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Tobacco, Nicotine, and Addiction social consequences". It added that "this term is generally applied when the ingestion of such substances is viewed by a large segment of the society as undesirable". This definition suffers from several of the deficiencies noted above. As with the pre-1964 WHO definitions, it refers only to the substances and not to the users and the context. It establishes the consequences of the process (toxicity, adverse social effects) as defining criteria of the process itself. It appears to be directed principally toward illicit drugs or others "viewed by a large segment of the society as undesirable", thereby apparently omitting alcohol, which is approved and used by a large majority of the adult populations of most occi- dental countries. Nevertheless, this report does clearly indicate that compulsive use is the primary problem, and that physical dependence and tolerance, though important, are secondary. Diagnostic and Statistical Manual (DSM-III-R) The widely used Diagnostic and Statistical Manual (DSM-III-R) oftheAmerican Psychiatric Association (1987) employs a more flexible definition of "psychoactive substance de- pendence", which most North American psychiatrists now use interchangeably with "addiction". The defining criteria are given as at least three of: (1) substance often taken in larger amounts or over a longer period than the person intended (2) persistent desire or one or more unsuc- cessful efforts to cut down or control substance use (3) a great deal of time spent in activities necessary to get the substance (e.g., theft), taking the substance (e.g., chain smok- ing), or recovering from its effects (4) frequent intoxication or withdrawal symptoms [at times] when [the user is or should be] expected to fulfill major role obligations at work, school, or home (e.g., does not go to work because hung over, goes to school or work "hfgh", [is] intoxi- cated while taking care of his or her children), or when substance use is physi- cally hazardous (e.g., drives when intoxicated) (5) important social, occupational, or rec- reational activities given up or reduced because of substance use (6) continued substance use despite knowl- edge of having a persistent or recurrent social, psychological, or physical prob- lem that is caused or exacerbated by the use• oj' the substance (e.g., keeps using heroin despite family arguments about it, cocaine-induced depression, or hav- ing an ulcer made worse by drinking) (7) marked tolerance: need for markedly increased amounts of substance (i.e., at least a 50% increase) in order to achieve intoxication or desired effect, or mark- edly diminished effect with continued use of the same amount (8) characteristic withdrawal symptoms [specific for the different types of psy- choactive substance] (9) substance often taken to relieve or avoid withdrawal symptoms. This definition is unusual, in that the need for only three of the items listed above permits a diagnosis of dependence to be made on the basis of only compulsive or uncontrolled use (first six items) without reference to tolerance or physical dependence, or conversely on the basis of only tolerance and physical depend- ence (last three items) without reference to compulsive use or loss of control. It is also different from most other definitions in that untoward physical or social consequences are not defining criteria per se, but simply indices of the strength of the compulsion to continue using the substance despite knowledge of the adverse effect (item 6). Report of the U.S. Surgeon General (1988) A very important definition to be considered in the present context is that employed in the 1988 report of the U.S. Surgeon General (U.S. DHHS 1988) on the health consequences of smoking, in which nicotine is identified un- equivocally as addicting. Three primary crite- ria of addiction are stated: (1) drug-seeking and drug-taking behaviour is driven by strong, often irresistible, urges and can persist despite a desire to quit or even repeated attempts to quit; (2) the drug has psychoactive or mood- altering effects in the brain; (3) the drug is capable of functioning as a reinforcing agent that directly strengthens behaviour leading to further drug-taking. A number of other features 4 Royal Society of Canada

