Dose-dependent model of caffeine effects on human vigilance during total sleep deprivation
Abstract
Caffeine is the most widely consumed stimulant to counter sleep-loss effects. While the pharmacokinetics of caffeine in the body is well-understood, its alertness-restoring effects are still not well characterized. In fact, mathematical models capable of predicting the effects of varying doses of caffeine on objective measures of vigilance are not available. In this paper, we describe a phenomenological model of the dose-dependent effects of caffeine on psychomotor vigilance task (PVT) performance of sleep-deprived subjects. We used the two-process model of sleep regulation to quantify performance during sleep loss in the absence of caffeine and a dose-dependent multiplier factor derived from the Hill equation to model the effects of single and repeated caffeine doses. We developed and validated the model fits and predictions on PVT lapse (number of reaction times exceeding 500 ms) data from two separate laboratory studies. At the population-average level, the model captured the effects of a range of caffeine doses (50-300 mg), yielding up to a 90% improvement over the two-process model. Individual-specific caffeine models, on average, predicted the effects up to 23% better than population-average caffeine models. The proposed model serves as a useful tool for predicting the dose-dependent effects of caffeine on the PVT performance of sleep-deprived subjects and, therefore, can be used for determining caffeine doses that optimize the timing and duration of peak performance.
Integrity signals
Registry
Cites
Statistics
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?
The impact of caffeine on performance appears to be greater under conditions that would negatively impact performance, such as acute caffeine withdrawal or sleep deprivation.
“The impact of caffeine appears to be greater under conditions that would negatively impact performance, such as acute caffeine withdrawal (74–76) or sleep deprivation (71, 77).”
From The Safety of Ingested Caffeine: A Comprehensive Review (2017) · cites this paper as [77]
Cites
The Elements of Statistical Learning
Hastie, T., Tibshirani, R., & Friedman, J. (2009) · Springer Series in Statistics · doi:10.1007/978-0-387-84858-7 · Cited by 25,970 · see citing works
The Elements of Statistical Learning
Hastie, T., Friedman, J., & Tibshirani, R. (2001) · Springer Series in Statistics · doi:10.1007/978-0-387-21606-5 · Cited by 24,162 · see citing works
The Elements of Statistical Learning: Data Mining, Inference, and Prediction
Ruppert, D. (2004) · Journal of the American Statistical Association · doi:10.1198/jasa.2004.s339 · Cited by 18,736 · see citing works
Feinleib, M., & Zar, J. H. (1975) · Journal of the American Statistical Association · doi:10.2307/2285423 · Cited by 12,671 · see citing works
Brown, R. A., Hastie, T. J., & Tibshirani, R. J. (1991) · Biometrics · doi:10.2307/2532174 · Cited by 8,262 · see citing works
Koyak, R. A., Hastie, T. J., & Tibshirani, R. J. (1991) · Journal of the American Statistical Association · doi:10.2307/2290538 · Cited by 7,717 · see citing works
Two-Process Model of Sleep Regulation
Binder, M. D., Hirokawa, N., & Windhorst, U. (2008) · Springer eBooks · doi:10.1007/978-3-540-29678-2_6166 · Cited by 3,895 · see citing works
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 · see citing works
Hastie, T. J., & Tibshirani, R. J. (2014) · Wiley StatsRef: Statistics Reference Online · doi:10.1002/9781118445112.stat03141 · Cited by 3,156 · see citing works
Dinges, D. F., & Powell, J. W. (1985) · Behavior Research Methods, Instruments, & Computers · doi:10.3758/bf03200977 · Cited by 1,750 · see citing works
Maximizing sensitivity of the Psychomotor Vigilance Test (PVT) to sleep loss
Basner, M., & Dinges, D. F. (2011) · Sleep · doi:10.1093/sleep/34.5.581 · Cited by 958 · see citing works
Maintaining alertness and performance during sleep deprivation: modafinil versus caffeine
Wesensten, N. J., Belenky, G. L., Kautz, M. A., Thorne, D. R., Reichardt, R. M., & Balkin, T. J. (2001) · Psychopharmacology · doi:10.1007/s002130100916 · Cited by 404 · see citing works
Self-citationPsychomotor Vigilance Performance: Neurocognitive Assay Sensitive to Sleep Loss
Dorrian, J., Rogers, N. L., & Dinges, D. F. (2004) · CRC Press eBooks · doi:10.3109/9780203998007-4 · Cited by 404 · see citing works
Kamimori, G. H., Karyekar, C. S., Otterstetter, R., Cox, D. S., Balkin, T. J., Belenky, G. L., & Eddington, N. D. (2002) · International Journal of Pharmaceutics · doi:10.1016/s0378-5173(01)00958-9 · Cited by 390 · see citing works
Self-citationDose‐Dependent Pharmacokinetics and Psychomotor Effects of Caffeine in Humans
Kaplan, G. B., Greenblatt, D. J., Ehrenberg, B. L., Goddard, J. E., Cotreau, M. M., Harmatz, J. S., & Shader, R. I. (1997) · The Journal of Clinical Pharmacology · doi:10.1002/j.1552-4604.1997.tb04356.x · Cited by 387 · see citing works
Caffeine disposition after oral doses
Bonati, M., Latini, R., Galletti, F., Young, J. F., Tognoni, G., & Garattini, S. (1982) · Clinical Pharmacology and Therapeutics · doi:10.1038/clpt.1982.132 · Cited by 353 · cited 4× · see citing works
“The pharmacokinetics (PK) of caffeine and its dose-dependent metabolism in humans have been well characterized (Bonati et al., 1982; Denaro et al., 1990), and its mechanism of action (antagonism of adenosine receptors) is also well-understood (Bertorelli et al.”
