Breakthrough for trauma treatment: safety and efficacy of MDMA-assisted psychotherapy compared to paroxetine and sertraline

This review (2019) details the potential superiority of MDMA-assisted psychotherapy as a treatment for PTSD compared to the conventional treatment options paroxetine and sertraline.

Abstract

“Unsuccessfully treated posttraumatic stress disorder (PTSD) is a serious and life-threatening disorder. Two medications, paroxetine hydrochloride and sertraline hydrochloride, are approved treatments for PTSD by the Food and Drug Administration (FDA). Analyses of pharmacotherapies for PTSD found only small to moderate effects when compared with placebo. The Multidisciplinary Association for Psychedelic Studies (MAPS) obtained Breakthrough Therapy Designation (BTD) from the FDA for 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for treatment of PTSD on the basis of pooled analyses showing a large effect size for this treatment. This review covers data supporting BTD. In this treatment, MDMA is administered with psychotherapy in up to three monthly 8-h sessions. Participants are prepared for these sessions beforehand, and process material arising from the sessions in follow-up integrative psychotherapy sessions. Comparing data used for the approval of paroxetine and sertraline and pooled data from Phase 2 studies, MAPS demonstrated that MDMA-assisted psychotherapy constitutes a substantial improvement over available pharmacotherapies in terms of safety and efficacy. Studies of MDMA-assisted psychotherapy had lower dropout rates compared to sertraline and paroxetine trials. As MDMA is only administered under direct observation during a limited number of sessions, there is little chance of diversion, accidental or intentional overdose, or withdrawal symptoms upon discontinuation. BTD status has expedited the development of MAPS phase 3 trials occurring worldwide, leading up to a planned submission seeking FDA approval in 2021.”

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

Summary

Introduction

MDMA-assisted psychotherapy for the treatment of posttraumatic stress disorder (PTSD) was granted breakthrough therapy designation by the Food and Drug Administration on August 16, 2017.

PTSD is considered a serious and life-threatening disorder that can lead to fractured relationships, depression, decreased daily functioning, diminished cognitive and psychosocial functioning, substance abuse, and high-cost healthcare utilization.

There are two approved oral medications for PTSD, sertraline hydrochloride (Zoloft) and paroxetine hydrochloride (Paxil), and trauma-focused psychotherapies (e.g., eye movement desensitization, cognitive processing therapy, prolonged exposure). However, many individuals fail to tolerate or respond to available treatments, including trauma-focused psychotherapies.

MAPS held six phase 2 trials of MDMA-assisted psychotherapy for PTSD that were submitted to the FDA. The data supporting the approval of these drugs for PTSD was extracted from the drug labels.

Here, we present the evidence from phase 2 trials showing that MDMA-assisted psychotherapy was superior to two approved SSRIs for treatment of PTSD.

Efficacy and Durability of Response: MDMA vs SSRIS

MDMA-Assisted Psychotherapy

MDMA is a ring-substituted phenethylamine that promotes empathy and compassion for self and others. It also enhances levels of the neurohormone oxytocin, and increases the ability to tolerate distressing memories, as well as increasing reward from pleasant memories and less distress in response to social exclusion.

Investigators have developed standardized psychotherapeutic methods for combining MDMA and psychotherapy, which include up to 3 sessions with MDMA and up to 12 non-drug sessions. Participants may use eye shades, and listen to a program of music designed to support the therapy.

Phase 2 Trials of MDMA-Assisted Psychotherapy for PTSD Treatment

Six Phase 2 studies of MDMA-assisted psychotherapy were conducted with patients with PTSD. The studies used the Clinician-Administered PTSD Scale for DSM-IV (CAPS-IV) as the primary efficacy measure and included three preparatory psychotherapy sessions, two to three blinded, 8-h experimental psychotherapy sessions, and three non-drug integrative psychotherapy visits following each experimental session.

Data from six phase 2 studies showed that the active dose group (MDMA 75 – 125 mg, n = 72) was statistically superior to the control group at the primary endpoint.

17 and 35 subjects who had previously taken paroxetine and sertraline, respectively, were randomized to receive MDMA therapy. Of these, 20/38 (52.6%) no longer met criteria for PTSD after receiving active doses of MDMA.

Sertraline Phase 3 Trials for PTSD

Sertraline was investigated for treatment of PTSD in four studies of similar design with a 12-week flexible dose. Two of the four studies failed to find a significant difference between the sertraline and placebo treated groups on any of the primary efficacy outcomes.

A combination of two positive studies found that sertraline significantly reduced PTSD symptoms in women but not in men. However, a longer-term study found that sertraline reduced relapse rates in both males and females.

Paroxetine Phase 3 Trials for PTSD

Paroxetine demonstrated superiority over placebo on change from baseline for the CAPS-2 total score and proportion of responders assessed by the Clinical Global Impression-Global Improvement Scale.

In studies 1 and 2, paroxetine was significantly better than placebo on both outcome measures (LOCF and OC). Paroxetine was better than placebo at 4, 8, and 12-week time points (LOCF and OC analyses).

