Medicine:Amplified placebo effect

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The amplified placebo effect, also known as the enhanced placebo effect, is a phenomenon in psychology and medicine in which a person in a blinded clinical trial suspects that they have received the active drug due to functional unblinding and this results in the person experiencing amplified placebo effects.[1][2][3][4][5] The unblinding resulting in the effect is caused by subtle psychoactive effects and side effects of the active drug.[1][4][6][7] The amplified placebo effect is especially relevant and discussed in the context of psychiatric drug trials.[1][2][3][4][5][6]

There are large placebo responses and effects in clinical trials of psychiatric drugs such as antidepressants and anxiolytics.[1][8][6] For example, antidepressants typically improve depressive symptoms by about 10 points on a depression rating scale, whereas placebos improve symptoms by about 8 points on the scale, with about a 2-point advantage for antidepressant over placebo and at least 80% of the treatment benefit being fully attributable to the placebo response.[1][9][8][10][11] Hence, most of the improvement in depressive symptoms with antidepressants is due to the placebo response, and the benefit potentially attributable to drug effects, though statistically significant, is modest, and in fact below accepted thresholds for clinical significance.[1][9][12][13][14][15] These findings are based on comprehensive meta-analyses and have been repeatedly replicated over time.[1][9][8][16][15][17][18] The placebo response consists of the placebo effect (i.e., positive expectations) and of other components such as regression to the mean, spontaneous remission, and methodological bias, whereas the drug response is a combination of the drug effect and the placebo response, with the difference between the drug response and the placebo response typically assumed to represent the drug effect.[1][19][6]

A person's belief about whether they are taking an active drug or placebo has been shown to have a substantial impact on their therapeutic outcome, with stronger positive expectations resulting in greater therapeutic improvement.[1][20][6][21] For example, in a trial of escitalopram for social anxiety disorder, all patients were given the drug, but half were truthfully told that they were receiving the drug ("overt" group) and half were deceptively told that they were receiving an active placebo ("covert" group).[22][1][23][24] The "overt" group experienced twice as much improvement in anxiety symptoms as the "covert" group in this trial (Cohen's d = 2.24 versus 1.13, respectively).[22][1][23][24] In addition, this study design showed neurobiological differences between groups putatively underlying the differing therapeutic outcomes, such as differences in amygdala activity and the dopaminergic system.[23][24][25] Relatedly, placebos are not inert, but produce real biological changes and associated therapeutic improvement.[22][26]

Due to unblinding caused by drug effects like subtle psychoactive effects and side effects, many patients and clinicians are able to correctly guess whether the patient received the active drug or placebo in antidepressant trials.[1][27][28][29] In addition, better blinding integrity reduces differences in improvement between active drug and placebo, while blinding failure results in larger differences in improvement between active drug and placebo, although more research is needed in this area.[28][6][1][30] Similarly, side effects have been found to be related to greater differences in improvement between active drug and placebo, though mixed findings exist as well.[1][31][32][33] Along these lines, trials of antidepressants with active-placebo instead of inert-placebo control groups show substantially reduced drug advantage over placebo that is no longer statistically significant.[31][12][34]

It has been proposed and maintained by some academics, including Irving Kirsch, Joanna Moncrieff, and Michael P. Hengartner, that the amplified placebo effect can easily account for the small advantage of antidepressants over placebo in clinical trials, and hence that antidepressants exert their benefits in the treatment of depression entirely via placebo mechanisms rather than via drug effects.[5][4][3][9][35][10][12] Put another way, antidepressants themselves could be said to effectively be "active placebos".[20][36] However, Moncrieff has proposed that antidepressants may also cause an emotional blunting phenomenon that can reduce both positive and negative affect and thereby be additionally useful in improving certain symptoms in some people.[3][37] Regardless of whether antidepressants work entirely via placebo mechanisms or not, they do still appear to provide genuine therapeutic benefits with large effect sizes in people with depression or anxiety when the placebo response component of improvement is included.[38][10][39][40][41][42]

It has been proposed that psychedelic drugs used for therapeutic purposes such as treatment of depression may act as active "super placebos"[43][44] and may have greater therapeutic benefits than conventional antidepressants.[45][38] However, due to issues like the inverse placebo effect caused by unblinding, psychedelics may actually be no more effective than traditional antidepressants.[45][38][46][47][48] Owing to concerns about potential adverse effects and other problems, Moncrieff has critiqued use of psychedelics for treatment of psychiatric disorders.[49][50]

The amplified placebo effect was first proposed and described by Kirsch and Moncrieff in the late 1990s.[2][32][36][51]

See also

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 "Placebo Effect in the Treatment of Depression and Anxiety". Front Psychiatry 10: 407. 2019. doi:10.3389/fpsyt.2019.00407. PMID 31249537. 
