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Background: Previously we observed in patients suffering from a metastatic carcinoid tumor that irritability, aggression and lack of impulse control are associated with low levels of plasma tryptophan and presumably with low brain serotonin function. In rats we showed that a diet of low tryptophan resulted in higher stress responses and higher corticosterone production. Here we tested in carcinoid patients whether tryptophan depletion due to tumor 5-HT overproduction is associated with high cortisol production., Methods: Urinary excretion of cortisol, serotonin, 5-hydroxyindole acetic acid (the main metabolite of serotonin a marker of tumor activity), plasma levels of tryptophan and platelet content of serotonin (index of peripheral serotonin synthesis) were determined in metastatic midgut carcinoid patients. Patients (N = 25) were divided into two groups based on their plasma tryptophan levels (< or = 25 micromol/l, n = 12 and > or = 49 micromol/l, n = 13)., Results: Carcinoid patients with low plasma tryptophan levels had significantly higher urinary excretion of free cortisol (p < 0.01), independent of tumor activity. The inter-individual differences in the low tryptophan group, however, were substantial., Conclusions: In a subgroup of the patients suffering from metastatic carcinoid disease the cerebral access of plasma tryptophan is impaired, thus rendering cerebral serotonin neurotransmission suboptimal and leading to hypercortisolism. The present study provides further support to the idea that low serotonergic function is a risk for developing stress-associated psychopathology.