Editing Psilocybin (section)

===Pharmacodynamics===
{{See also|Psychedelic drug#Pharmacology}}
{{Psilocin activities|float=right}}

Psilocybin is a [[serotonergic psychedelic]] that acts as a [[prodrug]] of [[psilocin]], the [[active metabolite|active form]] of the drug.<ref name="HolzeSinghLiechti2024" /><ref name="DoddNormanEyre2023">{{cite journal | vauthors = Dodd S, Norman TR, Eyre HA, Stahl SM, Phillips A, Carvalho AF, Berk M | title = Psilocybin in neuropsychiatry: a review of its pharmacology, safety, and efficacy | journal = CNS Spectr | volume = 28 | issue = 4 | pages = 416–426 | date = August 2023 | pmid = 35811423 | doi = 10.1017/S1092852922000888 | url = https://www.cambridge.org/core/services/aop-cambridge-core/content/view/AA1FB4F49C14BA3F398238D6E5A3947A/S1092852922000888a.pdf/div-class-title-psilocybin-in-neuropsychiatry-a-review-of-its-pharmacology-safety-and-efficacy-div.pdf}}</ref> Psilocin is a close [[structural analog|analogue]] of the [[monoamine neurotransmitter]] [[serotonin]] and, like serotonin, acts as a [[binding selectivity|non-selective]] [[agonist]] of the [[serotonin receptor]]s, including behaving as a [[partial agonist]] of the serotonin [[5-HT2A receptor|5-HT<sub>2A</sub> receptor]].<ref name="HolzeSinghLiechti2024" /><ref name="DoddNormanEyre2023" /><ref name="TylšPáleníčekHoráček2014" /> It shows high [[affinity (pharmacology)|affinity]] for most of the serotonin receptors, with the notable exception of the serotonin [[5-HT3 receptor|5-HT<sub>3</sub> receptor]].<ref name="HolzeSinghLiechti2024" /><ref name="DoddNormanEyre2023" /><ref name="TylšPáleníčekHoráček2014" /> Psilocin's affinity for the serotonin 5-HT<sub>2A</sub> receptor is 15-fold higher in humans than in rats due to species differences.<ref name="TylšPáleníčekHoráček2014" /><ref name="GallaherChenShih1993">{{cite journal | vauthors = Gallaher TK, Chen K, Shih JC | date = 1993 | title = Higher affinity of psilocin for human than rat 5-HT2 receptor indicates binding site structure | journal = Medicinal Chemistry Research | volume = 3 | issue = | pages = 52–66 | url = https://scholar.google.com/scholar?cluster=2484757771892655822}}</ref> In addition to interacting with the serotonin receptors, psilocin is a [[partial monoamine releasing agent|partial]] [[serotonin releasing agent]] with lower [[potency (pharmacology)|potency]].<ref name="RothmanPartillaBaumann2012" /><ref name="BloughLandavazoDecker2014" /> Unlike certain other psychedelics such as [[LSD]], it appears to show little affinity for many other [[biological target|target]]s, such as [[dopamine receptor]]s.<ref name="GeigerWurstDaniels2018" /><ref name="HolzeSinghLiechti2024" /><ref name="FradetKellyDonnelly2025" /><ref name="RickliMoningHoener2016" /><ref name="BindingDB-Psilocin" /><ref name="PDSP-Psilocin" /> Psilocin is an agonist of the mouse and rat but not human [[trace amine-associated receptor 1]] (TAAR1).<ref name="GainetdinovHoenerBerry2018"/><ref name="RickliMoningHoener2016" /><ref name="ShaharBotvinnikEsh-Zuntz2022" />

Psilocybin's and psilocin's psychedelic effects are mediated specifically by agonism of the serotonin 5-HT<sub>2A</sub> receptor.<ref name="HolzeSinghLiechti2024" /><ref name="DoddNormanEyre2023" /> [[Binding selectivity|Selective]] serotonin 5-HT<sub>2A</sub> receptor [[receptor antagonist|antagonist]]s like [[volinanserin]] block the [[head-twitch response]] (HTR), a behavioral proxy of psychedelic-like effects, induced by psilocybin in rodents, and the HTR is similarly absent in serotonin 5-HT<sub>2A</sub> receptor [[knockout mice]].<ref name="DoddNormanEyre2023" /><ref name="TylšPáleníčekHoráček2014">{{cite journal | vauthors = Tylš F, Páleníček T, Horáček J | title = Psilocybin - summary of knowledge and new perspectives | journal = Eur Neuropsychopharmacol | volume = 24 | issue = 3 | pages = 342–356 | date = March 2014 | pmid = 24444771 | doi = 10.1016/j.euroneuro.2013.12.006 | url = https://www.researchgate.net/publication/259517753}}</ref><ref name="Erkizia-SantamaríaAlles-PascualHorrillo2022">{{cite journal | vauthors = Erkizia-Santamaría I, Alles-Pascual R, Horrillo I, Meana JJ, Ortega JE | title = Serotonin 5-HT2A, 5-HT2c and 5-HT1A receptor involvement in the acute effects of psilocybin in mice. In vitro pharmacological profile and modulation of thermoregulation and head-twich response | journal = Biomed Pharmacother | volume = 154 | issue = | pages = 113612 | date = October 2022 | pmid = 36049313 | doi = 10.1016/j.biopha.2022.113612 | url = | doi-access = free }}</ref><ref name="ShaharBotvinnikEsh-Zuntz2022">{{cite journal | vauthors = Shahar O, Botvinnik A, Esh-Zuntz N, Brownstien M, Wolf R, Lotan A, Wolf G, Lerer B, Lifschytz T | title = Role of 5-HT2A, 5-HT2C, 5-HT1A and TAAR1 Receptors in the Head Twitch Response Induced by 5-Hydroxytryptophan and Psilocybin: Translational Implications | journal = Int J Mol Sci | volume = 23 | issue = 22 | date = November 2022 | page = 14148 | pmid = 36430623 | pmc = 9698447 | doi = 10.3390/ijms232214148 | doi-access = free | url = }}</ref> There is a significant relationship between psilocybin's hallucinogenic effects and serotonin 5-HT<sub>2A</sub> receptor [[receptor occupancy|occupancy]] in humans.