Tobacco Documents Online

I I I I I I I I I I I Pharmacologic Basis and Treatment of Cigarette Smoking JACK E. HENNINGFIELD, Ph.D. --- - Data are reviewed which support the contention of the American Psychiatric Association and the U.S. Pub- lic Health Service that cigarette smokers may become addicted to nicotine. Available data indicate that 1) to- bacco use shares many factors in common with previ- ously studied forms of drug abuse-most notably, narcotic addiction, 2) the rate and pattern of cigarette smoking are partially determined by nicotine dose level, and 3) nicotine meets established criteria for a proto- typic drug of abuse. These findings have implications for the understanding and treatment not only of ciga- rette smoking but of other forms of drug abuse and psy- chiatric disorders in which tobacco use is a cofactor. (J Clin Psychiatry 45 [12, Sec. 21:24-34, 1984) FIGURE 1. Production and Fate of Cigarette Smoke Constit ents' The literature is replete with historical accounts, anec- dotes, and lore regarding the origins, use, and effects of tobacco.' The following legend has been passed down by the American Indians in various forms:2 There once was a great famine across all the land. There was no food to eat and the earth would yield no harvest. -Finally, the Great Spirit sent a naked female messenger to replenish the lands and save his people. Where she touched the land with her left hand, the earth turned green with corn and the people were nourished. Where she touched the land with her right hand, potatoes grew and the people's stomachs were full. Then she sat down; from her place of rest grew tobacco. There are various interpretations of this tale. Some hold that its origins mark tobacco as a curse, while others view it as a blessing, that just as potatoes and corn were food for the body, tobacco was food for the soul. In any case, the American Indians knew centuries ago what is now being discovered in laboratory studies-that tobacco is a sub- stance that alters mood and feeling states. This property is termed "psychoactivity." Further, it is now known that the critical psychoactive constituent of tobacco is nicotine, and that nicotine meets criteria for a drug of abuse. Why did it take so long to determine scientifically that tobacco contained a drug of abuse that is equivalent to.the cocaine in coca leaves and ethanol in alcoholic beverages? Part of the answer lies in the historical, social, and cultural context of tobacco use. Throughout the history of explora- From the Addiction Research Center, National Institute on Drug Abuse, and the Department of Psychiatry and Behavioral Sciences, 73u Johns Hopkins University School of Medicine. Reprint requests to: Jack E. Henningfield, Ph. D. , NIDA Addicriort Re- search Center, P0. Box 5180, Baltimore, MD 21224. 24 .CO. .CO •TAR CEJt TO LUNOS wHE RE ABSORRTION OCCURS AKORYTION 1ACTOI+ln . ~NNAtAT1pN ~ -AMO • iNNAlAT1ON DEITM • NNAIAT,ONDURATiON • W Oi SMORE • A{SORRTiON CNARACTERISTIC. OrINDIVIDUAICONSTITUENT: 'Reprinted, with permission, from Thompson and Dews r tion and development of the Americas, tobacco played substantial role in trading and economy. Although this rol diminished relative to other commodities, tobacco remain a $16 billion a year industry, and tobacco sales yield mor than $8 billion a year in tax revenues.' Cigarette smokin; became an important accoutrement for social interaction: and the "cigarette break" was as much a part of the militar and many private sector jobs as leave time. There wen practical and scientific impediments as well. Tobacco use is remarkably difficult to study in certaii respects, particularly in its most common form, cigarettf smoking. A schematic drawing of the cigarette smokinF process (see Figure 1) illustrates some of the complexitie~ involved. As shown in the figure, the most fundamenta variable of study-the dose of the ingested substance-i: difficult to measure. With most other forms of drug use this is a relatively simple procedure: the amount of mor phine per injection, of ethanol per drink, or of ampheta mine per tablet can be precisely specified and measured However, the nature and quantity of constituents in an, given puff of a cigarette is a function of multiple factors including cigarette constitution and inhalation parameter. Frequently, experiments designed to assess the role of nicc tine are confounded by the other constituents in th; smoke." Another problem is that, until the last few dec ades, there has not been a systematic technology for quanti. tating the subjective effects of drugs, or more specificall; their psychoactivity. Such a technology is available now however, that has been widely validated with a number c. substances and lends itself readily to the study of tobacco. Two other features of cigarette smoking behavior hinde research and also obscure the values of cigarette yields pro- vided by the Federal Trade Commission (FTC). First, be TOeACCOS/dOttE iSCOMfRISEDor I,IC,GAMETTE CONSTITUENTS •OROANIC MATTEF •NICOTiNIC ALkVEOIOS •ADDITIVES ANO /)i RY ROl YSIS RROOUCT S I

