FDA rejects first psychedelic to treat PTSD, calling for more study

The Food and Drug Administration has rejected for now the first attempt to win approval of MDMA to treat post-traumatic stress disorder — a major blow for advocates who for decades have pushed to integrate illegal psychedelic drugs into mainstream medical care.

On Friday, Lykos Therapeutics announced that federal regulators declined to approve its current application for MDMA — commonly known by its street name ecstasy — to treat PTSD alongside psychotherapy. Instead, the agency requested another large study, which could take several years to conduct, according to the company.

Lykos Therapeutics said it plans to contest the FDA’s request, saying it believes the existing data is adequate to prove the drug’s efficacy.

The decision comes at a fraught moment for the agency, with some researchers and watchdog groups contending that the FDA has been too willing to approve therapies without convincing evidence, while veterans groups and lawmakers have emphasized the dire plight of those suffering from a debilitating disorder that affects an estimated 5% of U.S. adults. In June, an independent committee of experts convened by the FDA recommended against approving the treatment, raising concerns about the validity of clinical research and the potential for harm from the first-of-its-kind treatment.

The FDA’s decision marks a stunning setback for the Multidisciplinary Association for Psychedelic Studies (MAPS), a nonprofit focused on research and education that founded Lykos under a different name to run clinical trials and commercialize MDMA. When MAPS announced in 2015 the formation of what is now Lykos, it projected winning FDA approval by 2021. MAPS didn’t respond to requests for comment.

“We intend to work tirelessly and use all available regulatory pathways to find a reasonable and expeditious path forward,” Amy Emerson, chief executive of Lykos, said in a statement. The company plans to seek a meeting with the FDA to ask for reconsideration of the decision.

In a statement, the FDA said there were “significant limitations to the data contained in the application” that prevented the agency from concluding the drug is safe and effective.

“The agency recognizes that there is great need for additional treatment options for mental health conditions such as PTSD,” the FDA wrote. “We will continue to encourage research and drug development that will further innovation for psychedelic treatments and other therapies to address these medical needs.”

Psychedelics are enjoying a cultural moment as investors pour hundreds of millions of dollars into research, celebrities highlight health benefits of consuming microdoses of the substances and two states have legalized programs for psilocybin, the compound found in hallucinogenic mushrooms, for treating mental health ailments. But public health experts worry the marketplace is outpacing the science. Pills, chocolates and gummies marketed as offering mind-bending trips are easily purchased online or in smoke and vape shops, raising concerns about the risks of those unregulated products.

One late-stage clinical participant, Ronald Bowman, 63, of New York, said he was “heartbroken and disgusted” by the news. The retired real estate and construction executive said his experience with MDMA-assisted therapy, while grueling, was life changing in helping treat PTSD sparked by the deaths of employees and friends in the Sept. 11, 2001, terrorist attacks. The delays in research will cost lives from suicides and substance abuse, he said.

“It took 10 years to get us to this point and now the FDA wants to kick the can down the road,” Bowman said. “How many people have to die?”

The FDA’s decision underscores its mission to approve only drugs that show efficacy and sufficient safety for patients, said Aaron S. Kesselheim, a professor of medicine at Harvard Medical School, who has been critical of the agency’s approvals of some drugs. The FDA “is just saying there is substantial flaws in the data that lead us to believe that the drug won’t work,” Kesselheim said. “It does not mean never — but this is the process.”

It is not clear what effect the decision will have on other companies aiming to shepherd psychedelic compounds from clinical trials to FDA approval. As doubts emerged over MDMA’s chances in recent months, rival companies have tried to differentiate their approaches from MAPS and Lykos.

The FDA worked with MAPS over decades as it blazed a path to approving psychedelic drugs for treating mental health conditions, with the agency designating MDMA a “breakthrough therapy” in 2017.

MDMA’s potential for abuse landed it in the Drug Enforcement Administration’s most strictly regulated category of drugs, which are considered to have no accepted medical use.

But increasingly, scholars have researched its role in altering human perception and helping people process memories of traumatic events. Studies by MAPS found that MDMA, combined with various forms of psychotherapy, brought meaningful relief from PTSD symptoms relative to a placebo.

The findings from Lykos’s key clinical trials, published in 2021 and 2023, captivated people suffering from PTSD, as well as technology luminaries and investors who saw enormous business potential. Until recent months, many close observers of psychedelic medicine expected that MDMA would be the first to win FDA approval.

But there were lingering regulatory concerns about how Lykos designed its trials, which consisted of three eight-hour, therapist-guided sessions with participants receiving MDMA or a placebo.

To deliver convincing results, participants in clinical trials should not know whether they receive the drug being tested or a placebo — a cornerstone of clinical trials known as blinding. If they know they are getting the drug, they might expect to feel better and overstate their improvement. While MAPS described its studies as “blind,” it was virtually impossible to mask the mind-altering properties of MDMA.

The FDA had voiced its concern about blinding to Lykos’s predecessor in 2016, suggesting the company compare the drug against a low dose of MDMA that “would have enough physiological effect to limit recognizability as placebo,” according to an agency review. But the developer pushed back, arguing that such a low dose had exacerbated anxiety in past participants.

To mitigate the risk of bias, MAPS ensured that the people evaluating the symptoms of participants — though not their therapists — would not know whether they had received the drug or a placebo. The FDA signed off on the protocol, but its concern remained.

The agency in 2020 suggested surveying participants about whether they knew what medication they were getting. MAPS agreed, and the results were striking: 94% of participants who got MDMA, and 75% of those who got the placebo, correctly guessed their group in a study last year.

Some experts said the FDA’s rejection underscores how researchers will continue to grapple with the long-standing problem that patients in clinical trials know when they have been given psychedelics.

“I don’t know any real way around it,” said Albert Garcia-Romeu, a professor of psychiatry and behavioral sciences at Johns Hopkins University School of Medicine who is studying psilocybin. “It’s been a conundrum with these drugs since the first research on them in the ‘50s and ‘60s.”

Many drugs have presented challenges to effectively blinding participants, including Spravato, a nasal spray derived from ketamine that was approved by the FDA in 2019. But for Lykos, combining the drug with therapy appeared to elevate concerns for some advisory committee members: If therapists could also tell whether trial participants received the drug, they might treat them differently and affect the outcomes.

At the FDA’s request, an independent advisory committee reviewed the MDMA studies in June. In addition to bias concerns, panel members grappled with allegations of patient abuse aired during public comments — even though the FDA said it had not substantiated those claims.

The committee overwhelmingly voted that there is not enough evidence to show the MDMA-assisted therapy is effective in treating PTSD, and the benefits of the drug do not outweigh the risks. Members of the committee also raised concerns about the standards and effectiveness of psychotherapy received by clinical trial participants. The practice is not regulated by the FDA but overseen by state agencies.

On Friday, Lykos criticized the structure and conduct of the advisory committee, claiming the panel veered outside of the available scientific evidence.

In recent weeks, supporters of the drug intensified their public push for it to be approved, with some arguing that any bias couldn’t account for the magnitude of the benefit in the clinical trials. More than 700 veterans, as well as 14 groups supporting veterans, wrote to President Joe Biden urging that the FDA approve the drug by this weekend’s deadline.

But others had publicly urged the agency to reject the application.

“The FDA followed the science and did not cave to political pressure funded by Lykos’s donors and investors,” said Neşe Devenot, a psychedelics ethics researcher. “This decision protects the future of the psychedelic field by avoiding a rush to market with preventable harms.”