Tetrahydrocannabinol#Marinol

{{Further|Dronabinol}}THC, referred to as dronabinol in the pharmaceutical context, is approved in the United States as a capsule or solution to relieve chemotherapy-induced nausea and vomiting and HIV/AIDS-induced anorexia.{{Cite web |date=September 2004 |title=Marinol (Dronabinol) |url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/018651s021lbl.pdf |publisher=U.S. Food and Drug Administration}}

THC is an active ingredient in nabiximols, a specific extract of Cannabis that was approved as a botanical drug in the United Kingdom in 2010 as a mouth spray for people with multiple sclerosis to alleviate neuropathic pain, spasticity, overactive bladder, and other symptoms.{{cite web|title=Sativex Oromucosal Spray – Summary of Product Characteristics|url=http://www.medicines.org.uk/emc/medicine/23262|publisher=UK Electronic Medicines Compendium|language=en|date=March 2015|access-date=2017-06-01|archive-date=2016-08-22|archive-url=https://web.archive.org/web/20160822231728/http://www.medicines.org.uk/emc/medicine/23262|url-status=dead}}Multiple Sclerosis Trust. October 2014 [http://www.mstrust.org.uk/information/publications/factsheets/sativex.jsp Sativex (nabiximols) – factsheet] {{Webarchive|url=https://web.archive.org/web/20150920025939/http://www.mstrust.org.uk/information/publications/factsheets/sativex.jsp |date=2015-09-20 }} Nabiximols (as Sativex) is available as a prescription drug in Canada.{{cite web |title=Health products containing cannabis or for use with cannabis: Guidance for the Cannabis Act, the Food and Drugs Act, and related regulations |url=https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applications-submissions/guidance-documents/guidance-cannabis-act-food-and-drugs-act-related-regulations/document.html |publisher=Government of Canada |access-date=19 October 2018 |date=11 July 2018 |archive-date=19 October 2018 |archive-url=https://web.archive.org/web/20181019121912/https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applications-submissions/guidance-documents/guidance-cannabis-act-food-and-drugs-act-related-regulations/document.html |url-status=live }} In 2021, nabiximols was approved for medical use in Ukraine.{{cite news |url=https://life.pravda.com.ua/health/2021/04/9/244505/ |vauthors= |work=УП.Життя (UP.Life) |date=9 April 2021 |language=Ukrainian |title=В Україні легалізували використання медичного канабісу, але не всього |trans-title=In Ukraine, some medical cannabis has been legalized, but not all |access-date=10 April 2021 |archive-date=9 April 2021 |archive-url=https://web.archive.org/web/20210409202156/https://life.pravda.com.ua/health/2021/04/9/244505/ |url-status=live }}

Side effects of THC include red eyes, dry mouth, drowsiness, short-term memory impairment, difficulty concentrating, ataxia, increased appetite, anxiety, paranoia, psychosis (i.e., hallucinations, delusions), decreased motivation, and time dilation, among others.{{cite book | vauthors = Ng T, Keshock MC | chapter = Tetrahydrocannabinol (THC) |date=2024 | title = StatPearls | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK563174/ |access-date=2024-08-20 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=33085321 }}{{Cite web |title=Short-Term Effects of Cannabis Consumption {{!}} Washington State Liquor and Cannabis Board |url=https://lcb.wa.gov/education2ch/short-term_effects_of_cannabis_consumption |access-date=2024-08-20 |website=lcb.wa.gov}}

Chronic usage of THC may result in cannabinoid hyperemesis syndrome (CHS), a condition characterized by cyclic nausea, vomiting, and abdominal pain that may persist for months to years after discontinuation.

