Mental states such as beliefs and expectations can strongly influence the outcome of disease, the experience of pain, and even success of surgery. A placebo effect is said to occur when a positive expectation improves an outcome; similarly, a nocebo effect is said to occur when a negative expectation causes a treatment to have a more negative effect than it otherwise would. For example, when a patient anticipates a side effect of a medication, he/she can suffer that effect even if the "medication" is actually an inert substance. Both placebo and nocebo effects are presumably psychogenic, but they can induce measurable changes in the body and the brain. 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 noc?b?, "I shall harm", from noce?, "I harm") was coined by Walter Kennedy in 1961 to denote the counterpart to the use of placebo (Latin plac?b?, "I shall please", from place?, "I please"); as 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.
Evidence suggests that the symptoms of electromagnetic hypersensitivity are caused by the nocebo effect.
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
In a paper, 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" (p. 268).
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")." (p.1435)
- ^ a b Beauregard, Mario (2012). Brain Wars The Scientific Battle over the Existence of the Mind and the Proof That Will Change the Way We Live Our Lives. Canada: HarperCollins. ISBN 9781443407069.
- ^ a b c d Hauser W, Hansen E, Enck P (2012). "Nocebo phenomena in medicine: their relevance in everyday clinical practice". Dtsch Arztebl Int. 8 (8): 459-65. doi:10.3238/arztebl.2012.0459.
- ^ Enck, Paul (12 August 2012). "Beware the Nocebo Effect". The New York Times. Retrieved 2014.
- ^ "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.
- ^ a b Kennedy (1961), p.204
- ^ Benedetti, F.; Lanotte, M.; Lopiano, L.; Colloca, L. (June 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.
- ^ Miller (2003)
- ^ Tracey (2011)
- ^ McGlashan, Evans & Orne (1969); Stam (1984); Stam & Spanos (1987).
- ^ Colloca, Luana; Miller, Franklin G. (September 2011). "The Nocebo Effect and Its Relevance for Clinical Practice". Psychosomatic Medicine. 73 (7): 598-603. doi:10.1097/PSY.0b013e3182294a50.
- ^ Barsky, Arthur J. (6 February 2002). "Nonspecific Medication Side Effects and the Nocebo Phenomenon". JAMA. 287 (5): 622. doi:10.1001/jama.287.5.622.
- ^ Stathis, P; Smpiliris, M; Konitsiotis, S; Mitsikostas, DD (March 2013). "Nocebo as a potential confounding factor in clinical trials for Parkinson's disease treatment: a meta-analysis". European Journal of Neurology. 20 (3): 527-33. doi:10.1111/ene.12014. PMID 23145482.
- ^ Mitsikostas, Dimos D.; Mantonakis, Leonidas; Chalarakis, Nikolaos. "Nocebo in clinical trials for depression: A meta-analysis". Psychiatry Research. 215 (1): 82-86. doi:10.1016/j.psychres.2013.10.019.
- ^ Rubin, GJ; Nieto-Hernandez, R; Wessely, S (January 2010). "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.
- ^ Geary, James (4 March 2010). "The Man Who Was Allergic to Radio Waves". Popular Science. Retrieved 2014.
- ^ Murray, Danielle; Stoessl, A. Jon (December 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.
- ^ Enck, Paul; Benedetti, Fabrizio; Schedlowski, Manfred (July 2008). "New Insights into the Placebo and Nocebo Responses". Neuron. 59 (2): 195-206. doi:10.1016/j.neuron.2008.06.030.
- ^ a b c d Stewart-Williams & Podd (2004), p.326
- ^ Colloca, L; Benedetti, F (Oct 2007). "Nocebo hyperalgesia: how anxiety is turned into pain". Current Opinion in Anesthesiology. 20 (5): 435-9. doi:10.1097/aco.0b013e3282b972fb. PMID 17873596.
- ^ Zusne & Jones (1989), p.57; Róheim (1925).
- ^ "New drug trial puts six men in intensive care". New Scientist. 15 March 2006. Retrieved 2012.
- ^ "Catastrophic immune response may have caused drug trial horror". New Scientist. 17 March 2006. Retrieved 2012.
