Editing Psilocybin (section)

==Interactions==
{{See also|Psychedelic drug#Interactions|Trip killer#Serotonergic psychedelic antidotes|Head-twitch response#Modulators of the head-twitch response}}

Serotonin [[5-HT2A receptor|5-HT<sub>2A</sub> receptor]] [[receptor antagonist|antagonist]]s can block the hallucinogenic effects of serotonergic psychedelics like psilocybin.<ref name="HalmanKongSarris2024" /><ref name="SarparastThomasMalcolm2022">{{cite journal | vauthors = Sarparast A, Thomas K, Malcolm B, Stauffer CS | title = Drug-drug interactions between psychiatric medications and MDMA or psilocybin: a systematic review | journal = Psychopharmacology (Berl) | volume = 239 | issue = 6 | pages = 1945–1976 | date = June 2022 | pmid = 35253070 | pmc = 9177763 | doi = 10.1007/s00213-022-06083-y | url = }}</ref> Numerous drugs act as serotonin 5-HT<sub>2A</sub> receptor antagonists, including [[antidepressant]]s like [[trazodone]] and [[mirtazapine]], [[antipsychotic]]s like [[quetiapine]], [[olanzapine]], and [[risperidone]], and other agents like [[ketanserin]], [[pimavanserin]], [[cyproheptadine]], and [[pizotifen]].<ref name="HalmanKongSarris2024" /><ref name="YatesMelon2024">{{Cite journal |vauthors=Yates G, Melon E |date=January 2024 |title=Trip-killers: a concerning practice associated with psychedelic drug use |journal=Emerg Med J |volume=41 |issue=2 |pages=112–113 |doi=10.1136/emermed-2023-213377 |pmid=38123961 |url=https://web.archive.org/web/20250511111827oe_/https://s3.amazonaws.com/crawl.prod.proquest.com/fpcache/71f445805bfb61341cbc438c8ae23bd3.pdf?X-Amz-Security-Token=IQoJb3JpZ2luX2VjEBMaCXVzLWVhc3QtMSJIMEYCIQDETX7YpaG5THA%2FNbKR0d92wr6h%2Bgg9preNcKjAsEqo%2BQIhAIlPGGWOeUc23LqhBzRYbxvSXB9aqSe2vVonl4nacAhhKp0CCLz%2F%2F%2F%2F%2F%2F%2F%2F%2F%2FwEQABoMNTE4MzQ2ODQ4MzQxIgy9ji58Qtbi%2BavuKeYq8QEDL1U5KZDQ0bXFyVapeqJgE%2FX6x8DcJfFU8DAXYZPSQEwrIdfPbZWcYsH340deru%2FUHnNaGGpuHFoVzui%2FMbqBz7MANcowj%2FL1%2BQZzQ5hXh5KM3BW8E6NRzrQyuPRmBy7kQUkx8%2BjTN%2BXSMgF%2FCAs6Dn9fScgBGz3ddkwRZXDkjasqMP65RCPKhagK68cyMbf3oX%2BKS8a4Kltc2rk3CnWEhOKrZU4mIxq07DikLAXQbl8YRZJIkeOhN5TgBaLWJqyn1td2VWCMymAaFsqtPWHwXnEfsolRlfDooe6QXfE2YwX5PxBVJU7GPXRgrAqPjwtJMOCHgsEGOpwBYif%2BaDMBdz3IEghuvCvorAS0mkHzdcOz%2Fi7AzuN9nch%2FIm8llhMsN41aAWHuSG25pnhhftauFsg7rbGsrW2nl2kq2upi9zP7y%2Fnqk93jcP0kr0jM8zU12bYoSTsToQJsshH4N%2BTQUMwlzRQfeVv8MXdq%2BgSTTzJrWNwT1yNzye3rSHjvOumbNl6sgBISw7QqRzhB6hZTuf8AcI%2B7&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20250511T111826Z&X-Amz-SignedHeaders=host&X-Amz-Credential=ASIAXRL7BHBKRAKCQVVB%2F20250511%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Expires=3600&X-Amz-Signature=20bb1b90e4c8dbaa4115c954387617ebe2f55269bdd517692f1380193ed3f769}}</ref> Such drugs are sometimes called "[[trip killer]]s" because they can prevent or abort psychedelics' hallucinogenic effects.<ref name="Jayasinha2024">{{Cite thesis | vauthors = Jayasinha BG |degree = Masters of Arts |title=Towards Safer Trips: Exploring Harm Reduction Strategies for Recreational Psychedelic Use in Aotearoa New Zealand |date=8 February 2024 |access-date=3 October 2024 |publisher=University of Otago |url=https://ourarchive.otago.ac.nz/esploro/outputs/graduate/Towards-Safer-Trips-Exploring-Harm-Reduction/9926550679501891 }}</ref><ref name="YatesMelon2024" /><ref name="Suran2024">{{Cite journal |vauthors=Suran M |date=February 2024 |title=Study Finds Hundreds of Reddit Posts on "Trip-Killers" for Psychedelic Drugs |journal=JAMA |volume=331 |issue=8 |pages=632–634 |doi=10.1001/jama.2023.28257 |pmid=38294772}}</ref> Serotonin 5-HT<sub>2A</sub> receptor antagonists that have been specifically shown in clinical studies to diminish or abolish psilocybin's effects include ketanserin, risperidone, and [[chlorpromazine]].<ref name="HalmanKongSarris2024" /><ref name="SarparastThomasMalcolm2022" />

