The Coâ•'Occurring Use and Misuse of Cannabis and Tobacco: a Review

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HORIZONS REVIEW doi:10.1111/j.1360-0443.2012.03837.x

The co-occurring use and misuse of cannabis and

tobacco: a reviewadd_3837 1221..1233

Arpana Agrawal1, Alan J. Budney2 & Michael T. Lynskey1 Department of Psychiatry,Washington University School of Medicine, Saint Louis, MO, USA1 and Department of Psychiatry, University of Arkansas for Medical Sciences, Little Rock, AR, USA2

ABSTRACT

Aims Cannabis and tobacco use and misuse frequently co-occur. This review examines the epidemiological evidence supporting the life-time co-occurrence of cannabis and tobacco use and outlines the mechanisms that link these drugs to each other. Mechanisms include (i) shared genetic factors; (ii) shared environmental influences, including (iii) route of administration (via smoking), (iv) co-administration and (v) models of co-use. We also discuss respiratory harms associated with co-use of cannabis and tobacco, overlapping withdrawal syndromes and outline treatment implications for co-occurring use. Methods Selective review of published studies. Results Both cannabis and tobacco use and misuse are influenced by genetic factors, and a proportion of these genetic factors influence both cannabis and tobacco use and misuse. Environmental factors such as availability play an important role, with economic models suggesting a complementary relationship where increases in price of one drug decrease the use of the other. Route of administration and smoking cues may contribute to their sustained use. Similar withdrawal syndromes, with many symptoms in common, may have important treatment implications. Emerging evidence suggests that dual abstinence may predict better cessation outcomes, yet empirically researched treatments tailored for co-occurring use are lacking. Conclusions There is accumulating evidence that some mechanisms linking cannabis and tobacco use are distinct from those contributing to co-occurring use of drugs in general. There is an urgent need for research to identify the underlying mechanisms and harness their potential etiological implications to tailor treatment options for this serious public health challenge.

Keywords Cannabis, co-administration, genetics, marijuana, nicotine, policy, tobacco, treatment.

Correspondence to: Arpana Agrawal, Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid, CB 8134, St Louis, MO 63110, USA. E-mail: [email protected] Submitted 26 August 2011; initial review completed 17 October 2011; ﬁnal version accepted 16 January 2012

INTRODUCTION past month use in 2010 [3]. In Australia, while population trends also indicate a similar increase from 9.1% in According to the Centers for Disease Control (CDC), 2007 to 10.3% in 2010, recent cannabis use appears to tobacco kills more people world-wide than human immu- have declined in youth since 1998 [7]. Despite cross- nodeﬁciency virus (HIV), tuberculosis and malaria com- national variations in rates of use, cannabis smoking has bined [1,2]. One in ﬁve deaths in the United States are been and continues to be associated with adverse effects attributable to cigarette smoking [1], and more than on school, employment, relationships, cognitive process- 27.4% of the United States population aged 12 years and ing, mental health, health (primarily respiratory) and older reported past month use of a tobacco product, pri- health-care utilization [8]. Independently, each of these marily cigarette smoking, in 2010 [3]. Cannabis (mari- psychoactive substances is associated, to varying degrees, juana) remains the most commonly used illicit drug in with considerable morbidity [9,10]. However, given these most developed nations [4]. Rates in the United States associated harms, what is perhaps most alarming is have been stable [5], with recent trends indicating a slight that the use of cannabis and tobacco (primarily as increase, especially in youth [6]. Compared with 2002, tobacco cigarettes) co-occurs frequently across the when 6.2% of those aged 12 years and older in the United life-span [11,12]. In this review we discuss life-time States reported past month cannabis use, 6.9% reported co-occurrence, which indicates the use and misuse of

