Caffeine: cognitive and physical performance enhancer or psychoactive drug?

Simone Cappelletti, Daria Piacentino, Gabriele Sani, Mariarosaria Aromatario, Simone Cappelletti, Daria Piacentino, Gabriele Sani, Mariarosaria Aromatario

Abstract

Caffeine use is increasing worldwide. The underlying motivations are mainly concentration and memory enhancement and physical performance improvement. Coffee and caffeine-containing products affect the cardiovascular system, with their positive inotropic and chronotropic effects, and the central nervous system, with their locomotor activity stimulation and anxiogenic-like effects. Thus, it is of interest to examine whether these effects could be detrimental for health. Furthermore, caffeine abuse and dependence are becoming more and more common and can lead to caffeine intoxication, which puts individuals at risk for premature and unnatural death. The present review summarizes the main findings concerning caffeine's mechanisms of action (focusing on adenosine antagonism, intracellular calcium mobilization, and phosphodiesterases inhibition), use, abuse, dependence, intoxication, and lethal effects. It also suggests that the concepts of toxic and lethal doses are relative, since doses below the toxic and/or lethal range may play a causal role in intoxication or death. This could be due to caffeine's interaction with other substances or to the individuals' preexisting metabolism alterations or diseases.

Keywords: Abuse; caffeine; coffee; dependence; energy drinks; safety doses; toxicity.

References

    1. Lee R.A., Balick M.J. Rx: Caffeine. Explore (NY), 2006;2(1):55–59. doi: 10.1016/j.explore.2005.10.012.
    1. Weinberg B.A., Bealer B. The World of Caffeine: The Science and Culture of the World's Most Popular Drug. New York: Routledge; 2001. pp. 1–41.
    1. Porciúncula LO, Sallaberry C, Mioranzza S, Botton PH Rosemberg DB. The Janus face of caffeine. Neurochem. Int. 2013;63(6):594–609.
    1. Eskelinen M.H., Ngandu T., Tuomilehto J., Soininen H., Kivipelto M. Midlife coffee and tea drinking and the risk of late-life dementia: a population-based CAIDE study. J. Alzheimers Dis. 2009;16(1):85–91. doi: 10.3233/JAD-2009-0920.
    1. Espinosa J., Rocha A., Nunes F., Costa M.S., Schein V., Kazlauckas V., Kalinine E., Souza D.O., Cunha R.A., Porciúncula L.O. Caffeine consumption prevents memory impairment, neuronal damage, and adenosine A2A receptors upregulation in the hippocampus of a rat model of sporadic dementia. J. Alzheimers Dis. 2013;34(2):509–518. doi: 10.3233/JAD-111982.
    1. Dall'Igna OP, Fett P, Gomes MW, Souza DO, Cunha RA, Lara DR. Caffeine and adenosine A(2a) receptor antagonists prevent beta-amyloid (25-35)-induced cognitive deficits in mice. Exp. Neurol. 2007;203:241–245.
    1. Cunha R.A., Agostinho P.M. Chronic caffeine consumption prevents memory disturbance in different animal models of memory decline. J. Alzheimers Dis. 2010;20(Suppl. 1):S95–S116. doi: 10.3233/JAD-2010-1408.
    1. Einöther S.J., Giesbrecht T. Caffeine as an attention enhancer: reviewing existing assumptions. Psychopharmacology (Berl.) 2013;225(2):251–274. doi: 10.1007/s00213-012-2917-4.
    1. Rogers P.J., Heatherley S.V., Mullings E.L., Smith J.E. Faster but not smarter: effects of caffeine and caffeine withdrawal on alertness and performance. Psychopharmacology (Berl.) 2013;226(2):229–240. doi: 10.1007/s00213-012-2889-4.
    1. Griffiths R.R., Mumford G.K. Caffeine reinforcement, discrimination, tolerance, and physical dependence in laboratory animals and humans. In: Schuster C.R., Kuhar M.J., editors. In: Handbook of Experimental Pharmacology. Heidelberg: Springer-Verlag; 1996. pp. 315–341. (Handbook of Experimental Pharmacology).
    1. Postuma R.B., Lang A.E., Munhoz R.P., Charland K., Pelletier A., Moscovich M., Filla L., Zanatta D., Rios Romenets S., Altman R., Chuang R., Shah B. Caffeine for treatment of Parkinson disease: a randomized controlled trial. Neurology. 2012;79(7):651–658. doi: 10.1212/WNL.0b013e318263570d.
    1. Chen X., Lan X., Roche I., Liu R., Geiger J.D. Caffeine protects against MPTP-induced blood-brain barrier dysfunction in mouse striatum. J. Neurochem. 2008;107(4):1147–1157.
    1. Chen J.F., Xu K., Petzer J.P., Staal R., Xu Y.H., Beilstein M., Sonsalla P.K., Castagnoli K., Castagnoli N., Jr, Schwarzschild M.A. Neuroprotection by caffeine and A(2A) adenosine receptor inactivation in a model of Parkinson’s disease. J. Neurosci. 2001;21(10):RC143.
    1. Another Reason to Have a Second Cup of Coffee?. Available at: A. [ccessed July 20, 2014.].
    1. Tavani A., La Vecchia C. Coffee, decaffeinated coffee, tea and cancer of the colon and rectum: a review of epidemiological studies, 1990-2003. Cancer Causes Control. 2004;15(8):743–757. doi: 10.1023/B:CACO.0000043415.28319.c1.
    1. Green Tea. Available at: [Accessed July 20, 2014].
    1. Arnaud M.J. Metabolism of caffeine and other components of coffee. In: Garattini S., editor. Caffeine, coffee and health. New York: Raven Press; 1993. pp. 43–95.
    1. Fredholm B.B., Bättig K., Holmén J., Nehlig A., Zvartau E.E. Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol. Rev. 1999;51(1):83–133.
    1. Weathersbee P.S., Lodge J.R. Caffeine: its direct and indirect influence on reproduction. J. Reprod. Med. 1977;19(2):55–63.
    1. Fenster L., Quale C., Hiatt R.A., Wilson M., Windham G.C., Benowitz N.L. Rate of caffeine metabolism and risk of spontaneous abortion . Am. J. Epidemiol. 1998;147(5):503–510. doi: 10.1093/oxfordjournals.aje.a009477.
