{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T21:20:28Z","timestamp":1791321628115,"version":"4.3.1"},"reference-count":31,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2024,5,28]],"date-time":"2024-05-28T00:00:00Z","timestamp":1716854400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["E! 113377"],"award-info":[{"award-number":["E! 113377"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000275","name":"Leverhulme Trust","doi-asserted-by":"publisher","award":["RC\u20102015\u2010011"],"award-info":[{"award-number":["RC\u20102015\u2010011"]}],"id":[{"id":"10.13039\/501100000275","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Drug Testing and Analysis"],"published-print":{"date-parts":[[2025,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Hexahydrocannabinol (HHC), hexahydrocannabiphorol (HHCP) and their acetates, HHC\u2010O and HHCP\u2010O, respectively, are emerging in Europe as alternatives to tetrahydrocannabinol (THC). This study aimed to elucidate the metabolic pathways of the semi\u2010synthetic cannabinoids HHC, HHCP, HHC\u2010O and HHCP\u2010O from incubation with human hepatocytes. The metabolites of HHC were also identified in authentic urine samples. HHC, HHCP, HHC\u2010O and HHCP\u2010O were incubated with primary human hepatocytes for 1, 3 and 5\u2009h. Authentic urine samples from cases screened positive for cannabis in blood using ELISA but confirmed negative were analysed both non\u2010hydrolysed and hydrolysed for HHC metabolites. Potential metabolites were identified using ultra\u2010high performance liquid chromatography (UHPLC) coupled to a quadrupole time\u2010of\u2010flight mass spectrometer (QToF\u2010MS). HHC and HHCP were primarily metabolised through monohydroxylation (monoOH), followed by oxidation to a carboxylic acid metabolite. HHC\u2010O and HHCP\u2010O were rapidly metabolised to HHC and HHCP, respectively. In authentic urine samples, 18 different metabolites were identified, and 99.3% of hydroxylated metabolites were glucuronidated. 11\u2010OH\u2010HHC, 5\u2032OH\u2010HHC and another metabolite with a monoOH on the side chain were the only metabolites present in all 16 urine samples. The metabolism of HHC and HHCP were similar, although the longer alkyl side chain of HHCP (heptyl) led to greater hydroxylation on the side chain than HHC (pentyl). The use of HHC and HHCP can be differentiated from the use of THC and other phytocannabinoids, but the use of the acetate analogues may not be differentiable from their non\u2010acetate analogues.<\/jats:p>","DOI":"10.1002\/dta.3740","type":"journal-article","created":{"date-parts":[[2024,5,28]],"date-time":"2024-05-28T06:14:10Z","timestamp":1716876850000},"page":"372-386","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Human metabolism of the semi\u2010synthetic cannabinoids hexahydrocannabinol, hexahydrocannabiphorol and their acetates using hepatocytes and urine samples"],"prefix":"10.1002","volume":"17","author":[{"given":"Karin","family":"Lindbom","sequence":"first","affiliation":[{"name":"Division of Clinical Chemistry and Pharmacology, Department of Biomedical and Clinical Sciences Link\u00f6ping University  Link\u00f6ping Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2322-0367","authenticated-orcid":false,"given":"Caitlyn","family":"Norman","sequence":"additional","affiliation":[{"name":"Division of Clinical Chemistry and Pharmacology, Department of Biomedical and Clinical Sciences Link\u00f6ping University  Link\u00f6ping Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5615-1199","authenticated-orcid":false,"given":"Steven","family":"Baginski","sequence":"additional","affiliation":[{"name":"Leverhulme Research Centre for Forensic Science, School of Science and Engineering University of Dundee  Dundee UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7679-4403","authenticated-orcid":false,"given":"Lucas","family":"Krebs","sequence":"additional","affiliation":[{"name":"Institute for Chemistry and Bioanalytics, School of Life Sciences University of Applied Sciences Northwestern Switzerland  Muttenz Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6712-652X","authenticated-orcid":false,"given":"Darta","family":"Stalberga","sequence":"additional","affiliation":[{"name":"Division of Clinical Chemistry and Pharmacology, Department of Biomedical and Clinical Sciences Link\u00f6ping University  Link\u00f6ping Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0857-6261","authenticated-orcid":false,"given":"Tobias","family":"Rautio","sequence":"additional","affiliation":[{"name":"Department of Physics, Chemistry and Biology Link\u00f6ping University  Link\u00f6ping Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6756-2276","authenticated-orcid":false,"given":"Xiongyu","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Physics, Chemistry and Biology Link\u00f6ping University  Link\u00f6ping Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4222-9597","authenticated-orcid":false,"given":"Robert","family":"Kronstrand","sequence":"additional","affiliation":[{"name":"Division of Clinical