National

MONOGRAPH SERIES

U S DEPARTMENT OF HEALTH EDUCATION, AND WELFARE Public Health Service Alcohol Drug Abuse, and Mental Health Administration
Cigarette Smoking as a

Dependence Process

Editor:

Norman A. Krasnegor, Ph.D

NIDA Research Monograph 23

January 1979

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

RockviIle, Maryland 20857
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, intergrative research reviews and significant original research Its

dual publication emphasis is rapid and targeted dissemination to the scientific

and professional community

Editorial Advisory Board

Avram Goldstein, M.D.

Addiction Research Foundation

Palo Alto, California

Jerome Jaffe, M.D.

College of Physicians and Surgeons

Columbia University, New York

Reese T Jones, M.D.

Langley Porter Neuropsychiatric lnstitute

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, DC

Lee Robins, Ph.D.

Washington University School of Medicine

St Louis, Missouri

NIDA Research Monograph series

Karst J. Besteman

ACTING DIRECTOR, NIDA

William Pollin, M.D.

DIRECTOR, DIVISION OF RESEARCH, NIDA

Robert C. Petersen, Ph.D.

EDITOR-IN-CHIEF

Eleanor W. Waldrop

MANAGING EDITOR

Parklawn Building 5600 Fishers Lane Rockville Maryland 20857
Cigarette Smoking as a

Dependence Process
ACKNOWLEDGMENT

The meeting on which this monograph is based, held

June 19, 1978, was sponsored by the National Institute

on Drug Abuse and the Committee on Substance Abuse and

Habitual Behavior of the National Research Council.

The National Institute on Drug Abuse has obtained

permission from the copyright holders to reproduce

certain previously published material as noted in

the text. Further reproduction of this material

is prohibited without specific permission of the

copyright holders. With these exceptions, the contents of this monograph are in the public domain

and may be used and reprinted without special

permission. Citation as to source is appreciated.

Library of Congress catalog card number 79-60046

DHEW publication number (ADM) 79-800

Printed 1979

NIDA Research Monographs are indexed in the Index

Medicus. They are selectively included in the

coverage of BioSciences Information Service, Chemical

Abstracts, Psychological Abstracs, and Psychopharmacology Abstracts.

i v
Foreword

The 1979 Smoking and Health report and its press coverage are giving new prominence to the health risks of smoking. At the same

time, the tobacco industry advocates “personal choice” and no

restrictions on smoking, and manufacturers are producing more cigarettes of lowered tar/nicotine content. Most importantly, millions

of individuals--from preteens to adults--are making personal decisions about smoking: to begin to smoke; to change to cigarettes

delivering less tar and nicotine (but no less carbon monoxide); to

stop smoking; and, for most of those who stop, to “light up” again

after a period of abstinence.

Once a person starts to smoke, future choices are less freely made,

because smoking is addictive. The nature of the dependency is not

well understood, and new knowledge is vitally needed. Hence the dependence process is the focal point of this volume.

The findings of researchers who are now seeking answers to questions

about smoking should someday make it possible to influence more individual smoking decisions and to lessen the high economic and social

costs of smoking. This will come through increased knowledge of such

areas as: social and psychological factors in the initiation of

smoking; just what makes cigarette smoking “rewarding”--and also

dependence-producing; the effects of nicotine and the many other solid and gaseous compounds in cigarette smoke; the sites of action of

nicotine in the brain and of possible compounds which may alter or

block its effects; the nature of smoking withdrawal and abstinence

syndromes.

v
This volume on Cigarette Smoking as a Dependence Process presents

the results of some of the research is now beginning to

answer such questions and to raise still further questions for which

answers are needed. The National Institute on Drug Abuse offers

this monograph with thanks to all those who are carrying forward

this work and with an invitation to other qualified investigators

to join them. As part of NIDA’s fulfillment of its charge to carry

out and support research on tobacco-smoking behavior, this book

takes its place with Research Monograph No. 17, Research on Smokin Behavior (1977), and sections on smoking within monographs on

the broader subject of substance abuse: No. 20, Self-Administration

of Abused Substances (1978), and No. 25, Behavioral Analysis and

Treatment of Substance Abuse (forthcoming).

We hope that these publications as well as the research reported

are a significant contribution to the continuing effort to reduce

the toll of disabilities and deaths related to cigarette smoking.

William Pollin, M.D.

Director

Division of Research

National Institute on Drug Abuse

vi
Preface

Cigarette smoking is a dangerous habit. It can lead to a variety

of ailments and serious disorders,

bilitating and fatal illness,

from impaired breathing to desuch as heart disease and cancer.

Cigarette smoking is “slow-motion suicide,” in the words of

Joseph A. Califano, Jr., Secretary of Health, Education, and

Welfare.

Such facts are widely known and accepted by most--including many

who smoke. Yet, some 54 million Americans smoked 615 billion cigarettes last year. The immediate question that comes to mind is

“why”?

Surveys find 90 percent of smokers saying they have tried to quit

or probably would if they had an effective way to do so. In the

past 15 years, 30 million smokers have quit the habit, almost all

of them on their own. Again, the question is “why”?

If this habit were merely an irritating or unpleasant practice, it

might be interesting to explore as another curious facet of human

behavior. But the smoking habit is a case of widespread selfinjury with enormous health consequences that cost the Nation an

estimated $27 billion a year, not to mention the personal toll in

sickness and death. We face a major public health problem created

by millions of individual decisions to risk well-being for a puff

of smoke. Why?

There are many theories to explain such behavior but only pieces

of possible answers. Because of the magnitude of the problem,

those concerned with protecting the public health are compelled to

promote the prevention of smoking in the first place and to find

ways to help others break the habit. To achieve those ends, we

must understand the basis of the smoking habit and its mechanism.

The papers collected in this monograph are steps toward that understanding.

vii
The authors of these papers are among the first to admit that they

do not have final answers, that questions far outnumber answers

in this field. But good questions lead to solutions, and this

effort represents a move toward that goal.

The health consequences of smoking have been studied intensively,

as reflected by more than 30,000 articles on the subject and the

research summarized in the 1979 Report of the Surgeon General on

Smoking and Health. But, until recently, little serious research

has been conducted into the reasons why the smoking habit begins

and how it maintains its hold. Simply put, that is the subject

of these scientific papers. To define the habit that leads individuals to act counter to common sense, and to discover why.

It is appropriate that the National Institute on Drug Abuse assume

leadership in the exploration of these questions because smoking

is surely the most widespread example of drug dependency. The

drug, nicotine, for example, is but one of the 2,000 components

of cigarette smoke and a pack-a-day smoker of cigarettes selfadministers more than 50,000 puffs--or doses--a year. That is indeed drug dependency. The smoking habit is an excellent subject

for research into the biological, behavioral, and psychosocial

aspects of the dependency process.

This kind of research can help us learn why more than 4,000 youngsters take up the habit daily; why women, smoking in greater numbers than ever, find it more difficult than men to quit; why some

individuals can break the habit “cold turkey” and others find it

impossible to quit. There are many other questions that need answers: Is the smoking habit a “true” drug addiction, or is it a

learned social or behavior pattern? Are there nicotine receptor

sites in the central nervous system that can be blocked by medication to break the habit?

Why, in other words, do people persist in the habit despite knowledge of the health consequences? And how can they be helped?)

Such questions are explored in these papers in the hope that the

theories they present, the clues they offer, and the ideas they

prompt will lead to the answers we need.

John M. Pinney

Director

Office on Smoking and Health

viii
Contents

Foreword

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

Preface

John M. Pinney . . . . . . . . . . . . . . vii

Chapter 1 Introduction

Norman A. Krasnegor . . . . . . . . . . . . . 1

Part I. PSYCHOSOCIAL FACTORS

Chapter 2 Smoking as an Addictive Disorder

Jerome H. Jaffe and Maureen Kanzler . . . . . . . . 4

Chapter 3 Psychological Analysis of Establishment and

Maintenance of the Smoking Habit

Daniel Horn . . . . . . . . . . . . . . . 2 4

Chapter 4 Cigarette Smoking as a precursor of Illicit

Drug Use

John A. O'Donnell . . . . . . . . . . . . 30

Chapter 5 Patterns of Tobacco Use in the United States

Dorothy E. Green . . . . . . . . . . . . . 44

Part II. BEHAVIORAL FACTORS

Chapter 6 Nicotine as a Discriminative Stimulus to Behavior:

Its Characterization and Relevance to Smoking

Behavior

John A. Rosecrans . . . . . . . . . . . . . 5 8

Chapter 7 Nicotine Self-Administration in Rats

H. M. Hanson, C. A. Ivester, and B. R. Morton . . . . . 7 0

Chapter 8 The Effects of d-Amphetamine, Meprobamate, and

Lobeline on the Cigarette Smoking Behavior of

Normal Human Subjects

C. R. Schuster, B. R. Lucchesi, and G. S. Emley . . . 9 1

i x
Part II. BEHAVIORAL Factors (continued)

Chapter 9 Tobacco Dependence: Is Nicotine Rewarding

or Aversive?

M. A. H. Russell . . . . . . . . . . . . . 100

Chapter 10 Regulation, Withdrawal, and Nicotine Addiction

Stanley Schachter . . . . . . . . . . . . . 123

Part III. PSYCHOBIOLOGICAL FACTORS

Chapter 11 Acute and Chronic Effects of Nicotine in Rats

and Evidence for a Noncholinergic Site of Action

L. G. Abood, K. Lowy, and H. Booth . . . . . . . 136

Chapter 12 Tolerance to the Effects of Tobacco

Murray E. Jarvik . . . . . . . . . . . . . 150

Chapter 13 The Tobacco Withdrawal Syndrome

Saul M. Shiffman . . . . . . . . . . . . . 158

Part IV. IMPLICATIONS AND DIRECTIONS FOR FUTURE RESEARCH

Chapter 14 Implications and Directions for Future Research

Norman A. Krasnegor . . . . . . . . . . . . 186

Participants in Symposium on Cigarette Smoking as a Dependence

Process . . . . . . . . . . . . . . . . . . .190

List of Monographs . . . . . . . . . . . . . . .191

x
Chapter 1

Introduction

Norman A. Krasnegor, Ph.D

Cigarette smoking is of interest to the National Institute on Drug

Abuse both because of the public health problems associated with

this form of substance abuse and our view that this behavior represents a prototypic dependence process. The scientific data which

link cigarette smoking with risks to health have been well and amply

documented in the first Surgeon General’s Report on Smoking and

Health (USDHEW 1964) and the recently updated version of that document (USDHEW 1979).

Despite this linkage, relatively little scientific research has been

conducted to describe and analyze the cigarette smoking habit itself

or the factors which are responsible for its initiation, development,

maintenance, and cessation. Health risks associated with tobacco

use are predicated upon the necessary existence of a chronic, habitual pattern of cigarette smoking. Scientific data which characterize

the smoking habit are essential, therefore, because they can provide

an understanding of the dependence process and guide the development and testing of efficacious treatment strategies.

This monograph is based upon a meeting held at the National Academy

of Sciences in June 1978, sponsored by NIDA and the Committee on

Substance Abuse and Habitual Behavior of the National Research

Council. The intent of the meeting was to review current knowledge

concerning the psychosocial, behavioral, and psychobiological factors

which characterize the dependence process associated with cigarette

smoking and make cessation of it difficult. This volume, which

includes papers presented at the symposium, is designed to provide

an overview for the scientific community on the smoking habit and

an agenda to guide future research in this area.

The monograph is divided into four sections. In the first, psychosocial factors relating to the dependence process associated with

cigarette smoking are explored. A stimulating discussion of how to

characterize the habit is presented by Drs. Jerome Jaffe and Maureen

Kanzler.

Patterns and trends in tobacco use in the United States are detailed

in Dr. Dorothy Green’s chapter. Cigarette smoking as a precursor

1
of illicit drug abuse, based on a sample of young men, is discussed

by social scientist Dr. John A. O'Donnell. The dean of American

researchers in the area of cigarette smoking, Dr. Daniel Horn, provides a perspective on the psychological factors involved in the

establishment and maintenance of the habit.

The second section, on behavioral factors, is devoted to discussions

of theoretical and empirical data on the role played by nicotine in

the dependence process. Dr. Rosecrans develops arguments concerning

the properties of nicotine as a discriminative stimulus. The wellknown English researcher, Dr. Michael A. H. Russell, presents his

perspective on the dependence liability of nicotine and the smoking

dependence process. Dr. Schuster and his coworkers report findings

on the effects of nicotine on smoking behavior, while Dr. Schachter

discusses his social psychological experiments designed to determine

the relationship of nicotine to withdrawal and addiction. The paper

by Dr. Hanson and his colleagues provides convincing empirical evidence that nicotine is a reinforcer. This information is of special

interest because it demonstrates an experimental model of nicotine

self-administration and because it provides a method for studying

pharmacological and behavioral variables associated with the reinforcing efficacy of the drug.

The third section is devoted to psychobiological phenomena associated

with the smoking process. The paper by Drs. Abood and Lowy provides

evidence suggesting the existence of a central noncholinergic receptor that is specific for nicotine, an exciting field of investigation.

Further, the techniques described offer a methodological approach

to the study of ways to centrally block the reinforcing effects of

nicotine.

The papers by Drs. Jarvik and Shiffman discuss their observations

respectively on the development of tolerance to cigarette smoking

and the withdrawal symptoms associated with cessation of smoking.

This latter work is of particular importance because abstinence

symptoms have been correlated strongly with the relapse to smoking

after cessation.

The final section, by Dr. Krasnegor, is a brief agenda for future research on smoking. It is hoped that this listing of research needs

will be used by members of the scientific community as a focus in

planning and carrying out their research and as a guide in requesting

extramural funding support from the National Institute on Drug Abuse.

REFERENCES

U.S. Department of Health, Education, and Welfare, Public Health

Service. Smoking and Health, Report of the Advisory Committee to

the Surgeon General of the Public Health Service, P.H.S. Publication No. 1103, 1103, Government Printing Office. 1964.

U.S. Department of Health, Education, and Welfare, Public Health

Service. Smoking and Health, A Report of the Surgeon General

P.H.S Publication No. 79-50066, U.S. Government Printing Office.

1979.

2
Part I

Psychosocial Factors
Chapter 2

Smoking as an Addictive Disorder

Jerome H. Jaffe, M.D., and Maureen Kanzler, Ph.D.

Bishop Bartolome de las Casas, observing the use of "tabacos" by

Spanish settlers in the New World, wrote that 'When reproached for

such a disgusting habit, [they] replied that they found it impossible to give it up. I cannot understand what enjoyment or advantage they derive from it" (de las Casas, in Corti 1932, pp.42-43).

Today, appro mximately 450 years after de las Casas recorded those

observations, we are still considering the same two questions

in regard to cigarette smoking: Why don't people give it up? And

what advantage or enjoyment do they derive from it? Some work has

been done in the interval and some of the researchers who have

contributed greatly to our knowledge are participants in this symposium. Because of their work we can now formulate some reasonable

hypotheses about the origins of the "enjoyment or advantage" people

derive from smoke of tobacco leaves, and we even have a considerable body of experience about helping people give up the habit.

De las Casas would be happy to know that giving it up is not impossible, although for some tobacco users giving it up is difficult

and relapse is common.

The title of this monograph refers to smoking as a "dependence

process." Resemblance between tobacco use and consumption of other

substances that produce dependence has been debated throughout history. In 1604, James I, in his Counterblaste tobacco (Corti

1932) appeared to view tobacco and the process of becoming habituated as quite analogous to the process by which a drinker of alcohol became drunkard. Three hundred years later , Sir Humphrey

Rolleston, whose committee recommendations in 1926 set the tom

for the British response to opiate dependence, was asked whether

tobacco smoking was not properly viewed as an addiction. In his

reply, Sir Humphrey differed from James I:

This question turns on the meaning attached to the word

"addiction", and may therefore be a verbal problem. The

Ministry of Health's Departmental Committee on Morphine

and Heroin Addiction (1926) defined an addict as a "person

4
Who, not requiring the continued use of a drug for the relief of the symptoms of organic disease, has acquired, as

a result of repeated administration, an over powering desire for its continuance, and in whom withdrawal of the

drug leads to definite symtoms of mental or physical distress or disorder." That smoking produces a craving for

more when an attempt is made to give it up... is undoubted,

but it can seldom be accurately described as overpowering,

and the effects of its withdrawal, though there maybe

definite restlessness and instability, cannot be compared

with the physical distress caused by withdrawal in morphine addicts. To regard tobacco as a drug of addiction

my be all very well in a humorous sense, but it is hardly accurate (Rolleston 1926).

In at least one sense Rolleston was correct: this issue is a semantic one. And when semantic problems arise, there is always a possibility that the arguments about whether tabacco smoking is properly grouped with other forms of nonmedical drug use will divert

energy from more pragmatic questions. We do not have to ascertain

whether all aspects of tobacco use resemble other drug- using behaviors in all of their particulars. The problems posed by alcohol, opiate and cocaine use differ from each other in a number of

significant ways.

The essential question is to what degree conceptualizing tobacco

use as one of the addictive disorders is of help in directing us

toward appropriate means to deal with problems that tobacco use

causes.

Not all dependence on drugs results in problems for society and/or

the individual. Caffeine consumption is viewed by many as appropriately claased with other forms of dependence, and caffeine dependence can be found in the International Classification of Diseases (ICD 8). There is a caffeine withdrawal syndrome and caffeine

can be abused to the point where it causes problems and disrupts

behavior (Gilbert 1976). But so long as the price of coffee remains within reasonable bounds, scientists and policymakers alike

will think about caffeine primarily as something that adds immeasurably to the beverage served at the coffee break and without which

it is difficult to start the day. For the most part, no grant

applications are submitted to develop preventive treatments for

caffeine dependence; there no debates in the halls of Congress

about taxing it; and coffee drinkers are not forced to sit in the

rear of airplanes. Perhaps some day caffeine may become of concern

to behavioral scientists, but, for the present, the personal and

social costs of this dependence appear to be relatively low. Tobacco dependence, on the other hand, has enormous cost to the individual who develops smoking-related diseases, and diseases 

in turn affect the economic well-being of society.

There are several significant areas in which tobacco use resembles

other drug use, as well as a few areas in which it diverges.

5
When we begin to examine the ways in which tobacco use resembles

other drug-using behaviors, we find ourselves asking the identical

questions: What factors -- biological, psychological, sociological

and pharmacological -- determine whether there will be exprimentation with the drug,a progression to casual or recreational use,

or on to intensive (or excessive) use? What factors are associated with (or cause) compulsive (addictive or dependent) use, and

which factors are associated with relapse after abstinence has been

achieved? Although the factors are interactive, we assume with

tobacco, as with other drug-using behaviors, that certain factors

could act primarily at one stage while others might exert their

effects at other stages.

The objective of this brief overview is not to attempt to Summarize all the factors involved in tobacco-using behavior, but to

point out a few notable similarities and differences between tobacco use and the drug-using behaviors that are more commonly viewed

as "addictions" and to speculate on what the future may hold.

SOME INTERESTING PSYCHOLOGICAL PARALLELS RELATED TO INITIAL USE

As with most other forms of nonmedical drug use, the initial experimentation and regular use of tobacco begin in youth. In the

present climate, which is considerably less approving of cigarette

use than it once was, the behavior often is seen more commonly

among the less wall adjusted (Smith 1970) and less scholastically

successful (Borland and Rudolph 1975; Simon and Primavera 1976).

and especially among those who have friends who smoke (Iarson and

Silvette 1975).

Although there is great overlap between the psychological characteristics of smokers and nonsmokers, in study after study, cigarette smokers on averaqe tend to be more extroverted (Smith 1970),

more intolerant of rules, more adventuresome and risk-taking and,

in some studies, more angry (Thomas 1973) than appropriately matched

nonsmokers (for additional references see Larson and Silvette 1971,

1975). While it can be argued that some of these differences may

be a result of smoking, they are observed even among young people

just beginning to smoke (Smith 1969) and they seem to persist when

the smoker becomes abstinent (Thomas 1973). Eysenck (1973) has

postulated that the smoker is an extrovert who is usually at less

than his or her optimal leve1 of arousal and therefore uses nicotine

to raise the level of arousal. Such a view leads to a "normalizing"

hypothesis to account for the maintenance of the habit hat least

some smokers. Yet many of these same personality characteristics

seem to be associated with exprimentation with other drugs, e.g.,

LSD, opiates and alcohol (Hamburg, Kraemer and Jahnke 1975: Jaffe,

1977) which are not commonly viewed as inducing arousal, an observation which is difficult to reconcile with Eysenck's hypothesis.

Most of those who begin to smoke cigarettes believe that they will

some day give them up (Lieberman 1969). Very few cigarette smokers

at present start out to become dependent. We most infer from their

behavior that gradually the capacity to choose is eroded and, while

6
the user may want to believe s/he can stop at any time, the behavior indicates that this is not case. The attitudes and beliefs

about the likelihood of becoming dependent are not very different

among those who begin to use opiates and alcohol.

With tobacco users, as with users of other drugs, there are numerous theories that attempt to account for the transition from experimentation to continued use. With most other drugs observers are

willing to attribute the ongoing behavior, at least in part, to the

effects of the drug itself; but even with the opiates and alcohol,

researchers recognize that, in certain social settings, the act of

using the drug (rather than its pharmacological effects) may continue to provide some of the reinforcement. So it is with cigarettes -- it is a matter of degree.

Russell, Peto and Patel (1974) investigated motives for smoking in

two groups -- one composed of "normal" smokers, the other an addicted group of heavy smokers attending a withdrawal clinic. A

factor analysis of their responses to a questionnaire separated a

"pharmacological addiction" dimension from the sensorimotor, indulgent, and psychosocial factors. The sensorimotor and indulgent factors appeared to be related to the individual's ability to experience pleasure or its enhancement by smoking and to the act of manipulating the cigarette. The psychosocial factor reflected association of cigarette smoking with a desired public image and with

ease in social situations. In this, as in other studies using

factor analysis (e.g., Ikard, Green and Horn 1969: Mc Kennell 1970)

an addictive dimension repeatedly emerges, but is always accompanied

by nonpharmacological factors. However, the mere presence of nonpharmacological factors in the maintenance of smoking does not serve

to distinguish cigarette smoking from other drug-using behaviors.

Social reinforcers symbolic aspects of the drug-taking behavior

are also postulated to play a major role in the development of a

variety of drug-using behaviors and, indeed, of deviant behaviors

in general (Jessor and Jessor l977). Again, the objective here is

to point to parallels rather than to survey the literature.

PHARMACOLOGICAL FACTORS IN CONTINUED USE

For many years researchers have assumed that, after smoking has

been initiated through psychosocial factors, the behavior becomes

habitual because the pharmacological effects of nicotine are reinforcing (for references see Ejrup 1965; Larson and Silvette 1971

and 1975; Jarvik 1973). Russell (1971 and 1976) has emphasized

that a small "bolus" of nicotine reaches the brain within seconds

after a puff from a tobacco cigarette is inhaled. If nicotine is

a reinforcer then the hundreds of puffs inhaled each day should

produce well-established puff-inhalation habit. There appears

to be support for the view that it is, indeed, nicotine which is

then major reinforcing component in cigarette smoking (although it

may not be the only reinforcer). When nicotine and tar content

are varied independently, it is the nicotine content that is correlated with ratings of strength and satisfaction (Goldfarb et al.

1976). When provided with low- or non-nicotine cigarettes,

7
most smokers complain bitterly or refuse to continue smoking them

(see Jarvik 1973). Nevertheless, reliable laboratory evidence that

nicotine is a reinforcer of drug-taking behavior has been more difficult to develop than comparable evidence for drugs like morphine,

amphetamine or cocaine. In contrast to the latter drugs, which

animals will self-administer over a wide range of doses, animal

self-administration of nicotine has been more difficult to induce

(however, see Hanson, this volume). When it does occur, it appears

to be less powerful reinforcer of behavior than drugs such as

cocain and amphetamine, at least as judged by the number of lever

presses that the animal will make for a single dose of nicotine

(Yanagita 1976).

Nicotine has both peripheral and central effects. The peripheral

effects, such as inhibition of stomach contraction, acceleration

of heart rate, release of epinephrine from the adrenal gland, and

effects mediated by peripheral release of noradrenaline do not seem

to be of major importance in reinforcings smoking. Most of these

can be blocked without altering. the psychological effects in man

(Carruthers 1976). The central effects are obviously more relevant.

But which ones? Nicotine appears to produce multiple effects --

and in this respect the problem of identifying the site of the reinforcing effects of nicotine is unlike the problem of determining which of the multiple effects produced by the opioids or

alcohol are responsible for their reinforcing properties. In man,

nicotine produces an alerting pattern in the EEG and be behavioral

arousal (Domino 1973: Larson and Silvette 1975). It also stimulates

release of a number of hormonal substances from the CNS (Husain

et al. 1975: Winternitz and Quillen 1977: Cryer et al. 1976). Animal studies indicate that nicotine releases norepinephrine and dopamine from brain tissue (See Goodman 1974; Larson and Silvette 1975;

Russell 1976). Depending on the dose, it may increase or decrease

the release of acetylcholine (Armitage, Hall, and Sellers 1969;

Russell 1976). It may also affect brain levels of serotonin. However, with nicotine, as with other drugs, these effects on neurotransmitters do not tell us how nicotine reinforces smoking behavior.

BIOLOGICAL FACTORS IN CONTINUED AND DEPENDENT USE

Many people drink alcohol; a relatively small proportion become dependent. Not all of those who use opiates become dependent. With

the latter drugs, those who become dependent tend to come from disturbed families where alcoholism and, often, a history of sociopathy

or other psychiatric illness is prominent (See Jaffe 1977). One at

first suspects that it is the stress of growing up in such family

that leads to the later tendency to overuse alcohol or illicit drugs.

However, the search for the basis of vulnerability to dependence

on drugs has taken some surprising turns over the last decade. For

males, a genetically transmitted biological vulnerability to alcoholism, that may be independent of disturbed family background, appears to be fairly well established (Schuckit, Goodwin, and Winokur

1972: Goodwin et al. 1973; Goodwin et al. 1974). Less defined and

only suggested by the discovery of opioid receptors and endogenous

opioids is a possible vulnerability to opiate addiction. Even before this discovery, some opiate users maintained that they used

8
opiates not to get high but to feel normal -- not to alleviate withdrawal symptoms but to experience a state of normality that the

nonuser enjoys without the benefit of exogenous substances. The

existence of a syndrome characterized by relative inactivity in an

endogenous opioid such that exogenous substances could at

least theoretically act to "normalize" the user's feeling state

has not yet been demonstrated. Although the existence of a biological vulnerability to tobacco dependence is also speculative, the

possibility of such a biological substrate cannot be excluded.

While we are speculative, we might note one of the effects

produced by cigarette smoking is a sharp rise in cortisol (wintemitz

and Quillen 1977: Cryer et al. 1976). We can assume that this effect is mediated by release of ACTH. Since it seems that a molecule of ß-endorphin is released each time a molecule of ACTH is released (Guillemin et al. 1977) we cannot rule out possibility that

cigarette smoking and release of B-endorpine are related. We might

also note that alcohol and opiate use are not only more likely

to be smokers but they smoke much more heavily (Dreher and Fraser

1968) and often find it easier to give up opiates or alcohol than

cigarettes. Only the arrogance of ignorance accepts as proven that

which can only be an hypothesis at present — that each and every

alcoholic, opiate user, and smoker would be able to function

better without the substance in question. Certainly we believe

that there are millions of current tobacco users who will function

better if they stop smoking, but that is not the same as assuming

that all will be able to give it up without cost in terms of psychological functioning.

We need to know more about the where and the how of tobacco's effect on the brain and the rest of the central nervous system. We

also need to know whether there are people who actually function

better when smoking. the studies that have been carried out on

heavy smokers acutely deprived of nicotine do not answer this

question.

PHYSICAL DEPENDENCE AND WITHDRAWAL

The existence of physical depedence is an inference made from the

observation of a stereotyped withdrawal syndrome which occurs when

a chronically administered drug is discontinued. The withdrawal

syndrome following smoking cessation is not as well studied as other

forms of withdrawal, but few who are knowledgeable doubt that it

exists. It differs in time course and character from that following alcohol or opiate deprivation. The onset smoking withdrawal

symptoms may occur within hours of the last cigarette or may be

delayed for days. The symptoms may last from days to months. Like

the other withdrawal syndromes, there are associated physiological

changes, e.g., decreased heart rate, EEG slowing. In addition to

craving for tobacco, other symptoms have been reported following

the cessation of smoking, such as restlessness, dullness, sleep

disturbances, gastrointestinal disturbances, drowsiness, headache,

amnesia, and impairment of concentration, judgment, and psychomotor

performance (for references see Guilford 1966; Larson and Silvette

1975: Russell 1971; Jaffe and Jarvik 1978; Shiffman and Jarvik 1976).

9
As little as 90 minutes of deprivation may increase irritability

(Schechter and Rand 1974).

However, there are areas of smoking withdrawal that are virtually

unexplored, including the factors that determine the severity of

the syndrome, the time course of its development and decay, the

degree to which it can be conditioned to internal and external (enviromental) stimuli,and the ralatiation of the type and severity of

the withdrawal phenomena to subject craving, to successful cesaation and to relapse after cessation.

with other drugs, the problem of tolerance is usually discussed in

relation to physical dependence. It is apparent that tolerance to

nicotine can develop quickly and that tolerance levels can influenced. The are now hundreds of thousands of smokers who every

day purchase cigarettes delivering only 0.1 mg of nicotine. Many

smokers who at first find such cigarettes to be totally unsatisfying can become accustomed to them. But we know very little about

the nature of tolerance to nicotine and the factors regulating its

development.

TITRATION

If smoking leads to physical dependence and if the withdrawal syndrome is an aversive state, then one might expect to find that smokers would try to avoid withdrawal by maintaining their tobacco (or

nicotine) intake. Indeed, it has been proposed that heavy smokers

don't get any significant positive effects from nicotine, but smoke

primarily to avoid withdrawal (Schachter 1978). This general proposition has provided the basis for a number of experiments that

ask the related questions: Do smokers smoke tobacco primarily to

get nicotine? (i.e., Is nicotine the reinforcer in tobacco smoking?) Do smokers adjust (titrate) their level of smoking to maintain a given level of nicotine in the body? The experiments have

included: (1) administration of nicotine (orally, subcutaneously, and

intravenously) coupled with observation of the number of cigarettes

smoked (or number of puffs taken) and/or degree of satisfaction

(see Jarvik 1973; Russell 1976; kumar et al. 1977; Schuster, this volum); (2) changing the nicotine content of the tobacco and measuring

the smoking patterns (Jarvik 1973) and sometimes the plasma levels of

nicotine (Russell et al. 1975): and (3) administering various drugs

that alter the pharmacological effects of nicotine (Jarvik 1973) or

its disposition (schachter 1978) and then observing smoking behavior

and the psychological effects of smoking. The evidence from most of

these studies strongly supports the view that within limits heavy

smokers do attempt to regulate their plasma nicotine levels by adjusting the rate and amount of tobacco smoked. Heavy smokers appear

to be more consistent in reducing intake of high nicotine cigarettes

to avoid unusually high plasma levels of nicotine than in increasing the number of low nicotine cigarettes to avoid unusually low

levels (Russell et al. 1975). There are several possible explanations for this general finding: (1) Very high plasma nicotine levels maybe aversive for all smokers, while sharp drops in plasm

levels my be aversive for only a subgroup of smokers. Alternatively,

10
the task of trying to maintain plasma levels of nicotine by smoking

a very low nicotine cigarette may itself be aversive because of the

characteristics of the cigarette, the accumulation of carbon monoxide, or because the absence of the reinforcer (nicotine) is itself a frustrating situation.

Most titration and nicotine manipulation experiments also demonStrate that in confirmed cigarette smokers factors other than nicotine contribute to the maintenance of behavior, at least over the

short run. For example, although they complain bitterly, participants in experiments will continue to smoke cigarettes with little

or no nicotine for a period of a week or more (Jarvik 1973). such

participants are of course free to stop smoking at any time. In

one experiment, an intravenous dose of nicotine equivalent to the

content of single cigarette had effect at all on the latency

to puff on a real cigarette or on the amount smoked (Kumar et al.

1977). That short run puffing behavior does not correspond perfectly with nicotine intake or plasma levels does not necessarily

mean that tobacco smoking is a distinct form of substance-using

behavior. Perfect titration of plasma levels of drug is not found

in the classic addictive disorders. Alcoholics titrate alcohol

levels imperfectly. Depending on environmental circumstances and

schedules of reinforcement, such such individuals may tolerate major

decrease in plasma levels. Similarly, some opiate-dependent subjects may continue to work for intravenous opiates when maintained

on high cross-tolerance-inducing doses of methadone (Martinet al.

1973). Many, given adequate motivation, will voluntarily accept

withdrawal from chronically administered opiates. In addition,

addicts may continue to inject themselves and experience opiatelike effects while on blocking doses of narcotic antagonists (O'Brien

1976). It is likely that with nicotine, as with other drugs,

the act of drug use itself acquires secondary reinforcing properties; and also, despite the development of tolerance, the acute

effects of each dose of nicotine may continue to produce effects

that are distinct from relief of withdrawal. We should not expect

a perfect correlation between nicotine levels and smoking behavior

any more than we expect such correlations among the "classic" addictive disorders.

CESSATION AND RELAPSE

Most smokers, like most drug users, have a remarkable capacity for

denial; they appear to that the bad effects caused by drugs

happen to other people. But for many smokers there comes a time

when some element of self-preservation or concern about cost dictates discontinuing tobacco use. At such times an attempt to stop

is often successful, at least in the short run -- just as it is for

users of other drugs. But the relapse rate is high, just as it

seem to be for other addictive substances. Hunt, Barnett, and

Branch (1971) plotted relapse rates for heroin users, cigarette

smokers, and alcoholics. The plotted curves for percent of relapse

over a one-year period were virtually identical. In considering

these curves we need to keep two points in mind. They represent

data taken from individuals who sought "treatment." Evidence is

1 1
mounting that for both alcohol and opiate use the number of individuals who change their use patterns without formal help may exceed,

by far, the number who seek formal treatment (Cahalan, Cisin, and

Crossley 1969). It is estimated that, at present, thirty million

nonsmoking Americans were once regular cigarette smokers. Most of

these stopped without formal treatment. We do not have great deal

of information on the relapse rate for this large population. It

is entirely possible that those who seek formal treatment may constitute a selected group with more severe forms of dependence or a

greater propensity to relapse

TREATMENT

The "treatment" of tobacco dependence, like that of other dependence

disorders, has been approached from many perspectives, none of which

is entirely satisfactory and some of which appear to be relatively

ineffectual. This area has recently been reviewed (Bernstein and

Mc Alister 1976: Schwartz 1977).

As with heroin and alcohol, the reasons for relapse in tobacco dependence appear to be multiple. Indeed, relapse is probably overdetermined and is the result of an interaction among several factors -- the personality of the individual, degree of concern about

health, the functional utility of smoking, susceptibility to the

pharmacological effects of tobacco, the degree to which withdrawal

phenomenona become linked to enviromental stimuli, and exposure

to environment situations which is some way induce smoking. What

is not at all clear is the relative contribution of these various

factors.

SOME POTENTIALLY IMPORTANT DIFFERENCE BETWEEN TOBACCO

USE AND OTHER FORMS OF DRUG DEPENDENCE

Despite the parrallels which may be drawn between tobacco use

the use of other dependence-producing substances, there are some

the use of other dependence-producing substances, there are some

does not induce the acute behavioral toxicity that is seen with

alcohol, opiates, amphetamines, cocaine, and hallucinogens. me

adverse effects of tobacco are exclusively remote and stem from

chronic use rather than from occasional indulgence. There are no

reports of acute fatal tobacco overdosage as a result of smoking or

induced aberrant behavior. The tobacco user presents little danger

to other people (albeit there may be some annoyance from the smoke

and some smokers cause fires) and his/her productivity is not lowered until smoking persists for many years and leads to impairment

of health. Furthermore, the liklihood that regular users of tobacco will suffer a medical illness appears to be directly related

to total dose of certain tobacco constituents over time (Gori 1976).

This situationoffers hope that there may be some level and some

patterns of regular use which are relatively free of hazard. While

this is theoretically true of other drugs, we have thus far been

unsuccessful in finding ways to control their acute toxicity or

their effects on behavior.

12
In the case of other drug-using behaviors, we believe we identified the pharmacological reinforcer. We believe that most drinkers

of gin and tonic want the gin more than the fizz or the quinine,

that people who drink paregoric want the morphine not the camphor. In contrast, we are not entirely certain that nicotine is

the only reinforcer of tobacco-using behavior. Although Russell

(1976) has stated his conviction that nicotine is the reinforcing

component of cigarette smoking, there have been inconsistencies

among the experiments performed over the past twenty years that remain to be resolved. Certainly, the acute effects of nicotine in

the nonsmoking human volunteer have not been as thoroughly explored

as have the effects of opioids, alcohol, or amphetamines in nondependent subject groups. For a substance that exerts such a remarkable hold over so many people, nicotine appears to be less than our

most dramatic reinforcer in animals. There is no "mystique" about

the nicotine "high" that in any way resembles that associated with

the use of alcohol, opiates, cocaine, or marijuana. It is curious

that it is easier to finddescriptions of the acute effects of the

latter substances, which are used by only a small fraction of the

population, than comparable descriptions of the subjective effects

of tobacco, which is used by millions.

low. To a large degree this is because the cost of other drugs,

Compared to other drugs, the cost of a daily ration of tobacco is

such as alcohol, marijuana, and most synthetic substances, has been

sharply increased as a result of deliberate social policies -- either

through taxation or by legal prohibition that adds the costs of

maintaining an illicit distribution system to the cost of the drug

itself. In terms of understanding the differences between tobacco

and other substances, we need to recognize that at present it remains among the relatively inexpensive commodities in most industrialized countries, and for most people it is among the the easiest

to obtain. Since there is evidence to suggest that the consumption

of cigarettes, like other commodities (Peto 1974, 1976; Sehm 1978)

and other drugs (Popham, Schmidt, and De Lint 1975), is responsive

to changes in price, a number of countries are considering taxation

schedules that would reduce overall consumption. In 1976, a bill

was introduced into the United States Senate that would have

raised the taxes on various cigarettes in proportion to the content

of tar and nicotine (Hart 1976).

The social acceptability of tobacco use and dependence is, at present, in a class by itself. In most developed countries, moderate

use of alcohol is accepted and approved. Publice consumption of such

beverage is part of the fabric of society. Nevertheless, it is

considered dishonorable to be seen as an excessive user or to dependent on alcohol, and (despite the prominence of a number of former

alcoholics) most people would rather not advertise their difficulties

in keeping alcohol use at moderate levels. Most people dependent

on tobacco, on the other hand, do not behave as if the continued use

represents either a personal inadequancy or a behavior that ought to

be kept out of the public eye.

For a long time, regular smoking, including heavy smoking, was so

13
common that it was almost "normal." Under such circumstances, it

is understandable that textbooks and diagnostic schemes concerned

with psychiatric, behavior and medical disorders made no mention

of tobacco dependence (see Jaffe 1977). Curiously, the eighth edition of the International Classification of Diseases (ICD #8) listed

caffeine dependence but did not include tobacco dependence. In

the forthcoming ICD # 9, tobacco dependence will be included. Similarly, The American Psychiatric Association's Diagnostic and Statistical Manual, second edition (DSM-II) includes glue sniffing as

a disorder but not tobacco use. In the forthcoming revision, DsMIII, a proposal has been made to include, among the substance use

disorders (i.e., alcoholism, opiate dependence, etc.), a category

designated "Tobacco Use Disorder." Since DSM-III is, at this time,

still in draft form, the criteria for Tobacco Use Disorder cannot

be considered final. It is worthwhile emphasizing, however, that

just as the inclusion of alcoholism (or alcohol dependence) as a

disorder does not imply that every use of alcohol is a disorder,

the inclusion of the category Tobacco Use Disorder does not imply

that every use of tobacco is an indication of a psychiatric abnormality. Indeed, in the current version, even the presence of physical dependence on tobacco (as evidenced by withdrawal symptomatolgy

upon cessation) is not a sufficient for classifying the

behavior as Tobacco Use Disorder, in an otherwise healthy individual.

Mention is made of this possible change in DSM-III primarily to indicate that the climate in which tobacco use occurs is changing

rapidly and this change my change the behavior itself (Jaffe 1977).

A LOOK TO THE FUTURE

If our analysis of similarities and differences in relation to other

addictive disorders is accurate, what changes should use expect in

the near future and what kinds of questions merit our concern?

First, there will be no total victory. Despite our concern about

the adverse health consequences of tobacco use in general, and about

cigarette smoking in particular, a campaign against tobacco use and

tobacco users is not likely to lead to an unconditional surrender --

certainly not in the near future, and probably not within foreseeable future. If history teaches us anything about the nonmedical

use of drugs, it is that, within the limits of the means which free

societies will tolerate, the nonmedical use of drugs that produce

relaxation or pleasure can be reduced but not eliminated. This view

does not imply that increased societal concern and efforts to discourage tobacco use will be without effects. It does imply that in

all probability ten years from now there will still be millions of

people smoking tobacco every day.

Second, we can predict that the characteristics of the population

that smoke will change. History tells us that when there was no

clear cut social disapproval of opiate use (as in Britain and the

united states in the mid-19th century) opium and morphine were included in patent medicines and could be purchased at the local grocery store; opiates were consumed openly and dependence on opiates

was widespread. When social reform and legislation focussed on the

dangers of opiate use, the social climate change. "Respectable"

14
elements within society disavowed both medical and nonmedical use.

Eventually opiate use, even in a medical context, became tinged

with a hint of immorality, and nonmedical use of opiates became

more and more identified with sociopathic elements (See Musto 1973).

Some trends suggest that the changing attitudes toward smoking are

now beginning to produce changes in the population of smokers.

Not long ago cigarette smoking was a behavior that was typical of

men in the upper socioeconomic grups; now, men from lower socioeconomic groups and woman from higher socioeconomic groups may be

over represented (Task Force 1976). These demographic changes imply

that some of those who continue to smoke at present may have a

greater need to do so, or more emotional liabilities. The heavy heaviest smokers and those with the most emotional difficulties are

the least likely to successfully give up smoking (Dreher

Fraser 1968). The heavy smokers of tomorrow may be even more difficult to help than those of today.

Third, we can expect cigarette manufacturers to continue to compete

in lowering tar levels in cigarettes. Over the past decade, both

nicotineand tar levels have been reduced by all major cigarette

companies. The mean tar level of the average cigarette is substantially lower than it was only five years earlier (See Wynder 1976).

This trend is likely to continue until all the cigarette Manufacturers have at least one entry to compete with the very low tar/nicotine brands that deliver only 0.1 - 0.2 mg nicotine and 1 - 2 mg

tar per cigarette. If the degree of dependence is a function of

the daily in take of nicotine, this trend toward nicotine delivery may tend to offset the effects of the self-selection process

induced by the changing social climate. The average smoker of tomorrow may have more emotional need for nicotine but may be less

pharmacologically dependent. However, much depends on the degree

to which tolerance develops to the effects of nicotine and to which

effects.

Just as we have found no single "best approach" to alcoholism or

opiate dependence, we will find no single approach to prevention and treatment of tobacco dependence. Yet it is possible that

studies looking for an optimal approach will undertaken; it is

equally likely that the populations using cigarettes and the patterms of use will have changed by the work is published.

If the prediction that lower nicotine levels in cigarettes of the

future will lead to lower levels of nicotine dependence is correct,

the major problem will continue to be motivating smokers to try to

stop rather than finding new and dramatic way of helping those

who do seek help to succeed. On the other hand, efforts to understand the reasons for relapse will take on increasing importance.

