Tobacco Documents Online

5. Hollister LE, Johnson K, Boukhabza D, Gillespie HK. Aversive ef- fects of naltrexone in subjects not dependent on opiates. Drug Alco- hol Depend. 1981; 8:37-41. 6. Hughes JR, Hatsukami DK, Pickens RW, Krahn D, Malin S, Luknic A. Effect of nicotine on the tobacco withdrawal syndrome. Psy- chopharm. 1984; 83:82-87. 7. Jaffc JH, Kanzler M. Smoking as an addictive disorder. Pp. 4-23 in NA Krasnegor (Ed.) Cigarette Smokinq as a Dependence Process, Washing- ton, DC: U.S. Government Printing Office, NIDA Research Mono- graph, 1979. 8. Jarvis MJ, Raw M, Russell MAH, Feyerahend C. Randomized con- trolled trial of nicotine chewing gum. Brit. Med. J. 1982; 285:537-540. 9. Nemeth-Coslett R, Henningfield JE, O'Keeffe MK, Griffiths RR. Effects of inecamylamine on human cigarette smoking and subjec- tive ratings. Psychopharm. 1986; 88:420-425. 10. Polin, W. The role of the addictive process as a Key Step in causa- tion of all tobacco-related diseases. J. Am. Med. Assoc. 1984; 252:2874. 11. Resnick RB, Schuyten-Resnick E, Washton AM. Assessment of nar- cotic antagonists in the treatment of opioid dependence. Ann. Rev. Pharmacol. Toxicol. 1980; 20:463-474. 12. Russell MAH. Tobacco smoking and nicotine dependence. Pp. 1- 46 in RJ Gibbons, Y Israel, H Kalant, RE Popham, W Schmidt, RG Smart (Eds.) Research Advances in Alcohol and Drug Problems, New York: Wiley, 1976. 13. Russell MAH, Merrirnan R, Stapleton J, Taylor W. Effect of nico- tine chewing gmn as an adjunct to general practitioners' advice against smoking. Brit. Med. J. 1983; 287:1782-1785. 14. Schneider NG, Jarvik ME. Nicotine gum vs. placebo gum: Com- parisons of withdrawal symptoms and success rates. Pp. 83-101 in J Grabowski, SM Hall (Eds.) Pharmacological Adjuncts in Smoking Cessation, Washington, DC: U.S. Government Printing Office, NIDA Research Monograph 53, DHHS Pub. No. (ADM)85-1333, 1979. 15. Tennant FS, Tarver AL. Withdrawal from nicotine dependence us- ing niecamylamine: Comparison of threc-week and six-wcek dosage schedules. Pp. 291-297 in LS Harris (Ed.) Problems of Drug Dependence 1984, Washington, DC: U.S. Government Printing Office, NIDA Research Monograph 55, DHHS Pub. No. (ADM)85-1393, 1985. 16. Washton AM, Gold MS, Pottash AC. Naltrexonc in addicted phy- sicians and business executives. Pp. 185-190 in LS Harris (Ed.) Problems of Dri±g Dependence 1984, Washington, DC: U.S. Govern- ment Printing Office, NIDA Research Monograph 55, DHHS Pub. No. (ADM)85-1393, 1985. 17. West RJ, Jarvis MJ, Russell MAH, Carruthers ME, Feyerabend C. Nicotine replacement on cigarette withdrawal syndrome. Brit. J. Ad- dict. 1984; 79:215-219. 18. Wikler A. Opioid Dependence: Mechanisms and Treatment. New York: Plenum Press, 1980. 9 8

II: Smoking Behavior and Tobacco Dependence 00 fA ~ ®

Overview: Smoking Behavior and Tobacco Dependence Ellen R. Gritz, Ph.D. Director, Division of Cancer Control Jonsson Comprehensive Cancer Center University of California, Los Angeles Introduction In 1985, biomedical and social scientists have at their command the most sophisticated research techniques ever developed to study the phar- macological and psychoactive properties of chemical-containing sub- stances. The papers presented in this section summarize widely accept- ed findings regarding the dependence-producing properties of nicotine and the psychosocial factors influencing regular cigarette smoking. However, defining cigarette smoking as a form of substance dependence, or addiction, does not occur solely in the context of science and medi- cine. It has profound consequences for society in sociocultural, economic, legal and political contexts, and thus implications for public policy. Remember, we are discussing the dependence-producing properties of a self-administered substance that is the leading cause of premature death and disease in the U.S. today. Before introducing the three papers which constitute this section, a brief historical survey of tobacco may broaden our understanding of this public health perspective. Tobacco use in society Tobacco, native to the western hemisphere, was well integrated into the cultures of the South, Central and North American peoples when European explorers first reached our shores in the 15th and 16th centu- ries. An early record of tobacco use is depicted on a Mayan stone monu- ment in the remote Yucatan site of Palenque (c. 600-900 A.D.): "God L smoking a large cigar" portrays a man-figure taking in smoke in a magico- religious representation (11). The gods and spirits, it is widely held, crave tobacco smoke so intensively that they are unable to resist it.... Just as the tobacco shaman of the Warao requires tobacco smoke with tremendous physiological and psychological urgency, and is literally sick without it, so the gods await their gift of tobacco smoke with the craving of the addict, and will enter into mutually beneficial relationships with man so long as he is able to provide the drug.... No wonder that in the indigenous world tobacco was considered too sacred for secular or purely