Expectancy effects cannot be neglected in MDMA-assisted therapy research

A commentary on a phase 3 trial of MDMA-assisted therapy for PTSD raises concerns about expectancy effects. The trial reported positive results, but most participants correctly guessed their treatment assignment, and expectations were not measured. The authors argue these effects were minimal, but the commentary contends that without measuring expectations, it remains possible that placebo or nocebo effects contributed to the observed outcomes.

Study at a glance

Abstract

In their recent paper titled “MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial”, Mitchell et al.1 report on the results from a study researching the potential use of 3,4-methylenedioxy methamphetamine-assisted therapy (MDMA-AT) for the treatment of posttraumatic stress disorder (PTSD). We applaud the efforts made to further establish the efficacy of MDMA-AT in the treatment of PTSD. Yet, we have some concerns regarding the discussion of potential expectancy effects in this trial. Expectancy effects typically occur when participants in a clinical trial identify which treatment arm they were assigned to, and subsequently expect symptom alleviation if they are in the treatment group (i.e., placebo effects) or symptom worsening if they are in the control group (i.e., nocebo effects). Mitchell et al. put forth several arguments as to why they believe expectancy effects were minimal in this trial. However, as most of the participants broke the blind, and participants’ expectations were not measured, the authors’ arguments are merely speculative, and it remains possible that expectancy effects may have contributed to the observed effects of MDMA-AT.