From rave drug to PTSD treatment: Will the FDA approve MDMA-assisted therapy?

Midomafetamine (MDMA), often referred to as molly or ecstasy, has historically been perceived as a party drug. Popular among college students, and often seen at raves and music festivals, MDMA is typically associated with dancing all night and enhanced feelings of infatuation or connection with others. Unexpectedly, another effect of MDMA may be its ability to help treat individuals suffering from post-traumatic stress disorder (PTSD). With a lack of novel and effective treatments for PTSD, scientists are looking to redefine MDMA from a rave drug to a therapeutic.

PTSD, which affects millions of people worldwide, is a disorder that typically develops after experiencing a traumatic event. Common treatments for PTSD include medications, such as selective serotonin reuptake inhibitors (SSRIs), and talk therapy. However, even for patients who receive both forms of treatment, remission rates hover around 50%. Importantly, there have been no newly approved drug treatments for PTSD in the past 25 years.

Throughout the past decade, there has been a surge of preclinical and clinical trials studying the therapeutic potential of psychedelic drugs. Many of these studies have shown promise for the treatment of a variety of psychiatric disorders including anxiety, treatment-resistant depression and PTSD. Some of these clinical trials have assessed the use of the psychedelic MDMA for treating PTSD.

"Psychedelic research will continue to develop and lead to more rigorous and efficacious results. This ongoing research will advise scientists and practitioners on how best to take MDMA out of the club and into the clinic."

-- Anna Tsyrulnikov

Following the completion of two Phase 3 clinical trials for PTSD treatment, the company Lykos Therapeutics submitted a New Drug Application to the U.S. Food and Drug Administration (FDA) for MDMA capsules. In both of Lykos’ previous clinical trials, participants received three doses of MDMA or a placebo, in conjunction with talk therapy. In comparison with the control group, 67% and 71% of participants in the MDMA-treated group showed a significant reduction in PTSD symptomology in the first and second trials, respectively.

Although these results suggested that MDMA-assisted therapy is effective at treating PTSD, several observers identified potential flaws in the studies’ design, which may indicate greater risks beneath the surface.

One of the primary concerns discussed by the advisory committee was functional unblinding. This occurs when participants can tell whether they received the placebo or the active drug based on the effects they feel. Without proper controls, expectation bias can powerfully influence the results of a study. Properly controlling experiments using drugs like psychedelics, which can induce alterations in visual and time perception, has been a highly debated topic for years. Although there is no perfect answer to this problem, the FDA has previously worked with Lykos’ parent company and approved the study design for these trials.

Another prominent issue that arose from these trials was the quality and standardization of therapy associated with psychedelic treatment. Talk therapy can be difficult to standardize and is not regulated by the FDA for approval of drug treatments. In addition to creating more variation in the outcomes of the therapy provided, a lack of standardization may create concerns for the safety of patients, especially as MDMA may increase their vulnerability.

Unfortunately, this issue surfaced during one of Lykos’ previous clinical trials when a participant experienced sexual misconduct from a therapist. After being reported, Lykos banned the therapist from working with them further. Although this issue does not present an inherent flaw in the safety and efficacy of MDMA itself, these serious concerns must be addressed and mitigated through proper training and regulation of clinicians involved in psychedelic-assisted therapy.

Other, more trivial, concerns were brought up as well, such as the addictive potential of MDMA—despite it being well known that people rarely abuse the drug—and potential cardiovascular effects, which suggest greater caution should be taken for individuals at risk of heart problems.

Ultimately, these concerns led the committee to vote against the approval of MDMA-assisted therapy. Although the FDA typically weighs the advisory committee’s suggestions heavily, this is not always the case. The FDA will make a final decision on whether or not to approve the treatment in August 2024.

For novel therapeutics with unique concerns like MDMA, FDA approval will likely require a paradigm shift in the way these treatments are regulated. It will eventually come down to the evolution of regulatory systems to decide when individuals who are suffering from PTSD and other psychiatric disorders will be able to receive this new treatment. Regardless of the FDA’s final decision, psychedelic research will continue to develop and lead to more rigorous and efficacious results. This ongoing research will advise scientists and practitioners on how best to take MDMA out of the club and into the clinic.

Update 8/12/24

During the writing of this article, the FDA released a complete response letter that rejected the approval of MDMA-assisted therapy. This conclusion will be addressed in a follow-up article next week.