Matters Arising: MAPS’ Pivotal Phase 3 Trial Advances Scientific Discourse in Nature Medicine

Letters in Nature Medicine address important challenges in evaluating psychedelic-assisted therapies 

The recent publication of results of the first Phase 3 clinical trial of MDMA-assisted therapy for posttraumatic stress disorder (PTSD) have sparked scientific discourse among clinicians and researchers around the world: Highly statistically significant results and exceptional outcomes for people living with difficult-to-treat conditions for an average of nearly 15 years should be closely examined. In the case of this study, among participants with severe, chronic PTSD who received MDMA-assisted therapy, 88% experienced a clinically-significant reduction in symptoms and 67% no longer qualified for a PTSD diagnosis.

“Science doesn’t happen in a vacuum,” shares Jennifer Mitchell, Ph.D., lead author of the first Phase 3 publication. “It is only through working together that we can enable the field of psychedelic medicine to move forward with accuracy and precision, and so we are delighted to find so many voices joining this conversation.” Since the inception of clinical trials of MDMA-assisted therapy for PTSD in 2000, rigorous scientific inquiry and emerging science have been essential to continual improvements in the research sponsored by the Multidisciplinary Association for Psychedelic Studies (MAPS) and conducted by MAPS Public Benefit Corporation (MAPS PBC).

Given the unique experiential nature of psychedelic therapies, study blinding via placebo has long been a matter of particular concern for researchers seeking to evaluate the effectiveness of any psychedelic intervention (Burke et al., 2021). Some are skeptical of the trial design, analysis of adverse effects, and cost-effectiveness of MDMA-assisted therapy compared to other first-line interventions (Halvorsen et al., 2021). This week, Nature Medicine published these critiques alongside a response letter from researchers Jennifer Mitchell, Ph.D., Allison Coker, Ph.D., and Berra Yazar-Klosinski, Ph.D., all of whom served as authors of the peer-reviewed journal article reporting on the results.

Burke et al. speaks to the profound challenge of adequately blinding clinical trials of psychedelics without introducing other confounds to the efficacy and safety data that arise with active placebo controls or active drug comparisons.

In the Phase 3 paper, Mitchell et al. referenced the placebo adjusted effect sizes of MDMA-assisted therapy with other pharmacological treatments (i.e. sertraline), but did not include a comparison between MDMA-assisted therapy and other trauma-focused psychological treatments such as prolonged exposure therapy or cognitive processing therapy, which some healthcare guidelines designate as the first-line interventions for PTSD.

“MDMA-assisted therapy for PTSD is founded in a trauma-focused approach, which holds the goals of PTSD symptom reduction and improvement of the overall functioning, wellbeing, and quality of life of the participant,” states Michael Mithoefer, M.D., MAPS PBC’s Senior Medical Director for Medical Affairs, Training, and Supervision. “While the scope of sessions goes beyond trauma processing to include exploration of other psychological, interpersonal, and spiritual aspects of the participant’s life, the approach holds processing of traumatic experiences — and the thoughts, feelings and behaviors resulting from them — as an essential central component of the therapy.”

Halvorsen et al. suggest that the Phase 3 trial’s lack of a pragmatic comparison to a common trauma-focused psychological treatment is insufficient for MDMA-assisted therapy to be designated as a breakthrough therapy. Such pragmatic studies can inform health policy decisions, such as those governing insurance coverage or clinical guidelines issued by professional associations. However, the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) regulate pharmacotherapies, not psychological therapies, therefore these drug development regulatory programs do not call for a comparison to psychological interventions (Mitchell et al., 2021).

Regulatory Affairs Manager for MAPS PBC, Allison Coker, Ph.D., notes, “The ‘Breakthrough Therapy’ designation granted for MDMA for PTSD by the FDA is not a final assessment of the drug’s impact, but an FDA mechanism to expedite the drug development process for drugs with preliminary evidence indicating that they could offer substantial improvement over available therapy for treating a serious condition. We are eager to complete the second Phase 3 trial of MDMA-assisted therapy and conduct further post-approval research to evaluate MDMA as an adjunct to other trauma-focused therapies, compare the treatment among subgroups of PTSD diagnoses, and integrate emerging neuroscience in our work.”

The second Phase 3 clinical trial is currently enrolling participants. Prior to the hopeful approval in 2023 of MDMA-assisted therapy for PTSD, the FDA has granted permission for an Expanded Access program in which 50 treatment-resistant PTSD patients can receive the treatment prior to FDA approval. MAPS plans to support pragmatic studies to explore other treatment protocols such as group therapy and cognitive-behavioral conjoint therapy for couples. Additionally, MAPS is funding a formal commitment to health equity: a holistic plan to create more pathways to access MDMA-assisted therapy for those historically marginalized by the mental health field and society at large.

NOTE
The safety and efficacy of MDMA-assisted therapy is currently under investigation. It has not yet been approved by the FDA, does not work for everyone, and carries risks even in therapeutic settings. These statements are no guarantee of future FDA approval or availability of MDMA-assisted therapy. These statements necessarily involve known and unknown risks and uncertainties, which may cause actual outcomes to differ materially from our results.

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ABOUT MAPS
Founded in 1986, MAPS is a 501(c)(3) non-profit research and educational organization that develops medical, legal, and cultural contexts for people to benefit from the careful uses of psychedelics and marijuana. MAPS is sponsoring the most advanced psychedelic therapy research in the world: Phase 3 clinical trials of MDMA-assisted therapy for PTSD. Since its founding, MAPS has raised over $110 million for psychedelic therapy and medical marijuana research and education and has earned the Guidestar Platinum Seal of Transparency.

ABOUT MAPS PUBLIC BENEFIT CORPORATION (MAPS PBC)
MAPS Public Benefit Corporation (MAPS PBC) catalyzes healing and well-being through psychedelic drug development, therapist training programs, and sales of prescription psychedelics while prioritizing public benefit above profit. Founded in 2014, MAPS PBC is a wholly-owned subsidiary of the Multidisciplinary Association for Psychedelic Studies (MAPS), a 501(c)(3) non-profit organization.