• Users Online: 550
  • Home
  • Print this page
  • Email this page
Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contacts Login 

 Table of Contents  
Year : 2017  |  Volume : 4  |  Issue : 3  |  Page : 123-128

Placebo response in clinical trials: Taming the human brain

1 Medical Writing, Tata Consultancy Services, Noida, India
2 Department of Physiology, All Institute of Medical Sciences, New Delhi, India

Date of Web Publication16-Oct-2017

Correspondence Address:
Raj Kumar Yadav
Department of Physiology, All India Institute of Medical Sciences, New Delhi - 110 029
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijcep.ijcep_36_17

Rights and Permissions

The use of placebo in comparative clinical trials has exposed another lesser known side of the placebo, i.e., the placebo response. The placebo response is now being increasingly discussed, not only to adjust for the true clinical efficacy of a drug but also to understand the basis of psychological therapy, and benefits in therapeutic areas such as neurological disorders, especially pain. The mechanism of placebo action is multifaceted and works on the levels of brain and biochemical signaling, stimulated by priming and expectations. The imaging data show that certain areas of the brain are hyperactive while some are hypoactive during the placebo-mediated response, and trigger a biochemical pathway that relieves the symptoms. The data also suggest that the extent of benefit, i.e., the effect size of placebo response is directly proportional to positive expectations associated with the treatment, trust on the treating doctor, and certain beliefs associated with previous treatment. Although placebos incite a positive response, these might compromise or artifact the true efficacy of the drugs, thereby necessitating the need of addressing or minimizing the placebo response. Furthermore, it is important to identify the factors that modulate the placebo response, such as severity and natural burning out of the disease. Therefore, it is important to take a two-pronged approach- first, placebo as a treatment, for example, in neurological diseases, and second, adequately designed studies that minimize the placebo response. In this article, we discuss the placebo response, the mechanism behind it, its implications in clinical trials, and how to address the same.

Keywords: Clinical trials, implications, mechanism, placebo response

How to cite this article:
Bhardwaj P, Yadav RK. Placebo response in clinical trials: Taming the human brain. Int J Clin Exp Physiol 2017;4:123-8

How to cite this URL:
Bhardwaj P, Yadav RK. Placebo response in clinical trials: Taming the human brain. Int J Clin Exp Physiol [serial online] 2017 [cited 2018 Nov 14];4:123-8. Available from: http://www.ijcep.org/text.asp?2017/4/3/123/216726

  Introduction Top

Clinical trials for long have embraced the use of placebo in almost all the trials, so much so that the use has become an epitome of evidence supporting efficacy and safety of tested interventions. The use of placebo takes its glory from the study designs that control for the biasing factors, thereby mandating the use of a comparator that allows evaluating the active treatment versus a situation when no intervention was given (placebo). This trend is increasingly evident now and can be attributed to a harmony between patients and the treating physicians. Interestingly, the placebo response is more pronounced in active comparator trials as patients have a surety of receiving treatment.[1],[2]

As a so-called “inert-treatment,” placebo is supposed to provide an insight into the true efficacy and safety of the intervention. However, time and again the cumulative data suggest that it has something more than its “inert” nature. The data show that such positive effect is evident even when the truth is disclosed to the recipients.[3] Placebo response may be stronger in pediatric patients,[4] and up to 41% of children showed benefit in an abdominal pain-related functional gastrointestinal disorders trial.[5] This psychological priming, rather taming, of the human brain makes it believe that the body is being treated, and it is going to show a benefit. This essentially outlines the need to understand this powerful interaction between human body and brain. Besides, this aspect is being now increasingly explored to understand the complex mind-body interaction, and how certain mind games and behavior can impact the human body in either direction.

The emerging data from physiological, psychological, immune-neuroendocrinology studies suggest that this interaction can be utilized in a number of ways to benefit the human beings in health and disease.

  The Mechanism of Placebo Effect Top

The earliest evidence supporting this interaction between brain and body dates back to Pavlov, where a conditioning effect was seen on hunger. This reflects into many of our daily activities, and we think that this is just a habit. However, these habits are nothing, but how we have primed ourselves or tamed our brain/thinking. Despite having witnessed this daily “placebo” effect, we remain unaware of the mechanism of this placebo effect or priming.