hedonistic use. (16, pp. 455-457) While we know little about the early specific ritual use of the tobacco plant (primarily the species Nicotiana rustica, higher in nicotine content than Nicotiana tabacum, our common commercial species), we do know it served as a ritual narcostimulant, especially in South America (16). The prominent anthropologist, Johannes Wilbert, has described the potent , pharmacologlc effects oI LIIe most ancient ivr,ii of tobacco ingestion, drinking a liquid preparation of tobacco boiled or steeped in water or macerated in spittle; alternatively, it could be licked from the fingers or from a stick dipped in the liquid or taken through the nose (16). The toxic effects of nicotine (e.g., pallor and tremor) were apparent after as few as two or three doses of the concentrated liquid and repeated ingestion of large doses was used by shamans to induce intensive dream visions, ac- companied by the more severe toxic effects of nausea, vomiting and even a comatose state. Tobacco was taken by itself or mixed with hallucino- gens such as Coca datura, Banisteriopsis caapi (yahuasca) or the cactus Trichocer- eus pachanoi. In contrast to its currently recognized role as a major cause of the leading killers, heart disease and cancer, tobacco served as a medicinal and hygenic agent in the folk medicine of many pre-Columbian cultures (11,16). Tobacco's reputation as a healing agent was carried to Europe. Nicot, the 16th century French ambassador to Lisbon after whom the tobacco ge- nus is named, defined Nicotiana in his French-Latin dictionary as follows (16): "This is an herb of marvelous virtue against wounds, ulcers, noli me tangere [lupus of the face], herpes, and all other things." And in mid-17th century Europe, the smoking and chewing of tobacco served as a prophylactic agent and therapeutic remedy for the plague (10,11). It is a matter of history how rapidly tobacco use spread around the world and became a part of the everyday culture of most societies, a.so- cially accepted recreational and habitual behavior. This occurred despite a variety of civil banning attempts, religious prohibitions and horrible punishments, including mutilation and the death penalty. Disapproval ot tobacco consumption was not based on known disease-producing ac- tions; in 1568, Benzoni called it" .. a pestiferous and wicked poison from the devil .."(11). Nor was it based on more than anecdotal reports of dependence. According to Las Casas in 1877, "I knew Spaniards who were accustomed to take tobacco, and, being reprimanded for it by telling 12 13

them it was vice, they replied that they were unable to cease using it. I do not know what pleasure or benefit they found in it" (11). Thus, the policy governing licit use of tobacco dcpended upon the attitudes and beliefs of governmental and/or religious leaders. Of course, economic fac- tors were important then, as now, for sales and revenue purposes (taxa- tion), only the stakes arc much higher in the 20th century. High tar and nicotine cigarettes, those with high dependence-producing potential, are aggressively marketed in the developing countries by American and Eu- ropean tobacco companies and the growing of tobacco as a major cash crop is encouraged (2,3). Tobacco dependence This discussion brings us to the 20th century, when an exploration of the pharmacologic properties of nicotine was undertaken and the role of nicotine as a reinforcing and dependence-producing pharmacologic agent first became recognized. The powerful range of effects of tobacco on the central nervous system, peripheral nervous system and directly upon major body organs is largely attributed to nicotine, which is respon- sible for about 95% of the total alkaloid content in tobacco and is the most powerful alkaloid (5,6). However, the scientific study and dcfini- tion of nicotine dependence occurred much later than the investigation of the pharmacodynamics and physiologic actions of the chernical. Indced, the landmark Report of the Surgeon General in 1964, while estab- lishing the causal relationship between smoking and lung cancer, was only able to term smoking an "habituation" (15). Beginning in the early 1970s, the role of nicotine as a primary rein- forcer in smoking behavior was seriously proposed, supporting scicn- tific evidence brought forth, and the dependence-producing nature of cigarette smoking discussed (7,9,12,13,14). A major issue in the consider- ation of dependence was the similarities and differences between cigarette smoking and other well known drugs of abuse, such as alcohol, heroin and barbiturates (8). That issue, at least on a medical decision-making level, was resolved in 1980 by the American Psychiatric Association in the Diagnostic and Statistical Manual (f Mental Disorders (DSM-III). That prestigious medical association established a Tobacco Dependence Disorder, which located cigarette smoking in the category of Substance Use Disorders and re- quired evidence of tolerance or withdrawal as part of the diagnostic criteria (1). Impairment in social or