Tobacco Documents Online

I I I I I I I I I I I I I I ~ I I 1 Tobacco smoking and nicotine dependence Jerome H. Jaffe 1.1 Introduction Over the past 20 years there has been a major reassessment of the way that the medicaJ and behavioural sciences vicw the habitual use of tobacco. For more than 400 years there was little question that the use of tobacco could be a habit that is exceedingly persistent and resistant to change, but until recently there was strong reluctance to consider the tobacco habit a form of drug depen- dence, analogous in most respects to the chronic use of morphine, cocaine, or alcohol. The situation has changed. Prestigious national and international organizations now recognizc heavy tobacco use to be a form of dependence (or addiction), a dependence that is the major factor keeping hundreds of tnilliotu of people smoking a substance that causes disease and death (Royal College of Physicians 1977; Surgeon General 1979, 1985, 1986; APA 1980, 1987; WHO 1985). In May of 1988, the Surgeon General of the United States released a report entitled Nrcotiae Addiction. The 600-page report, which incorporated the contributions of more than 50 scientists, and cited more than 2500 published scientific papers, drew the following three major conclusions: 1. Cigarettes and other forms of tobacco are addictive. 2. Nicotinc is the drug in tobacco that causes addiction. 3. The phartnacologieal and behavioural processes that determine tobacco addiction are similar to those that determine addiction to drugs such as heroin and cocaine. This chapter (which was completed before the release of the 1988 US Surgeon General's report) summarizes the rationale for the earlier separation of tobacco use from other varieties of drug dependence. The chapter also sumraa- rizes some of the findings from the large body of recent research which have forced the scientific community to include this most common form of drug dependence with the others. 1.2 Nicotine as a drug of dependence 1.2.1 The exclttsion of tobacco use as drug dependence in the light of current views about tobacco dependence, it is reasonable to ask how it was possible to consider the behaviour as anything other than a form of I

I I I I I I I I I I I I I Z Alicotine Psychopharmacology drug dependence. Two major beliefs about addiction or drug dependence seem to have played a role. Firstly, marked drug toleran« and dramatic, obvious, and severe withdrawal phenomcna were considered inherent aspects,of the 'true addictions'. Secondly, addictions (morbid cravings for drugs) were asso- ciated primarily, if not exclusively, with drugs which at some stage in their tue ' induce states of intoxication, thereby affecting the users' judgemcnt, person- ality, and will-power. It is not difficult to see in the writings of respected scholars and researchers of the not too distant past how these beliefs could lead to a sharp distinction between tobacco use and other patterns of drug taking that were readily categorized as addictions. Sir Humphrey Rolleston (Rolleston 1926), who headed the committee which set the tone for the British response to opiate dependence for many years to come, wrote: The Ministry of Health's Departmentai Coaursittee on Morphinc and Heroin Addiction (1926) defined an addict as a'penon who, not requiring the continued use of a drug for the relief of the syMptoms of organic disease, has acquired, as a result of repe2ted administrauon, an overpowrrin= desire for its continuance, and in whom withdrawal of the drug lcads to definite symptoms of mental or physical distress or disorder.' That smoking produces a craving for more when an attempt is made to give it up ... is undoubted, but it can seldom be accurately described as overpowering, and the effects of its withdrawal, though there may be definite rectktmess and instabitity; cannot be compared with the physical distress caused by withdrawal in morphine addicts. To regard tobacco as a dtvg of addiction ma,y be all very wd1 in a htunorous sensc, but it is hardly accurate Louis Lewin (1931), sometimes called the Father of Psychopharmacology, was unimpressed by either the degree to which nicotine tolerance develops or the severity of the tobacco withdrawal syndrome. It is, moreover, common knowledge that the use of tobaao for smoking and chewing does not necasiute a progressive increase of the dose as in the case in other toxic substanees and thaz the symptoms due to withdrawal of tobaeao, if they octur at aA, are easily overcome. These latter consist of an cctreae feeling of disoomfort and eventually bad humour and dejection. It is very exceptionally thai graver symptoms occur. Lewin gave significant weight to the differences between the effects of nicotine and other psychoactive drugs on mental functions. Smoking does not ea11 forth an exultation of internal weU-bdng as does the use of wine, but it adjusts the working condition of the mind and the disposition of many mentally active persons to a kind of serenity or'quieti.nm' during which the aetivity of thought is in no way disturbed, and froat a pbysieal point of view a certain ealmneas of movement ocarrs. Paradoxically, perhaps, from a present-day perspective, Lewin recognized the power over behaviour which could be exerted by nicotine.  p ~ ~ Ca ~ F+ C70 I

