MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study

[James Morris-Lent]

https://www.nature.com/articles/s41591-021-01336-3

The buzz of the internet.

Not to be a downer but this study should be considered unblinded (and uncontrolled) and has subjective outcomes.

Also, everybody wants to talk about the MDMA but this study is more accurately about 'MDMA-enhanced (talk) therapy' which looks like something (some of) the authors made up and have been using (see THERAPIST MANUAL). I.e. this is not "CBT+MDMA vs. CBT+placebo" but "Our sweet MDMA-enhanced therapy we made up vs. Our sweet therapy but you actually didn't get the MDMA (LOL)"

Anyway if people are serious about investigating psychedelic drugs for mental illnesses, it seems like investing in dose-response studies would be the play to get around the problem of blinding (and control). Also keep the data clean by not wrapping it up in whoevers' favorite hobby psychotherapy.

Abstract


Post-traumatic stress disorder (PTSD) presents a major public health problem for which currently available treatments are modestly effective. We report the findings of a randomized, double-blind, placebo-controlled, multi-site phase 3 clinical trial (NCT03537014) to test the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for the treatment of patients with severe PTSD, including those with common comorbidities such as dissociation, depression, a history of alcohol and substance use disorders, and childhood trauma. After psychiatric medication washout, participants (n = 90) were randomized 1:1 to receive manualized therapy with MDMA or with placebo, combined with three preparatory and nine integrative therapy sessions. PTSD symptoms, measured with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5, the primary endpoint), and functional impairment, measured with the Sheehan Disability Scale (SDS, the secondary endpoint) were assessed at baseline and at 2 months after the last experimental session. Adverse events and suicidality were tracked throughout the study. MDMA was found to induce significant and robust attenuation in CAPS-5 score compared with placebo (P < 0.0001, d = 0.91) and to significantly decrease the SDS total score (P = 0.0116, d = 0.43). The mean change in CAPS-5 scores in participants completing treatment was −24.4 (s.d. 11.6) in the MDMA group and −13.9 (s.d. 11.5) in the placebo group. MDMA did not induce adverse events of abuse potential, suicidality or QT prolongation. These data indicate that, compared with manualized therapy with inactive placebo, MDMA-assisted therapy is highly efficacious in individuals with severe PTSD, and treatment is safe and well-tolerated, even in those with comorbidities. We conclude that MDMA-assisted therapy represents a potential breakthrough treatment that merits expedited clinical evaluation.

Randomization, masking and bias minimization

....

An inactive placebo with therapy was utilized as the comparator to isolate the efficacy of the MDMA itself. Although low-dose MDMA improved blinding in phase 2 studies, it led to decreased effectiveness compared with an inactive placebo in a PTSD population, making it easier to detect a difference between the active and comparator groups15. The use of inactive placebo also allows for uncontaminated comparison of safety data between groups. Therefore, an inactive placebo was determined in partnership with the FDA as a more conservative statistical comparison, and the study utilized observer-blinded efficacy assessments to minimize bias in efficacy measurements.

Discussion

....
....

There are several limitations to the current trial. ...
... Last, given the subjective effects of MDMA, the blinding of participants was also challenging and possibly led to expectation effects14. However, although blinding was not formally assessed during the study, when participants were contacted to be informed of their treatment assignment at the time of study unblinding it became apparent that at least 10% had inaccurately guessed their treatment arm. Although anecdotal, at least 7 of 44 participants in the placebo group (15.9%) inaccurately believed that they had received MDMA, and at least 2 of 46 participants in the MDMA group (4.3%) inaccurately believed that they had received placebo.

 

[Milo]

I ran across this comment on twitter related to the paper:

 

[rvallee]

There's some MD in the replies saying you can mimic MDMA with low dose Adderall and cannabis and seriously where do these people get so confidently wrong to the point of saying absurd things like this? This is not even close to be true. As a sham placebo sure, to compare for no effect, but in no way would it be a convincing control, let alone be close enough to mimic the effects.

Typical Howard, rules only matter in achieving the outcome he wants.