View source for Placebo

{{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}}) can be roughly defined as a [[wiktionary:sham|sham]] medical treatment.<ref name=aspmn/><ref name=":0">{{Cite journal |last=Lombardi |first=F |date=2025 |title=Shedding Light on the Placebo Effect |url=https://philpapers.org/rec/LOMSLO |journal=Think |publisher=Cambridge University Press |volume=24 |issue=70 |pages=43–48 |doi=10.1017/S1477175625000223 |url-access=}}</ref> 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 }}</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]] 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" /> Placebos in clinical trials should ideally be indistinguishable from so-called verum treatments under investigation, except for the latter's particular hypothesized medicinal effect.<ref>{{Cite journal |last1=Blease |first1=Charlotte |last2=Annoni |first2=Marco |date=April 2019 |title=Overcoming disagreement: a roadmap for placebo studies |url=https://www.researchgate.net/publication/331766597 |journal=Biology & Philosophy |language=en |volume=34 |issue=2 |article-number=18 |doi=10.1007/s10539-019-9671-5 |issn=0169-3867}}</ref> This is to [[blinded experiment|shield test participants]] (with their [[consent]]) from knowing who is getting the placebo and who is getting the treatment under test, as patients' and clinicians' expectations of [[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>[[Katharina A. Schwarz|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">{{cite journal |vauthors=Hróbjartsson A, Gøtzsche PC |date=January 2010 |editor1-last=Hróbjartsson |editor1-first=Asbjørn |title=Placebo interventions for all clinical conditions |url=http://nordic.cochrane.org/sites/nordic.cochrane.org/files/public/uploads/ResearchHighlights/Placebo%20interventions%20for%20all%20clinical%20conditions%20(Cochrane%20review).pdf |journal=The Cochrane Database of Systematic Reviews |volume=106 |issue=1 |article-number=CD003974 |doi=10.1002/14651858.CD003974.pub3 |pmc=7156905 |pmid=20091554 |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 |archive-date=2019-04-02 |access-date=2018-06-25}}</ref> 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">{{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" /> but have no impact on the [[disease]] itself.<ref name="CochraneHrob2010" /><ref name="acs" />

==Etymology and definition==
The [[Latin]] term {{lang|la|placebo}} means ''[I] shall be pleasing''.<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 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> 

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 |journal=Biology & Philosophy |language=en |volume=34 |issue=2 |page=18 |doi=10.1007/s10539-019-9671-5 |s2cid=254281187 |issn=1572-8404}}</ref> One definition states that a [[Medical treatment|treatment]] process is a placebo when none of the characteristic treatment factors are effective (remedial or harmful) in the [[patient]] for a given [[disease]].<ref>{{Cite journal |last=Howick |first=Jeremy |date=2017 |title=The relativity of 'placebos': defending a modified version of Grünbaum's definition |url=https://link.springer.com/article/10.1007/s11229-015-1001-0 |journal=Synthese |volume=194 |issue=4 |pages=1363–1396 |doi=10.1007/s11229-015-1001-0 |url-access=subscription }}</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|article-number=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 |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==
{{redirect|Placebo effect}}
{{further|Alternative medicine#Perceived mechanism of effect}}

The placebo effect is well-documented phenomenon, though it remains widely misunderstood and surrounded by misconceptions.<ref name=":0" /> Several studies have questioned its clinical relevance, fueling ongoing debate about its actual effectiveness. A 2001 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" /> 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 that 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, particularly due to concerns about the adequacy of the methodology used.<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|url-access=subscription }}</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 |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 journal |title=Apples, oranges, and placebos: Heterogeneity in a meta-analysis of placebo effects|url=https://psycnet.apa.org/record/2001-05525-013 |journal=Advances in Mind-Body Medicine }}</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|url-access=subscription }}</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|url-access=subscription }}</ref> 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 journal|last=Gross|first=Liza|date=February 2017|title=Putting placebos to the test|journal=PLOS Biology|volume=15|issue=2|article-number=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 |journal=Psychotherapy and Psychosomatics |volume=86 |issue=2 |pages=99–107 |doi=10.1159/000449470 |issn=0033-3190 |pmid=28183096 |s2cid=40594851 |doi-access=free |hdl-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>

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/>

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 |doi=10.1146/annurev.psych.59.113006.095941 |pmid=17550344}}</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>

