The DOI matches its Crossref record; 47 of the 48 references it cites were found in a registry or an index.
A Genetic Variation in the Adenosine A2A Receptor Gene (ADORA2A) Contributes to Individual Sensitivity to Caffeine Effects on Sleep
Open accessAbstract
Caffeine is the most widely used stimulant in Western countries. Some people voluntarily reduce caffeine consumption because it impairs the quality of their sleep. Studies in mice revealed that the disruption of sleep after caffeine is mediated by blockade of adenosine A2A receptors. Here we show in humans that (1) habitual caffeine consumption is associated with reduced sleep quality in self-rated caffeine-sensitive individuals, but not in caffeine-insensitive individuals; (2) the distribution of distinct c.1083T>C genotypes of the adenosine A2A receptor gene (ADORA2A) differs between caffeine-sensitive and -insensitive adults; and (3) the ADORA2A c.1083T>C genotype determines how closely the caffeine-induced changes in brain electrical activity during sleep resemble the alterations observed in patients with insomnia. These data demonstrate a role of adenosine A2A receptors for sleep in humans, and suggest that a common variation in ADORA2A contributes to subjective and objective responses to caffeine on sleep.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Variation in the expression of genes such as cytochrome P450 1A2 (CYP1A2) [91] and adenosine A2A receptor (ADORA2A) [92] are suggested to modulate the rate of metabolism and sensitivity.”
From The effect of caffeine on subsequent sleep: A systematic review and meta-analysis (2023) · cites this paper as [92]
In the citing paper
“For example, common variants of the gene encoding for the A2a receptor can disrupt sleep (51) or cause anxiety in some individuals (52) after ingesting caffeine.”
From The Safety of Ingested Caffeine: A Comprehensive Review (2017) · cites this paper as [51]
Citations
Cites
(1970) · Cited by 24,983
Rechtschaffen, A. (1968) · Medical Entomology and Zoology · Cited by 11,772
Van Dongen, H. P. A., Maislin, G., Mullington, J. M., & Dinges, D. F. (2003) · Sleep · doi:10.1093/sleep/26.2.117 · Cited by 3,173
Fredholm, B. B., Bättig, K., Holmén, J., Nehlig, A., & Zvartau, E. E. (1999) · Pharmacological Reviews · doi:10.1016/s0031-6997(24)01396-6 · Cited by 2,624 · cited 2×
“In doses typically contained in coffee, tea, energy drinks, foods, and pharmaceutical formulations,(6) caffeine acts as an adenosine receptor antagonist.(5) Adenosinergic mechanisms appear to be critically involved in wake–sleep processes in humans.”
BackgroundAggressiveness, hypoalgesia and high blood pressure in mice lacking the adenosine A2a receptor
Ledent, C. A., Vaugeois, J., Schiffmann, S. N., Pedrazzini, T., Yacoubi, M. E., Vanderhaeghen, J. J., Costentin, J., Heath, J. K., Vassart, G., & Parmentier, M. (1997) · Nature · doi:10.1038/41771 · Cited by 918
Rajaratnam, S. M., & Arendt, J. (2001) · The Lancet · doi:10.1016/s0140-6736(01)06108-6 · Cited by 711
Barone, J. J., & Roberts, H. R. (1996) · Food and Chemical Toxicology · doi:10.1016/0278-6915(95)00093-3 · Cited by 705
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
Beta/Gamma EEG Activity in Patients with Primary and Secondary Insomnia and Good Sleeper Controls
Perlis, M. L., Smith, M. T., Andrews, P. J., Orff, H. J., & Giles, D. E. (2001) · SLEEP · doi:10.1093/sleep/24.1.110 · Cited by 502
Beta EEG activity and insomnia
Perlis, M. L., Merica, H., Smith, M. T., & Giles, D. E. (2001) · Sleep Medicine Reviews · doi:10.1053/smrv.2001.0151 · Cited by 353
Spectral characteristics of sleep EEG in chronic insomnia