Third party payment of costs of smoking treatment programs will be

considered, discussed argued -- but our crystal ball is too

murky to see the likely outcome of the argument. Since, at present,

medical insurance is expected to cover the cost of treatment of

the health problems caused by smoking, it would seem to be economic

15
common sense to cover costs of effective smoking cessation treatments. But two realities of the present health system in the U.S.

make make such a change unlikely. First, with national attention riveted

on spiralling cost of health care, adding the potential cost of

treating fifty million smokers to the total health care bill will

not be popular. Second, it is quite apparent that most smokers can

stop without formal help. What criteria can be used to allocate

limited treatment resources to those who really require them? what

criteria might be used to define a qualified provider of treatment?

And what procedures could be used to deter the development of a

smoking treatment "rip-off" in which marginal practitioners submit

bills for the treatment of hundreds of smokers — over and over and

overagain?

We must assume that unless there develops a totally unforeseen Puritanical view of tobacco use, we will continue to be concerned with

the adverse health effects of tobacco rather than the use of tobacco

per se. This being the case, the issue of less hazardous smoking

viewed the studies which showed that health hazards of smoking were

dose-related over time. He has computed critical values for intake

of tar, nicotine, and other cigarette components below which there

did not appear to be a statistically significant increased risk of

morbidity. more recently, Gori and his coworkers have concluded

that some cigarettes now on the market are "less hazardous" than

others. The nuances of terminology are worthy of note. currently,

it is considered "bad form" in the medical community to speak of

"safer" cigarettes since that would imply that existing cigarettes

have some degree of safety. "Less hazardous" on the other hand

implies that all cigarettes are hazardous, but some may be less so.

Despite his sensitivity to such semantic nuances, Gori's views have

generated considerable controversy in the medical and smoking cessaCigarette manufacturers are now offering cigarettes with markedly

reduced tar and nicotine In general, there is a positive correlation between tar and nicotine content and amount of carbon monoxide

delivered when the cigarettes are smoked on a machine (Philip Morris

co. personal communication). However, there is considerable variability in CO delivery among brands with similar tar delivery. In

any event, CO delivery of individual cigarette brands has not yet

been made public information and may not be available for another

year. Since cardiovascular disease may be more related to carboxyhemoglobin (CoHgB) levels than to nicotine and tar intake (see

Aronow 1976), it is important to know what happens to the CoHgb of

the smoker as, tar and nicotine are reduced. Vogt (1977) reported

that CO in expired air in his subjects exhibit a dose response

relationship with the number of cigarettes/day his subjects said

they smoked. Vogt, working with men who volunteered for the Multiple Risk Factor Intervention Trial program, found no correlation

between the amount of tar and nicotine delivered by the cigarette

and the CO level; but he did not indicate the brands his

subjects smoked or the proportion of subjects smoking the very low

tar/nicotine brands. In our own work, we have also found that

16
carbon monoxide in expired air correlates substantially and positivily with the number of cigarettes smoked per day (r = .52) in

a group of 34 female smokers. The correlation with CO is increased

(r = .62) if the total weight of the tobacco, smoked is used in the

calculations (Jaffe and Kanzler, unpublished data). Schachter (1978),

reviewing his own work as well as studies of other workers on cigarette smoking, finds much support for the view that heavy smokers

tend to "titrate" their body levels of nicotine. Such a view leads

us to be concerned that those who attempt to reduce tar and nicotine intake by changing brands may merely smoke more cigarettes or

inhale those they smoke more deeply, thereby developing higher carboxyhemoglobin levels as the price for reduced tar and nicotine

intake.

In a study in which we induced twelve female smokers to switch to

less hazardous brands, we did not find CO in expired breath to increase as the smokers switched to brands with lower tar and nicotine.

However, in our group twelve female smokers, there was no appreciable increase in number of cigarette smoked per day. It is possible that the monitoring of CO may have served to inhibit what

might have been an increase in number of cigarettes smoked under

other circumstances (Jaffe et al. 1978).

There are obviously some parallels between this approach to "less

hazardous" cigarette smoking and the use of methadone in the treatment of heroin use or the "responsible drinking" approach to alcohol problems. Both views assume that the drug use in question will

continue and that the most pragmatic approach is to find ways to

live with the drug that cause the least harm to the individual

and society. But, before we can become advocates of "less hazardous"

smoking we need to know more about the "tradeoffs." How much are

the risks risks reduced, and are the benefits, if any, also reduced? To

what extent does the body adjust to decreased nicotine intake so

that lower levels produce effects similar to those once produced by

higher levels? And of equal practical significance, what are the

best ways to induce smokers to switch to less hazardous brands?

The "less hazardous use" approach to smoking-related problems can

generate hostile reactions from some anti-smoking groups, reactions

that are analogous to those that temperance and "total abstinence

for alcoholics" advocates often exhibit toward the proponents of

"responsible drinking" and social drinking for selected ex-alcoholics.

There are also obvious parallels to the bitter schism that has divided those concerned about opiate abuse into pro- and anti-methadone

maintenance camps. Many of the criticisms of the "less hazardous"

smoking approach reflect realistic concerns (just as do some of the

reactions to methadone maintenance and responsible drinking). For

example, what level of risk would be acceptable? And for Which

kinds of disability -- cancer, emphysema, heart disease?

Equally important is the concern that even discussion possibility of a less hazardous cigarette will undermine the effort to

deter smoking among young people who, as with their use of other

drugs, generally deny the possibility of becoming dependence or of

sustaining impairment of health. We might expect that the effort

17
to develop information on the nature of tobacco dependence and the

risks of altered patterns of tobacco use may have a number of valuable byproduction for the understanding of human biology and behaveior. Certainly, there is still much to be learn about where and

how tobacco produces its reinforcing effects. Can we be certain

that the same sites and and receptors involved in these effects are

responsible for its adverse effects on health? Is there a possibility of developing agents more selective than nicotine? Might

such agents offer people who enjoy the effects of tobacco (or find

that tobacco helps them regulate their internal state in some useful way) some of the same effects without the risk? In the present climate, it is difficult to forget that the discovery of endorphins was a byproduct of research that was motivated by concerns

abut opiate dependence.

With tobacco, as with caffeine, dependence per se carries no social

stigma. This contrasts sharply with our present attitudes toward

dependence on opiates and alcohol, which elicit such grave concern

that it is often difficult to persuade physicians to provide dying

patients with enough opiates for relief of pain. It is possible

that the increasing awareness of tobacco as a substance that induces

dependence will not in itself alter or have a significant effect on

the use patterns of the public at large; and that dependence will

continue to be of importance only when people wish to change their

behavior but find that change is exceedingly difficult or requires

special help. We can expect the rediscovery of tobacco as a

dependence-inducing substances to sharpen public recognition that

in proportion to its impact on health we have grossly undersupported

research on tobacco dependence. Over the past decade we have spent

hundreds of millions of dollars on the study of diseases known

to be directly caused by the prolonged use of large amounts of

tobacco. But the few scientists who felt that it was important to

examine tobacco dependence itself rather than the diseases it induces were viewed more with tolerance than with respect. This

monograph is a sign that this attitude is changing and that the

future will see more interest in the nature of tobacco dependence

within the scientific community. If additional funding follows the

increasing interest, we would do well to begin now to set priorities

and frame the important questions.

REFERENCES

Aronow, W.S. carbon monoxide and cardiovascular disease. In:

Wynder, E.L.; Hoffmann, D.; and Gori, G.B., eds. Modifying the Risk

for the Smoker. Vol. I, DHEW pub NO. (NIH) 76-1221, 1976, pp. 321-328.

Armitage, A.K.; Hall, G.H.; and Sellers, C.M. Effects of nicotine

on electrocortical activity and acetylcholine release from cat cerebral cortex. Br J Pharmacol, 35:152-160, 1969.

Bernstein, D.A., and Mc Alister, A. The modification of smoking behavior: Progress and problems. Addictive Behav, 1:89-102, 1976.

18
Borland, B.R., and Rudolph, J.P. Relative effects of low socioeconomic status, parental smoking and poor scholastic performance

on smoking among high school students. Soc Sci Med, 9:27-30, 1975.

Cahalan, D.; Cisin, I.H.; and , H.M. American Drinking Practices: A National Study of Drinking Behaviors and Attitudes. New

Brunswick, N.J.: Rutgers center of Alcohol Studies, 1969.

Carruthers, M. Modification of the noradrenaline related effects

of smoking by Beta-blockade. Psycho1 Med, 6:251-256, 1976.

Corti, C. A History of Smoking. New York: Harcourt Brace, 1932.

Cryer, P.E.; Haymond, M.W.; Santiago, J.V.; and Shah, S.D. Norepinerphrine and epinephrine release and adrenergic mediation

 associated hemodynamic and metabolic events. New England J Med,

295(11):573-577, 1976.

Domino, E.F. Neuropsychopharmacology of nicotine and tobacco smoking. In: Dunn, W.L., Jr., ed. Smoking Behavior: Motives and Incentives. Washington, D.C.: Winston and Sons, 1973. pp. 5-31.

Dreher, K.F., and Fraser, J.G. Smoking habits of alcoholic outpatients. Int J Addictions, 3:65-80, 1968.

Ejrup, B. The role of nicotine in smoking pleasure, nicotinism,

and treatment. In: Von Euler, V.S., ed. Tobacco alkaloids ad Related Compouds. Oxford: Pergamon, 1965. pp. 333-346.

Eysenck, H.J. Personality and the maintenance of the smoking habit.

In: Dunn, W.L., Jr., ed. Smoking Behavior: Motives and Incentives.

Washington, D.C.: Winston and Sons, 1973. pp. 113-146.

Gilbert, R.M. caffeine as a drug of abuss. m: Gibbons, R.J.;

Israel, Y.; Kalant, H.; Popham, R.E.; Schmidt, W.; and Smart, R.G.,

eds. Research Advances in Alcohol and Drug Problems. Vol. 3. New

York: John Wiley , 1976 . pp. 49-176.

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.

Goodman, F.R. Effects P.R. Effects of nicotine on distribution and release of

14C-Norepinephrine and 14C-Dopamine in rat brain striatum and hypothalamus slices. Neuropharmacol, 13:1025-1032, 1974.

Goodwin, D.; Schulsinger, F.; Hermansen, L.; Guze, S.B.; and

Winokur, G. Alcohol problems in adoptees raised apart from alcoholic biological parents. Arch Gen Psychiat, 28:238-243, 1973.

Goodwin, D.; Schulsinger, F.; Moller, N.; Hermansen, L.; Winokur, G.;

and Guze, S.B. Drinking problems in adopted and non-adopted sons

of alcoholics. Arch Gen Psychiat, 31:164-169, 1974.

19
Gori, G.B. Low risk cigarettes: A prescription. Science, 194:

1243-1246, 1976.

Guilford, J.S. Factors Related to Successful Abstinence from Smoking. American Institute for Research, Pittsburgh, 1966.

Guillemin, R.; Vargo, T.; Rossier, J.; Minick, S.; Ling, N.;

Rivier, C.; Vale, W.; and Bloom, F. B-endorphin and adrenocarticotropin are secreted concomitantly by the pituitary gland. Science,

197:1367, 1977.

Hamburg, B.A.; Kraemer, H.C.; and Jahnke, W. A hierarchy of drug

use in adolescence: Behavioral and attitudinal correlates of substantial drug use. Amer J Psychiat, 132:1155-1163, 1975.

Hart, G. Tax reform amendments of 1976—H.R.10612. Congressional

Record, 122(99): Washington, D.C., June 24, 1976.

Hunt, WA; Barnett, L.W.; and Branch, L.G. Relapse rates in addiction program. J clin Psychol, 27:455-456, 1971.

Husain, M.K.; Frantz, A.G.; Ciarochi, F.; and Robinson, A.G. Nicotine-stimulated release of neurophysin and vasopressin in humans.

J Clin Endocrin Metab, 41:1113-1117, 1975.

Ikard, F.F.; Green, D.E.; and Horn, D. A scale to differentiate

between types of smoking as related to the of affect.

Int J Addiction, 4:649-659, 1969.

Jaffe, J.H. Factors in the etiology of drug use and drug dependence -- two models: opiate USe and tobacco USE. In: Schecter, A.

ed. Rehabilitation and Treatment Aspects Of Drug Dependence.

Cleveland: CRC Press, 1977. pp. 23-68.

Jaffe, J.H. Tobacco use as a mental disorder: The rediscovery of

a medical problem. In: 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 Research Monograph 17. DHEW Pub.

No. (ADM)78-581. Washington, D.C.: Superintendent of Documents,

U.S. Government Printing Office, 1977. pp. 202-217.

Jaffe, J.H., and Jarvik, M.E. Tobacco use and tobacco use disorder.

In: Lipton, M.A., Di Mascio, A., and Killam, K.F., eds. Psychology: A Generation of Progress. New York: Raven Press,

978. pp. 1665-1676.

Jaffe, J.H., and Kanzler, M. Unpublished data.

Jaffe, J.H.; Kanzler, M.; Cohen, M.; and Kaplan, T. Inducing low

tar/nicotine cigarette smoking in women. Br J Addict, 73:271-281.

1978.

Jarvik, M,E. Further observations on nicotine as the reinforcing

agent in smoking. In: Dunn, W.L., Jr., ed. Smoking Behavior

Motives and Incentives. Washington, D.C.: Winston, 1973. pp. 33-49.

20
Jessor, R., and Jessor, S.L. Problem Behavior and Psychosocial

Development: A Longitudinal Study of Youth. New York: Academic

Press, 1977.

Kumar, R.; Cake, E.C.; Lader, M.H.; Russell, M.A.H. Is nicotine

important in tobacco smoking? Clin Pharmacol Ther, 21:520-529, 1977.

Larson, P.S., and silvette, H. Tobacco: Experimental and Clinical

Studies, Supplement 2. Baltimore: Williams and Wilkens, 1971.

Larson, P.S., and Silvette, H. Tobacco: Experimental and Clinical

Studies, Supplement 3. Baltimore: Williams and Wilkens, 1975

Lieberman Research, Inc. The Teenager looks at Cigarette Smoking.

American Cancer Society, 1469.

Martin, W.R.; Jasinski, D-R.; Haertzen, C.A.; Kay, D.C.; Jones, B.E.;

Mansky, P.A.; and Carpenter, R.W. Methadone — A reevaluation.

Arch Gen Psychiat, 28:286-295, 1973.

Mc Kennell, A.C. Smoking motivation factors. Br J Clin Psychol

9:8-22, 1970.

Musto, D.F. The American Disease. New Haven: Yale University

Press, 1973.

O'Brien, C.P. Experimental analysis of conditioning factors in

human narcotic addiction. Pharmacol Rev, 27:533-543, 1976.

Peto, J. Price and consumption of cigarettes: A case for intervention? Br J Pre Soc Med, 28(4):241-245, 1974.

Peto, J. Taxes, smoking, and health. (Letter) Lancet 1(7954):

301, 1976.

Philip Morris Co. (Personal communication) 1978.

Popham, R.E.; Schmidt, W.; and De Lint, J. The prevention of alcoholism: Epidemiological studies of the effects control measures. Br J Addict, 70:125-144, 1975.

Rolleston, H. Medical aspects of tobacco. Lancet, 1:961-965, 1926.

Russell, M.A.H. Cigarette smoking : Natural history of a dependence

disorder. Br J Med Psychol, 44:1-16, 1971.

Russell, M.A.H. Smoking and nicotine dependence. In: Gibbins, R.J.

Israel, Y. Kalane, H., Popham, R.I., Schmidt, W., and Smart, R.G., ,

eds. Research Advances in Alcohol and Drug Problems, Vol. 3. New

York: John Wiley, 1976, pp. 1-40.

Russell, M.A.H.; Peto, J.; and Patel, U.A. The classification of

smoking by factorial structure of motives. J R Statist Soc, 137(3):

313-333, 1974.

21
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.

Schachter, S. Pharmacological and psychological determinants of

smoking. Arm Int Med, 88(1):104-114, 1978.

Schechter, M.D., and Rand, M.J. Effect of acute deprivation of

smoking on aggression and hostility. Psychopharmacologia, 35:

19-28, 1974.

Schuckit, M., Goodwin, D., and Winokur, G. A study of alcoholism

in half siblings. Amer J Psychiat, 128:1132-1136, 1972.

Schwartz, J.L. Smoking cures: Ways to kick an unhealthy habit.

In: Jarvik, M.E.; Cullen, J.W.; Gritz, E.R.; Vogt, T.M.; and

West, L.J. Research on Smoking Behavior. National Institute on

Drugs Abuse Research Monograph 17. DHEW Pub. No. (ADM)78-581. Washington, D.C.: Superintendent of Documents, U.S., Government Printing Office, 1977. pp. 308-336.

Sehm, M. Price and aggregate demand for cigarettes (author's abstract). Smoking and Health Bull. USDHEW Pub. No. (CDC) 78-8702:

175, 1978.

Shiffman, S.M., and Jarvik, M.E. Smoking withdrawal symptoms in

two weeks of abstinence. Psychopharmacologia, 50:35-39, 1976.

Simon, W.E., and Primavera, L.H. The personality of the cigarette

smoker: Some empirical data. Int J Addictions 11:81-94, 1976.

Smith, G.M. Relations between personality and smoking behavior

in preadult subjects. J Consult Clin Psychol, 33:710-715, 1969.

Smith, G.M. Personality and smoking: A Review of the empirical

literature. In: Hunt, W.A., ed. Learning Mechanisms in Smoking.

Chicago: Aldine Pub Co., 1970. pp. 42-61.

Task Force on Tobacco and Cancer, Report to the Board of Directors,

American Cancer Society, 1976.

Thomas, C.B. The relationship of smoking and habits of nervous

tension. In: Dunn, W.L., Jr., ed. Smoking Behavior: Motives and

Incentives. Washington, D.C.: Winston and Sons, 1973. pp. 157-170.

Vogt, T.M. Smoking behavioral factors as predictors of risks. In:

Jarvik, M.E.; Cullen, J.W.; Gritz, E.R.; Volt, T.M.; and West, L.J.

Research on Smoking Behavior. National Institute on Drug Abuse

Research Monograph 17. DHEW Pub. No. (ADM)78-581. Washington, D.C.:

Superintendent of Documents, U.S. Government Printing Office, 1977.

pp. 98-111.

Winternitz, W.W., and Quillen, D. Acute hormonal response to cigarette smoking. J Clin Pharmacol, 17:389-397, 1977.

22
Wynder, E.L.; Hoffman, D.; Gori, G.B., eds. Modifying the Risk for

the Smoker. Proceedings of the 3rd World Conference on Smoking and

Health, Vol. 1. DHEW Pub. No. (NIH) 76-1121, 1976. 564 pp.

Yanagita, T. Brief review the use of self-administration techniques for predicting drug dependence potential. In: Thompson, T.,

and Unna, K.R., eds. Predicting Dependence Liability of Stimulant

and Depressant Drugs. Baltimore: University Park Press. 1976.

pp. 231-242.

AUTHORS

Jerome H. Jaffe, M.D.

Professor of Psychiatry

College of Physicians & Surgeons

of Columbia University

722 West 168th Street

New York, New York 10032

Maureen Kanzler, Ph.D.

Assistant Professor of Clinical Psychology

College of Physicians & Surgeons

of Columbia University

722 West 168th Street

New York, New York 10032

23
Chapter 3

Psychological Analysis of

Establishment and Maintenance of

the Smoking Habit

Daniel Horn, Ph.D.

I began studying smoking habits about 30 years ago, primarily because of an interest in the epidemiology of cancer, and continued

partly to help me decide whether or not I should continue to smoke.

Eventually I became persuaded that I would be better off if I

stopped smoking cigarettes, and I accomplished this quite easily

by continuing to smoke only a pipe. Because of the publicity associated with the publication of our American Cancer Society studies

on the effect of smoking on health (Hammond and Horn 1954, 1958),

I found myself the target of innumerable personal accounts of how

people had given up smoking. Not only would friends and associates

do this, but strangers would approach me on the commuter trains

into Manhattan with detailed accounts of how they had accomplished

the feat. Partly because it seemed a waste to ignore this fund of

information, I began to move into a more scientific concern about

the smoking habit, its development, and its alteration.

During these many years I have developed certain prejudices about

statements on cigarette smoking. First, I deplore attempts by

people who apply their personal standards to others’ behavior to

characterize it as “illogical” or “abnormal.” A form of behavior

that was regularly engaged in at some time by approximately threefourths of the males in the United States born around the time of

World War I, as I was, hardly seems appropriately characterized as

abnormal. It was not until the early 1950’s that scientific information became available which persuaded a majority of us that we

would be better off if we did not smoke. Although more than half

of us did eventually quit smoking, many of us found that the behavior had become so integral a part of our way of functioning that it

was difficult to quit. For some, quitting demanded such an investment of effort that it seemed better to postpone trying to a later,

more propitious time, but in the meantime to “hedge one’s bet” by

seeking a filtered cigarette.

My prejudices also encompass those who feel that only the rare individual successfully quits smoking. Roughly a million adults a year

have successfully quit smoking in the past few years. During the

2 4
late 1960’s, with the support of a bombardment of antismoking

announcements on television, the number of persons quitting reached

as high as 3 or 4 million a year (Horn 1970, 1979). Since the long

term success rate during that period was between one-fourth and onethird of those who were trying to quit, we have had as many as 10

million persons trying to quit in a single year.

Also, I deplore those who characterize quitting smoking as a tortured, almost impossible process. For many people, it is easy; for

most it is somewhere between easy and difficult; and only for a

minority is it really difficult.

Finally, the demands of the smoking public have pushed the industry

into developing and promoting cigarettes that produce lower and

lower emissions of harmful ingredients. These have now been demonstrated to be of lesser degrees of harm than those being used formerly, though they are far from being demonstrated as innocuous.

Average tar and nicotine levels, which have been dropping since the

early 1950’s, have dropped another 10 percent in the past 2 years

alone and are now down to 16.6 mg of tar and 1.09 mg of nicotine

(Horn, unpublished data), compared to the 42 mg of tar and 3 mg of

nicotine in the cigarettes before the 1950’s.

In addition to those who quit smoking and those who change to cigarettes delivering less tar and nicotine, increasing numbers of individuals do not become smokers. Until about 25 years ago, cigarette

smoking was a habit that was growing rapidly in each successive

cohort of males born in the United States. It began to take hold

even more rapidly among successive generations of young women.

This phenomenon has slowed and turned around during the past 25

years. The taking up of smoking by young men is now substantially

lower than it used to be, and the growth of the habit among young

women has probably now peaked, at a level appreciably below the

former peak among men (Horn et al. 1959; U.S.DHETW 1972, 1976).

SMOKING AS A LEARNING PROCESS

I have explored the initiation and establishment of the smoking habit

as a learning process partly, no doubt, because of the assumption

that what can be learned can be unlearned. This has been basic to

the descriptive model o f personal choice health behavior about which

I have written, summarizing much of research on smoking (Horn

1976). We have investigated the factors that characterize this class

of behavior with the objective of finding out how to maximize its

benefits while minimizing its harmful effects.

Initiation of the Behavior1

The initiation of personal choice health behavior is usually exploratory in nature. Typically, it takes place in rather young people,

sometimes in young children. It is largely dependent on: first,

the availability of opportunity to engage in the behavior; second,

having a fairly high degree of curiosity about the effects of the

behavior; and third, in finding it a way of expressing either conformity to the behavior of others (such as parents, older siblings

25
or age-equals) or rebellion against what are seen as unreasonable

proscriptions against the behavior.

Characteristically, the greater the availability or the opportunity

for expressing the behavior, the less is the necessity for a strong

commitment either to conformity with the behavior of others or to

rebellion against proscriptions by others (Horn et al. 1959). We

know that smoking, for example, is much more common in children of

parents who are themselves regular smokers, and this is partly because of the ready availability of cigarettes to children when there

is already a smoker in the household and partly because use of

cigarettes by older members of the family sets an example of acceptable behavior and stimulates curiosity about what makes the cigarrette so attractive (Horn et al. 1959).

When smoking first begins to be widespread in a culture, it tends

to be taken up with increasing frequency by successive waves of

young people. Nevertheless! substantial numbers of older people

may turn to it, especially if it can serve as a convenient substitute for previously well-established behavior, as was the case with

cigarettes replacing cigar and pipe smoking in many male populations

between 1910 and 1950. We are seeing a similar phenomenon now in

Third World countries where the promotion of cigarette smoking is

increasing rapidly (Eckholm 1978).

Establishment of the Behavior

The establishment of personal choice health behavior can be influenced by at least three groups of factors. In the case of cigarette

smoking developing as a continuing habit in adolescents, these are,

first, the costs/benefits evaluation of the behavior; second, common

stereotypes that characterize perception of behavior; and third,

psychological factors characterizing both personal structure and

personality integration factors, particularly as they reflect the

relationship of the individual and his needs to society and its

demands.

The costs that go into the evaluation of the costs/benefit balance

may include the harmful effects on health (both physical and mental),

economic cost, and the harmful effects on society, such as economic

or as a form of pollution. The benefits may include positive effects

on health (both physical and mental), economic advantages, social

utility (especially in terms of the facilitation of personal interactions), psychological utility (both in terms of the increase of

positive effect or the reduction of negative effect) and benefits

to society.

There may also be quite separate evaluations of a costs/benefits

analysis for the individual and a costs/benefits analysis for

society, since for some individuals, one of these may be more persuasive than the other in producing attempts to change behavior.

For political leaders, the costs/benefits for society usually take

precedence over the costs/benefits analysis for the individual.

26
When the behavior which appears to be most logical on the basis of

a costs/benefits balance and the actual behavior of the individual

are quite different, another set of factors consisting of rationalizations or some other set of beliefs may come into play to reduce

the dissonance between the “logical” behavior and the actual behavior . In the case of cigarette smoking, the costs for the past

twenty or so years have largely reflected the increasing evidence

of the harmful effects of smoking on health, but in addition to

that, such concerns as esthetic values, the contribution of smoking

to various forms of pollution, and economic values related to the

financial cost either to the individual or to society, have come

into play.

The benefits are wide, ranging from the facilitation of social

interaction, which is perceived or appears as one of the most valuable benefits of taking up smoking, to the reduction of tension and

to the enhancement of states of pleasure which tend to be a later

development in the appreciation of benefits. Such common remarks

as “I can always give up smoking before it hurts me,” or “I don’t

really smoke enough for it to do any damage,” or “The kind of cigarette I smoke (or the way I smoke it) is not very likely to hurt

anyone” are characteristic of beliefs of the individual who perceives potential costs as higher than benefits and yet who continues

to smoke.

Perceptual stereotypes tend to develop as a kind of mythology about

what smoking is like, what smokers are like, and why people smoke.

These tend to be superficial and frequently inaccurate systems of

beliefs and are likely to be derived either from the exaggerations

of advertising on the one hand or the exaggerations of counteradvertising by antismoking groups on the other. In general, the

greater the role played by superficial and inaccurate beliefs about

the behavior, whether positive or negative, the more difficult it

is to develop a sound decision-making process on the part of the

individual or society as a whole.

A variety of patterns of psychological forces may enter into the

determination of personal choice health behavior, in particular,

those that reflect the conflict engendered in individuals by the

demands of society and his own inner demands. In the case of

smoking behavior and health, we have identified two such factors

(Milne and Colman 1973). One depends on the strength of the conflict

perceived by the individual between the satisfaction of his own needs

and the demands imposed on him by society or by its authority figures.

The second factor is a reflection of the urgency to the individual of

maintaining control over his own behavior and over his own destiny

as opposed to being subject either to the control of others or to

the vagaries of chance as represented by “good luck” or by “bad

luck.”

Management of Affect

Although the factors that contribute to the establishment of the

habit probably continue for a time to be important in the mainten2 7
ance of smoking behavior. we have found the model developed bv

Tomkins (1966) and extended by us (Horn and Waingrow 1966; Ikard,

Green. and Horn 19691 to describe the psychological utility of

smoking in terms of its affect management capabilities describes

well the use of smoking even in as young a population as college

students. The use of cigarettes to help in the management of affect,

by augmenting positive affective states and reducing negative affective states, is probably developed quickly; and as the number of cigarettes used per day increases usually up to the ages of 35 or 40, the

individual may shift from using cigarettes for one purpose to using

them for multiple purposes.

This approach to characterizing smoking behavior has been of some use

in developing educational programs for altering smoking behavior, as

a logical application of this knowledge carries with it implications

for interfering with the establishment and maintenance of the behavior. Our critical need at this point is to identify the common patterns that predict establishment of the smoking habit and to find

ways of interfering with that process.

FOOTNOTE

1 . With minor changes, the sections of this paper on “Initiation of

the Behavior” and “Establishment of the Behavior” were included in

an article by Dr. Horn entitled “A model for the study of personal

choice health behaviour,” in The International Journal of Health

Education, 19(2):89-98, 1976. Dr. Horn was then Director of the

National Clearinghouse for Smoking and Health, Bureau of Health

Education, Center for Disease Control, Department of Health, Education, and Welfare. During 1975 and early 1976 he served as a

Special Consultant to the World Health Organization.

REFERENCES

Eckholm, E. Cutting Tobacco’s Toll. Worldwatch Paper 18. Washington, D. C.: Worldwatch Institute, 1978. 40 pp.

Hammnond, E.C., and Horn, D. The relationship between human smoking

habits and death rates. JAMA, 155(15) :1316-1328, 1954.

Hammond, E.C., and Horn, D. Smoking and death rates--report on

forty-four months of follow-up of 187,783 men. JAMA, 166(10):1159-

1172, 1958.

Horn, D. What’s happening to smoking behavior? In: National Conference on Smoking and Health: A Summary of Proceedings. National

Interagency Council on Smoking and Health, 1970. pp. 15-20.

Horn,D. A model for the study of personal choice health behaviour.

International Journal of Health Education, 19(2):89-98, 1976.

2 8
Horn, D. How much real progress have we made in the fight against

smoking? American Lung Association Bulletin, 65(1):6-9, 1979.

Horn, D.; Courts, F.A.; Taylor, R.M.; and Solomon, E.S. Cigarette

smoking among high school students. American Journal of Pubic

Health, 49:1497, 1959.

Horn, D., and Waingrow , S. Some dimensions of a model for smoking

behavior change. American Journal of Public Health, 56:21, 1966.

Ikard, F.F.; Green, D.E.; and Horn, D. A scale to differentiate

between types of smoking as related to the management of affect.

International Journal of Addictions, 4:646, 1969.

Milne, A.M., and Colman, J.G. Development of a teenager’s selftesting kit (cigarette smoking). Final Report. Education and

Public Affairs, Washington, D. C., 1973.

Tomkins, S.S. Psychological model for smoking behavior. American

Journal of Public Health, 56:12 (Part II), 17-20, 1966.

U.S.DHEW. National Clearinghouse for Smoking and Health. Teenage

Smoking--National Patterns: 1968, 1970. U.S. Department of Health,

Education, and Welfare Publication No. (HSM)72-7508, 1972.

U.S.DHEW. National Clearinghouse for Smoking and Health. Teenage

Smoking--National Patterns: 1972, 1974. U.S. Department of Health,

Education, and Welfare Publication No. (NIH)76-931, 1976.

AUTHOR

Daniel Horn, Ph.D.

R. D. 1, Box 182

Frenchtown, New Jersey 08825

2 9
Chapter 4

Cigarette Smoking as a Precursor

of Illicit Drug Use

John A. O’Donnell, Ph.D.

This paper will focus on one question: can the variable of cigarette use be seen as a predictor, and possibly a cause, of other

forms of drug use? Alcohol use and marihuana use will be employed

as competitive predictors and causes.

Many surveys establish that there is a statistical association

between cigarette use, or tobacco use, and use of other drugs.

An association has been found for junior high and senior high

school students of both sexes (Block 1975; Blum et al. 1970;

Josephson 1974; Roth 1972; Shapiro 1975; Spevack and Pihl 1976;

Whitehead, Smart and Laforest 1972; Wolfson et al. 1972). It has

been reported at the college level (Goode 1972; Groves 1974;

Johnson 1973; Steffenhagen, McAree and Nixon 1972), for U.S.

military personnel in Germany (Prendergast, Preble and Tennant

1973), and for medical students (Lipp et al. 1972). Only one

study (Whitehead 1974) reports no association between tobacco

and most other drugs, and this was based on a methodological error;

when the correct analysis is done the usual associations emerge.

None of these studies paid adequate attention to the time order in

which drugs were used. Even investigators who conceptualized cigarette use as the predictor of other drug use, like Goode (1972)

and Johnson (1973), made the error of measuring current cigarette

use, and use of heroin and other drugs at any tune.

One study has quasi-longitudinal data. Johnston (1973) asked

about use during the high school years, and separately about use

in the year after high school graduation. Those who started use

of any drug in that year showed a higher percentage of cigarette

users in the high school years than did the continuing nonusers.

This is highly suggestive, but not conclusive, because the new

users of each drug were outnumbered by those who had used it in

high school. Conceivably, though not probably, that early use had

preceded cigarette use, which would reverse the relationship for the

entire group of users.

30
In a true longitudinal study, Smith and Fogg (1978) measured

cigarette use in 1969, when their 651 Boston students were in the

7th or 8th grade. This use predicted their classification five

years later into one of three categories--nonusers, early

users, and late users (of marihuana and hashish). Measures of attitudes towards smoking and smokers were also predictive.

Finally, Kandel and her associates (Kandel 1975; Kandel, Kessler

and Margulies 1978) surveyed 5500 students representative of New

York State high school students. Questionnaires were completed

in the fall of 1971, the spring of 1972, and by almost 1000 of

the seniors again in late 1972. Much of the time Kandel’s variable

TABLE 1

Time Order of Use of Drugs in the National Sample (Percentages)

ALCOHOL and

Cigarettes

Marihuana

Psychedelics

Stimulantsl

Sedatives1

Heroin

Opiates1

Cocaine

CIGARETTES and

Marihuana

Psychedelics

Stlmulants1

Sedatives1

Heroin

Opiates1

Cocaine

MARIHUANA and

Psychedelics

Stimulants1

Sedatives1

Heroin

Opiates1

Cocaine

Number Who

Have Used

Each Pair

of Drugs

(n = 2510)

Percentage in which

Drug Other Time

in CAPS Drug

First First

Order

unknown

1Quasi-medical use excluded

*Less than half of one percent

31
is “legal drugs,” meaning cigarettes or hard liquor or beer or

wine, and sometimes it is “cigarettes or hard liquor,” so that it

is not possible to separate out the independent effects of cigarettes. Some data make it clear that cigarette use alone, at

time 1, predicted use of marihuana and other drug use at time 2,

beyond the effects of hard liquor and beer or wine. But the large

majority were using cigarettes and one or more kinds of alcohol

at time 1, and there seem to be no data on the time order of use

existing at time 1.

Kandel did regard her data as sufficient to establish that drug

use involves four stages, and that each is almost a necessary

condition for the next. The first involves beer and/or wine, the

second hard liquor and cigarettes. Marihuana use is the third

stage, and other illicit drugs the fourth.

Let us now examine the question with data collected in late 1974

and early 1975. The primary sample was a nationwide probability

sample of 2510 men, then 20 to 30 years old inclusive, selected

from Selective Service records. It may be regarded as representative of young men in the United States, except for Alaska and

Hawaii (O’Donnell et al. 1976). A secondary sample of 294, of

the same ages, was drawn from high drug use areas in New York

City. It should not be regarded as representative of any population, but it is a sample of the general population, not a sample

from a prison or treatment agency.

Table 1 presents the temporal relationships of alcohol, cigarette

and marihuana use with each other and with other drugs. It

should be noted that no drug was invariably the first. Still,

the preponderance is clear, and any of the three could be an

efficient predictor of the use of other drugs.

The first row of table 1 shows that alcohol normally preceded

cigarettes in this sample; if the indeterminate cases are distributed like the known cases, alcohol was first in 71 percent of the

cases where both were used. Cigarettes, in turn, normally preceded marihuana. It should be added that the interview inquired

about regular cigarette use. The word “regular” should always be

understood, though I will often omit it.

Earlier studies (O’Donnell and Clayton 1978; O’Donnell and Clayton,

forthcoming) have suggested the hypothesis of a causal chain, begining with alcohol use, leading to marihuana use, leading in turn to

the use of other drugs. Cocaine is used as an example of “other

drugs” in table 2. Lifetime use of marihuana is shown as an ordinal

variable across the top, ranging from no use, through increasingly

heavier degrees of use; the total row at the bottom shows that the

percentage of those who used cocaine increases as marihuana use increases. This zero-order relationship, seen in the bottom row, is

repeated in all other rows essentially unchanged, with extent of

alcohol use controlled.

3 2
The zero-order relationship of cocaine use with alcohol use may be

seen in the last column; again, cocaine use increases linearly with

alcohol use, though not as strongly as it did with marihuana use.

But this zero-order relationship disappears in each of the other

columns, when marihuana use is controlled. The findings are precisely what one would expect if marihuana use comes after alcohol

use but before cocaine use in the causal chain. The marihuanacocaine relationship is not reduced by control on a prior variable,

alcohol, while the alcohol-cocaine relationship disappears when controlled on an intervening variable, marihuana use.

Despite this evidence for alcohol’s causal status, we have regarded marihuana use as the crucial variable. Part of the reason

is an historical accident; most of the debate in the literature

has been in terms of the marihuana-heroin relationship. But part

relates to practical considerations. Almost all men used alcohol,

and the users tended to bunch at the high use end of the scale,

as can be seen from the column of n’s in table 2. The marihuana

variable offered a better distribution for prediction purposes.

Finally, while both alcohol and marihuana were associated with other

drugs, the zero-order relationship was stronger for marihuana. Table

2 shows that the percentage of cocaine use ranged from under 1

to 58 percent as marihuana use increased from none to heavy, while

the corresponding range for alcohol was only from zero to 22.

This, of course, is to be expected if almost all of the effect of

alcohol on cocaine use is indirect, through marihuana, with little

or no direct effect.

One practical use for predictors would be in prevention of drug use.

The analysis thus far suggests that one way to prevent or reduce

cocaine use would be to reduce the marihuana and alcohol use that

predict it. But to fall in the “heavy” categories of alcohol and

marihuana use might take years of use, and the use of cocaine (or

other drug) could have started before the prediction is firm. For

prevention purposes, what is needed are predictors which can be

easily measured at an early point in time.

Age at first use of marihuana seems to be such a predictor. Table

3 shows, for both samples, that the earlier marihuana use began,

the more likely was the use of heroin and of other opiates.

Similar tables, not included here, show that it is an equally

powerful predictor of the use of other drugs, of illicit drug

sales, and of criminal behavior.

To sum up the above and much other work, marihuana use normally,

though not universally, precedes other kinds of illicit drug use,

and has strong statistical associations with them, We have tested

for spuriousness on the variables we have available, have seen no

indications that these associations are spurious, and we believe

that intervening variables between marihuana use and, for example,

heroin use have been identified. These statements are sufficient

for the assertion of a causal connection, by one conception of causality widely used in survey research (O’Donnell and Clayton 1978).

3 3
TABLE 2

Use of Cocaine, by Extent of Lifetime Use of Alcohol and Marihuana (Percentages)

Extent of

Lifetime Use

of Alcohol

n

a None

(2510) (1128)

Extent of Lifetime Use of Marihuana

Experimental Light Moderate

(4231 (231) (227)

Heavy

(501)

Total

None (76) 0 _b 0 0 0

Experimental (93) 0 0 0 0 (1 o f 2) 1

Light (491) 0 0 4 37 53 7

Moderate (318) 0 2 0 24 40 8

Heavy (599) *

c

1 2 16 54 14

Heaviest (933) 0 1 6 20 63 22

Total (2510) * 1 4 22 58

aParentheses indicate numbers of individuals; figures without parentheses are percentages.

bA dash indicates there were no cases in the cell.

cAn asterisk means less than one-half of one percent.
TABLE 3

Use of Heroin and Use of Opiates, Including Heroin, by

Age at First Use of Marihuana, in Two Samples

Age at First

Use of Marihuana

A. National Sample

Percent Used Percent Used

Heroin Opiates

16 or less (288)

17-18 (329)

19-20 (346)

21 or more (419)

Never used (1128)

Total (2510)

B . New York City Sample

14 or less (41)

15-16 (61)

17-18 (53)

19 or more (65)

Never used (74)

Total (294)

One user among 1128 men.

The statistical associations and time order hold for alcohol too.

We have not directly examined the possibility of spurious relationships for alcohol, but it seems most unlikely that they could be

completely spurious, because of the apparent causal path through

marihuana. The question now becomes: do cigarettes too have some

causal impact?

The question can be clarified by considering the hypothetical

causal model in figure 1, where the four variables are arranged

from left to right in the tune order established by table 1. The

problem would be to assign values to the path coefficients of the

35
FIGURE 1

Hypothetical Causal Model

arrows shown, especially the values of arrows 4 and 5; does cigarette use affect marihuana use, and does it affect illicit drug

use directly, in addition to whatever effect it has through

marihuana use?

Problems arise because of the unnumbered arrows, which represent all

other influences which impinge on the endogenous variables. There

must be many variables which at one point influence a person’s

alcohol behavior, later his starting to use marihuana, and so on--

factors such as unconventionality, rebelliousness, and curiousity.

If these had been measured and could be added to the model, the

model would be complex, but the solution of its linear structural

equations would be straightforward. These measures are not available,

however, so any attempt to use the model as it stands would confound

the effects of these variables with those of the variables included

in the model, producing incorrect values for the coefficients.

A second problem arises with the arrow from alcohol to cigarettes.

Are we Justified in determining time order, and using a singleheaded arrow, when alcohol is known to be first only 59 percent

of the time? It would appear safer to take cigarette use as an

exogenous variable too, and replace the arrow between it and

alcohol with a symbol indicating that we are taking the correlation

between the two as given and unexplained. But this in turn would

mean that we can never isolate the effect of cigarettes; part of

its apparent effect would be due to its correlation with alcohol

use. The converse is also true; the effect of alcohol use would

be partly-confounded with that of cigarette use. For both

practical and theoretical reasons, therefore, we cannot expect an

exact measurement of their relative influences.

3 6
We can get some hints, however, from simpler approaches. Two

smoking variables are available. One, which might be labeled

“Heaviest Smoking”, refers to the number of cigarettes smoked

daily during the heaviest period of smoking. It is related to

marihuana use in table 4. There is a low degree of association--a

gamma of .218.

Table 5 uses the second smoking variable, age at first regular use

of cigarettes. The expected negative association with marihuana

is found, but it is weak--a gamma of only -.107 when based on the

age differences among cigarette users, increasing to -.248 when

the nonusers also contribute to the association.

By both measures, then, it appears cigarette use may be seen as

a predictor, and possibly a cause, of marihuana use, but hardly

as an efficient predictor or an important cause.

To examine its relationship with other drug use, an index of nonmedical drug use was constructed. This index summarizes in one

number each man’s lifetime use of sedatives, stimulants, psychedelics, heroin, other opiates and cocaine. The index weights

each category of use, for each drug class, by the frequency of

that category in the sample, so that the drugs used by fewer men,

and the higher frequencies of use, receive higher scores. The

range of scores in the sample is from 420 to 992, but 70 percent

of the sample score below 500, because few men used drugs beyond

marihuana. The relationship of cigarettes to this index was

examined in two ways.

First, the index was divided into five categories and crosstabulated against the "Heaviest Smoking” variable, within categories of lifetime extent of alcohol and marihuana use. Using

Kendall’s tau c and the .05 level, the pattern of findings was

clear. Smoking continued to be significantly, though not strongly,

associated with the index when controlled on alcohol use,

suggesting that alcohol is a prior variable.

When marihuana use was controlled, the association between smoking

and the index was not significant for one category, the men who

did not use marihuana, but was significant in each of the other

four categories where the extent of marihuana use varied. This

is precisely the opposite of what happened when the alcohol

association with the index was controlled on marihuana use. There,

the association remained significant among the non marihuana

users, but disappeared in the four categories of users. The

implications may be summed up in a few statements.

1. Use of the six drug classes with which we are concerned here

was rare and minimal among men who did not use marihuana.

