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The future of psychedelic research was dealt its biggest setback in years after the FDA declined to approve midomafetamine (MDMA) capsules for post-traumatic stress disorder (PTSD) earlier this month, according to experts who spoke with MedPage Today.

"I was disappointed that a treatment that looked like it could be helpful to people would not be available," said Jerrold Rosenbaum, MD, director of the Center for Neuroscience of Psychedelics at Massachusetts General Hospital in Boston, expressing a common opinion among those contacted for this story.

The agency declined to approve the treatment after overwhelmingly negative votes from an advisory committee in June. In that highly anticipated meeting, the Psychopharmacologic Drugs Advisory Committee voted 9-2 that the available data failed to show MDMA was effective in treating patients with PTSD and 10-1 that its risks outweigh the benefits, even with a proposed risk evaluation and mitigation strategy (REMS).

The decision appeared to show that the FDA and the medical community want more data before introducing a psychedelic drug to the market.

While psychedelic research has had a revival in the last decade, some of the data have been challenged. The BMJ placed an expression of concern on a meta-analysis of psilocybin trials, suggesting its methodology overestimated benefits for depression. In addition, three papers about MDMA-assisted therapy published in Psychopharmacology, which were co-written by authors affiliated with drug developer Lykos Therapeutics, were due to concerns about unethical conduct.

Concerns about misconduct during the trials -- specifically, one in which an unlicensed therapist was accused of sexual misconduct with a patient from the study -- were also aired at the FDA advisory meeting. The agency recently into those allegations, according to the Wall Street Journal.

Still, leaders in the field of psychedelic research believe the FDA rejection could be an opportunity to regroup as companies prepare to follow in Lykos' footsteps with other psychedelic drugs in the coming years.

Learning the Wrong Lessons

While Lykos ran into several challenges in its effort to bring its therapy to market, several experts told MedPage Today they worry the field could be learning the wrong lessons from the agency's decision not to approve it.

"We're all kind of waiting to see what the complete response letter is," said Paul Hutson, PharmD, the director of the Transdisciplinary Center for Research in Psychoactive Substances at the University of Wisconsin-Madison.

Without the full response letter to help explain the FDA's decision, Hutson suggested that leaders in the field could take away the wrong lessons. One issue of particular concern is whether the FDA took issue with the psychotherapy in Lykos' trials.

"I'm concerned that there will be some protocol that makes it even more onerous to provide the skilled therapy along with the drug therapy," he said.

He added that the entire field of psychedelic research will be focused on whether the FDA will clarify how that psychotherapy should be approached for future psychedelic treatments.

Where Lykos Failed, Others Might Succeed

One area of concern expressed by the FDA advisory committee was the seemingly intractable problem of functional unblinding.

"There were too many gaps and negatives that the FDA thought that the only thing really they could do was to say, 'You need to come up with another study that doesn't have a lot of these flaws,'" said Rosenbaum, who presented information about psychedelic research practices during the FDA advisory committee meeting.

He argued that he doesn't see functional unblinding as a major issue for the field moving forward. One reason, he said, is that the FDA was clear throughout the process that it would not be a deal-breaker. He noted that better trial design will be needed to account for those issues.

Frederick Barrett, PhD, director of the Center for Psychedelic and Consciousness Research at Johns Hopkins University in Baltimore, noted that blinding will likely not be an issue, because several useful study designs can prove a psychedelic's efficacy and safety without relying on blinding.

In fact, he noted that the FDA's own regulatory code outlines that could be used, including dose comparison control, no-treatment control, active-treatment control, or historical control.

"This is written into law as the definition of the canonical ways that the FDA thinks about and can consider controls in trials," Barrett said.

He explained that psychedelic researchers should be running "studies in all of these different designs and then look at the sum total, because each of these designs has flaws and benefits."

That process has already begun. Several studies have shown promising results for psilocybin for depression, specifically for patients with treatment-resistant bipolar type II depression and as a therapy with or without antidepressants.

Most notably, Compass Pathways is working on for patients with treatment-resistant depression. Earlier this month, Cybin announced plans to start its own for the treatment of major depressive disorder.

Barrett noted the FDA decision on Lykos' application for MDMA is "just the beginning" for the researchers attempting to bring these drugs to market.

Better Research Needed

These concerns have been well known within the field, so this setback was likely the result of people outside the field deciding that more needed to be proven, Rachel Yehuda, PhD, the director of the Center for Psychedelic Psychotherapy and Trauma Research at Mount Sinai in New York City, told MedPage Today.

"In the last few years, there's been so much hype that it's almost seemed like a foregone conclusion: This is happening, this is coming," Yehuda said. "And the people that weren't so sure about it weren't necessarily speaking or were not necessarily being heard."

Yehuda said the important thing is whether the field can find a way to move forward and address these concerns, especially since there are few good treatments for many of these conditions right now.

She noted that throughout the discussion around this approval process, "nobody thought that the psychedelic drug was dangerous."

"The events of the last few months underscore the need for more really good research conducted in the way that standard research is conducted -- generally by academics and in conservative, safe environments," she concluded.

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