In tone-setting verdict, FDA rejects MDMA as a therapy aid for PTSD

The Food and Drug Administration has rejected a bid to get MDMA approved as a therapy aid for people with post-traumatic stress disorder, a decision that puts off a major milestone for the field of psychedelics.

The verdict Friday comes at a pivotal time for this area of research, which has, after decades of dismissal from top drug regulators and companies, recently gained momentum through the work of advocacy groups and powerful organizations like the Department of Veterans Affairs. A bipartisan group of 80 lawmakers this month urged the Biden administration to approve the treatment developed by Lykos Therapeutics, a California-based biotechnology company.

Had the agency complied, MDMA would have become part of the first psychedelic-assisted therapy cleared in the U.S. It also would have created another treatment option for PTSD, which, according to VA estimates, affects around five out of every 100 adults in the country in any given year. These people are often prescribed cognitive behavioral therapy or so-called SSRI drugs to help with symptoms, but a large portion don’t respond.

According to Lykos, the FDA concluded that it couldn’t approve the therapy based on the data submitted, and requested the company run another Phase 3 trial to further study the safety and efficacy of MDMA. Lykos said it plans to ask for the agency to reconsider its decision.

“The FDA’s decision to request another Phase 3 study is a major setback for the field,” said Jennifer Mitchell, a professor of neurology, psychiatry and behavioral sciences at the University of California, San Francisco, in Lykos’ statement.

The pharmaceutical industry has long been intrigued by the mind-altering effects of MDMA — also known as midomafetamine or the party drug ecstasy — and whether they may be useful in treating various mental health conditions. The thinking goes that MDMA makes patients more emotionally open and able to connect with their therapist during psychotherapy sessions, which research suggests leads to better outcomes.

For years, Lykos, formerly known as MAPS Public Benefit Corp., has tried to test that hypothesis through a series of clinical trials focused on PTSD. The two largest indicated that participants given MDMA along with psychotherapy experienced significant reductions in the severity of their symptoms.

“I don’t know of any other psychoactive substance that affects your experience of another person in quite the same way. It’s remarkable,” said Anya Bershad, an assistant professor of psychiatry at the University of California, Los Angeles, whose research focuses on how MDMA alters social behavior.

“Psychotherapy is a great tool across diagnoses, and if we can find a way to make it a little bit more effective, especially for patients where other treatments aren’t working as well,” that would be “really exciting,” Bershad added.

Since positive results are exceedingly rare in mental health drug trials, Lykos was confident its findings would be enough to secure approval.

FDA staff weren’t so convinced, however. In early June, the regulator convened a panel of experts in psychiatry, medicine and drug development, and asked them to assess the evidence Lykos had gathered. In that meeting, agency scientists expressed doubts about the strength of Lykos’ results and criticized some of the ways the company collected and analyzed data.

One sticking point in particular was that, because MDMA elicits unmistakable changes to cognition and the senses, most of the participants in Lykos’ studies were able to decipher if they had been given the drug or a placebo. Both FDA staff and agency advisers feared that this so-called functional unblinding may have swayed the results in an overly positive direction.

That issue isn’t specific to MDMA, though, and psychedelics developers and regulators have yet to agree on how to adequately address it in clinical trials.

“Functional unblinding is a problem for everybody. So if that’s the basis of rejection, then we might as well all go home,” said Gul Dölen, a psychology professor at the University of California, Berkeley, who has conducted studies on the effects of MDMA on the brain.

At the committee meeting, FDA staff also noted alleged ethics violations in the studies, including sexual misconduct and data suppression. Many of the experts shared those concerns, leading them to vote almost unanimously against the therapy.

“I’m not convinced at all that this drug is effective based on the data I saw,” Rajesh Narendran, a psychiatry professor at the University of Pittsburgh and the committee’s chair, said at the time.

The decisively negative vote may have nudged the FDA toward a rejection, because while the agency isn’t required to follow the recommendations of its advisers, it typically does.

Experts have debated to what extent the FDA’s decision will affect the broader psychedelics field. Some don’t expect much of an impact. Analysts at the investment firm Leerink Partners, for instance, viewed many of the issues raised during the advisory committee meeting as specific to MDMA-assisted therapy.

But given that Lykos’ application is the first of its kind to go before the FDA, others see the rejection as a landmark verdict.

“This is not just a niche application,” Dölen said. “This is going to set the tone.”

Dölen said she would worry if the FDA rejected the treatment because it didn’t want or know how to regulate the therapy component of Lykos’ application. During the advisory committee meeting, there were questions about the amount psychotherapy contributed to the results, and how the psychotherapy protocol would be standardized if the FDA granted approval.

Drug companies “will sell more medicine, more patented medicine, if it doesn’t have to be combined with therapy,” Dölen said. “And in my view, the protection that we need most in this space is making sure that the requirement of therapy is in place, because otherwise, I think these drugs are not going to be efficacious and potentially going to do harm.”

In its statement, Lykos acknowledged how the combination of MDMA and therapy “raises unique research questions,” but stood by its data, arguing the evidence is “sufficient” and “in line with the relevant FDA guidance.” The company also called out the advisory committee, both for its “limited number of subject matter experts” and the “nature of [their] discussion, which at times veered beyond the scientific content” presented.

The FDA’s request for another trial is “deeply disappointing,” according to Lykos’ CEO Amy Emerson, who added that such a trial would take several years to complete. The company claims it can answer many of the FDA’s outstanding questions with existing data, Emerson said.

“No matter what, we as researchers believe that we need more research in this area,” Bershad said.

Editor’s note: This story has been updated with additional information from Lykos’ statement.

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