“Like a celestial chaperone, the placebo leads us through the uncharted passageways of the mind… What we see, ultimately, is that the mind can carry out its difficult and wondrous missions unprompted by little pills.”
Placebo responses are complex, multiform, and multimodal.1–3 Their neural substrates are many interacting neuronal systems that orchestrate changes in pain (endogenous opioids; CCK; DA), motor control (DA, in dorsal stratum), mood, anxiety, memory, motivation (DA, serotonin, GABA, HPA axis)
Both conscious expectations (augmented by desires, hope, and belief) and unconscious conditioning (“embodied experiences”4 or “remembered wellness”5) can move the molecules of change along the distributed biological systems, subserving cognition, emotions, pain control, reward, and learning.
Expectations and Brain Reward Circuitry
The neural circuitry of reward has its headquarters in the NAc and is implemented by a convergent network in the ventral tegmental area (VTA), hippocampus, amygdala, orbital frontal cortex (OFC), ACC, globus pallidus, ventral pallidum, and the thalamus (Figure 1).6 The areas involved in attention, executive decisions, and emotional memories help the brain negotiate the path to the reward. DA is released in a tonic and phasic manner during anticipation of and after possession, respectively, of reward guided by uncertainty principle and the element of surprise.7 With 0.5 probability of reward, 29% of DA cells are tonically activated.8 The phasic DA activation takes place after the reward, and this is stronger when reward has come as a surprise. Phasic DA activation is followed by an increase in endogenous opioids (the NAc shell contains opioids receptors responsive to DA). Thus, the circuitry of anticipation of reward is different from having a reward in possession.9
Placebos activate the brain’s reward circuitry.
Figure courtesy of Devdutt Nayak, MD.
When expectancy (eg, positive verbal suggestions) creates the possibility of therapeutic benefits in placebo responsiveness, cortical PFC neurons send glutamate input (when the probability of reward is ≥ 0.5) to DA neurons in the reward circuitry. This input gets integrated in the spiny GABAergic inhibitory neurons, which causes further cascading of DA.10 With this “winner-take-all” concept, the NAc is able to capture the attention of the PFC and modulate arousal, autonomic tone, and emotionality in a unified manner to make the brain seek reward of therapeutic benefit, even when no active treatment is offered. The expectant state primes the pump of DA transmission and creates a motivational state that signals desire and facilitates the memory and behavior associated with fulfilling that desire.11 Both DA and endogenous opioids play a key role in the modulation of placebo responsiveness in an efficiently functioning reward system. In one study, there was a positive correlation between the NAc responses to monetary awards and increased placebo responsiveness.3
Placebo-induced secretion of DA in the nigrostriatal pathway in Parkinson’s disease has been demonstrated by verbal suggestions,12 sham deep brain stimulation (DBS),13 and sham repeated transcranial stimulation (rTMS) applications.14 The fact that the resulting motor improvement in performance can be objectively evaluated by blinded examiners has given it signatory merit, demonstrating the brain’s ability for cognitive learning through reinforced expectations and neuronal changes involving the subthalamic nucleus, substantia nigra, and thalamus. Both subjective well-being and enhanced performance have been observed. De la Fuentes-Hernandez et al.15 were the first to demonstrate the placebogenic induction of DA with apomorphine as pharmacologic control in the striatum. Patients in the placebo arm with a declared possibility of a 50/50 chance of getting apomorphine, but actually receiving placebo, exhibited a more than 200% increase of DA in the striatum comparable to the response to amphetamine in healthy subjects. A DA spike was obtained with the use of sham rTMS14 and sham DBS, even from a single neuron recording in the subthalamic nucleus.16 In another study, it was shown that both positive and negative expectations could drive the motor performance up or down, similar to bidirectional pain modulation, by encouraging or discouraging verbal suggestions in other instances.17
The motor placebo response can also be seen in an intact motor system. As shown in a placebo caffeine study, a significant increase in muscle work and decrease in muscular fatigue can be conditioned to enhance performance.18 The authors suggested that placebo could push the envelope of muscular performance in athletes a little farther through modulation of a “central governor” of fatigue.
The Opioid System
The era of understanding the biological basis of placebo effect was ushered in by Levine et al.19 with the observation that the opioid antagonist nalaxone interfered with placebo analgesia in pain from tooth extraction and raised the possibility that the endogenous opioid system was implicated.
