On Tuesday, the FDA asked a panel of experts to weigh in on whether the evidence shows that MDMA, also known as ecstasy, is a safe and efficacious treatment for PTSD. The answer was a resounding no. Just two out of 11 panel members agreed that MDMA-assisted therapy is effective. And only one panel member thought the benefits of the therapy outweighed the risks.
The outcome came as a surprise to many, given that trial results have been positive. And it is also a blow for advocates who have been working to bring psychedelic therapy into mainstream medicine for more than two decades. This isn’t the final decision on MDMA. The FDA has until August 11 to make that ruling. But while the agency is under no obligation to follow the recommendations of its advisory committees, it rarely breaks with their decisions.
Today on The Checkup, let’s unpack the advisory committee’s vote and talk about what it means for the approval of other recreational drugs as therapies.
One of the main stumbling blocks for the committee was the design of the two efficacy studies that have been completed. Trial participants weren’t supposed to know whether they were in the treatment group, but the effects of MDMA make it pretty easy to tell whether you’ve been given a hefty dose, and most correctly guessed which group they had landed in.
In 2021, MIT Technology Review’s Charlotte Jee interviewed an MDMA trial participant named Nathan McGee. “Almost as soon as I said I didn’t think I’d taken it, it kicked in. I mean, I knew,” he told her. “I remember going to the bathroom and looking in the mirror, and seeing my pupils looking like saucers. I was like, ‘Wow, okay.’”
The Multidisciplinary Association for Psychedelic Studies, better known as MAPS, has been working with the FDA to develop MDMA as a treatment since 2001. When the organization met with the FDA in 2016 to hash out the details of its phase III trials, studies to test whether a treatment works, agency officials suggested that MAPS use an active compound for the control group to help mask whether participants had received the drug. But MAPS pushed back, and the trial forged ahead with a placebo.
No surprise, then, that about 90% of those assigned to the MDMA group and 75% of those assigned to the placebo group accurately identified which arm of the study they had landed in. And it wasn’t just participants. Therapists treating the participants also likely knew whether those under their supervision had been given the drug. It’s called “functional unblinding,” and the issue came up at the committee meeting again and again. Here’s why it’s a problem: If a participant strongly believes that MDMA will help their PTSD and they know they’ve received MDMA, this expectation bias could amplify the treatment effect. This is especially a problem when the outcome is based on subjective measures like how a person feels rather than, say, laboratory data.
Another sticking point was the therapy component of the treatment. Lykos Therapeutics (the for-profit spinoff of MAPS) asked the FDA to approve MDMA-assisted therapy: that’s MDMA administered in concert with psychotherapy. Therapists oversaw participants during the three MDMA sessions. But participants also received three therapy sessions before getting the drug, and three therapy sessions afterwards to help them process their experience.
Because the two treatments were administered together, there was no good way to tell how much of the effect was due to MDMA and how much was due to the therapy. What’s more, “the content or approach of these integrated sessions was not standardized in the treatment manuals and was mainly left up to the individual therapist,” said David Millis, a clinical reviewer for the FDA, at the committee meeting.
Several committee members also raised safety concerns. They worried that MDMA’s effects might make people more suggestible and vulnerable to abuse, and they brought up allegations of ethics violations outlined in a recent report from the Institute for Clinical and Economic Review.
Because of these issues and others, most committee members felt compelled to vote against MDMA-assisted therapy. “I felt that the large positive effect was denuded by the significant confounders,” said committee member Maryann Amirshahi, a professor of emergency medicine at Georgetown University School of Medicine, after the vote. “Although I do believe that there was a signal, it just needs to be better studied.”
Whether this decision will be a setback for the entire field remains to be seen. “To make it crystal clear: It isn’t MDMA itself that was rejected per se, but the specific, poor data set provided by Lykos Therapeutics; in my opinion, there is still a strong chance that MDMA, with a properly conducted clinical Phase 3 trial program that addresses those concerns of the FDA advisory committee, will get approved.” wrote Christian Angermayer, founder of ATAI Therapeutics, a company that is also working to develop MDMA as a therapy.
If the FDA denies approval of MDMA therapy, Lykos or another company could conduct additional studies and reapply. Many of the committee members said they believed MDMA does hold promise, but that the studies conducted thus far were inadequate to demonstrate the drug’s safety and efficacy.
Psilocybin is likely to be the next psychedelic therapy considered by the FDA, and in some ways, it might have an easier path to approval. The idea behind MDMA is that it alleviates PTSD by helping facilitate psychotherapy. The therapy is a crucial component of the treatment, which is problematic because the FDA regulates drugs, not psychotherapy. With psilocybin, a therapist is present, but the drug appears to do the heavy lifting. “We are not offering therapy; we are offering psychological support that’s designed for the patient’s safety and well-being,” says Kabir Nath, CEO of Compass Pathways, the company working to bring psilocybin to market. “What we actually find during a six- to eight-hour session is most of it is silent. There’s actually no interaction.”
That could make the approval process more straightforward. “The difficult thing … is that we don’t regulate psychotherapy, and also we don’t really have any say in the design or the implementation of the particular therapy that is going to be used,” said Tiffany Farchione, director of the FDA’s division of psychiatry, at the committee meeting. “This is something unprecedented, so we certainly want to get as many opinions and as much input as we can.”
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Earlier this week, I explored what might happen if MDMA gets FDA approval and how the decision could affect other psychedelic therapies.
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