MDMA as psychiatric treatment moves closer to US approval

The psychedelic drug MDMA, also known as ecstasy or molly, has passed another key hurdle on its way to regulatory approval as a treatment for mental illness. A second large clinical trial has found that the drug — in combination with psychotherapy — is effective at treating post-traumatic stress disorder (PTSD). The results allow the trial’s sponsor to now seek approval from the US Food and Drug Administration (FDA) for MDMA’s use as a PTSD treatment for the general public, which might come as soon as next year.

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“It’s an important study,” says Matthias Liechti, a psychopharmacologist who studies MDMA at the University of Basel in Switzerland, but who was not involved with the trial or its sponsor. “It confirms MDMA works.”

In June, Australia became the first country to allow physicians to prescribe MDMA for treating psychiatric conditions. MDMA is illegal in the United States and other countries because of the potential for its misuse. But the Multidisciplinary Association for Psychedelic Studies (MAPS), a non-profit organization in San Jose, California, has long been developing a proprietary protocol for using MDMA as a treatment for PTSD and other disorders. MAPS has been campaigning for its legalization — a move that could encourage other countries to follow suit.

In 2021, researchers sponsored by MAPS reported the results of a study¹ in which 90 people received a form of psychotherapy developed by the organization alongside either MDMA or a placebo. After three treatment sessions, 67% of those who received MDMA with therapy no longer qualified for a PTSD diagnosis, compared with 32% of those who received therapy and a placebo.

The results were widely hailed as promising, but the FDA typically requires two placebo-controlled trials before a drug can be approved. The results of a second trial, involving 104 further individuals with PTSD and published on 14 September in Nature Medicine², were similar to those of the original: 71% of people who received MDMA alongside therapy lost their PTSD diagnosis, compared with 48% of those who received a placebo and therapy. The drug seemed to work just as well in people who had other mental illnesses, such as depression, and in those who’d had PTSD for a long time. It also seemed to work equally well across racial and ethnic groups.

‘A communication lubricant’

Jennifer Mitchell, a neurologist at the University of California, San Francisco, who led both studies, says that one of the most promising things about the latest trial is the low drop-out rate: only 9% of participants left the study. Most were individuals who received the placebo, and thus were more likely to continue having symptoms. By contrast, a recent study³ comparing psychotherapies in veterans with PTSD reported drop-out rates of up to 56% for prolonged exposure therapy, a commonly used approach in which patients undertake the difficult task of addressing the traumatic event that triggered their condition.

MDMA doesn’t make the therapy process more “fun”, Mitchell says, but the drug seems to induce self-compassion in a way that other therapies don’t. She calls it “a communication lubricant” that helps people to recall traumatizing events and talk to their therapists without experiencing shame or horror.

“It’s nice to see it could be replicated,” Liechti says. Although the trials are small, he says, the immense improvement in symptoms makes the results statistically significant. But he adds that questions remain as to whether some people will need more than three treatment sessions, and whether the effects will last long-term.

A MAPS spokesperson says that the organization plans to seek formal FDA approval before the end of this year, and that because the agency has already designated MDMA as a ‘breakthrough therapy’ — a category for treatments that address serious or life-threatening conditions — it will be evaluated quickly. If approved, MDMA will no longer be strictly illegal in the United States, and researchers will be able to seek federal funding to pursue larger clinical trials of the drug and ask additional questions. Mitchell wants to study why some people don’t respond to MDMA, and whether taking it in certain contexts or alongside different types of therapy improves its effect.

Vaile Wright, senior director of health-care innovation at the American Psychological Association (APA) in Washington DC, says that the scale of the improvement in the MAPS trials is significant for a PTSD treatment. But she notes that MDMA is unlikely to be the solution for everyone. “I see this as one solution to a very complicated problem that needs multiple solutions,” she says. The APA has urged caution around the drugs, stating last year that there was a “lack of adequate scientific evidence to endorse the use of psychedelics” outside controlled trials.

Placebo concerns

Erick Turner, a psychiatrist at Oregon Health & Science University in Portland, says that the difference between the MDMA and placebo groups is impressive, but doubts that it is as big as it seems. Because MDMA produces an intense psychedelic experience, around 94% of people who received the drug and 75% of those who didn’t correctly guessed which group they were in. “That is not a blinded study,” Turner says.

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‘Blinding’ participants and providers to who is getting the drug is particularly important in psychiatry trials, because people tend to feel better if they think they are taking an active drug. Responding to this criticism, Mitchell says that this happens with many drugs that work extremely well — people correctly guess which trial group they’re in because their symptoms are gone.

But even if MDMA is safe, Turner says, it doesn’t meet the FDA’s usual criteria for a well-controlled study. To partially address the placebo concern, the FDA approved a special protocol that MAPS used in this study: an independent evaluator who was not involved in the treatment session and who didn’t know whether a participant had received the drug. The evaluator examined each person before and after treatment to assess their improvement.

The FDA still has to work out how it will regulate the drug, given that MAPS has said MDMA should only be given in the context of therapy, both for efficacy and safety reasons. Mitchell says she worries about people trying MDMA on their own: it could be harmful to people with heart conditions, for instance. And it hasn’t been tested in people with a family history of schizophrenia, which could be triggered by the drug. If people have bad reactions to taking the drug when they are not in a controlled environment, she says, MDMA might regain the harmful reputation that led to it being banned in the first place.