TThe Food and Drug Administration on Friday rejected MDMA as a treatment for post-traumatic stress disorder, in a blow to drug activists and veterans who have long campaigned for the psychedelic treatment. Although two Phase 3 trials showed the treatment was effective, strong opposition from an agency scientific advisory committee in June and allegations of missing data on side effects and bias in the study may have doomed Lykos Therapeutics’ application.
Lykos and its parent organization, MAPS, had been working to gain approval for MDMA for decades. The company said in a statement that it had received a “complete response letter” from the FDA denying the application “based on the data submitted.” It says the issues raised by the FDA mirror those raised at the ad-comm meeting.
The FDA requested that Lykos conduct an additional Phase 3 trial to further investigate the safety and efficacy of MDMA, and Lykos said it will request a meeting with the FDA to request reconsideration of the decision.
“The FDA’s request for another study is deeply disappointing, not only for all those who have dedicated their lives to this groundbreaking effort, but especially for the millions of Americans with PTSD, along with their loved ones, who have not had any new symptoms in recent years.” seen treatment options. more than two decades,” said Amy Emersonthe CEO of Lykos. “Although conducting a new Phase 3 study would take several years, we continue to maintain that many of the requests previously discussed with the FDA and submitted at the Advisory Committee meeting can be addressed with existing data, requirements following approval or by reference to the scientific literature.”
The FDA generally cannot, by law, disclose the reasons for a rejection, but a spokesperson said in a statement: “As discussed at the Meeting of the Advisory Committeethere are significant limitations to the data in the application that prevent the agency from concluding that this drug is safe and effective for the proposed indication.” It added that the agency recognizes the need for additional treatments for PTSD and other mental health conditions and will “continue to encourage research and drug development that will promote innovation for psychedelic treatments and other therapies to meet these medical needs.”
Existing therapies do not work well for many of the estimated patients 13 million Americans with PTSDand no new drug has been approved for the condition in more than two decades.
Several members of MAPS previously said they expected FDA approval and were unprepared for recent questions about data integrity. The ad’s rejection of evidence from the two trials was a “gut punch,” MAPS Director Kris Lotlikar said during a public webinar in July. “We’re still fighting a lot of deep-seated stigmas about psychedelics,” he said at the time. “Whatever the outcome, we’re just going to keep going and do what we can to make this happen.”
Boris Heifets, a neuroscience researcher at Stanford University who studies psychedelics, told STAT he was surprised by the FDA’s decision, adding that he had expected the agency to approve the drug with the requirement for post-approval studies. “PTSD is a major public health problem, and the only way you’re going to get any traction is by pulling up a string of investment in better treatments,” he said. “I was honestly expecting a more positive signal here… now we’re wondering, will the FDA ever approve this stuff?”
The FDA, he noted, approved the depression treatment esketamine with far less compelling data than that of Lykos — and he suspects that if a larger pharmaceutical company had conducted the trials, MDMA would have won approval.
The excitement surrounding MDMA therapy reached a fever pitch last year, when positive Phase 3 trial data made FDA approval seem inevitable. When MAPS founder Rick Doblin walked across a stage at a 12,000-person conference in Denver last year, he was welcomed as a messiah bringing the promise of legal psychedelics to the masses.
The premature celebrations began to subside March this yearwhen the Institute for Clinical and Economic Review think tank published a damning report, rating the evidence for MDMA therapy as ‘insufficient’ and raising questions about possible research misconduct. ICER researchers spoke to a handful of study participants who had “severe negative outcomes” that did not appear to be reflected in the study data. published research.
“We hope that ongoing and future rigorous research will examine how we can maximize the benefits and minimize the harms” of adding MDMA to psychotherapy, David Rind, ICER’s chief medical officer, said in a statement after the FDA’s decision.
The think tank’s report had also warned of a culture of advocacy that was undermining scientific standards, with MDMA research being treated as “a religious movement”. One participant in the Phase 3 study, Sarah McNamee, later shared this the advertising comm her therapists said she was “part of a movement” and “helping make history,” even as she struggled with suicidal thoughts. These allegations, which the FDA said it was investigating, significantly undermined the credibility of Lykos’ results.
“Zealots are bad scientists,” Peter Pitts, former deputy commissioner for external affairs at the FDA, said after the ad comm meeting. “You can’t avoid science because you believe in your heart that something is true, you have to prove it.”
Several psychedelic researchers, including those who had previously worked with MAPS, were concerned about the allegations. “We need to tread carefully and not repeat some of the mistakes of the past, but get it right this time,” says Charles Grob, a professor of psychiatry at the University of California, Los Angeles, who conducted the first MDMA study in the 1990s. of MAPS.
There was a sense of despondency over the FDA’s decision, especially among veteran communities where PTSD is common. “From a veteran’s point of view, it feels like the game is set in stone,” says Jesse Gould, founder of Heroic Hearts Project, a nonprofit focused on helping veterans with PTSD. “There seems to be something wrong here… something is not being tracked, especially when veterans’ lives are at stake every day.” Noting that countries such as Peru and Mexico allow psychedelic treatments for PTSD, he added: “That is an absolute shame for this country.”
Brett Waters, co-founder of Reason for Hope, a nonprofit organization for veterans that advocates for approval of psychedelics, said in a statement: “It is difficult to see how the FDA’s decision can be justified if it lacks sufficient resources features to ensure slow, gentle development. rollout of this new treatment. … Instead, veterans will continue to be forced to leave the country or find underground suppliers of psychedelics.
In addition to concerns about data integrity in Lykos’ studies, there were also questions about how to regulate the therapeutic side of treatment, especially given the cases of therapist misconduct during the clinical trials. All MDMA studies were conducted in patients under the supervision of therapists working in pairs, one licensed and one unlicensed.
In a phase 2 study, this was an unlicensed therapist accused of sexual abuse in a civil court complaint from a participant in the MAPS process. The therapist did not deny having sex with the patient, but claimed he had no ‘duty of care’. During the ad comm meeting, patient representative Elizabeth Joniak-Grant said it was important not to “cover up” the incident. “It was sexual misconduct,” she said, which was especially concerning given the large number of PTSD patients who have experienced sexual trauma.
Lykos conducted studies using a loosely defined form of therapy, rather than an established and well-researched protocol such as cognitive behavioral therapy. The FDA made clear that it only regulated drugs, not therapies, but the lack of clear guidance around Lykos’ therapeutic practices complicated interpretation of the results, while several ad comm members warned that the unlicensed therapists were creating significant liability.
“Our biggest nightmare is that the risks will turn out to be greater than expected,” said Anya Bershad, a professor of psychiatry at the University of California, Los Angeles. Lykos’ form of therapy included “very specific components not found in other therapies,” such as physical touch, music and room design, all of which are difficult to enforce once approved.
Most concerns were not about MDMA itself, but about Lykos and its ability to do rigorous science. Too many psychedelics researchers, says Philip Corlett, a professor of psychiatry at Yale University, seemed to assume that MDMA was effective. “I’m more concerned about the general attitude of the doctors and scientists in the field, and what I perceive as a rush for whatever reason, whether fame or financial incentives, to be first,” he said. “That is dangerous, these are human lives.”
This story has been updated with a comment from the FDA.