decrease was not so great as when stimuli were totally absent.

The fact that both the drug and the stimuli are determinants of the

rate of responding may explain the results when dose is manipulated

with this schedule. Although there is some tendency for rate to increase

with increases in dose, in general, dose-response functions are flat

relative to those generated by other schedules. Therefore, the strength

of cocaine’s ability to control responding does not seem to change with

its magnitude (dose) under second-order schedules. On the other hand,

since rates are often high under such schedules, there are limits to the

possible increases.

Two related procedures or schedules that have been used to compare

different doses of cocaine in the absence of any confounding influence

are concurrent schedules and preference procedures. In these procedures

responding on different levers is maintained by different doses and the

primary dependent variable is the relative frequency of occurrence of

the alternative responses. These procedures have also been used with

other reinforcers such as food and intracranial stimulation and have

been found to be sensitive to differences in reinforcer magnitude.

With concurrent schedules, responding is maintained by two or more

simultaneously operating schedules. In a study by Iglauer and Woods

(1974), responding was maintained in rhesus monkeys under a concurrent

two-lever VI schedule of cocaine injections with a 5-min time-out

following each injection. In this study, relative reinforcing efficacy was

evaluated by comparing relative response frequencies on the two levers.

A standard dose of cocaine (0.05 or 0.1 mg/kg) was available under a

variable interval 1-min schedule on one of two levers: the dose available

under an identical schedule on the second lever (variable-dose lever)

was varied to include both higher and lower doses of cocaine (0.013 to

0.8 mg/kg). The proportion of responses occurring on the variable-dose

lever increased as the dose available on that lever increased; in all

cases, the larger of the two doses presented for comparison was

preferred.

Another method designed to compare reinforcing properties involves the

use of discrete choice trials. In a study by Johanson and Schuster

(1975), rhesus monkeys were given an opportunity to choose between

two drug solutions, and injections were followed by a l5-min time-out

period. The number of trials during which one option rather than the

other one was selected was counted and used as the measure of

reinforcing efficacy. As in the Iglauer and Woods (1974) study, higher

doses of cocaine were preferred to lower doses. Similar results have

been found by Brady and Griffiths in baboons (1977).

60
From this review two overall conclusions can be stressed. First of all,

cocaine self-administration occurs under a variety of experimental

situations and is not restricted to a narrow range of conditions.

Unfortunately it is impossible in the absence of direct comparisons to

conclude that the strength of cocaine’s reinforcing properties is unique

to cocaine. However, the ubiquitous use of cocaine in experimental

studies reflects not only an interest in this drug but as well the ease

of conditioning animals to self-administer it so that other variables can

then be studied. The second point is that the pattern of cocaine selfadministration and the circumstances under which it occurs are similar

to behavior controlled by nondrug reinforcers, such as food and water.

Although the direct or nonspecific actions of drugs can markedly affect

absolute rates of drug-maintained responding, by manipulating schedule

parameter values or using nonrate measures, dose-response functions

indicate that response strength increases with dose. Of particular

importance is the demonstration that persistent and excessive drugseeking behavior is determined by an interaction between the drug’s

schedule of presentation and its specific pharmacological properties.

This means that our general knowledge of how behavior is controlled

may be useful in understanding the mechanisms of cocaine selfadministration.

TOXICITY

Regardless of the nature of a drug’s reinforcing properties and predicted

dependence potential, there would be little public concern or action if

the use of cocaine at the levels determined by the organism did not

lead to toxicity. Deleterious consequences resulting from the drug selfadministration of any drug can range from death to subtle changes in

the ability of the person to cope with environmental demands. Any

drug can cause serious damage if given in excessive doses over extended

times, so the assessment of toxicity must include judgments of relative

risks. Clearly, in the case of recreational drugs where there is not

therapeutic justification, the safest option is to use no drug.

Despite the importance of toxicity studies, there have been only a few

studies in which the toxic consequences of cocaine self-administration

have been systematically evaluated (Deneau et al. 1969). Most of the

studies reviewed in the previous section examined cocaine selfadministration under conditions of limited access. Under these conditions

intake is remarkably well regulated and signs of drug toxicity are seldom

seen even when drug availability continues on a daily basis for years.

However, these conditions of access are determined by the experimenter,

not the organism. In contrast, in a study by Johanson et al. (1976),

access to drug was not limited; regulation disappeared and extreme and

somewhat unexpected toxicity was produced. More specifically, naive

untrained rhesus monkeys were exposed to continuous around-the-clock

access to one of a variety of psychomotor stimulant drugs in order to

simulate conditions of availability in humans. In addition to measuring

drug intake, food intake was monitored and behavioral observations were

made. For two monkeys, each lever press resulted in the infusion of

0.2 mg/kg cocaine. Both monkeys began taking drug the very first day

of its availablity and the number of infusions self-administered per day

ranged from 100 to 500 (a total of 20 to 100 mg/kg). However, both

6 1
monkeys died following convulsions after 3 to 5 days of access. Food

intake was almost totally suppressed during this period and behavioral

changes including restlessness, stereotypic movements, dysmetria,

tremors, mydriasis, piloerection, and ataxia were observed. Similar

results were also noted with amphetamine and related drugs. Although

there were indications that some amphetamine-like drugs had less toxicity

than cocaine, the number of monkeys tested was too small to verify

this conclusion. Furthermore, in a similar study by Downs et al. (1979),

the authors claim that the toxicity of cocaine in amphetamineexperienced monkeys was not as great (2 of 3 died) and was less than

that of methylphenidate (3 of 4 died). Unfortunately, except for weight

loss, the condition of the surviving monkey on cocaine was not described,

but its drug intake was low relative to the other monkeys. Taken as

a whole, despite minor differences, these studies would indicate that

under conditions where there are no outside restraints on drug

availability, animals can suddenly increase their drug-taking behavior to

the point of severe toxicity. In contrast, the intake of cocaine under

other conditions (i.e., limited access) is surprisingly regulated. These

differences may very well have implications for resolving the argument

between those who claim that cocaine is a safe recreational drug and

those who describe cases where users appear to “lose control” of their

drug taking. Some people may regulate their cocaine use either by

limiting their access or by a variety of other means and, like monkeys

maintained on cocaine for years, remain healthy. Others, however, for

reasons we do not understand, are described by clinicians as losing

control. The toxicity which is then produced can be extreme.

OTHER FACTORS CONTRIBUTING TO DEPENDENCE POTENTIAL

Factors which contribute to the loss of regulation in an individual could

either be internal (e.g., personality) or external. Although we may not

understand all these factors, two lines of experimental evidence give us

some clues. The first is that the reinforcing properties of cocaine,

despite qualitative similarity to other reinforcers, are relatively powerful.

The second is that some of the acute effects of cocaine in improving

performance are seductive. That this indirect effect may wane with

time and increased dose is not always appreciated.

In addition to the studies reviewed in the previous sections, there have

also been numerous studies designed to directly compare the strength

of the reinforcing properties of cocaine to other reinforcers, both drug

and nondrug. It is assumed that there is a direct relationship between

relative reinforcing properties and degree of dependence potential.

Therefore, if experimental studies demonstrate that the strength of

cocaine’s reinforcing properties is extreme, it may be concluded that

this property is one important factor contributing to its excessive illicit

use. While there is a good deal of evidence that would lead to this

conclusion, as will be described below, the assessment of relative

reinforcing properties is difficult and time-consuming and only a few

drugs have been evaluated. Many more studies would be required to

show that cocaine is a uniquely powerful reinforcer, relative to others,

particularly since it is unlikely that rankings are static. As emphasized

before, reinforcing properties are a result of a dynamic interaction

62
between the drug and the environmental contingencies, and this is no

less true when comparisons across reinforcers are made.

Two types of procedures have been used with animals to measure the

reinforcing strength or efficacy of different drugs. One procedure which

has been used extensively to compare drugs, including cocaine, is the

progressive ratio schedule. In this schedule, responding is maintained by

a drug under a ratio schedule. After responding is well established, the

number of responses required for each drug infusion is systematically

increased until responding declines to below some criterion, i.e., animals

at these high ratios no longer continue to respond in order to get the

drug. The ratio value which leads to this cessation in responding is

called the breaking point. Although responding is maintained under a

ratio schedule, the breaking point, not rate of responding, is used as

the index of reinforcing efficacy. It does not matter how long an animal

takes to complete the ratio (within limits) but simply whether or not it

is finished. Using this procedure, Yanagita (1973) demonstrated that

breaking point was a direct function of the dose of cocaine. At the

highest dose of 0.48 mg/kg, animals continued responding even when

6,400 to 12,800 responses had to be made for each drug infusion.

Cocaine’s breaking point was 2 to 16 times higher than that for

methamphetamine and amphetamine. Similar results were found by

Bedford et al. (1978). Griffiths et al. (1975, 1978) determined that the

breaking point for cocaine was higher than for other stimulant or

anorectic drugs including methylphenidate, diethylpropion,

chlorphentermine, and fenfluramine. However, secobarbital at the

highest dose tested showed reinforcing properties comparable to cocaine.

Studies using dogs have also demonstrated that cocaine sustains

responding at higher FR values than. d-amphetamine, mazindol,

fenfluramine (Risner and Silcox 1981), or nicotine (Risner and Goldberg

1983). It can be concluded from these studies that the reinforcing

strength of cocaine is high.

Similar results have been found using a choice procedure (Johanson and

Schuster 1975). In this procedure, described in a previous section, the

number of trials during which one option rather than the other one is

selected is used as the measure of reinforcing efficacy in much the

same way as breaking point is used in the progressive ratio procedures.

Similarly, this index is independent of rate of responding. It was found,

as might be expected, that higher doses of cocaine were preferred to

lower ones. In addition, while preference between cocaine and

methylphenidate was dose dependent (Johanson and Schuster 1975),

cocaine was generally preferred over diethylpropion (Johanson and

Schuster 1977) and procaine (Johanson and Aigner 1981). Interestingly,

in a choice procedure comparing cocaine to d,l-cathinone, these two

drugs had similar efficacy (Woolverton and Johanson 1984). Cathinone,

like cocaine, is the active alkaloid of a plant which is chewed

recreationally by inhabitants of Africa and the Middle East. In many

countries the chewing of the khat leaves has been a source of concern

for years. However, unlike coca leaves, khat leaves must be chewed

fresh, and the active alkaloid, cathinone, has only recently been isolated.

Given the similarities between cathinone and cocaine and the results of

63
Woolverton and Johanson (1984), we would predict that cathinone, if it

became available, would also be extensively abused.

In addition to comparisons between cocaine and other drugs, there have

also been choice studies utilizing alternative nondrug reinforcers. For

instance, monkeys preferred even low doses of cocaine to the opportunity

to have visual contact with other monkeys (Woolverton, personal

communication). Even more compelling, monkeys given a choice between

food and cocaine preferred the latter and without experimenter

intervention might have starved (Aigner and Balster 1978). Although

clearly far more studies of this type are necessary, their implications

are profound. Cocaine may be such a powerful reinforcer that the

survival of the organism is threatened and therapeutic interventions

designed to develop alternative life-styles (i.e., reinforcers) will have

difficulty succeeding.

An alternative approach to assessing the strength of a reinforcer is to

determine its resistance to the effects of punishment. The effects of

punishment on behavior controlled by a variety of events other than

drugs have been studied extensively. Punishment is a process of reducing

the probability of a response as a consequence of: (1) the presentation of

a stimulus or (2) the removal of a stimulus contingent on the response.

In animal studies, the most frequently used punishing stimuli have been

electric shock delivery and time-out from positive reinforcement. The

degree of response suppression is dependent upon the intensity of the

punishing event and its schedule of presentation, as well as the time

delay between response and consequence. All else being equal, it could

be assumed that the greater the difficulty in decreasing the selfadministration of a particular drug, the greater is its reinforcing strength.

The effects of punishment of cocaine self-administration have been

demonstrated in several studies. Grove and Schuster (1974) examined

the ability of punishment to suppress responding maintained by cocaine

injections in monkeys under a FR 1 schedule during daily 3-hr sessions.

Punishment was accomplished by delivering a brief electric shock ranging

from 1 to 8 mA at the onset of each injection. Responding maintained

by both 0.1 and 0.2 mg/kg cocaine decreased as a function of the

intensity of the shock. However, the degree of suppression expressed as

a percent of control rates was the same for the two doses. That is,

increasing the magnitude of reinforcement did not seem to attenuate

the effects of punishment as might be expected if one assumes that

higher doses of cocaine have greater reinforcing efficacy. This finding,

however, is difficult to interpret because the baseline rates of responding

maintained by the different doses of cocaine were not the same. Because

responding was maintained under a ratio schedule, the rates maintained

by the higher dose were lower.

In a study by Bergman and Johanson (1981), responding was maintained

in rhesus monkeys by 0.1 mg/kg cocaine under a FR 10 schedule. During

single test sessions, the onset of each infusion was accompanied by the

delivery of electric shock. At intermediate intensity levels, the shock

initially reduced, but did not eliminate, cocaine-maintained responding.

Although test sessions with electric shock were separated by at least

64
three nonpunished sessions, adaptation to the suppressant effects of the

shock occurred within five punishment test sessions for all monkeys.

On the other hand, adaptation did not occur with higher intensity levels

that had produced complete response suppression. This may imply that

for punishment to be effective, it must be severe enough to initially

eliminate all drug-taking behavior. It may also imply that cocaine selfadministration is difficult to punish.

Further evidence of this is also shown in a study by Johanson (1977)

using the discrete trial choice procedure previously described. Rhesus

monkeys were given a choice between two alternatives of intravenous

cocaine. These alternatives were initially equal in dose, but in subsequent

comparisons they differed in magnitude. Electric shock was delivered

at the onset of the delivery of one of the alternatives. When the two

doses were equal, the nonshocked alternative was chosen. For some

animals, the shocked alternative was preferred even when the dose of

this alternative was only twice as high. Other animals continued to

select the nonshocked alternative. However, as the dose of the shocked

alternative further increased, all animals preferred the higher dose. It

seems, therefore, that the effects of punishment can be overcome by

increasing magnitude of reinforcement, and for some animals the

necessary difference may be small.

The studies on the effects of punishment on cocaine self-administration

lead to the conclusion that cocaine has strong and robust reinforcing

properties. Unfortunately, comparable studies have not been done with

other drugs so it is impossible to make any statements about relative

strength in this context. While comparisons across drugs within the

same class may be useful in the assessment of relative dependence

potential, comparisons across drug classes may be difficult to interpret.

This is because some drugs, delivered noncontingently, have differential

effects on behavior that has been suppressed by punishment. For

instance, certain drugs such as the barbiturates attenuate the suppressant

effects of punishment, whereas other drugs such as the amphetamines

generally do not. It would be interesting to determine whether these

differential effects generalize to a situation where the drugs themselves

also function as reinforcers. One might predict that under similar

conditions, responding maintained by a barbiturate would be more

difficult to suppress with punishment than responding maintained by

cocaine.

Another demonstation that cocaine possesses strong positive reinforcing

properties emerges from studies of conditioned taste aversions. If certain

consequences (e.g., lithium chloride-induced illness) occur following the

presentation of a novel fluid or food (e.g., saccharin solution) to an

animal, the animal on subsequent presentations consumes less of that

substance. This response has been termed conditioned taste aversion or

gustatory avoidance conditioning. Initially, it was believed that only

agents that induce illness could produce a gustatory avoidance response.

However, subsequent studies have demonstrated that the administration

of psychoactive substances including psychomotor stimulants can also

induce this type of avoidance response (Cappell and LeBlanc 1978). Just

as the valence of the reinforcing properties of electric shock can be

6 5
altered by environmental context (i.e., shock will maintain responding),

even drugs which are positive reinforcers can have aversive properties

under certain conditions (e.g., d-amphetamine). The effects of cocaine

in this paradigm have been inconsistent. Some investigators report a

weak efficacy (Booth et al. 1977; D’Mello et al. 1979; Goudie et al.

1978; Foltin et al. 1981; Foltin and Schuster 1982) while others report

that cocaine produces no avoidance responses (Cappell and LeBlanc 1978).

Although the reasons for the discrepancy are unclear, most investigators

would agree that cocaine is a weak agent, at best, in inducing a gustatory

avoidance response and its ability to do so is easily altered by minor

changes in procedure (Foltin and Schuster 1982). In contrast, other

drugs of abuse produce far greater aversions which are robust (Cappell

and LeBlanc 1978). It is conceivable that the inability to modulate the

positive reinforcing properties of cocaine may be another reason for its

extreme dependence potential.

The studies that have been reviewed to assess the dependence potential

of cocaine have evaluated the direct reinforcing properties of the drug.

But drugs may also have dependence potential because of their indirect

effects. For instance, if a drug improves performance necessary to the

well-being of a person, the desire to use the drug regardless of its other

effects may increase. A drug with both direct positive reinforcing

properties and indirect ones may have the greatest dependence potential

of all.

Since cocaine was first used experimentally, its ability to enhance

performance has been extolled (Freud 1884). There are many anecdotal

reports of enhancement, and the effects reported by cocaine users not

only include feelings of euphoria but also include claims of greater skills

across a variety of dimensions. Experimental evidence substantiating

these anecdotal claims is limited, but it does lend some support to the

hypothesis that “things go better with” cocaine. While many of these

studies are with humans (see Fischman, this volume), animal studies also

exist. In general, the effects of cocaine on operant performance are

similar to those of other psychomotor stimulants (Kelleher and Morse

1968). Regardless of the event maintaining responding the effects of

cocaine are rate-dependent, with low rates increased with low or

intermediate doses and high rates decreased in a dose-dependent manner

(Smith 1964; Spealman et al. 1977; Herling et al. 1979; Barrett 1976).

This is true even when the effects of cocaine are evaluated using a

self-administration paradigm (Spealman and Kelleher 1979). So although

high doses may eliminate responding, there are lower doses which at

least increase low-rate performance. Many other studies (e.g., Crow

1976; Schechel and Boff 1964; Torrelio and Izquierdo 1976) which have

claimed that cocaine specifically enhances performance can also be

interpreted within the context of rate dependency. Whether such

increases in rate of responding can be used as evidence of enhanced

performance is not clear. The use of other approaches not involving

rate measures has received little attention in the animal literature.

There is one report by Thompson (1977), however, showing that cocaine

can increase breaking point maintained by food in pigeons.

66
Although the notion that cocaine enhances performance is widespread,

particularly among users, it is clear that there is little experimental

evidence in animals supporting it. To a large extent this is due to the

fact that little research has been done in this area either in animals

or humans (see Fischman, this volume). Additional studies will be

required in this area to determine cocaine’s effects on many types of

performances, e.g., learning, motor, sensory, etc. Even if these studies

were to demonstrate that acutely administered cocaine can improve

performance, great care should be made in interpreting such findings.

The effects of cocaine will always be dependent on dose and are likely

to change with repeated exposure to the drug. Even if improved

performance can be demonstrated with acutely administered cocaine, a

deterioration in performance may be seen either with higher doses or

when drug is repeatedly administered. But findings that acutely

administered cocaine can have positive effects is important in

understanding why humans use cocaine. That these enhancing effects

may be transitory or dose-dependent does not negate their influence in

producing subsequent drug use.

REFERENCES

Aigner, T.G., and Balster, R.L. Choice behavior in rhesus monkeys:

Cocaine versus food. Science, 201:534-535, 1978.

Altshuler, H.L., and Phillips, P.E. Intragastric self-administration of

drugs by the primate. In: Ho, B.T., Richards, D.W., and Chute, D.L.,

eds, Drug Discrimination and State-Dependent Learning. New York:

Academic Press, 1978. pp. 263-280.

Balster, R.L., and Schuster, C.R. A comparison of d-amphetamine, 1-

amphetamine, and methamphetamine self-administration in rhesus

monkeys. Pharmac Biochem Behav, 1:67-71, 1973a.

Balster, R.L., and Schuster, C.R. Fixed-interval schedule of cocaine

reinforcement: Effect of dose and infusion duration. J Exper Anal

Behav, 20:119-129, 1973b.

Barrett, J.E. Effects of alcohol, chlordiazepoxide, cocaine and

pentobarbital on responding maintained under fixed-interval schedules

of food or shock presentation. J Pharmacol Exp Ther, 196:605-615,

1976.

Bedford, J.A.; Baily, L.P.; and Wilson, M.C. Cocaine reinforced

progressive ratio performance in the rhesus monkey. Pharmac Biochem

Behav, 9:631-638, 1978.

Bergman. J., and Johanson. C.E. The effects of electric shock on

responding maintained by cocaine in rhesus monkeys. Pharmac Biochem

Behav, 14:423-426, 1981.

Booth, D.A.; Pilcher, C.W.T.; D’Mello, G.D.; and Stolerman, I.P.

Comparative potencies of amphetamine, fenfluramine and related

compounds in taste aversion experiments in rats. Br J Pharmac, 61:

669-677, 1977.

Brady, J.V., and Griffiths, R.R. Drug-maintained performance and the

analysis of stimulant reinforcing effects. In: Ellinwood, E.H.. and

Kilbey, M.M., eds. Cocaine and Other Stimulants. New York: Plenum

Press, 1977, pp. 599-613

6 7
Cappell, H., and LeBlanc, A.E. Gustatory avoidance conditioning by

drugs of abuse. In: Milgram, N.W.; Krane, K.; and Alloway, T.M.,

eds. Food Aversion Learning. New York: Plenum Press, 1978.

Crow, T.J. Enhancement by cocaine of intra-cranial self-stimulation in

the rat. Life Sciences, 9:375-381, 1970.

Deneau, G.A.; Yanagita, T.; and Seevers, M.H. Self-administration of

psychoactive substances by the monkey: A measure of psychological

dependence. Psychopharmacologia (Berl.), 16:30-48, 1969.

D’Mello, G.D.; Goldberg, D.M.; Goldberg, S.R.; and Stolerman, I.P.

Conditioned taste aversion and operant behavior in rats: Effects of

cocaine and a cocaine analogue (WIN 35,428). Neuropharmacology,

18:1009-1010, 1979.

Downs, D.A.; Harrigan, S.E.; Wiley, J.N.; Robinson, T.E.; and Labay, R.J.

Continuous stimulant self-administration in rhesus monkeys. Res

Comm Psycho1 Psychiat Behav, 4:39-49, 1979.

Downs, D.A., and Woods, J.H. Codeine- and cocaine-reinforced

responding in rhesus monkeys: Effects of dose on response rates under

a fixed-ratio schedule. J Pharmacol Exp Ther, 191:179-188, 1974.

Ferster, C.B., and Skinner, B.F. Schedules of Reinforcement. New York:

Appleton-Century-Crofts, 1957.

Foltin, R.W., and Schuster, C.R. The effects of cocaine in a gustatory

avoidance paradigm: A procedural analysis. Pharmac Biochem Behav,

16:347-352, 1982.

Foltin, R.W.; Preston, K.L.; Wagner, G.C.; and Schuster, C.R. The

aversive stimulus properties of repeated infusions of cocaine.

Pharmacol Biochem Behav, 15:71-74, 1981.

Freud, S. Uber coca. Zentbl. Ther., 2:289-314, 1884.

Goldberg, S.R. Comparable behavior maintained under fixed-ratio and

second-order schedules of food presentation, cocaine injection, or damphetamine injection in the squirrel monkey. J Pharmacol Exp Ther

186:18-30, 1973.

Goldberg, S.R., and Kelleher, R.T. Behavior controlled by scheduled

injections of cocaine in squirrel and rhesus monkeys. J Exper Anal

Behav, 25:93-104, 1976.

Goldberg, S.R., and Kelleher, R.T. Reinforcement of behavior by cocaine

injections. In: Ellinwood, E.H., and Kilbey, M.M., eds. Cocaine and

Other Stimulants. New York: Plenum Press, 1977, pp. 523-544.

Goldberg, S.R.; Kelleher, R.T.; and Goldberg, D.M. Fixed-ratio

responding under second-order schedules of food presentation or

cocaine injection. J Pharmacol Exp Ther, 218:271-281, 1981.

Goldberg, S.R.; Kelleher, R.T.; and Morse, W.H. Second-order schedules

of drug injection. Fed Proc, 34:1771-1776, 1975.

Goldberg, S.R.; Morse, W.H.; and Goldberg, D.M. Behavior maintained

under a second-order schedule of intramuscular injection of morphine

or cocaine in rhesus monkeys. J Pharmacol Exp Ther, 199:278-286,

1976.

Goldberg, S.R.; Spealman, R.D.; and Kelleher, R.T. Enhancement of

drug-seeking behavior by environmental stimuli associated with cocaine

or morphine injections. Neuropharmacology 18:1015-1017, 1979.

Goudie, A.J.; Dickins, D.W.; and Thornton, E.W. Cocaine-induced

conditioned taste aversions in rats. Pharmac Biochem Behav, 8:757-

761, 1978.

68
Griffiths, R.R.; Findley, J.D.; Brady, J.V.; Dolan-Gutcher, K.; and

Robinson, W.W. Comparison of progressive-ratio performance

maintained by cocaine, methylphenidate, and secobarbital.

