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.

Summary

PTSD is a common and debilitating condition with immeasurable social and economic costs. It is associated with several comorbid conditions, including childhood trauma, alcohol and substance use disorders, depression, suicidal ideation and dissociation.

MDMA induces serotonin release and has been shown to enhance fear memory extinction, modulate fear memory reconsolidation, and bolster social behavior in animal models. Here, we assess the efficacy and safety of MDMA-assisted therapy in individuals with severe PTSD.

Results

Participants were recruited from 7 November 2018 to 26 May 2020, and 46 were randomized to MDMA and 44 to placebo. The mean duration of PTSD diagnosis was 14.8 years for MDMA and 13.2 years for placebo.

MDMA significantly attenuated PTSD symptoms in patients as measured by the CAPS-5 total severity score. The mean change in CAPS-5 scores from baseline to 18 weeks after baseline was 24.4 in the MDMA-assisted therapy group compared with 13.9 in the placebo with therapy group.

The effect size of MDMA-assisted therapy compared to placebo with therapy was 0.91 in the de jure estimand and 0.97 in the de facto estimand. MDMA significantly reduced clinician-rated functional impairment as assessed with the SDS over the same period.

MDMA was equally effective in participants with comorbidities that are often associated with treatment resistance. There was no effect of SSRI history on effectiveness of MDMA.

MDMA therapy was effective in reducing depression symptoms in participants with PTSD, as measured by the Beck Depression Inventory II (BDI-II). Additionally, 14 of 42 participants in the MDMA group and 2 of 37 participants in the placebo group met the criteria for remission after three sessions.

The MDMA group experienced more transient, mild to moderate treatment-emergent adverse events, including muscle tightness, decreased appetite, nausea, hyperhidrosis and feeling cold. No increase in adverse events related to suicidality was observed in the MDMA group.

Two participants reported three serious adverse events (SAEs), one participant reported two SAEs of suicidal behavior, and one participant reported one SAE of suicidal ideation that led to self-hospitalization. Five participants in the placebo group and three participants in the MDMA group reported AESIs.

Participants attended three preparatory sessions, three experimental sessions, nine integration sessions and four endpoint assessments over 18 weeks, concluding with a final study-termination visit. They were given medication taper and were assessed at baseline, after the first experimental session and 18 weeks after the second experimental session.

MDMA-assisted therapy decreased CAPS-5 total severity scores by 10 points, and decreased SDS total score by 3 points. MDMA sessions were not otherwise followed by a lowering of mood.

Suicidality was tracked throughout the study using the Columbia Suicide Severity Rating Scale. The number of participants who reported suicidal ideation varied throughout the visits, but prevalence never exceeded baseline.

Discussion

Three doses of MDMA given in conjunction with manualized therapy over the course of 18 weeks significantly mitigated PTSD symptoms and functional impairment.

This study compares the effects of MDMA-assisted therapy for PTSD with those of sertraline and paroxetine, and shows that MDMA-assisted therapy has a larger effect size than either of these medications.

Although 65.5% of participants in the current trial had a recent history of SSRI treatment, there was no obvious effect of previous SSRI use on therapeutic efficacy.

The serotonin transporter and serotonin levels in the amygdala are important in the generation, consolidation, retrieval and reconsolidation of fear memories. MDMA may enhance the extinction of fear memories by reopening an oxytocin-dependent critical period of neuroplasticity.

MDMA may help participants process traumatic content by facilitating self-compassion and decreasing PTSD-related shame and anger. The acute prosocial and interpersonal effects of MDMA may also support the quality of the therapeutic alliance.

PTSD is a strong predictor of disability in both veteran and community populations. The treatment identified here improves social and family functioning, which could provide major medical cost savings.

PTSD is a particularly persistent and incapacitating condition when expressed in conjunction with other disorders of mood and affect. MDMA-assisted therapy appears to be effective in treating PTSD in those with complicated PTSD and dual diagnoses.

Participants with dissociative subtype PTSD who received MDMA-assisted therapy had significant symptom reduction, suggesting that MDMA-assisted therapy may be an effective treatment for this population.

MDMA was not shown to induce or potentiate abuse potential, cardiovascular risk or suicidality in this study. It also had a transient increase in blood pressure, which was expected.

The current trial has several limitations, including a small population, lack of racial and ethnic diversity, short-term follow-up data, and blinding of participants. However, given the subjective effects of MDMA, the blinding of participants was challenging and possibly led to expectation effects.

We may soon be confronted with enormous economic and social repercussions of PTSD, exacerbated by the COVID-19 pandemic. MDMA-assisted therapy may provide improved patient safety and treatment efficacy in individuals with severe PTSD.

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Methods

This was a randomized double-blind study conducted at 15 sites in the United States, Canada and Israel to compare the efficacy of MDMA-assisted therapy with placebo with therapy.

Participants were recruited through print and internet advertisements, referrals from treatment providers, and by word of mouth. They were required to provide written informed consent and to comply with lifestyle modifications, including a medically supervised discontinuation of psychiatric medications for a minimum of five half-lives plus one additional week before the baseline assessments.

The protocol was amended three times during enrollment to add clarity to eligibility criteria, add terms of suicidal ideation and behavior as AESIs, increase the frequency of suicidality assessments following experimental sessions, and add an option for some telemedicine visits.

Participants were randomized to either the MDMA-assisted therapy group or the placebo with therapy group. They were blinded to group assignment until after the database was locked.

