A nocebo effect is said to occur when negative expectations of the patient regarding a treatment cause the treatment to have a more negative effect than it otherwise would have. For example, when a patient anticipates a side effect of a medication, they can suffer that effect even if the "medication" is actually an inert substance. The complementary concept, the placebo effect, is said to occur when positive expectations improve an outcome. Both placebo and nocebo effects are presumably psychogenic, but they can induce measurable changes in the body. One article that reviewed 31 studies on nocebo effects reported a wide range of symptoms that could manifest as nocebo effects including nausea, stomach pains, itching, bloating, depression, sleep problems, loss of appetite, sexual dysfunction and severe hypotension.
Etymology and usage
The term nocebo (Latin nocēbō, "I shall harm", from noceō, "I harm") was coined by Walter Kennedy in 1961 to denote the counterpart to the use of placebo (Latin placēbō, "I shall please", from placeō, "I please"; a substance that may produce a beneficial, healthful, pleasant, or desirable effect). Kennedy emphasized that his use of the term "nocebo" refers strictly to a subject-centered response, a quality inherent in the patient rather than in the remedy". That is, Kennedy rejected the use of the term for pharmacologically induced negative side effects such as the ringing in the ears caused by quinine. That is not to say that the patient's psychologically induced response may not include physiological effects. For example, an expectation of pain may induce anxiety, which in turn causes the release of cholecystokinin, which facilitates pain transmission.
In the narrowest sense, a nocebo response occurs when a drug-trial subject's symptoms are worsened by the administration of an inert, sham, or dummy (simulator) treatment, called a placebo. According to current pharmacological knowledge and the current understanding of cause and effect, a placebo contains no chemical (or any other agent) that could possibly cause any of the observed worsening in the subject's symptoms. Thus, any change for the worse must be due to some subjective factor. Adverse expectations can also cause the analgesic effects of anesthetic medications to disappear.
The worsening of the subject's symptoms or reduction of beneficial effects is a direct consequence of their exposure to the placebo, but those symptoms have not been chemically generated by the placebo. Because this generation of symptoms entails a complex of "subject-internal" activities, in the strictest sense, we can never speak in terms of simulator-centered "nocebo effects", but only in terms of subject-centered "nocebo responses". Although some observers attribute nocebo responses (or placebo responses) to a subject's gullibility, there is no evidence that an individual who manifests a nocebo/placebo response to one treatment will manifest a nocebo/placebo response to any other treatment; i.e., there is no fixed nocebo/placebo-responding trait or propensity.
McGlashan, Evans & Orne (1969, p. 319) found no evidence of what they termed a "placebo personality". Also, in a carefully designed study, Lasagna, Mosteller, von Felsinger and Beecher (1954), found that there was no way that any observer could determine, by testing or by interview, which subject would manifest a placebo reaction and which would not. Experiments have shown that no relationship exists between an individual's measured hypnotic susceptibility and their manifestation of nocebo or placebo responses.
Side effects of drugs
It has been shown that, due to the nocebo effect, warning patients about side effects of drugs can contribute to the causation of such effects, whether the drug is real or not. This effect has been observed in clinical trials: according to a 2013 review, the dropout rate among placebo-treated patients in a meta-analysis of 41 clinical trials of Parkinson's disease treatments was 8.8%. A 2013 review found that nearly 1 out of 20 patients receiving a placebo in clinical trials for depression dropped out due to adverse events, which were believed to have been caused by the nocebo effect. A 2018 review found that half of patients taking placebos in clinical trials report intervention-related adverse events.
Verbal suggestion can cause hyperalgesia (increased sensitivity to pain) and allodynia (perception of a tactile stimulus as painful) as a result of the nocebo effect. Nocebo hyperalgesia is believed to involve the activation of cholecystokinin receptors.
Ambiguity of medical usage
Stewart-Williams and Podd argue that using the contrasting terms "placebo" and "nocebo" to label inert agents that produce pleasant, health-improving, or desirable outcomes versus unpleasant, health-diminishing, or undesirable outcomes (respectively), is extremely counterproductive. For example, precisely the same inert agents can produce analgesia and hyperalgesia, the first of which, from this definition, would be a placebo, and the second a nocebo.
