Factors That Affect Caffeine Sensitivity

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Caffeine sensitivity refers to how much effect caffeine has on our bodies. People who have unusual caffeine sensitivity may experience significant symptoms — such as anxiety, tremors, headache, palpitations, and insomnia — after ingesting even small amounts of caffeine-containing foods. People with caffeine sensitivity should generally try to avoid caffeine altogether.

How sensitive a person is to caffeine is determined by several factors including age and sex, but the biggest factor is genetic.

In women, caffeine sensitivity is also strongly modulated by the use of contraceptives , and by pregnancy.

How Caffeine Is Metabolized

Caffeine is rapidly absorbed from the intestines into the bloodstream, and it readily crosses the blood-brain barrier into the brain. It also freely crosses the placenta in pregnant women.

In the brain, caffeine binds to the adenosine receptors, thus preventing adenosine from attaching to them. Because adenosine sends the brain a message that it is time to sleep, blocking the adenosine receptors has the effect of producing wakefulness.

Caffeine is metabolized in the liver by an enzyme called CYP1A2 to theophylline, paraxanthine, and theobromine, and is then excreted by the kidneys into the urine. The half-life of caffeine is typically 4 - 6 hours, which is typically how long caffeine affects us.

What Affects Caffeine Sensitivity?

Sensitivity to caffeine is largely determined by the activity of the CYP1A2 enzyme in the liver. The more active the CYP1A2, the less sensitive we are to caffeine. Several factors affect CYP1A2 activity:

  • Age: CYP1A2 activity tends to decrease with age, so older people tend to be more sensitive to caffeine
  • Sex: Women tend to have lower CYP1A2 activity than men.
  • Oral Contraceptive Use and Pregnancy: Estrogens inhibit CYP1A2 activity and caffeine sensitivity increases
  • Genetic Makeup: Several gene variants have now been identified that affect CYP1A2 activity.

Our Genes and Caffeine Sensitivity

Genetic testing has revealed three general categories of caffeine sensitivity related to our genetic makeup:

  • Hypersensitive to Caffeine: These individuals have very low CYP1A2 activity. They will have a strong response to even small amounts of caffeine, and will commonly experience jitters and insomnia.
  • Normal Sensitivity to Caffeine: This is the vast majority of individuals. They can consume up to 400 mg of caffeine per day without adverse side effects.
  • Low Sensitivity to Caffeine: These people have very high CYP1A2 activity, and often experience no effect at all from consuming caffeine. Smokers often have increased CYP1A2 activity.

While genetic testing can categorize your level of caffeine sensitivity, having formal testing is generally not necessary for you to know — at least generally speaking — whether or not you are very sensitive to caffeine. And if you are, it is likely that nobody needs to tell you to cut back.​

Pregnancy and Caffeine Sensitivity

Pregnancy reliably increases sensitivity to caffeine. The half-life of caffeine in pregnant women is often four times longer than it is for non-pregnant women — often up to 16 hours. Furthermore, caffeine readily enters the bloodstream of the fetus — and the fetus has very very little CYP1A2 activity.

While serious adverse effects on the fetus caused by the mother’s caffeine intake have not been documented, this issue has not been studied extensively. In general, pregnant women should try to limit or avoid caffeine.

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Additional Reading
  • Cornelis MC, Byrne EM, Esko T, et al. The Coffee and Caffeine Genetics Consortium. Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption. Molecular Psychiatry 20, 647-656 (May 2015) | doi:10.1038/mp.2014.107

  • Grant DM, Tang BK, Kalow W. Variability in caffeine metabolism. Clinical Pharmacology & Therapeutics, 33(5), 591-602, 1983.

  • Grosso LM, Bracken MB. Caffeine metabolism, genetics, and perinatal outcomes: a review of exposure assessment considerations during pregnancy. Ann Epidemiol 2005; 15:460.