Medical experts who advise the Food and Drug Administration are not convinced MDMA is ready for general use to help treat post-traumatic stress disorder, recommending at a meeting Tuesday the agency hold off on an approval.
The experts convened at the request of the FDA, which is reviewing a new drug application from Lykos Therapeutics, a California-based biotechnology company. Lykos has for years been testing MDMA — also known as midomafetamine or ecstasy — in clinical trials, with two late-stage studies showing it offered significant benefits to PTSD patients when given alongside psychotherapy.
But concerns about how Lykos conducted the trials, as well as the safety of MDMA, swayed the advisers, who voted 9-2 that the therapy doesn’t appear effective for PTSD, and 10-1 that its risks outweigh its likely benefit.
“I’m not convinced at all that this drug is effective based on the data I saw,” said Rajesh Narendran, a psychiatry professor at the University of Pittsburgh and the committee’s chair, during the meeting.
While the FDA isn’t required to follow the guidance of its advisory committees, it typically does. The agency should make a decision on Lykos’ application by Aug. 11.
If approved, MDMA would become the first psychedelic-assisted therapy available in the U.S. It would also mark the first time in more than two decades the FDA cleared a new treatment for PTSD, a disease that, by some estimates, affects roughly 13 million people in the country in any given year.
Panelists were keenly aware of this, and of the standard they might set as more investment flows into studying psychedelics for mental health disorders. “A lot of what we may do may become precedent,” said Maryann Amirshahi, a panelist and a professor of emergency medicine at Georgetown University. “So I think we need to proceed cautiously.”
PTSD is currently treated with so-called SSRI medications. While these drugs can address the depression and anxiety often experienced by patients, their full effects usually aren’t felt for several months and, even then, research indicates that response rates rarely exceed 60%.
“So many people with PTSD are really suffering. And that unmet need has enormous consequences,” said Kelly O’Donnell, director of clinical training at the NYU Langone Center for Psychedelic Medicine, during a presentation Lykos gave as part of Tuesday’s meeting.
Together, Lykos’ two trials evaluated close to 200 people with moderate to severe PTSD. Both hit their main goals, which revolved around an 80-point scale where higher scores signal more severe symptoms. Participants underwent three treatment sessions over the course of 18 weeks and, by the end, those in the MDMA arm had a roughly 10-point greater reduction in their scores compared to the control group.
“It’s been so rewarding to see how quickly and meaningfully patients improved,” said O’Donnell, who worked with the physicians and therapists on the studies. She claims participants who received MDMA-assisted therapy appeared to “visibly brighten” over the treatment period, experiencing benefits like better sleep, reduced symptoms and improved self worth.
Several people who participated in Lykos’ studies spoke at Tuesday’s meeting of the benefits they experienced from receiving MDMA therapy. Others associated with MDMA research highlighted the pressing need for new PTSD treatments, particularly among military veterans.
Despite such testimony, approval now looks less likely after the panel’s vote. Both the FDA and its advisers identified a lengthy list of issues with the ways Lykos collected and analyzed clinical data. Among them were concerns the trials didn’t enroll a diverse enough group of participants or adequately characterize the therapy’s addictive potential.
FDA staff also questioned the overall strength of Lykos’ results. Typically, the strongest support for a drug comes from placebo-controlled studies in which participants don’t know what treatment they’ve been assigned. But compounds like MDMA alter mood and cognition, and can elicit unmistakable psychedelic effects that make it near impossible to keep patients in the dark.
Indeed, the vast majority of participants in Lykos’ studies figured out their treatment arm before the study concluded. The fear, according to the FDA, is that this “functional unblinding” swayed trial results to be more positive than they actually were.
Several panelists highlighted this issue in making their votes Tuesday. ‘Without accounting for what [participants’] expectation was, and somehow incorporating that into some kind of statistical model, I think it’s just meaningless,” said Narendran. “So I just feel very convinced that I had to vote no.”
Additionally, all participants in the key studies received psychotherapy. Experts said they aren’t sure how much that contributed to the results, or how Lykos and the FDA plan to standardize the psychotherapy protocol should the drug gain approval.
FDA staff have been troubled, too, by the safety data Lykos submitted. They argue the company hasn’t provided a clear enough picture of how its drug affects heart and liver function — known health concerns tied to MDMA use.
More broadly, Lykos’ case has been marred by ethics violations. In one of the company’s earlier studies, a participant reported sexual misconduct by the psychiatrist and her unlicensed therapist husband who were administering treatment.
The prominent drug pricing watchdog ICER also recently claimed that it had heard some therapists in Lykos’ studies had encouraged patients to report favorable outcomes but not report any “substantial harms” they experienced. A number of study participants and outside researchers echoed these concerns at the meeting’s open public hearing, with three accusing Lykos of misleading the FDA and the committee.
Tiffany Farchione, an official in the FDA’s psychiatry drugs division, said the agency is taking these allegations “very seriously” and has been conducting “inspections,” but didn’t provide many more details.
“I have real concerns with the validity of the data and the allegations of misconduct,” said Kim Witczak, the panel’s consumer representative. “I can’t in good conscious support something where this many harms are being reported and just say, ‘Oh, someone somewhere is investigating it.’”
Editor’s note: This story has been updated with additional details from the meeting.