Tobacco, Nicotine, and Addiction are regarded as helping to delineate the pic- ture of fully established addiction, though not necessary for its definition. These include consistent and repetitive patterns of drug use, persistence of such use despite adverse conse- quences, frequent relapse, tolerance, physical dependence, persistent recurrent craving to use the drug (especially during periods of absti- nence), and effects that the user finds pleasur- able or euphoriant. Some of these defining or descriptive features seem repetitious or redundant. For example, persistence of use despite adverse consequences does not appear to differ from use driven by strong or irresistible urges. Pleasurable or euphoriant effects are, by definition, psychoac- tive or mood-altering effects, and are generally regarded as identical to, or closely related to, the postulated reinforcing effects. Neverthe- less, this definition/description, like the pre- ceding one in this section, gives primary em- phasis to the production and expression of drug-seeking and drug-taking behaviour, and only secondary importance to tolerance and physical dependence. Furthermore, adverse consequences are seen as important in their own right, but not as defining criteria of addic- tion; as in the DSM-III definition, they are used only as indices of the strength of the urge or need to continue using the drug. Dr. Jerome H. Jaffe A final definition to be considered here is that proposed by Dr. Jerome H. Jaffe, an interna- tionally recognized expert in the field of addictions, and author of the chapter on Drug Addiction and Drug Abuse in Goodman and Gilman's The Pharmacological Basis o f Thera- peutics (Jaffe 1985). In that chapter Dr. Jaffe has defined addiction as "a behavioral pattern of drug use, characterized by overwhelming involvement with the use of a drug (compulsive use), the securing of its supply, and a high tendency to relapse after withdrawal". This definition makes no reference whatever to the motivation for drug use, to tolerance and physi- cal dependence, or to the noxious consequences of drug use. Rather, it puts all the emphasis on the behavioural features of drug use, and uses the term in a purely descriptive rather than a mechanistic sense. This definition seems also to be directed principally toward use of illicit drugs such as heroin and cocaine, because of its inclusion of "the securing of its supply" as a defining characteristic. With licit substances such as alcohol that can be purchased easily, addiction does not usually involve any major preoccupation with the securing of a supply. 3. Canadian Legal Definition Canadian federal legislation already contains a definition of addiction. Section 2 of the Nar- cotic Control Act' offers the following defini- tion of a "narcotic addict": °`narcotic addict"means a person who, through the use of narcotics, (a) has developed a desire or need to continue to take a narcotic, or (b) has developed a psychological or physical dependence on the ef- fect of a narcotic. This is a very wide definition which, if the word "tobacco" were substituted for "narcotic", would virtually compel the conclusion that tobacco is addicting. This definition of "narcotic addict" must, however, be seen in the light of the special circumstances involved in its enactment in 19£1(Solomon and Green 1982, Le Dain 1973). A Special Committee of the Senate reported in 1955 on the `Traffic in Narcotic Drugs in Canada" and strongly recommended (p. xix) "the provision of suitable treatment facilities for drug addicts". Part II of the Narcotic Con- trol Act of 1961 responded to this recommenda- tion by requiring the sentencing j udge, if s atisfied "that the convicted person is a narcotic addict", to sentence the person "to custody for treat- ment for an indeterminate period". The 1955 Senate Committee had relied on the World Health Organization definition of addiction, current in the 1950s and discussed earlier in this document. The 1961 definition in the Narcotic Control Act was much broader. Part II of the Narcotic Control Act, however, has never been proclaimed in force - in part because of its draconian nature under the guise of treatment and in part its questionable con- stitutionality (Le Dain 1973, pp. 924 et seq.). 'Revised Statutes of Canada 1985, c. N-l. Royal Society of Canada 2501446257 5 • - - . _ _ . _ r-~n •~~,,.~.a~-+r•r . . . . . . . . . . . .. . . _ ... .. . . . . . : ~.7•.~.- . . . .. . . . . . . . ... . . . . . . . . . . . . . . . . . . . . ..