2. The effect of alcohol on nonmedical drug use operates almost

entirely through its effect on marihuana use, with little or

no direct effect.

3 7
Lifetime

TABLE 4

Lifetime Extent of Marihuana Use, by Number of Cigarettes Used Daily

During Period of Heaviest Smoking (Percentages)

Number of Cigarettes Used Daily

no. reg. Less 1-4 5-14 15-24 25-34 35-44 45+

Marihuana

Use (n)1

cig. use than 1

(766) (25)

Never 60

Less than 10 times 16

10-99 times 10

100-999 times 9

1000 or more times 5

100

48

16

16

8

12

100

(116)

54

16

13

14

3

100

(229) (491)

41 38

14 17

14 14

16 17

15 14

100 100

gamma = .218

(308)

39

17

12

20

13

101

(365) (208)

34 33

20 18

21 20

12 12

12 17

99 100

1

2 cases missing; unknown on number of cigarettes used dally
Lifetime

Marihuana

Use

Never

Less than 10 times

10-99 times

l00-999 times

1000 or more times

TABLE 5

Lifetime Extent of Marihuana Use, by Age at First Regular

Use of Cigarettes (Percentages)

(n)1

14 or

earlier

(518)

15-16 17-18 19+

(452) (425) (348)

(1128) 35 36 42 42

(423) 17 17 19 17

(356) 15 16 16 17

(338) 15 18 14 14

(264) 19 13 10 9

101 100 101 99

gamma = -.107 (on 4 age columns)

= -.248 (on all 6 columns)

Tobacco Never

but no Used

reg. cig. Tobacco

(467) (299)

52 73

20 9

13 6

10 8

5 4

100 100

1One case missing; age at first use of cigarettes unknown
3 . The effect of cigarette use on nonmedical drug use is direct,

as well as indirect through marihuana use. But the effect is

small. While statistically significant, the value of tau-c

is usually below .lO with the control on marihuana, and no

higher than .20 without that control.

The second approach uses the second of the two smoking variables

employed earlier, age at first regular use of cigarettes. Corresponding to this are age at first use of alcohol and age at first

use of marihuana. These were not grouped into categories, but the

full range of ages was used, as was the full range of index scores.

The correlations and some partial correlations are presented in

table 6, using computer labels like “CigAge” for “Age at first

regular use of cigarettes,” to save space.

TABLE 6

Correlations and Partial Correlations Among

Age Variables and Drug Use Index

A . Correlation Matrix (Pearson r

1

)

CigAge MarAge Drug Use

AlcAge .324 .314 -.281

(1718) (1375) (2427)

CigAge .242 -.112

(1074) (1741)

MarAge -.419

(1379)

1All correlations are significant at the .00l level.

B. Partial Correlations

Variables Control on Partial r (n) Signif.

CigAge-Drug Use AlcAge -.023

CigAge-Drug Use MarAge -.012 (1073) NS

CigAge-Drug Use AlcAge & MarAge .037 (1072) NS

AlcAge-Drug Use CigAge -.261 (1717) .001

AlcAge-Drug Use MarAge -.174 (1371) .001

AlcAge-Drug Use CiAge & MarAge -.177 (1072) .001

MarAge-Drug Use CigAge - .407 (1073) .001

Mar-Age-Drug Use AlcAge -.363 (1374) .001

MarAge-Drug Use CigAge & AlcAge -.364 (1072) .001

40
As might be expected, the three age variables are positively correlated--men who began to use alcohol or cigarettes or marihuana

early tended to use the others at early ages too. Also as expected,

each of the age variables is negatively correlated with the drug

use index--the earlier a man started to use one of these three,

the more likely he was to become involved in nonmedical drug use.

The marihuana correlation with drug use is -.419. This leaves

most of the variance unexplained, but .4 is a quite respectable

correlation in social science research, and would be enough to

suggest what we already know from table 3, that age at first use

of marihuana may be a useful predictor of other drug use. Further,

as may be seen in the lowest panel, the correlation is hardly

reduced at all by controls on the other age variables.

The correlation of Alcohol Age with Drug use is lower, at -.281,

and is appreciably reduced by a control on Marihuana Age, though

still significant. It might have some independent and additive

predictive power.

Finally, and of most relevance here, the correlation between

Cigarette Age and Drug Use is only -.112. It is statistically

significant, largely because it is based on 1700 cases, but its

substantive importance could not be great. And even that little

importance completely disappears when the relationship is controlled on either Alcohol Age or Marihuana Age.

DISCUSSION

It is the writer’s impression, though not yet confirmed by any

data found in the older literature, that up to a decade or so ago

it was rare for anyone without prior smoking experience to experiment with marihuana. That inhibitory factor would have produced

an association between smoking and drug use, easily seen as a

causal connection, and it would have been plausible to predict

that a decrease in smoking would lead to a decrease in drug use.

But that inhibition, if indeed it did exist, seems to be disappearing. In late 1974, when the sample of young men was interviewed, of 299 men who had never used tobacco in any form, 27

percent had used marihuana. Of 467 who had used tobacco, but not

cigarettes, 48 percent had used marihuana, while of the 1743 who had

 used cigarettes regularly, 62 percent used it. The differences

suggest that some inhibition may still persist, but 27 and 48

are not negligible percentages. By a few years ago there were

confirmed marihuana users, and users of other drugs, who quite

seriously stated they would never use tobacco because tobacco has

health hazards.

The association of cigarette use with drug use therefore may be

partially a causal connection. It appears likely that much of

it may be spurious, due to the fact that both are connected with

alcohol use, and almost certainly with personality and social

4 1
variables that have been studied with respect to single substances,

but not with respect to several simultaneously. Whatever the

nature of the association, it is small, and would not suggest

that cigarette use would be a useful predictor of later drug use.

REFERENCES

Block, J.R. Behavioral and demographic correlates of drug use

among students in grades 7-12. In: Lettieri, D.J., ed. Predicting Adolescent Drug Abuse. Rockville, Md.: National Institute

on Drug Abuse, 1975. pp. 263-276.

Blum, R.H., and Associates. Students. and Drugs II: College and

High School Observations. San Francisco: Jossey-Bass, 1970.

399 pp.

Goode, E. Cigarette smoking and drug use on a college campus.

Intl J Addictions, 7(1) :133-140, 1972.

Groves, W.E. Patterns of college student drug use and lifestyles.

In: Josephson, E. and Carroll, E.E., eds. Drug Use: Epidemiological and Sociological Approaches. New York: John Wiley, 1974.

pp. 241-275.

Johnson, B.D. Marihuana Users and Drug Subcultures. New York:

John Wiley, 1973. 290 pp:

Johnston, L. Drugs and American Youth. Ann Arbor, Mich.:

Institute for Social Research, 1973. 273 pp.

Josephson, E. Trends in adolescent marihuana use. In: Josephson,

E. and Carroll, E.E., eds. Drug Use: Epidemiological and

Sociological Approaches. New York: John Wiley, 1974. pp. 177-

205.

Kandel, D. Stages in adolescent involvement in drug use. Science

190 (4217): 912-914, 1975.

Kandel, D.; Kessler, R.C.; and Margulies, R.Z. Antecedents of

adolescent initiation into stages of drug use: a developmental

analysis. J Youth and Adolescence 7(1):3-40, 1978.

Lipp, M.; Tinklenberg,

and Peterson, M.

J.; Benson, S.; Melges F.; Taintor, Z.;

Medical student use of marijuana, alcohol and

cigarettes: a study of four schools. Intl J Addictions 7(1):

141-152, 1972.

O’Donnell, J.A., and Clayton, R.R. The stepping-stone hypothesis--

marihuana, heroin and causality. Paper presented at Meeting of the

American Sociological Association, San Francisco, September, 1978.

To be published in Addictive Diseases.

4 2
O’Donnell, J.A., and Clayton, R.R. Determinants of early marihuana

use. In Friedman, A.S., Beschner, C. and Pittell, S. Youth Drug

Abuse: Problems, Issues, and Treatment. Lexington, Mass.: Lexington,

Books, forthcoming.

O’Donnell, J.A.; Voss, H.L.; Clayton, R.R.; Slatin, G.T. and

Room, R.G.W. Young Men and Drugs: A Nationwide Survey. National

Institute on Drug Abuse Research Monograph 5. DHEW pub . No.

(ADM)76-311. Washington, D.C. : Superintendent of Documents,

U.S. Government Printing Office, 1976.

Prendergast, T.J., Preble, M.R.; and Tennant, F.S. Drug use and

its relation to alcohol and cigarette consumption in the military

community of West Germany. Intl J Addictions 8(5):741-754, 1973.

Roth, R. Student drug abuse in southeastern Michigan and profiles

of the abusers. In: Einstein, S., and Allen, S., eds. Student

Drug Surveys. Farmingdale, N.Y.: Baywood, 1972. pp. 55-66.

Shapiro, R.D. Alcohol, tobacco and illicit drug use among adolescents. Intl J Addictions 10(3):387-390, 1975.

Smith, G.M. and Fogg, C.P. Psychological predictors of early use,

late use and nonuse of marihuana among teenage students. In:

Kandel, D.B. Longitudinal Research on Drug Use. New York: Wiley,

1978. pp. 101-113

Spevack, M. and Pihl, R.O. Nonmedical drug use by high school

students: a three-year survey study. Intl J Addictions 11(5):

755-792, 1976.

Steffenhagen, R.A.; McAree, C.P.; and Nixon, H.L. Drug use among

college females: socio-demographic and social psychological

correlates. Intl J Addictions 7(2):285-303, 1972.

Whitehead, P.C. Multidrug use: supplementary perspectives. Intl

J Addictions 9(2) :185-204, 1974.

Whitehead, P.C.; Smart, R.G.; and Laforest, L. Multiple drug use

among marihuana smokers in eastern Canada. Intl J Addictions

7(1): 179-190, 1972.

Wolfson, E.A.; Lavenhar, M.A.; Blum, R.; Quinones, M.A.; Einstein,

S.; and Louria, D.B. Survey of drug abuse in six New Jersey high

schools: I. Methodology and general findings. In: Einstein, S.,

and Allen, S., eds. Student drug Surveys. Farmingdale, N.Y.:

Baywood, 1972. pp. 9-32

AUTHOR

John A. O’Donnell, Ph.D.

Department of Sociology

University of Kentucky

Lexington, Kentucky 40506

4 5
Chapter 5

Patterns of Tobacco Use in the

United States

Dorothy E. Green, Ph.D.

From the time of World War I until the mid-1960’s, when the health

hazards of cigarette smoking became common knowledge, the number

of smokers grew at increasingly rapid rates. After the publication

of the Report of the Advisory Committee to the Surgeon General in

1964 (USDHEW 1964) both government and private organizations

undertook to inform the public of the health consequences of

smoking and thus to halt the increase in numbers of smokers. This

paper describes the patterns of tobacco use since this effort began.

Shortly after the Surgeon General’s report was issued, the National

Clearinghouse for Smoking and Health (NCSH) was established in the

Public Health Service. Since 1964, several surveys of tobacco use

patterns among adults, teenagers, and health professionals have

been conducted by private organizations for the NCSH. The data

presented below are drawn from these surveys.

DEMOGRAPHIC DATA ON ADULT CIGARETTE SMOKERS

Surveys of adult tobacco use were made in 1964, 1966, 1970, and

1975 (USDHEW 1969; USDHEW 1973; USDHEW 1976a). In 1975, sample

size was approximately 12,500; in each of the three earlier surveys,

it was about 5,000. Additionally, except in 1964, followup studies

were made of persons previously surveyed.

Age and Sex

At the time of the Surgeon General’s report, a little over half

the men (52.4 percent) and almost one-third of the women (32.5

percent) were cigarette smokers. (Data from the two surveys of

national probability samples of adults age 21 and over conducted

in the fall of 1964 and the spring of 1966 have been combined.)

By 1975, these percentages had dropped to 39.3 percent of the men

and 28.9 percent of the women.

In that ten-year period, the greatest decreases in smoking among

men occurred during the first five years, when male smoking dropped

from 52.4 percent to 42.2 percent. Decreases occurred in every

4 4
age group, except that between 1970 and 1975 there was a slight

increase in the proportion of men age 65 and over who smoke.

The decrease in female smoking between 1964 and 1975 was not so

large, but occurred in every age group except those age 55 and

over. There was a small increase in the youngest age group--age

21-24--from 1970 to 1975, but a substantial decline as compared

with the 1960’s.

The increases in the proportion of smokers in the older age groups

do not, of course, reflect the taking up of smoking by senior

citizens, but simply the aging of a population which included

large numbers of smokers. The percentages are much smaller than

would have been predicted from earlier data on this cohort. The

slight increase in young women who smoke follows the trend in

teenage girls’ smoking, discussed below.

Marital Status

In 1975, the majority of the respondents (78 percent of the men

and 71 percent of the women) replied that they were married. Since

married persons comprise such a large part of the total population,

their smoking rates parallel those of the population as a whole.

In the married group there is a slight drop since 1970 in the

proportion of current smokers: from 40 percent to 38 percent for

males, and from 32 percent to 28 percent for females.

About the same percentage of males who have never been married and

males who are married are current smokers. Single females have a

slightly higher rate than those who are married (31 percent and

28 percent respectively). Both males and females show a substantially lower smoking rate than in 1964-66 or in 1970 (61 percent

of single males and 33 percent of single females were current

smokers in 1964-66; comparable data for 1970 were 56 percent and

36 percent.

The highest smoking rates are among those who are divorced or

separated. While only one-third of the respondents who are married

and living with spouse are smokers, 60 percent of the men and 50

percent of the women who arc divorced or separated are smokers.

This represents a substantial decrease from the 1970 data showing

that 76 percent of the men who were divorced or separated were

smokers; but at the same time, it represents an increase from the

44 percent rate for women reported in that year. This is comparable to findings in the earlier surveys.

Men who are widowed have a slightly lower smoking rate (36 percent)

than those who are married (38 percent). Widowed women, however,

have a much lower rate (19 percent) of cigarette smoking than do

married women (28 percent). This probably reflects the lower

smoking rate among older women. The proportion of smokers among

both males and females in this marital category (widowed) is little

different from that observed in 1964-66 or 1970.

45
To summarize the marital status category, the data show that men

and women who are divorced or separated are more likely to be

cigarette smokers than are persons who are married, widowed, or

single. In all marital categories, a greater proportion of men

than of women are smokers.

Educational Level

The smoking rates are lowest for those who never went to high

school--37 percent for men and 18 percent for women. Because

educational level is related to income, there may be a correlation

between income and the cost of cigarettes for persons in this

education group.

At all other educational levels there is a decided inverse relationship between the amount of education and smoking behavior,

with a smaller proportion of smokers at higher educational levels.

Among males, those who attended high school but not college showed

46 percent current smokers, those with some college, 36 percent,

and those who graduated from college, 28 percent. Comparable

proportions for women are 32 percent, 32 percent, and 21 percent.

An examination of quit rates shows that half of the college graduates who ever smoked cigarettes are now former smokers.

Occupation

Among males, white collar workers (including sales personnel) are

much less likely to be current smokers (36 percent) than are those

in all other occupations (47 percent). This finding is consistent

with the relationship between educational level and smoking behavior.

two-fifths of the women in the sample reported that they are

employed outside the home. Of these employed woman, one-third are

current smokers, while only 27 percent of those who classify themselves as housewives are smokers. This finding tallied with previous evidence of greater prevalence of smoking among working women.

Among the employed women, white collar workers are somewhat more

likely to smoke than arc those in other occupations (34 percent

and 32 percent, respectively)--a relationship opposite to that

found among men.

Income

Family income is related to smoking rates with both males and

females, but in different ways. Men in relatively affluent families are less likely to smoke, while women in this group are more

likely to be current smokers. Only 35 percent of the men who

reported an annual family income of $20,000 or mare are cigarette

smokers, while 46 percent of the men in the $7,500-$10,000 range

are smokers. Among women, however, there is an increase in smoking

from 24 percent for those in families earning under $3,000 to 34

percent for those with incomes of $20,000 or more.

46
REMEDIAL ACTION--SETTING LIMITS

There has been a growing feeling that nonsmokers have a right to

be allowed to breathe air free from contaminants in cigarette

smoke. A dramatic change in attitude has taken place over the

years toward agreement with the statement, “The smoking of cigarettes should be allowed in fewer places than it is now.” Only

52 percent agreed with this statement in 1964 and 1966, but 57

percent agreed in 1970, and 70 percent in 1975. Between 1970 and

1975, this increase took place among current smokers (from 42

percent to 51 percent), among former smokers (from 61 percent to

77 percent), and among those who have never smoked (68 percent to

82 percent). This means that more than half the present smokers

would like to see smoking allowed in fewer places than it is now,

despite the fact that there are more and more restrictions on

places where people are allowed to smoke.

Since so many people would like to see smoking allowed in fewer

places, it is not surprising to find that nearly two-thirds (63

percent) of the respondents say that it is annoying to be near a

person who is smoking cigarettes. Ten years ago less than half

of the total number of respondents (46 percent) agreed with this,

and now even more than a third of the smokers (35 percent) do so.

A ban on cigarette advertising was advocated by a little over onethird (36 percent) of the 1964 respondents. By 1970, this had

increased to 60 percent, Since then, television and radio commercials advertising cigarettes have been banned. Because these two

media were the most widely used for advertising cigarettes, it

might be presumed that such a ban would satisfy the public. This

is not so. In 1975, 56 percent believed that cigarette advertising

should be stopped completely. This view is subscribed to by 51

percent of the men and 60 percent of the women. Two out of five

smokers would like to see cigarette advertising stopped, perhaps

because some smokers who are trying to quit find that the advertisements make it more difficult. A second possibility is that,

while they continue to smoke, they are loath to see the younger

generation take it up.

Because of the growing feeling that smoking should be regulated

more stringently, questions were added to the 1975 survey to

explore the matter of regulation more fully.

First, the question, “Do you favor stronger Federal regulations

concerning cigarette smoking?” elicited 52 percent “yes” responses

from men and 60 percent from women. More than 40 percent of current

smokers even favor such regulations.

Another area explored was whether management has the right to

prohibit smoking in its place of business. Only 16 percent of the

respondents felt that management should not have the right, while

78 percent thought they should have the right; the other 6 percent

were undecided. Eighty percent of the women and 75 percent of the

men thought that management should have the right to prohibit

4 7
smoking. Of those who felt this way, 28 percent believed that they

should be able to do this only when smoking is a safety hazard?

while 72 percent said they should have this privilege whether it

is a safety hazard or not.

Respondents were asked if they found it annoying to be near a person

smoking cigarettes. Those who said “yes” were asked whether they

found cigarette smoking more annoying than several other things

that might be bothersome. The majority of these respondents

expressed the belief that cigarette smoking is more annoying than

someone’s smoking a pipe, cracking knuckles, chewing gum, and

humming or whistling. At the same time, a greater number of people

said that smoking cigars is more unpleasant than cigarettes, and

about the same number found cigarette smoking more annoying than

drinking alcoholic beverages as found drinking alcoholic beverages

more irritating than smoking.

TEENAGE SMOKING

The widespread use of cigarettes among teenagers, with its attendant

health hazards, has prompted four national surveys of teenage smoking in the United States. The first was completed in January 1968

and the last in January 1974, with intermediate surveys in 1970 and

1972 (USDHEW 1972; USDHEW 1976b). About 2500 young people (12

through 18 years old) were interviewed in each survey.

Trends in Prevalence of Teenage Smoking

During the six years covered by the surveys, the proportion of boys

who smoke at least once a week changed very little, except for an

increase in 1970. This increase was most marked in the 17- and

18-year olds. In 1972, this proportion had dropped back to the

1968 level and remained there in 1974. Among girls, however, there

has been a gradual increase in the proportion of smokers in every

age group. This has had the effect of practically eliminating the

difference in smoking behavior of the two sexes. In 1968, the

proportion of girls reporting that they smoked cigarettes regularly

was only about one-half that of boys. By 1970, this ratio had

risen to almost two-thirds, and in 1972 to about 85 percent. The

difference between the smoking behavior of boys and that of girls

had disappeared by January 1974.

Discussion

Overall, the proportion of teenagers who smoke cigarettes regularly,

including those who smoke at least once a week, has increased from

12 percent in 1968 to 16 percent in 1974. This increase has taken

place almost exclusively among girls. Traditionally, cigarette

smoking was a custom indulged in by men and boys and was not usual

among women and girls. About the time of World War II, smoking

among women began to increase, but it never quite reached the level

of male smoking. In the late 1960’s, men began to quit smoking, so

that the proportions of men and women smokers approached each other

more closely. We have already mentioned that the smoking behavior

4 8
of boys did not change appreciably during the late 1960’s and early

1970’s, but smoking among girls gradually increased. In fact, it

rose to the point where, in 1974, boys and girls were smoking in

the same proportions.

While the reasons for the disappearance of differences between

boys’ and girls’ smoking behavior are not immediately apparent, it

is likely that they are. the same as the reasons that account for

the disappearance of many other differences between boys and girls,

in dress, hair styles, etc. In order to understand the phenomenon

of teenage smoking, it is important to recognize the differences

between those who take up smoking and those who do not. Since

adolescence is a period of exploration, it is natural for teenagers

to experiment with smoking, just as they do with other “adult”

behavior. But which experimenters become smokers and which do not?

By the time a boy or girl is 18 years old, only about one in three

is a smoker, although most have tried it. How do we explain the

differences in behavior? One way is to look at the differences

between teenage smokers and teenage nonsmokers. Until adolescence,

there is no question that the family exerts the greatest of all

influences upon children; but, as they grow up, outside influences

become stronger. How much does the family situation affect the

smoking practices of the teenager? Several characteristics of the

family were examined, and all were found to be related to smoking

practices.

First, teenagers in intact families (that is, those in which both

parents were present) were less likely to smoke than were those in

homes where there was not both a mother and a father. About one

teenager in five lives in a home without both parents, some because

one parent is dead or the parents divorced, and some, particularly

the older teenagers, because they have left the family home and

have set up their own living arrangements. They have adopted a

lifestyle that is somewhat precocious; perhaps smoking is one

characteristic of this lifestyle. Another family characteristic

that is related to teenage smoking is socioeconomic status, as

measured by education of the parents. Those with better-educated

parents are less likely to smoke than are those with less welleducated parents. This is consistent with studies of adults which

find that the higher the educational level a person has attained,

the more likely he is to have quit smoking, if he ever did so. In

spite of the notion that adolescents, in rebellion against their

parents, reject the customs and beliefs of their elders, they do

not turn away from their parents’ smoking practices. Parents who

smoke are likely to have children who smoke. In fact, teenagers

with two parents who use cigarettes are more than twice as likely

to smoke as are those with no parent who indulges in this habit.

Teenagers emulate older brothers and sisters, too. A boy or girl

with an older sibling who smokes is extremely likely to be a

smoker as well. If a teenager has both a parent and an older

sibling who smoke, the likelihood of becoming a smoker is amplified.

In fact, he or she is four times as likely to smoke as is one who

has no smoking example in the immediate family. Smoking appears

to be one of those customs which families as a whole either adopt

4 9
or do not adopt. Just as in some families a coffee pot is always

on the back of the stove, in some homes cigarettes are readily

available for family members to help themselves.

Teenagers not only have families who smoke; they also have friends

who smoke. Almost nine out of ten smokers acknowledge that at

least one of their four best friends smokes on a regular basis,

while only one in three of the nonsmokers claims a smoker among

his or her four best friends. At the other extreme, one in five

nonsmokers claims that none of his or her four best friends has

even experimented with smoking, while only one in a hundred of the

smokers makes this claim.

When we discuss parents’ and older siblings’ smoking patterns, we

can talk about their influence on teenagers, since presumably these

older family members set the stage for them. But when we talk about

friends’ smoking, there is no way to guess who influenced whom. Did

Tom’s friends exert pressure to get him to smoke? Did Tom urge his

friends to smoke? Did he select friends because they smoked, or did

they select him because he smoked? Or do they share the same kind

of lifestyle, congenial to all in this group, that includes cigarette smoking? Tom cannot tell us; no one can. It is likely,

however, that Tom and his friends share a life pattern that includes

smoking.

One aspect of the teenage lifestyle is the practice of working outside the home, either full time or part time. Teenagers who work at

some time during the year are twice as likely to be smokers as are

those who do not work. Perhaps the nonworking minority is somewhat

more protected, and less likely to have achieved much independence.

Those who work often participate with adults in a work situation,

and therefore are more likely to experiment with smoking and other

adult behaviors.

Another aspect of the teenage lifestyle is reflected in educational

and vocational aspirations. The college-bound teenager probably has

priorities that differ from those of peers who plan to terminate

formal academic education with high school. The high school student

in a college preparatory course is less likely to smoke than is one

in any other course. This is consistent with the finding that offspring of parents who went to college are less likely to smoke.

Thus the theory that smoking is related to socioeconomic status is

supported.

HEALTH PROFESSIONALS: SMOKING AND HEALTH

People in the health professions are the authorities on matters

pertaining to health. They are looked to for advice and are expected

to be exemplars in preventive medicine. This is certainly true of

cigarette smoking. For example, a recent survey of adults showed

that more than three out of four feel that doctors should set a good

example by not smoking. Thus, it is essential to know how these

important exemplars see their roles, how they perceive smoking in

relation to diseases, and how they act with regard to cigarette

smoking both personally and professionally.

50
In an NCSH survey (unpublished) approximately 2,500 individuals

representing each of four groups of health professionals were

studied in 1975: physicians, dentists, pharmacists, and nurses.

The same groups had been studied in the period between the spring

of 1967 and the summer of 1969.1 One purpose of the current study

was to assess the changes that have taken place during the intervening years.

Findings

In three of the four groups the proportion of smokers has decreased

markedly. Only among nurses has the proportion of smokers stayed

at about the same rate as in 1969. The proportion of physicians

who smoked dropped from 29.6 percent in 1967 to 21.0 percent in

1975. During the same 8-year period, smoking among dentists

decreased from 34.3 percent to 23.3 percent. In 1968, 34.5 percent

of pharmacists smoked, compared with 27.5 percent in 1975. Nurses

were smoking at about the same rate in both surveys--37.3 percent

in 1969 and 38.9 percent in 1975.

Among physicians, there was little or no difference in smoking

behavior by age group: 21 percent of those under 40 are current

smokers, and 21 percent of those 40 and over are smokers. Both

these proportions represent substantial decreases from the 1967

survey, when 33 percent of those under 40 and 29 percent of those

40 and over were smokers. The same pattern holds for dentists:

in 1975, 24 percent in both the younger and older age groups were

current smokers. Both were down from 1967, when 36 percent of

those under 40 and 33 percent of those 40 and over were current

smokers. Among pharmacists, the decrease in proportion of smokers

was more noticeable in the younger age group than in the older.

The percent of pharmacists under 40 who were current smokers

decreased from 36 percent in 1968 to 25 percent in 1975. The corresponding percentages for those 40 and over were 35 percent in

1968 and 29 percent in 1975. As the other health professionals do,

nurses under 40 show a decrease from 1969 to 1975--from 39 percent

to 34 percent. However, 35 percent of the nurses 40 and over were

smokers in 1969, and 42 percent were smokers in 1975. This increase

reflects the fact that women 40 and over in 1975 were in the 33- to

40-year age group in 1969 and smoked at a much higher rate than the

older nurses who have since left the profession.

In comparing health professionals with the adult population in

general, it is appropriate to compare three of the groups with

males and one group with females. Physicians in the sample included

92.9 percent males; dentists, 99.2 percent; and pharmacists, 90.0

percent. Nurses included 97.5 percent females.

A 1975 national probability sample of adults showed that 39 percent

of the males and 29 percent of the females were current smokers.

The proportion of smokers in each of the three predominantly male

health professional groups was much lower than that of males in

the general population, but nurses were smoking at a higher rate

than women in general.

51
Three out of every five health professionals surveyed had a history

of smoking, but t e majority in all groups except nursing had quit

smoking. The highest quit rate was found among physicians--64

percent of all those who had ever smoked were former smokers at

the time of the 1975 survey. This was closely followed by 61 percent of the dentists and 55 percent of the pharmacists who had once

smoked but had quit. These proportions are higher than the quit

rate of 43 percent in the male population who had ever smoked.

Nurses had a quit rate of 36 percent--slightly above the quit rate

of 34 percent of smokers in the female population.

Physicians have been the leaders in giving up smoking; 55 percent

of former smokers have not smoked in 10 or more years. This compares with 46 percent of former smokers in the male population.

Dentists were next in quitting, with 50 percent of former smokers

having quit 10 or more years ago. Pharmacists began quitting at

about the same time as other men in the population; 47 percent of

former smokers among them quit 10 or more years ago.

Women did not start to quit smoking in large numbers as early as

men. Of the former smokers among the female population in 1975.

only 36 percent had not smoked for 10 or more years. However, 

like other health professionals, nurses lead their general population group in quitting smoking. Among their former smokers, 43

percent of nurses have not smoked for 10 or more years.

Smokers in the predominantly male health professions smoked fewer

cigarettes per day than males in the general population, while

there was little difference between nurses and their female counterparts in the general population. As well as smoking fewer

cigarettes, physicians, dentists, and pharmacists also tended to

smoke cigarettes lower in tar and nicotine than did males in the

general population. While one in five in these health professions

smoked cigarettes with a “tar” level of 15 mg or below, only one

male in eight in the general population smoked these low “tar”

cigarettes. Similarly, a larger proportion of nurses smoked lowtar cigarettes than did smokers in the general female population.

Most health professionals who are still smoking cigarettes started

smoking before the relationship between smoking and disease was

well known. A majority of them have made at least one attempt to

stop, at rates similar to those among the general population of

smokers: physicians 63 percent, dentists 64 percent, pharmacists

61 percent, nurses 55 percent, adult males 64 percent, and adult

females 60 percent.

In summary, changes in the smoking habits of these groups of health

professionals have been towards the reduction of smoking and, for

the most part, have exceeded and predated changes among the general

population. Nurses were formerly among the group of heaviest

smokers in the female population. Now that there is an Increasing

rate of quitting among older nurses and a reduced rate of taking

up smoking by younger nurses, this is beginning to change.

5 2
Relationship between Cigarette Smoking and Selected Diseases

People in the health professions generally see cigarette smoking

as either a major cause or a contributing cause of diseases of the

lung. In fact, 9 out of 10 physicians and dentists say that

smoking is a major or contributing cause of lung cancer, chronic

bronchitis, and pulmonary emphysema. Between 80 percent and 90

percent of pharmacists and nurses agree. In every case, this

represents an increase from the population holding these opinions

in earlier surveys.

Even greater increases were observed in the proportion seeing

smoking as a cause of heart disease. The proportion of physicians

increased from 71 percent to 78 percent. Corresponding proportions

for dentists were 60 percent to 75 percent; for pharmacists, 46

percent to 63 percent; for nurses, 60 percent to 74 percent.

Perception of Responsibility as a Health Professional

People in the health professions see cigarette smoking as a serious

health hazard. How do they see themselves as serving to reduce the

incidence of disease and death caused wholly or partly by smoking?

First, they believe it is their responsibility to set a good

example by not smoking cigarettes. Ninety-one percent of physicians, 88 percent of dentists, 87 percent of nurses, and 73 percent

of pharmacists agree they have this responsibility. The majority

also agree it is their responsibility to convince people to stop

smoking. Three-quarters of physicians and nurses, 61 percent of

dentists, and 51 percent of pharmacists subscribe to this. Many

in the health professions also believe they should be more active

than they have been in speaking to lay groups about cigarette

smoking. In fact, 82 percent of physicians, 74 percent of nurses,

and 68 percent of dentists and pharmacists agree they should be

more active.

Since health professionals profess a feeling of responsibility

toward their patients’ (or customers’) smoking, smokers in these

groups have changed their behavior accordingly. Health professionals are much less likely to smoke in the presence of patients or

customers than they were in the earlier surveys. In all four professions, more of them report that they never smoke in front of a

patient (or customer) (physicians, 39 to percent; dentists, 50

to 65 percent; pharmacists, 22 to 41 percent; nurses, 60 to 89 percent) . Although a slightly smaller proportion of nurses, compared

with doctors and dentists, feel that they should set a good example,

they include the largest proportion who say they do not smoke in

front of patients. Perhaps they face more restrictions of where

they are allowed to smoke at their places of work. Indeed, 80

percent of the nurses who are presently employed say that smoking

is restricted to certain times or places, or prohibited entirely,

at the place where they work.

5 3
Just as health professionals feel increasingly that they should be

doing something about smoking, they are less pessimistic than they

were earlier about their ability to effect change. For example,

in 1967 three-fourths of the physicians agreed that “there is no

method around today to really help a smoker who wants to quit but

can’t do it on his own.” By 1975, fewer than half of them agreed

with this statement. The proportion of dentists agreeing with it

dropped from 58 percent to 33 percent. It is interesting to note

that nurses have been most optimistic about the possibility of

helping people to quit.

USE OF OTHER FORMS OF TOBACCO

Since the mid-1960’s, the proportion of pipe smokers among males

has decreased from about one in five to about one in eight. Among

women, it has remained at less than one in a hundred. Cigar smoking

has also decreased, from 28 percent in the 1964-1966 surveys to

18 percent in 1975 in males. Women have not usually smoked cigars;

fewer than 1 percent reported smoking cigars in any of the surveys.

The use of snuff has remained at about 3 percent for males and less

than 2 percent for females over the time of the surveys. Chewing

tobacco is used, and has been used, by about 6 percent of the males

and 1 percent of the females (USDHEW 1976a). These forms of tobacco

are used by such a sma11 percent of the population that little

attention has been paid to trying to decrease the prevalence of

their use.

SUMMARY

Overall, then, the picture of decrease in cigarette smoking is an

encouraging one, with the exception of the increased rate of smoking

among teenage girls. However, this change probably reflects the

tenor of the times and an alteration in the concept of what has

traditionally been considered “feminine” behavior.

FOOTNOTE

1 . The 1975 survey was conducted for NCSH by Chilton Research

Service; the 1967 and 1969 surveys were conducted by National

Opinion Research Center.

REFERENCES

U.S. Dept. of Health, Education, and Welfare, Public Health

Service. Smoking and Health, Report of the Advisory Committee to

the Surgeon General of the Public Health Service. PHS Pub. No. 1103.

Washington, D.C.: Superintendent of Documents, U.S. Govt. Printing

Office, 1964. 387 pp.

U.S. Dept. of Health, Education, and Welfare, Public Health Service.

Use of Tobacco--Practices, Attitudes, Knowledges and Beliefs, U.S.

Fall 1964 and Spring 1966. National Clearinghouse for Smoking and

Health, 1969.

54
U.S. Dept. of Health, Education, and Welfare, Public Health

Service. Teen-Age Smoking: National Patterns of Cigarette

Smokign, Age 12 through 18, in 1968 and 1970 DHEW pub. NO.

(HSM) 72-750, Washington, D.C., 1972.

U.S. Dept. of Health, Education, and Welfare, Public Health

Service. Adult Use of Tobacco--1970. National Clearinghouse

for Smoking and Health. DHEW pub. No. (HSM) 73-8727, 1973.

U.S. Dept. of Health, Education, and Welfare, Public Health

Service. Adult Use of Tobacco--1975. Center for Disease Control

and National Cancer Institute, 1976a .

U.S. Dept. of Health, Education, and Welfare, Public Health

Service. Teen-Age Smoking: National Patterns of Cigarette

Smoking, Ages 12 through 18, in 1972 and 1974. DHEW Pub. No.

(NIH) 76-931, Washington, D.C., 1976b .

AUTHOR

Dorothy E. Green, Ph.D.

Consulting Research Psychologist

3509 N. Dickerson Street

Arlington, Virginia 22207

55

Part II

Behavioral Factors
Chapter 6

Nicotine as a Discriminative

Stimulus to Behavior: Its

Characterization and Relevance to

Smoking Behavior

John A. Rosecrans, Ph.D.

INTRODUCTION

One of the major objectives of research being conducted in our

laboratory over the last decade has been to determine the neurochemical and pharmacological mechanisms by which nicotine produces its behavioral effects in experimental animals. The goal

of this research has been to assist in identifying which of

nicotine’s effects may contribute to its use in tobacco by humans.

The generalization of our findings to tobacco use, however, is

contingent upon our ability to develop behavioral procedures

which are specific to nicotine and analogous to nicotine’s effects

in humans. Much progress has been made in this regard, and it is

felt that we have been successful in developing an animal model

of nicotine effects which will provide important information

relevant to drug dependency problems.

The experimental model developed in this laboratory relies upon

the ability of nicotine to exert stimulus control of behavior

(Rosecrans and Chance 1977; 1978). In this approach an animal or

human subject is required to discriminate between drug and nondrug states in order to receive a positive reinforcement. For

example, food-deprived rats are trained to press one of two levers

(for liquid reinforcement) in an operant chamber after they are

administered nicotine (200-400 μg/kg s.c.), while the opposite

lever is reinforced following saline administration on a different

day. After repeated daily exposure to this procedure, the animal

soon learns to detect the effects of nicotine. Thus, the drug is

acting as a discriminative stimulus.

Human subjects can be studied in an analogous way. In studies just

initiated in our laboratory, human subjects can obtain a financial

reward for pressing the correct lever in a similar two-lever drug

discrimination task, In this situation each subject must detect

differences in nicotine level when allowed to smoke cigarettes

differing in nicotine content (0.3 vs. 1.3 mg nicotine per cigarette).

58
Tar content, taste, and other parameters have been equalized to prevent the smoker from using other cues to solve the problem. As with

our animal studies, human subjects will be allowed access to the

discrimination task following random exposure in each session to

either the high or low nicotine cigarette. This latter experiment

is extremely important, as it will allow us to determine whether

nicotine can be studied in human subjects using procedures developed

from our animal experiments.

USES OF THE MODEL

It should be understood that we are not studying the effects of

nicotine on behavior. Rather, these procedures are used to measure

drug detection. This is an important distinction, since drugs from

different pharmacological classes may be shown to induce the same

degree of behavioral disruption in animals, but may not be similar

in terms of quality as a discriminative stimulus (DS). Put in another way, a rat may exhibit equivalent behavioral disruption by specific doses of both d-amphetamine and morphine, but it will be able

to discriminate between them because of the qualitatively different

DS properties. These procedures, therefore! provide a very specific

model which can be used to study the mechanism of drug action within

a given pharmacological class.

The discriminative stimulus model has provided us with a unique tool

by which to study nicotine. To determine mechanism of action or

central cite of action, several neuropharmacological manipulations

can be utilized in animals trained to detect nicotine, to attenuate

or mimic the nicotine DS. In the experiments to be summarized in

this paper, rats are first trained to discriminate between doses of

nicotine and saline. Once this is achieved, animals can be challenged

with suspected antagonists or given experimental or known compounds

to determine if such compounds produce effects similar to those of

nicotine. From such studies one can determine: 1) the receptor

mechanisms involved, or 2) the structure-activity relationships involved in the nicotine-receptor interaction. In addition, such

studies can be conducted centrally via chronically implanted cannulae

at various sites to study the locus of action of the nicotine DS within the brain. Neurochemical interactions have been studied by

evaluating the ability of nicotine to produce its DS effects in rats

chronically depleted of specific biogenic amines. At present, we are

also exploring ways of studying ongoing brain area biogenic amine

function under nicotine and saline conditions, via the use of radioisotopes and centrally placed push-pull cannula.

Specific Behavioral Techniques Used in Animal Studies

At approximately 10 weeks of age, rats were trained to press first

one lever, then the other, in a two-lever operant chamber. Discrimination training began with four preliminary training sessions of

15 minutes duration in which each correct bar press was reinforced

(Chance et al. 1977). Subsequent sessions started with a 2.5 minute

period during which no responses were reinforced; a variable interval

of 15 seconds (VI - 15 sec) schedule was in effect for the remaining

5 9
12.5 minutes. Every session was preceded by 10 minutes with subcutaneous injection of either nicotine or saline. During the four

preliminary training sessions, nicotine and saline injections were

alternated daily; thereafter, 2 days of one treatment were followed

by 2 days of the other. By means of this double alternation schedule

of drug administration, each treatment was preceded equally often by

a session with the same and the opposite treatment. One lever was

reinforced after the injection of nicotine, and the opposite lever

was reinforced following saline. For half of the subjects, the

right lever was rewarded after nicotine and the left lever was rewarded after saline. These conditions were reversed for the remaining animals.

After 40 discrimination training sessions, responding was relatively

stable. The same animals continued to receive either 200 or

400 μg/kg of nicotine and saline according to a double alternation

sequence. However, test sessions 2.5 minutes in duration were interposed during which no responses were reinforced. An odd number of

training sessions, usually one or three, separated two successive

test sessions. All experimental manipulations were accomplished

during test sessions, That is, drug antagonism or drug generalization studies were conducted during these test sessions. During test

sessions, rats made 85-95 percent of their responses on the nicotinecorrect lever following a training of nicotine, while response rates

following a dose of saline were only l0-15 percent on the same lever.

Thus, these animals exhibited an ability to discriminate between

nicotine and saline of 70-85 percent.

NICOTINE AS A DISCRIMINATIVE STIMULUS: MECHANISM AND

SITE OF ACTION

The DS approach has been very useful in studying the mechanism of

action of nicotine, especially since this drug appears to elicit

behavioral changes within other tasks which are contingent on

baseline arousal levels prior to drug exposure (Rosecrans 1971a ;

1971b. Thus, nicotine produced stimulant effects when the baseline

arousal levels were low, while reverse effects were observed if

arousal levels were high. These variable effects, while important

to the overall behavioral pharmacology of nicotine, cause difficulty

in attempts to correlate behavior with central mechanisms or neurochemical events. The advantage of DS procedures is that the subjects

are not responding to a specific effect of the drug on behavior, but

to the presence of the drug within the CNS. Furthermore, the specificity of and sensitivity to the nicotine cue did not change in

relation to time-duration or dose-response relationships across

different schedules of reinforcement which elicit high (FR 10 sec)

or low (DRL 10 sec) rates of responding (Chance et al. 1977).

Furthemore, to learn a DS task, an experimental subject must develop some degree of behavioral tolerance to a specific training dose

of nicotine to perform the operant schedule.

Domino (1967) was one of the first to investigate nicotine’s CNS

mechanisms in a systematic way and clearly showed that nicotine

acts at specific non-muscarinic receptor sites. He and coworkers,

6 0
by studying various neurophysiological parameters in cats, showed

that nicotine’s arousal effects could be antagonized by mecamylamine,

a centrally acting nicotinic blocking drug, but not by the muscarinic

blocker, atropine. In addition, they were unable to block the nicotine effect by the quarternary nicotinic peripheral blocker, hexamethonium, indicating nicotine’s central site of action. These

workers also showed that arecoline (a muscarinic agonist) had the

exact opposite profile (atropine, but not mecamylamine, blocked

arecoline’s arousal effect), suggesting that each drug was acting on

separate N-cholinergic and M-cholinergic receptors. This research

was extended using the DS paradigm (Schechter and Rosecrans 1971;

Hirschhorn and Rosecrans 1974) and an identical profile for the action of nicotine was observed (see table 1).

TABLE 1

Mechanism of the Nicotine (200-400 μg/kg s.c.) DS: Drug

Antagonism Studies

Results vs.

Nicotine

complete

antagonism

Drug Antagonist

Mecamylamine (s.c.)

1 mg/kg; 30 min prior

Hexamethonium (s.c.)

1 mg/kg; 10 min prior

Atropine (s.c.)

0.5-20 mg/kg; 30 min prior

Dibenamine (i.p.)

10-20 mg/kg; 30 min prior

Propranolol (i.p.)

1-4 mg/kg; 30 min prior

Methyl-paratyrosine (i.p.)

30-200 mg/kg; 2 hr prior

p-Chlorophenylalanine (p.o.)

