Tobacco Documents Online

r„" Part II. BEHAVIORAL FACTORS (continued) Chapter 9 Tobacco Dependence: Is Nicotine Rewarding or Aversive? M. A. H. RusseZ2 . . . . . . . . . . . . . . 100 Chapter 10 Regulation, Withdrawal, and Nicotine Addiction StanZey Schachter . . . . . . . . . . . . . .123 Part III. PSYCHOBIOLOGICAL FACTORS Qiapter 11 Acute and Chronic Effects of Nicotine in Rats and Evidence for a Noncholinergic Site of Action L. G. Abood, K. Lorvy, and H. Booth ... .....136 Chapter 12 Tolerance to the Effects of Tobacco Murray E. Jarvik . . . . . . . . . . . . . .150 Chapter 13 The Tobacco Withdrawal Syndrome SauZ M. 9hi ft3nan . . . . . . . . . . . . . .158 Part IV. IND?LICATIONS AND DIRECTIONS FOR FUIURE 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 TIMN 0152367

Chapter 1 i ntroduction 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 repre- sents 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 docu- ment (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, habit- ual 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 develop- ment 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 meeti.ng 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 commtmity on the smoking habit and an agenda to guide future research in this area. The monograph is divided into four sections. In the first, psycho- social factors relating to the dependence process associated with cigarette smoking are explored. A stinulating 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 ; TIMN 0152368

of illicit drug abuse, based on a sample of young men, is discussed by social scientist Dr. John A. 0'Ibnnell. The dean of American researchers in the area of cigarette smoking, Dr. Ifaniel Horn, pro- vides 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 well- known 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 evi- dence 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 rein- forcing 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 recep- tor 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. 'Ihi.s 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 re- search on•smoking. It is hoped that this listing of research needs will be used by members of the scientific commoity 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. Smok'ng_ and Health, Report of the Advisory Committee to the Surgeon'~enerato t e blic Health Service, P.H.S. Publica- tion No. 1103, U.S. 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. Pub ic~"-ation-W.79-5-0 066, U.S. Government Printing Office. 1979. 2

Partl Psychosocial Factors I ; TIMN 0152370

Chapter 2 Smoking as an Addictive Disorder Jerome H. Jaffe, M.D., and Maureen Kanzler, Ph.D. Bishop Bartolnme de las Casas, observing the use of "tabacos" by Spanish settlers In the New World, wrote that Vhen reproached for such a disgusting habit, [they] replied that they found it inpos- sible to give it up. I csnnot understand what enjoyment or advan- tage they derive from it" (de las Casas, in Corti 1932, pp,42-43). 7bday, appmxfmately 450 years after de las Casas racorded those observations, we are still considering the same two guestions in regard to cigarette snaking: hhy don't people give it up? 14nd what advantage or enjoyment do they derive fram it? Some wnrk has been done in the interval and some of the researchers who have contributied greatly to our kmwledge are participants in this sym- posium. Because of their •aork we can now fornulate same reasonable hypotheses about the origins of the "enjoynent or advantage" people derive from the smoke of tobaooo leaves, and we even have a aon- siderable body of experience about helping people give up the habit. Die las Casas would be happy to kmw that giving it up is not irpos- sible, although for some tobacco users.giving it up is difficult and relapse is ooamnn. The title of this monograph refers to smoking as a "dependence process." Pesemblance between tobaooo use and`oonsmption of other substances that produce dependence has been debated throughout his- tory. In 1604, James I, in his O~unterblaste to 7bbaoco ((brti 1932) appeaxed to view bobacao process o habitu- ated as quite anaLoc.pu.s to the process by which a drinker of alca- hol becane a drudcasd. Three huidred years later, Sir Humphrey Bolleston, whose conmittee reooinmandations in 1926 set the tone for the British response to opiate dependence, was asked whether tobacao smdcing was not properly viewed as an addiction. In his reply, Sir Humphiey differed fran James I: This question turns on the meaning attached to the ward "addiction", and nay therefore be a verbal problem. 7he Ministry of Health's Departmsntal Cbnmi.ttee on Nlorphine and Heroin Addietirn (1926) defined an addict as a "person 4 -,TIMN 0152371

