{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T13:26:02Z","timestamp":1785763562179,"version":"3.56.0"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,2,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Recently, tetrahydrocannabinol (THC) isomers and other semi-synthetic cannabinoids have been introduced into the consumer market as alternatives to botanical cannabis. To assess the prevalence of these potential new analytical targets, a liquid chromatography-tandem mass spectrometry confirmation method was developed for the quantitation of seven cannabinoid metabolites and the qualitative identification of four others in urine. The validated method was applied to authentic urine specimens that screened positive by immunoassay (50\u2009ng\/mL cutoff; n\u2009=\u20091300). The most commonly observed analytes were 11-nor-9-carboxy-\u03948-THC (\u03948- THCCOOH) and \u03949-THCCOOH, with the combination of the two being the most prominent analyte combination found. In addition to these metabolites, \u039410-THCCOOH was observed in 77 specimens. This is the first study to report \u039410-THCCOOH in authentic urine specimens, with this analyte always appearing in combination with \u03949-THCCOOH. Cross-reactivity studies were performed for (6aR,9R)-\u039410-THCCOOH using the Beckman Coulter EMIT\u00ae II Plus Cannabinoid immunoassay and demonstrated cross-reactivity equivalent to the \u03949-THCCOOH cutoff, providing added confidence in the reported prevalence and detection patterns. Additionally, 11-nor-9(R)-carboxy-hexahydrocannabinol (9(R)-HHCCOOH) was the most abundant stereoisomer (n\u2009=\u200912) in specimens containing HHC metabolites alone (n\u2009=\u200914). This is in contrast to 9(S)-HHCCOOH, which was the predominant stereoisomer in specimens containing \u03948- and\/or \u03949-THCCOOH. Although HHC and \u039410-THC metabolites are emerging toxicology findings, based on these specimens collected between April 2022 and May 2024, an analytical panel containing \u03948- and \u03949-THCCOOH appears to be sufficient for revealing cannabinoid exposure within workplace monitoring and deterrence programs.<\/jats:p>","DOI":"10.1093\/jat\/bkae091","type":"journal-article","created":{"date-parts":[[2024,11,26]],"date-time":"2024-11-26T02:06:39Z","timestamp":1732586799000},"page":"96-103","source":"Crossref","is-referenced-by-count":8,"title":["LC\u2013MS\u2013MS confirmation of 11-nor-9-carboxy-tetrahydrocannabinol (\u03948, \u03949, \u039410) and hexahydrocannabinol metabolites in authentic urine specimens"],"prefix":"10.1093","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9103-8770","authenticated-orcid":false,"given":"Amy L","family":"Patton","sequence":"first","affiliation":[{"name":"Division of Forensic Toxicology, Armed Forces Medical Examiner System , 115 Purple Heart Drive, Dover AFB, DE 19902,","place":["United States"]},{"name":"SNA International, Contractor Supporting the Armed Forces Medical Examiner System , Alexandria, VA 22314,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luette","family":"Muir","sequence":"additional","affiliation":[{"name":"Division of Forensic Toxicology, Armed Forces Medical Examiner System , 115 Purple Heart Drive, Dover AFB, DE 19902,","place":["United States"]},{"name":"SNA International, Contractor Supporting the Armed Forces Medical Examiner System , Alexandria, VA 22314,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4035-6095","authenticated-orcid":false,"given":"Joshua Z","family":"Seither","sequence":"additional","affiliation":[{"name":"Division of Forensic Toxicology, Armed Forces Medical Examiner System , 115 Purple Heart Drive, Dover AFB, DE 19902,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4228-7276","authenticated-orcid":false,"given":"Jeffrey P","family":"Walterscheid","sequence":"additional","affiliation":[{"name":"Division of Forensic Toxicology, Armed Forces Medical Examiner System , 115 Purple Heart Drive, Dover AFB, DE 