The conceptual thought around placebo effect can be attributed to the severity of the disease, positive thinking/expectations, conditioning/priming, harmonious relations with treating doctors, and compassionate support from paramedical staff and family/friends. This in turn triggers a positive response leading to neurotransmitters and releasing endogenous opioids, and neuromodulation [Figure 1].
Figure 1: Conceptual framework for placebo response

Click here to view

The key players that modulate these effects are patients' understanding of the disease and their expectations from the treatment, severity and impact of the disease, patient–doctor relationship, patients' state of mind, and social and environmental factors. When the treatment is administered, whether active or placebo, it is administered with a trust that it will bring an improvement in the clinical symptoms.[6] However, the effect size of placebo response is variable, and different individuals respond differently.[7] In a recent pilot study, the benefit was directly related to hope of healing and indicates self-healing as the core of this benefit.[8] The three key fields spanning the understanding so far have been described here.

Priming and expectation

In layperson's language, placebo works by priming the brain, where brain believes that a particular intervention will benefit the body. The simplest example from the day-to-day life is where just a peck from the mother on child's hurt hand takes away the pain. Another example is where doctor assures patient that there will be a benefit and as a miracle patient experiences benefit/relief.[9] This expectation for the positive outcome seems to play a key role in placebo-related benefit, along with other factors such as optimism and social conditioning and may produce a medium-sized benefit.[10] Positive expectations may also enhance the treatment response, and the extent of benefit seems to be related to the strength of belief/expectation.[11],[12] Such benefit of positive impact is apparent even when the treatment remains unchanged when only the expectation with the “so-called” new treatment is changed.

The data also show that lower is the expectation of receiving active treatment, for example, in multi-treatment arms, lower is the placebo response,[13],[14] and vice-versa.[15] Placebo effects may be exaggerated by having positive discussions with the patients. The data show that patients have better learning experiences in clinical set-up versus healthy people. Similar is the case with preconditioning, which tends to deliver maximum benefit out of placebos. In either situation, the previous impact has a large influence on the overall outcome.

Effects on brain

The imaging data show that on receiving treatment for pain, the regional blood flow reduces in the left basomedial/basolateral and right ventrolateral amygdala, including amygdala-frontal projections to dorsolateral prefrontal cortex (DLPFC), rostral anterior cingulate cortices (rACC), anterior insular cortex (AIC), and subcortical areas hypothalamus, thalamus, amygdala, and periaqueductal.[16],[17],[18],[19] Similar results were noted in another study, where DLPFC, insula, and nucleus accumbens correlated with placebo analgesia.[20] These findings indicate a specific functional connectivity that clearly suggests that cognition and expectation, essentially a function of DLPFC, play an important role in the placebo effect. The expectation related to pain and its treatment has been evaluated quite extensively. One study shows that the magnitude of expectation was dependent on the functional connectivity between right frontoparietal network and rACC, and associated pain relief was dependent on the functional connectivity between the somatosensory areas and the cerebellum.[21] Another study shows that the functional connectivity between the dorsomedial prefrontal cortex and insula predicted the magnitude and probability of pain relief with placebo.[22] Similar results were observed in a meta-analysis using data from 11 imaging studies, where left anterior cingulate, right precentral and lateral prefrontal cortex, and the left periaqueductal gray were particularly active during expectation phase.[23] Significant placebo response was noted for placebo analgesia in experimental conditions, where pain processing was lowered in the thalamus, AIC, and anterior cingulate cortex, and was proportional in nature.[17]

Having discussed the mechanism of placebo response in detail, it is should also be noted that the size of the placebo effect varies largely. This seems to be driven by the expectation and optimism that a patient has had associated with the treatment.[24],[25] Therefore, when the patient knows that treatment is being given, the benefit is higher versus when the patient is unaware of the fact that treatment is given.[26],[27]

Biochemical trail

The above findings clearly suggest that cortical regions play a key role in managing placebo effect and triggering the pain relief through inhibition of pain regulating pathways. Endogenous neuropeptides such as opioids, oxytocin, cholecystokinin (CCK), and cannabinoids are known to regulate the pain pathways.[28],[29],[30] There could be non-opioid pathways engaged as well.

