Trouble for ecstasy? What the MDMA setback could mean for psychedelics

The psychedelic drug MDMA is nearing the end of a decades-long effort to enter mainstream medicine, but instead of rejoicing, its supporters are now wondering whether the treatment will actually be commercialized in the near future.

Last week, Food and Drug Administration advisers delved into research gaps and missteps and overwhelmingly rejected evidence supporting MDMA as an effective treatment for post-traumatic stress disorder.

It was a harsh public reckoning over the future of the drug and a deflating moment for those involved in psychedelic research.

“It really doesn’t feel like the data has been given due consideration,” says Ingmar Gorman, a psychologist and investigator in the MDMA clinical trials that have come under intense scrutiny last year. last week. “The hope has always been that if we do the science and we do it 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, shaking up the market and generating a flood of bad press. Investors and scientists have stepped up their efforts in the sector in recent years, pouring billions into drugs like psilocybin, ketamine and LSD.

Insiders don’t view the FDA dustup as an existential threat to the broader psychedelic program. But some concerns raised about the research may serve as lessons for future efforts to gain FDA approval, says Frederick Barrett, director of the Johns Hopkins Center for Psychedelics and Consciousness Research.

“We need to look inward and look at all the studies that are going on now and make sure that we’re doubling down on the most rigorous methods,” he says.

But more than anything, he says the FDA’s problems are an indictment of how the drugmaker, Lykos Therapeutics, conducted the trials. “There’s a lot of disappointment within the committee, but there’s also a lot of disappointment at (the sponsor) for putting forward such a vulnerable application.”

What could happen to MDMA now?

Despite the negative results, it is not impossible that the agency still approves the treatment against the recommendation of its advisory committee.

In fact, Dr. Srinivas Rao believes there is a “low probability” of outright rejection.

Instead, the agency could come back with a very strict set of safeguards and requirements to conduct more in-depth research once the product is on the market, or the drug manufacturer could be asked to conduct another clinical trial before FDA approval.

“It’s a bit of a game of chance,” says Rao, CEO of Atai Life Sciences, a biotechnology company invested in mental health and psychedelics. “To oppose the committee so aggressively is difficult. On the other hand, there is a lot of pressure to get this approved.”

Gorman says the panel overlooked key points about research supporting MDMA-assisted therapy and appeared swayed by yet-to-be-proven allegations of ethical misconduct that FDA staff said they were not supposed to take taken into account in their recommendations.

“Now what worries me is that this becomes political, right? » he said, “What is the FDA going to do?” Will they oppose the advisory committee’s vote?

Matthew Johnson believes MDMA will eventually be approved, even if it doesn’t happen before the FDA’s August deadline.

“It seems like a daunting task,” says Johnson, a principal investigator at mental health provider Sheppard Pratt’s Center of Excellence for Psilocybin Research and Treatment. “You crane your neck, especially if something goes wrong. »

In the long term, some researchers argue that this is actually a much-needed level in the field, dampening the hype and forcing a dialogue about the riskier sides of this treatment.

“I don’t see this as a setback for the field. That’s certainly the case for Lykos,” says Alan Davis, director of the Center for Psychedelic Drug Research and Education at Ohio State University. “The message of this negative vote is that research needs to be done more thoughtfully.”

Where did the MDMA trial go wrong?

The application from Lykos — a pharmaceutical company incubated by the Multidisciplinary Association for Psychedelic Studies, or MAPS — arrived at the FDA under a cloud of controversy.

Former trial participants had claimed that adverse events were not reported – including suicidal feelings after treatment – and that bias among those running the trials had skewed the results. A recent report questioning the validity of the data amplified these concerns, as did the public hearing during which some accused the study sponsor of being a “therapeutic cult.”

Informed that the FDA was actively investigating these claims, committee members were then left to draw their own conclusions about their veracity.

“In this day and age, understandably, who wants to be on the side of some sort of argument against people who claim that a clinical trial was harmful? It’s a bad idea,” Gorman says. “I think it was moved to the FDA advisory committee.”