Merica, H., Blois, R., & Jm, G. (1998) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.1998.00189.x · Cited by 351
Association between A2a receptor gene polymorphisms and caffeine-induced anxiety
Alsene, K., Deckert, J., Sand, P., & de Wit, H. (2003) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300232 · Cited by 334
Prevalence and Patterns of Problematic Sleep Among Older Adolescents
Ohayon, M. M., ROBERTS, R. E., Zulley, J., Smirne, S., & Priest, R. G. (2000) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1097/00004583-200012000-00019 · Cited by 331
Rétey, J., Adam, M., Honegger, E., Khatami, R., Luhmann, U. F. O., Jung, H. H., Berger, W., & Landolt, H. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0505414102 · Cited by 260
Self-citationFoster, F., & Wulff, K. (2005) · Nature reviews. Neuroscience · doi:10.1038/nrn1670 · Cited by 255
Erlich, H. A., Gelfand, D. H., & Saiki, R. K. (1988) · Nature · doi:10.1038/331461a0 · Cited by 250
Rasmussen (2002) · Pharmacogenetics · doi:10.1097/00008571-200208000-00008 · Cited by 241
Caffeine Use as a Model of Acute and Chronic Insomnia
Bonnet, M. H., & Arand, D. L. (1992) · SLEEP · doi:10.1093/sleep/15.6.526 · Cited by 236
Caffeine Attenuates Waking and Sleep Electroencephalographic Markers of Sleep Homeostasis in Humans
Landolt, H., Rétey, J., Tönz, K., Gottselig, J. M., Khatami, R., Buckelmüller, I., & Achermann, P. (2004) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300526 · Cited by 211
Self-citationCaffeine intake (200 mg) in the morning affects human sleep and EEG power spectra at night
Landolt, H.-P., Werth, E., Borbély, A. A., & Dijk, D.-J. (1995) · Brain Research · doi:10.1016/0006-8993(95)00040-w · Cited by 209
Self-citationCaffeine Reduces Low-Frequency Delta Activity in the Human Sleep EEG
Landolt, H. (1995) · Neuropsychopharmacology · doi:10.1016/0893-133x(94)00079-f · Cited by 198
Self-citationInvolvement of DARPP-32 phosphorylation in the stimulant action of caffeine
Lindskog, M., Svenningsson, P., Pozzi, L., Kim, Y. D., Fienberg, A. A., Bibb, J. A., Fredholm, B. B., Nairn, A. C., Greengard, P., & Fisone, G. (2002) · Nature · doi:10.1038/nature00817 · Cited by 180
Genetic and Environmental Influences on Insomnia, Daytime Sleepiness, and Obesity in Twins
Watson, N. F., Goldberg, J. H., Arguelles, L., & Buchwald, D. (2006) · SLEEP · doi:10.1093/sleep/29.5.645 · Cited by 166
Bonnet, M. H., Balkin, T. J., Dinges, D. F., Roehrs, T., Rogers, N. L., & Wesensten, N. J. (2005) · SLEEP · doi:10.1093/sleep/28.9.1163 · Cited by 164
Deckert, J., Nöthen, M. M., Franke, P. E., Delmo, C. D., Fritze, J., Knapp, M., Maier, W., Beckmann, H., & Propping, P. (1998) · Molecular Psychiatry · doi:10.1038/sj.mp.4000345 · Cited by 162
Age-Related Changes in the Time Course of Vigilant Attention During 40 Hours Without Sleep in Men
Adam, M., Rétey, J., Khatami, R., & Landolt, H. (2006) · SLEEP · doi:10.1093/sleep/29.1.55 · Cited by 154
Self-citationEvidence for Genetic Linkage Between a Polymorphism in the Adenosine 2A Receptor and Panic Disorder
Hamilton, S. P., Slager, S. L., Baisre, A., Heiman, G. A., Klein, D. F., Hodge, S. E., Weissman, M. M., Fyer, A. J., & Knowles, J. A. (2003) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300311 · Cited by 147
Caffeine Self-administration, Withdrawal, and Adverse Effects Among Coffee Drinkers
Hughes, J. R. (1991) · Archives of General Psychiatry · doi:10.1001/archpsyc.1991.01810310029006 · Cited by 140
Interindividual Variation in Sleep Duration and Its Association With Sleep Debt in Young Adults
Klerman, E. B., & Dijk, D. (2005) · SLEEP · doi:10.1093/sleep/28.10.1253 · Cited by 138
Low-dose caffeine discrimination in humans.
