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Someone please explain to me the pharmacology of mescaline

If I'm not mistaken, the emerging consensus is that thujone/absinthe/wormwood/the green fairy is only psychoactive because of the CH3CH2OH consumed along with it.
 
Phener said:
MAOI definately makes sense with MESCALINE.
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No no no, read Vecktor's post again: MAO-substrate, not inhibitor.
It blocks MAO by being metabolized itself (and usually one takes several 100 mg of mescaline,so yeah, there is some material floating around) and not by just binding to the active site and remaining stuck there.

I would agree so far. As plain PEA without an alpha-alkyl-residue it makes a good MAO-substrate.


- Murphy
 
MurphyClox said:
No no no, read Vecktor's post again: MAO-substrate, not inhibitor.
It blocks MAO by being metabolized itself (and usually one takes several 100 mg of mescaline,so yeah, there is some material floating around) and not by just binding to the active site and remaining stuck there.

I would agree so far. As plain PEA without an alpha-alkyl-residue it makes a good MAO-substrate.


- Murphy
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It seems like I have to say this over and over. Mescaline is not a substrate for MAO! Once again, repeat after me, mescaline is not a substrate for MAO! The data showing this goes back to the 1960's. It is a substrate for another amine oxidase, SSAO. The data show that in the presence of semicarbazide, there is no metabolism of mescaline in liver extracts. Semicarbazide is a specific inhibitor of SSAO, but not MAO. Hence the name, Semicarbazide Sensitive Amine Oxidase. MAO is a flavoenzyme, SSAO is a quinoprotein. Shulgin is partly responsible for this misconception, since he speculated about MAO metabolism in Pihkal, in spite of preexisting data to the contrary. However, the high doses of mescaline are due to its low affinity for the 5HT2a receptor, not its metabolism by MAO.
 
Very interesting. I wasn't aware of this and considered it commonly accepted that mescaline and all related congeners were suitable substrate for MAO. Speaking about liver extracts, how well is MAO-B studied in this respect? As far as I'm aware it occurs almost exclusively in the brain.


Peace! - Murphy
 
learn something new every day, A couple of 1950's papers come up on searching for mescaline and amine oxidase. it may be the case in rodent homogenates that it is indeed mostly metabolised by the semicarbazide sensitive enzyme, a couple of questions then arise... why in man is the phenylacetic acid seen and not any trace of the acetaldehyde? why do MAOI's increase the effects of mescaline in man. if you search on science direct a few later papers come up which might give some answers, I don't have access at the moment.
 
This one seems interesting:

Oxidative metabolism of mescaline in the central nervous system-II: Oxidative deamination of mescaline and 2,3,4-trimethoxy-β-phenylethylamine by different mouse brain area in vitro

Don't have access tho :-/
 
As I said earlier, it seems that mescaline's phamacology is still not totally understood, even with it being the model that most other psychedelic drugs are compared to. :p
 
Well, I looked this up and it looks like at least for the brain metabolism of mescaline, this above statement holds not true.
Look at the comparative data of the brain metabolism (expressed in total measured radioactivity after applying tritium-marked mescaline in animals either untreated with any inhibitor, or treated with pargyline (an acetylene, i.e. MAO-selective), or treated with semicarbazide (SSAO-selective):


(from: Biochem Pharmacol 1974, 23, p.273)

