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{{Short description|Central nervous system stimulant}}{{About|the stimulant drug}}{{pp-move-indef}}{{Use dmy dates|date=August 2021}}{{cs1 config |name-list-style=vanc |display-authors=6}}

factoids

| tradename = monograph|caffeine-caffeine-and-sodium-benzoate-injection-caffeine-citrate}}| MedlinePlus = | DailyMedID = Caffeine| pregnancy_AU = A| pregnancy_AU_comment = | pregnancy_category = Physical dependence>Physical: Moderate 13% and variable low–high 10-73% Psychological: Low–moderate| addiction_liability = Relatively low: 9%Oral administration>By mouth Medical: intravenous Uncommon: Insufflation (medicine), coffee enema>enema, Rectal administration, Caffeine patch>transdermal, topical| class = StimulantAdenosinergicEugeroicNootropicAnxiogenic Analeptic AnorecticParasympathomimeticCholinesterase inhibitor Phosphodiesterase inhibitorDiuretic| ATC_prefix = N06B| ATC_suffix = C01D11V04|CG30}} | legal_AU = Unscheduled| legal_AU_comment = | legal_BR = | legal_BR_comment = | legal_CA = | legal_CA_comment = | legal_DE = Unscheduled| legal_DE_comment = | legal_NZ = | legal_NZ_comment = | legal_UK = GSL| legal_UK_comment = | legal_US = | legal_US_comment = | legal_EU = | legal_EU_comment = | legal_UN = | legal_UN_comment = | legal_status = | bioavailability = 99%| protein_bound = 10–36%| metabolism = Primary: CYP1A2Minor: CYP2E1, CYP3A4,CYP2C8, CYP2C9| metabolites = • Paraxanthine 84% • Theobromine 12% • Theophylline 4%TITLE=PHARMACOLOGY OF CAFFEINE PUBLISHER=NATIONAL ACADEMIES PRESS (US) CHAPTER=2, PHARMACOLOGY OF CAFFEINE ARCHIVE-DATE=28 SEPTEMBER 2021 URL-STATUS=LIVE, WEBSITE=DRUGBANK ACCESS-DATE=8 AUGUST 2014 ARCHIVE-DATE=4 MAY 2015 URL-STATUS=LIVE, Infants (full term): 8 hoursInfants (premature): 100 hours JOURNAL = PHARMACOLOGICAL REPORTS ISSUE = 1 DATE = FEBRUARY 2016 DOI = 10.1016/J.PHAREP.2015.06.138, 19471083, | excretion = Urine (100%)| CAS_number = 58-08-2| CAS_supplemental = | PubChem = 2519| IUPHAR_ligand = 407| DrugBank = DB00201| ChemSpiderID = 2424| UNII = 3G6A5W338E| KEGG = D00528| ChEBI = 27732| ChEMBL = 113| NIAID_ChemDB = | PDB_ligand = CFFWEBSITE=CHEMSPIDER ARCHIVE-DATE=14 MAY 2019 URL-STATUS=LIVE, Theine| IUPAC_name = 1,3,7-Trimethyl-3,7-dihydro-1H-purine-2,6-dione| C = 8| H = 10| N = 4| O = 2| SMILES = CN1C=NC2=C1C(=O)N(C(=O)N2C)C| StdInChI = 1S/C8H10N4O2/c1-10-4-9-6-5(10)7(13)12(3)8(14)11(6)2/h4H,1-3H3| StdInChI_comment = | StdInChIKey = RYYVLZVUVIJVGH-UHFFFAOYSA-N| density = 1.23| density_notes = | melting_point = 235| melting_high = 238 WEBSITE=PUBCHEM COMPOUNDACCESS-DATE=16 OCTOBER 2014BOILING POINT178 Â°C (SUBLIMES)MELTING POINT238 DEG C (ANHYD), CAFFEINEWEBSITE=CHEMSPIDERACCESS-DATE=16 OCTOBER 2014ARCHIVE-DATE=14 MAY 2019URL-STATUS=LIVE, | boiling_point = | boiling_notes = | solubility = | sol_units = | specific_rotation = }}Caffeine is a central nervous system (CNS) stimulant of the methylxanthine class.JOURNAL, Nehlig A, Daval JL, Debry G, Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects, Brain Research. Brain Research Reviews, 17, 2, 139–170, 1992, 1356551, 10.1016/0165-0173(92)90012-B, 14277779, It is mainly used as a eugeroic (wakefulness promoter) or as a mild cognitive enhancer to increase alertness and attentional performance.JOURNAL, Camfield DA, Stough C, Farrimond J, Scholey AB, Acute effects of tea constituents L-theanine, caffeine, and epigallocatechin gallate on cognitive function and mood: a systematic review and meta-analysis, Nutrition Reviews, 72, 8, 507–522, August 2014, 24946991, 10.1111/nure.12120, free, doi, JOURNAL, Wood S, Sage JR, Shuman T, Anagnostaras SG, Psychostimulants and cognition: a continuum of behavioral and cognitive activation, Pharmacological Reviews, 66, 1, 193–221, January 2014, 24344115, 3880463, 10.1124/pr.112.007054, Caffeine acts by blocking binding of adenosine to the adenosine A1 receptor, which enhances release of the neurotransmitter acetylcholine.JOURNAL, Ribeiro JA, Sebastião AM, Caffeine and adenosine, Journal of Alzheimer's Disease, 20, Suppl 1, S3-15, 2010, 20164566, 10.3233/JAD-2010-1379, free, doi, Caffeine has a three-dimensional structure similar to that of adenosine, which allows it to bind and block its receptors.BOOK, Hillis DM, Sadava D, Hill RW, Price MV, Principles of Life, 2, 102–103, 2015, Macmillan Learning, 978-1-4641-8652-3, Caffeine also increases cyclic AMP levels through nonselective inhibition of phosphodiesterase.JOURNAL, Faudone G, Arifi S, Merk D, The Medicinal Chemistry of Caffeine, Journal of Medicinal Chemistry, 64, 11, 7156–7178, June 2021, 34019396, 10.1021/acs.jmedchem.1c00261, 235094871, Caffeine is a bitter, white crystalline purine, a methylxanthine alkaloid, and is chemically related to the adenine and guanine bases of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). It is found in the seeds, fruits, nuts, or leaves of a number of plants native to Africa, East Asia and South America,BOOK, Caballero B, Finglas P, Toldra F, Encyclopedia of Food and Health, Elsevier Science, 2015, 978-0-12-384953-3,weblink 17 June 2018, 561, and helps to protect them against herbivores and from competition by preventing the germination of nearby seeds,BOOK, Myers RL, The 100 Most Important Chemical Compounds: A Reference Guide, Greenwood Press, 2007, 978-0-313-33758-1,weblink registration, 17 June 2018, 55, as well as encouraging consumption by select animals such as honey bees.JOURNAL, Wright GA, Baker DD, Palmer MJ, Stabler D, Mustard JA, Power EF, Borland AM, Stevenson PC, Caffeine in floral nectar enhances a pollinator's memory of reward, Science, 339, 6124, 1202–4, March 2013, 23471406, 4521368, 10.1126/science.1228806, 2013Sci...339.1202W, The best-known source of caffeine is the coffee bean, the seed of the Coffea plant. People may drink beverages containing caffeine to relieve or prevent drowsiness and to improve cognitive performance. To make these drinks, caffeine is extracted by steeping the plant product in water, a process called infusion. Caffeine-containing drinks, such as coffee, tea, and cola, are consumed globally in high volumes. In 2020, almost 10 million tonnes of coffee beans were consumed globally.WEB,weblink Global coffee consumption, 2020/21, Statista, 10 March 2021, 3 March 2021,weblink live, Caffeine is the world's most widely consumed psychoactive drug.JOURNAL, Ferré S, Caffeine and Substance Use Disorders, Journal of Caffeine Research, 3, 2, 57–58, June 2013, 24761274, 3680974, 10.1089/jcr.2013.0015, Unlike most other psychoactive substances, caffeine remains largely unregulated and legal in nearly all parts of the world. Caffeine is also an outlier as its use is seen as socially acceptable in most cultures and even encouraged in others.Caffeine has both positive and negative health effects. It can treat and prevent the premature infant breathing disorders bronchopulmonary dysplasia of prematurity and apnea of prematurity. Caffeine citrate is on the WHO Model List of Essential Medicines.BOOK, WHO Model List of Essential Medicines,weblink 18th, World Health Organization, 23 December 2014, 34 [p. 38 of pdf], October 2013, April 2013, 23 April 2014,weblink" title="web.archive.org/web/20140423005004weblink">weblink live, It may confer a modest protective effect against some diseases,JOURNAL, Cano-Marquina A, Tarín JJ, Cano A, The impact of coffee on health, Maturitas, 75, 1, 7–21, May 2013, 23465359, 10.1016/j.maturitas.2013.02.002, including Parkinson's disease.JOURNAL, Qi H, Li S, Dose-response meta-analysis on coffee, tea and caffeine consumption with risk of Parkinson's disease, Geriatrics & Gerontology International, 14, 2, 430–9, April 2014, 23879665, 10.1111/ggi.12123, 42527557, Some people experience sleep disruption or anxiety if they consume caffeine,JOURNAL, O'Callaghan F, Muurlink O, Reid N, Effects of caffeine on sleep quality and daytime functioning, Risk Management and Healthcare Policy, 11, 263–271, 7 December 2018, 30573997, 6292246, 10.2147/RMHP.S156404, free, doi, but others show little disturbance. Evidence of a risk during pregnancy is equivocal; some authorities recommend that pregnant women limit caffeine to the equivalent of two cups of coffee per day or less.JOURNAL, Jahanfar S, Jaafar SH, Effects of restricted caffeine intake by mother on fetal, neonatal and pregnancy outcomes, The Cochrane Database of Systematic Reviews, 6, CD006965, June 2015, 2015, 26058966, 10.1002/14651858.CD006965.pub4, 10682844, Cochrane Pregnancy and Childbirth Group, JOURNAL, American College of Obstetricians and Gynecologists, ACOG CommitteeOpinion No. 462: Moderate caffeine consumption during pregnancy, Obstetrics and Gynecology, 116, 2 Pt 1, 467–8, August 2010, 20664420, 10.1097/AOG.0b013e3181eeb2a1, Caffeine can produce a mild form of drug dependence â€“ associated with withdrawal symptoms such as sleepiness, headache, and irritability â€“ when an individual stops using caffeine after repeated daily intake.BOOK, Malenka RC, Nestler EJ, Hyman SE, Sydor A, Brown RY, Molecular Neuropharmacology: A Foundation for Clinical Neuroscience, 2009, McGraw-Hill Medical, New York, 978-0-07-148127-4, 375, 2nd, Chapter 15: Reinforcement and Addictive Disorders, Long-term caffeine use can lead to mild physical dependence. A withdrawal syndrome characterized by drowsiness, irritability, and headache typically lasts no longer than a day. True compulsive use of caffeine has not been documented., WEB, American Psychiatric Association, Substance-Related and Addictive Disorders,weblinkweblink" title="web.archive.org/web/20140701175148weblink">weblink 1 July 2014, dead, American Psychiatric Publishing, 10 July 2015, 1–2, 2013, Substance use disorder in DSM-5 combines the DSM-IV categories of substance abuse and substance dependence into a single disorder measured on a continuum from mild to severe. ... Additionally, the diagnosis of dependence caused much confusion. Most people link dependence with "addiction" when in fact dependence can be a normal body response to a substance. ... DSM-5 will not include caffeine use disorder, although research shows that as little as two to three cups of coffee can trigger a withdrawal effect marked by tiredness or sleepiness. There is sufficient evidence to support this as a condition, however it is not yet clear to what extent it is a clinically significant disorder., JOURNAL, Juliano LM, Griffiths RR, A critical review of caffeine withdrawal: empirical validation of symptoms and signs, incidence, severity, and associated features, Psychopharmacology, 176, 1, 1–29, October 2004, 15448977, 10.1007/s00213-004-2000-x, Results: Of 49 symptom categories identified, the following 10 fulfilled validity criteria: headache, fatigue, decreased energy/ activeness, decreased alertness, drowsiness, decreased contentedness, depressed mood, difficulty concentrating, irritability, and foggy/not clearheaded. In addition, flu-like symptoms, nausea/vomiting, and muscle pain/stiffness were judged likely to represent valid symptom categories. In experimental studies, the incidence of headache was 50% and the incidence of clinically significant distress or functional impairment was 13%. Typically, onset of symptoms occurred 12–24 h after abstinence, with peak intensity at 20–51 h, and for a duration of 2–9 days., 5572188, Tolerance to the autonomic effects of increased blood pressure and heart rate, and increased urine output, develops with chronic use (i.e., these symptoms become less pronounced or do not occur following consistent use).JOURNAL, Robertson D, Wade D, Workman R, Woosley RL, Oates JA, Tolerance to the humoral and hemodynamic effects of caffeine in man, The Journal of Clinical Investigation, 67, 4, 1111–7, April 1981, 7009653, 370671, 10.1172/JCI110124, Caffeine is classified by the US Food and Drug Administration as generally recognized as safe. Toxic doses, over 10 grams per day for an adult, are much higher than the typical dose of under 500 milligrams per day.JOURNAL, Heckman MA, Weil J, Gonzalez de Mejia E, Caffeine (1, 3, 7-trimethylxanthine) in foods: a comprehensive review on consumption, functionality, safety, and regulatory matters, Journal of Food Science, 75, 3, R77–R87, April 2010, 20492310, 10.1111/j.1750-3841.2010.01561.x, free, doi, The European Food Safety Authority reported that up to 400 mg of caffeine per day (around 5.7 mg/kg of body mass per day) does not raise safety concerns for non-pregnant adults, while intakes up to 200 mg per day for pregnant and lactating women do not raise safety concerns for the fetus or the breast-fed infants.JOURNAL, ((EFSA Panel on Dietetic Products, Nutrition and Allergies )), 2015, Scientific Opinion on the safety of caffeine, EFSA Journal, 13, 5, 4102, 10.2903/j.efsa.2015.4102, free, doi, A cup of coffee contains 80–175 mg of caffeine, depending on what "bean" (seed) is used, how it is roasted, and how it is prepared (e.g., drip, percolation, or espresso).JOURNAL, Awwad S, Issa R, Alnsour L, Albals D, Al-Momani I, Quantification of Caffeine and Chlorogenic Acid in Green and Roasted Coffee Samples Using HPLC-DAD and Evaluation of the Effect of Degree of Roasting on Their Levels, Molecules, 26, 24, 7502, December 2021, 34946584, 8705492, 10.3390/molecules26247502, free, doi, Thus it requires roughly 50–100 ordinary cups of coffee to reach the toxic dose. However, pure powdered caffeine, which is available as a dietary supplement, can be lethal in tablespoon-sized amounts.{{TOC limit}}

