Aims: Recurrent hypoglycaemia leads to an attenuation of hypoglycaemic symptoms and hormonal counterregulatory responses. This phenomenon poses a severe problem in the treatment of patients with diabetes mellitus, but the underlying neuroendocrine mechanisms are unclear. On the basis of animal experimental findings, we hypothesized that counterregulatory attenuation represents a basic adaptive learning process relying on synaptic long-term potentiation or depression. If so, attenuation should be prevented by blocking glutamatergic N-methyl-d-aspartate (NMDA) receptors. Methods: Sixteen healthy young men participated in two conditions, separated by 4weeks. Participants received the NMDA antagonist memantine over 5days (15mg/day) in one condition and placebo in the other one. After 3days of drug administration, participants underwent two hypoglycaemic clamps on day 4 and another one on day 5. We assessed blood concentrations of counterregulatory hormones (cortisol, ACTH, epinephrine, norepinephrine, growth hormone and glucagon) as well as subjective symptoms of hypoglycaemia and word-list recall as an indicator of short-term memory. Results: Counterregulatory responses of all hormones as well as neuroglycopenic and autonomic symptom ratings showed robust attenuation following the third as compared to the first hypoglycaemia (p<0.05). NMDA receptor antagonization by memantine impaired memory function but did not alter any neuroendocrine measure of counterregulatory attenuation (p > 0.17). Conclusions: Attenuation of the endocrine as well as symptomatic counterregulatory response to recurrent hypoglycaemia is not prevented by the NMDA receptor blocker memantine. Our results do not support the view that adaptation to repeated hypoglycaemia relies on NMDA receptor-mediated plastic processes involving long-term potentiation or depression.