Ecstasy-Assisted Psychotherapy Effective, Durable for PTSD

Methlylenedioxymethamphetamine (MDMA), also known as "ecstasy," combined with psychotherapy provides lasting and clinically meaningful relief of symptoms in patients with treatment-resistant posttraumatic stress disorder (PTSD), new research shows.

Dr. Michael Mithoefer

A long-term follow-up study, led by Michael Mithoefer, MD, a psychiatrist in private practice in Mount Pleasant, South Carolina, showed that 74% of patients with PTSD who were unresponsive to other treatments sustained symptom resolution for an average of 3.5 years.

"So the effect of the MDMA-assisted psychotherapy sessions was not just a transient effect. It was also reassuring that subjects did not report drug dependency or other harms," Dr. Mithoefer told Medscape Medical News.

The study was published online November 20 in the Journal of Psychopharmacology.

"Spectacular" Results

"The results obtained by Dr. Mithoefer and colleagues seem spectacular," José Carlos Bouso, PhD, from the Neurosciences Research Program, Hospital del Mar Medical Research Institute in Barcelona, Spain, told Medscape Medical News.

"The fact that the benefits achieved persisted a long time seem to show the promising efficacy of their treatment. Although there are a series of confounding variables in the interpretation of the results, the good news is that subjects were, after the treatment and at the follow-up, better than at baseline, and that MDMA was a safe treatment," said Dr. Bouso, who was not involved in the study.

"The effect size of the treatment is really impressive; it's much larger than what you see with SSRIs [selective serotonin reuptake inhibitors]," Matthew W. Johnson, PhD, of the Behavioral Pharmacology Research Unit, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, in Baltimore, Maryland, noted in a telephone interview with Medscape Medical News. He was also not involved in the study.

Some patients with PTSD do not respond to existing pharmacologic and psychotherapeutic treatments, and a wider array of effective treatment options remains a "crucial need," Dr. Mithoefer and colleagues note in their article.

MDMA is thought to enhance PTSD psychotherapy by helping a patient access emotionally upsetting memories and change how they react to those memories.

In the original study, which was previously reported by Medscape Medical News, 20 adults with long-standing treatment-resistant PTSD were randomly assigned to psychotherapy with MDMA (n = 12) or with an inactive placebo (psychotherapy-only; n = 8), each treatment administered during 2 8-hour sessions scheduled 3 to 5 weeks apart, accompanied by weekly nondrug psychotherapy sessions.

At the end of the controlled study, the 8 participants who had received nondrug psychotherapy were offered MDMA-assisted psychotherapy (on the same schedule). Seven accepted and completed the crossover arm of the study, which resulted in 19 of the 20 study participants receiving MDMA-assisted psychotherapy.

All 19 patients who received MDMA-assisted treatment in the original trial participated in the long-term follow-up, with 16 out of 19 completing all of the long-term outcome measures, which were administered from 17 to 74 months after the final MDMA session (mean, 45.4 months).

As previously reported, at the end of the original study, there was a significantly greater decrease in the Clinician-Administered PTSD Scale (CAPS) scores for the MDMA-treated patients compared with the placebo-treated patients. The Impact of Events Scale–Revised (IES-R) self-report showed similar results, with significantly improved PTSD symptoms for the MDMA group.

Safe, Effective, Durable

The long-term follow-up data show that, on average, patients maintained statistically and clinically significant gains in symptom relief, although 2 patients did relapse.

"We found that the mean CAPS and IES-R scores at LTFU [long-term follow-up] for the 16 completers were not statistically different from their 2-month (short-term) mean scores," the investigators report in their article.

Importantly, they say that no patient developed a substance abuse problem with any illicit drug after their MDMA-assisted psychotherapy and that there was no evidence of neurocognitive decline.

"These results indicate that there was a favorable long-term risk/benefit ratio for PTSD treatment with just a few doses of pure MDMA administered in a supportive setting," they say.

Dr. Bouso made the point that fear is the "central key in PTSD, and MDMA seems to allow patients to reexperience the traumatic event in the absence of fear. In this sense, MDMA is quite different to classical antianxiety drugs. MDMA does not induce cognitive torpor, so it does not cover the reprocessing of traumatic memories [but] allows them to be managed under patient's subjective control."

Some of the comments patients wrote on the long-term follow-up questionnaire they completed reflect this, such as the following:

MDMA "increased my ability to stay with and handle getting though emotions."
"The MDMA provided a dialogue with myself I am not often able to have, and there is the long-term effect of an increased sense of well-being. "
"I was always too frightened to look below the sadness. The MDMA and the support allowed me to pull off the controls, and I...knew how and what and how fast or slow I needed to see my pain."

Dr. Johnson said "at the pure biological level, we don't have a good explanation" for why the benefits of MDMA seem to be so durable. However, MDMA seems to provide access to memories, thoughts, and feelings surrounding the trauma "with a sense of clarity and emotional security; people may have more self-empathy about the role they played [in the traumatic event] and whether or not they were at fault in any way."

"Looking at it through this lens," he explained, may help explain how taking something once or twice may provide lasting benefits. Unlike psychoactive medications that only work when they are taken daily, "MDMA seems to help the patient have more of a learning-based experience."

Larger Studies to Come

Dr. Mithoefer said further studies of MDMA-assisted psychotherapy are underway or planned. "We are currently conducting another phase 2 study of MDMA-assisted psychotherapy with veterans, firefighters, and police officers with PTSD stemming from active duty," he told Medscape Medical News. "Other similar phase 2 studies have been approved and will soon be starting in Colorado, Vancouver, and Israel, and protocols are in development in Australia, Jordan, and England."

"If these phase 2 studies continue to show good results, then we plan to move into larger, multicenter phase 3 trials in a few years," Dr. Mithoefer added.

"Whether or not MDMA will be approved for clinical use will depend on the results of at least 2 phase 3 trials. Our results thus far are very promising, but we still have a long way to go to definitively prove safety and efficacy," he said.

Dr. Bouso looks forward to more research on MDMA-assisted psychotherapy. "We need more controlled studies in order to see if their promising results may be replicated. If so, we will have a safe drug [MDMA] that may be act as an excellent coadjuvant tool for many different psychotherapy techniques," he told Medscape Medical News.

The research was supported by the Multidisciplinary Association for Psychedelic Studies (MAPS), a nonprofit organization. Three authors are employed by MAPS. Dr. Mithoefer reported being a medical monitor for other studies of MDMA-assisted psychotherapy that are being conducted 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. Bouso and Dr. Johnson have disclosed no relevant financial relationships.

J Psychopharmacol. Published online November 20, 2012. Full article