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Review
TRENDS in Neurosciences Vol.25 No.6 June 2002
The placebo effect in Parkinson’s
disease
Raúl de la Fuente-Fernández and A. Jon Stoessl
The biochemical bases of the placebo effect are still incompletely known. We
show here that the placebo effect in Parkinson’s disease is due, at least in part,
to the release of dopamine in the striatum. We propose that the placebo effect
might be related to reward mechanisms. The expectation of reward (i.e. clinical
benefit) seems to be particularly relevant. According to this theory, brain
dopamine release could be a common biochemical substrate for the placebo
effect encountered in other medical conditions, such as pain and depression.
Other neurotransmitters or neuropeptides, however, are also likely to be
involved in mediating the placebo effect (e.g. opioids in pain disorders,
serotonin in depression).
Raúl de la FuenteFernández
A. Jon Stoessl*
Pacific Parkinson’s
Research Centre,
University of British
Columbia, Purdy Pavilion,
2221 Wesbrook Mall,
Vancouver, BC, Canada
V6T 2B5.
*e-mail: jstoessl@
interchange.ubc.ca
The word placebo is Latin for ‘I shall please’ [1,2].
Types of placebo include pills, injections and surgical
procedures. It is assumed that a placebo is devoid of
any specific effect for the medical condition being
treated, but researchers have often been mesmerized
by the positive responses of patients to these ‘inert’
interventions. This response is known as the ‘placebo
effect’ [3,4]. Stewart Wolf defined this as ‘any effect
attributable to a pill, potion, or procedure, but not to
its pharmacodynamic or specific properties’ [5]. This
is only one among a great number of proposed
definitions [6,7]. At the heart of them all is the concept
that a placebo must lack any specific properties.
Interestingly, however, the placebo effect can be very
specific [8], and this specificity depends upon the
information available to the recipient [9]. For
example, placebos can have opposite effects on heart
rate, or blood pressure, depending on whether they
are given as tranquillizers or as stimulants [8].
Hence, we should distinguish carefully between the
placebo as an agent and the placebo effect. Following
the principle that any treatment that provides benefit
to the patient ought to be incorporated into clinical
practice, we should learn to maximize the placebo
effect inherent in any active treatment [10].
There is evidence to suggest that the placebo effect
is related to the patient’s expectation. Two alternative
theories have traditionally been proposed to explain
the placebo effect [11]: (1) the mentalistic theory,
according to which the patient’s expectation is the
primary basis for the placebo effect, and (2) the
conditioning theory, which states that the placebo
effect is essentially a conditioned response. Models
have been developed to support one or other of these
theories [8,12–14]. For example, expectation and
conditioning could activate different biochemical
pathways in placebo analgesia [15,16]. Naturally,
both mechanisms could contribute to the placebo
effect in any given patient. One potential problem
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with the conditioning theory of the placebo effect is
that placebo responses can occur in subjects without
previous drug experience [17]. Importantly, the
theories can be reconciled if, as some recent
refinements of the Pavlovian conditioning theory
suggest, what is learned in Pavlovian conditioning is
in fact an expectation [8,18,19].
Many medical conditions are susceptible to the
placebo effect [3,4]. Although a recent meta-analysis
has called its importance into question [20], new
evidence supporting the expectation theory of the
placebo effect suggests that the studies included in
this analysis might not have been optimal to address
the issue (reviewed in Ref. [21]).
Pain, depression and Parkinson’s disease are
among the disorders in which the placebo effect can be
prominent [22–24]. This raises the possibility that the
effect might be mediated by changes in
neurotransmitter or neuropeptide transmission [25].
It is worth noting that patients with Parkinson’s
disease often experience depression and pain [26].
Indeed, depression can precede the occurrence of
motor dysfunction in Parkinson’s disease [27],
suggesting that it is a primary defect (i.e. endogenous
depression) rather than a consequence of chronic
motor disability (i.e. reactive depression).
