The difference between 'placebo group' and 'placebo control': a case study in psychedelic microdosing

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.

A critical evaluation of QIDS-SR-16 using data from a trial of psilocybin therapy versus escitalopram treatment for depression

“…These facet-level differential responses were present even when controlling for relative expectancy, strengthening the inferences we can draw on direct treatment effects of PT versus, for example, a placebo-related action (Szigeti et al, 2022). Conversely, these results are suggestive that PT and SSRI therapies may be equivalent with respect to other facets of depression, most notably reduced appetite and suicidality (although note the SIDAS result in Carhart-Harris et al, 2021).…”

History repeating: guidelines to address common problems in psychedelic science

“…Another easy-toimplement solution is to use blinded analysis of the primary outcome measures, 111 or to keep raters blind to the full design of the study including which compound is being tested for further recommendations, see Even et al 112 We see some progress in this area, given that new statistical tools are under development aiming to 'control for' participants who broke the blind during the study, and a new scale has been developed to formally assess whether participants broke blind. 113…”

History repeating: A roadmap to address common problems in psychedelic science

“…Another easy-to-implement solution is to use blinded analysis of the primary outcome measures (Hrobjartsson et al, 2012), or to keep raters blind to the full design of the study including which compound is being tested (for further recommendations, see: Even et al, 2000). We see some progress in this area, given that new statistical tools are under development aiming to 'control for' participants who broke the blind during the study, and a new scale has been developed to formally assess whether participants broke blind (Szigeti et al, 2022).…”