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American Tobacco

Health Consequences of Smoking, Nicotine Addiction, A Report of the Surgeon General

Date: 16 May 1988
Length: 617 pages
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Us Department, O.F. Health And Human Services

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TABLE 6.~ntinued to Attritmte Caffeine Marijuana Lysergic scld diethylamide C-nlorprome2ine Physical de.nee d~ such that will e~t'0mpe~ies abr,pt ,,l~inee~ Tolerance develops Therapeutic use in t~ffivA~lent of medal disorder + Griflith~ Bigelow. Liebs0n (19~6k ~ av~ Pfeiffer {)943). Ho~t et eL (1934). Grimths and Wcodson (1988a) + Carney (19~2), Eddy emd IDow~ (192gl, Grlffiths and Wcodsoa (1988a) J~s AMA (1983), Gilman et eL (19S5), Medical Economies Company (19~7k and othe~ *? Jo~s and Benowitz (1976k Mevdels~ et eL (1984), Ford and McMinan (1972k Beardsley eL at. (19~6~ + McMillan et at. (1970), Weft et aL (1968), Babor et al. (1975), Cane et al (1986~ +s AMA (1983k Gilman et al. (19~5}, I~edi~l E¢onomlcs Company (1967), and others l.~5~ll et al. (19~6) + Isbell et al. (1956) ?7 AMA (1983),+Gilman e~ al (I~5), Medical E~oaomlc~ Company t19~?), and o*J',ers ? Bat~ess~L~i (~9~0) +m AMA (19~3), Gil~a~ et at 11985), Medical F.covom]cs Company (19~71, and others N(fJ~ + in (~ ;¢.~t~'~ that drug sdminlst ratlon pv0d~ t}te effect. - indi~de~ that drug ~dminlst rat ion ~oes not pr~t,~e the effect: ? ir~i<~t es t ~',at available scient i~c d~ta art* inad~uate to draw conclm • FurLher dLsc~ss,on can t~ found in ot her chapters ca" thi~ Repot t ' A~ ald to stop ¢igarat te smc~ing and ~o treat nK~tlr~ de~ AS topic~ ae~tt~etic (~arely ~1 fo~ ear. ~mSel eye, and thr~L = ( ] ) ~s st rcog ~halge~ics ~or ~reatt~ent of bpth ~ and ¢hr0n~c paia • 12} t r~tment for myocaTdial infa~ (~m. anx~[y~m, and r~d~k-t~ I¢f¢ vent~l~r w0rk.h~d ~d ~ardml vxygea requi~'~t$), 13) fc~r obstetn¢ a~a~, (4) ~ ~U: reed k~tion to msoc4Ji ihductm~. {5) t r~t merit for p~Jmonar7 edema. (6~ ~ cowgh ~p~sanL [7} t~t~t for ~ diarrhea "(1) .~ a~tlsep~ ~geht On skin, (21 intrave~,.sly Io great ~. L~ ( uterine ~elax~nt ), (3) t ~t~t rnent of .pe<ti~it y by local or intr~t henri inject ic*~ cf dilute ~b~mlute alco]lc~ ~ uti~n, t4i vehicle in de~matol~g;¢ p~m~tica~ (ant ~septi~ acL.onI astringent e<t ~;~, Cooling eff~t ), (S) t reatr.tent o~- alco;io] withdrawal i l I Iheorp~e~ted with ~ t he.ounce- e~a]ges~ (e~., asplnn } ~ tr~t Ot~i~ry ~emt~ t m and relieve inflammatory p~i~ (scant s~teatiC~ data to substant i~tel, i21 in comblnat lO~ with e~ot ~lkalold IO tr~L mi~r~i~ hee~ee~he. (3) in combination "~th ~Tml~atho~im~i¢ eg~nt~ pte~s~ big ano]'e~'t ic prope~ies in v~.t -loss rn~ic~t io~% (4~ ~ sllmul~nL iS} t reaLW, e.nt (cllr~;~l tz~h,I tot ]~ inf~mt ap~ea of tmdete~ne~ origin. (6p ~vely for treatment Of ~n~*~l ,~er~otm sy~em depressant ~nin~ • ( 1J AS ~ntlemetlc for ~ cheroot herapy pat ~e~L (2) gla~om~ t re~t ment
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TABLE 6.--Continued , No(w at ~'~ent, but ~ ~ in ~ I11 as ~,~b.en~?y aid, t2) lts ~ in m ai~ and op~ a~mn trestcc~nt, 13J ~ ~d)u~t m terminal ~c~r p~uent therapy tQ red~e ~o~ a~tges~ nee~ ~,d indoce ~r~quility ~I) lv~trm~n~nt of ~y~hotk: disorder f0~t~ (21 t reatre~nt for rt~ms~ ~md vomlt ;e~. (31 reltef of p;%*surgetW restl~ and apprehension. ~4) ~l~*~meht for ~te. intt~mlt tent p~hyrl~. ~5) as a~junct in tetanus t reatra~nt* (6) to control mania n mnif~t~ons in mani~iep~esmve illn~* 17) t reetmem f~ int r~c~ib]e hi~up~ (~) treetmerit of child ren'~ sex, re bel~vior~t d~order~ cha~ by c~mb~i~ or hyperexettabl~ bt~mvior, (9) ~ st'egnd~tine U~t t ~ent for rm~ychotie a~xle~y ~.-]L~n~' w~ ~ m~oved, bm the ~creme~ s~res ~ a te~ic~ s~d a~ety ~le susa~sted ~ "~1~"
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severe mood swings (Mello and Mendelson 1970; Mello 1968; Isbell et al. 1950); erratic supplies of opioids may be associated with sociop- athic drug-seeking and withdrawal-related mood effects (Jasinski 1977); erratic supply of tobacco can also result in disruption of ongoing activities in an effort to obtain tobacco or as a consequence of withdrawal. Consideration of multiple factors such as the dependence potential of a drug, the extent of its actual use, and the degree to which it produces adverse effects can be used to access the overall liability associated with the use of a drag (i.e., "abuse liability"} (Brady