Individual differences in personality traits may influence susceptibility to placebo and nocebo (negative placebo) effects. People with a more optimistic outlook tend to exhibit stronger placebo responses, while those with higher levels of anxiety are more likely to experience nocebo effects.<ref>{{cite journal | last1=Kern | first1=Alexandra | last2=Kramm | first2=Christoph | last3=Witt | first3=Claudia M. | last4=Barth | first4=Jürgen | title=The influence of personality traits on the placebo/nocebo response | journal=Journal of Psychosomatic Research | publisher=Elsevier BV | volume=128 | year=2020 | issn=0022-3999 | doi=10.1016/j.jpsychores.2019.109866 | doi-access=free | article-number=109866 | pmid=31760341 | url=https://www.zora.uzh.ch/id/eprint/183343/9/Kern_et_al._%282020%29_Manuskript.pdf | access-date=2025-04-09}}</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 | article-number = 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. Capsules 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]]''. 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 |type=Review |volume=25 |issue=5 |pages=bmjebm–2019–111209 |doi=10.1136/bmjebm-2019-111209 |pmc=6930978 |pmid=31243047}}</ref> but a review of such trials noted that they 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">{{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 |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> 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 |page=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 is more effectual.<ref name="Rosenberg2010_176" />

=== Depression ===
In 2008, a [[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 | article-number = e45 | date = February 2008 | pmid = 18303940 | pmc = 2253608 | doi = 10.1371/journal.pmed.0050045 | doi-access = free }}</ref> However, other authors expressed 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 found that the Kirsch study had "important flaws in the calculations."<ref name="FountoulakisMöller2010" /> The authors concluded that although a large percentage of the placebo response was due to expectancy, this was not true for the active drug.<ref name="FountoulakisMöller2010" /> 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>

===Negative effects===
{{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=Merriam-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>

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>

==Ethics==
{{see also|Medical ethics|Philosophy of medicine}}

===In research trials===
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]]. 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 | url = https://repositorio.uchile.cl/handle/2250/165152 }}</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 |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>

Referring specifically to [[homeopathy]], the [[House of Commons of the United Kingdom]] Science and Technology Committee has stated:{{Blockquote|In the Committee's view, homeopathy is a placebo treatment and the Government should have a policy on prescribing placebos. The Government is reluctant to address the appropriateness and ethics of prescribing placebos to patients, which usually relies on some degree of patient deception. Prescribing of placebos is not consistent with informed patient choice—which the Government claims is very important—as it means patients do not have all the information needed to make choice meaningful. A further issue is that the placebo effect is unreliable and unpredictable.<ref name=inquiry_cfm>{{cite web |author1=UK Parliamentary Committee Science |author2=Technology Committee |url=http://www.parliament.uk/business/committees/committees-archive/science-technology/s-t-homeopathy-inquiry/ |archive-url=https://web.archive.org/web/20120224202602/http://www.parliament.uk/business/committees/committees-archive/science-technology/s-t-homeopathy-inquiry/ |archive-date=2012-02-24 |title=Evidence Check 2: Homeopathy }}</ref>}}

In his 2008 book ''[[Bad Science (Goldacre book)|Bad Science]]'', [[Ben Goldacre]] argues that instead of deceiving patients with placebos, doctors should use the placebo effect to enhance effective medicines.<ref name="bad-science">{{cite book | first = Ben | last = Goldacre |title=Bad Science |publisher=Fourth Estate |year=2008| chapter=5: The Placebo Effect |isbn=978-0-00-724019-7}}</ref> [[Edzard Ernst]] has argued similarly that "As a good doctor you should be able to transmit a placebo effect through the compassion you show your patients."<ref>{{cite journal | title = Empathy and ethics: five minutes with Edzard Ernst | journal = The BMJ | volume = 360 | issue = 1 | pages = k309| date = January 2018 | pmid = 29371199| doi = 10.1136/bmj.k309 | last1 = Rimmer | first1 = Abi | s2cid = 3511158 }}</ref> In an opinion piece about homeopathy, Ernst argues that it is wrong to support [[alternative medicine]] on the basis that it can make patients feel better through the placebo effect.<ref name="Ernst-homeopathy"/> His concerns are that it is deceitful and that the placebo effect is unreliable.<ref name="Ernst-homeopathy">{{cite news|title=No to homeopathy placebo | newspaper=The Guardian|url=https://www.theguardian.com/commentisfree/2010/feb/22/science-homeopathy-clinical-trials|date=22 February 2010|access-date=29 April 2019}}</ref> Goldacre also concludes that the placebo effect does not justify alternative medicine, arguing that unscientific medicine could lead to patients not receiving prevention advice.<ref name="bad-science"/>
Placebo researcher [[Fabrizio Benedetti]] also expresses concern over the potential for placebos to be used unethically, warning that there is an increase in "quackery" and that an "alternative industry that preys on the vulnerable" is developing.<ref name="Benedetti">{{cite journal |last1=Benedetti |first1=Fabrizio |title=The science of placebos is fuelling quackery |journal=Knowable Magazine |date=3 March 2022 |doi=10.1146/knowable-030222-3 |s2cid=247265071 |url=https://knowablemagazine.org/article/society/2022/science-placebos-fuelling-quackery |access-date=17 March 2022|doi-access=free |url-access=subscription }}</ref>

