{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T06:15:04Z","timestamp":1786947304126,"version":"build-2736575974"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2024,6,5]],"date-time":"2024-06-05T00:00:00Z","timestamp":1717545600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Canopy Growth Corporation"},{"name":"Canopy Growth Corporation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,8,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>In recent years, potential therapeutic applications of several different cannabinoids, such as \u03949-tetrahydrocannabinol (\u03949-THC), its isomer \u03948-THC and \u03949-tetrahydrocannabivarin (\u03949-THCV), have been investigated. Nevertheless, to establish dose\u2013effect relationship and to gain knowledge of their pharmacokinetics and metabolism, sensitive and specific analytical assays are needed to measure these compounds in patients. For this reason, we developed and validated an online extraction high-performance liquid\/liquid chromatography\u2013tandem mass spectrometry (LC\/LC\u2013MS-MS) method for the simultaneous quantification of 13 cannabinoids and metabolites including the \u03948 and \u03949 isomers of THC, THCV and those of their major metabolites in human plasma. Plasma was fortified with cannabinoids at varying concentrations within the working range of the respective compound and 200\u2009\u00b5L was extracted using a simple one-step protein precipitation procedure. The extracts were analyzed using online trapping LC\/LC\u2013atmospheric pressure chemical ionization\u2013MS-MS running in the positive multiple reaction monitoring mode. The lower limit of quantification ranged from 0.5 to 2.5\u2009ng\/mL, and the upper limit of quantification was 400\u2009ng\/mL for all analytes. Inter-day analytical accuracy and imprecision ranged from 82.9% to 109% and 4.3% to 20.3% (coefficient of variance), respectively. Of 534 plasma samples following controlled oral administration of \u03948-THCV, 236 were positive for \u03948-THCV (median; interquartile ranges: 3.5\u2009ng\/mL; 1.8\u201311.9\u2009ng\/mL), 383 for the major metabolite (\u2212)-11-nor-9-carboxy-\u03948-tetrahydrocannabivarin (\u03948-THCV-COOH) (95.4\u2009ng\/mL; 20.7\u2013328\u2009ng\/mL), 260 for (\u2212)-11-nor-9-carboxy-\u03949-tetrahydrocannabivarin (\u03949-THCV-COOH) (5.8\u2009ng\/mL; 2.5\u201316.1\u2009ng\/mL), 157 for (\u2212)-11-hydroxy-\u03948-tetrahydrocannabivarin (11-OH-\u03948-THCV) (1.7\u2009ng\/mL; 1.0\u20133.7\u2009ng\/mL), 49 for \u03948-THC-COOH (1.7\u2009ng\/mL; 1.4\u20132.3\u2009ng\/mL) and 42 for \u03949-THCV (1.3\u2009ng\/mL; 0.8\u20131.6\u2009ng\/mL). We developed and validated the first LC\/LC\u2013MS-MS assay for the specific quantification of \u03948-THC, \u03949-THC and THCV isomers and their respective metabolites in human plasma. \u03948-THCV-COOH, 11-hydroxy-\u03948-THCV and \u03949-THCV-COOH were the major \u03948-THCV metabolites in human plasma after oral administration of 98.6% pure \u03948-THCV.<\/jats:p>","DOI":"10.1093\/jat\/bkae048","type":"journal-article","created":{"date-parts":[[2024,6,4]],"date-time":"2024-06-04T06:32:25Z","timestamp":1717482745000},"page":"499-506","source":"Crossref","is-referenced-by-count":9,"title":["LC\u2013MS-MS quantification of \u03948-THC, \u03949-THC, THCV isomers and their main metabolites in human plasma"],"prefix":"10.1093","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8095-612X","authenticated-orcid":false,"given":"Cristina","family":"Sempio","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, University of Colorado, Anschutz Medical Campus , 12705 E Montview Blvd, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Campos-Palomino","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University of Colorado, Anschutz Medical Campus , 12705 E Montview Blvd, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jelena","family":"Klawitter","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University of Colorado, Anschutz Medical Campus , 12705 E Montview Blvd, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Harrison","sequence":"additional","affiliation":[{"name":"Clinical