hexahydrocannabinol

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.{{Citation needed|date=April 2025}}

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.{{Citation needed|date=April 2025}}

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).{{Citation needed|date=April 2025}}

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.{{Citation needed|date=April 2025}}

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.{{cite journal | vauthors = Nasrallah DJ, Garg NK | title = Studies Pertaining to the Emerging Cannabinoid Hexahydrocannabinol (HHC) | journal = ACS Chemical Biology | volume = 18 | issue = 9 | pages = 2023–2029 | date = September 2023 | pmid = 37578929 | pmc = 10510108 | doi = 10.1021/acschembio.3c00254 }}{{cite journal | vauthors = Ujváry I | title = Hexahydrocannabinol and closely related semi-synthetic cannabinoids: A comprehensive review | journal = Drug Testing and Analysis | volume = 16 | issue = 2 | pages = 127–161 | date = February 2024 | pmid = 37269160 | doi = 10.1002/dta.3519 }}

Several research groups have successfully synthesized (+)-HHC and (-)-HHC using citronellal and olivetol,{{cite journal | vauthors = Lee YR, Xia L |title=Efficient one-pot synthetic approaches for cannabinoid analogues and their application to biologically interesting (-)-hexahydrocannabinol and (+)-hexahydrocannabinol |journal=Tetrahedron Letters |date=2008 |volume=49 |page=3283 |doi= 10.1016/j.tetlet.2008.03.075}} as well as other related compounds.{{cite journal | vauthors = Maurya V, Appayee C | title = Enantioselective Total Synthesis of Potent 9β-11-Hydroxyhexahydrocannabinol | journal = The Journal of Organic Chemistry | volume = 85 | issue = 2 | pages = 1291–1297 | date = January 2020 | pmid = 31833372 | doi = 10.1021/acs.joc.9b02962 | s2cid = 209343301 }} While similar compounds have previously been identified in cannabis,{{cite journal | vauthors = Ahmed SA, Ross SA, Slade D, Radwan MM, Khan IA, ElSohly MA | title = Minor oxygenated cannabinoids from high potency Cannabis sativa L | journal = Phytochemistry | volume = 117 | pages = 194–199 | date = September 2015 | pmid = 26093324 | pmc = 4883105 | doi = 10.1016/j.phytochem.2015.04.007 | bibcode = 2015PChem.117..194A }} 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.{{cite journal | vauthors = Harvey DJ, Brown NK | title = In vitro metabolism of the equatorial C11-methyl isomer of hexahydrocannabinol in several mammalian species | journal = Drug Metabolism and Disposition | volume = 19 | issue = 3 | pages = 714–716 | date = May 1991 | pmid = 1680642 | url = http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=1680642 }}{{cite journal | vauthors = Harvey DJ, Brown NK | title = Comparative in vitro metabolism of the cannabinoids | journal = Pharmacology, Biochemistry, and Behavior | volume = 40 | issue = 3 | pages = 533–540 | date = November 1991 | pmid = 1806943 | doi = 10.1016/0091-3057(91)90359-a | s2cid = 25827210 }}

Several structurally related HHC analogs have been found to be naturally occurring in Cannabis including cannabiripsol,{{cite journal | vauthors = Boeren EG, Elsohly MA, Turner CE | title = Cannabiripsol: a novel Cannabis constituent | journal = Experientia | volume = 35 | issue = 10 | pages = 1278–1279 | date = October 1979 | pmid = 499397 | doi = 10.1007/BF01963954 | s2cid = 19529732 }} 9α-hydroxyhexahydrocannabinol, 7-oxo-9α-hydroxyhexa-hydrocannabinol, 10α-hydroxyhexahydrocannabinol, 10aR-hydroxyhexahydrocannabinol and 1′S-hydroxycannabinol, 10α-hydroxy-Δ(9,11)-hexahydrocannabinol and 9β,10β-epoxyhexahydrocannabinol.{{cite journal | vauthors = Radwan MM, ElSohly MA, El-Alfy AT, Ahmed SA, Slade D, Husni AS, Manly SP, Wilson L, Seale S, Cutler SJ, Ross SA | title = Isolation and Pharmacological Evaluation of Minor Cannabinoids from High-Potency Cannabis sativa | journal = Journal of Natural Products | volume = 78 | issue = 6 | pages = 1271–1276 | date = June 2015 | pmid = 26000707 | pmc = 4880513 | doi = 10.1021/acs.jnatprod.5b00065 }}