Tobacco, Nicotine, and Addiction Nevertheless, the definition of "narcotic addict" is still in force, but is only applicable to the unproclaimed Part II of the Act. Because of these special circumstances, little weight can be given to the only definition of "addict" now contained in federal legislation. 4. Conclusion The foregoing review of definitions of drug dependence or addiction indicates that these definitions have undergone a necessary and continuing evolution, as new clinical and ex- perimental information has been acquired. It is clear that, despite the differences among them, there are very important common elements. These are summarized as follows in the 1988 report of the U.S. Surgeon General: "According to current conceptualizations, the central and common element across all forms of drug dependence is that a psychoactive drug has come to control behavior to an extent that it is considered detrimental to the individual or society". However, the last portion of this summary appears to contradict the idea, implicit in both the D SM-III-R and the Surgeon General's definitions, that detrimental consequences are not defining criteria of addiction. Therefore the one uncontestable common element in pres- ent-day definitions is that "a psychoactive drug has come to control behavior". This single major element is the point of departure for our own definition, and for our subsequent assessment of its applicability to nicotine contained in tobacco products. III. BASIS FORAN IMPROVED TERMINOLOGY 1. Factors Bearing on the Amount and Character of Drug Use Drug use is not sharply divisible into "normal" and "abnormal" patterns, dr into "social use", "abuse", and "addiction". Abundant evidence shows that it falls on a continuum of amounts and frequencies, and is subject to a variety of factors to be considered below. It is desirable to review these factors before defining"addiction". Psychoactivity and reinforcement All known drugs that have at various times been considered "addicting", "dependence producing", or "habituating" are psychoactive drugs with demonstrated reinforcing proper- ties. In other words, they alter mood or perception in a manner that is regarded by most, but not all, users as pleasurable or desirable, and some aspect of this action reinforces (i.e., increases the likelihood of) renewed or repeated sel f-administration of such drugs. These reinforcing effects are not by themselves sufficient to produce dependence or addiction. Occasional, moderate users of such drugs usually experience qualitatively similar pleasurable and reinforcing effects. Yet these user's are not considered by most observ- ers to be dependent or addicted, because they are able to use or abstain at will, and the quantities they use are small. Therefore some additional factors must contribute to the pro- duction of addiction. Individual variables Individual factors may render some persons more sensitive than others to the reinforcing effects, or less sensitive to the disagreeable or punishing effects that may normally limit consumption of a drug. Such individual differ- ences may be of genetic or constitutional origin in some cases. The importance of genetic fac- tors has been studied in greatest depth in relation to susceptibility to alcohol addiction, but there is no a priori reason to doubt that it is also relevant to other drug addictions. There is evidence that sensitivity to many effects of nicotine in mice, and the ability to develop tolerance to these effects, are influenced by genetic factors (Collins et al. 1988). It is there- fore probable that genetic influences also mod- ify the reinforcing effects and the development of dependence. In other cases, differences in susceptibility may be due to emotional or physical discomfort that makes the same drug effects more highly valued by the user, e.g., anxiety or tension that may make the relaxant effects of alcohol, benzodiazepines or barbitu- rates more attractive to the user. In yet other cases, the social practices and values of the social group to which the user belongs may enhance the value of the drug effects by ena- bling the user's personality and behaviour to conform better to the group norms. For example, ~ 0 0 ~ .A ~ rQ cn 03 6 Royal Society of Canada