==Mechanisms==
The mechanism for how placebos could have effects is uncertain. From a sociocognitive perspective, intentional placebo response is 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 |work=Biosemiotic Medicine |pages=117–132 |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===
[[File:"Miracle Cure!" Health Fraud Scams (8528312890).jpg|thumb|right|The subjective effects of placebos may be related to expectations, yet similar effects have been noted in open-label studies.]]

In psychology, the two main hypotheses of the placebo effect are expectancy theory and [[classical conditioning]].<ref name="podd" />

In 1985, [[Irving Kirsch]] hypothesized that placebo effects are produced by the self-fulfilling effects of response expectancies, in which the belief that one will feel different leads a person to actually feel different.<ref>{{cite journal | vauthors = Kirsch I |year=1985|title=Response expectancy as a determinant of experience and behavior|journal=American Psychologist|volume=40|issue=11|pages=1189–1202|doi=10.1037/0003-066X.40.11.1189}}</ref> According to this theory, the belief that one has received an active treatment can produce the subjective changes thought to be produced by the real treatment. Similarly, the appearance of effect can result from classical conditioning, wherein a placebo and an actual stimulus are used simultaneously until the placebo is associated with the effect from the actual stimulus.<ref>{{cite journal | vauthors = Voudouris NJ, Peck CL, Coleman G | title = Conditioned response models of placebo phenomena: further support | journal = Pain | volume = 38 | issue = 1 | pages = 109–16 | date = July 1989 | pmid = 2780058 | doi = 10.1016/0304-3959(89)90080-8 | s2cid = 40356035 }}</ref> Both conditioning and expectations play a role in placebo effect,<ref name="podd">{{cite journal | vauthors = Stewart-Williams S, Podd J | title = The placebo effect: dissolving the expectancy versus conditioning debate | journal = Psychological Bulletin | volume = 130 | issue = 2 | pages = 324–40 | date = March 2004 | pmid = 14979775 | doi = 10.1037/0033-2909.130.2.324 | s2cid = 10297875 }}</ref> and make different kinds of contributions. Conditioning has a longer-lasting effect,<ref>{{cite journal | vauthors = Klinger R, Soost S, Flor H, Worm M | title = Classical conditioning and expectancy in placebo hypoalgesia: a randomized controlled study in patients with atopic dermatitis and persons with healthy skin | journal = Pain | volume = 128 | issue = 1–2 | pages = 31–9 | date = March 2007 | pmid = 17030095 | doi = 10.1016/j.pain.2006.08.025 | s2cid = 27747260 }}</ref> and can affect earlier stages of information processing.<ref name="Colloca et al 2008">{{cite journal | vauthors = Colloca L, Tinazzi M, Recchia S, Le Pera D, Fiaschi A, Benedetti F, Valeriani M | title = Learning potentiates neurophysiological and behavioral placebo analgesic responses | journal = Pain | volume = 139 | issue = 2 | pages = 306–14 | date = October 2008 | pmid = 18538928 | doi = 10.1016/j.pain.2008.04.021 | s2cid = 27342664 }}</ref> Those who think a treatment will work display a stronger placebo effect than those who do not, as evidenced by a study of acupuncture.<ref>{{cite journal | vauthors = Linde K, Witt CM, Streng A, Weidenhammer W, Wagenpfeil S, Brinkhaus B, Willich SN, Melchart D | title = The impact of patient expectations on outcomes in four randomized controlled trials of acupuncture in patients with chronic pain | journal = Pain | volume = 128 | issue = 3 | pages = 264–71 | date = April 2007 | pmid = 17257756 | doi = 10.1016/j.pain.2006.12.006 | s2cid = 25561695 }}</ref>