Kinesia paradoxica: psychologically driven
dopamine release?
A remarkable phenomenon sometimes encountered in
advanced Parkinson’s disease is that a patient who is
usually severely impaired can perform very effective
movements during a short period of time, under
certain unusual circumstances (e.g. a fire). This
phenomenon, called kinesia paradoxica (or
paradoxical kinesia), has long puzzled neurologists
[28]. Two theories have been put forward to explain it.
According to one, the motor activity in kinesia
paradoxica could be mediated by non-dopamine
system(s) (i.e. neural pathways mostly activated by
emergency situations or stress). Alternatively, the
damaged nigrostriatal dopamine system of patients
with Parkinson’s disease could be activated in
particular situations, either by environmental stimuli
or by the psychological response to such stimuli.
According to the latter theory, kinesia paradoxica
would reflect a substantial, psychologically induced
release of endogenous dopamine. In keeping with this
notion, animal experiments have shown that, in the
presence of arousing stimuli, dopaminergic neurons of
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TRENDS in Neurosciences Vol.25 No.6 June 2002
the substantia nigra increase their firing rate and
release dopamine in the striatum [29–31]. Moreover,
when compared to control subjects, patients with
Parkinson’s disease show verbal kinesia paradoxica –
an increase in word counts and discourse duration
when talking about emotional experiences [32].
However, animal models of kinesia paradoxica seem
to favour non-dopamine-mediated mechanisms
[33,34]. For example, rats rendered akinetic by
intraventricular injections of 6-hydroxydopamine and
treated with a combination of dopamine D1 and D2
receptor antagonists were still able to swim and
escape from an ice bath [33]. It remains unclear,
however, whether these animal models are
appropriate to study the kinesia paradoxica
encountered in patients with Parkinson’s disease [25].
The placebo effect in Parkinson’s disease: results of
clinical trials
Although some clinical trials have shown only a modest
placebo effect in Parkinson’s disease (e.g. see Ref. [35]),
there is ample evidence for a strong placebo effect in
this disorder. Thus, in a double-blind trial of pergolide
as a treatment for Parkinson’s disease, Diamond and
colleagues [36] found a significant improvement with
respect to baseline in both the pergolide-treated group
(17% improvement after four weeks and 30% after
24 weeks) and the placebo group (16% improvement
after four weeks and 23% after 24 weeks). In this study,
there was no significant difference between the
pergolide-treated and placebo groups.
Shetty and colleagues [37] have recently reviewed
98 relevant articles that were published between
January 1969 and April 1996, finally selecting 36 that
satisfied their inclusion criteria. Twelve of these
articles reported an improvement following placebo
treatment in Parkinson’s disease. The magnitude of
the improvement was 9–59% of that seen in the active
drug group. Retrospective analysis of the Deprenyl
and Tocopherol Antioxidative Therapy of
Parkinsonism (DATATOP) study found a slightly
lower percentage of patients experiencing
improvement during placebo therapy (21%). More
recently, Goetz and colleagues [38] reported that 14%
of the patients enrolled in a six-month, randomized,
multicentre, placebo-controlled clinical trial of
ropinirole monotherapy achieved a 50% improvement
in motor function while on placebo treatment. In this
study, all domains of parkinsonian disability were
subject to the placebo effect, but bradykinesia and
rigidity tended to be more susceptible than tremor,
gait or balance.
The importance of including a placebo group when
investigating the efficacy of surgical treatments
(e.g. transplantation) for Parkinson’s disease has
been emphasized by several authors [24]. Although
the effect of an imitation operation was modest in
some studies [39], others reported placebo
improvement of the same magnitude as that seen in
the transplant group [40].
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303
Several factors could explain the differences in
the magnitude of the placebo response among
different trials. These include differences in the
information given to patients and differences in
group characteristics or surgical procedures [21].
Importantly, it should be emphasized that the only
two studies to have focused on the placebo effect in
Parkinson’s disease both found the effect to be
strong [37,38].
