Targeting Treatment-Resistant OUD With Ketamine-Assisted Mindfulness Oriented Recovery Enhancement

This study is a Phase II, two-arm, parallel randomized controlled trial designed to evaluate the efficacy of Mindfulness-Oriented Recovery Enhancement combined with Ketamine-Assisted Psychotherapy (KetaMORE) compared to Ketamine-Assisted Psychotherapy paired with a support group control condition for individuals with opioid use disorder receiving medications for opioid use disorder (MOUD), including buprenorphine. Participants will be randomized in a 1:1 ratio to one of two conditions: (1) Ketamine-Assisted Psychotherapy combined with Mindfulness-Oriented Recovery Enhancement, or (2) Ketamine-Assisted Psychotherapy combined with a support group providing nonspecific therapeutic support without mindfulness training. Both groups will receive identical ketamine dosing and psychotherapy components; the conditions will differ only in the adjunctive behavioral intervention. Mindfulness-Oriented Recovery Enhancement is a manualized, evidence-based intervention integrating mindfulness training, cognitive reappraisal, and savoring techniques to reduce craving, negative affect, and maladaptive reward processing associated with substance use. The support group control condition is designed to match therapist contact and group support while excluding mindfulness-based content. Participants will complete assessments at baseline, during treatment, post-treatment, and follow-up. Primary outcomes will include number of days of opioid use and time to first opioid use lapse. Secondary outcomes will include opioid craving and mood symptoms. Ecological momentary assessments will be used to capture daily fluctuations in substance use, craving, and affect throughout the study period.