Caffeine, making human lives a little easier one cup at a time.

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Coffee, so the legend goes, was discovered in the 9th century by a goat herder, called Kaldi, in Ethiopia. Kaldi noticed that his goats got frisky and would dance after eating a particular type of berry.

Displaying admirable bravery, or remarkable stupidity, Kaldi tried some himself and was so impressed he told the local monks. The monks also liked them, the berries kept them alert during long evening prayers, and coffee quickly spread from there.

Is this story true? Almost certainly not. But it does show that coffee has always been appreciated as much for its stimulant effects as its flavour.

It’s been embraced everywhere by tired humans who need to stay awake.

Coffee stimulates, of course, because it contains caffeine. So, it’s probably no coincidence that the only beverage, apart from water, that is consumed more than coffee is our other great source of caffeine, tea.

Billions of people every day start their day consuming caffeine in the form of either tea or coffee. If you add all the other ways that we consume caffeine, it’s estimated that at least 80% of the world’s population consumes it daily.

That’s a lot of caffeine but how much do most of us know about how caffeine affects our bodies? How much do we know about how caffeine pick us up and give us a little bit of extra energy?

How, that is, caffeine has become the fuel that makes our busy modern lives possible.

What is Caffeine?

Caffeine is a small molecule that is found in about sixty plants including yerba mate, guarana, and, of course, tea and coffee.

The plants probably produce caffeine as either a deterrent, it is toxic to some organisms like insects, or as a way of encouraging pollinators to return to the plant.

Which has more caffeine? Coffee or tea

Tea actually has more caffeine (2-3% by weight versus 1-2% for coffee beans) but the different brewing processes results in a cup of coffee generally having more caffeine than a cup of tea.

If you want the plant with the higher levels of caffeine then guarana is the plant you’re looking for. Guarana contains twice the amount of caffeine that coffee beans. This is why it is a popular ingredient in high caffeine energy drinks.

Chemically, caffeine is a purine alkaloid which means it contains a double ring structure. You can see the double ring in the figure below. This structure makes caffeine look a little bit like a molecule called adenosine which, as we’ll see, is important for it’s stimulant effects.

In its pure form caffeine is a white, bitter powder and taking 5-10 grams of pure caffeine will most likely result in your death from ventricular fibrillation (which is when the ventricles of the heart quiver, or fibrillate, instead of pumping blood).

In more realistic dosages caffeine results in the pleasant buzz or perk up we get from our morning cup.

Caffeine is a Drug

By any definition you care to use caffeine is most certainly a drug. Caffeine is a small molecule that, as we’ll see, interacts with cellular receptors in our brain to produce physiological changes in our body.

In a way, anyone who absolutely needs their morning cup of tea or coffee has a drug dependency.

Caffeine, though, has a couple of attributes that make it a remarkably effective drug that it is trivial, despite what baristas may think, to administer.

The First-Pass Effect and Why Caffeine Hits Hard

Whenever we consume anything it will pass into the gut and be absorbed into the bloodstream. Possibly after being broken down into smaller bits in the stomach.

Because we don’t want toxic things making their way into our general circulatory system. The blood supply from the stomach goes directly to the liver which can process the things we’ve eaten into less toxic or more useful chemicals. This is called the first pass effect or first pass metabolism.

Many drugs can’t be administered orally because they will be broken down in the gut or metabolised by the liver. But caffeine is unusually tough.

Almost no caffeine is broken down during first pass metabolism. So if you drink a cup of coffee all of the caffeine will get into your blood stream. We get value for money when we drink a cup of tea or coffee.

How Caffeine Reaches the Brain: Crossing the Blood-Brain Barrier

The body is very protective of the brain. It encloses it in a solid cranium for physical protection but the body also takes steps to protect our brains from the things that we may ingest.

To achieve this the cells that make up the capillaries in the brain are packed together very tightly and are surrounded by specialised cells. Together this provides a protective filter that prevents molecules moving freely from the blood stream to the brain.

Apart from simple substances like water and oxygen, only certain molecules are able to cross the blood brain barrier, generally lipid soluble or amphiphilic molecules (see the second emulsions post for a refresher on amphiphilic molecules).

The blood brain barrier is a big concept in pharmacology. If you are designing a drug that needs to get into the brain, say for a brain tumour, it needs to be able to cross the blood brain barrier.

Caffeine, who’s effects are caused in the brain, is both amphiphilic and small. It is able to pretty easily cross the blood brain barrier.

When we drink a cup of coffee, not only is almost all the caffeine making it into out general circulation but a good deal of that caffeine is making it’s way to our brain.

What it does in our brain is the secret to the buzz that we get from caffeine.

