FDA advisors voted against MDMA therapy – researchers are still fighting for it

Some 13 million Americans struggle with post-traumatic stress disorder (PTSD). Existing therapies only bring relief for a fraction of patients, and new treatments are sorely needed, according to psychiatrists wrestling with the scale of the problem. So, there was distinct disappointment when an advisory committee at the US Food and Drug Administration (FDA) voted earlier this month against a therapy that many had hoped could offer the first new treatment for PTSD in 25 years.

A number of experts who study psychedelics have since spoken out in support of MDMA-assisted therapy for PTSD and have sharply criticised the recommendations of the FDA's Psychopharmacological Drugs Advisory Committee. But some are still optimistic that the treatment might be approved when the FDA delivers its final decision in August.

While MDMA, also commonly known as ecstasy or molly, is listed as a Schedule 1 controlled substance in the US and so is illegal to use outside research, there has been a growing number of studies suggesting that when used with psychotherapy it could have potential for treating PTSD and some other mental health conditions.

Ahead of the meeting, FDA approval of MDMA-assisted therapy for PTSD seemed likely, says Sandeep Nayak, an assistant professor of psychiatry at Johns Hopkins University, who investigates psychedelics as treatments for substance use and mood disorders. About two-thirds of people who received three sessions of MDMA and talk therapy no longer qualified for a PTSD diagnosis at the end of two Phase 3 clinical trials.

It's an outcome that is "almost double that of existing medications", says Gül Dölen, a neuroscientist at the University of California, Berkeley, who researches the mechanisms of how psychedelics achieve therapeutic effects. "What's more, [the treatment] led to durable improvements in these patients lasting at least six months." 

About half of people who enroll in current gold standard PTSD treatments drop out, which is "absurd", says Loree Sutton, a psychiatrist and retired Brigadier General in the US Army. She says new treatments are essential. "We have to do better." 

"Even if there are risks, we've got to figure this out, because we cannot not let this treatment be available," adds Rachel Yehuda, a professor of psychiatry and neuroscience at the Icahn School of Medicine at Mount Sinai who has conducted studies on the effects of MDMA-assisted therapy for PTSD. "Without it, we're just leaving too many people in suffering that they don't need to be in, and that is not right."

The FDA is currently considering an application from California-based drug company Lykos Therapeutics for using MDMA capsules taken in conjunction with therapy in the treatment of PTSD. In the recent FDA advisory meeting, committee members cited apparent flaws in study design and data collection.

The nine-hour hearing concluded with committee members voting 9-2 that the available data do not show "that the drug is effective" for PTSD, and voting 10-1 that the benefits of MDMA do not outweigh the risks.

Critics point out that just one member of the FDA advisory committee had expertise in psychedelics, and argue that the committee may have misunderstood aspects of the treatment.

"There are so many different issues and angles to this dumpster fire, which indeed I would say it is," says Franklin King, a psychiatrist at Mass General Hospital and Harvard Medical School, who is overseeing a study of psilocybin-assisted therapy for irritable bowel syndrome and another of MDMA-assisted therapy for fibromyalgia. "The biggest issue is that the advisory committee members really showed a kind of astounding lack of knowledge about the subject matter."

The panel spent some time, for example, debating whether it should be voting on efficacy and safety of "the drug" or the drug-assisted therapy model that the clinical trials investigated. Excluding the therapy from the efficacy evaluation "doesn't make sense, scientifically speaking", says Eduardo Schenberg, director of the Instituto Phaneros, a psychedelic research and therapy group in São Paolo, who has conducted research into MDMA-assisted psychotherapy for victims of sexual abuse with severe PTSD.

The BBC contacted the 11 committee members asking if they had any response to the criticisms raised by researchers quoted in this article. One member, Kim Witczak, a drug safety advocate and the committee's consumer representative, replied. "This is a new territory and it must be treaded carefully," she wrote in an email. "The time to be cautious is now, not afterwards."

The committee's vote is non-binding, but it could influence the FDA's decision to approve the treatment, which will be announced by August 11. Historically, the FDA has declined to approve 67% of drugs that received a negative vote by its advisory committees. 

An FDA spokesperson declined an interview request, citing the application's pending status. But below are the main areas of debate raised by the committee surrounding the treatment, and why many experts believe it might still be approved.

