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.
“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]
The Introduction says chronic effects of caffeine have received considerably less study and that conclusions about them have largely been extrapolated from acute studies or epidemiological investigations. That supports a limited evidence base for chronic effects, but the paper does not establish that the cited opinions and advisories were based on a small collection of studies or discuss their publicity in scientific, lay, or media outlets. (LLM, conf=0.78)
Experimental — accuracy not yet measuredCaffeine acutely increases peripheral vascular resistance.
“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]
The Results report an acute rise in systolic blood pressure, and the Discussion says tolerance to that rise develops with continued caffeine use. The paper does not report an increase in peripheral vascular resistance; its Discussion instead says a direct effect on vascular resistance is unlikely to explain the pressor response (page not available in our copy). (LLM, conf=0.88)
Experimental — accuracy not yet measuredTolerance to caffeine's hemodynamic effects rapidly develops.
“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]
Caffeine acutely increases blood pressure.
“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]
Earlier studies claiming tolerance to pressor effects of caffeine did not mirror normal staggered caffeine consumption.
“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]
The effects of CAF on epinephrine are blunted within 1-4 d of ingestion.
“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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“These observations suggest two hypotheses: first, habitual coffee consumers may develop tolerance to caffeine, thus smoothing its effects on blood pressure (Ammon et al., 1983; Robertson et al., 1981); second, substances other than caffeine”
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“They kept to their normal dietary habits, although caffeine intake (coffee, tea, cola) was prohibited 1 week prior to and during the entire experiment to avoid caffeine tolerance (Robertson et al. 1981).”
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“Tolerance to the adenosine receptor-mediated effects of epinephrine release (1), FFA release (11), and increased blood pressure (25) have been observed.”
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“Of note, complete tolerance can develop after several days of caffeine use with respect to humoral and hemodynamic variables such as blood pressure, heart rate, plasma renin activity, plasma catecholamines, or urinary catecholamines ( 20 ,48).”
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“withdrawal from dietary caffeine over the critical 4-day period in which tolerance to caffeine and withdrawal symptoms are reported (27), and it is unique in the examination of the influence that prior caffeine use may have on epinephrine and ergogenic responses during high-intensity exercise.”
BackgroundInfluentialAdenosine actions and adenosine receptors after 1 week treatment with caffeine
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Coffee Consumption and the Risk of Coronary Heart Disease and Death
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Effects of caffeine on alertness
Zwyghuizen‐Doorenbos, A., Roehrs, T., Lipschutz, L., Timms, V., & Roth, T. G. (1990) · Psychopharmacology · doi:10.1007/bf02245786 · Cited by 173 · see citing works
“A previous objective study of the daytime effects of caffeine on human blood pressure and urinary catecholamine levels demonstrated nearly complete tolerance within 3 days of administering 250 mg caffeine thrice daily, with meals ( Robertson et al. 1981 ).”
BackgroundGreen tea catechins, caffeine and body-weight regulation
Westerterp‐Plantenga, M. S. (2010) · Physiology & Behavior · doi:10.1016/j.physbeh.2010.02.005 · Cited by 171 · see citing works
“[53,54] administrated 250 mgoral caffeine to nine subjects who were not used to coffee.”
Acute and long-term cardiovascular effects of coffee: Implications for coronary heart disease
Riksen, N. P., Rongen, G. A. P. J. M., & Smits, P. (2008) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2008.10.006 · Cited by 166 · see citing works
“have reported that the pressor response and the increase in (nor)epinephrine levels in response to the administration of 250 mg of caffeine in healthy subjects was no longer present after three days of daily caffeine administration (Robertson et al., 1981).”
