Self-Administration

of Abused Substances:

Methods for Study

U.S. DEPARTMENT OF HEALTH, EDUCATION AND WELFARE

Public Health Service Alcohol, Drug Abuse, and Mental Health Administration
Self-Administration of Abused Substances:

Methods for Study

Editor:

Norman A. Krasnegor, Ph.D.

NIDA Research Monograph 20

July 1978

DEPARTMENT OF HEALTH. EDUCATION, AND WELFARE

Public Health Service

Alcohol, Drug Abuse, and Mental Health Administration

National Institute on Drug Abuse

Division of Research

5600 Fishers Lane

Rockville, Maryland 20857

For sale by the Superintendent of Documents

U.S. Government Printing Office, Washington, D.C. 20402

Stock No. 017-024-00794-3
The NIDA Research Monograph series is prepared by the Division of Research of

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

conferences, integrative research reviews and significant original research. Its

dual publication emphasis is rapid and targeted dissemination to the scientific

and professional community.

Editorial Advisory Board

Avram Goldstein, M.D.

Addiction Research Foundation

Polo Alto, California

Jerome Jaffe, M.D.

College of Physicians and Surgeons

Columbia University New York

Reese T. Jones, M.D.

Langley Porter Neuropsychiatric Institute

University of California

San Francisco, California

William McGlothlin, Ph.D.

Department of Psychology. UCLA

Los Angeles, California

Jack Mendelson, M.D.

Alcohol and Drug Abuse Research Center

Harvard Medical School

McLean Hospital

Belmont, Massachusetts

Helen Nowlis, Ph.D.

Office of Drug Education, DHEW

Washington, D C

Lee Robins, Ph.D.

Washington University School of Medicine

St Louis, Missouri

NIDA Research Monograph series

William Pollin, M.D.

DIRECTOR, NIDA

Marvin Snyder, Ph.D.

ACTING DIRECTOR, DIVISION OF RESEARCH, NIDA

Robert C. Petersen, Ph.D.

EDITOR-IN-CHIEF

Eleanor W. Waldrop

MANAGING EDITOR

Parklawn Building. 5600 Fishers Lane, Rockville, Maryland 20857
Self-Administration of Abused Substances:

Methods for Study
ACKNOWLEDGMENTS

This monograph is based on papers presented at a technical review conducted by Plog Research, Inc., Reseda,

California, under NIDA Contract No. 271-77-3413.

The conference took place on February 14 and 15, 1978,

in Reston, Virginia.

Library of Congress catalog card number 78-63094

NIDA Research Monographs are indexed in the Index Medicus.

They are selectively included in the coverage of BioSciences

Information Service, Chemical Abstracts, Psychological

Abstracts, and Psychopharmacological Abstracts.

DHEW Publication No. (ADM) 80-727

Formerly DHEW Publication No. (ADM) 78-727

Printed 1978 Reprinted 1979

iv
Foreword

In July of 1975, the National Institute on Drug Abuse held a conference on the possible commonalities inherent in four substance use

patterns : cigarette smoking, alcohol drinking, excessive caloric

intake, and illicit drug use. The consensus of the conferees was

that there may be a set of basic processes which underlie these

four behaviors and that the scientific evidence may be available

and accessible if the data on each of these patterns are assessed

within a broad framework. By widening the perspective, it is

hoped that features common to substance abuse behavior can be

discovered from the gestalt of this generic approach.

While it is clear that there are numerous ways to conceptualize

and study substance abuse behavior (e.g., psychodynamics, personality theory, etc.), the papers in this volume focus upon methodological approaches used to study self-administration of abused

substances by humans under controlled laboratory conditions.

This unique monograph illustrates the convergence of techniques

used by behavioral scientists working in this area of inquiry

and can serve as a point of reference for others who wish to

conduct similar research.

William Pollin, M.D.

Director

National Institute on Drug Abuse

v
Technical Review Participants

Thomas F. Babor, Ph.D.

Research Psychologist

Jerome II. Jaffe, M.D.

Alcohol and Drug Abuse Research

Center

The McLean Hospital

Belmont, Massachusetts 02178

Professor of Psychiatry

College of Physicians and Surgeons

Columbia University

422 West 168th Street

New York, New York 10032

George E. Bigelow, Ph.D.

Department of Psychiatry

Baltimore City Hospital

Baltimore, Maryland 21224

Marian W. Fischman, Ph.D.

University of Chicago

Department of Psychiatry

Box 411

950 East 59th Street

Chicago, Illinois 60637

Marshal F. Folstein M.D.

Department of Psychiatry and

Behavioral Sciences

The Johns Hopkins Hospital

Baltimore, Maryland 21205

Roland R. Griffiths, Ph.D.

Department of Psychiatry and

Behavioral Sciences

The Johns Hopkins University

School of Medicine

Baltimore, Maryland 21205

Ellen R. Gritz, Ph.D.

University of California

Department of Psychiatry

School of Medicine

Neuropsychiatric Institute

650 Westwood Plaza

Los Angeles, California 90024

Leonard Heston, M.D.

University of Minnesota

Department of Psychiatry

Research Unit

Medical School, Box 392

Mayo Memorial Building

420 Delaware Street, S.E.

Minneapolis, Minnesota 55455

Murray E. Jarvik, M.D.

Professor of Psychiatry

and Pharmacology

University of California

School of Medicine

Neuropsychiatric Institute

The Center for the Health Sciences

650 Westwood Plaza

Los Angeles, California 90024

Reese T. Jones, M.D.

Department of Psychiatry

University of California

San Francisco, California 94143

Maureen B. Kanzler, Ph.D.

Department of Biological Psychiatry

New York State Psychiatric

Institute

722 West 168th Street

New York, New York 10032

Ira Liebson, M.D.

City of Baltimore

Department of Hospitals

4940 Eastern Avenue

Baltimore, Maryland 21224

Richard Marcus, Ph.D.

Research Psychologist

National Institute on Alcohol and

Alcohol Abuse

5600 Fishers Lane

Rockville, Maryland 20857

Paul R. McHugh, M.D.

Chairman and Psychiatrist-in-Chief

Department of Psychiatry and

Behavioral Sciences

The Johns Hopkins University

School of Medicine

Baltimore, Maryland 21205

v i
Nancy K. Mello, Ph.D.

Associate Professor

of Psychology

Alcohol and Drug Abuse Research

Center

The McLean Hospital

Harvard Medical School

Belmont, Massachusetts 02178

Jack H. Mendelson, M.D.

Professor of Psychiatry

Alcohol and Drug Abuse Research

Center

The McLean Hospital

Harvard Medical School

Belmont, Massachusetts 02178

Roy W. Pickens, Ph.D.

University of Minnesota

Department of Psychiatry,

Research Unit

Medical School

420 Delaware Street, S.E.

Minneapolis, Minnesota 55455

Charles R. Schuster, Ph.D.

Professor of Psychiatry and

Pharmacological and Physiological Sciences

The University of Chicago

Department of Psychiatry

950 East 59th Street

Chicago, Illinois 60037

Harlan Shannon, Ph.D.

The NIDA Addiction Research

Center

P.O. Box 12390

Lexington, Kentucky 40583

Maxine Stitzer, Ph.D.

Behavioral Pharmacology

Research Unit

Department of Psychiatry

D Building 5 West

Baltimore City Hospitals

4940 Eastern Avenue

Baltimore, Maryland 21224

Eberhard H. Uhlenhuth, M.D.

The University of Chicago

Department of Psychiatry

950 East 59th Street

Chicago, Illinois 60637

Orland W. Wooley, Ph.D.

Department of Psychiatry

University of Cincinnati

College of Medicine Building

231 Bethesda Avenue

Cincinnati, Ohio 45267

Susan C. Wooley, Ph.D.

Department of Psychiatry

University of Cincinnati

College of Medicine Building

231 Bethesda Avenue

Cincinnati, Ohio 45267

Conference Moderator

Norman A. Krasnegor, Ph.D.

Division of Research

National Institute on Drug Abuse

5600 Fishers lane

Rockville, Maryland 20857

vii
Contents

Foreword

William Pollin . . . . . . . . . . . . . . . . . . . . . v

Technical Review Participants . . . . . . . . . . . . . , . . vi

Chapter 1 Introduction and Implications

Norman A. Krasnegor . . . . . . . . . . . . . . . . . . . i

I. DRUGS AND ETHANOL

Chapter 2 Drug Seeking: A Behavioral Analysis in Animals

and Humans

Marian W. Fischman and Charles R. Schuster . . . . . . . . 4

Chapter 3 Experimental Drug Self-Administration: Generality

Across Species and Type of Drug

Roland R. Griffiths, George R. Bigelow,

and Ira Liebson . . . . . . . . . . . . . . . . . . . . . 24

Chapter 4 Therapeutic Self-Medication as a Context for

Drug Abuse Research

George E. Bigelow, Ira Liebson, Julia Kaliszak,

and Roland R. Griffiths . . . . . . . . . . . . . . . . . 44

Chapter 5 Drug Abuse Research in Outpatient Clinics

Maxine Stitzer and George E. Bigelow . . . . . . . . . . 59

Chapter 6 Drug Self-Administration in Humans

Chris E. Johanson and Eberhard H. Uhlenhuth . . . . . . . 68

Chapter 7 Experimental Studies of Sedative Self-Administration

by Humans

Roy W. Pickens and Leonard L. Heston . . . . . . . . . . 86

Chapter 8 Marihuana, Alcohol, and Polydrug Use: Human

Self-Administration Studies

Nancy K. Mello and Jack H. Mendelson . . . . . . . . . . 93

Chapter 9 Heroin Self-Administration: An Operant Analysis

Jack H. Mendelson and Nancy K. Mello . . . . . . . . . . 128

Chapter 10 Studying Social Reactions to Drug SelfAdministration

Thomas F. Babor . . . . . . . . . . . . . . . . . . . . . 149

viii
II. FOOD AND TOBACCO

Chapter 11 Defective Long-Term Caloric Regulation in Obesity

Marshal F. Folstein and Paul R. McHugh . . . . . . . . . 182

Chapter 12 Methods and Findings in Study of Food Regulation

in Obesity

Susan C. Wooley and Orland W. Wooley . . . . . . . . . . . 189

Chapter 13 Tobacco Smoking and Nicotine Tolerance

Reese T. Jones, Thomas R. Farrell III,

Ronald I. Herning . . . . . . . . . . . . . . . . . . . . 202

Chapter 14 Tobacco and Nicotine Self-Administration in Humans:

The Evolution of a Methodology

Jerome H. Jaffe and Maureen B. Kanzler . . . . . . . . . . 209

Chapter 15 Patterns of Puffing in Cigarette Smokers

Ellen R. Gritz . . . . . . . . . . . . . . . . . . . . . . 221

Chapter 16 Self-Administration of Cigarettes With Varying

Tobacco and Nicotine Content

Murray E. Jarvik . . . . . . . . . . . . . . . . . . . . . 236

List of Monographs . . . . . . . . . . . . . . . . . . . . . . 244

i x
Chapter 1

Introduction and Implications

Norman A. Krasnegor, Ph.D.

This monograph is the first in a series of related volumes which

will address different aspects of an area of research which has

been termed “substance abuse.” For the purposes of this exposition,

the definition has been restricted to include only four behavioral

categories, namely: excessive caloric intake, and use of ethanol,

illicit drugs, and tobacco. These behaviors in their extreme form

have generally been labelled as addictions (for example, to drugs

and alcohol) or forms of dependency (cigarette smoking and overeating). Thus, the focus of the definition is upon the pattern of

excessive habitual use of these substances by individuals who

exhibit such behaviors chronically over a period of years.

Of particular interest is the question, are these four separate

behavioral patterns, or conversely, can they be understood

as manifestations of the same more basic processes? The papers

that follow address one aspect of a quest to determine empirically

whether there are commonalties among the several substance abuse

behaviors. Specifically, this monograph was organized to provide

the reader with an appreciation of the methods used by behavioral

scientists to observe and study the self-administration of

cigarettes, alcohol, food and illicit drugs by humans under controlled laboratory conditions.

It is necessary to point out that many of the techniques employed

have been adapted from paradigms originally designed to study the

self-administration of these same substances in laboratory animals.

This application of methodology represents a significant and

important step in the field of substance abuse research. Thus,

the rigor of the preclinical laboratory is being brought to bear

in an applied problem area, thereby helping to upgrade the scientific quality of the observations made. In addition, the data

derived from using such methods with human subjects has the

salutary effect of confirming the validity of animal models of, selfadministration.

During the course of the two-day conference which led to the publication of this monograph, a number of creative ideas and suggestions were presented concerning new directions for the study of

1
substance self-administration in humans. It was suggested, for

example, that behavioral measurement techniques ought to be combined

with those of the pharmacokineticist to correlate a substance’s

fate and distribution in the body with its behavioral effect.

Another useful direction concerns the investigation of substance

abuse patterns and the resultant interaction phenomena that accrue

when two or more substances are used concurrently or sequentially.

For instance, data now available indicate that use of alcohol

increases the probability and amount of cigarette smoking. Whether

this observation relates to behavioral, pharmacological, or both

types of interactions is not yet known; however, research on these

questions would appear to be essential to elucidate commonalities

and determine mechanisms which may underlie such usage patterns.

“Binges” appear to occur in people who abuse substances from the

categories germane to this monograph. Such behavioral excesses

often have been reported in connection with the start of treatment

designed to alter the self-administration frequency of food, alcohol,

illicit drugs, and cigarettes. Is this behavior pattern a commonality that can be studied systematically, and can it enlighten us

about some of the variables which control substance use? Similarly,

one might conduct experiments to determine what are the necessary

and sufficient conditions to maintain substance use behaviors once

such patterns are established. Answers to these questions would

help immeasurably to target and tailor our treatment efforts.

Further studies aimed at elucidating historical determinants of

substance use behavior should be initiated to help us understand

and characterize substance abuse patterns in groups at risk.

Finally, an important area to explore is the relationship between

subjective state and self-administration of various substances.

The mapping of affect and mood on a baseline of self-administration

behavior can provide a rich and comprehensive analysis of the total

organism and insights into the motivational factors involved in

substance abuse.

The additional reason for our interest in this research domain is

that substance abuse has major implications for the public health.

That is, the continual and substantial use of these four categories of substances has been linked etiologically and causally

to the onset of major chronic illnesses: cardiovascular;

hepatic, pulmonary, and neoplastic diseases. An understanding

of substance abuse behavior, therefore, has a potential for

impacting significantly upon health care and the health delivery

system.

I am extremely pleased that the National Institute on Drug Abuse

is in the forefront of developing the knowledge base in this

emerging field, and I look forward to a continued and broadened

interest in substance abuse research by the scientific community.

Hopefully, this volume will provide a stimulus toward this goal.

2
I. Drugs and Ethanol
Chapter 2

Drug Seeking: A Behavioral Analysis in

Animals and Humans

Marian W. Fischman, Ph.D., and

Charles R. Schuster, Ph.D.

Although data have been available for at least 20 years indicating

that nonhuman organisms will self-administer morphine and ethanol.

(Richter and Campbell 1940; Headlee, Coppock, and Nichols 1955;

Reach 1957), the bulk of the data on drug-taking behavior has been

collected during the past decade and has formed the basis for the

development of an animal model of drug abuse. As has been indicated

in several comprehensive reviews on the subject (Schuster and

Thompson 1969; Schuster and Johanson 1974; Goldberg 1976; Johanson

1978; Woods 1978) this research has shown that drugs can serve as

reinforcers for laboratory animals, and are therefore capable of

controlling behavior in the same manner as other more extensively

studied reinforcers such as food and water. The establishment of

the fact that drug-taking is an operant, maintained and controlled

by its consequences, has provided the basis for its investigation

within the framework of behavior analysis. Viewing human drug

taking as a class of responses within the conceptual context of

behavior analysis makes possible a functional evaluation of a broad

range of variables that may influence that behavior. There is a

large body of data available from the analysis of other reinforcers

which can be applied to the study of the variables important in

influencing drug-taking. Studied in this light, the illicit use of

drugs is a behavior problem comparable to other repetitive behaviors

maintained by certain schedules of food or water reinforcement.

The factors which affect it are the same as those which modify all

behavior and much can be gained from examining sources of control

utilizing nondrug reinforcers.

A major advantage of investigating the behavioral aspects of human

drug abuse within the conceptual context of behavior analysis is

the way in which the abuser is evaluated. Traditional approaches

to the problems of drug taking in humans view that behavior as

pathological and the abuser as abnormal. With the development of

an animal model of human drug abuse, what has perhaps been most

surprising is the universality of drug-taking behavior. Given the

opportunity, a wide range of laboratory animals including rats,

cats, dogs, monkeys and apes will self-administer most of the drugs

4
that are used by man for non-medical purposes. As has recently

been pointed out by Goldstein (1976) discussing opiate use, in the

absence of “countervailing influences in human society,” drug use

might well be the normal rather than the aberrant response. The

best that we can hope to do with the problem of drug abuse, given

the presence of drugs in our society, is to offer help to those

who need it and limit the dimensions of the problem. The amazing

frequency of heroin use in Viet Nam by U.S. soldiers who were not

involved with heroin before or after their tour of duty offers

strong support for the contention that drug abuse is not an aberrant pattern of behavior but instead, a response under the control

of a variety of environmental stimuli (Robins, Helzer and Davis

1975).

This paper is concerned with addressing some of the issues involved

in proceeding from an animal model of drug-taking behavior to a

human model in which drug self-administration by humans is studied

under controlled laboratory conditions. Of specific interest are

the kinds of generalization that can be made from these studies

to the actual abuse of drugs in society.

As was pointed out earlier, this model utilizes the concept that

drugs, under appropriate conditions, can maintain or suppress

behavior in much the same way as other more traditionally studied

reinforcing stimuli. In order to take advantage of the generality

of reinforcers, there is a need to systematically investigate

their similarities and differences. Some of these studies have

been done, and we will give examples of areas in which the commonality of effect has been demonstrated as well as point out specific

areas where drugs, because of their diverse pharmacological properties, may differ from other reinforcers. In addition to their

reinforcing properties, drugs have other effects. There may, for

example, be substantial differences in the toxicity produced by

drugs with equal reinforcing effects. Thus, another important

aspect of drug abuse to be described in this paper involves the

biological and behavioral consequences produced by the self-administered drug. The concept of drug use as pathological behavior will

be discussed, and an alternative way of evaluating the same behavior

will be described. Applications of the principles derived from

utilization of this model will be suggested and, lastly, the advantages and disadvantages of collecting subjective measures of

drug effects will be examined.

his discussion is not meant to be a comprehensive review of the

literature in these areas. Rather, specific examples will be

taken from research reports in order to provide illustrations for

our discussion of some considerations in the extrapolation of

animal laboratory data to research on human drug taking.

DRUGS AS REINFORCERS

he presentation of a stimulus event known to be a reinforcer under

one set of conditions may not have the same effect under other

5
conditions. The most obvious example of this is the fact that food

presentation will not always control responding in a non-fooddeprived animal. In the same way, a variety of variables can

modify the ability of drug presentation to serve as a reinforcer.

Drugs maintain behavior only under certain conditions; rates and

patterns of responding for drug presentation depend on variables

such as drug history of the organism, schedule of drug injection

and dose of drug injected. A number of different studies have

shown that the same variables which affect behavior maintained by

traditional reinforcers like food also modify behavior maintained

by drug reinforcers. Goldberg (1973), for example, demonstrated

the similarity of effect of varying the amount of food or dose of

drug on behavior. Increasing the dose of cocaine or the amount

of food presented resulted first in an increase and then a decrease

in the average response rate under 10- or 30- response fixed ratio

(FR) schedules. The pattern of responding, high at the beginning

of the session and lower at the end of the session, was similar

for both reinforcers. Further, when a second-order fixed interval

(FI) schedule of FR components was introduced, response rate remained constant as drug dose or amount of food was varied. The

effect of changing the parameter value of the reinforcer was the

same regardless of the reinforcer, although different from that

seen under simple FR schedules. Thus the schedule of reinforcement

under these conditions was more important in the control of behavior

than the nature of the reinforcer.

The similarity of drugs to more traditional reinforcing stimuli is

shown by the fact that the same drug can serve to either maintain

or suppress the behavior it follows. Thus, it is well known that

under some circumstances animals will respond vigorously to receive

electric shocks which, under other conditions, they will vigorously

respond to avoid (Kelleher and Morse 1968; McKearney 1968). In the

same way, certain drugs have been shown to have functionally different stimulus properties depending on the schedule parameters being

used. For example, physically dependent rhesus monkeys will respond

either to postpone or terminate the injection of naloxone or nalorphine (Goldberg, Hoffmeister, Schlichting and Wuttke 1971; Holz and

Gill 1975; Kandel and Schuster 1977). On the other hand, Woods,

Downs and Carney (1975) have reported responding maintained by

comparable doses of naloxone in morphine-dependent monkeys. The

similarity of shock and drug in their ability to control behavior

in a variety of ways is impressive. Clearly, in these cases, it

is not the stimulus controlling the behavior, but the scheduling

of that stimulus that modifies the behavior.

An impressive example of the ability of scheduled stimulus events

to control behavior is seen with second order schedules of food

or drug presentation. These schedules maintain long orderly

sequences of responding but limit the frequency of reinforcer

presentations which may decrease responding. In these schedules

a brief stimulus is presented at the end of each unit schedule

and paired with the reinforcer which is only presented according

to a schedule of the unit schedules (Gollub 1977). A number of

6
studies have indicated that high rates of responding over prolonged

periods of time can be maintained with minimal presentations of

the reinforcing stimulus. The implication for drug-maintained

behavior in humans is obvious. Drug-taking generally involves a

chain of behaviors including obtaining the money, looking for a

source of drug, buying and preparing it, and only then taking it

and experiencing its effects. All the parts of this sequence have

stimulus properties which can be conditioned because of their

association, albeit occasional, with the drug. These conditioned

reinforcers can then serve to maintain drug-taking or even to reinitiate it after some period of abstinence.

Further evidence for the similarity of drugs to other reinforcers

has been accumulated through manipulation of deprivation conditions.

Such manipulations have been shown to alter responding maintained

by food, water and sex in a lawful and predictable fashion (Ferster

and Skinner 1957). Similarly, responding maintained by opiate

injections has been shown to vary as a function of these parameters.

Just as food satiation can be accomplished by giving the animal

graded amounts of food prior to an experimental session, so drug

satiation has been studied by administering a range of doses of

the reinforcer just prior to the experimental session. Under these

circumstances, as with other reinforcing stimuli, responding maintained by morphine (other drugs have rarely been studied in this

way) is decreased with opiate pretreatment (Thompson and Schuster

1964; Thompson 1968). This concept forms the basis for the use of

methadone maintenance therapy with heroin addicts (Dole and Nyswander 1965). The effects of opiate deprivation in physically

dependent animals are opposite to those of satiation; increasing

the deprivation of morphine-dependent monkeys from 6-24 hours

causes an increase in response rate (Thompson and Schuster 1964).

There also seems to be a comparability of the effects of deprivation when discrimination behavior is examined. In a series of

studies investigating the effects of food deprivation on responding

maintained by food presentation under variable interval extinction

(VI EXT) in pigeons, Powell (1971, 1973) reported that the increase

in responding during the extinction stimulus was four times as great

when food deprivation was increased from 24-72 hours as when deprivation was increased from 24-48 hours. Similarly, a loss of stimulus

control has been shown when opiate deprivation is increased in opiate

dependent animals. Woods and Schuster (1968) showed, that physically

dependent monkeys responding under a multiple variable interval extinction (mult VI EXT) schedule for morphine showed an increase in

responding during the extinction portion of the schedule as

morphine deprivation was increased. In general, the data showing

a relationship between deprivation level and stimulus control have

not been collected for non-opiate drug reinforcers. There is,

however, some preliminary evidence from our laboratory indicating

that the same relationship does not hold for drugs in the stimulant

class. Preliminary data have been reported by Johanson (1978)

indicating that there is no breakdown in stimulus control when the

7

304-494 0 - 79 - 2
time between 3-hour sessions is varied from 1-45 hours for monkeys

responding under a fixed-ratio or fixed-interval 5-min schedule of

0.2 mg/kg cocaine delivery. Similar data were found with pentobarbital in nondependent animals.

Because drugs have pharmacological as well as reinforcing effects,

there are limitations in their functional similarity to nondrug

reinforcers. With repeated intake of a drug, metabolic as well

as behavioral changes occur which modify the organism and its

relationship to the environment. Thus, the physical dependence

caused by long term opiate intake or the flashbacks reported after

LSD ingestion may indicate changes in the organism which permanently alter the pattern of its interaction with its environment.

It is possible that, at least for drug reinforcers, we have to

differentiate between variables responsible for initiation of

responding and those responsible for its long term maintenance.

This may also be true for nondrug reinforcers; the data are simply

not available.

It should be clear from the above examples that both drug and other

reinforcer-maintained responding can be affected similarly by

a number of different variables. As previously mentioned, this

enables us to study drug taking using procedures developed for

research in the area of behavior analysis. This methodological

approach allows us to precisely quantify the behavior in question

as well as to utilize the principles derived from the study of

behavior maintained by other stimulus events in developing a model

of human drug abuse.

CONSEQUENCES OF DRUG SELF-ADMINISTRATION

The concept of drug abuse involves more than the statement that an

organism is self-administering a drug for nonmedical purposes.

Implicit in the word abuse is the idea that there are toxic behavioral and physiological consequences associated with this drug

self-administration. As has been argued elsewhere (Renault and

Schuster 1972), society is not primarily concerned with whether a

drug is self-administered, but rather whether or not a drug produces physiological and/or behavioral effects which are deleterious

to the individual or society. Clearly, there is no moral outrage

concerning the many people who self-administer large doses of

caffeine in coffee every day despite the fact that this is a drug

with clear-cut CNS stimulant properties. In examining the problem

of human drug taking, there has been minimal research on differentiating use and abuse.

It is frequently difficult to measure behavioral consequences of

drug taking in people involved in the activities of their daily

lives. Procedures most commonly used for evaluation of drug

effects in humans have relied heavily on personal subjective

reports (Fraser et al. 1961; Hollister et al. 1968; Teasdale and

Hinkson 1971) as well as short term structured performance tests

(Mirsky and Kornetsky 1964). There have been few attempts to

collect data in more naturalistic environments using a range of

8
reinforcers and evaluating interactions of reinforcers and behaviors.

To this end, Brady and his colleagues have built a unique programmed

residential environment in which drug-behavior interactions can be

assessed in a reasonably naturalistic setting over extended periods

of time. They have designed a system which allows a substantial

amount of experimental control including the manipulation, measurement and recording of pharmacological and environmental variables

relevant to the analysis of antecedents and consequences of drugtaking (Emurian, Emurian, Bigelow and Brady 1976). The high level

of experimental control possible in their studies allows for a

systematic manipulation of appropriate variables and careful analysis of any change in behavior. Such research can be invaluable

in validating hypotheses derived from less complex laboratory models

and should be encouraged.

When the consequences of drug-taking are evaluated, clearly the

amount and pattern of intake are both very relevant. Compulsive

repetitive drug self-administration is very different in its

effects from the well regulated intake of a drug. The concept of

controlled drug use is important in the assessment of toxic consequences. Data collected in the animal laboratory indicate that

when animals are given limited access to a wide range of drugs,

they will self-administer them in similar amounts with similar

patterns of intake across a number of different species and drugs

(e.g., Johanson 1978). Clearly, this intake of drug has not resulted in a loss of schedule or stimulus control. In fact, under

conditions of limited access there do not appear to be irreversible

toxic effects produced by drugs. However, there are substantial

data indicating that unlimited access to drug reinforcement can

lead very rapidly to irreversible toxic consequences (Johanson,

Balster and Bonese 1976). The implications of this for societal

regulation of recreational drugs is quite apparent. The common

phenomenon of not having an alcoholic drink before 5 p.m. is a

self-control procedure designed to provide only limited access

to alcohol in order to avoid toxic consequences. Unfortunately,

little cultural regulation exists in relation to the recreational

use of other drugs.

DRUG SELF-ADMINISTRATION: NORMAL OR ABNORMAL?

It has been suggested by a number of different investigators that

drug dependence is a disease, characterized by a readily recognizable set of symptoms (Martin, Haertzen and Hewett 1978; Lindesmith 1937). Thus, Martin et al. (1978) have called this syndrome

hypophoria and define it as a “negative feeling state” similar to,

but not the same as, depression, since these drug abusing patients

with negative self-image view their rejection as a failure of others

to appreciate them. Drugs reverse their feelings of inadequacy by

producing feelings of wellbeing and reducing need states. Senay

and his colleagues (personal communication) have collected a substantial amount of data showing that chronic drug users are likely

to be diagnosable as depressed. More than 60 percent of a 600 subject sample requesting treatment at drug abuse treatment centers in

9
Chicago were diagnosed as severely depressed based on their responses on a series of pencil and paper measuring instruments

including the Hopkins Symptom Checklist and the Beck Depression

Scale. After nine months of treatment 20 percent of that sample

still scored in the severely depressed range.

A possible alternative, but not necessarily opposite, way of looking at the drug user is as an organism who lacks other available

reinforcers, or the repertoire to obtain other reinforcers. Thus,

both the depression and the drug-seeking behavior may be the product

of inadequate reinforcement schedules. As has been pointed out by

Renault and Schuster (1972), the strength and immediacy of drug

reinforcement make it likely that drug taking, particularly when

it is intravenous, will be able to override other behaviors which

depend on long chains of conditioned reinforcers and a final payoff which is frequently remote. The frequently noted communality

of drug users may reflect the fact that the more traditional

reinforcers in human society are not available or not as potent

as for non-drug-users. It has been hypothesized that the depressed

patient is someone who is not responsive to the contingencies of

reinforcement but shows more responsivity to contingencies as the

depression is alleviated (Ferster 1966). In the same way, the drug

abuser may be responding to this lack of reinforcers by selfadministering an immediate-acting potent reinforcer. Similarly,

the observation by Martin et al. (1978) that “drug-abusers feel

unpopular, inept and not respected or appreciated” may he another

way of saying that these people lack either the repertoire to

obtain the traditional reinforcers of our society or the conditioning history to utilize those reinforcers. The depressed symptomatology measured by Senay and his colleagues may also be interpreted in this light.

APPLICATIONS OF THE SELF-ADMINISTRATION MODEL

One application of an animal model of human drug abuse is the preclinical assessment of the abuse liability of new drugs. As we

stated earlier in this paper, it has been found that animals selfadminister the same drugs which humans take for nonmedical purposes. These include opiates, barbiturates, alcohol and stimulants

(Schuster and Thompson 1969; Schuster and Johanson 1974). Further,

the patterns of intake in the animals are similar to those seen

in humans illicitly abusing them. Thus, the cycles of high stimulant intake alternating with days of low intake are reminiscent of

the pattern reported for humans (Johanson, Balster and Bonese 1976;

Kramer, Fischman and Littlefield 1967). Finally, the behavioral

and physiological consequences of repetitive drug self-administration are similar in animals and humans. It is for these reasons

that the assumption is made that if animals readily self-administer

a specific drug, it is likely that humans will abuse it with the

same toxic consequences as are observed in animals.

10
There is no difficulty in choosing appropriate animals for the

preclinical assessment of the abuse liability of new compounds.

A number of different species have been used in the development

of the model, and since they are all laboratory animals their

past drug and conditioning histories are known and can be controlled.

This is clearly not the case when we do drug abuse research using

human subjects . The use of human research subjects in the study

of drug self-administration is ethically limited to those people

who have previously abused the drug being studied. The fact that

we use a subject population with a prior drug-taking history means

that our subjects are selected according to certain characteristics

which may not be typical of the population at large. The observation that morphine has different subjective effects in the opiate

abuser as opposed to the non-opiate abuser (Lasagna et al. 1955;

Smith and Beecher 1959) lends credence to this statement. There

is also evidence from the animal laboratory indicating that drugtaking behavior is modifiable by the subject’s prior history

(Goldberg 1973; Schlichting, Goldberg, Wuttke and Hoffmeister 1971)

although the way in which these variables interact has not been

systematically investigated. If, in fact, the non-drug abusing

population does not respond to drugs in the same way as the abuser

population, we must take care when doing studies on the prediction of abuse liability as well as the assessment of toxic

consequences of drugs. It may well be, for example, that in

normals the only performance effects that we can expect to see are

deficits (Pillard and Fisher 1978). The true “normal," by definition, is probably functioning at or near optimal performance

levels and therefore there would be a ceiling effect on any possible

performance facilitation. In contrast the drug users’ performance

may be enhanced because they start at a different performance

baseline.

The view of the drug user as a self-medicator fits into this analysis. Teasdale and Hinkson (1971) presented data suggesting that

stimulant abusers viewed themselves as deficient in certain personality traits and that these deficits disappeared, as measured

by a series of pencil and paper checklist instruments, after

stimulant ingestion. In the same way, there is more objective

evidence from the animal laboratory indicating that specific

abused drugs may function to aid the organism in adapting to some

potentially toxic effects of aversive environmental stimulation.

Hutchinson (personal communication) has found that certain stressful stimuli can cause an increase in blood pressure in squirrel

monkeys. If these animals are maintained on nicotine, those same

stimuli have little effect on blood pressure.

A second application of the animal model of drug abuse is in the

development of therapeutic treatment programs for human drug

abusers. The self-administration model assumes that those variables

which modify drug-taking behavior are the same in animals and in

humans. In order to determine the validity of this assumption, and

thereby make this information available for use in treatment programs we must test some of the principles with human research

11
subjects . A substantial amount of research has been carried out in

the animal laboratory isolating the variables that maintain drugtaking, a necessary first step in developing procedures for reducing

drug abuse in humans. We must, however, move on from the isolation

of variables to a consideration of ways in which these can be

therapeutically applied.

Contingent time out from positive reinforcement has been shown to

be effective in the animal laboratory in suppressing behavior

maintained by more traditional reinforcers such as food (Ferster

1958; Holz, Azrin, Ayllon 1963). Recently, a systematic series

of studies addressing this topic of contingent time out from

positive reinforcement after a drinking response by alcoholic

subjects has been reported (Bigelow, Liebson and Griffiths 1974;

Griffiths, Bigelow and Liebson 1974, 1977). Initially, it was

demonstrated that when 10 or 15 minutes of physical and social

isolation was the immediate consequence of each drink, alcoholics

given access to substantial amounts of alcohol in a residential

hospital research ward suppressed their drinking behavior to

approximately one-half of baseline levels. Secondly, the procedure was adapted to determine which aspect of the isolation was

controlling the drinking. It was found that contingent restriction

of either social interactions or of physical activity was successful in suppressing drinking. In fact, contingent time out suppressed the drinking response as a function of the number of other

available privileges; the greater the number of restrictions, the

greater the effect of the time out. These data demonstrate the

control of drug-taking behavior by more than one variable and

indicate the need to study effects of manipulating a range of

variables in developing any successful drug abuse treatment program.

A recent operant approach, using the principles just described, to

the development of therapeutic procedures for maintaining drug

abstinence, was reported by Hunt and Azrin (1973) for use with

alcoholics. The theoretical basis for their methodology was also

the concept of time out from reinforcement contingent on the

ingestion of alcohol. In order to maximize the effects of the

time out, the reinforcers assumed to be maintaining nondrinking

behavior in the alcoholics were grouped closely in time and increased in magnitude. Thus, community reinforcers such as jobs,

family and social relations were rearranged such that each research

subject had a job, intensive family counseling, a place to socialize and legal help if necessary, all contingent on abstention from

drinking alcohol. Alcoholics on this program drank less, worked

more and spent more time with their families and out of institutions

than a matched control group of alcoholics. It is clear that the

manipulation of a wide range of contingencies was effective in

suppressing the drinking behavior. This is an excellent example

of the way in which principles from the animal and human laboratory

were utilized to design a successful drug abuse treatment program.

Data collected using the methodology of behavior analysis suggested

the relevant manipulations.

12
Another possible therapeutic manipulation is the reduction of drugtaking through pretreatment with other less toxic substances. Thus,

it has been reported that pretreatment with etonitazine, codeine

and meperidine decreases the rate of responding by rats maintained

by morphine while dexoxadrol and dextromethorphan do not (Weeks and

Collins 1964). This procedure has been extended to humans who

were given the opportunity to ride an exercise bicycle for saline

or 4 mg i.v. hydromorphone several times per week before and during

a period of daily maintenance on 100 mg of oral methadone (Jones

and Prada 1975). Measures of pupillary change and reports of

“liking” in response to the hydromorphone dropped to saline control

levels during the methadone maintenance period and bicycle riding

for the hydromorphone dropped substantially, occurring only intermittently in two of the six subjects. Studies such as this one

can be useful in designing treatment programs which utilize principles of drug substitution such as methadone maintenance.

Since morphine pretreatment decreases the rate of morphine self-administration (Thompson and Schuster 1964) it is tempting to predict

that this principle will hold for other classes of drugs. For

example, Lucchesi, Schuster and Emley (1967) studying cigarette..

smoking in humans found that the intravenous infusion of 22 mg of

nicotine over 6 hours caused a 27 percent decrease in the number of

cigarettes smoked (as well as a significant decrease in the amount

of each cigarette smoked) compared with a 6-hour period when saline

was administered intravenously. That this was not simply a toxic

effect is suggested by the fact that subjects were not able to correctly discriminate whether they were receiving nicotine or saline.

A further extrapolation from the opiate data might be the prediction that other drugs in the same class as nicotine (i.e.,

stimulants) should also cause a decrease in the rate of nicotine

(or cigarette) self-administration. In an unpublished study by

Schuster and Emley (personal communication) three volunteer research

subjects, who were unaware of the purpose of the study, were observed during a series of 6-hour experimental sessions while they

were engaged in a number of simple behavioral tasks. Subjects

were pretreated with a range of doses of d-amphetamine or meprobamate as well as placebo at the beginning of each 6-hour session.

In addition, they received 2.5 mg of lobeline (a naturally occurring

alkaloid similar in action to nicotine but less potent [Volle and

Koelle 1975]) three times a day for 4 days and were tested each

day. During each daily session the number of cigarettes smoked

and the weight of all remaining butts were recorded. Table 1

presents the mean number of cigarettes smoked and the mean butt

weight during each pretreatment condition. Perhaps the most

striking finding in this study is the degree of regulation shown

by each subject during the placebo pretreatment condition. The

number of cigarettes smoked by each subject during each day of this

condition was: (S-1) 8, 8, 8, 9, 8; (S-2) 9, 9, 10, 9, 9; (S-3)

10, 11, 11, 11, 13, 13, 13, 10. Given the fact that each session

was 6 hours in length, the stability of intake is impressive. dAmphetamine caused an increase in the number of cigarettes smoked

in 2 of the 3 subjects tested and had no effect in one subject (S-1).

13
TABLE 1

THE EFFECTS OF DRUG PRETREATMENT ON CIGARETTE SMOKING IN

HUMANS, DURING 6-HOUR EXPERIMENTAL SESSION*

Pretreatment

Condition

Mean # Cigarettes Mean Butt

Smoked ± S. D. Weight ± S.D.

Placebo 9.6 ± 1.2** .505 ± 0.11**

d-Amphetamine

5.0 mg

7.5 mg

Meprobamate

12.25 ± 3.1 .463 ± .026

12.3 ± 4.5. .456 ± .012

400 mg (n=2) 10.0 ± 1.4 .504 ± .002

600 mg 10.0 ± 1.7 .475 ± .039

800 mg (n=2) 11.0 ± 2.8 .472 ± .006

Lobeline***

2.5 mg day 1 11.6 ± 3.2 .471 ± .029

day 2 (n=2) 10.0 ± 0 .514 ± .Oll

day 3 10.7 ± 2.5 .505 ± .015

day 4 11.3 ± 3.0 .489 ± .015

* N=3 unless otherwise noted

** Standard error of the mean of all three means

*** Administered t.i.d. and tested daily for four days

This does not simply reflect an increase in the number of cigarettes

lit but not smoked since butt size showed a small decrease (i.e.,

more of each cigarette was smoked). Meprobamate had no effect in

any of the subjects at any of the doses tested. Lobeline was

administered in a dose of 2.5mg three times each day so that plasma

levels would be relatively constant. It was hypothesized that

if nicotine infusions could cause a decrease in cigarette smoking,

lobeline, a compound with similar actions on the body, should also

have the same effect. This, however, was not the case. No change

in cigarette consumption was recorded in any of the 3 subjects

tested, an indication that attempting to substitute this dose

regimen of lobeline for nicotine in the treatment of cigarette

smokers would ‘probably be unsuccessful. Thus, cigarette smoking

is a complex phenomenon, and the use of a substance with physiological actions similar to nicotine is insufficient to cause a

change in cigarette consumption.

14
SUBJECTIVE MEASURES

The pertinence of laboratory studies of drug reinforcement using

nonhuman subjects to the design of experiments using human subjects.

cannot be overestimated. Clearly, the development of an animal

model of drug dependence has created a factual and conceptual basis

for the design of investigations of drug-taking behavior in humans.

Operant research has traditionally taken advantage of the existing

behavioral repertoire of the organism. Thus, the already present

discrete pecking behavior of the pigeon has been used by experimenters as a key-peck response, and the exploratory behavior of

rats has been utilized in the shaping of a lever-press response.

In a similar fashion, humans are capable of verbal behavior and it

would be a mistake to ignore this unique behavioral repertoire.

Behavioral pharmacology and psychopharmacology, both studying drugbehavior interactions, have developed along parallel lines; the

former within an operant framework and the latter utilizing the

more traditional methodology of psychology. One of the most useful

psychopharmacological tools in the assessment of drug effects in

humans has been the subjective report of a drug’s effect, usually

assessed with a standard drug effects questionnaire such as the

Addiction Research Center Inventory. Operant psychologists have

tended to shy away from the utilization of verbal reports as an

indication of drug effects because of its historical association

with inner mental processes. Verbal behavior is, however, an

operant in and of itself, which may be divided into response classes

for investigative purposes (Skinner 1957). Initial research by

Greenspoon (1951, 1955) in the area of the behavioral analysis

of verbal behavior has been corroborated and extended by a substantial number of other investigators (see Holz and Azrin 1966

for a review of this literature). They have shown that verbal

behavior, when the response is well defined and the reinforcer

consistently applied, comes under the control of reinforcement

contingencies in the same manner as other behaviors.

In evaluating the abuse potential of psychotropic drugs in humans,

a recently described approach (Fischman 1977; Jasinski 1977) is to

establish a profile of the effects of a standard known drug of

abuse and use that profile as a template against which the abuse

liability of other drugs in the same class can be assessed. Subjective effects are clearly important in this evaluation of a

drug’s effects in humans. These are valid measures which, when

taken under relatively standard conditions? have been shown to

vary lawfully with the dose and drug administered (Martin and

Fraser 1961; Martin, Sloan, Sapira et al. 1971; Fischman, Schuster

Resnekov et al. 1976; Fischman 1977; Jasinski 1977).

Holtzman and his colleagues (Shannon and Holtzman 1977,

Schaefer and Holtzman 1977) have recently reported a procedure

for use in the animal laboratory which, they speculate, measures

behavior in rats or squirrel monkeys that is under the stimulus

control of specific drugs in much the same way as subjective

15
effect reports of humans. Animals were trained in a two-choice,

discrete trial avoidance paradigm to discriminate morphine from

saline. Similarity to morphine was then evaluated for representative narcotic analgesics, analgesics with mixed agonist and antagonist properties, and nonopioid psychoactive drugs by determining

their dose-response characteristics. Discriminative effects

equivalent to those of morphine were found for the narcotic analgesics and narcotic antagonists which produce morphine-like subjective effects in humans. Thus, the functional similarity between

the lever-press response in rats or monkeys and the humans’ verbal

reports has been shown. Both of these responses can be brought

under stimulus control of drugs.

Implicit in the use of subjective effects questionnaires is the

acceptance of verbal behavior as a reliable response class, and

the understanding that the report of a drug’s effects is verbal

behavior under the stimulus control of the specific drug being

tested. In the same way that we accept the data collected in the

animal laboratory with a rat or monkey lever-pressing, we must

remember that verbal behavior is under the control of a range of

contingencies, some of which may be as important or more important

than the stimulus control exerted by the physiological effects

of the drug being studied. Thus, a study by Schachter and Singer

(1962) indicates the potent effects of external stimuli in the

assessment of a drug’s effect. Subjects, ignorant of what they

were receiving, were injected with epinephrine and then allowed

to interact with a second “subject” (really someone trained

by the experimenter) who behaved either in a highly euphoric or

very angry fashion. They were then asked to rate how angry and

how happy they felt. They all reported heart palpitations and

tremors of the hands and legs. Those exposed to the euphoric

second subject reported being more happy than angry; the opposite

was true for those exposed to the angry second subject. In the

same way, it is stated that the lower the dose and the less potent

the drug, the more likely it is that environmental stimuli will

play a part in determining a specific drug response. Anecdotal

reports by recreational marihuana users indicate that an abrupt

change in mood by one of a group who have smoked together will

often be the stimulus for mood change in everyone else in the

group. This does not mean that subjective drug effects data are

too variable to be useful. It simply indicates that we must

exert great care to administer our questionnaires under standard

conditions, controlling the drug-taking environment and contingencies as much as possible.

A second area of concern in the utilization of subjective measures

of drug effects is the tendency by some investigators to ascribe

causality to what is simply a response. Thus, the equating of

“reinforcing” with “euphorogenic” (Mello 1977). This has nothing

to do with the verbal behavior being measured - only with the

inappropriateness of the experimenter’s verbal behavior. The

danger lies in generalizing from the response to the cause. We

do not assume that the presentation of a food pellet maintains

16
lever pressing in the rat because of its euphoric effect, and, by

analogy, we have no reason to assume that drugs are self-administered

because of their euphoric effects. The stimulus properties of the

drug being self-administered are maintaining the drug-taking; the

subjective effects are simply one of the behavioral measures being

taken. Further, at this point we have no data to indicate that

these variables even co-vary. In fact, another paper in this monograph discusses research designed to investigate this question.

Johanson and Uhlenhuth (1978) gave human research subjects the

opportunity to choose between d-amphetamine (5 or 10 mg) or diethylpropion (25 or 50 mg) and placebo as well as between doses of the

two drugs. At the same time, mood change was assessed using the

Profile of Mood States (POMS). Their results suggest that there is

no simple relationship between the reinforcing properties of these

two drugs, as measured by the frequency that subjects chose to

self-administer them, and their mood changes, as measured by their

Arousal score on the Profile of Mood States. In fact, there appear

to be more dysphoric effects reported after ingestion of the more

highly preferred drug and dose of drug. Clearly more research must

be done ‘in this area.

A drug’s profile of action in humans should also include some basic

physiological and behavioral measures. In animal self-administration studies we have the luxury of studying a wide range of doses

of a specific drug in order to be sure that we are presenting

appropriate doses to the animal. Because human research subjects

are more limited in number we should obtain as many measures as

possible in each subject to determine that the dose range in question is both safe and effective. In addition, it is obvious that

when we maintain human subjects in a hospital facility for some

period of time we should collect as much information as possible

on many different measures. Just as animal laboratory studies

are frequently designed to assess the behavioral effects of the

drug being self-administered using, for example, multiple schedules

(Johanson 1978), so the human studies should do the same.

CONCLUSION

This paper has attempted to discuss some of the issues involved

in proceeding from an animal to a human model of drug-taking

behavior. As was pointed out, we use animal models because the

phenomenon under study is complex and demands vigorous control

over both past conditioning and drug histories as well as the

current behavioral contingencies. Further, for ethical, medical

and legal considerations, it is impossible to make the appropriate

manipulations necessary for an analysis of the phenomenon under

study using human subjects. It should be emphasized that although

research with humans is necessary, the majority of the systematic

studies carried out in this area must be implemented in the animal

laboratory. Carefully selected studies should then be done with

humans to establish the generality of our model across species.

Given the fact of evolution, coupled with the generality of the

data already collected across infra-human species using drugs as

17
reinforcers; we have every reason to expect that this generality

will continue to prevail when human subjects are tested. Since

we do not have the luxury of running a large number of human studies,

each subject that we test is a precious commodity and we must look

systematically for similarities and differences in effects of drug

reinforcers on behavior, carefully based on an analysis of the

currently available data from the animal laboratory. Such validation of an animal model of drug abuse may be one of the most

important reasons for conducting human drug self-administration

studies.

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Pillard, R.C. and Fisher, S. Normal humans as models for psychopharmacologic therapy. In: Lipton, M.A., DiMascio, A., and

Killam, K.F., eds. A Generation of Progress. New York: Raven

Press, 1978. pp. 783-790.

Powell, R.W. Evidence of interaction between deprivation effects

and stimulus control. J Exp Anal Behav , 16:95-104, 1971.

Powell, R.W. Effects of stimulus control and deprivation upon

discriminative responding. J Exp Anal Behav , 19:351-360, 1973.

Renault, P.F. and Schuster, C.R. On the treatment of stimulant

abuse. Perspect Biol Med, 15:561-565, 1972..

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2 1
Robins, L.N., Helzer, J.E. and Davis, D. Narcotic use in Southeast

Asia and afterward: An interview study of 898 Vietnam returnees.

Arch Gen Psych, 32:955-961, 1975.

Schachter, S. and Singer, J.E. Cognitive, social and physiological

determinants of emotional state. Psychol Rev, 69:379-399, 1962.

Schaefer, G.L. and Holtzman, S.G. Discriminative effects of morphine in the squirrel monkey. J Pharm and Exp Ther, 201:67-75,

1977.

Schlichting, U.U.; Goldberg, S.R.; Wuttke, W. and Hoffmeister, F.

d-Amphetamine self-administration by rhesus monkeys with different

self-administration histories. Proceedings of the European Society

for the Study of Drug Toxicity, 1970, Excerpta Medicine International

Congress Series, 220:62-69, 1971.

Schuster, C.R. and Johanson, C.E. The use of animal models for the

study of drug abuse. In: Gibbins, R.J.; Yedy, I.; Kalant, H.;

Popham, R.E.; Schmidt, IV. and Smart, R.G., eds. Research Advances

in Alcohol and Drug Problems, Vol I. New York, John Wiley and

Sons, Inc., 1974. pp. 1-31.

Schuster, C.R. and Thompson, T. Self-administration of and behavioral dependence on drugs. Annual Review of Pharmacology, 9:483-

502, 1969.

Shannon, H.E. and Holtzman, S.G. Further evaluation of the discriminative effects of morphine in the rat. J Pharm Exp Ther ,

201:55-66, 1977.

Skinner, B.F. Verbal Behavior. New York: Appleton-CenturyCrofts, 1957.

Smith, GM. and Beecher, H.K. Measurement of "mental clouding"

and other subjective effects of morphine. J Pharm Exp Ther,

126:50-62, 1959.