19902,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5062-9753","authenticated-orcid":false,"given":"Erin L","family":"Karschner","sequence":"additional","affiliation":[{"name":"Division of Forensic Toxicology, Armed Forces Medical Examiner System , 115 Purple Heart Drive, Dover AFB, DE 19902,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,11,26]]},"reference":[{"key":"2025022411350965900_R1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s42238-022-00168-3","article-title":"Potency and safety analysis of hemp delta-9 products: the hemp vs. cannabis demarcation problem","volume":"5","author":"Johnson","year":"2023","journal-title":"J Cannabis Res"},{"key":"2025022411350965900_R2","article-title":"Budding Hemp Farmers Struggle to Find Success in the \u2018Green Rush\u2019","author":"Hagemann"},{"key":"2025022411350965900_R3","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1089\/can.2022.0126","article-title":"The dark side of cannabidiol: the unanticipated social and clinical implications of synthetic \u0394(8)-THC","volume":"8","author":"Geci","year":"2023","journal-title":"Cannabis Cannabinoid Res"},{"key":"2025022411350965900_R4","article-title":"Improved Methods for Converting Cannabidiol into Delta 8-tetrahydrocannabinol","volume-title":"World Intellectual Property Organization International Bureau","author":"Adair","year":"2020"},{"key":"2025022411350965900_R5","doi-asserted-by":"publisher","first-page":"357","DOI":"10.15288\/jsad.23-00008","article-title":"Delta-8, Delta-10, HHC, THC-O, THCP, and THCV: what should we call these products?","volume":"84","author":"Rossheim","year":"2023","journal-title":"J Stud Alcohol Drugs"},{"key":"2025022411350965900_R6","doi-asserted-by":"publisher","first-page":"1936","DOI":"10.1002\/dta.3159","article-title":"Emergence of the less common cannabinoid \u03948-Tetrahydrocannabinol in a doping sample","volume":"13","author":"Rzeppa","year":"2021","journal-title":"Drug Test Anal"},{"key":"2025022411350965900_R7","article-title":"Hexahydrocannabinol (HHC) and Related Substances","volume-title":"European Monitoring Centre for Drugs and Drug Addiction (EMCDDA)","author":"Ujv\u00e1ry","year":"2023"},{"key":"2025022411350965900_R8","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1002\/dta.3519","article-title":"Hexahydrocannabinol and closely related semi-synthetic cannabinoids: a comprehensive review","volume":"16","author":"Ujv\u00e1ry","year":"2024","journal-title":"Drug Test Anal"},{"key":"2025022411350965900_R9","doi-asserted-by":"publisher","first-page":"4295","DOI":"10.1007\/s00044-014-0972-6","article-title":"Evaluation of phytocannabinoids from high potency cannabis sativa using in vitro bioassays to determine structure-activity relationships for cannabinoid receptor 1 and cannabinoid receptor 2","volume":"23","author":"Husni","year":"2014","journal-title":"Med Chem Res"},{"key":"2025022411350965900_R10","doi-asserted-by":"publisher","first-page":"949","DOI":"10.1021\/jo00318a021","article-title":"Factors influencing double-bond stability in cannabinoids","volume":"46","author":"Dalzell","year":"1981","journal-title":"J Org Chem"},{"key":"2025022411350965900_R11","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1021\/acs.chemrestox.1c00388","article-title":"Novel \u03948-tetrahydrocannabinol vaporizers contain unlabeled adulterants, unintended byproducts of chemical synthesis, and heavy metals","volume":"35","author":"Meehan-Atrash","year":"2022","journal-title":"Chem Res Toxicol"},{"key":"2025022411350965900_R12","doi-asserted-by":"publisher","DOI":"10.3390\/molecules29061249","article-title":"Chemistry and pharmacology of delta-8-tetrahydrocannabinol","volume":"29","author":"Abdel-Kader","year":"2024","journal-title":"Molecules"},{"key":"2025022411350965900_R13","article-title":"Methods for Preparing Cannabinoids by Base-promoted Double-bond Migration","volume-title":"World Intellectual Property Organization International Bureau","author":"Adair","year":"2020"},{"key":"2025022411350965900_R14","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/jat\/bkab029","article-title":"Emergence