Editing Psilocybin (section)

====Depression====
[[Clinical trial]]s, including both [[open-label study|open-label trial]]s and [[blinded experiment|double-blind]] [[randomized controlled trial]]s (RCTs), have found that single doses of psilocybin produce rapid and long-lasting [[antidepressant]] effects outperforming [[placebo]] in people with [[major depressive disorder]] and [[treatment-resistant depression]].<ref name="WangKimChoi2024">{{cite journal | vauthors = Wang SM, Kim S, Choi WS, Lim HK, Woo YS, Pae CU, Bahk WM | title = Current Understanding on Psilocybin for Major Depressive Disorder: A Review Focusing on Clinical Trials | journal = Clin Psychopharmacol Neurosci | volume = 22 | issue = 2 | pages = 222–231 | date = May 2024 | pmid = 38627070 | pmc = 11024689 | doi = 10.9758/cpn.23.1134 | url = }}</ref> Combined with brief [[psychotherapy|psychological support]] in a [[Phases of clinical research#Phase 2|phase 2]] trial, it has been found to produce [[dose dependency|dose-dependent]] improvements in depressive symptoms, with 25{{nbsp}}mg (a moderate dose) more effective than 10{{nbsp}}mg (a low dose), and 10{{nbsp}}mg more effective than 1{{nbsp}}mg (non-psychoactive and equivalent to placebo).<ref name="WangKimChoi2024" /><ref name="GoodwinAaronsonAlvarez2022">{{cite journal | vauthors = Goodwin GM, Aaronson ST, Alvarez O, Arden PC, Baker A, Bennett JC, Bird C, Blom RE, Brennan C, Brusch D, Burke L, Campbell-Coker K, Carhart-Harris R, Cattell J, Daniel A, DeBattista C, Dunlop BW, Eisen K, Feifel D, Forbes M, Haumann HM, Hellerstein DJ, Hoppe AI, Husain MI, Jelen LA, Kamphuis J, Kawasaki J, Kelly JR, Key RE, Kishon R, Knatz Peck S, Knight G, Koolen MH, Lean M, Licht RW, Maples-Keller JL, Mars J, Marwood L, McElhiney MC, Miller TL, Mirow A, Mistry S, Mletzko-Crowe T, Modlin LN, Nielsen RE, Nielson EM, Offerhaus SR, O'Keane V, Páleníček T, Printz D, Rademaker MC, van Reemst A, Reinholdt F, Repantis D, Rucker J, Rudow S, Ruffell S, Rush AJ, Schoevers RA, Seynaeve M, Shao S, Soares JC, Somers M, Stansfield SC, Sterling D, Strockis A, Tsai J, Visser L, Wahba M, Williams S, Young AH, Ywema P, Zisook S, Malievskaia E | title = Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression | journal = N Engl J Med | volume = 387 | issue = 18 | pages = 1637–1648 | date = November 2022 | pmid = 36322843 | doi = 10.1056/NEJMoa2206443 | url = }}</ref> The antidepressant effects of psilocybin with psychological support have been found to last at least 6{{nbsp}}weeks following a single dose.<ref name="WangKimChoi2024" /><ref name="GoodwinAaronsonAlvarez2022" /><ref name="RaisonSanacoraWoolley2023">{{cite journal | vauthors = Raison CL, Sanacora G, Woolley J, Heinzerling K, Dunlop BW, Brown RT, Kakar R, Hassman M, Trivedi RP, Robison R, Gukasyan N, Nayak SM, Hu X, O'Donnell KC, Kelmendi B, Sloshower J, Penn AD, Bradley E, Kelly DF, Mletzko T, Nicholas CR, Hutson PR, Tarpley G, Utzinger M, Lenoch K, Warchol K, Gapasin T, Davis MC, Nelson-Douthit C, Wilson S, Brown C, Linton W, Ross S, Griffiths RR | title = Single-Dose Psilocybin Treatment for Major Depressive Disorder: A Randomized Clinical Trial | journal = JAMA | volume = 330 | issue = 9 | pages = 843–853 | date = September 2023 | pmid = 37651119 | pmc = 10472268 | doi = 10.1001/jama.2023.14530 }}</ref><ref name="GoodwinNowakowskaAtli2025" />

