Glucagon-like peptide 1 receptor agonists in substance use disorders: A systematic review of ClinicalTrials.Gov

Background: Substance use disorders (SUDs) are widely prevalent and associated with high morbidity and mortality. Current treatments have limited efficacy and there are no United States Food and Drug Administration (FDA)-approved treatments for several SUDs (such as methamphetamine, cocaine, and cannabis use disorders). Emerging evidence suggests glucagon-like peptide 1 receptor agonists (GLP-1RAs) may improve outcomes related to SUD. Therefore, a systematic survey of ongoing clinical trials that are evaluating the effects of GLP-1RAs for SUDs is warranted. Methods: We searched ClinicalTrials.gov from inception to July 2, 2025 (preregistered at: https://osf.io/x58ne/). Inclusion required a GLP-1RA intervention targeting SUDs and outcomes regarding substance use (e.g., urine toxicology, Timeline Follow-Back, craving). Trials excluding individuals with SUDs were excluded. Results: Of 192 records, 33 met criteria: alcohol use disorder (n = 15), nicotine/tobacco (n = 9), cocaine (n = 4), opioid (n = 4), methamphetamine (n = 1), and none for cannabis. Agents studied included semaglutide (n = 15), exenatide (n = 8), tirzepatide (n = 6), liraglutide (n = 2), dulaglutide (n = 1), and pemvidutide (n = 1). Outcomes and designs were heterogeneous and often mixed self-report with objective indices. Most studies used older GLP-1RAs, focused mainly on alcohol or nicotine/tobacco use disorder, and used a range of outcome measures relying on self-reported and objective measures of substance use. Conclusions: While GLP-1RAs may represent a paradigm shift for treating SUD, current trials have focused on alcohol and nicotine/tobacco use disorders, with notable gaps for methamphetamine and cannabis use disorders. Trials testing next-generation GLP-1RAs with FDA recommended endpoints are needed to define efficacy and safety across SUDs.