Aside from the ethics allegations, which Lykos denies, some of the biggest sticking points for advisers might, in reality, not be as important to federal regulators.

For example, the panel focused on “functional unblinding” – the fact that many trial participants could know whether they had received the study drug instead of a placebo.

But that doesn’t necessarily constitute a deal-breaker, Johnson says. He emphasizes that this concern is not unique to psychedelics. “This is very common with psychoactive drugs, which are used in psychiatry,” he says. “There will be no perfect solution to this blinding problem.”

Another criticism against the app has been criticism of the specific form of talk therapy that goes hand in hand with the medication. Councilors were troubled by what some of them considered an “experimental” approach.

Dr. Jerry Rosenbaum rejects this characterization, saying the therapy contained “central elements” of many evidence-based treatments.

“Rather, it was a generic therapy,” says Rosenbaum, director of the Center for Psychedelic Neuroscience at Mass General Hospital, who presented on Lykos’s behalf the need for increased treatment for PTSD.

Gorman acknowledges that the Lykos treatment protocol is more “open” and not as directed as other approaches like cognitive behavioral therapy. However, he says considerable effort was made to ensure therapists adhered to the protocol – a fact that was lost in the committee’s discussions.

The idea that therapy sessions weren’t standardized, thereby undermining results, is “simply false,” he says.

Ultimately, Rosenbaum thinks all this back-and-forth distracts from the fact that the FDA doesn’t even regulate psychotherapy. “People would be free to vary therapy to a certain extent. »

It’s not just about the data, it’s also about the “vibe”

In its application, Lykos describes MDMA as an enabler of the therapeutic process, which is why it has received so much attention. However, this should not be as much of a hindrance for other psychedelics.

“The rest of us are studying molecules that don’t require the same degree of therapy,” says Kabir Nath, CEO of Compass Pathways, a biotechnology company that is conducting Phase III clinical trials of psilocybin.

Johnson says that relying on an “idiosyncratic” form of therapy, which can seem more “new age,” has made MDMA-assisted therapy increasingly difficult to sell.

In his view, this only added to a “vibe” that was already creeping into the broader debate, largely based on widely publicized allegations that some people involved in the trials had overlooked troubling events and broached the search as a “movement” rather than a “movement”. a scientific enterprise.

“There’s a concern about the cultish vibe in the field in general…the vibe that ‘we’re waking up humanity,'” he says.

Even if he has no direct knowledge of what influenced the results (some participants claim he does), the mere perception can be enough to create distrust. “You need to do everything you can to let people know that you don’t have that kind of religious zeal, that you follow the data and the evidence.”

The fact that about 40% of trial participants had tried MDMA before enrolling in the study only fueled speculation about the reliability of the results.

Some omissions during the trials were even harder to ignore. The researchers did not collect data on participants’ experiences with the drug, such as euphoria – information that FDA staff needed to assess abuse potential – or perform laboratory work related to the profile safety of the medicine.

Although these were legitimate errors, Barrett was perplexed by some of the discussions. He said advisers seemed to suggest that little was known about the drug’s toxicity, although it was well studied before the trials. And in his opinion, they had unfounded fears that patients would seek out illegal drugs like cocaine after taking MDMA.

“It just kind of broke my brain,” he says, “I didn’t understand where such comments could come from.”

The level of resistance to the Lykos app didn’t surprise OSU’s Alan Davis, given all the controversy.

“Personally, I think we don’t yet have a full picture or a complete understanding of all of these potential issues,” Davis says. “More importantly, we absolutely do not yet have the infrastructure in the United States to address the specific types of risks that might arise in psychedelic therapy.”

Lykos’ bumpy ride could be a lesson for others in the psychedelic space.

Nath says his company, Compass, has no plans to change the design or protocol of its psilocybin trial, but it reinforces the need to show “consistency” with the therapeutic component and collect relevant data on side effects.

“It’s definitely going to affect sentiment,” he says. “Over time, this should not make a difference to our trajectory from a development or regulatory perspective.”