{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T00:13:23Z","timestamp":1788567203761,"version":"build-2803163510"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T00:00:00Z","timestamp":1742774400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T00:00:00Z","timestamp":1742774400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100008678","name":"Universit\u00e4t Leipzig","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100008678","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>The semi-synthetic cannabinoid hexahydrocannabinol (HHC) has become a highly discussed topic in forensic toxicology since 2022 due to its legal availability at this time and its psychoactive effects. This study aimed to investigate the pharmacokinetics, effects, and immunological detectability of HHC after oral (25\u00a0mg HHC fruit gum) and inhalative (three puffs from HHC vape) consumption with three participants per group. Serum (up to 48\u00a0h), urine (up to five days), and saliva (up to 48\u00a0h) samples were collected at different relevant time points and analyzed by HPLC-MS\/MS for (9<jats:italic>R<\/jats:italic>)\/(9<jats:italic>S<\/jats:italic>)-HHC, 11-hydroxy-HHC, and (9<jats:italic>R<\/jats:italic>)\/(9<jats:italic>S<\/jats:italic>)-HHC carboxylic acid with a fully validated method. Additionally, immunological detectability was investigated with three different commercially available tests. To address the psychoactive effects, the subjective \u201chigh\u201d feeling (scale 0\u201310) was monitored and different psychophysical tests (e.g. modified Romberg test, walk and turn) were conducted. Overall, the pharmacokinetics and effects of HHC were comparable to tetrahydrocannabinol (THC). However, the route of administration as well as inter-individual factors played a crucial role regarding maximum concentrations, pharmacokinetic profiles, and psychoactive effects.<\/jats:p>","DOI":"10.1038\/s41598-025-93931-4","type":"journal-article","created":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T13:55:38Z","timestamp":1742824538000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Preliminary pharmacokinetic and psychophysical investigations after controlled oral and inhalative consumption of hexahydrocannabinol (HHC)"],"prefix":"10.1038","volume":"15","author":[{"given":"Lisa","family":"H\u00f6fert","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Franz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cedric","family":"Gro\u00df","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delen","family":"Kuntze","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bronislav","family":"Jur\u00e1sek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Kucha\u0159","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Dre\u00dfler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susen","family":"Becker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven","family":"Baumann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,3,24]]},"reference":[{"key":"93931_CR1","doi-asserted-by":"crossref","unstructured":"Casati, S. et al. Hexahydrocannabinol on the light cannabis market: the latest \u2018new\u2019 entry. Cannabis Cannabinoid Res. 9, (2022).","DOI":"10.1089\/can.2022.0253"},{"key":"93931_CR2","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1002\/dta.3519","volume":"16","author":"I Ujv\u00e1ry","year":"2023","unstructured":"Ujv\u00e1ry, I. Hexahydrocannabinol and closely related semi-synthetic cannabinoids: A comprehensive review. Drug Test. Anal. 16, 127\u2013161 (2023).","journal-title":"Drug Test. Anal."