However, some trials have not found psilocybin to significantly outperform placebo in the treatment of depression.<ref name="WangKimChoi2024" /> In addition, a phase 2 trial found that two 25{{nbsp}}mg doses of psilocybin 3{{nbsp}}weeks apart versus daily treatment with the [[selective serotonin reuptake inhibitor]] (SSRI) [[escitalopram]] (Lexapro) for 6{{nbsp}}weeks (plus two putatively non-psychoactive 1{{nbsp}}mg doses of psilocybin 3{{nbsp}}weeks apart) did not show a [[statistical significance|statistically significant]] difference in reduction of depressive symptoms between groups.<ref name="WangKimChoi2024" /><ref name="Carhart-HarrisGiribaldiWatts2021">{{cite journal | vauthors = Carhart-Harris R, Giribaldi B, Watts R, Baker-Jones M, Murphy-Beiner A, Murphy R, Martell J, Blemings A, Erritzoe D, Nutt DJ | title = Trial of Psilocybin versus Escitalopram for Depression | journal = N Engl J Med | volume = 384 | issue = 15 | pages = 1402–1411 | date = April 2021 | pmid = 33852780 | doi = 10.1056/NEJMoa2032994 | url = }}</ref> However, reductions in depressive symptoms were numerically greater with psilocybin, some [[outcome measure|secondary measures]] favored psilocybin, and the rate of [[remission (medicine)|remission]] was statistically higher with psilocybin (57% with psilocybin vs. 28% with escitalopram).<ref name="WangKimChoi2024" /><ref name="Carhart-HarrisGiribaldiWatts2021" /> In any case, the antidepressant [[effect size]] of psilocybin over escitalopram appears to be small.<ref name="HsuTsaiKao2024">{{cite journal | vauthors = Hsu TW, Tsai CK, Kao YC, Thompson T, Carvalho AF, Yang FC, Tseng PT, Hsu CW, Yu CL, Tu YK, Liang CS | title = Comparative oral monotherapy of psilocybin, lysergic acid diethylamide, 3,4-methylenedioxymethamphetamine, ayahuasca, and escitalopram for depressive symptoms: systematic review and Bayesian network meta-analysis | journal = BMJ | volume = 386 | issue = | pages = e078607 | date = August 2024 | pmid = 39168500 | pmc = 11337322 | doi = 10.1136/bmj-2023-078607 | url = }}</ref>

[[Unblinding|Functional unblinding]] by their psychoactive effects and [[subject-expectancy effect|positive psychological expectancy effect]]s (i.e., the [[placebo effect]]) are major limitations and sources of [[bias (statistics)|bias]] of clinical trials of psilocybin and other psychedelics for treatment of depression.<ref name="MuthukumaraswamyForsythLumley2021">{{cite journal | vauthors = Muthukumaraswamy SD, Forsyth A, Lumley T | title = Blinding and expectancy confounds in psychedelic randomized controlled trials | journal = Expert Rev Clin Pharmacol | volume = 14 | issue = 9 | pages = 1133–1152 | date = September 2021 | pmid = 34038314 | doi = 10.1080/17512433.2021.1933434 | url = }}</ref><ref name="LedwosRosenblatBlumberger2022">{{cite journal | vauthors = Ledwos N, Rosenblat JD, Blumberger DM, Castle DJ, McIntyre RS, Mulsant BH, Husain MI | title = A Critical Appraisal of Evidence on the Efficacy and Safety of Serotonergic Psychedelic Drugs as Emerging Antidepressants: Mind the Evidence Gap | journal = J Clin Psychopharmacol | volume = 42 | issue = 6 | pages = 581–588 | date = 2022 | pmid = 36193898 | doi = 10.1097/JCP.0000000000001608 | url = }}</ref><ref name="HovmandPoulsenArnfred2023">{{cite journal | vauthors = Hovmand OR, Poulsen ED, Arnfred S, Storebø OJ | title = Risk of bias in randomized clinical trials on psychedelic medicine: A systematic review | journal = J Psychopharmacol | volume = 37 | issue = 7 | pages = 649–659 | date = July 2023 | pmid = 37403379 | pmc = 10350724 | doi = 10.1177/02698811231180276 | url = }}</ref><ref name="SzigetiHeifets2024">{{cite journal | vauthors = Szigeti B, Heifets BD | title = Expectancy Effects in Psychedelic Trials | journal = Biol Psychiatry Cogn Neurosci Neuroimaging | volume = 9 | issue = 5 | pages = 512–521 | date = May 2024 | pmid = 38387698 | doi = 10.1016/j.bpsc.2024.02.004 | url = }}</ref> Relatedly, most of the therapeutic benefit of conventional [[antidepressant]]s like the SSRIs for depression appears to be attributable to the [[placebo response]].