The neglect of sex: A call to action for including sex as a biological variable in placebo and nocebo research

Abstract

Sex differences exist in the prevalence, progression and treatment efficacy of a wide array of medical conditions. While the placebo and nocebo effects have become increasingly relevant in the clinical arena, little is known about the influence of biological sex on placebo and nocebo effects. This paper discusses the existing, relatively limited and sometimes conflicting evidence about how sex impacts the occurrence and magnitude of the placebo and nocebo effects, mainly focusing on pain studies. We present recent evidence that when compared to men, women suffering from chronic orofacial pain may derive greater benefit from the placebo effect for analgesia. Nonetheless, we broadly argue that the field is not currently positioned to draw definitive conclusions and propose several important factors that may explain the inconsistency in the literature and that should be taken into account in future research. These include the specific target symptom of the placebo or nocebo manipulation and whether or not the target is related to the medical condition, the placebo or nocebo induction method, the sex of the experimenter or physician, and so forth. Future research should intentionally include sex a biological variable to favor translation of placebo and nocebo mechanisms into clinical applications.

Keywords: Conditioning; Expectations; Experimental settings; Gender; Randomized clinical trials; Social learning.