Why Some People Can't Handle Caffeine

Caffeine is one of the most widely consumed psychoactive substances in the world, valued for its stimulating effects on the brain and body. To understand how caffeine works, it is necessary to examine its biological mechanisms and the genetic factors that influence caffeine sensitivity.

What is Caffeine?

Caffeine is a naturally occurring central nervous system stimulant in the methylxanthine class, a group of drugs with stimulatory and bronchodilatory (or the ability to open up airways and lungs) effects. These drugs are often used to treat patients with conditions restricting airways, such as asthma, chronic obstructive pulmonary disease, and apnea (Gottwalt & Tadi, 2023). For this reason, caffeine can be used to stimulate breathing in premature infants and prevent apnea, or pauses in breathing (Oñatibia-Astibia et al., 2016).

Though caffeine is primarily sourced from coffee beans, it is also found in certain varieties of tea and cacao beans. It is also used as an additive in soda and energy drinks. Prescription or over-the-counter drugs such as cold, allergy, and pain medications may also contain caffeine. Many weight-loss supplements also have caffeine (Petre, 2023).

Figure 1. Common sources of caffeine, with the amount of caffeine per serving (Lane, 2020).

How Caffeine Works in the Body

Once caffeine is consumed, it gets absorbed by the gut which then flows into the bloodstream. Because caffeine is both water-soluble and fat-soluble, it travels easily in blood plasma and can cross the fatty membranes of the blood-brain barrier, a highly selective network of semi-permeable membranes that protects the central nervous system. After entering the brain, caffeine binds to adenosine receptors, blocking adenosine from attaching to them instead (Evans et al., 2024) (Fig 2). Adenosine is a compound that normally promotes sleepiness and relaxation by slowing down neural activity. By preventing this process, caffeine increases alertness, reduces fatigue, and can improve concentration, reaction time, and even mood in the short term.

Figure 2. Caffeine attaching to adenosine receptors and blocking adenosine (Jaeger, 2021).

Once in the body, caffeine is primarily broken down in the liver by an enzyme called CYP1A2. This enzyme is responsible for metabolizing more than 90% of the caffeine consumed. Its activity helps determine how long caffeine stays in the body and how strong its effects are. The efficiency of CYP1A2 can influence everything from the intensity of stimulation to how soon someone may feel the need for another cup of coffee (Mahdavi et al., 2023).

The Genetics of Caffeine Sensitivity

The CYP1A2 enzyme is responsible for the differences in how people respond to caffeine. Fast metabolizers break down caffeine quickly, meaning its effects wear off sooner. However, slow metabolizers process caffeine more slowly, leading to prolonged effects and a higher chance of side effects such as insomnia.

Another important gene, ADORA2A, affects how the brain responds to caffeine by influencing the sensitivity of adenosine receptors. Genetic testing can reveal whether you have variants in these genes that impact your caffeine tolerance (Mégane Erblang et al., 2019).

Other factors like body weight, age, sex, and certain medications also influence how your body handles caffeine. Habitual caffeine intake can lead to tolerance, reducing its noticeable effects over time. Additionally, people with anxiety disorders or heart conditions may experience stronger negative reactions and are often advised to limit their caffeine intake (Liu et al., 2024).

Key Takeaways

While caffeine offers benefits like increased alertness and improved focus, its effects can vary greatly from person to person. Factors such as genetics, enzyme activity, habitual use, and underlying health conditions all influence how caffeine is processed and tolerated. By understanding these variables, individuals can make more informed choices about their caffeine intake.

References

1. Erblang, M., Drogou, C., Gomez-Merino, D., Metlaine, A., Boland, A., Deleuze, J. F., Thomas, C., Sauvet, F., & Chennaoui, M. (2019). The Impact of Genetic Variations in ADORA2A in the Association between Caffeine Consumption and Sleep. Genes, 10(12), 1021. https://doi.org/10.3390/genes10121021

2. Evans, J., Richards, J. R., & Battisti, A. S. (2025). Caffeine. In StatPearls. StatPearls Publishing. http://www.ncbi.nlm.nih.gov/books/NBK519490/

3. Gottwalt, B., & Tadi, P. (2025). Methylxanthines. In StatPearls. StatPearls Publishing. http://www.ncbi.nlm.nih.gov/books/NBK559165/

4. Jaeger, K. (2021, April 7). I Tried a Coffee Nap. Health in a Hurry. https://blogs.uww.edu/healthinahurry/2021/04/07/i-tried-a-coffee-nap/

5. Lane, A. (2020, February 12). Foods with Caffeine. Healthful Lane Nutrition. https://healthfullane.com/2020/02/12/foods-with-caffeine/

6. Liu, C., Wang, L., Zhang, C., Hu, Z., Tang, J., Xue, J., & Lu, W. (2024). Caffeine intake and anxiety: A meta-analysis. Frontiers in Psychology, 15, 1270246. https://doi.org/10.3389/fpsyg.2024.1270246

7. Oñatibia-Astibia, A., Martínez-Pinilla, E., & Franco, R. (2016). The potential of methylxanthine-based therapies in pediatric respiratory tract diseases. Respiratory Medicine, 112, 1–9. https://doi.org/10.1016/j.rmed.2016.01.022

8. Petre, A. (2020, June 3). What Is Caffeine, and Is It Good or Bad for Health? Healthline. https://www.healthline.com/nutrition/what-is-caffeine