Abstract
The clinical role of the placebo effect is a topic of increasing interest for the scientific community. Focus is shifting from the inert role of placebos in randomized controlled trials (RCTs) to potential effects in clinical applications, since the phenomenon is thought to be inherent in routine clinical practice, affecting therapy success rates. Mediation of the mind-brain-body relationship involves both psychosocial and neurobiological factors, the interaction of which comprises the placebo mechanisms. Psychosocial factors include environmentally induced expectations, reward expectations, and even conditioned responses to certain stimuli. Expectations also depend on previous experience of the patient with a similar procedure and can affect future responses. Moreover, the supportive bedside behavior of the clinician and the positive framing of information provided to the patient have proven to be of great importance, setting the foundations for reconsideration of standardized practices. Neurobiological mechanisms mediate these effects through neurotransmitter and neuromodulator pathways. The best understood mechanisms are those regulating non-opioid- and opioid-mediated analgesic responses that implicate specific brain regions of pain control and activation of endogenous opioids. Other responses concern, among others, hormonal control, motor performance, and antidepressant responses. Although mechanisms underlying placebo responses are not as yet completely elucidated, there is substantial evidence suggesting that placebo effects are indicative of healthy functioning of intact brain structures and occur through actual functional changes, and are not simply subjective symptom reports. These effects can be utilized in treatment optimization while maintaining an ethical and respectful manner toward the patient and the standardized disclosure procedures.
Similar content being viewed by others
References
Price DD, Finniss DG, Benedetti F (2008) A comprehensive review of the placebo effect: recent advances and current thought. Annu Rev Psychol 59:565–590
Carlino E, Piedimonte A, Benedetti F (2016) Nature of the placebo and nocebo effect in relation to functional neurologic disorders. Handb Clin Neurol 139:597–606
Colloca L, Benedetti F (2005) Placebos and painkillers: is mind as real as matter? Nat Rev Neurosci 6:545–552
Vase L, Riley JL III, Price DD (2002) A comparison of placebo effects in clinical analgesic trials versus studies of placebo analgesia. Pain 99:443–452
Hróbjartsson A, Gøtzsche PC (2001) Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. New Engl J Med 344:1594–1602
Ito K, Corrigan B, Romero K, Anziano R, Neville J, Stephenson D et al (2013) Understanding placebo responses in Alzheimer’s disease clinical trials from the literature meta-data and CAMD database. J Alzheimers Dis 37:173–183
Ongaro G, Kaptchuk TJ (2019) Symptom perception, placebo effects, and the Bayesian brain. Pain 160:1–4
Schmid J, Theysohn N, Gass F, Benson S, Gramsch C, Forsting et al (2013) Neural mechanisms mediating positive and negative treatment expectations in visceral pain: a functional magnetic resonance imaging study on placebo and nocebo effects in healthy volunteers. Pain 154:2372–2380
Carlino E, Benedetti F (2016) Different contexts, different pains, different experiences. Neurosci 338:19–26
Amanzio M, Pollo A, Maggi G, Benedetti F (2001) Response variability to analgesics: a role for non-specific activation of endogenous opioids. Pain 90:205–215
Bingel U, Wanigasekera V, Wiech K, Mhuircheartaigh RN, Lee MC, Ploner M et al (2011) The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil. Sci Transl Med 3:70
Pollo A, Torre E, Lopiano L, Rizzone M, Lanotte M, Cavanna A et al (2002) Expectation modulates the response to subthalamic nucleus stimulation in Parkinsonian patients. Neuroreport 13:1383–1386