The serotonin [[5-HT1A receptor|5-HT<sub>1A</sub> receptor]] [[partial agonist]] [[buspirone]] has been found to markedly reduce psilocybin's hallucinogenic effects in humans.<ref name="HalmanKongSarris2024" /><ref name="SarparastThomasMalcolm2022" /><ref name="BrandtKavanaghTwamley2018" /><ref name="PokornyPrellerKraehenmann2016" /> Conversely, the serotonin 5-HT<sub>1A</sub> receptor antagonist [[pindolol]] has been found to potentiate the hallucinogenic effects of the related psychedelic [[dimethyltryptamine]] (DMT) by 2- to 3-fold in humans.<ref name="PokornyPrellerKraehenmann2016" /><ref name="Strassman1996" /> [[Selective serotonin reuptake inhibitor]]s (SSRIs) may modify psilocybin's effects.<ref name="HalmanKongSarris2024" /><ref name="SarparastThomasMalcolm2022" /><ref name="BeckerHolzeGrandinetti2022" /> One clinical trial found that psilocybin's hallucinogenic and "good drug" effects were not modified by the SSRI [[escitalopram]], but that its "bad drug effects" such as [[anxiety]], as well as [[ego dissolution]], were reduced, among other changes.<ref name="SarparastThomasMalcolm2022" /><ref name="HalmanKongSarris2024" /><ref name="BeckerHolzeGrandinetti2022">{{cite journal | vauthors = Becker AM, Holze F, Grandinetti T, Klaiber A, Toedtli VE, Kolaczynska KE, Duthaler U, Varghese N, Eckert A, Grünblatt E, Liechti ME | title = Acute Effects of Psilocybin After Escitalopram or Placebo Pretreatment in a Randomized, Double-Blind, Placebo-Controlled, Crossover Study in Healthy Subjects | journal = Clin Pharmacol Ther | volume = 111 | issue = 4 | pages = 886–895 | date = April 2022 | pmid = 34743319 | pmc = 9299061 | doi = 10.1002/cpt.2487 | url = }}</ref>

[[Benzodiazepine]]s such as [[diazepam]], [[alprazolam]], [[clonazepam]], and [[lorazepam]], as well as [[alcohol (drug)|alcohol]], which act as [[GABAA receptor positive allosteric modulator|GABA<sub>A</sub> receptor positive allosteric modulator]]s, have been limitedly studied in combination with psilocybin and other psychedelics and are not known to directly interact with them.<ref name="SarparastThomasMalcolm2022" /><ref name="HalmanKongSarris2024" /> But these [[GABAergic]] drugs produce effects such as [[anxiolytic|anxiolysis]], [[sedation]], and [[amnesia]], and may therefore diminish or otherwise oppose psychedelics' effects.<ref name="HalmanKongSarris2024" /><ref name="Jayasinha2024" /><ref name="YatesMelon2024" /><ref name="Suran2024" /><ref name="Olsen2018">{{cite journal | vauthors = Olsen RW | title = GABA<sub>A</sub> receptor: Positive and negative allosteric modulators | journal = Neuropharmacology | volume = 136 | issue = Pt A | pages = 10–22 | date = July 2018 | pmid = 29407219 | pmc = 6027637 | doi = 10.1016/j.neuropharm.2018.01.036 }}</ref> Because of this, recreational users often use benzodiazepines and alcohol as "trip killers" to manage difficult hallucinogenic experiences with psychedelics, such as experiences with prominent anxiety.<ref name="Jayasinha2024" /><ref name="YatesMelon2024" /><ref name="Suran2024" /> This strategy's [[drug safety|safety]] is not entirely clear and might have risks,<ref name="Jayasinha2024" /><ref name="SarparastThomasMalcolm2022" /><ref name="YatesMelon2024" /><ref name="Suran2024" /> but benzodiazepines have been used to manage psychedelics' adverse psychological effects in clinical studies and in [[emergency department|Emergency Rooms]].