Breaking News: F.D.A. Panel Votes Against MDMA-Assisted Therapy for PTSD
On Tuesday, the Food and Drug Administration’s Psychopharmacologic Drugs Advisory Committee voted overwhelmingly to reject MDMA-assisted therapy in the treatment of post traumatic stress disorder, or PTSD. The FDA will issue its final decision on the matter in mid-August but in the majority of cases, the federal agency’s decisions align with the vote of the independent panelists on advisory committees.
The process that led to Tuesday’s vote began in 2001, when the non-profit organization Multidisciplinary Association for Psychedelic Studies (MAPS) submitted an Investigational New Drug application to the FDA to research MDMA as a treatment for PTSD. Over the next 23 years, MAPS worked to show the drug’s efficacy through a series of clinical studies on people with PTSD. In 2014, MAPS spun out a public benefit corporation to take charge of its clinical research arm, which now operates as a for profit pharmaceutical company named Lykos. Late last year, after completion of two phase 3 clinical trials, Lykos submitted a new drug application for MDMA-assisted therapy for treating PTSD. The FDA gave the application an expedited review. At the end of a nine-hour meeting, the FDA Advisory Committee voted that they did not feel the available data showed MDMA was effective in treating PTSD (9 yeses, 2 nos). Nor did the committee think the benefits of MDMA-assisted therapy outweigh the risks (10 yeses, 1 no). (For more on how FDA advisory committees work, read our interview with Suzanne Robotti.)
Over the course of the day, a central theme was how unprecedented an approval of MDMA-assisted therapy would be - and how the FDA should consider an application that combines the use of a drug with psychotherapy. In her introduction, FDA’s Division of Psychiatry director Tiffany Farchione characterized some of the key tensions at the heart of the FDA’s decision. First, the agency does not regulate psychotherapy, but the clinical trials for the drug tested it for use in conjunction with psychotherapy. She emphasized that safety questions remain, and that the study design does not adequately control for functional unblinding, meaning participants knew that they’d received MDMA, which could lead to bias and expectancy effects. For months, experts have speculated that if MDMA is approved, it would come with a hefty Risk Evaluation and Mitigation Strategies (REMS) notification — a series of recommendations the FDA issues to a medication prescriber about how to safely use the medicine. This meeting gave viewers a preview of how the agency is thinking about the risks and benefits of the drug, and how it could potentially manage them via REMS. Throughout the meeting, many committee members encouraged the agency to proceed with caution.
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The first chunk of the meeting included a presentation from Lykos about the results of their clinical trials. This presentation reiterated study results they’ve previously reported that found that participants’ PTSD symptoms, as measured by a standard PTSD scale called CAPS-5, decreased significantly after receiving three rounds of MDMA-assisted therapy, and that those effects persisted for at least 6 months after participants’ last dose.
Ahead of the meeting, the FDA also released a briefing document in which it laid out its concerns with the study’s methodological shortcomings and potential safety issues associated with MDMA-assisted therapy. Throughout Lykos’s presentation, the company repeated two major ideas that seemed like an attempt to get ahead of that criticism. First, the company emphasized the idea that MDMA is “not a new drug,” as Lykos’s senior medical director and head of clinical science Alia Lilienstein put it. “It has been studied since its discovery in the 1900s,” she said. Lykos also described the psychotherapy aspect of MDMA-assisted therapy as a “personalized patient-directed experience,” one that allowed therapists to respond to patients’ needs.
From the start, it was clear the committee did not find Lykos’s arguments convincing. In a question session after Lykos’s presentation, committee members asked a battery of questions: What guidelines were there about the clinical trials’ therapeutic approach? Was the therapy tested against other therapeutic methods? Did the company evaluate the quality of therapy? And were there any measures to ensure that participants were getting roughly the same quality of therapy? Additionally, they brought up other adverse effects that seemingly weren’t considered in the clinical trial, including the potential for substance abuse and abuse relapse, MDMA overdoses, and effects of long-term use.
During that Q&A session, committee members introduced several other factors that could potentially have confounded Lykos’s findings. For example, roughly 40% of participants in the study had previously tried MDMA, which panelist and sociologist Elizabeth Joniak-Grant said could indicate that participants engaged in self-selection. Jess Fiedorowicz, head and chief of the department of mental health at the Ottawa Hospital, raised the possibility that selection bias might also have been part of participant recruitment. (Lykos’s chief scientific officer Berra Yazar-Klosinski said that participants were recruited via “standard methods,” such as a recruitment website. When Joniak-Grant pushed back on this, saying there was no such thing as a standardized approach, Lykos’s Lilienstein added that participants were also recruited via clinician referrals and MAPS’s larger network.)
During a presentation by the FDA reviewers David Millis and Olivia Morgan, it appeared the agency shared many of the committee members’ concerns about the ambiguity of Lykos’s data. Millis mentioned functional unblinding of participants, therapists, and clinicians involved in the study; a lack of data collected about adverse events associated with the trials; ambiguity in how to interpret data from Lykos’s follow-up study; and issues with the safety data.
