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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
Effects of Caffeine on Plasma Renin Activity, Catecholamines and Blood Pressure
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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
“The tolerance to cardiovascular effects of caffeine is paralleled by a decrease in caffeine-induced increase in plasma adrenaline, noradrenaline, and renin levels (Robertson et al., 1981).”
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Caffeinated energy drinks a growing problem
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A Review of Caffeine’s Effects on Cognitive, Physical and Occupational Performance
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Coffee Consumption and Risk of Type 2 Diabetes: A Systematic Review
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Adenosine, Adenosine Receptors and the Actions of Caffeine
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“Urinary epinephrine and norepinephrine Of two studies that assessed urinary epinephrine and norepinephrine (Robertson et al. 1981; Lane 1994; cf. Tables 1, 2), one showed decreased levels of epinephrine during caffeine abstinence relative to a caffeine condition (Lane 1994).”
van Dam, R. M., Hu, F. B., & Willett, W. C. (2020) · New England Journal of Medicine · doi:10.1056/nejmra1816604 · Cited by 508
Coffee consumption and risk for type 2 diabetes mellitus
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“Because of these complex physiologic effects of caffeine and because tolerance to the humoral and hemodynamic effects of caffeine typically develops with long-term use (12), it is difficult to extrapolate findings from short-term metabolic studies to longterm use of coffee and other caffeinated beverages.”
BackgroundIso, H., Date, C., Wakai, K., Fukui, M., Tamakoshi, A., & and the JACC Study Group* (2006) · Annals of Internal Medicine · doi:10.7326/0003-4819-144-8-200604180-00005 · Cited by 462
“The acute effect of decreased insulin sensitivity induced by caffeine (17) is known to be tolerated after several days of caffeine use (18).”
BackgroundAre we dependent upon coffee and caffeine? A review on human and animal data
Nehlig, A. (1999) · Neuroscience & Biobehavioral Reviews · doi:10.1016/s0149-7634(98)00050-5 · Cited by 453
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Energy Beverages: Content and Safety
Higgins, J. P., Tuttle, T. D., & Higgins, C. L. (2010) · Mayo Clinic Proceedings · doi:10.4065/mcp.2010.0381 · Cited by 429
“The human body develops a tolerance to caffeine quickly, usually 3 to 5 days after regular use, and when this happens, it noticeably weakens the already limited diuretic effect of caffeine.(26,27) Moreover, the human kidneys are masters at ensuring that proper homeostatic conditions are maintained.”
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“Habitual use of caffeine has been reported to lead to haemodynamic tolerance after 1–4 days [34] and we therefore excluded from our meta-analysis studies of duration less than 1 week.”
Clinically Significant Pharmacokinetic Interactions Between Dietary Caffeine and Medications
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“[3,21,22] Caffeine physical-dependence and withdrawal symptoms after the end of drug use have been documented in numerous case reports and experimental studies.”
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Keijzers, G. B., De Galan, B. E., Tack, C. J., & Smits, P. (2002) · Diabetes Care · doi:10.2337/diacare.25.2.364 · Cited by 358
“Chronic use of caffeine (and related methylxanthine derivatives) is known to result in attenuation of both humoral and pressor effects that are associated with acute ingestion (37), perhaps due to upregulation of adenosine receptors (38).”
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“The acute effects of coffee are transient and, with regular intake, tolerance develops to the hemodynamic and humoral effects of caffeine (6).”
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“In some studies, however, no signi®cant effect of acute caffeine intake on plasma renin activity was observed (Passmore et al, 1987; Nussberger et al, 1990), or else the increase was attenuated after chronic administration of caffeine (Robertson et al, 1981, 1984; Eggertsen et al, 1993).”
BackgroundMethodInfluentialCaffeine Use in Sports, Pharmacokinetics in Man, and Cellular Mechanisms of Action
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“However, in a subsequent study that examined the chronic effects of caffeine ingestion (150 mg/day for 7 days), tolerance to these effects was developed after 1–4 days (97).”
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“This is likely due to clearing of caffeine from the system as there is an inverse relationship with the level of plasma caffeine and the response to caffeine administration (Robertson et al., 1981).”
Astrup, A., Toubro, S., Cannon, S., Hein, P., Breum, L., & Madsen, J. (1990) · The American Journal of Clinical Nutrition · doi:10.1093/ajcn/51.5.759 · Cited by 309
Genetics of caffeine consumption and responses to caffeine
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“(Evans and Griffiths 1992; Robertson et al. 1981), such that the effects of caffeine in habitual consumers are quite different from caffeine-naïve individuals.”
The clinical toxicology of caffeine: A review and case study
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Caffeine physical dependence: a review of human and laboratory animal studies
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Coffee, Caffeine, and Risk of Type 2 Diabetes
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“However, whether this effect pertains to long-term coffee consumption is unclear because other components of coffee may modify this effect and because tolerance may develop (23).”
BackgroundThe Health Consequences of Caffeine
Curatolo, P. W., & ROBERTSON, D. (1983) · Annals of Internal Medicine · doi:10.7326/0003-4819-98-5-641 · Cited by 269
Self-citationCoffee, diabetes, and weight control
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Immunomodulatory effects of caffeine: Friend or foe?
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Effects of caffeine on performance and mood: withdrawal reversal is the most plausible explanation
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Caffeine and cardiovascular health
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The effect of daily caffeine use on cerebral blood flow: How much caffeine can we tolerate?
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Godos, J., Pluchinotta, F. R., Marventano, S., Buscemi, S., Li Volti, G., Galvano, F., & Grosso, G. (2014) · International Journal of Food Sciences and Nutrition · doi:10.3109/09637486.2014.940287 · Cited by 210
“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”
Benefits of Caffeine Ingestion on Sprint Performance in Trained and Untrained Swimmers
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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.”
BackgroundCoffee consumption and risk of incident gout in men: A prospective study
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Cardiovascular effects of coffee and caffeine
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“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
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“[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
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“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*
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Hemodynamic and Humoral Effects of Caffeine in Autonomic Failure
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Self-citationAcute and chronic effects of caffeine on performance, mood, headache, and sleep
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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
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Pharmacological Rationale for the Clinical Use of Caffeine
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“[8-10) Following cessation of intake, a charac-”
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“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
Caffeine, Body Fluid-Electrolyte Balance, and Exercise Performance
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Does This Patient Have Hypertension?
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Thermogenic ingredients and body weight regulation
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“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”
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Tarnopolsky, M. A. (1994) · Sports Medicine · doi:10.2165/00007256-199418020-00004 · Cited by 150
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Chronic caffeine consumption increases the number of brain adenosine receptors
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Should caffeine abuse, dependence, or withdrawal be added to DSM-IV and ICD-10?
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“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).”
BackgroundJohansson, 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
The effect of caffeinated, non-caffeinated, caloric and non-caloric beverages on hydration
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“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
“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
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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
“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
Caffeine in the management of patients with headache
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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
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 130
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
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
Wake up and smell the coffee. Caffeine, coffee, and the medical consequences.
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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.
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Caffeine and exercise: metabolism and performance.
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“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
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Caffeine Affects Cardiovascular and Neuroendocrine Activation at Work and Home
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“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
“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
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
Does caffeine alter muscle carbohydrate and fat metabolism during exercise?
Graham, T. E., Battram, D. S., Dela, F., El‐Sohemy, A., & Thong, F. S. L. (2008) · Applied Physiology, Nutrition, and Metabolism · doi:10.1139/h08-129 · Cited by 112
“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
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 109
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
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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