This analysis of the Phase 2 MDMA trial data (n=63) found that sleep quality improved significantly more in the group that received MDMA (75-125mg) than the placebo/control (0-40mg) group. The sleep quality kept improving and was significantly better at the 12-month follow-up.
Abstract
“Sleep disturbances (SDs) are among the most distressing and commonly reported symptoms in posttraumatic stress disorder (PTSD). Despite increased attention on sleep in clinical PTSD research, SDs remain difficult to treat. In Phase 2 trials, 3,4-methylenedioxymethamphetamine (MDMA)–assisted psychotherapy has been shown to greatly improve PTSD symptoms. We hypothesized that MDMA-assisted psychotherapy would improve self-reported sleep quality (SQ) in individuals with PTSD and be associated with declining PTSD symptoms. Participants in four studies (n = 63) were randomized to receive 2–3 sessions of active MDMA (75–125 mg; n = 47) or placebo/control MDMA (0–40 mg, n = 16) during all-day psychotherapy sessions. The PSQI was used to assess change in SQ from baseline to the primary endpoint, 1–2 months after the blinded sessions. Additionally, PSQI scores were measured at treatment exit (TE) and 12-month follow-up. Symptoms of PTSD were measured using the CAPS-IV. At the primary endpoint, CAPS-IV total severity scores dropped more after active MDMA than after placebo/control (−34.0 vs. −12.4), p = .003. Participants in the active dose group showed more improvement in SQ compared to those in the control group (PSQI total score ΔM = −3.5 vs. 0.6), p = .003. Compared to baseline, SQ had improved at TE, p < .001, with further significant gains reported at 12-month follow-up (TE to 12-months ΔM = −1.0), p = .030. Data from these randomized controlled double-blind studies provide evidence for the beneficial effects of MDMA-assisted psychotherapy in treating SDs in individuals with PTSD.”
Authors: Linnae Ponte, Lisa Jerome, Scott Hamilton, Michael C. Mithoefer, Berra B. Yazar-Klosinski, Eric Vermetten & Allison A. Feduccia
Summary
Sleep Quality Improvements After MDMA-Assisted Psychotherapy for the Treatment of Posttraumatic Stress Disorder
The associations between sleep disturbance and posttraumatic stress disorder are complex and multidirectional, with evidence supporting a causal association between traumatic stress and sleep disturbance. Sleep disturbance may also be a core feature of PTSD.
Among mental health disorders, PTSD is unique in that sleep problems are included in two of the diagnostic criteria. Additionally, patients with PTSD who report significant sleep disturbance also report higher levels of substance use, more severe health-related complaints, depression, and suicidality.
Improvements in sleep quality are associated with clinically relevant reductions in the severity and impact of PTSD symptoms. However, current research shows that only 40% of individuals who complete CBT-I treatment experience clinical improvement in insomnia.
Several pharmacological approaches are available to treat sleep disturbance, including prazosin, doxazosin, and terazosin. However, evidence suggests that standard-of-care PTSD treatment is underutilized and that PTSD often persists following trauma-focused treatment.
MDMA – assisted psychotherapy has been shown to improve symptoms of chronic, treatment-resistant PTSD, including the Clinician-Administered PTSD Scale for DSM-IV. The effects of MDMA last 3 – 6 hr and are characterized by feelings of euphoria, increased well-being, and sociability.
Long-term follow-up data showed that participants in the first MDMA-assisted psychotherapy trial for PTSD maintained statistically and clinically significant gains in PTSD symptom relief, and that 63% of participants reported improved sleep at long-term follow-up.
We conducted secondary analyses using pooled data collected in four previously discussed randomized, placebo-controlled trials to explore sleep quality and the associations between sleep quality and PTSD symptom severity.
Participants and Procedure
Four randomized, double-blind Phase 2 studies with similar study designs took place at four sites in the United States, Canada, and Israel.
CONSORT Flow Diagram
The PSQI was used in two Phase 2 trials investigating MDMA-assisted psychotherapy for PTSD, but the data from these trials were not included in this study.
Participants were recruited through referrals by health professionals, Internet advertisements, and word of mouth. They were required to have PTSD symptoms that had lasted at least 6 months and a CAPS-IV total severity score of 50 or higher.
All psychiatric medications were tapered and discontinued prior to participation, except anxiolytics and sedative-hypnotics, which could be resumed 10 days after each experimental session.
Participants in randomized, controlled, double-blind studies underwent 8-hr blinded sessions with either active-dose MDMA or a control dose. Therapists performed manualized psychotherapy throughout the study.
Therapy occurred in a designated space with a sofa or futon and aesthetically pleasing surroundings. Participants spent time focusing attention on their inner experience and interacting with the co-therapy team.