Research, Canopy Growth Corporation , 1 Hershey Drive, Smiths Falls, ON K7A 0A8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica N","family":"Peters","sequence":"additional","affiliation":[{"name":"Clinical Research, Canopy Growth Corporation , 1 Hershey Drive, Smiths Falls, ON K7A 0A8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"MacNair","sequence":"additional","affiliation":[{"name":"Clinical Research, Canopy Growth Corporation , 1 Hershey Drive, Smiths Falls, ON K7A 0A8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehdi","family":"Haghdoost","sequence":"additional","affiliation":[{"name":"Clinical Research, Canopy Growth Corporation , 1 Hershey Drive, Smiths Falls, ON K7A 0A8, Canada"},{"name":"Department of Behavioral Science, University of Kentucky , 109, 1100 Veterans Dr, Lexington, KY 40508, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcel","family":"Bonn-Miller","sequence":"additional","affiliation":[{"name":"Clinical Research, Canopy Growth Corporation , 1 Hershey Drive, Smiths Falls, ON K7A 0A8, Canada"},{"name":"Charlotte\u2019s Web , 700 Tech Ct., Louisville, CO 80027, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanna","family":"Babalonis","sequence":"additional","affiliation":[{"name":"Department of Behavioral Science, University of Kentucky , 109, 1100 Veterans Dr, Lexington, KY 40508, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2137-4645","authenticated-orcid":false,"given":"Marilyn A","family":"Huestis","sequence":"additional","affiliation":[{"name":"Institute for Emerging Health Professions, Thomas Jefferson University , 901 Walnut Street, Philadelphia, PA 19107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uwe","family":"Christians","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University of Colorado, Anschutz Medical Campus , 12705 E Montview Blvd, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6413-4820","authenticated-orcid":false,"given":"Jost","family":"Klawitter","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University of Colorado, Anschutz Medical Campus , 12705 E Montview Blvd, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,6,5]]},"reference":[{"key":"2024082121410373400_R1","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1002\/med.20135","article-title":"Pharmacological and therapeutic secrets of plant and brain (endo)cannabinoids","volume":"29","author":"Hanus","year":"2009","journal-title":"Medicinal Research Review"},{"key":"2024082121410373400_R2","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1002\/dta.1531","article-title":"A review of the cultivation and processing of cannabis (Cannabis sativa L.) for production of prescription medicines in the UK","volume":"6","author":"Potter","year":"2014","journal-title":"Drug Testing and Analysis"},{"key":"2024082121410373400_R3","first-page":"362","article-title":"Delta(8)-THC: legal status, widespread availability, and safety concerns","volume":"6","author":"Babalonis","year":"2021","journal-title":"Cannabis and Cannabinoid Research"},{"key":"2024082121410373400_R4","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1093\/jat\/bkac007","article-title":"An enhanced LC-MS-ms technique for distinguishing delta8- and delta9-tetrahydrocannabinol isomers in blood and urine specimens","volume":"46","author":"Reber","year":"2022","journal-title":"Journal of Analytical Toxicology"},{"key":"2024082121410373400_R5","doi-asserted-by":"crossref","DOI":"10.1016\/j.addbeh.2022.107374","article-title":"Delta-8 THC use in US adults: sociodemographic characteristics and correlates","volume":"133","author":"Livne","year":"2022","journal-title":"Addictive Behaviors"},{"key":"2024082121410373400_R6","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1002\/cpt1973143353","article-title":"Delta-8- and delta-9-tetrahydrocannabinol comparison in man by oral and intravenous administration","volume":"14","author":"Hollister","year":"1973","journal-title":"Clinical Pharmacology & Therapeutics"},{"key":"2024082121410373400_R7","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1159\/000136375","article-title":"Comparative