As the FDA evaluates ecstasy treatment for PTSD, questions mount about the evidence

In a matter of months, the Food and Drug Administration is expected to decide whether the drug commonly known as ecstasy can be used as a treatment for post-traumatic stress disorder.

An approval by the agency would represent an enormous milestone for the movement to bring psychedelics into the mainstream of mental health care. An FDA rejection of MDMA, the abbreviation of the drug's chemical name, would deal a major setback to the effort.

Clinical trials have inspired optimism in the drug for its potential to help the millions of Americans who experience PTSD. Accounts from some of those who've participated in the trials describe the treatment as transformational.

But new and troubling questions about this research are now threatening to upset the final stretch in the drug's path to market.

The allegations surfaced in a draft report released in March by the Institute for Clinical and Economic Review, a nonprofit that evaluates clinical trials and drug prices, which found "substantial concerns about the validity of the results" of the MDMA clinical trials.

The ICER report was followed in April by a citizen petition to the FDA. In that document, a group of concerned people allege possible misconduct and ethical violations that could compromise the MDMA research. The petition asked the agency to hold a public meeting to address the concerns.

If true, the claims could jeopardize the drug's chances of receiving FDA approval, a decision that is expected to come by early August.

"There's the possibility that the data might not be representative of what's actually happened in clinical trials," says Neşe Devenot, one of the authors of the citizen petition and a senior lecturer in the writing program at Johns Hopkins University who is involved in psychedelic research. "I don't think this has been publicly reckoned with."

That may soon happen. The FDA announced Thursday that it plans to hold a public advisory committee meeting on MDMA-assisted therapy on June 4.

At the heart of the controversy are the organizations that have pioneered research into MDMA: the Multidisciplinary Association for Psychedelic Studies, and the public benefit corporation incubated by MAPS, which was recently rebranded as Lykos Therapeutics.

Lykos sponsored the clinical trials of MDMA. The results are included in the company's application to the FDA seeking approval to market the drug for therapy-assisted PTSD treatment.

Researchers and clinicians involved in the trials have pushed back strongly against the accusations that their clinical data isn't sound.

Jennifer Mitchell, lead author of the published papers from the Phase 3 trials, says she stands behind their findings.

"I didn't feel any pressure from the sponsor to come up with anything different than what the data was providing," says Mitchell, a professor of neurology and psychiatry at the University of California, San Francisco and associate chief of staff for research at the San Francisco VA Medical Center. "I wouldn't have continued to work with them if I had felt that."

Promising MDMA research for PTSD

The Phase 3 trials evaluated MDMA-assisted therapy, a protocol in which the drug is given under the supervision of two therapists.

In the second stage of the trials, 94 people with moderate and severe PTSD received either the drug or a placebo during three sessions, each spaced a month apart. There were also follow up "integration" sessions to help people process their experiences while on MDMA.

By the end of the trial, about 71% of participants in the MDMA arm no longer met the diagnostic criteria for PTSD, compared to about 48% who underwent the same therapy but took a placebo instead. Those findings built on promising results from earlier studies.

The study documented various adverse events in both groups — ranging from nausea and anxiety to heart palpitations — but none of them qualified as serious. The treatment was "generally well tolerated."

"Consistent with PTSD, suicidal ideation was observed in both groups," the authors reported in the journal Nature Medicine, "MDMA did not appear to increase this risk, and no suicidal behavior was observed."

Casey Tylek, a participant in the Phase 3 trials, says he had no experience with the drug prior to the study.

Tylek was in the placebo group, but was later given the opportunity to undergo the therapy with MDMA.

"It was incredibly powerful," says Tylek, a veteran who lives in Massachusetts, "I truly don't know if I would be alive today if I hadn't gone through that trial."

ICER report raises concerns

In its report, ICER acknowledges that the MDMA data suggest it would be an "important addition to treatment options for PTSD," but it questions whether the published findings tell the full story.

Among the concerns, the ICER report details a well-known challenge in psychedelic research around how to make sure study participants don't know if they got the experimental treatment or a placebo. Most of those in the MDMA group were able to identify they had received the drug. It also suggests the method used to assess PTSD — considered the gold-standard — showed improvements in symptoms after the treatment, even though some people were worse overall.

Beyond that, however, the report brings up the possibility that "very strong prior beliefs" among therapists, investigators and patients influenced the results.

"Concerns have been raised by some that therapists encouraged favorable reports by patients and discouraged negative reports by patients including discouraging reports of substantial harms, potentially biasing the recording of benefits and harms," the report states.

ICER does not identify the sources who were interviewed, although it did include two trial participants, a "trial therapist" and those who worked on a podcast called Cover Story, says Dr. David Rind, the chief medical officer for ICER.

"This was a very unusual review," says Rind.

The podcast, produced by New York Magazine and the nonprofit media organization Psymposia, brought to light claims by a participant named Meaghan Buisson, who appeared in a video of two therapists, a married couple, engaged in what Buisson described as inappropriate physical contact while she was under the influence of MDMA at a Phase 2 trial site in Canada.

MAPS determined the therapists "substantially deviated" from the treatment manual. The organization also barred the two therapists from becoming providers of MDMA-assisted therapy in affiliation with MAPS, and health authorities were notified in Canada and the U.S.

The podcast also interviewed two people (their full names were not revealed) who said they received MDMA in the large-scale, or Phase 3, trials and experienced feelings of suicidality and other distress after the studies.

The ICER report is yet to be finalized, but Rind says their analysis showed "there's still a lot of uncertainty" about the treatment.

