Hexahydrocannabinol

From LIMSWiki
Jump to navigationJump to search

Hexahydrocannabinol
Legal status
Legal status
Identifiers
  • (6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-1-ol
CAS Number
  • 6692-85-9 (unspecified stereochemistry)
    946512-74-9 (6aR,10aR)
PubChem CID
ChemSpider
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC21H32O2
Molar mass316.485 g·mol−1
3D model (JSmol)
  • CCCCCC1=CC(=C2[C@@H]3CC(CC[C@H]3C(OC2=C1)(C)C)C)O
  • InChI=1S/C21H32O2/c1-5-6-7-8-15-12-18(22)20-16-11-14(2)9-10-17(16)21(3,4)23-19(20)13-15/h12-14,16-17,22H,5-11H2,1-4H3/t14?,16-,17-/m1/s1
  • Key:XKRHRBJLCLXSGE-VNCLPFQGSA-N

Hexahydrocannabinol (HHC) is a hydrogenated derivative of tetrahydrocannabinol (THC). It is a naturally occurring phytocannabinoid that has rarely been identified as a trace component in Cannabis sativa,[1][2] but can also be produced synthetically by firstly acid cyclization of cannabidiol and then hydrogenation of tetrahydrocannabinol. The synthesis and bioactivity of HHC was first reported in 1940 by Roger Adams.[3]

HHC is a psychoactive substance with effects reportedly similar to that of THC. HHC vaporizers have been openly sold at head shops and convenience stores since at least the early 2020s in North America and Europe.[4][5]

Pharmacology

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.[6][7]

Chemistry

Several research groups have successfully synthesized (+)-HHC and (-)-HHC using citronellal and olivetol,[8] as well as other related compounds.[9] While similar compounds have previously been identified in cannabis,[10] 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 hydrogenation of THC. 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.[11][12]

Several structurally related HHC analogs have been found to be naturally occurring in Cannabis including cannabiripsol,[13] 9α-hydroxyhexahydrocannabinol, 7-oxo-9α-hydroxyhexa-hydrocannabinol, 10α-hydroxyhexahydrocannabinol, 10aR-hydroxyhexahydrocannabinol and 1′S-hydroxycannabinol,[10] 10α-hydroxy-Δ(9,11)-hexahydrocannabinol and 9β,10β-epoxyhexahydrocannabinol.[14]

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.[15][16]

Delta-9-THC was discovered to partly metabolize into 11-Hydroxy-THC and alpha,10 alpha-epoxy-hexahydrocannabinol along with 1,2-epoxy-hexahydrocannabinol.[17] 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.[18]

Hexahydrocannabinol should not be confused with the related compounds 9-Nor-9β-hydroxyhexahydrocannabinol (9-Nor-9Beta-HHC) or 9-Hydroxyhexahydrocannabinol (9-OH-HHC) or 11-Hydroxyhexahydrocannabinol (11-OH-HHC and 7-OH-HHC), all of which have also sometimes been referred to as "HHC".[citation needed]

Legality

In the United Kingdom, HHC would likely be considered illegal under the Psychoactive Substances Act 2016. Although HHC is covered by the Psychoactive Substances Act 2016 in the UK, it is not explicitly listed in the legislation. As a result, penalties associated with HHC may be less severe compared to other, explicitly mentioned substances like for example THC.

Several European countries have banned the sale of HHC in 2023.[19][verification needed]

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).[20]

In France, the ANSM announced the ban on production, sale and use of HHC and two of its derivatives, HHCO and HHCP, from 13 June 2023.[21][19]

HHC has been banned in Sweden since 11 July 2023, and in Italy since 28 July 2023.[22]

In Luxembourg, Ministry of Health announced on 1 August 2023 that HHC would be regulated in that country by extending its list of psychotropic substances from 2009 to all "synthetic cannabinoid receptor agonists" and "synthetic cannabinomimetics [sic]", with semi-synthetic cannabinoids such as HHC falling within the scope of that regulation.[23]

