Drugs and placebos: what's the difference?: Understanding the molecular basis of the placebo effect could help clinicians to better use it in clinical practice.

D efining a drug is an easy task: It is a molecule delivered to the body to produce a biological effect. Its mode of action is to alter one or more biochemical pathways, for instance, by binding to a receptor or by modifying the activity of an enzyme. Defining a placebo is a bit more complicated. A placebo is usually defined in pharmacological terms as an inert substance with no pharmacological action. However, this definition is superficial, as the effectiveness of a placebo comprises many things, including the words, rituals, symbols and meanings that accompany its use. Thus, the placebo is not the substance alone, but its administration together with a concomitant set of sensory and social stimuli that tell the patient that he or she is being treated. Indeed, a placebo is the entire ritual of the therapeutic act. Most of the confusion about the placebo effect comes from the different usage and meaning that clinicians who conduct a clinical study and neuroscientists assign to the word. Clinicians are generally interested in any positive effects to be seen within a control group of patients, regardless of the cause of those effects. In the absence of a drug, improvements can result from many factors including the spontaneous remission of a disease, statistical regression to the mean, the patient or doctor’s bias, or the patient’s expectation of improvement. By contrast, neuroscientists are only interested in those improvements that derive from active processes in the patient’s brain, such as expectations of benefit and learning mechanisms. Clinical trials are only aimed at establishing whether patients who take the true treatment, be it pharmacological or not, are better off than those who take the placebo. Although this pragmatic approach yields fruitful results in a clinical trial setting, it is virtually useless to neuroscientists who want to understand what is going on in the brain when a placebo is given, that is, when a therapeutic ritual is performed without the actual administration of any therapy.