a b c Juliano LM, Griffiths RR (October 2004). "A critical review of caffeine withdrawal: empirical validation of symptoms and signs, incidence, severity, and associated features". Psychopharmacology. 176 (1): 1–29. doi: 10.1007/s00213-004-2000-x. PMID 15448977. S2CID 5572188. 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. Carreon CC, Parsh B (April 2019). "How to recognize caffeine overdose". Nursing (Clinical tutorial). 49 (4): 52–55. doi: 10.1097/01.NURSE.0000553278.11096.86. PMID 30893206. S2CID 84842436. 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 a b Fintel M, Langer GA, Duenas C (November 1984). "Effects of low sodium perfusion on cardiac caffeine sensitivity and calcium uptake". Journal of Molecular and Cellular Cardiology. 16 (11): 1037–1045. doi: 10.1016/s0022-2828(84)80016-4. PMID 6520875. Theobromine (12%): Dilates blood vessels and increases urine volume. Theobromine is also the principal alkaloid in the cocoa bean ( chocolate).

A systematic review and meta-analysis from 2014 found that concurrent caffeine and L-theanine use has synergistic psychoactive effects that promote alertness, attention, and task switching; [57] these effects are most pronounced during the first hour post-dose. [57] Physical performanceAccording 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. [140] Energy drinks 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). [167] It is also a competitive antagonist of the ionotropic glycine receptor. [168] Effects on striatal dopamine 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. [49] [50] Children, adolescents, and adults with ADHD are more likely to consume caffeine, perhaps as a form of self-medication. [50] [51] Enhancing performance Cognitive performance

Jamieson RW (2001). "The essence of commodification: caffeine dependencies in the early modern world". Journal of Social History. 35 (2): 269–294. doi: 10.1353/jsh.2001.0125. JSTOR 3790189. PMID 18546583. S2CID 22532559. Nehlig A (2010). "Is caffeine a cognitive enhancer?" (PDF). Journal of Alzheimer's Disease. 20 (Suppl 1): S85–94. doi: 10.3233/JAD-2010-091315. PMID 20182035. S2CID 17392483. Archived from the original (PDF) on 31 January 2021. 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. Since this observation was first published, caffeine addiction has been added as an official diagnosis in ICDM9. 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 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. [219] Products Caffeine content in select food and drugs [220] [221] [222] [223] [224] Institute of Medicine (US) Committee on Military Nutrition Research (2001). "2, Pharmacology of Caffeine". Pharmacology of Caffeine. National Academies Press (US). Archived from the original on 28 September 2021 . Retrieved 15 December 2022.Consumption of 1–1.5 grams (1,000–1,500mg) per day is associated with a condition known as caffeinism. [138] Caffeinism usually combines caffeine dependency with a wide range of unpleasant symptoms including nervousness, irritability, restlessness, insomnia, headaches, and palpitations after caffeine use. [139] Rodopoulos N, Wisén O, Norman A (May 1995). "Caffeine metabolism in patients with chronic liver disease". Scandin 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