The earliest evidence of cocoa bean use comes from residue found in an ancient Mayan pot dated to 600 BCE. , Withdrawal can cause mild to clinically significant distress or impairment in daily functioning. Caffeine can accumulate in individuals with severe liver disease, increasing its half-life..  Caffeine consumption before constant load exercise is associated with reduced perceived exertion. Xocolatl was believed to fight fatigue, a belief probably attributable to the theobromine and caffeine content. Although the mechanism of action of caffeine in apnea of prematurity is not known, several mechanisms have been hypothesized. "We want people ingesting caffeine pills and supplements to know that caffeine is a drug, and overuse is potentially harmful, especially when mixed with other pharmaceuticals for euphoria." J. Physiol.  The American Psychiatric Association's DSM-5 does not include the diagnosis of a caffeine addiction but proposes criteria for the disorder for more study. These ingredients must appear in food ingredient lists. , Caffeine is toxic to birds and to dogs and cats, and has a pronounced adverse effect on mollusks, various insects, and spiders.  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.  It may protect people from liver cirrhosis. Caffeine is defined as a drug because it stimulates the central nervous system, causing increased alertness. 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. a "total synthesis"), and two years later, he also derived the structural formula of the compound.  Due to this inconclusive evidence on clinical significance, the DSM-5 classifies caffeine-use disorder as a “condition for further study”. The drug caffeine can sometimes have moderate to severe interactions with other medications a person may be taking.  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.  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”. Caffeine antagonizes the activational aspect of behavioral control, but has no effect on the inhibitory behavioral control.  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. Doses as low as 100 mg/day, such as a 6 oz cup of coffee or two to three 12 oz servings of caffeinated soft-drink, may continue to cause sleep disruption, among other intolerances. 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. Available for Android and iOS devices.  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. Caffeine is considered to be the most commonly used psychoactive drug in the world. Caffeine is not to be used as a substitute for sleep. 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