Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The neuroscience of placebo effects: connecting context, learning and health

Key Points

  • Placebo effects are effects of the context surrounding medical treatment. They can have meaningfully large impacts on clinical, physiological and brain outcomes.

  • Effects of placebo treatments are consistent across studies from different laboratories. These effects include reduced activity in brain areas associated with pain and negative emotion, and increased activity in the lateral and medial prefrontal cortex, ventral striatum and brainstem.

  • Placebo effects in pain, Parkinson disease, depression and emotion are enabled by engagement of common prefrontal–subcortical motivational systems, but the similarity across domains in the way these systems are engaged has not been directly tested.

  • Meaningfully large placebo effects are likely to require a mixture of both conceptual belief in the placebo and prior experiences of treatment benefit, which engage brain learning processes.

  • In some cases, placebo effects are self-reinforcing, suggesting that they change symptoms in a way that precludes extinction. The mechanisms that drive these effects remain to be uncovered, but doing so could have profound translational implications.


Placebo effects are beneficial effects that are attributable to the brain–mind responses to the context in which a treatment is delivered rather than to the specific actions of the drug. They are mediated by diverse processes — including learning, expectations and social cognition — and can influence various clinical and physiological outcomes related to health. Emerging neuroscience evidence implicates multiple brain systems and neurochemical mediators, including opioids and dopamine. We present an empirical review of the brain systems that are involved in placebo effects, focusing on placebo analgesia, and a conceptual framework linking these findings to the mind–brain processes that mediate them. This framework suggests that the neuropsychological processes that mediate placebo effects may be crucial for a wide array of therapeutic approaches, including many drugs.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Elements of treatment context.
Figure 2: Paradigms for assessing placebo effects.
Figure 3: The neurophysiology of placebo analgesia.
Figure 4: Concepts, associations and the representation of context.


  1. 1

    Committee on Advancing Pain Research, Care, and Education in Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research (ed. Institute of Medicine of the National Academies) 1–350 (The National Academies Press, 2011).

  2. 2

    Benedetti, F. Placebo effects: from the neurobiological paradigm to translational implications. Neuron 84, 623–637 (2014). This review discusses the pharmacological foundation of many types of placebo effects and addresses the translational and ethical implications of placebo studies.

    CAS  Article  Google Scholar 

  3. 3

    Walsh, B. T., Seidman, S. N., Sysko, R. & Gould, M. Placebo response in studies of major depression: variable, substantial, and growing. JAMA 287, 1840–1847 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  4. 4

    Benedetti, F., Carlino, E. & Pollo, A. How placebos change the patient's brain. Neuropsychopharmacology 36, 339–354 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  5. 5

    Meissner, K. The placebo effect and the autonomic nervous system: evidence for an intimate relationship. Phil. Trans. R. Soc. B 366, 1808–1817 (2011). This review focuses on the evidence that placebos influence autonomic nervous system responses, including effects on gastrointestinal, cardiovascular and pulmonary functions.

    Article  PubMed  PubMed Central  Google Scholar 

  6. 6

    Pressman, A., Avins, A. L., Neuhaus, J., Ackerson, L. & Rudd, P. Adherence to placebo and mortality in the Beta Blocker Evaluation of Survival Trial (BEST). Contemp. Clin. Trials 33, 492–498 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  7. 7

    Schenk, L. A., Sprenger, C., Geuter, S. & Buchel, C. Expectation requires treatment to boost pain relief: an fMRI study. Pain 155, 150–157 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  8. 8

    Colloca, L., Lopiano, L., Lanotte, M. & Benedetti, F. Overt versus covert treatment for pain, anxiety, and Parkinson's disease. Lancet Neurol. 3, 679–684 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  9. 9

    Rohsenow, D. J. & Marlatt, G. A. The balanced placebo design: methodological considerations. Addict. Behav. 6, 107–122 (1981).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10

    Kirsch, I. et al. Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med. 5, e45 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  11. 11

    Flood, A., Lorence, D., Ding, J., McPherson, K. & Black, N. A. The role of expectations in patients' reports of post-operative outcomes and improvement following therapy. Med. Care 31, 1043–1056 (1993).

    CAS  Article  Google Scholar 

  12. 12

    Goetz, C. G. et al. Placebo response in Parkinson's disease: comparisons among 11 trials covering medical and surgical interventions. Mov. Disord. 23, 690–699 (2008).

    Article  Google Scholar 

  13. 13

    Wampold, B. E. et al. A meta-analysis of outcome studies comparing bona fide psychotherapies: empiricially,” all must have prizes”. Psychol. Bull. 122, 203–215 (1997).

    Article  Google Scholar 

  14. 14

    Kleijnen, J., de Craen, A. J., van Everdingen, J. & Krol, L. Placebo effect in double-blind clinical trials: a review of interactions with medications. Lancet 344, 1347–1349 (1994).

    CAS  Article  Google Scholar 

  15. 15

    Flaten, M. A., Simonsen, T. & Olsen, H. Drug-related information generates placebo and nocebo responses that modify the drug response. Psychosomat. Med. 61, 250–255 (1999).

    CAS  Article  Google Scholar 

  16. 16

    Kong, J. et al. Expectancy and treatment interactions: a dissociation between acupuncture analgesia and expectancy evoked placebo analgesia. Neuroimage 45, 940–949 (2009).

    Article  Google Scholar 

  17. 17

    Atlas, L. Y. et al. Dissociable influences of opiates and expectations on pain. J. Neurosci. 32, 8053–8064 (2012). This paper used pharmacological fMRI of remifentanil, an opioid agonist, to examine how placebo effects combine with drug effects during open drug administration and found that placebo analgesia and opioid analgesia have additive, dissociable effects on pain and brain responses.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18

    Atlas, L. Y., Wielgosz, J., Whittington, R. A. & Wager, T. D. Specifying the non-specific factors underlying opioid analgesia: expectancy, attention, and affect. Psychopharmacology 231, 813–823 (2014).

    CAS  Article  Google Scholar 

  19. 19

    Benedetti, F. et al. The specific effects of prior opioid exposure on placebo analgesia and placebo respiratory depression. Pain 75, 313–319 (1998).

    CAS  Article  Google Scholar 

  20. 20

    Maren, S., Phan, K. L. & Liberzon, I. The contextual brain: implications for fear conditioning, extinction and psychopathology. Nat. Rev. Neurosci. 14, 417–428 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21

    Buchel, C., Geuter, S., Sprenger, C. & Eippert, F. Placebo analgesia: a predictive coding perspective. Neuron 81, 1223–1239 (2014). This review focuses on placebo analgesia from a Bayesian predictive-coding perspective and addresses the relationship between expectations, experience and decision making.