who, not requiring the continued use of a drug for the re- lief of the symplrnis of organic disease, has acqaired, as a result of repeated administration, an overpowering de- sire for its continuance, and in wham withdrawal of the drug leads to definite symptans of inental or physical dis- tress or disorder." That smking pzmduces a craving for moxo 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, tlrough there may be definite restlessness and instability, cannot be compared with the p!iysical distress caused by withdrawal in mor- phine addicts. Zb regard tobacco as a drug of addiction may be all very well in a humrous sense, but it is hard- ly accurate (Iaolleston 1926). In at least one sense Rolleston was correct: this issue is a senen- tic one. And when senantic problems arise, there is always a pos- sibility that the argunents about whether tobacco snoking is prop- erly grouped with other forms of r»nmedieal drug use will divert energy fran more pragmatic questions. We do not have to asoertain whether all aspects of tobacco use resemble other drug-using be- haviors in all of their particulars. The problems posed by aloo- hol, opiate and eocaine use differ from each other in a number of significant ways. Zhe essential question is to what degree oocloeptualizing tobacco use as one of the ar3dictive disorders is of help in directing us toward appropriate means to deal arith pxoblems that tobacco use causes. Not all dependence on drugs results in problens for society and/or the individual. Chffeine consunQtion is viewed by many as appro- priately classed with other fornis of dependence, and caffeine de- penc3enoe can be found in the International Classificat3on of Dis- eases (ICD 8). There is a caffeine withdrawal syndmne and caffeine can be abused to the point where it causes problems and disrupts behavior (Gilbert 1976). But so lorg as the price of coffee re- veins within reasonable bounds, scientists and policymakers alike will think aboutwaaffeine primnrily as samething that adds inmeas- urably to the beverage served at the coffee break and without which it is difficult to start the day. Fbr the most part, no grant applications are submitted to develop preventive trsatments for caffeine dependenees there are no debates in the hails of cbngress about taxing it; and coffee drinkers are not forced to sit in the rear of airplanes. Perhaps saoe day caffeine may beeaos of concern to behavioral scientists, but, for the present, the personal and social costs of this dependence appear to be relatively low. Th- bacco dependenee, on the other hand, has enornpus cost to the indi- vidual who develops sroking-related diseases, and these diseases in turn affect the eoonanic wel.l-being of society. There are several significant areas in which tobacco use resenbles other drug use, as well as a few areas in which it diverges. 5 ,TIMN 0152372 '

F3ien we begin to examine the ways in which tobacco use resembles other drug-using behaviors, we find ourselves asking the identical qusstions: Wiat factors - biological, psychological, sociological and pharmacological - determine whether there will be experimenta- ticn with the drug, a progression to casual or recreatiociall use, or on to intensive (or excessive) use? Wat factors aze associ- ated with (or cause) cartpulsive (addictive or dependent) use, and which factors are associated with relapse after abstinence has been achieved? Although the factors are interactive, we asstme with tobacco, as with other drug-using behaviors, that certain factors could act primarily at one stage while others might expst their effects at other stages. The objective of this brief overview is not to attempt to stmmt.~r- ize all the factors involved in tobacco-using behavior, but to point out a few notable similarities and differences between to- bacco use and the drug-using behaviors that are nnt+re cammnly viewed as "addictions" and to speculate on what the future may hold. SCME INfFm.S'tIIv- PSYmIAGICAL PARAIdEIS FzATID TO INITIAL USE As with most other forms of nonmedical drug use, the initial ex- perimentation 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 nnre canronl.y among the less well adjusted (Snith 1970) and less scholastically successful (Barland and Rudolph 1975; Simon and Prinavera 1976), and especially atnong those who have friends who smoke (Iarsai and Silvette 1975). Although there is great overlap between the psychological charac- teristics of snakers and ncnsmokers, in study after study, ciga- rette saakers on average tend to be nore extroverted (9mith 1970), more intolerant of rules, nore adventurescme and risk-taking and, in some studies, nnre angry (T4oms 1973) than appropriately matched nonmnokers (for additional references see Larsai and Silvette 1971, 1975). Mile it can be argued that some of these differences may be a result of smdcing, they are observed even anmong young people just beginning to smoke (Smith 1969) and they seem to persist when the smker becaaes abstinent (2lsonns 1973). Eysenck (1973) has postulated that the smoker is an extrovert who is usually at less than his or her optimal level of arousal and therefore uses nicotine to raise the level of arousal. Sudi a view leads to a "normalizing" hypothesis to accamt for the maintenance of the habit in at least same smokers. Yet many of these sane personality characteristics seem to be associated with experimentation with other drugs, e.g., LSD, opiates and alcohol (Haeburg, Kra.eeer and Jahnke 1975; Jaffe, 1977) which are not acambnly viewed as inducing arousal, an obser- vation which is difficult to reconcile with Eysenck's hypothesis. Most of those who begin to smoke cigarettes believe that they will some day give thesn up (Lieberman 1969). Very few cigarette smok.ers at present start out to become dependent. We must infer fram their behavior that gradually the capacity to choose is eroded and, while 6 TIMN 0152373

