{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T06:16:53Z","timestamp":1786947413722,"version":"build-2736575974"},"reference-count":20,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2024,4,30]],"date-time":"2024-04-30T00:00:00Z","timestamp":1714435200000},"content-version":"vor","delay-in-days":32,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,6,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Hexahydrocannabinol (HHC), 6,6,9-trimethyl-3-pentyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-1-ol, is a semi-synthetic cannabinoid that has presented challenges to analytical laboratories due to its emergence and spread in the drug market. The lack of information on human pharmacokinetics hinders the development and application of presumptive and confirmatory tests for reliably detecting HHC consumption. To address this knowledge gap, we report the analytical results obtained from systematic forensic toxicological analysis of body-fluid samples collected from three individuals suspected of drug-impaired driving after HHC consumption. Urine and plasma samples were analyzed using non-targeted liquid chromatography\u2013high-resolution tandem mass spectrometry. The results provided evidence that HHC undergoes biotransformation reactions similar to other well-characterized cannabinoids, such as \u22069-tetrahydrocannabinol or cannabidiol. Notably, HHC itself was only detectable in plasma samples, not in urine samples. The observed Phase I reactions involved oxidation of C11 and the pentyl side chain, leading to corresponding hydroxylated and carboxylic acid species. Additionally, extensive glucuronidation of HHC and its Phase I metabolites was evident.<\/jats:p>","DOI":"10.1093\/jat\/bkae022","type":"journal-article","created":{"date-parts":[[2024,4,30]],"date-time":"2024-04-30T16:59:32Z","timestamp":1714496372000},"page":"350-358","source":"Crossref","is-referenced-by-count":12,"title":["Insights into the human metabolism of hexahydrocannabinol by non-targeted liquid chromatography\u2013high-resolution tandem mass spectrometry"],"prefix":"10.1093","volume":"48","author":[{"given":"Florian","family":"Pitterl","sequence":"first","affiliation":[{"name":"Institute of Legal Medicine, Medical University of Innsbruck , Muellerstrasse 44, Innsbruck 6020,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion","family":"Pavlic","sequence":"additional","affiliation":[{"name":"Institute of Legal Medicine, Medical University of Innsbruck , Muellerstrasse 44, Innsbruck 6020,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianmei","family":"Liu","sequence":"additional","affiliation":[{"name":"Forensic Chemistry Division, Cayman Chemical Company , 1180 E Ellsworth Rd., Ann Arbor, MI 48108,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0963-8268","authenticated-orcid":false,"given":"Herbert","family":"Oberacher","sequence":"additional","affiliation":[{"name":"Institute of Legal Medicine, Medical University of Innsbruck , Muellerstrasse 44, Innsbruck 6020,","place":["Austria"]},{"name":"Core Facility Metabolomics, Medical University of Innsbruck , Muellerstrasse 44, Innsbruck 6020,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,3,29]]},"reference":[{"key":"2024110408355607200_R1","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1126\/science.92.2380.115","article-title":"Marihuana","volume":"92","author":"Adams","year":"1940","journal-title":"Science"},{"key":"2024110408355607200_R2","article-title":"Hexahydrocannabinol (HHC) and Related Substances","author":"The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA)","year":"2023"},{"key":"2024110408355607200_R3","doi-asserted-by":"crossref","first-page":"1630","DOI":"10.1021\/jm00127a038","article-title":"The importance of the orientation of the C9 substituent to cannabinoid activity","volume":"32","author":"Reggio","year":"1989","journal-title":"Journal of Medicinal Chemistry"},{"key":"2024110408355607200_R4","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1089\/can.2022.0253","article-title":"Hexahydrocannabinol on the light cannabis market: the latest \u201cnew\u201d entry","volume":"9","author":"Casati","year":"2022","journal-title":"Cannabis and Cannabinoid Research"},{"key":"2024110408355607200_R5","doi-asserted-by":"crossref","first-page":"5200","DOI":"10.1021\/ja00720a033","article-title":"Structural studies of cannabinoids. Theoretical and proton magnetic resonance analysis","volume":"92","author":"Archer","year":"1970","journal-title":"Journal of the American Chemical Society"},{"key":"2024110408355607200_R6","first-page":"577","article-title":"Pharmacology and toxicology of major constituents of marijuana\u2014on the metabolic activation of cannabinoids and its mechanism","volume":"22","author":"Yamamoto","year":"2003","journal-title":"Journal of Toxicology: Toxin Reviews"},{"key":"2024110408355607200_R7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jpba.2018.08.021","article-title":"Untargeted rat brain metabolomics after oral administration of a single high dose of cannabidiol","volume":"161","author":"Citti","year":"2018","journal-title":"Journal Pharmaceutical and Biomedical Analysis"},{"key":"2024110408355607200_R8","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1124\/dmd.120.000350","article-title":"Cytochrome P450\u2013catalyzed metabolism of cannabidiol