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Tolerance to the humoral and hemodynamic effects of caffeine in man.
Open accessAbstract
Acute caffeine in subjects who do not normally ingest methylxanthines leads to increases in blood pressure, heart rate, plasma epinephrine, plasma norepinephrine, plasma renin activity, and urinary catecholamines. Using a double-blind design, the effects of chronic caffeine administration on these same variables were assessed. Near complete tolerance, in terms of both humoral and hemodynamic variables, developed over the first 1-4 d of caffeine. No long-term effects of caffeine on blood pressure, heart rate, plasma renin activity, plasma catecholamines, or urinary catecholamines could be demonstrated. Discontinuation of caffeine ingestion after 7 d of administration did not result in a detectable withdrawal phenomenon relating to any of the variables assessed.
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“These opinions and advisories are based upon a relatively small collection of caffeine studies that have been publicised in both scientific and lay literature and in the media over the past few decades [10], [17], [25].”
From No Evidence of Dehydration with Moderate Daily Coffee Intake: A Counterbalanced Cross-Over Study in a Free-Living Population (2014) · cites this paper as [25]
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“In short-term studies, it has been shown to increase blood pressure and peripheral vascular resistance, but tolerance rapidly develops. 4”
From Acute Effect of Caffeine on Arterial Stiffness and Aortic Pressure Waveform (2001) · cites this paper as [4]
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“In short-term studies, it has been shown to increase blood pressure and peripheral vascular resistance, but tolerance rapidly develops. 4”
From Acute Effect of Caffeine on Arterial Stiffness and Aortic Pressure Waveform (2001) · cites this paper as [4]
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“In short-term studies, it has been shown to increase blood pressure and peripheral vascular resistance, but tolerance rapidly develops. 4”
From Acute Effect of Caffeine on Arterial Stiffness and Aortic Pressure Waveform (2001) · cites this paper as [4]
In the citing paper
“Earlier studies which claimed to show tolerance to the pressor effects of caffeine [11,[16][17][18] have not mirrored 'normal' staggered caffeine consumption but are characterized by a prior period of prolonged abstinence followed by a high dose of caffeine administered once or twice daily.”
From Central and peripheral effects of sustained caffeine use: tolerance is incomplete (2002) · cites this paper as [11]
In the citing paper
“the effects of CAF on epinephrine are blunted within 1-4 d (36) of ingestion”
From The Glucose Intolerance Induced by Caffeinated Coffee Ingestion Is Less Pronounced than That Due to Alkaloid Caffeine in Men (2006) · cites this paper as [36]
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Citations
Cites
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BackgroundAge and prior caffeine use alter the cardiovascular and adrenomedullary responses to oral caffeine
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Is habitual caffeine use a preventable cardiovascular risk factor?
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“These results indicate that the effects of caffeine on the immune system may be subject to the development of tolerance, just as tolerance to caffeine develops in the CNS (1, 35, 36).”
BackgroundEffects of Coffee on Ambulatory Blood Pressure in Older Men and Women
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“Although the lack of a dose effect is evidence against a causal association and could indicate bias, persons who regularly consume caffeine develop a tolerance to the effects of caffeine within certain levels of consumption (Robertson et al., 1981; Evans and Griffith, 1992; Shi et al., 1993), which could have minimize…”
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Hydration: Issues for the 21st Century
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“In particular, the results on caffeine are difficult to interpret, as chronic caffeine intake leads to metabolic adaptation((250)) which makes it difficult to compare an outcome of short term controlled trials with that of long term epidemiological cohort or cross-sectional investigations.”
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“In addition, because previous research has generally shown that caffeine tolerance plateaus (Denaro et al., 1991; Robertson et al., 1981) and withdrawal effects abate (Griffiths et al., 1986; Hughes et al, 1993) within 3– 5 days of continuous use, the present study employed 7 consecutive days of…”
MethodAcute blood pressure elevations with caffeine in men with borderline systemic hypertension
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“These opinions and advisories are based upon a relatively small collection of caffeine studies that have been publicised in both scientific and lay literature and in the media over the past few decades [10,17,25].”
BackgroundIs Caffeine Addictive?—A Review of the Literature
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“Silverman and coworkers recruited sixty-two adults through ads promoting a study of the effect of foods—including caffeine—on behavior and mood (23).”
BackgroundBehavioral Effects of Caffeine
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Acute effects of caffeine ingestion at rest in humans with impaired epinephrine responses
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“However, tolerance to caffeine-induced increases in blood pressure (Robertson et al. 1981; Ammon et al. 1983) and plasma catecholamines (Robertson et al. 1981) has been reported in healthy volunteer subjects, and discontinuation of caffeine consumption caused no detectable withdrawal phenomena on a variety of humoral…”
BackgroundInfluentialCoffee Consumption and Risk of Cardiovascular Events After Acute Myocardial Infarction
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“Second, the acute effects of caffeine could be transient because partial tolerance to the humoral and hemodynamic effects of caffeine among habitual drinkers might develop after several days of use (14).”