Figure 1 Overview of mechanisms contributing to the life-time co-occurrence of cannabis and tobacco use cannabis and tobacco at any point (and not necessarily 70 at the same time). Discussion of the implications of 60 57.9 Cigarette smoker simultaneous use (i.e. used on the same occasion) and 50 Never smoked tobacco co-administration (e.g. mulling: adding tobacco to can- 40 nabis joints; or blunts: rolling cannabis in cigar paper) is also presented.The extent of and mechanisms underlying 30

the co-occurring use of these psychoactive substances, Prevalence (%) 20 11.9 the consequences and the treatment implications remain 10 research questions of considerable interest. Figure 1 pro- 2.5 0.3 0 vides an overview of these various mechanisms: we Ever use cannabis Cannabis Use Disorder discuss (i) the epidemiology of life-time co-occurrence of 100 cannabis and tobacco use; (ii) the mechanisms underly- 90 90 ing life-time co-occurring use, including shared genetic Ever used cannabis 80 Never used cannabis and environmental factors and economic factors; (iii) 70 route of administration as a contributing factor; (iv) res- 60 piratory complications associated with co-occurring use; 50 46.8 (v) overlapping withdrawal features; and (vi) treatment 40 30 approaches for smokers with cannabis problems and Prevalence (%) 19.1 cannabis users with nicotine dependence. 20 10 5.5 0 EPIDEMIOLOGY Ever smoked tobacco Nicotine dependent

Figure 2 shows the extent of life-time co-occurring can- Figure 2 Prevalence of cannabis use, cigarette smoking, cannabis nabis and tobacco use in the United States, based on data use disorders (past 12 months) and nicotine dependence (based on the Fagerström Test of Nicotine Dependence [127]) in those aged collected by the National Household Survey on Drug Use 12 and older from the 2009 National Household Survey of Drug and Health (NSDUH) in 2009 (estimated using available Use and Health (NSDUH) [5]. For instance, 57.9% of cigarette data: http://www.icpsr.umich.edu/icpsrweb/SAMHDA/ smokers (including former smokers) report ever using cannabis studies/29621; accessed 2 March 2012; archived at compared with 11.9% of those who have never smoked cigarettes. http://www.webcitation.org/65rnDa1WO). In the US Nicotine dependence based on Fagerstrom Test for Nicotine population aged 12 years and older, life-time prevalence Dependence. Both cannabis use disorder (abuse/dependence) and of cigarette smoking was 60.6% for females and 69.3% nicotine dependence are recent for males. Cannabis use was reported by 37.1% of females cannabis users (versus 46.8% of non-users) reported and 46.4% of males. Importantly, 57.9% of cigarette being cigarette smokers at some point during their life- smokers (compared with 11.9% of non-smokers) time. Similarly elevated rates of recent (not lifetime) nico- reported a life-time history of cannabis use while 90% of tine dependence in cannabis users and cannabis use

© 2012 The Authors, Addiction © 2012 Society for the Study of Addiction Addiction, 107, 1221–1233 Cannabis and tobacco review 1223 disorders in cigarette smokers are noted (Fig. 2). Addi- growing evidence for reverse gateways reﬂects increasing tionally, both disorders co-occur, with 4.9% (versus ease of access to cannabis relative to cigarettes, the sale 1.2%) of those with past month nicotine dependence of which to minors may now be more stringently moni- reporting past year cannabis use disorders and 37.5% tored, remains to be investigated. (versus 12.9%) of those with cannabis use disorders meeting criteria for nicotine dependence. Escalation of use in reverse gateways

While gateways and reverse gateways have referred traditionally to substance initiation, there is also over- MECHANISMS OF CO-OCCURRING USE whelming support for associations between cannabis use As indicated in Fig. 2 and the literature [13], most can- and escalation of tobacco involvement. In the study by nabis users report a life-time history of cigarette smoking. Patton and colleagues [22], daily cannabis use was asso- Cigarette smoking, however, is reported commonly in ciated with a 3.6-fold increase in nicotine dependence. users of a variety of illicit psychoactive drugs (e.g. in In data from the United States, cannabis use was associ- NSDUH, more than 90% of cocaine and methamphet- ated with a more rapid transition into daily smoking and amine users report cigarette smoking). None the less, the nicotine dependence [25,26]. co-occurring use of cannabis and tobacco may extend Based on these epidemiological trends, there has been beyond the mechanisms underlying general co-use of increasing research into the factors that contribute to substances. In the following sections, we describe evi- co-occurring use and misuse of cannabis and tobacco. dence accumulating from the literature on the putative Perhaps the strongest and most consistent contributor mechanisms connecting cannabis and tobacco use; an to co-occurring cannabis and tobacco use are shared overview may be found in Fig. 1. genetic inﬂuences.