Carlino E, Piedimonte A, Romagnolo A, Guerra G, Frisaldi E, Vighettia S et al (2019) Verbal communication about drug dosage balances drug reduction in Parkinson’s disease: behavioral and electrophysiological evidences. Parkinsonism Relat Disord 65:184–189
Kaptchuk TJ, Kelley JM, Conboy LA, Davis RB, Kerr CE, Jacobson E et al (2008) Components of placebo effect: randomised controlled trial in patients with irritable bowel syndrome. BMJ 336:999–1003
Finniss DG, Kaptchuk TJ, Miller F, Benedetti F (2010) Biological, clinical and ethical advances of placebo effects. Lancet 375:686–695
Rief W, Glombiewski JA, Gollwitzer M, Schubö A, Schwarting R, Thorwart A (2015) Expectancies as core features of mental disorders. Curr Opin Psychiatry 28:378–385
Lidstone SC, Schulzer M, Dinelle K, Mak E, Sossi V, Ruth TJ et al (2010) Effects of expectation on placebo-induced dopamine release in Parkinson disease. Arch Gen Psychiatry 67:857–865
Setlow B, Schoenbaum G, Gallagher M (2003) Neural encoding in ventral striatum during olfactory discrimination learning. Neuron 38:625–636
Tobler PN, Fiorillo CD, Schultz W (2005) Adaptive coding of reward value by dopamine neurons. Science 307:1642–1645
Schultz W (2006) Behavioral theories and the neurophysiology of reward. Annu Rev Psychol 57:87–115
De la Fuente-Fernández R, Ruth TJ, Sossi V, Schulzer M, Calne DB, Stoessl AJ et al (2002) Expectation and dopamine release: mechanism of the placebo effect in Parkinson’s disease. Science 293:1164–1166
Goetz CG, Laska E, Hicking C, Damier P, Mueller T, Nutt J et al (2008) Placebo influences on dyskinesia in Parkinson’s disease. Mov Disord 23:700–707
Espay AJ, Norris MM, Eliassen JC, Dwivedi A, Smith MS, Banks C et al (2015) Placebo effect of medication cost in Parkinson disease: a randomized double-blind study. Neurology 84:794–802
Olanow CW, Fahn S, Muenter M, Klawans H, Hurtig H, Stern M et al (1994) A multicenter double-blind placebo-controlled trial of pergolide as an adjunct to sinemet® in Parkinson’s disease. Mov Disord 9:40–47
Barker Bausell R, Lao L, Bergman S, Lee WL, Berman BM (2005) Is acupuncture analgesia an expectancy effect? Preliminary evidence based on participants’ perceived assignments in two placebo-controlled trials. Eval Health Prof 28:9–26
Linde K, Witt C, Streng A, Weidenhammer W, Wagenpfeil S, Brinkhaus B et al (2007) The impact of patient expectations on outcomes in four randomized controlled trials of acupuncture in patients with chronic pain. Pain 128:264–271
Amanzio M, Benedetti F (1999) Neuropharmacological dissection of placebo analgesia: expectation-activated opioid systems versus conditioning-activated specific subsystems. J Neurosci 19:484–494
Colloca L, Grillon C (2014) Understanding placebo and nocebo responses for pain management. Curr Pain Headache Rep 18:419
Klinger R, Kothe R, Schmitz J, Kamping S, Flor H (2017) Placebo effects of a sham opioid solution: a randomized controlled study in patients with chronic low back pain. Pain 158:1893–1902
Benedetti F (2013) Placebo and the new physiology of the doctor-patient relationship. Physiol Rev 93:1207–1246
Berna C, Kirsch I, Zion SR, Lee YC, Jensen KB, Sadler P et al (2017) Side effects can enhance treatment response through expectancy effects: an experimental analgesic randomized controlled trial. Pain 158:1014–1020
Rief W, Glombiewski JA (2012) The hidden effects of blinded, placebo-controlled randomized trials: an experimental investigation. Pain 153:2473–2477
De Craen AJM, Roos PJ, De Vries AL, Kleijnen J (1996) Effect of colour of drugs: systematic review of perceived effect of drugs and of their effectiveness. BMJ 313:1624–1626
Hadamitzky M, Lückemann L, Pacheco-López G, Schedlowski M (2020) Pavlovian conditioning of immunological and neuroendocrine functions. Physiol Rev 100:357–405
Pacheco-López G, Riether C, Doenlen R, Engler H, Niemi MB, Engler A et al (2009) Calcineurin inhibition in splenocytes induced by pavlovian conditioning. FASEB J 23:1161–1167