<ref name="SarparastThomasMalcolm2022" /><ref name="KaminskiReinert2024">{{cite journal | vauthors = Kaminski D, Reinert JP | title = The Tolerability and Safety of Psilocybin in Psychiatric and Substance-Dependence Conditions: A Systematic Review | journal = The Annals of Pharmacotherapy | volume = 58 | issue = 8 | pages = 811–826 | date = August 2024 | pmid = 37902038 | doi = 10.1177/10600280231205645 }}</ref><ref name="LeikinKrantzZell-Kanter1989">{{cite journal | vauthors = Leikin JB, Krantz AJ, Zell-Kanter M, Barkin RL, Hryhorczuk DO | title = Clinical features and management of intoxication due to hallucinogenic drugs | journal = Medical Toxicology and Adverse Drug Experience | volume = 4 | issue = 5 | pages = 324–350 | year = 1989 | pmid = 2682130 | doi = 10.1007/bf03259916 | publisher = Springer Science and Business Media LLC }}</ref><ref name="HalpernSuzukiHuertas2010">{{Cite book | vauthors = Halpern JH, Suzuki J, Huertas PE, Passie T |title=Addiction Medicine |publisher=Springer New York |year=2010 |isbn=978-1-4419-0337-2 |publication-place=New York, NY |pages=1083–1098 |chapter=Hallucinogens |doi=10.1007/978-1-4419-0338-9_54}}</ref><ref name="GartnerWanSimmons2024">{{cite journal | vauthors = Gartner HT, Wan HZ, Simmons RE, Sollee DR, Sheikh S | title = Psychedelic mushroom-containing chocolate exposures: Case series | journal = The American Journal of Emergency Medicine | volume = 85 | issue =  | pages = 208–213 | date = November 2024 | pmid = 39288500 | doi = 10.1016/j.ajem.2024.09.038 }}</ref> A clinical trial of psilocybin and [[midazolam]] coadministration found that midazolam clouded psilocybin's effects and [[memory impairment|impaired memory]] of the experience.<ref name="LimaSoaresTeixeira2024">{{cite journal | vauthors = Lima G, Soares C, Teixeira M, Castelo-Branco M | title = Psychedelic research, assisted therapy and the role of the anaesthetist: A review and insights for experimental and clinical practices | journal = British Journal of Clinical Pharmacology | volume = 90 | issue = 12 | pages = 3119–3134 | date = December 2024 | pmid = 39380091 | doi = 10.1111/bcp.16264 }}</ref><ref name="NicholasBanksLennertz2024">{{cite journal | vauthors = Nicholas CR, Banks MI, Lennertz RC, Wenthur CJ, Krause BM, Riedner BA, Smith RF, Hutson PR, Sauder CJ, Dunne JD, Roseman L, Raison CL | title = Co-administration of midazolam and psilocybin: differential effects on subjective quality versus memory of the psychedelic experience | journal = Translational Psychiatry | volume = 14 | issue = 1 | pages = 372 | date = September 2024 | pmid = 39266503 | pmc = 11393325 | doi = 10.1038/s41398-024-03059-8 }}</ref> Benzodiazepines might interfere with the therapeutic effects of psychedelics like psilocybin, such as sustained [[antidepressant]] effects.<ref name="BarnettVestDelatte2025">{{cite journal | vauthors = Barnett BS, Vest MF, Delatte MS, King Iv F, Mauney EE, Coulson AJ, Nayak SM, Hendricks PS, Greer GR, Murnane KS | title = Practical considerations in the establishment of psychedelic research programs | journal = Psychopharmacology | volume = 242 | issue = 1 | pages = 27–43 | date = January 2025 | pmid = 39627438 | pmc = 11742797 | doi = 10.1007/s00213-024-06722-6 | quote = Furthermore, benzodiazepines might attenuate the antidepressant effects of psychedelics (Hibicke et al. 2024). }}</ref><ref name="HibickeBillacNichols2024">{{cite journal | vauthors = Hibicke M, Billac G, Nichols CD | title = Preadministration of Lorazepam Reduces Efficacy and Longevity of Antidepressant-Like Effect from a Psychedelic | journal = Psychedelic Medicine | volume = 2 | issue = 1 | pages = 10–14 | date = March 2024 | pmid = 40051761 | doi = 10.1089/psymed.2023.0037 | pmc = 11658646 }}</ref>

