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Ketamine-assisted Mindfulness-Oriented Recovery Enhancement for opioid use disorder: a randomized controlled trial

Nature Mental Health volume 4, pages 605–614 (2026) Cite this article

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Abstract

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 (N = 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.

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Fig. 1: Study procedures.
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Fig. 2: CONSORT diagram.
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Fig. 3: Effect of study treatments on instances of drug use.
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Data availability

Due to the sensitive nature of the clinical data, including substance use and ketamine treatment information from individuals with addiction, public deposition of raw data poses unacceptable risks of re-identification, stigma and harm. Participants were not consented for public data sharing. To protect confidentiality and comply with ethical and legal standards for vulnerable populations, raw data cannot be made publicly available. De‑identified aggregated data will be provided upon reasonable request (that is, meta‑analysis) after publication of this manuscript and is contingent on an approved data‑sharing agreement sent to egarland@health.ucsd.edu.

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Acknowledgements

This work was supported by a gift from T. and R. Andrew. E.L.G. was also supported by UG3DA062106 (principal investigator (PI): E.L.G.), R01DA056537 (PI: E.L.G.) and R01DA057631 (PI: E.L.G.) from the National Institutes of Health during the preparation of this manuscript. Opinions, interpretations, conclusions and recommendations are those of the authors and are not necessarily endorsed by the National Institutes of Health. We also acknowledge D. River for informing the conceptual framework underpinning this study.

Author information

Authors and Affiliations

  1. Department of Psychiatry, University of California San Diego, La Jolla, CA, USA

    Eric L. Garland & Hannah Pfeffer

  2. Sanford Institute for Empathy and Compassion, University of California San Diego, La Jolla, CA, USA

    Eric L. Garland

  3. Huntsman Mental Health Institute, University of Utah, Salt Lake City, UT, USA

    Benjamin R. Lewis & Madeleine Odette

  4. Numinus LLC, Murray, UT, USA

    Paul Thielking

  5. Division of Epidemiology, University of Utah, Salt Lake City, UT, USA

    Jincheng Shen

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  6. Jincheng Shen
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Contributions

E.L.G. and B.R.L. conceived and designed the study, and acquired funding. E.L.G. as PI had overall responsibility for the management of the study, with support from B.R.L. and P.T. E.L.G. provided training and supervision to the MORE therapists. B.R.L. and P.T. administered the ketamine. M.O. and H.P. assisted with study coordination. J.S. analyzed the data. E.L.G. wrote the first draft of the report. All authors contributed to, and approved, the final manuscript. E.L.G. and J.S. had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Corresponding author

Correspondence to Eric L. Garland.

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Competing interests

E.L.G. is the Director of UCSD ONEMIND (Optimized Neuroscience-Enhanced Mindfulness Intervention Design). UCSD ONEMIND provides MORE, mindfulness-based therapy and cognitive behavioral therapy in the context of research trials for no cost to research participants; however, E.L.G. has received honoraria and payment for delivering seminars, lectures and teaching engagements (related to training clinicians in mindfulness) sponsored by institutions of higher education, government agencies, academic teaching hospitals and medical centers. E.L.G. also receives royalties from the sale of books related to MORE. E.L.G. was previously a licensor to BehaVR, LLC. E.L.G. is Founder of MORE Science Institute. The other authors declare no competing interests.

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Nature Mental Health thanks Dan Petrovitch, Andrew J. Saxon and Max Spaderna for their contribution to the peer review of this work.

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Garland, E.L., Lewis, B.R., Thielking, P. et al. Ketamine-assisted Mindfulness-Oriented Recovery Enhancement for opioid use disorder: a randomized controlled trial. Nat. Mental Health 4, 605–614 (2026). https://doi.org/10.1038/s44220-026-00625-5

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