Review
Neuroimmunomodulation 2005;12:195–200
DOI: 10.1159/000085651
Mechanisms of the Placebo Effect and
of Conditioning
France Haour
INSERM U732, Hôpital Saint Antoine, Paris, France
Key Words
Placebo effect  Conditioning  Endogenous opioids
Abstract
A placebo is a sham treatment, such as a pill, liquid, or
injection without biological activity, used in pharmacol-
ogy to control for the activity of a drug. However, in many
cases this placebo induces biological or psychological
effects in the human. Two theories have been proposed
to explain the placebo effect: the conditioning theory,
which states that the placebo effect is a conditioned re-
sponse, and the mentalistic theory, which sees the pa-
tient’s expectation as the primary cause of the placebo
effect. The mechanisms involved in these processes are
beginning to be understood through new techniques of
investigation in neuroscience. Dopamine and the endor-
phins have been clearly shown to be mediators of pla-
cebo effects. Brain imaging has demonstrated that pla-
cebos can mimic the effect of the active drugs and
activate the same brain areas. This is the case for pla-
cebo-dopamine in Parkinson’s disease, for placebo-an-
algesics or antidepressants, and for placebo-caffeine in
the healthy subject. It remains to be understood how
conditioning and expectation are able to activate mem-
ory loops in the brain that reproduce the expected bio-
logical responses.
Copyright © 2005 S. Karger AG, Basel
© 2005 S. Karger AG, Basel
1021–7401/05/0124–0195$22.00/0
Fax +41 61 306 12 34
E-Mail karger@karger.ch Accessible online at:
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Received: September 7, 2004
Accepted: February 22, 2005
The Placebo Effect
The administration of pills, liquids or injections of
substances without specific effect in relation to the disease
of the patient is able to induce biological or psychological
responses [1–3] as long as the patients believe they could
be receiving the real drug. This phenomenon has made it
necessary to include placebo series in all clinical trials for
over 60 years now, even though the mechanism of the
placebo effect is still largely unknown. Scientific investi-
gation is in the paradoxical situation of taking into ac-
count a parameter for which there is still no completely
proven scientific rationale.
Most pathologies are susceptible to the placebo effect
[4], with variable intensity however [5–7]. The percentage
of response is particularly high in the treatment of pain
(30–90%), anxiety and depression. The placebo response
is not observed in all patients but responsiveness is not
associated with any psychological profile [2]. Patients
may be responsive or not, depending on the information
available as well as the particular context [8, 9].
The word placebo is Latin for ‘I shall please.’ This im-
mediately emphasises the psychological connotation of
the placebo effect. If the placebo is a-specific, the placebo
effect itself is highly specific and depends on the informa-
tion available to the patient [10, 11]. For example, a pla-
cebo will have the opposite effect on heart rhythm and
blood pressure when it is administered as a stimulant
than when it is given as an inhibitor [11]. This clearly in-
dicates that the effect is linked to the expectation of the
France Haour
INSERM U732, Hôpital Saint Antoine
184 rue du Faubourg Saint Antoine
FR–75571 Paris Cedex 12 (France)
Tel. +33 1 49 28 46 88, Fax +33 1 43 40 82 70, E-Mail fhaour@st-antoine.inserm.fr
patient and that cognitive emotional and mental process-
es are involved. The necessity for a multidisciplinary ap-
proach, including neurobiology and the human and social
sciences, has made any research in this field difficult.
However, new techniques of investigation and results in
the neurosciences are providing interesting information.
The placebo effect has been traditionally studied ac-
cording to two theories: the conditioning theory, for
which the placebo effect is a conditioned Pavlovian re-
sponse, and the mentalistic theory, for which the patient
expectation is the primary cause of the placebo effect.
Conditioning has been studied mainly in animals, yield-
ing experimental and clinical data confirming both theo-
ries [9, 11–15]. In humans, conditioning and expectation
are probably acting simultaneously.