the user may want to believe s/he can stop at any time, the behav- ior indicates that this is not the case. 7he attitudes and beliefs about the likelihood of becaning dependent are not very different among those who begin to use opiates and alcohol. With tobacco usars, as with users of other drugs, there are nimer- ous theories that attempt to account for the transition fran experi- mentatioai to continued use. With most other drugs obsQrvess are willing to attribute the ongoing behavior, at least in part, to the effects of the drug itself; but even with the opiates and alcotrol, researchers recognize that, in certain social settings, the act of using the drug (rather than its pharmacological effects) may con- tinue to provide some of the reinforcenent. So it is with ciga- rettes - it is a matter of degree. Russell, Peto and Patel (1974) investigated nm4tives for smoking in two groups - one camposed of "normal" smokers, the other an ad- dicted group of heavy smokers attending a witthdxaeaall clinic. A factor analysis of their responses to a questionnaire separated a "pharmacological addiction" dimension fram the sensorinotor, indul- gent,and psychosocial factors. The sensorim»ter and indulgent fac- tors appeared to be related to the individual's ability to experi- ence pleasure or,its enhancement by smoking and to the act of man- ipulating the cigarette. 7he psychosocial.,factor reflected associ- atian 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 IHorn 1969; Mc Kennell 1970) an addictive dimension repeatedly emezges, but is always acoompanied by nonpharmacological factors. Iiowever, the mez+e presmzce of non- pharmacological factors in the maintenance of smoking does not serve to distinguish cigarette smoking fram other drug-aaing behaviors. Social reinforcers and symbolic aspects of the drug-taking behavior are also postulated to play a major role in the developnsnt of a variety of drug-using behaviors and, indeed, of deviant behaviors in general (Jessor and Jessor 1977). Again, the objective here is to point to parallels rather than to survey the literature. PHARNACO?MCAL FAC'1C42S IN OCtTPIIVI]ID USE For many years researchers'hanre+ assused that, afte= smoking has been initiated through psyehosocial factors, the behaniar beatmes habitual because the pharmacological effects of nicotine are rein- forcing (for references eee Ejrup 1965; Larson and Silvette 1971 and 1975= Jarvik 1973). Russell (1971 and 1976) has emphasized that a ama7.l "bolus" of nicotine reaches the brain within seconds after a puff froam a tobacco cigarette is i.nhaled. If nicotine is a reinforcer, then the hiaidreds of puffs inhaled each day should produce a well-established puff-inhalatien habit. There appears to be support for the viedv that it is, indeed, nicotine which is the major reinforcing eonponeet in cigarette smoking (although it may not be the only reinforcer). tdien nicotine and tar content are varied independently, it is the nicotine content that is eorre- lated with ratings of strength and satisfactian (Goldfarb et al. 1976). Men provided with lear or rnn-nieotine cigarettes, I i 7

