Expectation and Dopamine Release: Mechanism of the Placebo Effect in Parkinson's Disease

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Science  10 Aug 2001:
Vol. 293, Issue 5532, pp. 1164-1166
DOI: 10.1126/science.1060937


The power of placebos has long been recognized for improving numerous medical conditions such as Parkinson's disease (PD). Little is known, however, about the mechanism underlying the placebo effect. Using the ability of endogenous dopamine to compete for [11C]raclopride binding as measured by positron emission tomography, we provide in vivo evidence for substantial release of endogenous dopamine in the striatum of PD patients in response to placebo. Our findings indicate that the placebo effect in PD is powerful and is mediated through activation of the damaged nigrostriatal dopamine system.

The simple act of receiving any treatment (active or not) may, in itself, be efficacious because of expectation of benefit (1). This is the placebo effect—a potential confounder in assessing the efficacy of any therapeutic intervention (2, 3). Placebo-controlled studies were designed precisely to control for such an effect (4). It has been assumed that the placebo response is not mediated directly through any physical or chemical effect of treatment (5). In Parkinson's disease (PD), the placebo effect can be prominent (6, 7).

We asked whether the placebo effect in PD is produced by activation of the pathway primarily damaged by degeneration [i.e., the nigrostriatal dopaminergic system (8, 9)]. To answer this question, we took advantage of the ability of positron emission tomography (PET) to estimate pharmacologically or behaviorally induced dopamine release based on the competition between endogenous dopamine and [11C]raclopride (RAC) for binding to dopamine D2/D3 receptors (10–14). We hypothesized that if the placebo effect is mediated through the activation of the pathway relevant to the disorder under study, we should be able to detect placebo-induced release of endogenous dopamine in PD.

We examined the striatal RAC binding potential of six patients with PD (group 1, placebo group) under two conditions (15): Condition 1, a placebo-controlled, blinded study in which the patients did not know when they were receiving placebo or active drug (apomorphine) (16)—all patients received both placebo and active drug; and condition 2, an open study in the same patients without placebo.

We found a significant decrease in striatal RAC binding potential [17% for the caudate nucleus (range, 8 to 25%); 19% for the putamen (range, 8 to 28%); P < 0.005 for both, two-tailed paired t test] when the patients received placebo compared with open baseline observations (Table 1). This placebo-induced change in RAC binding potential was present in each patient and in each striatal subregion, although it was greatest in the posterolateral part of the putamen (Table 1). The magnitude of the placebo response was comparable to that of therapeutic doses of levodopa (17), or apomorphine (see below) (18). There were no differences in the striatal RAC binding potential between this group of patients when studied without placebo and a second group of patients matched by age and severity of parkinsonism studied exclusively in an open fashion (group 2, open group) (15) (Fig. 1).

Figure 1

Placebo-induced changes in RAC binding potential in the striatum ipsilateral (A) and contralateral (B) to the more affected body side of patients with PD. The ROIs are on the head of the caudate nucleus (Caud) and on the putamen, from rostral to caudal, P1, P2, P3 (15). Comparisons were made between the group of patients studied in an open fashion (group 2, open group; open bars) and the group of patients studied both with (solid bars) and without (hatched bars) placebo intervention (group 1, placebo group). Within-subject placebo-induced changes in RAC binding potential tended to be greater in the striatum contralateral to the more affected body side (20%) than in the ipsilateral striatum (17%). The placebo group and the open group did not differ in their baseline placebo-free RAC binding potential values [for the caudate nucleus, 1.96 ± 0.22 (SD) versus 2.07 ± 0.40, respectively; two-tailed t test, t = –0.55 (df = 10), P = 0.59; for the putamen, 2.37 ± 0.34 versus 2.42 ± 0.42, t = –0.20 (df = 10), P = 0.84]. Error bars, SEM.

Table 1

Striatal RAC binding potential (mean ± SD) of PD patients (group 1) scanned at open baseline and after receiving placebo (n = 6).