I I I I I I I I I I I I I I I I I J CLIN PSYCHIATRY 45:12 (SEC. 2) - DECEMBER 1984 havioral aspects of smoking differ across individuals and probably bear little resemblance to parameters set in FTC smoking machines (2-second-long, 35-mi puffs, taken at 1- minute intervals).' Second, cigarette smoking is an interac- tive process in which the parameters of each puff and subsequent inhalation may vary as a function of smoke fla- vor, heat, nicotine content, time since last cigarette, time since last puff, puff number, and so forth. These factors at least partially explain the apparently slow accumulation of findings from such an important area. The persistent use of tobacco despite numerous health warnings renders untenable the theory that cigarette smok- ing is a simple voluntary pleasure. This paper will summa- rize recent findings from studies on why people smoke, with emphasis placed on the pharmacologic aspects of the maintenance and treatment of cigarette smoking. In addi- tion, some implications of the current understanding of cig- arette smoking as it relates to psychiatry will be discussed. CIGARETTE SMOKING AND DRUG DEPENDENCE: COMMONALITIES The suggestion that cigarette smoking was a form of drug dependence was not initially based on direct tests of abuse liability or dependence potential but on the observa- tion of the many commonalities between cigarette smoking and known forms of drug abuse. Because the prototypic form of drug abuse involves the opiates, opioid dependence is the standard by which cigarette smoking should be evalu- ated. The following is a brief systematic comparison of cigarette smoking and drug abuse, with emphasis on the commonalities between opioid dependence and cigarette smoking."' Historical-Regulatory As with many drugs of abuse, the literature ranges from advocating the use of tobacco for medicinal purposes to de- nouncing it as a precursor to other drug use and/or as an indication of moral decay. For example, in 1885 The New York Times editorialized; "The decadence of Spain began when the Spaniards adopted cigarettes and if this pernicious habit obtains among adult Americans the ruin of the Repub- lic is close in hand"10 Attempts to eliminate tobacco use from any culture into which it has been introduced have been unsuccessful. Between 1895 and 1921, 14 states com- pletely banned the use of cigarettes, and the remaining states (except Texas) had laws that regulated the use of ciga- rettes and their possession by minors. These attempts to control tobacco use by legislation were as ineffective as ef- forts by previous governments.' An apparent exception to this trend is the moderate success in the selective restriction of cigarette smoking in public areas in the United States." Acquisition and Maintenance Most smokers begin smoking at an early age, smoke for some time period, attempt to quit, then relapse. This devel- CIGARE'TTE SMOKING opmental pattern shares a number of-similarities with de- pendence-producing drugs. For exampCe, both the opium and tobacco smoking habits develop rapidly. Cocteau's dic- tum regarding opium smoking, that "he who has smoked will smoke," is equally true for tobacco.'2 In both cases, simple exposure to the substance ("experimentation") usu- ally leads to chronic use." To the extent that experimenta- tion leads to ultimate chronic use, tobacco appears to have an "addictive potential" similar to that of opium. Social Factors Social pressure from peers and family members is also critical in initiating the process of dependence on tobacco and other abused substances.116 Adolescents who smoke are more likely to have friends who smoke, siblings who smoke, and parents who smoke." Conversely, a prime pre- dictor of treatment success is the presence of friends and/or peers who have been successfully treated for their depen- dency.'"" The social acceptability of tobacco use may be a major factor in its initial use in many cases. In a study at the Addiction Research Center, Haertzen (personal communi- cation) found that use of cigarettes, as well as alcohol and coffee, was generally supported by parents of drug users, whereas use of illicit substances was discouraged. Relapse Hunt and his co-workers have revealed striking similari- ties among cigarette smoking, alcoholism, and opioid de- pendence in terms of the temporal pattern of relapse."II As shown in Figure 2, the rate of relapse for all three sub- stances is highest during the first few months after quitting and then gradually tapers off, with only 25% abstaining at 6 months. Another parallel has to do with the types of situa- tions in which the relapse episodes occur. Marlatt and Gor- don" and ShiffmanZ` recently found similar situational and contextual factors present during the relapse episodes of al- coholics, tobacco smokers, and heroin addicts. Tolerance and Physiologic Dependence Tolerance develops to many of the effects of tobacco and nicotine, and it is plausible that a mild form of physiologic dependence occurs. The phenomenon of nicotine and to- bacco smoke tolerance has been extensively studied.u Fol- lowing several hours of deprivation (e.g., overnight sleep), tolerance is diminished and a person is sensitive to the ef- fects of nicotine." One consequence of this rapid loss of tolerance is that the first cigarettes of the day, or the first few of a series of nicotine injections, have the strongest and most pleasurable effects. Figure 3 shows the development of tolerance to the self-reported positive effects ("eupho- ria") produced by repeated nicotine injections.=' The sub- ject was given nicotine injections at 10 minute intervals until he terminated the test. Prior to one test, the subject was given 10 mg of the ganglionic blocker mecanmylamine HCI. Mecamylamine attenuated the peak effects but not the course of development of tolerance. 1 25

