In the previous article, the history and utility of caffeine in different sporting contexts were described. This text will go more in-depth into the mechanisms of how caffeine can improve performance and discuss individual differences in gene variants that affect caffeine metabolism.
Mechanism of action
Caffeine is an adenosine receptor antagonist, meaning that it prevents adenosine from binding to cells, thereby blocking its actions. One major role of adenosine is to decrease the concentration of neurotransmitters in the central nervous system (CNS), including serotonin, dopamine, acetylcholine (involved in voluntary muscle contraction), noradrenaline, and glutamate.1 Two (out of the four) adenosine receptor subtypes, A1 and A2A, are widely expressed in the brain and are believed to confer the benefits of caffeine. Caffeine is structurally similar to adenosine and can therefore bind to its receptors. This leads to an increase in neurotransmitters and motor unit firing rate, causing pain to be suppressed. This has positive effects on mood, vigilance, focus, and alertness.
Other adenosine receptors that caffeine can bind to are found in adipose tissue and skeletal muscle. By binding to these tissues, caffeine increases the breakdown and utilisation of fats as energy and slightly reduces glucose uptake. This can be beneficial for performance during submaximal exercise as it lowers the dependence on glycogen.2 High-intensity exercise is also beneficially affected as caffeine can facilitate glycolysis. That is, the breakdown of stored glucose (glycogen) to be used as fuel.2
Genetics and interindividual effects
Over recent years, accumulating evidence has suggested that exercise performance is influenced by variations in the CYP1A2 gene that codes for a protein called cytochrome p450 1A2. This gene is responsible for caffeine breakdown in the liver.2 Simply put, DNA is made up of four compounds (nucleotides) called Adenine (A), Guanine (G), Cytosine (C), and Thymine (T). These form the pairs A-T and C-G, and their order determines the protein that the gene codes for. For example, the first 10 nucleotides of the CYP1A2 gene are GAAGGTGACA. This only shows one side of the base pairs, the other complementary strand of DNA has the opposite of the base pairs.
The three variants of the CYP1A2 gene are AA, AC, and CC.3 This means that a specific position on the DNA is occupied by different nucleotides, which in this case alters how we react to caffeine ingestion. Remember that chromosomes come in pairs, as one is inherited from each parent. The AA variant indicates that both chromosomes have adenine nucleotides, whereas AC states that one chromosome has adenine whereas the other has cytosine. One paper including 101 people reported that 49% had the AA variant, 43% had the AC variant, and 8% had the CC variant.4
Caffeine levels in the blood peak 30-120 minutes after ingestion,5 and it has a half-life of 4-6 hours. The latter is highly individual; values ranging between 3-10 hours have been reported.5 The rate at which caffeine is metabolised (broken down) is influenced by the aforementioned gene variants. AA is the fastest, AC is intermediate, and CC is the slowest. This begs the question, how do these genotypes relate to exercise performance?
To answer that, Womack et al. (2012)6 conducted a study on 35 recreationally trained cyclists (age: 25.0 ± 7.3; VO2max: 59.35 ± 9.72 mL/kg/min) by assessing their 40km bike time trial performance on two different occasions. The subjects were randomised and blinded to consume either 6 mg/kg body weight of caffeine or a placebo one hour prior to the time trial. Blood was taken from the subjects to test which CYP1A2 gene variant they had. Whilst both groups improved performance from caffeine ingestion vs placebo, the AA group improved by 4.9% while the C-carriers (AC or CC) only improved by 1.8%.
In a similar set of experiments by Guest et al. (2021)4 including 101 athletes from different sports (age ∼25; VO2max ∼44-49 mL/kg/min), the athletes completed multiple 10km bike time trials. Again, the subjects were tested for their CYP1A2 gene variant. Upon ingesting 4 mg/kg of caffeine, the AA gene group decreased their time-trial performance by 6.8% compared to placebo. In comparison, the AC group’s performance was unaffected by the caffeine and the CC group went 13.8% slower. Using statistical testing, the authors concluded that caffeine had a “moderate” positive effect on performance whereas the CC group had a “very large” negative effect on performance.
Concluding remarks
Current research about the CYP1A2 variant and exercise performance is somewhat confusing and contradictory. The notion that caffeine is detrimental to performance in the CC variant carriers is not incontestably supported.2 However, it seems that if anything, the AA variant carriers are more susceptible to performance benefits from caffeine supplementation, particularly in endurance events. It must also be noted that the majority of research assessing the relationship between caffeine and genotype has included males. As some research indicates sex-based differences in the responses to caffeine ingestion,7 one cannot exclude the possibility that the CYP1A2 genotype is affected by sex. Nevertheless, whilst caffeine on average is performance enhancing in a range of activities, some people may not get the benefits and even experience detriments in their performance.
References
- Guest NS, VanDusseldorp TA, Nelson MT, et al. International society of sports nutrition position stand: caffeine and exercise performance. J Int Soc Sports Nutr. 2021;18(1):1. doi:10.1186/s12970-020-00383-4
- Barreto G, Grecco B, Merola P, Reis CEG, Gualano B, Saunders B. Novel insights on caffeine supplementation, CYP1A2 genotype, physiological responses and exercise performance. Eur J Appl Physiol. 2021;121(3):749-769. doi:10.1007/s00421-020-04571-7
- CYP1A1 cytochrome P450 family 1 subfamily A member 1 [Homo sapiens (human)] – Gene – NCBI. Accessed April 7, 2023. https://www.ncbi.nlm.nih.gov/gene/1543
- Guest N, Corey P, Vescovi J, El-Sohemy A. Caffeine, CYP1A2 Genotype, and Endurance Performance in Athletes. Med Sci Sports Exerc. 2018;50(8):1570. doi:10.1249/MSS.0000000000001596
- Blanchard J, Sawers SJ. The absolute bioavailability of caffeine in man. Eur J Clin Pharmacol. 1983;24(1):93-98. doi:10.1007/BF00613933
- Womack CJ, Saunders MJ, Bechtel MK, et al. The influence of a CYP1A2 polymorphism on the ergogenic effects of caffeine. J Int Soc Sports Nutr. 2012;9(1):7. doi:10.1186/1550-2783-9-7
- Mielgo-Ayuso J, Marques-Jiménez D, Refoyo I, Del Coso J, León-Guereño P, Calleja-González J. Effect of Caffeine Supplementation on Sports Performance Based on Differences Between Sexes: A Systematic Review. Nutrients. 2019;11(10):2313. doi:10.3390/nu11102313
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