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on the interpersonal behavior of dependent patients.

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Int J Addict,

Thompson, T. and Schuster, C.R. Morphine self-administration, foodreinforced and avoidance behaviors in rhesus monkeys. Psychopharmacologia, 5:87-94, 1964.

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Int J Addict, 3:199-206, 1968.

22
Volle, R.L. and Koelle, G.B. Ganglionic stimulating and blocking

agents. In: Goodman, L.S. and Gilman, A., eds. The Pharmacological Basis of Therapeutics. New York: MacMillan, 1975, pp. 565-

574.

Weeks, J.R. and Collins, R.J. Factors affecting voluntary morphine

intake in self-maintained addicted rats. Psychopharmacologia, 6:

267-279, 1964.

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In: Lipton, M.A. , DiMascio, A. and Killam, K.F. eds., Psychopharmacologia: A Generation of Progress. New York: Raven Press,

1978, pp. 595-608.

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1968.

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ACKNOWLEDGMENT

This research was supported by grants from the National Institute

on Drug Abuse DA-00024 and DA-01491, Charles R. Schuster, Principal

Investigator.

AUTHORS

Marian W. Fischman, Ph.D.

Department of Psychiatry

Charles R. Schuster, Ph.D.

Departments of Psychiatry &

Pharmacological & Physiological Sciences

The University of Chicago

Pritzker School of Medicine

950 East 59th Street

Chicago, Illinois 60637

23

304-494 0 - 79 - 3
Chapter 3

Experimental Drug Self-Administration:

Generality Across Species and Type of Drug

Roland R. Griffiths, Ph.D., George E. Bigelow, Ph.D.,

and Ira Liebson, M.D.

Abstract. Human drug self-administration methods in residential

settings have been developed, and research has examined a range of

variables which systematically influence the drug taking behavior.

Confidence in the results with these methods is increased by the

demonstration of two types of generality: across species and across

drug. Across species generality is demonstrated by the fact that

similar effects on drug taking are obtained in human and infrahuman

experiments when the same variables are manipulated (including:

type of drug; dose of drug; response requirement to obtain drug;

punishment of drug self-administration; and drug preloads). Across

drug generality is demonstrated in human research by the fact that

manipulation of major variables (including dose of drug; response

requirement to obtain drug; and minimum interingestion interval)

produces similar effects on the self-administration of different

drugs (e.g., ethanol, diazepam and pentobarbital). Across drug

generality is also demonstrated by the finding that the selfadministration of different drugs produces similar effects on the

social behavior of the drug user. Demonstration of across species

and across drug generality suggests that common processes may underlie various aspects of drug self-administration, and supports the

supposition of a generalized behavioral phenomenon of substance

self-administration.

INTRODUCTION

Human research characterizing the effects of chronic administration

of various drugs began more than 40 years ago at the Addiction Research Center (cf. Jasinski 1973 and Wikler 1977 for reviews of this

early research). In 1964 Mendelson reported a classic set of studies

involving chronic administration of ethanol to alcoholics. In 1965

Mello and Mendelson published their first of many subsequent studies

which involved free choice ethanol self-administration by alcoholics

in a hospital ward setting (cf. Mello 1972 for a review of this early

work).

24
Over the last 15 years, the technology for studying self-administration of drugs in residential ward settings has been developed and

refined. Bigelow, Griffiths, and Liebson (1975a, b) have reviewed

the historical development of these procedures for analyzing human

drug self-administration and have commented upon the importance of

some of the major methodological characteristics which have evolved.

Typically drugs are made available for ingestion to volunteers with

histories of drug abuse under conditions which permit the gathering

of empirical information concerning the patterns and effects of drug

self-administration. The experiment is usually conducted over the

course of several weeks, and the subject is sequentially exposed to

different experimental conditions using a within subject methodology.

These experimental procedures involving controlled laboratory environments were originally developed in the analysis of ethanol selfadministration and they have subsequently been extended to the

analysis of other drugs of abuse. Research has been reported on the

self-administration of marihuana (Miles, Congreave, Gibbins, Marshman, Devenyi, and Hicks 1974; Mendelson, Rossi, and Meyer 1974),

opiates (Jones and Prada 1975; Meyer, Mirin, Altman, and McNamee 1976;

Angle and Parwatikar 1973), sedatives (Griffiths, Bigelow, and Liebson

1976b; Pickens, Cunningham, Heston, Eckert, and Gustafson 1977) and

nicotine (Mello and Mendelson 1971; Griffiths, Bigelow and Liebson

1976a). Presently, a considerable literature exists concerning the

behavioral pharmacological relationships observed in studies of human

drug self-administration, and this methodology appears to provide a

fruitful context within which to study an experimental model of the

phenomenon of substance abuse.

Confidence in the results of research utilizing experimental human

drug self-administration methods is increased to the extent that they

can be replicated across a range of conditions. Such generalizability

of results is important for establishing that the results are not

merely artifacts of the experimental situation. The present paper

will review the evidence that has established two major types of

generality of drug self-administration results: across species and

across drug generality.

ACROSS SPECIES GENERALITY

Across species generality has been established by comparing the results

of human drug self-administration studies with similar studies done

with infrahuman subjects. In infrahuman drug self-administration research animals are given access to an operandum, and responding on

the operandum results in delivery of drug. This model has been established using a variety of animal species (e.g., rat, dog, cat,

monkey, baboon), types of operandum (e.g., lever press, panel press)

and routes of drug administration (e.g., intravenous, oral, intragastric, inhalation). As with the human drug self-administration procedures, these animal techniques have been developed over the last

15 years (cf. Schuster and Thompson 1969 and Spealman and Goldberg

1978 for reviews).

25
In spite of vast methodological differences between the human and

infrahuman drug self-administration research, some convergence of

results is apparent. The present section will review the major

classes of experimental manipulations that have been undertaken in

drug self-administration research and emphasize those instances in

which there is a good correspondence in results of the human and

infrahuman research.

Type of Drug The type of drug available is perhaps the most basic

druq variable that has been shown to be a determinant of druq selfadministration in humans and infrahumans. For example, Fig. 1

presents representative individual subject drug self-administration

data showing that selected doses of pentobarbital or secobarbital

maintain regular daily self-administration in both humans and baboons.

In contrast, the drug vehicle (placebo or saline) and chlorpromazine

failed to maintain self-administration. These data show that drugs

differ with respect to their capacity to maintain self-administration

behavior in both animals and man. Other research has shown that

there is a good relationship between those drugs self-administered

by laboratory animals and those abused by man (e.g., Deneau,

Yanagita, and Seevers 1969; Griffiths, Brady, and Snell 1978a,b).

For instance, with a standard drug substitution procedure, baboons

will self-administer the opiate drugs heroin, morphine and codeine,

the sedative compounds pentobarbital, secobarbital and methaqualone,

as well as the stimulant compounds cocaine, amphetamine and methylphenidate. All of these compounds have been associated with

numerous reports describing their abuse. In contrast, the baboon

will not self-administer the opiate antagonists naloxone and nalorphine, the sedative phenobarbital, the major tranquilizer chlorpromazine and the anorectic drugs phenylpropanolamine and fenfluramine. These data correspond well to the fact that human abuse of

these drugs is relatively rare (cf. Griffiths, Brady, and Bradford

1978 for a comprehensive review of this literature with stimulant

compounds).

Drug Dose Drug dose is a variable that influences virtually all

pharmacological responses, and therefore it is not surprising to

find that it directly affects human and infrahuman drug self-administration. Fig. 2 shows that under some conditions in both humans

and baboons, increasing doses of a reinforcing drug (in this case

ethanol or cocaine) are associated with increasing levels of drug

self-administration. Other animal drug self-administration studies

have shown that when a wide range of doses is examined, the total

number of infusions varies as an inverted U-shaped function when

dose per infusion is varied. In the data shown in Fig. 2 it is

probable that further increases in drug doses would have eventually

produced toxic or debilitating drug effects and produced decreases

in drug intake, thus resulting in an inverted U-shaped function.

Response Requirement Fig. 3 illustrates the commonality of effect

upon both human and animal drug self-administration of variations

in the response cost (amount of behavior) required to obtain single

26
FIGURE 1

ACROSS SPECIES GENERALITY:

Effect of Type of Drug on Self-Administration

Effect of type of drug on drug self-administration in

humans and baboons. Each graph shows the amount of drug selfadministered by one representative subject over consecutive daily

sessions. The drug, dose, and route of administration are indicated.

The human experiment (Griffiths, Bigelow, and Liebson, unpublished

data) utilized general methods described previously (Griffiths,

Bigelow, and Liebson 1976b) to study the effect of various drugs

at several doses under double blind conditions. The baboon experiment (Griffiths, unpublished data) al so utilized general

methods described previously (Griffiths, Winger, Brady, and

Snell 1976).

27
FIGURE 2

ACROSS SPECIES GENERALITY:

Effect of Drug Dose on Self-Administration

Effect of drug dose on self-administration. The human

data are replotted from an experiment involving two alcoholic subjects (Griffiths, Bigelow, and Liebson 1976b). Data points

indicate means, brackets indicate ± one standard error of the

mean, and numerals indicate total number of observations at each

dose. The baboon experiment (Griffiths, unpublished) utilized

general procedures described previously (Griffiths, Winger, Brady,

and Snell 1976) with four baboon subjects. Data points show mean

number of injections per day on days 8 through 12 of drug exposure.

Brackets indicate ± one standard error of the mean and numerals

indicate total number of observations at each dose.

28
FIGURE 3

ACROSS SPECIES GENERALITY:

Effect of Work Requirement on Drug Self-Administration

Effect of work requirement on drug self-administration.

Human data are replotted from an experiment involving oral drug

self-administration in three volunteer sedative abuser subjects

(Bigelow, Griffiths, and Liebson 1976). Data points indicate means,

brackets indicate ± one standard error of the mean, and numerals

indicate total number of observations at each cost level. Baboon

data are derived from an experiment involving intravenous drug

maintained progressive ratio performance in two baboons (Griffiths,

Findley, Brady, Gutcher, and Robinson 1975). Data points indicate

means, brackets indicate ± one standard error of the mean, and

numerals indicate total number of observations at each cost level.

29
doses of drug. In the human experiment (Bigelow, Griffiths, and

Liebson 1976) volunteer sedative abusers were permitted to selfadminister orally up to twenty 30 mg sodium pentobarbital doses

daily. Each dose was purchased with tokens earned by riding a

stationary exercise bicycle. The number of tokens (and, therefore,

the amount of exercise) required to obtain drug doses was varied

in a mixed order across days. In the animal experiment (Griffiths,

Findley, Brady, Gutcher, and Robinson 1975) baboons could selfadminister intravenously up to eight 12.0 mg/kg sodium secobarbital

doses daily. Each injection was consequent upon a fixed number of

responses on a lever. The number of lever presses required to

obtain drug doses was progressively increased across days. Similar

effects of response cost variations are observed in both animals

and humans: as the response requirement increases, drug selfadministration decreases. This relationship has been observed

repeatedly in both animal and human studies and has been observed

across a variety of drug classes.

Punishment Another variable that has been shown to affect drug

self-administration in human and infrahuman subjects is punishment. Punishment refers to the reduction of the future probability

of a behavior as a result of the occurrence of some event contingent on the behavior. Fig. 4 shows the suppression of drug selfadministration by contingent punishment manipulations in both

humans and rhesus monkeys. In the human experiment (Griffiths,

Bigelow, and Liebson 1977) ethanol self-administration by volunteer

alcoholic subjects was suppressed by several different contingent'

time out procedures which differed in suppressive potency. Time

out periods were scheduled as an immediate consequence to each

instance of ethanol self-administration and involved restriction

of the subject's social interactions, physical and recreational

activities, or both of these simultaneously. In the animal experiment (Grove and Schuster 1974) various intensities of contingent

electric shock were superimposed upon a cocaine self-administration

baseline.

Conditioned Stimuli The importance of antecedent environmental

stimuli has been emphasized in a major current theory concerning the

etiology of relapse to drug abuse. It is speculated that environmental stimuli previously paired with either opiate drug use or

drug withdrawal can come to elicit the symptoms of drug withdrawal

which are subjectively perceived as craving (Wikler 1965). Both

animal and human studies have confirmed that such conditioned

withdrawal can be established under controlled conditions (Goldberg

1970; O'Brien, Testa, O'Brien, Brady, and Wells 1977). The degree

to which this conditioning phenomenon is relevant to the relapse

to drug self-administration remains to be empirically determined.

Similarly, the relevance of this stimulus elicited conditioned

withdrawal/craving phenomenon to drugs other than narcotics has

yet to be determined.

30
FIGURE 4

ACROSS SPECIES GENERALITY:

Effect of Punishment on Drug Self-Administration

Effect of punishment on drug self-administration. Human

data are replotted from an experiment which compared three contingent time out procedures in suppressing oral ethanol self-administration in fourteen alcoholic subjects (Griffiths, Bigelow, and

Liebson 1977). Heights of bars indicate means, brackets indicate

one standard error of the mean and numerals indicate total number

of observations at each time out condition. Monkey data are replotted from an experiment demonstrating the suppression of

intravenous cocaine self-administration by contingent electric

shock in three rhesus monkeys (Grove and Schuster 1974). Heights

of bars indicate means, brackets indicate one standard error of

the mean and numerals indicate total number of observations at

each shock intensity.

31
Drug Preload: Preload doses of drugs represent one type of antecedent stimulus which has clearly been shown to influence drug

self-administration behavior in both animals and man. Fig. 5

shows that under some conditions priming doses of drug can increase subsequent drug self-administration behavior. In the

human experiment (Bigelow, Griffiths, and Liebson 1977) volunteer

alcoholics were permitted to self-administer ethanol orallywhile

occasionally receiving various presession doses of ethanol. In

the animal experiment (Gerber and Stretch 1975) squirrel monkeys

with prior histories of cocaine self-administration were studied

under extinction conditions (saline self-administration) while

occasionally receiving various presession doses of d-amphetamine.

These data illustrate that in both animals and humans presession

drug doses can result in increases in drug seeking behavior. It

should be noted that the relationship of drug preload to drug

self-administration is complex, since other studies in humans

(Jones and Prada 1975) and animals (Griffiths, Wurster, and Brady

1975) have shown that under other conditions preloads with drugs

that are pharmacologically similar to the self-administered drug

can result in reductions of subsequent drug self-administration

behavior.

Historical Variables A wide range of historical influences

modulate drug self-administration in animals and humans. It should:

be recognized that many of the variables described in this paper

require a history before they can exert an influence on drug selfadministration (e.g., stimuli which elicit conditioned withdrawal

effects). There are numerous other historical influences which

probably influence drug self-administration, including the pharmacological and behavioral history of a subject. Finally, further

exploration of historical variables may ultimately explain some

paradoxical forms of drug self-administration. For instance, a

number of animal studies have shown that under certain conditions

electric shock can maintain responding when shock is delivered as

a consequence of responding (Morse and Kelleher 1970). A subsequent study has extended this work by demonstrating that morphine

dependent monkeys with certain histories will self-administer the

opiate antagonist naloxone (Woods, Downs, and Carney 1975). These

results are interesting because electric shock, for virtually all

animals, and naloxone, for morphine dependent animals are usually

considered to be "noxious"

to avoid.

stimuli which animals will readily learn

Although more research is necessary to determine all the

conditions under which such seemingly aberrant behavior can be

established, the phenomenon can cautiously be interpreted as indicating an important role for the organism's history. Some data from

an ongoing experiment suggest that analogous phenomena may occur

with human drug self-administration. The experiment involves a

double blind comparison of self-administration of various doses of

placebo, pentobarbital, diazepam or chlorpromazine in volunteer

subjects with histories of sedative drug abuse (Griffiths, Bigelow,

and Liebson, unpublished). Of the fourteen subjects exposed to

several doses of chlorpromazine , most stopped self-administering

32
FIGURE 5

ACROSS SPECIES GENERALITY:

Effect of Drug Preload on Self-Administration

Effect of drug preload on self-administration. Human

data are replotted from an experiment in which the effects of

oral ethanol preloads were studied on subsequent ethanol selfadministration in four volunteer alcoholic subjects (Bigelow,

Griffiths, and Liebson 1977). Data points indicate means,

brackets indicate + one standard error of the mean, and numerals

indicate total number of observations at each preload dose.

Monkey data are replotted from an experiment in which the effects

of intravenous d-amphetamine were studied on saline self-administration in three squirrel monkeys which had histories of cocaine

self-administration (Gerber and Stretch 1975). Data points

indicate means, brackets indicate + one standard error of the mean,

and numerals indicate total number of observations at each preload

dose.

33
the drug after several initial days of drug availability. Fig. 1,

for example, shows the data for a representative subject. However,

one of the subjects reliably self-administered chlorpromazine

(approximately 250 mg/day) at rates above placebo. The subject

had no history of psychosis, and therefore it is not likely that

the drug was self-administered because of the antipsychotic

properties. The subject reported that he thought the drug was

probably a barbiturate, and that he felt it helped him sleep at

night. It is possible that future research will indicate that

such idiosyncratic instances of drug self-administration are

somewhat analogous to responding maintained by shock, and that

these phenomena will be shown to be dependent upon the subject's

history.

ACROSS DRUG GENERALITY

A second area in which significant generality of human experimental

drug self-administration results has been demonstrated is across

different classes of drugs. Across drug generality is demonstrated

by the fact that manipulation of major variables produces similar

effects on self-administration of different drugs. The discussion

here will focus upon data from human studies only. As in the

preceding section, the discussion will be organized under the types

of manipulations which have shown across drug generality.

Dose of Drug Several studies have examined the effects of manipulatinq dose of drug on human self-administration of nicotine (see

Jaffe and Jarvik 1978 for review) and various sedative drugs

(Griffiths, Bigelow, and Liebson 1976b; Pickens, Cunningham, Heston,

Eckert, and Gustafson 1977). Since very different methods were

utilized in each of these studies, it is difficult to compare

results between experiments. However, in one of the studies

(Griffiths, Bigelow, and Liebson 1976b) similar experimental conditions were used to examine the effects of drug dose on selfadministration of pentobarbital, diazepam and ethanol in drug

abuser and alcoholic subjects. As shown in Fig. 6, with all three

drugs increasing doses were associated with increasing levels of

drug self-administration. As mentioned earlier, it is likely that

higher doses of drug would have produced severe drug effects that

would be associated with a descending limb to this dose effect

function.

Response Requirement Several studies have demonstrated that increasing the response requirement or response cost to obtain

alcohol decreases the total amount of alcohol consumed by alcoholic

subjects (Mello, McNamee, and Mendelson 1968; Bigelow and Liebson

1972; Babor, Greenberg, Mendelson, and Kuehnle 1977). These findings have recently been extended to two additional sedative drugs,

pentobarbital and diazepam (Bigelow, Griffiths, and Liebson 1976).

Fig. 7 shows the results of two of these studies (Bigelow and

Liebson 1972; Bigelow, Griffiths, and Liebson 1976) in which drug

abuser or alcoholic subjects could obtain drug by either riding an

34
FIGURE 6

ACROSS DRUG GENERALITY:

Effect of Drug Dose on Human Drug Self-Administration

Effect of drug dose on human self-administration of

pentobarbital, diazepam and ethanol. Data are replotted from an

experiment involving oral drug self-administration by volunteer

sedative abuser or alcoholic subjects (Griffiths, Bigelow, and

Liebson 1976b). Two subjects were exposed to each of the three

drugs. Data points indicate means, brackets indicate ± one

standard error of the mean and numerals indicate total number

of observations at each interingestion interval.

35
FIGURE 7

ACROSS DRUG GENERALITY:

Effect of Work Requirement on Human

Drug Self-Administration

Effect of work requirement on human self-administration

of pentobarbital, diazepam and ethanol. Data are replotted from

experiments involving oral drug self-administration by volunteer

sedative abusers (Bigelow,Grifflths, and Liebson 1976) and

alcoholics (Bigelow and Liebson 1972). Two subjects were exposed

to diazepam and ethanol and three subjects were exposed to pentobarbital. Data points indicate means, brackets indicate ± one

standard error of the mean, and numerals indicate total number of

observations at each cost level.

36
exercycle or pulling a lever. With all three drugs, increasing

the response requirement was associated with systematic decreases

in the amount of drug self-administered.

Interingestion Interval Another variable which produces similar

effects across different drugs is the minimum interval which is

experimentally imposed between successive drug ingestions. Fig. 8

presents the results from several studies (Bigelow, Griffiths, and

Liebson 1975a; Griffiths, Bigelow, and Liebson 1976b) which examined

the effects of interingestion interval manipulation on selfadministration of pentobarbital, diazepam and ethanol in sedative

abuser or alcoholic subjects. Procedures were similar to those

utilized in the other human drug self-administration studies, except that the minimum interval subjects were required to wait

between successive doses of drug was varied from day to day. Under

these conditions increases in the minimum interingestion interval

uniformly reduced the number of ingestions (as well as percent of

available ingestions) consumed.

Effects of Drug Self-Administration on Social Behavior A final

area where there appears to be some across drug generality is the

acute effects of moderate doses of self-administered drugs on the

social behavior of experienced users. Most relevant research in

this area has been done with ethanol's effects on the social behavior of alcoholics, and it has been clearly demonstrated in a

variety of situations (e.g., Mendelson 1964; Griffiths, Bigelow,

and Liebson 1974; 1975) that the acute effects of moderate ethanol

doses uniformly increase social behavior of alcoholics (see

Griffiths, Bigelow, and Liebson 1978 for review). This general

finding has been extended to three other drugs of abuse: heroin,

d-amphetamine and marihuana. Babor, Meyer, Mirin, McNamee, and

Davies (1976) showed that although increasing doses of intravenous

heroin were associated with decreases in the overall rates of

social interactions among hospitalized drug abuser subjects over

a ten day period, the acute effects of heroin were associated with

increases in social interactions immediately after injection.

Griffiths, Stitzer, Corker, Bigelow, and Liebson (1977) have shown

that d-amphetamine also produces dose related increases in social

behavior of drug abusers and normals under several different experimental conditions. For marihuana, the evidence for drug

facilitated socializing is both more complex and tenuous. Babor,

Rossi, Sagotsky, and Meyer (1974a, b) have noted that free choice

marihuana smoking in a hospital ward situation is a social activity

around which verbal interaction and other types of social behavior

are invariably centered; however, these investigators have also

noted that marihuana smoking may decrease subsequent verbal interaction in a structured group situation.

DISCUSSION

The preceding sections have provided a partial review of human

drug self-administration studies in residential settings with

37
FIGURE 8

ACROSS DRUG GENERALITY:

Effect of Minimum Interingestion Interval on

Human Drug Self-Administration

Effect of minimum interingestion interval on human

self-administration of pentobarbital, diazepam and ethanol. Data

are replotted from experiments involving oral drug self-administration by volunteer sedative abuser (Griffiths, Bigelow, and

Liebson 1976b) and alcoholic (Bigelow, Griffiths, and Liebson

1975a) subjects. Two subjects were exposed to pentobarbital and

diazepam and four subjects were exposed to ethanol. Data points

indicate means, brackets indicate ± one standard error of the

mean, and numerals indicate total number of observations at each

interingestion interval.

38

304-494 0 - 79 - 4
emphasis on those results which have shown across species and

across drug generality. Such replication of results across major

aspects of the experimental situation is important to establishing

the reliability of the procedures. The systematic replication of

some of the human results in an animal drug self-administration

model is particularly dramatic because besides species differences,

there are numerous additional experimental and methodological

differences. The demonstration of across species generality

suggests that the experimental findings are robust, reflect basic

underlying processes of drug self-administration, and are not

artifacts of the human or animal experimental models. The replication of human drug self-administration results across different

types of pharmacological agents also suggests that similar behavioral pharmacological processes underlie the self-administration

of various drugs. It should be noted, however, that the demonstration of across drug generality does not imply that there are not

important differences in the self-administration of different drugs.

An important area of generality which has not been addressed in

the current paper is the generality of results from the residential

laboratory to clinical phenomena observed in the "natural environment." The establishment of such generality will require objective

clinical observation in combination with sociological and epidemiological studies.

The demonstration of across species and across drug generality

suggests that common processes underlie these various forms of

drug self-administration, and supports the supposition of a

generalized behavioral phenomenon of substance self-administration.

It is likely that further characterization of these common processes will be valuable to understanding the etiology of, and to

developing treatment strategies for various forms of substance abuse.

REFERENCES

Angle, H. V., and Parwatikar, S. Methadone self prescripted by

heroin addicts in an inpatient detoxification program. Psychol

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Babor, T. F., Greenberg, I., Mendelson, J. H., and Keuhnle, J. C.

Experimental analysis of the "happy hour:" Effects of purchase

price on drinking behavior. Proceedings of The Committee on

Problems of Drug Dependence, Cambridge, Mass., 1977.

Babor, T. F.; Meyer, R. E.; Mirin, S. M.; McNamee, H. B.; and

Davies, M. Behavioral and social effects of heroin self-administration and withdrawal. Arch Gen Psychiat, 33:363-367, 1976.

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Babor, T. F.; Rossi, A. M.; Sagotsky, G.; and Meyer, R. E. Group

behavior: Patterns of smoking. In: Mendelson, J. H., Rossi, A. M.,

and Meyer, R. E., eds. The Use of Marihuana: A Psychological and

Physiological Inquiry. New York: Plenum Press, 1974a. pp. 47-59.

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ACKNOWLEDGMENTS

Preparation of this manuscript was supported in part by National

Institute on Drug Abuse grants DA-01147, DA-01022, and National

Institute on Drug Abuse Research Scientist Development Award DA-00050.

The discussion of across species generality is based on a previous

paper by Griffiths and Bigelow (1978).

AUTHORS

Roland R. Griffiths, Ph.D., George E. Bigelow, Ph.D., and

Ira Liebson, M.D., Departments of Psychiatry, The Johns Hopkins

University School of Medicine, and Baltimore City Hospitals,

Baltimore, Maryland.

43
Chapter 4

Therapeutic Self-Medication as a Context

for Drug Abuse Research

George E. Bigelow, Ph.D., Ira Liebson, M.D.,

Julia Kaliszak, and Roland R. Griffiths, Ph.D.

The majority of our laboratory's research on substance self administration has been conducted with chronic substance abusers to whom

drugs or alcohol have been made available specifically for research

purposes. Elsewhere we have described the experimental methodology

which has been developed and utilized in these residential laboratory drug self administration studies (Bigelow, Griffiths, and

Liebson 1975a; 1975b), and recent reviews have summarized many of

the behavioral relationships observed (Griffiths, Bigelow, and

Liebson in press; Griffiths and Bigelow in press). Among the

purposes of these basic human laboratory studies is to identify

relationships which may be relevant to the prevention or treatment

of drug abuse. Thus, at times the implicit assumption is made that

behavioral relationships observed among abusers in nontherapeutic

situations will generalize to nonabusers and/or to therapeutic

situations. However, the extent of such generalizability has yet

to be determined.

This paper will describe and present preliminary data from two experimental contexts currently being developed for the study of drug

self administration. It is hoped that these contexts will extend

the experimental analysis of drug self administration and help to

reveal the determinants of drug self administration by nonabusers

and within therapeutic situations. Both of the studies to be

described examine drug self administration within the context of

therapeutic self medication. The first examines the self administration by nonabusers of anorectic medications prescribed as an

aid to weight loss. The second examines the self administration

of methadone by dependent patients during voluntary self regulated

detoxification.

44
SELF-ADMINISTRATION OF THERAPEUTICALLY PRESCRIBED MEDICATIONS BY

NON-DRUG-ABUSERS

Many abused substances also have therapeutic indications and are

frequently prescribed to and self-administered by non-drug-abuser

patients. This self-administration of legitimate prescription

medications can provide a valuable context for the experimental

study of drug self-administration. This context can permit

analysis of influences upon self-administration of abused drugs

in the absence of the phenomenon of drug abuse and with patients

who are not habitual drug abusers.

We will describe here preliminary results obtained in a comparative

double blind evaluation of self-administration of anorectic medications by overweight women enrolled in an outpatient weight control

program. The study compared two chemically related anorectic medications of presumably differing reinforcing efficacy. d-Amphetamine

is a reinforcing drug which is readily self-administered by animals

and has been widely abused by humans. Fenfluramine is not a reinforcer; it has dysphoriant properties (Griffith, Nutt, and

Jasinski 1975); it is not readily self administered by animals

(Woods and Tessel 1974); and it is rarely abused by humans

(Griffiths, Brady, and Snell, in press). In the present study drug

self-administration was compared for placebo, fenfluramine and

d-amphetamine in weight control patients who were given substantial

self control over the extent of their drug taking. The study was

intended to assess the relevance of the concepts of reinforcing

efficacy or abuse liability to the control of drug self-administration by non-drug-abuser patients being prescribed these drugs as part

of a medical treatment regimen.

Method

Participants. Volunteer participants were solicited from among

employees at Baltimore City Hospitals by placing a notice in the

employee newsletter announcing an experimental weight control

program involving medications. Criteria for acceptance into the

program included being female, employed at the Hospital, at least

20 percent overweight, without any medical contraindications such

as hypertension, and with a history of failure at previous weight

control efforts. Volunteers received medical and psychiatric

screening and provided their written informed consent prior to

participation.

Characteristics of the forty-eight participants are summarized in

Table 1. They appear to be typical of the general weight control

treatment population. Their age averaged 38, and they were an

average of 41.6 percent overweight. All had failed at previous

weight control attempts; the table shows the percent of patients

who had previously tried various types of weight loss procedures.

45
TABLE 1

SUMMARY OF PARTICIPANTS CHARACTERISTICS (N=48)

Sex: Female

Age (mean and range): 38 (20-54)

% Overweight (mean and range): 41.6 (20-111)

Prior Weight Loss Attempts

(% of patients, and type): 93.7% Personal Attempts

54.2% Organized Program

60.4% Prescribed Medications

39.6% OTC Medications

Procedure. The study was conducted within the context of a behavioral self-management treatment program for overweight in which

patients were asked to self-record and self-evaluate their eating

and exercise habits throughout each day, and were provided weekly

individual counseling sessions to discuss their eating and exercise habits. Patients enrolled in a five week treatment program,

with medications being prescribed only during the last four weeks.

They were informed that the purpose of this study was to compare

several different medications which were already in clinical use

for the treatment of overweight. The specific drugs to be used

were not identified. Volunteers were informed of a variety of

side effects which they might experience, and they were informed

that they would not necessarily receive active drug. Patients

were also informed that they would be paid $15.00 at the end of

the five weeks if they reported to their weekly counseling sessions

for weighin; it was clear that payment was not contingent upon taking

medications.

The first week of the study was a baseline self-recording period

without medication and without structured self-evaluation, during

which patients were instructed to observe and record their eating

and exercise habits but not to attempt weight loss.

At the beginning of the four week drug period patients were randomly assigned to one of three medications -- placebo (N=18), fenfluramine (N=17), or &hetamine (N=13). All medications were

dispensed double blind and were prepared in identically appearing

opaque capsules. Doses of the active drugs in each capsule were

5 mg d-amphetamine, and 20 mg fenfluramine. These are the standard

recommended therapeutic doses of each drug, and these doses have

previously been shown to be equipotent in facilitating weight loss

in a controlled outpatient clinical evaluation (Stunkard, Rickels,

and Hesbacher 1973). Patients were informed that the average

proper dose was three capsules per day -- one capsule three times

per day about one hour before meals (this corresponds to the normal

46
therapeutic recommendation for both d-amphetamine and fenfluramine).

However, patients were told that since individuals differ in their

sensitivity to the drugs' effects and side effects they should selfregulate their own medication intake in the range of 0 to 6 capsules

per day.

Only a small amount of medication was dispensed to each patient at

any one time; on day one of the drug period each patient was given

12 medication capsules. Patients were told to report back to the

clinic to pick up additional medication whenever they needed it;

on these subsequent visits patients were given enough capsules to

bring the number in their possession up to 18 capsules. Patients

were told to bring their medication bottle with them at each visit

so the remaining capsules could be counted. The clinic dispensary

was open sixteen hours per day, seven days per week, to facilitate

medication pickups regardless of patients' work shifts.

Results

Figure 1 presents three related measures of the maintenance of

self-administration of the three medications. The top panel

shows the mean number of medication capsules self-administered in

each of the three medication groups: placebo, 43.3; fenfluramine,

27.8; and d-amphetamine, 42.2. Pairwise t tests revealed that

the number of capsules self-administered of fenfluramine was

significantly less than that of placebo (p<0.025, one tailed) and

significantly less than that of d-amphetamine (p<0.05, one tailed).

The number of capsules self-administered of placebo and d-amphetamine did not differ significantly.

The above measures of the amount of drug self-administered may

reflect differences in the effective potencies of the different

medications. Therefore, the remaining two panels of Figure 1 present data concerning the temporal persistence of drug self-administration, which should be uninfluenced by variations in the acute

effective dose. The middle panel shows, for each drug group, the

mean duration of medication use. This duration measure is the

number of days from the beginning of the drug period until the last

capsule was taken; medication was not necessarily taken on every

day during this period. The mean durations of medication use were:

placebo, 23.2 days; fenfluramine, 18.9 days; and d-amphetamine,

26.7 days. The bottom panel shows the mean number of days medication was actually taken; this is the duration of use minus any

gaps of nonuse of greater than 2 day duration (shorter gaps may

have gone undetected). The resulting mean numbers of days of

medication self-administration were: placebo, 21.2; fenfluramine,

16.7; and d-amphetamine, 25.7. Pairwise t tests revealed the same

results for both the duration and the number of days measures:

self-administration of d-amphetamine was better maintained than

that of fenfluramine (p<0.005, one tailed), but the differences

between placebo and fenfluramine and between placebo and

47
FIGURE 1

Placebo Fenfluramine d-Amphetamine

Three measures of the maintenance of drug self-adninistration are

shown for each medication group; the number of medication capsules

self-administered, the duration of medication use, and the number

of days of medication self-administration. Heights of bars indicate

means; brackets indicate ± one standard error of the mean.

48
d-amphetamine were borderline insignificant in all cases

(0.05< p < 0.10, one tailed).

Another way of assessing the persistence of drug self administration is to examine the pattern of dropout from medication use

over time. This is done in Figure 2, which shows over consecutive

days the percent of patients in each drug group who continued to

use their assigned medication. Patients were considered as continuing medication use through the day they took their last dose,

even if they had temporarily suspended use prior to that time.

As can be seen, there is no overlap in the data for the three

medication groups, except during the early days when all patients

were continuing their medication use. Fenfluramine use falls off

most rapidly; placebo use falls off next most rapidly; and

d-amphetamine use is most strongly maintained. The percentages

of patients continuing medication use through day 28 were:

fenfluramine, 29.4 percent; placebo, 38.9 percent; and d-amphetamine, 76.9 percent. Pair-wise z tests for differences between

these proportions revealed that &hetamine use was significantly

better maintained on day 28 than either placebo (p<0.02, one tailed)

or fenfluramine (p<0.005, one tailed), but that placebo and fenfluramine did not differ significantly from one another.

Weight change during the 4 week drug study was quite variable

between patients, and there were no significant differences between the three medication groups. On the average patients lost

weight at the rate of approximately three-quarter pounds per week;

this rate is modest, but is within the appropriate range to be

sought in a gradual weight loss program.

Discussion

Overall, these data show that self-administration of d-amphetamine

is most well maintained, that self-administration of fenfluramine

is least well maintained, and that self-administration of placebo

is intermediate. Two main points should be noted in these data.

First, these results show that the concept of drug reinforcement

appears to be a relevant influence upon the medication-taking behavior of normal non-drug-abuser patients who have received

prescription medications as part of a medical treatment regimen.

Second, the potency of this drug reinforcement is not so great

that it produces any significant deviation from the appropriate

pattern of medication intake.

The rank ordering of these compounds with respect to the maintenance

of self-administration corresponds to the ranking one would expect

if medication taking were controlled by drug reinforcement. It

differs from the ranking one would expect if medication taking

were controlled by therapeutic efficacy (i.e., both d-amphetamine

and fenfluramine self-administration would be better-maintained

than that of placebo), and it differs from the ranking one would

49
FIGURE 2

For each of the three medication groups the percent of patients continuing to use the

medication is shown over consecutive days.
expect if medication taking were controlled by the physicians'

instructions and/or by the patients' expectations (i.e., selfadministration of all three medications would be equally well

maintained). Thus, this study demonstrates that one of the major

variables which influences drug self-administration by drug abusers

(drug reinforcement) has generalized applicability as a determinant

of nonabusive drug self-administration by non-drug-abuser patients.

Perhaps most importantly, these data demonstrate that the context

of therapeutic self-medication can serve as a sensitive experimental setting for investigating behavioral pharmacological

factors involved in drug self-administration and drug abuse.

The fact that the phenomenon of drug reinforcement can reveal its

influence without leading to deviation from the prescribed appropriate pattern of drug intake is especially interesting. Thus,

the data from this study indicate that &hetamine was not an

especially potent reinforcer in this context. While it maintained

greater persistence of drug self-administration over time it did

not lead to increases in total medication intake or increases in

drug seeking behavior (as assessed by frequency of clinic visits

to pick up additional medication). Except in very rare instances

patients picked up medications only at the time of their scheduled

weekly weighin and counseling sessions. Thus, the limited amount

of medication (18 doses) dispensed to patients at each pickup may

have functioned as a ceiling on the extent of their self-administration. It is possible that d-amphetamine self-administration

would be less restrained if larger numbers of capsules were dispensed at any one time. Still, d-amphetamine was not sufficiently

reinforcing to maintain additional visits to the clinic to pick up

medication. Overall, the lack of any strong reinforcing effect of

amphetamine is impressive. No patient self-administered even as

much as half of the available medication, patients tended to drop

out of medication use as time passed, and no patient showed a

pattern of progressively increasing drug intake.

Despite the fact that d-amphetamine's reinforcing effect influenced

patients' medication intake, the extent of their drug use was conservative. When given the opportunity to self-regulate their drug

intake patients self-administered less medication than if they had

followed the usual prescription directive for these drugs of 'one

capsule three times per day. Other investigators have also reported this finding of conservative self-medication by patients

permitted to self-regulate their intake of prescription medications

generally thought to possess reinforcing properties. For example,

Sechzer (1971) has permitted patients during the immediate postsurgical recovery period to self-administer narcotic analgesics

via intravenous infusion in a manner quite similar to that used in

infrahuman laboratory studies and has found that, on the average,

patients self-administer less medication than would be given

according to the usual physician-determined regimens. In two

51
separate studies Winstead and colleagues have permitted unselected

psychiatric inpatients to self-medicate on request with either

diazepam (Winstead et al. 1974) or propoxyphene (Winstead, Parker,

and Willi 1977). In both cases it was noted that self-medication

was quite conservative; diazepam was self-administered at an

average rate of one dose (10 mg) per three patient days, and

propoxyphene at an average rate of one dose (100 mg) per fourteen

patient days. Despite these low rates Winstead and colleagues

have been able to identify significant demographic, psychometric

and situational correlates of drug self-administration. These

data support the thesis of this paper that the self-administration

of prescribed medications by non-drug-abusers can provide a valuable

research context for identifying and studying influences upon drug

self-administration.

The data from the present study and the other data reviewed indicate both that prescription drug self-administration provides a

sensitive and orderly dependent measure and that studies in this

context can be conducted without significant risk of overmedication.

Since the vast majority of drugs possessing significant abuse

potential are dispensed by legitimate medical order or prescription,

there exists a great potential for study of drug self-administration

which has been in the past largely ignored. Because studies in this

context can be conducted with non-drug-abusers, the relationships discovered may be of particular relevance to prevention of drug abuse.

SELF-REGULATED DETOXIFICATION BY DRUG DEPENDENT PATIENTS

The previous section has dealt with prescription self-medication

situations in which one can examine influences upon the drug selfadministration of relatively drug naive non-drug-abusers who are

being exposed to a drug of potential abuse liability. In this

section we describe a situation in which one can examine influences

upon the process of discontinuing chronic drug use by drug abusers.

A major goal of drug abuse treatment is the termination of drug

self-administration. Human laboratory drug self-administration

research is, however, typically conducted with patients who have

volunteered to take, rather than to stop taking, drugs. Conducting

drug self-administration with chronic drug users who are attempting

to discontinue their drug use may yield unique information about

factors which can enhance the transition from being drug dependent

to being drug abstinent.

Method

Participants. Participants have been 8 methadone maintenance

patients who expressed a desire to detoxify and who volunteered

to do so in our residential hospital research unit. Age averaged

26.5 years (range 20-37). Patients averaged over 8 years since

their first narcotics addiction (range 4-16) and over 2 years of

52
prior methadone maintenance (range 1⁄4-6). Six patients were white

and two black. None were currently living with a spouse; all were

unemployed; three were under legal supervision (parole, probation,

or pretrial).

Procedure. Following several days on the residential research

ward at their stable daily methadone dose patients were given

self control of their methadone intake and instructed that they

would be responsible for decreasing their dose to zero and that

they could do this in whatever pattern or schedule they wished,

but should plan to complete the detoxification within six weeks.

During the self-regulation period patients could obtain small

doses of methadone (ranging, between patients, from 2 mg to 5 mg)

any time between 11:30 a.m. and 9:30 p.m.; each dose was dispensed

contingent upon 5 minutes of exercise on a stationary exercise

bicycle. The total daily methadone allowable ranged, between

patients, from 120 percent to 150 percent of the patient's prior

stable dose. At the beginning of dose self-regulation patients

were informed of their prior stable dose and of the number and

magnitude of the doses available for self-administration. Staff

provided no instructions, suggestions, or feedback to patients

concerning what might be an "appropriate" sequence of dosages;

patients were told they were free to choose whatever they wished.

Within the thirty minutes preceding each daily session patients

completed a 59 item symptom checklist describing how they felt

during the preceding 24 hours. The checklist included item

clusters concerning symptoms of overdose, withdrawal, psychological

distress, sleep disturbance, and libido disturbance. Patients

indicated the severity of each symptom on a four point scale

ranging from 0 (not at all) to 3 (severe).

Results

Figure 3 shows the total daily dose of methadone self-administered

over consecutive days for each patient enrolled in the self-regulated methadone detoxification procedure. Six of these patients

progressively decreased their methadone dose, and five at some

point achieved a zero or near zero dose level. Also, six of the

eight patients at some time self-administered a daily dose greater

than that at which they began self-regulation. Three patients

chose to be discharged into continued methadone maintenance

(patients B, T, S); one of these (T) had failed ever to make any

significant dose reduction below his initial maintenance level.

Figure 4 shows for two patients their self-report symptomatology

scores and their total daily methadone dose over consecutive days.

Symptomatology scores increased dramatically during the latter

portions of the detoxification. Patients did not regulate their

dose so as to minimize symptomatology, but continued to decrease

their dose despite increasing symptomatology.

53
FIGURE 3

SELF-REGULATED METHADONE DETOXIFICATION

CONSECUTIVE DAYS

Total daily methadone intake over consecutive days is shown for each of eight patients participating in self-regulated methadone detoxification; Open circles indicate the stable maintenance

dose prior to self-regulation. Filled circles indicate the period of dose self-regulation.
FIGURE 4

For two patients the daily self-administered methadone dose is shown along with two daily

symptom checklist scores.
Discussion

These data are descriptive of the phenomenon of voluntary selfregulated detoxification. They are presented to demonstrate that

the process of self-regulated detoxification is orderly and

amenable to laboratory study. Our laboratory is now in the process

of developing this self-regulated detoxification procedure as a

context for experimental studies of influences upon methadone selfadministration.

Self-regulated detoxification has previously been reported and

recommended as an improved detoxification treatment procedure for

narcotics addicts (Raynes and Patch 1973; Razani et al. 1975).

In both of those reports the focus was upon achieving detoxification

rather than upon examining patterns of or influences upon methadone

self-administration; consequently patients were not permitted complete freedom to increase and decrease their doses as they wished.

Angle and Parwatikar (1973) have reported a self-regulated detoxification study in which the focus was upon analysis of the behavior

of methadone self-administration. They noted that scheduling a

24 hour leave from the hospital appeared to trigger a relapse to

maximal methadone self-administration. However, the phenomenon

did not replicate when a second 24 hour leave was scheduled later

in the study.

The possibility of studying influences upon relapse may be a

desirable outgrowth of studies of self-regulated detoxification.

The procedure of self-regulation can permit relapse to occur under

experimentally controlled conditions. As is known from followup

studies the occurrence of relapse is highly probable shortly after

detoxification. The present data indicate that a phenomenon

analogous to relapse can be observed prior to completion of detoxification.

Finally, it should be noted that because the joint phenomena of

detoxification and relapse are so widespread with all of the

addictive or substance abuse disorders, comparative studies of selfregulated detoxification and relapse may provide an especially

interesting dimension upon which to look for commonalities and

differences among different varieties of substance self-administration.

COMMENT

The intent of this paper is advocacy of the increased use of

therapeutic self-medication contexts for studies of drug abuse

related phenomena. There are several bases for this advocacy.

One is that self-medication contexts can provide unique opportunities to study phenomena of special interest to the drug abuse

field. For example, if we wish to develop behavioral pharmacological

56
principles relevant to prevention and treatment, it is necessary

to analyze how drug self-administration is influenced in non-drugabusers (the prevention analogue), and in patients attempting to

terminate chronic drug use (the treatment analogue). The present

studies indicate that in the self-medication context these situations can be studied under sufficiently rigorous conditions of

objective measurement and experimental control to permit analysis

of influences upon drug self-administration. A second major basis

for advocating self-medication as a research context is the accessibility of drug self-administration to study in this context.

Self-medication is widespread and occurs for therapeutic reasons.

Research in such a therapeutic context can be conducted relatively

nonintrusively compared to techniques involving introduction of

drugs purely for research purposes. Thus. therapeutic self-medication would appear to offer considerable-potential for drug

related research. The actual yield of this research context

yet to be determined.

abuse

has

REFERENCES

Angle, H. V., and Parwatikar, S. Methadone self prescription by

heroin addicts in an inpatient detoxification program. Psychol Rec,

23:209-214, 1973.

Bigelow, G., Griffiths, R. R., and Liebson, I. Experimental models

for the modification of human drug self administration: Methodological

developments in the study of ethanol self administration by alcoholics.

Fed Proc, 34:1785-1792, 1975a.

Bigelow, G., Griffiths, R. R., and Liebson, I. Experimental human

drug self administration: Methodology and application to the study

of sedative abuse. Pharmacol Rev, 27:523-531, 1975b.

Griffith, J. O., Nutt, J. G., and Jasinski, D. R. A comparison of

fenfluramine and amphetamine in man. Clin Pharmacol Therap,

18:563-570, 1975.

Griffiths, R. R., and Bigelow, G. Commonalities in human and

infrahuman drug self administration. In: Fishman, J., ed. The

Bases of Addiction. Berlin: Dahlem Konferenzen, 1978. In press.

Griffiths, R. R., Bigelow, G., and Liebson, I. Experimental human

drug self administration: Generality of relationships across species

and type of drug. This NIDA volume.

Griffiths, R. R., Brady, J. V., and Snell, J. D. Relationship

between anorectic and reinforcing properties of appetite suppressant

drugs: Implications for assessment of abuse liability. Biolog

Psychiat, 1978. In press.

Raynes, A. E., and Patch, V. 0. An improved detoxification technique

for heroin addicts. Arch Gen Psychiat, 29:417-419, 1973.

57
Razani, J., Chisholm, D., Glasser, M., and Kappeler, T. Self

regulated methadone detoxification of heroin addicts. Arch Gen

Psychiat, 32:909-911, 1975.

Sechzer, P. H. Studies in pain with the analgesic demand system.

Anesthesia and Analgesia, 50:1-10, 1971.

Stunkard, A., Rickels, K., and Hesbacher, P. Fenfluramine in the

treatment of obesity. Lancet, 1:503-505, 1973.

Winstead, D. K., Anderson, A., Eilers, M. K., Blackwell, B., and

Zaremba, A. L. Diazepam on demand. Arch Gen Psychiat, 30:349-351,

1974.

Winstead, D. K., Parker, M., and Willi, F. J. P. Propoxyphene on

demand. Arch Gen Psychiat, 34:1463-1468, 1977.

Woods, J. H., and Tessel, R. E. Fenfluramine: amphetamine congener

that fails to maintain drug taking behavior in the rhesus monkey.

Science, 185:1067-1069, 1974.

ACKNOWLEDGMENTS

This research was supported by United States Public Health Service

research grants DA-01022, DA-01472, and DA-01943, and by Research

Scientist Development Award DA-00050.

AUTHORS

George Bigelow, Ph.D., Ira Liebson, M.D., Julia Kaliszak, and

Roland R. Griffiths, Ph.D.

Departments of Psychiatry

Baltimore City Hospitals, and

The Johns Hopkins University School of Medicine

Baltimore, Maryland

58
Chapter 5

Drug Abuse Research in Outpatient Clinics

Maxine Stitzer, Ph.D., and George E. Bigelow, Ph.D.

Drug abuse research ultimately seeks to understand the pharmacological, environmental and historical determinants of drug ingestion

in humans. Significant advances have been made recently in developing methodologies for studying determinants of drug abuse in human addict populations. These methodologies are characterized by

direct observation and objective quantification of the behavior of

primary interest in drug abuse research, namely, drug ingestion

itself. Drug self-administration experiments seek to identify

variables which, when manipulated, will lead to orderly changes in

observable drug ingestion behavior. Human self-administration

studies are characteristically conducted in hospital ward settings

with inpatient participants. In these settings, experimental control can be exerted over many significant variables which influence drug ingestion so that the variables of interest can be

isolated and studied. In particular, daily routine, nutrition,

availability of drugs, and the social and environmental context of

drug use are controlled in inpatient settings. Specific methodologies have been developed for studying self-administration in

hospital ward settings of a variety of drugs including ethanol

(Bigelow, Griffiths and Liebson 1975; Mello 1972; Nathan and

O'Brian 1970), sedatives (Bigelow, Griffiths and Liebson 1976;

Pickens et al. 1977), narcotics (Angle and Parwatikar 1973; Jones

and Prada 1975; Meyer et al. 1976), nicotine (Griffiths, Bigelow

and Liebson 1976), and marihuana (Mendelson et al. 1976).

Inpatient settings, however, are not always necessary or ideal for

conducting drug abuse research, and in fact may have certain disadvantages. First, inpatient research is limited to a population

of drug abusers who are willing and able to give up several weeks

of their time in order to live on a hospital ward while participating. Secondly, inpatient research, while controlling environmental context of drug ingestion, at the same time creates an

atypical or artificial context for the occurrence of this behavior.

Outpatient clinics can also provide a setting for drug self-administration research. Methadone maintenance clinics and other drug

abuse treatment facilities constitute a naturalistic setting for

conducting research with readily available and appropriate subject

59
populations. The present paper will describe drug self-administration research that has been conducted in outpatient settings.

