The psychedelic drug MDMA is near the end of a decades-long effort to enter mainstream medicine but instead of celebrating, supporters now find themselves wondering if the treatment will actually make it to market anytime soon.
Last week, advisers to the Food and Drug Administration pored over shortcomings and missteps in the research and overwhelmingly rejected the evidence supporting MDMA as an effective treatment for post-traumatic stress disorder
It was a harsh public reckoning over the drug’s future and a deflating moment for those involved in psychedelic research.
“It really doesn't feel like the data was given its proper due,” says Ingmar Gorman, a psychologist and investigator in the MDMA clinical trials that came under intense scrutiny last week. “The hope was always, if we do the science and we do the science right, the data will speak for itself.”
The advisory committee’s rejection of the drug also raised fears about the future of other psychedelics currently being studied for their therapeutic potential, rattling the market and generating a flood of bad press. Investors and scientists have doubled down on the sector in recent years and funneled billions into drugs like psilocybin, ketamine, and LSD.
Insiders don’t view the FDA dust-up as an existential threat to the broader psychedelic agenda. But certain concerns raised about the research can offer lessons for future efforts to win FDA approval, says Frederick Barrett, director of the Johns Hopkins Center for Psychedelic and Consciousness Research.
“We have to turn inward and look at all of the studies that are ongoing right now and make sure that we are doubling down on the most rigorous methods,” he says.
More than anything though, he says the troubles at the FDA are an indictment of how this drug maker, Lykos Therapeutics, ran the trials. “There’s a lot of disappointment in the committee, but there's also a lot of disappointment in [the sponsor] for putting forward such a vulnerable application."
What could happen to MDMA now?
Despite the negative showing, it’s not beyond the realm of possibility that the agency still approves the treatment against the recommendation of its advisory committee.
In fact, Dr. Srinivas Rao thinks there’s a “low probability” of an outright rejection.
Instead, the agency could come back with a very strict set of safeguards and requirements to do further research once it's on the market, or the drug maker could be asked to do another clinical trial before FDA approval.
“It’s a bit of a coin flip,” says Rao, CEO of Atai Life Sciences, a biotech company invested in mental health and psychedelics. “Going against the committee that aggressively is fraught. On the other hand, there's a lot of pressure for this to get approved.”
Gorman says the panel overlooked key points about the research supporting MDMA-assisted therapy and seemed swayed by still-to-be-proven allegations of ethical misconduct that FDA staff said weren’t supposed to factor into their recommendations.
“Now my concern is that it becomes political, right?” he says “What’s the FDA going to do? Are they going to oppose the vote made by the advisory committee?”
Matthew Johnson thinks MDMA will eventually get approved, even if that doesn’t happen by the FDA’s August deadline.
“It does seem like a tall ask,” says Johnson, senior researcher for the Center of Excellence for Psilocybin Research and Treatment at mental health provider Sheppard Pratt. “You’re sticking your neck out, especially if something goes wrong.”
In the long run, some researchers maintain this is actually a much-needed level set for the field, tamping down the hype and forcing a dialogue about the riskier sides of this treatment.
“I don’t see it as a setback for the field. Certainly it is for Lykos,” says Alan Davis, director of the Center for Psychedelic Drug Research and Education at the Ohio State University. “The messaging from this downvote is that research needs to be more thoughtfully done.”
Where did the MDMA trial go wrong?
The application from Lykos — a drug company incubated by the Multidisciplinary Association for Psychedelic Studies, or MAPS — arrived at the FDA under a cloud of controversy.
Former trial participants had alleged adverse events were not reported — including feelings of suicidality after the treatment — and that bias among those running the trials had skewed the results. A recent report questioning the validity of the data amplified those concerns, as did the public hearing in which some accused the study sponsor of being a “therapy cult.”
Told that the FDA was actively investigating the claims, committee members were then left to draw their own conclusions about their veracity.
“In our time and understandably, who wants to be on the side of sort of arguing against people who are alleging harm in a clinical trial? That's a bad look,” says Gorman. ”I think that that got transferred to the FDA advisory panel.”
