Effects of caffeine on the human circadian clock in vivo and in vitro
Open accessAbstract
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.
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Caffeine later in the day disrupts sleep and delays circadian timing.
“caffeine later in the day disrupts sleep and delays circadian timing (52,53).”
From Impact of Sleep and Circadian Rhythms on Addiction Vulnerability in Adolescents (2018) · cites this paper as [52]
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Cites
The Measurement of Observer Agreement for Categorical Data
Landis, J. R., & Koch, G. G. (1977) · Biometrics · doi:10.2307/2529310 · Cited by 81,148 · see citing works
Forming inferences about some intraclass correlation coefficients.
McGraw, K. O., & Wong, S. P. (1996) · Psychological Methods · doi:10.1037/1082-989x.1.1.30 · Cited by 6,903 · see citing works
A circadian gene expression atlas in mammals: Implications for biology and medicine
Zhang, R., Lahens, N. F., Ballance, H. I., Hughes, M. E., & Hogenesch, J. B. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1408886111 · Cited by 2,304 · see citing works
Nehlig, A., Daval, J., & Debry, G. (1992) · Brain Research Reviews · doi:10.1016/0165-0173(92)90012-b · Cited by 1,463 · see citing works
Zeitzer, J. M., Dijk, D., Kronauer, R. E., Brown, E. N., & Czeisler, C. A. (2000) · The Journal of Physiology · doi:10.1111/j.1469-7793.2000.00695.x · Cited by 1,175 · see citing works
A Phase Response Curve to Single Bright Light Pulses in Human Subjects
Khalsa, S. B. S., Jewett, M. E., Cajochen, C., & Czeisler, C. A. (2003) · The Journal of Physiology · doi:10.1113/jphysiol.2003.040477 · Cited by 1,040 · see citing works
Adenosine receptors as drug targets — what are the challenges?
Chen, J., Eltzschig, H. K., & Fredholm, B. B. (2013) · Nature Reviews Drug Discovery · doi:10.1038/nrd3955 · Cited by 899 · see citing works
Entrainment of the Human Circadian Clock to the Natural Light-Dark Cycle
Wright, K. P., McHill, A. W., Birks, B. R., Griffin, B. R., Rusterholz, T., & Chinoy, E. D. (2013) · Current Biology · doi:10.1016/j.cub.2013.06.039 · Cited by 783 · see citing works
Self-citationBright light resets the human circadian pacemaker independent of the timing of the sleep-wake cycle
Czeisler, C. A., Allan, J. S., Strogatz, S. H., Ronda, J. M., Sánchez, R., Ríos, C. D., Freitag, W. O., Richardson, G. S., & Kronauer, R. E. (1986) · Science · doi:10.1126/science.3726555 · Cited by 770 · see citing works
Adenosine A2A, but not A1, receptors mediate the arousal effect of caffeine
Huang, Z.-L., Qu, W.-M., Eguchi, N., Chen, J.-F., Schwarzschild, M. A., Fredholm, B. B., Urade, Y., & Hayaishi, O. (2005) · Nature Neuroscience · doi:10.1038/nn1491 · Cited by 640 · see citing works
Sex difference in the near-24-hour intrinsic period of the human circadian timing system
Duffy, J. F., Cain, S. W., Chang, A., Phillips, A. J. K., Münch, M. Y., Gronfier, C., Wyatt, J. K., Dijk, D., Wright, K. P., & Czeisler, C. A. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1010666108 · Cited by 601 · see citing works
Self-citationCryptochrome mediates circadian regulation of cAMP signaling and hepatic gluconeogenesis
Zhang, E. E., Liu, Y., Dentin, R., Pongsawakul, P. Y., Liu, A. C., Hirota, T., Nusinow, D. A., Sun, X., Landais, S., Kodama, Y., et al. (2010) · Nature Medicine · doi:10.1038/nm.2214 · Cited by 567 · see citing works
Structure of the Adenosine A2A Receptor in Complex with ZM241385 and the Xanthines XAC and Caffeine