},{"key":"93931_CR3","unstructured":"Nationalrat \u00d6sterreich. Bundesgesetz \u00fcber den Schutz vor Gesundheitsgefahren im Zusammenhang mit Neuen Psychoaktiven Substanzen (Neue-Psychoaktive-Substanzen-Gesetz, NPSG). (accessed  31 May 2024); https:\/\/www.ris.bka.gv.at\/GeltendeFassung.wxe?Abfrage=Bundesnormen&Gesetzesnummer=20007605"},{"key":"93931_CR4","unstructured":"Gesetz \u00fcber den Verkehr mit Bet\u00e4ubungsmitteln (BtMG). (accessed  24 April 2024);  https:\/\/www.gesetze-im-internet.de\/btmg_1981\/"},{"key":"93931_CR5","unstructured":"Eidgen\u00f6ssisches Departement des Innern. Verordnung des EDI \u00fcber die Verzeichnisse der Bet\u00e4ubungsmittel, psychotropen Stoffe, Vorl\u00e4uferstoffe und Hilfschemikalien (Bet\u00e4ubungsmittelverzeichnisverordnung, BetmVV-EDI). (accessed  31 May 2024); https:\/\/www.fedlex.admin.ch\/eli\/cc\/2011\/363\/de#annex_1\/lvl_u1"},{"key":"93931_CR6","unstructured":"Bundesministerium f\u00fcr Gesundheit. F\u00fcnfte Verordnung zur \u00c4nderung der Anlage des Neue-psychoaktive-Stoffe-Gesetzes. (accessed  28 June 2024); https:\/\/www.recht.bund.de\/bgbl\/1\/2024\/210\/VO.html"},{"key":"93931_CR7","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1002\/dta.3570","volume":"16","author":"L H\u00f6fert","year":"2024","unstructured":"H\u00f6fert, L., Becker, S., Dre\u00dfler, J. & Baumann, S. Quantification of (9R)- and (9S)-hexahydrocannabinol (HHC) via GC\u2013MS in serum\/plasma samples from drivers suspected of cannabis consumption and immunological detection of HHC and related substances in serum, urine, and saliva. Drug Test. Anal. 16, 489\u2013497 (2024).","journal-title":"Drug Test. Anal."},{"key":"93931_CR8","doi-asserted-by":"crossref","unstructured":"Schirmer, W., Auw\u00e4rter, V., Kaudewitz, J., Sch\u00fcrch, S. & Weinmann, W. Identification of human hexahydrocannabinol metabolites in urine. Eur. J. Mass. Spectrom. 29, (2023).","DOI":"10.1177\/14690667231200139"},{"key":"93931_CR9","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.3390\/metabo13121169","volume":"13","author":"C Falck J\u00f8rgensen","year":"2023","unstructured":"Falck J\u00f8rgensen, C., Rasmussen, S., Linnet, B., Thomsen, R. & K. & Evidence of 11-hydroxy-hexahydrocannabinol and 11-Nor-9-carboxy-hexahydrocannabinol as novel human metabolites of \u22069-tetrahydrocannabinol. Metabolites 13, 1169 (2023).","journal-title":"Metabolites"},{"key":"93931_CR10","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1093\/jat\/bkad079","volume":"47","author":"SK Manier","year":"2023","unstructured":"Manier, S. K., Valdiviezo, J. A., Vollmer, A. C., Eckstein, N. & Meyer, M. R. Analytical toxicology of the semi-synthetic cannabinoid hexahydrocannabinol studied in human samples, pooled human liver S9 fraction, rat samples and drug products using HPLC\u2013HRMS-MS. J. Anal. Toxicol. 47, 818\u2013825 (2023).","journal-title":"J. Anal. Toxicol."},{"key":"93931_CR11","doi-asserted-by":"publisher","unstructured":"H\u00f6fert, L. et al. Verteilung von Hexahydrocannabinol (HHC) und dessen Metaboliten in verschiedenen sektionstoxikologischen Asservaten. Poster presentation at the annual meeting of the German society of forensic medicine. Potsdam  https:\/\/doi.org\/10.13140\/RG.2.2.31198.65607 (2024).","DOI":"10.13140\/RG.2.2.31198.65607"},{"key":"93931_CR12","doi-asserted-by":"crossref","unstructured":"Reggio, P. H., Greer, K. V. & Cox, S. M. The importance of the orientation of the C9 substituent to cannabinoid activity. J. Med. Chem. 32, (1989).","DOI":"10.1021\/jm00127a038"},{"key":"93931_CR13","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1111\/j.1749-6632.1971.tb13985.x","volume":"191","author":"H Edery","year":"1971","unstructured":"Edery, H., Grunfeld, Y., Ben-Zvi, Z. & Mechoulam, R. Structural requirements for cannabinoid activity. Ann. N.Y. Acad. Sci. 191, 40\u201353 (1971).","journal-title":"Ann. NY Acad. Sci."},{"key":"93931_CR14","doi-asserted-by":"crossref","first-page":"2424","DOI":"10.2174\/1570159X21666230623104624","volume":"21","author":"S Graziano","year":"2023","unstructured":"Graziano, S. et al. Hexahydrocannabinol pharmacology, toxicology, and analysis: the first evidence for a recent new psychoactive substance. Curr. Neuropharmacol. 