‘Placebo’ originated from the Latin word ‘placere’ which means ‘to please’. From the birth of medicine, doctors used to prescribe pleasing remedies such as sugar pill, electuary or pharmaceutical syrup, all of which have no pharmacodynamic action. Now-a-days doctors sometimes use normal saline rather than opioid to alleviate pain.

During Second World War, Henry Becher discovered the placebo effect as a medic. After running out of pain-killing morphine, he replaced it with a simple saline solution but continued telling the wounded soldiers it was Placebo Army Medicmorphine to calm them. To his surprise, almost half of the soldiers reported that the inert saline solution actually reduced or erased their pain.

All the above inert substances act as placebos which work by psychodynamic rather than pharmacodynamic means and often produce responses equivalent to active drug. According to Price et al, 2008, a real placebo affects psychobiological phenomenon occurring in the patient’s brain after the administration of an inert substance, or of a sham physical treatment.


Now-a-days research is being conducted to solve the mystery of mechanism of placebo effect. Here, main mechanisms of placebo effect are highlighted.



Expectation is one of the main factors involved in placebo effect. In other words, a patient who knows to be under scrutiny may expect a better therapeutic benefit because of the many examinations that he or she undergoes, the special attention by the medical personnel, and the trust in the new therapy under investigation. Thus expectation acts a psychological factor and the patient feels better. Expectation acts on the brain by several mechanisms.

Modulation of Anxiety by Expectation

Anxiety has been found to be reduced after administration of placebo. If one expects a distressing symptom to subside shortly, anxiety tends to decrease.It is also same in case of Nocebo effect, an inert substance is administered along with negative verbal suggestions of clinical worsening like increase of pain.  These anxiogenic verbal suggestions are capable of turning tactile stimuli into pain.

Thus modulation of anxiety plays a big role in the effect of placebo.

Expectation of Reward

Another pathway for placebo effect is reward mechanism by expectation. This mechanism is mediated by special neuronal circuits linking cognitive, emotional and motor response. Dopamine is one of the major neurotransmitters in reward pathway. The nucleus accumbens has a central role in dopamine-mediated reward mechanisms together with the ventral tegmental area. Other regions are also involved such as amygdala, the periaqueductal gray, and some areas in the thalamic, hypothalamic, and subthalamic (pallidum) regions. Not only dopamine, opioid activity also increases in nucleus accumbens in placebo response.


Learning is another mechanism that is central to placebo responsiveness. A patient is regularly consuming aspirin for headache. If the patient is given sugar pill resembling aspirin, with the same shape, color and taste of the pill, then he will experience pain decrease. Also countless other stimuli such as some hospitals, diagnostic and therapeutic equipment and medical personnel features will have the same effect. It is evident that if placebos are given prior to the experience of the drug, the response may be present but small. So, placebo response is a learning phenomenon.


Alzheimer’s disease patients have impairment of prefrontal cortex. This region has been found to be activated by placebo-induced expectation of benefit, such as pain reduction. So patients show less placebo effect than other patients. Also, Alzheimer’s patients have a tendency to forget what medication they are taking. Thus learning pathway of placebo response is also not working.


Fabrizio Benedetti, Elisa Carlino, Antonella Pollo (2011). How Placebos Change the Patient’s Brain. Neuropsychopharmacology 36: 339-354

Tor D. Wager, Lauren Y. Atlas (2015). The neuroscience of placebo effects: connecting context, learning and health. Nature Reviews Neuroscience 16: 403–418

Price DD, Finniss DG, Benedetti F (2008). A comprehensive review of the placebo effect: recent advances and current thought. Annu Rev Psychol 59: 565-590

Susan Perry. The Power of the Placebo
Source: Society for Neuroscience