A hand in a blue glove holds a white pill against a black background.
A hand in a blue glove holds a white pill against a black background.

Why Lykos Therapeutics’ MDMA data had a bad trip

An FDA advisory panel voted against recommending the psychedelic MDMA for PTSD, puncturing excitement around the drug’s potential.

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Excitement around the use of psychedelic drugs to treat mental health disorders has hit new highs in the last decade. Two weeks ago, an independent expert advisory panel reporting to the Food and Drug Administration (FDA) delivered a hammer blow to that hype.

The panel considered a pair of clinical trials organized by Lykos Therapeutics (1,2). These trials used the “party drug” 3,4-methylenedioxymethamphetamine (MDMA) in combination with psychotherapy to treat post-traumatic stress disorder (PTSD). Based on Lykos Therapeutics’ data, the 11-person panel voted 9-2 that the drug was not effective, and 10-1 that the risks of the drug outweighed its benefits.

The vote will inform whether the FDA approves MDMA in a mid-August meeting. The advisory panel’s decision has already rippled through the psychedelics community. “Six months ago, if you’d asked me the chances of the advisory committee recommending no, I would have said there's a very small, five percent chance,” admitted Balázs Szigeti, a researcher at Imperial College London’s Centre for Psychedelic Research.

In March, the Institute for Clinical and Economic Review (ICER) — a non-profit that independently analyzes clinical treatments — published a damning report that wobbled certainty around MDMA’s approval by highlighting potential cases of misconduct and insufficient reporting of safety data (3). ICER gave Lykos Therapeutics’ trial its lowest possible rating: “I” or insufficient. However, some problems raised by both ICER and the FDA panel have dogged psychedelics research for years.

This was death by a thousand cuts. 
- Boris Heifets, Stanford University

The experts noted that almost all trial participants correctly guessed whether they had received MDMA or a placebo, knowledge which might make them react differently to each treatment. Additionally, nearly half of the volunteers had previously tried psychedelics. It’s unlikely that people with previous negative experiences with psychedelics would volunteer for the trial, raising the risk of bias (4). 

But Szigeti and Boris Heifets, an anesthesiologist and psychedelics researcher at Stanford University, said that Lykos Therapeutics could feel hard done by on these points. “Traditionally, the FDA doesn't care about blind breaking or expectancy,” said Szigeti, pointing to earlier trials of selective serotonin reuptake inhibitors (SSRIs), where expectancy and blinding were rarely measured (5). “Some people in psychedelics [research] feel there is a double standard,” he added. Heifets dismissed the idea that the trial could have used a psychedelic-naïve cohort. “It's ridiculous. It's a disservice to people who have mental health conditions, many of whom have comorbid drug use,” he said.

Nevertheless, these were far from the only concerns with the company’s data. Some criticism, said Heifets, reflected errors in Lykos Therapeutics’ trial processes. The most serious failing, he added, was “not vigorously investigating and sanctioning sexual assault by an unlicensed therapist in a Phase 2 trial.” This assault produced a public acknowledgement from the company (6). An FDA investigation into further potential misconduct allegations will report its findings between now and August. Put together, these numerous issues may prove enough to sink MDMA at the approval stage. “This was death by a thousand cuts,” said Heifets.

Behind this process, patients remain in the lurch. “The underlying reality remains that we have an urgent and still unmet need for treating severe mental health conditions like PTSD,” said Heifets. If the drug’s passage does stop here, the focus will move to other efforts, like COMPASS PathwaysCOMP360 trial into the use of psilocybin for treatment-resistant depression. Both Heifets and Szigeti acknowledged pressure on the FDA to approve MDMA from industry and patient groups. This, they said, meant that the embattled drug’s approval was still in the balance. “I wouldn’t count it out,” said Heifets. 

References

  1. Mitchell, J.M., Bogenschutz, M., Lilienstein, A. et al. MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nat Med  27, 1025–1033 (2021).
  2. Mitchell, J.M., Ot’alora G.,M., van der Kolk, B. et al. MDMA-assisted therapy for moderate to severe PTSD: A randomized, placebo-controlled phase 3 trial. Nat Med  29, 2473–2480 (2023).
  3. 3,4-Methylenedioxymethamphetamine Assisted Psychotherapy for Post-Traumatic Stress Disorder (PTSD) Draft Evidence Report. Institute for Clinical and Economic Review (2024).
  4. Hovmand, O.R., Poulsen, E.D., Arnfred, S., & Storebø, O.J. Risk of bias in randomized clinical trials on psychedelic medicine: A systematic review. J Psychopharmacol  37, 649–659 (2023). 
  5. Lin, Y.-H., Sahker, E., Shinohara, K. et al. Assessment of blinding in randomized controlled trials of antidepressants for depressive disorders 2000–2020: A systematic review and meta-analysis. eClinicalMedicine  50, 101505 (2022).
  6. Statement: Public Announcement of Ethical Violation by Former MAPS-Sponsored Investigators. MAPS (2022).


Top Image:
MDMA’s approval hangs in the balance after a negative FDA panel hearing.
Credit: iStock.com/Ward DeWitt
Top Image:
MDMA’s approval hangs in the balance after a negative FDA panel hearing.
Credit: iStock.com/Ward DeWitt
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