Why drinking coffee wakes you up

By Alice de Bernardy

Caffeine is considered to be the most widely used drug in the world.1 It is found in many dietary components of our daily lives: not only in coffee and tea, either, but also in soft drinks and even chocolate. While a typical cup of coffee contains around 100 mg of caffeine, its consumption varies greatly in different communities and cultures. Finland and Sweden are among the highest consumers of caffeine, drinking on average the equivalent of 4 cups of coffee per day. The US show a contrasting profile, consuming about half as much caffeine, and coming from sodas and chocolate drinks in a greater proportion. The associated population also extends to a younger age compared to other countries.1 Unfortunately, assessing the effects of caffeine on an individual is known to be considerably difficult, with the wide range of components consumed with coffee (such as milk or sugar) making it harder to discern the consequences of caffeine intake individually.2

There is a myriad of past research articles specifically focusing on caffeine’s biochemical properties. In light of this, the scope of this article only covers the main effects of caffeine, particularly in how it increases awareness and wakefulness. That said, it should be noted that caffeine has a variety of effects, such as mild analgesic properties.1

A common field of research in caffeine consumption is its biomolecular properties. Owing to its hydrophobic structure, the small molecule can easily cross lipid membranes, including the highly restrictive blood-brain-barrier and the placental barrier. As a result, humans typically absorb 99% of ingested caffeine, causing it to quickly reach an equilibrium between blood concentration and various tissues. Interestingly, while humans and many other animals readily absorb caffeine, bioavailability in horses can only reach 39%.3

Once in the circulation, caffeine exhibits a half-life of approximately 3 hours and remains the same throughout life. However, many factors still affect its metabolism and the time caffeine stays in our body. As an example, caffeine’s half-life is 100 hours in prenatal babies, later decreasing to 23 hours in new-borns and dropping to the adult level after 6 months. Other examples include smokers, who metabolise caffeine 30% to 50% faster than average, and women on the pill, for whom it takes twice as long to eliminate a cup of coffee.1

Comparatively, animal models for caffeine metabolism are not representative of our own biology, given the large differences in their metabolism. As an example, 40% of caffeine absorbed in rats is metabolised into trimethyl derivatives, while this only represents 8% in humans; and due to the pharmacologically active nature of some of these metabolites, it is tricky to extend conclusions from animals to humans.1

Nevertheless, prior research has found that the feeling of energisation associated with the consumption of caffeine mainly comes from its role as an antagonist to adenosine receptors A1 and A2A.2,4,5,6

In the central nervous system, A1 receptor activation by adenosine inhibits adenylate cyclase, which results in decreased cell activity and neurone firing.4 When caffeine attaches to the receptor, it prevents adenosine from binding and activating it. Thus, caffeine binding results in an increase in neurone firing following the upregulation of adenylate cyclase activity. In a similar yet opposite manner, A2Areceptors activate adenylate cyclase upon adenosine binding. Therefore, when caffeine binds the receptor, it prevents the activation of adenylate cyclase and ultimately decreases cell activity. It is believed that A1 receptors are expressed in neurons promoting wakefulness, with A2A receptors in sleep-promoting neurons (amongst others), caffeine induces a net increase in signalling to remain awaken and a decrease in sleep signalling.5,6

With caffeine consumption varying amongst individuals, so does their sensitivity to it. Past investigations have found contradictory results in the effects that different individuals feel following caffeine consumption. Studies assessing the effects of caffeine are also challenging to draw significant conclusions from, especially since a person’s daily caffeine consumption is usually at low doses. Additionally, any resulting physiological or behavioural changes can be difficult to identify, with the issue only exacerbated by outside factors from everyday life.2 Different studies reported a great variety of reactions from one individual to another– depending, for example, on whether they are used to consuming caffeine, or if they are prone to anxiety.2,7,8

One proposed theory that could explain the mass popularity of coffee is the widely debated withdrawal reversal hypothesis.7,8 Studies found that, upon acute caffeine withdrawal, regular coffee-drinkers scored lower in an awareness test than non-coffee-drinkers. When given a caffeinated drink, the chronic consumers’ score improved and went back to the calculated baseline. In contrast, however, the non-consumers did not score better with caffeine, though they did report an increase in alertness and tension.7

Consequently, the withdrawal reversal hypothesis states that chronic caffeine consumption (which is what makes coffee so popular in so many people’s daily routine) arises from the need to counteract the effects of caffeine withdrawal, rather than from how it may increase performance. This creates a vicious cycle of craving caffeine to escape its withdrawal symptoms, with the drug used to avoid an increasing feeling of tiredness and hence to feel ‘normal’.7

Over time, this theory has been refuted by other studies, with many arguing that a better performance from non-caffeine consumers after being given caffeine has been observed in different experimental setups, thus demonstrating a net beneficial impact of caffeine consumption on anyone – regular consumer or not.8

Although caffeine is registered amongst the most widespread and dominant drugs on earth, cases of caffeine abuse – referred to as caffeinism, which describes people who drink over 10 cups of coffee a day – are very rare. Indeed, people generally consume caffeine within a relatively low range, adapting the amount they consume to their own sensitivity and preferences.1,2 While there might never be a single answer to the question of how caffeine affects individuals, each person should still follow their own intuition for how much they feel is safe for them to consume.2


  1. Fredholm BB, Bättig K, Holmén J, Nehlig A, Zvartau EE. Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev 1999;51:83–133.
  2. Smith A. Effects of caffeine on human behavior. Food Chem Toxicol 2002;40:1243–55. https://doi.org/10.1016/s0278-6915(02)00096-0.
  3. Arnaud M. Metabolism of Caffeine and other components of coffee. Researchgate.net 1993. https://www.researchgate.net/publication/311253694_Metabolism_of_caffeine_and_other_components_of_coffee (accessed November 4, 2022).
  4. Fredholm BB. Adenosine, adenosine receptors and the actions of caffeine. Pharmacol Toxicol 1995;76:93–101.https://doi.org/10.1111/j.1600-0773.1995.tb00111.x.
  5. Lopes JP, Pliássova A, Cunha RA. The physiological effects of caffeine on synaptic transmission and plasticity in the mouse hippocampus selectively depend on adenosine A1 and A2A receptors. Biochem Pharmacol 2019;166:313–21. https://doi.org/10.1016/j.bcp.2019.06.008.
  6. Lazarus M, Shen H-Y, Cherasse Y, Qu W-M, Huang Z-L, Bass CE, et al. Arousal effect of caffeine depends on adenosine A2A receptors in the shell of the nucleus accumbens. J Neurosci 2011;31:10067–75. https://doi.org/10.1523/JNEUROSCI.6730-10.2011.
  7. Rogers PJ, Martin J, Smith C, Heatherley SV, Smit HJ. Absence of reinforcing, mood and psychomotor performance effects of caffeine in habitual non-consumers of caffeine. Psychopharmacology (Berl) 2003;167:54–62. https://doi.org/10.1007/s00213-002-1360-3.
  8. Nguyen-Van-Tam ASCB. Beneficial effects of caffeinated coffee ad effects of withdrawal. Researchgate.net 2001. https://www.researchgate.net/publication/230595581_Beneficial_effects_of_caffeinated_coffee_and_effects_of_withdrawal (accessed November 4, 2022).

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