Examine individual changes

'{{Short description|Hydrogenated derivative of THC}} {{Infobox drug | IUPAC_name = (6a''R'',10a''R'')-6,6,9-trimethyl-3-pentyl-6a,7,8,9,10,10a-hexahydrobenzo[''c'']chromen-1-ol | image = Hexahydrocannabinol.svg | width = 220 | image2 = HHC 3D BS.png | width2 = 220 | licence_US = | legal_UK = PSA | legal_US = Unscheduled In general Uncontrolled | CAS_number = 6692-85-9 | CAS_supplemental = (racemic)<BR>946512-74-9 (6aR,10aR) | PubChem = 16050328 | ChemSpiderID = 13178711 | C = 21 | H = 32 | O = 2 | smiles = CCCCCC1=CC(=C2[C@@H]3CC(CC[C@H]3C(OC2=C1)(C)C)C)O | StdInChI = 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 | StdInChIKey = XKRHRBJLCLXSGE-VNCLPFQGSA-N }} '''Hexahydrocannabinol''' ('''HHC''') is a [[hydrogenation|hydrogenated]] derivative of [[tetrahydrocannabinol]] (THC). It is a naturally occurring [[phytocannabinoid]] that has rarely been identified as a trace component in ''[[Cannabis sativa]]'',<ref name="Hanuš_2016">{{cite journal | vauthors = Hanuš LO, Meyer SM, Muñoz E, Taglialatela-Scafati O, Appendino G | title = Phytocannabinoids: a unified critical inventory | journal = Natural Product Reports | volume = 33 | issue = 12 | pages = 1357–1392 | date = November 2016 | pmid = 27722705 | doi = 10.1039/c6np00074f | s2cid = 34267092 | doi-access = free}}</ref><ref name="Basas-Jaumandreu_2020">{{cite journal | vauthors = Basas-Jaumandreu J, de Las Heras FX | title = GC-MS Metabolite Profile and Identification of Unusual Homologous Cannabinoids in High Potency Cannabis sativa | journal = Planta Medica | volume = 86 | issue = 5 | pages = 338–347 | date = March 2020 | pmid = 32053835 | doi = 10.1055/a-1110-1045 | hdl-access = free | s2cid = 211113472 | hdl = 2117/188476}}</ref> but can also be produced synthetically by [[hydrogenation]] of [[cannabis extract]]s.<ref>{{cite patent | country = US | number = 9694040 | inventor = Scialdone MA | title = Hydrogenation of cannabis oil | assign1 = Research Grow Labs | gdate = 10 November 2016 | postscript = . }}</ref> The synthesis and bioactivity of HHC was first reported in 1940 by [[Roger Adams]] using tetrahydrocannabinol prepared from [[cannabidiol]].<ref>{{cite journal | vauthors = Adams R, Pease DC, Clark JH | title = Structure of Cannabidiol. VI. Isomerization of Cannabidiol to Tetrahydrocannabinol, a Physiologically Active Product. Conversion of Cannabidiol to Cannabinol | journal = Journal of the American Chemical Society | volume = 62 | issue = 9 | pages = 2402–2405 | date = September 1940 | doi = 10.1021/ja01866a040 }}</ref> HHC is a [[psychoactive substance]] with effects reportedly similar to that of THC.<ref>{{cite journal | vauthors = Docampo-Palacios M, Ramirez G, Tesfatsion T, Okhovat A, Pittiglio M, Ray K, Cruces W |title=Saturated Cannabinoids: Update on synthesis strategies and biological studies of these emerging cannabinoid analogs. | journal = ChemRxiv |date=3 August 2023 |doi=10.26434/chemrxiv-2023-3hk1c}}</ref> HHC vaporizers have been openly sold at [[head shop]]s and [[convenience store]]s since at least the early 2020s in North America and Europe. <ref>{{cite book | title = Technical Report: Hexahydrocannabinol (HHC) and related substances |date= 2023 | publisher = European Monitoring Centre for Drugs and Drug Addiction| doi = 10.2810/852912 | url = https://www.emcdda.europa.eu/publications/technical-reports/hhc-and-related-substances_en |author1= European Monitoring Centre for Drugs and Drug Addiction. }}</ref><ref>{{Cite journal | vauthors = Ujváry I |title=Hexahydrocannabinol and closely related semi-synthetic cannabinoids: A comprehensive review | journal = Drug Testing and Analysis | year=2023 |doi=10.1002/dta.3519 |pmid=37269160 |s2cid=259046522 }}</ref> == Chemistry == Several research groups have successfully synthesized (+)-HHC and (-)-HHC using [[citronellal]] and [[olivetol]],<ref>{{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}}</ref> as well as other related compounds.<ref>{{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 }}</ref> The Elucidation of HHC and related hydrogenated cannabinoid epimers were elucidated using various NMR spectroscopic techniques (ie, NOSY, COSY, ¹H) and the diasteromers were isolated using LC-MS and SCFC.<ref>{{Cite journal | vauthors = Collins A, Ramirez G, Tesfatsion T, Ray KP, Caudill S, Cruces W |date=2023 |title=Synthesis and Characterization of the Diastereomers of HHC and H4CBD |journal=Natural Product Communications |language=en |volume=18 |issue=3 |pages=1934578X2311589 |doi=10.1177/1934578X231158910 |issn=1934-578X|doi-access=free }}</ref> While similar compounds have previously been identified in cannabis,<ref name="Ahmed Ross Slade et al 2015">{{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 }}</ref> 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.<ref>{{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 }}</ref><ref>{{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 }}</ref> Similar structural analogs of HHC have been demonstrated to bind to the [[CB1 receptor|CB₁ receptor]] and produce cannabinoid effects in animals, with the 9β-HHC enantiomer being much more active than 9α-HHC.