Initiation of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) results in a lower risk of developing various incident substance use disorders (SUDs), suggests a study involving US veterans with type 2 diabetes (T2D). Its use also protects against adverse clinical outcome in people with pre-existing SUDs.
“These observational data suggest a potential role for GLP-1 RAs in both the prevention and the treatment of various SUDs, warranting further evaluation,” the researchers said.
Electronic health records were used to conduct an emulation of eight parallel, new-user, active comparator target trials: seven trials for each incident SUD outcome (protocol 1) and one for adverse outcomes in people with pre-existing SUD (protocol 2).
The research team assigned participants from a base population of 606,434 US veterans with T2D to one of the two protocols and followed them for up to 3 years. Trial 1 (primary trial) of protocol 1 included a total of 524,817 new users of GLP-1 RAs or sodium-glucose cotransporter-2 (SGLT-2) inhibitors. Protocol 2 included 81,617 initiators of GLP-1 RAs and SGLT-2 inhibitors.
The use of GLP-1 RAs, compared with SGLT-2 inhibitors, significantly correlated with a reduced risk of developing disorders related to alcohol use (hazard ratio [HR], 0.81, 95 percent confidence interval [CI], 0.78‒0.85; net 3-year risk difference [NRD] per 1,000 people, ‒5.57). [BMJ 2026;392:e086886]
GLP-1 RA initiation also conferred protective benefits against disorders related to cannabis use (HR, 0.86, 95 percent CI, 0.81‒0.90; NRD, ‒2.25), cocaine use (HR, 0.80, 95 percent CI, 0.72‒0.88; NRD, ‒0.97), nicotine use (HR, 0.80, 95 percent CI, 0.74‒0.87; NRD, ‒1.64), and opioid use (HR, 0.75, 95 percent CI, 0.67‒0.85; NRD, ‒0.86), and other SUDs (HR, 0.87, 95 percent CI, 0.81‒0.94; NRD, ‒1.12) and composite outcome of all incident SUDs (HR, 0.86, 95 percent CI, 0.83‒0.88; NRD, ‒6.61).
Notably, people with pre-existing SUDs also benefitted from using GLP-1 RAs, which reduced the risk of SUD-related emergency department visits (HR, 0.69, 95 percent CI, 0.61‒0.78; NRD, ‒8.92), hospital admissions (HR, 0.74, 95 percent CI, 0.65‒0.85; NRD, ‒6.23), and mortality (HR, 0.50, 95 percent CI, 0.32‒0.79; NRD, ‒1.52), as well as drug overdose (HR, 0.61, 95 percent CI, 0.42‒0.88; NRD, ‒1.49) and suicidal ideation or attempt (HR, 0.75, 95 percent CI, 0.67‒0.83; NRD, ‒9.95).
“Analyses of treatment adherence showed directionally consistent results with analyses of treatment initiation for both incident SUDs and adverse outcomes among participants with pre-existing SUDs,” the researchers said.
Mechanism
These findings add to the growing evidence on the role of GLP-1 RAs in SUDs. [Nat Commun 2024;15:4548; Ann Intern Med 2024;177:1016-1027; Nature 2024;633:758-760; Nature 2025;638:308-310; Nat Biotechnol 2025;43:455-457; Science 2023;381:930-931]
“Consistent with mechanistic evidence, our results show that GLP-1 RA-related agonism may prevent addiction phenotypes across all major drug classes (reduced incident SUD across alcohol, cannabis, nicotine, cocaine, and opioids) and provide clinically meaningful harm reduction among people with an established SUD (fewer SUD-related deaths and other adverse events),” the researchers said.
“Our results are generally consistent in direction and magnitude with the existing clinical research, including trials showing reduced heavy alcohol consumption among those with obesity, reduced drinking in an experimental bar setting, and pharmacoepidemiological analyses showing that GLP-1 RAs are associated with lower incidence and recurrence of alcohol use disorder, reduced need for tobacco use related care, lower incidence and relapse of cannabis use disorder, and reduced risk of opioid overdose in patients with opioid use disorders,” they added. [JAMA Netw Open 2024;7:e2435247; Mol Psychiatry 2024;29:2587-2598; JAMA Psychiatry 2025;82:395-405; JCI Insight 2022;7:e159863]