Griffiths, R. R., Evans, S. M., Heishman, S. J., Preston, K. L., Sannerud, C. A., Wolf, B., & Woodson, P. P. (1990) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)20216-6 · Cited by 133
The Use of Caffeine Versus Prophylactic Naps in Sustained Performance
Bonnet, M. H., Gomez, S. A., Wirth, O., & Arand, D. L. (1995) · SLEEP · doi:10.1093/sleep/18.2.97 · Cited by 117
Rétey, J., Adam, M., Gottselig, J. M., Khatami, R., Dürr, R., Achermann, P., & Landolt, H. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.1538-06.2006 · Cited by 117
Self-citationDrapeau, C., Hamel-Hébert, I., Robillard, R., Selmaoui, B., Filipini, D., & Carrier, J. (2006) · Journal of Sleep Research · doi:10.1111/j.1365-2869.2006.00518.x · Cited by 115
Goldstein, A., Warren, R. A., & Kaizer, S. (1965) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)27091-4 · Cited by 112
PSYCHOTROPIC EFFECTS OF CAFFEINE IN MAN. II. ALERTNESS, PSYCHOMOTOR COORDINATION, AND MOOD
Goldstein, A., Kaizer, S., & Warren, R. A. (1965) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)27160-9 · Cited by 109
Reinforcing and subjective effects of caffeine in normal human volunteers
Stern, K., Chait, L. D., & Johanson, C. E. (1989) · Psychopharmacology · doi:10.1007/bf00442010 · Cited by 101
Enhanced stimulant and metabolic effects of combined ephedrine and caffeine*1
HALLER, C. (2004) · Clinical Pharmacology & Therapeutics · doi:10.1016/j.clpt.2003.11.375 · Cited by 86
Neurophysiological aspects of primary insomnia: Implications for its treatment
Cortoos, A., Verstraeten, E., & Cluydts, R. (2006) · Sleep Medicine Reviews · doi:10.1016/j.smrv.2006.01.002 · Cited by 71
Gottselig, J. M., Adam, M., Rétey, J., Khatami, R., Achermann, P., & Landolt, H. (2006) · Journal of Sleep Research · doi:10.1111/j.1365-2869.2006.00497.x · Cited by 71
Self-citationCaffeine metabolism and coffee-attributed sleep disturbances
Levy, M., & Zylber‐Katz, E. (1983) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.1983.105 · Cited by 66
Pharmacokinetic and pharmacodynamic responses to caffeine in poor and normal sleepers
Tiffin, P. A., Ashton, H., Marsh, R., Kamali, F., Ashton, H., & Marsh, R. (1995) · Psychopharmacology · doi:10.1007/bf02246500 · Cited by 54
Reasons for changing caffeinated coffee consumption: the Rancho Bernardo Study.