Ader R, Cohen N (1975) Behaviorally conditioned immunosuppression. Psychosom Med 37:333–340
Pacheco-López G, Engler H, Niemi MB, Schedlowski M (2006) Expectations and associations that heal: immunomodulatory placebo effects and its neurobiology. Brain Behav Immun 20:430–446
Khan KJ, Dubinsky MC, Ford AC, Ullman TA, Taley NJ, Moayyedi P (2011) Efficacy of immunosuppressive therapy for inflammatory bowel disease: a systematic review and meta-analysis. Am J Gastroenterol 106:630–642
Theodosis-Nobelos P, Asimakopoulou E, Kokkinos S, Skavatsos D, Triantis C (2020) The placebo effect in pain management. Pharmakeftiki 32:78–93
Goebel MU, Trebst AE, Steiner J, Xie YF, Exton MS, Frede S et al (2002) Behavioral conditioning of immunosuppression is possible in humans. FASEB J 16:1869–1873
Goebel MU, Meykadeh N, Kou W, Schedlowski M, Hengge UR (2008) Behavioral conditioning of antihistamine effects in patients with allergic rhinitis. Psychother Psychosom 77:227–234
Benedetti F, Pollo A, Lopiano L, Lanotte M, Vighetti S, Rainero I (2003) Conscious expectation and unconscious conditioning in analgesic, motor, and hormonal placebo/nocebo responses. J Neurosci 23:4315–4323
Marshall GD (2004) Neuroendocrine mechanisms of immune dysregulation: applications to allergy and asthma. Ann Allergy Asthma Immunol 93:11–17
Langewitz W, Izakovic J, Wyler J, Schindler C, Kiss A, Bircher AJ (2005) Effect of self-hypnosis on hay fever symptoms - a randomised controlled intervention study. Psychother Psychosom 74:165–172
Kirchhof J, Petrakova L, Brinkhoff A, Benson S, Schmidt J, Unteroberdörster M et al (2018) Learned immunosuppressive placebo responses in renal transplant patients. Proc Natl Acad Sci U S A 115:4223–4227
Haour F (2005) Mechanisms of the placebo effect and of conditioning. NeuroImmunoModulation 12:195–200
Frisaldi E, Carlino E, Zibetti M, Barbiani D, Dematteis F, Lanotte M et al (2017) The placebo effect on bradykinesia in Parkinson’s disease with and without prior drug conditioning. Mov Disord 32:1474–1478
Carlino E, Piedimonte A, Frisaldi E (2014) The effects of placebos and nocebos on physical performance. Handb Exp Pharmacol 225:149–157
Carlino E, Benedetti F, Pollo A (2014) The effects of manipulating verbal suggestions on physical performance Z Psychol 222:154–164
Carlino E, Guerra G, Piedimonte A (2016) Placebo effects: from pain to motor performance. Neurosci Lett 632:224–230
Eippert F, Bingel U, Schoell ED, Yacubian J, Klinger R, Lorenz J et al (2009) Activation of the opioidergic descending pain control system underlies placebo analgesia. Neuron 63:533–543
Levine JD, Gordon NC, Fields HL (1978) The mechanism of placebo analgesia. Lancet 312:654–657
Wager TD, Rilling JK, Smith EE, Sokolik A, Casey KL, Davidson RJ et al (2004) Placebo-induced changes in fMRI in the anticipation and experience of pain. Science 303:1162–1167
Benedetti F (1999) Inducing placebo respiratory depressant responses in humans via opioid receptors. Eur J Neurosci 11:625–631
Benedetti F, Lanotte M, Colloca L, Ducati A, Zibetti M, Lopiano L (2009) Electrophysiological properties of thalamic, subthalamic and nigral neurons during the anti-parkinsonian placebo response. J Physiol 587:3869–3883
Chen X, Zhang J, Wang X (2016) Hormones in pain modulation and their clinical implications for pain control: a critical review. Hormones 15:313–320
Benedetti F, Mayberg HS, Wager TD, Stohler CS, Zubieta JK (2005) Neurobiological mechanisms of the placebo effect. J Neurosci 25:10390–10402
Asimakopoulou E, Theodosis-Nobelos P, Triantis C (2018) Pain assessment and management in intensive care unit: pharmacological and non-pharmacological approaches. Hell J Nurs 57:349–336
Benedetti F, Amanzio M, Casadio C, Oliaro A, Maggi G (1997) Blockade of nocebo hyperalgesia by the cholecystokinin antagonist proglumide. Pain 71:135–140