300 mg/kg; 72 hr prior

Receptor Blocked

N-cholinergic

central acting

N-cholinergic

peripheral acting

M-cholinergic

central acting

adrenergic

ß-adrenergic

catecholamine

synthesis I

5-hydroxytryptamine

synthesis

no effect

no effect

no effect

no effect

some

blockade

no effect

Thus, it appears that the behavioral effects of nicotine are contingent upon stimulation of a specific N-cholinergic receptor. The

possibilities that other animal systems may be involved and that

there may be a dopamine (DA) neuron link have also been considered

(Rosecrans, Chance, and Schechter 1976). Research conducted in this

laboratory indicates that rats trained to discriminate nicotine

(400 μg/kg, s.c.) vs. saline will generalize to nicotine injected

into the hippocampus; hut if the rats are dopamine-depleted (65

percent), no generalization to the trained s.c. nicotine cue occurs

following injection of nicotine into the hippocampus. Additional

support that DA is involved with nicotine’s pharmacological effects

61
comes from human research in which smokers appear to have a lower

incidence of Parkinson’s disease than nonsmokers (Kessler 1973).

The theoretical model proposed suggests that nicotine is somehow

metabolized to nicotinic acid. which will alter the amount of DOPA

available to DA neurons. Support for this theoretical model has

also been obtained at the Medical College of Virginia in studies

where nicotinic acid, given to rats orally, facilitated the accumulation of DA following i.p. doses of DOPA (Black 1977). The hippocampus may thus be a primary site of nicotinic action and DA may

also be involved in the action of nicotine (figure 1). DA systems,

however, appear to affect cholinergic systems quite indirectly, via

either the septum or N. Accumbens.

Schechter and Rosecrans (1972a) also studied arecoline in this paradigm and showed that atropine, but not mecamylamine, antagonized its

DS effects. Methylatropine, a peripherally acting muscarinic blocker,

was unable to antagonize the DS, indicating arecoline produced its

effect via a central M-cholinergic stimulation. Schechter and

Rosecrans (1972b) also showed that rats could be trained to discriminate nicotine from arecoline, which suggests that there are separate

central N- and M-cholinergic receptors.

Other research (Rosecrans and Chance 1977) has indicated that peripheral doses of nicotine (100-400 μg/kg, S.C.) will generalize to

nicotine administered via the intraventricular (iv-t) route of doses

ranging from 16-32 μg. The mechanism of ivt generalization also

appears to be a function of N-cholinergic stimulation. In addition,

generalization studies involving nicotine metabolites (cotinine)

have indicated that nicotine is not producing its effects via some

active metabolite. Support for this has also been obtained by correlating behavior to brain area nicotine levels (Rosecrans and Chance

1977). Time-duration and dose-response experiments indicated a close

relationship between behavior and physiological drug level. This

research delineates how nicotine produces stimulus control of behavior in rats. Parametric studies have provided information describing

the duration and mechanism of action of nicotine (Rosecrans and

Chance 1977).

SPECIFICITY OF THE NICOTINE DS

Four years ago a research program designed to search out known chemical compounds which might produce DS effects similar to those of

nicotine was initiated in this laboratory. We began by studying

d-amphetamine under a variety of training conditions and observed

this stimulant to be quite unlike nicotine (Chance et al. 1977).

In addition, other types of stimulants such as caffeine and magnesium

pemoline were found to be devoid of nicotine-like effects. The

responses elicited indicated that the rats studied perceived these

compounds as unlike either nicotine or saline. Response rates on the

nicotine-current lever never averaged 60 percent following doses of

d-amphetamine, indicating that a CNS effect was perceived but was

qualitatively different from nicotine. In addition, drugs such as

LSD or morphine elicited only saline-like responding.

62
FIGURE 1

CATECHOLAMINE - CHOLINERGIC

INTERRELATIONSHIPS

A description of the interrelations between catecholamine and neuron connections. Abbreviations are:

DA = dopamine; ACh = acetylcholine; NE = norepinephrine.

FIGURE 2

Structures of nicotine analogs and metabolites.

Respective ED-50 generalization doses with nicotine

were as follows: Nicotine = 52.4 μg/kg; 3PMP = 263.4

μg/kg; nornicotine = 960.5 μg/kg; cotinine did not

generalize with nicotine.

63
To complete this study we also evaluated a series of nicotine and

pyridine derivatives. Nicotine metabolites such as cotinine were

inactive, but nornicotine did produce a partial generalization.

Interestingly, lobeline, a compound considered to act like nicotine,

was also without effect (Schechter and Rosecrans 1972c). The consensus of studies indicated that only one compound, 3 PMP (figure 2),

which is a chemical isomer of nicotine, had a significant nicotinelike effect (Rosecrans et al. 1978). In fact, Kallman et al. (1978)

have shown that 3 PMP appears to act like nicotine centrally. That

is, it appears to be producing its stimulus effects by stimulating

N-cholinergic receptors.

Finally, it should be added that the ability to exert stimulus control of behavior is not a property only of nicotine. Most psychoactive drugs exert DS control of behavior. In many instances there is

a good correlation between stimulus strength, drug abuse, and therapeutic potential within a specific psychopharmacological class of

compounds (Over-ton 1978). The intriguing aspect of nicotine in

relation to other psychoactive drug classes is its apparent specificity. It should be kept in mind, however, that we have been

limited in our research to the numbers of chemical compounds available for study. The picture could change as other chemicals are

synthesized.

RELEVANCE TO SMOKING BEHAVIOR

To understand better how our research efforts may correlate to real

world events, a model describing the sequence of events leading to

drug dependency in man has been developed (figure 3). We have broken

the sequence into three stages, which helps separate out all the contingencies involved in the development of drug dependency. The DS

properties of a specific agent appear to us to fit into stages II and

III.

For a drug to be abused, it first must be recognized by the individual

(Discriminative Stimulus). Thus, there must be a state change, which

is contingent upon the detection level of the individual. This, plus

the quality of the state change, will have a direct bearing on the

probability that the drug will be used again (Reinforcement Potential). For example, cocaine produces strong qualitative state changes

in animals and is rapidly self-administered, suggesting it to be

reinforcing. LSD, on the other hand, also produces a profound state

change, but the probability of continued self-administration is low,

suggesting it may be somewhat aversive. Nicotine produces a potent

DS effect in animals, but some will argue that it does not produce

the same rate of continued self-administration observed with other

reinforcing drugs. At least, many investigators have had difficulty

demonstrating self-administration of nicotine by animals. Thus, what

is it about nicotine which leads to its being used initially? This

is an issue we have discussed much in our laboratory, and as yet we

have not developed an adequate hypothesis, at least in terms of a

behavioral or neurochemical mechanism. We are satisfied at this time

that the nicotine DS model does provide us with a good animal analog

to human drug effects and that much of the information we obtain

appears quite relevant to how this drug produces its effects in man.

64
In the process associated with nicotine use, the drug may not always

be the primary reinforcer for smoking behavior. Instead, other psychological and sociological variables associated with the act of

smoking may also be primary reinforcers, and nicotine becomes a

secondary reinforcer once the habitual use stage occurs (figure 3).

At this stage the discriminative stimulus properties of nicotine

become important. The repeated pairing of task performance with the

nicotine may provide the necessary signal for maintenance of the

smoking behavior. This phenomenon, sometimes called state-dependent

learning, is also a prominent property of other psychoactive drugs

(Weingartner 1978; Overton 1978), and there is no reason to believe

that it is not also the case with nicotine.

Our hypothesis, then, suggests that the maintenance of smoking

behavior (or the dependency stage) may be in part related to the

state-dependent or discriminative stimulus properties of nicotine.

Experimental evidence for such a hypothesis is lacking in man, but

we do have some support for such a concept in animal subjects

(Rosecrans and Chance 1977). In one study, rats were trained in a

one-trial learning paradigm to avoid a shock under saline or nicotine conditions. After the initial training sessions rats were

reexposed to the apparatus 24 hours later. The data jndicated that

rats trained in the nicotine state avoided the shock less often

after a repeated exposure unless nicotine was readministered prior

to the test session. Thus, nicotine provided the stimulus which

enabled the rat to avoid being shocked.

According to our hypothesis a smoker would need to maintain a

constant level of nicotine to adequately perform certain behaviors.

This point is speculative, though, and should be tested. However,

the specific nature of the nicotine DS suggests that this property

of nicotine is one of the many factors important for the maintenance

of smoking behavior.

DIRECTIONS FOR FUTURE RESEARCH

There are three research areas that need to be expanded:

1) Sites and mechanisms of nicotine action

There is much to be learned about the way in which nicotine produces its effects. Until now, little effort has been given to

pursuing how and where nicotine exerts its many pharmacological

effects. In this respect, areas to be further explored include:

a) brain sites of nicotine action; b) neurochemical mechanisms,

specifically DA-ACh interactions (figure 1); and c) studies

investigating the mechanisms of behavioral tolerance, physical

dependence, and state-dependent learning. This last area is of

special importance as it relates to dependence in human subjects.

2) Human research

The hypothesis developed in this paper suggests that nicotine could

be acting as a reinforcer of smoking behavior via its DS or state6 5
FIGURE 3

Stage I

Acute Pharmacological

Experience

Stage II

Development of

Habitual Behavior

Stage III

Drug Dependence

An overview of the sequence of events leading to drug dependence,

as viewed by this laboratory.

66
dependent properties. This question needs to be studied in depth in

human subjects. The necessary methodologies have been developed,

and what is needed now is some fundamental research into the question.

3) Organic molecular mechanisms of nicotine:

therapeutic implications

The fact that millions of humans smoke tobacco suggests that many

people obtain some benefit from this behavior. Furthermore, if

this behavior can be associated with nicotine, then one could

suggest that nicotine could have potential as a therapeutic agent.

The history of the pharmacology of marihuana is relevant to this

point. At present, much research is being devoted to studying the

possible therapeutic potential of the tetrahydrocannabinols and

synthetic derivatives, even though many consider this drug to be

potentially dangerous. Thus, one wonders if some time should be

devoted to studying nicotine analogs with the same point of view.

Such research would serve two purposes. First, a nicotine-like

compound could conceivably be developed which has psychotherapeutic

potential. Second, a research program designed to synthesize

nicotine analogs would also assist us in determining the structure

and configuration of the nicotine receptor.

ACKNOWLEDGMENTS

This research has been supported by grants from the A. M. A.

Education Research Foundation and the Council for Tobacco

Research. In addition the author wishes to express his thanks

to Drs. M. D. Schechter, I. D. Hirschhorn, W. T. Chance and

M. J. Kallman for their research efforts over the years.

REFERENCES

Black, M. J. Alteration of L-Dopa effect on brain dopa and dopamine levels with nicotinic acid and N-Methyl nicotinamide. Richmond, Va.: Medical College of Virginia, 1977. (Ph.D. dissertation;

unpublished.)

Chance, W.T.; Murfin, D.; Krynock, G.M.; and Rosecrans, J.A. A

description of the nicotine stimulus and tests of its generalization to amphetamine. Psychopharmacol, 55:19-26, 1977.

Domino, E.F. Electroencephalographic and behavioral arousal

effects of small doses of nicotine: A neuropsychological study.

Ann N.Y. Acad Sci, 142:216-244, 1967.

6 7
Hirschhorn, I.D., and Rosecrans, J.A. Studies on the tune course

and the effect of cholinergic and adrenergic receptor blockers on

the stimulus effect of nicotine. Psychopharmacol, 40:109-120,

1974.

Kallman, M.J., Spencer, R.M.; Chance, W.T., and Rosecrans, J.A. A

comparison of nicotine and structurally related compounds as

discriminative stimuli, 1978 (in press).

Kessler, I.J. Parkinson’s disease. Perspectives on epidemiolology

and pathogenesis. In: Perspectives on Parkinson’s disease. New

York: Academic Press, Inc., 1973. pp. 88-105.

Overton, D.A. Major theories of state dependent learning. In:

Ho, B.T., Richards, D.W. , III, and Chute, D.L., ed. Drug Discrimination and State Dependent Learning. New York: Academic Press,

Inc., 1978. pp. 283-318.

Rosecrans, J.A. Effects of nicotine on behavioral arousal and

brain 5-hydroxytryptamine function in female rats selected for

differences in activity. European J Pharmacol, 14:29-37, 1971a.

Rosecrans, J .A. Effects of nicotine on brain area 5-hydroxytryptamine function in male and female rats separated for differences of activity. European J Pharmacol, 16:123-137, 1971b.

Rosecrans, J.A., and Chance, W.T. Cholinergic and non cholinergic

aspects of the discriminative stimulus properties of nicotine.

In: La1, Harbans, ed. Discriminative Stimulus Properties of

Drugs. New York: Plenum Press, 1977. pp. 155-185.

Rosecrans, J.A., and Chance, W.T. The discriminative stimulus

properties of N- and M-cholinergic receptor stimulants. In: Ho,

B.T., Richards, D.W., III, and Chute, D.L., ed. Drug Discrimination and State Dependent Learning. New York: Academic Press,

Inc., 1978. pp. 119-130.

Rosecrans, J.A.; Chance, W.T.; and Schechter, M.D. The discriminative stimulus properties of nicotine, d-amphetamine, and morphine

in dopamine-depleted rats. Psychopharm Comm, 2:349-356, 1976.

Rosecrans, J.A.; Spencer, R.M.; Krynock, G.M.; and Chance, W.T.

Discriminative stimulus properties of nicotine and nicotine

related compounds. In: Battig, K., ed. Behavioral Effects

of Nicotine. Basel. Switzerland: S. Karger, 1978. pp.70-82.

Schechter, M.D., and Rosecrans. J.A. CNS effect of nicotine as

the discriminative stimulus for the rat in a T-maze. Life Sci, 10:

821-832, 1971.

6 8
Schechter, M.D., and Rosecrans, J.A. Nicotine as a discriminative

cue in rats: Inability of related drugs to produce a nicotinelike cueing effect. Psychopharmacol, 25:374-387, 1972a.

Schechter, M.D.,and Rosecrans, J.A. Effect of mecamylamine on

discrimination between nicotine- and arecoline-produced cues.

European J Pharmacol, 17:179-182, 1972b.

Schechter, M.D., and Rosecrans, J.A. Atropine antagonism of

arecoline cued behavior in the rat. Life Sci, 11:517-523, 1972c.

Schechter, M.D.. and Rosecrans, J.A. Nicotine as a discriminative

stimulus in rats depleted of norepinephrine or 5-hydroxytryptamine.

Psychopharmacol, 24:417-429, 1972d.

Weingartner , H. Human state dependent learning. In: Ho, B.T.;

Richards, D.W., III; and Chute, D.L., ed. Drug Discrimination

and State Dependent Learning. New York: Academic Press, Inc.,

1978. pp. 361-382.

AUTHOR

John A. Rosecrans, Ph.D.

Professor of Pharmacology

Virginia Commonwealth University

M.C.V. Station Box 726

Richmond, Virginia 23298

69
Chapter 7

Nicotine Self-Administration

in Rats

H. M. Hanson, Ph.D., C. A. Ivester, and B. R. Morton

INTRODUCTION

Contrasted with the voluminous and still burgeoning literature

devoted to laboratory study of the self-administration of morphine, cocaine, amphetamine and the barbiturates, studies of the

self-administration of nicotine have been few in number. The

entire literature available to us is less than a dozen papers;

Clark (1969), Lang et al. (1977), and Hanson, Ivester and Morton

(1977) reported data collected with rats, Deneau and Inoki (1967)

and Yanagita (1973) with primates.

The reasons for this apparent neglect of a compound selfadministered by a large percentage of the human population are

uncertain. Techniques for such studies have long been available,

and the feasibility of the study of the self-administration of

nicotine was demonstrated by Deneau and Inoki (1967) 10 years

ago. It is likely that the less dramatic effects demonstrable in

the laboratory with nicotine compared to the effects possible

with morphine or cocaine may have overshadowed the potential

importance of such studies and have resulted in investigators

directing their efforts toward the study of substances yielding

more striking and voluminous data.

The studies of nicotine self-administration to be reported in

this paper were undertaken based on the assumption that nicotine

is the substance in tobacco smoke that leads to man's use of

tobacco. It was further assumed that such studies were relevant

to understanding smoking in humans, and as a model could lead to

a successful pharmacological "treatment" for smoking.

METHODS

Because of their small size, ease of maintenance,and the possibility of assembling a large colony for study, the rat was chosen

as an experimental animal. Four hundred to 500-gram male albino

70
rats (Sprague-Dauley-derived, Buckshire Corporation) were lmplanted with Weeks-Davis type jugular cannulae using ether

anesthesia. After recovery from the anesthetic, the rats were

fitted with Weeks-type "saddle and leash" restraint devices to

protect the catheters and placed in individual operant conditioning cages. For two days following surgery the rats were

infused with nicotine solution or saline every 30 minutes; on the

third day operant conditioning levers were placed in the chambers

and all further Infusions were dependent on lever depressions.

Thirteen-second injections of 0.1 ml of solution were delivered

following every lever depression (FR 1). Responses emitted

during an infusion were ignored.

Food and water were available at all times; the room housing the

rats was maintained at 21-22°C; lights were on in the room

12 hours daily from 6:00 a.m. to 6:00 p.m. Patency of individual

catheters was checked at weekly intervals or following the

completion of a particular study. All data collected with a

particular rat for a study were discarded if testing indicated

that the catheter had failed.

A group of 42 identical test cages were used for the studies to

be reported. Rats were randomly assigned to test chambers and to

studies. Where noted, more than a single compound was tested

in individual rats. A total of 276 rats were used to collect

the data.

RESULTS

Self-Administration of Nicotine; Dose-Response Relationship

Groups of 9-10 rats (N=59) were implanted with jugular cannulae and

placed in the test chambers with the operant levers removed. Every

30 minutes for two days the rats were given automatic injections of

saline, or 3.75, 7.5, 15, 30, or 60 μg/kg of nicotine. At the end

of the 48-hour period the automatic injections were stopped and the

operant conditioning levers were placed in the chambers; for the

next 10 days each lever press resulted in an injection of the

same dose of nicotine or saline as was given in the pretreatment

period.

The data collected are shown in figure 1 as mean square root

responses for each of the groups. The horizontal line indicates

the mean number of responses emitted by the saline control group

over the l0-day test period. The vertical lines are standard

errors. A linear function fitted to the data by the method of

least squares is also shown. The value for 60 μg/kg of nicotine

was omitted from this estimation. Doses greater than 60 μg/kg

resulted in even lower response rates, suggesting that for naive

rats doses of 30-60 μg/kg are maximally reinforcing; it can be

noted, however, that doses in excess of 100 μg/kg, which resulted

in convulsions following each injection, were self-administered

at rates significantly higher than saline controls.

71
FIGURE 1

Dose response relationship for self-administration of nicotine.

Data points represent average number of infusions of various nicotine solution over a 10-day period. The horizontal line is the

saline control group mean; the vertical lines show standard errors.

It was concluded based on these data that rats will selfadminister nicotine at rates significantly higher than control

levels over a relatively wide range of doses, and that it is

possible to demonstrate a relationship between dose level and

rate of self-administration.

72
Effects of Pretreatment with Nicotine on Nicotine Self-Administration

Groups of 10-14 rats were implanted with jugular catheters and

placed in individual cages as in the preceding experiment. The

rats were assigned randomly to two groups receiving automatic

injections of either saline or nicotine (60 μg/kg) every

30 minutes. After two days the rats were divided into four

groups and assigned to one of four treatment conditions, selfadministering nicotine or saline after pretreatment with either

saline or nicotine.

FIGURE 2

SIX Hour Periods

Cumulative response curves of self-admnistration of nicotine

(160 μg/kg) or saline over a 5-day period following pretreatment

with injections every 30 minutes of either nicotine (60 μg/kg) or

saline for two days. The curves are identified by the treatments

given during the two phases of the study. The mean values on the

final day of the study are significantly different.

The data, collected over a 5-day period of self-administration,

are shown in figure 2 as cumulative curves. Only the data

collected during the last three days of the study were analyzed.

The means of the groups were significantly different from each

other. The shape of the curves indicated that both groups

self-administering nicotine were increasing their rates of

response while the other two groups self-administering saline

were decreasing their average response rates over the 5-day

period.

73
It was concluded that a significant increase in response rates as

a result of nicotine self-administration compared with saline is

demonstrable in as short a period as 5 days. Pretreatment with

automatic nicotine injections was found to significantly increase

the rate at which nicotine is self-administered, compared with

animals pretreated with saline. Pretreatment with automatic

nicotine injections was found to significantly depress the rate

of saline self-administration: the decreased rates might be

considered in some way analogous to withdrawal symptoms seen

following exposure to opiates. Further study of this effect is

indicated.

Based on these data, in order to facilitate training, all rats

except for those used in special studies were subjected to a

2-day period of automatic injections of nicotine before being

allowed to self-administer the compound.

Course of Nicotine Self-Administration

The data examined so far were gathered over very short periods of

time (up to 10 days) following first exposure to lever-controlled

injections of nicotine. If longer periods of exposure are

considered, the trend toward increasing daily dosages noticed in

figure 2 becomes even more pronounced. Data collected with

4 rats self-administering nicotine (60 μg/kg) over a 30-day

period are shown in figure 3 as cumulative curves. The rats,

which were selected to represent a range of response rates,

showed an overall acceleration in response rates.

It is possible this tendency to increase daily dose levels is due

to the development of tolerance, either to the reinforcing

actions of nicotine (requiring higher dosages) or alternatively,

to the limiting side effects produced by nicotine (allowing

higher dose levels). This tendency to increase the rate of

administration has been noted in all rats studied to date.

Correlated with the increase in total nicotine intake is a slow

but consistent increase in the amount of nicotine necessary to

induce a convulsion.

That this phenomenon is not restricted to short exposures is

illustrated in figure 4. In a manner similar to that in figure 3,

cumulative curves, representing responding over a 5-month period,

are shown for 4 additional rats. The increments in this case

equal 5 days, which "washes out" minor day-to-day fluctuations.

The cumulative curves of these animals also show accelerating

rates of response. It should be noted that all 4 of these rats

were subjected to a variety of pharmacological treatments, which

changed response rates on a daily basis but did not seem to have

affected the overall course of responding.

74
FIGURE 3

Cumulative curves of self-administration of nicotine for 4 rats

over a 30-day period. The total number of responses for each animal is indicated under its respective identification number.

75
FIGURE 4

Cumulative curves of self-administration of nicotine for 4 rats

over a period of five months. The numbers are for animal identification.

During the last 5-day period shown in the figure, the rat with

the greatest nicotine intake (Number 15-64) averaged 44 responses

a day, equalling 2.64 mg/kg of nicotine, a high but by no means

unusual rate of self-administration.

Extinction of Lever Pressing Reinforced by Nicotine

Reports of systematically collected extinction data following

reinforcement with drug infusions are practically nonexistent in

the self-administration literature. The data that are available

are almost entirely devoted to the study of "cross-self-adminstration" of selected compounds and are usually single animal

studies. [See, however, Yokel and Pickens (1976)]. We felt that

76
in order to unequivocally categorize nicotine as a reinforcing

substance, extinction data was necessary.

Following our standard procedure, 12 rats were implanted with

cannulae, placed in individual cages, pretreated for 2 days with

nicotine infusions (60 μg/kg) every 30 minutes and on the third

day given operant conditioning levers. All further nicotine

infusions were dependent on lever depressions. After 12 days of

self-administration, saline was substituted for the nicotine

solution. and lever pressing was recorded for 24 more days (extinction).

FIGURE 5

Extinction of lever pressing following reinforcement by nicotine

infusions. Data shown are means and standard errors of the data

transformed to square roots. Extinction was begun on the twelfth

day of the study, as indicated by the vertical arrow.

The data collected are shown in figure 5 expressed as the means

and standard errors of the square roots of the values. The group

of rats showed the usual increase in response rate for the first

12 days of the study. The mean rate of response on Day 12 was

approximately 50 percent higher than on Day 1, a statistically

significant difference (paired values t-test). After withdrawal

of nicotine the mean rates continued to increase on Days 13-15,

77
the difference in mean rates reaching significance compared with

Day 12 by Day 15. The rates thereafter decreased day by day,

reaching the lowest point on Day 22 followed by a slight overall

increase through Day 36. The rate of responding in extinction

was significantly different from the mean rate on Day 12 by

Day 18 and thereafter.

Nicotine self-administration appears to generate extinction data

comparable to that following other types of reinforcement. The

prolonged period of increased rates of response at the beginning

of extinction is unusual but is somewhat similar to the effects

we have seen in extinction following reinforcement with morphine.

Considering the fact that the animals were reinforced on a FR 1

schedule and were exposed to this schedule and to extinction

24 hours a day, the course of extinction was dramatically prolonged, which again is very similar to extinction following

morphine (unpublished data).

The Effects of Selected Compounds on Nicotine Self-Administration

The effects of 9 compounds were studied in groups of rats selfadministering nicotine (60 μg/kg). Compounds with a range of

pharmacological actions were selected, all of which have received

intensive study in a variety of behavioral and neurophysiological

experiments.

Groups of 10 or more rats self-administering either nicotine

solution or saline were selected from the colony for a particular

study. Individual rats were used repeatedly; however, no rat was

used more than once for the study of a particular compound. No

rat was selected for study that had not been in the colony for at

least 3 weeks; nicotine-self-administering animals were not

selected for study unless their average daily response rate fell

outside the 95 percent confidence limits of an historical salineself-administering reference group and showed clear evidence of

circadian rhythm in responding (greater number of responses

during 12-hour dark period).

All compounds were administered orally twice daily for 3 days

(9:00 a.m. and 9:00 p.m.) after a 3-day period of twice daily

dosing with water at the same times. Data were also collected

for 3 days following drug administration as an additional control. The patency of the catheters was tested on Day 10 of the

study.

The data collected are shown in figures 6-14 as the means and

standard errors of the square roots of the number of injections

for consecutive 6-hour periods over the 3-day period. The arrows

below the abscissa indicate the times of dosing. The doses

selected for study were large enough in all cases to show pharmacological activity in some appropriate test system. All dosages

of the compounds were calculated as the weight of the base

compound and administered dissolved or suspended in water.

78
FIGURE 6

Effects of 4 mg/kg mecamylamine b.i.d. on nicotine and saline selfadministration. The vertical lines indicate standard error of the

mean. Mecamylamine was administered at the times indicated by the

arrows; dosing with water was done at comparable time periods for

the preceding 3 days.

Mecamylamine and Pentolinium: The effects of 4 mg/kg p.o. of the

ganglionic blocker, mecamylamine, are shown in figure 6. The

difference between the two curves was significant at all time

intervals, the mean response rate of the nicotine group being

generally 7 times that of the saline group. Although it is more

pronounced in the later figures, a clear circadian rhythm is in

evidence for the data collected preceding treatment. Following

the first dose of mecamylamine, a dramatic and highly significant

increase (approximately 4-fold) in nicotine self-administration

occurred. The rats appeared active and slightly tremulous

within 5 minutes of dosing. Repeated lever responses were

emitted during the next 15-20 minutes followed by quiescence and

assumption of the usual sleep posture. The total effect lasted

no more than 45 minutes. No overt signs of high nicotine dosage

were seen. The remaining doses did not produce similar effects

but resulted in a slow decrease in response rates. The average

number of nicotine injections for the 24-hour period immediately

following the 3-day mecamylamine treatment period was significantly lower than the average number of responses emitted the day

preceding treatment. A similar, but nonsignificant, decrease was

also seen for the control group. The last 3 days of the study

7 9
resulted in a slow daily increase in response rates. Mean

responses on the last day of the study are not significantly

different from the mean responses on the last pretreatment day,

suggesting the original control levels had been recovered.

This effect of mecamylamine, considering the known nicotineblocking activity of this compound [Stone, Meckelnburg, and

Torchiana (1958)] , was not unexpected. The dramatic increase in

self-administration following mecamylamine appears very similar

to the effect seen following the administration of naloxone to

rats self-administering morphine (unpublished data), and perhaps in

similar fashion could be understood as a direct receptor blockade.

The marked lack of effect following the remaining five doses in the

series is puzzling and no ready explanation is presently available.

FIGURE 7

Effects of pentolinium, 10 mg/kg p.o. b.i.d. See figure 6 for

details of the study.

For comparison with mecamylamine, the peripheral ganglionic

blocker pentolinium was tested in groups of rats self-administering nicotine or saline. The data collected are shown in

figure 7.

The distinctive pattern of responding controlled by the lightdark cycle is clearer with these groups of rats. The separation

in response rates between the two groups is clear and was statistically significant throughout the study. In sharp contrast to

the effects produced by mecamylamine, pentolinium had no measurable effect on either nicotine or saline self-administration.

80
These data lend much weight to the conclusion that the effects

seen with mecamylamine were due to the central nervous system

activity of the compound and, by extrapolation, that the locus of

the reinforcing activity of nicotine is also in the central

nervous system.

FIGURE 8

Effects of amphetamine, 4 mg/kg p.o. b.i.d. See figure 6 for

details.

Amphetamine and Caffeine: Figures 8 and 9 show the effects of

the central nervous system stimulants, amphetamine and caffeine,

on nicotine and saline self-administration. The doses tested,

amphetamine, 4 mg/kg p.o. and caffeine, 20 mg/kg p.o., produced

increased activity and, in the case of amphetamine, stereotype

within 15 minutes following the first dose and throughout the

testing period. The rate of responding was significantly increased for the animals self-administering saline during the drug

test period for both amphetamine and caffeine. No significant

change in nicotine self-administration was seen following dosing

with caffeine at any interval; however, amphetamine produced a

statistically significant increase in responding during the

usually inactive periods when the room lights were on (i.e., the

13th, l4th, 17th, 18th, etc., 6-hour recording periods) compared

with similar data collected before and after dosing. Response

rates were not significantly changed during the "dark periods."

8 1
FIGURE 9

Effects of caffeine, 20 mg/kg p.o. b.i.d. See figure 6 for details.

These effects would appear to be due to general increases in

activity and not to any interaction with the pharmacological

agents studied. It is interesting to note that the rats did not

increase responding (increase nicotine intake) above the control

level during the normal periods of high responding (dark periods),

even though the immediate effects of dosing as well as the

long-term effects would have been present. It is possible that

limiting side effects of nicotine may have controlled the actual

maximal amount tolerated, and the rats were demonstrating something akin to titration of the dose of nicotine.

Ethanol, Chlordiazepoxide, Phenobarbital and Diphenylhydantoin:

The data collected with ethanol, chlordiazepoxide, phenobarbital

and diphenylhydantoin are shown in figures 10, 11, 12 and 13.

These four compounds, although differing widely in their pharmacological activities and tested at doses which produced observable sedation and ataxia, unexpectedly increased nicotine selfadministration following the 3-day dosing period, compared with

predosing control levels. This Increased responding was not seen

in the saline self-administering control groups. In the case of

chlordiazepoxide and diphenylhydantoin, the increase in rates

occurred soon after dosing was initiated in the case of

diphenylhydantoin had reached levels some three times higher than

the predosing control levels by the last day of the study.

8 2
FIGURE 10

Effects of ethanol, 905 mg/kg p.o. b.i.d. See figure 6 for details.

An explanation for this unexpected effect is not readily available. The fact that the saline self-administering group did not

show a comparable increase suggests that simple stimulation was

not a factor. Since the response rates remained high or continued to Increase after dosing had stopped, some fundamental

change may have occurred, perhaps a change in the metabolic rate

of nicotine, or possibly an increase in tolerance to the limiting

side effects of nicotine. Some support is offered for this first

possibility by the known ability of these compounds to modify

enzymatic systems. Assuming that convulsions and the preconvulsant state are some of the limiting side effects of nicotine,

dosing with anticonvulsants, such as phenobarbital and dilantin,

could possibly unmask the reinforcing properties of high doses of

nicotine by preventing these side effects and thereby "allowing"

higher dosages of nicotine to be self-administered, leading to the

more rapid development of tolerance.

From the data available, none of these four compounds could be

considered to have a specific effect on nicotine self-administration.

8 3
FIGURE 11

Effects of chlordiazepoxide, 10 mg/kg p.o. b.i.d. See figure 6 for details.
FIGURE 12

Effects of phenobarbital, 30 mg/kg p.o. b.i.d. See figure 6 for details.
FIGURE 13

Effects of diphenylhydantoin, 300 mg/kg p.o. b.i.d. See figure 6 for details.
FIGURE 14

Effects of chlorpromazine, 2 mg/kg p.o. b.i.d. See figure 6 for details.
Chlorpromazine: The data collected with chlorpromazine are shown

in figure 14. The dose used, 2 mg/kg p.o., produced ataxia and

sedation which became more pronounced with succeeding doses. In

spite of the severity of the side effects produced by the dosing

regimen, there were no significant changes in the overall rates

of nicotine self-administration other than disruption of the

normal circadian rhythm. The saline self-administration control

group, surprisingly, did not show a similar effect. The response

rates for this group were, of course, very low. Normal patterns

of responding were recovered 2 days after cessation of dosing; at

approximately the same time sedation and ataxia were no longer

noted.

DISCUSSION

While clearly possessing reinforcing properties, nicotine can only

be classified as relatively weak in this regard when it is compared

with morphine, amphetamine, or cocaine (Pickens et al. 1978). Of

particular interest in the study of nicotine self-administration,

and a factor which differentiates it from other compounds, is the

remarkably slow onset of self-administration in the rat, complemented by the tendency gradually to increase the daily dosage

over extended periods of exposure. This slow increase in the

daily rate of nicotine self-administration could be explained as

due to the development of tolerance either to the reinforcing

properties or to the limiting side-effects of nicotine. Concurrent administration with an appropriate dose of the peripherally-acting ganglionic blocker, pentolinium, might yield data

of interest in this regard since at least some of nicotine's side

effects, but not its actions on the central nervous system, would

be blocked by this treatment.

The difficulties experienced by Lang et al. (1977) in demonstrating the reinforcing properties of nicotine are easily understood

considering they studied acquisition of lever pressing for only

90 hours. It would seem likely that longer periods of exposure

would have yielded data comparable to those presented here.

The surprising resistance to extinction generated following a

short period of reinforcement by nicotine suggests that "feedback" from this reinforcement system is poor; we would expect

that partial schedules of reinforcement would be poorly supported

by nicotine. To date we know of no studies of partial reinforcement schedules using nicotine infusions as a reinforcer. It would

appear, however, that any attempt to demonstrate the control of

lever pressing by partial schedules of reinforcement would be

most likely to succeed if done after a significant daily intake

of nicotine had been established. The implications of this

unusual resistance to extinction are obvious in any comparison

with human smoking and may be of use in understanding the problems of withdrawal from smoking.

88
The effects on nicotine self-administration of standard compounds

studied clearly demonstrate the difficulties in achieving pharmacological manipulation of nicotine self-administration. Mecamylamine,

which is a specific blocker of nicotine's actions, produced a

dramatic but short-lived increase in nicotine self-administration. Several explanations are possible; the most likely would

appear to be a direct blockade of nicotine at the receptor site

in the central nervous system, the appropriate comparison being

with the interaction of naloxone and morphine. If this is true,

an effort to identify specific nicotine receptor sites would be

of value. Still to be accommodated in such an explanation is the

unusual resistance to extinction observed (the rats were selfadministering saline in extinction, the perfect analog of

"blockade" of nicotine) following a short period of nicotine

reinforcement. Also to be explained is the apparent ineffectiveness of additional doses of mecamylamine in either increasing or

decreasing nicotine self-administration.

The constancy of the rates of nicotine self-administration

following heroic doses of a stimulant, such as amphetamine, or

depressants, such as chlorpromazine or phenobarbital suggests

that in spite of all its apparent fragility as a reinforcer, in

these studies of nicotine we were dealing with a major behavioral

control which was not easily disrupted. The implications for the

study of smoking are again obvious.

RECOMMENDATIONS FOR FURTHER RESEARCH

1. Systematic studies of self-administration of nicotine should

be extended to other species, such as the monkey, even though

the rat may well remain the test animal of choice.

2. Self-administration of the main metabolites of nicotine

should be studied, since it is possible the "reinforcing"

properties of nicotine are shared with those of a metabolic

byproduct.

3 . To better bring nicotine into the mainstream of self-administration studies, partial schedules of reinforcement could be

studied with either rats or primates.

4. While technically somewhat difficult, the study of "sensitive"

schedule-controlled behaviors, reinforced by food and water

concurrently with nicotine self-administration, might allow

the study of the nicotine abstinence syndrome in laboratory

animals.

5. Comparative studies of several representative compounds, using

resistance to extinction as a measure of reinforcing "potency,"

might allow the ordering of compounds in terms of abuse potential. Techniques other than substitution or repeated

extinction would probably be most fruitful.

8 9
REFERENCES

Clark, M.S.G. Self-administered nicotine solutions preferred to

placebo by the rat. Brit J Pharmacol, 35:376, 1969.

Deneau, G.A., and Inoki, Ft. Nicotine self-administration in

monkeys. Ann NY Acad Sci, 142:277-279, 1967.

Hanson, H.M.; Ivester, C.A.; and Morton, B.R. The effects of

selected compounds on the self-administration of nicotine in

rats. Fed Proc, 36:1040, 1977.

Lang, W.J.; Latiff, A.A.; McQueen, A.; and Singer, G. Selfadministration of nicotine with and without a food delivery

schedule. Pharmacol Biochem Behav, 7:65-70, 1977.

Pickens, R.; Meisch, R.A.; and Thompson, T. Drug self-administration: An analysis of the reinforcing effects of drugs.

Vol. 12. In: Iverson, L.L.; Iverson, S.B.; and Snyder, S.H.; eds.

Handbook of Pharmacology. New York: Plenum Press, 1978. pp. 1-37.

Stone, C.A.; Meckelnburg, K.L.; and Torchiana, M.L. Antagonism

of nicotine-induced convulsions by ganglionic blocking agents.

Arch Int Pharmcodyn Ther, 117:419-434, 1958.

Yanagita, T. An experimental framework for evaluation of dependence liability of various types of drugs in monkeys. Bull

Narcotics, 25:57-64, 1973.

Yokel, R.A., and Pickens, R. Extinction responding following

amphetamine self-administration: Determination of reinforcement

magnitude. Physiol Psychol, 4:39-42, 1976.

AUTHORS

H. M. Hanson, Ph.D.

C. A. Ivester

B. R. Morton

Merck Institute for Therapeutic Research

West Point, Pennsylvania 19486

9 0
Chapter 8

The Effects of d-Amphetamine,

Meprobamate, and Lobeline on the

Cigarette Smoking Behavior of

Normal Human Subjects

C. R. Schuster, Ph.D., B. R. Lucchesi, M.D., Ph.D.,

and G. S. Emley, M.S.

In the mid 1960’s at the University of Michigan my colleagues,

B.R. Lucchesi and C.S. Emley, and I conducted a series of experiments designed to investigate the effects of various drugs on the

cigarette smoking behavior of normal volunteer subjects. One of

our major interests was the role of nicotine in cigarette smoking

behavior.

The subjects used in this experiment were male and female volunteers ranging in age from 21 to 30 years. Each volunteer was

given an interview and a complete physical and psychiatric

examination before being accepted as a subject. They were told

that the purpose of the experiment was to determine the effects

of psychoactive drugs on several types of performance tasks and

to see how these behavioral changes correlated with changes in

various physiological systems. At the end of the experiment the

subjects were completely informed of the details of the experiment

and the drugs they had been given.

Each subject was confined to a soundproof room for six hours per

day for a minimum of 12 experimental days. Heart rate, EKG and

blood pressure were continuously monitored. Smoking was permitted

ad libitum and a standard breakfast and lunch were provided.

Behavioral procedures including time estimation, hand steadiness

and a vigilance or monitoring task were scheduled at various times

throughout the six hour session. All experimental days had

identical testing schedules. The number of cigarettes smoked

during the six hour period was recorded and the residual portion

of each cigarette was weighed at the end of each session. The

subjects were instructed to report any subjective effects attributable to the drug.

In the first experiment we investigated the effects of intravenously

infused nicotine bitartrate. The results of this experiment have

been presented in detail elsewhere (Lucchesi, Schuster and Emley

1967). In summary, this study demonstrated that doses of 2-4 mg/

hour of intravenously infused nicotine produced a small but

91
significant decline in cigarette smoking frequency and the amount

of each cigarette consumed, as estimated by weighing the butts at

the end of the day. Of great importance is the fact that at this

dosage of nicotine the subjects did not report any unpleasant side

effects and were unable to discriminate the drug days from saline

control days. Further, the nicotine infusion produced no changes

in any of the behaviors generated by the performance tasks, suggesting that its effect on cigarette smoking behavior was specific.

We interpreted our data as suggesting that cigarette smoking was

a form of drug-seeking behavior and that the drug was nicotine.

That the infusion of nicotine produced only small decrements in

cigarette smoking behavior could readily be attributable to the

fact that cigarette smoking was under strong stimulus control and

that the act itself had through association with nicotine become

a powerful conditioned reinforcer. Although recent experimental

evidence has seriously questioned this role of nicotine (Kumar

et al. 1977), it is still my opinion that cigarette smoking is a

form of drug-seeking behavior and that nicotine is the drug being

sought.

EXPERIMENTS WITH d-AMPHETAMINE, MEPROBAMATE, AND LOBELINE

In subsequent experiments, which have not been reported previously,

we studied the effects of orally administered lobeline, d-amphetamine and meprobamate on cigarette smoking behavior. These drugs

were selected because at the time these experiments were conducted

they were being used alone or in combination by clinical investigators attempting to develop a program of pharmacotherapy for

aiding smokers to reduce or cease their cigarette use.

Lobeline is an alkaloid which is the principal constituent of

Lobelia,which is obtained from the herb, Lobelia lnflata. Lobeline

shares many of the actions of nicotine and cross tolerance has

been demonstrated. Because of the pharmacologic similarity,

lobeline has been suggested as a substitute for nicotine in people

attempting to decrease their tobacco use (Dorsey 1936). Various

commercial preparations containing lobeline have been marketed

as smoking deterrents.

Neprobamate and amphetamine were suggested as pharmacotherapeutic

aids in smoking programs to alleviate the anxiety (meprobamate)

or sleepiness (amphetamine) associated with the cessation of

cigarette smoking.

The experiments to be reported here differ from the clinical work

in that WC used naive subjects who were unaware of the drug being

administered. They did not come to us for aid in reducing their

cigarette consumption and were not aware that we were studying

their cigarette smoking behavior. In contrast, in all of the

clinical investigations the subjects were selected because of a

desire to stop smoking.

The method used in this study was identical to that used in the

first study except that the drugs were given orally rather than

intravenously. All drugs were encapsulated in identical gelatin

9 2
capsules. The subjects took 2 capsules with milk just before

breakfast. The d-amphetamine was given in dosages of 5.0, 7.5,

and in some cases 10 mg. The meprobamate was given in dosages

of 400 and 800 mg. The drug sessions were always randomized

with placebo sessions. Following the testing of these drugs,

the subjects were given 3 placebo capsules daily which they took

with each meal for 3 consecutive days. This was followed by a

5 day chronic lobeline regimen. The lobeline capsules (2 mg/

tablet) which were made from commercially available lobeline

sulfate (with antacids) were crushed, mixed with lactose, and

encapsulated in a gelatin capsule. The subjects took 3 lobeline

capsules per day (one with each meal) for 5 consecutive days and

were tested in the experimental procedure on days 1, 3, and 5 of

the chronic regimen. This was the dosage regimen suggested by

the manufacturer for the use of this product.

Six subjects were used in this series of studies. One subject

failed to complete the lobeline portion of the study, reducing

the number of subjects to five during the final stage of the

experiment.

Figure 1 (bottom section) shows the number of cigarettes smoked

during the placebo control and d-amphetamine sessions for each

subject . The placebo values are means of at least 6 sessions.

The d-amphetamine data represents individual sessions. This

illustrates that for subjects 2, 3, 4 and 6 there was a significant

Increase in cigarette smokng frequency during the d-amphetamine

sessions. The upper graph shows the corresponding residual weights

of the cigarettes. It can be seen that the amount of each cigarette consumed was not consistently affected by d-amphetamine.