BackgroundMethodInfluentialWESENSTEN, N. J., KILLGORE, W. D. S., & BALKIN, T. J. (2005) · Journal of Sleep Research · doi:10.1111/j.1365-2869.2005.00468.x · Cited by 306 · cited 3× · see citing works
“In the majority of these studies, caffeine has been administered as a single bolus dose of 600 mg (Wesensten et al., 2002; Wesensten et al., 2005) or as smaller, repeated doses of 50, 100, 200, or 300 mg (Kamimori et al., 2005; LaJambe et al., 2005).”
BackgroundInfluentialSelf-citationBalkin, T. J., Bliese, P. D., Belenky, G., Sing, H., Thorne, D. R., Thomas, M., Redmond, D. P., Russo, M., & Wesensten, N. J. (2004) · Journal of Sleep Research · doi:10.1111/j.1365-2869.2004.00407.x · Cited by 271 · see citing works
Self-citationCaffeine reversal of sleep deprivation effects on alertness and mood
Penetar, D. M., McCann, U. D., Thorne, D., Kamimori, G. H., Galinski, C., Sing, H. C., Thomas, M., & Belenky, G. L. (1993) · Psychopharmacology · doi:10.1007/bf02244933 · Cited by 208 · see citing works
Self-citationPharmacokinetic–Pharmacodynamic Modelling: History and Perspectives
Csajka, C., & Verotta, D. (2006) · Journal of Pharmacokinetics and Pharmacodynamics · doi:10.1007/s10928-005-9002-0 · Cited by 194 · see citing works
Sleep Deprivation: Clinical Issues, Pharmacology, and Sleep Loss Effects
Lee, K. A. (2005) · SLEEP · doi:10.1093/sleep/28.6.769 · Cited by 188 · see citing works
Simulation of daytime vigilance by the additive interaction of a homeostatic and a circadian process
Achermann, P., & Borbély, A. A. (1994) · Biological Cybernetics · doi:10.1007/bf00197314 · Cited by 180 · see citing works
Bonnet, M., Balkin, T., Dinges, D., Roehrs, T., Rogers, N., & Wesensten, N. (2005) · Sleep · doi:10.1093/sleep/28.9.1163 · Cited by 171 · see citing works
Self-citationPC-PVT: A platform for psychomotor vigilance task testing, analysis, and prediction
Khitrov, M. Y., Laxminarayan, S., Thorsley, D., Ramakrishnan, S., Rajaraman, S., Wesensten, N. J., & Jaques Reifman, A. (2013) · Behavior Research Methods · doi:10.3758/s13428-013-0339-9 · Cited by 162 · see citing works
Self-citationEffects of caffeine on mood and performance: a study of realistic consumption
Brice, C. F., & Smith, A. P. (2002) · Psychopharmacology · doi:10.1007/s00213-002-1175-2 · Cited by 148 · see citing works
Killgore, W. D. S., Kahn-Greene, E. T., Grugle, N. L., Killgore, D. B., & Balkin, T. J. (2009) · Sleep · doi:10.1093/sleep/32.2.205 · Cited by 132 · see citing works
Self-citationKillgore, W. D. S., Rupp, T. L., Grugle, N. L., Reichardt, R. M., Lipizzi, E. L., & Balkin, T. J. (2008) · Journal of Sleep Research · doi:10.1111/j.1365-2869.2008.00654.x · Cited by 131 · see citing works
Self-citationRétey, 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 119 · see citing works
Dose-dependency of caffeine metabolism with repeated dosing
Denaro, C. P., Brown, C. R., Wilson, M., Jacob, P., & Benowitz, N. L. (1990) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.1990.150 · Cited by 108 · see citing works
Cheng, W., Murphy, T. L., Smith, M. T., Cooksley, W. G. E., Halliday, J. W., & Powell, L. W. (1990) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.1990.66 · Cited by 95 · see citing works
Multiple caffeine doses maintain vigilance during early morning operations.
