A Review of the Theoretical and Biological Understanding of the Nocebo and Placebo Phenomena.
OBJECTIVE
Placebos are commonly used in experimental and patient populations and are known to influence treatment outcomes. The mechanism of action of placebos has been investigated by several researchers. This review investigates the current knowledge regarding the theoretical and biological underpinning of the nocebo and placebo phenomena.


METHODS
Literature was searched using PubMed using the following keywords: nocebo, placebo, μ-opioid, dopamine, conditioning, and expectancy. Relevant papers were selected for review by the authors.


RESULTS
The roles of conditioning and expectancy, and characteristics associated with nocebo and placebo responses, are discussed. These factors affect nocebo and placebo responses, although their effect sizes vary greatly, depending on inter-individual differences and different experimental paradigms. The neurobiology of the nocebo and placebo phenomena is also reviewed, emphasizing the involvement of reward pathways, such as the μ-opioid and dopamine pathways. Neurobiological pathways have been investigated in a limited range of experimental paradigms, with the greatest efforts on experimental models of placebo analgesia. The interconnectedness of psychological and physiological drivers of nocebo and placebo responses is a core feature of these phenomena.


CONCLUSIONS
Further research is needed to fully understand the underpinnings of the nocebo and placebo phenomena. Neurobiology pathways need to be investigated in experimental paradigms that model the placebo response to a broader range of pathologies. Similarly, although many psychological factors and inter-individual characteristics have been identified as significant mediators and moderators of nocebo and placebo responses, the factors identified to date are unlikely to be exhaustive.
Deakin University, IMPACT Strategic Research Centre, School of Medicine, Barwon Health, Geelong, Australia; Department of Psychiatry, The University of Melbourne, Parkville, Victoria, Australia; The Centre for Youth Mental Health, Parkville, Victoria, Australia. Electronic address: seetald@barwonhealth.org.au.
Seetal
S
Dodd
Deakin University, IMPACT Strategic Research Centre, School of Medicine, Barwon Health, Geelong, Australia; Department of Psychiatry, The University of Melbourne, Parkville, Victoria, Australia; The Florey Institute for Neuroscience and Mental Health, Parkville, Victoria, Australia.
Olivia M
OM
Dean
Psychiatry and Mental Health Department, Centro Hospitalar Lisboa Norte, Lisbon, Portugal; Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal.
João
J
Vian
Deakin University, IMPACT Strategic Research Centre, School of Medicine, Barwon Health, Geelong, Australia; Department of Psychiatry, The University of Melbourne, Parkville, Victoria, Australia; The Centre for Youth Mental Health, Parkville, Victoria, Australia; The Florey Institute for Neuroscience and Mental Health, Parkville, Victoria, Australia.
Michael
M
Berk
D000698:Analgesia / Q000379:methods; D006801:Humans; D064786:Nocebo Effect; D010146:Pain / Q000188:drug therapy; D015990:Placebo Effect; D012201:Reward
conditioning; dopamine; expectancy; nocebo; pharmacology; placebo; treatment; µ-opioid