Dore, A. S., Robertson, N. J., Errey, J. C., Ng, I. W., Hollenstein, K., Tehan, B. G., Hurrell, E., Bennett, K. A., Congreve, M., Magnani, F., et al. (2011) · Structure · doi:10.1016/j.str.2011.06.014 · Cited by 557 · see citing works
Circadian rhythms persist without transcription in a eukaryote
O'Neill, J. S., Gerben Van Ooijen, A., Dixon, L. E., Troein, C., Corellou, F., Bouget, F., Reddy, A. B., & Millar, A. J. (2011) · Nature · doi:10.1038/nature09654 · Cited by 514 · see citing works
Self-citationcAMP-dependent signaling as a core component of the mammalian circadian pacemaker
O'Neill, J. S., Maywood, E. S., Chesham, J. E., Takahashi, J. S., & Hastings, M. H. (2008) · Science · doi:10.1126/science.1152506 · Cited by 418 · see citing works
Self-citationHirota, T., Lewis, W. G., Liu, A. C., Lee, J. W., Schultz, P. G., & Kay, S. A. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0811410106 · Cited by 283 · see citing works
Rétey, J. V., Adam, M., Khatami, R., Luhmann, U. F. O., Jung, H. H., Berger, W., & Landolt, H.-P. (2007) · Clinical Pharmacology & Therapeutics · doi:10.1038/sj.clpt.6100102 · Cited by 278 · see citing works
Wright, K. P., Hughes, R. J., Kronauer, R. E., Dijk, D., & Czeisler, C. A. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.201530198 · Cited by 254 · see citing works
Self-citationIsojima, Y., Nakajima, M., Ukai, H., Fujishima, H., Yamada, R. G., Masumoto, K., Kiuchi, R., Ishida, M., Ukai‐Tadenuma, M., Minami, Y., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0908733106 · Cited by 246 · see citing works
Genetic polymorphism of the adenosine A2A receptor is associated with habitual caffeine consumption
Cornelis, M. C., El‐Sohemy, A., & Campos, H. (2007) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/86.1.240 · Cited by 231 · see citing works
A neuronal ryanodine receptor mediates light-induced phase delays of the circadian clock
Ding, J., Buchanan, G. F., Tischkau, S. A., Chen, D., Kuriashkina, L. R., Faiman, L. E., Alster, J. M., McPherson, P. S., Campbell, K. P., & Gillette, M. U. (1998) · Nature · doi:10.1038/28639 · Cited by 227 · see citing works
Doi, M., Ishida, A., Miyake, A., Sato, M., Komatsu, R., Yamazaki, F., Kimura, I., Tsuchiya, S., Kori, H., Seo, K., et al. (2011) · Nature Communications · doi:10.1038/ncomms1316 · Cited by 143 · see citing works
Caffeine alters plasma adenosine levels
Conlay, L. A., Conant, J. A., deBros, F., & Wurtman, R. (1997) · Nature · doi:10.1038/38160 · Cited by 133 · see citing works
Monroe, D. G., Secreto, F. J., Subramaniam, M., Getz, B. J., Khosla, S., & Spelsberg, T. C. (2005) · Molecular Endocrinology · doi:10.1210/me.2004-0381 · Cited by 133 · see citing works
The Effects of Caffeine on Sleep inDrosophilaRequire PKA Activity, But Not the Adenosine Receptor
Wu, M. N., Ho, K. S., Crocker, A. J., Yue, Z., Koh, K., & Sehgal, A. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.1653-09.2009 · Cited by 130 · see citing works
Histone methyltransferase MLL3 contributes to genome-scale circadian transcription
Valekunja, U. K., Edgar, R. S., Oklejewicz, M., van der Horst, G. T. J., O'Neill, J. S., Tamanini, F., Turner, D. J., & Reddy, A. B. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1214168110 · Cited by 123 · see citing works
Self-citationRacial differences in the human endogenous circadian period
Smith, M. R., Burgess, H. J., Fogg, L. F., & Eastman, C. I. (2009) · PLoS ONE · doi:10.1371/journal.pone.0006014 · Cited by 113 · see citing works
