Long-term Follow-Up Outcomes of MDMA-assisted Psychotherapy for Treatment of PTSD: A Longitudinal Pooled Analysis of Six Phase 2 Trials

MDMA-assisted psychotherapy showed a very large effect (d=1.58, 56% no longer met PTSD criteria) which improved at 12-months follow-up (d=0.43, 67%).

Abstract

“Rationale: Posttraumatic stress disorder (PTSD) is a chronic condition that has wide-ranging negative effects on an individual’s health and interpersonal relationships. Treatments with long-term benefits are needed to promote the safety and well-being of those suffering from PTSD.

Objectives: To examine long-term change in PTSD symptoms and additional benefits/harms after 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for treatment of PTSD.

Methods: Participants received two to three active doses of MDMA (75-125 mg) during blinded or open-label psychotherapy sessions with additional non-drug therapy sessions. PTSD symptoms were assessed using the Clinician-Administered PTSD Scale for DSM IV (CAPS-IV) at baseline, 1 to 2 months after the last active MDMA session (treatment exit), and at least 12 months post final MDMA session (LTFU). A mixed-effect repeated-measures (MMRM) analysis assessed changes in CAPS-IV total severity scores. The number of participants who met PTSD diagnostic criteria was summarized at each time point. Participants completed a long-term follow-up questionnaire.

Results: There was a significant reduction in CAPS-IV total severity scores from baseline to treatment exit (LS mean (SE) = – 44.8 (2.82), p < .0001), with a Cohen’s d effect size of 1.58 (95% CI = 1.24, 1.91). CAPS-IV scores continued to decrease from treatment exit to LTFU (LS mean (SE) = – 5.2 (2.29), p < .05), with a Cohen’s d effect size of 0.23 (95% CI = 0.04, 0.43). The number of participants who no longer met PTSD criteria increased from treatment exit (56.0%) to LTFU (67.0%). The majority of participants reported benefits, including improved relationships and well-being, and a minority reported harms from study participation.

Conclusions: PTSD symptoms were reduced 1 to 2 months after MDMA-assisted psychotherapy, and symptom improvement continued at least 12 months post-treatment. Phase 3 trials are investigating this novel treatment approach in a larger sample of participants with chronic PTSD.”

Authors: Lisa Jerome, Allison A. Feduccia, Julie B. Wang, Scott Hamilton, Berra Yazar-Klosinski, Amy Emerson, Michael C. Mithoefer & Rick Doblin

Notes

This paper is included in our ‘Top 10 Articles on Psychedelics in the Year 2020‘

“The present analysis extends the follow-up of participants across six phase 2 clinical trials who had participated in a treatment protocol consisting of two or three 8-h psychotherapy sessions combined with MDMA for treatment of PTSD.”

The studies were similar in design and the data of them was combined to get 107 participants, 74 of which were in the active (MDMA) group. At the endpoint 91 completed the follow-up, of which 83 also the questionnaire.

“Compared to baseline, 82.0% of participants achieved a clinically significant drop of 15 points or greater in CAPS-IV total scores [PTSD structured interview/measure] at treatment exit, and 26.4% had a 15-point or greater decrease from treatment exit to LTFU [long term follow-up]. There were 11 (12.1%) participants who experienced a relapse, defined as a 15-point or greater drop in CAPS-IV scores at treatment exit but then a 15-point or greater increase in scores from treatment exit to LTFU.”

“At 12-month follow-up, 97.6% of participants across studies reported experiencing benefits, and among the participants who reported benefits, 92.2% reported that some to all benefits lasted with 53.2% indicating large benefits that lasted or continued to grow.”

These results are phenomenal. Of the participants that experienced harm (8.4%) the most identified cause was worsened mood. Of those (9 participants) that relapsed, all had one or more significantly stressful event.

“At LTFU, 8 of 83 participants (9.6%) reported having used Ecstasy or MDMA between treatment exit and long-term follow-up.”

Only two of those hadn’t used it before and all were using it therapeutically or recreationally.

