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Genes, caffeine, and performance. Should we really care?

Updated: Nov 15, 2022

Genetic testing is becoming more and more popular, so popular that you can test pretty much everything from lactose intolerance to the risk of having breast cancer.

I did my first genetic testing many years ago, analysing my dietary and physical performance profile. At that time it was quite new and exciting, and later, when I became a nutritionist, I even enrolled for a genetic specific training to learn about the association of various gene variations with certain food responses. Although i strongly believe there is a huge potential in this field, at the moment, we are at the very beginning of starting to understand the relationship between genes and foods.

The relationship between genome and nutrition is bidirectional.

The genetic background of one person can indeed define the metabolic response, nutritional state, and the susceptibility to nutrient related diseases. But the nutrients can also up - or down- regulate the gene expression, and consequently, the metabolic responses.

It’s a fascinating, and extremely complex area of research. But let’s just focus on caffeine.

I discovered that my genetic makeup puts me in a category of “slow caffeine metabolisers”. As usual, I spent a bit of time analysing existing research trying to understand what exactly doest this mean. My main question was whether caffeine may really a positive or negative effect on my health and physical performance?

Overall, the impact of caffeine on our health is mixed. The caffeine consumption seems to reduce the risk of obesity, diabetes, mental health issues, Parkinson's disease and heart disease. However, recent research also suggests that the effects of coffee on health aren’t the same for everyone and may depend on genetics and other factors.

You might have heard many contradictory messages and health advice about caffeine. Some advocate a complete caffeine abstinence, while others praise health benefits of coffee.

I love coffee, and I bet I’m not alone. If you were reading my previous posts, you know that I’m not into any radical statements, especially in complex subjects like caffeine. My approach is really to find the perfect balance in nutrition. And for each of us this balance is very different. How to find it – is the million-dollar question.

Caffeine metabolism

So, let’s look into caffeine metabolism first.

95 % of caffeine metabolism is done in the liver, by an enzyme called the cytochrome P450 1A2. This enzyme is encoded by the CYP1A2 gene.

About half of us has a variant in the CYP1A2 gene that is supposedly associated with a slow caffeine metabolism.

When you are a slow metaboliser, the circulation of the caffeine in your body may take 5 times longer than those who metabolise it quicker. The half-life of caffeine (or the time needed for the concentration of the chemical substance to be reduced by half) ranges between 2 and 10 hours. It means that if you are a slow metaboliser, you may potentially have a higher cumulative effect of caffeine because it just stays in your system longer.

Hence, if you keep drinking a lot of coffee but your genetic profile put you in a slow metaboliser category, you might potentially experience more negative health effects compared to fast metabolisers.

The half-life of caffeine in the body cannot simply be measured by how stimulated you feel. That’s why, in addition to caffeine metabolism, it’s also important to look at what effect caffeine has on the central nervous system

Caffeine effect on central nervous system

There is another widely researched gene, called ADORA2 which is responsible for its stimulating effect. Again, genetic testing may show whether you have certain polymorphisms in the ADORA2 genome, contributing to your individual sensitivity of caffeine on sleep. I found that this ADORA2A gene contains at least 6 identified (as of 2019) polymorphisms associated with sleep-sensitivity to caffeine.

Quick note - most commercially available genetic tests will only check for 1 polymorphism in CYP1A2 gene, but not in ADORA2A.

That’s only half of the full picture.

The 2nd (and arguably more important) half is actually related to non-genetic factors, impacting the way caffeine is metabolised and utilised in the body. These include the diet, liver disease, medication, smoking, pregnancy, contraceptive pills and alcohol intake.

Even a grapefruit juice can decrease caffeine clearance by 23% and prolongs half-life by 31%.

Interestingly, oral contraceptives can double caffeine half-life. If you are on oral contraceptive or hormone replacement therapy, you might need to keep an eye on your caffeine consumption.

Quick note on the safety of caffeine.

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 that the safe amount of caffeine intake is close to 400mg /day (~4 cups of coffee). If you want a bit more precise figure, it's generally up to 6 mg/ kg of body weight/day for those with normal sensitivity.

But what if you use caffeine in your sport nutrition for its ergogenic (performance enhancing) effect, in addition to your usual coffee consumption?

Since 2005 when WADA and IOC removed the ban on caffeine, more and more recreational and professional athletes use bars, gels, and other sport nutrition products, does anyone who use stop nutrition products even know how much caffeine is in his/her diet per day?

And how much caffeine is safe for someone, who belongs to the category of slow metabolisers, like I am and half of population ?

Well, to get an answer, you'll need to:

  • estimate carefully your caffeine intake form foods and supplements,

  • observe your personal sensitivity (sleep, anxiety, headaches, nervousness) to caffeine,

  • account for genetic & especially all non-genetic factors.