studies in man and in laboratory animals on 8 - and 9-trans-tetrahydrocannabinol","volume":"9","author":"Karniol","year":"1973","journal-title":"Pharmacology"},{"key":"2024082121410373400_R8","article-title":"WHO Expert Committee on Drug Dependence: Forty-First Report","volume-title":"License: CC BY-NC-SA 3.0 IGO","author":"World Health Organization","year":"2019"},{"key":"2024082121410373400_R9","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1089\/can.2021.0124","article-title":"Consumer experiences with delta-8-THC: medical use, pharmaceutical substitution, and comparisons with delta-9-THC","volume":"8","author":"Kruger","year":"2023","journal-title":"Cannabis and Cannabinoid Research"},{"key":"2024082121410373400_R10","doi-asserted-by":"crossref","DOI":"10.1186\/s42238-021-00115-8","article-title":"Delta-8-THC: delta-9-THC\u2019s nicer younger sibling?","volume":"4","author":"Kruger","year":"2022","journal-title":"Journal of Cannabis Research"},{"key":"2024082121410373400_R11","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1037\/pha0000565","article-title":"A crowdsourcing survey study on the subjective effects of delta-8-tetrahydrocannabinol relative to delta-9-tetrahydrocannabinol and cannabidiol","volume":"31","author":"Bergeria","year":"2023","journal-title":"Experimental and Clinical Psychopharmacology"},{"key":"2024082121410373400_R12","doi-asserted-by":"crossref","first-page":"3915","DOI":"10.1111\/bph.15865","article-title":"Review of delta-8-tetrahydrocannabinol (delta(8)-THC): comparative pharmacology with delta(9)-THC","volume":"179","author":"Tagen","year":"2022","journal-title":"British Journal of Pharmacology"},{"key":"2024082121410373400_R13","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1111\/j.1556-4029.2010.01441.x","article-title":"Potency trends of delta9-THC and other cannabinoids in confiscated cannabis preparations from 1993 to 2008","volume":"55","author":"Mehmedic","year":"2010","journal-title":"Journal of Forensic Sciences"},{"key":"2024082121410373400_R14","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1111\/bph.13000","article-title":"The phytocannabinoid, delta(9)-tetrahydrocannabivarin, can act through 5-HT(1)A receptors to produce antipsychotic effects","volume":"172","author":"Cascio","year":"2015","journal-title":"British Journal of Pharmacology"},{"key":"2024082121410373400_R15","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-020-77175-y","article-title":"In vitro and in vivo pharmacological activity of minor cannabinoids isolated from Cannabis sativa","volume":"10","author":"Zagzoog","year":"2020","journal-title":"Scientific Reports"},{"key":"2024082121410373400_R16","doi-asserted-by":"crossref","DOI":"10.1186\/s42238-020-0016-7","article-title":"Delta9-tetrahydrocannabivarin (THCV): a commentary on potential therapeutic benefit for the management of obesity and diabetes","volume":"2","author":"Abioye","year":"2020","journal-title":"Journal of Cannabis Research"},{"key":"2024082121410373400_R17","doi-asserted-by":"crossref","first-page":"2450","DOI":"10.1111\/j.1476-5381.2011.01410.x","article-title":"Delta8-tetrahydrocannabivarin prevents hepatic ischaemia\/reperfusion injury by decreasing oxidative stress and inflammatory responses through cannabinoid CB2 receptors","volume":"165","author":"Batkai","year":"2012","journal-title":"British Journal of Pharmacology"},{"key":"2024082121410373400_R18","doi-asserted-by":"crossref","first-page":"1770","DOI":"10.1002\/cbdv.200790152","article-title":"Human cannabinoid pharmacokinetics","volume":"4","author":"Huestis","year":"2007","journal-title":"Chemistry and Biodiversity"},{"key":"2024082121410373400_R19","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/S0009-3084(02)00144-5","article-title":"Cannabidiol: an overview of some chemical and pharmacological aspects. Part I: chemical aspects","volume":"121","author":"Mechoulam","year":"2002","journal-title":"Chemistry and Physics of Lipids"},{"key":"2024082121410373400_R20","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1093\/jat\/25.6.476","article-title":"Identification