Rethinking Caffeine: A Deeper Look at What's Happening in Your Body

If you take caffeine seriously, you probably already know it's more than just a morning pick-me-up. However, even the most informed consumers tend to think of caffeine primarily as a support for focus and attention.* Caffeine is the most widely consumed bioactive compound in the world, with roughly 80% of people taking it in daily through coffee, tea, and other beverages. ¹

What is Caffeine?

Caffeine belongs to a class of naturally occurring compounds called methylxanthines. ² Its molecular structure is similar enough to adenosine, one of the body's most important signaling molecules, that it can bind to the same cellular receptors. That structural similarity is the foundation of nearly everything caffeine does in your body.

Caffeine occurs naturally in more than 60 plant species. Coffee and tea together make up about 83% of global caffeine intake, with soft drinks making up most of the rest. ² Other natural caffeine sources include kola nut, cacao, yerba mate, and guarana. On average Americans consume around 193 mg of caffeine each day; Scandinavians consume roughly twice that. ¹ 

But how do you know the amount of caffeine you are consuming? And what does that mean for how you feel after drinking it? Check out the chart below to better understand the amount of caffeine in some common beverages, then read on to learn what happens in your body after drinking your favorite caffeinated beverage.

How Caffeine Works: More Mechanisms Than You Think

Adenosine Receptors

Most people learn that caffeine "blocks adenosine receptors.” However, there are four adenosine receptor subtypes (A₁, A₂A, A₂B, and A₃), and they don't all do the same thing. ³ At concentrations typical of dietary intake, caffeine primarily binds with and affects the A₁ and A₂A receptors. These adenosine receptors are distributed differently throughout the brain and body, each having distinct functional roles. ³

A₁ receptors are concentrated in the hippocampus, cerebral cortex, and cerebellum, and are associated with inhibiting nerve cell activity. A₂A receptors are concentrated in dopamine-rich regions of the brain. ² Blocking each receptor subtype produces different physiological outcomes and the amount of caffeine consumed also makes a difference.

Dopamine Receptors: Not What You'd Expect

Caffeine's support for alertness* involves dopamine but not by increasing dopamine release. A neuroimaging study found that caffeine increased the availability of dopamine receptors in the brain, possibly through blocking the adenosine A₂A receptors, which makes dopamine receptors more available at the cell surface.⁴

This is a very different physiological process than if caffeine caused a surge in dopamine, and it may help explain why caffeine's alerting effects feel different from those of other stimulants.

Noradrenaline and the Stress Response

Caffeine also activates the pathways of another neurotransmitter, noradrenaline (norepinephrine). It does this by decreasing adenosine's inhibitory effects on certain nerve terminals in the brainstem region responsible for noradrenaline signaling. This signaling process is one of the body's most potent internal regulatory systems, playing an important role in the stress response.³

The Inflammatory Response

Interestingly, caffeine also interacts with the body’s normal inflammatory signaling processes. The binding of caffeine with adenosine A₂A receptors also affects the cyclooxygenase-2 (COX-2) enzyme - a major player in the body’s natural inflammatory response. ³ This may help explain why caffeine is commonly included in formulations that decrease discomfort related to menstrual cramping or occasional tension headaches.

Caffeine and the Cardiovascular System: A Mixed Picture

Caffeine, consumed in the range of 80–250 mg, can lead to short-term increases in systolic and diastolic blood pressure.⁵ This is primarily due to the noradrenaline response described earlier. As caffeine binds to adenosine receptors, an increase in sympathetic nervous system activity, guided by epinephrine and norepinephrine, occurs.

Caffeine can affect blood vessel function and also blood flow.⁵ This apparent paradox, enhanced blood flow alongside increased blood pressure, highlights how caffeine's vascular effects are genuinely multifaceted and not always predictable in any direction. Interestingly, caffeine’s cognitive benefits* appear to be neurochemical in nature, not simply the result of blood flow to the brain.

Why More Isn't Always More

Possibly the most under-appreciated aspect of caffeine pharmacology is the inverted-U or biphasic dose-response patterns, meaning that more caffeine doesn’t necessarily equate to more of the desired effect. In preclinical research, very low amounts of caffeine have actually been shown to inhibit the effects of certain compounds, while moderate doses enhance them.³ And higher amounts of caffeine appear to shift the dominant mechanism toward sympathetic nervous system activation: the classic stimulant picture. 

The transition point between these effects varies by individual, as does the amount of time it takes for your body to process caffeine. In general, it takes about 5-6 hours for your body to eliminate half of the caffeine you have consumed and 10-12 hours to eliminate it completely.⁵ However, this can vary from individual to individual, and those who drink caffeine regularly may notice fewer effects as someone else, even when consuming the same mount. ⁶

In the liver, the CYP1A2 enzyme metabolizes approximately 95% of ingested caffeine. "Fast metabolizers" (a specific CYP1A2 genotype) clear caffeine more quickly than "slow metabolizers," creating two- to threefold differences in clearance time. ⁶ On top of that, differences in the adenosine A₂A receptor gene (ADORA2A) create variability in how people subjectively and objectively respond to caffeine,  including individual differences in jitteriness and effects on sleep quality.⁵

Other factors that meaningfully alter caffeine metabolism include age, sex, hormonal status (oral contraceptive use slows clearance), liver function, obesity, smoking, and diet. During pregnancy, caffeine's half-life extends from the typical 5-6 hours to 10–15 hours. ⁶

Caffeine as a Synergist

Caffeine has appeared in over-the-counter formulations for decades. The scientific rationale is related to the mechanisms described earlier: adenosine receptor antagonism, enhancement of noradrenaline pathways; possible effects on the COX-2 enzyme, and digestive system effects that may increase absorption of co-administered compounds.³

A Cochrane systematic review of 27 comparisons involving over 4,000 participants found that adding caffeine to a standard formula increased the proportion of people experiencing mitigated discomfort compared to the standard formula alone.³

But what about the jitteriness? As described above, genetics plays a role in how each person metabolizes coffee. While those who are more caffeine sensitive might experience jitteriness at around 200 mg of caffeine consumed, up to 400 mg of caffeine per day is deemed safe for most adults.⁷ 

The Bigger Picture

Caffeine is worth taking seriously, both as a morning pick-me-up and when exploring a supplement for occasional discomfort. As described here, the science behind the caffeine component is more compelling than you might expect. Relivaid combines 50 mg of caffeine as a complementary ingredient to endocannabinoid-like palmitoylethanolamide (PEA) and ginger, a botanical with extensive traditional use, in a formula designed for occasional symptoms such as tension headaches, menstrual cramps, inflammation, and muscle or joint aches.*

References

1. Sawynok J. Pain. 2011. doi:10.1016/j.pain.2010.10.011

2. Heckman MA et al. Journal of Food Science. 2010. doi:10.1111/j.1750-3841.2010.01561.x

3. Derry CJ et al. Cochrane Database of Systematic Reviews. 2014. doi:10.1002/14651858.cd009281.pub3 

4. Volkow ND et al. Translational Psychiatry. 2015. doi:10.1038/tp.2015.46

5. EFSA. EFSA Journal. 2015. doi:10.2903/j.efsa.2015.4102

6. Nehlig A. Pharmacological Reviews. 2018. doi:10.1124/pr.117.014407

7. Evans J et al. Caffeine. National Library of Medicine. StatPearls. 2024