<ref name="Kirsch2019">{{cite journal|vauthors=Kirsch I|title=Placebo Effect in the Treatment of Depression and Anxiety|journal=Front Psychiatry|volume=10|pages=407|date=2019|pmid=31249537|pmc=6584108|doi=10.3389/fpsyt.2019.00407|doi-access=free}}</ref><ref name="HengartnerPlöderl2018">{{cite journal|vauthors=Hengartner MP, Plöderl M|title=False Beliefs in Academic Psychiatry: The Case of Antidepressant Drugs|journal=Ethical Human Psychology and Psychiatry|date=July 2018|volume=20|issue=1|pages=6–16|issn=1559-4343|eissn=1938-9000|doi=10.1891/1559-4343.20.1.6|s2cid=149608377}}</ref> It has been proposed that psychedelics like psilocybin may in fact act as [[active placebo|active]] "[[super placebo]]s" when used for therapeutic purposes.<ref name="DupuisVeissière2022">{{cite journal | vauthors = Dupuis D, Veissière S | title = Culture, context, and ethics in the therapeutic use of hallucinogens: Psychedelics as active super-placebos? | journal = Transcult Psychiatry | volume = 59 | issue = 5 | pages = 571–578 | date = October 2022 | pmid = 36263513 | doi = 10.1177/13634615221131465 | url = }}</ref><ref name="vanElkYaden2022">{{cite journal | vauthors = van Elk M, Yaden DB | title = Pharmacological, neural, and psychological mechanisms underlying psychedelics: A critical review | journal = Neurosci Biobehav Rev | volume = 140 | issue = | pages = 104793 | date = September 2022 | pmid = 35878791 | doi = 10.1016/j.neubiorev.2022.104793 | url = | quote = In addition, the strong prior expectations that many people have about psychedelics directly contribute to the psychedelic experience and as a consequence it has been suggested that psychedelics may act as a ‘super-placebo’ (Hartogsohn, 2016). Specifically, strong prior expectations (e.g., that a specific intervention will likely trigger a mystical experience) will increase the likelihood of having e.g., a mystical-type experience (Maij et al., 2019), and this placebo-effect is further boosted by the psychedelic-induced suggestibility. | hdl = 1887/3515020 | hdl-access = free }}</ref> As of September 2024, psilocybin and other psychedelics (excluding [[MDMA]]) have only been assessed in up to phase 2 clinical trials for psychiatric disorders and have not yet completed larger and more rigorous [[Phases of clinical research#Phase III|phase 3]] trials or received regulatory approval for medical use.<ref name="AdisInsight">{{cite web | title=Psilocybin - COMPASS Pathways | website=AdisInsight | date=15 May 2024 | url=https://adisinsight.springer.com/drugs/800050861 | access-date=5 September 2024}}</ref><ref name="WangKimChoi2024" /><ref name="YaoGuoLu2024">{{cite journal | vauthors = Yao Y, Guo D, Lu TS, Liu FL, Huang SH, Diao MQ, Li SX, Zhang XJ, Kosten TR, Shi J, Bao YP, Lu L, Han Y | title = Efficacy and safety of psychedelics for the treatment of mental disorders: A systematic review and meta-analysis | journal = Psychiatry Res | volume = 335 | issue = | pages = 115886 | date = May 2024 | pmid = 38574699 | doi = 10.1016/j.psychres.2024.115886 | url = }}</ref>

