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Our hypothesis is that reducing release of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) with modafinil will enhance symptomatic and hormonal responses to hypoglycaemia.Nine healthy men received, in random order, two 100-mg doses of modafinil or placebo, followed by an insulin clamp in which plasma glucose was either reduced stepwise to 2.4 mmol/l or was sustained at euglycaemia (four studies). Catecholamines, symptom scores and cognitive function were measured.Modafinil had no effect on the measured parameters during euglycaemia. During hypoglycaemia, autonomic symptom scores were significantly higher with modafinil (increase at lowest plasma glucose concentration 271.3±118.9 vs 211.2±80.4/40 min, p=0.019), and the heart rate response was increased (12,928±184 vs 6773±148 bpm/140 min, p=0.016). Deterioration in performance of two cognitive tasks was reduced: Stroop colour-word test (613±204 vs 2375±161/65 min, p=0.009) and accuracy of a simple reaction task (11.3±1.8 vs 9.4±3.7, p=0.039).We conclude that modafinil improves adrenergic sensitivity and some aspects of cognitive function at hypoglycaemia, possibly by reducing neuronal central GABA concentrations.