Q&A: MDMA-assisted psychotherapy, in the right hands, effectively treats PTSD

The evidence base is growing for a psychoactive substance in the treatment of PTSD, according to the co-author of a systematic review and meta-analysis exploring the therapy’s potential.

The substance, 3,4-methylenedioxymethamphetamine (MDMA), uses the intended active ingredient in illicit Ecstasy or Molly products, resulting in elevated mood, a feeling of bonding and increased energy in patients with the mental disorder, C. Michael White, PharmD, FCP, FCCP, the head of the pharmacy practice department and a distinguished professor of pharmacy practice at the University of Connecticut, and colleagues reported.

“While MDMA-assisted psychotherapy has been shown to be an effective therapy for PTSD patients with a reasonable safety profile, use of unregulated MDMA or use in the absence of a strongly controlled psychotherapeutic environment has considerable risks,” White and colleagues wrote in The Journal of Clinical Pharmacology.

In an interview with Healio Primary Care, White discussed the evidence to support MDMA-assisted psychotherapy, the best candidates to receive it and more.

Healio Primary Care: What prompted you to conduct this research?

White: In 2014, I was working on a review article on to guide emergency room clinicians and paramedics when I came across a literature base that used MDMA-enhanced psychotherapy as a treatment for PTSD.

At the time, the literature base was very limited but promising, so I crafted a second review specifically on this topic. Since that time, a number of phase 2 clinical trials and a phase 3 clinical trial have been completed. Thus, it seemed like a good time to conduct a systematic review with meta-analysis to further explore the impact of MDMA-enhanced psychotherapy on PTSD.

Healio Primary Care: Based on current evidence, how does the safety and efficacy of MDMA-assisted psychotherapy compare with other PTSD treatments?

White: Current guidance for PTSD suggests that psychotherapy is first-line therapy, with pharmacologic options like selective serotonin reuptake inhibitors and venlafaxine reserved for people without access to psychotherapy or for whom psychotherapy has not been adequately successful.

MDMA-assisted psychotherapy is characteristically different than selective serotonin reuptake inhibitors and venlafaxine therapy in that it is not consumed daily, but over the course of two or three intensive MDMA-enhanced psychotherapy sessions. So MDMA taken in the absence of concurrent psychotherapy is unlikely to replicate the results of these clinical trials.

In general, selective serotonin reuptake inhibitors and venlafaxine produce reductions in Clinician-Administered PTSD Scale scores around six points to 14 points more than control, and about 33% of people withdrew from the trials. MDMA-enhanced psychotherapy reduced Clinician-Administered PTSD Scale scores by 22 more points than control, were 3.6-fold more likely to experience a clinically significant improvement in PTSD, and fewer than 10% of patients withdrew from the MDMA trials.

There were some adverse events with MDMA-enhanced psychotherapy, including anxiety, jaw clenching, dizziness, nausea and excessive sweating, but therapy was generally well-tolerated. The MDMA used in these trials was commercial grade, not off the street or illicit. Illicit MDMA products are likely contaminated or adulterated and the dosage of MDMA varies widely, which would change the benefit-to-harm balance.

Healio Primary Care: Who would be good candidates for MDMA-assisted psychotherapy?

White: Adding a few MDMA-assisted psychotherapy sessions to a patient’s regimen seems especially well-suited for patients with moderate to severe disease who are not well-treated with psychotherapy alone. MDMA-assisted psychotherapy would be an intermediate care step before moving to chronic selective serotonin reuptake inhibitors or venlafaxine therapy.

However, the selective serotonin reuptake inhibitors, venlafaxine and MDMA-enhanced psychotherapy were compared vs. control, not directly each other.

Healio Primary Care: If approved, how comfortable do you think providers would be with administering this type of therapy? What challenges would they face?

White: Psychotherapists will need to be specially trained to incorporate these extensive MDMA-enhanced sessions into their patients’ treatment plans. The reason that adverse events were so low is because the environment was so well-controlled, meaning it is not only the length of the treatment session that was altered but also the way psychotherapy was used. If MDMA-assisted psychotherapy is ever approved by the FDA, the logistics of whether and how psychologists would be able to be involved in conducting or assisting in these sessions vs. having them restricted to psychiatrists will also need to be worked out.

Many psychotherapists would be interested in using this therapy because it can allow a patient unable to share the full nature of their traumatic experiences to be in an environment where they feel they can do so without overwhelming suffering in the process.

Healio Primary Care: Is MDMA-assisted psychotherapy being evaluated for other conditions? If so, how promising does the treatment appear to be for those conditions?

White: There are preliminary studies looking at MDMA-assisted psychotherapy for anxiety and depression but its role in treating these disorders is unknown at this time. Psilocybin-enhanced psychotherapy, or hallucinogenic mushrooms, is much better studied for refractory depression, with promising results. Taken together, there looks to be a role for psychedelics in the treatment of mental health disorders for those who cannot be treated with standard therapies.

Healio Primary Care: What are the next steps for this line of research?

White: The next step would be to directly assess psychotherapy-resistant patients randomized to MDMA-enhanced psychotherapy or other pharmacotherapy to clarify which is a superior second-line therapeutic option.

Healio Primary Care: Anything else to add?

White: The DEA’s default designation of substances of abuse as Schedule 1 drugs makes it very difficult to discover their potential role in disease treatment. The emergence of CBD as a treatment for refractory seizures in Lennox-Gestaut and Dravet’s syndrome, as well as MDMA as a treatment for PTSD, could have come decades earlier had it not been for this designation. We need to advocate for a system where access can be restricted while rational research is still allowed to progress.

Reference:

Smith KW, et al. J Clin Pharmacol. 2021;doi:10.1002/jcph.1995.