Caffeine Metabolism and Your Genes

Whether you start your morning with a cup of coffee or tea, caffeine remains the most popular ‘drug’ of choice for a large percentage of the population.

Caffeine wakes us up by blocking the adenosine receptor. Adenosine builds up in the brain over the course of a day, causing us to feel sleepy. By blocking the adenosine receptor with caffeine, you no longer feel sleepy. But when the caffeine wears off, the adenosine is still there – causing the rebound effect of feeling even sleepier.

Caffeine also acts as a central nervous system stimulant, increasing reaction time.

Caffeine molecule

 

Genes determine how quickly your body processes and eliminates the caffeine and whether it is likely to make you jittery or anxious.

The CYP1A2 gene encodes the enzyme that breaks down caffeine. Other drugs can also be broken down with the CYP1A2 gene (e.g., clozapine, olanzapine, theophylline), so be careful with caffeine with certain medications.[ref]

People with genetic variants in the CYP1A2 gene can break down caffeine more slowly, causing them to feel the effects of caffeine longer.


Caffeine Sensitivity Genes:

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CYP1A2 gene:

This gene codes for the enzyme that metabolizes or breaks down the caffeine in the body.

  • If you are a slower metabolizer, you will feel the effects of caffeine for a longer time.
  • If you are a fast metabolizer, you will break down and get rid of caffeine more quickly from your system.

Check your genetic data for rs762551 (23andMe v4, v5; AncestryDNA):

  • C/C: Slower metabolizer of caffeine
  • A/C: Intermediate metabolizer of caffeine
  • A/A: Fast metabolizer of caffeine[ref]

Members: Your genotype for rs762551 is .


ADORA2A Gene (Adenosine 2A receptor):

This gene codes for the adenosine receptor protein, which, among other things, helps regulate dopamine and glutamine release in the brain. Caffeine partially blocks the receptor. Both of the variants listed below are very common.

Check your genetic data for rs5751876 (23andMe v4, v5)

  • C/C: no increase in anxiety from caffeine
  • C/T: no increase in anxiety from caffeine
  • T/T: high caffeine dose more likely to make you anxious[ref][ref]

Members: Your genotype for rs5751876 is .

Check your genetic data for rs2298383 (23andme v5 only):

  • T/T: no increase in anxiety from caffeine (avg. amount)
  • C/T: no increase in anxiety from caffeine
  • C/C: high caffeine dose more likely to make you anxious[ref][ref]

Members: Your genotype for rs2298383 is .

Interesting studies on ADORA2A:

  • While the two variants above are tied to increased anxiety with caffeine, they are also found to correspond with increased anxiety in general (not linked to caffeine).[ref]
  • Have dry eyes? These two ADORA2 variants lead to slightly increased tear volume with caffeine consumption.[ref]
  • A study found that those who were more susceptible to anxiety from caffeine were, also likely to have a higher habitual caffeine intake. Those drinking more coffee tended to build up a tolerance to the anxiety-inducing effects regardless of genotype.[ref]

Lifehacks:

CYP1A2 inhibitors: Slowing Down Caffeine Metabolism

Curcumin is an inhibitor of CYP1A2 in humans and in animals. A recent animal study found that curcumin prevented liver damage from aflatoxin B exposure.[ref] A potent carcinogen, aflatoxin B is a toxin produced by mold (Aspergillus) and is sometimes found in peanuts, corn, and other grains. Curcumin can be taken as a supplement and is also found in the spice, turmeric.

Other inhibitors of CYP1A2 include ciprofloxacin (antibiotic) and cimetidine (aka Tagamet).[ref] Keep in mind that caffeine metabolism may be altered when taking a CYP1A2 inhibitor.

In other words: If you are normally a fast metabolizer and drink coffee or tea with dinner, you may have problems sleeping if you couple that caffeine with a CYP1A2 inhibitor like Tagamet, curcumin, or ciprofloxacin.

Diet and Lifestyle:

Looking for a way to pep up your morning coffee without adding caffeine? Here are a couple of options:

  • Include Bulletproof Brain Octane Oil in your coffee.
  • Add Lion’s Mane and Chaga mushroom extracts with cognitive benefits (my new favorite!).

More of a tea person? Black teas have the highest caffeine content, ranging from 25 – 50 mg per 8oz cup, while white tea has a much lower caffeine content. If you are a slow caffeine metabolizer, try switching to white tea.

Coffee consumption studies:

If your beverage of choice in the morning is coffee, here are some studies on the effects:

  • A meta-analysis study showed that coffee consumption (4 cups a day) decreased the risk of breast cancer in postmenopausal women by 10%.[ref] Another study indicates that the reduction in risk (found to be closer to 30% for those drinking 5 cups a day) may be due to something else in coffee other than caffeine because other caffeinated drinks did not give the same result.[ref]
  • For those with the BRCA1 mutation, one study found that coffee consumption before age 35 for those with the C-allele reduced their risk of breast cancer by 64%.[ref]
  • Another meta-analysis found that high coffee consumption may lead to a decreased risk of pancreatic cancer.[ref]

Recap of your genes:


Related Articles and Genes:

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Modafinil: Will it work for you?
Modafinil is being used as a nootropic drug that increases alertness and gives a sense of well being — to some users. Like most drugs, individual results seem to vary. One reason for the variation is a common genetic variation in the COMT gene.