occupational functioning, while a potential consequence of the reaction of others to smoking, is not a direct effect of tobacco use and so was excluded from the definition, as was the concept of tobacco dependence as substance abuse. The essential features of the Tobacco Dependence Disorder are continuous use of tobacco for at least one month with either: (1) unsuccessful attempts to stop or significantly reduce the arnount of tobacco use on a permanent basis; (2) the development of Tobacco Withdrawal; or (3) the presence of a serious physical dis- order (e.g., respiratory or cardiovascular disease) that the individu- al knows is exacerbated by tobacco use (1, p. 178). [The Tobacco Withdrawal Syndrome was separately defined and included among the Organic Mental Disorders in the DSM-III.]. The American Psychiatric Association was careful to qualify its defini- tion of Tobacco Dependence so that dysphoria or illness in connection with the behavior was a necessary criterion: In practice, this diagnosis will be given only when the individu- al is seeking professional help to stop smoking, or, in thc judg- nunt of the diagnostician, the use of tobacco is seriously affect- ing the individual's physical health. It should also be noted that a heavy smoker who has never tried to stop smoking, who has never developed Tobacco Withdrawal, and who has no tobacco- related serious disorder, according to the criteria in this manual, does not have the disorder of Tobacco Dependence, even though physiologically the individual is almost certainly dependent on tobacco (1, pp. 176-177). Scientific evidence for tobacco dependence There are clearly some social and policy-directed interpretations im- plicit in this discussion of the syndrome. The APA was establishing a criterion that stipulated that if his/her smoking wasn't bothering the smok- cr, either in terms of health or behavior (regarding stopping), then the diagnosis of a dependency disorder was not warranted. The scientific determination of the criteria for tobacco dependence has continued to progress and, in particular, the Addiction Research Center of the National Institute on Drug Abuse has conducted a series of care- ful studies comparing nicotine and smoking to a variety of drugs of abuse. The conclusion which has emerged from this research is a strong state- ment of the dependence-producing properties of nicotine. Jack Henning- field, a noted scientist in this area, will present the findings of these studies. His multifaceted discussion of dependence will include: the orderliness ofsmoking behavior and its sensitivity to nicotine i>> nipulations; its dis- criminability, psychoactivity, reinforcing and euphoriant properties; and its physiologic dependence potential. 14 15

The second presenter in this section is Ovide Pomerleau, who has ex- plored in his research the ways in which nicotine and smoking may pro- vide direct physiological and psychological reinforcement, independent of the relief of withdrawal. In this biobehavioral conceptualization of smoking, he discusses both the positive and negative reinforcing conse- quences of smoking. The former include pleasure and its enhancement, the facilitation of task performance and the improvement of memory; the latter include the reduction of anxiety and tension, antinociception, the avoidance of weight gain and the relief of nicotine withdrawal. Dr. Pomerleau also outlines the putative neuroregulatory mechanisms for these reinforcing actions in an intriguing linking together of the multi- ple chemical systems governing our brains and behavior. Both Drs. Henningfield and Pomerleau have been careful to cmpha- size the complexity of smoking behavior and its multifactorial nature. Saul Shiffman develops this sector of the overall diagram, pointing out the interrelationship and interaction between pharmacologic and psy- chosocial factors in smoking. His paper concentrates on two issues: the role of health beliefs in continued smoking and motivation to stop; and the role of stress as it may facilitate the initiation of smoking and impede cessation. Dr. Shiffman will illustrate his discussion with findings from his own research on the situational and affective analysis of relapse crises and on successful and unsuccessful coping mechanisms. He points to the increased effectiveness of combining the pharmacologic agent and a be- havioral program in studies evaluating nicotine chewing gurrr as an ad- junct in smoking cessation treatment. Conclusion In concluding this overview, let me offer a few remarks on the policy implications of defining tobacco smoking in terms of nicotine depen- dence. First of all, underscoring the medical aspect of nicotine depen- dence by placing a treatment tool (a prescription product) solely under the control of physicians/dentists can be both a blessing and a curse. For the first time, practitioners have an agent in their pharmacopcia to treat smoking whic lriias survived the stringent tests of placebo-controlled de- signs. Nicotine gum and, possibly, other new pharmacologic