Additionally, [[motivation]] may contribute to the placebo effect. The active goals of an individual changes their somatic experience by altering the detection and interpretation of expectation-congruent symptoms, and by changing the behavioral strategies a person pursues.<ref name="Geers et al">{{cite journal | vauthors = Geers AL, Weiland PE, Kosbab K, Landry SJ, Helfer SG | title = Goal activation, expectations, and the placebo effect | journal = Journal of Personality and Social Psychology | volume = 89 | issue = 2 | pages = 143–59 | date = August 2005 | pmid = 16162050 | doi = 10.1037/0022-3514.89.2.143 }}</ref> Motivation may link to the meaning through which people experience illness and treatment. Such meaning is derived from the culture in which they live and which informs them about the nature of illness and how it responds to treatment.{{cn|date=November 2023}}

===Placebo analgesia===
[[Functional imaging]] upon [[placebo analgesia]] suggests links to the activation, and increased functional correlation between this activation, in the [[anterior cingulate]], [[prefrontal cortex|prefrontal]], [[orbitofrontal cortex|orbitofrontal]] and [[insular cortex|insular]] cortices, [[nucleus accumbens]], [[amygdala]], the [[brainstem]]'s [[periaqueductal gray matter]],<ref>{{cite journal | vauthors = Oken BS | title = Placebo effects: clinical aspects and neurobiology | journal = Brain | volume = 131 | issue = Pt 11 | pages = 2812–23 | date = November 2008 | pmid = 18567924 | pmc = 2725026 | doi = 10.1093/brain/awn116 }}</ref><ref>{{cite journal | vauthors = Lidstone SC, Stoessl AJ | title = Understanding the placebo effect: contributions from neuroimaging | journal = Molecular Imaging and Biology | volume = 9 | issue = 4 | pages = 176–85 | year = 2007 | pmid = 17334853 | doi = 10.1007/s11307-007-0086-3 | s2cid = 28735246 }}</ref> and the [[spinal cord]].<ref name="autogenerated2007">{{cite journal | vauthors = Goffaux P, Redmond WJ, Rainville P, Marchand S | title = Descending analgesia--when the spine echoes what the brain expects | journal = Pain | volume = 130 | issue = 1–2 | pages = 137–43 | date = July 2007 | pmid = 17215080 | doi = 10.1016/j.pain.2006.11.011 | s2cid = 20841668 }}</ref><ref>{{cite journal | vauthors = Qiu YH, Wu XY, Xu H, Sackett D | title = Neuroimaging study of placebo analgesia in humans | journal = Neuroscience Bulletin | volume = 25 | issue = 5 | pages = 277–82 | date = October 2009 | pmid = 19784082 | pmc = 5552608 | doi = 10.1007/s12264-009-0907-2 }}</ref><ref>{{cite journal | vauthors = Zubieta JK, Stohler CS | title = Neurobiological mechanisms of placebo responses | journal = Annals of the New York Academy of Sciences | volume = 1156 | issue = 1 | pages = 198–210 | date = March 2009 | pmid = 19338509 | pmc = 3073412 | doi = 10.1111/j.1749-6632.2009.04424.x | bibcode = 2009NYASA1156..198Z }}</ref>

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===
{{Further|Neural top–down control of physiology}}