So, what does science tell us about caffeine and physical performance, based on our genetic makeup?

I'm particularly interested in endurance sports, especially in distance running.

Unfortunately, we don't have that many quality endurance studies for this topic. They are typically performed in a short duration (between 30 and 60 min) in a restricted setting on a bike, sometimes on non-exercising population. And most of them are limited to only 1 polymorphism in the CYP1A2 gene association analysis.

After doing scientific literature search, i selected only few experiments that seem to be more related to the endurance.

A 2018 study recruited 101 competitive athletes (participants exercise on average 8h+/week,, for at least 3 yr. in their given sport). They were from 3 different fields: endurance (triathlon, marathon, cycling), power (powerlifting, boxing) or mixed (football, rugby, basket). These 101 participants were split into “slow metaboliser," "fast metabolisers," and "normal metabolisers".

The protocol was to cycle 10km. Not necessarily my definition of endurance, but that’s what we’ve got.

Study results were quite interesting.

The “slow metaboliser" cycling times were slower by 4.8% after consuming 2 mg of caffeine per kilogram of body weight and slower by 6.8% after consuming 4 mg of caffeine per kilogram of body weight.

Basically, the more caffeine they ingested, the slower was their cycling time trial result.

On the other hand, the “fast metaboliser” cycling time was 13.7% faster after consuming 4 mg of caffeine per kilogram of bodyweight versus placebo.

Unfortunately, out of 101 participants only 8 were in a "slow metaboliser" category. And among these 8 athletes, a very small proportion came from endurance category. The VO2Max in this group (averaging 44 +/- 12) was lower than in a “fast metaboliser group”. And they were also heavier (average weight 92.8 +/- 24 kg) than other participants, suggesting that they were probably not endurance athletes.

What this study really suggests, is that fast metabolisers may potentially benefit from higher doses of caffeine. But regarding slow metabolisers, I can’t draw any meaningful outcomes simply because the sample os participants was too small and not representative.

Salineto et al. (2017), Algrain et al. (2016) in their smaller studies couldn’t find any superior ergogenic effect of caffeine in “fast metabolisers”.

But they reported that caffeine is likely to cause nervousness, insomnia, gastrointestinal upset, hyper activeness, irritability, muscular pain and/or headache in the C (slow) vs the AA (fast) genotype. And these side effects can potentially impact the performance.

Womack et al., (2012) also looked at cyclists, genotype, and caffeine. I like this study more because it measured the performance at 40km distance (not 10 km or 3 km, which is not really my definition of endurance) in 35 participants with VO2Max at 59.35 +/- 9.7. Cyclists either got a placebo or 6mg/kg of caffeine in a capsule. The “fast” group improved their time trial by 4.9 %, however the “slow” group also improved their performance by only 1.8%. Again, the difference is still quite small to me to make a big claim.

The mechanism of caffeine’s effects on athletic performance is not yet clear. And an additional genetic element is even more difficult to account in a whole picture.

So, before I consider cutting out my morning coffee, I want to see more specific data under endurance training protocols. It would be great to combine more than 1 polymorphisms and to control for other genetic variations, for example related to pain, such as the bradykinin beta 2 receptor (BDKRB2).

I would also love to see more data on female athletes, given that there is an interaction between caffeine and female sex hormones. Unfortunately, most of the sport research is done on male athletes, so extra care should be taken before extrapolating the male findings to the female population.

What’s the conclusion?

The most obvious conclusion is that it’s difficult to make a general statement about the health impacts of caffeine. The answer to the question, “Is coffee good for me?” is: “It depends.”

If you are curious and want to get tested, I’d suggest having the largest possible raw genetic data (like 23&Me), because there is more than 1 gene and more than one SNP (single nucleotide polymorphisms) potentially involved in your individual response to caffeine. I personally found and checked at least 10 SNPs in my raw data, after going through many research papers, and I’m sure we will find many more additional SNPs associated with caffeine impact on health in the future. A lot of commercial companies promising to get you a sport performance advice based on your genetic profile profile will currently check 1 SNP or 2 SNP and charge you a significant amount of $$ for a meaningless conclusion, so save your money and don’t get trapped into this marketing ad.

From the mixed data on caffeine, even within a particular genotype, the effects can vary. 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. Remember all non-genetic factors that you need to consider!

If caffeine ingestion causes you to experience nervousness, insomnia, gastrointestinal upset, irritability, anxiety, muscular pain, and/or headache, then perhaps you may have the genotype that does not benefit or, even worse, impairs your physical performance after caffeine ingestion.

For recreational athletes, coffee before training is probably going to be better than taking pre-workout supplements containing high amounts of caffeine. The well-accepted dosage of caffeine to improve performance is between 3 and 6, 60 min before exercise.

And one more advice, don’t take any other vitamins or minerals at the same time as your morning coffee, you simply won’t properly absorb them.

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