Placebo and nocebo effects: from observation to harnessing and clinical application

Abstract

Placebo and nocebo effects are salubrious benefits and negative outcomes attributable to non-specific symbolic components. Leveraging advanced experimental and analytical approaches, recent studies have elucidated complicated neural mechanisms that may serve as a solid basis for harnessing the powerful self-healing and self-harming capacities and applying these findings to improve medical practice and minimize the unintended exacerbation of symptoms in medical practice. We review advances in employing psychosocial, pharmacological, and neuromodulation approaches to modulate/harness placebo and nocebo effects. While these approaches show promising potential, translating these research findings into clinical settings still requires careful methodological, technical, and ethical considerations.

Fig. 1. Different approaches and potential neural mechanisms to harness placebo effects.

A Psychosocial approaches, including valuable information and enhanced conditioning (i.e., verbal suggestion precedes conditioning), modulate the reward system (e.g., ventromedial prefrontal cortex [vmPFC], nucleus accumbens [NAc], and ventral tegmental area [VTA]). Trustful doctor–patient relationships rely on the brain-to-brain coupling in the temporoparietal junction (TPJ), insula, and ventrolateral prefrontal cortex (vlPFC). B Intranasally administered oxytocin/vasopressin travels to the brain via olfactory and trigeminal nerve fibers and may modulate placebo-related brain activities in the anterior cingulate cortex (ACC), NAc, hypothalamus, amygdala, hippocampus, and brainstem. C Neuromodulational approaches including transcranial magnetic stimulation (TMS) and electrical stimulation (tES) target key regions in the prefrontal cortex (e.g., dorsolateral prefrontal cortex [DLPFC] and orbitofrontal cortex [OFC]) to modulate the reward system and descending pain modulation system (e.g., periaqueductal gray [PAG] and rostral ventromedial medulla [RVM]) to harness placebo effects.