Objective: Melatonin is a mediator in the establishment of the circadian rhythm of biological processes. It is produced in the pineal gland mainly during the night by stimulation of adrenergic beta1- and alpha1-receptors. Sleep disturbances are common side-effects of beta-blockers. The influence of specific beta-blockade as well as that of combined alpha-and beta-blockade on melatonin production has not been investigated in humans before.
Methods: We performed a randomized, double-blind, placebo-controlled, cross-over study in 15 healthy volunteers. Subjects received single oral doses of 40 mg (R)-propranolol, 40 mg (S)-propranolol, 50 mg (R)-atenolol, 50 mg (S)-atenolol, 25 mg (R,S)-carvedilol, 120 mg (R,S)-verapamil or placebo at 1800 hours. Urine was collected between 2200 hours and 0600 hours, and 6-sulfatoxy-melatonin (aMT6s), the main metabolite of melatonin which is almost completely eliminated in urine, was determined by radioimmunoassay (RIA).
Results: Mean nocturnal excretion of aMT6s in urine after intake of the drugs was as follows (in microg): placebo 26; (R)-propranolol 24 (-7%, NS); (S)-propranolol 5 (-80%, P < 0.001); (R)-atenolol 27 (+7%, NS); (S)-atenolol 4 (-86%, P < 0.01); (R,S)-carvedilol 23 (-10%, NS); (R,S)-verapamil 29 (+14%, NS). These data show that only the specifically beta-blocking (S)-enantiomers of propranolol and atenolol decrease the nocturnal production of melatonin whereas the non-beta-blocking (R)-enantiomers have no effect. Unexpectedly, (R,S)-carvedilol which inhibits both alpha- and beta-adrenoceptors does not decrease melatonin production.
Conclusion: These findings indicate that beta-blockers decrease melatonin release via specific inhibition of adrenergic beta1-receptors. Since lower nocturnal melatonin levels might be the reason for sleep disturbances, further clinical studies should investigate whether or not oral administration of melatonin might avoid this well-known side-effect of beta-blockers. The reason why (R,S)-carvedilol does not influence melatonin production remains to be determined.