    1. Daly J. Mechanism of action of caffeine. In: Garattini S., editor. Caffeine, Coffee, and Health. New York: Raven Press; 1993. pp. 97–149.
    1. Benowitz N.L. Clinical pharmacology of caffeine. Annu. Rev. Med. 1990;41:277–278. doi: 10.1146/annurev.me.41.020190.001425.
    1. Safranow K., Machoy Z. Methylated purines in urinary stones. Clin. Chem. 2005;51(8):1493–1498. doi: 10.1373/clinchem.2005.048033.
    1. Mandel H.G. Update on caffeine consumption, disposition and action. Food Chem. Toxicol. 2002;40(9):1231–1234. doi: 10.1016/S0278-6915(02)00093-5.
    1. Klebanoff M.A., Levine R.J., DerSimonian R., Clemens J.D., Wilkins D.G. Maternal serum paraxanthine, a caffeine metabolite, and the risk of spontaneous abortion. N. Engl. J. Med. 1999;341(22):1639–1644. doi: 10.1056/NEJM199911253412202.
    1. Kalow W., Tang B.K. Caffeine as a metabolic probe: exploration of the enzyme-inducing effect of cigarette smoking. Clin. Pharmacol. Ther. 1991;49(1):44–48. doi: 10.1038/clpt.1991.8.
    1. Eteng M.U., Eyong E.U., Akpanyung E.O., Agiang M.A., Aremu C.Y. Recent advances in caffeine and theobromine toxicities: a review. Plant Foods Hum. Nutr. 1997;51(3):231–243. doi: 10.1023/A:1007976831684.
    1. Tarka S.M., Jr, Arnaud M.J., Dvorchik B.H., Vesell E.S. Theobromine kinetics and metabolic disposition. Clin. Pharmacol. Ther. 1983;34(4):546–555. doi: 10.1038/clpt.1983.212.
    1. Shively CA, Tarka SM , Jr, Arnaud MJ, Dvorchik BH, Passananti GT, Vesell ES. High levels of methylxanthines in chocolate do not alter theobromine disposition. Clin. Pharmacol. Ther. 1985;37(4):415–424.
    1. Rostami-Hodjegan A., Nurminen S., Jackson P.R., Tucker G.T. Caffeine urinary metabolite ratios as markers of enzyme activity: a theoretical assessment. Pharmacogenetics. 1996;6(2):121–149. doi: 10.1097/00008571-199604000-00001.
    1. Lelo A., Birkett D.J., Robson R.A., Miners J.O. Comparative pharmacokinetics of caffeine and its primary demethylated metabolites paraxanthine, theobromine and theophylline in man. Br. J. Clin. Pharmacol. 1986;22(2):177–182. doi: 10.1111/j.1365-2125.1986.tb05246.x.
    1. Birkett D.J., Dahlqvist R., Miners J.O., Lelo A., Billing B. Comparison of theophylline and theobromine metabolism in man. Drug Metab. Dispos. 1985;13(6):725–728.
    1. Gates S., Miners J.O. Cytochrome P450 isoform selectivity in human hepatic theobromine metabolism. Br. J. Clin. Pharmacol. 1999;47(3):299–305. doi: 10.1046/j.1365-2125.1999.00890.x.
    1. Stavric B. Methylxanthines: toxicity to humans. 1. Theophylline. Food Chem. Toxicol. 1988;26(6):541–565. doi: 10.1016/0278-6915(88)90007-5.
    1. Aldridge A., Bailey J., Neims A.H. The disposition of caffeine during and after pregnancy. Semin. Perinatol. 1981;5(4):310–314.
    1. Parsons W.D., Neims A.H. Effect of smoking on caffeine clearance. Clin. Pharmacol. Ther. 1978;24(1):40–45.
    1. Brown C.R., Jacob P., III, Wilson M., Benowitz N.L. Changes in rate and pattern of caffeine metabolism after cigarette abstinence. Clin. Pharmacol. Ther. 1988;43(5):488–491. doi: 10.1038/clpt.1988.63.
    1. Cook D.G., Peacock J.L., Feyerabend C., Carey I.M., Jarvis M.J., Anderson H.R., Bland J.M. Relation of caffeine intake and blood caffeine concentrations during pregnancy to fetal growth: prospective population based study. BMJ. 1996;313(7069):1358–1362. doi: 10.1136/bmj.313.7069.1358.
    1. Nakajima M., Yokoi T., Mizutani M., Kinoshita M., Funayama M., Kamataki T. Genetic polymorphism in the 5′-flanking region of human CYP1A2 gene: effect on the CYP1A2 inducibility in humans. J. Biochem. 1999;125(4):803–808. doi: 10.1093/oxfordjournals.jbchem.a022352.
    1. Holtzman S.G., Mante S., Minneman K.P. Role of adenosine receptors in caffeine tolerance. J. Pharmacol. Exp. Ther. 1991;256(1):62–68.
    1. Ribeiro J.A., Sebastião A.M. Caffeine and adenosine. J. Alzheimers Dis. 2010;20(Suppl. 1):S3–S15.
    1. Ferré S., Fredholm B.B., Morelli M., Popoli P., Fuxe K. Adenosine-dopamine receptor-receptor interactions as an integrative mechanism in the basal ganglia. Trends Neurosci. 1997;20(10):482–487. doi: 10.1016/S0166-2236(97)01096-5.
    1. Smits P., Boekema P., De Abreu R., Thien T., van ’t Laar A. Evidence for an antagonism between caffeine and adenosine in the human cardiovascular system. J. Cardiovasc. Pharmacol. 1987;10(2):136–143. doi: 10.1097/00005344-198708000-00002.
    1. Cameron O.G., Modell J.G., Hariharan M. Caffeine and human cerebral blood flow: a positron emission tomography study. Life Sci. 1990;47(13):1141–1146. doi: 10.1016/0024-3205(90)90174-P.
    1. Namdar M., Schepis T., Koepfli P., Gaemperli O., Siegrist P.T., Grathwohl R., Valenta I., Delaloye R., Klainguti M., Wyss C.A., Lüscher T.F., Kaufmann P.A. Caffeine impairs myocardial blood flow response to physical exercise in patients with coronary artery disease as well as in age-matched controls. PLoS One. 2009;4(5):e5665. doi: 10.1371/journal.pone.0005665.
