I recently did an ancestry gene test and discovered that I'm in the 50% of the population who are slow caffeine metabolisers (CYP1A2 AC and CC genotype). I was a little curious to find out what this means and what positive or negative effects caffeine can have on our health and performance?
Numerous studies have linked caffeine with positive health effects like reduced risk of obesity, diabetes, and heart disease. However, recent research suggests that the effects of coffee on health aren’t the same for everyone, and may depend on genetics and other factors.
I love coffee—and I know I’m not alone.
Caffeine is the most widely consumed psychoactive substance globally, 90% of adults consume caffeine regularly (coffee, tea, cola, energy drinks, pre-workout supplements and more).
We've been told that coffee is healthy for us, but what if it not?
Caffeine is metabolised by an enzyme in the liver that is encoded by the CYP1A2 gene. Unfortunately, about 50% of the population has a variant in the CYP1A2 gene that leads to the slow metabolism of caffeine.
Certain genes can dictate the metabolism of caffeine. Fast caffeine metabolisers take between 4-6 hours to lower caffeine levels by half, the half-life of caffeine. A slow caffeine metabolisers take between 8-10 hours to drop caffeine levels by half. Those with neither the fast or slow genes take between 4-8hr to drop caffeine levels by half. The half-life of caffeine is not constant.
It worth noting that the half-life of caffeine in the body can not simply be measured by how stimulated you feel.
Following oral consumption, caffeine is absorbed into the blood and body tissues. Absorption takes 30-45 minutes [3]. Caffeine is then distributed throughout the body and it easily passes into the brain, breast milk and the placenta.
Several individual, non-genetic factors, can also impact the way caffeine is metabolised and utilised in the body, including liver disease, smoking, diet, pregnancy, alcohol intake, medications, and metabolism [5].
The use of oral contraceptives almost doubles caffeine half-life, mainly during the second half of the menstrual cycle (the luteal phase) [6].
Alcohol intake of 50g per day prolongs caffeine half-life by 72% and decreases caffeine clearance by 36% [7].
Grapefruit juice decreases caffeine clearance by 23% and prolongs half-life by 31% [8].
During pregnancy, caffeine metabolism is reduced, particularly during the third trimester [9].
Further research into caffeine could categorise populations by genotype and consider caffeine consumption's impact on various functions. A better understanding of the factors influencing caffeine intake could help identify critical factors affecting the quality of life and/or susceptibility to disease [7,10].
As with all studies, a significant proportion of participants can experience a "positive" outcome of the tested hypothesis. But, this doesn't mean the hypothesis holds for everybody. What about the people in the study who had "negative" experience or no significant change at all?
The one size fits all dietary advice is often calculated as an average response of the population. As an example, the dietary guidelines tell us to consume two servings of dairy per day. People with lactose intolerance or with a whey or casein sensitivity will not flow this advice general advice.
What are the negative impacts of caffeine?
Caffeine is a stimulant drug, which means it speeds up the messages traveling between the brain and the body. The over-consumption of caffeine can cause feelings of anxiety, hyperactivity, nervousness and sleep disturbance [1]. Caffeine is one of the most comprehensively studied ingredients in the food supply. Yet, despite our considerable knowledge of caffeine and centuries of safe consumption in foods and beverages, questions and misconceptions about the potential health effects associated with caffeine persist.
"Caffeine can negatively affect our health if it is not consumed in moderation. Caffeine can cause nutrient depletion of important nutrients, like vitamin B6, and interfere with nutrient absorption of essential minerals, including calcium, iron, magnesium, B-vitamins, and vitamin-D." [2]
Slow caffeine metabolisers are:
Associated with a higher risk of heart disease [19]
Associated with a higher risk of hypertension [20]
Associated with impaired fasting glucose [21]
May not have the protective effects against some cancers that it appears to for “fast metabolisers” [22,23]
A recent umbrella review of 218 meta-analyses concluded that coffee presented statistical harm only in pregnancy and possible fracture risk for women. [4]
That said, in some cases, caffeine appears to be beneficial even for slow metabolisers. For example, caffeine is neuroprotective and reduces the risk of Parkinson’s disease in both slow and fast metabolisers. [24] Further research has even shown that fast—not slow—metabolisers of caffeine may be at higher risk of bone loss. [25]
Caffeine and blood pressure
A 2018 study aimed to investigate whether the CYP1A2 genotype influenced the blood pressure response to caffeine. [11] Thirty-seven participants (19–50 years old) took place in the study and were categorised according to genotype: “fast metaboliser” and "slow metaboliser.”
All groups had their blood pressure assessed before and 1 hour after caffeine ingestion. It was observed that the slow metaboliser had an increase in blood pressure compared to the fast metabolisers. [11]
Caffeine and Sleep
Caffeine is associated with a higher core body temperature. Lower core body temperature has been associated with improved sleep quality and quantity. A 2014 study showed that consuming caffeine at night increased latency to sleep, increased wakefulness, decreased sleep efficiency, and decreased slow-wave and REM sleep quality and quantity [12,13].