The evidence for placebo working through the opioid-CKK systems comes to the studies where opioid antagonist seemed to prevent while CCK antagonists seem to increase the analgesic effects of placebo.[31],[32] This works through activation of μ-opioid neurotransmission in the brain including DLPFC, the anterior cingulate cortex, the insula, and the nucleus accumbens.[33] The alterations in opioidergic neurotransmission are also associated with changes in dopamine levels, and endogenous opioids work together with dopamine in eliciting placebo effect.[34] The proof came from disruption of placebo analgesia following naloxone administration that disrupts the endogenous opioid release.[32]

The data show that nonopioid mechanism may also work in the background of placebo analgesia, largely by conditioning. This is mediated by the endogenous cannabinoids,[28] and oxytocin, which works through oxytocinergic pathway.[30] The difference between opioid and nonopioid mechanisms can be demonstrated using previous exposure to naloxone and rimonabant, i.e., opioid- and cannabinoid-mediated placebo responses, respectively.

Imaging studies also suggest that dopamine release following activation of nucleus accumbens, which is involved in reward mechanisms, seems to modulate the placebo effect.[35] This also means that placebo response may enhance the reward learning in healthy individuals.[36] It is believed that the placebo works through a neuroimmune pathway, and therefore such pathways are now being increasingly studied, especially due to technology advancement.

The possible mechanism of placebo response was first proposed by Fuente-Fernandez while studying patients with Parkinson's disease.[37] There were two-blinded treatment scenarios-patients received an apomorphine versus placebo and an apomorphine only. Results demonstrated that the placebo response was achieved by endogenous dopamine release across the parts of striatum using the positron emission tomography (PET) scan of the brain using raclopride. This benefit directly correlated with the extent of endogenous dopamine release; however, there was a large variability in the response across the study population. The extension study supported these findings and suggested that for some patients, the magnitude of benefit with placebo can be as strong as the active treatment. Another study showed that placebo activates the dopamine receptors in the brain (ventral and dorsal striatum, both),[38] which could be due to the altered firing rate of neurons specific brain regions.[39],[40]

  When it Is and When it Is not Top

Patients may often show benefit due to natural burning out of the disease (e.g., chronic pancreatitis), spontaneous remission (e.g., inflammatory bowel disease), incorrectly defined or inadequate efficacy measures (e.g., less stringent clinically meaningful important difference), less severe or very severe disease, methodological complexities and shortcomings, and unknown factors.[41],[42] Importantly, these factors may impact patients differently, and often may bias the results even when a proper randomization was done since many of these factors work in the background.

One very common finding in clinical trials is that more is the severity of the symptoms, more is the treatment benefit. In such cases, placebo response can be attributed to the increased severity of the disease/symptoms at baseline, and such biases can be addressed using regression analysis. This is, however, not the placebo response.

Sometimes, the benefit is extended by natural burning out of the disease, which is not the placebo response but actually the natural “dying out” of the disease. To rule out any confusion, the natural history of the disease should be taken into consideration. A meta-analysis showed that at half of the time, the placebo response could be explained by spontaneous remission or natural burning out of the disease or variation.[43]

Therefore, it is important to understand that drugs and placebos act differently, even though the result is same. In this context, one should understand that the benefit extended by the drugs is longer lasting versus placebo, mainly by addressing the root cause of the problem or relieving the symptoms by blocking/enhancing certain pathways. In addition, increasing the dose increase may also help differentiate between a drug and a placebo. This also means that placebos may be especially helpful in psychological disorders.

Besides psychological disorders, placebo has shown efficacy in other diseases as well, for example, irritable bowel syndrome, where a psychological intervention showed a positive effect.[44]

  Clinical Implications Top

The placebo effect may sometimes, therefore, compromise/enhance the efficacy of the drug in clinical trials, especially when patients are not sure if they are or are not getting an active drug.[45],[46] At times, there could be no difference observed between placebo and active treatment.[47] However, in real-world they are always sure that they are getting an active treatment, thereby increasing the effect size versus that observed in clinical trials. This effect has been observed with sham surgeries for pain, as well.[48]

Patients may have a response or maybe the better clinical outcome(s), which sometimes may apparently reduce the cost of the treatment. Interestingly, the higher the patient perceived price of the treatment was, greater was the benefit.[49],[50],[51]

There have been suggestions to elicit placebo response such as speaking positively about treatments, cultivating encouragement, trust, reassurance, support, respect uniqueness, exploring values, and “creating ceremony.”[52] It is believed that such practice would induce a positivity in the patients and help them heal better.[53],[54] However, the use of placebo for additional benefit to the patients should be ethical and should complement their active treatment in clinical practice.

