The FDA is considering approving MDMA, or ecstasy, to treat PTSD, but its future is uncertain.
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The decades-long effort to bring the psychedelic drug MDMA into mainstream medicine is nearing its end, but instead of celebrating, supporters are questioning whether the treatment will be available anytime soon.
Last week, advisers to the U.S. Food and Drug Administration pored over flaws and missteps in the studies and overwhelmingly rejected evidence supporting MDMA as an effective treatment for post-traumatic stress disorder
It was a grim moment of public reflection on the future of the drug and a frustrating moment for those involved in psychedelic research.
“It feels like these data are really underserved,” said Ingmar Gorman, a psychologist and investigator on the MDMA clinical trial, which came under intense scrutiny last week. “We always hope that if we do science and do it correctly, the data will speak for itself.”
The advisory committee’s rejection of the drug also raised concerns about the future of other psychedelics currently being studied for their therapeutic potential, disrupting the market and generating a lot of negative press. Investors and scientists have doubled down on the industry in recent years, pouring billions of dollars into drugs like psilocybin, ketamine and LSD.
Industry insiders do not view the FDA dispute as an existential threat to the broader psychedelics agenda. But Frederick Barrett, director of the Center for Psychedelic and Consciousness Research at Johns Hopkins University, said some of the concerns raised about the study could provide lessons for future efforts to win FDA approval.
“We have to look inward at all the research that’s going on and make sure we double down on the most rigorous methods possible,” he said.
But most importantly, he said the FDA’s troubles were an indictment of the drugmaker, Lykos Therapeutics, for missteps in conducting its trials. “There was a lot of disappointment in the committee; [the sponsor] presents such a vulnerable application.
What happens to MDMA now?
Despite the poor performance, the agency is still likely to approve the treatment against the advice of its advisory committee.
In fact, Dr Srinivas Rao thinks outright rejection is “very unlikely”.
Instead, the agency may establish a very strict set of safeguards for the drug’s use or require another clinical trial before approval.
“It’s a bit like flipping a coin,” said Rao, CEO of Atai Life Sciences, a biotech company that invests in mental health and psychedelics. “Active opposition to the committee is worrying. On the other hand, there is also a lot of pressure to get approval.
Gorman said the panel ignored key points in the research supporting MDMA-assisted treatment and appeared to be influenced by yet-to-be-proven allegations of ethical misconduct that FDA staff said should not be included in their recommendations.
“Now my concern is it’s going to become politicized, right?” he said. “What will the FDA do? Will they object to the advisory committee’s vote?”
Matthew Johnson believes MDMA will eventually be approved, even if it doesn’t happen by the FDA’s August deadline.
“That does seem like a tall order,” said Johnson, a senior researcher at the Sheppard Pratt Center of Excellence for Psilocybin Research and Treatment, a mental health provider. “You’re taking a risk, especially if something goes wrong.”
In the long term, some researchers believe this is actually the level of soreness the field needs, quelling the hype and forcing conversations about the riskier aspects of this treatment.
“I don’t think this is a setback for the field. It’s certainly for Lycos,” said Alan Davis, director of the Center for Psychedelic Research and Education at Ohio State University. “The message of this rejection is that research needs to be conducted more thoughtfully.”
What went wrong with the MDMA trial?
The application for Lykos, a pharmaceutical company incubated by the Multidisciplinary Association for Psychedelic Studies (MAPS), arrived at the FDA amid controversy.
Former trial participants claimed that no adverse events were reported – including feelings of suicide after treatment – and that bias among those conducting the trials skewed the results. These concerns were amplified by a recent report questioning the validity of the data, with some at public hearings accusing the study sponsors of being a “treatment cult.”
Informed that the FDA was actively investigating these claims, committee members then came to their own conclusions as to their veracity.
“In our day and age, it’s understandable that who wants to side with people in clinical trials who claim to have been harmed? That looks bad,” Gorman said. “I think this has been transferred to the FDA advisory panel.”