In a PTSD population, low-dose MDMA improved blinding in phase 2 studies, but led to decreased effectiveness compared with an inactive placebo. Therefore, an inactive placebo was utilized as the comparator, and an observer-blinded and centralized independent rater pool was used.

The three-item mean and work-related impairment were calculated from live video interviews with independent raters, and the study design, visit number, treatment assignment, and all data collected by the therapy team after baseline were blinded.

Participants underwent screening assessments, provided written informed consent, underwent physical examination, laboratory testing, electrocardiogram, and 1-min rhythm strip, and began psychiatric medication taper if needed. Adverse events were electronically captured using Medrio EDC versions R40 – 40.7.

In accordance with FDA guidance, adverse events that were potentially associated with QT interval prolongation, cardiac arrhythmias, abuse liability, and suicidal ideation and behavior were reported as AESIs.

Participants underwent three 90-min preparatory sessions of therapy with a two-person therapist team in preparation for experimental sessions. After completion of the preparatory period, participants were assessed for final eligibility and randomization was confirmed prior to randomization.

Three 8-h experimental sessions of MDMA-assisted therapy or therapy with inactive placebo control were conducted, spaced 4 weeks apart. Each session began with a qualitative urine drug screen, pregnancy screen, and C-SSRS.

In each experimental session, participants received a single divided dose of 80 – 180 mg MDMA or placebo. If tolerability issues emerged, the supplemental dose and/or dose escalation could be withheld, but there were no instances in which the supplemental dose was withheld due to tolerability issues.

The protocol required that one person per therapy team was licensed to provide psychotherapy, and that all therapists took part in a five-part training process. Blood pressure, body temperature and heart rate were measured at the end of each experimental session.

Independent raters conducted CAPS-5 and SDS assessments 3 weeks after each of the first two experimental sessions, and 8 weeks after the third experimental session. The independent raters demonstrated high inter-rater reliability of the CAPS-5 total severity scores.

Participants who were not compliant with drug use lifestyle modifications on study, disclosed cannabis use at study entry but abstained for the duration of the study, and requested further integrative visits were assessed for the presence of AESIs.

MDMA-assisted therapy for PTSD was compared to placebo with therapy on a scale from 0 to 80, with moderate PTSD defined from a rationally derived severity range of 23 – 34 (ref. 40) and severe PTSD as 35.

The secondary objective of this trial was to evaluate the efficacy of MDMA-assisted therapy for PTSD compared with placebo with therapy in clinician-rated functional impairment.

The sample size was calculated to achieve 90% power at an alpha of 0.049 using estimated effect size and variance and covariance parameter estimates.

The intent-to-treat set consisted of 91 participants, but one participant declined to participate. The modified intent-to-treat set consisted of 90 participants who had completed at least one blinded experimental session and at least one post-treatment assessment.

The SAP was guided by the ICH E9 (R1) guidelines and used a de jure estimand of the mITT set for assessing treatment efficacy from the CAPS-5 and SDS data while on the study drug.

One participant in the placebo group completed only the baseline assessment, discontinued treatment, but provided CAPS data at the T4 timepoint, 18 weeks after baseline. This participant was excluded from the de jure estimand, but was included in the de facto estimand sensitivity analysis.

The efficacy of MDMA treatment was tested by comparing the change from baseline to the third experimental session in CAPS-5 and SDS scores between treatment groups in a two-sided test. A hierarchical testing strategy was used to control for type I error.

An independent data monitoring committee monitored adverse events for safety and conducted an administrative interim analysis, which recommended that no additional participants should be added.

The primary and secondary efficacy comparisons were performed using the MMRM method. Additional baseline covariates were assessed in exploratory analyses, and the BDI-II score was assessed as an exploratory efficacy outcome measure.

The primary safety analysis evaluated TEAEs in participants who received at least one dose of the study drug or placebo.

Data availability

The data that support the findings of this study are available from the sponsor, but restrictions apply to the availability of these data. Data can be requested from the authors upon reasonable request.

Code availability

MDMA may affect socio-emotional processing, and the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) was developed and evaluated in military veterans.

The authors thank all of the participants, the principal investigators, and the study coordinators for their work on this challenging research study. They are especially grateful to Charleston study coordinator S. Sadler, who passed away prior to the end of the study. The authors thank many people for their help with the study, including therapists, researchers, and administrators. They also acknowledge the many people who donated their time and money to make the study possible. The authors thank the site physicians, nurses, research assistants, volunteers, night attendants, physical examiners and all site staff, as well as the MAPS PBC internal team for their work in clinical trial management, monitoring of study data, administration, adherence rating and supervision programs, and code of ethics.

MAPS, a 501(c)(3) non-profit organization, provided the MDMA and funded this study from private donations. MAPS PBC was the trial organizer and provided the study design and data analysis.

Author contributions

J.M.M., B.Y.-K., S.H. and A.C. had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. R.D. obtained funding for the study.

Competing interests

A.E., R.M., C.H., A.D.B., S.C., A.C., and J.B.W. declare financial competing interests, as do A.L., B.Y.-K. and R.D., who received salary support for full-time employment with MAPS PBC for this study and other work. The authors disclose personal fees or grants from companies in the field, but these are unrelated to the present work. The authors also disclose non-financial relationships with organizations in the field.

available at https://doi.org/10.1038/s41591-021-01336-3.

Nature Medicine thanks Philip Cowen, Kirsty James and the other reviewer(s) for their contributions to the peer review of this work.