of delta-8 tetrahydrocannabinol in DUID investigation casework: method development, validation and application","volume":"46","author":"Chan-Hosokawa","year":"2022","journal-title":"J Anal Toxicol"},{"key":"2025022411350965900_R15","article-title":"Making Delta 8 THC, Delta 10 THC, and\/or Cannabinol from CBD","volume-title":"World Intellectual Property Organization International Bureau","author":"Hartman","year":"2020"},{"key":"2025022411350965900_R16","doi-asserted-by":"publisher","first-page":"1357","DOI":"10.1039\/C6NP00074F","article-title":"Phytocannabinoids: a unified critical inventory","volume":"33","author":"Hanu\u0161","year":"2016","journal-title":"Nat Prod Rep"},{"key":"2025022411350965900_R17","doi-asserted-by":"publisher","first-page":"2881","DOI":"10.1039\/p19840002881","article-title":"Base-catalysed double-bond isomerizations of cannabinoids: structural and stereochemical aspects","volume":"1","author":"Srebnik","year":"1984","journal-title":"J Chem Soc Perkin"},{"key":"2025022411350965900_R18","article-title":"Isomers of THC","volume-title":"WHO Expert Committee on Drug Dependence","author":"Cannazza","year":"2018"},{"key":"2025022411350965900_R19","doi-asserted-by":"publisher","first-page":"2424","DOI":"10.2174\/1570159X21666230623104624","article-title":"Hexahydrocannabinol pharmacology, toxicology, and analysis: the first evidence for a recent new psychoactive substance","volume":"21","author":"Graziano","year":"2023","journal-title":"Curr Neuropharmacol"},{"key":"2025022411350965900_R20","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1002\/dta.3570","article-title":"Quantification of (9 R)- and (9 S)-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","volume":"16","author":"H\u00f6fert","year":"2024","journal-title":"Drug Test Anal"},{"key":"2025022411350965900_R21","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/rcm.9711","article-title":"Identification and quantification of both isomers of hexahydrocannabinol, (9R)-hexahydrocannabinol and (9S)-hexahydrocannabinol, in three different matrices by mass spectrometry","volume":"38","author":"Bottinelli","year":"2024","journal-title":"Rapid Commun Mass Spectrom"},{"key":"2025022411350965900_R22","doi-asserted-by":"publisher","first-page":"2023","DOI":"10.1021\/acschembio.3c00254","article-title":"Studies pertaining to the emerging cannabinoid hexahydrocannabinol (HHC)","volume":"18","author":"Nasrallah","year":"2023","journal-title":"ACS Chem Bio"},{"key":"2025022411350965900_R23","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpba.2023.115918","article-title":"The first LC\u2013MS\u2013MS stereoselective bioanalytical methods to quantitatively detect 9R- and 9S-hexahydrocannabinols and their metabolites in human blood, oral fluid and urine","volume":"240","author":"Kobidze","year":"2024","journal-title":"J Pharm Biomed Anal"},{"key":"2025022411350965900_R24","doi-asserted-by":"publisher","DOI":"10.3390\/ph17020249","article-title":"Disposition of hexahydrocannabinol epimers and their metabolites in biological matrices following a single administration of smoked hexahydrocannabinol: a preliminary study","volume":"17","author":"Di Trana","year":"2024","journal-title":"Pharmaceuticals"},{"key":"2025022411350965900_R25","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-38188-5","article-title":"Synthesis and pharmacological activity of the epimers of hexahydrocannabinol (HHC)","volume":"13","author":"Russo","year":"2023","journal-title":"Sci Rep"},{"key":"2025022411350965900_R26","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1177\/14690667231200139","article-title":"Identification of human hexahydrocannabinol metabolites in urine","volume":"29","author":"Schirmer","year":"2023","journal-title":"Eur J Mass Spectrom"},{"key":"2025022411350965900_R27","doi-asserted-by":"publisher","DOI":"10.1002\/dta.3740","article-title":"Human metabolism of the semi-synthetic cannabinoids