The Placebo and Nocebo Effect

  • Stephen P. GlasserEmail author
  • William Frishman


There are four general reasons for clinical improvement in a patient’s condition: (1) natural history of the disease; (2) specific effects of the treatment; (3) regression to the mean; and (4) nonspecific effects of the treatment that are attributable to factors other than the specific active components. The latter effect is included under the heading ‘placebo effect’. In this chapter the placebo effect will be discussed, with some emphasis on regression to the mean. Placebos (‘I will please’) and their lesser known counterpart’s nocebo’s (I will harm’) are sham treatments. The difference is in the response to the inert therapy. A beneficial response to an inert substance is a placebo response; a side effect to an inert substance is a nocebo response.


Placebo Nocebo Regression to the mean Placebo mechanisms Placebo in clinical trials Placebo ethics Placebo characteristics 


  1. 1.
    Turner JA, Deyo RA, Loeser JD, Von Korff M, Fordyce WE. The importance of placebo effects in pain treatment and research. JAMA. 1994;271:1609–14.PubMedCrossRefGoogle Scholar
  2. 2.
    Benson H, Epstein MD. The placebo effect. A neglected asset in the care of patients. JAMA. 1975;232:1225–7.PubMedCrossRefGoogle Scholar
  3. 3.
    Stedman’s Medical Dictionary. Melmon and Morrelli’s clinical pharmacology: basic principles in therapeutics. In: Melmon K, Morrelli H, Hoffman B, Mierenberg D, editors. 3rd ed. New York: McGraw-Hill; 1992. p. 896.Google Scholar
  4. 4.
    Packer M, Medina N, Yushak M. Hemodynamic changes mimicking a vasodilator drug response in the absence of drug therapy after right heart catheterization in patients with chronic heart failure. Circulation. 1985;71:761–6.PubMedCrossRefGoogle Scholar
  5. 5.
    Chalmers TC. Prophylactic treatment of Wilson’s disease. N Engl J Med. 1968;278:910–1.PubMedGoogle Scholar
  6. 6.
    Garrison FH. History of medicine. 4th ed. Philadelphia: Saunders; 1929.Google Scholar
  7. 7.
    Stedman’s Medical Dictionary. Baltimore: Williams & Wilkins; 1990. Stedman’s Medical Dictionary.Google Scholar
  8. 8.
    White L, Tursky B, Schwartz G. Placebo: theory, research, and mechanisms. New York: Guilford Press; 1985. 474 p.Google Scholar
  9. 9.
    Shapiro AK. Factors contributing to the placebo effect: their implications for psychotherapy. Am J Psychother. 1961;18:73–88.Google Scholar
  10. 10.
    Byerly H. Explaining and exploiting placebo effects. Perspect Biol Med. 1976;19:423–36.PubMedGoogle Scholar
  11. 11.
    Lind JA. A treatise of the scurvy. Edinburgh;1753.Google Scholar
  12. 12.
    Hill AB. The clinical trial. Br Med Bull. 1951;7:278–82.PubMedGoogle Scholar
  13. 13.
    Beecher HK. The powerful placebo. JAMA. 1955;159:1602–6.CrossRefGoogle Scholar
  14. 14.
    Lasagna L, Mosteller F, Von Felsinger JM, Beecher HK. A study of the placebo response. Am J Med. 1954;16:770–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Wolf S, Pinsky RH. Effects of placebo administration and occurrence of toxic reactions. JAMA. 1954;155:339–41.CrossRefGoogle Scholar
  16. 16.
    Davis JM. Don’t let placebos fool you. Postgrad Med. 1990;88:21–4.PubMedGoogle Scholar
  17. 17.
    Nies A, Spielberg S. Principles of therapeutics. In: Hardman JG, Limbird LE, editors. Goodman and Gilman’s the pharmacological basis of therapeutics. 9th ed. New York: McGraw Hill; 1996.Google Scholar
  18. 18.
    Makuch RW, Johnson MF. Dilemmas in the use of active control groups in clinical research. IRB. 1989;11:1–5.PubMedCrossRefGoogle Scholar
  19. 19.
    Ederer F. Serum cholesterol changes: effects of diet and regression toward the mean. J Chronic Dis. 1972;25:277–89.PubMedCrossRefGoogle Scholar
  20. 20.
    The National Diet-Heart Study Final Report. Circulation. 1968;37:I1–428.Google Scholar
  21. 21.
    Yudkin PL, Stratton IM. How to deal with regression to the mean in intervention studies. Lancet. 1996;347:241–3.PubMedCrossRefGoogle Scholar
  22. 22.
