Nurturing The Brain – Part I, Caffeine

Overall, more than 85% of children and adults consume caffeine regularly. But what does it do to the brain?

Coffee is one of the most consumed beverages in the world. According to Euromonitor, the United States is the country with the highest amount of total coffee consumption (971 tons per year), closely followed by Brazil (969 tons). However, when analyzed per capita, coffee consumption is actually highest in northern Europe, with Finland taking the lead, followed by Norway and the Netherlands. According to the National Coffee Association of the US (NCA), 54% of Americans over the age of 18 drink coffee on a daily basis and 25% drink only occasionally; only 22% never drink coffee at all. But coffee is not the only dietary source of caffeine. Other common sources include tea, chocolate, caffeinated soda, energy drinks, over-the-counter analgesics and cold remedies, and weight-loss aids.

Caffeine’s actions in the central nervous system (CNS) are mainly due to its effect as an adenosine receptor antagonist. Adenosine is a metabolite of ATP, which acts as a neurotransmitter, although it cannot be considered a classical neurotransmitter since it is not stored in synaptic vesicles or released in a calcium-dependent mechanism by neurons. Adenosine can be generated from ATP released by neurons or glia through the action of extracellular enzymes, or it can be directly released by neurons through membrane transporters. It’s an important modulator of the nervous system, interacting with many neurotransmitters. There are four receptor subtypes for adenosine (A1, A2A, A2B, and A3); due to its structural similarity with adenosine, caffeine can bind to all of them, thereby blocking their interaction with adenosine.

In general, adenosine has an inhibitory effect in the CNS, increasing drowsiness and sleep. Caffeine’s stimulatory effects are therefore primarily associated with its capacity to block adenosine receptors, antagonizing their effects.

Some metabolites of caffeine also have marked pharmacological activity. The metabolites theophylline, paraxanthine and theobromine are also adenosine receptor antagonists. Theophylline can actually be three to five times more potent than caffeine as an inhibitor of both adenosine A1 and A2A receptors. Therefore, besides its direct effects, caffeine’s action can be further increased, or at least maintained, by the action of its own metabolites.

Even though the action of caffeine occurs primarily by blocking adenosine receptors, there are important secondary effects affecting different classes of neurotransmitters that adenosine modulates, including noradrenaline, dopamine, serotonin, acetylcholine, glutamate, and GABA. This is reflected on the wide range of effects that caffeine has on the CNS that include increased motor activity, cortical activation, information processing rate, and cerebral energy metabolism rate.

These actions of caffeine can also have detrimental effects. Just as the main reason for coffee consumption is increasing wakefulness, unsatisfactory sleep is one of the main reasons people cease drinking coffee. It is well known that caffeine delays the onset and decreases the quality of sleep. However, these effects are quite variable, probably due to different metabolic rates or to differences in the sensitivity to caffeine between individuals. Some people have no sleep problems whatsoever despite regularly consuming caffeine in the evening.

Due to its actions in increasing alertness, attention, and cognitive function, and in elevating mood, caffeine has been associated with a decrease in depressive symptoms, fewer cognitive failures, and lower risk of suicide. However, high doses of caffeine can, in rare cases, induce psychotic and manic symptoms. The most common mood effect is increased anxiety, but it is mostly associated with a potentiation of pre-existing anxiety and panic disorders.

Some therapeutic uses of caffeine have been proposed. Studies using adenosine receptor antagonists, including caffeine, have shown a reduction in damages caused by spinal cord injury, stroke, and by neurodegenerative diseases such as Parkinson’s and Alzheimer’s diseases. Neuroprotective effects of caffeine have been demonstrated in animal models of brain injury and it is likely that similar effects may occur in humans.

Caffeine is potentially addictive. In fact, the latest edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) has included caffeine intoxication and withdrawal as substance-related and addictive disorders. Caffeine withdrawal is now an officially recognized diagnosis, and criteria for caffeine use disorder have been proposed for additional study. As anyone who has experienced it may guess, caffeine withdrawal is characterized, according to DSM-5, by headache, marked fatigue or drowsiness, dysphoric mood, depressed mood, or irritability, difficulty concentrating, and flu-like symptoms (nausea, vomiting, or muscle pain/stiffness).

Although high doses of caffeine may have negative side-effects, the regular consumption of an average dose of caffeine (280 mg/day, corresponding to three 8 fl. oz. cups of American coffee or to four to five 1 fl. oz. cups of Espresso) seems to be mostly harmless or even beneficial.


Fredholm BB, Bättig K, Holmén J, Nehlig A, & Zvartau EE (1999). Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacological reviews, 51 (1), 83-133 PMID: 10049999

Lara DR (2010). Caffeine, mental health, and psychiatric disorders. Journal of Alzheimer’s disease : JAD, 20 Suppl 1 PMID: 20164571

National Coffee Association (2009). National Coffee Drinking Trends. Accessed online 25 January 2015.

Nehlig A, Daval JL, & Debry G (1992). Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects. Brain research. Brain research reviews, 17 (2), 139-70 PMID: 1356551

Petzer JP, & Petzer A (2014). Caffeine As A Lead Compound For The Design Of Therapeutic Agents For The Treatment Of Parkinson’s Disease. Current medicinal chemistry PMID: 25544641

Rivera-Oliver M, & Díaz-Ríos M (2014). Using caffeine and other adenosine receptor antagonists and agonists as therapeutic tools against neurodegenerative diseases: a review. Life sciences, 101 (1-2), 1-9 PMID: 24530739

Snel J, & Lorist MM (2011). Effects of caffeine on sleep and cognition. Progress in brain research, 190, 105-17 PMID: 21531247

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Sara Adaes, PhD

Sara Adaes, PhD, has been a researcher in neuroscience for over a decade. She studied biochemistry and did her first research studies in neuropharmacology. She has since been investigating the neurobiological mechanisms of pain at the Faculty of Medicine of the University of Porto, in Portugal. Follow her on Twitter @saradaes
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