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Coffee: Who can drink and who should limit? Ask your genes

Posted by : Rashida , on Mon, Dec 31, 2018
Coffee: Who can drink and who should limit? Ask your genes

Coffee rich in polyphenols, including chlorogenic and caffeic acid, lactones, diterpenes, niacin(Vitamin B3) and its precursor trigonelline, magnesium and potassium prevents diabetes, stroke & cancer excellent for health…but is it good for you? Ask your genes.

Caffeine is a stimulant, alkaloid (1) which is found naturally in coffee, tea, cacao beans, guarana and kola nuts, though it has been identified in more than 60 plant species (2). It is the most widely consumed psychoactive substance in the world, and it has been estimated that ∼90% of adults consume caffeine on a regular basis. Caffeine can exert a wide variety of physiologic effects that range from adverse (e.g., anxiety, restlessness, increased heart rate, tremors, agitation, nervousness, and insomnia) to pleasurable (e.g., alertness, elevated mood, and increased energy) (3).



Caffeine molecule

Source: PubChem (

The pathway of caffeine in our body

Caffeine metabolism mainly involves liver, central nervous system and kidney. Caffeine easily passes through body membranes, enters the bloodstream through the lining of the mouth, throat, and stomach. Caffeine is rapidly and completely absorbed in humans, with 99 percent being absorbed within 45 minutes of ingestion (4). Caffeine travels through the small intestine, where it is absorbed, then metabolized in liver cells and is mostly metabolized through the liver enzyme cytochrome P450 1A2 (CYP1A2). The peak plasma level for caffeine range from 6-10mg/L and the mean time to reach peak concentration ranged from 30 minutes to 2 hours (5). Paraxanthine constitutes the highest percentage (84%) of metabolite produced when caffeine is broken down followed by theobromine (12%) and theophylline (4%) (6).


Paraxanthine increases lipolysis, that leads to elevated glycerol and free fatty acid levels in the blood plasma. Theophylline relaxes smooth muscles in the brochi, which has been beneficial to those with asthma and is the reason why after drinking caffeine a person often feels the need touse the bathroom as it is affecting the smooth muscles of the colon.  Theobromine increases the amount of oxygen and nutrients that can be used by the brain and muscles.The caffeine metabolites are then filtered by the kidneys and they exit the body with the urine (7).

Caffeine action in the brain:

Caffeine as well as theophylline and paraxanthine, caffeine metabolites, similar to adenosine moleculebind to the adenosine receptors and inhibits the effects of adenosine.


Caffeine’s effect on blocking adenosine could be possibly the reason for influencing the disruptions to sleep, alertness following caffeine ingestion Adenosine has been shown to down regulate various neurotransmitters such as dopamine, serotonin, glutamate, acetylcholine and norepinephrine (8). Evidence suggests that dopamine system works efficiently when adenosine is blocked by caffeine. Elevated levels of adenosine in the blood cause the adrenal glands to release adrenaline, which further adds to the feelings of alertness and energy (9).

Caffeine takes a certain amount of time to work through your system. A study showed that the half-life of caffeine in healthy adults is 5.7 hours, paraxanthine (~3 h), theobromine ( ~6 h ) and theophylline ~7 h respectively(10).However the clearance of caffeine can vary to up to 40-fold within and between individuals depending on age, ethnicity, medical conditions, smoking status, genetics and drug interaction.  For instance, Asian and African populationsappear to metabolize caffeine at slower rate than Caucasians (11). Likewise,people with a specific variation of the gene PDSS2 process caffeine more slowly than others and therefore, need less coffee for the same stimulant effects (12).


Genetics of caffeine metabolism:

Caffeine metabolism is influenced by several other genes.CYP1A2 gene contains instructions for an enzyme that breaks down 95% of the caffeine and basically determines how quickly the body breaks down and clears away caffeine, depending on which individuals are commonly referred to as fast and slow metabolisers. Slow metabolizers are likelyto feel the effects of caffeine for a longer time and fast metabolizer are likely to break down and get rid of caffeine more quickly from your system (13).AHR gene contains instructions for a protein that is responsible for the production of the CYP1A2 enzyme,  determines how the CYP1A2 gene is switched on and off (14). ADORA2A gene provides instructions for the adenosine receptor A2A found in the brain and play a role in the down regulation of dopamine and glutamate release (15).


GENES involved in caffeine metabolism (16)



Involved in caffeine metabolism


Caffeine sensitivity


Influences rewarding effects of caffeine

Genes near GCKR & MLXIPL

Involved in glucose and lipid metabolism


Associated with coffee consumption


Associated with caffeine induced anxiety


Caffeine is associated with catecholamine release.


Caffeine consumption


Factors that influences caffeine metabolism:

Dietary factors:

A number of dietary factors also affect caffeine metabolism.Grapefruit juice consumption decreases caffeine clearance by 23% and prolongs half-life by 31% (17).

