What should constitute a control condition in psychedelic drug trials?

Over the past decade there has been a surge in interest in placebo-controlled trials using non-classical 3,4-methylenedioxymethamphetamine (MDMA) and classical psychedelics such as psilocybin, lysergic acid diethylamide (LSD) and N,N-dimethyltryptamine (DMT) to treat neuropsychiatric disorders. However, the success and reliability of these trials depend on the design of the trials, the choice of control conditions, and the ability to blind both participants and researchers. When appropriate control conditions are lacking, it becomes difficult to disentangle placebo and expectation effects from medication effects. Here we explore the neurobiology of placebo and expectation effects, alongside the methodological considerations for selecting suitable control conditions in psychedelic trials. This includes examining the advantages and disadvantages of various control conditions and proposing new directions to enhance the validity of these trials and their regulatory science. By addressing these factors, we aim to improve the reliability of psychedelic research in uncovering the therapeutic benefits of psychedelics beyond placebo and expectation effects. To improve the reliability of research on the therapeutic benefits of psychedelics beyond placebo and expectation effects, the authors discuss the methodological considerations for selecting suitable control conditions in psychedelic trials and the neurobiology of placebo and expectation effects.