Editing Mescaline (section)

====Metabolism====
[[File:Metabolism of mescaline.png|thumb|right|500px|[[Drug metabolism|Metabolism]] of mescaline in humans and/or animals.<ref name="Dinis-OliveiraPereiradaSilva2019" />]]

The primary [[metabolic pathway]] of mescaline is [[oxidative deamination]].<ref name="Dinis-OliveiraPereiradaSilva2019" /><ref name="CasselsSáez-Briones2018" /><ref name="VamvakopoulouNarineCampbell2023" /><ref name="KapadiaFayez1970">{{cite journal | vauthors = Kapadia GJ, Fayez MB | title = Peyote constituents: chemistry, biogenesis, and biological effects | journal = J Pharm Sci | volume = 59 | issue = 12 | pages = 1699–1727 | date = December 1970 | pmid = 5499699 | doi = 10.1002/jps.2600591202 | url = }}</ref> The specific [[enzyme]]s mediating the deamination of mescaline are controversial however.<ref name="Dinis-OliveiraPereiradaSilva2019" /><ref name="KapadiaFayez1970" /><ref name="SmythiesJohnstonBradley1967" /> [[Monoamine oxidase]] (MAO), [[diamine oxidase]] (DAO; histamine oxidase), and/or other enzymes may be responsible.<ref name="Dinis-OliveiraPereiradaSilva2019" /><ref name="KapadiaFayez1970" /><ref name="SmythiesJohnstonBradley1967">{{cite journal | vauthors = Smythies JR, Johnston VS, Bradley RJ | title = Alteration by pretreatment with iproniazid and an inactive mescaline analogue of a behaviour change induced by mescaline | journal = Nature | volume = 216 | issue = 5111 | pages = 196–197 | date = October 1967 | pmid = 6057240 | doi = 10.1038/216196a0 | bibcode = 1967Natur.216..196S | url = }}</ref> [[Preclinical research|Preclinical studies]] of mescaline given in combination with inhibitors of MAO and/or DAO, such as [[iproniazid]], [[pargyline]], and [[semicarbazide]], have been conducted, but findings have been conflicting.<ref name="Dinis-OliveiraPereiradaSilva2019" /><ref name="KapadiaFayez1970" /><ref name="Patel1968" /><ref name="MusacchioGoldstein1967">{{cite journal | vauthors = Musacchio JM, Goldstein M | title = The metabolism of mescaline-14-C in rats | journal = Biochem Pharmacol | volume = 16 | issue = 6 | pages = 963–970 | date = June 1967 | pmid = 6040403 | doi = 10.1016/0006-2952(67)90268-7 | url = }}</ref><ref name="SmythiesJohnstonBradley1967" /> Mescaline has been reported to be a poor or negligible [[substrate (biochemistry)|substrate]] of highly purified human MAO ''[[in-vitro]]''.<ref name="KapadiaFayez1970" /><ref name="Patel1968" /><ref name="McEwen1965">{{cite journal | vauthors = McEwen CM | title = Human plasma monoamine oxidase. 1. Purification and identification | journal = J Biol Chem | volume = 240 | issue = 5 | pages = 2003–2010 | date = May 1965 | pmid = 5888801 | doi = 10.1016/S0021-9258(18)97417-X| doi-access = free | url = }}</ref>