Soroko, S. B., Chang, J. C., & Barrett-Connor, E. L. (1996) · Journal of the American College of Nutrition · doi:10.1080/07315724.1996.10718571 · Cited by 44
Dose-related caffeine discrimination in normal volunteers
Evans, S., & Griffiths, R. R. (1991) · Behavioural Pharmacology · doi:10.1097/00008877-199109000-00011 · Cited by 41
Factors influencing the subjective response to caffeine
Chait, L. D. (1992) · Behavioural Pharmacology · doi:10.1097/00008877-199206000-00005 · Cited by 31
The Influence of Caffein Alkaloid on the Quality and Amount of Sleep
Hollingworth, H. L. (1912) · The American Journal of Psychology · doi:10.2307/1413116 · Cited by 17
Arousal and Behavior: Biopsychological Effects of Caffeine
Nehlig, A. (2004) · CRC Press eBooks · doi:10.1201/9780203618851-10 · Cited by 12
Bastien, C., & Bonnet, M. H. (2001) · Sleep Medicine Reviews · doi:10.1053/smrv.2001.0169 · Cited by 11
Flagged first, then by citations
1 of the 48 references couldn’t be matched to a known paper.
Research works printed but not linked: 7
- Bonnet M.H., 1995, Sleep (Rochester), 18, 97
- Bonnet M.H., 1992, Sleep, 15, 526
- Goldstein A., 1965, J. Pharmacol. Exp. Ther., 149, 156
- Chait L.D., 1992, Behav. Pharmacol., 3, 219
- Goldstein A., 1965, J. Pharmacol. Exp. Ther., 150, 146
- Evans S.M., 1991, Behav. Pharmacol., 2, 345
- Griffiths R.R., 1990, J. Pharmacol. Exp. Ther., 252, 970
Cited by
Sorted by citations
Neurocognitive consequences of sleep deprivation
Goel, N., Rao, H., Durmer, J., & Dinges, D. (2009) · Seminars in Neurology · doi:10.1055/s-0029-1237117 · Cited by 2,154
Control of sleep and wakefulness
Brown, R. E., Basheer, R., McKenna, J. T., Strecker, R. E., & McCarley, R. W. (2012) · Physiological Reviews · doi:10.1152/physrev.00032.2011 · Cited by 1,477
Fredholm, B. B., IJzerman, A. P., Jacobson, K. A., Linden, J. M., & Müller, C. E. (2011) · Pharmacological Reviews · doi:10.1124/pr.110.003285 · Cited by 1,307
Sleep Deprivation and Vigilant Attention
Lim, J., & Dinges, D. F. (2008) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1417.002 · Cited by 1,213
Caffeinated energy drinks a growing problem
Reissig, C. J., Strain, E. C., & Griffiths, R. R. (2009) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2008.08.001 · Cited by 1,026
Metadata
- Authors
- Rétey, J. V., Adam, M., Khatami, R., Luhmann, U. F. O., Jung, H. H., Berger, W., & Landolt, H.-P.
- Affiliations
- University of Zurich (CH)
- University Hospital Zurich (CH)
- Corresponding author
- Landolt, H-P
- Venue
- Clinical Pharmacology & Therapeutics
- Publisher
- Wiley
- Published
- 2007-02-28
- Volume
- 81
- Issue
- 5
- Pages
- 692-698
- ISSN
- 0009-9236 (ISSN-L)
- 1532-6535
- OpenAlex
- W2035474281
- Cited by
- 278
- References
- 48
- Citations by year
- 2026: 11 · 2025: 11 · 2024: 12 · 2023: 14 · 2022: 8 · 2021: 12 · 2020: 22 · 2019: 17 · 2018: 13 · 2017: 13 · 2016: 16 · 2015: 17 · 2014: 14 · 2013: 10 · 2012: 26
- FWCI
- 9.75
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Clinical Pharmacology & Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Coffee research and impacts
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and related disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Keywords
- caffeine, adenosine A2A receptor, caffeine sensitivity, sleep quality, genetic variation, insomnia, habitual caffeine consumption
- MeSH terms
- Adult, Aged, Alleles, Central Nervous System Stimulants, Caffeine, Data Interpretation, Statistical, DNA, Electroencephalography, Female, Genotype, Humans, Male, Middle Aged, Surveys and Questionnaires, Sleep, Genetic Variation, Polysomnography, Reverse Transcriptase Polymerase Chain Reaction, Internet, Receptor, Adenosine A2A
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review