    Article  CAS  Google Scholar 

  22. 22

    Sterzer, P., Frith, C. & Petrovic, P. Believing is seeing: expectations alter visual awareness. Curr. Biol. 18, R697–R698 (2008).

    CAS  Article  Google Scholar 

  23. 23

    Summerfield, C. & de Lange, F. P. Expectation in perceptual decision making: neural and computational mechanisms. Nat. Rev. Neurosci. 15, 745–756 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24

    Summerfield, C. & Egner, T. Expectation (and attention) in visual cognition. Trends Cogn. Sci. 13, 403–409 (2009).

    Article  Google Scholar 

  25. 25

    Edelson, M., Sharot, T., Dolan, R. J. & Dudai, Y. Following the crowd: brain substrates of long-term memory conformity. Science 333, 108–111 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26

    Plassmann, H., O'Doherty, J., Shiv, B. & Rangel, A. Marketing actions can modulate neural representations of experienced pleasantness. Proc. Natl Acad. Sci. USA 105, 1050–1054 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27

    Hare, T. A., Malmaud, J. & Rangel, A. Focusing attention on the health aspects of foods changes value signals in vmPFC and improves dietary choice. J. Neurosci. 31, 11077–11087 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28

    Plassmann, H. & Wager, T. D. in The Interdisciplinary Science of Consumption (eds Kringelbach, M., Knutson, B. & Preston, S.) 219–240 (2014).

    Google Scholar 

  29. 29

    Beedie, C. J. & Foad, A. J. The placebo effect in sports performance. Sports Med. 39, 313–329 (2009).

    Article  Google Scholar 

  30. 30

    Boot, W. R., Simons, D. J., Stothart, C. & Stutts, C. The pervasive problem with placebos in psychology why active control groups are not sufficient to rule out placebo effects. Persp. Psychol. Sci. 8, 445–454 (2013).

    Article  Google Scholar 

  31. 31

    Carlino, E., Frisaldi, E. & Benedetti, F. Pain and the context. Nat. Rev. Rheumatol. 10, 348–355 (2014).

    CAS  Article  Google Scholar 

  32. 32

    Sherman, R. & Hickner, J. Academic physicians use placebos in clinical practice and believe in the mind–body connection. J. Gen. Intern. Med. 23, 7–10 (2008).

    Article  Google Scholar 

  33. 33

    Ochoa, J. L. Chronic pains associated with positive and negative sensory, motor, and vaso-motor manifestations: CPSMV (RSD; CRPS?). Heterogeneous somatic versus psychopathologic origins. Contemp. Neurol. 2, 1–20 (1997).

    Google Scholar 

  34. 34

    Barrett, B. et al. Placebo, meaning, and health. Perspect. Biol. Med. 49, 178–198 (2006).

    Article  Google Scholar 

  35. 35

    Enck, P., Benedetti, F. & Schedlowski, M. New insights into the placebo and nocebo responses. Neuron 59, 195–206 (2008).

    CAS  Article  Google Scholar 

  36. 36

    Vase, L., Petersen, G. L., Riley, J. L. & Price, D. D. Factors contributing to large analgesic effects in placebo mechanism studies conducted between 2002 and 2007. Pain 145, 36–44 (2009).

    Article  Google Scholar 

  37. 37

    Vase, L., Riley, J. L. & Price, D. D. A comparison of placebo effects in clinical analgesic trials versus studies of placebo analgesia. Pain 99, 443–452 (2002).

    Article  Google Scholar 

  38. 38

    Kaptchuk, T. J. et al. Components of placebo effect: randomised controlled trial in patients with irritable bowel syndrome. BMJ 336, 999–1003 (2008). This clinical trial of placebo acupuncture found that patients with irritable bowel syndrome improved most when clinicians delivered treatment in a warm, supportive manner, which provides evidence that the patient–care provider relationship can influence treatment outcomes.

    Article  PubMed  PubMed Central  Google Scholar 

  39. 39

    Kaptchuk, T. J. et al. Placebos without deception: a randomized controlled trial in irritable bowel syndrome. PLoS ONE 5, e15591 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40

    Kam-Hansen, S. et al. Altered placebo and drug labeling changes the outcome of episodic migraine attacks. Sci. Transl Med. 6, 218ra5 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Rutherford, B. R., Roose, S. P. & Sneed, J. Mind over medicine: the influence of expectations on antidepressant response. J. Am. Psychoanal. Assoc. 57, 456–460 (2009).

    Article  Google Scholar 

  42. 42

    Kirsch, I. Listening to Prozac but hearing placebo: a meta-analysis of antidepressant medication. Prevent. Treat. 1, Article 2A (1998).

    Google Scholar 

  43. 43

    Leuchter, A. F., Hunter, A. M., Tartter, M. & Cook, I. A. Role of pill-taking, expectation and therapeutic alliance in the placebo response in clinical trials for major depression. Br. J. Psychiatry 205, 443–449 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  44. 44

    Lidstone, S. C. et al. Effects of expectation on placebo-induced dopamine release in Parkinson disease. Arch. Gen. Psychiatry 67, 857–865 (2010). This study examined placebo effects in patients with PD and found that the strength of expectations for treatment influenced both clinical symptom reduction and striatal dopamine binding.

    CAS  Article  Google Scholar 

  45. 45

    de la Fuente-Fernandez, R. et al. Expectation and dopamine release: mechanism of the placebo effect in Parkinson's disease. Science 293, 1164–1166 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46

    Kemeny, M. E. et al. Placebo response in asthma: a robust and objective phenomenon. J. Allergy Clin. Immunol. 119, 1375–1381 (2007).

    Article  Google Scholar 

  47. 47

    Luparello, T., Lyons, H. A., Bleecker, E. R. & McFadden, E. R. Jr. Influences of suggestion on airway reactivity in asthmatic subjects. Psychosomat. Med. 30, 819–825 (1968).

    CAS  Article  Google Scholar 

  48. 48

    Wechsler, M. E. et al. Active albuterol or placebo, sham acupuncture, or no intervention in asthma. N. Engl. J. Med. 365, 119–126 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. 49

    Vase, L., Robinson, M., Verne, G. & Price, D. The contributions of suggestion, desire, and expectation to placebo effects in irritable bowel syndrome patients. An empirical investigation. Pain 105, 17–25 (2003).

    Article  Google Scholar 

  50. 50

    Avins, A. L. et al. Placebo adherence and its association with morbidity and mortality in the studies of left ventricular dysfunction. J. Gen. Intern. Med. 25, 1275–1281 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  51. 51

    Pollo, A., Vighetti, S., Rainero, I. & Benedetti, F. Placebo analgesia and the heart. Pain 102, 125–133 (2003).

