Because serotonin (5-HT) precursor or reuptake inhibitors improve obstructive sleep apnea (OSA), we hypothesized that brain serotonergic activity may be decreased in OSA. To test this hypothesis, we measured the cortisol response to the ingestion of L-5-hydroxytryptophan (L-5-HTP), a 5-HT precursor that is decarboxylated to 5-HT in the brain. Either L-5-HTP or an identical-looking placebo was administered at 0800, and blood was obtained over the following 4 h for serum cortisol determination. A placebo-controlled ACTH stimulation test was performed to evaluate adrenal function. We found that a group of 11 OSA patients had significantly higher cortisol production after L-5-HTP administration compared with a group of 11 control nonapneic subjects. The pretest cortisol levels and ACTH stimulation test results were not different between the two groups. We conclude that the cortisol response to L-5-HTP was elevated in the OSA patients studied, most likely as a result of increased hypophyseal 5-HT activity. We speculate that the 5-HT postsynaptic receptors that induce corticotropin releasing factor production and release are upregulated, or supersensitized, as a result of a brain 5-HT-deficient state that exists during sleep in OSA. We anticipate that medullary serotonergic neurons that affect ventilation would be altered similarly.