MDMA-assisted psychotherapy for treatment of PTSD: study design and rationale for phase 3 trials based on pooled analysis of six phase 2 randomized controlled trials

This largest double-blind, placebo-controlled study to date (2019) on MDMA-assisted therapy for PTSD finds significant improvements (Cohen’s d=0.8) and no significant adverse effects. This study is on the pooled (n=105) data of MAPS‘ phase II FDA trials.

Abstract

“Background: Posttraumatic stress disorder is a prevalent mental health condition with substantial impact on daily functioning that lacks sufficient treatment options. Here we evaluate six phase 2 trials in a pooled analysis to determine the study design for phase 3 trials of MDMA-assisted psychotherapy for PTSD.

Methods: Six randomized, double-blind, controlled clinical trials at five study sites were conducted from April 2004 to February 2017. Active doses of MDMA (75–125 mg, n = 72) or placebo/control doses (0–40 mg, n = 31) were administered to individuals with PTSD during manualized psychotherapy sessions in two or three 8-h sessions spaced a month apart. Three non-drug 90-min therapy sessions preceded the first MDMA exposure, and three to four followed each experimental session.

Results: After two blinded experimental sessions, the active group had significantly greater reductions in CAPS-IV total scores from baseline than the control group [MMRM estimated mean difference (SE) between groups − 22.0 (5.17), P < 0.001]. The between-group Cohen’s d effect size was 0.8, indicating a large treatment effect. After two experimental sessions, more participants in the active group (54.2%) did not meet CAPS-IV PTSD diagnostic criteria than the control group (22.6%). Depression symptom improvement on the BDI-II was greatest for the active group compared to the control group, although only trended towards significant group differences [MMRM, estimated mean difference (SE) between groups − 6.0 (3.03), P = 0.053]. All doses of MDMA were well tolerated, with some expected reactions occurring at greater frequency for the active MDMA group during experimental sessions and the 7 days following.

Conclusions: MDMA-assisted psychotherapy was efficacious and well-tolerated in a large sample of adults with PTSD. These studies supported expansion into phase 3 trials and led to FDA granting Breakthrough Therapy designation for this promising treatment.”

Authors: Michael C. Mithoefer, Allison A. Feduccia, Lisa Jerome, Anne Mithoefer, Mark Wagner, Zach Walsh, Scott Hamilton, Berra Yazar-Klosinski, Amy Emerson & Rick Doblin

Notes

The cost-effectiveness of MDMA-assisted psychotherapy is further analyzed in Marseille et al (2020) and is based on the outcomes of the current paper.

This paper is also discussed in a press release by MAPS and in an article on Psychedelic Support.

Summary

Posttraumatic stress disorder (PTSD) is a prevalent mental health condition that lacks sufficient treatment options.

Introduction

Posttraumatic stress disorder (PTSD) is a serious debilitating disorder with lifetime prevalence estimated at nearly 4% globally and over 8% in the USA. It can have profound negative consequences for individuals with PTSD, including obesity, hypertension, and suicidality.

Treatments for PTSD include psychotherapies and medications. However, most individuals with PTSD do not respond adequately to current treatments, and many individuals with PTSD require long-term use of medications to maintain effectiveness.

The combination of psychotherapy with pharmacotherapy using 3,4-methylenedioxymethamphetamine (MDMA) is a promising approach to the treatment of PTSD. MDMA was first synthesized in 1912 by Merck, but it was not until the early 1970s that MDMA was first used in combination with psychotherapy.

Six phase 2 randomized trials of MDMA-assisted psychotherapy for treatment of PTSD were conducted from 2004 to 2017, and all demonstrated acceptable safety and promising efficacy results. MDMA doses were selected based on tolerability and subjective effects reported in several prior phase 1 studies. Two phase 3 trials started in 2018 with Breakthrough Therapy Designation.

We pooled data from six phase 2 trials to determine the optimal design of phase 3 trials for MDMA-assisted psychotherapy among individuals with PTSD from a range of causes.

Participants

Participants were recruited through internet advertisements, referrals by health professionals, and word of mouth. They had chronic PTSD symptoms lasting longer than 6 months and an inadequate response to at least one pharmacotherapy and/or psychotherapy.

Participants underwent extensive screening by independent examiners, including psychological assessments, physical examinations, laboratory testing, and ECG, and medical and therapy records from outside providers were reviewed. Participants were excluded if they met criteria for past or current psychotic disorder or Bipolar Disorder 1, or current borderline personality disorder.

Protocols and treatments

After screening and enrollment, participants were randomized to receive placebo/control (0 mg placebo; 25 mg, 30 mg, or 40 mg MDMA) or active doses of MDMA (75 mg, 100 mg, or 125 mg MDMA) at approximately 1:2 ratio. Doses were administered during two 8-h psychotherapy sessions spaced 3 – 5 weeks apart.

