Every month, the BCSP brings you one essential read to keep you up to date with the leading topics in psychedelic science. This month, postdoctoral researcher Sean Noah explains “Expectancy effects in psychedelics trials” by Dr. Balázs Szigeti and Dr. Boris D. Heifets, published in 2024 in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging. See more on the article in BCSP’s resource database.
Psychedelic drugs show potential to treat psychiatric conditions including post-traumatic stress disorder, treatment-resistant depression, and substance use disorder. Clinicians are increasingly accepting psychedelics as treatments — largely because of respected results from double-blind, placebo-controlled clinical trials. Such trials are the gold standard method for assessing the efficacy of new treatments before they can be administered to patients.
What is a double-blind study?
In theory, in a double-blind study, neither the researcher nor the participant knows who is receiving a placebo (the control group) or the drug (the experimental group). But unlike many new drugs under investigation, psychedelics bring unique challenges to this established approach.
One of the greatest challenges is adequate masking. In a randomized trial comparing a psychedelic to an inactive placebo, many study participants can easily detect psychedelics’ profound psychoactive effects, thereby breaking the experimental blind.
Without an adequate blind, study participants’ expectations about the efficacy of psychedelics for improving their well-being can influence the study’s outcomes.
Sometimes, researchers attempt to address the masking issue by using an active placebo, a drug that causes noticeable physiological effects intended to make patients unsure about whether they received the study drug or not. But active placebos often are ineffective in their blinding because of the distinct subjective effects of psychedelics.
Take niacin for example. The drug, which is sometimes given as an active placebo, can cause a flushing reaction and a tingling feeling, but these effects hardly resemble visual and other effects of psychedelics. That means that study participants can often tell whether they’ve ingested the placebo or the psychedelic, opening up room for their expectations about psychedelics to influence how they perceive the treatment. Without an adequate blind, study participants’ expectations about the efficacy of psychedelics for improving their well-being can influence the study’s outcomes.
When positive thinking collides with scientific rigor
In their new review article, published in the journal Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, Dr. Balázs Szigeti and Dr. Boris Heifets study how participants’ expectations about the benefits of psychedelic-assisted therapy could skew psychedelic clinical trial results toward positive outcomes. The authors observe that despite the precedent for using peer-reviewed questionnaires to assess expectancy effects in other types of studies and clinical trials, only one high-dose psychedelic trial has measured expectancy effects.
In all the high-dose psychedelic trials surveyed by the authors, patients were able to correctly guess whether they were assigned to the psychedelic or placebo group at a rate of 95 percent.
Poor blinding integrity underscores the need for more widespread expectancy measurement in future trials: In all the high-dose psychedelic trials surveyed by the authors, patients were able to correctly guess whether they were assigned to the psychedelic or placebo group at a rate of 95 percent.
Because of the lack of expectancy measurement, the effects of expectancy on positive therapeutic outcomes in psychedelic trials remain unknown. The possibility that expectancy contributes to the positive therapeutic outcomes observed in psychedelic trials makes interpreting study results more difficult. Therefore, in their article, Dr. Szigeti and Dr. Heifets call for more widespread measurement of these effects in the future.
These measurements could consist of conducting surveys before the drug administration that ask about the participant’s beliefs and their confidence that the treatment will improve their condition. Such measures would improve the rigor of psychedelic clinical trials and allow for evaluation of the contributions of expectancy to the effects of psychedelics.
However, the authors also acknowledge that expectancy and drug effects might combine to enhance psychedelic-assisted therapy, observing the possibility that “the psilocybin treatment effect should be considered as the sum of placebo effect and drug effect, rather than the difference between them.”
In other words, expectations about positive health outcomes from psychedelic-assisted therapy could be additive with drug effects, resulting in improvements in outcome measures that are greater than either effect alone.
Want to read more? Dive into the full article or learn more in BCSP’s resource database.