I I I I I I I I I I I I I I I ~ I I Tobacco smolang and nicotirte dependence 3 'i'hcre is no hope for the inveterate cigarcue-smoker. Not even the prospect of premature death serves to bring about a laucning of the pusion, even if the organism W given waraing in this respect. I have frequently made this observation in many etses where I have been consulted. Yolenri non fit injuria! Such foolish folk, who woutd rather die of nicotinism than curb their passion for smoking, are also subject to predes- " tination. Their ashes supply them with the final object of thcir dcsires. The central importance of physical dependence and of psychotoxicity also appeared to have formed the basis for the efforts in 1952 and again in 1957 of the W H O Expert Committees on Drugs Liable to Produce Addiction to propose formal criteria for differcntiating a drug `habit' from a drug `addiaion'. According to those criteria, both conditioas are a result of repeated consumption of a drug. Drug addiction was seea as 'a state of periodic or chronic rntoxicatioR produced by the repeated consumption of a drug', and the urge to use the drug was seen as 'an overpowering desire or nee% (coniptilsion)' in contrast to only a`desire' in the case of a habit; furthermo, the compulsion to use implied a willingness to violate socially accepted nortri.i (`obta9n it by any means'). In an addiction, tolerance and physical dependence were present, while in a habit there was no physical dependence and no abstinence syndromc. In an addiction, the behaviour was harmful to the indi- vidual and society; in a habit the harm was only to the individual (WHO 1957). From our present-day perspective, it is apparent that the WHO Expert Committees tried to make use of three often non-correlated dimensions in making the distinction between addictions and habits: (1) the degree to which the drug comes to exert control over behaviour (or the individual losa flexibility with respect to drug use): (2) the severity of the manifestatiott.s of physical dependence; (3) `thc deg= to which the use of the drug produces psychotoxicity and causes advargc effects to the individual and/or society. The emphasis placed by these WHO Expert Committees on the concept of drug `intoxication' rather than on a more morally-neutral term such as `rcin.forcing effects' of the drug should not be seen as either arbitrary or moralistic. The words used to describe s;elf-administered drugs or the people who use them are not always comparable in different lanEuaQes. The English word 'addiction' (derived from a Latin legal term for consigning a person as slave over to a master) implies only that the individual is controlled (enslaved) by the drug-using behaviour. In other languages, however, the very words used for addiction carry additional implications. Thus, In Hungarian the word for addict means literally one who uses stupefying drugs; in Chinese the character for addiction conveys the idea of hidden or secret sickness. In the Spanish I

I I I I I I I I I I I I I I I I I 4 Nicotine Psychopharmncology 'estupefaciente' and the French `droguc', the notion of intoxication is incor- porated into lhe very words used for drugs which are self-administered for non-therapeutic purposes. • 1.2.2 A Surgeon General's report fn the 1964 report of the Advisory Committee of the US Surgeon General on Smoking and Health, these WHO Fxpert Comrnittcc criteria were used as the basis for viewing tobacco use as a 'habit' rather than an addiction. The committee was also influenced by another consideration that may have been only implied by the then operative 1957 W H O Expert Committee criteria. The prevailing view among psychiatrists was, that 'addiction to potent drugs is based upon serious pcrsonality defects from underlying psycbologic or psychiatric disorders which may become manifest in other ways if the drugs are removed'. It was obvious to the committee that this is not the case with the overwhelming majority of tobacco smokers. However, the primary reasons for the decision to call heavy, even compulsive smoking a`habit' but not an 'addiction' were_ (1) the absence of clear evidence of nicotine-induced physical dependence in animal models; (2) the belief that symptoms observed when smokers stop tobacco use were `secondary to the deprivation of a desired object or habitual experience' (and not a specific nicotine withdrawal syndrome); (3) the variable duration of these cessation symptoms; (4) the non-fatal nature of sudden cessation of tobacco use; (5) the belief that the obvious tolerance of smokers for nicotine was of low grade and of