From the Editor
“When it kicked in, it was like an epiphany. I could see all these things from combat I was afraid to look at before, and I had a totally new perspective. I relived the parts of me I had lost. I realized I had viewed myself as a monster, and I was able to start to have some compassion for myself. It was a turning point, and for the next year I continued to get better.”
In a recent article on MDMA (often called Molly or Ecstasy), The New York Times quotes U.S. Marine Nigel McCourry, who has PTSD, talking about his experience taking the drug. So – is there a role for MDMA in the treatment of PTSD? In a new paper published in The Lancet Psychiatry, researchers seem to find there is. In the study, therapy sessions were enhanced with MDMA; after the sessions, 68% of the patients no longer met the clinical criteria for PTSD.
The paper has gained international attention. The New York Times covered it (and quoted McCourry). So did Global News with an online article headlined: “‘Party drug’ MDMA touted as breakthrough therapy for PTSD patients.” The Independent’s story begins: “MDMA ‘cures’ sufferers’ post-traumatic stress disorder in a few weeks during study.”
MDMA: Colourful pills – helpful pills?
In this Reading, we consider the paper behind the headlines, and the Comment piece that accompanies it. We also consider what to tell patients if they ask about MDMA for PTSD.
MDMA and PTSD
“3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers: a randomised, double-blind, dose-response, phase 2 clinical trial”
Michael C Mithoefer, Ann T Mithoefer, Allison A Feduccia, Lisa Jerome, Mark Wagner, Joy Wymer, Julie Holland, Scott Hamilton, Berra Yazar-Klosinski, Amy Emerson, Rick Doblin
The Lancet Psychiatry, 1 May 2018 Online First
Post-traumatic stress disorder (PTSD) is a major public health problem, particularly among military veterans. Prevalence of PTSD in military personnel and veterans (17·1%) and first responders (10–32%) is much higher than the lifetime occurrence in the general population (8%). In addition to the severe psychological burden, chronic PTSD is associated with increased medical morbidity, occupational and relationship problems, decreased quality of life, overall decreased life satisfaction and happiness, and increased risk of suicide.
Treatment options for PTSD include pharmacotherapy and psychotherapies. The two medications approved by the US Food and Drug Administration (FDA) for PTSD, sertraline and paroxetine, reduce symptom severity with limited effectiveness, especially in veterans. Off-label prescription of drugs, including antidepressants, antipsychotics, mood stabilisers, and benzodiazepines, is common, although risks and benefits for PTSD have not been established in randomised controlled trials. Trauma-focused psychotherapies are more effective than pharmacotherapy. A meta-analysis of trials for military- related PTSD found that both cognitive processing therapy and prolonged exposure therapy had large effect sizes with 49–70% of participants attaining clinically meaningful symptom improvement; however, 60–72% of veterans receiving either of these therapies retained their PTSD diagnosis. High dropout (27–40%) occurs with trauma-focused psychotherapies, partially due to adverse outcomes, such as worsening symptoms, admission to hospital, or disengagement from treatments. Relatively few randomised clinical trials of military-related PTSD have been done.
Development of new treatments should address the common reasons for treatment avoidance, failure, and dropout. One approach to developing more effective psychotherapy is to administer a drug during psychotherapy sessions intended to catalyse the psychotherapeutic process. 3,4-methylenedioxymethamphetamine (MDMA) has shown promise as a psychotherapeutic adjunct. Two published clinical trials of MDMA-assisted psychotherapy showed large effect sizes (1·24 and 1·05) with low dropout (8·7% and 14·3%) and durable improvements (average 45 months in 74% of one cohort). Most participants had crime- related PTSD, such as sexual abuse, assault, and rape. Therefore, we aimed to assess the efficacy and safety of MDMA-assisted psychotherapy in military veterans, firefighters, and police officers with PTSD resulting from their service.
So begins a new paper by Mithoefer et al.
Here’s what they did:
- The study was a dose-response, phase 2 clinical trial at an outpatient clinic in South Carolina.
- Inclusion criteria included age 18 or older, PTSD for longer than 18 months, and a score of 50 or more on a Clinically-Administered PTSD Scale (CAPS-IV).
- The primary outcome measure was a CAPS-IV score; other outcomes considered depressive symptoms and sleep quality.
- “Depending on the dose groups, MDMA was administered orally at 30 mg (active control), 75 mg, or 125 mg in two blinded experimental sessions spaced 3–5 weeks apart…”
- Participants received psychotherapy, in addition to the MDMA, with a complicated protocol: “The first MDMA session was preceded by three 90-min psychotherapy sessions to establish a therapeutic alliance and prepare participants for the MDMA experience. MDMA was administered at monthly intervals…” Then: “Participants randomly assigned to receive 125 mg of MDMA had one open-label session (within 3–5 weeks of the previous blinded MDMA session) with associated integrative visits and a 2-month follow-up with outcomes assessed (end of stage 1). Participants randomly assigned to receive 30 mg or 75 mg of MDMA crossed over to have one 90-min preparatory session (within 5 months of the primary endpoint), then three open-label sessions spaced a month apart with flexible dosing of MDMA (100–125 mg) followed by the integrative visits and outcome assessments…”
- Statistical analyses were done. Note: “This trial was a pilot dose-response study; therefore, it was not powered to detect statistical signifi”
Here’s what they found:
- 26 service personnel were enrolled. In terms of background: 22 were veterans; 5 were firefighters; 1 was a police officer.
- Participants had moderate-to-severe PTSD, with a mean baseline CAPS-IV total score of 87.1.
- “These 26 participants were randomly assigned to receive 30 mg (n=7), 75 mg (n=7), or 125 mg (n=12) of MDMA plus psychotherapy…”
- “The mean change in the CAPS-IV total score from baseline to 1 month after the second blinded experimental session of MDMA plus psychotherapy was –11·4 (SD 12·7) for the 30 mg group, –58·3 (9·8) for the 75 mg group, and –44·3 (28·7) for the 125 mg group… The 75 mg (p=0·0005) and 125 mg (p=0·004) MDMA groups had significantly greater improvements in PTSD symptom severity than the 30 mg MDMA group (ANOVA for mean change in CAPS-IV total score p=0·001); no significant differences were found between the 75 mg and 125 mg groups (p=0·185).”
- “Compared with the 30 mg group, Cohen’s d effect sizes were large: 2·8 (95% CI 1·19–4·39) for the 75 mg group and 1·1 (0·04–2·08) for the 125 mg group.”
- The treatment was well tolerated.
- Scores on secondary measures like depression and sleep quality showed improvement.
MDMA-assisted psychotherapy with 75 mg or 125 mg resulted in marked improvement of PTSD symptoms in veterans and first responders with chronic PTSD who had failed previous treatment. This study extends findings of significant results combining MDMA with the same manualised psychotherapy for treating crime-related PTSD, and supports the durability of symptomatic improvement seen in a previous report. Participants in the comparator group of 30 mg receiving the same psychotherapy had significantly less symptom remission than the active dose groups of 75 mg and 125 mg, indicating that adequate doses of MDMA potentiate the effects of psychotherapy.
- This paper has generated much attention.
- That said, there are a few problems with it. Let’s start here: the sample size is small. The randomization was also quirky: 26 participants divided unevenly with almost half in the 125 mg group.
- And the results are a bit unusual. 75 mg was very helpful; 125 mg, not so much. The authors speak to this: “An unexpected finding was that the 75 mg dose led to larger decreases in CAPS-IV total score than the 125 mg dose. This difference might have been due to chance in this small sample size or might be due to other reasons. For example, participants of the 125 mg group had a higher mean baseline depression score than the other groups, and therefore could have been harder to treat. Another possible explanation is that the 75 mg dose might have allowed for more focused processing of traumatic experiences than the 125 mg dose, and might be the optimal dose for at least some patients.” These are reasonable explanations. That said, this much is clear: response wasn’t dose dependent. (!)
- We should also ask about the funding. According to the paper: “MAPS Public Benefit Corporation (MPBC), a wholly owned subsidiary of the Multidisciplinary Association for Psychedelic Studies (MAPS), was the trial organiser. Both the funder and MPBC assisted with study design; monitoring of study data; analysis, management, and interpretation of data; preparation, review, and approval of manuscript; and decision to submit the manuscript for publication. The funder had no role in data collection or study conduct. The first author had full access to all the data in the study and had final responsibility for the decision to submit for publication.” You can read about the Board of MAPS here: http://www.maps.org/about/board. There are no psychiatrists on the board. The chair has a Ph.D. in public policy and is a “Holotropic Breathwork practitioner;” other members include a “civil libertarian” and a fund manager.
- The paper runs with a Comment from Andrea Cipriani and Philip J. Cowen, both of Oxford University. “3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in service personnel” can be found here: https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(18)30170-6/fulltext. They note a few problems with the study: “Mithoefer and colleagues used a low-dose strategy (30 mg of MDMA as the control group), and acknowledged that differences in the subjective effect of this dose and the two active doses (75 mg and 125 mg) might have compromised blinding for the participants;” “However, the absence of a dose-response of the two active treatments and the wide CIs for the 125 mg dose (Cohen’s d 1·1 [95% CI 0·04–2·08]) raise some doubts about the robustness of the MDMA effect;” “[I]t is worth noting that 22 of the 26 participants were recruited via internet advertisement or word of mouth, which is likely to have enriched the sample with those keen to try the effect of MDMA, perhaps with resultant expectancy effects; this potential bias might limit the external validity of the findings.”
They close on a cautionary note:
This current study describes the therapeutic use of MDMA by committed experts in a specialised setting in a small group of participants, most of whom self- referred for the trial. The unmet need for better PTSD treatment, particularly in veterans and first responders, is undoubted. However, the generalisability of the benefit of MDMA-assisted psychotherapy to more mainstream psychiatry remains to be established, recalling perhaps the famous American watchword, ‘Will it play in Peoria?’
- What to say to patients about MDMA and its effects on PTSD? Besides mentioning some of the limitations of the study, it may be helpful to note that there are clear problems with MDMA use in non-controlled settings.
Reading of the Week. Every week I pick articles and papers from the world of Psychiatry.