Gateways and reverse gateways Shared genetic predispositions

A gateway drug (which is used prior to other drugs) Individual differences in tobacco use (or smoking initia- is distinguished by sequence, association (use of the tion, heritability, h2 = 75%), cannabis use (h2 = 48%), gateway drug is associated with an increased likelihood of nicotine dependence (h2 = 60%) and cannabis abuse/ using other drugs) and, controversially, causation (use dependence (h2 = 50–60%) are partly attributable to of the gateway drug has a causal influence on use of genetic factors (or h2) [27,28]. There is robust evidence other drugs) [14,15]. Historically, while the most fre- from twin studies suggesting that these heritable influ- quent debate surrounds the role of cannabis as a gateway ences on tobacco and cannabis use and misuse overlap drug for other illicit psychoactive substances, cigarette with each other, with liability to use and misuse of other smoking may serve as a gateway drug for cannabis use. psychoactive substances and with a general vulnerability For example, Yu & Williford [16], in their study of 16–24- to externalizing behaviors. year-olds found that alcohol and cigarettes served as a gateway to cannabis use. Even in former daily smokers A general liability to externalizing problems the risk of developing cannabis dependence is elevated Consistent with a problem behavior model [29], the ear- [17], suggesting that tobacco exposure, particularly liest studies investigated genetic factors that also played a cigarette smoking, increases the likelihood of cannabis role in the etiology of impulsivity and conduct disorder use [18]. These findings require further study, particu- [30]. Recently, Hicks and colleagues [31] found that larly to examine the potential role of confounders such genetic factors for externalizing problems also influence as conduct problems and other externalizing psychopa- cannabis and tobacco misuse indicating that, to some thology [18]. degree, the genetic underpinnings of cannabis and To some extent, sequence of drug use reflects ease of tobacco use are attributable to a predisposition to access and youth may use cigarettes and tobacco prior to disinhibition. cannabis due to its availability. However, there is now growing support for reverse gateways (the use of can- A general propensity to drug use and misuse nabis prior to and increasing the risk for tobacco use) [19–21]. Patton and colleagues [22] found that, while a Additionally, a number of twin studies find that underly- majority of teenagers smoked cigarettes prior to experi- ing all forms of substance use behavior is a shared genetic menting with cannabis, in a subset, first use of cannabis propensity to use and misuse drugs. Examining this preceded onset of cigarette smoking, representing a hypothesis, Young and colleagues [32] reported that reversal of the conventional sequence [23,24]. Whether while the genetic overlap across alcohol, tobacco and these individuals represent a unique group or whether cannabis use was modest (r = 0.14–0.31), shared genetic

© 2012 The Authors, Addiction © 2012 Society for the Study of Addiction Addiction, 107, 1221–1233 1224 Arpana Agrawal et al. influences played a significantly more prominent role The varying degree to which shared genetic factors when examining alcohol, tobacco and cannabis depen- influence cannabis and tobacco use and misuse is partly dence symptoms (r = 0.56–0.62). Expanding this to dependent on the stage of cannabis and tobacco involve- include other substances, Kendler and colleagues [33] ment that is under study, as shown in Fig. 3. Genetic found that an overwhelming 83% of the genetic variance factors reflecting a predisposition to disinhibition, impul- in cannabis abuse/dependence symptoms was shared sivity, sensation-seeking and general problem behavior with genetic influences on alcohol, nicotine, caffeine and are more likely to contribute to early onset of cannabis cocaine abuse/dependence. However, for nicotine depen- and tobacco use [37,38]. Maintenance of substance use dence, these shared factors were responsible for only 37% followed by development of problems (e.g. cannabis of the genetic variance. Thus, while there is consistent abuse/dependence and nicotine dependence) is also support for common genetic factors influencing use and genetically influenced, but these genes may be less related misuse of multiple substances, the extent to which these to disinhibition and more to positive reinforcement and general factors impact the co-occurring use and misuse shared features of abuse/dependence (e.g. common of cannabis and tobacco remains unclear. genetic influences on cannabis and tobacco withdrawal symptoms). Two influential studies examined the impact of these potentially etiologically distinct sources of Genetic overlap between liability to tobacco and cannabis use genetic overlap by examining the shared genetic influ- A few studies have specifically interrogated the genetic ences across cannabis use, nicotine use, cannabis abuse/ overlap between cannabis and tobacco involvement. In a dependence and nicotine dependence. Importantly, these study of US twins [34], the high correlation between can- studies specified that a proportion of the genetic influ- nabis and tobacco use during adolescence was attribut- ences on nicotine dependence was in common with and able primarily to shared environmental factors (e.g. at age contingent upon exposure to nicotine use [39]. When

