Tales of the unexpected: psychedelic trial design solutions

This article spotlights problematic assumptions and practices in clinical psychedelic research that together hamper the field’s ability to demonstrate causal identification, contributing to confusion and misunderstanding: (1) the main problematic assumption is that pretreatment expectancy causes therapeutic response; while expectancy predicts response to most treatments, it is becoming increasingly clear that the same is not true for psychedelic therapy—and we offer a plausible hypothesis for why; (2) the main problematic practice is the double-blind procedure, which is ecologically invalid, ethically questionable, and fails to achieve its purpose (causal identification) due to functional unblinding; we propose alternative trial designs that can circumvent the need for participant blinding while improving our ability to draw strong inferences regarding the causal action of psychedelic therapy.