CRITICAL METHODOLOGICAL DECISIONS IN PSYCHEDELIC DRUG TRIALS

Over the past decade there has been a surge in interest in placebocontrolled trials using non-classical 3,4-methylenedioxymethamphetamine (MDMA) and classical psychedelics such as psilocybin, lysergic acid diethylamide (LSD) and N,Ndimethyltryptamine (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. Principal Investigators need to make critical methodological decisions as they trials of psychedelic drugs. The first decision concerns the selection of the control, for example whether to use an active control or a placebo. The second decision concerns the adoption of methodologies aimed at reducing the effects of placebo or of the active control. Approaches range from independent verification of the appropriateness of subjects selection to the use of study designs aimed at manipulating expectations and reducing placebo response. The third decision concerns ensuring the blinding of the ratings to minimize the risk of biased assessments. The fourth decision concerns the selection of the appropriate measures to evaluate outcome. The fifth and final decision involves the selection of the appropriate statistical analysis plan. These methodological considerations require examining the advantages and disadvantages of these approaches with the goal of enhancing the validity of these trials and their regulatory science. By doing so, we aim to improve the reliability of psychedelic research in uncovering the therapeutic benefits of psychedelics beyond placebo and expectation effects.

References

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