U.S. flag

An official website of the United States government

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

Cover of StatPearls

StatPearls [Internet].

Show details


; ; .

Author Information and Affiliations

Last Update: June 8, 2023.

Continuing Education Activity

Caffeine is a naturally occurring central nervous system (CNS) stimulant of the methylxanthine class and is the most widely taken psychoactive stimulant globally. This drug is most commonly sourced from the coffee bean but can also be found naturally occurring in certain types of tea and cacao beans, and it is also an additive to soda and energy drinks. The primary goal of caffeine consumption is to combat fatigue and drowsiness, but there are many additional uses. This activity reviews the mechanism of action, adverse event profile, toxicity, dosing, pharmacodynamics, and monitoring of caffeine, pertinent for clinicians and other interprofessional team members where caffeine is already in use or might be necessary.


  • Review the FDA-approved on-label indications of caffeine, as well as other non-FDA uses.
  • Identify the proposed mechanism of action of caffeine.
  • Summarize the contraindications and associated risks associated with caffeine use.
  • Outline interprofessional team strategies for improving care coordination and communication when considering or using caffeine or controlling its use by patients to improve outcomes.
Access free multiple choice questions on this topic.


Caffeine is a naturally occurring central nervous system (CNS) stimulant of the methylxanthine class and is the most widely taken psychoactive stimulant globally. This drug is most commonly sourced from the coffee bean but can also be found naturally occurring in certain types of tea and cacao beans. It is also an additive to soda and energy drinks. The primary goal of caffeine consumption is to combat fatigue and drowsiness, but there are many additional uses.[1]

The FDA has approved caffeine for use in the treatment of apnea of prematurity and prevention and treatment of bronchopulmonary dysplasia of premature infants.[2][3][4] Non-FDA-approved uses of caffeine include treating migraine headaches and post-dural puncture headaches and enhancing athletic performance, especially in endurance sports.[5][1] Caffeine has links with decreased all-cause mortality.[6][7] It is also under investigation for its efficacy in treating depression and neurocognitive declines, such as those seen in Alzheimer and Parkinson disease.[8][9][10]

Mechanism of Action

Caffeine’s primary mechanism of action is on the adenosine receptors in the brain. As it is both fat and water-soluble, it readily crosses the blood-brain barrier, resulting in antagonism to all four adenosine receptor subtypes (A1, A2a, A2b, A3). Specifically, the antagonism of the A2a receptor is responsible for the wakefulness effects of caffeine.[11][12]

Adenosine receptors are not limited to the CNS but are present throughout the body. In cardiac muscle, direct antagonism of receptor A1 results in positive inotropic effects. Likewise, adenosine receptor antagonism stimulates the release of catecholamines, contributing to the systemic stimulatory effects of caffeine and further stimulating cardiac inotropy and chronotropy. At the vascular level, caffeine undergoes a complex interaction to control vascular tone, which includes direct antagonism of vascular adenosine receptors to promote vasodilation, as well as stimulation of endothelial cells to release nitric oxide. This action promotes further relaxation of vascular smooth muscle cells. This vasodilation becomes counteracted by increased sympathetic tone via catecholamine release and positive cardiac inotropic and chronotropic effects, promoting vasoconstriction. As there are multiple constriction and dilatation mechanisms at work, the overall result is individualized and dependent upon caffeine dose, the frequency of use, and comorbidities such as diabetes or hypertension. Overall, caffeine seems to increase systolic blood pressure by approximately 5 to 10 mmHg in individuals with infrequent use. However, there is little to no acute effect on habitual consumers.[13][12]

Furthermore, adenosine receptor blockage stimulates respiratory drive by increasing medullary ventilator response to carbon dioxide, stimulating central respiratory drive, and improving diaphragm contractility. Caffeine increases renal blood flow, glomerular filtration, and sodium excretion resulting in diuresis. It is also a potent stimulator of gastric acid secretion and gastrointestinal (GI) motility.[12][14]

Metabolism of caffeine primarily occurs in the liver via the cytochrome P450 oxidase system, specifically enzyme CYP1A2. Metabolism results in 1 of 3 dimethylxanthine, including paraxanthine, theobromine, and theophylline, each with unique effects on the body. These metabolites are then further metabolized and excreted in the urine.[13][15]