The paper will review some of the experimental questions that have

been explored in these settings and discuss methodologies that have

been developed for self-administration research in outpatient settings, primarily methadone maintenance clinics. We will

focus on two broad research areas that have been explored in outpatient settings. The first concerns evaluation of the abuse liability of compounds whose reinforcing potential for human drug addicts is unknown. The second concerns identifying treatment interventions which will influence the quantity and pattern of drug ingestion in human addicts.

Two basic approaches are possible for' studying drug self-administration in outpatient settings. In one approach, the drug selfadministration of interest to the investigator is that which takes

place outside the clinic, while the independent variable is some

intervention which takes place at the clinic. Drug ingestion outside the clinic can be assessed by client self-report or, more

objectively, by urinalysis results. This is not entirely satisfactory, however, since urinalysis results yield little information

about quantitative or temporal aspects of drug ingestion. A

second approach is to study ingestion of abused drug directly by

offering a limited quantity of these drugs at the outpatient

clinic. This latter approach has the advantage of achieving direct

experimental control over a portion of drug use. This paper will

focus primarily on research which has utilized drug ingestion at

the clinic as a primary dependent variable.

Outpatient Studies of Reinforcing Efficacy

One question that has been explored in outpatient drug self-administration research concerns the reinforcing efficacy of drugs. A

drug acts as a reinforcer if it maintains self-administration

behavior, and drugs which maintain self-administration presumably

have abuse potential for the populations studied. Self-administration studies may evaluate the reinforcing efficacy of a compound whose abuse potential is unknown by comparing self-administration of the unknown with that of a nonreinforcing placebo and

with that of a drug which is known or presumed to be reinforcing.

Schuster, Smith and Jaffe (1971) conducted such a study designed

to evaluate the reinforcing efficacy of pentazocine, a mixed narcotic agonist and antagonist with unknown abuse potential in humans.

Self-administration of pentazocine was compared with self-administration of placebo as well as with self-administration of codeine

and methadone, both of which were presumed to be reinforcers for

narcotics-dependent individuals. Participants were eligible for

methadone maintenance and were on a waiting list for maintenance

treatment. During the waiting period they were offered the chance

to come to the clinic daily for ten days to pick up bottles of medication which might help them with their addiction problem. Medication bottles for each participant contained either 400 mg pentazocine, 400 mg codeine, 40 mg methadone or 400 mg dextrose placebo. The

study showed that clients assigned to methadone or codeine picked

up more drug than did those assigned to pentazocine or placebo.

60
However, drug pickup dropped off dramatically for all compounds,

including methadone and codeine. The results indicated that pentazocine may have less reinforcing efficacy and abuse potential than

either methadone or codeine, but the results were also somewhat

equivocal as they failed to demonstrate the presumed high reinforcing efficacy of methadone and codeine. A second study (Schuster

1975) replicated the results for methadone and placebo under conditions where clients were required to swallow medication at the

clinic.. This procedure ensured that drug pickup behavior was

maintained by the drug ingestion consequence rather than by some

other consequence such as the opportunity to sell the medication.

Again, there was a high attrition rate for subjects in the methadone

group with more than 60% of the group lost from participation by the

end of ten days. The finding that methadone failed to maintain high

rates of drug pickup was surprising, since methadone regularly maintains daily clinic attendance in the context of drug treatment programs, and suggests that the procedures employed may not have been

optimal for assessing abuse liability in the outpatient setting.

As Schuster (1975) points out, many other factors are involved in

maintenance of self-administration besides the pharmacological properties of the drug. Of utmost importance may be the response cost

for obtaining the drug and the availability of alternative drug

sources. The problems engendered by a high response cost for drug

pickup may be circumvented by studying self-administration of drugs

which are offered to individuals who are already attending a drug

treatment clinic regularly. Studies which have examined reinforcing

efficacy of altered methadone dose are illustrative of this approach.

In one study (Goldstein et al. 1974) methadone maintenance clients

were allowed to alter their own methadone dose by ± 5mg each week

in order to determine whether large dose increments would be selfselected by clients. However, requests for increases in methadone

which resulted in doses above 50 mg also resulted in loss of medication take-home privileges. Under these conditions, 62.7% of the 59

clients studied raised their dose by at least 10 mg at some point

during the study, but median dosage of the clinic population increased by only 10 mg during 25 study weeks. Thus, increases in

stable methadone dose did not appear to be highly reinforcing. In

Goldstein's study, however, many clients were essentially faced with

a choice between higher methadone doses or continuing their takehome privileges. In addition, the size of each dose increase allowed

was quite small. These factors could account for the lack of clear

reinforcing effects of methadone dose increases.

Self-Regulation of Methadone Doses

A recent study conducted at Baltimore City Hospitals has shown more

clearly that methadone dose increases can act as reinforcers for

clients maintained on stable doses of methadone. In this study 23

clients enrolled at a maintenance clinic were given an opportunity

to regulate their own dose for a single day on 6 separate occasions.

Doses could be altered up or down by as much as 20 mg or 50% of the

stable dose, whichever was smaller. The dose self-regulation opportunity was offered twice a week for three consecutive weeks. Clients

chose to alter their dose on 97.1% of opportunities and chose dose

61
increases on 94.3% of opportunities. Of the dose increases selected,

81.2% were the maximum allowable size. Figure 1 shows typical patterns of dose self-regulation which were observed over successive

self-regulation opportunities. The majority of clients (56.5%) always took maximum allowable dose increments. A smaller percentage

(21.7%) took gradually larger dose increments on successive opportunities, while an additional 21.7% of clients showed unsystematic

patterns of dose adjustment. This study showed that acute methadone

dose increases act as a reinforcer for methadone maintained clients,

since these clients will reliably self-administer acute dose increases in the choice situation.

FIGURE 1

SUCCESSIVE OPPORTUNITIES

Acute (single day) methadone dosage alterations selected by nine

individuals clients on six successive opportunities. Doses could

be altered by as much as ± 20 mg on each occasion.

of dosage alteration emerged:

Three patterns

stable increases, progressive increases and unsystematic alterations. Percent of clients studied

Who showed each type of pattern is indicated. Examples of dosage

alterations selected by three representative clients are shown for

each pattern.

62
The studies reviewed, using several specific experimental designs

and methodologies, have shown that it is feasible to study drug selfadministration in outpatient settings when a portion of drug ingestion which is under direct experimental observation constitutes the

behavior of interest. Using drug self-administration methodologies,

it has been possible to differentiate some drugs according to their

relative abuse liability and to demonstrate reliable self-administration of methadone dose increases in narcotics dependent individuals.

Self-administration methodologies have also been used in outpatient

settings to study the influence of treatment interventions on drug

ingestion. Liebson et al. (1973), for example, took advantage of

the reinforcing properties of methadone to reduce excessive use of

ethanol in a group of narcotics dependent individuals with concurrent alcoholism. To accomplish this, a contingent arrangement was

designed which encouraged ingestion of disulfiram at the clinic.

Participants were methadone maintained clients who had a substantial

drinking problem in addition to their narcotics dependence. These

clients were initially assigned randomly to contingent or noncontingent conditions. The noncontingent group were offered disulfiram

(Antabuse (R) ) and encouraged to take it at home. The contingent

group were required to ingest disulfiram daily at the clinic in

order to receive their full dose of methadone. Because methadone

was a reinforcer for these clients, the contingent arrangement maintained high rates of disulfiram ingestion. The study revealed

striking differences in the amount of ethanol intake (as measured

via self-reports and regular breath alcohol tests) of clients under

the two conditions. Clients who were required to ingest disulfiram

as a condition of receiving their methadone drank ethanol less frequently than those who were simply instructed to take disulfiram at

home. In this experiment, ingestion of disulfiram at the clinic was

encouraged by contingencies which took advantage of the reinforcing

properties of methadone, and this in turn had a large impact on selfadministration of ethanol in the natural environment.

Control of Benzodiazepine Use by Methadone Clinics

Abuse of benzodiazepine tranquilizers is also common among narcotics

dependent individuals maintained on methadone. In a group of 57

clients, for example, enrolled in a methadone maintenance clinic at

Baltimore City Hospitals during January, February, and March of 1975,

40% showed benzodiazepine positives on 80% or more of urines tested

for this drug class, while only 20% of clients were entirely benzodiazepine free. Similarly, out of 50 new admissions to methadone

maintenance from September, 1976 to November, 1977, 40% showed consistent benzodiazepine positives over the first three months of

enrollment. Consequently, a study was designed whose purpose was

two-fold: first, to gain experimental control over a portion of

benzodiazepine use among these abusers; and second, to influence

this observable portion of drug self-administration by offering incentives contingent upon discontinuation of benzodiazepine use.

Five clients have participated in this ongoing experiment. These

clients were selected on the basis of benzodiazepine use as revealed

63
in clinical interviews and confirmed by urinalysis results. The

clients received prescriptions for diazepam (Valium), 20 mg per

day, which they were free to request or refuse at the dispensary

window throughout the course of the study. If Valium was requested

the client was required to swallow one 10 mg tablet at the dispensary

under nursing supervision and was given the second 10 mg tablet to

ingest away from the clinic later in the day. Following a six week

baseline period during which Valium was available, clients were

offered a choice between continuing Valium ingestion at the clinic

or receiving a clinic privilege: Clients could obtain a single

methadone take home day by refusing Valium at the clinic window on

four consecutive days. By refusing Valium every day of the week, a

maximum of two nonconsecutive take home days could be earned each

week. The incentive period lasted six weeks and was followed by a

return to baseline. After six weeks of baseline a second choice was

offered between Valium ingestion and a different clinic privilege.

This time four consecutive days of Valium refusal resulted in the

opportunity to self-regulate methadone dose for a single day by as

much as ± 20 mg. Again, a maximum of two dose self-regulation opportunities-could be earned each week by refusing all available Valium.

Figure 2 shows results for individual clients participating in this

study. During the six week baseline periods, 99.0% of available

Valiums were requested at the dispensary. When take home privileges

could be earned by Valium refusal, only 17.6% of available Valiums

were requested by five clients, while 77.4% of available Valiums

were requested by four clients during the period when dosage selfregulation could be obtained by Valium refusal. The opportunity to

obtain methadone take home medication resulted in dramatic reduction

of Valium ingestion at the clinic while the dosage self-regulation

opportunity was much less potent in influencing Valium self-administration. The relative effectiveness of methadone take home and

dosage self-control privileges were not fully assessed in this study,

however. It is likely, for example, that the effectiveness of limited

dosage self-control as a contingent reinforcer may be related to the

size of the allowable dose alteration, with larger allowable dose

increases having better reinforcing efficacy. Nevertheless, this

study has demonstrated that a portion of the drug use of drug abusers

can be brought under experimental observation and control and that

this observable portion of drug use can be influenced by contingent

privileges which are available in the context of a drug treatment

clinic.

Outpatient clinics thus provide a useful natural setting in which

drug abuse research can be conducted. Sufficient experimental control can be gained to generate orderly data without unduly restricting the environmental context of experiments or the activities of the

subject population. A variety of research areas can be explored with

a readily available population of appropriate subjects. Information

can be obtained which has direct relevance for improved treatment

of drug abusers. Hopefully the potential of outpatient clinics for

drug self-administration research will continue to be expanded.

64
FIGURE 2

SUCCESSIVE WEEKS

Number of 10 mg Valiums requested by five individual clients during 24 successive weeks of a contingency study. Two 10 mg Valiums

were available daily to each client throughout the study. The first

and third six week blocks were baseline periods. During the first

contingency period (second column from left) methadone take home privileges could be earned by Valium refusal. During the second contingency period (fourth column from left), limited methadone dosage selfcontrol could be earned by Valium refusal.

65
REFERENCES

Angle, H.V. and Parwatikar, S. Methadone self prescription by heroin

addicts in an inpatient detoxification program. Psychol Rec, 23:209-

214, 1973.

Bigelow, G.E., Griffiths, R.R., and Liebson, I.A. Experimental

models for the modification of human drug self administration: Methodological developments in the study of ethanol self administration by

alcoholics. Fed Proc, 34:1785-1792, 1975.

Bigelow, G.E., Griffiths, R.R., and Liebson, I.A. Experimental human

drug self administration: Methodology and application to the study

of sedative abuse. Pharmacol Rev, 27:523-531, 1976.

Goldstein, A., Hansteen, R.W., Horns, W.H., and Rado, M. Control of

methadone dosage by patients. Proc First Nat Drug Abuse Conf. New York:

Nat Assoc Prev Addic Narcotics 1974.

Griffiths, R.R., Bigelow, G.E., and Liebson, I.A. Facilitation of

human tobacco self administration by ethanol: A behavioral analysis.

J Exp Anal Behav, 25:279-292, 1976.

Jones, B.E., and Prada, J.A.. Drug seeking behavior during methadone

maintenance. Psychopharmacologia (Berl.), 41:7-10, 1975.

Liebson, I.A., Bigelow, G.E., and Flamer, R.. Alcoholism among methadone patients:

483-485, 1973.

A specific treatment method. Am J Psychiat, 130(4):

Mello, N.K. Behavioral studies of alcoholism. In: Kissin, B., and

Begleiter, H., eds. The Biology of Alcoholism. Vol. 2. New York:

Plenum Press, 1972.

Mendelson, J.H.; Kuehnle, J.C.; Greenberg, I.; and Mello, N.K.

Operant acquisition of marihuana in man. J Pharm Exp Therap, 198:42-

53, 1976.

Meyer, R.E.; Mirin, S.M.; Altman, J.L.; and McNamee, H.B. A behavioral paradigm for the evaluation of narcotic antagonists. Arch Gen

Psychiat, 33:371-377, 1976.

Nathan, P. and O'Brian, J. An experimental analysis of the behavior

of alcoholics and nonalcoholics during prolonged experimental drinking: A necessary precursor to behavior? Behav Therap, 2:419, 1970.

Pickens, R.; Cunningham, M.R.; Heston, L.L.; Eckert, E.; and Gustafson, L.

humans.

Dose preference during pentobarbital self administration by

J Pharm Exp Therap, 203:310-318, 1977.

Schuster, C.R., Smith, B., and Jaffe, J.H. Drug abuse in heroin

users. Arch Gen Psychiat, 24:359-362, 1971.

Schuster, C.R. Drugs as reinforcers in monkey and man. Pharmacol

Rev, 27:511-521, 1975.

66
AUTHORS

Maxine Stitzer, Ph.D.

George E. Bigelow, Ph.D.

Baltimore City Hospitals

Baltimore, Maryland 21224

67
Chapter 6

Drug Self-Administration in Humans

Chris E. Johanson, Ph.D., and

Eberhard H. Uhlenhuth, M.D.

Over the last 25 years, there have been increasing research

efforts to understand the basis of illicit psychotropic drug use

in humans. A major portion of this effort includes studies

investigating pharmacological and environmental variables affecting the self-administration of psychotropic drugs using an animal

model of human drug abuse (Schuster and Thompson 1969; Schuster

and Johanson 1974). Such studies have not only been useful in

delineating factors which contribute to the initiation and

maintenance of drug use, but have also provided a methodology

for predicting the abuse potential of new compounds before they

are introduced to the marketplace (Johanson and Schuster 1977b;

Thompson and Unna 1977). Obviously, there are a number of

practical and ethical advantages of using animals in studies

where potentially harmful drugs are administered. Both the

range of manipulations and the degree of experimental rigor can

be greater. On the other hand, it is essential to validate the

findings of animal studies if we are to have any confidence in

the predictive utility of our animal model for human drug abuse

problems.

Studies have found that the major classes of drugs serving as positive reinforcers in infra-human organisms are those commonly used

illicitly by humans (Schuster and Johanson 1974). Further, the

patterns of intake (cyclical vs. continuous) of various classes of

drugs are similar in animals and humans (Deneau, Yanagita, and

Seevers 1969; Johanson, Balster, and Bonese 1976; Kramer, Fischman

and Littlefield 1967; Schuster 1970). There are functional similarities as well. Altering availability, dose, pharmacological

and environmental history, or pretreatment with other drugs has

similar effects across a variety of species including humans

(Johanson 1978). Likewise, the effects of repeated drug administration, including tolerance, physical dependence, and toxicity

are remarkably similar between animals and humans (Jaffe 1975).

68
As previously mentioned, one important use of animal drug selfadministration studies is to provide a methodology for predicting

the abuse potential of new compounds. It is assumed that psychotropic drugs have as an inherent pharmacological property the

capacity to serve as positive reinforcers and that this capacity

is directly related to their abuse potential. It is also assumed

that this capacity is relative, so that it is possible to rank

drugs in their ability to function as positive reinforcers along

a continuum. Therefore, it might be possible to discover drugs

with similar therapeutic efficacy but with different potentials

for abuse (Griffiths, Brady, and Snell 1978; Thompson 1977).

In developing a methodology for predicting abuse potential using

animals, it would be ideal to first determine whether the procedures being tested rank drugs known to be abused by humans

correctly, i.e., according to their relative frequency of abuse

(Martin 1977). Unfortunately, obtaining valid, reliable estimates

of a drug’s actual abuse in society is an enormous methodological

problem, since the pharmacological effect of the drug alone does

not determine drug use. It would seem useful, therefore, to

attempt to replicate certain animal studies, using humans, to

determine whether similar results are found. However, in recent

years, there has been an increased concern with the ethics of

human drug research. These ethical considerations limit the participation of humans in self-administration studies. Nevertheless,

the replication of a few carefully selected experiments in humans

could help to determine the validity and hence predictive utility

of an animal model of drug abuse. Ultimately such an animal

model might serve to decrease the necessity for human subjects in

drug abuse research.

Although drug abuse and considerations of abuse potential have

been studied extensively in humans, the direct approach of studying actual drug-taking behavior is relatively new. Generally,

the assessment of abuse potential has been based upon a comparison

of the profile of action of a new drug with one of known abuse

potential. One of the principal measures in such comparisons

is the subjective judgment of institutionalized, ex-addict

subjects; these subjects are given a drug and asked whether they

like it or whether it resembles any drug they have ever used

(Haertzen 1966, 1974; Martin and Fraser 1961). In some instances,

mood scales purporting to measure a drug’s ability to produce

euphoria are used, on the assumption that a drug's euphorigenic

properties are the basis of its abuse. Clearly, the results of

this type of study are difficult to compare with animal studies

where the frequency of drug-seeking or drug-taking behavior is

the measure used to assess abuse potential. The present study

was an outgrowth of years of laboratory studies using infra-human

research subjects. An attempt has been made to adapt the methods

69
used in animals for human subjects in order to determine the comparability of results. In addition, however, changes in mood

were measured to determine whether self-administration behavior is

related to alterations in mood as is often assumed. If such

relations are found, they would validate the use of such mood

changes as predictors of actual drug use and suggest mechanisms

which contribute to drug abuse.

A procedure which has proven effective in differentiating drugs

in terms of their reinforcing properties in animals involves

giving an organism a choice between compounds (Findley, Robinson,

and Peregrino 1972; Johanson 1975; Johanson and Schuster 1975,

1977a). Choice in this case is considered a measure of preference.

This research has shown that animals prefer many drugs over saline,

high doses of a drug over low doses, and certain drugs over others.

For example, cocaine is generally preferred to diethylpropion

even when there is a 10-20 fold difference in dose (Johanson and

Schuster 1977a). This potency difference is larger than that seen

when comparing other behavioral properties of these two drugs

(Johanson 1978). The finding that diethylpropion is not as reinforcing as cocaine corresponds well with reports of the relative

incidence of abuse of diethylpropion (Jasinski, Nutt, and Griffith

1974) and suggests the possible usefulness of the choice procedure

in predicting the relative abuse liability of drugs.

The first study using human subjects was designed to be methodologically similar to the previously conducted animal studies. Human subjects were given a choice between two psychomotor stimulant

drugs, d-amphetamine and diethylpropion. Since the results of this

study indicated the usefulness of this method, a second study was

done where humans were given a choice between diazepam and placebo.

Diazepam was tested because of the increasing concern over its purported abuse as well as our desire to determine the utility of this

method with a drug from another pharmacological class.

Study 1: Self-Administration of d-Amphetamine (AMP) and Diethylpropion (DEP)

METHODS

Subjects: Three female and seven male subjects between the ages

of 21 and 37 participated. All subjects were volunteers I

recruited by placing advertisements in a student newspaper. All

subjects were considered normal on the basis of extensive psychological screening, physical examination, ECG, complete blood

chemistries, blood count, differential and routine urinalysis.

Subjects signed a consent form prior to participation which outlined the study in detail and indicated all possible side effects

of any drug they would be given. They were specifically informed

that they would not be told what drug they ingested at the time,

except that it would be either a psychomotor stimulant, minor

tranquilizer or placebo, and the dose would be within the daily

therapeutic range. Except for the actual drug ingested, subjects

70
were completely informed of all other procedural details as outlined below.

Procedure: Each subject participated in three to six different

choice experiments involving d-amphetamine (5 and 10 mg), diethylpropion (25 and 50 mg) and placebo (dextrose) given in capsules

for oral ingestion.. During each of these experiments, subjects

were given a choice either between one of the two drugs and placebo or between AMP and DEP. For each subject, the procedure was

identical across all experiments except for the drug choices

available. The procedure was similar for all 10 subjects except

as noted below.

Each experiment consisted of 9 sessions, three per week. During

the initial (sampling) sessions, the subjects were given an opportunity to experience the effects of each of the two choice drugs

before being asked to choose between them in later (choice)

sessions. The first 5 subjects had 6 sampling and 3 choice

sessions, and the last 5 subjects had 4 sampling and 5 choice

sessions. Subjects were unaware of the actual drug dispensed but

each drug and dose was associated with a different colored capsule. The capsule colors associated with the different doses of

the two drugs were assigned randomly across subjects to partially

avoid problems of color preference.

Subjects reported to the laboratory any 3 mornings each week

between 9 and 11 a.m. During the sampling sessions, they ingested

a capsule and filled out a mood scale form (see below). The color

of the capsule alternated every session so that each of the two

possible choices was ingested either 2 or 3 times. Subjects were

told to note the color of the capsule and try to associate it with

its effects, whatever they might be. They were informed that

they would be asked to choose between the 2 colors in later

sessions. The subjects then were free to leave the laboratory but

were asked to remain within the university complex for the next six

hours. In addition, they took 3 additional mood forms with them

to fill out 1, 3 and 6 hours after drug ingestion.

During the subsequent choice sessions, the procedure was identical

except that the subjects were asked to choose which of the 2

colored capsules they would like to ingest, ‘The number of choices

for each color was the dependent variable used for assessing

preference.

The initial experiments were designed to determine whether subjects

preferred d-amphetamine or diethylpropion over placebo. If both

drugs at either dose were preferred, they were compared to each

other in additional experiments. Table 1 shows the number of

subjects given each of the 8 possible combinations as a choice.

Subjects participated in a maximum of 6 experiments. The decision

as to which experiments each subject participated in were based

on the following considerations. In the first two experiments,

the lowest dose of each drug was compared to placebo. If either

71

304-494 0 - 79 - 6
TABLE 1

Number of Subjects Participating in Each

Experiment in Study 1.1

Placebo 5 mg AMP 10 mg AMP

25 mg DEP 10 8 3

50 mg DEP 1 7 4

5 mg AMP 10

10 mg AMP 2

1The column and row headings for each box

indicate the two possible choices.

TABLE 2

Subscales for Each Form of the

Profile of Mood States

Subscale

1

2

3

4

5

6

7*

8

9

65-Item Scale 72-Item Scale

Anxiety Anxiety

Depression Depression

Anger Anger

Vigor Vigor

Fatigue Fatigue

Confusion Confusion

Arousal Arousal

Friendliness

Elation

*Subscale (1 + 4) - (5 + 6)

72
5 mg AMP or 25 mg DEP was not preferred to placebo, the higher

dose of that drug (10 mg AMP or 50 mg DEP) was compared to placebo.

If a dose of each drug was found which was preferred to placebo,

they were compared to each other in additional experiments. The

dose of the drug NOT preferred in this comparison was increased

to the limits of the dose range (10 mg AMP or 50 mg DEP). I f

subjects participated in additional experiments, a comparison was

made between other possible combinations of AMP and DEP.

Profile of Mood States (POMS): The scale used to assess changes

in mood was the POMS (McNair, Lorr, and Doppleman 1971). With

the first five subjects a form of the P0MS using 65 adjectives

was used. Subsequently a revised version having 72 adjectives

became available and this was used with the remaining five subjects. The adjectives in the POMS are those used commonly to

describe momentary mood states, Subjects were asked to check how

they felt AT THAT MOMENT in relation to that adjective on a 4

(the 65-item scale) or 5 point scale (the 72-item scale) from not

at all (0) to very (3 or 4). Table 2 shows the different subscales for each version of the POMS. Except for Arousal, these

subscales have been determined empirically using factor analysis.

The names are given for convenience. The measure of Arousal is

derived by combining four of the subscales as noted in the table.

Changes in mood for each subscale were determined for each hour

following drug ingestion (1, 3 and 6) as the difference from hour

0. It is these difference scores which were used in all data

analyses.

RESULTS

Drug vs. Placebo: All 10 subjects initially were given a choice

between 5 mg AMP and placebo and between 25 mg DEP and placebo.

Since the number of choices possible differed among subjects

(3 or 5), the results were expressed as a mean of the percent

drug choices for each subject who participated in each experiment.

As Figure 1 shows, both drugs were preferred to placebo with the

preference being greater for 5 mg AMP (85%) than for 25 mg DEP

(63%). While not all subjects chose drug consistently, only one

subject out of 10 chose placebo over 50% of the time for both

5 mg of AMP and 25 mg of DEP. When given a choice between 10 mg

AMP and placebo, he chose drug on all sessions. However, given

a choice between 50 mg DEP and placebo, he still chose placebo

consistently. A second subject also preferred placebo to both

doses of DEP on every choice. With these exceptions, all subjects

preferred the psychomotor stimulant drugs to placebo on the

majority of trials.

AMP vs. DEP: Since not all subjects were in each experiment and

the number of choices varied among subjects, the results are

expressed as the mean of the percent of AMP choices of each subject. The two subjects who did not prefer either dose of DEP to

placebo were not used in any further analyses. As shown in Figure

2, both doses of AMP were preferred to 25 mg DEP. The higher dose

73
FIGURE 1

DRUG VS PLACEBO

d-Amphetamine Diethylpropion

5 mg 25 mg

The percent choice of 5 mg d-amphetamine and 25 mg diethylpropion over placebo. The percent is a mean of individual percent drug choices for 10 subjects in Study 1. Only 1 subject

chose 5 mg d-amphetamine less than 50% and 2 subjects chose 25

mg diethylpropion less than 50%.

of AMP was chosen on every possible occasion over the low dose of

DEP. Increasing the dose of DEP to 50 mg decreased this preference. In the comparison between 5 mg AMP and 50 mg DEP, there was

still an overall preference for AMP. On the other hand, 10 mg

AMP and 50 mg DEP were chosen approximately the same number of

trials. This was true both within subjects as well as across

subjects.

This equal preference seems surprising and may largely be an

artifact as a result of the design of the study. Subjects who

preferred 5 AMP over 50 mg DEP were not tested in the comparison

between 10 mg AMP and 50 mg DEP on the assumption that if 5 mg

AMP was preferred, 10 mg AMP also would be. If we assume that

these subjects would have chosen 10 mg AMP over 50 mg DEP, the

7 4
FIGURE 2

AMPHETAMINE VS DIETHYLPROPION

Diethylpropion (mg)

The percent choice of 5 mg (left bars) and 10 mg d-amphetamine (middle bars) compared to 2 doses of diethylpropion in

study 1. The solid lines are the means of individual percent

choices for subjects participating in each experiment (see Table

1). The dotted lines are the same means assuming that all 8 subjects Were in every comparison. For instance, if a subject chose

5 mg d-amphetamine rather than 25 mg diethylpropion on 4 of the 5

choice, it would be assumed that he would choose 10 mg d-amphetamine compared to 25 mg diethylpropion the same number of times.

The bar on the right is the percent choice of amphetamine rather

than diethylpropion regardless of dose.

percent choice of 10 mg AMP over 50 mg DEP would be 69% (see Fig.

2). In addition, if all comparisons between AMP and DEP are

averaged together, regardless of dose, AMP is preferred to DEP

70% of the time. If it is assumed that the 2 subjects who did

not prefer either dose of DEP to placebo would have always preferred AMP to DEP, this overall percentage would have been even

higher. In general, therefore, AMP is preferred to DEP. It is

important to note, however, that it appears that this preference

75
declines as the dose of DEP increases. It is possible that higher

doses of DEP would have been preferred to AMP. We can only conclude that, in the range of doses commonly used for therapeutic

purposes, AMP is preferred to DEP.

POMS: Although the POMS data could be analyzed a variety of ways,

this preliminary analysis will include only the Arousal score

since it has been shown in other studies in our laboratory to be

sensitive to the effects of psychomotor stimulants. Data are

included only from the 5 subjects who filled out the 65-item

checklist. Fig. 3 shows the difference scores for each drug at

both doses for 1, 3 and 6 hours after drug ingestion. Comparable

scores for placebo are also shown. In general, both AMP and DEP

FIGURE 3

SUBJECTIVE AROUSAL SCORES

The Arousal scores derived from the Profile of Mood States

for hours 1, 3, and 6 expressed as a difference from the

score for hour 0 shown separately for placebo, 5 and 10 mg d-amphetamine and 25 and 50 mg diethylpropion in Study 1. The scores

are the means of 5 subjects who fitted out the 65-item version.

The Arousal score is the sum of factors 5 and 6 subtracted from

the sum of factors 1 and 4.

76
increased Arousal relative to placebo. The effect for DEP peaked

at hour 1 while AMP’s effect peaked at hour 3. The order of increase was 50 mg DEP>l0 mg AMP>5 mg AMP>25 mg DEP which is

certainly compatible with the choice data. On the other hand,

at hour 6 Arousal was considerably decreased by all drugs, particularly DEP, relative to placebo. How these 2 effects might

combine and affect preference is difficult to predict. Preliminary analysis of changes in individual POMS scores failed to reveal

any differences in the effects of the drugs on Arousal that reflect differences in preference. This was as well true for all

the individual subscales of the POMS (Johanson and Uhlenhuth 1977).

It seems, therefore, that while the POMS Arousal scale is sensitive to the effects of both AMP and DEP, the change produced is

not related to preference in a straightforward manner. Further

analysis of the POMS data is currently being conducted which may

reveal subtler systematic differences related to drug preference.

Study 2: Self-Administration of Diazepam (DZ).

METHODS

Subjects: Three female and eight male normal volunteer subjects

participated. They were screened and prepared in exactly the same

manner as subjects in Study 1.

Procedure: The subjects participated in 4 or 5 different choice

experiments involving diazepam (2, 5 and 10 mg) vs. placebo, 5 mg

d-amphetamine vs. placebo or d-amphetamine vs. diazepam (DZ) . The

procedure was identical to Study 1 except that in each experiment

all subjects had 4 initial sampling sessions designed to provide

experience with the effects of each of the 2 choice drugs followed

by 5 choice sessions.

In the initial experiments, an attempt was made to determine

whether 5 mg AMP and 2 or 3 doses of DZ (2, 5 or 10 mg) were

preferred to placebo. In additional experiments, DZ and AMP

were compared to each other. Table 3 shows the number of subjects

given each of the possible combinations as a choice.

The strategy was first to determine whether one or more doses of

DZ were preferred to placebo. If so, the lowest preferred dose

was compared to AMP. If, regardless of dose, DZ was not preferred and the subject was scheduled to participate in additional

experiments, 2 mg DZ was compared to 5 mg AMP.

RESULTS

Although all subjects had 5 choice opportunities, the results are

expressed as a mean of the percent drug choices for each subject

who participated in each experiment in order to permit comparison

of the results to Study 1. Figure 4 shows the results of the

experiments comparing the 3 doses of DZ (2, 5 and 10 mg) and 5 mg

AMP to placebo. As in the first study, AMP was preferred to placebo

77
TABLE 3

Number of Subjects Participating in Each

Experiment in Study 2.1

2 mg DZ 5 mg DZ 10 mg DZ

Placebo 10 11 10

5 mg AMP 8 2

10 mg AMP 1

1The column and row headings for each box

indicate the two possible choices.

The lowest dose of DZ (2 mg) was chosen on approximately half the

trials. Preference varied considerably among subjects, with 4

subjects choosing DZ less than 2 times, 4 subjects choosing DZ

4 or 5 times and the other 3 choosing the drug 2 or 3 times.

However, the higher doses of DZ were seldom chosen by any subjects.

Similarly, in the comparison between 2 mg DZ and 5 mg AMP, DZ was

only preferred on 25% of the choices. Figure 5 (top panel) shows

the results from a typical subject. Compared to placebo this subject only preferred the lowest dose of D&which in turn was not

preferred to 5 mg AMP.

As mentioned above, the higher doses of DZ were seldom chosen over

placebo. However, 2 subjects did prefer 5 mg DZ on the majority

of choice sessions. Therefore, this dose of DZ was compared to

5 mg AMP. In that comparison one of the subjects preferred DZ,

and in a subsequent experiment even preferred 5 mg DZ to 10 mg AMP

(Fig. 5). The second subject, however, preferred 5 mg AMP to the

DZ. In general, therefore, DZ was seldom preferred either to

placebo or to AMP.

The analyses of the POMS data are incomplete at this time, as this

study is still in progress.

DISCUSSION

The present studies are important in two respects. The first concerns the design of methodologies for the prediction of the abuse

potential of new compounds. Over the last 15-20 years, attempts

have been made using an animal model of drug abuse to develop ways

of determining, prior to the introduction of new drugs on the

market, whether they might be abused. The strategy is to find

procedures which measure the reinforcing properties of drugs along

a continuum of increasing strength or efficacy. The assumption

78
FIGURE 4

DRUG VS PLACEBO

Dose (mg)

The percent choice of 5 mg d-amphetamine (left bar) and-three

doses of diazepam over placebo. The percent is a mean of

individual percent drug choices for subjects in study 2 (see

Table 3).

79
FIGURE 5

DOSE (mg)

The number of choices for each alternative in 4 experiments for 2 subjects in study 2. The drug is indicated by

the hatching of the bar and dose is shown below each bar.

80
has been that the reinforcing properties of drugs in animals are

correlated with their abuse potential in humans.

One of the problems faced in this endeavor has been the validation

of results. Investigators have studied drugs, such as heroin and

amphetamine, whose frequency of abuse is presumably known. However, there are enormous methodological problems in making estimates of actual abuse, and it is not at all clear whether these

estimates are adequate for validating an animal model. Therefore,

the initial study was similar to a previous animal experiment

where the reinforcing properties of intravenous cocaine and

diethylpropion were compared. In this animal experiment both

drugs were preferred to saline over a large dose range (Johanson

and Schuster 1975, 1977a). In addition, although cocaine was

generally preferred to diethylpropion, there was some indication

that increasing the dose of diethylpropion decreased this preference . The dose required was 10 to 20 times that of cocaine. In

other animal studies comparing these two drugs behaviorally, the

potency difference was only 4- to 6-fold (Johanson 1978). It seems,

therefore, that in addition to a potency difference between these

two drugs, this study indicates that cocaine is more efficacious

as a positive reinforcer. Similar results have been found in other

animal studies (Griffiths, Brady, and Snell 1977). Certainly,

the reports of their relative abuse, however inaccurate they may be,

agree with this rank order.

Although the results of the present study using humans may indicate

that diethylpropion is a weaker reinforcer, they are not conclusive.

Despite the use of low oral doses, the subjects generally preferred

both d-amphetamine and diethylpropion over placebo. This result

corresponds to the fact that animals self-administer both of these

drugs at a greater frequency than saline (placebo) (Griffiths,

Brady, and Snell 1977; Johanson and Schuster 1975, 1977a).

In comparisons between these two drugs, d-amphetamine was generally

preferred. However, as the dose of diethylpropion was increased,

preference for d-amphetamine decreased much as was found in the

animal study. In the comparison between 10 mg d-amphetamine and

50 mg diethylpropion, both were equally preferred., but by

projecting data of all the subjects (see Fig. 3), amphetamine

appears to be preferred. Since higher doses of diethylpropion

were not tested, it is difficult to assign a potency

ratio for the two drugs. However, the estimated potency difference (1:5) is certainly similar to that recognized therapeutically

and found in other behavioral studies using both animals and humans

(Griffiths, Brady, and Snell 1978; Jasinski, Nutt, and Griffith

1974; Jonsson 1969). These other studies, regardless of species,

do not conclude that d-amphetamine and diethylpropion differ in

abuse potential. Clearly additional research in both animals and

humans is necessary to determine whether there is any significant

difference in the abuse potential of these two drugs. What is

significant, however, is that the results from both animal and

human studies are similar.

81
This is also true in the second study. Except at the lowest dose

of 2 mg, few subjects chose diazepam over placebo. Even at the

2 mg dose, preference was just over 50%, which may only indicate

that subjects could not discriminate this drug from placebo. In

addition, with one exception, doses of diazepam which were preferred over placebo were not preferred to 5 mg d-amphetamine.

Unfortunately, these results cannot be compared-directly to animal

studies. Perhaps due to its insolubility in water, there is only

one published report of diazepam self-administration in animals

(Yanagita and Takahashi 1973). This experiment involved very high

doses of drug under conditions of unlimited access. Although

3 of the 4 monkeys self-administered the drug at rates above

saline, the authors state that this drug was not as potent a reinforcer as many other drugs tested under similar conditions (Yanagita and Takahashi 1973). Furthermore, in other animal experiments

where chlordiazepoxide has been made available, rates of selfadministration have been relatively low, similar to those for

saline (Johanson and Balster 1978). Although, in another animal

study using a choice procedure, chlordiazepoxide was preferred to

saline, secobarbital was overwhelming preferred to chlordiazepoxide

(Findley, Robinson, and Peregrino 1972). Therefore, while the

benzodiazepines may be capable of maintaining some responding,

other drugs are readily preferred in animal studies as well

as the present one with humans.

The second aspect of these studies concerns the relationship between the self-administration of drugs and their effects on subjective rating scales. It has been assumed that particular

changes in mood states, such as increased euphoria, are good

predictors of the abuse potential of a drug (Haertzen 1966, 1974).

If an unknown drug produces a profile of action on a variety of

subjective and perhaps physiological measures similar to a drug

known to be abused, then their abuse potentials are considered

similar.

A study by Jasinski, Nutt, and Griffith (1974) is an excellent

example of research making this assumption. They compared orally

administered d-amphetamine and diethylpropion in humans by assessing their relative profiles of action on a variety of subjective

and physiological measures. The effects of both drugs were

qualitatively similar, although diethylpropion was 1:6 to 1:11

as potent as d-amphetamine.

In the present study, subjective effects were measured using a

derived measure (Arousal) from the Profile of Mood States. While

all doses of both d-amphetamine and diethylpropion increased

Arousal, the potency difference was not as great as in the

Jasinski, Nutt, and Griffith (1974) study. In addition, the

changes in Arousal were seen at much lower doses. On the other

hand, there is some indication that increases in Arousal were

not predictive of preference. Clearly, these results should only

be considered preliminary, as it is possible to do additional

analyses of the POMS involving other combinations of subscales.

82
Although these results are not conclusive, they do cast doubt on

the assumption that mood changes and drug self-administration are

related in a straightforward predictive matter.

The results of the present studies indicate that it is possible to

develop methodologies of drug self-administration in humans which

are sensitive to different drugs. The comparability of results

with animal studies helps validate an animal model of human drug

abuse. In addition, human studies of drug self-administration can

provide important information on the relationship between a drug’s

reinforcing efficacy and its mood altering properties. Application of this combination of methodologies can provide new insights

into the motivational basis for drug abuse.

REFERENCES

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

of psychoactive substances by the monkey. A measure of psychological dependence. Psychopharmacologia, 16:30-48, 1969.

Findley, J.F., Robinson, W.W., and Peregrino, L. Addiction to

secobarbital and chlordiazepoxide in the rhesus monkey by means

of a self-infusion preference procedure. Psychopharmacologia,

26:93-114, 1972.

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, 1977 (in press).

Griffiths, R.R., Brady, J.V., and Snell, J.D. Relationship between

anorectic and reinforcing properties of appetite suppressant drugs:

implications for assessment of abuse liability. Biol Psychiatry,

1978 (in press).

Haertzen, C.A. Development of scales based on patterns of drug

effects using the Addiction Research Center Inventory. Psychol

Rep, 18:163-194, 1966.

Haertzen, C.A. Subjective effects of narcotic antagonists. In:

Braude, M.C. et al., eds. Narcotic Antagonists. New York: Raven

Press, 1974. pp. 383-398.

Jaffe, J.H. Drug addiction and drug abuse. In: Goodman, L.S.

and Gilman, A., eds. The Pharmacological Basis of Therapeutics.

New York: MacMillan Publishing Co., Inc., 1975. pp. 284-324

Jasinski, D.R., Nutt, J.G., and Griffith, J.D. Effects of diethylpropion and d-amphetamine after subcutaneous and oral administration. Clin Pharmacol Ther, 16:645-652, 1974.

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Johanson, C.E. Pharmacological and environmental variables

affecting drug preference in rhesus monkeys.

27:343-355, 1975.

Pharmacol Rev,

Johanson, C.E. Effects of intravenous cocaine, diethylpropion,

d-amphetamine and perphenazine on responding maintained by food

-delivery and shock avoidance in rhesus monkeys. J Pharmacol

Exp Ther, 204:118-129, 1978.

Johanson, C.E. and Balster, R.L. A summary of the results of

self-administration studies using substitution procedures in

primates. (In preparation).

Johanson, C.E., Balster, R.L., and Bonese, K. Self-administration

of psychomotor stimulant drugs: The effects of unlimited access.

Pharm Biochem Behav, 4:45-51, 1976.

Johanson, C.E., and 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.H. and Kilbey, M.M., eds. Cocaine and Other

Stimulants. New York: Plenum Press, 1977a. pp. 545-570.

Johanson, C.E., and Schuster, C.R. Procedures for the preclinical

assessment of the abuse potential of psychotropic drugs in animals.

In: Thompson, T. and Unna K., eds. Predicting Dependence Liability of Stimulant and Depressant Drugs. Baltimore: University

Park Press, 1977b. pp. 203-229

Johanson, C.E., and Uhlenhuth, E.H. Drug preference in humans.

Presented at the 85th Meeting of the American Psychological Association, San Francisco, 1977,

Jonsson, C.O. Behavioral studies of diethylpropion in man. In:

Sjoquist, F. and Tottie, M., eds. Abuse of Central Stimulants.

New York: Raven Press, 1969. pp. 71-80.

Kramer, J.C., Fischman, V.S.,

abuse.

and Littlefield, D.C. Amphetamine

J. Amer. Med. Assoc., 201:305-309, 1967.

Martin, W.R. Assessment of depressant abuse potentiality. In:

Thompson, T. and Unna K., eds. Predicting Dependence Liability

of Stimulant and Depressant Drugs.

1977. pp. 9-15.

Baltimore University Press,

Martin, W.R., and Fraser, H.F. A comparative study of physiological and subjective effects of heroin and morphine administration

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McNair, D.M., Lorr, M., and Droppleman, L.F. Profile of Mood

States (Manual). San Diego, Educational and Industrial Testing

Service, 1971.

Schuster, C.R. Psychological approaches to opiate dependence and

self-administration by laboratory animals. Fed Proc 29(1) :2-5,

1970.

Schuster, C.R., and Johanson, C.E. The use of animal models for

the study of drug abuse. In: Gibbins, R.J. et al., eds. Research

Advances in Alcohol and Drug Problems. New York: John Wiley and

Sons, 1974. pp. 1-31.

Schuster, C.R., and Thompson, T. Self-administration of and behavioral dependence on drugs. Ann Rev Pharmacol , 9:483-502, 1969.

Thompson, T. Predicting abuse liability of sedatives and stimulants.

In: Thompson, T. and Unna K., eds. Predicting Dependence Liability of Stimulant and Depressant Drugs. Baltimore: University

Press, 1977. pp. l-8.

Thompson, T., and Unna, K., eds. Predicting Dependence Liability

of Stimulant and Depressant Drugs. Baltimore University Park

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Yanagita, T., and Takahashi, S. Dependence liability of several

sedative-hypnotic agents evaluated in monkeys. J Phannacol

Exp Ther, 185:307-315, 1973.

ACKNOWLEDGMENT

This work was supported in part by Research Scientist Award

number MH-18, 611 from the National Institute of Mental Health.

AUTHORS

Chris E. Johanson, Ph.D.

Eberhard H. Uhlenhuth, M.D.

The University of Chicago

Pritzker School of Medicine

Department of Psychiatry

950 East 59th Street

Chicago, Illinois 60637

85
Chapter 7

Experimental Studies of Sedative

Self-Administration by Humans

Roy W. Pickens, Ph.D., and Leonard L. Heston, M.D.

Recently we reported an experimental study of pentobarbital selfadministration by humans (Pickens et al. 1977). In that study,

relations were determined between daily drug intake and blood serum

levels during self-administration and measures of metabolic and CNS

tolerance to pentobarbital. We also used a self-administration choice

procedure to determine relative preference for various doses of pentobarbital. In this paper we will review our findings and discuss

implications of the results. Additional details of the study can

be found in the original published report.

Our subjects were eleven adults with confirmed histories of sedative

drug abuse. Ten of the eleven had a prior history of treatment for

drug abuse and four of the eleven had a prior history of seizures

related to sedative withdrawal. Almost all were women, with only

one male included to assess generality of the results. The subjects

ranged in age from 26 to 63 years and weighed between 44 and 93 kg.

All subjects were self-administering sedative drugs on hospital admission when they were informed of the project and invited to participate as research subjects. Written consent was obtained in all

cases prior to testing. Subjects were maintained on sedative drugs

for the duration of the research project, after which they were

gradually withdrawn and given appropriate treatment for drug dependence .

In the first part of the study, subjects were tested to determine

degree of central nervous system (CNS) tolerance and metabolic

tolerance to pentobarbital. This was accomplished by measuring the

degree of sedation and drug metabolic half-life following 200 mg

pentobarbital administration. Subjects were examined hourly at 1,

2, and 3 hours postdrug for slurred speech, ataxia, and sleep.

CNS tolerance was considered minimal if a subject slept and showed

slurred speech or ataxia during this time, moderate if only slurred

speech or ataxia was seen and marked if none of the above signs

was seen. Blood samples were also obtained at 2-4 hr intervals

for 18 hrs postdrug and analyzed by gas chromatography for quantitative pentobarbital content. Drug metabolic half-life was determined from rate of decline in drug serum levels over the postdrug

period.

86
Although all subjects were self-administering sedative drugs on

hospital admission, a wide range of metabolic and CNS tolerance

was seen (see Table 1). Three subjects showed pentobarbital halflives within the normal range (21-42 hours), four subjects showed momoderate increases in metabolic rate (t1⁄2 = 13-21 hours) and four

subjects showed marked increases in metabolic rate (t1⁄2 = 5-12 hours).

Four subjects were minimally tolerant, two subjects were moderately

tolerant, and five subjects were markedly tolerant to the CNS effects of pentobarbital. As might be expected, subjects who showed

metabolic tolerance to pentobarbital also showed CNS tolerance

as well, with the correlation between the two measures being rb =

+0.73 (p < .05).

Following metabolic half-life and CNS tolerance determination, subjects were allowed to self-administer pentobarbital for four days

to determine relations between tolerance and drug taking behavior.

During drug self-administration, subjects were given a 50 mg dose

of pentobarbital upon each request to the nursing staff, who then

verified the oral drug consumption. Drug was available 24 hrs/day

for self-administration except that a 30-min minimal interval was

imposed between successive drug requests to minimize intoxication.

Amount of drug taken was determined each day, and pentobarbital

blood serum level was obtained on the morning after each self-

-administration day. These results were then correlated with

measures of CNS tolerance and metabolic tolerance to pentobarbital.

For all subjects, drug intake ranged between 312.5 and 675.0 mg

pentobarbital per day and blood serum levels ranged between 2.0

and 3.9 μg/ml (Table 1) . The correlation between drug intake and

blood serum level of pentobarbital on the morning after each selfadministration day was r = +0.49, which was not significant statistically (p > .05) . However, factors other than drug intake also

influence drug serum level. One of these is drug metabolic rate,

which controls the rate of elimination of drug from the body. Higher

metabolic rates would result in more drug being eliminated from

the body overnight, producing lower drug serum levels on the following morning. When differences in metabolic rate were controlled

by a partial correlation test, the relationship between drug intake

and drug serum level increased to r12.3 = +0.64, which was statistically significant at p < .01 (t = 3.77, df = 8).

The correlation between drug intake and metabolic tolerance was

r = +0.33, while that between drug intake and CNS tolerance was

r-b = +0.47.

f icant.

Neither of these correlations was statistically signiThe failure to obtain significant correlations between

drug intake and degree of CNS or metabolic tolerance was surprising,

as these factors are frequently reported together in case studies

of human sedative abuse. While the direction of the correlations

indicated that more drug was self-administered each day by subjects

showing shorter drug half-lives and greater degrees of CNS tolerance,

the failure to find statistically significant relationships may be

due to the present experimental design (only 11 subjects, relatively imprecise measures of CNS and metabolic tolerance, etc.). Alter87

304-494 0 - 79 - 7
TABLE 1

Pentobarbital CNS tolerance, half-life and self-administration characteristics (mean ± S.E.M.) for

individual subjects

Subject

F1

F2

F3

F 4

F5

F6

F7

F8

F9

F1O

M1

Initial Testing Self-Administration

CNS tolerancea Half-life Drug intake Serum level

hr mg/day μg/ml

+ 6.6 525.0 ± 47.8 3.0 ± 0.3

0 14.5 473.5 ± 62.5 2.8 ± 0.5

++ 13.5 337.5 ± 47.3 2.0 ± 0.3

0 17.5 420.0 ± 30.0 3.9 ± 0.2

0 22.4 312.5 ± 42.7 2.7 ± 0.5

0 31.7 362.5 ± 31.5 3.0 ± 0.2

++ 6.6 360.0 ± 29.1 2.3 ± 0.3

++ 24.2 600.0 ± 35.0 3.6 ± 0.4

++ 16.2 400.0 ± 47.4 3.6 ± 0.7

++ 9.1 460.0 ± 40.0 2.9 ± 0.3

+ 5.5 675.0 ± 47.8 3.3 ± 0.9

a

0, minimal or absent; +, moderate; ++, marked.
natively, since significant relationships were obtained between metabolic and CNS tolerance to pentobarbital and between drug intake and

blood serum level during self-administration, the results may indicate that CNS and metabolic tolerance are not the sole determinants

of daily drug intake in fixed-dose pentobarbital self-administration.

