caffeine is a natural trimethylxanthine alkaloid which acts as a pesticide and perhaps herbicide and thus protects the growth of coffee bean plant and similar plants (tea, kola, cacao plants) which produce it.
coffee drinking became popular in Europe in mid-17th century
chocolate was introduced to Europe by the Spaniards and became a popular beverage by 1700.
caffeine was 1st isolated in 1819 and its structure elucidated by the end of the 19th century.
theophylline was first extracted from tea leaves around 1888.
1st Coca-cola recipe invented in 1885 based on coca leaves & the kola nut.
initially Coca Cola also contained ~9mg cocaine per glass but this was removed in 1903 but retained coca flavoring using a cocaine-free coca leaf extract.
Coca-Cola drink created controversy in the U.S. in 1911 over concerns of its caffeine content causing unwanted behaviour, and caffeine was soon added to the U.S. list of “habit-forming” and “deleterious” substances and foods and drinks containing it must label it accordingly.
interacts with mTOR complex (relevant to all facets in learning and memory)
caffeine downregulates a signaling partner of the mTOR complex pathway in a dose-related manner: p70s6k
in 'normal' individuals, excessive levels of caffeine might be pathological in terms of learning and memory function, but these would be at extremely high doses, and in almost a steady-state system due to chronic administration
effects of its 3 main dimethylxanthine metabolites each with methylxanthine effects:
paraxanthine (84%)
theobromine (12%)
theophylline (4%)
pharmacokinetics
almost completely absorbed from GIT within 45min of oral intake.
metabolized by the polymorphic cytochrome P450 1A2 (CYP1A2) enzyme.
individuals who are homozygous for the CYP1A2*1A allele are “rapid” caffeine metabolizers, whereas carriers of the variant CYP1A2*1F are “slow” caffeine metabolizers.
severe liver disease may result in half life of 96hrs.
clinical effects
Intake of coffee was associated with an increased risk of nonfatal AMI only among individuals with slow caffeine metabolism (odds ratio 2.3 (CI 1.4-3.9) for those aged < 59yrs drinking 4 or more cups of coffee per day). 1)
in a very large UK study over 11 years with avg age 56yrs published in 2021, 0.5-3 cups coffee per day was associated with a 12% reduction in all cause mortality, 17% reduction in mortality from cardiovasc disease, and 21% lower risk of stroke 2)
frequent intake results in pharmacologic tolerance to caffeine:
heavy intakes of 750-1200mg/day may result in complete tolerance
in middle-aged adults who regularly drink coffee, there was little to no association between habitual caffeine intake, sleep quality, and daytime sleepiness3)
lower regular intakes result in incomplete tolerance