...s.R+e...~~ J CL1N PSYCHIATRY 45:12 (SEC. 2) - DECEMBER 1984 HENNINGFIELD I I I I I I I I I I I I FIGURE 2. Relapse Rates After Achievement of Abstinence from Tobacco, Alcohol, or Heroin' 75 m Q 50 25 • HEROIN • SMOKING o ALCOHOL oL i i i.J I 3 6 9 12 2 WEEKS MONTHS 'Reprinted, with permission, from Hunt et al.'0 Abstinence from cigarette smoking may be accompa- nied by mild physiologic changes, such as irkcreased heart rate, hand tremor, skin temperature, and electrophysiologic responses,Z'"9 and subjective changes, such as increased de- sire to smoke and irritabiliry.Z"0 Findings suggesting that nicotine is critical to these effects are that administration of nicotine-delivering chewing gum reduces abstinence-asso- ciated discomfort and the desire to smoke."'" Preliminary investigations of the possible occurrence of an abstinence- induced withrawal syndrome indicate that clinical aspects of the syndrome are very mild compared to those which may accompany abstinence from opioids, sedatives, and al- cohol in compulsive users of these drugs.'Z'" It is plausible that tobacco abstinence more closely resembles cocaine ab- stinence rebound effects than an opioid-like withdrawal syndrome. Patterns of Drug Self-Administration One characteristic of drug dependence is that orderly patterns of administration develop which transcend individ- ual, and even species, differences. Tobacco use is no excep- tion: when relatively unrestricted, people" and nonhuman primates'S smoke in orderly patterns from day to day. Inter- estingly, these patterns resemble those of stimulant self-ad- ministration in animals which are free to self-inject the drug using an automated apparatus." This pattern differs from 26 FIGURE 3. Ratings of "Liking" One Minute After Nicotine Injec- tion (Triangles Indicate Pretreatment with 10 mg Mecamy- lamine)' - ~ 100r , izi H-ALB z I C~ ? 50~ k-1k, I ~ a ~- Pretreat ~. C-l" zl.*~ T ~ ~ I %-*~ 0 1 I I i i I I i I I I I i I I I 5 10 15 NICOTINE INJECTIONS(3.Omq) ' Reprinted, with permission, from Thompson and Dews." the "loading up" pattern seen when alcohol or sedatives are presented to animals following overnight abstinence." Deprivation Effects Another characteristic of substance abuse is that depri- vation of the substance increases the tendency for the sub- stance to be used when it becomes available. A laboratory study of smoking by volunteers showed that the tendency to smoke was directly related to the amount of time that the subjects were deprived of cigarettes." Orderly deprivation- satiation effects may even occur within the smoking of a single cigarette. For instance, the interval between puffs tends to increase and the duration of each puff tends to de- crease from the first to the last puff of the cigarette."'JE Implications of Commonalities At first blush, cigarette smoke and opioids appear to produce vastly differing effects: large doses of opioids can produce a debilitating sedation that is not produced by ciga- rette smoking. However, the effects which seem to define compulsive use of opioids and other drugs are shared with tobacco. These commonalities among phenomena associ- ated with use of tobacco and drugs of abuse provide com- pelling, yet circumstantial, evidence that tobacco use is an orderly and addictive form of behavior. These commonali- ties do not indicate which elements of tobacco smoke are critical to the behavior. The conceptual leap from addictive behavior to drug abuse or dependence can only be made or the basis of evidence that a specific psychoactive drug i: critical to the behavior. The next two sections will address these issues. REGULATION OF NICOTINE OR TOBACCO SMOKE INTAKE Many studies have assessed the extent to which cigarette smokers regulate their intake of smoke and thereby main• I

I I I I I I I I I I I I I I I I I I J CLIN PSYCHIATRY 45:12 (SEC. 2) - DECEMBER 1984 tain a consistent level of nicotine in the body.`' These stud- ies are important because 1) they help reveal the extent to which nicotine controls smoking behavior, and 2) there has been a trend toward the production and sale of cigarettes with lower tar and nicotine deliveries,M19 under the assump- tion that they are less harmful.°a" To the extent to which persons make compensatory changes in their smoking be- havior when nicotine levels of cigarettes are decreased, the possible health benefits of lower tar and nicotine cigarettes will be negated. Manipulation of Nicotine Delivery The most common paradigm used to assess nicotine reg- ulation has been to alter the nicotine delivery of the ciga- rette and then determine whether there are compensatory changes in cigarette smoking behavior. Compensation is typically measured by 1) changes in the number of ciga- rettes smoked, 2) changes in patterns of puffing and inhal- ing (i.e., smoking topography), or 3) changes in various biochemical measures of smoke intake (i.e., expired air carbon monoxide, saliva thiocyanate, plasma cotinine)." Three exhaustive reviews of studies on nicotine regula- tion have been published in the last 3 years.""' In brief, Gritz" concluded that "Almost all of the studies demon- strate some increase in smoking as cigarette nicotine co:i., tent falls below accustomed levels, and a decrease in smoking when cigarette nicotine content is unusually high." Moss and Prue' and McMorrow and Foxx' also found that the majority of studies showed some degree of nicotine reg- ulation by smokers; however, they noted that several methodologic issues limited the conclusions that could be drawn. Foremost is the extent to which changes in smoking behavior produce corresponding changes in actual intake of nicotine. McMorrow and Foxx noted that the results of studies documenting changes in behavior more consistently supported the regulation hypothesis than did studies mea- suring actual changes in body nicotine levels. Furthermore, many studies have employed commer- cially available cigarettes (brand-switching); since such cigarettes differ in a number of ways other than nicotine level (i.e., tar delivery, taste), the extent to which nicotine is responsible for the changes in smoking behavior is not always clear. This issue is partially resolved by the use of cigarettes that vary the delivery of nicotine but not that of other constituents. Smoke Dilution with Ventilated Filters The results of studies utilizing smoke dilution devices (One-Step-at-a-Time) generally have been consistent with the results of the brand-switching studies. That is, moderate compensatory increases in smoking behavior occur as a function of smoke dilution, while physiologic measures yield less consistent data.