BackgroundSympathomimetic effects of paraxanthine and caffeine in humans*
Benowitz, N. L., Jacob, P., Mayan, H., & Denaro, C. P. (1995) · Clinical Pharmacology & Therapeutics · doi:10.1016/0009-9236(95)90025-x · Cited by 166 · see citing works
Hemodynamic and Humoral Effects of Caffeine in Autonomic Failure
Onrot, J., Goldberg, M. R., Biaggioni, I., Hollister, A. S., Kincaid, D., & Robertson, D. M. (1985) · New England Journal of Medicine · doi:10.1056/nejm198508293130905 · Cited by 166 · see citing works
Self-citationAcute and chronic effects of caffeine on performance, mood, headache, and sleep
James, J. E. (1998) · Neuropsychobiology · doi:10.1159/000026514 · Cited by 157 · see citing works
The hemodynamic and neurohumoral phenotype of postural tachycardia syndrome
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“commonpractice in professional endurance type athletes (47), may elevate plasma caffeine concentration to values > 15 ,tg/ ml (48), which is similar to the concentration used in the pres-”
MethodCoffee consumption and risk of type 2 diabetes, cardiovascular diseases, and cancer
van Dam, R. M. (2008) · Applied Physiology, Nutrition, and Metabolism · doi:10.1139/h08-120 · Cited by 161 · see citing works
Pharmacological Rationale for the Clinical Use of Caffeine
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“[8-10) Following cessation of intake, a charac-”
Wu, T., Willett, W. C., Hankinson, S. E., & Giovannucci, E. L. (2005) · Diabetes Care · doi:10.2337/diacare.28.6.1390 · Cited by 157 · see citing works
“Although acute administration of caffeine induces insulin resistance (3,5,6), complete tolerance can develop after several days, as assessed by blood pressure, plasma renin activity, and plasma catecholamines (24,25).”
BackgroundCaffeine tolerance and choice in humans
Evans, S. M., & Griffiths, R. R. (1992) · Psychopharmacology · doi:10.1007/bf02245285 · Cited by 154 · see citing works
Caffeine, Body Fluid-Electrolyte Balance, and Exercise Performance
Armstrong, L. E. (2002) · International Journal of Sport Nutrition and Exercise Metabolism · doi:10.1123/ijsnem.12.2.189 · Cited by 153 · see citing works
Does This Patient Have Hypertension?
Reeves, R. A. (1995) · JAMA · doi:10.1001/jama.1995.03520390071036 · Cited by 153 · see citing works
Thermogenic ingredients and body weight regulation
Hursel, R., & Westerterp‐Plantenga, M. S. (2010) · International Journal of Obesity · doi:10.1038/ijo.2009.299 · Cited by 152 · see citing works
“71 However, in a subsequent study that examined the chronic effects of caffeine ingestion (150 mg da−1 for 7 days), tolerance to these effects was developed after 1–4 days”
BackgroundCaffeine and Endurance Performance
Tarnopolsky, M. A. (1994) · Sports Medicine · doi:10.2165/00007256-199418020-00004 · Cited by 151 · see citing works
Vestal, R. E., Eiriksson, C. E., Musser, B., Ozaki, L., & Halter, J. B. (1983) · Circulation · doi:10.1161/01.cir.67.1.162 · Cited by 151 · see citing works
Chronic caffeine consumption increases the number of brain adenosine receptors
Boulenger, J., Patel, J. B., Post, R. M., Parma, A. M., & Marangos, P. J. (1983) · Life Sciences · doi:10.1016/0024-3205(83)90119-4 · Cited by 150 · see citing works
Should caffeine abuse, dependence, or withdrawal be added to DSM-IV and ICD-10?
Hughes, J. R., Oliveto, A. H., Helzer, J. E., Higgins, S. T., & Bickel, W. K. (1992) · American Journal of Psychiatry · doi:10.1176/ajp.149.1.33 · Cited by 148 · see citing works
Johansson, B., Ahlberg, S., van der Ploeg, I., Brené, S., Lindefors, N., Persson, H., & Fredholm, B. B. (1993) · Naunyn-Schmiedeberg's Archives of Pharmacology · doi:10.1007/bf00165391 · Cited by 144 · see citing works
Lane, J. D., Adcock, R. A., Williams, R. B., & Kuhn, C. M. (1990) · Psychosomatic Medicine · doi:10.1097/00006842-199005000-00006 · Cited by 145 · see citing works
“The most frequently cited studies (11, 12) do offer evidence that the effects of an acute caffeine dose on resting levels of blood pressure, catecholamines, and plasma renin activity may disappear after several days of chronic administration of high caffeine doses (750 mg/day).”
