Failure of circadian entrainment may result in a cyclically recurring sleep-wake disorder that affects a number of sighted individuals and more than half of totally blind people. The circadian periods of such patients is typically longer than average, resulting in the circadian pacemaker would be the treatment of choice in such patients. However, few substances have been shown to affect the period of the mammalian circadian pacemaker and none have been validated in humans. A series of detailed clinical reports have suggested that vitamin supplementation (vitamin B12) is an effective treatment for non-24-h sleep-wake disorder in sighted patients, allowing them to maintain stable sleep times. The mechanism by which vitamin B12 supplementation exerts this therapeutic action on sleep timing is unknown. Based on the data in those reports, we hypothesize that the mechanism by which vitamin B12 supplementation stabilizes the sleep-wake cycle of such patients is by shortening the intrinsic period of the circadian pacemaker. Moreover, by shortening circadian period, we hypothesize that vitamin B12 realigns the phase relationship between the circadian system and the timing of sleep, resulting in improved sleep quality at night and greater alertness during the day. We propose to test the vitamin B12's effects on circadian period in a placebo-controlled double-blind study in healthy subjects, using the forced desynchrony protocol to measure circadian period precisely. Preliminary results from this study will reveal whether the efficacy of vitamin B12 supplementation in treating this circadian rhythm sleep disorder is via a direct action on the human circadian pacemaker. This study will also add substantially to understanding the basic properties of the human circadian timing system, and to understanding the entrainment mechanisms by which the circadian system is synchronized to the solar day. This study is designed to collect preliminary data that should reveal the mechanism of action of a safe and inexpensive CAM treatment for a circadian rhythm sleep disorder suffered by more than half of all totally blind people and by sighted patients with non-24-h-sleep-wake disorder. Identification of a CAM therapy that alters this fundamental property of the circadian pacemaker could also prove to be beneficial to the larger group of patients with delayed sleep phase syndrome, and to the significant fraction of the population that suffers from sleep onset insomnia combined with difficulty waking in the morning.

National Institute of Health (NIH)
National Center for Complementary & Alternative Medicine (NCCAM)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Special Emphasis Panel (ZAT1-JH (04))
Program Officer
Stoney, Catherine
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brigham and Women's Hospital
United States
Zip Code
Lane, Jacqueline M; Chang, Anne-Marie; Bjonnes, Andrew C et al. (2016) Impact of Common Diabetes Risk Variant in MTNR1B on Sleep, Circadian, and Melatonin Physiology. Diabetes 65:1741-51
Pomplun, Marc; Silva, Edward J; Ronda, Joseph M et al. (2012) The effects of circadian phase, time awake, and imposed sleep restriction on performing complex visual tasks: evidence from comparative visual search. J Vis 12:
Lim, Andrew S P; Chang, Anne-Marie; Shulman, Joshua M et al. (2012) A common polymorphism near PER1 and the timing of human behavioral rhythms. Ann Neurol 72:324-34
Duffy, Jeanne F; Cain, Sean W; Chang, Anne-Marie et al. (2011) Sex difference in the near-24-hour intrinsic period of the human circadian timing system. Proc Natl Acad Sci U S A 108 Suppl 3:15602-8
Chang, Anne-Marie; Buch, Alison M; Bradstreet, Dayna S et al. (2011) Human diurnal preference and circadian rhythmicity are not associated with the CLOCK 3111C/T gene polymorphism. J Biol Rhythms 26:276-9
Duffy, Jeanne F; Czeisler, Charles A (2009) Effect of Light on Human Circadian Physiology. Sleep Med Clin 4:165-177
Lee, Jung H; Wang, Wei; Silva, Edward J et al. (2009) Neurobehavioral performance in young adults living on a 28-h day for 6 weeks. Sleep 32:905-13
Munch, M Y; Cain, S W; Duffy, J F (2007) Biological Rhythms Workshop IC: sleep and rhythms. Cold Spring Harb Symp Quant Biol 72:35-46
Duffy, Jeanne F; Wright Jr, Kenneth P (2005) Entrainment of the human circadian system by light. J Biol Rhythms 20:326-38