- Barber, T.X., "Death by Suggestion: A Critical Note", Psychosomatic Medicine, Vol.23, No.2, (March-April 1961), pp. 153-155.
- Barker, J.C., Scared to Death: An Examination of Fear, its Cause and Effects, Frederick Muller, (London), 1968.
- Barrett, G.V. & Franke, R.H., ""Psychogenic" Death: A Reappraisal", Science, Vol.167, No.3916, (16 January 1970), pp. 304-306.
- Barsky, A.J., Saintfort, R., Rogers, M.P. & Borus, J.F., "Nonspecific Medication Side Effects and the Nocebo Phenomenon", Journal of the American Medical Association, Vol.287, No.5, (6 February 2002), pp.622-627.
- Cannon, W.B., "'Voodoo' Death", American Anthropologist, Vol.44, No.2, (April-June 1942), pp.169-181.
- Charcot, J.M., "The Faith-Cure", The New Review, Vol.VIII, (January 1893), pp.18-31.
- Cohen, S.I., "Psychosomatic Death: Voodoo Death in a Modern Perspective", Integrative Psychiatry, Vol.3, No.1, (March 1985), pp.46-51.
- Dein, S., "Psychogenic Death: Individual Effects of Sorcery and Taboo Violation", Mental Health, Religion and Culture, Vol.6, No.3, (November 2003), pp.195-202.
- Di Blasi, Z., Harkness, E., Edzard, E., Georgiou, A. & Kleijnen, J., "Influence of Context Effects on Health Outcomes: A Systematic Review", The Lancet, Vol.357, No.9258, (10 March 2001), pp.757-762.
- Goddard, H.H., "The Effects of Mind on Body as Evidenced by Faith Cures", American Journal of Psychology, Vol.10, No.3, (April 1899), pp.431-502.
- Hahn, R.A., "The Nocebo Phenomenon: Concept, Evidence, and Implications for Public Health", Preventive Medicine, Vol.26, No.5, (September 1997), pp.607-611.
- Hahn, R.A. & Kleinman, A, "Belief as Pathogen, Belief as Medicine: "Voodoo Death" and the "Placebo Phenomenon" in Anthropological Perspective", Medical Anthropology Quarterly, Vol.14, No.4, (August 1983), pp.3, 16-19.
- Harrington, E.R., The Nocebo Effect: A Meta-Analysis of the Effect of Suggestion on Reports of Physical Symptoms, (Ph.D. Dissertation), Temple University, 1998.
- Houston, W.R., "The Doctor Himself as a Therapeutic Agent", Annals of Internal Medicine, Vol.11, No.8, (February 1938), pp.1416-1425.
- Kennedy, W P., "The Nocebo Reaction", Medical World, Vol.95, (September 1961), pp.203-205.
- Kirsch, I., "Response Expectancy as a Determinant of Experience and Behavior", American Psychologist, Vol.40, No.11, (November 1985), pp.1189-1202.
- Kirsch, I., "Response Expectancy Theory and Application: A Decennial Review", Applied and Preventive Psychology, Vol.6, No.2, (Spring 1997), pp.69-79.
- Lasagna, L., Mosteller, F., von Felsinger, J.M. & Beecher, H.K., "A Study of the Placebo Response", American Journal of Medicine, Vol.16, No.6, (June 1954), pp.770-779.
- Lorenz, J., Hauck, M., Paura, R.C., Nakamura, Y., Zimmermann, R., Bromm, B. & Engela, A.K., "Cortical Correlates of False Expectations During Pain Intensity Judgments -- A Possible Manifestation of Placebo/Nocebo Cognitions", Brain, Behavior, and Immunity, Vol.19, No.4, (July 2005), pp.283-295.
- McGlashan, T.H., Evans, F.J. & Orne, M.T., "The Nature of Hypnotic Analgesia and Placebo Response to Experimental Pain", Psychosomatic Medicine, Vol.31, No.3, (May-June 1969), pp.227-246.
- Merton, R.K., "The Unanticipated Consequences of Purposive Social Action", American Sociological Review, Vol.1, No.6, (December 1936), pp.894-904. 