[[Psilocin]], the [[active metabolite|active form]] of psilocybin, is a [[substrate (biochemistry)|substrate]] of the [[monoamine oxidase]] (MAO) [[enzyme]] [[MAO-A]].<ref name="ThomannKolaczynskaStoeckmann2024" /><ref name="HolzeBeckerKolaczynska2023" /><ref name="TylšPáleníčekHoráček2014" /> The exact extent to which psilocin (and by extension psilocybin) is [[drug metabolism|metabolized]] by MAO-A is not fully clear, but has ranged from 4% to 33% in different studies based on [[metabolite]] [[excretion]].<ref name="ThomannKolaczynskaStoeckmann2024" /><ref name="HolzeBeckerKolaczynska2023" /><ref name="TylšPáleníčekHoráček2014" /> Circulating levels of psilocin's [[deamination|deaminated]] [[metabolite]] are far higher than those of free unmetabolized psilocin with psilocybin administration.<ref name="DoddNormanEyre2023" /><ref name="HaslerBourquinBrenneisen1997" /> Combination of MAO-substrate psychedelics with [[monoamine oxidase inhibitor]]s (MAOIs) can result in [[overdose]] and [[toxicity]].<ref name="HalmanKongSarris2024" /> Examples of MAOIs that may potentiate psychedelics behaving as MAO-A substrates, such as psilocin, include [[phenelzine]], [[tranylcypromine]], [[isocarboxazid]], and [[moclobemide]], as well as [[harmala alkaloid]]s like [[harmine]] and [[harmaline]] and chronic [[tobacco]] [[smoking]].<ref name="HalmanKongSarris2024" /><ref name="SvedWeeksGrace2022">{{cite journal | vauthors = Sved AF, Weeks JJ, Grace AA, Smith TT, Donny EC | title = Monoamine oxidase inhibition in cigarette smokers: From preclinical studies to tobacco product regulation | journal = Front Neurosci | volume = 16 | issue = | pages = 886496 | date = 2022 | pmid = 36051642 | pmc = 9424897 | doi = 10.3389/fnins.2022.886496 | doi-access = free | url = }}</ref> An early clinical study of psilocybin in combination with short-term tranylcypromine pretreatment found that tranylcypromine marginally potentiated psilocybin's [[human body|peripheral]] effects, including [[pressor]] effects and [[mydriasis]], but overall did not significantly modify its psychoactive and hallucinogenic effects, although some of its emotional effects were said to be reduced and some of its perceptual effects were said to be amplified.<ref name="FradetKellyDonnelly2025" /><ref name="BarnettKoonsVandenEynde2024">{{cite journal | vauthors = Barnett BS, Koons CJ, Van den Eynde V, Gillman PK, Bodkin JA | title = Hypertensive Emergency Secondary to Combining Psilocybin Mushrooms, Extended Release Dextroamphetamine-Amphetamine, and Tranylcypromine | journal = J Psychoactive Drugs | volume = | issue = | pages = 1–7 | date = June 2024 | pmid = 38903003 | doi = 10.1080/02791072.2024.2368617 | url = | doi-access = free }}</ref><ref name="VojtĕchovskýHortSafratová1968">{{cite journal | vauthors = Vojtĕchovský M, Hort V, Safratová V | title = [Influence of MAO inhibitors on psilocybine induced psychosis] | language = Czech | journal = Act Nerv Super (Praha) | volume = 10 | issue = 3 | pages = 278–279 | date = October 1968 | pmid = 5702524 | doi = | url = }}</ref>

Psilocin may be metabolized to a minor extent by the [[cytochrome P450]] (CYP450) [[enzyme]]s [[CYP2D6]] and/or [[CYP3A4]] and appears unlikely to be metabolized by other CYP450 enzymes.<ref name="ThomannKolaczynskaStoeckmann2024" /><ref name="FradetKellyDonnelly2025" /> The role of CYP450 enzymes in psilocin's metabolism seems to be small, and so considerable [[drug interaction]]s with CYP450 [[enzyme inhibitor|inhibitor]]s and/or [[enzyme inducer|inducer]]s may not be expected.<ref name="ThomannKolaczynskaStoeckmann2024" /><ref name="FradetKellyDonnelly2025" /> Psilocin's major [[metabolic pathway]] is [[glucuronidation]] by [[UDP-glucuronosyltransferase]] enzymes including [[UGT1A10]] and [[UGT1A9]].<ref name="SarparastThomasMalcolm2022" /> [[Diclofenac]] and [[probenecid]] are inhibitors of these enzymes that theoretically might inhibit the metabolism of and thereby potentiate psilocybin's effects,<ref name="SarparastThomasMalcolm2022" /> but no clinical research or evidence on this possible interaction exists.<ref name="SarparastThomasMalcolm2022" /> Few other drugs are known to influence UGT1A10 or UGT1A9 function.<ref name="SarparastThomasMalcolm2022" />