PROJECT SUMMARY/ABSTRACT Cannabis is the most common psychoactive drug co-used with alcohol among individuals with alcohol use disorder (AUD). The current proposal advances our team’s research on the impact of cannabis use (CU) and cannabis-alcohol co-use on alcohol-related outcomes. Findings from clinical studies indicate that CU is strongly linked with alcohol use, although evidence regarding whether cannabis reduces or increases drinking is mixed. Our research has demonstrated that Δ-9-tetrahydrocannabinol (THC) acutely reduces relative alcohol value and consumption in heavy cannabis and alcohol co-users under controlled laboratory conditions. Evidence from animal models on cannabidiol (CBD) suggests CBD may also reduce alcohol craving and consumption. An important gap in current clinical research is lack of human laboratory studies that examine alcohol consumption in relation to cannabis varying in cannabinoid composition (THC and CBD). Moreover, aside from data on pharmacodynamic interactions between cannabis and alcohol, no human laboratory studies have examined the combined effects of alcohol and cannabis (i.e., marijuana; simultaneous use-SAM) on alcohol consumption. Finally, no previous study has evaluated the impact of cannabis on alcohol use within the same individual under both controlled laboratory conditions and in the natural environment. This project will provide the most comprehensive tests of the impact of cannabis on alcohol outcomes using a multi-method design: (1) controlled laboratory administration of THC versus CBD smoked alone versus simultaneously with alcohol and (2) ecological momentary assessment (EMA) of event-level contextual factors that can help elucidate the associations between CU and alcohol-related outcomes in daily life contexts. The laboratory phase will employ a 3 (within-subjects cannabinoid dose: 12% THC/<1% CBD, 12% CBD/<1%THC, placebo) X 2 (between-subjects: cannabis + an alcohol-priming dose versus cannabis + alcohol placebo) mixed factorial design to examine these effects on subsequent drinking in 200 nontreatment-seeking heavy episodic alcohol drinkers who use cannabis weekly (Aim 1). Data from this laboratory phase will be integrated with smartphone- based data on CU patterns (amount, THC/CBD ratio, potency, mode), context (location, social), alcohol craving, consumption, and consequences collected from the same individuals over a 4-week EMA period. Integration of laboratory and EMA data enables examining the unique influences of laboratory-based cannabis state-dependent alcohol response variables and field-based CU and contextual factors on alcohol craving, consumption, and consequences (Aim 2). Cannabis (medical and recreational) and SAM motives and AUD severity will be explored as potential moderators of the associations between CU and alcohol behaviors in the natural environment (Aim 3). This research is well-aligned with the objectives of the Collaborative Research on Addiction at NIH and has i...