Neuroscience Forefront ReviewThe placebo effect: From concepts to genes
Graphical abstract
Introduction
The placebo effect is a fascinating and important psychobiological phenomenon whereby treatment cues trigger improvement. While traditionally viewed as a nuisance variable to be controlled for, the past three decades have seen a surge in interest in the placebo effect in light of some remarkable clinical and laboratory discoveries that have demonstrated its potential power to improve patient outcomes. Furthermore, recent advances in neuroimaging and genetics have allowed researchers to begin to understand the brain mechanisms underlying the placebo effect as well as to explore its genetic bases. In this review, we highlight some historical and pioneering studies on the placebo effect, present a recently developed conceptual framework for understanding the placebo effect in which verbal, contextual, and social cues elicit expectancies that drive the placebo effect via learning, outline behavioral studies that demonstrate how distinct forms of learning shape the placebo effect, and review what is currently known about neurobiological and genetic bases of the placebo effect. The possibility that genetic variations could be used to predict individual placebo and nocebo responses is particularly exciting as it suggests a way that future placebo interventions could be individually targeted to patients to maximize their benefits.
Section snippets
Historical and pioneering studies on the placebo effect
Many researchers have proposed that the history of prescientific medicine is in fact the history of the placebo effect (Wolf, 1950, Moerman, 1997, Shapiro and Shapiro, 1997). However, it was not until placebos began to be used as controls in clinical trials that they became a mainstay of modern medicine. One of the first documented uses of placebos as controls was a trial conducted by Benjamin Franklin and Antoine Lavoisier who were commissioned by Louis XVI in 1784 to test Franz Mesmer’s claim
Conceptual framework for understanding the placebo effect
Not surprisingly, the pioneering placebo studies just described have led to great interest in understanding how the placebo effect is formed. Many attempts have been made to conceptualize the placebo effect, including expectancy theory (Kirsch, 1985), classical conditioning accounts (Wickramasekera, 1980), context effects (Di Blasi et al., 2001), and the meaning response (Moerman and Jonas, 2002). In the current review, we adopt Colloca and Miller’s (2011a) recently proposed framework based on
Learning mechanisms
In this section, we describe various types of learning phenomena that give rise to placebo effects and explain how these findings can be integrated within an integrated framework (Colloca and Miller, 2011a, Colloca, 2014).
Neurobiology of the placebo effect
A deeper understanding of the behavioral mechanisms underlying the placebo effect has produced excellent experimental models for examining the neurobiological systems involved in producing placebo effects. In particular, neuroimaging techniques such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) have led to significant advances in our understanding of the neurobiological mechanisms of placebo effects (Colloca et al., 2008). As with behavioral studies, the
Genetic influences on the placebo effect
Genetic variation is another important factor that may influence (and help predict) placebo effects. While the study of the genes that influence the placebo effect (Hall et al., 2015), is only just emerging, its potential to improve our understanding of the mechanisms underlying the placebo effect is promising. Importantly, greater understanding of how different genes influence the placebo effect may eventually allow researchers and clinicians to tailor treatment settings to individuals in
Conclusions
The placebo effect is a robust phenomenon that influences responses to both active and placebo treatments across many diseases and health settings. By viewing the placebo effect as a learned response triggered via the expectancies elicited by verbal, contextual, and social cues, research on the placebo effect can be integrated into a single conceptual framework. Advances in neuroimaging have greatly increased our understanding of the neurobiology of the placebo effect, particularly for placebo
Acknowledgments
This research was funded by University of Maryland Baltimore (Colloca), National Institute of Nursing Research grant P30NR014129 and R01NR012686 (Dorsey), and University of Sydney Australia (Colagiuri).
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