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Logo of jcinvestThe Journal of Clinical Investigation
J Clin Invest. 1981 April; 67(4): 1111–1117.
PMCID: PMC370671

Tolerance to the humoral and hemodynamic effects of caffeine in man.


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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Selected References

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  • Beavo JA, Rogers NL, Crofford OB, Hardman JG, Sutherland EW, Newman EV. Effects of xanthine derivatives on lipolysis and on adenosine 3',5'-monophosphate phosphodiesterase activity. Mol Pharmacol. 1970 Nov;6(6):597–603. [PubMed]
  • Robertson D, Frölich JC, Carr RK, Watson JT, Hollifield JW, Shand DG, Oates JA. Effects of caffeine on plasma renin activity, catecholamines and blood pressure. N Engl J Med. 1978 Jan 26;298(4):181–186. [PubMed]
  • Robertson D, Johnson GA, Robertson RM, Nies AS, Shand DG, Oates JA. Comparative assessment of stimuli that release neuronal and adrenomedullary catecholamines in man. Circulation. 1979 Apr;59(4):637–643. [PubMed]
  • Carey RM, Douglas JG, Schweikert JR, Liddle GW. The syndrome of essential hypertension and suppressed plasma renin activity. Normalization of blood pressure with spironolactone. Arch Intern Med. 1972 Dec;130(6):849–854. [PubMed]
  • Passon PG, Peuler JD. A simplified radiometric assay for plasma norepinephrine and epinephrine. Anal Biochem. 1973 Feb;51(2):618–631. [PubMed]
  • Robertson D, Heath EC, Falkner FC, Hill RE, Brilis GM, Watson JT. A selective and sensitive assay for urinary metanephrine and normetanephrine using gas chromatography mass spectrometry with selected ion monitoring. Biomed Mass Spectrom. 1978 Dec;5(12):704–708. [PubMed]
  • Colton T, Gosselin RE, Smith RP. The tolerance of coffee drinkers to caffeine. Clin Pharmacol Ther. 1968 Jan-Feb;9(1):31–39. [PubMed]
  • Berkowitz BA, Spector S. Effect of caffeine and theophylline on peripheral catecholamines. Eur J Pharmacol. 1971 Jan;13(2):193–196. [PubMed]
  • Clutter WE, Bier DM, Shah SD, Cryer PE. Epinephrine plasma metabolic clearance rates and physiologic thresholds for metabolic and hemodynamic actions in man. J Clin Invest. 1980 Jul;66(1):94–101. [PMC free article] [PubMed]
  • FitzGerald GA, Hossmann V, Hamilton CA, Reid JL, Davies DS, Dollery CT. Interindividual variation in kinetics of infused epinephrine. Clin Pharmacol Ther. 1979 Dec;26(6):669–675. [PubMed]
  • Kalsner S. Mechanism of potentiation of contractor responses to catecholamines by methylxanthines in aortic strips. Br J Pharmacol. 1971 Oct;43(2):379–388. [PMC free article] [PubMed]
  • Snider SR, Waldeck B. Increased synthesis of adrenomedullary catecholamines induced by caffeine and theophylline. Naunyn Schmiedebergs Arch Pharmacol. 1974;281(2):257–260. [PubMed]
  • Berkowitz BA, Tarver JH, Spector S. Release of norepinephrine in the central nervous system by theophylline and caffeine. Eur J Pharmacol. 1970 Apr;10(1):64–71. [PubMed]
  • Bondaryóv MG. The influence of analeptic drugs on the pontine vasomotor center. Nurs Mirror Midwives J. 1967 Apr 28;124(4):171–186. [PubMed]
  • Somlyo AV, Somlyo AP. Electromechanical and pharmacomechanical coupling in vascular smooth muscle. J Pharmacol Exp Ther. 1968 Jan;159(1):129–145. [PubMed]
  • Goldstein A, Kaizer S. Psychotropic effects of caffeine in man. 3. A questionnaire survey of coffee drinking and its effects in a group of housewives. Clin Pharmacol Ther. 1969 Jul-Aug;10(4):477–488. [PubMed]
  • Goldstein A, Kaizer S, Whitby O. Psychotropic effects of caffeine in man. IV. Quantitative and qualitative differences associated with habituation to coffee. Clin Pharmacol Ther. 1969 Jul-Aug;10(4):489–497. [PubMed]
  • Jick H, Miettinen OS, Neff RK, Shapiro S, Heinonen OP, Slone D. Coffee and myocardial infarction. N Engl J Med. 1973 Jul 12;289(2):63–67. [PubMed]
  • Prineas RJ, Jacobs DR, Jr, Crow RS, Blackburn H. Coffee, tea and VPB. J Chronic Dis. 1980;33(2):67–72. [PubMed]
  • Bertrand CA, Pomper I, Hillman G, Duffy JC, Micheli I. No relation between coffee and blood pressure. N Engl J Med. 1978 Aug 10;299(6):315–316. [PubMed]
  • Dawber TR, Kannel WB, Gordon T. Coffee and cardiovascular disease. Observations from the framingham study. N Engl J Med. 1974 Oct 24;291(17):871–874. [PubMed]
  • Klatsky AL, Friedman GD, Siegelaub AB. Coffee drinking prior to acute myocardial infarction. Results from the Kaiser-Permanente Epidemiologic Study of Myocardial Infarction. JAMA. 1973 Oct 29;226(5):540–543. [PubMed]
  • Hennekens CH, Drolette ME, Jesse MJ, Davies JE, Hutchison GB. Coffee drinking and death due to coronary heart disease. N Engl J Med. 1976 Mar 18;294(12):633–636. [PubMed]

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