Dopamine, expectation and reward
The dopaminergic system has long been implicated in
reward mechanisms [41,42]. Animal experiments
have shown that the midbrain dopaminergic cell
groups A8, A9 and A10 are activated by primary
rewards, reward-predicting stimuli and novel stimuli
[43,44]. Although three major dopamine-containing
pathways (the nigrostriatal, mesolimbic and
mesocortical pathways) participate in these
responses, the projection to the nucleus accumbens
has received the greatest attention [41,42]. Release of
dopamine in the nucleus accumbens occurs during
intracranial self-stimulation, a paradigm in which an
animal repeatedly presses a lever to electrically
stimulate its own dopaminergic projections. This
behaviour has been associated with the rewarding
properties of dopamine release. Most drugs of abuse
(including cocaine, amphetamine, opioids, alcohol and
nicotine) are characterized by their ability to increase
dopamine levels in the nucleus accumbens. Indeed,
the basis of drug dependence seems to be related to
the rewarding experience of such dopamine release
[45]. Interestingly, there is an emerging concept that
several human behavioural disorders, including
drug-seeking behaviour, might be related to what has
been called the ‘reward deficiency syndrome’ [46–48].
Individuals with this syndrome are thought to search
for ‘unnatural rewards’ to compensate for an intrinsic
reward deficit; that is, they seek unnatural
stimulation of dopamine release to compensate for
hypoactive dopamine-mediated signalling in their
nucleus accumbens.
A crucial aspect of the reward theory that remains
unclear is whether dopamine release occurs in
relation to the reward itself (i.e. to the perception of
the reward) or to the expectation of the reward. In an
elegant experiment using the intracranial selfstimulation paradigm, Garris and colleagues [49]
provided evidence that it is the expectation of the
reward that triggers dopamine release in the nucleus
accumbens. This is in keeping with previous
experiments showing that dopaminergic neurons are
activated after stimuli that predict a reward [44]. We
hypothesized that, if the expectation of a reward
triggers dopamine release, not only in the nucleus
accumbens but also in the nigrostriatal pathway, the
placebo effect in patients with Parkinson’s disease
could be related to the expectation of clinical benefit,
and could be mediated by the release of dopamine in
the striatum [50].
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304
(a)
TRENDS in Neurosciences Vol.25 No.6 June 2002
(b)
(a)
Caudate
RAC binding potential
3.0
2.5
2.0
1.5
1.0
0.5
0.0
Baseline
After placebo
Baseline
(b)
Placebo
Putamen
Fig. 1. [11C]raclopride
(RAC)–PET scans of a
patient with Parkinson’s
disease at open baseline
(a) and after placebo
administration (i.e. saline
injected; b). The placeboinduced decrease in
striatal radioactivity
(indicated by the less
intense red colour) is
thought to reflect an
increase in the synaptic
level of dopamine, which
inhibits RAC from binding
to dopamine D2 receptor
sites.