15, RG = 0 and RSE=0.75, where RG is genetic correlation such a contingency was imposed on both cannabis and and RSE is shared environmental correlation), with the tobacco involvement, Neale and colleagues [40] found role of overlapping genetic inﬂuences becoming more that, while there was considerable genetic overlap prominent during late adolescence and early adulthood (RG = 0.82) between cannabis and tobacco initiation,

(e.g. at age 17–19, RG = 0.75 and RSE = 0.25). This high after accounting for this genetic overlap, the residual degree of genetic overlap has also been found between genetic covariance between cannabis and tobacco pro- cannabis and regular tobacco smoking (RG = 0.60–0.75) gression was modest (RG = 0.38). In a sample of adoles- [35] and between early cannabis use and nicotine depen- cent twins, after accounting for that initial genetic dence (RG = 0.4–0.5) [36]. overlap, Huizink and colleagues [41] also found no

Figure 3 Stages of progression from drug use to drug use disorders, followed by cessation or persistence and the inﬂuential role of withdrawal and treatment on these latter stages

© 2012 The Authors, Addiction © 2012 Society for the Study of Addiction Addiction, 107, 1221–1233 Cannabis and tobacco review 1225 further evidence for shared genetic influences on can- early adolescence, includes those environmental factors nabis and tobacco progression. Both these studies con- that are shared by members of a twin pair—these may cluded that shared genetic factors have the strongest include familial factors (e.g. parental monitoring) that influence at earlier stages of cannabis and tobacco use, both twins are exposed to or differing environments (e.g. while genes specific to each drug are of particular impor- recreational activities) that are perceived by both twins in tance at later stages. a similar manner. These shared environments are distinguished from the second, which is individual-specific Genes for cannabis and nicotine involvement environment (e.g. life events experienced by one twin but not the other). Individual-specific environmental expo- The most widely studied genetic variants for tobacco sures are uncorrelated across members of a twin pair and involvement are part of the cluster of genes encoding the are found to be highly significant contributors to can- alpha 5, alpha 3 and beta 4 subunits (CHRNA5/A3/B4) nabis and tobacco use and their life-time co-occurring of the cholinergic nicotinic receptor [42]. Specifically, use across adolescence and adulthood [34]. Like genetic rs16969968, a variant in this gene cluster that causes an influences, environmental influences on cannabis and amino acid coding change in the gene, has been associ- tobacco use may be classified broadly as those that impact ated with cigarettes smoked per day at P-values exceeding general externalizing behaviors, those that impact all 10E-70 (b=1.03) [43–45]. Each increasing copy of the forms of drug involvement and those specifically linking risk allele contributed to an increase in smoking quantity cannabis and tobacco use. of one cigarette per day. In addition to CHRNA5/A3/B4, genetic variants in CYP2A6, the cytochrome P450 2A6 Peer influences gene, involved in the oxidation of nicotine and its meta- bolic product, cotinine, have also been implicated [45]. Peer deviance is among the leading correlates of general Studies of cannabis involvement have seen less success. externalizing psychopathology, including early onset of The most biologically plausible polymorphisms are in drug use; for instance, Lynskey and colleagues reported the gene encoding the cannabinoid receptor 1 (CNR1)to that vulnerability to substance use was associated which endocannabinoids bind and the gene encoding strongly with self-reported affiliations with deviant peers fatty acid amide hydrolase (FAAH), which encodes the [11]. While peer affiliations are governed, in part, by the enzyme involved in the metabolism of cannabinoids and same heritable factors that influence substance use lipids [46]. However, multiple studies have shown no [48–50], they continue to play an environmental role in relationship with these polymorphisms [46]. sustained drug involvement [51]. While the role of peer Which of these genes are drug-specific in their action affiliations may be viewed as tautological (i.e. we examine and which genes might contribute to the genetic covari- the characteristics of a population of drug-using indi- ance between cannabis and tobacco involvement? It is viduals by using population membership as a covariate), expected that genes involved in metabolism, such as several studies report the independent effect of peers on CYP2A6 (for nicotine) and FAAH (for cannabis), are drug use and externalizing psychopathology [52–56]. highly likely to have drug-specific effects. We are unaware of any published association results for CYP2A6 and can- Availability, exposure opportunity and drug use nabis involvement or for FAAH and tobacco involvement. Policy-oriented tobacco research indicates that a number In contrast, given the widespread evidence for receptor of interventions aimed at reducing access to tobacco cross-talk, it is intriguing to speculate that chronic use of among youth leads to significant declines in experimen- cannabis may modify nicotinic receptor activity and vice tation and tobacco use [57]. Such interventions include versa. Supporting this possibility, for CNR1, Chen and laws placing age restrictions on the purchase of tobacco colleagues [47] found multiple polymorphisms to be asso- products and tax-driven increases in the price (and, by ciated with nicotine dependence but not with smoking implication, availability) of tobacco products. Parallel initiation. research has indicated that self-reported measures of availability and age at first opportunity to use cannabis Overlapping environmental factors [58,59] are strong predictors of onset of cannabis use, As with genetic influences, environmental factors influ- and tobacco smokers tend to report earlier opportunities encing life-time co-occurrence of cannabis and tobacco to use cannabis [58]. Intriguingly, there is evidence use may be common to a general externalizing domain, to for genetic influences on self-reported availability [60]. all forms of drug use or to the co-use of cannabis and However, whether the effects of tobacco smoking on tobacco alone. Twin studies identify two sources of envi- availability of cannabis are purely environmental or ronmental variation and covariation in cannabis and include activation of genetic vulnerabilities remains tobacco use. The first, which is more prominent during unexplored.

