Measuring and appraising placebo effects in clinical trials: contemporary challenges and approaches in psychiatry

Placebo effects are among the greatest paradoxes in medical research. Although more data on placebos are available from placebo-controlled trials than on any treatment in medicine, there has been comparatively little deep interrogation of issues related to their measurement, appraisal, and interpretation. Most of the work that has been done, including that in psychiatry, is narrowly focused on strategies for mitigating placebo effects and the challenges they might pose. In this Review, paper 2 of 2 on reconceptualising placebo and nocebo effects, we shift our focus from clinical practice to clinical trials. First, we review established and emerging approaches for navigating placebo effects in randomised controlled trials. Second, we examine three major challenges in contemporary psychiatric research that have recently highlighted the topic of placebo effects: (1) blinding and expectancy in psychedelic trials, (2) large placebo responses in interventional psychiatry trials (ie, device or procedure-based therapeutics), and (3) implications of overlapping neurobiological mechanisms between placebo effects and psychiatric treatments.