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.{{cite journal | vauthors = Turner CE, Hadley KW, Fetterman PS, Doorenbos NJ, Quimby MW, Waller C | title = Constituents of Cannabis sativa L. IV. Stability of cannabinoids in stored plant material | journal = Journal of Pharmaceutical Sciences | volume = 62 | issue = 10 | pages = 1601–1605 | date = October 1973 | pmid = 4752104 | doi = 10.1002/jps.2600621005 }}{{cite journal | vauthors = Garrett ER, Gouyette AJ, Roseboom H | title = Stability of tetrahydrocannabinols II | journal = Journal of Pharmaceutical Sciences | volume = 67 | issue = 1 | pages = 27–32 | date = January 1978 | pmid = 22740 | doi = 10.1002/jps.2600670108 }}

Delta-9-THC was discovered to partly metabolize into 11-hydroxy-THC and alpha,10 alpha-epoxy-hexahydrocannabinol along with 1,2-epoxy-hexahydrocannabinol.{{cite journal | vauthors = Narimatsu S, Watanabe K, Matsunaga T, Yamamoto I, Imaoka S, Funae Y, Yoshimura H | title = Cytochrome P-450 isozymes involved in the oxidative metabolism of delta 9-tetrahydrocannabinol by liver microsomes of adult female rats | journal = Drug Metabolism and Disposition | volume = 20 | issue = 1 | pages = 79–83 | date = January 1992 | pmid = 1347001 | url = http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=1347001 }} 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.{{cite journal | vauthors = Golombek P, Müller M, Barthlott I, Sproll C, Lachenmeier DW | title = Conversion of Cannabidiol (CBD) into Psychotropic Cannabinoids Including Tetrahydrocannabinol (THC): A Controversy in the Scientific Literature | journal = Toxics | volume = 8 | issue = 2 | pages = 41 | date = June 2020 | pmid = 32503116 | pmc = 7357058 | doi = 10.3390/toxics8020041 | doi-access = free }}

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|date=December 2021}}

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.{{Citation needed|date=April 2025}}

Several European countries have banned the sale of HHC in 2023.{{verify source|reason=Although this is a reliable site (France's Agence nationale de sécurité du médicament et des produits de santé), cited article on it merely mentions that "in Europe, other countries have recently banned the sale of HHC such as Austria, Belgium, Denmark and UK" - whilst confirmation for Austria could be easily obtained, there's nothing that could be found easily to confirm the banning of HHC in Denmark or Belgium (and in Britain legally HHC remains in grey area to this day, so THAT STATEMENT IS NOT ENTIRELY CORRECT).|date=February 2024}}

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).{{cite web |url=https://www.ages.at/en/ages/office-for-tobacco-coordination/news-and-product-warnings#accordion-24442 |title=Office for Tobacco Coordination - News and Product Warnings - AGES - Hexahydrocannabinol (HHC), new regulation in the NPSV |website=Österreichische Agentur für Gesundheit und Ernährungssicherheit |access-date=7 February 2024 }}