The social milieu of smoking enced subjective reactions to tobacco and cannabis was modest [72]. In addition, implicit cognitive processes (i.e. Considering the conclusions from the research literatures an expectancy that cannabis smoking is less unpleasant, described above it seems not unreasonable to propose that based on prior experiences with tobacco smoking) may there may be aspects of the environment, including peer also play a role in cross-drug adaptation. This latter affiliations and access, that specifically encourage both hypothesis implies that, in addition to a predisposition to life-time and simultaneous use of tobacco and cannabis substance use, some individuals may have a preference and that, in particular, such environments may specifi- for (or an absence of aversion from) smoked substances. cally encourage smoking as a route of administration While it is limited, there is evidence for genetic influ- [20,61,62]. ences on route of administration. One twin study identi- fied variations in the extent to which heritable factors Route of administration influence tobacco use by route of administration. Genetic An intriguing aspect of cannabis and tobacco co-use is factors explained 16% of the variance in cigarette that, for both drugs, the predominant route of adminis- smoking and up to 73% of the variance in dip (smokeless tration is via inhalation. The aero-respiratory adapta- chewed tobacco) use, while they were found to have no tions afforded by smoking one drug may facilitate the use appreciable impact on pipe and cigar use [73]. Thus, it is of the other such that cigarette smokers may be more possible that the influence of a shared route of adminis- likely to continue smoking cannabis past a preliminary tration is governed partially by genetic factors. phase of experimentation, partly because the sensation of inhaled smoke is less unpleasant than it would be in non- Co-administration cigarette smokers. For instance, in a prior study of a rep- resentative US sample [62], even after accounting for a Cannabis can be smoked by itself (e.g. marijuana ciga- life-time history of nicotine dependence and other cova- rettes, or in bongs or pipes) or can be rolled with small riates, those using smoked forms of tobacco were more amounts of tobacco to facilitate smoking (referred to as likely, compared with those using non-smoked forms, to ‘mulling’ in some countries) [20,74,75]. Some studies report cannabis use and, importantly, meet criteria for contend that these small amounts of tobacco produce cannabis use disorders. However, vanLeeuwen and col- nicotine withdrawal which cannabis users stave off by leagues [63] argue that if route of administration (i.e. sustained use of tobacco-containing cannabis prepara- smoking) were important, then early onset of tobacco use tions [76,77]. Preliminary research also indicates that would predict the subsequent use of cannabis more cannabis and tobacco are often smoked on the same occa- strongly than early use of alcohol, which is not the case in sion, and that these simultaneous users are at greater risk their cohort of Dutch adolescents. We posit that route of for cannabis use disorders [78]. Similar increases in can- administration may be an additional (not in lieu of) adap- nabis involvement have been noted in those who report tive mechanism that contributes to sustained cannabis chasing cannabis with tobacco smoking (i.e. closely fol- use in tobacco smokers. lowing cannabis smoking with tobacco) [79]. In both If it does, how does this cross-drug adaptation occur? those co-administering tobacco and cannabis and those It is not as simple as variation in smoking topography, smoking cigarettes and joints on the same occasion, an with multiple studies failing to find any differences in additional source of respiratory adaption may arise from inhalation patterns, lung capacity measured by breath additives in manufactured tobacco. For instance, in addi- holding, puff volume or other characteristics [64–67] of tion to flavorants, cigarettes typically contain compounds inhaled drug use between cannabis smokers with those (e.g. salicylates) that have anti-inflammatory and anes- who smoke both cannabis and cigarettes. Smoking may thetic effects which may facilitate cannabis inhalation serve as a cue—persistent exposure to smoking cues [80]. along with the associated pharmacological effects may An additional form of co-administration occurs in the well be learned, conditioned cues that can trigger use or form of blunt smoking [81,82]. Blunts are prepared by relapse [68]. There is also the possibility that cigarette removing a majority of the tobacco from a cigar paper smokers experience more positive subjective reactions to and rolling cannabis in it and can contain more cannabis cannabis smoking and, therefore, continue to use it. and tobacco than other tobacco-containing cannabis Distinct from aero-respiratory adaptation, these experi- preparations [83]. This is consistent with the epidemio- ences reflect drug sensitivity, including experiences such logical observation of elevated rates of cannabis use dis- as dizziness, giggling, a pleasurable rush or buzz and orders in blunt versus joint smokers [84]. While there is a nausea [69–71], although coughing is also included. distinct ethnic subculture surrounding blunt usage in the This effect may be environmental; one twin study noted United States, Cooper & Haney [85] found that blunts that the extent to which the same genetic factors influ- produced greater increases in carbon monoxide levels