Metformin
A decades-old diabetes drug now holds promise for increasing healthspan. Research shows that metformin may reduce the risk of some of the diseases of aging, thus increasing the number of years someone is healthy.

ABCC11 gene: Ear wax and no body odor
The ABCC11 gene determines both the type of earwax a person has and whether they have no armpit or body odor.

Genetics of Double Eyelashes
Ever wonder why Elizabeth Taylor had such compelling eyes? It turns out that she probably carried a mutation for doubled eyelashes, also known as distichiasis.

References:

Arita, Reiko, et al. “Caffeine Increases Tear Volume Depending on Polymorphisms within the Adenosine A2a Receptor Gene and Cytochrome P450 1A2.” Ophthalmology, vol. 119, no. 5, May 2012, pp. 972–78. PubMed, https://doi.org/10.1016/j.ophtha.2011.11.033.

Childs, Emma, et al. “Association between ADORA2A and DRD2 Polymorphisms and Caffeine-Induced Anxiety.” Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, vol. 33, no. 12, Nov. 2008, pp. 2791–800. PubMed Central, https://doi.org/10.1038/npp.2008.17.

Healy, D. P., et al. “Interaction between Oral Ciprofloxacin and Caffeine in Normal Volunteers.” Antimicrobial Agents and Chemotherapy, vol. 33, no. 4, Apr. 1989, pp. 474–78. PubMed Central, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC172463/.

Hohoff, Christa, et al. “Association of Adenosine Receptor Gene Polymorphisms and in Vivo Adenosine A1 Receptor Binding in the Human Brain.” Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology, vol. 39, no. 13, Dec. 2014, pp. 2989–99. PubMed, https://doi.org/10.1038/npp.2014.150.

John R. Horn, PharmD, and PharmD Philip D. Hansten. “Get to Know an Enzyme: CYP1A2.” Pharmacy Times, vol. 0, Nov. 2007. www.pharmacytimes.com, https://www.pharmacytimes.com/view/2007-11-8279.

Koonrungsesomboon, Nut, et al. “The Impact of Genetic Polymorphisms on CYP1A2 Activity in Humans: A Systematic Review and Meta-Analysis.” The Pharmacogenomics Journal, vol. 18, no. 6, Dec. 2018, pp. 760–68. PubMed, https://doi.org/10.1038/s41397-017-0011-3.

Kotsopoulos, Joanne, et al. “The CYP1A2 Genotype Modifies the Association between Coffee Consumption and Breast Cancer Risk among BRCA1 Mutation Carriers.” Cancer Epidemiology, Biomarkers & Prevention: A Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology, vol. 16, no. 5, May 2007, pp. 912–16. PubMed, https://doi.org/10.1158/1055-9965.EPI-06-1074.

Lafranconi, Alessandra, et al. “Coffee Intake Decreases Risk of Postmenopausal Breast Cancer: A Dose-Response Meta-Analysis on Prospective Cohort Studies.” Nutrients, vol. 10, no. 2, Jan. 2018, p. E112. PubMed, https://doi.org/10.3390/nu10020112.

Lowcock, Elizabeth C., et al. “High Coffee Intake, but Not Caffeine, Is Associated with Reduced Estrogen Receptor Negative and Postmenopausal Breast Cancer Risk with No Effect Modification by CYP1A2 Genotype.” Nutrition and Cancer, vol. 65, no. 3, 2013, pp. 398–409. PubMed, https://doi.org/10.1080/01635581.2013.768348.

Ran, Heng-Quan, et al. “Coffee Consumption and Pancreatic Cancer Risk: An Update Meta-Analysis of Cohort Studies.” Pakistan Journal of Medical Sciences, vol. 32, no. 1, Feb. 2016, pp. 253–59. PubMed, https://doi.org/10.12669/pjms.321.8761.

Renda, Giulia, et al. “Genetic Determinants of Cognitive Responses to Caffeine Drinking Identified from a Double-Blind, Randomized, Controlled Trial.” European Neuropsychopharmacology: The Journal of the European College of Neuropsychopharmacology, vol. 25, no. 6, June 2015, pp. 798–807. PubMed, https://doi.org/10.1016/j.euroneuro.2015.03.001.

—. “Genetic Determinants of Cognitive Responses to Caffeine Drinking Identified from a Double-Blind, Randomized, Controlled Trial.” European Neuropsychopharmacology: The Journal of the European College of Neuropsychopharmacology, vol. 25, no. 6, June 2015, pp. 798–807. PubMed, https://doi.org/10.1016/j.euroneuro.2015.03.001.

Rogers, Peter J., et al. “Association of the Anxiogenic and Alerting Effects of Caffeine with ADORA2A and ADORA1 Polymorphisms and Habitual Level of Caffeine Consumption.” Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology, vol. 35, no. 9, Aug. 2010, pp. 1973–83. PubMed, https://doi.org/10.1038/npp.2010.71.

Zhang, Ni-Ya, et al. “Curcumin Prevents Aflatoxin B₁ Hepatoxicity by Inhibition of Cytochrome P450 Isozymes in Chick Liver.” Toxins, vol. 8, no. 11, Nov. 2016, p. E327. PubMed, https://doi.org/10.3390/toxins8110327.


About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and also an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.