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Recently, the U.S. Food and Drug Administration (FDA) rejected the use of the hallucinogen MDMA (commonly known as ecstasy) for treating post-traumatic stress disorder (PTSD). FDA’s scientific advisors overwhelmingly concluded that the effectiveness of MDMA in treating PTSD has not been proven and that its risks outweigh its benefits.

For decades, the nonprofit organization MAPS has been conducting clinical trials on MDMA, a synthetic drug that can induce serotonin release by binding to presynaptic serotonin transporters. Early animal and clinical studies suggested it might be promising for PTSD treatment.

MAPS’s subsidiary, Lykos Therapeutics, submitted an application to the FDA, citing two clinical trials with around 200 PTSD patients who received either MDMA or a placebo. Over 80% of patients treated with MDMA showed significant symptom improvement, and follow-ups conducted 6-24 months later indicated that these effects persisted in some participants.

However, FDA’s scientific advisors had concerns about these trials, noting that they lacked critical psychological and physiological safety data. A major issue was that both participants and their therapists could almost always tell whether they were receiving MDMA or a placebo. Additionally, about 40% of the trial participants had used MDMA illegally before the trial, potentially biasing the sample. Many sought other treatments, including psychedelics, during and after the trials, suggesting their improvements might not be solely due to MDMA.

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Post-traumatic stress disorder (PTSD) refers to a mental health condition triggered by experiencing, witnessing, or confronting real or threatened death, serious injury, or threats to physical integrity.

PTSD’s occurrence is associated with numerous factors that can be categorized into familial, socio-psychological (e.g., gender, age, marital status, economic status, childhood trauma, domestic violence, war), and biological factors (e.g., genetic factors, neuroendocrine factors, neurochemical factors).

Selective serotonin reuptake inhibitors (SSRIs), approved by the FDA for PTSD treatment, are first-line medications but nearly half of the patients do not respond to them.

On September 14, 2023, researchers from the University of California, San Francisco and MAPS published a study in the prestigious medical journal Nature Medicine titled “MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial.”

This multi-center, randomized, double-blind, placebo-controlled phase 3 trial (MAPP2) evaluated the safety and efficacy of MDMA-assisted therapy for moderate to severe PTSD. The study met its primary and secondary endpoints by reducing PTSD symptoms and functional impairment in a diverse population with moderate to severe PTSD and was generally well-tolerated overall.

On May 10, 2021, the team published the results of their Phase 3 clinical trial MAPP1 in Nature Medicine, demonstrating that MDMA-assisted therapy for PTSD is well-tolerated and meets both primary and secondary endpoints. The treatment was shown to reduce the severity of PTSD symptoms and improve functional impairment.

The research team highlighted that these findings indicate MDMA-assisted therapy effectively alleviates PTSD symptoms and functional impairment in a diverse population with moderate to severe PTSD, maintaining good overall tolerability. After summarizing these clinical trial results further, the team submitted a new drug application for MDMA-assisted therapy to the FDA. However, this application was rejected by the FDA's scientific advisory committee. Although the FDA is not bound to follow the recommendations of its scientific advisory committee when deciding whether to approve a new drug, it usually does so.

References

  1. Mitchell, J.M., Ot’alora G., M., van der Kolk, B. et al. MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial. Nat Med 29, 2473–2480 (2023). https://doi.org/10.1038/s41591-023-02565-4.

  2. Mitchell, J.M., Bogenschutz, M., Lilienstein, A. et al. MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nat Med 27, 1025–1033 (2021). https://doi.org/10.1038/s41591-021-01336-3.