Participants were blinded to group assignment after completing the primary endpoint. They completed the CAPS-IV and PSQI at baseline, the primary endpoint, at TE (i.e., 2 months after the third active MDMA session for MP4, MP8, MP12), and at a 12-month follow-up assessment.
Sleep Quality
A 19-item PSQI was used to assess participants’ sleep quality. A cutoff score of 5 was shown to discriminate between good and poor sleepers, and the PSQI demonstrated high internal consistency, good test – retest reliability, and a diagnostic sensitivity and specificity of 89.6% and 86.5%, respectively.
The PSQI is used to assess sleep disturbances in civilians and military veterans with PTSD. A 3-point drop in the PSQI score represents a clinically meaningful difference.
PTSD Symptoms
The CAPS-IV is a 23-item, semistructured interview that assesses the frequency and intensity of individual DSM-IV PTSD symptoms on separate 5-point (i.e., 0 – 4) Likert scales. It has demonstrated high internal consistency with alpha values ranging from .85 to .87.
Data Analysis
Data from four studies were pooled into two treatment groups and analyzed using independent samples t tests and Hedges’ g. The pilot studies were not powered to detect statistical significance, so no power analyses were performed prior to the individual Phase 2 trials or for this exploratory analysis.
We performed a mixed-effect repeated model (MMRM) to assess the impact of MDMA on CAPS-IV scores at three time points and 12 month follow-up. A subgroup analysis was performed to assess the impact of a clinically significant drop of 3 points or more on the PSQI at primary endpoint. The association between change in CAPS-IV and PSQI scores from baseline to TE was assessed using Pearson’s correlations (two-tailed) and a chi-square test. Age and race were added to the full model, and race did not meet the prespecified criteria of p .05.
Sample Characteristics
The sample was composed of 34 male and 29 female participants, with a mean age of 40.80 years. Most participants had experienced combat-related trauma, followed by sexual assault, child abuse, accidents, and “other” trauma.
Blinded Endpoint
Active doses of MDMA improved CAPS-IV total scores and PSQI scores compared to the control group. More participants in the active group reported a PSQI score drop of 3 points or more than in the control group.
Significant differences between groups were detected at the primary endpoint for three of seven PSQI subscale scores. Participants in the active group saw greater improvement in sleep quality, sleep latency, and daytime dysfunction compared to the control group.
Participants in the active-dose group received zolpidem, melatonin, and zopiclone on the first night and zolpidem, melatonin, and zopiclone on the second night.
Open-Label Endpoints: Treatment Exit and Long-Term Follow-Up
All participants received active doses of MDMA at some point during the study in either blinded or open-label sessions. The CAPS-IV and PSQI scores significantly decreased from baseline to TE and baseline to 12-month follow-up, with scores continuing to decline at 12-month follow-up.
A clinically significant drop of 3 points or more on the PSQI at the primary endpoint was associated with lower CAPS-IV scores at TE and 12-month follow-up.
Discussion
The present results provide evidence that MDMA-assisted psychotherapy improves sleep quality and PTSD symptoms in individuals with PTSD. At 12-month follow-up, 21 out of 63 participants no longer met the criteria for sleep disturbance.
We observed that individuals in the active dose group required less time to fall asleep and reported less daytime dysfunction, which is consistent with findings from studies of objective measures of sleep.
Although sleep-specific items from the CAPS-IV were retained, participants with a clinically meaningful improvement in sleep quality demonstrated more PTSD symptom improvement at TE and 12-month follow-up.
MDMA can temporarily hamper sleep in healthy controls and individuals with PTSD, with worsening insomnia lasting for approximately 3 days. However, improved sleep assessed 1 – 2 months later demonstrates that these acute effects are transient.
The present study had several limitations, including a small sample size and reliance on self-report assessments. It also used subjective measures, which may have underestimated total sleep time and overestimated sleep onset latency.
Future researchers should strive to elucidate the extent to which MDMA may differentially impact sleep symptoms, including well-established PTSD-associated sleep symptoms, and more recently identified PTSD-associated sleep symptoms, such as acting-out dreams and symptoms of OSA.
Although it is unclear whether MDMA-assisted psychotherapy impacts the underlying hyperarousal symptoms of PTSD, it is possible that the trials are enrolling a more treatment-resistant population.
This report included the largest sample to date of data regarding sleep from participants with PTSD enrolled in clinical trials of MDMA-assisted psychotherapy.
Open Practices Statement
The analyses of the pilot studies were not formally preregistered at ClinicalTrials.gov, and access to the data and materials is limited to researchers who complete a data use proposal.