    1. Fastbom J., Pazos A., Palacios J.M. The distribution of adenosine A1 receptors and 5′-nucleotidase in the brain of some commonly used experimental animals. Neuroscience. 1987;22(3):813–826. doi: 10.1016/0306-4522(87)92961-7.
    1. Goodman R.R., Synder S.H. Autoradiographic localization of adenosine receptors in rat brain using [3H]cyclohexyladenosine. J. Neurosci. 1982;2(9):1230–1241.
    1. Svenningsson P., Nomikos G.G., Fredholm B.B. The stimulatory action and the development of tolerance to caffeine is associated with alterations in gene expression in specific brain regions. J. Neurosci. 1999;19(10):4011–4022.
    1. Svenningsson P., Nomikos G.G., Ongini E., Fredholm B.B. Antagonism of adenosine A2A receptors underlies the behavioural activating effect of caffeine and is associated with reduced expression of messenger RNA for NGFI-A and NGFI-B in caudate-putamen and nucleus accumbens. Neuroscience. 1997;79(3):753–764. doi: 10.1016/S0306-4522(97)00046-8.
    1. Supinski G.S., Deal E.C., Jr, Kelsen S.G. The effects of caffeine and theophylline on diaphragm contractility. Am. Rev. Respir. Dis. 1984;130(3):429–433.
    1. Endo M. Calcium release from the sarcoplasmic reticulum. Physiol. Rev. 1977;57(1):71–108.
    1. Tarnopolsky M.A. Effect of caffeine on the neuromuscular system--potential as an ergogenic aid. Appl. Physiol. Nutr. Metab. 2008;33(6):1284–1289. doi: 10.1139/H08-121.
    1. Goldstein E.R., Ziegenfuss T., Kalman D., Kreider R., Campbell B., Wilborn C., Taylor L., Willoughby D., Stout J., Graves B.S., Wildman R., Ivy J.L., Spano M., Smith A.E., Antonio J. International society of sports nutrition position stand: caffeine and performance. J. Int. Soc. Sports Nutr. 2010;7(1):5. doi: 10.1186/1550-2783-7-5.
    1. Osswald H, Schnermann J. Methylxanthines and the kidney. Handb. Exp. Pharmacol. 2011;200:391–412.
    1. Umemura T., Ueda K., Nishioka K., Hidaka T., Takemoto H., Nakamura S., Jitsuiki D., Soga J., Goto C., Chayama K., Yoshizumi M., Higashi Y. Effects of acute administration of caffeine on vascular function. Am. J. Cardiol. 2006;98(11):1538–1541. doi: 10.1016/j.amjcard.2006.06.058.
    1. Chesley A., Hultman E., Spriet L.L. Effects of epinephrine infusion on muscle glycogenolysis during intense aerobic exercise. Am. J. Physiol. 1995;268(1 Pt 1):E127–E134.
    1. Graham T.E. Caffeine and exercise: metabolism, endurance and performance. Sports Med. 2001;31(11):785–807. doi: 10.2165/00007256-200131110-00002.
    1. Taylor C., Higham D., Close G.L., Morton J.P. The effect of adding caffeine to postexercise carbohydrate feeding on subsequent high-intensity interval-running capacity compared with carbohydrate alone. Int. J. Sport Nutr. Exerc. Metab. 2011;21(5):410–416.
    1. Battram D.S., Shearer J., Robinson D., Graham T.E. Caffeine ingestion does not impede the resynthesis of proglycogen and macroglycogen after prolonged exercise and carbohydrate supplementation in humans. J. Appl. Physiol. (1985) 2004;96(3):943–950.
    1. Pedersen DJ, Lessard S.J., Coffey V.G., Churchley E.G., Wootton A , Ng T, Watt MJ, Hawley JA. High rates of muscle glycogen resynthesis after exhaustive exercise when carbohydrate is coingested with caffeine. J. Appl. Physiol. (1985). . 2008;105(1):7–13.
    1. Spriet L.L., MacLean D.A., Dyck D.J., Hultman E., Cederblad G., Graham T.E. Caffeine ingestion and muscle metabolism during prolonged exercise in humans. Am. J. Physiol. 1992;262(6 Pt 1):E891–E898.
    1. Rush JW, Spriet LL. Skeletal muscle glycogen phosphorylase a kinetics effects of adenine nucleotides and caffeine. J. Appl. Physiol. (1985). 2001;91(5):2071–2078.
    1. Rudolph T, Knudsen K. A case of fatal caffeine poisoning. Acta Anaesthesiol. Scand. 2010;54(4):521–523.
    1. Klatsky A.L., Hasan A.S., Armstrong M.A., Udaltsova N., Morton C. Coffee, caffeine, and risk of hospitalization for arrhythmias. Perm. J. 2011;15(3):19–25.
    1. Mehta A., Jain A.C., Mehta M.C., Billie M. Caffeine and cardiac arrhythmias. An experimental study in dogs with review of literature. Acta Cardiol. 1997;52(3):273–283.
    1. Usman A., Jawaid A. Hypertension in a young boy: an energy drink effect. BMC Res. Notes. 2012;5:591. doi: 10.1186/1756-0500-5-591.
    1. Berger A.J., Alford K. Cardiac arrest in a young man following excess consumption of caffeinated “energy drinks”. Med. J. Aust. 2009;190(1):41–43.
    1. Balasubramaniam R, Chawla S, Grace AA, Huang CL. Caffeine-induced arrhythmias in murine hearts parallel changes in cellular Ca(2+) homeostasis. Am. J. Physiol. Heart Circ. Physiol. . 2005;289(4):1584–1593.
    1. Pelchovitz D.J., Goldberger J.J., Jeffrey J., Goldberger M.D. Caffeine and cardiac arrhythmias: a review of the evidence. Am. J. Med. 2011;124(4):284–289. doi: 10.1016/j.amjmed.2010.10.017.
    1. Prineas R.J., Jacobs D.R., Jr, Crow R.S., Blackburn H. Coffee, tea and VPB. J. Chronic Dis. 1980;33(2):67–72. doi: 10.1016/0021-9681(80)90029-6.
