Lessebo effect

The lessebo effect is a phenomenon in psychology and medicine in which a person in a blinded clinical trial knows that they might receive placebo due to the existence of a placebo control group in the trial and this results in the person experiencing diminished placebo effects (positive expectations) and therapeutic improvement. It has been described in several contexts including clinical trials of treatment for depression, schizophrenia, Parkinson's disease, and rheumatoid arthritis. The phenomenon was first named the "lessebo effect" by Mark Sinyor and colleagues in 2010. They showed in a meta-analysis that antidepressant and placebo response rates are influenced by the presence of a placebo arm and by the number of treatment arms (and thus likelihood of receiving placebo) in trials. A closely related but slightly distinct concept is the inverse placebo effect, which the lessebo effect has sometimes been inappropriately confused and conflated with.

See also

References

  1. 1 2 3 A Mestre T (2020). "Nocebo and lessebo effects". Int Rev Neurobiol. 153: 121–146. doi:10.1016/bs.irn.2020.04.005. PMID 32563285.
  2. 1 2 3 Sinyor M, Levitt AJ, Cheung AH, Schaffer A, Kiss A, Dowlati Y, Lanctôt KL (March 2010). "Does inclusion of a placebo arm influence response to active antidepressant treatment in randomized controlled trials? Results from pooled and meta-analyses". J Clin Psychiatry. 71 (3): 270–279. doi:10.4088/JCP.08r04516blu. PMID 20122371.
  3. ↑ Henkel V, Casaulta F, Seemüller F, Krähenbühl S, Obermeier M, Hüsler J, Möller HJ (December 2012). "Study design features affecting outcome in antidepressant trials". J Affect Disord. 141 (2–3): 160–167. doi:10.1016/j.jad.2012.03.021. PMID 22658811.
  4. ↑ Papakostas GI, Fava M (January 2009). "Does the probability of receiving placebo influence clinical trial outcome? A meta-regression of double-blind, randomized clinical trials in MDD". Eur Neuropsychopharmacol. 19 (1): 34–40. doi:10.1016/j.euroneuro.2008.08.009. PMID 18823760.
  5. ↑ Rutherford BR, Sneed JR, Roose SP (2009). "Does study design influence outcome?. The effects of placebo control and treatment duration in antidepressant trials". Psychother Psychosom. 78 (3): 172–181. doi:10.1159/000209348. PMC 3785090. PMID 19321970.
  6. ↑ Woods SW, Gueorguieva RV, Baker CB, Makuch RW (September 2005). "Control group bias in randomized atypical antipsychotic medication trials for schizophrenia". Arch Gen Psychiatry. 62 (9): 961–970. doi:10.1001/archpsyc.62.9.961. PMID 16143728.
  7. ↑ Mestre TA, Shah P, Marras C, Tomlinson G, Lang AE (April 2014). "Another face of placebo: the lessebo effect in Parkinson disease: meta-analyses". Neurology. 82 (16): 1402–1409. doi:10.1212/WNL.0000000000000340. PMC 4001195. PMID 24658930.
  8. ↑ Mestre TA, Lang AE, Okun MS (March 2016). "Factors influencing the outcome of deep brain stimulation: Placebo, nocebo, lessebo, and lesion effects". Mov Disord. 31 (3): 290–296. doi:10.1002/mds.26500. PMID 26952118.
  9. ↑ Mestre TA, McDermott MP, Lobo R, Ferreira JJ, Lang AE (July 2023). "The Lessebo Effect in Disease Modification Trials in Parkinson's Disease". Mov Disord. 38 (7): 1346–1350. doi:10.1002/mds.29414. PMID 37093589.
  10. ↑ Sung YK, Lee YH (January 2023). "The lessebo effect in randomized controlled trials of rituximab in patients with rheumatoid arthritis: a meta-analysis". Z Rheumatol. 82 (Suppl 1): 44–50. doi:10.1007/s00393-021-01126-9. PMID 34761312.
  11. ↑ Ansari M, Elliott SI, Holmes SE, Sanacora G (February 2026). "Placebo Effects in the Treatment of Depression-Implications for the Psychedelic Renaissance". Neurol Clin. 44 (1): 63–75. doi:10.1016/j.ncl.2025.08.009. PMID 41232997.
  12. ↑ Williams ZJ, Barnett H, Szigeti B (March 2026). "Psychedelic Therapy vs Antidepressants for the Treatment of Depression Under Equal Unblinding Conditions: A Systematic Review and Meta-Analysis". JAMA Psychiatry. doi:10.1001/jamapsychiatry.2025.4809. PMID 41848744.
  13. ↑ Hamzelou, Jessica (20 March 2026). "Mind-altering substances are (still) falling short in clinical trials". MIT Technology Review. Retrieved 20 March 2026.
  14. ↑ 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.
  15. ↑ Meshkat S, Lin Q, Sousa-Ho R, Demchenko I, Zeifman RJ, Fang H, Reichelt AC, Zhang Y, Burback L, Winkler O, Greenshaw A, Monson CM, Vermetten E, Jetly R, Lou W, Husain MI, Burke MJ, Bhat V (February 2026). "Magnitude of Response in Treatment and Control Groups within Psychedelic Trials for Psychiatric Disorders: A Meta-Analysis". Eur Psychiatry: 1–35. doi:10.1192/j.eurpsy.2026.10168. PMID 41705428. A further methodological consideration is that psychedelic trials may be especially susceptible to lessebo effects attenuated improvement when participants infer assignment to placebo or a sub-therapeutic condition, particularly in settings characterized by strong prior expectations and imperfec masking [48,49].