Medicine:Inverse placebo effect

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Not to be confused with Nocebo.

The inverse placebo effect, also known as the "knowcebo" effect (or "know-cebo" effect) or suppressed placebo effect, is a phenomenon in psychology and medicine in which a person in a blinded clinical trial knows that they have received placebo due to functional unblinding problems and this results in the person experiencing diminished placebo effects.[1][2][3][4] The effect is especially relevant in trials of strongly psychoactive drugs such as psychedelics.[1][2][3]

There are large placebo responses and effects in clinical trials of psychiatric drugs such as antidepressants and anxiolytics.[3][5][6][1] For example, traditional 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 attributable to the placebo response.[3][5][6][1] 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.[5][1]

The inverse placebo effect is known to occur prominently in clinical trials of treatments that have overt psychoactive effects and are impossible to blind such as psychedelic drugs like psilocybin, other hallucinogens like ketamine, and entactogens like MDMA.[3][1][2] In these kinds of contexts, it is usually very obvious to a person when they receive a placebo instead of the drug due to the lack of expected psychological changes, and this results in disappointment and a diminished placebo response.[3][1][2] Whereas placebos in traditional antidepressant trials reduce depressive symptoms typically by around 8 points, they have been found to reduce symptoms by around 4 points in psychedelic drug trials, a decrease and hence diminished improvement of approximately 50% attributable to the inverse placebo effect.[3][2][7][8] In general, functional unblinding, for instance due to often obvious side effects, is known to amplify differences in improvement between active drugs and placebos, including in the case of traditional antidepressants.[1][5][9][10]

The inverse placebo effect can result in inflated effect sizes in terms of differences in improvement between active drug and placebo and can thereby distort clinical trial findings.[3][1][2][8] Psychedelic drugs may improve depressive symptoms typically by around 10 to 12 points in clinical trials, similar to the improvement with traditional antidepressants.[3][2] Due to the inverse placebo effect and blunted placebo-group improvement however, the difference in improvement between the psychedelic drug and placebo can be much greater than with a traditional antidepressant (e.g., 6–7 points instead of 2 points).[3][11][1][2][8] This in turn results in an illusion of unusually large effect sizes.[3][1][2][8] It has been found that the inverse placebo effect or placebo suppression accounts for approximately 55% of the difference in improvement between psychedelics and placebo.[2]

When psychedelics have instead been indirectly compared to open-label traditional antidepressants rather than to placebos and hence there are equal unblinding conditions, it has been found that there is no difference in effectiveness between psychedelics and traditional antidepressants.[3][11][2] Similarly, in a direct head-to-head trial with no placebo group, psilocybin was no more effective than the selective serotonin reuptake inhibitor (SSRI) and traditional antidepressant escitalopram (Lexapro) for treating depression.[11][2][12][13] Due to their strong psychoactive effects and unblinding, psychedelics themselves have been found to effectively always be open-label (~90–95% correct treatment-allocation guess rate).[2]

Concerns about functional unblinding and consequent amplified placebo and inverse placebo effects prominently contributed to the rejection of the MDMA for the treatment of post-traumatic stress disorder (PTSD) by the Food and Drug Administration (FDA) in the United States in 2024.[1][2][14][15][16][17][18] On the other hand, the FDA approved esketamine (Spravato) for treatment-resistant depression in 2019 despite significant albeit less marked problems with unblinding and potential amplified placebo effects as well.[17][19][20][21][8]