Tobacco, Nicotine, and Addiction a shy or inhibited person may find cocaine par- ticularly valuable if it permits easier accom- modation to a group of dynamic, extraverted, and aggressive friends or business associates. Route of administration The route of administration of the drug, by influencing the speed with which the reinforc- ing effects are perceived, can markedly influ- ence the strength of reinforcement. Intrave- nous or inhalational use of a psychoactive drug, which can deliver effective doses to the brain within seconds, is usually far more rein- forcing than oral ingestion of the same drug in the same or even larger doses (Kalant et al. 1978). Classical conditioning Frequently repeated use of the drug in a spe- cif c context (e.g., in a particular social setting, or during certain specific activities, or at par- ticular times of the day) can result in classical (Pavlovian) conditioning, so that the context itself comes to elicit the drug use or the desire for it (Wikler 1968). This is referred to as stimulus-controlled drug use (Kalant et al. 1978), and its appearance means that the drug use can no longer be regarded as a voluntary behaviour. Social and psychological environment Factors arising from the social and psychologi- cal environment also affect the degree of proba- bility that the foregoing factors may generate a pattern of compulsive use of a drug by a particular individual. For example, the great majority of those American troops in Viet Nam who became "addicted" to heroin during their military service in the Viet Nam war were quite successful in ceasing their use of heroin on their return to civilian life in the United States (Robins et al. 1977). It appears that the intense stress of war service, the low price and easy availability of heroin, widespread peer- group example and inducement to use the drug, and a high degree of'acceptance of the practice in the social milieu surrounding them, all contributed to the risk of use by individuals who did not use it in a different social context. Similarly, the cost of alcohol (in constant dol- lars) has been shown to have a marked effect on the level of consumption, even by drinkers Royal Society of Canada who are defined clinically as alcoholics (Babor 1985). When the price rises, consumption falls even among alcoholics, as shown by a corre- sponding fall in the incidence and death rate of alcoholic cirrhosis (Popham et al. 1976). The inverse relation between price and consump- tion has even been confirmed experimentally (Babor et al. 1978). This relationship probably applies to all drugs, as to most other commodi- ties. For example, the rapid increase in the use of "crack" (an impure preparation of the free base of cocaine) is generally attributed to the fact that its price is much lower than that of conventional preparations of cocaine. The rela- tionship has also been demonstrated with respect to tobacco. Russell (1973) found an inverse relationship between relative price and the average consumption of cigarettes among British men between 1946 and 1971; that is, as price rose, consumption fell, and as price fell, consumption rose. Research on smokers in the U.S. shows that a 10% increase in the price of cigarettes is associated with a 4% decrease in consumption among adults and a 14% de- crease among adolescents (Lewit et al 1981, Lewit and Coate 1982). Thus during periods when the relative price of cigarettes is declin- ing, we can expect corresponding increases in the percentage of smokers and the amount smoked. Factors such as these contribute importantly to the development of "compulsive" drug use. 2. Working Definition of Addiction Though North American experts increasingly regard dependence as identical with addiction, the continued broad acceptance of the term "addiction" (see Section 111.3), in both profes- sional and lay circles, makes it preferable to use the term "addiction" in the present report. As noted above, the dominant element in all the definitions reviewed is the presence of a strong, pervasive drug-taking behaviour that is very difficult to cease, even when damaging consequences of the drug use make the person wish to stop. All other features found in earlier definitions, including tolerance, physical de- pendence, and damage to health or social functioning, are consequences of the high levels of drug use generated by addiction, rather 7

