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

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

Psychopharmacology, 2019

https://doi.org/10.1007/s00213-019-05249-5

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 ofMDMA (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 MDMAwere 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.

Trial registration ClinicalTrials.gov Identifier: NCT00090064, NCT00353938, NCT01958593, NCT01211405, NCT01689740, NCT01793610.

Keywords : MDMA .MDMA-assisted psychotherapy . Posttraumatic stress disorder . Anxiety . Psychedelic

 

Introduction
Posttraumatic stress disorder (PTSD) is a serious debilitating disorder with lifetime prevalence estimated at nearly 4% globally and over 8% in the USA (Kilpatrick et al. 2013; Koenen et al. 2017). Symptoms of PTSD include intrusive thoughts and memories, negative effects on cognition and mood, hyperarousal and reactivity, and avoidance that do not remit for at least 1 month subsequent to exposure to a traumatic event (Koenen et al. 2017). Individuals with PTSD may experience a substantial reduction in quality of life and relationships, and the disability resulting from PTSD can have further negative consequences such as obesity (Scott et al. 2008), hypertension (Kibler et al. 2009), comorbid mental
health conditions, and suicidality (Dorrington et al. 2014; Tarrier and Gregg 2004). In addition to these profound costs to individuals with PTSD, the disorder also exerts a substantial economic toll through lost productivity and treatment costs (Marshall et al. 2000).

Widely used treatments for PTSD include psychotherapies and medications. A recent review identified trauma-focused psychotherapies as first-line treatments for PTSD (Lee et al. 2016); however, while a substantial proportion of individuals with PTSD respond to psychotherapies [e.g., cognitive processing therapy (Monson et al. 2006; Resick et al. 2008) and prolonged exposure therapy (Foa et al. 2007)], these therapies may be difficult to access and are ineffective for many (Koenen et al. 2017; Steenkamp et al. 2015). A variety of medications have also been used to address PTSD symptoms, but only two drugs—sertraline and paroxetine—are approved by the FDA for PTSD. Extant pharmacotherapies, however, are ineffective for many individuals with PTSD, with an estimated 40–60% of patients not responding adequately (Bradley et al. 2005; Brady et al. 2000; Steenkamp et al. 2015). They may have problematic side effects and generally require long-term use to maintain effectiveness (Lee et al. 2016). In sum, the sizable proportion of cases of PTSD are persistent (Koenen et al. 2017) and the shortcomings of currently available treatments make the development of novel PTSD treatments a research priority.

A promising approach to the treatment of PTSD is the combination of psychotherapy with pharmacotherapy using 3,4-methylenedioxymethamphetamine (MDMA). Interest in the therapeutic potential of MDMA for trauma-related psychopathology developed in the context of the broader potential for MDMA to catalyze psychotherapeutic processes by facilitating communication and connection between therapists and patients (Nichols 1986). MDMAwas first synthesized in 1912 by Merck, but it was not until the early 1970s that MDMA was first used in combination with psychotherapy. Case reports from that period described therapeutic benefits, although no clinical trials were conducted at that time. Recreational use of Ecstasy, tablets purported to contain MDMA, became popular in the 1980s, leading to its classification as a Schedule 1 controlled substance in 1985. The scheduling of MDMA made its use in therapy illegal and created obstacles to clinical research. A non-profit organization, the Multidisciplinary Association for Psychedelic Studies (MAPS), filed a Drug Master File (DMF) application in 1986, followed by an Investigational New Drug (IND) application in 2001, embarking on the FDA drug development process to study the safety and efficacy of MDMA as an adjunct to psychotherapy for PTSD (Greer and Tolbert 1986; Grof 2001; Mithoefer 2011, 2017; Mithoefer et al. 2018).

After nonclinical toxicity studies and an investigatorinitiated phase 1 study of MDMA were completed (Frith et al. 1987; Grob et al. 1996, 1998), six phase 2 randomized trials of MDMA-assisted psychotherapy for treatment of PTSD were conducted from 2004 to 2017. Active doses of MDMA (75–125 mg) or control doses of inactive placebo or low-dose MDMA (25–40 mg) were combined with manualized inner-directed psychotherapy (Mithoefer 2017) in which participants were supported by a male and female therapy team (Mithoefer et al. 2011, 2018). The therapeutic model described in the Treatment Manual was based upon initial work with classic psychedelics (Grof 2001; Mithoefer 2017) and early reports of MDMA in a therapeutic setting (Greer and Tolbert 1986). Four of these MAPS-sponsored studies have been published (Mithoefer et al. 2011, 2013, 2018; Oehen et al. 2013; Ot’alora et al. 2018), and all six studies demonstrated acceptable safety and promising efficacy results. The MDMA doses selected for phase 2 trials (control—0 mg, 25 mg, 30 mg, 40 mg; active—75 mg, 100 mg, 125 mg) were based on tolerability and subjective effects reported in several prior phase 1 studies (Cami et al. 2000; de la Torre et al. 2000; Grob et al. 1998; Harris et al. 2002; Liechti et al. 2001). Low doses (25 mg, 30 mg, 40 mg) produce some changes in subjective effects that could presumably enhance blinding as an active placebo but would be inadequate for a therapeutic response (Harris et al. 2002). The FDA, after reviewing all available data in 2016, granted Breakthrough Therapy Designation in 2017 and approved the designs of two phase 3 trials that started in 2018.

To optimize the design of the phase 3 trials, we pooled data from six phase 2 trials that had similar study objectives and designs. We aimed to determine how many MDMA sessions are needed to achieve a clinically significant response, what demographic and other baseline variables might impact outcomes, which safety parameters are essential, the optimal dose, and how best to minimize bias and enhance blinding. To that end, the aim of this paper is to present pooled data from randomized clinical trials at different study sites that evaluated the efficacy and safety profile of MDMA-assisted psychotherapy among individuals with PTSD from a range of causes.

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