On the other hand, the data from antipsychotic trials indicate that placebo response grossly affects the efficacy data, and could pose a major challenge.[55] There could be specific patient and disease characteristics that manipulate the placebo response size. These factors should be considered while conceptualizing a study, and planning the biostatistical analyses.

  Quick Fix Top

Placebo effect size can vary largely and can be as high as up to 60% in sleep trials[56] and 40% psychiatric trials.[13] In general double-blind, randomized controlled trials will address the placebo effect since both the groups receive a blinded drug, and the effect would be the same in the treatment groups. This ensures that active treatment yields a treatment benefit over and above the placebo, and hence can be used to effectively treat a disease. However, some thoughts contradict this proposal. This is because the expectation is that subtracting the placebo effect from the drug should yield the true effect size and give a true estimate of drug's efficacy. This also has implication in power calculation and should be taken into consideration.[57] In a meta-analysis of fibromyalgia trials, the placebo effect size for pain, and other outcomes were estimated. Placebo effect size increased with increasing strength of the active drug and was also impacted by age, gender, and disease duration.[58]

Carefully and thoughtfully designed clinical trials may limit the biases to a large extent, and address or minimize the “placebo” response size.[59],[60] A recent study shared the perspective on identify placebo response and responder predictors.[61] Another precaution is a careful and thorough study of the natural history of the disease. Furthermore, objective endpoints should be preferred over subjective ones to avoid biased results. For example, a run-in period may help to identify the limiting factors and fix these accordingly. The data show a lot of focus is now directed toward innovative trial designs to not only rule out the placebo effect[59] but also harness some benefit out of this.[62] Researchers have been brain-storming to minimize placebo effect by introducing newer clinical trials designs, especially where psychological outcome(s) are being measured.[63] In addition, there have been suggestions to assess patients' expectations in clinical trials, which may help to understand and address such biases.[64]

Having said this, it is of clinical importance that placebo response is maintained below the clinical threshold to minimize the possible interference with the clinical effect of the tested drug.[65]

  Interventions Where Core Efficacy Depends on the Placebo Response Top

We have been struggling for long to find out the placebo arms for lifestyle interventions, especially those active interventions that seem to influence beliefs and mind, for example, counseling, yoga, and meditation, also referred to as mindfulness-based stress reduction or cognitive therapy (MBSR or MBCT). The data show that MBSR-based interventions could have a different mechanism of action versus placebo, and activates higher-order brain regions, possibly orbitofrontal and cingulate cortices while placebo may decrease pain-related brain activation.[66] Seemingly, yoga and meditation positively impact the body, and it is imperative that mastering such technique take a good amount of time, during which the brain becomes conditioned and produce (placebo) response. This could be a reason that higher-order brain regions are activated in MBSR-based interventions. PET imaging of novices versus experienced meditators mat help us in understanding the impact on the brain in a better way. An interesting article published over a decade back raised a very interesting question-yoga is a better treatment or better placebo.[67] In a comment to a paper published by Raina et al.,[68] the author questioned if better expectation with yoga led to better effect in yoga group versus exercise group in a study including alcoholic patients. This seems plausible as now we know that response has to do a lot with the expectation. Therefore, it is increasingly difficult to segregate the benefit of psychological interventions such as yoga-meditation/MBSR and counseling versus placebo response, where the outcome is derived based on psychological impact.

Similar is the case with psychological interventions, which seem to work on the basis of psychoneuroimmunology,[69] although there is no significant data published around it.