`°-" For example, in the Hen- ningfield and Griffiths study," as smoke concentration was decreased by increasing the ventilation, the number of puffs per cigarette increased dramatically, while the number of CIGARETTE SMOKING cigarettes smoked changed only slightly, and expired air CO levels were variable but not significantly changed. Shortened Cigarettes Presenting subjects with shortened cigarettes varies the amount of smoke available per cigarette while holding con- stant other factors such as taste and smoke constituents. Chait and Griffiths'a presented smokers with either full or half-length cigarettes and assessed a variety of topography measures and expired air carbon monoxide levels over a 100-minute period. When given half-length cigarettes, sub- jects smoked 75% more cigarettes and made a number of complex adjustments in smoking topography (e.g., higher puffing rates). Through these mechanisms, subjects main- tained the same intake of smoke (as measured by CO levels) as when smoking full-length cigarettes (see also reference 49). Nicotine Preloading Studies Both oral and intravenous nicotine administration can decrease subsequent cigarette smoking in experimental set- tings in which c~garette smoking can occur relatively freely.`5 In cigarette smoking treatment programs, adminis- tradon of nicotine-delivering gum results in improved treat- ment efficacy as well as reduced cigarette smoking rates.SO'" These studies suggest that nicotine itself is critical to the rate at which cigarettes are smoked. Antagonist Studies Like the opioids, nicotine has a specific cellular site of action (viz., cholinergic nicotinic receptors). At least a par- tial blockade of nicotine's effects can be achieved by admin- istration of nicotine antagonists. When mecamylamine (a centrally acting nicotinic blocker) was given to smokers who were not trying to quit smoking (and were presumably trying to maintain their usual nicotine intake), the subjects increased their smoking rates.'=" Overview of the Nicotine Regulation Data Although controversy exists, the data reviewed here generally support the hypothesis that nicotine is one of the major functional constituents in tobacco smoke. In addi- tion, the results of these studies are comparable to those obtained in similarly conducted studies with other drugs. For instance, when drug dose is increased for either ani- mals or humans which are free to self-administer the drug, there are compensatory reductions in number of doses taken, although actual drug intake tends to increase some- what; opposite results are obtained when drug dose is de- creased.Z'''° In addition, when drug preloading strategies are used in treatment settings (e.g., methadone maintenance for opioid dependence), supplemental drug use continues to oc- cur, providing a further point of similarity in the behavioral pharmacology of nicotine with drugs known to be abused. That is, the rate of self-administration of the drug is not a simple function of drug dose or overall drug intake. 27

I I I I I I I I I I I I I I I I J CLIN PSYCHIATRY 45:12 (SEC. 2) - DECEMBER 1984 ABUSE LIABILITY OF NICOTINE The preceding sections have shown that tobacco use may occur as an addictive behavior that shares many fea- tures of prototypic forms of drug dependence, and evidence has been provided that nicotine plays a functional role in the behavior. However, if nicotine's role is like that of the CNS-affecting agents present in substances of abuse (e.g., the cocaine in coca leaves), then nicotine, in the absence of the multitude of stimuli associated with cigarette smoking, should be an abusable substance. Objective methods for abuse liability assessment were available before the recent interest in nicotine.' With consideration given to the fact that nicotine has more rapid effects than many other drugs of abuse, these methods were readily adapted to studies of the abuse potential of nicotine." A concept central to many discussions of drug abuse is that the substance produces "damage" or "debilitation." This aspect of tobacco de- pendence will not be addressed here as there are extensive data indicating the actual toxicity of tobacco, and the wide- spread perception by smokers that their habit is harmful." Two kinds of studies are critical in the assessment of the abuse potential of a new compound. The first type of study is called the "single-dose" or "abuse potential" study since ~ MO SC)INE ~ I eUPSL fVORP~NE I PEq~AZOCIN: FIGURE 4. Liking Scale Scores of the Single-Dose Question- naire' P IS 30 r*_ 0•AMPHETAMIHE (SC) ra / P 7.5 15 30 PENTOeARDITAL (PO) - I 0 P 1 2 0 / P+T • P 40 00 40+ 50T A-9-THC (P0) • , J , i P,75 I.6 3 P 5 10 20 ~. CHLORDIAZEPOXIDE (PO) ZOMEPIRAC (P0) P 120 240 P 50 100 200 DRUG DOSE (mg) • ..-.-1' I P 200 400 800 'N ranges from 6 (pentobarbital and chlordiazepoxide) to 13 (d-am- phetamine). The high dose of each drug except zomepirac pro- duced significant (p <.05) increases in scores above placebo. Data are peak response, which occurred from =1 minute (nicotine) to 5 hours (buprenorphine). Morphine and zomepirac data are from the same group of subjects as pentobarbital and chlordiazepoxide data. The "P + T" point on the pentazocine graph is the score given to 40 mg pentazocine combined with 50 mg tripelennamine. The "M" :>oint on the o-9-THC graph is the score, from the same subjects, :)btained after smoking a marijuana cigarette that contained 10 mg '186 by weight) G-9-THC. Reprinted, with permission, from Jasinski ?t al.' HENNINGFIELD it involves the measurement of responses indicative of abuse potential following the measurement of single doses of drugs. The goals of the single-dose study are to deter- mine whether the drug is psychoactive, whether it is a eu- phoriant, and what other substance(s) it is identified as. The second type of study is called