“The pharmacologic effects of MDMA administered within a course of psychotherapy engender a unique therapeutic process that seems to enhance treatment engagement, reduce treatment discontinuation, and extend treatment effects.”

Summary

Long-term follow-up outcomes of MDMA-assisted psychotherapy for treatment of PTSD: a longitudinal pooled analysis of six phase 2 trials

Posttraumatic stress disorder (PTSD) can have negative effects on an individual’s health and interpersonal relationships.

Introduction

Posttraumatic stress disorder (PTSD) affects 3% to 4% of the general population, 17% of US war veterans, and 32% of emergency personnel and first responders.

Evidence-based treatments for PTSD include pharmacotherapies and/or psychotherapies, which appear to perform moderately well when compared with placebo. However, many people with PTSD still fail to adequately respond to or tolerate available pharmacological or psychotherapeutic interventions.

In 2017, the Food and Drug Administration designated 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy as a Breakthrough Therapy after preliminary results from phase 2 clinical trials. MDMA-assisted psychotherapy is a drug-assisted psychotherapy similar to psychedelic-assisted psychotherapies, such as those using psilocybin or LSD.

MDMA-assisted psychotherapy may have therapeutic effects due to changes in brain activity associated with emotional memory processing, an increase in emotional empathy for self and others, and greater self-compassion.

Participants in six phase 2 clinical trials who received MDMA for treatment of PTSD experienced significant reductions in Clinician-Administered PTSD Scale for DSM IV (CAPS-IV) total severity scores at the 1-to 2-month follow-up compared with participants who received 0 – 40 mg MDMA (placebo/control dose).

The long-term benefit of MDMA-assisted psychotherapy was supported by preliminary evidence from the first phase 2 trial. This analysis pooled data from all six phase 2 trials to examine long-term effects of MDMA-assisted psychotherapy on PTSD symptoms and other benefits/harms.

Methods

To examine long-term changes in PTSD symptoms after MDMA-assisted psychotherapy, six phase 2 trials were pooled and analyzed. Participants were recruited through Internet advertisements, referrals by healthcare professionals, and word of mouth.

In these trials, participants were randomized to either a control group (inactive placebo) or an active dose group (75 mg, 100 mg, or 125 mg MDMA). The studies were approved by Institutional Review Boards, and all participants provided written consent for participation.

MDMA treatment

Participants began treatment with three preparatory therapy sessions, followed by two 8-h psychotherapy sessions, spaced a month apart, with administration of active MDMA or a comparator/placebo dose. They received brief telephone calls for 7 days after the experimental sessions.

Participants who received 100 mg or 125 mg in a blinded segment had a third active dose session, and participants in the control group had two to three blinded sessions. Two participants in one study served as open-label lead-ins during supervision of new therapy teams.

Long-term follow-up assessment occurred 12 months after the final active dose MDMA session for each participant and included completion of the CAPS-IV and a LTFUQ.

Assessments

We administered outcome measures at baseline, 1 to 2 months post two or three experimental sessions, and at long-term follow-up.

The Clinician-Administered PTSD Scale for DSM IV (CAPS-IV) is a semi-structured interview used to assess PTSD symptom severity and diagnosis. It yields a total severity score and a diagnostic score.

The LTFUQ was used to determine whether participants perceived any benefits or harms from study participation and to track elements of recovery that were not included in measures of PTSD symptoms.

The Long-Term Follow-Up Questionnaire (LTFUQ) was administered in English in studies in the USA (MP-1, MP-8, and MP-12) and Canada (MP-4), and was translated into Hebrew for study MP-9.

Suicidal ideation and behavior were collected using the clinician-administered Columbia Suicide Severity Rating Scale.

Statistical analysis

Data from six phase 2 trials were pooled to assess the long-term effects of MDMA-assisted psychotherapy on PTSD symptoms and other benefits/harms. A mixed-effect model repeated-measures analysis was used to compare changes in CAPS-IV total severity scores at baseline, treatment exit, and long-term follow-up.