"You have a group of people who are very upset about how these trials went," he says. "We couldn't tell, even though we talked with people where this happened, whether that represents a tiny fraction of bad events or a number of bad events large enough to have rendered the trial just not believable."

Pushback against the allegations

According to Rind, MAPS and Lykos had "very little" engagement with ICER on the draft report.

But since then, a group of more than 70 clinicians, investigators and others involved in the Phase 3 MDMA trials have published a detailed response, saying that certain aspects of the trials were "misrepresented" and that a number of assertions amount to "hearsay."

Willa Hall, a clinical psychologist in the Phase 3 trials, says she and her colleagues were shocked by how ICER described their work.

"I didn't recognize the study that they were talking about," Hall told NPR. "I think a lot of us felt quite insulted actually by that characterization. I saw nothing like that. I only saw professionalism."

In their response, Hall and her colleagues write that "[ICER] does not note the many measures taken to train, support, and evaluate therapists on those trials—measures that met, and in some cases exceeded, the accepted standards in the field of psychotherapy research."

They also take issue with ICER relying on "a small number of undisclosed study participants and unnamed 'experts' rather than validated research outcomes." The critiques that participants knew they received the treatment or that the measure of PTSD symptoms might not capture someone's overall condition would also apply to other clinical trials, unrelated to MDMA, they say.

UCSF's Jennifer Mitchell says the clinical trial was designed to safeguard against bias.

Therapists on site were not collecting key data from participants about their PTSD symptoms following the sessions. Instead, that was being done online by "independent assessors" who didn't know who had received the treatment or a placebo.

Hall says therapists "meticulously" captured any adverse events. "We encouraged our participants to be very honest," she says. "We're all invested in knowing how it works and what are the risks for people."

Still, Mitchell acknowledges she doesn't have full insight into what was going on at each trial site on a given day.

"This is my own frustration," she says. "I can't attest to what was happening at one of the sites in Israel on a day to day basis, or on one of the sites in Canada."

But she contends that ICER tried to conduct an investigation without access to the full data.

The FDA granted MDMA "breakthrough therapy" status, she says, which means the agency was involved in the study design and "many aspects" of the trial.

"So there's no keeping things from the FDA," Mitchell says.

The ICER report points out that therapists and participants in the study were "pulled heavily from the existing community of those interested and involved in the use of psychedelics for possible psychological benefits."

For her part though, Mitchell says she's not what some would call a "true believer."

"My personal feeling is that psychedelics are complicated compounds and they do not work for everyone," she says.

Petition adds to controversy ahead of the FDA meeting

On the heels of the ICER report, Neşe Devenot and four others, including Meaghan Buisson, submitted the citizen petition to the FDA calling for a public advisory meeting about the Lykos' application for MDMA.

In it, they ask for extended time for stakeholders who are concerned about the "risks and shortcomings" of the research.

"Evidence from multiple sources indicates that the sponsor has engaged in a pattern of systematic and deliberate omission of adverse events from the public record while minimizing documented harms," the petition states.

It continues: "We cannot rule out the possibility that MAPS/Lykos manipulated clinical trial data to hide adverse events from regulatory agencies."

The petition cites media reports and public statements from figures at Lykos and MAPS — and disclosures from a former employee of the MAPS public benefit corporation "who prefers to maintain anonymity at this juncture."

In addition, the petition alleges that clinical trial investigators would phone MAPS in the event of an incident during the trial to see whether that should be reported as an adverse event and that a suicide attempt during a dosing session was discouraged from being reported.

In an email to NPR, a spokesperson for MAPS rejects the claim.

It's not clear if the FDA's decision to hold a meeting was influenced by Devenot's petition, which has over 80 signatures.

Alaina Jaster, who has a doctorate in pharmacology and toxicology, is another author of the petition.

"We need to listen to people [in the trials] who are having these experiences, instead of telling them that they are liars and that they're going to ruin the psychedelic renaissance," says Jaster who hosts a podcast on psychedelics.

"None of us are against this as a useful tool, or none of us are against treating mental health. We don't have any monetary interests in this not going through," she says.

Neşe Devenot and Brian Pace, another author of the petition, are affiliated with Psymposia, the media organization that produced the podcast, but Devenot says they were not involved in the podcast and are unpaid board members.

In response to the petition's call for a public meeting, a spokesperson for Lykos sent NPR a statement in April saying the company supports holding an advisory meeting. "The voice of the PTSD patient is incredibly important," the email reads.

MAPS "remains fully supportive of comprehensive, high-quality research; careful analysis of safety and efficacy; and stringent regulatory oversight of any psychedelic-assisted therapy research or delivery," according to the statement it also sent to NPR in April. "We stand behind Lykos' execution of the clinical program and support the clinical results."

One of those who signed the petition after seeing it posted online is Dr. Boris Heifets, an anesthesiologist at Stanford University whose lab studies psychedelics, including MDMA.

"I don't know if the allegations are true, it just makes me deeply sad if there was actually malfeasance for such an important trial," says Heifets. "The MDMA Phase 3 trials were very important for mental health, important for a lot of people who may benefit from this therapy."

Learning about MAPS several decades ago was, in part, what inspired Heifets to get involved in this type of research.

He says he donates $100 a year to MAPS and that they have supplied his lab with MDMA. He also consults for one company that's developing a derivative of MDMA.

Heifets says the petition contains some "very strong allegations," particularly the claim that certain adverse events were not disclosed.

"I want to hear MAPS respond," he says. "I would really like to understand the risk profile of this drug before it's approved, not after."

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