Caffeine – humankind’s favourite drug

More people consume caffeine more often than any other drug. Worldwide the predominant sources of caffeine are tea and coffee, although colas, ‘energy’ drinks, mate, guarana, and cocoa (chocolate) also contribute significantly to consumption.

After consumption of a caffeine-containing drink, caffeine is distributed rapidly throughout the body, reaching its highest concentration in the bloodstream and in the brain within 30-40 minutes. Caffeine and its metabolites are then gradually eliminated from the body, mainly in the urine. For adults, the elimination half-life of caffeine – the time it takes for half of the caffeine consumed to be eliminated from the body – is around 3 to 6 hours.

In the amounts consumed in tea, coffee, cola, etc the effects of caffeine on our physiology and behavior occur primarily through antagonism (blocking) of the body’s own adenosine at adenosine A1 and A2a receptors. These cell-surface receptors are distributed throughout the body, including the brain, and by preventing the normal action of adenosine, caffeine consumption can result in significant cardiovascular, cerebrovascular, renal, gastrointestinal and metabolic effects. Adenosine is also closely involved in the regulation of sleep and wakefulness, and it plays an important role in preventing cell damage during hypoxia and ischaemia (damage caused by loss of glucose and oxygen supply).

However, when caffeine is consumed on a regular basis, there are changes in adenosine signaling that tend to counter the effects of caffeine and, at least in part, maintain normal functioning. This is called tolerance. For example, caffeine causes vasoconstriction (constriction of blood vessels), and when frequent caffeine consumers stop consuming caffeine the opposite effect, vasodilation, occurs leading to increased cerebral blood flow to the brain.  This in turn can cause headache (i.e. caffeine withdrawal headache) which ceases when caffeine consumption resumes, or after several days of abstinence, due to readjustment of adenosine signaling back to normal.

The alerting and performance effects of caffeine
A strong motive for consumption of caffeine-containing drinks is the recognition of caffeine’s potential psychostimulant properties – ‘I can’t start the day without a coffee,’ and ‘caffeine keeps me going when I begin to flag.’ Unfortunately, tolerance to the effects of caffeine on alertness and associated effects on mental performance (e.g. vigilance and speed of information processing) means that in this respect frequent caffeine consumers gain very little or no net benefit from their habit. Although this conclusion is disputed by some researchers, it is supported by evidence from an increasing number of studies which have measured alertness and mental performance in frequent caffeine consumers compared with infrequent consumers (essentially non-consumers) and/or with long-term abstinent frequent consumers.

Fortunately, on the other hand, tolerance also develops to the tendency of caffeine to increase feelings of anxiety and ‘jitteriness,’ even in people who are predisposed to this effect. So, while frequent caffeine consumers don’t gain an increase in alertness above normal, they are not made more anxious by caffeine.
Caffeine, however, does benefit physical performance, including, athletic performance. This effect does not appear to be subject to substantial tolerance.

Caffeine and blood pressure and risk of cognitive decline
A reliable effect of caffeine is that it increases blood pressure, and in frequent consumers this is at best only partly offset by tolerance. The blood pressure effect of caffeine is potentially very important for health. For example, it has been argued that by increasing blood pressure (due its vasoconstrictive effect) caffeine consumption may contribute substantially to the prevalence of cardiovascular disease and stroke, and by implication to an increased risk of cognitive decline in older age (a significant cause of cognitive decline and dementia in older age is stroke and  transient ischaemic episodes linked to underlying vascular disease (atherosclerosis)). Reassuringly, however, tea and coffee consumption have not generally been found to be associated with these adverse effects, and some studies even suggest protective effects. Presumably other effects must outweigh the consequences of the increase in blood pressure. For example, polyphenols present in tea and coffee may reduce risk via vasorelaxant effects and effects on blood cholesterol, blood coagulation and inflammatory processes. Also, theanine, which is present in tea but not in coffee, reduces the blood pressure raising effect of caffeine.

Finally, caffeine itself may exert a positive effect by enhancing the naturally neuroprotective actions of adenosine. During ischaemia there is a large increase in extracellular adenosine which, acting via adenosine A1 and A2a receptors, helps to counter some of the key processes that lead to cell death. It’s possible that frequent exposure to caffeine modifies the adenosine system to increase its neuroprotective function.

Additional reading
Fredholm BB, Bättig K, Holmén J, Nehlig A and Zvartan EE (1999) Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacological Reviews 51:83-133.
Graham TE (2001) Caffeine and exercise, Sports Medicine 31:785-807.
James JE (1997) Understanding Caffeine: A Biobehavioral Analysis, Thousand Oaks CA, Sage.
Rogers P J (2007) Caffeine, mood and mental performance in everyday life. Nutrition Bulletin 32 (Suppl.1):84-89.
Rogers  PJ, Hohoff C, Heatherley SV, Mullings EL, Maxfield PJ, Evershed RP, Deckert J and Nutt D J (2010) Association of the anxiogenic and alerting effects of caffeine with ADORA2A and ADORA1 polymorphisms and habitual level of caffeine consumption. Neuropsychopharmacology 35:1973-1983.

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