  2. ↑ 2.0 2.1 2.2 "Listening to placebos: the contested lessons of antidepressants debates". Hist Philos Life Sci 47 (1): 3. January 2025. doi:10.1007/s40656-024-00656-0. PMID 39786698. "In "Listening to Prozac but hearing placebo", Irving Kirsch and Guy Sapirstein argued, on the basis of a meta-analysis of 19 clinical trials and approximately two thousand patients, that antidepressant medications were only marginally superior to placebos, with an effect size of only 0.39 (1998). This finding, in their view, suggested that the efficacy of antidepressants could be due to an enhanced placebo effect – that is, that the 'wonder drugs' were no more than active placebos, pills that, while lacking any kind of specific pharmacological efficacy for the treated condition, do produce physiological side effects that stimulate the placebo effect.". 
  3. ↑ 3.0 3.1 3.2 3.3 "Against the stream: Antidepressants are not antidepressants - an alternative approach to drug action and implications for the use of antidepressants". BJPsych Bull 42 (1): 42–44. February 2018. doi:10.1192/bjb.2017.11. PMID 29388527. 
  4. ↑ 4.0 4.1 4.2 4.3 "Are antidepressants as effective as claimed? No, they are not effective at all". Can J Psychiatry 52 (2): 96–97; discussion 102. February 2007. doi:10.1177/070674370705200204. PMID 17375864. "[...] antidepressants are active drugs and, as such, produce a range of physiological effects when ingested. These effects may indicate to assessors or trial participants whether they are taking the antidepressant or the placebo; thus, the double-blind design is often penetrated in trials of antidepressants and other psychotropic agents. This is especially likely to happen in contemporary trials in which subjects are forewarned in detail about the randomized design, the use of placebo, and the nature of likely side effects. Patients on antidepressants may therefore experience an amplified placebo effect as a consequence of suspecting that they are taking the active drug. Similarly, raters may inflate ratings for individuals they suspect to be taking the active drugs on the basis of reported side effects. [...] Therefore, the clinical significance of small differences in rating scale scores in RCTs comparing antidepressants with placebo is unclear. These differences could easily be accounted for by nonspecific pharmacologic effects, such as sedation, or by amplified placebo effects.". 
  5. ↑ 5.0 5.1 5.2 "Antidepressants and the Placebo Effect". Z Psychol 222 (3): 128–134. 2014. doi:10.1027/2151-2604/a000176. PMID 25279271. "[...] analyses of the published data and the unpublished data [...] reveals that most (if not all) of the benefits [of antidepressants] are due to the placebo effect. [...] Even the small statistical difference between antidepressants and placebos may be an enhanced placebo effect, due to the fact that most patients and doctors in clinical trials successfully break blind.". 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 "Expectancy Effects, Failure of Blinding Integrity, and Placebo Response in Trials of Treatments for Psychiatric Disorders: A Narrative Review". JAMA Psychiatry 82 (5): 531–538. May 2025. doi:10.1001/jamapsychiatry.2025.0085. PMID 40072447. 