Uses

Medical

Caffeine is used for both preventionJOURNAL, Kugelman A, Durand M, A comprehensive approach to the prevention of bronchopulmonary dysplasia, Pediatric Pulmonology, 46, 12, 1153–65, December 2011, 21815280, 10.1002/ppul.21508, 28339831, and treatmentJOURNAL, Schmidt B, 30123372, 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, Biology of the Neonate, 88, 3, 208–13, 2005, 16210843, 10.1159/000087584, of bronchopulmonary dysplasia in premature infants. It may improve weight gain during therapyJOURNAL, Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, Solimano A, Tin W, 22587234, Caffeine therapy for apnea of prematurity, The New England Journal of Medicine, 354, 20, 2112–21, May 2006, 16707748, 10.1056/NEJMoa054065,weblink 19 September 2018, 22 April 2020,weblink live, free, doi, and reduce the incidence of cerebral palsy as well as reduce language and cognitive delay.JOURNAL, Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, Solimano A, Tin W, 22983543, Long-term effects of caffeine therapy for apnea of prematurity, The New England Journal of Medicine, 357, 19, 1893–902, November 2007, 17989382, 10.1056/NEJMoa073679, free, doi, JOURNAL, Schmidt B, Anderson PJ, Doyle LW, Dewey D, Grunau RE, Asztalos EV, Davis PG, Tin W, Moddemann D, Solimano A, Ohlsson A, Barrington KJ, Roberts RS, Survival without disability to age 5 years after neonatal caffeine therapy for apnea of prematurity, JAMA, 307, 3, 275–82, January 2012, 22253394, 10.1001/jama.2011.2024, free, doi, On the other hand, subtle long-term side effects are possible.JOURNAL, Funk GD, Losing sleep over the caffeination of prematurity, The Journal of Physiology, 587, Pt 22, 5299–300, November 2009, 19915211, 2793860, 10.1113/jphysiol.2009.182303, Caffeine is used as a primary treatment for apnea of prematurity,JOURNAL, Mathew OP, Apnea of prematurity: pathogenesis and management strategies, Journal of Perinatology, 31, 5, 302–10, May 2011, 21127467, 10.1038/jp.2010.126, free, doi, but not prevention.JOURNAL, Henderson-Smart DJ, De Paoli AG, Prophylactic methylxanthine for prevention of apnoea in preterm infants, The Cochrane Database of Systematic Reviews, 12, CD000432, December 2010, 2010, 21154344, 10.1002/14651858.CD000432.pub2, 7032541, It is also used for orthostatic hypotension treatment.JOURNAL, Gibbons CH, Schmidt P, Biaggioni I, Frazier-Mills C, Freeman R, Isaacson S, Karabin B, Kuritzky L, Lew M, Low P, Mehdirad A, Raj SR, Vernino S, Kaufmann H, The recommendations of a consensus panel for the screening, diagnosis, and treatment of neurogenic orthostatic hypotension and associated supine hypertension, J. Neurol., 264, 8, 1567–1582, August 2017, 28050656, 5533816, 10.1007/s00415-016-8375-x, WEB, Caffeine: Summary of Clinical Use,weblink IUPHAR Guide to Pharmacology, The International Union of Basic and Clinical Pharmacology, 13 February 2015, 14 February 2015,weblink" title="web.archive.org/web/20150214013439weblink">weblink live, JOURNAL, Gupta V, Lipsitz LA, Orthostatic hypotension in the elderly: diagnosis and treatment, The American Journal of Medicine, 120, 10, 841–7, October 2007, 17904451, 10.1016/j.amjmed.2007.02.023, Some people use caffeine-containing beverages such as coffee or tea to try to treat their asthma.JOURNAL, Alfaro TM, Monteiro RA, Cunha RA, Cordeiro CR, Chronic coffee consumption and respiratory disease: A systematic review, The Clinical Respiratory Journal, 12, 3, 1283–1294, March 2018, 28671769, 10.1111/crj.12662, 4334842, Evidence to support this practice is poor. It appears that caffeine in low doses improves airway function in people with asthma, increasing forced expiratory volume (FEV1) by 5% to 18% for up to four hours.JOURNAL, Welsh EJ, Bara A, Barley E, Cates CJ, Caffeine for asthma, The Cochrane Database of Systematic Reviews, 1, CD001112, January 2010, 2010, 20091514, 7053252, 10.1002/14651858.CD001112.pub2, Welsh EJ, The addition of caffeine (100–130 mg) to commonly prescribed pain relievers such as paracetamol or ibuprofen modestly improves the proportion of people who achieve pain relief.JOURNAL, Derry CJ, Derry S, Moore RA, Caffeine as an analgesic adjuvant for acute pain in adults, The Cochrane Database of Systematic Reviews, 12, CD009281, December 2014, 2019, 25502052, 6485702, 10.1002/14651858.cd009281.pub3, Consumption of caffeine after abdominal surgery shortens the time to recovery of normal bowel function and shortens length of hospital stay.JOURNAL, Yang TW, Wang CC, Sung WW, Ting WC, Lin CC, Tsai MC, The effect of coffee/caffeine on postoperative ileus following elective colorectal surgery: a meta-analysis of randomized controlled trials, International Journal of Colorectal Disease, 37, 3, 623–630, March 2022, 34993568, 8885519, 10.1007/s00384-021-04086-3, 245773922, Caffeine was formerly used as a second-line treatment for ADHD. It is considered less effective than methylphenidate or amphetamine but more so than placebo for children with ADHD.JOURNAL, Grimes LM, Kennedy AE, Labaton RS, Hine JF, Warzak WJ, Caffeine as an Independent Variable in Behavioral Research: Trends from the Literature Specific to ADHD, Journal of Caffeine Research, 2015, 5, 3, 95–104, 10.1089/jcr.2014.0032, JOURNAL, Downs J, Giust J, Dunn DW, Considerations for ADHD in the child with epilepsy and the child with migraine, Expert Review of Neurotherapeutics, 17, 9, 861–869, September 2017, 28749241, 10.1080/14737175.2017.1360136, 29659192, Children, adolescents, and adults with ADHD are more likely to consume caffeine, perhaps as a form of self-medication.JOURNAL, Temple JL, Review: Trends, Safety, and Recommendations for Caffeine Use in Children and Adolescents, Journal of the American Academy of Child and Adolescent Psychiatry, 58, 1, 36–45, January 2019, 30577937, 10.1016/j.jaac.2018.06.030, 58539710,

Enhancing performance

Cognitive performance

Caffeine is a central nervous system stimulant that may reduce fatigue and drowsiness. At normal doses, caffeine has variable effects on learning and memory, but it generally improves reaction time, wakefulness, concentration, and motor coordination.JOURNAL, Bolton S, Null G, Caffeine: Psychological Effects, Use and Abuse, Orthomolecular Psychiatry (journal), Orthomolecular Psychiatry, 10, 3, 202–211, 1981,weblinkweblink" title="web.archive.org/web/20081006073801weblink">weblink 2008-10-06, live, JOURNAL, Nehlig A, 17392483, Is caffeine a cognitive enhancer?, Journal of Alzheimer's Disease, 20, Suppl 1, S85–94, 2010, 20182035, 10.3233/JAD-2010-091315, Caffeine does not usually affect performance in learning and memory tasks, although caffeine may occasionally have facilitatory or inhibitory effects on memory and learning. Caffeine facilitates learning in tasks in which information is presented passively; in tasks in which material is learned intentionally, caffeine has no effect. Caffeine facilitates performance in tasks involving working memory to a limited extent, but hinders performance in tasks that heavily depend on this, and caffeine appears to improve memory performance under suboptimal alertness. Most studies, however, found improvements in reaction time. The ingestion of caffeine does not seem to affect long-term memory. ... Its indirect action on arousal, mood and concentration contributes in large part to its cognitive enhancing properties.,weblinkweblink" title="web.archive.org/web/20210131210348weblink">weblink dead, 31 January 2021, The amount of caffeine needed to produce these effects varies from person to person, depending on body size and degree of tolerance. The desired effects arise approximately one hour after consumption, and the desired effects of a moderate dose usually subside after about three or four hours.Caffeine can delay or prevent sleep and improves task performance during sleep deprivation.BOOK, Snel J, Lorist MM, Human Sleep and Cognition Part II - Clinical and Applied Research, Effects of caffeine on sleep and cognition, Progress in Brain Research, 190, 105–17, 2011, 21531247, 10.1016/B978-0-444-53817-8.00006-2, 978-0-444-53817-8, Shift workers who use caffeine make fewer mistakes that could result from drowsiness.JOURNAL, Ker K, Edwards PJ, Felix LM, Blackhall K, Roberts I, Caffeine for the prevention of injuries and errors in shift workers, The Cochrane Database of Systematic Reviews, 5, CD008508, May 2010, 2010, 20464765, 4160007, 10.1002/14651858.CD008508, Ker K, Caffeine in a dose dependent manner increases alertness in both fatigued and normal individuals.JOURNAL, McLellan TM, Caldwell JA, Lieberman HR, A review of caffeine's effects on cognitive, physical and occupational performance, Neuroscience and Biobehavioral Reviews, 71, 294–312, December 2016, 27612937, 10.1016/j.neubiorev.2016.09.001, free, doi, A systematic review and meta-analysis from 2014 found that concurrent caffeine and {{smallcaps all|L}}-theanine use has synergistic psychoactive effects that promote alertness, attention, and task switching; these effects are most pronounced during the first hour post-dose.JOURNAL, Camfield DA, Stough C, Farrimond J, Scholey AB, 42039737, Acute effects of tea constituents L-theanine, caffeine, and epigallocatechin gallate on cognitive function and mood: a systematic review and meta-analysis, Nutrition Reviews, 72, 8, 507–22, August 2014, 24946991, 10.1111/nure.12120, free, doi,

Physical performance

Caffeine is a proven ergogenic aid in humans. Caffeine improves athletic performance in aerobic (especially endurance sports) and anaerobic conditions.JOURNAL, Pesta DH, Angadi SS, Burtscher M, Roberts CK, The effects of caffeine, nicotine, ethanol, and tetrahydrocannabinol on exercise performance, Nutrition & Metabolism, 10, 1, 71, December 2013, 24330705, 3878772, 10.1186/1743-7075-10-71, free, doi, Quote: {{blockquote|Caffeine-induced increases in performance have been observed in aerobic as well as anaerobic sports (for reviews, see [26,30,31])...}} Moderate doses of caffeine (around 5 mg/kg) can improve sprint performance,JOURNAL, Bishop D, 1884713, Dietary supplements and team-sport performance, Sports Medicine, 40, 12, 995–1017, December 2010, 21058748, 10.2165/11536870-000000000-00000, cycling and running time trial performance, endurance (i.e., it delays the onset of muscle fatigue and central fatigue),JOURNAL, Conger SA, Warren GL, Hardy MA, Millard-Stafford ML, 7109086, Does caffeine added to carbohydrate provide additional ergogenic benefit for endurance?, International Journal of Sport Nutrition and Exercise Metabolism, 21, 1, 71–84, February 2011, 21411838, 10.1123/ijsnem.21.1.71,weblinkweblink" title="web.archive.org/web/20201114083710weblink">weblink dead, 14 November 2020, JOURNAL, Liddle DG, Connor DJ, Nutritional supplements and ergogenic AIDS, Primary Care, 40, 2, 487–505, June 2013, 23668655, 10.1016/j.pop.2013.02.009, Amphetamines and caffeine are stimulants that increase alertness, improve focus, decrease reaction time, and delay fatigue, allowing for an increased intensity and duration of training ...Physiologic and performance effects{{•, Amphetamines increase dopamine/norepinephrine release and inhibit their reuptake, leading to central nervous system (CNS) stimulation{{•}}Amphetamines seem to enhance athletic performance in anaerobic conditions 39 40{{•}}Improved reaction time{{•}}Increased muscle strength and delayed muscle fatigue{{•}}Increased acceleration{{•}}Increased alertness and attention to task }} and cycling power output. Caffeine increases basal metabolic rate in adults.JOURNAL, Acheson KJ, Zahorska-Markiewicz B, Pittet P, Anantharaman K, Jéquier E, Caffeine and coffee: their influence on metabolic rate and substrate utilization in normal weight and obese individuals, The American Journal of Clinical Nutrition, 33, 5, 989–97, May 1980, 7369170, 10.1093/ajcn/33.5.989, 4515711,weblinkweblink dead, 15 February 2020, JOURNAL, Dulloo AG, Geissler CA, Horton T, Collins A, Miller DS, Normal caffeine consumption: influence on thermogenesis and daily energy expenditure in lean and postobese human volunteers, The American Journal of Clinical Nutrition, 49, 1, 44–50, January 1989, 2912010, 10.1093/ajcn/49.1.44, JOURNAL, Koot P, Deurenberg P, Comparison of changes in energy expenditure and body temperatures after caffeine consumption, Annals of Nutrition & Metabolism, 39, 3, 135–42, 1995, 7486839, 10.1159/000177854, Caffeine ingestion prior to aerobic exercise increases fat oxidation, particularly in persons with low physical fitness.JOURNAL, Collado-Mateo D, Lavín-Pérez AM, Merellano-Navarro E, Coso JD, Effect of Acute Caffeine Intake on the Fat Oxidation Rate during Exercise: A Systematic Review and Meta-Analysis, Nutrients, 12, 12, 3603, November 2020, 33255240, 10.3390/nu12123603, 7760526, free, doi, Caffeine improves muscular strength and power,JOURNAL, Grgic J, Trexler ET, Lazinica B, Pedisic Z, Effects of caffeine intake on muscle strength and power: a systematic review and meta-analysis, Journal of the International Society of Sports Nutrition, 15, 11, 2018, 29527137, 5839013, 10.1186/s12970-018-0216-0, free, doi, and may enhance muscular endurance.JOURNAL, Warren GL, Park ND, Maresca RD, McKibans KI, Millard-Stafford ML, Effect of caffeine ingestion on muscular strength and endurance: a meta-analysis, Medicine and Science in Sports and Exercise, 42, 7, 1375–87, July 2010, 20019636, 10.1249/MSS.0b013e3181cabbd8, Caffeine also enhances performance on anaerobic tests.JOURNAL, Grgic J, 3548657, Caffeine ingestion enhances Wingate performance: a meta-analysis, European Journal of Sport Science, 18, 2, 219–225, March 2018, 29087785, 10.1080/17461391.2017.1394371,weblink 2 December 2019, 5 March 2020,weblink" title="web.archive.org/web/20200305143255weblink">weblink live, Caffeine consumption before constant load exercise is associated with reduced perceived exertion. While this effect is not present during exercise-to-exhaustion exercise, performance is significantly enhanced. This is congruent with caffeine reducing perceived exertion, because exercise-to-exhaustion should end at the same point of fatigue.JOURNAL, Doherty M, Smith PM, Effects of caffeine ingestion on rating of perceived exertion during and after exercise: a meta-analysis, Scandinavian Journal of Medicine & Science in Sports, 15, 2, 69–78, April 2005, 15773860, 10.1111/j.1600-0838.2005.00445.x, 19331370, Caffeine also improves power output and reduces time to completion in aerobic time trials,JOURNAL, Southward K, Rutherfurd-Markwick KJ, Ali A, 46959658, The Effect of Acute Caffeine Ingestion on Endurance Performance: A Systematic Review and Meta-Analysis, Sports Medicine, 48, 8, 1913–1928, August 2018, 29876876, 10.1007/s40279-018-0939-8, an effect positively (but not exclusively) associated with longer duration exercise.JOURNAL, Shen JG, Brooks MB, Cincotta J, Manjourides JD, Establishing a relationship between the effect of caffeine and duration of endurance athletic time trial events: A systematic review and meta-analysis, Journal of Science and Medicine in Sport, 22, 2, 232–238, February 2019, 30170953, 10.1016/j.jsams.2018.07.022, free, doi,

Specific populations

Adults

For the general population of healthy adults, Health Canada advises a daily intake of no more than 400 mg. This limit was found to be safe by a 2017 systematic review on caffeine toxicology.JOURNAL, Wikoff D, Welsh BT, Henderson R, Brorby GP, Britt J, Myers E, Goldberger J, Lieberman HR, O'Brien C, Peck J, Tenenbein M, Weaver C, Harvey S, Urban J, Doepker C, Systematic review of the potential adverse effects of caffeine consumption in healthy adults, pregnant women, adolescents, and children, Food and Chemical Toxicology, 109, Pt 1, 585–648, November 2017, 28438661, 10.1016/j.fct.2017.04.002, Systematic review, free, doi,

Children

In healthy children, moderate caffeine intake under 400 mg produces effects that are "modest and typically innocuous".JOURNAL, Temple JL, Review: Trends, Safety, and Recommendations for Caffeine Use in Children and Adolescents, Journal of the American Academy of Child and Adolescent Psychiatry, 58, 1, 36–45, January 2019, 30577937, 10.1016/j.jaac.2018.06.030, Review, free, doi, JOURNAL, Castellanos FX, Rapoport JL, Effects of caffeine on development and behavior in infancy and childhood: a review of the published literature, Food and Chemical Toxicology, 40, 9, 1235–1242, September 2002, 12204387, 10.1016/S0278-6915(02)00097-2,weblink 2 December 2019, 27 July 2020,weblink live, As early as six months old, infants can metabolize caffeine at the same rate as that of adults.JOURNAL, Temple JL, Bernard C, Lipshultz SE, Czachor JD, Westphal JA, Mestre MA, The Safety of Ingested Caffeine: A Comprehensive Review, Frontiers in Psychiatry, 8, 80, 80, May 26, 2017, 28603504, 5445139, 10.3389/fpsyt.2017.00080, free, doi, Higher doses of caffeine (>400 mg) can cause physiological, psychological and behavioral harm, particularly for children with psychiatric or cardiac conditions. There is no evidence that coffee stunts a child's growth.BOOK, Levounis P, Herron AJ, The Addiction Casebook, 2014, American Psychiatric Pub, 978-1-58562-458-4, 49, {{google books, y, _aWTAwAAQBAJ, 45, }} The American Academy of Pediatrics recommends that caffeine consumption is not appropriate for children and adolescents and should be avoided.JOURNAL, Schneider MB, Benjamin HJ, Committee on Nutrition and the Council on Sports Medicine and Fitness, Sports drinks and energy drinks for children and adolescents: are they appropriate?, Pediatrics, 127, 6, 1182–1189, June 2011, 21624882, 10.1542/peds.2011-0965, free, doi, This recommendation is based on a clinical report released by American Academy of Pediatrics in 2011 with a review of 45 publications from 1994 to 2011 and includes inputs from various stakeholders (Pediatricians, Committee on nutrition, Canadian Pediatric Society, Centers for Disease Control & Prevention, Food and Drug Administration, Sports Medicine & Fitness committee, National Federations of High School Associations). For children age 12 and under, Health Canada recommends a maximum daily caffeine intake of no more than 2.5 milligrams per kilogram of body weight. Based on average body weights of children, this translates to the following age-based intake limits:WEB,weblink Caffeine in Food, 6 February 2012, Health Canada, 24 August 2020, 10 August 2020,weblink live, {| class="wikitable"! scope="col" | Age range! scope="col" | Maximum recommended daily caffeine intake| 4–6| 45 mg (slightly more than in 355 ml (12 fl. oz) of a typical caffeinated soft drink)| 7–9| 62.5 mg| 10–121|2}} cup of coffee)

Adolescents

Health Canada has not developed advice for adolescents because of insufficient data. However, they suggest that daily caffeine intake for this age group be no more than 2.5 mg/kg body weight. This is because the maximum adult caffeine dose may not be appropriate for light-weight adolescents or for younger adolescents who are still growing. The daily dose of 2.5 mg/kg body weight would not cause adverse health effects in the majority of adolescent caffeine consumers. This is a conservative suggestion since older and heavier-weight adolescents may be able to consume adult doses of caffeine without experiencing adverse effects.