See also

  • Lessebo effect
  • Amplified placebo effect

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 "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. 
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 "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. 
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 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/. "But with psychedelics, the difference between active drug and placebo is much greater. That's partly because people who get the psychedelic drug know they're getting it and are expecting the drug to improve their symptoms, [...] But it's also partly because of the effect on those who know they're not getting it. It's pretty obvious when you're getting a placebo, says Szigeti, and it can be disappointing. Scientists have long recognized the "nocebo" effect as placebo's "evil twin"—essentially, when you expect to feel worse, you will. The disappointment of getting a placebo is slightly different, and Szigeti calls it the "knowcebo effect." "It's kind of like a negative psychedelic effect, because you have figured out that you're taking the placebo," he says. This phenomenon can distort the results of psychedelic drug trials. While a placebo in a traditional antidepressant drug trial improves symptoms by eight points, placebos in psychedelic trials improve symptoms by a mere four points, says Szigeti. If the active drug similarly improves symptoms by around 10 points, that makes it look as though the psychedelic is improving symptoms by around six points compared with a placebo. It "gives the illusion" of a huge effect, says Szigeti." 
  4. ↑ Leader, John Francis (2009). The 'knowcebo' effect; an investigation into the relationship between knowledge, anticipation and the placebo effect (Thesis). Retrieved 20 March 2026.
  5. ↑ 5.0 5.1 5.2 5.3 "Placebo Effect in the Treatment of Depression and Anxiety". Front Psychiatry 10: 407. 2019. doi:10.3389/fpsyt.2019.00407. PMID 31249537. 
  6. ↑ 6.0 6.1 "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. 
  7. ↑ "Comparative oral monotherapy of psilocybin, lysergic acid diethylamide, 3,4-methylenedioxymethamphetamine, ayahuasca, and escitalopram for depressive symptoms: systematic review and Bayesian network meta-analysis". BMJ 386. August 2024. doi:10.1136/bmj-2023-078607. PMID 39168500. 
  8. ↑ 8.0 8.1 8.2 8.3 8.4 "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. 
  9. ↑ "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. 
  10. ↑ "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. 
  11. ↑ 11.0 11.1 11.2 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/. 
  12. ↑ "Current Understanding on Psilocybin for Major Depressive Disorder: A Review Focusing on Clinical Trials". Clin Psychopharmacol Neurosci 22 (2): 222–231. May 2024. doi:10.9758/cpn.23.1134. PMID 38627070. 
  13. ↑ "Trial of Psilocybin versus Escitalopram for Depression". New England Journal of Medicine 384 (15): 1402–1411. April 2021. doi:10.1056/NEJMoa2032994. PMID 33852780. 
  14. ↑ "State of the Science: MDMA-assisted psychotherapy for the treatment of posttraumatic stress disorder". J Trauma Stress. March 2026. doi:10.1002/jts.70060. PMID 41820235. 
  15. ↑ "MDMA-Assisted Therapy for Post-Traumatic Stress Disorder: Regulatory Challenges and a Path Forward". CNS Drugs 39 (4): 339–343. April 2025. doi:10.1007/s40263-025-01162-y. PMID 39955464. 
  16. ↑ "Psychedelic medicine: mechanisms, evidence, and translation to practice". BMJ 392. February 2026. doi:10.1136/bmj-2024-081723. PMID 41730563. 
  17. ↑ 17.0 17.1 "Issues in Clinical Trial Design-Lessons From the FDA's Rejection of MDMA". JAMA Psychiatry 82 (6): 545–546. June 2025. doi:10.1001/jamapsychiatry.2025.0442. PMID 40238126. 
  18. ↑ "Too big to fail? Comparing effect sizes of MDMA assisted therapy to unmasking bias". Psychopharmacology (Berl). September 2025. doi:10.1007/s00213-025-06886-9. PMID 40906191. 
  19. ↑ "Are we repeating mistakes of the past? A review of the evidence for esketamine". Br J Psychiatry 219 (5): 614–617. May 2020. doi:10.1192/bjp.2020.89. PMID 32456714. 
  20. ↑ "Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation". Am J Psychiatry 178 (5): 383–399. May 2021. doi:10.1176/appi.ajp.2020.20081251. PMID 33726522. 
  21. ↑ "The role of dissociation in ketamine's antidepressant effects". Nat Commun 11 (1): 6431. December 2020. doi:10.1038/s41467-020-20190-4. PMID 33353946. Bibcode: 2020NatCo..11.6431B. 



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