EXCEED THE SPACE PROVIDED. In our just-completed project, we have shown that nightly oral administration of 10 mg melatonin can entrain (synchronize) free-running circadian rhythms in eight of nine blind people to the 24.0-hour day, resulting in improved nighttime sleep and daytime alertness. The one person who did not entrain had the longest pre-treatment free-running period (24.9 h). In addition, we have shown that 10 mg of melatonin has a direct soporific action when given to blind subjects when their free-running circadian rhythms are inverted. Most recently, we have found that the dose can be stepped down to 0.5 mg in three out of three of these people. We have further found that they could also be entrained to a de novo 0.5 mg dose (their longest free- running period was 24.4 h). The pre-treatment period appears to predict the likelihood of entrainment to melatonin and the steady-state phase of entrainment, which is consistent with several important principles established in animal studies. The study of blind people provides an opportunity to understand the physiology of the circadian system in humans unperturbed by the light/dark cycle. Therefore, our projects are of both clinical and scientific importance. There are approximately 200,000 totally blind people in the U.S. About 50% of these people have free- running circadian rhythms which may be corrected with appropriate diagnosis and treatment. The goal of this project will be to determine the efficacy of the 0.5 mg dose, with the prediction that it will work only in people with relatively short periods (<24.5 h). In treatment failures with the 0.5 mg dose, we will test the efficacy of higher doses. We will also determine if it is necessary that treatment be initiated on the day when the circadian clock is in a certain phase. Blind subjects who successfully entrain with melatonin will be followed for one year to assess the long-term benefits and risks of melatonin administration. This resubmitted competitive renewal will provide valuable information for recommending the optimal dosing regimen for testing the efficacy and safety of melatonin in a large, multi-center study of the blind. PERFORMANCE SITE ========================================Section End===========================================

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Special Emphasis Panel (ZRG1-BDCN-6 (01))
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Brady, Linda S
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Oregon Health and Science University
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Lewy, A J (2007) Melatonin and human chronobiology. Cold Spring Harb Symp Quant Biol 72:623-36
Schoenhard, John A; Muldowney 3rd, James A S; Emens, Jonathan S et al. (2007) Plasminogen activator inhibitor-1 has a circadian rhythm in blind individuals. Thromb Haemost 98:479-81
Lewy, Alfred J (2007) Current understanding and future implications of the circadian uses of melatonin, a neurohormone discovered by Aaron B. Lerner. J Invest Dermatol 127:2082-5
Lewy, Alfred J; Emens, Jonathan; Jackman, Angela et al. (2006) Circadian uses of melatonin in humans. Chronobiol Int 23:403-12
Lewy, Alfred J; Lefler, Bryan J; Emens, Jonathan S et al. (2006) The circadian basis of winter depression. Proc Natl Acad Sci U S A 103:7414-9
Lewy, Alfred J; Emens, Jonathan S; Lefler, Bryan J et al. (2005) Melatonin entrains free-running blind people according to a physiological dose-response curve. Chronobiol Int 22:1093-106
Emens, Jonathan S; Lewy, Alfred J; Lefler, Bryan J et al. (2005) Relative coordination to unknown ""weak zeitgebers"" in free-running blind individuals. J Biol Rhythms 20:159-67
Lewy, Alfred J; Emens, Jonathan S; Bernert, Rebecca A et al. (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
Lewy, Alfred J; Emens, Jonathan; Sack, Robert L et al. (2003) Zeitgeber hierarchy in humans: resetting the circadian phase positions of blind people using melatonin. Chronobiol Int 20:837-52
Lewy, Alfred J; Emens, Jonathan S; Sack, Robert L et al. (2002) Low, but not high, doses of melatonin entrained a free-running blind person with a long circadian period. Chronobiol Int 19:649-58

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