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Human studies are essential to elucidate psychological mechanisms of placebo and nocebo responses.Specific strategies to utilize conditioning, to reduce conditioned responses, or enhance extinction learning are feasible.Animal model allow a deeper characterization of their pharmacological and neurochemical mechanisms.Novel study designs are available but so far lack application in gastroenterology.The investigation of the placebo and the nocebo effect and their mechanisms has a rather short history of less than 20 years, especially in gastroenterology, and only the last 5 years have resulted in substantial improvement of understanding. Placebo refers to symptom improvement following a treatment, nocebo to the opposite, symptom worsening. Among the factors driving this progress are traditional psychological models derived from learning (conditioning) theory bridging into clinical science, new animal models to investigate the pharmacology of placebo analgesia, and novel study designs to overcome limitations of traditional randomized and placebo-controlled study designs in drug testing. These are explored here for their implementation and application in gastroenterology, with a focus on visceral pain and nausea.