Posttraumatic Growth After MDMA-Assisted Psychotherapy for Posttraumatic Stress Disorder

Ingmar Gorman, Alexander B. Belser, Lisa Jerome, Colin Hennigan, Ben Shechet, Scott Hamilton, Berra Yazar-Klosinski, Amy Emerson, and Allison A. Feduccia

Journal of Traumatic Stress, 2020, 1-10.

Doi : 10.1002/jts.22479

 

3,4-Methylenedioxymethamphetamine (MDMA)–assisted psychotherapy for posttraumatic stress disorder (PTSD) has been shown to significantly reduce clinical symptomatology, but posttraumatic growth (PTG), which consists of positive changes in self-perception, interpersonal relationships, or philosophy of life, has not been studied with this treatment. Participant data (n = 60) were pooled from three Phase 2 clinical studies employing triple-blind crossover designs. Participants were required to meet DSM-IV-R criteria for PTSD with a score higher than 50 on the Clinician-Administered PTSD Scale (CAPS-IV) as well as previous inadequate response to pharmacological and/or psychotherapeutic treatment. Data were aggregated into two groups: an active MDMA dose group (75–125 mg of MDMA; n = 45) or placebo/active control (0–40 mg of MDMA; n = 15). Measures included the Posttraumatic Growth Inventory (PTGI) and the CAPS-IV, which were administered at baseline, primary endpoint, treatment exit, and 12-month follow-up. At primary endpoint, the MDMA group demonstrated more PTG, Hedges’ g = 1.14, 95% CI [0.49, 1.78], p < .001; and a larger reduction in PTSD symptom severity, Hedges’ g = 0.88, 95% CI [−0.28, 1.50], p < .001, relative to the control group. Relative to baseline, at the 12-month follow-up, within-subject PTG was higher, p < .001; PTSD symptom severity scores were lower, p < .001; and two-thirds of participants (67.2%) no longer met criteria for PTSD. MDMA-assisted psychotherapy for PTSD resulted in PTG and clinical symptom reductions of large-magnitude effect sizes. Results suggest that PTG may provide a new mechanism of action warranting further study.

 

A novel treatment for posttraumatic stress disorder (PTSD) utilizing 3,4 methylenedioxymeth-amphetamine (MDMA) to enhance psychotherapy first entered clinical trials in 2000 (Bouso, Doblin, Farr´e, Alc´azar, & G´omez-Jarabo, 2008), and six randomized controlled studies had been completed as of 2017 (Feduccia, Holland & Mithoefer, 2017). Results from these trials demonstrate that MDMA-assisted psychotherapy produces significant reductions in PTSD symptoms (Mithoefer et al., 2018; Mithoefer, Wagner, Mithoefer, Jerome, & Doblin, 2011; Oehen, Traber, Widmer, & Schnyder, 2013; Ot’alora et al., 2018) and that these reductions endure (Mithoefer et al., 2013). Results of a pooled analysis of six Phase 2 studies (Mithoefer et al., 2019) demonstrated that two psychotherapy sessions with active doses ofMDMA more than doubled PTSD symptom reduction compared to psychotherapy with placebo controls (estimated mean difference between groups=−22.0, SE = 5.17), d = 0.8. The Food and Drug Administration (FDA) designated MDMA-assisted psychotherapy as a Breakthrough Therapy in 2017, indicating that the treatment addresses a serious or life-threatening condition and may have preliminary evidence demonstrating substantial improvement over existing therapies for PTSD.

However, posttraumatic growth (PTG), defined as positive posttrauma changes in self-perception, interpersonal relationships, or philosophy of life, has not yet been studied as an independent outcome or a mechanism of symptom reduction with MDMA-assisted psychotherapy. Given the high incidence and prevalence of PTSD, it is critical to pursue promising treatments and explore and model possible mechanisms of action (Kessler et al., 2005). The reported lifetime prevalence of PTSD in the general population of the United States is approximately 6.8%, and the disorder affects about 7.7 million U.S. adults in any given year (Kessler et al., 2005). According to the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V; American Psychiatric Association [APA], 2013), individuals diagnosed with PTSD will persistently reexperience aspects of the traumatic event, avoid trauma-related stimuli, and experience negative thoughts or feelings as well as increased hyperarousal
and reactivity related to the trauma. Existing PTSD research has tended to focus on symptom severity as a primary outcome while neglecting positive life changes that may accompany an engagement with trauma in a psychotherapeutic intervention, independent of symptom reduction. Although one criterion for a clinical diagnosis according to DSM-5 is for the ailment to cause “clinically significant distress or impairment in social, occupational, or other important areas of functioning” (APA, 2013), and although functional impairment has been closely linked to the severity of PTSD symptomatology, few intervention PTSD trials have evaluated whether functioning in these domains improves (Rodriguez, Holowka, & Marx, 2012).