The levels of total radioactivity in the brain are actually higher after pargyline-administration than without. Furthermore, the authors state:
[…] (2) Pargyline pretreatment has a pronounced effect on the amine concentration in brain. Semicarbazide pretreatment also raises the mescaline concentration, without, however, decreasing significantly the concentrations of the acids below the control values (Table 2). In vitro semicarbazide and other DAO inhibitors have only slight influence on mescaline oxidation. These observations, together with the relatively rapid elimination of mescaline from brain suggest several pathways of mescaline metabolism: oxidation by MAO; oxidative degradation to 3,4,5-trimethoxy-benzoic acid; N-acetylation; and probably transamination, besides secernation into the CSF and outflow from brain with the blood stream. Evidence for mescaline transamination is very indirect at present. We assume this type of reaction on grounds of the in vivo effect of semicarbazide on mescaline metabolism, the slight inhibitory activity of DAO inhibitors on mescaline degradation by brain homogenates and furthermore on the lack of effect of DAO inhibitors on 2,3,4-TMPEA metabolism in vitro and in vivo.
[...]Despite the Pargyline effect on mescaline metabolism, we are still doubtful about the formation of 3,4,5-TMPAA in brain, and consequently about the correctness of the suggestions concerned with brain metabolism of mescaline, made above. Indeed there was no convincing argument against the assumption that the metabolites of mescaline found in brain were of peripheral origin. It was necessary, therefore, to clarify this problem.
The results obtained after the intraperitoneal injections of labelled 3,4,5-TMPAA showed (Table 4) that only a small amount if any of this acid in brain, after i.p. injection of mescaline, is of peripheral origin, since the proportion of 3,4,5-TMPAA penetrating from blood into brain is small.
Still better evidence was obtained for the oxidative metabolism of mescaline, and the formation of 3,4,5-TMPAA in brain by intraventricuiar mescaline injections. Despite chloralhydrate narcosis, the elimination rate of mescaline and the concentration profile of 3,4,5-TMPAA in brain was practically identical with that observed after intra-peritoneal injection of mescaline, although the brain-blood ratios differed very considerably in the two experiments (Tables 3 and 5).
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Peace! - Murphy


P.S. This excerpts are actually taken from part 4 of the article which mimac suggested.
 
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Further support that mescaline is actually a MAO-substrate seems to come from this publication (I only read the abstract though):

Shah, N. S.; Himwich, H. E.
"Mescaline-8-14C in mice. Effect of amine oxidase inhibitors on metabolism."
Neuropharmacology 1971, 10(5), p.547-56
Abstract
Pretreatment of mice with the monoamine oxidase inhibitor, tranylcypromine , or the mono- and diamine oxidase inhibitor, iproniazid before i.p. administration of mescaline (I) decreased the level of 3,4,5-trimethoxyphenylacetic acid and increased that of N-acetylmescaline in the liver, plasma, and urine, but had no effect on these levels in the brain.
Semicarbazide, a diamine oxidase inhibitor, had no effect on the levels of I metabolites. Incubation of brain slices, homogenates, or subcellular fractions with I revealed that 2-8% of added I was oxidatively deaminated to 3,4,5-trimethoxyphenylacetic acid but yielded no evidence of N-acetylation of I.
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Am I reading this entirely wrong or are they suggesting that semicarbazide-administration had no effect on mescaline's metabolism whatsoever?! This would actually mean that mescaline is not a substrate of SSAO (or DAO) at all, at least not in the brain.


Peace! - Murphy



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P.S.: Well, looks like we have to differ indeed between hepatic and brain metabolism. This sounds convincing to me:

Shah, N. S.
"Comparative study on the metabolism of 3,4-dimethoxyphenylethylamine-C14 and mescaline-C14 by rabbit, mouse, and rat brain homogenates."
Archives Internationales de Pharmacodynamie et de Therapie 1971, 193(2), p.357-61.
Abstract
Brain homogenates of rabbit, mouse, and rat were highly active in the oxidative deamination of 3,4-dimethoxyphenylethylamine (I) as compared to that of mescaline. Iproniazid [54-92-2] (10^-3 M) effectively blocked the deamination of I but not that of mescaline. Semicarbazide (10^-3 M) exerted no inhibition on the metabolic transformation of I and mescaline.
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P.P.S.: And to comment on Vecktor's question why always the phenylacetic acid is found but never the corresponding acetaldehyde: Could it be that oxidation of the former happens way to fast in the brain? (More asking than knowing here, to be honest)
 
MAO and mescaline?