Psychopharmacologia, 43:81-83, 1975.

Griffiths, R.R.; Bigelow, G.E.; and Henningfield, J.E. Similarities in

animal and human drug taking behavior. In: Mello, N.K., ed. Advances

in Substance Abuse: Behavioral and Biological Research. Greenwich,

Conn: JAI Press, 1980, pp. 1-90,

Griffiths, R.R.; Brady, J.V.; and Snell, J.D. Progressive ratio

performance maintained by drug infusions: Comparison of cocaine,

diethylpropion, chlorphentermine and fenfluramine.

Psychopharmacology, 56:5-13, 1978.

Grove, R.N., and Schuster, C.R. Suppression of cocaine selfadministration by extinction and punishment. Pharmac Biochem Behav,

2:199-208, 1974.

Herling, S.; Downs, D.A.; and Woods, J.H. Cocaine, d-amphetamine, and

pentobarbital effects on responding maintained by food or cocaine in

rhesus monkeys. Psychopharmacology, 64:261-269, 1979.

Iglauer, C., and Woods, J.H. Concurrent performances: Reinforcement

by different doses of intraveous cocaine in rhesus monkeys. J Exper

Anal Behav, 22:179-196, 1974.

Johanson, C.E. The effects of electric shock on responding maintained

by cocaine injections in a choice procedure in the rhesus monkey.

Psychopharmacology, 53:277-282, 1977.

Johanson, C.E., and Aigner, T. Comparison of the reinforcing properties

of cocaine and procaine in rhesus monkeys. Pharmac Biochem Behav,

15:49-53, 1981.

Johanson, C.E., and Balster, R.L. A summary of the results of a drugself-administration study using substitution procedures in rhesus

monkeys. Bull Narc, 30:43-54, 1978.

Johanson, C.E. Balster, R.L.; and Bonese, K. Self-administration of

psychomotor stimulant drugs: The effects of unlimited access.

Pharmac Biochem Behav, 4:45-51, 1976.

Johanson, C.E. Schuster, C.R. .A choice procedure for drug

reinforcers: Cocaine and methylphenidate in the rhesus monkey. J

Pharmacol Exp Ther, 193:676-688, 1975.

Johanson, C.E., and Schuster, C.R. A comparison of cocaine and

diethylpropion under two different schedules of drug presentation. In:

Ellinwood, E., and Kilbey, M.M., eds. Cocaine and Other Stimulants.

New York: Plenum Press, 1977, pp. 545-570.

Johanson, C.E., and Schuster, C.R. Animal models of drug selfadministration. In: Mello, N.K., ed. Advances in Substance Abuse:

Behavioral and Biological Research. Vol. II. Greenwich, Conn: JAI

Press, 1981, pp. 219-297.

Katz, J.L. A comparison of responding maintained under second-order

schedules of intramuscular cocaine injection or food presentation in

squirrel monkeys. J Exper Anal Behav, 32:419-431, 1979.

Katz, J.L. Second-order schedules of intramuscular cocaine injection

in the squirrel monkey: Comparisons with food presentation and effects

of d-amphetamine and promazine. J Pharmacol Exp Ther, 212:405-

411, 1980.

Kelleher, R.T. Conditioned reinforcement in second-order schedules. J

Exper Anal Behav, 9:475-485, 1966.

69
Kelleher, R.T. Characteristics of behavior controlled by scheduled

injections of drugs. Pharmacol Rev, 27:307-323, 1975.

Kelleher, R.T., and Goldberg, S.R. Fixed-interval responding under

second-order schedules of food presentation or cocaine injection. J

Exper Anal Behav, 28:221-231, 1977.

Kelleher, R.T., and Morse, W.H. Determinants of the specificity of

behavioral effects of drug. Ergebnisse der Physiologie, 60:1-56, 1968.

Pickens. R., and Thompson, T. Cocaine-remforced behavior in rats:

Effects of reinforcement magnitude and fixed-ratio size. J Pharmacol

Exp Ther, 161:122-129, 1968.

Risner, M.E., and Goldberg, S.R. A comparison of nicotine and cocaine

self-administration in the dog: Fixed-ratio and progressive-ratio

schedule of intravenous drug infusion. J Pharmacol Exp Ther, 224:

319-326, 1983.

Risner, M.E., and Jones, B.E. Self-administration of CNS stimulants by

dog. Psychopharmacologia, 43:207-213, 1975.

Risner, M.E., and Silcox, D.L. Psychostimulant self-administration by

beagle dogs in a progressive-ratio paradigm. Psychopharmacology, 75:

25-30, 1981.

Scheckel, C.L., and Boff, E. Behavioral effects of interacting imipramine

and other drugs with d-amphetamine, cocaine, and tetrabenazine.

Psychopharmacologia, 5:198-208, 1964.

Schuster, C.R.; Renault, P.E.; and Blaine, J. An analysis of the

relationship of psychopathology to non-medical drug use. In: Pickens,

R., and Heston, L.L., eds. Psychiatric Factors in Drug Abuse. New

York: Grune and Stratton, 1979, pp. 1-19

Siegel, R.K.; Johnson, C.A.; Brewster, J.M.; and Jarvik, M.E. Cocaine

self-administration in monkeys by chewing and smoking. Pharmacol

Biochem Behav, 4:461-467, 1976.

Smith, C.B. Effects of d-amphetamine upon operant behavior of pigeons:

Enhancement by reserpine. J Pharmacol Exp Ther, 146:167-174, 1964.

Spealman, R.D.; Goldberg, S.R.; Kelleher, R.T.; Goldberg, D.M.; and

Charlton, J.P. Some effects of cocaine and two cocaine analogs on

schedule-controlled behavior of squirrel monkeys. J Pharmacol Exp

Ther, 202:500-509, 1977.

Spealman, R.D., and Kelleher, R.T. Behavioral effects of selfadministered cocaine: Responding maintained alternately by cocaine

and electric shock in squirrel monkeys. J Pharmacol Exp Ther, 210:

206-214, 1979.

Stretch, R. Discrete-trial control of cocaine self-injection behavior in

squirrel monkeys: Effects of morphine, naloxone, and chlorpromazine.

Canad J Physiol Pharmacol 55:778-790, 1977.

Thompson, D.M. Effects of cocaine and fenfluramine on progressiveratio performance. Pharmacol Biochem Behav, 7:555-558, 1977.

Thompson, T., and Unna, K., eds. Predicting Dependence Liability of

Stimulant and Depressant Drugs.

1977. 

Baltimore: University Park Press,

Torrelio, M., and Izquierdo, J.A. Pre-trial cocaine and performance in

rat. Psychopharmacologia, 45:283-285, 1976.

Weeks, J.R. Experimental morphine addiction: Method for automatic

intravenous injections in unrestrained rats. Science, 138:143-144, 1962.

70
Wilson, M.C., and Schuster, C.R. Interactions between atropine,

chlorpromazine and cocaine on food reinforced behavior. Pharmac

Biochem Behav, 3:363-375, 1975.

Wilson, M.C.; Hitomi, M.; and Schuster, C.R. Self-administration of

psycomotor stimulants as a function of unit dosage.

Psychopharmacologia (Berl.), 22:271-281, 1971.

Woods, J.H., and Schuster, C.R. Reinforcement properties of morphine,

cocaine, and SPA as a function of unit dose. Int J Addictions, 3:231-

237, 1968.

Woolverton, W.L., and Johanson, C.E. Preference in rhesus monkeys

given a choice between cocaine and d,l-cathinone. J Exp Anal Behav,

41:35-43, 1984.

Woolverton, W.L., and Schuster, C.R. Intragastric self-administration in

rhesus monkeys under limited access conditions: Methodological studies.

J Pharmacol Methods, 10:93-106, 1983.

Yanagita, T. An experimental framework for evaluation of dependence

liability in various types of drugs in monkeys. Bull Narc, 25:57-64,

1973.

Yanagita, T.; Deneau, G.A.; and Seevers, M.H. Evaluation of

pharmacologic agents in the monkev bv long-term intravenous selfor programmed administration. Excerpta Med Int Congr Ser, 87:453-

457. 1965.

Young, A.M., and Woods, J.H. Behavior maintained by intravenous

injection of codeine, cocaine, and etorphine in the rhesus macaque

and the pigtail macaque. Psychopharmacology, 70:263-271, 1980.

ACKNOWLEDGEMENTS

The preparation of this manuscript was supported by grant DA 00250

from the National Institute on Drug Abuse.

AUTHOR

Chris E. Johanson, Ph.D.

The University of Chicago

Department of Psychiatry

950 East 59th Street

Chicago, IL 60637

7 1
The Behavioral Pharmacology of

Cocaine in Humans

Marian W. Fischman

In 1977, in response to a perceived rise in the use of

cocaine in this country, the National Institute on Drug

Abuse presented an "...attempt to summarize our

admittedly limited knowledge of cocaine through a series

of reports by leading workers in the cocaine area"

(Petersen and Stillman 1977, p. 1). One of the chapters

in that monograph was entitled, "What are the Effects of

Cocaine in Man?" (Byck and Van Dyke 1977). The most

striking aspect of the response to that question was how

little was actually known at that time. In fact, fewer

than 10 laboratory studies investigating the effects of

cocaine in humans were listed in the bibliography.

Since then, the topic has received considerably more

attention in several laboratories, allowing a more

complete description of the behavioral pharmacology of

cocaine in humans.

This paper reviews the available laboratory data on the

behavioral and physiological effects of cocaine in

humans. Since cocaine is self-administered via a number

of different routes, wherever possible the effects of

using this drug orally, intranasally, intravenously, and

by smoking are described. A major theme in the selfreports of cocaine users is the insistence that they can

do anything better under the influence of cocaine. The

currently available data, reviewed in this paper, do not

support this idea. In addition, since cocaine and

amphetamine have very similar profiles of action, it is

appropriate to use the laboratory data on amphetamine's

effects to predict cocaine's effects. These, too, would

not lead us to believe that cocaine is a good

performance-enhancer. We would also predict that

cocaine would have toxic and disruptive effects similar

to those seen with amphetamine. Thus, the existence of

a cocaine psychosis after repeated cocaine use is

predictable on the basis of empirical laboratory

evidence showing the development of an amphetamine

psychosis after continuous amphetamine administration

(Griffith et al. 1972). Although questions about the

consequences of repeated cocaine use still remain, the

72
research reviewed here has provided the foundation on

which these studies can be built.

ROUTES OF COCAINE ADMINISTRATION

Oral

Coca leaves have been harvested and chewed for more than

3000 years (Carroll 1977) by the Indians living in the

area of the Andes Mountains in South America. They chew

a combination of coca leaves and an alkaline substance

to release the cocaine from the leaves. Paly et al.

(1980a) measured plasma levels of cocaine in Peruvian

Indians who were allowed to chew measured amounts of

coca leaves under controlled laboratory conditions.

Plasma levels reaching 95 ng/mg peaked shortly after

cessation of chewing, and the levels achieved appeared

to be related to the amount of cocaine in the chewed

leaves. Despite elevated plasma levels, little "high"

was reported in these chewers (Byck et al. 1980),

perhaps due to the slow change in cocaine blood level.

It was suggested that absorption occurred through the

mucous membrane of the mouth as well as through the

lower gastrointestinal tract since saliva containing the

coca juice was swallowed as chewing continued. The

correlation between dose and plasma level was also found

by Holmstedt et al. (1978), who reported that the

stimulating or energizing effect of the coca seemed to

be well correlated with the rising concentrations of

cocaine in the blood.

The most complete series of studies with oral cocaine

was carried out by Sigmund Freud in the late 188Os, who

described in some detail the results of his selfexperimentation with pure cocaine. He described the

onset of action as occurring within 10-20 minutes, with

a stimulant effect which lasted for as long as 4-5

hours. Little has been added to his enthusiastic

description of the stimulant and euphorigenic qualities

of oral cocaine. Some of the other effects he

hypothesized, however, such as its substitution for

morphine, have not withstood the tests of time or

further experimentation.

In an attempt to eliminate buccal absorption and

determine whether or not cocaine was inactivated in the

gastrointestinal tract, Van Dyke et al. (1978)

administered cocaine-filled gelatin capsules. Under

these conditions, peak plasma concentrations were

reached at approximately 65 minutes after ingestion

(Wilkinson et al. 1980) and dissipated about as rapidly

as after intravenous administration.

73
Intravenous

Cocaine was first isolated from coca leaves in 1860

(Mortimer 1901), and, once available in a pure and

considerably less cumbersome form, it was inevitable

that it would be used by other routes of administration.

The intravenous (i.v.) route of administration has

remained a popular one with "serious," and perhaps more

experienced drug users , since the drug goes rapidly to

the brain; and subjective effects, including an intense

"rush," are reported within 1 or 2 minutes (Resnick et

al. 1977; Javaid et al. 1978). Estimates of dose made

by laboratory subjects suggest that the average dose of

cocaine injected intravenously by users in a

recreational setting is approximately 16 mg/injection

(Fischman et al. 1976). Cocaine plasma levels are

correlated with dose of intravenous cocaine (Barnett et

al. 1981; Javaid et al. 1983), and plasma levels of

approximately 300 ng/ml have been recorded after single

32 mg doses (Javaid et al. 1978). It appears that the

elimination half-life of cocaine by this route is

approximately 40 minutes (Kogan et al. 1977; Javaid et

al. 1983) although it has been suggested that this value

is dose-related, increasing at very high doses (Barnett

et al. 1981).

Intranasal

The most common nonmedical method of cocaine selfadministration is "snorting," or inhaling. The

crystalline substance is inhaled in its hydrochloride

form, and is then absorbed through the nasal mucous

membranes. A "line" of powder (20-30mg) is laid out and

inhaled, and the user experiences approximately 20-40

minutes of stimulation, although no initial "rush."

Repeated intranasal use of cocaine has potentially

adverse physical consequences, including chronic

rhinitis and, rarely, a perforated nasal septum. Peak

plasma levels after intranasal crystalline cocaine occur

at 30-40 minutes subsequent to inhalation (Javaid et al.

1978; Wilkinson et al. 1980) and not until 60 minutes

after intranasal administration of the drug via cotton

soaked with cocaine solution (Van Dyck et al. 1976).

Peak plasma levels of 150-200 ng/ml are obtained after

inhalation of 96 mg crystalline cocaine (Javaid et al.

1978). The half-life for intranasal cocaine

administered as a powder or a 10% topically applied

solution is approximately the same as after intravenous

administration (Wilkinson et al. 1980; Javaid et al.

1983).

Smoked

The smoking of coca paste has been reported to be

widespread in Peru, Ecuador, Colombia, and Bolivia (Jeri

et al. 1980). The coca paste, containing solvents, is

7 4
mixed with tobacco or marijuana and smoked. Subjects

tested in a research setting and allowed to smoke

controlled amounts of coca paste on tobacco cigarettes

showed peak plasma levels as high as 975 ng/ml within 5-

10 minutes after smoking 0.5 g paste (Paly et al.

1980b). Plasma half life of cocaine was similar to that

after other routes of administration. In subjects

allowed to smoke ad libitum for 90 minutes, blood levels

were fairly constant and similar during a second 90-

minute session (Paly et al. 1982), indicating excellent

dose regulation.

A more efficient method of self-administering cocaine

via the smoking route has emerged in recent years.

Cocaine is taken as the water-soluble hydrochloride when

self-administered orally, intravenously, and

intranasally. However, cocaine hydrochloride decomposes

at the high temperatures necessary for smoking. Cocaine

"free base," in which the cocaine alkaloid is "freed"

from the hydrochloride salt (see Siegel 1982 for a

review of this), has a melting point of 98°C and is

volatile at temperatures above 90° , therefore providing

an active drug for smoking. Extraction kits for

converting the hydrochloride to the base are

commercially available. Perez-Reyes et al. (1982)

allowed subjects to smoke 50 mg cocaine free base and

determined that no more than 32% could have been

inhaled. Users interviewed by Siegel (1982) indicated

that they generally began with approximately 81 mg of

the base, and increased the amount of each "hit" to as

high as 252 mg with the development of tolerance.

Although no pharmacokinetic or blood level studies have

been published, Siegel (1982) has reported that chronic

cocaine free base smokers have shown plasma levels of

800-900 ng/ml 3 hours after smoking.

PHYSIOLOGICAL EFFECTS

The primary physiological parameters measured after

cocaine administration have been cardiovascular

functions. When administered intravenously in doses

ranging from 8-32 mg, cocaine, like amphetamine,

produces a dose-related increase in heart rate and blood

pressure which begins 2-5 minutes after injection and

peaks approximately 6-8 minutes later regardless of dose

(Fischman et al. 1976; Resnick et al. 1977). These

effects appear to parallel plasma levels, peaking early

and showing decreases over the first 30 minutes after

injection (Javaid et al. 1978). Cocaine has not been

shown to have any effect on the electrocardiogram in

i.v. doses of 4-32 mg (Fischman et al. 1976) nor, in

doses of 10 and 25 mg, on respiratory rate and body

temperature (Resnick et al. 1977). Intranasal cocaine

administered in crystalline or in solution form has

similar effects excepting that onset is delayed. Peak

effects occur approximately 30 minutes after drug

75
administration (Resnick et al. 1977; Javaid et al.

1978), and the cardiovascular changes dissipate within

the next 30 minutes, while blood levels are still

elevated. Oral doses of 30-200 mg/day given in divided

doses do not affect pulse, temperature, blood pressure,

or respiration (Post et al. 1974b). These oral doses

did, however, have a suppressive effect on both rapid

eye movement (REM) sleep and total sleep. The effect of

cocaine on REM sleep appears to be dose-related although

this could be an artifact of the number of days of use

as the drug was administered daily for 6 days in an

ascending series. Cocaine’s effects on sleep parallel

those seen after amphetamine (e.g., Rechtschaffen and

Maron 1964), an indication of the similarity of action

of these drugs.

SUBJECTIVE EFFECTS

Cocaine’s mood elevating properties were first described

almost 100 years ago (Freud, in Donoghue and Hillman

1963), and the drug still retains its reputation as the

euphoriant of choice among stimulant users. Experienced

drug users, however, often cannot differentiate among

cocaine, amphetamine, methamphetamine, and

methylphenidate (Martin et al. 1970; Fischman et al.

1976), all of which appear to have similar profiles of

action.

A consistent profile of cocaine’s effects generally

emerges when normal volunteers are administered the drug

and answer standard drug effects questionnaires. When

the Profile of Mood States (POMS), a five-point

adjective checklist, was administered after intravenous

cocaine, generally dose-related increases in a number of

scale scores were obtained. These were: Confusion,

Anxiety, Friendliness, Vigor, Elation, Arousal, and

Positive Mood (Fischman et al. 1983a; 1983b). Scores on

selected scales of the Addiction Research Center

Inventory (ARCI), a true-false test measuring drug

effects, have also consistently reflected the stimulant

properties of cocaine. Increases, generally doserelated, were found in scores on the amphetamine (A)

scale (Fischman et al. 1976; Resnick et al. 1977) as

well as the morphine-benzedrine general scale (MBG,

thought to be a measure of a drug’s euphoric effects)

and benzedrine general (BG) scale. Decreases were found

on the pentobarbital-chlorpromazine-alcohol general

(PCAG) scale which measures sedative effects (Fischman

et al. 1976; 1983a; 1983b). Cocaine also resulted in

increased scores on scales of “pleasantness” (Resnick

et al. 1977), “high” (Fischman et al. 1983a; 1983b;

Resnick et al. 1977), and “stimulated” (Fischman et al.

1983a; 1983b) as well as decreased scores on ratings of

“hunger” (Resnick et al. 1977). Subjects who had

substantial histories of i.v. cocaine use generally

rated 16 mg i.v. cocaine as similar to the average dose

76
that they were self-injecting outside of the laboratory,

and 24, 32, and 48 mg all as among the highest doses

they had ever experienced (Fischman et al. 1976; 1983a;

1983b). The "high" obtained from i.v. cocaine began as

an intense "rush," peaked approximately 3-5 minutes

after injection, and was dissipated within 30-40

minutes, when subjects indicated that they would like

another dose of drug (Javaid et al. 1978).

Subjects' reports of cocaine's effects after intranasal

administration were quite similar to those after

intravenous administration but less intense, slower in

onset and without the initial "rush." Doses of 25-100

mg were followed by increases in "high" (Resnick et al.

1977; Van Dyke et al. 1979) and "pleasantness" (Resnick

et al. 1977) scale scores, as well as the A (Resnick et

al. 1977; Fischman and Schuster 1980) and MBG (Fischman

and Schuster 1980) scales of the ARCI. Doses as high as

96 mg did not affect scores on any of the scales of the

POMS. When cocaine was administered as a solution, peak

"high" ratings occurred within 5-15 minutes and returned

to baseline values between 2 and 4 hours after drug

administration (Van Dyke et al. 1979). When the white

powder was inhaled, subjects reported that their maximum

"high" occurred 15-20 minutes after inhalation (Resnick

et al. 1977; Javaid et al. 1978) and returned to

baseline levels within 60-90 minutes (Javaid et al.

1978).

Cocaine given by the oral route appears to be effective

in producing an increase in "high" ratings (Van Dyke et

al. 1978). Subjects swallowed a gelatin capsule

containing 2 mg/kg cocaine, and reported a "high" which

peaked at 75 minutes and was dissipated approximately

three hours after swallowing the drug. This

effectiveness of cocaine via the oral route is expected

in view of the reported use patterns of the Andean

Indians since ancient times. Interestingly, until

recently textbooks of pharmacology have stated that

cocaine is rapidly hydrolyzed, and thereby rendered

ineffective in the gastrointestinal tract (e.g., Ritchie

and Cohen 1975). Clearly this is not so, although the

delay in effect might indicate that the drug is not well

absorbed until it reaches the small intestine.

When cocaine is smoked as the base, 37 mg of smoked base

and 20 mg of i.v. cocainehave approximately comparable

effects (Perez-Reyes et al. 1982) as measured by peak

scores and duration of effect on the POMS. ARCI and

"high" scales. Smoking caused significantly greater

effects on the Vigor scale of the POMS and the

"pleasantness" score. Degree of self-reported craving

for another dose of cocaine at 30 minutes was greater

after smoking the drug as compared with taking it

intravenously.

77
The apparent acute stimulant and euphoriant properties

of cocaine led to examination of its potential as an

antidepressant in a group of depressed patients (Post et

al. 1974). Oral doses ranging from 5 mg/day to 100

mg/day had no consistent effects on mood of the

depressed patients studied. Intravenous doses of 2.5-25

mg often were effective in causing mood change, with

doses associated with marked physiological effects

usually resulting in intense mobilization of affect and

tearfulness. Milder changes in vital signs were usually

accompanied by more positive affective changes. Resnick

et al. (1977) reported that one subject who received 25

mg i.v. cocaine showed marked crying in response to the

drug. However, this subject had reported feeling

depressed at the start of the experimental session. It

thus seems that not all of cocaine's effects have been

described as euphoria-producing. The baseline affective

state of the subject may well play a role in the effect

of cocaine on observed mood and verbal report of its

effect.

Resnick et al. (1977) reported a biphasic response to

cocaine beginning with a stimulant effect followed 30-60

minutes after drug by a "crashing" effect,

"characterized by feelings of anxiety, depression,

fatigue, and wanting more cocaine." This cocaine

"crash" has been described by "street" users, but with

the exception of Resnick et al. (1977) generally has not

been described in laboratory studies. Fischman and

Schuster (1980) reported that between 4 and 8 hours

after intranasal self-administration of 96 mg, scores on

the PCAG scale (a sedative scale) of the ARCI were

substantially elevated and a composite stimulant score

(A + MBG + BG) was substantially lower than after

inhalation of placebo. This is somewhat longer than

might be expected for a "crash" effect based on the data

from) Resnick's laboratory.

TOLERANCE

There is anecdotal evidence that cocaine users can

increase their intake of cocaine to levels that might be

lethal to the cocaine-naive user. Although no long-term

repeated dose studies have been carried out with cocaine

in humans, Fischman et al. (in press) have demonstrated

the development of an acute tolerance to the

cardiovascular and subjective effects of intravenous

cocainewhen it is given 1 hour after a 96 mg intranasal

pretreatment as compared with the effects of the same

intravenous dose given after a placebo intranasal

pretreatment. In addition, when research subjects were

allowed to self-administer 16 or 32 mg cocaine

intravenously every 6-10 minutes for an hour, the

initial injections of drug exerted maximal

cardiovascular and subjective effects, with subsequent

repeated injections within an hour having smaller

78
effects (Fischman and Schuster 1982). This apparent

tachyphylaxis does not appear to be dispositional

because blood levels rose at a rate consistent with the

dose being administered repeatedly.