In the second part of the study we determined relative preference

for various doses of pentobaribtal using a self-administration choice

procedure. Drug dispensing was from an automatic vending machine.

Subjects were allowed to obtain their daily drug supply by selecting between two identically-appearing drug capsules available in adjoining channels of the machine. Each day, one machine channel always

contained 50 mg pentobarbital (standard compound), whereas the other

channel contained either 30, 50, 100, 150, or 200 mg pentobarital

(test compound) . Subjects were instructed to start each morning by

alternately selecting capsules from the two channels until a preference developed, and then to take capsules from the preferred channel

for the remainder of the day. If no preference developed, subjects

were to alternate between channels for the entire day. Standard

and test compounds were assigned to channels on a random basis daily.

Every second day was a control day, in which 50 mg pentobarbital

(standard compound) appeared in both vending channels. The machine

was programmed to record drug selections and to require a 30-min

minimum interval between successive drug deliveries. All testing

was double blind.

Dose preference was expressed as a preference ratio, the ratio of test

capsule selections to total capsule selections (standard + test) for a

given day. Ratio values of 0.5 indicated no preference between test

and standard compound, whereas ratio values greater than 0.5 indicated a preference for the test over the standard compound, and ratio

values less than 0.5 indicated a preference for the standard over the

test compound.

All of the subjects showed highest preference ratios for intermediate

capsule doses (50-150 mg). The most preferred pentobarbital dose was

50 mg for two subjects (F8 and M1), 100 mg for one subject (F6) and

150 mg for three subjects (F7, F9, and F10). No subject most preferred the 30 mg or 200 mg test doses (Figure 1).

From individual data, two types of preference profiles were seen.

Four of the subjects (F6, F8, F10, and Ml) showed curvilinear relations between preference ratio and capsule dose. As. pentobarbital

dose increased, preference ratio initially increased and then declined.

Low preference ratios (<0.5) were obtained at both the lowest and

highest test doses, indicating a preference for the standard over

the test compound. Highest preference ratios were obtained at the

intermediate test doses (50-150 mg/capsule), indicating a preference

for the test over standard.

The remaining two subjects (F7 and F9) showed a preference for only

a single dose of pentobarbital.

test dose to the 50 mg standard.

Both subjects preferred the 150 mg

At all other test doses these two

subjects alternated between channel selections, indicating no preference between test and standard compound. While preference for a

single intermediate dose of pentobarbital also produced a curvilinear

dose preference function, these subjects differed from the four

89
Pentobarbital Dose (mg)

FIGURE 1 Preference ratios for 30, 50, 100, 150, and 200 mg/capsule

pentobarbital, using 50 mg pentobarbital as the comparison standard.

Replications are shown in parenthesis beside each test dose. Vertical lines are + S.E.M. * are control days when 50 mg pentobarbital

was available in-both vending channels. Vertical lines for this

data point indicate range of differences in frequency of channel

selection. Data shown are for 5 female subjects (F6-F10). Data for

male subject (Ml) are not presented, as additional procedures involving this subject were not described in the present report.

90
subjects reported above in not showing a preference for the standard

over the test compound at any dose tested.

For all subjects, daily pentobarbital intake increased with increases

in dose available for self-administration. While theoretically the

same total amount of drug could be taken each day at all test doses,

there was approximately a 2-fold increase in intake over a 6-fold

range of test doses. However, there was no effect of the increased

drug intake on measures of the subject’s grooming, self-maintenance,

or social behaviors. In fact, throughout the study the subjects

rarely appeared overtly intoxicated, although this may be more a

function of the type of subject employed (middle-aged females) than a

characteristic of pentobarbital abusers in general. More recent work

with young male sedative abusers has supported this observation.

Our research has produced a number of interesting findings. As might

be expected, statistically significant correlations were found between degree of CNS tolerance and metabolic tolerance to pentobarbital in human sedative abusers. However, neither could be reliably

used to predict drug intake in pentobarbital self-administration.

While blood serum levels of pentobarbital were not significantly related to the preceding day’s drug intake, when the subject’s degree

of metabolic tolerance to pentobarbital was taken into account, a

significant relationship was found between serum level and drug intake. Intermediate pentobarbital doses (50-150 mg) were preferred

to both lower (30 mg) and higher (200 mg) doses during oral selfadministration. Total daily drug intake was influenced by capsule

dose, and possibly by subject characteristics as well.

Human studies of drug self-administration provide data relevant to

many aspects of drug dependence. However, these studies contain

two major sources of subject variability that affect outcome results.

One of these is past drug history, which includes the various pharmacological and behavioral aspects of previous drug use. Even when

subject characteristics are well-defined, differences may still exist

among subjects in terms of past history of drug use. For example,

while the subjects in the present study were primarily middle-aged

women with sedative abuse problems, they nevertheless differed considerably in terms of types of drugs used, the dosage, duration, and

conditions of drug use, etc. Unfortunately, in conducting studies of

this type such information cannot always accurately be obtained.

Past drug history factors may be expected to increase data variability

and thereby possibly obscure significant results. This occurred in

the present study, for example, when a significant correlation between drug intake and drug serum level was obtained only after the

subjects’ differences in metabolic rate were taken into account.

Drug history factors are not typically involved to the same extent

in experimental studies of self-administration by rats and monkeys.

In addition to drug history, genetic factors also would be expected

to influence results of human drug self-administration studies.

Genetic differences may be expected to occur at any point from absorption to excretion where drug interacts with tissue. The pharmacologic

action of most drugs probably depends on events at the cell membrane

91
where drugs interact with receptor glycoproteins: individual variation in the affinity of receptors for drug, in most cases genetically

controlled, would, of course, be associated with variation in whatever intercellular events are induced by the affected receptors.

Some of the intracellular events would be temporary and depend on

continued presence of drug at the receptor site, but others could be

quite persistent, as would be needed to account for cellular tolerance. Mechanisms producing persistent change are known to exist,

although an example linking such change to drug action through specific steps has not been demonstrated so far as we know. Interactions

between drug and events occurring before and after drug-membrane

interactions would change the concentration of drug or possibly the

concentration of active metabolites at receptor sites, and thus account for individual differences in drug response. Variation due to

genes, though still unexplored, could well be of central importance

in liability to drug abuse.

REFERENCE

Pickens, R. ; Cunningham, M.R. ; Heston, L.; Eckert, E. ; and Gustafson,

L.K. Dose preference during pentobarbital self-administration by

humans. J Pharmacol Exp Ther, 203:310-318, 1977.

ACKNOWLEDGMENT

This work was supported by Grant DA 00939 from the National Institute

on Drug Abuse, and by Special Appropriation in Psychiatry, State of

Minnesota.

AUTHORS

Roy W. Pickens, Ph.D. and Leonard L. Heston, M.D., Department of Psychiatry, Research Unit, University of Minnesota, Box 392 Mayo, Minneapolis, Minnesota 55455

92
Chapter 8

Marihuana, Alcohol, and Polydrug Use:

Human Self-Administration Studies

Nancy K. Mello, Ph.D., and Jack H. Mendelson, M.D.

Although the examination of patterns of drug self-administration

in human subjects is a relatively recent development, the value

of this approach for the study of substance abuse has now been

amply demonstrated in many laboratories. Advances in techniques

for the analysis of behavior have been paralleled by an expansion of and refinement in the types of questions asked. This

review will discuss some dependent variables that can be studied

in a human drug self-administration paradigm. These issues will

be considered in the context of a quasi-historical review of

some operant procedures we have developed and their advantages

and limitations. Finally, some data obtained on patterns of

alcohol, marihuana and multiple-drug self-administration will

be described.

DEPENDENT VARIABLES IN HUMAN DRUG SELF-ADMINISTRATION

Over the past fourteen years, our clinical research program

has studied the self-administration of a number of abused

drugs in human volunteers with a history of drug use or

addiction. Multi-disciplinary studies have been conducted

on an inpatient research ward and each individual has been

observed before, during, and after a period of self-regulated

drug intoxication. This approach permits study of an encapsulated sequence of the basic behavioral disorder, drug abuse,

under clinical research ward conditions.

Our objective has been to study natural or relatively unconstrained drug use patterns, and to correlate these with a

number of biological and behavioral variables. We have

attempted to devise situations where the pattern of drug

self-administration would simulate, as closely as possible,

drug use patterns in the natural environment. Two general

categories of dependent variables can be examined in such

studies: drug-effect variables and patterns of drug selfadministration.

93
Drug Effect Variables

The pharmacological actions of drugs are defined by effects on

many aspects of behavioral and biological function. Studies

of physiological responses to drugs may include examination of

many systems such as neuroendocrine hormones, plasma lipid

levels and sleep EEG (Mendelson 1970; Mendelson and Mello 1976;

Mendelson et al. 1978). Behavioral studies may explore drugrelated changes in subjective states, perceptual and cognitive

function, social interaction and objective measures of performance. Another drug-effect variable is the fine-grain analysis

of operant responding, including inter-response time analysis.

Many other examples of drug-effect variables could be listed.

However, the main point is to distinguish drug-effect variables

and patterns of drug self-administration.

Patterns of Drug Self-Administration

The pattern of drug self-administration is itself an important

dependent variable which may be central to our understanding of

human substance abuse. Basic and human behavioral pharmacology

have repeatedly shown that the schedule of drug reinforcement,

i.e., the dose and frequency of drug availability, influences

the effects of drugs on behavior (Kelleher, Goldberg, and

Krasnegor 1976). By observing an individual’s drug self-administration pattern, we can study the self-imposed schedule of

reinforcement. However, this is only possible if the individual

determines his own pattern of drug use.

Examination of the self-imposed pattern of drug use may assist

in the identification of factors which contribute to the maintenance of drug abuse. The diversity of individuals with drug

abuse problems, and the fact that no single psychological,

social or biological factor appears to predict drug abuse,

suggest that it may be more productive to try to determine how

drug abuse is maintained than to focus exclusively on etiological factors. Moreover, as we study the self-administration of

different drugs under similar conditions. we house to be able to

compare use patterns across drugs. Eventually, this type of

analysis should help to identify some commonalities and

differences in the determinants’ of patterns of heroin abuse,

alcohol abuse, marihuana and tobacco use, stimulant and hallucinogen abuse, etc. If an analysis of drug use patterns can

reveal commonalities which transcend particular drug effects,

such information might be generalizable to future forms of

drug abuse as well. Although we cannot now predict the

specific types of future drug abuse problems, some type of

substance abuse seems almost inevitable. Clarification of factors which maintain drug self-administration should facilitate

development of more effective intervention procedures.

94
The pattern of drug self-administration can be operationally

defined by the following measures:

(1) Number of drug self-administration occasions (per

hour; per day; per week)

(2) Drug dose per occasion

(3) Interval between drug self-administration occasions,

i.e., the distribution of drug doses over a 24-hour

period.

Although it could be argued that drug use also affects the subsequent pattern of drug self-administration, and that this also

should be classed as a drug effect variable, we feel the distinction between drug use patterns and drug effects has both

conceptual and methodological advantages.

This approach to the study of human drug self-administration

and the questions posed are different from studies which

attempt to manipulate human drug use patterns by variation

of the conditions necessary for drug acquisition. It has been

demonstrated that manipulation of conditions such as responsecost, the time of drug availability, the dose of drug available,

can change both the amount and frequency of drug use (Griffiths,

Bigelow, and Liebson 1976a; Bigelow, Griffiths, and Liebson

1976; Mello et al. 1968; Pickens et al. 1977; Babor et al. 1978).

Factors such as drug dose and response-cost also effect drug

self-administration in animal models in a similar way (Griffiths

and Bigelow 1978).

Since the use patterns of several drugs have been shown to be

modified by manipulation of acquisition variables, these studies

may have implications for social controls of drug use, i.e.,

hours of drug availability, taxation and price, etc. (Popham,

Schmidt and deLint 1975). However, the identification of common

controlling variables cannot be interpreted to suggest that the

use patterns of different drugs are identical. Rather, use

patterns appear to be quite different depending upon the pharmacological action and rate of absorption and disposition of the

particular drug.

Limitations of Drug Self-Administration Studies

One disadvantage of the study of spontaneous drug selfadministration patterns is that precise time-dose-response

relationships between the various drug-effect variables

cannot be established since drug dose, frequency, and interdose intervals will vary on an unpredictable basis. Yet, this

variability constitutes the drug self-administration pattern

which is our primary dependent variable.

95
One alternative is to ignore drug self-administration patterns

and to focus instead on drug-effect variables. The most

efficient way to do this is to use a programmed drug administration regimen in which fixed doses are administered every

4 to 6 hours. This permits precise dose-time correlations

with whatever drug-effect variable has been selected for

study.

Programmed drug administration is the traditional method used

to examine the basic pharmacological effects of drugs. The

pioneering studies of drug effects conducted at the Lexington

Addiction Research Center employed programmed drug administration with only one exception (Wikler 1952). The first studies

of the effects of alcohol intoxication in alcoholics were conducted in a programmed administration paradigm (Mendelson 1964).

It is evident that programmed dose paradigms are useful for

asking different types of questions than self-administration

paradigms. However, there are also other factors which may

limit the utility of a programmed dosage paradigm, even for

the study of drug-effect variables. When the effects of programmed alcohol administration and spontaneous self-regulated

alcohol consumption were compared in eight alcoholic subjects,

it was found that biological drug-effect variables varied

markedly between the two alcohol administration conditions

(Mello and Mendelson 1970). Each subject served as his own

control during a 20-day programmed alcohol administration

regimen and during a 20-day spontaneous alcohol self-administration paradigm. Programmed alcohol administration was

associated with greater toxicity (gastritis, vomiting) during

intoxication than spontaneous drinking. Subjects were able

to tolerate higher doses of alcohol during the spontaneous

self-administration paradigm and distributed alcohol consumption to achieve higher peak blood alcohol levels than

were measured during programmed administration. The severity

of alcohol withdrawal signs and symptoms after cessation of

drinking was markedly greater after spontaneous drinking than

after programmed alcohol administration, even in those

subjects that drank equivalent quantities of alcohol in each

condition.

It was concluded that the pattern of drinking was more critical

than duration of drinking as a determinant of biological

reactions to alcohol intoxication and withdrawal. These data

seemed to justify our pursuit of self-determined patterns of

drug self-administration, both as a primary dependent

variable, and as the most sensitive and reality-concordant

baseline against which to correlate biological as well as

behavioral drug effect variables.

96
TECHNIQUES TO STUDY HUMAN DRUG SELF-ADMINISTRATION

Operant techniques to study human drug self-administration

have developed in parallel with those used in basic behavioral

pharmacology, and are derived from concepts and procedures for

the experimental analysis of behavior (Skinner 1938, 1953).

Operant procedures have been shown to produce orderly sequences

of responding which provide an objective index of the relative

reinforcing consequences of various drugs (or competing reinforcers such as money) at any point in time. It is possible

to directly observe the amount and frequency of drug selfadministration, and the behavioral consequences of drug use

intoxication, without reliance upon retrospective self-reports.

Drug acquisition in real life involves engaging in a variety

of behaviors, since drugs are not available without some expenditure of effort or money. Consequently, it seems realistic

to require performance on an operant task to obtain drugs in

a clinical research setting. The nature of the task can vary

from performance on a relatively simple schedule of reinforcement, to complex procedures which concurrently assess variables

such as timing behavior or memory function. When we designed

our first operant paradigm to study alcohol self-administration

by alcoholics, we thought it necessary to use a very simple task

so that subjects could perform, and earn alcohol, irrespective

of their intoxication level (Mello and Mendelson 1965). We

anticipated that if alcohol reinforcement was made contingent

upon successful performance of a complex discrimination task,

the subject would not be able to sustain his initial performance

as he became progressively more inebriated. Of course, this

would preclude examination of behavior to acquire alcohol, and

would only yield data on the effects of alcohol on some aspect

of perceptual or cognitive function, which was not the primary

goal. Subsequently, we learned that this concern about task

complexity was unrealistic, since the behavioral tolerance of

alcohol addicts for alcohol permits them to perform very complex

tasks with accuracy, even when blood alcohol levels exceed

250 mg/100 ml (Mello 1973).

Study of drug acquisition using operant techniques permits examination of a wide range of behavioral variables: e.g., time,

duration, and pattern of operant work for the drug; the rate

of operant work [assessed by both analog (cumulative recorder)

measures and quantitative inter-response time measures]; the

time and number of drug purchases; the effects of each successive drug use occasion on both rate and duration of operant

responding. The effects of drug use on operant response patterns. and choices between alternative reinforcers, for

example, marihuana vs. money; alcohol vs. marihuana; can also

be examined. Such data provide direct measures of performance

capacity and permit inferences about intervening variables such

as “motivation," sometimes postulated to affect performance.

97
There are a variety of ways to examine human drug self-administration. Since the technical aspects of the behavioral procedures define and limit the type of data acquired, some discussion of procedures is necessary. It may be of some historical interest to review the types of operant procedures we

have developed and comment on their advantages and limitations.

The first machine designed for the study of alcohol selfadministration in alcoholic subjects is shown in Figure 1

(Mello and Mendelson 1965) . The subject could work at the

system at any time by turning on the ignition switch and

could select whether to work for alcohol or money reinforcement.

The subjects’ task was to press the center response key which

was transluminated with a number of colored stimulus lights

associated with a series of simple schedules of reinforcement.

These schedules occurred in an irregular sequence and included

Fixed Ratios of 360, 240, 120, and 60; Fixed Intervals of 1,

2, and 3 minutes; Extinction of one minute; and Differential

Reinforcement of No Responding. Subjects were told to press

the translucent response key in order to make the key color

change as often as possible, since reinforcement occurred

only when the colors changed. Upon completion of the response

requirement, ten ml of bourbon or 3 nickels were directly

dispensed, and the key color and schedule changed. The value

of a single alcohol or money reinforcement was equated and

subjects could use money earned to buy alcohol. In an effort

to make the task more interesting, a gambling contingency was

added. When reinforcement became available, subjects could

choose to take that reinforcement or try for double-or-nothing

by pressing the yes or no key at the right of the operant panel.

Subjects worked at the operant task for a 14-day period of

alcohol availability. After seven days, when subjects’ response

behavior failed to come under control of the various schedules

of reinforcement, explicit verbal descriptions of the schedule

requirements associated with the various colored lights were

provided. Subjects still failed to respond under schedule

control, except for one component: differential reinforcement

of no responding. When that particular stimulus light appeared

on the response key, subjects usually left the room. This

behavior was adventitiously reinforced since the light associated with another schedule came on during their absence.

Rates of operant responding and time spent at the machine

were unimpaired by alcohol intoxication. Subjects maintained

relatively high blood alcohol levels (200 to 300 mg/100 ml)

throughout the period of alcohol access. Subjects usually

worked for 1.5 to 2 oz of alcohol before removing the glass.

Each glass removal shut off the machine for a period of 10

minutes. An immediate alcohol reinforcement was consistently

preferred to money reinforcement, even though money could be

used to buy an equivalent amount of alcohol at any time.

98
FIGURE 1

Operant Manipulation Used to study alcohol self-administration by alcoholic subjects

(Mello 1972). Reprinted with permission of Plenum Publishing Corporation, © 1972.

From The Biology of Alcoholism, Vol. II, Physiology and Behavior, Kissin and Begleiter, eds.
Despite the ease and simplicity of the operant task, subjects

complained continually about the machine. They were bored,

and they did not gamble (double-or-nothing) except on rare

occasions. Distaste for the machine was illustrated by the

fact that one subject incorporated distorted thoughts and perceptions about the operant instrument in his hallucinatory

experiences and delusional ideations during alcohol withdrawal.

Negative reactions to the task did not prevent subjects from

working for alcohol. However, since response behavior did not

come under control of any of the operant schedules of reinforcement provided, these data suggested that analysis of

drug effects on schedule control, in the usual sense, would

be very difficult in alcoholic subjects. Subsequently, we

have used a simple fixed ratio or fixed interval schedule

rather than multiple schedules for drug acquisition studies.

An additional fourteen subjects were studied under comparable

experimental conditions over a 7-day period of alcohol availability (Mello et al. 1968). The machine shown in Figure 1

was modified so that the subjects task was to press the

response key whenever a light of 500 msec duration appeared,

i.e., an observing response. The light onset occurred at

irregular intervals which ranged between 2.5 and 10 seconds.

Errors of omission or of commission resulted in the loss of

all accumulated points. Alcohol and money acquisition were

contingent upon completion of a Fixed Ratio of 16 or 32 consecutive responses to the signal light.

Although differences in response-cost did not change the

amount of alcohol earned per session (as defined by removal

of the receptacle glass), the average blood alcohol levels

maintained by the FR 16 group were almost twice as high as in

the FR 32 group. Subjects required to work twice as hard for

alcohol tended to drink half as much, Individual blood alcohol

levels were highly variable within and between days and no

subject earned all the alcohol potentially available.

Subjects complained about the demands of the operant task,

and pounded the machine in frustration after an omission or

commission error. However they were able to perform at all

levels of intoxication and the accuracy of performance was

unrelated to blood alcohol levels. Most subjects did not

work for money, and only five subjects gambled (double-ornothing) with any consistency. The occurrence of gambling

was also unrelated to blood alcohol levels. These data

suggest that risk taking as defined by this task cannot be

predicted on the basis of intoxication. The accuracy of

performance at blood alcohol levels which averaged 200 mg/

100 ml testifies to the behavioral tolerance for alcohol

developed by alcohol addicts.

100
Figure 2 shows a machine that was developed to study group

drinking behavior (Mendelson, Mello and Solomon 1968). The

subjects’ task was to steer a model automobile and keep it

on the moving road on a revolving drum. Each time the auto

touched a metal contact on the road, a point was registered.

After 120 points were earned, 10 ml of bourbon was the automatically dispensed into a common reservoir.

subject could earn about 60 points per minute or 3600

points per hour, the maximum amount of alcohol that could

be earned each hour was about 300 ml or 10 oz. Each subject

had an ignition key and could work at the machine at any

time. Each subject could also withdraw as much alcohol

from the reservoir as he wished at any time by activating

the ignition switch. The total time each subject worked,

the number of 10 ml alcohol reinforcements earned, and the

amount of alcohol each subject withdrew were automatically

recorded. Subjects were permitted to work at the driving

machine to earn alcohol for a period of 30 days.

Subjects took turns working at the driving machine and their

ability to perform was not discernibly impaired, even at blood

alcohol levels over 200 mg/100 ml. No subject drank continuously throughout the 30-day period and no subject drank as

much alcohol as was available. Subjects spontaneously terminated drinking episodes on several occasions, four of which

were correlated with an obvious stress situation on the ward.

There were seldom clearly definable events which accompanied

resumption of drinking by these subjects. All subjects showed

discernible increases in anxiety and agitation during intoxication and appeared far more depressed and anxious when they

terminated drinking than when they initiated a subsequent

drinking episode. Two subjects drank more than one fifth of

bourbon per day on an average and maintained blood alcohol

levels that fluctuated between 50 and 250 mg/100 ml. A third

subject drank during three separate episodes of 8, 6, and

7 days respectively. A fourth subject became agitated,

depressed, and assaultive and left the study after 3 days

of drinking.

These subjects evolved a stable pattern of group interaction and maintained their mutually defined roles in relation

to alcohol acquisition. One subject consistently removed more

from the group alcohol reservoir than he contributed and

another consistently contributed more than he removed, The

free-loader appeared to be the leader of the group. Another

subject contributed an amount of alcohol to the group reservoir approximately equivalent to the amount that he withdrew.

This machine was considerably more acceptable to the subjects

than the machine shown in Figure 1. Subjects perceived the

driving machine as more of a game than a performance task.

101
FIGURE 2

Driving machine used to study group alcohol acquisition patterns (Mendelson, Mello, and

Solomon 1968). Reprinted with permission of Williams and Wilkins Co., Baltimore, © 1968,

from The Addictive States, A. Wikler, ed..
Relocation of our laboratory to Washington prevented further

studies with these instruments and necessitated the development of a non-automated, portable instrument shown in Figure

3 (Mello and Mendelson 1972). While new automated instruments were being constructed, these simple hand-held manipulanda permitted study of operant work-contingent drinking

patterns in alcoholic individuals. Subjects could work for

alcohol or for cigarettes by depressing a button which in turn

activated a mechanical counter inside the box. Subjects could

earn one ounce of alcohol or one cigarette by approximately

five minutes of performance on a Fixed Ratio of 1000

schedule of reinforcement. Points earned were exchanged

for color-coded tokens each day.

Tokens could be used to buy alcohol or cigarettes directly

dispensed from an apparatus shown in Figure 4. To activate

the dispenser, the subject turned on an ignition switch with

a coded ignition key which indicated to the circuitry who was

activating the dispenser and when. After the subject set a

glass receptacle over the photocell, a signal came on indicating that the dispenser would receive tokens. One oz of alcohol

was dispensed into the glass for each token deposited, The

circuitry recorded the time of purchase, the number of purchases, and the subjects’ identification number. Subjects

could also buy alternative reinforcers such as 15 minutes

of television time.

The major disadvantage of the portable manipulandum was that

no analysis of time, duration or rate of operant work was

possible since responses could not be recorded by the programming circuitry. However the manipulanda proved to’ be

tamper proof and yielded reliable data on drinking patterns

to be described in a later section of this review. The

manipulandum was also used to study marihuana self-administration patterns (Mendelson, Rossi, and Meyer 1974).

The behavioral tolerance for alcohol shown by alcoholics

throughout these several studies persuaded us that it was

possible to couple work-contingent alcohol acquisition with

the assessment of behavioral drug-effect variables in addition

to operant performance. Consequently, we designed and constructed an operant system which could be used to evaluate

various aspects of perceptual or cognitive function. Each

response panel was located in a separate operant booth,and

six subjects could work at their machines in relative

privacy.

There was considerable debate about whether alcohol

directly affected short term memory function. The machine

was first programmed to evaluate this question using a

titrated delayed matching-to-sample procedure. The operant

response panel is shown in Figure 5 (Mello 1973).

103

304-494 0 - 79 - 8
FIGURE 3

OPERANT MANIPULANDUM

Mechanical device used to study alcohol self-administration

patterns in alcoholic subjects (Mello and Mendelson 1972).

Reprinted with permission of the publisher, American Psychosomatic Society, © 1972, from Psychosomatic Medicine, Vol. 34,

No. 2.

104
FIGURE 4

SCHEMATIC DIAGRAM OF ALCOHOL AND CIGARETTE DISPENSER PANEL
FIGURE 5

SCHEMATIC DIAGRAM OF RESPONSE PANEL

SEQUENCE OF EVENTS IN A MATCHING TO SAMPLE TRIAL

Responses to the Inter-trial Interval

observing key

start a trial

Sample key on

until response

ratio complete

Delay Interval Comparison keys on

until response ratio

complete or for

20 seconds

Procedure used to study alcohol self-administration and the effects of alcohol on

short term memory function in alcoholic subjects (Mello 1973). Reprinted with

permission of Plenum Publishing Corporation, New York, © 1973, from Alcohol Intoxication and Withdrawal: Experimental Studies, M. Gross, ed.
subjects’ task was to select the comparison key which contained

a picture identical to that which had previously appeared on

the sample key. Short term memory was defined as the interval

between the offset of a picture on sample key and the onset of

pictures on four comparison keys. Attention to the sample

stimulus was ensured by requiring the subject to make an

observing response (FR 10) to turn on the sample stimulus.

The subject then pressed the sample key until the picture

projected on it went off. After a delay interval elapsed,

four pictures were projected on the comparison keys. Selection

of one of the comparison keys ended the trial. The length of

the delay interval increased with each correct match trial and

decreased with each incorrect trial in 4 second increments.

The possible delay ‘intervals ranged from 0 to six minutes.

The matching-to-sample stimuli included pictures of the

ward staff? movie stars and political figures, household

objects, liquor and cigarette labels, nude figures, trigrams

and abstract geometric designs - a total of 120 stimulus sets

in several different sequences.

In order to encourage the subject to perform as well as

possible, completion of four correct trials was required

to earn a single token. Correct trials were indicated -

in the correct counter at the upper left of the panel. How -

ever, if 4 error trials occurred before completion of 4 correct

trials, each counter reset to 0 and the subject was required to

begin accumulating correct trials again in order to earn tokens

to buy alcohol. After completion of four correct trials, a

single token was directly dispensed into the token bank shown

on the right of the operant panel. The bank was clear plastic,

and the subject could see the number of tokens he had earned

at any time, Each subject had the only key to his token bank

and could remove tokens to purchase alcohol from the dispenser (Fig, 4) whenever he wished.

All subjects maintained high blood alcohol levels and performance for alcohol was sustained throughout a twelve day period

of alcohol access. Alcohol had no discernible effect on “short

term memory” defined operationally by the interval between

sample stimulus offset and comparison stimulus onset. Subjects

were able to match correctly at the longest delay intervals

even when blood alcohol levels exceeded 300 mg/100 ml. Subjects

with a history of alcoholic “blackouts” performed as well as

subjects who had never experienced blackouts during intoxication.

The conclusion that alcohol does not impair “short term memory”

and that the alcoholic “blackout” probably cannot be accounted

for by an alcohol-specific disruption of memory (Mello 1973)

has been confirmed in other laboratories (cf. Mello and Mendelson 1978 for review),

107
This machine was probably the most powerful tool for assessing

both alcohol acquisition behavior and the effects of alcohol

on cognitive function that we have developed. Perhaps because

a continuously changing array of visual stimuli was provided,

subjects found the task challenging and interesting. Since

subjects were highly motivated to acquire alcohol, they

appeared to perform at the limit of their capacity. Unfortunately, a de emphasis on intramural research by the

National Institute on Alcohol Abuse and Alcoholism during

the early 1970’s prevented further studies with this instrument. However, this study demonstrated the feasibility of

asking questions related to drug-effects in combination with

questions about drug self-administration patterns.

After return of the laboratory to Boston, we again developed

a simple hand-held operant manipulandum for the study of drug

acquisition patterns. The manipulandum was about the size of

a pack of cigarettes and weighed about 198 grams. Initially,

the manipulandum was attached to a movable cable which could

be connected to coded terminals permitting subjects to work

at the operant task either in their individual bedrooms or

in a central day room. Subsequently, the manipulandum was

modified to be completely portable. Each response transmits

a radio frequency signal on a discrete band which activates

the programming and recording circuitry in an adjacent room.

Points earned are registered on a central panel and subjects

always have a record of their earnings. Unlike the portable

manipulandum shown in Figure 3, this manipulandum permits

analysis of automatically recorded operant response patterns.

Each manipulandum is color coded and labeled with the subject’s

number to permit easy identification by the ward staff and to

discourage subjects from exchanging manipulanda.

Subjects are required to press the button on the manipulandum

on a fixed interval one-second schedule of reinforcement

(FI 1 sec). Only the first response after one second elapsed

was recorded as a point by the programming circuitry. Subjects

can earn one point for 300 effective responses or five minutes

of sustained operant work. The prices of different drugs or.

money reinforcers are assigned a certain point cost which can

be easily translated into time required at the operant task.

The price of drugs or money can be adjusted to reflect the

current price prevailing in the Boston area. Whenever a

subject elects to purchase a drug, the points spent are

immediately deducted from his reinforcement point accumulation.

Subjects are allowed to work on the operant task at any time

and a record of their point accumulation is continuously

available.

108
We have used this simple procedure to study alcohol, marihuana,

and heroin self-administration.

are well tolerated by subjects,

The manipulanda and the task

and subjects have not been able

to tamper with or destroy the device. Subjects are able to

perform the task while talking, reading, watching television,

eating. Although the manipulandum can be used with virtually

any schedule of reinforcement, we have continued to employ

an FI l-second schedule to permit comparisons across successive

studies with different samples of drug users.

In summary our experience with these several operant drugacquisition procedures suggest the following general conclusions. Subjects will accept complicated and challenging

procedures which maintain their interest (e.g. Fig. 5). If

acquisition of a meaningful reinforcer (drugs or money) is

contingent upon accurate performance, subjects will usually

perform to the limit of their capacity. Severe intoxication

produces surprisingly little performance impairment in alcohol

addicts because of behavioral tolerance. The generality of

this degree of behavioral tolerance to other categories of

drug abuse remains to be determined. However it appears

feasible to study drug self-administration patterns with a

task that simultaneously assesses some drug-effect variable.

A task which requires minimal attention or effort to perform,

such as our current simple schedule procedure, is also

accepted by subjects and yields reliable data on drug selfadministration patterns as well as operant responding. The

relative ease of construction and maintenance of a portable

manipulandum must be balanced against the complexities of

construction and maintenance of a device which involves

coded filmstrips, special recording procedures, and continual

adjustment as did the machine shown in Figure 5. The most

realistic compromise is probably to use a simple procedure

to study drug self-administration patterns, and to assess

cognitive and perceptual variables separately in a situation

where relatively larger volumes of drug are provided as a

reinforcer for accurate performance. A common failure to

reinforce accurate performance with a consequence that is

significant for the subject has contributed to the numerous

inconsistencies in data on the behavioral effects of

alcohol (Mello and Mendelson 1978).

The importance of a mechanical dispenser for drug and money

reinforcers cannot be over-emphasized. The machine is consistently neutral and cannot encourage or discourage drug

purchase. Although staff can be trained to dispense drugs

without comment, some attitude about further drug use by an

intoxicated individual is inevitably conveyed. It is

impossible to evaluate the extent to which the attitude

of a staff drug-dispenser may have influenced the basic datum,

drug self-administration patterns.

109
PATTERNS OF ALCOHOL, MARIHUANA, AND POLYDRUG SELF-ADMINISTRATION

This section will summarize selected data on alcohol, marihuana

and polydrug self-administration and illustrate the application

of several of the techniques previously described. In each of

the studies to be described, volunteer subjects lived on a

clinical research ward for several weeks. Behavioral studies

were conducted simultaneously with physiological, biochemical

and neuroendocrine studies designed to examine the biological

effects of chronic drug use. Subjects were observed during a

drug free baseline, a period of drug self-administration and

a post-drug baseline period. An own-control design is essential for human drug self-administration studies, since the use

of normal control groups in the conventional sense is precluded

by medical and ethical considerations. Moreover, occasional

drug users are not sufficiently drug tolerant to permit meaningful comparisons with heavy users or addicts.

ALCOHOL SELF-ADMINISTRATION

A number of stereotypes and beliefs about alcoholism often

appear in the clinical literature, despite accumulating evidence

to the contrary. One persistent belief is that the alcohol

addict has a predictable and invariant drinking pattern, i.e.,

to drink as much as possible. This stereotype is linked to

the concept of “craving,” usually defined as a loss of control

over drinking, with the implication that each time an alcoholic starts to drink he is compelled to continue until he

reaches a state of severe intoxication. The circularity inherent in this reasoning is evident, i.e., craving is defined

by the behavior it is invoked to explain. Empirical observations

of alcoholics allowed to self-administer alcohol have not supported this view (cf. Mello 1975 for review).

Two groups of four subjects were allowed to work for alcohol and

cigarettes for periods of 30 and 62 consecutive days respectively

(Mello and Mendelson 1972). The operant manipulandum shown in

Figure 3 was used and a fixed ratio of 1,000 responses was

required to earn a single token which could be used to buy one

cigarette or one oz of bourbon from an automated dispenser

(Fig. 4) . Subjects were able to earn one token in about 5

minutes of rapid performance, or about 12 oz of alcohol per

hour. The task could easily be performed while watching

television, eating, drinking, or talking. Each subject had

a color-coded manipulandum and an identical colored token

to prevent exchanges between subjects. The volume of alcohol

and the number of cigarettes purchased by each subject were

recorded by the programming circuitry and checked against

the number of colored tokens in the dispenser. Blood alcohol

levels were measured daily at 8 am, 4 pm and 12 midnight.

110
The earning and spending pattem of a typical subject during

the pre-alcohol baseline, the alcohol availability and alcohol

withdrawal periods is shown in Figure 6. The pattern of earning

and spending for cigarettes is shown in the top row. The

pattern of earning and spending for alcohol is shown in the

middle row. Daily mean blood alcohol levels are shown in

the bottom row. Partial withdrawal signs (tremor and gastritis) are indicated as asterisks. The type and duration

of alcohol withdrawal signs and symptoms are shown at the

right of the middle row.

Each subject could work for points for alcohol during the last

day of the pre-alcohol baseline period. The number of points

earned that day was sufficient to sustain a period of drinking

of 3 to 6 days. Throughout the remainder of the drinking

period, there was a clear dissociation between periods of

earning and spending. Subjects alternated between working to

earn points for alcohol and spending points earned for a workfree drinking spree. This pattern persisted throughout the

30 and 62 alcohol available periods and was strikingly similar

in all subjects. Fluctuations in the average blood alcohol

levels correlated roughly with the pattern of spending for

alcohol. Subjects sustained relatively high blood alcohol

levels averaging between 130 and 200 mg/100 ml for periods

up to 62 days. No subject drank all the alcohol available

and all subjects tolerated the discomfort of withdrawal symptoms

during the intermittent periods of self-imposed abstinence.

These abstinent periods were unexpected in view of the relatively trivial performance requirement involved. Ability to perform was not impaired by intoxication.

Although all subjects showed a dissociation between working and

drinking, subjects worked and drank at different times. Some

member of the group was always working; while others were drinking. It is unlikely that the observed behavior represented

satiation for alcohol, since other subjects given alcohol with

no operant work requirement sustained blood alcohol levels

which averaged above 200 mg/100 ml for periods of 14 to 20

days (Mello and Mendelson 1972). Similarly, the decrease in

operant work for cigarettes does not reflect decreased interest in smoking since subjects attempted to acquire cigarettes

from staff throughout the study.

These subjects described themselves as periodic spree drinkers. The observed pattern of discordant working and drinking is probably more comparable to their real world experience than a stable alcohol intake permitted by an unlimited

supply. Since the subjects determined their pattern of

alcohol self-administration, it is reasonable to assume that

this was their preferred or accustomed pattern. This technique appeared to result in an adequate simulation of normal

111
FIGURE 6. From Mello and Mendelson (1972). Reprinted with permission of American Psychosomatic

Society, © 1972, from Psychosomatic Medicine, Vol. 34, NO. 2.
drinking patterns by chronic alcoholic individuals in a

clinical research ward context. A similar alternation

between working and drinking has also been reported by

Nathan and co-workers in alcoholics who worked at a

comparably simple task (photo cell interruption) for

points that could be converted into alcohol (Nathan

et al. 1970; Nathan, O’Brien, and Lowenstein 1971).

MARIHUANA SELF-ADMINISTRATION

Recently a number of multidisciplinary studies of marihuana

self-administration have been conducted in our laboratory

(Mendelson, Rossi, and Meyer 1974; Mendelson et al. 1976a).

Biological studies of marihuana effects examined in a selfadministration paradigm have been included- studies of the

effects of marihuana: on CNS structure (Kuehnle et al.

1977); on pituitary gonadal hormones (Mendelson et al. 1974,

1978); and on cardiac and pulmonary function (Bernstein,

Kuehnle and Mendelson 1976). Behavioral studies have examined the effects of marihuana on mood, memory and social

interactions (Mendelson et al. 1976a). In addition to

studies of the pattern of marihuana self-administration,

the hypothesis that marihuana induces an “amotivational”

syndrome was also examined (Mendelson et al. 1976b).

Among the effects often ascribed to marihuana are apathy,

lethargy, diminished “drive” and ambition, decreased productivity and goal directedness, and indolence.

Marihuana self-administration patterns were examined in 12

casual and 15 heavy users, allowed to work for marihuana for

21 consecutive days. "Motivation” was inferred from time

spent at the operant task working for marihuana and for

money. Subjects worked at the portable operant manipulandum

previously described on an FI 1 sec schedule. One marihuana

cigarette cost 6 points or 30 minutes of sustained operant

work. Each marihuana cigarette contained approximately 1 gm

of marihuana (1.8 to 2.3 percent THC) . Subjects could also

work for money at the cost of 50 cents per 6 points or 30

minutes of sustained operant work.

All subjects smoked some marihuana every day. Casual marihuana smokers smoked an average of 2.6 cigarettes per day

and heavy marihuana users smoked an average of 5.7 cigarettes per day. However, both groups showed a linear

increase in marihuana smoking over the 21 day period of

marihuana availability. On the final day of marihuana

availability, the casual users smoked an average of

5.8 cigarettes and the heavy users smoked an average

of 14.3 cigarettes.

113
All subjects worked longer at the operant task and earned

far more points than were required to buy the quantity of

marihuana they actually smoked. The heavy user group

worked between 6.7 and 14.4 hours per day even though

2.2 to 3 hours of work were required for the 4.3 to 6

cigarettes usually smoked per day. Throughout the period

of marihuana use, heavy users worked up to an average of

10 hours each day. The casual marihuana users worked between

5 and 11.1 hours each day, even though the number of cigarettes smoked (2-3 per day) required only 1 to 1.5 hours of

operant work. No subject stopped operant work even when

he smoked ten or more marihuana cigarettes per day. Moreover,

periods of maximal operant work coincided with periods of

maximal marihuana smoking, i.e., between 4 pm and 12 midnight

each day.

Subjects worked more for money than for marihuana, and the

dollars saved far exceeded dollars spent on marihuana by both

the casual and the heavy marihuana users. At the conclusion

of the study, the heavy user group had saved an average of

$242.38 (+ $19.22 S.E.) and the casual users had saved an

average of $233.17 (+ $26.31 S.E.). These earnings reflected

sustained operant work and saving during the period of marihuana availability. Since both casual and heavy marihuana

users sustained operant work for both money and marihuana

reinforcement during a period of unrestricted marihuana smoking,

these data appear to argue strongly against simplistic descriptions of marihuana effects and amotivation (Mendelson

et al. 1976b).

A typical cumulative record of response on a FI 1 second

schedule of reinforcement during the period of active marihuana use is shown in Figure 7. Although only the first

response after an interval of one second had elapsed was

counted as an effective response by the programming circuitry,

subjects typically responded at a much higher rate than required. The response requirements were carefully explained

to the subjects but most reported they preferred to respond

at a comfortable rate. In most instances, this resulted in

the emission of approximately 600 responses for each point

earned, when 300 responses distributed over 5 minutes would

have sufficed. A rate of 120 responses per minute or 2

responses per second was typically seen. Sustained high

rates of operant responding by casual and heavy marihuana

users during the period of active marihuana smoking are

also inconsistent with the notion that marihuana induces

an “amotivational” syndrome.

114
FIGURE 7

Cumlative record of responses for marihuana on an FI 1 sec sechedule of reinforcement.
POLYDRUG USE: MARIHUANA, ALCOHOL AND TOBACCO

Operant procedures for the examination of single drug selfadministration patterns can also be extended to study the

concurrent self-administration of two or more drugs. Polydrug

use appears to be an increasingly frequent drug use pattern,

according to clinical and epidemiological studies (Bourne

1975; Benvenuto, Lau, and Cohen 1975). The possible combinations of drugs abused simultaneously appear almost infinite

and defy any effort at simple categorization. However, survey

data suggest that marihuana is often used in combination with

alcohol (Goode 1969; Grupp 1972; Carlin and Post 1971; Tec

1973) and alcohol is perhaps the most commonly used and abused

recreational drug available today. Tobacco use frequently

accompanies alcohol use and it has recently been shown that

alcohol facilitates cigarette smoking in alcoholics (Griffiths,

Bigelow and Liebson 1976b).

The way in which alcohol and marihuana interact and influence

concurrent use patterns has long been a subject of speculation.

However, there is a prevailing impression that the combined use

of mariiuana and alcohol leads to a subjective enhancement of

the positive or euphorigenic properties of marihuana (Hollister

1976; Manno et al. 1974). Since the combined effects of alcohol

and marihuana are thought to be facilitatory, we were interested

in exploring the effects of concurrent access to marihuana and

alcohol on use patterns and subjective effects. We were interested in learning whether concurrent access to marihuana and

alcohol led to an increase, a decrease, or no change in use

patterns of these drugs. On the basis of data demonstrating

that alcohol induced an enhancement of tobacco use, we postulated that marihuana and alcohol use would be increased under

concurrent access conditions (Mello, Mendelson, and Kuehnle

1978).

Sixteen adult male volunteers with a history of concurrent

alcohol and marihuana use were studied in groups of four on

a clinical research ward. Patterns of drug use during 10

days of concurrent access to marihuana and alcohol were

compared with successive five day periods when only alcohol

or only marihuana was available.. Two groups were studied

in the alcohol-first sequence and two groups were studied

in the marihuana -first sequence. A drug free control

period preceded and followed the 20-day period of spontaneous drug self-administration.

Drug use patterns were assessed by performance on the simple

operant task used in studies of marihuana self-administration

described previously. Subjects could earn money (50 cents)

or marihuana (a 1 gm cigarette containing 1.8 to 2.3 percent

116
THC) by working at the operant task on a Fixed Interval onesecond schedule of reinforcement for 30 minutes. Alcohol

(1 oz) was available as wine, beer, or distilled spirits for

15 minutes of operant work.

Typical cumulative records of performance for concurrent access to

marihuana and alcohol are shown in Figures 8 and 9. Subjects

tended to work at a high sustained rate for drug or money

reinforcements. Subjects usually emitted appropriately

twice the number of responses required to earn a single

point. These data are comparable to operant responding for

marihuana (Mendelson et al. 1976c) and for heroin (Mendelson and

Mello 1978, this volume). Examination of drug effects on interresponse distributions is currently in progress.

The major finding of this study was that concurrent access to

alcohol and marihuana resulted in a significant decrease in

alcohol consumption, in comparison to the five-day baseline

period of only alcohol availability. Fourteen of the sixteen

subjects studied decreased alcohol use when marihuana was

also available (p < .01) and the magnitude of the decrease in

drinking was significant for seven subjects (p < .05).

During the ten-day period of alcohol and marihuana access,

subjects gradually increased marihuana smoking and this

increase was significant (p < .001) as evaluated by a trend

analysis. However, this increase cannot be attributed to the

concurrent availability of alcohol, since a similar trend was

seen in our previous study of casual and heavy marihuana use

under comparable experimental conditions (Mendelson et al.

1976 b & c). Although twelve subjects increased marihuana

smoking when alcohol was also available (p < .05), the magnitude of this increase was statistically significant in only

two instances.

Figure 10 illustrates the most common drug use pattern observed, i.e., an increase in marihuana use and decrease in

alcohol during the period of concurrent marihuana and alcohol

availability. This subject was a heavy marihuana user who

smoked an average of 9 cigarettes per day during the baseline

period of marihuana availability. He was also a heavy drinker

and consumed an average of 12 drinks per day during the baseline period of alcohol availability. Peak blood alcohol

levels ranged between 50 and 150 mg/100 ml during the hours

of maximum drinking. When both alcohol and marihuana were

concurrently available, marihuana smoking increased slightly

to an average of 10 cigarettes per day. Alcohol consumption

decreased to a mean of 5 drinks per day. Peak blood alcohol

levels never exceeded 65 mg/1000 ml during the period of

concurrent marihuana and alcohol access.

117
FIGURE 8

Cumulative records of responding. The step pen reset after 300 responses and deflections

of the baseline pen indicate completion of 300 effective responses on an FI 1 sec schedule.
FIGURE 9

Cumulative records of responding. The step pen reset after 300 responses and deflections

of the baseline pen indicate completion of 300 effective responses on an FI 1 sec schedule.
FIGURE 10

CONSECUTIVE DAYS

120
Subjects usually used alcohol and marihuana together during

the period of concurrent availability. Despite the temporal

concordance of marihuana and alcohol use there were no

instances of adverse reactions or other evidence of toxic

drug interactions as has been reported by others following

low acute doses of alcohol and marihuana (Sulkowski and

Vachon 1977).

Only six of the sixteen subjects studied were consistent

tobacco users who smoked an average of 15.9 cigarettes per

day. Tobacco use was significantly correlated (p < .05)

with both alcohol and marihuana use. Tobacco use also

accompanied alcohol use and marihuana use during the single

drug availability period. These data are consistent with

previous reports of alcohol-induced increases in tobacco

use (Griffiths, Bigelow, and Liebson 1976b) and survey reports

of a high correlation between marihuana and tobacco use

(O’Donnell 1976).

Data obtained are not consistent with the hypothesis that the

simultaneous availability of marihuana and alcohol will lead

to a significant increase in the use of both drugs. Only two

of the sixteen subjects increased consumption of both alcohol

and marihuana during the simultaneous access conditions, even

though alcohol and marihuana were usually used together.

These data suggest the importance of defining conditions

under which multiple drug access will result in a depression

of the use of one or more drugs; an increase in the use of one

or both drugs; or no change in drug use as a function of single

or multiple drug access. It will be important to attempt to

identify the interacting pharmacological and behavioral variables

which control patterns of multiple drug use. It will also be

necessary to determine the generality of these findings with

other groups of heavy drinkers and alcoholic individuals.

Analysis of the subjective consequences of single and concurrent drug use is in progress.

SUMMARY AND CONCLUSIONS

Data have been presented to illustrate some ways in which

operant procedures can be used to study self-administration

patterns of a variety of substances. Operant procedures for

drug self-administration studies have also been shown to be

useful for concurrent examination of a variety of drugeffect variables, especially the effects of drugs on biological function. Behavioral data were selected to illustrate

some clinical research findings which are contrary to conventional wisdom and common expectation. We have seen that

alcohol addicts do not maintain a constant pattern of alcohol intake and do not drink all the alcohol available when

121
given unrestricted access to alcohol in a self-administration

paradigm. Rather, alcohol addicts tend to alternate periods

of alcohol intoxication and operant work, even though periods

of abstinence working are accompanied by partial withdrawal

symptoms. These data are inconsistent with the notion that

alcohol abuse is maintained by either the avoidance of withdrawal signs and symptoms or an uncontrollable “craving” for

alcohol (Mello and Mendelson 1972; Mello 1975). Studies of

marihuana self-administration are not consistent with the

notion that marihuana induces an "amotivational” syndrome

(Mendelson et al. 1976 b & c). Studies of polydrug use

involving alcohol and marihuana indicate that concurrent

access to these drugs is not necessarily associated with

increased use of alcohol and marihuana as would be predicted

from data on alcohol and tobacco (Griffiths, Bigelow, and

Liebson 1976b). Rather, the simultaneous availability of marihuana and alcohol was associated with a significant decrease

in alcohol consumption in comparison to a baseline period when

only alcohol was available (Mello, Mendelson, and Kuehnle 1978).

