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{{short description|Substance or treatment of no therapeutic value}}
{{cs1 config|name-list-style=vanc}}
{{other uses|Placebo (disambiguation)}}
[[File:Cebocap.jpg|thumb|Placebos are typically inert tablets, such as sugar pills.]]
A '''placebo''' ({{IPAc-en|p|l|ə|ˈ|s|iː|b|oʊ}} {{respell|plə|SEE|boh}}) canis bea roughlysubstance definedor astreatment awhich [[Wikt:sham|sham]]is medicaldesigned treatmentto have no therapeutic value.<ref name=aspmn/> Common placebos include inert tablets (like sugar pills), inert injections (like [[Saline (medicine)|saline]]), [[sham surgery]],<ref>{{cite web | url=https://www.wsj.com/articles/SB10001424052702304680904579365414108916816 | title=The FDA Wants You for Sham Surgery | work=Wall Street Journal | date=18 February 2014 | access-date=8 January 2015 | last = Gottlieb | first = Scott | name-list-style = vanc }}</ref> and other procedures.<ref name="Lanotte">{{cite journal | vauthors = Lanotte M, Lopiano L, Torre E, Bergamasco B, Colloca L, Benedetti F | title = Expectation enhances autonomic responses to stimulation of the human subthalamic limbic region | journal = Brain, Behavior, and Immunity | volume = 19 | issue = 6 | pages = 500–509 | date = November 2005 | pmid = 16055306 | doi = 10.1016/j.bbi.2005.06.004 | s2cid = 36092163 }}</ref>
 
Placebos are used in [[Randomized controlled trial|randomized clinical trials]] to test the efficacy of [[Drug|medical treatments]]. In a [[Placebo-controlled study|placebo-controlled]] [[clinical trial]], soany theychange servein the [[scientific control|control]] group is known as epistemologicalthe tools''placebo toresponse'', screenand outthe difference between this and the ‘noise’result of clinicalno researchtreatment is the ''placebo effect''.<ref name="chaplin" /> Placebos in clinical trials should ideally be indistinguishable from so-called verum treatments under investigation, except for the latter’slatter's particular hypothesized remedialmedicinal factor(s)effect.<ref>{{Cite journal |lastlast1=Blease |firstfirst1=Charlotte |last2=Annoni |first2=Marco |date=April 2019 |title=Overcoming disagreement: a roadmap for placebo studies |url=https://www.researchgate.net/publication/331766597_Overcoming_disagreement_a_roadmap_for_placebo_studies331766597 |journal=Biology & Philosophy |language=en |volume=34 |issue=2 |doi=10.1007/s10539-019-9671-5 |issn=0169-3867}}</ref> This is to [[blinded experiment|preventshield thetest recipient or others from knowingparticipants]] (with their [[consent]]) whetherfrom aknowing treatmentwho is activegetting orthe placebo and who is getting the treatment under inactivetest, as patients' and clinicians' expectations aboutof [[efficacy]] can influence results.<ref>{{cite web |date=9 April 2016 |title=placebo |url=http://www.dictionary.com/browse/placebo |access-date=21 January 2017 |work=Dictionary.com}}</ref><ref>{{cite web |title=placebo |url=http://www.thefreedictionary.com/placebo |access-date=21 January 2017 |work=TheFreeDictionary.com}}</ref>
 
The idea of a placebo effect was discussed in 18th century psychology,<ref>Schwarz, K. A., & Pfister, R.: ''Scientific psychology in the 18th century: a historical rediscovery.'' In: ''Perspectives on Psychological Science'', Nr. 11, pp. 399–407.</ref> but became more prominent in the 20th century. Modern studies find that placebos can affect some outcomes such as [[pain]] and [[nausea]], but otherwise do not generally have important clinical effects.<ref name="CochraneHrob2010" /> Improvements that patients experience after being treated with a placebo can also be due to unrelated factors, such as [[regression to the mean]] (a statistical effect where an unusually high or low measurement is likely to be followed by a less extreme one).<ref name="acs" /> The use of placebos in clinical medicine raises ethical concerns, especially if they are disguised as an active treatment, as this introduces dishonesty into the doctor–patient relationship and bypasses [[informed consent]].<ref name="Newman">{{cite book |last=Newman |first=David H. |title=Hippocrates' Shadow |publisher=Scribner |year=2008 |isbn=978-1-4165-5153-9 |pages=134–159}}</ref>
Placebos are also popular because they can sometimes produce relief through psychological mechanisms (a phenomenon known as the "placebo effect"). They can affect how patients perceive their condition and encourage the body's chemical processes for relieving pain<ref name="acs" /> and a few other symptoms,<ref name="quattrone-barbagallo" /> and evidence suggests it can have an impact on curing the disease itself, such as the case of skin disease cured by a patient of Albert Mason. In particular situations, some researchers believe it does not have an effect on curing a disease.<ref name="CochraneHrob2010" /><ref name="acs" />▼
 
▲Placebos are also popular because they can sometimes produce relief through psychological mechanisms (a phenomenon known as the "placebo effect"). They can affect how patients perceive their condition and encourage the body's chemical processes for relieving pain<ref name="acs">{{cite web |date=10 April 2015 |title=Placebo Effect |url=https://www.cancer.org/treatment/treatments-and-side-effects/clinical-trials/placebo-effect.html |url-status=live |archive-url=https://web.archive.org/web/20200522232756/https://www.cancer.org/treatment/treatments-and-side-effects/clinical-trials/placebo-effect.html |archive-date=2020-05-22 |access-date=2021-06-27 |publisher=American Cancer Society}}</ref> and a few other symptoms,<ref name="quattrone-barbagallo" /> and evidence suggests it canbut have anno impact on curing the [[disease]] itself, such as the case of skin disease cured by a patient of Albert Mason. In particular situations, some researchers believe it does not have an effect on curing a disease.<ref name="CochraneHrob2010" /><ref name="acs" />
Improvements that patients experience after being treated with a placebo can also be due to unrelated factors, such as [[regression to the mean]] (a statistical effect where an unusually high or low measurement is likely to be followed by a less extreme one).<ref name="acs" /> The use of placebos in clinical medicine raises ethical concerns, especially if they are disguised as an active treatment, as this introduces dishonesty into the doctor–patient relationship and bypasses [[informed consent]].<ref name="Newman">{{cite book | first = David H. | last = Newman | name-list-style = vanc |title=Hippocrates' Shadow |publisher=Scribner |year=2008| pages=134–159 |isbn=978-1-4165-5153-9}}</ref> While it was once assumed that this deception was necessary for placebos to have any effect, there is some evidence that placebos may have subjective effects even when the patient is aware that the treatment is a placebo (known as "[[Open-label trial|open-label]]" placebo).<ref name="onlinelibrary.wiley.com">{{cite journal |title=Effects of placebos without deception compared with no treatment: A systematic review and meta-analysis |date=2017 |doi=10.1111/jebm.12251 |url=https://onlinelibrary.wiley.com/doi/full/10.1111/jebm.12251 |last1=Charlesworth |first1=James E.G. |last2=Petkovic |first2=Grace |last3=Kelley |first3=John M. |last4=Hunter |first4=Monika |last5=Onakpoya |first5=Igho |last6=Roberts |first6=Nia |last7=Miller |first7=Franklin G. |last8=Howick |first8=Jeremy |journal=Journal of Evidence-Based Medicine |volume=10 |issue=2 |pages=97–107 |pmid=28452193 |s2cid=4577402 |doi-access=free }}</ref>
 
In a [[Placebo-controlled study|placebo-controlled]] [[clinical trial]] any change in the [[scientific control|control]] group is known as the '''placebo response''', and the difference between this and the result of no treatment is the '''placebo effect'''.<ref name="chaplin" /> Some researchers now recommend comparing the experimental treatment with an existing treatment when possible, instead of a placebo.<ref name="michels" />
 
