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Factors Affecting Response to Caffeine Intake

It’s arguably the most popular and prevalent ergogenic in pre workout and fat burner supplements. Even so, there’s a lot that science still has to piece together concerning how best to use caffeine as an ergogenic.

For the average individual, dosage and time of supplementation are two factors that standout as the most important determinants of caffeine’s ergogenic effect. But as this article will touch on, there are a number of other factors (i.e. training status, genetics, food intake) that can also have a large bearing on an individuals’ response to caffeine.

Originally thought to mediate its ergogenic effect by increasing fat burning1, research has since confirmed that caffeine’s performance effects are mediated largely through the central nervous system by blocking something called adenosine receptors1.

Understanding Caffeine & Adenosine caffeine_adenosine_molecules

What are adenosine receptors? Without getting too technical, adenosine is a substance in the brain that normally binds to adenosine receptors and acts as a natural sedative. Binding of adenosine to adenosine receptors causes the receptors to undergo a change in shape that in turn triggers a biochemical cascade leading to a relaxed cell state or slowing of activity. In contrast, when caffeine binds to adenosine receptors, it blocks (i.e. antagonises) adenosine’s effect; leading to increased neural activity and stimulation2.

On a practical level, the blocking of adenosine receptors is thought to mediate several performance improvements by:

  • Decreasing muscle pain perception and perceived exertion3
  • Increasing motor unit recruitment and force generation capacity4, 5

But it may come as news to readers that caffeine’s ergogenic effects are not mediated solely by caffeine itself. Rather, metabolites of caffeine (i.e. paraxanthine and theophylline) generated when caffeine is metabolised in the liver actually have a higher affinity for adenosine receptors than caffeine itself6. And because an individual’s ability to metabolise caffeine is largely genetically determined, this can be a key factor affecting the ergogenic response to caffeine.

Genetic Influences on Caffeine Metabolism

Cytochrome P450 1A2 (or CYP1A2) is the fancy name for the gene that encodes expression of the enzyme that plays a major role in metabolising caffeine in the liver. Whether an individual is homozygous (identical pairs of genes) or heterozygous (dissimilar pairs of genes) for the A allele has a large bearing on the inducibility of the enzyme (i.e. the amount it can be stimulated).

For example, individuals with homozygous AA possess high CYP1A2 enzyme activity and therefore may experience a more rapid accumulation of caffeine metabolites than their C allele counterparts7. One study in trained cyclists’ found that those carrying the AA allele performed significantly better during a 40km time trial than those carrying the C allele, after ingesting 6mg/kg of caffeine7.

Effect of Training Status on Response to Caffeine

cup_of_coffeeIn contrast with the above study, a more recent study published in 2015 found the opposite effect in untrained (i.e. recreational) cyclists. In this study recreational cyclists (i.e. ~2 rides per week) who were AC heterozygotes (i.e. slow caffeine metabolisers) performed better during a 3-km time trial than AA homozygotes (i.e. fast caffeine metabolisers)8. While the big difference in distance (i.e. 3km vs 40km) may have affected results, another key factor was thought to be the effect of training status on response to caffeine8.

Interestingly, studies have shown that expression of the all important caffeine metabolising enzyme CYP1A2 is influenced by training, with both acute and chronic exercise training leading to increased expression9, 10. What’s more, adenosine receptor density in skeletal and cardiac muscle has been shown to be greater in endurance-trained than untrained men11.

Time of Day

While some disagreement exists between studies, there is evidence suggesting the time of day caffeine is consumed can effect its ergogenic potential. More specifically, a number of studies have shown caffeine to have greater ergogenic effect when consumed in the morning versus afternoon8, 12, 13. However, studies show that caffeine ingestion in the morning serves simply to improve performance to the level seen with afternoon performance in the absence of caffeine. Interestingly, there is also evidence showing that CYP1A2 activity is elevated in the morning compared with the evening, thus providing a plausible mechanism by which morning caffeine (or coffee) supplementation may work14.

Mode of Administration

One fascinating area of new research concerning caffeine is its possible ergogenic effect when used as a mouth rinse or in the form of chewing gum. A couple of studies have shown improved high intensity cycling performance when a 1.2% caffeine mouth rinse solution was used15, 16. It turns out that caffeine absorption in the mouth is much more rapid and can produce a quicker response to ingested caffeine, which typically takes 1-2 hours when ingested orally17. Since this initial discovery, caffeinated chewing gum has been developed to take advantage of absorption at the 'buccal mucosa' in the oral cavity. Again, several studies have shown benefit18-20, however, some studies have shown no positive ergogenic effect21. As such, more research is needed to determine how to optimise the ergogenic effects of caffeine when administered via a mouth rinse or chewing gum.

Feeding Status

Feeding status is yet another factor shown to affect response to caffeine intake, however, effects are much more ambiguous. While some studies show benefit when caffeine is ingested 2 hours following a meal15, 16, still others show an ergogenic benefit when ingested 6-12 hours following fasting22, 23.

A 2015 study looking at the effect of both caffeine mouth-rinsing and oral ingestion asserts that the response to caffeine ingestion does not appear to be mediated by feeding status8. Yet another interesting recent study examined the effect of caffeine administration in combination with a carbohydrate mouth rinse solution (or on its own) on exercise capacity when performed in a carbohydrate restricted or glycogen-depleted state. Compared with placebo and caffeine alone, the combination of a 10% carbohydrate solution mouth rinse (10 seconds) at 4-minute intervals with caffeine (2 x 200mg doses) provided significant improvement in high-intensity interval running capacity (65min vs 52min vs 36min respectively). Subjects in this study had only consumed 2 x 25g of whey protein isolate in the preceeding 10 hours before their exercise test and therefore had depleted carbohydrate (i.e. glycogen reserves).

This latest study seems to suggest if someone is training in a carbohydrate-depleted state, they may benefit more from ingesting caffeine, particularly if the exercise is of a intermittent high-intensity nature.

But with conflicting studies, the jury is still out on the effect of feeding status on response to caffeine. Anecdotally, however, it is common for individuals to take caffeine on an empty stomach (i.e. first thing in morning), with the typical morning coffee being a classic example. Despite some conflicting research, there's enough sound theoretical and mechanistic evidence for individuals to continue their caffeine use in this vein.


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