MDMA-Assisted PTSD Therapy Rejected by FDA

The US Food and Drug Administration (FDA) has rejected the use of MDMA-assisted therapy for post-traumatic stress disorder (PTSD), according to an announcement from the therapy’s drugmaker, Lykos Therapeutics.

The FDA has requested an additional Phase 3 study to further examine the safety and efficacy of midomafetamine, and Lykos plans to meet with the FDA to discuss reconsideration and resubmission.

Rejected, for now

The FDA’s decision comes after a key advisory panel voted that the available data does not suggest that the therapy is effective for patients with PTSD, and that the benefits do not outweigh the risks. The rejection represents a significant milestone for the development of other psychedelics-based therapies, especially when considering the lack of treatment options available for patients with PTSD.

The FDA previously granted Breakthrough Therapy Designation to MDMA for the treatment of PTSD, allowing it to move more efficiently through the development and review process. This came after emerging evidence suggested that the empathogen MDMA, also known as the party drug ecstasy, may hold promise in treating the condition.

However, its status as a Schedule 1 compound necessitates a special license for its research. This represents the highest restriction – meaning the government classes it as having “no currently accepted medical use and a high potential for abuse.”

The Multidisciplinary Association for Psychedelic Studies (MAPS) – now known as Lykos Therapeutics – published two randomized, double-blind and placebo-controlled Phase 3 trials, MAPP1 and MAPP2, hinting at the possible efficacy of MDMA-assisted therapy.

The first trial assessed 90 patients with severe PTSD who received either MDMA or a placebo paired with three psychotherapy sessions. 32% of those who received the placebo and psychotherapy no longer qualified for a PTSD diagnosis – rising to 67% for those who received MDMA and psychotherapy.

In the second trial, 104 participants with moderate to severe PTSD were treated with therapy and MDMA or placebo. By the end of the study period, 71.2% of participants in the MDMA group no longer met diagnostic criteria for PTSD compared to 47.6% in the placebo group.

Concern among some experts

Considering the results from these trials, some proponents of psychedelic therapies were deeply disappointed by the decision, including the founder and CEO of Terran Biosciences, Dr. Sam Clark. Terran has one of the industry’s largest psychedelic development programs, including psychedelics such as psilocybin and LSD as well as empathogens such as MDMA.

“The current treatments for PTSD are woefully inadequate, and two Phase 3 trials have already shown MDMA-assisted psychotherapy to be the most effective treatment to date,” Clark wrote in a statement. “There are over 13 million Americans suffering from PTSD and every day around 20 US veterans die from suicide. This decision will deny this potentially lifesaving medication to those who desperately need it now.”

However, some experts supported the FDA’s decision, having been unsatisfied with the design and running of the trials. In particular, the blinding of the participants to their treatment.

“The concerns raised by the FDA’s consulting panel, as well as those outlined in the citizen petition, highlight significant issues in the trials conducted by Lykos Therapeutics (formerly MAPS),” said Dr. Sergio Pérez Rosal, medical doctor specialized in anesthesia, intensive care and emergency medicine. He holds an MSc in neuroscience and psychology, and is a co-founder of the OVID Clinics, the first psychedelic medicine clinic in Germany.

“There was functional unblinding, meaning that it wasn’t hard to guess what you were getting, placebo versus [MDMA],” said Dr. Jeffrey Lieberman, the Lawrence C. Kolb Professor of Psychiatry at Columbia University Medical Center. “People should have had a more comparable, active placebo.”

“The altered states of consciousness induced by psychedelics make it nearly impossible to maintain a true double-blind setup, which is considered the gold standard in clinical research,” said Pérez Rosal.

Concerns were also raised about inconsistency in the way the psychotherapy was delivered across the various study sites.

“The method in which the psychotherapy was administered was not standardized, and seemed like it was really variable. Any time you do a study with psychotherapy, there is rigorous standardization where there is a manual, training and test-retest reliability – it doesn't sound like that was the case,” Lieberman explained.

Furthermore, three research papers on the effects of MDMA-assisted psychotherapy – which feature several authors affiliated with MAPS/Lykos – have since been retracted in the wake of the FDA’s rejection. These were due to “protocol violations amounting to ethical misconduct”, after a trial participant at one study site in Canada accused a therapist involved in the study of sexual assault.

This is not yet the end of the road for MDMA-assisted therapy, however, as Lykos plan to ask the FDA to reconsider their decision as well as discuss the recommended steps to resubmit a request for regulatory approval in the future.

“It’s important to recognize that this would not signify the end of efforts to validate MDMA as a therapeutic medicine,” said Pérez Rosal. “Instead, it would likely delay the process of making this treatment accessible to patients who could potentially benefit from it.”

“This delay, while frustrating, could have a silver lining. It presents an opportunity to address the valid critiques raised by the advisory committee and the FDA, potentially leading to more rigorous and scientifically sound research,” Pérez Rosal said.

About the interviewees

Dr. Jeffrey Lieberman is the Lawrence C. Kolb Professor of Psychiatry at Columbia University Medical Center. His work focuses on advancing the understanding of schizophrenia and the clinical effectiveness of antipsychotic drugs, and he served as president of the American Psychiatric Association 2013–2014.

Dr. Sergio Pérez Rosal is a medical doctor specialized in anesthesia, intensive care and emergency medicine. He holds an MSc in neuroscience and psychology from Kings College London, and is training in cognitive behavioral psychotherapy. He is the co-founder of the OVID Clinics, the first psychedelic medicine clinic in Germany.