Posttraumatic growth has been defined as “positive psychological change experienced as a result of the strugglewith highly challenging life circumstances” (Calhoun & Tedeschi, 1999; Tedeschi & Calhoun, 2004). Tedeschi and Calhoun (1996) grouped these positive changes into three main categories: changes in self-perception, changes in interpersonal relationships, and changes in philosophy of life. The authors of the Posttraumatic Growth Inventory (Tedeschi & Calhoun, 1996; PTGI), a widely used and validated measure of PTG, identified five factors underlying the construct: relating to others, new possibilities, personal strengths, spiritual change, and appreciation of life (Taku, Cann, Calhoun,&Tedeschi, 2008). Research using the PTGI has concentrated on how the struggle with adversity affects these factors (Shakespeare-Finch & Lurie-Beck, 2014). Calhoun and Tedeschi (1998) theorized that psychotherapy
may facilitate PTG and that this growth may play a role in the consolidation of symptom reduction. The results of a meta-analysis of 42 studies on PTSD that assessed both PTSD symptoms and PTG found that “both positive and negative posttrauma outcomes can co-occur” and that evidence exists for a significant relation between them, moderated by age and trauma type (Roepke, 2015). Roepke (2015) identified 12 randomized controlled trials that used a measure to assess PTG before and after a clinical intervention. Only five of the studies found that the intervention achieved statistically significant growth as compared to a control condition; these included group cognitive behavioral stress management (Antoni et al., 2001; Penedo et al., 2006), an online cognitive behavioral therapy intervention for PTSD symptoms (Knaevelsrud, Liedl, & Maercker, 2010), an online intervention for complicated grief (Wagner, Knaevelsrud, & Maercker, 2007), and written or spoken disclosure about adversity (Slavin- Spenny, Cohen, Oberleitner, & Lumley, 2011). For these five studies, Cohen’s d effect sizes ranged from small to large, with none exceeding an effect size value of 1.0. A review of the extant literature revealed no studies in which PTG was assessed in either a trial of psychotropic medication or medication-assisted psychotherapy.

The peer-reviewed literature on the PTG construct is not without criticism. Self-report of PTG may not necessarily reflect actual growth, evidenced by observable changes, but may rather indicate perceived change. This was supported by Frazier and colleagues (2009), who found no correlation between perceived growth and actual growth except for an association between perceived growth and increased distress from pre- to posttrauma. As an alternative, PTG could be understood as a motivated positive illusion that serves a protective function (McFarland & Alvaro, 2000). However, evidence contrary to this perspective has also been reported—high PTG prior to or soon after traumatic event exposure has been associated with significantly higher levels of posttraumatic stress at 15 months postevent or later (Blix, Birkeland, Hansen & Heir, 2016; Engelhard, Lommen, & Sijbrandij, 2014).

It is possible that MDMA-assisted psychotherapy may promote PTG among individuals with PTSD. The drug is associated with complex pharmacodynamics and pharmacokinetics (de la Torre et al., 2004; Hysek et al., 2012; Simmler et al., 2013) and with beneficial subjective effects, including improved self reported well-being, enhanced interpersonal closeness, more empathy for self and others, reduced distress in response to social exclusion and prosociality (Bershad, Miller, Baggott, & de Wit, 2016; Kamilar-Britt & Bedi, 2015), enhanced introspection, and emotional openness (Bedi, Van Dam, & Redman, 2010; Greer & Tolbert, 1986, Bershad et al., 2016). However, little has been published regarding the effect of this MDMA treatment on participants, beyond the primary outcome of PTSD symptom reduction. Could MDMA-assisted psychotherapy improve participants’ lives in other ways? Do participants report having better relationships, increased appreciation for life, or an enhanced sense of personal efficacy after engaging with their trauma in therapy? Such changes can be understood as PTG and positive psychological changes as a result of dealing with extremely negative experiences, such as military combat, life-threatening illness, or sexual assault (Tedeschi & Calhoun, 2004).

In this exploratory secondary analysis of data pooled from three Phase 2 trials, we hypothesized that MDMA-assisted psychotherapy would influence PTG positively while also reducing trauma symptoms. The examination of PTG in a clinical-trial context represents an advance in evaluation psychotherapy research, as it has yet to be studied as an outcome in medicationassisted psychotherapy. Our secondary objective was to evaluate whether reduction of PTSD symptoms was correlated with changes in PTG.

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