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Jitters and Java: Your Genes May Affect Your Response to Caffeine

Your DNA has a say in your caffeine buzz, but it’s still not clear how genes affect gut sensitivity to caffeine.

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For most people, ingesting small or moderate amounts of caffeine (say 2-6 mg per kg of body mass) improves physical performance and can also lessen mental fatigue, especially when someone is short on shut-eye. Some people seem to think that more is always better, including when it comes to caffeine use, but the truth is that crushing caffeine is often a recipe for problems. Still, there is wide variation in how people respond to caffeine. One person might be able to down lattes all day long with no ill effects, while another may be stricken with jitters and stomach distress with a single energy drink.

While there are undoubtedly several reasons behind this variability in the response to caffeine, genetics appear to be one of the key factors. This isn’t really a surprise, as people’s genes affect practically every behavior or physiological response they have, from their fondness for cruciferous vegetables to their preference for different types of humor. (Personally, I’m a broccoli lover who appreciates the cringe-type comedy of The Office.) If you can figure out a way to reliably measure a human trait or behavior, it’s basically guaranteed that there is going to be some amount of genetic contribution to that characteristic.

As it relates to athletic performance and caffeine supplementation, the gene that has most often been studied encodes for something called CYP1A2, a member of the cytochrome P450 superfamily of enzymes. These particular enzymes are responsible for making some essential substances your body needs (like cholesterol) as well as metabolizing drugs and other foreign substances like caffeine. Approximately 90% of caffeine metabolism is carried out by the CYP1A2 enzyme, making it a strong candidate for examining how people’s genetics influence their responsiveness to caffeine ingestion.

Another gene that may be influential when it comes to caffeine responsiveness is ADORA2A, which encodes for a receptor (adenosine receptor A2A) that caffeine interacts with. Adenosine receptors are found in your brain (among other tissues), and caffeine works on them to help maintain vigor, wakefulness, and mental acuity. Basically, caffeine binds to these receptors and prevents adenosine, a neural-slowing substance, from making you feel mentally and physically knackered.

Over the past few years, the growing availability of direct-to-consumer genetic testing companies has allowed the public to get their genes analyzed for any and all manner of reasons. I’ve always wondered about these services but was never curious enough to pony up the dough for a test. However, as I was writing about caffeine in my book The Athlete’s Gut, my interest in subjecting myself to this sort of testing was piqued. What finally pushed me to get it done was working with a student in our lab who has an interest in doing research on the topic of caffeine, performance, and genetics. I started searching the web for companies that test for both CYP1A2 and ADORA2A, and I ultimately came across one (Orig3n) that was offering a nice holiday discount.

After ordering Orig3n’s test, it took just a few days for the collection kit to arrive in the mail, which consisted primarily of a cotton swab that I was to rub on the inside of my cheeks. Easy-peasy. I then dropped my cheek cells and swab back in the mail and waited eagerly for my results. It took about 5-6 weeks for my data to come in, which Orig3n provides through a smartphone app.

Before we look at my results, it’s worth briefly mentioning that although I was curious about how these two genes affect the way the gut responds to caffeine, I was unable to track down much of any research on the topic. Thus, the focus of this article is largely on the performance effects of caffeine but not the gut. So, what did I ultimately learn about how I respond to caffeine ingestion?

Let’s examine each gene individually.

CYP1A2 (Sometimes) Drives the Rate of Caffeine’s Decay

Most commercial genetic tests for CYP1A2 classify people as “slow” and “fast” caffeine metabolizers based on single nucleotide polymorphisms, or SNPs, within the CYP1A2 gene. (In overly simplistic terms, a SNP is a coding difference at a single spot on the genome.) Without going deep into the nitty-gritty details, these slow and fast groups are usually based on a particular SNP named rs762551. People who have a fast variant (typically labelled the AA variant) supposedly break down caffeine into its metabolites more rapidly. If you have a slow variant (AC or CC) of this SNP, caffeine stays in your system a bit longer. While this may sound like a good thing, if caffeine hangs around too long, it may produce some counterproductive physiological effects such as constricting the vessels supplying blood to the heart and muscles.

Although categorizing people into speedy and sluggish groups makes things seem cut and dry, in reality, using these basic groupings probably oversimplifies how the CYP1A2 gene impacts caffeine metabolism and its physiological effects. In fact, one of the studies that is almost always cited when justifying the CYP1A2 gene’s impact on caffeine metabolism only found an influence of genotype among people who smoke, while failing to find any such effects among non-smokers.

