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Review
. 2011 Jan;36(1):339-54.
doi: 10.1038/npp.2010.81. Epub 2010 Jun 30.

How Placebos Change the Patient's Brain

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Free PMC article
Review

How Placebos Change the Patient's Brain

Fabrizio Benedetti et al. Neuropsychopharmacology. .
Free PMC article

Abstract

Although placebos have long been considered a nuisance in clinical research, today they represent an active and productive field of research and, because of the involvement of many mechanisms, the study of the placebo effect can actually be viewed as a melting pot of concepts and ideas for neuroscience. Indeed, there exists not a single but many placebo effects, with different mechanisms and in different systems, medical conditions, and therapeutic interventions. For example, brain mechanisms of expectation, anxiety, and reward are all involved, as well as a variety of learning phenomena, such as Pavlovian conditioning, cognitive, and social learning. There is also some experimental evidence of different genetic variants in placebo responsiveness. The most productive models to better understand the neurobiology of the placebo effect are pain and Parkinson's disease. In these medical conditions, the neural networks that are involved have been identified: that is, the opioidergic-cholecystokinergic-dopaminergic modulatory network in pain and part of the basal ganglia circuitry in Parkinson's disease. Important clinical implications emerge from these recent advances in placebo research. First, as the placebo effect is basically a psychosocial context effect, these data indicate that different social stimuli, such as words and rituals of the therapeutic act, may change the chemistry and circuitry of the patient's brain. Second, the mechanisms that are activated by placebos are the same as those activated by drugs, which suggests a cognitive/affective interference with drug action. Third, if prefrontal functioning is impaired, placebo responses are reduced or totally lacking, as occurs in dementia of the Alzheimer's type.

Figures

Figure 1
Figure 1
After the administration of a placebo, a clinical improvement may occur for a variety of reasons. Whereas the clinical trialist is interested in any improvement that may take place in a clinical trial, the neurobiologist is only interested in the psychosocial–psychobiological effects after the administration of a placebo. These include a number of mechanisms, such as anxiety, reward, learning, and genetics.
Figure 2
Figure 2
Neural network involved in placebo analgesia and nocebo hyperalgesia. A descending pain inhibitory opioidergic system starts from the cerebral cortex and goes down to the hypothalamus (HYPO), periaqueductal gray (PAG), rostroventromedial medulla (RVM), and spinal cord. The dopaminergic reward system, in which dopaminergic neurons in the ventral tegmental area (VTA) project to the nucleus accumbens (NAcc), is also involved. These opioidergic and dopaminergic networks are antagonized by at least two mechanisms, which are at the basis of nocebo hyperalgesia. On one hand, a cholecystokininergic (CCKergic) system antagonizes the opioidergic circuit at different levels, for example, in the rostroventromedial medulla. On the other hand, deactivations of μ-opioids and D2–D3 dopamine receptors occur in the nucleus accumbens during nocebo hyperalgesia.
Figure 3
Figure 3
Neural circuit involved in the placebo response in Parkinson's disease. The changes observed in this circuit have been obtained after pharmacological preconditioning with apomorhine, which suggests that learning is important for these changes to occur. A release of dopamine in both the ventral and dorsal striatum (Str) occurs. The neurons of the subthalamic nucleus (STN) and substantia nigra pars reticulata (SNr) have been found to decrease their firing rate, whereas the neurons in the ventral anterior and anterior ventral lateral thalamus (Th) have been found to increase their discharge. The nuclei in italics and the broken lines indicate the part of the circuit that has not been studied. Although the release of dopamine in Str and the neuronal changes in STN, SNr, and Th were found in different studies (de la Fuente–Fernandez et al, 2001, and Benedetti et al, 2004, , respectively), the neuronal changes in STN, SNr, and Th are likely to derive from dopamine release in Str.
Figure 4
Figure 4
Interference between placebo/expectation effects and drug action. (a) When a syringe, or any other medical device, is presented, the patient's brain starts activating placebo/expectation mechanisms, such as opioid, dopamine, and cholecystokinin (CCK) release (step 1). Then the drug is injected (step 2). Its effect may be because of its own pharmacodynamic action and/or of an interference with expectation-activated mechanisms (step 3). In this situation, there is no way to say which of these two mechanisms takes place. (b) If placebo/expectation mechanisms are eliminated using a hidden (unexpected) administration, any observed effect is likely to be because of the specific pharmacodynamic action of the drug itself, for any expectation-related mechanism is no longer present.

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