Patient expectations are a feature of treatment strategy rather than a source of bias

On June 4, 2024, a group of advisers to the US Food and Drug Administration (FDA) voted that the drug MDMA was not proven effective for treating Post Traumatic Stress Disorder (PTSD).Members of an independent scientific advisory committee voted 9 to 2 that human trials of MDMA did not prove its efficacy.They also voted 10 to 1 that the risks of MDMA, also known as ecstasy, outweigh its benefits.By way of background, MDMA is a synthetic compound that can evoke euphoria among individuals who take it.The nonprofit group Multidisciplinary Association for Psychedelic Studies (MAPS) has been running MDMA clinical trials using an MDMA treatment protocol that involves a series of psychotherapy sessions along with three sessions in which a team of two therapists administers MDMA.Although the actual mechanism of effect is unknown, it is postulated that MDMA helps patients with PTSD open up to their therapists about traumatic events that they might otherwise be reluctant to confront.Thus, any therapeutic benefit of MDMA for PTSD is embedded in a treatment strategy that includes the drug, the psychotherapy, and the patient's expectations.The FDA Advisory Committee reviewed two clinical trials conducted by MAPS in which a total of 194 patients with PTSD received either MDMA plus psychotherapy or a placebo plus psychotherapy 1,2.In their application to the FDA, MAPS reported that more than 80% of patients receiving both MDMA and psychotherapy saw significant improvements in symptoms of PTSD, compared to about 60% of patients receiving placebo and psychotherapy.In each trial, twice as many patients receiving MDMA and psychotherapy no longer met criterial for PTSD than patients who received psychotherapy and placebo.A major concern of the Advisory Committee was the functional unblinding in which patients and therapists could almost always discern whether they had received MDMA or placebo.This was neither unexpected nor hidden by the investigators.In the 2023 trial, the investigators reported that 94% of MDMA subjects correctly guessed they were receiving the psychedelic; and 76% of the placebo patients similarly guessed correctly 2.The concern about this unblinding was magnified because the outcome was not a "hard" endpoint like death or major morbidity but a "soft" endpoint of a change in a symptom-based rating scale.It is certainly true that patient expectations have a powerful influence on the outcomes of treatment, and this effect is not limited to psychiatric disorders.It has been 30 years since it was first demonstrated that high adherers to placebo in a randomized controlled trial of beta blockers after heart attack were less likely to die during follow up than poor adherers 3.Remarkably, the adherence effect in reducing mortality was greater than the effects of the beta