On the other hand, there was no decrease in the amomt of each

cigarette consumed, at least as revealed by the weight of the

cigarette butts.

Figure 2 shows the corresponding data for meprobamate sessions

and placebo sessions. As can be observed, there was no significant

change attributable to meprobamate at the dosages of 400 and 800 mg

in cigarette smoking frequency or the residual weights of

cigarettes consumed.

Figure 3 shows the effects of chronic lobeline on cigarette smoking.

Lobeline did not produce a decline in the number of cigarettes

smoked or the amount consumed in any of the 5 subjects tested.

In fact, subject 1 actually showed a sizable increase in the number

of cigarettes smoked as well as the amount consumed on day 5 of

the chronic lobeline regimen.

From these data it can be concluded that only d-amphetamine had

any significant effect upon cigarette smoking frequency under the

present experimental conditions. At the dosage levels employed,

d-amphetamine produced both physiological and behavioral effects.

93
FIGURE 1

The effects of various doses of d-amphetamine on the cigarette

smoking behavior of six subjects. The top panel shows the average

weight of the unsmoked portion of the cigarette and the lower

panel shows the number of cigarettes smoked. The data for the

placebo condition represent the average of six sessions and the

vertical brackets indicate the standard error. The data for the

drug sessions represent the single determination at each dose

level.

9 4
FIGURE 2

The effects of various doses of meprobamate on the cigarette smoking

behavior of six subjects. The top panel shows the average weight

of the unsmoked portion of the cigarette and the lower panel shows

the number of cigarettes smoked. The data for the placebo condition

represent the averaqe of six sessions and the vertical brackets

indicate the standard error. The data for the drug sessions represent the singe determination at each dose level.

95
FIGURE 3

The effects of repeated administration of lobeline on the cigarette

smoking behavior of five subjects. The top panel shows the weight

of the unsmoked portion of the cigarette and the lower panel shows

the number of cigarettes smoked. Placebo sessions represent an

average of six sessions and the lobeline data are for sessions

conducted on days 1, 3, and 5 of the chronic dosing regimen.

96
Figure 4 shows the mean heart rate under placebo conditions and

for the highest dosage of d-amphetamine (7.5 or 10 mg). It is

clear that on days when subjects received these doses of damphetamine, heart rate was consistently elevated over the 6 hour

session. In addition systolic blood pressure showed a small but

consistent increase over the 6-hour session. These effects

probably represent a combination of the sympathomimetic actions

FIGURE 4

The effects of d-amphetamine on heart rate over the six-how

session average for the six subjects, The placebo data represent

an average of six sessions for each subject. The drug data are

derived from a singe session in which the highest dose of d-amphetamine was administered.

97
of d-amphetamine and the effects of increased nicotine

intake, since the subjects were smoking more frequently. It is

of importance to note that d-amphetamine also produced increased

rates of responding on the vigilance task. This suggests that

the actions of d-amphetamine on smoking frequency were not

specific.

In contrast, neither lobeline nor meprobamate produced any changes

in heart rate, blood pressure, or behavior generated by the performance tasks.

by one

Further, with the exception of drowsiness reported

subject at the 800 mg dose of meprobamate, subjects did not

report any subjective effects associated with the administration

of any of the drugs.

If this study had been conducted more recently, a number

of additional measures could have been obtained. Clearly,

blood nicotine levels would provide important additional data.

For example, it is conceivable that the drugs employed in this

study might have altered puff frequency and/or duration. Further,

the depth of inhalation of smoke might have been changed by these

drugs. Measures of blood nicotine levels would be the ideal way

to resolve these questions.

experiments were carried out,

Unfortunately, at the time these

the methodology for the measurement

of nicotine levels in blood was not available.

CONCLUSIONS

Despite the limitations of this study, I believe we can still

reach some important conclusions. First, lobeline sulfate at the

recommended dosages does not produce any effect upon cigarette

smoking behavior under the same conditions where nicotine does.

It thus seems unlikely that lobeline has comparable pharmacologic

actions allowing it to substitute for nicotine.

The data on d-amphetamine as well are of interest for theoretical

reasons. It has been suggested that the mechanism underlying the

reinforcing action of nicotine is its ability to produce EEG

arousal through its actions on the ascending reticular activating

system (Jarvik 1970). If this is the case, one would assume that

d-amphetamine should substitute for nicotine since it as well

produces EEG arousal through stimulation of the ARAS. The fact

that amphetamines cause an increase in cigarette smoking frequency

clearly does not support this hypothesis.

The fact that meprobamate failed to alter cigarette smoking frequency does not necessarily indicate that anxiety is not a factor

in the control of cigarette smoking frequency. The efficacy of

meprobamate as an anti-anxiety agent is highly questionable.

Clearly, studies with more efficacious drugs (e.g., the benzodiazepines) are necessary.

One final observation concerns the stability of cigarette smoking

frequency observed in the subjects of these experiments under the

placebo conditions. The small size of the standard errors bracket98
ing the placebo averages indicates that there was little variance

in both the measures of cigarette smoking frequency and the amount

of each cigarette consumed. Observation of the times when subjects

smoked indicated that this occurred with high probability during

“break” times from the performance tasks. It would be of great

interest to determine in future research whether smoking frequency

could be altered by manipulation of the timing of these “break”

periods. This would help to clarify the relative importance of

pharmacologic and environmental control over cigarette smoking

patterning and frequency.

ACKNOWLEDGMENT

This study was supported by a grant from the American Medical

Association Research and Education Foundation, Committee for

Research on Tobacco and Health.

REFERENCES

Dorsey, J.L. Control of the tobacco habit. Ann Int Med, 10:

628-631, 1936.

Jarvik, M. E. The role of nicotine in the smoking habit. In:

Junt, W.A., ed. Learning Mechanisms in Smoking.

Aldine, 1970. pp. 155-190.

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 observation on certain cardiovascular effects associated

with the tobacco alkaloid. Clin Pharmacol, 8:789-796, 1967.

AUTHORS

Charles R. Schuster, Ph.D.

The University of Chicago

Pritzker School of Medicine

Departments of Psychiatry and

Pharmacological and Physiological Sciences

950 East 59th Street

Chicago, Illinois 60637

B.R. Lucchesi, M.D., Ph.D.

The University of Michigan

Department of Pharmacology

Ann Arbor, Michigan 48104

G.S. Emley, M.S.

Foundation for Behavioral Research

Augusta, Michigan 49012

9 9
Chapter 9

Tobacco Dependence: Is Nicotine

Rewarding or Aversive?

M. A. H. Russell, M.B., MRCP, MRCPsych

To understand tobacco smoking is like doing a large and very difficult jigsaw puzzle. I shall focus on the role of nicotine in tobacco use partly because it may be a kind of straight edge to the puzzle which we can usefully begin to piece together without getting

lost among all the pieces that go in the middle. But the role of

nicotine interests me for another very practical reason. If it is

an important factor, and if most people do smoke chiefly to dose

themselves with nicotine, the present low-tar, low-nicotine approach

to safer cigarettes is obviously wrong, and it would be more logical

to develop low-tar, medium-nicotine (or even high-nicotine) cigarettes (Russell 1976a).

We know that tobacco smoking is highly dependence-producing. We know

that nicotine has numerous pharmacological effects, peripherally and

in the brain, which are potentially reinforcing. We know that it

has effects on behavior and performance which are potentially reinforcing. We know that it induces tolerance in animals and that they

become dependent on nicotine injections to maintain performance.

We know that most smokers absorb nicotine in amounts sufficient to

produce these rewarding effects, that they acquire tolerance to some

of its actions, and that they suffer from physical as well as psychological withdrawal effects when they stop smoking. We also know that

the rapid absorption of nicotine through the lungs produces intravenous-like high-nicotine boli in the blood which reach the brain

within a few seconds after each inhaled puff. The possibility that

this produces a rapid puff-by-puff pharmacological reinforcement in

the reward centers in the brain some 70,000 times a year would go

a long way toward explaining the high dependence-producing potency

of cigarette smoking (Russell 1976b).

If we could prove that nicotine is what smokers seek, we could be

confident that the puzzle was virtually completed. Unfortunately

this is not the case and we cannot escape the nagging fact that

powerful addictive syndromes occur where pharmacological factors

clearly play no part. One does not have to look far for examples

such as gambling, nail-biting, and the desire for sweet tastes

100
or high-fat and high-cholesterol foods. With tobacco smoking

there are numerous nonpharmacological components which could make

it equally dependence-producing. Nicotine titration studies have

attempted to prove that people smoke for nicotine. But, as I shall

go on to show, these data do not disprove (indeed they can be better

fitted to support) the hypothesis that people smoke and inhale for

nonpharmacologic effects such as taste, aroma, sensorimotor ritual,

and the local irritation by nicotine and other components of tobacco

to sensory receptors in the lungs and respiratory tracts, and

that the pharmacological effects of nicotine are aversive and tend

to inhibit inhalation rather than reinforce it.

Definition of “Dependence” and “Addiction”

If we agree that tobacco smoking is for many a form of dependence,

what does this mean? There are some who restrict the term “addiction”

to compulsive syndromes which are maintained largely by the need

to relieve or avoid physical withdrawal effects. The issue of “physical” versus “psychological” dependence is a somewhat false dichotomy,

as the two are so interwoven. I use the terms “dependence” and “addiction” interchangeably to refer to a state in which the urge or

need for something is so strong that the individual suffers or has

great difficulty in going without it! and in extreme cases cannot

stop doing it, or using it, when it is available. How high a degree

of dependence is required before the condition is labelled a “dependence disorder” or “addiction” is somewhat arbitrary.

I would like to emphasize one point. It is the strength of the urge

or need which is important, not whether it is predominantly pharmacologically or nonpharmacologically determined. Strong social or

psychological rewards can produce a higher degree of dependence

than weak pharmacological ones.

To what extent, then, does tobacco smoking depend on pharmacological

as opposed to social or other nonpharmacological reinforcement?

And to what extent do smokers smoke for positive rewards (pharmacological, nonpharmacological or acquired by conditioning) as opposed to seeking relief from, or avoidance of, unpleasant withdrawal

effects (pharmacological, nonpharmacological or conditioned)? In

other words, how much is smoking maintained by positive versus

negative reinforcement?

Expressed Motives of Smokers

Many smokers find it difficult to explain why they smoke. Some will

say they smoke because they find it pleasurable, that it helps them

to relax, or simply that they are addicted. There are obvious

pitfalls to accepting such statements at face value. When people

find themselves doing something frequently and to some extent

against their better judgment, they may tend to attribute this to

pleasure, addiction, or some such “rational” explanation. They are,

however, unable to tell us what makes the behavior pleasurable, relaxing, or addictive. Nevertheless, the statements of smokers them101
selves are an essential starting point in determining the motives

underlying the dependence.

A number of people, such as Horn in the U.S.A. (Ikard, Green and

Horn 1969) and McKennell (1973) in Britain, have used factor analysis

to make systematic studies of the responses of smokers to questions

on motives for smoking. We have done a similar study (Russell, Peto,

and Patel 1974) using a 34-item questionnaire combining various aspects of the earlier work of Horn and Mckennell. We obtained six

factors representing various motives for smoking: psychosocial, indulgent, sensorimotor, stimulation, addictive, and automatic. Unlike previous studies, we did not obtain a sedative smoking factor.

Items designed to form a sedative factor loaded instead on the addictive and stimulation factors. It is not intended here to discuss

the factor structure, but it may be that the negative affect and

agitation which smoking apparently sedates are generated by cigarette

withdrawal, and that in such cases “sedative” smoking is withdrawal

relief smoking rather than smoking for sedation of negative affect

due to other causes.

The most striking finding of our study was the clear-cut separation

of the factors and their items into two distinct clusters, which we

interpreted as representing pharmacological and nonpharmacological motives. This is shown in figure 1 where the items have been plotted

according to their loadings on the first two unrotated factors, which

respectively accounted for 18 percent and 8 percent of the variance.

The “pharmacological” cluster was comprised of the addictive, automatic, stimulation, and sedative smoking items. The psychosocial,

sensorimotor, and indulgent factor items were all in the "nonpharmacological” cluster. Some validation is provided by the correlation

of the “pharmacological” group of factors with cigarette consumption; it was these factors that also differentiated a criterion

group of addicted heavy smokers attending a withdrawal clinic from

the main sample of normal smokers (figure 2). The questionnaire

has since been modified and further validation will be sought by

examining the relation of factor scores to blood nicotine and COHb

levels and to clinical outcome.

Pharmacological studies have shown that in smoking doses nicotine

is predominantly a stimulant drug but that it also has some sedative

actions (Russell 1976b). The self-report data of smokers suggested

similar effects! and this led us to label the two main item clusters

as “pharmacological” and “nonpharmacological.” The addictive factor items were concerned with craving and the relief of withdrawal

symptoms, or, in other words, with negative reinforcement smoking.

The high correlation between the positive effects of stimulation and

the negative addictive factor items suggests that once sufficient

nicotine is taken in to provide stimulation, withdrawal effects are

likely to occur. This does not appear to ha pen to the same extent

with indulgent smoking (smoking for pleasure). How much the pleasurable aspects depend on nicotine is obviously an important question.

As a final caution, it should be emphasized that stimulation, sedation, and withdrawal relief smoking do not necessarily indicate

102
FIGURE 1

Loadings of 34 items on the first two unrotated factors

St Stimulation, I: Indulgent, P: Psychosocial, Sm: Sensorlmotor,

Ad: AddIctwe, A: Automatic, Sd: Sedative.

Loadings of 34 questionnaire items on the first two unrotated factars. The upper left cluster is comprised of "nonpharmacologica1"

motives for smoking from the psychosocial, sensorimotor, and indulgent smoking factors. The "pharmacological" items representing stimulation, sedative, addictive, and automatic smoking are all in the

lower right cluster. (Reprinted with permission from Russell, M.A.H.;

Pete, J.; and Patel, U.A. The classification of smoking by factorial

structure of motives. Journal of the Royal Statistical Society,

Series A, 137:373-333, 1974. © 1974, Royal Statistical Society.)

103
FIGURE 2

Mean factor scores by sex for Main & Smoking Clinic samples

Mean factor scores by sex for "Main" sample of normal smokers (N=175) and "Smoking Clinic" sample (N=103).

There is no difference between the samples in scores on the indulgent, psychosocial and sensorimotor factors,

but the differences on the other factors are highly significant (p<.001). (Reprinted with permission from

Russell, Peto, and Patel, 1974. ©1974, Royal Statistical Society. See citation, figure 1.)
pharmacological mediation. It is possible that a similar factor

structure with the same two main clusters of items could have been

obtained by applying a similar questionnaire to regular gamblers.

Nevertheless, the evidence so far available from this kind of approach suggests that smoking depends on a mixture of pharmacological

and nonpharmacological motives and that pharmacological motives

dominate in the case of addicted heavy smokers.

Onset and Maintenance of Smoking

Daniel Horn (this volume) has discussed the factors involved in the

establishment and maintenance of the smoking habit-two quite distinct processes. He has perhaps paid insufficient attention to one

outstanding British study by Bynner (1969, 1970) which greatly clarifies the process of recruitment to smoking in schoolboys. It is

also worth emphasizing the finding of McKennell and Thomas (1967)

that of those teenagers who smoke more than a single cigarette,

only 15 percent avoid going on to become regular dependent smokers.

Why this escalation should be almost inevitable may be explained in

the following way: The first few cigarettes are usually unpleasant,

but skill is quickly acquired to limit the intake of smoke to a comfortable level. Tolerance to the unpleasant side effects of nicotine soon develops, thus lowering the threshold for further attempts.

If the psychosocial rewards are sufficiently strong to cause the

act to be repeated in the face of the side effects and physical discomfort, there is little chance that it will not continue, as the

side effects rapidly disappear. The factors controlling the onset

of smoking are summarized in figure 3, and those determining its

maintenance are shown in figure 4.

In the early stages, smoking is intermittent and is usually confined

to social situations. A few remain occasional social smokers for

many years. But, in the majority, consumption gradually rises and

ceases to be confined to social situations. After a few years

smoking occurs with great regularity. Inhalation also increases

gradually in most smokers until nicotine is absorbed in sufficient

quantities to exert numerous potentially rewarding pharmacological

effects. It is not known, however, whether the establishment of

inhalation coincides with or determines the development of a regular smoking pattern. Many smokers then progress to a further stage

of smoking for a predominantly negative reason: avoidance or relief

of the effects of withdrawal. What proportion of smokers reach this

stage, how long it takes, and to what extent the withdrawal effects

are mediated by pharmacological as opposed to nonpharmcological

factors are unknown.

Noninhaled Smoking

Some cigarette smokers do not inhale and consequently absorb little

nicotine. Systematic comparison of noninhalers and inhalers could

throw much light on the importance of pharmacological vs. nonpharmacological factors, but to my knowledge this has not been done. Apart

from novices and occasional social smokers, some heavy (two-pack-aday) smokers do not inhale; this is confirmed by low plasma nicotine

105
FIGURE 3

The main psychosocial factors determining the onset of smoking. On

the right are the positive reinforcers or incentives to smoke. Anticipation of adulthood includes an impatience to be grown up and

a tendency to participate in the activities of older teenagers, such

as drinking, taking an interest in the opposite sex, going to dances

and coffee bars, and staying out late. On the left are the factors

that discourage smoking; two of these-the sensory discomfort of

the first few cigarettes and the unpleasant side effects of nicotine-soon disappear as the act is repeated, thereby lowering the

threshold for mother attempts. (Reprinted with permission from

Russell, M. A. H. The smoking habit and its classification. The

Practitioner, 212: 791-800, 1974. ©1974, The Practitioner.

106
FIGURE 4

Factors controlling the maintenance and discontinuance of smoking.

For most people below middle age, the factors motivating continued

smoking are stronger than the motives to stop. The "Mastery" motive

is the wish to show will power and gain control over the habit.

"Aesthetic" refers to the feeling that smoking is dirty and messy,

while "Example" concerns those who wish to stop to set a good example to children or other impressionable groups. (Reprinted with

permission from Russell, M.A.H. The smoking habit and its classification. The Practitioner,

The Practitioner.)

212:791-800, 1974. ©1974,

107
and COHb levels (figure 5). Such smokers may, however, be highly

dependent in terms of craving and difficulty in giving up smoking.

We do not know how many cigarette smokers are noninhalers, nor do we

know whether they have lower ratings of dependence (with or without

control for daily consumption). To study this would require measures

of COHb or expired air CO, for smokers themselves do not reliably

Know the extent to which they inhale.

FIGURE 5

Plasma nicotine concentration in an inhaling smoker and a noninhaler during and after smoking one cigarette. The inhaler smoked only

one pack a day and had little difficulty giving up smoking. The

noninhaler smoked more than three packs a day and suffered intense

craving when he tried unsuccessfully to quit. (Reprinted from

Feyerabend, C.; Levitt. T.: and Russell. M.A.H. A rapid estimation

of nicotine in-biological fluids. Journal of Pharmacy and Pharmacology, 27:433-436, 1975, with permission. ©1975, Journal of

pharmacy and Pharmacology.)

108
Though less rapid than absorption through the lungs, it is generally

held that with snuffing, tobacco-chewing, and noninhaled pipe and

cigar smoking, absorption of nicotine through the nose or mouth is

sufficient to provide a pharmacologically rewarding effect. The

role of pH in determining the rate of absorption is crucial (Russell

1976b). Nicotine-containing chewing gum with a buffer to keep the

pH in the mouth at about 8.5 produces plasma nicotine levels comparable to inhaled cigarette smoking, but absorption is much slower

(Russell, Feyerabend, Cole 1976; Russell et al. 1977). The few

snuff users we have tested have had high plasma nicotine levels.

But what about noninhaled pipe and cigar smoking? Although the

pH of air-cured tobacco smoke is alkaline (about pH 8.5), is the

buffering capacity of the smoke sufficient to bring the pH of

saliva in the mouth up to this level? I am not aware of any studies

which show this. There is, however, one recent English study which

suggests that nicotine absorption from noninhaled cigar smoking

may be minimal (Turner, Sillett, McNicol 1977).

TABLE 1

Blood Nicotine and COHb Levels from Cigar Smoking

in Primary and Secondary Pipe and Cigar Smokers*

Before 20 min 40 min 60 min 120 min

NICOTINE (ng/ml)

1° (N=5) 3.3 4.0 4.3 5.1 4.5

2° (N=5) 12.8 30.7 45.6 36.2 24.7

COHb (%)

l ° (N=5) 0.8 1.0 1.0 0.9 1.0

2° (N=5) 2.9 6.6 8.4 9.6 8.1

The cigar was discarded at 60 minutes.

Abstracted from Turner, J.A.M.; Sillett, R.W.; and McNichol, M.W.

Effect of carboxyhaemoglobin and plasma nicotine concentrations in

primary pipe and cigar smokers and ex-cigarette smokers. British

Medical Journal, 2:1387-1387, 1977. ©1977, British Medical Journal. Reproduced by permission.

*Primary pipe and cigar smokers are those who have never been regular cigarette smokers. Secondary pipe and cigar smokers are ex-cigarette smokers who have switched to a pipe or cigars, which they

then tend to inhale (Castleden and Cole, 1973; Cowie, Sillett and

Ball, 1973).

109
Turner and his colleagues measured plasma nicotine and COHb levels

of smokers before, during, and after the smoking of a large cigar

(12.4 an, 6.2 g). The results in table 1 show clearly that the

noninhaling primary pipe and cigar smokers absorbed virtually

no nicotine. The authors claim that these smokers were nevertheless

addicted in terms of craving and suffering when they could not

smoke. The authors believed that their study seriously challenges

the role of nicotine in tobacco dependence. They did not, however,

make systematic ratings of dependence. True primary pipe and cigar

smokers are an atypical minority of the smoking population. The

fact that ex-cigarette smokers who switch to a pipe or cigars often

continue inhaling is an indication that, once experienced, the inhalation of tobacco smoke is difficult to forgo.

Though further study is obviously necessary, it would seem that

strong dependence may occur in cigarette smokers, pipe smokers,

and cigar smokers who do not inhale and who consequently absorb

little nicotine. This suggests that tobacco dependence can be

mediated by nonpharmacological factors such as taste, smell, sensorimotor ritual, and the like. Indeed, nicotine itself may contribute to the flavor, sharpness, irritancy, etc., and may be

rewarding for these effects apart from its pharmacological actions.

Nicotine Intake from Cigarette Smoking

It comes as no surprise to find wide individual variation among

smokers in blood nicotine levels just after a cigarette. Values

range from below 10 ng/ml to more than 50 ng/ml, with an average

for heavy smokers of around 35 ng/ml. Neither is it unexpected

that the individual smoker tends to obtain a fairly consistent

peak nicotine level after each cigarette, whether it is smoked in

the morning or afternoon, from one day or week to the next.

Of the majority of smokers, who do inhale, we are nowhere near the

stage of knowing whether they smoke for some positive effect of the

blood nicotine peaks, whether they smoke to avoid the pharmacological

effects of falling below a certain blood nicotine trough, or indeed

whether the nicotine intake and its pharmacological effects are

merely incidental to inhalation which is determined by nonpharmacological factors. It would seem from preliminary pharmacokinetic

findings (Russell and Feyerabend, 1978) that the predominant blood

profile for inhalers who smoke one cigarette per hour or less is one

of repeated high nicotine peaks (figure 6), whereas the accumulation

of nicotine in the body of those who smoke at least one cigarette every

30 minutes would tend to show smaller peaks relative to the overall

level (figure 7). They might more likely, therefore, be motivated

by the need for “trough maintenance.” Very tentatively I suggest

that if nicotine has a pharmacologically reinforcing role, trough

maintenance may be the main motive for the addicted smoker, while

who smoke less heavily.

optimal peak effects may be more important to indulgent smokers,

The peak blood nicotine levels of the two

types, however, do not appear to differ greatly, and peak blood

nicotine does not correlate with cigarette consumption, r = .02

(Russell et al. 1975 and 1977).

110
FIGURE 6

Plasma nicotine concentrations in an inhaling smoker while smoking

at a rate of one cigarette per hour for seven hours. Although there

is some accumulation of nicotine, the predominant profile is one of

prominent blood nicotine peaks following each cigarette. This illustrates the characteristic pattern of the "peak seeker" type of

smoker mentioned in the text. (Figure reproduced with permission

from Russell, M.A.H.; Feyerabend, C.; and Cole, P.V. Plasma nicotine levels after cigarette smoking and chewing nicotine gum.

British Medical Journal, 1:1043-1046, 1976. ©1976, British Medical Journal.)

111
FIGURE 7

Plasma nicotine concentrations in an inhaling smoker while smoking

at a rate of three cigarettes per hour for seven hours. Blood samples were taken just before and two minutes after each cigarette.

The blood nicotine builds up to a “steady state” with peaks which

are small relative to the overall level. This illustrates the

characteristic pattern of the “trough-maintainer” type of smoker

suggested in the text. (Reprinted from Russell, M.A.H., and

Feyerabend, C. Cigarette smoking: a dependence on high nicotine

boli. Drug Metabolism Review, 8•29-57, 1978, by courtesy of

Marcel Dekker, Inc., ©1978.)

112
It is tempting to postulate a three-stage process, with smokers beginning to smoke for psychosocial reasons, the majority then learning to inhale and progressing to smoking for the effects of the

sharp blood nicotine peaks that follow each cigarette (peak-seekers),

and some finally going on to a third stage of negative reinforcement

smoking to avoid the withdrawal effects of dropping below a certain

blood nicotine level (trough-maintainers).

As mentioned, however, the issue is far more complex: Noninhalers

may also progress to a second stage of regular indulgent smoking

for positive nonpharmacological rewards, as well as to a third

stage of negative withdrawal relief smoking mediated by nonpharmacological factors. Further complexities arise from interactions

between pharmacological and nonpharmacological components, due to

conditioning and other processes. Plausible as all this may seem,

with many resemblances to other drug addictions, it has yet to be

established that smokers do indeed smoke for the pharmacological

effects of nicotine rather than for nonpharmacological reasons.

Use of low-Tar, Low-Nicotine Cigarettes

What can be learned from studies of the use of low-nicotine cigarettes? Among English cigarette smokers, only 10 percent of men

and 18 percent of women regularly smoke low-nicotine brands. Most

low-nicotine brands smoke in Britain have standard deliveries of

0.6 to 0.8 mg nicotine; yet it is still possible to maintain high

blood nicotine levels, of 40 ng/ml or more, by smoking these brands.

It is only when the nicotine yield is reduced to 0.4 mg or less that

this becomes difficult, and relatively very few people smoke cigarettes of this type.

The lack of popularity of low-nicotine cigarettes may seem to

provide evidence of a need for nicotine. Similarly, the tendency

when smoking them to smoke more cigarettes or take larger and more

frequent puffs and inhale more deeply has been interpreted as

reflecting a need to titrate nicotine. There is a serious objection

to this interpretation, however. low-nicotine cigarettes also

have low yields of other consituents, such as tar, which contribute

to the taste and satisfaction of the smoke.

often also difficult to light and to smoke.

Indeed, they are

Regulation of Nicotine Intake

Self-regulation of nicotine intake, or nicotine titration, is

probably the most useful approach for studying the role of nicotine in smoking. It has been comprehensively discussed by

Schachter (this volume). As he points out, there are numerous

studies showing that smokers modify their smoking patterns to

compensate for a reduction of the tar and nicotine yields of

their cigarettes. But, as mentioned above, owing to the high

correlation (70.9) of tar and nicotine yields, we cannot know

113
from such studies whether the smokers are regulating their intake

of nicotine rather than tar or some other factor.

Only one study, by Goldfarb et al. (1976), has used cigarettes in

which tar and nicotine yields were independently varied. The number of cigarettes smoked was unaffected by tar yield but varied

inversely with nicotine yield, although insufficiently to maintain

urinary nicotine excretion constant. While most studies have shown

that compensation on low nicotine cigarettes is often only partial

(Russell 1976b, Sutton et al. 1978), we have found that smokers

lower their intake very accurately when switched to high nicotine

cigarettes. Blood nicotine levels on cigarettes yielding 3.2 mg

nicotine averaged 29 ng/ml, compared to 30 ng/ml on cigarettes yielding 1.3 mg nicotine (Russell et al. 1975). It seems, therefore, that

that self-regulation downwards to avoid an excessive intake may be

more sensitive and complete than compensation upwards to avoid a

reduction in nicotine and/or tar intake.

There have been very few direct studies of nicotine titration, i.e.,

those which avoid confoundment with tar intake and other factors.

They have, however, with one exception, been most convincing in

their support for nicotine titration. For example, Stolerman et al.

(1973) showed that central cholinergic blockade with mecamylamine

caused smokers to increase the number of cigarettes smoked by

26.5 percent and the number of puffs by 25.3 percent compared to

placebo. In the study by Lucchesi et al. (1967), intravenous nicotine infusion reduced the number of cigarettes smoked by an average

of 29.8 percent compared to saline. Furthermore, 22 mg of IV nicotine bitartrate (about 7.3 mg base) caused a mean decrease of about

2.5 cigarettes during the 6-hour infusion period. The nicotine delivered by 2.5 cigarettes in the mid-1960’s, though not stated by

the authors, would have been about 7 mg. Titration of similar

accuracy was demonstrated during Schachter’s manipulation of urinary

nicotine excretion via its pH (Schachter, Kozlowski and Silverstein

1977). It would take too long to go fully into our own failure

to replicate Lucchesi’s findings (Kumar et al. 1977). This could

have had something to do with the extreme artificiality of our experimental conditions. Although our subjects continued to puff at

baseline levels during and just after the IV nicotine, it is possible

that they titrated by inhaling less. We did not measure blood nicotine levels, so we do not know whether or not this was so.

The sensitivity of the nicotine titration demonstrated in these more

direct studies is in keeping with the view that self-regulation of

nicotine intake downwards is more sensitive and complete than compensation upwards. One other direct approach has been to study the

effect on smoking behavior of nicotine-containing chewing gum. Two

studies have shown a modest inhibitory effect (Kozlowski, Jarvik and

Gritz 1975; Russell et al. 1976). In our study (table 2), a dose

of 20 mg nicotine per day taken in the gum reduced cigarette consumption by 17 percent (p < .05) and COHb by 41 percent (p < .01) compared

to placebo gum. About 90 percent of the nicotine in the gum is released, but much of this is no doubt swallowed, absorbed in the gut,

114
TABLE 2

Effect of Nicotine Chewing Gum on Plasma Nicotine Levels

During ad libitum Smoking (means of 41 subjects)

No gum Placebo gum Nicotine gum

Cigarettes per day 33.3 23.0 20.9

COHb(%) 8.5 7.2 6.3

Plasma nicotine (ng/ml) 30.1 24.7 27.4

Note: One piece of gum containing 2 mg nicotine was chewed hourly

for 30 min to a total of ten pieces per day. The specific effect

of nicotine (as opposed to the effect of placebo gum) accounted

for 17% of the reduction in daily cigarette consumption (23.0-20.9)

÷ (33.3-20.9) x 100 = 17. By similar calculation it accounted for

41% of the reduction in COHb and hence degree of inhalation.

Adapted from Russell, Wilson, Feyerabend, and Cole. Effect of

nicotine chewing-gum smoking behaviour and as an aid to cigarette withdrawal. British Medical Journal, 2:391-393, 1976.

© 1976, British Medical Journal. Reprinted by permission.)

and metabolized in the liver before reaching the systemic circulation.

It is not known how much of the 20 mg daily dose would have been

absorbed through the mouth. Nevertheless, despite the extra nicotine from the gum, the average plasma level of 27.4 ng/mg (table 2)

was not significantly different from the base-line level of 30.1 ng/ml

when smoking normally without gum, showing once again fairly accurate

downward titration. On the placebo gum, the small decrease in plasma nicotine (p < .05) suggests that a drop in plasma nicotine may be

better tolerated than an excess.

Adaptation and Compensation

Theoretically, a smoker may adjust to a dilution of nicotine (and

tar) content of smoke either by adapting to a lower dose or by compensating to maintain intake, smoking more cigarettes or increasing

the intensity of puffing and inhalation. The degree of compensation

may range from nil, to partial, to complete. The reduction of nicotine (and tar) intake to which adaptation is required will obviously

vary accordingly. Adaptation to a lower dose will only be complete

when any negative affect or discomfort has subsided. The time

courses of adaptation and of compensatory changes in smoking pattern

115
may differ, and they may also interact. For example, the degree of

compensation may be reduced as adaptation to a lower intake reduces

the urge for a higher intake. Increase in the intensity of puffing

may generate discomfort of a different kind (from that generated by

the reduced intake), to which adaptation of a different kind may or

may not occur. For example, to increase puff volume from 40 ml to

60 ml to maintain smoke intake per puff may involve little effort,

but an increase from 60 ml to 80 ml may make the smoker aware of

some awkwardness or discomfort. There are further complexities.

For example, a smoker may be able to take a larger puff of diluted

smoke, sufficient to maintain nicotine (and tar) dosage per puff,

but the dilution may reduce impact and flavor below an acceptable

level. Response to such interactions will vary, depending on the

degree to which the smoker requires to maintain nicotine (and tar)

intake on a per puff basis or on a per cigarette or per unit of time

basis. Furthermore, the unit of time may refer to the time taken

to smoke one cigarette or to longer periods in which several cigarettes are smoked.

Most studies of smokers’ responses to changing to low-nicotine cigarettes have been focused on demonstrating a significant compensatory

change in a group of smokers. They have been less concerned with

individual differences and have not attempted to measure the degree

of compensation. We have recently examined the extent to which

smokers compensate for the dilution of smoke produced by ventilated

cigarette holders (Sutton et al. 1978). There were no changes in

the number of cigarettes smoked. However, measures of plasma nicotine and COHb showed, on average, partial compensation of about

40 percent on Holder 2 (60 percent dilution), but on Holder 1 (20 percent dilution) there was no significant compensation (see figure 8).

Individual differences were marked, ranging from full compensation

to none at all. About half the subjects were clear-cut noncompensators. A similar 50/50 differentiation of individual smokers into

compensators and noncompensators has been observed by others (Cherry

and Forbes 1972; Freedman and Fletcher 1976; Forbes et al. 1976).

A further finding, shown in figure 8, was that the degree of compensation on Holder 2 did not change between 2 days and 7 days, but

adaptation to the lower nicotine intake did improve over this time.

Withdrawal symptoms subsided and subjective satisfaction on Holder 2

increased. How much this difference in the short term trends of these

two processes would be reflected in the long term is obviously an

important question. The adaptation acquired over this short period

was transient. Plasma nicotine and COHb had returned to former

levels five days after the holders were abandoned. The only long

term study, by Freedman and Fletcher (1976), suggested that adaptation acquired over several months could be maintained and that

smokers who had adapted to a lower tar and nicotine intake at mouth

level (based on butt analysis) did not increase it again when they

reverted to smoking stronger cigarettes.

These findings highlight the fact that compensation is, on average,

only Partial and that some smokers compensate while others do not.

This contrasts strikingly with the very accurate downward titration

116
FIGURE 8

Amount of compensation when using ventilated cigarette holders,

based on the means of 18 subjects. The observed and “expected”

blood nicotine and COHb levels on the holders are expressed as

percentages of the mean no-holder levels. The “expected” levels

are based on the dilution factors of the two holders, about

20 percent for Holder 1 and 60 percent for Holder 2. The shaded

areas represent the difference between the observed and “expected”

levels, which is a measure of the amount of compensation. The

lined area (for COHb on Holder 1 at 2 days) indicates a negative

O-E difference, i.e., observed levels were lower than “expected”

levels. Thus, though there was significant compensation on Holder

2 on all measures, there was clearly none on Holder 1. Significance

of O-E differences: *p<.02, **p<.01, ***p<.001. (From Sutton,

S.R.; Feyerabend. C.; Cole, P. V.; and Russell, M. A. H. Adjustment

of smokers by ventilated cigarette holders. Clinical Pharmacology

and Therapeutics, 24. 395-405, 1978. ©1978, The C. V. Mosby Co.

117
of nicotine in the experiments cited previously and may be partly

explained by the fact that it requires some effort by the smoker

to increase smoke intake but no effort to reduce it. Although

satisfaction is reduced when the smoke is diluted, this is not necessarily due entirely to failure to maintain nicotine intake. Other

factors such as the effort of compensation, loss of taste and impact

of the smoke in the mouth, throat, and lungs may contribute. It

would appear on balance that smokers tolerate a decrease in nicotine

intake better than an increase.

The Role of Nicotine

Our uncertainty about the role of nicotine in tobacco dependence is

reflected in the title of this conference where tobacco and nicotine

are linked, ambiguously, as “tobacco/nicotine.” As I see it, the

stroke between them proclaims loudly what we don’t know, and it

is on this issue that I have tried to focus.

In terms of unequivocal evidence that people smoke for nicotine, even

the few direct studies which purport to show that people smoke to

obtain a pharmacological effect from nicotine and that titration

indicates a need for nicotine, could be interpreted as showing nicotine to be pharmacologically aversive. Thus, when Lucchesi administered nicotine intravenously, smoking was inhibited (Lucchesi,

Schuster, and Emley 1976); but when Stolerman blocked the pharmacological effects of nictotine, his subjects could smoke more (Stolerman et al. 1973). Similarly, Schachter’s subjects could smoke more

when nicotine excretion was increased (Schachter, Kozlowski, and

Silverstein 1977). In other words, these studies could be seen as

showing that excessive nicotine is aversive; they do not show that

smaller amounts are pharmacologically rewarding. Can we be sure

that people are not dependent on inhalation for nonpharmacological

reasons such as taste, smell, ritual, sensory stimulation to the lungs

and respiratory tract-to which nicotine might contribute? Are

bu

people perhaps addicted to inhalation for nonpharmacological rewards

t inhibited from indulging more because they find excessive nicotine pharmacologically aversive? Simply because nicotine has so many

pharmacological effects in smoking doses, it does not necessarily

follow that these effects are reinforcing rather than aversive. Is

there, indeed, any evidence that nicotine is rewarding?

Evidence that nicotine can be pharmacologically rewarding is scanty.

Firstly, throughout history people have never shown a strong inclination to inhale smoke, however aromatic or flavorful, which does

not contain a psychoactive drug. This historical evidence is compelling but only circumstantial. On the other hand, there is a

surprising lack of evidence beyond the anecdotal level that animals

will learn to self-inject nicotine as avidly as they do other addictive drugs. Until attending this conference I was aware of only

two incomplete reports (Clark 1969; Deneau and Inoki 1967). The

careful studies of Hanson and his colleagues (this volume) are a

major contribution to this area. A preliminary reservation is that

they may not have shown conclusively that their rats were indeed

118
seeking nicotine as opposed to increasing the rate of lever-pressing

due to its stimulant action. The study design did not include a

free choice situation, which could have gone a long way to settle

this question.

Apart from the historical evidence and animal self-administration

studies, there is the well-known pioneer study by Johnston (1942).

He reported that when smokers were given hypodermic injections of

nicotine they “almost invariably thought the sensation pleasant.”

He also reported that the craving following withdrawal of cigarettes

was relieved by injection of nicotine. Has Johnston, all those

years ago, done what all of us have failed to do, namely shown that

nicotine is both a positive and negative reinforcer for human

smokers? Unfortunately, he has not. His studies were uncontrolled

and nonblind. However, his approach to the question has been more

direct and relevant than any of our efforts. We still lack a direct

study in humans to show that nicotine is pharmacologically reinforcing. Whether or not it is rewarding in optimal doses, it certainly seems to become aversive when these are exceeded, and the

implications for safer cigarettes remain the same. Less tar and

CO will be taken in by smokers if their cigarettes combine a low

tar and low CO delivery with a medium to high, rather than low,

nicotine delivery.

Summary and Conclusions

The role of nicotine in tobacco dependence is discussed. Review of

the data available in the literature raises many questions but

provides few answers beyond the following conclusions.

(1) Pharmacological reinforcement is not an essential feature of

addictive behavior.

(2) There are many nonpharmacological factors involved in tobacco

smoking, and these appear to be sufficient to generate strong dependence in smokers who do not inhale.

(3) The low acceptability of low-nicotine cigarettes is not necessarily due to the low nicotine. Nonpharmacological factors are

also involved.

(4) Smokers who inhale seem to tolerate a decrease in nicotine intake better than an increase.

(5) Simply because nicotine has many pharmacological effects in

smoking doses, it does not follow that these effects are reinforcing

rather than aversive.

(6) Evidence is scanty that animals will self-inject nicotine as

avidly as they do other addictive drugs.

(7) Apart from circumstantial historical evidence that people have

never shown a strong inclination to inhale smoke that does not con119
tain a psychoactive drug, there is no direct experimental study

which shows that nicotine is pharmacologically rewarding or reinforcing in humans.

(8) Whether or not nicotine is pharmacologically rewarding in optimal doses, it seems to become aversive when these doses are exceeded.

(9) The hypothesis that people smoke and inhale for nonpharmacological rewards, including the taste and irritancy of nicotine itself, but are inhibited from smoking more because they find excessive nicotine pharmacologically aversive, has not yet been disproved.

(10) The implications for safer cigarettes remain the same no matter whether nicotine is rewarding or aversive. The safer cigarette

should have a low tar, low CO, but medium to high rather than low

nicotine yield.

ACKNOWLEDGMENTS

I thank the Medical Research Council and Department of Health and

Social Security for financial support. I am also grateful for

helpful comments from my colleagues, J. Richard Eiser, Martin Raw,

and Stephen Sutton.

REFERENCES

Bynner, J.M. The Young Smoker. Government Social Survey. London:

HMSO, 1969.

Bynner, J.M. Behavioural research into children’s smoking: Some

implications for anti-smoking strategy.

Journal, 90:159, 1970.

Royal Society of Health

Castleden, C.M., and Cole, P.V. Inhalation of tobacco smoke by

pipe and cigar smokers. Lancet, 2:21-22, 1973.

Cherry, W.H., and Forbes, W.F. Canadian studies aimed toward a

less harmful cigarette. J Natn Cancer Inst, 48:1765-1773, 1972.

Clark, M.S.G. Self-administered nicotine solutions preferred to

placebo by the rat. Brit J Pharmacol, 35:367P, 1969.

Cowie, J.; Sillett, R.W.; and Ball, K.P. Carbon monoxide absorption

by cigarette smokers who change to smoking cigars. Lancet, 1:

1033-1035, 1973.

Deneau, C.A., and Inoki, R. Nicotine self-administration in monkeys. Ann N Y Acad Sci, 142:277-279, 1967.

120
Feyerabend, C.; Levitt, T.; and Russell, M.A.H. A rapid gas-liquid

chromatographic estimation of nicotine in biological fluids. J

Pharm Pharmacol, 27:434-436, 1975.

Forbes, W.F.; Robinson, J.C.; Hanley, J.A.; and Colbum, H.N.

Studies on the nicotine exposure of individual smokers. 1. Changes

in mouth-level exposure to nicotine on switching to lower nicotine

cigarettes. Int J Addict, 11:333-950, 1976.

Freedman, S., and Fletcher, C.M. Changes of smoking habits and

cough in men smoking cigarettes with 30% NSM tobacco substitute.

Brit Med J 1:1427-1430, 1976.

Goldfarb, T.L.; 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.

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, 1969.

Johnston, L.M. Tobacco smoking and nicotine. Lancet, 2:742, 1942.

Kozlowski, L.T.; Jarvik, M.E.; and Gritz, E.R. Nicotine regulation

and cigarette smoking. Clin Pharmacol Ther, 17:93-97, 1975.

Kumar, R.; Cooke, E.C.; Lader, M.H.; and Russell, M.A.H. Is nicotine important in tobacco smoking? Clin Pharmacol Ther, 21:520-

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.

McKennell, A. C. A comparison of two smoking typologies. Research

Paper No 12. London: Tobacco Research Council, 1973.

McKennell, A.C., and Thomas, R.K. Adults’ and Adolescents’ Smoking

Habits and Attitudes. Government Social Survey. London: HMSO, 1967.

