Efforts to make MDMA legally available as a psychotherapeutic catalyst hit a daunting roadblock in August. The Food and Drug Administration (FDA) declined to approve a new drug application submitted in February by Lykos Therapeutics, a company created by the Multidisciplinary Association for Psychedelic Studies (MAPS).
The FDA was following the recommendation of an advisory panel that had expressed several concerns about two Phase 3 studies of MDMA's safety and effectiveness in treating post-traumatic stress disorder (PTSD), including inadvertent unblinding of subjects, potential underreporting of adverse events, and allegedly inadequate assessment of MDMA's abuse potential. The FDA requested an additional Phase 3 trial, which would take years and millions of dollars. Lykos described that request as "deeply disappointing," saying it hoped existing evidence could resolve the agency's concerns.
The advisory committee overwhelmingly concluded that MDMA's effectiveness had not been demonstrated and that its benefits had not been shown to outweigh its risks. Given the "many problems with the data," one panelist said, there are "a lot of questions I would have about how effective the treatment is."
The two clinical trials compared subjects who received MDMA in conjunction with psychotherapy to subjects who underwent the same sort of therapy but received placebos. On their face, the results of those studies are impressive.
The first study, published by Nature Medicine in 2021, involved 90 subjects with "severe PTSD," as measured by the -Clinician-Administered PTSD Scale for DSM-5 (CAPS-5). That questionnaire is designed to assess problems such as "intrusive distressing memories," hypervigilance, an exaggerated startle response, sleeplessness, difficulty in concentrating, avoidance of cues associated with a traumatic event, and "feelings of detachment or estrangement from others." The second study, reported in the same journal two years later, involved 104 subjects with "moderate to severe PTSD." Both studies found that subjects who received MDMA saw larger reductions in their CAPS-5 scores than the control group did.
The differences were substantial. On average, CAPS-5 scores, which range from 0 to 80, fell by more than 24 points in the MDMA group in the 2021 study, compared to about 14 points in the placebo group. At the end of the study, two-thirds of the MDMA group "no longer met the diagnostic criteria for PTSD," compared to one-third of the control group. In the 2023 study, the average score decreases were about 24 points and about 15 points, respectively. More than 70 percent of the MDMA group no longer qualified for a PTSD diagnosis, compared to 48 percent of the control group.
The FDA's advisers worried that the negative effects of MDMA-assisted psychotherapy may have been underreported. In the 2021 study, the researchers noted that some "treatment-emergent adverse events" were more common in the MDMA group. But they said those effects "were typically transient" and "mild to moderate in severity." They included "muscle tightness, decreased appetite, nausea, hyperhidrosis [excessive sweating] and feeling cold." The authors added that "no increase in adverse events related to suicidality was observed in the MDMA group."
The results of the 2023 study were similar. The authors said psychiatric adverse events, most commonly suicidal ideation, insomnia, and anxiety, "occurred at a similarly high frequency in both groups."
According to the 2023 study, no incidents of "MDMA abuse, misuse, physical dependence or diversion" were reported. FDA clinical reviewer David Millis apparently deemed that suspicious. "We noticed a striking lack of abuse-related adverse events," he said. While that could be due to underreporting, it also could be due to a lack of such events.
Another reason the FDA's advisers were skeptical is the likelihood that subjects, who were randomly assigned to the two groups and theoretically did not know whether they were taking MDMA, surmised which group they were in based on the presence or absence of the drug's expected effects. "Although we do have two positive studies," Millis said, "the results are in the context of dramatic functional unblinding."
That is undeniably a problem for any study that tries to rigorously assess a drug's benefits, especially when the measured outcome is psychological. But when a drug has recognizable psychoactive effects, this problem is hard to overcome.
In the case of MDMA, it is hard to imagine how a truly and fully blind study could be conducted, given the distinctive effects that users have long reported. It would be paradoxical if the very properties that make MDMA interesting and potentially beneficial became an insurmountable obstacle to FDA approval.
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