- Miller, F.G., "William James, Faith, and the Placebo Effect", Perspectives in Biology and Medicine, Vol.48, No.2, (Spring 2005), pp.273-281.
- Miller, F.G., "Sham Surgery: An Ethical Analysis", The American Journal of Bioethics, Vol.3, No.4, (Fall 2003), pp.41-48.
- Milton, G.W., "Self-Willed Death or the Bone-Pointing Syndrome", The Lancet, (23 June 1973), pp.1435-1436.
- Perlman, L, "Nonspecific, Unintended, and Serendipitous Effects in Psychotherapy", Professional Psychology: Research and Practice, Vol.32, No.3, (June 2001), pp.283-288.
- Phillips, D.P., Liu, G.C., Kwok, K., Jarvinen, J.R., Zhang, W. & Abramson, I.S., "The Hound of the Baskervilles effect: natural experiment on the influence of psychological stress on timing of death", British Medical Journal, Vol.324, No.7327, (22-29 December 2001), pp.1443-1446.
- Pyysiäinen, I., "Mind and Miracles", Zygon, Vol.37, No.3, (September 2002), pp.729-740.
- Rief, W., Avorn, J. & Barsky, Arthur J., "Medication-Attributed Adverse Effects in Placebo Groups: Implications for Assessment of Adverse Effects", Archives of Internal Medicine, Vol.166, No.2), (23 January 2006), pp.155-160.
- Richter, C.P., "On the Phenomenon of Sudden Death in Animals and Man", Psychosomatic Medicine, Vol.XIX, No.3, (May-June 1957), pp.191-198.
- Róheim, G., "The Pointing Bone", The Journal of the Royal Anthropological Institute of Great Britain and Ireland, Vol.55, (January-June 1925), pp.90-114.
- Rubel, A.J., "The Epidemiology of a Folk Illness: Susto in Hispanic America", Ethnology, Vol.3, No.3, (July 1964), pp.268-283.
- Shapiro, A.K., "A Contribution to a History of the Placebo Effect", Behavioral Science, Vol.5, No.2 (April 1960) pp.109-135.
- Shapiro, A.K., "Semantics of the Placebo", Psychiatric Quarterly, Vol.42, No.4, (December 1968), pp.653-695.
- South, R., "A Sermon Delivered at Christ-Church, Oxon., Before the University, Octob. 14. 1688: Prov.XII.22 Lying Lips are abomination to the Lord", pp.519-657 in South, R., Twelve Sermons Preached Upon Several Occasions (Second Edition), Volume I, Printed by S.D. for Thomas Bennet, (London), 1697.
- Spiegel, H., "Nocebo: The Power of Suggestibility", Preventive Medicine, Vol.26, No.5, (1 September 1997), pp.616-621.
- Staats, P., Hekmatb, H. & Staats, A., "Suggestion/Placebo Effects on Pain: Negative as Well as Positive", Journal of Pain and Symptom Management, Vol.15, No.4, (April 1998), pp.235-243.
- Stam, H.J., Hypnotic Analgesia and the Placebo Effect: Controlling Ischemic Pain, (Ph.D. Dissertation), Carleton University, (Ottawa, Canada), 1984.
- Stam, H.J. & Spanos, N., "Hypnotic Analgesia, Placebo Analgesia, and Ischemic Pain: The Effects of Contextual Variables", Journal of Abnormal Psychology, Vol.96, No.4, (November 1987), pp.313-320.
- Stewart-Williams, S. & Podd, J., "The Placebo Effect: Dissolving the Expectancy Versus Conditioning Debate", Psychological Bulletin, Vol.130, No.2, (March 2004), pp.324-340.
- Tracey, Irene et al. "The Effect of Treatment Expectation on Drug Efficacy: Imaging the Analgesic Benefit of the Opioid Remifentanil", Science Translational Medicine, Vol.3, No.70, (16 February 2011), pp.70ra14.
- Wilson, I., The Bleeding Mind: An Investigation into the Mysterious Phenomenon of Stigmata, Paladin, (London), 1991.
- Zusne, L. & Jones, W.H., Anomalistic Psychology: A Study of Magical Thinking (Second Edition), Lawrence Erlbaum Associates, (New York), 1989.