substitutes currently being developed, provide a potentially effective smoking- intervention tool. Formerly, many practitioners felt they lacked the cotn- petence to treat or counsel patients in smoking cessation. On the other hand, the dangers of providing a "magic bullet;' at least in the patient's eyes, loom large; hard work and behavioral/psychosocial learning and practice are still an integral part of every successful smoking cessation effort. If too much faith or emphasis is placed upon this tool, then both physicians and patients can become discouraged when the effort is difficult or initially unsuccessful. Both may fail to recognize the complexity of the disorder and the need for a "coping" model rather than a "mastery" model in treatment strategy. Second, there are policy implications for third party reimbursers of medical expenses. Providers of treatment for nicotine dependence, such as physicians and psychologists, should receive reimbursement at a rate comparable to treatment for other medical and mental health conditions. Certainly the dollar expenditure for treating smoking dependence is ex- trao_rdinarily cost-effective compared with that for treating lung cancer, not to mention the inestimable price of human suffering. Third, the widespread acceptance of tobacco dependence may have pro- found implications for the tobacco litigation being conducted in this coun- try (4). Dependence introduces a non-voluntary quality into smoking be- havior; this is especially poignant when one considers that most smoking initiation occurs in the teenage years when adolescents consider them- selves healthy and invulnerable to the diseases of later life, no matter what the cause. The tobacco industry is firmly opposed to acknowledging tobacco dependence and worked long and hard to have such a warning removed from the set of new Surgeon General's rotational warnings on cigarette packages. Finally, the inclusion of tobacco use among the dependence-producing behaviors carries powerful implications for substance abuse prevention programs with youth. It means we have the charge to educate and arm vulnerable adolescents against the dangers of tobacco as a companion and prototype of drugs of abuse, as a conveyor of adverse health effects both immediately and distantly in time, and finally, as perhaps the most in- sidious form of substance dependence they may ever face in their lives. This charge alone, if carried out successfully, can help us attain the Sur- geon General's goal of producing a smokcfree society in the year 2000. References 1. American Psychiatric Association. Diagnostic and Statistical Manual, Third Edition. Washington, DC: American Psychiatric Association, 1980. 2. Canadian Council on Smoking and Health. Proceedings on the 5th World Conference on Smoking and Health, Volumes 1 and 2. Win- nipeg, Canada, 1983. 3. Currie K, and Ray L. Going up in smoke: The case of British Ameri- can Tobacco in Kenya. Social Sci. & Med. 1984; 19(11):1131-1139. 16 17

4. Garner DA. Cigarette dependency and civil liability: A modest proposal. Southern Cal f Law Review 1980; 53:1423-1465. 5. Goodman AG, Goodman LS, Gilman A. (Eds.) The Pharmacological Basis of Therapeutics, Sixth Edition. New York: MacMillan, 1980. 6. Gorrod JW Jenner P. The metabolism of tobacco alkaloids. Pp. 35- 78 in WJ Hayes, Jr. (Ed.) Essays in Toxicology, Volume 6. New York: Academic Press, 1975. 7. Gritz ER. Smoking behavior and tobacco abuse. Pp. 91-158 in NK Mello (Ed.) Advances in Substance Abuse. Greenwich, CT JAI Press, 1980. 8. Jaffe JH, Kanzler M. Smoking as an addictive disorder. Pp. 4-23 in NA Krasnegor (Ed.) Cigarette Smoking as a Dependence Process. NIDA Research Monograph 23. Rockville, MD: Department of Health, Education, and Welfare. PHS.ADAMHA.NIDA, 1979. 9. Jarvik ME. The role of nicotine in the smoking habit. Pp. 155-190 in WA Hunt (Ed.) Learning Mechanisms in Smoking. Chicago: Aldine, 1970. 10. Laufer B. Introduction of Tobacco into Europe. Chicago: Field Museum of National History, Anthropology Leaflet No. 19, 1924. 11. Robicsek F. The Smoking Gods. Norman, OK: University of Okla- homa Press, 1978. 12. Russell MAH. Cigarette smoking: Natural history of a dependence disorder. Brit. J. Med. Psych. 1971; 44:1-16. 13. Russell MAH. Tobacco smoking and nicotine dependence. Pp. 1-47 in RJ Gibbons, Y Israel, H Kalant, RE Popham, W Schmidt, RG Smart (Eds.) Research Advances in Alcohol and Drug Problems. New York: Wiley, 1976. 14. U.S. Dcpartment of Health, Education, and Welfare. NA Krasnegor (Ed.) CiXarette Smoking as a Dependence Process. NIDA Research Mono- graph 23. Rockville, MD: Department of Health, Education, and Wel- fare. PHS.ADAMHA.NIDA, 1979. 15. U.S. Public Health Service. Smoking and Health. Report of the Advi- sory Committee to the Surgeon General of the Public Health Serv- ice. Washington, DC: U.S. Department of Health, Education, and Welfare, Public Health Service Publication No. 1103, 1964. 