A second problem is that the same effect, such as immunosuppression, may be desirable for a subject with an autoimmune disorder, but be undesirable for most other subjects. Thus, in the first case, the effect would be a placebo, and in the second, a nocebo. A third problem is that the prescriber does not know whether the relevant subjects consider the effects that they experience to be desirable or undesirable until some time after the drugs have been administered. A fourth problem is that the same phenomena are being generated in all the subjects, and these are being generated by the same drug, which is acting in all of the subjects through the same mechanism. Yet because the phenomena in question have been subjectively considered to be desirable to one group but not the other, the phenomena are now being labelled in two mutually exclusive ways (i.e., placebo and nocebo); and this is giving the false impression that the drug in question has produced two different phenomena.
Ambiguity of anthropological usage
Some people maintain that belief kills (e.g., "voodoo death": Cannon (1942) describes a number of instances from a variety of different cultures) and belief heals (e.g., faith healing). A "self-willed" death (due to voodoo hex, evil eye, pointing the bone procedure, etc.) is an extreme form of a culture-specific syndrome or mass psychogenic illness that produces a particular form of psychosomatic or psychophysiological disorder which results in a psychogenic death. Rubel (1964) spoke of "culture bound" syndromes, which were those "from which members of a particular group claim to suffer and for which their culture provides an etiology, diagnosis, preventive measures, and regimens of healing".
Certain anthropologists, such as Robert Hahn and Arthur Kleinman, have extended the placebo/nocebo distinction into this realm in order to allow a distinction to be made between rituals, like faith healing, that are performed in order to heal, cure, or bring benefit (placebo rituals) and others, like "pointing the bone", that are performed in order to kill, injure or bring harm (nocebo rituals). As the meaning of the two inter-related and opposing terms has extended, we now find anthropologists speaking, in various contexts, of nocebo or placebo (harmful or helpful) rituals:
- that might entail nocebo or placebo (unpleasant or pleasant) procedures;
- about which subjects might have nocebo or placebo (harmful or beneficial) beliefs;
- that are delivered by operators that might have nocebo or placebo (pathogenic, disease-generating or salutogenic, health-promoting) expectations;
- that are delivered to subjects that might have nocebo or placebo (negative, fearful, despairing or positive, hopeful, confident) expectations about the ritual;
- which are delivered by operators who might have nocebo or placebo (malevolent or benevolent) intentions, in the hope that the rituals will generate nocebo or placebo (lethal, injurious, harmful or restorative, curative, healthy) outcomes; and, that all of this depends upon the operator's overall beliefs in the harmful nature of the nocebo ritual or the beneficial nature of the placebo ritual.
Yet, it may become even more terminologically complex; for, as Hahn and Kleinman indicate, there can also be cases where there are paradoxical nocebo outcomes from placebo rituals (e.g. the TGN1412 drug trial), as well as paradoxical placebo outcomes from nocebo rituals (see also unintended consequences). Writing from his extensive experience of treating cancer (including more than 1,000 melanoma cases) at Sydney Hospital, Milton (1973) warned of the impact of the delivery of a prognosis, and how many of his patients, upon receiving their prognosis, simply turned their face to the wall and died a premature death: "there is a small group of patients in whom the realization of impending death is a blow so terrible that they are quite unable to adjust to it, and they die rapidly before the malignancy seems to have developed enough to cause death. This problem of self-willed death is in some ways analogous to the death produced in primitive peoples by witchcraft ('pointing the bone')".
A number of researchers have pointed out that the harm caused by communicating with patients about potential treatment adverse events raises an ethical issue. Informing a patient about what harms a treatment is likely to cause is required to respect autonomy. Yet the way in which potential harms are communicated could cause additional harm, which may violate the ethical principle of non-maleficence. It may be possible that nocebo effects can be reduced while respecting autonomy using different models of informed consent, including the use of a framing effect  and the authorized concealment. In fact, it has been argued that forcing patients to learn about all potential adverse events against their will could violate autonomy.
