FDA’s MDMA ruling raises the bar for psychedelic research

There are two FDA-approved medications for PTSD, both selective serotonin reuptake inhibitors. The FDA has not approved a new medication for PTSD since 2001.

The currently approved medications for PTSD are helpful, but there is a substantial effectiveness gap. As a result, patients with long-standing PTSD are often treated with three or more psychotropic medications, most of which do not have validated effectiveness for PTSD.

Studies conducted by Lykos suggested that midomafetamine (MDMA) in combination with specific behavioral therapy might be the most effective medication for the treatment of PTSD. Thus, there was enormous excitement earlier this year about the therapeutic potential of MDMA leading up to an FDA advisory panel.

In June, the advisory panel voted 9-2 against the conclusion that Lykos had demonstrated the safety and efficacy of their treatment and 10-1 against the conclusion that the Lykos treatment (MDMA plus behavioral therapy) demonstrated a favorable balance of risks and benefits. The concerns raised by the advisory panel echoed concerns raised earlier by the Institute for Clinical and Economic Review (ICER) in its draft report.

The FDA’s recent decision is consistent with input received from its advisory panel in requiring an additional phase 3 trial to address these concerns.

In my view, these are the key issues raised by the ICER report and FDA advisory panel:

Trial sizes

Lykos had conducted two very small phase 3 studies, with about 40 to 50 participants per group. Although the group sizes were sufficient to generate robust signals of efficacy, they were not sufficient to protect the study from problems that challenged their validity or to establish the balance of risks and benefits for study participants.

Potential bias

One threat to the validity of the study was that patients and their treaters could tell whether they received drug or placebo. The fact that patients in the studies were often MDMA-experienced and that they participated to try to get MDMA approved created a potential for bias in their reporting of their treatment experiences that accentuated the response differences between drug and placebo. Further, ICER asserted that some therapists in the trials were similarly highly motivated to see MDMA approved. It is alleged that they coached some study participants about how they should report their experiences, augmenting bias concerns. If the study results were biased, then we cannot be confident that the findings can be generalized broadly to the community of people with PTSD.

Ambiguity

Another issue is related to the fact that the FDA reviewed the combination of a specific psychotherapy with MDMA rather than the medication by itself. While the study results could be interpreted as establishing the effectiveness of the combination, Lykos never established that the behavioral intervention added anything to the intrinsic effectiveness of MDMA, particularly in relation to typical supportive psychotherapy. Since that is a core aspect of their “product,” it was an obvious gap.

Safety

An issue related to the safety of MDMA was that nearly half of the study participants sought MDMA illegally after the study was completed. There are two ways to view this observation. First, it may be the case that MDMA administered in the context of treatment has greater abuse liability than previously appreciated. Clearly, MDMA is a widely used recreational drug and its potential for misuse merits caution. Second and equally important, it may simply be the case that MDMA is a long-term treatment for many patients. Some people highlighted evidence that many patients no longer met PTSD criteria at the end of the Lykos trial as support for the idea that short-term treatment could “cure” PTSD. That may be true for some patients. However, for many patients in the study, their MDMA-seeking suggests that intermittent MDMA administration on a long-term basis might be a common maintenance strategy. The phase 3 conducted by Lykos provided little insight into this issue and it may not be addressed by the additional study required by the FDA.

A clear path forward

Overall, MDMA remains an extremely promising potential treatment for PTSD. The additional phase 3 study required by the FDA will serve to broaden our understanding of the safety and effectiveness of MDMA in combination with the Lykos behavioral intervention. Hopefully the additional study will also remove the cloud that now sits over Lykos and MDMA as a consequence of the problems and limitations of the Lykos phase 3 program.

The bad news about the non-approval of MDMA is disappointing in some respects. However, it may have some positive effects in the long run. The standards that will be needed for FDA approval of psychoactive drugs, particularly drugs that are developed in combination with specific psychotherapies, are getting sorted out. It is extremely important to establish a clear path for the FDA approval of drugs like MDMA and psychedelic drugs that seem to have great potential to alleviate suffering and to restore function in patients with PTSD and depression.