Tobacco, Nicotine, and Addiction than essential features of it. They may contribute to or modify an existing addiction, but they are not essential criteria of addiction. There are numerous individual cases of heavy users of alcohol, opiates or other drugs who, because of protective features in their consti- tutions and environments, continue to func- tion at acceptable levels and suffer no obvious damage to health, but whose drug use is en- tirely comparable to that of clinically defined addicts. Therefore, we propose the following definition of drug addiction: Drug addiction is a strongly estab- lished pattern,of behaviour charac- terized by (1) the repeated sel f-ad- ministration of a drug in amounts which reliably produce reinforcing psycho-active effects, and (2) great difficulty in achieving voluntary long- term cessation of such use, even when the user is strongly motivated to stop. Notes: i) By "drug", we mean any substance other than a normal body constitueitt or one required for normal bodily function (e.g., food, water, oxygen) which, when ap- plied to or introduced into a living organ- ism, has the effect of altering bodily function. ii) By "repeated self-administration" we mean any pattern of continuous or inter- mittent drug-taking that includes periods of sustained intake at levels sufficient to produce reinforcing psychoactive effects. iii) By "reinforcing effects" we mean those that increase the probability of repeat- ing the behaviour (in this case, the drug- taking behaviour) that led to those effects. iv) By "psychoactive effects" we mean those drug effects resultingin changes in mood, perception and cognitive function, such as euphoria, tranquilization, hallucina- tions, arousal, improved endurance, etc. v) By "long-term cessation",we mean cessa- tion of the pattern of use described above, the cessation being maintained indefi- nitely over a period measured in years rather than in weeks or months. 3. Dependence As noted earlier, the WHO Expert Committee on Drug Dependence recommended that the term "addiction" be dropped from scientific and clinical use, and that it be replaced by the term "dependence". Though the term addic- tion continues to be widely employed, it has become increasingly common to use it inter- changeably with dependence. Indeed, this is done quite expressly in the Surgeon General's 1988 report on tobacco and addiction. We feel that the use of the term "dependence", without specific qualification, is ambiguous. In the 1964 report of the WHO Expert Committee, ambiguity was already evident in that depend- ence was defined in terms of both a psychic or behavioural component that was always pres- ent, and a physical component that might or might not be present. This is further compli- cated by the fact that a physical (physiological) dependence is clearly present in some indi- viduals with respect to drugs or substances that have nothing to do with drug addiction (e.g., the diabetic patient is physiologically dependent on insulin), but the definition does not differentiate between this type of physical dependence and the type identified by a with- drawal reaction in a chronic user of alcohol, heroin, or nicotine, for example. Moreover, it is widely recognized (e.g., Jaffe 1985) that someone can be made 'physically dependent on a drug by repeated medical administration of that drug (e.g., morphine administered to a patient by a nurse or physi- cian for relief of pain) in doses sufficient to produce a withdrawal reaction when the drug is stopped, yet show no subsequent opiate- seeking behaviour. Therefore physical depend- ence may be an accompaniment of addiction, but it may also occur in the absence of addic- tion, and addiction (as defined above) may occur in the absence of physical dependence. Therefore, there is a risk that use of the term "dependence" might be interpreted as imply- ing a different process than "addiction", or one of lesser magnitude or gravity. 8 Royal Society of Canada

Tobacco, Nicotine, and Addiction 4. Habituation As noted above, the term "habituation" was employed in earlier WHO Expert Committee reports to refer to a process that was consid- ered to be distinctly less serious than "addiction". This differentiation does indeed mirror popu- lar usage. In everyday speech, it is common to refer to something as "just a habit", to distin- guish it from something more serious that might be regarded as a problem, a dependence, or an addiction. In this sense, however, "habituation" to a psy- choactive drug is a vague term that can not be satisfactorily differentiated from regular, mod- erate "social" use. Moreover, it is not at all clear that, in terms of operant psychology, one can differentiate meaningfully between the proc- esses by which a behavior becomes established as a habit and those by which it acquires the features described above in relation to "addic- tion". It may be a matter of degree rather than of kind, and the point of differentiation is blurred. "Habituation" also has other technical mean- ings that are applicable to the use ofpsychoactive drugs. In experimental psychology it is used to designate the gradual loss of response to a sustained or regularly repeated stimulus. In relation to a drug it means the gradual loss of effect on repeated administration of the same dose, and thus is essentially the same as "tolerance". Therefore, we agree with the WHO recommendation (1964) that the term "habituation" no longer be employed in this context. In any event, once stimulus-controlled drug taking behaviour is present, "habituation" is no longer applicable. 