PET study: dopamine release in response to placebo
treatment in Parkinson’s disease
Using PET with [11C]raclopride (RAC), we found that
patients with Parkinson’s disease release
substantial amounts of dopamine in the dorsal
striatum (i.e. caudate and putamen) in response to
subcutaneous injection of saline (Fig. 1) [50]. In this
paradigm, changes in RAC binding between baseline
and post-activation states (in this case, in response
to placebo injection) represent a change in synaptic
dopamine levels, reflecting the release of endogenous
dopamine. Placebo-induced changes in striatal RAC
binding potential (BP) (17% in the caudate nucleus,
19% in the putamen) (Fig. 2) were of similar
magnitude to those obtained after therapeutic doses
of levodopa or apomorphine [50,51]. Indeed, the
magnitude of the placebo-induced change in RAC BP
in Parkinson’s disease patients was comparable to
that obtained in healthy volunteers after
amphetamine administration [52]. The effect
showed a slight increasing rostrocaudal gradient, in
contrast to the magnitude of dopamine loss in
Parkinson’s disease, which is maximal in the
posterior putamen. All patients showed a
biochemical placebo effect (i.e. changes in RAC BP)
but only half reported clinical benefit in motor
function after placebo administration. Interestingly,
the estimated amount of dopamine release was
greater in those patients who perceived a placebo
effect than in those who did not (22% and
12% decreases in RAC BP in the caudate nucleus,
respectively; 24% and 14% decreases in the
putamen, respectively) (Fig. 2). Based on the known
relationship between dopamine levels in the
putamen and motor function, we concluded that the
placebo effect in Parkinson’s disease was triggered
by the expectation of reward (i.e. the expectation of
clinical benefit). This idea was confirmed when we
analysed placebo-induced changes in the ventral
striatum (nucleus accumbens). This region displayed
a decline in RAC binding similar to that seen in the
caudate and putamen. However, in contrast to
results from the dorsal striatum, the magnitude of
placebo-induced changes was not significantly
different between patients who experienced clinical
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RAC binding potential
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
Baseline
Placebo
TRENDS in Neurosciences
Fig. 2. Individual [11C]raclopride (RAC) binding potential values at open
baseline (without placebo intervention) and after subcutaneous
administration of placebo (saline), for patients who either did (solid
squares, solid lines) or did not (open squares, broken lines) perceive a
placebo-induced clinical benefit. Placebo-induced RAC binding
potential changes were highly significant for both the caudate nucleus
(a) and putamen (b) (P <0.005 for both regions, two-tailed paired t-test).
This indicates that there is a strong placebo effect in Parkinson’s disease
and that this is mediated by the release of dopamine in the striatum. It is
assumed that the clinical effect is related to increased dopamine levels
in the putamen.
benefit and those who did not (R. de la FuenteFernandez et al., unpublished). Because the
perception of clinical benefit must be rewarding, this
finding suggests that dopamine is released within
the ventral striatum in relation to the expectation of
reward (i.e. the expectation of clinical benefit)
rather than the reward itself (i.e. the perception of
clinical benefit).
Controlling for confounding factors
As noted earlier, dopaminergic neurons are activated
not only in relation to reward, but also in response to
novel stimuli [43,44]. Hence, one could argue that our
results reflect the novelty of the test situation. To
address this, and other, potential issues, we studied a
second group of patients with Parkinson’s disease
(matched with the first for age and severity of
parkinsonism) in an open fashion (i.e. without placebo
intervention), as a control group. We found no
differences in placebo-free, open baseline RAC BP
between the patients described above and this second
control group (Fig. 3). It could also be argued that the
placebo-induced changes in RAC BP might be
secondary to stress associated with the subcutaneous
injection itself. If this were so, both placebo-tested
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2.5
305
(a)
Control group
Caudate
2.5
Control group
Placebo group
RAC binding potential
3.0
RAC binding potential
2.0
1.5
1.0
0.5
Placebo group
2.0
1.5
1.0
0.5
0.0
Caudate
0.0
Putamen
APO 0
(b)
APO 2
Putamen
3.0
and placebo-free (control) groups should have a
similar degree of change induced by subcutaneous
injections of apomorphine. However, this was not the
case, and RAC BP values were lower in the placebo
group than in the open, placebo-free control group for
each dose of apomorphine (Fig. 4). These observations
strengthen the view that the changes in RAC BP were
a true reflection of the placebo effect and not a
manifestation of either novelty or stress-induced
dopamine release.
2.5
2.0
1.5
1.0
0.5
0.0
APO 0
Conclusions and implications
Acknowledgements
Our work is supported by
the Canadian Institutes of
Health Research, the
National Parkinson
Foundation (Miami, FL,
USA), the British
Columbia Health
Research Foundation
(Canada) (R.F-F.), the
Pacific Parkinson’s
Research Institute
(Vancouver, BC, Canada)
(R.F-F.), and the Canada
Research Chairs program
(A.J.S.). We would also
like to acknowledge the
contributions of Tom Ruth
and the UBC-TRIUMF PET
team.
