Evidence from mouse models suggests that brain serotonergic pathways control blood glucose. We hypothesized that sumatriptan (5HT -receptor agonist) would alter glucose homeostasis in humans. We conducted a two-visit random-order double-blinded placebo-controlled cross-over trial in 10 overweight adults that were otherwise healthy. Participants received sumatriptan (single dose, 100 mg) or placebo before undergoing a 60-min intravenous glucose tolerance test, followed by a 120-min hyperinsulinaemic euglycaemic clamp. Glucose excursion was greater during intravenous glucose tolerance test with sumatriptan compared with placebo iAUC 316 (268-333) vs. 251 (197-319) min/mmol/L p = .047. This was probably explained by a combination of reduced circulating insulin levels iAUC 1626 (1103-2733) vs. 2336 (1702-3269) min/pmol/L, p = .005, reduced insulin sensitivity M/I-value 2.11 (1.15, 4.05) vs. 3.03 (1.14, 4.90) mg/kg/min per pmol/L, p = .010 and glucose effectiveness S 0.17 (0.12, 0.21) vs. 0.22 (0.18, 0.65)/min, p = .027. 5HT receptors have a glucoregulatory role in humans, probably acting on insulin secretion, insulin sensitivity and glucose effectiveness.