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Are Monoamine oxidase inhibitors (MAOIs) as dangerous as they are made out to be? I am new to pharmacology, but here is my understanding of MAOIs and antidepressants in general:

  • There is a presynaptic neuron that stores serotonin in vesicles. The serotonin is made by tryptophan.

  • Release of serotonin from the presynaptic neuron stimulates various 5-hydroxytryptamine (5-HT) receptors in the postsynaptic neuron. The serotonin goes back to the presynaptic neuron via the serotonin transporter (SERT or 5-HTT) transporter. Most of this serotonin is repackaged into various vesicles while some of the other serotonin is broken down by MAO enzyme.

  • Selective Serotonin Reuptake Inhibitors (SSRIs) inhibit the SERT transporter to various degrees depending on which one it is. This increases the availability of serotonin to bind to various postsynaptic 5-HT receptors.

  • Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) inhibit both the SERTs and norepinephrine transporters (NETs) to varying degrees depending on the medication which increases availability of both serotonin and norepinephrine to bind to various postsynaptic 5-HT receptors and beta and alpha-1 receptors.

  • MAOIs don't inhibit SERT, NET or dopamine transporter (DAT) but they inhibit the MAO enzymes. So serotonin and norepinephrine travel back to presynaptic neurons and are stored in various vesicles. They are not broken down by the MAO enzymes.

Now it seems that if you inhibit the MAO enzymes, there is more tyramine which leads to an increase in catecholamines. This could cause a stroke.

Are there any agents that decrease tyramine in the first place? Wouldn't this make a person not have to follow a restrictive diet?

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    Welcome to SE Biology. Please finish the Tour to learn about this site. There are two points I would suggest you consider. The abbreviation MAO may be familiar to you, but I would have to do an Internet search to find what it means. I shouldn’t have to do that, so please define it once, and also (and especially) in your title. The second point is whether this is a question about pharmacology or are you just floating an idea to get comments. Clearly if you are new to a field where what you suggest is not the practice, your reasoning is flawed. Better then to recast the question in that way.
    – David
    Commented Jun 4, 2021 at 19:47
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    I'm going to repeat David's request that you spell out acronyms on first use. Also, have you tried to find agents that safely and effectively eliminate tyramine issues with MAOIs? Seems unlikely that one exists and yet doctors aren't prescribing it.
    – Carey Gregory ♦
    Commented Jun 5, 2021 at 19:55
  • True, everything you say is correct: just a small detail, that you already know.. MAO enzymes have two isoforms (MAO-A and MAO-B). Now, as you said, tyramine (NA, adrenaline, dopamine) is a substrate for both isoforms.. however third generation of MAOIs differs from the previous generation by being selective and reversible for MAO-A, which means that at least MAO-B can still metabolize tyramine.. and thus the European Food Safety Authority recommends "[less than] 50 mg [of tyramine] for those taking third generation MAOI" efsa.onlinelibrary.wiley.com/doi/epdf/10.2903/j.efsa.2011.2393
    – program
    Commented Jun 8, 2021 at 17:36
  • @program Perhaps you could turn that into an answer?
    – Carey Gregory ♦
    Commented Jun 9, 2021 at 3:36

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MAO enzymes have two isoforms (MAO-A and MAO-B).

MAO isoforms

Now, as you said on the description, tyramine (as well as noradrenaline, adrenaline, dopamine)

is a substrate for both isoforms A and B of MAO reference

There's also three types of MAOIs reference:

  • first generation - irreversible nonselective (older)
  • second generation - irreversible, selective drugs
  • third generation - reversible, selective MAO-A [also known as RIMAs (reversible inhibitors of MAO-A)]

Regarding the tyramine and RIMAs reaction reference

reversibility allows competition and so ingested tyramine (or other dietary amine) is able to displace the inhibitor from the enzyme and be metabolized in the normal way, in the gut and liver

Although better than the previous generations, RIMAs still have their limitations (to be metabolized normally) and in that sense the European Food Safety Authority recommends

[less than] 50 mg [of tyramine] for those taking third generation MAOI reference

to sum up, the best solution when taking this sort of medication is still follow a restrictive diet, low in tyramine (or other dietary amines).

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