FDA Declines To Approve MDMA-Assisted Psychotherapy as a PTSD Treatment

The FDA, which approved the protocols for the studies it now questions, is asking for an additional Phase 3 clinical trial, which would take years and millions of dollars.

The Food and Drug Administration (FDA) declined on Friday to approve MDMA-assisted psychotherapy as a treatment for post-traumatic stress disorder (PTSD). The agency has asked Lykos Therapeutics, which submitted the new drug application (NDA) in February, to conduct an additional Phase 3 clinical trial, which would take years and millions of dollars. It is a major setback that dismayed veteran advocates and others who see MDMA as a potentially life-changing psychotherapeutic catalyst for people struggling with longstanding psychological challenges that currently approved treatments have not adequately addressed.

"The FDA request for another study is deeply disappointing, not just for all those who dedicated their lives to this pioneering effort, but principally for the millions of Americans with PTSD, along with their loved ones, who have not seen any new treatment options in over two decades," said Amy Emerson, CEO of Lykos Therapeutics, a company created by the Multidisciplinary Association for Psychedelic Studies (MAPS), in a press release. "While conducting another Phase 3 study would take several years, we still maintain that many of the requests that had been previously discussed with the FDA and raised at the Advisory Committee meeting can be addressed with existing data, post-approval requirements or through reference to the scientific literature."

The decision was a huge disappointment to advocates of a treatment that the FDA recognized as a "breakthrough therapy" in 2017—especially since the two Phase 3 trials, which were published by Nature Medicine in 2021 and 2023, had found that subjects who took MDMA fared substantially better than subjects who underwent the same psychotherapy but took a placebo. In the 2021 study, two-thirds of the MDMA group "no longer met the diagnostic criteria for PTSD," compared to a third of the control group. In the 2023 study, more than 70 percent of the MDMA group no longer qualified for a PTSD diagnosis, compared to 48 percent of the control group.

The FDA's decision nevertheless was unsurprising in light of an advisory panel's June 4 recommendation against approval. The committee, which included just one scientist with experience in psychedelic research, overwhelmingly concluded that MDMA's effectiveness had not been adequately established and that its benefits had not been shown to outweigh its risks. The FDA's concerns are rather puzzling, given that Lykos worked with the agency every step of the way to develop an acceptable research protocol.

The FDA declined to release the letter to Lykos in which it detailed those concerns, which it said is confidential. But the company's response suggests that the issues identified by the agency are similar to the ones highlighted by its advisers.

The company noted concerns that "Lykos' clinical data were insufficient to demonstrate durability." Lykos "believes that the data included in the NDA provide sufficient evidence of efficacy and durability in line with the relevant FDA guidance," the company said. "FDA's draft guidance for industry on psychedelic drugs indicates that endpoint data should be collected at 12 weeks; Lykos' Phase 3 studies collected endpoint data at 18 weeks, with additional exploratory endpoints collected six months or more later."

The advisory panel also raised "questions about expectancy bias stemming primarily from participants with prior MDMA use." The concern was that subjects whose previous experience with MDMA was positive would be primed to expect good results in the clinical trials, which might have skewed the results. But Lykos notes that it "aligned with the FDA" on "a variety of bias minimization measures in the study design" and that "prior MDMA use among participants was not previously viewed as detrimental." About 30 percent of the subjects in the company's Phase 2 trials reported prior MDMA use, a fact that "was shared with FDA before establishing the inclusion and exclusion criteria in the Phase 3 trial design."

In the two Phase 3 trials, Lykos noted, the data indicated that "prior illicit MDMA use had no impact on the results." There "was no meaningful difference in primary outcome measure…or adverse events reported between the subgroup of Phase 3 participants who reported prior illicit MDMA use and the subgroup of participants who did not."

The FDA's advisers also worried about "functional unblinding"—the likelihood that subjects surmised which group they were in based on the presence or absence of MDMA's distinctive psychoactive effects. "Functional unblinding is a known research challenge for psychiatric drugs with psychoactive effects," Lykos noted after the advisory committee's vote, and "it was discussed extensively with the FDA" during the development of the Phase 3 research protocol. "While there is no perfect solution to functional unblinding, we took many steps to minimize its potential impact, including the use of independent, blinded third-party clinician raters to assess outcomes," the company said. "The weight of evidence suggests a very low likelihood that the observed [MDMA] effect can be adequately explained by functional unblinding."

The advisory committee "also raised psychotherapy as a concern, with some recommending" that Lykos "further characterize the extent to which psychotherapy contributes to treatment benefit and if it is even necessary," the company noted on Friday. "Lykos acknowledges that [MDMA]-assisted therapy represents a novel combination of drug and therapy that raises unique research questions and will continue to engage the FDA as appropriate on these challenges."

In June, Lykos said "significant steps were taken to ensure standardization and consistency in the psychological intervention across therapists, sites, and treatment groups, and to thus allow for valid comparison between the [MDMA] and placebo groups." The success of those efforts, it said, "is supported by the lack of variability in treatment outcomes between Phase 3 clinical sites."

The FDA's advisers "raised questions regarding potential cardiovascular issues and hepatoxicity," Lykos noted in June. The company said that it "will continue to work with the FDA to characterize the data and/or collect new data to address these potential risks, if required," and that it is "confident that these can be safely addressed in a post-marketing environment."

As Lykos noted, issues such as prior MDMA use and functional unblinding were recognized all along, and the FDA previously did not view them as insurmountable barriers to approval. The psychotherapeutic component likewise was part of these studies from the beginning, and the FDA approved research protocols that included it.

In a Lykos press release, Jennifer Mitchell—a neurologist at the University of California, San Francisco, who participated in the research—pointed out that developing the clinical trials was "an enormously complex undertaking" that the researchers tackled "over the course of many years…in consultation with the FDA and with an agreed Special Protocol Assessment in place." She called the FDA's decision "a major setback for the field."

Prior to the decision, bipartisan groups of senators and representatives wrote letters to the agency underlining the need for better PTSD treatments. "Existing treatments and medicines for PTSD, the last of which FDA approved nearly 25 years ago, have not decreased the frequency of suicide within the veteran community," Sens. Michael F. Bennet (D–Colo.), Rand Paul (R–Ky.), and 17 of their colleagues wrote. "As a nation, we cannot allow our veterans to continue to suffer in silence and must identify treatments proven to drastically decrease the adverse effects of PTSD."

Reps. Jack Bergman (R–Mich.), J. Luis Correa (D-Calif.), and 59 of their colleagues suggested that criticism of the Lykos research was misguided. "As this application has made its way through the regulatory review process, certain groups and individuals have voiced criticism of the application," they wrote. "It is our understanding that while these critics may be well-intentioned, their criticism is not necessarily reflective of the science, but rather their personal ideological beliefs and biases related to the medicalization of substances like MDMA."

Lykos is asking the FDA to reconsider its request for another Phase 3 trial, hoping that existing evidence will suffice to resolve the agency's concerns. "MAPS and our supporters have been advocating for the development and supporting the FDA-approved research of MDMA-assisted therapy for more than 38 years," MAPS founder Rick Doblin said in a press release. "MAPS will continue working towards safe, legal access to this therapy for the more than 350 million people living with PTSD worldwide."

MDMA would have been the first psychedelic approved as a medicine by the FDA. But ballot initiatives in Oregon and Colorado have legalized the use of psilocybin in psychotherapy. Taylor West, executive director of Oregon's Healing Advocacy Fund, suggests that state-level reform is a promising alternative in light of the FDA's decision, telling The New York Times that "the path to creating access to safe, psychedelic-assisted therapy is not going to run through Washington, D.C."