Hexahydrocannabinol

Hexahydrocannabinol
Identifiers
IUPAC name
  • (6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-1-ol
CAS Number
PubChem CID
ChemSpider
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC21H32O2
Molar mass316.485 g·mol−1
3D model (JSmol)
SMILES
  • CCCCCC1=CC(=C2[C@@H]3CC(CC[C@H]3C(OC2=C1)(C)C)C)O
InChI
  • 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. 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 hydrogenation of cannabis extracts.[3] HHC was first synthesized in 1947 by Roger Adams using natural THC found in Cannabis sativa.[4] Several research groups have successfully synthesized (+)-HHC and (-)-HHC using citronellal and olivetol,[5] as well as other related compounds.[6] While similar compounds have previously been identified in cannabis,[7] 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, Δ8-THC, or Δ9-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.[8][9]Similar structural analogs of HHC has been demonstrated to bind to the CB1 receptor and produces cannabinoid effects in animals, with the 9β-HHC enantiomer being much more active than 9α-HHC.[10] 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 a typical THC. Since HHC is found naturally in the cannabis plant, humans have likely been unknowingly consuming small amounts of this cannabinoid for centuries.

Several structurally related HHC analogs have been found to be naturally occurring in Cannabis including Cannabiripsol,[11] 9α-hydroxyhexahydrocannabinol, 7-oxo-9α-hydroxyhexa-hydrocannabinol, 10α-hydroxyhexahydrocannabinol, 10aR-hydroxyhexahydrocannabinol and 1′S-hydroxycannabinol,[7] 10α-hydroxy-Δ(9,11)-hexahydrocannabinol and 9β,10β-epoxyhexahydrocannabinol.[12]

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.[13][14]

Delta-9-THC was discovered to partly metabolize into 11-Hydroxy-THC and alpha,10 alpha-epoxy-hexahydrocannabinol along with 1,2-epoxy-hexahydrocannabinol.[15] 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.[16]

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".

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. ↑ US 9694040, Scialdone MA, "Hydrogenation of cannabis oil", issued 10 November 2016, assigned to Research Grow Labs.
  4. ↑ US 2419937, Adams R, "Marihuana active compounds", issued 6 May 1947.
  5. ↑ 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.
  6. ↑ 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.
  7. 1 2 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. doi:10.1016/j.phytochem.2015.04.007. PMC 4883105. PMID 26093324.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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. PMID 2738895.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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.
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