The Neuroscience Behind the Placebo Effect

by Viatcheslav Wlassoff, PhD | December 7, 2017 

As a child, did you ever feel better after your mother kissed your bumped knee? How do you think that worked? The power of suggestion—or the placebo effect—is a powerful psychological phenomenon that affects every aspect of our lives, dictating our preferences for food, drink, medication, social activities, and more.

Pioneering experiments describing the use of sham drugs date back to the late 18^th century. A version of John Quincy’s Lexicon Medicum published in 1811 defines the placebo as ‘an epithet given to any medicine adapted more to please than to benefit the patient’. However, physicians of the past tended to use forms of treatment that they assumed were ineffective, as opposed to the modern day usage of inert substances.

A wide variety of conditions have been proven to be amenable to placebos, including depression, sleep disorders, Parkinson’s disease, and pain². The placebo effect has been shown to impart tangible changes on the immune system similar to those who received real medication, where patients given syrup had increased white blood cell counts. Remarkably, patients with Parkinson’s disease stopped experiencing tremors and muscle stiffness after taking inert sugar pills. The success of mirror therapy in relieving phantom pain in amputees can be thought of as another example of the power of suggestion.

How our minds are fooled is not fully understood. The placebo effect may be an evolutionary adaptation that allows the brain to make quick decisions and assumptions about the environment. Consider this: if we had to analyse every single stimulus that our environment threws at us, we’d go mad in no time.

Scientists have identified that the psychological mechanisms of the placebo effect lie in both conscious expectations and learning. Although learning and expectations are not mutually exclusive, they are heavily dependent on each other.

To explain, when we expect a drug to reduce pain levels, our brains release endogenous endorphinsthat in turn are responsible for alleviating pain. On the other hand, the learning process involves integrating environmental and social cues in order to generate an internal expectation and subsequent placebo response. Experiencing repeated patterns of learning conditions (as in classical conditioning – think Pavlov’s dogs), causes a person to respond in a way that has spill-over-effects effects that influence unconscious physiological processes. 

Multiple studies have singled out the ventromedial prefrontal cortex (vmPFC) as a main player in mediating the placebo effect. Other areas of significant importance are the dorsolateral PFC, lateral orbitofrontal cortex, periaqueductal grey area, rostroventral medulla, and nucleus accumbens-ventral striatum.

In short, the complex underlying neuronal circuits involve the higher functioning areas of the brain (frontal cortices) and the seat of unconscious processes such as breathing, the brainstem. Interestingly, rsearch reports that the placebo effect is absent in those with Alzheimer’s disease (due to degeneration of the frontal cortex) and in patients subjected to external suppression of frontal cortex function via transcranial magnetic stimulation.

The endogenous opioid system and its role in placebo-induced analgesia is perhaps the best studied neurotransmitter system involved in the placebo effect. Naloxone, an opioid receptor antagonist, has been found to nullify the effects of placebo pain-killers. Other systems that have been implicated include the cannabinoid system.

These neuroanatomical and neurobiological findings likely have much room for growth and refinement considering that different placebo responses have been found to invoke different parts of the placebo circuit.

Given the complicated psychological mechanisms behind the placebo, it comes as no surprise that various factors are able to modulate its strength. Social context has a real impact on the placebo effect, as it fosters preconceived notions regarding treatment. For example, several trials showed that similar benefits were experienced by both groups of patients who underwent either traditional or sham Chinese acupuncture (the latter involving superficial needling at non-acupuncture points). The physician attitude and appearance of competency, as well as the cost, branding, shape, size, color, and taste of the pills were able to affect the perceived treatment efficacy.

It is common beleif that one must be unaware of the placebo in order for the placebo effect to work. Not so, argue a group of researchers from the University of Basel (Switzerland) and Harvard Medical School. They demonstrated that participants who were told that they were getting placebos and who received detailed explanations of the placebo effect experienced significant relief from heat-induced pain compared to those that were not told that they were given bogus drugs.

These surprising results underscore the formidable effects of the placebo effect and how much more there is still left to learn. Furthermore, this study opens doors to more ethically designed placebo-controlled studies. Withholding potentially beneficial treatment from patients in placebo-controlled trials is considered inherently unethical. However, with this study, it appears that full disclosure may not be that different to the traditional practices of keeping placebo patient groups in the dark.

In order to manipulate the placebo effect for clinical benefit, the notion of placebo responders and non-placebo responders was investigated. Are some people more amenable to the power of suggestion than others? If so, is it due to unchangeable genetic makeup or individual personality? Other questions that come to mind regard the persistency of the placebo effect. For how long does it last and does it transfer to other types of placebos? To illustrate, will a person responding to placebo painkillers for pain relief also respond to placebo antidepressants for improved moods?

In conclusion, we know that the placebo is a strong weapon in the clinician’s armamentarium. Despite that, the unpredictable variability of its effects obligates future research that enables us to get a better understanding of exactly when and for how long the placebo effect will work.

References: 

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Price DD, Finniss DG, Benedetti F. A comprehensive review of the placebo effect: recent advances and current thought. Annu. Rev. Psychol. 2008. 59:565–90. doi:10.1146/annurev.psych.59.113006.095941

Colloca L, Miller FG. How placebo responses are formed: a learning perspective. Philosophical Transactions of the Royal Society B: Biological Sciences. 2011;366(1572):1859-1869. doi:10.1098/rstb.2010.0398.

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Miller FG, Colloca L, Kaptchuk TJ. The placebo effect: illness and interpersonal healing. Perspectives in biology and medicine. 2009;52(4):518. doi:10.1353/pbm.0.0115.

Buckalew LW, Coffield KE. An investigation of drug expectancy as a function of capsule color and size and preparation form. J Clin Psychopharmacol. 1982 Aug;2(4):245-8. PMID: 7119132

Howe LC, Goyer, J. P., & Crum, A. J. Harnessing the placebo effect: Exploring the influence of physician characteristics on placebo response. Health Psychology. 2017;36(11):1074-82. doi:10.1037/hea0000499.

Locher C, Frey Nascimento A, Kirsch I et al. Is the rationale more important than deception? A randomized controlled trial of open-label placebo analgesia. Pain. 2017 Dec;158(12):2320-2328. doi:10.1097/j.pain.0000000000001012.

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