EFFECTS ON LEARNING

Most research on drug-behavior interactions has

concentrated on studying the effects of drugs on

previously learned tasks (i.e., on performance rather

than on acquisition). However, behavior in transition

might be more sensitive to a drug’s effects than a well

learned response would be. Fischman (1978) described a

procedure adapted from the animal laboratory (Boren

1967; Thompson and Moersbacher 1979) for repeatedly

measuring acquisition of behavior in individual research

subjects.

Volunteer research subjects, working for points which

could be exchanged for money, were required to learn a

fixed sequence of 10 responses on 3 response keys. The

sequence of 10 correct responses was changed for each

10-minute session. Within 10 sessions subjects showed

stable acquisition curves from session to session as

indicated by consistent within-session response rates

and numbers of errors. This behavioral baseline on the

repeated acquisition task was used to assess the effects

of intravenous and intranasal cocaine. Seven subjects

were tested with two determinations at each dose of drug

(administered according to a modified Latin square

design). Repeated acquisition tests were given predrug, in conjunction with drug administration, and 20

and 35 minutes after drug administration. Four

different repeated acquisition tasks were thus studied

within a 1-hour experimental session.

Response rate was generally unaffected by cocaine

regardless of the dose administered (figure 1). The

number of errors per 10-minute session, however,

increased in a dose-related fashion following both

intranasal and intravenous administration of cocaine and

was highest after 32 mg intravenous cocaine, the largest

i.v. dose administered. Verbal reports of cocaine’s

effects correlated with its other behavioral effects and

with peak plasma level. Scores on both the POMS and the

ARCI showed changes similar to those seen after

administration of cocaine in other experimental

situations (e.g., Fischman and Schuster 1980). Thus,

both learning and verbal report of drug effect were

maximally affected by intravenous cocaine immediately

after injection, and by intranasal cocaine 20 minutes

after inhalation. These data suggest that, at

sufficient doses, cocaine interferes with tasks

involving the acquisition of new behavior patterns, the

first time that a cocaine-induced disruption in an

operant task in humans has been demonstrated. This is

79
Figure 1. Effects of cocaine on learning new behavior

patterns. Data collected during each pre-drug

repeated acquisition task were averaged across

subjects; the mean (± SEM indicated by broken

horizontal lines) is used as the baseline score.

Change from baseline is shown for number of errors and

response rate during each of the three 10-minute postdrug tests. Cocaine was inhaled at doses of 4, 64,

and 96 mg, and 32 mg was injected intravenously. S

indicates an intravenous saline injection.

80
important since cocaine clearly has central nervous

system effects as evidenced by the verbal reports of

subjects describing its mood-altering effects. Despite

such reliable effects on verbal report, it has been

difficult to show other behavioral effects of this drug

when it is administered in single doses in the dose

range taken for recreational purposes.

EFFECTS ON PERFORMANCE

It has been suggested that the Andean Indians chew coca

because it reduces hunger, produces a sensation of

warmth, and enhances working ability (Hanna 1971). In

fact, interviews with Indian coca-chewers yielded

statements reflecting the belief that chewing enabled

them to work harder: "Yes, I chew; I work hard.”

(Negrete and Murphy 1967, p. 14) In an initial study of

the response of coca chewers to exercise (Hanna 1970) it

was found that chewers, as compared to non-chewers,

showed a lower exercise and recovery heart rate after

using a bicycle ergometer, suggesting a slight advantage

for the chewers. However, a more careful examination of

the control group data indicated that the two groups

were not well matched, and a second study using a

bicycle ergometer and comparing matched groups of cocachewers and non-chewers found no differences between the

two groups in energy expenditure or efficiency over a

range of work levels. Thus, the belief that coca use

makes work easier was not supported.

There have been a number of suggestions that long-term

regular ingestion of cocaine through the chewing of coca

leaves causes deficits in such behaviors as attention,

speed of responding, accuracy on tests, etc. (Cagliotti

1980; Zapata-Ortiz 1970). In an effort to investigate

possible performance deficits of long-term coca chewers,

Negrete and Murphy (1967) compared their performance to

performance by a group of non-chewers using a battery of

“intelligence” tests, auditory and visual memory tests,

and attention tests. In general, controls scored better

than chewers, although the differences were not

substantial. A causal relationship between coca chewing

and lower test scores was not demonstrated, and the

results could have been due to variables other than coca

chewing since groups were not well matched and testing

was not blind. Further, the differences in test scores

between the two groups was not reflected in their

general social functioning or work behavior.

Cocaine users, as with coca chewers, frequently report

that the drug enhances performance, but, with few

exceptions this effect has never been investigated

experimentally. Freud's self-experimentation led him to

conclude that cocaine enhanced physical and mental

capacity and restored the fatigued person to maximal

alertness (in Donoghue and Hillman 1963). Resnick et al.

81
(1980), however, reported that neither 10 nor 25 mg

cocaine administered intravenously or intranasally had

an effect on hand-grip strength. Inhalation of 96 mg

cocaine also had no effect on performance of a reaction

time task in rested subjects (Fischman and Schuster

1980). However, when subjects were deprived of sleep

for 24-48 hours, which resulted in a fatigue-induced

decrement in performance, inhalation of 96 mg cocaine

reversed (after 24 hours) or partially reversed (after

48 hours) the decrement. Freud also indicated that his

cocaine-induced increase in physical capacity as

measured by performance on a dynamometer was greatest

when his condition was poor. No other research has been

carried out investigating the effects of cocaine on

performance in humans. Substantial data do exist,

however, indicating that, in general, the amphetamines

have minimal effects on performance in the non-sleepdeprived subject (see reviews by Weiss and Laties 1962;

Weiss 1968) but are generally successful in returning to

its pre-deprivation level performance which has

deteriorated due to fatigue (Kornetsky et al. 1959).

Laties and Weiss (1981) have recently pointed out,

however, that the small changes induced by amphetamines

can result in the one or two percent improvement which

can make the difference in a close athletic competition.

Such data are not available for cocaine, but its short

duration of action argues against the usefulness of such

an effect.

SELF-ADMINISTRATION

As indicated by another article in this monograph (see

Johanson), cocaine is a potent reinforcer, readily selfadministered by laboratory animals and often used as the

training drug for drug-naive animals. In addition,

reports of illicit cocaine use indicate substantial

increases during the past 5 to 10 years, both in the

drug-taking population as a whole and particularly in

young adults (Richards 1981). Cocaine-related emergency

room visits have also increased as indicated by the

DAWN1 survey data.

Only limited data are available describing cocaine selfadministration by humans under controlled laboratory

conditions (see Fischman and Schuster 1982). Subjects

given a choice between injections of i.v. cocaine or

saline approximately once every 6 minutes for 1 hour

consistently chose cocaine (16 or 32 mg). As with

laboratory animals, drug injections were fairly

regularly spaced and intravenous cocaine intake reached

224 mg, with plasma levels of approximately 1200 ng/ml.

This kind of regulation in intake was also seen with

subjects allowed to smoke cocaine paste during a 90-

minute limited access procedure (Paly et al. 1982).

Subjects self-administering i.v. cocaine indicated that

they felt high, stimulated, "weird; and anorexic for 2-3

82
hours after these sessions; several subjects indicated

that they had difficulty sleeping 8-14 hours later.

Cocaine, therefore, has been shown to serve as a

positive reinforcer in humans and can maintain drugtaking behavior under limited access conditions daily

for a two-week period.

SYNTHETIC LOCAL ANESTHETICS

Although the reinforcing properties of cocaine have been

documented in the laboratory for both human and nonhuman research subjects, it is only recently that other

local anesthetics have been similarly studied (Ford and

Balster 1977; Hammerbeck and Mitchell 1978; Woolverton

and Balster 1979; Johanson 1980). Drugs such as

procaine, chloroprocaine, and dimethocaine are selfadministered by rhesus monkeys, while lidocaine,

proparacaine, and procainamide do not appear to serve as

positive reinforcers in those animals. These data have

been puzzling, since, in general, drugs which serve as

reinforcers in animals do so in humans (Johanson and

Balster 1978), and it is assumed that this property is

an important factor in their dependence potential.

Despite these reports of local anesthetic selfadministration in non-humans, however, none of the drugs

mentioned above appear to be commonly abused by humans.

A traditional approach to the evaluation of a drug's

dependence potential is to compare its spectrum of

action to that of a known drug of abuse (Fischman 1977;

Jasinski 1977). Similarity to the prototype along

several dimensions is then used to predict possible

abuse liability. Two recently published studies have

investigated the cardiovascular and subjective effects

of synthetic local anesthetics using such an approach

(Fischman et al. 1983a, 1983b). In both studies

volunteer subjects were tested with a range of

intravenous doses of cocaine and matched intravenous

doses of either procaine or lidocaine. The effects of

the two local anesthetics on verbal report of drug

effect (as measured by the POMS, the ARCI, a series of

visual analog scales evaluating drug effects, and a drug

identification question), and measures of heart rate and

blood pressure were compared to the effects of cocaine

using the same measures.

In the preceding comparative studies, only cocaine had

significant effects on heart rate and blood pressure,

similar to those previously reported for this drug after

intravenous administration. When the effects of 16, 32,

and 48 mg cocaine on verbal report were compared with

those of placebo, there was a dose-related increase in

stimulant scale scores on the ARCI, POMS and Visual

Analog Rating Scales. In contrast, matched doses of

lidocaine or procaine did not produce any effects

different from placebo except on the "high" and

83
"stimulated" scales of the Visual Analog Scale. The

only measurable effect was a small but significant

increase in "high" and "stimulated" scores after 96 mg

procaine as compared with placebo. Subjects identified

both 48 and 96 mg procaine as cocaine and were accurate

in identifying saline as placebo and cocaine as cocaine.

All doses of lidocaine and 16 and 32 mg procaine were

identified as placebo.

There has, however, been one report of subjects giving

similar ratings of "high" to cocaine and lidocaine when

these two drugs were topically administered in solution

intranasally in matched doses of 0.19, 0.38 and 0.75

mg/kg (Van Dyck et al. 1979). However, statistical tests

were not applied to the data, making interpretation

difficult. It seems likely that the two lower doses of

cocaine were not discriminable from placebo. Although

cocaine plasma levels were not reported by Van Dyck et

al. in this study, levels after 1.5 mg/kg delivered by

the same route in another study resulted in peak plasma

levels of 130-165 ng/ml (Van Dyck et al. 1976).

Extrapolating from this dose, we would expect 0.75 mg/kg

to yield a peak plasma level of 65-80 ng/ml, with slow

onset, and the lower doses to yield correspondingly

lower plasma levels. Fischman et al. (unpublished) have

found that doses of inhaled crystalline cocaine yielding

peak plasma levels below 50-55 ng/ml do not appear to

produce a response of "high" in volunteer subjects.

Thus, the report of similar subjective effects of

cocaine and lidocaine may be due to the very low doses

of cocaine used.

The data from Fischman et al. (1983b) indicate that

procaine and cocaine share some stimulus properties

(i.e., procaine was identified as cocaine), and at the

highest dose tested procaine caused increases in "high"

and "stimulated" scores. To the extent that shared

stimulus properties predict shared reinforcing

properties, the obvious implication is that procaine

might be expected to be a reinforcer in humans. In

fact, preliminary data indicate that this is true

(Fischman and Schuster, unpublished). Procaine,

however, is not thought to be abused by humans. This

descrepancy could be due to several factors. First of

all, it may well be thatwhatpasses for cocaine "on the

street" is, in fact, another local anesthetic such as

procaine. Procaine is commonly misrepresented as

cocaine or mixed with illegally sold cocaine, providing

a less expensive substitute or filler in the sale of

cocaine. Perhaps the "filler" is, in this case, not

inactive but is being used for its own properties.

Another factor to be considered in evaluating the abuse

potential of procaine is its very short half-life.

Procaine has been estimated to have a 7.7 minute

elimination half-life in humans (Seifen et al. 1979),

and that of cocaine is approximately 40 minutes after

84
intravenous injection (Javaid et al. 1978). Frequent

injections of drug would thus be necessary to maintain

intoxication. This is precisely what is seen with

rhesus monkeys who self-administer large numbers of

procaine injections rapidly (Ford and Balster 1977;

Johanson 1980), but would generally be inconvenient for

humans to arrange. Potency differences are also

relevant. There appears to be a 6-to-10-fold potency

difference between cocaine and procaine when the animal

self-administration and discriminative stimulus property

data are examined (Woolverton and Balster 1982). In

rats, for example, cocaine was found to be 9 times more

potent as a discriminative stimulus than procaine.

Since 8 mg of i.v. cocaine has been found to be a strong

reinforcer in humans, we would expect that 96 mg

procaine should be a sufficient dose to be a reinforcer.

Thus, the necessity of both frequent injections and

substantial amounts of a drug might well be sufficient

reason for its lack of "street" popularity except,

perhaps, as an adjunct and component of cocaine

mixtures.

TOXICITY

No laboratory studies have been carried out to

investigate high-dose or repeated-dose cocaine toxicity.

On the other hand, an increasing number of clinical

reports have described the deleterious effects of

repeated cocaine use via various routes of

administration. Regardless of the route, the effects

are similarly debilitating (Rappolt et al. 1978;

Carbajal 1980; Siegel 1982). Gay et al. (1975) have

described the "Advanced Stimulation 'Caine' Reactions"

as divisible into three categories: (1) Early

Stimulation is accompanied by excitement, apprehension,

nausea, vomiting, and twitching of voluntary muscles; (2)

Advanced Stimulation is characterized by hyperkinesis,

convulsions, increases in pulse and blood pressure, and

irregular respiration; and (3) Depression is accompanied

by loss of reflexes, unconsciousness, circulatory and

respiratory failure, and perhaps death. Siegel (1982)

has pointed out that heavy chronic cocaine smokers often

exhibit hallucinations and persecutory delusions and are

generally incapable of regulating their drug intake. A

recent report of iatrogenous cocaine psychosis (Lesko et

al. 1983) described similar symptomatology in a young

man given a topical anesthetic solution of dyclonine

hydrochloride and cocaine which he was allowed to apply

to the inside of his mouth as needed for pain due to

oral ulcers. The hallucinations, paranoid ideation,

hyperactivity, and repetitive behavior patterns

disappeared within 60 hours of cessation of the cocaine.

These symptom descriptions appear to be

indistinguishable from the toxic syndrome produced by

the amphetamines. This latter effect has been produced

85
in human research subjects under controlled laboratory

conditions (Angrist and Gershon 1969; Griffith et al.

1972) and indicates that in sufficient doses a toxic

psychosis can develop in anyone regardless of pre-drug

psychiatric status. Because of the similarity in action

between cocaine and the amphetamines, there is no reason

to believe that cocaine toxicity will be any less severe

or general than that seen after amphetamine. The fact

that the cocaine toxic psychosis has not been

demonstrated under controlled laboratory conditions

should not be taken to mean that it does not exist.

This is a situation in which all of the other available

data indicate that the similarities between cocaine and

amphetamine are far more striking than their

differences, and we can readily predict similar toxic

effects. Clinical reports support this prediction.

CONCLUSION

Laboratory studies with human research subjects have

indicated that cocaine's cardiovascular and subjective

effects mimic those reported for other stimulant drugs

such as the amphetamines, diethylpropion, and

methylphenidate. Differences observed reside primarily

in factors related to dosing regimens, duration of

action, etc. Furthermore, these effects generally

increase with increases in cocaine plasma level. In

addition, as with nonhuman research subjects, cocaine

clearly functions as a positive reinforcer.

When given concurrent alternative substances to selfadminister (e.g., saline versus cocaine), subjects

generally chose cocaine over saline and showed

predictable increases in heart rate as well as verbal

report of its stimulant effects early in the session.

However, there does appear to be an acute tolerance to

its effects.

The data collected in the laboratory have all been

collected under limited access conditions. It has been

pointed out in another paper in this monograph

(Johanson) that rhesus monkeys allowed to selfadminister cocaine under limited access conditions do so

with well-regulated intake and few signs of toxicity.

However, results from unlimited access procedures

indicate substantial toxicity including convulsions and

death. It is possible that with a less restricted drugtaking schedule for humans, other toxic effects would

also emerge. The data indicating development of an

amphetamine toxic psychosis provide the clues for what

this toxicity might be, and point out the potentially

serious consequences of repeated cocaine use.

86
FOOTNOTE

l

DAWN, the Drug Abuse Warning Network, monitors drugrelated emergency room visits and deaths. Now funded by

the National Institute on Drug Abuse, it was funded

jointly by NIDA and the Drug Enforcement Administration

(DEA) from 1972 to 1980.

REFERENCES

Angrist, B.M., and Gershon, S. Amphetamine abuse in New

York City 1966 to 1968. Seminars in Psych, 1:195-207,

1969.

Barnett, G.; Hawks, R.; and Resnick, R. Cocaine

pharmacokinetics in humans. J of Ethnopharm, 3:353-

366, 1981.

Byck, R., and Van Dyke, C. What are the effects of

cocaine in man? In: Petersen, R.C. and Stillman,

R.C., eds. Cocaine: 1977. National Institute on

Drug Abuse Research Monograph 13. DHEW Pub. No. (ADM)

77-741. Washington, D.C.: Supt. of Docs., U.S. Govt.

Print. Off., 1977. pp. 97-118.

Byck, R.; Van Dyke, C.; Jatlow, P.; and Barash, P.

Clinical pharmacology of cocaine. In: Jeri, F.R.,

ed. Cocaine, 1980. Lima: Pacific Press, 1980. pp.

250-256.

Cagliotti, C. Some considerations about the chewing of

coca leaf in the Argentine Republic. In: Jeri, F.R.,

ed. Cocaine, 1980. Lima: Pacific Press, 1980. pp.

137-144.

Carbajal, C. Psychosis produced by nasal aspiration of

cocaine hydrochloride. In: Jeri, F.R., ed. Cocaine,

1980. Lima: Pacific Press, 1980. pp. 127-136.

Carroll, E. Coca: The plant and its use. In:

Petersen, R.C. and Stillman, R.C., eds. Cocaine;

1977. National Institute on Drug Abuse Research

Monograph 13. DHEW Pub. No. (ADM) 77-741.

Washington, D.C.: Supt. of Docs., U.S. Govt. Print.

Off., 1977. pp. 35-46.

Fischman, M.W. Evaluating the abuse potential of

psychotropic drugs in man. In: Thompson, T., and

Unna, K., eds. Predicting Dependence Liability of

Stimulant and Depresant Drugs. Baltimore:

University Park Press, 1977. pp. 261-284.

Fischman, M.W. Cocaine and amphetamine effects on

repeated acquisition in humans. Fed Proc, 37:618,

1978.

Fischman, M.W., and Schuster, C.R. Cocaine effects in

sleep-deprived humans. Psychopharm, 72:1-8, 1980.

Fischman, M.W., and Schuster, C.R. Cocaine selfadministration in humans. Fed Proc, 41:241-246, 1982.

Fischman, M.W.; Schuster, C.R.; and Hatano, Y. A

comparison of the subjective and cardiovascular

effects of cocaine and lidocaine in humans. Pharm

Biochem Behav, 18:123-127, 1983a.

87
Fischman, M.W.; Schuster, C.R.; Javaid, J.I.; Hatano,

Y.; and Davis. J. Acute tolerance development to the

cardiovascular and subjective effects of cocaine. J

Pharm Exp Ther, in press.

Fischman, M.W.; Schuster, C.R.; and Raifer, S. A

comparison of the subjective. and cardiovascular

effects of procaine and cocaine in humans. Pharm

Biochem Behav, 18:711-716, 1983b.

Fischman, M.W.; Schuster, C.R.; Resnekov, L.; Shick,

J.F.E.; Krasnegor, N.A.; Fennell, W.; and Freedman,

D.X. Cardiovascular and subjective effects of

intravenous cocaine administration in humans. Arch

Gen Psych, 33:983-989, 1976.

Ford, R.D., and Balster, R.L. Reinforcing properties of

intravenous procaine in rhesus monkeys. Pharm Biochem

Behav, 6:289-296, 1977.

Freud, S. In: Donoghue, A.K., and Hillman, J., eds.

The Cocaine Papers. Vienna, Zurich: Dunquin Press,

1963. pp. 62.

Gay, G.R.; Inaba, D.S.; Sheppard, C.W.; and Newmeyer,

J.A. Cocaine: History, epidemiology, human

pharmacology, and treatment. A perspective on a new

debut for an old girl. Clin Toxicol, 8:149-178, 1975.

Griffith, J.D.; Cavanaugh, J.; Held, J.; and Oates, J.A.

Dextroamphetamine: Evaluation of psychomimetic

properties in man. Arch Gen Psych, 26:97-100, 1972.

Hammerbeck, D.M., and Mitchell, C.L. The reinforcing

properties of procaine and &hetamine compared in

rhesus monkeys. J Pharm Exp Ther, 204:558-569, 1978.

Hanna, J.M. The effects of coca chewing on exercise in

the Quechua of Peru. Human Biol, 42:1-11, 1970.

Hanna, J.M. Further studies on the effects of coca

chewing on exercise. Human Biol, 43:200-209, 1971.

Holmstedt, B.; Lindgren, J.E.; Rivier, L.; and Plowman,

T. Cocaine in the blood of coca chewers. Botanical

Museum Leaflets, 26:199-201, 1978.

Jasinski, D.R. Clinical evaluation of sedativehypnotics for abuse potential. In: Thompson, T. and

Unna, K., eds. Predicting Dependence Liability of

Stimulant and Depressant Drugs. Baltimore:

University Park Press, 1977. pp. 285-290.

Javaid, J.E.; Fischman, M.W.; Schuster, C.R.;

Dekirmenjian, H.; and Davis, J.M. Cocaine plasma

concentration: Relation to physiological and

subjective effects in humans. Science, 202:227-228,

1978.

Javaid, J.I.; Musa, M.N.; Fischman, M.W.; Schuster,

C.R.; and Davis, J.M. Kinetics of cocaine in humans

after intravenous and intranasal administration.

Biopharm Drug Disp, 4:9-18, 1983.

Jeri, F.R.; Sanchez, C.C.; del Pozo, T.; Fernandez, M.:

and Carbajal, C. Further experience with. the

syndromes produced by coca paste smoking, In: Jeri,

F.R., ed. Cocaine, 1980. Lima: Pacific Press, 1980.

pp. 76-85.

88
Johanson, C.E. The reinforcing properties of procaine,

chloroprocaine and proparacaine in rhesus monkeys.

Psychopharm, 67:189-194, 1980.

Johanson, C.E., and Balster, R.L. A summary of the

results of a drug self-administration study using

substitution procedures in rhesus monkeys. Bull

Narc, 30:43-54, 1978.

Kogan, M.J.; Verebey, K.G.; DePace, A.C.; Resnick, R.B.;

and Mule, S.J. Quantitative determination of

benzoylecgonine and cocaine in human biofluids by gasliquid chromatography. Analytical Chem, 49:1965-1969,

1977.

Kornetsky, C.; Mirsky, A.F.; Kessler, E.K.; and Dorff,

J.E. The effects of dextro-amphetamine on behavioral

deficits produced by sleep loss in humans. J

Pharm, 127:46-50, 1959.

Laties, V.G., and Weiss, B. The amphetamine margin in

sports. Fed Proc, 40(12):2689-2692, 1981.

Lesko, L.M.; Fischman, M.W.; Javaid, J.I.; and Davis,

J.M. Iatrogenous cocaine psychosis. New Eng J Med,

307:1153, 1982.

Martin, W.R.; Sloan, J.W.; Sapira, J.D.; and Jasinski,

D.R. Physiologic, subjective and behavioral effects

of amphetamine, methamphetamine, ephedrine,

phenmetrazine, and methylphenidate in man. Clin

Pharm Ther, 12:245-258, 1971.

Mortimer, W.G. History of Coca. "The Divine Plant of

the Incas. (1901) Reprinted: San Francisco, CA:

And/Or Press, 1974. 576 pp.

Negrete, J.C., and Murphy, H.B.M. Psychological deficit

in chewers of coca leaf. Bull Narc, 19:11-18, 1967.

Paly, D.; Jatlow, P.; Van Dyke, C.; Cabieses, F.; and

Byck, R. Plasma levels of cocaine in native Peruvian

coca chewers. In: Jeri, F.R., ed. Cocaine, 1980.

Lima: Pacific Press, 1980a. pp. 86-89.

Paly, D.; Jatlow, P.; Van Dyke, C.; Jeri, F.R.; and

Byck, R. Plasma cocaine concentrations during cocaine

paste smoking. Life Sciences, 30:731-738, 1982.

Paly, D.; Van Dyke, C.; Jatlow, P.; Jeri, F.R.; and

Byck, R. Cocaine: Plasma levels after cocaine paste

smoking. In: Jeri, F.R., ed. Cocaine, 1980. Lima:

Pacific Press, 1980b. pp. 106-110.

Petersen, R.C., and Stillman, R.C., eds. Cocaine;

1977. National Institute on Drug Abuse Research

Monograph 13. DHEW Pub. No. (ADM) 77-741.

Washington, D.C.: Supt. of Docs., U.S. Govt. Print.

Off., 1977.