- Chinese Restaurant Syndrome
- Clinical trial
- Malice (legal term)
- Medical anthropology
- Observer-expectancy effect
- Placebo studies
- Post hoc ergo propter hoc
- Psychosomatic illness
- Scientific control
- Self-fulfilling prophecy
- Subject-expectancy effect
- The Mad Gasser of Mattoon
- Therapeutic effect
- Thomas theorem
- Vasovagal episode
- Häuser, Hansen & Enck 2012.
- Enck & Häuser 2012.
- "Merriam-Webster Online Dictionary". Merriam-Webster. noceo. Charlton T. Lewis and Charles Short. A Latin Dictionary on Perseus Project.
- Harper, Douglas. "placebo". Online Etymology Dictionary. placeo. Charlton T. Lewis and Charles Short. A Latin Dictionary on Perseus Project.
- Kennedy 1961.
- Benedetti et al. 2007.
- Miller 2003.
- Bingel et al. 2011.
- Bishop, Felicity L.; Aizlewood, Lizzi; Adams, Alison E. M. (9 July 2014). Newman, Christy Elizabeth (ed.). "When and Why Placebo-Prescribing Is Acceptable and Unacceptable: A Focus Group Study of Patients' Views". PLOS ONE. 9 (7): e101822. Bibcode:2014PLoSO...9j1822B. doi:10.1371/journal.pone.0101822. ISSN 1932-6203. PMC 4089920. PMID 25006673.
- McGlashan, Evans & Orne 1969.
- Stam 1984. sfn error: no target: CITEREFStam1984 (help)
- Stam & Spanos 1987.
- Colloca & Miller 2011.
- Barsky et al. 2002.
- Stathis et al. 2013.
- Mitsikostas, Mantonakis & Chalarakis 2014.
- Howick, Jeremy; Webster, Rebecca; Kirby, Nigel; Hood, Kerry (11 December 2018). "Rapid overview of systematic reviews of nocebo effects reported by patients taking placebos in clinical trials". Trials. 19 (1): 674. doi:10.1186/s13063-018-3042-4. ISSN 1745-6215. PMC 6288933. PMID 30526685.
- Rubin, Nieto-Hernandez & Wessely 2010. sfn error: no target: CITEREFRubinNieto-HernandezWessely2010 (help)
- Geary, James (4 March 2010). "The Man Who Was Allergic to Radio Waves". Popular Science. Retrieved 1 December 2014.
- Colloca, Luana (May 2008). "The role of learning in nocebo and placebo effects". Pain. 136 (1–2): 211–8. doi:10.1016/j.pain.2008.02.006. PMID 18372113. S2CID 44220488.
- Enck, Benedetti & Schedlowski 2008.
- Stewart-Williams & Podd 2004.
- Colloca & Benedetti 2007.
- Zusne & Jones 1989, p. 57.
- Róheim 1925.
- Rubel 1964.
- Hahn & Kleinman 1983.
- "New drug trial puts six men in intensive care". New Scientist. AFP. 15 March 2006. Retrieved 11 February 2012.
- Bhattacharya, Shaoni; Coghlan, Andy (17 March 2006). "Catastrophic immune response may have caused drug trial horror". New Scientist.
- Milton 1973.
- Alfano, Mark (2015). "Placebo effects and informed consent". Am J Bioeth. 15 (10): 3–12. doi:10.1080/15265161.2015.1074302. ISSN 1745-6215. PMID 26479091. S2CID 45271769.
- Colloca, Luana; Finniss, Damien (8 February 2012). "Nocebo effects, patient-clinician communication, and therapeutic outcomes". JAMA. 307 (6): 567–8. doi:10.1001/jama.2012.11. PMC 6909539. PMID 22318275.
- Howick, Jeremy (2020). "Unethical informed consent caused by overlooking poorly measured nocebo effects". Journal of Medical Ethics: medethics-2019-105903. doi:10.1136/medethics-2019-105903. PMID 32063581.
- Barber, Theodore Xenophon (1961). "Death by suggestion. A critical note". Psychosomatic Medicine. 23: 153–5. doi:10.1097/00006842-196103000-00006. PMID 13686785. S2CID 5451746.
- Barker, J.C. (1968). Scared to Death: An Examination of Fear, its Cause and Effects. London: Frederick Muller.