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“This finding is somewhat surprising because tolerance to the cardiovascular effects of orally administered caffeine has been demonstrated at doses both lower and higher than the 600 mg/70 kg per day caffeine maintenance dose used in the present study (Robertson et al. 1981; Ammon et al. 1983; Denaro et al. 1991).”
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Caffeine abstention in the management of anxiety disorders
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EB/RP gene family encodes tubulin binding proteins
Juwana, J.-P., Henderikx, P., Mischo, A., Wadle, A., Fadle, N., Gerlach, K. L., Arends, J. W., Hoogenboom, H. R., Pfreundschuh, M. G., & Renner, C. (1999) · International Journal of Cancer · doi:10.1002/(sici)1097-0215(19990412)81:2 · Cited by 84
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Effects of caffeine on human aggressive behavior
Cherek, D. R., Steinberg, J. L., & Brauchi, J. T. (1983) · Psychiatry Research · doi:10.1016/0165-1781(83)90101-4 · Cited by 59
Additive Pressor Effects of Caffeine and Stress in Male Medical Students at Risk for Hypertension
Shepard, J. D., Al’Absi, M., Whitsett, T. L., Passey, R. B., & Lovallo, W. R. (2000) · American Journal of Hypertension · doi:10.1016/s0895-7061(99)00217-4 · Cited by 58
“Earlier studies of tolerance averaged BP over periods of time as long as 12 h after a single dose of caffeine.(46,47) Because serum levels of caffeine peak about 1 h after consumption, averaging BP over such a long period reduces the likelihood of observing acute pressor effects.”
BackgroundShearer, J., & Graham, T. E. (2014) · Nutrition Reviews · doi:10.1111/nure.12124 · Cited by 64
Tunnicliffe, J. M., Erdman, K. A., Reimer, R. A., Lun, V. M. Y., & Shearer, J. (2008) · Applied Physiology, Nutrition, and Metabolism · doi:10.1139/h08-124 · Cited by 61
“Near complete tolerance to hemodynamic and selected endocrine responses can be observed within 24–96 h of caffeine exposure (Robertson et al. 1981).”
BackgroundTheophylline Improves Hypoglycemia Unawareness in Type 1 Diabetes
de Galan, B. E., Tack, C. J., Lenders, J. W. M., Pasman, J. W., Elving, L. D., Rüssel, F. G. M., Lutterman, J. A., & Smits, P. (2002) · Diabetes · doi:10.2337/diabetes.51.3.790 · Cited by 57
“Long-term use of theophylline (and related methylxanthine derivatives) is subject to the emergence of tolerance for many of its effects (31).”
BackgroundAnxiety and caffeine consumption in people with anxiety disorders
Lee, M. A., Cameron, O. G., & Greden, J. F. (1985) · Psychiatry Research · doi:10.1016/0165-1781(85)90078-2 · Cited by 58
“0165-1781/85/$03.30 0 1985 Elsevier Science Publishers B.V. increase plasma and urinary catecholamines (Robertson et al., 1981).”
BackgroundInfluentialThe Effect of Caffeine on Cardiac Rate, Rhythm, and Ventricular Repolarization
Sutherland, D. J., McPherson, D. D., Renton, K. W., Spencer, C., & Montague, T. J. (1985) · CHEST Journal · doi:10.1378/chest.87.3.319 · Cited by 57
Hemodynamic effects of dietary caffeine, sleep restriction, and laboratory stress
James, J. E., & Gregg, M. E. (2004) · Psychophysiology · doi:10.1111/j.1469-8986.2004.00248.x · Cited by 56
Relation between coffee drinking and blood pressure: Analysis of 6,321 subjects in the Paris region
Lang, T., Patrice Degoulet, A., Aimé, F., Fouriaud, C., Jacquinet-Salord, M. C., Laprugne, J., Main, J., Oeconomos, J., Phalente, J., & Prades, A. (1983) · The American Journal of Cardiology · doi:10.1016/0002-9149(83)90580-5 · Cited by 55
Nirengi, S., Amagasa, S., Homma, T., Yoneshiro, T., Matsumiya, S., Kurosawa, Y., Sakane, N., Ebi, K., Saito, M., & Hamaoka, T. (2016) · SpringerPlus · doi:10.1186/s40064-016-3029-0 · Cited by 56
Effect of chronic caffeine intake on choice reaction time, mood, and visual vigilance
Judelson, D. A., Armstrong, L. E., Sökmen, B., Roti, M. W., Casa, D. J., & Kellogg, M. D. (2005) · Physiology & Behavior · doi:10.1016/j.physbeh.2005.06.011 · Cited by 55
“Although the physiological tolerance to caffeine has been well-demonstrated [13,14], the extent to which psychomotor tolerance develops is unclear [15–18,29,35].”
