Appearance of hexahydrocannabinols as recreational drugs and implications for cannabis drug testing – focus on HHC, HHC-P, HHC-O and HHC-H

References

• EMCDDA. European Drug Report 2023: Trends and Developments. 2023. Available from: https://www.emcdda.europa.eu/publications/european-drug-report/2023_en.
   Google Scholar
• Helander A, Bäckberg M, Beck O. Drug trends and harm related to new psychoactive substances (NPS) in Sweden from 2010 to 2016: experiences from the STRIDA project. PLoS ONE. 2020;15(4):e0232038. doi: 10.1371/journal.pone.0232038.
   PubMed Web of Science ®Google Scholar
• Lea Houston M, Morgan J, Kelso C. Narrative review of the pharmacodynamics, pharmacokinetics, and toxicities of illicit synthetic cannabinoid receptor agonists. Mini Rev Med Chem. 2024;24(1):92–109. doi: 10.2174/1389557523666230515163107.
   PubMed Web of Science ®Google Scholar
• de Oliveira MC, Vides MC, Lassi DLS, et al. Toxicity of synthetic cannabinoids in K2/spice: a systematic review. Brain Sci. 2023;13(7):990. doi: 10.3390/brainsci13070990.
   PubMed Web of Science ®Google Scholar
• Yoganathan P, Claridge H, Chester L, et al. Synthetic cannabinoid-related deaths in England, 2012-2019. Cannabis Cannabinoid Res. 2022;7(4):516–525. doi: 10.1089/can.2020.0161.
   PubMedGoogle Scholar
• Helander A, Johansson M, Andersson A, et al. Analytical and medico-legal problems linked to the presence of Delta-8-tetrahydrocannabinol (Delta-8-THC): results from urine drug testing in Sweden. Drug Test Anal. 2022;14(2):371–376. doi: 10.1002/dta.3190.
   PubMed Web of Science ®Google Scholar
• United Nations. Convention on psychotropic substances; 1971. Available from: https://www.unodc.org/pdf/convention_1971_en.pdf.
   Google Scholar
• Ujváry I. Hexahydrocannabinol and closely related semi-synthetic cannabinoids: a comprehensive review. Drug Test Anal. 2023;16(2):127–161. doi: 10.1002/dta.3519.
   PubMed Web of Science ®Google Scholar
• Adams R, Pease DC, Cain CK, et al. Structure of cannabidiol. VI. Isomerization of cannabidiol to tetrahydrocannabinol, a physiologically active product. Conversion of cannabidiol to cannabinol. J Am Chem Soc. 1940;62(9):2402–2405. doi: 10.1021/ja01866a040.
   Google Scholar
• Docampo-Palacios ML, Ramirez GA, Tesfatsion TT, et al. Saturated cannabinoids: update on synthesis strategies and biological studies of these emerging cannabinoid analogs. Molecules. 2023;28(17):6434. doi: 10.3390/molecules28176434.
   PubMed Web of Science ®Google Scholar
• Graziano S, Varì MR, Pichini S, et al. Hexahydrocannabinol pharmacology, toxicology, and analysis: the first evidence for a recent new psychoactive substance. Curr Neuropharmacol. 2023;21(12):2424–2430. doi: 10.2174/1570159X21666230623104624.
   PubMed Web of Science ®Google Scholar
• Casati S, Rota P, Bergamaschi RF, et al. Hexahydrocannabinol on the light cannabis market: the latest "new" entry. Cannabis Cannabinoid Res. 2022;9(2):622–628. doi: 10.1089/can.2022.0253.
   PubMedGoogle Scholar
• Tanaka R, Kikura-Hanajiri R. Identification of hexahydrocannabinol (HHC), dihydro-iso-tetrahydrocannabinol (dihydro-iso-THC) and hexahydrocannabiphorol (HHCP) in electronic cigarette cartridge products. Forensic Toxicol. 2023;42(1):71–81. doi: 10.1007/s11419-023-00667-9.
   PubMed Web of Science ®Google Scholar
• Har någon erfarenhet av HHC/hexahydrocannabinol. Available from: https://www.flashback.org/p86324323#p86324323.
   Google Scholar
• Basas-Jaumandreu J, de Las Heras FXC. GC-MS metabolite profile and identification of unusual homologous cannabinoids in high potency cannabis sativa. Planta Med. 2020;86(5):338–347. doi: 10.1055/a-1110-1045.
   PubMed Web of Science ®Google Scholar
• Hanuš LO, Meyer SM, Muñoz E, et al. Phytocannabinoids: a unified critical inventory. Nat Prod Rep. 2016;33(12):1357–1392. doi: 10.1039/c6np00074f.