- Barrett, G. V.; Franke, R. H. (1970). "'Psychogenic' Death: A Reappraisal". Science. 167 (3916): 304–306. Bibcode:1970Sci...167..304B. doi:10.1126/science.167.3916.304. PMID 5460605. S2CID 31798499.
- Barsky, Arthur J.; Saintfort, R.; Rogers, M. P.; Borus, J. F. (2002). "Nonspecific Medication Side Effects and the Nocebo Phenomenon". JAMA. 287 (5): 622–7. doi:10.1001/jama.287.5.622. PMID 11829702.
- Benedetti, F.; Lanotte, M.; Lopiano, L.; Colloca, L. (2007). "When words are painful: Unraveling the mechanisms of the nocebo effect". Neuroscience. 147 (2): 260–271. doi:10.1016/j.neuroscience.2007.02.020. PMID 17379417. S2CID 7737716.
- Cannon, Walter B. (1942). "'Voodoo' Death". American Anthropologist. 44 (2): 169–181. doi:10.1525/aa.1942.44.2.02a00010.
- Charcot, J.M. (January 1893). "The Faith-Cure". The New Review. 8 (44): 18–31.
- Cohen, Sanford I. (1985). "Psychosomatic death: Voodoo death in a modern perspective". Integrative Psychiatry. 3 (1): 46–51.
- Colloca, Luana; Miller, Franklin G. (2011). "The Nocebo Effect and its Relevance for Clinical Practice". Psychosomatic Medicine. 73 (7): 598–603. doi:10.1097/PSY.0b013e3182294a50. PMC 3167012. PMID 21862825.
- Colloca, Luana; Benedetti, Fabrizio (2007). "Nocebo hyperalgesia: How anxiety is turned into pain". Current Opinion in Anesthesiology. 20 (5): 435–439. doi:10.1097/aco.0b013e3282b972fb. PMID 17873596. S2CID 24905510.
- Dein, Simon (2003). "Psychogenic death: Individual effects of sorcery and taboo violation". Mental Health, Religion & Culture. 6 (3): 195–202. doi:10.1080/13674670310001633478. S2CID 144763261.
- Blasi, Zelda Di; Harkness, Elaine; Ernst, Edzard; Georgiou, Amanda; Kleijnen, Jos (2001). "Influence of context effects on health outcomes: A systematic review". The Lancet. 357 (9258): 757–762. doi:10.1016/S0140-6736(00)04169-6. PMID 11253970. S2CID 6740675.
- Enck, Paul; Benedetti, Fabrizio; Schedlowski, Manfred (2008). "New Insights into the Placebo and Nocebo Responses". Neuron. 59 (2): 195–206. doi:10.1016/j.neuron.2008.06.030. PMID 18667148. S2CID 2614166.
- Enck, Paul; Häuser, Winfried (10 August 2012). "Beware the Nocebo Effect". The New York Times.
- Goddard, Henry H. (1899). "The Effects of Mind on Body as Evidenced by Faith Cures". The American Journal of Psychology. 10 (3): 431–502. doi:10.2307/1412143. JSTOR 1412143.
- Hahn, Robert A. (1997). "The Nocebo Phenomenon: Concept, Evidence, and Implications for Public Health". Preventive Medicine. 26 (5): 607–611. doi:10.1006/pmed.1996.0124. PMID 9327466.
- Hahn, Robert A.; Kleinman, Arthur (1983). "Perspectives of the Placebo Phenomenon: Belief as Pathogen, Belief as Medicine: 'Voodoo Death' and the 'Placebo Phenomenon' in Anthropological Perspective". Medical Anthropology Quarterly. 14 (4): 3–19. doi:10.1525/maq.1983.14.4.02a00030.
- Harrington, E.R. (1998), The Nocebo Effect: A Meta-Analysis of the Effect of Suggestion on Reports of Physical Symptoms (PhD Dissertation), Temple University
- Häuser, Winfried; Hansen, Ernil; Enck, Paul (2012). "Nocebo Phenomena in Medicine". Deutsches Ärzteblatt Online. 109 (26): 459–65. doi:10.3238/arztebl.2012.0459. PMC 3401955. PMID 22833756.
- Houston, W. R. (1938). "The Doctor Himself as a Therapeutic Agent". Annals of Internal Medicine. 11 (8): 1416. doi:10.7326/0003-4819-11-8-1416.