<ref>{{cite journal | vauthors = Reggio PH, Greer KV, Cox SM | title = The importance of the orientation of the C9 substituent to cannabinoid activity | journal = Journal of Medicinal Chemistry | volume = 32 | issue = 7 | pages = 1630–1635 | date = July 1989 | pmid = 2738895 | doi = 10.1021/jm00127a038 }}</ref> 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 typical THC. Several structurally related HHC analogs have been found to be naturally occurring in Cannabis including [[cannabiripsol]],<ref>{{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 }}</ref> 9α-hydroxyhexahydrocannabinol, 7-oxo-9α-hydroxyhexa-hydrocannabinol, 10α-hydroxyhexahydrocannabinol, 10aR-hydroxyhexahydrocannabinol and 1′S-hydroxycannabinol,<ref name="Ahmed Ross Slade et al 2015"/> 10α-hydroxy-Δ(9,11)-hexahydrocannabinol and 9β,10β-epoxyhexahydrocannabinol.<ref>{{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 | display-authors = 6 | 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 }}</ref><ref>{{cite news |last1=Peter |first1=Alexendra |title=HHC (Hexahydrocannabinol) |url=https://happy-420.de/collections/hhc |access-date=22 June 2023 |publisher=Happy420}}</ref> 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.<ref>{{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 }}</ref><ref>{{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 }}</ref> Delta-9-THC was discovered to partly metabolize into [[11-Hydroxy-THC]] and alpha,10 alpha-epoxy-hexahydrocannabinol along with 1,2-epoxy-hexahydrocannabinol.<ref>{{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 }}</ref> [[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.<ref>{{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 }}</ref> 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}} == Legality == HHC is not controlled by the International Drug Conventions, like the Single Convention on Narcotic Drugs or like the Convention on Psychotropic Substances, therefore and in the meantime, HHC is not regulated and is legal in most countries for recreational use and the drug is sold in some countries through headshops, smartshops and grocery stores, however the sale, shopping, import, transport, export, possession or manufacture of the drug could be persecuted if is sold for human consumption or under the several analogue acts in many countries and too a few countries could ban the drug if they find it like something worrisome or if they find that the drug has a high abuse potential or if they find that the drugs is causing health problems like addiction or overdoses. The [[Agence nationale de sécurité du médicament et des produits de santé|ANSM]] announced the ban (production, sale and use) of HHC and two of its derivatives, [[HHC-acetate]] (HHCO) and [[hexahydrocannabiphorol]] (HHCP), on [[France|French]] territory from June 13, 2023.<ref>{{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}}</ref><ref name=":1">{{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}}</ref> In the [[United Kingdom]], HHC would likely be considered illegal under the [[Psychoactive Substances Act 2016]]. Several European countries ([[Denmark]], [[Belgium]], [[Austria]]) also recently{{when|date=June 2023}} banned the sale of HHC.<ref name=":1" /> [[File:LegalityMap.png|thumb|474x474px]], Legality of HHC by country, blue color are countries where HHC is legal and red color are countries where HHC is forbidden. HHC has been banned in Sweden since July 11, 2023, and in Italy since July 28, 2023.<ref>{{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}}</ref> HHC has been banned in Lithuania since November 23, 2022. HHC has been banned in Slovenia since November 15th, 2023.<ref>{{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}}</ref> HHC is fully legal for recreational use without restrictions in Germany, however the German expert committee for narcotics has, in a meeting on December 4, 2023, suggested to add HHC to the NpSG annex.<ref>{{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}}</ref>, making that the drug can be sold only and just with a license given by the government and limiting its use to medical, industrial, scientific, collecting or research purposes and the will not can be sold for recreatinal use or psychoactive use like a recreational drug or like a psychoactive drug, the issue with all this, is that this drug prohibition conducts that appear new psychoactive substances into de market that could be more dangerous and that people will consume like a legal alternative because other drugs were outlawed, furthermore the prohibition doesn t solution or resolve the drug use, and so thus the drugs were banned the people will continue abusing, misusing and using drugs and prohibitionism doesn t help to reduce the drug use and much less the appearance of new drugs, is bad and wrong that the german state attempts to control, restrict, regulate or ban any type of drug, which should do the governnent is regulate the drugs in the same way that alcohol and tobacco instead of ban or prohibit the drugs, this recommendation has to date not been enacted still by the Federal Government, although this is likely to occur in February of 2024. == See also == * [[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]] == References == {{Reflist}} {{Cannabinoids}} [[Category:Benzochromenes]] [[Category:Cannabinoids]]'