I was originally expecting that Orig3n’s analysis would tell me that I’m a slow caffeine metabolizer, primarily because I tend to have more side effects from caffeine ingestion than the average person. My basic logic for thinking this was that if I break down caffeine slowly, then it would stay in my system longer, causing more anxiety, jitteriness, gut troubles, and the like. To be honest, though, this thought pattern was based on little more than overly simplistic reasoning. And as it turns out, I’m actually a member of the fast-metabolizing AA group (or as Orig3n so encouragingly put it, the “gifted” group).

So, what does this actually mean on a practical level? Well, it means that as a supposed fast metabolizer, my physical endurance could be improved to a greater extent from caffeine use than a slow metabolizer’s. The key word to emphasize here is could, because of the roughly 10 studies that have investigated this idea, only a couple have shown that fast metabolizers get more out of using caffeine. It’s also important to keep in mind that many other factors (smoking, contraceptive use, diet, menstrual phase, drugs, etc.) induce changes in CYP1A2 activity, which means that even if you’re supposedly a fast metabolizer based on your CYP1A2 gene, your actual CYP1A2 enzyme activity could be lower (or higher) than average. In my opinion, it’s still too early to make clear conclusions about whether, and to what extent, CYP1A2 gene variants influence the ergogenic properties of caffeine in situations where improving physical performance is the goal.

ADORA2A as a Neural Regulator

After being a bit surprised by my CYP1A2 results, I was curious to see what Orig3n’s analysis had to say about my ADORA2A gene. In previous studies, people with a particular variant of an ADORA2A SNP were prone to experiencing anxiety when they were administered caffeine. It totally made sense, then, when Orig3n’s analysis informed me that I was a member of this susceptible group that feels uneasy with caffeine. This group is referred to as TT in studies, or what Orig3n calls the “adapt” group.

Although I drank 2-3 cups of coffee throughout my college days, nowadays I stick mostly to 1-2 cups per day of nearly decaffeinated java. I fill my coffee maker with about 80% decaf and 20% fully caffeinated coffee. (Thankfully, my wife tolerates this low-octane version, otherwise it would surely be a source of marital dispute.) I’ve learned through trial and error that too much caffeine makes me jittery, anxious, and causes my mind to race. It also makes my heart feel like it’s beating out of my chest and leads me to hyperventilate mildly when I’m faced with stressful situations, which are clearly not desirable responses when I’m aiming to come across as cool, calm, and collected.

In contrast to the CYP1A2 SNP mentioned earlier, very few studies have looked at this ADORA2A SNP and whether it modifies caffeine’s performance-enhancing properties. One study found that among 12 women with a self-reported sensitivity to caffeine, only women with a TT variant improved their performance on a cycling test. This is the variant of the ADORA2A gene that I have, and if you ignore the fact that this was a small study done with only women, it suggests that I should profit more from caffeine supplementation than people with the other two variants (TC and CC)—at least in terms of my endurance performance.

What exactly should I make of all this data? Well, the fact that my experiences and genetic analysis tell me that I’m apt to get anxious with caffeine is reassuring in that both pieces of information are in congruence. If Orig3n’s analysis had told me something different (like that I’m in a group that isn’t supposed to get anxious with caffeine), I’m not sure that would’ve impacted my caffeine use moving forward. Nonetheless, I found the whole process of getting my genes analyzed fascinating, and I could see this sort of testing being beneficial for some people. Had I known of my genetic predisposition to getting anxious with caffeine 10 years ago, I probably could have avoided a few situations where I overdid it with coffee before stress-provoking events.

Final Thoughts

It’s obvious that more research needs to be done on how different genes impact people’s responses to pounding lattes and energy drinks. This is true when it comes to the health effects of caffeine as well as its ability to modify physical performance. My experience of getting tested for two genes involved in dictating the responsiveness to caffeine was certainly interesting, but with so many unknowns in this scientific field, it’s hard to know exactly what to make of my results. Hopefully in the next 5 to 10 years our collective knowledge in this area will advance to the point that more personalized recommendations based on genetics will be feasible, but for the time being, relying on personal experiences will likely continue to be just as, if not more, important.

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