New data from the field of neurobiology should now
be integrated. First, it has been shown that, beside classic
neurotransmitters, the adult nervous tissue synthesises
hormones (steroids, endorphins, growth factors), many
immune mediators (cytokines, prostaglandins) and ex-
presses the corresponding receptors [16–23]. Mimicry
and functional correspondence is therefore possible be-
tween the brain and the body. Second, complex functions
such as the immune responses can react to Pavlovian con-
ditioning in animals and humans [13, 24–26]. Last, brain
imaging (PET) has shown that the placebo effect is asso-
ciated with specific and localised changes in brain func-
tions. For example, in the case of Parkinson’s disease
(treatment with dopamine agonists) a placebo for dopa-
mine is associated with the release of endogenous dopa-
mine and binding to the corresponding receptors [27, 28].
There is a similar effect for caffeine: a placebo effect is
associated with a release of dopamine in the thalamus and
dopamine binding to the putamen [29], steps which are
observed following the consummation coffee. Caffeine
and placebo-caffeine clearly share the same mechanism
of action on the brain.
A better understanding of the mechanisms of the pla-
cebo effect is fundamental and very important for clinical
pharmacology. It will also provide a better understanding
in the growing field of ‘alternative’ medicine. Moreover,
conditioning, expectation and the placebo effect cannot
be ignored in the field of psychotherapies.
Pharmacology of the Placebo Effect
Placebo effects are obtained in an average of 30% of
humans. In a study of more than 1,000 patients treated
for various types of pain, the average efficiency was 35%
196 Neuroimmunomodulation 2005;12:195–200
[3, 30]. Experimental pain in the healthy adult is the least
sensitive to the placebo effect, while pain related to anxi-
ety, such as heart diseases, is the most sensitive (up to
90% respond).
Interestingly, when the placebo is effective, the phar-
macology is similar to the active drug [1, 3]. The placebo
effect depends on the route of administration as well as
the formulation (intravenous, intramuscular, oral; drops,
pills). The latency of the effect is usually shorter than for
the drug, with an earlier peak of activity. Dose-effect re-
lationships are obtained and the placebo is active for
about 2 weeks in the treatment of pain. Like the active
drugs, placebos can induce side-effects (nocebo) and cre-
ate dependency.
Conditioning and the Placebo Effect
The biological response to a placebo is very similar to
a conditioned response. As demonstrated by Pavlov [24]
for salivation in dogs, many biological responses can be
associated with visual, auditory or gustatory stimuli
(conditioning stimulus). Following the conditioning pe-
riod, in which drugs and stimuli are given simulta-
neously, the conditioning stimulus is able to induce the
same biological effect as the drug. Relevant data from
animal studies have been published in the field of pain,
behaviour and immunomodulation [13, 14, 23, 30–
32].
Conditioning of complex functions such as inflamma-
tion and immune response have been well investigated
[13, 25, 33–36]. For example, the immunosuppressive
effect of cyclophosphamide can be recalled after the con-
ditioning period by exposure to the conditioning stimu-
lus [13–34, 37]. Similarly, conditioning can prolong
heart graft survival in the rat [33]. These results indicate
that conditioning triggers memory loops, integrating
nervous and immune systems. The mediators of these
effects are beginning to be investigated but are probably
multi-factorial [36].
In humans, conditioned responses have been ob-
tained in the field of pain, immune response, addiction,
psychopharmacology, regulation of glycaemia [3, 12, 26,
32, 35, 38, 39].
Conditioning is therefore concerned with learning
and adaptation. In the animal world, the adaptive aspect
was probably useful in order to recognize adequate food
and behaviour. Conditioning is also likely to be at work
in healthy humans as well as in patients under treatment.
This is confirmed by the fact that the placebo effect is
Haour
more pronounced when the patient has already been
treated with the active product [40].
Expectation and the Placebo Effect
The conditioning theory cannot explain the placebo
effects in patients who have never been exposed to the
drug [9, 41]. Moreover, the prolonged effect of placebos
is not compatible with the extinction phenomenon that
has been described in Pavlovian conditioning. In the ab-
sence of previous exposure to the treatment, expectation
and hope for improvement are likely to be the trigger of
the placebo effect. However, conditioning and expecta-
tion are probably acting together and the two theories can
be reconciled, since animal conditioning shows that what
is learned in Pavlovian conditioning is actually expecta-
tion [42].