HHC has been banned in Lithuania since 23 November 2022, and in Slovenia since 15 November 2023.[24]

HHC has been banned in the Czech Republic since 6 March 2024.[25]

In Germany, manufacture and sale of products containing HHC and other synthetically produced cannabinoids, such as THCP and HHCP, became outlawed on 27 June 2024 (possession and consumption of those products remain legal). Previously, the German expert committee for narcotics had suggested that HHC be added to the annex of Novel Psychoactive Substances Act (NpSG) [de] in a meeting on 4 December 2023.[26] This recommendation was enacted by the Bundesrat on 14 June 2024, and was published in the Bundesgesetzblatt on 26 June.

In Russia, Deputy of the Moscow City Duma Darya Besedina sent a request on 1 March 2024 to the Russian Ministry of Internal Affairs to clarify the legal status of HHC, HHCP and THCP in Russia. According to the answer from the Ministry that Besedina published, HHC and HHCP are not prohibited in Russia, but THCP is banned.[27]

In Malta, Parliamentary Secretary of Reforms and Equality Rebecca Buttigieg announced on 27 September 2024 that "all HHC products will be banned from Maltese markets."[28]

HHC has been banned in Poland as of 14 April 2023.

See also

References

  1. ^ Hanuš LO, Meyer SM, Muñoz E, Taglialatela-Scafati O, Appendino G (November 2016). "Phytocannabinoids: a unified critical inventory". Natural Product Reports. 33 (12): 1357–1392. doi:10.1039/c6np00074f. PMID 27722705. S2CID 34267092.
  2. ^ 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. PMID 32053835. S2CID 211113472.
  3. ^ 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.
  4. ^ European Monitoring Centre for Drugs and Drug Addiction. (2023). Technical Report: Hexahydrocannabinol (HHC) and related substances. European Monitoring Centre for Drugs and Drug Addiction. doi:10.2810/852912. ISBN 978-92-9497-855-4.
  5. ^ Ujváry I (2024). "Hexahydrocannabinol and closely related semi-synthetic cannabinoids: A comprehensive review". Drug Testing and Analysis. 16 (2): 127–161. doi:10.1002/dta.3519. PMID 37269160. S2CID 259046522.
  6. ^ Nasrallah DJ, Garg NK (September 2023). "Studies Pertaining to the Emerging Cannabinoid Hexahydrocannabinol (HHC)". ACS Chemical Biology. 18 (9): 2023–2029. doi:10.1021/acschembio.3c00254. PMC 10510108. PMID 37578929.
  7. ^ Ujváry I (February 2024). "Hexahydrocannabinol and closely related semi-synthetic cannabinoids: A comprehensive review". Drug Testing and Analysis. 16 (2): 127–161. doi:10.1002/dta.3519. PMID 37269160.
  8. ^ 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.
  9. ^ 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. PMID 31833372. S2CID 209343301.
  10. ^ a b Ahmed SA, Ross SA, Slade D, Radwan MM, Khan IA, ElSohly MA (September 2015). "Minor oxygenated cannabinoids from high potency Cannabis sativa L". Phytochemistry. 117: 194–199. Bibcode:2015PChem.117..194A. doi:10.1016/j.phytochem.2015.04.007. PMC 4883105. PMID 26093324.
  11. ^ Harvey DJ, Brown NK (May 1991). "In vitro metabolism of the equatorial C11-methyl isomer of hexahydrocannabinol in several mammalian species". Drug Metabolism and Disposition. 19 (3): 714–716. PMID 1680642.
