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Cited by 631Coffee research and impactsAlkaloids: synthesis and pharmacologyAdenosine and Purinergic Signaling

Caffeine: Cognitive and Physical Performance Enhancer or Psychoactive Drug?

Open access
Cappelletti, Simone, Daria, Piacentino, Sani, Gabriele, Aromatario, Mariarosaria·2015·Current Neuropharmacology
DOI 10.2174/1570159x13666141210215655PMC PMC4462044
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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.

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Written from the paper’s full text.

TL;DR

This review summarizes caffeine’s pharmacokinetics, mechanisms of action, cardiovascular and central nervous system effects, and its potential for abuse, dependence, intoxication, and lethal toxicity. It argues that toxic and lethal doses are relative, because interactions, preexisting disease, and genetic/metabolic differences can make even sub-toxic doses harmful.

Key findings

  • Caffeine’s main mechanism is competitive adenosine receptor antagonism, especially A1 and A2A, which can occur at low dietary doses; intracellular calcium mobilization and phosphodiesterase inhibition require higher doses unlikely from usual dietary sources.
  • Caffeine half-life in humans ranges from 2 to 12 hours; CYP1A2 accounts for about 95% of caffeine clearance, and caffeine is demethylated mostly to paraxanthine (84%), theobromine (12%), and theophylline (4%).
  • Acute toxic caffeine levels are not well established, but for adults are approximately 10 g/day, comparable to about 100 cups of coffee; life-threatening overdoses usually involve caffeine-containing medications, with blood concentrations in excess of 80 mg/l, and lethal cases often involve supplements or other substances.
  • Human studies provide scarce evidence that caffeine induces arrhythmias in healthy or predisposed subjects, though heavy coffee intake (10 cups/day) was associated with increased sudden cardiac death risk in 117 patients with coronary artery disease (odds ratio=55.7); cognitive benefits remain debated and may reflect relief from withdrawal rather than enhancement.

Methods

  • Conceptual review including retrospective, prospective, and cross-sectional studies examining caffeine’s mechanisms of action, use, abuse, dependence, intoxication, and death.
  • Electronic search of Pubmed, INFORMA healthcare, EMBASE, and PsycINFO from database inception to July 20, 2014, without language restriction; search terms combined caffeine with pharmacokinetics, pharmacodynamics, heart, brain, abuse, dependence, intoxication, or death.
  • The database search selected 29,421 potentially relevant titles, and 20 additional potentially eligible articles were identified by hand-searching reference lists; no unpublished studies were found, and no evidence of language bias or significant publication bias was reported.

Limitations

  • The paper states that tolerance research is limited because most studies compare caffeine-naïve individuals with habitual users or habitual users before/after abstinence; since 80% of the population reports regular caffeine use, nonusers are a selected, atypical subpopulation, and few studies compare repeated caffeine administration with placebo.
  • The paper states that caffeine dependence studies are mainly observational and have difficulty verifying exact caffeine products and amounts, and that many caffeine consumers simultaneously use nicotine or alcohol, which may have overlapping effects.
  • Evident from the text: this is a conceptual review rather than a systematic review or meta-analysis, and although it reports search counts and bias comments, it does not present a formal study-selection flow, quality appraisal, or quantitative synthesis.

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Registry

Crossref · 10.2174/1570159x13666141210215655

Cites

192 of 192 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 134 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Heavy coffee intake (10 cups per day) is associated with increased risk of sudden cardiac death in patients with a history of coronary artery disease who suffered from sudden cardiac arrest vs controls with coronary artery disease (odds ratio=55.7).

    “The same authors found a very significant association between heavy coffee intake (10 cups per day) and increased risk of sudden cardiac death in 117 patients with a history of coronary artery disease who suffered from sudden cardiac arrest vs. controls with coronary artery disease (odds ratio=55.7) [69].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] 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 10.1016/j.amjmed.2010.10.017 21435415

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  • Premisecitation

    Caffeine acts as a nonselective competitive inhibitor of phosphodiesterases.

    “Caffeine acts as a nonselective competitive inhibitor of phosphodiesterases [55].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] 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 10.1016/j.amjcard.2006.06.058 17126666

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  • Premisenone given

    The ability of caffeine to block adenosine receptors can be observed at low doses, such as those contained in a single cup of coffee.

    “The ability of caffeine to block adenosine receptors can be observed also at low doses, such as those contained in a single cup of coffee.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Caffeine ingestion produced an increase in systolic and diastolic blood pressures in the brachial artery.

    “A double-blind, randomized study [55] showed that caffeine ingestion produced an increase in systolic and diastolic blood pressures in the brachial artery, in agreement with previous studies that highlighted how acute caffeine ingestion elevated peripheral blood pressure [80, 86, 91] and augmented the forearm blood flow response to acetylcholine, an endothelium-dependent vasodilator.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] 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 10.1016/j.amjcard.2006.06.058 17126666

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  • Premisecitation

    Caffeine does not acutely induce any statistically and clinically significant changes in P-wave indices (PR interval, QRS duration, corrected QT interval, and RR interval) after intake of moderate amounts of caffeine or high-caffeine energy drinks.

