Background: Sleep disturbances are common side effects of betablockers. In order to investigate the influence of these drugs on melatonin production we performed a randomized, double-blind, placebo-controlled, cross-over study in 15 healthy volunteers.Methods: Subjects received single oral doses of 40 mg (R)-propanolol, 40 mg (S)-propanolol, 50 mg (R)-atenolol, 50 mg (S)-atenolol, 25 mg (R,S)-carvedilol and placebo at 6 p.m. Urine was collected between 10 p.m. and 6 p.m., and 6-sulfatoxy-melatonin (SOM), the main metabolite of melatonin, which is almost completely eliminated in urine, was determinated by RIA.Results: Mean nocturnal excretion of SOM in urine after intake of the drugs was as follows: Placebo 26 μg; (R)-propanolol 24 μg (-7%, n.s.); (S)-propranolol 5 μg (-80%, p < 0.001); (R)-atenolol 27 μg (+7%, n.s.); (S)-atenolol 4 μg (-86%, p < 0.01); (R,S)-carvedilol 23 μg (-10%, n.s.).Conclusion: Our data indicate that only the betablocking (S)-enantiomers of propranolol and atenolol decrease the nocturnal production of melatonin whereas the non-betablocking (R)-enantiomers show no effect. These findings might explain why betablockers may cause sleep disturbances. As a consequence, administration of melatonin might be a helpful tool in order to avoid this side effect. The reason why carvedilol, which inhibits both α- and β-adrenoceptors, does not influence the production of melatonin, remains to be determined.