5. Addicting Drug or Addicted User? Any drug that is used by some people in a "compulsive" and addicted manner can also be used by others in a voluntary and non-addicted manner. For example, over 85% of North American adults use alcohol, yet only 5-10% of drinkers use it in a manner which would be regarded clinically as alcoholism or alcohol addiction. Even heroin, which is regarded by many as the prototypic addicting drug, has been estimated to be used addictively by not more than 301/ . of those who try the drug (Robins et al. 1977). This is not surprising, given the importance ofandividual, social and environmental factors that modify the risk of addiction to any specific drug in a particular user. Nevertheless, it appears to be true that the proportions of addicted and non-addicted users vary not only in different populations and circumstances, but also with different drugs. Clinical, epidemiological and laboratory experience suggests that cocaine and heroin, for example, are likely to give rise to addiction in a higher percentage of users than alcohol or benzodiazepines are. In contrast, some other drugs (e.g., corticosteroids), which can occasionally give rise to euphoriant effects and addictive patterns of use, do so with such rarity that in those cases the users are considered ab- errant and the drugs themselves are not re- garded as addicting. Therefore, for nicotine in tobacco cigarettes to be considered an addicting drug, it is not neces- sary to prove that all users of it become ad- dicted, nor is it sufficient to show that in rare instances a user becomes addicted. Rather, it is necessary to show that the proportion of users who do become addicted is at least com- parable to that found among users of alcohol, opiates, or other drugs that are regarded virtu- ally universally as addicting. IV. EVIDENCE CONCER.NING NICOTINE AND TOBACCO 1. Introduction This portion of the report deals briefly with the major pieces of evidence bearing on each of the components of the definition of"addiction" given above, as they relate specifically to nicotine and to tobacco. These are: repeated use, psy- choactive effects, reinforcement, and difficulty of cessation. More detailed coverage of these and other topics can be found in the 1988 report ofthe U.S. Surgeon General (U.S. DHHS 1988). Only selected studies are summarized briefly here, together with more recent evidence Royal Society of Canada 9

Tobacco, Nicotine, and Addiction and some that relates specifically to Canadian experience. 2. Repeated Use Prevalence o f regular smoking There can be no doubt whatever that regular smoking of tobacco cigarettes is still widely prevalent in Canada. Of Canadians aged 15 and over, 33% smoke cigarettes, pipes or cigars at least occasionally and 28% smoke cigarettes regularly, usually every day (Figure 1). Among adolescents, aged 15-19, about 18% are "regu- lar" smokers. Rates of smoking in some groups are much higher. For example, more than half of young males (aged 20-44) with elementary school education are regular smokers (Millar 1988). Since smokers die sooner than non- smokers (U.S. DHHS 1989), smokers are un- derrepresented in older age groups. Amount of smoking by individual smokers Those who do smoke tend to smoke a lot. Of Canadian smokers aged 15 and over, 90% of those surveyed in 1986 reported that they usually smoked every day (Millar 1988). Of these "regular" smokers, 80% smoked more than 10 cigarettes per day. Only 10.6% of U.S. smokers smoked five or fewer cigarettes a day in 1985 (U.S. DHHS 1988, p.149). The average smoker uses 20-25 cigarettes a day (Kozlowski 1986). By comparison, only 23% of drinkers drink seven or more drinks per week (Statistics Canada 1987) and a much smaller proportion drink every day (Figure 2). Although average tar and nicotine levels have declined in recent years, 80% of smokers still smoke cigarettes with medium or high nicotine content (0.6-1.2 mg) (Millar 1988). Many smok- ers