Consumption of broccoli and brassica vegetables increased caffeine clearance through increased CYP1A2 activity whereas apiaceous vegetablesinhibits CYP1A2 activity (18).

The flavonoid, quercetin, found widely in fruit and vegetables, affects the metabolism of caffeine and paraxanthine and mainly decreases the urinary excretion of the latter compound by 32%; it also changes the excretion of several other metabolites of caffeine (19).

Heterocyclic amines and polycyclic aromatic hydrocarbons present in chargrilled meat are likely to induce CYP1A2 activity (20).

Smoking: Smoking stimulates caffeine clearance (21), research suggests that some individuals with certain genotype metabolize caffeine at 1.6 times the rate of the other genotypes.

Pregnancy: Maternal coffee consumption and CYP1A2 activity during pregnancy have been associated with fetal survival and growth. High maternal CYP1A2 activity was associated with spontaneous abortion and intrauterine growth problems. For instance, women with certain genotypes who consumed more than 300 mg caffeine per day had an increased risk for recurrent pregnancy loss (22).

Ethnicity: Ethnic differences also exist for CYP1A2 activity. Lower enzyme activity was measured by caffeine metabolism in Asian and African populations compared with Caucasians (23).

Others: Factors such as oral contraceptives, pregnancy, ethnicity, age, and smoking, various medicines(fluvoxamine, omeprazole) (24) have all been suggested to affect the metabolism of caffeine (25).


Increases speed of caffeine metabolism              (makes caffeine effect abates more quickly)

Decreases speed of caffeine metabolism         (makes caffeine’s effects lasts longer)

Cruciferous vegetables ( broccoli, cauliflower, cabbages, radishes)

Grape fruit juice, Apiaceous vegetables ( carrots, celery, parsnips, parsley)



Grilled meat


Tobacco, smoke

Liver disease

Lean people

Obese people

Younger people

Older people


The effect of CYP1A2 on interindividual differences of caffeine metabolism:

This enzyme is involved in synthesis of cholesterol, steroids and other lipids and determines the speed of caffeine metabolism. It is responsible for the demethylation of caffeine into different metabolites such as paraxanthine, theobromine, and theophylline.Fast metabolizers might not feel anything at all (called hyposensitivity), while slow metabolizers could feel jittery after drinking the same amount (hypersensitivity).  The AHR gene also effects how caffeine-sensitive a person will be because it works to turn the CYP1A2 gene on and off. Those who drink four or more cups of coffee per day are more likely to be carriers of this AHR gene variant (27).

Inducers and Inhibitors of CYP1A2 enzyme (28)



Broccoli, brussel sprout, charcoal- grilled meat, insulin, methylcholanthrene, modafinil, nafcillin, B- napthoflavone, omeprazole, tobacco smoke

Amiodaroe, cimeitiine, ciprofloxacin, flurorquinolones, fluvoxamine, furafylline interferon, methoxsalen, mibefradil, ticlopidine.


Effect of ADORA2A on interindividual differences of caffeine metabolism:

Adenosine receptors are partly responsible for caffeine tolerance. Animal studies have shown that chronic intake of caffeine increases the density of A1 receptors, which are believed to be responsible for caffeine tolerance. Whereas another study (29) shows that ADORA2A may affect habitual caffeine intake by regulating the appetitive properties of caffeine and are associated with caffeine induced anxiety and sleep impairment among individuals with certain genetic variations (30) Such individuals are commonly referred to as “ Caffeine sensitive” individuals.

Interactions between adenosine and dopamine receptors play a key role in dopamine-potentiating effects of caffeine. The dopamine system is implicated in the rewarding effects of cocaine and opioids, as well as natural rewards such as food and sex. Few studies have directly examined the effect of dopamine polymorphisms on caffeine response in human subjects and found that a polymorphism in DRD2 (rs1110976) was associated with caffeine-induced anxiety in the Caucasian subjects. An interaction was reported between ADORA2A rs5751876 and DRD2 rs1079597 that was associated with higher anxiety than either polymorphism alone (31).

Caffeine and health:

The role of caffeine in cardiovascular disease has also been extensively studied (32). Acute ingestion of caffeine or coffee, but not decaffeinated coffee, invokes a rise in systolic and diastolic blood pressure, increases in catecholamine release, and vasodilatation (33) However, effects of chronic caffeine consumption in habitual drinkers are quite different. Some epidemiological studies find that regular coffee intake slightly increases blood pressure, while others find no difference. Whether caffeine is implicated in cardiovascular diseases is still being debated.One study found that intake of caffeinated coffee was associated with increased risk of nonfatal myocardial infarction in individuals homozygous for the slow allele CYP1A2*1F, marked by A➔C substitution at position 734 (34).

