Adults who survive an overdose of opioids, alcohol, or other substances face substantially elevated risk of a subsequent overdose. Prior studies report that 15% or more of survivors experience a repeat overdose within a year, with the highest risk concentrated in the weeks immediately following the index event.1,2 Effective post-overdose interventions remain limited: medications for opioid use disorder reduce repeat overdose risk substantially but reach only a small minority of survivors, and no widely used pharmacotherapy addresses the broader range of substances involved in overdose events.3 Glucagon-like peptide-1 (GLP-1) receptor agonists, a class of medications originally approved for type 2 diabetes and later for obesity, have drawn growing interest as potential treatments for substance use disorders. GLP-1s are expressed in brain regions that govern motivation and reward. Preclinical and clinical studies have shown that GLP-1s reduce alcohol intake, blunt the pleasurable effects of opioids and stimulants, and might reduce cravings across multiple substance classes.4,5 A recent large cohort study of U.S. veterans with type 2 diabetes and a pre-existing substance use disorder found that GLP-1 initiation was associated with roughly 40% lower risk of overdose compared to other diabetes medications.6 Whether this signal extends to patients who have already experienced an overdose, regardless of their original indication for GLP-1 therapy, has not been established.
We studied 683,800 U.S. adults with an emergency department or inpatient overdose encounter that occurred between January 1, 2017, and March 9, 2026. Patients who had already been prescribed a GLP-1 before their overdose were excluded so that all GLP-1 exposure occurred after the overdose event. We accounted for demographics, social vulnerability and rurality based on latest address, BMI category, diabetes, mental health diagnoses, and medications for opioid, alcohol, or nicotine use disorder. To assess robustness, we repeated the analysis for three subgroups: patients whose first overdose involved alcohol, patients whose first overdose did not involve alcohol, and patients not receiving any addiction-treatment medications.
Active GLP-1 use after an overdose was associated with a 39% lower risk of a repeat overdose between 30 days and three years after the overdose event, compared to patients who were never prescribed a GLP-1, as seen in Figure 1. Patients who started a GLP-1 and later discontinued it still had a 20% lower risk than patients who never used a GLP-1, suggesting that the association with lower overdose risk might extend beyond the period of active treatment. The pattern was consistent across initial overdose type: patients whose first overdose involved alcohol had a 40% lower risk during active GLP-1 use, while those whose first overdose did not involve alcohol had a 37% lower risk. Patients who discontinued a GLP-1 retained a similar protective association in both subgroups (18% lower risk for alcohol, 24% lower risk for non-alcohol). The association was still present when patients on medications for opioid, alcohol, or nicotine use disorder were excluded, with a 44% lower risk during active GLP-1 use and a 28% lower risk after discontinuation. This suggests the finding is not explained by the addiction-treatment medications some patients were already taking.
Patients who start GLP-1s after an overdose differ in important ways from those who do not; they might have more consistent engagement with their healthcare team, better access to care, or other unmeasured differences we could not capture. Some or all of the lower repeat-overdose risk could reflect those kinds of differences rather than the medication itself.