Pregnancy and breastfeeding

The metabolism of caffeine is reduced in pregnancy, especially in the third trimester, and the half-life of caffeine during pregnancy can be increased up to 15 hours (as compared to 2.5 to 4.5 hours in non-pregnant adults). Evidence regarding the effects of caffeine on pregnancy and for breastfeeding are inconclusive. There is limited primary and secondary advice for, or against, caffeine use during pregnancy and its effects on the fetus or newborn.The UK Food Standards Agency has recommended that pregnant women should limit their caffeine intake, out of prudence, to less than 200 mg of caffeine a day â€“ the equivalent of two cups of instant coffee, or one and a half to two cups of fresh coffee.WEB,weblink Food Standards Agency publishes new caffeine advice for pregnant women, 3 August 2009, 17 October 2010,weblink" title="web.archive.org/web/20101017165633weblink">weblink dead, The American Congress of Obstetricians and Gynecologists (ACOG) concluded in 2010 that caffeine consumption is safe up to 200 mg per day in pregnant women. For women who breastfeed, are pregnant, or may become pregnant, Health Canada recommends a maximum daily caffeine intake of no more than 300 mg, or a little over two 8 oz (237 mL) cups of coffee. A 2017 systematic review on caffeine toxicology found evidence supporting that caffeine consumption up to 300 mg/day for pregnant women is generally not associated with adverse reproductive or developmental effect.There are conflicting reports in the scientific literature about caffeine use during pregnancy.JOURNAL, Kuczkowski KM, 6475015, Caffeine in pregnancy, Archives of Gynecology and Obstetrics, 280, 5, 695–8, November 2009, 19238414, 10.1007/s00404-009-0991-6, A 2011 review found that caffeine during pregnancy does not appear to increase the risk of congenital malformations, miscarriage or growth retardation even when consumed in moderate to high amounts.JOURNAL, Brent RL, Christian MS, Diener RM, Evaluation of the reproductive and developmental risks of caffeine, Birth Defects Research Part B: Developmental and Reproductive Toxicology, 92, 2, 152–87, April 2011, 21370398, 3121964, 10.1002/bdrb.20288, Other reviews, however, concluded that there is some evidence that higher caffeine intake by pregnant women may be associated with a higher risk of giving birth to a low birth weight baby,JOURNAL, 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 Medicine, 12, 1, 174, September 2014, 25238871, 4198801, 10.1186/s12916-014-0174-6, free, doi, and may be associated with a higher risk of pregnancy loss.JOURNAL, 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 Nutrition, 19, 7, 1233–44, May 2016, 26329421, 10.1017/S1368980015002463, 10271029, free, doi, A systematic review, analyzing the results of observational studies, suggests that women who consume large amounts of caffeine (greater than 300 mg/day) prior to becoming pregnant may have a higher risk of experiencing pregnancy loss.JOURNAL, Lassi ZS, Imam AM, Dean SV, Bhutta ZA, Preconception care: caffeine, smoking, alcohol, drugs and other environmental chemical/radiation exposure, Reproductive Health, 11, Suppl 3, S6, September 2014, 25415846, 4196566, 10.1186/1742-4755-11-S3-S6, free, doi,

Adverse effects{{anchor|Side_effects}}

Physiological

Caffeine in coffee and other caffeinated drinks can affect gastrointestinal motility and gastric acid secretion.JOURNAL, Boekema PJ, Samsom M, van Berge Henegouwen GP, Smout AJ, Coffee and gastrointestinal function: facts and fiction. A review, Scandinavian Journal of Gastroenterology. Supplement, 34, 230, 35–9, 1999, 10499460, 10.1080/003655299750025525, JOURNAL, Cohen S, Booth GH, Gastric acid secretion and lower-esophageal-sphincter pressure in response to coffee and caffeine, The New England Journal of Medicine, 293, 18, 897–9, October 1975, 1177987, 10.1056/NEJM197510302931803, BOOK, Sherwood L, Kell R, Human Physiology: From Cells to Systems, 1st Canadian, 2009, Nelsen, 978-0-17-644107-4, 613–9, In postmenopausal women, high caffeine consumption can accelerate bone loss.WEB,weblink Caffeine in the diet, MedlinePlus, US National Library of Medicine, 30 April 2013, 2 January 2015, 5 January 2015,weblink" title="web.archive.org/web/20150105021454weblink">weblink live, JOURNAL, Rapuri PB, Gallagher JC, Kinyamu HK, Ryschon KL, Caffeine intake increases the rate of bone loss in elderly women and interacts with vitamin D receptor genotypes, The American Journal of Clinical Nutrition, 74, 5, 694–700, November 2001, 11684540, 10.1093/ajcn/74.5.694, free, doi, Acute ingestion of caffeine in large doses (at least 250–300 mg, equivalent to the amount found in 2–3 cups of coffee or 5–8 cups of tea) results in a short-term stimulation of urine output in individuals who have been deprived of caffeine for a period of days or weeks.JOURNAL, Maughan RJ, Griffin J, 41617469, Caffeine ingestion and fluid balance: a review, Journal of Human Nutrition and Dietetics, 16, 6, 411–20, December 2003, 19774754, 10.1046/j.1365-277X.2003.00477.x,weblinkweblink" title="web.archive.org/web/20190308212624weblink">weblink dead, 8 March 2019, This increase is due to both a diuresis (increase in water excretion) and a natriuresis (increase in saline excretion); it is mediated via proximal tubular adenosine receptor blockade.Modulation of adenosine receptor expression in the proximal tubule: a novel adaptive mechanism to regulate renal salt and water metabolism Am. J. Physiol. Renal Physiol. 1 July 2008 295:F35-F36 The acute increase in urinary output may increase the risk of dehydration. However, chronic users of caffeine develop a tolerance to this effect and experience no increase in urinary output.NEWS,weblink Really? The claim: caffeine causes dehydration, New York Times, 3 August 2009, O'Connor A, 4 March 2008, 3 September 2011,weblink" title="web.archive.org/web/20110903025747weblink">weblink live, JOURNAL, Armstrong LE, Casa DJ, Maresh CM, Ganio MS, 46352603, Caffeine, fluid-electrolyte balance, temperature regulation, and exercise-heat tolerance, Exercise and Sport Sciences Reviews, 35, 3, 135–40, July 2007, 17620932, 10.1097/jes.0b013e3180a02cc1, JOURNAL, Maughan RJ, Watson P, Cordery PA, Walsh NP, Oliver SJ, Dolci A, Rodriguez-Sanchez N, Galloway SD, A randomized trial to assess the potential of different beverages to affect hydration status: development of a beverage hydration index, The American Journal of Clinical Nutrition, 103, 3, 717–23, March 2016, 26702122, 10.3945/ajcn.115.114769, 378245, free, doi,

Psychological

Minor undesired symptoms from caffeine ingestion not sufficiently severe to warrant a psychiatric diagnosis are common and include mild anxiety, jitteriness, insomnia, increased sleep latency, and reduced coordination.JOURNAL, Tarnopolsky MA, Caffeine and creatine use in sport, Annals of Nutrition & Metabolism, 57, Suppl 2, 1–8, 2010, 21346331, 10.1159/000322696, free, doi, Caffeine can have negative effects on anxiety disorders.JOURNAL, Winston AP, Neuropsychiatric effects of caffeine, Advances in Psychiatric Treatment, 2005, 11, 6, 432–439, 10.1192/apt.11.6.432, free, doi, According to a 2011 literature review, caffeine use may induce anxiety and panic disorders in people with Parkinson's disease.JOURNAL, Vilarim MM, Rocha Araujo DM, Nardi AE, 5364016, Caffeine challenge test and panic disorder: a systematic literature review, Expert Review of Neurotherapeutics, 11, 8, 1185–95, August 2011, 21797659, 10.1586/ern.11.83, At high doses, typically greater than 300 mg, caffeine can both cause and worsen anxiety.JOURNAL, Smith A, Effects of caffeine on human behavior, Food and Chemical Toxicology, 40, 9, 1243–55, September 2002, 12204388, 10.1016/S0278-6915(02)00096-0, For some people, discontinuing caffeine use can significantly reduce anxiety.JOURNAL, Bruce MS, Lader M, Caffeine abstention in the management of anxiety disorders, Psychological Medicine, 19, 1, 211–4, February 1989, 2727208, 10.1017/S003329170001117X, 45368729, In moderate doses, caffeine has been associated with reduced symptoms of depression and lower suicide risk.JOURNAL, Lara DR, Caffeine, mental health, and psychiatric disorders, Journal of Alzheimer's Disease, 20, Suppl 1, S239–48, 2010, 20164571, 10.3233/JAD-2010-1378, free, doi, Two reviews indicate that increased consumption of coffee and caffeine may reduce the risk of depression.JOURNAL, Wang L, Shen X, Wu Y, Zhang D, 23377304, Coffee and caffeine consumption and depression: A meta-analysis of observational studies, The Australian and New Zealand Journal of Psychiatry, 50, 3, 228–42, March 2016, 26339067, 10.1177/0004867415603131, JOURNAL, Grosso G, Micek A, Castellano S, Pajak A, Galvano F, Coffee, tea, caffeine and risk of depression: A systematic review and dose-response meta-analysis of observational studies, Molecular Nutrition & Food Research, 60, 1, 223–34, January 2016, 26518745, 10.1002/mnfr.201500620, Some textbooks state that caffeine is a mild euphoriant,BOOK, {{google books, y, 6Rp0BgAAQBAJ, 558, |title=Psychiatry | vauthors = Kohn R, Keller M|publisher=John Wiley & Sons |year=2015 |isbn=978-1-118-84547-9 |veditors=Tasman A, Kay J, Lieberman JA, First MB, Riba M |volume=1 |location=New York |pages=557–558 |chapter=Chapter 34 Emotions |quote=Table 34-12... Caffeine Intoxication – Euphoria}}BOOK, {{google books, y, bD9UDgAAQBAJ, 153, |title=Psychiatry and Pedopsychiatry |vauthors=Hrnčiarove J, Barteček R |veditors=Hosák L, Hrdlička M, et al. |publisher=Karolinum Press |year=2017 |isbn=9788024633787 |location=Prague |pages=153–154 |chapter=8. Substance Dependence |quote=At a high dose, caffeine shows a euphoric effect.}}BOOK, {{google books, y, DfV-BwAAQBAJ, 214, |title=Encyclopedia of Behavioral Neuroscience |vauthors=Schulteis G |veditors=Koob GF, Le Moal M, Thompson RF |publisher=Elsevier |year=2010 |isbn=978-0-08-091455-8 |pages=214 |chapter=Brain stimulation and addiction |quote=Therefore, caffeine and other adenosine antagonists, while weakly euphoria-like on their own, may potentiate the positive hedonic efficacy of acute drug intoxication and reduce the negative hedonic consequences of drug withdrawal.}} while others state that it is not a euphoriant.BOOK, Salerno BB, Knights EK, Pharmacology for health professionals, 2010, Elsevier Australia, Chatswood, N.S.W., 978-0-7295-3929-6, 433, 3rd, In contrast to the amphetamines, caffeine does not cause euphoria, stereotyped behaviors or psychoses., BOOK, Ebenezer I, Neuropsychopharmacology and Therapeutics, 2015, John Wiley & Sons, 978-1-118-38578-4, 18, However, in contrast to other psychoactive stimulants, such as amphetamine and cocaine, caffeine and the other methylxanthines do not produce euphoria, stereotyped behaviors or psychotic like symptoms in large doses., Caffeine-induced anxiety disorder is a subclass of the DSM-5 diagnosis of substance/medication-induced anxiety disorder.

Reinforcement disorders

Addiction

Whether caffeine can result in an addictive disorder depends on how addiction is defined. Compulsive caffeine consumption under any circumstances has not been observed, and caffeine is therefore not generally considered addictive.BOOK, Nestler EJ, Hymen SE, Holtzmann DM, Malenka RC, Molecular Neuropharmacology: A Foundation for Clinical Neuroscience, McGraw-Hill Education., 3rd, 16, True compulsive use of caffeine has not been documented, and, consequently, these drugs are not considered addictive., However, some diagnostic models, such as the {{nowrap|ICDM-9}} and ICD-10, include a classification of caffeine addiction under a broader diagnostic model.JOURNAL, Budney AJ, Emond JA, Caffeine addiction? Caffeine for youth? Time to act!, Addiction, 109, 11, 1771–2, November 2014, 24984891, 10.1111/add.12594, Academics and clinicians, however, have not yet reached consensus about the potential clinical importance of caffeine addiction (or 'use disorder'), Some state that certain users can become addicted and therefore unable to decrease use even though they know there are negative health effects.JOURNAL, Meredith SE, Juliano LM, Hughes JR, Griffiths RR, Caffeine Use Disorder: A Comprehensive Review and Research Agenda, Journal of Caffeine Research, 3, 3, 114–130, September 2013, 24761279, 3777290, 10.1089/jcr.2013.0016, BOOK, Riba A, Tasman J, Kay JS, Lieberman MB, First MB, Psychiatry, 2014, 978-1-118-75336-1, 1446, John Wiley & Sons, Fourth, {{google books, y, l2KRBgAAQBAJ, 1446, }}Caffeine does not appear to be a reinforcing stimulus, and some degree of aversion may actually occur, with people preferring placebo over caffeine in a study on drug abuse liability published in an NIDA research monograph.BOOK, Fishchman N, Mello N, Testing for Abuse Liability of Drugs in Humans, U.S. Department of Health and Human Services Public Health Service Alcohol, Drug Abuse, and Mental Health Administration National Institute on Drug Abuse, Rockville, MD, 179,weblink dead,weblink" title="web.archive.org/web/20161222041641weblink">weblink 22 December 2016, dmy-all, Some state that research does not provide support for an underlying biochemical mechanism for caffeine addiction.JOURNAL, Nestler EJ, Cellular basis of memory for addiction, Dialogues in Clinical Neuroscience, 15, 4, 431–43, December 2013, 24459410, 3898681, 10.31887/DCNS.2013.15.4/enestler, DESPITE THE IMPORTANCE OF NUMEROUS PSYCHOSOCIAL FACTORS, AT ITS CORE, DRUG ADDICTION INVOLVES A BIOLOGICAL PROCESS: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type NAc neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement, BOOK, Miller PM, Principles of addiction comprehensive addictive behaviors and disorders, 2013, Elsevier Academic Press, 978-0-12-398361-9, 784, 1st, {{google books, y, 5gRNl3oIwWEC, 784, |access-date=11 July 2015|chapter=Chapter III: Types of Addiction|quote=Astrid Nehlig and colleagues present evidence that in animals caffeine does not trigger metabolic increases or dopamine release in brain areas involved in reinforcement and reward. A single photon emission computed tomography (SPECT) assessment of brain activation in humans showed that caffeine activates regions involved in the control of vigilance, anxiety, and cardiovascular regulation but did not affect areas involved in reinforcement and reward.}}JOURNAL, Nehlig A, Armspach JP, Namer IJ, SPECT assessment of brain activation induced by caffeine: no effect on areas involved in dependence, Dialogues in Clinical Neuroscience, 12, 2, 255–63, 2010, 20623930, 3181952, 10.31887/DCNS.2010.12.2/anehlig, Caffeine is not considered addictive, and in animals it does not trigger metabolic increases or dopamine release in brain areas involved in reinforcement and reward. ... these earlier data plus the present data reflect that caffeine at doses representing about two cups of coffee in one sitting does not activate the circuit of dependence and reward and especially not the main target area, the nucleus accumbens. ... Therefore, caffeine appears to be different from drugs of dependence like cocaine, amphetamine, morphine, and nicotine, and does not fulfil the common criteria or the scientific definitions to be considered an addictive substance.42, Other research states it can affect the reward system.JOURNAL, Temple JL, Caffeine use in children: what we know, what we have left to learn, and why we should worry, Neuroscience and Biobehavioral Reviews, 33, 6, 793–806, June 2009, 19428492, 2699625, 10.1016/j.neubiorev.2009.01.001, Through these interactions, caffeine is able to directly potentiate dopamine neurotransmission, thereby modulating the rewarding and addicting properties of nervous system stimuli., "Caffeine addiction" was added to the ICDM-9 and ICD-10. However, its addition was contested with claims that this diagnostic model of caffeine addiction is not supported by evidence.BOOK, Karch SB, Karch's pathology of drug abuse, 2009, CRC Press, Boca Raton, 978-0-8493-7881-2, 229–230, 4th, {{google books, y, G9E7gfJq0KkC, 229, | quote = The suggestion has also been made that a caffeine dependence syndrome exists ... In one controlled study, dependence was diagnosed in 16 of 99 individuals who were evaluated. The median daily caffeine consumption of this group was only 357 mg per day (Strain et al., 1994).Since this observation was first published, caffeine addiction has been added as an official diagnosis in ICDM 9. This decision is disputed by many and is not supported by any convincing body of experimental evidence. ... All of these observations strongly suggest that caffeine does not act on the dopaminergic structures related to addiction, nor does it improve performance by alleviating any symptoms of withdrawal}}WEB, ICD-10 Version:2015,weblink World Health Organization, 10 July 2015, 2015, F15 Mental and behavioural disorders due to use of other stimulants, including caffeine ....2 Dependence syndromeA cluster of behavioural, cognitive, and physiological phenomena that develop after repeated substance use and that typically include a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal state.The dependence syndrome may be present for a specific psychoactive substance (e.g., tobacco, alcohol, or diazepam), for a class of substances (e.g., opioid drugs), or for a wider range of pharmacologically different psychoactive substances. [Includes:]Chronic alcoholismDipsomaniaDrug addiction, 2 November 2015,weblink" title="web.archive.org/web/20151102042503weblink">weblink live, The American Psychiatric Association's {{nowrap|DSM-5}} does not include the diagnosis of a caffeine addiction but proposes criteria for the disorder for more study.JOURNAL, Addicott MA, Caffeine Use Disorder: A Review of the Evidence and Future Implications, Current Addiction Reports, 1, 3, 186–192, September 2014, 25089257, 4115451, 10.1007/s40429-014-0024-9, BOOK, Association American Psychiatry, Diagnostic and statistical manual of mental disorders : DSM-5, 2013, American Psychiatric Publishing, Washington [etc.], 978-0-89042-555-8, 792–795, 5th,weblink

