Neurobiology of Placebo: Interpreting its Evolutionary Origin, Meaning, Mechanisms, Monitoring, and Implications in Therapeutics

Placebo is defined as the therapeutic response to inert treatment. However, this is a bit simplistic because comprehending the biological basis of the placebo effect requires understanding the entire therapeutic context and the patient immersed in it. Placebo does not cure the disease but alleviates symptoms. The placebo impact must be seen in the context of the recipients’ cultural milieu, psychosocial background, the tone and tenor of the accompanying verbal communication (caring, indifferent, unfriendly), therapeutic rituals (e.g., tablet, injection, or a procedure, including diagnostic tests), symbols (white coat, syringe, the diagnostic paraphernalia), and its meanings to the patient (past experiences and personal hope). Placebo is the inert treatment juxtaposed against the broad context of the accompanying sensory and sociocultural inputs that signal benefit. It could also be the harm in the case of nocebo. A major objective of a standard clinical trial is to eliminate or at least minimise the influence of placebo. Many methods have been devised to measure and eliminate placebo responders in the trial populations. The neurological basis of the placebo effect is complex and must have an evolutionary basis because the susceptibility to placebos may be traced back to animals and birds. The placebo effect probably owes its evolutionary origin to signalling sickness and the ability to draw comfort from winning sympathetic attention and care from conspecifics. Pain being a complex sensory experience with a strong affective component, the neuronal pathways that reflect both sensory experience and the affective components have been explored in the study of the placebo effect. Placebo research, having expanded from psychology to neurology, presently involves research tools that include pharmacology, brain imaging, genetics, animal models, etc. This review will discuss multiple dimensions of the placebo effect, including evolutionary, cultural, psychosocial, and neurological aspects, in addition to providing cues for transformational implications in clinical trials and therapeutic modalities that benefit society. Contemporary medicine is demonising placebo because it is a confounder in clinical trials. It would be much more useful if the healthcare system can harness the therapeutic potential of the placebo effect by manipulating the therapeutic context.