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

This double-blind, placebo-controlled study (n=90) finds that MDMA-assisted therapy (3x 80-120mg) is effective (d=.91, large effect size) in the treatment of PTSD. 67% of those in the MDMA-group no longer qualified for PTSD (vs 32% for the therapy-only group). This study is part of the Phase III trial to get MDMA approved by the FDA.

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.“

Authors: Jennifer M. Mitchell, Michael Bogenschutz, Alia Lilienstein, Charlotte Harrison, Sarah Kleiman, Kelly Parker-Guilbert, Marcela Ot’alora G., Wael Garas, Casey Paleos, Ingmar Gorman, Christopher Nicholas, Michael Mithoefer, Shannon Carlin, Bruce Poulter, Ann Mithoefer, Sylvestre Quevedo, Gregory Wells, Sukhpreet S. Klaire, Bessel van der Kolk, Keren Tzarfaty, Revital Amiaz, Ray Worthy, Scott Shannon, Joshua D. Woolley, Cole Marta, Yevgeniy Gelfand, Emma Hapke, Simon Amar, Yair Wallach, Randall Brown, Scott Hamilton, Julie B. Wang, Allison Coker, Rebecca Matthews, Alberdina de Boer, Berra Yazar-Klosinski, Amy Emerson & Rick Doblin

Notes

MAPS wrote a press-release about this study (also see the great graphics on the second half of that page).

Introduction

PTSD, or Post-Traumatic Stress Disorder, is a terrible mental health disease for which there currently is no good treatment option available. The SSRIs currently approved by the FDA (paroxetine and sertraline) don’t help between 40 and 60% of patients. Similarly, the current psychotherapies (e.g. prolonged exposure, CBT) aren’t up to the task.

The pooled analysis of six Phase II trials (n=105, Jerome et al., 2020) has already shown MDMA (in combination with therapy) to possibly be the way to treat PTSD. That study showed CAPS-IV scores (a measure of PTSD) to drop by an average of 45 points, with a further drop of 5 points at the long-term follow-up. At that moment, 67% of participants no longer met the criteria for PTSD.

Results

The current study (n=90) followed a double-blind, placebo-controlled, randomized design. The measures (CAPS-5, SDS, BDI-II) were done by independent researchers. On average, participants had lived with PTSD for 14 years.

“The mean change in CAPS-5 scores from baseline to 18 weeks after baseline in the completers (per protocol set) was −24.4 (s.d. 11.6) (n=42) in the MDMA-assisted therapy group compared with −13.9 (s.d. 11.5) (n=37) in the placebo with therapy group.”

The effect size was large (d = 0.91), which means that there is a large difference between both groups (as you can see from the numbers above). Compared to doing nothing (baseline) the effect size is an even more impressive d = 2.1 (and d = 1.2 for the placebo plus therapy group).

Functional impairment (SDS) decreased, and scores on a measure of depression (BDI-II) also decreased by twice as much in the MDMA-group.

Participants with comorbidities (e.g. dissociative subtype, alcohol use disorder (AUD), addiction (SUD), severe childhood trauma) were just as receptive as those without comorbidities.

“At the primary study endpoint (18 weeks after baseline), 28 of 42 (67%) of the participants in the MDMA group no longer met the diagnostic criteria for PTSD, compared with 12 of 37 (32%) of those in the placebo group after three sessions. Additionally, 14 of 42 participants in the MDMA group (33%) and 2 of 37 participants in the placebo group (5%) met the criteria for remission after three sessions.”

These results are great and show that, in combination with therapy, MDMA is more effective than current treatments. A head-to-head comparison still needs to be done.

What is also promising is the safety profile. There were no increases in suicidality (SI). “Although the number of participants who reported suicidal ideation varied throughout the visits, prevalence never exceeded baseline and was not exacerbated in the MDMA group.”

Discussion

The authors are quick to point out the much smaller effect sizes of SSRIs, and seem to invite a direct comparison.

Earlier research points towards SSRIs themselves being a hinder to the effectiveness of MDMA-assisted therapy. An earlier study on data from the Phase 2 trial by Feduccia and colleagues (2020) indicated that. In the current study, 66% used SSRIs (and discontinued them before the study started) so it’s difficult to pick that apart in the current study.

Why MDMA may work (so well) for PTSD is also explained: “… data suggest that MDMA may exert its therapeutic effects through a well-conserved mechanism of amygdalar serotonergic function that regulates fear-based behaviors and contributes to the maintenance of PTSD. Perhaps by reopening an oxytocin-dependent critical period of neuroplasticity that typically closes after adolescence15, MDMA may facilitate the processing and release of particularly intractable, potentially developmental, fear-related memories.”

Or, as put in the next paragraphs, MDMA may help with recalling negative memories with more self-compassion.

One group that may be helped by MDMA-assisted therapy are veterans (16 participated in this study). The cost to the US government (not even considering the psychological and personal costs) of PTSD (and other service-related disabilities) is $73 billion.

Another great aspect of this study is the inclusion and analysis of data of those with comorbidities. It’s common for studies to study patients with only one indication (e.g. only depression but not suicidal ideation). By including those with substance use disorders, childhood traumas, and more, the external validity (how generalizable the results are) is greatly increased.

What can be better?

The current study only looked at data up to 5 weeks after the final integration session. Future studies (with these patients) will be able to show longer-term follow-up results. Based on the Phase 2 study (Jerome et al., 2020), we can expect scores to remain the same or improve.

Blinding is always difficult in these studies (the therapist will most likely guess correctly who has gotten MDMA or a placebo), still 10% of participants (vs 50% guess) incorrectly guessed which condition they were in.

This study was conducted with a small group of participants who might have been very enthusiastic about the effects of MDMA (i.e. expectancy effects). Larger trials with a more diverse group of patients should be able to help with the generalizability of these results. But note, this should not prevent MDMA-assisted therapy to be approved now.