© 2012 The Authors, Addiction © 2012 Society for the Study of Addiction Addiction, 107, 1221–1233 Cannabis and tobacco review 1227 and, in women, joints increased plasma tetrahydrocan- Health-related harms nabinol levels. Thus, blunt smokers may be at greater risk The highly carcinogenic effects of nicotine and other for the hemodynamic consequences of carbon monoxide, compounds contained in cigarettes and other tobacco- particularly because the relatively reduced plasma levels related products are well recognized [90]. Perhaps less of tetrahydrocannabinol may delay intoxication and, well appreciated is the fact that smoked cannabis can consequently, prolong blunt smoking. However, joint contain more tar and polycyclic aromatic hydrocarbons smokers consistently reported greater subjective liking than smoked tobacco [91]. While its link to lung cancer is than blunt smokers. Thus, the link between cannabis tenuous [64,92], cannabis smoking has been linked to preparation and development of cannabis use disorders chronic bronchitis and there is growing evidence for remains unclear. cannabis-related impairment of respiratory function Thus far, our discussion of the life-time co-occurring [93]. A cannabis joint can produce as much airflow use of cannabis and tobacco has focused on individual- obstruction as 2.5–6 tobacco cigarettes [94], and mul- specific mechanisms, both genetic and environmental. tiple population studies support the adverse respiratory Given the strong socio-political trends that follow the use effects of cannabis [95–98]. Taylor and colleagues [97] of these drugs, there is also extensive research into found that even after adjustment for tobacco use, respira- macro-environmental forces that may link these drugs. tory symptoms in young adult cannabis-dependent The next section highlights some of these economic subjects exceeded those observed in tobacco smokers models. smoking one to 10 cigarettes/day. Cannabis-dependent individuals experience wheezing, exercise-related short- Economic factors influencing co-use ness of breath, nocturnal wakening with chest tightness, morning sputum, coughing, chest sounds and phlegm Economic models of addiction posit that examination of production [98]. Individuals who use both cannabis and price elasticity—changes in patterns of use of a drug in tobacco have a markedly elevated risk of respiratory dis- conjunction with changes in price—can reveal impor- tress, compared with cannabis use or tobacco use alone tant clues about the rationale for drug choice. Such [97,99]. For instance, Moore and colleagues [98] found studies typically classify pairs of drugs as complements that even though those who smoked both cannabis and (as price of one drug increases and its use correspond- tobacco reported smoking as many cigarettes as those ingly decreases, use of other drug decreases) and substi- who smoked tobacco alone, there was a considerable tutes (as price of one drug increases, use of other drug elevation in odds of respiratory distress indicators and increases). While economic studies of cannabis and ciga- reduced lung functioning [99] in those who used both. rettes are scarce, there is growing support for cannabis and cigarettes serving as complements. Pacula [86] used The withdrawal syndrome data from the US National Longitudinal Survey of Youth to report that as cigarette prices increased (and cigarette Despite health-related harms, individuals continue to use decreased), marijuana use decreased as well, indicat- use cannabis and tobacco. A major barrier to successful ing complementarity. Two additional studies of US data cessation is the experience of withdrawal. Tobacco with- have reinforced this finding [87,88]. In a similar study drawal has been well documented [100]. The next itera- conducted in Australia, Cameron & Williams [89] found tion of the Diagnostic and Statistical Manual of Mental that a 10% monetary price increase in cannabis price Disorders (DSM-5) is considering the inclusion of can- resulted in a 1.32% drop in past 12-month cigarette nabis withdrawal as a criterion in the diagnosis of can- smoking. Decriminalization had no impact on cigarette nabis use disorders [101,102]. Based on multiple clinical smoking, nor did changes in cigarette prices influence [103,104] and epidemiological [105,106] studies, little past 12-month cannabis use. doubt remains concerning the reliability and validity of Policy changes can exert powerful effects on expres- the cannabis withdrawal syndrome. However, as a major- sion or suppression of genetic vulnerability. For instance, ity of cannabis users also smoke tobacco, it is necessary Boardman and colleagues found that genetic factors to examine both unique and shared components of the played a significantly greater role in smoking cessation in withdrawal syndrome that emerge consequent to cessa- those who quit after bans and restrictions on smoking tion of one or both drugs. Cannabis withdrawal is char- had begun to be imposed. These analyses suggested that acterized by anger, aggression or irritability, nervousness even crude indices of policy change can impact the or anxiety, sleep difficulties, decreased appetite or weight contribution of genetic influences. loss, psychomotor agitation or restlessness and depressed In the next sections, we shift our focus from the etiol- mood, and less commonly by physical symptoms such as ogy of co-occurring cannabis and tobacco involvement stomach pain or shakes/tremors [102]. Many of these to a discussion of its possible consequences. withdrawal features are also noted subsequent to tobacco

