Several research groups have successfully synthesized (+)-HHC and (-)-HHC using citronellal and olivetol,[8] as well as other related compounds.[9] HHC and related hydrogenated cannabinoid epimers were elucidated using various NMR spectroscopic techniques (ie, NOSY, COSY, 1H) and the diastereomers were isolated using LC-MS and SCFC.[10] While similar compounds have previously been identified in cannabis,[11] hexahydrocannabinol itself has rarely been isolated from the plant. The de Las Heras group in 2020 took lipid extract from Cannabis sativa seeds and discovered 43 cannabinoids in the crude extract; one of them being hexahydrocannabinol. It has two diastereomers at the methyl (9) position. HHC is typically made from CBD. There are no double bonds in the cyclohexyl ring like D8/D9 have—they have been removed from the structure and hydrogens have been added to the compound.[12][13] Similar structural analogs of HHC have been demonstrated to bind to the CB1 receptor and produce cannabinoid effects in animals, with the 9β-HHC enantiomer being much more active than 9α-HHC.[14] While HHC has been shown to bind to the CB1 receptor, it binds with weaker affinity than THC, which has typically been an indication that it is not as intoxicating as typical THC.
Several structurally related HHC analogs have been found to be naturally occurring in Cannabis including cannabiripsol,[15] 9α-hydroxyhexahydrocannabinol, 7-oxo-9α-hydroxyhexa-hydrocannabinol, 10α-hydroxyhexahydrocannabinol, 10aR-hydroxyhexahydrocannabinol and 1′S-hydroxycannabinol,[11] 10α-hydroxy-Δ(9,11)-hexahydrocannabinol and 9β,10β-epoxyhexahydrocannabinol.[16][17]
HHC itself has been found as a degradation byproduct of THC in a similar way that Cannabinol and Delta-8-THC can be formed by the Cannabis plant from Delta-9-THC degradation. The degradation of D9-THC that forms HHC is the reduction of the double carbon bonds that would typically make up the delta isomer position on THCs structure.[18][19]
Delta-9-THC was discovered to partly metabolize into 11-Hydroxy-THC and alpha,10 alpha-epoxy-hexahydrocannabinol along with 1,2-epoxy-hexahydrocannabinol.[20]Cannabidiol was discovered to partly metabolize into 9α-hydroxy-HHC and 8-hydroxy-iso-HHC inside the body. In the presence of alcohol, the methoxy or ethoxy analogs such as 9-methoxy-HHC, 10-methoxy-HHC, 9-ethoxy-HHC and 10-ethoxy-HHC can be formed.[21]
In Austria, HHC has been banned since 23 March 2023 due to the amendment of the New Psychoactive Substances Ordinance (known in German as Neue-Psychoaktive-Substanzen-Verordnung or NPSV).[24]
HHC has been banned in Sweden since July 11, 2023, and in Italy since July 28, 2023.[25]
HHC has been banned in Lithuania since November 23, 2022.
HHC has been banned in Slovenia since November 15th, 2023.[26]
The German expert committee for narcotics suggested that HHC be added to the annex of Novel Psychoactive Substances Act (NpSG) [de] in a meeting on December 4, 2023.[27] This recommendation has to date not been enacted by the German government, although this is likely to occur in February of 2024.
^Basas-Jaumandreu J, de Las Heras FX (March 2020). "GC-MS Metabolite Profile and Identification of Unusual Homologous Cannabinoids in High Potency Cannabis sativa". Planta Medica. 86 (5): 338–347. doi:10.1055/a-1110-1045. hdl:2117/188476. PMID32053835. S2CID211113472.
^US 9694040, Scialdone MA, "Hydrogenation of cannabis oil", issued 10 November 2016, assigned to Research Grow Labs.
^Adams R, Pease DC, Clark JH (September 1940). "Structure of Cannabidiol. VI. Isomerization of Cannabidiol to Tetrahydrocannabinol, a Physiologically Active Product. Conversion of Cannabidiol to Cannabinol". Journal of the American Chemical Society. 62 (9): 2402–2405. doi:10.1021/ja01866a040.
^Docampo-Palacios M, Ramirez G, Tesfatsion T, Okhovat A, Pittiglio M, Ray K, Cruces W (3 August 2023). "Saturated Cannabinoids: Update on synthesis strategies and biological studies of these emerging cannabinoid analogs". ChemRxiv. doi:10.26434/chemrxiv-2023-3hk1c.
^Ujváry I (2023). "Hexahydrocannabinol and closely related semi-synthetic cannabinoids: A comprehensive review". Drug Testing and Analysis. doi:10.1002/dta.3519. PMID37269160. S2CID259046522.
^Lee YR, Xia L (2008). "Efficient one-pot synthetic approaches for cannabinoid analogues and their application to biologically interesting (-)-hexahydrocannabinol and (+)-hexahydrocannabinol". Tetrahedron Letters. 49: 3283. doi:10.1016/j.tetlet.2008.03.075.
^Maurya V, Appayee C (January 2020). "Enantioselective Total Synthesis of Potent 9β-11-Hydroxyhexahydrocannabinol". The Journal of Organic Chemistry. 85 (2): 1291–1297. doi:10.1021/acs.joc.9b02962. PMID31833372. S2CID209343301.
^Reggio PH, Greer KV, Cox SM (July 1989). "The importance of the orientation of the C9 substituent to cannabinoid activity". Journal of Medicinal Chemistry. 32 (7): 1630–1635. doi:10.1021/jm00127a038. PMID2738895.
^Boeren EG, Elsohly MA, Turner CE (October 1979). "Cannabiripsol: a novel Cannabis constituent". Experientia. 35 (10): 1278–1279. doi:10.1007/BF01963954. PMID499397. S2CID19529732.
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