Interesting data. Here is another paper:

DEGRADATION OF MESCALINE BY AMINE OXIDASES

JPET December 1958 vol. 124 no. 4 282-289

E. Albert Zeller, James Barsky, Elaine R. Berman, Marshall S. Cherkas and James R. Fouts

Department of Biochemistry, Northwestern University, Medical School, Chicago, Illinois

Abstract

The oxidative deamination of mescaline by various tissue preparations from 9 vertebrate species was investigated. The mescaline oxidase of rabbit liver was found to be present in the mitochondrial and microsomal fractions of the cell. The inhibitor pattern for the rabbit liver enzyme resembled that characterizing a typical diamine oxidase (DO). Similar results were obtained for the oxidation of mescaline by a partially purified hog kidney DO (histaminase) and for sheep plasma spermine oxidase. These 3 enzymes are classified as belonging to the group of semicarbazide-sensitive diamine oxidases. The experimental evidence for the degradation of mescaline by particulate preparations from hog kidney and liver, and mouse liver, implicates the action of a semicarbazide-resistant monoamine oxidase in these species.


Here is yet another:

The Effects of Ring-Methoxyl Groups on Biological Deamination of Phenethylamines

Leland C. Clark Jr., Frederick Benington, Richard D. Morin
J. Med. Chem., 1965, 8 (3), pp 353–355
DOI: 10.1021/jm00327a016

Here is the data from the latter paper:



Clearly, mescaline does not react in the presence of semicarbazide. I would argue that the metabolism in liver and kidneys is quantitatively more significant to the pharmacokinetics than brain metabolism. Notice that 2C-H and 2,4,5-trimethoxyphenethylamine metabolism is not affected by semicarbazide, suggesting that they are indeed metabolized by MAO. You have to be careful with the older literature, since they often refer to SSAO as "serum amine oxidase".=D
 
I bet that her tripping made her more prone to the feelings of opiate withdrawal. You said she was withdrawling (sp) so maybe she just didn't have any opiates and the trip made her more aware of her being dope-sick. That's not a pharmacology based answer obviously, but a psychological one at least.
 
tryp2fun said:
Clearly, mescaline does not react in the presence of semicarbazide. I would argue that the metabolism in liver and kidneys is quantitatively more significant to the pharmacokinetics than brain metabolism. Notice that 2C-H and 2,4,5-trimethoxyphenethylamine metabolism is not affected by semicarbazide, suggesting that they are indeed metabolized by MAO. You have to be careful with the older literature, since they often refer to SSAO as "serum amine oxidase".=D
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The references I cited are actually newer than yours ;)

Anyway, I absolutely agree that we need to make a difference between the hepatic and the brain's metabolism of mescaline, as both seem to differ significantly. Which one is of higher importance for mescaline's pharmacology, well, that is beyond my expertise. I would appreciate others with insight into this topic to chime in, as I don't see my dispute with tryp2fun entirely put to a rest yet. (And by the way, didn't have such an entertaining and well-behaved controversy for long!)


Peace! - Murphy
 
MurphyClox said:
The references I cited are actually newer than yours ;)

Anyway, I absolutely agree that we need to make a difference between the hepatic and the brain's metabolism of mescaline, as both seem to differ significantly. Which one is of higher importance for mescaline's pharmacology, well, that is beyond my expertise. I would appreciate others with insight into this topic to chime in, as I don't see my dispute with tryp2fun entirely put to a rest yet. (And by the way, didn't have such an entertaining and well-behaved controversy for long!)


Peace! - Murphy
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I don't think this is a dispute, but a discussion. It doesn't make sense that mescaline is not an MAO substrate in the body but it is in the brain. Also, in one of the references, 3,4-dimethoxyphenethylamine metabolism is inhibited by iproniazid, but mescaline metabolism is not. Iproniazid is an MAO inhibitor, so that is not consistent with mescaline metabolism by MAO. I suspect that the brain metabolism is due to some other enzyme than MAO or SSAO, since it is not semicarbazide sensitive. Maybe P-450, though the brain is not a rich source of P-450.:\
 
vecktor said:
it is a beta blocker which explains the effect on BP and heart rate.
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Mescaline is also a strong partial agonist at the imidazoline 1 receptor, which likely plays a significant role in its blood-pressure lowering effects.
 
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