  Conclusion Top

Personally, we all, at one or the other point in time, rather many times, have experienced the placebo response even if we have believed it or not. Truly speaking, it has generally a positive side associated and has helped many patients to achieve a clinical benefit despite a difficult to treat disease. Therefore, it is of utmost importance to harness the power of placebo response by a positive approach, yet segregating it wisely from the ailments where an active pharmacological intervention is needed. How the placebo works may have deeper than visible roots as human brain and mind are complex and the mechanism of action of placebo unraveled so far may be just the tip of the iceberg.

In summary, more answers to this question might be available with continued research and insights into the human brain, particularly with advancing technology.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Rutherford BR, Mori S, Sneed JR, Pimontel MA, Roose SP. Contribution of spontaneous improvement to placebo response in depression: A meta-analytic review. J Psychiatr Res 2012;46:697-702.  Back to cited text no. 1
Woods SW, Gueorguieva RV, Baker CB, Makuch RW. Control group bias in randomized atypical antipsychotic medication trials for schizophrenia. Arch Gen Psychiatry 2005;62:961-70.  Back to cited text no. 2
Kam-Hansen S, Jakubowski M, Kelley JM, Kirsch I, Hoaglin DC, Kaptchuk TJ, et al. Altered placebo and drug labeling changes the outcome of episodic migraine attacks. Sci Transl Med 2014;6:218ra5.  Back to cited text no. 3
Janiaud P, Cornu C, Lajoinie A, Djemli A, Cucherat M, Kassai B, et al. Is the perceived placebo effect comparable between adults and children? A meta-regression analysis. Pediatr Res 2017;81:11-7.  Back to cited text no. 4
Hoekman DR, Zeevenhooven J, van Etten-Jamaludin FS, Douwes Dekker I, Benninga MA, Tabbers MM, et al. The placebo response in pediatric abdominal pain-related functional gastrointestinal disorders: A systematic review and meta-analysis. J Pediatr 2017;182:155-63.e7.  Back to cited text no. 5
Di Blasi Z, Harkness E, Ernst E, Georgiou A, Kleijnen J. Influence of context effects on health outcomes: A systematic review. Lancet 2001;357:757-62.  Back to cited text no. 6
Benedetti F. Placebo-Effects: Understanding the Mechanisms in Health and Disease. Oxford, UK: Oxford University Press; 2009.  Back to cited text no. 7
Stub T, Foss N, Liodden I. “Placebo effect is probably what we refer to as patient healing power”: A qualitative pilot study examining how Norwegian complementary therapists reflect on their practice. BMC Complement Altern Med 2017;17:262.  Back to cited text no. 8
Benedetti F. Placebo and the new physiology of the doctor-patient relationship. Physiol Rev 2013;93:1207-46.  Back to cited text no. 9
Peerdeman KJ, van Laarhoven AI, Keij SM, Vase L, Rovers MM, Peters ML, et al. Relieving patients' pain with expectation interventions: A meta-analysis. Pain 2016;157:1179-91.  Back to cited text no. 10
Krell HV, Leuchter AF, Morgan M, Cook IA, Abrams M. Subject expectations of treatment effectiveness and outcome of treatment with an experimental antidepressant. J Clin Psychiatry 2004;65:1174-9.  Back to cited text no. 11
Bjørkedal E, Flaten MA. Interaction between expectancies and drug effects: An experimental investigation of placebo analgesia with caffeine as an active placebo. Psychopharmacology (Berl) 2011;215:537-48.  Back to cited text no. 12
Papakostas GI, Fava M. Does the probability of receiving placebo influence clinical trial outcome? A meta-regression of double-blind, randomized clinical trials in MDD. Eur Neuropsychopharmacol 2009;19:34-40.  Back to cited text no. 13
