Modulating the endocannabinoid system in alcohol use disorder: A translational systematic review and meta-analysis of preclinical and human studies

Alcohol use disorder (AUD) is a chronic condition with a staggering global burden and yet limited pharmacological treatments. Convergent evidence implicates the endocannabinoid system (ECS) as a potential therapeutic target due to its broad regulatory role across reward, stress, and affective processes. We conducted a systematic review and meta-analysis of 63 preclinical and human studies evaluating ECS modulators for AUD. Preclinical studies were synthesized by mechanism of action, and meta-analyses were conducted for cannabinoid receptor (CB-1R) antagonists and inverse agonists, CB-1R agonists, and cannabidiol (CBD). Human studies were narratively synthesized due to methodological heterogeneity. Preclinical data meta-analyses demonstrated that CB-1R inverse agonists (SMD = -1.21) and CBD (SMD = -0.70) reduced alcohol intake, while CB-1R agonists increased consumption (SMD = +0.66). Dose-response analyses identified non-linear effects for CB-1R inverse agonists and CBD. In contrast, human studies showed inconsistent and generally null effects, with limited studies examining newer ECS modulators beyond rimonabant or CBD. While preclinical evidence supports ECS modulation, particularly CB-1R antagonism and CBD, as promising strategies for reducing alcohol use behaviors, clinical translation has been limited by safety concerns, methodological inconsistencies, and under-investigation of novel compounds. Mechanistically informed trials of novel compounds, including next-generation CB-1R antagonists and CBD, are needed to bridge this translational gap and yield new treatments for AUD.