In a previous blog on the use of psychedelics to treat mental health disorders, we reported that the US Food and Drug Administration (FDA) granted breakthrough therapy designation to MDMA (a.k.a., ecstasy) in 2017 as part of a drug-therapy treatment for post-traumatic stress disorder (PTSD) in adults. In order for the drug to be approved by the FDA, replicable results from a second clinical trial were needed. 

On January 4, 2024, Lykos Therapeutics, pursuing the first FDA-approved MDMA therapy, submitted a new drug application (NDA) containing findings from its two Phase 3 clinical trials. On August 9, 2024, the FDA issued a complete response letter (CRL) rejecting the NDA and requested that Lykos conduct an additional Phase 3 trial to further study the efficacy and safety of MDMA. The rejection was issued after the FDA’s Psychopharmacology Drugs Advisory Committee met in early June and voted 9-2 that the available data did not demonstrate that midomafetamine (Lykos’ propriety formulation of MDMA) was effective in treating PTSD, and the panel also voted 10-1 that the benefits of midomafetamine did not outweigh the risks.

In a press release, the former CEO of Lykos stated, “The issues expressed in the CRL echo those raised during the FDA Advisory Committee meeting on June 4, 2024. The Company and other stakeholders have expressed concerns around the structure and conduct of the Advisory Committee meeting, including the limited number of subject matter experts on the panel and the nature of the discussion, which at times veered beyond the scientific content in the briefing documents.” She added that conducting another study “would take several years.” Lykos plans to meet with the FDA regarding next steps for resubmission.

In its application, Lykos presented data from two randomized controlled clinical trials involving approximately 200 individuals with moderate to severe PTSD. All participants underwent talk therapy, with half receiving a placebo and the other half receiving MDMA in three separate dosing sessions. The results showed that patients in the MDMA groups experienced a more significant reduction in PTSD symptom severity compared to those in the placebo groups. 

The FDA Advisory Committee expressed concerns regarding the “functional unblinding” of the study design and its potential to bias the study results. Although the trials were double-blinded, the cognitive and sensory effects of MDMA, a hallucinogen, permitted most participants to discern whether they had received the placebo or the actual drug. According to Lykos, the company “took many steps to minimize its potential impact, including the use of independent, blinded third-party clinician raters to assess outcomes. The weight of evidence suggests a very low likelihood that the observed midomafetamine effect can be adequately explained by functional unblinding.” 

Another concern raised by the FDA Advisory Committee was the administration of the drug in conjunction with psychotherapy. Since the FDA does not regulate psychotherapy, the advisory committee found it challenging to assess the efficacy of the combined drug and therapy approach. Lykos contends that the practice of psychotherapy is already a regulated field with oversight by professional licensing boards and that the expectation is that healthcare professionals will use their clinical judgment guided by their governing boards to effectively deliver the combined treatment. To date, the FDA has not approved a psychotherapeutic process alongside a drug approval.

What does this mean for the future of psychedelic research? Some companies are moving away from psychotherapy as part of their treatment protocol in the hopes that it will expedite the FDA’s review of the psychedelic. Opinions diverge regarding the broader impact of the FDA's recent rejection. Some foresee a ripple effect across the psychedelics research community, while others view it as merely a temporary setback or an issue specific to Lykos’ clinical trials design and execution. The FDA's issuance of guidelines tailored for psychedelic clinical trials suggests that the agency is not opposed to the future medical use of these substances. Many scientists in the field remain optimistic, predicting that psilocybin (psychedelic mushrooms), currently undergoing Phase 2 and 3 trials, could become the first psychedelic approved by the FDA.