Editing Placebo (section)

==Effects==
{{redirect|Placebo effect}}
{{further|Alternative medicine#Perceived mechanism of effect}}

Placebo 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> 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, 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 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> 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 | last=Kern | first=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 | page=109866 | 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 | 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. 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 |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 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 | pages = 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>

===Psychedelics===
It has been proposed that psychedelics used for therapeutic purposes may act as [[active placebo|active]] "super placebos".<ref>{{Cite news |last=Borrell |first=Brendan |date=2024-03-21 |title=The Psychedelic Evangelist |url=https://www.nytimes.com/2024/03/21/health/psychedelics-roland-griffiths-johns-hopkins.html |access-date=2025-02-11 |work=The New York Times |language=en-US |issn=0362-4331}}</ref><ref name="DupuisVeissière2022">{{cite journal | vauthors = Dupuis D, Veissière S | title = Culture, context, and ethics in the therapeutic use of hallucinogens: Psychedelics as active super-placebos? | journal = Transcult Psychiatry | volume = 59 | issue = 5 | pages = 571–578 | date = October 2022 | pmid = 36263513 | doi = 10.1177/13634615221131465 | url = }}</ref><ref name="vanElkYaden2022">{{cite journal | vauthors = van Elk M, Yaden DB | title = Pharmacological, neural, and psychological mechanisms underlying psychedelics: A critical review | journal = Neurosci Biobehav Rev | volume = 140 | issue = | pages = 104793 | date = September 2022 | pmid = 35878791 | doi = 10.1016/j.neubiorev.2022.104793 | url = | quote = In addition, the strong prior expectations that many people have about psychedelics directly contribute to the psychedelic experience and as a consequence it has been suggested that psychedelics may act as a ‘super-placebo’ (Hartogsohn, 2016). Specifically, strong prior expectations (e.g., that a specific intervention will likely trigger a mystical experience) will increase the likelihood of having e.g., a mystical-type experience (Maij et al., 2019), and this placebo-effect is further boosted by the psychedelic-induced suggestibility. | hdl = 1887/3515020 | hdl-access = free }}</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>