A randomized, controlled pilot study of MDMA (±3,4-Methylenedioxymethamphetamine)- assisted psychotherapy for treatment of resistant, chronic Post-Traumatic Stress Disorder (PTSD)

Three doses of MDMA (125mg) showed the most promise in this pilot study (n=12) of MDMA psychotherapy for PTSD. The CAPS score (PTSD measure) was just shy of significance, self-reported improvement was significant.

Abstract

“Psychiatrists and psychotherapists in the US (1970s to 1985) and Switzerland (1988–1993) used MDMA legally as a prescription drug, to enhance the effectiveness of psychotherapy. Early reports suggest that it is useful in treating trauma-related disorders. Recently, the first completed pilot study of MDMA-assisted psychotherapy for PTSD yielded encouraging results. Designed to test the safety and efficacy of MDMA-assisted psychotherapy in patients with treatment-resistant PTSD; our randomized, double-blind, active-placebo controlled trial enrolled 12 patients for treatment with either low-dose (25 mg, plus 12.5 mg supplemental dose) or full-dose MDMA (125 mg, plus 62.5 mg supplemental dose). MDMA was administered during three experimental sessions, interspersed with weekly non-drug-based psychotherapy sessions. Outcome measures used were the Clinician-Administered PTSD Scale (CAPS) and the Posttraumatic Diagnostic Scale (PDS). Patients were assessed at baseline, three weeks after the second and third MDMA session (end of treatment), and at the 2-month and 1-year follow-ups. We found that MDMA-assisted psychotherapy can be safely administered in a clinical setting. No drug-related serious adverse events occurred. We did not see statistically significant reductions in CAPS scores (p = 0.066), although there was clinically and statistically significant self-reported (PDS) improvement (p = 0.014). CAPS scores improved further at the 1-year follow-up. In addition, three MDMA sessions were more effective than two (p = 0.016).”

Authors: Peter Oehen, Rafael Traber, Verena Widmer & Ulrich Schnyder

Notes

This study was one of the first to apply the double-blind placebo-controlled study design to MDMA-assisted therapy for PTSD. It is published (2012) shortly after Mithoefer et al. (2010) and served as a confirmation of the previous results (which it partly did, but no significance on the CAPS score) and test with another therapy team. Different in this study was the use of an active placebo (12.5mg MDMA) vs an inactive placebo.

In conclusion the authors recommend limiting the number of follow-up sessions, but expanding the introductory sessions from two to three (to strengthen the therapeutic alliance).

This study was supported by MAPS.

Summary

Introduction

Post-traumatic stress disorder is a common problem in everyday medical practice and a major and costly public health problem all over the world. Psychotherapy has been recognized as the most effective form of treatment for PTSD, but studies of Cognitive Behavior Therapy show high drop-out rates and limited effect on PTSD symptoms. Despite better understanding and growing efficacy of existing psychotherapies for PTSD, the only FDA-approved drugs for this indication, sertraline and paroxetine, show only modest effects on PTSD symptoms. MDMA-assisted psychotherapy is a novel approach to the treatment of PTSD.

Psychiatrists and psychotherapists used MDMA legally as a prescription drug, to enhance the effectiveness of psychotherapy, in the US and Switzerland. A pilot study found that MDMA-assisted psychotherapy was safe and effective for treating treatment-resistant PTSD.

MDMA, a substituted phenylethylamine, was first synthesized in 1912 by the pharmaceutical company Merck, and was later introduced to psychotherapy by the psychotherapist L Zeff. MDMA-assisted psychotherapy shows promising results in the treatment of chronic PTSD.

MDMA increases activity in the ventromedial prefrontal cortex and decreases activity of the left amygdala, possibly reversing some of the abnormalities associated with PTSD. This leads to a positively-toned cognitive-emotional state, with reduced fear.

MDMA may widen the window of acceptable affect, enhancing affect-related tolerance and reducing emotional numbing, which is crucial for the recovery from PTSD. The extensive release of oxytocin under MDMA therapy is postulated to be a prominent factor in improving the therapeutic alliance.