of low-nicotine cigarettes "get more" out of their cigarettes by puffing harder or blocking ventilation holes (Kozlowski et al. 1982), and a significant proportion of smokers (about 9% and increasing) smoke "roll-your-own" ciga- rettes, which are very high in nicotine and tar. Thus, few smokers actually take advantage of cigarettes with low tar and nicotine yields. In fact, Kozlowski (1989) has shown that very- low-yield cigarettes failed to capture a significant part of the market, even when heavily advertised. (The term "low-yield" can be used to cover both tar and nicotine, because they tend to move in parallel across the whole range of cigarette products.) Since significant blood levels of nicotine can be maintained with fewer than 10 cigarettes per day (see Section IV.3.a), this means that most smokers have pharmacologically significant levels of nico- tine in their bodies for most of the day. Studies of young people have yielded similar findings. Of students in grades 7-13 surveyed in Ontario in 1987, 24% reported smoking during the past year, about two-thirds of these smoked daily, and one-third smoked 6 or more cigarettes each day (Smart and Adlaf 1987). Of U. S. high school seniors surveyed in 1986, 30% had smoked at least once in the past 30 days. Of these, 65% smoked daily, 41% smoked at least half a pack a day, and 22% smoked a pack a day or more (Bachman et al. 1987). Experimentation and progression to regular smoking OfU.K. adults who had smoked at least once in their lives, 70% went on to smoke daily for five years or more (McKennell & Thomas 1967). Similarly, 75% of Irish adults who ever smoked at all, later became daily smokers for six months or more (O'Connor & Daly 1985). Among young people, 43% of high school seniors surveyed in the U.S. in 1987 who had tried one cigarette in their life had smoked at least once during the past 30 days; 29% had smoked daily and 18% had smoked one-half pack or more every day (Bachman et al. 1987). Among those who had tried 3 or more cigarettes, subsequent smoking was far more likely: 75% had smoked at least once during the previous 30 days; 48% had smoked daily; and 30% had smoked one-half pack or more. While few people begin smoking after high school, those who already smoke increase their daily intake once they graduate (Johnston et al. 1988). Summary Thus, it is clear that regular smoking of to- bacco cigarettes is still widespread in both Canada and the United States, among both adolescents and adults. The majority of those who experiment with smoking become regular daily smokers of substantial amounts, and 10 Royal Society of Canada

Tobacco, Nicotine, and Addiction FIGURE 1: SMOKING BEHAVIOUR OF CANADIANS BY AGE AND SEX,1988 (Labour Force Survey, 1986) ~ NEVER SMOKED O FORMER SMOKER ® REGULAR CIGARETTES ~ PIPE/C(GAR % Royal Society of Canada LV 'G' N KXA N I IX>V N AGE 11 ,..N... ., .. ~ .., ._ . . . ......... . ... .....

Tobacco, Nicotine, and Addiction FIGURE 2: DAILY CONSUMPTION OF ALCOLHOL AND CIGARETTES AMONG U.S. DRiNKERS AND REGULAR SMOKERS (National Health Interview Survey 1985) % 11-15 16-20 21-25 26-30 31-35 36-40 41+ NO. CIGARETTES/DRINKS PER DAY regularly smoke enough to sustain high blood levels of nicotine (see Section IV.3.2). 3. Psychoactive Effects of Nicotine This section consists of a review of evidence from a variety of sources suggesting that cig- arette smokers obtain nicotine in doses sufficient to act in the central nervous system (brain and spinal cord) and to produce psychoactive effects. While smokers attribute their smoking to a wide variety of motivating effects (McKennell 1970), most of these are consistent with the known psychopharmacological effects of nico- tine, which are discussed below. Plasma nicotine levels In abstinent subjects, the smoking of one ciga- rette elevates plasma nicotine levels by 12 approximately 10 ng/ml (Benowitz 1988), al- though this increase can vary markedly, de- pending on how the cigarette is smoked (U.S. DHHS 1988). Peak concentrations are attained as the cigarette is finished, and plasma levels then decline with a half-life of approximately two hours. In regular smokers, plasma nico- tine concentrations vary across the day-night cycle. In a group of heavy smokers (averaging 30 cigarettes per day), levels were lowest upon waking (approx. 5 ng/ml), rose within a few hours to a plateau (approx. 35 ng/ml), then declined through the night (Benowitz 1988). In view of the half-life of nicotine in humans and the high levels of nicotine attained by cigarette smokers, even 5-10 cigarettes a day are enough to ensure the maintenance of pharmacologi- cally significant blood levels of nicotine through- out the 24 hours of the day. Royal Society of Canada N cn 0 ~ ~ m N Q~ ~

