Sunday, 4 Jun 2023

Adjunctive MDMA Safe, Effective for Severe PTSD

Adding 3,4-methylenedioxymethamphetamine (MDMA) to integrative psychotherapy may significantly improve symptoms and well-being for patients with severe posttraumatic stress disorder (PTSD), including those with the dissociative subtype, new research suggests.

MAPP1 is the first phase 3 randomized controlled trial of MDMA-assisted therapy in this population. Participants who received the active treatment showed greater improvement in PTSD symptoms, mood, and empathy in comparison with participants who received placebo.

MDMA was “extremely effective, particularly for a subpopulation that ordinarily does not respond well to conventional treatment,” study co-investigator Bessel van der Kolk, MD, professor of psychiatry at Boston University School of Medicine, Boston, Massachusetts, told delegates attending the virtual European Psychiatric Association (EPA) 2021 Congress.

Growing Interest

In recent years, there has been a great deal of interest in the potential of MDMA for the treatment of PTSD, particularly because failure rates with most available evidence-based treatments have been relatively high.

As previously reported by Medscape Medical News, in 2017, the US Food and Drug Administration approved MDMA after granting the drug breakthrough therapy designation.

The MAPP1 investigators assessed 90 patients with PTSD (mean age, 41 years; 77% White; 66% women) from 50 sites. For the majority of patients (84%), trauma history was developmental. “In other words, trauma [occurred] very early in life, usually at the hands of their own caregivers,” Kolk noted.

In addition, 18% of the patients were veterans, and 12% had combat exposure. The average duration of PTSD before enrollment was 18 years. All patients underwent screening and three preparatory psychotherapy sessions at enrollment.

Participants were randomly assigned to receive MDMA 80 mg or 120 mg (n = 46) or placebo (n = 44) followed by three integrative psychotherapy sessions lasting a total of 8 hours. A supplemental dose of 40 or 60 mg of MDMA could be administered from 1.5 to 2 hours after the first dose.

The patients stayed in the laboratory on the evening of the treatment session and attended a debriefing the next morning. The session was repeated a month later and again a month after that. In between, patients had telephone contact with the raters, who were blinded to the treatment received.

Follow-up assessments were conducted 2 months after the third treatment session and again at 12 months. The primary outcome measure was change in Clinician Administered PTSD Scale for DSM 5 (CAPS-5) score from baseline.

“Dramatic Improvement”

Results showed that both the MDMA and placebo groups experienced a statistically significant improvement in PTSD symptoms, “but MDMA had a dramatically significant improvement, with an effect size of over 0.9,” Kolk said.

The MDMA group also reported enhanced mood and well-being, increased responsiveness to emotional and sensory stimuli, a greater sense of closeness to other people, and a greater feeling of empathy.

Patients also reported having heightened openness, “and clearly the issue of empathy for themselves and others was a very large part of the process,” said Kolk.

“But for me, the most interesting part of the study is that the Adverse Childhood Experiences scale had no effect,” he noted. In other words, “the amount of childhood adverse experiences did not predict outcomes, which was very surprising because usually those patients are very treatment resistant.”

Kolk added that the the dissociative subtype of PTSD was first described in DSM-5 and that patients are “notoriously unresponsive to most unconventional treatments.”

In the current study, 13 patients met the criteria for the subtype, and investigators found they “did better than people with classical PTSD,” Kolk said. He added that this is a “very, very important finding.”

Carefully Controlled

Overall, 82% of patients reported a significant improvement by the end of the study; 56% reported that they no longer had PTSD.

In addition, 67% of patients no longer met diagnostic criteria for PTSD. These included patients who had crossed over to active treatment from the placebo group.

Eleven patients (12%) experienced relapse by 12 months; in nine of the cases, this was due to the presence of additional stressors.

There were “very few adverse side effects” during the study, Kolk noted. In addition, “there were really no serious mental side effects,” despite the patients’ “opening up so much very painful material,” he added.

The most common adverse events among the MDMA group were muscle tightness (63%), decreased appetite (52%), nausea (30%), hyperhidrosis (20%), and feeling cold (20%). These effects were “quite small [and] the sort of side effects you would expect in response to an amphetamine substance like MDMA,” said Kolk.

“An important reason why we think the side effect profile is so good is because the study was extremely carefully done, very carefully controlled,” he added. “There was a great deal of support, [and] we paid an enormous amount of attention to creating a very safe context in which this drug was being used.”

However, he expressed concern that “as people see the very good results, they may skimp a little bit on the creation of the context and not have as careful a psychotherapy protocol as we had here.”

“On the Right Track”

Commenting on the findings for Medscape Medical News, David Nutt, MD, PhD, Edmond J. Safra Professor of Neuropsychopharmacology, Imperial College London, United Kingdom, said the results are proof that the investigators’ “earlier smaller trials of MDMA were on the right track.

“This larger and multicenter trial shows that MDMA therapy can be broadened into newer research groups, which augurs well for the much larger rollout that will be required once it gets a license,” said Nutt, who was not involved with the research.

He added, “the prior evidence of the safety of MDMA has [now] been confirmed.”

The study represents an “important step in the path to the clinical use of MDMA for PTSD,” Nutt said.

The study was sponsored by the Multidisciplinary Association for Psychedelic Studies. The investigators and Nutt have reported no relevant financial relationships.

European Psychiatric Association (EPA) 2021 Congress: Abstracts O206 and O209. Presented April 11, 2021.

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