Breakthrough for Trauma Treatment: Safety and Efficacy of MDMA-Assisted Psychotherapy Compared to Paroxetine and Sertraline
Allison A. Feduccia, Lisa Jerome, Berra Yazar-Klosinski, Amy Emerson, Michael C. Mithoefer and Rick Doblin
Frontiers in Psychiatry, 2019, Volume 10, Article 650.
Unsuccessfully treated posttraumatic stress disorder (PTSD) is a serious and lifethreatening 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.
Clinical Trial Registration : www.ClinicalTrials.gov, identifiers NCT00090064, NCT00353938, NCT01958593, NCT01211405, NCT01689740, NCT01793610.
Keywords : methylenedioxymethamphetamine, posttraumatic stress disorder, breakthrough therapy, sertraline, paroxetine, anxiety
Breakthrough therapy designation (BTD) is one of the Food and Drug Administration’s (FDA) expedited drug development pathways. To be eligible for BTD, a sponsor must demonstrate that the investigational product is intended to treat a serious and life-threatening condition, with preliminary evidence supporting a substantial advantage at a clinically significant endpoint over existing drugs (1). On August 16, 2017, the FDA granted breakthrough therapy designation for MDMA-assisted psychotherapy for the treatment of posttraumatic stress disorder (PTSD). This application was among the 45% of applications granted BTD status in 2017 (2). The aim of this review is to summarize the data and rationale presented in the application that led FDA to grant this designation. PTSD is considered a serious and life threatening disorder and is associated with increased mortality, cardio-metabolic morbidity, and suicide risk. PTSD negatively impacts a person’s daily life, often resulting in fractured relationships, depression, decreased daily functioning, diminished cognitive and psychosocial functioning, substance abuse, and high-cost healthcare utilization ($34.9 billion in inflation-adjusted charges for hospitalizations (2002–2011) (3). Approximately 7% of the U.S. population, and 11.2–17.1% of veterans (4), will have PTSD sometime in their life (5).
Only two drugs, the selective serotonin reuptake inhibitors (SSRIs) sertraline hydrochloride (Zoloft) and paroxetine hydrochloride (Paxil), are approved oral medications for PTSD (6–8). These medications and trauma-focused psychotherapies (e.g., eye movement desensitization, cognitive processing therapy, prolonged exposure) are recommended as first-line treatments for PTSD (9–12). In a meta-analysis evaluating psychotherapy versus pharmacotherapy, trauma-focused psychotherapies resulted in greater and longer lasting improvements than medications (12). Meta-analyses and network meta-analyses found paroxetine, but not sertraline, performed better than placebo (13, 14). Hoskins and colleagues reported that SSRIs had a small effect size with respect to PTSD symptom reduction.
When compared to a control group, SSRIs either had insignificant effects or small/moderate effects, while trauma-focused therapies varied from small to large effects (12). The average dropout rate for the 55 studies included in the meta-analysis was 29% (0–79%) demonstrating that many individuals fail to tolerate or respond to available treatments (12), including trauma-focused psychotherapies, where the dropout can range from 28 to 68% (15, 16). A network meta-analysis reported that dropout rate for paroxetine and sertraline was greater than placebo (14).
The Multidisciplinary Association for Psychedelic Studies (MAPS) holds an Investigational New Drug Application (IND) for MDMA as an adjunct to psychotherapy for treatment of PTSD. MAPS has sponsored six phase 2 trials of MDMA-assisted psychotherapy for PTSD that lasted from April 2004 to March 2017. The safety and efficacy results from these trials were submitted to the FDA, along with a summary of the sertraline and paroxetine data that supported the New Drug Application (NDA) for approval of these drugs for the indication of PTSD. Sertraline and paroxetine summary data was extracted from documents found in the FDA drug database, including the Review and Evaluation of Clinical Data and the drug labels (17–20).
Here, we present the evidence included within the breakthrough therapy application showing that MDMA-assisted psychotherapy was superior in phase 2 trials in terms of safety and efficacy compared to the two approved SSRIs for treatment of PTSD. The control groups in the MDMA trials also received intensive psychotherapy (approximately 30 h), while SSRIs pivotal trials used a placebo without any type of therapy for comparison. Since the FDA does not regulate psychotherapy, the BT application did not compare MDMA-assisted psychotherapy to trauma-focused therapies. However, since trauma-focused therapies have evidence for the greatest effectiveness in reducing PTSD symptoms, we have included an additional section in this review comparing MDMA-assisted-psychotherapy with first-line psychological therapies.