Hexahydrocannabinol

Last updated
Hexahydrocannabinol
Hexahydrocannabinol.svg
HHC 3D BS.png
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
PubChem CID
ChemSpider
CompTox Dashboard (EPA)
Chemical and physical data
Formula C21H32O2
Molar mass 316.485 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 cannabidiol. The synthesis and bioactivity of HHC was first reported in 1940 by Roger Adams. [3]

Contents

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 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]

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. Legality HHC EU (corrected legend) Map.png
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

Related Research Articles

<span class="mw-page-title-main">Tetrahydrocannabinol</span> Chemical compound

Tetrahydrocannabinol (THC) is a terpenoid found in cannabis. It is the principal psychoactive constituent of cannabis and one of at least 113 total cannabinoids identified on the plant. Its chemical formula C21H30O2 includes compounds, the term THC usually refers to the delta-9-THC isomer with chemical name (−)-trans-Δ9-tetrahydrocannabinol. It is a colorless oil.

<span class="mw-page-title-main">Cannabinoid</span> Compounds found in cannabis

Cannabinoids are several structural classes of compounds found in the cannabis plant primarily and most animal organisms or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoactive compound in cannabis. Cannabidiol (CBD) is also a major constituent of temperate cannabis plants and a minor constituent in tropical varieties. At least 113 distinct phytocannabinoids have been isolated from cannabis, although only four have been demonstrated to have a biogenetic origin. It was reported in 2020 that phytocannabinoids can be found in other plants such as rhododendron, licorice and liverwort, and earlier in Echinacea.

<span class="mw-page-title-main">Cannabinol</span> Naturally-occurring cannabinoid

Cannabinol (CBN) is a mildly psychoactive cannabinoid that acts as a low affinity partial agonist at both CB1 and CB2 receptors. This activity at CB1 and CB2 receptors constitutes interaction of CBN with the endocannabinoid system (ECS).

<span class="mw-page-title-main">Tetrahydrocannabivarin</span> Homologue of tetrahydrocannabinol

Tetrahydrocannabivarin is a homologue of tetrahydrocannabinol (THC) having a propyl (3-carbon) side chain instead of pentyl (5-carbon), making it non-psychoactive in lower doses. It has been shown to exhibit neuroprotective activity, appetite suppression, glycemic control and reduced side effects compared to THC, making it a potential treatment for management of obesity and diabetes. THCV was studied by Roger Adams as early as 1942.

<span class="mw-page-title-main">11-Hydroxy-THC</span> Active metabolite of Δ9-THC

11-Hydroxy-Δ9-tetrahydrocannabinol, usually referred to as 11-hydroxy-THC is the main active metabolite of tetrahydrocannabinol (THC), which is formed in the body after Δ9-THC is consumed.

<span class="mw-page-title-main">Tetrahydrocannabutol</span> Chemical compound

Δ9-Tetrahydrocannabutol is a phytocannabinoid found in cannabis that is a homologue of tetrahydrocannabinol (THC), the main active component of Cannabis. Structurally, they are only different by the pentyl side chain being replaced by a butyl side chain. THCB was studied by Roger Adams as early as 1942

<span class="mw-page-title-main">9-Nor-9β-hydroxyhexahydrocannabinol</span> Chemical compound

9-Nor-9β-hydroxyhexahydrocannabinol is a cannabinoid first discovered from early modifications to the structure of THC, in a search for the simplest compound that could still fulfill the binding requirements to produce cannabis-like activity.

<span class="mw-page-title-main">AM-2389</span> Chemical compound

AM-2389 is a classical cannabinoid derivative which acts as a potent and reasonably selective agonist for the CB1 receptor, with a Ki of 0.16 nM, and 26× selectivity over the related CB2 receptor. It has high potency in animal tests of cannabinoid activity, and a medium duration of action. Replacing the 1',1'-dimethyl substitution of the dimethylheptyl side chain of classical cannabinoids with cyclopropyl or cyclopentyl results in higher potency than cyclobutyl, but only the cyclobutyl derivatives show selectivity for CB1 over CB2. High selectivity for CB1 over CB2 is difficult to achieve (cf. AM-906, AM-1235), as almost all commonly used CB1 agonists have similar or greater affinity for CB2 than CB1, and the only truly highly selective CB1 agonists known as of 2012 are eicosanoid derivatives such as O-1812.

<span class="mw-page-title-main">Tetrahydrocannabinolic acid</span> THC precursor

Tetrahydrocannabinolic acid is a precursor of tetrahydrocannabinol (THC), an active component of cannabis.

<span class="mw-page-title-main">8,9-Dihydrocannabidiol</span> Chemical compound

8,9-Dihydrocannabidiol is a synthetic cannabinoid that is closely related to cannabidiol (CBD) itself. that was first synthesized by Alexander R. Todd in 1940 derived from the catalytic hydrogenation of cannabidiol.