a distinct variety since excessive doses could still elicit toxic effects; (6) the varicty of interventions which seemed to be equally cfficaaous (or non- efficacious) in helping motivated amokers give up the behaviour. The absence of 'psychotoxic' effects was not emphasized. it is worth noting that this historic doeturunt expressed little doubt that the primary reason so many people smoked tobacco was to obtain nicotine. However, the door was left open to the possibility that other irritants in smoke, which contribute to the sensory experience, could play some role in the behaviour: By 1964 (too Iate for use in the US Surgeon General's report), the problems inhereat in attempting to use several uncorrelated dimensions to separate 'habits' from 'addictions' led the W HO Expert Committee to recommend abandoning both terms in favour of the concept of drug dependence and to emphasize that what constituted dependence was to be spelied out for each drug or drug category. Drug dependence was defined as 'a state, psychic and sometimes also physical, resulting from the interaction between a living I

I I I I I I I I I I I I I I I Tobncco smoking and nfcatine dependence - 5 organism and a drug, characteriaed by behavioural and other responses that a.tways includc a compulsion to take the drug on a continuous or periodic basis in order to experience its psychic effects, and sometimes to avoid the discom= foct of its absence. Tolerance may or may not be present. A person may be dependent on more than one drug' (Eddy et al. 1965). Despite this broader definition, in several subsequent reports w H O F,xpert Coaimittees developed eight categories of dependence-producing dru.gs, but made no reference to tobacco or nicotine. It was not until the report of 1974 ( W H O 1974) that the committee stated that: ... though not listed above, It (tobaccoJ clearly is a dcpendence-producing substancc wieh a capacity to cause physical harm to the user, and its use is so widespread as to constitute a public health problem. However, unlike the types of dependence-produciag drug just noted, it produces rclatively little stimulation or depression of the central nervous systau, or disturbance: in perception, mood, thinking, behaviour or motor tllncuon. Any such psychoto;de effects produced by tobacco, even when it is used in large amounts, are slight compared with those of the types of dependena-produein.g drugs listed above.... Attention has been restricted to the use of dependence- produana drugs apable of ezerting major psyehotouc effects Thus, it can be seen that the notions about the importance of sevzrerwith- drawai symptoms and drug-induced psychotoxic effects served to separate tobacco dependence from other drug-using patterns which, compared with the tobacco habit, often exerted less persistent and less pervasive control over the behaviour of the user. In the WHO-sponsored ninth version of Intcrnational Classification of Diseases (ICD-9) (WHO 1978), tobacco dependence is listed separately from other drugs because of the abseacc of 'psychotoxic effects'. But even the mention of tobacco dcpetdence is significant. Something happened between the 1960's and 1974. Just what happened may never be entirely clear, but several findings, decisions, and events seem worth noting. The failure of smokers to respond to health proaouncctaeats with a wholesale abandonment of smoking underscored the tenacity of the behaviour. Researchers in the field of the addictions took note. Pharmacologists began cmphasiune the importance of nicotine as the addictive agent in tobacco (Armitage er ai. 1968; Jarvik 1970), and around the same time an influential review focused attention on behavioural factors in the pharmacology of addic- tive processes (Schuster and Thompson 1969). The Addiction Research Unit at the Inslitute of Psychiatry in London created a unit to study tobacco dependence. In 1971, Michael Russell, a a:ember of that unit, published a short, but powerful summary of the argument for nicotine as a dependence- producing drug. Russell's paper in turn influenced Brecher (1972) in the United States, who wrote a widely read book (LicFt and Illicit DneYs) expres- sing a similar view, under the sponsorship of the respected Consumers Union. Simultaneously, in the United States, in the early 1970's there was increased boldness in describing tobacco use along with other forms of drug dependence in standard texts of pharmacology (see Jaffe 1975), and the committee to revise the American Psychiatric Association's (APA) Diagnostic and . I