    1. Gould L., Reddy C.V., Oh K.C., Kim S.G., Becker W. Electrophysiologic properties of coffee in man. J. Clin. Pharmacol. 1979;19(1):46–55. doi: 10.1002/j.1552-4604.1979.tb01616.x.
    1. Dobmeyer D.J., Stine R.A., Leier C.V., Greenberg R., Schaal S.F. The arrhythmogenic effects of caffeine in human beings. N. Engl. J. Med. 1983;308(14):814–816. doi: 10.1056/NEJM198304073081405.
    1. Caron M.F., Song J., Ammar R., Kluger J., White C.M. An evaluation of the change in electrocardiographic P-wave variables after acute caffeine ingestion in normal volunteers. J. Clin. Pharm. Ther. 2001;26(2):145–148. doi: 10.1046/j.1365-2710.2001.00336.x.
    1. Steinke L., Lanfear D.E., Dhanapal V., Kalus J.S. Effect of “energy drink” consumption on hemodynamic and electrocardiographic parameters in healthy young adults. Ann. Pharmacother. 2009;43(4):596–602. doi: 10.1345/aph.1L614.
    1. Ammar R., Song J.C., Kluger J., White C.M. Evaluation of electrocardiographic and hemodynamic effects of caffeine with acute dosing in healthy volunteers. Pharmacotherapy. 2001;21(4):437–442. doi: 10.1592/phco.21.5.437.34502.
    1. Donnerstein R.L., Zhu D., Samson R., Bender A.M., Goldberg S.J. Acute effects of caffeine ingestion on signal-averaged electrocardiograms. Am. Heart J. 1998;136(4 Pt 1):643–646. doi: 10.1016/S0002-8703(98)70011-0.
    1. Sutherland D.J., McPherson D.D., Renton K.W., Spencer C.A., Montague T.J. The effect of caffeine on cardiac rate, rhythm, and ventricular repolarization. Analysis of 18 normal subjects and 18 patients with primary ventricular dysrhythmia. Chest. 1985;87(3):319–324. doi: 10.1378/chest.87.3.319.
    1. Chelsky L.B., Cutler J.E., Griffith K., Kron J., McClelland J.H., McAnulty J.H. Caffeine and ventricular arrhythmias. An electrophysiological approach. JAMA. 1990;264(17):2236–2240. doi: 10.1001/jama.1990.03450170084027.
    1. Jackman M., Wendling P., Friars D., Graham T.E. Metabolic catecholamine, and endurance responses to caffeine during intense exercise. J. Appl. Physiol. 1996;81(4):1658–1663.
    1. Cheng M., Hu Z., Lu X., Huang J., Gu D. Caffeine intake and atrial fibrillation incidence: dose response meta-analysis of prospective cohort studies. Can. J. Cardiol. 2014;30(4):448–454. doi: 10.1016/j.cjca.2013.12.026.
    1. Corti R., Binggeli C., Sudano I., Spieker L., Hänseler E., Ruschitzka F., Chaplin W.F., Lüscher T.F., Noll G. Coffee acutely increases sympathetic nerve activity and blood pressure independently of caffeine content: role of habitual versus nonhabitual drinking. Circulation. 2002;106(23):2935–2940. doi: 10.1161/01.CIR.0000046228.97025.3A.
    1. Swartz M.F., Fink G.W., Sarwar M.F., Hicks G.L., Yu Y., Hu R., Lutz C.J., Taffet S.M., Jalife J. Elevated pre-operative serum peptides for collagen I and III synthesis result in post-surgical atrial fibrillation. J. Am. Coll. Cardiol. 2012;60(18):1799–1806. doi: 10.1016/j.jacc.2012.06.048.
    1. Anty R., Marjoux S., Iannelli A., Patouraux S., Schneck A.S., Bonnafous S., Gire C., Amzolini A., Ben-Amor I., Saint-Paul M.C., Mariné-Barjoan E., Pariente A., Gugenheim J., Gual P., Tran A. Regular coffee but not espresso drinking is protective against fibrosis in a cohort mainly composed of morbidly obese European women with NAFLD undergoing bariatric surgery. J. Hepatol. 2012;57(5):1090–1096. doi: 10.1016/j.jhep.2012.07.014.
    1. Arauz J., Moreno M.G., Cortés-Reynosa P., Salazar E.P., Muriel P. Coffee attenuates fibrosis by decreasing the expression of TGF-β and CTGF in a murine model of liver damage. J. Appl. Toxicol. 2013;33(9):970–979. doi: 10.1002/jat.2788.
    1. Arauz J., Zarco N., Segovia J., Shibayama M., Tsutsumi V., Muriel P. Caffeine prevents experimental liver fibrosis by blocking the expression of TGF-β. Eur. J. Gastroenterol. Hepatol. 2014;26(2):164–173. doi: 10.1097/MEG.0b013e3283644e26.
    1. Happonen P., Voutilainen S., Salonen J.T. Coffee drinking is dose-dependently related to the risk of acute coronary events in middle-aged men. J. Nutr. 2004;134(9):2381–2386.
    1. Hartley T.R., Lovallo W.R., Whitsett T.L. Cardiovascular effects of caffeine in men and women. Am. J. Cardiol. 2004;93(8):1022–1026. doi: 10.1016/j.amjcard.2003.12.057.
    1. Savoca M.R., MacKey M.L., Evans C.D., Wilson M., Ludwig D.A., Harshfield G.A. Association of ambulatory blood pressure and dietary caffeine in adolescents. Am. J. Hypertens. 2005;18(1):116–120. doi: 10.1016/j.amjhyper.2004.08.011.
    1. Palatini P., Ceolotto G., Ragazzo F., Dorigatti F., Saladini F., Papparella I., Mos L., Zanata G., Santonastaso M. CYP1A2 genotype modifies the association between coffee intake and the risk of hypertension. J. Hypertens. 2009;27(8):1594–1601. doi: 10.1097/HJH.0b013e32832ba850.
    1. Whitsett T.L., Manion C.V., Christensen H.D. Cardiovascular effects of coffee and caffeine. Am. J. Cardiol. 1984;53(7):918–922. doi: 10.1016/0002-9149(84)90525-3.