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.{{Cite news |date=2023-06-12 |title=Cannabis : le HHC sera interdit en France à partir de mardi |language=fr |work=Le Monde.fr |url=https://www.lemonde.fr/sante/article/2023/06/12/cannabis-le-hhc-sera-interdit-en-france-a-partir-de-mardi_6177293_1651302.html |access-date=2023-06-12}}{{Cite web |title=Actualité - L'ANSM classe l'hexahydrocannabinol (HHC) et deux de ses dérivés sur la liste des stupéfiants |url=https://ansm.sante.fr/actualites/lansm-classe-lhexahydrocannabinol-hhc-et-deux-de-ses-derives-sur-la-liste-des-stupefiants |access-date=2023-06-12 |website=ANSM |language=fr}}

HHC has been banned in Sweden since 11 July 2023, and in Italy since 28 July 2023.{{Cite web |title=Gazzetta Ufficiale |url=https://www.gazzettaufficiale.it/atto/serie_generale/caricaDettaglioAtto/originario?atto.dataPubblicazioneGazzetta=2023-07-25&atto.codiceRedazionale=23A04164&elenco30giorni=true&fbclid=IwAR0d8pv68emAlSwx5PPesHph7DtpXGIfcfaIaSbHuNDnEcBWRZf4ws750Ag |access-date=2023-08-06 |website=www.gazzettaufficiale.it}}

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.{{cite web |title=Hexahydrocannabinol (HHC) to be Regulated in Luxembourg |url=https://chronicle.lu/category/medical/46193-hexahydrocannabinol-hhc-to-be-regulated-in-luxembourg |website=Chronicle.lu |access-date=12 July 2024}}

HHC has been banned in Lithuania since 23 November 2022, and in Slovenia since 15 November 2023.{{Cite web |title=eUprava - Predlog predpisa |url=https://e-uprava.gov.si/si/drzava-in-druzba/e-demokracija/predlogi-predpisov/predlog-predpisa.html?id=15805 |access-date=2023-12-24 |website=e-uprava.gov.si}}

HHC has been banned in the Czech Republic since 6 March 2024.{{Cite web |title=Začíná platit zákaz držení a prodeje produktů s HHC, HHC-O a THCP|url=https://www.seznamzpravy.cz/clanek/domaci-zivot-v-cesku-zacina-platit-zakaz-drzeni-a-prodeje-produktu-s-hhc-hhc-o-a-thcp-247181 |access-date=2024-03-06 |website=seznamzpravy.cz/|date=6 March 2024 }}

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 {{ill|Novel Psychoactive Substances Act (NpSG)|de|Neue-psychoaktive-Stoffe-Gesetz}} in a meeting on 4 December 2023.{{Cite web |title=Sachverständigenausschuss für Betäubungsmittel nach § 1 Abs. 2 BtMG und Neue-psychoaktive-Stoffe nach § 7 NpSG |url=https://www.bfarm.de/DE/Bundesopiumstelle/Betaeubungsmittel/Sachverstaendigenausschuss/Sitzungen/Ergebnisse_59.html?nn=595366 |access-date=2024-01-15 |website=www.bfarm.de |language=de}} 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.{{cite web | vauthors = Besedina DS | date = 1 May 2024 | title = Status of chemicals in the Russian Federation | language = Russian | url = https://besedina.moscow/messaging/728 }}

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."{{Cite web |date=2024-09-27 |title=Watch: Malta bans HHC products 'to protect children, public health' |url=https://timesofmalta.com/article/watch-malta-bans-hhc-products-to-protect-children-public-health.1098676 |access-date=2024-10-04 |website=Times of Malta |language=en-gb}}

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

• 8-Hydroxyhexahydrocannabinol
• 11-Hydroxyhexahydrocannabinol
• 7,8-Dihydrocannabinol
• Cannabinol
• 9-Nor-9β-hydroxyhexahydrocannabinol
• 9-Hydroxyhexahydrocannabinol
• H4-CBD
• Hexahydrocannabihexol
• HU-243
• Canbisol
• Delta-8-THC
• Delta-10-THC
• Delta-11-THC
• Tetrahydrocannabiphorol
• THC-O-acetate
• Delta-6-Cannabidiol

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{{Cannabinoids}}

Category:Benzochromenes

Category:Cannabinoids