Cheese effect of MAOI's - reversible vs. irreversible ones

[dopamimetic]

I used to believe that it's not the reversibility, but the selectivity making the difference because tyramine could get oxidized by both isoforms and therefore the irreversible MAO-B inhibitors as well as the reversible MAO-AI moclobemide don't require diet. And the irreversible antidepressant ones target both enzymes.

But now I've read the following here:

This phenomenon is negligible with selective (reversible) MAO inhibitors such as moclobemide because of the rapid recover of the MAO enzyme which allows tyramine to be degraded, and therefore reversible inhibitors do not require adherence to MAOI diets.

This would implicate that one could combine low dose selegiline / rasagiline with moclobemide to replicate the seemingly superior efficacy of e.g. tranylcypromine with less dangers?

As a side note, I've recently acquired some rasagiline and took the first 0.5mg yesterday. Didn't have much hope because I've tried selegiline twice and it appeared not to work- maybe the pills were fake, I don't know unfortunately. Definite effect, stimulating without the stimulation if this makes sense - dopamine at its best. Very clear vision, focus and calm clean headspace and probably (hopefully) antidepressive. Interesting synergy with tobacco, feels almost like amphetamine but without the body load and no speedy urge.

Could make a decent ADHD med. If only caffeine was like that

 

[sekio]

It's both reversibility and selectivity that determine the "cheese effect". It is my knwoledge that only older less selective MAOIS have this problem.

 

[Xzbtya]

Yup, as stated above I believe MAO-A to be far more selective for tyramine than MAO-B which is selective for PEA and dopamine much more so. I'd love see more research with reversible MAO-A inhibitors from drug companies but the stigma still remains from irreversible inhibitors (at least in the US). Last I heard pharmaceutical grade methylene blue and methylene blue derivative were in phase three trials as antidepressants however, both being reversible MAO-A inhibitors at a relatively low dose.

 

[Memantine]

Reversible MAO inhibitors such as Moclobemide only occupy the MAO-A enzyme for about 80% if taken in sufficient doses. Therefore there is still some 'space' left for other substrates such as Tyramine.

 

[dopamimetic]

Hmm, I think otherwise (correct me if I'm wrong, please). There's no reason why a reversible inhibitor shouldn't be able to occupy all enzymes, but it doesn't disable them by doing so and has an affinity value (Ki?) like with usual drugs and receptors ... so unless we have some really unusually potent agent, the tyramine and other substrates will compete with it for binding and thus the reversible inhibitors are less effective than the irreversible ones overall, but also with a greatly reduced risk of side effects ... ?

 

[Memantine]

According to this article moclobemide doesn't work as a competitive inhibitor but it binds strongly to the MAO enzyme (although not covalently).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1188542/?page=4 page 217

In ex vivo animal experiments, moclobemide was found to produce an inhibition of up to 80% in the brain and liver 30 minutes after drug treatment, and enzyme activity recovered more than 100% after 16 hours (Da Prada et al 1989b).

I think you would need an enormous overdose of moclobemide in order to come close to a 100% inhibition of MAO-A.

 

[Xzbtya]

Hmm, I think otherwise (correct me if I'm wrong, please). There's no reason why a reversible inhibitor shouldn't be able to occupy all enzymes, but it doesn't disable them by doing so and has an affinity value (Ki?) like with usual drugs and receptors ... so unless we have some really unusually potent agent, the tyramine and other substrates will compete with it for binding and thus the reversible inhibitors are less effective than the irreversible ones overall, but also with a greatly reduced risk of side effects ... ?

I believe the case to be the that tyramine will displace a reversible inhibitor that is already bound to MAO-A. Either way reversible inhibitors do not covalently bond with or modify MAO-A to destroy it so therefore the body does not need to replace lost enzymes, making the reversible inhibitors much safer in the short and long term.

 

[serotonin2A]

Hmm, I think otherwise (correct me if I'm wrong, please). There's no reason why a reversible inhibitor shouldn't be able to occupy all enzymes, but it doesn't disable them by doing so and has an affinity value (Ki?) like with usual drugs and receptors ... so unless we have some really unusually potent agent, the tyramine and other substrates will compete with it for binding and thus the reversible inhibitors are less effective than the irreversible ones overall, but also with a greatly reduced risk of side effects ... ?

With irreversible inhibitors, the inhibition accumulates over time, and you can end up with complete inhibition. On the other hand, it is very difficult to get very high levels of occupation with reversible MAO inhibitors.

 

[dopamimetic]

Hmm yeah, I get the point about the irreversible inhibitors and accumulation, but why can't reversible ones also readily bind to (almost) all of the enzymes when dosed high enough? Isn't it then just a matter of affinity and concentration that decides whether the reversible inhibitor can be displaced by a substrate or not?

 

[belligerent drunk]

Hmm yeah, I get the point about the irreversible inhibitors and accumulation, but why can't reversible ones also readily bind to (almost) all of the enzymes when dosed high enough? Isn't it then just a matter of affinity and concentration that decides whether the reversible inhibitor can be displaced by a substrate or not?

What CZ-74 said. Also, is it correct to think of irreversible inhibition as very analogous to a chemical reaction in terms of stoichiometry since a covalent bond is formed? If so, then since enzymes are usually present in fairly small quantities/concentrations it wouldn't take a lot of irreversible inhibitor molecules to block most of the enzyme. Whereas with reversible inhibition you have a dynamical equilibrium, which first of all means that it is realistically impossible to achieve complete inhibition, and achieving high degree of inhibition requires high affinity and/or concentration.

 

[serotonin2A]

Hmm yeah, I get the point about the irreversible inhibitors and accumulation, but why can't reversible ones also readily bind to (almost) all of the enzymes when dosed high enough? Isn't it then just a matter of affinity and concentration that decides whether the reversible inhibitor can be displaced by a substrate or not?

Reversible inhibitors can produce nearly complete occupation. But going from 50% occupation to 99% occupation requires the ligand concentration to increase by two orders of magnitude. Effectively, you would have to take an overdose to achieve occupation levels that high.