The opioid system is a top-down regulatory system, working from the prefrontal areas of the anterior cingulate and insular cortex, along with the hypothalamus and the amygdala, to converge on the gray matter surrounding the third ventricle in the midbrain (periaquiductal grey, or PAG).6 Other noradrenergic and serotonergic neurons also project down on the afferent pain neurons. A comphrensive review by Pollo et al.20 marshalled the evidence of the link between the placebo-induced analgesia to endogenous opioid secretion by: suggestions alone; showing an increased concentration of endorphins in the CSF of placebo responders versus non-responders; production of typical opioid side effects like respiratory depression and a decrease in beta adrenergic activity of the heart during the placebo response. Many neuroimaging studies have further advanced our knowledge of placebo-induced analgesia with regard to timing, location, and by linking opioid specificity in the aforementioned opioid systems network.21
Intact PFC Is A Prerequisite For Placebo Responsiveness
The work of Benedetti and colleagues22 clarified the importance of prefrontal connectivity in producing placebo effects. When prefrontal networks are damaged, as in Alzheimer’s disease, the placebo component of analgesia is lost. This reduces the overall effectiveness of pain medications and necessitates a dose increase to make up for the loss. In a study employing an open/hidden treatment paradigm, investigators studied the impact of injecting the active drugs without patients’ knowledge by silencing the expectancy mechanism and eliminating therapeutic interaction and the psychosocial context that ostensibly drives the placebo effect.17 Studies evaluating patients with pain, anxiety, addiction, and Parkinson’s disease have shown a significant decrease of pharmacodynamic actions of the drug with use of hidden administration.23 Volkow et al.24 found that cocaine addicts had 50% less secretion of DA and experienced less of a “high” when hidden administration was used compared to when the drug was given openly. Recently, rTMS has been shown to inactivate the PFC, producing a loss of placebo response.25
Neuro Circuitry Similarities
The expectations can increase or decrease the magnitude of perception of anxiety. Expectations have also shown to activate specific brain areas (eg, the ACC, PFC, and insula). Thus, the neurocircuitry of anxiety and pain mechanisms may be similar (Figure 2).
The neurocircuitry of pain and anxiety are similar.
Figure courtesy of Devdutt Nayak, MD.
The ACC is an important anatomical component of DA and the opioid system. In one functional magnetic resonance imaging (fMRI) study,26 strong expectation of treatment effects were created by giving either midazolam (benzodiazepine agonist) or flumazenil (benzodiazepine antagonist) in unpleasant situations on day 1. On the second day, with similar unpleasant situations, placebo was given without informing participants. A significant placebo response of decreased anxiety occurred when the subjects thought they received midazolam, but no response was seen in those who thought they received flumazenil. The fMRI showed blood flow changes in the ACC and lateral OFC, very same areas as involved in placebo analgesia.21
The role of anxiety in producing placebo effects is driven home by studying nocebo effects, which are unpleasant placebo effects.
Neurobiology of Negative Expectations
Pharmacological studies in brain imaging techniques have become crucial to understanding how negative expectations amplify pain, and several brain regions like the ACC, PFC, and insula have been found to be activated during the anticipation of pain. CCK appears to play a pivotal role in the modulation of pain, antagonizing placebo-induced opioid release on the one hand, and mediating nocebo-induced facilitation of pain on the other.27 Research has shown that anticipatory anxiety produced by nocebo suggestions acts on two independent pathways: the HPA axis and the CCKergic pro-nociceptive system. By acting on anxiety, benzodiazepines can block both pathways and reduce pain. However, CCK antagonists (eg, proglumide) can prevent nocebo hyperalgesia but have no effect on HPA hyperactivity (Figure 2).28
The yin and yang of placebo/nocebo is mediated with opposing effects of opioid/CCKergic systems. The activation/deactivation balance of both DA and opioids in the nucleus accumbens account for the modulation of placebo and nocebo responses.29
As opposed to expectations, learning through associative conditioning is mostly unconscious. Price, Finnis, and Benedetti2 noted the parallel between the placebo response and classical conditioning. Endocrine, immune, and autonomic responses have been effectively conditioned by placebos. Pacheco- Lopez et al.30 advanced our knowledge of immune response substrates in behavioral conditioning and the resultant reflexive activation of the amygdala, insular cortex, and ventral median nucleus of the hypothalamus playing a role in placebo genesis. An afferent branch brings information of infection or injury and an efferent branch operating through cholinergic and catecholaminergic pathways provides output in the ANS (eg, cholinergic anti-inflammatory pathway). The stress response is also part of this reflexive arc, which activates the HPA axis.2 Present research is leaning toward a mixed role of expectancy and conditioning derived from previous experiences and social observational learning in mediating placebo responses.
Beecher’s31 astute observation on extreme analgesia produced in soldiers with serious injuries led him to speculate on innate pain-relieving mechanisms. Recently, a role for endocannabinoids was revealed in stress-induced analgesia independent of the opioid pathways. Hohman et al.32 demonstrated that stress-induced analgesia in rats could be inhibited by blockers of endocannabinoids that are released by higher cortical centers, such as the amygdala, and rapidly accumulated in the PAG to suppress pain perception. It appears that brain’s inner pharmacy is well-stocked with stress-reducing, pain relieving, immunity-boosting, and self-healing chemicals.
The neural substrates of placebo treatment have also been studied in depression as measured by electrical and metabolic changes. In one study, changes in brain glucose metabolism were measured using positron emission tomography in 17 patients hospitalized for unipolar depression.33 Following treatment with either fluoxetine or placebo, responders showed metabolic increases in cortical activity (PFC, ACC, insula) and metabolic decreases in the subgenual cingulate cortex, parahippo-campus, and thalamus after 6 weeks of either treatment. Fluoxetine responders showed additional increases in pons and decreases in caudate, insula, and hippocampus. There were no regional changes unique to placebo at 6 weeks. The drawback of the study was that it did not have enough placebo nonresponders, and for obvious ethical reasons, a no-treatment control group was not included.
