MDMA-assisted therapy is currently under formal review by the U.S. Food and Drug Administration (FDA) as a potential breakthrough treatment for a specific psychiatric condition. This evaluation marks a significant moment for the field of psychedelic medicine, potentially paving the way for a new therapeutic approach for individuals seeking relief from severe mental health challenges.
The Path to FDA Review
Post-traumatic stress disorder (PTSD) is the primary condition MDMA-assisted therapy aims to treat, affecting millions in the U.S., including veterans and victims of abuse. Current treatments, such as sertraline and paroxetine, offer only modest efficacy, highlighting the need for more effective interventions. The scientific journey to FDA review involved a rigorous multi-phase clinical trial process, with the Multidisciplinary Association for Psychedelic Studies (MAPS) sponsoring pivotal Phase 3 trials: MAPP1 and MAPP2.
The MAPP1 trial, which focused on patients with severe PTSD, demonstrated a significant reduction in symptoms. At the 18-week primary endpoint, 67% of participants receiving MDMA-assisted therapy no longer met the diagnostic criteria for PTSD, compared to 32% in the placebo group who received therapy alone. The MAPP2 trial, enrolling individuals with moderate-to-severe PTSD, yielded similar positive results, with 71.2% of the MDMA group no longer meeting PTSD criteria versus 47.6% of the placebo group. These studies, published in Nature Medicine, consistently showed that the MDMA-assisted therapy led to clinically meaningful improvements in PTSD symptoms and functional impairment, providing the evidence base submitted for FDA consideration.
The Formal New Drug Application and Review
Based on robust clinical trial data, Lykos Therapeutics, formerly MAPS Public Benefit Corporation, submitted a New Drug Application (NDA) to the FDA. An NDA is a comprehensive submission that a pharmaceutical company files with the FDA to seek approval to market a new drug in the United States, providing detailed information on the drug’s safety, efficacy, manufacturing, and labeling. This application was granted priority review by the FDA in February 2024, indicating an urgent unmet need for new PTSD treatments.
A central component of the FDA’s review process was the Psychopharmacologic Drugs Advisory Committee meeting on June 4, 2024. The purpose of an advisory committee is to provide independent, expert advice to the FDA on scientific and clinical matters related to drug approval. During this meeting, the committee voted 9-2 against recommending the treatment based on efficacy and 10-1 against recommending it based on the benefit-risk profile, even with a proposed risk evaluation and mitigation strategy.
The committee’s specific recommendations highlighted concerns that the data did not sufficiently demonstrate the therapy’s effectiveness and that its benefits did not outweigh the risks. Despite the negative vote, the advisory committee’s recommendation is non-binding. However, the FDA typically gives significant weight to these expert opinions when making its final decision on a New Drug Application.
Key Safety and Implementation Concerns
The advisory committee’s concerns stemmed from specific safety issues and challenges related to trial design and real-world implementation. One safety issue was the potential for cardiotoxicity, or heart risks, associated with MDMA. While trials reported no serious adverse events, the panel noted increases in blood pressure and heart rate; 46% of MDMA-treated participants experienced a systolic blood pressure increase of 20 mm Hg or more during sessions, compared to 17% in the placebo group.
Another significant concern was “functional unblinding” in the clinical trials. Participants often discerned whether they received MDMA or a placebo due to the drug’s pronounced psychoactive effects, which included “profound alterations in mood, sensation, suggestibility, and cognition.” An FDA analysis noted that approximately 90% of MDMA recipients and 75% of placebo recipients correctly guessed their treatment assignment, complicating result interpretation as participant expectation could have influenced outcomes.
The proposed Risk Evaluation and Mitigation Strategy (REMS), designed to ensure patient safety in a real-world setting, was also a point of contention. Committee members expressed doubts about the REMS’s sufficiency to manage risks such as MDMA’s abuse potential and potential for misconduct or bias in the trials. They concluded that the benefits of MDMA, even with the proposed REMS, did not outweigh its risks for PTSD treatment.
Next Steps and Potential Outcomes
The FDA’s final decision on Lykos Therapeutics’ New Drug Application for MDMA-assisted therapy for PTSD was anticipated by a Prescription Drug User Fee Act (PDUFA) target action date of August 11, 2024. There were three main potential outcomes for this review.
One was approval, which would have allowed MDMA-assisted therapy to be used medically under specific, controlled conditions. A second potential outcome was a Complete Response Letter (CRL), a rejection outlining deficiencies that must be addressed before resubmission. This would require Lykos to conduct an additional Phase 3 trial for more safety and efficacy data.
A third potential outcome was approval with a highly restrictive REMS, imposing strict conditions on how the therapy could be administered to mitigate identified risks. Had the FDA approved the drug, the Drug Enforcement Administration (DEA) would then need to reschedule MDMA from its current Schedule I classification, which designates drugs with no accepted medical use and high abuse potential, to make it legally accessible for medical use.