FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Previous Volume 343:1070-1077 October 12, 2000 Number 15 Next

	Full Text PDF Editorial by Arendt, J. Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

ABSTRACT

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.

Source Information

From the Sleep and Mood Disorders Laboratory, Department of Psychiatry, School of Medicine, Oregon Health Sciences University, Portland.

Address reprint requests to Dr. Sack at Mail Code L-469, Oregon Health Sciences University, Portland, OR 97201, or at sackr{at}ohsu.edu.

Full Text of this Article

This article has been cited by other articles:

• Zee, P. C. (2009). Circadian Rhythm Sleep Disorders. ACCP Sleep Med Brd Rev 4: 63-76 [Full Text]  
• Waller, E. A., Bendel, R. E., Kaplan, J. (2008). Sleep Disorders and the Eye. Mayo Clin Proc. 83: 1251-1261 [Abstract] [Full Text]  
• Burgess, H. J., Revell, V. L., Eastman, C. I. (2008). A three pulse phase response curve to three milligrams of melatonin in humans. J. Physiol. 586: 639-647 [Abstract] [Full Text]  
• Lewy, A. J. (2007). Melatonin and Human Chronobiology. Cold Spring Harb Symp Quant Biol 72: 623-636 [Abstract]  
• Fuller, P. M., Gooley, J. J., Saper, C. B. (2006). Neurobiology of the Sleep-Wake Cycle: Sleep Architecture, Circadian Regulation, and Regulatory Feedback. J Biol Rhythms 21: 482-493 [Abstract]  
• Lewy, A. J., Lefler, B. J., Emens, J. S., Bauer, V. K. (2006). The circadian basis of winter depression. Proc. Natl. Acad. Sci. USA 103: 7414-7419 [Abstract] [Full Text]  
• Revell, V. L., Burgess, H. J., Gazda, C. J., Smith, M. R., Fogg, L. F., Eastman, C. I. (2006). Advancing Human Circadian Rhythms with Afternoon Melatonin and Morning Intermittent Bright Light. J. Clin. Endocrinol. Metab. 91: 54-59 [Abstract] [Full Text]  
• Mistlberger, R. E., Skene, D. J. (2005). Nonphotic Entrainment in Humans?. J Biol Rhythms 20: 339-352 [Abstract]  
• Klerman, E. B. (2005). Clinical Aspects of Human Circadian Rhythms. J Biol Rhythms 20: 375-386 [Abstract]  
• Emens, J. S., Lewy, A. J., Lefler, B. J., Sack, R. L. (2005). Relative Coordination to Unknown "Weak Zeitgebers" in Free-Running Blind Individuals. J Biol Rhythms 20: 159-167 [Abstract]  
• Wise, M. E. J. (2004). Melatonin use in children. Psychiatr. Bull. 28: 343-343 [Full Text]  
• Lerchl, A., Luboshitzky, R. (2004). Melatonin Administration Alters Semen Quality in Normal Men. J Androl 25: 185-187 [Full Text]  
• Lewy, A. J., Emens, J. S., Bernert, R. A., Lefler, B. J. (2004). Eventual Entrainment of the Human Circadian Pacemaker by Melatonin is Independent of the Circadian Phase of Treatment Initiation: Clinical Implications. J Biol Rhythms 19: 68-75 [Abstract]  
• Scheer, F. A.J.L., Van Montfrans, G. A., van Someren, E. J.W., Mairuhu, G., Buijs, R. M. (2004). Daily Nighttime Melatonin Reduces Blood Pressure in Male Patients With Essential Hypertension. Hypertension 43: 192-197 [Abstract] [Full Text]  
• Kunz, D., Mahlberg, R., Muller, C., Tilmann, A., Bes, F. (2004). Melatonin in Patients with Reduced REM Sleep Duration: Two Randomized Controlled Trials. J. Clin. Endocrinol. Metab. 89: 128-134 [Abstract] [Full Text]  
• Fischer, S., Smolnik, R., Herms, M., Born, J., Fehm, H. L. (2003). Melatonin Acutely Improves the Neuroendocrine Architecture of Sleep in Blind Individuals. J. Clin. Endocrinol. Metab. 88: 5315-5320 [Abstract] [Full Text]  
• Hack, L. M., Lockley, S. W., Arendt, J., Skene, D. J. (2003). The Effects of Low-Dose 0.5-mg Melatonin on the Free-Running Circadian Rhythms of Blind Subjects. J Biol Rhythms 18: 420-429 [Abstract]  
• Rajaratnam, S. M. W., Dijk, D.-J., Middleton, B., Stone, B. M., Arendt, J. (2003). Melatonin Phase-Shifts Human Circadian Rhythms with No Evidence of Changes in the Duration of Endogenous Melatonin Secretion or the 24-Hour Production of Reproductive Hormones. J. Clin. Endocrinol. Metab. 88: 4303-4309 [Abstract] [Full Text]  
• Rivkees, S. A. (2003). Rest-Activity Patterns in Children With Hypopituitarism. Pediatrics 111: e720-724 [Abstract] [Full Text]  
• Klerman, E. B., Shanahan, T. L., Brotman, D. J., Rimmer, D. W., Emens, J. S., Rizzo, J. F. III, Czeisler, C. A. (2002). Photic Resetting of the Human Circadian Pacemaker in the Absence of Conscious Vision. J Biol Rhythms 17: 548-555 [Abstract]  
• Luboshitzky, R., Shen-Orr, Z., Nave, R., Lavi, S., Lavie, P. (2002). Melatonin Administration Alters Semen Quality in Healthy Men. J Androl 23: 572-578 [Abstract] [Full Text]  
• Dijk, D.-J., Lockley, S. W. (2002). Functional Genomics of Sleep and Circadian Rhythm: Invited Review: Integration of human sleep-wake regulation and circadian rhythmicity. J. Appl. Physiol. 92: 852-862 [Abstract] [Full Text]  
• Sharkey, K. M., Eastman, C. I. (2002). Melatonin phase shifts human circadian rhythms in a placebo-controlled simulated night-work study. Am. J. Physiol. Regul. Integr. Comp. Physiol. 282: R454-R463 [Abstract] [Full Text]  
• Wright, K. P. Jr., Hughes, R. J, Kronauer, R. E., Dijk, D.-J., Czeisler, C. A. (2001). Intrinsic near-24-h pacemaker period determines limits of circadian entrainment to a weak synchronizer in humans. Proc. Natl. Acad. Sci. USA 98: 14027-14032 [Abstract] [Full Text]  
• Klerman, E. B., Zeitzer, J. M., Duffy, J. F., Khalsa, S. B. S., Czeisler, C. A. (2001). Absence of an Increase in the Duration of the Circadian Melatonin Secretory Episode in Totally Blind Human Subjects. J. Clin. Endocrinol. Metab. 86: 3166-3170 [Abstract] [Full Text]  
• Kendall, A. R., Lewy, A. J., Sack, R. L. (2001). Effects of Aging on the Intrinsic Circadian Period of Totally Blind Humans. J Biol Rhythms 16: 87-95 [Abstract]  
• (2001). Synchronizing the Circadian Clocks of Blind People with Melatonin. JWatch Psychiatry 2001: 14-14 [Full Text]  
• (2000). Synchronizing the Circadian Clocks of Blind People with Melatonin. JWatch Neurology 2000: 2-2 [Full Text]  
• Arendt, J. (2000). Melatonin, Circadian Rhythms, and Sleep. NEJM 343: 1114-1116 [Full Text]