and quantitation of 11-nor-delta9-tetrahydrocannabivarin-9-carboxylic acid, a major metabolite of delta9-tetrahydrocannabivarin","volume":"25","author":"ElSohly","year":"2001","journal-title":"Journal of Analytical Toxicology"},{"key":"2024082121410373400_R21","doi-asserted-by":"crossref","first-page":"178S","DOI":"10.1002\/j.1552-4604.1981.tb02594.x","article-title":"The metabolism of delta 9-tetrahydrocannabinol and related cannabinoids in man","volume":"21","author":"Wall","year":"1981","journal-title":"Journal of Clinical Pharmacology"},{"key":"2024082121410373400_R22","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1093\/clinchem\/hvaa113","article-title":"Identifying and quantifying cannabinoids in biological matrices in the medical and legal cannabis era","volume":"66","author":"Karschner","year":"2020","journal-title":"Clinical Chemistry"},{"key":"2024082121410373400_R23","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1002\/dta.1998","article-title":"Simultaneous quantification of major cannabinoids and metabolites in human urine and plasma by HPLC-MS\/MS and enzyme-alkaline hydrolysis","volume":"9","author":"Aizpurua-Olaizola","year":"2017","journal-title":"Drug Testing and Analysis"},{"key":"2024082121410373400_R24","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1515\/cclm-2019-0600","article-title":"Validation of a liquid chromatography tandem mass spectrometry (LC-MS\/MS) method to detect cannabinoids in whole blood and breath","volume":"58","author":"Hubbard","year":"2020","journal-title":"Clinical Chemistry and Laboratory Medicine"},{"key":"2024082121410373400_R25","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1097\/FTD.0000000000000427","article-title":"An atmospheric pressure chemical ionization MS\/MS assay using online extraction for the analysis of 11 cannabinoids and metabolites in human plasma and urine","volume":"39","author":"Klawitter","year":"2017","journal-title":"Therapeutic Drug Monitoring"},{"key":"2024082121410373400_R26","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1097\/FTD.0000000000000583","article-title":"Simultaneous quantification of 13 cannabinoids and metabolites in human plasma by liquid chromatography tandem mass spectrometry in adult epilepsy patients","volume":"41","author":"Roslawski","year":"2019","journal-title":"Therapeutic Drug Monitoring"},{"key":"2024082121410373400_R27","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.chroma.2016.05.024","article-title":"Quantification of cannabinoids and their free and glucuronide metabolites in whole blood by disposable pipette extraction and liquid chromatography-tandem mass spectrometry","volume":"1453","author":"Scheidweiler","year":"2016","journal-title":"Journal of Chromatography A"},{"key":"2024082121410373400_R28","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1093\/jat\/bkab030","article-title":"Simultaneous quantification of 17 cannabinoids by LC-MS-MS in human plasma","volume":"46","author":"Sempio","year":"2022","journal-title":"Journal of Analytical Toxicology"},{"key":"2024082121410373400_R29","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.jchromb.2019.03.002","article-title":"Development and validation of an assay to measure cannabidiol and delta9-tetrahydrocannabinol in human EDTA plasma by UHPLC-MS\/MS","volume":"1112","author":"Ocque","year":"2019","journal-title":"Journal of Chromatography B, Analytical Technologies in the Biomedical and Life Sciences"},{"key":"2024082121410373400_R30","doi-asserted-by":"crossref","DOI":"10.1016\/j.biopha.2022.113899","article-title":"A new UHPLC-MS\/MS method for cannabinoids determination in human plasma: A clinical tool for therapeutic drug monitoring","volume":"156","author":"Manca","year":"2022","journal-title":"Biomedicine & Pharmacotherapy"},{"key":"2024082121410373400_R31","doi-asserted-by":"crossref","first-page":"S71","DOI":"10.1089\/can.2023.0038","article-title":"A two-phase, dose-ranging, placebo-controlled study of the safety and preliminary test of acute effects of oral delta(8)-tetrahydrocannabivarin in healthy