Sample

In six studies, 107 participants with moderate to severe PTSD received an active dose of MDMA in two to three blinded or open-label sessions. Eighty-three participants completed the long-term follow-up CAPS-IV assessment, and thirty participants from the control group crossed over to open-label active full-dose MDMA sessions.

Treatment exit and long-term follow-up CAPS

The primary efficacy evaluation showed significant reductions in PTSD symptom severity at treatment exit compared to baseline, and further decreases from treatment exit to long-term follow-up. The covariate analysis indicated that changes in CAPS-IV severity differed across studies.

Suicidal ideation and behavior

Four out of six studies administered the C-SSRS to participants with chronic PTSD, and 60.3% reported positive ideation at baseline, 1.5% reported positive behavior, and 24.2% reported positive ideation at long-term follow-up.

Long-term follow-up questionnaire: harms and benefits

97.6% of participants across studies reported experiencing benefits, and 92.2% reported that some to all benefits lasted. Seven participants reported experiencing harms, but all reported at least one benefit, and nine participants reported a relapse of PTSD symptoms since completing the active treatment phase.

Factors associated with having benefits vs. harms were assessed using available data. Those who reported any harms had higher baseline mean CAPS-IV scores and smaller reductions in CAPS-IV scores at treatment exit.

Current treatments and substance use at long-term follow-up

At LTFU, 26 of 55 participants reported therapy for PTSD, and 31 of 41 participants who reported therapy for any reason at baseline also reported therapy at LTFU. Nearly one-third of participants reported starting new medications since the study.

At long-term follow-up, 9.6% of participants reported having used Ecstasy or MDMA between treatment exit and long-term follow-up, and 22 participants reported decreasing alcohol consumption since study enrollment, while 17 participants reported staying the same or increasing alcohol consumption.

Discussion

In six phase 2 studies, participants with moderate to severe PTSD responded well to MDMA-assisted psychotherapy, with decreases in CAPS-IV scores that were sustained at long-term follow-up. Additionally, proportions of participants who reported positive suicidal ideation decreased from approximately 60% at baseline to 24% at long-term follow-up.

Participants who received two to three active doses of MDMA experienced high LTFU response rates and sustained effects of MDMA-assisted psychotherapy post-treatment, comparable to other PTSD treatments examined in longitudinal studies. Additionally, there was a low dropout rate and high follow-up rates.

In the present analysis, participants received two or three full active doses of MDMA alongside non-drug therapy sessions over the course of 3 to 4 months. The pharmacological effects of MDMA seem to enhance treatment engagement, reduce treatment discontinuation, and extend treatment effects.

Patients’ preferences have been shown to influence treatment refusal, discontinuation, and outcomes. MDMA-assisted psychotherapy could offer a novel treatment option for those who do not tolerate or respond to other treatments.

In addition to clinically and statistically significant improvements in PTSD symptoms, study participants reported benefits beyond decreased CAPS scores. These benefits might be explained in part by persistent psychological and interpersonal changes that may have resulted. Participants who received active doses of MDMA reported greater engagement in new activities, improved quality of life, and increased openness to further psychotherapy at LTFU, suggesting they were able to successfully integrate therapeutic experiences into their daily lives to cultivate continued healing and growth.

This study examined changes in the primary outcome measure (CAPS-IV) and self-reported questionnaire items at long-term follow-up (LTFU) in participants who received MDMA-assisted psychotherapy for PTSD. However, the lack of a control group limited causal inferences between MDMA-assisted psychotherapy and any long-term effects.

Approximately 94% of participants reported wanting additional experimental sessions at LTFU. This might suggest the need for additional treatment for PTSD or an interest in further psychological growth and enriched relationships.

There were large differences between those who reported having any benefits and those who reported having any harms. However, all seven participants reported at least one benefit from study participation.

Conclusion

Results support the use of MDMA-assisted psychotherapy for the treatment of PTSD, and suggest possible long-term benefits beyond PTSD symptom reduction.