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 causes recurrent insomnia and daytime sleepiness when the rhythms drift out of 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 cycle. Methods: We performed a crossover study involving seven totally blind subjects who had free-running circadian rhythms. The subjects were given 10 mg of melatonin or placebo daily, one hour before their preferred bedtime, for three to nine weeks. They were then given the other treatment. The timing of the production of endogenous melatonin was measured as a marker of the circadian 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 melatonin treatment (P<0.001). After entrainment, the subjects spent less time awake after the initial onset of sleep (P=0.05) and the efficiency of sleep 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 achieved. 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 most blind people who have free-running rhythms. (N Engl J Med 2000;343:1070-7.) (C) 2000, Massachusetts Medical Society.