There is no substitute for direct clinical observation of drug

use patterns and the effects of drugs on behavioral and biological variables under controlled conditions. The direct observation of patterns of drug use and assessments of the subjective and objective consequences of drug intoxication have

challenged many prevalent assumptions derived from retrospective reports by drug abusers during sobriety (Mello and

Mendelson 1978). It is our contention that direct clinical

observation of drug use patterns and associated drug effects

in the same individual over time is essential to an improved

understanding of the behavioral bases of drug abuse. The

experimental analysis of drug use patterns is one way to examine factors which maintain and perpetuate drug abuse. The

periodicity of drug use and the rate and duration of operant

behavior involved in drug acquisition are data which can

be measured directly without reliance on alleged intervening

variables such as “drug hunger.” On the basis of such information, certain inferences can be made concerning broader

questions about the phenomenology of drug abuse. It is of

interest to determine if there are consistencies in drug use

patterns within the behavior of a single individual, or between

individuals with comparable drug use histories. Comparisons

of drug use patterns across addictive disorders may eventually

permit identification of some reliable commonalities and

differences, that in turn will help to clarify the nature

of drug-related reinforcers.

An examination of factors which initiate and maintain periodic substance abuse episodes may prove more productive

than a search for origins, given the diversity of individuals

with substance abuse problems. A better understanding of

122
how drug self-administration is maintained should permit more

effective manipulation of critical maintenance variables and

lead to the development of more effective forms of intervention. Both the conceptual and technical aspects of an

operant analysis of drug self-administration behavior appear

to be optimally designed to facilitate our understanding of

how substance abuse is maintained.

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126
ACKNOWLEDGMENT

Preparation of this review was supported by grants DA 01676

and DA 4RG010 from the National Institute of Drug Abuse,

ADAMHA.

AUTHORS

Nancy K. Mello, Ph.D.

Jack H. Mendelson, M.D.

Alcohol and Drug Abuse Research Center

The McLean Hospital - Harvard Medical School

Belmont, Massachusetts 02178

127
Chapter 9

Heroin Self-Administration:

An Operant Analysis

Jack H. Mendelson, M.D., and Nancy K. Mello, Ph.D.

Over the past fifteen years, many investigators have studied

opiate self-administration patterns using animal models

(Schuster and Johanson 1974). Canparable studies of human

opiate self-administration and its consequences are a relatively recent development. In this review, some data on

heroin self-administration by heroin addicts will be described and compared with studies of primate models.

PRIMATE MODELS OF OPIATE SELF-ADMINISTRATION

A brief and selective review of some data obtained with primate

models illustrates that opiate self-administration is lawful

and orderly behavior, subject to control by schedules of reinforcement, discriminative stimuli, conditions of deprivation

and satiation, and a variety of other environmental factors.

It has been repeatedly shown that rhesus monkeys will selfadminister opiates and many other psychoactive drugs, to the

point of inducing physical dependence (Deneau 1969; Deneau,

Yanagita and Seevers 1969; Findley, Robinson and Peregrino

1972; Thompson 1968; Woods and Schuster 1970; Yanagita and

Takahashi 1970). The extent to which physical dependence

is necessary for a drug to remain “reinforcing” has been

studied by several groups. Three lines of evidence now

indicate that physical dependence is not a necessary or

sufficient condition for drug self-administration. It

has been shown that opiate drug self-administration will

occur at unit doses too low to induce physical dependence

(Woods and Schuster 1970). Moreover, naive monkeys will

self-administer opiates and barbiturates even if physical

dependence does not develop (Deneau, Yanagita and Seevers

1969; Winger, Stitzer and Woods 1975). Finally, stimulants

such as cocaine which have not been shown to produce physical

dependence are readily self-administered by monkeys (Balster

and Schuster 1973; Goldberg and Kelleher 1976; Johanson,

Balster and Bonese 1976).

It is well established that drug self-administration behavior

can come under the control of discriminative stimuli. Discriminative stimuli are an experimental analogue of the complex external-situational stimuli alleged to contribute to

the maintenance and relapse of drug abuse in man (Wikler 1973a).

128
The secondary reinforcing properties of visual stimuli, previously associated with drug reinforcement, can come to control

behavior leading to the presentation of the stimulus itself,

even in the absence of drug reinforcement (Goldberg 1976;

Goldberg, Morse and Goldberg 1976; Kelleher 1976).

Stimulus control of drug reinforced behavior has also been

demonstrated in association with conditions of narcotic antagonist-induced drug withdrawal (Goldberg 1976). If a visual

stimulus is paired with narcotic antagonist administration in

morphine-dependent animals, that stimulus can subsequently

elicit withdrawal signs in the absence of antagonist administration (Goldberg and Schuster 1967) and presentation of

the stimulus is associated with increased responding for

morphine reinforcement (Goldberg, Woods and Schuster 1969).

Stimulus control of withdrawal signs was found to persist for

60 to 120 days after monkeys had been abstinent from morphine

(Goldberg and Schuster 1970). This observation of protracted

abstinence phenomena in abstinent monkeys, elicited by a discriminative stimulus previously paired with narcotic antagonist

administration, is a provocative parallel to observations of

protracted abstinence in man (Martin and Jasinski 1969).

It has been repeatedly shown that relative conditions of deprivation or satiation influence responding for drug reinforcement, just as is the case for food and water reinforcement

(Thompson 1968; Thompson and Schuster 1968). Although opiate

reinforcement will maintain responding in nondependent monkeys,

conditions of drug withdrawal are most effective in enhancing

the reinforcing properties of opiates in dependent monkeys

(Schuster 1968; Schuster and Thompson 1969; Woods and Schuster

1968). The effect of antagonist-induced withdrawal on morphine-maintained responding is a function of the antagonist

dose, the order of antagonist dose administration (ascending

or descending) and the conditions of morphine access (limited

or unlimited) (cf. Goldberg, Woods and Schuster 1971; Schuster

1968; Schuster and Johanson 1974; Woods, Downs and Villarreal

1973). Following acute administration of the antagonist

naltrexone (0.005 to 0.020 mg/kg), an initial increase in

morphine-maintained responding did not result in an overall

increase in morphine intake, but rather was sufficient only

to maintain each animal’s usual morphine intake. In contrast

to the stability of morphine self-administration following

naltrexone-precipitated withdrawal, food-maintained responding

was profoundly disrupted for at least 24 hours (Mello and

Mendelson 1977).

The behavioral pharmacology of antagonist drugs is poorly

understood (Mello 1977). It has been repeatedly observed

that morphine-dependent monkeys will work to avoid and escape

from injections of antagonists (Goldberg et al. 1971;

Hoffmeister and Wuttke 1973a; Hoffmeister and Wuttke 1973b.

129
However, comfortable commonsense assumptions about the

behavioral effects of these compounds in opiate-dependent

monkeys have recently been challenged by the provocative

findings of Woods and co-workers (Woods, Downs and Carney

1975).

Monkeys trained to avoid antagonist infusions will work to

produce antagonist infusion at the same dose per injection,

after an unavoidable antagonist infusion has been superimposed upon the avoidance-escape schedule. Monkeys worked

for an injection of naloxone on a second-order schedule

FR 10 (FR 30:S) in which completion of each ratio of 30

responses was followed by a brief visual signal, and completion of 10 successive fixed ratios of 30 responses produced a single injection of naloxone (0.002 mg/kg/inj) followed by a one minute time out. The occasional delivery of

noncontingent naloxone injections further increased rates of

responding maintained by naloxone infusion and removal of

naloxone decreased responding (Woods, Downs and Carney 1975).

These data extend observations that presentation of an electric shock can maintain response behavior to opiate antagonists. Kelleher and co-workers (Kelleher, Riddle and Cook

1963), were the first to observe that response behavior of

squirrel monkeys can be maintained by the same electric

shock that animals previously worked to avoid. This finding

has been repeatedly reconfirmed (Kelleher and Morse 1968%;

McKearney 1969; McKearney 1972) and the contributing factors

in the behavioral history and the schedule of reinforcement

have been clarified and specified (cf. Morse and Kelleher

1970 for review).

These seemingly anomalous findings that monkeys will work to

produce the same event they previously worked to avoid

question our traditional assumptions about what constitutes

positive and negative reinforcement. The view that events

do not have inherently reinforcing or punishing properties,

but rather should be defined in terms of the way they influence behavior, has been most fully developed by Morse and

Kelleher (Kelleher and Morse 1968b; Morse and Kelleher 1970;

Morse and Kelleher 1977). There is now considerable evidence

that both the experimental history and the ongoing schedule

performance are critical determinants of how any event (food,

shock or drugs) will affect operant behavior. A variety of

seemingly “aversive” events extending from electric shock to

opiate antagonists can maintain operant response behavior which

leads to the administration of these events, under certain

conditions. It is the schedule on which these events are

presented, rather than the apparent properties of the events

themselves, which determines if responding is maintained to

produce, avoid, or escape from a particular consequence. The

130
extent to which these basic behavioral findings in primates

are generalizable to man remains to be determined. Certainly

data from basic behavioral studies and from behavioral pharmacology suggest numerous hypotheses concerning the maintenance

of opiate abuse in man which can be subject to experimental

test (cf. Mello 1977,’ 1978).

OPIATE SELF-ADMINISTRATION IN MAN

Unfortunately, there is no comparable reservoir of behavioral

data on patterns of opiate self-administration in humans.

Most studies of the effects of opiates in addicts have employed

a fixed-dosage opiate administration regimen consistent with

the traditional paradigms used in pharmacology (e.g. Fraser

et al. 1963; Haertzen and Hooks 1969; Himmelsbach 1942; Martin

and Fraser 1961). Wikler was one of the first to examine the

effects of self-determined patterns of morphine administration

in a single addict subject in 1952 (Wikler 1952).

Antagonist Effects on Heroin Self-Administration

Meyer and Mirin (1978) have examined the therapeutic potential

of narcotic antagonist drugs in heroin addicts who were allowed self-regulated access to increasing doses of intravenous

heroin on a variable dose, variable interval schedule of their

own choosing. Some of the major findings from these studies

are summarized as follows:

Naltrexone (50 mg) produces a total blockade of narcotic

effects for a period of 24 hours. These findings are consistent with the observations of Martin and co-workers

(Martin, Jasinski and Mansky 1973). Narcotic addicts report

no subjective effects when they self-administer heroin under

antagonist blockade. In the majority of addicts studied,

there was no objective evidence (miosis, changes in vital

signs, etc.) that heroin produced physiologic effects during

naltrexone blockade. However, six of the eleven subjects

who sampled heroin frequently during naltrexone blockade,

did show respiratory depression and pupillary constriction

after the first several heroin doses. Meyer and Mirin (1978)

suggest that these autonomic effects were not due to inadequate antagonist blockade, but rather were classically

conditioned responses which extinguished after repeated

blocked heroin injections. The importance of conditioning

effects associated with the ritual of heroin self-injection

has been clearly demonstrated by O’Brien (1976).

131
When naltrexone is administered to informed subjects, there

is little experimentation with heroin: e.g., 7 of 9 subjects

sampled heroin an average of 13 times (range 2 - 46) over a

10 day period of heroin availability while maintained on naltrexone blockade (75 mg/day P.O.). When naltrexone was administered under double-blind conditions, each of 22 subjects

sampled heroin occasionally. Over a 10 day period of heroin

access, 11 subjects took heroin on an average of 15.9 occasions, whereas the other 11 took heroin on an average of 4.3

occasions.

Both social and experiential factors appeared to influence

heroin self-administration on the research ward. Addicts

with a long history of heroin addiction persisted longer in

heroin self-administration under conditions of naltrexone

blockade (Meyer et al. 1978) and parallel findings have been

reported in an animal model (Meyer et al. 1976b). However,

all subjects self-administered significantly more heroin

under placebo conditions than under naltrexone blockade.

Frequency of heroin self-administration among the other

members of the group appeared to be the best predictor of

self-administration frequency in any individual. The relative contribution of these factors to the patterns of heroin

self-administration observed remains to be clarified.

Subjective Consequences of Heroin Self-Administration

In contrast to retrospective accounts by addicts, chronic

opiate use appears to be accompanied by an increase in

dysphoria, hypochondriasis and irritability as well as increased psychopathology, belligerence, negativism, motor

retardation and social isolation. These findings confirm

and extend previous observations of Wikler (1952) and

Haertzen and Hooks (1969). Subjects maintained on naltrexone throughout this period did not evidence a comparable increase in psychopathology or dysphoria. Although

it appeared that each heroin injection was associated with

a transient elevation in mood, even this transient mood

change diminished as a function of chronic drug intoxication (Meyer and Mirin 1978; Mirin, McNamee and Meyer

1976). These data attesting to the dysphoric consequences

of chronic heroin use are concordant with data on chronic

alcohol intoxication and challenge the notion that drugs

are used solely for their rewarding or euphorigenic

properties (Mello 1977, 1978).

Narcotic antagonist blockade not only reduced the frequency

of heroin self-administration but was also associated with

subjective reports of a diminution of “craving” for heroin.

Meyer and Mirin suggest that once subjects become aware of

the naltrexone blockade, they redefine the situation as one

132
of drug unavailability, even though heroin remains freely

available. In subjects who continued to self-administer

heroin during naltrexone blockade, “craving” scores remained

high (Meyer and Mirin 1978).

Initially, most patients did not continue antagonist medication on an outpatient basis for longer than one month after

they left the research ward. However, compliance was significantly enhanced by providing small but apparently powerful monetary reinforcements for naltrexone use outside the

hospital. The 10 to 20 percent of patients who are able

to find steady employment and are gradually able to change

their life styles, tend to maintain stable abstinence assisted by naltrexone.

Although Meyer and Mirin (1978) attempted to obtain information about operant patterns of heroin acquisition, this

effort was frustrated by several factors. These studies

were conducted using mechanical hand counters similar to

those which had previously been used in studies with alcohol

addicts (Mello and Mendelson 1972). Unfortunately, the

heroin addict subjects repeatedly tampered with and occasionally destroyed these manipulanda with the result that

it was not possible to relate heroin purchase patterns to

operant acquisition. Moreover, the mechanical hand counter

did not permit measures of operant response rate, response

persistence (hours of work), inter-response times, or

temporal patterns of operant responding. Finally, the

frequency of heroin self-administration was limited both

in terms of dosage and inter-dose interval; (a limitation

which is shared by our recent studies). Consequently,

behavioral data obtained described the presence or absence

of heroin purchase at the prescribed intervals and does

not provide information about the operant patterns or the

effects of drug use on heroin acquisition (cf. Meyer et al.

1976a; Meyer et al. 1976c; Meyer and Mirin 1978; Meyer et

al. 1978).

OPERANT ANALYSIS OF HEROIN SELF-ADMINISTRATION

We have reexamined the effects of naltrexone and naltrexone

placebo (under double-blind conditions) on heroin selfadministration patterns in a situation which permits a

detailed analysis of operant acquisition. These studies

of operant acquisition patterns for heroin are not a

replication of previous studies by Meyer and Mirin (1978),

but rather, represent a significant departure from those

studies in terms of the experimental goals, the rationale,

and most importantly, the technology applied. Previous

studies (Meyer et al. 1976a; Meyer et al. 1976b; Meyer et

al. 1978) were primarily concerned with determining if

133
“extinction” of heroin self-administration occurs under

conditions of antagonist blockade, as has been postulated

by Wikler Wikler 1973a and b). Meyer, Mirin and

co-workers have now concluded that “extinction” is not a

useful formulation for narcotic antagonist treatment since:

(a) many subjects did not administer heroin in the presence

of naltrexone and therefore “extinction” could not occur;

(b) suppression of heroin self-administration did not predict

compliance with outpatient naltrexone therapy ( Meyer and

Mirin 1978).

In order to evaluate the effects of heroin acquisition and

use, it is important to have an objective and quantifiable

measure of drug seeking behavior. Operant techniques

for the experimental analysis of behavior yield

objective and quantifiable data. Moreover, drug acquisition

patterns can be compared with acquisition of an alternative

reinforcer, money. Since drugs are not available to most

users without some expenditure of effort or money, it seems

realistic to require that an addict subject perform a simple

operant task to obtain drugs or money within the clinical

research setting. Comparison of drug acquisition patterns

of subjects maintained on placebo or naltrexone under

double-blind conditions provides another index of the effectiveness of these compounds in modifying heroin acquisition

and subjective drug reactions.

During the past year, twelve heroin addict volunteers have

participated in multidisciplinary clinical studies. Analysis

of these data is currently in progress. Some major behavioral

findings are summarized in the following sections.

Heroin Self-Administration Procedures

Adult male heroin addicts provided informed consent for

participation in a 34 day inpatient clinical study. Subjects

were studied in groups of four. A nine day drug-free baseline was followed by a ten day period of heroin availability

when either naltrexone (50 mg P.O.) or naltrexone placebo

was administered. The post-heroin baseline period included

a five day period of methadone detoxification, a 7 day

drug-free period and a final 3 day period when all subjects

were given naltrexone each day (50 mg. P.O.). Subjects

maintained on active naltrexone continued to receive naltrexone throughout the remainder of the study.

Subjects worked for heroin or for money on a simple operant

task. Subjects were required to choose whether to work for

money or heroin each time they activated their operant

instrument. They could work at any time. A portable

134
manipulandum transmits a signal to recording and programming apparatus after each response. Only the first

response after a fixed interval of one second had elapsed

was counted as an “effective” response, by the circuitry

(an FI 1 sec schedule of reinforcement). Approximately

ninety minutes of sustained performance on an FI 1 sec

schedule earned 18 purchase points which could be used to

buy one 10 mg dose of heroin or exchanged for $1.50 in cash

upon completion of the study. Points earned for money

could not be exchanged for points earned for heroin. A

record of points earned was continuously available.

Subjects self-administered heroin intravenously under

supervision of a physician. The total amount of heroin

available each day was 40 mg. Four ten mg doses were

available each day at 8:00 am, 2:00 pm, 8:00 pm and 2:00

am. Subjects could omit any dose but could not receive

a larger or smaller dose than 10 mg. Medical considerations

precluded unlimited heroin access.

Representative behavioral data for one subject maintained

on naltrexone blockade and one subject maintained on

naltrexone placebo are shown in Figures 1 and 2. Statistical evaluation of these data has not been completed,

but these graphs illustrate some clear trends in heroin

and money acquisition and use.

Effects of Naltrexone Blockade

The number of doses of heroin taken, the number of hours

worked for money and for heroin, and the number of purchase

points earned for money and heroin over consecutive days of

the study are shown in Figure 1 for a subject (1-HA1) maintained on active naltrexone throughout the period of heroin

availability.

On days 8 and 9 of the pre-heroin baseline period, the

subject worked most of the time for heroin points and

earned enough to self-administer the maximum amount of

heroin available for the first two days of heroin availability. This subject administered only two doses of

heroin. He immediately perceived the absence of heroin

effects and concluded that he received active naltrexone.

This subject did not work for, or attempt to self-administer

heroin throughout the remainder of the study. At the

conclusion of the study, this subject was allowed to convert unused heroin points earned on baseline days 8 and

9 into points for money so he was not penalized for working

in anticipation of unblocked heroin.

135

304-494 0 - 79 - 10
FIGURE 1

CONSECUTIVE DAYS

136
The findings obtained with subjects under naltrexone

blockade confirm previous reports of the effectiveness of

the naltrexone (Martin, Jasinski and Mansky 1973) but are

not consistent with previous reports of intermittent heroin

sampling during naltrexone administration (Meyer and Mirin

1978; Meyer et al. 1978). Subject 1-HA1 reported a seven

year history of heroin addiction.

This subject earned an equivalent or greater number of points

for money during the’ first 15 days of naltrexone blockade

than during the drug-free baseline. Naltrexone was administered daily throughout the remainder of the study. The

fact that this subject remained in the study and continued

to work for money when his peers were self-administering

heroin is of interest. Although it might be assumed that

a subject would become despondent and not work for anything

in the presence of active heroin use by others, this was

clearly not the case. Rather naltrexone maintenance appeared to be associated with increased operant work for

money, even in an environment of active heroin use.

Effects of Naltrexone Placebo

Figure 2 presents heroin self-administration and earning

data for a subject maintained on naltrexone placebo during

the ten day period of heroin availability. A maximum of

four 10 mg doses of intravenous heroin was available each

day, once every six hours. Accumulation of 72 points per

day (6 hours of work) was required to purchase all four

heroin doses.

Figure 2 shows a subject who took all the available heroin

doses except one on the first day of heroin availability.

Most subjects earned enough heroin points during days 8

and 9 of the pre-heroin baseline period to support about

two days of heroin use. One subject earned just enough

for two doses of heroin. Since subjects had already accumulated enough heroin points to support one or two days of

use, heroin earnings were usually somewhat depressed during

the first two days of heroin availability as is shown in

Figure 2.

Only three subjects took all the heroin doses available

throughout the ten day heroin period. Other subjects

occasionally missed one or two heroin doses and one subject

only took two doses per day during the ten day period of

heroin availability. One subject often slept through the

2:00 am heroin dose, even though he had earned enough points

to buy heroin. Although heroin is a powerful reinforcer

which allegedly exerts strong control over self-administration

137
FIGURE 2

CONSECUTIVE DAYS

138
behavior, these data suggest this control is not invariant

and may be modulated by a desire to sleep or to acquire

money.

During the period of heroin self-administration, subjects

tended to earn just enough heroin points to insure heroin

administration. On day 9, subjects often increased earning

of heroin points so that the final day of heroin availability

was almost heroin work-free (Figure 2). Since excess points

earned for heroin could not be converted into money, subjects

carefully monitored their earned-spent ratios to avoid

accumulation of unusable points. Subjects adjusted their

earning rates so precisely that there was a surplus of only

one or two purchase points following the period of heroin

availability.

In terms of total time spent at the operant task, subjects

tended to work an equivalent or a greater number of hours

during the period of heroin availability than during the

baseline period. However, it is evident that points earned

for money were greatly suppressed in comparison to baseline

during period of heroin availability (Figure 2). The

degree of suppression is particularly dramatic when these

heroin users are compared to subjects on active naltrexone

during the same period (Figure 1).

During the five days of methadone detoxification, time spent

in operant work and points earned were equivalent to or

greater than during the drug free baseline period. Work to

acquire money was not impaired during methadone detoxification and was initially sustained during the subsequent drugfree period.

Although naltrexone administration was associated with a

decrease in earnings and tine spent in operant work, this

effect cannot be attributed to naltrexone. During this

three day period, subjects spent more time off the ward,

arranging job interviews and planning for their transition

back into the community. Subject 2-HA1 continued to earn

money at a higher rate than during drug-free baseline

periods when naltrexone was administered. The sustained

performance of the subjects maintained on naltrexone blockade is another indication that naltrexone does not impair

operant performance or motivation to acquire money.

Operant Response Patterns

A typical cumulative record of responding for points for

heroin under an FI 1 sec schedule of reinforcement is shown

139
in Figure 3. This record is from day five of the period of

heroin availability during late afternoon, about 90 minutes

after the 2:00 pm heroin dose.

The cumulative record provides a direct analogue read-out

of rate of response.’ Each response advances a pen l/4 mm

and the paper moves at approximately 11 inches per hour.

The response pen reset after 300 responses. Each deflection

of the baseline pen indicates that 300 effective responses

have been emitted. Each response after a fixed interval. of

one second has elapsed is defined as an effective response.

Deflections of the pen above the response record indicate

the reinforcement condition, upward deflections indicate a

subject is working for heroin and no deflections indicate

that a subject is working for money.

Figure 4 shows a typical cumulative record of responses for

money by the same subject on Day 5 of the period of heroin

availability. All other features of the record are identical

to those described for Figure 3.

These records are typical of operant response patterns by

heroin addicts for heroin or money under an FI 1 sec schedule

of reinforcement. Subjects consistently responded at very

high running rates, punctuated by brief pauses. Subjects

consistently responded at rates faster than once per second,

even though faster responses had no programmed consequence.

Subjects reported that they preferred to respond at a rate

that was comfortable, and this was invariably faster than

required by the schedule of reinforcement.

Cumulative records of operant responding for heroin are

very similar to cumulative records of responding for marihuana

and alcohol under an FI 1 sec schedule of reinforcement

(Mello and Mendelson 1978, this volume). Qualitative examination

of cumulative records did not reveal major changes in response

patterns following an acute 10 mg dose of heroin. An analysis of inter-response times prior to and following heroin

self-administration is currently in progress.

The response cost for heroin, defined in terms of sustained

work required for a single dose of heroin (90 minutes), was

considerably greater than in our previous studies of marihuana, alcohol and multiple drug self-administration (15 or

30 minutes) (Mello and Mendelson 1978). Operant work for

heroin acquisition was also more stable and consistent

than we have seen previously. Subjects carefully monitored

their point accumulation and adjusted their work output to

earn just enough for the heroin available. The accumulation

of points during baseline to support two days of work-free

heroin and the increase in heroin points earned on the ninth

day of heroin availability, are reminiscent of the alternate

140
FIGURE 3

Cumulative record of responses for heroin on a FI 1 sec schedule of reinforcement.
FIGURE 4

Cumulative record of responses for money on an FI 1 sec schedule of reinforcement.
working and drinking pattern shown by alcohol addicts (Mello

and Mendelson 1972). However, heroin addicts did not elect

to remain abstinent for several days and precipitate withdrawal signs and symptoms as the alcohol addicts did (Mello

and Mendelson 1972). Despite occasional missed doses, heroin

use was sustained throughout the period of availability.

Individual variability in heroin self-administration is

also seen in primate models of opiate self-administration.

These studies illustrate the feasibility of applying procedures for the experimental analysis of behavior to the

study of heroin self-administration in man. Patterns of

heroin acquisition and the consequences of chronic heroin

use can be examined in a clinical research ward setting.

Further interpretation of these findings will require completion of data analyses now in progress.

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ACKNOWLEDGMENT

This research and preparation of this review were supported by

grants DA01676 and DA 4RG010 from the National Institute of

Drug Abuse, ADAMHA.

AUTHORS

Jack H. Mendelson, M.D.

Nancy K. Mello, Ph.D.

Alcohol and Drug Abuse Research Center

The McLean Hospital - Harvard Medical School

Belmont, Massachusetts 02178

148
Chapter 10

Studying Social Reactions to

Drug Self-Administration

Thomas F. Babor, Ph.D.

Behavioral scientists have become increasingly aware of the social

context of drug taking behavior (Goode 1969; Kandel 1974) and of the

mediating role that, the social environment exerts in the manifestation

of drug effects (Schachter and Singer 1962; Nowlis 1958). In spite

of this recognition, little research attention has been given to the

group dynamics surrounding the act of drug self-administration, and

even less to the social effects of repetitive drug use. In part,

this can be attributed to inadequacies inherent in current methodological approaches which rely almost entirely on retrospective surveys

of drug users or laboratory experiments of acute drug intoxication

(Sadava 1975).

Not until almost 30 years after publication of the classic LaGuardia

study on the effects of marihuana (Mayor’s Committee on Marihuana

1945) did a small number of collaborative research groups begin to

develop procedures for the experimental analysis of repeated drug

self-administration (Mendelson 1964). The major characteristics of

this approach came to include subject participation in a controlled

residential laboratory; free access to a limited range of social,

recreational and instrumental (operant) stimuli; repeated assessments

during successive periods of drug availability and drug nonavailability; and optional drug self-administration as both an independent

and dependent variable (see Bigelow, Griffiths, and Liebson 1975,

1976; and Mello 1972 for reviews of procedural developments and representative research). In the present paper we will review those studies

in which the effects of optional drug self-administration on social

behavior were investigated. Because the major thrust of much research

on drug self-administration has been behavioral and biomedical, few

studies have been designed explicitly to investigate social effects.

Nevertheless, social assessments have been incorporated into a sufficient number of studies of marihuana, heroin and alcohol to generate

a significant body of literature. What follows will summarize some

of the representative studies, discuss their methodological limitations,

and evaluate their contributions to the understanding of both drug

effects and social behavior.

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By way of introduction it would seem important to address two issues

concerning the pursuit of knowledge on the social effects of drugs.

The first can be phrased in this manner: Why should social reactions

be an important focus of drug self-administration research? One of

the most obvious reasons to focus on social reactions is that this is

the kind of behavior that policy makers, public health officials and

the general public are interested in knowing about. There is a general belief that some of the most complex and meaningful components

of social functioning are altered by drugs. Inadequate role performance, antisocial behavior, faulty communication, distorted social

perceptions, sexual inadequacy, deteriorated social relations, and

lack of conventional motivation have all been attributed to the

negative consequences of drug use. Ironically, an equally impressive

array of behavioral changes has been attributed to the positive consequences of drugs: facilitated communication, sexual arousal,

enhanced self-esteem, insightful social perceptions, feelings of

intimacy and closer identification with others. It is often these

molar units of social behavior which intrigue the psychologist in all

of us, but to date not enough has been derived from either survey

studies or laboratory investigations to provide a scientific basis

for our often contradictory notions about drug effects.

Another reason to focus on the social effects of drugs is theoretical.

It has been proposed, for example, that the reinforcing properties of

drugs are in part related to the personality functions altered during

drug intoxication (Teasdale and Hinkson 1971). By providing an empirical basis for these generalizations, self-administration research can

play an important role in theory development.

And for those less interested in drugs than in more fundamental

questions about social processes, self-administration research offers

a means of studying how complex behaviors are mediated by biochemical,

physiological and affective changes (Russell 1960; Nowlis 1958). The

interdisciplinary nature of self-administration research has great

potential for integrating data from different levels of analysis. By

viewing drugs as tools for systematically varying the biological substrate of behavior, drug research need no longer be considered an

illegitimate offspring of pure science.

The second issue relevant to the study of social behavior in drug

self-administration research is this: How can self-administration

studies facilitate an understanding of the social effects of drugs?

Although drug effects on humans have been studied intensively in the

experimental laboratory, the dosage, setting and conditions of administration are often unrepresentative of self-determined usage in the

natural environment (Jones 1971). By allowing subjects to choose the

timing and context of drug use in naturalistic settings, the selfadministration paradigm permits a more realistic analysis of the

relation between the pattern of consumption and the consequences of

drug use. As Mello and Mendelson (1970) have shown, it is often the

pattern of consumption, and not absolute dosage, which determines the

individual's reaction to a drug.

Another advantage of the self-administration paradigm is that it simulates the natural social context of drug use. One of the more universal

aspects of drug use is that it takes place in face to face. social

settings. There is compelling evidence that this social context exerts

150
a powerful influence on the labeling of and reaction to internal

changes induced by drugs (Schachter and Singer 1962; Nowlis 1958;

Pliner and Cappell 1974; Sice et al. 1975). Although the group nature

of much self-administration research has been dictated more by the

economy of batch processing than by an appreciation of social context,

self-administration research can provide valuable data on the influence

of the prevailing social environment.

Further justification for using the self-administration paradigm

derives from the fact that it allows the rare luxury of studying

social reactions within a time frame adequate for the assessment of

a full range of social reactions. As much as questionnaire and other

retrospective methods seek to give substance to drug use patterns,

nothing provides a better alternative to selective recall than empirical observation. Drug effects are influenced by tolerance, dependence,

and by a variety of nonpharmacological factors, and the contributions

of these factors change over time. By providing an opportunity to

observe the consequences of both acute and chronic intoxication, selfadministration research makes it possible to describe drug effects in

their true complexity, a fact which will become apparent as we review

those self-administration studies which have treated social variables

as consequences of drug self-administration. Marihuana, heroin and

alcohol, the three drugs which have received most of the research

attention, will be discussed in succession. Because our research

group at McLean Hospital has struggled with many of the methodological

problems in this area, our own research efforts will be reviewed in

some detail.

MARIHUANA

In 1938 Fiorello H. LaGuardia, then mayor of New York, commissioned

the first comprehensive scientific study of marihuana. Responding to

the same kind of public pressure which was to give impetus to future

drug research (Mendelson, Rossi, and Meyer 1974) Laguardia requested

that the New York Academy of Medicine investigate the social, as well

as the physical, implications of marihuana use. Although the mayor’s

scientific committee focused primarily on the acute and chronic effects

of fixed doses of marihuana, their clinical studies of volunteer prisoners also included observations of informal social interaction

following self-selected doses (Mayor’s Committee on Marihuana 1945).

This procedure was motivated in part by a desire to observe global

reactions to marihuana under conditions approximating the natural

environment.

Recognizing the possible contributions of contextual factors in mediating

social reactions to drugs, the researchers simulated the setting of the

“tea pad party” during two informal group smoking sessions. It was

reported that laughter, joking, restlessness and conversation, observed

soon after the initiation of smoking, gradually gave way to general

relaxation. While marihuana had a “convivial” effect on group members,

“a mental state characterized by a sense of well-being, relaxation and

unawareness of surroundings, followed by drowsiness, was present in

most instances when the subject was left undisturbed” (Mayor’s Committee on Marihuana 1945, p. 215).

151

304-494 0 - 79 - 11
One year after the publication of the Laguardia report, the results

of a second clinical study were published by Williams et al. (1946).

Six prisoner volunteers were allowed to self-administer marihuana

cigarettes (of undetermined dosage) during a 39-day period of confinement on a hospital ward. The subjects smoked an average of 17 cigarettes a day. Clinical observation suggested that subjects became more

talkative, carefree, and physically active during the first few days

of marihuana smoking, but this was followed by a longer period of

decreased activity and lack of motivation. While lacking methodological controls and empirical observations, these early studies

demonstrated the feasibility of investigating drug effects on complex

social behavior.

It was not until the renewal of interest in clinical self-administration studies in the early 1970’s that it became possible to investigate

social reactions in a systematic way. Miles and his colleagues (1974)

studied six male volunteers, all regular marihuana users, during a 70-

day period which included 42 days of free access to 1 g (.09% THC)

marihuana cigarettes, and beverage alcohol. Drug self-administration

and concomitant activities were observed at half hour intervals 24

hours per day. During the initial period of marihuana availability,

a slight suppression in mean daily conversation was noted, but with

continued smoking there was a progressive increase in social interaction. During the drug period subjects were found to make significantly greater use of passive entertainment facilities such as

television, radio and phonograph. Although the authors concluded

that no changes in social behavior could be attributed to the introduction or removal of the drug, their methodology, like those of

previous studies, contains limitations which preclude such unequivocal

statements. Little is said of the possible confounding influence of

concomitant alcohol use and tolerance development, and there is no

attempt to distinguish acute effects from the more general measure of

average daily conversation.

The powerful and often interacting contributions of such variables as

dosage, tolerance, individual differences, expectancy, setting and

social influence became evident to the McLean Hospital research group

during a series of clinical studies on marihuana self-administration

begun in 1971. The initial investigation of 20 marihuana users was

performed at the request of the National Commission on Marihuana and

Drug Abuse (Mendelson et al. 1972; Mendelson, Rossi, and Meyer 1974).

Since that time an additional 75 subjects have been studied in related

investigations of marihuana self-administration. While the primary

focus of these studies has been on biological and behavioral concomitants, the interdisciplinary nature of the research program gave ample

opportunity for the systematic study of interpersonal behavior.

In the National Commission study separate groups of 10 casual and 10

heavy marihuana users lived on a closed research ward for 31 days. A

S-day drug-free period preceded and followed 21 days of work-contingent

access to 1 g (2% THC) marihuana cigarettes. Special attention was

devoted to the observation of marihuana smoking patterns? informal

affiliation networks, and verbal interaction in formal discussion

groups (Babor et al. 1974a,b). The data indicated very strongly that

marihuana smoking, in addition to being a subjective drug experience,

is also a social activity around which communication and other types

152
of social behavior are organized. Specifically, the subjects rarely

chose to smoke alone. More than 94% of all marihuana consumed by

either type of user was smoked in a place where other subjects were

present. In addition to observing marihuana smoking patterns in

informal social settings, subjects were also studied in task-oriented

discussion groups each afternoon during the three phases of the

investigation. Each discussion was tape recorded and later coded

according to Bales’ Interaction Process Analysis (Bales 1950). Both

casual and heavy users showed a marked decrement in verbal interaction

during groups occurring in the first quarter of the marihuana smoking

period (Babor et al. 1974b. While the heavy users tended to exceed

pre-drug levels of interaction after the first quarter of the drug

period, total interaction among the casual users continued to diminish.

The results suggested that the heavy users accommodated themselves

better to the long-term effects of marihuana. The results also

indicated that while the quality of interaction shifted away from

task-oriented responses, there was no general disruption of verbal

interaction.

These findings were supported by correlational analyses in which

individual levels of intoxication (as determined by self-reports)

were correlated with amount and quality of output. Total interaction

decreased at higher levels of intoxication, and this relationship was

found most consistently in the category of attempted answers. In

general, interaction tended to be more positive and less task-oriented

during intoxication.

The fruitfulness of studying marihuana effects in both formal and

informal social settings led to a major refinement in observational

methods which were next applied to an investigation of 10 four-person

groups of moderate and heavy marihuana users (Babor, Mendelson, and

Kuehnle 1976; Mendelson et al. 1976). Twenty-six of the male volunteers were systematically observed before, during and after a 21-day

period of self-determined marihuana use. The subjects were free to

choose from a variety of activities, including sleep, work and recreation, those which they preferred during and after intoxication.

Because previous studies had lacked control groups, 11 additional

subjects not having access to marihuana were studied under identical

experimental conditions to determine the effects, if any; of the

experimental procedures, institutionalization, group development and

other extraneous factors. Additional data were obtained by means of

the Behavior Inventory (BI) Checklist, a computerized observational

system designed to obtain a representative sample of each subject’s

daily activity. Trained research aides observed each subject once

every hour during fifteen-second time intervals. The time at which

hourly observations were initiated varied randomly from day to day.

Immediately following observation, the subject ’ s primary (predominant)

and secondary (nonpredominant) activities were coded according to a

list of 20 possible behaviors. The list included sleep, watching

television, listening to music, watching others, reading, testing,

vital signs, talking, stationary play (games), active play (sports),

operant work, “no apparent activity ,” and several miscellaneous cate-

. In addition, social affiliation patterns were coded on a

grid representing subjects and staff in the immediate proximity of

the smoker. Reliability and validity of the procedure were checked

and found to be uniformly high (Babor, Mendelson, and Kuehnle 1976).

153
Changes in interpersonal behavior were analyzed by combining selected

BI categories reflecting three levels of social interaction. Social

isolation refers to situations where the subject was alone or in

presence of others but neither interacting nor coacting. Social

interaction refers to situations where the subject’s primary or

secondary activity was a stimulus or response to the behavior of

another (e.g., conversation, ping pong) . Social coaction applies to

situations where the subject engages with others in some mutual task

or activity (e.g., watching television, listening to music) but without direct communication or interaction.

During the 21-day smoking period moderate users consumed an average

of 2.6 cigarettes per day while heavy users smoked more than twice

this number daily (5.7) . Smokers in both groups gradually increased

consumption during the period of availability, a pattern suggestive

of physiological and/or psychological tolerance. As in our previous

study, marihuana smoking typically occurred within a social context.

More than 80 percent of each subject’s marihuana was consumed in the

presence of at least one other subject.

Immediate changes* in social behavior were analyzed by comparing

percent time observed in each level of interaction during the hour

immediately preceding and immediately following marihuana smoking.

Figure 1 shows that one hour after intoxication moderate users were

interacting significantly less and coacting significantly more than

during the hour preceding smoking. Daily changes in social behavior

were evaluated by correlating the number of marihuana cigarettes

smoked each day with the percent daily waking time observed in each

level of interaction. The correlation coefficients, averaged across

subjects ‘and shown in table 1, gave no evidence of a marihuana-related

change in daily amounts of isolation, coaction or interaction. These

TABLE 1. Average Pearson Correlation Coefficients:

Number of Marihuana Cigarettes Consumed per Day Correlated

With Measures of Three Categories of Social Interaction

Interaction Same Day Next Day1

Category Moderate Heavy Moderate - Heavy

Isolation -.08 -.17* -.06 .08

Coaction .06 -.08 .19* -.03

Interaction .02 .26* -. 15** -.02

‘Average Pearson Correlation coefficients, next day, are means of

partial correlations. The effect of the number of marihuana cigarettes

smoked on the next day has been partialed out of the relationship.

* p< .05

** p< .01

*NOTE: In this discussion the words “change” and “reaction” are used

advisedly. Because of methodological limitations, to be discussed

later, it cannot be assumed that behavioral changes following single

and daily drug doses are determined solely by the pharmacological

action of the drug. The term “drug effect” therefore has been avoided.

154
FIGURE 1

Interaction, Coaction

and Isolation Before and After

Marihuana Smoking

Isolation Coaction Interaction

findings suggest that the acute reactions to marihuana by moderate

users are transitory and are more than compensated by the greater

opportunity for interaction afforded by the social context before

marihuana smoking.

Individual correlations between the three indexes and amount smoked

daily were next computed using a one day time lag. These statistics

were used to estimate delayed reactions resulting from variations in

daily marihuana intake. Averages of the moderate users’ correlation

coefficients (table 1) showed that the more a subject smoked on the

preceding day the less he tended to interact on the following day.

The cumulative effect of these delayed reactions was evident in the

analysis of persistent and chronic changes in social behavior. These

were evaluated by comparing baseline averages with those measured

155
during successive five day blocks of the smoking period. Moderate

users engaged in less interaction and more coaction during the entire

drug period (persistent reaction), but interaction returned to its

initial baseline level during the final drug-free period. Control

subjects, on the other hand, showed no consistent variations in social

behavior over the course of the experiment.

In contrast to the moderate users, heavy users showed relatively mild

alterations in social behavior (cf. fig. 1, table 1). Of the five

dependent measures, only the correlations with daily amount smoked

showed significant variations. On days of heavier consumption heavy

users were found to be less isolated and to engage in more interaction

than on days of lighter consumption. In the absence of acute reactions,

the daily changes suggest that heavy users were interacting more in

response to the social circumstances of marihuana use than to the

pharmacological action of the drug.

In order to obtain a more refined picture of the social reactions to

marihuana, and to determine whether the immediate changes observed in

the moderate users were trans-situational, all subjects were observed

daily in a task-oriented group discussion situation similar to that

employed in our previous research (Babor et al. 1974b). The discussion

task was chosen because of its simplicity and comparability from one

topic to another. No verbal or intellectual skills are required, and

performance is affected minimally by repetition. Further, the task

resembles many employment situations where individuals meet to discuss

practical, theoretical, or “human relations” problems.

Ongoing interaction (who speaks to whom) and role behavior were

observed according to Robert Bales’ procedures. Developed out of a

long tradition of small group research, Bales’ (1970) methods were

used to quantify the amount of verbal interaction given and received,

as well as the social role of each participant in terms of the following bipolar dimensions: dominant-submissive, friendly-unfriendly,

task oriented-nontask oriented. The results indicated that during

intoxication, moderate users were less task-oriented and participated

less in group discussion. No significant changes on any of the dependent measures were noted for the heavy users, although there was a trend

toward less task-orientation during intoxication (Babor et al. 1978).

The findings emerging from our research on the social reactions to

marihuana can be summarized as follows: (1) While marihuana may be a

“sociogenic” drug (i.e., it brings people together by serving as a

focus of interaction) in the sociological sense proposed by Goode (1969),

following intoxication there is a shift from a social, verbal, external

focus of attention to a more internal, detached, contemplative orientation. (2) In formal discussion situations, there is also a reduction

in task orientation which is reflected both in the content of the

interaction and the role of the communicator. (3) The general lack

of social reactions in heavy users suggests that social effects are

mitigated by behavioral tolerance which may develop after continued

marihuana use. (4) When combined with systematic observational procedures, the drug self-administration paradigm provides a fruitful

means of describing acute and chronic social reactions in both formal

and informal settings.

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HEROIN

The literature of drug abuse is replete with descriptions of the

social effects of acute and chronic heroin intoxication. Ausubel

(1958), for example, describes the opiate effect as primarily depressant, consisting of analgesia, sedation, drowsiness, decreased motor

activity, and lethargy. Habitual users surveyed by Chein and his

colleagues (1964) reported loss of vitality during addiction as well

as a general deterioration in social relations and leisure pursuits.

Because of the confounding influence of the addict’s lifestyle and

social environment, it was not possible to obtain a clear estimate of

the social effects of heroin until the initiation of clinical studies

in controlled settings.

The first of these studies consisted of programmed heroin administration

in doses increasing from 10 mg to 95 mg over a 60-day period. Under

these conditions Fraser et al. (1963) observed five prisoner addicts

during a three-month period of gradual addiction and withdrawal. Compared with placebo, heroin was found to increase physical activity

and sociability after the first dose. But during a period of chronic

intoxication activity became depressed and social affiliation was

reduced. Self-report ratings, obtained from these and nine additional

subjects by Haertzen and Hooks (1969) revealed less motivation for

social and sexual activity, neglect of social affairs, and greater

irritation in social situations. These findings suggest that chronic

heroin intoxication induces persistent changes in subjective feeling

states, social perceptions and interpersonal behavior. However, they

leave unanswered many questions about the underlying dynamics of these

reactions. Partially in an attempt to address these issues our collaborative group at McLean Hospital undertook an exploration of the

heroin addiction cycle as part of a larger interdisciplinary investigation of the efficacy of narcotic antagonists (Meyer et al. 1976).

In the first of a series of three studies, groups of four addict

volunteers lived on an experimental research ward for 60 days. During

this time heroin was made available for self-administration under

blocked (heroin antagonist) and unblocked conditions. The unblocked

heroin condition lasted 10 days, during which time the available dose

increased from 6 to 60 mg/day. All subjects chose to self-administer

the maximum available daily dose, although the frequency of administration varied from group to group. Procedures identical to those used

in our research on marihuana self-administration were employed to

measure variations in social behavior during the cycle of addiction

and withdrawal (Babor et al. 1976b). In addition, psychiatric interviews and semantic differential rating scales were used to evaluate

concomitant changes in social adjustment and subjective feeling states

(Mirin et al. 1976).

The results of the hourly observations are shown in figure 2. Reactions

to heroin self-administration were most pronounced in the categories

of isolation and social interaction, which varied inversely during the

periods of addiction and detoxification. Time spent in social interaction decreased from a drug-free level of 47% to a low of 12% late

in the heroin phase.

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FIGURE 2

Average percent daily waking time spent in isolation, coaction,

and interaction. Babor et al. 1976b.

Medical Association.

Copyright 1976, American

Reprinted, with permission, from Arch Gen

Psychiatry, 33:363-367, 1976.

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Although the results suggest strongly that social interaction is

directly affected by heroin self-administration and withdrawal, it

is conceivable that certain extraneous nonpharmacologic factors also

influenced the results. One such factor could have been expectancy.

Since patients were fully cognizant that they were receiving heroin

and later methadone, they may have been reacting to expected rather

than actual drug effects. Another possible extraneous factor is

behavioral contagion. This refers to the spread of drug reactions

from one group member to another through a process of modeling and

imitation. In a subsequent series of studies using a modified

design, an attempt was made to distinguish between these sources of

variance by controlling for expentancy (through double blind administration of naltrexone and placebo) and by manipulating the numbers

of blocked and unblocked members within successive groups. Observations identical to those employed on the first 12 subjects were repeated

on 37 additional subjects. The findings were very consistent with

the results of our first study. Unblocked subjects interacted least

and were most isolated in the late stages of heroin acquisition and

in this respect they differed significantly from blocked subjects.

The identification of significant modifications in social interaction

during the addiction cycle raised additional questions about the underlying dynamics of these effects. Do chronic reactions represent the

accumulation of acute effects, or are they related more to the development of abstinence symptoms? Is there evidence that acute positive

effects compensate for the chronic negative effects, thereby suggesting

a possible reinforcing mechanism of heroin? Finally, do the immediate

effects of heroin satisfy specific personality needs, for example, by

increasing dominance, reducing hostility or facilitating interaction?

To identify acute behavioral and social changes taking place after

heroin administration on the research ward, all observations that

preceded and followed each drug administration were analyzed. Because

heroin doses were escalating gradually, the data were summarized at

both lower (first five days of heroin) and higher (second five days)

dose levels. As shown in figure 3, subjects indicated somewhat

less interaction following lower doses and significantly more interaction following higher doses. Even though subjects were interacting

more after higher doses than before, the absolute level of interaction

was significantly less than that seen at lower doses. This means that

while interaction was generally declining during the heroin phase, the

effect of higher doses was to reverse this effect temporarily.

In addition to the hourly observations conducted on the research ward,

subjects were also studied while participating in a 45 minute therapy

group (Babor et al. 1976a). Ongoing interaction (who speaks to whom)

and role behavior were observed according to procedures used in the

marihuana research described previously (Babor et al. 1978). In

addition, a five-point interpersonal hostility scale was used to assess

verbal and nonverbal hostility. These observations made it possible

to determine whether the immediate changes observed in the ward setting

generalize to the more socially demanding group therapy situation.

The results showed no significant changes in group participation or

role behavior. However, hostility differed significantly among phases,

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FIGURE 3

Social Interaction Before and After

Lower and Higher Doses of Heroin

LOWER DOSES HIGHER DOSES

(HEROIN DAYS 1 - 5) (HEROIN DAYS 6-10)

reaching its highest level during the latter part of the heroin

period. The increase in hostility correlated positively with dosage

level. In related findings, subjects reported increasingly dysphoric

mood states, while independent psychiatric observations revealed

greater somatic concern and belligerance (Mirin et al. 1976).

Considered in their totality, the results suggest a complicated

relationship between acute and chronic reactions to heroin and their

cumulative effects on physiological functioning, subjective states

and social behavior. Although single doses of heroin apparently provide a brief respite from dysphoric mood states, it is likely that

negative affect is intensified by physical dependency and the development of tolerance. Tolerance develops rapidly to the analgesic and

euphoric effects of opiates, thereby requiring the addict to increase

his dose to attain previous degrees of euphoria. As physical dependence develops, abstinence symptoms become more intense between doses.

These factors undoubtedly reduce the addict’s interest in social contact, which often involves frustration, competition and conflict in

the street environment. Aggression and social withdrawal may be two

means of coping with the internal changes being experienced during

the addiction cycle. Aggression would be more likely to occur in

those interpersonal situations perceived as threatening or frustrating.

Since hostile behavior is often punished or negatively reinforced, a

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more functional way of dealing with inner hostility would be to reduce

the possibility of interpersonal conflict by withdrawing from social

situations. Thus social withdrawal may be an avoidance response

intended to cope with negative feeling states and sources of frustration in the environment.

In summary, this research illustrates the importance of using an

interdisciplinary approach to study drug effects. Without the use

of multiple measures to monitor underlying changes at different levels

of analysis, factors mediating social reactions may only be inferred.

ALCOHOL

Despite the abundance of folklore attributing prosocial as well as

antisocial behavior to the effect of alcohol, social variables have

been considered in only a few self-administration studies of drinking.

McNamee, Mello and Mendelson (1968) report the results of nonsystematic

clinical observations of 12 alcoholics during a seven day period of

free access to 86 proof bourbon. Although subjects maintained a high

degree of social interaction, they tended to withdraw from social

contact during periods of maximum intoxication. Nine subjects demonstrated a progressive increase in anxiety and depression which correlated with amount of alcohol consumed. The emergence of assertiveness,

hostility and belligerence during chronic intoxication was also noted

in many of the subjects.