In a 2024 [[meta-analysis]] of RCTs of psychedelics and escitalopram for treatment of depression, only "high-dose" psilocybin (≥20{{nbsp}}mg) significantly outperformed escitalopram in terms of depressive symptom improvement.<ref name="HsuTsaiKao2024">{{cite journal | vauthors = Hsu TW, Tsai CK, Kao YC, Thompson T, Carvalho AF, Yang FC, Tseng PT, Hsu CW, Yu CL, Tu YK, Liang CS | title = Comparative oral monotherapy of psilocybin, lysergic acid diethylamide, 3,4-methylenedioxymethamphetamine, ayahuasca, and escitalopram for depressive symptoms: systematic review and Bayesian network meta-analysis | journal = BMJ | volume = 386 | issue = | pages = e078607 | date = August 2024 | pmid = 39168500 | pmc = 11337322 | doi = 10.1136/bmj-2023-078607 | url = }}</ref> It showed a large effect size over placebo but a small effect size over escitalopram ({{Abbrlink|SMD|standardized mean difference}} = 0.88 vs. 0.31, respectively).<ref name="HsuTsaiKao2024" /> A 2025 meta-analysis found a smaller, moderate effect size advantage of psilocybin relative to placebo ([[Hedges' g]] = 0.62).<ref name="BorgognaOwenPetrovitch2025" /> A 2024 [[network meta-analysis]] of RCTs of therapies for [[treatment-resistant depression]], with effectiveness measures being [[response rate (medicine)|response]] and [[remission rate]]s, likewise found that psilocybin was more effective than placebo and, considering both effectiveness and [[tolerability]] or [[drug safety|safety]], recommended it as a [[lines of therapy|first-line therapy]] along with [[ketamine]], [[esketamine]], and [[electroconvulsive therapy]] (ECT).<ref name="GuoGuoWang2024">{{cite journal | vauthors = Guo Q, Guo L, Wang Y, Shang S | title = Efficacy and safety of eight enhanced therapies for treatment-resistant depression: A systematic review and network meta-analysis of RCTs | journal = Psychiatry Res | volume = 339 | issue = | pages = 116018 | date = September 2024 | pmid = 38924903 | doi = 10.1016/j.psychres.2024.116018 | url = }}</ref> However, the [[quality of evidence]] was generally rated as low or very low.<ref name="GuoGuoWang2024" /> Meta-analyses of psychedelics for depression and other psychiatric conditions have found that psilocybin has the greatest number of studies and the most evidence of benefit, relative to other psychedelics like [[ayahuasca]] and [[LSD]].<ref name="HsuTsaiKao2024" /><ref name="BahjiLunskyGutierrez2025">{{cite journal | vauthors = Bahji A, Lunsky I, Gutierrez G, Vazquez G | title = Efficacy and Safety of Four Psychedelic-Assisted Therapies for Adults with Symptoms of Depression, Anxiety, and Posttraumatic Stress Disorder: A Systematic Review and Meta-Analysis | journal = J Psychoactive Drugs | volume = 57 | issue = 1 | pages = 1–16 | date = 2025 | pmid = 37968944 | doi = 10.1080/02791072.2023.2278586 | url = }}</ref><ref name="YaoGuoLu2024">{{cite journal | vauthors = Yao Y, Guo D, Lu TS, Liu FL, Huang SH, Diao MQ, Li SX, Zhang XJ, Kosten TR, Shi J, Bao YP, Lu L, Han Y | title = Efficacy and safety of psychedelics for the treatment of mental disorders: A systematic review and meta-analysis | journal = Psychiatry Res | volume = 335 | issue = | pages = 115886 | date = May 2024 | pmid = 38574699 | doi = 10.1016/j.psychres.2024.115886 | url = }}</ref><ref name="KoKopraCleare2023">{{cite journal | vauthors = Ko K, Kopra EI, Cleare AJ, Rucker JJ | title = Psychedelic therapy for depressive symptoms: A systematic review and meta-analysis | journal = J Affect Disord | volume = 322 | issue = | pages = 194–204 | date = February 2023 | pmid = 36209780 | doi = 10.1016/j.jad.2022.09.168 | url = }}</ref>

