MDMA Therapy Inches Closer to Approval

MDMA-assisted therapy seems to be effective in reducing symptoms of post-traumatic stress disorder, according to a study published on Thursday.

The research is the final trial conducted by MAPS Public Benefit Corporation, a company that is developing prescription psychedelics. It plans to submit the results to the Food and Drug Administration as part of an application for approval to market MDMA, the psychedelic drug, as a treatment for PTSD, when paired with talk therapy.

If approved, “MDMA-assisted therapy would be the first novel treatment for PTSD in over two decades,” said Berra Yazar-Klosinski, the senior author of the study, which was published in Nature Medicine, and the chief scientific officer at the company. “PTSD patients can feel some hope.”

PTSD affects about 5 percent of the adult population of the United States each year. But conventional therapies and medications only help, at best, around 50 percent of patients, said Dr. Stephen Xenakis, a psychiatrist and the executive director of the American Psychedelic Practitioners Association, who was not involved in the study.

“My clinical experience is that too many men and women have lost hope with conventional treatments and therapies and feel the only ‘out’ for them is committing suicide,” Dr. Xenakis said. “We need to do something more to help them, and MDMA-assisted therapy offers a new, potentially lifesaving option when done thoughtfully and professionally.”

MDMA, also known as Ecstasy or Molly, has been an illegal substance since 1985, when the Drug Enforcement Administration classified it as a Schedule 1 drug, placing it in the highest category for controlled drugs that the agency deems of no medical use and that have a high potential for abuse.

Before that, MDMA was administered by an estimated hundreds of therapists in North America and Europe for couples counseling, personal growth and to address trauma.

“The big tragedy to point out is that it was pretty clear in the late 1970s and early 1980s that MDMA had incredible therapeutic potential,” said Rick Doblin, founder of the Multidisciplinary Association for Psychedelic Studies (MAPS), a nonprofit group that owns MAPS PBC. “All the suffering since then, because MDMA was criminalized, is enormous.”

MAPS has been advocating the legalization of MDMA-assisted therapy since 1986, and supporting research of its use in treating PTSD since 2001. The Heffter Research Institute, another nonprofit group, has been doing the same for psilocybin, the active ingredient in magic mushrooms, since 1993.

The F.D.A. in 2017 granted “breakthrough therapy” status to MDMA-assisted therapy as a treatment for PTSD. The designation allows the development of promising experimental drugs to be fast-tracked. Psilocybin-assisted therapy for treatment-resistant depression was granted breakthrough status in 2018.

The 104 participants in the new study had been diagnosed with moderate to severe PTSD and had lived with the condition for an average of 16 years. They included victims of childhood trauma, combat veterans, survivors of sexual assault and others. Many had a history of suicidal thoughts and also suffered from comorbidities such as depression and alcohol use disorder.

Each participant worked with a two-person therapy team and received three 90-minute preparatory, talk therapy sessions followed by three treatment cycles, spaced one month apart. Each consisted of an eight-hour experimental session in which the participant took either MDMA or a placebo paired with talk therapy, and then attended three 90-minute talk therapy sessions.

During the experimental sessions, 53 participants were given MDMA and 51 were given an inactive placebo. Neither the therapists nor the participants were informed which patients had received the MDMA.

The participants in the group that were given MDMA experienced significantly greater reductions in their PTSD symptoms compared with those in the group that were given a placebo, according to the research article.

By the end of the study, 86.5 percent of people in the MDMA group achieved a measurable reduction in severity of symptoms, researchers reported. About 71 percent in the MDMA group improved enough that they no longer met the criteria for a PTSD diagnosis. Of those who took the placebo, 69 percent improved and nearly 48 percent no longer qualified for a PTSD diagnosis.

The findings were similar to the results of the first Phase 3 study of MDMA-assisted therapy for PTSD, published in Nature Medicine in 2021. For the 90 participants in that study, 67 percent in the group given MDMA no longer qualified for a PTSD diagnosis two months after treatment, compared with 32 percent in the placebo group.

One notable difference in the most recent study was the diversity of participants, said Jennifer Mitchell, a neuroscientist at the University of California San Francisco and the lead author of both studies.

More than a quarter of the participants in the new study were Hispanic or Latino and about 34 percent were nonwhite, whereas about 9 percent of participants in the 2021 study were Hispanic or Latino and 22 percent were nonwhite.