Dependence and withdrawal

{{see also|Caffeine-induced anxiety disorder|caffeine-induced sleep disorder|caffeinism}}Withdrawal can cause mild to clinically significant distress or impairment in daily functioning. The frequency at which this occurs is self-reported at 11%, but in lab tests only half of the people who report withdrawal actually experience it, casting doubt on many claims of dependence.JOURNAL, Temple JL, Caffeine use in children: what we know, what we have left to learn, and why we should worry, Neuroscience and Biobehavioral Reviews, 33, 6, 793–806, June 2009, 19428492, 2699625, 10.1016/j.neubiorev.2009.01.001, and most cases of caffeine withdrawal were 13% in the moderate sense. Moderately physical dependence and withdrawal symptoms may occur upon abstinence, with greater than 100 mg caffeine per day, although these symptoms last no longer than a day. Some symptoms associated with psychological dependence may also occur during withdrawal. The diagnostic criteria for caffeine withdrawal require a previous prolonged daily use of caffeine.BOOK, Desk reference to the diagnostic criteria from DSM-5, American Psychiatric Association, 2013, 978-0-89042-556-5, Arlington, VA, 238–239, Following 24 hours of a marked reduction in consumption, a minimum of 3 of these signs or symptoms is required to meet withdrawal criteria: difficulty concentrating, depressed mood/irritability, flu-like symptoms, headache, and fatigue. Additionally, the signs and symptoms must disrupt important areas of functioning and are not associated with effects of another condition.The ICD-11 includes caffeine dependence as a distinct diagnostic category, which closely mirrors the DSM-5's proposed set of criteria for "caffeine-use disorder".WEB,weblink" title="icd.who.int/browse11/l-m/en#weblink">weblink ICD-11 – Mortality and Morbidity Statistics, icd.who.int, 18 November 2019, 1 August 2018,weblink" title="archive.today/20180801205234/https://icd.who.int/browse11/l-m/en%23weblink">weblink live,   Caffeine use disorder refers to dependence on caffeine characterized by failure to control caffeine consumption despite negative physiological consequences. The APA, which published the DSM-5, acknowledged that there was sufficient evidence in order to create a diagnostic model of caffeine dependence for the DSM-5, but they noted that the clinical significance of the disorder is unclear.American Psychiatric Association (2013). "Substance-Related and Addictive Disorders". American Psychiatric Publishing. pp. 1–2. Retrieved 18 November 2019. Due to this inconclusive evidence on clinical significance, the DSM-5 classifies caffeine-use disorder as a "condition for further study".Tolerance to the effects of caffeine occurs for caffeine-induced elevations in blood pressure and the subjective feelings of nervousness. Sensitization, the process whereby effects become more prominent with use, occurs for positive effects such as feelings of alertness and wellbeing. Tolerance varies for daily, regular caffeine users and high caffeine users. High doses of caffeine (750 to 1200 mg/day spread throughout the day) have been shown to produce complete tolerance to some, but not all of the effects of caffeine. Doses as low as 100 mg/day, such as a {{cvt|6|oz|g}} cup of coffee or two to three {{cvt|12|oz|g}} servings of caffeinated soft-drink, may continue to cause sleep disruption, among other intolerances. Non-regular caffeine users have the least caffeine tolerance for sleep disruption.WEB,weblink Information about caffeine dependence, 9 July 2003, Caffeinedependence.org, Johns Hopkins Medicine,weblink" title="web.archive.org/web/20120523135807weblink">weblink 23 May 2012, 25 May 2012, Some coffee drinkers develop tolerance to its undesired sleep-disrupting effects, but others apparently do not.JOURNAL, 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, Pharmacological Reviews, 51, 1, 83–133, March 1999, 10049999,

Risk of other diseases

{{See also|Health effects of coffee}}A neuroprotective effect of caffeine against Alzheimer's disease and dementia is possible but the evidence is inconclusive.JOURNAL, Santos C, Costa J, Santos J, Vaz-Carneiro A, Lunet N, Caffeine intake and dementia: systematic review and meta-analysis, Journal of Alzheimer's Disease, 20, Suppl 1, S187-204, 2010, 20182026, 10.3233/JAD-2010-091387, free, doi, JOURNAL, Panza F, Solfrizzi V, Barulli MR, Bonfiglio C, Guerra V, Osella A, Seripa D, Sabbà C, Pilotto A, Logroscino G, Coffee, tea, and caffeine consumption and prevention of late-life cognitive decline and dementia: a systematic review, The Journal of Nutrition, Health & Aging, 19, 3, 313–28, March 2015, 25732217, 10.1007/s12603-014-0563-8, 11586/145493, 8376733, free, Regular consumption of caffeine may protect people from liver cirrhosis.JOURNAL, Muriel P, Arauz J, Coffee and liver diseases, Fitoterapia, 81, 5, 297–305, July 2010, 19825397, 10.1016/j.fitote.2009.10.003, It was also found to slow the progression of liver disease in people who already have the condition, reduce the risk of liver fibrosis, and offer a protective effect against liver cancer among moderate coffee drinkers. A study conducted in 2017 found that the effects of caffeine from coffee consumption on the liver were observed regardless of how the drink was prepared.WEB, Coffee and the Liver,weblink 2023-05-12, British Liver Trust, en, 12 May 2023,weblink live, Caffeine may lessen the severity of acute mountain sickness if taken a few hours prior to attaining a high altitude.JOURNAL, Hackett PH, Caffeine at high altitude: java at base cAMP, High Altitude Medicine & Biology, 11, 1, 13–7, 2010, 20367483, 10.1089/ham.2009.1077, 8820874, One meta analysis has found that caffeine consumption is associated with a reduced risk of type 2 diabetes.JOURNAL, Jiang X, Zhang D, Jiang W, Coffee and caffeine intake and incidence of type 2 diabetes mellitus: a meta-analysis of prospective studies, European Journal of Nutrition, 53, 1, 25–38, February 2014, 24150256, 10.1007/s00394-013-0603-x, Dose-response analysis suggested that incidence of T2DM decreased ...14% [0.86 (0.82-0.91)] for every 200 mg/day increment in caffeine intake., 5566177, Regular caffeine consumption may reduce the risk of developing Parkinson's disease and may slow the progression of Parkinson's disease.JOURNAL, Hong CT, Chan L, Bai CH, The Effect of Caffeine on the Risk and Progression of Parkinson's Disease: A Meta-Analysis, Nutrients, 12, 6, 1860, June 2020, 32580456, 10.3390/nu12061860, 7353179, free, doi, JOURNAL, Liu R, Guo X, Park Y, Huang X, Sinha R, Freedman ND, Hollenbeck AR, Blair A, Chen H, Caffeine intake, smoking, and risk of Parkinson disease in men and women, American Journal of Epidemiology, 175, 11, 1200–7, June 2012, 22505763, 3370885, 10.1093/aje/kwr451, Caffeine increases intraocular pressure in those with glaucoma but does not appear to affect normal individuals.JOURNAL, Li M, Wang M, Guo W, Wang J, Sun X, 668498, The effect of caffeine on intraocular pressure: a systematic review and meta-analysis, Graefe's Archive for Clinical and Experimental Ophthalmology, 249, 3, 435–42, March 2011, 20706731, 10.1007/s00417-010-1455-1, The DSM-5 also includes other caffeine-induced disorders consisting of caffeine-induced anxiety disorder, caffeine-induced sleep disorder and unspecified caffeine-related disorders. The first two disorders are classified under "Anxiety Disorder" and "Sleep-Wake Disorder" because they share similar characteristics. Other disorders that present with significant distress and impairment of daily functioning that warrant clinical attention but do not meet the criteria to be diagnosed under any specific disorders are listed under "Unspecified Caffeine-Related Disorders".BOOK, Desk reference to the diagnostic criteria from DSM-5, 2013, American Psychiatric Publishing, American Psychiatric Association, 978-0-89042-556-5, Washington, DC, 825047464,

Energy crash

Caffeine is reputed to cause a fall in energy several hours after drinking, but this is not well researched.JOURNAL,weblink Pharmacokinetic profile of a novel sustained-release caffeine with extended benefits on alertness and mood: A randomized, double-blind, single-dose, active-controlled, crossover study, Morde A, Sudhakar K, Rambabu M, Shankar A, Rai D, Pawar K, Acharya M, Bakan M, Nalawade P, Nayakwadi R, Padigaru M, 1 November 2021, Current Research in Behavioral Sciences, 2, 100036, 10.1016/j.crbeha.2021.100036, WEB,weblink Can Yerba Mate tea actually crush your afternoon fatigue? Here’s what the science says, www.sciencefocus.com,weblinkweblink Suffering from caffeine crashes now you're back in the office? Here's what to do about it (no, you don't have to quit coffee forever), 13 September 2021, Glamour UK,

Overdose

{{Expand section|date=November 2019|with=practical management of overdose, see {{PMID|30893206}}}}(File:Main symptoms of Caffeine overdose.svg|thumb|upright=1.3|Primary symptoms of caffeine intoxicationWEB,weblink Caffeine (Systemic), 25 May 2000, MedlinePlus,weblink" title="web.archive.org/web/20070223063601weblink">weblink 23 February 2007, 3 August 2009, |alt=Torso of a young man with overlaid text of main side-effects of caffeine overdose.)Consumption of {{convert|1|–|1.5|g|mg}} per day is associated with a condition known as caffeinism.JOURNAL, Neuropsychiatric effects of caffeine, Winston AP, Hardwick E, Jaberi N, Advances in Psychiatric Treatment, 2005, 432–439, 10.1192/apt.11.6.432, 11, 6, free, doi, Caffeinism usually combines caffeine dependency with a wide range of unpleasant symptoms including nervousness, irritability, restlessness, insomnia, headaches, and palpitations after caffeine use.BOOK, Caffeinism: History, clinical features, diagnosis, and treatment, {{google books, y, sm2ZySXTm7oC, 331, |pages=331–344 |title=Caffeine and Activation Theory: Effects on Health and Behavior |veditors=Smith BD, Gupta U, Gupta BS |year=2007 |publisher=CRC Press |isbn=978-0-8493-7102-8 |vauthors=Iancu I, Olmer A, Strous RD |access-date=15 January 2014}}Caffeine overdose can result in a state of central nervous system overstimulation known as caffeine intoxication, a clinically significant temporary condition that develops during, or shortly after, the consumption of caffeine.WEB,weblink" title="icd.who.int/browse11/l-m/en#weblink">weblink ICD-11 – Mortality and Morbidity Statistics, icd.who.int, 25 November 2019, 1 August 2018,weblink" title="archive.today/20180801205234/https://icd.who.int/browse11/l-m/en%23weblink">weblink live, This syndrome typically occurs only after ingestion of large amounts of caffeine, well over the amounts found in typical caffeinated beverages and caffeine tablets (e.g., more than 400–500 mg at a time). According to the DSM-5, caffeine intoxication may be diagnosed if five (or more) of the following symptoms develop after recent consumption of caffeine: restlessness, nervousness, excitement, insomnia, flushed face, diuresis, gastrointestinal disturbance, muscle twitching, rambling flow of thought and speech, tachycardia or cardiac arrhythmia, periods of inexhaustibility, and psychomotor agitation.BOOK, Diagnostic and Statistical Manual of Mental Disorders, American Psychiatric Association, 22 May 2013, American Psychiatric Association, 978-0-89042-555-8, Fifth, en, 10.1176/appi.books.9780890425596, 2027.42/138395, 10.1.1.988.5627, registration,weblink According to the International Classification of Diseases (ICD-11), cases of very high caffeine intake (e.g. > 5 g) may result in caffeine intoxication with symptoms including mania, depression, lapses in judgment, disorientation, disinhibition, delusions, hallucinations or psychosis, and rhabdomyolysis.

Energy drinks

High caffeine consumption in energy drinks (at least one liter or 320 mg of caffeine) was associated with short-term cardiovascular side effects including hypertension, prolonged QT interval, and heart palpitations. These cardiovascular side effects were not seen with smaller amounts of caffeine consumption in energy drinks (less than 200 mg).

Severe intoxication

{{As of|2007}} there is no known antidote or reversal agent for caffeine intoxication. Treatment of mild caffeine intoxication is directed toward symptom relief; severe intoxication may require peritoneal dialysis, hemodialysis, or hemofiltration.JOURNAL, Carreon CC, Parsh B, How to recognize caffeine overdose, Nursing, 49, 4, 52–55, April 2019, 30893206, 10.1097/01.NURSE.0000553278.11096.86, Clinical tutorial, 84842436, JOURNAL, Fintel M, Langer GA, Duenas C, Effects of low sodium perfusion on cardiac caffeine sensitivity and calcium uptake, Journal of Molecular and Cellular Cardiology, 16, 11, 1037–1045, November 1984, 6520875, 10.1016/s0022-2828(84)80016-4, Intralipid infusion therapy is indicated in cases of imminent risk of cardiac arrest in order to scavenge the free serum caffeine.

Lethal dose

Death from caffeine ingestion appears to be rare, and most commonly caused by an intentional overdose of medications.JOURNAL, Murray A, Traylor J, January 2019, Caffeine Toxicity, StatPearls [Internet], Mini-review, 30422505, In 2016, 3702 caffeine-related exposures were reported to Poison Control Centers in the United States, of which 846 required treatment at a medical facility, and 16 had a major outcome; and several caffeine-related deaths are reported in case studies. The LD50 of caffeine in rats is 192 milligrams per kilogram, the fatal dose in humans is estimated to be 150–200 milligrams per kilogram (2.2 lb) of body mass (75–100 cups of coffee for a {{cvt|70|kg}} adult).WEB,weblink Caffeine {{!, C8H10N4O2 |access-date=2022-03-01 |website=pubchem.ncbi.nlm.nih.gov |publisher=National Center for Biotechnology Information |archive-date=2 March 2022 |archive-url=https://web.archive.org/web/20220302033943weblink |url-status=live }}JOURNAL, Peters JM, 1967, Factors Affecting Caffeine Toxicity: A Review of the Literature,weblink dead, The Journal of Clinical Pharmacology and the Journal of New Drugs, 7, 3, 131–141, 10.1002/j.1552-4604.1967.tb00034.x,weblink" title="web.archive.org/web/20120112134847weblink">weblink 12 January 2012, There are cases where doses as low as 57 milligrams per kilogram have been fatal.JOURNAL, Evans J, Richards JR, Battisti AS, January 2019, Caffeine, StatPearls [Internet], Mini-review, 30137774, A number of fatalities have been caused by overdoses of readily available powdered caffeine supplements, for which the estimated lethal amount is less than a tablespoon.NEWS, Caffeine powder poses deadly risks, New York Times,weblink 18 May 2015, Carpenter M, 18 May 2015, 25 January 2022,weblink live, The lethal dose is lower in individuals whose ability to metabolize caffeine is impaired due to genetics or chronic liver disease.JOURNAL, Rodopoulos N, Wisén O, Norman A, May 1995, Caffeine metabolism in patients with chronic liver disease, Scandinavian Journal of Clinical and Laboratory Investigation, 55, 3, 229–42, 10.3109/00365519509089618, 7638557, A death was reported in 2013 of a man with liver cirrhosis who overdosed on caffeinated mints.NEWS, 11 October 2013, Man died after overdosing on caffeine mints, The Independent,weblink 13 October 2013, Cheston P, Smith L, 12 October 2013,weblink" title="web.archive.org/web/20131012002244weblink">weblink live, NEWS, 11 October 2013, Warning over caffeine sweets after father dies from overdose, The Telegraph,weblink dead, 13 October 2013,weblink" title="web.archive.org/web/20131011113121weblink">weblink 11 October 2013, Prynne M,

Interactions

Caffeine is a substrate for CYP1A2, and interacts with many substances through this and other mechanisms.WEB, Caffeine Drug Monographs,weblink UpToDate, 28 November 2018, 25 April 2013,weblink live,

Alcohol

{{see also|Caffeinated alcoholic drink}}According to DSST, alcohol causes a decrease in performance on their standardized tests, and caffeine causes a significant improvement.JOURNAL, Mackay M, Tiplady B, Scholey AB, Interactions between alcohol and caffeine in relation to psychomotor speed and accuracy, Human Psychopharmacology, 17, 3, 151–6, April 2002, 12404692, 10.1002/hup.371, 21764730, When alcohol and caffeine are consumed jointly, the effects of the caffeine are changed, but the alcohol effects remain the same.JOURNAL, Liguori A, Robinson JH, Caffeine antagonism of alcohol-induced driving impairment, Drug and Alcohol Dependence, 63, 2, 123–9, July 2001, 11376916, 10.1016/s0376-8716(00)00196-4, For example, consuming additional caffeine does not reduce the effect of alcohol. However, the jitteriness and alertness given by caffeine is decreased when additional alcohol is consumed. Alcohol consumption alone reduces both inhibitory and activational aspects of behavioral control. Caffeine antagonizes the effect of alcohol on the activational aspect of behavioral control, but has no effect on the inhibitory behavioral control.JOURNAL, Marczinski CA, Fillmore MT, Dissociative antagonistic effects of caffeine on alcohol-induced impairment of behavioral control, Experimental and Clinical Psychopharmacology, 11, 3, 228–36, August 2003, 12940502, 10.1037/1064-1297.11.3.228, The Dietary Guidelines for Americans recommend avoidance of concomitant consumption of alcohol and caffeine, as taking them together may lead to increased alcohol consumption, with a higher risk of alcohol-associated injury.