<ref name="HolzeSinghLiechti2024" /><ref name="HalberstadtGeyer2011" /><ref name="MadsenFisherBurmester2019">{{cite journal | vauthors = Madsen MK, Fisher PM, Burmester D, Dyssegaard A, Stenbæk DS, Kristiansen S, Johansen SS, Lehel S, Linnet K, Svarer C, Erritzoe D, Ozenne B, Knudsen GM | title = Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels | journal = Neuropsychopharmacology | volume = 44 | issue = 7 | pages = 1328–1334 | date = June 2019 | pmid = 30685771 | pmc = 6785028 | doi = 10.1038/s41386-019-0324-9 | url = }}</ref> Psilocybin's psychedelic effects can be blocked by serotonin 5-HT<sub>2A</sub> receptor antagonists like [[ketanserin]] and [[risperidone]] in humans.<ref name="Canal2018">{{cite journal | vauthors = Canal CE | title = Serotonergic Psychedelics: Experimental Approaches for Assessing Mechanisms of Action | journal = Handb Exp Pharmacol | series = Handbook of Experimental Pharmacology | volume = 252 | issue = | pages = 227–260 | date = 2018 | pmid = 29532180 | pmc = 6136989 | doi = 10.1007/164_2018_107 | isbn = 978-3-030-10560-0 | url = | quote = Reports from clinical trials conclude that the psychedelic effects of psilocybin and LSD are mediated by 5-HT2A receptors, because they are blocked by ketanserin (40 mg, P.O.), typically viewed as a selective 5-HT2A antagonist (Kometer et al. 2012; Kraehenmann et al. 2017; Preller et al. 2017; Quednow et al. 2012). Haloperidol, typically viewed as a selective dopamine D2 antagonist, is much less effective than ketanserin at blocking psilocybin's effects, but risperidone, an antipsychotic with combined D2/5-HT2 activity, is as effective as ketanserin (Vollenweider et al. 1998).}}</ref><ref name="HolzeSinghLiechti2024" /><ref name="DoddNormanEyre2023" /><ref name="HalberstadtGeyer2011" /><ref name="Vollenweider1998" /> Activation of serotonin 5-HT<sub>2A</sub> receptors in [[layer V]] of the [[medial prefrontal cortex]] (mPFC) and consequent [[glutamate]] release in this area has been especially implicated in the hallucinogenic effects of psilocybin and other serotonergic psychedelics.<ref name="DeGregorioEnnsNuñez2018">{{cite book | vauthors = De Gregorio D, Enns JP, Nuñez NA, Posa L, Gobbi G | chapter = D-Lysergic acid diethylamide, psilocybin, and other classic hallucinogens: Mechanism of action and potential therapeutic applications in mood disorders | title = Psychedelic Neuroscience | series = Progress in Brain Research | volume = 242 | pages = 69–96 | date = 2018 | pmid = 30471683 | doi = 10.1016/bs.pbr.2018.07.008 | isbn = 978-0-12-814255-4 | url = | quote = Noteworthy, the activation of postsynaptic 5HT2A receptor in layer V of the medial prefrontal cortex (mPFC) is considered to be responsible for the visual hallucinations produced by LSD and other psychedelic drugs such as psilocybin (Jakab and Goldman-Rakic, 1998; Vollenweider and Kometer, 2010) (see Fig. 2). [...] Although the classic hallucinogens LSD and psilocybin do not have a direct affinity for glutamate receptors, several animal studies have highlighted that glutamate carries a significant weight of the overall downstream effects of LSD and hallucinogenic action. The activation of postsynaptic cortical 5HT2A increases extracellular glutamate release in the synaptic cleft which is reversed by selective 5-HT2A antagonists (Vollenweider et al., 1998), AMPA (α-amino-3-hydroxyl-5-methyl4-isoxazole-propionic acid) receptor antagonists (Zhang and Marek, 2008), agonists and positive allosteric modulators of mGluR2 (metabotropic glutamate receptor 2) (Benneyworth et al., 2007), and selective antagonists of the NR2B subunit of NMDA (N-methyl-D-aspartate) receptors (Lambe and Aghajanian, 2006). In particular, microdialysis in rats confirmed that systemic hallucinogen administration leads to a time-dependent increase in prefrontal cortex (PFC) glutamate levels, an effect which is blocked by administration with the selective 5HT2A antagonist M100907 (Muschamp et al., 2004). }}</ref><ref name="MarekSchoepp2021">{{cite book | vauthors = Marek GJ, Schoepp DD | chapter = Cortical influences of serotonin and glutamate on layer V pyramidal neurons | title = 5-HT Interaction with Other Neurotransmitters: Experimental Evidence and Therapeutic Relevance - Part B | series = Progress in Brain Research | volume = 261 | pages = 341–378 | date = 2021 | pmid = 33785135 | doi = 10.1016/bs.pbr.2020.11.002 | isbn = 978-0-444-64258-5 | url = }}</ref><ref name="Halberstadt2015" /><ref name="HalberstadtGeyer2018" /><ref name="WillinsMeltzer1997">{{cite journal | vauthors = Willins DL, Meltzer HY | title = Direct injection of 5-HT2A receptor agonists into the medial prefrontal cortex produces a head-twitch response in rats | journal = J Pharmacol Exp Ther | volume = 282 | issue = 2 | pages = 699–706 | date = August 1997 | pmid = 9262333 | doi = 10.1016/S0022-3565(24)36840-5| url = }}</ref> In addition, region-dependent alterations in brain glutamate levels may be related to the experience of [[ego dissolution]].