Scaling Up: Multisite Open-Label Clinical Trials of MDMA-Assisted Therapy for Severe Posttraumatic Stress Disorder

Abstract

Background: Posttraumatic stress disorder (PTSD) is a debilitating mental health condition associated with serious adverse health outcomes and functional impairment. Previous MDMA–assisted therapy (MDMA-AT) studies have shown promising results in single site studies. Two open-label studies tested this modality in multisite clinical trials to assess the feasibility of scaling this manualized therapy across 14 North American sites. Method: Cotherapist dyads were trained in the manualized MDMA-AT protocol and administered three experimental sessions 3 to 5 weeks apart among participants with severe PTSD. Cotherapist dyads were provided clinical supervision and evaluated for protocol adherence by centralized raters. Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) assessed change in symptoms severity. Results: Adherence rating scores were high across cotherapist dyads ( M = 95.08%, SD = 3.70%) and sites ( M = 95.23%, SD = 2.20%). CAPS-5 scores decreased following 3 MDMA-AT sessions at 18 weeks post baseline (Δ M = −29.99, Δ SD = 13.45, p < .0001, n = 37, Cohen’s d = 2.2, confidence interval [1.97, 2.47]). MDMA was well tolerated. Conclusions: These findings corroborate previous results that MDMA-AT can achieve significant improvements in PTSD symptom severity and demonstrate scalability of manualized therapy across clinic sites in the United States and Canada.

MDMA-assisted therapy for posttraumatic stress disorder: A pooled analysis of ethnoracial differences in efficacy and safety from two Phase 2 open-label lead-in trials and a Phase 3 randomized, blinded placebo-controlled trial

“…Findings from two multisite Phase 2 open-label lead-in trials (NCT03282123, NCT03485287; Wang et al, 2021) and the first Phase 3 randomized, blinded placebo-controlled trial (NCT03537014; Mitchell et al, 2021) corroborated efficacy and safety findings observed in Phase 2 trials. Wang et al (2021) found significant improvements in PTSD symptoms after three dosing sessions at the primary endpoint of 18 weeks post-baseline in 37 participants, with 76% no longer meeting criteria for PTSD. Mitchell et al (2021) found that the MDMA-AT group ( n = 46) reported significantly greater reductions in PTSD symptoms at primary endpoint compared to the placebo-assisted therapy (Placebo-AT) group ( n = 44).…”

“…A thorough description of the procedures for preparatory, dosing, and integration sessions in the MDMA-AT protocol can be found in Wang et al (2021) and Mitchell et al (2021).…”

“…The purpose of the present study was to conduct a secondary analysis using pooled data from the two aforementioned Phase 2 open-label trials (Wang et al, 2021) and one Phase 3 RCT (Mitchell et al, 2021) to compare efficacy and safety of MDMA-AT between BIPOC and non-Hispanic White participants. These data were selected for analysis because they assessed PTSD symptoms according to the most up-to-date diagnostic criteria (Diagnostic and Statistical Manual of Mental Disorders, 5th edition [DSM-5]).…”

Altered brain activity and functional connectivity after MDMA-assisted therapy for post-traumatic stress disorder

“…3,4-methylenedioxymethamphetamine-assisted therapy (MDMA-AT) is hypothesized to reduce the fear response associated with re-experiencing traumatic memories, and therefore may facilitate tolerable processing of traumatic content in patients with PTSD (Mithoefer et al 2011). Phase 2 and 3 trials have demonstrated promise for MDMA-AT as a viable treatment for PTSD (Mitchell et al 2021; Mithoefer et al 2019; Wang et al 2021; Jerome et al 2020). In healthy individuals, acute administration of MDMA has been shown to enhance positive and reduce negative affect during the recollection of autobiographical memories, while preserving vividness and emotional intensity (Carhart-Harris et al 2014).…”

“…Phase 2 and 3 trials have demonstrated promise for MDMA-AT as a viable treatment for PTSD (Mitchell et al 2021;Mithoefer et al 2019;Wang et al 2021;Jerome et al 2020). In healthy individuals, acute administration of MDMA has been shown to enhance positive and reduce negative affect during the recollection of autobiographical memories, while preserving vividness and emotional intensity (Carhart-Harris et al 2014).…”