Chemistry and Pharmacology, Department of Biomedical and Clinical Sciences Link\u00f6ping University  Link\u00f6ping Sweden"},{"name":"Department of Forensic Genetics and Forensic Toxicology National Board of Forensic Medicine  Link\u00f6ping Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8015-5728","authenticated-orcid":false,"given":"Henrik","family":"Gr\u00e9en","sequence":"additional","affiliation":[{"name":"Division of Clinical Chemistry and Pharmacology, Department of Biomedical and Clinical Sciences Link\u00f6ping University  Link\u00f6ping Sweden"},{"name":"Department of Forensic Genetics and Forensic Toxicology National Board of Forensic Medicine  Link\u00f6ping Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,5,28]]},"reference":[{"key":"e_1_2_8_2_1","volume-title":"Hexahydrocannabinol (HHC) and Related Substances","author":"Ujv\u00e1ry I","year":"2023"},{"key":"e_1_2_8_3_1","unstructured":"European Monitoring Centre for Drugs and Drug Addiction (EMCDDA).EU Early Warning System Formal Notification. [Notification of 6a 7 8 9 10 10a\u2010hexahydro\u20106 6 9\u2010trimethyl\u20103\u2010pentyl\u20106H[1]dibenzo[b d]pyran\u20101\u2010ol (hexahydrocannabinol; HHC) in Europe.] EU\u2010EWS\u2010RCS\u2010FN\u20102022\u20100031.2022."},{"key":"e_1_2_8_4_1","unstructured":"European Monitoring Centre for Drugs and Drug Addiction (EMCDDA).EU Early Warning System Formal Notification. [Notification of (6 6 9\u2010trimethyl\u20103\u2010pentyl\u20106a 7 8 9 10 10ahexahydrobenzo[c]chromen\u20101\u2010yl) acetate (hexahydrocannabinol acetate; HHC acetate) in Europe.] EU\u2010EWS\u2010RCS\u2010FN\u20102022\u20100035.2022."},{"key":"e_1_2_8_5_1","unstructured":"European Monitoring Centre for Drugs and Drug Addiction (EMCDDA).EU Early Warning System Formal Notification. [Notification of 3\u2010heptyl\u20106a 7 8 9 10 10a\u2010hexahydro\u20106 6 9\u2010trimethyl\u20106H\u2010dibenzo[b d]pyran\u20101\u2010ol (hexahydrocannabiphorol; HHC\u2010P) in Europe.] EU\u2010EWS\u2010RCS\u2010FN\u20102023\u20100001.2023."},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/cen\u201010128\u2010feature1"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1055\/a\u20101110\u20101045"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010019\u201056785\u20101"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010023\u201038188\u20105"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/dta.3519"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11419\u2010023\u201000667\u20109"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1089\/can.2022.0253"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/dta.3570"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749\u20106632.1971.tb13985.x"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.3c00254"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1177\/14690667231200139"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/0091\u20103057(91)90359\u2010A"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpba.2023.115918"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/jat\/bkad079"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/dta.2888"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248\u2010019\u20100381\u20103"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/jat\/bkae030"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14153"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/dta.3203"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.7812\/TPP\/19.200"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbdv.200790152"},{"issue":"4","key":"e_1_2_8_27_1","first-page":"149","article-title":"Chemistry, metabolism, and toxicology of cannabis: clinical implications","volume":"7","author":"Sharma P","year":"2012","journal-title":"Iran J Psychiatry"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1080\/00498254.2023.2194981"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1093\/jat\/bkad065"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI107431"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1093\/jat\/bkac036"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.26828\/cannabis\/2023\/000164"}],"container-title":["Drug Testing and Analysis"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/dta.3740","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T21:18:50Z","timestamp":1760390330000},"score":1,"resource":{"primary":{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/10.1002\/dta.3740"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,28]]},"references-count":31,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2025,3]]}},"alternative-id":["10.1002\/dta.3740"],"URL":"https:\/\/doi.org\/10.1002\/dta.3740","archive":["Portico"],"relation":{},"ISSN":["1942-7603","1942-7611"],"issn-type":[{"value":"1942-7603","type":"print"},{"value":"1942-7611","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,28]]},"assertion":[{"value":"2024-03-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-05-15","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-05-28","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}