    1. Böttcher M., Czernin J., Sun K.T., Phelps M.E., Schelbert H.R. Effect of caffeine on myocardial blood flow at rest and during pharmacological vasodilation. J. Nucl. Med. 1995;36(11):2016–2021.
    1. Mahmud A., Feely J. Acute effect of caffeine on arterial stiffness and aortic pressure waveform. Hypertension. 2001;38(2):227–231. doi: 10.1161/01.HYP.38.2.227.
    1. Hatano Y., Mizumoto K., Yoshiyama T., Yamamoto M., Iranami H. Endothelium-dependent and -independent vasodilation of isolated rat aorta induced by caffeine. Am. J. Physiol. 1995;269(5 Pt 2):H1679–H1684.
    1. Banerjee P., Ali Z., Levine B., Fowler D.R. Fatal caffeine intoxication: a series of eight cases from 1999 to 2009. J. Forensic Sci. 2014;59(3):865–868. doi: 10.1111/1556-4029.12387.
    1. Karatzis E., Papaioannou T.G., Aznaouridis K., Karatzi K., Stamatelopoulos K., Zampelas A., Papamichael C., Lekakis J., Mavrikakis M. Acute effects of caffeine on blood pressure and wave reflections in healthy subjects: should we consider monitoring central blood pressure? Int. J. Cardiol. 2005;98(3):425–430. doi: 10.1016/j.ijcard.2003.11.013.
    1. Forman J., Aizer A., Young C.R. Myocardial infarction resulting from caffeine overdose in an anorectic woman. Ann. Emerg. Med. 1997;29(1):178–180. doi: 10.1016/S0196-0644(97)70326-3.
    1. Wilson RE, Kado HS, Samson R, Miller AB. A case of caffeine-induced coronary artery vasospasm of a 17-year-old male. Cardiovasc. Toxicol. 2012;12(2):175–179.
    1. Baum M., Weiss M. The influence of a taurine containing drink on cardiac parameters before and after exercise measured by echocardiography. Amino Acids. 2001;20(1):75–82. doi: 10.1007/s007260170067.
    1. Benjo A.M., Pineda A.M., Nascimento F.O., Zamora C., Lamas G.A., Escolar E. Left main coronary artery acute thrombosis related to energy drink intake. Circulation. 2012;125(11):1447–1448. doi: 10.1161/CIRCULATIONAHA.111.086017.
    1. Worthley M.I., Prabhu A., De Sciscio P., Schultz C., Sanders P., Willoughby S.R. Detrimental effects of energy drink consumption on platelet and endothelial function. Am. J. Med. 2010;123(2):184–187. doi: 10.1016/j.amjmed.2009.09.013.
    1. Grobbee D.E., Rimm E.B., Giovannucci E., Colditz G., Stampfer M., Willett W. Coffee, caffeine, and cardiovascular disease in men. N. Engl. J. Med. 1990;323(15):1026–1032. doi: 10.1056/NEJM199010113231504.
    1. Zhang W., Lopez-Garcia E., Li T.Y., Hu F.B., van Dam R.M. Coffee consumption and risk of cardiovascular diseases and all-cause mortality among men with type 2 diabetes. Diabetes Care. 2009;32(6):1043–1045. doi: 10.2337/dc08-2251.
    1. Lopez-Garcia E., van Dam R.M., Willett W.C., Rimm E.B., Manson J.E., Stampfer M.J., Rexrode K.M., Hu F.B. Coffee consumption and coronary heart disease in men and women: a prospective cohort study. Circulation. 2006;113(17):2045–2053. doi: 10.1161/CIRCULATIONAHA.105.598664.
    1. Hirsch A.T., Gervino E.V., Nakao S., Come P.C., Silverman K.J., Grossman W. The effect of caffeine on exercise tolerance and left ventricular function in patients with coronary artery disease. Ann. Intern. Med. 1989;110(8):593–598. doi: 10.7326/0003-4819-110-8-593.
    1. Greenberg J.A., Dunbar C.C., Schnoll R., Kokolis R., Kokolis S., Kassotis J. Caffeinated beverage intake and the risk of heart disease mortality in the elderly: a prospective analysis. Am. J. Clin. Nutr. 2007;85(2):392–398.
    1. Leathwood P.D., Pollet P. Diet-induced mood changes in normal populations. J. Psychiatr. Res. 1982-1983;17(2):147–154. doi: 10.1016/0022-3956(82)90016-4.
    1. Rusted J. Caffeine and cognitive performance: Effects on mood or mental processing. In: Gupta B.S., Gupta U., editors. Caffeine and behavior: Current views and research trends. Washington: CRC Press; 1999. pp. 221–229.
    1. Baldwin H.A., File S.E. Caffeine-induced anxiogenesis: the role of adenosine, benzodiazepine and noradrenergic receptors. Pharmacol. Biochem. Behav. 1989;32(1):181–186. doi: 10.1016/0091-3057(89)90230-X.
    1. Loke W.H., Hinrichs J.V., Ghoneim M.M. Caffeine and diazepam: separate and combined effects on mood, memory, and psychomotor performance. Psychopharmacology (Berl.) 1985;87(3):344–350. doi: 10.1007/BF00432719.
    1. Sicard B.A., Perault M.C., Enslen M., Chauffard F., Vandel B., Tachon P. The effects of 600 mg of slow release caffeine on mood and alertness. Aviat. Space Environ. Med. 1996;67(9):859–862.
    1. Nehlig A. Is caffeine a cognitive enhancer? J. Alzheimers Dis. 2010;20(Suppl. 1):S85–S94. doi: 10.1007/s00213-005-0084-6.
    1. James J.E., Rogers P.J. Effects of caffeine on performance and mood: withdrawal reversal is the most plausible explanation. Psychopharmacology (Berl.) 2005;182(1):1–8. doi: 10.1007/s00213-005-0084-6.
    1. Jarvis M.J. Does caffeine intake enhance absolute levels of cognitive performance? Psychopharmacology (Berl.) 1993;110(1-2):45–52. doi: 10.1007/BF02246949.
    1. Committee on Military Nutrition Research . Caffeine for the sustainment of mental task performance. Formulations for military operations. Washington: National Academy Press; 2001. pp. 61–65.
    1. Bhattacharya S.K., Satyan K.S., Chakrabarti A. Anxiogenic action of caffeine: an experimental study in rats. J. Psychopharmacol. 1997;11(3):219–224. doi: 10.1177/026988119701100304.