Sinyor M, Levitt AJ, Cheung AH, Schaffer A, Kiss A, Dowlati Y, et al. 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 2010;71:270-9.  Back to cited text no. 14
Flaten MA, Aslaksen PM, Finset A, Simonsen T, Johansen O. Cognitive and emotional factors in placebo analgesia. J Psychosom Res 2006;61:81-9.  Back to cited text no. 15
Faria V, Ahs F, Appel L, Linnman C, Bani M, Bettica P, et al. Amygdala-frontal couplings characterizing SSRI and placebo response in social anxiety disorder. Int J Neuropsychopharmacol 2014;17:1149-57.  Back to cited text no. 16
Wager TD, Rilling JK, Smith EE, Sokolik A, Casey KL, Davidson RJ, et al. Placebo-induced changes in FMRI in the anticipation and experience of pain. Science 2004;303:1162-7.  Back to cited text no. 17
Bingel U, Lorenz J, Schoell E, Weiller C, Büchel C. Mechanisms of placebo analgesia: RACC recruitment of a subcortical antinociceptive network. Pain 2006;120:8-15.  Back to cited text no. 18
Craggs JG, Price DD, Perlstein WM, Verne GN, Robinson ME. The dynamic mechanisms of placebo induced analgesia: Evidence of sustained and transient regional involvement. Pain 2008;139:660-9.  Back to cited text no. 19
Schweinhardt P, Seminowicz DA, Jaeger E, Duncan GH, Bushnell MC. The anatomy of the mesolimbic reward system: A link between personality and the placebo analgesic response. J Neurosci 2009;29:4882-7.  Back to cited text no. 20
Kong J, Jensen K, Loiotile R, Cheetham A, Wey HY, Tan Y, et al. Functional connectivity of the frontoparietal network predicts cognitive modulation of pain. Pain 2013;154:459-67.  Back to cited text no. 21
Hashmi JA, Baria AT, Baliki MN, Huang L, Schnitzer TJ, Apkarian AV, et al. Brain networks predicting placebo analgesia in a clinical trial for chronic back pain. Pain 2012;153:2393-402.  Back to cited text no. 22
Amanzio M, Benedetti F, Porro CA, Palermo S, Cauda F. Activation likelihood estimation meta-analysis of brain correlates of placebo analgesia in human experimental pain. Hum Brain Mapp 2013;34:738-52.  Back to cited text no. 23
Kirsch I. How Expectancies Shape Experience. Washington, DC: American Psychological Association; 1999.  Back to cited text no. 24
Price DD, Finniss DG, Benedetti F. A comprehensive review of the placebo effect: Recent advances and current thought. Annu Rev Psychol 2008;59:565-90.  Back to cited text no. 25
Amanzio M, Pollo A, Maggi G, Benedetti F. Response variability to analgesics: A role for non-specific activation of endogenous opioids. Pain 2001;90:205-15.  Back to cited text no. 26
Colloca L, Lopiano L, Lanotte M, Benedetti F. Overt versus covert treatment for pain, anxiety, and Parkinson's disease. Lancet Neurol 2004;3:679-84.  Back to cited text no. 27
Benedetti F, Amanzio M, Rosato R, Blanchard C. Nonopioid placebo analgesia is mediated by CB1 cannabinoid receptors. Nat Med 2011;17:1228-30.  Back to cited text no. 28
Benedetti F, Amanzio M, Vighetti S, Asteggiano G. The biochemical and neuroendocrine bases of the hyperalgesic nocebo effect. J Neurosci 2006;26:12014-22.  Back to cited text no. 29
Kessner S, Sprenger C, Wrobel N, Wiech K, Bingel U. Effect of oxytocin on placebo analgesia: A randomized study. JAMA 2013;310:1733-5.  Back to cited text no. 30
Eippert F, Bingel U, Schoell ED, Yacubian J, Klinger R, Lorenz J, et al. Activation of the opioidergic descending pain control system underlies placebo analgesia. Neuron 2009;63:533-43.  Back to cited text no. 31
Benedetti F. The opposite effects of the opiate antagonist naloxone and the cholecystokinin antagonist proglumide on placebo analgesia. Pain 1996;64:535-43.  Back to cited text no. 32
Wager TD, Scott DJ, Zubieta JK. Placebo effects on human mu-opioid activity during pain. Proc Natl Acad Sci U S A 2007;104:11056-61.  Back to cited text no. 33