    Article  Google Scholar 

  52. 52

    Benedetti, F., Arduino, C. & Amanzio, M. Somatotopic activation of opioid systems by target-directed expectations of analgesia. J. Neurosci. 19, 3639–3648 (1999).

    CAS  Article  Google Scholar 

  53. 53

    Bingel, U. et al. The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil. Sci. Transl Med. 3, 70ra14 (2011).

    Article  CAS  Google Scholar 

  54. 54

    Saper, C. B. The central autonomic nervous system: conscious visceral perception and autonomic pattern generation. Annu. Rev. Neurosci. 25, 433–469 (2002).

    CAS  Article  Google Scholar 

  55. 55

    Price, J. Prefrontal cortical networks related to visceral function and mood. Ann. NY Acad. Sci. 877, 383–396 (1999).

    CAS  Article  Google Scholar 

  56. 56

    Wager, T. D. et al. Brain mediators of cardiovascular responses to social threat, part II: prefrontal–subcortical pathways and relationship with anxiety. Neuroimage 47, 836–851 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  57. 57

    Phelps, E. A. et al. Activation of the left amygdala to a cognitive representation of fear. Nat. Neurosci. 4, 437–441 (2001).

    CAS  Article  Google Scholar 

  58. 58

    Grings, W. W., Schell, A. M. & Carey, C. A. Verbal control of an autonomic response in a cue reversal situation. J. Exp. Psychol. 99, 215–221 (1973).

    Article  Google Scholar 

  59. 59

    Geuter, S. & Büchel, C. Facilitation of pain in the human spinal cord by nocebo treatment. J. Neurosci. 33, 13784–13790 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. 60

    Nakamura, Y. et al. Investigating dose-dependent effects of placebo analgesia: a psychophysiological approach. Pain 153, 227–237 (2012).

    Article  Google Scholar 

  61. 61

    Eippert, F. et al. Activation of the opioidergic descending pain control system underlies placebo analgesia. Neuron 63, 533–543 (2009). This study demonstrated, for the first time, that placebo-induced reductions in pain-related fMRI activity are reversible by naloxone.

    CAS  Article  Google Scholar 

  62. 62

    Benedetti, F., Amanzio, M., Vighetti, S. & Asteggiano, G. The biochemical and neuroendocrine bases of the hyperalgesic nocebo effect. J. Neurosci. 26, 12014–12022 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  63. 63

    Johansen, O., Brox, J. & Flaten, M. A. Placebo and nocebo responses, cortisol, and circulating β-endorphin. Psychosomat. Med. 65, 786–790 (2003).

    CAS  Article  Google Scholar 

  64. 64

    Guo, J. Y. et al. Placebo analgesia affects the behavioral despair tests and hormonal secretions in mice. Psychopharmacology 217, 83–90 (2011).

    CAS  Article  Google Scholar 

  65. 65

    Benedetti, F. et al. Conscious expectation and unconscious conditioning in analgesic, motor, and hormonal placebo/nocebo responses. J. Neurosci. 23, 4315–4323 (2003). This multiday study separated placebo effects that depend on conditioning from those that depend on instructions, and found that placebo effects on pain and motor performance in PD reverse immediately with instructions, whereas placebo effects on growth hormone and cortisol mimic pharmacological conditioning.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. 66

    Crum, A. J., Corbin, W. R., Brownell, K. D. & Salovey, P. Mind over milkshakes: mindsets, not just nutrients, determine ghrelin response. Health Psychol. 30, 424–429 (2011).

    Article  Google Scholar 

  67. 67

    Woods, S. C. & Ramsay, D. S. Pavlovian influences over food and drug intake. Behav. Brain Res. 110, 175–182 (2000).

    CAS  Article  Google Scholar 

  68. 68

    Ader, R. & Cohen, N. Behaviorally conditioned immunosuppression and murine systemic lupus erythematosus. Science 215, 1534–1536 (1982).

    CAS  Article  Google Scholar 

  69. 69

    Goebel, M. U. et al. Behavioral conditioning of immunosuppression is possible in humans. FASEB J. 16, 1869–1873 (2002).

    CAS  Article  Google Scholar 

  70. 70

    Schedlowski, M. & Pacheco-Lopez, G. The learned immune response: Pavlov and beyond. Brain Behav. Immun. 24, 176–185 (2010).

    Article  Google Scholar 

  71. 71

    Exton, M. S. et al. Behaviorally conditioned immunosuppression in the rat is regulated via noradrenaline and β-adrenoceptors. J. Neuroimmunol. 131, 21–30 (2002).

    CAS  Article  Google Scholar 

  72. 72

    Pacheco-Lopez, G. et al. Neural substrates for behaviorally conditioned immunosuppression in the rat. J. Neurosci. 25, 2330–2337 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. 73

    Ober, K. et al. Plasma noradrenaline and state anxiety levels predict placebo response in learned immunosuppression. Clin. Pharmacol. Ther. 91, 220–226 (2012).

    CAS  Article  Google Scholar 

  74. 74

    Kamenica, E., Naclerio, R. & Malani, A. Advertisements impact the physiological efficacy of a branded drug. Proc. Natl Acad. Sci. USA 110, 12931–12935 (2013).

    CAS  Article  Google Scholar 

  75. 75

    Tversky, A. & Kahneman, D. Judgment under uncertainty: heuristics and biases. Science 185, 1124–1131 (1974).

    CAS  Article  Google Scholar 

  76. 76

    Staudinger, M. R. & Buchel, C. How initial confirmatory experience potentiates the detrimental influence of bad advice. Neuroimage 76, 125–133 (2013).

    Article  Google Scholar 

  77. 77

    Wager, T. D., Matre, D. & Casey, K. L. Placebo effects in laser-evoked pain potentials. Brain Behav. Immun. 20, 219–230 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  78. 78

    Martini, M., Lee, M., Valentini, E. & Iannetti, G. Intracortical modulation, and not spinal inhibition, mediates placebo analgesia. Eur. J. Neurosci. 41, 498–504 (2015).

    CAS  Article  Google Scholar 

  79. 79

    Halperin, E., Russell, A. G., Trzesniewski, K. H., Gross, J. J. & Dweck, C. S. Promoting the Middle East peace process by changing beliefs about group malleability. Science 333, 1767–1769 (2011).

    CAS  Article  Google Scholar 

  80. 80

    Petrovic, P. et al. Placebo in emotional processing — induced expectations of anxiety relief activate a generalized modulatory network. Neuron 46, 957–969 (2005). This study demonstrated that placebo anxiolytics modulate BOLD responses to emotional images and that these modulations were paralleled by fMRI activation in some of the same brain regions as previously found in placebo analgesia.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  81. 81

    Zhang, W., Guo, J., Zhang, J. & Luo, J. Neural mechanism of placebo effects and cognitive reappraisal in emotion regulation. Prog. Neuropsychopharmacol. Biol. Psychiatry 40, 364–373 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  82. 82

    Zhang, W. & Luo, J. The transferable placebo effect from pain to emotion: changes in behavior and EEG activity. Psychophysiology 46, 626–634 (2009). This study, which found that a placebo analgesic also modulated negative affect and EEG responses to unpleasant pictures, represents one of the few studies to formally examine placebo effects across domains.