I I I I I I I I I I I I I I 6 Nicotine Psychopharmacology Statistical Manual (DSM) was at least debating the need to include tobacco dependencc among the diagnostic possibiifties. In 1977, the Royal Coltege of Physicians described tobacco smoking as a form of drug dependeace comparable to other forms of addiction. An early proposal to create specfal criteria for tobacco dependence because of the large nurnbcr of dependent smokers in the population was abandoned (see Jaffe and Jarvik 1978), but tobauo dependence was included in D S M-III in 1980 (AP A 1980). Emboldened by these developments in the academic and professional world, the National Institute on Drug Abuse made a decision in the late 1970's to increase funding for research on tobacco use and dependence. All of these events and decisions helped to fuel the great increase in research on tobacco dependence, only some.of which is highlighted in this introductory chapter. 1.2.3 Recent changes in the concept of drug dependence The concept of tobacco use as a form of drug dependence cannot be discussed without some consideration of the way in which ideas about drug dependence have continued to evolve. For a variety of reasons, the criteria for diagnosing drug dependence incorporated into DSM-IIi in 1980 continued to give inordi- nate weight to evidence of withdrawal syinptocns (physical dependence), thus continuing the confusing ovcrlap between biological adaptations to the admin- istration of a drug and drug dependence as a bio-behavioural syndrome in which physical dependence, when present, is but one element. Meanwlule, a WHO working group on nomenelature of drug and alcohol-related problems was developing a terminology and a diagnostic framework that could better incorporate newer research findings and evolving concepts. The most impor- tant of these concepts were that: (1) dependence is a clustering of phenomena - cognitive, behaviotual, and Physiological; (2) learning is a central element in the dependence process; (3) multiple criteria are neceusry for its assessment and evidence of physical dependence (neuroadaptation) is just one and not necessarily the most irapoitant; (4) the dependence syndrome is not absolute but exist.s in different degrees. These ideas, as well as :otne suggested 'dimensions' for deciding to what degree dependenee exists, were incorporated into a W H O memorandum (Edwards et cl. 1981). Thus, in a movement away from the effort to develop criteria for types of dependence based on pharmacological categories, this WHO group proposed a general model of dependence which was applicable across a broad range of pharmacological agents. For the first time in 15 yeats, W H O definitions and terminology coincided with that in at least one standard pharmacology textbook (Jaffe I975,1980). After considerable debate, most of the ideas of the WHO memorandum, including the notion of a syndrome that ~ W CD ~ ~

Tobacco smoking and nicotine dependence - 7 I I I I I I I I 'I I I I I I I I I vaties in intensity, werc incorporated into a revised version of the APA's Diagnostic and Statistical Manual (D S M-I II•R) in 1987. The D S M-I II-R criteria for drug dependence (I'ablc 1.1) were designed to a considerable eztent to assess the phenomena or dimensions of the drug-dependence syndrome as' described in the 1981 WHO memorandum (Edwards et Ql. 1981). Evidence of physical dependence and tolerance, once the central feature of dependence in previous conceptualizations, now became one of sevcral characteristic features. The material to be suummarized here will touch upon the degree to which tobacco use meets this set of criteria. Because of its historical signi- ficaace, and because of older perceptions of the central importance of with- drawal symptoms, evidence for tobacco physical dependence will be considered first. Tahle 1.1. Diagnostic criteria for psychoactive substance dependence of the American Psychiatric Association (1987) A. At least three o f the following: (1) substance oftea taken in larger amounts or over a longer period than the person intendnd (2) persistent desire or one or more unsuccessful efforts to cut down or control substance use (3) a gw deal of time spent in aaivities necrssary to act the substance (for exarapte, theft), taking the substance (for ezample, chain smokiar), or recovering from its effetu (4) frequent intouituion or withdrawal symptoms when expected to fulfil major role obligations at work. school or home (for example, does not go to work because hung over, goes to school or work 'high', intoxicated while taking care of his or her children), or when substsaee use is physically barasdous (for exatnple, drives when intoxi2ted) (S)- naportant social, occupational or recreational activities given up or reduced because of substanee use (6) continued substance use despite knowledge of having a persistent or recurrent social, psychological or physical problem that is caused or exacerbated by the use of the substance (for example, keeps using heroin despite family arguments about it, cocsiao-induced depression, or having an ulcer made worse by ~ (7) marked tolernace: need for markedly increased amounts of the substance (i.e. at least a 50 per cent inereasc) in order to achieve intoxication or desaYd effect, or markedly diminishing effect with continued use of the same amount Note: The following items may not apply to cannabis, hallucinogetu, or phencyclidine (PCP): (8) characteristic withdrawal symptoms (see specific withdrawal syndromes under Psyehoactive Substance-induced Organie Mental Disorders) (9) substance often takea to rrlieve or avoid withdnwal symptoms B. Seme symptoms of the distnrbancr have persisted for at least one month, or have occutred repe=redly over a longer period of time I

