Caffeine Tolerance

In this article, we will discuss how quickly caffeine tolerance develops, as well as why caffeine tolerance develops. Without further ado, let us jump into it.

What is Caffeine?

Caffeine is a molecule found in a number of plants and is often synthesized for pharmaceutical purposes, as well. The molecule is a nervous system stimulant.

How quickly does Caffeine Tolerance Occur?

Tolerance, desensitization to caffeine varies considerably – one study shows certain levels of desensitization from a single day of caffeine consumption relative to the next [1]. Other studies argue that a few days are enough to see incomplete tolerance, and yet others show that a few days are enough for complete tolerance [2]. In these cases, more caffeine is needed to get certain physiological responses like increased blood pressure, and there is a consistent tolerance in the central nervous system [3]. Interestingly, in the peripheral nervous system, there are inconsistent effects of caffeine tolerance – meaning that it may still have an impact on the peripheral nervous system, regardless of tolerance [3].

Understanding the Physiology

Caffeine antagonizes adenosine molecules by binding a series of adenosine receptors, reducing the effect of those adenosine receptors in the forebrain [4][5]. This is possible, because the structure of caffeine and adenosine are so similar [4]. Adenosine promotes restfulness and sleep in neurons through the binding of their respective receptors, leading to sleep promoting pathways; however, since caffeine binds these receptors, it stops the action of adenosine [5]. However, as we consume caffeine, cells across the body begin synthesizing more receptors to put into the cell membrane and an increase in the creation and release of adenosine leads to lowered effects of caffeine, unless we consume more caffeine to interact with the increased number of receptors [4][6].

Caffeine, acutely, also increases the release of catecholamines like epinephrine and norepinephrine from the adrenal glands, but this effect is short lived as it only occurs in the first 1-2 days of caffeine intake, then disappears [1].

Also, keep in mind that the clearance of caffeine could be increased by increased activity or quantity of cytochrome P450 enzyme in the liver, which inactivates caffeine for excretion. If this were to happen, caffeine would have a short lived impact.


In summary, tolerance varies, but can be as quick as significant decreases after one day to several days (less than a week, however). Tolerance occurs as caffeine binds the adenosine receptors in the body, leading to an antagonizing effect and as adenosine is needed, the brain dumps greater and greater amounts of adenosine into circulation, as well as increases cell receptor number (increasing chances of binding adenosine), so there is an increased need to increase the population of caffeine molecules, and so on and so forth.

Writer: Nicolas Verhoeven
[1] Robertson, D., Wade, D., Workman, R., Woosley, R. L., & Oates, J. A. (1981). Tolerance to the humoral and hemodynamic effects of caffeine in man. Journal of Clinical Investigation, 67(4), 1111-1117. doi:10.1172/jci110124

[2] Shi, J., Benowitz, N. L., Denaro, C. P., & Sheiner, L. B. (1993). Pharmacokinetic-pharmacodynamic modeling of caffeine: Tolerance to pressor effects. Clinical Pharmacology and Therapeutics, 53(1), 6-14. doi:10.1038/clpt.1993.3

[3] Cappelletti, S., Daria, P., Sani, G., & Aromatario, M. (2015). Caffeine: Cognitive and Physical Performance Enhancer or Psychoactive Drug? Current Neuropharmacology, 13(1), 71-88. doi:10.2174/1570159x13666141210215655

[4] Ribeiro, J. A. (2010). Caffeine and adenosine. Journal of Alzheimer's Disease, 20(1), 3-15. doi:10.3233/JAD-2010-1379

[5] Sheth, S., Brito, R., Mukherjea, D., Rybak, L., & Ramkumar, V. (2014). Adenosine Receptors: Expression, Function and Regulation. International Journal of Molecular Sciences, 15(2), 2024-2052. doi:10.3390/ijms15022024

[6] Marangos, P. J., Boulenger, J., & Patel, J. (1984). Effects of chronic caffeine on brain adenosine receptors: Regional and ontogenetic studies. Life Sciences, 34(9), 899-907. doi:10.1016/0024-3205(84)90207-8

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