Abstract The most effective treatment to tackle the ongoing opioid crisis in the US is buprenorphine, one of several medications for opioid use disorder (OUD). Buprenorphine reduces overdose mortality by up to 70%, increases treatment retention, and suppresses illicit opioid use, making it one of the most important interventions in reversing the overdose epidemic. However, more than 30% will discontinue buprenorphine by 12 weeks due in part to the emergence of craving for opioids, leading to relapse and heightened risk of an overdose. Unfortunately, there are currently no evidence-based adjuncts to buprenorphine to reduce cue-reactivity and the risk of early treatment discontinuation. Therefore, research to identify interventions that can be used as adjuncts to buprenorphine is urgently needed. Glucagon-like peptide-1 (GLP-1) agonists, FDA-approved medications for the treatment of diabetes and obesity, potentiate insulin release, inhibit glucagon release, delay gastric emptying, and reduce food intake. The activation of GLP-1 receptors, which are highly expressed in the brain, reduce the hedonic value of food and appear to have similar effects on reward valuation for substances of misuse, raising the possibility that these medications could be repurposed for the treatment of OUD. Preliminary clinical studies suggest GLP-1 agonists may impact substance use in humans, but these studies were based on older formulations such as exenatide and liraglutide. The newer formulations such as semaglutide have greater homology to native GLP-1 and are associated with fewer gastrointestinal adverse events. Data are therefore lacking to validate the use of newer, more efficacious formulations in terms of safety profiles and initial impact on cue-reactivity and OUD-related outcomes. Our central hypothesis is that semaglutide will demonstrate attenuation of cue-reactivity providing preliminary evidence of its utility as an adjunct to buprenorphine to prevent relapse. This proposal will be the first placebo-controlled randomized trial of the weekly formulation of semaglutide as an adjunctive treatment to buprenorphine in individuals with OUD by evaluating cue-induced craving. We will also study the safety and tolerability of semaglutide over the course of the 12-week trial. This innovative R21 has public health impact because it will contribute to the identification of an effective pharmacotherapy adjunct to buprenorphine for OUD and is highly responsive to the NIDA programmatic goals of identifying novel treatment strategies for individuals with OUD. The NIDA Director has specifically cited the need to conduct OUD research with medications with targets other than opioid receptors, and to repurpose existing medications including GLP-1 agonists. If successful, results from this study will lay the groundwork for the design of an adequately powered efficacy trial to determine whether semaglutide treatment can improve OUD-related outcomes for those receiving buprenorph...