Using self-report behavioral assessments, Tamerin, Weiner and

Mendelson (1970) obtained similar results in a study of 13 male

alcoholics. Subjects’ expectancies prior to drinking were compared

to self-reports obtained during the experimental period of ethanol

self-administration. Subjects reported significantly more dysphoria,

sexuality and aggression during intoxication than they had predicted

during sobriety. The findings suggested that alcoholics drink in

order “to regress, rebel and more comfortably act out (p. 1703),” and

not, as many have assumed from alcoholics’ retrospective accounts, to

be more sociable or to feel better.

In contrast to those self-administration studies where subjects are

studied concurrently in homogeneous groups, Griffiths, Bigelow and

Liebson (1974) employed a design where five male alcoholics participated

consecutively. In the initial phase of each subject’s program a maximum daily dose of 12 oz of 95 proof ethanol was available on randomly

selected days. In the second phase the same amount of ethanol was

available during successive days on a nonrandom schedule. Social

interaction, defined as behavior which required the presence of or

involved another person, was observed on a random schedule. Social

interaction was found to be significantly greater on ethanol days

than on nonethanol days in both random and successive scheduling conditions. Although it is suggested that increased social interaction

may be one of the reinforcing effects of drinking, the authors avoid

implicating alcohol, qua pharmacological agent, directly with this

effect. Their methodology, as well as their interpretation, leaves

open the possibility that the subject’s expectancy or other factors

in the ward environment contributed to the increased socialization.

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Two recent studies manipulated psychological “trait” variables to

observe their interaction with alcohol self-administration and social

behavior. Martorano (1974) used observational and self-report procedures to study the effects of alcohol and assertion training on

social perception in one group of four alcoholics. Observers’ ratings

indicated decreased cooperation and communication during alcohol intoxication, a pattern which tended to be exacerbated following assertion

training. Thornton et al. (1976) investigated the relation between

socialization, drinking behavior and the introversion-extroversion

personality factor in 98 alcoholics participating in a six-week treatment and research program. Socializing increased significantly in

the early stages of drinking. Drinking alcoholics maintained a

higher rate of socializing than a control group of nondrinking

alcoholics. Although extroverted alcoholics socialized at a significantly higher rate than introverted alcoholics, the personality

factor did not interact with drinking.

In a series of related investigations, Nathan and his colleagues

(Nathan et al. 1970; Nathan, O’Brien, and Norton 1971; Tracey and

Nathan 1976) studied alcoholic and nonalcoholic drinkers during

alternating periods of isolation (confinement to bedroom) and socialization (free access to all ward areas). Points earned on a simple

operant device could be used to purchase alcohol and/or relief from

isolation. In one study (Nathan et al. 1970) 11 alcoholic subjects

participated in three separate groups for periods ranging from 30 to

42 days. A nondrinking phase of six days preceded and followed an

interim period of alcohol availability. Several observational procedures were employed to obtain time samples of social behavior but

no statistics are reported. According to the authors, the “average”

subject , when drinking, attempted more often to initiate communication,

was more aggressive verbally, and failed more often to respond to

another person’s initiation of communication. No consistent preference

for drinking was demonstrated during either isolation or socialization

periods. In another report (Nathan, O’Brien, and Norton 1971), one

four-person group of alcoholics was compared to a matched group of

nonalcoholic drinkers. Each group was observed during a 33-day study

having alternating three day periods of isolation and socialization.

Although the alcoholic subjects were demonstrably more isolated than

the nonalcoholics, neither group showed social changes which could be

attributed to either the experimental condition (isolation vs. socialization) or the availability of alcohol. Finally, in yet another.

study (Tracey and Nathan 1976), a single group of four female alcoholics

was observed over a period of 22 days, 12 of which provided access to

alcohol. As in the previous studies, attendance at the ward bar was

not affected by the isolation/socialization condition.

the results of previous studies,

Compared to

the authors suggest that socialization patterns of female alcoholics were more like those of the male

nonalcoholics than the male alcoholics.

In our own research at McLean Hospital ten four-person groups of

nonalcoholic drinkers were observed during a 30-day investigation of

the effects of purchase price on alcohol self-administration (Babor,

Mendelson, Greenberg and Kuehnle, in press) . Frequency of alcohol

consumption (number of drinks per day) over a 20-day period was correlated with the three daily measures of social behavior derived from

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the Behavior Inventory. Data from 11 heavy drinkers, shown in table

2, indicates that the more subjects drank on a given day the more they

engaged in social interaction. On the day after alcohol consumption,

however, subjects interacted less in direct proportion to the amount

they drank on the previous day.

TABLE 2. Average Pearson Correlation Coefficients:

Number of Alcoholic Drinks Consumed per Day Correlated

With Measures of Three Categories of Social Interaction

Interaction

Category Same Day Next Day1

Isolation -.0l .09

Coaction -.20** .16*

Interaction .17* -.26**

1Average Pearson Correlation coefficients, next day, are means of

partial correlations. The effect of the number of drinks consumed on

the next day has been partialed out of the relationship.

* p< .05

** p < .01

To date research relating alcohol self-administration to changes in

social interaction has not generated a consistent set of findings.

Findings from a number of studies suggest that socializing increases

among alcoholics during alcohol self-administration, particularly at

low and moderate doses and during the initial period of an experimental

drinking period (McNamee, Mello and Mendelson 1968; Griffiths, Bigelow

and Liebson 1974; Thornton et al. 1976). Studies by Nathan and his

colleagues (Nathan et al. 1970; Nathan, O’Brien and Norton 1971;

Tracey and Nathan 1976), however, have yielded findings which are

somewhat equivocal on this question. Because studies differ markedly

in the nature and sophistication of methodology, it is extremely

important to weigh methodological issues when seeking to integrate

inconsistent findings.

METHODOLOGICAL ISSUES

Having reviewed some of the major studies of social reactions to drug

self-administration, and having presented in some detail methods and

findings emerging from our own research, it is fitting that a more

critical evaluation of methodological issues be presented. In what

follows drug self-administration studies will be discussed in terms of

sampling and group composition, specification of the independent variable, dependent variables and assessment procedures, and problems

related to research design.

Sampling and Group Composition

The procedure used to choose a representative subset of the population

to which the researcher wishes to generalize results is commonly called

sampling. Ideally, subjects should be sampled randomly from the population of interest. The absence of any allusion to random sampling

procedures in the studies reviewed above attests to the relative

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difficulty of employing this precaution in drug self-administration

research. Because of cost, effort and ethical considerations, random

sampling is rarely attempted, even from the more restricted populations of interest such as addicts or alcoholics. Another reason for

the lack of random sampling is that the boundaries of the addict and

alcoholic populations are unknown, so appropriate sampling frames and

probabilistic methods cannot be applied. Thus nonprobabilistic procedures are the rule rather than the exception in all self-administration research conducted to date. As a consequence, inferences from

such samples are risky since subjects may not accurately reflect the

population itself.

In general the sampling procedures employed in these studies can be

classified as either accidental or purposive. In accidental or haphazard sampling the researcher includes any cases that happen to be

available from the general population of interest. This is mostly

the case in studies where subjects are drawn from institutions with

so-called “captive” populations. Thus prisoner volunteers have been

a convenient source of recruiting marihuana users (Williams et al.

1946), and alcoholics (Nathan et al. 1970; McNamee, Mello and

Mendelson 1968). Hospitalized patients undergoing detoxification or

treatment have been another pool of alcoholic subjects (Griffiths,

Bigelow and Liebson 1974; Thornton et al. 1976; Nathan, O’Brien and

Norton 1971) and narcotic addicts (Babor et al. 1976). In two reports

no information is given on methods of recruitment (Martorano 1974;

Tamerin, Weiner and Mendelson 1970).

Purposive sampling involves some use of judgment by the researcher who

attempts to select a representative cross section of the population.

One method is to select subjects from a large pool of volunteers

solicited through newspaper advertisements (Babor et al. 1974a,b;

Babor et al. 1978; Tracey and Nathan 1976). These subjects are usually

screened to fit into some predetermined drug use category such as

casual marihuana user (Babor et al. 1974a,b) or female alcoholic (Tracey

and Nathan 1976). One limitation of this procedure is that the requirements of volunteering often exclude large segments of the population

who, for whatever reasons, have neither the time nor the inclination

to volunteer. In the absence of statements clarifying the limits of

generalizability, there is an implicit assmuption in many of these

studies that the subjects sampled are representative of the group

sharing their primary designation. Because of the predominance of

nonprobabilistic sampling procedures, inferences from such samples

should be cautious, qualified and conservative.

An issue related to representativeness is that of sample size. The

studies reviewed here are based on samples ranging from four (Tracey

and Nathan 1976; Martorano 1974) to 98 subjects (Thornton et al. 1976).

To the extent that small sample size increases the risk of sampling

bias and statistical error, this factor should be taken into account in

evaluating the results. This is particularly true when the problem of

group composition is considered.

With the exception of one study (Griffiths, Bigelow, and Liebson 1974),

research subjects in all of these investigations were studied in

groups living together in a controlled setting. Despite some rather

compelling evidence (Hare 1976) that social, personality and demographic

164
characteristics affect, group development and functioning, researchers

have generally failed to consider individual differences, either as

mediating variables or as a source of statistical error variance.

Reiss and Salzman (1973) define the “compositional effect” as the

influence on a group of the individuals who compose the group. In

much drug self-administration research it is generally assumed either

that group members are equivalent on various personal, social or demographic characteristics, or that homogeneity on some factors (e.g.,

sex, drug use history, age) sufficiently restricts intersubject variance.

Age may be one of the most important compositional factors since

differences in tolerance, dependence and value orientations tend to

be age-related. Variations in age among subjects are greatest in those

studies relying on accidental sampling procedures. The difference

between oldest and youngest subjects exceeds 20 years in some studies

(Tamer-in, Weiner and Mendelson 1970; Nathan, O’Brien and Norton 1971;

Martorano 1974; Thornton et al. 1976). Personality factors may also

be important since traits such as dominance, sociability and neuroticism

will affect rates of interaction, interpersonal compatibility and group

cohesiveness . In the only study relevant to the contribution of personality variables (Thornton et al. 1976) , it was found that the

introversion-extroversion dimension did not differentiate alcoholics’

social response to alcohol. However, it was reported that extroverted

alcoholics socialized at significantly higher rates than introverted

subjects. Conceivably, failure to match subjects or otherwise control

for personality factors could lead to erroneous inferences from data

comparing groups of drinkers on their social response to alcohol.

The issue of group composition becomes particularly acute when

considering those studies where the results of a single group were

considered alone (Williams et al. 1946; Tracey and Nathan 1976;

Martorano 1974) or in comparison to another group having a different drug use history (Nathan, O’Brien, and Norton 1971). Without

replications across groups of comparable drug users, it is impossible

to ascertain the degree to which drug reactions interact with differences

in group composition.

Independent Variables

Although optional drug self-administration is common to all of the

studies reviewed, the method in which this variable is operationalized

differs from one study to another. The most common procedure is to

treat drug use over a period of days as a dichotamous variable. Thus

comparisons are most often made between blocks of drug days and blocks

of nondrug days (Martorano 1974; Tamer-in, Weiner and Mendelson 1970;

Griffiths, Bigelow and Liebson 1974). This method presents some problems when there is large variability among subjects. It is also a

rather gross variable which is susceptible to sequence effects when

drug and nondrug blocks are not randomized or counterbalanced.

In research at the McLean Hospital an effort has been made to consider

different aspects of drug self-administration as independent variables.

Immediate intoxication was defined in one study (Babor et al. 1974b)

by ratings on a subjective intoxication scale which correlated significantly with physiological parameters. Number of self-administrations

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per day has also been used (Babor et al. in press). These measures

have same advantage over the more diffuse measure of drug use because

(1) they constitute continuous variables; (2) they allow a more

accurate assessment of within subject variability on the dependent

variable; and (3) they are more sensitive to the subject’s individual

pattern of drug use.

One important distinction when discussing the definition of the

independent variable in these studies is that between drugs versus

drug self-administration. When the subject determines the frequency,

timing, dosage and social circumstances of drug administration, a

number of nonpharmacological variables are introduced into the determination of drug effects. Since most of these studies fail to specify

or define what they consider to be the independent variable, there is

a tendency for the terms drug and drug self-administration to be used

interchangeably. The importance of this distinction will become evident

in discussing research design issues and the problems of interpretation

and generalizability.

Dependent Variables and Assessment Procedures

The dimensions of social behavior investigated as dependent variables

in these studies can be classified in five categories. While these

categories by no means exhaust the social behaviors affected by drugs,

they do cover some of the major variables worthy of attention. The

first and most frequently investigated category is aimed at providing

a gross description of interpersonal activity. Described variously

as social interaction (McNamee, Mello and Mendelson 1968; Thornton

et al. 1976; Griffiths, Bigelow and Liebson 1974; Babor et al. 1976b,

socialization (Nathan et al. 1970; Nathan, O’Brien and Norton 1971)

and social contact (Martorano 1974), this variable is often considered

in contrast to the total absence of interpersonal activity. The latter

condition has been defined variously as social isolation (Nathan et al.

1970; Babor et al. 1976b), no interaction (Griffiths, Bigelow and

Liebson 1974) or solitary activity (Miles et al. 1974). An intermediate level of sociability, called coaction, has been employed in

our research to describe parallel activity which is neither interactive

nor isolated (Babor et al. 1976b; Babor et al. in press). One advantage

of this latter differentiation is suggested by comparing the social

reactions of heroin addicts and moderate marihuana smokers. Although

both groups demonstrated less interaction during periods of chronic

intoxication, the heroin addicts became more isolated while the marihuana smokers favored coaction (Babor et al. 1976b; Babor et al. in

press) . As suggested previously in the discussion of heroin research,

voluntary isolation may represent a social avoidance response, while

coaction may merely imply greater attention to the subjective experience.

A second dependent variable investigated in these studies deals with

sane of the more qualitative dimensions of interpersonal behavior. In

our group interaction studies (Babor et al. 1976a; 1978) Bales’ (1970)

procedures were used to measure what some social psychologists consider to be the major dimensions of social behavior, namely, dominance

vs. submissiveness, positive vs. negative, task orientation vs. nontask

orientation. Variants of these dimensions, such as assertiveness

(McNamee, Mello and Mendelson 1968), hostility (Babor et. al. 1976a)

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and cooperation (Martorano 1974) have been investigated in other

self-administration studies.

Subjective feelings states indicative of certain social orientations

is the fourth category investigated as a dependent variable. In one

study (Martorano 1974) an adjective check list was administered twice

daily to measure phenomenological aspects of friendliness, warmth and

abrasiveness. In another study (Tamerin, Weiner and Mendelson 1970)

a modified Q-sort test was administered on five occasions to measure

feelings of aggression and sexuality before, during and after a period of alcohol self-administration.

Nonverbal behavior is the fifth category of social behavior investigated. To the extent that voluntary or concious control of nonverbal

behavior is minimal, it is likely to provide an even more sensitive

measure of drug effects than verbal behavior. To date nonverbal

behavior has not been investigated extensively in drug self-administration research, although several measures were included in the

Behavior Inventory used by Babor et al. (1976b). Body orientation

and eye contact were used to classify subjects as affiliating or isolated, and ratings were also made of posture and head position. As

expected, the latter measures were sensitive to the acute effects of

heroin. With the ready availability of video tape technology future

researchers may find it fruitful to concentrate on one or several of

the following nonverbal behaviors: eye contact, postural relaxation,

body lean, speech intonation, touching, facial activity, hand movements and physical distance.

The procedures used in these studies are so diverse that it would be

difficult to compare findings from one study to another, even when

the same dependent variable, such as “social interaction,” is under

investigation. For those interested in conducting further research

on social reactions to drug self-administration, several points

should be considered when choosing dependent variables and assessment

procedures. In several studies an attempt has been made to apply the

measurement procedure at different times after the ingestion of the

drug and during the course of repeated drug self-administration (Babor

et al. 1976b; Babor et al. in press). Because the effects of drug

self-administration are often cumulative, and are modified over time

by tolerance and dependence, it would seem important to monitor acute

as well as chronic effects. In studying social reactions to heroin

self-administration, for example, it was found that a daily trend

toward reduced interaction was temporarily reversed by single doses

of heroin late in the addiction cycle (cf. figure 3). Similarly,

changes in social interaction following single doses of marihuana

were different from those observed when an entire day of drug use was

monitored (cf. figure 1, table 1). As Nash (1960) has pointed out:

“acute effects of a single dose of a drug may differ qualitatively as

well as quantitatively from the chronic effects of repeated doses”

(p. 146).

Another consideration is the use of reactive vs. nonreactive measures.

Nonreactive measures are those which do not require direct participation by the subject. Structured observation, particularly when

conducted at random time intervals in an unobtrusive manner, is the

most commonly employed nonreactive procedure. Its main advantage is

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that the subject is less likely to modify his or her behavior as a

function of the measurement procedure itself. Reactive measures, on

the other hand, require some response on the part of the subject,

either through performance on some task or reports of psychological

processes. A disadvantage of reactive measures is that the process

of measurement may generate expectancies, heighten arousal, or increase

motivation, all factors which could temporarily suppress an otherwise

prominent drug effect. Evidence for such an effect can be found in

a study of subjective reactions to marihuana conducted by Rossi et al.

(1974). Subjects who believed their mood reports would be used to

assess the acute effects of marihuana gave a different pattern of

response than those who believed their responses would be used to

assess mood at that time of day regardless of drug ingestion.

A procedure which combines the naturalness of nonreactive measures

with the greater control afforded by reactive tests is the “situational”

test (Fiske 1960). Designed to evoke behavioral reactions to realistic problems, the situational test consists of a contrived situation

occurring in a natural setting which requires an adaptive rather than

a test response. The “human relations” discussion task used in our

group interaction studies (Babor et al. 1974b; 1976a; 1978) is an

example. The situation generates verbal interaction similar to that

occurring in natural settings and the subjects are unaware of the purpose or nature of the observations.

A major consideration in the evaluation and selection of any measurement

procedure is the extent to which it is reliable and valid. With few

exceptions the procedures employed in these studies were developed by

the researchers themselves or adopted and modified from the work of

other researchers. Given the pervasive use of nonstandardized instruments , it is unfortunate that reliability data is lacking in all but

a few (Griffiths, Bigelow and Liebson 1974; Babor et al. 1974b; 1976a;

1978) of the research reports. Similarly, there is almost total neglect

in these studies of the crucial question of external and/or internal

validity. In our research the validity of at least one of our

behavioral categories was checked by correlating the daily frequency

of “operant responding” observations with the actual output recorded

on an automated counter (Babor, Mendelson, and Kuehnle 1976). Convergent validity was examined by comparing the consistency of social

reactions in both formal and informal situations (Babor et al. 1976a,b;

1978, in press).

One final consideration concerning the choice and measurement of

dependent variables relates to the unit of analysis. In addition to

the social reactions of the individual ingesting the drug, Lennard,

Epstein and Katzung (1967) have suggested the following parameters as

worthy of inquiry: (1) changes in the behavior of other persons interacting with the intoxicated person; (2) changes in the structure and

process of the group; (3) the extent to which characteristics of the

group mediate the behavior of the subject; and (4) the extent to which

changes in the subject’s behavior are perceived by other group members.

Research Design

The ostensible purpose of research design is to control or minimize

the effects of extraneous variables so that changes in the dependent

168
variable can be clearly observed and causal inferences can be made

unambiguously. The design feature common to all of the drug selfadministration studies reviewed here is repeated measurement of social

behavior over an extended period of time. With one exception

(Thornton et al. 1976) each study attempts to compare the subject’s

behavior during drug self-administration to that same subject’s behavior during periods when the drug is not available. Although repeated

measurements and within-subjects comparisons are acceptable procedures,

they contain certain inherent limitations. If these problems are not

controlled or eliminated by use of commonly accepted experimental precautions, they can introduce needless error variance and experimental

bias into the results, and seriously compromise the validity and

generalizability of the findings. The major design problems which

plague many drug self-administration studies, particularly those

focusing on social behavior, will be discussed in terms of control

group comparisons, sequence effects, social system phenomena, sample

size and placebo effects.

An elementary if not essential feature of good scientific research is

the use of a control group or control condition as a standard of comparison for the experimental treatment. While all of the reviewed

studies have made some provision for comparing behavior under conditions of drug availability (experimental) and drug unavailability

(control), many of the designs are compromised by problems related

to the sequential order in which conditions are presented. The

sequence common to many self-administration studies consists of a

predrug or baseline phase, a drug availability or drug self-administration phase, and a postdrug or drug withdrawal phase. The rationale

for this abstinence-drug-abstinence design is not clearly explained

by most researchers but two considerations appear to be paramount.

The first is that the sequence of conditions resembles the standard

ABA design in which an experimental treatment (B) is interspersed

between one or more control conditions (A). This design permits the

researcher to logically detect linear effects caused by extraneous

factors such as learning, maturation, habituation, order of presentation, repeated testing, the mere passage of time, or familiarity with

the experimental procedures. Examples of linear trends resulting

from extraneous factors can be found in the results of several studies

(cf. Miles et al. 1974; Babor et al. 1974b; Nathan, O’Brien and Norton

1971; Tracey and Nathan 1976). In the study by Nathan, O’Brien and

Norton (1971) attendance at the ward bar, a dependent measure of

socialization, increased progressively during the study regardless of

phase (predrinking, drinking, postdrinking) or condition (isolation

vs socialization). Similarly, the four subjects in the Tracey and

Nathan (1976) study progressively increased spending to purchase time

spent out of their rooms, possibly because confinement became more

aversive during the course of the 33-day study period. Although the

inclusion of predrug and postdrug control conditions can assist with

the detection of linear trends, only a crossover or randomized blocks

design can completely control for this source of bias. This was

achieved in the design used by Griffiths, Bigelow and Liebson (1974),

who randomly distributed days of ethanol availability with an equal

number of ethanol nonavailability days.

169
The second ostensible rationale for the pervasive use of the

abstinence-drug-abstinence design is that in many ways it simulates

the actual conditions of drug self-administration and withdrawal

resulting from use of dependence-producing drugs like alcohol and

heroin. With experimental induction of the addiction cycle, however,

the researcher is left with three distinct conditions (abstinence,

drug, and withdrawal), and the problem of sorting out the effects of

order and sequence again becomes a serious methodological issue.

This problem can be overcome to some extent by the addition of

another abstinence period following the cessation of withdrawal symptoms (cf. Babor et al. 1976a,b).

Another design feature which provides a better estimate of extraneous

sources of experimental bias is the inclusion of a no-drug control

group. Ideally the control subjects should be studied under conditions identical to those of the experimental subjects, including

optional access to drug self-administration. This was accomplished

to a major extent in only two studies (Thornton et al. 1976; Babor

et al. in press) . In the Thornton et al. (1976) study subjects who

did not avail themselves of the opportunity to drink served as a

control group. One problem with this method of selecting control

subjects, however, lies in the very fact that these subjects voluntarily refused alcohol. This in itself (and not the absence of

alcohol per se) may have constituted the characteristic distinguishing

them from those who chose to drink, and may have contributed in part

to the observed differences in socialization. This problem was overcome in a study of moderate and heavy marihuana smokers (Babor et al.

in press) where both control subjects and control conditions were

employed. Control subjects were selected from participants in an

ethanol self-administration study. These subjects, comparable in

background characteristics to the moderate marihuana smokers, also

were exposed to an identical sequence of control and experimental

conditions (predrug, drug, postdrug). To control further for the

minimal amount of alcohol ingested by these subjects, observations

occurring within an hour after drinking were eliminated from the

analysis. An unquestionable advantage of this procedure is illustrated

in Figure 4 which shows five-day means of daily sleep time for control

subjects and marihuana subjects. Had only the marihuana smokers been

included in the analysis, the data might have suggested that chronic

marihuana smoking, rather than confinement on a clinical research

ward, is associated with increased sleep during the middle period.

One design feature sorely lacking in these studies is the use of

either a placebo control group or placebo control condition. The use

of a placebo is essential if the researcher is interested in differentiating between reactions mediated by the pharmacological action

of the drug, on the one hand, and that deriving from such nonpharmacological factors as suggestion and expectancy on the other. Because

researchers have been interested in rather gross social reactions,

they have perhaps not felt the need to examine the extent to which

acute doses precipitate placebo reactions. Further, it can be argued

that the utility of placebos in such research would be vitiated by

the possibility that experienced drinkers and drug users would

quickly detect the absence of pharmacological effect during repeated

self-administration trials. This indeed proved to be the case in

double blind studies of heroin self-administration under either

170
FIGURE 4

Averages of daily sleep time for successive 5-day blocks (excluding

day 26) of 31-day marihuana self-administration study. Sleep data

obtained by means of hourly observations. Mendelson and Kuehnle,

in Psychopharmacology, 50:11-19, 1976. Copyright 1976. Reprinted

with permission of the publisher.

blocked (naltrexone) or unblocked conditions conducted at McLean

Hospital. It did not take many heroin challenges before subjects

receiving naltrexone realized that they were, in effect, the unfortunate

members of the placebo control group. A more feasible alternative to

the placebo control group would therefore be the placebo control condition. Placebo doses of marihuana, alcohol or heroin could easily

have been distributed randomly among the actual doses available to

research subjects. By carefully observing or measuring the responses

to these doses, researchers would be in a better position to estimate

the contribution of nonpharmacological factors to both acute and chronic

reactions. Major problems of interpretation could also be avoided.

as exemplified-in the data presented in figures 1 and 3, and tables 1

and 2. While acute and daily doses of heroin. marihuana and alcohol

were found to be associated with systematic changes in social behavior,

it was impossible to ascertain how much subjects were responding to

psychological expectancies, social rituals, and other factors related

to recreational drug use. The pervasive tendency for interaction to

coalesce around drug self-administration, and for recreational activity

to coincide with the period of maximum intoxication, constitutes a

major interpretational problem.

Without the benefit of a placebo condition researchers risk confounding

drug effects with the psychosocial factors surrounding the act of drug

self-administration. A growing body of evidence suggests that such

factors can exert a profound influence on the manifestation of both

drug effects and placebo reactions. One of the first psychologists

to identify these sources of confounding is Vincent Nowlis (Nowlis and

Nowlis 1956; Nowlis 1958; 1960). In studies of subjective and behavioral reactions to various drugs Nowlis often observed a contagion

of mood and behavior among subjects undergoing testing in a group setting. The influence of the group on drug effects has also been noted

171
by others. Fiske (1960) has observed that “the group tone or atmosphere exercises a major constraint on the subject’s dispositions”

(p. 317), while Nash (1960) points out that this “special form of

suggestion may give rise to error when subjects are examined in groups”

(p. 141). Nowlis and Nowlis (1956) argue that since this source of

error cannot be controlled in group settings the group itself must be

considered the unit of analysis. In the McLean Hospital studies of

marihuana, heroin and alcohol self-administration various statistical

procedures have been employed to analyze this phenomenon. When cluster

analysis was applied to daily measures of operant work output,

physical activity, mood state, hours of sleep and the three levels of

social behavior, it was found that marihuana smokers clustered uniformly according to the groups they were studied in. The tendency

for individual behavior to covary in group settings has received

little research attention, but it is likely the result of a social

influence process which includes behavioral contagion, social facilitation and conformity pressures. Of all the self-administration studies

reviewed, only one attempted to control for this factor by running

subjects consecutively rather than concurrently (Griffiths, Bigelow

and Liebson 1974). In drug self-administration studies conducted at

the McLean Hospital analysis of variance is applied routinely to test

for differences across groups exposed to similar treatment conditions.

If drug effects are more consistent within than between groups it is

likely that social factors are mediating the manifestation of drug

effects. In one study (Babor et al. in press) significant drug X

groups interaction effects were noted in analyses of each of the three

indices of social behavior (isolation, coaction, interaction). Only

in the case of interaction was there a consistent directional variation

across all study groups. Although percent daily interaction decreased

in each of three moderate user groups during the drug period, the

greatest decrements occurred in groups which interacted most during

the predrug baseline. Among heavy users, some groups showed significant

increases while other groups, paradoxically, showed significant decreases.

The potential sources of experimental error and confounding associated

with group composition, group development and behavioral contagion

pose a serious challenge to those who would investigate social reactions to drug self-administration. In those studies where these factors

were neither acknowledged nor controlled the validity and generalizability of the findings can be seriously questioned. This is particularly

true of studies reporting the results of only one group of subjects

(Williams et al. 1946; Miles et al. 1974; Tracey and Nathan 1976;

Martorano 1974), since there is no way of replicating findings across

groups. It should be emphasized that while repeated measures on the

same subjects increase the reliability of measurement, this in no

way affects the degree to which the results are generalizable to the

broader population of interest. As Nash (1960, p. 137) points out:

“The fewer subjects selected from a given population, the smaller the

likelihood of a given drug effect being detected, and the less precise

is the estimate of that effect . . . the investigator’s energies are

more richly rewarded by an increase in the number of subjects selected

than by a corresponding increase in the number of observations collected per subject.”

172
Failure to control for extraneous sources of variance can render the

dependent measure relatively insensitive. For example, three studies

by Nathan and his associates (Nathan et al. 1970; Nathan, O’Brien and

Norton 1971; Tracey and Nathan 1976) failed to establish any consistent

relationship between ethanol self -administration and preference for

socialization, as measured by time spent working on an operant work

device. A recent review of this research (Griffiths, Bigelow and

Liebson, in press) pointed to a number of extraneous factors which

could have interfered both directly and indirectly with the subject’s

preference for socialization while under the influence of alcohol.

These include locating the operant task in the subject’s private room,

permitting subjects to allocate point earnings for the purchase of

both ethanol and time out of social isolation, the sharing of drinks

among subjects, and the effects of accumulating surplus points on

subsequent socializing. To the extent that these design limitations

constitute sources of error variance, it is not surprising that the

researchers failed to find a relationship between ethanol and socialization.

To some extent inefficient design features and small sample size can

be compensated by the judicious use of established statistical procedures in conjunction with accessory information. For example,

differences in baseline (predrug) measures of social behavior or personality can be corrected by means of analysis of covariance or by use

of difference scores. Analysis of variance can be used to partition

the variance associated with drug self-administration from that associated with differences between study groups. Trend analysis can be

applied to detect systematic variations associated with the passage

of time (e.g., linear trends) and with the introduction of the experimental condition (e.g., curvilinear trend). One alternative to merely

aggregating data across subjects and conditions is to use correlational

procedures to relate each subject’s drug self-administration pattern

to his or her dependent measures (cf. tables 1 and 2). Partial correlations can be used to control for known sources of bias, and

coefficients can be summed across subjects to determine the magnitude

and consistency of the effect. Another correlational procedure which

could be applied to the analysis of equally spaced repeated measurements in drug self-administration research is autocorrelation (Huba

et al. 1976). By providing knowledge of the serial dependency structure of the time series, autocorrelation can quantify longitudinal

stability and help to detect cyclical fluctuations. To date these

statistical procedures have been used sparingly, if at all. Several

studies failed to report statistical analyses of social measures even

when quantitative data was collected (Nathan et al. 1970; Nathan,

O’Brien and Norton 1971; Tracey and Nathan 1976).

CONCLUSION

In this paper an attempt has been made to deal with the pitfalls as

well as the potential benefits of studying social reactions to drug

self-administration. Having reviewed some 30 years of drug selfadministration research, the scientific purist might be tempted to

conclude that not much has been learned beyond how to confound drug

effects with error variance. In a discussion of basic principles of

research design, Nash (1960) distinguishes between essential features

which must be incorporated into a scientific experiment, and economic

173
design features which merely increase the efficiency of experimentation.

Cited as essential design features are elimination or segregation of

any factors which introduce bias into the experiment; comparison of

drug-related observations-with those obtained under control or standard

conditions; representative sampling; random assignment to treatment

conditions; fulfillment of the assumptions underlying the analysis

of variance. Applying these criteria, few of the studies reviewed

would seem to qualify as scientific experiments. While a number of

interesting findings have emerged from these studies, there has been

a tendency to confuse covariation with causal relations, if not by

the researchers themselves, then by those who cite the findings in

support of some hypothesis. Before definitive statements can be made

about the relation between drugs and social behavior, researchers

will have to provide a sufficient demonstration of the nonspuriousness of these covariations.

There is no doubt that mundane realism is accomplished at the cost of

experimental efficiency, but all too often researchers have used the

self-administration paradigm as a license to dispense with some of

the most conventional precautions of good social research. In part,

this state of affairs can be attributed to the fact that the social

assessments included in many of these studies were ancillary to the

major purpose of the research, which was typically focused on detecting

the biomedical concomitants of chronic drug self-administration.

Nevertheless, there is no intrinsic reason why interdisciplinary

research could not be designed so as to satisfy the criteria of

“good science” at each level of analysis.

All this is not to say that the studies we have reviewed have been

done in vain. Considering the descriptive nature of much of this

research, it can be said that its value lies in providing an elementary

comprehension of the relation between drug self-administration and

social behavior. It appears that single and repeated doses of marihuana and heroin result in a general suppression of social interaction.

Interestingly, unlike marihuana, chronic heroin intoxication is associated with almost total withdrawal from the social environment. In

the case of alcohol self-administration by alcoholics, the evidence

suggests that socializing increases during the early stages of drinking

but at higher doses or with prolonged drinking social withdrawal may

occur. These studies have also been instructive in suggesting the

possible mediating role of affective states, physiological mechanisms,

biochemical alterations, personality variables and the prevailing

social environment.

Unfortunately, there has been little attempt to go beyond descriptive

statements to the level of integration and analysis. Furthermore,

the hypothesis generating value of this research has not been generally

exploited. One notable exception to this statement is the work of the

Baltimore City Hospital group. Following their study demonstrating

an association between ethanol self-administration and increased social

interaction (Griffiths, Bigelow and Liebson 1974), it was hypothesized

that the reinforcing social consequences of drinking may be one of the

factors maintaining drinking behavior. A subsequent series of related

experimental studies resulted in a confirmation and elaboration of

this hypothesis (Griffiths, Bigelow and Liebson 1975; 1977). By

moving from the descriptive, hypothesis-generating stage to a more

174
experimental, hypothesis-testing approach, this research illustrates

the potential contributions of self-administration research. But

until researchers begin to demonstrate greater interdisciplinary

coordination, experimental sophistication and sensitivity to the

complexity of factors affecting human social behavior, the potential

contributions of drug self-administration research will not be realized.

ACKNOWLEDGMENT

The writing of this paper was supported in part by Research

Scientist Development grant 1 K01 AA 00025-01

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AUTHOR

Thomas F. Babor, Ph.D.

Research Psychologist

Alcohol and Drug Abuse Research Center

Harvard Medical School and

McLean Hospital

Belmont, Massachusetts 02178

179

II. Food and Tobacco
Chapter 11

Defective Long-Term Caloric

Regulation in Obesity

Marshal F. Folstein, M.D., and Paul R. McHugh, M.D.

INTRODUCTION

Our methods for the study of overeating were first devised for

investigations of ingestive behavior in animals but have been

applied now to the study of humans.

We began our work in an attempt to test the assumption that the

ventromedial hypothalamus is a “satiety center” (McHugh, et al. ,

1975; McHugh, Moran, and Balston, 1975; McHugh and Moran, 1977;

and in press). This commonly held idea derives from the observed

change in feeding behavior that follows destruction of the ventromedial hypothalamus. Animals with such neural lesions overeat and

grow fat. The seemingly logical assumption that the overeating was

a result of a disturbance in satiation is susceptible to direct

testing. If satiety is viewed as an inhibition on feeding produced

by food itself, then a graded inhibition of feeding should follow

the intake of nutrients. If there is a disorder of satiety then

the inhibition produced by a given nutrient quantity should be less

than normal. To study this question, we installed chronic intragastric cannulae through which nutrients can be infused directly

into the gastrointestinal tract in normal and hypothalamic hyperphagia monkeys.

ANIMAL EXPERIMENTS

These rhesus Monkeys weighing from 4 to 8 kgms were trained to take

all of their food in the form of Purina Monkey Chow in a 4-hour

period. Prior to the feeding period we infused a nonnutrient solution (saline) or 135, 270, or 540 ccs of a nutrient (Carnation

Instant Breakfast in milk) containing 1.1 kilocalories per cc. The

reduction in food intake produced by the nutrient was graded in a

dose response fashion. The crucial observation, however, was that

no differences between normal and hypothalamically lesioned monkeys

were found. Both groups showed an identical reduction in feeding

for each nutrient infusion. Thus the overeating with hypothalamic

lesions cannot be attributed to a loss of satiety as we defined it.

However, when chow and infusions were converted to calories, we

182
found that the overeating animals were consuming 850 + 25 kilocalories of Purina Monkey Chow per day. Infusing Carnation Instant

Breakfast into their stomachs reduced the chow they ate in a quite

precise way. Specifically, we found that the total calories (chow

eaten plus calories infused) did not change significantly from

850 ± 25 kilocalories. This result indicated that the total

calories taken each day was quite precisely regulated and that

feeding was controlled by a graded satiety signal to maintain this

regulation.

By employing the same paradigm of intragastric infusions prior to

meals, we demonstrated this capacity for the precise regulation of

caloric intake in normal monkeys. The precision could be demonstrated in a range of caloric infusions from 0 to 300 Kcal. This

relationship was sustained whether the infusions were given 0-20

hours before meals and whether the infusions were of fat, protein,

or carbohydrate.

These results in the normal and the overeating, hypothalamically

lesioned monkey demonstrate that both appear to be regulating a

caloric intake and maintain that intake over a range of preloads.

The level maintained need not be physiologically appropriate, since

the overeating animal is rapidly gaining weight. However, the precision of behavior is impressive and suggests the search for similar

precision in the feeding behaviors of humans.

HUMAN EXPERIMENTS

The literature on human feeding is contradictory. Some investigators

report that humans can, and others that they cannot, compensate for

extra calories given as preloads (Wooley 1971; Wooley et al. 1972;

Nisbett 1972; Spiegel 1973; Schacter and Rodin 1974; Hunt et al.

1975; Booth et al. 1976; Hibscher and Herman 1977). We decided to

carry out our own investigation in subjects who had applied for a

weight reduction program but had not lost more than 5 pounds of

weight. Subjects were all at least 20 percent overweight; average

weight was 250 pounds. The average age was 42. Subjects were

volunteers for this research program and were provided with full

informed consent. (For further information on the subjects, see

table 1.) A normal control group was taken from the community and

was matched for age, sex, and social class.

Dx

Obese

Controls

TABLE 1

Sample Short-Term Regulation

Hours

N Age Wt. Ht. Fasting

34 42 231 65 6

15 42 146 65 5

183

304-494 0 - 79 - 13
All the subjects were asked to fast for 5 hours before the test,

which was conducted in the evening at the weight reduction class.

The subjects were asked to participate for two sessions on successive weeks. On both weeks, self-rating visual analog scales for

hunger and fullness were filled out before and after the test meals

(Robinson, MCHugh and Folstein 1975; Folstein et al. 1977). During

the first session, the subjects were required to ingest 400 ccs of

Carnation Instant Breakfast and whole milk with a caloric value of

540 calories. During the second session, they were asked to take

400 ccs of Carnation Instant Breakfast and milk containing a total

caloric value of 270 calories. Fifteen minutes after these mandator-y meals, the subjects were given the opportunity to approach

a table on which were cups containing 200 ccs of the same Carnation

Instant Breakfast solution that they had ingested in the mandatory

meal. Subjects were instructed that they could ingest as much or

as little from these cups as they wished. A comparison was drawn

between their caloric intake of the concentrated and of the dilute

nutrient.

This method was similar to that employed in our monkeys study where

we also investigated feeding after a standard known preload, and

where the total calories taken were estimated. There are some

important differences between the two experiments, however. The

nutrient used as the preload and that ingested in the “meal” were

the same in the human experiment rather than different as in the

monkey study. The human subjects ate in a group setting. There

was no attempt to estimate the calories taken before the test,

although the subjects were asked to fast for 5 to 6 hours prior to

the start of the study. Also, both the preload and the feedings

were orally ingested rather than one being infused intragastrically.

Despite these differences in design, the results obtained were similar. Both normal and obese individuals control their caloric intake

in response to the calories ingested in the preload. In an effort

to observe the accuracy of this reduction, we devised a method to

estimate the individual’s error in caloric regulation. If there

were a perfect control, subjects should take as many calories in

dilute form as in concentrated form. Accordingly, we established

the following ratio: Calories taken in concentrated form minus

those taken in the dilute form divided by the calories in the concentrated form. This ratio provides an error rate (multiplying

this by 100 would give a percentage) which can be applied to both

individuals and groups.

The error rate for the normal individuals was less than 1 percent.

That for obese individuals was 4 percent. Also, we noted that

there was no statistical difference in the obese group between

the calories taken with the concentrated or the dilute preload

(table 2).

184
TABLE 2

Normal Subjects Regulate Calories

Preload Calories Volume

Concentration Ingested Ingested Error

1.1 Kcal/cc 649 ± 61 590 ± 55 cc

.78 Kcal/cc 651 ± 54 838 ± 69 cc -.3%

Normal subject ingested the same number of calories of

each concentration. But more volume of the dilute

nutrient was ingested.

Obese Subjects Regulate Calories

Preload Calories Volume

Concentration Ingested Ingested Error

1.1 Kcal/cc 723 ± 41 657 ± 50 cc

4%

.78 Kcal/cc 752 ± 39 965 ± 35 cc

Similarly obese subjects ingested the same number of

calories of each concentration and thus ingested a

greater volume of the dilute nutrient. However obese

subjects ingested more calories than normal subjects

723 vs. 649.

The analog scales for hunger and fullness for both the normal and

obese reflected the accuracy of the regulation. Whether the preloads were in the concentrated or dilute form, both the normal and

the obese individuals reported that similar calories had similar

effects on their hunger and fullness (table 3).

Next we observed the effects of increasing the delay between preload

and feeding upon caloric regulation. In this “long- term” experiment

the subjects were asked to eat only Carnation Instant Breakfast for

3 days and return to us the empty packages to determine how much

they had eaten (table 4). At the end of day 1, when they ingested

as much as they wanted, normal and obese subjects were asked to

ingest an extra 1000-2000 calories of the mixture of Carnation

Instant Breakfast and milk before going to bed. On the days

following, their caloric intake of Carnation Instant Breakfast was

documented. Prior to each meal subjects were instructed to fill

out analog scales of subjective hunger. Ratings were made each day

during the 3-day course of the experiment.

The results of the chronic experiment were different from those seen

in the acute study. Normal individuals again reduced their ingestion on the days after the excess of calories was given. Obese

subjects, on the other hand, ate just as much on the days after the

excess calories. This finding demonstrates that there was no effect

185
TABLE 3

Analog Scale Rating of Hunger and Fullness

Normal Weight

Preload Change in

Concentration

1.1 Kcal/cc

.78 Kcal/cc

Dx N.

Obese 35

Normals 16 43 153 ± 4

7 Normals

9 Normals

23 Obese

12 Obese

Hunger Fullness

Obese

Change in

Hunger Fullness

58 51 28 35

57 57 32 37

TABLE 4

Sample Long-Term Regulation

Age Weight

37 231 ± 9

Height

65 ± 6

66 ± 7

TABLE 5

Calories Ingested

Evening

Day 1 Preload Day 2

2501 1000 1927

1886 2000 1107

2839 1000 2788

3485 2000 3998

TABLE 6

Morning Hunger

Day 1 Day 2

Obese

Normals

64 -ns- 55

90- .001- 42

186

Day 3

1927

1558

2710

4100

Day 3

66

80
of the extra calories on ingestion (table 5). Furthermore, the

obese individuals did not show a significant change in their

hunger reports on the days after the excess, as did the normal

weight controls (table 6).

In summary: Whereas precise caloric intake occurs in normal and

obese individuals on an acute basis, obese subjects do not maintain caloric regulation when there is a long overnight delay between the preload and the subsequent meals.

DISCUSSION

These studies demonstrate a potential for accurate caloric regulation in human beings similar to that observed in our monkey experiments. We cannot say anything at present concerning the physiological importance of this regulation. However, a difference emerges

between normal and obese subjects. Obese subjects showed a small

short-term error. More important. however, they exhibit a large

long- term error. Preloads of up to 2000 calories given the night

before were shown to have no effect on ingestion on the next day.

These differences between short-and long-term control may in part

explain some of the difficulties in interpreting the literature on

obesity. The time intervals between preloads and feeding behavior

and sleep may be critical variables.

It is possible, however, to demonstrate a major difference in the

feeding controls of normal and obese individuals. This difference

may or may not be a causal factor in obesity. Further studies of

both thin and obese individuals are needed to determine the significance of caloric regulation in onset and maintenance of obesity.

ACKNOWLEDGMENTS

The work reported in this paper was supported by National Institute

of Health grants 14327-01 and Rol AM 19302-03.

We acknowledge the tireless work of M. Simonson and T. Moran, who

collected the data.

REFERENCES

Booth, D.A.; D’Mello, G.; Pilcher, C.W.; Stolerman, I.P. Paradoxical aversive property of dexamphetamine (proceedings). Br J Pharmacol, 57(3): 424-425, 1976.

Folstein, M.; Wakeling, A.; DeSouza, V. Analog, scale measurements

of the symptoms of patients suffering from anorexia nervosa. In:

Vigersky, R.A., ed. Anorexia Nervosa. New York: Raven Press, 1977.

Hibscher, J.A., and Herman, C. P. Obesity, dieting, and the expression

of “obese” characteristics.

1977.

J Comp & Physiol Psych, 91(2):374-380,

187
Hunt, J.N.; Cash, R.; Newland, P. Energy density of food, gastric

emptying, and obesity. Lancet, 2(7941):905-6, 1975.

McHugh, P.R.; Gibbs, J.; Falasco, J.D.; et al. Inhibitions of feeding examined in rhesus monkeys with hypothalamic disconnexions.

Brain, 98(3):441-54, 1975.

McHugh, P.R., and Moran, T.A. The accuracy of the regulation of caloric control in feeding. Am J Physiol, in press.

McHugh, P.R., and Moran, P.H. An examination of the concept of satiety in hypothalamic hyperphagia. In: Vigersky, R.A., ed. Anorexia

Nervosa, New York: Raven Press, 1977.

McHugh, P.R.; Moran, T.H.; Barton, G.N. Satiety: a graded behavioral

phenomenon regulating caloric intake. Science, 190 (4210): 167-9, 1975.

Nisbett, R.E. Eating behavior and obesity in men and animals. Adv

Psychosom Med 7:173-93, 1972.

Robinson, R.G.; McHugh, P.R.; Folstein, M.F. Measurement of appetite

disturbances in psychiatric disorders.

1975.

J Psychiat Res, 12 (1): 59-68,

Schachter, S., and Rodin, J. Obese Humans and Rats. New York: Halsted Press, 1974.

Spiegel, T.A. Caloric regulation of food intake in man. J Comp

Physiol Psychol, 84:24-37, 1973.

Wooley, O.W. Long-ten food regulation in the obese and nonobese.

Psychosom Med, 33:436-44, 1971.

Wooley, O.W.; Wooley, S.C.; Dunham, R.B. Can calories be perceived

and do they affect hunger in obese and nonobese humans? J Comp

Physiol Psychol ,80:250-8, 1972.

AUTHORS

Marshal F. Folstein, M.D.

Department of Psychiatry and Behavioral Sciences

The Johns Hopkins Hospital

The Johns Hopkins University School of Medicine

Baltimore, Maryland 21205

Paul R. McHugh, M.D.

Chairman and Psychiatrist-in-Chief

Department of Psychiatry and Behavioral Sciences

The Johns Hopkins Hospital

The Johns Hopkins University School of Medicine

Baltimore, Maryland 21205

188
Chapter 12

Methods and Findings in Study

of Food Regulation in Obesity

Susan C. Wooley, Ph.D., and Orland W. Wooley, Ph.D.

OBESITY AND SUBSTANCE ABUSE

The classification of obesity as a form of substance abuse poses an

immediate problem regarding the definition of abuse. Presumably,

somewhat different problems occur with respect to the definition of

abuse of alcohol, tobacco, and drugs, since, if increased risk to

physical or mental health is taken as a criterion, virtually any use

of these substances is undesirable. Cultural definitions of abuse

show an imperfect and often delayed relationship to medical Knowledge

of associated health risks. In practice, however, it is not difficult

to isolate cases of drug, alcohol, or tobacco abuse which clearly

merit investigation or intervention, and the problem of arriving at

a precise definition of the degree of substance use which should

constitute a therapeutic target can be postponed.

In the case of obesity, the problems surrounding definition of

substance abuse are absolutely fundamental. If increased actuarial

health risk is taken as the criterion, virtually all overweight people

are classified as abusers. However, in contrast to the cases of

smoking, drinking, or drug use, it frequently proves impossible to

detect anything unusual in the substance consumption patterns of a

group selected under this definition. Decades of investigation have

failed to show that, on the average, the obese eat any more than

people of normal weight or have a distinctive pattern of food

consumption.

Much interest was generated in the configuration of meal eating

patterns by the report that restriction of access to food to a single

time interval per day preceeded weight gain in the rat without increased

caloric intake. (Tepperman and Tepperman 1964; Cohn and Joseph 1959;

Cohn 1961). Early surveys of eating patterns of the obese had called

attention to patterns of meal skipping, concentration of eating in

evening hours and irregular timing of meals (Schachter and Gross

1968; Mayer, Monello, and Seltzer 1965). When scrutiny of eating

patterns in behavior modification programs revealed these features, as

well as rapid eating, eating in the absence of hunger, frequent

snacking, etc., it was assumed that eating patterns would be

"normalized” by teaching patients to eat slowly three regular meals a

189
day. However, further study has shown that eating patterns of the

lean are as varied and erratic as those of the obese. Statistical

comparisons on a multitude of dimensions, measured both in naturalistic

observations and taken from food diaries, have failed to isolate any

reproducible differences in eating styles of the obese and nonobese

(Kissileff, Jordan, and Levitz 1977; Player, Stunkard, and Co11 1977)

It is clearly possible that subtle but important variables have been

overlooked or that the important obese-normal differences occur over

longer time spans than typically studied, but until such discoveries

are made, obesity must be regarded as a deviant consequence for which

no deviant antecedent behavior is known.

Social definitions of food abuse are particularly arbitrary.

Consumption of most ordinary foods by the overweight is socially

disapproved, while exceedingly high intake in the absence of overweight

is not judged inappropriate. Indeed, overeating is at the heart of

many of our social customs. Interestingly, the numerous forms of

malnutrition and dietary imbalance in adults created by weight

consciousness and food faddism in our culture also escape social

disapproval, although these patterns probably carry significant health

risks and are a subject of immediate concern when observed in children

and, to a lesser extent, adolescents.

