High-Intensity Inpatient MDMA-Assisted Psychotherapy for PTSD

Posttraumatic stress disorder (PTSD) is a debilitating condition, which is characterized by re-experiencing, avoidance, and hyperarousal symptoms that have developed following a traumatic experience. Patients suffering from PTSD usually experience a strong negative impact from the disorder on their daily life, diminished cognitive and psychosocial functioning, fractured relationships, inability to maintain employment, substance abuse, high-cost healthcare utilization, increased depression, and suicide risk.

Current evidence-based treatments include trauma-focused therapies (e.g., EMDR and prolonged exposure) and pharmacotherapies (e.g., paroxetine and sertraline). However, PTSD often remains a chronic illness, with high rates of psychiatric and medical comorbidity. One promising new approach involves the use of certain psychoactive drugs as adjuncts to psychotherapy. One drug that has shown particularly promising effects when used within such a substance-assisted therapy approach, is 3,4-methylenedioxymethamphetamine (MDMA). The main rationale behind MDMA-assisted therapy is that MDMA acts as a catalyst to therapy, by reducing the fear response to anxiety provoking stimuli, including previous trauma and traumatic memories. In addition, MDMA enhances introspection and increases interpersonal trust, which can benefit the therapeutic alliance. From a clinical perspective, MDMA alters cognition very slightly, produces only mild sensory alterations, and does not induce a clouding of consciousness, while patients sustain a clear memory of the experience. These subjective effects of MDMA seem to create a productive psychological state that can enhance the therapeutic process.

In the past two decades, several Phase 2 and 3 studies have demonstrated superior efficacy of manualized MDMA-assisted therapy over therapy with placebo or low dose MDMA. These studies provided evidence that chronic PTSD, independent of cause, may be treatable with two to three sessions of MDMA-assisted therapy and associated non-drug preparatory and integrative therapy sessions.

The efficacy and acceptable risk-benefit safety ratio demonstrated in these studies and the potential regulatory approval of this novel therapy, raises several questions, both on how MDMA-assisted therapy could be implemented in national healthcare infrastructures, and on how to tailor the treatment to different PTSD subpopulations. For example, until now MDMA-assisted therapy has solely been studied as an outpatient treatment that takes places over the course of several months. However, a significant percentage of patients with PTSD might benefit from an inpatient setting with an increased frequency of therapy sessions. Several recent studies have investigated such a high intensity inpatient approach to the treatment of PTSD, in which daily trauma focused therapies such as EMDR and prolonged exposure are integrated within a one- to two-week treatment program that includes physical and other activities. In addition to the promising efficacy of this approach, it also offers several other potential benefits, such as increased safety and lower dropout rates. Studying the feasibility of such a high-intensity inpatient approach to MDMA-assisted therapy could broaden its potential future application to a wider range of PTSD subpopulations, including patients with common comorbid conditions that are currently being excluded from MDMA-assisted therapy studies, such as substance use disorders, personality disorders and patients with a higher risk for suicidality. Furthermore, intensifying MDMA-assisted therapy within several weeks of inpatient treatment, might also further increase its efficacy and higher the probability of long-term durability of its effects on PTSD symptoms, by optimizing the integration process in the days and weeks following MDMA sessions.

This open-label pilot study aims to gather supportive data on the feasibility, safety and efficacy of such a High-Intensity approach to delivering MDMA-assisted therapy (HI-MAP). As an initial pilot study, it will focus on a population of treatment-refractory PTSD patients with current moderate to severe PTSD which did not benefit from at least two evidence-based psychotherapies (e.g., EMDR and Prolonged Exposure) for PTSD. This corresponds with the current Dutch standard of care, which recommends to intensify treatment at this stage. Two Experimental Sessions of manualized MDMA-assisted therapy spaced two weeks apart will be integrated within a four-week inpatient treatment program, with preparatory and integrative therapy. The study will be conducted at ARQ Centre'45, a specialized PTSD treatment center, which has been offering high intensity inpatient treatments for years and which has also functioned as a primary study site in a multisite European Phase 2 study into the effects of outpatient MDMA-assisted therapy for the treatment of PTSD.

• Sheehan Disability Scale [Time frame: From Baseline to 1 month after final integrative psychotherapy session]