Meta-chlorophenylpiperazine (m-CPP), a probe of central serotonergic function, elevates core temperature in rodents, nonhuman primates, and humans via serotonin receptor-mediated mechanisms. To further characterize the thermoregulatory aspects of this response, we studied 16 healthy volunteers using multiple core and skin temperature recording sites. Compared to placebo, intravenous m-CPP (0.08 mg/kg) produced statistically significant biphasic changes in rectal temperature, characterized by initial hypothermia (-0.04 degrees C at 12 minutes) followed by progressive hyperthermia (+0.17 degrees C at 90 minutes). m-CPP also produced significant increases in plasma norepinephrine concentrations. Analysis of the skin temperature recordings suggests that the effector mechanism primarily responsible for m-CPP-induced core hyperthermia is increased metabolic thermogenesis. Individual differences in the magnitude of the hyperthermia were independent of m-CPP plasma concentrations but were found to be linearly correlated with the level of the previous night's core rectal temperature minimum and mean. It appears that m-CPP activates a mode of metabolic thermogenesis governed by a nocturnally sensitive proportional control mechanism. The operation of such a proportional controller is characterized by a set point and a gain, and has been implicated in the general economy of mammalian energy balance.