title: Effects of caffeine on the human circadian clock in vivo and in vitro.
abstract: Caffeine's wakefulness-promoting and sleep-disrupting effects are well established, yet whether caffeine affects human circadian timing is unknown. We show that evening caffeine consumption delays the human circadian melatonin rhythm in vivo and that chronic application of caffeine lengthens the circadian period of molecular oscillations in vitro, primarily with an adenosine receptor/cyclic adenosine monophosphate (AMP)-dependent mechanism. In a double-blind, placebo-controlled, ~49-day long, within-subject study, we found that consumption of a caffeine dose equivalent to that in a double espresso 3 hours before habitual bedtime induced a ~40-min phase delay of the circadian melatonin rhythm in humans. This magnitude of delay was nearly half of the magnitude of the phase-delaying response induced by exposure to 3 hours of evening bright light (~3000 lux, ~7 W/m(2)) that began at habitual bedtime. Furthermore, using human osteosarcoma U2OS cells expressing clock gene luciferase reporters, we found a dose-dependent lengthening of the circadian period by caffeine. By pharmacological dissection and small interfering RNA knockdown, we established that perturbation of adenosine receptor signaling, but not ryanodine receptor or phosphodiesterase activity, was sufficient to account for caffeine's effects on cellular timekeeping. We also used a cyclic AMP biosensor to show that caffeine increased cyclic AMP levels, indicating that caffeine influenced a core component of the cellular circadian clock. Together, our findings demonstrate that caffeine influences human circadian timing, showing one way that the world's most widely consumed psychoactive drug affects human physiology.
authors.affiliation: Sleep and Chronobiology Laboratory, Department of Integrative Physiology, Center for Neuroscience, University of Colorado Boulder, Boulder, CO 80309-0354, USA.
authors.forename: Tina M
authors.initials: TM
authors.lastname: Burke
authors.affiliation: Sleep and Chronobiology Laboratory, Department of Integrative Physiology, Center for Neuroscience, University of Colorado Boulder, Boulder, CO 80309-0354, USA.
authors.forename: Rachel R
authors.initials: RR
authors.lastname: Markwald
authors.affiliation: Sleep and Chronobiology Laboratory, Department of Integrative Physiology, Center for Neuroscience, University of Colorado Boulder, Boulder, CO 80309-0354, USA.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: McHill
authors.affiliation: Sleep and Chronobiology Laboratory, Department of Integrative Physiology, Center for Neuroscience, University of Colorado Boulder, Boulder, CO 80309-0354, USA.
authors.forename: Evan D
authors.initials: ED
authors.lastname: Chinoy
authors.affiliation: Sleep and Chronobiology Laboratory, Department of Integrative Physiology, Center for Neuroscience, University of Colorado Boulder, Boulder, CO 80309-0354, USA.
authors.forename: Jesse A
authors.initials: JA
authors.lastname: Snider
authors.affiliation: Sleep and Chronobiology Laboratory, Department of Integrative Physiology, Center for Neuroscience, University of Colorado Boulder, Boulder, CO 80309-0354, USA.
authors.forename: Sara C
authors.initials: SC
authors.lastname: Bessman
authors.affiliation: Sleep and Chronobiology Laboratory, Department of Integrative Physiology, Center for Neuroscience, University of Colorado Boulder, Boulder, CO 80309-0354, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Jung
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK. kenneth.wright@colorado.edu oneillj@mrc-lmb.cam.ac.uk.
authors.forename: John S
authors.initials: JS
authors.lastname: O'Neill
authors.affiliation: Sleep and Chronobiology Laboratory, Department of Integrative Physiology, Center for Neuroscience, University of Colorado Boulder, Boulder, CO 80309-0354, USA. kenneth.wright@colorado.edu oneillj@mrc-lmb.cam.ac.uk.
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Wright
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D015374:Biosensing Techniques; D002110:Caffeine / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D057906:Circadian Clocks / Q000187:drug effects*; D002940:Circadian Rhythm / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D049449:Luminescence; D008297:Male; D008550:Melatonin / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D055815:Young Adult
chemical_list: D034741:RNA, Small Interfering; D002110:Caffeine; D000242:Cyclic AMP; D008550:Melatonin