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A key FDA panel voted down approving MDMA-assisted therapy to treat PTSD. pixdeluxe/Getty Images
  • An expert panel of the Food and Drug Administration reviewed two studies on MDMA-assisted therapy for the treatment of PTSD.
  • The studies showed that the therapy improved symptoms of PTSD over 18 weeks and lasted for several months after treatment.
  • Issues with the study design and safety led many committee members to vote against recommending the approval of this treatment right now.

A expert panel of the Food and Drug Administration (FDA) voted against recommending MDMA-assisted therapy as a treatment for PTSD.

Findings from two clinical trials presented at a public meeting on June 4 showed that MDMA-assisted therapy improved symptoms of PTSD over 18 weeks of treatment. These improvements appear to last for several months after the treatment period, researchers found.

However, the FDA meeting raised a number of ethical and safety issues about the two clinical trials that drug manufacturer Lykos Therapeutics used to make their case to the FDA’s Psychopharmacologic Drugs Advisory Committee.

When considering whether MDMA is effective in patients with post-traumatic stress disorder, the committee voted 2-to-9 against.

For the question of whether the benefits of MDMA, with FDA’s proposed risk evaluation and mitigation strategy (REMS), outweighs its risks for the treatment of PTSD, the committee voted 1-to-10 against.

Prior to the meeting, the FDA extended the public comment period, allowing more time for critics and supporters to weigh in on MDMA as a treatment for PTSD. Several veterans groups submitted public comments urging the FDA to approve MDMA-assisted therapy.

About 7% of veterans will experience PTSD at some point during their lifetime, compared to about 6% in the general population, according to the U.S. Department of Veterans Affairs. However, for some groups of veterans the rate is as high as 29%.

In the end, concerns about the trials outweighed the benefits of MDMA-assisted therapy seen in the trials.

“I think that some of the data was promising, but given that 40% [of participants] had previously used MDMA” may have impacted the efficacy and durability of the treatment, said Elizabeth Joniak-Grant, PhD, a sociologist and qualitative research consultant at the University of North Carolina, Chapel Hill, said in the meeting.

In addition, “I am concerned with the lack of diversity and what that would mean for the general population,” she added.

This research is “on the right track,” Walter S. Dunn, MD, PhD, assistant clinical professor at University of California Los Angeles, said during the meeting. “A tweak here and there can address some of the safety concerns we brought up.”

“We are in dire need of new treatments for PTSD … and this has the potential to make a difference,” he added.

MDMA is a synthetic oral drug that acts as a stimulant and a hallucinogen. It was first synthesized in 1912 and was used as a treatment by some psychiatrists and therapists until the mid 1980s.

Around that time, MDMA became a popular street drug, known as “ecstasy” or “molly.” This led to the Drug Enforcement Agency (DEA) classifying it as a Schedule I drug. This restricted use of the drug as a treatment for psychiatric diseases.

However, in 2017 the FDA granted MDMA breakthrough therapy designation for its use with psychotherapy for PTSD. This allowed additional clinical trials to be carried out.

“MDMA is not a new drug, and while it can be misunderstood due to its illicit counterpart, it actually has a well-documented history in the psychiatric field,” Amy Laverdiere, program lead at Lykos, said during the meeting.

She explained that MDMA is thought to work by “[catalyzing] the effectiveness of psychotherapy by facilitating memory recollection and extending the patient’s window of tolerance for revisiting distressing thoughts or experiences.”

Studies also show that MDMA improves self-awareness and enhances the therapeutic relationship between a patient and their therapist, Laverdiere said.

In 2020, an estimated 13 million Americans had PTSD, not all of them veterans.

“Although PTSD is associated with exposure to deployment and combat, consequent to a number of potential experiences, civilian trauma is actually more common,” Jerry Rosenbaum, MD, director of the Center for Neuroscience of Psychedelics at Massachusetts General Hospital Research Institute, and professor of psychiatry at Harvard Medical School, said during the meeting.

“Individuals exposed to sexual violence, for example, or an unexpected death in the family or a life-threatening traumatic event may also develop PTSD,” he said.

Current treatment options for PTSD include psychotherapy and serotonin reuptake inhibitors (SSRIs).

Rosenbaum said while psychotherapy can lead to clinically meaningful reductions in PTSD symptoms, many patients stop therapy due to increased distress. In addition, there is limited access to this type of treatment.

Clinical studies show that SSRIs improve symptoms of PTSD more than placebo, although fewer than 60% of people with PTSD benefit from these drugs, and less than 30% of patients have full remission of their symptoms, according to the FDA’s briefing document.

