Effects of semaglutide (Ozempic, Wegovy) and tirzepatide (Mounjaro and Zepbound) on incidence and outcomes of stimulant use disorders and opioid use disorder in real-world populations: target trial emulation using patient electronic health records ABSTRACT/PROJECT SUMMARY There is a steady rise in the incidence and associated death of StUDs including methamphetamine use disorder (MUD) and cocaine use disorder (CUD). Among people aged 12 or older in 2022, 0.6 percent (or 1.8 million people) had MUD and 0.5 percent (or 1.4 million people) had CUD in the past year. Currently, there are no treatments approved by the U.S. Food and Drug Administration for StUDs and there is a critical unmet need. Clinical anecdotes that patients treated with semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA) approved for treating type 2 diabetes (T2DM) in 2017 and for weight management in 2021 reported reduced desire to drink and smoke have attracted attention regarding its potential to treat addiction. Currently, several registered clinical trials are ongoing to evaluate the effect of semaglutide on alcohol consumption and smoking cessation. Preclinical studies have investigated the effects of semaglutide or other GLP1R agonists on nicotine, alcohol, or opioids. However, little attention has been placed on the effects of semaglutide on StUDs; the present project will help address this gap. The proposed study would utilize TriNetX Analytics, a nationwide electronic health records (EHR) database, to evaluate semaglutide’s association with changes in both the incidence of StUDs (MUD, CUD) and clinical outcomes associated with StUDs. Outcomes will be separately assessed by age groups, sex, and race and in patients with co-occurring mental disorders or other substance use disorders (SUDs) including alcohol, nicotine, opioid, and cannabis use disorders, whenever sample sizes permit. Our methodology is based on our successful use of TriNetX Analytics to evaluate semaglutide’s association with reduced incidence and relapse of cannabis use disorder.