  7. ↑ "The psychoactive effects of psychiatric medication: the elephant in the room". J Psychoactive Drugs 45 (5): 409–415. 2013. doi:10.1080/02791072.2013.845328. PMID 24592667. ""Amplified" placebo effects may also contribute to drug-placebo differences in randomized controlled trials (Moncrieff, Wessley & Hardy 1998). Apart from their direct action on symptoms, psychoactive and physical effects may reveal to researchers and participants in placebo-controlled trials who is receiving active medication and who is not, causing the placebo effect of medication to be amplified and to exceed that produced by inert placebo tablets. Placebo-controlled studies cannot therefore in principle establish whether a drug works, if it does, by reversing an underlying pathological process or by inducing an altered mental and physical state which may directly affect manifestations of the disorder or subvert the double-blind design of clinical trials.". 
  8. ↑ 8.0 8.1 8.2 "False Beliefs in Academic Psychiatry: The Case of Antidepressant Drugs". Ethical Human Psychology and Psychiatry 20 (1): 6–16. July 2018. doi:10.1891/1559-4343.20.1.6. ISSN 1559-4343. 
  9. ↑ 9.0 9.1 9.2 9.3 "The Emperor's New Drugs: Medication and Placebo in the Treatment of Depression". Placebo. Handbook of Experimental Pharmacology. 225. Springer Berlin Heidelberg. 2014. pp. 291–303. doi:10.1007/978-3-662-44519-8_16. ISBN 978-3-662-44518-1. 
  10. ↑ 10.0 10.1 10.2 Rief, Winfried; Kelley, John M.; Nestoriuc, Yvonne (2023). "Placebo and nocebo effects in depression: Implications for treatment and clinical trial designs". Placebo Effects Through the Lens of Translational Research. Oxford University PressNew York. p. 215–228. doi:10.1093/med/9780197645444.003.0016. ISBN 978-0-19-764544-4. https://academic.oup.com/book/54240/chapter/422452817. Retrieved 21 March 2026. 
  11. ↑ "A narrative review of the placebo effect: historical roots, current applications, and emerging insights". Eur J Clin Pharmacol 81 (5): 625–645. May 2025. doi:10.1007/s00228-025-03818-6. PMID 40080139. "A meta-analysis found significant variability in placebo symptom improvement, with the greatest response observed in depression, followed by anxiety, and the least in obsessive–compulsive disorder. Approximately 80% of the symptom improvement seen with antidepressants in clinical trials also occurs in the placebo group [145].". 
  12. ↑ 12.0 12.1 12.2 "Statistically Significant Antidepressant-Placebo Differences on Subjective Symptom-Rating Scales Do Not Prove That the Drugs Work: Effect Size and Method Bias Matter!". Front Psychiatry 9: 517. 2018. doi:10.3389/fpsyt.2018.00517. PMID 30386270. 
  13. ↑ "Empirically derived criteria cast doubt on the clinical significance of antidepressant-placebo differences". Contemp Clin Trials 43: 60–2. July 2015. doi:10.1016/j.cct.2015.05.005. PMID 25979317. 
  14. ↑ "Estimates of the minimal important difference to evaluate the clinical significance of antidepressants in the acute treatment of moderate-to-severe depression". BMJ Evid Based Med 27 (2): 69–73. April 2022. doi:10.1136/bmjebm-2020-111600. PMID 33593736. 
  15. ↑ 15.0 15.1 "Efficacy of new-generation antidepressants assessed with the Montgomery-Asberg Depression Rating Scale, the gold standard clinician rating scale: A meta-analysis of randomised placebo-controlled trials". PLOS ONE 15 (2). 2020. doi:10.1371/journal.pone.0229381. PMID 32101579. Bibcode: 2020PLoSO..1529381H. 
  16. ↑ "Considering the methodological limitations in the evidence base of antidepressants for depression: a reanalysis of a network meta-analysis". BMJ Open 9 (6). June 2019. doi:10.1136/bmjopen-2018-024886. PMID 31248914. 
  17. ↑ "Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis". Lancet 391 (10128): 1357–1366. April 2018. doi:10.1016/S0140-6736(17)32802-7. PMID 29477251. 
