PROJECT SUMMARY/ABSTRACT Over 2 million Americans struggle with opioid use disorder (OUD) and the risks associated with misuse of opioids have prompted a public health crisis. The FDA has approved three medications for the treatment of OUD that have been grouped under the term Medication Assisted Treatment (MAT), which includes methadone, naltrexone and buprenorphine-containing products. MATs have demonstrated benefit in the treatment paradigm for OUD as overall mortality is reduced by as much as fifty percent. However, relapse and treatment discontinuation are common within the first 5 to 12 weeks of MAT, suggesting an unmet therapeutic need. Residual psychiatric symptoms such as insomnia, anxiety and depression have been postulated as key risk factors for relapse and treatment discontinuation in patients on buprenorphine. Since longer treatment retention is correlated with better long-term outcomes, the development of an adjunctive medication that could be added to the buprenorphine treatment paradigm to alleviate key residual psychiatric symptoms associated with treatment failure would address an important unmet need. Therefore, this research proposal seeks to evaluate the safety and efficacy of brexpiprazole as adjunctive treatment to buprenorphine/naloxone in OUD. Key milestones for this project include submission and FDA approval of an IND application to conduct first-in-human studies on the safety and tolerability of adjunctive use of brexpiprazole with buprenorphine/naloxone, followed by initiation of a 12-week exploratory efficacy study. Under the UG3 program, we have proposed IND-enabling safety and tolerability studies to evaluate brexpiprazole as adjunctive treatment to buprenorphine/naloxone in both animals (i.e. nonclinical toxicology) and treatment-seeking patients with moderate to severe OUD (i.e. Phase 1). Under the UH3 phase we have proposed an exploratory 12-week study to measure key residual psychiatric symptoms, relapse and treatment retention in treatment-seeking patients with moderate to severe OUD treated with buprenorphine/naloxone monotherapy vs. adjunctive brexpiprazole plus buprenorphine/naloxone. The overarching hypothesis is that adjunctive brexpiprazole will attenuate the residual symptoms that persist on buprenorphine/naloxone monotherapy, resulting in better treatment retention and potentially improving long-term treatment outcomes.