The median lethal dose of THC in humans is not fully known as there is conflicting evidence. A 1972 study gave up to 90 mg/kg of THC to dogs and monkeys without any lethal effects. Some rats died within 72 hours after a dose of up to 36 mg/kg.{{cite journal |vauthors=Thompson GR, Rosenkrantz H, Schaeppi UH, Braude MC |title=Comparison of acute oral toxicity of cannabinoids in rats, dogs and monkeys |journal=Toxicology and Applied Pharmacology |volume=25 |issue=3 |pages=363–72 |date=July 1973 |pmid=4199474 |doi=10.1016/0041-008X(73)90310-4 |bibcode=1973ToxAP..25..363T |quote=In dogs and monkeys, single oral doses of Δ9-THC and Δ8-THC between 3000 and 9000/mg/kg were nonlethal.}} A 2014 case study based on the toxicology reports and relative testimony in two separate cases gave the median lethal dose in humans at 30 mg/kg (2.1 grams THC for a person who weighs 70 kg; 154 lb; 11 stone), observing cardiovascular death in the one otherwise healthy subject of the two cases studied.{{cite journal |vauthors=Hartung B, Kauferstein S, Ritz-Timme S, Daldrup T |title=Sudden unexpected death under acute influence of cannabis |journal=Forensic Science International |volume=237 |pages=e11–e13 |date=April 2014 |pmid=24598271 |doi=10.1016/j.forsciint.2014.02.001 }} A different 1972 study gave the median lethal dose for intravenous THC in mice and rats at 30–40 mg/kg.{{cite journal |vauthors=Nahas GC |title=UNODC - Bulletin on Narcotics - 1972 Issue 2 - 002 |journal=United Nations: Office on Drugs and Crime |date=1 January 1972 |pages=11–27 |url=https://www.unodc.org/unodc/en/data-and-analysis/bulletin/bulletin_1972-01-01_2_page003.html |language=en |access-date=2022-12-11 |archive-date=2022-12-11 |archive-url=https://web.archive.org/web/20221211181839/https://www.unodc.org/unodc/en/data-and-analysis/bulletin/bulletin_1972-01-01_2_page003.html |url-status=live }} A 2020 fact sheet published by the U.S. Drug Enforcement Administration stated that "[n]o deaths from overdose of marijuana have been reported."{{cite web |url=https://www.dea.gov/sites/default/files/2020-06/Marijuana-Cannabis-2020_0.pdf |title=Drug Fact Sheet: Marijuana/Cannabis |work=Drug Enforcement Administration |publisher=United States Department of Justice |date=April 2020 |access-date=9 February 2025 }}

Formal drug–drug interaction studies with THC have not been conducted and are limited. The elimination half-life of the barbiturate pentobarbital has been found to increase by 4{{nbsp}}hours when concomitantly administered with oral THC.

{{See also|Effects of cannabis|Long-term effects of cannabis|Cannabis in pregnancy}}

{{For|a review of the mechanisms behind endocannabinoid synaptic transmission|Endocannabinoid system}}

The actions of Δ⁹-THC result from its partial agonist activity at the cannabinoid receptor CB₁ (K_i = 40.7 nM{{cite journal | vauthors = Bow EW, Rimoldi JM | title = The Structure–Function Relationships of Classical Cannabinoids: CB1/CB2 Modulation | journal = Perspectives in Medicinal Chemistry | volume = 8 | pages = 17–39 | date = 28 June 2016 | pmid = 27398024 | pmc = 4927043 | doi = 10.4137/PMC.S32171 }}), located mainly in the central nervous system, and the CB₂ receptor (K_i = 36 nM), mainly expressed in cells of the immune system.{{cite journal | vauthors = Pertwee RG | title = The pharmacology of cannabinoid receptors and their ligands: an overview | journal = International Journal of Obesity | volume = 30 | issue = Suppl 1 | pages = S13–S18 | date = April 2006 | pmid = 16570099 | doi = 10.1038/sj.ijo.0803272 | doi-access = free }} The psychoactive effects of THC are primarily mediated by the activation of (mostly G-coupled) cannabinoid receptors, which result in a decrease in the concentration of the second messenger molecule cAMP through inhibition of adenylate cyclase.{{cite journal | vauthors = Elphick MR, Egertová M | title = The neurobiology and evolution of cannabinoid signalling | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 356 | issue = 1407 | pages = 381–408 | date = March 2001 | pmid = 11316486 | pmc = 1088434 | doi = 10.1098/rstb.2000.0787 }} The presence of these specialized cannabinoid receptors in the brain led researchers to the discovery of endocannabinoids, such as anandamide and 2-arachidonoyl glyceride (2-AG).{{Citation needed|date=December 2020}}