    “As regards the effects of caffeine on the human electrocardiogram [69] after the intake of moderate amounts of caffeine [72] or high-caffeine energy drinks [73], it was noticed that caffeine does not acutely induce any statistically and clinically significant changes in P-wave indices, i.e., PR interval, QRS duration, corrected QT interval (QTc), and RR interval [74].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [69] 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 10.1016/j.amjmed.2010.10.017 21435415

      Not checked in the free run.

    • cites [72] 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 10.1056/NEJM198304073081405 6835272

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    • cites [73] 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 10.1046/j.1365-2710.2001.00336.x 11350538

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  • May combine two claims. 57
  • Classified as probably not a substantial claim. 53

  • May combine two claims.

    Premisecitation

    High caffeine doses induce adenosine antagonism and phosphodiesterases inhibition, interacting with the sympathetic nervous system and inducing β1-receptor activation, resulting in positive inotropic and chronotropic effects accountable for augmented heart rate and conductivity.

    “High caffeine doses induce adenosine antagonism and phosphodiesterases inhibition, interacting with the sympathetic nervous system and inducing β1-receptor activation. This results in positive inotropic and chronotropic effects, accountable for an augmented heart rate and conductivity [63].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [63] Rudolph T Knudsen K A case of fatal caffeine poisoning. Acta Anaesthesiol. Scand. 2010 54 4 521 523 20096021

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    Premisecitation

    Caffeine has been shown to elevate blood pressure in both normotensive and hypertensive prone men, partly by inhibiting adenosine action, leading to elevated noradrenalin release and vasoconstriction.

    “Caffeine has been shown to elevate blood pressure in both normotensive and hypertensive prone men, partly by inhibiting adenosine action, leading to elevated noradrenalin release and vasoconstriction [87, 88].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [87] 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 10.1016/j.amjcard.2003.12.057 15081447

      Not checked in the free run.

    • cites [88] 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 10.1016/j.amjhyper.2004.08.011 15691625

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    Premisecitation

    Caffeine can induce calcium release from the sarcoplasmic reticulum and inhibit its reuptake.

    “Caffeine can induce calcium release from the sarcoplasmic reticulum [50] and can also inhibit its reuptake [51].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [50] 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 6476593

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    • cites [51] Endo M. Calcium release from the sarcoplasmic reticulum Physiol. Rev 1977 57 1 71 108 13441

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    These mechanisms of action require very high doses of caffeine, unlikely to be present in the standard diet, which contains moderate amounts of caffeine.

    “These mechanisms of action require very high doses of caffeine, unlikely to be present in the standard diet, which contains moderate amounts of caffeine.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Although adrenaline concentration increases with caffeine ingestion, the degree of the release is six times lower than the boost noted during exercise.

    “It is interesting to note that although adrenaline concentration increases with caffeine ingestion, the degree of the release is six times lower than the boost noted during exercise [78].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [78] 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 10.1001/jama.1990.03450170084027 2214101

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Higher concentrations of caffeine increase intracellular cAMP and cGMP by nonspecific phosphodiesterases inhibition, which affects cardiac contractility secondary to calcium release; this may increase susceptibility for arrhythmias.

    “In fact, higher concentrations of caffeine increase intracellular cAMP and cyclic guanosine monophosphate (cGMP) by a nonspecific phosphodiesterases inhibition, which affects cardiac contractility secondary to calcium release. The latter mechanism may increase the susceptibility for arrhythmias.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Caffeine blocks adenosine receptors, mainly A1 and A2A subtypes, competitively antagonizing their action and causing increased release of dopamine, noradrenalin, and glutamate.

    “Caffeine blocks adenosine receptors, mainly A1 and A2A subtypes, competitively antagonizing their action [40, 41] and causing an increased release of dopamine, noradrenalin, and glutamate [42, 43].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [40] Holtzman S.G. Mante S. Minneman K.P. Role of adenosine receptors in caffeine tolerance J. Pharmacol. Exp. Ther 1991 256 1 62 68 1846425

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    • cites [41] Ribeiro J.A. Sebastião A.M. Caffeine and adenosine. J. Alzheimers Dis 2010 20 Suppl. 1 S3 S15 20164566

      Not checked in the free run.

    • cites [42] 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 10.1016/S0166-2236(97)01096-5 9347617

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    • cites [43] 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 10.1097/00005344-198708000-00002 2441163

      Not checked in the free run.

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    Premisecitation

    In habitual caffeine consumers, caffeine's adrenergic effects were greatly attenuated and acute proarrhythmic effect was somewhat reduced.

    “It was also demonstrated that in habitual caffeine consumers, caffeine’s adrenergic effects were greatly attenuated and acute proarrhythmic effect was somewhat reduced [80].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [80] 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 10.1016/j.cjca.2013.12.026 24680173

      Not checked in the free run.

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    Premisecitation

    Acute caffeine ingestion increases blood pressure and catecholamine levels and decreases heart rate.

