Hypothalamic-Pituitary-Adrenal Activity in Adverse Events Reporting after Placebo Administration

Participants of clinical trials who receive a placebo treatment often report a variety of adverse events, sometimes called nocebo effects. The reason why these adverse events occur is not clear, and understanding the underlying mechanisms represents a challenge that is likely to improve the interpretation of clinical trials as well as medical practice. Here, we studied 192 healthy subjects who received placebo oxygen through a mask after reading (READ) or not reading (NO-READ) a list of possible adverse events of oxygen breathing: headache, chest pain, abdominal pain, and cough. The whole hypothalamus-pituitary-adrenal axis was assessed just before and right after placebo breathing by measuring the hypothalamic corticotropin-releasing hormone (CRH), pituitary adrenocorticotropic hormone (ACTH), and adrenal cortisol (COR). In addition, both state and trait anxiety were assessed. We found that 64.5% of the NO-READ group reported no adverse events, 30.2% had one, and only 5.2% had two adverse events. In contrast, only 20.8% of the READ group reported no adverse events, whereas 1, 2, 3, and 4 adverse events were reported with a frequency of 21.8%, 19.8%, 19.8%, and 17.7%, respectively. In addition, when the READ group reported three and four adverse events, CRH, ACTH, and COR were significantly increased compared to the NO-READ group, along with an increase in state anxiety scores. These data indicate that hypothalamic-pituitary-adrenal activity and state anxiety are increased in those subjects who report many adverse events after reading a list of adverse events, thus highlighting a possible neuroendocrine mechanism after placebo administration.