Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and THC-O-acetate: Difference between pages

{{Short description|Acetate ester of tetrahydrocannabinol (THC)}}

{{cs1 config|name-list-style=vanc|display-authors=6}}

{{Infobox drug

| Verifiedfields = changed

| verifiedrevid = 470476361

| IUPAC_name = (6a''R'',10a''R'')-6,6,9-Trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6''H''-benzo[''c'']chromen-1-yl acetate

| image = THC-O-acetate.svg

| image2 = THC-O-acetate 3D BS.png

<!--Clinical data-->| tradename =

| legal_UK = Class B

| legal_US = Schedule I

<!--Identifiers-->| CAS_number_Ref = {{cascite|changed|??}}

| CAS_number = 23132-17-4

| UNII = VHV54M2AES

| PubChem = 198013

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 171383

<!--Chemical data-->| C = 23

| H = 32

| O = 3

| smiles = O=C(Oc2cc(cc1OC([C@@H]3CC/C(=C\[C@H]3c12)C)(C)C)CCCCC)C

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 1S/C23H32O3/c1-6-7-8-9-17-13-20(25-16(3)24)22-18-12-15(2)10-11-19(18)23(4,5)26-21(22)14-17/h12-14,18-19H,6-11H2,1-5H3/t18-,19-/m1/s1

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = DEWSJDIJFWQLOA-RTBURBONSA-N

}}

'''THC-O-acetate (THC acetate''' '''ester''', '''O-acetyl-THC''', '''THC-O''', '''AcO-THC''') is the [[acetate]] [[ester]] of [[tetrahydrocannabinol|THC]]. The term ''THC-O-acetate'' and its variations are commonly used for two types of the substance, dependent on which cannabinoid it is synthesized from. The difference between Δ⁸-THC and Δ⁹-THC is bond placement on the cyclohexene ring.<ref>{{cite web | vauthors = Sabaghi D |date=February 16, 2023 |title=Delta-8 And -9 THC-O Are Controlled Substances, DEA Says |url=https://www.forbes.com/sites/dariosabaghi/2023/02/16/delta-8-and9-thc-o-are-controlled-substances-dea-says/?sh=7d5c2068754f |website=[[Forbes]]}}</ref>

==Physical data, chemistry, and properties==

[[Image:D8-THC-O-acetate.svg|200px|thumb|left|O-acetyl-Δ⁸-THC [https://pubchem.ncbi.nlm.nih.gov/compound/14589394], CAS# 23050-54-6]]

[[Image:THC-esters_structure.png|200px|thumb|left|Esters of Δ⁹-THC: Top (from left); THC acetate, THC propionate, THC phosphate, THC-NE, Bottom; THC morpholinylbutyrate, THC piperidinylpropionate, THC hemisuccinate, THC hemiglutarate]]

THC acetate ester (THC-O or THCOA) can be synthesized from [[Tetrahydrocannabinol|THC]],<ref name="Cannabis Alchemy">{{cite book| vauthors = Gold D |isbn=978-1-5795-1095-4|title=Cannabis Alchemy: Art of Modern Hashmaking|publisher=Ronin Publishing (2010)|year=1974|url=http://www.kindgreenbuds.com/cannabis-alchemy/thc-acetate/}}</ref><ref name="Marijuana Chemistry">{{cite book| vauthors = Starks M |isbn=978-0-9141-7139-3|title=Marijuana Chemistry: Genetics, Processing, Potency|publisher=Ronin Publishing|year=1990|url=https://books.google.com/books?id=1YeyucgLHnQC&q=marijuana+chemistry}}</ref> or from [[Tetrahydrocannabinolic acid|THCA]].

The acetylation of THC does not change the properties of the compound to the same extent as with other acetate esters, as the parent compound (THC) is already highly [[lipophilic]], but potency is nonetheless increased to some extent. While the acetate ester of Δ⁹-THC is the best studied, the acetate esters of other isomers, especially [[Delta-8-THC|Δ⁸-THC]] but also [[Delta-10-THC|Δ¹⁰-THC]] are also known, as are other esters such as THC-O-propionate, [[THC-O-phosphate]], [[THC hemisuccinate]], THC hemiglutarate, [[THC morpholinylbutyrate]], THC piperidinylpropionate,<ref name="pmid36825573">{{cite journal | vauthors = Banerjee A, Hayward JJ, Trant JF | title = "Breaking bud": the effect of direct chemical modifications of phytocannabinoids on their bioavailability, physiological effects, and therapeutic potential | journal = Organic & Biomolecular Chemistry | volume = 21 | issue = 18 | pages = 3715–3732 | date = May 2023 | pmid = 36825573 | doi = 10.1039/d3ob00068k }}</ref> THC naphthoyl ester (THC-NE),<ref>[https://patents.google.com/patent/US20210251947A1/en Elkarim NS. Stable formulations of dronabinol. Patent US20210251947]</ref> and [[THC-VHS]], as well as the hydrogenated derivative [[HHC-O-acetate]] and the ring-expanded [[abeo-HHC acetate]].