and Lukas 1984; Griffiths et al. 1985; Yanagita 1987). For example, caffeine produces only minimal (if any) disruptive behavioral or physiological effects and is not generally regarded as posing a serious public health problem even though self-administration may be widespread (e.g., caffeine in teaor coffee) (Griffiths and Woodson 1988a,b). In contrast, drugs which produce disruptive physiological and behavioral changes even when self-administered infrequently may be considered to represent a more serious health hazard (e.g., LSD). Drugs may fall anywhere on the continuum defined by these parameters, and the relative impact on health is most effectively determined by a comprehensive assessment of these interactive behavioral and physiological dimensions (Griffiths, Brady, Snell 1978b; Griffiths et al. 1985; Brady and Lukas 1984; Yanagita 1987). Identification of Dependence-Producing Drugs Independent of whether use of a substance has been observed to lead to addiction, it is possible to directly and objectively test a chemical to determine if it is addicting. Such tests provide data used by Federal (e.g., FDA~ Drug Enforcement Administration) and International (e.g., WHO) agencies as to how to regulate chemicals. In fact, new drugs are usually evaluated and regulated ("scheduled") before they are ever made available for medical application. Such decisions rely heavily upon the known properties of addicting drugs and on the methods used to test for such properties (bath described in this Chapter). Although the physicechemical structure of the drug is one determinant of the stimulus effects produced by drug adminis- tration, simply knowing the drug structure is rarely sufficient to predict the nature and magnitude of possible drug effects (Barnett, Trsie, Willette 1978); behavioral and physiological testing in animals and humans is usually necessary. When there is convergent evidence from multiple measures of dependence potential; then the drug is appropriately regarded as addicting or dependence producing. Whether humans outside the laboratory actually become addicted will depend on additional factors such as availability, price, and social acceptability of the drug (US DHHS 1987; also see discussion by Katz and Galdberg 1988). O 394 •
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Table 6 provides a comparison of several drugs in terms of the major measures that have been reviewed in this Chapter. As shown in the table, drugs known to produce widespread problems in a given population are characterized by positive responses with most of these measures (cocaine, morphine-like drugs, alcohol, and nicotine). Conversely, drugs not contributing to such problems have fewer positive responses on the various tests (cholorpremazine). Intermedi- ate drugs are associated with intermediate levels of difficulty in management of use. Comparison Among Drugs Within a given class of drugs, it is sometimes possible to rate their .celative efficacy as reinforcers by how much behavior was affected (e.g., how many lover prossos would occur or how much money would be paid) (Griffiths etal. 1981; Yanagita 1987). For instance, the slowor onsetting/offsotting formulations of opioids, barbiturates, stimulants, and nicotine appear to hays a lower dependence poten- tial than the quicker onsotting and offsetting formulations (Jaffe 1985). The practical gonecaiity of such comparisons, however, is limited beeauso many other factors determine the overall level of depon- dence that might dovolop, the extent 'of social and/or personal damage, and the resulting level of social concern (Yanagita 1987; Katz and Goldberg 1988). For example, the increasing availability and decreasing relative price of cocaine in recen.t years are major factors contributing to increased levels of use and resultant social damage (US DHHS 1987). Analogously, the widespread ready availability and the relatively low cost of tobacco products and alcohol have probably contributed to the much higher rates of addiction and mortality associated with alcohol and tobacco than with drugs such as cocaine, even though cocaine may appear to be a more offoctivo reinforcer in animals. Social or cultural factors may also contribute to the spread and levels of drug use. For example, sensational press reporting may have contributed to the populariza- tion of barbiturates in the 1960s (Breoher 1972), and the mass marketing and advertising