- Kennedy, WP (1961). "The nocebo reaction". Medical World. 95: 203–5. PMID 13752532.
- Kirsch, Irving (1985). "Response expectancy as a determinant of experience and behavior". American Psychologist. 40 (11): 1189–1202. doi:10.1037/0003-066X.40.11.1189.
- Kirsch, Irving (1997). "Response expectancy theory and application: A decennial review". Applied and Preventive Psychology. 6 (2): 69–79. doi:10.1016/S0962-1849(05)80012-5.
- Lasagna, Louis; Mosteller, Frederick; von Felsinger, John M.; Beecher, Henry K. (1954). "A study of the placebo response". The American Journal of Medicine. 16 (6): 770–779. doi:10.1016/0002-9343(54)90441-6. PMID 13158365.
- Lorenz, Jürgen; Hauck, Michael; Paur, Robert C.; Nakamura, Yoko; Zimmermann, Roger; Bromm, Burkhart; Engel, Andreas K. (2005). "Cortical correlates of false expectations during pain intensity judgments—a possible manifestation of placebo/nocebo cognitions". Brain, Behavior, and Immunity. 19 (4): 283–295. doi:10.1016/j.bbi.2005.03.010. PMID 15890494. S2CID 40078373.
- McGlashan, Thomas; Evans, Frederick J.; Orne, Martin (May 1969). "The nature of hypnotic analgesia and placebo response to experimental pain". Psychosomatic Medicine. 31 (3): 227–46. doi:10.1097/00006842-196905000-00003. PMID 4892726. S2CID 45824998.
- Merton, Robert K. (1936). "The Unanticipated Consequences of Purposive Social Action". American Sociological Review. 1 (6): 894–904. doi:10.2307/2084615. JSTOR 2084615.
- Miller, Franklin G. (2005). "William James, Faith, and the Placebo Effect". Perspectives in Biology and Medicine. 48 (2): 273–281. doi:10.1353/pbm.2005.0059. PMID 15834199. S2CID 37123891.
- Miller, Franklin G. (2003). "Sham Surgery: An Ethical Analysis". The American Journal of Bioethics. 3 (4): 41–48. doi:10.1162/152651603322614580. PMID 14744332. S2CID 2223466.
- Milton, G.W. (1973). "Self-Willed Death or the Bone-Pointing Syndrome". The Lancet. 301 (7817): 1435–1436. doi:10.1016/S0140-6736(73)91754-6. PMID 4122997.
- Mitsikostas, Dimos D.; Mantonakis, Leonidas; Chalarakis, Nikolaos (2014). "Nocebo in clinical trials for depression: A meta-analysis". Psychiatry Research. 215 (1): 82–86. doi:10.1016/j.psychres.2013.10.019. PMID 24210741. S2CID 24653639.
- Murray, Danielle; Stoessl, A. Jon (2013). "Mechanisms and therapeutic implications of the placebo effect in neurological and psychiatric conditions". Pharmacology & Therapeutics. 140 (3): 306–318. doi:10.1016/j.pharmthera.2013.07.009. PMID 23880289.
- Perlman, Lawrence M. (2001). "Nonspecific, unintended, and serendipitous effects in psychotherapy". Professional Psychology: Research and Practice. 32 (3): 283–288. doi:10.1037/0735-7028.32.3.283.
- Phillips, D. P.; Liu, G. C.; Kwok, K.; Jarvinen, J. R.; Zhang, W.; Abramson, I. S. (2001). "The Hound of the Baskervilles effect: Natural experiment on the influence of psychological stress on timing of death". BMJ. 323 (7327): 1443–1446. doi:10.1136/bmj.323.7327.1443. PMC 61045. PMID 11751347.
- Pyysiainen, Ilkka (2002). "Mind and Miracles". Zygon. 37 (3): 729–740. doi:10.1111/1467-9744.00449.
- Rief, Winfried; Avorn, Jerry; Barsky, Arthur J. (2006). "Medication-Attributed Adverse Effects in Placebo Groups". Archives of Internal Medicine. 166 (2): 155–60. doi:10.1001/archinte.166.2.155. PMID 16432082.
