{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T01:08:43Z","timestamp":1793149723895,"version":"4.5.0"},"reference-count":38,"publisher":"American Chemical Society (ACS)","issue":"27","license":[{"start":{"date-parts":[[2020,7,1]],"date-time":"2020-07-01T00:00:00Z","timestamp":1593561600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,7,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>A second-generation kilogram-scale synthesis of the psychedelic tryptamine psilocybin has been developed. The synthesis was designed to address several challenges first encountered with the scale-up of previously described literature procedures, which were not optimized for providing consistent yield and purity of products, atom economy, or being run in pilot plant-scale reactors. These challenges were addressed and circumvented with the design of the second-generation route, which featured an optimized cGMP large-scale Speeter\u2013Anthony tryptamine synthesis to the intermediate psilocin with improved in-process control and impurity removal over the three steps. Psilocin was subsequently phosphorylated directly with phosphorous oxychloride for the first time, avoiding a tedious and poor atom economy benzyl-protecting group strategy common to all previously described methods for producing psilocybin. In this report, the challenges encountered in a 100 g scale first-generation literature-based synthesis are highlighted, followed by a detailed description of the newly developed second-generation synthesis to provide over one kilogram of high-purity psilocybin under cGMP.<\/jats:p>","DOI":"10.1021\/acsomega.0c02387","type":"journal-article","created":{"date-parts":[[2020,7,1]],"date-time":"2020-07-01T12:35:24Z","timestamp":1593606924000},"page":"16959-16966","source":"Crossref","is-referenced-by-count":40,"title":["Direct Phosphorylation of Psilocin Enables Optimized\ncGMP Kilogram-Scale Manufacture of Psilocybin"],"prefix":"10.1021","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5539-6343","authenticated-orcid":true,"given":"Robert B.","family":"Kargbo","sequence":"first","affiliation":[{"name":"Usona Institute , 2800 Woods Hollow Road , , ,","place":["Madison, Wisconsin, United States, 53711"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0895-0791","authenticated-orcid":true,"given":"Alexander","family":"Sherwood","sequence":"additional","affiliation":[{"name":"Usona Institute , 2800 Woods Hollow Road , , ,","place":["Madison, Wisconsin, United States, 53711"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Walker","sequence":"additional","affiliation":[{"name":"Almac Sciences , 20 Seagoe Industrial Estate , ,","place":["Craigavon, United Kingdom, BT63 5QD"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas V.","family":"Cozzi","sequence":"additional","affiliation":[{"name":"University of Wisconsin School of Medicine and Public Health , , , ,","place":["Madison, Wisconsin, United States, 53706"]},{"name":"Alexander Shulgin Research Institute , 1483 Shulgin Road , , ,","place":["Lafayette, California, United States, 94549"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond E.","family":"Dagger","sequence":"additional","affiliation":[{"name":"Stonehedge Pharmaceutical Consulting, LLC , 13121 Old Annapolis Road , , ,","place":["Mount Airy, Maryland, United States, 21771"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Sable","sequence":"additional","affiliation":[{"name":"Promega Corporation , 2800 Woods Hollow Road , , ,","place":["Madison, Wisconsin, United States, 53711"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelsey","family":"O\u2019Hern","sequence":"additional","affiliation":[{"name":"Usona Institute , 2800 Woods Hollow Road , , ,","place":["Madison, Wisconsin, United States, 53711"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristi","family":"Kaylo","sequence":"additional","affiliation":[{"name":"Usona Institute , 2800 Woods Hollow Road , , ,","place":["Madison, Wisconsin, United States, 53711"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tura","family":"Patterson","sequence":"additional","affiliation":[{"name":"Usona Institute , 2800 Woods Hollow Road , , ,","place":["Madison, Wisconsin, United States, 53711"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary","family":"Tarpley","sequence":"additional","affiliation":[{"name":"Usona Institute , 2800 Woods Hollow Road , , ,","place":["Madison, Wisconsin, United States, 53711"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Poncho","family":"Meisenheimer","sequence":"additional","affiliation":[{"name":"Usona Institute , 2800 Woods Hollow Road , , ,","place":["Madison, Wisconsin, United States, 53711"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2020,7,1]]},"reference":[{"key":"2026090317381937300_cit1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/17512433.2018.1415755","article-title":"Novel Psychotherapeutics\n- A Cautiously Optimistic\nFocus on Hallucinogens","volume":"11","author":"Sherwood","year":"2018","journal-title":"Expert Rev. 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Psychopharmacol."},{"key":"2026090317381937300_cit5","doi-asserted-by":"publisher","first-page":"1165","DOI":"10.1177\/0269881116675512","article-title":"Rapid and sustained\nsymptom reduction following psilocybin treatment for anxiety and depression\nin patients with life-threatening cancer: a randomized controlled\ntrial","volume":"30","author":"Ross","year":"2016","journal-title":"J. Psychopharmacol."},{"key":"2026090317381937300_cit6","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1001\/archgenpsychiatry.2010.116","article-title":"Pilot study of psilocybin\ntreatment\nfor anxiety in patients with advanced-stage cancer","volume":"68","author":"Grob","year":"2011","journal-title":"Arch. Gen. 