In hindsight I should have clarified - I was referring to mammalian biosynthesis which when applied to mescaline is novel and generally unheard of. Specifically the process that occurs when mescaline is metabolised.
I'm of the opinion that mescalines 3,4,5-trimethoxy pattern is a "special case" for the PEA class and this has some bearing on the activity of 2-×, 4-× and 6-× mescaline analogs.
Essentially it seems that mescaline is a weakly active prodrug which is metabolised into at least 1 active metabolite which hasn't been characterised afaik. This active metabolite is likely
more potent than mescaline itself, I estimate in the 20-80mg range. The implications are that all potency comparisons with mescaline need revising including Shulgins MU (mescaline units) concept; and that all receptor activity analyses of mescaline are inaccurate in the sense that they refer to a prodrug (eg Vyvanse behaves very unlike amphetamine). It's ironic that mescaline is the prototypical PEA psychedelic yet appears to be the only PEA which behaves as a weakly active prodrug. Other potential candidates include TOMSO and metaescaline from PiHKAL which both produce a tomso effect.
The efficacy of this "bioactivation" process varies from person to person due to subjective differences in the biochemical environment (enzyme levels, endogenous secondary amine levels etc). Some people report sub-500mg doses to be sufficiently active but others require larger doses. A small percentage of people find mescaline completely inactive.
This "bioactivation" begins when
SSAO deaminates mescaline into it's aldehyde which is a key intermediate (I theorise that using 3,4,5-TMeO-phenylethanol will form the same aldehyde via the ADH enzyme). As convenient as it might be for the mescaline-derived aldehyde to somehow be aminated with an endogenously produced secondary amine (of which there are several), I (and the people who rediscovered this in 2013) consider it unlikely since dimethyl-M is largely inactive and the piperidyl- & pyrrolidinyl- analogs aren't likely to be active (at least not at the desired receptors or in the desired manner).
This "bioactivation" idea was rediscovered in 2013 by accident (I was a member of the now inactive forum) and during the course of investigations an older webpage was found which highlighted the uniqueness of mescalines metabolism and importance of it's aldehyde metabolite (so clearly someone was already aware). One user tried it
with intriguing results.
Further clues into the endogenous amines involved were given by Oswald who found that allylbenzene intermediate metabolites are aminated with endogenous piperidine, dimethylamine and pyrrolidine. These secondary amines can be formed from dietary precursors (lysine, choline and arginine respectively) which allows the psychonaut to tailor the bioactivation process and influence the outcome. Tests performed using this understanding led to very interesting results.
Since the mescaline aldehyde metabolite is a key intermediate in this scenario it must be protected from attack by ALDH which forms the carboxylic acid (phenacetylaldehyde → phenylacetic acid). Thus the use of ALDHIs becomes relevant and equally avoidance of common items which induce ALDH as this would effectively make mescaline less active by suppressing it's key intermediate metabolite (many common foods & supplements induce ALDH).
Things which inhibit SSAO would also make mescaline less active by impeding the formation of it's key intermediate aldehyde metabolite (with the exception of caffeine).
Of course, if the presupposition is that mescaline is the primary active drug then using an
SSAOI should make mescaline more potent. YMMV.
I digress... this "aldehyde-centric" potentiation concept is applicable to all phenethylamines and tryptamines which are deaminated by MAO or SSAO, but the 3,4,5-trimethoxy PEA substitution appears to be a special case. The current consensus overlooks the relevance of ALDH and tends to assume that drugs are the "primary active" per se, with little consideration for the possibility that they might also be acting as prodrugs. This has implications in the design of 3,4,5 substituted PEAs and related analogs (eg 2-×, 4-× or 6-× mescaline).
