The placebo-reward hypothesis: dopamine and the placebo effect

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Summary

Based on the observation that the placebo effect in Parkinson's disease was mediated by the release of endogenous dopamine in both the dorsal and ventral striatum, in 2002 we formally proposed the placebo-reward hypothesis. This hypothesis establishes a link between the placebo effect and reward mechanisms, and predicts that the activation of the ventral striatum should be present in any placebo response, in any medical condition. In keeping with this prediction, functional neuroimaging studies have shown placebo-induced activation of the reward circuitry in Parkinson's disease, depression, and pain. In fact, recent evidence suggests that the release of dopamine in the ventral striatum likely triggers the activation of the endogenous opioid system in placebo analgesia. The placebo-reward hypothesis also supports the notion that the expectation of clinical benefit plays a major role in the placebo effect. Probability and trust, two key factors involved in shaping expectations, must therefore be essential to the development of placebo responses. The ventral loop of the basal ganglia circuitry (anterior cingulate cortex–ventral striatum–ventral pallidum– mediodorsal nucleus of the thalamus –anterior cingulate cortex) is a fundamental component of the neuroanatomy of the placebo effect.

Introduction

Recent neuroimaging studies have documented how the brain responds to placebo administration in subjects with Parkinson's disease (PD), depression, and pain [1, 2, 3, 4]. These investigations validate previous observations on the power of placebos to evoke substantial clinical benefits in a great number of medical conditions [5]. It is also apparent that the placebo effect may prolong survival [6]. A meta-analysis of placebo-controlled trials in which mortality was a study endpoint, showed that study participants allocated to the placebo arm who adhered to the trial protocol (i.e., those who took the placebo as specified in the trial protocol) had a lower mortality rate than those who did not [6]. From an evolutionary perspective, this observation supports the notion that placebo responses have adaptive properties that evolved from natural selection when effective treatments were lacking [7, 8]. Converging evidence indicates that the expectation of clinical benefit (expectation of reward) is a major trigger for the placebo effect. Functional neuroimaging studies verify that placebo-induced expectations induce brain responses similar to those observed in reward processing [8]. These brain activations can, by themselves, have healing effects, and can also promote “healthy” behaviours, including adherence to trial protocols.

Section snippets

Placebos and rewards: “Story of a candy”

A candy is likely the first “sugar pill” (placebo) we are exposed to typically during childhood. Sometimes the candy is given to the child to alleviate pain (placebo administration) or as a reward. In both cases, the predicted outcome is positive and satisfying for the child. Either the pain disappears and the child goes back to baseline (placebo response) or the child obtains pleasurable sensations compared to baseline (reward response). This establishes a link between the placebo effect and

The placebo-reward hypothesis

Basically, the striatum can be divided into dorsal striatum (for motor control), and ventral striatum [9]. The nucleus accumbens is the major component of the ventral striatum. It has long been recognized that, among the several brain structures of the reward circuitry (essentially, the limbic system), the dopaminergic projections to the nucleus accumbens are particularly implicated in reward processing [10]. Both natural (e.g., food and sex) and unnatural (e.g., drugs of abuse) rewards are

Testing the placebo-reward hypothesis: Neuroimaging studies

A distinction should be made between the clinical placebo effect and the (underlying) biochemical placebo effect. Although multiple clinical studies had previously shown that subjects with PD often develop prominent clinical placebo responses (i.e., significant objective improvement in motor function) [15], the biochemical substrate for this placebo-induced clinical benefit remained unknown for many years. In 2001, we found that the biochemical substrate for the clinical placebo effect in PD

The placebo effect: Cognition, probability, and trust

Appropriate placebo investigations can be used to test a number of predictions derived from the placebo-reward hypothesis. For example, subjects with lesions in the ventral loop of the basal ganglia circuitry are expected to lack major placebo responses. In addition, the analysis of the different components of this loop (anterior cingulate cortex – ventral striatum – ventral pallidum – mediodorsal nucleus of the thalamus – anterior cingulate cortex) [9] could shed some light on whether the

The placebo effect according to Darwin

Although many of the above considerations still remain beyond our reach, some concepts and predictions are easier to tackle if one accepts that the beneficial response to placebos has been subject to natural selection. According to evolutionary theory, placebo responses would occur in relation to adaptive, unconscious or subconscious brain processes. Fine-tuned probabilistic calculations, as those previously mentioned, are therefore not expected to play a major role. After all, humans are not

Conflict of interests

No conflicts of interest to declare.

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