Editing Psilocybin (section)

====Metabolism====
[[File:Metabolism of psilocybin in humans and mice.png|class=skin-invert-image|thumb|right|500px|[[Drug metabolism|Metabolism]] of psilocybin and [[psilocin]] in humans and mice.<ref name="ThomannKolaczynskaStoeckmann2024" /><ref name="FradetKellyDonnelly2025" />]]

Psilocybin is [[dephosphorylation|dephosphorylated]] into its [[active metabolite|active form]] [[psilocin]] in the body.<ref name="MacCallumLoPistawka2022" /><ref name="DoddNormanEyre2023" /><ref name="LoweToyangSteele2021" /> Psilocybin is [[metabolism|metabolized]] in the [[intestine]]s, [[liver]], [[kidney]]s, [[blood]], and other [[tissue (biology)|tissue]]s and [[bodily fluid]]s.<ref name="OttovanderHeijdenSchoones2025" /><ref name="Dinis-Oliveira2017" /><ref name="ThomannKolaczynskaStoeckmann2024">{{cite journal | vauthors = Thomann J, Kolaczynska KE, Stoeckmann OV, Rudin D, Vizeli P, Hoener MC, Pryce CR, Vollenweider FX, Liechti ME, Duthaler U | title = In vitro and in vivo metabolism of psilocybin's active metabolite psilocin | journal = Front Pharmacol | volume = 15 | issue = | pages = 1391689 | date = 2024 | pmid = 38741590 | pmc = 11089204 | doi = 10.3389/fphar.2024.1391689 | doi-access = free | url = }}</ref> There is significant [[first-pass metabolism]] of psilocybin and psilocin with [[oral administration]].<ref name="OttovanderHeijdenSchoones2025" /><ref name="ThomannKolaczynskaStoeckmann2024" /> No psilocybin has been detected in the blood in humans after oral administration, suggesting virtually complete dephosphorylation into psilocin with the first pass.<ref name="OttovanderHeijdenSchoones2025" /><ref name="DoddNormanEyre2023" /><ref name="LoweToyangSteele2021" /><ref name="ThomannKolaczynskaStoeckmann2024" /> It is also said to be converted 90% to 97% into psilocin.<ref name="StraussGhoshMurray2022">{{cite journal | vauthors = Strauss D, Ghosh S, Murray Z, Gryzenhout M | title = Psilocybin containing mushrooms: a rapidly developing biotechnology industry in the psychiatry, biomedical and nutraceutical fields | journal = 3 Biotech | volume = 12 | issue = 12 | pages = 339 | date = December 2022 | pmid = 36340802 | pmc = 9633885 | doi = 10.1007/s13205-022-03355-4 | url = }}</ref> The [[competitive inhibitor|competitive]] [[phosphatase inhibitor]] β-glycerolphosphate, which inhibits psilocybin dephosphorylation, greatly attenuates the behavioral effects of psilocybin in rodents.<ref name="TylšPáleníčekHoráček2014" /><ref name="ThomannKolaczynskaStoeckmann2024" /><ref name="Horita1963">{{cite journal | vauthors = Horita A | title = Some biochemical studies on psilocybin and psilocin | journal = Journal of Neuropsychiatry | volume = 4 | date = 1963 | pages = 270–273 | pmid = 13954906 | url = https://apps.dtic.mil/sti/tr/pdf/AD0291057.pdf#page=3}}</ref> Psilocybin undergoes dephosphorylation into psilocin via the [[acid]]ic environment of the [[stomach]] or the actions of [[alkaline phosphatase]] (ALP) and non-specific [[esterase]]s in tissues and fluids.<ref name="PepeHesamidelaCerda2023"/><ref name="Dinis-Oliveira2017">{{cite journal | vauthors = Dinis-Oliveira RJ | title = Metabolism of psilocybin and psilocin: clinical and forensic toxicological relevance | journal = Drug Metab Rev | volume = 49 | issue = 1 | pages = 84–91 | date = February 2017 | pmid = 28074670 | doi = 10.1080/03602532.2016.1278228 | url = }}</ref><ref name="TylšPáleníčekHoráček2014" />