Aside from the ethical allegations, which Lykos denies, some of the major sticking points for the advisers may, in reality, not be as big of a deal for federal regulators.
For example, the panel fixated on “functional unblinding” — the fact many trial participants could tell whether they had received the study drug instead of a placebo.
But this is not necessarily a deal-breaker, says Johnson. He points out this concern is not unique to psychedelics. “That's very common with psychoactive drugs, which are used in psychiatry,” he says. “There's not going to be any perfect solution to this blinding problem.”
Another strike against the application was criticism of the specific form of talk therapy that goes hand-in-hand with the drug. Advisers were troubled by what some of them saw as an “experimental” approach.
Dr. Jerry Rosenbaum rejects this characterization, saying the therapy had "core elements" of a lot of evidence-based treatments.
“If anything, it was a generic therapy,” says Rosenbaum, director of the Center for Neuroscience of Psychedelics at Mass General Hospital, who presented on behalf of Lykos about the need for more PTSD treatment.
Gorman acknowledges the Lykos' therapy protocol is more “open-ended,” and not as directed as other approaches like cognitive-behavioral therapy. However, he says there were extensive efforts to ensure that therapists adhered to the protocol — a fact that was lost in the committee’s discussion.
The whole idea that therapy sessions were not standardized, which then undermines the findings, is “just false,” he says.
In the end, Rosenbaum believes all this back-and-forth distracted from the fact that the FDA doesn’t even regulate psychotherapy. “People would be free to vary the therapy to some extent.”
It’s not just the data, but the ‘vibe’
In its application, Lykos describes MDMA as a catalyst for the therapeutic process, which is why it received so much attention. That is not expected to be as much of a hold-up for other psychedelics, though.
“The rest of us are studying molecules that don't require the same degree of therapy,” says Kabir Nath, CEO of Compass Pathways, a biotech company that’s running phase III clinical trials on psilocybin.
Johnson says relying on an “idiosyncratic” form of therapy, one that can sound more “new agey,” made MDMA-assisted therapy an ever tougher sell.
In his view, it simply added to a “vibe” that was already creeping into the broader discussion, largely based on the widely publicized allegations that some involved in the trials had overlooked troubling events and approached the research as more of a “movement” than a scientific endeavor.
“There is a concern about the cult-like vibe in the field in general… the vibe that ‘we're waking humanity up,’” he says.
Even though he has no direct knowledge this influenced the findings (some participants maintain it did), just the perception can be enough to seed mistrust. “You need to bend over backwards to let people know that you don't have this kind of religious zeal, that you're following the data and the evidence.”
The fact that about 40% of those in the trials had tried MDMA before enrolling in the study only fueled speculation about whether the findings could be trusted.
Certain oversights in the trials were even harder to ignore. Researchers didn’t collect data on participants' experiences on the drug, such as euphoria — information that FDA staff needed to weigh the abuse potential — or do lab work related to the drug’s safety profile.
While these were legitimate mistakes, Barrett was perplexed by some of the discussion. He says advisers seemed to suggest not much was known about the drug’s toxicity, although this was well studied before the trials. And to his mind, they had unfounded concerns that patients would seek out illegal drugs like cocaine after taking MDMA.
“It just broke my brain a little bit,” he says, “I didn't understand where comments like that could be coming from.”
The level of resistance to the Lykos application wasn’t surprising to OSU’s Alan Davis, given all the controversy.
“Personally, I think that we don't yet have a full picture and understanding around all of those potential issues,” says Davis. “More importantly, we absolutely don't have the infrastructure yet in the United States to address the types of specific risks that could come up as part of psychedelic therapy.”
The bumpy ride for Lykos may hold some lessons for others in the psychedelic space.
Nath says his company, Compass, has no plans to change its psilocybin trial design or protocol, but this does reinforce the need to show “consistency” with the therapy component and collect relevant data on side effects.
“It's clearly going to affect sentiment,” he says, “Over time, this should not make any difference to our trajectory from a development or regulatory perspective.”
300x250 Ad
300x250 Ad