Perez-Reyes, M.; DiGuiseppi, S.; Ondrusek G.; Jeffcoat,

A.R.; and Cook, C.E. Free-base cocaine smoking.

Clin Pharm Ther, 32:459-465, 1982.

Post, R.M.; Gillin, J.C.; Wyatt, R.J.; and Goodwin, F.K.

The effect of orally administered cocaine on sleep of

depressed patients. Psychopharm, 37:59-66, 1974b.

Post, R.M.; Kotin, J.; and Goodwin, F.K. The effects of

cocaine on depressed patients. Amer J Psych, 131:511-

517, 1974a.

89
Rappolt, R.T., Sr.; Gay, G.; Inaba, D.S.; Rappolt, N.;

and Rappolt, R.T., Jr. Use of Inderal (propanololAyerst) in l-a (early stimulative) and 1-b (advanced

stimulative) classification of cocaine and other

sympathomimetic reactions. Clin Toxicol, 13:325-332,

1978.

Rechtschaffen, A., and Maron, L. The effect of

amphetamine on the sleep cycle. Electroenceph Clin

Neurophysiol, 16:438-445, 1964.

Resnick, R.B.; Kestenbaum, R.S.; and Schwartz, L.K.

Acute systemic effects of cocaine in man: A

controlled study by intranasal and intravenous routes.

Science, 195:696-699, 1977.

Resnick, R.B.; Kestenbaum, R.S.; and Schwartz, L.K.

Acute systemic effects of cocaine in man: A

controlled study by intranasal and intravenous routes.

In: Jeri, F.R., ed. Cocaine, 1980. Lima: Pacific

Press, 1980. pp. 17-20.

Richards, L., ed. Demographic Trends and Drug Abuse

1980-1995. National Institute on Drug Abuse Research

Monograph 35. DHEW Pub. No. (ADM) 81-1069.

Washington, D.C.: Supt. of Docs., U.S. Govt. Print.

Off., 1981. pp. 99.

Ritchie, J.M., and Cohen, P.J. Local anesthetics. In:

Goodman, L.S., and Gilman, A., eds. The

Pharmacological Basis of Therapeutics, 5th edition.

New York: MacMillan, 1975. pp. 379-403.

Seifen, A.B.; Ferrari, A.A.; Seifen, E.E.; Thompson,

D.S.; and Chapman, J. Pharmacokinetics of intravenous

procaine infusion in humans. Anesthes Analges,

58:382-386, 1979.

Siegel, R.K. Cocaine smoking. J Psychoactive Drugs,

14:271-359, 1982.

Thompson, D.M., and Moerschbaecher, J.M. Drug effects

on repeated acquisition. In: Thompson, T., and Dews,

P.B., eds. Advances in Behavioral Pharmacology,

2:229-260, 1979.

Van Dyke, C.; Barash, P.G.; Jatlow, P.; and Byck, R.

Cocaine: Plasma concentrations after intranasal

application in man. Science, 191:859-861, 1976.

Van Dyke, C.; Jatlow, P.; Ungerer, J.; Barash, P.G.; and

Byck, R. Oral cocaine: Plasma concentrations and

central effects. Science, 200:211-213, 1978.

Van Dyke, C.; Jatlow, P.; Ungerer, J.; Barash, P.; and

Byck, R. Cocaine and lidocaine have similar

psychological effects after intranasal application.

Life Sciences, 24:271-274, 1979.

Weiss, B. Enhancement of performance by amphetaminelike drugs. In: Sjoquist, F., and Tottie, M., eds.

Abuse Of Central Stimulants. New York: Raven Press,

1968. pp. 31-66.

Weiss, B. and Laties, V.G. Enhancement of human

performance by caffeine and the amphetamines. Pharm

Rev, 14:1-36, 1962.

90
Wilkinson, P.; Van Dyke, C.; Jatlow, P.; Barash, P,; and

Byck, R. Intranasal and oral cocaine kinetics. Clin

Pharm Ther, 27:386-394, 1980.

Woolverton, W.L., and Balster, R.L. Reinforcing

properties of some local anesthetics in rhesus

monkeys. Pharm Biochem Behav, 11:669-672, 1979.

Woolverton, W.L., and Balster, R.L. Behavioral

pharmacology of local anesthetics: Reinforcing and

discriminative stimulus effects. Pharm Biochem Behav,

16:491-500, 1982.

Zapata-Ortiz, V. The chewing of coca leaves in Peru.

Int J Addic, 5:287-294, 1970.

ACKNOWLEDGMENT

Preparation of this manuscript was supported by National

Institute on Drug Abuse grant DA-01491.

AUTHOR

Marian W. Fischman, Ph.D., The University of Chicago,

Department of Psychiatry, 950 East 59th Street, Chicago,

Illinois 60637

91
Changing Patterns of Cocaine

Use: Longitudinal Observations,

Consequences, and Treatment

Ronald K. Siegel

INTRODUCTION

In 1858 the Austrian frigate Novara was sent to South America on

a most unusual mission. The Novara was named after the city in

which the Austrians had defeated the Italians, thereby stopping a

threatening cultural and political renaissance. On board the

Novara was a trade expert, Doctor Scherzer, who was intrigued by

another Italian “renaissance” started by Milan neurolgist Paola

Mantegazza. Mantegazza had published an 1857 paper proclaiming

the medical importance of coca that he had chewed while a

resident of Peru (Mantegazza 1857). The paper was the newest

curiosity of the European medical community which even awarded

Mantegazza a prize for this work in 1859 (Mortimer 1901). The

Novara stopped in Peru and Scherzer took a quantity of coca

leaves back to the great chemist Wohler at the University of

Gottingen in Germany. Wohler’s assistant, Albert Nieman, named

the isolated alkaloid “cocaine” in 1859/1860 (Phillips and Wynne

1980). The isolation and naming of the alkaloid signalled the

start of 125 years of changing patterns of cocaine use. Prior to

that time, only coca products were available, and the patterns of

their use had not changed substantially in over 4700 years.

For most of its early history, cocaine remained hidden and

unidentified in the protective envelope of the coca leaf. The

coca plant (Erthroxylum spp.) produces at least 14 different

alkaloids as defensive agents to ward off foraging animals. The

bitterness, numbing, and psychoactive properties of these

alkaloids perform this defensive function effectively, teaching

animals to avoid the plant and thus contributing to its

evolutionary survival. Interestingly, compared with other

tropical American crops, coca is relatively pest free.

Herbivorous insects are rarely observed on plants and damage to

the leaves is relatively minor.

Accidental encounters with ingestion of coca exposed early man to

the effects of its alkaloids. From 3000 B.C. to the middle of

the 16th century, coca was used by the indigenous peoples of

92
South America in religious, magical, medical, and recreational

contexts. Little information is available on the psychopharmacological consequences of this use, but patterns changed very

little during this period. The leaves were chewed whole or in

powdered form , smoked with or without tobacco, or else swallowed

in various infusions.

In 1580 coca was introduced to Europe, where it eventually, by

the middle of the 19th century, found its way into widespread

medical use. Coca products included preparations of leaves,

extracts, wines, liquors, cordials, lozenges, cigars, cigarettes,

and chewing gum, among many other forms. Patterns of use were

largely confined to medical applications, although sane

nonmedical uses were also reported.

After the isolation of cocaine in 1859/1860 by Nieman (a crude

alkaloid, named “erythroxylon,” was isolated by Gaedecke in

1855), early experimentation revealed stimulant and local

anesthetic properties (Siegel and Hirscham 1983). The medical

community became enthusiastic about this new wonder drug, the

patent medicine manufacturers exploited it, and the nonmedical

use of cocaine for pleasure began to grow rapidly. Fostered by

glowing reports from the patent medicine advertisements,

encouraged by the research and writings of Sigmund Freud (who was

strongly influenced by Mantegazza), and pushed by the

euphoria-enhancing techniques of intranasal and intravenous

administration, the pattern of use began to change.

In addition to the numerous coca products, cocaine itself started

to appear in flake crystals, tablets/ solutions for inject ion,

ointments, and nasal sprays. Both coca and cocaine were also

used in a variety of soft drinks and tonics, the most famous

being Coca-Cola. Indeed, “during the seventeen years Coca-Cola

contained cocaine [until 1903], the drink and drug became so

closely identified that ‘dope,’ as in ‘let’s have a dope’ became

the established, common term for Coca-Cola” (Ashley 1975, p. 49).

Observations on these patterns of use were made in both the

medical and lay press during the early 20th century. Many of

these articles suggested that cocaine was associated with

uncontrollable addiction, physical and psychological

deterioration, demoralization, and criminal violence. Federal

legislation, beginning with the Pure Food and Drug Act of 1906

and the Harrison Act of 1914, effectively launched a period of

cocaine prohibition by restricting and controlling all aspects of

its manufacture, possession, sale, distribution, and use. Both

the medical and nonmedical use of cocaine gradually declined, and

general interest in the drug all but disappeared between 1930 and

the late 1960s.

Cocaine continued to be used, albeit by relatively few users,

during this period of prohibition. The primary route of

ministration was intranasal, although the intravenous route was

also employed. In the early 197Os, cocaine was “rediscovered” as

a recreational drug of choice. As with its initial introduction

93
a century before, contemporary users began to experiment with new

preparations and patterns of use.

SHORT-TERM OBSERVATIONS OF USERS (1970-1983)

A number of studies have provided observations of contemporary

patterns of cocaine use in the period 1970 to 1983. These

studies have concentrated on selected populations of users that

were seen at only a single point of time during this period.

When reviewed chronologically, these observations suggest that

patterns of cocaine use were changing rapidly throughout the

period 1970 to 1983 and in particular for long-term users. For

individuals engaged in continued use this change was

characterized by increased dosage and frequency of use resulting

in decreasing positive effects and increasing negative reactions

including physical and psychological dysfunction. This changing

pattern is also examined (see following sections) in a series of

longitudinal observations made on a sample of users studied at

multiple points of time during this sane period.

Users entered the 1970s with attitudes that supported their

beliefs that cocaine was a "safe recreational drug." Gay and

Inaba (1976) suggested that the rediscovery of cocaine in the

1970s was inevitable because its effect of euphoria and

stimulation "reinforces and boosts what we recognize as the

highest aspirations of American initiative, energy, frenetic

achievement, and ebullient optimism" (p. 251).

Phillips and Wynne (1980) interviewed and observed a group of

cocaine users and dealers in 1975 in a study of user beliefs and

myths regarding cocaine. among the myths endorsed by users were:

cocaine is an aphrodisiac; cocaine increases creative and

physical performance; there are no bad effects associated with

cocaine use; the cost of cocaine is related to its purity; and a

cold shower is an antidote for cocaine intoxication. Widespread

belief in these "street" myths appeared to support continued use

of cocaine.

Gottlieb (1976) also interviewed and observed a number of cocaine

users who expressed similar beliefs: cocaine is an aphrodisiac;

cocaine facilitates the learning process; cocaine improves

physical activity; and cocaine "is not addictive." While users

preferred the intranasal route of administration, Gottlieb

reported the growing experimentation with intrabuccal and

sublingual routes of administration, the rediscovery of drinking

cocaine in alcoholic beverges such as cordials, and the smoking

of cocaine hydrochloride alone or in combination with marijuana

or tobacco.

The consequences of this early use were repotted by Ashley (1975)

who interviewed and observed 81 cocaine users, all of whom

reported experiencing euphoria, sexual stimulation, increased

energy, and reduced fatigue and appetite. His respondents also

reported a wide range of other positive effects including

increased mental lucidity and muscular strength. Not

94
surprisingly, these users agreed “that cocaine was a ‘good’ drug,

and virtually all were certain it should be used in moderation”

(p. 156). Reports of adverse effects were more variable and

appeared to be dependent on the pattern of use. In this regard,

Ashley observed three patterns of use: moderate, chronic

moderate, and heavy. Sixty of his respondents were moderate

users (0.25-0.50 grams/day for “a few” days) who reported minor

adverse reactions such as lassitude. Fourteen were chronic

moderate users (0.25-0.50 grams/day for prolonged periods) who

reported mild insomnia, occasional impotency, irritability, and

personality changes. The remaining four heavy users (chronic use

of 2.0-4.0 grams/day) reported insomnia, impotency, irritability,

personality changes, and paranoia. Importantly, Ashley’s

respondents noted a tendency to escalate dosages which resulted

in increased adverse reactions. Consequently, they reported

adjusting dosages or abstaining for brief periods in order to

control use. Lassitude was the only withdrawal symptom noted by

these users.

Using a more careful interview and questionnaire study, Resnick

and Schuyten-Resnick (1976) described five profiles of typical

cocaine-using behavior, based on the patterns of drug use

established by the National Commission on Marihuana and Drug

Abuse. These patterns included experimental (short-term and

nonpatterned); recreational (use in social settings among

friends); circumstantial (use for specific effect); intensified

(daily use); and compulsive (high frequency and intensity).

These researchers described intensified users as using from 3 to

20 times a day. Compulsive users were characterized as having a

high degree of psychological dependence: “The most striking

feature of this pattern is that the drug use dominates the

individual’s life and precludes other social functioning” (p.

221).

As Ashley had predicted, consequences of adverse reactions

appeared dependent on the pattern of use. Users following the

more intensified and compulsive patterns of use started to show

up in treatment centers seeking clinical attention. Gay and

Inaba (1976) traced an increase in cocaine users seekity clinical

attention beginning in the middle of 1970. Chronic cocaine abuse

was marked by psychological dependence, a withdrawal depression,

and sleep disturbances.

In an interview study of 17 recreational users, Grinspoon and

Bakalar (1976) found that even intranasal users experienced

common psychological problems including insomnia, irritability,

and anxiety. Physical problems included rhinitis and weight

loss. Toxic eftects, psychosis, and loss of psychomotor control

were considered rare reactions for these users.

However, with intravenous patterns of use, the problems appeared

to escalate. In a series of in-depth case studies, Spotts and

Shontz (1976, 1980) examined the lifestyles of nine American

cocaine users. The users in their studies were primarily

intravenous users with an average of 5 to 9 years of experience

95
with cocaine. They concluded that low levels of usage were

associated with use of cocaine to enhance sensory pleasures, to

make the real world seem like an imaginary paradise, and to help

the user compensate for inability or unwillingness to accept

responsibilities. Relatively higher levels of usage were

associated with use of cocaine to provide necessary support for

the self-concept, as a means to provide the drive and energy

needed to succeed, or as a way of inducing a state of blissful

oblivion to overwhelming life problems. These researchers found

that at high levels of use the sensory pleasure is often

counterbalanced by adverse react ions including tension, anxiety ,

paranoia, hallucinations, and fear of overdose and subsequent

death. Interestingly, following completion of the study, Spotts

and Shontz report that of the nine respondents “two of them are

now dead, one is in prison, and one has been convicted of a

felony involving cocaine. These chilling statistics highlight

the danger and volatile nature of the world of the heavy cocaine

user” (1980, p. 492).

Siegel (1979) cited the growing popularity of smoking cocaine

free base and a concanitant increase in negative reactions:

Free base parties have became increasingly popular, and

the practice has spread, . . .Unlike intranasal users,

cocaine smokers do not appear to titrate or adjust

dosage. Consequently, both frequency and quantity of

dosages escalate rapidly.. . This pattern of use is

similar to that found with intravenous heroin and

cocaine and has an associated high potential for

dependency and overdose. (p. 373)

User beliefs, however, strongly supported the smoking of cocaine

free base with attitudes that it was “the ultimate high,” “the

greatest thing since sex,” “gives you the ecstatic illusion of a

synthetic heaven,” and is capable of producing mind-expanding

experiences (Anvil 1979; Raye 1980; Davidson 1981). Smoking of

cocaine free base continued throughout this period. Siegel

(1982) studied 32 users seeking clinical attention for problems

related to cocaine free base. Of the 32 users studied, 20

engaged exclusively in individual compulsive patterns of smoking,

seven engaged in exclusively social compulsive patterns (usually

with a single smoking partner), and five engaged equally often in

both individual and social smoking. All users reporting initial

periods of intensified use started with one gram per day (range

0.5-3.0) and escalated over the course of the intensified period

to an average of 7.0 grams per day (range 2.0-28.0). All the

users were diagnosed as having a Cocaine Smoking Disorder, an

organic mental disorder with associated features of euphoria,

dysphoria, and schizophreniform psychosis.

While these studies were being conducted on cocaine users in the

United States, a series of reports began to emerge on abuse of

coca paste in Peru and other countries in South America (Aramayo

and Sanchez 1980; Jeri et al. 1978, 1980; Noya 1978; Valladolid

1979). Taken together, these reports suggested that the chronic

96
smoking of coca paste was associated with successive stages of

psychopatholgy: euphoria, dysphoria, hallucinosis, and

psychosis. Jeri and colleagues (1978) reported a characteristic

profile of these coca paste users. Users experienced an initial

euphoria followed almost immediately by compulsive anxiety to

smoke more paste, depression, irritability, suspiciousness,

paranoid thinking, excitement, and visual, auditory, and tactile

hallucinations. In addition to toxic effects (e.g., convulsions

and seizures) resulting from chronic or high dose usage,

psychosocial dysfunction as well as psychological impairment was

commonly reported.

Cocaine smokers were not the only users reporting such adverse

reactions. As both the dosages and chronicity of cocaine use

escalated, these adverse consequences became ubiquitous among all

classes of users. Helfrich and coworkers (1983) found a profile

similar to the coca paste users after examining a group of

cocaine users who sought treatment. Examination of these

patients revealed impairment in several areas: psychological,

interpersonal, financial, physical, and vocational. The

dysfunction appeared to be independent of the route of

administration. This latter finding was consistent with a

telephone interview study of users seeking help for

cocaine-related problems (McConnell 1983). In the telephone

study, users reported an average use of 8 grans per day, 6 days

per week, with 56 percent reporting such use for 2 years.

Symptoms included nosebleeds, exhaustion, headaches, seizures,

paranoia, panic attacks, and violence towards others.

LONG-TERM OBSERVATIONS AND CHANGING LEGAL STATUS (1970-1983)

The period 1970 to 1983 was marked by a steady increase in

virtually all aspects of cocaine use (Siegel 1982). Importation

of cocaine, paraphernalia sales, cocaine-related stories in the

media, samples of cocaine submitted by users for analysis,

hospital and treatment center admissions for cocaine, cocainerelated deaths, seizures of illicit cocaine, cocaine-related

crimes and arrests, among many other parameters, increased

dramatically.

The changing patterns of cocaine use, as well as changing

attitudes, have been reflected in the nature of legal defenses

raised in cocaine-related crimes during 1970 to 1983 (Siegel

1983). Initially, cocaine was viewed as a "non-addictive" and

non-narcotic recreational drug that was not as dangerous as the

law maintained. The first evidentiary hearings on the scientific

and medical nature of cocaine were held in Commonwealth v. Miller

(366 Mass. 387,318 N.E.2d 909[D.Ct.1976]) in 1976. Here the

constitutionality of cocaine's classification as a "narcotic" was

successfully challenged and the judge issued 125 findings of fact

regarding the state of knowledge about cocaine as a relatively

safe drug in typical patterns of social-recreational use.

Defenses from 1976 to 1981 attempted to educate the trier of fact

about these opinions and thus, hopefully, to temper the judgment

and disposition of the cases. These defenses met with

97
considerable success in lower courts, but higher courts have held

that it is valid to classify cocaine as a narcotic for purposes

of punishment. As cocaine use spread and effects of toxicity and

dependency became recognized, defenses based on cocaine- induced

diminished capacity or insanity started to emerge in courts. The

effects of cocaine on criminal responsibility, on credibility of

witnesses, and as a causative factor in accidental deaths or

homicides were raised as mitigating factors in guilt or penalty

phases of criminal trials. By 1983, cocaine appeared to be

replacing phencyclidine as the novel drug defense of the decade.

The forensic issue that most clearly illustrates the changing

patterns of cocaine use is the quantity necessary for charges of

possession and sales. Some courts, particularly Federal courts,

have permitted an inference of intent to sell to be drawn from

the fact that a large quantity of a drug was involved, despite

the absence of a statutory presumption. Thus, in the early 1970s

possession of more than a gram of cocaine was often viewed as

possession for sale. As users escalated their patterns and

dosages, particularly with smoking cocaine free base, possession

of larger amounts for personal use became more common. It was

not unusual to find that intranasal users might possess a week’s

supply of several grams or a cocaine smoker might use as much as

1 ounce or more. Consequently, by 1980 many jurisdictions viewed

1 ounce of cocaine or less as simple possession for personal use.

One aspect of a changing pattern in cocaine use was clear: there

were more users in general, more intensified and compulsive users

in particular, and more cocaine-related psychological, physical,

and legal problems. Another aspect of this changing pattern was

less clear: did individual long-term users manifest parallel

changing patterns of cocaine use? In other words, do the

recreational and circumstantial users cited in the above studies

escalate use to more intensified and compulsive patterns of use?

Does increased use of cocaine increase the incidence of negative

and toxic effects? Is long-term use of cocaine inevitably

associated with an escalating dependency marked by more frequent

use? If not, what factors control and maintain stable patterns

of chronic use? A longitudinal study of a small sample of users

was begun in 1975 to provide information on these questions as

well as the consequences of long-term use dur iry this period.

Preliminary findings from the first 4 years of this study have

been reported elsewhere (Siegel 1977, 1980). Only those results

relevant to the question of changing patterns of use will be

discussed below.

LONGITUDINAL STUDY OF USERS (1975-83)

Methods

A total of 118 cocaine users were recruited for study in 1974.

Of these, 19 were selected for interview and questionnaire study

while 99 (85 males, 14 females) were selected for a more

comprehensive longitudinal study. All 99 users (18-38 years old)

were social-recreational users who met the initial requirement of

98
having used a minimum of 1 gram of cocaine per month for 12

months (range 1-4 grams). The majority of users were students

(73 percent,) while others listed their occupations as

housewives, business people, writers, attorneys, physicians,

secretaries, teachers, or unemployed. Exaninations and tests

were performed on each subject at 6-month intervals for 4 years

(1975, 1976, 1977, 1978) and then at approximately 18-month

intervals for another 5 years. Examination procedures included a

personal history questionnaire, drug history questionnaire,

subjective drug effects questionnaire, mental status exanination,

the Minnesota Multiphasic Personality Inventory (MMPI), the

Experiential World Inventory (EWI), in-depth interviews, and

physical examinations (for most subjects). In addition, assays

were performed on samples of cocaine used by these subjects. An

important caveat is that a number of users dropped out of the

study throughout the years or could not be located for followup

examinations. Several followup examinations in the last 5 years

of the study were conducted via telephone, and these were

restricted to questionnaires and interviews. Nevertheless, a

total of 61 users participated in all phases of the first 4 years

of study and 50 users were available for followup in 1983. Eight

additional users who refused followup examinations reported that

they had stopped all cocaine use.

Preparations and Purity

All subjects used cocaine hydrochloride available through illicit

markets. The average purity of their samples fluctuated

throughout the years of the study: 43.2% in 1975; 56.2% in 1976;

52.1% in 1977; 60.8% in 1978; 25.0% in 1979; 13.9% in 1980; 48.7%

in 1981: 58.0% in 1982; and 75.0% in 1983. When cocaine free

base was prepared, the average purity of the final product was

95.0%. The most common adulterants and diluents were mannitol,

lactose, inositol, lidocaine, and phenylpropanolanine.

Routes of Administration

All subjects employed the intranasal route at the start of the

study period. By the end of the first year, 14 percent had

experimented with smoking cocaine hydrochloride on tobacco or

marijuana cigarettes. By 1978, 39 percent of the users had

smoked cocaine as the hydrochloride or free base and 10 percent

classifed themselves as primarily cocaine free base smokers. For

the last 5 years of study, there were two distinct populations of

users: intranasal users (90 percent) and cocaine free base

smokers (10 percent). Throughout the study, users experimented

with other routes including injection (n=5) and oral (n=ll).

Dosages and Dose Regimes

Intranasal users administered cocaine in amounts (uncorrected for

purity) of 20 g per &ministration if a "cokespoon" was employed

or 50 g if “lines” were used. Throughout 1975-1978, intranasal

users averaged between 1 and 4 grams (uncorrected weight) per

month. From 1978 to 1983, intranasal users, approximately 90

99
percent of the sample, averaged between 1 and 3 grams per week.

Cocaine free base smokers, approximately 10 percent of the

sample, used approximately 100 mg of free base per “hit” or

inhalation. Throughout 1975-1978, smokers averaged 1 gram per

day during periods of use. From 1978 to 1983, smokers averaged

1.5 grams per day. The temporal spacing of hits and the total

duration of a smoking episode varied considerably . Inhalations

were repeated as often as every 5 minutes during binges ranging

from 30 minutes to 96 hours. Individual consumption ranged from

1 gram to 30 grams per 24-hour period, although some users

reported smoking up to 150 grams in 72 hours. Smoking episodes

continued until supplies of cocaine were depleted or users became

exhausted and fell asleep.