of tobacco products is likely to have contributed to the use of these products, ospecially among women and ospecially in the case of smokeless tobacco products (Ernster 1985, 1986; Warner 1986b; Davis 1987; Tye, Warrior, Giants 1987). Four oxamplos of drugs associated with striking changes in the prevalence of use among various populations as well as associated morbidity are: alcohol, for which use and associated disoases decreased during the Prohibition years early in the 20th century; lysorgic acid diethylamide (LSD), for which use and associated hospitalizations were elevated during the 1960s; cocaine, for which use and associated hospitalizations increased during the 1970s 305
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(Crowiey and Rhine 1985; Levine 1984; Nahas and Frick 1991; Dupont, Goldstein, Brown 1979; Holder 1987; US DHHS 1987); tobacco, in which consumption of smokeless tobacco products in- creased among youth in 1970s and cigarette consumption increased sharply among women in the 1950s and 1960s (US DHHS 1991, 1986; Appendix A). As discussed in the aforementioned references, the changes in use of these drugs were not due to changes in the pharmacologic actions of the drug or sudden changes in genetic constitution of the populations, but rather to changes in factors such as availability, cost, social acceptability, regulatory controls, market- ing efforts, and general perceptions about the risks associated with use. Finally, various other factors contribute to the level of social concern and may be only indirectly related or unrelated to the pharmacologic properties of the drug itself. For instance, the observations on transmission of AIDS by way of shared needles among i.e. drug users and on cancer caused by tobacco smoke carcinogens have greatly increased the liability of use attributed to these drugs in recent years. Environmental Determinants of Drug Dependence Including Behavioral Cond/tionlng A common feature of use of all dependence.producing drugs is that the positive (satisfaction symptoms) and negative (e.g., withdrawal symptoms) effects may become conditioned responses to associated environmental stimuli, The implications of this are important for understanding the chronic and self-sustaining nature of drug dependencies. Such conditioning is a powerful behavioral mechan- ism by which the drug comes to control an increasing amount of the behavior of the drug user (Thompson and Schuster 1968; Goldberg 1976a). Some of the important environmental determinants of drug dependence are discussed elsewhere in this Chapter in the context of drug self-administration studies. These factors include: (I) the behavioral or economic cost of the drug itself or of taking the drug, (2) direct pressure to take the drug by making other reinforcers contingent upon drug taking, and (3) the other ongoing activities of the person (e.g., demanding work schedule) that tend to enhance drug taking. The focus of the present Section is on environmental stimuli that may contribute to drug dependence by evoking urges to use drugs, and by eliciting bodily responses that mimic the usual effects of either drug taking or drug withdrawal reactions. 306 •
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Drug Taking as a Learned Behavior The interface between a drug and its effects is the behavior of obtaining and ingesting the drug. Such behavior is learned behavior, and as discussed earlier in this Chapter, many of the factors that modulate this behavior are similar to those which modulate other learned behaviors including eating, exercise, and occupational skills (Thompson and Schuster, 1968). Technically, drug taking is "operant behavior" and includes "respondent" or "classically conditioned" components. The basic governing principle of operant behavior is that it occurs in the context of certain stimuli and is either strengthened or weakened by the nature of the consequence (a positive reinforcer strengthens the response and a punisher weakens the response} (Skinner 1938, 1953). Thus, for example, a friend might offer a drug (antecedent stimulus); the drug is ingested (operant behavior or response); and the effects of the drug strengthen the behavior (positive reinforcement). Respondent conditioning occurs simultaneously and further contributes to the strength of the behavior (Bouton and Swartzentruber 1986). A drug might serve as an unconditioned stimulus which elicits a