Effects of direct cannabinoid receptor modulation on alcohol craving and withdrawal: a systematic review

Abstract Background Alcohol use disorder (AUD) is a prevalent condition associated with significant morbidity and mortality rates. Existing pharmacological and psychosocial treatments offer limited long-term effectiveness. At present, there is a critical need for novel AUD treatments. The endogenous cannabinoid system (ECS) may offer some therapeutic promise for AUD, given that it appears to play a role in alcohol use motivation, while alcohol alters ECS function. Since craving and withdrawal are key AUD symptoms and represent important treatment targets, the role of the ECS in mediating craving and withdrawal should be fully explored. Exploitation of the ECS may have potential as a treatment target for AUD. Objective This review synthesizes results from preclinical investigations into the impact of cannabinoid (CB) receptor modulation on measures of craving and withdrawal since the discovery of the CB1 receptor. Method Researchers identified studies published between 1988 and 2026 involving direct CB receptor modulation, measuring outcomes pertaining to craving or withdrawal, and containing a control group were included in qualitative synthesis. Studies focused on alcohol consumption were not analyzed unless craving or withdrawal-related outcomes were reported. Risk of bias was examined using the SYRCLE tool for preclinical studies. Results Thirty-nine studies met inclusion criteria, all preclinical. Overall, CB1 activation generally increases craving-related behaviors, while antagonism tends to attenuate craving and some withdrawal-related outcomes, although dose-dependent effects were also reported. CB2 may mediate reinforcing effects of alcohol, but direction of effects is inconsistent. Evidence regarding withdrawal is limited and inconsistent. Conclusions Preclinical evidence suggests that cannabinoid receptor modulation influences alcohol craving and withdrawal-related behaviors. Integration of these behavioral findings with the broader ECS literature suggests that CB1-mediated reward and motivational processes, and CB2-mediated neuroimmune signaling may represent important mechanisms underlying these phenotypes. Greater methodological standardization and clinical investigation are needed to confirm these mechanisms and determine their translational potential for AUD treatment. Trial registration The protocol was pre-registered through Prospero (registration CRD42022309872) on 5/31/22.