On August 9 a drugmaker announced that the U.S. Food and Drug Administration had informed the company that it would not approve the psychedelic MDMA for use in psychotherapy for post-traumatic stress disorder (PTSD). The FDA asked Lykos Therapeutics, which had filed a new drug application with the regulatory agency, for an additional late-stage clinical trial to further study MDMA’s safety and efficacy—an effort that would require significant additional funding and likely take years to complete.
The decision immediately drew dismayed reactions from patient advocates and experts involved in developing and studying psychedelic therapies. “It’s a true disappointment,” says Jennifer M. Mitchell, a neuroscientist at the University of California, San Francisco, who led the phase 3 clinical trials of MDMA-assisted therapy for PTSD. “From my perspective, I thought we met the criteria that the FDA requested, and I absolutely stand by our data.”
“These treatments are very much needed, not only for veterans but for so many other people who are feeling despair in their lives,” says Stephen Xenakis, a retired brigadier general in the U.S. Army and a psychiatrist. “The thing that most bothers me is that the FDA and MAPS [the nonprofit organization Multidisciplinary Association for Psychedelic Studies] have been working together for years, so my feeling is this really is a failure of the government in being able to lead.”
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Lykos has not made the FDA’s letter of rejection publicly available. But in a statement, the company said that the issues the agency raised mirror those discussed in an FDA advisory committee meeting in June by a panel of psychiatric experts who had voiced concerns about MDMA’s effectiveness and safety. One major issue the panel raised was the inability to distinguish MDMA from a placebo effect because most trial participants correctly guessed whether they received the drug or a placebo. This issue, called functional unblinding, is a well known and common problem in many trials that involve psychoactive pharmaceuticals. In its recent statement, Lykos said it had previously responded to the ”substantive issues” raised in the advisory committee meeting. In those earlier responses, the company had said that functional unblinding “was discussed extensively with the FDA” in meetings to determine phase 3 trial design in 2017 and that Lykos took “many steps” to try to minimize the effects of the issue.
PTSD affects some 13 million Americans, and existing therapies bring relief to only a fraction of them. Veterans are disproportionately affected: in fiscal year 2021 up to 10 percent of male veterans and 19 percent of female ones were diagnosed. On average, around 17 veterans die by suicide each day, according to the U.S. Department of Veterans Affairs.
In the run-up to the FDA announcement, 80 bipartisan lawmakers and 730 veterans signed three letters to President Joe Biden urging approval for the therapy. “The FDA bureaucracy did not have the intestinal fortitude to question its advisory panel more deeply,” says Representative Jack Bergman of Michigan, who is a retired lieutenant general of the U.S. Marine Corps and led one of the two letters from lawmakers. Bergman says he plans to call a meeting between FDA leadership and Congress. “My question to the FDA is ‘Tell me what your definitive next steps are to get the science advanced enough to enable veterans to benefit from breakthrough therapies,’” he says, “because there will be veterans who take their lives today.”
Lykos intends to request a meeting with the FDA to ask the agency to reconsider its decision to require another clinical trial and to discuss the possibility of the company using the existing data to resubmit a new application instead. If the FDA refuses, it is unclear what the next steps would be. “To my knowledge, Lykos doesn’t have the money to run another phase 3 study,” says Natalie Gukasyan, an assistant professor of psychiatry at Columbia University Irving Medical Center.
Most of the funding for research on MDMA-assisted therapy was raised through philanthropic donations to MAPS, which has been working since 1986 to make MDMA an FDA-approved drug. MAPS founded Lykos (then MAPS Public Benefit Company) in 2014 as a public benefit corporation—a type of business that often aims to provide free or subsidized services while also generating profit—to bring MDMA-assisted therapy to market. Even if Lykos secures the funding for another clinical trial, the process “could take years,” says David Presti, a neuroscientist at the University of California, Berkeley.
The FDA’s decision was based on data from two phase 3 clinical trials that involved a total of nearly 200 participants. In both studies, published in Nature Medicine, more than two thirds of participants who received three rounds of talk therapy, spaced one month apart, combined with MDMA, no longer qualified for a PTSD diagnosis at the end of the study. In comparison, 32 to 48 percent of participants who received a placebo paired with talk therapy no longer qualified for such a diagnosis. For those who received MDMA, the results endured for at least six months.
“What we really need to understand is “What does it mean that [the FDA] didn’t find the data compelling?” because the data are compelling,” says Rachel Yehuda, a professor of psychiatry and neuroscience at the Icahn School of Medicine at Mount Sinai. More details are also needed on what, exactly, the FDA seeks to discover in an additional phase 3 trial, Yehuda says. “What’s at stake here is not whether a drug performs better than placebo but whether a drug performs better than the current standard of care,” she adds.
An FDA spokesperson explained the agency’s decision in an e-mail to Scientific American: “As discussed in the advisory committee meeting, there are significant limitations to the data contained in the application that prevent the agency from concluding that this drug is safe and effective for the proposed indication.” The spokesperson added that the FDA does not generally discuss reasons for turning down an application for a new drug.
“While it’s disappointing, the additional data the FDA is asking for is ultimately meant to improve understanding of the treatment,” says Walter Dunn, a psychiatrist at the Department of Veterans Affairs Greater Los Angeles Healthcare System and the University of California, Los Angeles, who served on the FDA advisory committee. Dunn was the lone committee member who voted in favor of MDMA-assisted therapy on both questions of efficacy and safety at the meeting and the only member with experience researching psychedelics. “It’s a continuous process—it’s not as if once it’s out, it’s out,” Dunn adds. “Even the people on the [advisory committee] who voted against approval indicated that this looks like a very promising treatment.”