The half-life of caffeine is approximately 5 hours in the average adult. However, multiple factors can influence metabolism. Half-life is reduced by up to 50% in smokers compared to nonsmokers. Conversely, pregnant patients, especially those in the final trimester, will demonstrate a prolonged half-life upwards of 15 hours. Newborns will also have a significantly prolonged half-life, up to 8 hours for full-term and 100 hours for premature infants, due to reduced activity of cytochrome P450 enzymes and immature demethylation pathways. Children older than nine months will have similar half-life eliminations to that of adults. Additionally, patients with liver disease or those taking cytochrome inhibitors will also experience prolonged half-lives due to reduced enzyme activity.[16][17]


Caffeine has nearly 100% oral bioavailability and is the primary route of administration. Caffeine can be sourced from coffee beans, cacao beans, kola nuts, tea leaves, yerba mate, the guarana berry, as an additive to sodas and energy drinks, or consumed as powder or tablets.[1] When taken orally, onset typically occurs in 45 to 60 minutes and lasts approximately 3 to 5 hours. Absorption is somewhat delayed when taken with food. It can be administered via the parenteral route, which is a common method when treating apnea of prematurity in newborns or post-dural puncture headaches.

Alternatively, caffeine can be absorbed rectally, insufflated, or inhaled. Consumption via insufflation or inhalation is generally a form of misuse with the intention of "getting high." These routes lead to significantly faster absorption, usually within minutes, and bypass the first-pass metabolism. Although this route can lead to a faster onset of action, multiple studies have shown lower bioavailability from inhalation of caffeine; approximately 60% to 70%. When taken via this route, the duration of action is shorter.[15][18]

Adverse Effects

As with most drugs or medications, there is a long list of adverse effects associated with their use, and caffeine is no different. The adverse effects of caffeine range from mild to severe to even fatal and are generally related to the dose consumed and an individual’s sensitivity to the drug. The most common side effects are listed below. Mortality is usually associated with cardiac arrhythmia, hypotension, myocardial infarction, electrolyte disturbances, and aspiration.[19][7]


Anxiety, restlessness, fidgeting, insomnia, facial flushing, increased urination, muscle twitches or tremors, irritability, agitation, elevated or irregular heart rate, GI upset


Disorientation, hallucinations, psychosis, seizure, arrhythmias, ischemia, rhabdomyolysis

Caffeine can also cause withdrawal symptoms if habitual users abruptly stop.  These symptoms usually begin 12 to 24 hours from last consumption, peak in 1 to 2 days, and may persist for up to 1 week. Withdrawal is preventable if caffeine is tapered off instead of abruptly discontinued. If symptoms do arise, they are promptly reversible by re-administration of caffeine.[20]

Lastly, when used to treat apnea of prematurity, there is evidence of an increased risk of necrotizing enterocolitis in neonates.[21]


Although there are no absolute contraindications to caffeine, there are some medical conditions in which caution is necessary, which includes[7][22][14][17]:

  • Severe anxiety
  • Cardiovascular disease or symptomatic cardiac arrhythmias
  • Peptic ulcer disease or gastroesophageal reflux disease
  • Hepatic impairment
  • Renal impairment
  • Seizures (as may lower seizure threshold)
  • Pregnancy

American College of Obstetricians and Gynecologists (ACOG) considers 200 mg daily safe during pregnancy.[23] There is no evidence to suggest caffeine increases the risk of congenital malformations.[24] However, some studies have concluded that high caffeine consumption during pregnancy (more than 400 mg per day) may be associated with lower birth weights from intrauterine growth restriction, increased risk of miscarriage, but not preterm birth.[25][26] However, the evidence regarding lower birth weight and miscarriage is presently inconclusive and pending further investigation.[27] Caffeine is considered a pregnancy class C drug.[23]


The average dose of caffeine is 2.4 mg/kg per day for adults; however, daily doses of up to 400 mg are considered safe.[28] Consumption of 100 mg of caffeine generally increases blood levels by 5 to 6 mg/L.[29] There are reports of severe intoxication that causes altered mentation, vomiting, and hypotension at levels of 80 mg/L. The average blood level of patients who succumb to caffeine toxicity is 180 mg/L (+/- 97 mg/L).[30]

