The FDA has rejected Lykos Therapeutics' application for MDMA-assisted therapy for post-traumatic stress disorder (PTSD), delivering a significant blow to the burgeoning field of psychedelic medicine. The decision, based on concerns over insufficient scientific evidence and flawed study design, casts a shadow over the future of psychedelic treatments and their path to regulatory approval.
The rejection follows a negative vote from an FDA advisory committee in June, where panelists raised concerns about the trial's design and data. Paul Holtzheimer, deputy director for research at the National Center for PTSD and a member of the advisory board, acknowledged the urgent need for new PTSD treatments but cautioned against the premature introduction of therapies with uncertain safety and efficacy profiles.
Key Issues in the FDA's Decision
Several factors contributed to the FDA's rejection. One major concern was the issue of "functional unblinding" in the clinical trials. Due to MDMA's psychoactive effects, a significant proportion of participants could accurately guess whether they were receiving the drug or a placebo. This unblinding introduces potential bias, as participants' expectations of improvement or disappointment could influence the reported outcomes.
According to the advisory committee's notes, 90% of those prescribed the drug accurately ascertained that they were receiving midomafetamine. Likewise, 75% of those receiving placebo treatment accurately guessed what treatment arm they were in.
Another point of contention was the role and necessity of psychotherapy in the treatment. The FDA questioned whether the observed benefits were primarily due to the drug itself or the accompanying therapy, and whether the specific type of psychotherapy used by Lykos was essential.
Setbacks for Lykos Therapeutics
The FDA's decision has triggered significant repercussions for Lykos Therapeutics. The company has announced a 75% reduction in staff and the resignation of its founder, Rick Doblin, from the board. Lykos now faces the daunting task of potentially conducting another Phase 3 trial, a process that could take years and require substantial additional funding.
Broader Implications for Psychedelic Research
The rejection of Lykos' MDMA therapy raises broader questions about the challenges of developing and regulating psychedelic treatments. The difficulty of blinding clinical trials, the complexities of combining drugs with psychotherapy, and the need for robust safety data all pose significant hurdles.
"The way it’s been framed is that the FDA is against psychotherapy and that they don’t regulate psychotherapy; they just want to be about drugs," Doblin told Big Think. "That’s not the case. The FDA doesn’t regulate psychotherapy — that’s very true — but they understand that it’s not just about giving a drug."
The Question of Blinding
When designing a clinical trial, the gold standard is to conduct a double-blind, randomized control trial where researchers try to reduce bias by ensuring that some trial participants don’t know they’re getting the drug in question. In many drug trials, that problem is addressed with an inactive placebo like a sugar pill, but seeing as psychedelics have such noticeable effects, psychedelic scientists often turn to active placebos instead.
Doblin says the FDA chose to take this risk, in a move that helped ensure participant safety but threatened the integrity of the trial design itself. "The FDA chose therapy with inactive placebo, and that kind of got lost. They betrayed their agreement with us by saying, ‘Oh, now we don’t believe these results because of the functional unblinding.’ We negotiated eight months in a special protocol assessment process with the FDA to come up with the design. The media has missed this whole real point that we understand functional unblinding. We discussed functional unblinding with the FDA at length, and that’s why they chose the inactive placebo."
Future Directions
Despite the setback, interest in psychedelic therapies remains strong. Researchers are exploring a range of compounds, from psilocybin to ketamine, for various mental health conditions. However, the FDA's decision serves as a reminder of the rigorous standards required for regulatory approval and the challenges of navigating the complex landscape of psychedelic research.
Lykos, in particular, is all about the FDA. Lykos will eventually succeed, I believe."
MAPS the nonprofit has plans of its own. Doblin tells me he just got off a two-hour call with a woman from Rwanda who wants to bring MDMA to Rwanda. MAPS’ itinerary of global humanitarian projects so far includes work in Somaliland, Denmark, Bosnia, and an upcoming training in Ukraine in the first quarter of 2025.
Inner Healing Intelligence
MAPS’ treatment strategy is based on the assumption that it can. "Therapists should trust that any fear, memories, etc. that keep coming up are doing so to be healed, to be more fully understood, and that the participant’s psyche/inner healer knows when the best time is for this to occur," states MAPS’ treatment manual. "This very process of surrendering ego/directed functions to self/inner healer may be the method of therapeutic action that is so hard to come by without the help of MDMA."