Russell, M.A.H. The smoking habit and its classification, The

Practitioner, 212:791-800, 1974.

Russell, M.A.H.; Peto, J.; and Patel, U.A. The classification of

smoking by factorial structure of motives. J Roy Statist Soc A,

137:313-333, 1974.

Russell, M.A.H.; Wilson, C.; Patel, U.A.; Cole, P.V.; and Feyerabend,

C. Plasma nicotine levels after smoking cigarettes with high,

medium and low nicotine yields. Brit Fled J 2:414-416, 1975.

Russell, M.A.H. Low-tar medium-nicotine cigarettes: A new approach

to safer smoking. Brit Med J 1:1430-1433, 1976a.

121
Russell, M.A.H. Tobacco smoking and nicotine dependence. In:

Gibbins, R.J., et al., eds. Research Advances in Alcohol and Drug

Problems. Vol. III. New York: Wiley and Sons, 1976b, pp. 1-47.

Russell, M.A.H.; Feyerabend, C.; and Cole, P.V. Plasma nicotine

levels after cigarette smoking and chewing nicotine gum. Brit

Med J, 1:1043-1046, 1976.

Russell, M.A.H.; Wilson, C.; Feyerabend, C.; and Cole, P.V. Effect

of nicotine chewing-gum on smoking behaviour and as an aid to cigarette withdrawal. Brit Med J, 2:391-393, 1976.

Russell, M.A.H.; Sutton, S.R.; Feyerabend, C.; Cole, P.V.; and

Saloojee, Y. Nicotine chewing-gum as a substitute for smoking.

Brit Med J, 1:1060-1063, 1977.

Russell, M.A.H., and Feyerabend, C. Cigarette smoking: a dependence on high nicotine boli. Drug Metabolism Reviews, 8:29-57,

1978.

Schachter, S.; Kozlowski, L.T.; and Silverstein, B. Effects of

urinary pH on cigarette smoking.

1977.

J Exp Psycho1 (Gen), 106:13-19,

Stolerman, I.P.; Goldfarb, T.; Fink, R.; and Jarvik, M.E. Influencing cigarette smoking with nicotine antagonists. Psychopharmacologia, 28:247-259, 1973.

Sutton, S.R.; Feyerabend, C.; Cole, P.V.; and Russell, M.A.H. Adjustment of smokers to dilution of tobacco smoke by ventilated

cigarette holders. Clin Pharmacol Ther, 24:395-405, 1978.

Turner, J.A.M.; Sillett, R.W.; and McNicol, M.W. Effect of cigar

smoking on carboxyhaemoglobin and plasma nicotine concentrations in

primary pipe and cigar smokers and ex-cigarette smokers.

2:1387-1389, 1977.

Erit Med J,

AUTHOR

Michael A.H. Russell, M.B., MRCP, MRCPsych

Addiction Research Unit

The Institute of Psychiatry

The Maudsley Hospital

Denmark Hill

London, S.E.5

England

122
Chapter 10

Regulation, Withdrawal, and

Nicotine Addiction

Stanley Schachter, Ph.D.

Most of us who do research on smoking have at some time championed

the hypothesis that cigarette smoking, with nicotine as the active

agent, is an addiction. Sometimes, however, it is difficult to

figure out why that conviction is so strong. The data supporting

the proposition are not particularly good; in fact, looked at with

a ruthless eye, they are rather flimsy. I intend to review and

evaluate the data relevant to the addiction hypothesis and to attempt to understand just why they are so weak.

Most studies of the addiction hypothesis have focused on the

regulation of nicotine intake. I know of twelve studies in which

subjects were supplied with high- or low-nicotine cigarettes and

a record kept of how much they smoked. Two of these (Finnegan,

Larson, and Haag 1945, Goldfarb, Jarvick, and Glick 1970) found no

differences--subjects smoked no more low- than high-nicotine

cigarettes. One study (Ashton and Watson 1970) found exquisitely

precise regulation, and nine (Frith 1971; Goldfarb et al. 1976;

Herman 1974; Jarvik et al. 1970; Johnston 1942; Kozlowski et al.

1975; Kumar et al. 1977; Russell et al. 1973; and Schachter 1977b )

did find that subjects smoked more low- than high-nicotine cigarettes. It was not precise regulation, by any means; but in all

cases subjects did smoke somewhat more of the low- than of the

high-nicotine cigarettes. So far so good: in 10 of 12 studies the

amount smoked varied inversely with the nicotine content of the

cigarette.

Though these studies indicate some degree of regulation, they do

not as yet establish just what is being regulated; for, as we know,

the nicotine and tar contents of cigarettes covary. When I last

correlated the nicotine and tar contents of commercially available

cigarettes, the correlation coefficient was +.91. We note then

that two of these twelve studies attempted in some fashion to

manipulate tar and nicotine content independently. Both studies

(Goldfarb et al. 1976; Schachter 1977b) found the same result--

smokers track nicotine content, not tar content.

There have been three studies which preloaded subjects either with

nicotine chewing gum or nicotine capsules (Brantmark et al. 1973;

123
Jarvik et al. 1970; Kozlowski et al. 1975). All report the same

effect: Subjects on nicotine gum or capsules smoke less than

subjects on placebo. The effects in all cases are quite small

but statistically significant. In addition, Stolerman et al.

(1973) have demonstrated that administration of a nicotine antagonist increases cigarette smoking.

Finally, there have been two studies using the IV infusion technique. Lucchesi, Schuster, and Emley (1967) find good evidence

for regulation, and the study by Kumar et al. does not. In other

contexts (Schachter 1977a), I have spelled out why I think this is

so. It looks as if a reasonable case can be made for the proposition that smoking is addicting and something of a case for the

proposition that nicotine or one of its metabolites is the

addicting agent.

Why then do I speak of the data supporting the proposition as

“flimsy”? For two reasons: First, when we speak of regulation,

we tend to think in terms of fairly precise set-point models.

Presumably there is a “nicostat” sensing nicotine and regulating

intake so as to keep nicotine at some constant level. Yet with

a single exception (Ashton and Watson 1970), the data indicate

extraordinarily crude and imprecise regulation. A typical

instance of just how crude can be seen in Table 1, which presents

the data of a study I did some years ago (Schachter 1977b) on a

group of long time, very heavy smokers. In alternate weeks, subjects

smoked high- or low-nicotine cigarettes. The low-nicotine cigarettes

contained 0.3 mg of nicotine per cigarette; the high-nicotine cigarettes contained 1.3 mg of nicotine--more than a fourfold difference.

Though all of the subjects did smoke somewhat more low- than highnicotine cigarettes, on the average they smoked only 25 percent more

low-nicotine cigarettes--hardly the exquisite titration that setpoint models suggest.

The second reason for discomfort with the addiction hypothesis is

that exceptions to an addiction model are so common. Though it is

known (Isaac and Rand 1972) that plasma-level nicotine is zero on

awakening in the morning, there are heavy smokers who will not

light up their first cigarette of the day till afternoon. There

are smokers who smoke only at parties or while they are working,

and otherwise not at all. Some orthodox Jewish smokers, forbidden

to smoke on the Sabbath, appear able to do so without a whimper.

And so on.

Just how to cope with such blatant exceptions is problematic.

Perhaps it is necessary to invent typologies (e.g., McKennell 1973;

Russell 1974; Tomkins 1968) to accommodate the distressing apparent

variety of smokers, but I find this an unsatisfying scientific

strategem and admission of defeat.

As a working hypothesis, I propose instead that we consider virtually all long-time smokers as addicted and attempt to understand

the exceptions to maintaining a constant nicotine level in terms

of such notions as self-control, concern with health, restraints,

and so on. Certainly all smokers are aware of the dangers and

124
TABLE 1

The Effects of Nicotine Content on Cigarette Smoking

Subjects

JA

SS

RR

RS

DR

RA

JE

Mean

Cigarettes Smoked per Day

Low High

(0.3 mg) (1.3 mg)

Nicotine Nicotine

31.25 21.50

55.00 40.50

42.50 30.75

22.75 20.00

70.75 58.75

30.25 26.25

48.00 44.25

42.93 34.57

% Increase

High to Low

Cigarettes

+ 45.3

+ 35.8

+ 38.2

+ 13.8

+ 20.4

+ 15.2

+ 8.5

+ 25.3

expense of smoking. To the extent that such concerns are prominent,

the smoker probably inhibits smoking by such devices as imposing an

upper limit on daily consumption, scheduling smoking, restricting

smoking to particular occasions, and so on. All of these are devices

which are designed to lower consumption and which would tend to mask

such behavioral manifestations of addiction as tracking nicotine content. If this is correct, we should also expect other less obvious

manifestations of addiction to be present. Of these I would suggest

that the key will be the withdrawal syndrome. Obviously, anyone can

give up smoking, limit daily intake, or restrict smoking to particular times or occasions if he is willing and able to put up with the

withdrawal syndrome. If it is correct that virtually all longtime

smokers are addicted, it should be anticipated that smokers who do

not smoke in the morning will be grumpier and more irritable at that

time of day than in the afternoon; that heavy smokers who switch to

very low-nicotine brands will be chronically more volatile than heavy

smokers who don’t switch, and so on.

In order to test this sort of expectation, Perlick (1977) designed

an experiment in which she measured irritability in two groups of

smokers and a control group of nonsmokers. Unrestrained, heavy

smokers were compared with a matched group of mostly former heavy

smokers who, though still smoking, were deliberately cutting down.

In fact, most of this second group were smoking less than half of

their former regular intake.

125
We have, then, two groups of experimental subjects: one smoking

to heart’s content and the other deliberately restricting intake

by any or all of a variety of devices such as switching to lownicotine brands, buying only one pack a day, smoking only on the

hour, and so on.

Within the context of a study of aircraft noise, these subjects

individually watched a television drama and rated how annoying

they found each of a series of simulated overflights. The laboratory had been designed by Eugene Galanter to look like a living

room in Queens, near Kennedy Airport. Every 30 seconds or so a

horrendous racket pervaded the room as the stereo audio system

reproduced the noise of a jet taking off or landing. There were

three experimental conditions: In one, the subjects were permitted

ad lib smoking of high-nicotine (1.3 mg) cigarettes; in a second,

ad lib smoking of low-nicotine (0.3 mg) cigarettes; finally, in a

third condition, they were prevented from smoking.

Before getting to the results, let us examine the actual amount. of

smoking by these two groups of smokers during the experiment. Do

they behave during the experiment as on questionnaires they say

they do in real life? They do. In those conditions in which they

were permitted to smoke, restrained smokers took an average of 20.6

puffs (3.3 cigarettes) during the two-hour experimental session.

This is just about half the amount smoked by unrestrained smokers,

who puffed an average of 39.5 times (5.3 cigarettes).

Let us examine next the impact of the nicotine manipulation on the

heavy, unrestrained smokers. The logic of the general argument

demands the demonstration that irritability is a consequence of

nicotine shortage. The data are presented in Figure 1. Along the

ordinate is plotted the average annoyance rating. It can be seen

that when permitted ad lib smoking of high-nicotine cigarettes,

unrestrained smokers are just about as irritated by this noxious

series of noises as are the control nonsmokers. However, when prevented from smoking or permitted to smoke only low-nicotine cigarettes, their irritability increases markedly. It does appear that,

for the unrestrained smoker, irritability is a clear consequence of

depleted nicotine. Incidentally, Perlick found precisely the same

pattern for eating behavior, which is also presumed to be one of the

key nicotine withdrawal symptoms. At one point during the experiment

subjects had the opportunity to nibble freely at the contents of a

large jar of jelly beans. Subjects in the no- or low-nicotine

conditions ate twice as many jelly beans as did high-nicotine or

nonsmoker subjects.

Let us turn next to the group of highly restrained smokers. If it

is correct that the price of successful self-control is a chronic

state of withdrawal, we should anticipate high irritability in all

conditions, for even in the high-nicotine condition these former

heavy smokers are getting considerably less nicotine than was their

wont. The results are presented in Figure 2, where it can be seen

that in all conditions these highly restrained smokers are irritable.

Further, Perlick showed that these restrained smokers eat more when

126
FIGURE 1

NICOTINE MANIPULATION

The effects of nicotine on the irritability of heavy smokers

and nonsmokers.

127
FIGURE 2

NICOTINE MANIPULATION

The effects of nicotine deprivation on the irritability of heavy smokers, nonsmokers,

and restrained smokers.
given free access to jelly beans and also do not do as well at a

proofreading task requiring concentration. Restrained smokers,

then, appear to be chronically more irascible, to nibble more, and

to have poorer concentration than unrestrained smokers. It is

possible to control and restrict smoking, but at a price, and the

price appears to be a chronic state of withdrawal.l It does appear

that one of the exceptions to a purely addictive view of smoking is

in reality no exception. I suspect that this will be the case with

most of these exceptions, and that by taking account of withdrawal

we can understand those studies (Finnegan, Larson, and Haag 1945;

Goldfarb, Jarvik, and Glick 1970) that fail to show nicotine regulation. I would certainly suggest that any future studies of nicotine

regulation make systematic provision for the measurement of withdrawal. I would also suggest that of the numerous possible indices

of withdrawal, weight change may be by far the simplest and most

reliable. Given what we know of the effects on weight of giving up

smoking and what we know of the effects of nicotine deprivation on

eating, it’s not an unreasonable guess that those subjects who fail

to regulate nicotine will be the most likely to increase weight.

I would like to conclude that by jointly considering withdrawal and

regulation we can cope with the numerous apparent exceptions to an

addictive model of cigarette smoking and also dispose of the hateful

necessity to invent typologies to account for the apparent diversity

of types of smokers. Though I do believe that this conclusion is

valid for most smokers and smoking phenomena, I am not yet ready to

declare it universal, for there does seem to be at least one “type”

(dreadful word) of smoker for whom none of this seems to make sense.

This is the sort of person who has smoked for most of his or her

life and has never smoked more than 10 or 15 cigarettes a day. This

person inhales, smokes medium- to high-nicotine cigarettes, but by

his own self-description gives no indication that he is addicted.

He may not light up his first cigarette of the day until cocktail

time and can go for days without smoking and not think about it,

until he goes to a party or some such event. Further, he insists

that he is in no way trying to cut down or limit his smoking. Despite

extensive and long-time exposure to nicotine, we seem to have a nonaddicted and nonaddictable animal.

For years I have tried to prove that among his other attributes this

“type” of smoker is a liar, but so far with no success. In a first

attempt to study regulation in this group, I was able to identify

four such people and ran them simultaneously with the group already

described in the study in which subjects smoked either 0.3 mg or

1.3 mg nicotine cigarettes in alternate weeks (Schachter, 1977b).

These subjects, as a group, gave no sign of regulation, for two of

them smoked more of the high-nicotine and two smoked more of the lownicotine cigarettes.

Since my theme has been, “If they don’t regulate, look for withdrawal,”

let us next examine this “type” of smoker for indications of withdrawal. Perlick was able to locate 15 such smokers, who incidentally

were roughly matched with her group of restrained former heavy smokers.

Both groups had smoked for about 8.5 years and both groups currently

129
averaged about 11.5 cigarettes a day. The irritability data for

this group are presented on the right hand side of Figure 3. They

stand in fascinating contrast to all of the other groups of subjects,

for their irritability rating has absolutely no relationship to the

nicotine manipulation. In all three conditions, their annoyance

rating is quite low and on a par with the two groups that are not

suffering withdrawal--nonsmokers and heavy smokers in the high

nicotine conditions.

One obvious problem in interpreting these data is that two hours

without smoking may be small deprivation to someone who smokes only

10-15 cigarettes a day. It may be that with a longer period of

deprivation even these subjects would manifest withdrawal. However,

several sub-analysts suggest that this would not be the case. First,

even for such subjects, one might expect that annoyance ratings made

at the end of the experimental period would be higher than those

made at the beginning. This is certainly the case for the heavy

and the restrained smokers in the nicotine deprivation condition.

Both groups are markedly more annoyed at the end of the experiment

than at the beginning. There is no such effect at all for this

group, of apparently nonaddicted smokers; they are just as tranquil

at the end of the experiment as at the beginning.

Secondly, thanks to a questionnaire, Perlick knew when the subjects

had smoked their last cigarette before coming to the experiment.

If it is simply a matter of time, one would expect that those who

had smoked their last cigarette long before coming to the experiment

would be more irritable than those who had smoked shortly before

the experiment. Not so. For this group of subjects, there is no

relationship between time of last pre-experiment cigarette and the

mean level of annoyance during the experiment.

There is, then, experimental evidence suggesting that some smokers

are not addicted and apparently are nonaddictable. Some of these

subjects have smoked for 30 years and never smoked more than 10 or

so cigarettes a day. I think there are few such people--perhaps

5 to 10 percent of the smoking population--but I harp on them

because I suspect that they are an extraordinary scientific resource.

If we can understand these “freaks,” we may begin to make steps in

discovering what addiction is about.

FOOTNOTE

1. One alternative interpretation of these data must be considered.

It is conceivable that naturally irascible people are more

likely to restrain their smoking. If so, these results could

be attributable to self-selection rather than withdrawal.

Acutely aware of this possibility, Perlick (1977) compared

these groups on numbers of personality and demographic variables

and found no differences between the two groups.

130
FIGURE 3

NICOTINE MANIPULATION

The effects of nicotine deprivation on the irritability of heavy smokers, nonsmokers,

restrained smokers, and light unrestrained smokers.
REFERENCES

Ashton, H., and Watson, D.W. Puffing frequency and nicotine intake

in cigarette smokers. Brit Med J, 3:679-681, 1970.

Brantmark, B.; Ohlin, P.; and Westling, H. Nicotine-containing

chewing gum as an anti-smoking aid.

1973.

Psychopharmacologia, 31:191-200,

Finnegan, J.K.; Larson, P.S.; and Haag, H.B. The role of nicotine

in the cigarette habit. Science, 102:94-96,1945.

Frith, C.C. The effect of varying the nicotine content of cigarettes on human smoking behaviour. Psychopharmacologia, 19:188-192,

1971.

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.

Goldfarb, T.L.; 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.

Herman, C.P. External and internal cues as determinants of the

smoking behavior of light and heavy smokers. J Pers Soc Psychol,

30:664-672, 1974.

Isaac, P.F., and Rand, M.J. Cigarette smoking and plasma levels

of nicotine. Nature, 236-308, 1972.

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.

Johnston, L.M. Tobacco smoking and nicotine. Lancet, 2:742, 1942.

Kozlowski, L.T.; Jarvik, M.E.; and Gritz, E.R. Nicotine regulation

and cigarette smoking. Clin Pharmacol Ther, 17:93-97, 1975.

Kumar, R.; Cooke, E.C.; Lader, M.H.; and Russell, M.A.H. Is

nicotine important in tobacco-smoking? Clin Pharmacol Ther,

21:520-529, 1977.

Lucchesi, B.R.; Schuster, C.R.; and Emley, G.S. The role of

nicotine as a determinant of cigarette smoking in man with observations of certain cardiovascular effects associated with the tobacco

alkaloid. Clin Pharmacol Ther, 8:789-796, 1967.

McKennell, A.C. A comparison of two smoking typologies (Research

Paper 12). London: Tobacco Research Council, 1973.

132
Perlick, D. The withdrawal syndrome: nicotine addiction and the

effects of stopping smoking in heavy and light smokers. (Unpublished doctoral dissertation). New York: Columbia University,

1977.

Russell, M.A.H.; Wilson, C.; Patel, U.A.; Cole, P.V.; and

Feyerabend, C. Comparison of effect on tobacco consumption and

carbon monoxide absorption of changing to high and low nicotine

cigarettes. Brit Med J, 4:512-516, 1973.

Russell, M.A.H. Realistic goals for smoking and health.

254-258, 1974.

Lancet,

Schachter, S. Nicotine as addicting agent. Proceedings of the

Conference on Commonalities in Substance Abuse and Habitual

Behavior. Washington, D.C.: National Academy of Sciences, 1977a.

Schachter, S. Nicotine regulation in heavy and light smokers.

J Exp Psychol: General, 106:5-12, 1977b.

Stolerman, I.P.; Goldfarb, T.L.; Fink, R.; and Jarvik, M.E.

Influencing cigarette smoking with nicotine antagonists.

Psychopharmacologia, 28:247-259, 1973.

Tomkins, S. A modified model of smoking behavior. In: Borgatta,

E.F., and Evans, R.R., eds., Smoking, Health and Behavior.

Chicago: Aldine, 1968.

AUTHOR

Stanley Schachter, Ph.D.

Department of Psychology

1400 Schermerhorn

Columbia University

New York, New York 10027

133

Part III

Psychobiological Factors
Chapter 11

Acute and Chronic Effects of

Nicotine in Rats and Evidence for a

Noncholinergic Site of Action

L. G. Abood, Ph.D., K. Lowy, M.D., and H. Booth

Since the discovery that acetylcholine is a neurotransmitter in

the autonomic nervous system and that its action consists of a

muscarinic and nicotinic component, the action of nicotine has

been attributed mainly to effects on nicotitic cholinergic

synapses (Domino 1965; Larson and Silvette 1975). Although the

action of nicotine in the autonomic nervous system or in certain

brain areas can be understood in terms of either its agonistic

or antagonistic action at nicotinic cholinergic synapses, a close

perusal of the literature reveals that its neuropharmacological

effects are considerably more complex and cannot be entirely

explained by this mechanism. Recently we have observed that when

the natural form of nicotine, which is the (-)-isomer, is injected directly into a rat's lateral or third ventricle, there occurs

a characteristic prostration-immobilization syndrome lasting for

from 0.5 - 2 min (Abood et al. 1978). The syndrome can be prevented or antagonized by the intraventricular administration of

a number of newly synthesized nicotine or piperidine derivatives,

but not by a variety of antinicotinic or numerous psychotropic

agents. These observations, along with those involving electrophysiological and receptor binding measurements, led to the

conclusion that the prostration syndrome may not be mediated by

cholinergic mechanisms.

Additional pharmacological and electrophysiological studies on

the acute effects of nicotine as well as observations on the

chronic effects following continuous intraventricular infusion

of nicotine into the lateral ventricles of freely moving rats

are described in this report.

MATERIALS AND METHODS

All studies were performed on male Sprague-Dawley rats weighing

between 150-200 g. The anesthetized rat was introduced into a

Kopf stereotactic instrument, and a stainless steel cannula

(#220 DK 1 rat cannula, obtained from David Kopf) was inserted

stereotactically, aiming at either the lateral or third ventricle

136
It was attached to the skull by means of acrylic cement and four

small set screws. A bipolar Formvar coated nichrome electrode

of 0.2 mm thickness and 3/4 mm vertical tip separation was inserted with leads into the region of the dorsal hippocampus.

Electrical Recordings From Conscious Rats

Electrical recordings were made from freely moving conscious rats

by way of a light shielded flexible cable leading into a Grass

P-15-B preamplifier set for an amplification of 1000 and a filter

band between 3-30 cycles/set. The amplifier output was connected

to an FM tape recorder and a Grass dynagraph. Analysis of electrical activity was accomplished by two LINC-8 programs operating

on the output from the tape recorder. Spectral analysis was done

LINC-8 of a fast Fourier transform program modified for use by

LINC-8. Another program was used to plot histograms of amplitude

distribution recorded from representative sections of the tape

recordings.

3H-Nicotine Binding to Glass and Tissue

In an effort to develop a receptor binding assay for nicotine,

an extensive investigation was undertaken utilizing various neural

membrane preparations, synaptosomes, brain homogenates, and brain

slices; however, none of these proved to be satisfactory. The

ligands used in this exploratory study were 125I bungaratoxin,

14C-d-tubocurarine, and 3H-nicotine. The techniques for measuring binding to cell-free preparations included equilibrium dialysis, centrifugation, gel filtration, and filtration through glass

fiber filters. Although some stereospecific or specific nicotine

binding could be demonstrated with fresh rat brain slices, the

most satisfactory data were obtained by measuring 3H-nicotine

binding directly to Whatman GE/F glass fiber filters in the

absence of any tissue preparations.

The procedure for measuring 3H-nicotine binding to glass fiber

filters is described elsewhere (Abood et al. 1978). Briefly,

it consists of filtering a solution (0.05M Tris, pH 7.5) of

10-8M 3H-nicotine (0.2 curies/mole) in the absence or presence

of 10-5M (-) or (+)-nicotine or nicotine analogues and then filtering in vacuo through Whatman GF/B glass fiber filters (2.1 cm).

After washing the filters with 10 ml 0.05M Tris, pH 7.5, the

filter is transferred to vials and radioactivity measured by liquid

scintillation. Although some success was obtained in measuring

specific nicotine binding to fresh rat brain slices, no specific

or stereospecific binding was demonstrable to synaptosomes, neural

membranes, or brain homogenates, employing all known techniques

for measuring binding (see "Results").

Chronic Intraventricular Infusion of Nicotine

Chronic microinfusion of nicotine into the lateral ventricles of

rats was accomplished by means of Alzet osmotic minipumps Model

137
1701 (Wei and Loh 1976). The minipump was inserted subcutaneously

and was connected by means of a fine catheter to a 24 gauge stainless steel cannula stereotactically implanted into the lateral

ventricles. The reservoir of the minipump contained 170 μl of

10 mg/ml solution of nicotine HCl, and the delivery rate was

about 1 μl/hr (i.e.,10 μg nicotine/hr). In order to determine

the reliability of the minipumps, they were tested for their remaining Contents 1-2 weeks later either by measuring optical

absorbance at 260 nM or by the use of 3H-nicotine and measuring

residual radioactivity.

RESULTS

Psychopharmacological Effects of Nicotine Given Intraventricularly

Within 1-10 sec following the intraventricular administration of

2-10 μg of (-)-nicotine HCl the rats became prostrate and immobile,

manifesting occasional seizures and tremors together with various

autonomic changes (tachycardia, hyperpnea, and urination-defecation). The dose-response relationship was monotonic in this

range. In order to produce a comparable response with (+)-

nicotine, the required dose was at least 100 times greater than

for (-)-nicotine. A variety of agents were tested for their

ability to prevent the prostration immobilization syndrome of

(-)-nicotine, including a series of synthetic derivatives of

nicotine and piperidine (table 1). When 10 μg of either the

benzyl or 4-azido-2-nitrophenyl derivatives of either piperidine

or nicotine was given intraventricularly 2 min prior to 4 μg of

(-)-nicotine, the prostration syndrome could be prevented. A

wide variety of psychotropic neurotransmitters, cholinergic

agents (e.g., naloxone, d-tubocurarine anticholinergics, and

physostigmine), and d-tubocurarine were ineffective. Azapetine,

an adrenergic blocker having a structural relationship to

nicotine, possessed moderate antagonist activity. Neither

chlorpromazine nor diazepam had any effect in antagonizing nicotine or on binding.

3H-Nicotine Binding to Glass Fiber Filters

In general, a good correlation was observed between the behavioral

antagonism of a given agent and its ability to compete with 3Hnicotine for binding to glass fiber filters (table 1). The most

effective antagonists-such as N-ANPP, N-benzyl and N-ONPS derivatives of nicotine, and piperidine-were also the most effective

agents in blocking nicotine binding. The (+)-isorcler of nicotine,

which possessed about 1 percent of the efficacy of (-)-nicotine

in producing the prostration syndrome, was 10 percent as effective as

the natural nicotine in blocking binding. Although some stereospecific and specific binding of nicotine could be demonstrated

with fresh brain slices, the magnitude of the binding was small

and somewhat variable; therefore, such data were not included. No

specific binding to neural membranes, synaptosomes, or homogenates

prepared from rat brain was demonstrable.

138
TABLE 1

Antagonism of various agents to prostration syndrome in rats and

to 3H-nicotine binding to glass filters. The dose of (-)-nicotine

was 4 μg, which was given 1 min after the test agent. All drugs

were given intraventricularly at doses of 10 μg, except for

(+)-nicotine and piperidine, which were given at 100 μg. At least

8 rats were used for each drug tested behaviorally, while the

standard error in the binding studies is within 6 percent of the

mean. Binding is expressed as moles x 1014/glass fiber filter.

N-ANPP = 4-azide-2-nitrophenyl; N-ONPS = 2-nitrophenylsulfenyl.

139
Electrical Recordings of Dorsal Hippocampus After (-) and (+)-

Nicotine and Benzyl Nicotine

Spontaneous electrical activity recorded from the dorsal hippocampus of unanesthetized, freely moving rats before and after the

administration of 4 μg of (-)-nicotine bitartrate revealed marked

changes in both the frequency and amplitude of the electrical

pattern (figure 1 a-d; figure 2 a-d). Frequency analyses of the

electrical record are presented as oscillographic displays from

fast Fourier transform (figure 1 a-d). The control record indicated a frequency range of 6-8 cycles/sec with a minor component

in the 12-14 cycles/sec range (figure 1 a). Within 1 min after

the administration of 4 μg of (-)-nicotine, when the rat was

completely prostrate and immobile, the 5-8 cycle/sec activity

greatly diminished (figure 1 b). When 10 μg of N-benzyl nicotine

was given intraventricularly about 30 sec after the record in

figure 1 b, the electrical pattern within 30 sec reverted to one

resembling the control (figure 1c). For comparison, a frequency

histogram is presented of a record from an animal given 200 μg

of (+)-nicotine bitartrate, a dose which produced only minimal

prostration, muscle weakness, and inactivity (figure 1d). A

slight shift to lower frequencies was noted, with a peak value at

about 5 cycles/sec. A computer analysis was performed on the amplitudes of the electrical recordings, and the results are presented

in the form of histograms (lower tracings, figure 2 a-d). During

the control period the amplitudes varied over a large range

between 200-400 μV. After (-)-nicotine, when the animal was prostrate, the higher amplitudes at 400 μV disappeared, while the

major component was at 200 μV. The flattening of the electrical

recording after (-)-nicotine is evident in the upper tracing

(figure 2b). After 10 μg of benzyl nicotine, the electrical

record and the amplitude distribution resembled the control pattern; however, the 300-400 μV amplitude components did not reach

the control level (figure 2c). After 200 μg of (+)-nicotine,

the histogram and electrical pattern varied only slightly from

the control records, the major difference being an increase in

the 200 μV component (figure 2d).

Electrical Activity of Hippocampus During Nicotine Infusion

The electrical activity was recorded from the dorsal hippocampus

of freely roving rats throughout the period of the intraventricular infusion of nicotine at a rate of 10 μg/hr (figure 3 a-d).

The electrical pattern of the hippocampus is displayed in the

upper oscillographic tracings of figure 3a and 3b; and in the

tracing below is displayed a corresponding amplitude histogram

of the upper record. The amplitude range before the infusion

began had a broad spectrum ranging up to 400 μV (figure 3a); but

after 48 hours of infusion the amplitude range narrowed considerably, with a maximum of 100 μV (figure 3b). After 6 days of infusion the amplitude histogram and electrical record resembled

the control record (figure 3c), and two days following the removal

of the minipump the records were unchanged (figure 3d). A spec140
tral analysis of the frequency employing fast Fourier transform

revealed after 1.6 hours of nicotine a broad spectrum up to 30/

sec with a major component in 5-7/sec range (figure 4a). After

48 hours of nicotine infusion the higher frequency components

almost vanished and only the 5-7/sec component remained (figure

4b). After 6 days of infusing nicotine, the frequency spectrum

returned to the pattern seen in the control (figure 4c); and two

figure 4d). removal of the minipump the pattern remained unchanged

FIGURE 1

Spectral frequency analyses of electrical recordings of rat

dorsal hippocampus after (-)- or (+)-nicotine and N-benzyl nicotine. a = control, b = 1 min after 4 μg (-)-nicotine, c = same

rat given 200 μg (+)-nicotine 2 days later (control record identical), d = a rat given 10 μg N-benzyl nicotine 30 sec after (-)-

nicotine. The records are typical of at least 5 individual rats

for each drug. See text. Each dot on the abscissa represents

a scale of 5 cycles/sec.

Chronic Nicotine Administration and Tolerance

In an effort to determine whether tolerance developed with

repeated intraventricular administration of nicotine, rats were

exposed to various dosage regimes of nicotine (table 2). When

rats received 10 μg of nicotine for 3 consecutive days, they all

responded (prostration immobilization syndrome) on day 1, while

141
FIGURE 2

Electrical record and amplitude histograms corresponding to

record described in figure 1 a-d. The bar represents a scale

of l0-4 V on the abscissa.

TABLE 2

Effects of various dosage regime on behavioral response of rats

to nicotine. From 5-10 rats were represented in each schedule.

Nicotine was administered into left lateral ventricles.

Dosage Schedule Incidence of Prostration

Syndrome

10 μg nicotine daily for 3

consecutive days

All of rats responded day 1,

50 percent on day 2, 20 percent on day 3, 90 percent

response after 3 days recovery.

Tolerance.

10 μg nicotine every other day Most rats fully responded for

for 10 days each day drug was given.

No tolerance.

2 μg nicotine day 1, 4 μg day Response on day 4 to 10 μg

2, 10 μg day 3 nicotine.

Alzet minipump (10 μg/hr Normal response to 10 μg

for 10 days. nicotine on day after infusion

ended.

142
FIGURE 3

Amplitude histogram of hippocampal electrical activity following chronic intraventricular infusion of nicotine. Same rat and legend as in figure 4 a-d.
FIGURE 4

Frequency analysis of hippocampal electrical activity following chronic intraventricular Infusion of nicotine. a = control, b = 48 hrs of nicotine infusion,

c = 6 days of nicotine, d = 2 days after infusion was discontinued.
50 percent responded on day 2 and only 20 percent on day 3. I f

10 μg of nicotine was given every other day for 10 days, most of

the rats responded each day the drug was given. After 10 μg of

nicotine was given for 5 consecutive days, none of the rats responded to 10 μg of nicotine on day 6; however, most of the animals responded on the second day after discontinuing the nicotine.

If rats were given 2 μg of nicotine on the first day, 4 μg on the

second day, and 10 μg of nicotine on the third day, they all

responded to 10 μg of nicotine on the fourth day.

Effect of Nicotine on Drain Levels of Met-Enkephalin

Regional brain levels of met-enkephalin were measured in rats

sacrificed 1-2 minutes following the intraventricular injection

of 10 μg of nicotine. The animals were still prostrate at the

time of sacrifice. No significant differences were observed

between the saline- and nicotine-injected rats in any of the

three brain regions (table 3). The determinations were made by

Dr. S. Chanda, utilizing the technique of radioimmune assay.

TABLE 3

Effect of nicotine on enkephalin of rat brain regions.

Enkephalin = TYR-GLY-GLY-PHE-MET in pmoles/g wet wt.

All rats received 10 μg nicotine intraventricularly

1-2 minutes before sacrifice. Results are average

of 6 rats.

Nicotine Saline

Telencephalon 128 ± 39 97 ± 29

Diencephalon 149 ± 55 152 ± 36

Mesencephalon 223 ± 48 243 ± 34

DISCUSSION

The major conclusion from this study is that the action of nicotine in producing the prostration immobilization syndrome does

not appear to be mediated by cholinergic mechanisms in the brain.

Among the reasons for this conclusion are the following:

1) the syndrome cannot be simulated by a number of cholinergic

agents in doses up to 100 μg; included among such agents were

acetylcholine, oxotremorine, pilocarpine, physostigmine, and

a-lobeline; 2) a variety of agents know-n to block the nicotinic

cholinergic receptor were ineffective in either preventing or

reversing the behavioral effect of nicotine; and 3) the nicotine

and piperidine analogues which were effective in blocking the

behavioral effect of nicotine did not interfere with the binding

145
of 125 I bungarotoxin or 3H-d-tubocurarine to neural membranes

(Abood et al. 1978). In an effort to determine the possible

relationship of nicotine to town neurotransmitters, a wide variety

of substances, in addition to those described, were injected

intraventricularly (in doses up to 100 μe) and found to have no

similar effect. These included noradrenalin, dopamine, serotonin,

glutamic acid, sminobutyric acid, met-enkephalin, and morphine,

as well as a variety of antagonists to known neurotransmitters. I t

would appear, therefore, that this behavioral effect of nicotine

is quite unique and distinct, while being largely unrelated to

any known neurotransmitter system.

The brain sites associated with the prostration syndrome exhibit

a high degree of stereospecificity, the natural (-)-isomer of

nicotine being at least 100 times as effective as the (+)-isomer.

Since the optical purity of the stereoisomers can be determined

with only about 99 percent accuracy, it is conceivable that the

(+)-isomer is completely inactive. Domino (1965) compared the

two isomers of nicotine on established conditioned avoidance and

seizure threshold in rats as well as hypertension in dogs and

concluded that the (-)-isomer was only 8 times as active as the

(+)-isomer. Pfeiffer (personal communication) reported a similar

difference in man with the two Isomers. Although the (+)-nicotine

used by both investigators was not as optically pure as the material

used in the present study, the difference between the results cannot

be accounted for by the difference in purity. A more plausible

explanation is that the ventricular sites associated with the

prostration syndrome are distinct from those involved in the

behavioral and peripheral parameters measured by Domino (1965).

Another conclusion from this study is that tolerance in rats to

the behavioral effect of nicotine develops after repeated injections, but the responsiveness returns to the initial level

within 2 days following the last injection. Even after the rats

received a continuous infusion of nicotine for 7 days, they still

responded 1 day after stopping infusion to 10 μg of nicotine

injected into the lateral ventricles. With continuous infusion

of nicotine into the lateral ventricles, a marked change occurred

in electrical pattern of the dorsal hippocampus 24 hours after

infusion began, but the electrical activity returned to normal by

the end of the third day. Despite the fact that the electrical

pattern changed so markedly, there were no marked behavioral

effects during 7 days of infusing nicotine.

FUTURE OBJECTIVES AND DIRECTIONS

The present study raises a number of important questions concerning both the acute and chronic effects of nicotine on behavior. The most fundamental question pertains to the nature of

the prostration-immobilizatlon syndrome produced by nicotine

administered intraventricularly to rats and its possible relationship to the behavioral effects of tobacco in man. It is

recognized that the doses used to produce this effect in rats are

comparatively large, so that any comparison with smoking would be

146
difficult and somewhat conjectural. Some similarity has been observed in EEG changes associated with smoking in man (Murphee et al.

1967; Philips 1971) and after intravenous administration of small

doses of nicotine in cats (Domino and Yamamoto 1965). Nicotine in

both cats and man produces a desynchrony in the EEG, which has

been interpreted as both an "arousal" (Domino and Yamamoto 1965;

Philips 1971) and an opposite tranquilizing effect (Murphee et

al. 1967). In our studies with intraventricularly administered

nicotine, both the electrical recordings and behavioral responses

tend to suggest that the preponderant effect is a depressant one;

however, at lower doses (1 μg) the rats appear more active and

hyperexcitable. Precise and detailed psychophysical measurements

are needed in order to distinguish the two kinds of effects in

animals as well as man.

Another question concerns the nature and localization of the

sites for nicotine's action in the brain. If, as the present

study seems to suggest, the sites are noncholinergic and may be

unrelated to other known neurotransmitters, the question then

arises as to chemical nature of the endogenous substrate for

this particular site. As to the location of the sites, they

would appear to be somewhere within or near the lining of the

lateral or third ventricles. To date it has not been possible

to produce the prostration syndrome by injecting nicotine directly

into brain structures immediately adjacent to the ventricles or

into innumerable deeper brain structures.

Since a large number of neurohumoral substances, including biogenic amines and neuropeptides, are present in the hypothalamus

(Hokfelt et al. 1978), and since synaptic terminals for known

neurotransmitters have been detected in the linings of the lower

third ventricles, the hypothalamus has been considered as a

possible site for nicotine. Although the injection of nicotine

into the ventricular region in the vicinity of the hypothalamus

will elicit the prostration syndrome, the administration of nicotine into various nuclei of the hypothalamus has falled to produce

any behavioral response. In view of the fact that a number of

neuropeptides, such as B-endorphin, enkephalins, substance P, and

angiotensin II are associated with the hypothalamus, the possibility

exists that nicotine may promote their release and that the behavioral effects are due directly to the peptides. Nicotine has been

shown to promote the release of catecholamines from the hypothalmus

(Hall and Turner 1972) and to inhibit the release of serotonin

(Goodman and Weiss 1973), but neither neurotransmitter mimics

the action of nicotine. The brain is also known to contain

amines which possess nicotinic cholinergic actions, the most

noteworthy being piperidine (Von Euler 1944; Abood et al. 1961).

Although piperidine possesses tranquilizing (Abood et al. 1961)

and soporific actions (Dolezalova et al. 1973), it does not

produce the prostration syndrome seen with intraventricularly

administered nicotine.

It does not appear from the present studies that the behavioral

147
effects of nicotine are associated with changes in the levels of

brain met-enkephalin. Another finding that would tend to exclude

the involvement of endogenous opioid peptides in the action of

nicotine is that naloxone did not prevent or modify the behavioral

effects of nicotine. Furthermore, morphine itself did not mimic

or prevent the effects of nicotine.

Finally, some comment should be made concerning the inability

to demonstrate specific nicotine binding to neural tissue,

whereas both specific and stereospecific binding is readily

demonstrable to glass. One possibility is that the sites are

either destroyed during disruption of the tissue or that released

endogenous substances interfere with binding. Another is that

the binding affinity is too low to detect with the 3H-nicotine

used, a problem that might be rectified with material having a

100-fold greater specific activity. The fact that the response

to nicotine is so fleeting (often lasting only 10-30 seconds) is

suggestive of a relatively low affinity. Since nicotine would

appear to be highly potent when injected intraventricularly, the

receptors may be close to the site of administration. Since many

drugs bind stereospecifically to glass, it is difficult to attach

much significance to the fact that nicotine also binds stereospecifically. It is of interest, nevertheless, that the data

with the glass filters correlate well with the in vivo effects

of the various nicotine derivatives. Conceivably, the technique

could be useful as an initial screening for nicotine agonists or

antagonists.

ACKNOWLEDGMENT

This research was supported by a grant from the Council of Tobacco

Research and USPH grant DA 00464.

REFERENCES

Abood, L.G.; Lowy, K.; Tometsko, A.; and Booth, H. Electrophysiological, behavioral and chemical evidence for a noncholinergic, stereospecific site for nicotine in rat brain. J Neurosci, 3:327-333, 1978.

Abood, L.G.; Rinaldi, F., and Eagleton, V. Distribution of

piperidine in the brain and its possible significance in behavior.

Nature, 201-202, 1961.

Dolezalova, H.E.; Giacobini, E.; Seiler, N., and Schneider, H.H.

Determination of piperidine in snail brain. Brain Res, 55: 242-

244, 1973.

148
Domino, E.F. Some comparative pharmacological actions of (-)-

nicotine, its optical isomer, and related compounds. Tobacco

Alkaloids and Related Compounds, 1965.

Domino, E.F., and Yamamoto, K. Nicotine effects on the sleep

cycle of cat. Science, 150: 637-638, 1965.

Goodman, F.R., and Weiss, G.B. Alterations of 5-hydroxytryptamine

-

14C efflux by nicotine in rat brain area slices. Neuropharmacol

12: 955-965, 1973.

Hall, G.H., and Turner, D.M. Effects of nicotine on the release of

3H-Noradrenaline from the hypothalamus. Brit J Pharmacol, 21:

1829, 1972.

Hokfelt, T. et al. Arminergic and peptidergic pathways in the nervous system with special reference to the hypothalamus. In:

Reichlin, S., Baldessarini, R.J., and Martin, J.B., eds. The

Hypothalamus. New York: Raven Press, 1978.

Larson, P.S., and Silvette, H. Tobacco, Experimental and Clinical

Studies. Supplement 3. Baltimore: Williams and Wilkins, 1975.

Murphee, H.B.; Pfeiffer, C.C.; and Price, L.M. EEG changes in

man following smoking. Ann N.Y. Acad sci, 142: 245-260, 1967.

Pfeiffer, C.C. Personal communication.

Philips, c. The EEG changes associated with smoking.

physiology, 8: 64-74, 1971.

