A brief history of placebo

History of medicine is the history of placebo. Over the course of several centuries, treatments with a physical and spiritual approach were the rule. Clinical trials have become the gold standard to test the efficacy of new treatments only over the past few decades. We have learned that the placebo response, that is, the global response to a placebo, consists of many factors: one of them is the placebo effect, that is, the real psychobiological phenomenon. Other factors include, but are not limited to, spontaneous remission, regression to the mean, unidentified covariables, and background noise. There is not a single placebo effect but many, and the different placebo effects are associated with demonstrable brain changes and the modification of endogenous chemicals in a way that may share similar mechanisms with pharmacological agents. The major mediators of the placebo effects are expectations and conditioning. They are interrelated, affect each other and operate in animals and humans. The nocebo effect goes in the opposite direction, whereby negative expectations may lead to negative outcomes. This brief overview on the emergence of the concept of placebo helps us understand how modern research approaches placebo and nocebo from a psychological, biological and neuroscientific perspective.