Tobacco

Smoking tobacco increases caffeine clearance by 56%.JOURNAL, Zevin S, Benowitz NL, Drug interactions with tobacco smoking. An update, Clinical Pharmacokinetics, 36, 6, 425–438, June 1999, 10427467, 10.2165/00003088-199936060-00004, 19827114, Cigarette smoking induces the cytochrome P450 1A2 enzyme that breaks down caffeine, which may lead to increased caffeine tolerance and coffee consumption for regular smokers.JOURNAL, Bjørngaard JH, Nordestgaard AT, Taylor AE, Treur JL, Gabrielsen ME, Munafò MR, Nordestgaard BG, Åsvold BO, Romundstad P, Davey Smith G, Heavier smoking increases coffee consumption: findings from a Mendelian randomization analysis, International Journal of Epidemiology, 46, 6, 1958–1967, December 2017, 29025033, 5837196, 10.1093/ije/dyx147,

Birth control

Birth control pills can extend the half-life of caffeine, requiring greater attention to caffeine consumption.JOURNAL, Benowitz NL, Clinical pharmacology of caffeine, Annual Review of Medicine, 41, 277–88, 1990, 2184730, 10.1146/annurev.me.41.020190.001425,

Medications

Caffeine sometimes increases the effectiveness of some medications, such as those for headaches.JOURNAL, Gilmore B, Michael M, Treatment of acute migraine headache, American Family Physician, 83, 3, 271–80, February 2011, 21302868, Caffeine was determined to increase the potency of some over-the-counter analgesic medications by 40%.BOOK, Benzon H, Practical management of pain, 978-0-323-08340-9, 508–529, Fifth, 12 September 2013, Elsevier Health Sciences, The pharmacological effects of adenosine may be blunted in individuals taking large quantities of methylxanthines like caffeine.WEB, Vitamin B4, R&S Pharmchem,weblink April 2011, dead,weblink" title="web.archive.org/web/20110715213918weblink">weblink 15 July 2011, Some other examples of methylxanthines include the medications theophylline and aminophylline, which are prescribed to relieve symptoms of asthma or COPD.JOURNAL, Gottwalt B, Prasanna T, Methylxanthines, StatPearls, September 29, 2021, 32644591,weblink 15 November 2021, 20 March 2022,weblink live,

Pharmacology

Pharmacodynamics

{{Synapse map}}File:Caffeine and adenosine.svg|thumb|Caffeine's primary mechanism of action is as an (adenosine receptor antagonist]] in the brain.|alt=Two skeletal formulas: left â€“ caffeine, right â€“ adenosine.)In the absence of caffeine and when a person is awake and alert, little adenosine is present in CNS neurons. With a continued wakeful state, over time adenosine accumulates in the neuronal synapse, in turn binding to and activating adenosine receptors found on certain CNS neurons; when activated, these receptors produce a cellular response that ultimately increases drowsiness. When caffeine is consumed, it antagonizes adenosine receptors; in other words, caffeine prevents adenosine from activating the receptor by blocking the location on the receptor where adenosine binds to it. As a result, caffeine temporarily prevents or relieves drowsiness, and thus maintains or restores alertness.

Receptor and ion channel targets

Caffeine is an antagonist of adenosine A2A receptors, and knockout mouse studies have specifically implicated antagonism of the A2A receptor as responsible for the wakefulness-promoting effects of caffeine. Antagonism of A2A receptors in the ventrolateral preoptic area (VLPO) reduces inhibitory GABA neurotransmission to the tuberomammillary nucleus, a histaminergic projection nucleus that activation-dependently promotes arousal. This disinhibition of the tuberomammillary nucleus is the downstream mechanism by which caffeine produces wakefulness-promoting effects. Caffeine is an antagonist of all four adenosine receptor subtypes (A1, A2A, A2B, and A3), although with varying potencies. The affinity (KD) values of caffeine for the human adenosine receptors are 12 Î¼M at A1, 2.4 Î¼M at A2A, 13 Î¼M at A2B, and 80 Î¼M at A3.JOURNAL, Froestl W, Muhs A, Pfeifer A, 10511507, Cognitive enhancers (nootropics). Part 1: drugs interacting with receptors, Journal of Alzheimer's Disease, 32, 4, 793–887, 2012, 22886028, 10.3233/JAD-2012-121186,weblinkweblink" title="web.archive.org/web/20201115231222weblink">weblink dead, 15 November 2020, Antagonism of adenosine receptors by caffeine also stimulates the medullary vagal, vasomotor, and respiratory centers, which increases respiratory rate, reduces heart rate, and constricts blood vessels. Adenosine receptor antagonism also promotes neurotransmitter release (e.g., monoamines and acetylcholine), which endows caffeine with its stimulant effects;WEB,weblink World of Caffeine, World of Caffeine, 15 June 2013, 19 December 2013, 10 December 2013,weblink" title="web.archive.org/web/20131210195155weblink">weblink dead, adenosine acts as an inhibitory neurotransmitter that suppresses activity in the central nervous system. Heart palpitations are caused by blockade of the A1 receptor.Because caffeine is both water- and lipid-soluble, it readily crosses the blood–brain barrier that separates the bloodstream from the interior of the brain. Once in the brain, the principal mode of action is as a nonselective antagonist of adenosine receptors (in other words, an agent that reduces the effects of adenosine). The caffeine molecule is structurally similar to adenosine, and is capable of binding to adenosine receptors on the surface of cells without activating them, thereby acting as a competitive antagonist.JOURNAL, Fisone G, Borgkvist A, Usiello A, 7578473, Caffeine as a psychomotor stimulant: mechanism of action, Cellular and Molecular Life Sciences, 61, 7–8, 857–72, April 2004, 15095008, 10.1007/s00018-003-3269-3, In addition to its activity at adenosine receptors, caffeine is an inositol trisphosphate receptor 1 antagonist and a voltage-independent activator of the ryanodine receptors (RYR1, RYR2, and RYR3).WEB, Caffeine,weblink IUPHAR, International Union of Basic and Clinical Pharmacology, 2 November 2014, 2 November 2014,weblink" title="web.archive.org/web/20141102064047weblink">weblink live, It is also a competitive antagonist of the ionotropic glycine receptor.JOURNAL, Duan L, Yang J, Slaughter MM, Caffeine inhibition of ionotropic glycine receptors, The Journal of Physiology, 587, Pt 16, 4063–75, August 2009, 19564396, 2756438, 10.1113/jphysiol.2009.174797,

Effects on striatal dopamine

While caffeine does not directly bind to any dopamine receptors, it influences the binding activity of dopamine at its receptors in the striatum by binding to adenosine receptors that have formed GPCR heteromers with dopamine receptors, specifically the A1–D1 receptor heterodimer (this is a receptor complex with one adenosine A1 receptor and one dopamine D1 receptor) and the A2A–D2 receptor heterotetramer (this is a receptor complex with two adenosine A2A receptors and two dopamine D2 receptors).JOURNAL, Ferré S, Role of the central ascending neurotransmitter systems in the psychostimulant effects of caffeine, Journal of Alzheimer's Disease, 20, Suppl 1, S35–49, 2010, 20182056, 10.3233/JAD-2010-1400, 9361505, By targeting A1-A2A receptor heteromers in striatal glutamatergic terminals and A1 receptors in striatal dopaminergic terminals (presynaptic brake), caffeine induces glutamate-dependent and glutamate-independent release of dopamine. These presynaptic effects of caffeine are potentiated by the release of the postsynaptic brake imposed by antagonistic interactions in the striatal A2A-D2 and A1-D1 receptor heteromers., free, doi, The A2A–D2 receptor heterotetramer has been identified as a primary pharmacological target of caffeine, primarily because it mediates some of its psychostimulant effects and its pharmacodynamic interactions with dopaminergic psychostimulants.JOURNAL, Ferré S, Bonaventura J, Tomasi D, Navarro G, Moreno E, Cortés A, Lluís C, Casadó V, Volkow ND, Allosteric mechanisms within the adenosine A2A-dopamine D2 receptor heterotetramer, Neuropharmacology, 104, 154–60, May 2016, 26051403, 5754196, 10.1016/j.neuropharm.2015.05.028, JOURNAL, Bonaventura J, Navarro G, Casadó-Anguera V, Azdad K, Rea W, Moreno E, Brugarolas M, Mallol J, Canela EI, Lluís C, Cortés A, Volkow ND, Schiffmann SN, Ferré S, Casadó V, Allosteric interactions between agonists and antagonists within the adenosine A2A receptor-dopamine D2 receptor heterotetramer, Proceedings of the National Academy of Sciences of the United States of America, 112, 27, E3609–18, July 2015, 26100888, 4500251, 10.1073/pnas.1507704112, Adenosine A2A receptor (A2AR)-dopamine D2 receptor (D2R) heteromers are key modulators of striatal neuronal function. It has been suggested that the psychostimulant effects of caffeine depend on its ability to block an allosteric modulation within the A2AR-D2R heteromer, by which adenosine decreases the affinity and intrinsic efficacy of dopamine at the D2R., 2015PNAS..112E3609B, free, doi, JOURNAL, Ferré S, Mechanisms of the psychostimulant effects of caffeine: implications for substance use disorders, Psychopharmacology, 233, 10, 1963–79, May 2016, 26786412, 4846529, 10.1007/s00213-016-4212-2, The striatal A2A-D2 receptor heteromer constitutes an unequivocal main pharmacological target of caffeine and provides the main mechanisms by which caffeine potentiates the acute and long-term effects of prototypical psychostimulants., Caffeine also causes the release of dopamine in the dorsal striatum and nucleus accumbens core (a substructure within the ventral striatum), but not the nucleus accumbens shell, by antagonizing A1 receptors in the axon terminal of dopamine neurons and A1–A2A heterodimers (a receptor complex composed of one adenosine A1 receptor and one adenosine A2A receptor) in the axon terminal of glutamate neurons. During chronic caffeine use, caffeine-induced dopamine release within the nucleus accumbens core is markedly reduced due to drug tolerance.JOURNAL, Ferré S, An update on the mechanisms of the psychostimulant effects of caffeine, J. Neurochem., 105, 4, 1067–1079, 2008, 18088379, 10.1111/j.1471-4159.2007.05196.x, 33159096, On the other hand, our 'ventral shell of the nucleus accumbens' very much overlaps with the striatal compartment..., free, doi,

Enzyme targets

Caffeine, like other xanthines, also acts as a phosphodiesterase inhibitor.JOURNAL, Ribeiro JA, Sebastião AM, Caffeine and adenosine, Journal of Alzheimer's Disease, 20, Suppl 1, S3-15, 2010, 20164566, 10.3233/JAD-2010-1379, free, 10451/6361, As a competitive nonselective phosphodiesterase inhibitor,JOURNAL, Essayan DM, Cyclic nucleotide phosphodiesterases, The Journal of Allergy and Clinical Immunology, 108, 5, 671–680, November 2001, 11692087, 10.1067/mai.2001.119555,weblink dead, 21528985,weblink 25 February 2020, caffeine raises intracellular cyclic AMP, activates protein kinase A, inhibits TNF-alphaJOURNAL, Deree J, Martins JO, Melbostad H, Loomis WH, Coimbra R, Insights into the regulation of TNF-alpha production in human mononuclear cells: the effects of non-specific phosphodiesterase inhibition, Clinics, 63, 3, 321–328, June 2008, 18568240, 2664230, 10.1590/S1807-59322008000300006, JOURNAL, Marques LJ, Zheng L, Poulakis N, Guzman J, Costabel U, Pentoxifylline inhibits TNF-alpha production from human alveolar macrophages, American Journal of Respiratory and Critical Care Medicine, 159, 2, 508–511, February 1999, 9927365, 10.1164/ajrccm.159.2.9804085, and leukotrieneJOURNAL, Peters-Golden M, Canetti C, Mancuso P, Coffey MJ, Leukotrienes: underappreciated mediators of innate immune responses, Journal of Immunology, 174, 2, 589–594, January 2005, 15634873, 10.4049/jimmunol.174.2.589, free, doi, synthesis, and reduces inflammation and innate immunity. Caffeine also affects the cholinergic system where it is a moderate inhibitor of the enzyme acetylcholinesterase.JOURNAL, Karadsheh N, Kussie P, Linthicum DS, Inhibition of acetylcholinesterase by caffeine, anabasine, methyl pyrrolidine and their derivatives, Toxicology Letters, 55, 3, 335–342, March 1991, 2003276, 10.1016/0378-4274(91)90015-X, JOURNAL, Pohanka M, Dobes P, Caffeine inhibits acetylcholinesterase, but not butyrylcholinesterase, International Journal of Molecular Sciences, 14, 5, 9873–9882, May 2013, 23698772, 3676818, 10.3390/ijms14059873, free, doi,

Pharmacokinetics

File:Caffeine metabolites.svg|thumb|upright=1.3|Caffeine is metabolized in the liver via a single demethylation, resulting in three primary metabolites, paraxanthine (84%), theobromine (12%), and alt=A diagram featuring 4 skeletal chemical formulas. Top (caffeine) relates to similar compounds paraxanthine, theobromine and theophylline.(File:Caffeine metabolism.png|thumb|upright=1.3|Urinary metabolites of caffeine in humans at 48 hours post-doseBOOK, Arnaud MJ, Pharmacokinetics and Metabolism of Natural Methylxanthines in Animal and Man, Methylxanthines, Handbook of Experimental Pharmacology, 200, 200, 33–91, 19 August 2010, 20859793, 10.1007/978-3-642-13443-2_3, 978-3-642-13442-5, )Caffeine from coffee or other beverages is absorbed by the small intestine within 45 minutes of ingestion and distributed throughout all bodily tissues.JOURNAL, Liguori A, Hughes JR, Grass JA, 24067050, Absorption and subjective effects of caffeine from coffee, cola and capsules, Pharmacology, Biochemistry, and Behavior, 58, 3, 721–6, November 1997, 9329065, 10.1016/S0091-3057(97)00003-8, Peak blood concentration is reached within 1–2 hours.JOURNAL, Blanchard J, Sawers SJ, 10502739, The absolute bioavailability of caffeine in man, European Journal of Clinical Pharmacology, 24, 1, 93–8, 1983, 6832208, 10.1007/bf00613933, It is eliminated by first-order kinetics.JOURNAL, Newton R, Broughton LJ, Lind MJ, Morrison PJ, Rogers HJ, Bradbrook ID, 12291731, Plasma and salivary pharmacokinetics of caffeine in man, European Journal of Clinical Pharmacology, 21, 1, 45–52, 1981, 7333346, 10.1007/BF00609587, Caffeine can also be absorbed rectally, evidenced by suppositories of ergotamine tartrate and caffeine (for the relief of migraine)JOURNAL, Graham JR, Rectal use of ergotamine tartrate and caffeine alkaloid for the relief of migraine, The New England Journal of Medicine, 250, 22, 936–8, June 1954, 13165929, 10.1056/NEJM195406032502203, and of chlorobutanol and caffeine (for the treatment of hyperemesis).JOURNAL, Brødbaek HB, Damkier P, [The treatment of hyperemesis gravidarum with chlorobutanol-caffeine rectal suppositories in Denmark: practice and evidence], da, Ugeskrift for Laeger, 169, 22, 2122–3, May 2007, 17553397, However, rectal absorption is less efficient than oral: the maximum concentration (Cmax) and total amount absorbed (AUC) are both about 30% (i.e., 1/3.5) of the oral amounts.JOURNAL, Teekachunhatean S, Tosri N, Rojanasthien N, Srichairatanakool S, Sangdee C, Pharmacokinetics of Caffeine following a Single Administration of Coffee Enema versus Oral Coffee Consumption in Healthy Male Subjects, ISRN Pharmacology, 2013, 147238, 147238, 8 January 2013, 23533801, 3603218, 10.1155/2013/147238, free, doi, Caffeine's biological half-life â€“ the time required for the body to eliminate one-half of a dose â€“ varies widely among individuals according to factors such as pregnancy, other drugs, liver enzyme function level (needed for caffeine metabolism) and age. In healthy adults, caffeine's half-life is between 3 and 7 hours. The half-life is decreased by 30-50% in adult male smokers, approximately doubled in women taking oral contraceptives, and prolonged in the last trimester of pregnancy. In newborns the half-life can be 80 hours or more, dropping very rapidly with age, possibly to less than the adult value by age 6 months. The antidepressant fluvoxamine (Luvox) reduces the clearance of caffeine by more than 90%, and increases its elimination half-life more than tenfold; from 4.9 hours to 56 hours.WEB,weblink Drug Interaction: Caffeine Oral and Fluvoxamine Oral, Medscape Multi-Drug Interaction Checker, Caffeine is metabolized in the liver by the cytochrome P450 oxidase enzyme system, in particular, by the CYP1A2 isozyme, into three dimethylxanthines,WEB, Caffeine, The Pharmacogenetics and Pharmacogenomics Knowledge Base,weblink 25 October 2010, 17 July 2011,weblink" title="web.archive.org/web/20110717130823weblink">weblink dead, each of which has its own effects on the body:

• Paraxanthine (84%): Increases lipolysis, leading to elevated glycerol and free fatty acid levels in blood plasma.
• Theobromine (12%): Dilates blood vessels and increases urine volume. Theobromine is also the principal alkaloid in the cocoa bean (chocolate).
• Theophylline (4%): Relaxes smooth muscles of the bronchi, and is used to treat asthma. The therapeutic dose of theophylline, however, is many times greater than the levels attained from caffeine metabolism.

1,3,7-Trimethyluric acid is a minor caffeine metabolite. 7-Methylxanthine is also a metabolite of caffeine.WEB, 7-Methylxanthine, Inxight Drugs,weblink 24 August 2022, 24 August 2022,weblink live, JOURNAL, Singh H, Singh H, Latief U, Tung GK, Shahtaghi NR, Sahajpal NS, Kaur I, Jain SK, Myopia, its prevalence, current therapeutic strategy and recent developments: A Review, Indian J Ophthalmol, 70, 8, 2788–2799, August 2022, 35918918, 10.4103/ijo.IJO_2415_21, 9672758, 251281523, free, doi, Each of the above metabolites is further metabolized and then excreted in the urine. Caffeine can accumulate in individuals with severe liver disease, increasing its half-life.JOURNAL, Verbeeck RK, 27888650, Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction, European Journal of Clinical Pharmacology, 64, 12, 1147–61, December 2008, 18762933, 10.1007/s00228-008-0553-z, A 2011 review found that increased caffeine intake was associated with a variation in two genes that increase the rate of caffeine catabolism. Subjects who had this mutation on both chromosomes consumed 40 mg more caffeine per day than others.JOURNAL, Cornelis MC, Monda KL, Yu K, Paynter N, Azzato EM, Bennett SN, Berndt SI, Boerwinkle E, Chanock S, Chatterjee N, Couper D, Curhan G, Heiss G, Hu FB, Hunter DJ, Jacobs K, Jensen MK, Kraft P, Landi MT, Nettleton JA, Purdue MP, Rajaraman P, Rimm EB, Rose LM, Rothman N, Silverman D, Stolzenberg-Solomon R, Subar A, Yeager M, Chasman DI, van Dam RM, Caporaso NE, Genome-wide meta-analysis identifies regions on 7p21 (AHR) and 15q24 (CYP1A2) as determinants of habitual caffeine consumption, PLOS Genetics, 7, 4, e1002033, April 2011, 21490707, 3071630, 10.1371/journal.pgen.1002033, free, doi, Gibson G, This is presumably due to the need for a higher intake to achieve a comparable desired effect, not that the gene led to a disposition for greater incentive of habituation.

