Editing Psilocybin (section)

====Distribution====
Psilocin, the active form of psilocybin, is extensively [[distribution (pharmacology)|distributed]] to all [[tissue (biology)|tissue]]s through the [[bloodstream]].<ref name="MacCallumLoPistawka2022" /> Its [[volume of distribution]] is 505 to 1,267{{nbsp}}L.<ref name="OttovanderHeijdenSchoones2025" /> Psilocybin itself is [[hydrophilic]] due to its [[phosphate]] [[functional group|group]] and cannot easily cross the [[blood–brain barrier]].<ref name="FradetKellyDonnelly2025" /><ref name="MacCallumLoPistawka2022" /> Conversely, psilocin is [[lipophilic]] and readily crosses the blood–brain barrier to exert effects in the [[central nervous system]].<ref name="MacCallumLoPistawka2022" /> The [[plasma protein binding]] of psilocybin is 66% and hence it is moderately plasma protein-bound.<ref name="ČamparaKovačić2024" />

[[File:Psilocin intramolecular hydrogen bond and pseudo-ring system.png|class=skin-invert-image|thumb|right|300px|Theoretical [[intramolecular force|intramolecular]] [[hydrogen bond]] and [[Ring (chemistry)#Rings and ring systems|pseudo-ring system]] occurring with [[psilocin]] (4-HO-DMT) but not with [[bufotenin]] (5-HO-DMT).<ref name="GumpperNichols2024" /><ref name="McBride2000" />]]