<span class="mw-page-title-main">Tetrahydrocannabiphorol</span> Cannabinoid agonist compound

Tetrahydrocannabiphorol (THCP) is a potent phytocannabinoid, a CB1 and CB2 agonist which was known as a synthetic homologue of THC, but for the first time in 2019 was isolated as a natural product in trace amounts from Cannabis sativa. It is structurally similar to Δ9-THC, the main active component of cannabis, but with the pentyl side chain extended to heptyl. Since it has a longer side chain, its cannabinoid effects are "far higher than Δ9-THC itself." Tetrahydrocannabiphorol has a reported binding affinity of 1.2 nM at CB1, approximately 33 times that of Δ9-THC (40 nM at CB1).

<span class="mw-page-title-main">Δ-8-Tetrahydrocannabinol</span> Isomer of tetrahydrocannabinol

Δ-8-tetrahydrocannabinol is a psychoactive cannabinoid found in the Cannabis plant. It is an isomer of delta-9-tetrahydrocannabinol, the compound commonly known as THC, with which it co-occurs in hemp; natural quantities of ∆8-THC found in hemp are low.

<span class="mw-page-title-main">Tetrahydrocannabiorcol</span> Chemical compound

Δ9-Tetrahydrocannabiorcol (Δ9-THCC, (C1)-Δ9-THC) is a phytocannabinoid found in Cannabis pollen. It is a homologue of THC and THCV with the alkyl side chain replaced by a smaller methyl group. Unlike THC and THCV, THCC has negligible affinity for the CB1 and CB2 cannabinoid receptors because of the smaller methyl group and does not have psychoactive effects as a result, but conversely it is significantly more potent than THC or THCV as an activator of the TRPA1 calcium channel which plays an important role in pain perception, and it has been shown to produce analgesic effects via activation of spinal TRPA1 channels. THCC was studied by Roger Adams as early as 1942.

<span class="mw-page-title-main">Δ-10-Tetrahydrocannabinol</span> Isomer of tetrahydrocannabinol

Δ-10-Tetrahydrocannabinol is a positional isomer of tetrahydrocannabinol, discovered in the 1980s. Two enantiomers have been reported in the literature, with the 9-methyl group in either the (R) or (S) conformation; of these, the (R) enantiomer appears to be the more active isomer as well as the double bond in the 10th position instead of the 9th maintaining about 30 to 40 percent the potency of delta-9-THC. Δ10-THC has rarely been reported as a trace component of natural cannabis, though it is thought to be a degradation product similar to cannabinol rather than being produced by the plant directly. However, it is found more commonly as an impurity in synthetic delta-8-THC produced from cannabidiol and can also be synthesized directly from delta-9-THC.

<span class="mw-page-title-main">11-Hydroxy-Delta-8-THC</span> Metabolite of delta-8-THC

11-Hydroxy-Delta-8-tetrahydrocannabinol is an active metabolite of Δ8-THC, a psychoactive cannabinoid found in small amounts in cannabis. It is an isomer of 11-OH-Δ9-THC, and is produced via the same metabolic pathway. It was the first cannabinoid metabolite discovered in 1970.

<span class="mw-page-title-main">9-Hydroxyhexahydrocannabinol</span> Synthetic cannabinoid

9-Hydroxyhexahydrocannabinol (9-OH-HHC) is a semi-synthetic derivative of tetrahydrocannabinol. It is formed as an impurity in the synthesis of Delta-8-THC, and retains activity in animal studies though with only around 1/10 the potency of Δ9-THC, with the 9α- and 9β- enantiomers having around the same potency.

<span class="mw-page-title-main">11-Hydroxyhexahydrocannabinol</span> Chemical compound

11-Hydroxyhexahydrocannabinol is an active metabolite of tetrahydrocannabinol (THC) and a metabolite of the trace cannabinoid hexahydrocannabinol (HHC).

Cannabinoids are compounds found in the cannabis plant or synthetic compounds that can interact with the endocannabinoid system. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (Delta-9-THC), the primary intoxicating compound in cannabis. Cannabidiol (CBD) is another major constituent of some cannabis plants. At least 113 distinct cannabinoids have been isolated from cannabis.

<span class="mw-page-title-main">H4-CBD</span> Chemical compound

H4CBD is a cannabinoid that was first synthesized by Alexander R. Todd in 1940 derived from the catalytic hydrogenation of cannabidiol.

<span class="mw-page-title-main">8-Hydroxyhexahydrocannabinol</span> Cannabinoid metabolite

8-Hydroxyhexahydrocannabinols are active primary metabolites of hexahydrocannabinol (HHC) in animals and trace phytocannabinoids. The 8-OH-HHCs are produced in notable concentrations following HHC administration in several animal species, including humans. They have drawn research interest for their role in HHC toxicology and stereoisomeric probes of the cannabinoid drug/receptor interaction.

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 (2023). "Hexahydrocannabinol and closely related semi-synthetic cannabinoids: A comprehensive review". Drug Testing and Analysis. doi:10.1002/dta.3519. PMID   37269160. S2CID   259046522.
  7. ↑ https://pubs.acs.org/doi/10.1021/acschembio.3c00254
  8. ↑ https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/abs/10.1002/dta.3519
  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.
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  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.
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  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.
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  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. 1 2 "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.
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