FDA Advisors Shot Down MDMA as Treatment for PTSD. What Went Wrong?

Advisors to the Food and Drug Administration (FDA) overwhelmingly voted against recommending the use of MDMA-assisted therapy as a treatment for post-traumatic stress disorder (PTSD) on Tuesday. The panel cited concerns about the integrity of the data submitted by the drug’s sponsor, Lykos Therapeutics, and reports of ethical misconduct during the trial.

The panel’s vote signals a setback for Lykos and reflects the challenges in regulating psychedelics for mental health treatment.

During the day-long meeting, a prominent concern among the panelists was that most study participants were aware of whether they received the treatment and that therapists involved in the study may have expressed a positive bias towards MDMA, more commonly known as ecstasy or Molly.

The panelists raised safety questions, too, including the increased risk for cardiovascular issues and how the agency will monitor for adverse events. However, the major questions were not about the drug itself but about the potential for misconduct by therapists when dealing with patients who are particularly vulnerable under the influence of MDMA.

Ultimately, the panel voted 9–2 that MDMA-assisted therapy was not effective for treating PTSD and 10–1 that the benefits did not outweigh the risks of the treatment.

“I absolutely agree that we need new and better treatments for PTSD,” Paul Holtzheimer, MD, an FDA advisor and deputy director for research at the National Center for PTSD at the Department of Veterans Affairs, said at the meeting. “However, I also note that premature introduction of a treatment can actually stifle development, 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.”

During the public comment period, panelists heard from people who lauded MDMA-assisted therapy, saying it gave them the tools to overcome PTSD.

“Within the very first hour of the MDMA session, I felt an intense sense of repair, a spontaneous rewiring of my mind to body… What used to feel like a tsunami of overwhelming panic was merely a puddle at my feet,” said Cristina Pearse, who was a participant in the trial and now runs a non-profit to support victims of sexual violence. “Each day we postpone this therapy, I ask, ‘At what cost? How many more people need to die before we approve an effective therapy?’”

While the vote on Tuesday is non-binding, the FDA often follows its advisory panel’s recommendations. The agency is expected to make a final decision on whether to approve the treatment in mid-August.

If the FDA chooses to approve the treatment, MDMA would be the first Schedule 1 psychedelic—a drug classified by the government as having a high potential for abuse and no medical benefit—to have a medical use. It would also be the first time in nearly 25 years that a new treatment is available for PTSD, a condition that affects about 13 million adults in the United States.

How MDMA Therapy Works

Currently, there are only two medications approved for PTSD: Zoloft (sertraline) and Paxil (paroxetine). The response rates for these drugs rarely exceed 60%, and fewer than a third of patients on these treatments achieve full remission.

MDMA is in a subclass of psychedelic drugs called “empathogens,” which can improve feelings of trust, empathy, and connectedness to others. Lykos representatives said the drug can help people recall memories, improve their tolerance for revisiting distressing thoughts or experiences, and improve self-awareness.

The FDA panel considered data from two phase 3 clinical trials submitted by Lykos. The most recent trial found that 71% of people who took MDMA improved enough that they no longer met the criteria for PTSD. That finding supports an earlier study, in which 67% in the treatment group no longer qualified for a PTSD diagnosis, compared to 32% in the placebo group.

Participants had three treatment sessions that were eight or more hours long. They took two doses of MDMA a couple of hours apart under the guidance of a certified therapist. They then had nine follow-up sessions to help describe the experiences of medication sessions and work through the trauma.

When the results are taken at face value, “participants appear to experience clinically meaningful, durable improvements in their PTSD symptoms,” Tiffany Farchione, MD, FAPA, director of the division of psychiatry at the FDA.

Data Integrity Concerns

Despite the successful cases in the trial, the panel expressed skepticism about “functional unblinding,” in which the participants and/or the researchers become aware of which treatment the participants are receiving.

It’s hard to design a double-blinded trial in which participants do not notice the mind-altering effects of psychedelics. In each study, about 95% of people who took MDMA correctly guessed they were in the treatment group, which could affect their assessment of the drug.

It’s also likely that the therapists in the study could easily guess which patients received the drug and which did not. That could skew how the therapists interacted with their patients.

Another concern among the panelists was that many of the study participants may have had a favorable outlook on MDMA already. About 40% of people in each trial had taken MDMA before. Plus, only about 5% dropped out from the MDMA groups in both trials.

That “very low” dropout rate could indicate that participants had a “high level of interest in engagement and allegiance” in the trial, said panelist Jess Fiedorowicz, PhD, chief of the Department of Mental Health at The Ottawa Hospital.

Lykos collected long-term follow-up data. However, the FDA said those results may be unreliable because a quarter of participants never completed the study, and many used other therapeutic drugs in the interim, which could skew the results.