In conditioning, a neutral stimulus [[saccharin]] is paired in a drink with an agent that produces an unconditioned response. For example, that agent might be [[cyclophosphamide]], which causes [[immunosuppressive|immunosuppression]]. After learning this pairing, the taste of saccharin by itself is able to cause immunosuppression, as a new conditioned response via neural top-down control.<ref>{{cite journal | vauthors = Ader R, Cohen N | title = Behaviorally conditioned immunosuppression | journal = Psychosomatic Medicine | volume = 37 | issue = 4 | pages = 333–40 | year = 1975 | pmid = 1162023 | doi = 10.1097/00006842-197507000-00007 | s2cid = 15306042 }}</ref> Such conditioning has been found to affect a diverse variety of not just basic physiological processes in the immune system but ones such as [[Serum iron|serum iron levels]], [[DNA oxidation|oxidative DNA damage]] levels, and [[insulin]] secretion. Recent reviews have argued that the placebo effect is due to top-down control by the brain for immunity<ref name="Pacheco">{{cite journal | vauthors = Pacheco-López G, Engler H, Niemi MB, Schedlowski M | title = Expectations and associations that heal: Immunomodulatory placebo effects and its neurobiology | journal = Brain, Behavior, and Immunity | volume = 20 | issue = 5 | pages = 430–46 | date = September 2006 | pmid = 16887325 | doi = 10.1016/j.bbi.2006.05.003 | s2cid = 11897104 }}</ref> and pain.<ref>{{cite journal | vauthors = Colloca L, Benedetti F | title = Placebos and painkillers: is mind as real as matter? | journal = Nature Reviews. Neuroscience | volume = 6 | issue = 7 | pages = 545–52 | date = July 2005 | pmid = 15995725 | doi = 10.1038/nrn1705 | s2cid = 9353193 }}</ref> Pacheco-López and colleagues have raised the possibility of "neocortical-sympathetic-immune axis providing neuroanatomical substrates that might explain the link between placebo/conditioned and placebo/expectation responses."<ref name="Pacheco"/>{{rp|441}} There has also been research aiming to understand underlying neurobiological mechanisms of action in pain relief, [[immunosuppression]], [[Parkinson's disease]] and [[Depression (mood)|depression]].<ref name=Neurobiology2005>{{cite journal | vauthors = Benedetti F, Mayberg HS, Wager TD, Stohler CS, Zubieta JK | title = Neurobiological mechanisms of the placebo effect | journal = The Journal of Neuroscience | volume = 25 | issue = 45 | pages = 10390–402 | date = November 2005 | pmid = 16280578 | doi = 10.1523/JNEUROSCI.3458-05.2005 | pmc = 6725834 }}</ref>

Dopaminergic pathways have been implicated in the placebo response in pain and depression.<ref>{{cite journal | vauthors = Murray D, Stoessl AJ | title = Mechanisms and therapeutic implications of the placebo effect in neurological and psychiatric conditions | journal = Pharmacology & Therapeutics | volume = 140 | issue = 3 | pages = 306–18 | date = December 2013 | pmid = 23880289 | doi = 10.1016/j.pharmthera.2013.07.009 }}</ref>

==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="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
* Response bias from subjects, including scaling bias, answers of politeness, experimental subordination, conditioned answers;
* [[Reporting bias]] from experimenters, including misjudgment and irrelevant response variables.
* Non-inert ingredients of the placebo medication having an unintended physical effect

==History==
{{main|Placebo in history}}
[[File:James Gillray, "Metallic Tractors", showing Elisha Perkins Wellcome M0010466.jpg|thumb|A quack treating a patient with ''[[Perkins tractors|Perkins Patent Tractors]]'' by [[James Gillray]], 1801. [[John Haygarth]] used this remedy to illustrate the power of the placebo effect.]]

The word placebo was used in a medicinal context in the late 18th century to describe a "commonplace method or medicine" and in 1811 it was defined as "any medicine adapted more to please than to benefit the patient." Although this definition contained a derogatory implication<ref name="Shapiro">{{cite journal |author=Shapiro AK |title=Semantics of the placebo |journal=Psychiatric Quarterly |volume=42 |issue=4 |pages=653–695 |year=1968 |pmid=4891851 |doi=10.1007/BF01564309 |s2cid=2733947 |doi-access=free }}</ref> it did not necessarily imply that the remedy had no effect.<ref name="Kaptchuk">{{cite journal |author=Kaptchuk TJ |title=Powerful placebo: the dark side of the randomised controlled trial |journal=The Lancet |volume=351 |issue=9117 |pages=1722–1725 |date=June 1998 |pmid=9734904 |doi=10.1016/S0140-6736(97)10111-8 |s2cid=34023318 }}</ref>

It was recognized in the 18th and 19th centuries that drugs or remedies often were perceived to work best while they were still novel:<ref>Arthur K. Shapiro, Elaine Shapiro, ''The Powerful Placebo: From Ancient Priest to Modern Physician'', 2006, {{ISBN|1421401347}}, chapter [https://books.google.com/books?id=ypA7PVahQkgC&pg=PT9 "The Placebo Effect in Medical History"]</ref>