Preliminary meta-analyses suggest that the improvements in depressive symptoms with psilocybin are [[dose dependence|dose-dependent]] and that higher doses may result in greater improvements than lower doses.<ref name="LiHuChen2022">{{cite journal | vauthors = Li NX, Hu YR, Chen WN, Zhang B | title = Dose effect of psilocybin on primary and secondary depression: a preliminary systematic review and meta-analysis | journal = J Affect Disord | volume = 296 | issue = | pages = 26–34 | date = January 2022 | pmid = 34587546 | doi = 10.1016/j.jad.2021.09.041 | url = }}</ref><ref name="PerezLanglestMallet2023">{{cite journal | vauthors = Perez N, Langlest F, Mallet L, De Pieri M, Sentissi O, Thorens G, Seragnoli F, Zullino D, Kirschner M, Kaiser S, Solmi M, Sabé M | title = Psilocybin-assisted therapy for depression: A systematic review and dose-response meta-analysis of human studies | journal = Eur Neuropsychopharmacol | volume = 76 | issue = | pages = 61–76 | date = November 2023 | pmid = 37557019 | doi = 10.1016/j.euroneuro.2023.07.011 | url = | doi-access = free }}</ref><ref name="SwieczkowskiKwaśnyPruc2025">{{cite journal | vauthors = Swieczkowski D, Kwaśny A, Pruc M, Gaca Z, Szarpak L, Cubała WJ | title = Efficacy and safety of psilocybin in the treatment of Major Depressive Disorder (MDD): A dose-response network meta-analysis of randomized placebo-controlled clinical trials | journal = Psychiatry Res | volume = 344 | issue = | pages = 116337 | date = February 2025 | pmid = 39754904 | doi = 10.1016/j.psychres.2024.116337 | url = }}</ref> One meta-analysis found that the highest assessed dose in clinical trials, 30 to 35{{nbsp}}mg per 70{{nbsp}}kg body weight, was the most effective, with an [[effect size]] (Hedges' g) of 3.059 (relative to 1.289 overall), but based on only one study for that dosing subgroup.<ref name="LiHuChen2022" /> This meta-analysis included both RCTs and [[prospective study|prospective]] open-label studies, and it calculated effect sizes by comparing to the placebo group or by using pre-treatment (baseline) values.<ref name="LiHuChen2022" /> Another meta-analysis, which included only RCTs, found that 25{{nbsp}}mg was the most effective dose, relative to lower doses like 10{{nbsp}}mg and 0.215{{nbsp}}mg/kg body weight (~15{{nbsp}}mg for a 70-kg person).<ref name="SwieczkowskiKwaśnyPruc2025" /> A third meta-analysis found that half of the maximal antidepressant effect of psilocybin occurred with a dose of about 10{{nbsp}}mg/kg body weight, while 95% of the maximal effect occurred at a dose of about 41{{nbsp}}mg/kg body weight, and that higher doses might especially be better for treatment-resistant depression.<ref name="PerezLanglestMallet2023" /> The risk of [[adverse effect]]s was also greater with higher doses.<ref name="PerezLanglestMallet2023" />