The FDA, however, also took partial responsibility for some of the methodological problems. At some point the agency had suggested to Lykos that they make changes to their study protocol, such as adding an active placebo condition like niacin or a low dose of MDMA. Lykos said those substitutes might exacerbate anxiety in participants, and the FDA signed off on their phase 3 trial design without the active placebo they’d suggested. The FDA also pointed to a lack of data on participants’ cardiac and liver health. Committee member Carla Canuso, head of neuropsychiatry clinical development at the pharmaceutical company Jannsen, asked why cardiac and liver lab tests weren’t required. “It was missed,” Farchione said, bluntly. “The primary reviewer just assumed there were labs and didn’t notice that it wasn’t there. It’s a hole in the program that the applicant and we have to take responsibility for.”
Among psychedelics advocates, and even critics, the physical risks of MDMA are not always a part of the discussion. Many discount cardiac issues as anomalous and report that the abuse potential of the drug is low. But throughout the FDA committee’s discussions, members were concerned with some missing safety data in Lykos’s MDMA application. “There are significant holes in the data,” said Maryann Amershahi, a toxicologist at Georgetown University, as the group discussed evidence for the safety of the drug. She went on to emphasize that if the drug is approved and available to the general public, there is little data on drug-drug interactions or MDMA’s long-term potential for abuse. Others said they were less concerned about that lack of data, and more concerned about reports of a patient abused by therapists during a MAPS-run trial. “If this happened in a highly controlled trial, as [MDMA] is rolled out how could that be controlled or monitored?” asked Paul Holtzheimer, director of the Veterans Affairs Posttraumatic Stress Disorder Brain Bank. Members also considered how rolling out MDMA outside a controlled scientific study would be potentially messier. Should the agency recommend specific parameters to discharge a patient after their session? How does a provider know when a patient has stopped tripping?
In the end, the committee’s votes reflected their apprehension about Lykos’s data. Committee chair Rajesh Narendran, an attending psychiatrist at Resolve Crisis Services in Pittsburgh and a radiology and psychiatry professor at the University of Pittsburgh, said he was “not convinced at all” that the drug would be effective until researchers could better understand and account for expectancy effects and bias in the data. “Going forward, for psychedelics to be approved, there will need to be a more complex design,” he said. “I don’t think this is an adequately controlled trial for this to be approved.”
Tuesday’s meeting made it clear that the FDA has real trepidations with Lykos’s application. The committee’s vote is not binding, meaning the FDA could still choose to approve MDMA-assisted therapy for PTSD. But according to a 2023 JAMA article, if an FDA committee recommended approving a drug, the agency followed suit 97% of the time. If committees recommended against approval, the FDA’s final decision matched that recommendation 67% of the time.
The Microdose reached out to Lykos for comment. “While we are disappointed in the vote, we are committed to continuing to collaborate with the FDA with their ongoing review of our NDA over the coming weeks,” Lykos CEO Amy Emerson said in an emailed statement. “We will also work with the FDA to determine the most appropriate post-marketing plans to address the outstanding questions raised today, including how best to support the responsible integration of MDMA-assisted therapy into the healthcare system.”
Some other tidbits worth noting:
It was clear that many committee members and FDA representatives were aware of the report released by the Institute for Clinical and Economic Review (ICER), a nonprofit research institute. The ICER report included serious concerns about the study’s methodology, which were echoed in this FDA meeting. At a public meeting last week, one of ICER’s advisory councils met and also voted that they were not confident in the clinical trial results. The ICER report also made allegations about ethical misconduct and abuse, including those made in comments by former MAPS clinical trial participant Meaghan Buisson, who was sexually assaulted by her therapists in the company’s phase 2 trial. When asked about these issues, the FDA’s Farchione said the agency would conduct its own inspections but had nothing else to say on the matter. Right before the committee began its discussions and voting, FDA’s Office of Neuroscience director Teresa Buracchio told the group that the agency considered such reports to be unverified until the FDA’s own inspection begins, and that the members were to consider only information presented within briefing documents and presented by public commenters.
The potential REMS laid out by the FDA are strikingly similar to Oregon’s psilocybin services program: they require two facilitators to be onsite during dosing, for participants to be briefed on what to expect, for an emergency plan to be in place, and another adult to pick up the patient after a session.
FDA risk management analyst Victoria Sammarco presents on MDMA risk management. Everyone on the panel agreed that at least two clinicians needed to be in the room with participants during dosing sessions, but no agreement was reached on what kind of credentials should be required of clinicians. Lykos suggested that just one of the facilitators should be required to be a clinician, and perhaps the other could be a trainee, which could help keep costs down and make the treatment more accessible. But some members of the committee felt both clinicians should be licensed, citing how power dynamics between a licensed professional and a trainee could lead to an underreporting of misconduct. “The idea that a trainee would make a report against the supervisor when they’re dependent on that supervisor for a positive evaluation is a bit idealistic,” said Melissa Barone, a psychologist at Veterans Affairs in Maryland.
While Lykos floated the possibility that the company could help train and credential clinicians to administer the drug, several members said the company should not be involved in the process, and that an impartial third party should implement or evaluate clinician training instead. “If Lykos is the gatekeeper for training, if a single entity holds the keys to everything, it can get distorted,” said Walter Dunn, an assistant clinical professor of psychiatry at the University of California, Los Angeles. “Potentially this is why some of the abuses occur — because it was in the hands of a few individuals.” Therapy is, again, outside the purview of FDA approval, but will likely continue to be a hot topic as the FDA weighs the role of psychotherapy in Lykos’s application.
One moment of levity from a very long and serious day: at one point the audio/visual system distorted into what can only be described as a very trippy visual for all those watching the meeting online.