{{Blockquote|We know that, in Paris, fashion imposes its dictates on medicine just as it does with everything else. Well, at one time, pyramidal elm bark<ref>the inner bark of [[Ulmus campestris]]: Simon Morelot, ''Cours élémentaire d'histoire naturelle pharmaceutique...'', 1800, [https://books.google.com/books?id=9JUT4F0xFaYC&pg=PA349 p. 349] "the elm, pompously named ''pyramidal''...it had an ephemeral reputation"; Georges Dujardin-Beaumetz, ''Formulaire pratique de thérapeutique et de pharmacologie'', 1893, [https://archive.org/details/bub_gb_L_6gFIvUKCcC/page/n706 p. 260]</ref> had a great reputation; it was taken as a powder, as an extract, as an elixir, even in baths. It was good for the nerves, the chest, the stomach—what can I say?— it was a true panacea. At the peak of the fad, one of Bouvard's {{sic}} patients asked him if it might not be a good idea to take some: "Take it, Madame", he replied, "and hurry up while it [still] cures." [dépêchez-vous pendant qu'elle guérit]
|author=[[Pierre Marc Gaston de Lévis, Duke of Lévis|Gaston de Lévis]] quoting [[Michel-Philippe Bouvart]] in the 1780s<ref name="levis">[[Pierre Marc Gaston de Lévis, Duke of Lévis|Gaston de Lévis]], ''Souvenirs et portraits, 1780–1789'', 1813, [https://books.google.com/books?id=bxXZmvs_15gC&pg=PA240 p. 240]</ref>
}}

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> 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/><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===
{{main|Placebo-controlled study}}

The placebo effect makes it more difficult to evaluate new treatments. Clinical trials control for this effect by including a group of subjects that receives a sham treatment. The subjects in such trials are blinded as to whether they receive the treatment or a placebo. If a person is given a placebo under one name, and they respond, they will respond in the same way on a later occasion to that placebo under that name but not if under another.<ref name="pmid18440407">{{cite journal | vauthors = Whalley B, Hyland ME, Kirsch I | title = Consistency of the placebo effect | journal = Journal of Psychosomatic Research | volume = 64 | issue = 5 | pages = 537–541 | date = May 2008 | pmid = 18440407 | doi = 10.1016/j.jpsychores.2007.11.007 }}</ref>

Clinical trials are often double-blinded so that the researchers also do not know which test subjects are receiving the active or placebo treatment. The placebo effect in such clinical trials is weaker than in normal therapy since the subjects are not sure whether the treatment they are receiving is active.<ref name="autogenerated2003">{{cite journal | vauthors = Vase L, Riley JL, Price DD | title = A comparison of placebo effects in clinical analgesic trials versus studies of placebo analgesia | journal = Pain | volume = 99 | issue = 3 | pages = 443–452 | date = October 2002 | pmid = 12406519 | doi = 10.1016/S0304-3959(02)00205-1 | s2cid = 21391210 }}</ref>

==Cultural influences==
Anthropologists argue that culture affects the ways in which individuals perceive medication, from different rituals and methods of healing, leading to placebo. Hahn and Kleinman (1983) propose an "ethnomedicogenic thesis" of placebo, wherein the ethnomedical system generates a feedback loop: cultural beliefs influence the disease state produced and effective treatments reinforce the belief system.<ref>Hahn, R. A., & Kleinman, A. (1983). Belief as Pathogen, Belief as Medicine: "Voodoo Death" and the "Placebo Phenomenon" in Anthropological Perspective. ''Medical Anthropology Quarterly'', ''14''(4), 3–19.</ref> 

"Symbolic effectiveness," a term coined by Claude Levi-Strauss relating to Shamanism, can result in a placebo effect as symbols displayed by the Shaman provide the patient with a form of "verbal expression" that can create a healing response within the patient.<ref>Apud, I., & Romaní, O. (2019). Medical anthropology and symbolic cure: from the placebo to cultures of meaningful healing. Anthropology & Medicine, 27(2), 160–175. https://doi-org.ezproxy-f.deakin.edu.au/10.1080/13648470.2019.1649542</ref> Apud and Romaní say that Shamans are a sort of psychoanalytical therapist, while many other cultural rituals and practices such as religion provide a psychological effect on the medical outcome of the patient, resulting in a placebo effect.<ref>Apud, I., & Romaní, O. (2019). Medical anthropology and symbolic cure: from the placebo to cultures of meaningful healing. Anthropology & Medicine, 27(2), 160–175. https://doi-org.ezproxy-f.deakin.edu.au/10.1080/13648470.2019.1649542</ref>

