BY: MEGAN LOW

Arguably one of the most polarized questions of mankind is this: is caffeine effective on you? Some people swear by it, almost as if needing their morning coffee for sustenance; and others, like me, still fall asleep after a cup. If you find yourself in the former category, this is the culprit to blame:

Caffeine also known as 1,3,7-Trimethylpurine-2,6-dione

A methylated derivative of the purine base xanthine found in over 60 plants. While caffeine is commonly associated with coffee, this methylxanthine is also found in tea, cocoa and sodas.

Image Source

It works as a stimulant by blocking adenosine receptors, primarily two of the four A1, A2A, A2B, and A3 identified, A1 and A2A (1), from adenosine itself which is sleep promoting. Additionally, it promotes the release of the flight-or-fight adrenaline hormone, which increases heart rate, rate of muscle contraction, and the release of free fatty acids for energy (2).

Upon ingestion, caffeine is rapidly absorbed into our circulatory system, distributed to most tissues and organs, and undergoes metabolism in the liver. Now, how we process that individual-to-individual may be very different, based on physiological factors such as gastric evacuation and intestinal absorption (3). And just like with alcohol, gender and age play a role in how we absorb or metabolize these compounds. Older people are more susceptible to sleep disturbances, and males and females experience different cardiovascular responses depending on estradiol levels, which may be attributed to differences in circulating steroid hormones (3, 4). Maybe you’ve also heard that it’s from building a tolerance through habitual consumption. But the diversified responses among your peers on how much caffeine really affects them also depend on genetic factors!

Interestingly, a single nucleotide substitution at a specific location on a gene (known as polymorphism) can determine if you are a slow or fast caffeine metabolizer. During the first phase of drug metabolism which includes caffeine, cytochrome P450 acts as a catalyst for the oxidation reaction, so it’s no surprise that the gene encoding this cytochrome is reported as one of the reasons for variability in caffeine sensitivity (5). In this case, it is an A to C allele substitution at position 163 on the gene. The C allele is related to lower metabolic enzyme activity. Because the caffeine is being converted more slowly, there is longer exposure to internal caffeine levels which can seemingly amplify the effects. Conversely, 163A allele carriers experience less since they are fast metabolizers (6, 7).

Polymorphisms on another gene, ADORA2A, which controls the expression of A2A adenosine receptors, were shown to cause varying severities of caffeine-induced sleep impairment. This was measured by an increase in electroencephalogram (EEG) beta activity. Depending on genotype (C/C, C/T or T/T), EEG patterns of subjects administered caffeine during non-REM sleep could mimic that of insomnia patients. In general, polymorphisms at two locations on this gene are linked to the feeling of wakefulness or anxiety/jitters associated with the effects of caffeine. The C/C majority also considered themselves caffeine sensitive while T/T genotypes reported themselves as insensitive (1). There is an antagonistic interaction between A2A adenosine and D2 dopamine receptors that influences the dopaminergic effects of caffeine (8). Therefore, a polymorphism on DRD2, the gene for dopamine D2 receptors, was also found to affect caffeine-induced anxiety (1, 9).

As much as these factors are key determinants, it isn’t just intrinsic factors we were born with like age, gender or genetic predisposition. Things like tobacco use also reduces sensitivity of caffeine, while on the opposite, pregnancy increases sensitivity. Smokers experience about twice the caffeine metabolism than non-smokers, possibly due to polycyclic aromatic hydrocarbons found in cigarettes that increase enzyme activity in the liver. Smoking also accelerates the demethylation of caffeine, causing caffeine to have a shorter half life in the body (3, 7). The effects are thus dampened for smokers. On the other hand, caffeine in pregnant women takes a longer time to metabolize, and stays in the system for longer (3, 10).

Although caffeine may sound like it comes with unfavorable consequences (who would want to lose sleep?), low to moderate dosages can improve alertness, reaction time, attention and physical performance. If that doesn’t sell it for you, sometimes a long drive or boring class is all the reason you need to caffeinate yourself, whether that may take a cup or three, since you know it could come all the way down to the genes!

Before caffeine (Image Source)

After caffeine (Image Source)

References

1. Genetics of caffeine consumption and responses to caffeine https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4242593/
2. Establishing a relationship between the effect of caffeine and duration of endurance athletic time trial events: A systematic review and meta-analysis https://www.sciencedirect.com/science/article/pii/S1440244018304596
3. Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects https://www.sciencedirect.com/science/article/pii/016501739290012B
4. Gender Differences in Subjective and Physiological Responses to Caffeine and the Role of Steroid Hormones https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3621315/
5. Basic Review of the Cytochrome P450 System https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4093435/
6. Caffeine metabolism rate influences coffee perception, preferences and intake https://www.sciencedirect.com/science/article/pii/S0950329316301161
7. Caffeine: Cognitive and Physical Performance Enhancer or Psychoactive Drug? https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4462044/
8. Evidence for adenosine/dopamine receptor interactions: indications for heteromerization. https://www.ncbi.nlm.nih.gov/pubmed/11008067
9. Influence of genetic polymorphisms and habitual caffeine intake on the changes in blood pressure, pulse rate, and calculation speed after caffeine intake: A prospective, double blind, randomized trial in healthy volunteers https://www.sciencedirect.com/science/article/pii/S1347861319300118
10. Drug metabolism in pregnancy, infancy and childhood https://www.sciencedirect.com/science/article/pii/0163725887900969
11. Genetic determinants of cognitive responses to caffeine drinking identified from a double-blind, randomized, controlled trial https://www.sciencedirect.com/science/article/pii/S0924977X15000772