Tobacco, Nicotine, and Addiction Nicotine levels in the human brain The concentration of nicotine in the central nervous system (CNS) of human subjects who smoke has not been measured. Theoretically this could be done by analyzing brain tissue ob- tained at autopsy from smokers who had died suddenly, shortly after smoking. Such studies do not appear to have been carried out. However, work done on experimental animals has shown that, after intravenous or intraperitoneal in- jection of nicotine, the concentration in the brain is approximately four times as high as that in venous blood plasma (Stalhandske and Slanina 1972, Mansner and Mattila 1977). If the same ratio applies to humans, as seems likely on the grounds of general similarity of drug distribution in the tissues of most species of mammals, a mean day-time nicotine concen- tration of 35 ng/ml in the plasma of smokers may correspond to a mean concentration of about 140 ng/ml (approximately 1 micromole per kg) in the brain. Effects of CNS levels of nicotine Studies in animals clearly demonstrate that at concentrations of around 1 micromolar, nico- tine exerts diverse actions within the central nervous system. These include enhanced re- lease of certain neurotransmitters (Giorguieff 1984) and increased electrophysiologic activity (Clarke 1990). When "smoking doses" of nicotine are admini- stered to laboratory animals, several psy- chopharmacological effects are seen which may help to explain why the drug is reinforcing (for reviews see Clarke 1987, U.S. DHHS 1988). For example, nicotine stimulates a variety of conditioned and unconditioned behaviours, and can alter the electroencephalogram (EEG) in a direction consistent with increased arousal; it can improve the performance of various tasks, particularly under stressful conditions; and it suppresses appetite for sweet foods. It is widely held among experts in the field of research on drug addiction that, for a drug to have the potential for giving rise to drug abuse and addiction, it must produce effects that are subjectively detectable by the user, and that produce "reinforcement" (as defined by operant behavioural principles). These topics are reviewed briefly below. In general, animal Royal Society of Canada studies provide evidence that nicotine per se plays an important role in cigarette smoking, irrespective of social factors which may modu- late.the behaviour in humans. Comparison of effects of cigarette smoke and nicotine When nicotine is injected in doses intended to reproduce concentrations encountered during cigarette smoking, it tends to mimic the effects of cigarette smoke. Examples include effects on the heart and blood vessels (Armitage et al. 1968), electrocortical desynchrony (Hall 1970, Domino 1973) as well as other changes in the electroencephalogram (Ashton et al. 1980), and increased release of the neurotransmitter dopamine from various sites in the brain (Fuxe et al. 1986). Reversal of smoking withdrawal symptoms by nicotine Cessation of smoking is attended by diverse withdrawal symptoms (see Table 2). The relative intensities of these symptoms vary from individual to individual, but certain symptoms are significantly correlated with pre-abstinence plasma nicotine levels (West and Russell 1985). In other words, the higher the mean plasma level of nicotine was before smoking was stopped, the greater are the probability and severity of tltese symptoms. The importance of nicotine in the maintenance of smoking is slfown by the ability of nicotine (delivered in polacrilex gum or by transdermal patch) to reverse many of the individual symp- toms that cons*:~t~ite, the tobacco withdrawal syndrome' (Ja:''t~is Ar'~2. 1982, Hughes et al. 1984, West et• al. 1984, Schneider et al. 1984, Abelin et al. 1989). Thus, the smoker who is physically dependent on nicotine continues to smoke, at least in part, to obtain enough nico- tine to prevent or treat nicotine withdrawal symptoms. This is consistent with the observa- tion that 58% of regular smokers smoke their first cigarette of the day within 30 minutes of waking (Burson-Marsteller 1987). Alteration of smoking behaviour by nicotine antagonists Most drugs produce their effects by combining with or binding to specific "receptors", i.e., specialized molecular structures on the surfaces 13 :~,.,~.~.~..r...y..... ,_.__.......___-__.---....