21, 2424\u20132430 (2023).","journal-title":"Curr. Neuropharmacol."},{"key":"93931_CR15","doi-asserted-by":"crossref","first-page":"2619","DOI":"10.1007\/s00204-024-03769-4","volume":"98","author":"LK Janssens","year":"2024","unstructured":"Janssens, L. K. et al. Investigation of the intrinsic cannabinoid activity of hemp-derived and semisynthetic cannabinoids with \u03b2-arrestin2 recruitment assays\u2014and how this matters for the harm potential of seized drugs. Arch. Toxicol. 98, 2619\u20132630 (2024).","journal-title":"Arch. Toxicol."},{"key":"93931_CR16","doi-asserted-by":"crossref","unstructured":"Lindbom, K. et al. Human metabolism of the semi-synthetic cannabinoids hexahydrocannabinol, hexahydrocannabiphorol and their acetates using hepatocytes and urine samples. Drug Test. Anal. Early view. (2024).","DOI":"10.1002\/dta.3740"},{"key":"93931_CR17","doi-asserted-by":"crossref","first-page":"249","DOI":"10.3390\/ph17020249","volume":"17","author":"A Di Trana","year":"2024","unstructured":"Di Trana, A. et al. Disposition of hexahydrocannabinol epimers and their metabolites in biological matrices following a single administration of smoked hexahydrocannabinol: A preliminary study. Pharmaceuticals 17, 249 (2024).","journal-title":"Pharmaceuticals"},{"key":"93931_CR18","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/jat\/bkae030","volume":"48","author":"R Kronstrand","year":"2024","unstructured":"Kronstrand, R., Roman, M., Green, H. & Truver, M. T. Quantitation of hexahydrocannabinol (HHC) and metabolites in blood from DUID-cases. J. Anal. Toxicol. 48, 235\u2013241 (2024).","journal-title":"J. Anal. Toxicol."},{"key":"93931_CR19","first-page":"185","volume":"76","author":"FT Peters","year":"2009","unstructured":"Peters, F. T. et al. Anhang B Zur Richtlinie der GTFCh Zur qualit\u00e4tssicherung Bei forensisch-toxikologischen Untersuchungen\u2014Anforderungen an die validierung von analysenmethoden. Toxichem. Krimtech.  76, 185\u2013208 (2009).","journal-title":"Toxichem Krimtech"},{"key":"93931_CR20","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1002\/jat.3440","volume":"37","author":"MN Newmeyer","year":"2017","unstructured":"Newmeyer, M. N. et al. Evaluation of divided attention psychophysical task performance and effects on pupil sizes following smoked, vaporized and oral cannabis administration. J. Appl. Tox.  37, 922\u2013932 (2017).","journal-title":"J. Appl. Tox"},{"key":"93931_CR21","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1093\/jat\/29.5.390","volume":"29","author":"MZ Karlov\u0161ek","year":"2005","unstructured":"Karlov\u0161ek, M. Z. & Bala\u017eic, J. Evaluation of the post-rotational nystagmus test (PRN) in determining alcohol intoxication. J. Anal. Toxicol. 29, 390\u2013393 (2005).","journal-title":"J. Anal. Toxicol."},{"key":"93931_CR22","unstructured":"The National Highway Traffic Safety Administration (NHTSA). Standardized field sobriety testing procedures (PDF). New Jersey (US) police reference card. (2024)."},{"key":"93931_CR23","unstructured":"Shouse California Law Group. The finger-to-nose test in DUI investigations. (accessed  29 January 2025); https:\/\/www.shouselaw.com\/ca\/dui\/fst\/finger-to-nose-test"},{"key":"93931_CR24","doi-asserted-by":"crossref","unstructured":"Kobidze, G. et al. The first LC-MS\/MS stereoselective bioanalytical methods to quantitatively detect 9R- and 9S-hexahydrocannabinols and their metabolites in human blood, oral fluid and urine. J. Pharm. Biomed. Anal. 240, (2024).","DOI":"10.1016\/j.jpba.2023.115918"},{"key":"93931_CR25","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1007\/s00213-002-1033-2","volume":"161","author":"S Wachtel","year":"2002","unstructured":"Wachtel, S., ElSohly, M., Ross, S., Ambre, J. & de Wit, H. Comparison of the subjective effects of \u22069-tetrahydrocannabinol and marijuana in humans. Psychopharmacology 161, 331\u2013339 (2002).","journal-title":"Psychopharmacology"},{"key":"93931_CR26","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1373\/clinchem.2010.152439","volume":"57","author":"EL Karschner","year":"2011","unstructured":"Karschner, E. L., Darwin, W. D., Goodwin, R. S., Wright, S. & Huestis, M. A. Plasma cannabinoid pharmacokinetics following controlled oral \u22069-tetrahydrocannabinol and oromucosal cannabis extract administration. Clin. Chem. 57, 66\u201375 (2011).","journal-title":"Clin. Chem."