Noble F, Wank SA, Crawley JN, Bradwejn J, Seroogy KB, Hamon M et al (1999) International union of pharmacology. XXI. Structure, distribution, and functions of cholecystokinin receptors. Pharmacol Rev 51:745–781
Timothy Walsh B, Seidman SN, Sysko R, Gould M (2002) Placebo response in studies of major depression: variable, substantial, and growing. JAMA 287:1840–1847
Mayberg HS, Silva A, Brannan SK, Tekell JL, Mahurin RK, McGinnis S et al (2002) The functional neuroanatomy of the placebo effect. Am J Psychiatry 159:728–737
Ikemoto S, Panksepp J (1999) The role of nucleus accumbens dopamine in motivated behavior: a unifying interpretation with special reference to reward-seeking. Brain Res Rev 31:6–4
Schultz W (2000) Multiple reward signals in the brain. Nat Rev Neurosci 1:199–207
Knutson B, Cooper JC (2005) Functional magnetic resonance imaging of reward prediction. Curr Opin Neurol 18:411–417
Dursun E, Gezen-Ak D (2019) Vitamin D basis of Alzheimer’s disease: from genetics to biomarkers. Hormones 18:7–15
Benedetti F, Arduino C, Costa S, Vigghetti S, Tarenzi L, Rainero I et al (2006) Loss of expectation-related mechanisms in Alzheimer’s disease makes analgesic therapies less effective. Pain 121:133–144
Hall KT, Lembo AJ, Kirsch I, Ziogas DC, Douaiher JKB et al (2012) Catechol-O-methyltransferase val158met polymorphism predicts placebo effect in irritable bowel syndrome. PLoS One 7:e48135
Hotamisligil GS, Breakefield XO (1991) Human monoamine oxidase a gene determines levels of enzyme activity. Am J Hum Genet 49:383–392
Furmark T, Appel L, Henningsson S, Åhs F, Faria V, Linnman C et al (2008) A link between serotonin-related gene polymorphisms, amygdala activity, and placebo-induced relief from social anxiety. J Neurosci 28:13066–13074
Benedetti F, Amanzio M, Rosato R, Blanchard C (2011) Nonopioid placebo analgesia is mediated by CB1 cannabinoid receptors. Nat Med 17:1228–1230
Hall KT, Loscalzo J, Kaptchuk TJ (2015) Genetics and the placebo effect: the placebome. Trends Mol Med 21:285–294
Van Laarhoven AIM, Vogelaar ML, Wilder-Smith OH, Van Riel PLCM, Van De Kerkhof PCM, Kraaimaat FW et al (2011) Induction of nocebo and placebo effects on itch and pain by verbal suggestions. Pain 152:1486–1494
Benedetti F, Amanzio M, Vighetti S, Asteggiano G (2006) The biochemical and neuroendocrine bases of the hyperalgesic nocebo effect. J Neurosci 26:12014–12022
Varelmann D, Pancaro C, Cappiello EC, Camann WR (2010) Nocebo-induced hyperalgesia during local anesthetic injection. Anesth Analg 110:868–870
Weihrauch TR, Gauler TC (1999) Placebo-efficacy and adverse effects in controlled clinical trials. Arzneimittelforschung 49:385–393
Miller FG, Wendler D, Swartzman LC (2005) Deception in research on the placebo effect. PLoS Med 2(9):e262
Burke W, Brown Trinidad S, Press NA (2014) Essential elements of personalized medicine. Urol Oncol 32(2):193–197
Hazin R, Brothers KB, Malin BA, Koenig BA, Sanderson SC, Rothstein MA et al (2013) Ethical, legal, and social implications of incorporating genomic information into electronic health records. Genet Med 15:810–816
Kaptchuk TJ (2002) The placebo effect in alternative medicine: can the performance of a healing ritual have clinical significance? Ann Intern Med 136:817–825
Carlino E, Vase L (2018) Can knowledge of placebo and nocebo mechanisms help improve randomized clinical trials? Int Rev Neurobiol 138:329–357
Darragh M, Booth RJ, Consedine NS (2014) Consedine investigating the “placebo personality” outside the pain paradigm. J Psychosom Res 76:414–421
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Theodosis-Nobelos, P., Filotheidou, A. & Triantis, C. The placebo phenomenon and the underlying mechanisms. Hormones 20, 61–71 (2021). https://doi.org/10.1007/s42000-020-00243-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s42000-020-00243-5