==Pharmacology==

It is a metabolic [[prodrug|pro-drug]], with its subjective effects being felt around 30 minutes after ingestion.<ref name="Cannabis Alchemy"/><ref>{{cite book | vauthors = Starks M |title=Marijuana Potency |url=https://books.google.com/books?id=_tVJAQAAIAAJ |publisher=And/Or Press |access-date=3 April 2023 |pages=174 |date=1977|isbn=978-0-915904-27-3 }}</ref>{{Better source needed|date=May 2024}}

===Psychedelic claims===

In a 2023 study, anecdotal claims surrounding THC-O-acetate's supposed ability to initiate [[psychedelic experience]]s were shown to not be significant. Answers using the Mystical Experience Questionnaire (MEQ) were under the threshold of a true experience, and those who had used classical psychedelics such as [[LSD]] or [[psilocybin]] consistently scored lower on the MEQ. When asked directly, 79% of the participants said it was either "not at all" or "a little" like a psychedelic experience.<ref>{{cite journal | vauthors = Kruger DJ, Bone CC, Meacham MC, Klein C, Kruger JS | title = THC-O-Acetate: Scarce Evidence for a Psychedelic Cannabinoid | journal = Journal of Psychoactive Drugs | pages = 1–5 | date = June 2023 | pmid = 37381980 | doi = 10.1080/02791072.2023.2230573 | s2cid = 259285965 }}</ref>

==History==

THC acetate ester was investigated as a possible non-lethal incapacitating agent as part of the [[Edgewood Arsenal experiments]] at some point between 1949 and 1975. It was noted to have about twice the capacity to produce [[ataxia]] (lack of voluntary coordination of muscle movements) as did [[tetrahydrocannabinol|THC]] when administered to [[dog]]s.<ref name="edgewood">

{{cite book|author=Committee on Toxicology, National Research Council|isbn=978-0-309-07772-9|title=Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants|publisher=The National Academies Press|year=1984|page=79|url=http://books.nap.edu/openbook.php?record_id=9136&page=79}}</ref>

Author D. Gold provided synthesis instructions for this compound (calling it "THC acetate") in his 1974 book ''Cannabis Alchemy: Art of Modern Hashmaking'', in which it is described as follows;<ref name="Cannabis Alchemy" />

{{blockquote|"The effect of the acetate is more spiritual and psychedelic than that of the ordinary product. The most unique property of this material is that there is a delay of about thirty minutes before its effects are felt."}}

The U.S. [[Drug Enforcement Administration|DEA]] first encountered THC-O-acetate as an apparent [[Designer drug|controlled substance analogue]] of THC in 1978. It was made in an analogous manner to how aspirin ([[acetylsalicylic acid]]) is made from willow bark ([[salicylic acid]]).<ref>{{cite web | url = https://www.erowid.org/library/books_online/future_synthetic/future_synthetic.shtml | vauthors = Cooper DA | title = Future Synthetic Drugs of Abuse. | work = Drug Enforcement Administration | location = McLean, Virginia }}</ref> The incident was described by Donald A. Cooper of the DEA thus:

{{blockquote|"Given the world wide ready availability of marijuana, it is somewhat difficult to produce a viable argument for making [controlled substance analogs (CsA's)] of [[cannabinoids]]. However, ten years ago (1978) an attempt to produce CsA's from [[cannabis extract]]s was encountered in the [[Jacksonville, Florida]] area. In this case a concentrated extract of cannabis had been obtained by a [[soxhlet extractor|soxhlet extraction]]. The extract had been [[acetylation|acetylated]] with [[acetic anhydride]], and in the final step, the excess acetic anhydride removed by [[distillation]] (reference is unretrievable due to its appearance in an underground periodical). The product contained neither quantities of nonderivatized cannabinoid nor any identifiable plant fragments. Since this single instance, no acetylated cannabinoid samples have been reported by a DEA laboratory. Therefore, this instance is assumed to represent an isolated occurrence and as such, will serve to terminate our discussion of cannabinoid CsA's."}}

