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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. doi: 10.3109/00365519509089618. PMID 7638557. 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 DMPX [210] 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. [211] [ unreliable source?] Many other xanthine analogues constituting the adenosine receptor antagonist class have also been elucidated. [212] a b c Karch SB (2009). Karch's pathology of drug abuse (4thed.). Boca Raton: CRC Press. pp.229–230. ISBN 978-0-8493-7881-2. The suggestion has also been made that a caffeine dependence syndrome exists... In one controlled study, dependence was diagnosed in 16 of 99individuals who were evaluated. The median daily caffeine consumption of this group was only 357mg per day (Strain et al., 1994).
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. [140] 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 400–500mg 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. [141] According to DSST, alcohol causes a decrease in performance on their standardized tests, and caffeine causes a significant improvement. [153] When alcohol and caffeine are consumed jointly, the effects of the caffeine are changed, but the alcohol effects remain the same. [154] For example, consuming additional caffeine does not reduce the effect of alcohol. [154] However, the jitteriness and alertness given by caffeine is decreased when additional alcohol is consumed. [154] Alcohol consumption alone reduces both inhibitory and activational aspects of behavioral control. Caffeine antagonizes the activational aspect of behavioral control, but has no effect on the inhibitory behavioral control. [155] 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. 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 (350mL) serving. [232] 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. [233] Other beverages Nehlig A, Armspach JP, Namer IJ (2010). "SPECT assessment of brain activation induced by caffeine: no effect on areas involved in dependence". Dialogues in Clinical Neuroscience. 12 (2): 255–63. doi: 10.31887/DCNS.2010.12.2/anehlig. PMC 3181952. PMID 20623930. 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. 42Conger SA, Warren GL, Hardy MA, Millard-Stafford ML (February 2011). "Does caffeine added to carbohydrate provide additional ergogenic benefit for endurance?" (PDF). International Journal of Sport Nutrition and Exercise Metabolism. 21 (1): 71–84. doi: 10.1123/ijsnem.21.1.71. PMID 21411838. S2CID 7109086. Archived from the original (PDF) on 14 November 2020. a b c d van Dam RM, Hu FB, Willett WC (July 2020). "Coffee, Caffeine, and Health". The New England Journal of Medicine. 383 (4): 369–378. doi: 10.1056/NEJMra1816604. PMID 32706535. S2CID 220731550. activehours:........xxxxxxxx........ - put 24 . or x characters - which indicate from hour 0 to hour 23 of the day. Caffeine will a b Introduction to Pharmacology (thirded.). Abingdon: CRC Press. 2007. pp.222–223. ISBN 978-1-4200-4742-4. Archived from the original on 14 January 2023 . Retrieved 25 August 2017.
WHO Model List of Essential Medicines (PDF) (18thed.). World Health Organization. October 2013 [April 2013]. p.34 [p. 38 of pdf]. Archived (PDF) from the original on 23 April 2014 . Retrieved 23 December 2014. Death from caffeine ingestion appears to be rare, and most commonly caused by an intentional overdose of medications. [144] 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. [144] The LD 50 of caffeine in rats is 192 milligrams per kilogram, the fatal dose in humans is estimated to be 150–200 milligrams per kilogram (2.2lb) of body mass (75–100 cups of coffee for a 70kg (150lb) adult). [145] [146] There are cases where doses as low as 57 milligrams per kilogram have been fatal. [147] 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. [148] The lethal dose is lower in individuals whose ability to metabolize caffeine is impaired due to genetics or chronic liver disease. [149] A death was reported in 2013 of a man with liver cirrhosis who overdosed on caffeinated mints. [150] [151] Interactions Chocolate derived from cocoa beans contains a small amount of caffeine. The weak stimulant effect of chocolate may be due to a combination of theobromine and theophylline, as well as caffeine. [237] A typical 28-gram serving of a milk chocolate bar has about as much caffeine as a cup of decaffeinated coffee. By weight, dark chocolate has one to two times the amount of caffeine as coffee: 80–160mg per 100g. Higher percentages of cocoa such as 90% amount to 200mg per 100g approximately and thus, a 100-gram 85% cocoa chocolate bar contains about 195mg caffeine. [221] Tablets No-Doz 100mg caffeine tablets Pure anhydrous caffeine is a bitter-tasting, white, odorless powder with a melting point of 235–238°C. [10] [11] Caffeine is moderately soluble in water at room temperature (2g/100 mL), but very soluble in boiling water (66g/100 mL). [193] It is also moderately soluble in ethanol (1.5g/100 mL). [193] It is weakly basic (pK a of conjugate acid = ~0.6) requiring strong acid to protonate it. [194] Caffeine does not contain any stereogenic centers [195] and hence is classified as an achiral molecule. [196] 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. [46]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 2.5mg/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 2.5mg/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. [72] Pregnancy and breastfeeding a b American College of Obstetricians and Gynecologists (August 2010). "ACOG CommitteeOpinion No. 462: Moderate caffeine consumption during pregnancy". Obstetrics and Gynecology. 116 (2 Pt 1): 467–8. doi: 10.1097/AOG.0b013e3181eeb2a1. PMID 20664420. Smith A (September 2002). "Effects of caffeine on human behavior". Food and Chemical Toxicology. 40 (9): 1243–55. doi: 10.1016/S0278-6915(02)00096-0. PMID 12204388. a b c Burchfield G (1997). Meredith H (ed.). "What's your poison: caffeine". Australian Broadcasting Corporation. Archived from the original on 26 July 2009 . Retrieved 15 January 2014.
Robertson D, Wade D, Workman R, Woosley RL, Oates JA (April 1981). "Tolerance to the humoral and hemodynamic effects of caffeine in man". The Journal of Clinical Investigation. 67 (4): 1111–7. doi: 10.1172/JCI110124. PMC 370671. PMID 7009653. Peters JM (1967). "Factors Affecting Caffeine Toxicity: A Review of the Literature". The Journal of Clinical Pharmacology and the Journal of New Drugs. 7 (3): 131–141. doi: 10.1002/j.1552-4604.1967.tb00034.x. Archived from the original on 12 January 2012. Koot P, Deurenberg P (1995). "Comparison of changes in energy expenditure and body temperatures after caffeine consumption". Annals of Nutrition & Metabolism. 39 (3): 135–42. doi: 10.1159/000177854. PMID 7486839. Iancu I, Olmer A, Strous RD (2007). "Caffeinism: History, clinical features, diagnosis, and treatment". In Smith BD, Gupta U, Gupta BS (eds.). Caffeine and Activation Theory: Effects on Health and Behavior. CRC Press. pp.331–344. ISBN 978-0-8493-7102-8 . Retrieved 15 January 2014.Bishop D (December 2010). "Dietary supplements and team-sport performance". Sports Medicine. 40 (12): 995–1017. doi: 10.2165/11536870-000000000-00000. PMID 21058748. S2CID 1884713.
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