UCLA

Cannabis is the most widely used illicit substance across the globe and the most commonly used drug among those who drink alcohol (SAMHSA, 2017). Importantly, alcohol and cannabis co-use has been shown to be associated with an increased risk for a host of negative outcomes (Volkow, Baler, Compton, & Weiss, 2014), including increases in heavy drinking, higher prevalence of alcohol use disorder (AUD) (Blanco et al., 2016; Weinberger, Platt, & Goodwin, 2016), and poorer AUD treatment prognoses (Mojarrad, Samet, Cheng, Winter, & Saitz, 2014; Subbaraman, Metrik, Patterson, & Swift, 2017). However, the detrimental effects of the co-use of alcohol and cannabis have not been uniformly shown in the literature, as some research suggests that alcohol and cannabis may be substitutes for each other, and that cannabis use may be associated with overall lower levels of alcohol consumption (Risso, Boniface, Subbaraman, & Englund, 2020). Taken together, despite the frequent co-use of alcohol and cannabis, their clinical correlates, underlying mechanisms, and the role of sex differences remain poorly understood. This dissertation seeks to fill identified gaps within the literature of co-use of alcohol and cannabis by expanding on the literature on sex differences underlying the co-use (Study 1). Next, it probes clinical associations related to varying levels of alcohol and cannabis co-use, identifying relevant factors related to co-use (Study 2). Lastly, Study 3 investigates mechanisms relating substance-induced and cue-induced craving for alcohol and cannabis. Study 1 (Venegas, Meredith, Green, Cooper, & Ray, 2020) aimed to elucidate the effects of controlled alcohol administration on the urge to use cannabis and considered sex-dependent effects. A community sample of non-treatment-seeking heavy drinkers reporting cannabis use in the past six months completed an intravenous alcohol administration paradigm. Participants rated their urge to use cannabis and drink alcohol, in addition to subjective effects of alcohol, at baseline and at rising levels of breath alcohol concentration (BAC). Results showed that males reported increases in the urge to use cannabis at rising BACs, but females did not. Urge for alcohol significantly predicted urge for cannabis across rising levels of BAC and this relationship was stronger in males than in females. Lastly, stimulation, but not sedation, was positively associated with the urge for cannabis. Overall, these results suggest that the pharmacological effects of alcohol on the urge to use cannabis are sex dependent and that the stimulant effects of alcohol are associated with a greater urge for cannabis. Study 2 (Venegas, Du, Cooper, & Ray, 2022) examined demographic and clinical correlates of varying levels of cannabis co-use in a large community sample of heavy drinkers. Results revealed that younger age, male gender, and concurrent tobacco were robust predictors of alcohol and cannabis co-use. Further, individuals who reported more frequent cannabis use also exhibited more problematic drinking profiles, such as more drinking days, more frequent heavy drinking days, and higher levels of tonic alcohol craving. Taken together, this study identified the negative impact of more intense cannabis co-use among heavy drinkers as well as predictors of heavier co-use patterns. Next steps in this line of research suggest the need for tailored intervention strategies among this specific subgroup of drinkers. Study 3 (Venegas & Ray, 2023) utilized a novel experimental pharmacology paradigm employed remotely via Zoom to test the pharmacological effects of cannabis on craving for alcohol and the pharmacological effects of alcohol on craving for cannabis, both in the absence and presence of drug cues. It employed a crossover design, such that across two counterbalanced and randomized experimental sessions, a community sample of alcohol and cannabis co-users underwent a series of drug administration followed by a cue-reactivity paradigm. Specifically, in one experimental session, participants administered alcohol, followed by a cannabis cue-reactivity paradigm; in another experimental session, they administered cannabis, followed by an alcohol cue-reactivity paradigm. Results revealed that exposure to alcohol/cannabis cues resulted in significant increases in subjective craving, across both experimental sessions. These findings suggest that cue-reactivity robustly increases craving, over and above the pharmacological priming effects of alcohol/cannabis administration. Importantly, the cross-substance effects of alcohol/drug administration and cues were modest. The successful completion of these projects has provided valuable clinical data as to the nature of the co-use of alcohol and cannabis, including sex differences, risk factors, and mechanisms underlying co-use. An overarching pattern of results indicated that younger, male-identifying, comorbid tobacco users may be an identifiable subgroup of drinkers at heightened risk for co-use and associated negative consequences. Further, it appeared that the stimulating effects of alcohol were associated with increases in cannabis craving following alcohol administration, whereas the sedative effects of alcohol were not. Alcohol and cannabis co-users were most sensitive to the cue-reactive, as opposed to the pharmacological, effects of alcohol/cannabis on subjective craving. Lastly, the cross-substance effects of alcohol/drug administration and cues were modest. Collectively, results from this series of studies may be used to inform intervention development and further experimental studies for the sizeable group of individuals who co-use alcohol and cannabis.