a Nicotine Psychophnrmocoloyry I I I I I I I I I I I I I I I -1.3 Criteria for drug dependence 1.3.1 Withdrawal symptoms 1.3.1.1 The evidence for a tobacco (nicotine) withdrawal syndrome As early as 1942, Johnston reported that injections of nicotine rclieved withdrawal symptoms experienced when a cisarette smoker stopped smoking. In 1945, it was reported that some smokers given low nicotine cigarettes experienced symptoms, now recognized as tobacco-withdrawal symptoms (Finnegan et al. 1945). However, carefully controlled experiments on tobacco withdrawal comparable to those used to establish the nature and specificity of opiate, barbiturate, and alcohol withdrawal syndromes were not carried out until many years later. Over the past decade there have been numerous studies on the characteristics and time course of the tobacco withdrawal syndrome and its relationship to reduction in nicotine intake. These studies were aided in substantial measure by better methods to measure body levels of nicotine, assess nicotine intake, observe and record withdnwal phenomena, and manipuiate levels of nicotine in the body. Many experiments have been carried out using nicotine polacrilex (nicotine gum); several have employed either intravenous nicotine, nicotine nasal solutions, nicotine patches which permit nicotine to be absorbed through the skin, or in at least one, a dgarette-like device which delivers nicotine vapour. Nevertheless, the demonsttaiion of which signs and symptoms are spedfic to nicotine deprivation remains partially incomplete because of Ifmi- tations on the forms and doses of nicotine that can be given safely to human voiunteers, and because not ai] researchers use the same instruments to observe and record the signs and symptoms of withdrawal. Only a few experiments have involved repetitive intravenous nicotine doses, or nicotine inhaled in a form that is rapidly absorbed into the circulation. Either of these methods would tuimic better the sudden sharp increascs and brain levels of nicotine which occur when cigarette smoke is inhaled than do buccal, nasal, or transdermal routes. Despite these limitations there is reatarkable consistency in the sigas and symptoms reported from various parts of the world when cigarette smokers stop smoking.l3ese include craving for tobacco (nicotine), irritability, impa- tience, frustration or anQer, aaxiety, difficulty concentratfng. restlessness, decreascd heart rate, increased appetite, weight gain, depreuion, disturbed sleep, constipaiion. difficulty in socializing, deereased levels of adrenaline and noradrenaline in urine, altered ekctroencephalographic patterns while awake (increased slow waves) and while asleep (increased REM sleep), and decre- meats in performance on a variety of cognitive tasks (Myrsten a a!. 1977; Elgerot 1978; Gailford 1966; Ryan 1973; Larson and Silve2te 1975; Shiffman and Jarvik 1976; Wesaes and Warburton 1984; Jarvis st a!. 1982; West et aL 1984; Hughes et a!. 1984; Hughes and Hatsukarni 1986; Fagerstrom 1988; t`? Q? ~ ~ ~ ~

I Tobacco smokng and nicotine dependence _ 9 I I I I I I I I I I I I I I I I I hienningfield and Jasinski 1988). Some of these symptoms are also seen after cessation of stnohcless tobacco (for example, snuff) (Hatsukami et al. 1987) although overall syndrome severity may not be as great; also, some of the symptoms may be due to the ending of direct effects of nicotine. Only some of - these symptoms are listed as criteria in DSM-III-R (APA 1987) bbecause ttlat documcnt gave greater weight to symptoms observed in recent controlled prospective studies in the United States. The consistency of the pattern of tobacco withdrawal symptoms in different countries argues for a biologically based and largely unlearned syndrome. However, the most persuasive evidence that components of the syndrome ate due to withdrawal of aicotine is that in double-blind studies, nicotine is far superior to placebo in suppressing or preventing the appearance of many of the signs and symptoms (Hughes er al. 1984; Sch:leider et al. 1984; West et al. 1984; Fagerstrom 1988; Stitzer and Gross 1988; Henningfield and Jasinski 1988). In placebo-gum controlled studies, certain signs and symptoms appear to be more consistently suppressed than others by currently available dosage forms of nicotine gum. Irritability and impatience were reduced in at Ieast five independent studies; arudety and difficulty concentrating were reduced in at least two studies. Other sy7nptoms where nicotine vessus placebo-gum differ- ences