Ketamine + Mindfulness for Opioid Addiction: RCT Results

The opioid crisis continues to claim lives at staggering rates, and current treatments — while helpful for many — leave a significant number of patients struggling with cravings and relapse. A 2026 randomized controlled trial published in Nature Mental Health by Sevelius and colleagues tested a novel combination: ketamine-assisted psychotherapy (KAP) paired with Mindfulness-Oriented Recovery Enhancement (MORE). The results suggest this pairing could offer a powerful new approach for opioid use disorder (OUD).

Study Design

The trial enrolled 68 participants with opioid use disorder and randomized them to one of two groups. The first group received KAP combined with MORE — a structured mindfulness-based intervention specifically designed for addiction recovery. The second group received MORE alone, without ketamine. This design allowed researchers to isolate the added benefit of ketamine on top of an already evidence-based therapeutic approach.

MORE, developed by Dr. Eric Garland, integrates mindfulness meditation, cognitive reappraisal, and savoring of positive experiences. It has shown efficacy for chronic pain and opioid misuse in prior studies. The question this trial posed was straightforward: does adding ketamine to MORE produce better addiction outcomes than MORE by itself?

Participants were assessed on drug use frequency, cravings, and related psychiatric symptoms at multiple time points throughout the study.

Key Findings

The KAP + MORE group showed significantly fewer instances of drug use compared to the MORE-only group. Cravings for opioids were also markedly lower in the ketamine-assisted arm. These were not marginal differences — the combination treatment produced clinically meaningful reductions that exceeded what mindfulness therapy achieved on its own.

This is particularly significant because MORE is not a weak comparator. It is an active, evidence-based therapy. The fact that adding ketamine produced additional measurable benefit above and beyond MORE speaks to ketamine's unique contribution to the recovery process.

The study also tracked safety outcomes. Ketamine was administered in controlled settings with appropriate medical oversight, and the treatment was well-tolerated. No serious adverse events were attributed to the ketamine intervention.

Why the Combination Works

The rationale for pairing ketamine with mindfulness-based therapy draws on what we know about ketamine's neurobiological effects. Ketamine promotes neuroplasticity — the brain's ability to form new neural connections and modify existing ones. This creates what researchers sometimes call a "window of plasticity," a period during which the brain is more receptive to new learning and behavioral change.

Mindfulness training during or following this window of enhanced plasticity may allow therapeutic skills to take root more deeply. Rather than simply reducing cravings pharmacologically, the combination approach helps patients develop new cognitive and emotional patterns that support sustained recovery.

This aligns with the mechanism behind ketamine-assisted psychotherapy more broadly. The principle is consistent across applications: ketamine opens the neuroplastic window, and the accompanying therapy provides the tools and insights that patients carry forward after the window closes.

At Isha Health, our collaborative care model operates on a similar principle. While we focus primarily on depression and related conditions rather than OUD, the core logic is the same — ketamine treatment is most effective when paired with therapeutic support that helps patients integrate their experience and build lasting change.

The Opioid Crisis Context

The need for new OUD treatments cannot be overstated. Despite the availability of medications like buprenorphine and methadone, many patients either do not access these treatments, do not respond fully, or discontinue them. Relapse rates remain high, and the psychological dimensions of addiction — shame, trauma, conditioned cravings — often persist even when physical dependence is managed.

Ketamine-assisted therapy addresses dimensions of addiction that pharmacological maintenance alone may not reach. The combination with mindfulness specifically targets the craving and emotional dysregulation components that drive relapse, while also addressing co-occurring depression and anxiety that frequently accompany OUD.

This study adds to earlier research on ketamine for substance use disorders, including work on ketamine for alcohol use disorder and studies of ketamine for cocaine dependence. A pattern is emerging: ketamine's benefits for addiction may be as significant as its benefits for depression.

Looking Ahead

The Sevelius et al. trial is a rigorous RCT in a high-impact journal, which lends considerable weight to the findings. Larger, multi-site trials will be needed to confirm these results and determine optimal dosing and treatment duration. Researchers will also want to understand which patients benefit most and whether the effects are sustained over longer follow-up periods.

For patients dealing with co-occurring depression and substance use challenges, the growing evidence base for ketamine is encouraging. Review Isha Health's clinical outcomes and explore our approach to ketamine for alcohol addiction.

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Related Articles

• Ketamine and Alcohol Use Disorder: The Montreal Model
• Ketamine for Alcohol Addiction
• How Does Ketamine Work?

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