    “A number of studies have demonstrated that acute caffeine ingestion increases blood pressure and catecholamine levels and decreases heart rate [74, 89].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [74] 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 10.1345/aph.1L614 19299320

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    • cites [89] 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 10.1097/HJH.0b013e32832ba850 19451835

      Not checked in the free run.

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    Premisecitation

    The effects of caffeine in low doses can be replicated by a selective A2A receptor antagonist, but not by a selective A1 receptor antagonist.

    “Finally, it has been shown that the effects of caffeine in low doses can be replicated by a selective A2A receptor antagonist, but not by a selective A1 receptor antagonist [49].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [49] 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 10.1016/S0306-4522(97)00046-8 9219939

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    Premisecitation

    Caffeine, besides influencing cognitive performance, increases the perception of alertness and wakefulness and sometimes induces anxiety, especially at high doses.

    “Caffeine, besides influencing cognitive performance, increases the perception of alertness and wakefulness [105, 106] and sometimes induces anxiety, especially at high doses [107-109].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [105] 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 17284734

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    • cites [106] Leathwood P.D. Pollet P. Diet-induced mood changes in normal populations J. Psychiatr. Res 1982-1983 17 2 147 154 10.1016/0022-3956(82)90016-4 6764931

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    • cites [107] Rusted J. Gupta B.S. Gupta U. Caffeine and cognitive performance: Effects on mood or mental processing. Caffeine and behavior: Current views and research trends 1999 Washington CRC Press 221 229 10.1201/9781439822470.ch13

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    • cites [108] 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 10.1016/0091-3057(89)90230-X 2543990

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    • cites [109] 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 10.1007/BF00432719 3936091

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Antagonism of A1 and A2 receptors can cause seizures and cerebral vasoconstriction.

    “Furthermore, antagonism of A1 and A2 receptors can cause seizures and cerebral vasoconstriction.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    In patients with coronary artery disease, caffeine at a dose of 250 mg had no effect on exercise duration, time to onset of angina, and time to onset of ST-segment depression, although peak blood pressure increased by 7 mmHg.

    “A study of patients with coronary artery disease, in which exercise stress tests were carried out, showed that caffeine at a dose of 250 mg had no effect on exercise duration, time to onset of angina, and time to onset of ST-segment depression, although peak blood pressure increased by 7 mmHg [103].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [103] 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 10.1161/CIRCULATIONAHA.105.598664 16636169

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    Interpretationcitation

    There seems to be a relevant acute effect of caffeine ingestion on central hemodynamics, but not on peripheral pressure.

    “Therefore, there seems to be a relevant acute effect of caffeine ingestion on central hemodynamics, but not on peripheral pressure.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Karatzis et al. observed, after acute administration of caffeine, an increase of central blood pressure, but not of peripheral systolic blood pressure.

    “Karatzis et al. [94] observed, after the acute administration of caffeine, an increase of central blood pressure, but not of peripheral systolic blood pressure.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [94] 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 10.1111/1556-4029.12387 24502704

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  • May combine two claims.

    Interpretationreasoning

    Doses below the toxic and/or lethal range may play a causal role in intoxication or death due to caffeine's interaction with other substances or to the individuals' preexisting metabolism alterations or diseases.

    “This could be due to caffeine’s interaction with other substances or to the individuals' preexisting metabolism alterations or diseases.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Moderate-to-high consumers develop tolerance to caffeine and only low or nonconsumers can eventually benefit from an acute administration.

    “Besides, moderate-to-high consumers develop tolerance to caffeine and only low or nonconsumers can eventually benefit from an acute administration [10].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Griffiths R.R. Mumford G.K. Schuster C.R. Kuhar M.J. Caffeine reinforcement, discrimination, tolerance, and physical dependence in laboratory animals and humans In: Handbook of Experimental Pharmacology 1996 Heidelberg Springer-Verlag 315 341 Handbook of Experimental Pharmacology 10.1007/978-3-642-60963-3_9

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    Premisecitation

    The ingestion of caffeine at a dose of 150 mg enhances cognitive performance for at least 10 hours.

    “In 2001, the Institute of Medicine Food and Nutrition Board Committee on Military Nutrition Research reported that the ingestion of caffeine at a dose of 150 mg enhances cognitive performance for at least 10 hours [113].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [113] Jarvis M.J. Does caffeine intake enhance absolute levels of cognitive performance? Psychopharmacology (Berl.) 1993 110 1-2 45 52 10.1007/BF02246949 7870897

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    Premisecitation

    Coffee and caffeine-containing products affect the cardiovascular system, with positive inotropic and chronotropic effects, and the central nervous system, with locomotor activity stimulation and anxiogenic-like effects.

    “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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [63] Rudolph T Knudsen K A case of fatal caffeine poisoning. Acta Anaesthesiol. Scand. 2010 54 4 521 523 20096021

      Not checked in the free run.

    • cites [117] 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 10.1007/BF00845371 7154064

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  • May combine two claims.

