MAO-A inhibitors with phenetylamines

[The Neural]

From wiki:

"between 20% and 50% of mescaline is excreted in the urine unchanged, and the rest being excreted as the carboxylic acid form of mescaline, a likely result of MAO degradation."

Taken from study (do not have access):

THE ABSORPTION, DISTRIBUTION AND URINARY EXCRETION OF MESCALINE IN THE DOG

1. The plasma levels of mescaline in dog plasma have been determined following intravenous, intramuscular, and oral administration of 20 mgm./kgm. of mescaline sulfate. The decay curves follow the characteristic slope usually related to differences in the route of administration. The intensity...

jpet.aspetjournals.org

which was with dogs, and we all know how little that applies to humans.

I assume however that this is far more relevant:

"Mescaline, 3,4,5-trimethoxyphenylacetic acid, N-acetyl-β-(3,4-dimethoxy-5-hydroxyphenyl) ethylamine and N-acetyl-mescaline have been identified in human urine after mescaline administration in the following amounts: mescaline 55–60%, 3,4,5-trimethoxyphenylacetic acid 27–30%, N-acetyl-β-(3,4,dimethoxy-5-hydroxyphenyl) ethylamine 5% and N-acetylmescaline less than 0.1%. Five other metabolites have been partially characterized.

Chromatographic evidence is presented for the presence of mescaline, 3,4,5-trimethoxyphenylacetic acid, N-acetylmescaline and N-acetyl-β-(3,4-dimethoxy-5-hydroxyphenyl) ethylamine in the cerebrospinal fluid in man after oral mescaline administration."

taken from this study:

Metabolic fate of mescaline in man - Psychopharmacology

Human subjects given C14-mescaline by mouth excrete an average of 87% of the dose during the first 24 hours and an average of 92% during the first 48 hours. Average half-life of mescaline in six hours.The composition of the urine in respect to the various metabolites of mescaline from hour to...

link.springer.com

to which I do not have access to, is back from 1966, on humans, and refers to the molecule as C14-Mescaline. Is that a radioactive isotope? Will this extra bond vary the metabolic pathway in a way that the observations above would not apply to mescaline?

 

[Solipsis]

Sorry to drag this up but it seemed interesting.

- Caffeine is an inhibitor of both MAO and SSAO.

- "Dietary Phenolic Compounds Interfere with the Fate of Hydrogen Peroxide in Human Adipose Tissue but Do Not Directly Inhibit Primary Amine Oxidase Activity."

talks about quercetin and kaempferol which are present in bridgesii and thought to be what makes that more psychedelic despite the not-high and unreliable mesc content.
It says that resveratrol and kaempferol are very poor MAO inhibitors at best and nothing at all for SSAO's, instead there is some different interaction with the related tissues and metabolism.

- I read that reference mentioned in the previous post but it says very little about what is responsible for the metabolism and more about the metabolites that have been detected. Says something about N-acetylation probably preceding O-demethylation (on the 6 position) and that deamination is virtually not happening but none of that seems very significant or relevant.

As we know the main metabolite is the mesc acetic acid analogue and that study doesn't say why.
In general it's just kind of assumed its done by some sort of amine oxidase but that doesnt tell us which one.

- I read that harmine / harmaline is not only a substrate for MAO-A but also SSAO so that seems very interesting. Does seem to highly suggest it is SSAO to focus on.

- I wonder if the reason terscheckii is apparently rather powerful is because trichocereine which is a tertiary amine, inhibits SSAO's, at the very least i believe it interferes with what metabolizes mescaline.

- SSAO's are called that because they are sensitive to inhibition to semicarbazide. Which is a structure that can almost exactly be found in the structure of caffeine.

I'm very interested in finding a cyclic or tertiary amine which is considered safe and even ubiquitous in natural diets, ideally one which is not a substrate for MAO-B (and for safety ofc neither a real significant one of MAO-A) and which should be one for SSAO's.
I really don't like caffeine tho. Hmm maybe more something like theobromine then..

Uric acid... LOL

 

[downwardsfromzero]

Thanks for raising this point. Here's a good review article about SSAO/PAO:

Semicarbazide-Sensitive Amine Oxidases: Enzymes with Quite a Lot to Do, attached.

There are
large species differences in the specificities of SSAO,
but the non-physiological amine benzylamine is a good
substrate for the mammalian enzymes. Indeed, plasma
SSAO has sometimes been referred to as benzylamine
oxidase. The physiological substrates are believed to
include aminoacetone (Lyles and Chalmers, 1992),
methylamine (Precious et al., 1988), 2-phenylethyl-
amine, tyramine (Young et al., 1982) and dopamine
(Lizcano et al., 1991a, 1991b). Many of the substrates
for SSAO are also oxidatively deaminated by MAO, but
aminoacetone and methylamine are not MAO sub-
strates. Although 5-HT is not a substrate for SSAO
from most sources, it is a good substrate for the enzyme
from pig and human dental pulp (Nordqvist et al., 1982;
O’Sullivan et al., 2003a, 2003b). SSAO also catalyses
the oxidative deamination of a number of xenobiotics
(see Tipton and Strolin Benedetti, 2001), including
mescaline and the anti-malarial drug, primaquine.

EDIT: But then again:

For example, mescaline
has been shown to be oxidised more efficiently than
benzylamine by pig plasma SSAO (Buffoni and Della
Corte, 1972) but the human enzyme has no detectable
activity towards this substrate.

I'm very interested in finding a cyclic or tertiary amine which is considered safe and even ubiquitous in natural diets, ideally one which is not a substrate for MAO-B (and for safety ofc neither a real significant one of MAO-A) and which should be one for SSAO's.

Hordenine, perhaps? OK, maybe it's a bit stimulating but it's kind of the tyramine version of trichocerine, so to speak, and thus seems likely to be a substrate for PAO.

 

[downwardsfromzero]

Here's the other paper, mentioned above in post #21.

Quite an interesting (and, call me squeamish, at times brutal) read.

Imagine that - being catheterised, fed 500mg radioactive mescaline, then having blood samples taken every hour! If you're really lucky, they take your cerebrospinal fluid as well... Them were the days