APO 1
TRENDS in Neurosciences
RAC binding potential
Fig. 3. Mean
[11C]raclopride (RAC)
binding potentials in the
placebo-free, open
baseline state for control
(i.e. no previous placebo
exposure; open bars,
n = 6) and previously
placebo-tested (solid
bars, n = 6) groups. The
two groups were matched
for age and clinical
severity of parkinsonism.
There were no differences
between the open
baseline RAC binding
potentials of the control
and previously
placebo-tested groups,
for either the caudate
nucleus (P = 0.59) or the
putamen (P = 0.84). This
suggests that our
observations do not
simply reflect the novelty
of the test situation.
Error bars, ± 1 SE.
TRENDS in Neurosciences Vol.25 No.6 June 2002
The power of placebos to alleviate a great number of
medical conditions has long been recognized [3,4].
Parkinson’s disease is among the disorders in which
the placebo effect can be substantial [24,36–38,40],
and PET studies have indicated that the placebo
effect in Parkinson’s disease is related to the release
of dopamine in the striatum [50]. Other factors can
also contribute to increased dopamine-mediated
neurotransmission in response to placebo treatment.
For example, Guttman and colleagues [53] have
recently shown placebo-induced downregulation of
the dopamine transporter. Interestingly, the nucleus
accumbens is also susceptible to placebo-induced
dopamine release in Parkinson’s disease, supporting
the notion that placebos can activate reward
mechanisms.
Dopamine, which is sometimes known as the
‘pleasure molecule’ [47], could potentially be
involved in the placebo effect encountered in other
medical conditions, such as pain and depression
[21]. For example, there is structural,
electrophysiological and biochemical evidence for
opioid–dopamine interactions in the mesolimbic and
mesocortical pathways [54]. This provides a
morphological substrate to explain the opioidinduced release of dopamine in the nucleus
accumbens. Indeed, enhanced activity of dopamine
in the nucleus accumbens seems to play a role in
analgesia [55]. Alternatively, the release of
endogenous endorphins in placebo analgesia [56]
could be modulated by dopamine-mediated
mechanisms [57].
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APO 1
APO 2
TRENDS in Neurosciences
Fig. 4. Caudate (a) and putamen (b) mean [11C]raclopride (RAC) binding
potentials for control (open bars) and placebo-tested (green bars)
groups, both before (APO 0) and after subcutaneous administration of
particular doses of apomorphine (APO 1 = 0.03 mg kg−1; APO 2 = 0.06 mg
kg−1). Note that RAC binding potential values for APO 0 represent true
baseline values for the control group, and placebo-related values for
the placebo-tested group (these patients had received subcutaneous
injections of saline, in a blind fashion). In response to apomorphine,
patients in the placebo group had significantly lower RAC binding
potential values than patients in the control group. This eliminated
other potential confounding factors (e.g. the stress associated with the
subcutaneous injection of saline) from our observations of a powerful
biochemical placebo effect in Parkinson’s disease. Error bars, ± 1 SE.
Finally, placebos could also be efficacious in longterm substitution programmes for the treatment of
drug addiction [5]. Most drugs of abuse (including
cocaine, amphetamine, heroin, alcohol and nicotine,
to name but a few) release dopamine in the nucleus
accumbens, and such dopamine-mediated activation
seems to be related to the dependence properties of
these drugs [58,59]. We have seen that placebos can
induce release of dopamine in the nucleus accumbens.
Indeed, there is evidence to suggest that placebos can
be addictive, causing withdrawal symptoms when
treatment is discontinued [2,5]. There are reports of
successful saline substitution for the active drug in
morphine addicts [60], and methadone substitution
programmes for heroin addicts can also benefit from
the use of placebos [61]. Although there is the
potential for placebo addiction, a reduction in the use
of illicit drugs would represent a major achievement
in terms of health and social safety.
306
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