Chemistry

Pure anhydrous caffeine is a bitter-tasting, white, odorless powder with a melting point of 235–238 Â°C. Caffeine is moderately soluble in water at room temperature (2 g/100 mL), but very soluble in boiling water (66 g/100 mL). It is also moderately soluble in ethanol (1.5 g/100 mL).BOOK, The Merck Index, 12th, Susan Budavari, Merck & Co., Inc., Whitehouse Station, NJ, 1996, 268, It is weakly basic (pKa of conjugate acid = ~0.6) requiring strong acid to protonate it.This is the pKa for protonated caffeine, given as a range of values included in JOURNAL, Prankerd RJ, Critical Compilation of pK(a) Values for Pharmaceutical Substances, Profiles of Drug Substances, Excipients, and Related Methodology, 33, 1–33 (15), 2007, 22469138, 10.1016/S0099-5428(07)33001-3, 978-0-12-260833-9, Brittain HG, Academic Press, {{google books, y, D3vBu5Tx4XwC, 15, }} Caffeine does not contain any stereogenic centersBOOK, Klosterman L, The Facts About Caffeine (Drugs), Benchmark Books (NY), 2006, 43, 978-0-7614-2242-6,weblink and hence is classified as an achiral molecule.BOOK, Vallombroso T, Organic Chemistry Pearls of Wisdom, Boston Medical Publishing Corp, 2001, 43, 978-1-58409-016-8, The xanthine core of caffeine contains two fused rings, a pyrimidinedione and imidazole. The pyrimidinedione in turn contains two amide functional groups that exist predominantly in a zwitterionic resonance the location from which the nitrogen atoms are double bonded to their adjacent amide carbons atoms. Hence all six of the atoms within the pyrimidinedione ring system are sp2 hybridized and planar. The imidazole ring also has a resonance. Therefore, the fused 5,6 ring core of caffeine contains a total of ten pi electrons and hence according to Hückel's rule is aromatic.WEB,weblink Chemistry of Caffeine, Keskineva N, Chemistry Department, East Stroudsburg University, 2 January 2014, dead,weblink" title="web.archive.org/web/20140102193955weblink">weblink 2 January 2014,

Synthesis

File:Caffeine biosynthesis.tif|thumb|upright=1.3|One biosynthetic route of caffeine, as performed by Camellia and Coffea speciesWEB,weblink Caffeine biosynthesis, The Enzyme Database, Trinity College Dublin, 24 September 2011, 22 March 2012,weblink" title="web.archive.org/web/20120322205814weblink">weblink live, WEB,weblink MetaCyc Pathway: caffeine biosynthesis I, MetaCyc database, (SRI International]], 12 July 2017, 29 May 2018,weblink live, )File:Caffeine synthesis-en.svg|thumb|upright=1.3|One laboratory synthesis of caffeine]]The biosynthesis of caffeine is an example of convergent evolution among different species.JOURNAL, Denoeud F, Carretero-Paulet L, Dereeper A, Droc G, Guyot R, Pietrella M, Zheng C, Alberti A, Anthony F, Aprea G, Aury JM, Bento P, Bernard M, Bocs S, Campa C, Cenci A, Combes MC, Crouzillat D, Da Silva C, Daddiego L, De Bellis F, Dussert S, Garsmeur O, Gayraud T, Guignon V, Jahn K, Jamilloux V, Joët T, Labadie K, Lan T, Leclercq J, Lepelley M, Leroy T, Li LT, Librado P, Lopez L, Muñoz A, Noel B, Pallavicini A, Perrotta G, Poncet V, Pot D, Rigoreau M, Rouard M, Rozas J, Tranchant-Dubreuil C, VanBuren R, Zhang Q, Andrade AC, Argout X, Bertrand B, de Kochko A, Graziosi G, Henry RJ, Ming R, Nagai C, Rounsley S, Sankoff D, Giuliano G, Albert VA, Wincker P, Lashermes P, The coffee genome provides insight into the convergent evolution of caffeine biosynthesis, Science, 345, 6201, 1181–4, September 2014, 25190796, 10.1126/science.1255274, 2014Sci...345.1181D, free, doi, JOURNAL, Huang R, O'Donnell AJ, Barboline JJ, Barkman TJ, Convergent evolution of caffeine in plants by co-option of exapted ancestral enzymes, Proceedings of the National Academy of Sciences of the United States of America, 113, 38, 10613–8, September 2016, 27638206, 5035902, 10.1073/pnas.1602575113, 2016PNAS..11310613H, free, doi, MAGAZINE,weblink How Plants Evolved Different Ways to Make Caffeine, The Scientist, Williams R, 21 September 2016, Caffeine may be synthesized in the lab starting with dimethylurea and malonic acid.{{clarify|reason=refs are for multiple routes and image is not this route|date=March 2017}}BOOK, Temple NJ, Wilson T, Beverages in Nutrition and Health, Humana Press, Totowa, NJ, 2003, 172, 978-1-58829-173-8, PATENT, US, 2785162, patent, Process for the formylation of a 5-nitrouracil, 12 March 1957, 23 April 1954, Swidinsky J, Baizer MM, New York Quinine and Chemical Works, Inc., JOURNAL, Zajac MA, Zakrzewski AG, Kowal MG, Narayan S, 43220488, A Novel Method of Caffeine Synthesis from Uracil, Synthetic Communications, 2003, 33, 19, 3291–3297, 10.1081/SCC-120023986,weblinkweblink" title="web.archive.org/web/20120318051053weblink">weblink 2012-03-18, live, Commercial supplies of caffeine are not usually manufactured synthetically because the chemical is readily available as a byproduct of decaffeination.WEB, Tilling S, Bristol University,weblink Crystalline Caffeine, 3 August 2009, 5 August 2011,weblink" title="web.archive.org/web/20110805224827weblink">weblink live,

Decaffeination

File:CaffeineCrystals Fibrous 10xDarkField.jpg|thumb|upright=1.3|Fibrous crystals of purified caffeine. Dark-field microscopyDark-field microscopyExtraction of caffeine from coffee, to produce caffeine and decaffeinated coffee, can be performed using a number of solvents. Following are main methods:

• Water extraction: Coffee beans are soaked in water. The water, which contains many other compounds in addition to caffeine and contributes to the flavor of coffee, is then passed through activated charcoal, which removes the caffeine. The water can then be put back with the beans and evaporated dry, leaving decaffeinated coffee with its original flavor. Coffee manufacturers recover the caffeine and resell it for use in soft drinks and over-the-counter caffeine tablets.WEB, Senese F, How is coffee decaffeinated?, General Chemistry Online, 20 September 2005,weblink 3 August 2009, 18 January 2012,weblink" title="web.archive.org/web/20120118123537weblink">weblink live,
• Supercritical carbon dioxide extraction: Supercritical carbon dioxide is an excellent nonpolar solvent for caffeine, and is safer than the organic solvents that are otherwise used. The extraction process is simple: {{CO2}} is forced through the green coffee beans at temperatures above 31.1 Â°C and pressures above 73 atm. Under these conditions, {{CO2}} is in a "supercritical" state: It has gaslike properties that allow it to penetrate deep into the beans but also liquid-like properties that dissolve 97–99% of the caffeine. The caffeine-laden {{CO2}} is then sprayed with high-pressure water to remove the caffeine. The caffeine can then be isolated by charcoal adsorption (as above) or by distillation, recrystallization, or reverse osmosis.
• Extraction by organic solvents: Certain organic solvents such as ethyl acetate present much less health and environmental hazard than chlorinated and aromatic organic solvents used formerly. Another method is to use triglyceride oils obtained from spent coffee grounds.

"Decaffeinated" coffees do in fact contain caffeine in many cases â€“ some commercially available decaffeinated coffee products contain considerable levels. One study found that decaffeinated coffee contained 10 mg of caffeine per cup, compared to approximately 85 mg of caffeine per cup for regular coffee.JOURNAL, McCusker RR, Fuehrlein B, Goldberger BA, Gold MS, Cone EJ, Caffeine content of decaffeinated coffee, Journal of Analytical Toxicology, 30, 8, 611–3, October 2006, 17132260, 10.1093/jat/30.8.611, University of Florida News, free, doi, 30 August 2013, 18 July 2008,weblinkweblink" title="web.archive.org/web/20080718213236weblink">weblink dead,

Detection in body fluids

Caffeine can be quantified in blood, plasma, or serum to monitor therapy in neonates, confirm a diagnosis of poisoning, or facilitate a medicolegal death investigation. Plasma caffeine levels are usually in the range of 2–10 mg/L in coffee drinkers, 12–36 mg/L in neonates receiving treatment for apnea, and 40–400 mg/L in victims of acute overdosage. Urinary caffeine concentration is frequently measured in competitive sports programs, for which a level in excess of 15 mg/L is usually considered to represent abuse.BOOK, Baselt R, Disposition of Toxic Drugs and Chemicals in Man, 11th, Biomedical Publications, Seal Beach, CA, 2017, 335–8, 978-0-692-77499-1,

Analogs

Some analog substances have been created which mimic caffeine's properties with either function or structure or both. Of the latter group are the xanthines DMPXJOURNAL, Seale TW, Abla KA, Shamim MT, Carney JM, Daly JW, 3,7-Dimethyl-1-propargylxanthine: a potent and selective in vivo antagonist of adenosine analogs, Life Sciences, 43, 21, 1671–84, 1988, 3193854, 10.1016/0024-3205(88)90478-x, and 8-chlorotheophylline, which is an ingredient in dramamine. Members of a class of nitrogen substituted xanthines are often proposed as potential alternatives to caffeine.WEB, Kennerly J, N Substituted Xanthines: A Caffeine Analog Information File, 22 September 1995,weblink 6 November 2015, 4 November 2015,weblink live, {{unreliable source?|date=November 2015}} Many other xanthine analogues constituting the adenosine receptor antagonist class have also been elucidated.BOOK, Müller CE, Jacobson KA, Xanthines as Adenosine Receptor Antagonists, Methylxanthines, Handbook of Experimental Pharmacology, 200, 200, 151–99, 19 August 2010, 20859796, 3882893, 10.1007/978-3-642-13443-2_6, 978-3-642-13442-5, Fredholm BB, Some other caffeine analogs:

• Dipropylcyclopentylxanthine
• 8-Cyclopentyl-1,3-dimethylxanthine
• 8-Phenyltheophylline

Precipitation of tannins

Caffeine, as do other alkaloids such as cinchonine, quinine or strychnine, precipitates polyphenols and tannins. This property can be used in a quantitation method.{{clarify|reason=Is this an application of caffeine to determine polyphenols and tannins, or a method of determining caffeine?|date=January 2022}}Plant Polyphenols: Synthesis, Properties, Significance. Richard W. Hemingway, Peter E. Laks, Susan J. Branham (page 263)

Natural occurrence

(File:Coffee beans2.jpg|thumb|Roasted coffee beans)Around thirty plant species are known to contain caffeine.WEB,weblink 28 Plants that Contain Caffeine, caffeineinformer.com, 6 August 2020, 11 December 2021,weblink live, Common sources are the "beans" (seeds) of the two cultivated coffee plants, Coffea arabica and Coffea canephora (the quantity varies, but 1.3% is a typical value); and of the cocoa plant, Theobroma cacao; the leaves of the tea plant; and kola nuts. Other sources include the leaves of yaupon holly, South American holly yerba mate, and Amazonian holly guayusa; and seeds from Amazonian maple guarana berries. Temperate climates around the world have produced unrelated caffeine-containing plants.Caffeine in plants acts as a natural pesticide: it can paralyze and kill predator insects feeding on the plant.JOURNAL, Nathanson JA, 42711016, Caffeine and related methylxanthines: possible naturally occurring pesticides, Science, 226, 4671, 184–7, October 1984, 6207592, 10.1126/science.6207592, 1984Sci...226..184N,weblinkweblink" title="web.archive.org/web/20190227050812weblink">weblink dead, 27 February 2019, High caffeine levels are found in coffee seedlings when they are developing foliage and lack mechanical protection.JOURNAL, Frischknecht PM, Ulmer-Dufek J, Baumann TW, Purine alkaloid formation in buds and developing leaflets of Coffea arabica: Expression of an optimal defence strategy?, Phytochemistry, 25, 613–6, 1986, 10.1016/0031-9422(86)88009-8, 3, 1986PChem..25..613F, In addition, high caffeine levels are found in the surrounding soil of coffee seedlings, which inhibits seed germination of nearby coffee seedlings, thus giving seedlings with the highest caffeine levels fewer competitors for existing resources for survival.JOURNAL, Baumann TW, Metabolism and excretion of caffeine during germination of Coffea arabica L, Plant and Cell Physiology, 25, 8, 1431–6, 1984, 10.1093/oxfordjournals.pcp.a076854, Caffeine is stored in tea leaves in two places. Firstly, in the cell vacuoles where it is complexed with polyphenols. This caffeine probably is released into the mouth parts of insects, to discourage herbivory. Secondly, around the vascular bundles, where it probably inhibits pathogenic fungi from entering and colonizing the vascular bundles.JOURNAL, van Breda SV, van der Merwe CF, Robbertse H, Apostolides Z, 17751471, Immunohistochemical localization of caffeine in young Camellia sinensis (L.) O. Kuntze (tea) leaves, Planta, 237, 3, 849–58, March 2013, 23143222, 10.1007/s00425-012-1804-x, 2013Plant.237..849V, 2263/20662,weblink free, Caffeine in nectar may improve the reproductive success of the pollen producing plants by enhancing the reward memory of pollinators such as honey bees.The differing perceptions in the effects of ingesting beverages made from various plants containing caffeine could be explained by the fact that these beverages also contain varying mixtures of other methylxanthine alkaloids, including the cardiac stimulants theophylline and theobromine, and polyphenols that can form insoluble complexes with caffeine.BOOK, Balentine DA, Harbowy ME, Graham HN, Tea: the Plant and its Manufacture; Chemistry and Consumption of the Beverage, Caffeine Consumption, 1998, CRC Press, Spiller GA, 978-0-429-12678-9,

Products

{| class="sortable wikitable" style="width:35%; float:right; clear:right; margin:0 0 0.5em 1em; font-size:85%;"Center for Science in the Public Interest, 1996,weblinkweblink" title="web.archive.org/web/20070614144016weblink">weblink 14 June 2007, 3 August 2009, WEB, Caffeine Content of Beverages, Foods, & Medications, Erowid, The Vaults of Erowid, 7 July 2006,weblink 3 August 2009, 10 June 2006,weblink" title="web.archive.org/web/20060610035059weblink">weblink live, WEB,weblink Caffeine Content of Drinks, Caffeine Informer, 8 December 2013, 2 August 2021,weblink" title="web.archive.org/web/20210802055714weblink">weblink live, ! scope="col" | Product! scope="col" style="width:26%;" | Serving size! scope="col" style="width:12%;" | Caffeine per serving (mg)! scope="col" style="width:12%;" | Caffeine (mg/L)| Caffeine tablet (regular-strength)| 1 tablet100}}|—| Caffeine tablet (extra-strength)| 1 tablet200}}|—| Excedrin tablet| 1 tablet65}}|—coffee percolator>Percolated coffee{{convertmLabbr=on|lk=on}}}}80}}–135386}}–652drip brew>Drip coffee{{convertmLabbr=on}}}}115}}–175555}}–845Coffee, decaffeinated}}{{convertmLabbr=on}}}}5}}–1524}}–72| Coffee, espresso{{convert–mLabbr=on}}}}100}}1691}}–2,254Tea â€“ black, green, and other Tea#Processing and classification>types, â€“ steeped for 3 min.{{convertmLabbr=on}}}}22}}–74CHIN JM, MERVES ML, GOLDBERGER BA, SAMPSON-CONE A, CONE EJ > TITLE = CAFFEINE CONTENT OF BREWED TEAS VOLUME = 32 PAGES = 702–4 PMID = 19007524 DOI-ACCESS = FREE VAUTHORS = RICHARDSON B PUBLISHER=ELMWOOD INN URL-STATUS=DEAD ARCHIVE-DATE=27 DECEMBER 2011, 124}}–418 mate (beverage)>yerba mate (loose leaf){{convertg|abbr=on}}}}85}}TRADITIONAL YERBA MATE IN BIODEGRADABLE BAG >PUBLISHER=GUAYAKI YERBA MATE ACCESS-DATE=17 JULY 2010 ARCHIVE-DATE=29 JUNE 2014, dead, 358|prefix=approx. }}| Coca-Cola{{convertmLabbr=on}}}}34}}96}}| Mountain Dew{{convertmLabbr=on}}}}54}}154}}| Pepsi Zero Sugar{{convertmLabbr=on}}}}69}}194}}| Guaraná Antarctica{{convertmLabbr=on}}}}30}}100}}| Jolt Cola{{convertmLabbr=on}}}}280}}403}}| Red Bull{{convertmLabbr=on}}}}80}}320}}| Coffee-flavored milk drink{{convert–mLabbr=on}}}}33}}–19766}}–354Cocoa solids>Cocoa, dry powder, unsweetened [unspecified strain]| 100 gWEBSITE=FDC.NAL.USDA.GOV, |—| Cocoa solids, defatted, Criollo strain| 100 g| 1130|—| Cocoa solids, defatted, Forastero strain| 100 g| 13weblink|—| Cocoa solids, defatted, Nacional strain| 100 g| 240|—| Cocoa solids, defatted, Trinitario strain| 100 g| 630|—Dark chocolate>Chocolate, dark, 70-85% cacao solids| 100 gWEBSITE=FDC.NAL.USDA.GOV, |—| Chocolate, dark, 60-69% cacao solids| 100 g| Chocolate, dark, 45- 59% cacao solids| 100 gWEBSITE=FDC.NAL.USDA.GOV, |—Milk chocolate>Candies, milk chocolate| 100 gWEBSITE=FDC.NAL.USDA.GOV, |—| Hershey's Special Dark (45% cacao content)1 bar ({{convertgabbr=on|disp=or}})}}31}}|—| Hershey's Milk Chocolate (11% cacao content)1 bar ({{convertgabbr=on|disp=or}})}}10}}|—Products containing caffeine include coffee, tea, soft drinks ("colas"), energy drinks, other beverages, chocolate,JOURNAL, Matissek R, 83555251, Evaluation of xanthine derivatives in chocolate: nutritional and chemical aspects, {{INIST, 2861730, |journal=European Food Research and Technology |volume=205 |issue=3 |pages=175–84 |year=1997 |doi=10.1007/s002170050148}} caffeine tablets, other oral products, and inhalation products. According to a 2020 study in the United States, coffee is the major source of caffeine intake in middle-aged adults, while soft drinks and tea are the major sources in adolescents.JOURNAL, van Dam RM, Hu FB, Willett WC, Coffee, Caffeine, and Health, The New England Journal of Medicine, 383, 4, 369–378, July 2020, 32706535, 10.1056/NEJMra1816604, 220731550, Energy drinks are more commonly consumed as a source of caffeine in adolescents as compared to adults.