The idea of a ''placebo effect''—a therapeutic outcome derived from an inert treatment—was discussed in 18th century psychology,<ref>Schwarz, K. A., & Pfister, R.: ''Scientific psychology in the 18th century: a historical rediscovery.'' In: ''Perspectives on Psychological Science'', Nr. 11, pp. 399–407.</ref> but became more prominent in the 20th century. An influential 1955 study entitled ''The Powerful Placebo'' firmly established the idea that placebo effects were clinically important,<ref name="Hrob2001">{{cite journal | vauthors = Hróbjartsson A, Gøtzsche PC | title = Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment | journal = The New England Journal of Medicine | volume = 344 | issue = 21 | pages = 1594–1602 | date = May 2001 | pmid = 11372012 | doi = 10.1056/NEJM200105243442106 | doi-access = free }}</ref> and were a result of [[Neural top–down control of physiology|the brain's role in physical health]]. A 1997 reassessment found no evidence of any placebo effect in the source data, as the study had not accounted for [[regression to the mean]].<ref name="Kienle & Kiene" /><ref name=Hrob2004/>
 
==Etymology==
''Placebo''The [[Latin]] term {{lang|la|placebo}} (pronounced /plaˈkebo/ or /plaˈt͡ʃebo) ismeans [[Latin]] for [''[I] shall be pleasing.''. It was used as a name for the [[Vespers]] in the [[Office of the Dead]], taken from its [[incipit]], a quote from the [[Vulgate]]'s Psalm 116:9 ([[Psalm 116114]]:9 in modern bibles), ''{{lang|la|placēbō Dominō in regiōne vīvōrum''}}, "[I] shall please the Lord in the land of the living.".<ref>{{Cite web|title=Placebo (origins of technical term)|url=https://www.thefreedictionary.com/Placebo+(origins+of+technical+term)|access-date=2021-02-07|website=TheFreeDictionary.com}}</ref><ref>{{Bibleverse|Psalms|114:9}}</ref><ref name=Jacobs00>{{cite journal |author=Jacobs B |title=Biblical origins of placebo |journal=Journal of the Royal Society of Medicine |volume=93 |issue=4 |pages=213–214 |date=April 2000 |pmid=10844895 |pmc=1297986 |doi=10.1177/014107680009300419 }}</ref> From that, a ''singer of placebo'' became associated with someone who falsely claimed a connection to the deceased to get a share of the funeral meal, and hence a flatterer, and so a deceptive act to please.<ref name="Shapiro"/>
 
==Definitions==
The definition of "''placebo"'' has been debated.<ref>{{Cite journal |last1=Blease |first1=Charlotte |last2=Annoni |first2=Marco |date=2019-03-14 |title=Overcoming disagreement: a roadmap for placebo studies |url=https://doi.org/10.1007/s10539-019-9671-5 |journal=Biology & Philosophy |language=en |volume=34 |issue=2 |pages=18 |doi=10.1007/s10539-019-9671-5 |s2cid=254281187 |issn=1572-8404}}</ref> One definition states that a [[Medical treatment|treatment]] process t is a placebo when none of the ''characteristic treatment factors C'' are effective (remedial or harmful) in the [[patient]] X for a given [[disease]] D.<ref>{{Cite journal |last=Howick |first=Jeremy |date=2017-04-01 |title=The relativity of 'placebos'‘placebos’: defending a modified version of Grünbaum'sGrünbaum’s definition |url=https://doilink.springer.orgcom/article/10.1007/s11229-015-1001-0 |journal=Synthese |language=en |volume=194 |issue=4 |pages=1363–1396 |doi=10.1007/s11229-015-1001-0 |s2cid=255066625 |issn=1573-0964}}</ref>
 
In a clinical trial, a ''placebo response'' is the measured response of subjects to a placebo; the ''placebo effect'' is the difference between that response and no treatment.<ref name=chaplin>{{cite journal |year=2006 | vauthors=Chaplin S |journal=Prescriber | volume=17 | issue=5 |title=The placebo response: an important part of treatment |doi=10.1002/psb.344 |pages=16–22 | s2cid=72626022 |doi-access=free }}</ref> The placebo response may include improvements due to natural healing, declines due to natural disease progression, the tendency for people who were temporarily feeling either better or worse than usual to return to their average situations ([[regression toward the mean]]), and errors in the clinical trial records, which can make it appear that a change has happened when nothing has changed.<ref>{{Cite journal|last1=Kaptchuk|first1=Ted J|last2=Hemond|first2=Christopher C|last3=Miller|first3=Franklin G|date=2020-07-20|title=Placebos in chronic pain: evidence, theory, ethics, and use in clinical practice|journal=BMJ|volume=370|language=en|pages=m1668|doi=10.1136/bmj.m1668|pmid=32690477|s2cid=220633770|issn=1756-1833|doi-access=free}}</ref> It is also part of the recorded response to any active medical intervention.<ref name=eccles>{{cite journal | vauthors = Eccles R | title = The powerful placebo in cough studies? | journal = Pulmonary Pharmacology & Therapeutics | volume = 15 | issue = 3 | pages = 303–308 | year = 2002 | pmid = 12099783 | doi = 10.1006/pupt.2002.0364 }}</ref>
 
Measurable placebo effects may be either ''objective'' (e.g. lowered [[blood pressure]]) or ''subjective'' (e.g. a lowered perception of pain).<ref name="aspmn">{{cite journal |last1=Ashar |first1=Yoni K. |last2=Chang |first2=Luke J. |last3=Wager |first3=Tor D. |year=2017 |title=Brain Mechanisms of the Placebo Effect: An Affective Appraisal Account |url=https://www.annualreviews.org/doi/abs/10.1146/annurev-clinpsy-021815-093015 |journal=Annual Review of Clinical Psychology |type= |volume= 13|issue= |pages= 73–98|doi=10.1146/annurev-clinpsy-021815-093015 |pmid=28375723|doi-access=free }}</ref>
 
==Effects==
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{{further|Alternative medicine#Perceived mechanism of effect}}
 
Placebos can improve patient-reported outcomes such as [[pain]] and [[nausea]].<ref name=CochraneHrob2010>{{cite journal | vauthors = Hróbjartsson A, Gøtzsche PC | title = Placebo interventions for all clinical conditions | journal = The Cochrane Database of Systematic Reviews | volume = 106 | issue = 1 | pages = CD003974 | date = January 2010 | pmid = 20091554 | doi = 10.1002/14651858.CD003974.pub3 | pmc = 7156905 | editor1-last = Hróbjartsson | editor1-first = Asbjørn | url = http://nordic.cochrane.org/sites/nordic.cochrane.org/files/public/uploads/ResearchHighlights/Placebo%20interventions%20for%20all%20clinical%20conditions%20(Cochrane%20review).pdf | access-date = 2018-06-25 | archive-date = 2019-04-02 | archive-url = https://web.archive.org/web/20190402005647/https://nordic.cochrane.org/sites/nordic.cochrane.org/files/public/uploads/ResearchHighlights/Placebo%20interventions%20for%20all%20clinical%20conditions%20(Cochrane%20review).pdf | url-status = dead }}</ref><ref>{{cite journal |last1=Benedetti |first1=Fabrizio |title=Mechanisms of Placebo and Placebo-Related Effects Across Diseases and Treatments |journal=Annual Review of Pharmacology and Toxicology |date=1 February 2008 |volume=48 |issue=1 |pages=33–60 |doi=10.1146/annurev.pharmtox.48.113006.094711 |pmid=17666008 |url=https://doi.org/10.1146/annurev.pharmtox.48.113006.094711 |access-date=17 March 2022 |issn=0362-1642}}</ref> butA also2001 objectivemeta-analysis of the placebo effect looked at trials in 40 different medical conditions, and concluded the only one where it had been shown to have a significant effect was for pain.<ref name="Hrob2001" /> Another Cochrane review in 2010 suggested that placebo effects are apparent only in subjective, continuous measures, and in the treatment of pain and related conditions. The review found that placebos do not appear to affect the actual diseases, or outcomes suchthat are not dependent on a patient's perception. The authors, [[Asbjørn Hróbjartsson]] and [[Peter C. Gøtzsche]], concluded that their study "did not find that placebo interventions have important clinical effects in general".<ref name="CochraneHrob2010" /> This interpretation has been subject to criticism, as the existence of placebo effects seems undeniable.<ref>{{Cite journal |last1=Vase |first1=Lene |last2=Petersen |first2=Gitte Laue |last3=Riley |first3=Joseph L. |last4=Price |first4=Donald D. |date=2009-09-01 |title=Factors contributing to large analgesic effects in placebo mechanism studies conducted between 2002 and 2007 |url=https://www.sciencedirect.com/science/article/pii/S0304395909002164 |journal=PAIN |volume=145 |issue=1 |pages=36–44 |doi=10.1016/j.pain.2009.04.008 |issn=0304-3959 |pmid=19559529 |s2cid=5790594}}</ref><ref>{{Cite journal |last1=Spiegel |first1=D |last2=Kraemer |first2=H |last3=Carlson |first3=R W |date=2001-10-01 |title=Is the placebo powerless |url=https://doi.org/10.1056/NEJM200110253451712 |journal=The New England Journal of Medicine |volume=345 |issue=17 |pages=1276; author reply 1278–9 |doi=10.1056/nejm200110253451712 |issn=1533-4406 |pmid=11680452}}</ref><ref>{{Cite web |title=APA PsycNet |url=https://psycnet.apa.org/record/2001-05525-013 |access-date=2023-09-16 |website=psycnet.apa.org |language=en}}</ref><ref>{{Cite journal |last1=Wampold |first1=Bruce E. |last2=Imel |first2=Zac E. |last3=Minami |first3=Takuya |date=April 2007 |title=The story of placebo effects in medicine: Evidence in context |url=https://onlinelibrary.wiley.com/doi/10.1002/jclp.20354 |journal=Journal of Clinical Psychology |language=en |volume=63 |issue=4 |pages=379–390 |doi=10.1002/jclp.20354 |pmid=17279527}}</ref><ref>{{Cite journal |last1=Wampold |first1=Bruce E. |last2=Minami |first2=Takuya |last3=Tierney |first3=Sandra Callen |last4=Baskin |first4=Thomas W. |last5=Bhati |first5=Kuldhir S. |date=July 2005 |title=The placebo is powerful: Estimating placebo effects in medicine and psychotherapy from randomized clinical trials |url=https://onlinelibrary.wiley.com/doi/10.1002/jclp.20129 |journal=Journal of Clinical Psychology |language=en |volume=61 |issue=7 |pages=835–854 |doi=10.1002/jclp.20129 |issn=0021-9762 |pmid=15827993}}</ref> For example, recent research has linked placebo interventions to improved motor functions in patients with [[Parkinson's disease]].<ref name="quattrone-barbagallo">{{Cite journal|last1=Quattrone|first1=Aldo|last2=Barbagallo|first2=Gaetano|last3=Cerasa|first3=Antonio|last4=Stoessl|first4=A. Jon|date=August 2018|title=Neurobiology of placebo effect in Parkinson's disease: What we have learned and where we are going|journal=Movement Disorders |volume=33|issue=8|pages=1213–1227|doi=10.1002/mds.27438|issn=1531-8257|pmid=30230624|s2cid=52294141}}</ref><ref>{{Cite andjournal|last=Gross|first=Liza|date=February immune2017|title=Putting placebos to the test|journal=PLOS Biology|volume=15|issue=2|pages=e2001998|doi=10.1371/journal.pbio.2001998|issn=1545-7885|pmc=5319646|pmid=28222121 |doi-access=free }}</ref><ref>{{Cite journal|last1=Enck|first1=Paul|last2=Bingel|first2=Ulrike|last3=Schedlowski|first3=Manfred|last4=Rief|first4=Winfried|date=March 2013|title=The placebo response in medicine: minimize, maximize or personalize?|url=https://www.researchgate.net/publication/235756144|journal=Nature Reviews Drug Discovery|language=en|volume=12|issue=3|pages=191–204|doi=10.1038/nrd3923|pmid=23449306|s2cid=24556504|issn=1474-1776}}</ref> Other objective outcomes affected by placebos include [[Immune system|immune]] and [[Endocrine system|endocrine]] parameters.,<ref name=":1">{{Cite journal |last1=Tekampe |first1=Judith |last2=van Middendorp |first2=Henriët |last3=Meeuwis |first3=Stefanie H. |last4=van Leusden |first4=Jelle W.R. |last5=Pacheco-López |first5=Gustavo |last6=Hermus |first6=Ad R.M.M. |last7=Evers |first7=Andrea W.M. |date=2017-02-10 |title=Conditioning Immune and Endocrine Parameters in Humans: A Systematic Review |url=https://doi.org/10.1159/000449470 |journal=Psychotherapy and Psychosomatics |volume=86 |issue=2 |pages=99–107 |doi=10.1159/000449470 |issn=0033-3190 |pmid=28183096 |s2cid=40594851 |issn=0033doi-3190access=free |doihdl-access=free |hdl=2066/170318}}</ref><ref name="Pacheco" /> end-organ functions regulated by the [[autonomic nervous system]],<ref>{{Cite journal |last=Meissner |first=Karin |date=2011-06-27 |title=The placebo effect and the autonomic nervous system: evidence for an intimate relationship |journal=Philosophical Transactions of the Royal Society B: Biological Sciences |volume=366 |issue=1572 |pages=1808–1817 |doi=10.1098/rstb.2010.0403 |issn=0962-8436 |pmc=3130407 |pmid=21576138}}</ref> and [[sport]] performance.<ref>{{Cite journal |last1=Hurst |first1=Philip |last2=Schipof-Godart |first2=Lieke |last3=Szabo |first3=Attila |last4=Raglin |first4=John |last5=Hettinga |first5=Florentina |last6=Roelands |first6=Bart |last7=Lane |first7=Andrew |last8=Foad |first8=Abby |last9=Coleman |first9=Damian |last10=Beedie |first10=Chris |date=2020-03-15 |title=The Placebo and Nocebo effect on sports performance: A systematic review |url=https://www.tandfonline.com/doi/full/10.1080/17461391.2019.1655098 |journal=European Journal of Sport Science |language=en |volume=20 |issue=3 |pages=279–292 |doi=10.1080/17461391.2019.1655098 |issn=1746-1391 |pmid=31414966 |s2cid=199662279 |hdl-access=free |hdl=2436/622641}}</ref>
 
Placebos are believed to be capable of altering a person's perception of pain. According to the American Cancer Society, "A person might reinterpret a sharp pain as uncomfortable tingling."<ref name="acs" />
A 2001 [[Cochrane Collaboration]] meta-analysis of the placebo effect looked at trials in 40 different medical conditions, and concluded the only one where it had been shown to have a significant effect was for pain.<ref name="Hrob2001" /> That's because placebos do not appear to affect the actual diseases, or outcomes that are not dependent on a patient's perception.<ref name=CochraneHrob2010/> However, exceptions do exist: one example is [[Parkinson's disease]], where recent research has linked placebo interventions to improved motor functions.<ref name="quattrone-barbagallo">{{Cite journal|last1=Quattrone|first1=Aldo|last2=Barbagallo|first2=Gaetano|last3=Cerasa|first3=Antonio|last4=Stoessl|first4=A. Jon|date=August 2018|title=Neurobiology of placebo effect in Parkinson's disease: What we have learned and where we are going|journal=Movement Disorders |volume=33|issue=8|pages=1213–1227|doi=10.1002/mds.27438|issn=1531-8257|pmid=30230624|s2cid=52294141}}</ref><ref>{{Cite journal|last=Gross|first=Liza|date=February 2017|title=Putting placebos to the test|journal=PLOS Biology|volume=15|issue=2|pages=e2001998|doi=10.1371/journal.pbio.2001998|issn=1545-7885|pmc=5319646|pmid=28222121 |doi-access=free }}</ref><ref>{{Cite journal|last1=Enck|first1=Paul|last2=Bingel|first2=Ulrike|last3=Schedlowski|first3=Manfred|last4=Rief|first4=Winfried|date=March 2013|title=The placebo response in medicine: minimize, maximize or personalize?|url=https://www.researchgate.net/publication/235756144|journal=Nature Reviews Drug Discovery|language=en|volume=12|issue=3|pages=191–204|doi=10.1038/nrd3923|pmid=23449306|s2cid=24556504|issn=1474-1776}}</ref>
 
Measuring the extent of the placebo effect is difficult due to confounding factors.<ref name=Hrob2004>{{cite journal | vauthors = Hróbjartsson A, Gøtzsche PC | author-link1 = Asbjørn Hróbjartsson | author-link2 = Peter C. Gøtzsche | title = Is the placebo powerless? Update of a systematic review with 52 new randomized trials comparing placebo with no treatment | journal = Journal of Internal Medicine | volume = 256 | issue = 2 | pages = 91–100 | date = August 2004 | pmid = 15257721 | doi = 10.1111/j.1365-2796.2004.01355.x | s2cid = 21244034 | doi-access = free }} Gøtzsche's biographical article has further references related to this work.</ref> For example, a patient may feel better after taking a placebo due to regression to the mean (i.e. a natural recovery or change in symptoms),<ref name="Kienle & Kiene">{{cite journal | vauthors = Kienle GS, Kiene H | title = The powerful placebo effect: fact or fiction? | journal = Journal of Clinical Epidemiology | volume = 50 | issue = 12 | pages = 1311–8 | date = December 1997 | pmid = 9449934 | doi = 10.1016/s0895-4356(97)00203-5 }}</ref><ref name="How much?">{{cite journal | vauthors = McDonald CJ, Mazzuca SA, McCabe GP | title = How much of the placebo 'effect' is really statistical regression? | journal = Statistics in Medicine | volume = 2 | issue = 4 | pages = 417–27 | year = 1983 | pmid = 6369471 | doi = 10.1002/sim.4780020401 }}</ref><ref name=RTM>{{cite journal | vauthors = Barnett AG, van der Pols JC, Dobson AJ | title = Regression to the mean: what it is and how to deal with it | journal = International Journal of Epidemiology | volume = 34 | issue = 1 | pages = 215–20 | date = February 2005 | pmid = 15333621 | doi = 10.1093/ije/dyh299 | doi-access = free }}</ref> but this can be ruled out by comparing the placebo group with a no treatment group (as all the placebo research does). It is harder still to tell the difference between the placebo effect and the effects of [[response bias]], [[observer bias]] and other flaws in trial methodology, as a trial comparing placebo treatment and no treatment will not be a [[blinded experiment]].<ref name=CochraneHrob2010/><ref name="Kienle & Kiene"/> In their 2010 meta-analysis of the placebo effect, [[Asbjørn Hróbjartsson]] and [[Peter C. Gøtzsche]] argue that "even if there were no true effect of placebo, one would expect to record differences between placebo and no-treatment groups due to bias associated with lack of blinding."<ref name=CochraneHrob2010/> Hróbjartsson and Gøtzsche concluded that their study "did not find that placebo interventions have important clinical effects in general".<ref name=CochraneHrob2010/> This interpretation has been subject to cricitism, as the existence of placebo effects seems undeniable.<ref>{{Cite book |last=HOWICK |first=JEREMY |editor-first1=Miriam |editor-first2=Jeremy R. |editor-first3=Harold |editor-last1=Solomon |editor-last2=Simon |editor-last3=Kincaid |chapter=Measuring Placebo Effects |date=2016 |chapter-url=https://www.taylorfrancis.com/chapters/edit/10.4324/9781315720739-20/measuring-placebo-effects-jeremy-howick |title=The Routledge Companion to Philosophy of Medicine |access-date=2023-09-16 |publisher=Routledge |doi=10.4324/9781315720739 |isbn=978-1-315-72073-9|s2cid=260685592 }}</ref><ref>{{Cite journal |last1=Vase |first1=Lene |last2=Petersen |first2=Gitte Laue |last3=Riley |first3=Joseph L. |last4=Price |first4=Donald D. |date=2009-09-01 |title=Factors contributing to large analgesic effects in placebo mechanism studies conducted between 2002 and 2007 |url=https://www.sciencedirect.com/science/article/pii/S0304395909002164 |journal=PAIN |volume=145 |issue=1 |pages=36–44 |doi=10.1016/j.pain.2009.04.008 |pmid=19559529 |s2cid=5790594 |issn=0304-3959}}</ref><ref>{{Cite journal |last1=Spiegel |first1=D |last2=Kraemer |first2=H |last3=Carlson |first3=R W |date=2001-10-01 |title=Is the placebo powerless |url=https://doi.org/10.1056/NEJM200110253451712 |journal=The New England Journal of Medicine |volume=345 |issue=17 |pages=1276; author reply 1278–9 |doi=10.1056/nejm200110253451712 |issn=1533-4406 |pmid=11680452}}</ref><ref>{{Cite web |title=APA PsycNet |url=https://psycnet.apa.org/record/2001-05525-013 |access-date=2023-09-16 |website=psycnet.apa.org |language=en}}</ref><ref>{{Cite journal |last1=Wampold |first1=Bruce E. |last2=Imel |first2=Zac E. |last3=Minami |first3=Takuya |date=April 2007 |title=The story of placebo effects in medicine: Evidence in context |url=https://onlinelibrary.wiley.com/doi/10.1002/jclp.20354 |journal=Journal of Clinical Psychology |language=en |volume=63 |issue=4 |pages=379–390 |doi=10.1002/jclp.20354|pmid=17279527 }}</ref><ref>{{Cite journal |last1=Wampold |first1=Bruce E. |last2=Minami |first2=Takuya |last3=Tierney |first3=Sandra Callen |last4=Baskin |first4=Thomas W. |last5=Bhati |first5=Kuldhir S. |date=July 2005 |title=The placebo is powerful: Estimating placebo effects in medicine and psychotherapy from randomized clinical trials |url=https://onlinelibrary.wiley.com/doi/10.1002/jclp.20129 |journal=Journal of Clinical Psychology |language=en |volume=61 |issue=7 |pages=835–854 |doi=10.1002/jclp.20129 |pmid=15827993 |issn=0021-9762}}</ref> [[Jeremy Howick]] has argued that combining so many varied studies to produce a single average might obscure that "some placebos for some things could be quite effective."<ref name="howickquote" /> To demonstrate this, he participated in a systematic review comparing active treatments and placebos using a similar method, which generated a conclusion that there is "no difference between treatment and placebo effects".<ref>{{cite journal |vauthors=Howick J, Friedemann C, Tsakok M, Watson R, Tsakok T, Thomas J, Perera R, Fleming S, Heneghan C |date=May 2013 |title=Are Treatments More Effective than Placebos? A Systematic Review and Meta-Analysis |journal=[[PLOS One]] |volume=11 |issue=1 |pages=e62599 |bibcode=2013PLoSO...862599H |doi=10.1371/journal.pone.0062599 |pmc=3655171 |pmid=23690944 |doi-access=free}}</ref>
 
One way in which the magnitude of placebo [[analgesia]] can be measured is by conducting "open/hidden" studies, in which some patients receive an analgesic and are informed that they will be receiving it (open), while others are administered the same drug without their knowledge (hidden). Such studies have found that analgesics are considerably more effective when the patient knows they are receiving them.<ref>{{cite journal | vauthors = Price DD, Finniss DG, Benedetti F |date=2008 |title = A comprehensive review of the placebo effect: recent advances and current thought | journal = Annual Review of Psychology | volume = 59 | issue = 1 | pages = 565–90 | date = 2008 | pmid = 17550344 | doi = 10.1146/annurev.psych.59.113006.095941 |pmid=17550344}}</ref>▼
In a study in 2010, patients given open-label placebo in the context of a supportive patient-practitioner relationship and a persuasive rationale had clinically meaningful symptom improvement that was significantly better than a no-treatment control group with matched patient-provider interaction.<ref name=":0">{{Cite journal |last1=Kaptchuk |first1=Ted J. |last2=Friedlander |first2=Elizabeth |last3=Kelley |first3=John M. |last4=Sanchez |first4=M. Norma |last5=Kokkotou |first5=Efi |last6=Singer |first6=Joyce P. |last7=Kowalczykowski |first7=Magda |last8=Miller |first8=Franklin G. |last9=Kirsch |first9=Irving |last10=Lembo |first10=Anthony J. |date=2010-12-22 |title=Placebos without Deception: A Randomized Controlled Trial in Irritable Bowel Syndrome |journal=PLOS ONE |language=en |volume=5 |issue=12 |pages=e15591 |doi=10.1371/journal.pone.0015591 |pmid=21203519 |pmc=3008733 |bibcode=2010PLoSO...515591K |issn=1932-6203|doi-access=free }}</ref><ref name="howickquote">{{cite journal | vauthors = Hutchinson P, Moerman D | title = The Meaning Response, "Placebo" and Method | journal = Perspectives in Biology and Medicine | volume = 15 | issue = 2 | pages = 361–378| date = October 2018 | pmid = 30293975| doi = 10.1353/pbm.2018.0049 | s2cid = 52934614 | url=https://www.researchgate.net/publication/327981708}}</ref>
 
===Factors influencing the power of the placebo effect===
A review published in ''[[JAMA Psychiatry]]'' found that, in trials of antipsychotic medications, the change in response to receiving a placebo had increased significantly between 1960 and 2013. The review's authors identified several factors that could be responsible for this change, including inflation of baseline scores and enrollment of fewer severely ill patients.<ref>{{cite journal | vauthors = Rutherford BR, Pott E, Tandler JM, [[Melanie Wall|Wall MM]], Roose SP, Lieberman JA | title = Placebo response in antipsychotic clinical trials: a meta-analysis | journal = JAMA Psychiatry | volume = 71 | issue = 12 | pages = 1409–21 | date = December 2014 | pmid = 25321611 | pmc = 4256120 | doi = 10.1001/jamapsychiatry.2014.1319 }}</ref> Another analysis published in ''Pain'' in 2015 found that placebo responses had increased considerably in [[neuropathic pain]] clinical trials conducted in the United States from 1990 to 2013. The researchers suggested that this may be because such trials have "increased in study size and length" during this time period.<ref>{{cite journal | vauthors = Tuttle AH, Tohyama S, Ramsay T, Kimmelman J, Schweinhardt P, Bennett GJ, Mogil JS | title = Increasing placebo responses over time in U.S. clinical trials of neuropathic pain | journal = Pain | volume = 156 | issue = 12 | pages = 2616–26 | date = December 2015 | pmid = 26307858 | doi = 10.1097/j.pain.0000000000000333 | s2cid = 23246031 }}
* {{lay source |template = cite magazine|vauthors = Dahl M |url= https://www.thecut.com/2015/10/placebo-effect-is-getting-stronger.html|title = The Placebo Effect Is Getting Stronger — But Only in the U.S.|date = October 9, 2015 |website = The Cut}}</ref>
 
[[childhood|Children]] seem to have a greater response than [[adults]] to placebos.<ref>{{cite journal | vauthors = Rheims S, Cucherat M, Arzimanoglou A, Ryvlin P | title = Greater response to placebo in children than in adults: a systematic review and meta-analysis in drug-resistant partial epilepsy | journal = PLOS Medicine | volume = 5 | issue = 8 | pages = e166 | date = August 2008 | pmid = 18700812 | pmc = 2504483 | doi = 10.1371/journal.pmed.0050166 | editor1-last = Klassen | editor1-first = Terry | doi-access = free }}</ref>
 
The administration of the placebos can determine the placebo effect strength. Studies have found that taking more pills would strengthen the effect. Besides, capsulesCapsules appear to be more influential than pills, and injections are even stronger than capsules.<ref name="Rosenberg2010_176">{{cite book |last1=Rosenberg |first1=Robin |last2=Kosslyn |first2=Stephen |title=Abnormal Psychology |date=2010 |publisher=Worth Publishers |isbn=978-1-4292-6356-6 |page=176 |url=https://books.google.com/books?id=2Nh-RAAACAAJ |access-date=7 December 2020 |language=en}}</ref>
 
Some studies have investigated the use of placebos where the patient is fully aware that the treatment is inert, known as an ''[[Open-label trial|open-label placebo]]''.<ref name="Blease2019">{{cite journal |last1=Blease |first1=CR |last2=Bernstein |first2=MH |last3=Locher |first3=C |title=Open-label placebo clinical trials: is it the rationale, the interaction or the pill? |journal=BMJ Evidence-Based Medicine |date=26 June 2019 |volume=25 |issue=5 |doi=10.1136/bmjebm-2019-111209 |pmid=31243047 |type=Review |pmc=6930978 |pages=bmjebm–2019–111209}}</ref> A 2017 meta-analysis based on 5 studies found some evidence that open-label placebos may have positive effects in comparison to no treatment,<ref name="canterbury">{{Cite journal |title=Effects of placebos without deception compared with no treatment: A systematic review and meta-analysis |date=2017 |doi=10.1111/jebm.12251 |url=https://onlinelibrary.wiley.com/doi/full/10.1111/jebm.12251 |last1=Charlesworth |first1=James E.G. |last2=Petkovic |first2=Grace |last3=Kelley |first3=John M. |last4=Hunter |first4=Monika |last5=Onakpoya |first5=Igho |last6=Roberts |first6=Nia |last7=Miller |first7=Franklin G. |last8=Howick |first8=Jeremy |journal=Journal of Evidence-Based Medicine |volume=10 |issue=2 |pages=97–107 |pmid=28452193 |s2cid=4577402 |doi-access=free }}</ref> which may open new avenues for treatments,<ref name="Blease2019" /> but noted the trials were done with a small number of participants and hence should be interpreted with "caution" until further better controlled trials are conducted.<ref name="onlinelibrary.wiley.com"/> An updated 2021 systematic review and meta-analysis based on 11 studies also found a significant, albeit slightly smaller overall effect of open-label placebos, while noting that "research on OLPs is still in its infancy".<ref>{{Cite journal |last1=von Wernsdorff |first1=Melina |last2=Loef |first2=Martin |last3=Tuschen-Caffier |first3=Brunna |last4=Schmidt |first4=Stefan |date=2023 |title=Effects of open-label placebos in clinical trials: a systematic review and meta-analysis |journal=Scientific Reports |language= |volume=11 |issue=1 |pages=3855 |bibcode=2021NatSR..11.3855V |doi=10.1038/s41598-021-83148-6 |issn= |pmc=7887232 |pmid=33594150}}</ref>▼
 
If the person dispensing the placebo shows their care towards the patient, is friendly and sympathetic, or has a high expectation of a treatment's success, then the placebo would be more effectual.<ref name="Rosenberg2010_176" />▼
 
In the ''Epigenetics and Anticipation'' book by [[Springer Science+Business Media|Springer]], Goli (2022) integrates many of the specific and non-specific factors influencing the placebo effect in the perceived healing response formula, developed based on main placebo studies.<ref>{{Citation |last=Goli |first=Farzad |title=Body, Meaning, and Time: Healing Response as a Transtemporal and Multimodal Meaning-Making Process |date=2022 |url=https://link.springer.com/10.1007/978-3-031-17678-4_6 |work=Epigenetics and Anticipation |series=Cognitive Systems Monographs |volume=45 |pages=79–97 |editor-last=Nadin |editor-first=Mihai |access-date= |place=Cham |publisher=Springer International Publishing |language=en |doi=10.1007/978-3-031-17678-4_6 |isbn=978-3-031-17677-7}}</ref>▼
 
▲Some studies have investigated the use of placebos where the patient is fully aware that the treatment is inert, known as an ''[[Open-label trial|open-label placebo]]''. Clinical trials found that open-label placebos may have positive effects in comparison to no treatment, which may open new avenues for treatments,<ref name="Blease2019">{{cite journal |last1=Blease |first1=CR |last2=Bernstein |first2=MH |last3=Locher |first3=C |date=26 June 2019 |title=Open-label placebo clinical trials: is it the rationale, the interaction or the pill? |journal=BMJ Evidence-Based Medicine |datetype=26 June 2019Review |volume=25 |issue=5 |pages=bmjebm–2019–111209 |doi=10.1136/bmjebm-2019-111209 |pmid=31243047 |type=Review |pmc=6930978 |pagespmid=bmjebm–2019–11120931243047}}</ref> Abut 2017a meta-analysisreview basedof onsuch 5trials studiesnoted foundthat somethey evidencewere thatdone open-labelwith placebosa maysmall havenumber positiveof effectsparticipants inand comparisonhence toshould nobe treatmentinterpreted with "caution" until further, better-controlled trials are conducted.<ref name="canterburyonlinelibrary.wiley.com">{{Citecite journal |title=Effects of placebos without deception compared with no treatment: A systematic review and meta-analysis |date=2017 |doi=10.1111/jebm.12251 |url=https://onlinelibrary.wiley.com/doi/full/10.1111/jebm.12251 |last1=Charlesworth |first1=James E.G. |last2=Petkovic |first2=Grace |last3=Kelley |first3=John M. |last4=Hunter |first4=Monika |last5=Onakpoya |first5=Igho |last6=Roberts |first6=Nia |last7=Miller |first7=Franklin G. |last8=Howick |first8=Jeremy |journal=Journal of Evidence-Based Medicine |volume=10 |issue=2 |pages=97–107 |pmid=28452193 |s2cid=4577402 |doi-access=free }}</ref> which may open new avenues for treatments,<ref name="Blease2019" /> but noted the trials were done with a small number of participants and hence should be interpreted with "caution" until further better controlled trials are conducted.<ref name="onlinelibrary.wiley.com"/> An updated 2021 systematic review and meta-analysis based on 11 studies also found a significant, albeit slightly smaller overall effect of open-label placebos, while noting that "research on OLPs is still in its infancy".<ref>{{Cite journal |last1=von Wernsdorff |first1=Melina |last2=Loef |first2=Martin |last3=Tuschen-Caffier |first3=Brunna |last4=Schmidt |first4=Stefan |date=2023 |title=Effects of open-label placebos in clinical trials: a systematic review and meta-analysis |journal=Scientific Reports |language= |volume=11 |issue=1 |pages=3855 |bibcode=2021NatSR..11.3855V |doi=10.1038/s41598-021-83148-6 |issn= |pmc=7887232 |pmid=33594150}}</ref>
===Symptoms and conditions===
A 2010 Cochrane Collaboration review suggests that placebo effects are apparent only in subjective, continuous measures, and in the treatment of pain and related conditions.<ref name="CochraneHrob2010" /> Anyway, several objective outcomes are affected as well, like [[Parkinson's disease]] symptoms,<ref name="quattrone-barbagallo" /> [[Immune system|immune]] and [[Endocrine system|endocrine]] parameters,<ref name=":1" /><ref name="Pacheco" /> end-organ functions regulated by the [[autonomic nervous system]],<ref>{{Cite journal |last=Meissner |first=Karin |date=2011-06-27 |title=The placebo effect and the autonomic nervous system: evidence for an intimate relationship |journal=Philosophical Transactions of the Royal Society B: Biological Sciences |volume=366 |issue=1572 |pages=1808–1817 |doi=10.1098/rstb.2010.0403 |issn=0962-8436 |pmc=3130407 |pmid=21576138}}</ref> [[sport]] performance,<ref>{{Cite journal |last1=Hurst |first1=Philip |last2=Schipof-Godart |first2=Lieke |last3=Szabo |first3=Attila |last4=Raglin |first4=John |last5=Hettinga |first5=Florentina |last6=Roelands |first6=Bart |last7=Lane |first7=Andrew |last8=Foad |first8=Abby |last9=Coleman |first9=Damian |last10=Beedie |first10=Chris |date=2020-03-15 |title=The Placebo and Nocebo effect on sports performance: A systematic review |url=https://www.tandfonline.com/doi/full/10.1080/17461391.2019.1655098 |journal=European Journal of Sport Science |language=en |volume=20 |issue=3 |pages=279–292 |doi=10.1080/17461391.2019.1655098 |pmid=31414966 |s2cid=199662279 |issn=1746-1391|hdl=2436/622641 |hdl-access=free }}</ref> and others.
 
▲If the person dispensing the placebo shows their care towards the patient, is friendly and sympathetic, or has a high expectation of a treatment's success, then the placebo would beis more effectual.<ref name="Rosenberg2010_176" />
====Pain====
Placebos are believed to be capable of altering a person's perception of pain. "A person might reinterpret a sharp pain as uncomfortable tingling."<ref name="acs">{{cite web|date=10 April 2015|title=Placebo Effect|url=https://www.cancer.org/treatment/treatments-and-side-effects/clinical-trials/placebo-effect.html|url-status=live|archive-url=https://web.archive.org/web/20200522232756/https://www.cancer.org/treatment/treatments-and-side-effects/clinical-trials/placebo-effect.html|archive-date=2020-05-22|access-date=2021-06-27|publisher=American Cancer Society}}</ref>
 
▲In the 2022 book ''Epigenetics and Anticipation'' bookpublished by [[Springer Science+Business Media|Springer]], Goli (2022) integrates many of the specific and non-specific factors influencing the placebo effect in the perceived healing response formula, developed based on main placebo studies.<ref>{{Citation |last=Goli |first=Farzad |title=Body, Meaning, and Time: Healing Response as a Transtemporal and Multimodal Meaning-Making Process |date=2022 |url=https://link.springer.com/10.1007/978-3-031-17678-4_6 |work=Epigenetics and Anticipation |series=Cognitive Systems Monographs |volume=45 |pages=79–97 |editor-last=Nadin |editor-first=Mihai |access-date= |place=Cham |publisher=Springer International Publishing |language=en |doi=10.1007/978-3-031-17678-4_6 |isbn=978-3-031-17677-7}}</ref>{{Relevance inline|date=March 2024}}
▲One way in which the magnitude of placebo analgesia can be measured is by conducting "open/hidden" studies, in which some patients receive an analgesic and are informed that they will be receiving it (open), while others are administered the same drug without their knowledge (hidden). Such studies have found that analgesics are considerably more effective when the patient knows they are receiving them.<ref>{{cite journal | vauthors = Price DD, Finniss DG, Benedetti F | title = A comprehensive review of the placebo effect: recent advances and current thought | journal = Annual Review of Psychology | volume = 59 | issue = 1 | pages = 565–90 | date = 2008 | pmid = 17550344 | doi = 10.1146/annurev.psych.59.113006.095941 }}</ref>
 
==== Depression= ===
In 2008, a controversial meta-analysis led by psychologist [[Irving Kirsch]], analyzing data from the [[Food and Drug Administration]] (FDA), concluded that 82% of the response to antidepressants was accounted for by placebos.<ref>{{cite journal | vauthors = Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT | title = Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration | journal = PLOS Medicine | volume = 5 | issue = 2 | pages = e45 | date = February 2008 | pmid = 18303940 | pmc = 2253608 | doi = 10.1371/journal.pmed.0050045 | doi-access = free }}</ref> However, thereother authors areexpressed serious doubts about the used methods and the interpretation of the results, especially the use of 0.5 as the cut-off point for the [[effect size]].<ref name="TurnerRosenthal2008">{{cite journal | vauthors = Turner EH, Rosenthal R | title = Efficacy of antidepressants | journal = BMJ | volume = 336 | issue = 7643 | pages = 516–7 | date = March 2008 | pmid = 18319297 | pmc = 2265347 | doi = 10.1136/bmj.39510.531597.80 }}</ref> A complete reanalysis and recalculation based on the same FDA data discoveredfound that the Kirsch study had "important flaws in the calculations". The authors concluded that although a large percentage of the placebo response was due to expectancy, this was not true for the active drug. Besides confirming drug effectiveness, they found that the drug effect was not related to depression severity.<ref name="FountoulakisMöller2010">{{cite journal | vauthors = Fountoulakis KN, Möller HJ | title = Efficacy of antidepressants: a re-analysis and re-interpretation of the Kirsch data | journal = The International Journal of Neuropsychopharmacology | volume = 14 | issue = 3 | pages = 405–12 | date = April 2011 | pmid = 20800012 | doi = 10.1017/S1461145710000957 | doi-access = free }}</ref>
 
Another meta-analysis found that 79% of depressed patients receiving placebo remained well (for 12 weeks after an initial 6–8 weeks of successful therapy) compared to 93% of those receiving antidepressants. In the continuation phase however, patients on placebo relapsed significantly more often than patients on antidepressants.<ref>{{cite journal | vauthors = Khan A, Redding N, Brown WA | title = The persistence of the placebo response in antidepressant clinical trials | journal = Journal of Psychiatric Research | volume = 42 | issue = 10 | pages = 791–6 | date = August 2008 | pmid = 18036616 | doi = 10.1016/j.jpsychires.2007.10.004 }}</ref>
Line 66 ⟶ 55:
{{main|Nocebo}}
 
A phenomenon opposite to the placebo effect has also been observed. When an inactive substance or treatment is administered to a recipient who has an expectation of it having a ''negative'' impact, this intervention is known as a '''nocebo''' ([[Latin]] ''{{lang|la|nocebo''}} = "I shall harm").<ref>{{cite web|url=https://www.merriam-webster.com/dictionary/nocebo|title=nocebo|access-date=22 January 2017|publisher=MirriamMerriam-Webster Incorporated}}</ref> A '''nocebo effect''' occurs when the recipient of an inert substance reports a negative effect or a worsening of symptoms, with the outcome resulting not from the substance itself, but from negative expectations about the treatment.<ref>{{cite journal | vauthors = Häuser W, Hansen E, Enck P | title = Nocebo phenomena in medicine: their relevance in everyday clinical practice | journal = Deutsches Ärzteblatt International | volume = 109 | issue = 26 | pages = 459–65 | date = June 2012 | pmid = 22833756 | pmc = 3401955 | doi = 10.3238/arztebl.2012.0459 }}</ref><ref name="autogenerated4">{{cite web |url=http://priory.com/medicine/Nocebo.htm |title=The Nocebo Effect |publisher=Priory.com |date=10 February 2007 |access-date=2009-07-08}}</ref>
 
Another negative consequence is that placebos can cause [[Adverse effect (medicine)|side-effects]] associated with real treatment.<ref>{{cite journal |vauthors=Shapiro AK, Chassan J, Morris LA, Frick R |year=1974 |title=Placebo induced side effects |journal=Journal of Operational Psychiatry |volume=6 |pages=43–6 |url=http://psycnet.apa.org/?fa=main.doiLanding&uid=1977-04006-001 }}</ref> Failure to minimise nocebo [[Adverse effect (medicine)|side-effects]] in clinical trials and clinical practice raises a number of recently explored ethical issues.<ref>{{Cite journal|last=Howick|first=Jeremy|date=2020|title=Unethical informed consent caused by overlooking poorly measured nocebo effects|journal=Journal of Medical Ethics|volume=47|issue=9|pages=medethics-2019-105903|doi=10.1136/medethics-2019-105903|pmid=32063581|s2cid=211134874|url=https://ora.ox.ac.uk/objects/uuid:07126ead-92c8-4b82-87b2-7e677aaf98b5}}</ref>
 
Withdrawal symptoms can also occur after placebo treatment. This was found, for example, after the discontinuation of the [[Women's Health Initiative]] study of [[Hormone replacement therapy (menopause)|hormone replacement therapy]] for [[menopause]]. Women had been on placebo for an average of 5.7 years. Moderate or severe [[Drug withdrawal|withdrawal]] symptoms were reported by 4.8% of those on placebo compared to 21.3% of those on hormone replacement.<ref>{{cite journal | vauthors = Ockene JK, Barad DH, Cochrane BB, Larson JC, Gass M, Wassertheil-Smoller S, Manson JE, Barnabei VM, Lane DS, Brzyski RG, Rosal MC, Wylie-Rosett J, Hays J | title = Symptom experience after discontinuing use of estrogen plus progestin | journal = JAMA | volume = 294 | issue = 2 | pages = 183–93 | date = July 2005 | pmid = 16014592 | doi = 10.1001/jama.294.2.183 | doi-access = free }}</ref>
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Knowingly giving a person a placebo when there is an effective treatment available is a bioethically complex issue. While placebo-controlled trials might provide information about the effectiveness of a treatment, it denies some patients what could be the best available (if unproven) treatment. [[Informed consent]] is usually required for a study to be considered ethical, including the disclosure that some test subjects will receive placebo treatments.
 
The ethics of placebo-controlled studies have been debated in the revision process of the [[Declaration of Helsinki]].<ref>{{cite journal | vauthors = Howick J | title = Questioning the methodologic superiority of 'placebo' over 'active' controlled trials | journal = The American Journal of Bioethics | volume = 9 | issue = 9 | pages = 34–48 | date = September 2009 | pmid = 19998192 | doi = 10.1080/15265160903090041 | s2cid = 41559691 }}</ref> Of particular concern has been the difference between trials comparing inert placebos with experimental treatments, versus comparing the best available treatment with an experimental treatment; and differences between trials in the sponsor's developed countries versus the trial's targeted developing countries.<ref>{{cite journal | vauthors = Kottow M | title = The improper use of research placebos | journal = Journal of Evaluation in Clinical Practice | volume = 16 | issue = 6 | pages = 1041–4 | date = December 2010 | pmid = 20663001 | doi = 10.1111/j.1365-2753.2009.01246.x }}</ref>
 
Some suggest that existing medical treatments should be used instead of placebos, to avoid having some patients not receive medicine during the trial.<ref name="michels">{{cite journal | vauthors = Michels KB | title = The placebo problem remains | journal = Archives of General Psychiatry | volume = 57 | issue = 4 | pages = 321–2 | date = April 2000 | pmid = 10768689 | doi = 10.1001/archpsyc.57.4.321 }}</ref>
 
===In medical practice===
The practice of doctors prescribing placebos that are disguised as real medication is controversial. A chief concern is that it is deceptive and could harm the doctor–patient relationship in the long run. While some say that blanket consent, or the general consent to unspecified treatment given by patients beforehand, is ethical, others argue that patients should always obtain specific information about the name of the drug they are receiving, its side effects, and other treatment options.<ref>{{cite journal | vauthors = Asai A, Kadooka Y | title = Reexamination of the ethics of placebo use in clinical practice | journal = Bioethics | volume = 27 | issue = 4 | pages = 186–93 | date = May 2013 | pmid = 22296589 | doi = 10.1111/j.1467-8519.2011.01943.x | s2cid = 11300075 }}</ref> This view is shared by some on the grounds of [[Autonomy#Medicine|patient autonomy]].<ref>{{cite journal | vauthors = Chua SJ, Pitts M | title = The ethics of prescription of placebos to patients with major depressive disorder | journal = Chinese Medical Journal | volume = 128 | issue = 11 | pages = 1555–7 | date = June 2015 | pmid = 26021517 | doi = 10.4103/0366-6999.157699 | pmc = 4733778 | doi-access = free }}</ref> There are also concerns that legitimate doctors and pharmacists could open themselves up to charges of fraud or malpractice by using a placebo.<ref>{{cite journal|last1=Malani|first1=Anup | name-list-style = vanc |title=Regulation with Placebo Effects|journal=Chicago Unbound|date=2008|volume=58|issue=3 |pages=411–72 |pmid=19353835 |url=https://chicagounbound.uchicago.edu/cgi/viewcontent.cgi?article=2640&context=journal_articles|access-date=30 March 2018}}</ref> Critics also argued that using placebos can delay the proper diagnosis and treatment of serious medical conditions.<ref>{{cite journal | vauthors = Altunç U, Pittler MH, Ernst E | title = Homeopathy for childhood and adolescence ailments: systematic review of randomized clinical trials | journal = Mayo Clinic Proceedings | volume = 82 | issue = 1 | pages = 69–75 | date = January 2007 | pmid = 17285788 | doi = 10.4065/82.1.69 }}</ref>
 
Despite the abovementioned issues, 60% of surveyed physicians and head nurses reported using placebos in an Israeli study, with only 5% of respondents stating that placebo use should be strictly prohibited.<ref>{{Cite journal|last1=Nitzan|first1=Uriel|last2=Lichtenberg|first2=Pesach|date=2004-10-23|title=Questionnaire survey on use of placebo|journal=BMJ: British Medical Journal|volume=329|issue=7472|pages=944–946|doi=10.1136/bmj.38236.646678.55|issn=0959-8138|pmid=15377572|pmc=524103|doi-access=free}}</ref> A ''British Medical Journal'' editorial said, "that a patient gets pain relief from a placebo does not imply that the pain is not real or organic in origin{{Spaces}}...the use of the placebo for 'diagnosis' of whether or not pain is real is misguided."<ref name="Spiegel">{{cite journal|vauthors=Spiegel D|date=October 2004|title=Placebos in practice|journal=BMJ|volume=329|issue=7472|pages=927–8|doi=10.1136/bmj.329.7472.927|pmc=524090|pmid=15499085}}</ref> A survey in the United States of more than 10,000 physicians came to the result that while 24% of physicians would prescribe a treatment that is a placebo simply because the patient wanted treatment, 58% would not, and for the remaining 18%, it would depend on the circumstances.<ref name=kane>[http://www.medscape.com/viewarticle/731485_7 Doctors Struggle With Tougher-Than-Ever Dilemmas: Other Ethical Issues] Author: Leslie Kane. 11/11/2010</ref>
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==Mechanisms==
The mechanism for how placebos could have effects is uncertain. An open-label study in 2010 showed that it had an effect even when patients were clearly told that the placebo pill they were receiving was an inactive (i.e., "inert") substance like a sugar pill that contained no medication. These results challenge the "conventional wisdom" that placebo effects require "intentional ignorance".<ref name=":0" /> From a sociocognitive perspective, this intentional placebo response attributesis attributed to the “ritual effect” that induces anticipation for transition to a better state.<ref>{{Citation |last1=Goli |first1=Farzad |title=The Ritual Effect: The Healing Response to Forms and Performs |date=2016 |url=http://dx.doi.org/10.1007/978-3-319-35092-9_5 |work=Biosemiotic Medicine |pages=117–132 |access-date= |place=Cham |publisher=Springer International Publishing |isbn=978-3-319-35091-2 |last2=Farzanegan |first2=Mahboubeh|series=Studies in Neuroscience, Consciousness and Spirituality |volume=5 |doi=10.1007/978-3-319-35092-9_5 }}</ref> A placebo presented as a [[stimulant]] may trigger an effect on [[heart rhythm]] and [[blood pressure]], but when administered as a [[depressant]], the opposite effect.<ref>{{cite book | vauthors = Kirsch I |year=1997 |chapter=Specifying non-specifics: Psychological mechanism of the placebo effect |editor=Harrington A |title=The Placebo Effect: An Interdisciplinary Exploration |location=Cambridge |publisher=Harvard University Press |pages=166–86 |isbn=978-0-674-66986-4}}</ref>
 
===Psychology===
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Since 1978, it has been known that placebo analgesia depends upon the release of [[endogenous opioids]] in the brain.<ref>{{cite journal | vauthors = Levine JD, Gordon NC, Fields HL | title = The mechanism of placebo analgesia | journal = Lancet | volume = 2 | issue = 8091 | pages = 654–7 | date = September 1978 | pmid = 80579 | doi = 10.1016/s0140-6736(78)92762-9 | s2cid = 45403755 }}</ref> Such analgesic placebos activation changes processing lower down in the brain by enhancing the descending inhibition through the periaqueductal gray on spinal [[Withdrawal reflex|nociceptive reflexes]], while the expectations of anti-analgesic nocebos acts in the opposite way to block this.<ref name="autogenerated2007"/>
 
Functional imaging upon placebo analgesia has been summarized as showing that the placebo response is "mediated by "'top-down"' processes dependent on frontal cortical areas that generate and maintain cognitive expectancies. [[Dopamine pathways|Dopaminergic reward pathways]] may underlie these expectancies".<ref>{{cite journal | vauthors = Faria V, Fredrikson M, Furmark T | title = Imaging the placebo response: a neurofunctional review | journal = European Neuropsychopharmacology | volume = 18 | issue = 7 | pages = 473–85 | date = July 2008 | pmid = 18495442 | doi = 10.1016/j.euroneuro.2008.03.002 | s2cid = 40020867 }}</ref> "Diseases lacking major 'top-down' or cortically based regulation may be less prone to placebo-related improvement".<ref>{{cite journal | vauthors = Diederich NJ, Goetz CG | title = The placebo treatments in neurosciences: New insights from clinical and neuroimaging studies | journal = Neurology | volume = 71 | issue = 9 | pages = 677–84 | date = August 2008 | pmid = 18725593 | doi = 10.1212/01.wnl.0000324635.49971.3d | s2cid = 29547923 }}</ref>
 
===Brain and body===
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==Confounding factors==
Placebo-controlled studies, as well as studies of the placebo effect itself, often fail to adequately identify confounding factors.<ref name=acs/><ref name=Golomb>{{cite journal | vauthors = Golomb BA, Erickson LC, Koperski S, Sack D, Enkin M, Howick J | title = What's in placebos: who knows? Analysis of randomized, controlled trials | journal = Annals of Internal Medicine | volume = 153 | issue = 8 | pages = 532–5 | date = October 2010 | pmid = 20956710 | doi = 10.7326/0003-4819-153-8-201010190-00010 | s2cid = 30068755 }}</ref><ref name="hrob2010">{{cite journal | vauthors = Hróbjartsson A, Kaptchuk TJ, Miller FG | title = Placebo effect studies are susceptible to response bias and to other types of biases | journal = Journal of Clinical Epidemiology | volume = 64 | issue = 11 | pages = 1223–9 | date = November 2011 | pmid = 21524568 | pmc = 3146959 | doi = 10.1016/j.jclinepi.2011.01.008 }}</ref> False impressions of placebo effects are caused by many factors including:<ref name=acs/><ref name="Kienle & Kiene" /><ref name="hrob2010" /><ref name="podd" /><ref name=Golomb>{{cite journal | vauthors = Golomb BA, Erickson LC, Koperski S, Sack D, Enkin M, Howick J | title = What's in placebos: who knows? Analysis of randomized, controlled trials | journal = Annals of Internal Medicine | volume = 153 | issue = 8 | pages = 532–5 | date = October 2010 | pmid = 20956710 | doi = 10.7326/0003-4819-153-8-201010190-00010 | s2cid = 30068755 }}</ref>
* [[Regression to the mean]] (natural recovery or fluctuation of symptoms)
* Additional treatments
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}}
 
Placebos have featured in medical use until well into the twentieth century.<ref name=HistoricalOverview>{{cite journal | vauthors = de Craen AJ, Kaptchuk TJ, Tijssen JG, Kleijnen J | title = Placebos and placebo effects in medicine: historical overview | journal = Journal of the Royal Society of Medicine | volume = 92 | issue = 10 | pages = 511–515 | date = October 1999 | pmid = 10692902 | pmc = 1297390 | doi = 10.1177/014107689909201005}}</ref> In 1955 [[Henry K. Beecher]] published anAn influential paper1955 study entitled ''The Powerful Placebo'' whichfirmly proposedestablished the idea that placebo effects were clinically important.,<ref name="Hrob2001"/>{{cite Subsequentjournal | vauthors = Hróbjartsson A, Gøtzsche PC | title = Is the placebo powerless? An re-analysis of hisclinical materials,trials however,comparing foundplacebo with no treatment | journal = The New England Journal of Medicine | volume = 344 | issue = 21 | pages = 1594–1602 | date = May 2001 | pmid = 11372012 | doi = 10.1056/NEJM200105243442106 | doi-access = free }}</ref> and were a result of [[Neural top–down control of physiology|the brain's role in themphysical health]]. A 1997 reassessment found no evidence of any "placebo effect" in the source data, as the study had not accounted for [[regression to the mean]].<ref name="Kienle & Kiene" /><ref name=Hrob2004/><ref>Stoddart, Charlotte, ''[https://knowablemagazine.org/article/mind/2023/how-placebo-effect-went-mainstream How placebo effect went mainstream]'', [[Knowable Magazine]], June 27, 2023</ref>
 
===Placebo-controlled studies===
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{{reflist}}
==Further reading==
* {{Cite book|title=Placebos |first=Kathryn T |last=Hall |publisher=The MIT Press |year=2022 |isbn=978-02625442520-262-54425-2 }}
* {{Cite book|title=Neurobiology of the placebo effect. Part I|last=Colloca|first=Luana|isbn=9780128143261978-0-12-814326-1|location=Cambridge, MA|oclc=1032303151|date=2018-04-20}}
* {{Cite book|title=Neurobiology of the placebo effect. Part II|last=Colloca|first=Luana|date=2018-08-23|isbn=9780128154175978-0-12-815417-5|edition=1st|location=Cambridge, MA, United States|oclc=1049800273}}
* {{Cite book|title=Suggestible You: The Curious Science of Your Brain's Ability to Deceive, Transform, and Heal |year=2016 |last=Erik |first=Vance |isbn=978-14262178901-4262-1789-0 |publisher=National Geographic}}
 
==External links==
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[[Category:Clinical research]]
[[Category:Deception]]
[[Category:Ethically disputed medical practices]]
[[Category:Mind–body interventions]]
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