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These observations indicate that there is placebo-induced release of endogenous dopamine in the striatum (19). The estimated release of dopamine was greater in patients who perceived placebo benefit than in those who did not (20). This suggests a “dose-dependent” relation between the release of endogenous dopamine and the magnitude of the placebo effect.

We next asked whether there might be an interaction between the effects of the placebo and the active drug (21). The placebo response could synergistically enhance the benefit of an active drug, in which case double-blind, placebo-controlled studies would overestimate the active drug effect. Alternatively, the placebo effect could mask (or decrease) the specific effect of an active drug, which would lead to the opposite conclusion in the interpretation of a placebo-controlled study.

After adjusting for differences in “baseline” RAC binding potential, we found no significant differences in the response to apomorphine between the open group and the placebo group (combining patients who perceived a placebo effect and those who did not) (22). However, the degree of apomorphine-induced change in RAC binding potential tended to be lower in patients who perceived a placebo effect compared with those who did not and with patients studied in an open fashion (Fig. 2). We explored whether this observation could reflect a floor effect in the placebo group (i.e., whether the technique was insensitive for further reductions in RAC binding), but this did not appear to be the case (Fig. 3) (23). We conclude that the placebo response does not potentiate the effect of an active drug. Indeed, our results suggest that in some patients, most of the benefit obtained from an active drug might derive from a placebo effect.

Figure 2

Apomorphine-induced changes in RAC binding potential in the caudate nucleus (A) and putamen (B) before (APO_0) and after (APO_1 = 0.03 mg/kg, and APO_2 = 0.06 mg/kg) subcutaneous injection of apomorphine. Patients studied in an open fashion (open bars) had higher RAC binding potential values than those included in the placebo group [independently of whether they did not (hatched bars) or did (solid bars) perceive a placebo effect]. The decline in RAC binding potential induced by an incremental dose of apomorphine tended to be less pronounced in patients who perceived a placebo effect as compared with those who did not, and with patients studied in an open fashion: interaction term (group × apomorphine dose) evaluated by repeated measures ANCOVA, F = 4.66 (df = 2, 9), P = 0.041 for the caudate nucleus;F = 3.40 (df = 2, 9), P = 0.079 for the putamen. Error bars, SEM.

Figure 3

Linear regression plots for patients without (n = 3; open symbols, thin lines) and with (n = 3; solid symbols, thick lines) perceived placebo effect: (A) caudate and (B) putamen RAC binding potential values against apomorphine dose (APO_dose). The four slopes were significantly different from zero (P < 0.01), but they did not differ significantly between patients with and without perceived placebo effect (for the caudate nucleus, –3.2 versus –5.1, respectively, P = 0.28; for the putamen, –3.8 versus –6.5, P = 0.15).

The dopaminergic system is involved in the regulation of several cognitive, behavioral, and sensorimotor functions, and particularly in reward mechanisms (24–28). However, our experiments did not involve a direct reward. We conclude that dopamine release in the nigrostriatal system is linked to expectation of a reward—in this case, the anticipation of therapeutic benefit (29, 30). All patients were familiar with the effect of an active drug (levodopa), and such previous experience may have enhanced their expectation. We found that the level of expectation may determine experience (20)—patients who perceived a placebo effect had higher release of dopamine than those who did not.

Our observations indicate that the placebo effect in PD is mediated by an increase in the synaptic levels of dopamine in the striatum. Expectation-related dopamine release might be a common phenomenon in any medical condition susceptible to the placebo effect. PD patients receiving an active drug in the context of a placebo-controlled study benefit from the active drug being tested as well as from the placebo effect. By contrast, in the usual clinical practice setting, active drugs may be devoid of placebo effect. We found no evidence to suggest that the placebo effect synergistically augments the action of active drugs (in fact, a trend for the opposite was observed), so positive conclusions derived from placebo-controlled studies are not impugned by our findings.

  • * To whom correspondence should be addressed. E-mail: jstoessl{at}


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