GLP-1RAs Show Emerging Potential for Treating Alcohol, Nicotine, and Opioid Substance Use Disorders

Substance Use Disorders (SUDs) are a leading cause of global mortality and morbidity, with alcohol, nicotine, and opioids accounting for a significant burden. Current pharmacotherapies for SUDs often exhibit moderate efficacy, inconsistent compliance, and high relapse rates, highlighting an urgent need for novel treatment modalities. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), primarily licensed for type 2 diabetes and obesity, have emerged as promising candidates due to their central action on neural reward circuits, offering a mechanistically distinct approach.

This review synthesized emerging evidence on GLP-1RAs for Substance Use Disorders, analyzing preclinical studies on neural reward circuits and early clinical findings, particularly with semaglutide. It also considered subgroup analyses and observational data, assessing evidence across alcohol, nicotine, and opioid use disorders. The review aimed to identify the current state of research and outline future directions for defining the therapeutic role of GLP-1RAs in addiction medicine.

GLP-1 receptors are notably expressed in mesolimbic regions, which are critical components of the brain's reward system. Preclinical studies consistently demonstrate that GLP-1RAs lead to decreases in drug use, suppress nucleus accumbens efflux of dopamine, and inhibit relapse-like behaviors across animal models of alcohol, nicotine, and opioids.

Early clinical findings, particularly from studies involving semaglutide, indicate reductions in both alcohol and cigarette consumption in human subjects. However, these early clinical results remain inconsistent and are limited by small sample size. Subgroup analyses and observational data suggest that GLP-1RAs may exert potentially larger effects in individuals with co-occurring obesity and metabolic disease, possibly due to additional metabolic modes of action. For opioid use disorder, current evidence is primarily limited to animal models but shows comparable efficacy to established therapies.