“Don’t talk to me until I’ve had my cup of coffee.” Perhaps you’ve seen this printed on a number of mugs or heard it in the morning from a coworker. It seems like everyone and their mother (and their father and their brother and their sister!) is hooked on caffeine because it helps us feel awake and alert. In fact, caffeine is the most consumed stimulant in the world! It is naturally found in many plants and, as a result, is in many of our dietary staples, such as chocolate, tea, and coffee.1Temple, J.L., et al., The Safety of Ingested Caffeine: A Comprehensive Review. Front Psychiatry, 2017. 8:80. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5445139/
Despite its popularity, some people say caffeine doesn’t affect them. How can one substance be so widely consumed for stimulation by some people and yet have no effect on others? Before we jump into this question, let’s first discuss how caffeine works.
How does caffeine work?
To understand how caffeine makes you feel more awake, we have to understand what happens in the body to make you feel more tired. A molecule called adenosine builds up over the day and binds to the adenosine receptor (think of this like adenosine’s docking station). When adenosine binds, the receptor blocks signals that keep the body awake and alert and, therefore, we start to feel tired.2Urry, E. and H.P. Landolt, Adenosine, caffeine, and performance: from cognitive neuroscience of sleep to sleep pharmacogenetics. Curr Top Behav Neurosci, 2015. 25:331-66. https://pubmed.ncbi.nlm.nih.gov/24549722/ However, caffeine, which has a very similar shape to adenosine, can also bind to these receptors. This binding blocks adenosine from being able to dock, allowing the body to keep sending signals to stay awake (this link has a brief video if you want a visual).3Ribeiro, J.A. and A.M. Sebastião, Caffeine and adenosine. J. Alzheimers Dis., 2010. 20 Suppl 1:S3-15. https://pubmed.ncbi.nlm.nih.gov/20164566/ Our bodies completely absorb caffeine within an hour after consumption, and caffeine usually has a half-life of 3-7 hours in adults (meaning, after 3-7 hours, half of the caffeine you consumed has been used up). These absorption and use times, as well as caffeine’s effects, can vary depending on the person, affected by things like diet (including what other ingredients are in the caffeinated food or drink), smoking, and genetics.1Temple, J.L., et al., The Safety of Ingested Caffeine: A Comprehensive Review. Front Psychiatry, 2017. 8:80. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5445139/4Thorn, C.F., et al., PharmGKB summary: very important pharmacogene information for CYP1A2. Pharmacogenet Genomics, 2012. 22(1):73-77. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3346273/
So, are there people whom caffeine doesn’t affect?
Effectively, yes, but technically, no. It’s not quite a black and white answer. What we classify as caffeine tolerance can be split into two types: a natural tolerance and an acquired tolerance.
Those with a natural tolerance aren’t really unaffected by caffeine, but rather, metabolize it quickly, leaving little caffeine left to bind to adenosine receptors. Caffeine is largely (~95%) metabolized in the liver by a molecule called CYP1A2.5Cornelis, M.C., et al., Genome-wide association study of caffeine metabolites provides new insights to caffeine metabolism and dietary caffeine-consumption behavior. Hum Mol Genet, 2016. 25(24):5472-5482. https://pubmed.ncbi.nlm.nih.gov/27702941/ Genetic variations of this molecule change how fast it metabolizes caffeine. Based on a study looking at populations from Arkansas, Italy, and China, most people (51-67%) have a version that metabolizes caffeine at an intermediate rate, but some people (20-37%) have a version that’s considered an “ultrarapid metabolizer” and breaks down caffeine much more quickly.4Thorn, C.F., et al., PharmGKB summary: very important pharmacogene information for CYP1A2. Pharmacogenet Genomics, 2012. 22(1):73-77. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3346273/6Butler, M.A., et al., Determination of CYP1A2 and NAT2 phenotypes in human populations by analysis of caffeine urinary metabolites. Pharmacogenetics, 1992. 2(3):116-27. https://pubmed.ncbi.nlm.nih.gov/1306111/ Most likely, these people are the ones who don’t feel caffeine’s effects as readily and may need to consume more at once to do so. However, the U.S. Food and Drug Administration and supporting research suggest that healthy adults should not consume any more than 400 mg of caffeine per day (about 4-5 cups of coffee, or 8 cups of tea).1Temple, J.L., et al., The Safety of Ingested Caffeine: A Comprehensive Review. Front Psychiatry, 2017. 8:80. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5445139/7Spilling the Beans: How Much Caffeine is Too Much? 2018 (cited 2021). https://www.fda.gov/consumers/consumer-updates/spilling-beans-how-much-caffeine-too-much This recommendation is lower for adults taking certain medications, pregnant people, and children.
Alternatively, those with an acquired tolerance develop it over time with regular caffeine consumption. Research on mice and rats has shown that, since caffeine blocks adenosine receptors, the body eventually produces more receptors over time to counterbalance the caffeine and, thus, has more docking chances for the adenosine molecules.8Nehlig, A., et al., Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects. Brain Res Brain Res Rev, 1992. 17(2):139-70. https://pubmed.ncbi.nlm.nih.gov/1356551/ This often causes consumers to up their caffeine intake, either by consuming more at a time or by consuming it more often. This can create a cycle, but since there is an upper limit on how much caffeine we should consume on a daily basis, increasing caffeine consumption isn’t always an option – and it can lead to nasty side effects such as dependency, where you require caffeine just to feel a normal level of awake, not to mention staving off headaches from withdrawal.8Nehlig, A., et al., Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects. Brain Res Brain Res Rev, 1992. 17(2):139-70. https://pubmed.ncbi.nlm.nih.gov/1356551/
If I acquire tolerance to caffeine, is there anything I can do to reverse it?
The good news is, yes! The bad news is that you have to consume less caffeine to do it. Just as consuming more caffeine over time increases the number of adenosine receptors your body makes, consuming less caffeine over time should signal to your body that you don’t need as many receptors anymore, since they’re not being blocked. However, this has only been scientifically proven in mice and rats, since it would be virtually impossible to monitor the total number of adenosine receptors in humans over time.8Nehlig, A., et al., Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects. Brain Res Brain Res Rev, 1992. 17(2):139-70. https://pubmed.ncbi.nlm.nih.gov/1356551/
But what if I’m someone with “ultrarapid metabolizers?” Or just someone who doesn’t like coffee or caffeine? Are there other ways I can feel more awake?
Luckily, you have options other than caffeine to help you stay more awake and have more energy over time. Harvard Health Publishing, a publication from Harvard Medical School, released an article titled, “9 tips to boost your energy – naturally.” The list of science-backed tips includes some of these other options, including staying hydrated and limiting alcohol. Another good way to boost your energy is through your diet. Many vitamins and minerals can affect your energy levels since they’re vital in various brain and body functions. This review breaks down why energy levels change and what role vitamins and minerals play. Consuming adequate amounts of these vitamins and minerals may be the answer for both caffeine consumers and non-consumers alike. There are options for everyone to get the energy boost they need!
To wrap it up, caffeine does affect everyone, but not to the same degree because some people have natural or acquired caffeine tolerance, and that’s perfectly normal!