    Interpretationcitation

    High caffeine concentrations may cause marked hypotension secondary to vasodilation and, thus, ventricular fibrillation, which could be a possible mechanism of cardiovascular collapse.

    “High caffeine concentrations may cause marked hypotension secondary to vasodilation and, thus, ventricular fibrillation, which could be a possible mechanism of cardiovascular collapse [93].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [93] 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 7503265

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    Premisenone given

    WADA continues to measure caffeine levels through urinary concentration testing within its Monitoring Program to investigate patterns of misuse of substances in sport.

    “However, the WADA continues to measure caffeine levels through urinary concentration testing within its Monitoring Program, in order to investigate patterns of misuse of substances in sport.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Caffeine elevated peripheral blood pressure versus placebo, and the blood pressure response was not abolished after five days of caffeine doses of 600 mg/day.

    “found that caffeine elevated peripheral blood pressure vs. placebo and the blood pressure response was not abolished after five days of caffeine doses of 600 mg/day.”
    Quote in the paperSubstantial claim

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    Premisenone given

    Since the introduction of Red Bull in Austria in 1987 and in the US in 1997, the energy drink market has enormously expanded.

    “Since the introduction of Red Bull in Austria in 1987 and in the US in 1997, the energy drink market has enormously expanded.”
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    Premisenone given

    There are increasing reports of caffeine abuse, dependence, and withdrawal syndromes.

    “There are increasing reports of caffeine abuse, dependence, and withdrawal syndromes,”
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    Premisenone given

    The most common dietary source of caffeine is coffee, but cocoa beverages, soft drinks, energy drinks, medications, and specialized sports foods and supplements also contribute to regular intake.

    “The most common dietary source of caffeine is coffee, but cocoa beverages, soft drinks, energy drinks, medications, and specialized sports foods and supplements also contribute to regular intake.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Instant coffee generally contains less caffeine than roast and ground coffee, but is usually consumed in greater volumes.

    “Instant (also known as soluble) coffee generally contains less caffeine than roast and ground coffee, but is usually consumed in greater volumes.”
    Quote in the paperNot a substantial claim

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    Premisenone given

    A moderate dose of caffeine (3-5 mg/kg body weight) taken an hour before hard training or competition significantly increases performance as compared to placebo, with minimal side effects.

    “A moderate dose of caffeine (3-5mg/kg body weight) taken an hour before a hard training or competition, has been found to significantly increase performance as compared to placebo, with the athletes affected by minimal side effects.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Because of varying amounts of caffeine consumed in each country, it is difficult to set an international standard.

    “Because of thevarying amounts of caffeine consumed in each country, it is difficult to set an international standard.”
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    Premiseown data

    The caffeine content of drugs varies from 16 mg to 200 mg per tablet.

    “The caffeine content of drugs varies from 16 mg to 200 mg per tablet (Table 2).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisereasoning

    The caffeine content of a cup of tea is usually less than 60 mg, but a strong cup of tea may contain more caffeine than a weak cup of regular coffee.

    “The caffeine content of a cup of tea is usually less than 60 mg, but a strong cup of tea may contain more caffeine than a weak cup of regular coffee (Table 2).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    About 180 ml of a soft drink contain 30-70 mg of caffeine, and major brands of cola sold in Europe contain about 120 mg of caffeine per liter.

    “About 180 ml of a soft drink contain 30-70 mg of caffeine. The major brands of cola sold in Europe contain about 120 mg of caffeine per liter (Table 2).”
    Quote in the paperNot a substantial claim

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    Premisenone given

    Recent literature suggests that the development of caffeine tolerance is partial and may differ with regard to caffeine's central versus peripheral effects.

    “The recent literature suggests that the development of caffeine tolerance is partial and may differ with regard to caffeine’s central vs. peripheral effects.”
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    In sports, caffeine use is very common.

    “In sports, caffeine use is very common.”
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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Energy drinks contain high concentrations of caffeine, as well as other performance-enhancing substances such as guarana, taurine, and B vitamins.

    “Energy drinks contain high concentrations of caffeine, as well as other performance-enhancing substances, such as guarana, taurine, and B vitamins.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Tolerance to the peripheral effects of caffeine may be variable depending on the response system assessed, but appears less consistent than tolerance to its central effects.

    “Therefore, tolerance to the peripheral effects of caffeine may be variable, depending on the response system assessed, but it appears to be less consistent than tolerance to its central effects.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Regulation of energy drinks, including labeling, permissible maximum caffeine levels, and health warnings, has been rather complex in most countries, with one of the most lax normative frameworks in the US.

    “The regulation of energy drinks, including their labeling, permissible maximum caffeine levels, and health warnings, has been rather complex in most countries, with one of the most lax normative frameworks in the US.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Caffeine withdrawal symptoms manifest after 12-24 hours, peak at 24-48 hours, and persist for about one week.