Patterns of Use

All 99 users were classified initially as social-recreational

users, since use generally occurred in social settings among

friends or acquaintances who wished to share an experience

perceived by them as acceptable and pleasurable. Such use was

primarily motivated by social factors and did not tend to

escalate to more individually oriented patterns of use. Use

tended to occur in weekly or biweekly episodes. From 1975 to

1978, 75 percent (n=46) of the users still in the study (N=61)

engaged in episodes of more frequent use (see below) but remained

primarily social users. From 1978 to 1983, 50 percent (n=25) of

the users still in the study (N=50) remained social-recreational

(with continuing episodes of increased use), 32 percent (n=16) of

the users became primarily circumstantial-situational users, 8

percent (n=4) became intensified users, and 10 percent (n=5)

became compulsive users. Importantly, this latter compulsive

group consisted entirely of cocaine free base smokers.

An important caveat is that all users had episodes of decreased

use or abstinence interposed between periods of use in their

normal patterns. Thus, users reported abstaining from cocaine

for periods ranging from a few days to several months. For

example, from 1978 to 1983, four social-recreational users

reported no use for 2 years. During this same period, all

compulsive users reported periods of social use as well as brief

periods of abstinence. And most users in all categories reported

that supplies of cocaine were often unavailable, thus resulting

in regular periods of nonuse. However abstinence also occurred

during periods of cocaine availability.

Thus, 25 social-recreational users at the beginning of the study

remained in this pattern of use after 9 years. Throughout this

period, these users continued to report positive effects of

intoxication including euphoria and stimulation, although they

also reported negative effects including nasal problems,

restlessness, and attentional difficulties. By restrictiting

themselves to social patterns of use, they reported the ability

to titrate their doses and thereby minimize these negative

effects. Reliefs in cocaine as an “ideal safe drug” which

facilitated social behavior, the economics of supply, and the

100
legal risks of use all seemed to contribute to maintaining stable

patterns of use which did not change substantially for these

people. The incompatibility of cocaine use with other activities

(e.g., work) also served as controlling determinants.

Circumstantial-situational use was defined as a task-specific,

self-limited use which was variably patterned, differing in

frequency, intensity, and duration. This use was motivated by a

perceived need or desire to achieve a known and anticipated drug

effect deemed desirable to cope with a specific condition or

situation, Use tended to occur in four or five episodes per

week. Sixteen of the social-recreational users adopted this

pattern of use by 1983. The major motivations cited by users

were to increase energy or performance at work and to enhance

mood during periods of boredom or depression.

Four users became classified as intensified cocaine users by

1983. Intensified use is characterized by long-term patterned

use at least once a day. Such use was motivated chiefly by a

perceived need to achieve relief from a persistent problem or

stressful situation or a desire to maintain a certain selfprescribed level of performance. While sane social - recreational

users referred to their periods of intensified use as short-term

runs or binges, these four users reported that they were on

repeated runs of several months’ duration and did not return to

social pat terns of use.

Compulsive use is characterized by high frequency and high

intensity levels of relatively long duration, producing sane

degree of dependence. The dependence is such that the individual

user does not discontinue such use without experiencing

physiological discanfort or psychological disruption. The five

compulsive users found here were all cocaine free base snokers.

Use tended to occur in episodes of continuous smoking for periods

of several hours to 96 hours. These users were characterized by

significantly reduced individual and social functioning. The

motivation to continue compulsive levels of use was primarily

related to a need to elicit the euphoria and stimulation of

cocaine in the wake of increasing tolerance. Compulsive users

were also motivated by the desire to avoid the discomfort and

depression of withdrawal. Consequently, compulsive users were

preoccupied with obtaining adequate and sufficient amounts of

cocaine in order to forestall an abstinence-like syndrome. When

compulsive users were sufficiently well supplied so that

preoccupation with obtaining cocaine did not occur, it was common

to find an equally intense preoccupation with using such

supplies.

Acute and Chronic Effects

Users reported that a variety of acute intoxication effects were

perceived as positive. These included: euphoria, stimulation,

reduced fatigue, diminished appetite, garrulousness, sexual

stimulation, increased mental ability, and increased sociability.

Other acute effects were experienced as negative: restlessness,

101
anxiety, hyperexcitability, irritability, and paranoia. During

1975-1978 all users reported experiencing some positive effects

in all intoxications and negative effects in only 3 percent of

the intoxications. However, during 1979-1983 all users, except

compulsive users, reported positive effects in all intoxications

but negative effects in approximately 40 percent of the

intoxications. Compulsive users reported the absence of positive

effects in 15 percent of the intoxications and negative effects

in 82 percent of the intoxications. The acute and chronic

effects reported by these compulsive users, all of whan were

smoking cocaine free base, did not differ substantially from

those seeking clinical attention. These are discussed elsewhere

(Siegel 1982).

Several positive and negative chronic effects were reported by

users. The positive effects included: a generalized feeling of

increased energy, increased sensitivity to cocaine, general mood

elevation, and weight loss. Negative effects included restlessness or irritability, attentional or perceptual disturbances,

nasal problems, and fatigue or lassitude. During 1975-1978,

users reported a gradual reduction in the frequency of these

chronic positive effects and a concomitant increase in the

frequency of chronic negative effects such as fatigue (Siegel

1980, table 2). From 1979 to 1983, there appeared to be no

further changes in the relative frequency of positive and

negative effects for social-recreational users. Overall, these

social users reported some chronic positive effects in all

intoxications while negative effects were experienced in 11

percent of the intoxications. Conversely, the ratio of chronic

positive to negative effects appeared to decrease with patterns

of increased use. Thus, circumstantial users reported percentage

ratios of 74 percent (positive effects) to 25 percent (negative

effects) and intensified users reported 56 percent (postive

effects) to 32 percent (negative effects). Compulsive users

reported chronic positve effects in all intoxications and

negative effects in 71 percent of the intoxications.

Toxic Crisis Reactions

In addition to the negative effects described above, users

reported adverse physical and psychological toxic reactions.

Toxic physical reactions were defined as acute crises consisting

of at least one of the following symptoms: myoclonic jerking,

chest pains, nausea or vomiting, respiration difficulties or

failure, seizures or convulsions, or unconsciousness. More

commonly experienced physical symptoms such as blurred vision,

nasal problems, or insomnia were not classified as crisis

reactions. Toxic psychological reactions were defined as acute

crises with at least one of the following symptoms:

hallucinations with delusions, violent loss of impulse control,

or attempted suicide. More commonly experienced psychological

symptoms such as psychomotor agitation, depression, paranoia, or

situational impotency were not classified as crisis reactions

here.

102
During 1975-1978, users reported no toxic physical or psychological crisis react ions. From 1979-1983, the social-recreational

users continued to report no toxic physical or psychological

crises. Also during 1979-1983, 18 percent of the circumstantial

users reported an average of four physical crises and one

psychological crisis, all instances of impulse dyscontrol. All

intensified users reported an average of two physical crises and

one psychological crisis. All compulsive users also reported

experiencing adverse crises during this latter period. The

incidence of these reactions was so frequent that canpulsive

users could not accurately estimate their number. However, they

reported that both physical and psychological crises developed in

approximately 10 percent of their intoxications. The nature of

these toxic crises for compulsive users has been discussed

elsewhere (Siegel 1982).

Personality Profiles

During 1975-1978, retesting with the MMPI detected no

pathological deviations from normal T-score means for adults.

However, a slight but insignificant elevation in D scales

(Depression) and Pa scales (Paranoia) was noted for 7 percent of

the users on at least one retest during this period. Also during

this period, the EWI retesting indicated that 38 percent of the

users displayed elevated Euphoria scales. This suggests

increased happiness and contentment with life. Concomitantly, 5

percent showed increased suspiciousness or paranoia, but this was

usually directed at concern over their own bodies

(hypochondriacal complaints, perceptual disturbances, rhinit is)

rather than paranoid ideation concerning others.

From 1979 to 1983, retesting continued only with the EWI. The

social-recreational and circumstantial-situational users showed

no significant abnormal scores during this period. Most

displayed elevated euphoria scales but these were not

significant. The four intensified users did not show abnormal

T-scores but all showed elevated scores on scales suggesting

concern centering around their bodies, egocentricity, and

disturbances in social adjustment and comnunication. The five

compulsive users displayed marked elevations in almost all

T-scores. The typical configuration of these scores suggested a

paranoid profile with features of depression, reduced frustration

tolerance, problems of social adjustment and communication,

disturbances in sleep-wake rhythms, and difficulties in impulse

regulation.

Multiple Drug Use

At the beginning of the study, all subjects had past and current

(1975) histories of multiple drug use. Prior to their cocaine

use, they reported experience with alcohol (100%), marijuana

(100%), amphetamines (27%), barbiturates (20%), hallucinogens

(10%), diazepam (10%), methaqualone (2%), and opiates (2%).

During 1975-1978, the average percentage of subjects using other

drugs were: alcohol-85%; marijuana-66%; amphetanines-8%;

103
hallucinogens-5%; diazepam-4%; opiates-4%; and methaqualone-4%.

During 1978-1983, the following distribution was reported:

alcohol-70%; methaqalone-30%; marijuana-24%; hallucinogens-18%;

diazepam-13%; opiates-10%; and amphetanines-2.5%. An important

caveat is that these drugs were not necessarily coadministered

with cocaine. Many of these drugs were used to treat the

hyperexcitability and stimulation produced during periods of

excessive cocaine use.

Treatment

Since all users were monitored on a regular basis, few sought

independent treatment for cocaine-related problems. Nonetheless,

a number were given referrals for specific complaints: two users

developed perforated septums; two developed skin problems

associated with cocaine smoking: and six became involved in legal

problems associated with possession of cocaine. Following toxic

crisis reactions, two users summoned paramedics and one user want

to the emergency room of a local hospital. One intensified and

one compulsive user chose to enter a formal clinical treatment

program.

Most users initiated self-control strategies in order to treat

their own negative effects and crisis reactions. The most common

strategy was to titrate or restrict the amount of cocaine used in

a given period of time. This was usually accomplished by

purchasing or carrying a limited anount of cocaine at a time.

Social-recreational users reported success in this method. A few

users attempted to control use by combining supplies of cocaine

with cocaine substitutes, commercial products containing local

anesthetics and stimulants that mimic the effects of cocaine.

Other users initiated strategies whereby they periodically

abstained from cocaine in an effort to “detoxify” and/or “recover

from cocaine effects” for periods ranging from a few days to a

few months. The most common negative effects prompting

abstinence were nasal problems and irritability. Three major

strategies were employed. In avoidance strategies, users

attempted to avoid all contact with cocaine, cocaine

paraphernalia, and cocaine users. Some users reported that it

was effective simply to avoid dealers or other social users.

Others engaged in destruction of paraphernalia, and still others

employed physical constraints by taking a vacation. In aversion

strategies, users sought out and embraced information and stories

containing aversive stimuli. Perhaps the most common stories

were those that circulated about individuals suffering toxic

reactions. These folklore stories told of frequent incidents of

bizarre behavior, economic distress, casualties in the

criminaljustice system, and toxic overdoses. The stories

appeared to generate much concern and anxiety, prompting at least

one intensified user to seek counseling and encouraging many

others to return for periodic followup examinations throughout

the study. In these exams, users would ask for verification of

the folklore as well as explanations for cocaine-related effects.

In self-initiated contingency contracting, which differs from

104
clinical models (Anker and Crowley 1982), users made a public

pledge to family or peers and asked for support in maintaining

abstinence. This support took the form of denial of cocaine

supplies, tight controls over financial resources, and careful

monitoring of behavior. Surprisingly, pledges were often made to

dealers so that they would no longer supply cocaine, and many

users reported such contracts were honored by their dealers.

However, since the contracts were initiated and maintained

verbally, they were easily broken after periods ranging from 1

week to 6 months.

Discussion

Considering the escalating toxicity and dependency associated

with long-term use of stimulant drugs, the most apparent aspect

of these findings is that many of the social-recreational cocaine

users do not change their long-term pattern of use and do not

appear to develop toxic crisis reactions that may warrant

clinical attention. Thus, this population of users differs

substantially from those "abusers" who experience physical or

psychological dysfunction and seek clinical treatment (Helfrich

et al. 1983; Kleber, this volume; Siegel 1982).

Fully 50 percent of the social users available for followup in

1983 retained this pattern of use from 1975-1983. One common

factor cited for such controlled recreational use is the

rate-limiting effect of cocaine's high financial cost. Fourteen

of these users were students in 1975 and, throughout the study

period, graduated and entered higher income levels. Yet only

three escalated use from the initial social patterns. Two users,

who were law students and became attorneys, developed

circumstantial-situational patterns: the third, a medical student

who became a physician, became a compulsive user. The 12

ex-students who remained social users, as well as the other users

in this category, all reported stable patterns of cocaine use

independent of increased income available for the drug. Thus,

the notion that cocaine use is exclusively limited by cost is not

supported in this group.

Surprisingly, social-recreational users maintained relatively

stable patterns of use when supplies were available and when they

were not purposely abstaining. These users ranked cocaine as

their recreational drug of choice. It was viewed by users as a

social drug which facilitated social behavior. When restricted

to social situations, users reported that cocaine was "ideal" in

terms of convenience of use, minimal bulk, rapid onset of

effects, minimal duration of action with few side effects, a high

degree of safety, and minimal after effects. Users reported that

this set and setting were the major factors controlling the

pattern of use. In addition, they reported that the inconsistent

quality of street cocaine, together with a rapidly developing

tolerance to the euphoric effects, contributed to controlled use.

Legal risks, supply, and cost were cited as minor factors.

105
The intranasal cocaine users averaged between 1 and 4 grams per

month during 1975 to 1978. From 1979 to 1983, these users

increased use to an average between 1 and 3 grams per week. The

hypothesis that increased dosayes result in increased risks of

negative effects and toxicity is partially supported by findings

here. Social-recreational users averaged 1 gram per week during

1979-1983 and manifested significant increases in acute and

chronic negative effects despite the absence of crisis reactions.

Circumstantial-situational users averaged 2 grams per week during

1979-1983 and displayed increased chronic negative effects in 25

percent of the intoxications as well as Some crisis reactions.

Three of these users reported an average of four physical crises

and one psychological crisis. Intensified users averaged 3 grams

per week during the some period and reported chronic negative

effects in 32 percent of the intoxications along with an average

of two physical and one psychological crises. The relative

reduction of crises in the intensified users may be partially

related to behavioral tolerance that could be associated with

daily patterns of use. Tolerance may also explain the reduction

in positive effects reported by both circumstantial-situational

and intensified users. However, such tolerance seems to have

been easily overshadowed by the escalating dosages of compulsive

use. Indeed, compulsive users, all of whom smoked cocaine free

base, reported experiencing chronic positive effects in all

intoxications, negative effects in 71 percent of the

intoxications, and crises in 10 percent of the intoxications.

Compulsive users also manifested profiles of a paranoid disorder,

while most other users only displayed profiles of heightened

euphoria.

The hypothesis that long-term use of cocaine is inevitably

associated with an escalating dependency marked by more frequent

patterns of use is not supported by these findings. While little

is known about the 41 users who dropped out of the study at sane

time during the 9 years, 8 social-recreational users who refused

to report for followup examinations after 1979 explained that

they had stopped all use of cocaine. During 1979-1983, several

users reported abstaining for periods ranging from a few days to

several months. Four social-recreational users stopped all use

for 2 years in the middle of the study. Even compulsive users

reported periods of social use or brief periods of abstinence.

Thus, users periodically attempted to treat themselves with

strategies of controlled use, forced abstinence, or even multiple

drug use.

OVERVIEW

The year 1970 began with an increase in the nonmedical use of

cocaine. Most users began as experimental users engaged in

short-term, nonpatterned trials of cocaine with varying

intensity. These users were primarily motivated by curiosity

about cocaine and a desire to experience the anticipated drug

effects of euphoria, stimulation, and enhanced sexual desire

(Siegel 1977). Some users experienced little or no drug effect,

which supported their belief that cocaine was a subtle,

106
over-priced drug undeserviry of continued use. Other users who

experienced a “kick” or "rush" expressed a desire to continue

use.

From 1970 to 1983 these users separated into various patterns of

use and abuse. Short-term observations of these users suggested

that intensified and compulsive patterns of use resulted in

physical and psychological problems. Observations of users

seeking clinical attention confirmed the presence of serious

dependency, dysfunction, and toxicity. Longitudinal observations

confirmed many of these findings but revealed that many users who

adopt social-recreational patterns appear to control use with no

escalation to more individual-oriented patterns, thus

circumventing toxic crises.

Taken together, however, the increased frequency of negative

effects and crisis reactions, the escalation of some users to

canpulsive smoking of cocaine free base, the rising psychosocial

and financial and legal costs, all indicate that the last 13

years of changing patterns of cocaine use have been the most

unlucky of its 125 year history. Given the promise of cocaine as

a "renaissance" of the 185Os, the "medical miracle" of the 187Os,

and the "safe recreational drug" of the 197Os, these 13 years

have also been disillusioning. As Mantegazza, who may have

started it all, might have commented, as he did upon recovering

from a coca intoxication full of blissful and fantastic images

only to realize that they were mere hallucinations:

One sighs deeply or laughs madly.

(Mantegazza 1859, p. 39)

SUMMARY

The literature describing contemporary cocaine use from 1970 to

1983 has been reviewed. Short-term studies published on users

observed an initial period of social-recreational use supported

by the belief that cocaine was safe. By the end of this period,

both dosages and chronicity of cocaine use showed an escalation

marked by increased adverse reactions. A longitudinal study

tracked 99 social-recreational users from 1975 to 1983. By 1983,

41 users had dropped out of the study while eight others had

stopped all use. Of the 50 continuing users still in the study

in 1983, 25 remained primarily social users with few negative

effects and no toxic physical or psychological crises. The

remaining 25 users, while engaged in some social use, were more

frequently involved in other patterns. Sixteen users frequently

escalated to circumstantial-situational patterns marked by some

toxic physical effects but no psychological crises. Four users

developed intensified (daily) patterns of use with episodes of

both physical and psychological crisis reactions. Five users

became compulsive users, smoking cocaine free base, and

experienced crisis reactions in approximately 10 percent of their

intoxications. The majority of users attempted to treat the

107
hyperexcitability and stimulation of excessive cocaine use with

multiple drug use or self-initiated strategies of controlled use

or short-term abstinence. It is concluded that many of the

social users are capable of controlling use with no escalation to

more individual-oriented patterns. Others, by escalating

patterns of use, increase the risks of dependency and toxicity.

ACKNOWLEDGMENTS

Preparation of this report was supported by Contract 280-83-2379

from the National Institute on Drug Abuse.

REFERENCES

Anker, A.L., and Crwley, T.J. Use of contingency contracts in

specialty clinics for cocaine abuse. In Harris. L.S., ed.

Problems of Drug Dependence 1981. National Institute on Drug

Abuse Research Monograph 41. (NTIS PB #82-190760). Comittee

on Problems of Drug Dependence, Inc., 1982. pp. 452-459.

Anvil, J.M. Freebase Cocaine. The Greatest Thing Since Sex.

Philadelphia: Flash Post Express, 1979.

Aramayo, G., and Sanchez. M. Clinical manifestations using

cocaine paste. In: Jeri, F.R., ed. Cocaine 1980. Lima: Pacific

Press, 1980. pp. 120-126.

Ashley, R. Cocaine. Its History, Uses and Effects. New York:

St. Martin's Press, 1975.

Davidson, T. The Natural Process. Base-ic Instructions and

Baking Soda Recipe. Tustin: Star Publications, 1981.

Gay, G.R., and Inaba, D.S. Acute and chronic toxicology of

cocaine abuse: Current sociology, treatment, and rehabilitation.

In Mule, S.J., ed. Cocaine: Chemical, Biological, Clinical,

Social and Treatment Aspects. Cleveland: CRC Press, 1976. pp.

245-252.

Gottlieb, A. The Pleasures of Cocaine. Berkeley: And/Or Press,

1976.

Grinspoon, L., and Bakalar, J.B. Cocaine. A Drug and Its Social

Evolution. New York: Basic Books, 1976.

Helfrich, A.A., Crwley, T.J., Atkinson, C.A., and Post, R.D. A

clinical profile of 136 cocaine abusers. In Harris, L.S., ed.

Problems of Drug Dependence 1982. National Institute on Drug

Abuse Research Monograph 43. DHHS Pub. No. (ADM) 83-1264.

Washington, D.C.: Supt. of Docs., U.S. Govt. Print. Off., 1983.

pp. 343-350.

108
Jeri, F.R., Sanchez, C.C., Del Pozo, T., and Fernandez, M. El

sindrome de la pasta de coca. Observaciones en un grupo de 158

pacientes del Area de Lima. Separata de la Revista de la

Sanidad del Ministerio del Interior, 39:1-18, 1978.

Jeri, F.R., Sanchez, C.C., Del Pozo, T., Fernandez, M., and

Carbajal, C. Further experience with the syndranes produced by

coca paste smoking. In Jeri, F.R., ed. Cocaine 1980. Lima:

Pacific Press, 1980. pp. 76-85.

Mantegazza, P. Ymportancia dietetica y medicinal de la Coca. El

Commercio Journal, Jan. 14, 1857.

Mantegazza, P. Sulle Virtio Igienche e Medicinale della Coca, a

Sugli Alimenti Nervosi in Generale [On the Hygienic and

Medicinal Virtues of Coca]. Milan, 1859. In Andrews, G. and

Solomon, D., eds. (Forti, L., and Alhadeff, G., trans.) The

Coca Leaf and Cocaine Papers. New York: Harcourt Brace

Jovanovich, 1975, pp. 38-42.

McConnell, H. Cocaine helpline probes 'hidden' abuser profile.

The Journal, 12(7):4, 1983.

Mortimer, W.G. History of Coca. "The Divine Plant" of the Incas.

New York: J.H. Vail, 1901.

Noya, N.D. Coca and cocaine: A perspective from Bolivia. In

Petersen, R.C., ed. The International Challenge of Drug Abuse.

National Institute on Drug Abuse Research Monograph 19. DHEW

Pub. No. (ADM) 78-654. Washington, D.C.: Supt. of Docs., U.S.

Govt. Print. Off., 1978. pp. 82-90.

Phillips, J.L., and Wynne,R.D. Cocaine. The Mystique and the

Reality. New York: Avon, 1980.

Raye, Pipe Dreams. An Inside Look at Free-Base Cocaine.

Cotati: Family Publishing, 1980.

Resnick, R.B., and Schuyten-Resnick, E. Clinical aspects of

cocaine: Assessment of cocaine abuse behavior in man. In: Mule,

S.J., ed. Cocaine: Chemical, Biological, Clinical, Social and

Treatment Aspects. Cleveland: CRC Press, 1976. pp. 219-228.

Siegel, R.K. Cocaine: Recreational use and intoxication. In

Petersen, R.C., and Stillman, R.C., eds. Cocaine: 1977.

National Institute on Drug Abuse Research Monograph 13. DHEW

Pub. No. (ADM) 77-741. Washington, D.C.: Supt. of Docs., U.S.

Govt. Print. Off., 1977. pp. 119-136.

Siegel, R.K. Cocaine smoking. New England Journal of Medicine,

300(7):373, 1979.

Siegel, R.K. Long-term effects of recreational cocaine use: A

four year study. In Jeri, F.R., ed. Cocaine 1980. Lima:

Pacific Press, 1980. pp. 11-16.

Siegel, R.K. Cocaine smoking. J. Psychoactive Drugs,

14(4):277-359, 1982.

Siegel, R.K. Cocaine: New issues for defense and prosecution.

Drug Law Report, 1983, in press.

Siegel, R.K., and Hirschman, A. Moreno and the first study on

cocaine: A historical note and translation. Journal of

Psychoactive Drugs, 15(3):219-220, 1983.

Spotts, J.V., and Shontz, F.C. The Life Styles of Nine American

Cocaine Users: Trips to the Land of Cockaigne. National

Institute on Drug Abuse Research Issues 16. DHEW Pub. NO. (ADM)

76-392. Washington, D.C.: Supt. of Docs., U.S. Govt. Print.

Off., 1976.

109
Spotts, J.V., and Shontz, F.C. Cocaine Users. New York: The

Free Press, 1980.

Valladolid, M.N. Sindrome de pasta basica de cocaina. Revista

de Neuro-Psiquiatria, 42:114-134, 185-208, 1979.

AUTHOR

Ronald K. Siegel, Ph.D.

Department of Psychiatry and Biobehavioral Sciences

School of Medicine

University of California, Los Angeles

Mailing Address

P.O.B. 84358

Veterans ministration Branch

Los Angeles, California 90073

110
Cocaine Abuse: A Review of

Current and Experimental

Treatments

Herbert D. Kleber and Frank H. Gawin

Cocaine abuse is a rececntly revived drug problem that is again generating great

popular concern. Unfortunately, scientitic evaluation of cocaine abuse

treatment has been surprisingly sparse kind no consensus exists regarding

optimal treatment strategies. This review summarizes current treatment issues

and regimens. as well as preliminary data on new, approaches to cocaine abuse

treatment.

