BIOLOGY

I am Italian and I do not drink coffee; what a shame! I actually do drink coffee, occasionally, in the afternoon. I take it merely as a drug, when I am extremely tired and I need to study hard. After five minutes it already gives me a huge effect: I get over-excited, I need to move, I act as a drunk person for a few minutes. For the following two hours I stay focused, I can easily visualize abstract concepts, intersections between pathways, and connections between topics. Later on I start to feel bad, a sort of nausea interchanged with moments of excitement, with events of tachycardia in the evening. But as an Italian who lives in Switzerland, I also eat chocolate, with moderation. During a road trip in Scotland, I was already walking in the rain for 30 km, with a 15 kg bag on my shoulders, without eating for several hours. I was sad, depressed and tired, looking for a spot for my tent. I finally decided to gulp down some chocolate squares. After five minutes I was singing Franco Battiato’s song “Summer on a solitary beach”, feeling happiness in my veins.
I wanted to know more about my sensitivity to both coffee and chocolate, so I decided to study their metabolism. If you are also sensitive, you may discover why here.

Coffee, as everyone knows, contains caffeine, which is metabolized by the cytochrome P450 enzymes in the liver, in particular by CYP1A2, and transformed in paraxanthine, theobromine and theophylline. Importantly, CYP1A2 is also involved in the secondary metabolism, by transforming, for example, theobromine and theophylline. The commonly known effect of paraxanthine is the increase in blood pressure. For what concerns theobromine, it induces a heartbeat increase, a reduction in the blood pressure, a stimulation of vasodilatation, muscle relaxation, and urine production, encircled with events of sleeplessness and anxiety. Finally, theophylline induces muscle relaxation, heartbeat and blood pressure increase, reduction of immunity response and decrease of inflammation.
And chocolate? Chocolate mainly contains three chemicals: theobromine and theophylline are two of them. Surprised? The third one is called phenylethylamine, a potent stimulant of the central nervous system.
As already mentioned, theobromine and theophylline are metabolized by the CYP1A2 enzyme. This enzyme is associated with several different genetic variations affecting the metabolism. A slower metabolizer will tend to have greater effects, for a genetic reason. Therefore, I can easily tell myself I am a slow metabolizer, even without performing a genetic test.
On the other hand, phenylethylamine is mainly metabolized by MAO-A and MAO-B, two important mitochondrial enzymes. The psycho-active effects of this drug are due to its accumulation in the brain. Slower is the metabolism of the MAO enzymes and higher are the effects of this compound. When it is accumulated in the brain, it causes the release of dopamine and norepinephrine, generating a sensation of happiness and love.

What do chocolate and coffee have in common? As already mentioned, the secondary metabolites we obtain from caffeine are also the same that we find in a chocolate bar. Therefore, my happiness cannot be explained through the biological effect of theobromine and theophylline: phenylethylamine is indeed the reason.
In a 2013 paper, caffeine was shown to be able to interact with MAO enzymes A and B, working as a weak inhibitor. Modifications of caffeine were shown to work as strong inhibitors. As a theoretical consequence, consuming coffee with a chocolate square helps to increase the effects of phenylethylamine.
The most plausible explanation for my sensitivity to chocolate is, therefore, my sensitivity to coffee. If the CYP1A2 enzyme does not work properly, theobromine and theophylline will tend to accumulate without being metabolized. In addition, since these two compounds are structurally very similar to caffeine (Figure 1) and since it was shown that modifications of the original structure tend to generate a strong inhibition of MAOs, the accumulation of phenylethylamine may be due to the increased levels of non-metabolized theobromine and theophylline.
Basically, my chocolate sensitivity probably does not depend on the unique properties of cocoa, but on the shared properties of coffee and cocoa.

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Figure 1 – Caffeine (left) and theobromine (right) structures.

A few final curiosities: MAO inhibitor drugs were widely used as antidepressants. Now they mostly have been replaced because of their side effects. Moreover, the combination of MAO inhibitors and phenylethylamine constitute a legal drug, which however causes addiction and can be extremely dangerous.
In conclusion, I want to give all of you a personal advice, in particular for chocolate lovers. Instead of looking for combinations of synthetized and dangerous drugs, if you are not hyper-sensitive to coffee, like I am, try to eat some chocolate with a cup of coffee under the conditions of an empty stomach.
It is the best natural and safe way to get drugs. Then go into the shower and sing Shakira. Do that, please!

M.M.

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