    “symptoms manifested themselves after 12-24 hours, reached a peak at 24-48 hours, and persisted for about one week [151].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [151] Shapiro R.E. Caffeine and headaches. Curr. Pain Headache Rep. 2008 12 4 311 315 10.1007/s11916-008-0052-z 18625110

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    In recent years, regulatory upper limits have been set for beverages in which caffeine is not contained naturally but added either from a natural or a synthetic source.

    “In the recent years, to limit this phenomenon, regulatory upper limits have been set for those beverages in which caffeine is not contained naturally, but added either from a natural or a synthetic source.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Countless brands of energy drinks can now be found, with caffeine content ranging from 50 mg to 500 mg per can or bottle.

    “Countless brands can now be found, with caffeine content ranging from a modest 50 mg to an alarming 500 mg per can or bottle.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    A cup is usually assumed to contain 180 ml of coffee, but an espresso may contain as little as 40 ml.

    “A cup is usually assumed to contain 180 ml of coffee, but an espresso may contain as little as 40 ml [157].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [157] 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 10.1161/01.HYP.0000120965.63962.93 14967827

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Genetic factors may also contribute to an individual's vulnerability to caffeine-related disorders.

    “Genetic factors may also contribute to an individual’s vulnerability to caffeine-related disorders.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Several studies suggest that energy drinks may serve as a gateway to other forms of substance dependence.

    “Furthermore, several studies suggest that energy drinks may serve as a gateway to other forms of substance dependence.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Cocoa and chocolate drinks contribute 4-5 mg of caffeine per cup, and dark chocolate and cooking chocolate contribute 0.7-0.9 mg per gram.

    “Cocoa and chocolate drinks contribute to the diet with 4-5 mg of caffeine per cup, dark chocolate and cooking chocolate with 0.7-0.9 mg per gram.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Decaffeinated coffee must contain less than 0.1% caffeine by dry weight to comply with regulations, corresponding to about 3-5 mg of caffeine in a cup.

    “Decaffeinated coffee, regardless of the method of decaffeination, must contain less than 0.1% caffeine by dry weight to comply with regulations. This corresponds to about 3-5 mg of caffeine in a cup of decaffeinated coffee.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Robusta coffees contain about twice as much caffeine as arabicas.

    “Robusta coffees contain about twice as much caffeine than arabicas.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    The amount of caffeine contained in a cup of coffee varies greatly depending on its origin or blend composition, the brewing method, and the strength of the brew.

    “The amount of caffeine contained in a cup of coffee can vary greatly, depending on its origin or the composition of the blend, the brewing method, and the strength of the brew.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The sympathetic nervous system has an important role in regulating blood pressure.

    “The sympathetic nervous system has an important role in regulating blood pressure [156].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [156] 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 10.1097/10.PSY.0000107884.78247.F9 14747639

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Prior to 2004, caffeine was included in the WADA Prohibited List with a legal urinary concentration limit of 12 μg/ml.

    “Prior to 2004, caffeine was included in the World Anti-Doping Agency (WADA) Prohibited List of substances and methods, with a legal urinary concentration limit of 12μg/ml;”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Both the type of tea and the infusing time can affect the amount of caffeine.

    “Both the type of tea and the infusing time can affect the amount of caffeine.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Reissig et al. have described several negative effects of excessive caffeine consumption.

    “Reissig et al. [159] have described several negative effects of excessive caffeine consumption.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [159] Cherniske S. Caffeine Blues: Wake Up to the Hidden Dangers of America's #1 Drug. 1998 1st ed New York Warner Books Inc 35

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Response differences between nonusers and habitual caffeine users may reflect genetic differences or an atypical response to caffeine that might have led to nonusers' caffeine avoidance.

    “Response differences may merely reflect genetic differences between nonusers and habitual users, or an atypical response to caffeine that might have led to nonusers’ caffeine avoidance.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: 80% of the population report regular use of caffeine.

  • May combine two claims.

    Premisereasoning

    The WADA revision was based on the acknowledgment that caffeine enhances performance at doses impossible to differentiate from daily caffeine use and that monitoring caffeine use via urinary concentration is not completely reliable.

    “This revision was based on the acknowledgment that caffeine enhances performance at doses that are impossible to differentiate from daily caffeine use and that the practice of monitoring caffeine use via urinary concentration is not completely reliable.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Tea contains more caffeine than coffee by dry weight, but less weight is used to brew a cup of tea.

    “Teacontains more caffeine than coffee by dry weight, but less weight is used, in general, to brew a cup of tea.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisereasoning

    The NCAA has a urinary concentration limit of 15 μg/ml, so athletes in the NCAA must take into account that caffeine is still on the list of controlled substances.

    “has a urinary concentration limit of 15μg/ml; thus, athletes in the NCAA must take into account that caffeine is still on the list of controlled substances.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    These effects can cause both psychological and physical dependence.

    “These effects can cause both psychological and physical dependence.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Caffeine's psychological effects are a direct result of caffeine-induced chemical activation of different neuronal pathways through alterations in neurotransmitters' release.

    “they are a direct result of the caffeine-induced chemical activation of different neuronal pathways through alterations in neurotransmitters’ release.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Dependence can be a normal body response to a substance.