Since this chapter will deal with treatment of the cocaine abuser, it is important

from the outset to define what is meant by that term. Although in some settings

any use of ilegal drugs equals abuse. such a definition is more legal than

medical and will not he used here. Instead. the definition of drug abuse found

elswhere in the field will be employed. namely...“the nonprescription use of

psychoactive chemicals by an individual to alter his her psychological state in a

situation in which the individiual or society incurs some harm” (Kleber 1974).

The great majority of cocaine users applying for treatment fit into this

definition. The most common exception is the individual who defines his use as

recreational. controlled and nonharmful. but is brought to treatment by

another (e.g. spouse, parent), while the significant other views the cocaine use

as harmful and needing to be stopped at once. It can be argued. of course. that

the existence of such a dispute is in itself evidence that “harm” is occurring.

Alternatively, it may be argued that the legal definition is being imposed in such

cases. These issues lead to the question of who “needs” treatment? A broad

answer is: any cocaine user who finds that be cannot stop or significantly cut

back his use in spite of the presence of problems arising from the use.

The above definitions approximate the DSM-III criteria for cocaine abuse: “a

pattern of pathological use. impairment in social or occupational functioning

due to cocaine use, and duration of disturbance of at least one month,“but are

broader in their locus on the individual’s self-perception of harm.

It should also he noted that the studies and impressions reviewed here are based

only on patients who appear for treatment. It is probable that some cocaine

abusers, like some alcohol and nicotine abusers, are able to stop use without

treatment. No data is available indicating what proportion of those who want to

cease cocaine use are able to do so without treatment. Similarly, the strategies

employed and difficulties experienced by those who cease use without

treatment have not been systematically studied. although Siegel has described

longitudinal use patterns which include cessation and abstinence (this volume).

111
COCAINE, ABUSE AND CONCURRENT DISORDERS: DIAGNOSIS

Our clinical experience and the literature agree that individuals who abuse

cocaine arc not a homogenous class. Distinctions in characterization of cocaine

abusers with clear treatment relevance exist primarily along dimensions of

psychiatric symptoms and behavioral-psychosocial disruption.

Greater variation in severity of use may exist in patients seeking treatment for

cocaine abuse than in patients seeking treatment for abuse of other substances

(Gawin and Kleber 1983a, Gold 1983). The typical cocaine user probably,

begins his her use in a similar way to the typical marijuana user. albeit at a later

age. Like marijuana. cocaine has been labelled by popular culture as

“recreational," and most who try it do so with the firm belief that they will have

no difficulty in controlling their consumption. Many people are successful in

such an endeavor; some, however, increase their use and appear for treatment.

The point at which treatment is sought can vary dramatically. Because

of cocaine’s expense, significant psychosocial disruption leading to treatment

can often occur without extreme abuse. The actual abuse in such cases is

similar to that occurring with substances such as nicotine and marijuana. At the other end of the cocaine abuse spectrum lies very heavy intravenous (Gawin and Kleber 1983a) or freebase cocaine abuse (Siegel 1982),

which is continuous for prolonged periods, in a pattern very similar to that

observed in intravenous methamphetamine addicts (Kramer et al. 1967) over a

decade ago. Treatment needs within this diverse population vary based on

severity. Flexibility is therefore necessary in designing treatments for cocaine

abusers.

Route of administration has been used as an indication of the probability that

disruptive use patterns will develop. This has prompted recent controversy

(Helfrich et al. 1983). Severe cocaine abuse has been considered a sequel of

administration by routes that provide very rapid changes in plasma stimulant

levels, such as intravenous use or cocaine freebase smoking (Siegel 1982;

Van Dyke and Bach 1982). Intranasal use has been popularly considered

comparatively mild abuse of a “nonaddicting,” “safe” stimulant (Grinspoon

and Bakalar 1976). Preliminary evaluations of patients appearing for treatment

contradict the assumption that intranasal administration is not associated with

severe cocaine abuse. Route of administration is not significantly related to

psychosocial disruption (Gawin and Kleber 1983a: Helfrich et al. 1983),

neuroendocrine abnormalities (Gawin and Kleber 1983b), or psychiatric

diagnoses (Gawin and Kleber 1983a; Weiss et al. 1983). These data support the

impression that severe cocaine abuse can develop with any route of

administration. However. our experience and that of others is also that

intravenous abusers or cocaine freebase smokers are more likely to develop

significant distress requiring treatment. Epidemiologic study comparing

distress and the need for treatment with mode of administration in the general

population of cocaine users has not been done and should be extremely difficult

to implement. Since severity of cocaine abuse cannot be determined simply on

112
the basis of route of administration, other factors, such as dosage. pattern and

duration of use, degree of psychosocial disruption and impulse control, and

medical and psychiatric characteristics. also require evaluation in assessing

severity of cocaine usage and treatment needs. No research clearly: demarcating

the contribution of each of these factors or of others to “severity” has been

done; therefore. assessments remain based, at present. on clinical impressions

and evaluation.

Variations also exist in the psychiatric characterization of cocaine abusers.

Detailed modern psychiatric descriptions are limited. Past attempts have

focused on nondiagnostic characterization using instruments such as the

MMPI (Helfrich et al. 1983; Siegel 1977) or have focused on personality

attributes or psychoanalytic formulations of cocaine abusers (Khantzian 1979;

Wieder and Kaplan 1969; Wurmser 1974). and the relevance of such work to

treatment decisions is unclear. Drug abusers, in general, have been observed to

self-regulate painful feelings and psychiatric symptoms via their drug use

(Khantzian 1981; Rounsaville et al. 1982). If cocaine use occurs as selfmedication. conventional treatments modulating self-medicated

symptoms would be indicated. The most important and clearly treatable

disorders of this type correspond to DSM-III axis I categories. Only two

studies of DSM-III axis I symptomatology in cocaine abusers exist. Weiss et

al. (1983) recently presented DSM-III diagnostic data for 30 hospitalized

cocaine abusers, and Gawin and Kleber (1983a) reported Axis 1 data on 17

outpatient cocaine abusers. These independent studies generated very similar

results, with depressive disorders (Major depression, Dysthymic disorder.

Atypical depression) appearing in 30 percent and bipolar disorders (including

Cyclothymic disorder) in 20 percent of each sample. Also, a smaller hut

possibly important sub-group of patients with Attention Deficit DisorderResidual Type (ADD) existed in each sample. Thus a large proportion of

cocaine abusers could be self-medicating. Since more and larger studies have

not yet been done and methodologic problems require clarification (Gawin and

Kleber 1983a). the actual prevalence, and therapeutic relevance. of Axis l-like

psychiatric disorder in cocaine abusers requires further examination.

Accurate psychiatric and behavioral characterization of the cocaine abuser is

important because symptomatology appearing during abstinence could

theoretically provide important guides both to when and what pharmacological

adjuncts are indicated (Gawin and Kleber 1983c). However, the meaning and

importance of such symptoms are at present based only on the self-medication

hypothesis. Two further issues confuse the interpretation of symptoms in

cocaine abuse. First. definitive diagnoses of psychiatric illness other than

substance abuse are difficult to make in the context of active drug abuse

because symptoms may arise secondarily from the drug use itself, rather than

preceding the drug abuse. Second, clarification between the acute depressive

symptomatology occurring immediately after an episode of cocaine use (the

post-cocaine “crash”) and more enduring symptomatology independent of

specific use episodes is also difficult. Thus investigators in the studies thus far

have attempted to circumvent these issues by gathering extensive historical and

113
corroborating family history data, and by repeated longitudinal evaluations

isolated from periods of acute cocaine use and post-cocaine symptomatology

However, these "diagnostic" studies must be considered tentative in the

absence of prospective study or more elaborate investigation because

exclusinoary criteria based on substance abuse could not be applied

The “diagnoses” in the studies cited may nonetheless be useful as simple

descriptions of the clinical state of cocaine abusers. Since symptoms in the

cocaine abuser could indicate the presence of enduring cocaine-induced

disorders which mimic psychiatric syndromes, or subclinical susceptibility

to psychopathology aggravated by cocaine abuse. and both of these potential

consequences of cocaine use could be responsive to conventional therapies, it is

possible that distinctions between antecedent or consequent symptomatology

would not determine initial pharmacological treatment choice. Such

distinctions could. however, still affect issues such as duration of treatment or

prophylactic treatment and require evaluation.

Two groups of pilot efforts that reflect diagnosis in the context of cocaine abuse

treatment have been reported. These studies are all non-blind, non-placebo

preliminary examinations. The first group consists of descriptions of a total of

seven cocaine abusers with diagnoses of ADD by Khantzian et al. (1983a.

l983b) and Weiss et al. (1983). Six responded to appropriate stimulant

medications. The second study consists of a structured open trial of lithium and

desipramine (Gawin and Kleber 1983c) in which lithium administration was

associated with cessation of cocaine abuse and diminished cocaine craving in

several cyclothymic patients, while non-cyclothymic cocaine abusers did not

appear to benefit from lithium. Desipramine also appeared beneficial. but

independently of diagnosis. This treatment is discussed more fully in the

discussion of pharmacotherapy below. In all, these reports indicate that ADDResidual Type and cyclothymic disorder bipolar disorder may comprise

subgroups of cocaine abusers with distinct treatment needs. More definitive

research is obviously needed to substantiate these studies. Future research

would benefit from uniform attention to diagnostic issues and to nonhomogeneity among cocaine abusers.

Treatment of thc acute complications sometimes associated with cocaine abuse

is based on clinical experience rather than rigorous comparisons. Medical

complications of acute cocaine use and their treatment are reviewed elsewhere

(Gay 1982). Acute psychiatric complications occur in three areas. These

include dysphoric agitation, psychotic symptoms, and acute, severe post-use

depression. Gay (1982) and Rappolt et al. (1977) employ, diazepam for

transient agitation and desribe dramatic amelioration of symptoms with

addition of propranolol for more persistent cases. Neuroleptics are routinely

used for brief periods for severe cocaine-associated psychotic symptoms. The

present authors employ chlorpromazine because of its sedative properties and

because evidence from primate studies indicates that a potential interaction

between cocaine’s epileptogenic effects and decreased seizure threshold

associated with neuroleplics does not occur. Instead chlorpromazine

substantially antagonizes epileptogenic and lethal effects of cocaine (Guinn et

114
al. 1980). It should be noted that the same study reported increased seizure

susceptibility and decreased mean lethal cocaine dose with propranolol. but the

clinical significance of this is unclear, since Gay et al. (1982) have administered

propranolol in several hundred cases without major untoward effects. Finally,

suicidal ideation and other depressive symptomatology often occur during the

post-cocaine “crash.” Such symptoms are usually transient, require no acute

treatment other than close observation, and resolve following sleep

normalization (Gawin and Kleber 1983a). Prolonged severe depression was

discussed earlier. Also, psychotic symptoms may be short-lived in cocaine

abuse and usually remit following sleep normalization.

COCAINE ABUSE TREATMENT STRATEGIES

Strategies devised to treat cocaine abuse have existed since its intractable lure

for some first became obvious almost a century ago. During this period no

generally accepted or successful treatment has emerged. Chronic cocaine abuse

has been assumed to cause no physiologic withdrawal state on discontinuation

because of insufficient evidence for an abstinence syndrome of major

physiological changes. like the classic sort characterizing sedative or opiate

withdrawal (Glatt 1974; Grinspoon and Bakalar 1980; Woods and Downs

1973). Cocaine abuse has thus been assumed to be a “psychological

dependence” rather than one involving neurophysiological adaptations, and

currently used treatments consist of psychological strategies aimed at

modifying addictive behaviors. Issues related to current psychological

strategies will be discussed first, followed by a summary of evidence indicating

cocaine abuse may cause neuroadaptation. The latter includes a review of

pharmacological strategies, aimed at reversal of such adaptation, which may

hold future potential as adjuncts in cocaine abuse treatment.

Current Treatments

Only two comprehensive efforts at cocaine abuse treatment are described in the

modern literature. Both are nonpharmacological, but each involves a very

different approach to treatment. Anker and Crowley (1982) have adapted the

behavioral method of contingency contracting (Boudin 1972; Ross and Jones

1973) for cocaine abuse. The contract involves such contingencies as the

therapist’s holding letters of notification of cocaine abuse or resignation of

professional licenses, written by the patient with content chosen specifically

because of severe irrevocable personal effects, and mailing them to drug

enforcement authorities, employers, or licensing boards upon finding evidence

of cocaine use in urinalysis or after missed urinalysis. Such treatment appears

to effectively induce abstinence in those willing to take part. Anker and

Crowley report 48% of their sample were willing to engage in this treatment,

with over 90% cocaine abstinence during the duration of the “contract." Over

half of these patients relapsed following completion of the "contract”(Crowley

1982), however, even though the sample was a presumably well motivated and

well educated group. The patients declining “contracts” (52%) were treated

with supportive psychotherapy which was also used as an additional

intervention in those accepting contracts. All noncontract patients nonetheless

115
dropped out and or resumed cocaine abuse within 2 to 4 weeks. In this case, the

consequences used with the behavioral treatment technique may have been

unnecessarily punitive and may reduce the clients’ willingness to become

involved in treatment. Anker and Crowley present no comparisons of severity

of cocaine use and thus ignore the likely possibility that cocaine abusers with

severe craving and problems of control recognize their inability to comply and

consequently avoid what for them would simply become destructive treatment.

In addition to problems of long-term efficacy and possible inapplicability to

more severe cocaine abuse, obvious ethical problems exist in those cases where

the procedure could have been based on positive reinforcement or on less

aversive techniques. That is, when negative rather than positive reinforcement

procedures arc applied, an obligation to use the least deleterious technique

exists. Variations in “contract” design, such as employing contingencies

graduated in severity. or a top contingency level with less drastic consequences,

or applying positive contingencies for abstinence (e.g.. starting with a sum of

money from the patient and giving part back each week for clean urines) could

also circumvent the problems noted. Some cases might optimally need a

combination of both positive and negative reinforcement. These variations

have not yet been examined in cocaine abuse treatment. Thus, optimal ways of

applying the promising approach of contingency contracting will become clear

only after further investigation. Broader behavioral intervention techniques

have been widely applied and studied in treatment of diverse forms of drug

abuse (Grabowski et al. 1984) but other behavioral techniques have not been

subject to outcome studies in cocaine abuse. Cocaine abusers are usually

treated with more conventional psychotherapies. Except for one description,

however. such treatments and their orientations have not been reported in the

literature. In the one study reported, Siegel (1982) describes a treatment

approach using frequent supportive psychotherapy sessions, self-control

strategies, “exercise therapy,” and liberal hospitalization during initial

“detoxification." This treatment aims at initially separating the user from the

use-fostering environment via external controls, and then gradually facilitating

internalization of controls through psychotherapy. Half of Siegel’s sample of

32 heavy cocaine smokers dropped out, but 80% of those remaining were

cocaine-free at 9-month followup.

Almost all psychotherapeutic treatment of cocaine abusers can be organized

around three dimensions (Rounsaville et al. 1983). These are: (1) To help the

abuser recognize deleterious effects of cocaine use and accept the need to stop

it. Anker et al.‘s treatment approach emphasizes this area. (2) To help the

abuser manage impulsive behavior in general. and cocaine use in particular; for

example, exploring ways to disassociate the abuser from cocaine use situations

and cocaine sources. Such supportive functions are emphasized in Siegel’s

treatment approach. (3) To bring the abuser to an understanding of the

functions that cocaine has played in his life and to help him serve these

functions without drugs. For example. cocaine can serve narcissistic needs

through the glamor associated with its use (or by direct pharmacological

effects). needs for identity via the social networks and drug-using subculture

associated with it. and anaclitic needs via possible facilitation of intimate

interpersonal interactions. among many others. These three dimensions are

116
present, in varying degrees. in virtually all cocaine abuse treatment programs.

They correspond closely to behavioral, supportive, and psychodynamic

orientations to psychotherapy. The authors feel all three orientations are

necessary in the treatment of cocaine abusers, but their admixture is best

determined by taking into account the needs of the individual cocaine abuser at

the time of seeking treatment. rather than by simple program structure. For

example, patients in Anker and Crowley’s (1982) study who refused

contingency contracts could be approached from psychodynamic or supportive

perspectives. The authors’ clinical impression is that severe cocaine abusers

acutely attemptingabstinencedo not respond to psychodynamic interventions.

while moderate abusers may be more readily able to utilize them. Hence choice

of primary therapeutic orientation might shift from behavioral to psychodynamic to supportive as severity increases, The authors’approach to the

psychotherapy of cocaine abusers is described more fully elsewhere

(Rounsaville et al. 1983). These notions have not as yet received any empirical

testing.

Whether inpatient or outpatient treatment is indicated, and for whom, is also

somewhat controversial. Siegel’s study and earlier work in stimulant abuse

(AMA Council 1978; Connell 1970) both strongly advocate hospitaliration for

initial detoxification. However, in Anker and Crowley’s (1982) study and

Gawin and Kleber’s (1983c) study using pharmacological adjuncts,

hositaliration was usually not indicated. It is likely that this also reflects

severity. Siegel’s subjects were very heavy cocaine smokers who were minimally

treated with adjunctive pharmacotherapy and may have been incapable of

combating cocaine craving without hospitalization and seclusion from cocaine

sources. These circumstances can require hospitalization, as can the existence

of severe acute depressive or psychotic symptoms, multiple drug dependence

especially involving sedative drugs, and previous failure(s) of the outpatient

approach. The question needs to be raised, however, of whether inpatient

treatment for the initial treatment of cocaine abuse is not too uniformly

employed. It is known that relapse following hospitalization is quite high. This

is consistent with studies of animal behavior (Goldberg et al. 1979; Spealman et

al. 1977) and clinical work (Maddux and Desmond 1982; Wikler 1973) with

drug abusers that point out the importance of environment and conditioning in

drug-taking behavior. Cocaine abusers ultimately have to maintain abstinence

within the general setting where abuse developed. and our impression is that a

period of abstinence within the context of everyday stimuli and stressors, akin

to a period of “extinction,” is a necessary prerequisite to consistent long-term

reductions in craving. Hospitalization in many cases may thus simply delay

confrontation with fundamental issues determining long-term outcome. Also,

since many subjects in Gawin and Kleber’s study were also severe abusers but

did not require hospitalization, severity alone may not be an index of need for

inpatient treatment. This area requires further attention and clarification. The

current almost ubiquitous presence of cocaine in many areas of American life

makes it unlikely that the former user will simply be able to avoid temptation.

Like the former cigarette smoker or alcoholic, the person attempting to give up

cocaine must make the drug “psychologically unavailable” since it is so hard to

make it physically unavailable.

117
A final psychological approach to cocaine abuse is the self-help group modeled

after A.A. Some former abusers have reported significant help either from

A.A. or N.A. (Narcotics Anonymous). Structure. group support, a religious

tenor, and availability of an around-the-clock helping network have been of

important assistance for some abusers. Some inpatient programs combine the

confrontation groups long in use at residential therapeutic communities for

narcotic addicts such as Daytop Village with heavy N.A. emphasis. No

outcome studies of these programs for cocaine abusers have been reported.

Treatment of chronic cocaine abuse as currently practiced is vaguely defined

and difficult to evaluate. The more structured treatments of Anker and

Crowley (1982) and Siegel (1982), which are both intensive efforts, can claim

long-term effectiveness in 25% and 40% of the total number of patients initially

seeking treatment. Most other cocaine abuse treatment presently heing

conducted has received no systematic evaluation. is based on nonspecific

psychological treatments for general substance misuse with no particular

attention to the specific difficulties of cocaine abuse, and appears to be even less

effective than the treatments reviewed above. Such treatment, focused on

simple abstinence and psychotherapeutic management., has been recently

characterized as “ineffective and idealistic” (Van Dyke and Byck, in press).

Treatment strategies for abusers of other stimulants, such as amphetamine

(AMA Council 1978; Connell 1970) have been similar to the treatment

described by Siegel and provide no additional knowledge applicable to cocaine

abuse treatment. There thus appears to be a substantial need for new and

effective treatments of cocaine abuse.

Potential New Directions in Treatment

Despite the past assumption that cocaine abuse is a “psychological addiction,”

it is plausible that chronic cocaine abuse could lead to neurophysiologic

adaptations which require more than psychological intervention. Cocaine

exerts its effects neurochemically. The nervous system’s usual response to

persistent neurochemicat perturbation is compensatory adaptation. It is

illogical to assume that this does not occur or is unimportant in cocaine abuse.

This does not rnean a classic abstinence syndrome and tolerence uniformly

occur; rather chronic high dose use may generate sustained neurophysiological

modification whose clinical expression is psychological.

Neuroadaptation following extensive chronic cocaine use is suggested by

presence of persistent post-cocaine symptomatology (Blum 1976; Ellinwood

1977; Jaffe 1980; Siegel 1982). evidence that enduring neurophysiologic

changes occur in animals following chronic cocaine administration (Banerjee

et al. 1979; Borison et al. 1979; Chanda et al. 1979; Pert et al. 1979; Taylor et

at. 1979). preliminary data indicating neuroendocrine abnormalities may be

associated with cocaine ”withdrawal”(Gawin and Kleber 1983b). and reports

that pharmacologic interventions (Cronson and Flemenbaum 1978; Ellinwood

1977; Gold and Byck 1978; Mandell and Knapp 1976; Resnick et al. 1977;

Smith and Wesson 1980) may facilitate cocaine abstinence. Pharmacologic

interventions in cocaine abuse could thus be useful, but pharmacotherapy

118
aimed at correcting presumably cocaine-altered neurophysiologic states has

not been systematically examined.

The following review outlines evidence indicating that desipramine, lithium.

and methylphenidate could each facilitate cocaine abstinence, by different

mechanisms. Although these are the same treatments discussed earlier in

relationship to diagnosis, we wish to make clear that the following discussion

pertains to the possible use of these agents as general treatments, irrespective of

distinctions in symptomatology. Some points at which “diagnosis” may

interact with general treatments will. however, be noted.

Tricyclic Antidepressants (TCAs)

Animal research on neurotransmitter and receptor changes following chronic

cocaine suggests long-term effects possibly reversible by treatment with TCAs.

Studies of receptor changes in animals, measured by radioligand binding,

report increased beta-adrenergic (Banerjee et al. 1979; Chanda et al. 1979; Pert

et al. 1979), alpha-adrenergic (Pert et al. 1979), and dopaminergic (Borison et

al. 1979; Taylor et al. 1979) receptor binding. Receptor supersensitivity (betaadrenergic or dopaminergic) could be a neurochemical substrate for postcocaine dysphoria or craving.

One study (Gawin and Kleber 1983b) also shows some human cocaine abusers

have elevated plasma growth hormone and decreased plasma prolactin,

findings that are consistent with the adrenergic and dopaminergic receptor

changes in animals. Beta-adrenergic supersensitivity has been hypothesized to

be a cause of depressive illness, and beta-adrenergic subsensitivity, which can

be induced by different types of antidepressant treatments may explain

antidepressant effectiveness (Charney et al. 1981; Maggi et al. 1980; Sulser et

al. 1978). Dopaminergic receptor changes following antidepressant treatment

(Koide and Matshushita 1981; Naber et al. 1980) also are in the opposite

direction from those occurring following chronic cocaine use, and could be

even more important, since dopamine may mediate acute cocaine euphoria

(Wise 1980), and craving or dysphoria after chronic cocaine could be based on

adaptations within dopaminergic systems (Gawin and Kleber 1983c).

Additional support comes from studies done on amphetamine. Evidence from

acute experiments in humans (Fischman et al. 1976), observations of the

post-use state (Cassems et al. 198 I; Kosman and Unna 1968; Leith and Barrett

1976; Schildkraut et al. 1971; Watson et al. 1972) as well as animal behavioral

(Colpaert et al. 1979; Leith and Barrett 1976; Leith and Barrett 1981),

electrophysiological (Colpaert et al. 1979; Kokinidis and Zacharko 1980; Leith

and Barrett 1976; Leith and Barrett 1981; Simpson 1974; Simpson and Annau

1977), and neurochemical studies (Post et al. 1976; Schildkraut et al. 1971;

Watson et al. 1972) indicate that generalization to cocaine from amphetamine

data is appropriate. Reports indicate that treatment with TCAs reverses

chronic amphetamine-induced decreases in self-stimulation (Simpson 1974), a

possible model for stimulant craving and its treatment. TCAs also appear to

have effects opposite to those of cocaine on urinary MHPG (Cobbin et al. 1979;

Goodwin et al. 1975: Perry et al. 1981).

119
These data lend neurochemical plausibility to the clinical observation that

TCA therapy can be helpful in treating the cocaine abuser (Blum 1976;

Ellinwood 1977; Siegel 1982; Smith and Wesson 1980). However, little

systematic evaluation of TCA treatment of cocaine abusers has been done.

