Coffee with a shot of biochemistry

Have you ever wondered what happens in your body when you drink a cup of coffee? Like, what the molar concentration of caffeine in your tissues are and what proportion of your cell-surface receptors are occupied by caffeine at chemical equilibrium?¹ Well, biochemistry is here to help.

In this post, we’re going to dive into what happens at the molecular level when you drink a cup of coffee, with a special focus on getting actual ballpark numbers for things.

Caffeine is normally regarded as a central nervous system stimulant, but it actually also interacts with other organs such as our lungs, heart, and kidneys. For our purposes, we’ll focus on caffeine’s interaction with the Adenosine A2A receptors in the nerve cells of our basal ganglia, which contributes to the stimulatory effects of caffeine (via things like dopamine regulation).

Our first question: what is the concentration of caffeine around the nerve cells of our basal ganglia?

For our purposes, we’ll make the simplifying assumption that our body is one homogeneous aqueous solution.² In other worlds, when you ingest caffeine, it spreads evenly throughout your body, including in your brain.

Let’s assume there’s 100mg of caffeine in a cup of coffee and 40L of water in the human body (according to Nestle, a trustworthy source).

Using the molecular weight of caffeine and expressing the answer in molar concentration (moles of molecules per liter):

So when you drink a single cup of coffee, the caffeine level in your tissues rises to 12.9 μM (micromolar).

What does this concentration of “12.9 μM” mean exactly?

Well, for starters, pure water has a concentration of 55 M, so 12.9 μM means that for every one molecule of caffeine, there are 4,200,000 molecules of water.

And if we estimate our hypothetical neuron to have a volume of 10,000 μm³, then 12.9 μM means that for every neuron in our brain, we have 129,000,000 molecules of caffeine.³

Pretty crazy when you put it like that!

Next, let’s look at how these caffeine molecules are interacting with your neurons.

When scientists analyze drugs, one thing they’ll consider is the dissociation constant Kd, which is a measurement (borrowed from chemistry) of how likely two things are to react. The lower the dissociation constant, the more “powerful” the drug.

Let [C] be the concentration of caffeine, and [A] be the concentration of the Adenosine A2A receptors we’re looking at. Then:

The Kd value of caffeine for A2A turns out to be 2.4 μM. If we plug in⁴ our caffeine concentration of 12.9 μM, we see that [C]/[AC] = 0.19.

In other words, with a single cup of coffee, about 84% of our Adenosine A2A receptors become occupied (and deactivated) by caffeine.

Of course, this is a very simplified calculation⁵. One study put the actual occupancy at around 50% (for the related A1 receptors).

As a side note, a caffeine dose of 5g or more is considered lethal. One reason for this toxicity is that at higher concentrations of caffeine, caffeine starts occupying a significant percentage of other critical cellular receptors that have higher Kd values. At normal caffeine doses, caffeine will still occasionally bind to these other receptors, but not enough to disrupt normal bodily functions.

To recap, when you drink a cup of coffee, the caffeine molecules inside diffuse throughout your body. Even though you ingest mere milligrams, you still end up with hundreds of millions of caffeine molecules per cell. These molecules end up blocking as much as half of the Adenosine A2A receptors in your brain.

Trillions⁶ of chemical reactions are happening in your body every second, and with every sip of coffee, you shift the equilibrium of those reactions.

Something to think about in the line at Starbucks!

¹ It’s okay if you haven’t. You’re still normal, I promise.

² This is known among drug scientists as the single compartment model.

³ If you want to try calculations like this yourself, here are some helpful rules of thumb. Of particular usefulness is the fact that 1nM means 1 molecule per 1μm³.

⁴ Technically, 12.9 μM is our initial concentration of caffeine, not our concentration at equilibrium, so you would need to solve a quadratic equation to determine equilibrium. However, if the amount of A2A receptor is much smaller, then the difference between initial and equilibrium concentration will be small. This paper puts the number of A2A receptors per cell at around 100,000 (a cool fact in itself!) versus 129,000,000 caffeine molecules, so we should be good.

⁵ For example, we didn’t factor in the fact that caffeine competes for occupancy of the Adenosine A2A receptors with other molecules, including adenosine itself. This makes the equilibrium equations much more complex.

⁶ A severe underestimate. The actual number is something like 10²¹.