<ref name="MasonKuypersMüller2020">{{cite journal | vauthors = Mason NL, Kuypers KP, Müller F, Reckweg J, Tse DH, Toennes SW, Hutten NR, Jansen JF, Stiers P, Feilding A, Ramaekers JG | title = Me, myself, bye: regional alterations in glutamate and the experience of ego dissolution with psilocybin | journal = Neuropsychopharmacology | volume = 45 | issue = 12 | pages = 2003–2011 | date = November 2020 | pmid = 32446245 | pmc = 7547711 | doi = 10.1038/s41386-020-0718-8 | doi-access = free }}</ref> The [[cryo-EM]] [[protein–ligand complex|structure]]s of the serotonin 5-HT<sub>2A</sub> receptor with psilocin, as well as with various other psychedelics and serotonin 5-HT<sub>2A</sub> receptor agonists, have been solved and published by [[Bryan L. Roth]] and colleagues.<ref name="GumpperJainKim2025">{{cite journal | vauthors = Gumpper RH, Jain MK, Kim K, Sun R, Sun N, Xu Z, DiBerto JF, Krumm BE, Kapolka NJ, Kaniskan HÜ, Nichols DE, Jin J, Fay JF, Roth BL | title = The structural diversity of psychedelic drug actions revealed | journal = Nature Communications | volume = 16 | issue = 1 | pages = 2734 | date = March 2025 | pmid = 40108183 | doi = 10.1038/s41467-025-57956-7 | pmc = 11923220 }}</ref><ref name="GumpperDiBertoJain2022">{{cite conference | vauthors = Gumpper RH, DiBerto J, Jain M, Kim K, Fay J, Roth BL | title = Structures of Hallucinogenic and Non-Hallucinogenic Analogues of the 5-HT2A Receptor Reveals Molecular Insights into Signaling Bias | conference = University of North Carolina at Chapel Hill Department of Pharmacology Research Retreat September 16th, 2022 – William and Ida Friday Center | date = September 2022 | url = https://www.med.unc.edu/pharm/wp-content/uploads/sites/930/2022/07/COMPLETE-PHARM-RETREAT-PROGRAM-2022-UPDATE.pdf#page=37}}</ref>

Although serotonin 5-HT<sub>2A</sub> receptor agonism mediates the [[hallucinogen]]ic effects of psilocybin and psilocin, activation of other serotonin receptors also appears to contribute to these compounds' [[psychoactive drug|psychoactive]] and behavioral effects.<ref name="HalberstadtGeyer2011">{{cite journal | vauthors = Halberstadt AL, Geyer MA | title = Multiple receptors contribute to the behavioral effects of indoleamine hallucinogens | journal = Neuropharmacology | volume = 61 | issue = 3 | pages = 364–381 | date = September 2011 | pmid = 21256140 | pmc = 3110631 | doi = 10.1016/j.neuropharm.2011.01.017 | url = }}</ref><ref name="DoddNormanEyre2023" /><ref name="TylšPáleníčekHoráček2014" /><ref name="CameronBenetatosLewis2023">{{cite journal | vauthors = Cameron LP, Benetatos J, Lewis V, Bonniwell EM, Jaster AM, Moliner R, Castrén E, McCorvy JD, Palner M, Aguilar-Valles A | title = Beyond the 5-HT2A Receptor: Classic and Nonclassic Targets in Psychedelic Drug Action | journal = J Neurosci | volume = 43 | issue = 45 | pages = 7472–7482 | date = November 2023 | pmid = 37940583 | pmc = 10634557 | doi = 10.1523/JNEUROSCI.1384-23.2023 | url = }}</ref><ref name="CordnerPrandovszkyPedicini2022">{{cite journal | vauthors = Cordner Z, Prandovszky E, Pedicini M, Liu H, Macias L, Pletnikov M, Tamashiro K, Yolken R | title = ACNP 61st Annual Meeting: Poster Abstracts P271-P540: P314. Psilocybin Alters Behavior and the Intestinal Microbiota in a Wild Type Mouse Model by Mechanisms That Are Not Fully Dependent on 5HT2A and 5HT2C Receptors | journal = Neuropsychopharmacology | volume = 47 | issue = Suppl 1 | pages = 220–370 (245–246) | date = December 2022 | pmid = 36456694 | pmc = 9714399 | doi = 10.1038/s41386-022-01485-0 | url = | quote = Psilocybin induced a robust head twitch response, increased exploratory behavior in the elevated plus maze, increased social behavior in the social interaction test, and decreased immobility in the forced swim test. Co-administration of ketanserin fully blocked the head twitch response without significantly altering psilocybin’s effects on other behavioral outcomes. In a separate cohort, treatment with psilocybin produced broad alteration of the intestinal microbiome, with particularly marked changes in the large intestine that were only partially blocked by pre-treatment with ketanserin. Finally, transplantation of intestinal contents from psilocybin-treated mice to naive untreated mice resulted in behavioral changes consistent with the effects of psilocybin treatment. [...] Our findings demonstrate that a single dose of psilocybin leads to behavioral changes in mice that are relevant for studies of resilience and affective disorders. Our results further indicate that the behavioral changes may not be fully dependent on psilocybin’s agonism of 5HT2A and 5HT2C receptors. Further, psilocybin appears to broadly alter the intestinal microbiome and transplantation of intestinal contents reproduces behavioral change associated with psilocybin treatment, suggesting a previously unknown microbiome-gut-brain mechanism of action.}}</ref><ref name="SinghShaharWolf2022">{{cite journal | vauthors = Singh S, Botvinnik A, Shahar O, Wolf G, Lotan A, Lerer B, Lifschytz T | title = ACNP 61st Annual Meeting: Poster Abstracts P271-P540: P426. Translational Implications of Marble Burying in ICR Mice for the Anti-Obsessional Effects of Psilocybin | journal = Neuropsychopharmacology | volume = 47 | issue = Suppl 1 | pages = 220–370 (309–309) | date = December 2022 | pmid = 36456694 | pmc = 9714399 | doi = 10.1038/s41386-022-01485-0 | url = }}</ref> Serotonin [[5-HT1A receptor|5-HT<sub>1A</sub> receptor]] activation seems to inhibit the hallucinogenic effects of psilocybin and other psychedelics.