Finally, one could define abuse of food in terms of behavioral

departures from population averages. It can be inferred that

application of a quantitative criterion would result in the isolation

of a group containing lean and overweight people roughly in proportion

to their numbers in the general population (Garrow 1974; Johnson,

Burke, and Mayer 1956; Hampton et al. 1967; Stefanik et al. 1961;

Kissileff, Jordan, and Levitz 1977). A criterion of qualitative

abnormality would lead to the detection of peculiarities of eating

behavior, some associated with obesity, and some which lead to no

maladjustment other than the potential for being regarded as eccentric

in addition to the clinically defined “eating disorders” which are associated with emotional distress (usually on the part of the patient,

though occasionally only by those around him). Extreme binge eating,

waking to eat during the night, refusing food, and regurgitating after

eating are some of these. The latter is of special interest because

it appears to be on the increase. It is possible that publicity has

merely increased the detection rate, but recent studies have reported

very high incidence rates in college females (Boskind-Lodahl 1976).

Clearly this is abuse of food in the most literal sense of the word,

but is a behavior adopted primarily to achieve social conformity by

controlling weight. Eating disorders are of great intrinsic interest

and their careful study may be useful in understanding normal

regulation and more subtle regulatory defects. With the exception of

the bulimarexic syndrome, however, they are relatively rare and do not

have the priority of importance of obesity. Indeed, in many instances,

eating disorders seem to be the outcome of attempts to control or

prevent obesity and may be counted among the unfortunate results of

our ignorance about obesity itself.

190
OBESITY AS AN ERROR IN REGULATION

The difficulty with which researchers must contend is that obesity

represents an error in regulation which may be quite small - too small

to be detected by many of the methods of measurement which have been

developed. Periods of imbalance leading to weight gain may be

restricted to a relatively short time period in an individual’s life

span, with normalization during static obesity. Finally, it is unclear

what form most regulatory errors take, and there may be several subtypes

which cause obesity.

The first type of error, which is usually assumed to be the main cause

of obesity, is an increase in food intake above normal levels while

energy expenditure remains constant. It should be noted that

increased food intake does not automatically lead to weight gain.

Studies of overfeeding have shown that lean volunteers nearly always

fail to gain at expected rates and a few gain nothing at all on

dietary increases as high as 1,500 calories a day given for periods of

many weeks (Miller and Mumford 1966; Miller, Mumford, and Stock

1967; Sims et al. 1968; Ashworth et al. 1962). It has not been

possible to account for differences in rate of weight gain by

variations in spontaneous motor activity. Individual differences in

thermogenic responses to food are considered the most likely

explanation, i.e.,

of excess heat.

diet-induced waste of calories through production

Thus, increased food intake within a particular range will lead to

weight gain only in predisposed individuals. In searching for the

causes of increased food intake which lead to weight gain, a

tentative distinction should be made between an initial gain to a

given level of obesity and regain of weight lost after cessation of

diets. While the processes may be similar, there are reasons to

suggest that they may not be. Initial gains may involve proliferation

of fat cells, while later gains involve only increases in cell size.

The process of weight loss may have effects on subsequent behavior and

physiologic responses to food. Since dieting by definition requires

that the person ignore internal signals of hunger and satiety,

important conditioning processes may be affected. Meal patterns and

food preferences may be permanently altered. The effort of dieting

may produce an obsessive preoccupation with food or an intention to

self-starve which leads to binge eating. Naturally, not all gains

occurring after weight loss are due to unusually high food intake,

since severe caloric restriction may lead to decreases as high as 20

to 30 percent in basal metabolic rate (Wiley and Newburgh 1931;

Howard et al. 1977) which are not reversed immediately with refeeding.

Thus, weight is often regained during periods of relative hypophagia.

For these and other reasons, prospective studies of the development of

obesity are to be much preferred to studies of static obesity or weight

regain. They are, of course, exceedingly hard to do.

The second major type of regulatory error is a decrease in energy

expenditure while food intake is held constant or at “average”

levels. Decreased physical activity in middle age is widely held to

be a significant cause of obesity. As Warwick, Toft, and Garrow

191
(1977) note, individual differences in metabolic rate within the

“normal” range may account for differences as great as 700 calories

per day in individuals, without measurable differences in gross motor

activity or food intake. Finally, the fact that obese and nonobese

groups are found to have equal caloric intake is not incompatible

with obesity, even if the groups are assumed to have identical levels

of physical activity, since any group of obese subjects will contain

a sizable proportion of individuals who have recently been or are on

low calorie reducing diets at the time of the study. These individuals

will have diet-induced reductions in resting metabolic rate, so that the

energy expenditure of the obese sample is almost of necessity lower

than that of the lean control group. What remains to be explained is

why intake is not adjusted to lower levels of expenditure, as evidently

occurs in people who maintain a stable weight despite presumed

fluctuations in activity.

Finally, there is a third kind of regulatory error in which neither

activity level or food intake differs from average, but there is a

bias in the metabolic system toward increased fat storage. It has

been shown, for example, that genetically obese Zucker rats deposit

more fat in the first week of life without accompanying hyperphagia

(Boulange, Planche, and de Gasquet 1977). Presumably there is the

potential for considerable variation in how much energy is wasted and

how much is conserved. Obesity of this type may have no behavioral

antecedents.

METHODS OF MEASUREMENT

Methods for studying energy expenditure are obviously of great

importance, but fall outside the scope of this paper. It is worth

noting, however, that simple measures of resting metabolic rate show

important relationships to changes in diet and should probably be

included in more studies. Adequate measurement of energy output

during normal activity is exceedingly difficult. The best systems are

too cumbersome and obtrusive for extensive use, while the more practical

continuous monitoring of heart rate has been reported by Dauncey and

James (1977) to have very large measurement errors when used in

relatively sedentary individuals. Experience in using activity diaries

in patients suggest that compliance is quite good, and such diaries

should perhaps at least be used in research designs in which subjects

serve as their own controls. A convenient system is found in the

Jordan-Levitz manual for analysis of food intake and energy expenditure.

Development of methodology for study of eating behavior in humans has

met with many problems which have made it difficult to test the

generalizability of results of animal experiments. In addition to the

obvious limitations on the kinds of manipulations which can be

performed on humans, simple measurement of hunger and food intake has

proved complex. Humans have rather definite expectations about how

much of what kinds of foods should be eaten at what times, and, in

addition, typically think about of the meaning of their behavior in

experimental settings. Thus, in the series of experiments by Schachter

and his colleagues, reduction in subsequent intake following

experimental meals was taken as evidence of sensitivity to internal

192
cues on the part of nonoverweight subjects (Schachter 1968). However,

using essentially the same experimental design but with the caloric content of the preloads disguised, it was found that neither obese nor lean

subjects adjusted intake to the actual calories of 200 versus 600 calorie preloads (Wooley 1972). Instead, both responded to the apparent

calories, manipulated by appearance and mode of presentation.

Speigel (1973) obtained the same results using disguised liquid

preloads varying in caloric density from .25 cal/ml to 1.8 cal/ml;

Wooley, Wooley and Dunham (1972a) found cyclamate and glucose solutions

to have indistinguishable effects on hunger ratings and liking for

sweet solutions, both producing greater subjective satiety at higher

concentrations. These results strongly suggest that in this

experimental paradigm short term adjustments to undisguised food

preloads by lean subjects are attributable to cognitive and sensory factors.

The failure of obese subjects to reduce intake following preloads

requires another kind of explanation. Given the knowledge or belief

that they have already consumed a substantial quantity of food, why

don’t obese subjects respond by a reduction in additional food intake

as do lean subjects? A probable answer to this question lies in the

findings of Herman and Polivy (1975) on disinhibition of dietary

restraint. These investigators found that subjects who were selected

for a history of chronic dieting ate more, not less, following

preloading with rich foods such as milkshakes. Consumption of a

forbidden food made them feel that they had already violated their

planned control and had nothing to lose by eating more. Obese samples

selected without regard to this variable usually contain high

proportions of restrained eaters. Statistical averaging of their

tendency to eat more after experimental preloads with the more normal

responses of unrestrained obese subjects usually leads to a finding

that the preloads have either no effect or a statistically insignificant increase.

To determine whether subjects could perceive differences in caloric

values of foods eaten when this was made the explicit experimental

task, Wooley, Wooley, and Dunham (19724) asked subjects to guess

whether they had eaten a high or low calorie liquid meal given on a

random schedule over twenty successive days. Hunger ratings and

guesses were made at fixed intervals during the twenty-four -hours

following each experimental meal. At no point in time were subjects’

guesses better than chance. Hunger ratings were related to guesses

about the caloric content of the meals, whether correct or incorrect,

and showed a cyclic relationship to mealtimes, the latter possibly

also influenced by expectations.

Do these findings mean that there-is no short term regulation in

humans? Not necessarily. There are two reported studies in which

short term effects of disguised preloads on subsequent intake have

been observed demonstrating that such regulation can occur and will be

observed, when the experimental conditions are right (Booth, Campbell,

and Chase 1970; Booth, Chase, and Campbell 1970). Unfortunately,

comparison of described procedures provides no clue as to what was

done differently in these experiments than in those with negative

outcomes. One can only conclude that intake of an experimental meal

193
in a laboratory is a rather unstable dependent variable, susceptible

to extraneous influences which are not easily controlled. The same

criticism can be made of hunger ratings; but, beyond this, even the

logic of hunger ratings is open to question, since there is an

implicit assumption that hunger exists as a continuous subjective

experience which is correlated with hours of deprivation and

unrelated to external stimuli. Common sense suggests this is not

true. For example, a few additional minutes of food

deprivation cannot account for the increase in hunger experienced as

one puts down a difficult piece of work and prepares to leave for

lunch. Indeed the thought and sight of food produce marked

physiologic changes. These conditioned responses anticipatory to

food ingestion are logically viewed as a component of hunger but

are clearly situational. l-lunger is perhaps best defined as

the probability of having an appetitive response in the presence of

food stimuli. The sensitivity of hunger ratings would doubtless be

improved if they were obtained under conditions standardized with

respect to imagined or actual food cues , preferably with reference to

hunger for a particular food or set of foods. Booth (1976) has found

subjects’ ratings of how much they would like to eat of each item on a

list of foods to be a sensitive measure of hunger and satiety.

New Approaches to Study of Appetite Regulation

To avoid the problems inherent in use of subjective ratings and intake

of conventional foods in laboratory settings, three new approaches to

the study of appetite regulation have been developed. The first

retains experimental observation of food intake as a measure, while

seeking to change the nature of the feeding experience so that

stereotyped or cognitively controlled behaviors are minimized and

dependence on internal cues maximized. An example of such an approach

is the use of all liquid diets delivered from concealed reservoirs or

pump operated feeding machines (Hashim and Van Itallie 1965; Jordan

1969). In these instances? the nature of the food is changed and the

normal behaviors involved in food ingestion replaced by such behaviors

as lever pressing. In some instances, food has been delivered

directly to the stomach to remove oropharyngeal sensations. In these

paradigms the subjects’ ability to cognitively monitor his intake is

obviously impaired. Finally, when used as a substitute for regular

eating for long periods of time, it seems reasonable to assume that

biologic hunger signals will eventually override extraneous influences

in determining intake. The major disadvantage is that the

artificiality of the procedures leads to results which may not

generalize to other situations. In particular, the low palatability

of liquid diets may have a distorting influence on observed intake

patterns and subjects may never experience the normal appetitive

responses which precede meal eating. Nevertheless, this model has

permitted study of responses to diet dilution and enrichment, an

important model in animal experimentation. A number of such

experiments have now been done. In contrast to the findings of

prompt compensation in animals, humans have usually shown sluggish

responses, often failing to adjust the volume of intake until the

second week after the caloric density is changed (Wooley 1971;

Spiegel 1973; Leitzmann et al. 1977).

194
A second new approach to hunger measurement has been the use of

conditioned salivary responses to the sight of food. The potential

advantage of this technique which led to its development was the fact

that salivation was an involuntary behavior which was not subject to

the same cognitive controls as food intake measures. In an initial

study (Wooley and Wooley 1973), it was found that salivation rate

(measured by obtaining pre and postexperimental weights of cotton

dental rolls inserted in the mouth for three two minute collection

intervals) increased with hours since last meal and was related

to palatability of the food stimuli. During collection periods

subjects were instructed to attend to actual foods placed directly

in front of them. These values were compared to baseline levels

obtained while subjects read. It has since been found that the

sensitivity of the measure is increased by the use of only one dental

roll, placed under the tongue, and one two-minute collection is

sufficient (Wooley, Wooley, and Williams 1977a). The method is,

therefore, quite simple to use and well tolerated by subjects. The

chief methodologic requirement is that the testing situation

sufficiently approximate prior ones in which the conditioned response

was acquired. Thus the setting should be a familiar one in which

subjects have eaten at least once, the foods should be familiar ones

liked by the subject, and they should expect to eat the food

immediately after the tests are completed. However, we have found

that even thinking of food produces salivary increases if the subject

has a specific food in mind. Use of imagined stimuli (Wooley,

Wooley, and Williams 1977b), which permits repeated measures and which

subjects can carry out anywhere with a timer, increases the flexibility

of the method. Responses to imagined food stimuli are greater with

images of highly preferred vs. neutral. foods and increase with hours

of deprivation. Conditioned salivation has been found to be reliably

affected by differences in caloric levels of preloads, even when these

are disguised. Preload differences as small as 150 calories (of

carbohydrate) influence salivation rate to palatable food viewed one

hour later. To test the assumption that salivation rate reflects

hypothalamic activity, the effects of amphetamine and fenfluramine

were studied. Amphetamine was found to suppress salivation to the

sight of food, an effect measurable for up to two days after a dose

of 10 mg. Fenfluramine, which is believed to act through different

neural pathways and which has the effect of reduced meal size rather

than delayed meal onset in rats, was found to have no effect on

salivary responses to food in humans (Wooley et al. 1977).

Comparison of obese and lean subjects showed that a preload sufficient

to entirely suppress responses to the sight of food one hour later in

lean subjects (900 calories) did not suppress salivation in the obese

(Wooley, Wooley, and Woods 1975). In a subsequent study, caloric value

of preloads was held constant while protein content was varied.

obese and lean subjects showed satiety following high protein meals,

with no obese-nonobese differences apparent (Wooley and Wooley 1977).

This finding is interesting because it is one of several recent studies

suggesting that regulation of protein intake is independent of caloric

regulation and takes place through a separate mechanism. Wurtman and

Wurtman (1977) reported that anoretic doses of fenfluramine suppressed

195
caloric intake but not protein intake in the rat, whereas

d-amphetamine suppressed both proportionately. This tends to suggest

protein regulation is mediated by hypothalamic centers, since it is

disturbed by amphetamine, whose site of action is in the hypothalamus

and since protein content of diet influences salivary responses. On

the other hand, Anderson, Leprohon and Coscina (1977) report that the

hyperphagia and weight gain produced in MH lesioned rats occur while

protein intake is maintained at control levels. Finally, increases

in protein density of the diet have been reported to produce decreased

ad lib intake in both children (Ditschuneit, Jung, and Ditschuneit

1977) and rats (Hershberger, Jenkins, and Martin 1977). Whatever

the mechanisms involved, these findings underscore the importance of

keeping separate manipulations of protein and calories in studies of

regulatory processes,

The finding of sustained appetitive responses to food in the obese

even after substantial preloading is consistent with one of the most

frequently replicated findings of the work by Schachter, Rodin and

associates regarding eating behavior and obesity. This is the

observation that the obese show an exaggerated response to palatable

food stimuli (see Wooley, Tennenbaum, and Wooley 1978). This finding

has been obtained using such diverse measures as intake of test foods,

food selections at cafeterias varying in palatability of offerings,

salivary responses to food, and insulin secretion to the sight of food.

Taken together these measures suggest a strong physiologic as well as

behavioral response to food stimuli which is characteristic of high

levels of hunger. However, a caution needs to be introduced in

interpreting these findings. In order to separately assess the effects

of high body weight per se and a pattern of chronic dieting, Wooley,

Wooley, and Williams (1977c) selected a group of nonobese subjects who

scored high on the Herman-Polivy (1975) measure of dietary restraint.

Measurements of appetitive salivary response following preloads of

disguised caloric value in restrained eaters showed the same failure of calories to inhibit appetite as was observed in previous obese

samples. This was not true of a matched control group of nonobese

unrestrained eaters. The correlation of dietary restraint and

overweight is so high that one must admit there is a very serious

confounding of obesity and restraint in virtually all cross sectional

studies. Much of this work needs to be redone, and it is

strongly recommended that restraint scores be controlled or at least

recorded in subjects of any study of eating behavior.

Finally, a third new approach to the study of feeding has been the

observation of food choices, food intake, and parameters of eating

style in natural settings. In most such studies, raters record the

data and rate weight unobserved by the subjects or in such a way that

the observation process cannot influence the behavior (e.g., recording

choices as people exit a cafeteria line). The obvious advantage to

this procedure is that it dispenses with the problems of demand

characteristics which pervade laboratory studies and allows access to

large sample sizes, sometimes numbering in the thousands. As such,

it is an excellent means of testing simple hypotheses which require

only single observations of overt behaviors. The disadvantages are

that the same subject cannot be studied under varying conditions, and,

196
although sometimes subjects are approached for questioning as they

leave the site of the study, the amount of information which can

reasonably be obtained from a sufficient percent of the sample to avoid

selection bias is quite limited. However, institutional settings in

which the same individuals can bc observed over time and in which some

experimental manipulations can be carried out, offer a promising

modification of this approach. Rodin (personal communication) has ‘begun a longitudinal study in a dormitory setting in which observations

extend over a period of years and in which there is access to additional subject information. It might be noted that high school students, college students, and pregnant women constitute particularly

important populations for study, since they are likely to contain a

larger than average number of people who become overweight for the

first time.

Researchers of alcoholism and drug abuse have made wide use of the

model of relatively long term observation of subjects in inpatient

settings with ad lib access to substances of interest. Such an

experimental model might profitably be employed in studies of food

Two problems would arise, however. First, confinement of subjects

would alter activity patterns. The advantage of being able to

measure energy expenditure, therefore, would be somewhat offset

by the limitations placed on spontaneous variation in activity.

Secondly, the chronic motivation of most overweight people to lose

weight often causes them to use any interruption of normal stresses

and responsibilities as an opportunity to go on a reducing diet.

Careful subject selection could counteract this problem to some

extent. Eating behavior, like other important forms of substance

consumption, is firmly rooted in social customs, personal habits, and

variation in psychological states. Thus, while much is lost in

laboratory study, much might be gained in the form of better

understanding of physiologic variables governing eating patterns in

humans which have, to this day, largely eluded discovery.

REFERENCES

Anderson, G.; Leprohon, C.; and Coscina, D. Protein intake regulation

during the development of hypothalamic obesity. Abstract to be

published in the proceedings of the Second International Congress on

Obesity, Washington, D.C., October 1977.

Ashworth, N.; Creedy, S.; Hunt, J.; and Mahon, S. Effect of nightly

food supplements on food intake in man. Lancet, 2: 685, 1962.

Booth, D. Appetite and satiety as metabolic expectancies. Paper

presented at the International Symposium on Food Intake and Chemical

Senses, Fukuoka, Japan, September 1976.

Booth, D.; Campbell, A.; and Chase, A. Temporal bounds of

postingestive glucose induced satiety in man. Nature, 228: 1104, 1970.

197
Booth, D.; Chase, A.; and Campbell, A. Relative effectiveness of

protein in later stages of appetite suppression in man. Phys and

Behav, 5: 1299, 1970.

Boskind-Lodahl, M. Cinderella’s stepsisters: a feminist perspective

on anorexia nervosa and bulimia. Signs: J of Women and Culture in

Society, 2: 342, 1976.

Boulange, A.; Planche, E.; and de Gasquet, P. Excess fat storage and

normal energy intake in the newborn Zucker rat (fa/fa) . Abstract to

be published in the proceedings of the Second International Congress

on Obesity, Washington, D.C., October 1977.

Cohn, C. Meal eating, nibbling, and body metabolism. J Am Diet Assoc,

38: 433, 1961.

Cohn, c., and Joseph, D.

force feeding.

Changes in body composition attendant on

Am J Phys, 196: 965, 1959.

Dauncey, M., and James, W. Estimation of 24 hour energy expenditure

using a human calorimeter and heart rate. Abstract to be published in

the proceedings of the Second International Congress on Obesity,

Washington, D.C., October 1977.

Ditschuneit, H.; Jung, F.; and Ditschuneit, II. Treatment of obese

children with low CHO, protein rich diet. Abstract to be published in

the proceedings of the Second International Congress on Obesity,

Washington, D.C., October 1977.

Carrow, J. Energy Balance and Obesity in Man. New York: American

Elsevier, 1974.

Hampton, M.; Huenemann, R.; Shapiro, L.; and Mitchell, B. Calorie and

nutrient intakes of teen-agers. J Am Diet Assoc, 50: 385, 1967.

Hashim, S.; and Van Itallie, T. Studies in normal and obese subjects

using a monitored food dispensing device.

1965.

Ann NY Acad Sci, 111: 654,

Herman, C., and Polivy, J. Anxiety, restraint, and eating behavior.

J Abn Psych, 84:666, 1975.

Hershberger, T.; Jenkins, T.; and Martin, R. Effect of diet

composition on food intake and energy efficiency of Zucker rats.

Abstract to be published in the proceedings of the Second

International Congress on Obesity, Washington, D.C., October 1977.

Howard, A.; Grant, A.; Challand, G.; Wraight, E.; and Edwards, 0.

Thyroid metabolism in obese subjects after a very low calorie diet.

Abstract to be published in the proceedings of the Second International

Congress on Obesity, Washington, D.C., October 1977.

Johnson, M.; Burke, B.; and Mayer, J. Relative importance of

inactivity and overeating in the energy balance of obese high school

girls. Am J Clin Nutr 4: 37, 1956.

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Jordan, H., and Levitz, L. Jordan-Levitz manual for analysis of

food intake and energy expenditure. In: Bray, G.A., ed. Obesity

in Perspective, (Fogarty International Series on Preventive Medicine,

Volume 2, Part 1). Washington, D.C.: Superintendent of Documents,

U.S. Government Printing Office, 1975.

Jordan, H. voluntary intragastric feeding: oral and gastric

contributions to food intake and hunger in man. J Comp, Phys Psych,

68: 498, 1969.

Kissileff, K.; Jordan, H.; and Levitz, L. Eating habits of obese and

normal weight humans. Abstract to be published in the proceedings of

the Second International Conference on Obesity, Washington, D.C.,

October 1977.

Leitzmann, C.; Overbeck, D.; Aign, IV.; Stratum, P.; and Cremer, H.

The influence of energy density on food intake. Abstract to be

published in the proceedings of the Second International Congress on

Obesity, Washington, D.C., October 1977.

Mayer, J.; Monello, L.; and Seltzer, C. Hunger and satiety sensations

in man. Postgrad Med, 37(6): A97, 1965.

Mayer, J .; Stunkard, A.; and Coll, M. Eating in public places: There

is no “obese eating style”, it’s where you eat that matters. Paper

presented at the Association for the Advancement of Behavior Therapy.

Atlanta, Georgia, 1977.

Miller, D., and Mumford, P. Obesity: Physical activity and nutrition.

Proc Nutr Soc, 25: 100, 1966.

Miller, D.; Mumford, P.; and Stock, M. Gluttony: thermogenesis in

overeating man. Am J Clin Nutr, 20: 1223-1229, 1967.

Schachter, Stanley. Obesity and eating. Science. 161:751-6, 1968.

Schacter, S., and Gross, L. Manipulation of time and eating behavior.

J Per and Soc Psych, 10: 98, 1968.

Sims, E.; Goldman, R.;

D. Experimental obesity in man. Trans Assoc Am Phys, 81: 153, 1968.

Gluck, C.; Horton, E.; Kelleher, P.; and Rowe,

Spiegel, T. Caloric regulation of food intake in man. J Com Phys

Psych, 84: 24, 1973.

Stefanik, P.; Bullen, B.; Healed, F.; and Mayer, J. Observations of

physical performance, skin fold measurements, activity expenditures,

and food consumption in college women. Res Quart, 2: 229, 1961.

Tepperman, H., and Tepperman, J. Adoptive hyperlipogenesis. Fed Proc,

23: 73, 1964.

199

304-494 0 - 79 - 14
Warwick, P.; Toft, R.; and Garrow, J. Individual differences in energy

expenditure . Abstract to be published in the proceedings of the

Second International Congress on Obesity, Washington, D.C., October

1977.

Wiley, F., and Newburgh, L. The doubtful notion of “luxosconsumption."

J Clin Invest, 10: 733, 1931.

Wooley , O. Longterm food regulation in the obese and nonobese.

Psychosom Med, 33: 436, 1971.

Wooley, O., and Wooley, S. Effect of prior protein intake on appetite

for palatable food. Paper presented to American Psychological

Association Convention, Los Angeles, California, 1977.

Wooley, 0.; Wooley, S.; and Dunham, R. Calories and sweet taste:

effects on sucrose preference in the obese and nonobese. Phys and

Behav, 9: 765, 1972a.

Wooley, 0.; Wooley, S.; and Dunham, R. Can calories be perceived and

do they affect hunger in obese and nonobese humans? J Comp Phys Psych,

80: 250, 1972b.

Wooley, O. Wooley , S.; and Williams, B. Appetite measure made more

sensitive. Abstract to be published in the proceedings of the Second

International Congress on Obesity, Washington, D.C., October 1977a.

Wooley, 0.; Wooley, S.; and Williams, B. Restraint of appetite and

sensitivity to calories. Abstract to be published in the proceedings

of the Second International Congress on Obesity, Washington, D.C.,

October 1977b.

Wooley, S.; Wooley, 0.; and Williams, B. Appetite for highly and

minimally palatable foods: effects of deprivation. Abstract to be

published in the proceedings of the Second International Congress on

Obesity, Washington, D.C., October 1977c.

Wooley, 0.; Wooley, S.; Williams, B.; and Nurre, C. Differential

effects of amphetamine and fenfluramine on appetite for palatable

food in humans. Int J Obesity 1: 293, 1977.

Wooley, 0.; Wooley, S.; and Woods, W. Effect of calories on appetite

for palatable food in obese and nonobese humans. J Comp Phys Psych

89: 619, 1975.

Wooley, S. Physiologic vs. cognitive factors in short term food

regulation in the obese and nonobese. Psychosom Med, 34: 62, 1972.

Wooley, S.; Tennenbaum D.; and Wooley, O. A naturalistic observation

of the influence of palatability on food choices of the obese and

nonobese. Int J Obesity, In press.

200
Wooley, S., and Wooley, 0. Salivation to sight and thought of food: a

new measure of appetite. Psychosom Med, 35: 136, 1973.

Wurtman, J., and Wurtman, R. Fenfluramine and fluoxetine spare protein

consumption while suppressing caloric intake by rats. Science, 198:

1178, 1977.

AUTHORS

Susan Clark Wooley, Ph.D., Associate Professor of Psychology in the

Department of Psychiatry, University of Cincinnati, 7207 College of

Medicine Building, 231 Bethesda Avenue, Cincinnati, Ohio 45267.

Orland Wayne Wooley , Ph.D. , Associate Professor of Psychology in the

Department of Psychiatry, University of Cincinnati, 7215 College of

Medicine Building, 231 Bethesda Avenue, Cincinnati, Ohio 45267.

201
Chapter 13

Tobacco Smoking and Nicotine Tolerance

Reese T. Jones, M.D., Thomas R. Farrell III.

and Ronald I. Herning, Ph.D.

Nicotine and tetrahydrocannabinol are commonly self-administered. A

puff on a tobacco cigarette can be considered one dose of the fairly

potent drug, (or substance, if you will), nicotine. By that measure,

tobacco smokers consume about 3 x 1O13 doses of nicotine annually.

The numbers regarding cannabis self-administration are less precise,

but if each cannabis cigarette provides 5 to 10 doses of tetrahydro~

cannabinol (THC) taken as deep inhalations, then large number of

THC doses are taken each year. Yet animals will not self-administer

either cannabis or tobacco. We wondered what it is about the smoking

process or the pharmacology of cannabis or tobacco or nicotine and

THC that makes for such behavior.

Our laboratory has been concerned with the phenomenon of tolerance

anddependence, both as to characteristics and mechanisms. We are

particularly interested in how self-administration of a drug might

change as tolerance and dependence to the drug or to related drugs

develops. Much of our work has focused on cannabis; thus an interest

in tobacco consumption seems to be a logical progression because of

the many similarities in the two substances. This report makes some

tine.

comparisons between cannabis and tobacco and describes the results of

some preliminary studies in humans given intravenous doses of nicoSome readers might be skeptical about the utility of any comparisons

between cannabis and tobacco. Tobacco is probably used more often,

by more people in the world, than any other psychoactive drug. Cannabis, although receiving much attention in recent years, is still not

used as intensively or extensively. Thus, the current pattern of

cannabis and tobacco drug seeking behavior appears quite different.

However, if one considers some of the important general factorsin any

drug seeking behavior, perhaps differences in current level of use

maybe partially understood, at least to the extent that useful predictions can be made about future patterns of self-administration as

the factors change.

Drug seeking and self-administration are modified by such variables as:

202
1. Availability

2. Rewards- both psychosocial and pharmalogic

3. State of the organism - including degree of tolerance and

dependence

4 . Setting- including peer influences and contingencies

5. Set- learning and expectation.

Despite similarities that will be described in a moment, there are

still obvious differences in the availability of cannabis and tobacco.

Cannabis is still not readily and continuously available to the older

potential user. Although many young adults are in the right setting

and have developed correct Expectations to enhance cannabis

seeking behavior, the majority of people have not. 'The importance

of such factors as the state of the organism is still unclear regarding both tobacco and cannabis self-administration. Tolerance and

dependence develop to both drugs. Both drugs can offer an array

of psychosocial and pharmacologic rewards, though some of the rewards may be changing rapidly as society's attitudes change regarding both tobacco and cannabis smoking.

If tobacco users are asked why they smoke, the answers are similar

to those given by cannabis users when they are asked why they smoke

cannabis. Tobacco smokers give the following reasons for smoking

(Ikard et al. 1969):

1. Stimulation - increased energy and arousal

2. Relaxation and to enhance social interactions

3. Manipulation and handling of things (the cigarettes or pipe)

4. Habit

5. To decrease unpleasant affect-- tension, anxiety, anger

6. Because it's "addictive" - to decrease craving

Not all tobacco smokers give all the reasons. There appear to be

subgroups of smokers who think they smoke for one or more of the

above. The same list of reasons can be culled from the responses of

cannabis smokers in various studies when they were asked why they

smoke (O'Donnell et al. 1976). Some might question reason number six

as not in keeping with usual experience. The high level of dependence that develops to tobacco has been described in detail in recent

reviews (Jarvik et al. 1977; Russell 1977). Cannabis users in countries where very frequent use of potent materials possible occasionally include reason number six to explain self-administration.

For reasons too complicated to go into here, our society is troubled

when drug users cite (or are assumed to have) reason number six to

explain self-administration of a drug. Russell (1977) discusses why

a high level of dependence on tobacco should be expected. These

reasons include:

1. Rapid and numerous reinforcements from the inhalation of

tobacco smoke (about 10 per cigarette).

2. The rapid clearance and metabolism of nicotine

a. Allows frequent and repeated use,

Makes for the rapid onset of withdrawal symptoms.

3. Complex pharmacologic effects, both central and peripheral,

perhaps satisfying a variety of needs.

203
4. Psychologic and social rewards from use, especially in youth.

5. Pattern of use allows generalization and conditioning to

other activities.

6. Combined pharmacologic effects and ritual.

7. No marked performance impairment - perhaps enhances some

performance .

8. Great social acceptability.

9. High availability - inexpensive relative too other psychoactive drugs.

The psychology of tetrahydrocannabinol (THC) and cannabis

smoking is such that reasons one through six could well apply to THC,

nicotine, cannabis and tobacco. The performance impairments after

cannabis are often subtle, as judged by the user, when compared to

other central nervous system intoxicants. Reasons eight and nine

may be changing for both substances. Thus, as judged by experience

with tobacco, perhaps cannabis could be a substance with a high

dependence liability if only a few factors change.

The abstinence symptoms following cessation of prolonged tobacco or

prolongedcannabis intoxication have many similarities (Jarvik 1977;

Jones, Benowitz, and Bachman 1976; Nowlan and Cohen 1977). The

rapidly appearing tobacco abstinence symptoms include irritability,

restlessness, sleep disturbances, gastrointestinal disturbances,

headache, anxiety and decreased concentration, judgment, psychomotor

performance, dullness and drowsiness. Except for the drowsiness and

dullness, all the other symptoms appear with similar intensity during

cannabiswithdrawal and follow a similar time course. Of course, the

relationship between drug seeking behavior and such dysphoric withdrawal symptoms is not a simple one, but is certainly worthy of consideration. Could differences in expectations andavailability

account for different self-administration patterns? Perhaps the fact

that animals won't self administer either tobacco or cannabis not

only makes the study of drug seeking behavior and its relationship to

dependence difficult, but also points out yet another similarity

between cannabis and tobacco.

For all the above reasons, we thought it interesting to attempt to

investigate tobacco seeking behavior in tobacco dependent individuals

using a research strategy similar to that used in our cannabis studies.

As have other investigators, we thought it important to focus on the

role of nicotine in maintaining and altering such behavior. The

study of the role of THC concerning cannabis self-administration would

be analogous study. As Jarvik points out (Jarvik et al. 1977),

we found that the relationship between nicotine ingestion, at least

when administered in the peripheral circulation, and snaking behavior

may well be a complicated one because of the rapid tolerance that develops to many nicotine effects.

Nicotine alone has been administered to man in relatively few studies

(Lucchesi, Schuster, and Emley 1967; Jarvik 1977; Kumar et al. 1977).

The intravenous infusion either had no effect on con current smoking

behavior or minimal effects. Prior to doing a study where we wanted

to measure smoking behavior, we investigated the physiologic and subjective effects of repeated, rapid injections of nicotine to abstinent cigarette smokers and noncigarette smokers. The 700 microgram

204
nicotine doses given to the smokers were slightly less than those

likely to be delivered by moderate potency cigarettes (Russell 1976).

The 300 microgram dosage given to nonsmokers was determined in pilot

studies as representing an average acceptable dose. An attempt was

made to mimic the rapid administration of a dose of nicotine produced

by the inhalationof tobacco smoked during a typical puff.

The eight smokers regularly consumed 20 to 50 cigarettes daily, with

an average of 30. The nonsmokers had enough past experience with

tobacco to understand the symptoms of nicotine toxicity. None had

ever been regular smokers. All were young adults. The subjects

arrived in the laboratory at about 8 a.m., having not

smoked for the previous eight to ten hours. During the four hour

experimental session, the subjects lay quietly in bed with an intravenous catheter in a forearm vein. Under single blind conditions in

an alternatingorder, eitherplacebo (saline) or nicotine

was injected into the catheter rapidly over a three second interval,

with the injections spacedabout to 30 minutes apart. Thus, the

interval between nicotine injections was approximately one hour. The

injections always were given at the beginning of a three minute period when the subjects lay quietly with their right arm extended for

the measurement of finger tremor, thus providing a quiet recording

period with minimal activity. Subjects were asked to report mood and

symptoms before and after each injection and were asked periodically

about craving for a tobacco cigarette. A battery of physiologic

measures were taken continually during the experiment. These included

heart rate as measured by electrocardiogram, skin temperature, finger

tremor as measured by power spectral analysis of an accelerometer

taped to the index finger, and blood pressure, measured with a cuff

on the right arm.

The heart rate changes are illustrated in Figure 1. All subjects

had a significant increase in heart rate after the nicotine injections (p < .0001). The smokers had a significant increase in heart

rate after the first three nicotine injections but no significant

change after the fourth. Then nonsmokers had a significant heart rate

increase after all four injections. The average latency from beginning of injections for the peak heart rate change was 97 seconds with

a standard deviation of 3.7 seconds and did not differ for the smokers

and nonsmokers. The placebo injections produced no change in heart

rate.

Blood pressure or finger tremor did not change after nicotine injection. The finger skin temperature gradually decreased through the

course of the experiment, probably reflecting a cumulative vasoconstrictive effect of nicotine.

Seven of the eight smokers reported the nicotine injections to be

rapidly followed by a pleasurable, stimulant-like sensation that many

of them termed a "rush". Four of the nonsmokers reported similar

effects. Four of the smokers so enjoyed this feeling that they

requested substantially higher doses. The smokers did not report a

consistent decrease in their desire to smoke tobacco during the experiment. All subjects experienced feelings of skin flushing and warmth,

205
FIGURE 1

PEAK HEART RATE CHANGE AFTER IV NICOTINE
lightheadedness, cool extremities, increased heart rate and some

dizziness. The effects were short lived and disappeared three to four

minutes post injection. All subjects were able to discriminate the

placebo injections from the nicotine. All subjects reported the

subjective effects at the fourth nicotine injection to be much less

than those experienced after the initial injection. Thus, in the

smokers rapid tolerance to the nicotine, cardiac and subjective

effects occurred during the experiment. A similar trend was evident

in the non smoker subjects. The smoker group was more tolerant to

nicotine effects than the nonsmokers. Both groups had a similar time

of occurrence of peak heart rate change. The peak heart rate occurs

at about 97 seconds after nicotine injection into the forearm,

a tine at which one would expect rapidly rising brain concentrations. This is consistent with the notion that many nicotine

effects are centrally mediated.

It may well be that single bolus injections of nicotine have a quite

different pharmacology than nicotine administered in a sequence of

eight to ten boli, as would occur after puffing on a tobacco cigarette. However, the relatively rapid development of tolerance to some

effects of nicotine suggests that the pharmacologic effects of

nicotine are not major determinants of smoking behavior throughout the

smoking day. Eight hours without tobacco appears to be time enough

to lose some degree of tolerance, since our subjects gave some evidence of having lost a degree of their acquired nicotine tolerance during the night of abstinence. If a similar pattern of tolerance acquisition and loss occurs with smoked material, it may well be that in the

two pack a day smoker it is only the first few inhalations in the

morning or the first few cigarettes that are of positive reinforcement

value, at least in terms of nicotine related effects. The self-administration of tobacco that occurs for the rest of the day may well

be mainly to avoid the dysphoria associated with abstinence.

Tolerance or dependence are quite often thought of as relatively

slowyly developing phenomena. The pharmacokinetics and pharmacodynamics of both nicotine and tetrahydrocannabinol are such that

things happen relatively rapidly. The development or relative

loss of tolerance throughout the 24 hour cycle may be such that

the reinforcing properties of such druqs vary at differing times

of the day. Experiments should be designed to take such temporal

criteria into account. The measurement of rate or amount of

self-administered drugs without independent manipulation of tolerance levels can be misleading, at least in terms of providing

explanations or reasons for drug self-administration.

REFERENCES

Ikard, F.F.; Green, D.E.; and Horn, D. A scale to differentiate

between types of smoking as related to the management of affect.

Int J Addict, 4:649-659, 1969.

207
Jarvik, M.E.; Cullen, J.W.; Gritz, E.R.; Vogt, T.M.; and West, L.J.;

eds . Research on Smoking Behavior, National Institute on Drug Abuse

Monograph 17. DHEW Publication No. (ADM) 78-581. Washington, D.C.:

Superintendent of Documents, U.S. Government Printing Office, 1977.

Jarvik, M.E. Biological factors underlying the smoking habit.

In: Jarvik, M.E. et al., eds. Research on Smoking Behavior, National Institute on Drug Abuse Monograph 17. See above .

Jones, R.T.; Benowitz, N.L.; and Bachman, J. Clinical studies of

cannabis tolerance and dependence. Ann NY Acad Sci, 282:221-239,

1976.

Kumar, R.; Cooke, E.C.; Lader, M.H.; and Russell, M.A.H. Is nicotine

important in tobacco smoking? Clin Pharmacol Ther, 21:520-529, 1977.

Lucchesi, BR.; Schuster, C.R.; and Emley, G.S. The role of nicotine

as a determinant of cigarette smoking frequency in man with observations of certain cardiovascular effects associated with the tobacco

alkaloid. Clin Pharmol Ther, 8:789-796, 1967.

Nowlan, R. and Cohen, S. Tolerance to marijuana: heart rate and

subjective “high.” Clin Pharmacol Ther, 22:550-556, 1977.

O’Donnell, J.A.; Voss, H.L.; Clayton, R.R.; Slatin, G.T.; and

Room, R.G.W., eds. Young Men and Drugs: A Nationwide Survey, National Institute on Drug Abuse Monograph 5. DHEW Publication No.

(ADM) 76-311. Washington, D.C.: Superintendent of Documents, U..S.

Government Printing Office, 1976.

Russell, M.A.H. Tobacco smoking and nicotine dependence. In:

Gibbins, R.J., ed.

New York:

Research Advances in Alcohol and Drug Problems.

John Wiley and Sons, Inc. , 1976.

Russell, M.A.H. Smoking problems, an overview. In: Jarvik, M.E.

et al., eds. Research on Smoking Behavior, National Institute on

Drug Abuse Monograph 17. See above.

AUTHORS

Reese T. Jones, M.D.

Thomas R. Farrell III

Ronald I. Herning, Ph.D.

Department of Psychiatry

University of California, San Francisco

San Francisco, California 94143

208
Chapter 14

Tobacco and Nicotine Self-Administration

in Humans: The Evolution of a Methodology

Jerome H. Jaffe, M.D., and Maureen B. Kanzler, Ph.D.

The role of response cost in tobacco smoking behavior and the

development of productive methods for its study have interested

my coworkers and me for a good many years. Our work was stimulated in part by the observations of Lucchesi, Schuster, and

Emley (1967). These investigators found that when human cigarette

smokers are given intravenous infusions of nicotine under laboratory conditions, they continue to smoke, although their consumption of cigarettes is reduced.

Some scientists hypothesize that people smoke primarily for the

effects of nicotine. Thus one might assume that these subjects

continued to smoke because the dose of intravenous nicotine was

inadequate. We made quite a different assumption, namely, the

behavior was related to response cost.

To draw some parallels from observations on self-administration of

food, people tend to eat at a sumptuous buffet long after they are

no longer hungry. The marginal cost of eating more of the food is

zero. If dessert is included in the price of a restaurant meal,

most people will eat it, no matter how filling the preceding dishes;

otherwise, they are likely to forego dessert. People who are hungry often will wait several hours for food in order to get it at

considerably lower cost. In short, it appears that response cost

is more important over a certain range than the biological drives

of hunger and satiation.

In the experiments of Lucchesi and coworkers, cigarettes had been

simply and casually available; the response cost for smoking a

cigarette approached zero. On the basis of such a characterization

one might logically ask next: In a similar experiment, how would

smokers behave if the response cost of the cigarettes was systematically varied?

By 1973, when our group returned to work on the role of response

cost in smoking, much additional work had been done. It had been

found that when nicotine levels in cigarettes are varied, smokers

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attempt to titrate body levels of nicotine by altering the number

or depth of puffs or the number of cigarettes smoked (Ashton and

Watson 1970; Frith 1971). In other studies, smokers were given

preloads of oral nicotine or nicotine antagonists, and the number

of cigarettes smoked was the dependent variable (Jarvik, Glick,

and Nakamura 1970; Kozlowski, Jarvik, and Gritz 1975). NO one,

however, had undertaken a study in which nicotine levels and

response cost for tobacco were both systematically varied.

Preliminary Experiments

First we wanted to find the most effective methods to investigate

how cigarette smoking varies as a function of response cost. We

also wanted to work toward an acceptable definition of that concept.

In collaboration with Dr. Miriam Cohen, Dr. Maureen Kanzler and I

first took an approach used in many laboratory experiments involving

self-administration of alcohol or other drugs. Subjects perform

some simple work (button pressing, bicycle riding, etc.) which is

directly rewarded with a unit of the drug or paid for by tokens

or credits which can be exchanged for the drug. Dr. Murray Jarvik

lent us a device that dispensed a cigarette after the subject turned

a handle an arbitrary number of times. The turning generated an

electrical current, and the experimenter could vary the total

energy required to produce a reinforcement. This procedure was

abandoned, chiefly because it was difficult to make the machine

tamper-proof. We also considered using bicycles, but a personal

trial made it clear that, without energy output calibrations,

pushing the pedals simply amounted to spending time sitting on a

seat.

Next we instituted a procedure in which we viewed response cost as

the total effort required to obtain a cigarette. Normally, once a

smoker has bought a pack or carton of cigarettes, the response cost

is as low as reaching into a shirt pocket. To observe the effect

of increasing that cost, we recruited three hospitalized, detoxified

male drug abusers on a research ward. They were paid a small fee

to participate in an B-day experiment in which they were required

to walk to the nurses’ station to obtain free cigarettes. These

were of a brand delivering more than 1.0 mg nicotine, but the cigarettes could be smoked only to a line drawn at the halfway point.

Subjects were cooperative when each trip produced eight of these

half cigarettes. There was little complaint at four cigarettes per

trip, but dissatisfaction mounted sharply when each trip produced

only one or two.

Data were orderly for the more stable subjects: consumption went

down as response cost went up and then rose again, but not to the

starting point, as response cost was lowered. The experiment was

repeated for another 8 days, with response cost varied from one

trip per half cigarette to one per 20 half cigarettes. Although

there was a very crude orderliness in the data, the “noise” caused

by medical and psychiatric complications among the subjects motivated us to reassess our own cost/benefit ratio for this kind of

210
research. Me also wanted to find a procedure that would provide a

finer measure of tobacco consumption. Thus, in this preliminary

work, we did not even reach the stage of using preloading of nicotine.

We then tried working with paid subjects who were not hospitalized

and not obviously psychologically impaired, so that we could control

their periods of abstinence and observe their intake with greater

precision. These volunteers were observed in the laboratory for

S-hour periods during which they were permitted to smoke and were

charged $.00 to $.50 for each puff in some cases, for each quarter

cigarette. Under these conditions we were able to vary either cost

per puff (or quarter cigarette) or the nicotine content per puff

(or quarter cigarette) by selecting from various commercial brands.

By direct observation, we noted the number of puffs (or quarters),

inter-puff interval and puff duration. This arrangement did not

permit a precise measure of actual nicotine intake, but it did yield

orderly data. For example, as the price per quarter of a cigarette

increased, the inter-puff interval decreased, the tobacco became a

more valuable commodity, and the subjects did not wish to see it

bum unpuffed (See figure 1).

The major problem with this procedure was that our informed consent

requirements made the nature of the dependent variables quite obvious

and introduced a number of variables related to subject attitudes.

For example, one subject informed us in advance that it would not

make much difference whether we charged $.005 or $.0l per puff but

that under no circumstances would he smoke when the price reached

$.02 per puff. He correctly predicted his own behavior. However,

he lit a cigarette immediately when the session was over. Other

subjects did not predict their behavior, but showed changes in

smoking style (changes in puff duration and inter-puff interval) as

the price went up. The subject in figure 1 smoked quarter cigarettes

over a wide price range, $.005 to $.35 per quarter cigarette! but

the number smoked decreased, and smoking finally stopped entirely

at $. 50 per quarter.

It became apparent, however, that while this approach would yield

some orderly relationships with some subjects, it would not provide

answers to certain questions we had come to believe were of greater

practical importance.

A New Approach to Cost and Nicotine Content

With the advent of low tar/low nicotine cigarettes, our group began

to wonder less about the role of nicotine plasma levels in short term

regulation of smoking and more about the relationship between response

cost (or economic cost) and the nicotine content of cigarettes that

subjects in the real world would consume over the long run.

Findings from most laboratory experiments in which animals are able

to self-administer drugs show that, other factors being equal, they

will make more responses for larger doses than for smaller ones.

Humans might reasonably be expected to do the same. Yet many people

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FIGURE 1

Price (In $) Per Quarter Cigarette

Average interpuff interval during baseline (whole cigarettes) and

during smoking of quarter cigarettes at different prices. Number

at base of bars shows number of quarter cigarettes smoked during

the experimental session. Four whole cigarettes were smoked under

ad lib conditions (*).

212
buy low tar/low nicotine cigarettes, even though the cost of the

less potent cigarettes is the same as those delivering several times

the nicotine per puff. It seems apparent that these people are

concerned about their health. They are trying simultaneously to

obtain nicotine and to avoid a future aversive consequence, the

brand selection being a resultant of the interaction of the two sets

of reinforcers. We wondered what would happen if the reinforcers

were arranged to be summative rather than tending to cancel each

other.

Method for the Pilot Study

We devised a method to explore this question with ambulatory smokers

going about their usual daily activities. Our primary interest was

to study the relationship between overall response cost and nicotine

content of cigarettes purchased. We recognized, however, that cognitive factors were also operative. Our subjects might perceive

that as medical researchers we believed low nicotine/low tar cigarettes were less hazardous than, other brands, and these perceptions

might affect their behavior.

We began the pilot study by identifying through questionnaire a

group of smokers at our own institution who met the following

criteria:

1. They smoked cigarettes of at least 1.0 mg nicotine

per cigarette as determined by the FTC method.

2. They smoked at least 20 cigarettes per day.

3. They were willing to participate in a study of “Safer

Smoking.”

We offered 23 smokers who met these criteria, 16 women and 7 men,

an opportunity to obtain cigarettes from us at $4.50 per carton,

while the usual cost in local stores ranged from $4.65 to $6.00.

We also offered to pay subjects each time they provided us with a

set of smoked butts. We asked for butts both during a two-week baseline observation period and each time a subject changed brands.

After baseline information was obtained on the brand and number of

cigarettes smoked, we weighed the butts collected. The proportion

of the cigarette each subject usually smoked was determined by subtracting average butt weight (minus filter) from the whole cigarette

weight (minus filter). Then we developed an estimate of daily nicotine intake. This was based on nicotine delivered according to published FTC figures , number of cigarettes smoked per day, and the

proportion of each cigarette smoked. We used these values to develop

two experimental groups matched for nicotine intake. After matching,

the groups were assigned to one of two programs by a flip of a coin.

A third group served as controls. This consisted of seven women who

met the original criteria but were not contacted until the study had

been underway for three months.

After the baseline period, cigarettes were made available for purchase for about three hours per day, three times per week, at the

213
office of one of the researchers. Subjects could purchase any brand.

At the time of each purchase, for most subjects approximately once

a week, subjects were asked to estimate the number of cigarettes

smoked each day, the number given away or purchased elsewhere, “bummed,” etc. Subjects also filled out a check list designed to measure

withdrawal symptoms.