16. Wilbert J. Magico-religious use of tobacco among South American Indians. Pp. 439-461 in V Rubin (Ed.) Cannabis and Culture. The Hague: Mouton, 1975. How Tobacco Produces Drug Dependence Jack E. Henningfield, Ph.D. Chief, Biology of Dependence and Abuse Potential Assessment Laboratory Addiction Research Center National Institute on Drug Abuse and Assistant Professor of Behavioral Biology Department of Psychiatry and Behavioral Sciences The,Johns Hopkins [Iniversity School cf Medicine Baltimore, Maryland Introduction The main purpose of this paper is to summarize some of the data which reveal tobacco use to be a dependence process and nicotine as a model dependence-producing drug in order to show the mechanism of tobac- co dependence. On the one hand, the mechanism of tobacco dependence is quite simple: when tobacco products are used as advertised by manufac- turers (and most consumers actually use them this way), nicotine is de- livered to the central nervous system; repeated use then leads to nicotine dependence. On the other hand, any form of drug dependence is a conr plex interaction of pharmacologic and nonpharrnaeologic factors in which the relative contribution of each factor may vary. An appreciation of the complexities is useful in understanding the biological process of tobacco dependence and may be necessary in the development of effective treatments. Tobacco use and cocaine use. To better understand tobacco depen- dence, it may be useful to place it in the context of another dependence process: cocaine dependence. Such a perspective provides a variety of in- teresting issues to consider when discussing why people use tobacco. If ten scientists, clinicians, and cocaine users were asked to explain why de- pendence to cocaine is so powerful, they would probably provide ten different reasons. Among them, they might say that cocaine is a power- ful reinforcer for animals and humans; it is a powerful cuphoriant; it en- hances mood and affect; it enhances performance on a variety of tasks; it controls behavior via its effects on catecholamines; compulsive 18 19

~10 cocaine users have personality defects which make them vulnerable to dependence; and once tolerant to cocaine, abstinence is unpleasant for users and is to be avoided at all costs. Alternatively, some might say that the process is essentially nonpharmacologic because some users do not have difficulty controlling or ending their patterns of use. There are many other reasons that might be given for the use of co- caine. Most of these explanations are not mutually exclusive: each one may contribute to any individual case of cocaine dependence. A similar illustration could be made for heroin, alcohol and barbiturates. It is now well-established that tolerance may develop to the intoxicating and de- bilitating effects of most drugs of abuse; physical dependence and with- drawal are neither necessary nor sufficient to produce compulsive drug use; and the effects of drugs that lead to their compulsive use arc diverse and not necessarily apparent to an observer. A few other observations about patterns of cocaine use may help shed some light on the extent and perniciousness of tobacco dependence. In just a few decades, we have seen the social attitude regarding cocaine use shift from relatively limited to a significant public health concern. Why? As cocaine use becomes widespread and continues to increase, cocaine- related emergency room admissions and deaths have dramatically in- creased. Additionally, there now exists a growing and vocal population of patients seeking treatment for a disorder over which they have little control. What brought about this drastic change? The pharmacology of cocaine has not changed. Rather, a highly addictive drug with perceived low toxicity became rnore widely available and socially acceptable, and its relative price declined, a process not dissimilar to that of tobacco in the first few decades of the Twentieth Century. Overview and definitions. We will review the data that now con- clusively show that tobacco use leads to nicotine dependence. When pat- terns of nicotine use are surveyed in the context of other drugs of de- pendence, it is evident that nicotine is more similar to other drugs than it is different from them. Some of these similarities will be described in the next section of this paper. To determine that a chemical can control the behavior of a potential user, there are relatively standard methods of testing used in studies with both human and animal subjects: the results of recent studies will be described later in this paper. Finally, a few in]- plications of these observations for the pharmacologic treatment of tobac- co dependence will be offered. The approach taken here is an empirical or descriptive approach in which tobacco/nicotine are characterized with respect to other substances of abuse, not necessarily with respect to any particular definition of a 20 dependence-producing substance. This course is taken because, while defi- iutions will continue to evolve, the pharmacology of known substances will not. In other words, as will be described later, nicotine is known