Jerrold Rosenbaum, MD: Functional Unblinding in Pivotal Studies and the Future of Psychedelic Medicine

In June, an expert panel from the Food and Drug Administration (FDA) reviewed two studies of MDMA-assisted therapy for the treatment of post-traumatic stress disorder (PTSD).  While both studies demonstrated that MDMA-assisted therapy improved PTSD symptoms over 18 weeks and improvements persisted for several months after treatment, many committee members voted against recommending the approval of this treatment due to concerns about the study design.

In a commentary published in the Journal of Clinical Psychiatry, Jerrold Rosenbaum, MD, Director of the Center for the Neuroscience of Psychedelics, discusses the critical issue of functional unblinding in clinical trials for psychedelic medicines, focusing on MDMA-assisted therapy for PTSD and psilocybin for treatment-resistant depression. Functional unblinding is what occurs when participants or investigators are able to guess what treatment the participant is receiving because of the unmistakable effects of the drug.

Challenges in Psychedelic Research

The psychoactive nature of substances like MDMA and psilocybin makes it difficult to maintain true blinding in clinical trials. Participants often experience distinct perceptual changes that can make it easy to tell whether they received the active drug or a placebo.

Functional unblinding may lead to expectancy effects, where participants’ beliefs about their treatment assignment may influence their reported outcomes. This can potentially inflate the apparent efficacy of the treatment.  Our inability to calculate the impact of functional unblinding on the reported efficacy outcomes contributes to uncertainty about the validity of the findings and may ultimately make it difficult to approve potentially effective treatments.

Proposed Solutions

Rosenbaum notes that for a study drug that cannot be adequately blinded, the approval process would benefit from enhanced guidelines or criteria for approval and suggested the following:

1. 1. For the study drug, there should be a plausible mechanism of action.
   2.  All subject assessments should be done by blinded remote raters trained to not elicit subject beliefs about treatment assignment. 
   3. There should be a robust effect size for response and remission. 
   4. The study drug should present a favorable risk/benefit profile in terms of safety or potential risk mitigation. 
   5. Durability of response should be distinct from the natural history of a chronic or recurrent condition. 
   6. The FDA should also take into consideration positive and negative testimonials. 

Rosenbaum notes that these criteria provide a path forward for the evaluation of psychedelic compounds and the possible approval of MDMA for the treatment of PTSD.  

Rosenbaum JF. Functional Unblinding in Pivotal Studies and the Future of Psychedelic Medicine. J Clin Psychiatry. 2024 Aug 21;85(3):24com15504.