BackgroundThe effect of caffeinated, non-caffeinated, caloric and non-caloric beverages on hydration
Grandjean, A. C., Reimers, K. J., Bannick, K. E., & Haven, M. C. (2000) · Journal of the American College of Nutrition · doi:10.1080/07315724.2000.10718956 · Cited by 140 · see citing works
“Additionally, caffeine tolerance develops after habitual consumption [18,28,29], and individual response is highly variable [20,25].”
BackgroundTilting Plant Metabolism for Improved Metabolite Biosynthesis and Enhanced Human Benefit
Ncube, B., & Staden, J. V. (2015) · Molecules · doi:10.3390/molecules200712698 · Cited by 148 · see citing works
“Xanthines also produce numerous physiological effects that include positive inotropic and chronotropic effects on the heart, decreased airway resistance in the lung, and respiratory stimulation [44,69].”
BackgroundCardiovascular Manifestations of Substance Abuse
Frishman, W. H., Vecchio, A. D., Sanal, S., & Ismail, A. (2003) · Heart Disease · doi:10.1097/01.hdx.0000080713.09303.a6 · Cited by 139 · see citing works
Battram, D. S., Arthur, R., Weekes, A., & Graham, T. E. (2006) · The Journal of Nutrition · doi:10.1093/jn/136.5.1276 · Cited by 135 · see citing works
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“All protocols were separated by at least 4 days to allow for resensitization of each individual to the physiological effects of caffeine (13, 28).”
BackgroundRieg, T., Steigele, H., Schnermann, J., Richter, K., Osswald, H., & Vallon, V. (2005) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.104.080432 · Cited by 133 · see citing works
“Both effects could be blocked with theophylline (Robertson et al., 1981; Fredholm, 1984).”
BackgroundInfluence of caffeine on information processing stages in well rested and fatigued subjects
Lorist, M. M., Snel, J., & Kok, A. (1994) · Psychopharmacology · doi:10.1007/bf02245217 · Cited by 133 · see citing works
Caffeine in the management of patients with headache
Lipton, R. B., Diener, H., Robbins, M. S., Garas, S. Y., & Patel, K. (2017) · The Journal of Headache and Pain · doi:10.1186/s10194-017-0806-2 · Cited by 134 · see citing works
Caffeine increases endurance and attenuates force sensation during submaximal isometric contractions
Plaskett, C., & CAFARELLI, E. (2001) · Journal of Applied Physiology · doi:10.1152/jappl.2001.91.4.1535 · Cited by 131 · see citing works
Caffeine and creatine use in sport
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“oral contraceptive use, and other drugs can alter metabolism and excretion of metabolites. The habitual consumption of caffeine also influences metabolism by downregulating many of the physiological effects (tachyphylaxis). For example, several days of habitual caffeine consumption attenuated acute ingestion-induced r…”
BackgroundConney, A. H. (2003) · PubMed · Cited by 131 · see citing works
Effects of chronic caffeine on brain adenosine receptors: Regional and ontogenetic studies
Marangos, P. J., Boulenger, J., & Patel, J. B. (1984) · Life Sciences · doi:10.1016/0024-3205(84)90207-8 · Cited by 128 · see citing works
Effects of the acute administration of caffeine in patients with schizophrenia
Lucas, P. B., Pickar, D., Kelsoe, J., Rapaport, M., Pato, C., & Hommer, D. (1990) · Biological Psychiatry · doi:10.1016/0006-3223(90)90429-6 · Cited by 125 · see citing works
Wake up and smell the coffee. Caffeine, coffee, and the medical consequences.
Chou, T. M. (1992) · PubMed Central · Cited by 124 · see citing works
Metabolically active functional food ingredients for weight control
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“The lack of long-term effect of caffeine alone on body weight may be attributed to development of tolerance to its thermogenic effect, as has been shown for cardiovascular effects (114,140).”
