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

TL;DR

This paper reviews clinical trials of GLP-1 receptor agonists for treating substance use disorders, finding most focus on alcohol and nicotine with limited data on other drugs.

Contribution

The study provides a systematic review of GLP-1RA trials for SUDs, highlighting current focus areas and gaps in research.

Findings

Most trials focus on alcohol and nicotine use disorders with mixed outcomes.

Few trials exist for stimulant use disorders and none for cannabis use disorder.

Older GLP-1RAs are predominantly used, with a need for next-generation trials.

Abstract

•Thirty-three trials of GLP-1 receptor agonists for substance use disorders identified.•Most trials are focused on alcohol and nicotine with heterogenous outcomes.•Few trials for stimulant use disorders, and none for cannabis use disorder.

Thirty-three trials of GLP-1 receptor agonists for substance use disorders identified.

Most trials are focused on alcohol and nicotine with heterogenous outcomes.

Few trials for stimulant use disorders, and none for cannabis use disorder.

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.

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.

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.

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.