    1. El Yacoubi M., Ledent C., Parmentier M., Costentin J., Vaugeois J.M. The anxiogenic-like effect of caffeine in two experimental procedures measuring anxiety in the mouse is not shared by selective A(2A) adenosine receptor antagonists. Psychopharmacology (Berl.) 2000;148(2):153–163. doi: 10.1007/s002130050037.
    1. Sawyer D.A., Julia H.L., Turin A.C. Caffeine and human behavior: arousal, anxiety, and performance effects. J. Behav. Med. 1982;5(4):415–439. doi: 10.1007/BF00845371.
    1. Rogers P.J., Hohoff C., Heatherley S.V., Mullings E.L., Maxfield P.J., Evershed R.P., Deckert J., Nutt D.J. Association of the anxiogenic and alerting effects of caffeine with ADORA2A and ADORA1 polymorphisms and habitual level of caffeine consumption. Neuropsychopharmacology. 2010;35(9):1973–1983. doi: 10.1038/npp.2010.71.
    1. Rhoads D.E., Huggler A.L., Rhoads L.J. Acute and adaptive motor responses to caffeine in adolescent and adult rats. Pharmacol. Biochem. Behav. 2011;99(1):81–86. doi: 10.1016/j.pbb.2011.04.001.
    1. Kaplan GB, Greenblatt DJ, Ehrenberg BL, Goddard JE, Cotreau MM, Harmatz JS, Shader RI. Dose-dependent pharmacokinetics and psychomotor effects of caffeine in humans. J. Clin. Pharmacol. 1997;37(8):693–703.
    1. Sudakov S.K., Medvedeva O.F., Rusakova I.V., Figurina I.B. Effect of short-term and chronic caffeine intake on rats with various anxiety level. Bull. Exp. Biol. Med. 2001;132(6):1177–1179. doi: 10.1023/A:1014511415473.
    1. Maia L., de Mendonça A. Does caffeine intake protect from Alzheimer’s disease? Eur. J. Neurol. 2002;9(4):377–382. doi: 10.1046/j.1468-1331.2002.00421.x.
    1. Ritchie K., Carrière I., de Mendonca A., Portet F., Dartigues J.F., Rouaud O., Barberger-Gateau P., Ancelin M.L. The neuroprotective effects of caffeine: a prospective population study (the Three City Study) Neurology. 2007;69(6):536–545. doi: 10.1212/01.wnl.0000266670.35219.0c.
    1. Joghataie M.T., Roghani M., Negahdar F., Hashemi L. Protective effect of caffeine against neurodegeneration in a model of Parkinson’s disease in rat: behavioral and histochemical evidence. Parkinsonism Relat. Disord. 2004;10(8):465–468. doi: 10.1016/j.parkreldis.2004.06.004.
    1. Glade M.J. Caffeine-Not just a stimulant. Nutrition. 2010;26(10):932–938. doi: 10.1016/j.nut.2010.08.004.
    1. Snel J., Lorist M.M. Effects of caffeine on sleep and cognition. Prog. Brain Res. 2011;190:105–117. doi: 10.1016/B978-0-444-53817-8.00006-2.
    1. Doré AS, Robertson N, Errey JC, Ng I, Hollenstein K, Tehan B, Hurrell E, Bennett K, Congreve M, Magnani F, Tate CG, Weir M, Marshall FH. Structure of the adenosine A(2A) receptor in complex with ZM241385 and the xanthines XAC and caffeine. Structure. 2011;19(9):1283–1293.
    1. Sebastião A.M., Ribeiro J.A. Adenosine receptors and the central nervous system. Handbook Exp. Pharmacol. 2009;193(193):471–534. doi: 10.1007/978-3-540-89615-9_16.
    1. Federico S., Spalluto G. Therapeutic potential of A2 and A3 adenosine receptor: a review of novel patented ligands. Expert Opin. Ther. Pat. 2012;22(4):369–390. doi: 10.1517/13543776.2012.669375.
    1. Eskelinen M.H., Kivipelto M. Caffeine as a protective factor in dementia and Alzheimer’s disease. J. Alzheimers Dis. 2010;20(Suppl. 1):S167–S174. doi: 10.3233/JAD-2010-1404.
    1. Rosim F.E., Persike D.S., Nehlig A., Amorim R.P., de Oliveira D.M., Fernandes M.J. Differential neuroprotection by A(1) receptor activation and A(2A) receptor inhibition following pilocarpine-induced status epilepticus. Epilepsy Behav. 2011;22(2):207–213. doi: 10.1016/j.yebeh.2011.07.004.
    1. Schenone S., Brullo C., Musumeci F., Bruno O., Botta M. A1 receptors ligands: past, present and future trends. Curr. Top. Med. Chem. 2010;10(9):878–901. doi: 10.2174/156802610791268729.
    1. Xiao D., Cassin J.J., Healy B., Burdett T.C., Chen J.F., Fredholm B.B., Schwarzschild M.A. Deletion of adenosine A₁ or A(₂A) receptors reduces L-3,4-dihydroxyphenylalanine-induced dyskinesia in a model of Parkinson’s disease. Brain Res. 2011;1367:310–318. doi: 10.1016/j.brainres.2010.08.099.
    1. Camilo O., Goldstein L.B. Seizures and epilepsy after ischemic stroke. Stroke. 2004;35(7):1769–1775. doi: 10.1161/01.STR.0000130989.17100.96.
    1. Chen JF, Chern Y. Impacts of methylxanthines and adenosine receptors on neurodegeneration: human and experimental studies. Handb. Exp. Pharmacol. 2011;200:267–310.
    1. Cupino T.L., Zabel M.K. Alzheimer’s silent partner: cerebral amyloid angiopathy. Transl. Stroke Res. 2014;5(3):330–337. doi: 10.1007/s12975-013-0309-7.
    1. Salvemini D., Kim S.F., Mollace V. Reciprocal regulation of the nitric oxide and cyclooxygenase pathway in pathophysiology: relevance and clinical implications. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2013;304(7):R473–R487. doi: 10.1152/ajpregu.00355.2012.