to be a dependence-producing substance, not simply because it qualifies on the basis of prevalent definitions of dependence (13), but rather because its effects on critical measures are sitnilar to those of known dependence- producing substances, such as heroin, cocaine, and alcohol. For the purposes of the discussion at hand, it is helpful to define a few terms whose usages vary widely. Drug dependence or drug abuse: substance- seeking behavior that is controlled, in part, by the central nervous sys- tern activity of a constituent drug; nonpharmacologic factors may be oper- ative; tolerance and withdrawal are neither necessary nor sufficient. The term drug addiction is sometimes used interchangeably with drug depen- dence, but will not be used in this paper because of its more widespread imprecise usage that includes non-drug-mediated habitual behavior. De- pendence potential: the direct effects of a drug that lead to tolerance and to physical dependence. Tolerance is assessed by the occurrence of diminished responsiveness to the drug and physical dependence is assessed by a syn- drome of withdrawal symptoms when drug administration is terminat- ed. Abuse liability: the effects of the drug which result in its control over behavior and hence in its control over self-administration of the drug, often in the face of mounting costs and adverse effects. Comparison of tobacco dependence to other forms of drug dependence Tobacco and its use are complex. Tobacco use is a common behavior which, at first blush, would seem very simple to study and to understand. On the contrary, as we now know, tobacco products themselves, like other drugs, are exceedingly complex mixtures of naturally occurring and syn- thesized substances which can obscure studies of the action of individu- al components. The drug-seeking behavior, which is the interface be- tween the substances and their effects, is no less complex and is the result of interaction among drug and non-drug factors. Tobacco use is an orderly and controlled behavior. Despite the complexities of tobacco usage, a systematic analysis reveals that the be- havior is orderly and lawfully determined by the same parameters that control other forms of drug self-administratiou. Though estimates vary, it has been demonstrated that one-third to two-thirds of all people who experimentally smoke as few as two cigarettes go on to become regular and dependent smokers (6). Moreover, a recent survey (conducted by 21

01N myself and colleagues at the Addiction Research Centcr-unpublished data) of patterns of development of dependence has shown that, with both cigarettes and smokeless forms of tobacco (as with other drugs of abuse) there is a marked escalation of dosage over time ("graduation") which may continue for several years before relative stability of intake occurs (Figure 1). Once patterns of smoking have stabilized, they become regular from day to day and even from cigarette to cigarette. For instance, when cigarette smokers are permitted to smoke in a laboratory situation that permits measurement with little external restraint or experimental interference, patterns of cigarette smoking resemble those of animals who self- administer stimulants such as amphetamine and cocaine. A microanaly- sis of patterns of puffing and inhaling similarly rcvcals an orderly and controlled behavior. Depriving cigarette smokers of cigarettes for inter- vals as brief as 60 minutes can result in increased cigarette smoking and increased preference for nicotine. Tobacco use is sensitive to nicotine dose manipulations. IDose can be clinically and experimentally varied in many ways. These methods in- clude changing the nicotine and/or tar level of the cigarette smoke, provid- ing nicotine by other routes of administration (e.g., 1 V, polacrilex or chewing gum), or blocking nicotine's actions at the ganglia with peripherally-acting (e.g., pentolinium) or centrally-acting (e.g., mecarnyla- mine) blockers (4). The general findings which have emerged from such studies may be summarized as follows: (1) nicotine dose is a functional determinant of tobacco intake; (2) when nicotine intake levels deviate from an upper and lower boundary, compensatory changes in tobacco self-administration occur (15); (3) pretreating cigarette smokers with nicotine by other routes of administration decreases tobacco self-adrninistration and/or reduces the level of preferred nicotine dose level; (4) pretreatment of cigarette smokers with mecamylamine, but not pentolinium, increases levels of tobacco self-administration and/or increases levels of preferred nicotine dose, showing that the effect is centrally mediated; (5) increasing the rate of nicotine excretion from the body by decreasing urinary pH levels increases the amount of tobacco smoked (see Bcnowitz in this volume). These findings are often lumped under the rubric "the nicotine dose titra- tion hypothesis." In spite of the data summarized above, however, the va- lidity of the titration hypothesis continues to be debated, and the out- come seems