    Article  PubMed  PubMed Central  Google Scholar 

  83. 83

    Schienle, A., Übel, S., Schöngaßner, F., Ille, R. & Scharmüller, W. Disgust regulation via placebo: an fMRI study. Soc. Cogn. Affect. Neurosci. 9, 985–990 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  84. 84

    Schienle, A., Übel, S. & Scharmüller, W. Placebo treatment can alter primary visual cortex activity and connectivity. Neuroscience 263, 125–129 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  85. 85

    Schmidt, L., Braun, E. K., Wager, T. D. & Shohamy, D. Mind matters: placebo enhances reward learning in Parkinson's disease. Nat. Neurosci. 17, 1793–1797 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  86. 86

    Mayberg, H. S. et al. The functional neuroanatomy of the placebo effect. Am. J. Psychiatry 159, 728–737 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  87. 87

    Leuchter, A. F., Cook, I. A., Witte, E. A., Morgan, M. & Abrams, M. Changes in brain function of depressed subjects during treatment with placebo. Am. J. Psychiatry 159, 122–129 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  88. 88

    Apkarian, A. V., Bushnell, M. C., Treede, R. D. & Zubieta, J. K. Human brain mechanisms of pain perception and regulation in health and disease. Eur. J. Pain 9, 463–484 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  89. 89

    Watson, A. et al. Placebo conditioning and placebo analgesia modulate a common brain network during pain anticipation and perception. Pain 145, 24–30 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  90. 90

    Wager, T. D. et al. Placebo-induced changes in fMRI in the anticipation and experience of pain. Science 303, 1162–1167 (2004). This study used a heat pain model to examine the neural basis of placebo analgesia and was the first fMRI study of placebo analgesia.

    CAS  Article  PubMed  Google Scholar 

  91. 91

    Price, D. D., Craggs, J., Verne, G. N., Perlstein, W. M. & Robinson, M. E. Placebo analgesia is accompanied by large reductions in pain-related brain activity in irritable bowel syndrome patients. Pain 127, 63–72 (2007).

    Article  PubMed  Google Scholar 

  92. 92

    Koyama, T., McHaffie, J. G., Laurienti, P. & Coghill, R. C. The subjective experience of pain: where expectations become reality. Proc. Natl Acad. Sci. USA 102, 12950–12955 (2005).

    CAS  Article  PubMed  Google Scholar 

  93. 93

    Keltner, J. et al. Isolating the modulatory effect of expectation on pain transmission: a functional magnetic resonance imaging study. J. Neurosci. 26, 4437–4443 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  94. 94

    Geuter, S., Eippert, F., Attar, C. H. & Büchel, C. Cortical and subcortical responses to high and low effective placebo treatments. Neuroimage 67, 227–236 (2013).

    Article  PubMed  Google Scholar 

  95. 95

    Wiech, K. et al. Anterior insula integrates information about salience into perceptual decisions about pain. J. Neurosci. 30, 16324–16331 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  96. 96

    Lee, H. F. et al. Enhanced affect/cognition-related brain responses during visceral placebo analgesia in irritable bowel syndrome patients. Pain 153, 1301–1310 (2012).

    Article  PubMed  Google Scholar 

  97. 97

    Lu, H.-C. et al. Neuronal correlates in the modulation of placebo analgesia in experimentally-induced esophageal pain: a 3T-fMRI study. Pain 148, 75–83 (2009).

    Article  PubMed  Google Scholar 

  98. 98

    Atlas, L. Y., Bolger, N., Lindquist, M. A. & Wager, T. D. Brain mediators of predictive cue effects on perceived pain. J. Neurosci. 30, 12964–12977 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  99. 99

    Kong, J. et al. Brain activity associated with expectancy-enhanced placebo analgesia as measured by functional magnetic resonance imaging. J. Neurosci. 26, 381–388 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  100. 100

    Wager, T. D., Atlas, L. Y., Leotti, L. A. & Rilling, J. K. Predicting individual differences in placebo analgesia: contributions of brain activity during anticipation and pain experience. J. Neurosci. 31, 439–452 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  101. 101

    Elsenbruch, S. et al. Neural mechanisms mediating the effects of expectation in visceral placebo analgesia: an fMRI study in healthy placebo responders and nonresponders. Pain 153, 382–390 (2012).

    Article  Google Scholar 

  102. 102

    Kong, J. et al. Functional connectivity of the frontoparietal network predicts cognitive modulation of pain. Pain 154, 459–467 (2013).

    Article  Google Scholar 

  103. 103

    Atlas, L. Y. & Wager, T. D. in Placebo (eds Benedetti, F., Enck, P., Frisaldi, E. & Schedlowski, M.) 37–69 (Springer, 2014).

    Book  Google Scholar 

  104. 104

    Koban, L., Ruzic, L. & Wager, T. D. in Placebo and Pain (eds Colloca, L., Flaten, M. A. & Meissner, K.) 89–102 (Academic, 2013).

    Book  Google Scholar 

  105. 105

    Amanzio, M., Benedetti, F., Porro, C. A., Palermo, S. & Cauda, F. Activation likelihood estimation meta-analysis of brain correlates of placebo analgesia in human experimental pain. Hum. Brain Mapp. 34, 738–752 (2013).

    PubMed  Google Scholar 

  106. 106

    Woo, C.-W., Roy, M., Buhle, J. T. & Wager, T. Distinct brain systems mediate the effects of nociceptive input and self-regulation on pain. PLoS Biol. 13, e1002036 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. 107

    Lorenz, J. et al. Cortical correlates of false expectations during pain intensity judgments — a possible manifestation of placebo/nocebo cognitions. Brain Behav. Immun. 19, 283–295 (2005).

    Article  Google Scholar 

  108. 108

    Aslaksen, P. M., Bystad, M., Vambheim, S. M. & Flaten, M. A. Gender differences in placebo analgesia: event-related potentials and emotional modulation. Psychosomat. Med. 73, 193–199 (2011).

    CAS  Article  Google Scholar 

  109. 109

    Colloca, L. et al. Learning potentiates neurophysiological and behavioral placebo analgesic responses. Pain 139, 306–314 (2009).

    Article  Google Scholar 

  110. 110

    Watson, A., El-Deredy, W., Vogt, B. A. & Jones, A. K. Placebo analgesia is not due to compliance or habituation: EEG and behavioural evidence. Neuroreport 18, 771–775 (2007).