    Asmar R, Safar M, Queneau P. Evaluation of the placebo effect and reproducibility of blood pressure measurement in hypertension. Am J Hypertens. 2001;14:546–52.PubMedCrossRefGoogle Scholar
  23. 23.
    Oh VM. Magic or medicine? Clinical pharmacological basis of placebo medication. Ann Acad Med Singapore. 1991;20:31–7.PubMedGoogle Scholar
  24. 24.
    Kelly JP. Anatomical organization of the nervous system. In: Kandel ER, Schwartz JH, Jessel TM, editors. Principles of neural science. 3rd ed. New York: Elsevier; 1991. p. 276–92.Google Scholar
  25. 25.
    Voudouris NJ, Peck CL, Coleman G. The role of conditioning and verbal expectancy in the placebo response. Pain. 1990;43:121–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Levine JD, Gordon NC, Bornstein JC, Fields HL. Role of pain in placebo analgesia. Proc Natl Acad Sci U S A. 1979;76:3528–31.PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Hersh EV, Ochs H, Quinn P, MacAfee K, Cooper SA, Barasch A. Narcotic receptor blockade and its effect on the analgesic response to placebo and ibuprofen after oral surgery. Oral Surg Oral Med Oral Pathol. 1993;75:539–46.PubMedCrossRefGoogle Scholar
  28. 28.
    Kojo I. The mechanism of the psychophysiological effects of placebo. Med Hypotheses. 1988;27:261–4.PubMedCrossRefGoogle Scholar
  29. 29.
    Egbert LD, Battit GE, Welch CE, Bartlett MK. Reduction of postoperative pain by encouragement and instruction of patients. A study of doctor-patient rapport. N Engl J Med. 1964;270:825–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Amsterdam EA, Wolfson S, Gorlin R. New aspects of the placebo response in angina pectoris. Am J Cardiol. 1969;24:305–6.PubMedCrossRefGoogle Scholar
  31. 31.
    Glasser SP, Clark PI, Lipicky RJ, Hubbard JM, Yusuf S. Exposing patients with chronic, stable, exertional angina to placebo periods in drug trials. JAMA. 1991;265:1550–4.PubMedCrossRefGoogle Scholar
  32. 32.
    Boissel JP, Philippon AM, Gauthier E, Schbath J, Destors JM. Time course of long-term placebo therapy effects in angina pectoris. Eur Heart J. 1986;7:1030–6.PubMedGoogle Scholar
  33. 33.
    McGraw BF, Hemberger JA, Smith AL, Schroeder JS. Variability of exercise performance during long-term placebo treatment. Clin Pharmacol Ther. 1981;30:321–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Thadani U and Wittig T. A Randomized, Double-Blind, Placebo-Controlled, Crossover, Dose-Ranging Multicenter Study to Determine the Effect of Sublingual Nitroglycerin Spray on Exercise Capacity in Patients with Chronic Stable Angina. Clin Med Insights Cardiol. 2012;6: 87–95.Google Scholar
  35. 35.
    Acute and chronic antianginal efficacy of continuous twenty-four-hour application of transdermal nitroglycerin. Steering Committee, Transdermal Nitroglycerin Cooperative Study. Am J Cardiol. 1991;68:1263–73.Google Scholar
  36. 36.
    Beecher HK. Surgery as placebo. A quantitative study of bias. JAMA. 1961;176:1102–7.PubMedCrossRefGoogle Scholar
  37. 37.
    Diamond EG, Kittle CF, Crockett JE. Evaluation of internal mammary artery ligation and sham procedures in angina pectoris. Circulation. 1958;18:712–3.Google Scholar
  38. 38.
    Diamond EG, Kittle CF, Crockett JE. Comparison of internal mammary artery ligation and sham operation for angina pectoris. Am J Cardiol. 1960;5:484–6.Google Scholar
  39. 39.
    Cobb LA. Evaluation of internal mammary artery ligation by double-blind technic. N Engl J Med. 1989;260:1115–8.CrossRefGoogle Scholar
  40. 40.
    Carver JR, Samuels F. Sham therapy in coronary artery disease and atherosclerosis. Pract Cardiol. 1988;14:81–6.Google Scholar
  41. 41.
    van Rij AM, Solomon C, Packer SG, Hopkins WG. Chelation therapy for intermittent claudication. A double-blind, randomized, controlled trial. Circulation. 1994;90:1194–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Lamas GA, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL, et al. Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. JAMA. 2013;309:1241–50. doi: 10.1001/jama.2013.2107.PubMedCrossRefGoogle Scholar
  43. 43.
