Placebos are drugs or other sources of treatment that are physically and pharmacologically inert, without any direct therapeutic effects. The neurobiological mechanisms of the placebo effect remain a matter of great research interest.

The placebo response is a set of complex psycho-neurobiological mechanisms; it is believed that verbal suggestions and conditioning cues can recruit simple forms of memory capable of triggering multiple types of responses, including autonomic and neuroendocrine responses, emotions and motivated behaviors. Therefore, this is a rather complex research subject that needs to incorporate diverse fields of neuroscience, such as pharmacology, neurophysiology and cognitive and behavioral neuroscience.

I’ve previously talked about the placebo effect, at the time focusing mostly on placebo analgesia, the most extensively studied placebo effect. However, the placebo effect is ubiquitous in the context of treatments that encompass the suggestion of an effect by verbal, social or physical cues. These can elicit expectations, memories and emotions that can affect disease outcomes. There are some interesting studies on the placebo effect in depression and Parkinson’s disease, for example.

The existence of placebo effect on depression, regardless of the mechanisms, seems somewhat intuitive: it’s reasonable to assume that expectations, memories and emotions will most likely influence the outcome of anti-depressant therapy. The fact that there are reported placebo effects on learning and on motor performance in Parkinson’s disease is a bit more surprising.

Research has been unveiling some of the neurochemical mechanisms of the placebo effect. Beyond reporting a “therapeutic” outcome, many studies have also reported neurophysiological changes correlating to the observed clinical improvements.

For instance, placebo administration has been shown to increase dopamine binding in the striatum in patients with Parkinson’s disease. The level of dopamine binding was correlated with the patient’s perceived improvement in clinical outcomes. Other studies also showed that placebos could increase neuronal firing in certain areas of the brain associated with Parkinson’s disease and that these increased neuronal discharges correlated with improved motor performance. Placebos were therefore able to reproduce the effects of dopamine drugs through what may be called expectation-induced dopamine release. In depression, placebo administration has been shown to reduce glucose metabolism in critical brain regions.

Other studies have also shown an anxiolytic-like placebo effect associated with altered activity in different brain regions, some known to be associated with the placebo effect in the context of analgesia, thereby indicating that placebo effects in different conditions may have some shared mechanisms. Other studies directly addressed this question by exam­ining whether placebo suggestions about pain outcomes could influence emotional outcomes. Indeed, it was found that a placebo analge­sic effectively reduced the unpleasantness of negative images by reducing amygdala and insula responses, central to emotional processing.

Thus, this again provides evidence of shared mechanisms. But although many placebo-associated processes may be common to different pathologies, there will most likely be specific effects on specific brain systems and outcomes depending on the context. Direct comparisons of the brain mecha­nisms underlying placebo effects in different contexts would be enlightening but are still lacking. But despite recent findings in other contexts, placebo analgesia is still the source of most of what is known about the neurobiology of the placebo effect.

Therefore, it is far from clear which brain pathways are essential for the effects on each type of outcome. There is a complex neuronal circuitry giving rise to placebo effects. Evidence has linked it to prefrontal–sub­cortical neuronal pathways that are involved in valuation, emotion and expectation. These systems can affect both sensory and functional and affective aspects of pain, as well as other affective and motivational pro­cesses, through interactions with the striatum and amygdala. Placebo effects are partially dependent on endogenous opioid release, but numerous other molecules have also been linked to its effect, namely dopamine and oxytocin.

There is still a lot to discover about the placebo effect, and it is of extreme relevance to healthcare approaches. Besides determining the brain mechanisms underlying these effects, research may eventually allow us to understand how a placebo-like effect may be intentionally induced for therapeutic purposes.

As written by Ted J. Kaptchuk and Franklin G. Miller in The New England Journal of Medicine:

“Medicine has used placebos as a methodologic tool to challenge, debunk, and discard ineffective and harmful treatments. But placebo effects are another story; they are not bogus. With proper controls for spontaneous remission and regression to the mean, placebo studies use placebos to elucidate and quantify the clinical, psychological, and biologic effects of immersion in a clinical environment. In other words, research on placebo effects can help explain mechanistically how clinicians can be therapeutic agents in the ways they relate to their patients in connection with, and separate from, providing effective treatment interventions. Of course, placebo effects are modest as compared with the impressive results achieved by lifesaving surgery and powerful, well-targeted medications. Yet we believe such effects are at the core of what makes medicine a healing profession.”

References

Benedetti F (2014). Placebo effects: from the neurobiological paradigm to translational implications. Neuron, 84 (3), 623-37 PMID: 25442940

Kaptchuk TJ, & Miller FG (2015). Placebo Effects in Medicine. The New England journal of medicine, 373 (1), 8-9 PMID: 26132938

Leuchter AF, Hunter AM, Tartter M, & Cook IA (2014). Role of pill-taking, expectation and therapeutic alliance in the placebo response in clinical trials for major depression. The British journal of psychiatry : the journal of mental science, 205 (6), 443-9 PMID: 25213159

Lidstone SC, Schulzer M, Dinelle K, Mak E, Sossi V, Ruth TJ, de la Fuente-Fernández R, Phillips AG, & Stoessl AJ (2010). Effects of expectation on placebo-induced dopamine release in Parkinson disease. Archives of general psychiatry, 67 (8), 857-65 PMID: 20679593

Petrovic P, Dietrich T, Fransson P, Andersson J, Carlsson K, & Ingvar M (2005). Placebo in emotional processing–induced expectations of anxiety relief activate a generalized modulatory network. Neuron, 46 (6), 957-69 PMID: 15953423

Petrovic P, Kalso E, Petersson KM, & Ingvar M (2002). Placebo and opioid analgesia– imaging a shared neuronal network. Science (New York, N.Y.), 295 (5560), 1737-40 PMID: 11834781

Wager TD, & Atlas LY (2015). The neuroscience of placebo effects: connecting context, learning and health. Nature reviews. Neuroscience, 16 (7), 403-18 PMID: 26087681

Zhang W, & Luo J (2009). The transferable placebo effect from pain to emotion: changes in behavior and EEG activity. Psychophysiology, 46 (3), 626-34 PMID: 19298627

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