  12. ^ Harvey DJ, Brown NK (November 1991). "Comparative in vitro metabolism of the cannabinoids". Pharmacology, Biochemistry, and Behavior. 40 (3): 533–540. doi:10.1016/0091-3057(91)90359-a. PMID 1806943. S2CID 25827210.
  13. ^ Boeren EG, Elsohly MA, Turner CE (October 1979). "Cannabiripsol: a novel Cannabis constituent". Experientia. 35 (10): 1278–1279. doi:10.1007/BF01963954. PMID 499397. S2CID 19529732.
  14. ^ Radwan MM, ElSohly MA, El-Alfy AT, Ahmed SA, Slade D, Husni AS, et al. (June 2015). "Isolation and Pharmacological Evaluation of Minor Cannabinoids from High-Potency Cannabis sativa". Journal of Natural Products. 78 (6): 1271–1276. doi:10.1021/acs.jnatprod.5b00065. PMC 4880513. PMID 26000707.
  15. ^ Turner CE, Hadley KW, Fetterman PS, Doorenbos NJ, Quimby MW, Waller C (October 1973). "Constituents of Cannabis sativa L. IV. Stability of cannabinoids in stored plant material". Journal of Pharmaceutical Sciences. 62 (10): 1601–1605. doi:10.1002/jps.2600621005. PMID 4752104.
  16. ^ Garrett ER, Gouyette AJ, Roseboom H (January 1978). "Stability of tetrahydrocannabinols II". Journal of Pharmaceutical Sciences. 67 (1): 27–32. doi:10.1002/jps.2600670108. PMID 22740.
  17. ^ Narimatsu S, Watanabe K, Matsunaga T, Yamamoto I, Imaoka S, Funae Y, et al. (January 1992). "Cytochrome P-450 isozymes involved in the oxidative metabolism of delta 9-tetrahydrocannabinol by liver microsomes of adult female rats". Drug Metabolism and Disposition. 20 (1): 79–83. PMID 1347001.
  18. ^ Golombek P, Müller M, Barthlott I, Sproll C, Lachenmeier DW (June 2020). "Conversion of Cannabidiol (CBD) into Psychotropic Cannabinoids Including Tetrahydrocannabinol (THC): A Controversy in the Scientific Literature". Toxics. 8 (2): 41. doi:10.3390/toxics8020041. PMC 7357058. PMID 32503116.
  19. ^ a b "Actualité - L'ANSM classe l'hexahydrocannabinol (HHC) et deux de ses dérivés sur la liste des stupéfiants". ANSM (in French). Retrieved 2023-06-12.
  20. ^ "Office for Tobacco Coordination - News and Product Warnings - AGES - Hexahydrocannabinol (HHC), new regulation in the NPSV". Österreichische Agentur für Gesundheit und Ernährungssicherheit. Retrieved 7 February 2024.
  21. ^ "Cannabis : le HHC sera interdit en France à partir de mardi". Le Monde.fr (in French). 2023-06-12. Retrieved 2023-06-12.
  22. ^ "Gazzetta Ufficiale". www.gazzettaufficiale.it. Retrieved 2023-08-06.
  23. ^ "Hexahydrocannabinol (HHC) to be Regulated in Luxembourg". Chronicle.lu. Retrieved 12 July 2024.
  24. ^ "eUprava - Predlog predpisa". e-uprava.gov.si. Retrieved 2023-12-24.
  25. ^ "Začíná platit zákaz držení a prodeje produktů s HHC, HHC-O a THCP". seznamzpravy.cz/. 6 March 2024. Retrieved 2024-03-06.
  26. ^ "Sachverständigenausschuss für Betäubungsmittel nach § 1 Abs. 2 BtMG und Neue-psychoaktive-Stoffe nach § 7 NpSG". www.bfarm.de (in German). Retrieved 2024-01-15.
  27. ^ Besedina DS (1 May 2024). "Status of chemicals in the Russian Federation" (in Russian).
  28. ^ "Watch: Malta bans HHC products 'to protect children, public health'". Times of Malta. 2024-09-27. Retrieved 2024-10-04.

Notes

This article is a direct transclusion of the Wikipedia article and therefore may not meet the same editing standards as LIMSwiki.

Retrieved from "https://www.limswiki.org/index.php?title=Hexahydrocannabinol&oldid=58373"