The Food and Drug Administration rejected MDMA as a treatment for post-traumatic stress disorder on Friday, in a blow to drug activists and veterans who’ve long campaigned for the psychedelic treatment. Although two Phase 3 trials suggested the treatment was effective, strong opposition by an agency scientific advisory committee in June and allegations of missing adverse event data and research bias may have doomed the application by Lykos Therapeutics.
Lykos and its parent organization, MAPS, had been working for decades toward winning approval of MDMA. The company said in a statement it had received a “complete response letter” from the FDA denying its application “based on the data submitted.” It said the issues raised by the FDA echo those brought up during the ad comm meeting.
The FDA requested that Lykos conduct an additional Phase 3 trial to further study the safety and efficacy of MDMA, and Lykos said it will request a meeting with the FDA to ask for reconsideration of the decision.
“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, the Lykos CEO. “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.”
Several members of MAPS previously said they were expecting FDA approval, and were unprepared for recent questions about data integrity. The ad comm rejection of the evidence from the two trials was a “gut punch,” MAPS executive director Kris Lotlikar said at a public webinar in July. “We’re still fighting a lot of deeply rooted stigma about psychedelics,” he said at the time. “Whatever the outcome, we’re just going to press forward and do whatever we can to make this happen.”
Existing therapies don’t work well for many of the estimated 13 million Americans with PTSD, and no new drug for the disorder has been approved in more than two decades.
Boris Heifets, a neuroscience researcher at Stanford University who studies psychedelics, told STAT he was surprised at the FDA’s decision, adding he’d expected the agency would approve the drug with a requirement for post-approval studies. “PTSD is a major public health issue, and the only way you’ll get any traction is to throw out a little rope for investment in better treatments,” he said. “I was honestly expecting a more positive signal here … now we wonder, will FDA ever approve this stuff?”
The FDA, he noted, approved the depression treatment esketamine with far less convincing data than Lykos’ — and he suspects that if a bigger pharmaceutical company had run the trials, MDMA would have won approval.
Excitement around MDMA-therapy built to a crescendo last year when positive Phase 3 trial data made FDA approval seem inevitable. When MAPS founder Rick Doblin strode across a stage at a 12,000-person conference in Denver last year, he was received like a messiah delivering the promise of legal psychedelics to the masses.
The premature celebrations began to wind down in March this year, when the Institute for Clinical and Economic Review think tank published a damning report, which rated evidence for MDMA-therapy as “insufficient” and raised questions about possible trial misconduct. ICER researchers spoke with a handful of trial participants who had “severe negative outcomes” that didn’t seem to be reflected in the trial data, a finding reinforced by STAT’s reporting on a Phase 2 trial incident of suicidal ideation that wasn’t evident in published research.
“We hope that ongoing and future careful research will examine how to maximize the benefits and minimize the harms” of adding MDMA to psychotherapy, ICER’s chief medical officer David Rind said in a statement after the FDA’s decision.
The think tank’s report had also warned about a culture of advocacy that undermined scientific standards, with MDMA research treated like “a religious movement.” One Phase 3 trial participant, Sarah McNamee, later told the ad comm her therapists said she was “part of a movement” and “helping make history” even as she struggled with suicidal ideation. These allegations, which the FDA said it was investigating, significantly undermined the credibility of Lykos’ results.
“Zealots make bad scientists,” Peter Pitts, a former associate commissioner for external relations at the FDA, said after the ad comm meeting. “You can’t skirt science because you believe in your heart something is true, you have to prove it.”
Several psychedelic researchers, including those who’d previously worked with MAPS, were concerned by the allegations. “We need to proceed cautiously and not repeat some of the mistakes of the past and do it right this time,” said Charles Grob, psychiatry professor at University of California, Los Angeles, who conducted MAPS’ first MDMA study in the 1990s.
There was a sense of despondency at the FDA’s decision, especially among veteran communities where PTSD is prevalent. “From a veteran’s standpoint, it feels like the game is fixed,” said Jesse Gould, founder of Heroic Hearts Project, a nonprofit focused on helping veterans with PTSD. “There seems to be something off here … something isn’t tracking, especially when on a daily basis veteran lives are at stake.” Noting that countries like Peru and Mexico allow psychedelic treatment for PTSD, he added, “That’s an absolute embarrassment to this country.”
Brett Waters, co-founder of Reason for Hope, a veterans nonprofit advocating for approval of psychedelics, said in a statement, “It is hard to see how the FDA’s decision can be justified when it has plenty of tools to ensure a slow, cautious roll-out of this novel treatment. … Instead, veterans will continue to be forced to leave the country or to seek underground providers” of psychedelics.
In addition to concerns about data integrity in Lykos’ trials, there were also questions about how to regulate the therapeutic side of treatment, especially given instances of therapist misconduct during the clinical trials. All MDMA studies were conducted with patients supervised by therapists working in pairs, one licensed and one unlicensed.
In a Phase 2 trial, an unlicensed therapist was accused of sexual assault in a civil court complaint by a MAPS trial participant. The therapist did not deny having sex with the patient but claimed he didn’t have a “duty of care.” At the ad comm meeting, patient representative Elizabeth Joniak-Grant said it was important not to “gloss over” the incident. “It was sexual misconduct,” she said, which was especially concerning given the large number of PTSD patients who’ve experienced sexual trauma.
Lykos conducted trials 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 regulated only drugs, not therapy, but the lack of clear guidance around Lykos’ therapeutic practices complicated interpretation of results, while several ad comm members warned the unlicensed therapists created significant liability.
“Our biggest nightmare is it’ll turn out the risks are bigger than anticipated,” said Anya Bershad, a psychiatry professor at the University of California, Los Angeles. Lykos’ form of therapy had “very specific components that are not found in other therapies,” such as physical touch, music, and the design of the room, all of which could be hard to enforce post-approval.
Most of the concerns were focused not on MDMA itself, but Lykos and its ability to conduct rigorous science. Too many psychedelics researchers, said Philip Corlett, a psychiatry professor at Yale University, seemed to assume MDMA was effective. “I’m more concerned about the general attitudes of the clinicians and scientists in the field, and what I perceive to be rushing for whatever reason, be it fame or monetary incentives, to be first,” he said. “That’s dangerous, these are people’s lives.”