Localization of Adenosine Receptor Messenger RNAs in the Rat Eye
Kvanta, A., Seregard, S., Sejersen, S. S., et al. (1997) · Experimental Eye Research · doi:10.1006/exer.1996.0352 · Cited by 110 · see citing works
Caffeine and light effects on nighttime melatonin and temperature levels in sleep-deprived humans
Wright, K. P., Badia, P., Myers, B. L., Plenzler, S. C., & Hakel, M. D. (1997) · Brain Research · doi:10.1016/s0006-8993(96)01268-1 · Cited by 110 · see citing works
Self-citationCombination of Light and Melatonin Time Cues for Phase Advancing the Human Circadian Clock
Burke, T. M., Markwald, R. R., Chinoy, E. D., Snider, J. A., Bessman, S. C., Jung, C. M., & Wright, K. P. (2013) · SLEEP · doi:10.5665/sleep.3110 · Cited by 106 · see citing works
Self-citationSmall molecule modifiers of circadian clocks
Chen, Z., Yoo, S. H., & Takahashi, J. S. (2012) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-012-1207-y · Cited by 102 · see citing works
Absence of Circadian Phase Resetting in Response to Bright Light Behind the Knees
Wright, K. P., & Czeisler, C. A. (2002) · Science · doi:10.1126/science.1071697 · Cited by 96 · see citing works
Self-citationByrne, E. M., Johnson, J., McRae, A. F., Nyholt, D. R., Medland, S. E., Gehrman, P., Heath, A. C., Madden, P. A. F., Montgomery, G. W., Chenevix‐Trench, G., et al. (2012) · SLEEP · doi:10.5665/sleep.1962 · Cited by 96 · see citing works
Caffeine lengthens circadian rhythms in mice
Oike, H., Kobori, M., Suzuki, T., & Ishida, N. (2011) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2011.06.049 · Cited by 94 · see citing works
Shryock, J. C., Ozeck, M. J., & Belardinelli, L. (1998) · Molecular Pharmacology · doi:10.1016/s0026-895x(24)13255-5 · Cited by 79 · see citing works
Chen, G., & van den Pol, A. N. (1997) · Journal of Neurophysiology · doi:10.1152/jn.1997.77.6.3035 · Cited by 72 · see citing works
Narishige, S., Kuwahara, M., Shinozaki, A., Okada, S., Ikeda, Y., Kamagata, M., Tahara, Y., & Shibata, S. (2014) · British Journal of Pharmacology · doi:10.1111/bph.12890 · Cited by 68 · see citing works
Circadian Periodicity in Neurospora : Alteration by Inhibitors of Cyclic AMP Phosphodiesterase
Feldman, J. F. (1975) · Science · doi:10.1126/science.173018 · Cited by 64 · see citing works
Caffeine increases light responsiveness of the mouse circadian pacemaker
van Diepen, H. C., Lucassen, E. A., Yasenkov, R., Groenen, I., IJzerman, A. P., Meijer, J. H., & Deboer, T. (2014) · European Journal of Neuroscience · doi:10.1111/ejn.12715 · Cited by 63 · see citing works
Wright, K. P., Myers, B. L., Plenzler, S. C., Drake, C. L., & Badia, P. (2000) · Brain Research · doi:10.1016/s0006-8993(00)02557-9 · Cited by 53 · see citing works
Self-citationIshihara, K., Miyasita, A., Inugami, M., Fukuda, K., Yamazaki, K., & Miyata, Y. (1985) · Psychological Reports · doi:10.2466/pr0.1985.57.2.391 · Cited by 48 · see citing works
Wu, P. H., Phillis, J. W., & Nye, M. J. (1982) · Life Sciences · doi:10.1016/0024-3205(82)90676-2 · Cited by 45 · see citing works
Increased Coherence of Circadian Rhythms in Mature Fibroblast Cultures
O'Neill, J. S., & Hastings, M. H. (2008) · Journal of Biological Rhythms · doi:10.1177/0748730408326682 · Cited by 39 · see citing works
Self-citationCircadian modulation of the ryanodine receptor type 2 in the SCN of rodents
Díaz‐Muñoz, M., Dent, M. A. R., Granados‐Fuentes, D., et al. (1999) · Neuroreport · doi:10.1097/00001756-199902250-00007 · Cited by 37 · see citing works