In humans, various factors can be considered: reduc-
tion of stress and anxiety, release of endorphins or dopa-
mine as well as the quality of the relationship with the
therapist [11]. Quantification is difficult, since the pla-
cebo effect is linked to individual beliefs as well as cogni-
tive and emotional information. In a very simple experi-
ment for which the stress aspect is minor, one can notice
that placebo-caffeine decreases motor performance in
people who expect this effect and increases them in those
who expect a positive effect [11]. Therefore one could as-
sume that conditioning leads to expectation, but the pro-
cess is not automatic and depends on the information
available to the patient and his perception of his illness,
the drug and the therapist [11].
It remains to be understood more precisely how the
expectation of a response produces the expected re-
sponse.
Pain and Placebo
The placebo effect is well documented for pain of var-
ious pathologies [4–7, 15, 30, 43]. For the treatment of
migraine a meta-analysis indicated that 26–32% of the
patients respond to placebos [7], the response can reach
90% for other types of pain. Naloxone administration can
antagonise the placebo effect, which is a first indication
of the mechanism of placebo analgesia [5, 43]. This effect
of an opiate antagonist suggests that placebos can induce
the release of endogenous opioids, a theory that has gained
further support from the recent observation that placebo
analgesia is associated with patterns of cerebral blood
Placebo Effect and Conditioning
flow activation in the cingular cortex similar to those seen
after injection of active opioids [44]. Similar stimulations
are observed during hypnosis-induced analgesia [7]. Fi-
nally, PET scan analysis [45] has shown a release of en-
dogenous opioids during prolonged pain and that free
micro-opioid receptors are decreased in the cingular cor-
tex, amygdale and thalamus. This decrease suggests re-
ceptor occupancy and is correlated with the subjective
intensity of the pain.
Placebo analgesia might also involve a reduction in
stress [4]. As a matter of fact, experimental pain in the
healthy volunteer is less sensitive to the placebo effect
than spontaneous pain. Under such conditions, in which
pain can be released at any time, the level of stress is re-
duced compared to uncontrollable pain. A placebo anal-
gesia can nevertheless be observed by fMRI [46]. For ex-
ample, pain induced by heat activates the somatosensory
cortex, thalamus, midbrain, anterior insula, cingular cor-
tex and cerebellum [46]. A placebo analgesia is correlated
with a reduction of the brain response. When pain is an-
ticipated, the placebo induces stimulation of the prefron-
tal cortex and the midbrain. This suggests that these ac-
tivations precede the reduction of pain and could be as-
sociated with the release of endogenous opioids in the
midbrain [46].
These two recent studies provide neuronal pathways
for placebo analgesia and for the various (sensory, emo-
tional and cognitive) parameters involved in pain percep-
tion.
Parkinson’s Disease and Placebo
Parkinson’s disease is characterised by the degenera-
tion of dopaminergic neurons in the substantia nigra and
a deficit of dopamine release in the striatum. The alter-
ation of the nigro-stiatal pathway results in motor dys-
functions which may be associated with pain and depres-
sion [7]. The disease is treated by a dopaminergic agonist
(L-dopa). This neurodegenerative disease paradoxically
is sensitive to the placebo effect as demonstrated in sev-
eral clinical trials [7, 27, 28, 50]. De la Fuente-Ramirez
et al. [27, 28] used a labelled dopaminergic agonist (raclo-
pride) which binds to D1 and D2 dopamine receptors to
visualize dopamine receptors in the brain [27, 28]. Pa-
tients received L-dopa or placebo, tomography and clini-
cal parameter assessment were performed immediately
after treatment. When L-dopa was injected, it occupied
the dopamine receptors in the striatum. The binding po-
tential of the radioactive raclopride was decreased and
Neuroimmunomodulation 2005;12:195–200 197
there was an improvement in clinical symptoms. When
placebo was injected, some patients exhibited the same
pattern and the decrease in raclopride-binding capacity
correlated with the changes in clinical symptoms. This
leads to the conclusion that the placebo effect is linked to
the release of dopamine in the remaining neurones of the
patient’s brain. In spite of the neuronal degeneration, the
placebo effect follows pathways that are used by the ac-
tive drug.
Homeopathy and Placebo
Starting in the 18th century, homeopathy is a treat-
ment based on the principle of the similarity between the
toxic effect of a drug in a healthy person and the symp-
toms of the patient [51]. For example, the compound used
for malaria treatment (China officinalis) induces a ma-
laria-like effect in healthy individuals. Several dilutions
of the active product are achieved to decrease toxicity and
vigorous shaking is supposed to potentiate the effect. The
therapeutic approach also takes into account the entire
characteristic set of symptoms of the patient and not just
of the disease.
