Are there non-responders to caffeine?

Caffeine is one of the most performance enhancing drugs available to athletes, with research demonstrating that it has ergogenic effects on a range of exercise types, including aerobic endurance, strength, and repeated anaerobic activities. Athletes are of course aware of this, and research tends to suggest that around three-quarters of athletes utilise caffeine either immediately before or during competitions. But new research indicates that the effects are not as general as you may think, and could have no effect or even harm performances for some athletes.

Individual response and caffeine

Last year I published a paper and wrote on HMMR Media about the individual variance in caffeine response. The general recommendations often suggested regarding the use of caffeine in sport—3-6 mg/kg of bodyweight, around 60 minutes beforehand—might not be appropriate for everyone due to both genetic and environmental reasons.

Since that paper’s publication, a well-designed and well-controlled study exploring the impact of variation within a gene called CYP1A2 has been published, which explores the topic even more. The research demonstrates that individuals with the CC genotype demonstrate no ergogenic effects from 2 mg/kg of caffeine consumed 60 minutes prior to an aerobic activity, and actually performed worse than placebo when they consumed 4 mg/kg. As such, the authors of that study suggested that higher doses of caffeine should perhaps be avoided by those genotypes, given its potential to harm performance.

Exploring the non-responders phenomenon

Building on this, another recent review article, published in the journal Nutrients, explored the impact of various different genetic variants on the performance-enhancing effects of caffeine. Within that article, the authors suggested that around 33% of subjects in research trials exploring the use of caffeine in endurance sport demonstrate no performance enhancing effects of caffeine on performance. Typically, individuals who demonstrate no improvements from a specific intervention—in this case caffeine—are often termed non-responders. Such a term is most often utilized in regards to exercise programs to describe individuals who demonstrate no improvements in fitness following exercise.

The concept of non-responders is hardly new. In 2017, I wrote an article discussing whether non-responders to exercise actually exist, suggesting that they likely don’t. The main crux of my argument, which I expand on in a soon-to-be-published paper, is that the research that finds “non-responders” often only utilizes a single exercise type, and a single exercise test. So, whilst a person who shows no improvement in VO2max following aerobic training might be labelled as a non-responder, in actual fact, they likely could respond to different types of exercise (such as resistance training), or show improvements in different exercise tests, such as lactate threshold or heart rate at a given workload. Additionally, as I suggested in one of my papers on caffeine, it’s not clear how repeatable this lack of response is; i.e., is a person always a “non-responder” to a given exercise type in a given measure, or is this state transient; i.e. would they perhaps be a responder if the training programme were repeated? As a result, it might be better to state that person “did not respond”, as opposed to labelling them as a “non-responder”.

In a letter to the editor following up on the most recent review article, Jozo Grgic, a researcher from Victoria University in Melbourne, also provides some insight into whether non-responders to caffeine exist. In his letter, Grgic explores the reliability of a test. Whenever we undertake an exercise test, there is often some form of error present within that test. This error can be partially down to biological variation; if I undertake a maximal bench press test today, and one tomorrow, I’m unlikely to get the same results, even though I won’t have gotten appreciably stronger or weaker over the course of a day. This variation is often termed the coefficient of variation (CV), which for most valid and reliable exercise tests—the ones used in caffeine research—is typically less than 3%. Grgic mentions that most of the “non-responders” in caffeine research often fall within this CV range, such that it isn’t clear whether they actually didn’t respond, or just performed slightly differently, due to natural biological variation, on the test. When controlling for this, the number of non-responders drops from 33% to 5% – much lower.

Grgic then goes on to explore other aspects that could affect this rate of non-response. Similar to my comments regarding exercise non-response, if we increase the number of exercise tests used to determine whether caffeine works or not, we see a reduction in non-responders; that is, subjects may not see an improvement in lower body strength, for example, but do in upper body strength. As a result, that person is not a non-responder in general, but just specifically to that given exercise test. Additionally, caffeine is ergogenic across a range of doses, most commonly from 3-9 mg/kg, and so whilst a person may exhibit no performance enhancement at 3 mg/kg, they might at 9 mg/kg – and this is rarely tested.

Finding the right dose

The jury is therefore still out on whether anyone is a general non-responder to caffeine. However, returning the study from Guest and colleagues exploring CYP1A2, this study clearly showed that, for people with a specific version of this gene, 4 mg/kg of caffeine reduces performance. So, should they never consume caffeine prior to exercis? Not necessarily; as I explored in my own letter to the editor, these individuals may require a different caffeine ingestion strategy, specifically around timing. As such, it’s not that they will always find that caffeine makes their performance worse, just that it does so at a specific dose, when consumed a specific period of time prior to exercise.

So what does this all mean for athletes? Well, if you’re using caffeine and not seeing a performance improvement, it’s time to start experimenting, both with different doses, and different timings, in order to see which works best for you. It’s unlikely that anyone is a true non-responder to caffeine—that is that they won’t ever gain performance enhancing effects from caffeine—merely that they just need to find the dose and timing that works best for them. Given the potential for caffeine to enhance performance, this is good news!