hexahydrocannabinol, hexahydrocannabiphorol and their acetates using hepatocytes and urine samples","author":"Lindbom","year":"2024","journal-title":"Drug Test Anal"},{"key":"2025022411350965900_R28","doi-asserted-by":"publisher","DOI":"10.3390\/metabo13121169","article-title":"Evidence of 11-hydroxy-hexahydrocannabinol and 11-nor-9-carboxy-hexahydrocannabinol as novel human metabolites of \u0394(9)-tetrahydrocannabinol","volume":"13","author":"J\u00f8rgensen","year":"2023","journal-title":"Metabolites"},{"key":"2025022411350965900_R29","doi-asserted-by":"publisher","first-page":"2493","DOI":"10.1007\/s00216-009-3431-3","article-title":"Plasma and urine profiles of \u03949-tetrahydrocannabinol and its metabolites 11-hydroxy-\u03949-tetrahydrocannabinol and 11-nor-9-carboxy-\u03949-tetrahydrocannabinol after cannabis smoking by male volunteers to estimate recent consumption by athletes","volume":"396","author":"Brenneisen","year":"2010","journal-title":"Anal Bioanal Chem"},{"key":"2025022411350965900_R30","article-title":"ANSI\/ASB Standard 036: Standard Practices for Method Validation in Forensic Toxicology","author":"American Academy of Forensic Sciences Standards Board","year":"2019"},{"key":"2025022411350965900_R31","article-title":"Emit II Plus Cannabinoid Assay","author":"Coulter"},{"key":"2025022411350965900_R32","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1093\/jat\/bkad042","article-title":"\u22068-THC-COOH cross-reactivity with cannabinoid immunoassay kits and interference in chromatographic testing methods","volume":"47","author":"Mullen","year":"2023","journal-title":"J Anal Toxicol"},{"key":"2025022411350965900_R33","doi-asserted-by":"publisher","first-page":"1007","DOI":"10.1373\/clinchem.2009.141754","article-title":"Validation of an enzyme immunoassay for detection and semiquantification of cannabinoids in oral fluid","volume":"56","author":"Schwope","year":"2010","journal-title":"Clin Chem"},{"key":"2025022411350965900_R34","doi-asserted-by":"publisher","first-page":"866","DOI":"10.1093\/jat\/bkac013","article-title":"Prevalence of cannabidiol, \u22069- and \u22068-tetrahydrocannabinol and metabolites in workplace drug testing urine specimens","volume":"46","author":"Vikingsson","year":"2022","journal-title":"J Anal Toxicol"},{"key":"2025022411350965900_R35","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1093\/jat\/bkad068","article-title":"Prevalence of \u22068-tetrahydrocannabinol carboxylic acid in workplace drug testing","volume":"47","author":"Vikingsson","year":"2023","journal-title":"J Anal Toxicol"},{"key":"2025022411350965900_R36","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1080\/00365513.2024.2333023","article-title":"LC-MS\u2013MS analysis of 11-nor-9-carboxy-hexahydrocannabinol (HHC-COOH) and 11-hydroxy-hexahydrocannabinol (HHC-OH) for verification of hexahydrocannabinol (HHC) intake","volume":"84","author":"Pettersson-Pablo","year":"2024","journal-title":"Scand J Clin Lab Invest"}],"container-title":["Journal of Analytical Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jat\/advance-article-pdf\/doi\/10.1093\/jat\/bkae091\/60879332\/bkae091.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jat\/article-pdf\/49\/2\/96\/60879332\/bkae091.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jat\/article-pdf\/49\/2\/96\/60879332\/bkae091.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,24]],"date-time":"2025-02-24T11:35:24Z","timestamp":1740396924000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jat\/article\/49\/2\/96\/7908529"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,26]]},"references-count":36,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2024,11,26]]},"published-print":{"date-parts":[[2025,2,15]]}},"URL":"https:\/\/doi.org\/10.1093\/jat\/bkae091","relation":{},"ISSN":["0146-4760","1945-2403"],"issn-type":[{"value":"0146-4760","type":"print"},{"value":"1945-2403","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,3]]},"published":{"date-parts":[[2024,11,26]]}}}