  18. ↑ "Response to acute monotherapy for major depressive disorder in randomized, placebo controlled trials submitted to the US Food and Drug Administration: individual participant data analysis". The BMJ 378. August 2022. doi:10.1136/bmj-2021-067606. PMID 35918097. 
  19. ↑ "Antidepressants and the placebo response". Epidemiol Psichiatr Soc 18 (4): 318–322. 2009. doi:10.1017/s1121189x00000282. PMID 20170046. 
  20. ↑ 20.0 20.1 "Depression: why drugs and electricity are not the answer". Psychol Med 52 (8): 1401–1410. June 2022. doi:10.1017/S0033291721005031. PMID 35100527. 
  21. ↑ "A model of placebo response in antidepressant clinical trials". Am J Psychiatry 170 (7): 723–733. July 2013. doi:10.1176/appi.ajp.2012.12040474. PMID 23318413. 
  22. ↑ 22.0 22.1 22.2 "Why we need more research into the placebo response in psychiatry". Psychol Med 50 (14): 2317–2323. October 2020. doi:10.1017/S0033291720003633. PMID 33028433. "This has also recently been demonstrated to be the case in social anxiety disorder. Patients openly given escitalopram improved with an effect size twice that of patients who received escitalopram but were told it was an 'active placebo' (d = 2.24 v. d = 1.13, respectively) (Faria et al., 2017).". 
  23. ↑ 23.0 23.1 23.2 "Revisiting the SSRI vs. placebo debate in the treatment of social anxiety disorder: the role of expectancy effects, neural responsivity, and monoamine transporters". Front Psychol 16. 2025. doi:10.3389/fpsyg.2025.1531725. PMID 40420982. 
  24. ↑ 24.0 24.1 24.2 "Do You Believe It? Verbal Suggestions Influence the Clinical and Neural Effects of Escitalopram in Social Anxiety Disorder: A Randomized Trial". EBioMedicine 24: 179–188. October 2017. doi:10.1016/j.ebiom.2017.09.031. PMID 29033138. 
  25. ↑ "Expectancy effects on serotonin and dopamine transporters during SSRI treatment of social anxiety disorder: a randomized clinical trial". Transl Psychiatry 11 (1): 559. November 2021. doi:10.1038/s41398-021-01682-3. PMID 34732695. 
  26. ↑ "Functional Neuroimaging Correlates of Placebo Response in Patients With Depressive or Anxiety Disorders: A Systematic Review". Int J Neuropsychopharmacol 25 (6): 433–447. June 2022. doi:10.1093/ijnp/pyac009. PMID 35078210. 
  27. ↑ "A systematic review and meta-analysis of the success of blinding in antidepressant RCTs". Psychiatry Res 307. January 2022. doi:10.1016/j.psychres.2021.114297. PMID 34861421. 
  28. ↑ 28.0 28.1 "The relationship between blinding integrity and medication efficacy in randomised-controlled trials in patients with anxiety disorders: A systematic review and meta-analysis". Acta Psychiatr Scand 150 (4): 187–197. October 2024. doi:10.1111/acps.13741. PMID 39126319. 
  29. ↑ "How blind is blind? Assessment of patient and doctor medication guesses in a placebo-controlled trial of imipramine and phenelzine". Psychiatry Res 19 (1): 75–86. September 1986. doi:10.1016/0165-1781(86)90094-6. PMID 3538107. 
  30. ↑ "Systematic review of blinding assessment in randomized controlled trials in schizophrenia and affective disorders 2000-2010". Psychother Psychosom 82 (3): 152–160. 2013. doi:10.1159/000346144. PMID 23548796. 
  31. ↑ 31.0 31.1 "Lessons learned from placebo groups in antidepressant trials". Philos Trans R Soc Lond B Biol Sci 366 (1572): 1879–1888. June 2011. doi:10.1098/rstb.2010.0394. PMID 21576145. 