The advisory committee’s decision has come under fire from other researchers with expertise in psychedelics. Many of them have pointed out that the committee members seemed unaware about basic concepts about the application—including the fact that therapy is an essential component of the treatment. “We’ve been working closely with the FDA since 2001, so the idea that this would suddenly be derailed by a committee of people that, by their own admission, [were] out of their depth, is surprising and very upsetting,” says Michael Mithoefer, a clinical psychiatry faculty member at the Medical University of South Carolina, who has been working on the MDMA-assisted therapy trials since 2001. “I was expecting a delay, but I wasn’t expecting this—this is extreme.”
In addition to the concerns about functional unblinding, the advisory committee’s reservations included that the psychotherapy that accompanied the administration of the drug was not standardized across trial sites, that some participants had previously tried MDMA and that Lykos did not collect certain safety data from participants, such as electrocardiograms.
Concerns were also raised in the meeting about ethical violations by a therapist involved in a sexual relationship with a trial participant that occurred after the conclusion in 2015 of the main part of a mid-stage (phase 2) clinical trial of MDMA therapy in Canada. On August 10, the journal Psychopharmacology issued retraction notices for three papers, some of whose authors were affiliated with Lykos, that analyzed various aspects of the phase 2 trial. In doing so, the journal cited “protocol violations amounting to unethical conduct" related to the research. Lykos told the New York Times that it disagrees with the retractions and plans to file an official complaint.
The news website STAT reported that some of the authors said that a correction would have sufficed and that Lykos said that the exclusion of data from the four participants from the site in question did not change the overall findings from these three papers. Data from the phase 2 studies were not under review in the drug application that was just rejected by the FDA—only the late-stage phase 3 data were assessed.
Psychedelic-assisted therapy represents “radically new territory for contemporary biomedicine,” U.C. Berkeley’s Presti says. So it’s understandable that the FDA is “a little skittish” about how to move forward. “However, in my opinion, it’s highly unlikely that truly transformational effects are going to be accomplished with traditional pharmacology,” he says. “So we have got to figure out how to make [psychedelic] treatments available because the data we have indicate stunningly positive therapeutic outcomes.”
Howard Kornfeld, a clinical faculty member at U.C. San Francisco, says the FDA’s rejection of Lykos’s application—given its strong safety and efficacy data—is an outlier in the agency’s decision-making over the past five years. “I think the goalpost was changed—and not to another 10 yards but a whole football field,” he says. “At its core, I think the FDA followed its advisory panel out of a fear of a new paradigm.”
For others, a far-reaching new therapy justifies regulators treading with caution. “There are many uncertainties in our understanding of the safety and effectiveness of the specific combination of MDMA and the psychotherapy developed by Lykos Therapeutics,” wrote David Rind, chief medical officer of the Institute for Clinical and Economic Review, a nonprofit organization that evaluates the cost-effectiveness of medications, in a statement sent to Scientific American. The organization issued a report in June that was critical of Lykos’s data.
Franklin King, a psychiatrist at Massachusetts General Hospital and Harvard Medical School, contends that a “fundamental problem” that any psychedelic treatment faces is the fact that clinical trials are designed to study a drug in isolation—but therapy is an integral part of psychedelic interventions. “The FDA does not have the purview to analyze behavioral interventions,” King says.
That does not mean that it’s impossible to conduct rigorous, randomized controlled trials with psychedelics, he adds. But it does mean that scientists and regulators will have to grapple with “some really deep challenges when it comes to understanding what’s going on with psychedelics, how to study them and how to apply them.” King adds that stigma—especially for MDMA, which is still tainted by its association as a club drug known as ecstasy or molly—remains a significant obstacle for bringing psychedelics into mainstream medicine as well.
Other countries have shown less trepidation in embracing MDMA-assisted therapy. Australia approved it as a treatment for PTSD in July 2023, and a panel of experts in the Netherlands recommended such treatment to the Dutch government in June 2024.
When drug approvals do materialize, patients will be waiting. For Laura Lynn MacDonald, age 55, a clinical trial participant in Madison, Wis., MDMA-assisted therapy was “a life-altering and lifesaving treatment.”
MacDonald developed PTSD after being sexually abused when she was 12 years old. Throughout her life, she sought out psychotherapy and medications to ameliorate her symptoms, but none brought lasting relief. In 2021 MacDonald took part in Lykos’s second phase 3 trial; she received the placebo, however. “I gained a lot of personal insights during the placebo sessions, but my core PTSD symptoms continued,” she says. Like other participants who received a placebo, at the end of the trial, she was permitted to receive MDMA psychotherapy. A year later, she says, “my life has transformed.” Her PTSD symptoms are gone, and she no longer has to take medications “to get through my days.”
Last Friday, speaking with Scientific American after learning that the FDA had rejected MDMA-assisted therapy, her voice trembled with emotion. “I’m really upset,” she said. “I feel like they are invalidating the life-changing experience I had.”
“My hope was that so many other women who are suffering the overwhelming effects of their past trauma could know that this is a possibility—that in [three months] and in three doses of MDMA, you can have prolonged relief from suffering,” she said. “What a miss.”
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