the "self-administration study" because it measures the conditions under which a subject will voluntarily take the substance. The self-admin- istration study determines whether the drug serves as a bio- logically effective positive reinforcer. Variants of these two strategies are conducted in both animal and human subjects, thereby providing a means of establishing the biologic gen- erality of the phenomena while controlling the possible con- founding influence of personality, social, or cultural variables. A high degree of concordance between findings from animal and human studies has been established over a wide range of drugs.Jb'" This section will focus on the results from studies using human volunteers. Single-Dose Studies of Abuse Potential In these studies, volunteers are given a range of doses of the test compound and placebo under double-blind condi- tions. Individuals with histories of drug abuse are used as subjects because they can accurately discriminate com- pounds with a potential for abuse and can compare the ef- fects of the compounds to those of abused drugs.` In a study at the Addiction Research Center, nicotine was given both intravenously and in the form of tobacco smoke over a range of doses to eight subjects with histories of drug abuse.s' Three doses of nicotine and placebo were given intravenously, and three doses of research cigarettes (con- trolled nicotine delivery) and an unlit cigarette were inhaled according to a standardized puffing procedure. Each dose was given to each subject on four different occasions. Self- reported (subjective), observer-reported (behavioral), and physiologic variables were measured before, during, and after drug administration. Nicotine produced a similar profile of effects across a variety of measures, when given by both methods of admin- istration. In brief, nicotine was shown to be psychoactive, as evidenced by its reliable discrimination from placebo. Its self-reported effects peaked within one minute after admin- istration (by either route) and dissipated within a few min- utes: peak and duration of response were directly related to the dose. Two measures of euphoria used in this and other studies are the Liking Scale (Single Dose Questionnaire) and the Morphine Benzedrine Group (MBG) Scale (Addic- tion Research Center Inventory, or ARCI).° Figure 4 shows responses on the 5-point Liking Scale, which asked how much the drug was liked (0="not at all," 4="an awful lot"). As shown in the figure, nicotine produced responses on the Liking Scale similar to those of more commonly studied drugs of abuse such as morphine and d-ampheta- mine. Figure 5 shows responses to nicotine, tobacco, other drugs of abuse, and simulated gambling (the test was taken 1 28 , 2046399529

I I I I I I I I I I I I I I I I I J CLIN PSYCHIATRY 45:12 (SEC. 2) - DECEMBER 1984 CIGARETTE SMOKING FIGURE 5. Scores on the Euphoriant Scale for Compulsive Be- FIGURE 6. Patterns of LV. Nicotine Self-Administration During haviors' 3-Hour Sessions in Six Subjects' EUPHORIANTS FOR COMPULSIVE BEHAVIORS I.V. NICOTINE INJECTtONS J Q B PENT08ARB. 10 6 7 d AMPHET. U N ~ 4 4 m ~ P D P D = 3 DIAZEPAM IV NICOTINE U ~ 7 2 Q 6 Z 0 I ~ 5 ~ P D P D 0 N B ETHANOL 6 TOBACCO a 6 w 5 ~ 4 P 0 P 0 µg/kg 10 MORPHINE SKW 1 22 7 KUL~ 22 4 PEuii u i i i ti i i i 18 P 0 P D P SG PLACEBO (P),DRUG (D) or SIMULATED GAMBLING (SG) 'Mean scores (N=7 to 12) on the Morphine Benzedrine Group (MBG) scale of the Addiction Research Center Inventory (ARCI).' Mean placebo scores were compared to scores at the highest dose tested (which also yielded the greatest MBG scale score eleva- tions). In "simulated gambiing;' compulsive gamblers rated their feelings as though they were "winning at gambling" (unpublished data, Hickey, Haertzen, and Henningfieid). AII drugs (and gambling) produced significant elevations in MBG scale scores (p <.05, Stu- dent's t test). while compulsive gamblers simulated the way they felt when winning at gambling). The ARCI data are consistent with the Liking Scale data, confirming that nicotine, given by both routes of administration, was a euphoriant. When asked to identify the injections from a list of commonly used and abused drugs, subjects more frequently identified nicotine injections as cocaine. Similar results for intravenous and inhaled nicotine were also obtained on several physiologic measures, in- cluding pupil diameter, blood pressure, and skin tempera- ture. These similarities in subjective and physiologic responses to nicotine given as either tobacco smoke or in- travenous nicotine confirmed that nicotine was the critical pharmacologic compound that accounted for these effects of tobacco smoke. A subsequent study showed that nico- tine's subjective and physiologic effects could be blocked by oral pretreatment with mecamylamine." Studies with an- imals have also shown that nicotine produces discriminable effects, and the data suggest that animals identify nicotine as being more similar to cocaine than to placebo or pento- barbital, but not identical to cocaine (for a review, see ref- erence 59). Self-Administration Studies The methods developed in animal studies can be used to assess the ability of a drug to maintain self-administration (drug-seeking behavior). This is a critical finding, which establishes whether the pharmacologic activity of the drug LAI ii 18 K0, ~ 27 BE 27 ~ 3 HOURS J 'Pattern of nicotine deliveries (vertical marks) obtained during the session in which the 1.5 mg per injection dose was available for subjects SK, KU and PE, and from a representative session at the 1.5 mg dose for subjects BE, KO, and LA. The unit dose for each subject, expressed as micrograms of nicotine per kilogram body weight, is indicated on the right. Numbers of injections per session were inversely related to this expression of unit dose (r=.91). itself is sufficient