For the treatment of apnea of prematurity, caffeine is administered as a 20 mg/kg loading dose, followed by 5 to 10 mg/kg per day of caffeine citrate via enteral or parenteral routes with therapeutic index goals of 5 to 25 mg/L.[31][32]


Caffeine consumption is generally recognized as safe. Most substances do not require FDA approval for additive caffeine as long as it falls within safe levels dictated by the statute. The typical dose of caffeine is roughly 70 to 100 mg per drink. Although there is no specific daily allowance for caffeine, doses of up to 400 mg a day are considered safe.[33]

The exact LD50 for humans is variable and largely dependent on sensitivity to caffeine. However, it is estimated to be 150 to 200 mg/kg. There are, however, case reports of doses as low as 57 mg/kg being fatal. A toxic dose of caffeine, or a dose at which significant unfavorable side effects begin to occur, for example, tachycardia, arrhythmia, altered mentation, and seizure, is estimated to be approximately 1.2 grams, while estimates of a life-threatening dose are in the range of 10 to 14 grams.[19][34]

Ultimately, treatment is primarily supportive in cases of mild ingestions. For more severe ingestions, additional interventions may be necessary. Patients may require intubation for airway protection from vomiting or altered mental status. Benzodiazepines can be given to abort any seizures that develop. Patients may require vasopressors to combat persistent hypotension if intravenous (IV) fluid resuscitation alone fails. The first-line vasopressor should be either phenylephrine or norepinephrine. However, phenylephrine is the ideal choice due to its pure alpha agonism as well as reflex bradycardia. Magnesium and beta-blockers can be used to combat cardiac arrhythmias secondary to the hyperadrenergic response.[34] The ultra-short acting beta-1 selective blocker esmolol has been used successfully in several case reports for this indication. In the event of lethal arrhythmias, patients will require defibrillation and resuscitation per ACLS protocol.[22] Activated charcoal, intralipid infusion, and hemodialysis can help prevent further metabolism and subsequent effects of caffeine overdose.[19][35]

Enhancing Healthcare Team Outcomes

Caffeine consumption is relatively safe in limited amounts. The problem is that many people today are consuming high-energy drinks that contain massive amounts of caffeine, which can lead to complications. Today the issue of caffeine toxicity has been worsened with high-energy drinks. These concentrated caffeinated beverages are not only toxic themselves, but the problem becomes exacerbated when the individual combines caffeine use with other illicit agents, such as tobacco and alcohol. Over the past few years, there have been reports of many deaths following the consumption of such combinations.

Dealing with caffeine toxicity or side effects, or using caffeine therapeutically, requires an interprofessional healthcare team for optimal results. For therapeutic use, query the patient about other potential caffeine sources so that toxicity is not an issue with therapy.  Team members are in a prime position to educate the public on the dangers of high-energy drinks and related foods. Clinicians, nursing staff, and pharmacists must be prepared to offer counsel to patients who may be overindulging in caffeine. While there are no absolute contraindications to caffeine, the public should be advised to avoid caffeine if they have cardiac disorders, panic disorder, anxiety, or elevated stress levels. An interprofessional team is the best means by which to convey this message. [Level 5]

