Unmasking bias and MDMA-assisted therapy

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 is larger than the treatment vs control effect size for MDMA. These findings do not prove that effects of MDMA-AT are entirely or even partially due to unmasking, however, our findings do indicate that MDMA-AT’s effect sizes are not too large to be due to unmasking.