  32. ↑ 32.0 32.1 Kirsch, Irving; Sapirstein, Guy (1998). "Listening to Prozac but hearing placebo: A meta-analysis of antidepressant medication.". Prevention & Treatment 1 (2). doi:10.1037/1522-3736.1.1.12a. ISSN 1522-3736. https://psychrights.org/research/digest/CriticalThinkRxCites/KirschandSapirstein1998.pdf. "Experiencing more side effects, patients in active drug conditions conclude that they are in the drug group; experiencing fewer side effects, patients in placebo groups conclude that they are in the placebo condition. This can be expected to produce an enhanced placebo effect in drug conditions and a diminished placebo effect in placebo groups. Thus, the apparent drug effect of antidepressants may in fact be a placebo effect, magnified by differences in experienced side effects and the patient's subsequent recognition of the condition to which he or she has been assigned. Support for this interpretation of data is provided by a meta-analysis of fluoxetine (Prozac), in which a correlation of .85 was reported between the therapeutic effect of the drug and the percentage of patients reporting side effects (Greenberg, Bornstein, Zborowski, Fisher, & Greenberg, 1994).". 
  33. ↑ "How side effects can improve treatment efficacy: a randomized trial". Brain 147 (8): 2643–2651. August 2024. doi:10.1093/brain/awae132. PMID 38701224. 
  34. ↑ "Active placebos versus antidepressants for depression". Cochrane Database Syst Rev 2004 (1). 2004. doi:10.1002/14651858.CD003012.pub2. PMID 14974002. 
  35. ↑ "The serotonin theory of depression: a systematic umbrella review of the evidence". Mol Psychiatry 28 (8): 3243–3256. August 2023. doi:10.1038/s41380-022-01661-0. PMID 35854107. "It is often assumed that the effects of antidepressants demonstrate that depression must be at least partially caused by a brain-based chemical abnormality, and that the apparent efficacy of SSRIs shows that serotonin is implicated. Other explanations for the effects of antidepressants have been put forward, however, including the idea that they work via an amplified placebo effect or through their ability to restrict or blunt emotions in general [19, 20].". 
  36. ↑ 36.0 36.1 Kirsch, Irving; Sapirstein, Guy (1999). "Listening to Prozac but hearing placebo: A meta-analysis of antidepressant medications.". How expectancies shape experience.. Washington: American Psychological Association. p. 303–320. doi:10.1037/10332-012. ISBN 978-1-55798-586-6. https://content.apa.org/books/10332-012. Retrieved 22 March 2026. "Results show a substantial placebo effect in antidepressant medication and also a considerable benefit of medication over placebo. They also indicate that the placebo component of the response to medication is considerably greater than the pharmacological effect. Findings further suggest that antidepressants might function as active placebos, in which the side effects amplify the placebo effect by convincing patients that they are receiving a potent drug. [...] Experiencing more side effects, patients in active drug conditions conclude that they are in the drug group; experiencing fewer side effects, patients in placebo groups conclude that they are in the placebo condition. This can be expected to produce an enhanced placebo effect in drug conditions and a diminished placebo effect in placebo groups. Thus, the apparent drug effect of antidepressants may in fact be a placebo effect, magnified by differences in experienced side effects and the patient's subsequent recognition of the condition to which he or she has been assigned." 
  37. ↑ "The psychoactive effects of antidepressants and their association with suicidality". Curr Drug Saf 6 (2): 115–121. April 2011. doi:10.2174/157488611795684622. PMID 21375477. 
  38. ↑ 38.0 38.1 38.2 "Placebo Effects in the Treatment of Depression-Implications for the Psychedelic Renaissance". Neurol Clin 44 (1): 63–75. February 2026. doi:10.1016/j.ncl.2025.08.009. PMID 41232997. "Large-scale clinical trials have demonstrated that antidepressants have statistically significant and clinically meaningful efficacy in improving depressive symptoms, and have undoubtedly provided lifesaving benefits to many over the decades.3 However, it is well known that a substantial portion of the observed response in clinical trials (and likely in clinical practice) can be attributed to contextual effects, not directly related to the pharmacologic effects of the treatment. Placebo response rates frequently reach 30% to 40% in clinical trials of antidepressants, compared to typical 50% response rates in the active treatment arms.4,5 Indeed, it is thought that over 80% of the mean improvement in depression rating scales observed in clinical trials with standard oral antidepressant medications can be accounted for by contextual, nonpharmacological factors. [...]". 