The Institute for Clinical and Economic Review (ICER), a nonprofit that examines the costs and effectiveness of drugs, released a report ahead of the advisory panel meeting saying that there is “insufficient” evidence that the therapy would benefit patients. Other groups, like the American Psychiatric Association, urged regulators to closely monitor patients and drug dispensing.

Farchione said that while some of the flaws in the data collection could have been avoided, she acknowledged that the agency created robust guidelines for designing robust psychedelics studies years after Lykos began its trials. Companies that are running current and future clinical trials may have a better roadmap to follow.

“We’ve been learning as we go,” Farchione said.

Safety Concerns About MDMA

The FDA’s main role is to set guidelines for safe and effective drug use. The agency said that if Lykos’ therapy were approved, it would implement a special safety program called a Risk Evaluation and Mitigation Strategy (REMS).

REMS would require that MDMA be given only in certain qualified healthcare spaces, that multiple certified healthcare providers be present during treatment, and that patients be monitored afterward. If people are discharged from the health center too soon after treatment, they could be vulnerable to falling, wandering off, or otherwise behaving unsafely.

In the clinical trials, the major adverse event was increased blood pressure and heart rate in the treatment group. Some of the panelists noted that the company didn’t collect enough data on cardiovascular outcomes to know exactly what the risk of MDMA use was.

Lykos also failed to collect information on the abuse potential of a drug that generates feelings of euphoria and elevated mood.

Additionally, the clinical trials included mostly White participants. Some panelists noted that the safety and efficacy could differ in non-White groups.

Reports of Misconduct During the Trials

During the trials, two therapists were in the room with the participants, but only one was required to be licensed. In 2022, a trial participant who received the MDMA treatment was sexually abused and assaulted by a licensed therapist and her husband, who was not licensed.

The panelists discussed whether it would be safer to have two fully licensed therapists in the room with each patient, to avoid a power dynamic that might hinder one from intervening in the case of misconduct by the other.

The quality of the psychotherapy is perhaps the most important part of MDMA-assisted therapy. But the FDA doesn’t oversee the therapists themselves—that’s largely the job of state licensing boards and other groups. The FDA can say that MDMA must be given alongside therapy, but that’s about the extent of the agency’s oversight, according to Farchione, director of the FDA’s psychiatry division.

“We don’t regulate psychotherapy, and we don’t really have any say in the design or the implementation of the particular therapy that is going to be used,” Farchione said.

The Multidisciplinary Association for Psychedelic Studies, the sponsor of the clinical trials, created a training manual to guide therapists through the treatment. The manual says the main therapeutic goal is to tap into patients’ “inner healing intelligence” and explains that people on MDMA may have “spiritual experiences” and other “transpersonal experiences that might transcend conventional Western concepts of consciousness and its relationship to the physical body.”

A citizen petition to the FDA asked that the public comment period be extended, citing various safety concerns. The petition states that “directing patients to let go of boundaries is not consistent with contemporary trauma-informed practice, which emphasizes building personal boundaries and increasing a sense of control in patients who have experienced trauma.”

There have been no studies specifically comparing how the guidance in the manual compares to other kinds of psychotherapy.

Sarah McNamee, a trial participant, submitted a public comment stressing that using a drug that can amplify experience and suggestibility also increases psychotherapy’s potential for harm. She said her therapist encouraged her to be a “representative of the movement to legalize MDMA therapy.”

“At the same time that I was turning into a firm advocate of MDMA therapy, I was also relentlessly suicidal and was clinically decompensating in a, frankly, spectacular way,” McNamee wrote.

A Learning Lesson for Psychedelics-Assisted Psychotherapies

Walter Dunn, MD, PhD, an assistant clinical professor of psychiatry at the University of California Los Angeles, was the only panelist to vote in favor of the Lykos therapy in both votes. Still, he raised concerns about Lykos being the “sole gatekeepers” of the training that psychotherapists must complete to administer the company’s MDMA-assisted therapy. Most of the critical comments about the therapy seemed to be directed at the company itself, he added.

“If we’re able to disentangle the two, then I think it would provide more assurance about this being rolled out in a safer manner,” Dunn said.

Designing a two-factor study, separately testing the effects of the MDMA and the psychotherapy, would make for a stronger study, several panelists agreed.

“The way that it is presented in the application makes it impossible to disentangle the two—MDMA is not administered without the psychotherapy, and the psychotherapy is really vague. It seems like it was not standardized, and that makes it really hard to determine how effective it is and how safe it is for patients in a really vulnerable state when they’re under the influence of MDMA,” said panelist Melissa Barone, PsyD, a trauma recovery psychologist at the VA of Maryland.

Lykos is the first company to put a psychedelic-assisted therapy candidate up for review by the FDA. Other companies are testing the use of psychedelics like psilocybin, ketamine, and LSD to treat mental health conditions like treatment-resistant depression, anxiety, and anorexia nervosa. Despite the unfavorable outcomes, the FDA meeting provided learning lessons for other companies in the psychedelics-assisted therapy space.