THC is a lipophilic molecule{{cite journal | vauthors = Rashidi H, Akhtar MT, van der Kooy F, Verpoorte R, Duetz WA | title = Hydroxylation and further oxidation of delta9-tetrahydrocannabinol by alkane-degrading bacteria | journal = Applied and Environmental Microbiology | volume = 75 | issue = 22 | pages = 7135–41 | date = November 2009 | pmid = 19767471 | pmc = 2786519 | doi = 10.1128/AEM.01277-09 | quote = Δ9-THC and many of its derivatives are highly lipophilic and poorly water soluble. Calculations of the n-octanol-water partition coefficient (Ko/w) of Δ9-THC at neutral pH vary between 6,000, using the shake flask method, and 9.44 × 106, by reverse-phase high-performance liquid chromatography estimation. | bibcode = 2009ApEnM..75.7135R }} and may bind non-specifically to a variety of entities in the brain and body, such as adipose tissue (fat).{{cite journal | vauthors = Ashton CH | title = Pharmacology and effects of cannabis: a brief review | journal = The British Journal of Psychiatry | volume = 178 | issue = 2 | pages = 101–06 | date = February 2001 | pmid = 11157422 | doi = 10.1192/bjp.178.2.101 | quote = Because they are extremely lipid soluble, cannabinoids accumulate in fatty tissues, reaching peak concentrations in 4–5 days. They are then slowly released back into other body compartments, including the brain. ... Within the brain, THC and other cannabinoids are differentially distributed. High concentrations are reached in neocortical, limbic, sensory and motor areas. | doi-access = free }}{{cite journal | vauthors = Huestis MA | title = Human cannabinoid pharmacokinetics | journal = Chemistry & Biodiversity | volume = 4 | issue = 8 | pages = 1770–804 | date = August 2007 | pmid = 17712819 | pmc = 2689518 | doi = 10.1002/cbdv.200790152 | quote = THC is highly lipophilic and initially taken up by tissues that are highly perfused, such as the lung, heart, brain, and liver. }} THC, as well as other cannabinoids that contain a phenol group, possess mild antioxidant activity sufficient to protect neurons against oxidative stress, such as that produced by glutamate-induced excitotoxicity.

THC targets receptors in a manner far less selective than endocannabinoid molecules released during retrograde signaling, as the drug has a relatively low cannabinoid receptor affinity. THC is also limited in its efficacy compared to other cannabinoids due to its partial agonistic activity, as THC appears to result in greater downregulation of cannabinoid receptors than endocannabinoids. Furthermore, in populations of low cannabinoid receptor density, THC may even act to antagonize endogenous agonists that possess greater receptor efficacy. However while THC's pharmacodynamic tolerance may limit the maximal effects of certain drugs, evidence suggests that this tolerance mitigates undesirable effects, thus enhancing the drug's therapeutic window.{{cite journal | vauthors = Pertwee RG | title = The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin | journal = British Journal of Pharmacology | volume = 153 | issue = 2 | pages = 199–215 | date = January 2008 | pmid = 17828291 | pmc = 2219532 | doi = 10.1038/sj.bjp.0707442 }}

Recently, it has been shown that THC is also a partial autotaxin inhibitor, with an apparent IC50 of 407 ± 67 nM for the ATX-gamma isoform.{{cite journal | vauthors = Eymery MC, McCarthy AA, Hausmann J | title = Linking medicinal cannabis to autotaxin-lysophosphatidic acid signaling | journal = Life Science Alliance | volume = 6 | issue = 2 | pages = e202201595 | date = February 2023 | pmid = 36623871 | pmc = 9834664 | doi = 10.26508/lsa.202201595 }} THC was also co-crystallized with autotaxin, deciphering the binding interface of the complex. These results might explain some of the effects of THC on inflammation and neurological diseases, since autotaxin is responsible of LPA generation, a key lipid mediator involved in numerous diseases and physiological processes. However, clinical trials need to be performed in order to assess the importance of ATX inhibition by THC during medicinal cannabis consumption.

With oral administration of a single dose, THC is almost completely absorbed by the gastrointestinal tract.{{Cite web | url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/018651s033lbl.pdf | title=Highlights of prescribing information | website=www.accessdata.fda.gov}} However, due to first-pass metabolism in the liver and the high lipid solubility of THC, only about 5 to 20% reaches circulation. Following oral administration, concentrations of THC and its major active metabolite 11-hydroxy-THC (11-OH-THC) peak after 0.5 to 4{{nbsp}}hours, with median time to peak of 1.0 to 2.5{{nbsp}}hours at different doses. In some cases, peak levels may not occur for as long as 6{{nbsp}}hours. Concentrations of THC and 11-hydroxy-THC in the circulation are approximately equal with oral administration. There is a slight increase in dose proportionality in terms of peak and area-under-the-curve levels of THC with increasing oral doses over a range of 2.5 to 10{{nbsp}}mg. A high-fat meal delays time to peak concentrations of oral THC by 4{{nbsp}}hours on average and increases area-under-the-curve exposure by 2.9-fold, but peak concentrations are not significantly altered. A high-fat meal additionally increases absorption of THC via the lymphatic system and allows it to bypass first-pass metabolism.{{cite journal | vauthors = Tagen M, Klumpers LE | title = Review of delta-8-tetrahydrocannabinol (Δ8 -THC): Comparative pharmacology with Δ9 -THC | journal = Br J Pharmacol | volume = 179 | issue = 15 | pages = 3915–3933 | date = August 2022 | pmid = 35523678 | doi = 10.1111/bph.15865 | url = | doi-access = free }} Consequently, a high-fat meal increases levels of 11-hydroxy-THC by only 25% and most of the increase in bioavailability is due to increased levels of THC.