Scott DJ, Stohler CS, Egnatuk CM, Wang H, Koeppe RA, Zubieta JK, et al. Individual differences in reward responding explain placebo-induced expectations and effects. Neuron 2007;55:325-36.  Back to cited text no. 34
Knutson B, Cooper JC. Functional magnetic resonance imaging of reward prediction. Curr Opin Neurol 2005;18:411-7.  Back to cited text no. 35
Turi Z, Mittner M, Paulus W, Antal A. Placebo intervention enhances reward learning in healthy individuals. Sci Rep 2017;7:41028.  Back to cited text no. 36
de la Fuente-Fernández R, Ruth TJ, Sossi V, Schulzer M, Calne DB, Stoessl AJ, et al. Expectation and dopamine release: Mechanism of the placebo effect in Parkinson's disease. Science 2001;293:1164-6.  Back to cited text no. 37
Lidstone SC, Schulzer M, Dinelle K, Mak E, Sossi V, Ruth TJ, et al. Effects of expectation on placebo-induced dopamine release in Parkinson disease. Arch Gen Psychiatry 2010;67:857-65.  Back to cited text no. 38
Benedetti F, Lanotte M, Colloca L, Ducati A, Zibetti M, Lopiano L, et al. Electrophysiological properties of thalamic, subthalamic and nigral neurons during the anti-Parkinsonian placebo response. J Physiol 2009;587:3869-83.  Back to cited text no. 39
Frisaldi E, Carlino E, Lanotte M, Lopiano L, Benedetti F. Characterization of the thalamic-subthalamic circuit involved in the placebo response through single-neuron recording in Parkinson patients. Cortex 2014;60:3-9.  Back to cited text no. 40
Weimer K, Colloca L, Enck P. Placebo effects in psychiatry: Mediators and moderators. Lancet Psychiatry 2015b; 2:246-57.  Back to cited text no. 41
Häuser W, Bartram-Wunn E, Bartram C, Reinecke H, Tölle T. Systematic review: Placebo response in drug trials of fibromyalgia syndrome and painful peripheral diabetic neuropathy-magnitude and patient-related predictors. Pain 2011;152:1709-17.  Back to cited text no. 42
Krogsbøll LT, Hróbjartsson A, Gøtzsche PC. Spontaneous improvement in randomised clinical trials: Meta-analysis of three-armed trials comparing no treatment, placebo and active intervention. BMC Med Res Methodol 2009;9:1.  Back to cited text no. 43
Flik CE, Bakker L, Laan W, van Rood YR, Smout AJ, de Wit NJ, et al. Systematic review: The placebo effect of psychological interventions in the treatment of irritable bowel syndrome. World J Gastroenterol 2017;23:2223-33.  Back to cited text no. 44
Morral A, Urrutia G, Bonfill X. Placebo effect and therapeutic context: A challenge in clinical research. Med Clin (Barc) 2017;149:26-31.  Back to cited text no. 45
Holtedahl R, Brox JI, Tjomsland O. Placebo effects in trials evaluating 12 selected minimally invasive interventions: A systematic review and meta-analysis. BMJ Open 2015;5:e007331.  Back to cited text no. 46
Howick J, Friedemann C, Tsakok M, Watson R, Tsakok T, Thomas J, et al. Are treatments more effective than placebos? A systematic review and meta-analysis. PLoS One 2013;8:e62599.  Back to cited text no. 47
Gu AP, Gu CN, Ahmed AT, Murad MH, Wang Z, Kallmes DF, et al. Sham surgical procedures for pain intervention result in significant improvements in pain: Systematic review and meta-analysis. J Clin Epidemiol 2017;83:18-23.  Back to cited text no. 48
Andrade C. Cost of treatment as a placebo effect in psychopharmacology: Importance in the context of generic drugs. J Clin Psychiatry 2015;76:e534-6.  Back to cited text no. 49
Espay AJ, Norris MM, Eliassen JC, Dwivedi A, Smith MS, Banks C, et al. Placebo effect of medication cost in Parkinson disease: A randomized double-blind study. Neurology 2015;84:794-802.  Back to cited text no. 50
Waber RL, Shiv B, Carmon Z, Ariely D. Commercial features of placebo and therapeutic efficacy. JAMA 2008;299:1016-7.  Back to cited text no. 51
Barrett B, Muller D, Rakel D, Rabago D, Marchand L, Scheder JC, et al. Placebo, meaning, and health. Perspect Biol Med 2006;49:178-98.  Back to cited text no. 52