Beverages

Coffee

The world's primary source of caffeine is the coffee "bean" (the seed of the coffee plant), from which coffee is brewed. Caffeine content in coffee varies widely depending on the type of coffee bean and the method of preparation used;WEB, Caffeine, International Coffee Organization,weblink 1 August 2009, dead,weblink" title="web.archive.org/web/20090327113321weblink">weblink 27 March 2009, even beans within a given bush can show variations in concentration. In general, one serving of coffee ranges from 80 to 100 milligrams, for a single shot (30 milliliters) of arabica-variety espresso, to approximately 100–125 milligrams for a cup (120 milliliters) of drip coffee.WEB, Coffee and Caffeine FAQ: Does dark roast coffee have less caffeine than light roast?,weblink 2 August 2009, 14 December 2010,weblink" title="web.archive.org/web/20101214060638weblink">weblink live, WEB, All About Coffee: Caffeine Level, Jeremiah's Pick Coffee Co,weblinkweblink" title="web.archive.org/web/20080318102343weblink">weblink 18 March 2008, 3 August 2009, Arabica coffee typically contains half the caffeine of the robusta variety.In general, dark-roast coffee has very slightly less caffeine than lighter roasts because the roasting process reduces caffeine content of the bean by a small amount.

Tea

Tea contains more caffeine than coffee by dry weight. A typical serving, however, contains much less, since less of the product is used as compared to an equivalent serving of coffee. Also contributing to caffeine content are growing conditions, processing techniques, and other variables. Thus, teas contain varying amounts of caffeine.JOURNAL, Hicks MB, Hsieh YH, Bell LN, Tea preparation and its influence on methylxanthine concentration, Food Research International, 1996, 29, 325–330, 10.1016/0963-9969(96)00038-5, 3–4, Tea contains small amounts of theobromine and slightly higher levels of theophylline than coffee. Preparation and many other factors have a significant impact on tea, and color is a very poor indicator of caffeine content. Teas like the pale Japanese green tea, gyokuro, for example, contain far more caffeine than much darker teas like lapsang souchong, which has very little.

Soft drinks and energy drinks

Caffeine is also a common ingredient of soft drinks, such as cola, originally prepared from kola nuts. Soft drinks typically contain 0 to 55 milligrams of caffeine per 12 ounce ({{convert|12|USfloz|mL|disp=out}}) serving.WEB, Nutrition and healthy eating,weblink Mayo Clinic, 18 November 2015, 22 November 2015,weblink" title="web.archive.org/web/20151122063906weblink">weblink live, By contrast, energy drinks, such as Red Bull, can start at 80 milligrams of caffeine per serving. The caffeine in these drinks either originates from the ingredients used or is an additive derived from the product of decaffeination or from chemical synthesis. Guarana, a prime ingredient of energy drinks, contains large amounts of caffeine with small amounts of theobromine and theophylline in a naturally occurring slow-release excipient.JOURNAL, Bempong DK, Houghton PJ, Steadman K, 1993, The xanthine content of guarana and its preparations, Int J Pharmacog, 0925-1618, 31, 3, 175–181, 10.3109/13880209309082937,weblink

Other beverages

• Mate is a drink popular in many parts of South America. Its preparation consists of filling a gourd with the leaves of the South American holly yerba mate, pouring hot but not boiling water over the leaves, and drinking with a straw, the bombilla, which acts as a filter so as to draw only the liquid and not the yerba leaves.WEB,weblink Drinking mate in Buenos Aires, Martinez-Carter K, 9 April 2012, BBC, 23 February 2019, 24 February 2019,weblink" title="web.archive.org/web/20190224005245weblink">weblink live,
• Guaraná is a soft drink originating in Brazil made from the seeds of the Guaraná fruit.
• The leaves of Ilex guayusa, the Ecuadorian holly tree, are placed in boiling water to make a guayusa tea.BOOK, Rätsch C, The Encyclopedia of Psychoactive Plants: Ethnopharmacology and Its Applications, 2005, Simon and Schuster, 9781594776625, PT1235,weblink en,
• The leaves of Ilex vomitoria, the yaupon holly tree, are placed in boiling water to make a yaupon tea.
• Commercially prepared coffee-flavoured milk beverages are popular in Australia.NEWS, Smith S, Flavoured milk and iced coffee sales on the rise,weblink 9 March 2021, The Weekly Times, News Corp, 18 October 2017, 17 April 2019,weblink live, Examples include Oak's Ice Coffee and Farmers Union Iced Coffee. The amount of caffeine in these beverages can vary widely. Caffeine concentrations can differ significantly from the manufacturer's claims.JOURNAL, Desbrow B, An examination of consumer exposure to caffeine from commercial coffee and coffee-flavoured milk, Journal of Food Composition and Analysis, 2012, 28, 2, 114, 10.1016/j.jfca.2012.09.001, 10072/49194, free,

Cacao solids

Cocoa solids (derived from cocoa bean) contain 230 mg caffeine per 100 g.The caffeine content varies between cocoa bean strains. Caffeine content mg/g (sorted by lowest caffeine content):

• Forastero (defatted): 1.3 mg/g
• Nacional (defatted): 2.4 mg/g
• Trinitario (defatted): 6.3/g
• Criollo (defatted): 11.3 mg/g

Chocolate

Caffeine per 100 g:

• Dark chocolate, 70-85% cacao solids: 80 mg
• Dark chocolate, 60-69% cacao solids: 86 mg
• Dark chocolate, 45- 59% cacao solids: 43 mg
• Milk chocolate: 20 mg

The stimulant effect of chocolate may be due to a combination of theobromine and theophylline, as well as caffeine.JOURNAL, Smit HJ, Gaffan EA, Rogers PJ, 22069829, Methylxanthines are the psycho-pharmacologically active constituents of chocolate, Psychopharmacology, 176, 3–4, 412–9, November 2004, 15549276, 10.1007/s00213-004-1898-3,

Tablets

(File:No-Doz.jpg|thumb|right|No-Doz 100 mg caffeine tablets)Tablets offer several advantages over coffee, tea, and other caffeinated beverages, including convenience, known dosage, and avoidance of concomitant intake of sugar, acids, and fluids. A use of caffeine in this form is said to improve mental alertness.WEB, Caffeine tablets or caplets,weblink 2021-10-24, Cleveland Clinic, 24 October 2021,weblink live, These tablets are commonly used by students studying for their exams and by people who work or drive for long hours.BOOK, {{google books, y, YdpL2YCGLVYC, 195, |page=195 |title=The World of caffeine: The Science and Culture of the World's Most Popular Drug | vauthors = Weinberg BA, Bealer BK |publisher=Routledge |year=2001 |isbn=978-0-415-92723-9 |access-date=15 January 2014}}

Other oral products

One U.S. company is marketing oral dissolvable caffeine strips.NEWS,weblink LeBron James Shills for Sheets Caffeine Strips, a Bad Idea for Teens, Experts Say, ABC News, Abcnews.go.com, 10 June 2011, 25 May 2012, 4 September 2011,weblink" title="web.archive.org/web/20110904052531weblink">weblink live, Another intake route is SpazzStick, a caffeinated lip balm.NEWS, Shute N,weblink Over The Limit:Americans young and old crave high-octane fuel, and doctors are jittery, U.S. News & World Report, 15 April 2007, dead,weblink" title="web.archive.org/web/20140108071216weblink">weblink 8 January 2014, Alert Energy Caffeine Gum was introduced in the United States in 2013, but was voluntarily withdrawn after an announcement of an investigation by the FDA of the health effects of added caffeine in foods.NEWS, F.D.A. Inquiry Leads Wrigley to Halt 'Energy Gum' Sales,weblinkweblink 2022-01-01, limited, 9 May 2013, New York Times, 8 May 2013, Associated Press, {{cbignore}}

Inhalants

Similar to an e-cigarette, a caffeine inhaler may be used to deliver caffeine or a stimulant like guarana by vaping.NEWS, Caffeine Inhalers Rush to Serve the Energy Challenged,weblink 2015-07-22, 2023-07-29, Alex Williams, The New York Times, In 2012, the FDA sent a warning letter to one of the companies marketing an inhaler, expressing concerns for the lack of safety information available about inhaled caffeine.WEB,weblink 2012 – Breathable Foods, Inc. 3/5/12, www.fda.gov, en, 22 May 2017, 8 May 2017,weblink live, NEWS, Greenblatt M, FDA to Investigate Safety of Inhalable Caffeine,weblink 30 July 2023, ABC News, 20 February 2012,

Combinations with other drugs

• Some beverages combine alcohol with caffeine to create a caffeinated alcoholic drink. The stimulant effects of caffeine may mask the depressant effects of alcohol, potentially reducing the user's awareness of their level of intoxication. Such beverages have been the subject of bans due to safety concerns. In particular, the United States Food and Drug Administration has classified caffeine added to malt liquor beverages as an "unsafe food additive".WEB,weblink Food Additives & Ingredients > Caffeinated Alcoholic Beverages, 17 November 2010, fda.gov, Food and Drug Administration, 24 January 2014, 27 February 2014,weblink" title="web.archive.org/web/20140227205153weblink">weblink live,
• Ya ba contains a combination of methamphetamine and caffeine.
• Painkillers such as propyphenazone/paracetamol/caffeine combine caffeine with an analgesic.

History

Discovery and spread of use

File:Kahvihuone.jpg|thumb|Coffeehouse in PalestinePalestineAccording to Chinese legend, the Chinese emperor Shennong, reputed to have reigned in about 3000 BCE, inadvertently discovered tea when he noted that when certain leaves fell into boiling water, a fragrant and restorative drink resulted.BOOK, Evans JC, 1992, Tea in China: The History of China's National Drink, Greenwood Press, 978-0-313-28049-8, 2, Shennong is also mentioned in Lu Yu's Cha Jing, a famous early work on the subject of tea.BOOK, Yu L, The Classic of Tea: Origins & Rituals, Ecco Pr, 1995, 978-0-88001-416-8, {{page needed|date=January 2014}}The earliest credible evidence of either coffee drinking or knowledge of the coffee plant appears in the middle of the fifteenth century, in the Sufi monasteries of the Yemen in southern Arabia.BOOK, Weinberg BA, Bealer BK, The World of Caffeine: The Science and Culture of the World's Most Popular Drug, 2001, 3–4, 978-0-415-92723-9, Routledge,weblink From Mocha, coffee spread to Egypt and North Africa, and by the 16th century, it had reached the rest of the Middle East, Persia and Turkey. From the Middle East, coffee drinking spread to Italy, then to the rest of Europe, and coffee plants were transported by the Dutch to the East Indies and to the Americas.WEB, Meyers H, "Suave Molecules of Mocha" – Coffee, Chemistry, and Civilization, New Partisan, 7 March 2005,weblinkweblink" title="web.archive.org/web/20050309110855weblink">weblink 9 March 2005, 3 February 2007, Kola nut use appears to have ancient origins. It is chewed in many West African cultures, in both private and social settings, to restore vitality and ease hunger pangs.JOURNAL, Lovejoy PE, 1980, Kola in the History of West Africa (La kola dans l'histoire de l'Afrique occidentale),weblink Cahiers d'Études Africaines, 20, 77/78, 97–134, 10.3406/cea.1980.2353, 4391682, 0008-0055, The earliest evidence of cocoa bean use comes from residue found in an ancient Mayan pot dated to 600 BCE. Also, chocolate was consumed in a bitter and spicy drink called xocolatl, often seasoned with vanilla, chile pepper, and achiote. Xocolatl was believed to fight fatigue, a belief probably attributable to the theobromine and caffeine content. Chocolate was an important luxury good throughout pre-Columbian Mesoamerica, and cocoa beans were often used as currency.BOOK, Ried K, Dark Chocolate and (Pre-)Hypertension, 21 June 2012, Watson RR, Preedy VR, Zibadi S, Chocolate in Health and Nutrition, 313–325, Humana Press, 10.1007/978-1-61779-803-0_23, 978-1-61779-802-3, Xocolatl was introduced to Europe by the Spaniards, and became a popular beverage by 1700. The Spaniards also introduced the cacao tree into the West IndiesWEB, Bekele FL, The History of Cocoa Production in Trinidad and Tobago,weblinkweblink 2020-12-01, live, 21 May 2022, and the Philippines.REPORT, Peace and Equity Foundation,weblink A primer on PEF's Priority Commodities: an Industry Study on Cacao, Philippines, 2016, May 21, 2022, 2 May 2021,weblink live, The leaves and stems of the yaupon holly (Ilex vomitoria) were used by Native Americans to brew a tea called asi or the "black drink".BOOK, Fairbanks CH, Charles M. Hudson (author), Hudson MC, Black Drink, University of Georgia Press, 2004, The function of black drink among the Creeks, 978-0-8203-2696-2, 123, Archaeologists have found evidence of this use far into antiquity,JOURNAL, Crown PL, Emerson TE, Gu J, Hurst WJ, Pauketat TR, Ward T, Ritual Black Drink consumption at Cahokia, Proceedings of the National Academy of Sciences of the United States of America, 109, 35, 13944–9, August 2012, 22869743, 3435207, 10.1073/pnas.1208404109, 2012PNAS..10913944C, free, doi, possibly dating to Late Archaic times.

