Entrainment of free-running circadian rhythms by melatonin in blind people

Background: Most totally blind people have circadian rhythms that are "free -running'' (i.e., that are not synchronized to environmental time cues and that oscillate on a cycle slightly longer than 24 hours). This condition ca uses recurrent insomnia and daytime sleepiness when the rhythms drift out o f phase with the normal 24-hour cycle. We investigated whether a daily dose of melatonin could entrain their circadian rhythms to a normal 24-hour cyc le. Methods: We performed a crossover study involving seven totally blind subje cts who had free-running circadian rhythms. The subjects were given 10 mg o f melatonin or placebo daily, one hour before their preferred bedtime, for three to nine weeks. They were then given the other treatment. The timing o f the production of endogenous melatonin was measured as a marker of the ci rcadian time (phase), and sleep was monitored by polysomnography. Results: At base line, the subjects had free-running circadian rhythms with distinct and predictable cycles averaging 24.5 hours (range, 24.2 to 24.9) . These rhythms were unaffected by the administration of placebo. In six of the seven subjects the rhythm was entrained to a 24.0-hour cycle during me latonin treatment (P<0.001). After entrainment, the subjects spent less tim e awake after the initial onset of sleep (P=0.05) and the efficiency of sle ep was higher (P=0.06). Three subjects subsequently participated in a trial in which a 10-mg dose of melatonin was given daily until entrainment was a chieved. The dose was then reduced to 0.5 mg per day over a period of three months; the entrainment persisted, even at the lowest dose. Conclusions: Administration of melatonin can entrain circadian rhythms in m ost blind people who have free-running rhythms. (N Engl J Med 2000;343:1070 -7.) (C) 2000, Massachusetts Medical Society.