All cigarettes were sold at $4.50 per carton, but subjects were given

refunds for each empty pack returned. Those in Group A were offered

$.10/pack rebate regardless of the brand purchased. Subjects in

Group B were given a progressive incentive rebate for returned packs:

$.05 for brands delivering 1.0 mg or more nicotine per cigarette;

$.10 for “lights” (0.9-0.6 mg nicotine); $.20 for “lows” (0.5-0.4

mg nicotine), and $.30 for “very lows” (0.1- 0.2 mg nicotine per cigarette). Thus, in Group B, the net cost of a pack of very low nicotine

cigarettes would be $.15 if all empty packs were returned. At the

time of the study cigarettes were selling at between $4.50-$6.00,

depending on place of purchase.

Because we were concerned that some subjects might inhale more deeply

when smoking the lower nicotine cigarettes and thus develop higher

carboxy hemoglobin levels, we wanted to monitor carbon monoxide in

exhaled breath. A delay in obtaining equipment postponed this monitoring until the study had been underway for several weeks. Thereafter, a breath sample was obtained at each purchase.

For any given subject, the study extended over a 3-month period.

Then both groups were again given an opportunity to purchase any

brand at $4.50 per carton, with a $.05/pack rebate for returned

empty packs. At the 3-month point, we obtained a sample of butts, a

breath sample for CO, and some additional data from the control group

of women who had been identified earlier. We continued to obtain

followup data once a month for two to four months on both the subjects who completed the 12-week experiment and the control group.

Results and Interpretation

There were important behavioral differences between the men and the

women in this study. Fewer men (7) volunteered to participate and

a higher proportion dropped out. In addition, the behavior of the

men who remained in the study tended toward erratic compliance with

study requirements. Four of the seven completed the 12 weeks, and

these four showed substantial reductions in nicotine and tar consumption. Because of the small N, however, we will focus on the results

from the women.

Twelve of the 16 women who started completed 12 weeks; 13 completed

at least 8 weeks. The dropout rate was similar for Groups A and B.

The most striking finding was that all of the women who remained for

more than a few weeks changed to lower nicotine brands. For both

groups the estimated mean nicotine intake level dropped relatively

rapidly over the first 6 weeks and then continued to decline more

gradually. For both groups the differences from baseline to the 6th

week were statistically significant (p < .01) and remained so through

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the 12th week. We believe these differences were also biologically

significant (see figure 2). The mean daily tar intake at baseline

for the combined experimental groups was 492 mg (±163) as compared

to 401 mg (±126) for the controls. At 12 weeks the intake for the

experimental group was 126 mg (±162) compared to 393 mg (±260) for

controls. The difference is significant at the .01 level.

There was no significant difference between the two experimental

groups in terms of tar and nicotine intake. Although the subjects

in Group 3 switched more rapidly to lower nicotine cigarettes, within

a week or two those in Group A, without the special economic incentive, followed suit. Under the experimental conditions, the degree

of economic incentive offered did not increase the tendency to change

brands. We need to point out, however, that the cost of cigarettes

for our subjects is ordinarily so low that our capacity to lower the

cost of the low tar/low nicotine cigarettes was limited. We might

also note that under most circumstances it is a rise in price of the

commodity regularly purchased that changes behavior rather than a

decrease in an alternative commodity.

Furthermore, because we were our own “salespeople,” and because we

were trying to measure CO and nicotine withdrawal, each encounter

at the purchasing site sharply raised the subjects’ awareness of the

medical implications of smoking.

While in this experiment extra monetary incentives for change did

not cause a greater rate of change in the brand of cigarettes purchased, payment apparently was sufficient to motivate most of our

subjects to buy cigarettes from us. This situation (purchasing from

us) increased the subjects’ awareness of the disparity between the

health risks of their behavior and their perception of themselves

as rational beings. We believe that the results of this pilot project support the view that health concerns rather than different cost

of low tar brands motivated the switching behavior. But the economic

incentives did play a role in that they brought our subjects into a

situation in which they experienced cognitive dissonance (an uncomfortable disparity between their health concerns and their use of

high tar cigarettes) -- a dissonance they reduced by changing to

lower tar/lower nicotine cigarettes.

Several other methodological issues arose during this study. One

concerned the validity of subjects’ reports. While we could look at

actual purchases, subjects could give away or save the cigarettes

they purchased from us or buy additional cigarettes elsewhere. At

each visit, therefore, we questioned them, in a nonjudgmental manner,

implying that it was all right to buy supplementary cigarettes as

long as they told us.

Additional methods were introduced to crosscheck the subjects’ selfreports. For instance, every tenth pack was marked with a label on

which the subject was to record the dates and times the first and last

cigarettes in that pack were smoked. If the subject slept before

completing a pack, hours of sleep were recorded. These labels should

have provided a measure of waking time required to smoke 20 cigarettes.

215

304-494 0 - 79 - 15
FIGURE 2

Cigarette and nicotine intake per day for two groups over twelve weeks.
The subjects admitted, however, that every time they came to the

labelled pack they took pride in slowing down their smoking rate.

Thus, while subject reports of number of cigarettes smoked per day

correlated quite well (r=.82) with actual purchases? both estimates

of consumption correlated less well with values derived from the

data on hours to smoke one pack.

Whether one is interested in the titration hypothesis or in the

public health implications of less hazardous cigarettes, it is worth

noting that over the long run our subjects as a group showed no

significant increase in the number of cigarettes smoked. Most reported concern about smoking more as they changed to lower tar and

nicotine brands. We told them that the drop in tar and nicotine

would more than compensate for any increase in smoking that might

occur. Some subjects did show increases in number of cigarettes

smoked per day as they changed brands, but these increases tended to

be transient and modest in magnitude.

Our subjects did tend to consume more of each cigarette as the nicotine content decreased. For eight female subjects who switched from

high nicotine (at least 1.0 mg nicotine per cigarette) to very low

nicotine (0.2 mg or less) cigarettes, the proportion smoked changed

from 76 percent to 83 percent. Despite this tendency to smoke a

larger proportion of each cigarette and perhaps to inhale more deeply,

however, we did not observe any increase in CO levels in exhaled

breath. Indeed, although the number of observations were limited,

we observed some tendency toward decrease in these levels (see figure

3) . However we should note that participation in the project may

have inhibited an increase in the number of cigarettes that might

have occurred under more natural conditions. If the number of

cigarettes had gone up we might have seen increases in CO levels.

We conclude that factors other than nicotine content, probably social

factors, health concerns and long standing associations between smoking and other behaviors (e.g., drinking coffee, drinking alcohol),

play a role in determining the number of cigarettes smoked per day.

In this pilot study, our estimate of each smoker’s daily nicotine and

tar intake was based on the self-reported number of cigarettes smoked

and the total tobacco smoked per cigarette, estimated from butts returned. The weight of tobacco smoked was compared to the weight

consumed when the cigarette was smoked by the FTC method. FTC

figures for nicotine and tar yields were then used to derive the

figure for each subject’s daily intake. This approach is admittedly

not as sophisticated as actually measuring the nicotine depositied

in filters, as was done by Turner, Sillett, and Ball (1974). Even

that measurement, however, provides only an indirect estimate. For

those whose primary interest is titration of body nicotine levels,

more invasive techniques such as the measure of plasma nicotine or

cotinine may be required.

217
FIGURE 3

NICOTINE CONTENT OF CIGARETTE mg)

Carbon monoxide in expired air of subjects smoking

cigarettes delivering decreasing amounts of nicotine.

218
Changes in Tolerance to Nicotine

In the work with human subjects described here we encountered some

problems that are more easily controlled when working with animals.

For one thing, in a typical animal experiment measuring work an animal will do for differing doses of a reinforcer or for different

reinforcers (e.g., using a progressive ratio design), access to drugs

is controlled so that tolerance and physical dependence do not develop. In our work, subjects were assumed to be in some ways dependent

on tobacco when they began the study. Based on a number of studies

(see Larson and Silvette 1975), we believed them to be tolerant to

nicotine. We also believed that as they changed to lower nicotine

cigarette brands they would lose some of this tolerance. In examining the relationship between cost and nicotine content in brand

selection? therefore, we were looking at a situation that we believe

was changing over time.

If our experiment is viewed as exploring factors that determine a

subject’s self-selection of cigarettes that are delivering varying

doses of nicotine per puff, we should recognize that the difference

in response cost or price necessary to induce a change to a brand

delivering a lower nicotine dose per puff be greater than the

difference required to maintain self-selection of that dose. Once

subjects adjust to the new nicotine dose, the new brand of cigarettes

may be more reinforcing than it was when the change first occurred.

Two findings in our pilot work are consistent with the view that

subjects do lose tolerance to nicotine after shifting to low nicotine

cigarettes. First, while many subjects initially complained that the

lower nicotine brands were unsatisfying, most adapted to them. As

the study progressed, some subjects reported that cigarettes delivering only half as much nicotine as their original brands were quite

satisfactory.

The second observation is that during the 2- to 4-month followup

period, only 1 of 12 female subjects who remained in the study for

12 weeks returned to purchasing cigarettes delivering 1.0 mg of more

nicotine. One other has been smoking lights (0.8 mg per cigarette).

The remaining ten are smoking either low (0.5 mg) or very low (0.1-

0.2 mg) brands. We cannot be certain what factors are maintaining

the behavior (i.e., paying the same price for very little nicotine

that could purchase two to ten times as much). Neither can we be

certain how long it will last.

Conclusion

We feel that we have begun to develop a model for studying selfadministration of tobacco which falls somewhere between laboratory

and marketing models. We believe that further use of this model may

help to tell us more about why people smoke and about the kinds of

price changes that might lead to less hazardous smoking for the

population as a whole.

219
REFERENCES

Ashton, H., and Watson, D.W. Puffing frequency and nicotine intake

in cigarette smokers. Br Med J 3:679-681, 1970.

Frith, C.D. The effect of varying the nicotine content of cigarettes

on human smoking behaviour. Psychopharmacologia, 19:188-192, 1971.

Jarvik, M.E.; Glick, S.D.; and Nakamura, R.K. Inhibition of cigarette smoking by orally administered nicotine. Clin Pharmacol Ther,

11:574-576, 1970.

Kozlowski, L.T.; Jarvik, M.E.; and Gritz, E.R. Nicotine regulation

and cigarette smoking. Clin Pharmacol Ther, 17:93-97, 1975.

Larson, P.S., and Silvette, H. Tobacco: Experimental and Clinical

Studies. Suppl. 3. Williams & Wilkins, Baltimore, 1975.

Lucchesi, B.R.; Schuster, C.R.; and Emley, G.S. The role of nicotine

as a determinant of cigarette smoking frequency in man with the observations of certain cardiovascular effects associated with tobacco

alkaloid Clin Pharmacol Ther, 8:789-796, 1967.

Turner, J.A.McM.; Sillett, R.W.; and Ball, K.P. Some effects of

changing to low-tar and low-nicotine cigarettes. Lancet, 2:737-739,

1974.

AUTHORS

Jerome H. Jaffe, M.D., Chief, Department of Biological Psychiatry

Maureen Kanzler, Ph.D., Research Scientist, Department of Biological

Psychiatry

New York State Psychiatric Institute

722 West 168th Street

New York, New York 10032

220
Chapter 15

Patterns of Puffing in Cigarette Smokers

Ellen R. Gritz. Ph.D.

Cigarette smoking is an integral part of the life of 30 percent of

the adult females and 40 percent of the adult males in this country

(USDHEW, 1976). Its prevalence and tenacity in the behavioral repertoire of so many people must be explained in terms of powerful

reinforcing value. As psychopharmacologists, we have a strong conviction that nicotine, a potent drug with multiple central and peripheral nervous system effects (Volle and Koelle 1975; Russell 1976)

is the primary reinforcer in cigarette tobacco.

A growing literature has been devoted to establishing nicotine seeking as a basic mechanism in smoking. Titration, the self-regulation

of smoking and presumably nicotine intake, has been demonstrated both

behaviorally and physiologically using variables such as number of

cigarettes and puffs, butt nicotine residue, and the quantity of nicotine found in various body fluids (Ashton and Watson 1970; Frith

1971; Russell et al. 1975; Lucchesi, Schuster, and Emley 1967;

Goldfarb et al. 1976; Gritz, Baer-Weiss, and Jarvik 1976).

It is perplexing to investigators in this field that nicotine titration has been only moderately demonstrated; people seem to smoke for

reasons other than to self-administer nicotine. Some of these reasons

may be inherent in the secondary reinforcing value acquired by components of the behavior. In the first place, secondary reinforcers such

as the sight, smell, and handling of a cigarette are capable of developing great strength through association with a primary reinforcer

which, in this case, is delivered at the rate of once per puff. For

the “average” pack-a-day smoker, this amounts to 73,000 reinforcements

per year. It is very possible that overlearning and stereotypy of

motor behavior may mask or prevent titration of nicotine intake. Secondly, when smoking is studied in a laboratory situation and experimental cigarettes are used, results may be confounded by taste aversions and changes in the burning and filtration properties of the

cigarettes.

Two experiments performed in naturalistic situations with commercial

cigarettes also indicate that smokers do titrate intake by changing

the way in which they smoke their cigarettes. Russell et al. (1975)

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gave smokers cigarette: of high, medium, and low nicotine content

in their work environment. The number of high nicotine cigarettes

smoked was reduced 38% and the number of low nicotine cigarettes

increased an average of two cigarettes compared to the medium

nicotine cigarettes. Plasma nicotine levels were more similar

in the high and medium nicotine conditions than in the medium and

low nicotine conditions. Russell concluded that the plasma nicotine levels obtained after smoking depended more on how the cigarette was smoked than on the nicotine content of the cigarette,

since the low nicotine cigarettes had tight filters and were very

aversive in drawing quality.

In the second experiment, Vogt, Selvin, and Billings (submitted for

publication) demonstrated a similar effect with smokers enrolled in

a disease prevention program. The general aim of the study was to

help participants reduce their levels of smoking, serum cholesterol,

and blood pressure. Measures of expired air carbon monoxide (CO)

and serum thiocyanate (SCN) were taken at the beginning and up to

a year following treatment to correlate with smoking. SCN and CO

values correlated with change in the number of cigarettes smoked?

but opposite to the predicted direction. Those who failed to quit

smoking and only cut down on the number of cigarettes smoked actually increased their exposure per cigarette. Presumably they

compensated for smoking fewer cigarettes by smoking them more

thoroughly.

Both studies demonstrate that smokers changed their puffing pattern

when their cigarette or nicotine intake was varied. Furthermore,

relatively little attention has been paid to the “finer grain” behaviors in smoking: the parameters of puffing, which include number

of puffs, duration, volume, inter-puff interval and depth of inhalation. Fredericksen, Miller, and Peterson (1977) observed changes

in the topographical components of smoking behavior (i.e., cigarette

duration, puff frequency, puff volume, and inter-puff interval) during an experimental session after subjects were instructed to alter

one or more components. They reported a strong interrelationship

between components, such that changes in one produced compensatory

adjustment in others.

The series of studies reported in this paper represents an initial

attempt to assess some of the parameters of puffing. In the first

study, the rate at which cigarettes were presented to smokers was

increased to twice and four times baseline (ad lib) rates. In a

subsequent pilot study, the role of visual variables in the stimulus control of smoking was evaluated by comparing a baseline

smoking condition to conditions in which subjects smoked through

transparent (lucite) and opaque (wooden) “smoke screens.” Finally,

some observations will be offered from an exploratory study in

which puffing parameters were analyzed when subjects smoked their

own cigarettes and specially prepared nicotine-free tobacco cigarettes under conditions of smoking deprivation and no deprivation.

222
EXPERIMENT 1

Subjects

Eleven paid volunteers from the Veterans Administration Hospital

Brentwood gave informed consent to participate in the experiment.

Subjects were drug-free male patients who ranged in age from 26 to 56

years (mean = 40.6) and who smoked an average of one pack of cigarettes per day.

Apparatus

All subjects smoked each cigarette through a modified plastic holder.

The holder contained a sensing device, a thermistor, which was activated whenever air passed over it. The cigarette holder was attached

to a freely extending lead that could be either held in the hand or

affixed to an opaque panel. The cigarette holder apparatus was interfaced with a Vetter 8-channel magnetic tape recorder which recorded

the occurrence and duration of each puff, and starting time of each

cigarette. The tapes were played back into an IBM 360/91 computer

at the University of California, Los Angeles, Health Sciences Computing Facility via a Sykes floppy disc system.

Procedure

Each subject served in four conditions in a repeated measures design:

baseline (ad lib smoking), two and four times baseline rate, and

opaque smoke screen. The baseline condition always occurred first;

the order of the remaining three conditions was randomized. In the

two and four times baseline conditions, cigarettes were presented at

timed intervals and subjects were required only to light each cigarette. In the smoke screen condition, the opaque screen was positioned so that subjects could remain seated and merely turn their

heads to take a puff on a cigarette. Cigarettes were kept constantly

lit from the opposite side of the panel and out of view of the subject. Subjects were free to smoke or take puffs on an ad lib basis

in all conditions. Television and reading material were available

during the two-hour session.

EXPERIMENT 2

Subjects

Four paid volunteers from the Veterans Administration Hospital Brentwood gave informed consent to participate in the experiment. Subjects were drug-free male patients who ranged in age from 40 to 60

years (mean = 51) and who smoked an average of 47.5 cigarettes per

day.

Apparatus

The cigarette holder and opaque screen were identical to those used in

Experiment 1. In addition, a clear lucite screen of identical dimensions was used.

223
Procedure

Each subject served in three conditions in a repeated measures design:

baseline (ad lib smoking), opaque screen, lucite screen. The order of

conditions was randomized for each subject. As in the previous experiment, sessions were two hours in length and subjects were free to

smoke or take puffs on an ad lib basis in all conditions. Television

and reading material were available. During the two smoke screen

conditions, the cigarette holder was affixed to the panels as described in Experiment 1. When the lucite screen was used subjects

could see the lighting and burning of each cigarette on the opposite side of the panel.

EXPERIMENT 3

Subjects

Nine paid male volunteers who were either UCLA staff or students, or

outpatients from the Veterans Administration Hospital Brentwood participated in the experiment. Subjects ranged in age from 21 to 40

(mean = 29) and smoked an average of one pack of cigarettes per day.

Apparatus

The cigarette was affixed in a Fleisch flow meter which was connected

in series with a Statham strain gauge and a magnetic tape drive. The

air flow produced by puffing (puff volume) created a differential

pressure, which was converted into a variable resistance; i.e., a

constant current of 10 mamp was passed through the Statham strain

gauge, and the voltage across it was measured. The voltage was recorded as an analog signal on magnetic tape, to be later digitized and

analyzed on an IBM 360/91 computer at the Health Sciences Computing

Facility, UCLA.

Nicotine-free tobacco, genetically bred at the University of Kentucky,

was processed into unfiltered cigarettes and donated by International

Flavors and Fragrances, Inc.

Procedures

Each subject reported to the laboratory on two separate occasions,

once having been deprived of smoking since the previous evening, and

once in a non-deprived state. Subjects smoked two cigarettes through

the apparatus, one of their own brand, and one which was nicotine

free. The order of cigarettes was balanced across subjects and cigarettes were smoked 45 minutes apart.

RESULTS

Experiment 1

Data was calculated on all puff-to-puff intervals excluding the interval between completing one cigarette and lighting the next. Short

224
puffs following the first puff of each cigarette were also eliminated from the analyses, as they represent an artifact of inhaling

to light up.

Subjects smoked an average of 5.5 cigarettes (range = 4-7) in two

hours of ad lib smoking.

five or six cigarettes.

Nine of eleven subjects smoked either

Subjects lit a cigarette approximately

every 20 minutes in baseline, every 10 minutes in the doubled

rate, and every five minutes in the quadrupled rate condition.

The puff-to-puff (P-P) interval is defined as the time lapsed

from the onset of one puff to the onset of the following puff

(Figure 1).

FIGURE 1

Polygraph record of a typical baseline cigarette:

heavy and light smoker

When visual records of the pattern of puffing were examined, the

presence of two distinct types of smokers was revealed: a group

(n = 5) who had a mixture of long (5 seconds or greater) and short

(less than 5 seconds) P-P intervals, and a group (n = 6) who had

almost exclusively long P-P intervals. The former were, on the

average, heavy smokers (mean = 30 cigarettes/day) and were older

(mean = 54 years), compared to the latter group who were, on the

average, lighter smokers (mean = 18 cigarettes/ day) and younger

(mean = 30 years). Therefore, comparisons between these two

subgroups were made on a post hoc basis.

225
Figure 2 presents the number of long and short P-P intervals for

light and heavy smokers across conditions. It can be seen that

the light smokers do not markedly increase the number of P-P intervals even when given quadruple the baseline number of cigarettes.

On the other hand, the heavy smokers continue to increase the number of both long and short P-P intervals across conditions.

FIGURE 2

Number of long and short puff-to-puff intervals for heavy

and light smokers in baseline, doubled rate and

quadrupled rate conditions (mean and s. e. )

226
Figure 3 depicts the number of long P-P intervals across conditions

for the entire group and for the light and heavy smoker subgroups.

FIGURE 3

Number of long puff-to-puff intervals for heavy and light

smokers in baseline, doubled rate and quadrupled rate

conditions (mean and s.e.)

The between condition effect was significant (F = 4.55, df = 2,20,

p<0.05) for all subjects, but does not reach significance for

either subgroup.

227
There was no significant change in the duration of the long P-P

interval across conditions. The mean duration ranged from 73.4

to 83.4 seconds across conditions. Light smokers spaced their

puffs farther apart than heavy smokers (Figure 4).

FIGURE 4

Duration of Long puff-to-puff intervals for heavy and Light

smokers in baseline, doubled rate and quadrupled rate

conditions (mean and s.e.)

Heavy smokers attempted to maintain a constant number of puffs per

cigarette in the double-rate condition, decreasing only 1.5 puffs,

228
(n.s.), while light smokers decreased approximately three puffs per

cigarette (F = 3.81, df = 2,15, p<0.05) (Figure 5).

FIGURE 5

Number of puffs per cigarette for heavy and light

smokers in baseline, doubled rate and quadrupled

rate conditions (mean and s. e. )

For all subjects, the decrease in puffs/cigarette across conditions

was also significant (F = 4.91, df = 2,30, p<0.01). The rate of

lighting cigarettes in the quadrupled-rate condition was confounded

by the fact that subjects were often interrupted while smoking one

cigarette to light the next.

229
Smoking was depressed in the opaque screen condition for all subjects

(t = 2.81, df = 10, p<0.02) (Figure 6).

FIGURE 6

BASELINE OPAQUE LUCITE

SCREEN SCREEN

Number of long puff-to-puff intervals for heavy and light

smokers and smokers from Exp. 2 across baseline, opaque

and lucite screen conditions (mean and s.e.)

The number of long P-P intervals dropped markedly for both heavy and

light smokers compared to baseline values.. This figure also presents

data from Exp. 2.

Experiment 2

Subjects in Exp. 2, referred to in the figure as Exp. 2 smokers, were

heavier smokers than those in Exp. 1. This is evidenced by the fact

that the mean number of long P-P intervals in baseline was approximately double that of subjects in Exp. 1 (Figure 6). However, although subjects in Exp. 2 smoked a mean of 9.5 cigarettes in baseline,

their average number of puffs per cigarette (8.7) was similar to that

of the heavy smokers in Exp. 1.

Puffing was more depressed on the opaque smoke screen (51 percent of

baseline) than on the lucite smoke screen (63.6 percent of baseline),

although the overall difference among conditions was only marginally

significant (F = 3.02, df = 2,9, p<0.09).

230
Experiment 3

In this study, the four variables selected for analysis were puff

duration, puff volume, maximum rate of inhalation and location of

the maximum (Figure 7).

FIGURE 7

Diagram of variables used in puff pattern analyses, Exp. 3.

The first seven puffs on each cigarette were analyzed. Different

burning properties of the experimental nicotine free and commercial cigarettes precluded use of number of puffs as a variable.

Puff volume and maximum rate of inhalation are expressed in arbitrary units because of mechanical difficulties with calibration.

Puff duration was significantly shorter when subjects had abstained

from smoking than when they had not, regardless of cigarette nicotine content (F = 14.4, df = 1,8, p<0.005) (Table 1). Deprivation

also affected puff volume. Puffs were marginally greater in volume

in the nondeprived condition (F = 4.65, df = 1,8, p<0.063).

TABLE 1

Exp. 3: Summary of puff duration, puff volume

and maximum rate of inhalation

231

304-494 0 - 79 - 16
Nicotine content of the cigarette significantly affected only maximum rate of inhalation, or peakedness of the puff: the nicotinefree cigarettes were inhaled more sharply (F = 17.78, df = 1,8,

p<0.003). When subjects were deprived, the maximum rate of inhalation was differentially greater on the nicotine-free than on the

nicotine cigarettes (significant deprivation x nicotine content

interaction) (F = 26.05, df = 1,8, p<0.001).

The variables reflecting skewness of the puff showed no differences

between conditions on either variable.

DISCUSSION

The studies described in this paper were undertaken to further elucidate the manner in which smokers self-regulate nicotine intake.

This was done by examining some of the parameters of smoking behavior not routinely measured.

Although the number of cigarettes smoked per day was not included

as a variable in the design of these experiments, it was discovered

that there were differences in the way cigarettes were smoked by

light and heavy smokers. The small sample size of these two subgroups most likely accounted for the lack of statistically significant differences in the variables discussed in the paper. In

Exp. 1, the light smokers, who averaged 18 cigarettes per day, took

discrete, well-spaced puffs, while the heavy smokers, who averaged

30 cigarettes per day, often took rapid successive puffs. It is

likely that the short puff-to-puff intervals represent deep inhalations, an attempt by heavier smokers to maximize nicotine intake.

The light smokers attempted to titrate their smoking, that is, to

maintain a constant rate of puffing across all two-hour sessions,

even when lighting two and four times the number of cigarettes

smoked ad lib (Figure 2). On the other hand, the heavy smokers

demonstrated stereotypy of motor behavior; this is most clearly

seen by looking at the number of puffs per cigarette (Figure 5).

Heavy smokers took almost as many puffs/cigarette when smoking

at double their ad lib rate, while light smokers decreased the

number of puffs/cigarette by 33 percent. Puffs/cigarette were automatically decreased in the quadrupled rate condition since subjects

smoking one cigarette were often interrupted to light the next.

Spacing of puffs (duration of P-P interval) did not change significantly across conditions, and so does not seem to be a mechanism

in titration. We have as yet to examine sequential duration effects, either within a cigarette or over a two-hour session.

From the results of Exp. 1, it is clear that light smokers titrate

by regulating the total number of puffs and not by spacing of

puffs. Depth of inhalation and puff volume were not measured in

this study, but we can hypothesize from the pattern of “short”

puff-to-puff intervals in heavy smokers that depth of inhalation

is important in regulating nicotine intake. The study of Vogt

232
and his colleagues (submitted for publication) and other reports

(Schachter 1978) of smokers switching to low-nicotine cigarettes

suggest adaptations in inhalation do occur.

Some clues to the mechanisms operative in titration are provided

by Exp. 3. In this pilot exploration, there were significant changes

in puff duration and volume related to smoking deprivation, but not to

cigarette nicotine content (Table 1). Non-deprived smokers may take

longer, deeper (greater volume) puffs than deprived smokers because.

acute tolerance diminishes the effects of nicotine. The maximum

rate of inhalation changed significantly as a function of cigarette

nicotine content; however, this finding may have been confounded by

the differential burning and filtration properties of the cigarette

used. We are beginning a replication of this study in which light

and heavy smokers will be compared, and cigarettes used will be identical in burning properties and filtration.

Another dimension to the regulation of puffing was added by the use

of opaque and transparent “smoke screens” (Figure 6). The number

of puff-to-puff intervals radically decreased (approximately 50 percent) when ad lib smoking was compared to opaque screen condition.

The clear screen depressed smoking somewhat less than the opaque

screen, although subjects still took 36 percent fewer puffs. The

depression of puffing may be due to a loss of stimulus control, of

the secondary reinforcing value of lighting, handling factors, and

visual factors (in the opaque condition), or to the generally aversive nature of puffing at a cigarette stuck in a board.

We may conclude from these studies of puffing behavior that there

are differences among subjects in the way cigarettes are smoked,

that these differences are very likely a function of the overall

rate at which subjects smoke, and that lighter smokers do try to

titrate their smoking behavior, while heavier smokers show stereotypy in the puffing variables measured. Heavy smokers may have

greater tolerance to nicotine than light smokers. They may thus

be able to increase their intake up to some limit without experiencing the toxic effects to which light smokers may be more sensitive. Then again, heavy smokers may be like the obese individual who will eat whenever food is presented, ignoring satiety

mechanisms. The parallels have yet to be explored.

233
REFERENCES

Ashton, H., and Watson, D.W. Puffing frequency and nicotine intake

in cigarette smokers. Br Med J 2:679-681, 1970.

Frederiksen, L.W,; Miller, P.M.; and Peterson, G.L. Topographical

components of smoking behavior. Addict Behav, 2:55-61, 1977.

Frith, C.D. The effect of varying the nicotine content of cigarettes on smoking behavior. Psychopharmacology, 19:188-192, 1971.

Goldfarb, T.; Gritz, E.R.; Jarvik, M.E.; and Stolerman, I.P. Reactions to cigarettes as a function of nicotine and “tar.” Clin

Pharmacol Ther, 19:767-772, 1976.

Gritz, E.R.; Baer-Weiss, V.; and Jarvik, M.E. Titration of nicotine intake with full-length and half-length cigarettes. Clin

Pharmacol Ther, 20:552-556, 1976.

Lucchesi, B.R.; Schuster, C.R.; and Emley, G.S. The role of nicotine as a determinant of cigarette smoking frequency in man with

observation of certain cardiovascular effects associated with the

tobacco alkaloid. Clin Pharmacol Ther, 8:789-796, 1967.

Russell, M.A.H.; Wilson, C.; Patel, U.A.; Feyerbend, C.; and

Cole, P.V. Plasma nicotine levels after smoking cigarettes with

high, medium, and low nicotine yields. Br Med J, 2:414-416, 1975.

Russell, M.A.H. Tobacco smoking and nicotine dependence. In:

Gibbons, R.J.; Israel, Y.; Kalant, H.; Popham, R.E.; Schmidt, W.;

and Smart, R.G.; eds. Research Advances in Alcohol and Drug

Problems. New York: John Wiley & Sons, 1976

Schachter, S. Pharmacological and psychological determinants of

smoking. Ann Intern Med, 88:104-114, 1978.

United States Department of Health, Education, and Welfare. Adult

Use of Tobacco, 1975. National Clearinghouse for Smoking and Health,

Bureau of Health, Education, Center for Disease Control, Public

Health Service, 1976.

Vogt, T.M.; Selvin, S.; and Billings, J.H. Smoking cessation program: baseline carbon monoxide and thiocyanate levels as predictors

of outcome. (Submitted for publication.)

Volle, R.L. and Koelle, G.B. Ganglionic stimulating and blocking

agents. In: Goodman, L.S. and Gilman, A., eds. The Pharmacological

Basis of Therapeutics. New York: The Macmillan Company, 1975.

234
AUTHOR

Ellen R. Gritz, Ph. D.

Departnent of Psychiatry and Biobehavioral Sciences

Neuropsychiatric Institute

School of Medicine

University of California

760 Westwood Plaza

Los Angeles, California 90024

Veterans Administration Hospital Brentwood

Los Angeles, California 90073

235
Chapter 16

Self-Administration of Cigarettes With

Varying Tobacco’ and Nicotine Content

Murray E. Jarvik, M.D., Ph.D.

Of all the self-administered substances discussed in this volume,

alcohol, heroin, and food, none is self-administered at a higher

rate than cigarette smoke. A chain smoker can light a cigarette every

five to ten minutes, and puffing occurs once every twenty or thirty

seconds. Of course, the average pack-a-day smoker only uses twenty

cigarettes per day, but even so, with nine or ten puffs per cigarette

this amounts to more than 70,000 puffs per year. We want to know

what factors maintain such high rates of responding in a habit so

apparently meaningless as the sucking in of smoke from burning vegetable matter. We surmise that smoking is really drug seeking behavior,

and that smokers attempt to regulate their levels of nicotine intake.

Probably the nicotine is sought because it produces some pleasurable

sensation by an action on the brain or it reduces unpleasant sensations also by acting upon the brain.

If a smoker is attempting to keep the level of nicotine constant,

say in the blood, and if we lower the amount of nicotine available

in a cigarette, then he should compensate by smoking more. One indirect way to test this hypothesis is to give shortened cigarettes

to smokers and measure the smoking response. Each cigarette will

deliver not only less nicotine but all other components of the cigarette which have been burned and converted into smoke. We can test

the nicotine hypothesis directly by lowering or raising the nicotine

content of cigarettes and seeing whether subjects will smoke more or

less in accordance with the content.

There have been a few other attempts to vary nicotine levels in cigarettes and see whether compensatory behavior resulted. One of

the reasons why such studies have been few is that cigarettes

varying in nicotine content simply have not been available. The

first published experiment in which nicotine was varied by comparing

low nicotine cigarettes with the same type of cigarettes to which

nicotine had been added was by Finnegan, Larson, and Haag (1945).

They found that some smokers smoked the same number of cigarettes

whether the nicotine content was low or normal. These subjects expressed great dissatisfaction with the cigarettes. On the other

hand smokers who tended to increase their consumption of low nico236
tine cigarettes tended not to miss the nicotine. Thus, they provided

evidence that some smokers will compensate for the lack of nicotine by

smoking more. More recently Russell et al. (1975) found that smokers

did attempt to compensate for low nicotine levels in experimental

cigarettes by smoking more, but not nearly enough to compensate for

the diminution in nicotine. Correspondingly, the blood levels of

nicotine fell in these subjects who were unable to compensate. Subject satisfaction with these low nicotine cigarettes was low.

Goldfarb, Jarvik, and Glick (1970) in our laboratory found that lettuce cigarettes were disliked by smokers. When nothing else was

available they did smoke them, but to a lesser extent than their own

cigarettes. Adding nicotine to these cigarettes did not increase

their acceptability even though subjects were able to accept the

change in strength. One explanation is that the aversiveness of the

burning lettuce swamped all other effects. However, another possibility is that nicotine in regular cigarettes interacts in some way with

other components, perhaps the tar, to produce the effects desired by

the smoker. Gritz, Baer-Weiss, and Jarvik (1976) gave smokers full

length cigarettes and instructed them to smoke in their usual way on

some days, and on other days only half way down, to a red mark. On

a different day, subjects were given cigarettes cut in half. When 24-

hour urinary contents were measured it was found that the nicotine

excreted was highest for the whole cigarettes, lower for the proximally smoked cigarettes and lowest for the distally smoked cigarettes.

The amount extracted from half cigarettes was more than half the

amount extracted from the full cigarettes, so apparently some compensation occurred, perhaps in the way the cigarettes were smoked.

Nicotine can also be taken by routes other than inhalation.

Chewing tobacco and snuffing snuff used to be fairly popular ways of

using tobacco and presumably of absorbing nicotine. Johnston (1942)

administered nicotine hypodermically and felt that it substituted for

smoking, but his studies were uncontrolled. Lucchesi, Schuster, and

Emley (1967) found that intravenous nicotine produced some diminution in smoking, but Kumar et al. (1977) could not produce any effect on

rate of smoking with intravenous nicotine. The Lucchesi experiment

was probably a more valid estimate of intravenous nicotine action

because the Kumar study undoubtedly used inadequate amounts of nicotine. Kumar et al. (1977), however, found that preloading with high

nicotine but not low nicotine cigarettes did diminish subsequent

smoking and one would have to ascribe this effect to the nicotine

alone since all other factors were held constant. Nicotine chewing

gum (Russel, Feyerabend, and Cole 1976; Kozlowski, Jarvik, and Gritz

1975) or even nicotine swallowed in orally administered capsules

(Jarvik et al, 1970) produced decreases in smoking. One possible

explanation is that the subject attempted to titrate his nicotine

levels by smoking less in the face of increased levels produced by

these other types of administration.

Another approach used in our laboratory was to block nicotine with

mecamylamine, a drug that crosses the blood brain barrier. This

produced an increase in smoking. Pentolinium, a peripheral blocking

agent, produced no such effect (Stolerman et al. 1973).

237
The existence of some attempt to titrate nicotine intake shows that

nicotine seeking plays at least some role in smoking. The lack of

perfect titration indicates that other factors, presumably secondary

reinforcers, play a role in maintaining the smoking behavior. It is

possible or even likely that a smoker’s need or desire for nicotine

may fluctuate with time and with the effect that he desires from the

nicotine. Until we can identify these factors we assume that his nicotine need is constant over time and of course assumption probably

is an added source of variance. At any rate if we assume that the

smoker attempts to keep his nicotine intake constant within limits,

then the way he can control the nicotine intake is to vary the rate

at which he lights cigarettes, to modify his puffing rate, and to

change the topography of each puff. The present experiment examined

the first two variables.

In Experiment 1 nine paid volunteers from the Veterans Administration

Hospital Brentwood participated. Their ages ranged from 25 to 50

years and they reported smoking an average of 18.5 cigarettes per

day.

Subjects were tested in an air-conditioned room where they sat for two

hours watching television. They were instructed to insert the cigarette into a special cigarette holder containing a thermistor which

was activated whenever air passed over it. This device was connected

through appropriate circuitry to a Vetter 8-channel physiological

magnetic tape recorder which recorded the puffs against time. Puffs

were later analyzed with special counting apparatus.

Each subject was tested in four different conditions. On the first

day they smoked their own brand of cigarettes and on successive occasions these same brands were given in whole, half, quarter and oneeighth lengths with random orders. Subjective evaluations of satisfaction with cigarettes were made at the end of each session and a

seven-point semantic differential scale was used.

The results can be seen in Table 1. As the cigarette length decreased

the number of cigarettes smoked increased (F=14.85, p<0.001) with a

linear trend (F=18.30, p<0.03). T-tests performed between all possible pairs of means for number of cigarettes were significant at the

.01 level except between half and quarter lengths.

The number of puffs was greater for shorter cigarettes and the

differences were significant (F=3.91, p<0.02) and linear (F=6.38,

p<0.03). Differences between whole and quarter, half and quarter, and

half and eighth, were significant by t-tests. The average number of

puffs per cigarette, of course, decreased with decreasing length.

Satisfaction was inversely proportional to length, i.e., shorter

cigarettes were less satisfying. These changes were also highly

significant.

The second experiment was designed to examine the effects of varying

both nicotine content and length of cigarettes. Twenty-eight male and

one female volunteers from the Veterans Administration Hospital

Brentwood participated in this study. They were 23 to 54 years of age

238
TABLE 1

Condition

Number of cigarettes

Mean 15.2 10.3 8.2 5.4

s.d. (6.4) (3.5) (2.3) (1.8)

Number of Puffs

Mean

s.d.

Puffs per cigarette

43.7 3.8 53.7 54.0

(19.9) (15.4) (14.6) (11.5)

2.9 4.2 6.5 9.7

Satisfaction Ratings

Mean

s.d.

2.7 3.6 4.9

(1.4) (1.1) (1.4)

5.2

(1.2)

Size of Cigarette

1/8 1/4 1/2 1

Number of Cigarettes, Puffs, and Satisfaction Ratings

In Z-Hour Sessions

As a Function of Cigarette Size
and smoked at least a pack a day. Experimental cigarettes were used

and these were supplied by Dr. Gio Gori of the National Cancer Institute. The cigarettes were made from the same tobacco, but the low

nicotine cigarettes delivered 0.2 mg nicotine per cigarette and the

high had nicotine added so that they delivered 2.0 mg nicotine per

cigarette.

A 2x2 factorial design with repeated measures was used; all subjects

served in all four conditions. Again sessions took place in the same

experimental rooms, subjects were allowed to smoke ad lib but always

through the holder that counted their puffs. After each session

strength and satisfaction ratings were made of the cigarettes smoked

in that session. It can be seen in Table 2 that subjects smoked more

low nicotine cigarettes and also puffed more on low nicotine cigarettes than on high nicotine cigarettes. Similarly subjects smoked

more quarter length than full length cigarettes. All of these differences were highly significant. Although they puffed more on the

long than on the short cigarettes, they puffed proportionately more on

the short cigarettes when the factor of length is taken into account.

The number of puffs per cigarette remained constant in the face of

changing nicotine content. This indicates that number of cigarettes

smoked and not puffing rate was used to compensate for change in

nicotine content.

The satisfaction ratings were low and approximately equal for both nicotine content and length. There is a suggestion that subjects disliked all of these experimental cigarettes since their satisfaction

rating ranged around 4.0 or lower, whereas subjects rated their own

cigarettes in the previous experiment about 5.2. It is very likely

that the nicotine deliveries were either too high or too low, certainly not the middle range of 1.0 to 1.5 that they were used to.

Strength was accurately judged by the subjects.

In the first study it was clear that the subjects did not smoke eight

times as many of the one-eighth cigarettes but only three times as

many. The lack of perfect titration was not unexpected. First of

all, a small cigarette is much stronger than a long one, because it has

less filtering capacity. Lighting the small cigarette is more difficult and it takes more effort to smoke the additional number of small

cigarettes to equal the tobacco or smoke content of the longer ones.

The satisfaction ratings show a linear trend with longest cigarettes

being liked most. This meant that subjects preferred the length they

were used to. Familiarity probably plays an important role in satisfaction rating of all sorts of things. As a general rule one probably

prefers a familiar form of stimulation to a new one particularly if

one has had an opportunity to seek out an optimal level of that type

of stimulation in the past. Since cigarettes varying pretty widely in

nicotine content are available on the market, one can assume that the

subjects already selected their favorite brands on the basis of a

desirable level of nicotine delivery and any deviation would be less

preferred.

The number of puffs per cigarette decreased monotonically with the

length of the cigarette. But subjects took proportionately more puffs

on the shorter cigarettes. It may take more puffs to light one of

240
Long

Quarter

Cigarettes

Low High

Mean

s.d.

7.0 5.7

(2.8) (2.7)

Mean 14.0 11.7

s.d. (10.4) (10.2)

TABLE 2

Puffs

Low High

58.8 50.7

(29.6) (32.4)

49.9 40.3

(48.1) (33.9)

Number of Cigarettes and Puffs in 2-Hour Sessions

As a Function of

Cigarette Size and Nicotine Content

Puffs/Cigarette

Low High

8.4 8.9

3.6 3.4
the shortest cigarettes than to smoke it, and this tends to give a

disproportionate weighting of this measure to the shorter cigarettes.

Also subjects tended to smoke the shorter cigarettes right down to

the end, whereas they stopped smoking or even put out the longer

cigarettes before they burned down to the end.

In the second experiment, although there was a significant effect of

nicotine content in the expected direction, the subjects fell short

of perfect titration. There was less than a 20 percent change in the

smoking rate related to nicotine, and one might have expected a tenfold

change since there was a tenfold difference in nicotine delivery.

Similarly, although the long cigarette was four times the length of

the short, there was only about a 50 percent change in the number of

short cigarettes smoked. Such factors as behavioral stereotypy,

inertia, and a change in puffing parameters may have contributed to

these results.

In summary, it is clear that subjects do regulate their nicotine

intake and attempt to keep it within optimal limits. We assume that

we were measuring smoking under basal conditions where titration

should be optimal. Since people smoke more under conditions of stress

or boredom (Fuller and Forrest, 1973) they may adjust their nicotine

intake to maintain a comfortable level. In future studies we will

vary stress and measure nicotine in blood and possibly spinal fluid.

REFERENCES

Finnegan, J.K.; Larson, P.S.; and Haag, H.G. The role of nicotine

in the cigarette habit. Science, 102:24-96, 1945.

Fuller, R.G.C., and Forrest, D.W. Behavioral aspects of cigarette

smoking in relation to arousal level. Psychol Rep, 33:115-121, 1973.

Goldfarb, T.L.; Jarvik, M.E.; and Glick, S.D. Cigarette nicotine

content as a determinant of human smoking behavior. Psychopharmacologia, 17:89-93, 1970.

Gritz, E.R.; Baer-Weiss, V.; and Jarvik, M.E. Titration of nicotine

intake with full-length and half-length cigarettes. Clin Pharmacol

Ther, 20:552-556, 1976.

Jarvik, M.E.; Glick, S.D.; and Nakamura, R.K. Inhibition of cigarette smoking by orally administered nicotine.

11(4):574-576, 1970.

Clin Pharmacol Ther,

Johnston, L.V. Tobacco smoking and nicotine.

1942.

The Lancet, 2:742,

242
Kozlowski, L.T.; Jarvik, M.E.; and Gritz, E.R. Nicotine regulation

and cigarette smoking. Clin Pharmacol Ther, 17(1):93-97, 1975.

Kumar, R.; Cooke, E.C.; Lader, M.H.; and Russell, M.A.H. Is nicotine important in tobacco smoking? Clin Pharmacol Ther, 21(5):

520-529, 1977.

Lucchesi, B.R.; Schuster, C.R.; and Emley, G.S. The role of nicotine as a determinant of cigarette smoking frequency in man with

observations of certain cardiovascular effects associated with the

tobacco alkaloid. Clin Pharmacol Ther, 8:789-796, 1967.

Russell, M.A.H.; Wilson, C.; Patel, U.A.; Feyerabend, C.; and

Cole, P.V. Plasma nicotine levels after smoking cigarettes with

high, medium and low nicotine yields. Br Med J, 2:414-416, 1975.

Russell, M.A.H.; Feyerbend, C.; and Cole, P.V. Plasma nicotine

levels after cigarette smoking and chewing nicotine gum. Br Med J

1:1043-1046, 1976.

Stolerman, I.P.; Goldfarb, T.; Fink, R.; and Jarvik, M.E. Influencing cigarette smoking with nicotine antagonists. Psychopharmacologia, 28:247-259, 1973.

AUTHOR

Murray E. Jarvik, M.D., Ph.D.

Professor of Psychiatry and Pharmacology

Department of Psychiatry and Biobehavioral Sciences and

Department of Pharmacology

School of Medicine

University of California

Los Angeles, California 90024

Chief, Psychopharmacology Unit

Veterans Administration Hospital Brentwood

Los Angeles, California 90073

243
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cannabinoid levels in the human body by immunoassay, liquid and

dual column chromatography and mass spectroscopy techniques. 120 pp.

GPO Stock #017-024-00510-0 $1.95 NTIS PB #251 905/AS $7.25

8 Rx:3 TIMES/WK LAAM - METHADONE ALTERNATIVE. Jack Blaine, M.D.,

and Pierre Renault, M.D., editors. Comprehensive summary of

development of LAAM (Levo-alpha-acetyl methadol), a new drug for

treatment of narcotic addiction. 127 pp.

Not available from GPO NTIS PB #253 763/AS $7.25

9 NARCOTIC ANTAGONISTS: NALTREXONE. Demetrios Julius, M.D., and

Pierre Renault, M.D., editors. Progress report of development,

pre-clinical and clinical studies of naltrexone, a new drug for

treatment of narcotic addiction. 182 pp.

GPO Stock #017-024-00521-5 $2.55 NTIS PB #255 833/AS $9

10 EPIDEMIOLOGY OF DRUG ABUSE: CURRENT ISSUES. Louise G. Richards,

Ph.D.) and Louise B. Blevens, editors. Conference Proceedings. Examination of methodological problems in surveys and data collection. 259 pp.

GPO Stock #017-024-00571-l $2.60 NTIS PB #266 69l/AS $10.75

11 DRUGS AND DRIVING. Robert Willette, Ph.D., editor. State-of-the

art review of current research on the effects of different drugs on

performance impairment, particularly on driving. 137 pp.

GPO Stock #017-024-00576-2 $1.70 NTIS PB #269 602/AS $8

12 PSYCHODYNAMICS OF DRUG DEPENDENCE. Jack D. Blaine, M.D., and

Demetrios A. Julius, M.D., editors. A pioneering collection of papers

to discover the part played by individual psychodynamics in drug dependence. 187 pp.

GPO Stock #017-024-00642-4 $2.75 NTIS PB #276 084/AS $9

245
13 COCAINE: 1977. Robert C. Petersen, Ph.D . , and Richard C. Stillman,

M.D. , editors.

and limits of

A series of reports developing a picture of the extent

current knowledge of the drug, its use and misuse. 223 pp.

GPO Stock #017-024-00592-4 $3 NTIS PB #269 175/AS $9.25

14 MARIHUANA RESEARCH FINDINGS: 1976. Robert C. Petersen, Ph.D.,

editor, Technical papers on epidemiology, chemistry and metabolism,

toxicological and pharmacological effects, learned and unlearned behavior, genetic and immune system effects, and therapeutic aspects

of marihuana use. 251 pp.

GPO Stock #017-024-00622-0 $3 NTIS PB #271 279/AS $10.75

15 PEVIEW OF INHALANTS: EUPHORIA TO DYSFUNCTION. Charles Wm. Sharp ,

Ph.D., and Mary Lee Brehm, Ph.D., editors. A broad review of inhalant

abuse, including sociocultural, behavioral, clinical, pharmacological,

and toxicological aspects. Extensive bibliography.

GPO Stock #017-024-00650-5 $4.25 NTIS PB #275 798/AS $12.50

16 THE EPIDEMIOLGY OF HEROIN AND OTHER NARCOTICS. Joan Dunne Rittenhouse, Ph.D., editor. Task Force report on measurement of heroinnarcotic use, gaps in knowledge and how to address them, improved research technologies, and research implications. 249 pp.

GPO Stock #017-024-00690-4 $3.50 NTIS PB #276 357/AS $9.50

17 RESEARCH ON SMOKING BEHAVIOR. Murray E. Jarvik, M.D., Ph.D.,

et al., editors. State-of-the-art of research on smoking behavior,

including epidemiology, etiology, socioeconomic and physical consequences of use, and approaches to behavioral change. From a NIDAsupported UCLA conference. 383 pp.

GPO Stock #017-024-00694-7 $4.50 NTIS PB #276 353/AS $13

18 BEHAVIORAL TOLERANCE: RESEARCH AND TREATMENT IMPLICATIONS.

Norman A. Krasnegor, Ph.D., editor. Conference papers discuss

theoretical and empirical studies of nonpharmacologic factors in

development of tolerance to a variety of drugs in animal and human

subjects.

GPO Stock #017-024-00699-8 $2.75 NTIS PB #276 337/AS $8

19 THE INTERNATIONAL CHALLENGE OF DRUG ABUSE. Robert C. Petersen,

Ph.D., editor. A monograph based on papers presented at the World Psychiatric Association 1977 meeting in Honolulu. Emphasis is on emerging

patterns of drug use, international aspects of research, and therapeutic

issues of particular interest worldwide.

In Press

246

U.S. GOVERNMENT PRINTING OFFICE : 1979-0-304-494
DHEW Publication No. (ADM) 80-727

Formerly DHEW Publication No. (ADM) 78-727

Printed 1977 Reprinted 1979