Psychedelic Therapy Scrutinized by FDA Advisory Committee?

On June 4, the Food and Drug Administration (FDA) held a meeting of its Psychopharmacologic Drugs Advisory Committee. The FDA maintains 50 independent committees focused on different fields. Although not required to, it convenes these expert panels when facing difficult decisions.¹ In this case, the subject was 3,4-methylenedioxymethamphetamine (MDMA), a Schedule I controlled substance, which shows promise for treating posttraumatic stress disorder.

For decades, the nonprofit Multidisciplinary Association for Psychedelic Studies (MAPS) pursued research on MDMA with psychotherapy, a combination it calls MDMA-assisted therapy (MDMA-AT). In 2014, MAPS formed a wholly owned, for-profit subsidiary, the MAPS Public Benefit Corporation, which took over drug development. In 2021, it published results from a phase 3 trial, describing MDMA-AT as “highly efficacious in individuals with severe PTSD [posttraumatic stress disorder].”² Last year, MAPS Public Benefit Corporation completed a second phase 3 trial, reporting similar results.³ In December, it filed a new drug application seeking FDA approval. In January, it rebranded itself Lykos Therapeutics and announced $100 million in outside investment; MAPS lost its controlling interest.

In May, the FDA announced the advisory committee would review the MDMA data, likely because Lykos’ application combines a drug, the agency’s specialty, with psychotherapy, which falls outside its purview. Another factor may have been a March report from the Institute for Clinical and Economic Review (ICER), a nonprofit that evaluates clinical data. ICER rated publicly available trial data on MDMA-AT “insufficient.”

On June 4, after hearing from Lykos, the FDA, and the public, the advisory committee voted on MDMA-AT’s safety and efficacy. Members voted 9 to 2 that available data do not demonstrate MDMA-AT’s effectiveness. They voted 11 to 1 that MDMA-AT’s benefits would not outweigh its risks, even if approved with strict limitations. The advisory committee’s questions focused on perceived gaps in trial data, unblinding and expectation bias, sexual misconduct claims, study recruitment methods, and alleged research misconduct. The meeting drew mixed reactions.⁵ Critics claimed the advisory committee was biased and misunderstood the drug-therapy combination.⁶ Patients and advocacy groups said it overlooked the significant unmet need for posttraumatic stress disorder treatments.⁶ Others praised the advisory committee for objectively scrutinizing the data.⁶ This Viewpoint analyzes its decisions and what they mean for psychedelic research.

Unblinding concerned the advisory committee. Because MDMA alters thought and affect, participants and clinicians could usually identify the trial groups to which participants were randomized. Critics said the advisory committee overemphasized unblinding and applied a double standard because other psychoactive drugs pose similar challenges.⁶ But the advisory committee believed unblinding could account for much of the observed difference in outcomes between cohorts. Furthermore, members perceived a lack of steps taken to minimize unblinding. The FDA had urged Lykos to use another psychoactive substance or low doses of MDMA as controls instead of a placebo. In 2023 draft guidance, it recommended complementary study designs pairing placebo-controlled trials with nonplacebo-controlled studies having low-, middle-, and high-dose groups.⁷ However, the second phase 3 MDMA-AT trial was already underway.

Concerns regarding trial recruitment and prestudy expectation bias also rankled the advisory committee. Approximately 40% of all participants had experience using MDMA, exacerbating expectancy concerns. Members worried experience might have encouraged participants to enroll knowing they enjoyed or benefitted from MDMA, making them more likely than MDMA-naive participants to be categorized as positive responders, potentially causing Lykos to overestimate efficacy. Similarly, members said the abundance of people with MDMA experience may have caused Lykos to underestimate adverse events because experienced participants may be more accustomed to MDMA’s effects.

Some members said they might overlook unblinding, but multiple shortcomings compounded the problem.⁵ The FDA made other recommendations that were seemingly ignored. Years ago, it suggested measuring abuse-related adverse events described in 2017 industry guidance.⁸ Examples include subjective effects that could be perceived as neutral or beneficial, such as euphoria, which the FDA believes increase the risk of abuse. Lykos chose not to record them.⁹ The FDA lamented the omission, claiming it impedes its safety assessment and recommendations for product labeling, patient monitoring, and controlled substance rescheduling.