   PubMed Web of Science ®Google Scholar
• Williams PL, Moffat AC, King LJ. Combined high-performance liquid chromatography and radioimmunoassay method for the analysis of Delta 9-tetrahydrocannabinol metabolites in human urine. J Chromatogr. 1979;186:595–603. doi: 10.1016/s0021-9673(00)95280-4.
   PubMed Web of Science ®Google Scholar
• Jones AB, ElSohly HN, ElSohly MA. Analysis of the major metabolite of Delta 9-tetrahydrocannabinol in urine. V. Cross-reactivity of selected compounds in a radioimmunoassay. J Anal Toxicol. 1984;8(6):252–254. doi: 10.1093/jat/8.6.252.
   PubMed Web of Science ®Google Scholar
• Thermo Fisher Scientific. CEDIA Multi Level THC Assay. Available from: https://www.thermofisher.com/document-connect/document-connect.html?url=https%3A//assets.thermofisher.com/TFS-Assets/CDD/Package-Inserts/10006559-CEDIA-Multi-Level-THC-EN.pdf.
   Google Scholar
• Hansson T, Helander A, Beck O, et al. Uniform analyzes of drugs in urine needed for rule of law. Läkartidningen. 2015;112:DLHH.
   PubMedGoogle Scholar
• Stephanson N, Josefsson M, Kronstrand R, et al. Accurate identification and quantification of 11-nor-Delta(9)-tetrahydrocannabinol-9-carboxylic acid in urine drug testing: evaluation of a direct high efficiency liquid chromatographic-mass spectrometric method. J Chromatogr B Analyt Technol Biomed Life Sci. 2008;871(1):101–108. doi: 10.1016/j.jchromb.2008.06.047.
   PubMed Web of Science ®Google Scholar
• Harvey DJ. The mass spectra of the trimethylsilyl derivatives of cis- and trans- hexahydrocannabinol and their hydroxy and acid analogues. Biomed Mass Spectrom. 1981;8(8):366–372. doi: 10.1002/bms.1200080810.
   PubMedGoogle Scholar
• Harvey DJ, Martin BR, Paton WD. Identification of metabolites of delta1- and delta1(6)-tetrahydrocannabinol containing a reduced double bond. J Pharm Pharmacol. 1977;29(8):495–497. doi: 10.1111/j.2042-7158.1977.tb11376.x.
   PubMed Web of Science ®Google Scholar
• Höfert L, Becker S, Dreßler J, et al. Quantification of (9R)- and (9S)-hexahydrocannabinol (HHC) via GC-MS 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. 2023. doi: 10.1002/dta.3570.
   PubMed Web of Science ®Google Scholar
• Derne AS, Pape E, Jouzeau JY, et al. Immunological detection of hexahydrocannabinol (HHC) in oral fluid. Drug Test Anal. 2023. doi: 10.1002/dta.3595.
   PubMed Web of Science ®Google Scholar
• Watanabe K, Matsunaga T, Kimura T, et al. Stereospecific and regioselective hydrolysis of cannabinoid esters by ES46.5K, an esterase from mouse hepatic microsomes, and its differences from carboxylesterases of rabbit and porcine liver. Biol Pharm Bull. 2005;28(9):1743–1747. doi: 10.1248/bpb.28.1743.
   PubMed Web of Science ®Google Scholar
• Huestis MA, Henningfield JE, Cone EJ. Blood cannabinoids. I. Absorption of THC and formation of 11-OH-THC and THCCOOH during and after smoking marijuana. J Anal Toxicol. 1992;16(5):276–282. doi: 10.1093/jat/16.5.276.
   PubMed Web of Science ®Google Scholar
• Harvey DJ, Brown NK. In vitro metabolism of the equatorial C11-methyl isomer of hexahydrocannabinol in several mammalian species. Drug Metab Dispos. 1991;19(3):714–716.
   PubMed Web of Science ®Google Scholar
• Schirmer W, Auwärter V, Kaudewitz J, et al. Identification of human hexahydrocannabinol metabolites in urine. Eur J Mass Spectrom (Chichester). 2023;29(5–6):326–337. doi: 10.1177/14690667231200139.
   PubMed Web of Science ®Google Scholar
• Manier SK, Valdiviezo JA, Vollmer AC, et al. Analytical toxicology of the semi-synthetic cannabinoid hexahydrocannabinol studied in human samples, pooled human liver S9 fraction, rat samples, and drug product using HPLC-HRMS/MS. J Anal Toxicol. 2023;47(9):818–825. doi: 10.1093/jat/bkad079.
   PubMed Web of Science ®Google Scholar
• Russo F, Vandelli MA, Biagini G, et al. Synthesis and pharmacological activity of the epimers of hexahydrocannabinol (HHC). Sci Rep. 2023;13(1):11061. doi: 10.1038/s41598-023-38188-5.
   PubMed Web of Science ®Google Scholar