BackgroundEffect of caffeine ingestion on perception of effort and subsequent work production.
Cole, K. J., Costill, D., Starling, R., Goodpaster, B., Trappe, S., & Fink, W. (1996) · International Journal of Sport Nutrition · doi:10.1123/ijsn.6.1.14 · Cited by 131 · see citing works
Caffeine and exercise: metabolism and performance.
Graham, T. E., Rush, J. W. E., & Soeren, M. H. V. (1994) · Canadian Journal of Applied Physiology · doi:10.1139/h94-010 · Cited by 123 · see citing works
“Of particular interest is the dampening of the catecholamine response following chronic caffeine use (Robertson et al., 1981).”
BackgroundCoffee Drinking Is Dose-Dependently Related to the Risk of Acute Coronary Events in Middle-Aged Men
Happonen, P., Voutilainen, S., & Salonen, J. T. (2004) · The Journal of Nutrition · doi:10.1093/jn/134.9.2381 · Cited by 120 · see citing works
Magkos, F., & Kavouras, S. A. (2004) · Sports Medicine · doi:10.2165/00007256-200434130-00002 · Cited by 116 · see citing works
Caffeine Affects Cardiovascular and Neuroendocrine Activation at Work and Home
Lane, J. D., Pieper, C. F., Phillips-Bute, B. G., Bryant, J. E., & Kuhn, C. M. (2002) · Psychosomatic Medicine · doi:10.1097/01.psy.0000021946.90613.db · Cited by 118 · see citing works
“Several studies have suggested that caffeine pressor effects disappear after a few days (46, 47).”
BackgroundHabitual coffee consumption and blood pressure: An epidemiological perspective
Geleijnse, J. M. (2008) · Vascular Health and Risk Management · doi:10.2147/vhrm.s3055 · Cited by 117 · see citing works
“From experimental research it has become clear the caffeine administration acutely raises BP, but tolerance to this effect develops rapidly and heavy coffee drinkers are less likely to show a BP response after caffeine intake (Robertson et al 1981; Ammon et al 1983; Myers 1988).”
Circulatory effects of coffee in relation to the pharmacokinetics of caffeine
Smits, P., Thien, T. A., & Laar, A. V. (1985) · The American Journal of Cardiology · doi:10.1016/0002-9149(85)90412-6 · Cited by 117 · see citing works
Karatzis, E., Papaioannou, T. G., Aznaouridis, K., Karatzi, K., Stamatelopoulos, K., Zampelas, A., Papamichael, C., Lekakis, J., & Mavrikakis, M. (2005) · International Journal of Cardiology · doi:10.1016/j.ijcard.2003.11.013 · Cited by 116 · see citing works
Does caffeine alter muscle carbohydrate and fat metabolism during exercise?
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“There are a number of reports that caffeine increases circulating levels of epinephrine (Robertson et al. 1981; Van Soeren et al. 1993; Arciero et al. 1995; Graham and Spriet 1995), and Graham et al.”
BackgroundNon-Drug Treatment of Hypertension
Kaplan, N. M. (1985) · Annals of Internal Medicine · doi:10.7326/0003-4819-102-3-359 · Cited by 114 · see citing works
Pathophysiology, Diagnosis, and Treatment of Orthostatic Hypotension and Vasovagal Syncope
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“It is suggested that patients avoid consuming caffeine with dinner, as this is when tolerance to its effects is most likely.(23,113) In a study by Dewey et al using caffeine, it was shown that a few patients with Parkinsonism and OH showed improvements in SBP and symptoms of syncope.”
BackgroundRR‐variation: The autonomic test of choice in diabetes
Genovely, H., & Pfeifer, M. A. (1988) · Diabetes/Metabolism Reviews · doi:10.1002/dmr.5610040305 · Cited by 110 · see citing works
Renal and cardiovascular effects of caffeine: a dose-response study
Passmore, A. P., Kondowe, G. B., & Johnston, G. D. (1987) · Clinical Science · doi:10.1042/cs0720749 · Cited by 107 · see citing works
- 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 › 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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