    1. Yadav S., Gupta S.P., Srivastava G., Srivastava P.K., Singh M.P. Role of secondary mediators in caffeine-mediated neuroprotection in maneb- and paraquat-induced Parkinson’s disease phenotype in the mouse. Neurochem. Res. 2012;37(4):875–884. doi: 10.1007/s11064-011-0682-0.
    1. Chu YF, Chang WH, Black RM, Liu JR, Sompol P, Chen Y, Wei H, Zhao Q, Cheng I H. Crude caffeine reduces memory impairment and amyloid (1-42) levels in an Alzheimers mouse model. Food Chem. 2012;135(3):2095–2102.
    1. Palacios N., Gao X., McCullough M.L., Schwarzschild M.A., Shah R., Gapstur S., Ascherio A. Caffeine and risk of Parkinson’s disease in a large cohort of men and women. Mov. Disord. 2012;27(10):1276–1282. doi: 10.1002/mds.25076.
    1. Sonsalla P.K., Wong L.Y., Harris S.L., Richardson J.R., Khobahy I., Li W., Gadad B.S., German D.C. Delayed caffeine treatment prevents nigral dopamine neuron loss in a progressive rat model of Parkinson’s disease. Exp. Neurol. 2012;234(2):482–487. doi: 10.1016/j.expneurol.2012.01.022.
    1. Prasanthi J.R., Dasari B., Marwarha G., Larson T., Chen X., Geiger J.D., Ghribi O. Caffeine protects against oxidative stress and Alzheimer’s disease-like pathology in rabbit hippocampus induced by cholesterol-enriched diet. Free Radic. Biol. Med. 2010;49(7):1212–1220. doi: 10.1016/j.freeradbiomed.2010.07.007.
    1. Chen X., Ghribi O., Geiger J.D. Caffeine protects against disruptions of the blood-brain barrier in animal models of Alzheimer’s and Parkinson’s diseases. J. Alzheimers Dis. 2010;20(Suppl. 1):S127–S141. doi: 10.3233/JAD-2010-1376.
    1. Dragicevic N., Delic V., Cao C., Copes N., Lin X., Mamcarz M., Wang L., Arendash G.W., Bradshaw P.C. Caffeine increases mitochondrial function and blocks melatonin signaling to mitochondria in Alzheimer’s mice and cells. Neuropharmacology. 2012;63(8):1368–1379. doi: 10.1016/j.neuropharm.2012.08.018.
    1. Gao Y., Phillis J.W. CGS 15943, an adenosine A2 receptor antagonist, reduces cerebral ischemic injury in the Mongolian gerbil. Life Sci. 1994;55(3):PL61–PL65. doi: 10.1016/0024-3205(94)00889-2.
    1. Laska E.M., Sunshine A., Mueller F., Elvers W.B., Siegel C., Rubin A. Caffeine as an analgesic adjuvant. JAMA. 1984;251(13):1711–1718. doi: 10.1001/jama.1984.03340370043028.
    1. Diamond S., Balm T.K., Freitag F.G. Ibuprofen plus caffeine in the treatment of tension-type headache. Clin. Pharmacol. Ther. 2000;68(3):312–319. doi: 10.1067/mcp.2000.109353.
    1. Ward N., Whitney C., Avery D., Dunner D. The analgesic effects of caffeine in headache. Pain. 1991;44(2):151–155. doi: 10.1016/0304-3959(91)90129-L.
    1. Yücel A., Ozyalçin S., Talu G.K., Yücel E.C., Erdine S. Intravenous administration of caffeine sodium benzoate for postdural puncture headache. Reg. Anesth. Pain Med. 1999;24(1):51–54. doi: 10.1097/00115550-199924010-00010.
    1. Esmaoglu A., Akpinar H., Uğur F. Oral multidose caffeine-paracetamol combination is not effective for the prophylaxis of postdural puncture headache. J. Clin. Anesth. 2005;17(1):58–61. doi: 10.1016/j.jclinane.2004.04.003.
    1. Shapiro R.E. Caffeine and headaches. Curr. Pain Headache Rep. 2008;12(4):311–315. doi: 10.1007/s11916-008-0052-z.
    1. Griffiths R.R., Woodson P.P. Caffeine physical dependence: a review of human and laboratory animal studies. Psychopharmacology (Berl.) 1988;94(4):437–451. doi: 10.1007/BF00212836.
    1. Griffiths R.R., Evans S.M., Heishman S.J., Preston K.L., Sannerud C.A., Wolf B., Woodson P.P. Low-dose caffeine physical dependence in humans. J. Pharmacol. Exp. Ther. 1990;255(3):1123–1132.
    1. Lovallo W.R., Whitsett T.L., al'Absi M., Sung B.H., Vincent A.S., Wilson M.F. Caffeine stimulation of cortisol secretion across the waking hours in relation to caffeine intake levels. Psychosom. Med. 2005;67(5):734–739. doi: 10.1097/01.psy.0000181270.20036.06.
    1. Dager S.R., Layton M.E., Strauss W., Richards T.L., Heide A., Friedman S.D., Artru A.A., Hayes C.E., Posse S. Human brain metabolic response to caffeine and the effects of tolerance. Am. J. Psychiatry. 1999;156(2):229–237.
    1. James J.E. Critical review of dietary caffeine and blood pressure: a relationship that should be taken more seriously. Psychosom. Med. 2004;66(1):63–71. doi: 10.1097/10.PSY.0000107884.78247.F9.
    1. Lovallo W.R., Wilson M.F., Vincent A.S., Sung B.H., McKey B.S., Whitsett T.L. Blood pressure response to caffeine shows incomplete tolerance after short-term regular consumption. Hypertension. 2004;43(4):760–765. doi: 10.1161/01.HYP.0000120965.63962.93.
    1. Eisenberg S. Looking for the Perfect Brew. Sci. News. 1988;133:252–253. doi: 10.2307/3972326.
    1. Cherniske S. Caffeine Blues: Wake Up to the Hidden Dangers of America's #1 Drug. 1st ed. New York: Warner Books Inc; 1998. p. 35.
    1. Reissig C.J., Strain E.C., Griffiths R.R. Caffeinated energy drinks--a growing problem. Drug Alcohol Depend. 2009;99(1-3):1–10. doi: 10.1016/j.drugalcdep.2008.08.001.