relatively involuntary response (e.g., nicotine and morphine can elicit feelings of pleasure and/or nausea); when physical dependence has occurred, drug abstinence can also elicit certain responses (e.g., anxiety and urges to take the drug). Any environmental or even internal stimulus can become part of this conditioning process by repeated association with the elicited response. For example, the taste of alcohol, the smell of' smoke, "thinking" about use of the substance, and the sight of cocaine- or opioid-associated paraphernalia can elicit feelings associ- ated with either the administration or withdrawal of the drug (Childress, McLenan, O'Brien 1986a,b; Ludwig 1986; Ludwig and Stark 1974; Erben 1977; Gotestam and Melin 1983; Pickeus, Bigelow, Griffiths 1973; Rickard-Figueroa and Zeichner 1985; Levine 1974). The simultaneous operation of both operant and respondent conditioning can converge to generate and maintain powerful chains of behavior over which the individual may have little control. As shown earlier in this Chapter, highly addicting drugs are those which are very effective at reinforcing behavior and eliciting responses. Their power can be increased by factors such as drug deprivation, which may be associated with a discomforting with- drawal syndrome. In the presence of withdrawal, the person may behave in a way to relieve the discomfort of a withdrawal syndrome', in this case the withdrawal syndrome itself may be said to be functioning as a negative reinforcer. When drugs are readily available, as with tobacco for most people or opioids for physicians, these behavioral conditioning processes may be very subtle because the drug can be taken in a pattern that avoids excessive discomfort. For example, early interoceptive or subjective withdrawal cues that 307
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are evident upon waking in the morning signal that "it is time to smoke a cigarette," and thus the smoker neither "forgets to smoke" nor experiences pronounced withdrawal symptoms. As implied by the foregoing discussion, the strength and persis- tence of drug-seeking behavior are not just functions of the drug itself or of withdrawal. Rather, they are determined by many factors, such as the number of times that certain reponses are associated with certain stimuli, the presence or absence of such stimuli, the subjective discomfort occurring as part of withdrawal, and the availability of the drug. The convergence of so many environmental and subjective forces can result in extremely persistent behavior that may appear disproportionate to the pleasure actually experi- enced when the drug is taken (e.g., the few minutes of pleasure from the postdinner cigarette or when heroin is taken after 8 to 12 hr of deprivation). In fact, the subjective pleasure itself may be very mild, and the person may describe the role of the drug as "simply maintaining feelings of normalcy or comfort" and not as "getting high" per se. The scientific basis for these observations has been actively and systematically studied since the pioneering work of Wikler and others (Wikler 1973) and has been reported and reviewed in detail elsewhere (Goudie and Demellweek 1986; O'Brien, Ehrman, Ternes 1986; Grabowski and Cherek 1983; Grabowski and O'Brien 1981; Childress, McLenan, O'Brien 1986a,b; McLellan et el. 1986; Wikler 1973; Meyer and Mirin 1979). Drug-Associated Stimuli Modulate Drug Seeking Stimuli associated with drug effects may come to elicit ("trigger") those same effects or sometimes opposite effects (withdrawal re. sponses). For example, increased heart rate induced by stimulant administration may become associated with multiple environmental stimuli - the color of the tablet, the individual who provided it, and the office environment in which the drug was taken. These stimuli may act alone or in concert. One stimulus may produce a slight heart rate change; two such stimuli may produce a larger change; and the presentation of many such stimuli may have a synergistic effect. Other stimuli may counteract or facilitate these effects (Schindler, Katz, Goldberg, in press). The response produced in relation to environmental correlates may differ qualitatively from the direct drug effect. For instance, the direct effect of a drug may be a heart rate increase, whereas the conditioned or learned response to drug.associated stimuli may be either a decrease or an increase in heart rate. Changes may be particularly evident for agents with biphasie effects such as nicotine. Whatever the direction of change in response value, the events may be of physiological and behavioral significance (for example, see Childreas, McLellan, O'Brien 1986a,b; O'Brien, Ehrman, Ternes Q 308 •