In this study, 12 patients with chronic, treatment-resistant PTSD received three MDMA sessions and a 1-year follow-up. The study attempted to optimize blinding by using 25mg of MDMA as an “active placebo”, and to examine whether reductions in PTSD symptoms would remain stable at the 1-year follow-up.

Recruitment and screening procedure

We recruited subjects for the study by calling psychiatric hospitals, trauma counseling centers, psychiatrists and psychotherapists in the German-speaking part of Switzerland. Medical evaluation included a medical history, standard physical examination, an electrocardiogram, metabolic profile, measurement of thyroid hormones, serum electrolytes, HIV test, urinary drug test and pregnancy test.

Subjects

We enrolled 12 subjects (10 female, 2 male; mean age = 41.4 years, SD 11.2 years) with PTSD and treatment-resistant symptoms, who had previously undergone at least 6 months of psychotherapy and 3 months of treatment with an SSRI. Seven of 12 subjects had experienced one or more evidence-based therapies.

One subject had previously used ecstasy, one had consumed magic mushrooms several times, and the other subjects were completely naive to psychedelic drugs. Two subjects discontinued treatment after the first experimental MDMA session.

The study group included six subjects with PTSD, one with sexual abuse, one with medical treatment, two with motor vehicle accidents and two with life-threatening illness.

Description of study design

Eight subjects were randomized to the full dose and four to the “active placebo” condition, and received three doses of MDMA in three all-day-long MDMA-assisted psychotherapy sessions. The full dose produced no significant effects, but the low dose might produce slight alterations in perception.

Outcome measures

Two measures of PTSD symptoms were used, including the Clinician-Administered PTSD Scale (CAPS), which had excellent psychometric properties.

The CAPS and SCID I substance abuse module were administered at baseline, 3-weeks after MDMA-session #2, 3-weeks after MDMA-session #3, and two, six, and 12 months after the MDMA-session #3 (follow-up). Pregnancy tests were performed in women of childbearing potential, before each MDMA session.

After preliminary analysis of data showed insufficient clinical response to the experimental treatment, two additional sessions of MDMA-assisted psychotherapy were allowed for subjects deemed to show insufficient response.

MDMA

MDMA was synthesized by Lipomed AG and prepared by the Bichsel Laboratory in Interlaken, Switzerland. Quality control and randomization were performed by R Brenneisen.

Psychotherapy

Subjects with PTSD were given MDMA at 10 a.m. and instructed to remain reclining on the mattress, focus their attention inward, keep their eyes closed as much as possible and allow the inner process to unfold.

MDMA-assisted psychotherapy is a non-directive approach that focuses on experiencing and supporting the subject’s experience. Focused body work is performed with explicit consent and respects individual boundaries and vulnerabilities.

One male and one female therapist were present during the entire session. The subjects received 12 non-drug psychotherapy sessions after each MDMA experience, and were contacted via telephone by one of the therapists on a daily basis for one week.

Further assessment and safety measures

Subjects’ blood pressure, heart rate and body temperature were measured before and after each MDMA session, and the degree of psychological distress was monitored repeatedly during the course of each MDMA session.

Statistical analysis

CAPS and PDS scores were analyzed using an F1-LD-F1 model with the experimental intervention condition serving as a between-group factor. Given insufficient sample size for formal analysis, participants’ scores were compared across the two stages to see if third MDMA session improved scores compared to only two MDMA sessions. To compare the magnitude of the difference between maximally-observed value and baseline value between treatment groups, a lower confidence bound was computed for the difference of increase. This bound was then used to show that the full-dose group had a higher average increase than the placebo group.

Efficacy

Figure 2 shows that the average CAPS scores in the full-dose group decreased 15.6 points (23.5%) with time, as compared to an increase in the “active placebo” group. The PDS scores also decreased in the full-dose group, as compared to an increase in the “active placebo” group.

