Despite recent progress, and at least three medications approved for the treatment of opioid use disorder (OUD), the number of deaths due to opioid overdose remains unacceptably high. As such, there is need for new treatments. To this end, glucagon-like peptide-1 receptor agonists (GLP-1RAs), dual GLP-1RA+glucose-dependent insulinotropic polypeptide (GIP) receptor agonists (e.g., tirzepatide), and triple agonists (e.g., GLP-1RA +NeuropeptideY1/Y2 receptor agonists), show promise. Here, we review preclinical and clinical data. In the preclinical studies, acute administration of exendin-4 (Ex-4) and the longer acting liraglutide, semaglutide, tirzepatide, and other dual and triple agonists reduced opioid taking and/or opioid seeking when elicited by exposure to drug-related cues, the drug itself, or by stress. Chronic treatment with GLP-1RAs also reduced responding for opioids, but tolerance occurred with chronic administration of higher doses of GLP-1RAs. In the human studies, one small clinical trial found a 40% reduction in opioid craving following treatment with the GLP-1RA liraglutide. Three other clinical trials are ongoing, with two testing the efficacy of semaglutide, and one tirzepatide, as adjunctive treatments to buprenorphine or methadone. Pending completion of these clinical trials, recent studies used data from the electronic health record, the TriNetX database, and Medicare claims and found a 40% reduction in opioid overdose and in hospital admissions for OUD in patients treated with a GLP-1RA or a GLP-1RA/GIP agonist for type two diabetes and/or for obesity. Thus, while additional clinical trials are needed, these data hold promise for GLP-1RAs as a novel treatment for OUD in humans.