“We worked long and hard to get a study population that’s more in line with the general population with PTSD,” Dr. Mitchell said. “This isn’t just privileged people with lots of time and resources.”

The increase in participant diversity coincided with an increase in the number of therapists of color, to 28 percent in the new study, up from 11 percent in 2021. MAPS PBC said it also offered participants transportation to and from study sites as well as stipends to make up for lost wages or to cover child or elder care.

The diversity of participants is “certainly an improvement over prior studies,” said Albert Garcia-Romeu, a psychopharmacologist at the Johns Hopkins University School of Medicine who was not involved in the research. But he added that “it will be critical to see more Black and Indigenous folks enrolled, considering the substantial health disparities these groups face.”

As in previous studies of MDMA-assisted therapy, the treatment was generally well-tolerated, according to the data presented about adverse events. Common side effects, primarily for those in the MDMA group, included muscle tightness, nausea, decreased appetite and sweating.

Two participants in the MDMA group and one in the placebo group experienced serious suicidal ideation during the study, but no suicide attempts were reported.

“People in both groups had certain adverse events that would be concerning, like suicidality, at comparable rates, though it’s notable that most people in the study were already struggling with those challenges beforehand,” Dr. Garcia-Romeu said.

Seven participants overall also experienced cardiovascular issues, including faster heartbeats. According to Dr. Paul Summergrad, a professor of psychiatry at Tufts University School of Medicine who was not involved in the research, while these events “were generally not severe,” they might indicate that a cardiologist should evaluate older patients or ones with known heart problems before treatment with MDMA.

MAPS PBC said it had worked closely with the F.D.A. to determine the study methods and the number of participants needed to assess the safety and efficacy of the new treatment.

Most participants correctly guessed whether they had received a placebo or MDMA. This is a typical challenge across psychiatry research and is something “the authors acknowledge and did everything possible to mitigate,” said Dr. Steven Zalcman, chief of the adult pathophysiology and biological interventions development branch at the National Institute of Mental Health, who was not involved in the research.

The researchers are now working on a follow-up study examining the long-term durability of the effects of MDMA-assisted therapy. Findings from Phase 2 studies sponsored by MAPS indicated that the benefits lasted at least 12 months for most participants who received the drug.

MAPS PBC plans to submit a new drug application to the F.D.A. seeking approval for MDMA-assisted therapy. The agency, which does not comment on pending drug reviews, could reach a decision within a year.

Some outside experts said they did not believe the study’s results would meet the F.D.A.’s criteria for approval.

“The benefits in the active group were really not much greater than the benefits in the placebo group,” said Dr. Allen Frances, a professor emeritus of psychiatry at Duke University. “MDMA treatment would add huge costs to the treatment system while providing only a small, specific benefit — and thus result in a massive misallocation of already very scarce resources.”

Dr. Akua Prieto Brown, the medical director of Alchemy Community Therapy Center in Oakland, Calif., who also was not involved in the study, criticized this “scarcity mind-set,” however, and said that the focus for health care professionals should instead be “on increasing treatment options for a condition that is notoriously difficult to treat.”

Disagreements among mental health practitioners are to be expected, Dr. Xenakis said, adding that “tectonic shifts of this dimension are disruptive and can produce more fractures among the professionals than agreement.”

Federal approval for MDMA-assisted therapy would also mean the drug would have to receive a less serious ranking for controlled substances by the D.E.A. and from states.

Therapist training is another potential bottleneck. The company already oversees its own therapist education program and is working with other partners, including universities, to increase training.

The specific standards and requirements that the F.D.A. might seek from prescribers, and what the agency would outline for the labeling instructions of MDMA-assisted therapy, are still open questions, said Amy Emerson, the chief executive of MAPS PBC.

“Drug-assisted therapy hasn’t been approved before, so there’s not a lot of precedent,” she said.

The company has not yet set a price for the drug, Ms. Emerson said, and it will not manage how much the therapy component will cost.

But it is contacting insurance companies, Medicaid and Medicare to try to secure coverage, Ms. Emerson said. The group is also working on patient access programs to help those who do not have coverage and who cannot pay out of pocket to receive discounts or even free treatment.

Given the hurdles that still lay ahead, “it feels a bit too early to really celebrate,” Dr. Doblin said. “But it’s been a long, long process, and it’s amazing that we are this far.”