HHC has 2 diastereomers that only differ by the orientation of the 9-methyl group, unlike D9-THC and D8-THC which have the double bond position next to the 9-methyl group that prevents this. The 9-methyl group orientation is believed to be important for cannabinoid binding affinity.
Research has found 9R-HHC to have a binding affinity of 15nM ± 0.8nM at CB1 and 13nM ± 0.4nM at CB2, while 9S-HHC has a binding affinity of 176nM ± 3.3nM at CB1 and 105nM ± 26nM at CB2.
The same study found Delta-9-THC to have a binding affinity of 15nM ± 4.4nM at CB1 and 9.1nM ± 3.6nM at CB2. 9R-HHC has a lower selectivity for CB2 (1.2x) compared to D9-THC (1.6x).
9R-HHC has an EC50 of 3.4nM ± 1.5nM at CB1 and 6.2nM ± 2.1nM at CB2 while 9S-HHC has an EC50 of 57nM ± 19nM at CB1 and 55nM ± 10nM at CB2. The same study found D9-THC to have an EC50 of 3.9nM ± 0.5nM at CB1 and 2.5nM ± 0.7nM at CB2.
The EC50 shows 9R-HHC has a lower selectivity for CB2 (0.55x) compared to THC (1.5x). HHC has been typically described as weaker than Delta-9-THC in psychoactive effects. HHC produces
11-Hydroxyhexahydrocannabinol and
8-Hydroxyhexahydrocannabinol among others as a metabolite which may contribute to its overall effect.[7][8]
Chemistry
Several research groups have successfully synthesized (+)-HHC and (-)-HHC using
citronellal and
olivetol,[9] as well as other related compounds.[10] 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.[11] While similar compounds have previously been identified in cannabis,[12] 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.[13][14]
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,[12] 10α-hydroxy-Δ(9,11)-hexahydrocannabinol and 9β,10β-epoxyhexahydrocannabinol.[16]
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.[17][18]
Delta-9-THC was discovered to partly metabolize into
11-Hydroxy-THC and alpha,10 alpha-epoxy-hexahydrocannabinol along with 1,2-epoxy-hexahydrocannabinol.[19]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.[20]
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).[23]
HHC has been banned in Sweden since July 11, 2023, and in Italy since July 28, 2023.[24]
HHC has been banned in Lithuania since November 23, 2022.
HHC has been banned in Slovenia since November 15, 2023.[25]
On March 1, 2024, Deputy of the Moscow City Duma
Darya Besedina sent a request to the Ministry of Internal Affairs of the Russian Federation about the legal status of HHC, HHC-P and THC-P in Russia. According to the answer Besedina published, HHC and HHC-P are not prohibited in Russia, but THC-P is prohibited.[26]
HHC has been banned in Czechia since March 6, 2024.[27]
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.[28] This recommendation has to date not been enacted by the
German government, although this is likely to occur in the first half 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.
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10.1055/a-1110-1045.
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S2CID211113472.
^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.
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^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.
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10.1021/acs.joc.9b02962.
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