to maintain drug-seeking behavior. The strategy is particulary useful in studies of nicotine because it is possible to study self-administration in the absence of the other stimuli associated with tobacco smoke inhalation (e.g., the tobacco brand, smell of the smoke, lighting-up rituals). In a recent study, volunteers were tested during 3-hour sessions in which 10 presses on a lever resulted in either a nicotine or placebo injection.GO Subjects were not permitted to smoke cigarettes for 1 hour before or during the study. A variety of safeguards ensured the safety of the subjects. As shown in Figure 6, all six subjects voluntarily self-adminis- tered nicotine. Patterns of self-administration (injections) were similar to those observed when human subjects smoke cigarettes and when rhesus monkeys take intravenous am- phetamine injections in comparable experimental situa- tions." One of the six subjects described above was not a drug abuser. For this subject the pattern of acquisition of nicotine self-administration developed gradually, over several ses- sions (Figure 7). As shown in the figure, double-blind sub- stitution of saline for nicotine resulted in extinction of the self-injection behavior. Similarly, when subjects were given access to both nicotine and placebo at the same time (by pressing alternate levers), they chose nicotine, confirming that nicotine had come to serve as a positive reinforcer.61 These data indicate that the pharmacologic activity of nico- tine itself (not just the injection behavior) was critical to the maintenance of the behavior. Nicotine self-administration has also been studied in a variety of nonhuman species, under a variety of experimen- tal conditions.62 The general finding is that nicotine is a highly efficacious reinforcer. However, the conditions un- der which it serves as a reinforcer are more restricted than 29 I

I I I I I I I I I I I I I I I I J CLIN PSYCHATRY 45:12 (SEC. 2) - DECEMBER 1984 FIGURE 7. Acquisition and Extinction of Nicotine Seif-Adminis- tration' I FR 10; INJECTION 16 N z 12 0 ~ 8 w ~ z 4 0 KO t-- SALINE--J t I 111111111 111 I 3 5 7 9 II 13 CONSECUTIVE SESSIONS 'Reprinted, with permission, from Henningfield et a1.10 with cocaine. It is plausible that nicotine self-administration in the form of cigarette smoke inhalation provides an ideal confluence of conditions for the establishment and mainte- nance of nicotine dependence in humans." Implications of Single-Dose and Self-Administration Studies The results of these studies provide direct evidence that nicotine, in doses comparable to those delivered by ciga- rette smoking, is an abusable drug. That is, nicotine meets the critical criteria of being psychoactive, producing eupho- riant effects, and serving as a reinforcer. These findings suggest that the role of nicotine in cigarette smoking is sim- ilar to the roles played by other drugs in the maintenance of other kinds of substance self-administration, e.g., mor- phine in opium use, tetrahydrocannabinol (THC) in mari- juana smoking, cocaine in coca leaf use, and ethanol in alcoholic beverage consumption. These findings have im- plications for public policy and have already been ex- pressed in a pamphlet issued by the U.S. Public Health Service entitled "Why People Smoke."6' These findings also have implications for treatment. Many previous efforts have been based on the conceptuali- zation of cigarette smoking as a simple behavioral habit. This has led to suggestions that smokers simply "take up alternative habits," or "hide their cigarettes"-strategies that obviously would not be taken seriously in treating drug abuse and alcoholism. The next section will discuss specific treatment implications of the conceptualization of cigarette smoking as a form of drug abuse. PHARMACOLOGICALLY BASED TREATMENTS Cigarette smoking is a prototypic form of drug abuse, in which nicotine is critical. To the extent to which cigarette smoking is similar to other forms of drug abuse, strategies 30 HENNINGFIELD of treatment that have been used for drug abusers may be applied to the tre.atment of cigarette smoking. While it is not the purpose of tkus paper to describe in detail the treat- ment of cigarette smoking, a few implications are worth mentioning. Pharmacologic treatment of drug abuse is basically of three types: substitution therapy (e.g., methadone for opi- ate dependence), in which a more manageable form of the drug is provided, according to a prearranged maintenance protocol; blockade therapy (e.g., naltrexone for opiate de- pendence), in which the effects of the abused drug are blocked by pretreatment with an antagonist; and nonspe- cific supportive therapy, in which the patient is treated symp- tomatically, as by the temporary use of benzodiazepines during alcohol detoxification." All three approaches may have applications in the treatment of cigarette smoking. Substitution (Nicotine Replacement Therapy) Until recently, a variety of putative nicotine substitutes have been available, but none actually delivered nicotine to the central nervous system. Some have contained lobeline, which is a partial nicotinic receptor agonist but of unproven efficacy."''`6Substitution of other stimulants for nicotine has also been attempted, but there is little evidence that these approaches are particularly effective.°''68 In fact, d-amphet- amine administration to smokers enhances the pleasure gained by smoking and increases the rate of smoking.