    Nissan S. Concerns about reliability in the Trial to Assess Chelation Therapy. JAMA. 2013;309:1293–4. doi: 10.1001/jama.2013.2778.CrossRefGoogle Scholar
  44. 44.
    Packer M. The placebo effect in heart failure. Am Heart J. 1990;120:1579–82.PubMedCrossRefGoogle Scholar
  45. 45.
    Archer TP, Leier CV. Placebo treatment in congestive heart failure. Cardiology. 1992;81:125–33.PubMedCrossRefGoogle Scholar
  46. 46.
    Randomised controlled trial of treatment for mild hypertension: design and pilot trial. Report of Medical Research Council Working Party on Mild to Moderate Hypertension. BMJ. 1977;1:1437–40.Google Scholar
  47. 47.
    Gould BA, Mann S, Davies AB, Altman DG, Raftery EB. Does placebo lower blood-pressure? Lancet. 1981;2:1377–81.PubMedCrossRefGoogle Scholar
  48. 48.
    Martin MA, Phillips CA, Smith AJ. Acebutolol in hypertension—double-blind trial against placebo. Br J Clin Pharmacol. 1978;6:351–6. PMC1429467.PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Moutsos SE, Sapira JD, Scheib ET, Shapiro AP. An analysis of the placebo effect in hospitalized hypertensive patients. Clin Pharmacol Ther. 1967;8:676–83.PubMedGoogle Scholar
  50. 50.
    Myers MG, Lewis GR, Steiner J, Dollery CT. Atenolol in essential hypertension. Clin Pharmacol Ther. 1976;19:502–7.PubMedGoogle Scholar
  51. 51.
    Pugsley DJ, Nassim M, Armstrong BK, Beilin L. A controlled trial of labetalol (Trandate), propranolol and placebo in the management of mild to moderate hypertension. Br J Clin Pharmacol. 1979;7:63–8. PMC1429617.PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    A DOUBLE blind control study of antihypertensive agents. I. Comparative effectiveness of reserpine, reserpine and hydralazine, and three ganglionic blocking agents, chlorisondamine, mecamyamine, and pentolinium tartrate. Arch Intern Med. 1960;106:81–96.Google Scholar
  53. 53.
    Effects of treatment on morbidity in hypertension: results in Patients with diastolic blood pressures averaging 115 through 119 mmHg by Veterans Administration cooperative study group on antihypertensive agents. JAMA. 1967;202:116–22.Google Scholar
  54. 54.
    Effects morbidity of treatment on in hypertension II. Results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. JAMA. 1970;213(7):1143–52. doi: 10.1001/jama.1970.03170330025003.
  55. 55.
    Hansson L, Aberg H, Karlberg BE, Westerlund A. Controlled study of atenolol in treatment of hypertension. BMJ. 1975;2:367–70.PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Wilkinson PR, Raftery EB. A comparative trial of clonidine, propranolol and placebo in the treatment of moderate hypertension. Br J Clin Pharmacol. 1977;4:289–94.PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    Raftery EB, Gould BA. The effect of placebo on indirect and direct blood pressure measurements. J Hypertens Suppl. 1990;8:S93–100.PubMedGoogle Scholar
  58. 58.
    Mutti E, Trazzi S, Omboni S, Parati G, Mancia G. Effect of placebo on 24-h non-invasive ambulatory blood pressure. J Hypertens. 1991;9:361–4.PubMedCrossRefGoogle Scholar
  59. 59.
    Dupont AG, Van der Niepen P, Six RO. Placebo does not lower ambulatory blood pressure. Br J Clin Pharmacol. 1987;24:106–9.PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    O’Brien E, Cox JP, O’Malley K. Ambulatory blood pressure measurement in the evaluation of blood pressure lowering drugs. J Hypertens. 1989;7:243–7.PubMedGoogle Scholar
  61. 61.
    Casadei R, Parati G, Pomidossi G, Groppelli A, Trazzi S, Di Rienzo M, et al. 24-hour blood pressure monitoring: evaluation of Spacelabs 5300 monitor by comparison with intra-arterial blood pressure recording in ambulant subjects. J Hypertens. 1988;6:797–803.PubMedCrossRefGoogle Scholar
  62. 62.
    Portaluppi F, Strozzi C, degli Uberti E, Rambaldi R, Trasforini G, Margutti A, et al. Does placebo lower blood pressure in hypertensive patients? A noninvasive chronobiological study. Jpn Heart J. 1988;29:189–97.PubMedCrossRefGoogle Scholar
  63. 63.
