Project Summary/Abstract We propose to further strengthen and sustain the successful Center of Biomedical Research Excellence (COBRE) on Opioids and Overdose at Rhode Island Hospital and affiliated research institutions. The motivation for this effort lies in the ongoing tremendous need for greater scientific understanding of the mechanisms underpinning vulnerability to opioid use and overdose and a need for more effective interventions to treat and prevent opioid misuse and overdose. We will approach these challenges through ongoing, cooperative partnership among senior scientists and early career investigators across several complementary disciplines. We will continue our unique and innovative mentoring strategy that, in addition to primary project advising, provides junior faculty members with specialized mentorship and services that empowers investigators to influence policy and practice through their research. Moreover, our four interdisciplinary cores provide infrastructure, consultation, and additional support services to ensure the successful career development of our Project Leaders. The long-term goal of the Center is to strengthen and sustain a critical mass of investigators specializing in opioids and overdose that benefits affected populations and enhances the competitiveness of affiliated investigators. The objective of this proposal is to strengthen and continue to develop the COBRE Center and to support the research activities of junior Project Leaders to ensure their transition to R01-funded scientists and enhance the critical mass of researchers. There are two Specific Aims—one related to the strengthening of our disease-specific research center, and one encompassing three Research Projects that are linked by the themes of opioids and overdose. Aim 1: Strengthen the cores needed to further develop and sustain our thematic multidisciplinary center of research excellence on opioids and overdose. Four cores will continue to strive to achieve this aim: our Administrative Core, Data and Research Methods Core, Translational and Transformative Core, and Community Engaged Research Core. Aim 2: Support the selection, mentorship, and career development of early career faculty Project Leaders. The three initial research projects are: Project 1: Nicole Weiss, PhD - Prediction of Return to Opioid Use During Immediate Community Reintegration, Project 2: Michael Bernstein, PhD- Optimizing Open Label Placebos for Chronic Pain Patients, and Project 3: new RPL to be assigned; R01 notice of award was received, effective 9/30/22, for originally planned researcher. The Center brings together an interdisciplinary group of accomplished senior scientists, promising junior investigators, and distinguished advisors and collaborators to work collectively to strengthen our center of excellence in an area of clinical research that is of critical public health importance.