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1986; Stewart, de Wit, Eikelboom 1984; Orabowski and O'Brien 1991; Childress at al., in press). These complex conditioning processes which can function to precipitate drug taking appear to function similarly for a variety of drugs including opioids and tobacco (Ternes 1977). Since the 1960s many researchem have shown that the role of associated stimuli is important for diverse biological reinforcers such as drugs, food, and sex. For example, Thompson and Schuster (1964) demonstrated that environmental stimuli paired with drugs could themselves come to generate drug seeking in monkeys.Schuster and Woods (1968), Davis and Smith (1976), and Carnathan, Meyer, and Cochin (1977) demonstrated that stimuli previously associated with drug taking could generate much drug-seeking behavior in animals during extinction of use when the drug is no longer available. Similar findings were obtained in a study of i.v. cocaine self- administrationin which human volunteers emitted high rates of lever pressing in the presence of cocaine-associated stimuli when the drug was not available (Katz and Goldberg 1988). Goldberg (1976b) reported that environmental stimuli associated with drug taking could help sustain substantial behavioral reper- toires in monkeys often far in excess of the behavior that was maintained when just the drug was given. Similarly, Meisch found that the taste and smell of alcohol, which were normally found to be highly aversive to rats, becan~e highly effective stimuli in their own right in the maintenance of alcohol-seeking behavior, even when alcohol was not actually available for the rats to consume (Meisch 1977). Lal and colleagues (1976) demonstrated that environmental stimuli previously associated with drug effects could, by producing drug-like responses, attenuate opiate withdrawal signs in rats. These and many other studies have shown conclusively that specific environmental stimuli associated with drug taking exert control over drug seeking, drug taking, and characteristics of the drug response itself. Environmental conditions in many forms can contribute to sustained drug use, and specific stimulus conditions can have well- defined drug-like properties. This phenomenon, which has been well documented in laboratory settings, is recognized as being powerful in clinical pharmacology, in which "placebo" effects (conditioned responses to drug.taking conditions) may be dramatic and difficult to separate from so-called direct drug effects. Both direct drug effects and these established through learning influence physiology and behavior, thereby contributing to the strength of addictive behav- iors. Recent reports suggest that conditioned effects can be attenuat- ed for some individuals through effective treatment specifically designed to extinguish, or alter through learning, these responses (Childrees, McLellan, O'Brien 1986a,b; MeLellan et al. 1986). ~o9
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The stimuli associated with drug effects also may generate further drug seeking and drug taking. Wikler (1973) and more recently Meyer and Mirin (1979) contributed substantially to both the conceptual framework and the data describing these complex phenomena. These investigators found that environmental stimuli which correlated with direct drug effects are pertinent to the acquisition, maintenance, and elimination of opioid taking by humans. Similar findings were observed in an intensive study of an alcoholic subject: alcohol.associated stimuli produced orderly re- sponses including urges to drink and even drinking itself (Pickens, Bigelow, Griffiths 1973). A series of studies by Goldberg and his colleagues (Goldberg 1970; Goldberg, Kelleher, Morse 1975; Goldberg and Kelleher 1977; Goldberg, Spoalman, Kelleher 1979) showed that environmental stimuli occasionally associated with morphine injec- tions or with ear!y withdrawal effects could lead to increased drug seeking and/or drug taking. Conditioned withdrawal Symptoms May Precipitate Drug Seeking Wikler (1948) first described the discomfort of long-abstinent patients on their return