    Article  Google Scholar 

  111. 111

    Yarkoni, T., Poldrack, R. A., Nichols, T. E., Van Essen, D. C. & Wager, T. D. Large-scale automated synthesis of human functional neuroimaging data. Nat. Methods 8, 665–670 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  112. 112

    Kross, E., Berman, M. G., Mischel, W., Smith, E. E. & Wager, T. D. Social rejection shares somatosensory representations with physical pain. Proc. Natl Acad. Sci. USA 108, 6270–6275 (2011).

    CAS  Article  Google Scholar 

  113. 113

    Davis, K. D., Taylor, S. J., Crawley, A. P., Wood, M. L. & Mikulis, D. J. Functional MRI of pain- and attention-related activations in the human cingulate cortex. J. Neurophysiol. 77, 3370–3380 (1997).

    CAS  Article  Google Scholar 

  114. 114

    Lindquist, K. A., Wager, T. D., Kober, H., Bliss-Moreau, E. & Barrett, L. F. The brain basis of emotion: a meta-analytic review. Behav. Brain Sci. 35, 121–143 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  115. 115

    Woo, C. W. et al. Separate neural representations for physical pain and social rejection. Nat. Commun. 5, 5380 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  116. 116

    Craig, A. D., Chen, K., Bandy, D. & Reiman, E. M. Thermosensory activation of insular cortex. Nat. Neurosci. 3, 184–190 (2000).

    CAS  Article  Google Scholar 

  117. 117

    Porreca, F., Ossipov, M. H. & Gebhart, G. Chronic pain and medullary descending facilitation. Trends Neurosci. 25, 319–325 (2002).

    CAS  Article  Google Scholar 

  118. 118

    Gebhart, G. Descending modulation of pain. Neurosci. Biobehav. Rev. 27, 729–737 (2004).

    CAS  Article  Google Scholar 

  119. 119

    Heinricher, M. & Fields, H. in Wall & Melzack's Textbook of Pain (eds McMahon, S., Koltzenburg, M., Tracey, I. & Turk, D. C.) 129–142 (Elsevier Health Sciences, 2013).

    Google Scholar 

  120. 120

    Fields, H. L. State-dependent opioid control of pain. Nat. Rev. Neurosci. 5, 565–575 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  121. 121

    Barbas, H., Saha, S., Rempel-Clower, N. & Ghashghaei, T. Serial pathways from primate prefrontal cortex to autonomic areas may influence emotional expression. BMC Neurosci. 4, 25 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  122. 122

    Keay, K. & Bandler, R. Parallel circuits mediating distinct emotional coping reactions to different types of stress. Neurosci. Biobehav. Rev. 25, 669–678 (2001).

    CAS  Article  Google Scholar 

  123. 123

    Wright, J. S. & Panksepp, J. Toward affective circuit-based preclinical models of depression: sensitizing dorsal PAG arousal leads to sustained suppression of positive affect in rats. Neurosci. Biobehav. Rev. 35, 1902–1915 (2011).

    Article  Google Scholar 

  124. 124

    Satpute, A. B. et al. Identification of discrete functional subregions of the human periaqueductal gray. Proc. Natl Acad. Sci. USA 110, 17101–17106 (2013).

    CAS  Article  Google Scholar 

  125. 125

    Linnman, C., Moulton, E. A., Barmettler, G., Becerra, L. & Borsook, D. Neuroimaging of the periaqueductal gray: state of the field. Neuroimage 60, 505–522 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  126. 126

    Buhle, J. T. et al. Common representation of pain and negative emotion in the midbrain periaqueductal gray. Soc. Cogn. Affect. Neurosci. 8, 609–616 (2013).

    Article  Google Scholar 

  127. 127

    Levine, J. D., Gordon, N. C. & Fields, H. L. The mechanism of placebo analgesia. Lancet 2, 654–657 (1978). This study demonstrated that placebo analgesia can be blocked with the opioid antagonist naloxone and was the first to demonstrate a biological mechanism for placebo.

    CAS  Article  Google Scholar 

  128. 128

    Benedetti, F. The opposite effects of the opiate antagonist naloxone and the cholecystokinin antagonist proglumide on placebo analgesia. Pain 64, 535–543 (1996).

    CAS  Article  Google Scholar 

  129. 129

    Wager, T. & Scott, D. Placebo effects on human μ-opioid activity during pain. Proc. Natl Acad. Sci. USA 104, 11056–11061 (2007).

    CAS  Article  Google Scholar 

  130. 130

    Scott, D. J. et al. Placebo and nocebo effects are defined by opposite opioid and dopaminergic responses. Arch. Gen. Psychiatry 65, 220–231 (2008).

    Article  Google Scholar 

  131. 131

    Zubieta, J. et al. Placebo effects mediated by endogenous opioid activity on μ-opioid receptors. J. Neurosci. 25, 7754–7762 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  132. 132

    Peciña, M. et al. Personality trait predictors of placebo analgesia and neurobiological correlates. Neuropsychopharmacology 38, 639–646 (2013).

    Article  CAS  Google Scholar 

  133. 133

    Eippert, F., Finsterbusch, J., Bingel, U. & Büchel, C. Direct evidence for spinal cord involvement in placebo analgesia. Science 326, 404 (2009). This study used fMRI to image the spinal cord and found that spinal responses to noxious stimuli are modulated with placebo, which implicates descending modulation.

    CAS  Article  Google Scholar 

  134. 134

    Matre, D., Casey, K. L. & Knardahl, S. Placebo-induced changes in spinal cord pain processing. J. Neurosci. 26, 559–563 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  135. 135

    Goffaux, P., de Souza, J., Potvin, S. & Marchand, S. Pain relief through expectation supersedes descending inhibitory deficits in fibromyalgia patients. Pain 145, 18–23 (2009).

    Article  Google Scholar 

  136. 136

    Petrovic, P., Kalso, E., Petersson, K. M. & Ingvar, M. Placebo and opioid analgesia — imaging a shared neuronal network. Science 295, 1737–1740 (2002). This PET study was the first to use neuroimaging to investigate mechanisms of the placebo response and found that both placebo analgesia and opioid analgesia induce changes in blood flow in the rostral ACC.

    CAS  Article  Google Scholar 

  137. 137

    Craggs, J. G., Price, D. D., Perlstein, W. M., Verne, G. N. & Robinson, M. E. The dynamic mechanisms of placebo induced analgesia: evidence of sustained and transient regional involvement. Pain 139, 660–669 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  138. 138

    Lui, F. et al. Neural bases of conditioned placebo analgesia. Pain 151, 816–824 (2010).