Obviously, our sleep has a downstream impact on both our health and performance and many health professionals agree that caffeine should not be consumed after 2 pm. (2pm + caffeine half-life (8hrs) = 10pm).
Caffeine and sports performance:
A 2018 study took 101 competitive endurance athletes and split them into “slow metaboliser," "fast metabolisers," and "normal metabolisers".
The “slow metaboliser" cycling times were slower by 4.8% after consuming 2mg of caffeine per kilogram of body weight and slower by 6.8% after consuming 4mg of caffeine per kilogram of body weight.
The “fast metaboliser” cycling time was 13.7% faster after consuming 4mg of caffeine per kilogram of bodyweight versus placebo.
No effects were observed among those who did not have fast or slow metabolism genes. The study concluded that consuming 2-4mg of caffeine only improved performance in those who had the fast metabolisers gene [14].
In 2018 Saunders conducted a randomised controlled trial in elite male athletes. One-hundred thirteen male athletes who competed in sports characterised by either endurance (e.g., marathon, triathlon, cycling, cross-country skiing), power (e.g. boxing, volleyball, dragon-boat, powerlifting), or a mixture of power and endurance (e.g., soccer, rugby, basketball, swimming) took part in the study [15].
Saunders aims to determine whether variation in caffeine metabolism modifies ergogenic (athletic power and endurance) effects of caffeine in a 10-km cycling trial. Anthropometric data, maximum aerobic capacity (VO2 peak), questionnaire on general health, caffeine intake, sports history, and saliva for DNA determination were all measured. Before the cycle time trial, physical tests were vertical jump, grip strength, and the Wingate 4 test (measures anaerobic power and capacity). [15]
Among the "fast caffeine metabolisers" 35 (71%) and 40 (82%) out of 49 men performed better during 2mg/kg or 4 mg/kg, respectively, compared to placebo. Among the "slow caffeine metabolisers" genotype, 2 (25%) and 1 (12%) out of 8 men performed better during 2mg/kg and 4 mg/kg caffeine, respectively, compared to placebo. [15]
Of those that were neither fast nor slow caffeine metabolisers, 26 (59%) and 28 (64%) out of 44 men performed better during 2mg/kg or 4 mg/kg caffeine, respectively, compared to placebo.
Heart rate increased by 4bpm in the "slow metaboliser group" after consuming both 2 and 4mg/kg. Saunders concluded that "caffeine had a significant positive effect in the timed cycle trial, but only for the fast metabolisers.” [15]
In 2015, Paton et al. reported that chewing gum containing 3-4 mg/kg caffeine improved performance in 20 male and female cyclists [16]. However, 13 (65%) were deemed positive responders, 5 (25%) negative responders, and 2 (10%) non-responders. The difference was assumed to be due to the rate of caffeine metabolism or absorption.
A 2020 study took 22-men, 13 fast metabolisers and 9 slow metabolisers and compared "movement velocity and power output in the bench press exercise with loads of 25, 50, 75, and 90% of one-repetition maximum (1RM); quality and quantity of performed repetitions in the bench press exercise performed to muscular failure with 85% 1RM; vertical jump height in a counter movement jump test; and power output in a Wingate test." [17]
The results of this study concluded that caffeine ingestion enhanced movement velocity and power output across all loads:
the quality and quantity of performed repetitions with 85% of 1RM
vertical jump height
power output in the Wingate test
The researchers did not find a significant genotype × caffeine interaction effect any of the performance outcomes. They concluded that resistance-trained men may experience acute improvements in resistance exercise, jumping, and sprinting performance following the ingestion of caffeine [17].
The mechanism of caffeine’s effects on athletic performance is not yet clear. Caffeine may reduce cardiac blood flow during exercise by blocking adenosine receptors [18], which could reduce performance in slow metabolisers and cause vasoconstriction to both the heart and skeletal muscles. Resting cardiac blood flow may not be affected compared to cardiac blood flow during exercise.
It seems that slow caffeine metabolisers should avoid caffeine before endurance-based exercises. Further research is needed to determine the impacts of caffeine under different training protocols.
How much caffeine is in your cup of coffee?
You can expect to get around 95mg of caffeine from an average cup of coffee.
However, this amount varies between different coffee drinks and can range from almost zero to over 500 mg. The caffeine content of coffee depends on:
Type of coffee beans: There are many coffee beans varieties available, which may naturally contain different amounts of caffeine.
Roasting: Lighter roasts have more caffeine than darker roasts, although the darker roasts have a deeper flavour.
Type of coffee: The caffeine content can vary significantly between regularly brewed coffee, espresso, instant coffee and decaf coffee.
Serving size: “One cup of coffee” can range anywhere from 30–700 ml (1–24 oz), greatly affecting the total caffeine content.