in severity were significant in at least one study include depression, hunger, somatic complaints, and sociability. At least three studies of nicotine gum.reporz a reduction in urge to use or craving for tobacco (Hjalmarson 1984; Schneider 1986; Stitzer and Gross 1988) but a number of other studies have not found such a reduction. Reduction in craving was seen with trans- dcrmal nicotine (Rose er al. 1985a). However, as pointed out by West (1988) much depends on how the questions are asked. Smokers may report severe craving endorsing the hi;ghest category on 'the craving scale, but if asked, they may also report that craving is helped by the use of the gum or other nicotine delivery forms. Equally persuasive support for the view that these various symptoms are related to nicotine withdrawal is the observation that some former smokers who stop smoking cigarettes with the aid of nicotiae gum develop physical dependence on the gum. When placebo gura is substituted for nicotine Zum in long-term users, nicotine withdrawal symptoms emerge (West and Russetl 1985a; Hughes et al. 1986). In one double-blind cross-over study of 8 smokers, who were using about 10 pieces of gum per day but had not smoked cigarettes for at least one month, placebo substitution resulted in irritability, in;dety, restlessness, impatience, difficulty concentrating and hunger, as well as craving for tobacco. Observer-rated withdrawal discomfort increased for 7 out of 8 subjects. In the two subjects who had the highest ratings of withdrawal discomfort iduriag placebo substitution, one relapsed to cigarettes, the other to known nicotine gum. Most subjects could discriminate placebo from nicatine gum on the basis of withdrawal discomfort, but not on the basis of taste or I

I I I I I I I I I I I I I I I 10 Nicotine PsychopharmacoIogy side-effects. The magnitude of withdrawal discomfort was comparable to that seen after smoking cessation (Hughes et al. 1986). In gum users who had stopped smoking for a year or more, nicotine withdrawal symptoms, vi+ithout craving for cigarettes, were observed (West and Russell 1985a). This pattern of suppression and re-emergencx of symptoms can leave little doubt that compo- nents of the tobacco withdrawal syndrome are due to nicotine withdrawal and not merely due to the eatotional experience associated with the loss of 'a desired object'. 1.3. 1.2 .isptcts of tobacro withdrawal in rreed oJJrrrther research Several aspects of the tobacco withdrawal syndrome are not yet fully explained. Firstly, why is there such an inconsistent relationship between apparent tobacco intake and the severity of the syndrome? Secondly, why is there such variability between individuals in the manifestations of withdrawal? Thirdly, why has it sometimes been so difficult to reduce craving for cigarette smoke (as opposed to other rymptoms) with nicotine itseIf? Fourthly, what explains the great variability in duration of withdrawal symptomatology? Fifthly, why is the sevcrity of tobaeco withdrawal a weak predictor of successful long-term abstinence? While most studies have shown that difficulty in quitting and the severity of tobacco withdrawal are directly related to the number of cigarettes smoked (Hughes er al. 1981; Surgeon Genera11985), others have found no relationship (HuYhes and Hatsuka,mi 1986; West and Russell 198Sb). A partial explanation for this inconsistent dose-withdrawal severity relationship so typical of other forms of drug dependence may lie in the tremendous discrepancy between nicotine intake as estimated from the number of cigarettes smoked and intake estimated from more direct biological measures. As a device for delivering nicotine the dgarette permits an btquisite degree of control and the po:sibility of varying intake of smoke constituents over a wide range. Smokers can vary not only frequency of each cigarette, but also puff frequency, puff volume, depth of inhalation. duration of inhalation, degree of dilution of smoke, and how close to the tip each cigarette is smoked (see Fig. 1.1). As a result, there can be wide variation in aicotine intake among smokers smoking a comparable number of cigarettes of the same brand. Russell and coworkers (Russell 1986) have found almost no correlation betweea plasma levels of nicotine in the afternoon and the nicotine content of the brand smoked. While the findings are not yet consistent, several groups have found correlations between biological measures of nicatine intake, such as levels of nicotine or its inactive metabolite cotinine, and either difficulty in quitting or response to treatment with nicotine gum (Hall et al. 1985; Zeidenbera et ai. 1977). West and Russell (198Sb) found that pre-abstinencc plasmi nicotine intake sienitiuntly predicted craving, hungcr, restlessness, inability to concentrate and overall withdrawal severity. Expired carbon monoxide level, which represents a more indirect estimate of nicotine intake, C3 W C.? I ~