    Article  Google Scholar 

  139. 139

    Bingel, U., Lorenz, J., Schoell, E., Weiller, C. & Buchel, C. Mechanisms of placebo analgesia: rACC recruitment of a subcortical antinociceptive network. Pain 120, 8–15 (2006).

    CAS  Article  Google Scholar 

  140. 140

    Borckardt, J. J. et al. Postoperative left prefrontal repetitive transcranial magnetic stimulation reduces patient-controlled analgesia use. Anesthesiology 105, 557–562 (2006).

    CAS  Article  Google Scholar 

  141. 141

    Krummenacher, P., Candia, V., Folkers, G., Schedlowski, M. & Schonbachler, G. Prefrontal cortex modulates placebo analgesia. Pain 148, 368–374 (2010).

    Article  Google Scholar 

  142. 142

    Stein, N., Sprenger, C., Scholz, J., Wiech, K. & Bingel, U. White matter integrity of the descending pain modulatory system is associated with interindividual differences in placebo analgesia. Pain 153, 2210–2217 (2012).

    Article  Google Scholar 

  143. 143

    Zhang, Y. Q., Tang, J. S., Yuan, B. & Jia, H. Inhibitory effects of electrically evoked activation of ventrolateral orbital cortex on the tail-flick reflex are mediated by periaqueductal gray in rats. Pain 72, 127–135 (1997).

    CAS  Article  Google Scholar 

  144. 144

    Zhang, S., Tang, J. S., Yuan, B. & Jia, H. Electrically-evoked inhibitory effects of the nucleus submedius on the jaw-opening reflex are mediated by ventrolateral orbital cortex and periaqueductal gray matter in the rat. Neuroscience 92, 867–875 (1999).

    CAS  Article  Google Scholar 

  145. 145

    Johansen, J. P. et al. Optical activation of lateral amygdala pyramidal cells instructs associative fear learning. Proc. Natl Acad. Sci. USA 107, 12692–12697 (2010).

    CAS  Article  Google Scholar 

  146. 146

    Helmstetter, F. J., Tershner, S. A., Poore, L. H. & Bellgowan, P. S. Antinociception following opioid stimulation of the basolateral amygdala is expressed through the periaqueductal gray and rostral ventromedial medulla. Brain Res. 779, 104–118 (1998).

    CAS  Article  Google Scholar 

  147. 147

    Schultz, W., Dayan, P. & Montague, P. R. A neural substrate of prediction and reward. Science 275, 1593–1599 (1997).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  148. 148

    Kober, H. et al. Prefrontal–striatal pathway underlies cognitive regulation of craving. Proc. Natl Acad. Sci. USA 107, 14811–14816 (2010).

    CAS  Article  Google Scholar 

  149. 149

    Zaki, J., Schirmer, J. & Mitchell, J. P. Social influence modulates the neural computation of value. Psychol. Sci. 22, 894–900 (2011).

    Article  Google Scholar 

  150. 150

    Demos, K. E., Heatherton, T. F. & Kelley, W. M. Individual differences in nucleus accumbens activity to food and sexual images predict weight gain and sexual behavior. J. Neurosci. 32, 5549–5552 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  151. 151

    Berridge, K. C. & Robinson, T. E. What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? Brain Res. Brain Res. Rev. 28, 309–369 (1998).

    CAS  Article  Google Scholar 

  152. 152

    Wager, T. D., Hughes, B., Davidson, M., Lindquist, M. L. & Ochsner, K. N. Prefrontal–subcortical pathways mediating successful emotion regulation. Neuron 59, 1037–1050 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  153. 153

    Navratilova, E. & Porreca, F. Reward and motivation in pain and pain relief. Nat. Neurosci. 17, 1304–1312 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  154. 154

    Schwartz, N. et al. Decreased motivation during chronic pain requires long-term depression in the nucleus accumbens. Science 345, 535–542 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  155. 155

    Metz, A. E., Yau, H.-J., Centeno, M. V., Apkarian, A. V. & Martina, M. Morphological and functional reorganization of rat medial prefrontal cortex in neuropathic pain. Proc. Natl Acad. Sci. USA 106, 2423–2428 (2009).

    CAS  Article  Google Scholar 

  156. 156

    Baliki, M. N. et al. Corticostriatal functional connectivity predicts transition to chronic back pain. Nat. Neurosci. 15, 1117–1119 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  157. 157

    Schweinhardt, P., Seminowicz, D. A., Jaeger, E., Duncan, G. H. & Bushnell, M. C. The anatomy of the mesolimbic reward system: a link between personality and the placebo analgesic response. J. Neurosci. 29, 4882–4887 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  158. 158

    Scott, D. J. et al. Individual differences in reward responding explain placebo-induced expectations and effects. Neuron 55, 325–336 (2007).

    CAS  Article  Google Scholar 

  159. 159

    Wanigasekera, V. et al. Baseline reward circuitry activity and trait reward responsiveness predict expression of opioid analgesia in healthy subjects. Proc. Natl Acad. Sci. USA 109, 17705–17710 (2012).

    CAS  Article  Google Scholar 

  160. 160

    Zhang, W., Qin, S., Guo, J. & Luo, J. A follow-up fMRI study of a transferable placebo anxiolytic effect. Psychophysiology 48, 1119–1128 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  161. 161

    Benedetti, F. et al. Placebo-responsive Parkinson patients show decreased activity in single neurons of subthalamic nucleus. Nat. Neurosci. 7, 587–588 (2004).

    CAS  Article  Google Scholar 

  162. 162

    Drevets, W. C. et al. Subgenual prefrontal cortex abnormalities in mood disorders. Nature 386, 824–827 (1997).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  163. 163

    Mayberg, H. S. et al. Deep brain stimulation for treatment-resistant depression. Neuron 45, 651–660 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  164. 164

    Petrovic, P. et al. A prefrontal non-opioid mechanism in placebo analgesia. Pain 150, 59–65 (2010).

    Article  Google Scholar 

  165. 165

    Ellingsen, D.-M. et al. Placebo improves pleasure and pain through opposite modulation of sensory processing. Proc. Natl Acad. Sci. USA 110, 17993–17998 (2013).

    CAS  Article  Google Scholar 

  166. 166

    Kessner, S., Sprenger, C., Wrobel, N., Wiech, K. & Bingel, U. Effect of oxytocin on placebo analgesia: a randomized study. JAMA 310, 1733–1735 (2013).

    CAS  Article  Google Scholar 

  167. 167

    Rahnev, D., Lau, H. & de Lange, F. P. Prior expectation modulates the interaction between sensory and prefrontal regions in the human brain. J. Neurosci. 31, 10741–10748 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  168. 168

    Kok, P., Brouwer, G. J., van Gerven, M. A. & de Lange, F. P. Prior expectations bias sensory representations in visual cortex. J. Neurosci. 33, 16275–16284 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  169. 169

    Flaten, M. A., Aslaksen, P. M., Lyby, P. S. & Bjorkedal, E. The relation of emotions to placebo responses. Phil. Trans. R. Soc. B 366, 1818–1827 (2011).