},{"key":"93931_CR27","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1093\/jat\/16.5.276","volume":"16","author":"MA Huestis","year":"1992","unstructured":"Huestis, M. A., Henningfield, J. E. & Cone, E. J. Blood cannabinoids. I. Absorption of THC and formation of 11-OH-THC and THCCOOH during and after smoking marijuana. J. Anal. Toxicol. 16, 276\u2013282 (1992).","journal-title":"J. Anal. Toxicol."},{"key":"93931_CR28","doi-asserted-by":"crossref","first-page":"3440","DOI":"10.3390\/molecules29143440","volume":"29","author":"A Di Trana","year":"2024","unstructured":"Di Trana, A. et al. QuEChERS extraction and simultaneous quantification in GC-MS\/MS of hexahydrocannabinol epimers and their metabolites in whole blood, urine, and oral fluid. Molecules 29, 3440 (2024).","journal-title":"Molecules"},{"key":"93931_CR29","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1038\/clpt.1984.168","volume":"36","author":"CW Chiang","year":"1984","unstructured":"Chiang, C. W. & Barnett, G. Marijuana effect and delta-9-tetrahydrocannabinol plasma level. Clin. Pharmacol. Ther. 36, 234\u2013238 (1984).","journal-title":"Clin. Pharmacol. Ther."},{"key":"93931_CR30","doi-asserted-by":"crossref","first-page":"171S","DOI":"10.1002\/j.1552-4604.1981.tb02593.x","volume":"21","author":"LE Hollister","year":"1981","unstructured":"Hollister, L. E. et al. Do plasma concentrations of \u22069-tetrahydrocannabinol reflect the degree of intoxication? J. Clin. Pharmacol. 21, 171S\u2013177S (1981).","journal-title":"J. Clin. Pharmacol."},{"key":"93931_CR31","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.forsciint.2016.09.007","volume":"268","author":"P Bondallaz","year":"2016","unstructured":"Bondallaz, P. et al. Cannabis and its effects on driving skills. Forensic. Sci. Int. 268, 92\u2013102 (2016).","journal-title":"Forensic Sci. Int."},{"key":"93931_CR32","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1002\/dta.3595","volume":"16","author":"AS Derne","year":"2024","unstructured":"Derne, A. S. et al. Immunological detection of hexahydrocannabinol (HHC) in oral fluid. Drug Test. Anal. 16, 638\u2013640 (2024).","journal-title":"Drug Test. Anal."},{"key":"93931_CR33","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1093\/jat\/bkad059","volume":"47","author":"CE Wolf","year":"2023","unstructured":"Wolf, C. E., Pokhai, A. A., Poklis, J. L. & Williams, G. R. The cross-reactivity of cannabinoid analogs (delta-8-THC, delta-10-THC and CBD), their metabolites and chiral carboxy HHC metabolites in urine of six commercially available homogeneous immunoassays. J. Anal. Toxicol. 47, 732\u2013736 (2023).","journal-title":"J. Anal. Toxicol."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-93931-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-93931-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-93931-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T13:56:56Z","timestamp":1742824616000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-93931-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,24]]},"references-count":33,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["93931"],"URL":"https:\/\/doi.org\/10.1038\/s41598-025-93931-4","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,24]]},"assertion":[{"value":"9 December 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 March 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 March 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"10086"}}