Kamimori, G. H., Johnson, D. E., Thorne, D., & Belenky, G. L. (2005) · PubMed · Cited by 71 · see citing works
Self-citationThe effect of caffeine on working memory load-related brain activation in middle-aged males
Klaassen, E. B., de Groot, R. H. M., Evers, E. A. T., Snel, J., Veerman, E. C. I., Ligtenberg, A. J. M., Jolles, J., & Veltman, D. J. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.06.026 · Cited by 68 · see citing works
Combining different models of sleep regulation
Achermann, P., & Borbély, A. A. (1992) · Journal of Sleep Research · doi:10.1111/j.1365-2869.1992.tb00028.x · Cited by 61 · see citing works
Cross‐over trials, carry‐over effects and the art of self‐delusion
Senn, S. J. (1988) · Statistics in Medicine · doi:10.1002/sim.4780071010 · Cited by 61 · see citing works
Rajdev, P., Thorsley, D., Rajaraman, S., Rupp, T. L., Wesensten, N. J., Balkin, T. J., & Jaques Reifman, A. (2013) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2013.04.013 · Cited by 58 · see citing works
Self-citationMultiple dose pharmacokinetics of caffeine administered in chewing gum to normal healthy volunteers
Syed, S. S., Kamimori, G. H., Kelly, W. F., & Eddington, N. D. (2005) · Biopharmaceutics & Drug Disposition · doi:10.1002/bdd.469 · Cited by 57 · see citing works
Self-citationLandolt, H., Rétey, J., & Adam, M. (2012) · Frontiers in Neurology · doi:10.3389/fneur.2012.00062 · Cited by 53 · see citing works
Caffeine effects on recovery sleep following 27 h total sleep deprivation.
LaJambe, C. M., Kamimori, G. H., Belenky, G. L., & Balkin, T. J. (2005) · PubMed · Cited by 50 · see citing works
Self-citationIncorporation of caffeine into a quantitative model of fatigue and sleep
Puckeridge, M., Fulcher, B., Phillips, A. J. K., & Robinson, P. A. (2010) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2010.12.018 · Cited by 49 · see citing works
Individualized performance prediction of sleep-deprived individuals with the two-process model.
Rajaraman, S., Gribok, A., Wesensten, N., Balkin, T., & Reifman, J. (2008) · Journal of applied physiology · doi:10.1152/japplphysiol.00877.2007 · Cited by 45 · see citing works
Self-citationRajaraman, S., Gribok, A., Wesensten, N., Balkin, T., & Reifman, J. (2009) · Sleep · doi:10.1093/sleep/32.10.1377 · Cited by 33 · see citing works
Self-citationDose-dependent caffeine pharmacokinetics during severe sleep deprivation in humans.
Kamimori, G. H., Lugo, S., Penetar, D. M., Chamberlain, A. C., Brunhart, G. E., Brunhart, A. E., & Eddington, N. D. (1995) · PubMed · Cited by 31 · see citing works
Self-citationRamakrishnan, S., Rajaraman, S., Laxminarayan, S., Wesensten, N., Kamimori, G., Balkin, T., & Reifman, J. (2013) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2012.11.015 · Cited by 21 · see citing works
Self-citationFayers, P. M., & King, M. T. (2008) · Quality of Life Research · doi:10.1007/s11136-008-9390-x · Cited by 17 · see citing works
Ramakrishnan, S., Laxminarayan, S., Thorsley, D., Wesensten, N., Balkin, T., & Reifman, J. (2012) · Annual International Conference of the IEEE Engineering in Medicine and Biology Society · doi:10.1109/embc.2012.6347257 · Cited by 6 · see citing works
Self-citationEffects of the cholinergic channel activator ABT-418 on cortical EEG: Comparison with (?)-nicotine
Radek, R. J., Briggs, C. A., Sullivan, J. P., Kang, C. H., & Arnerić, S. P. (1996) · Drug Development Research · doi:10.1002/(sici)1098-2299(199602)37:2 · Cited by 3 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
The Safety of Ingested Caffeine: A Comprehensive Review
Temple, J. L., Bernard, C., Lipshultz, S. E., Czachor, J. D., Westphal, J. A., & Mestre, M. A. (2017) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2017.00080 · Cited by 557 · see citing works
- Authors
- Ramakrishnan, S., Laxminarayan, S., Wesensten, N. J., Kamimori, G. H., Balkin, T. J., & Reifman, J.
- Affiliations
- Telemedicine & Advanced Technology Research Center (US)
- Walter Reed Army Institute of Research (US)
- Venue
- Journal of Theoretical Biology
- Publisher
- Elsevier BV
- Published
- 2014-10
- Volume
- 358
- Pages
- 11-24
- ISSN
- 0022-5193 (ISSN-L)
- OpenAlex
- W2171058933
- Cited by
- 33
- References
- 46
- Citations by year
- 2025: 2 · 2024: 3 · 2023: 1 · 2022: 1 · 2021: 1 · 2020: 3 · 2019: 4 · 2018: 6 · 2017: 4 · 2016: 3 · 2015: 5
- FWCI
- 5.55
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Theoretical Biology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and Work-Related Fatigue
- Health Sciences › Medicine › Pharmacology › Coffee research and impacts
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Keywords
- caffeine, total sleep deprivation, psychomotor vigilance task, sustained attention, dose-dependent effects, Hill equation, alertness, individual differences, mathematical modeling
- MeSH terms
- Attention, Caffeine, Dose-Response Relationship, Drug, Humans, Sleep Deprivation
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