<ref name="HalmanKongSarris2024">{{Cite journal |vauthors=Halman A, Kong G, Sarris J, Perkins D |date=January 2024 |title=Drug-drug interactions involving classic psychedelics: A systematic review |journal=J Psychopharmacol |volume=38 |issue=1 |pages=3–18 |doi=10.1177/02698811231211219 |pmc=10851641 |pmid=37982394}}</ref><ref name="BrandtKavanaghTwamley2018">{{cite journal | vauthors = Brandt SD, Kavanagh PV, Twamley B, Westphal F, Elliott SP, Wallach J, Stratford A, Klein LM, McCorvy JD, Nichols DE, Halberstadt AL | title = Return of the lysergamides. Part IV: Analytical and pharmacological characterization of lysergic acid morpholide (LSM-775) | journal = Drug Test Anal | volume = 10 | issue = 2 | pages = 310–322 | date = February 2018 | pmid = 28585392 | pmc = 6230476 | doi = 10.1002/dta.2222 | url = | quote = Additionally, pretreatment with the 5‐HT1A agonist buspirone (20 mg p.o.) markedly attenuates the visual effects of psilocybin in human volunteers.59 Although buspirone failed to completely block the hallucinogenic effects of psilocybin, the limited inhibition is not necessarily surprising because buspirone is a low efficacy 5‐HT1A partial agonist.60 The level of 5‐HT1A activation produced by buspirone may not be sufficient to completely counteract the stimulation of 5‐HT2A receptors by psilocin (the active metabolite of psilocybin). Another consideration is that psilocin acts as a 5‐HT1A agonist.30 If 5‐HT1A activation by psilocin buffers its hallucinogenic effects similar to DMT58 then competition between psilocin and a weaker partial agonist such as buspirone would limit attenuation of the hallucinogenic response.}}</ref><ref name="PokornyPrellerKraehenmann2016">{{cite journal | vauthors = Pokorny T, Preller KH, Kraehenmann R, Vollenweider FX | title = Modulatory effect of the 5-HT1A agonist buspirone and the mixed non-hallucinogenic 5-HT1A/2A agonist ergotamine on psilocybin-induced psychedelic experience | journal = Eur Neuropsychopharmacol | volume = 26 | issue = 4 | pages = 756–766 | date = April 2016 | pmid = 26875114 | doi = 10.1016/j.euroneuro.2016.01.005 | url = }}</ref><ref name="Strassman1996">{{cite journal | vauthors = Strassman RJ | title = Human psychopharmacology of N,N-dimethyltryptamine | journal = Behav Brain Res | volume = 73 | issue = 1–2 | pages = 121–124 | date = 1996 | pmid = 8788488 | doi = 10.1016/0166-4328(96)00081-2 | url = }}</ref> Some of psilocybin's non-hallucinogenic behavioral effects in animals can be reversed by antagonists of the serotonin 5-HT<sub>1A</sub>, [[5-HT2B receptor|5-HT<sub>2B</sub>]], and [[5-HT2C receptor|5-HT<sub>2C</sub> receptor]]s.<ref name="DoddNormanEyre2023" /><ref name="TylšPáleníčekHoráček2014" /> Psilocybin produces profoundly [[hypolocomotion|decreased locomotor]] and [[exploration|investigatory behavior]] in rodents, and this appears to be dependent on serotonin 5-HT<sub>1A</sub> receptor activation but not on activation of the serotonin 5-HT<sub>2A</sub> or 5-HT<sub>2C</sub> receptors.<ref name="Halberstadt2015" /><ref name="HalberstadtGeyer2018">{{cite book | vauthors = Halberstadt AL, Geyer MA | title = Behavioral Neurobiology of Psychedelic Drugs | chapter = Effect of Hallucinogens on Unconditioned Behavior | series = Current Topics in Behavioral Neurosciences | volume = 36 | pages = 159–199 | date = 2018 | pmid = 28224459 | pmc = 5787039 | doi = 10.1007/7854_2016_466 | isbn = 978-3-662-55878-2 | chapter-url = http://www.ouramazingworld.org/uploads/4/3/8/6/43860587/halberstadt2016.pdf | quote = Compared with phenylalkylamines, tryptamine hallucinogens produce a disparate profile of effects in the mouse BPM. Administration of psilocin or 5-MeO-DMT produces a profound suppression of locomotor activity, investigatory holepokes and rearings, and center duration in C57BL/6J mice (Halberstadt et al. 2011). Most of these effects are blocked by pretreatment with the 5-HT1A antagonist WAY-100635, whereas the 5-HT2C antagonist SB242084 is ineffective. | archive-date = August 29, 2017 | access-date = February 7, 2025 | archive-url = https://web.archive.org/web/20170829193524/http://www.ouramazingworld.org/uploads/4/3/8/6/43860587/halberstadt2016.pdf | url-status = bot: unknown }}</ref><ref name="HalberstadtKoedoodPowell2011">{{cite journal | vauthors = Halberstadt AL, Koedood L, Powell SB, Geyer MA | title = Differential contributions of serotonin receptors to the behavioral effects of indoleamine hallucinogens in mice | journal = J Psychopharmacol | volume = 25 | issue = 11 | pages = 1548–1561 | date = November 2011 | pmid = 21148021 | pmc = 3531560 | doi = 10.1177/0269881110388326 | url = }}</ref> In addition, the serotonin [[5-HT1B receptor|5-HT<sub>1B</sub> receptor]] has been found to be required for psilocybin's persisting [[antidepressant]]- and [[anxiolytic]]-like effects as well as acute hypolocomotion in animals.<ref name="FleuryNautiyal2024">{{cite journal | vauthors = Fleury S, Nautiyal K | title = ACNP 63rd Annual Meeting: Poster Abstracts P609-P914: P691. The Non-Hallucinogenic Serotonin 1B Receptor is Necessary for the Persisting Behavioral Effects of Psilocybin in Mice | journal = Neuropsychopharmacology | volume = 49 | issue = Suppl 1 | pages = 418–594 (466) | date = December 2024 | pmid = 39643635 | doi = 10.1038/s41386-024-02013-y | url = | doi-access = free }}</ref> In humans, ketanserin blocked psilocybin's hallucinogenic effects but not all of its cognitive and behavioral effects.<ref name="HalberstadtGeyer2011" /> Serotonin 5-HT<sub>2C</sub> receptor activation and downstream inhibition of the [[mesolimbic pathway|mesolimbic dopamine pathway]] may be involved in the limited [[addictive potential]] of serotonergic psychedelics like psilocybin.<ref name="CanalMurnane2017">{{cite journal | vauthors = Canal CE, Murnane KS | title = The serotonin 5-HT2C receptor and the non-addictive nature of classic hallucinogens | journal = J Psychopharmacol | volume = 31 | issue = 1 | pages = 127–143 | date = January 2017 | pmid = 27903793 | pmc = 5445387 | doi = 10.1177/0269881116677104 | url = }}</ref>

