Amplified placebo effect

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 proposed and described by Kirsch and Moncrieff in the late 1990s.[2][32][36][51] However, discussion of the phenomenon by other researchers goes back as early as at least the 1970s and 1980s.[52][53]

See also

References

  1. ^ a b c d e f g h i j k l m n Kirsch I (2019). "Placebo Effect in the Treatment of Depression and Anxiety". Front Psychiatry. 10: 407. doi:10.3389/fpsyt.2019.00407. PMC 6584108. PMID 31249537.
  2. ^ a b c Prati R (January 2025). "Listening to placebos: the contested lessons of antidepressants debates". Hist Philos Life Sci. 47 (1): 3. doi:10.1007/s40656-024-00656-0. hdl:11336/273132. 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. ^ a b c d Moncrieff J (February 2018). "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. doi:10.1192/bjb.2017.11. PMC 6001865. PMID 29388527.
  4. ^ a b c d Moncrieff J (February 2007). "Are antidepressants as effective as claimed? No, they are not effective at all". Can J Psychiatry. 52 (2): 96–97, discussion 102. 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. ^ a b c Kirsch I (2014). "Antidepressants and the Placebo Effect". Z Psychol. 222 (3): 128–134. doi:10.1027/2151-2604/a000176. PMC 4172306. 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. ^ a b c d e f Huneke NT, Fusetto Veronesi G, Garner M, Baldwin DS, Cortese S (May 2025). "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. doi:10.1001/jamapsychiatry.2025.0085. PMID 40072447.
  7. ^ Moncrieff J, Cohen D, Porter S (2013). "The psychoactive effects of psychiatric medication: the elephant in the room". J Psychoactive Drugs. 45 (5): 409–415. doi:10.1080/02791072.2013.845328. PMC 4118946. 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.
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  32. ^ a b Kirsch, Irving; Sapirstein, Guy (1998). "Listening to Prozac but hearing placebo: A meta-analysis of antidepressant medication" (PDF). Prevention & Treatment. 1 (2). doi:10.1037/1522-3736.1.1.12a. ISSN 1522-3736. 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).
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  35. ^ Moncrieff J, Cooper RE, Stockmann T, Amendola S, Hengartner MP, Horowitz MA (August 2023). "The serotonin theory of depression: a systematic umbrella review of the evidence". Mol Psychiatry. 28 (8): 3243–3256. doi:10.1038/s41380-022-01661-0. PMC 10618090. 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. ^ a b 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. 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.
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  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. 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.
  52. ^ Thomson R (January 1982). "Side effects and placebo amplification". Br J Psychiatry. 140: 64–68. doi:10.1192/bjp.140.1.64. PMID 7037102. The side effects produced by most psychotropic drugs may play a part in producing or amplifying placebo response, especially in double blind evaluations where both subjects and investigators are to remain ignorant of who is actually receiving the experimental drug. Several workers have commented upon the fact that side effects may reveal to the experimenters who is on what, thus allowing bias to interfere with clinical rating of improvement (e.g. Nash, 1962; Stallone et al, 1975; Letemendia and Harris, 1959). [...] Dinnerstein and Halm (1970) talk of drugs as being possible placebo amplifiers, i.e. non specific physiological effects produced by the pharmacological action of the drugs may act as magnifiers of any placebo effect by convincing subjects that the drug has potency. [...] These results provide strong empirical support for the experimental hypothesis and suggest that side effects may act as a placebo amplifier, contributing some of the variance commonly attributed to the specific chemical effect of the drug. [...] The 'placebo amplification' phenomenon, where the physiological effects (such as side effects) produced by drugs convince subjects already influenced favourably by the pill-taking ritual that the drug has potency, seems to account for a considerable proportion of the supposed clinical value of antidepressants. [...] The present results support Dinnerstein and Halm's (1970) placebo amplification hypothesis.
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