July 22, 2010 — Methlylenedioxymethamphetamine (MDMA), also known as “ecstasy,” added to psychotherapy may relieve symptoms of posttraumatic stress disorder (PTSD) in patients who are resistant to other treatments, according to a small, phase 2 pilot study. In addition, the patients reported “no drug-related serious adverse events, adverse neurocognitive effects, or clinically significant blood pressure increases,” write the study authors. “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,” write lead author Michael Mithoefer, MD, a psychiatrist in private practice in Mount Pleasant, South Carolina, and colleagues. Noting that this is “the first completed clinical trial” evaluating MDMA as a therapeutic adjunct, the authors add that “the promising results…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.” “These results were even stronger than we anticipated in a pilot study,” Dr. Mithoefer told Medscape Medical News. “They are encouraging, but it’s a first step. We ultimately have a long way to go and don’t have any clinical conclusions yet. The takeaway right now is that we need more research into something that looks like it may be very promising.” The study was published online July 19 in the Journal of Psychopharmacology. Decreased PTSD Fear Response? The current lifetime prevalence of PTSD in the US general population is between 6% and 10%, and is as high as 18% in returning US soldiers, according to the researchers. Although pharmacotherapy and psychotherapy are the most common treatments for PTSD, many of the drugs used “have limited efficacy,” and only sertraline and paroxetine are currently approved by the US Food and Drug Administration. In addition, “many psychotherapies for PTSD involve the induction and extinction of abnormal autonomic responses through revisiting traumatic experiences…with an appropriate level of emotional engagement,” the study authors explain. “Frequently, however, treatment may be ineffective when patients are unable to tolerate feelings associated with revisiting the trauma.” They note that MDMA was often used, before its 1985 classification as a schedule 1 controlled substance, by many psychiatrists as an adjunct to overall psychotherapy because of reports that it could temporarily “decrease feelings of fear while maintaining a clear-headed, alert state of consciousness.” The investigators sought to examine whether the decreased fear response generated by MDMA “may be useful in the treatment of PTSD, a condition that involves exaggerated and uncontrolled fear responses.” For this study, 20 patients older than 21 years (mean age, 40.4 years; 85% women; 100% white) with chronic PTSD (average duration, 19+ years) were enrolled between March 2004 and January 2008 and were randomly assigned to receive either an MDMA capsule (n = 12) or a placebo capsule (n = 8) during the course of two 8-hour “experimental psychotherapy sessions.” The 2 sessions were spaced 3 to 5 weeks apart, and all patients slept overnight in a supervised clinic afterward. The patients, all of whom had treatment-resistant symptoms at baseline, also received preparatory and follow-up nondrug psychotherapy, neurocognitive testing, and blood pressure and temperature monitoring. The Clinician-Administered PTSD Scale (CAPS) and the Impact of Events Scale–Revised (IES-R) self-report were also given at baseline, 4 days after each experimental session, and 2 months after the second session. In addition, “after [the] 2-month follow-up, placebo subjects were offered the option to re-enroll in the experimental procedure with open-label MDMA,” report the study authors. “We didn’t want to just test the drug,” explained Dr. Mithoefer. “We wanted to test the drug’s ability to catalyze psychotherapy. It’s important that people realize that MDMA should be used in the right way, and that it’s not a stand-alone solution for PTSD.” Significantly Fewer PTSD Symptoms At the end of the study, results showed a significantly greater decrease in CAPS scores for the MDMA-treated patients at all 3 time points after baseline compared with the placebo-treated patients (P = .013, P = .002, and P= .013, respectively). The IES-R showed similar results, with significantly improved PTSD symptoms for the MDMA group at all 3 time points vs the placebo group (P = .016, P = .006, and P = .038, respectively). In addition, the rate of clinical response for the MDA group was 83.3% vs 25% for the placebo group. Also, 10 patients in the MDMA group no longer met criteria for PTSD as listed in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, compared with 2 in the placebo group. The most common adverse effects (reported in both groups) were fatigue, headache, and nausea. Anxiety was also commonly reported by both groups, although slightly more frequently in those treated with MDMA. No serious adverse events were reported. A total of 7 of the 8 placebo-treated patients elected to participate in the open-label crossover portion of the study. Significant decreases for these patients were found in both CAPS (P < .05) and IES-R (P = .013) scores, "from the end of the control trial to 4-6 weeks after 2 MDMA sessions were completed." The clinical response rate was 100% for all 7 patients. "An unplanned observation was that all 3 [overall] subjects who reported being unable to work due to PTSD were able to return to work," write the authors. "MDMA-assisted psychotherapy can be administered to [patients with PTSD] without evidence of harm, and it may be useful in patients refractory to other treatments," they summarize. However, they note that this study should be considered "only a preliminary step" toward exploring MDMA-assisted psychotherapy and report that "a long-term outcome study is currently being conducted evaluating subjects from 1-5 years post-treatment." Another newly approved study will focus on US veterans with war-related PTSD. Limitations of this therapy cited include the requirements of concentrated periods of patient–therapist contact and of special clinics equipped for the longer sessions and overnight stays. "However, based on our results, this wasn't a drug that was needed many times. It was using it just a few times to catalyze the therapeutic process, and then you don't need it anymore," said Dr. Mithoefer, who noted that the small doses should also help combat worries of addiction. "Like anything we use in medicine, this agent needs to be treated with respect. It has risks as well as possible benefits," he added. May Lead to Better Agents for PTSD "I thought this was a very interesting study, and I'm favorably impressed with the results," Keith Young, MD, vice chair of research in the Department of Psychiatry at Texas A&M Health Science Center College of Medicine in Temple, and core leader for neuroimaging and genetics at the VA Center of Excellence for Research on Returning War Veterans in Waco, Texas, told Medscape Medical News. "We know from experience that [for] people who have had PTSD for 19 years, it's very difficult to get this kind of effect in them. And this study certainly shows that ecstasy has potential for being useful in improving psychotherapy," said Dr. Young, who was not involved with this study. "However, I think it will take a lot more work to convince people that it's going to be useful in the long run and that its potential problems and long-term side effects don't outweigh the improvements that may come from it," he added. Dr. Young noted that this would also be an expensive therapy to use in the future, because of the hospitalization requirement. "You wouldn't want to let a person back out on the street after giving them MDMA, as it has a relatively long eff ect. I think you'd need to keep people a minimum of 24 hours, which would be relatively expensive. It takes 24 hours for the drug levels to get down to relatively low levels, even though the behavioral effects really only last 8 hours." Overall, Dr. Young said he is "cautiously optimistic," and that results such as these may lead to the use of new compounds. "One of the things that happens when you take ecstasy is that the chemical oxytocin is released, which probably contributes to this feeling of well being. So perhaps there's something to bypassing the abuse potential of [MDMA] and going straight to taking oxytocin, which is starting to be prescribed for things like autism. "Potentially, this may lead us down pathways that take us to better drugs," he concluded. This study was supported by the Multidisciplinary Association for Psychedelic Studies (MAPS). Dr. Mithoefer reported being a medical monitor for other studies of MDMA-assisted psychotherapy being conducted by MAPS, and 2 other study authors are employed by MAPS. In addition, Dr. Mithoefer and 1 other study author reported receiving payment from MAPS "for conducting this research, and for working on development of a treatment manual, investigator training program, and protocols for additional studies." Dr. Young has disclosed no relevant financial relationships. J Psychopharm. Published online July 19, 2010. The South Carolina Phase II MDMA study results are reviewed in this article with great depth and detail, with comments and criticisms by participating researchers and other medical professionals.