PsychoVon Euler, U.S.

of brain. Acta Physiol Scand, 8:380-384, 1944.

Piperidine as a normally present constituent

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

Science, 193: 1262-1263, 1976.

AUTHORS

L.G. Abood, Ph.D.; K. Lowy, M.D.; and H. Booth

Center for Brain Research

University of Rochester Medical Center

Rochester, New York 14642

149
Chapter 12

Tolerance to the Effects of Tobacco

Murray E. Jarvik, M.D., Ph.D.

The question of whether cigarette smoking or other forms of tobacco

use can be considered an addiction comparable to addiction to heroin or alcohol always sparks a lively debate. For one thing, there

appear to be different styles of tobacco use. For another, there

is some question about how often heroin or alcohol use results in

addiction. And, finally, there is not even uniform agreement on the

meaning of “addiction.” The definition I prefer is that of Jaffe

(1975): “Addiction...(is) ...a behavioral pattern of compulsive

drug use, characterized by overwhelming involvement with the use

of a drug, the securing of its supply, and a high tendency to relapse after withdrawal.”

Tolerance and dependence are two phenomena which are closely related to addiction to heroin and alcohol. In this paper I want to

consider evidence concerning tolerance to tobacco and its components.

Since prominent theories of physical dependence consider tolerance

to be the basis of this state (Jaffe and Sharpless 1968; Martin

1968; Goldstein et al. 1974), this paper may be considered complementary to that of Shiffman (this volume), who deals with the dependence question. I can think of no example of a drug to which

dependence occurs which does not also involve tolerance. On the

other hand, tolerance may occur without dependence, for example, to

phenothiazines, or to antihistamines.

Tolerance is manifested by a decreasing response to repeated administration of the same dose of a drug, or by the requirement for

increasing doses in order to elicit the same response. Tolerance

to different effects of a given drug may vary widely.

Of the many thousands of substances contained in tobacco and tobacco smoke (Schmeltz and Hoffman 1976), three are of primary

biological importance: “tar,” carbon monoxide, and nicotine. There

is evidence that tolerance can develop to the effects of each of

these, and their interaction has scarcely been studied. Although

there is evidence that tolerance may develop to other components

such as acetone and phenol, it is unclear how much they contribute

to the pharmacological actions of cigarettes,

150
Three kinds of tolerance are apt to occur with tobacco use as with

other drug use: (1) drug dispositional or metabolic tolerance;

(2) tissue or pharmacodynamic tolerance; and (3) behavioral tolerance. The first refers to methods that the body uses to eliminate

the drug or to deactivate it. For most chemicals derived from

tobacco, the liver is the organ most heavily responsible for detoxifying or transforming them into inactive and eliminable forms.

The kidney is also important, especially for alkaloids whose water

solubility varies with the pH of the solution. The second refers

to changes in the ability of receptors to be activated by the drug

at its final site of action. The third refers to the way in which

the subject using the drug changes his behavior to adapt to the

effects which the drug repeatedly produces.

TAR

“Tar” is defined as the total particulate matter (TPM) collected

by a Cambridge filter after subtracting moisture and nicotine.

The polycyclic aromatic hydrocarbons are generally blamed for a

substantial portion of the carcinogenic activity of “tar.” They

are also powerful enzyme inducers and are undoubtedly responsibe

for much of the tolerance produced by smoking to themselves and a

variety of other compounds. The tar content of cigarette smoke

for all brands is determined yearly by the Federal Trade Commission which publishes a listing, along with nicotine content. Tar

and nicotine tend to covary and thus their effects may be confounded. Obviously, tar is obtained in the smoke from pipes and

cigars, but not from chewing tobacco and snuff. The latter do not

deliver pyrolysis products such as carbon monoxide and may thus

be somewhat safer than smoked tobacco.

It is known now that hepatic microsomal enzyme formation is induced by a number of carcinogens in the tar fraction of cigarette

smoke, including benzpyrene (Oates et al. 1975). This means that

smokers are rendered tolerant to both the therapeutic and toxic

effects of a wide variety of drugs (Swett 1974). Even the enzymes

in platelets are activated (Horns et a1.1976). Paradoxically,

just because of this type of enzyme induction, cigarette smokers

are more resistant to the effects of carcinogens but not enough to

prevent a wide variety of cancers.

Some examples of the effects of induction of microsomal enzymes

are cited by Hunter and Chasseaud (1976). Arylhydrocarbon hydroxylase is regularly induced by smoking. Benzpyrene hydroxylase and

aminoazo dye N-methylase were higher in placentae of pregnant

smoking women than of nonsmokers. Metabolism of benzodiazepines,

of propoxyphene, pentazocine and phenacetin is increased in smokers.

Xanthines such as theophylline are also metabolized more quickly

in smokers (Powell et al. 1977).

151
CARBON MONOXIDE

While levels of carbon monoxide achieved in the human body following cigarette smoking do not appear to be higher enough to materially affect psychological performance (Stewart 1975), the long term

effects may be quite significant. There are some (McGill 1977)

who contend that the atherogenic effects of cigarettes are largely

due to carbon monoxide. Indeed, the chronically high levels of

carboxyhemoglobin found in smokers can induce both a polycythemia

and increase in hemoglobin levels. These compensatory changes enable the smoker to cope with the oxygen deficit produced by cigarettes. Furthermore, since the latent oxygen carrying capacity of

the blood is increased by smoking, sudden cessation should make a

smoker more capable of functioning at high altitudes for a short

while than a nonsmoker.

NICOTINE

For most drug dependencies it has been shown that pharmacodynamic

tolerance is more important than drug dispositional tolerance.

For example, animals and humans tolerant to alcohol and barbiturates show significantly less sedation and ataxia than do nontolerant subjects at the same blood concentrations. Since the

liver and the kidneys largely control the blood concentration,

one would have to assume that tolerance must be occurring in the

brain. Methods of determining blood levels of nicotine with gas

chromatography or radioimmunoassay are too recently developed to

have produced many studies in tolerance.

In a recent study, Jones and colleagues (1978) showed that

smokers could tolerate higher intravenous doses of nicotine than

nonsmokers. Smokers reported generally pleasanter effects from

700 mcg. of nicotine intravenously than nonsmokers from 300 mcg.

In addition to the chronic tolerance demonstrated by the smokers,

both smokers and nonsmokers manifested acute tolerance. When the

same dose of nicotine was injected at about hourly intervals, each

succeeding injection elicited less of a response. This resembles

tachyphylaxis, and it may represent occupation of the receptor by

the drug or by some other substance such as a catecholamine released by the nicotine, or it may imply depletion of catecholamines.

The fate of 1 mg of nicotine base injected intravenously in humans

(actually as nicotine hydrogen tartrate) was intensively investigated by Beckett (1971). They found that smokers excrete nicotine

significantly faster than nonsmokers. None of the smokers reported

any nausea from the nicotine injections, but this was reported in

varying degrees by all nonsmokers. Haines et al. (1974) reported

that the plasma concentrations of nicotine were actually higher in

smokers than nonsmokers one minute after smoking, but these results

were confounded by the fact that nonsmokers were instructed to

smoke cigarettes. Obviously smokers were able to inhale more

effectively than nonsmokers in part because they had acquired

tolerance to the aversive effects of cigarette smoke on the respiratory passages. Indeed, some of the tolerance that smokers show to

152
cigarette smoke may be correlated with diminished function of the

respiratory epithelium and possible depression of taste and smell

(Kittel 1970).

The phenomenon of tolerance to tobacco and particularly to nicotine is reviewed by Larson and Silvette (1961, 1968, 1971, 1975)

in their four volumes on tobacco. There is a fair sized literature indicating that tolerance to nicotine can be developed in

invertebrates, fish, frogs and birds. It has also been demonstrated in mice, rats, dogs and in one donkey forced to inhale

smoke through a nasal catheter. In the latter study a donkey

initially exposed to the smoke from 20 cigarettes daily showed

marked impairment of bronchio-trachial transport of radioactive

iron oxide particles for several months. However, by the end of

eight months of exposure compensation had occurred and transport

was quite normal. Westfall and Brase (1969, 1971) showed in rats

that the tolerance to nicotine-induced elevations of urinary

catecholamines is due to increased enzymatic metabolism of these

amines. Both monamine oxidase and catechol-o-methyl transferase

activity of the liver were increased but nicotine oxidases were

unchanged.

Schechter and Rosecrans (1972) demonstrated behavioral tolerance

to the effects of nicotine in the rat. Nicotine (0.4 mg/kg) was

used as the discriminative stimulus in a T-maze. After a criterion of eight out of ten correct responses was attained, the

animals were given four daily injections of nicotine for five days.

The authors found that tolerance occurred, because discrimination

became much more difficult as time proceeded.

Tolerance to the effects of cigarette smoke was noted in dogs

given cigarette smoke via tracheostomy (Hammond et al. 1970). In

our laboratory Stolennan et al. (1973) showed the development of

both acute and chronic tolerance in rats. Nicotine administered

intraperitoneally to experimentally naive rats depressed activity

in a Y-shaped runway in a dose-related manner. After a single

intraperitoneal dose of nicotine, acute tolerance to the depressant action of a second dose developed with a definite time course,

becoming maximal after two hours and wearing off after about eight

hours. Repeated intraperitoneal doses of nicotine (3 times daily

for 8 days) elicited chronic tolerance, which persisted for at

least 90 days after the end of regular treatment with the drug.

Tolerance was also produced when nicotine was administered in rats’

drinking water and through reservoirs implanted subcutaneously.

It appears, then, that tolerance to nicotine in rats can develop

quickly, may be measured easily, and persists for prolonged periods

after withdrawal. In these experiments rapid withdrawal of nicotine did not produce the signs of illness which morphine withdrawal

regularly produced. The existence of prolonged tolerance to nicotine in rats suggested that the same phenomenon might exist in man

just as it does for opioids. If prolonged tolerance occurred in

exsmokers, then it might facilitate relapse, became such individuals would be more resistant to the negative effects of cigarettes.

153
Stolerman et al. (1974) examined the interaction between pairs of

injections of nicotine, which varied both in dose and in interval.

Two measures of spontaneous locomotor activity of rats in a T-maze

were taken: rears and entries. After a single treatment with

nicotine acute tolerance developed as indicated by a shift of the

dose response curve. The dose of nicotine required to produce a

given decrement in activity was multiplied by a factor of about

2.4 when a delay of two hours was taken between the two injections.

When the initial dose was varied, it was found that there was an

optimal level for producing tolerance. Higher doses were less

effective. An explanation for the relative ineffectiveness of

the higher doses in producing tolerance is not available. A

general debilitating effect of pretreatment with large doses

doesn’t seem to explain it, since rats given a saline challenge

exhibited normal motor activity. Perhaps the debilitating effects

of a large pretreatment dose and a challenge somehow summate.

QUESTIONS FOR FURTHER RESEARCH

The phenomenon of tolerance to the effects of tobacco products

has been clearly demonstrated both in humans and in animals.

Naturally enough, most of the emphasis has focussed upon nicotine,

but carbon monoxide and tar components also play an important

role. As with all other drugs, tolerance varies with subjects and

functions. Certain invertebrate forms which feed on the tobacco

plant have a high genetically determined tolerance. It is reasonable to assume that even in humans some of the variance in response to tobacco is innately determined and may account for some

of the high concordance in smoking behavior seen in identical

twins. Other forms of tolerance are clearly the result of experience and develop after exposure to tobacco products. Much more

research needs to be done to determine the degree of tolerance

which develops in different physiological and psychological functions after tobacco use. For example, it is evident that even in

heavy smokers of long duration the heart rate speeds up after

each cigarette. On the other hand, at least nausea and vomiting

diminish and disappear with continuing moderate use of cigarettes.

It would be very informative indeed to know what changes take

place at the putative sites of action of nicotine with chronic

use. Do nicotinic synapses at ganglia change in the same way as

nicotinic synapses in the brain? Do carbon monoxide and tar

constituents have any action on these components or on enzyme

systems elsewhere in the body? Answers to these questions will

enable us to understand better the physiological basis of the

smoking habit.

154
REFERENCES

Beckett, A. H.; Gorrod, J. W., and Jenner, P. The effect of

smoking on nicotine metabolism in vivo in man. J Pharm Pharmacol,

23:62S-67S, 1971.

Goldstein, A.; Aronow, L.; and Kalman, S. M. Principles of Drug

Action: The Basis of Pharmacology. Second Edition. New York :

John Wiley and Sons, l974.

Haines, C. F.; Mahajan, D. K.; Miljkovic, D.; Miljkovic, M.;

Vesell, E. S. Radioimmunoassay of plasma nicotine in habituated

and naive smokers. Clin Pharmacol Ther, 16(6):1083-1089, 1974.

Hammond, E. C.; Auerbach, 0.; Kirman, D.; and Garfinkel, L.

Effects of cigarette smoking on dogs. Arch Environ Health, 21:

740-753, 1970.

Horns, D. J.; Gerrard, J. M.; Rao, G. H. R.; Krivit, W.; and

White, J. G. Smoking and platelet labile aggregation stimulating

substance (LASS) synthesizing activity. Thrombosis Research,

9(6):661-668, 1976.

Hunter, J., and Chasseaud, L. F. Clinical Aspects of microsomal

enzyme induction. In: Bridges, J. W., Chasseaud, L. F., eds.

Progress in Drug Metabolism. Vol. 1. New York: John Wiley and

Sons, 1976. pp. 129-191.

Jaffe. J. H. Drug addiction and drug abuse. In: Goodman, L. S.,

and Gilman, A. The Pharmacological Basis of Therapeutics. 5th Ed.

New York: Macmillan Publishing Co., Inc., 1975. p. 285.

Jaffe, J. H., and Sharpless, S. I. Pharmacological denervation

supersensitivity in the central nervous system: a theory of

physical dependence. Proc Ass Res Nerv Ment Dis, 46:226-246,

1968.

Jones, R.T.; Farrell, T.R. III; Herning, R.I. Tobacco smoking

and nicotine tolerance. In: Krasnegor, N., ed. Self-Administration of Abused Substances: Methods for Study National Institute

On Drug Abuse Research Monograph No. (AIM) 78-727.

Washington, D.C.: Superintendent of Documents, U.S. Government

Printing Office, 1978. pp. 202-208.

Kittel, G. Moeglichkeiten der Olfaktometrie. Ermuedungsmessungen

bei Rauchern. Z Laryng Rhinol Otol, 49:376-386, 1970.

Larson, P. S.; Haag, H. B.; Silvette, H. Tobacco, Experimental

and Clinical Studies. Baltimore: Williams and Wilkens Co.,

196l.

Larson, P. S., and Silvette, H. Tobacco, Experimental and

Clinical Studies. Supplement I. Baltimore: Williams and Wilkins

Co., 1968.

155
Larson, P. S., and Silvette, H. Tobacco Experimental and

Clinical Studies. Supplement II. Baltimore: Williams and Wilkins

co., 1971.

Larson, P. S., and Silvette, H.

Clinical Studies.

Tobacco, Experimental and

Supplement III. Baltimore: Williams and Wilkins

co., 1975.

Martin, W. R. A homeostatic and redundancy theory of tolerance

to and dependence on narcotic analgesics. Proc Ass Res Nerv

Dis, 46:206-225, 1968.

McGill, H. C., Jr. Atherosclerosis: Problems in pathogenesis.

Atherosclerosis Review, 2:27-65, 1977.

Gates, J. A.; Azarnoff, D. L., Cohen, S. N.; Melmon, K. L.

Medicinal misadventures. Emergency Medicine, 7(7):115-118, 121,

125, 129, 133-134, 136-137, 1975.

Powell, J. R.; Thiercelin, J. F .; Vozeh, S., Sansom, L.; and

Riegelman, S. The influence of cigarette smoking and sex on theophylline disposition. Am Rev Respir Dis, 116(1):17-23, 1977.

Schechter, M. D., and Rosecrans, J. A. Behavioral tolerance to

an effect of nicotine in the rate.

195:52-56, 1972.

Arch Int Pharmacodyn Ther,

Schmeltz, I., and Hoffmann, D. Chemical studies on tobacco smoke.

XXXVIII. The phvsicochemical nature of cigarette smoke. In:

Wynder, E.L.; Hoffmann, D.; and Gori, G.B.; eds. Proceedings

3rd World Conference Smoking and Health. Vol. 1: Modifying the

risk for the smoker. DHEW Publication No. (NIH) 76-1221. Washington, D.C.: U.S. Government Printing Office; 1976. pp. 13-34.

Stewart, R. D. The effect of carbon monoxide on humans. Annu

Rev Pharmacol, 15:409-423, 1975.

Stolerman, I. P.; Bunker, P.; and Jarvik, M. E. Nicotine tolerance in rats: Role of dose and dose interval. Psychopharmacologia, 34:317-324, 1974.

Stolerman, I. P.; Fink, R., and Jarvik, M. E. Acute and chronic

tolerance to nicotine measured by activity in rats. Psychopharmacologia, 30:329-342, 1973.

Swett, C., Jr. Drowsiness due to chlorpromazine in relation to

cigarette smoking. A report from the Boston Collaborative Drug

Surveillance Program. Arch Gen Psychiat, 31:211-213, 1974.

156
Westfall, T. C., and Brase, D. A. Adrenal stimulation and monoamine oxidase (MAO) activity following daily nicotine treatment.

Fed Proc, 28(2):287, 1969.

Westfall, T. C., and Brase, D. A. Studies on the mechanism of

tolerance to nicotine-induced elevations of urinary catecholamines. Biochem Pharmacol, 20:1627-1635, 1971.

AUTHOR

Murray E. Jarvik, M. D. Ph. D.

Professor of Psychiatry and Pharmacology

Neuropsychiatric Institute

University of California

School of Medicine

760 Westwood Plaza

Los Angeles, California 90024

Chief, Psychopharmacology Unit

Veterans Administration Hospital Brentwood

Wilshire and Sawtelle Boulevards

Los Angeles, California 90073

157
Chapter 13

The Tobacco Withdrawal

Syndrome

Saul M. Shiffman, M.A., C.Phil.

Characterizing tobacco use as a dependence process necessarily

raises the issue of tobacco withdrawal, as the presence of an abstinence syndrome is crucial to the definition of drug dependence. Indeed, some of the initial reluctance to label tobacco as a dependenceproducing substance rested on doubts concerning the existence of a

tobacco withdrawal syndrome. This was the position taken by the Surgeon General in 1964, when first alerting the country to the dangers

of tobacco, Since then, there has been an accumulation of studies

which suggest that withdrawal from tobacco does produce a variety

of signs and symptoms which can be characterized as a tobacco withdrawal syndrome. Although the syndrome is variable and is only

roughly described and understood, its existence is no longer a matter

of great controversy. The focus has shifted from the somewhat semantic question of categorizing tobacco use to exploration of the

particulars of tobacco dependence and withdrawal. This paper reviews

the findings on tobacco withdrawal syndrome, focusing initially on

a description of the syndrome, and then on factors affecting its

severity and course. Finally, noting methodological issues which

need to be considered, goals and directions for further research

are discussed.

SYMPTOMS OF TOBACCO WITHDRAWAL

A number of physiological changes have been observed on withdrawal

from tobacco. Decreases in heart rate and diastolic blood pressure

are observed as early as six hours after withdrawal (Murphee and

Schultz 1968). These changes persist for at least three days and

perhaps for thirty (Weybrew and Stark 1967; Glauser et al. 1970).

Decreased excretion of both adrenaline and norepinephrine and various metabolic changes have also been observed (Myrsten et al. 1977;

Glauser et al. 1970). These indications of decreased arousal have

been supported by EEG studies showing a decrease in the peak alpha

frequency and increases in low frequency activity (Knott and

Venables 1977; Ulett and Itil 1969). Increases in sleeplike activity have been observed in the EEG records of deprived smokers

(Itil et al. 1971). It has also been demonstrated that, in sleep,

158
deprived smokers show decreases in REM latency and increases in

REM time (Kales et al. 1970). In contrast, however, Knott and

Venables (1978) report that deprived smokers showed hypersensitivity

to low intensity stimuli, as indicated by increased amplitude and

decreased latency in the evoked response. Thus, while withdrawal

from tobacco appears to produce physiological changes suggestive of

decreased arousal, this is not a uniform or easily characterized

pattern.

Another documented physical change resulting from abstinence is

weight gain. Wilhemsen (1968) observed a weight gain of 2.4 kg in

two months of abstinence, while Glauser et al. (1970) documented an

increase of 3.2 kg in one month. In Fletcher and Doll’s (1969) retrospective study of British physicians,

ing as much as 5.3 kg on the average.

the respondents reported gainAlthough the weight gain

itself is thus well documented, it is controversial whether it results from increased appetite and consumption or from metabolic

changes (Glauser et al. 1970). It has been demonstrated that withdrawal impairs the performance of smokers on psychomotor tasks requiring vigilance and/or tracking (Heimstra 1973). Not surprisingly,

deprived smokers do poorly in a driving simulation task (Heimstra

et al. 1967). The effects of tobacco deprivation on verbal learning

are complex, with indications of both facilitation and impairment.

Kleinman, Vaughn and Christ (1973) found that 24-hour deprivation

facilitated learning of easy paired associates, but impaired performance with hard pairs. They interpret this as an indication of hyperarousal, while Andersson (1975) reports mixed facilitation and impairment and interprets this as indicating shifting arousal. Myrsten

et al. (1977) found verbal learning essentially unaffected over five

days of abstinence. Thus, while psychomotor performance is reliably

impaired by abstinence, little can be said about its effects on

verbal learning.

Accompanying these objective changes in physiology and performance

are subjectively reported changes in physical symptoms, arousal,

and mood. These have been reported in studies of smokers sampled

while actually undergoing withdrawal, as well as in retrospective

studies of exsmokers up to 14 years after cessation. Although the

specific symptoms reported differ, as does the percentage of abstinent smokers reporting each symptom, a consistent pattern of symptoms

can still be discerned. Common among the physical symptoms reported

are nausea, headache, constipation, diarrhea, and increased appetite.

Also reported are disturbances of arousal, including drowsiness and

fatigue, as well as insomnia and other sleep disturbances (e.g.,

Guilford 1966). Inability to concentrate is a common complaint and

is consistent with objective assessments of the concentration of

smokers in abstinence (Perlick 1977; Heimstra 1973). Thus, the objective changes reviewed above appear to be reflected in the subjective experience and self-reports of deprived smokers.

Changes in mood or affective tone are prominent among the symptoms

reported in withdrawal from tobacco. Increased irritability and

hostility are common sequelae of abstinence from tobacco (Friedman

1972; Mausner 1970). Increases in aggressive behavior and its correlates have also been observed in abstinence (Schechter and Rand

159
1974; Hutchinson and Emley 1973). Increased anxiety is another affective change which is both reported and observed (Friedman 1972;

Nesbitt 1973). In addition to reports of these symptoms under neutral conditions, several studies suggest that deprived smokers are

more likely to respond with anxiety and irritability when stressed

(Myrsten et al. 1972; Frankenhaeuser et al. 1971). This may only be

true compared to nondeprived smokers, however, with smokers showing

decreased vulnerability to these dysphoric reactions to stress

(Heimstra 1973). In summary, withdrawal from smoking shifts the

smoker’s affective tone toward dysphoria, and increases anxiety

and irritability.

By far the most common and clinically most important symptom appearing following withdrawal from tobacco is craving for tobacco. The

best estimates indicate that 90 percent of all smokers in withdrawal

will crave (Guilford 1966). Moreover, among smokers who have been

abstinent for five to nine years, one out of five report that they

continue to have at least occasional craving for tobacco [Fletcher

and Doll 1969). The importance of craving lies not in its universality or persistence, but in its relation to the clinical goal of

modifying smoking behavior. Indeed, the importance of the tobacco

withdrawal syndrome in its entirety is based on its provocative

role in causing relapse among abstinent smokers.

SMOKING CESSATION, RELAPSE, AND MAINTENANCE

Since tobacco use--particularly cigarette smoking--was identified

as a major cause of “preventable” morbidity and mortality, concerted

attempts have been made to apply behavioral technology to the problem of smoking cessation, and, indeed, have become very successful

in producing cessation. At least one method--rapid smoking--is

claimed to produce cessation in more than 90 percent of clinic patients (Lichtenstein and Danaher 1976). Unfortunately, very little

headway has been made in producing long term maintenance of nonsmoking. It has been estimated that, on the average, only about 25 percent of those who successfully quit smoking will remain abstinent

for more than six months (Hunt and Matarazzo 1973). The focus of

clinical efforts in the treatment of smoking thus needs to shift

from producing cessation to encouraging maintenance and preventing

relapse.

It is self-evident that craving for cigarettes is a major cause of

relapse. The urge to smoke, when it becomes stronger than the exsmoker’s determination to quit, leads to relapse. In a retrospective study of treated smokers 18 months after treatment, Peterson

et al. (1968) found that over half of those who had relapsed cited

craving specifically as the cause.

Other withdrawal symptoms also play a role in relapse. In Peterson

et al.‘s study, 35 percent of the recidivists cited anxiety as the

cause of relapse, while 12 percent cited weight gain. In my analysis of questionnaire data collected by C. Hammen (personal conmmication 1973), I have found that 61 percent of smokers who were applying for treatment cited either anxiety or craving as the cause

160
for relapse in previous attempts. This is in line with estimates

by Guilford (1966) and Burns (1969). By providing immediate aversive consequences for smoking cessation, withdrawal symptoms thus

make continued abstinence difficult, and relapse probable.

FACTORS AFFECTING THE ABSTINENCE SYNDROME

Thus far, the emphasis has been on the uniformity of reports concerning the tobacco abstinence syndrome. The impression might be drawn

that every smoker, upon withdrawal from tobacco, becomes irritable

and anxious and is unable to think, work, sleep, drive, or carry on

normal social discourse for want of a cigarette. Fortunately, this

is not the case. The tobacco withdrawal syndrome is apparently quite

variable in character, severity, and duration. An examination of various studies reveals large differences in the frequency with which

particular symptoms are reported. Where Trahair (1967), for example,

reports that sleep disturbance was experienced by only ten percent of

exsmokers, Guilford (1966) reports that 31 percent of her subjects

suffered from insomnia. Similar examples of variability are commonly reported in the literature on smoking withdrawal. About

23 percent o

et al. 1977;

f abstinent smokers report no symptoms at all (Myrsten

Pederson and Lefcoe 1976; Wynder, Kaufman and Lesser

1967). While this has led some to conclude that there is no abstinence syndrome (e.g. USDHEW 1964), this conclusion is contradicted

by a mass of data, some of which has been cited above. A simpler

conclusion is that the abstinence syndrome is quite variable.

This impels us to tease out the causes of this variability. Research on the factors which affect the tobacco withdrawal syndrome is the major focus in the remainder of this paper.

Recent work in our laboratory at UCLA has focused on factors which

may affect the tobacco withdrawal syndrome. We have developed a 25

item questionnaire which measures the five symptom clusters which

comprise the syndrome: physical symptoms, psychological symptoms,

arousal, appetite, and craving for cigarettes. (Our appetite scale

subsequently proved to be unreliable and therefore does not figure

in our analysis.) Subscales assessing each of the symptom clusters

were created using factor analytic methods. The questionnaire was

then used to study sources of variance in the tobacco withdrawal

syndrome in 40 smokers who were attempting to quit smoking. These

subjects completed the questionnaire at the beginning of cessation

and then four times daily thereafter. (Most of the data reported

here are from a study published in part as Shiffman and Jarvik 1976.)

Baseline Cigarette Consumption

It is characteristic of withdrawal syndromes that their severity is

dose dependent (Jaffe 1971). Therefore, it is expected that heavy

smokers would report more severe withdrawal symptoms than light

smokers. A comparison of subjects smoking a pack or more (x=26.6)

per day with those smoking less than a pack (x=15.7) per day, however, revealed no overall differences in the severity of their symptoms.1

 This replicates our previous finding that light and heavy

161
smokers do not differ in craving when deprived for 48 hours (Gritz

and Jarvik 1973). In work currently under way on the effects of

brief deprivation (e.g., a two hour lecture), we have found same

dose-related effects on craving (Gritz 1978).

The inconsistency of this effect in our studies parallels the state

of the literature. Studies by Myrsten et al. (1977) and by Mausner

(1970) also report finding no differences between light and heavy

In contrast, Burns (1969) reports that subjects who reported withdrawal symptoms had smoked an average of 6.9 cigarettes/

day more than asymptomatic subjects (p<.01). Since this is smaller

than the mean difference between the light and heavy smoker groups

in our study (11.1), this discrepancy is puzzling. Wynder, Kaufman

and Lesser (1967) report that the proportion of abstinent smokers

reporting more than one withdrawal symptom increases with baseline

consumption. A chi squared analysis performed on their data reveals

that this association is highly significant (x2=15.81, df=2, p<.001).

Perhaps these discrepancies can be explained by the fact that Burns

and Wynder et al. studied the number of symptoms, while we studied

the severity of each symptom separately.

Another possible confound is that, because smokers can vary their

smoking consumption in other ways -- depth of inhalation, number of

puffs, etc. -- cigarette consumption may actually be a very poor

measure of dose. Also, differences in nicotine metabolism introduce variability in dose even among those who consume similar amounts

of nicotine. Thus, estimating a smoker’s dose may require measuring

serum levels of nicotine or its metabolites. In the one study which

has approached this, Zeidenberg et a1. (1977) found a high and significant correlation between serum cotinine levels before treatment

and self-reported “degree of difficulty” in smoking cessation. This

result held for men only, however, perhaps because of additional variability in the cotinine levels or the self-reports of the female

subjects . There is some indication that the severity of the abstinence syndrome is dose-dependent, but much ambiguity remains. Because dose dependency is so characteristic of withdrawal syndromes

from other substances, establishing this effect for tobacco would be

an important step towards an understanding of tobacco dependency.

Further research into the relationship should probably proceed along

the lines of Zeidenberg et al., using serum cotinine levels rather

than cigarette consumption as the independent variable. Dependent

measures should include more refined instruments than Zeidenberg et

al’s estimates of “difficulty” and should explore both the number of

withdrawal symptoms and their severity.

Diurnal Variations in Symptoms

Since our subjects were providing reports of symptoms at regular

intervals throughout the day, we were able to study diurnal variations in symptoms. One puzzling finding which emerged was that,

while light and heavy smokers reported the same average level of

arousal, they differed significantly in the diurnal pattern of

arousal.

162
FIGURE 1

Mean arousal ratings of light and heavy smokers for four

times of day. Ratings are based on the average of four

questionnaire items relating to arousal or alertness

(e.g., "Do you.feel unusually tired?"). Each data point

represents an average of 12 days’ ratings. The curves

for the two groups differ significantly in linear and

quadratic trends.

Figure 1 plots arousal by time of day for the two groups, with data

points at 7 AM, noon, 7 PM, and 11 FM, approximately. The figure

shows that the two groups report the same level of arousal upon

awakening. Whereas the heavy smokers then increase in arousal during the course of the day, the light smokers maintain this minimal

level of arousal throughout the day. Both groups show a drop in

arousal at bedtime, with the light smokers continuing to report

lower arousal. This result is difficult to interpret, particularly because this scale does not have a clear evaluative dimension. It is not clear, for example, whether the heavy smokers are

hyperaroused during the day, or the light smokers underaroused. At

bedtime, it appears that the heavy smokers may be suffering insomnia,

since they are reporting nearly as much arousal as they do upon awakening in the morning. This cannot be determined definitively from

the data, however, and this effect remains to be explored.

163
The other symptom cluster which shows significant diurnal variation

is craving. Craving is at its lowest point when the subject wakes

up, gradually rising to a peak in the evening, then falling again

at bedtime.

FIGURE 2

Smoking, craving, and relapse as a function of time of day. Ratings are based on the average of seven questionnaire items relating

to craving for cigarettes (e.g., “Do you have an urge to smoke a

cigarette right now?”), Note similarities among these functions,

all of which peak in the evening. Data on relapse from retrospective

interviews (Lichtenstein et al. 1977). Data on smoking from observation of clerical personnel (Meade and Wald 7977). Data on craving

from our questionnaire study of smokers in withdrawal.

Figure 2 shows this diurnal variation in craving. Plotted on the

same axis is data collected by Meade and Wald (1977) on the cigarette consumption of British office workers at similar times of

day. The figure shows that craving in abstinent smokers and ad

lib smoking have the same diurnal function. A third function

plotted on the same axis draws on data reported by Lichtenstein,

Antonuccio, and Rainwater (1977), who surveyed a group of smokers

who relapsed following a period of abstinence. The curve shows

the percentages of recidivists who said they had first relapsed

in the morning, afternoon, and evening. This function parallels

the diurnal functions of ad lib smoking and craving in withdrawal.

Thus, there is a consistent function which describes three different stages of the habit and its control (unrestricted smoking, ab164
stinence, and relapse). The meaning of the underlying function

has not been determined. Two different types of explanation are

plausible. One focuses on diurnal variation in the internal environment of the smoker, suggesting the influence of some metabolic

factor with diurnal variation2. The other explanation focuses on

the diurnal variation in the social environment: e.g., the timing

of work, meals, social contact, recreation, and so on, which affects

craving for tobacco. Research which accurately measures craving and

relates it to environmental stimulus events and circadian variations

in the internal environment could decide between these explanations.

A more comprehensive understanding of how craving varies with stimulus events and with time of day might prove helpful in designing interventions which help prepare the smoker to cope with his/her

craving.

Time Course and Duration

While the time course of the abstinence syndrome following abrupt

withdrawal from other dependence-producing substances has been systematically studied (Jaffe 1971), assessment of the course of the

tobacco withdrawal syndrome is made difficult by the subtlety and

variability of the symptoms (USDEW, 1964).

The onset of the syndrome appears to be rapid, with changes in mood

(Schechter and Rand 1974) and performance (Myrsten et al. 1972) evident as early as two hours after withdrawal. However, these early

effects are not easily distinguishable from the absence of nicotine

effects or the effects of simple frustration. Our research focused

on the course of withdrawal symptoms over the first two weeks of abstinence. Figures 3 - 6 show the progression of the four symptom

categories -- craving, arousal, physical symptoms, and psychological

symptoms -- over a twelve-day period.

(These curves are for all subjects and therefore obscure some important group differences which are discussed below.) Note that

these symptoms all decrease at first and then either level off

or rise again in the second week of abstinence. (The quadratic

curvature of each curve is statistically significant.)

This initial pattern of symptoms is consistent with Herold’s

(1967) findings concerning the percentage of deprived smokers

reporting craving, irritation, tiredness, and headache in the

first five days following abrupt withdrawal. Each symptom

shows a sharp decline during this period, and all show signs

of leveling off by day ten. Other studies also report data

suggesting a similar decrease in symptoms over time.

(Lichtenstein, Antonuccio and Rainwater, personal communication 1978; Guilford 1966).

165
FIGURES 3 and 4

Mean reported severity of physical and psychotogical symptoms over

12 days of withdrawal. After an initial decrease, these symptoms

level off. Ratings are based on the average of three items relating

to physical symptoms and four items renting to psychological discomfort, respectively (e.g., “Is your heart beating faster than

usual?”; “Are you more nervous than usual?”). Days have been paired

on ordinate in order to smooth the curves. Note small magnitude of

changes in ordinate scales.

166
FIGURES 5 and 6

DROWSINESS (“AROUSAL” INVERTED)

Mean drowsiness and craving ratings after 12 days of withdrawal.

Note initial drop and subsequent leveling off (Fig. 6) or rise

(Fig. 5). Drowsiness scale is simply an inversion of arousal

ratings. Days have been paired in order to smooth the curves.

Note small magnitude of changes in ordinate scales.

167
Thus, after a marked decline in the first week, the tobacco

withdrawal syndrome becomes increasingly less yielding. Indeed, figures 3-6 suggest that an aggravation of symptoms occurs after the second week of abstinence, and leaves open the

question of the syndrome’s subsequent course. Estimates of

the tobacco withdrawal syndrome’s duration have been made in

retrospective studies which ask exsmokers to recall how long

their discomfort or “difficulty” lasted. However, these studies produce contradictory findings. Burns (1969) reports

a range from one to twelve weeks, and Wynder, Kaufman, and

Lesser (1967) report that most symptoms were gone after four

weeks. In contrast, Mausner (1970 reports that, of the

exsmokers who ventured an estimate, fully two-thirds stated

that their difficulty had lasted between one month and five

years! In another retrospective study, 21 percent of the sample

of exsmokers reported at least intermittent craving for cigarettes five to nine years after cessation (Fletcher and Doll

1969). Thus, the duration of the tobacco withdrawal syndrome

appears to be extremely variable, and no definitive estimate

is yet available.

Degree of Deprivation

Even with continued use, reduction in the dose of a dependenceproducing substance typically results in the emergence of a

withdrawal syndrome (Jaffe 1971). It has been shown that

smokers changed to low-nicotine cigarettes often report the

gamut of withdrawal symptoms described above (Schachter 1977;

Finnegan, Larson, and Haag 1945). In order to study the withdrawal syndrome in partially deprived smokers, we divided our

sample into two groups: one was composed of totally abstinent

smokers who quit “cold turkey” and remained abstinent for the

entire period of the study; the second group consisted of

partially abstinent smokers who reduced their cigarette consumption by an average of 60 percent. With the exception of

the craving scores--which were lower in the cold turkey subjects--we found no overall differences in the severity of

the reported symptoms. We found that the two groups did differ

in the course of the withdrawal syndrome. Figures 7-9 show

the progression of physical symptoms, craving, and psychological symptoms as abstinence proceeded. In each case, the

totally abstinent subjects show a greater reduction of symptoms

early in the abstinence period.

168
FIGURE 7

Mean craving scores for partially and totally abstinent

smokers over 12 days of abstinence. Note the sharp

decline of craving in subjects who quit "cold turkey"

and remained abstinent. Days have been paired

in order to smooth the curve

169
FIGURES 8 and 9

PHYSICAL SYMPTOMS

PSYCHOLOGICAL SYMPTOMS

Mean reported severity of physical and psychological symptoms for

partially and totally abstinent smokers over 12 days of abstinence.

Note the sharp decline in symptom severity reported by the totally

abstinent subjects, who initially report more severe symptoms. Note

small magnitude of changes in ordinate scale.

170
Notice that early in abstinence the two groups are reporting similar levels of discomfort, but that four days later the completely

abstinent group is reporting less craving and fewer physical and

psychological symptoms. Thus, abrupt and total withdrawal from

tobacco is associated with a withdrawal syndrome that is no worse

than that seen in partial abstinence, and which subsides more

quickly.

One might speculate that continued smoking results in a prolongation of the abstinence syndrome, while complete abstinence results in a relatively rapid decrease in symptoms. Such causal

Interpretations of our data must be made with great caution, of

course, because our groups of partially and totally abstinent

subjects were formed post hoc. Therefore, it may be that the

course of the withdrawal syndrome is determined by some other

factor, and the degree of abstinence is in turn determined by

some combination of these factors. Nevertheless, there are

findings in our study and others which at least suggest that

the degree of abstinence does Indeed control the course of the

withdrawal syndrome. As figures 7-9 show, the two groups typically begin abstinence with very similar levels of discomfort,

and only diverge after a few days of abstinence. Moreover, informal analysis of our data suggests that craving rises when a

subject has been abstinent and then begins to smoke again. More

systematic observation of this phenomenon was made by Lichtenstein, Antonuccio, and Rainwater (personal communication 1978)

in a retrospective study of relapsed smokers. They found that

53 percent of their subjects reported that their craving decreased with time, as long as they were abstinent. In contrast,

42 percent reported that their craving was increased the day

after a relapse episode (only 18 percent reported decreased

craving). Similar phenomena are well known in other dependency

disorders; the alcoholic’s proverbial “one drink” is an example.

Thus, craving leads to smoking and smoking leads to craving in a

cycle of dependence.

Gradual Reduction and Chronic Withdrawal

This has important implications for methods of smoking cessation.

Despite the usefulness of gradual withdrawal in other dependency

disorders, and despite the congruence of this method with sound

behavioral principles, there is considerable evidence suggesting

that gradual withdrawal from tobacco is associated with treatment

failure (Guilford 1966; USDHEW 1975; Mausner 1970). Our

findings suggest an explanation for this discrepancy. Partial abstinence from smoking leads to more, rather than less,

discomfort in withdrawal, since the withdrawal syndrome experienced by those who “cut down” on smoking (by 60 percent) is as

severe as that in an abrupt cessation group and lasts longer.

The result is that a partially abstinent smoker is in a chronic

state of withdrawal. That such a condition is possible is confirmed by Perlick (1977) who observed “restrained smokers” who

were keeping their cigarette consumption chronically at about

171
50 percent of their normal intake. These smokers were compared

to unrestrained smokers while smoking high and low nicotine

cigarettes and no cigarettes. Perlick found that, even when

allowed to smoke high nicotine cigarettes, the restrained

smokers showed as much irritability as normal smokers deprived

of cigarettes. Moreover, they also showed impairments of concentration that were even greater than those observed in heavy

smokers. In other words, the showed signs of a severe abstinence syndrome even while smoking “ad lib" . Thus, the cigarettes indulged in by smokers who attempt to “cut down” may

serve only to prolong their withdrawal by intermittently reinforcing their symptoms and smoking behavior. Typically, this

chronic state of withdrawal leads to relapse and return to

baseline rates of smoking.

Although this explanation is plausible and fits the data available, it must be treated with caution pending further research.

Since all of the research relies on smokers who have chosen

whether to quit cold turkey or by gradual reduction, there is

still the possibility that smokers in some way predisposed to

experience a protracted withdrawal syndrome disproportionately

choose the gradual reduction method. What is needed is experimental research in which smokers are randomly assigned to cold

turkey or gradual reduction groups, and the effects on the

course of the abstinence syndrome evaluated.

Another direction for new research might be to determine the

threshold for the onset of the abstinence syndrome in gradual

reduction. Perhaps there is some rate or degree of reduction

which would not precipitate withdrawal, so that a smoker could

be weaned from tobacco. In addition to a “rate of reduction”

parameter, the onset of severe withdrawal may also be controlled

by the absolute dose, as well. It has been reported that in

gradual reduction programs, smokers tend to meet plateaus or

“stuck points” at certain levels of consumption, even when the

rate of reduction is slow and controlled by the smoker.

Levinson et al (1971) report that the most difficult “stuck

point” was at 12 cigarettes per day, and that most of the

premature terminations of treatment occurred at this level,

An intriguing possibility is that this constitutes some minimum

dose below which withdrawal is precipitated. In any case, the

relationship between degree of tobacco deprivation and the emergence of withdrawal symptoms deserves further study.

Other Factors Which May Affect the Abstinence Syndrome

In addition to the factors already cited, the tobacco withdrawal syndrome may be affected by a number of other variables

whose influence remains to be determined. One could speculate,

for example, on differences between types of smokers in the severity, pattern and/or course of abstinence. A study by Ikard

and Tomkins (1973) suggests rather tautologically that “addictive

smokers” experience more severe craving. The smokers in this

study were only deprived of tobacco for three hours, however,

172
so that the effects of this typology on the clinical abstinence

syndrome are still essentially unknown and deserving of study.

Other individual difference variables also deserve study. A

smoker’s smoking history, for example, may affect the withdrawal

syndrome, especially considering such variables as previous attempts to quit and the reason for failure. Since the symptoms

of withdrawal are relatively ill-defined, the smoker’s expectations and set are probably related to his/her experience of abstinence, as is his/her motivation to quit (cf. Barefoot and

Girodo 1972).

There is another major. factor whose relationship is potentially

important but unexpected: Fragmentary evidence suggests that

the abstinence syndrome is more severe in women than in men.

Unfortunately, relevant data are too seldom analyzed for this sex

difference. For example, Guilford (1966) reports data separately

by sex, but does not submit it to statistical analysis of the sex

difference. Yet, of 18 major symptoms reported by her subjects

in the first four days of abstinence, 15 show some sex difference.