A similar case reported in June 1995 in the [[United Kingdom]], and THC-O-acetate was ruled to be a Class A drug in that case. The description of that case appears to indicate the convicted manufacturer was using D. Gold's book ''Cannabis Alchemy'' as a guide.<ref name="Cannabis: The Genus Cannabis">{{cite book| vauthors = Brown DT |isbn=90-5702-291-5|title=Cannabis: The Genus Cannabis|publisher=Hardwood Academic Publishers|year=2003|page=82|url=https://books.google.com/books?id=EgicqjKEowQC&q=pirnabine&pg=PA80}}</ref>

THC acetate was also reported to have been found by [[New Zealand]] police in 1995, again made by acetylation of purified cannabis extracts with acetic anhydride.<ref name="Science and Justice">{{cite journal | vauthors = Valentine MD | title = Δ9-THC acetate from acetylation of cannabis oil. | journal = Science and Justice | date = 1995 | volume = 36 | issue = 3 | pages = 195–197 | doi = 10.1016/S1355-0306(96)72595-9 }}</ref>

Following legal changes in the United States since around 2018, especially the [[Legalization of non-medical cannabis in the United States|legalisation of cannabis]] in an increasing number of states and the passage of the [[2018 United States farm bill|2018 Farm Bill]]<ref>{{cite press release |author=<!--Not stated--> |title= President Trump Signed the Farm Bill into Law One Year Ago Today, USDA Highlights Implementation Accomplishments to Date |url= https://www.usda.gov/media/press-releases/2019/12/20/president-trump-signed-farm-bill-law-one-year-ago-today-usda |location= Washington D.C. |publisher= USDA Press |agency= USDA |date=2019-12-20 |access-date=2023-06-22}}</ref> which eased restrictions on the cultivation of industrial [[hemp]], THC-O-acetate has become increasingly available as a recreational drug, initially in the United States<ref>{{cite journal | vauthors = Holt AK, Poklis JL, Peace MR | title = ∆8-THC, THC-O Acetates and CBD-di-O Acetate: Emerging Synthetic Cannabinoids Found in Commercially Sold Plant Material and Gummy Edibles | journal = Journal of Analytical Toxicology | volume = 46 | issue = 8 | pages = 940–948 | date = October 2022 | doi = 10.1093/jat/bkac036 | pmid = 35674405 | pmc = 9564187 }}</ref> but subsequently in other countries also.{{Where|date=April 2023}} It may be produced from extracts of psychoactive strains of cannabis in states where this is permitted, in which case the product will be primarily O-acetyl-Δ⁹-THC, but it is also commonly produced from [[Delta-8-THC]] which is synthesised from [[cannabidiol]] extracted from hemp, in which case the product will be primarily O-acetyl-Δ⁸-THC. Since Δ⁹-THC and Δ⁸-THC are quite different in potency, the corresponding acetylated derivatives also will be, which may pose risks to consumers who are unaware of which isomer is in commercial products.

Concerns have also been raised about the lack of safety data or quality control testing given the limited history of human use and potentially toxic chemical reagents used during manufacture. The legal issue of whether purified THC-O-acetate is considered legal in jurisdictions where cannabis is legal is also complex and varies between jurisdictions.<ref>{{cite web | url = https://mjbizdaily.com/scientist-explains-safety-concerns-around-thc-o-acetate/ | vauthors = Drotleff L | title = THC-O-acetate safety concerns: Q&A with scientist James Stephens. | work = MJBizDaily | date = 3 August 2021 }}</ref><ref>{{cite web | url = https://acslabcannabis.com/blog/cannabinoids/thc-o-acetate-everything-you-need-to-know-about-safety-purity-and-effects/ | vauthors = Schmidt E | title = THC-O Acetate: Everything you need to know about safety, purity and effects. | work = ACS Laboratory | date = 5 August 2021 }}</ref><ref>{{cite journal | url = https://cen.acs.org/biological-chemistry/natural-products/Delta-8-THC-craze-concerns/99/i31 | vauthors = Erickson BE | title = Delta-8-THC craze concerns chemists. | journal = Chemical & Engineering News | volume = 99 | issue = 31 | date = 30 August 2021 }}</ref>

==Toxicity==

In 2022, researchers at Portland State University who screened for the presence of reacted ketene as N-benzylacetamide reported that [[α-Tocopheryl acetate|Vitamin E acetate]], [[Cannabidiol|CBD]]-acetate, [[Cannabinol|CBN]]-acetate and '''THC-O-acetate''' may break down to release [[Ketene|ketene gas]] when heated at {{convert|340|C|F}}.