In another study, placebo-induced changes were noted in the right PFC in patients with major depression.34 Subsequently, cognitive behavioral therapy (CBT)35 and interpersonal therapy36 have been reported to produce prominent pre-frontal decreases in glucose metabolism (including OFC, MFC, and dorsal ACC), but in very different regions from those seen in placebo. Reviewing these, Benedetti et al.37 argued that there is no common antidepressant response pathway in the brain, that placebo response is not a nonspecific psychological treatment effect, and that placebo response patterns match the active treatment patterns to which they are paired. More research with placebo-controlled psychotherapy (eg, CBT) and a wait-list no-treatment group is needed in this area.
During the past 25 years, research on biological mechanisms of placebo response has given it firm, scientific underpinnings and has spawned interest in studying the science behind the art of medical care. It has further established that you do not need a pill to produce placebo effect, and that sham devices, pretend surgery, and even encouraging words imbued with meaning can produce them. The review presented here on numerous clinical syndromes (pain, immune responses, anxiety, Parkinson’s disease, and major depression) helps us understand the following key points about the neurobiological mechanisms of placebo effects:
- Placebos activate neuronal circuits of expectation, reward, and learning.
- Similar biochemical pathways (DA, endogenous opioids, GABA, serotonin, HPA, and endocannabinoids) are used by drugs and placebos.
- Placebos act through conscious mechanisms (verbal suggestions, desire to get well, hopeful expectations, belief, and faith), as well as unconscious conditioning (psycho-neuro immune responses, positive transference in therapeutic relationship).
- The activation/deactivation balance between endogenous opioids/dopamine in the nucleus accumbens explains both placebo and nocebo responses
- Intact PFC circuitry is required to elicit a placebo response
- Placebo responses do happen “in our head,” but they are not “figments of our imagination.”
- Benedetti F. Mechanisms of placebo and placebo-related effects across diseases and treatments. Annu Rev Pharmacol Toxicol. 2008;48:33–60. doi:10.1146/annurev.pharmtox.48.113006.094711 [CrossRef]
- Price DD, Finniss DG, Benedetti F. A comprehensive review of the placebo effect: recent advances and current thought. Annu Rev Psychol. 2008;59:565–590. doi:10.1146/annurev.psych.59.113006.095941 [CrossRef]
- Enck P, Benedetti F, Schedlowski M. New insights into the placebo and nocebo responses. Neuron. 2008;59(2):195–206. doi:10.1016/j.neuron.2008.06.030 [CrossRef]
- Thompson JJ, Ritenbaugh C, Nichter M. Reconsidering the placebo response from a broad anthropological perspective. Cult Med Psychiatry. 2009;33(1):112–152. doi:10.1007/s11013-008-9122-2 [CrossRef]
- Stefano GB, Fricchione GL, Slingsby BT, Benson H. The placebo effect and relaxation response: neural processes and their coupling to constitutive nitric oxide. Brain Res Brain Res Rev. 2001;35(1):1–19. doi:10.1016/S0165-0173(00)00047-3 [CrossRef]
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- De la Fuente-Fernández r, Schulzer M, Stoessl AJ. Placebo mechanisms and reward circuitry: clues from Parkinson’s disease. Biol Psychiatry. 2004;56(2):67–71. doi:10.1016/j.biopsych.2003.11.019 [CrossRef]
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- De la Fuente-Fernandez r. The placebo-reward hypothesis: dopamine and the placebo effect. Parkinsonism Relat Disord. 2009;15(suppl 3):s72–s74. doi:10.1016/S1353-8020(09)70785-0 [CrossRef]
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- Brockman R. Aspects of psychodynamic neuropsychiatry iii: magic spells, the placebo effect, and neurobiology. J Am Acad Psychoanal Dyn Psychiatry. 2011;39(3):563–572. doi:10.1521/jaap.2011.39.3.563 [CrossRef]
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- De La Fuente-Fernández R. Uncovering the hidden placebo effect in deep-brain stimulation for Parkinson’s disease. Parkinsonism Relat Disord. 2004;10(3):125–127. doi:10.1016/j.parkreldis.2003.10.003 [CrossRef]
- Strafella AP, Ko JH, Monchi O. Therapeutic application of transcranial magnetic stimulation in Parkinson’s disease: the contribution of expectation. Neuroimage. 2006;31(4):1666–1672. doi:10.1016/j.neuroimage.2006.02.005 [CrossRef]
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- Pollo A, Carlino E, Benedetti F. The top-down influence of ergogenic placebos on muscle work and fatigue. Eur J Neurosci. 2008;28(2):379–388. doi:10.1111/j.1460-9568.2008.06344.x [CrossRef]
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