The Placebo-Fooled Brain

Emotions, stress, depression, anxiety, fear, memory, learning, anticipation, and expectation; all these factors modulate our experience of pain and are mirrored in one of the most fascinating and intriguing phenomena in analgesia: the placebo effect.

Research theories have been classically divided on whether placebo effects depend on conscious expectancy or unconscious learning and conditioning mechanisms. These views have been gradually converging into the current idea that defines the placebo response as a set of complex psycho-neurobiological events built up from both verbally induced expectation and learning processes such as conditioning or social learning, and modulated by emotions, motivation and attitude.

It is well known that placebo analgesia can arise from the description of an effect that, by creating the expectation of pain relief, actually induces it. Likewise, the remembrance of previous circumstances of pain relief can build up an expectation of an outcome that ends up occurring; however, this can also be interpreted as an unconscious learned behavior.

Regardless of the theories, what is clear is that the placebo effect is not caused by the mere administration of a sugar pill. The social context is the key element in creating the suggestion that a beneficial treatment is being received. Even subtle unconscious context cues associated with a pain relief experience, such as the color of the pill, can affect the placebo response.

Social learning is a major contributor; research has shown that the observation of a benefit in another person can induce placebo analgesia as effectively as by direct experience through a conditioning procedure. In a recently published study, it was tested how the observation of facial expressions with different emotional content (neutral, pain, and happy) affects the magnitude of placebo analgesia.

The participants underwent placebo conditioning and subsequently rated their pain associated with a stimulus. They were informed that a red cue would be followed by a laser stimulus, while a green cue would be followed by the same stimulus associated with an analgesic procedure (the sham analgesia). In the conditioning period, the green cue was indeed followed by a lower intensity stimulus, aimed at strengthening the expectation of pain relief associated with the sham treatment. In the test period, both cues were followed by laser stimuli of the same intensity. Each trial consisted of either a red or a green visual cue, followed by the stimulus delivered during the presentation of neutral, grimacing, or smiling facial expressions.

Interestingly, when the green cue was presented and the participants were expecting the placebo analgesia, the observation of facial expressions with an emotional content significantly enhanced the placebo analgesia. Although this potentiation was higher when observing happy faces, surprisingly, grimacing facial expressions were also effective. To interpret these results, the authors had to take into account the reduction of attention due to the distracting effect of observing facial expressions, and the expectation arising from the cues they received. This reflects the multifactorial nature of pain and of the placebo effect and how it can complexify its research.

An interesting phenomenon that depicts how learning mechanisms are key elements in placebo analgesia is pharmacological conditioning: repetitive exposure to pharmacological treatments can produce similar effects when the drug is replaced by a placebo, being able to reproduce the particular action of a drug and inducing physiologically specific effects. This has actually been translated into a clinical application of placebos as drug effect enhancers or even partial substitutes.

Neurochemically, placebo analgesia is known to be mediated by the release of neuromodulators that trigger the activation of endogenous analgesic activity. Endogenous opioids, one of our most important intrinsic pain-relieving systems, are a major part of the mechanism. Moreover, brain regions in which the endogenous opioid system becomes active during placebo administration associated with expectations of analgesia are also associated with learning, therefore contributing to the maintenance of placebo effects.

Changes in opioidergic neurotransmission have been linked to the dopaminergic and the cannabinoid systems; opioid- and cannabinoid-mediated pathways seem to be engaged in expectancy and conditioning while dopamine-mediated mechanisms are linked to reward, motivation and expectancy of the reward.

Although great advances have been made, there is still much research needed to fully elucidate the neurobiological mechanisms of placebo analgesia.


Colloca L, & Benedetti F (2006). How prior experience shapes placebo analgesia. Pain, 124 (1-2), 126-33 PMID: 16701952

Colloca L, & Benedetti F (2009). Placebo analgesia induced by social observational learning. Pain, 144 (1-2), 28-34 PMID: 19278785

Colloca L, Klinger R, Flor H, & Bingel U (2013). Placebo analgesia: psychological and neurobiological mechanisms. Pain, 154 (4), 511-4 PMID: 23473783

Jubb J, & Bensing JM (2013). The sweetest pill to swallow: how patient neurobiology can be harnessed to maximise placebo effects. Neuroscience and biobehavioral reviews, 37 (10 Pt 2), 2709-20 PMID: 24055773

Klinger R, Colloca L, Bingel U, & Flor H (2013). Placebo analgesia: Clinical applications. Pain PMID: 24333780

Peciña M, Stohler CS, & Zubieta JK (2013). Neurobiology of placebo effects: expectations or learning? Social cognitive and affective neuroscience PMID: 23887819

Valentini E, Martini M, Lee M, Aglioti SM, & Iannetti G (2013). Seeing facial expressions enhances placebo analgesia. Pain PMID: 24315986

Image via Thirteen / Shutterstock.

Sara Adaes, PhD

Sara Adaes, PhD, has been a researcher in neuroscience for over a decade. She studied biochemistry and did her first research studies in neuropharmacology. She has since been investigating the neurobiological mechanisms of pain at the Faculty of Medicine of the University of Porto, in Portugal. Follow her on Twitter @saradaes
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