On the fallibility of placebo control and how to address it: a case study in psychedelic microdosing

This preprint (2022) uses computational modelling to show that the combination of weak blinding and positive treatment expectancy can lead to activated expectancy bias (AEB), which is an uneven distribution of expectancy effects between the treatment arms due to patients recognizing their treatment allocation in psychedelic microdosing randomized controlled trials. The results demonstrate that a placebo control group is in itself not sufficient to control for expectancy effect and that placebo-controlled studies are more fallible than conventionally assumed.

Abstract

“In medical research, the gold standard experimental design is the blinded randomized controlled trial. Despite the central role of blinding, it is rare for trials to assess blinding integrity and to incorporate this information into the interpretation of results. Here we use computational modelling to show that the combination of weak blinding and positive treatment expectancy can lead to activated expectancy bias (AEB), which is an uneven distribution of expectancy effects between the treatment arms due to patients recognizing their treatment allocation. We show that this bias can inflate estimates of treatment effects and potentially create false positive findings. To counteract this bias, we introduce the Correct Guess Rate Curve (CGRC), a novel analytical tool that can estimate what would be the outcome of a perfectly blinded trial based on data from an imperfectly blinded trial. We apply CGRC to pseudo-experimental data generated by our computational model and show that the method produces AEB corrected results. Furthermore, to demonstrate the impact of AEB and the utility of the CGRC on empirical data, we re-analyzed data from a previously published self-blinding microdose trial. Results suggest that the observed placebo vs. microdose differences are susceptible to AEB, therefore, at risk of being false positives. These results demonstrate that a placebo control group is in itself not sufficient to control for expectancy effects, arguing that placebo-controlled studies are more fallible than conventionally assumed, which has implications for evidence-based medicine and numerous public health policies.”

Authors: Balázs Szigeti, David Nutt, Robin Carhartt-Harris & David Erritzoe

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Study details

Topics studied
Neuroscience Microdosing

Study characteristics
Theory Building

Participants
0 Humans

Authors

Authors associated with this publication with profiles on Blossom

Balazs Szigeti
Balazs Szigeti is involved in the Imperial College London-Beckley self-blinding microdosing study that at this moment hasn't found significant effects of microdosing.

David Nutt
David John Nutt is a great advocate for looking at drugs and their harm objectively and scientifically. This got him dismissed as ACMD (Advisory Council on the Misuse of Drugs) chairman.

Robin Carhart-Harris
Dr. Robin Carhart-Harris is the Founding Director of the Neuroscape Psychedelics Division at UCSF. Previously he led the Psychedelic group at Imperial College London.

David Erritzoe
David Erritzoe is the clinical director of the Centre for Psychedelic Research at Imperial College London. His work focuses on brain imaging (PET/(f)MRI).

Institutes

Institutes associated with this publication

Imperial College London
The Centre for Psychedelic Research studies the action (in the brain) and clinical use of psychedelics, with a focus on depression.

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