FDA advisers vote against first MDMA therapy to treat PTSD

(CNN) — A federal advisory committee on Tuesday voted overwhelmingly against of the use of MDMA, commonly known as ecstasy, as a treatment for post-traumatic stress disorder. The novel treatment has the potential to transform a field with significant need, but the committee had concerns about the integrity of the particular trials up for review.

After hearing presentations from the US Food and Drug Administration, treatment sponsor Lykos Therapeutics and members of the public, the independent committee voted on recommendations to be made to the FDA. Two of the 11 committee members said that they considered the treatment effective, while nine said that it was not. Only one committee member said that the benefits of the treatment outweigh the risks as presented, but the other 10 voted that they did not.

This was the first time FDA advisers have considered a psychedelic drug for medical use. MDMA is known as an entactogen, a class of psychoactive drugs that produce experiences of emotional communion, relatedness and emotional openness. It’s currently classified as a Schedule I drug under the Controlled Substances Act, and changing this status would be a marked shift.

The FDA has final say on whether the treatment is formally approved. The agency often follows recommendations from its independent advisory committees but does not have to do so.

About 5% of adults in the United States – about 13 million people – experience PTSD in any given year, according estimates from the National Center for PTSD. But current treatment options – including antidepressants and some specialized forms of cognitive behavioral therapy – are limited in their scope and effectiveness, with few alternatives available to help those don’t respond well to them.

At Tuesday’s meeting, Lykos Therapeutics presented positive data from two late-stage clinical trials that used MDMA in combination with therapy to treat PTSD. Many of the FDA advisory committee members applauded the exploration of this line of treatment and lauded the potential it holds, but several shortcomings – notably regarding bias in efficacy data and missing information about safety – raised critical doubts.

About 200 people participated in the Lykos trials, with a treatment program that involved three eight-hour sessions where participants took MDMA in the presence of two therapists. The MDMA sessions were spaced about a month apart, along with additional therapy sessions.

“Participants appear to experience rapid, clinically meaningful, durable improvement in their PTSD symptoms,” the FDA wrote in a briefing document about the studies.

But the agency also noted that “several factors make these data challenging to interpret and complicate the benefit-risk assessment for this application,” posing key questions for the members of the Psychopharmacologic Drugs Advisory Committee to consider.

The studies were designed to be double-blind, meaning neither the participants nor the researchers knew who received the MDMA treatment and who didn’t. This type of study is considered the gold standard because it helps reduce bias in results by minimizing the effects of external factors. But MDMA’s hallucinogenic effects have “profound alterations” on a person’s state of being, and the vast majority of participants knew which group they were in simply by the nature of their experience.

The Institute for Clinical and Economic Review, a nonprofit that conducts independent reviews of treatments, tests and procedures, also cited “substantial concerns about the validity of the results” of the Lykos trials in a report published in March. Those concerns centered around bias, both from the unblinding of the trial and from other influences on patient perspectives.

In addition to blurry data on efficacy, there were concerns about safety data, the FDA said.

MDMA is known to have potential for abuse, but the FDA cautions that the research did not appropriately assess this as an adverse event in the context of the treatment program.

Reports from illicit use of MDMA suggest that it may pose risks to both heart and liver health. The phase III clinical trials showed “significant increases in both blood pressure and pulse” among participants, the FDA said, but certain related assessments were incomplete. And liver health was assessed only in small groups from earlier phases of the clinical trials.

The unique factors of this type of treatment and the complexity of the considerations at hand were acknowledged throughout the committee meeting.

“I absolutely agree that we need new and better treatments for PTSD, especially in the somatic treatment space. However, I also note that premature introduction of a treatment can actually stifle development and stifle implementation and lead to premature adoption of treatments that are either not completely known to be safe not fully effective or not being used at their optimal efficacy,” said Dr. Paul Holtzheimer, deputy director for research at the National Center for PTSD.

As a member of the advisory committee, he voted against the treatment. “I think this is a really exciting treatment. I’m really encouraged by the results to date, but I feel that both from an efficacy and a safety standpoint it is still premature.”