The blinding problem

From the start of the meeting, committee members expressed concern about whether they could trust the trials' positive results. A primary issue was functional unblinding, or the ability of participants to tell whether they received a placebo or active drug – which has the potential to influence the outcome captured in the data. More than 90% of people in the MDMA group and 75% in the placebo group correctly guessed their treatment arm in the second Phase 3 trial.

Functional unblinding has been debated in the scientific literature for decades, Sutton says, and occurs particularly in interventions that produce strong effects. But it's especially pronounced in studies of drugs with psychoactive effects. "We all struggle with these design problems," says Harriet de Wit, a professor of psychiatry and behavioural neuroscience at the University of Chicago who has conducted extensive research on MDMA and other psychoactive drugs. "They're insoluble."

Several committee members raised concerns that talk therapy was not standardised across clinical trial sites

The FDA is aware of the challenges and intricacies of MDMA-assisted therapy, says Amy Emerson, the chief executive of Lykos Therapeutics. She says the agency has been working with her company and its parent non-profit, the Multidisciplinary Association for Psychedelic Studies (Maps), on trial design for around 20 years.

"It's almost like this came as a total surprise that this was the study design, when in fact the FDA approved this design," says Natalie Gukasyan, an assistant professor of psychiatry at Columbia University Irving Medical Center, whose research focuses on understanding and optimising the safety and efficacy of psychedelic-assisted therapy.

According to Nayak, the FDA itself has said that a trial can be well-controlled even with unblinding. In the case of MDMA-assisted therapy, "I do not think unblinding alone could explain the magnitude and durability" of the findings, he says. In his view, the treatment seems "efficacious".

In the committee meeting, however, Paul Holtzheimer, the deputy director of research at the US Department of Veterans Affairs' National Center for PTSD and a professor of psychiatry and surgery at Dartmouth Geisel School of Medicine, said he was "unconvinced by the acute efficacy of the treatment", as demonstrated by the data reported in the Phase 3 trials. "The difference between the active and the placebo group is statistically significant by [the authors'] analyses, but relatively small enough that I think the role of expectation bias cannot at all be discounted as potentially accounting for a lot of that difference."

Another issue the committee raised was the fact that 40% of participants had taken MDMA before – mostly on the order of two to four times in the past 10 years, Emerson says. The committee expressed concerns that people who had sought out the illegal drug likely had a more favourable view of it going into the trial, which could introduce positive bias.

But the data reported in the studies revealed no statistical differences between those who had and had not tried MDMA before, Emerson says. People who have tried MDMA outside of a legal, medical setting are also a "normal part" of the population, she adds, so "it felt valid to enroll that group".

Strengths and liabilities

Evidence suggests that MDMA-assisted and other psychedelic-assisted therapies work by reopening critical periods – finite windows of malleability when the brain is primed to learn new things. Dölen has found that critical periods only reopen when a psychedelic drug is given in a particular setting. In the case of MDMA for treating PTSD, that setting is psychotherapy. This would explain why people who take MDMA at raves usually do not report spontaneous recovery from PTSD, Dölen says. And it probably also explains why clinical trial participants experienced such "remarkable" improvements: they are literally rewiring their brain.

Among the questions asked by the advisory committee, however, was why MDMA was not given to subjects on its own, without any therapy. Dölen believes this may betray a lack of current scientific understanding of how the treatment works. "Without the biological mechanism to ground them, I think the advisory committee felt a little insecure about believing the data from the clinical trials."

While psychotherapy falls outside the FDA's regulatory duties, it was the subject of much discussion in the committee meeting. Walter Dunn, a psychiatrist at the Veterans Administration Greater Los Angeles Healthcare System and the University of California, Los Angeles, and the FDA committee member who has studied psychedelics, said in the meeting that the use of psychotherapy is both the "greatest strength" and also the "greatest liability" of the treatment. Several committee members raised concerns that talk therapy was not standardised across clinical trial sites.

Lykos Therapeutics insists it took "significant steps" to ensure consistency. But as King points out, talk therapy in general is not regulated at the federal or state level. "There's professional organisations that set guidelines, but you're not prevented from deviating from them as long as you don't do anything unethical."

He adds that if talk therapy standardisation is "a deal-breaker issue, then it'll affect every psychedelic". 

The potential for MDMA therapists to abuse patients came up as well. One participant from the Phase 2 clinical trial did experience such a violation, which Lykos reported to the FDA, Health Canada and the trial's Intuitional Review Board.

"It's absolutely unacceptable that someone was harmed and there was sexual misconduct," says Emerson at Lykos.