In six studies, 18 male/female therapy teams were present for all therapy sessions for a given participant. The therapy teams used a method called MAPS, which allows participants to revisit traumatic experiences while staying emotionally engaged.

Experimental sessions took place in a designated area that contained a futon or sofa, artwork or other objects intended to make the space esthetically pleasing, and eye shades. Participants listened to instrumental music during the experimental sessions.

Assessments

Blinded independent raters administered the CAPS-IV at baseline and at follow-up visits. Safety data were collected throughout treatment.

Primary outcome

The CAPS-IV is a semi-structured interview addressing the three symptom clusters of PTSD, and has a dichotomous diagnostic score assigned on the basis of meeting PTSD diagnostic criteria.

Safety outcomes

Safety was assessed by tracking spontaneously reported reactions and treatment-emergent adverse events (TEAEs) during experimental sessions and 7 days following, and by recording changes in cognitive function after two sessions with placebo dose or active dose MDMA in specific studies.

Statistical analysis

Data were pooled across six studies and analyzed. Active dose group received 75, 100, 125 mg MDMA, and control group received 0, 25, 30, 40 mg MDMA.

Group differences in baseline characteristics and demographics were evaluated with 2 tests or independent-samples t tests, and a mixed-effect repeated measure model (MMRM) was used to assess efficacy. Age, PTSD duration, sex, race, and prior self-reported Becstasy use were analyzed in the same way.

105 participants were enrolled and randomized, with a mean age of 40.5 (10.5), 87.6% white/Caucasian, and nearly sex balanced. Most participants had PTSD for 215.3 (190.3) months, and a lifetime history of positive suicidal ideation and/or behavior was 30.9%.

Primary outcome

The active group had the greatest estimated mean (SE) drop in scores compared to the control group, and the study, age, PTSD duration, sex, race, and prior Becstasy use did not predict outcome.

Secondary outcomes

According to CAPS-IVassessment, more participants in the active group did not meet PTSD diagnostic criteria, and depression symptom improvement was greatest for the active dose group.

Most participants in the active dose group had one additional open-label or blinded session after two blinded experimental sessions. The effect size increased from 1.4 to 1.9 after three sessions.

Safety and tolerability

Four treatment-emergent adverse events (TEAEs) were reported during the blinded treatment period, including one instance of suicidal ideation (30 mg), one SAE of exacerbation of ventricular extrasystoles (125 mg), and one SAE of suicidal behavior prior to MDMA exposure in the first experimental session.

The active dose group had higher rates of positive suicidal ideation than the control group at baseline, but the lifetime reports were similar between groups.

Discussion

By pooling data across six phase 2 trials, we found that participants with chronic PTSD who received active doses of MDMA combined with psychotherapy experienced significant symptom reductions. This finding informed the design of two phase 3 trials that were approved through a Special Protocol Assessment by the FDA.

The data show that after two blinded active doses of MDMA adjunctive with psychotherapy, participants with highly refractory PTSD (mean duration 215.3 months) had a significant effect compared to psychotherapy with control doses. In addition, depression symptoms trended toward greater improvement in participants receiving active MDMA compared to the control group.

Phase 2 data showed that 75 mg MDMA produced significant improvement, yet the sample size was small (n = 7). To gather more information about optimal dosing, 15 sites will employ a flexible dose regimen and blinded independent raters will administer the primary outcome measure.

MDMA was safe and tolerable in highly controlled therapeutic settings in a PTSD population, and the frequency of required vital measurements will be reduced in phase 3 trials to baseline, pre-supplemental dose, and session end.

MDMA at all doses tested was well tolerated, with most reactions being mild to moderate and resolving as MDMA effects dissipated or during the week following. However, during experimental sessions, the active MDMA group had higher incidences of some reactions, including anxiety, dizziness, jaw clenching, lack of appetite, and nausea. In phase 2 trials, participants received no related deaths or incidence of suicidal behavior after MDMA. The low dropout rate may be related to the propensity of MDMA to make trauma processing more tolerable with rapid symptom improvements.

MDMA was found to have a low potential for abuse in individuals with PTSD in a supportive environment with trained mental health professionals.

Limitations

The six trials were nearly gender balanced, but participants and therapists were predominantly White/ Caucasian. There were variations in study design, such as timing of outcome measures, doses tested, number of blinded experimental sessions, and number of participants in each dose group.

Conclusions

Based on the promising safety and efficacy results from six phase 2 trials, MDMA-assisted psychotherapy could become an FDA-approved treatment for PTSD by 2021.