You might be surprised to learn that although espresso has more caffeine per volume (30–50 ml has around 63 mg) than regular coffee, it usually contains less caffeine per serving since espresso servings tend to be small.
Caffeine recommendations:
We live in exciting times. At some point in the future, we’ll be able to create much more precise nutritional recommendations based on our genotype and epigenetic factors such as health status, lifestyle, physical activity, and goals.
The most obvious conclusion is that it’s impossible to make a general statement about the health impacts of caffeine. The answer to the question, “Is coffee good for me?” is: “It depends.”
From the conflicting data on caffeine, even within a particular genotype the effects are variable. In other words, some slow metabolisers might be adversely affected by caffeine where others aren’t, and the opposite might be true for fast metabolisers.
If caffeine ingestion causes you to experience nervousness, insomnia, gastrointestinal upset, hyperactiveness, irritability, anxiety, muscular pain, and/or headache, then you may have the genotype that does not benefit or, even worse, performs poorly after caffeine ingestion.
If you would like to find out whether you’re a “slow” or “fast” metaboliser. You can get this kind of genetic data through companies like 23andme or Ancestry.
For recreational athletes, coffee before training is probably going to be better than taking pre-workout supplements containing high amounts of caffeine. Save your money on "pre-workout" caffeine supplements as most of them have a large amount of caffeine that may give you a “buzz” but won’t deliver any real performance benefits. The most effective caffeine dose is 2-4mg/kg bodyweight (there's no additional benefit once the dose is greater than 5mg/kg).
I've not given up my morning cup of coffee, but these days I only consume one (maybe 2) cups of coffee in the morning after eating. I’m not a fan of consuming caffeine on an empty stomach as it seems to speed up the plumbing if you know what I mean. I also take my zinc and b-vitamins in the morning before breakfast and I know that caffeine can block the absorption of these essential nutrients.
REFERENCES:
Effects of coffee/caffeine on brain health and disease: What should I tell my patients? Astrid Nehlig. 2015
Effects of caffeine on health and nutrition: A Review. Tsedeke Wolde. 2014.
Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. B B Fredholm, et al. 1999
Coffee consumption and health: umbrella review of meta-analyses of multiple health outcomes. Poole R, et al. 2017
Interindividual Differences in Caffeine Metabolism and actors Driving Caffeine Consumption. Astrid Nehlig. 2018
Metabolism of caffeine and other components of coffee, in Caffeine, Coffee and Health. Le Marchand L, et al. 1997
Influence of alcohol and caffeine consumption on caffeine elimination. George J, et al. 1986
Lacking effect of grapefruit juice on theophylline pharmacokinetics. Fuhr U. et al. (1995)
Pregnancy-induced changes in drug metabolism in epileptic women. Bologa M, et al. 1991
Effects of coffee on driving performance during prolonged simulated highway driving. Mets M.A, et al. 2012
Coffee, caffeine, and sleep: A systematic review of epidemiological studies and randomized controlled trials. Clark, I, et al. 2016
Effects of caffeine on skin and core temperatures, alertness, and recovery sleep during circadian misalignment. McHill A.W. et al. (2014)
The influence of CYP1A2 genotype in the blood pressure response to caffeine ingestion is affected by physical activity status and caffeine consumption level. Rogerio NogueiraSoares, et al. 2018
Caffeine, CYP1A2 Genotype, and Endurance Performance in Athletes. Nanci Guest, et al. 2018
Caffeine, Genotyping, and Athletic Performance. Paul Richard Saunders. 2018
Effects of caffeine chewing gum on race performance and physiology in male and female cyclists. Paton C, et al. 2015
CYP1A2 genotype and acute effects of caffeine on resistance exercise, jumping, and sprinting performance. Jozo Grgic, et al. 2020
Caffeine impairs myocardial blood flow response to physical exercise in patients with coronary artery disease as well as age-matched controls. Namdar M, et al. 2018
Coffee, CYP1A2 genotype, and risk of myocardial infarction. Marilyn C Cornelis, et al. 2006
CYP1A2 genotype modifies the association between coffee intake and the risk of hypertension. Paolo Palatini, et al. 2009
Association of coffee consumption and CYP1A2 polymorphism with risk of impaired fasting glucose in hypertensive patients. Paolo Palatini, et al. 2015
Association of caffeine intake and CYP1A2 genotype with ovarian cancer. Marc T Goodman, et al. 2003
The CYP1A2 genotype modifies the association between coffee consumption and breast cancer risk among BRCA1 mutation carriers. Joanne Kotsopoulos , et al. 2007
Association between caffeine intake and risk of Parkinson's disease among fast and slow metabolizers. Eng-King Tan, et al. 2007
Coffee consumption and CYP1A2 genotype in relation to bone mineral density of the proximal femur in elderly men and women: a cohort study. Helena Hallström, et al. 2010