FDA advisers express skepticism as they debate MDMA therapy for PTSD

The psychedelic drug MDMA, which has been studied as a possible mental health treatment, may finally have a chance to be integrated into mainstream health care.

On Tuesday, scientific advisers to the Food and Drug Administration are deciding whether to recommend MDMA — in combination with talk therapy — as safe and effective as a treatment for post-traumatic stress disorder.

Pharmaceutical company Lykos Therapeutics, which funded the drug’s clinical trials, has asked the FDA to approve MDMA-assisted PTSD treatment. This is a crucial step in bringing the drug to market.

The committee is expected to vote on the strength of the evidence at 5:30 p.m. ET following public comments and discussion.

The FDA is not required to follow the committee’s recommendation.

Remarks made at the meeting by FDA staff and advisory committee members highlighted some major stumbling blocks: gaps in clinical research that could jeopardize its approval.

Agency staff focused on uncertainties and gaps in the data, unanswered questions about its abuse potential, and a lack of evidence supporting the psychological approach used in therapy sessions.

Some panel members explicitly addressed allegations that have surfaced regarding possible malpractice and bias in the trials that could have skewed the results.

FDA scientists did not share details but acknowledged that the agency was investigating some of the allegations, which surfaced in a petition to the agency and in outside reports about the trials.

The importance of this moment was not lost on the participants.

There are only two FDA-approved treatments for the disease, and MDMA would be the first to hit the market in decades. It would also be an important step in broader efforts to expand access to psychedelics.

“We’re exploring new territory,” said Kim Witczak, a consumer representative on the FDA advisory committee. “We want to organize it well.”

Lykos representatives highlighted positive results from clinical data collected during two nearly identical randomized controlled trials.

For example, one such study showed that 67% of participants in the MDMA treatment group no longer met diagnostic criteria for PTSD after three MDMA dosing sessions, compared to approximately 32% in the placebo group who underwent the sessions. therapy but did not receive. an active drug.

“Overall, these results support that MDMA, combined with psychological intervention, results in significant and significant reductions in PTSD symptoms and functional impairments in PTSD patients,” said Berra Yazar-Klosinski, scientific director of Lykos.

FDA staff and outside advisors, however, did not dwell on these encouraging results.

Although the study took steps to “blind” the study participants, there was much discussion around the fact that many of the study participants could tell that they had received the experimental drug, which which has led to so-called “functional unblinding,” which may ultimately affect the results. .

“Although we have two positive studies, the results come in the context of dramatic functional unblinding,” explains Dr. David Millis, clinical reviewer for the FDA.

Another potential sticking point could be the lack of data on how patients experienced the drug’s acute effects, including feelings such as “euphoria” or “high mood.” These data help inform the FDA’s assessments of the drug’s abuse potential.

“We noticed a striking absence of abuse-related adverse events,” Millis said, noting that the FDA advised the study sponsors to collect this type of data.

Although MDMA is currently listed as a Schedule III drug, the agency’s review found that it has the same potential for abuse as a Schedule II stimulant, a category that includes cocaine .

“We’re actually dealing with more and more serious cases of MDMA overdose, and so I’m less concerned about safety in the acute setting, but more chronically if they continue to abuse MDMA,” Maryann Amirshahi said , emergency professor. medicine at Georgetown University and a committee member.

About 40% of people enrolled in the MDMA study had already used MDMA before the study.

Alongside its positive results on the short-term effects of MDMA, Lykos presented data from a follow-up observational study intended to assess the sustainability of the treatment.

Although not yet published in a peer-reviewed journal, this data “suggests evidence of MDMA’s durability for at least six months,” Lykos’ Yazar-Klosinski said.

However, FDA staff pointed out various problems with this long-term data, including a 25% dropout rate and the fact that some participants underwent treatment and, in some cases, used illicit drugs, notably MDMA.

Data shared by Lykos showed a series of adverse events.

The majority of people in the study had a lifetime history of suicidal ideation, but during the study period, “the frequency of these symptoms was comparable between the two groups,” said Dr. Alia Lilienstein, Senior Medical Director of Lykos Therapeutics.

“Of note, no suicidal behavior or attempts were reported in the MDMA group,” she said.

This point is particularly controversial due to recent allegations that certain adverse events were not reported. A petition filed with the FDA calling for the advisory meeting outlined these and other concerns, citing an unnamed former employee of the drug company.

There is already a well-documented case of two therapists participating in Phase 2 trials with a participant who reported having inappropriate contact with her while under the influence of MDMA. The videos of the two therapists in bed with the participant were eventually made public through a podcast.

“Let’s try not to gloss over this mistake. It was sexual misconduct. This is particularly important,” said Elizabeth Joniak-Grant, sociologist and panel member.

Several other panelists asked questions along these lines.

Last month, a report from the Institute for Clinical and Economic Review, a group that evaluates clinical data and drug prices, concluded that there was insufficient evidence to assess the overall net benefit of MDMA-assisted therapy, after a lengthy investigation of the trial data.

This report indicated that it was possible that those involved in the trials, including therapists and investigators, encouraged the reporting of positive events and minimized adverse events.

The pharmaceutical company pushed back on the claims and said it stood by the data.

A public comment submitted to the FDA by a trial participant said her therapist encouraged her to view “worsening symptoms as evidence of healing and ‘spiritual awakening'” and that she and d Other participants later struggled with suicidal tendencies after the trial.

Dr. Walter Dunn, a UCLA psychiatrist and panelist, asked about claims in the ICER report that some participants may have been discouraged from participating in the long-term sustainability study.

“These were also investigated,” Lilienstein said with Lykos, “All participants interested in participating were given the opportunity to review their consent, and some chose not to participate after reviewing their consent, but otherwise everyone had the opportunity.”