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Psychopharmacol."},{"key":"2026090317381937300_cit10","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1177\/0269881119897615","article-title":"Long-term follow-up\nof psilocybin-assisted psychotherapy for psychiatric\nand existential distress in patients with life-threatening cancer","volume":"34","author":"Agin-Liebes","year":"2020","journal-title":"J. Psychopharmacol."},{"key":"2026090317381937300_cit11","volume-title":"PIHKAL: A Chemical Love\nStory","author":"Shulgin","year":"1991"},{"key":"2026090317381937300_cit12","volume-title":"TIHKAL: The Continuation","author":"Shulgin","year":"1997"},{"key":"2026090317381937300_cit13","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1016\/j.pharmthera.2003.11.002","article-title":"Hallucinogens","volume":"101","author":"Nichols","year":"2004","journal-title":"Pharmacol. 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U.S. Patent US3,192,1111965."},{"key":"2026090317381937300_cit20","doi-asserted-by":"publisher","first-page":"688","DOI":"10.1055\/s-0039-1691565","article-title":"An Improved, Practical,\nand Scalable Five-Step Synthesis of Psilocybin","volume":"52","author":"Sherwood","year":"2020","journal-title":"Synthesis"},{"key":"2026090317381937300_cit21","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1021\/np030059u","article-title":"Concise Large-Scale\nSynthesis of\nPsilocin and Psilocybin, Principal Hallucinogenic Constituents of\n\u201cMagic Mushroom\u201d","volume":"66","author":"Shirota","year":"2003","journal-title":"J. Nat. Prod."},{"key":"2026090317381937300_cit22","doi-asserted-by":"publisher","first-page":"935","DOI":"10.1055\/s-1999-3490","article-title":"Improvements\nto the Synthesis of Psilocybin and a Facile Method for Preparing the\nO-Acetyl Prodrug of Psilocin","volume":"1999","author":"Nichols","year":"1999","journal-title":"Synthesis"},{"key":"2026090317381937300_cit23","doi-asserted-by":"publisher","first-page":"1450","DOI":"10.1002\/anie.201910175","article-title":"Injury-Triggered\nBlueing Reactions of Psilocybe \u2033Magic\u2033 Mushrooms","volume":"59","author":"Lenz","year":"2020","journal-title":"Angew. Chem., Int. Ed."},{"key":"2026090317381937300_cit24","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1021\/acs.jnatprod.9b01061","article-title":"Synthesis and Biological Evaluation\nof Tryptamines Found in Hallucinogenic Mushrooms: Norbaeocystin, Baeocystin,\nNorpsilocin, and Aeruginascin","volume":"83","author":"Sherwood","year":"2020","journal-title":"J. Nat. 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Lett."},{"key":"2026090317381937300_cit31","doi-asserted-by":"publisher","first-page":"8125","DOI":"10.1016\/j.tet.2016.09.070","article-title":"Diethyl phosphorocyanidate (DEPC): a versatile reagent\nfor organic synthesis","volume":"72","author":"Harusawa","year":"2016","journal-title":"Tetrahedron"},{"key":"2026090317381937300_cit32","doi-asserted-by":"publisher","first-page":"1404","DOI":"10.1016\/j.tetlet.2018.02.066","article-title":"Exploration Of Chiral\nLewis Acid Mg2+ Catalysts In The Synthesis Of Aryl Organophosphate\nTriesters From Phosphorus Oxychloride Through A Three-Step, Two-Pot\nSubstitution Sequence","volume":"59","author":"Granger","year":"2018","journal-title":"Tetrahedron Lett."},{"key":"2026090317381937300_cit33","doi-asserted-by":"publisher","first-page":"314","DOI":"10.1002\/ajoc.201700638","article-title":"Selected Methods\nfor the Chemical Phosphorylation and Thiophosphorylation of Phenols","volume":"7","author":"Kozak","year":"2018","journal-title":"Asian J. Org. Chem."},{"key":"2026090317381937300_cit34","doi-asserted-by":"publisher","first-page":"846","DOI":"10.1021\/acs.oprd.8b00120","article-title":"Evolution of a Scale-Up\nSynthesis to a Potent\nGluN2B Inhibitor and Its Prodrug","volume":"22","author":"Kempson","year":"2018","journal-title":"Org. Process\nRes. Dev."},{"key":"2026090317381937300_cit35","unstructured":"Heim, R.; Hofmann, A.; Brack, A.; Kobel, H.; Cailleux, R.\n          Obtaining Psilocybin and Psilocin\nFrom Fungal Material. U.S. Patent US3,183,1721965."},{"key":"2026090317381937300_cit36","doi-asserted-by":"publisher","first-page":"942","DOI":"10.1039\/P29740000942","article-title":"Crystal structures\nof the Teonana\u0301catl hallucinogens.\nPart I. Psilocybin C12H17N2O4P","author":"Weber","year":"1974","journal-title":"J. Chem. Soc., Perkin Trans. 2"},{"key":"2026090317381937300_cit37","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1520\/JFS10282J","article-title":"X-Ray Powder\nDiffraction Data For Some Drugs, Excipients, And Adulterants In Illicit\nSamples","volume":"20","author":"Folen","year":"1975","journal-title":"J. Forensic Sci."},{"key":"2026090317381937300_cit38","unstructured":"Impurities in New Drug Products Q3A; International Conference\non Harmonization (ICH)."}],"container-title":["ACS Omega"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsomega.0c02387","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/5\/27\/16959\/68303406\/acsomega.0c02387.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/5\/27\/16959\/68303406\/acsomega.0c02387.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T21:38:23Z","timestamp":1788471503000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/acsodf\/article\/5\/27\/16959\/505388\/Direct-Phosphorylation-of-Psilocin-Enables"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,1]]},"references-count":38,"journal-issue":{"issue":"27","published-online":{"date-parts":[[2020,7,1]]},"published-print":{"date-parts":[[2020,7,14]]}},"URL":"https:\/\/doi.org\/10.1021\/acsomega.0c02387","relation":{},"ISSN":["2470-1343"],"issn-type":[{"value":"2470-1343","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,1]]}}}