PROJECT SUMMARY/ABSTRACT Opioid use disorder (OUD) is a pernicious and highly prevalent threat to public health, affecting 6.1 million US citizens in 2022. Buprenorphine is one of the most efficacious treatments for OUD, yet half of patients treated buprenorphine return to drug use within six months, suggesting that additional adjunctive interventions are indicated. Ketamine, a FDA-approved medication commonly used as an anesthetic agent, is a NMDA antagonist that has demonstrated efficacy for the treatment of depression and holds significant potential to improve OUD treatment outcomes—especially when combined with targeted psychotherapies for addiction. We have successfully integrated ketamine with Mindfulness-Oriented Recovery Enhancement (MORE), an evidence-based psychotherapy for OUD with established efficacy in treating opioid misuse and preventing OUD relapse. Building upon our pilot data indicating that MORE + ketamine reduces drug use in patients treated with buprenorphine, here we first propose a UG3-funded, Phase 2 placebo-controlled randomized clinical trial (RCT) to investigate the safety, preliminary efficacy, and psycho-physiological mechanisms of MORE + ketamine for treatment-resistant patients receiving buprenorphine for OUD. To enhance blinding integrity, this study will compare MORE + intramuscular (IM) ketamine to MORE + IM diphenhydramine as an active placebo condition. We will also examine whether MORE + ketamine reduces drug use by a) enhancing mindfulness-related psychological processes, b) modulating neurophysiological reward responses, and c) altering theta oscillations in frontal midline brain regions. If MORE + ketamine demonstrates safety and preliminary indications of efficacy in the UG3 study, we will proceed to the UH3 phase to confirm the efficacy of the MORE + ketamine intervention in a community- based Phase 3 RCT conducted in three clinic sites recruited from the NIDA Clinical Trials Network. Our central hypothesis is that relative to MORE + placebo, MORE + ketamine will result in less drug use, better treatment adherence, and more improvement in craving and psychiatric symptoms though a 12-month follow-up. Unfortunately, ketamine is currently being marketed for a wide array of applications, including the treatment of OUD, in the absence of efficacy data from controlled studies. Should MORE+ketamine demonstrate efficacy in the proposed trials, this therapy will be advanced along the FDA approval pathway into standard care for treatment-resistant patients with OUD on buprenorphine to reduce opioid-related mortality and morbidity in the United States.