    Article  Google Scholar 

  170. 170

    Roy, M., Shohamy, D. & Wager, T. D. Ventromedial prefrontal–subcortical systems and the generation of affective meaning. Trends Cogn. Sci. 16, 147–156 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  171. 171

    Chib, V. S., Rangel, A., Shimojo, S. & O'Doherty, J. P. Evidence for a common representation of decision values for dissimilar goods in human ventromedial prefrontal cortex. J. Neurosci. 29, 12315–12320 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  172. 172

    Hare, T. A., Camerer, C. F. & Rangel, A. Self-control in decision-making involves modulation of the vmPFC valuation system. Science 324, 646–648 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  173. 173

    Falk, E. B., Berkman, E. T., Whalen, D. & Lieberman, M. D. Neural activity during health messaging predicts reductions in smoking above and beyond self-report. Health Psychol. 30, 177–185 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  174. 174

    Wager, T. et al. An fMRI-based neurologic signature of physical pain. N. Engl. J. Med. 368, 1388–1397 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  175. 175

    Rescorla, R. A. Pavlovian conditioning. It's not what you think it is. Am. Psychol. 43, 151–160 (1988).

    CAS  Article  PubMed  Google Scholar 

  176. 176

    Gallistel, C. R. & Matzel, L. D. The neuroscience of learning: beyond the Hebbian synapse. Annu. Rev. Psychol. 64, 169–200 (2013).

    CAS  Article  PubMed  Google Scholar 

  177. 177

    Schoenbaum, G., Roesch, M. R., Stalnaker, T. A. & Takahashi, Y. K. A new perspective on the role of the orbitofrontal cortex in adaptive behaviour. Nat. Rev. Neurosci. 10, 885–892 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  178. 178

    Kirsch, I., Lynn, S. J., Vigorito, M. & Miller, R. R. The role of cognition in classical and operant conditioning. J. Clin. Psychol. 60, 369–392 (2004).

    Article  PubMed  Google Scholar 

  179. 179

    Stewart-Williams, S. & Podd, J. The placebo effect: dissolving the expectancy versus conditioning debate. Psychol. Bull. 130, 324–340 (2004).

    Article  PubMed  Google Scholar 

  180. 180

    Kirsch, I. Response expectancy as a determinant of experience and behavior. Am. Psychol. 40, 1189–1202 (1985).

    Article  Google Scholar 

  181. 181

    Voudouris, N. J., Peck, C. L. & Coleman, G. Conditioned placebo responses. J. Pers. Soc. Psychol. 48, 47–53 (1985).

    CAS  Article  PubMed  Google Scholar 

  182. 182

    Wickramasekera, I. A conditioned response model of the placebo effect; predictions from the model. Biofeedback Self Regul. 5, 5–18 (1980).

    CAS  Article  PubMed  Google Scholar 

  183. 183

    Carlino, E. et al. Role of explicit verbal information in conditioned analgesia. Eur. J. Pain 19, 546–553 (2015).

    CAS  Article  PubMed  Google Scholar 

  184. 184

    Montgomery, G. H. & Kirsch, I. Classical conditioning and the placebo effect. Pain 72, 107–113 (1997).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  185. 185

    Wendt, L. et al. Placebo-induced immunosuppression in humans: role of learning and expectation. Brain Behav. Immun. 29, S17 (2013).

    Article  Google Scholar 

  186. 186

    Benedetti, F., Amanzio, M., Baldi, S., Casadio, C. & Maggi, G. Inducing placebo respiratory depressant responses in humans via opioid receptors. Eur. J. Neurosci. 11, 625–631 (1999).

    CAS  Article  PubMed  Google Scholar 

  187. 187

    Morton, D. L., Watson, A., El-Deredy, W. & Jones, A. K. Reproducibility of placebo analgesia: effect of dispositional optimism. Pain 146, 194–198 (2009).

    Article  PubMed  Google Scholar 

  188. 188

    Morton, D. L., Brown, C. A., Watson, A., El-Deredy, W. & Jones, A. K. Cognitive changes as a result of a single exposure to placebo. Neuropsychologia 48, 1958–1964 (2010).

    Article  PubMed  Google Scholar 

  189. 189

    Doll, B. B., Jacobs, W. J., Sanfey, A. G. & Frank, M. J. Instructional control of reinforcement learning: a behavioral and neurocomputational investigation. Brain Res. 1299, 74–94 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  190. 190

    Biele, G., Rieskamp, J., Krugel, L. K. & Heekeren, H. R. The neural basis of following advice. PLoS Biol. 9, e1001089 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  191. 191

    Li, J., Delgado, M. R. & Phelps, E. A. How instructed knowledge modulates the neural systems of reward learning. Proc. Natl Acad. Sci. USA 108, 55–60 (2011).

    CAS  Article  PubMed  Google Scholar 

  192. 192

    Vase, L., Robinson, M., Verne, G. & Price, D. Increased placebo analgesia over time in irritable bowel syndrome (IBS) patients is associated with desire and expectation but not endogenous opioid mechanisms. Pain 115, 338–347 (2005).

    Article  PubMed  Google Scholar 

  193. 193

    Kirsch, I. & Henry, D. Extinction versus credibility in the desensitization of speech anxiety. J. Consult. Clin. Psychol. 45, 1052–1059 (1977).

    CAS  Article  PubMed  Google Scholar 

  194. 194

    Cliffer, K. D., Burstein, R. & Giesler, G. J. Jr. Distributions of spinothalamic, spinohypothalamic, and spinotelencephalic fibers revealed by anterograde transport of PHA-L in rats. J. Neurosci. 11, 852–868 (1991).

    CAS  Article  PubMed  Google Scholar 

  195. 195

    Willis, W. D. & Westlund, K. N. Neuroanatomy of the pain system and of the pathways that modulate pain. J. Clin. Neurophysiol. 14, 2–31 (1997).

    CAS  Article  PubMed  Google Scholar 

  196. 196

    Bandler, R., Keay, K. A., Floyd, N. & Price, J. Central circuits mediating patterned autonomic activity during active versus passive emotional coping. Brain Res. Bull. 53, 95–104 (2000).

    CAS  Article  PubMed  Google Scholar 

  197. 197

    Watkins, L. R. & Mayer, D. J. Organization of endogenous opiate and nonopiate pain control systems. Science 216, 1185–1192 (1982).

    CAS  Article  Google Scholar 

  198. 198

    Altier, N. & Stewart, J. The role of dopamine in the nucleus accumbens in analgesia. Life Sci. 65, 2269–2287 (1999).