Watanabe, A., Moriya, T., Nisikawa, Y., Araki, T., Hamada, T., Shibata, S., & Watanabe, S. (1996) · Brain Research · doi:10.1016/s0006-8993(96)00881-5 · Cited by 29 · see citing works
THE EFFECTS OF CAFFEINE AND THEOPHYLLINE ON THE PHOTOTACTIC RHYTHM OFCHLAMYDOMONAS REINHARDII
Goodenough, J., & Bruce, V. G. (1980) · Biological Bulletin · doi:10.2307/1540830 · Cited by 19 · see citing works
Cyclic nucleotides and circadian rhythm generation in Bulla gouldiana
Ralph, M. R., Khalsa, S. B. S., & Block, G. D. (1992) · Comparative Biochemistry and Physiology Part A Physiology · doi:10.1016/0300-9629(92)90363-u · Cited by 14 · see citing works
Shearman, L. P., & Weaver, D. R. (2001) · Journal of Biological Rhythms · doi:10.1177/074873001129002222 · Cited by 13 · see citing works
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Roenneberg, T., & Merrow, M. (2016) · Current Biology · doi:10.1016/j.cub.2016.04.011 · Cited by 1,004 · see citing works
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Wehrens, S. M. T., Christou, S., Isherwood, C., Middleton, B., Gibbs, M. A., Archer, S. N., Skene, D. J., & Johnston, J. D. (2017) · Current Biology · doi:10.1016/j.cub.2017.04.059 · Cited by 596 · see citing works
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Stothard, E. R., McHill, A. W., Depner, C. M., Birks, B. R., Moehlman, T. M., Ritchie, H. K., Guzzetti, J. R., Chinoy, E. D., LeBourgeois, M. K., Axelsson, J., et al. (2017) · Current Biology · doi:10.1016/j.cub.2016.12.041 · Cited by 303 · see citing works
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- Authors
- Burke, T. M., Markwald, R. R., McHill, A. W., Chinoy, E. D., Snider, J. A., Bessman, S. C., Jung, C. M., O’Neill, J. S., & Wright, K. P.
- Affiliations
- University of Colorado Boulder (US)
- MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
- Corresponding author
- Jung, Christopher M.
- Wright, Kenneth P.
- Venue
- Science Translational Medicine
- Published
- 2015-09-16
- Volume
- 7
- Issue
- 305
- Pages
- 305ra146-305ra146
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- PMC
- PMC4657156
- OpenAlex
- W1899622156
- Cited by
- 283
- References
- 48
- Citations by year
- 2026: 24 · 2025: 21 · 2024: 40 · 2023: 24 · 2022: 38 · 2021: 19 · 2020: 20 · 2019: 25 · 2018: 23 · 2017: 26 · 2016: 22 · 2015: 1
- FWCI
- 13.30
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science Translational Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (R01 HL081761)
- Howard Hughes Medical Institute
- Wellcome Trust (093734/Z/10/Z)
- Medical Research Council (MC_UP_1201/4)
- NIH/National Center for Advancing Translational Sciences Colorado Clinical and Translational Science Award (UL1 TR001082)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and Work-Related Fatigue
- Health Sciences › Medicine › Pharmacology › Coffee research and impacts
- Keywords
- caffeine, circadian clock, melatonin rhythm, circadian phase delay, adenosine receptors, cyclic AMP, clock gene expression, U2OS cells, bright light exposure, sleep disruption, psychoactive substances
- MeSH terms
- Cyclic AMP, Adult, Analysis of Variance, Caffeine, Circadian Rhythm, Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Male, Melatonin, Biosensing Techniques, RNA, Small Interfering, Cell Line, Tumor, Luminescence, Young Adult, Circadian Clocks, Healthy Volunteers
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