Review Questions


Nehlig A, Daval JL, Debry G. Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects. Brain Res Brain Res Rev. 1992 May-Aug;17(2):139-70. [PubMed: 1356551]
Mathew OP. Apnea of prematurity: pathogenesis and management strategies. J Perinatol. 2011 May;31(5):302-10. [PubMed: 21127467]
Kugelman A, Durand M. A comprehensive approach to the prevention of bronchopulmonary dysplasia. Pediatr Pulmonol. 2011 Dec;46(12):1153-65. [PubMed: 21815280]
Schmidt B. Methylxanthine therapy for apnea of prematurity: evaluation of treatment benefits and risks at age 5 years in the international Caffeine for Apnea of Prematurity (CAP) trial. Biol Neonate. 2005;88(3):208-13. [PubMed: 16210843]
Pesta DH, Angadi SS, Burtscher M, Roberts CK. The effects of caffeine, nicotine, ethanol, and tetrahydrocannabinol on exercise performance. Nutr Metab (Lond). 2013 Dec 13;10(1):71. [PMC free article: PMC3878772] [PubMed: 24330705]
Freedman ND, Park Y, Abnet CC, Hollenbeck AR, Sinha R. Association of coffee drinking with total and cause-specific mortality. N Engl J Med. 2012 May 17;366(20):1891-904. [PMC free article: PMC3439152] [PubMed: 22591295]
Lara DR. Caffeine, mental health, and psychiatric disorders. J Alzheimers Dis. 2010;20 Suppl 1:S239-48. [PubMed: 20164571]
Cunha RA, Agostinho PM. Chronic caffeine consumption prevents memory disturbance in different animal models of memory decline. J Alzheimers Dis. 2010;20 Suppl 1:S95-116. [PubMed: 20182043]
Arendash GW, Schleif W, Rezai-Zadeh K, Jackson EK, Zacharia LC, Cracchiolo JR, Shippy D, Tan J. Caffeine protects Alzheimer's mice against cognitive impairment and reduces brain beta-amyloid production. Neuroscience. 2006 Nov 03;142(4):941-52. [PubMed: 16938404]
Santos C, Costa J, Santos J, Vaz-Carneiro A, Lunet N. Caffeine intake and dementia: systematic review and meta-analysis. J Alzheimers Dis. 2010;20 Suppl 1:S187-204. [PubMed: 20182026]
Ferré S. An update on the mechanisms of the psychostimulant effects of caffeine. J Neurochem. 2008 May;105(4):1067-79. [PubMed: 18088379]
Fisone G, Borgkvist A, Usiello A. Caffeine as a psychomotor stimulant: mechanism of action. Cell Mol Life Sci. 2004 Apr;61(7-8):857-72. [PubMed: 15095008]
Echeverri D, Montes FR, Cabrera M, Galán A, Prieto A. Caffeine's Vascular Mechanisms of Action. Int J Vasc Med. 2010;2010:834060. [PMC free article: PMC3003984] [PubMed: 21188209]
Boekema PJ, Samsom M, van Berge Henegouwen GP, Smout AJ. Coffee and gastrointestinal function: facts and fiction. A review. Scand J Gastroenterol Suppl. 1999;230:35-9. [PubMed: 10499460]
Zandvliet AS, Huitema AD, de Jonge ME, den Hoed R, Sparidans RW, Hendriks VM, van den Brink W, van Ree JM, Beijnen JH. Population pharmacokinetics of caffeine and its metabolites theobromine, paraxanthine and theophylline after inhalation in combination with diacetylmorphine. Basic Clin Pharmacol Toxicol. 2005 Jan;96(1):71-9. [PubMed: 15667599]
Fredholm BB, Bättig K, Holmén J, Nehlig A, Zvartau EE. Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev. 1999 Mar;51(1):83-133. [PubMed: 10049999]
Verbeeck RK. Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction. Eur J Clin Pharmacol. 2008 Dec;64(12):1147-61. [PubMed: 18762933]
Laizure SC, Meibohm B, Nelson K, Chen F, Hu ZY, Parker RB. Comparison of caffeine disposition following administration by oral solution (energy drink) and inspired powder (AeroShot) in human subjects. Br J Clin Pharmacol. 2017 Dec;83(12):2687-2694. [PMC free article: PMC5698589] [PubMed: 28758694]
Kerrigan S, Lindsey T. Fatal caffeine overdose: two case reports. Forensic Sci Int. 2005 Oct 04;153(1):67-9. [PubMed: 15935584]
Juliano LM, Griffiths RR. A critical review of caffeine withdrawal: empirical validation of symptoms and signs, incidence, severity, and associated features. Psychopharmacology (Berl). 2004 Oct;176(1):1-29. [PubMed: 15448977]
