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Death by Chocolate - The Cheese Reaction

Imagine you just got back from a long day at work.

You’re exhausted. You freshen up and just crash. Its 2 a.m. and your phone rings. It's your best friend from college. You know that the poor dude’s been suffering from depression for a while now and that he’s been trying to get back on his feet. You pick up and you find out that he’s pretty bummed. So you grab some chocolate from the fridge and head out to his house.

You get there and you talk to him. A couple of hours of reminiscing and he’s feeling better. You break open the chocolate and your friend pulls out a bottle of wine and you guys celebrate. What isn’t made better by chocolate and wine right?  

But suddenly your friend gets a massive head ache and almost collapses. First, you panic. Then, your instincts kick in. You check his pulse and it is off the charts. You call emergency services and then you wait. How did this happen? All you did was give him chocolate.

Confused and anxious, you get him to the hospital. The paramedics and the medical team, calm him down and treat him. He stabilizes and you're relieved but curious about what happened. The next day, your friend’s psychiatrist pays him a visit and he tells you one phrase that puts everything in perspective for you: MAO inhibitors.

Pharmacology is such a vast and volatile field that it is ranked to be one of the most challenging medical specialties. One of the reasons why it's such a difficult field is because we put so many chemicals into our body and we have no way to understand and predict the exact effect that the particular chemicals will have. As a result, pharmacologists and physicians are constantly worried about unknown phenomena or adverse drug reactions. And one such adverse effect is known as the Cheese Reaction.

To understand the cheese reaction, we need to understand the action of the adrenergic system in the body and how adrenaline is synthesized and used. The following diagram outlines the basic synthesis of adrenaline.

 
adrenaline-synthesis
 

The thing that you must understand is that noradrenaline, once it is outside the cell, is broken down by Mono Amine Oxidase enzymes (MAO) and so it's action is kept in check. In the 1950s, a miracle drug for TB was introduced called iproniazid. As it’s use became wide spread, physicians began noticing that the patients on this drug were generally happier. Following this train of thought, they found out that iproniazid was an inhibitor of Mono Amine Oxidase which increased the amount of endogenous noradrenaline in the blood which had a euphoric effect. And so a new generation of antidepressants was born.

Soon, the use of mono amine oxidase inhibitors as antidepressants became widespread. A few years into it's use, a British pharmacist noticed that his wife, who was on MAO inhibitors suffered severe headaches after meals which predominantly consisted of bread and cheese. Other people began reporting similar incidents after consuming various food products like wine and coffee. Soon enough the drugs were put under scrutiny and a culprit behind these untoward reactions was found to be a small compound called tyramine.

Tyramine is a naturally occurring amine that is a derivative of tyrosine just like noradrenaline. In fact, post mortem studies in the early sixties revealed that tyramine is present in our own brains in trace amounts. But it becomes dangerous in high amounts because it acts as a noradrenaline releasing agent.

You see, normally noradrenaline is stored in vesicles and is only released when needed. Tyramine, however, has no regard for rules or personal space. Tyramine, very rudely barges into the same vesicles as the one in which noradrenaline is present. As a result, noradrenaline is pushed out into the cytoplasm and eventually into the blood stream. Normally, excess of nor adrenaline is kept in check by the mono amine oxidase enzyme, but in patients who are on MAO inhibitors, this enzyme is not functional. The result is an adrenergic surge which leads to tachycardia, vasoconstriction and a general increase in sympathetics.

Initially when physicians found out about this phenomenon and called it the “cheese reaction,” their way around the problem was to enforce dietary restrictions on their patients. However, this was not practical. I mean, imagine if you were depressed and you weren’t allowed to eat chocolates or drink coffee or consume alcohol. The treatment would probably cause further depression!

Fortunately, pharmacological research found a viable solution around this issue and we now have selective MAO inhibitors and reversible MAO inhibitors which do not have such drastic reactions. Furthermore, today we have more effective antidepressants and MAO inhibitors are only used in rare cases.

The story of the cheese reaction teaches us two important lessons as physicians. One is that we should never take any medication for granted and that we should always be aware of the medication that we are putting our patients on and be sure to advice them about potential hazards. And two is that believe it or not, death by chocolate is a real thing!

Author: Narendran Sairam (Facebook)

Sources and citations

Rodell, Victor W. Illustrated Biochemistry. McGrawhill , 2015.