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- Neurobiological Mechanisms of the Placebo Effect

Neurobiological Mechanisms of the Placebo Effect

Fabrizio Benedetti,1Helen S. Mayberg,2Tor D. Wager,3Christian S. Stohler,4 and Jon-Kar Zubieta5

1Department of Neuroscience, University of Turin Medical School, 10125 Turin, Italy, 2Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia 30322, 3Department of Psychology, Columbia University, New York, New York 10027, 4School of Dentistry, University of Maryland, Baltimore, Maryland 21201, and 5Department of Psychiatry and Molecular and Behavioral Neuroscience Institute, The University of Michigan, Ann Arbor, Michigan 48109

Key words: placebo; PET; fMRI; pain; stress; opioid receptors; Parkinson's disease; depression; antidepressants; human

Source: The Journal of Neuroscience, vol 25(45) pp10390-10402, November 2005




Any medical treatment is surrounded by a psychosocial context that affects the therapeutic outcome. If we want to study this psychosocial context, we need to eliminate the specific action of a therapy and to simulate a context that is similar in all respects to that of a real treatment. To do this, a sham treatment (the placebo) is given, but the patient believes it is effective and expects a clinical improvement. The placebo effect, or response, is the outcome after the sham treatment. Therefore, it is important to emphasize that the study of the placebo effect is the study of the psychosocial context around the patient.

The placebo effect is a psychobiological phenomenon that can be attributable to different mechanisms, including expectation of clinical improvement and pavlovian conditioning. Thus, we have to look for different mechanisms in different conditions, because there is not a single placebo effect but many. So far, most of the neurobiological mechanisms underlying this complex phenomenon have been studied in the field of pain and analgesia, although recent investigations have successfully been performed in the immune system, motor disorders, and depression. Overall, the placebo effect appears to be a very good model to understand how a complex mental activity, such as expectancy, interacts with different neuronal systems (Colloca and Benedetti, 2005Go; Finniss and Benedetti, 2005Go).

Recently, the placebo effect has reemerged in the public and scientific interest because of investigations of its biological substrates (de la Fuente-Fernandez et al., 2001Go; Mayberg et al., 2002Go; Petrovic et al., 2002Go; Lieberman et al., 2004Go; Wager et al., 2004Go; Colloca and Benedetti, 2005Go; Zubieta et al., 2005aGo). The public is interested in placebo effects because they promise increased self-control; the existence of placebo effects suggests that we must broaden our conception of the limits of endogenous human capability. Scientists are interested in placebo responses because the effects of belief on human experience and behavior provide an entry point for studying internal control of affective, sensory, and peripheral processes. The study of the placebo effect, at its core, is the study of how the context of beliefs and values shape brain processes related to perception and emotion and, ultimately, mental and physical health. The study of the placebo effect reflects a current neuroscientific thought that has as its central tenet the idea that "subjective" constructs such as expectation and value have identifiable physiological bases, and that these bases are powerful modulators of basic perceptual, motor, and internal homeostatic processes.

The study of the placebo effect also has immediate clinical and ethical implications, because the use of inactive (placebo) conditions in clinical trials when effective treatments are available has created an ethical controversy. However, it has been well documented that placebo effects can obscure those of active conditions, even for treatments that were eventually demonstrated to be effective. Thus, placebo effects may represent points of either strength or vulnerability for the expression and maintenance of various pathological states and their inherent therapeutic interventions.


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