  39. ↑ "Meta-Analysis of Placebo Response in Adult Antidepressant Trials". CNS Drugs 33 (10): 971–980. October 2019. doi:10.1007/s40263-019-00662-y. PMID 31573058. 
  40. ↑ "Comparative efficacy of placebos in short-term antidepressant trials for major depression: a secondary meta-analysis of placebo-controlled trials". BMC Psychiatry 20 (1): 437. September 2020. doi:10.1186/s12888-020-02839-y. PMID 32894088. 
  41. ↑ "Meta-analysis of the placebo response in antidepressant trials". J Affect Disord 118 (1-3): 1–8. November 2009. doi:10.1016/j.jad.2009.01.029. PMID 19246102. 
  42. ↑ "Magnitude of the Placebo Response Across Treatment Modalities Used for Treatment-Resistant Depression in Adults: A Systematic Review and Meta-analysis". JAMA Netw Open 4 (9): e2125531. September 2021. doi:10.1001/jamanetworkopen.2021.25531. PMID 34559231. 
  43. ↑ "Culture, context, and ethics in the therapeutic use of hallucinogens: Psychedelics as active super-placebos?". Transcult Psychiatry 59 (5): 571–578. October 2022. doi:10.1177/13634615221131465. PMID 36263513. 
  44. ↑ "Pharmacological, neural, and psychological mechanisms underlying psychedelics: A critical review". Neurosci Biobehav Rev 140. September 2022. doi:10.1016/j.neubiorev.2022.104793. PMID 35878791. "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.". 
  45. ↑ 45.0 45.1 "Psychedelic Therapy vs Antidepressants for the Treatment of Depression Under Equal Unblinding Conditions: A Systematic Review and Meta-Analysis". JAMA Psychiatry. March 2026. doi:10.1001/jamapsychiatry.2025.4809. PMID 41848744. 
  46. ↑ "Control Group Outcomes in Trials of Psilocybin, SSRIs, or Esketamine for Depression: A Meta-Analysis". JAMA Netw Open 8 (7): e2524119. July 2025. doi:10.1001/jamanetworkopen.2025.24119. PMID 40736734. 
  47. ↑ Hamzelou, Jessica (20 March 2026). "Mind-altering substances are (still) falling short in clinical trials". https://www.technologyreview.com/2026/03/20/1134419/psychedelics-overhyped-psilocybin-depression-placebo/. 
  48. ↑ Busby, Mattha (18 March 2026). "Psychedelics may be no better than antidepressants for depression". https://www.newscientist.com/article/2519824-psychedelics-may-be-no-better-than-antidepressants-for-depression/. 
  49. ↑ Moncrieff, Joanna (16 January 2025). "Alternative Approaches: The Good, the Bad and the Worrying: Psychedelics for Depression". Chemically Imbalanced: The Making and Unmaking of the Serotonin Myth. Flint. ISBN 978-1-80399-680-6. https://books.google.com/books?id=e0MkEQAAQBAJ. Retrieved 16 October 2025. 
  50. ↑ Joanna Moncrieff (2 September 2021). "Psychedelics – The New Psychiatric Craze!". https://joannamoncrieff.com/2021/09/02/psychedelics-the-new-psychiatric-craze/. 
  51. ↑ Drummond, D. Colin; Moncrieff, Joanna (1997). "The continuing search for the "elixir of temperance"". Addiction 92 (8): 961–964. doi:10.1111/j.1360-0443.1997.tb02974.x. ISSN 0965-2140. https://onlinelibrary.wiley.com/doi/10.1111/j.1360-0443.1997.tb02974.x. Retrieved 22 March 2026. "We would also emphasize that unblinding may affect patients as well as assessors, whose apparent response to the drug may then represent an enhanced placebo response to taking a physiologically active substance. The use of active placebos should therefore be considered, and suitable agents should be identified.". 



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