The response to drugs is affected by expectation, which in turn is sensitive to prior drug experiences. Here, we evaluate the effects of expectation on the responses to intravenous methylphenidate (0.5 mg/kg) in fifteen subjects who had minimal experience with stimulant drugs. We used positron emission tomography to measure brain glucose metabolism, which we used as a marker of brain function and tested them under four randomized conditions (1) expecting placebo and receiving placebo; (2) expecting placebo and receiving methylphenidate; (3) expecting methylphenidate and receiving methylphenidate; (4) expecting methylphenidate and receiving placebo. We show that methylphenidate-induced decreases in striatum were greater when subjects expected to receive methylphenidate than when they were not expecting it. We also show that the subjects' expectations affected their responses to placebo. That is, when subjects expected to receive methylphenidate but received placebo there were significant increases in ventral cingulate gyrus (BA 25) and nucleus accumbens (regions involved with emotional reactivity and reward). The effect was largest in subjects who, because of experimental randomization, had not experienced methylphenidate. Because subjects were told that methylphenidate could be experienced as pleasant, unpleasant or devoid of subjective effects these results suggest the involvement of the ventral cingulate and of the nucleus accumbens in processing expectation for "uncertain drug effects". Thus, the state of expectation needs to be considered as a variable modulating the reinforcing and therapeutic effects of drugs even in subjects who have no prior experience with the drug.