`' In early 1984, the Food and Drug Administration (FDA) ap- proved a nicotine resin complex (nicotine-delivering chew- ing gum) for use in the treatment of cigarette smoking. Use of the nicotine chewing gum has been proven to increase the rates of success of a variety of cigarette smoking treat- ment programs.50's' Under a wide range of conditions, the desire to smoke is reduced, although not eliminated, and abstinence-associated discomfort ("withdrawal") is less- ened."'"'70'" As might be surmised from experience gained in the treatment of opioid dependence with methadone," treat- ment programs are most efficacious when the nicotine chewing gum is used in conjunction with a behavioral pro- gram. For instance, an experimental program in San Fran- cisco has shown that a program combining rapid smoking treatment" with nicotine gum administration is more effec- tive than either treatment alone (S.M. Hall, personal com- munication). There are some caveats regarding the use of nicotine gum. The first is that cigarette smoking, like other forms ot drug abuse, is critically but only partially mediated by phar- macologic factors; therefore, the nicotine chewing gum should be used in conjunction with an appropriate ancillary treatment program. The second follows from the finding that persons who are most effectively treated with the gum may be selected on the basis of an eight-point question- naire," presented in the Appendix. A plausible corollary is that persons not indicated for treatment with the gum on the questionnaire should not be treated with the gum. In addi- 2046399531

J CLIN PSYCHIATRY 45:12 (SEC. 2) - DECEMBER 1984 I I I I I 1 I I I I I I I I I I I tion, persons who do not inhale cigarette smoke, thereby obtaining little nicotine,:' should not be treated with the nic- otine chewing gum. Nicotine Blockade Therapy (Mecamylamine) Another treatment strategy of promise has arisen from the observations that mecamylamine 1) attenuates the ef- fects of nicotine critical to its potential for producing abuse,5° and 2) is safe at doses that affect cigarette smok- ing." To the extent that cigarette smoking is comparable to opioid dependence, the blockade strategy may prove fruitful in a subpopulation of cigarette smokers. In the case of opioid users, it appears that naltrexone is indicated for about 5% of patients. If this finding holds true for cigarette smoking, this seemingly small percentage would represent millions of potential patients. Interestingly, three character- istics that correlate with success in naltrexone treatment are that the patient is highly motivated, well adjusted in society, and has a steady job." It seems likely that a substantially higher percentage of cigarette smokers than opioid depend- ent persons meet these criteria, suggesting that a higher per- centage of cigarette smokers would benefit from such a treatment approach. A preliminary clinical trial of inecamylamine for the treatment of cigarette smoking by Tennant and Tarver" was modeled after programs they had used to treat opioid-de- pendent persons with naltrexone. In a population of se- verely dependent cigarette smokers, mecamylamine reduced tobacco craving in 13 of 14 subjects tested, and half of the subjects quit smoking within 2 weeks of initia- tion of mecamylamine treatment. These preliminary results indicate that this treatment modality warrents further explo- ration. Nonspecific Therapeutic Support Nicotine produces several potentially therapeutic effects for cigarette smokers: it functions as an anxiolytic, im- proves performance on certain kinds of tasks, is an anorec- tant, and may provide a means of mood regulation. Although the euphoriant properties of drugs can stand apart from collateral therapeutic actions (as is the case with mor- phine, amphetamine, and alcohol), attention to such drug effects may enhance the efficacy of treatment. Since nico- tine, in the form of tobacco, is widely available, relatively inexpensive, and in a convenient form for precise dose reg- ulation, it provides an ideal means of self-medication for the cigarette smoker. As an anxiolytic, nicotine appears to reduce responsive- ness to stressful stimuli and to enhance mood.'s In addition, it reduces aggressive responses in experimental situations." Nicotine enhances performance on tasks involving speed, reaction time, vigilance, and concentration." These effects are strongest in cigarette smokers who are deprived of ciga- rettes but are also evident after administration of nicotine to nonsmokers or by increasing the nicotine dose in persons who are already smoking. Nicotine may also be a useful CIGARETTE SMOKING mood regulator, by virtue of its release of norepinephrine from the adrenal medulla." Norepinephrine release is also stimulated by excitement, exercise, sex, antidepressant drugs, and other drugs of abuse, suggesting that cigarette smoking may pharmacologically function to alleviate bore- dom and stress. Finally, as an anorectant,'a'80 nicotine ap- pears to function in three ways: 1) by decreasing the efficiency with which food is metabolized,"'B' 2) by specifi- cally reducing the appetite for foods containing simple car- bohydrates (sweets),89 and 3) by nonspecifically reducing the eating that may occur in times of stress.`° The consequence of not attending to the possible side effects of quitting cigarette smoking is well illustrated by the finding that many people who quit smoking relapse in times of stress.85 More recently, it was found that among people who had quit smoking, those who had increased ac- tivity of lipoprotein lipase in the adipose tissue were more likely 1) to gain weight after they quit smoking, and 2) to relapse to cigarette smoking." This finding does not mean that lipoprotein lipase activity is a cause of cigarette smok- ing, or that it has any direct involvement in the behavior. However, since it is a correlate of gaining weight and a predictor that smoking treatment will fail, it seems apparent that treatment of cigarette smoking must be accompanied by treatment of the weight control problem of these pa- tients. IMPLICATIONS FOR PSYCHIATRY AND POLYADDICTIONS When cigarette smoking was considered to be a volun- tary pleasure or a simple habit, there was little