    1. Kashkin K.B., Kleber H.D. Hooked on hormones? An anabolic steroid addiction hypothesis. JAMA. 1989;262(22):3166–3170. doi: 10.1001/jama.1989.03430220089036.
    1. American Psychiatric Association . Diagnostic and Statistical Manual of Mental Disorders. 2000.
    1. American Psychiatric Association; Diagnostic and Statistical Manual of Mental Disorderss; Arlington APA. 2013.
    1. WHO. Lexicon of alcohol and drug terms; World Health Organization; Geneva. 1995.
    1. Verheul R., van den Brink W., Geerlings P. A three-pathway psychobiological model of craving for alcohol. Alcohol Alcohol. 1999;34(2):197–222. doi: 10.1093/alcalc/34.2.197.
    1. World Health Organization. The ICD-10 classification of mental and behavioural disorders: clinical descriptions and diagnostic guidelines; World Health Organization; Geneva. 1992.
    1. Greden J.F. Anxiety or caffeinism: a diagnostic dilemma. Am. J. Psychiatry. 1974;131(10):1089–1092.
    1. Nawrot P., Jordan S., Eastwood J., Rotstein J., Hugenholtz A., Feeley M. Effects of caffeine on human health. Food Addit. Contam. 2003;20(1):1–30. doi: 10.1080/0265203021000007840.
    1. Higdon J.V., Frei B. Coffee and health: a review of recent human research. Crit. Rev. Food Sci. Nutr. 2006;46(2):101–123. doi: 10.1080/10408390500400009.
    1. Moffatt A.C., Osselton M.D., Widdop B., Galichet L.Y. Clarke’s Analysis of Drugs and Poisons in Pharmaceuticals, Body Fluids and Postmortem Material.; London: Pharmaceutical Press; 2011. p. 36.
    1. Dimaio V.J., Garriott J.C. Lethal caffeine poisoning in a child. Forensic Sci. 1974;3(3):275–278. doi: 10.1016/0300-9432(74)90056-9.
    1. Turner J.E., Cravey R.H. A fatal ingestion of caffeine. Clin. Toxicol. 1977;10(3):341–344. doi: 10.3109/15563657708992428.
    1. McGee M.B. Caffeine poisoning in a 19-year-old female. J. Forensic Sci. 1980;25(1):29–32.
    1. Bryant J. Suicide by ingestion of caffeine. Arch. Pathol. Lab. Med. 1981;105(12):685–686.
    1. Chaturvedi A.K., Rao N.G., McCoy F.E. A multi-chemical death involving caffeine, nicotine and malathion. Forensic Sci. Int. 1983;23(2-3):265–275. doi: 10.1016/0379-0738(83)90155-X.
    1. Garriott JC, Simmons LM, Poklis A, Mackell MA. Five cases of fatal overdose from caffeine containing look alike drugs. J. Anal. Toxicol. 1985;9(3):141–143.
    1. Winek C.L., Wahba W., Williams K., Blenko J., Janssen J. Caffeine fatality: a case report. Forensic Sci. Int. 1985;29(3-4):207–211. doi: 10.1016/0379-0738(85)90114-8.
    1. Morrow P.L. Caffeine toxicity: a case of child abuse by drug ingestion. J. Forensic Sci. 1987;32(6):1801–1805.
    1. Mrvos R.M., Reilly P.E., Dean B.S., Krenzelok E.P. Massive caffeine ingestion resulting in death. Vet. Hum. Toxicol. 1989;31(6):571–572.
    1. Riesselmann B., Rosenbaum F., Roscher S., Schneider V. Fatal caffeine intoxication. Forensic Sci. Int. 1999;103:49–52. doi: 10.1016/S0379-0738(99)00073-0.
    1. Holmgren P., Nordén-Pettersson L., Ahlner J. Caffeine fatalities--four case reports. Forensic Sci. Int. 2004;139(1):71–73. doi: 10.1016/j.forsciint.2003.09.019.
    1. Kerrigan S., Lindsey T. Fatal caffeine overdose: two case reports. Forensic Sci. Int. 2005;153(1):67–69. doi: 10.1016/j.forsciint.2005.04.016.
    1. Thelander G., Jönsson A.K., Personne M., Forsberg G.S., Lundqvist K.M., Ahlner J. Caffeine fatalities--do sales restrictions prevent intentional intoxications? Clin. Toxicol. (Phila.) 2010;48(4):354–358. doi: 10.3109/15563650903586752.
    1. Jabbar S.B., Hanly M.G. Fatal caffeine overdose: a case report and review of literature. Am. J. Forensic Med. Pathol. 2013;34(4):321–324. doi: 10.1097/PAF.0000000000000058.
    1. Jantos R., Stein K.M., Flechtenmacher C., Skopp G. A fatal case involving a caffeine-containing fat burner. Drug Test. Anal. 2013;5(9-10):773–776. doi: 10.1002/dta.1485.
    1. Bonsignore A., Sblano S., Pozzi F., Ventura F., Dell’Erba A., Palmiere C. A case of suicide by ingestion of caffeine. Forensic Sci. Med. Pathol. 2014;10(3):448–451. doi: 10.1007/s12024-014-9571-6.
    1. Bernstein G.A., Carroll M.E., Thuras P.D., Cosgrove K.P., Roth M.E. Caffeine dependence in teenagers. Drug Alcohol Depend. 2002;66(1):1–6. doi: 10.1016/S0376-8716(01)00181-8.
    1. Oberstar J.V., Bernstein G.A., Thuras P.D. Caffeine use and dependence in adolescents: one-year follow-up. J. Child Adolesc. Psychopharmacol. 2002;12(2):127–135. doi: 10.1089/104454602760219162.
    1. Strain E.C., Mumford G.K., Silverman K., Griffiths R.R. Caffeine dependence syndrome. Evidence from case histories and experimental evaluations. JAMA. 1994;272(13):1043–1048. doi: 10.1001/jama.1994.03520130081037.
    1. Svikis D.S., Berger N., Haug N.A., Griffiths R.R. Caffeine dependence in combination with a family history of alcoholism as a predictor of continued use of caffeine during pregnancy. Am. J. Psychiatry. 2005;162(12):2344–2351. doi: 10.1176/appi.ajp.162.12.2344.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi