All told, 68% of the group receiving a full dose of MDMA no longer qualified for a PTSD diagnosis compared to 29% in the active-placebo control group.
Michael Mithoefer, MD
In a controlled setting, the use of 3,4-methylenedioxymethamphetamine (MDMA) adjunct to psychotherapy for patients with posttraumatic stress disorder (PTSD) was found to be both effective and well-tolerated, with symptoms of the disorder reduced significantly after 12 months.
An average of 20 US veterans commit suicide each day, and there is a lack of available US Food and Drug Administration (FDA) approved therapies for PTSD outside of a trio of selective serotonin reuptake inhibitors. As of June 30, 2016, more than 868,000 veterans were receiving disability payments from the US Department of Veterans Affairs specifically for PTSD, with an estimated cost of over $17 billion per year—making the availability of more treatment options for PTSD not only an urgent clinical need but also a cost-efficiency need.
"Existing treatments are not adequate for at least 50% of patients, and even less, more like two-thirds of veterans with PTSD," Michael Mithoefer, MD, the lead author, told MD Magazine. "The burden of suffering, disability, increased medical utilization and death from PTSD is huge."
Patients received 13.5 hours of non-drug psychotherapy in conjunction with a duo of 8-hour sessions with MDMA. Just 1 month after their second day-long sessions, 68% of the group receiving a full dose of MDMA no longer qualified for a PTSD diagnosis compared to 29% in the low-dose (active-placebo) control group.
Led by Mithoefer, a member of the Department of Psychiatry and Behavioral Sciences at the Medical University of South Carolina, in Charleston, the phase 2, randomized, double-blind, dose-response trial included 26 patients, all of which were military veterans (n = 22) or first responders (firefighters, n = 3; police officers, n = 1). They were randomly assigned to receive doses of 30 mg (active control; n = 7), 75 mg (n = 7), or 125 mg (n = 12) MDMA plus psychotherapy.
The groups receiving 75- and 125-mg doses had significantly greater decreases in their PTSD symptom severity, as measured by the Clinician-Administered PTSD Scale (CAPS-IV) scores. The 75-mg group experienced a mean change of —58.3 (SD, 9.8) in their CAPS-IV scores, while the 125-mg group reported a mean decrease of –44.3 (SD, 28.7), compared with –11.4 (SD, 12.7; P = .001).
Cohen’s d effect sizes were reportedly “large,” according to Mithoefer and colleagues, registering at 2.8 (95% CI, 1.19 to 4.39) for the 75-mg group and 1.1 (95% CI, 0.04 to 2.08) for the 125-mg group compared with the active control group.
In an open-label crossover, conducted with full doses of 100-125 mg, symptoms of PTSD in the previous members of the active control group were decreased significantly (P = .01), while those in the 75-mg group that experienced a high response saw no further significant decreases (P = .81). After 12-month follow-up, symptoms were significantly reduced compared to baseline (mean CAPS-IV scores, 38.8 [SD, 28.1] vs. 87.1 [SD, 16.1]; P <.0001).
"[Surprisingly,] we also found that ratings of depression were improved, many participants reported stopping or decreasing use of alcohol, tobacco, and opiates following MDMA-assisted treatment," Mithoefer said. "This suggests that future research should explore other possible indications."
Philip Cowen, BSc, MB, BS, MD, FRCPsych, one of a duo of authors of an accompanying commentary, told MD Magazine that while the results are certainly intriguing, larger, phase 3 trials will be required to replicate the findings. He also noted that this is not an effect of MDMA alone, so it must be remembered that due to this and the fact that the illicitly-obtained form of MDMA (known as ecstasy) is often impure and contains an unknown amount of MDMA, it is imperative that those with PTSD should not utilize this treatment option on their own.
In total, 85 adverse events were reported by 20 of the participants, and although 4 (5%) were serious, 3 of them were determined to be unrelated to the study’s drug treatment.
In August 2017, the FDA granted Breakthrough Therapy Designation to MDMA-assisted psychotherapy for PTSD. The agency acknowledged that it “may demonstrate substantial improvement over existing therapies” and agreed to expedite both the development and review of the therapy.
The Multidisciplinary Association for Psychedelic Studies (MAPS), which conducted the trials, is planning—along with the FDA—phase 3 clinical trials of MDMA-assisted psychotherapy for PTSD which will begin in the summer of 2018 and will enroll 200 to 300 participants across 16 sites in the US, Canada, and Israel. If the phase 3 trials demonstrate significant efficacy and an acceptable safety profile, FDA approval is expected by 2021, according to MAPS.
"We do not think MDMA will, or should, be approved as a drug that patients could get at a pharmacy, rather it will be used only in licensed MDMA-assisted psychotherapy clinics where the therapists and physicians will have appropriate training and the MDMA will be administered directly to the patients," Mithoefer said.
As for how MDMA-assisted psychotherapy compares to other options being explored for PTSD treatment, such as ketamine or cannabinoids, Mithoefer noted that as of yet, they don’t know the answer. "There is some data on ketamine for PTSD but no comparison studies. An observational study of PTSD patients treated with medical cannabis (led by George Greer, MD) was promising, and MAPS is currently conducting a controlled clinical trial of different THC/CBD ratios of smoked cannabis for PTSD, so there will be more data before long," he said.
"Our model is different from these other trials in that MDMA is used, not to suppress symptoms, but to catalyze psychotherapy aimed at processing the underlying trauma," Mithoefer added.
The study, “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,” was published in The Lancet.