Tennant and Rawson (1983) reported anecdotal data that desipramine

facilitated abstinence in 14 cocaine abusers, but their study was based on a

rationale involving acute desipramine-induced decreases in noradrenalin

reuptake rather than receptor changes, and consequently 11 of their subjects

received desipramine less than 7 days. The other 3 subjects were not described.

Also. several methodologic shortcomings (Gawin and Kleber 1983c) and

limited followup make the meaning of this report unclear. Gawin and Kleber

(1983c) report prolonged desipramine treatment in 6 subjects, systematically

evaluating cocaine use, craving, and psychosocial function. All 6 demonstrated

prolonged abstinence (> 12 weeks). and craving decrease followed a delayed

time course consistent with desipramine’s time course for neuroreceptor

changes and its known clinical characteristics in depression. Unlike Tennant

and Rawson’s (1983) results, half of the patients continued cocaine use

throughout the first week and until the third week of treatment. Two of the

subjects had diagnoses of major depressive disorder, but the remainder did not,

and displayed desipramine-associated craving decreases and abstinencefacilitating effects despite lack of neurovgetative symptoms and prior

treatment failures. Although the above results are encouraging, the reports

cited were both non-blind and uncontrolled. Further more rigorous studies

with larger sample size are needed before any conclusions arc drawn regarding

desipramine use in cocaine abuse treatment.

Lithium Carbonate

Lithium carbonate treatment has been advocated for stimulant abuse

(Buchsbaum et al. 1977; Flemenbaum 1974; Gold and Byck 1978; Knapp and

Mandell 1975; Mandell and Knapp 1976; Resnick et al. 1977; VanKammen and

Murphy 1975) based on lithium’s antagonism of multiple acute stimulant

effects including euphoria. Lithium blocks behavioral (Berggren et al. 1978;

Cox et al. 1971; Davies et al. 1974; Furukawa et al. 1975; Lal and Sourkes 1972;

Poitou et al. l975), electrophysiologic (Cassems et al. 1973; Colpaert et al.

1979). and neurochemical (Cobbin et al. 1979; Scheel-Kruger et al. 1977;

Simpson and Annau 1977) effects of acute cocaine and amphetamine. Case

studies report blockade of amphetamine euphoria by lithium (Flemenbaum

1974), as does one doubleblind placebo-controlled study of 11 depressed

patients (VanKammen and Murphy 1975). Lithium had more variable results

on amphetamine euphoria in 8 patients with personality disorders (Angrist and

Gershon 1979). In several case studies (Cronson and Flemenbaum 1978; Gold

and Byck 1978; Mandell and Knapp 1976) lithium attenuated cocaine-induced

euphoria. Decreasing cocaine usage during the lithium treatment was also

reported. Lithium did not block i.v. cocaine euphoria in an experiment done on

6 methadone-treated opiate addicts with significant cocaine abuse (Resnick et

al. 1977). In the latter study (not a direct treatment evaluation). lithium

administration was associated with decreases in cocaine abuse. despite lack of

euphoria-attenuating effects. Studies of other stimulants (Huey et al. 1981;

120
Jarbe 1978; Wald et al. 1978) report similar results. In both studies of

stimulants reporting no lithium blockade (Resnick et al. 1977; Wald et al. 1978)

the agents were administered intravenously in relatively large boluses. Studies

using other routes of administration do report blockade. Lithium effects may

thus be competitively antagonized by large abrupt increases in stimulant blood

levels. Since much street cocaine use is intranasal, the practical impact of this

possibility on treatment is unclear and merits examination.

Overall, neurochemical evidence clearly indicates lithium has multiple acute

effects which counteract those of cocaine. Clinical evidence further indicates

that such properties may be useful in the treatment of stimulant abusers;

however placebo-controlled studies do not exist. In the study by Gawin and

Kleber (1983c) cited in the discussion of diagnosis, the responding cyclothymic

subjects did not use cocaine to test euphoria-blocking effects, but the

nonresponding patients reported cocaine euphoria was unchanged in intensity.

Some suggestion of decreased duration of euphoria was noted, but this did not

appear to be therapeutically useful.

Although the theoretical focus in lithium treatment of cocaine abuse has been

on blockade, another potential mechanism of action exists. Lithium is reported

to modulate fluctuations in functional receptor activity (Bunney and Garland

1983). Lithium’s effectiveness in bipolar patients could be due to damping of

abnormal oscillations of select neuroreceptor populations (Bunney et al. 1977).

Lithium might reverse cocaine-induced neurophysiologic changes in a manner

similar to that postulated for desipramine. Further, if cocaine causes receptor

changes, bipolar or cyclothymic patients might be more sensitive to both such

cocaine effects and to opposite lithium effects. This could explain any

diagnostic specificity found in lithium treatment of cocaine abuse. In all,

lithium’s efficacy, diagnostic specificity, and possible mechanisms of action in

cocaine abuse treatment all require further study.

Methylphenidate (MPH)

There is experimental evidence logically supporting possible clinical usefulness

of MPH as a general treatment for severe cocaine abuse. Stimulant “high” in

humans appears to be related to both plasma stimulant level prior to an

additive increment and to the characteristics of plasma level changes, rather

than to simple absolute plasma level (Van Dyke et al. 1982; Zahler et al. 1982).

Increases of plasma stimulant level in subjects with preexistent stimulant

concentrations may correspond to less euphoric effect than identical increases

in plasma level in subjects with a stimulant-free baseline. Similarly, increases

occurring slowly may correspond to less subjective euphoria than increases

occurring more rapidly. Self-administration data in animals also support this

phenomenon (Balster and Schuster 1973; Brady and Griffiths 1977) which has

been called “acute tolerance.”

Since methylphenidate produces euphoria indistinguishable from amphetamine (Brown et al. 1978) and, presumably, cocaine, MPH could produce

consistent tolerance-sustaining effects. Through such an acute “cross tolerance,”

a given dose of cocaine might be less euphorigenic and have less abuse liability.

121
This is similar to high dose methadone maintenance causing Longer term

tolerance to opiates, thereby reducing heroin euphoria and abuse. Unlike

methadone, however, MPH tolerance would end sooner, requiring more

frequent administration, due to its shorter half life.

Although MPH is an abusable euphorigen, it has advantages parallel to

methadone administration. The advantages of medical dispensation include

controlled dosage, decreased legal risk, economic stabilization, and a breaking

of “street” associations and secondary abuse reinforcers. In preliminary use,

cocaine abusers considered MPH far less desirable than cocaine, decreasing

compliance. Attenuated cocaine effects and decreased abuse were reported

when compliance occurred (Gawin and Kleber 1983d) in three pilot non-ADD

patients treated by the authors; but abstinence from cocaine was not sustained,

and it is unclear whether methylphenidate has practical utility as a general

treatment. In all, methylphenidate may be similar to lithium, with treatment

response in the few reports available occurring only in one diagnostic subgroup

(ADD-residual type) and not in other cocaine abusers.

The potential pharmacotherapies described simply represent the treatment

rationales available given the state of current theory and research. Much is

unknown, and other possibilities also exist.

Conclusions

Single focus approaches are generally ineffective in drug abuse treatment. A

number of approaches to cocaine abuse are in current use and a number of

issues require resolution. Preliminary data on pharmacologic treatments are

beginning to appear and pharmacologic adjuncts may show promise in the

future. However, it currently appears no more likely that any unimodal

approach to cocaine abuse treatment will arise than it has for opiate abusers.

Integration of various approaches based on the needs of the patients seems

indicated instead. A possible schema illustrating this and utilizing the

impressions and preliminary studies reviewed here is presented in figure I.

Before any such schema is used in clinical practice, however, detailed

comprehensive research will be needed.

122
FIGURE 1

Possible Future Guidelines for Cocaine Abuse Treatment

Cocaine Abuse Psychotherapeutic Pharmacotherapeutic

Seveity Approach Approach

Mild Behavioral with or None

without Psychodynamic

Moderate Supportive and Only if psychiatric

Psychodynamic with or diagnosis is present.

without Behavioral Choice of agent based on

sysptoms. If no treatble

diagnosis exists, general

treatment (desipramine)

may be usefully tried in

difficult cases.

Severe Supportive, with or General treatment

without hospitalization (desipramine) indicated

for acute phase; then as unless diagnosis dictates

in "moderate" another treatment choice

REFRENCES

Angrist, B. and Gershon, S. Variable attenuation of amphetamine effects by

lithium. American J. of Psychiatry, 136:806-810, 1979.

Anker, A.L., and Crowley, T.J. Use of contingency in speciality clinics for

cocaine abuse. In: Harris. L.S., ed. Problems of Drug Dependence 1981.

National Institute for Drug Abuse Research Monograph 41. Committee on

Problems of Drug Dcpendcnce Inc.: 452-459, 1982.

AMA Council on Scientific Affairs. Clinical aspects of amphetamine abuse.

JAMA, 240(21): 2317-2319, 1978.

Balster, R.L., and Schuster, C.R. Fixed interval schedule of cocaine

reinforcement: Effect of dose and infusion duration. J Exper Anal Behav,

20:119-129, 1973.

Banerjee, S.P. Sharma, V.K., King-Cheung, L.S., Chanda, S.K., and Rigg,

S.J. Cocaine and d-amphetamine induce changes in central B-adrenoceptor.

sensitivity: Effects of acute and chronic drug treatment. Brain Research,

175: 119-130, 1979.

Berggen, U., Tallstedt, G., and Ahlenius, S. The effect of lithium on

amphetanime-induced locomotor stimulation. Psychopharmacology, 59:

41-45, 1978

Blum, K. Depressive states induced by drugs of abuse: Clinical evidence.

theorectical mechanisms and proposed treatment. Part II. J Psychedelic

Drugs, 8:235-262, 1970.

123
Borison, R.L., Hitri, A., Klawans, H.L., and Diamond, B.I. A new animal

model for schizophrenia: Behavioral and receptor binding studies. In: E.

Usdin, ed. Catecholamines: Basic and Clinical Frontiers. New York:

Pergamon Pres, 1979.

Boudin, H.M. Contingency contracting as a therapeutic tool in the deceleration

of amphetamine use. Behav Ther, 3:604-608. 1972.

Brady, J., and Griffiths, R. Drug maintained performance and stimulant

reinforcing effects In. Ellinwood, E.H., and Kilbey, M.M. eds., Cocaine

and Other Stimulants. New York: Plenum Press, 1977.

Brown, W.A., Corriveau, P.; and Egert, M.H. Acute psychologic and

neuroendocrine effects of dextroamphetamine and methylphenidate.

Psychopharmacology, 58:189-195. 1978.

Buchsbaum, M.S., VanKammen, D., and Murphy, D. Individual differences

in average evoked responses to d- and 1- amphetamine with and without

lithium carbonate in depressed patients. Psychopharmacology, 51:129-

135, 1977.

Bunney, W.E., and Garland, B.I., Possible receptor effects of chronic lithium

administration. Neuropharmacology, 22:367-373, 1983.

Bunney, W.E., Post, R.M., Anderson, A.E., and Kopanda, R.T. A neuronal

receptor sensitivity mechanism in affective illness (a review of evidence).

Commun Psychopharmacol, 1:393-305, 1977.

Cassems, G., Actor, C., Kling, M., and Shildkraut, J.J. Amphetamine

withdrawal: Effects on threshold of intracranial reinforcement, Psychopharmacology, 73: 318-322, 1981.

Cassems, G.P., Mills, A.W., and Mills, A.W. lithtum and amphetamines:

Opposite effects on threshold of intracranial reinforcements. Psychopharmacologia, 30:283-290, 1973.

Chanda, S.K., Sharma, V.K., and Banerjee, S.P. B-adrenoceptor sensitivity

following psychotropic drug treatment. In: Usdin F., ed. Catecholamines:

Basic and Clinical Frontiers. New York: Pergamon Press, 1979.

Charney, D.S., Menkes, D.B., and Heninger, G.R. Receptor sensitivity and the

mechanism of action of antidepressant treatment. Arch Gen Psychiatry, 38:

1160-1180, 1981.

Cobbin, D.M., Requin-Blow, B., Williams, L.R., and Williams, W.O. Urinary

MHPG levels and tricyclic antidepressant drug selection. Arch Gen

Psychiatry, 36:1111-1114, 1979.

Colpaert, F.C., Niemegeers, C.J.; and Janssen, P.A. Discriminative stimulus

properties of cocaine: Neuropharmacological characteristics as

derived from stimulus generalization experiments. Pharm, Biochem and

Behav, 10:535-546, 1979.

Connell, P.H. Some observations concerning amphetamine misuse: Its

diagnosis. management. and treatment with special reference to research

needs. In: Wittenborn, J.R., Brill, H., Smith, J.P., and Wittenborn, S.A. et

al., eds. Drugs and Youth, Springfield, Il.: Charles C. Thomas 1970.

Cox, G., Harrison-Read, P.E., Steinberg, H., and Tomkiewics, M. Lithium

reduced drug-induced hyperactivity in rats. Nature, 232:336, 1971.

Cronson, A.J., and Flemenbaum, A. Antagonism of cocaine highs by lithium.

Am J Psychiatry, 135:856-857, 1978.

124
Crowley, T. Quoted in “Reinforcing Drug-Free Lifestyles.“ADAMHA News,

p. 3, August 27, 1982.

Davies, C., Sanger, D.L., Steinberg, H., Tombiewicz, M., and U'Prichard,

D.C. Lithium and a-methyl-p-tyrosine prevent “manic” activity in rodents.

Psychopharmacologia, 36:263, 1974.

Ellinwood, E.H. Amphetamine and cocaine. In: .Jarvik, M.E. ed. Psychopharmacology in the Practice in Medicine. New York: Appleton-CenturyCrofts, 1977. pp. 467-476.

Fischman, M.W., Schuster, C.R., Resnekov , I., Shick, J.F.E., Krasnegor, H.,

Fennel, W., and Freedman, D.X. Cardiovascular and subjective effect of

intravenous cocaine administration in humans. Arch Gen Psychiatry, 33:

983-989, 1976.

Flemenbaum, A. Does lithium block the effects of amphetatmine? A report of

three cases. Am J Psychother, 131:820-821, 1974.

Furukawa, T., Ushizima, I., and Ono, N. Modifications by lithium of

behavioral responses to methamphetamine and tetrabenazine. Psychopharmacologia, 42:243-248, 1975.

Gawin, F.H., and Kleber, H.D. Cocaine abuse: Abstinence symptomatology

and psychiatric diagnosis, l983a. submitted.

Gawin, F.H., and Kleber, H.D. Neuroendocrine findings in chronic cocaine

abusers. A preliminary report, 1983b, submitted.

Gawin, F.H., and Kleber, H.D. Cocaine abuse treatment. : An open pilot trial

with lithium and desipramine, Arch Gen Psych (In Press) 1983c.

Gawin, F.H., and Kleber, H.D. Methylphenidate treatments of non-ADD

cocaine abusers, l983d, submitted.

Gay, G.R. Clinical management of acute and chronic cocaine poisoning. Ann

 Emerg Med, 11:562-572, 1982.

Glatt, M.M. A Guide to Addiction and its Treatments, New York: Wiley, 1974.

Gold, M.S. 800 Cocaine The first two weeks. Mimeographed report. Fair

Oaks Hospital, Summit, N.J., 1983.

Gold, M.S., and Byck, R. Lithium, naloxone, endorphins, and opiate

receptors: Possible relevance to pathological and drug-induced manic-euphoric

states in man. The International Challenge of Drug Abuse. National

Institute of Drug Abuse Research Monograph Series 19 DHEW Pub. No.

(ADM) 78-654. Washington D.C.: Supt. of Docs., U.S. Gov. Print.

Off., 1978. pp. 192-209.

Goldberg, S.R., Spealman, R.D., and Kelleher, R.T. Enhancement of drug

seeking behavior by environmental stimuli associated with cocaine or morphine

injections. Neuropharmacology, 18:1015-1017, 1979.

Goodwin, F.K., Post, R.M., and Sack, R.I., Clinical evidence for

neurochemical adaptation to psychotropic drugs. In: Mandell, A.J. ed.

 Neurtobiological Mechanisms of Adaptation and Behavior. New York:

Raven Press, 1975. pp. 33-46.

Grabowski J., Stitzer, M.L., and Henningfield, J.E. Therapeutic applications

of behavioral techniques: An Overview. Behavioral Intervention Techniques in Drug Abuse Treatment. National Institute on Drug Abuse

Research Monograph 46. DHHS Pub. No. (ADM) 84-1282. Washington

D.C.: Supt of Docs., U.S. Govt. Print. Off., 1984 pp. l-7.

125
Grinspoon, L., and Bakalar, J. Cocaine. New York: Basic Books 1976

Grinspoon, L., and Bakalar, J. Drug dependence: Non-narcotic agents. In:

Kaplan, H.I. Freedman, A.M. and Sadock, B.J. eds. Comprehensive

Texbook of Psychiatry, 3rd Ed. Baltimore: Williams & Wilkins, 1980.

Guinn, M.M. Bedford, J.A. and Wilson, M.C. Antagonism of intravenous

cocaine lethality in nonhuman primates. Clin Toxicol, 16:499-508, 1980.

Helfrich, A.A., Crowley, T.J., and Atkinson, C.A. A clinical profile of 136

cocaine abusers. Problems of Drug Depencence, 1982. National Institute

on Drug Abuse Research Monograph 43. DHHS Pub. No. (ADM)

83-1264. Washington D.C.: Supt. of Docs., U.S. Govt. Print Off., 1983.

pp.343-350

Huey, L., Janowsky, D., Lewis, J., Abrams, A., Parker, D., and Clopton, P.

Effects of lithium carbonate on methylphenidaite and induced mood.

behavior and cognitive processes. Psychopharmacology, 73:161-164.

1981.

Jaffe, J.H. Drug addiction and drug abuse. In: Goodman, L.S. and Gilman, L.

eds. The Pharmacological Basis of Therapeutics, 6th ed. New York:

Macmillian, 1980.

Jarbe, T. Cocaine as a discriminative cue in rats Interactions with neuroleptics

and other drugs. Psychophamacology, 59:183-187, 1978.

Khantzian, E.J. Impluse problems and drug addiction: Cause and effect

relationships. In: Wishnie. H.A., and Nevis-Olesen, J. eds. Working with 

the Impulsive Person. New York: Plenum Press, 1979. pp. 97-112.

Khantzian, E.J. Self-selection and progression in drug dependence. In:

Shaffer, H. and Burglass, M.E., eds. Classic Contribution in the

Addictions. New York: Brunner Mazel. Inc., 1981 pp. 154-160.

Khantzian, E.J. Cocaine dependence. an extreme case and marked improvement with methylphenidate treatment. Am J Psychiatry, 1983a. 140:

784-785.

Khantzian E.J., Gawin F.H., Riordan, C., and Kleber H.D. Methylphenidate

treatment of cocaine dependence- A preliminary report. 1983b. submitted.

Kleber, H.D. Drug abuse. In: Bellak, L., ed. A Concise Handbook of

 Community Mental Health. New York: Grune and Stratton, 1974.

Knapp. S., and Mandell, A.J. Effects of lithium chloride on parameters of

biosynthetic capacity for 5-hydroxtryptamine in rat brain. J Pharm Exp

Ther, 193:812-823, 1975.

Knapp, S., and Mandell, A.J. Cocaine and lithium Neurobiological

antagonism in the serotonin biosynthetic system in rat brain. Life Sci, 18:

679-684, 1976.

Koide, T., and Matshuhita. H. An enhanced sensitivity of muscarinic

cholinergic receptor associated with dopaminergic recptor sub-sensitivity

after chronic antidepressant treatment. Life Sci, 28:1139, 1981.

Kokinidis, L., and Zacharko, R. Response sensitization and depression

following long-term amphetamine treatment in a self-stimulation paradigm.

Psychopharmacology, 68:73-76, 1980.

Kosman, M.E., and Unna, K.R. Effects of chronic administration of the

amphetamines and other stimulants on behavior. Clin Pharmacol Ther, 9:

224-254, 1968.

126
Kramer, J.C., Fischman, V.S. and Littlefield, D.C. Amphetamine abusepattern and effects of high doses taken intravenously. JAMA, 201: 305-309,

1967.

Lal, S., and Sourkes. T.L. Potentiation and inhibition of the amphetamine

stereotypy in rats by neuroleptics and other agents. Arch Int Pharmacodyn

Ther, 199:289-301, 1972.

Leith, N.J., and Barrett, R.J. Amphetamine and the reward system: Evidence

for tolerance and post-drug depression. Psychopharmacology, 46: 19-25.

1976.

Leith, N.J., and Barrett, R.J. Self-stimulation and amphetamine: Tolerance to

d and I isomers and cross tolerance to cocaine and methylphenidate.

Psychopharmacology, 74: 23-28, 1981.

Maddux, J.F.. and Desmond, D.P. Residence relocation inhibits opiate

dependence. Arch Gen Psychiatry, 39:1313- 1317, 1982.

Maggi, A., U’Prichard, D.C., and Enna, S.J. Differential effects of

antidepressant treatment on brain monoaminergic receptors. Eur J Pharmacol,

61:91-98, 1980.

Mandell, A.J., and Knapp, S. Neurobiological antagonism of cocaine by

lithium. In: Ellinwood, E.H. and Kilby, M.M. eds. Cocaine and Other

Stimulants. New York: Plenum Press, 1976 pp. 187-200.

Naber, D., Wirz-Justive, A., Kutka, M.S., and Wehr, T.A. Dopamine receptor

binding in rat striatum: Ultradian rhythm and its modification by chronic

imipramine. Psychopharmacology, 68:1-5, 1980.

Perry, G.F., Fitzsimmons, B., Shapiro, L., and Irwin, P. Clincial study of

mianserin. imipramine and placebo in depression: Blood level and MHPG

correlations. Brit J Clin Pharmacol, 5:35S-41S, 1981.

Pert, A., C., Rosenblatt, J., Squillace, K.M., and Post, R.M. Unpublished

Manuscript, 1979, cited in Post, R.M., Smith, S.S., Squillace, K.M. and

Tallman, J.P. Effect of chronic cocaine on behavior and cyclic amp in

cerebrospinal fluid of rhesus monkeys. Communic Psychopharmacol, 3,:

143-152, 1979.

Poitou, P., Boulu, R., and Bohoun, C. Effect of lithium and other drugs on the

amphetamine chlordiazepoxide hyperactivity in mice. Experimentia, 31:

99-101, 1975.

Post, R.M., Lopanda, R.T., and Black, K.E. Progressive effects of cocaine on

behavior and central amine metabolism in rhesus monkeys: Relationship to

kindling and psychosis. Biol Psychiatry, 11:403-419, 1976.

Rappolt, R.T., Gay, G.R., and Inaba, D.S. Propranolol: A specific antagonist

to cocaine. Clin Toxicol, 10: 265-271, 1977.

Resnick. R.B., Washton, A.M., LaPlaca, R.W., and Stone-Washton, N.

Lithium carbonate as a potential treatment for compulsive cocaine use: A

preliminary report. Presented at the Thirty-Second Annual Convention

and Scientific Meeting of the Society of Biological Psychiatry, Toronto,

Canada. April 28-May 1, 1977.

Ross, S.M., and Jones, C.J. Contingency contractingwithdrugabusers. Paper

presented at the 8lst Convention of the American Psychological

Association. Montreal, 1973.

127
Rounsaville, B.J., Weissman, M.M., Kleber, H., and Wilber, C. Heterogeneity

of psychiatric diagnosis in treated opiate addicts. Arch Gen Psychiatry, 39:

151-156, 1982.

Rounsaville, B.J., Gawin F.H., and Kleber, H.D., Psychotherapeutic

strategies in cocaine abuse treatment. 1983, submitted.

Scheel-Kruger, J., Braestrup, C., Nielson, M., Golembiowska, K., and

Mogilnicka, E. Cocaine: Discussion of the role of dopamine in the

biochemical mechanism of action. In: Ellinwood, E.H. and Kilbey, M.M.

eds. Cocaine and Other Stimulants. New York: Plenum Press 1977. pp.

373-407.

Schildkraut, J.J., Watson, R., Draskoczy, P.R., and Hartman, E.

Amphetamine withdrawal: Depression and MHPG excretion. Lancet, III:

485-486. 1971.

Siegel, R.K. Cocaine: Recreational use and intoxication. Cocaine 1977.

National Institute of Drug Abuse Research Monograph 13. DHEW Pub.

No. (ADM) 77-432. Washington D.C.: Supt. of Docs., U.S. Govt. Print

Off., 1977. pp. 119-136.

Siegel, R.K. Cocaine smoking. J Psychoactive Drugs, 14:271-359, 1982.

Simpson, D. Depressed rates of self-stimulation following chronic

amphetamine in the rat: Elevation of these depressed rates by desmethylimipramine. Paper presented at the Eastern Psychological Association,

April 19, 1974.

Simpson, D.M., and Annau, Z. Behavioral withdrawal following several

psychoactive drugs. Pharmacol Biochem Behav, 7:59-64, 1977.