to the active metabolite 7-hydroxy-cannabidiol","volume":"49","author":"Beers","year":"2021","journal-title":"Drug Metabolism and Disposition"},{"key":"2024110408355607200_R9","doi-asserted-by":"crossref","first-page":"2105","DOI":"10.1007\/s00414-020-02387-w","article-title":"Investigation of phase II metabolism of 11-hydroxy-\u0394-9-tetrahydrocannabinol and metabolite verification by chemical synthesis of 11-hydroxy-\u0394-9-tetrahydrocannabinol-glucuronide","volume":"134","author":"Hassenberg","year":"2020","journal-title":"International Journal of Legal Medicine"},{"key":"2024110408355607200_R10","first-page":"714","article-title":"In vitro metabolism of the equatorial C11-methyl isomer of hexahydrocannabinol in several mammalian species","volume":"19","author":"Harvey","year":"1991","journal-title":"Drug Metabolism and Disposition"},{"key":"2024110408355607200_R11","first-page":"439","article-title":"Identification of the in vivo liver metabolites of (\u2014)-delta 7-tetrahydrocannabinol produced by the mouse","volume":"8","author":"Harvey","year":"1980","journal-title":"Drug Metabolism and Disposition"},{"key":"2024110408355607200_R12","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1007\/s00216-018-1504-x","article-title":"A validated workflow for drug detection in oral fluid by non-targeted liquid chromatography-tandem mass spectrometry","volume":"411","author":"Reinstadler","year":"2019","journal-title":"Analytical and Bioanalytical Chemistry"},{"key":"2024110408355607200_R13","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1007\/s00216-014-8262-1","article-title":"Applying \u2018Sequential Windowed Acquisition of all Theoretical Fragment Ion Mass Spectra\u2019 (SWATH) for systematic toxicological analysis with liquid chromatography-high-resolution tandem mass spectrometry","volume":"407","author":"Arnhard","year":"2015","journal-title":"Analytical and Bioanalytical Chemistry"},{"key":"2024110408355607200_R14","doi-asserted-by":"crossref","first-page":"2534","DOI":"10.1093\/bioinformatics\/btn323","article-title":"ProteoWizard: open source software for rapid proteomics tools development","volume":"24","author":"Kessner","year":"2008","journal-title":"Bioinformatics"},{"key":"2024110408355607200_R15","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1002\/jms.1525","article-title":"On the inter-instrument and the inter-laboratory transferability of a tandem mass spectral reference library: 2. Optimization and characterization of the search algorithm","volume":"44","author":"Oberacher","year":"2009","journal-title":"Journal of Mass Spectrometry"},{"key":"2024110408355607200_R16","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1093\/jat\/8.6.252","article-title":"Analysis of the major metabolite of delta 9-tetrahydrocannabinol in urine. V. Cross-reactivity of selected compounds in a radioimmunoassay","volume":"8","author":"Jones","year":"1984","journal-title":"Journal of Analytical Toxicology"},{"key":"2024110408355607200_R17","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1002\/rcm.1071","article-title":"Cone voltage induced in-source dissociation of glucuronides in electrospray and implications in biological analyses","volume":"17","author":"Yan","year":"2003","journal-title":"Rapid Communications in Mass Spectrometry"},{"key":"2024110408355607200_R18","doi-asserted-by":"crossref","first-page":"2629","DOI":"10.1007\/s00216-022-03899-7","article-title":"In silico deconjugation of glucuronide conjugates enhances tandem mass spectra library annotation of human samples","volume":"414","author":"Huber","year":"2022","journal-title":"Analytical and Bioanalytical Chemistry"},{"key":"2024110408355607200_R19","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1002\/jms.1963","article-title":"Fragmentation pathways of drugs of abuse and their metabolites based on QTOF MS-MS and MSE accurate-mass spectra","volume":"46","author":"Bijlsma","year":"2011","journal-title":"Journal of Mass Spectrometry"},{"key":"2024110408355607200_R20","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1002\/bms.1200200510","article-title":"Electron impact-induced fragmentation of the trimethylsilyl derivatives of monohydroxy-hexahydrocannabinols","volume":"20","author":"Harvey","year":"1991","journal-title":"Biological Mass Spectrometry"}],"container-title":["Journal of Analytical Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jat\/advance-article-pdf\/doi\/10.1093\/jat\/bkae022\/57362452\/bkae022.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jat\/article-pdf\/48\/5\/350\/60386126\/bkae022.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jat\/article-pdf\/48\/5\/350\/60386126\/bkae022.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,4]],"date-time":"2024-11-04T08:36:29Z","timestamp":1730709389000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jat\/article\/48\/5\/350\/7660320"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,29]]},"references-count":20,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2024,3,29]]},"published-print":{"date-parts":[[2024,6,11]]}},"URL":"https:\/\/doi.org\/10.1093\/jat\/bkae022","relation":{},"ISSN":["0146-4760","1945-2403"],"issn-type":[{"value":"0146-4760","type":"print"},{"value":"1945-2403","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,6]]},"published":{"date-parts":[[2024,3,29]]}}}