- Richter, Curt P. (1957). "On the Phenomenon of Sudden Death in Animals and Man". Psychosomatic Medicine. 19 (3): 191–198. CiteSeerX 10.1.1.536.1405. doi:10.1097/00006842-195705000-00004. PMID 13432092. S2CID 41952151.
- Róheim, G (1925). "The Pointing Bone". The Journal of the Royal Anthropological Institute of Great Britain and Ireland. 55: 90–114. doi:10.2307/2843694. JSTOR 2843694.
- Rubel, Authur J. (1964). "The Epidemiology of a Folk Illness: Susto in Hispanic America". Ethnology. 3 (3): 268–283. doi:10.2307/3772883. JSTOR 3772883.
- Rubin, G. James; Nieto-Hernandez, Rosa; Wessely, Simon (2009). "Idiopathic environmental intolerance attributed to electromagnetic fields (formerly 'electromagnetic hypersensitivity'): An updated systematic review of provocation studies". Bioelectromagnetics. 31 (1): 1–11. doi:10.1002/bem.20536. PMID 19681059.
- Shapiro, Arthur K. (2007). "A contribution to a history of the placebo effect". Behavioral Science. 5 (2): 109–135. doi:10.1002/bs.3830050202.
- Shapiro, Arthur K. (1968). "Semantics of the placebo". The Psychiatric Quarterly. 42 (4): 653–695. doi:10.1007/BF01564309. PMID 4891851. S2CID 2733947.
- South, Robert (1727). "A Sermon Delivered at Christ-Church, Oxon., Before the University, Octob. 14. 1688: Prov.XII.22 Lying Lips are abomination to the Lord". Twelve Sermons Preached Upon Several Occasions. I (6th ed.). London: J. Bettenham. pp. 458–500.
- Spiegel, Herbert (1997). "Nocebo: The Power of Suggestibility". Preventive Medicine. 26 (5): 616–621. doi:10.1006/pmed.1997.0229. PMID 9327468. S2CID 7017712.
- Staats, Peter; Hekmat, Hamid; Staats, Arthur (1998). "Suggestion/Placebo Effects on Pain". Journal of Pain and Symptom Management. 15 (4): 235–243. doi:10.1016/S0885-3924(97)00363-1. PMID 9601159.
- Stam, Henderikus (1982). "Hypnotic analgesia and the placebo effect; controlling ischemic pain". doi:10.22215/etd/1982-00726. Cite journal requires
- Stam, Henderikus J.; Spanos, Nicholas P. (1987). "Hypnotic analgesia, placebo analgesia, and ischemic pain: The effects of contextual variables". Journal of Abnormal Psychology. 96 (4): 313–320. doi:10.1037/0021-843X.96.4.313. PMID 3693680.
- Stathis, P.; Smpiliris, M.; Konitsiotis, S.; Mitsikostas, D. D. (2013). "Nocebo as a potential confounding factor in clinical trials for Parkinson's disease treatment: A meta-analysis". European Journal of Neurology. 20 (3): 527–533. doi:10.1111/ene.12014. PMID 23145482. S2CID 41163200.
- Stewart-Williams, Steve; Podd, John (2004). "The Placebo Effect: Dissolving the Expectancy Versus Conditioning Debate". Psychological Bulletin. 130 (2): 324–340. doi:10.1037/0033-2909.130.2.324. PMID 14979775.
- Bingel, U.; Wanigasekera, V.; Wiech, K.; Ni Mhuircheartaigh, R.; Lee, M. C.; Ploner, M.; Tracey, I. (2011). "The Effect of Treatment Expectation on Drug Efficacy: Imaging the Analgesic Benefit of the Opioid Remifentanil". Science Translational Medicine. 3 (70): 70ra14. doi:10.1126/scitranslmed.3001244. PMID 21325618. S2CID 207775719.
- Wilson, Ian (1991). The Bleeding Mind: An Investigation into the Mysterious Phenomenon of Stigmata. London: Paladin. ISBN 978-0-586-09014-5.
- Zusne, L.; Jones, W.H. (1989). Anomalistic Psychology: A Study of Magical Thinking (2nd ed.). New York: Lawrence Erlbaum Associates.
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