Three MDMA sessions were more effective than two sessions in improving CAPS scores. The median prior psychotherapy treatment times were 123 and 39.9 months, respectively.

Rescue medication

Most subjects refused sleep medication after MDMA sessions, and those who did required lorazepam for anxiety/distress related to the processing of the traumatic memories were on antidepressants and/or benzodiazepines at enrollment. Acetaminophen or mefenamic acid were administered short-term for headache following MDMA sessions.

Spontaneously-reported reactions

The most commonly reported reactions were moderate insomnia, loss of appetite and restlessness in subjects receiving 125 mg MDMA and headache, moderate insomnia, restlessness, tight jaw, thirst and feeling cold in subjects receiving 25 mg MDMA.

Physiologic data

As seen in Table 4, the temperature increased significantly pre- to post-session in both groups, but systolic BP and HR did not change significantly.

Additional psychotherapy sessions

Eight out of 13 subjects who received full-dose MDMA required additional integrative psychotherapy sessions. Four additional sessions were provided to two subjects in the active placebo group.

Clinical response and LTFU

Clinical response was observed in four out of eight subjects in the full-dose group, with all still fulfilling PTSD criteria.

Three subjects received two full-dose sessions, two high-dose sessions and two high-dose sessions followed by a lower supplemental dose. The additional sessions did not improve their CAPS scores.

All four subjects in the active placebo group failed to respond to the treatment, while all four subjects in the stage 2 crossover group responded to the treatment. At the one-year follow-up, all four subjects had improved, with nine subjects showing a significant clinical improvement.

Blinding

The investigator’s guesses were correct in eight of the 14 full-dose subjects and uncertain in one full-dose subject. The subjects’ guesses were correct in four of the 14 full-dose subjects, uncertain in two and incorrect in two cases, and incorrect in two cases for the active placebo group.

Discussion

This small randomized pilot study of MDMA-assisted psychotherapy in a population of subjects with chronic, treatment-refractory PTSD demonstrated that this novel treatment method can be safely applied in an outpatient setting. The results indicated that three experimental MDMA sessions were significantly more effective than only two. All participants had received full-dose MDMA in either “Stage 1” or “Stage 2”, so comparisons by condition were not possible at the 12-month follow-up.

Three subjects (including one drop-out) experienced similar but milder psychotherapeutic processes to those receiving the full dose of MDMA, while two subjects showed no or only slightly pleasant changes in perception and relaxation, which wore off after about 1 hour.

We did not find a placebo response in our study of MDMA and PTSD, and three of five subjects in the active placebo group showed partial activation of the MDMA state.

The subjects tolerated MDMA therapy well and only one occasion of additional medication was needed. The prolonged and intensive exposure to traumatic material inherent in this treatment method can temporarily cause distress and anxiety which may require additional medication with benzodiazepines and/or additional psychotherapy sessions.

The results of this study are similar to those of Mithoefer and colleagues, except for the primary outcome measure, which is different. Other factors could have influenced outcomes, such as cultural differences, independent rater differences, therapist differences, or sample size.

Limitations

This exploratory study was underpowered and intended to serve as a proof of concept, but it also had the goal of addressing two basic challenges in the investigation of this novel method: the lack of recognized and standardized methods for the investigation of this type of combined therapy. Our findings suggest that subjects were successfully blinded to their study condition by using low-dose MDMA as an active placebo, and that the blinding occurred under both conditions.

The study by Mithoefer et al. (2011) used a low dose of MDMA to study the effects of MDMA on adherence. The low dose was less well tolerated psychologically, requiring more therapist interaction than the fully-active dose.

Conclusions

We recommend that future studies include three preparatory sessions before administration of MDMA, to strengthen the therapeutic alliance and minimize additional psychotherapy sessions.

MDMA-assisted psychotherapy was safely administered to treatment-resistant patients with chronic PTSD, but did not produce significant symptom reductions.