more dependent on the definitions used; therefore it may 22 DEPENDENCE PROCESS: DOSE GRADUATION 1 30 20 r_ Q 10 9 SMOKELESS `~ ---- - -----a --"ff- CIGARETTES 0 0 I r 0 1 2 3 4 5 6 7 8 YEARS OF TOBACCO USE 0 Figure 1. This figure shows a preliminary graph of results from a sur- vcy of smokeless tobacco users and cigarette smokers (unpublished data from the Addiction Research Center) regarding their daily tobacco in- take (shown on the y-axis) at various time points (shown on the x-axis), including and following their first day of tobacco use. Data from 32 sub- jects are presented for the smokeless tobacco function, and data from 13 representative subjects are presented for the cigarette function. The gradual escalation of dosage followed by relative stability is similar to that reported by persons dependent on alcohol, sedatives, stimulants and narcotics (opioids). 23

be most useful to simply discuss the phenomena in terms of dose-response relations as is done when other drugs of abuse are discussed. Nicotine has a significant physiologic dependence potential. An- other feature which nicotine shares with many other drugs of abuse is the development of tolerance and physiological dependence when the drug is repeatedly administered. While tolerance is not a factor that readily distinguishes drugs of abuse from non-abused drugs (e.g., chlorproma- zine), and physiologic dependence does not necessarily lead to abuse (e.g., most post-operative patients treated with narcotic analgesics do not sub- sequently abuse the drugs) these factors are nonetheless important to the understanding and treatment of drug dependence. Tolerance to drug effects is established either by the observation of a diminished response to repeated doses of a drug, or to the requirement for increasing doses to achieve the same effect. Tolerance to a variety of behavioral and physiologic effects of nicotine has been widely studied (2,18). More recently, it has been confirmed that tolerance also develops to those effects of nicotine considered critical to its abuse liability; namely, its psychoactive and euphoriant effects. For instance, in a study of in- travenous nicotine administration, when a subject was asked to rate the pleasurable effects from successive injections given at ten-minute inter- vals, scores decreased with serial injections (6). Tertnination of chronic nicotine administration is followed by an orderly syndrome of withdrawal phenomena which may include the following signs and symptoms: decreased heart rate, altered clectroencephalographic activity and evoked cortical potentials, increased desire to smoke, anxi- ety, irritability, difficulty concentrating, impaired cognitive performance abilities, headache, drowsiness, insomnia, gastrointestinal disturbances, decreased catecholarnine excretion, tremor and decreased basal metabolic rate. The syndrome may be reversed by nicotine replacement; the degree of reversal is dose-related such that low doses of nicotine may partially relieve withdrawal-related discomfort, and higher doses, or return to ad libitum tobacco use, may fully reverse the syndrome. The above materi- al is a composite of information available from several reviews (6,7), re- cently completed studies (11) and an unpublished series of studies from the Addiction Research Center. Taken together, these findings indicate that nicotine itself is critical to both the establishment and treatment of the syndrome. The studies confirm that a qualitatively similar syndrome of withdrawal occurs when repeated administration of cigarettes, smoke- less tobacco or nicotine gum is terminated, that the syndrome is charac- terized by behavioral and physiologic signs and symptoms, and that nico- tine gum (when administered correctly) can be used to treat withdrawal due to tobacco abstinence. Tobacco may produce useful effects. Tobacco, like many other sub- stances of abuse, produces effects often considered of utility or benefit to the user. Such effects are sometimes termed "therapeutic"; however, such a term may be misleading since (1) the most widely used forms of tobacco cause death and disease, and (2) it has not been clearly established to what degree the beneficial effects are direct actions of nicotine rather than a reversal of detrimental effects of withdrawal following long-term use of tobacco. In the nicotine dependent person nicotine can relieve anxi- ety and stress, can help control appetite and weight, alter mood and feeling state, and perhaps enhance performance and memory (5,7,15). In one of our recent studies of cognitive performance at the Addiction Research Center we found that performance on learned tasks and memory tests was significantly impaired following 8 to 12 hours of tobacco depriva- tion, and that such impairments could be reversed in dose-related fashion by administration of nicotine in the form of the polacrilex (unpublished data). Abuse liability of nicotine As the foregoing summary review has indicated, many effects of tobac- co and patterns of tobacco self-administration