Studies Illustrate Potential of MDMA-, Psilocybin-Assisted Therapies

In the opening session of the recent virtual Sana Symposium, Steering Committee Members Andrew Penn, RN, PMHNP, and Charles Raison, MD, delivered an update on the state of psychedelics research and progress being made toward Food and Drug Administration (FDA) approval of psychedelic-assisted psychotherapy interventions for several mental health conditions.

Penn, clinical professor at the University of California, San Francisco, School of Nursing, and Dr Raison, professor at the University of Wisconsin-Madison and director of clinical and translational research for the Usona Institute and director of research on spiritual health for Emory Healthcare, homed in on late-stage trials for MDMA-assisted therapy to treat post-traumatic stress disorder (PTSD) and the use of psilocybin for treatment-resistant depression (TRD) and major depressive disorder (MDD).

“We’ve all had patients who are kind of stuck,” Penn said. “There are different ways we can look at this ‘stuckness.’ Traditionally, we’ve approached these conditions with psychotherapy, which can engender some benefit, or with psychopharmacology—a pill taken on a daily basis. This is a different model. It’s using a drug only a handful of times in conjunction with psychotherapy to see if we can get better outcomes using both modalities combined.”

For nearly 20 years, a “gathering snowball” of evidence suggesting that 1 to 2 high doses of psilocybin can produce therapeutic benefits across a range of conditions, Dr Raison said. He then shared a Phase 2B study of the use of psilocybin for treatment-resistant depression published in the New England Journal of Medicine in 2022. The study found that a 25mg dose of psilocybin, combined with psychotherapy, produced a statistically significant drop in patients’ scores on the Montgomery Asberg Depression Rating Scale (MADRS) after 12 weeks. The effect was far more muted among patients who received 1-mg or 10-mg doses.

Dr Raison then shared a Phase 2 study conducted by Usona Institute researchers that used a randomized clinical trial to examine the effect of a single dose of psilocybin for MDD. Half the 104 study participants received a 25-mg dose of psilocybin, and half received niacin as a placebo. Niacin produced a similar response as the low-dose psilocybin of the previous study, however, the average MADRS score among patients receiving 25-mg of psilocybin decreased by 20 points with no decay in effectiveness.

While most patients receiving psilocybin saw their depression score decrease, 5 patients had their symptoms worsen.

“I am now completely convinced that a single high dose of psilocybin has a powerful, replicable antidepressant effect that can benefit many people with depression, we hope, but not everybody,” Dr Raison said. “The effects are various, and there’s a wide range with how people respond.”

Side effects of psilocybin use, most of which were found to be mild or moderate and occurring on the day of dosing, included increased blood pressure and heart rate, headaches, paranoia, and/or anxiety.

“Psychedelics can induce really challenging experiences for people,” Dr Raison said. “These can have longer-term effects. One of the great questions in the field now is the degree to which we need to worry about people having challenging or emotionally disturbing experiences during the psychedelic trip.”

People who have challenging experiences they were able to resolve often say those challenging experiences were what made them therapeutically improve, Dr Raison said. On the other hand, there are studies suggesting that experiences that last longer in a negative sense or if people fight against it, that can lead to long-term difficulties.

Penn then shared a study examining the use of MDMA to treat PTSD. MDMA decreases activity in the right amygdala, where fear signals are produced, and increases activity in the prefrontal cortex, where memories begin to contextualize.

“That’s valuable from a psychotherapeutic standpoint because we know as clinicians that working with people with PTSD, often 1 of 2 things happen when people begin talking about their trauma: One is they become overwhelmed by their memories and the experience of trauma is not tolerated, or they’ll tune out,” Penn said. “Either way, they are avoiding therapy. What MDMA may do is widen the optimal arousal zone where you are able to talk about traumatic experiences but not become totally overwhelmed and shut down.”

In a recent study, results of which were published in the journal Nature Medicine, patients went through an 18-week MDMA-assisted psychotherapy program that included 3 sessions of MDMA or placebo delivered at regular intervals. At the end of the Phase 3 study, 67% of patients treated with MDMA no longer had a PTSD diagnosis, while 32% of placebo-treated patients no longer had a PTSD diagnosis.

Beyond PTSD, Penn said MDMA is also currently being studied for several other conditions, including negative symptoms of schizophrenia, obsessive-compulsive disorder, co-occurring PTSD and opioid use disorder following childbirth, social anxiety, and eating disorders.

Reference

Penn A, Raison C. Updates in psychedelics: Where we are now and where we are headed. Presented at Sana Symposium; October 26-27, 2023; virtual.