The placebo-reward hypothesis: dopamine and 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.
References (24)
- et al.
Dopamine release in human ventral striatum and expectation of reward
Behav Brain Res
(2002) - et al.
The placebo effect in neurological disorders
Lancet Neurol
(2002) - et al.
Placebo mechanisms and reward circuitry: clues from Parkinson's disease
Biol Psychiatry
(2004) - et al.
The role of dopamine in the nucleus accumbens in analgesia
Life Sci
(1999) - et al.
Therapeutic application of transcranial magnetic stimulation in Parkinson's disease: the contribution of expectation
Neuroimage
(2006) - et al.
Individual differences in reward responding explain placebo-induced expectations and effects
Neuron
(2007) - et al.
Loss of expectation-related mechanisms in Alzheimer's disease makes analgesic therapies less effective
Pain
(2006) - et al.
Expectation and dopamine release: mechanism of the placebo effect in Parkinson's disease
Science
(2001) - et al.
The functional neuroanatomy of the placebo effect
Am J Psychiatry
(2002) - et al.
Placebo and opioid analgesia – imaging a shared neuronal network
Science
(2002)
A meta-analysis of the association between adherence to drug therapy and mortality
BMJ
The biochemical bases for reward. Implications for the placebo effect
Eval Health Prof
Cited by (77)
Interindividual differences in anhedonia moderate antidepressant placebo responses on heart rate in healthy individuals
2024, Journal of Affective Disorders ReportsPain and dyskinesia in Parkinson's disease may share common pathophysiological mechanisms – An fMRI study
2020, Journal of the Neurological SciencesCitation Excerpt :Firstly, neither subject nor examiner was blinded to medication state, increasing the risk of participation expectation bias and examiner bias to results, though we did attempt to minimise participant placebo or nocebo effects by informing them that dopaminergic medications may either increase, reduce or have no effect on their pain. Secondly, our group of dyskinetic PD patients did not experience more clinical pain compared to the non-dyskinetic group, so the presence of centrally sensitized pain mechanisms cannot be the only mechanism involved in the development of clinical pain [46]. A future assessment of PD patients suffering pain versus those without pain in conjunction with dyskinesia to see if pain sensitisation is more prominent would therefore be crucial.
Choice of practice-task order enhances golf skill learning
2020, Psychology of Sport and ExerciseCitation Excerpt :Also, in studies by Lemos et al. (2017) as well as Reeve and Tseng (2011), participants in autonomy-supportive groups reported significantly greater enjoyment, fun, curiosity, interest, and engagement than did participants in groups without possibility for choice. Expectations of success, or rewarding experiences, whether from the anticipation of choice per se or from performance advantages, are associated with dopamine release (de la Fuente-Fernández, 2009; Lidstone, Schulzer, Dinelle, Mak, Sossi, Ruth et al., 2010), which has directly or indirectly been shown to enhance movement effectiveness and efficiency (Foreman et al., 2014; Jenkinson & Brown, 2011; Meadows, Gable, Lohse, & Miller, 2016). Phasic increases in dopamine release resulting from positive experiences strengthen neural connections (Ashby, Turner, & Horvitz, 2010) which may be a mechanism underlying motor learning (Abe et al., 2011).
Determinants of placebo effects
2020, International Review of NeurobiologyCitation Excerpt :In research settings, the response may be dependent upon perceived probability of receiving active drug. In clinical settings, the response triggered by the expectation of reward is related to the patient's perception of trustworthiness of the provider or providers in general, rather than probability of receiving treatment, which is 100% in the clinical setting (de la Fuente-Fernández, 2009). However, unless specifically queried, a positive previous response to dopamine agonist (or any drug perceived by the patient to be similar to the study drug) or to the healthcare relationship is assumed.
Hierarchical control systems for the regulation of physiological homeostasis and affect: Can their interactions modulate mood and anhedonia?
2019, Neuroscience and Biobehavioral Reviews