Alcohol use disorder affects hundreds of millions worldwide, yet the pharmacological toolkit remains narrow and inadequate. A fresh synthesis of the endocannabinoid system's role in driving compulsive drinking could reshape how researchers prioritize the next generation of AUD therapies — but a stubborn gap between animal models and human outcomes demands scrutiny before clinical optimism takes hold.
This systematic review and meta-analysis pooled 63 preclinical and human studies examining endocannabinoid system (ECS) modulators in AUD contexts. Across animal studies, CB-1 receptor inverse agonists produced a large standardized mean difference of −1.21 in alcohol consumption reduction, while cannabidiol (CBD) yielded a moderate effect (SMD = −0.70). CB-1R agonists moved in the opposite direction, increasing consumption (SMD = +0.66). Notably, dose-response curves for both CB-1R inverse agonists and CBD were non-linear, suggesting that therapeutic windows may be narrow and easily missed at standard dosing. Human clinical data, however, showed inconsistent and largely null effects, with most trials focused on rimonabant — a CB-1R inverse agonist withdrawn from European markets due to psychiatric side effects — or early-phase CBD studies.
The preclinical-to-human translation problem here is not unique to the ECS field, but it is particularly acute. Animal models of alcohol consumption reliably capture reward-driven drinking but poorly replicate the neuroadaptive complexity of chronic human AUD, including withdrawal, craving architecture, and comorbid psychiatric conditions. The rimonabant experience serves as a cautionary tale: strong preclinical signals collapsed under the weight of real-world tolerability. CBD's cleaner safety profile makes it a more tractable candidate, but the moderate effect size in animals, combined with sparse and heterogeneous human data, means enthusiasm must remain measured. Emerging ECS targets — fatty acid amide hydrolase (FAAH) inhibitors, monoacylglycerol lipase modulators, and peripherally restricted CB-1R antagonists designed to sidestep central psychiatric risk — represent genuinely novel territory that this meta-analysis flags as critically under-investigated. This review is a valuable translational map, though the human evidence base is too thin and methodologically varied for firm clinical conclusions.