Aside from the ethics charges that Lykos denies, some of the consultants’ major sticking points may not actually be that big of an issue for federal regulators.
For example, the panel focused on “functional unblinding”—where many trial participants can tell whether they received the study drug instead of a placebo.
But that’s not necessarily a deal breaker, Johnson said. He points out that this concern is not unique to psychedelics. “This is common with psychoactive drugs used in psychiatry,” he said. “There will not be any perfect solution to this blinding problem.”
Another blow to the app has been criticism of specific talk therapies used alongside the drug. Consultants are troubled by what some of them consider an “experimental” approach.
Dr. Jerry Rosenbaum rejects this characterization and says the therapy has many core elements of evidence-based therapies.
“If anything, it’s a universal therapy,” said Rosenbaum, director of the Center for Psychedelic Neuroscience at Massachusetts General Hospital, who argued on behalf of Lykos that more PTSD treatments are needed.
Goleman acknowledged that Lykos therapy is more “open-ended” and not as targeted as other approaches such as cognitive behavioral therapy. However, he said there have been extensive efforts to ensure therapists adhere to the protocols – a fact that was overlooked in the committee’s discussions.
He said the whole idea that the treatment process was not standardized, thereby undermining the study results, was “completely wrong.”
Ultimately, Rosenbaum believes this back-and-forth distracts from the fact that the FDA doesn’t even regulate psychotherapy. “People have some freedom to change treatments.”
Not just data, but also “atmosphere”
In its application, Lykos describes MDMA as a catalyst for the therapeutic process, which is why it has received so much attention. However, this is not expected to be much of a hindrance to other psychedelics.
“The rest of us are working on molecules that don’t require the same level of treatment,” said Kabir Nath, CEO of Compass Pathways, a biotech company conducting Phase III clinical trials of psilocybin.
Johnson said relying on a “special” treatment, one that sounds “new age,” makes MDMA-assisted therapy an increasingly difficult sell.
In his view, this only adds to a “vibe” that has seeped into the wider discussion, largely based on widely publicized accusations that some people involved in the trial ignored disturbing events and dismissed the study as Think of it as a “movement” rather than a movement.
“There’s a general concern about a cult atmosphere in this space… ‘We’re awakening humanity,'” he said.
Although he had no direct knowledge that this would affect the study results (some participants insisted that it did), the perception alone was enough to spark distrust. “You need to do everything you can to let people know that you don’t have this religious fervor and that you’re following the data and the evidence.”
The fact that about 40% of the trial participants had tried MDMA before taking part in the study only fueled speculation about whether the findings were credible.
Certain oversights in the trial were harder to ignore. The researchers did not collect data on participants’ experiences with the drug, such as euphoria (information FDA staff need to weigh potential for abuse), nor did they perform laboratory work related to the drug’s safety.
While these were legitimate errors, Barrett said he was confused by some of the comments he heard: The consultant seemed to indicate little was known about the drug’s toxicity, even though it had been well-studied before this trial. In his view, they were unfounded fears that patients would seek out illegal drugs such as cocaine after taking ecstasy.
“It’s a little nerve-wracking for me,” he said. “I don’t understand where comments like that come from.”
Given all the controversy, OSU’s Alan Davis wasn’t surprised by the level of resistance to Lykos’ application.
“Personally, I don’t think we fully understand and understand all of these potential issues yet,” Davis said. “More importantly, we have absolutely no infrastructure in the United States to deal with the specific types of risks that can arise with psychedelic treatments.”
Lykos’s rocky journey may offer some lessons to others in the psychedelic field.
Nath said his company, Compass, has no plans to change its psilocybin trial design or protocol, but it does reinforce the need to show “consistency” in the treatment’s ingredients and collect data on side effects.
“This will obviously impact market sentiment,” he said. “It won’t have any impact on our trajectory from a development or regulatory perspective over time.”
