Caffeine-Resistance? Genetic & Environmental Factors Determine If You Feel or Don't Feel the "Boost" | Plus: 11 Non-Genetic Factors That In- & Decrease Caffeine's Effect

If you know the tricks you can increase and decrease your caffeine tolerance by varying environmental factors. Ramp up the amount of exercise, broccoli and smoked meats ➲ maximize the clearance and minimize the effects of caffeine.
Actually I had hoped no-one would see the comment I made in the discussion revolving around a recent article about caffeine, but since a promise is a promise and I was stupid enough to promise that I would write an article on the genetic and environmental underpinnings of caffeine-over- and -under-metabolizers, I am sitting right here, digging up study after study, to find ... well, nothing conclusive.

According to analysis Welfare et al. conducted and published in June 1999, there is actually no  significant polymorphism in CYP1A2 in Caucasians which could explain the interindividual variation in caffeine activity, we all know exists (Welfare. 1999) - meanwhile, scientists have identified a handful of polymorphism - albeit with partly unknown acute or chronic implications (see Table 1).
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One year before, Schrenk et al. had already reported that smokers have significantly increased CYP1A2 activities. Compared to a non-smoker, a nicotine-junkie is thus much more prone to become "caffeine resistant", solely because he is metabolizing and excreting the drug much faster (Schrenk. 1998). Genetics and sex, on the other hand, appeared to make only a minor difference.

Table 1: Polymorphisms linked to acute and chronic response to caffeine (Yang. 2010)
After Welfare's conclusion from 1999, it took another 3 years, before Rasmussen et al. published the results of an intriguing study in the peer-reviewed scientific journal Pharmacogenetics and Genomics. In said paper, Birgitte B. Rasmussen, Thomas H. Brix, Kirsten O. Kyvik and Kim Brøsen confirmed the observations Schrenk et al. had made and found, next to the caffeine ↔ nicotine and caffeine ↔ sex (male = high; female = low clearance) connections, another significant environmental effect: A highly significant reduction of caffeine clearance in women on oral contraceptives.
Did you know that the clearance of caffeine can vary to up to 40-fold within and between individuals (Kalow. 1991; Kashuba. 1998)? Or that Asian and African populations appear to metabolize caffeine at slower rate than Caucasians (Gunes. 2008)
No wonder, the scientists were after all also able to confirm that CYP1A2 does not only vary according to sex (higher activity in men vs. women = faster clearance in men vs. women), but is also induced by smoking and inhibited by oral contraceptives.
"In the subsequent analysis of heritability, we included 49 monozygotic twin pairs and 34 same gender dizygotic twin pairs concordant for non-smoking and non-use of oral contraceptives.

The intraclass correlation coefficient was 0.798 (95% confidence interval, 0.696–0.900) and 0.394 (95% confidence interval, 0.109–0.680) in the monozygotic and dizygotic twins, respectively." (Rasmussen. 2002)
Now that's a statistically significant correlation, but it does also show that even with identical genes, environmental (or epigenetic) influences are responsible for more than 20% of the effects of caffeine.

Figure 1: The caffeine metabolic ratio reflecting CYP1A2 activity in relation to smoking, oral contraceptive use and gender. Open squares are non-smokers and shaded circles are smokers. The points represent means and the error bars represent 95% confidence intervals (Rasmussen. 2002).
Upon closer scrutiny, Rasmussen et al. were even able to show that unique environmental effects seem to account for the remainder 0.275 (95% confidence interval, 0.178–0.423) of the inter-personal susceptibility to the effects of caffeine.

This does not change that the major determinant of CYP1A2 activity is still a genetic one, the fact that other studies, like Carmelli et al. (1990) report a heritability of only 36%, Kendler et al. (2007) who conducted one of the most recent investigations of the heritability of CYP1A2 activity say it's ~30-45% and rises from age 9–14 to remains stable, afterwards, I would not discard the possibility that your caffeine resistance or hyper-response is a result of certain dietary & lifestyle factors.

Now the question is: What are these environmental factors?