In addition to its psychedelic effects, psilocin has been found to produce [[psychoplastogen]]ic effects in animals, including [[dendritogenesis]], [[spinogenesis]], and [[synaptogenesis]].<ref name="HatzipantelisOlson2024">{{cite journal | vauthors = Hatzipantelis CJ, Olson DE | title = The Effects of Psychedelics on Neuronal Physiology | journal = Annu Rev Physiol | volume = 86 | issue = | pages = 27–47 | date = February 2024 | pmid = 37931171 | doi = 10.1146/annurev-physiol-042022-020923 | pmc = 10922499 | url = }}</ref><ref name="DoddNormanEyre2023" /><ref name="LyGrebCameron2018">{{cite journal | vauthors = Ly C, Greb AC, Cameron LP, Wong JM, Barragan EV, Wilson PC, Burbach KF, Soltanzadeh Zarandi S, Sood A, Paddy MR, Duim WC, Dennis MY, McAllister AK, Ori-McKenney KM, Gray JA, Olson DE | title = Psychedelics Promote Structural and Functional Neural Plasticity | journal = Cell Rep | volume = 23 | issue = 11 | pages = 3170–3182 | date = June 2018 | pmid = 29898390 | pmc = 6082376 | doi = 10.1016/j.celrep.2018.05.022 | url = }}</ref> It has been found to promote [[neuroplasticity]] in the brain in a rapid, robust, and sustained manner with a single dose.<ref name="HatzipantelisOlson2024" /><ref name="DoddNormanEyre2023" /> These effects appear to be mediated by [[intracellular]] serotonin 5-HT<sub>2A</sub> receptor activation.<ref name="HatzipantelisOlson2024" /><ref name="DoddNormanEyre2023" /><ref name="VargasDunlapDong2023">{{cite journal | vauthors = Vargas MV, Dunlap LE, Dong C, Carter SJ, Tombari RJ, Jami SA, Cameron LP, Patel SD, Hennessey JJ, Saeger HN, McCorvy JD, Gray JA, Tian L, Olson DE | title = Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors | journal = Science | volume = 379 | issue = 6633 | pages = 700–706 | date = February 2023 | pmid = 36795823 | pmc = 10108900 | doi = 10.1126/science.adf0435 | bibcode = 2023Sci...379..700V | url = }}</ref><ref name="LyGrebCameron2018" /> The psychoplastogenic effects of psilocybin and other serotonergic psychedelics may be involved in their potential therapeutic benefits in the treatment of [[psychiatric disorder]]s such as [[depression (mood)|depression]].<ref name="VargasMeyerAvanes2021">{{cite journal | vauthors = Vargas MV, Meyer R, Avanes AA, Rus M, Olson DE | title = Psychedelics and Other Psychoplastogens for Treating Mental Illness | journal = Frontiers in Psychiatry | volume = 12 | pages = 727117 | date = 2021 | pmid = 34671279 | pmc = 8520991 | doi = 10.3389/fpsyt.2021.727117 | doi-access = free }}</ref><ref name="Olson2021" /><ref name="DeVos2021" /> They may also be involved in the effects of [[microdosing]].<ref name="CalderHasler2023">{{cite journal | vauthors = Calder AE, Hasler G | title = Towards an understanding of psychedelic-induced neuroplasticity | journal = Neuropsychopharmacology | volume = 48 | issue = 1 | pages = 104–112 | date = January 2023 | pmid = 36123427 | pmc = 9700802 | doi = 10.1038/s41386-022-01389-z | url = }}</ref> Psilocin has also been reported to act as a highly [[potency (pharmacology)|potent]] [[positive allosteric modulator]] of the [[tropomyosin receptor kinase B]] (TrkB), one of the [[receptor (biochemistry)|receptor]]s of [[brain-derived neurotrophic factor]] (BDNF).<ref name="HatzipantelisOlson2024" /><ref name="FradetKellyDonnelly2025">{{cite journal | vauthors = Fradet M, Kelly CM, Donnelly AJ, Suppes T | title = Psilocybin and hallucinogenic mushrooms | journal = CNS Spectr | volume = 29| issue = 6| pages = 611–632 | date = January 2025 | pmid = 39789676 | doi = 10.1017/S1092852924002487 | url = | quote = Upon their activation by psilocin, 5-HT2A receptors initiate complex cascades of downstream signaling. The activation of both canonical Gq/11 and β-arrestin-2 seems necessary to produce psychedelic effects,133 and so is the coactivation of Gi/o and Src tyrosine kinase.134 These specific pathways are thought to differentiate 5-HT2A receptor agonists with psychedelic properties from other agonists of the same receptor such as ergoline and lisuride that do not have hallucinogenic effects. [...] Although strong evidence supports that 5-HT2A activity mediates most of psilocin’s psychedelic properties, this substituted tryptamine also binds to many other receptors135–137. In fact, psilocin’s binding affinity is even higher for some other serotonin receptors such as 5-HT2C, 5-HT1A, and 5-HT2B137. It is currently difficult to determine the clinical significance of psilocin’s interaction with these