Smith, D.E., and Wesson, D.R. Cocaine, In: Jeri, F.R., ed. Cocaine, 1980.

Lima, Peru: Pacific Press. 1980. pp. 49-61.

Spealman, R.D., Goldberg, S.R., and Kellaher, R.T. Some effects of cocaine

and two cocaine analogs on schedule-controlled behavior of squirrel

monkeys. J Pharmacol Exp Ther, 202:500-509, 1977.

Sulser, F., Vetulani, J., and Mobley, P. Mode of action of anti-depressant

drugs. Biochem Pharmacol, 27: 257-261. 1978.

Taylor, D.L., Ho, B.T., and Fagan, J.D. Increased dopamine receptor binding

in rat brain by repeated cocaine injection. Comm Psychopharm, 3:137-142,

1979.

Tennant, F.S., and Rawson, R.A. Cocaine and amphetamine dependence

treated with desipramine. Problems of Drug Dependence, 1982. National

Institute Drug Abuse Research Monograph 43 DHHS Pub. No. (ADM)

83-1264. Washington, D.C., Supt. Of Docs., U.S. Govt. Print. Off., 1983.

pp. 351-355.

Van Dyke, C., and Byck, R. Cocaine. Scientific American, 246:128-141, 1982.

Van Dyke, C., Ungerer, J., Jatlow, P., and Byck, R. Intranasal cocaine dose

relationships of psychological effects and plasma levels. Psychiatry in

Medicine, 12:1-13, 1982.

Van Dyke, C., and Byck, R. Cocaine use in man. Adv in Substance Abuse, 3, in

press.

VanKammen, D.P. and Murphy. D.L. Attenuation of the euphoriant and

activating effects of d-and l-amphetamine by lithium carbonate treatment.

Psychopharmacologia, 44:215-124, 1975.

128
Wald, D., Ebstein, R.P., and Belmaker, R.H. Haloperidol and lithium

blocking of the mood response to intravenous methylphenidate. Psychopharmacology, 57: 83-87, 1978.

Watson, R., Hartmann, E., and Schildkraut, J.J. Amphetamine withdrawal:

Affective state. sleep patterns and MHPG excretion. Am J Psychiatry, 129:

263-269, 1972.

Weiss, R.D., Mirin, S.M., and Michael, J.L. Psychopathology in chronic

cocaine abusers. Paper presented at the 136th Annual Meeting of the

American Psychiatric Association. New York, May 4. 1983.

Wieder, H., and Kaplan. E. Drug use in adolescents. Psychoanal St Child,

1969:24-399.

Wikler, A. Dynamics of drug dependence: Implications of a conditioning

theory for research and treatment. Arch Gen Psychiatry, 28: 611-616. 1973.

Wise, R.A. Direct action of cocaine on the brain: Mechanisms of complex

behavior. In: Cocaine, 1980. Jeri, F.R., ed. Lima, Peru: Pacific Press. 1980

pp. 21-28.

Woods, J.H., and Downs, D.A. The psychopharmacology of cocaine. In: Drug

 Use in America: Problems in Perspective, Appendix, Volume 1: Patterns

and Consequences of Drug Use. Washington, D.C.: Supt. of Docs. U.S.

Govt Print Off., 1973. pp. 116-139.

Wurmser, L. Psychoanalytic considerations of the etiology of compulsive drug

use. J Amer Psychoanal Assoc, 22:820-843, 1974.

Zahler, R., Wachtel, P., Jatlow, P., and Byck, R. Kinetics of drug effect by

distributed lags analysis: An application to cocaine. Clin Pharmacol Ther,

31(6):775-782, 1982.

AUTHORS

Herbert D. Kleber, M.D.

Department of Psychiatry

Yale University School of Medicine

Frank H. Gawin, M.D.

Departments of Pharmacology and Psychiatry

Yale University School of Medicine

Drug Dependence Unit

Connecticut Mental Health Center

34 Park Street

New Haven, Connecticut

06510

129
monograph series

While limited supplies last, single copies of the monographs may be

obtained free of charge from the National Clearinghouse for Drug

Abuse Information (NCDAI). Please contact NCDAI also for information about availability of coming issues and other publications of

the National Institute on Drug Abuse relevant to drug abuse research.

Additional copies may be purchased from the U.S. Government Printing

Office (GPO) and/or the National Technical Information Service

(NTIS) as indicated. NTIS prices are for paper copy. Microfiche

copies, at $6.50, are also available from NTIS. Prices from either

source are subject to change.

Addresses are:

NCADI

National Clearinghouse for Alcohol and Drug Information

P.O. Box 2345

Rockville, Maryland 20852

GPO

Superintendent of Documents

U.S. Government Printing Office

Washington, D.C. 20402

NTIS

National Technical Information

Service

U.S. Department of Commerce

Springfield, Virginia 22161

1 FINDINGS OF DRUG ABUSE RESEARCH. NCDAI out of stock

Vol. 1: GPO out of stock NTIS PB #272 867/AS $36.95

Vol. 2: GPO out of stock NTIS PB #272 868/AS $30.95

2 OPERATIONAL DEFINITIONS IN SOCIO-BEHAVIORAL DRUG USE RESEARCH

1975. Jack Elinson, Ph.D., and David Nurco, Ph.D., eds.

NCDAI out of stock

GPO out of stock NTIS PB #246 338/AS $18.95

3 AMINERGIC HYPOTHESES OF BEHAVIOR: REALITY OR CLICHE? Bruce J.

Bernard, Ph.D., ed. NCDAI out of stock

GPO out of stock NTIS PB #246 687/AS $18.95

4 NARCOTIC ANTAGONISTS: THE SEARCH FOR LONG-ACTING PREPARATIONS.

Robert Willette, Ph.D., ed. NCDAI out of stock

GPO out of stock NTIS PB #247 096/AS $11.95

130
5 YOUNG MEN AND DRUGS: A NATIONWIDE SURVEY. John A. O'Donnell,

Ph.D., et al. NCDAI out of stock

GPO out of stock NTIS PB #247 446/AS $18.95

6 EFFECTS OF LABELING THE "DRUG ABUSER": AN INQUIRY. Jay R.

Williams, Ph.D. NCDAI out of stock

GPO out of stock NTIS PB #249 092/AS $11.95

7 CANNABINOID ASSAYS IN HUMANS. Robert Willette, Ph.D., ed.

GPO out of stock NCDAI out of stock

NTIS PB #251 905/AS $18.95

8 Rx: 3x/WEEK LAAM - ALTERNATIVE TO METHADONE. Jack Blaine, M.D.,

and Pierre Renault, M.D., eds. NCDAI out of stock

Not available from GPO NTIS PB #253 763/AS $18.95

9 NARCOTIC ANTAGONISTS: NALTREXONE PROGRESS REPORT. Demetrios

Julius, M.D., and Pierre Renault, M.D., eds.

GPO out of stock NCDAI out of stock

NTIS PB #255 833/AS $18.95

10 EPIDEMIOLOGY OF DRUG ABUSE: CURRENT ISSUES. Louise G. Richards,

Ph.D., and Louise B. Blevens, eds. NCDAI out of stock

GPO out of stock NTIS PB #266 691/AS 524.95

11 DRUGS AND DRIVING. Robert Willette, Ph.D., ed.

NCDAI out of stock

GPO Stock #017-024-00576-2 $5.50 NTIS PB #269 602/AS $18.95

12 PSYCHODYNAMICS OF DRUG DEPENDENCE. Jack D. Blaine, M.D., and

Demetrios A. Julius, M.D., eds. NCDAI out of stock

GPO out of stock NTIS PB #276 084/AS $18.95

13 COCAINE: 1977. Robert C. Petersen, Ph.D., and Richard C.

Stillman, M.D., eds. NCDAI out of stock

GPO Stock #017-024-00592-4 $6 NTIS PB #269 175/AS $24.95

14 MARIHUANA RESEARCH FINDINGS: 1976. Robert C. Petersen, Ph.D.,

ed. NCDAI out of stock

GPO out of stock NTIS PB #271 279/AS $24.95

15 REVIEW OF INHALANTS: EUPHORIA TO DYSFUNCTION. Charles Wm. Sharp,

Ph.D., and Mary Lee Brehm, Ph.D., eds. NCDAI out of stock

GPO out of stock NTIS PB #275 798/AS $30.55

16 THE EPIDEMIOLOGY OF HEROIN AND OTHER NARCOTICS. Joan Dunne

Rittenhouse, Ph.D., ed. NCDAI out of stock

GPO out of stock NTIS PB #276 357/AS $24.95

17 RESEARCH ON SMOKING BEHAVIOR. Murray E. Jarvik, M.D., Ph.D., et

al., eds. NCDAI out of stock

GPO out of stock NTIS PB #276 353/AS $30.95

131
18 BEHAVIORAL TOLERANCE: RESEARCH AND TREATMENT IMPLICATIONS.

Norman A. Krasnegor, Ph.D., ed. NCDAI out of stock

GPO out of stock NTIS PB #276 337/AS $18.95

19 THE INTERNATIONAL CHALLENGE OF DRUG ABUSE. Robert C. Petersen,

Ph.D., ed. NCDAI out of stock

GPO out of stock NTIS PB #293 807/AS $30.95

20 SELF-ADMINISTRATION OF ABUSED SUBSTANCES: METHODS FOR STUDY.

Norman A. Krasnegor, Ph.D., ed. NCDAI out of stock

GPO out of stock NTIS PB #288 471/AS $24.95

21 PHENCYCLIDINE (PCP) ABUSE: AN APPRAISAL. Robert C. Petersen,

Ph.D., and Richard C. Stillman, M.D., eds. NCDAI out of stock

GPO Stock #017-024-00785-4 $7 NTIS PB #288 472/AS $30.95

22 QUASAR: QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIPS OF

ANALGESICS, NARCOTIC ANTAGONISTS, AND HALLUCINOGENS. Gene Barnett,

Ph.D.; Milan Trsic, Ph.D.; and Robert Willette, Ph.D.; eds.

GPO out of stock NCDAI out of stock

NTIS PB #292 265/AS $36.95

23 CIGARETTE SMOKING AS A DEPENDENCE PROCESS. Norman A. Krasnegor.

Ph.D., ed. NCDAI out of stock

GPO Stock #017-024-00895-8 $6 NTIS PB #297 721/AS $24.95

24 SYNTHETIC ESTIMATES FOR SMALL AREAS: STATISTICAL WORKSHOP PAPERS

AND DISCUSSION. Jos. Steinberg, ed. NCDAI out of stock

GPO out of stock NTIS PB #299 009/AS 524.95

25 BEHAVIORAL ANALYSIS AND TREATMENT OF SUBSTANCE ABUSE. Norman A.

Krasnegor, Ph.D., ed. NCDAI out of stock

GPO out of stock NTIS PB #80-112428 $24.95

26 THE BEHAVIORAL ASPECTS OF SMOKING. Norman A. Krasnegor, Ph.D.,

ed. (Reprint from 1979 Surgeon General's Report on Smoking and

Health.)

GPO out of stock NTIS PB #80-118755 $18.95

27 PROBLEMS OF DRUG DEPENDENCE. 1979: PROCEEDINGS OF THE 41ST

ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROELEMS OF DRUG

DEPENDENCE, INC. L.S. Harris, Ph.D., ed. NCDAI out of stock

GPO Stock #017-024-00981-4 $9 NTIS PB #80-175482 $42.95

28 NARCOTIC ANTAGONISTS: NALTREXONE PHARMACOCHEMISTRY AND

SUSTAINED-RELEASE PREPARATIONS. Robert Willette, Ph.D., and

Gene Barnett, Ph.D., eds. NCDAI out of stock

GPO out of stock NTIS PB #81-238875 $24.95

29 DRUG ABUSE DEATHS IN NINE CITIES: A SURVEY REPORT. Louis A.

Gottschalk, M.D., et al. NCDAI out of stock

GPO out of stock NTIS PB #80-178882 $18.95

132
30 THEORIES ON DRUG ABUSE: SELECTED CONTEMPORARY PERSPECTIVES. Dan

J. Lettieri, Ph.D.; Mollie Sayers; and Helen W. Pearson, eds.

GPO Stock #017-024-00997-1 $10

NCDAI out of stock

Not available from NTIS

31 MARIJUANA RESEARCH FINDINGS: 1980. Robert C. Petersen, Ph.D.,

ed.

GPO out of stock NTIS PB #80-215171 $24.95

32 GC/MS ASSAYS FOR ABUSED DRUGS IN BODY FLUIDS. Rodger L. Foltz,

Ph.D.; Allison F. Fentiman, Jr., Ph.D.; and Ruth B. Foltz.

GPO out of stock NTIS PB #81-133746 $24.95

33 BENZODIAZEPINES: A REVIEW OF RESEARCH RESULTS, 1980. Stephen I.

Szara, M.D., D.Sc., and Jacqueline P. Ludford, M.S., eds.

GPO Stock #017-024-01108-8 $5 NTIS PB #82-139106 $18.95

34 PROBLEMS OF DRUG DEPENDENCE, 1980: PROCEEDINGS OF THE 42ND

ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG

DEPENDENCE, INC. Louis S. Harris, Ph.D., ed. NCDAI out of stock

GPO Stock #017-024-01061-8 $8 NTIS PB #81-194847 $36.95

35 DEMOGRAPHIC TRENDS AND DRUG ABUSE, 1980-1995. Louise G.

Richards, Ph.D., ed. NCDAI out of stock

GPO out of stock NTIS PB #82-103417 $18.95

36 NEW APPROACHES TO TREATMENT OF CHRONIC PAIN: A REVIEW OF

MULTIDISCIPLINARY PAIN CLINICS AND PAIN CENTERS. Lorenz K.Y.

Ng, M.D., ed.

GPO out of stock NTIS PB #81-240913 $24.95

37 BEHAVIORAL PHARMACOLOGY OF HUMAN DRUG DEPENDENCE. Travis

Thompson, Ph.D., and Chris E. Johanson, Ph.D., eds.

NCDAI out of stock

GPO Stock #017-024-01109-6 $7 NTIS PB #82-136961 $30.95

38 DRUG ABUSE AND THE AMERICAN ADOLESCENT. Dan J. Lettieri, Ph.D.,

and Jacqueline P. Ludford, M.S., eds. A RAUS Review Report.

GPO Stock #017-024-01107-O $4.50 NCDAI out of stock

NTIS PB #82-148198 $18.95

39 YOUNG MEN AND DRUGS IN MANHATTAN: A CAUSAL ANALYSIS.

Richard R. Clayton, Ph.D., and Harwin L. Voss, Ph.D.

GPO Stock #017-024-01097-9 $5.50 NCDAI out of stock

NTIS PB #82-147372 $24.95

40 ADOLESCENT MARIJUANA ABUSERS AND THEIR FAMILIES. Herbert

Hendin, M.D., Ann Pollinger, Ph.D., Richard Ulman, Ph.D., and

Arthur Carr, Ph.D. NCDAI out of stock

GPO out of stock NTIS PB #82-133117 $18.95

41 PROBLEMS OF DRUG DEPENDENCE, 1981: PROCEEDINGS OF THE 43RD

ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG

DEPENDENCE, INC. Louis S. Harris, Ph.D., ed. NCDAI out of stock

Not available from GPO NTIS PB #82-190760 $42.95

133
42 THE ANALYSIS OF CANNABINOIDS IN BIOLOGICAL FLUIDS. Richard L.

Hawks, Ph.D., ed.

GPO Stock #017-024-01151-7 $5 NTIS PB #83-136044 $18.95

43 PROBLEMS OF DRUG DEPENDENCE, 1982: PROCEEDINGS OF THE 44TH

ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG

DEPENDENCE, INC. Louis S. Harris, Ph.D., ed. NCDAI out of stock

GPO out of stock NTIS PB #83-252-692/AS $42.95

44 MARIJUANA EFFECTS ON THE ENDOCRINE AND REPRODUCTIVE SYSTEMS.

Monique C. Braude, Ph.D., and Jacqueline P. Ludford. M.S., eds. A

RAUS Review Report. NCDAI out of stock

GPO Stock #017-024-01202-5 $4 NTIS PB #85-150563/AS $18.95

45 CONTEMPORARY RESEARCH IN PAIN AND ANALGESIA, 1983. Roger M.

Brown, Ph.D.; Theodore M. Pinkert, M.D., J.D.; and Jacqueline P.

Ludford, M.S., eds. A RAUS Review Report. NCDAI out of stock

GPO Stock #017-024-01191-6 $2.75 NTIS PB #84-184670/AS $13.95

46 BEHAVIORAL INTERVENTION TECHNIQUES IN DRUG ABUSE TREATMENT. John

Grabowski, Ph.D.; Maxine L. Stitzer, Ph.D., and Jack E.

Henningfield, Ph.D., eds.

GPO Stock #017-024-01192-4 $4.25 NTIS PB #84-184688/AS $18.95

47 PREVENTING ADOLESCENT DRUG ABUSE: INTERVENTION STRATEGIES.

Thomas J. Glynn, Ph.D.; Carl G. Leukefeld, D.S.W.; and

Jacqueline P. Ludford, M.S., eds. A RAUS Review Report.

GPO Stock #017-024-01180-1 $5.50 NTIS PB #85-159663/AS $24.95

48 MEASUREMENT IN THE ANALYSIS AND TREATMENT OF SMOKING BEHAVIOR.

John Grabowski, Ph.D., and Catherine S. Bell, M.S., eds.

GPO Stock #017-024-01181-9 $4.50 NCDAI out of stock

NTIS PB 84-145-184 $18.95

49 PROBLEMS OF DRUG DEPENDENCE, 1983: PROCEEDINGS OF THE 45TH

ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG

DEPENDENCE, INC. Louis S. Harris, Ph.D., ed. NCDAI out of stock

GPO Stock #017-024-01198-3 $12 NTIS PB 85-151553/AS $36.95

50 COCAINE: PHARMACOLOGY, EFFECTS, AND TREATMENT OF ABUSE. John

Grabowski, Ph.D., ed.

GPO Stock #017-024-01214-9 $4.50 NTIS PB 85-150381/AS $18.95

51 DRUG ABUSE TREATMENT EVALUATION: STRATEGIES, PROGRESS, AND

PROSPECTS. Frank M. Tims, Ph.D., ed.

GPO Stock #017-024-01218-1 $4.50 NTIS PB 85-150365/AS $18.95

52 TESTING DRUGS FOR PHYSICAL DEPENDENCE POTENTIAL AND ABUSE

LIABILITY. Joseph V. Brady, Ph.D., and Scott E. Lukas, Ph.D., eds.

GPO Stock #017-024-0204-1 $4.25 NTIS PB 85150373/AS $18.95

53 PHARMACOLOGICAL ADJUNCTS IN SMOKING CESSATION. John Grabowski,

Ph.D., and Sharon M. Hall, Ph.D., eds.

GPO Stock #017-024-01266-1 $3.50 NCDAI out of stock

134
54 MECHANISMS OF TOLERANCE AND DEPENDENCE. Charles Wm. Sharp,

Ph.D., ed. NCDAI out of stock

GPO Stock #017-024-01213-1 $8.50

55 PROBLEMS OF DRUG DEPENDENCE, 1984. PROCEEDINGS OF THE 46TH

ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG

DEPENDENCE, INC. Louis S. Harris, Ph.D., ed. NCDAI out of stock

GPO Stock #017-024-01242-4 $9.50

56 ETIOLOGY OF DRUG ABUSE: IMPLICATIONS FOR PREVENTION. Coryl LaRue

Jones, Ph.D., and Robert J. Battjes, D.S.W., eds.

GPO Stock #017-024-01250-5 $6.50

57 SELF-REPORT METHODS OF ESTIMATING DRUG USE: MEETING CURRENT

CHALLENGES TO VALIDITY. Beatrice A. Rouse, Ph.D., Nicholas J.

Kozel, M.S., and Louise G. Richards, Ph.D., eds.

GPO Stock #017-024-01246-7 $4.25 NCDAI out of stock

58 PROGRESS IN THE DEVELOPMENT OF COST-EFFECTIVE TREATMENT FOR DRUG

ABUSERS. Rebecca S. Ashery, D.S.W., ed.

GPO Stock #017-024-01247-5 $4.25 NCDAI out of stock

59 CURRENT RESEARCH ON THE CONSEQUENCES OF MATERNAL DRUG ABUSE.

Theodore M. Pinkert, M.D., J.D., ed.

GPO Stock #017-024-01249-1 $2.50

60 PRENATAL DRUG EXPOSURE: KINETICS AND DYNAMICS. C. Nora Chiang,

Ph.D., and Charles C. Lee, Ph.D., eds.

GPO Stock #017-024-01257-2 $3.50

61 COCAINE USE IN AMERICA: EPIDEMIOLOGIC AND CLINICAL PERSPECTIVES.

Nicholas J. Kozel, M.S., and Edgar H. Adams, M.S., eds.

GPO Stock #017-024-01258-1 $5

62 NEUROSCIENCE METHODS IN DRUG ABUSE RESEARCH. Roger M. Brown,

Ph.D., and David P. Friedman, Ph.D., eds.

GPO Stock #017-024-01260-2 $3.50

63 PREVENTION RESEARCH: DETERRING DRUG ABUSE AMONG CHILDREN AND

ADOLESCENTS. Catherine S. Bell, M.S., and Robert Battjes,

D.S.W., eds.

GPO Stock #017-024-01263-7 $5.50

64 PHENCYCLIDINE: AN UPDATE. Doris H. Clouet, Ph.D., ed.

GPO Stock #017-024-01281-5 $6.50

65 WOMEN AND DRUGS: A NEW ERA FOR RESEARCH. Barbara A. Ray, Ph.D.,

and Monique C. Braude, Ph.D., eds.

GPO Stock #017-024-01283-1 $3.25

135
66 GENETIC AND BIOLOGICAL MARKERS IN DRUG ABUSE AND ALCOHOLISM.

Monique C. Braude, Ph.D., and Helen M. Chao, Ph.D. eds.

GPO Stock #017-024-01291-2 $3.50 NCDAI out of stock

67 PROBLEMS OF DRUG DEPENDENCE, 1985. PROCEEDINGS OF THE 47TH

ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG

DEPENDENCE, INC. Louis S. Harris, Ph.D., ed. NCDAI out of stock

GPO Stock #017-024-01292-1 $18

68 STRATEGIES FOR RESEARCH ON THE INTERACTIONS OF DRUGS OF ABUSE.

Monique C. Braude, Ph.D., and Harold M. Ginzburg, M.D.,J.D.,M.P.H.,

eds.

GPO Stock #017-024-01296-3 $6.50 NCDAI out of stock

69 OPIOID PEPTIDES: MEDICINAL CHEMISTRY. Rao S. Rapaka, Ph.D.;

Gene Barnett, Ph.D.; and Richard L. Hawks, Ph.D., eds.

GPO Stock #017-024-1297-1 $11

70 OPIOID PEPTIDES: MOLECULAR PHARMACOLOGY, BIOSYNTHESIS, AND

ANALYSIS. Rao S. Rapaka, Ph.D., and Richard L. Hawks, Ph.D., eds.

GPO Stock #017-024-1298-O $12

71 OPIATE RECEPTOR SUBTYPES AND BRAIN FUNCTION. Roger M. Brown,

Ph.D.; Doris H. Clouet, Ph.D.; and David P. Friedman, Ph.D., eds.

GPO Stock #017-024-01303-O $6

72 RELAPSE AND RECOVERY IN DRUG ABUSE. Frank M. Tims, Ph.D., and

Carl G. Leukefeld, D.S.W., eds.

GPO Stock #017-024-01302-1 $6

73 URINE TESTING FOR DRUGS OF ABUSE. Richard L. Hawks, Ph.D., and

C. Nora Chiang, Ph.D.. eds.

GPO Stock #017-024-1313-7 $3.75

74 NEUROBIOLOGY OF BEHAVIORAL CONTROL IN DRUG ABUSE. Stephen I.

Szara, M.D., D.Sc., ed.

GPO Stock #017-024-1314-5 $3.75

75 PROGRESS IN OPIOID RESEARCH. PROCEEDINGS OF THE 1986 INTERNATIONAL NARCOTICS RESEARCH CONFERENCE. John W. Holaday, Ph.D.;

Ping-Yee Law, Ph.D.; and Albert Herz, M.D., eds.

GPO Stock #017-024-01315-3 $21

76 PROBLEMS OF DRUG DEPENDENCE, 1986. PROCEEDINGS OF THE 48TH

ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG

DEPENDENCE, INC. Louis S. Harris, Ph.D., ed.

GPO Stock #017-024-1316-1 $16

IN PRESS

77 ADOLESCENT DRUG ABUSE: ANALYSES OF TREATMENT RESEARCH.

Elizabeth R. Rahdert, Ph.D. and John Grabowski, Ph.D., eds.

136
DHHS Publication No (ADM)87-1326

Alcohol, Drug Abuse, and Mental Health Administration

Printed 1984 Reprinted 1987