Pyschedelic drug boosters assess challenges after FDA panel turns thumbs down on MDMA

In making this case, other potential applicants described the approach by Lykos, and its nonprofit parent, the Multidisciplinary Association for Psychedelic Studies, as an outlier in its clinical trial design and execution. They said that made it a weak candidate for the first test of whether the FDA will permit such drugs to go mainstream.

MAPS and Lykos combined the drug — better known by its street name, ecstasy — with psychotherapy, adding complexity to the design of an already challenging trial. Investigators didn’t collect certain lab tests or data on the potential for abuse that the FDA specifically requested. And the push has been dogged by a perception that MAPS’s evangelism for psychedelics has seeped into Lykos’s work of scientifically proving the therapy’s benefits, along with allegations of misconduct in clinical trials.

Kabir Nath, chief executive of Compass Pathways, said the vote was an opportunity to “pivot away from some of the, shall we say, psychedelic baggage,” referring to misconduct allegations. Compass is developing a synthetic form of psilocybin, a chemical found in hallucinogenic mushrooms, for severe depression. After Lykos, Compass Pathways is the next closest psychedelic developer to seeking FDA approval.

Unlike Lykos, the company is not pairing its drug with psychotherapy. It is testing a low, medium and higher dose to mask which version patients get and mitigate the risk of bias.

Investors saw the advisory panel vote as potentially negative for the whole category of drugs, however. Compass saw its stock drop by 15 percent the day after the vote, before rebounding to close down 2.6 percent. Shares of Mind Medicine, which is testing a form of LSD, and Atai Life Sciences, which is investing in psilocybin and DMT, fell 10 percent and 8.4 percent, respectively.

Some hope that the advisory committee’s strong recommendations against the Lykos application will provide a dose of reality to the psychedelics-as-medicine movement. The committee voted 9-2 that the Lykos trial did not prove effectiveness and 10-1 that its benefits did not outweigh the risks.

“My hope is that we will start to get a more balanced and nuanced picture of the real risks and benefits of psychedelics,” said David Yaden, a psychedelics researcher at the Johns Hopkins University School of Medicine, who has written about the psychedelics “hype bubble” driven by industry and media. “Maybe the committee hearings will help adjust some people’s understanding of the state of the evidence.”

Representatives of Lykos provided a statement from chief executive Amy Emerson, in which she pledged to continue working with the FDA and acknowledged the advisory committee meeting was “unprecedented in many ways,” including reviewing an application “that combines a drug and psychological intervention.”

Lykos delivered two studies to the FDA showing powerful reductions in PTSD symptoms, displaying the kind of statistical significance that is usually persuasive to regulators. Its work has won over many academics, clinicians and veterans groups, which have expressed profound disappointment with the advisory committee vote.

Following that vote, Amber Capone, co-founder of Veterans Exploring Treatment Solutions, urged the FDA to “carefully consider the compelling testimony from PTSD sufferers who have found relief through MDMA-assisted therapy.”

Discussion in the committee Tuesday quickly focused on how much to trust the positive study outcomes. One key concern was that 40 percent of the participants in the MDMA trials had previous experience with the drug, raising the prospect that such patients were predisposed to believe that it would help them and potentially biasing the results.

“If you had a prior positive experience, you’re probably going to have a positive experience again,” said Ritu Baral, a TD Cowen analyst. She called the trial conduct “subpar,” referring to the lack of data on lab tests for patient safety and that Lykos did not collect information the FDA had requested on euphoric reactions that could lead to abuse.

Then there was the design of the trial itself, in which patients were supposed to be blind to whether they had received actual MDMA or a placebo, but — owing to the drug’s mind-altering affect — the vast majority could tell what group they were in.

That challenge was well known to the FDA and isn’t unique to psychedelics. The lack of effective blinding came up during a 2019 advisory committee for Spravato, a nasal spray derived from ketamine, but members overwhelmingly endorsed it and the FDA approved it. But for Lykos, adding therapy to the mix appeared to compound concerns for some committee members: If therapists could also tell whether trial participants received the drug, they could treat them differently and affect the results.

“This is unusual. This is not something the FDA has seen before,” Srinivas Rao, chief executive of Atai Life Sciences, said of the potential for therapists to treat patients differently based on knowing what treatment group they were in.

Alia Lilienstein, senior medical director for Lykos, acknowledged the complicated design in Tuesday’s meeting, saying that the company is “creating a new field of medicine.”

MAPS’s founder, Rick Doblin, has pitched MDMA as a humanity-changing force for good that could eliminate the world’s trauma. While many in the industry respect Doblin’s success in ushering psychedelics into serious research, some have chafed at how the organization’s evangelism has colored perceptions of their work.

“I don’t agree with the idea of total elimination of trauma from the world, or, ‘we are going to solve climate change,’” said Ingmar Gorman, a psychologist and clinical investigator at a MAPS trial site. “A lot of us clinicians aren’t taking up that kind of rhetoric.”

Within the psychedelic community, “many of us are feeling shocked, surprised, confused and bewildered,” said Raquel Bennett, a ketamine specialist and founder of the KRIYA Institute, questioning why concerns about trial design hadn’t been addressed before.

“If FDA had concerns about any aspect of the methodology, they could have addressed it with MAPS at any point during the past several years,” she said.

The Institute for Clinical and Economic Review, an influential nonprofit, in March published a draft report on MDMA-assisted therapy that raised concerns that participants felt “pressured to report good outcomes and suppress bad outcomes.” During public comment on Tuesday, some raised allegations of misconduct, including a case of sexual abuse.

Though the FDA advised the committee that it considered reports of misconduct to be unverified, some members raised it in discussing their votes.

Those allegations carried weight alongside concerns about the study data and the therapy, said Elizabeth Joniak-Grant, a committee member who serves as a patient representative and voted against approval.

“Especially when you’re talking about sexual misconduct — it seems a bit impossible to ignore,” Joniak-Grant, a sociologist at the University of North Carolina at Chapel Hill, said in an interview.