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 acid cyclization and 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.[4] HHC vaporizers have been openly sold at head shops and convenience stores since at least the early 2020s in North America and Europe.[5][6]

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.[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 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.[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]

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

The ANSM announced the ban (production, sale and use) of HHC and two of its derivatives, HHC-acetate (HHCO) and hexahydrocannabiphorol (HHCP), on French territory from June 13, 2023.[21][22]

In the United Kingdom, HHC would likely be considered illegal under the Psychoactive Substances Act 2016.

Several European countries (Denmark, Belgium) also recently[when?] banned the sale of HHC.[22][verification needed]

Legality of HHC in EU as of November 2023.

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.

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. ^ 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.
  5. ^ 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.
  6. ^ 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.
  7. ^ Nasrallah, Daniel J.; Garg, Neil K. (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.
  8. ^ Ujváry, István (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.
  9. ^ 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.
  10. ^ 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.
  11. ^ Collins A, Ramirez G, Tesfatsion T, Ray KP, Caudill S, Cruces W (2023). "Synthesis and Characterization of the Diastereomers of HHC and H4CBD". Natural Product Communications. 18 (3): 1934578X2311589. doi:10.1177/1934578X231158910. ISSN 1934-578X.
  12. ^ 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.
  13. ^ 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.
  14. ^ 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.
  15. ^ 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.
  16. ^ 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.
  17. ^ 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.
  18. ^ 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.
  19. ^ Narimatsu S, Watanabe K, Matsunaga T, Yamamoto I, Imaoka S, Funae Y, Yoshimura H (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.
  20. ^ 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.
  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. ^ 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.
  23. ^ "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.
  24. ^ "Gazzetta Ufficiale". www.gazzettaufficiale.it. Retrieved 2023-08-06.
  25. ^ "eUprava - Predlog predpisa". e-uprava.gov.si. Retrieved 2023-12-24.
  26. ^ https://besedina.moscow/messaging/728
  27. ^ "Začíná platit zákaz držení a prodeje produktů s HHC, HHC-O a THCP". seznamzpravy.cz/. Retrieved 2024-03-06.
  28. ^ "Sachverständigenausschuss für Betäubungsmittel nach § 1 Abs. 2 BtMG und Neue-psychoaktive-Stoffe nach § 7 NpSG". www.bfarm.de (in German). Retrieved 2024-01-15.

Notes

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