REVIEW OF: Mitchell JM et al, Nat Med 2021;27(6):1025–1033

STUDY TYPE: Randomized controlled trial

MDMA (3,4-methylenedioxymethamphetamine, more commonly known as ecstasy or molly), is an amphetamine analog that also increases transmission of both serotonin and oxytocin. Prior to the FDA banning it from further research in 1985, MDMA had been developing a reputation for its ability to enhance the benefits of psychotherapy. These same effects were also gleaned on the street, where its perceived prosocial qualities and absence of violent tendencies led to its popularity in raves. In 2017, the FDA reversed course, granting MDMA breakthrough status to pursue an indication as an adjunct to psychotherapy for severe posttraumatic stress disorder (PTSD). This trial is the first phase III trial for that use.

In this study, researchers randomized 89 patients with PTSD to receive either MDMA or placebo in conjunction with manualized therapy for PTSD. Participants received three monthly doses of MDMA or placebo delivered over an eight-hour period. Each dose was followed by three weekly 90-minute “integration” sessions to help patients understand and incorporate their experience. The primary outcome of interest was reduction in PTSD scores on the Clinician-Administered PTSD Scale (CAP-5), while secondary outcomes evaluated changes in functioning.

The results were unusually robust. Reduction in CAP-5 scores were significantly greater in the active treatment cohort (p < 0.0001), and the effect size was large: 0.9 (by way of comparison, SSRI effect sizes for PTSD are typically in the 0.3–0.6 range). In addition, depression scores and functioning improved, and 67% of patients in the MDMA arm no longer met criteria for PTSD at endpoint (compared with 32% in the placebo arm). The benefits were apparent almost immediately and both accrued and persisted throughout the study. They appeared unhindered by duration or severity of PTSD symptoms, type of trauma, or degree of treatment resistance.

MDMA was well tolerated, with the most common side effects being muscle tightness, nausea, decreased appetite, and hyperhidrosis. There were no reports of suicidality, abuse, or serious adverse events associated with MDMA.

The major limitation of the study, as with many such studies, is that there is no way to ensure adequate blinding. To their credit, the investigators asked subjects to guess which medication they thought they had received. Many, though not all, were in fact able to guess correctly.

TCPR’S TAKE
This rigorously conducted study is almost unparalleled in the annals of psychopharmacology for its effect size and safety. While it remains to be seen whether the gains are enduring, two questions naturally arise: Why might MDMA be so effective, and what took us so long? The answer to the second question is straightforward. MDMA fell victim to the antidrug wave of the 1970s and 1980s that shunned research involving any illicit substances. As to the first question, while enhanced serotonin release is hardly novel, keep in mind that the brain is not a monolithic organ. MDMA seems to preferentially target the amygdala, which is believed to be integral to the pathophysiology of PTSD. The release of serotonin and oxytocin there holds out promise of offering a truly targeted biological approach when used in conjunction with PTSD-focused therapy.