© 2012 The Authors, Addiction © 2012 Society for the Study of Addiction Addiction, 107, 1221–1233 1228 Arpana Agrawal et al. cessation, which has led to direct comparisons of these Tobacco use influences treatment for cannabis withdrawal syndromes [107–109]. While the number of Studies of teens [116,117] and adults [118] indicate that withdrawal symptoms and the symptoms themselves are persistent tobacco use is associated with a poorer response reported equally across both syndromes, those experienc- to treatment for cannabis use disorders. For example, ing cannabis withdrawal are more likely to report irrita- among teens, persistent non-tobacco smokers and those bility and decreased appetite, while those experiencing who quit tobacco use relapsed to cannabis less rapidly and tobacco withdrawal are more likely to report appetite showed reduced odds of relapse to cannabis compared increase and craving. Importantly, the subjective experi- with persistent smokers or those who initiated smoking. ence of withdrawal severity appears comparable for both Among adults, current tobacco smokers reported more drugs, as are reports of withdrawal impeding successful psychosocial problems and achieved poorer cannabis cessation [109]. abstinence outcomes than ex-smokers [118]. Concurrent cessation of tobacco and cannabis and the associated withdrawal syndrome is typically expected Cannabis use impacts treatment for tobacco to be a challenging experience. In the only experimental study we know of, Vandrey and colleagues [107] found While limited, studies also suggest that cannabis use that simultaneous cessation of cannabis and tobacco, among tobacco smokers may predict poorer tobacco ces- compared with withdrawal from either drug alone, was sation outcomes [119–121]. An epidemiological study associated with greater aggression, anger and irritability, found that cannabis use among tobacco smokers pre- but only during day 2 of abstinence. Interestingly, dicted persistent tobacco use 13 years later, and was also comparable numbers of participants rated withdrawal associated with a lower probability of making a tobacco associated with dual abstinence as less severe than with- quit attempt [19]. In a clinical sample, cannabis use drawal from either drug alone. Revisiting the role of route reported at baseline greatly reduced the probability of of administration, the authors suggest that absence of sustained tobacco abstinence at a 6-month assessment smoking cues when abstaining from both substances following treatment with nicotine replacement therapy may reduce withdrawal severity in some individuals. (NRT) and counseling [120]. The etiology of these syndromes warrants examination, particularly from a genetic perspective. Nicotine Treatment approaches directed at co-use. withdrawal is heritable [110], with a proportion of these Multiple studies have addressed tobacco smoking in genes being distinct from those influencing other aspects treatment-seeking alcohol or opioid-dependent patients of smoking. While there have been no formal tests of the [122,123], but research into co-treatment of cannabis univariate heritability of cannabis withdrawal, one study and tobacco is lacking [117]. Although cannabis users indicates that variance in withdrawal may be captured were included in some of these studies (e.g. [124]), few of adequately by a factor representing general vulnerability the studies were performed in out-patient settings where to cannabis abuse/dependence [111]. There are no most treatment for cannabis occurs, and thus the gener- studies, however, of the extent to which shared genetic ality of these treatments for cannabis and tobacco co-use influences impact tobacco and cannabis withdrawal, remain unexplored. Testing tobacco cessation interven- either the syndrome in general or individual features. tions specifically in cannabis-dependent patients would The withdrawal syndrome that emerges during seem vitally important because, as discussed above, the simultaneous cessation has considerable implications for common route of administration and the tendency to use treatment. In the following sections, we briefly review a mixture of cannabis and tobacco may make quitting treatment strategies and implications. more difficult and require tailored interventions.