A 2025 network meta-analysis of RCTs of psilocybin for depression found that it did not significantly improve depression scores relative to placebo on day 2 post-dose but scores were improved day 8 and day 15 post-dose.<ref name="SwieczkowskiKwaśnyPruc2025" /> Depressive symptoms were improved only slightly more with psilocybin than with placebo.<ref name="SwieczkowskiKwaśnyPruc2025" /> Another 2024 meta-analysis found that depressive symptoms were improved on days 2, 14, and 42, with similar effect sizes.<ref name="MenonRamamurthyVenu2024">{{cite journal | vauthors = Menon V, Ramamurthy P, Venu S, Andrade C | title = Randomized Controlled Trials of Psilocybin-Assisted Therapy in the Treatment of Major Depressive Disorder: Systematic Review and Meta-Analysis | journal = Acta Psychiatr Scand | volume = | issue = | pages = | date = December 2024 | pmid = 39627679 | doi = 10.1111/acps.13778 | url = }}</ref> In the previously described dose-ranging phase 2 trial of psilocybin for depression, the time to median depressive event after administration of psilocybin was 92 to 189{{nbsp}}days for 25{{nbsp}}mg, 43 to 83{{nbsp}}days for 10{{nbsp}}mg, and 21 to 62{{nbsp}}days for 1{{nbsp}}mg, depending on the analysis.<ref name="GoodwinNowakowskaAtli2025">{{cite journal | vauthors = Goodwin GM, Nowakowska A, Atli M, Dunlop BW, Feifel D, Hellerstein DJ, Marwood L, Shabir Z, Mistry S, Stansfield SC, Teoh E, Tsai J, Young MB, Malievskaia E | title = Results From a Long-Term Observational Follow-Up Study of a Single Dose of Psilocybin for a Treatment-Resistant Episode of Major Depressive Disorder | journal = J Clin Psychiatry | volume = 86 | issue = 1 | pages = | date = March 2025 | pmid = 40047545 | doi = 10.4088/JCP.24m15449 | url = }}</ref> Repeated dosing of psilocybin is being explored for maximization and maintenance of depressive symptom improvement, with preliminary effectiveness observed.<ref name="Najib2024">{{cite journal | vauthors = Najib J | title = The role of psilocybin in depressive disorders | journal = Curr Med Res Opin | volume = 40 | issue = 10 | pages = 1793–1808 | date = October 2024 | pmid = 39177339 | doi = 10.1080/03007995.2024.2396536 | url = }}</ref><ref name="LegerUnterwald2022">{{cite journal | vauthors = Leger RF, Unterwald EM | title = Assessing the effects of methodological differences on outcomes in the use of psychedelics in the treatment of anxiety and depressive disorders: A systematic review and meta-analysis | journal = J Psychopharmacol | volume = 36 | issue = 1 | pages = 20–30 | date = January 2022 | pmid = 34519567 | doi = 10.1177/02698811211044688 | url = }}</ref><ref name="RosenblatMeshkatDoyle2024">{{cite journal | vauthors = Rosenblat JD, Meshkat S, Doyle Z, Kaczmarek E, Brudner RM, Kratiuk K, Mansur RB, Schulz-Quach C, Sethi R, Abate A, Ali S, Bawks J, Blainey MG, Brietzke E, Cronin V, Danilewitz J, Dhawan S, Di Fonzo A, Di Fonzo M, Drzadzewski P, Dunlop W, Fiszter H, Gomes FA, Grewal S, Leon-Carlyle M, McCallum M, Mofidi N, Offman H, Riva-Cambrin J, Schmidt J, Smolkin M, Quinn JM, Zumrova A, Marlborough M, McIntyre RS | title = Psilocybin-assisted psychotherapy for treatment resistant depression: A randomized clinical trial evaluating repeated doses of psilocybin | journal = Med | volume = 5 | issue = 3 | pages = 190–200.e5 | date = March 2024 | pmid = 38359838 | doi = 10.1016/j.medj.2024.01.005 | url = }}</ref>

Most clinical trials of psilocybin for depression have had [[conflict of interest|financial conflicts of interest]] and significant risk of bias.<ref name="BorgognaOwenPetrovitch2025">{{cite journal | vauthors = Borgogna NC, Owen T, Petrovitch D, Vaughn J, Johnson DA, Pagano LA, Aita SL, Hill BD | title = Incremental efficacy systematic review and meta-analysis of psilocybin-for-depression RCTs | journal = Psychopharmacology (Berl) | volume = | issue = | pages = | date = April 2025 | pmid = 40266291 | doi = 10.1007/s00213-025-06788-w | url = | doi-access = free }}</ref>