GLP-1 RAs in Substance Use Disorders: Emerging Evidence and Future Directions.

Substance use disorders (SUDs) are the leading causes of both global mortality and morbidity, and alcohol, nicotine, and opioids account for most of this burden. Existing pharmacotherapies are only moderately effective, have inconsistent compliance and regular relapse, and therefore, new treatment modalities are required. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), which have been licensed to treat type 2 diabetes and obesity, have emerged as potential therapeutic candidates for SUDs due to their central action on neural reward circuits. GLP-1 receptors are expressed in mesolimbic regions, and preclinical studies show decreases in drug use, suppression of nucleus accumbens efflux of dopamine, and inhibition of relapse-like behaviors in models of alcohol, nicotine, and opioids. Early clinical findings, particularly those from semaglutide, indicate reductions in both alcohol and cigarette consumption, although the results remain inconsistent and are limited by small sample size. Subgroup analysis and observational findings suggest that GLP-1RAs may have potentially larger effects in individuals with obesity and metabolic disease, which could also be due to metabolic modes of action. In opioid use disorder, evidence is currently limited to animal models but demonstrates comparable efficacy to established therapies. Collectively, GLP-1RAs represent an emerging and mechanistically novel therapeutic option for SUDs. Future research should prioritize large-scale randomized controlled trials, patient stratification, and long-term safety assessments to define their potential role as adjunct or standalone treatments in addiction medicine.