Dr. Walter Dunn, a staff psychiatrist at the Veterans Administration Greater Los Angeles Healthcare System and assistant clinical professor of psychiatry at the University of California Los Angeles, was the only committee member to vote in favor of the treatment on both questions of efficacy and the balance of risks and benefits.

His confidence in the risk-benefit analysis was low, he said; psychotherapy is an integral component of this treatment program, and it could be “the greatest strength of the treatment” but “also its greatest liability” – and it’s not within the FDA’s scope to regulate, he said. And specific guardrails the FDA outlined to be put in place with approval of the treatment to protect patient safety were incomplete.

“Ultimately, I’m voting yes because I’m putting on my clinician hat,” Dunn said. “Working in the VA, as a former servicemember myself, I have colleagues who deployed who have PTSD, and this has the potential to make a to make a difference. Now, that’s not without its risks.”

The questions are all familiar to Lykos, and the company has had conversations with the FDA throughout its research, CEO Amy Emerson told CNN before the meeting. The advisory committee meeting is the “next big milestone” in the process and an opportunity to gather even more information, she said.

“There’s just such an urgent patient need for new treatment options, and we really use that as our guiding light as we develop MDMA-assisted therapy,” she said. “All along, we’ve been really committed to safety, and that will always be top of mind.”

There is growing interest and support to explore the use of psychedelics as therapeutics. Along with MDMA, drugs like ketamine and psilocybin mushrooms are being studied in clinical trials to treat a variety of mental health disorders.

“Depression, PTSD, eating disorders – they’re all different. You can’t just lump these together and say, ‘Psychedelics are good for this,’” Emerson said. “You need to study it, you need to look at the safety and efficacy profiles of each, and we have to be careful to not treat these things as panaceas or like a magic bullet.”

The Lykos treatment is the first to reach this point in the process, and the way the FDA and its advisory board proceed could set key precedents.

“It’s an early but exciting moment. The promise is there, the potential is there, and we just have to find out through careful study and time how impactful these medications will be,” said Dr. Joshua Gordon, director of the National Institute of Mental Health.

Many questions remain about the specific conditions needed to achieve effective use of this treatment, and even the most supportive experts caution about the limitations of the treatment and recommend additional research.

“I hope that the drug gets approved but in a way where it can be made available and monitored in a responsible manner,” said Dr. Rachel Yehuda, director of the Center for Psychedelic Psychotherapy and Trauma Research at Mount Sinai’s Icahn School of Medicine, who is not a member of the FDA advisory committee. “My fear would be that we stop being curious, we stop asking the right questions, we stop trying to figure out mechanisms of action, we stop trying to perfect and scale like we do with any other treatment.”

It’s critical to protect vulnerable populations who may benefit from this treatment, experts say.

“There’s a recognition that psychedelics are probably uniquely susceptible to the blurring of the boundaries between strictly applied medical treatments that are provided by experienced clinicians under very well-monitored circumstances versus recreational use, so there’s a great interest in trying to get this as right as possible,” said Dr. Jon Alpert, chair of the American Psychiatric Association’s research council and chair of the Department of Psychiatry and Behavioral Sciences at the Albert Einstein College of Medicine.

“The last thing you want is for a promising treatment for a devastating condition to go off the rails in an unbounded, unmonitored kind of use.”

Also, the trials have excluded people who may be most vulnerable to substantial side effects of MDMA, such as adolescents and those with coinciding conditions such as schizophrenia or bipolar disorder, and it’s important to continue gathering data to understand how the treatment works in these populations, he said.

“Any FDA approval of MDMA must be accompanied by rigorous regulations, strict prescribing and dispensing controls, comprehensive patient education, and ongoing monitoring and surveillance systems,” the American Psychiatric Association wrote in a letter to the FDA’s advisory committee.

In addition to potentially setting a precedent in mental health treatment, the particular treatment program that Lykos has studied is “labor-intensive,” Yehuda said. It requires a significant amount of investment – both logistically and emotionally – from participants and providers, which is challenged by the shortage of mental health professionals in the US.

“We never had a situation where something that the government had deemed harmful gets a 180 and becomes an approved treatment for a condition,” she said. “Then, the question is, ‘Are we going to be able to use the moment in a way that really furthers the mental health of our population?’”

CNN’s Brenda Goodman contributed to this report.

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