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A US Food and Drug Administration (FDA) expert panel has found that the benefits of the psychedelic midomafetamine (MDMA) in combination with psychological intervention for the treatment of posttraumatic stress disorder (PTSD) do not outweigh the risks.

Only two of 11 members of the FDA's Psychopharmacologic Drugs Advisory Committee agreed that Lykos Therapeutics had proved that its MDMA-assisted therapy (MDMA-AT) was effective. In a second vote, only one panelist agreed the benefits outweighed the risks. 

"I voted yes because I'm putting on my clinician hat and we are in dire need of new treatments for PTSD," said Walter S. Dunn, MD, director of the Interventional Psychiatry Service at the West Los Angeles Veterans Affairs (VA) Medical Center. But even Dunn acknowledged that his enthusiasm was tinged by doubt about the drug's safety and efficacy. 

"I'm not convinced at all that this drug is effective," said panel chairperson Rajesh Narendran, MD, professor of radiology and psychiatry at the University of Pittsburgh School of Medicine. 

Summarizing the panel's views, he said that all had concerns about "functional unblinding" in Lykos' two pivotal trials. The majority of patients — and it appeared, therapists — were aware of who had received an active treatment, which probably biased results, they said.

The FDA advised Lykos in 2016 to consider using an active comparator instead of placebo to minimize bias and functional unblinding, but the company rejected the FDA's suggestions, said David Millis, MD, the lead reviewer from the FDA's Division of Psychiatry. 

Investigation Into Potential Harms

The panelists also felt that "expectation bias" among participants and therapists probably played a role in the positive results. Eighty-two percent to 86% of patients reported a significant improvement, with more than half saying they no longer had PTSD.

Panelists said results could be confounded by the fact that 40% of participants had used MDMA before the trial. They also noted that there were potentially unreported adverse events, no data on whether the drug could be abused or diverted, and at least one documented case of sexual assault during a phase 2 study.

Paul E. Holtzheimer, MD, a panel member and director of the VA's National Posttraumatic Stress Disorder Brain Bank, said he was not convinced of short- or long-term efficacy, in part because of functional unblinding but also because patients had psychotherapy and used traditional psychotropic medications and psychedelics during the follow-up period that was supposed to determine the durability of MDMA-AT's effect. 

Holtzheimer said he was also "concerned about patient boundary violations," citing the assault in the phase 2 study. "If this happened in a very highly controlled clinical trial," he said, "there is concern about, as this is rolled out to a larger population of clinicians, how that would be monitored [and] how that would be controlled." 

Some panelists also mentioned concerns about potential misconduct in trials and alleged data manipulation. A few speakers at the open public hearing said they had proof that patients had been harmed and that their reports were not part of the official data. 

Teresa Buracchio, MD, director of the FDA's Office of Neuroscience, cautioned the panel against taking outside source reports as gospel. "We consider them to be unverified at this point until we do inspections," she said, adding that the agency is currently investigating.

Incomplete Research on Side Effects

The FDA is not bound by the advisory panel's recommendations but frequently follows them. The agency is due to make a decision on the Lykos new drug application by August 11.

If approved, MDMA-AT would be the first psychedelic-based therapeutic cleared by the FDA for any condition in the US and the first PTSD medication to receive approval in 24 years. 

FDA officials said at the meeting that if the agency did approve MDMA-AT, they would recommend that MDMA — currently is considered to have no medical use — to be moved to Schedule II on the list of controlled substances, along with opioids and stimulants such as Adderall.

The Lykos MDMA product would also be subject to a Risk Evaluation and Mitigation Strategy that was still being worked out but would probably restrict dispensing to pharmacies on the site of healthcare providers who have been certified to deliver the drug. At least two healthcare providers — one of them licensed – would have to be on site, and patients would have to stay for at least 8 hours. 

Approximately 13 million American adults have PTSD. Seven percent of veterans will experience PTSD during their lifetime (compared with 6% of the general population), but for some service members, this proportion is reportedly as high as 29%. Sexual violence is also a main driver of PTSD, said Lykos consultant Jerry Rosenbaum, MD, director of the Center for the Neuroscience of Psychedelics at Massachusetts General Hospital in Boston. 

Lykos submitted efficacy results from two trials, MAPP1 and MAPP2, and safety data from those trials along with 18 previously published safety studies not conducted by the company. MAPP1 and MAPP2 showed significant improvement in PTSD symptoms, with few adverse events, Lykos told the panel. 

MDMA is known to have potential cardiovascular effects, but Lykos did not gather much data on elevated blood pressure and heart rate and had incomplete studies of the potential for cardiac arrhythmias. 

Panelists also expressed doubts about the Lykos psychological intervention, which was not standardized across sites or evidence based. They lamented that Lykos did not study its model against accepted PTSD interventions such as cognitive-behavioral therapy or eye movement desensitization and reprocessing. 

Some said it was difficult to tease out from the trial design whether therapy had any impact over and above the MDMA.

"The way it's presented in the application makes it impossible to untangle the two," said Melissa Decker Barone, PsyD, trauma recovery program staff psychologist at the VA Maryland Health Care System. 

'Ill-Defined, Vague Treatment' 

"We don't have strong evidence that the therapy is necessary to the observed effect," said Tiffany Farchione, MD, director of the Division of Psychiatry at the FDA's Office of Neuroscience. Farchione also noted that the FDA does not have the authority to regulate psychotherapy. 

Holtzheimer said the therapy element is "a bit of a black box," adding that "it's a relatively vague, ill-defined treatment."

Neşe Devenot, PhD, who was a co-author of a citizen petition to the FDA seeking an advisory committee meeting and alleging harms during trials, said during the public comment period that she had recently been "connected with a phase 3 participant whose PTSD symptoms were exacerbated by Lykos' clinical trial." She alleged that the Lykos intervention is a "therapy cult" that has no supportive science.

"The core idea of the therapy is that we all have an inner healing intelligence that can be accessed through MDMA and other nonordinary states of consciousness," said Kayla Greenstein, a psychology PhD candidate at the University of Sydney, Australia, in the public hearing. Greenstein said Lykos' therapy manual "is based on New Age psychospiritual theory." It "is not a safe therapy model," she said.

Panelists also had concerns about potential financial and other conflicts if Lykos were solely responsible for training therapists.

"As we've heard from the public commentary portion, there's some serious questions about the sponsor being able to educate and deliver the psychological intervention in a responsible way," said Dunn.

Alicia Ault is a Saint Petersburg, Florida–based freelance journalist whose work has appeared in publications including JAMA and Smithsonian.com. You can find her on X @aliciaault.