I don't pretend I could name them all, so I will just stick to those I can find within the hours I am willing to spend skimming study after study to abide by my promise:
  • meat, when it's cooked at high temperatures increases the clearance of caffeine (Sinha. 1994) - the exact extent is unknown and probably varies depending on the cooking method and overall consumption
  • broccoli and other brassica vegetables (similar effects have been reported for cumin and turmeric) increase the clearance of caffeine (Lampe. 2000) - in women the consumption of a high brassica diet (428g/day!) lead to 18% increase in CYP activity and thus caffeine clearance
  • exercise increases, specifically chronic exercise, increases the expression of CYP1A2 and thus the clearance of caffeine significantly - in a 1992 study by Vistisin by a whopping 70%! (Vistisen. 1992)
  • green tea extract increases the expression of CYP1A2 in the gut, already, consequently, your caffeine will be broken down before it even reaches the liver (Netsch. 2006) - interestingly enough, pure EGCG does not have this effect
  • gingko biloba increases CYP1A2 activity and caffeine clearance in the liver (Hellum. 2007) - specific data on the effect size is not available 
  • insulin at least if you are diabetic insulin will reduce the half-life of caffeine by increasing - you guessed it - CYP1A2 activity (Flockhart. 2007)
  • proton pump inhibitors such as omeprazole have also been shown to induce CYP1A2 activity and should thus likewise lower the half-life of caffeine (Flockhart. 2007)
  • lutein has been shown to be associated with low CYP1A2 activity and could thus decrease caffeine clearance (Marchand. 1997)
  • dill, celery, parsley, parsnips and carrot coins decreases the clearance of caffeine (Lampe. 2000) - in women the consumption of high amounts of apiaceous veggies led to a -13% reduction in CYP activity and a correspondingly reduced clearance of caffeine
  • naringin from grapefruit reduces the clearance of caffeine (Fuhr. 1993) - the extent in the single serving study was -23% oral clearance of caffeine and +31% half- life 
  • peppermint, chamomile, cannabis and dandelion teas are all relatively strong inhibitors of CYP1A2 activity and will thus increase the half-life and effects of caffeine
So, if you look at the first three inducers of caffeine clearance, I suppose you won't need an additional explanation why even non-pre-workout abusing physical culturists appear to be more or less resistant to the effects of caffeine, right? Right, ... meat + broccoli + exercise = massive increase in CYP1A2 activity and thus an increase in caffeine clearance that helps your liver to shuttle the CNS stimulant out of the system before it even gets to the central nervous system ;-)
The non-existent increase in the product of heart rate (HR) x systolic pressure (SBP) is a heart-protective habituation effects in older (62y) coffee junkies (Izzo. 1983)
Bottom line: Now that you know that you are doing to make caffeine less effectively, I would suggest you keep doing exactly that! Yes, you read me right! Exercise is good for you, and so are cruciferous vegetables. If you think you need a more pronounced boost from your morning coffee, work on improve your sleep schedule and / or reduce your training load (chances are you are overtraining and (ab-)using caffeine and other stims to make up for a lack of rest) - caffeine can replace adequate rest, once (see " Caffeine Works - Study Leaves No Doubt About It!" | read more), but not chronically. Don't fret! Look at the figure to the right-hand side!

That's actually a good thing: If the central nervous system didn't reduce it's own susceptibility to the stimulating effects of the world's favorite drug, coffee consumption would probably be associated with heart attacks and thus reductions, not increases in lifespan.

Yep! The findings of the Leisure World Cohort Study (Paganini-Hill. 2007), in which 8644 elderly women and 4980 elderly men were studied for 23 y, indicated that the daily consumption of up to 400 mg of caffeine significantly decreased (by 10%) the risk of dying from any cause (-10%).

And you know what? Studies like the one Mark Tarnopolsky and Cynthia Cupido published in volume 89 of the Journal of Applied Physiology in 2000 show: As long as you're not overtraining the physical ergogenic effects will remain intact, so that "caffeine potentiates low-frequency skeletal muscle force in habitual and nonhabitual caffeine consumers" (Tarnopolsky. 2000).