A third study found paroxetine to be significantly better than placebo on CAPS-2 total score, but not on CGI-I responders. The difference in mean change from baseline between paroxetine and placebo was roughly 6-14 units across the three studies.

Comparison: SSRIs vs. MDMA

MDMA showed a significant effect over the comparator group in six MAPS-sponsored phase 2 trials on change from Baseline to Primary Endpoint in CAPS-IV Total Severity, with a large between-group effect size. MDMA produced a rapid clinical response after a single MDMA dose.

Studies of sertraline and paroxetine did not find significant improvement until after 12 weeks of daily drug administration, while MDMA-assisted psychotherapy has been shown to last for at least 12 months in many participants.

Compliance and Safety: MDMA vs. SSRIS

The dropout rate in active MDMA-treated subjects in MAPS-sponsored Phase 2 trials was 6.8%, considerably less than SSRI-treated subjects. This may be due to the therapeutic effects of MDMA, as well as the therapeutic alliance and commitment to the course of psychotherapy.

In trials with paroxetine, the most common adverse events were nausea, headache, insomnia, diarrhea, dry mouth, decreased appetite, somnolence, libido decreased, abnormal ejaculation, female genital disorders, and impotence.

MDMA administered in single doses spaced a month apart in a controlled setting has several inherent benefits over chronic daily dosing of paroxetine or sertraline. Firstly, compliance is not an issue in studies of MDMA, and secondly, fewer side effects are reported after MDMA due to the limited number of administrations.

Paroxetine and sertraline may cause adverse effects during discontinuation. These effects are likely caused by neuroadaptations of decreased levels of serotonin transporters in neuronal membranes after use of SSRIs.

Single doses of MDMA have not produced discontinuation symptoms, but some adverse reactions are reported during the 7 days following an MDMA dose, including anxiety and fatigue. These symptoms are mild to moderate in severity, and nearly all resolve within 7 days of dosing.

Researchers have conducted retrospective studies in people reporting ecstasy use, and have found no evidence of long-term deleterious effects of discrete doses of MDMA. In contrast, three trials of MDMA-assisted psychotherapy have found no evidence of impairment after any dose of MDMA.

SSRIs are contraindicated with MAOIs and some other drugs, and patients are at risk of accidentally consuming a contraindicated medication. Overdoses have also been reported with both SSRIs, but clinicians collect concomitant medication information at each session before administering MDMA.

MDMA-assisted psychotherapy received BTD based on phase 2 clinical data that showed MDMA produced substantial clinical improvement and greater compliance than two approved drugs for PTSD, paroxetine and sertraline. MDMA will be administered directly to patients in licensed MDMA clinics under controlled conditions.

Comparison of MDMA-Assisted Psychotherapy vs. Trauma-Focused Therapies

In meta-analyses of randomized controlled trials, trauma-focused psychotherapies resulted in greater and more sustained response than pharmacotherapies and other psychological therapies. MDMA-assisted psychotherapy had an effect size of 0.9 compared to psychotherapy alone or low dose MDMA plus psychotherapy.

MDMA may help to speed up symptom improvement in PTSD patients by increasing neuroplasticity and altering brain activity in key networks for emotional-memory processing. It may also help patients to feel more comfortable processing traumatic memories.

A meta-analysis of five phase 2 MDMA-assisted psychotherapy trials found no significant differences in benefits of pharmacological, psychotherapeutic, or the combination at the end of treatment, except at the last available endpoint during long-term follow-up, at which point psychotherapeutic treatments were significantly better than medications.

Status of MDMA Dugs Development with Breakthrough Designation

BTD is intended to expedite the development and approval of promising treatments by allowing for more frequent interactions with the FDA.

MAPS and the FDA reached agreement for two multi-site Phase 3 trials of MDMA-assisted psychotherapy for patients with at least severe PTSD, which will enroll approximately 200-300 participants.

Conclusion

MDMA may have advantages over existing medications used as first-line PTSD treatments in terms of safety and side effect profiles, efficacy, and length of remission. MDMA-assisted psychotherapy has the potential to favorably impact the lives of thousands who suffer from PTSD world-wide.

Author Contributions

LJ, AF, AE, BY-K, RD, and MM contributed to the concept and design of the review, which was edited by RD.

Acknowledgments

The authors express great appreciation to the clinical investigators and MAPS staff who made this report possible.

Authors

Authors associated with this publication with profiles on Blossom

Rick Doblin
Rick Doblin Ph.D. is the founder of MAPS. His persistent work since 1986 has been one of the main drivers behind why psychedelics (including MDMA) are now coming back to therapy.

Michael Mithoefer
Michael Mithoefer is a psychiatrist and a Clinical Investigator and acting Medical Director of MAPS Public Benefit Corporation.

Institutes

Institutes associated with this publication

MAPS
MAPS stands for Multidisciplinary Association for Psychedelic Studies, it's the front runner in making psychedelics a legal way to use (and improve) in therapy.

Linked Clinical Trial

A Test of MDMA-Assisted Psychotherapy in People With Posttraumatic Stress Disorder
This randomized, double-blind, placebo-controlled trial (n=23) assessed the safety and effectiveness of MDMA-assisted therapy among people with chronic, treatment-resistant PTSD, including veterans.

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