BackgroundMethodResultInfluentialZhang, Y., Lee, E. T., Cowan, L. D., Fabsitz, R. R., & Howard, B. V. (2010) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2009.10.020 · Cited by 55
“Caffeine has also been related to acute decrease of insulin sensitivity [34], although prolonged use of caffeine may result in tolerance for such acute effect [35,36].”
Caffeine and cigarette smoking: behavioral, cardiovascular, and metabolic interactions
Brown, C. R., & Benowitz, N. L. (1989) · Pharmacology Biochemistry and Behavior · doi:10.1016/0091-3057(89)90559-5 · Cited by 53
Chronic Effects of Habitual Caffeine Consumption on Laboratory and Ambulatory Blood Pressure Levels
James, J. E. (1994) · European Journal of Cardiovascular Prevention & Rehabilitation · doi:10.1177/174182679400100210 · Cited by 53
Caffeine ingestion and isokinetic strength.
Bond, V., Gresham, K., McRae, J., & Tearney, R. J. (1986) · British Journal of Sports Medicine · doi:10.1136/bjsm.20.3.135 · Cited by 53
Light to moderate coffee consumption is associated with lower risk of death: a UK Biobank study
Simon, J., Fung, K., Raisi‐Estabragh, Z., Aung, N., Khanji, M. Y., Kolossváry, M., Merkely, B. P., Munroe, P. B., Harvey, N. C., Piechnik, S. K., et al. (2022) · European Journal of Preventive Cardiology · doi:10.1093/eurjpc/zwac008 · Cited by 54
Methylxanthines and Human Health: Epidemiological and Experimental Evidence
Beaudoin, M., & Graham, T. E. (2010) · Handbook of experimental pharmacology · doi:10.1007/978-3-642-13443-2_21 · Cited by 54
Caffeine: a toxicological overview
Abbott, P. J. (1986) · The Medical Journal of Australia · doi:10.5694/j.1326-5377.1986.tb139455.x · Cited by 53
Happonen, P., Voutilainen, S., Tuomainen, T., & Salonen, J. T. (2006) · PLoS ONE · doi:10.1371/journal.pone.0000117 · Cited by 52
“Tolerance to these acute humoral effects may develop in the course of one to four days of habitual consumption [11], but is not complete [12] and may be lost after abstinence for as little as 12 hours [13,14].”
BackgroundHigh-Dose Caffeine and Cardiac Rate and Rhythm in Normal Subjects
Newcombe, P. F., Renton, K. W., Rautaharju, P. M., Spencer, C., Bower, J. S., & Montague, T. J. (1988) · CHEST Journal · doi:10.1378/chest.94.1.90 · Cited by 52
Cardiovascular Pharmacology of the A2A Adenosine Receptor Antagonist, SCH 58261, in the Rat
Monopoli, A., Casati, C., Lozza, G., Forlani, A., & Ongini, E. (1998) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)37372-0 · Cited by 52
“Because tolerance to the cardiovascular effects of caffeine develops rapidly (Robertson et al., 1981), it would be interesting to investigate whether the effects of SCH 58261 alone undergo tolerance after a repeated-dose regimen.”
BackgroundAutonomic nervous system effects of acute doses of caffeine in caffeine users and abstainers
Zahn, T. P., & Rapoport, J. L. (1987) · International Journal of Psychophysiology · doi:10.1016/0167-8760(87)90070-5 · Cited by 52
“Tolerance may develop with habitual use (Jung et al.. 1981: Robertson et al., 1981).”
Background
Metadata
- Authors
- Robertson, D., Wade, D., Workman, R., Woosley, R. L., & Oates, J. A.
- Affiliations
- Vanderbilt University (US)
- Venue
- Journal of Clinical Investigation
- Published
- 1981-04-01
- Volume
- 67
- Issue
- 4
- Pages
- 1111-1117
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC370671
- OpenAlex
- W1970693682
- Cited by
- 501
- References
- 35
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 4 · 2023: 6 · 2022: 5 · 2021: 5 · 2020: 10 · 2019: 9 · 2018: 15 · 2017: 9 · 2016: 13 · 2015: 5 · 2014: 16 · 2013: 16 · 2012: 9
- FWCI
- 9.10
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Coffee research and impacts
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Keywords
- caffeine, tolerance (pharmacology and immunology), blood pressure, heart rate, plasma epinephrine, plasma norepinephrine, plasma renin activity, urinary catecholamines, methylxanthines, caffeine withdrawal, hemodynamic effects
- MeSH terms
- Adult, Blood Pressure, Caffeine, Catecholamines, Double-Blind Method, Drug Tolerance, Female, Hemodynamics, Humans, Male, Middle Aged, Renin
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