Clinical neuroscience and neurobiology of placebo and nocebo effects.

Placebo effects refer to changes in outcomes driven by learning and expectations, and they can shape responses to both pharmacologic and non-pharmacologic interventions. This chapter examines the neurobiology of placebo and nocebo effects, with an emphasis on findings from human research. Drawing primarily from controlled laboratory studies, we highlight neuroimaging and transcriptomic mechanisms that shed light on the formation of placebo and nocebo responses. In particular, this chapter highlights how expectations and contextual cues can enhance or diminish the efficacy of both pharmacologic and non-pharmacologic interventions. A focus is placed on the role of open-label, cost perception, branding, and treatment modality in modulating placebo effects. The neurochemical basis of placebo analgesia is also examined, with a central role identified for endogenous opioids, and additional contributions from the endocannabinoid and dopaminergic systems. Neuroimaging studies reveal brain networks and structural markers that predict placebo responsiveness. Genetic and transcriptomic insights add a molecular layer to this understanding as well as RNA expression profiles, helping to identify placebo responders. Finally, the chapter emphasizes the clinical relevance of nocebo effects, detailing how negative expectations and communication can worsen outcomes. We also discuss the clinical relevance of these mechanisms, particularly in rheumatology, where both functional and structural brain changes have been observed. It advocates for improved communication strategies, personalized consent, and ethical integration of placebo science to optimize pain care and clinical trial designs. Future research should focus on translating individual variability in placebo and nocebo effects into strategies for advancing personalized and precision medicine.