    “when in fact dependence can be a normal body response to a substance.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    The effects of caffeine use on the cardiovascular system are the result of direct and/or indirect actions of caffeine on the neuroendocrine control systems of vascular resistance, cardiac function, and electrolyte balance.

    “The effects of caffeine use on the cardiovascular system taken into account to evaluate the risk of acute and chronic cardiovascular diseases are also the result of the direct and/or indirect actions of caffeine on the neuroendocrine control systems of vascular resistance, cardiac function, and electrolyte balance.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    DSM-5 suggested the code 'substance use disorder', where the specific substance has to be indicated.

    “In an attempt to address this problem, the DSM-5 [162] suggested the code “substance use disorder”, where the specific substance has to be indicated,”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [162] American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders 2000

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Craving is characterized by behavior aimed at obtaining the substance and by intrusive thoughts that focus on the substance.

    “It is characterized by a behavior aimed at obtaining the substance and by intrusive thoughts that focus on the substance, such as intrusive thoughts about caffeine.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Craving is a key element in the genesis of substance addiction and relapse.

    “Craving is a key element in the genesis of substance addiction and relapse that often individuals with abuse or dependence encounter.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Many individuals who consume caffeine simultaneously consume other substances such as nicotine or alcohol, which may have overlapping effects.

    “Moreover, many individuals who consume caffeine simultaneously consume other substances, such as nicotine or alcohol, which may have overlapping effects.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Substance use disorder in DSM-5 combines the DSM-IV-TR categories of substance abuse and substance dependence into a single disorder measured on a continuum from mild to severe.

    “Substance use disorder in DSM-5 combines the DSM-IV-TR categories of substance abuse and substance dependence into a single disorder measured on a continuum from mild to severe.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [162] American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders 2000

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    DSM-5 substance use disorder severity is mild if 2 to 3 symptoms are present, moderate if 4 to 5 symptoms are present, and severe if 6 or more symptoms are present.

    “The disorder can occur in a broad range of severity, basing on the number of symptom criteria endorsed: mild, if 2 to 3 symptoms are present, moderate if 4 to 5 symptoms are present, and severe if 6 or more symptoms are present.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [162] American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders 2000

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Caffeine intoxication is a recognized clinical syndrome included in DSM-5 and ICD-10.

    “Caffeine intoxication is a recognized clinical syndrome included in the DSM-5 [162] and the World Health Organization’s International Classification of Diseases (ICD-10) [165].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [162] American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders 2000

      Not checked in the free run.

    • cites [165] Verheul R. van den Brink W. Geerlings P. A three-pathway psychobiological model of craving for alcohol Alcohol Alcohol 1999 34 2 197 222 10.1093/alcalc/34.2.197 10344781

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Caffeine, like other psychoactive substances, can induce abuse and dependence.

    “Caffeine, like other psychoactive substances, can induce abuse and dependence.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Some disorders are typically linked to recreational and professional athletes who consume caffeine to face fatigue and intense workouts.

    “Some disorders are typically linked to recreational and professional athletes who consume caffeine to face fatigue and intense workouts.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    In recent years caffeine use has increased, especially among young people, due to the wide diffusion of caffeinated beverages advertised as energy drinks.

    “In recent years caffeine use has increased, especially among young people, due to the wide diffusion of caffeinated beverages advertised as energy drinks.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Energy drink consumption may increase the risk of caffeine overdose in caffeine abstainers, as well as habitual caffeine users.

    “Energy drink consumption may increase the risk of caffeine overdose in caffeine abstainers, as well as habitual caffeine users.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Psychological craving occurs during abstinence, often leads to relapse, and is related to activation of the reward system in the medial forebrain bundle, including the dopaminergic meso-cortico-limbic pathway.

    “2) psychological craving that occurs during abstinence and often leads to relapse. It is related to the activation of the reward system, located in the brain in the medial forebrain bundle, which includes the dopaminergic meso-cortico-limbic pathway.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [164] WHO Lexicon of alcohol and drug terms 1995 World Health Organization Geneva

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Over the years, existing literature has applied DSM-IV-TR or previous criteria to assess dependence among populations of users.

    “Over the years, the existing literature has applied DSM-IV-TR [161] or previous criteria to assess dependence among populations of users.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [161] Kashkin K.B. Kleber H.D. Hooked on hormones? An anabolic steroid addiction hypothesis JAMA 1989 262 22 3166 3170 10.1001/jama.1989.03430220089036 2681859

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Caffeine, like alcohol and tobacco, is legally used, but unlike the last two, its sale in the form of high concentration drinks or tablets is not controlled or restricted.

    “Furthermore, caffeine, like alcohol and tobacco, is legally used, but, unlike the last two, its sale in the form of high concentration drinks or tablets is not controlled or restricted.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationreasoning

    Despite the wide diffusion of caffeine in drinks, foods, and medications, death from acute intoxication is relatively rare and is mostly caused by voluntary or involuntary ingestion of tablets containing pure caffeine in high concentrations.