How Caffeine Stimulates Us: The Science of Sleep Regulation

In short caffeine interferes with the way that the human body regulates cycles of sleep and wakefulness.

You’ve probably heard of the circadian rhythm that regulates our sleep. But there is another mechanism called the s-process.

The s-process is a process that represents a ‘pressure’ to sleep. During the day, as you go about your business, the levels of a molecule called adenosine begin to rise in your body and the higher the level of adenosine the sleepier you feel.

When you fall asleep adenosine gets recycled, it’s levels drop and the sleep ‘pressure’ decreases until, with the help of cortisol from the circadian rhythm, you wake up.

Adenosine Suppresses Excitory Neurotransmitters

Adenosine is able to cause sleep pressure by influencing the production of excitory neurotransmitters in the brain, two of the most important are dopamine and glutamate.

Cells are able to signal fatigue by releasing adensoine which binds to receptors on the surface of other cells causing them to stop producing dopamine and glutamate, lowering the general activity of neurons in your brain.

Adenosine is a byproduct of cellular metabolism. So, in our bodies the pressure to sleep is intimately tied to how much energy consumption is going on, the more you, and your cells, are doing the more tired you will feel (you can find out more about adenosine and energy in my beer post).

How Caffeine Blocks Adenosine Receptors to Wake You Up

So how does caffeine get involved in all this?

Once caffeine gets to the brain it is able to bind to receptors on the surface of neurons. It just so happens that these receptors are the very same ones that adenosine binds to in the s-process.

This isn’t that surprising given we’ve already seen the chemical similarity between the two molecules.

You may ask, if adenosine makes us tired and caffeine binds to the same receptor, why doesn’t caffeine make us tired?

The important difference between caffeine and adenosine is that adenosine activates the receptor but caffeine deactivates it.

When caffeine binds to the receptor, unlike adenosine, it doesn’t suppress the production of the excitory neurotransmitters.

The more coffee or tea you drink the more caffeine there will be in your brain competing with adenosine for the receptor sites. If caffeine is in the receptor then dopamine and glutamate will still be made and, as far as your brain is concerned, there is no more sleep pressure regardless of how tired your cells actually are.

Extra reading

I’ve really simplified all this but if you want to learn more there is a very good review on the topic here.

Pharmacological Feature	Caffeine Mechanism	Biological Impact
Oral Bioavailability	~100% (bypasses liver first-pass destruction)	Maximum potency reaches blood circulation.
Membrane Permeability	Amphiphilic (binds both water & lipids)	Crosses blood-brain barrier rapidly.
Receptor Activity	Adenosine Receptor Antagonist (A1, A2A, A2B, A3)	Prevents adenosine from triggering sleepiness.
Neurotransmitter Effect	Maintains Dopamine & Glutamate release	Increases alertness, focus, and heart rate.

Beyond the Brain: Systemic Effects on Heart Rate & Health

Now we’ve all overdosed on coffee or had too many Red Bulls and it seems like there is a lot more going on with caffeine than just suppressing sleep. And there is.

Adenosine receptors aren’t just found in the brain. They are all over the body.

There are four different subtypes of adenosine receptors in the human body (A₁, A_2A, A_2B and A₃) and caffeine interacts with all four types to a greater or lesser degree.

Because of this caffeine can have a bewildering array of effects on the human body. Too many to go into here, but to look at one example we can look at the adenosine receptors in our heart.

Extra reading

If you are interested in learning more about the effects of caffeine there is a pretty good scientific review of the topic here

The A₁ and A_2A receptors are found in the brain but they are also found in the heart where they, amongst other things, affect heart rate.

Because of this adenosine is used to treat some types of tachycardia (rapid heart beat). Adenosine, by interacting with A₁ and A_2A receptors, is able to slow the heart rate (as well as having sedative effects because of it’s activities in the brain as we saw above).

Just as occurs in the brain though, caffeine has the opposite effect to adenosine so, as we can all attest, if we’ve had too much coffee our heart rate will increase.

Conclusion

Considering how much caffeine most of us drink it’s properly fitting that we have some idea of how it works and how it provides the stimulus most of us so desperately need first thing in the morning (and then again at mid-morning, and then the afternoon).

It also probably not be the last time I’ll cover caffeine. We’ve covered the basic science of caffeine here but there has been a lot of research into it’s potential protective effects against neurodegenerative diseases, like Alzheimer’s and Parkinson’s, as well as diabetes and heart disease.

And, like any other drug, it may have some detrimental side effects, especially for vulnerable persons.

Thankfully I’m not a vulnerable person but I suspect even if I was they’d need to drag caffeine from my cold sleeping hands.