In another prospective study, the risk of acute myocardial infarction in heavy coffee drinkers was found to be higher in subjects possessing allele for lower catechol-O-methyl transferase (COMT) activity. (35)COMT is the main enzyme responsible for metabolism of catecholamines, which characterize body’s response to physiological and psychological stress and have been shown to damage myocardial cells at high concentrations. Caffeine may represent a chemical stress to the body due to its ability to potentiate catecholamine release.The finding of lower COMT activity with higher risk of myocardial infarction points to involvement of circulating catecholamines in caffeine’s effect on cardiovascular system, with the implication that slow metabolizing individuals could be at increased risk due to decreased ability to handle the stress associated with caffeine-induced catecholamine response.

Odds ratios of acute coronary events in 773 men initially free from CHD by joint categories of coffee intake and COMT genotype; predicted from a logistic model with age, smoking, family history of CHD, plasma vitamin C concentration, systolic blood pressure, serum HDL and LDL cholesterol concentration, and diabetes as covariates.




Caffeine intake amount

For SLOW metabolizers

For FAST metabolizers

1-2 cups (200 mg)/day

Does not increase heart attack risk


2-3 cups (300 mg/day)

Increased risk of heart attack by 36%

Decreased heart attack risk by 22%

4 cups or more/day

Increased risk of heart attack by 64%


4 cups or more/day for individuals <50 years of age

Increased risk of heart attack by 4 folds


100 mg/day for women with miscarriages

Increased risk of recurrent pregnancy loss or reduced fertility

No increased risk of recurrent pregnancy loss or miscarriages


Caffeine content in common foods:



Caffeine content (mg)/serve

Beverages, tea, instant, unsweetened, powder

40 /tsp

Beverages, coffee, instant, regular, powder

63 /tsp

Candies, dark chocolate coated coffee beans

336 /tsp

Beverages, coffee, instant, mocha, sweetened

47 /tsp

Cocoa, dry powder, unsweetened

12 /tsp

Beverages, coffee, brewed, espresso, restaurant-prepared

63 /tsp

Beverages, tea, instant, decaffeinated, unsweetened


Beverages, coffee, instant, decaffeinated, powder

2 / tsp

Beverages, Energy drink, RED BULL

75/8 fl oz

Chocolate, dark, 60-69% cacao solids

96/bar 112 g

Chocolate, dark, 70-85% cacao solids

81/bar 101 g

Chocolate, dark, 45- 59% cacao solids

70/bar 162 g

Candies, milk chocolate

9 / bar 44g

Beverages, carbonated, cola, fast-food cola

21/ 12 fl oz




Caffeine and sports performance:

Caffeine is well known to enhance sports performance. In fact, it’s really one of the few ergogenic supplements that is consistently shown to work. Even in this realm, however, results are quite variable. For example, some studies shown an overall enhancement in performance with caffeine, but even within that, improvements ranging from 5% to 156% have been seen in the same study. Some individuals may even perform worse. Slow metabolizers of Caffeine experiences decreased performance by an average of 13.7% in a cycle performance time trial as compared to fast metabolizers at different doses of Caffeine at the same exercise (36).

Another study showed that both 2 and 4 mg/kg caffeine improve 10-km cycling time, but only in those with certain genotypes whereas caffeine had no effect  or even diminished performance in individuals with other genotypes(37).For athletes interested in using caffeine to augment their performance, it may be beneficial to know your CYP1A2 genotype before your excursion into coffee-loading. Whether or not you can boost your endurance performance using caffeine may rely on how well you are sensitive to caffeine.


IN A NUTSHELL: Key Take Aways for clinicians

Fast metabolisers:

  • Metabolizes caffeine normally due to normal CYP1A2 enzyme activity.
  • Recommended up to 400 mg caffeine per day.
  • Lean and younger people are likely to metabolise caffeine faster than obese and older people.

Slow metabolisers:

  • Likely to have impaired metabolism of caffeine due to decreased CYP1A2 enzyme activity.
  • Likely to experience anxiety and jitters associated with caffeine consumption.
  • Grape fruit juice, apples, peppers, red wine, dark cherries and berries ( blue berries, bilberries, black berries and others), tomatoes, cruciferous vegetables such as broccoli, cabbage and sprouts and leafy green veggies, spinach, kale are known inducers of the enzyme and are likely to speed up caffeine metabolism.
  • Recommended < 200mg caffeine/ day.





Author Bio : Rashida Kadanawala, is a Clinical Dietitian Trainer, at Administration of Food and Nutrition, Ministry of health, Kuwait for over 7 years. Besides her role in training dietitians and developing programs; her zest lies in nutrition consultation and education in hospital and community settings. Rashida believes in empowering dietitians with evidence-based practice and offer best personalized Nutrition for patients, which is possible through Nutrigenetics. She focuses on staying fit by lifting weights, taking walks, yoga and eating real food. Her passion is to explore various aspects of Nutrition Science and she believes continuous learning and sharing is the only way to grow in all ventures. Rashida, an Indian by nationality, loves exploring new corners of the world, especially if they include a good wave to surf or a nice slope to descend.