GLP-1 receptor agonists at the crossroads of obesity and addiction: A review of shared neurobiology and translational evidence

Abstract

Obesity and substance use disorders (SUDs) are chronic relapsing conditions that may co-occur through convergent pathophysiological mechanisms involving dysregulated reward circuitry. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) – originally developed for type 2 diabetes and obesity – act on both peripheral metabolic and central reward pathways, positioning them as potential candidates for repurposing in addiction medicine. In this narrative review, we sought to synthesize the shared neurobiology of obesity and SUDs and critically evaluate emerging translational evidence supporting GLP-1 RAs as adjunctive treatments in addictive disorders. We conducted comprehensive searches of PubMed/MEDLINE, Embase, PsycINFO, and Web of Science from January 2015 through December 2025, supplemented by manual reference screening. Eligible studies included preclinical investigations of GLP-1 signaling on substance-related behaviors and pilot clinical trials assessing GLP-1 RAs in SUDs. Preclinical data consistently demonstrated that GLP-1 RAs can reduce intake and seeking of alcohol, nicotine, opioids, and psychostimulants through modulation of mesolimbic dopamine signaling. In addition, early clinical trials revealed therapeutic potential for reducing alcohol use, supporting smoking cessation, and mitigating post-cessation weight gain. However, the current evidence base is limited by modest sample sizes and insufficient follow-up periods. In conclusion, GLP-1 RAs represent a promising adjunctive pharmacotherapy for SUDs and may be particularly suitable for patients with co-occurring obesity. However, critical gaps remain regarding optimal dosing, long-term safety and efficacy, and their therapeutic potential in opioid and psychostimulant use disorders.