In addition, “several pharmacologic agents are used off-label and concurrently, despite lacking evidence of efficacy and not being approved for the PTSD indication,” said Rosenbaum, “which speaks to the demand from prescribers for novel-indicated therapeutics to provide our patients new tools to alleviate symptoms.”

In the meeting, Lykos presented data from its two phase 3 clinical trials, named MAPP1 and MAPP2. In these trials, people with PTSD underwent three treatment cycles of MDMA-assisted therapy over 9 to 15 weeks. Treatments were scheduled 3 to 5 weeks apart.

On average, people undergoing MDMA-assisted therapy saw a greater improvement in PTSD symptoms over 18 weeks, compared to the placebo group.

People taking MDMA also experienced functional improvements such as being able to pursue personal goals and maintain strong relationships.

The data also show that 67% of participants taking MDMA no longer met the diagnostic criteria for PTSD after 18 weeks, compared to 33% of the placebo group. Also 33% of participants treated with MDMA were in disease remission after three sessions, versus 5% in the placebo group.

“In this combination treatment, the acute effectiveness of MDMA facilitates the psychotherapy — strengthening the therapeutic alliance, facilitating the patient’s development of insights and tools, and continuing to cultivate long after the acute effects are worn off,” Kelley O’Donnell, MD, PhD, research assistant professor of psychiatry at NYU Grossman School of Medicine and director of clinical training at the NYU Langone Center for Psychedelic Medicine, said during the meeting.

In the trials, certain adverse events occurred more often in the MDMA group than the placebo group, including muscle tightness, decreased appetite, nausea, excessive sweating, and feeling hot or cold. People treated with MDMA also had a short-term increase in blood pressure and heart rate.

Researchers did not see an increase in suicidal thoughts in people taking MDMA, although Lykos’ documents for the meeting indicated that this is an “expected key risk in patients treated with [MDMA-assisted therapy].”

Tiffany R. Farchione, MD, director of the division of psychiatry in the office of neuroscience at the FDA, said the adverse events seen in the trials were consistent with the known effects of MDMA.

However, adverse events related to the potential misuse of the drug — such as euphoria or elated mood — were not adequately collected or reported, she said during the meeting.

“It is the lack of data collection on the subjective effects of MDMA that may have the greatest impact on our regulatory decision-making,” she said.

Further, the effects of MDMA can last for several hours, which can leave patients impaired and vulnerable during that time.

As a result, “if this product were to be approved, we believe the REMS [FDA’s risk evaluation and mitigation strategy] will be necessary to ensure safe use, and to mitigate the risk of serious harm that can result from patient impairment,” said Farchione.

The FDA’s REMS proposal included requirements that patients be informed about the risk of impairment that can result from MDMA use, as well as ensuring that two or more healthcare providers are at the clinic to monitor patients for at least 8 hours after treatment.

Another key concern cited in the FDA review released last week was the potential for “functional unblinding” of participants. The studies were designed as double-blind trials, which means participants are not supposed to know whether they received the MDMA capsule or a non-active placebo.

However, the effects of MDMA are so distinct that many trial participants in the MAPP2 study correctly guessed whether they received MDMA or placebo, the FDA review showed.

This unblinding could affect their treatment. It is also a common problem with clinical trials of psychedelics such as MDMA, LSD and psilocybin, and psychoactives such as cannabis.

“We rely on data from adequate and well-controlled trials to provide the basis for a substantial evidence of effectiveness,” David Millis, MD, clinical reviewer in the division of psychiatry at the FDA, said during the meeting.

“Among other characteristics, to be considered adequate and well-controlled, a study must incorporate a design that permits valid comparison with a control condition, and measures must be taken to minimize bias,” he said.

He added that the FDA had suggested that Lykos use active comparators — such as niacin or low-dose MDMA — instead of placebo in the trials. The company and the FDA, though, did not reach an agreement on how to handle the blinding for the studies, he said.

The FDA’s review pointed out other limitations of the trials. For example, around 25% of participants dropped out between the parent study and the follow-up visit. Further, some participants also had other treatments for PTSD. These could affect the study results.

An expert panel of the Food and Drug Administration reviewed finding from two phase 3 clinical trials looking at the use of MDMA-assisted therapy for the treatment of PTSD.

The studies showed that symptoms of PTSD improved in people who took MDMA with psychotherapy, compared to those who took an inactive placebo. People who took MDMA in combination with psychotherapy also had improvements in their daily functioning.

Committee members raised concerns about the design of the trial, safety concerns of MDMA-assisted therapy, and ethical concerns with the trial. As a result, a majority of members voted against recommending approval of this as a treatment for PTSD.