Cox C, Hashem NG, Tebbs J, Bookstaver PB, Iskersky V. Evaluation of caffeine and the development of necrotizing enterocolitis. J Neonatal Perinatal Med. 2015;8(4):339-47. [PubMed: 26757002]
Fabrizio C, Desiderio M, Coyne RF. Electrocardiogram Abnormalities of Caffeine Overdose. Circ Arrhythm Electrophysiol. 2016 Jul;9(7) [PubMed: 27406599]
ACOG CommitteeOpinion No. 462: Moderate caffeine consumption during pregnancy. Obstet Gynecol. 2010 Aug;116(2 Pt 1):467-468. [PubMed: 20664420]
Chen LW, Wu Y, Neelakantan N, Chong MF, Pan A, van Dam RM. Maternal caffeine intake during pregnancy is associated with risk of low birth weight: a systematic review and dose-response meta-analysis. BMC Med. 2014 Sep 19;12:174. [PMC free article: PMC4198801] [PubMed: 25238871]
Chen LW, Wu Y, Neelakantan N, Chong MF, Pan A, van Dam RM. Maternal caffeine intake during pregnancy and risk of pregnancy loss: a categorical and dose-response meta-analysis of prospective studies. Public Health Nutr. 2016 May;19(7):1233-44. [PMC free article: PMC10271029] [PubMed: 26329421]
Bracken MB, Triche EW, Belanger K, Hellenbrand K, Leaderer BP. Association of maternal caffeine consumption with decrements in fetal growth. Am J Epidemiol. 2003 Mar 01;157(5):456-66. [PubMed: 12615610]
Brent RL, Christian MS, Diener RM. Evaluation of the reproductive and developmental risks of caffeine. Birth Defects Res B Dev Reprod Toxicol. 2011 Apr;92(2):152-87. [PMC free article: PMC3121964] [PubMed: 21370398]
Poole R, Kennedy OJ, Roderick P, Fallowfield JA, Hayes PC, Parkes J. Coffee consumption and health: umbrella review of meta-analyses of multiple health outcomes. BMJ. 2017 Nov 22;359:j5024. [PMC free article: PMC5696634] [PubMed: 29167102]
Jones AW. Review of Caffeine-Related Fatalities along with Postmortem Blood Concentrations in 51 Poisoning Deaths. J Anal Toxicol. 2017 Apr 01;41(3):167-172. [PubMed: 28334840]
Cappelletti S, Piacentino D, Fineschi V, Frati P, Cipolloni L, Aromatario M. Caffeine-Related Deaths: Manner of Deaths and Categories at Risk. Nutrients. 2018 May 14;10(5) [PMC free article: PMC5986491] [PubMed: 29757951]
Francart SJ, Allen MK, Stegall-Zanation J. Apnea of prematurity: caffeine dose optimization. J Pediatr Pharmacol Ther. 2013 Jan;18(1):45-52. [PMC free article: PMC3626066] [PubMed: 23616735]
Koch G, Datta AN, Jost K, Schulzke SM, van den Anker J, Pfister M. Caffeine Citrate Dosing Adjustments to Assure Stable Caffeine Concentrations in Preterm Neonates. J Pediatr. 2017 Dec;191:50-56.e1. [PubMed: 29173321]
Neves DBDJ, Caldas ED. Determination of caffeine and identification of undeclared substances in dietary supplements and caffeine dietary exposure assessment. Food Chem Toxicol. 2017 Jul;105:194-202. [PubMed: 28366845]
Magdalan J, Zawadzki M, Skowronek R, Czuba M, Porębska B, Sozański T, Szpot P. Nonfatal and fatal intoxications with pure caffeine - report of three different cases. Forensic Sci Med Pathol. 2017 Sep;13(3):355-358. [PubMed: 28656354]
Muraro L, Longo L, Geraldini F, Bortot A, Paoli A, Boscolo A. Intralipid in acute caffeine intoxication: a case report. J Anesth. 2016 Oct;30(5):895-9. [PubMed: 27272169]

Disclosure: Justin Evans declares no relevant financial relationships with ineligible companies.

Disclosure: John Richards declares no relevant financial relationships with ineligible companies.

Disclosure: Amanda Battisti declares no relevant financial relationships with ineligible companies.

Copyright © 2024, StatPearls Publishing LLC.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

Bookshelf ID: NBK519490PMID: 30137774


  • PubReader
  • Print View
  • Cite this Page

Related information

  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...