This pilot study demonstrates that MDMA-assisted psychotherapy with close follow-up monitoring and support can be used with acceptable and short-lived side effects in a carefully screened group of subjects with chronic, treatment-resistant PTSD. In this group, MDMA-assisted psychotherapy compared with the same psychotherapy with inactive placebo produced clinically and statistically significant improvements in PTSD symptoms as measured by standard symptom scales. This difference was immediate and was maintained throughout the time period. There were no drug-related serious adverse events and no evidence of impaired cognitive function as measured by neuropsychological testing. The between-group effect size (1.24) of the study drug compares favorably with other treatment modalities for PTSD (Foa et al., 2009
), particularly given the treatment-refractory nature of the current sample. The clinical significance of the symptom reductions is indicated by the high percentage of subjects attaining a >30% reduction in CAPS scores and no longer meeting criteria for PTSD 2 months after MDMA-assisted psychotherapy, and by the report that all three subjects who had been unable to work because of PTSD were able to return to work.
The strengths of this study are its prospective, double-blind, crossover design, the use of a standardized primary outcome measure (CAPS) that is widely used for PTSD research (Weathers et al., 2001
), enrollment of chronic, treatment-resistant subjects who had moderate to severe PTSD, and the use of a blinded, independent rater. Subjects met well-defined inclusion and exclusion criteria. Groups were well matched; at baseline, subjects in both groups had nearly identical CAPS scores.
This study has several limitations and should be considered only a preliminary step toward exploring MDMA as a possible therapeutic adjunct. Sample size is small, as is appropriate in a Phase II pilot study. The majority of participants were female and all were Caucasian. Gender and/or ethnic differences in response to MDMA-assisted psychotherapy could exist. At baseline, the placebo group had a history of more prior psychotherapy than the MDMA group, which could mean that the placebo group was more treatment-resistant; however, this covariate proved non-significant. Furthermore, in the open-label phase, the placebo group had a response comparable to the MDMA group, so in fact, the placebo group proved not to be more resistant to MDMA-assisted psychotherapy.
Another important weakness of this study is the transparency of the blinding. We chose to use an inactive placebo in this initial trial in order to compare side effects of MDMA with those of placebo in this patient population. Although the independent rater remained effectively blinded because he was not present during experimental sessions, the novel subjective experience was a strong clue for the subjects, as was the subjects’ increase in pulse and blood pressure for the investigators. We have recently obtained a ‘may proceed’ letter from the FDA for a protocol for a three-arm, dose–response study that we expect will result in successful blinding. An argument against a placebo response having accounted for between-group outcome differences is the maintenance of treatment effect at 2-month follow-up, and the subjects’ having failed to respond to prior treatments during a course of PTSD lasting a mean of nearly 20 years. Nevertheless, a placebo effect cannot be ruled out and future studies must address this limitation.
Additional psychotherapy sessions were conducted more often after MDMA-assisted sessions than after psychotherapy-only sessions. This is a potentially confounding factor, but it is not a likely explanation for the difference in final outcome. Additional psychotherapy cannot explain the significant improvements in CAPS scores recorded 4 days after the first MDMA-assisted session, before any additional psychotherapy sessions occurred. In future studies, attempts should be made to limit additional psychotherapy sessions while retaining some flexibility to ensure subject safety while maintaining therapeutic effect. Another limitation is that measurement of the durability of symptom improvement was limited to 2 months after the second experimental session. We chose this interval because it is well beyond the acute effects of the drug and the immediate expectancy effects, but short enough to minimize effects from intervening events. A long-term outcome study is currently being conducted evaluating subjects from 1–5 years post-treatment. The absence of therapist adherence measures was an unavoidable weakness of this first pilot study. A treatment manual and adherence measures based on audio and video recordings from this study have now been developed for use in future clinical trials.
The use of zolpidem for sleep or benzodiazepines for anxiety during the study did not differ between the MDMA and placebo conditions, but deserves some discussion to clarify the intent. As is common with PTSD, most of the study subjects had pre-existing sleep disturbance. Zolpidem was offered frequently, often the night after an experimental session when subjects spent the night in the relatively unfamiliar environment of the clinic after a long day of emotional processing. Benzodiazepines were offered more sparingly so as to avoid suppressing ongoing emotional processing, which is considered an important element of the integration phase of therapy, while providing some symptomatic relief to help subjects effectively balance emotional processing with rest, work and other daily activities. The vast majority of benzodiazepine doses went to people who had used them before, and all subjects had previously taken psychiatric medications with significant anxiolytic properties that were not allowed during the study. It is important to note that a temporary increase in anxiety was sometimes a side effect of this treatment, but the fact that neither zolpidem nor benzodiazepines were administered significantly more often after MDMA sessions than after placebo sessions suggests that this side effect was caused by the psychotherapy in the setting of chronic PTSD rather than by MDMA administration.
An obvious feature of this treatment model is that it involves an initial period of concentrated patient-therapist contact (31
h over 2 months) including all-day therapy sessions and an overnight stay in the clinic. These are not usual features of psychotherapy practice in the outpatient setting. If MDMA-assisted psychotherapy is ultimately approved for use in clinical practice, it would likely occur in clinics specifically equipped for longer treatment sessions and overnight stays. This method also involves patient preparation and close follow-up to support further processing of emotions and integration of cognitive shifts that may occur. Both the preparation sessions and the integration sessions appear to be important for safety and therapeutic effect. In future studies we recommend that the number of 90-min preparation sessions be increased from two to three. This approach is initially more expensive than other outpatient treatments; however, given the chronic nature of treatment-resistant PTSD requiring ongoing psychiatric treatment and the associated high rates of medical comorbidity and disability, it has the potential to be more cost effective over time for a significant segment of the patient population. In this study the second session appeared to add depth to the overall therapeutic process and it provided the reassurance that subjects would have more than one opportunity to work through their issues. Nevertheless, the fact that most of the symptom improvement occurred after the first MDMA-assisted psychotherapy session suggests that it would be worthwhile for future studies to investigate the impact of number of sessions on strength and duration of PTSD symptom reduction.
The promising results of this initial pilot study suggest that further research is warranted to confirm our findings, distinguish and refine the essential elements of this approach, enhance the methodology, and elucidate the mechanisms involved.