However, while "very serious" and "very unfortunate", the issue of therapist misconduct falls to those who regulate practitioners, says Wim van den Brink, an emeritus professor of psychiatry and addiction at the University of Amsterdam. But it shouldn't be a reason to halt approval of an efficacious treatment, he says.

In future trials of psychedelic-assisted therapy, Gukasyan says, it might be preferable for pharmaceutical companies to work with professional societies to train and vet therapists, rather than oversee that part of the process themselves.

Gaps and accusations

The committee also raised questions about whether people who take MDMA in a clinical setting might develop an addiction afterward. Van den Brink says this is not based on reality: MDMA's primary effect is on serotonin, with a significantly lesser effect on the brain's dopaminergic system and little if any effect on the opiate system. People who take it too often also quickly develop tolerance due to serotonin depletion. "Here in the Netherlands, people have been using ecstasy for the last 40 years and we don't see anyone in addiction treatment for it," van den Brink says. "Most MDMA users take one or two MDMA pills once or twice per year."   

Although some side effects have been reported in MDMA-assisted psychotherapy, they have been deemed "largely transient and mild or moderate in severity", according to one systematic review of clinical trial studies. Most of those reported consisted of blurred vision, muscle tightness, decreased appetite and dilated pupils. In the Phase 3 trial, three participants experienced serious suicidal ideation during treatment, but they were split between those who received MDMA and the placebo. Seven participants also experienced cardiovascular issues such as faster heartbeats, suggesting that older patients or ones with known heart problems might need to consult a cardiologist before undergoing the treatment. 

It is important that regulators achieve clarity and consensus on how they understand and evaluate these issues moving forward – Natalie Gukasyan

Committee members also flagged a lack of certain data collected by Lykos, including electrocardiograms and liver function, and participant feelings of euphoria. It has led to a characterisation of the clinical trials as "flawed". According to Gukasyan, though, "every study will have limitations, so basically every study is flawed" if that logic is followed. 

Several members of the public also alleged in video or written testimony that clinical trial data were tampered with to appear more positive and to exclude adverse events. "I was just as concerned as anyone hearing those reports, and they'll have to be objectively evaluated," Sutton says. "But I have no reason to believe that there's been systemic malfeasance."

"Despite some very loud noise, we have yet to see any credible evidence that research misconduct occurred in Phase 3," King adds. He fears, however, the "air of controversy" may have influenced some committee members.

Lykos takes allegations of misconduct "very seriously," Emerson says, and investigates them all. The FDA is also conducting its own routine inspection process to validate its view of the data, she adds.

What happens next?

Despite the meeting's outcome, the experts who the BBC spoke to believe there is still a chance that the FDA will grant approval in August. Emerson also remains hopeful.

"The same things we needed to do before the [meeting] are the same things we need to do now, they're just a little more difficult and more public," she says. "We really believe in the FDA's ability to assess the information and go through their process."

Given the FDA's long involvement with the trial design, the strength of the data and all that's already known about MDMA, denying approval would "look a little ridiculous for the FDA", van den Brink says. "I don't think the FDA will follow [the committee's] advice."

A negative decision from the FDA would also likely impact on other studies of psychedelic-assisted therapy that are currently in the pipeline, Gukasyan says. "Though this is one drug from one company and others have handled their clinical trials differently, some of the concerns brought up at the advisory committee meeting are likely to affect nearly every other psychedelic [trial] – namely, the psychotherapy component and concerns about blinding," she says. "It is important that regulators achieve clarity and consensus on how they understand and evaluate these issues moving forward."

A rejection of MDMA-assisted therapy would also send "a very strong message" that psychedelic trials should focus on the effects of the drug alone rather than on the drug-therapy combination, King says – an approach that "fails millions of people".

"This whole episode only serves to reinforce the idea that anything that actually is a paradigm shift just doesn't fit into our regulatory system," he says.  

If the agency does wind up denying approval, van den Brink adds that the Netherlands could beat the US in becoming the first country to undertake a largescale, controlled rollout of MDMA-assisted therapy. (While Australia recognized MDMA as a medicine last July, its special access programme requires cumbersome permissions on an individual patient basis and only a few patients have received treatment, he says.)

Days after the FDA committee decision, a panel of Dutch experts issued a plan for a "naturalistic study" that, if approved, would provide MDMA-assisted therapy to 400 to 500 people with PTSD within the next five years. As van den Brink says, "We shouldn't leave patients with very serious problems on their own because a study is not perfect."

-bbc