FDA advisors reject MDMA therapy for PTSD, amid concerns over research

A panel of experts advising the Food and Drug Administration on the use of the psychedelic MDMA for post-traumatic stress disorder found on Tuesday that the available evidence fails to show that the drug is effective or that its benefits outweigh its risks.

It represents a major setback for proponents of the drug and its sponsor Lykos Therapeutics, potentially jeopardizing FDA approval of the treatment.

Following public comment and discussion, the panel voted 9-2 that MDMA – in combination with talk therapy – is not effective for treating PTSD. And they voted 10-1 that the benefits of MDMA treatment don’t outweigh its risks.

While the FDA puts stock in the panel’s advice, it does not have to follow their recommendation.

However, that would be surprising given the host of concerns raised during the all-day meeting.

Remarks during the meeting from FDA staff and members of the advisory panel highlighted some major shortcomings in the clinical research. These include uncertainties and gaps in the data, unanswered questions about its potential for abuse and a lack of evidence supporting the psychological approach used in the therapy sessions.

“It seems like there are so many problems with the data,” said Melissa Barone, one of the panelists and a psychologist with the VA Maryland Health Care System. “Each one alone might be okay, but when you pile them up on top of each other...”

Many members of the panel brought up allegations that have surfaced about possible misconduct and bias in the trials that could have skewed the results.

“I have real concerns with the validity of the data and the allegations of misconduct,” said Elizabeth Joniak-Grant, a sociologist and a member of the panel. “I can't in good conscience support something where these many harms are being reported.”

Scientists with the FDA didn’t share details, but acknowledged the agency was investigating some of the claims, which have surfaced in a petition to the agency and outside reports on the trials.

Dr. Walter Dunn, a psychiatrist at UCLA, was one of the few who voted in favor of the treatment's efficacy. He acknowledged the misconduct allegations, but said ultimately the effect sizes of the treatment were large enough to indicate it can be effective for PTSD.

A big moment for psychedelics

The significance of the moment was not lost on those in attendance though.

There are only two FDA-approved treatments for PTSD and MDMA would be the first to come on the market in decades. It would also be a milestone for the broader effort to expand access to psychedelics.

“We are charting new territory,” said Kim Witczak, a consumer representative on the FDA’s advisory committee. “We want to set it up right.”

Representatives of Lykos emphasized the positive findings in clinical data collected during two nearly identical randomized controlled trials.

For example, one of those studies showed 67% of participants in the MDMA treatment arm no longer met the diagnostic criteria for PTSD following three dosing sessions with MDMA, compared to about 32% in the placebo group who underwent the therapy sessions but did not receive an active drug.

“In totality, these results support [that] MDMA in combination with psychological intervention provides significant and meaningful reductions in PTSD symptoms and functional impairment in patients with PTSD,” said Berra Yazar-Klosinski, chief scientific officer for Lykos.

FDA staff and the advisors did not dwell on those rosy results, though.

While the study took steps to “blind” study participants, there was considerable discussion around the fact many of those in the study could tell they had received the experimental drug, leading to what’s known as “functional unblinding,” which can ultimately affect the results.

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

Another potential sticking point was the lack of data about how patients experienced the acute effects of the drug, including feelings like “euphoria” or “elevated mood.” That data helps inform the FDA’s assessments of the drug’s abuse potential.

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

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

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

About 40% of those enrolled in the MDMA study had a history of using it prior to the study.

Alongside its positive findings on the short-term effects of MDMA, Lykos presented data from a follow-up observational study intended to suss out the staying power of the treatment.

While not yet published in a peer-reviewed journal, that data “suggest evidence of MDMA’s durability to at least six months,” said Yazar-Klosinski with Lykos.

However, the FDA staff highlighted various issues with that long-term data, including a dropout rate of 25% and the fact that some participants sought therapy and, in some cases, used illicit drugs, including MDMA.

The form of talk therapy used in the MDMA sessions also troubled some on the panel who noted there wasn’t strong data to support its use outside of the trial. “The psychological intervention is still for me a bit of a black box,” said Dr. Paul Holtzheimer with the National Center for PTSD. “What was described is really a relatively vague, ill-defined treatment.”

Hearing from patients

Some of the strongest arguments for approval came from patients who spoke during the public comment period about the urgent need for an effective treatment. Some had taken part in the MDMA trials and said they found the medication to be transformative.

“I was fortunate enough to enroll and get accepted, ultimately changing my life forever,” said Nick Brown, a military veteran from Colorado, who described how the treatment gave him self-compassion and allowed him to “get better sleep, have better relationships, and live what feels like a completely new life.”

Other groups representing veterans echoed these sentiments.

“I fear what will happen to them if this therapy is not approved,” said Jonathan Lubecky, a veteran who underwent MDMA-assisted therapy ten years ago, “Imagine how many lives your vote could save. Imagine how many will be lost if you did vote against this vital therapy.”

But for all the promising anecdotes of recovery, there were also many involved in psychedelic research who raised concerns about how the trials were run and the persistent problems in the data.

Harsh critics speak out

Some of the harshest criticism came from several researchers who had initially petitioned the FDA to hold the public hearing, including Neşe Devenot, a researcher at Johns Hopkins University, who said the model of therapy “incentivized boundary violations.”

Data shared from Lykos showed a range of adverse events.

The majority of those in the study had a history of suicidal ideation in their lifetime, but during the study period “the frequency of these symptoms was comparable between the two groups, said Dr. Alia Lilienstein, senior medical director for Lykos Therapeutics.

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

That point is particularly contentious because of recent allegations that certain adverse events were not reported. The petition calling for the advisory meeting outlined these concerns and others, citing an unnamed former employee of the drug company.

There is already a well-documented case of two therapists in the Phase 2 trials with a participant who said they engaged in inappropriate contact with her while she was under the influence of MDMA. The videos of the two therapists in bed with the participant were eventually made public by a podcast.

“Let's try to not gloss over this misconduct. It was sexual misconduct. That's particularly important,” said Joniak-Grant, a sociologist and a member of the panel.

Several other panelists asked questions about the potential that MDMA, once available widely in therapeutic settings, could lead to other instances of unethical behavior.

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

That report stated that it’s possible those involved in the trials including therapists and investigators encouraged the reporting of positive events and downplayed adverse events.

The drug company has pushed back on the allegations and said it stands behind the data.

A public comment submitted to the FDA by one trial participant said her therapist encouraged her to view “worsening symptoms as evidence of healing and ‘spiritual awakening’” and that she and other participants later struggled with suicidality following the trial.

When asked if some participants may have been discouraged from participating in the long term durability study, Lillenstein said those claims had been investigated.

“All participants who were interested in participating were given the opportunity to review consent, and some chose not to participate after reviewing consent, but otherwise everyone was given the opportunity,” she said.