Ok, so this has been bugging me for a while and I can't figure out the answer.

Why is mescaline not broken down in the gut by monoamine oxidase?

I mean, it has a very exposed amine right on the ethyl group on the benzene ring. Yet it is obviously orally active and, as we all know, lasts very long suggesting that it isn't broken down quickly either. Other phenethylamines like amphetamine have a methyl group on the alpha carbon, so they are protected from de-amination by mao. But many other psychoactive phenethylamines don't have anything (as far as I can tell) which protects the amine group.

So then why are mescaline and other phenethylamines still orally active??

So either mao doesn't work the way I think it works, or mescaline is de-aminated into a compound which is itself psychoactive and is really the one responsible for its psychoactive effects.

Mescaline Molecule

it is broken down by monoamine oxidase (MAO-B)

That is why you need to take large amounts of the substance in order to have an effect. ( compared to more potent psychedelic phenethylamines or amphetamines)

The difference is, most psychedelic phenethylamines are not metabolized as quickly as tryptamines are by MAO-A. For the same reason this is why phenethylamines have longer duration in general, the rate can vary a lot too.

In order to get a lasting effect from mescaline, you need to take a large enough dose to 'saturate' the MAO-B enzyme, so that it cannot process anymore mescaline. You give it a larger dose than it can process then it will have to chew away at it, while the rest of the dose can have an effect on the CNS and psyche. This minimum saturation dose is around 50-100mg.

In this way, mescaline actually functions as a competitive inhibitor of MAO. And many drugs too, typically, since these enzymes are designed for feedback inhibition.

These type of 'inhibitors', really any molecule metabolized by MAO can also function as an 'inhibitor', the enzyme can only chew one at a time. They don't lock up the enzyme by bonding and changing the conformation the site like irreversible MAOI , or even like RIMA, which is also a noncompetitive inhibitor, but they simply bind more strongly than other ligands, so compete for the active site. Hordeine is a good example of this type of MAO-B inhibitor, it has a very high affinity to MAO-B compared to other phenethylamines, so it will bind to the enzyme first, preventing metabolism of the other phenethylamines until the hordeine is all used up.

This can actually be measured with doses less than 100mg being excreted very quickly compared to doses greater than 100mg. I believe Shulgin even recorded these self-experiments.

The same principle will work with any compound fundamentally, if you take a large enough dose of DMT orally ( grams), you will experience a psychedelic effect.

Other phenethylamines work in the same way they are just more potent agonists and more lipophilic molecules

This is very interesting - hordenine is known to be present in peyote and also in active Trichocereus cacti.

What about Phenethylamine? It's available as a health supplement (PEA), could it keep MAO-B busy and give more mileage to mescaline?

yep

i've tried this before but something i wouldn't really recommend pushing the phenethylamine dosage up to grams , as well as hordeine I would not recommend, since it seems to have a lot of adrenergic action, while it can potentiate the experience it also results in a lot of undesirable effects on blood pressure and other CNS stimulation.

But testing this around in the lower dose range was pretty interesting. Mixing phenethylamine and Mescaline definitely feels better than mixing hordeine with mescaline. Hordeine is enough to potentiate phenethylamine and give it some stimulation and euphoric effects, so its too strong to mix with mescaline.

I've wanted to investigate this further with other harder to access phenethylamines, that are typically inactive at normal dosages, but likely are powerful synergetically:

Examples : MDPEA, lophophine, 2C-O, 2C-D, 2C-H

Lophophine, 2C-O, and 2C-D are still active on their own, if the dose is high enough

Very interesting. Thank you Mindlusion.

Wow! Thank you so much for this informative response Mindlusion! This makes a lot of things make much more sense.