Psilocin (4-HO-DMT) is a close [[positional isomer]] of [[bufotenin]] (5-HO-DMT), which shows [[peripherally selective drug|peripheral selectivity]], and might be expected to have similarly restricted lipophilicity and blood–brain barrier permeability.<ref name="GumpperNichols2024">{{cite journal | vauthors = Gumpper RH, Nichols DE | title = Chemistry/structural biology of psychedelic drugs and their receptor(s) | journal = Br J Pharmacol | volume = | issue = | pages = | date = October 2024 | pmid = 39354889 | doi = 10.1111/bph.17361 | url = | quote = In contrast to DMT, psilocybin is orally active. [...] A structurally related molecule, [5-HO-DMT], known as bufotenine, is inactive after oral administration. How does the simple transposition of the hydroxy from the 4 to the 5 position alter the physicochemical properties of the DMT core? We asked that question more than four decades ago. In a study by Migliaccio et al. (1981), the 360 MHz proton NMR, the amine pKa values and the octanol–water Log P values were determined experimentally and compared for both psilocin and bufotenine (Figure 3a). The side chain protons in the NMR for bufotenine were shown to be rapidly rotating with no preference for gauche or trans conformations, whereas the side chain for psilocin was less mobile and was determined to favour a gauche (80%) versus trans (20%) conformation. Because psilocin is a weaker base but is also more lipid soluble, it was proposed that psilocin formed an intramolecular hydrogen bond, as illustrated in Figure 3a. In the energy-minimized structure of this conformation, the length of the hydrogen bond is 1.88 Å. The weaker pKa of psilocin relative to bufotenine means that psilocin is less highly ionized at pH 7.4—that is, 8.5% free base versus 0.53% for bufotenine at pH 7.4. Ionized amines must be unionized and desolvated to cross the blood–brain barrier; the intramolecular H bond in psilocin compensates for that as reflected by the higher lipophilicity of psilocin relative to bufotenine. Finally, the mechanism of deamination by MAO involves either a single electron transfer or a nucleophilic mechanism (Gaweska & Fitzpatrick, 2011; Zapata-Torres et al., 2015), either of which is more enzymically difficult when the amine electrons are hydrogen-bonded by the 4-hydroxy group (Figure 3a). Very recently, Lenz et al. (2022) have confirmed and extended the finding of the potential intramolecular hydrogen bond partially being responsible for slow MAO deamination as well as psilocin's enhanced ability to cross the blood–brain barrier. [...] This would explain why bufotenine is still an agonist at the 5-HT2A receptor but due to its poor physiochemical properties is not psychoactive in humans. }}</ref><ref name="McBride2000">{{cite journal | vauthors = McBride MC | title = Bufotenine: toward an understanding of possible psychoactive mechanisms | journal = J Psychoactive Drugs | volume = 32 | issue = 3 | pages = 321–331 | date = 2000 | pmid = 11061684 | doi = 10.1080/02791072.2000.10400456 | url = https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=802678b9f472ee113a9df8011e68672c3681623d}}</ref> But psilocin appears to form a [[tricyclic compound|tricyclic]] [[Ring (chemistry)#Rings and ring systems|pseudo-ring system]] wherein its [[hydroxyl group]] and [[amine]] interact through [[hydrogen bond]]ing.<ref name="GumpperNichols2024" /><ref name="McBride2000" /><ref name="PlazasFaraone2023">{{cite journal | vauthors = Plazas E, Faraone N | title = Indole Alkaloids from Psychoactive Mushrooms: Chemical and Pharmacological Potential as Psychotherapeutic Agents | journal = Biomedicines | volume = 11 | issue = 2 | date = February 2023 | page = 461 | pmid = 36830997 | pmc = 9953455 | doi = 10.3390/biomedicines11020461 | doi-access = free | url = }}</ref><ref name="LenzDörnerTrottmann2022">{{cite journal | vauthors = Lenz C, Dörner S, Trottmann F, Hertweck C, Sherwood A, Hoffmeister D | title = Assessment of Bioactivity-Modulating Pseudo-Ring Formation in Psilocin and Related Tryptamines | journal = ChemBioChem | volume = 23 | issue = 13 | pages = e202200183 | date = July 2022 | pmid = 35483009 | pmc = 9401598 | doi = 10.1002/cbic.202200183 | url = }}</ref> This in turn makes psilocin much less [[Chemical polarity|polar]], more lipophilic, and more able to cross the blood–brain barrier and exert central actions than it would be otherwise.<ref name="GumpperNichols2024" /><ref name="McBride2000" /><ref name="PlazasFaraone2023" /><ref name="LenzDörnerTrottmann2022" /> It may also protect psilocin from metabolism by [[monoamine oxidase]] (MAO).<ref name="GumpperNichols2024" /> In contrast, bufotenin is not able to achieve this pseudo-ring system.<ref name="GumpperNichols2024" /><ref name="McBride2000" /><ref name="PlazasFaraone2023" /><ref name="LenzDörnerTrottmann2022" /> Accordingly, bufotenin is less lipophilic than psilocin in terms of [[partition coefficient]].<ref name="GumpperNichols2024" /><ref name="McBride2000" /> But bufotenin does still show significant central permeability and, like psilocybin, can produce robust hallucinogenic effects in humans.<ref name="McBride2000" /><ref name="PlazasFaraone2023" /><ref name="ShenJiangWinter2010">{{cite journal | vauthors = Shen HW, Jiang XL, Winter JC, Yu AM | title = Psychedelic 5-methoxy-N,N-dimethyltryptamine: metabolism, pharmacokinetics, drug interactions, and pharmacological actions | journal = Curr Drug Metab | volume = 11 | issue = 8 | pages = 659–666 | date = October 2010 | pmid = 20942780 | pmc = 3028383 | doi = 10.2174/138920010794233495 | url = }}</ref><ref name="Ott2001a">{{cite journal | author = [[Jonathan Ott]] | title = Pharmañopo-psychonautics: human intranasal, sublingual, intrarectal, pulmonary and oral pharmacology of bufotenine | journal = Journal of Psychoactive Drugs | volume = 33 | issue = 3 | pages = 273–281 | year = 2001 | pmid = 11718320 | doi = 10.1080/02791072.2001.10400574 | s2cid = 5877023 }}</ref>