MDMA’s federal approval drama, briefly explained

Today, an Federal Drug Administration advisory committee held a public hearing to weigh the evidence on MDMA therapy for post-traumatic stress disorder, casting a non-binding vote against approving the treatment — indicating strong odds that the FDA will follow suit in their official determination, and setting a handful of precedents for efforts to legalize other psychedelics that are close behind.

The FDA’s decision is slated to arrive by August 11, and if MDMA therapy is approved, it will mark the true beginning of the end of the psychedelic prohibition that’s stifled research since 1970. It would also be the first new treatment for PTSD in over two decades, a condition which affects about 13 million Americans. But some leading researchers have called out a “psychedelic hype bubble” that inflates expectations relative to what the peer-reviewed evidence actually supports. As legalization looms, unfolding drama is putting the strength of the evidence to the test.

Lykos Therapeutics, the company that submitted the application back in February, is now fielding criticism over the integrity of its clinical trial data. The concerns run from methodological questions around developing placebos for psychedelic experiences that could bias results to questions of ethical misconduct, where internal pressures to report positive experiences may have affected participant responses.

Formerly known as the MAPS Public Benefit Corporation, Lykos Therapeutics — which grew out of MAPS, the organization that has been working toward MDMA approval since its founding in 1986 — ran two Phase 3 clinical trials, each with impressive results. The first trial found that MDMA therapy successfully treated 67 percent of participants, reducing their symptoms to the point where they no longer met the criteria for PTSD. In the placebo group, that number was 32 percent. The second trial found similar results: 71 percent from the treatment group no longer met PTSD criteria, compared to 48 percent from the placebo group.

In March, the Institute for Clinical and Economic Review, or ICER, a nonprofit that evaluates new medical treatments, published a report that highlighted the placebo bias and ethical concerns in Lykos’s data. A group of Lykos therapists and trial participants pushed back on criticisms, launching a still-unfolding saga.

Then, in April, a citizen petition was submitted to the FDA that has now racked up 88 signatories from across the field, calling for a public hearing to bring those neglected concerns to light for the FDA’s consideration. They don’t center on the risks of psychedelics in general, but Lykos’s application in particular, and their protocol that lays out how to manage the mixture of suggestibility-enhancing drugs with psychotherapy.

Today’s hearing from the Psychopharmacologic Drugs Advisory Committee was a full day affair, offering a forum for public comments, reviewing the evidence for safety and efficacy, and ultimately casting their vote that the evidence does not yet support approval.

On whether the available data suggests MDMA therapy is effective for treating PTSD, nine voted no, two voted yes. On whether the benefits of the treatment, along with the FDA-proposed risk evaluation and mitigation strategy, outweigh the risks for treating patients with PTSD, only one person out of 11 voted yes. “I don't think we’re quite there yet,” said Kim Witczak, a consumer representative on the the advisory committee.

Now, it’s up to the FDA to decide whether it agrees.

Amidst a deluge of headlines and editorials in prestigious journals that proclaim psychedelics as the start of a new paradigm in mental health treatment, ICER recently voted 14-1 that current evidence doesn’t demonstrate that MDMA–AT (MDMA-assisted therapy) is a net benefit, let alone better than other treatments. That caused a stir.

Some of ICER’s concerns have been well-known to researchers for years, like “functional unblinding.” Simply put, it’s very hard to prevent someone from knowing if you’ve given them a psychedelic, which undermines blinding, one of the key pillars of placebo-controlled research. Though it’s worth noting that unblinding is not an issue unique to psychedelics. Lapses in successful blinding have already been recognized in other approved drugs, from opioids and antidepressants to a version of ketamine.

And for unblinding to become a roadblock now would be a bit strange, since the FDA began working with MAPS on the design of their Phase 3 trials back in 2017, including a sign-off on the methodology for exactly these sorts of tricky questions.

Other concerns on the docket include safety, like cardiovascular risks from elevated heart rates and blood pressure, the contribution of psychotherapy to the overall effectiveness of the treatment, and the myriad tiny details of actually providing a complicated treatment like MDMA therapy.

But at the center of recent debate are ethical concerns in the actual conduct and guidance of Lykos’s MDMA trials. Beyond the placebo issues, ICER reported concerns that some participants felt “pressured to report good outcomes and suppress bad outcomes” so as not to hinder the overall success of MDMA’s approval.

Testimony submitted to the FDA by a participant in a MAPS phase 3 trial reportedly claimed that at least three people who received MDMA during the trial reported a worsening of suicidality in the ensuing weeks — a detail that didn’t show up in the published journal articles about the trial (Lykos responded that all adverse events were reported to the FDA).

Further, the same participant alleges that their trial therapists repeatedly told them that they were “helping make history,” and reminded them that their “responses and behaviors during and after the trial could jeopardize legalization.”

To learn about the potential effects of rolling out legal access to drugs like MDMA to millions of Americans, it’s important that study participants feel free to share everything about their experiences, not just the good stuff. Stifling participants with the political implications of their experiences speaks to a broader climate of “psychedelic evangelism,” which threatens to undermine the validity of the science pushing the movement forward.

As Olivia Goldhill reported in STAT, the FDA did not include concerns around data suppression in their pre-meeting documents, indicating that they haven’t found issue with reporting negative events from the trial. But during one oral presentation at the hearing by Neşe Devenot, a senior lecturer at Johns Hopkins University and a co-author on the citizen petition submitted to the FDA, she emphasized issues with Lykos’s particular therapy protocol, citing incidents of sexual misconduct and therapists restraining participants during MDMA sessions. Devenot added: “Lykos argues that its training will ensure that boundaries are maintained. But its intervention heightens risks for participants by incentivizing boundary violations," where we’re sure to see these issues raised.

While Lykos’s application is the first drug from the extended psychedelic arena to be considered for approval by the FDA, others aren’t far behind. A psilocybin analog received FDA breakthrough designation back in 2018 as a treatment for depression, and an LSD formula received the same for anxiety earlier this year.

The broader momentum toward legalizing psychedelic therapies will survive this particular approval either way, but there are significant stakes. The FDA’s verdict on Lykos’s application will set precedents for the other psychedelic drug applications that will surely follow. And if the application isn’t approved, that would push back the timeline on which patients suffering from PTSD could access the treatment (which, for critics of Lykos’s model, is a good thing, because they worry that we don’t know enough about Lykos’s treatment protocol to quantify the risks).

There’s also the matter of drug classification. If MDMA were approved, it would likely be rescheduled by the DEA from a Schedule I substance, which are defined as those without any accepted medical use, to something more lenient. That would have ripple effects across the psychedelic ecosystem.

A Schedule I status makes it difficult to get research funding, limits clinical trial enrollment, and limits the production of the drugs themselves. Rescheduling MDMA would ease all of these restrictions, ultimately supporting a more robust research base. Meanwhile, states that are moving ahead of the federal government in legalizing various forms of access to psychedelics — like Oregon’s adult-use model — would face less red tape.

Overall, the FDA has to decide whether the benefits of Lykos’s MDMA-AT proposal outweigh the risks. Today’s vote suggests they’re likely to say no, pushing the end of prohibition down the line. But, particularly when you’re dealing with psychedelics, anything can happen.

Update, June 4, 6:10 pm: This story has been updated to reflect the FDA’s advisory committee vote.