This article appears in Volume 62, Issue 2.
Photo by Brigitte Tohm on Unsplash
As the unofficial sponsor of late-night lab work and grant deadlines, caffeine is probably one of our favorite biologically active natural products. Produced by plants such as coffee, tea, cacao, and others, this natural alkaloid (1,3,7-trimethylxanthine) has become part of our daily life [1].
Long before caffeine was helping scientists stay awake, it already had an important ecological role in plants. It helps protect plants from insects and can also reduce the growth of nearby competing plants [2].
How caffeine keeps us awake
In the human body, this same plant defense compound helps keep us awake. Caffeine crosses the blood-brain barrier and mainly acts as an antagonist of adenosine receptors, which are involved in regulating sleep and wakefulness [3]. Adenosine is a neuromodulator that helps slow down brain activity. Its level gradually increases while we are awake, creating the feeling of tiredness [4, 5]. By blocking adenosine receptors, caffeine temporarily decreases sleepiness and promotes focus, and attention [3, 4]. Current research continues to investigate how caffeine affects the body, including its influence on sleep, cognition, and neuromuscular performance [2, 6, 7].
Why some people are more sensitive to caffeine
People respond to caffeine differently. Some people can drink an espresso late at night and still sleep normally, while others may feel jittery after half a cup of coffee or tea. Much of this difference is related to pharmacogenomics.
Genetics is one reason why people respond to caffeine differently. In the liver, most caffeine is metabolized by CYP1A2, an enzyme whose activity can vary among individuals. A common genetic variant in CYP1A2 is often used to describe people as fast or slow caffeine metabolizers. In general, people with the AA genotype metabolize caffeine faster, while those with AC or CC genotypes may clear caffeine more slowly and experience its effects for a much longer time [8].
However, CYP1A2 activity is not determined by genetics alone. It can also be affected by physiological conditions and lifestyle factors. For example, pregnancy and oral contraceptive use can slow caffeine metabolism, while smoking cigarettes can increase CYP1A2 activity and speed up caffeine clearance [8, 9].
Caffeine response is also influenced by the ADORA2A gene, which builds the adenosine A2A receptor to help regulate mood and alertness. Because people inherit different variations of this gene, their sensitivity to caffeine can vary considerably. For instance, individuals with the TT genotype are highly sensitive and may experience anxiety or sleep disruption from small amounts, while those with the CC genotype naturally tolerate much more caffeine with minimal effects [8].
Why coffee and tea feel different
One interesting point from a pharmacognosy perspective is that caffeine is rarely consumed alone. Coffee, green tea, matcha, and other sources of caffeine are composed of complex chemical mixtures. Their preparation methods may also contribute to their differing physiological effects and individual preferences [8, 9].
Leaves from Camellia sinensis are rich in catechins, as well as L-theanine, a non-proteinogenic amino acid that can cross the blood-brain barrier. L-theanine can influence neurotransmitter activity and is often associated with a calming effect. As a result, green tea and matcha may feel smoother than coffee for some people [9].
The chemical profile of coffee is reliant on the preparation method used. Without paper filtration, more cafestol and kahweol can remain in the drink. These diterpenes are associated with higher LDL cholesterol levels, while paper-filtered coffee contains much lower amounts [8].
So, the next time we reach for coffee or tea during a long workday, caffeine is doing more than just helping us stay awake. It is also an example of how plant chemistry, human metabolism, genetics, and daily habits can come together in everyday life.
References
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- Ionescu, C.; Lungu, P. F.; Rarinca, V.; Visternicu, M.; Ciobica, A.; Burlui, V.; Albert, C.; Nicoara, M. N.; Plavan, G. I.; Novac, B.; et al. Caffeine toxicity in zebrafish-Neurobehavioral changes, developmental defects, and oxidative stress: A review. Biomol Biomed 2025, 26 (7), 1032-1043.
- Chang, Y. H.; Cheng, Y. C.; Cheng, W. J. Age- and dose-specific effects of caffeine on sleep: A meta-analysis of controlled crossover trials. Sleep Med 2025, 136, 106874.
- Nagamine, T. A Pharmacological and Critical Review of Caffeine and Alpha-Lipoic Acid for Burning Mouth Syndrome. J Oral Rehabil 2026, 53 (2), 603-605.
- Chmiel, J.; Kurpas, D. The Caffeinated Brain Part 2: The Effect of Caffeine on Sleep-Related Electroencephalography (EEG)-A Systematic and Mechanistic Review. Nutrients 2026, 18 (8), 1220.
- Amoruso, P.; Lecce, E.; Scotto di Palumbo, A.; Sacchetti, M.; Bazzucchi, I. Caffeine as an Ergogenic Aid for Neuromuscular Performance: Mechanisms of Action from Brain to Motor Units. Nutrients 2026, 18 (2), 252.
- Awashra, A.; AbuBaha, M.; Mahafdah, B.; Sarama, A.; Alattar, D.; AbuBaha, B.; Abu-Khazneh, O.; Emara, A.; Milhem, A.; Elgendy, M. S.; et al. Caffeine as a cardiovascular protective agent: a comprehensive review of mechanisms and outcomes. Eur J Med Res 2026, 31, 534.
- Liu, X. Y.; Xu, S. H. Unraveling the complexities of caffeine: metabolism, genetics, evolution, and health. Hereditas 2026, 163 (1), 36.
