GLP-1 receptor agonists (GLP-1RAs) have shown preclinical effects on reward-seeking behavior across several substance classes, but human randomized controlled trial (RCT) evidence remains limited. This systematic review and meta-analysis evaluated the effects of GLP-1RAs on substance-use outcomes in adults with substance use disorders. Electronic databases and trial registries were searched from inception to April 30, 2026, for parallel-group or crossover RCTs comparing any GLP-1RA with placebo or control. Outcomes included days without alcohol consumption, cigarettes smoked per day (CPD), and Fagerström Test for Nicotine Dependence (FTND) scores. Five RCTs met the inclusion criteria, including 764 participants with follow-up ranging from six to 52 weeks. Three RCTs contributed alcohol-related outcomes, and four contributed tobacco-related outcomes. Random-effects meta-analysis showed no statistically significant effect on days without alcohol consumption (MD -1.96 days, 95% CI -17.97 to 14.05; I² = 74%), CPD (MD -0.55 cigarettes/day, 95% CI -1.76 to 0.65; I² = 45%), or FTND score (MD 0.02, 95% CI -0.32 to 0.36; I² = 0%). Risk-of-bias assessment using the Cochrane Risk-of-Bias (RoB) 2 tool rated three trials as low risk overall and two as having some concerns. Certainty of evidence assessed using GRADE (Grading of Recommendations, Assessment, Development and Evaluations) ranged from low to moderate. Current pooled RCT evidence does not demonstrate a statistically significant benefit of GLP-1RAs for alcohol or tobacco use outcomes. A possible signal of benefit in patients with comorbid alcohol use disorder and obesity should be interpreted as hypothesis-generating because of the small number of trials, clinical heterogeneity, and imprecision. Adequately powered, long-duration, agent-specific RCTs using standardized substance-use outcomes are required before clinical translation can be recommended.