Among these 15, 13 are more frequently reported by women. This

difference is statistically significant (sign test, N=l5, r=2,

p<. 005). Moreover, a chi square analysis of retrospective data

collected by Hammen (1973 personal communication) shows a trend

(p<.10) for women to report more frequently than men that their

past relapses were due to anxiety or craving. Data reported in

a number of other studies line up in the same direction, though

the effect fails to reach significance in the individual studies

(Trahair 1967; Peterson et al. 1968; Wynder, Lesser, and

Kaufman 1967). It seems likely, then, that women suffer from a

more severe abstinence syndrome than men. The importance of this

finding lies in its possible relation to another sex difference

in smoking cessation: it is well established that women are more

likely to fail in smoking cessation efforts (Gritz 1978).

Guilford (1966) has also presented data suggesting that the relationship between withdrawal symptoms and failure in smoking cessation is stronger for women than for men. Thus, women experience more discomfort in withdrawal and are more affected by it

in their attempts to quit smoking. It seems likely that this is

at least partly responsible for their reduced rates of successful

cessation.

Nor are organismic variables the only variables relevant here.

The method used to achieve cessation may well have an effect on

the subsequent withdrawal syndrome. Environmental factors, such

as the smoker’s social environment, are potentially powerful deteminants of the smoker’s experience of withdrawal. Many smokers cite a stressful event or situation, rather than an internal

feeling, as the precipitant of relaspse (Hammen, personal communication 1973). These and other events, such as social drinking,

may produce conditioned craving and are to be considered high

risk situations for relapse (Lichtenstein, Antonuccio, and

Rainwater 1977). Thus, in addition to the few factors whose influence on the tobacco withdrawal syndrome is known, there are

many other potentially important variables whose effects remain

to be determined.

173
METH0DOLOGICAL ISSUES

The influence of the factors discussed above on the tobacco withdrawal syndrome also touches on methodological issues. Since these

variables represent significant sources of variance in the withdrawal syndrome, they must be taken into account when withdrawal

effects are assessed. Research in this area must distinguish between

partial and total abstinence, for example, if the results are to

be consistent. This distinction is blurred in many studies, making the results difficult to interpret or compare. Similarly,

data should be reported separately for men and women and for

light and heavy smokers. Since some symptoms vary with tune of

day and probably with stimulus events, they should, where possible, be measured repeatedly and at fixed times during the day.

Other methodological issues in research on the tobacco withdrawal

syndrome involve the measuring process or operation itself. Because there is no accepted standard, no two studies in the literature use the same assessment device, making the results impossible

to compare across studies. Some studies use ratings of symptom

severity, where others simply use a present/absent symptom checklist method and still others an open-ended query. Consequently,

results may be reported as mean ratings or as percentage of subjects reporting a given symptom. Often, no distinction at all

is made among various symptoms, and subjects are simply asked

whether they experienced any symptoms, or, even more globally,

whether they experienced “difficulty” in giving up tobacco.

This is a major factor contributing to the variability of estimates

of the prevalence and duration of the withdrawal syndrome. Much

more clarity would result if the assessment instruments were made

homgeneous . A rating scale which taps several symptom clusters,

such as the one we have used in our studies, would probably meet

the requirements of most investigators.

Some measurement difficulties which arise in the study of withdrawal symptoms are kin to the difficulties inherent in measurement and operationalization of psychological constructs. Take,

for example, the mood changes that are reported in withdrawal.

Colloquial terms such as “nervous” and “irritable” are most natural and are therefore useful in obtaining self-reports. Unfortunate1y they are also quite ambiguous. It is unclear, for

example, whether they refer to tonic, baseline states or to

predispositions to overreact to certain stimuli. Does a smoker

in withdrawal show higher overall levels of anxiety or a proneness to react with greater anxiety when stressed? These two

interpretations imply different measurement operations, and

measurements of both varieties appear in the tobacco withdrawal

literature as measurements of “anxiety” or “irritability,” with

different findings resulting.

In order to avoid the ambiguity of colloquial language, one can

turn away from self-report methods, which require its use, to

observational studies which rely on more defined measurement

operations. Behavioral correlates of anxiety can be observed,

174
for example. As one moves further away from colloquial self-description, however, the interpretation of the data becomes increasingly problematic. Physiological measures such as galvanic

skin response are far removed from the affective state, “anxiety,”

and furthermore do not correlate well with other measures of

“anxiety.” A tradeoff is inevitable. The more operational the

measurement device, the less related it seems to the underlying

psychological construct, especially when the latter is a subjective state.

Differences in approach to this dilemma have resulted in different

conclusions about the tobacco withdrawal syndrome. In a number of

studies reported by Heimstra (1973), deprived smokers performed

presumably stressful tasks and rated their mood before and after

the task. Results showed that deprived smokers responded much

the way nonsmokers did, but that undeprived smokers showed significantly less response to the stressor. This suggests that

smoking protects against stress-induced mood changes, but that

withdrawal has no effect on mood. In contrast are a series of

studies in the Schachter laboratory (Nesbitt 1973; Silverstein

1976; Schachter 1978) which use the number of shocks that a subject will tolerate as a measure of his/her response to stress.

In these studies, undeprived smokers behave like nonsmokers and

deprived smokers show increased vulnerability to stress. This

suggests that smoking per se has no effect on reactions to stress,

but that withdrawal resultant over-responsiveness to stress.

Thus, self-report and indirect objective measurement of withdrawal symptoms sometimes produce inconsistent and even directly

contradictory results.3 This reflects a general problem in psychological assessment which will not be easily solved. However,

investigators studying the withdrawal syndrome should be aware of

the dilemma, and perhaps try to obtain measurements at both ends

of the spectrum wherever possible.

The cited studies by the Heimstra and Schachter groups also touch

on another issue of methodology: control groups. Data from deprived smokers are most interpretable when they can be compared

to data from smokers in an undeprived state and from nonsmokers.

Ideally, this allows one to tease out the effects of smoking per

se, the effects of abstinence, and the effects of smoker/

nonsmoker differences. An interesting and novel idea would be to

introduce a deprived nonsmoker group which is frustrated in sane

way. This would control for the effects of simple frustration,

which is conceptually distinct from a withdrawal syndrome, but has

some similar effects on mood.

Quite often, the comparison between nondeprived and deprived

smokers is made within subjects. This requires that baseline

data be collected while the subject smokes normally. This is

difficult to achieve in clinical settings, where smokers often

begin to modify their smoking behavior before formally beginning

treatment. In these cases, baseline measurements should begin

as early as possible while instructing the subject to maintain

175
usual smoking behavior. Where several staggered changes in

smoking behavior take place -- as in gradual reduction programs --

multiple baselines should be considered. In a truly ideal world,

one would also compare a smoker’s responses in withdrawal to the

presmoking baseline. As this is impossible, one cannot currently

distinguish between the effects of simple return to baseline upon

discontinuation of nicotine and true withdrawal effects, which

involve an overshoot of predrug baseline. If one assumes that

smokers and nonsmokers were similar prior to tobacco use (a

tenuous assumption), then the nonsmoker group provides a between

group comparison with predrug baseline.

Most of the research on withdrawal symptoms in long term abstinence from smoking consists of retrospective questionnaire

studies in which successful exsmokers are queried about their

experiences. Almost all of the studies which have a more controlled methodology are confined to short periods of deprivation

in the laboratory, and therefore have limited generalizability.

The retrospective studies, while more relevant to the experience

of a real life user giving up tobacco, suffer from the failings

of retrospective and post hoc correlational designs. For example,

while such studies show that successful abstainers report fewer

withdrawal symptoms than do their relapsed colleagues, this may

be an artifact of the retrospective viewpoint. Exsmokers may

simply “recall” finding withdrawal easier, whereas recidivists

justify their relapse with recollections of serious discomfort.

The risk of such bias, while present, is not nearly as great

when self-reports are collected during the actual period when

the subject is undergoing withdrawal. More such prospective,

real time studies of long term abstinence in clinical settings

are needed. Such data could readily be collected as part of

any clinical or experimental smoking cessation study. Investigators in the field of smoking cessation should document the

effects that withdrawal from tobacco has on their subjects. In

this manner, a great deal could be learned about the tobacco

withdrawal syndrome at very little cost.

DIRECTIONS FOR RESEARCH ON THE TOBACCO WITHDRAWAL SYNDROME

The relationship between withdrawal symptoms and smoking cessation efforts is what lends importance to research on the tobacco

withdrawal syndrome. To the extent that avoidance of withdrawal

symptoms motivates continued smoking, the problem of smoking

control becomes one of understanding and controlling the withdrawal syndrome. Especially as our clinical goals shift away

from smoking cessation per se to the prevention of relapse,

the withdrawal syndrome will have to become a major focus of

our efforts. And it is this clinical public health goal which

should, in turn, determine the direction of research on the tobacco withdrawal syndrome. The major foci of such research

should be (1) to clarify the relation between the withdrawal syndrome and the outcome of smoking cessation efforts; (2) identify

risk factors relevant to the withdrawal syndrome; and (3) formu176
late interventions which affect the withdrawal syndrome, with

a view toward encouraging maintenance of abstinence.

Although the association between withdrawal symptoms and failure

in abstinence from smoking is well established in retrospective

studies, this relationship deserves further exploration. Data

on withdrawal symptoms should be collected during the period of

initial withdrawal and then analyzed retrospectively for differences between eventual successes and failures. Parameters which

modify the association between symptoms and outcome should also

be identified. A symptom might have differing predictive power

among different subpopulations, for example. The Guilford

(1966) study is a model for this type of investigation, but

more of the same type are needed in order to understand how the

tobacco withdrawal syndrome affects smoking cessation.

Research should continue to study those factors which have already been tentatively identified as determinants of the severity

of the tobacco withdrawal syndrome. Besides leading to a better

understanding of the process underlying dependence on tobacco,

this would identify populations at risk for severe withdrawal

symptoms. The influence of factors such as sex, for example,

needs to be better documented and explored, Since the smoking

behavior of man and women differs in a number of important respects--e.g., dose, age at initiation, etc. (USDHEW 1975)--

studies are needed to analyze whether the sex difference is

reducible to these other variables.

More generally, the search for other factors affecting the withdrawal syndrome needs to be expanded. One strategy for such a

preliminary search would be to analyze data retrospectively,

observing the severity of the syndrome, and then attempting to

account for it by multiple regression on other variables. Among

the other variables whose influence warrants examination is the

method of smoking withdrawal. The differences between “cold

turkey” and gradual withdrawal should be studied in randomized

experiments. The effects of different antismoking therapies

should also be explored. This could be easily accomplished if

investigators and clinicians in this field agreed to measure

and report withdrawal symptoms on a standard instrument. A

quasi-experimental comparison among methods would then grow

naturally out of the accumulated literature.

The influence of environmental factors on withdrawal and relapse

also warrants investigation. One area of investigation that has

already been suggested involves explanations of diurnal variations in craving in terms of stimulus events occurring at different times of day. More broadly, the influence of environmental stimuli in producing conditioned withdrawal symptoms--

e.g., Wikler (1965)--should be explored with a view toward

identifying high risk situations. This has particular relevance to the clinical problem of preventing relapse. If high

risk relapse situations are identified, they would provide

177
natural targets for interventions. Some high risk situations

might be entirely avoidable, and methods might be devised for

reducing the risk of relapse in others.

Thus, a better understanding of the tobacco withdrawal syndrome

could be applied to increasing the probability of success in

smoking cessation efforts. Knowledge about individual differences in risk for severe withdrawal symptoms, for example, might

be used to screen patients for treatment, with high risk patients

receiving additional attention. If more is learned about the influence of cessation methods as well, perhaps matching of treatment methods and patient populations could be used to increase

treatment success or cost efficiency. The treatment of choice

might depend on the patient’s withdrawal syndrome risk factors.

Interventions which directly attack withdrawal symptoms need to

be developed and evaluated. Manipulation of patients’ expectations or attributions of withdrawal symptoms might be one way in

which to reduce their severity and affect relapse (cf.

Barefoot and Girodo 1972). If withdrawal symptoms are indeed

aggravated by conditioned responses to particular stimuli, it

might be possible to decondition or counter-condition these

responses as part of the therapy. Patients might also be provided with coping skills to deal with unavoidable withdrawal

symptoms. Smokers who suffer from inability to concentrate

might be taught to enhance their concentration, for example.

Also, progressive relaxation training or other anxiety and affect management techniques might prove useful to those who suffer

from anxiety or irritability in withdrawal.

For those smokers for whom weight gain is a major concern, weight

control measures might be incorporated into a smoking control

program, with the aim of improving maintenance of nonsmoking.

Controlling the withdrawal syndrome may be the key to controlling

relapse.

SUMMARY AND CONCLUSION

There is an identifiable syndrome which occurs on withdrawal

drawal from tobacco. The tobacco withdrawal syndrome is characterized objectively by changes in the EEG and cardiovascular

function, by decrements in psychomotor performance, and by

weight gain. Subjective symptoms of irritability, anxiety, Inability to concentrate, and disturbances of arousal are characteristic of tobacco users in withdrawal, and intense craving for

tobacco is almost universally reported. Although reports vary

regarding the prevalence, severity, and course of these symptoms,

there is nevertheless sufficient consensus to justify the conclusion that a withdrawal syndrome occurs in habitual tobacco users.

Among the factors which affect the severity of the tobacco withdrawal syndrome are the smoker’s sex and habitual dose. Other

factors, such as motivation for smoking and motivation for

178
quitting, remain to be Investigated. At least one symptom --

craving for tobacco -- shows diurnal variation. The early

course of the withdrawal syndrome depends on the smoker’s degree of deprivation. Totally abstinent smokers show a marked

decrease in all symptoms in the first week of abstinence, with

subsequent leveling off or increase in symptoms. Smoking among

partially abstinent smokers appears to prevent this early drop

and to maintain symptoms at their high initial levels, prolonging the withdrawal symptoms. This may explain the ineffectiveness of gradual withdrawal as a method of smoking cessation.

More research on, the tobacco withdrawal syndrome is warranted

because of the relation between withdrawal symptoms and relapse

in smoking cessation. Research in this area must consider a

number of methodological issues, including awareness of sources

of variability in symptoms. Standardized assessment of symptoms

would be a boon to research on the abstinence syndrome, making

results more comparable across studies. Much could be gained

from simply assessing and reporting withdrawal symptoms in smoking

cessation studies. Most studies in the literature are based on

retrospective self-reports of exsmokers, with all the limitations

attending to such data. More prospective, randomized experiments

using control groups and multiple measures are needed.

Ultimately, the goal of research on the tobacco withdrawal syndrome should be the development of applications in clinical technology for smoking control. Currently, three out of four smokers

who succeed in stopping smoking will relapse, most of them because of withdrawal symptoms. A better understanding of tobacco

withdrawal phenomena may help us to identify high risk populations

of smokers and match them to maximally efficient treatments. A

major focus for research should be on developing effective treatments which specifically attack tobacco withdrawal symptoms and

thereby discourage relapse. The health of millions of people

depends on it.

FOOTNOTES

1We did find a rather puzzling difference between these two

groups in their diurnal pattern of arousal, with some suggestion that heavy smokers may be more prone to insomnia. See the

section on diurnal variations.

2

Schachter, Silverstein and Perlick (1977) present such an explanation of smoking rates based on urinary pH, which affects the

excretion of nicotine. Their explanation, however, leads them

to predict that smoking rates will be higher in the morning, and

they present data suggesting this is the case. Meade and Wald’s

(1977) data are probably more reliable in estimating ad lib

smoking rates, as they are based on a larger sample and more

systematically study the effects of time of day.

3Although they do illustrate the point here, these two sets of

studies are not entirely contradictory. In the Heimstra (1973)

179
studies, the smokers perform like the nonsmokers on psychomotor tasks, with the deprived smokers showing impairment,

suggesting a withdrawal effect but no effect of smoking per

se. Also, the study by Perlick (1977) in the Schachter laboratory, shows a similar pattern of results with self-report

ratings of response to a stressor.

REFENRENCES

Andersson, K. Effects of cigarette smoking on learning and

retention. Psychopharmacologia, 41:1-5, 1975.

Barefoot, J. C., and Girodo, M. The misattribution of smoking

cessation symptoms. Canad J Behav Sci, 4(4):358-363, 1972.

Bums, B.H. Chronic chest disease, personality, and success

in stopping cigarette smoking. Brit J Prev Sot Med, 23:23-37,

1969.

Finnegan, J. K.; Larson, P. S.; and Haag, H. B. The role of

nicotine in the cigarette habit. Science, 102:94-96, 1945.

Fletcher, C., and Doll, R. A survey of doctors' attitudes to

smoking. Brit J Prev Soc Med, 23:145-153, 1969.

Frankenlmeuser, M.; Myrsten, A-L; Post, B.; and Johansson, G.

Behavioural and physiological effects of cigarette smoking in

a monotonous situation. Psychopharmacologia, 22:1-7, 1971.

Friedman, J. Psychopharmacological aspects of cigarette

smoking. Unpublished thesis, University of Melbourne, Australia,

1972.

Frith, C. D. Smoking behavior and its relation to the smoker's

immediate experience. Br J Soc Clin Psychol, 10:73-78, 1971.

Glauser, S.C.; Glauser, E. M.; Reidenberg, M. M.; Rusy, B. F.;

and Tallarida, R. J. Metabolic changes associated with the

cessation of cigarette smoking. Arch Environ Health, 20:

377-381, 1970.

Gritz, E. R. Women and smoking: A realistic appraisal. Paper

delivered at the International Conference on Smoking Cessation,

New York, 1978.

Gritz, E. R. The "intermission effect": Short-term deprivation

from smoking. Paper delivered at the 86th Annual Conference of

the American Psychological Association, Toronto, 1978.

Gritz, E. R., and Jarvik, M. E. Preliminary study: Forty-eight

hours of abstinence from smoking. Proceedings, 81st Annual

Convention, American Psychological Association, pp. 1037-1040.

180
Guilford, J. S. Factors Related to Successful Abstinence From

Smoking. Pittsburgh, Pa.: American Institutes for Research, 1966.

Hall, G. H., and Morrison, C. F. New evidence for a relationship

between tobacco smoking, nicotine dependence and stress. Nature,

243(5404): 199-201, 1973.

Hammen, C. Personal communication, 1973.

Heimstra, N. W. The effects of smoking on mood change. In: Dunn,

W. L., ed. Smoking Behavior Motives and Incentives. Washington,

D. C.: Winston and Sons, 1973. l97-207.

Heimstra, N. W., Bancroft, N. R. and Dekock, A. R. Effects of

smoking upon sustained performance in simulated driving task.

Ann N Y Acad Sci, 142:295-307, 1907.

Herold, R. Report regarding our effort to carry out the five-day

plan for nicotine withdrawal in the transformer factory “Karl

Liebknecht” at Berlin-Oberschone-Weide. Unpublished mimeo, 1967.

Hunt, W. A., and Matarazzo, J. D. Three years later: Recent

developments in the experimental modification of smoking behavior,

J Abnorm Psychol, 81(2): 107-114, 1973.

Hutchinson, R. R., and Emley, G.S. Effects of nicotine on avoidance,

conditioned suppression, and aggression response measures in

animals and man. In: Dunn, W. L., ed. Smoking Behavior: Motives

and Incentives. Washington, D. C.: Winston and Sons, 1973, pp.

171-196.

Ikard, F.F., and Tomkins, S. The experience of affect as a

determinant of smoking behavior: A series of validity studies.

J Abnorm Psychol, 81(2):172-181, 1973.

Itil, T. M.; Ulett, G. A.; Hsu, W.; Klingenberg, H.; and Ulett, J.

A. The effects of smoking withdrawal on quantatatively analyzed

EEG. Clin Electroenceph, 2(1):44-51, 1971.

Jaffe, J. H. Drug addiction and drug abuse. In: Goodman, L. S. and

Gilman, A., eds. The Pharmacological Basis of Therapeutics.

Fourth Edition. New York: Macmillan, 1971. pp. 276-313.

Kales, J. D.; Allen, C.; Preston, T. A.; Tan, T-L. Changes in REM

sleep and dreaming with cigarette smoking and following withdrawal.

Psychophysiology 7:347-348, 1970.

Kleinman, K. M.; Vaughn, R. L.; and Christ, T. S. Effects of

cigarette smoking and smoking deprivation on paired-associate

learning of high and low meaningful nonsense syllables.

Psychol Rep, 32:963-966, 1973.

Knapp, P.H.; Bliss, C. M.; and Wells, H. Addictive aspects in

heavy cigarette smoking. Am J Psychiatry, 119:966-972, 1963.

181
Knott, V.J., and Venables, P.H. Stimulus intensity control and

the cortical evoked response in smokers and nonsmokers. Psychophysiology, 15(3):186-192, 1978.

Knott, V. J., and Venables, P. H. EEG alpha correlates of nonsmokers, smokers, smoking, and smoking deprivation. Psychophysiology, 14(2):150-156, 1977.

Levinson, B. L.; Shapiro, D.; Schwartz, G. E.; and Turskey B. Smoking

elimination by gradual reduction. Behav Ther, 2:477-487, 1971.

Lichtenstein, E.; Antonuccio, D. O.; and Rainwater, E.

Personal communication, 1978.

Lichtenstein, E.; Antonuccio, D. O.; and Rainwater, E. Unkicking

the habit: The resumption of cigarette smoking. Paper presented

at the annual conference of the Western Psychological Association,

1977.

Lichtenstein, E., and Danaher, B. G. Modification of smoking

behavior: A critical analysis of theory, research, and practice.

In: Hersin, M.; Eisler, R. M.; and Miller, P. M., eds. Progress

in Behavior Modification. Vol III. New York: Academic Press,

1976. pp. 70-132.

Mausner, J. S. Cigarette smoking among patients with respiratory

disease. Am Rev Resp Dis, 102:704-713, 1970.

Meade, T. W., and Wald, N. J. Cigarette smoking patterns during

the working day. Brit J Prev Soc Med, 31:25-29, 1977.

Murphee, H. B. and Schultz, R. E. Abstinence effects in smokers.

Fed Proc, 27:220, 1968.

Myrsten, A-L; Elgerot, A.; and Edgren, B. Effects of abstinence

from tobacco smoking on physiological and psychological arousal

levels in habitual smokers. Psychosom Med, 39 (1):25-38, 1977.

Myrsten, A-L; Post, B.; Frankenhaeuser, M.; and Johansson, G.

Changes in behavioral and physiological activation induced by

cigarette smoking in habitual smokers. Psychopharmacologia, 27:

305-312, 1972.

Nesbitt, P. D. Smoking, physiological arousal, and emotional

response. J Pers Soc Psychol, 25:137-145, 1973.

Pederson, L. L., and Lefcoe, N. M. A psychological and behavioral

comparison of ex-smokers and smokers. J Chron Dis, 29:431-434,

1976.

182
Perlick, D. The withdrawal syndrome: Nicotine addiction and the

effects of stopping smoking in heavy and light smokers.

Unpublished disseration. New York: Columbia University, 1977.

Peterson, D. J.;. Lonergan, L. H.; Hardinge, M. G.; and Teel, C. W.

Results of a stop-smoking program. Arch Environ Health, 16:211-

214, 1968.

Phillips, C. The EEG changes associated with smoking,

Psychophysiology, 8(1):64-74, 1971.

Ryan, F. J. Cold turkey in Greenfield, Iowa: A follow-up study.

In: Dunn, W. L. , ed. Smoking Behavior: Motives and Incentives.

New York: Wiley, 1973. pp. 231-242.

Schachter, S. Pharmacological and psychological determinants

of smoking. Ann Intern Med, 88:104-114, 1978.

Schachter, S. Nicotine regulation in heavy and light smokers.

J Exp Psycho1 (Gen), 106(1):5-12, 1977.

Schachter, S., Silver-stein, B., and Per-lick, D. Psychological and

pharmacological explanations of smoking under stress.

(Gen), 106(1):31-40, 1977.

J Exp Psychol

Schechter, M. D., and Rand, M. J. Effect of acute deprivation of

smoking on aggression and hostility. Psychopharmacologia, 35:

19-28, 1974.

Shiffman, S. M., and Jarvik, M. E. Smoking withdrawal symptoms in

two weeks of abstinence. Psychopharmacology, 50:35-39, 1976.

Silverstein, B. An addiction explanation of nicotine-induced

relaxation. Unpublished dissertation. New York: Columbia

University, 1976.

Trahair, R.C.S. Giving up cigarettes: 222 case studies. Med J

Aust, 1:929-932, 1967.

Ulett, J. A. , and Itil, T. M. Quantitative electroencephalogram

in smoking and smoking deprivation. Science, 164:969-970, 1969.

U.S. Department of Health, Education, and Welfare, PHS, Center

for Disease Control, 1976. Adult Use of Tobacco - 1975.

U. S. Department of Health Education and Welfare, Smoking and

Health. Report of the Advisory Committee to the Surgeon General

of Public Health Service, 1964.

Weybrew, B. B., and Stark, J. D. Psychological and Physiological

Changes Associated with Deprivation from Smoking. U. S. Naval

Submarine and Medical Center Report No. 490., 1967

183
Wikler, A. Conditioning factors in opiate addiction and relapse.

In: Wilner, D. M., and Kassebaum, G. G., eds. Narcotics. New

York: McGraw-Hill, 1965. pp. 85-100.

Wilhemsen, L. One year’s experience in an anti-smoking clinic.

Scand J Resp Dis, 49:251-259, 1968.

Wynder, E. L.; Kaufman, P. L.; and Lesser, R. L. A short-term

follow-up study on ex-cigarette smokers, with special emphasis

on persistent cough and weight gain. Am Rev Resp Dis, 96:645-655,

1967.

Zeidenberg, P.; Jaffe, J. H.; Kanzler, M.; Levitt, M. D., Langone,

J. J.; and Van Vunakis, H. Nicotine: Cotinine levels in blood

during cessation of smoking. Comp Psychiatry, 18:93-101, 1977.

AUTHOR

Saul M. Shiffman, M.A., C. Phil.

Department of Psychiatry

School of Medicine

Neuropsychiatric Institute

and

Department of Psychology

University of California

Los Angeles, California 90024

184
Part IV

Implications and Directions

for Future Research
Chapter 14

Implications and Directions

for Future Research

Norman A. Krasnegor, Ph.D.

A new Surgeon General’s Report on Smoking and Health, which was issued in January 1979, carefully documents the scientific data on

the health risks associated with cigarette smoking. A major addition to that document is a series of five chapters on the behavioral

aspects of smoking. While much new information on this latter topic

is presented, one is struck by the imbalance between what is known

about the consequences of smoking and the behavior itself. more

specifically, it is clear that research on factors involved in the

establishment, maintenance, and cessation of cigarette smoking is

only in its formative stages.

Due to the implications of cigarette smoking behavior for the public health and the view that smoking is the prototypical dependence

process, the National Institute on Drug Abuse has established a

high priority

behavioral,

initiative designed to acquire new knowledge on the

biological, and psychosocial aspects of this type of

substance abuse, The Institute’s programmatic goal is focused upon

the systematic compilation of basic and applied scientific data

on variables which are causally related to the acquisition of the

behavior and the observed chronic usage patterns. Such information

can serve as a basis for designing feasible and effective treatment

strategies and enhance our understanding of dependence associated

with substance use.

A RESEARCH AGENDA

On the basis of the papers presented in this monograph and my involvement in the preparation of NIDA’s contribution to the Surgeon

General’s Report, I should like to provide a selected research agenda composed of topics which the National Institute on Drug Abuse

views as programmatic priorities. One caveat should be noted, however. The list developed below is meant to be a guide for researchers . It is not intended to be all-inclusive or exhaustive. The

order of presentation does not imply a rank order among priorities.

In general, the NIDA research program is focused upon cigarette smoking behavior and the dependence process associated with it. We

186
have interest in each stage of the behavior’s natural history (experimentation, establishment, maintenance, cessation, and relapse).

We view the problem area broadly and are desirous of supporting a

multidisciplinary approach to undertaking investigations in this

research domain. Accordingly, we would encourage investigators

from the biological, behavioral, and social sciences to apply their

methodologies to the field of smoking behavior research in order

that a comprehensive and balanced understanding can be achieved.

RESEARCH PRIORITIES

1. Peer Pressure

One of the most often cited reasons that people, particularly adolescents, begin smoking is that friends and acquaintances influence

those not smoking to take up the behavior and conform to group

norms. Peer pressure has been identified by Kandel as a psychosocial variable involved in experimentation with and use of marihuana.

Other researchers have emphasized peer pressure as a causative factor in other health-risk behaviors (such as reckless driving, excessive drinking, etc.).

Studies which undertake prospective investigations of peer pressure

as this construct relates to cigarette smoking should be initiated.

Both laboratory and field experiments should be carried out to determine the contribution of peer pressure to the initiation and

maintenance of smoking behavior.

2 . The Role of Nicotine

One of the central questions in the field of smoking behavior is the

role played by nicotine. Do people smoke cigarettes to maintain a

certain level of the drug?

What we know at present is that nicotine can be discriminated by

animals, it is intravenously self-administered by rats, it has a

central nervous system effect, and has been demonstrated to be titrated by smokers. In addition, the work of Abood and Lowy suggests

the existence of a specific nicotine receptor.

The methodologies of Hanson et al. and Abood and Lowy offer exciting

possibilities for studying the reinforcing effects of nicotine within the context of both an experimental analysis of behavior and

neuropsychopharmacology. We would encourage more research along

similar lines.

In the area of self-administration, we have particular interest in

developing animal models which employ the inhalation route of administration. This is the case because nicotine passes most rapidly into the brain via the lungs, and it may be that the reinforcing

efficacy of nicotine is enhanced when administered via this route.

Studies which explore the central site of action of nicotine and

drugs which block its effect are of high programmatic interest to

l87
the Institute. Such research could help to elucidate the neuropsychological and biochemical bases for the reinforcing effects of

the drug.

3. Withdrawal

Another important area of research is the characterization of symptoms associated with cessation of smoking, Dr. Shiffman has provided an excellent overview of the literature and a summary of his

own research. In general, our interest in withdrawal stems from

the anecdotal observation that smokers who relapse often claim that

they take up smoking after cessation because they cannot cope with

the withdrawal. Many questions need to be addressed. For example, is there a characteristic withdrawal pattern associated with

cessation? How does this vary with number of years that one has

smoked prior to cessation? How does withdrawal vary with the

strength of the cigarettes that were smoked? Is there an acute

withdrawal pattern?

4. Behavioral Pharmacology of Smoking

Our interest in this topic stems from the view that collecting

descriptive and quantitative information on the smoking act itself

can be useful in designing effective treatment. While there are

some data on topography of smoking (Dr. Lee Frederiksen), relatively

few experiments have been conducted to determine the rate of puffing, volume of puffing, inter-puff interval, etc. We would encourage studies on the relationship of such parameters to smoking history, nicotine content of cigarettes, stimulus control, etc.

5. Prolonging Abstinence

At present, there are a variety of methods (e.g., rapid smoking,

warm air, etc.) which can be employed to produce cessation. In

general, those smokers who finish such treatment do stop. The problem is that the relapse rate is extremely high. Between 70-80 percent of those who stop are likely to take up smoking again within

a year. Thus, we would encourage research designed to discover

procedures which will lead to a lengthening of abstinence.

6. Objective Methods for Validating Self-Reports

There are many reports in the literature on incidence and prevalence

of cigarette use and on the evaluation of treatment efficacy. Unfortunately, the analysis and conclusions are often based on selfreports only. While some studies do use significant others to corroborate self-reports, few have employed biological assays to validate such subjective data. Work on biological assays such as analysis of breath for CO content and blood for thiocyanate levels is

just getting under way. We would encourage more research on these

two biological assays and development of others to help supplement

self-reports with objective measures.

188
7. Longitudinal Studies of Smokers

Many of the research findings which appear in the literature are

based upon short term studies of smoking. While there are some

exceptions, the general picture suggests that followup in treatment

studies is conducted for up to one year. Yet more recent experiments show that a minimum of two years of followup is necessary to

evaluate treatment efficacy for smoking cessation programs. We

would encourage researchers to employ long term followup designs

when evaluating efficacy of modalities for cessation. In addition,

longitudinal studies should be designed to investigate the natural

history of spontaneous quitters. Thus, there are reports that 4 to

5 million smokers each year stop using cigarettes on their own.

We know virtually nothing about such people or their success at

achieving and maintaining abstinence.

8. Treatment Research

While there have been many different techniques to help people

stop smoking, the literature generally shows that the best that

can be achieved is a 40-50 percent abstinence rate at the end of

two years. This result represents a 10-20 percent improvement

over the general finding of a 30 percent success rate. New and

innovative techniques, particularly in the context of well-designedmulti-modal treatment approaches, should be carried out. Such research should include within the design appropriate control groups,

random assignment, objective measures of cigarette use (CO, thiocyanate, etc.), and longitudinal followup.

9. Drug/Cigarette Smoking, Interactions

Anecdotal observations suggest that alcoholics and heroin addicts

smoke at a high rate, particularly during periods of abstinence.

Experiments designed to study the interaction of cigarette smoking

with alcohol drinking reveal that the rate of consumption of both

substances increases when both are used together, compared to the

situation when each is used independently. Whether this is an interaction based on pharmacological or behavioral mechanisms is not

currently known. However, we would encourage investigators to

study the interaction of cigarette smoking with the self-administration of a variety of drugs. Such work would help to elucidate

the role that cigarette smoking may play in the maintenance of

other drug use.

We hope that this brief listing of selected research topics will

aid scientists who are interested in the field to focus their investigations. Further information pertaining to the programs on

cigarette smoking may be obtained by contacting the National Institute on Drug Abuse, Division of Research, 5600 Fishers Lane,

Rockville, Maryland 20857.

189
Participants

in Symposium on

Cigarette Smoking as a Dependence process

June 19, 1978

Leo G. Abood, Ph.D.

Center for Brain Research

University of Rochester

John A. Rosecrans, Ph.D.

Department of Pharmacology

MCV Station, Box 726

Virginia Commonwealth University

Richmond, Virginia 23298

Medical Center

Rochester, New York 14642

Dorothy E. Green, Ph.D.

Consulting Research Psychologist

3509 N. Dickerson Street

Arlington, Virginia 22207

Harley M. Hanson, Ph.D.

Merck Institute for Therapeutic Research 26-208

West Point, Pennsylvania 19486

Daniel Horn, Ph.D.

R.D. 1 Box 182

Frenchtown, New Jersey 08825

Jerome H. Jaffe, M.D.

College of Physicians and

Surgeons of

Columbia University

722 West 168th Street

New York, New York 10032

Murray E. Jarvik, M.D., Ph.D.

Department of Psychiatry

and Pharmacology

School of Medicine

Neuropsychiatric Institute

University of California - L.A.

760 Westwood Plaza

Los Angeles, California 90024

John A. O'Donnell, Ph.D.

Department of Sociology

University of Kentucky

Lexington, Kentucky 40506

Michael A.H. Russell, M.B., MRCP,

MRCPsych

Addiction Research Unit

Institute of Psychiatry

The Maudsley Hospital

101 Denmark Hill

London, S.E.5, England

Stanley Schachter, Ph.D.

Department of Psychology

1400 Schemerhorn

Columbia University

New York, New York 10027

Saul M. Shiffman, M.A., C.Phil.

Department of Psychiatry

School of Medicine

Neuropsychiatric Institute

and Department of Psychology

University of California - L.A.

760 Westwood plaza

Los Angeles, California 90024

Charles R. Schuster, Ph.D.

Departments of Psychiatry and

Pharmacological and Physiological Sciences

University of Chicago

Pritzker School of Medicine

950 East 59th Street

Chicago, Illinois 60637

190
National

lnstitute on

monograph series

While limited supplies last, single copies of the monographs may

be obtained free of charge from the National Clearinghouse for Drug

Abuse Information (NCDAI). Please contact NCDAI also for information about availability of coming issues and other publications of

the National Institute on Drug Abuse relevant to drug abuse research.

Additional copies may be purchased from the U.S. Government Printing

Office (GPO) and/or the National Technical Information Service (NTIS)

as indicated. NTIS prices are for paper copy. Microfiche copies,

at $3, are also available from NTIS. Prices from either source are

subject to change.

Addresses are:

NCDAI

National Clearinghouse for Drug Abuse Information

Rockville, Maryland 20857

GPO

Superintendent of Documents

U.S. Government Printing Office

Washington, D.C. 20402

NTIS

National Technical Information

Service

U.S. Department of Commerce

Springfield, Virginia 22161

1 FINDINGS OF DRUG ABUSE RESEARCH. An annotated bibliogragphy of

NIMH- and NIDA-supported extramural grant research, 1964-74.

Volume 1, 384 pp., Volume 2, 377 pp.

Vol.1: GPO out of stock NTIS PB #272 867/AS $14

Vol.2: GPO Stock #017-024-0466-g $5.05 NTIS PB #272 868/AS $13

191
2 OPERATIONAL DEFINITIONS IN SOCIO-BEHAVIORAL DRUG USE RESEARCH 1975.

Jack Elinson, Ph.D., and David Nurco, Ph.D., editors. Task Force

artictes proposing consensual definitions of concepts and terms used

in psychosocial research to achieve operational compbility. 167 pp.

GPO out of stock NTIS PB #246 338/AS $8

3 AMINERGIC HYPOTHESES OF BEHAVIOR: REALITY OR CLICHE? Bruce J.

Bernard, Ph.D., editor. Articles examining the relation of the brain

monoamines to a range of animal and human behaviors.

GPO Stock #017-024-00486-3 $2.25 NTIS PB #246 687/AS $8

4 NARCOTIC ANTAGONISTS: THE SEARCH FOR LONG-ACTING PREPARATIONS.

Robert Willette, Ph.D., editor. Articles reporting current alternative

inserted sustained-release or long-acting drug devices.

GPO Stock #017-024-00488-0 $1.10 NTIS PB #247 096/AS $4.50

5 YOUNG MEN AND DRUGS: A NATIONWIDE SURVEY. John A. O'Donnell,

Ph.D., et al. Report of a national survey of drug use by men 20-30

years old in 1974-5. 144 pp.

GPO Stock #017-024-00511-8 $2.25 NTIS PB #247 446/AS $8

6 EFFECTS OF LABELING THE "DRUG ABUSER": AN INQUIRY. Jay R.

Williams, Ph.D. Analysis and review, of the literature examining

effects of drug use apprehension or arrest on the adolescent. 39 pp.

GPO Stock #017-024-00512-6 $1.05 NTIS PB #249 092/AS $4.50

7 CANNABINOID ASSAYS IN HUMANS. Robert Willette, Ph.D., editor.

Articles describing current developments in methods for measuring

cannabinoid levels in the human body by immunoassay, liquid and

dual column chromatogmphy and mass spectroscopy techniques. 120 pp.

GPO Stock #017-024-00510-0 $1.95 NTIS PB #251 905/AS $7.25

8 Rx 3x/WEEK LAAM - ALTERNATIVE TO METHADONE. 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,

preclinical 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 #017-024-00571-1 $2.60 NTIS PB #266 691/AS $10.75

11 DRUGS AND DRIVING. Robert Willette, Ph.D., editor. State-of-theart 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

192
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

13 COCAINE: 1977. Robert C. Petersen, Ph.D., and Richard C.

Stillman, M.D., editors. A series of reports developing a picture

of the extent and limits of current knowledge of the drug, its use

and misuse. 223 pp.

GPO Stock #017-024-00592-4 $3 NTIS PB #269 175/AS $9.25

14 MARIHUANA RESEARCH FINDINGS: 1976. Robert C. Petersen, Ph.D.,

editor. Technical papers on epidemiology, chemistry and metabolism,

toxicological and pharmacological effects, learned and unlearned behavior, genetic and immune system effects, and therapeutic aspects

of marihuana use. 252 pp.

GPO Stock #017-024-00622-0 $3 NTIS PB #271 279/AS $10.75

15 REVIEW OF INHALANTS: EUPHOIA TO DYSFUNCTION. Charles Wm.

Sharp, Ph.D., and Mary Lee Brehm, Ph.D., editors. A broad review of

inhalant abuse, including sociocultural, behavioral, clinical, pharmacological, and toxicological aspects. Extensive bibliography. 347 pp.

GPO Stock #017-024-00650-5 $4.25 NTIS PB #275 798/AS $12.50

16 THE EPIDEMIOLOGY OF HEROIN AND OTHER NARCOTICS. Joan Dunne Rittenhouse, Ph.D.) editor. 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/B $13

18 BEHAVIORAL TOLERANCE: RESEARCH AND TREATMENT IMPLICATIONS.

Norman A. Krasnegor, Ph.D., editor. Conference papers discuss

theoretical and and empirical studies of nonpharmacologic factors in

development of tolerance to a variety of drugs in animal and human

subjects. 151 pp.

GPO Stock #017-024-00699-8 $2.75 NTIS PB #276 337/AS $8

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

193
20 SELF-ADMINISTRATION OF ABUSED SUBSTANCES: METHODS FOR STUDY.

Norman A. Krasnegor Ph.D., editor. Papers from a technical review on

methods used to study self-administration of abused substances. Discussions include overview, methodological analysis, and future planning

of research on a variety of substances: drugs, ethanol, food, and

tobacco. 246 pp.

Not available from GPO NIST PB #288 471/AS $10.75

21 PHENCYCLIDINE (PCP) ABUSE: AN APPRAISAL. Robert C. Petersen,

Ph.D., and Richard C. Stillman, M.D., editors. Monograph derived from

a technical review to assess the present state of knowledge about phencyclidine and to focus on additional areas of research. Papers are

aimed at a professional and scientific readership concerned about how

to cope with the problem of PCP abuse. 313 pp.

GPO Stock #017-024-00785-4 $4.25 NTIS PB #288 472/AS $11.75

22 QUASAR: QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIPS OF ANALGESICS, NARCOTIC ANTAGONISTS, AND HALLUCINOGENS. Gene Barnett,

Ph.D. Milan Trisc, Ph.D., and Robert E. Willette Ph.D., editors.

Reports an interdisciplinary conference on the molecular nature

of drug-receptor interactions. A broad range of quantitative techniques were applied to questions of molecular structure, correlation of molecular properties with biological activity, and molecular interactions with the receptor(s). 487 pp.

GPO Stock #017-024-00786-2 $5.25 NTIS PB #292/265/AS $15.00

Coming Issues:

24 SYNIHETIC ESTIMATES FOR SMALL AREAS: WORKSHOP PAPERS AND DISCUSSION. Joseph Steinberg, editor. Papers from a workshop consponsored

by NIDA and the National Center for Health Statistics on a class of

statistical approaches that yield needed estimates of data for states

and local areas. Methodology and application, strengths and weaknesses are discussed.

25 BEHAVIORAL ANALYSIS AND TREATMENT OF SUBSTANCE ABUSE. Norman A.

Krasnegor, Ph.D., editor. Technical review papers present commonalities in the behavioral analysis and treatment of substance abuse.

Specific behavior therapeutic approaches are presented for the

treatment of drug addiction, tobacco smoking, drinking, and obesity. An agenda for future research needs is included.

194
DEPARTMENT OF

HEALTH, EDUCATION, AND WELFARE

PUBLIC HEALTH SERVICE

ALCOHOL, DRUG ABUSE, AND

MENTAL HEALTH ADMINISTRATION

5600 FISHERS LANE

ROCKVILLE, MARYLAND 20857

OFFICIAL BUSINESS

Penalty for private use, $300

POSTAGE AND FEES PAID

U S DEPARTMENT OF H E W

HEW 396

THIRD CLASS

BULK RATE

NOTICE OF MAILING CHANGE

Check here if you wish to discontinue receiving this type of publication

Check here if your address has changed and you wish to continue receiving

this type of publication. (Be sure to furnish your complete address including

ZIP code )

Tear off cover with address label still affixed and send to

Alcohol, Drug Abuse, and Mental Health Administration

Printing and Publications Management Branch

5600 Fishers Lane (Rm 6C-02)

RockviIle, Maryland 20857

DHEW Publication No (ADM) 79-800

Printed 1979