Research Base for MDMA in Posttraumatic Stress Disorder
Preliminary and Phase 2 Studies
Due to the frequently treatment refractory nature of PTSD, there has been considerable interest in whether PAP may be a useful intervention, especially using MDMA. The first study to test MDMA assisted psychotherapy in patients with PTSD was published by US researchers in 2011 [9]. 22 patients with PTSD received either real MDMA or placebo during two drug–therapy sessions as well as both preparatory and follow-up psychotherapy. These additional therapy sessions involved two 90-minute sessions before the all-day drug administration, one session the morning immediately after drug administration, and three weekly 90-minute therapy sessions after each drug administration. During the drug administration sessions two therapists provided a therapy that was predominantly nondirective and supportive.
There was a substantial reduction in symptoms of PTSD after each of the two drug administration sessions compared to what was seen in the placebo group. Importantly, PTSD scores remained substantially improved in the patients who had real treatment two months later and these benefits were found to persist over several years in a longer term follow-up study [10]. During drug administration there were some temporary increases in blood pressure, pulse and body temperature but these were transient. Other potential side effects were also transient and there were no significant adverse events. Unfortunately, this study did not include a systematic assessment of mood or depressive symptoms.
A follow-up study by the same investigators involved the treatment of 26 civil and military ex-service personnel with PTSD [11]. Two sessions were again used, one month apart but on this occasion, patients were randomised to a low, moderate or high dose of MDMA. Clinical outcomes were substantially better in the moderate and high dose group than in the low dose group but there were no differences between the moderate and high dose groups themselves.
A separate trial by a different group investigating the effects of MDMA in 12 patients with treatment resistant PTSD [12]. The patients were randomised to receive either low-dose or ‘full dose’ MDMA during threeexperimental sessions (with a possibility of further sessions dependent on initial response) with weekly non-drug base psychotherapy sessions. Benefits were not significant on the clinician administered PTSD Scale (CAPS) although significant improvements were seen in the full dose but not the low dose group. There was a statistically significant improvement on the patient rated post-traumatic diagnostic Scale (PDS) scores.
A fourth study investigated the use of MDMA in 28 patients across multiple therapy teams in two drug therapy sessions [13]. This also compared a full dose (100 and 125mg) to a low dose (40mg) and narrowly failed to differences on the CAPS scale (p=0.0066) but found benefits of a full dose compared to a low dose on the PDS.
Interestingly, and perhaps importantly, a recent secondary analysis of data from four trials suggested that recent exposure to SSRI/SNRI medication, even when the drugs were withdrawn prior to commencing PAP, was associated with a poorer outcome compared to individuals who have not recently been on these medications [14]. This could indicate an interaction between recent drug exposure and PAP but could also suggest that patients who were recently withdrawn from these medications were experiencing a withdrawal syndrome which led to a poorer response to PAP.
Finally, a small study has recently been published describing outcomes of PAP with MDMA in three patients treated for PTSD secondary to sexual abuse and who have failed at least one previous psychotherapy or medication treatment [15]. The patients had a total of three MDMA treatments along with 12 other therapy sessions and all reported significant improvement with the grated 30% reduction in CAPS scores in all.
Phase 3 Research
A single modest phase 3 trial has recently been published reporting directly on the efficacy of MDMA assisted therapy for treatment of patients with PTSD in a multisite trial [16]. 90 patients with PTSD were randomised to receive either MDMA or placebo (during three dosing sessions), supported by three preparation and nine integration therapy sessions. There was a substantially greater reduction in PTSD (CAPS-5) scores in the MDMA group compared to the placebo group that persisted two months after the last experimental session. There was no evidence that MDMA resulted in elevations of suicidality, QT prolongation or abuse liability.
There was no SAE is in the MDMA group (two suicide related essays in the placebo group). There was a transient elevation of blood pressure and heart rate in the MDMA group and two patients had a transient increase in body temperature but neither of these effects required intervention. The most common side effects reported in the MDMA group were muscle tightness, decreased appetite nausea, sweating and feeling cold.