Rief W, Bingel U, Schedlowski M, Enck P. Mechanisms involved in placebo and nocebo responses and implications for drug trials. Clin Pharmacol Ther 2011;90:722-6.  Back to cited text no. 53
Bensing JM, Verheul W. The silent healer: The role of communication in placebo effects. Patient Educ Couns 2010;80:293-9.  Back to cited text no. 54
Agid O, Siu CO, Potkin SG, Kapur S, Watsky E, Vanderburg D, et al. Meta-regression analysis of placebo response in antipsychotic trials, 1970-2010. Am J Psychiatry 2013;170:1335-44.  Back to cited text no. 55
Winkler A, Rief W. Effect of placebo conditions on polysomnographic parameters in primary insomnia: A Meta-analysis. Sleep 2015;38:925-31.  Back to cited text no. 56
Hyde AJ, May BH, Xue CC, Zhang AL. Variation in placebo effect sizes in clinical trials of oral interventions for management of the Behavioral and Psychological Symptoms of Dementia (BPSD): A systematic review and meta-analysis. Am J Geriatr Psychiatry 2017;25:994-1008.  Back to cited text no. 57
Chen X, Zou K, Abdullah N, Whiteside N, Sarmanova A, Doherty M, et al. The placebo effect and its determinants in fibromyalgia: Meta-analysis of randomised controlled trials. Clin Rheumatol 2017;36:1623-30.  Back to cited text no. 58
Enck P, Klosterhalfen S. The placebo response in clinical trials-the current state of play. Complement Ther Med 2013;21:98-101.  Back to cited text no. 59
Imanaka T, Sato I, Tanaka S, Kawakami K. Predictive factors for the placebo effect in clinical trials for dry eye: A pooled analysis of three clinical trials. Br J Ophthalmol 2017. pii: bjophthalmol-2016-309887.  Back to cited text no. 60
Fu Y, Persson MS, Bhattacharya A, Goh SL, Stocks J, van Middelkoop M, et al. Identifying placebo responders and predictors of response in osteoarthritis: A protocol for individual patient data meta-analysis. Syst Rev 2016;5:183.  Back to cited text no. 61
Enck P, Bingel U, Schedlowski M, Rief W. The placebo response in medicine: Minimize, maximize or personalize? Nat Rev Drug Discov 2013;12:191-204.  Back to cited text no. 62
Fava M, Evins AE, Dorer DJ, Schoenfeld DA. The problem of the placebo response in clinical trials for psychiatric disorders: Culprits, possible remedies, and a novel study design approach. Psychother Psychosom 2003;72:115-27.  Back to cited text no. 63
Frisaldi E, Shaibani A, Benedetti F. Why we should assess patients' expectations in clinical trials. Pain Ther 2017;6:107-10.  Back to cited text no. 64
Iovieno N, Nierenberg AA, Parkin SR, Hyung Kim DJ, Walker RS, Fava M, et al. Relationship between placebo response rate and clinical trial outcome in bipolar depression. J Psychiatr Res 2016;74:38-44.  Back to cited text no. 65
Zeidan F, Emerson NM, Farris SR, Ray JN, Jung Y, McHaffie JG, et al. Mindfulness meditation-based pain relief employs different neural mechanisms than placebo and sham mindfulness meditation-induced analgesia. J Neurosci 2015;35:15307-25.  Back to cited text no. 66
Andrade C. Yoga: Better treatment or better placebo? Indian J Psychiatry 2002;44:83.  Back to cited text no. 67
[PUBMED]  [Full text]  
Raina N, Chakraborty PK, Basit MA, Samarth SN, Singh H. Evaluation of yoga therapy in alcohol dependence. Indian J Psychiatry 2001;43:171-4.  Back to cited text no. 68
Littrell J. The mind-body connection: Not just a theory anymore. Soc Work Health Care 2008;46:17-37.  Back to cited text no. 69


  [Figure 1]


Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  In this article
   The Mechanism of...
   When it Is and W...
   Clinical Implica...
  Quick Fix
   Interventions Wh...
   Article Figures

 Article Access Statistics
    PDF Downloaded108    
    Comments [Add]    

Recommend this journal