    CAS  Article  Google Scholar 

  199. 199

    Gear, R. W., Aley, K. O. & Levine, J. D. Pain-induced analgesia mediated by mesolimbic reward circuits. J. Neurosci. 19, 7175–7181 (1999).

    CAS  Article  Google Scholar 

  200. 200

    Helmstetter, F. J. Stress-induced hypoalgesia and defensive freezing are attenuated by application of diazepam to the amygdala. Pharmacol. Biochem. Behav. 44, 433–438 (1993).

    CAS  Article  Google Scholar 

  201. 201

    Butler, R. K. & Finn, D. P. Stress-induced analgesia. Prog. Neurobiol. 88, 184–202 (2009).

    CAS  Article  Google Scholar 

  202. 202

    Yang, J. et al. Central oxytocin enhances antinociception in the rat. Peptides 28, 1113–1119 (2007).

    CAS  Article  Google Scholar 

  203. 203

    Lund, I. et al. Repeated massage-like stimulation induces long-term effects on nociception: contribution of oxytocinergic mechanisms. Eur. J. Neurosci. 16, 330–338 (2002).

    Article  Google Scholar 

  204. 204

    Yang, J. et al. Oxytocin in the periaqueductal gray participates in pain modulation in the rat by influencing endogenous opiate peptides. Peptides 32, 1255–1261 (2011).

    CAS  Article  Google Scholar 

  205. 205

    Watkins, L. R., Kinscheck, I. B. & Mayer, D. J. Potentiation of opiate analgesia and apparent reversal of morphine tolerance by proglumide. Science 224, 395–396 (1984).

    CAS  Article  Google Scholar 

  206. 206

    Wiertelak, E. P., Maier, S. F. & Watkins, L. R. Cholecystokinin antianalgesia: safety cues abolish morphine analgesia. Science 256, 830–833 (1992).

    CAS  Article  Google Scholar 

  207. 207

    Dum, J. & Herz, A. Endorphinergic modulation of neural reward systems indicated by behavioral changes. Pharmacol. Biochem. Behav. 21, 259–266 (1984).

    CAS  Article  Google Scholar 

  208. 208

    Rodgers, R. J. & Hendrie, C. A. Social conflict activates status-dependent endogenous analgesic or hyperalgesic mechanisms in male mice: effects of naloxone on nociception and behaviour. Physiol. Behav. 30, 775–780 (1983).

    CAS  Article  Google Scholar 

  209. 209

    Langford, D. J. et al. Varying perceived social threat modulates pain behavior in male mice. J. Pain 12, 125–132 (2011).

    Article  Google Scholar 

  210. 210

    Shyu, B. C., Sikes, R. W., Vogt, L. J. & Vogt, B. A. Nociceptive processing by anterior cingulate pyramidal neurons. J. Neurophysiol. 103, 3287–3301 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  211. 211

    Logothetis, N. K. What we can do and what we cannot do with fMRI. Nature 453, 869–878 (2008).

    CAS  Article  Google Scholar 

  212. 212

    Moerman, D. E. Meaning, Medicine and the 'Placebo Effect' (Cambridge Univ. Press, 2002).

    Book  Google Scholar 

  213. 213

    Benedetti, F., Durando, J. & Vighetti, S. Nocebo and placebo modulation of hypobaric hypoxia headache involves the cyclooxygenase-prostaglandins pathway. Pain 155, 921–928 (2014).

    CAS  Article  Google Scholar 

  214. 214

    Orne, T. M. On the social psychology of the psychological experiment: with particular reference to demand characteristics and their implications. Am. Psychol. 17, 776–783 (1962).

    Article  Google Scholar 

  215. 215

    Xie, J. Y. et al. Cholecystokinin in the rostral ventromedial medulla mediates opioid-induced hyperalgesia and antinociceptive tolerance. J. Neurosci. 25, 409–416 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references


The authors thank J. Sills and E. Hitchcock for research support, the members of the Cognitive and Affective Neuroscience Lab, S. Maier and L. Watkins for helpful discussions, and L. Ruzic for help with the summary in Figure 3. This work was funded by grants NIMH 2R01MH076136 and R01DA027794 (to T.D.W.). This work was also supported in part by the Intramural Research Program of the US National Institutes of Health's National Center for Complementary and Integrative Health.

Author information



Corresponding author

Correspondence to Tor D. Wager.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information S1

Supplementary information S1 (table) (PDF 214 kb)

Supplementary information S2 (box)

Neuroimaging studies included in Figure 3 (PDF 170 kb)

PowerPoint slides



The combination of all of the elements surrounding a given event that can be psychologically meaningful, including interpersonal dynamics, situational features owing to a place or location, memories, goals for the future and internal body or brain states.


Stimuli that signify the occurrence, or evoke a representation, of another stimulus or internal experience.


Coordinated responses to biologically relevant events (such as threats and opportunities) that involve changes in multiple systems, including peripheral physiology.

Nocebo effects

Deleterious outcomes (for example, an increase in pain or an increase in negative side effects) owing to beliefs about the treatment context.

Placebo responders

Individuals who show an improvement in symptoms after receiving inert treatments (that is, placebos).

Placebo analgesia

A reduction in pain that can be attributed to the treatment context.

Response conditioning

The process of associating neutral stimuli with biologically meaningful outcomes, through which neutral stimuli may begin to induce anticipatory responses that are associated with the outcomes themselves.


A conscious, conceptual belief about the future occurrence of an event. It is a subclass of predictive processes, which may be conscious or unconscious.


Pain relief, which can be caused by many factors, including medical treatments (for example, opioid analgesia), features of the treatment context (placebo analgesia) and affective states (for example, stress-induced analgesia).


Receiving input from stimuli that can cause damage to tissues.

Descending pain modulation systems

Endogenous, biological mechanisms for suppressing ascending nociceptive information at the level of the spinal cord.

Pre-cognitive associations

Links between events and/or objects that exist outside conscious awareness. These links are generally created through conditioning procedures or innate (evolutionarily afforded) associations.

Conceptual processes

Processes that depend on an interpretation of the situational context and its relationship to prior information (for example, memories and rules), including interoceptive cues from the body, and which can be updated in response to verbally presented or symbolic information.


A conceptual, 'situational' pattern — inferred from a combination of sensory cues, internal motivation, interoceptive information and thoughts — that can activate scripts that guide behaviour based on the nature of the situation rather than any single cue.


Inferred causality; the process of assigning an observed effect (for example, a symptom) to an underlying cause or mechanism.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wager, T., Atlas, L. The neuroscience of placebo effects: connecting context, learning and health. Nat Rev Neurosci 16, 403–418 (2015).

Download citation

Further reading


Quick links