reason to treat it as anything else, or to consider it a factor in other kinds of drug abuse or other psychiatric disorders. Ciga- rette smoking should now be seen in a new light, however. It is now clear that cigarette smoking may occur as a form of drug dependence." Tobacco dependence disorder is listed in the Diagnostic and Statistical Manual, Third Edi- tion, of the American Psychiatric Association (DSM-III). The U.S. Public Health Service now considers cigarette smoking to be a form of drug dependence in which nicotine is the critical abuse-producing drug." It is evident that nico- tine has a variety of potentially therapeutic effects, although these are outweighed by the toxic effects documented in the various reports by the Surgeon General on smoking and health. Finally, there is now a rational basis for the treat- ment of cigarette smoking which is based on experience with other forms of drug abuse. These new findings and conclusions place a heavy burden on the health services profession as a whole, and on the psychiatric profession in particular. Previously, there was little reason to treat a disturbed patient any differently if he or she happened to be a ciga- rette smoker. It is now apparent that the cigarette-smoking patient should be considered as though it had been discov- ered that the person abused other drugs. That is, the possi- 31

I I I I I I I I I I I I I I I I I J CLIN PSYCHIATRY 45:12 (SEC. 2) - DECEMBER 1984 bility must be considered that the cigarette smoking is inter- acting with-the presenting complaints, either as a co-factor or as a means of self-medication. In the treatment of drug abusers, the patient who is also a cigarette smoker should be considered to be polyaddicted. It is no coincidence that most alcoholic patients and opioid users are cigarette smokers," or that more than 75% of compulsive gamblers smoke cigarettes (unpublished data from Hickey, Haertzel, and Henningfield). These findings are probably indicative of the commonalities among addic- tive disorders, and consistent with the hypothesis that each disorder is partially substitutional for the others. In any HENNINGFIELD case, it has been known by those who treat cigarette smok- ing that use of abused drugs is a relapse factor for cigarette smoking.90 One might then ask whether it is possible that cigarette smoking is a relapse factor for use of other drugs. The facts that nicotine is a psychoactive drug of abuse and that cigarette smoking may be addictive behavior have profound ramifications for psychiatry and other behavioral sciences. These findings are actually reason for encourage- ment, as this new enlightenment may help provide the key to unlock the doors to the treatment of cigarette smoking as well as to other disorders. APPENDIX Tolerance Questionnaire' Answer Score 1. How soon after you wake up do you smoke your first cigarette? 2. Do you find it difficult to refrain from smoking in places where it is forbidden, e.g., in church, at the library, etc? 3. Which of all the cigarettes you smoke in a day is the most satisfying one? 4. How many cigarettes a day do you smoke? 5. Do you smoke more during the morning than during the rest of the day? 6. Do you smoke if you are so ill that you are in bed most of the day? 7. What brand do you smoke? 8. How often do you inhale? Scoring The questions are scored so that higher points are always given for answers indicating a higher level of addiction to cigarettes. Question 1: One point is assigned to smoking within 30 minutes. Question 2, 5, and 6: Items are scored with one point for yes answers. Question 3: One point is assigned for answering "the first cigarette in the morning." Question 4: Smokers are categorized as light (score of 0, 1-15 cigarettes), moderate (score of 1, 16-25), and heavy smokers (score of 2, 26+). Question 7: The brands are classified into three categories with low (0), medium (1), and high (2) nicotine levels. Question 8: Frequency of inhalation is divided into three categories: never (0), often (1), and always (2). Scoring: A score of 6 or greater indicates a high probability that the smoker is tolerant to nicotine and that quitting will be accompanied by some physiologic discomfort. 'From Fagerstrom KO: Measuring degree of physical dependence to tobacco smoking with reference to individualization of treatment. Addictive Behaviors 3:235-241, 1978. REFERENCES 1. Austin GA: Perspectives on the History of Psychoactive Substance Use. NIDA Research Monograph Series No. 24. Washington, DC, US Government Printing Office, 1978 2. Ashton H, Stepney R: Smoking, Psychology and Pharmacology. Lon- don, Tavistock Publications, 1982 3. US Department of Health and Human Services: Smoking, Tobacco and Health (A Fact Book). Washington, DC, US Government Printing Office, 1980 4. McMorrow MJ, Foxx RM: Nicotine's role in smoking: An analysis of nicotine regulation. Psychol Bull 93:302-327, 1983 5. Moss RA, Prue DM: Research on nicotine regulation. Behav Ther 13:31-46, 1982 6. Jasinski DR, Johnson RE, Henningfield JE: Abuse liability assess- ment in human subjects. Trends in Pharmacological Sciences 5:196- 200, 1984 7. Kozlowski LT: Tar and Nicotine Rating May Be Hazardous to Your Health: Information for Smokers Who Are Not Yet Ready To Stop. Toronto, Alcoholism and Drug Addiction Research Foundation, 1982 8. Jaffe JH. Kanzler M: Smoking as an addictive disorder. In Krasnegor NA (ed): Cigarette Smoking as a Dependence Process. NIDA Re- search Monograph Series No. 23. Washington, DC, US Government Printing Office, 1979 9. Henningfield JE, Griffiths RR, Jasinski DR: Human dependence or tobacco and opioids: Common factors. In Thompson T, Johanson CE. (eds): Behavioral Pharmacology of Human Drug Dependence. Wastt• ington, DC, US Government Printing Office, 1981 32 2046399533

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