receptors. Although they do not seem to contribute to the hallucinogenic properties of psilocin, these other serotonin receptors could potentially play a role in mediating its therapeutic effect.136, 138–140 [...] Psilocin has a very low affinity for the serotonin transporter (SERT), and it does not interact directly with the norepinephrine transporter (NET) or the dopamine transporter (DAT).137 Although it has the potential to bind with D1 and D3 receptors, it has no direct activity on the widespread D2 receptors.137 It does not interact with adrenergic, opioid, muscarinic, histamine, or cannabinoid receptors.137 }}</ref><ref name="MolinerGirychBrunello2023">{{cite journal | vauthors = Moliner R, Girych M, Brunello CA, Kovaleva V, Biojone C, Enkavi G, Antenucci L, Kot EF, Goncharuk SA, Kaurinkoski K, Kuutti M, Fred SM, Elsilä LV, Sakson S, Cannarozzo C, Diniz CR, Seiffert N, Rubiolo A, Haapaniemi H, Meshi E, Nagaeva E, Öhman T, Róg T, Kankuri E, Vilar M, Varjosalo M, Korpi ER, Permi P, Mineev KS, Saarma M, Vattulainen I, Casarotto PC, Castrén E | title = Psychedelics promote plasticity by directly binding to BDNF receptor TrkB | journal = Nat Neurosci | volume = 26 | issue = 6 | pages = 1032–1041 | date = June 2023 | pmid = 37280397 | pmc = 10244169 | doi = 10.1038/s41593-023-01316-5 | url = }}</ref> But psilocybin has been found to inhibit [[hippocampus|hippocampal]] [[neurogenesis]] in rodents.<ref name="HatzipantelisOlson2024" />

Psilocybin produces profound [[anti-inflammatory]] effects mediated by serotonin 5-HT<sub>2A</sub> receptor activation in [[preclinical research|preclinical studies]].<ref name="FlanaganNichols2022">{{cite book | vauthors = Flanagan TW, Nichols CD | title = Disruptive Psychopharmacology | chapter = Psychedelics and Anti-inflammatory Activity in Animal Models | series = Current Topics in Behavioral Neurosciences | volume = 56 | pages = 229–245 | date = 2022 | pmid = 35546383 | doi = 10.1007/7854_2022_367 | isbn = 978-3-031-12183-8 | chapter-url = | quote = In our rodent acute asthma model, psilocin, the active metabolite of psilocybin, displays a similar anti-AHR efficacy and potency to that of (R)-DOI. Surprisingly, other tryptamines with very similar structures like N,N-dimethyltryptamine (DMT) and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) show no efficacy to reduce OVA-induced AHR. }}</ref><ref name="WulffNicholsThompson2023">{{cite journal | vauthors = Wulff AB, Nichols CD, Thompson SM | title = Preclinical perspectives on the mechanisms underlying the therapeutic actions of psilocybin in psychiatric disorders | journal = Neuropharmacology | volume = 231 | issue = | pages = 109504 | date = June 2023 | pmid = 36921889 | doi = 10.1016/j.neuropharm.2023.109504 | url = | quote = Interestingly, the anti-inflammatory effects of psychedelics acting at 5-HT2A receptors do not correlate with activation of either Gαq or β-arrestin recruitment (Flanagan et al., 2020), indicating psychedelics can recruit different effector pathways from those underlying behaviors for biological effects. [...] Psilocybin and certain other psychedelics have potent anti-inflammatory effects in preclinical models of human disease that could contribute to their efficacy. For example, delivery of psilocin directly to the lungs of rats via nebulization potently suppressed inflammation and restored normal breathing in a model of allergic asthma (Flanagan et al., 2020). The amount of psilocybin necessary for full effect was far below the threshold to produce behavioral effects, suggesting that sub-behavioral levels of psilocybin or other psychedelic may represent a new therapeutic strategy to treat inflammatory disorders. Interestingly, as mentioned above, neither the Gαq or β-arrestin signaling pathways seem to be involved in these effects (Flanagan et al., 2020). | doi-access = free }}</ref><ref name="Kinderlehrer2025">{{cite journal | vauthors = Kinderlehrer DA | title = Mushrooms, Microdosing, and Mental Illness: The Effect of Psilocybin on Neurotransmitters, Neuroinflammation, and Neuroplasticity | journal = Neuropsychiatr Dis Treat | volume = 21 | issue = | pages = 141–155 | date = 2025 | pmid = 39897712 | pmc = 11787777 | doi = 10.2147/NDT.S500337 | doi-access = free | url = }}</ref> These effects have a potency similar to that of [[(R)-DOI|(''R'')-DOI]], and its anti-inflammatory effects occur at far lower doses than those that produce hallucinogen-like effects in animals.<ref name="Nichols2022">{{cite journal | vauthors = Nichols CD | title = Psychedelics as potent anti-inflammatory therapeutics | journal = Neuropharmacology | volume = 219 | issue = | pages = 109232 | date = November 2022 | pmid = 36007854 | doi = 10.1016/j.neuropharm.2022.109232 | url = | quote = Remarkably, the IC50 dose for (R)-DOI in this prophylactic paradigm is ∼0.005 mg/kg, administered via nebulization or by intraperitoneal injection (Flanagan et al., 2021). This is > 50x less than the behavioral threshold dose. We have also shown that the drug psilocin, the active form of the prodrug psilocybin, has virtually the same potency as (R)-DOI (Flanagan et al., 2021), indicating that the effects are not limited to (R)-DOI or are chemotype dependent.