to environments in which they had previously used drugs and experienced withdrawal symptoms. Subse- quently, Wikler (1973), O'Brien (1975) and colleagues (O'Brien, Ehrman, Ternes !986; O'Brien et al. 1975} and several other researchers (Siegel 1975, 1976, 1978; Eikelbeom and Stewart 1979; Stewart, de Wit, Eikelboom 1984; Childress et al., in press) have made fundamental contributions to the identification of the complex interplay of factors modulating the physiological and behavioral components of abstinence. These and other studies have shown that the conditions established by abrupt withdrawal after chronic administration of a drug can serve as setting conditions which may result in further drug taking. In other words, for some individuals the onset or anticipation of abstinence symptoms may be strongly linked to reinitiation of drug self-administration. In turn, the drug effect reinforces the reinitiation of drug taking (Stewart, de Wit, Eikelboom 1984). Withdrawal symptoms and drug taking may thus become closely associated with a range of environmental stimuli. These stimuli then come to elicit abstinence symptoms and generate drug taking through a variety of powerful biobehavioral mechan- isms. In fact, McNeill and colleagues (1986) have concluded that the pattern of abstinence symptoms itself may be in part determined by conditioning factors. Environmental stimuli can lead to drug seeking by eliciting distressing conditioned withdrawal effects. Several thorough reviews on conditioning factors in drug dependence indicate that correlated behaviors and stimuli dramatically alter drug effects, withdrawal Q 810 •
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symptoms, and other features of substance use behaviors (Goudle and Demellweek 1986; O'Brien, Ehrman, Ternes 1986; Grabowski and Cherek 1983; Grabowski and O'Brien 1981). These interacting factors have also been described in a number of prominent medical and scientific texts (Jaffe 1986, 1987), as well as in the recent Second Triennial Report to Congress from the Secretory, Department of Health and Human Services (US DHHS 1987). One of the clearest observations of the contribution of environmen- tal factors in tobacco withdrawal was made by Hatsukami, Hughes, and Pickens (1985). They noted that the number of withdrawal signs increased substantially when cessation occurred in the natural envirenn)ent. Parallels exist in both laboratory research and natu- ralistic observation. Stitzer, Bigelow, and McCaul (1983) reviewed this literature and noted that individuals restrained from access to drugs for prolonged periods tend to return to use when the agents are again available; the implication is that environmental stimuli contribute to relapse. In a laboratory study, Thompson and Ostlund (1965) found that relapse to self-administration occurs rapidly for animals removed from, and then after extended periods returned to, the original environment but net for animals that undergo extinc- tion o~" self-administzation within that environment. In a reverse situation in humans, Robins, Davis, and Goodwin (1974) reported that individuals who experienced initial drug use in the stressful and ready-access conditions of the Vietnam war tended not to continue use on return to the United States. ' Relapse to Drug Dependence For many drug-dependent persons, achieving at least brief periods of drug abstinence is a readily achievable goal. Maintaining absti- nence, or avoiding relapse, however, poses a much greater overall challenge• There is a substantial base of data for these conclusions. Treatment outcome reviews concerning opioid (Platt 1986), alcohol (Miller and Hester 1986a; Peele 1987), and tobacco (Brownell et aL 1986; Lichtonstein 1982; Schwartz 1987) dependence show that clinical interventions are often successful in producing short-torm cessation of drug use but that relapse to use is a frequent posttreatment occurrence (Hunt, Barnett, Branch 1971; Brewnell, Marlatt et al. 1986). An important issue in the contemporary study of addictions is the degree to which relapse and recovery are generalizable across categories of substances (US DHHS 1986; Tiros and Leukefeld 1986; Marlatt 1979; Miller and Hester 1986a,b; Schwartz 1987). This Section examines rates and predictors of relapse across drug classes with emphasis on comparisons among alcohol, opioids, and tobacco. 311

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