3,4-Methylenedioxymethamphetamine assisted psychotherapy for treatment of chronic posttraumatic stress disorder : A randomized phase 2 controlled trial

Marcela Ot’alora G, Jim Grigsby, Bruce Poulter1, Joseph W Van Derveer III, Sara Gael Giron, Lisa Jerome, Allison A Feduccia, Scott Hamilton, Berra Yazar-Klosinski, Amy Emerson, Michael C Mithoefer and Rick Doblin

Journal of Psychopharmacology, 2018, 1-13

Doi : 10.1177/0269881118806297

 

Abstract

Background : Posttraumatic stress disorder often does not resolve after conventional psychotherapies or pharmacotherapies. Pilot studies have reported that 3,4-methylenedioxymethamphetamine (MDMA) combined with psychotherapy reduces posttraumatic stress disorder symptoms.

Aims : This pilot dose response trial assessed efficacy and safety of MDMA-assisted psychotherapy across multiple therapy teams.

Methods : Twenty-eight people with chronic posttraumatic stress disorder were randomized in a double-blind dose response comparison of two active doses (100 and 125 mg) with a low dose (40 mg) of MDMA administered during eight-hour psychotherapy sessions. Change in the Clinician- Administered PTSD Scale total scores one month after two sessions of MDMA served as the primary outcome. Active dose groups had one additional open-label session; the low dose group crossed over for three open-label active dose sessions. A 12-month follow-up assessment occurred after the final MDMA session.

Results : In the intent-to-treat set, the active groups had the largest reduction in Clinician-Administered PTSD Scale total scores at the primary endpoint, with mean (standard deviation) changes of −26.3 (29.5) for 125 mg, −24.4 (24.2) for 100 mg, and −11.5 (21.2) for 40 mg, though statistical significance was reached only in the per protocol set (p=0.03). Posttraumatic stress disorder symptoms remained lower than baseline at 12-month follow-up (p<0.001) with 76% (n=25) not meeting posttraumatic stress disorder criteria. There were no drug-related serious adverse events, and the treatment was well-tolerated.

Conclusions : Our findings support previous investigations of MDMA-assisted psychotherapy as an innovative, efficacious treatment for posttraumatic stress disorder.

Keywords
3,4-Methylenedioxymethamphetamine (MDMA), posttraumatic stress disorder, depression, sleep disturbance, oxytocin, serotonin

 

Introduction

Posttraumatic stress disorder (PTSD) is a disabling condition characterized by overwhelming negative emotions, panic, anxiety, intrusive re-experiencing of traumatic events, avoidance, negative alterations in cognition, and hyperarousal symptoms. Approximately 8% of the US population (24 m individuals) will suffer from PTSD in their lifetime (Kessler et al., 1995), and existing treatment approaches have limited effectiveness. Nonresponse and treatment dropout rates are high (Eftekhari et al., 2013; Goetter et al., 2015; Sareen et al., 2007), and at least 35% are left with debilitating symptoms that significantly impact quality of life. Individuals often feel fragmented and disconnected from self and others (Sareen et al., 2006). They seem to be continuously living a story that is in the distant past, and consequentially are not fully living in present time. The social impact includes alienation, loneliness, and functional impairment (Sareen et al., 2007). There is an immense need for innovative treatment options that improve outcomes, especially for PTSD refractory to psychotherapy and/or pharmacotherapies (Krystal et al., 2017). 3,4-Methylenedioxymethamphetamine (MDMA)-assisted psychotherapy is a novel approach that combines psychotherapy with limited administration of MDMA in a controlled setting to enable people suffering from PTSD to process trauma more effectively. Early reports of use in psychotherapy have suggested the potential utility of MDMA in psychotherapy (Bouso et al., 2008; Greer and Tolbert, 1986). Two previous randomized controlled trials showed promising safety and efficacy results for treatment of PTSD (Mithoefer et al., 2011, 2013, 2018; Oehen et al., 2013). MDMA’s unique subjective and therapeutic effects induce an optimal state that complements the process of working through traumatic memories while reducing the fear response (Mithoefer et al., 2016; Yazar-Klosinski and Mithoefer, 2017). Trauma theorists have asserted that emotional engagement is necessary for processing traumatic experiences (Foa, 2007; Jaycox et al., 1998) and, under the influence of MDMA, people are able to remain emotionally connected while working with difficult traumatic material.

This article presents results from a blinded, phase 2 dose response trial designed to evaluate the safety and efficacy of MDMA (40, 100, or 125 mg) as an adjunct to psychotherapy in 28 participants with chronic PTSD. PTSD symptom severity, dissociation, depression symptoms, and sleep quality were assessed at baseline, one-month after the second blinded session, after open-label sessions, and at 12 month follow-up. Safety outcomes were collected throughout the treatment period.

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