The lowest concentration of inhaled ketene that produces a physiologically negative response is 5 ppm (5 [[parts per million]]).<ref>{{cite book | url=https://www.ncbi.nlm.nih.gov/books/NBK224928/ | title=Ketene | date=21 March 2014 | publisher=National Academies Press (US) }}</ref> For this reason it is advised to exercise caution around THC-O acetate and other [[Acetate#Esters|acetate esters]] of inhaled drugs.

==Legal status==

===United Kingdom===

THC-O-acetate is a Class B drug in the [[United Kingdom]].<ref>{{cite web |url=http://www.legislation.gov.uk/uksi/2008/3130/contents/made |title=The Misuse of Drugs Act 1971 (Amendment) Order 2008 |publisher=Office of Public Sector Information |access-date=15 June 2009 }}</ref>

===United States===

THC-O-acetate is not directly listed under the Controlled Substances Act, but it is designated as a Schedule I controlled substance in the United States.<ref name = "Sabaghi_2023">{{cite web | vauthors = Sabaghi D |title=Delta-8 And -9 THC-O Are Controlled Substances, DEA Says |url=https://www.forbes.com/sites/dariosabaghi/2023/02/16/delta-8-and9-thc-o-are-controlled-substances-dea-says/ |access-date=2023-07-14 |website=Forbes |language=en}}</ref><ref>{{cite web | url = https://cannabusiness.law/wp-content/uploads/DEA-THCO-response-to-Kight.pdf | title = Response Letter: Control status under the Controlled Substances Act (CSA) of THC acetate ester (THCO) | publisher = U. S. Department of Justice, Drug Enforcement Administration | date = 13 February 2023 }}</ref> This designation is based upon a private letter ruling by DEA which communicated that THC-O-Acetate met the statutory definition of ‘''tetrahydrocannabinol''’. DEA reached this conclusion primarily on the basis that THC-O-Acetate is not known to occur in nature. Consequently, THC-O-Acetate cannot be derived from either ''‘Hemp’'' or ''‘Marihuana’'' without chemical conversion:<ref name = "Sabaghi_2023" /><ref>{{cite web | url = https://www.deadiversion.usdoj.gov/schedules/orangebook/c_cs_alpha.pdf | title = Controlled Substances, Alphabetical Order | work = Orange Book | publisher = Diversion Control Division, Drug Enforcement Agency, U.S. Department of Justice }}</ref>

{{Blockquote|text=“Delta-9-THCO and delta-8-THCO do not occur naturally in the cannabis plant and can only be obtained synthetically, and therefore do not fall under the definition of hemp…Thus, Δ9-THC-O and Δ8-THC-O meet the definition of 'tetrahydrocannabinols,' and they [and products containing Δ9-THC-O and Δ8-THC-O] are controlled in schedule I by 21 U.S.C. § 812(c) Schedule I, and 21 CFR § 1308.11(d).”}}

This was thought by some to conflict with the statutory definition of hemp.<ref>{{cite web |title=7 U.S. Code § 1639o - Definitions |url=https://www.law.cornell.edu/uscode/text/7/1639o |access-date=2023-07-14 |website=LII / Legal Information Institute |language=en}}</ref> The statutory definition is the following:

{{Blockquote|text="(1) HEMP.—The term 'hemp' means the plant Cannabis sativa L. and any part of that plant, including the seeds thereof and all derivatives, extracts, cannabinoids, isomers, acids, salts, and salts of isomers, whether growing or not, with a Δ9-THC concentration of not more than 0.3 percent on a dry weight basis."}}

Its sudden status in the early 2020s as both a Schedule I and widely commercially distributed chemical is a heavily debated topic, most notably in the United States.

== See also ==

* [[Acetylation]]

* [[Abeo-HHC acetate]]

* [[Cannabidiol diacetate]]

* [[Cod-THC]]

* [[Nabitan]]

* [[O-1057]]

* [[O-2694]]

* [[HHCP-O-acetate]]

* [[THCP-O-acetate]]

== References ==

{{Reflist}}

{{cannabinoids}}

{{DEFAULTSORT:Thc-O-Acetate}}

[[Category:Cannabinoids]]

[[Category:Acetate esters]]

[[Category:Benzochromenes]]

[[Category:Prodrugs]]

[[Category:Heterocyclic compounds with 3 rings]]