| doi-access = free }}</ref><ref name="FlanaganNichols2022" /><ref name="WulffNicholsThompson2023" /><ref name="FlanaganBillacLandry2021">{{cite journal | vauthors = Flanagan TW, Billac GB, Landry AN, Sebastian MN, Cormier SA, Nichols CD | title = Structure-Activity Relationship Analysis of Psychedelics in a Rat Model of Asthma Reveals the Anti-Inflammatory Pharmacophore | journal = ACS Pharmacol Transl Sci | volume = 4 | issue = 2 | pages = 488–502 | date = April 2021 | pmid = 33860179 | pmc = 8033619 | doi = 10.1021/acsptsci.0c00063 | url = }}</ref> Psilocybin's anti-inflammatory effects might be involved in its potential antidepressant benefits and might also have other therapeutic applications, such as treatment of [[asthma]] and [[neuroinflammation]].<ref name="FlanaganNichols2022" /><ref name="WulffNicholsThompson2023" /><ref name="FlanaganNichols2018">{{cite journal | vauthors = Flanagan TW, Nichols CD | title = Psychedelics as anti-inflammatory agents | journal = Int Rev Psychiatry | volume = 30 | issue = 4 | pages = 363–375 | date = August 2018 | pmid = 30102081 | doi = 10.1080/09540261.2018.1481827 | url = http://usdbiology.com/cliff/Courses/Advanced%20Seminars%20in%20Neuroendocrinology/Therapeutic%20Effects%20of%20Psychedelics%2019/Flanagan%20Nichols%2018%20IntRevPsychiatry%20Psychedelics%20as%20anti-inflammatory%20agents.pdf | quote = We have previously speculated that the anti-inflammatory effects of psychedelics mediated through serotonin 5-HT2A receptor activation are a key component of not only the anti-depressant effects of psilocybin, but also contribute to its long-lasting effects after only a single treatment (Kyzar, Nichols, Gainetdinov, Nichols, & Kalueff, 2017).}}</ref> They may also be involved in microdosing effects.<ref name="KuypersErritzoeKnudsen2019">{{cite journal | vauthors = Kuypers KP, Ng L, Erritzoe D, Knudsen GM, Nichols CD, Nichols DE, Pani L, Soula A, Nutt D | title = Microdosing psychedelics: More questions than answers? An overview and suggestions for future research | journal = J Psychopharmacol | volume = 33 | issue = 9 | pages = 1039–1057 | date = September 2019 | pmid = 31303095 | pmc = 6732823 | doi = 10.1177/0269881119857204 | url = }}</ref><ref name="Kinderlehrer2025" /> But psychedelics have been found to have anti-inflammatory effects only in the setting of preexisting [[inflammation]] and may be [[pro-inflammatory]] outside that context.<ref name="LowNgLim2024">{{cite journal | vauthors = Low ZX, Ng WS, Lim ES, Goh BH, Kumari Y | title = The immunomodulatory effects of classical psychedelics: A systematic review of preclinical studies | journal = Prog Neuropsychopharmacol Biol Psychiatry | volume = 136| issue = | pages = 111139 | date = September 2024 | pmid = 39251080 | doi = 10.1016/j.pnpbp.2024.111139 | url = | doi-access = free }}</ref> Psilocybin has been found to have a large, long-lasting impact on the [[gut microbiome|intestinal microbiome]] and to influence the [[gut–brain axis]] in animals.<ref name="KellyClarkeHarkin2023">{{cite journal | vauthors = Kelly JR, Clarke G, Harkin A, Corr SC, Galvin S, Pradeep V, Cryan JF, O'Keane V, Dinan TG | title = Seeking the Psilocybiome: Psychedelics meet the microbiota-gut-brain axis | journal = Int J Clin Health Psychol | volume = 23 | issue = 2 | pages = 100349 | date = 2023 | pmid = 36605409 | pmc = 9791138 | doi = 10.1016/j.ijchp.2022.100349 | url = }}</ref><ref name="CalderMockFriedli2023">{{cite journal | vauthors = Calder A, Mock S, Friedli N, Pasi P, Hasler G | title = Psychedelics in the treatment of eating disorders: Rationale and potential mechanisms | journal = Eur Neuropsychopharmacol | volume = 75 | issue = | pages = 1–14 | date = October 2023 | pmid = 37352816 | doi = 10.1016/j.euroneuro.2023.05.008 | url = | quote = Interestingly, both EDs and mood disorders are often comorbid with gastrointestinal symptoms and reduced diversity of the gut microbiome. (Lam et al., 2017) A dysregulated microbiome may constitute a development or maintenance factor for AN in particular. (Butler et al., 2021) It has been suggested that psychedelics exert some of their long-term effects via the microbiome. (Kuypers, 2019) Psilocybin has been shown to diversify the intestinal microbiome in mice, and this diversification appeared to be responsible for lasting antidepressant-like behavioral effects. (Cordner et al., 2022) Normalization of the gut microbiome may thus assist with recovery from both EDs and comorbid mood disorders, and presents an intriguing avenue for future research. (Kleiman et al., 2015)}}</ref><ref name="ReedFoldi2024">{{cite journal | vauthors = Reed F, Foldi CJ | title = Do the therapeutic effects of psilocybin involve actions in the gut? | journal = Trends Pharmacol Sci | volume = 45 | issue = 2 | pages = 107–117 | date = February 2024 | pmid = 38216431 | doi = 10.1016/j.tips.2023.12.007 | url = }}</ref><ref name="CordnerPrandovszkyPedicini2022" /><ref name="XuKissJones2024">{{cite journal | vauthors = Xu M, Kiss AJ, Jones JA, McMurray MS, Shi H | title = Effect of oral tryptamines on the gut microbiome of rats-a preliminary study | journal = PeerJ | volume = 12 | issue = | pages = e17517 | date = 2024 | pmid = 38846751 | pmc = 11155674 | doi = 10.7717/peerj.17517 | doi-access = free | url = }}</ref><ref name="LowYongAlrasheed2025">{{cite journal | vauthors = Low ZX, Yong SJ, Alrasheed HA, Al-Subaie MF, Al Kaabi NA, Alfaresi M, Albayat H, Alotaibi J, Al Bshabshe A, Alwashmi AS, Sabour AA, Alshiekheid MA, Almansour ZH, Alharthi H, Al Ali HA, Almoumen AA, Alqasimi NA, AlSaihati H, Rodriguez-Morales AJ, Rabaan AA | title = Serotonergic psychedelics as potential therapeutics for post-COVID-19 syndrome (or Long COVID): A comprehensive review | journal = Prog Neuropsychopharmacol Biol Psychiatry | volume = 137| issue = | pages = 111279 | date = February 2025 | pmid = 39909170 | doi = 10.1016/j.pnpbp.2025.111279 | url = }}</ref> These effects are partially but not fully dependent on its activation of the serotonin 5-HT<sub>2A</sub> and/or 5-HT<sub>2C</sub> receptors.