Chemical identification, isolation, and synthesis

(File:Friedlieb Ferdinand Runge.jpeg|thumb|upright|Friedlieb Ferdinand Runge, discoverer of caffeine)In 1819, the German chemist Friedlieb Ferdinand Runge isolated {{Vague|text=relatively pure|date=April 2024}} caffeine for the first time; he called it "Kaffebase" (i.e., a base that exists in coffee).BOOK, Runge FF, Neueste phytochemische Entdeckungen zur Begründung einer wissenschaftlichen Phytochemie, {{google books, y, KLg5AAAAcAAJ&pg=P146, |year=1820 |publisher=G. Reimer |location=Berlin |pages=144–159 |trans-title=Latest phytochemical discoveries for the founding of a scientific phytochemistry |access-date=8 January 2014}} According to Runge, he did this at the behest of Johann Wolfgang von Goethe.{{efn|In 1819, Runge was invited to show Goethe how belladonna caused dilation of the pupil, which Runge did, using a cat as an experimental subject. Goethe was so impressed with the demonstration that: {{blockquote|Nachdem Goethe mir seine größte Zufriedenheit sowol über die Erzählung des durch scheinbaren schwarzen Staar Geretteten, wie auch über das andere ausgesprochen, übergab er mir noch eine Schachtel mit Kaffeebohnen, die ein Grieche ihm als etwas Vorzügliches gesandt. "Auch diese können Sie zu Ihren Untersuchungen brauchen," sagte Goethe. Er hatte recht; denn bald darauf entdeckte ich darin das, wegen seines großen Stickstoffgehaltes so berühmt gewordene Coffein.}} ("After Goethe had expressed to me his greatest satisfaction regarding the account of the man [whom I'd] rescued [from serving in Napoleon's army] by apparent "black star" [i.e., amaurosis, blindness] as well as the other, he handed me a carton of coffee beans, which a Greek had sent him as a delicacy. 'You can also use these in your investigations,' said Goethe. He was right; for soon thereafter I discovered therein caffeine, which became so famous on account of its high nitrogen content.").This account appeared in Runge's book Hauswirtschaftlichen Briefen (Domestic Letters [i.e., personal correspondence]) of 1866. It was reprinted in: Johann Wolfgang von Goethe with F.W. von Biedermann, ed., Goethes Gespräche, vol. 10: Nachträge, 1755–1832 (Leipzig, (Germany): F.W. v. Biedermann, 1896), pages 89–96; see especially[{{google books |plainurl=y |id=MacwAAAAYAAJ|page=95}} page 95]}}BOOK, Weinberg BA, Bealer BK, The World of Caffeine: The Science and Culture of the World's Most Popular Drug, Routledge, 2001, 978-0-415-92723-9, xvii–xxi,weblink In 1821, caffeine was isolated both by the French chemist Pierre Jean Robiquet and by another pair of French chemists, Pierre-Joseph Pelletier and Joseph Bienaimé Caventou, according to Swedish chemist Jöns Jacob Berzelius in his yearly journal. Furthermore, Berzelius stated that the French chemists had made their discoveries independently of any knowledge of Runge's or each other's work.BOOK, 1825, Jahres-Bericht über die Fortschritte der physischen Wissenschaften von Jacob Berzelius, 4, {{google books, y, XJI8AAAAIAAJ, 1, |language=de |trans-title=Annual report on the progress of the physical sciences by Jacob Berzelius |vauthors=Berzelius JJ |quote=Caféin ist eine Materie im Kaffee, die zu gleicher Zeit, 1821, von Robiquet und Pelletier und Caventou entdekt wurde, von denen aber keine etwas darüber im Drucke bekannt machte. |trans-quote=Caffeine is a material in coffee, which was discovered at the same time, 1821, by Robiquet and [by] Pelletier and Caventou, by whom however nothing was made known about it in the press. |quote-page=180}} However, Berzelius later acknowledged Runge's priority in the extraction of caffeine, stating:BOOK, Jahres-Bericht über die Fortschritte der physischen Wissenschaften von Jacob Berzelius, {{google books, y, iGs1AAAAcAAJ&pag, 270, |volume=7 |year=1828 |trans-title=Annual Report on the Progress of the Physical Sciences by Jacob Berzelius |language=de |quote-page=270 | vauthors = Berzelius JJ |quote=Es darf indessen hierbei nicht unerwähnt bleiben, dass Runge (in seinen phytochemischen Entdeckungen 1820, p. 146-7.) dieselbe Methode angegeben, und das Caffein unter dem Namen Caffeebase ein Jahr eher beschrieben hat, als Robiquet, dem die Entdeckung dieser Substanz gewöhnlich zugeschrieben wird, in einer Zusammenkunft der Societé de Pharmacie in Paris die erste mündliche Mittheilung darüber gab.}} "However, at this point, it should not remain unmentioned that Runge (in his Phytochemical Discoveries, 1820, pages 146–147) specified the same method and described caffeine under the name Caffeebase a year earlier than Robiquet, to whom the discovery of this substance is usually attributed, having made the first oral announcement about it at a meeting of the Pharmacy Society in Paris."Pelletier's article on caffeine was the first to use the term in print (in the French form from the French word for coffee: ).ENCYCLOPEDIA, Pelletier PJ, Pierre Joseph Pelletier, Dictionnaire de Médecine, Cafeine, {{google books, y, rFw_AAAAcAAJ, 35, |access-date=3 March 2011 |language=fr |year=1822 |publisher=Béchet Jeune |volume=4 |location=Paris |pages=35–36}} It corroborates Berzelius's account:{{blockquote|Caffeine, noun (feminine). Crystallizable substance discovered in coffee in 1821 by Mr. Robiquet. During the same period â€“ while they were searching for quinine in coffee because coffee is considered by several doctors to be a medicine that reduces fevers and because coffee belongs to the same family as the cinchona [quinine] tree â€“ on their part, Messrs. Pelletier and Caventou obtained caffeine; but because their research had a different goal and because their research had not been finished, they left priority on this subject to Mr. Robiquet. We do not know why Mr. Robiquet has not published the analysis of coffee which he read to the Pharmacy Society. Its publication would have allowed us to make caffeine better known and give us accurate ideas of coffee's composition ...}}Robiquet was one of the first to isolate and describe the properties of pure caffeine,ENCYCLOPEDIA, Robiquet PJ, Robiquet, Dictionnaire Technologique, ou Nouveau Dictionnaire Universel des Arts et Métiers, Café, {{google books, y, vDdRAAAAYAAJ, |access-date=3 March 2011 |language=fr |year=1823 |publisher=Thomine et Fortic |volume=4 |location=Paris |pages=50–61}} whereas Pelletier was the first to perform an elemental analysis.JOURNAL, Dumas P, 1823, fr, Recherches sur la composition élémentaire et sur quelques propriétés caractéristiques des bases salifiables organiques, Studies into the elemental composition and some characteristic properties of organic bases, Annales de Chimie et de Physique, 24, 163–191, {{google books, y, -BIAAAAAMAAJ, 182, }}In 1827, M. Oudry isolated "théine" from tea,JOURNAL, Oudry M, Nouvelle Bibliothèque Médicale, 1, 1827, Note sur la Théine, Note on Theine, 477–479, {{google books, y, cGpEAAAAcAAJ, 477, |language=fr}} but in 1838 it was proved by MulderJOURNAL, Mulder GJ, 1838, Ueber Theïn und Caffeïn, 15, Journal für Praktische Chemie, 280–284, Concerning theine and caffeine, {{google books, y, HQHzAAAAMAAJ, 280, |doi=10.1002/prac.18380150124}} and by Carl JobstJOURNAL, Jobst C, 1838, Thein identisch mit Caffein, Theine is identical to caffeine, Liebig's Annalen der Chemie und Pharmacie, 25, 63–66, {{google books, y, teJSAAAAcAAJ, 63, |doi=10.1002/jlac.18380250106}} that theine was actually the same as caffeine.In 1895, German chemist Hermann Emil Fischer (1852–1919) first synthesized caffeine from its chemical components (i.e. a "total synthesis"), and two years later, he also derived the structural formula of the compound.Fischer began his studies of caffeine in 1881; however, understanding of the molecule's structure long eluded him. In 1895 he synthesized caffeine, but only in 1897 did he finally fully determine its molecular structure.

• JOURNAL, Fischer E, 1881, de, Ueber das Caffeïn, On caffeine, Berichte der Deutschen Chemischen Gesellschaft zu Berlin, 14, 637–644,weblink 10.1002/cber.188101401142, 17 June 2013, 15 October 2015,weblink" title="web.archive.org/web/20151015213939weblink">weblink live,
• JOURNAL, Fischer E, 1881, de, Ueber das Caffeïn. Zweite Mitteilung, On caffeine. Second communication., Berichte der Deutschen Chemischen Gesellschaft zu Berlin, 14, 1905–1915,weblink 10.1002/cber.18810140283, 2, 17 June 2013, 3 September 2015,weblink" title="web.archive.org/web/20150903215226weblink">weblink live,
• JOURNAL, Fischer E, 1882, de, Ueber das Caffeïn. Dritte Mitteilung, On caffeine. Third communication., Berichte der Deutschen Chemischen Gesellschaft zu Berlin, 15, 29–33,weblink 10.1002/cber.18820150108, 17 June 2013, 15 October 2015,weblink" title="web.archive.org/web/20151015213939weblink">weblink live,
• JOURNAL, Fischer E, Ach L, 1895, de, Synthese des Caffeïns, Synthesis of caffeine, Berichte der Deutschen Chemischen Gesellschaft zu Berlin, 28, 3135–3143,weblink 10.1002/cber.189502803156, 3, 17 June 2013, 15 October 2015,weblink" title="web.archive.org/web/20151015213939weblink">weblink live,
• JOURNAL, Fischer E, 1897, de, Ueber die Constitution des Caffeïns, Xanthins, Hypoxanthins und verwandter Basen, On the constitution of caffeine, xanthin, hypoxanthin, and related bases., Berichte der Deutschen Chemischen Gesellschaft zu Berlin, 30, 549–559,weblink 10.1002/cber.189703001110, 17 June 2013, 15 October 2015,weblink" title="web.archive.org/web/20151015213939weblink">weblink live, This was part of the work for which Fischer was awarded the Nobel Prize in 1902.WEB, 3 August 2009,weblink Nobel Prize Presentation Speech, Théel H, 1902, 10 August 2010,weblink" title="web.archive.org/web/20100810170148weblink">weblink live,

Historic regulations

Because it was recognized that coffee contained some compound that acted as a stimulant, first coffee and later also caffeine has sometimes been subject to regulation. For example, in the 16th century Islamists in Mecca and in the Ottoman Empire made coffee illegal for some classes.BOOK, Brown DW, A new introduction to Islam, Wiley-Blackwell, Chichester, West Sussex, 2004, 149–51, 978-1-4051-5807-7,weblink BOOK, Encyclopedia of the Ottoman Empire, Ágoston G, Masters B, 2009, {{google books, y, QjzYdCxumFcC, 138, 978-1-4381-1025-7, |page=138}}WEB,weblink Food Stories: The Sultan's Coffee Prohibition, Hopkins K, 24 March 2006, Accidental Hedonist, 3 January 2010, dead,weblink" title="web.archive.org/web/20121120105621weblink">weblink 20 November 2012, Charles II of England tried to ban it in 1676,WEB,weblink By the King. A PROCLAMATION FOR THE Suppression of Coffee-Houses, 18 March 2012, 27 June 2012,weblink" title="web.archive.org/web/20120627051249weblink">weblink live, {{harvnb|Pendergrast|2001|page=13}} Frederick II of Prussia banned it in 1777,{{harvnb|Pendergrast|2001|page=11}}{{harvnb|Bersten|1999|page=53}} and coffee was banned in Sweden at various times between 1756 and 1823.In 1911, caffeine became the focus of one of the earliest documented health scares, when the US government seized 40 barrels and 20 kegs of Coca-Cola syrup in Chattanooga, Tennessee, alleging the caffeine in its drink was "injurious to health".JOURNAL, Benjamin LT, Rogers AM, Rosenbaum A, Coca-Cola, caffeine, and mental deficiency: Harry Hollingworth and the Chattanooga trial of 1911, Journal of the History of the Behavioral Sciences, 27, 1, 42–55, January 1991, 2010614, 10.1002/1520-6696(199101)27:13.0.CO;2-1, Although the Supreme Court later ruled in favor of Coca-Cola in United States v. Forty Barrels and Twenty Kegs of Coca-Cola, two bills were introduced to the U.S. House of Representatives in 1912 to amend the Pure Food and Drug Act, adding caffeine to the list of "habit-forming" and "deleterious" substances, which must be listed on a product's label.WEB,weblink The Rise and Fall of Cocaine Cola, Lewrockwell.com, 25 May 2012, 13 March 2014,weblink" title="web.archive.org/web/20140313224045weblink">weblink live,

Society and culture

Regulations

{{see also|Energy drink#Regulations}}{{Globalize|section|United States|date=October 2020}}

United States

The US Food and Drug Administration (FDA) considers safe beverages containing less than 0.02% caffeine;WEB, CFR – Code of Federal Regulations Title 21,weblink U.S. Food and Drug Administration, 23 November 2015, 21 August 2015, 23 November 2015,weblink" title="web.archive.org/web/20151123152903weblink">weblink live, but caffeine powder, which is sold as a dietary supplement, is unregulated.NEWS, Sanner A, Sudden death of Ohio teen highlights dangers of caffeine powder,weblink 23 November 2015, The Globe and Mail, The Associated Press, Phillip Crawley, 19 July 2014, Columbus, Ohio, 31 December 2015,weblink" title="web.archive.org/web/20151231224644weblink">weblink live, It is a regulatory requirement that the label of most prepackaged foods must declare a list of ingredients, including food additives such as caffeine, in descending order of proportion. However, there is no regulatory provision for mandatory quantitative labeling of caffeine, (e.g., milligrams caffeine per stated serving size). There are a number of food ingredients that naturally contain caffeine. These ingredients must appear in food ingredient lists. However, as is the case for "food additive caffeine", there is no requirement to identify the quantitative amount of caffeine in composite foods containing ingredients that are natural sources of caffeine. While coffee or chocolate are broadly recognized as caffeine sources, some ingredients (e.g., guarana, yerba maté) are likely less recognized as caffeine sources. For these natural sources of caffeine, there is no regulatory provision requiring that a food label identify the presence of caffeine nor state the amount of caffeine present in the food.JOURNAL, Reissig CJ, Strain EC, Griffiths RR, Caffeinated energy drinks – a growing problem, Drug and Alcohol Dependence, 99, 1–3, 1–10, January 2009, 18809264, 2735818, 10.1016/j.drugalcdep.2008.08.001,weblink 28 February 2018, 12 June 2018,weblink live, The FDA guidance was updated in 2018.WEB, Guidance on Highly Concentrated Caffeine in Dietary Supplements, U.S. Food and Drug Administration, 16 April 2018,weblink 15 January 2024, {{PD-notice}}

Consumption

Global consumption of caffeine has been estimated at 120,000 tonnes per year, making it the world's most popular psychoactive substance. This amounts to an average of one serving of a caffeinated beverage for every person every day.NEWS, What's your poison: caffeine, Australian Broadcasting Corporation, 1997,weblink 15 January 2014, Burchfield G, Meredith H,weblink" title="web.archive.org/web/20090726194701weblink">weblink 26 July 2009, dead, The consumption of caffeine has remained stable between 1997 and 2015.JOURNAL, Verster JC, Koenig J, Caffeine intake and its sources: A review of national representative studies, Critical Reviews in Food Science and Nutrition, 58, 8, 1250–1259, May 2018, 28605236, 10.1080/10408398.2016.1247252, Review, free, doi, Coffee, tea and soft drinks are the most important caffeine sources, with energy drinks contributing little to the total caffeine intake across all age groups.

Religions

The Seventh-day Adventist Church asked for its members to "abstain from caffeinated drinks", but has removed this from baptismal vows (while still recommending abstention as policy).BOOK, The War on Coffee,weblink Robinette GW, 2018, 1, 978-0-9820787-6-1, 22, Graffiti militante, Google Books, Some from these religions believe that one is not supposed to consume a non-medical, psychoactive substance, or believe that one is not supposed to consume a substance that is addictive. The Church of Jesus Christ of Latter-day Saints has said the following with regard to caffeinated beverages: "... the Church revelation spelling out health practices (Doctrine and Covenants 89) does not mention the use of caffeine. The Church's health guidelines prohibit alcoholic drinks, smoking or chewing of tobacco, and 'hot drinks' – taught by Church leaders to refer specifically to tea and coffee."NEWS, Mormonism in the News: Getting It Right August 29, The Church of Jesus Christ of Latter-Day Saints, 2012,weblink 17 April 2016, 30 June 2019,weblink live, Gaudiya Vaishnavas generally also abstain from caffeine, because they believe it clouds the mind and overstimulates the senses.NEWS,weblink If Krishna does not accept my Chocolates, Who should I offer them to?, Dandavats.com, 19 April 2018, en-US, 20 April 2018,weblink" title="web.archive.org/web/20180420073754weblink">weblink live, To be initiated under a guru, one must have had no caffeine, alcohol, nicotine or other drugs, for at least a year.BOOK, Buxton J, The Politics of Narcotic Drugs: A Survey, 17 December 2010, 978-1857437591, 189, Routledge, Caffeinated beverages are widely consumed by Muslims. In the 16th century, some Muslim authorities made unsuccessful attempts to ban them as forbidden "intoxicating beverages" under Islamic dietary laws.BOOK, Campo JE, Encyclopedia of Islam, {{google books, y, OZbyz_Hr-eIC, 154, |access-date=1 November 2012 |date=1 January 2009 |publisher=Infobase Publishing |isbn=978-1-4381-2696-8 |page=154}}BOOK, Brown DW, A New Introduction to Islam, 24 August 2011, John Wiley & Sons, 978-1-4443-5772-1, 149,

Other organisms

File:Caffeinated spiderwebs modified.jpg|thumb|Caffeine effects on alt=Caffeine effects on spider webs{{See also|Effect of psychoactive drugs on animals}}The bacteria Pseudomonas putida CBB5 can live on pure caffeine and can cleave caffeine into carbon dioxide and ammonia.WEB,weblink Newly Discovered Bacteria Lives on Caffeine, Blogs.scientificamerican.com, 24 May 2011, 19 December 2013, 17 April 2015,weblink" title="web.archive.org/web/20150417180529weblink">weblink live, Caffeine is toxic to birdsWEB,weblink Why Caffeine is Toxic to Birds, Paul L, HotSpot for Birds, Advin Systems, 29 February 2012,weblink" title="web.archive.org/web/20111004163339weblink">weblink 4 October 2011, dead, and to dogs and cats,WEB, Caffeine,weblink 12 September 2014, 12 September 2014,weblink" title="web.archive.org/web/20140912133016weblink">weblink live, and has a pronounced adverse effect on mollusks, various insects, and spiders.JOURNAL, Noever R, Cronise J, Relwani RA, Using spider-web patterns to determine toxicity, NASA Tech Briefs, 19, 4, 82,weblink 29 April 1995, 25 August 2017, 24 May 2015,weblink live, This is at least partly due to a poor ability to metabolize the compound, causing higher levels for a given dose per unit weight. Caffeine has also been found to enhance the reward memory of honey bees.

Research

Caffeine has been used to double chromosomes in haploid wheat.JOURNAL, Thomas J, Chen Q, Howes N, Chromosome doubling of haploids of common wheat with caffeine, Genome, 40, 4, 552–8, August 1997, 18464846, 10.1139/g97-072,

See also

• Theobromine
• Theophylline
• Methylliberine
• Adderall
• Amphetamine
• Cocaine
• Nootropic
• Wakefulness-promoting agent

References

Notes

{{Notelist}}

Citations

{{Reflist}}

Bibliography

• BOOK, Bersten I, Coffee, Sex & Health: A history of anti-coffee crusaders and sexual hysteria, Helian Books, 1999, Sydney, 978-0-9577581-0-0,
• BOOK, Carpenter M, Caffeinated: How Our Daily Habit Helps, Hurts, and Hooks Us, 2015, 978-0142181805, Plume,
• BOOK, Pendergrast M, Mark Pendergrast, Uncommon Grounds: The History of Coffee and How It Transformed Our World, Texere, London, 2001, 1999, 978-1-58799-088-5,
• BOOK, Michael Pollan, Pollan M, 2021, This Is Your Mind on Plants., Penguin Press, 9780593296905,

External links

{{Sister project links|auto=yes}}

• GMD MS Spectrum
• Caffeine: ChemSub Online
• Caffeine at The Periodic Table of Videos (University of Nottingham)

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