    “Despite the wide diffusion of caffeine in the form of drinks, foods, and medications, death from acute intoxication is relatively rare and is mostly caused by voluntary or involuntary ingestion of tablets containing pure caffeine in high concentrations.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Some individuals abuse caffeine to enhance concentration and memory or improve physical performance, and in some cases develop a dependence syndrome.

    “Moreover, some individuals go on to abuse caffeine to enhance their concentration and memory or to improve their physical performance, and in some cases develop a dependence syndrome.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Caffeine is able to induce an abstinence syndrome during withdrawal after prolonged use and can lead to addiction and tolerance mechanisms.

    “It has been demonstrated that caffeine is able to induce an abstinence syndrome during withdrawal after prolonged use and can lead to addiction and tolerance mechanisms,”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The acute toxic level of caffeine is not well established, but for adults it is approximately 10 g/day, comparable to approximately 100 cups of coffee.

    “The acute toxic level of caffeine is not well established, but for adults it is approximately 10 g/day, which is comparable to a consumption of approximately 100 cups of coffee [167].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [167] Greden J.F. Anxiety or caffeinism: a diagnostic dilemma Am. J. Psychiatry 1974 131 10 1089 1092 4412061

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In psychiatry, physical craving occurs in substance addicts or alcoholics who stop taking drugs or drinking after a long period of excessive consumption and is mostly associated with physical withdrawal symptoms.

    “1) physical craving that occurs in substance addicts or alcoholics who stop taking drugs or drinking after a long period of excessive consumption; this type of craving is mostly associated with physical symptoms of the withdrawal type, such as increased heart rate, sweating, nausea, agitation, tremors, etc.;”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [164] WHO Lexicon of alcohol and drug terms 1995 World Health Organization Geneva

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In DSM-5, substance use disorder requires at least two symptoms from a list of eleven, whereas past diagnosis of substance abuse required only one symptom.

    “Whereas in the past a diagnosis of substance abuse required only one symptom, substance use disorder in the DSM-5 requires at least two symptoms from a list of eleven.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [162] American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders 2000

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In caffeine dependence, individuals consume extremely high doses, ignore safety issues, take combinations of two or more sources, and consume caffeine almost continuously for years.

    “In caffeine dependence, individuals start to consume extremely high doses, ignoring all safety issues; they take a combination of two or more different sources of caffeine, for example, coffee and energy drinks, although the combination is not proven to have any added desirable effects; they consume caffeine almost continuously for years, reaching an excessive cumulative duration of use.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Caffeine's psychological effects are responsible for its widespread use, as they can provide energy and improve cognitive skills.

    “Caffeine’s psychological effects are also responsible for its widespread use, as they can provide energy and improve cognitive skills;”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    On the basis of the known mechanisms of action, caffeine can be considered a psychostimulant, since its main effects are correlated to the interfering action on the neuroendocrine control systems.

    “On the basis of the known mechanisms of action, caffeine can be considered as a psychostimulant, since its main effects are correlated to the interfering action on the neuroendocrine control systems.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A 'substance dependence disorder' was coded by the American Psychiatric Association in 1989.

    “A “substance dependence disorder” was coded by the American Psychiatric Association (APA) in 1989 [160].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [160] Reissig C.J. Strain E.C. Griffiths R.R. Caffeinated energy drinks--a growing problem. Drug Alcohol Depend 2009 99 1-3 1 10 10.1016/j.drugalcdep.2008.08.001 18809264 PMC2735818

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Addiction and tolerance mechanisms may determine a reduction of the 'dangerous' cardiovascular effects, but may increase frequency and amounts of consumption.

    “which on the one hand may determine a reduction of the “dangerous” cardiovascular effects, but on the other hand may increase frequency and amounts of consumption.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Craving appears to be essentially the result of a stimulus evoking the substance, but sometimes its onset is not apparently linked with any stimulus; it tends to diminish with time, but can appear even after years of abstinence.

    “Once considered a manifestation of the withdrawal syndrome, craving appears to be essentially the result of a stimulus evoking the substance, but sometimes its onset is not apparently linked with any stimulus; it tends to diminish with time, but it can appear even after years of abstinence.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Caffeine causes the classic withdrawal syndrome, mediated by neuroendocrine and cortical neurotransmitter systems.

    “even if caffeine causes the classic withdrawal syndrome, mediated by neuroendocrine and cortical neurotransmitter systems,”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Substance craving was added to the DSM-5 list and problems with law enforcement were eliminated because of cultural considerations.

    “Substance craving was added to the list and problems with law enforcement were eliminated because of cultural considerations that made the criteria difficult to apply internationally.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [162] American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders 2000

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The revised substance use disorder, a single diagnosis, better matches the symptoms that individuals experience.

    “The revised substance use disorder, a single diagnosis, better matches the symptoms that individuals experience.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In one lethal case described by Chaturvedi et al., the concentration of caffeine was below fatal levels and above toxic levels, and the death was multi-chemical involving caffeine and nicotine.

