This computational analysis (2023) employs computational modelling to illustrate how weak blinding and positive treatment expectancy can cause an uneven distribution of expectancy effects, termed ‘activated expectancy bias’ (AEB). The study introduces the Correct Guess Rate Curve (CGRC), a tool to estimate the results of a perfectly blinded trial using data from an imperfect one, and re-analyzed the ‘self-blinding psychedelic microdose trial’ dataset (n=191) to demonstrate that placebo-microdose differences may be susceptible to AEB, thereby suggesting microdosing can be viewed as an active placebo.
Abstract of The difference between ‘placebo group’ and ‘placebo control’
“In medical trials, ‘blinding’ ensures the equal distribution of expectancy effects between treatment arms in theory; however, blinding often fails in practice. We use computational modelling to show how weak blinding, combined with positive treatment expectancy, can lead to an uneven distribution of expectancy effects. We call this ‘activated expectancy bias’ (AEB) and show that AEB can inflate estimates of treatment effects and create false positive findings. To counteract AEB, we introduce the Correct Guess Rate Curve (CGRC), a statistical tool that can estimate the outcome of a perfectly blinded trial based on data from an imperfectly blinded trial. To demonstrate the impact of AEB and the utility of the CGRC on empirical data, we re-analyzed the ‘self-blinding psychedelic microdose trial’ dataset. Results suggest that observed placebo-microdose differences are susceptible to AEB and are at risk of being false positive findings, hence, we argue that microdosing can be understood as active placebo. These results highlight the important difference between ‘trials with a placebo-control group’, i.e., when a placebo control group is formally present, and ‘placebo-controlled trials’, where patients are genuinely blind. We also present a new blinding integrity assessment tool that is compatible with CGRC and recommend its adoption.”
Authors: Balázs Szigeti, David J. Nutt, Robin L. Carhart-Harris & David Erritzoe
Summary of The difference between ‘placebo group’ and ‘placebo control’
In medical research, blinded randomized controlled trials are the gold standard experimental design. However, only 2 – 7% of trials report blinding integrity, and when blinding is assessed, it is found to be ineffective for about 50% of the trials.
Poor reporting of blinding integrity may be explained by several factors, including the lack of an accepted standard for assessing blinding integrity and a fear that weak blinding could cast doubt on positive trial outcomes.
A self-blinding citizen science trial was conducted on microdosing, where participants implemented their own placebo control based on online setup instructions without clinical supervision. It was completed by 191 participants, making it the largest placebo-controlled trial on psychedelic microdosing for a fraction of the cost.
Find this paper
https://doi.org/10.1038/s41598-023-34938-7
Open Access | Google Scholar | Backup | 🕊
Cite this paper (APA)
Szigeti, B., Nutt, D., Carhart-Harris, R. et al. The difference between ‘placebo group’ and ‘placebo control’: a case study in psychedelic microdosing. Sci Rep 13, 12107 (2023). https://doi.org/10.1038/s41598-023-34938-7
Study details
Compounds studied
Placebo
Authors
Authors associated with this publication with profiles on Blossom
Balazs SzigetiBalazs 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 LondonThe Centre for Psychedelic Research studies the action (in the brain) and clinical use of psychedelics, with a focus on depression.
Linked Research Papers
Notable research papers that build on or are influenced by this paper
Self-blinding citizen science to explore psychedelic microdosingThis self-blinding experiment (n=191) finds that the placebo and microdosing groups both experienced similar improvements in self-rated psychological well-being and cognitive function (e.g. mood, energy, creativity) after four weeks. This study provides more evidence that microdosing benefits can be attributed to expectancy (placebo) effects.
Evidence for tolerance in psychedelic microdosing from the self-blinding microdose trial
This pre-print reanalysed data from a placebo-controlled citizen science microdosing study (n=240) to investigate whether tolerance develops during microdosing. It was conceptualized that if tolerance develops, the probability of correctly guessing active microdoses should decrease with more microdoses. Linear regression models showed that correct microdose guess probability decreased with the number of microdoses taken (p=0.09) indicating that tolerance developed.