<p>Here, in this single-blinded clinical trial (NCT04892251), we assessed the safety and preliminary efficacy of ketamine-assisted psychotherapy (KAP) plus Mindfulness-Oriented Recovery Enhancement (MORE) for patients with opioid use disorder (OUD). People receiving buprenorphine for OUD were randomized (<i>N</i> = 68) to MORE + KAP or MORE-only. MORE involved 8 weeks of mindfulness, reappraisal and savoring training by telehealth videoconferencing. The MORE + KAP arm received a 0.5 mg kg⁻¹ intramuscular ketamine dose after week 5 and then 1 week later received a dose up to 1.0 mg kg⁻¹. The primary outcome was instances of drug use. Secondary outcomes included craving, distress, affective states and buprenorphine use. No serious ketamine-related adverse events occurred. The MORE + KAP arm reported significantly fewer instances of drug use after treatment and lower cravings at follow-up than the MORE-only arm. No between-groups differences were noted in distress or buprenorphine use. The MORE + KAP arm reported greater increases in mindfulness-related processes. During ketamine administration, 85% of participants reported experiencing a full mystical experience, which predicted reduced opioid craving. Adding intramuscular ketamine to MORE appears safe and may augment OUD treatment outcomes.</p>