1. most smokers oanglain bitterly or refuse to cositinne smoking them (sm Jarvik 1973). Nevertheless, reliable laboratory evidence that nicotine is a reinforcer of drug-taking behavior has been more dif- ficult to develop than cxitparable evidence for drugs like morphine, anQtietamine or cocaine. In contrast to the latter drugs, which anima].s will self-aaninister over a wide range of doses, an4nall self-administration of nicotine has been more difficult to induce (however, see Hanson, this volume). When it does oocur, it appears to be a less powerful reinforcer of behavior than drugs suah as cocaine and amphetatnine, at least as judged by the nurber of lever presses that the animal will aeke for a single dose of nicotine (Yanagita 1976). Nicotine has both peripheral and central effects. The pgeri.pheral effects, such as inhibition of stansch eontractions, aeceleration of heart rate, release of epinephrine fian the adrenal gland, and effects mediated by periphera]l release of noradrenaline do not seee to be of major inQortance in reinforcing sndcing. Most of these can be blocked without altering the psychological effects in man (Carruthers 1976). The central effects are obniously more relevant. But which ones? Nicotine appears to produce nmultiple effects -- and in this respect the problem of identifying the site of the re- inforcing effects of nicotine is not uilike the problem of deter- mining which of the nultiple effects produced by the opioids or alcdhol are responsible for their reinforcing properties. In man, nicotine produces an alerting pattern in the EHG and behavioral arousal (Danino 1973; Larson and Silvette 1975). It also stinulates release of a nunber of hormanal snbstanoes from the CNS (Husain et al. 1975; Winternitz and Quillen 1977; CCryer et al. 1976). Ani- nel studies indicate that nicotine releases norepinephrine and dopa- mine frcm brain tissue (See Goodman 1974; Larson and Silvette 1975; Russell 1976). Depending on the dose, it mny increase or decrease the release of acetylcholine (Axmitage, Hall, and Sellers 1969; Russell 1976). It may also affect brain,levels of serotonin. How- ever, with nicotine, as with other drugs, these effects on neuro- transtnitters do not tell us.how nicotine reinforces sndcing behavior. BIOIAGICAL FAGTCI2S IN CCNTINJID ANID DF.PENDfNr USE Many people drink alcahols a relatively sroall proportion beocme de- pendent.-'Not all of those who use opiates beoane dependent. With the latter drugs, those who becaone dependent tend to cane fran dis- turbed families where alcaholima and, often, a history of sociopathy or other psychiatric illness is prani.nent (See Jaffe 1977). <1ne at first suspects that it is the stress of growing up in such a family that leads to the later tendency to overuse aleohol or illicit drugs. However, the search for the basis of vulnerability to dependence on drugs has taken saae surprising turns over the last decade. For males, a genetically transmitted biological vulnerability to alco- holism, that may be independent of disturbed family background, ap- pears to be fairly well established (Scliuckit, Goodwin, and Winokur 1972; Goodwin et al. 1973s Geockwin 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 be- fore this discovery, sone opiate users maintaineci that they used TIMN 0152375

opiates not to get high but to feel rbrnal - not to alleviate with- drawal symptoans but to experience a state of noxma].ity that the ncnusPx enjoys without the benefit of exogenous substances. The existence of a syndrane characterized by relative inactivity in an endogenous opioid sysiten such that exogenous substances could at least theoretically act to "narnwlize" the user's feeling state has not yet been dennnstrated. Aithough the existence of a biolog- ical vulnerability to tabaceo dependence is also speculative, the possibility of such a biologicall substrate carmot be excluded. 4hil.e we are speculating, we might note that ane of the effects produced by cigarette smoking is a sharp rise in oortisol (Winteznitz and Quillen 1977; Cryer et al. 1976). Wb can assune that this ef- fect is mediated by release of ACTEI. Since it seems that a nale- cule of s-encbrphin is released each time a molecule of AClS is xe- leaseri (Giillemin et a1.1977) ve cannot rule out the possibility that cigarette smoking and release of S-endorphin are related. We might also note that aleoholics and opiate users are not anly more likely to be smdcers but they smdce maeh nnre 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 anly be an hypothesis at present - that each and every alcoholic, opiate user, and tobaceo smaker iaaild be able to functiaa better without the substance in questian. Oertainly we believe that there are mi].lians of crarent tobnceo users who will ftnction better if they stop smdcing, but that is nat the same as assuning that all will be able to give it up without cost in te.am of psycho- logical functioning. S,Ta need to know more about the where and the how of tobaeco's ef- fect an the brain and the rest of the central nervous systan. Ub also need to lQnow whether there are people who actually function better when smdcfng. 7he studies that have been carried out on heavy aedcers acutely deprived of nicotine do not anawer this question- PHYSICAL DbRMFiJCE ATD WITFDRAYM 7he existence of physicall dependence is an inference nede fraa the observatien of a stereotyped arithdraw®1 syndrome which oocurs when, a dix+anically adainishered drug is discontinued. 7he withdrawaaX syadraae following smoking cessation is not as well stuaied as other fot~as of withdrawal, but few who are )Qna+rle3geable doubt that it exists. It differs in time course and character fran that follow- ing alcohol or opiate deprivation. The onset of smoking withdrawal sympta: may occur within hours of the last cigarette or may be delayed for days. The synptans may last frcm days to moaths. Like the other withdrawal syndromes, thez+e are associated physiological changes, e.g., decreased heart rate, !:l1G slowing. In addition to craving for tobacoo, other spmptems have been reported following the cessation of snddng, such as restlessneas, dullness, sleep disturbances, gastrointestinal diatutbances, drowsiness, heedache, amnesia, and inpni.1 t of eoncentration, juagmsnt, and pspohamtor pcrfaYnoance (for references see Gdzilfor+d 1966; iarsco and Silvette 1975; Russell 1971; Jaffe and Jarvik 1978; Shiffnan and Jarvik 1976). 9 , TIMN 0152376