Mescaline appears not to be subject to metabolism by [[CYP2D6]] based on ''in-vitro'' studies with human liver microsomes.<ref name="pmid9264312">{{cite journal | vauthors = Wu D, Otton SV, Inaba T, Kalow W, Sellers EM | title = Interactions of amphetamine analogs with human liver CYP2D6 | journal = Biochemical Pharmacology | volume = 53 | issue = 11 | pages = 1605–1612 | date = June 1997 | pmid = 9264312 | doi = 10.1016/S0006-2952(97)00014-2 }}</ref> Similarly, the ''in-vitro'' [[cytotoxicity]] of mescaline does not appear to be affected by [[cytochrome P450]] (CYP450) [[enzyme inhibitor]]s.<ref name="MartinsGil-MartinsCagide2023">{{cite journal | vauthors = Martins D, Gil-Martins E, Cagide F, da Fonseca C, Benfeito S, Fernandes C, Chavarria D, Remião F, Silva R, Borges F | title = Unraveling the In Vitro Toxicity Profile of Psychedelic 2C Phenethylamines and Their N-Benzylphenethylamine (NBOMe) Analogues | journal = Pharmaceuticals (Basel) | volume = 16 | issue = 8 | date = August 2023 | page = 1158 | pmid = 37631071 | pmc = 10458253 | doi = 10.3390/ph16081158 | doi-access = free | url = }}</ref> Conversely, it was potentiated by the [[MAO-A]] inhibitor [[clorgiline]] but not by the [[MAO-B]] inhibitor [[rasagiline]].<ref name="MartinsGil-MartinsCagide2023" /> These findings were in contrast to those with the related compound [[2C-B]], which was potentiated by rasagiline but not by clorgiline.<ref name="MartinsGil-MartinsCagide2023" />

Circulating [[Cmax (pharmacology)|peak]] and [[area-under-the-curve (pharmacokinetics)|area-under-the-curve]] concentrations of mescaline and 3,4,5-trimethoxyphenylacetic acid (TMPAA) are similar with oral administration of mescaline.<ref name="KlaiberSchmidBecker2024" /> Conversely, levels of [[N-acetylmescaline|''N''-acetylmescaline]] (NAM) are far lower than those of mescaline or TMPAA.<ref name="KlaiberSchmidBecker2024" /> [[Intravenous injection]] of mescaline may result in less hepatic deamination than with oral administration.<ref name="VamvakopoulouNarineCampbell2023" />

[[Active metabolite]]s of mescaline might contribute to its psychoactive effects.<ref name="Doesburg-vanKleffensZimmermann-KlemdGründemann2023" /><ref name="Dinis-OliveiraPereiradaSilva2019" /><ref name="CasselsSáez-Briones2018" /> However, both TMPAA and NAM have been said to be inactive based on human tests.<ref name="CharalampousWalkerKinross-Wright1966" /> Similarly, 3,4,5-trimethoxyphenylethanol (TMPE), 3,4,5-trimethoxyphenylacetaldehyde (TMPA), and NAM all failed to produce mescaline-like effects in rodent [[drug discrimination]] tests.<ref name="CasselsSáez-Briones2018" /><ref name="Nichols1981" /><ref name="BrowneHo1975">{{cite journal | vauthors = Browne RG, Ho BT | title = Discriminative stimulus properties of mescaline: mescaline or metabolite? | journal = Pharmacol Biochem Behav | volume = 3 | issue = 1 | pages = 109–114 | date = 1975 | pmid = 1129346 | doi = 10.1016/0091-3057(75)90088-x | url = }}</ref>

[[3,4,5-Trimethoxyamphetamine]] (TMA), the α-[[methyl group|methyl]] [[structural analog|analogue]] of mescaline and an MAO-resistant psychedelic, is only about twice as [[potency (pharmacology)|potent]] as mescaline as a psychedelic in humans despite having similar [[serotonin receptor]] [[affinity (pharmacology)|affinity]].<ref name="Nichols1981">{{cite journal | vauthors = Nichols DE | title = Structure-activity relationships of phenethylamine hallucinogens | journal = J Pharm Sci | volume = 70 | issue = 8 | pages = 839–849 | date = August 1981 | pmid = 7031221 | doi = 10.1002/jps.2600700802 | url = https://bitnest.netfirms.com/external/10.1002/jps.2600700802}}</ref> This suggests that the deamination of mescaline have a relatively limited impact on its potency, compared to for example the [[2C (psychedelics)|2C]] series of psychedelics.<ref name="Nichols1981" />