<ref name="CordnerPrandovszkyPedicini2022" /> Some of psilocybin's  behavioral and potential therapeutic effects may be mediated by changes to the gut microbiome.<ref name="CordnerPrandovszkyPedicini2022" /><ref name="ReedFoldi2024" /><ref name="LowYongAlrasheed2025" /> Transplantation of intestinal contents of psilocybin-treated rodents to untreated rodents resulted in behavioral changes consistent with those of psilocybin administration.<ref name="CordnerPrandovszkyPedicini2022" />

Psilocybin and other psychedelics produce [[sympathomimetic]] effects, such as increased [[heart rate]] and [[blood pressure]], by activating the serotonin 5-HT<sub>2A</sub> receptor.<ref name="Wsół2023"/><ref name="NeumannDheinKirchhefer2024">{{cite journal | vauthors = Neumann J, Dhein S, Kirchhefer U, Hofmann B, Gergs U | title = Effects of hallucinogenic drugs on the human heart | journal = Front Pharmacol | volume = 15 | issue = | pages = 1334218 | date = 2024 | pmid = 38370480 | pmc = 10869618 | doi = 10.3389/fphar.2024.1334218 | doi-access = free | url = }}</ref><ref name="LeyHolzeArikci2023">{{cite journal | vauthors = Ley L, Holze F, Arikci D, Becker AM, Straumann I, Klaiber A, Coviello F, Dierbach S, Thomann J, Duthaler U, Luethi D, Varghese N, Eckert A, Liechti ME | title = Comparative acute effects of mescaline, lysergic acid diethylamide, and psilocybin in a randomized, double-blind, placebo-controlled cross-over study in healthy participants | journal = Neuropsychopharmacology | volume = 48 | issue = 11 | pages = 1659–1667 | date = October 2023 | pmid = 37231080 | pmc = 10517157 | doi = 10.1038/s41386-023-01607-2 | url = }}</ref> Long-term repeated use of psilocybin may result in risk of [[cardiac valvulopathy]] and other [[health complication|complication]]s by activating serotonin 5-HT<sub>2B</sub> receptors.<ref name="GeigerWurstDaniels2018" /><ref name="TagenMantuanivanHeerden2023">{{cite journal | vauthors = Tagen M, Mantuani D, van Heerden L, Holstein A, Klumpers LE, Knowles R | title = The risk of chronic psychedelic and MDMA microdosing for valvular heart disease | journal = J Psychopharmacol | volume = 37 | issue = 9 | pages = 876–890 | date = September 2023 | pmid = 37572027 | doi = 10.1177/02698811231190865 | url = }}</ref><ref name="RouaudCalderHasler2024">{{cite journal | vauthors = Rouaud A, Calder AE, Hasler G | title = Microdosing psychedelics and the risk of cardiac fibrosis and valvulopathy: Comparison to known cardiotoxins | journal = J Psychopharmacol | volume = 38 | issue = 3 | pages = 217–224 | date = March 2024 | pmid = 38214279 | pmc = 10944580 | doi = 10.1177/02698811231225609 | url = }}</ref><ref name="Wsół2023" /><ref name="NeumannDheinKirchhefer2024" />

There is little or no acute [[drug tolerance|tolerance]] with psilocybin, and hence its [[duration of action|duration]] is dictated by [[pharmacokinetics]] rather than by [[pharmacodynamics]].<ref name="HolzeSinghLiechti2024" /><ref name="HolzeBeckerKolaczynska2023" /> Conversely, tolerance and [[tachyphylaxis]] rapidly develop to psilocybin's psychedelic effects with repeated administration in humans.<ref name="GeigerWurstDaniels2018" /><ref name="Nichols2004">{{cite journal | vauthors = Nichols DE | title = Hallucinogens | journal = Pharmacol Ther | volume = 101 | issue = 2 | pages = 131–181 | date = February 2004 | pmid = 14761703 | doi = 10.1016/j.pharmthera.2003.11.002 | url = }}</ref><ref name="Halberstadt2015">{{cite journal | vauthors = Halberstadt AL | title = Recent advances in the neuropsychopharmacology of serotonergic hallucinogens | journal = Behav Brain Res | volume = 277 | issue = | pages = 99–120 | date = January 2015 | pmid = 25036425 | pmc = 4642895 | doi = 10.1016/j.bbr.2014.07.016 | url = }}</ref><ref name="HalberstadtGeyer2011" /> In addition, there is [[cross-tolerance]] with the hallucinogenic effects of other psychedelics such as LSD.<ref name="GeigerWurstDaniels2018" /><ref name="Nichols2004" /><ref name="Halberstadt2015" /><ref name="HalberstadtGeyer2011" /> Psilocybin produces [[downregulation]] of the serotonin 5-HT<sub>2A</sub> receptor in the brain in animals, an effect thought to be responsible for the development of tolerance to its psychedelic effects.<ref name="GeigerWurstDaniels2018" /><ref name="Nichols2004" /><ref name="Halberstadt2015" /><ref name="HalberstadtGeyer2011" /> Serotonin 5-HT<sub>2A</sub> receptors appear to slowly return over the course of days to weeks after psilocybin administration.<ref name="GeigerWurstDaniels2018" />