Treatment of cannabis and nicotine addiction Treatment options in co-users Brieﬂy, alternative approaches to treating co-use of Published clinical trials investigating treatments for tobacco and cannabis must ﬁrst determine whether to adults with cannabis use disorders suggest that approxi- intervene on both substances simultaneously or sequen- mately 50% are current tobacco smokers [112,113]. For tially, i.e. target one substance then the other. In relation adolescents receiving treatment for cannabis, the rate of to treatment of other non-cannabis substances and tobacco smoking appears even higher [114,115]. Rates tobacco, this issue has been somewhat controversial of the converse, the number of cannabis users among because of concern that intervening on tobacco will those seeking help with tobacco cessation is less clear, interfere with treatment for the other substance. but is probably a smaller, yet substantial proportion (see However, most studies suggest that simultaneous tobacco Fig. 1 [19]). treatment does not jeopardize outcomes for treating

© 2012 The Authors, Addiction © 2012 Society for the Study of Addiction Addiction, 107, 1221–1233 Cannabis and tobacco review 1229 addiction to alcohol or other illicit drugs [123]. Further, Declarations of interest as many cannabis users smoke a mixture of cannabis and Dr Agrawal receives peer-reviewed grant funding tobacco or chase cannabis use with tobacco, and as con- (no-cost extension) from ABMRF/The Foundation for ditioned cues associated with smoking both substances Alcohol Research. Dr Budney has consulted for GW may trigger use of either substance, a simultaneous ces- Pharmaceutical. sation approach with cannabis and tobacco may be most beneficial. Acknowledgements Specific options for treatment components to address co-use of tobacco and cannabis effectively can be gleaned This study was funded by grants DA23668 (to A.A.), readily from the extant evidence-based approaches for DA15186 and DA23526 (to A.J.B.) and DA18267 and each individual substance. 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