Unmasking bias and MDMA-assisted therapy

The FDA rejected MDMA-assisted therapy for PTSD partly due to concerns about functional unblinding, where participants or clinicians guess treatment assignment because of the drug's noticeable effects, potentially biasing trial results. The authors define unmasking bias and calculate its magnitude for two other drugs, ketamine and escitalopram, using published data. They find that unmasking bias for these two drugs exceeds the treatment-versus-control effect size observed in MDMA trials. This indicates that the effect sizes for MDMA-assisted therapy are not too large to be explained by unmasking bias, though the findings do not prove that the therapy's effects are entirely or partially due to this bias.

Study at a glance

Abstract

On August 9th the US Food and Drug Administration’s (FDA) rejected 3,4-methylenedioxymethamphetamine assisted therapy (MDMA-AT) as a treatment for post-traumatic stress disorder (PTSD) despite seemingly positive trial results. A major reason cited was functional unmasking, which combined with enthusiasm about MDMA, raised concerns about the objectivity of these trials. Here, we define what is 'unmasking bias' and calculate its magnitude for two drugs, ketamine and escitalopram, where data was available from the literature. Our results show that unmasking bias for these two drugs is larger than the treatment vs. control effect size for MDMA. Our findings do not prove that effects of MDMA-AT are entirely or even partially due to unmasking, however, they indicate that MDMA-AT’s effect sizes are not too large to be due to unmasking.