  • Flockhart, D. A. "Drug interactions: cytochrome P450 drug interaction table." Indiana University School of Medicine (2007).
  • Fuhr, Uwe, Klittich, K. and Staib, A.H. "Inhibitory effect of grapefruit juice and its bitter principal, naringenin, on CYP1A2 dependent metabolism of caffeine in man." British journal of clinical pharmacology 35.4 (1993): 431-436. 
  • Gunes, Arzu, and Marja-Liisa Dahl. "Variation in CYP1A2 activity and its clinical implications: influence of environmental factors and genetic polymorphisms." (2008): 625-637. 
  • Hellum, Bent H., Zhuohan Hu, and Odd Georg Nilsen. "The induction of CYP1A2, CYP2D6 and CYP3A4 by six trade herbal products in cultured primary human hepatocytes." Basic & clinical pharmacology & toxicology 100.1 (2007): 23-30.
  • Izzo Jr, Joseph L., et al. "Age and prior caffeine use alter the cardiovascular and adrenomedullary responses to oral caffeine." The American journal of cardiology 52.7 (1983): 769-773.
  • Kalow, Werner, and Bing-Kou Tang. "Use of caffeine metabolite ratios to explore CYP1A2 and xanthine oxidase activities." Clinical Pharmacology & Therapeutics 50.5 (1991): 508-519.
  • Kashuba, Angela DM, et al. "Quantitation of three-month intraindividual variability and influence of sex and menstrual cycle phase on CYP1A2, N-acetyltransferase-2, and xanthine oxidase activity determined with caffeine phenotyping*." Clinical Pharmacology & Therapeutics 63.5 (1998): 540-551.
  • Kendler, Kenneth S., John Myers, and Carol A. Prescott. "Specificity of genetic and environmental risk factors for symptoms of cannabis, cocaine, alcohol, caffeine, and nicotine dependence." Archives of General Psychiatry 64.11 (2007): 1313-1320.
  • Lampe, Johanna W., et al. "Brassica vegetables increase and apiaceous vegetables decrease cytochrome P450 1A2 activity in humans: changes in caffeine metabolite ratios in response to controlled vegetable diets." Carcinogenesis 21.6 (2000): 1157-1162.
  • Le Marchand, Loïc, et al. "Lifestyle and nutritional correlates of cytochrome CYP1A2 activity: inverse associations with plasma lutein and alpha-tocopherol." Pharmacogenetics and Genomics 7.1 (1997): 11-19.
  • Netsch, M. I., et al. "Induction of CYP1A by green tea extract in human intestinal cell lines." Planta medica 72.06 (2006): 514-520.
  • Paganini-Hill, Annlia, Claudia H. Kawas, and María M. Corrada. "Non-alcoholic beverage and caffeine consumption and mortality: the Leisure World Cohort Study." Preventive medicine 44.4 (2007): 305-310.
  • Rasmussen, Birgitte B., et al. "The interindividual differences in the 3-demthylation of caffeine alias CYP1A2 is determined by both genetic and environmental factors." Pharmacogenetics and Genomics 12.6 (2002): 473-478.
  • Schrenk, D., et al. "A distribution study of CYP1A2 phenotypes among smokers and non-smokers in a cohort of healthy Caucasian volunteers." European journal of clinical pharmacology 53.5 (1998): 361-367. 
  • Sinha, Rashmi, et al. "Pan-fried meat containing high levels of heterocyclic aromatic amines but low levels of polycyclic aromatic hydrocarbons induces cytochrome P4501A2 activity in humans." Cancer Research 54.23 (1994): 6154-6159. 
  • Tarnopolsky, Mark, and Cynthia Cupido. "Caffeine potentiates low frequency skeletal muscle force in habitual and nonhabitual caffeine consumers." Journal of applied physiology 89.5 (2000): 1719-1724.
  • Vistisen, Kirsten, Henrik E. Poulsen, and Steffen Loft. "Foreign compound metabolism capacity in man measured from metabolites of dietary caffeine." Carcinogenesis 13.9 (1992): 1561-1568.
  • Welfare, Mark R., et al. "Detailed modelling of caffeine metabolism and examination of the CYP1A2 gene: lack of a polymorphism in CYP1A2 in Caucasians." Pharmacogenetics and Genomics 9.3 (1999): 367-376.
  • Yang, Amy, Abraham A. Palmer, and Harriet de Wit. "Genetics of caffeine consumption and responses to caffeine." Psychopharmacology 211.3 (2010): 245-257.
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