The availability of energy appears to exert important regulatory functions in pituitary-adrenal stress responses. In two studies, the effects of short-term fasting and subsequent glucose administration on the free cortisol response to psychological stress and nicotine consumption were investigated. Study 1: After fasting for 8-11 h, healthy young men ingested either 100 g glucose (n = 13) or water (n = 12). One hour later they were exposed to a psychosocial stress task (Trier Social Stress Test). A third group also ingested 100 g glucose, but they were not exposed to any additional treatment (n = 10). Capillary blood glucose levels were in the lower euglycemic range before and significantly elevated after the glucose load (64.9 +/- 9.8 vs. 162.5 +/- 43.5 mg/dL; F = 149.04, P < 0.001). Although glucose load per se did not affect free cortisol levels, psychosocial stress induced a large cortisol response in glucose-treated subjects. In contrast, fasted subjects who received tap water did not respond to the Trier Social Stress Test with significant changes in cortisol levels (F = 6.27, P < 0.001). Both groups responded with a similar increase in heart rates (F = 33.53, P < 0.001) with no statistically significant difference between glucose and water-treated subjects. Study 2: Twelve habitual smokers received 100 g glucose or tap water after fasting for at least 8 h on two separate sessions (cross-over, random sequence). Forty-five min after glucose/water ingestion, they smoked two cigarettes with a nicotine content of 1.0 mg/cigarette. Subjects were euglycemic before smoking, with a significant rise of glucose levels after consumption of 100 g glucose (64.4 +/- 8.3 vs. 143.5 +/- 40.0 mg/dL; F = 40.25, P < 0.001). As in Exp 1, subjects showed a substantially larger free cortisol response to nicotine under glucose load compared with water load (F = 4.91, P < 0.001). From these data we conclude that the free cortisol response to stimulation is under significant control of center responsible for monitoring energy availability. Low glucose levels appear to inhibit adrenocortical responsiveness in healthy subjects. In agreement with results from animal studies, the present results suggest that ready access to energy is a prerequisite for hypothalamus-pituitary-adrenal stress responses.