have much in common with prototypic substances of abuse and the patterns of behavior which they engender. At this point it is reasonable to question whether nico- tine itself can control the user's behavior in the same way that heroin and cocaine can control a user's behavior. In other words, is nicotine a drug with significant liability for abuse? Recent investigations using methods which were developed to quantitate the abuse liability of other substances such as cocaine and heroin have confirmed that nicotine does meet es- tablished criteria as a drug with significant liability for abuse. I will pro- vide a brief summary of these findings. Nicotine is discriminated by animals and is psychoactive in humans. The most prominent feature of abused drugs is that they produce effects in the central nervous system that change the way the person or animal feels or behaves; such studies conducted with animals are often termed tests for "discriminative effects" whereas such studies with humans are commonly termed tests for "psychoactivity" Several well-controlled animal discrimination studies have been conducted with nicotine. The findings may be sununarized as follows: (1) nicotine produces dose-related discritninable effects; (2) effects are blocked by centrally-acting, but not peripherally-acting, ganglionic blockers; (3) animals trained to identify 24 25

other drugs rarely "niistake" (generalize) nicotine for saline or a barbiturate, but may mistake nicotine for amphetamine (17). Analogous studies with human subjects produce similar findings. These arc as follows: (1) nicotine produced dose-related psychoactivity (dis- criminable effects); (2) effects were attenuated by centrally-acting, but not peripherally-acting, ganglionic blockers; (3) above threshold dose lev- els, persons with histories of polydrug abuse often identified nicotine in- jections as cocaine or amphetamine (10). Nicotine is a euphoriant for humans. Another effect of most drugs of abuse is that the substance serves as a euphoriant. For drug abuse lia- bility studies, euphoria is operationally defined and quantitated using structured questionnaires. The most widely used and validated question- naires are various forms of the Drug Liking scale of the Single Dose Ques- tionnaire, and the Morphine Benzedrine Group (Nll3G) scale of the Ad- diction Research Center Inventory (14). In one such drug abuse liability study, volunteer subjects were given multiple doses of nicotine, both in- travenously and in the form of tobacco smoke. The results were clear and consistent: nicotine adtninistration produced dose-related increases in eu- phoriant scale scores. In fact, as shown in Figure 2, nicotine produced a steep dose effect curve that was similar to curves produced by cocaine, amphetarnine and morphine, but not to curves produced by the nona- bused analgesic, zomeperac. Interestingly, as shown in the figure, despite the common assumption that sugar is an addictive substance, intravenous injections of glucose did not produce the effects characteristic of mor- phine, cocaine, or nicotine. Nicotine is a reinforcer for animals. By definition, drugs that are voluntarily self-administered are positive reinforcers or rewards; a corol- lary of this observation is that the ability of a drug to control the behavior of a user is related to its efficacy as a reinforcer. Reinforcing efficacy of drugs is assessed using "self-administration" studies, in which the organism is permitted to take the drug to allow better control of non-drug fac- tors; the drug is often available via the intravenous route. Drug self- administration studies using animals are accurate tests of the ability of a compound to control behavior, and it has now been demonstrated that nicotine functions, to some degree, as a positive reinforcer for five spe- cies of animals (8). Whereas results in some studies were equivocal, re- cent studies, most notably by Goldberg and his colleagues (8) have con- firrned that nicotine can function as a highly efficacious reinforcer in animals. 2 1 w 0 lz 0 U 0 w J 2 U U) 1 1- Z Q 0 _ Ir O tZ D w 2 1 0 ~--0 ~ P 1 8 MORPHINE L (sc) ZOMEPERAC L (PO) 1 1 16 32 L 30 r° I '-!~' P 200 400 800 2 NICOTINE ~ I- (IV) 1 0 - O ~ I I I P .75 1.5 3.0 d-AMPHETAMINE 2 1 I I I P .75 15 30 GLUCOSE L (IV) . 2 1 0 LO I I I P 10g 20g 40g DRUG DOSE (MG) Figure 2. This figure presents data from a series of abuse liability studies conducted primarily at the Addiction Research Center. The cocaine data are standardized and reported from a study conducted by Fischman (3). The glucose data arc recently collected and previously unpublished from the Addiction Research Center. The findings that Liking Scale scores are directly related to dose and exceed placebo values are important in iden- tifying dependence-producing drugs. Intravcnous nicotine produced the same elevated dose-response function as the representative narcotic (mor- phinc) arid a prototypic stimulant (d-amphetaminc). These data are also consistent with the negligible abuse liability of zomeperac. 26 27