    Sassano P, Chatellier G, Corvol P, Menard J. Influence of observer’s expectation on the placebo effect in blood pressure trials. Curr Ther Res. 1987;41:304–12.Google Scholar
  64. 64.
    Lipicky R, DeFelice A, Gordon M, Hung J, Karkowsky A, Lawrence J, et al. Placebo in Hypertension Adverse Reaction Meta-Analysis (PHARM). Circulation. 2003;17:IV–452.Google Scholar
  65. 65.
    Michelson EL, Morganroth J. Spontaneous variability of complex ventricular arrhythmias detected by long-term electrocardiographic recording. Circulation. 1980;61:690–5.PubMedCrossRefGoogle Scholar
  66. 66.
    Pratt CM, Moye LA. The cardiac arrhythmia suppression trial. Casting suppression in a different light. Circulation. 1995;91:245–7.PubMedCrossRefGoogle Scholar
  67. 67.
    Influence of adherence to treatment and response of cholesterol on mortality in the coronary drug project research group. N Engl J Med. 1980;303:1038–41.Google Scholar
  68. 68.
    Gallagher EJ, Viscoli CM, Horwitz RI. The relationship of treatment adherence to the risk of death after myocardial infarction in women. JAMA. 1993;270:742–4.PubMedCrossRefGoogle Scholar
  69. 69.
    Coronary Drug Project Research Group. The Lipid Research Clinics Coronary Primary Prevention Trial results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA. 1984; 251:365–74.Google Scholar
  70. 70.
    Sackett DL, Haynes RB, Gibson E, Johnson A. The problem of compliance with antihypertensive therapy. Pract Cardiol. 1976;2:35–9.Google Scholar
  71. 71.
    Glynn RJ, Buring JE, Manson JE, LaMotte F, Hennekens CH. Adherence to aspirin in the prevention of myocardial infarction. The Physicians’ Health Study. Arch Intern Med. 1994;154:2649–57.PubMedCrossRefGoogle Scholar
  72. 72.
    Padula AM, Pressman AR, Vittinghoff E, Grady D, Neuhaus J, Ackerson L, et al. Placebo adherence and mortality in the Heart and Estrogen/Progestin Replacement Study. Am J Med. 2012;125:804–10. PMC3423204.PubMedCentralPubMedCrossRefGoogle Scholar
  73. 73.
    Rothman KJ, Michels KB. The continuing unethical use of placebo controls. N Engl J Med. 1994;331:394–8.PubMedCrossRefGoogle Scholar
  74. 74.
    Clark PI, Leaverton PE. Scientific and ethical issues in the use of placebo controls in clinical trials. Ann Rev Public Health. 1994;15:19–38.CrossRefGoogle Scholar
  75. 75.
    Schechter C. The use of placebo controls. N Engl J Med. 1995;332; author reply 2.Google Scholar
  76. 76.
    Alderman MH. Blood pressure management: individualized treatment based on absolute risk and the potential for benefit. Ann Intern Med. 1993;119:329–35.PubMedCrossRefGoogle Scholar
  77. 77.
    Horwitz RI, Viscoli CM, Berkman L, Donaldson RM, Horwitz SM, Murray CJ, et al. Treatment adherence and risk of death after a myocardial infarction. Lancet. 1990;336:542–5.PubMedCrossRefGoogle Scholar
  78. 78.
    Morganroth J, Borland M, Chao G. Application of a frequency definition of ventricular proarrhythmia. Am J Cardiol. 1987;59:97–9.PubMedCrossRefGoogle Scholar
  79. 79.
    Drici MD, Raybaud F, De Lunardo C, Iacono P, Gustovic P. Influence of the behaviour pattern on the nocebo response of healthy volunteers. Br J Clin Pharmacol. 1995;39:204–6.PubMedCentralPubMedCrossRefGoogle Scholar
  80. 80.
    Roberts AH. The powerful placebo revisited: magnitude of nonspecific effects. Mind/Body Med. 1995;1:35–43.Google Scholar
  81. 81.
    Glasser SP, Willard J, Defelice A, Lawrence J, Hung J, Obot E, et al. Is randomization to placebo safe? Risk in placebo-controlled angina trials: angina risk meta-analysis. Cardiology. 2011; 120(2):174–81. Epub 2012/01/21.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  1. 1.Division of Preventive MedicineUniversity of Alabama at BirminghamBirminghamUSA
  2. 2.The Department of MedicineNew York Medical CollegeNew York CityUSA

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