What likely caused the greatest confusion was the request that regulators approve a drug-therapy combination. Because the FDA regulates drugs, not psychotherapy, even the agency appeared uncertain how to proceed. “[We’re] learning as we go,” said FDA’s Tiffany Farchione. Advisory committee member John Hurtig, a professor of pharmacy, likened regulating MDMA-AT to “building the airplane while we’re flying it.” Members thought the psychotherapy component was vague and unstandardized, leaving them unsure how to assess it.

Lykos displayed a slide that contributed to this ambiguity. It listed several types of psychotherapy participants received during a long-term follow-up study, including well-known modalities such as cognitive behavioral therapy. The most-used modality, representing 69% of cases, was labeled “other.” One advisory committee member requested a definition, and Lykos said “other” described “talk therapy that doesn’t have a specific name.” This and similar discussions led members to believe the psychotherapy component might have muddled the results. In its defense, Lykos said independent raters judged treatment sessions to ensure clinicians followed its treatment manual. But the advisory committee found the manual’s description equally vague. One member said the psychotherapy remains “a black box.”

Allegations of research misconduct were another concern. Elizabeth Joniak-Grant, a sociologist, described one highly publicized case as sexual misconduct, urging others to acknowledge it. Advisory committee members asked whether FDA officials had investigated the incident and worried it might reflect a pattern of ethical transgressions. During a public comment period, speakers alleged that Lykos failed to report serious adverse events and discouraged some participants from enrolling in the long-term follow-up study. Members also questioned the company’s trial recruitment methods, which relied on researchers it had trained and other parties within its network.

Despite ensuing controversy, psychedelic researchers can learn from the advisory committee meeting. They should adopt complementary study designs or active comparators and follow FDA guidance when possible. Lykos could have done more to mitigate unblinding, and its lack of data on abuse-related adverse events seemingly eroded trust. Future trials should collect data on subjective effects, including those perceived as benign or beneficial.

Given concerns about participants’ having MDMA experience, researchers should ensure that people who have used the investigational drug are not overrepresented in study populations. If trials include psychological support, it should be evidence based, clearly defined, and uniformly applied. Recruitment methods should be unbiased and unlikely to enhance expectancy. When research misconduct is alleged, hiring independent auditors to investigate and sharing the results could help rebuild trust.

The FDA’s decision is expected on August 11, 2024, but the review period could be extended. On one hand, it usually follows committee advice, departing from it once a year on average.¹ Moreover, approving MDMA-AT would require disregarding not only the advisory committee’s opinion but also ICER’s. On the other hand, there is a pressing need for novel posttraumatic stress disorder treatments, and the FDA more frequently disregards advice that discourages approval. Furthermore, the agency has snubbed ICER and an advisory committee before. In 2021, it approved aducanumab for treating Alzheimer disease against ICER and committee advice. Controversy followed, the FDA’s judgment was questioned, and the manufacturer discontinued aducanumab this year. It is hoped that approving MDMA-AT will have better results

If the FDA declines to approve MDMA-AT, it could discourage future regulatory submissions for drug-therapy combinations. Conversely, a favorable decision might do little to promote drug-therapy submissions, given the advisory committee’s controversial votes. Advisory committee votes have an uncertain future. FDA Commissioner Robert Califf recently suggested deemphasizing them, which has also generated controversy.¹⁰

Since the June advisory committee meeting, other psychedelic drug companies have claimed they rely less on psychological support than Lykos has, and reviewing their new drug applications could be more straightforward. Furthermore, MDMA represents only a fraction of the psychedelic compounds in development. Regardless of the outcome for MDMA-AT, the need for novel treatments remains, and enthusiasm for psychedelic research will likely continue. Despite lingering uncertainty, the FDA appears broadly supportive of psychedelic medicine.

Corresponding Author: Mason Marks, MD, JD, Petrie-Flom Center for Health Law Policy, Biotechnology, and Bioethics at Harvard Law School, 1585 Massachusetts Ave, Cambridge, MA 02138 (mmarks@law.harvard.edu).

Published Online: July 30, 2024. doi:10.1001/jama.2024.13370

Conflict of Interest Disclosures: Dr Marks reported fees for academic research from the Petrie-Flom Center at Harvard Law School (funded by the Saisei Foundation) during the conduct of the study; grants from Mahindra Humanities Center at Harvard; a fee from the Massachusetts Medical Society for presenting academic legal research regarding psychedelics outside the submitted work; and fees for journalism related to psychedelic drug policy.

Additional Contributions: Dr Marks thanks I. Glenn Cohen, JD, and Susannah Baruch, JD, both at Petrie-Flom Center at Harvard Law School, for comments on manuscript drafts.