Psilocin is [[demethylation|demethylated]] and [[oxidative deamination|oxidatively deaminated]] by [[monoamine oxidase]] (MAO), specifically [[monoamine oxidase A]] (MAO-A), into 4-hydroxyindole-3-acetaldehyde (4-HIAL or 4-HIA).<ref name="DoddNormanEyre2023" /><ref name="LoweToyangSteele2021" /><ref name="ChenWangYong2025">{{cite journal | vauthors = Chen J, Wang Z, Yong CY, Goh EM, Moy HY, Chan EC | title = Elucidating the Phase I metabolism of psilocin in vitro | journal = Arch Toxicol | volume = 99| issue = 3| pages = 1085–1094| date = January 2025 | pmid = 39751877 | doi = 10.1007/s00204-024-03952-7 | bibcode = 2025ArTox..99.1085C | url = }}</ref> 4-HIAL is then further oxidated into 4-hydroxyindole-3-acetic acid (4-HIAA) by [[aldehyde dehydrogenase]] (ALDH) or into 4-hydroxytryptophol (4-HTOL or 4-HTP) by [[alcohol dehydrogenase]] (ALD).<ref name="DoddNormanEyre2023" /><ref name="LoweToyangSteele2021" /> Deamination of psilocin by MAO-A appears to be responsible for about 4% or 33% of its metabolism in different studies.<ref name="ThomannKolaczynskaStoeckmann2024" /><ref name="HolzeBeckerKolaczynska2023" /><ref name="TylšPáleníčekHoráček2014" /> In contrast to psilocin, its metabolites 4-HIAA and 4-HTP showed no affinity for or activation of multiple serotonin receptors and are considered inactive.<ref name="DoddNormanEyre2023" /><ref name="FradetKellyDonnelly2025" /><ref name="ThomannKolaczynskaStoeckmann2024" /> Based on ''in vitro'' studies, it has been estimated that MAO-A is responsible for about 81% of psilocin's [[Phase I metabolism|phase I]] hepatic metabolism.<ref name="ChenWangYong2025" /> Psilocin and its metabolites are also [[glucuronidation|glucuronidated]] by [[UDP-glucuronyltransferase]]s (UGTs).<ref name="OttovanderHeijdenSchoones2025" /><ref name="DoddNormanEyre2023" /><ref name="LoweToyangSteele2021" /><ref name="ThomannKolaczynskaStoeckmann2024" /> [[UGT1A10]] and [[UGT1A9]] appear to be the most involved.<ref name="OttovanderHeijdenSchoones2025" /><ref name="DoddNormanEyre2023" /><ref name="TylšPáleníčekHoráček2014" /> Psilocybin's glucuronidated metabolites include psilocin-''O''-glucuronide and 4-HIAA-''O''-glucuronide.<ref name="DoddNormanEyre2023" /><ref name="LoweToyangSteele2021" /><ref name="ThomannKolaczynskaStoeckmann2024" /> Approximately 80% of psilocin in [[blood plasma]] is in [[conjugation (biochemistry)|conjugated]] form, and conjugated psilocin levels are about fourfold higher than levels of free psilocin.<ref name="ThomannKolaczynskaStoeckmann2024" /><ref name="TylšPáleníčekHoráček2014" /> Plasma 4-HIAA levels are also much higher than those of free psilocin.<ref name="DoddNormanEyre2023" />

[[Norpsilocin]] (4-HO-NMT), formed from psilocin via demethylation mediated by the [[cytochrome P450]] [[enzyme]] [[CYP2D6]], is known to occur in mice ''[[in vivo]]'' and with human recombinant CYP2D6 ''[[in vitro]]'' but was not detected in humans ''in vivo''.<ref name="ThomannKolaczynskaStoeckmann2024" /> An oxidized psilocin metabolite of unknown [[chemical structure]] is also formed by hydroxyindole oxidase activity of CYP2D6.<ref name="ThomannKolaczynskaStoeckmann2024" /><ref name="TylšPáleníčekHoráček2014" /> Oxidized psilocin is possibly a [[quinone]]-type structure like psilocin iminoquinone (4-hydroxy-5-oxo-''N'',''N''-DMT) or psilocin hydroquinone (4,5-dihydroxy-''N'',''N''-DMT).<ref name="ThomannKolaczynskaStoeckmann2024" /><ref name="TylšPáleníčekHoráček2014" /> Additional metabolites formed by CYP2D6 may also be present.<ref name="ThomannKolaczynskaStoeckmann2024" /> Besides CYP2D6, [[CYP3A4]] showed minor activity in metabolizing psilocin, though the produced metabolite is unknown.<ref name="ThomannKolaczynskaStoeckmann2024" /> Other [[cytochrome P450]] [[enzyme]]s besides CYP2D6 and CYP3A4 appear unlikely to be involved in psilocin metabolism.<ref name="ThomannKolaczynskaStoeckmann2024" /> CYP2D6 [[pharmacogenomics|metabolizer phenotype]]s do not modify psilocin exposure in humans, suggesting that CYP2D6 is not critically involved in psilocin metabolism and is unlikely to result in interindividual differences in psilocin kinetics or effects.<ref name="FradetKellyDonnelly2025" /><ref name="ThomannKolaczynskaStoeckmann2024" /> Psilocybin and psilocin might inhibit [[CYP3A4]] and [[CYP2A6]] to some extent, respectively.<ref name="Manzano-NunezGomezToledo-Mendoza2025" />