For classic pharmacology, the doses are usually too low
to produce any biological effect but homeopathy is un-
dergoing a worldwide revival. In fact, clinical results are
obtained and practitioners are keen to obtain scientific
recognition. As a consequence, several clinical investiga-
tions (double-blind, placebo-controlled studies) have
been carried out on a large scale [52]. There is a lack of
conclusive evidence for the effectiveness of homeopathy
in most conditions. From randomized controlled trials
one can conclude that homeopathy is effective in the
treatment of influenza, allergies, post-operative ileus and
childhood diarrhoea [52].
It is therefore reasonable to think that most effects of
homeopathic treatments are using pathways common to
those of the placebo effect. This clearly illustrates the
power of placebos.
Psychotherapy and the Placebo Effect
The placebo effect has been especially involved in the
treatment of psychiatric disorders such as anxiety and
depression [47–49]. These raise the question of the effect
of psychotherapies in relation to the placebo effect. Psy-
chotherapies, whatever their theoretical and practical ap-
proaches and their qualities, clearly have something in
198 Neuroimmunomodulation 2005;12:195–200
common with placebos. We have already seen that the
placebo effect is the end result of conditioning and expec-
tation of the drug and the doctor. It seems reasonable to
assume that these two mechanisms are at work during
psychotherapy: context and ritual of the session and pa-
tient expectation. This second aspect is amplified by emo-
tions, verbalisation and the transfer that occurs during
psychotherapy.
This is important in connection with possible con-
trolled studies in psychotherapy. It seems that it is not
feasible to use placebo controls in psychotherapy studies
since, in a way, all psychotherapeutic approaches are pla-
cebogenic. Comparisons between psychotherapies or be-
tween psychotherapy and pharmacological treatment are
the only possible setup for evaluation.
Neurobiology and brain imaging [53–56], which now
make it possible to follow brain activity during a person’s
interactions, will probably shed some light on the pro-
cesses. For example, in the case of major unipolar depres-
sion [56] treated with an antidepressant (paroxetine) or
with cognitive psychotherapy, PET scans indicate that
clinical improvement obtained with psychotherapy in-
creases metabolism in the hippocampus and the dorsal
cingular cortex but decreases it in the frontal cortex. By
contrast, an increase in the prefrontal area and a decrease
in the hippocampus and the cingular cortex are observed
in patients who respond to paroxetine. In both cases cor-
tical and limbic area are modified and this approach
seems to be promising in spite of the apparent contradic-
tion in these results.
Conclusion
Experimental and clinical research provide two theo-
ries for the placebo effect: Pavlovian conditioning and
expectation of the treatments or therapists. Cognitive and
emotional functions are involved and probably both con-
tribute to the placebo effect, which is particularly pro-
nounced in the absence of organic lesions and in patients
treated for pain or psychopathologies. It is worth noting
that a placebo effect can be obtained in healthy humans
and in the presence of neurodegenerative lesions, such as
in Parkinson’s disease.
Dopamine and endogenous opioids have been clearly
demonstrated as mediators of placebo effects and brain
imaging indicates that placebos mimic and use the path-
ways of the active drugs. This is the case for dopamine
in Parkinson’s disease, analgesics, antidepressants and
caffeine. It seems that the placebo effect results from a
Haour
mental reproduction of the effect already experienced
with the drug. In the absence of previous treatment, ex-
pectation and hope for improvement are probably criti-
cal. It is worth noting that dopamine and brain areas rich
in dopamine terminals and receptors are particularly in-
volved. These regions are important for pleasure and
reward-related mechanisms [7, 56–58] and are probably
key points for understanding the placebo effect. The link
of this effect with memory, emotions, stress, pleasure,
rewards, empathy and expectation shows that we are at
the interface between neurobiology, psychology and
sociology.
A better understanding of the mechanisms remains
important for pharmacology, alternative medicine and
psychotherapy: to understand how conditioning and ex-
pectation can trigger memory pathways in the brain that
reproduce the expected response.

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