    “Only in one lethal case, described by Chaturvedi et al. [174], the concentration of caffeine was below the fatal levels and above the toxic levels: this was a case of multi-chemical death involving caffeine and nicotine.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [174] Bryant J. Suicide by ingestion of caffeine. Arch. Pathol. Lab. Med. 1981 105 12 685 686 6895464

      Not checked in the free run.

88 of 88

  • The paper relies on this without support.

    Caffeine use is increasing worldwide.

    “Caffeine use is increasing worldwide.”

  • The paper relies on this without support.

    Caffeine abuse and dependence are becoming more and more common.

    “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 paper relies on this without support.

    Caffeine abuse and dependence can lead to caffeine intoxication.

    “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 paper relies on this without support.

    Caffeine intoxication puts individuals at risk for premature and unnatural death.

    “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 paper relies on this without support.

    The majority of studies compare caffeine-naive individuals to habitual caffeine users, or habitual users before and after caffeine abstinence.

    “The majority of studies compare caffeine “naïve” individuals to habitual caffeine users, or habitual users before and after caffeine abstinence.”

  • The paper relies on this without support.

    80% of the population report regular use of caffeine.

    “As 80% of the population report regular use of caffeine, nonusers are much selected, atypical subpopulation.”

  • The paper relies on this without support.

    Very few studies compare individuals subjected to repeated caffeine administration versus controls taking placebo.

    “Furthermore, very few studies compare individuals subjected to repeated caffeine administration vs. controls taking placebo.”
7 of 7

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Estrogen regulates the effect of caffeine on the dopamine system, suggesting a complex interaction between caffeine, estrogen, and dopamine in the basal ganglia system.

    “Since estrogen has a neuroprotective or neurotrophic effect and regulates the dopamine system of the black striatum [7], estrogen regulates the effect of caffeine on the dopamine system and suggests that a complex interaction between caffeine, estrogen, and dopamine exists in the basal ganglia system [8].”

    From Effect of Caffeine Consumption on the Risk for Neurological and Psychiatric Disorders: Sex Differences in Human (2020) · cites this paper as [8]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Prineas citation points to a different reference

    Minor

    The text attributes the finding to Prineas et al. at reference [69], but entry 69 is by Pelchovitz et al.; Prineas et al. is entry 70. Other author-reference-number mismatches also occur in the text.

  • Theobromine is called the largest metabolite fraction despite the stated percentages

    Minor

    The paper calls theobromine the higher proportion of biologically active metabolites, but earlier says paraxanthine accounts for 84% of caffeine demethylation products and theobromine for 12%. It also identifies paraxanthine as biologically active.

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 5

  1. [17]Arnaud M.J. Garattini S. Metabolism of caffeine and other components of coffee Caffeine, coffee and health 1993 New York Raven Press 43 95
  2. [21]Daly J. Garattini S. Mechanism of action of caffeine. Caffeine, Coffee, and Health. 1993 New York Raven Press 97 149
  3. [163]American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorderss 2013 Fifth Edition (DSM-5) Arlington APA
  4. [170]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. 2011 4th ed London Pharmaceutical Press 36
  5. [174]Bryant J. Suicide by ingestion of caffeine. Arch. Pathol. Lab. Med. 1981 105 12 685 686 6895464

Cited by

Sorted by citations

Related

Authors
Cappelletti, S., Daria, P., Sani, G., & Aromatario, M.
Affiliations
Sapienza University of Rome (IT)
Corresponding author
Aromatario, Mariarosaria
ORCID
Venue
Current Neuropharmacology
Publisher
Bentham Science Publishers Ltd.
Published
2015-04-13
Volume
13
Issue
1
Pages
71-88
ISSN
1570-159X (ISSN-L)
DOI
10.2174/1570159x13666141210215655
PMC
PMC4462044
OpenAlex
W2314874570
Semantic Scholar
a83840eb0d48fe8a65daac85625a6173f17dbc6b
Cited by
631
References
189
Citations by year
2026: 58 · 2025: 81 · 2024: 86 · 2023: 93 · 2022: 76 · 2021: 71 · 2020: 49 · 2019: 49 · 2018: 35 · 2017: 19 · 2016: 11 · 2015: 3
FWCI
1.41
Type
journal article
Language
en
Open access
Locations
  • Current Neuropharmacology (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, other-oa)
Funders
National Collegiate Athletic Association
Topics
  • Health Sciences › Medicine › Pharmacology › Coffee research and impacts
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Alkaloids: synthesis and pharmacology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
Keywords
caffeine, cognitive enhancement, physical performance, adenosine antagonism, calcium mobilization, phosphodiesterase inhibition, caffeine toxicity, caffeine dependence, cardiovascular effects, central nervous system stimulation, anxiogenic effects, lethal dose, drug interactions, caffeine metabolism
MeSH terms
Central Nervous System Stimulants, Caffeine, Drug Utilization, Humans, Nootropic Agents, Substance-Related Disorders, Athletic Performance

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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