Hyland and Whalley conclude that carrying out a ritual, rather than believing in the ritual, may be an important factor in long-term placebo effects.<ref>Ostenfeld-Rosenthal, A. M. (2012). Energy healing and the placebo effect. An anthropological perspective on the placebo effect. Anthropology & Medicine, 19(3), 327–338. https://doi-org.ezproxy-f.deakin.edu.au/10.1080/13648470.2011.646943</ref> One anthropological perspective of rituals describe them as repetitive activities that intend to provide a sense of significance to one's life, giving them a sense that their bodily experience is in the hands of the world, out of their control as a result of patterns and rules, external to their own body.<ref>Brody, H. (2010). Ritual, medicine, and the placebo response. The problem of ritual efficacy, 151, 167.</ref> Rituals are an attempt to "control nature," meaning that they can heal which results in the individual experience of placebo.<ref>Brody, H. (2010). Ritual, medicine, and the placebo response. The problem of ritual efficacy, 151, 167.</ref>

==See also==
* {{section link|E. Morton Jellinek#Recognition of placebo effect}}
* [[List of effects]]
* [[List of topics characterized as pseudoscience]]
* [[Placebo button]]
* [[Self-fulfilling prophecy]]<ref>{{Cite book|last=Benedetti|first=Fabrizio|title=Placebo Effects|date=2008-10-16|publisher=Oxford University Press|doi=10.1093/acprof:oso/9780199559121.001.0001|isbn=978-0-19-955912-1}}</ref>

==References==
{{reflist}}
==Further reading==
* Benedetti, Fabrizio (2009). Placebo Effects. Oxford University Press. ISBN 978-0-19-920764-6.
* Benedetti, Fabrizio (2020). The Patient's Brain: The Neuroscience Behind the Doctor-Patient Relationship. Oxford University Press. {{ISBN|978-0-19-968071-5}}
* {{Cite book|title=Placebos |first=Kathryn T |last=Hall |publisher=The MIT Press |year=2022 |isbn=978-0-262-54425-2 }}

* {{Cite book|title=Neurobiology of the placebo effect. Part I|last=Colloca|first=Luana|isbn=978-0-12-814326-1|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=978-0-12-815417-5|edition=1st|location=Cambridge, MA, United States|oclc=1049800273}}
* Raz, Amir, and Campbell, Cory (2016). Placebo Talk: How Talking About Placebos Influences Their Effects. Oxford University Press. ISBN 978-0-19-968070-8.
* Raz, Amir (2023). The Suggestible Brain: Unraveling the Influence of Belief and Expectation on the Mind and Body. Cambridge University Press. ISBN 978-1-316-51497-6.
* {{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=978-1-4262-1789-0 |publisher=National Geographic}}
* [[Gavin Francis|Francis, Gavin]], "What Do You Expect?" (review of [[Kathryn T. Hall]], ''Placebos'', [[MIT Press]], 2022; 201 pp; and [[Jeremy Howick]], ''The Power of Placebos: How the Science of Placebos and Nocebose Can Improve Health Care'', [[Johns Hopkins University Press]], 2023; 304 pp.), ''[[The New York Review of Books]]'', vol. LXXII, no. 11 (26 June 2025), pp. 30–32. "[O]ur culture has become so medicalized and [[reductionism|reductionistic]] that warm and [[empathy|empathetic]] care, with its immense  proven benefits for the way that a patient feels and heals, has been deprioritized to an optional extra rather than a core element of medicine. A rebalancing is in order: doctors need more time with their patients and, yes, more use of honest placebos{{snd}}because they work." (p. 32.)

==External links==
* [http://programinplacebostudies.org/ Program in Placebo Studies & Therapeutic Encounter (PiPS)] ([[Beth Israel Deaconess Medical Center]] and [[Harvard Medical School]])

{{Wiktionary|placebo}}
{{Wikiquote|Placebo effect}}
{{Authority control}}

[[Category:Clinical research]]
[[Category:Deception]]
[[Category:Mind–body interventions]]