Evaluation of SeMaglutide as an Adjunct to buprenorphine treatment for the treatment of opioid use disorder: A pragmatic Randomized placebo-controlled Trial (SMART) ABSTRACT/PROJECT SUMMARY The opioid overdose epidemic is a public health crisis that shows little signs of abating. In the 12-month period ending in February 2022, over 100,000 people in the U.S. died of an overdose and more than 75,000 involved opioids. Buprenorphine as a treatment for Opioid Use Disorder (OUD) is highly effective in decreasing overdose deaths. but retention is challenging. However, BUP as a mono-therapy may be insufficient for eliminating illicit opioid use, craving, and stimulant co-use and BUP treatment retention is problematic. Stimulant use by individuals with OUD has been increasing. Importantly, BUP retention may be particularly challenging for individuals who use stimulants, and stimulant users may be more likely to continue illicit opioid use. Thus, stimulant use may be an important therapeutic target for individuals enrolled in BUP. BUP treatment retention is strongly associated with decreased mortality, with the risk of overdose increasing dramatically after discontinuing BUP. Semaglutide, a glucagon-like peptide-1 (GLP-1) analog, may have a beneficial treatment effect on illicit opioid use, craving, and stimulant co-use. Semaglutide, which was approved for treating type 2 diabetes in 2017 (Ozempic®) and for weight management in 2021 (Wegovy®), has superior receptor binding affinity and a longer duration of action relative to older GLP-1 analogs. Semaglutide also holds promise as a treatment for stimulant use disorders. The present study is a multi-site, randomized placebo controlled pragmatic trial with the primary objective of evaluating the impact of semaglutide, relative to placebo, as an adjunct to BUP on substance use outcomes with illicit opioid use as the primary outcome. Evaluating the effect of semaglutide, relative to placebo, as an adjunct to BUP on BUP retention is a secondary objective. While it is expected that semaglutide will be more effective as an adjunct than as a mono-therapy for OUD, the BUP dropout that will naturally occur during the trial provides the opportunity to explore the feasibility of, and collect some efficacy data on, the provision of semaglutide, relative to placebo, in individuals discontinuing BUP. The exploratory aim is to compare substance use outcomes and opioid-related overdoses for the semaglutide and placebo groups in individuals discontinuing BUP.