participants","volume":"8","author":"Peters","year":"2023","journal-title":"Cannabis and Cannabinoid Research"},{"key":"2024082121410373400_R32","article-title":"M10 Bioanalytical Method Validation and Study Sample Analysis. Guidance for Industry","author":"U.S. Department of Health and Human Services, FDA, Center for Drug Evaluation and Research and Center for Veterinary Medicine","year":"2022"},{"key":"2024082121410373400_R33","article-title":"Cannabis and Cannabis-Derived Compounds: Quality Considerations for Clinical Research\u2014Guidance for Industry","author":"U.S. Department of Health and Human Services, FDA, Center for Drug Evaluation and Research and Center for Veterinary Medicine","year":"2020"},{"key":"2024082121410373400_R34","article-title":"Liquid-Chromatography- Mass Spectrometry Methods. Approved Guideline C62-A","author":"Clinical and Laboratory Standards Institute (CLSI)","year":"2022"},{"key":"2024082121410373400_R35","doi-asserted-by":"crossref","first-page":"3019","DOI":"10.1021\/ac020361s","article-title":"Strategies for the assessment of matrix effect in quantitative bioanalytical methods based on HPLC-MS\/MS","volume":"75","author":"Matuszewski","year":"2003","journal-title":"Analytical Chemistry"},{"key":"2024082121410373400_R36","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1097\/YCO.0000000000000868","article-title":"Effects of cannabis legalization on the use of cannabis and other substances","volume":"36","author":"Assanangkornchai","year":"2023","journal-title":"Current Opinion in Psychiatry"},{"key":"2024082121410373400_R37","article-title":"Cannabis and its secondary metabolites: their use as therapeutic drugs, toxicological aspects, and analytical determination","volume":"6","author":"Goncalves","year":"2019","journal-title":"Medicines (Basel)"},{"key":"2024082121410373400_R38","doi-asserted-by":"crossref","DOI":"10.2196\/36667","article-title":"Using social media data to investigate public perceptions of cannabis as a medicine: narrative review","volume":"25","author":"Khademi","year":"2023","journal-title":"Journal of Medical Internet Research"},{"key":"2024082121410373400_R39","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1016\/j.sapharm.2015.09.002","article-title":"Medical marijuana patient counseling points for health care professionals based on trends in the medical uses, efficacy, and adverse effects of cannabis-based pharmaceutical drugs","volume":"12","author":"Parmar","year":"2016","journal-title":"Research in Social & Administrative Pharmacy"},{"key":"2024082121410373400_R40","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1097\/j.pain.0000000000001464","article-title":"An experimental randomized study on the analgesic effects of pharmaceutical-grade cannabis in chronic pain patients with fibromyalgia","volume":"160","author":"Van de Donk","year":"2019","journal-title":"Pain"},{"key":"2024082121410373400_R41","volume-title":"The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research","author":"National Academies of Sciences, Engineering and Medicine","year":"2017"}],"container-title":["Journal of Analytical Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jat\/advance-article-pdf\/doi\/10.1093\/jat\/bkae048\/58416809\/bkae048.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jat\/article-pdf\/48\/7\/499\/58875959\/bkae048.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jat\/article-pdf\/48\/7\/499\/58875959\/bkae048.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,22]],"date-time":"2024-08-22T01:58:21Z","timestamp":1724291901000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jat\/article\/48\/7\/499\/7688112"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,5]]},"references-count":41,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2024,6,5]]},"published-print":{"date-parts":[[2024,8,21]]}},"URL":"https:\/\/doi.org\/10.1093\/jat\/bkae048","relation":{},"ISSN":["0146-4760","1945-2403"],"issn-type":[{"value":"0146-4760","type":"print"},{"value":"1945-2403","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,9]]},"published":{"date-parts":[[2024,6,5]]}}}