The bioavailability of THC when smoking or inhaling is approximately 25%, with a range of 2% to 56% (although most commonly between 10 and 35%).{{cite journal | vauthors = Lucas CJ, Galettis P, Schneider J | title = The pharmacokinetics and the pharmacodynamics of cannabinoids | journal = Br J Clin Pharmacol | volume = 84 | issue = 11 | pages = 2477–2482 | date = November 2018 | pmid = 30001569 | pmc = 6177698 | doi = 10.1111/bcp.13710 | url = }}{{cite journal | vauthors = Foster BC, Abramovici H, Harris CS | title = Cannabis and Cannabinoids: Kinetics and Interactions | journal = Am J Med | volume = 132 | issue = 11 | pages = 1266–1270 | date = November 2019 | pmid = 31152723 | doi = 10.1016/j.amjmed.2019.05.017 | s2cid = 173188471 | url = }} The large range and marked variability between individuals is due to variation in factors including product matrix, ignition temperature, and inhalational dynamics (e.g., number, duration, and intervals of inhalations, breath hold time, depth and volume of inhalations, size of inhaled particles, deposition site in the lungs). THC is detectable within seconds with inhalation and peak levels of THC occur after 3 to 10{{nbsp}}minutes. Smoking or inhaling THC results in greater blood levels of THC and its metabolites and a much faster onset of action than oral administration of THC. Inhalation of THC bypasses the first-pass metabolism that occurs with oral administration. The bioavailability of THC with inhalation is increased in heavy users.

Transdermal administration of THC is limited by its extreme water insolubility. Efficient skin transport can only be obtained with permeation enhancement. Transdermal administration of THC, as with inhalation, avoids the first-pass metabolism that occurs with oral administration.

The volume of distribution of THC is large and is approximately 10{{nbsp}}L/kg (range 4–14{{nbsp}}L/kg), which is due to its high lipid solubility. The plasma protein binding of THC and its metabolites is approximately 95 to 99%, with THC bound mainly to lipoproteins and to a lesser extent albumin. THC is rapidly distributed into well-vascularized organs such as lung, heart, brain, and liver, and is subsequently equilibrated into less vascularized tissue. It is extensively distributed into and sequestered by fat tissue due to its high lipid solubility, from which it is slowly released. THC is able to cross the placenta and is excreted in human breast milk.

The metabolism of THC occurs mainly in the liver by cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP3A4.{{cite journal | vauthors = Qian Y, Gurley BJ, Markowitz JS | title = The Potential for Pharmacokinetic Interactions Between Cannabis Products and Conventional Medications | journal = Journal of Clinical Psychopharmacology | volume = 39 | issue = 5 | pages = 462–71 | year = 2019 | pmid = 31433338 | doi = 10.1097/JCP.0000000000001089 | s2cid = 201118659 }}{{cite journal | vauthors = Watanabe K, Yamaori S, Funahashi T, Kimura T, Yamamoto I | title = Cytochrome P450 enzymes involved in the metabolism of tetrahydrocannabinols and cannabinol by human hepatic microsomes | journal = Life Sciences | volume = 80 | issue = 15 | pages = 1415–19 | date = March 2007 | pmid = 17303175 | doi = 10.1016/j.lfs.2006.12.032 }} CYP2C9 and CYP3A4 are the primary enzymes involving in metabolizing THC. Pharmacogenomic research has found that oral THC exposure is 2- to 3-fold greater in people with genetic variants associated with reduced CYP2C9 function. When taken orally, THC undergoes extensive first-pass metabolism in the liver, primarily via hydroxylation. The principal active metabolite of THC is 11-hydroxy-THC (11-OH-THC), which is formed by CYP2C9 and is psychoactive similarly to THC. This metabolite is further oxidized to 11-nor-9-carboxy-THC (THC-COOH). In animals, more than 100 metabolites of THC could be identified, but 11-OH-THC and THC-COOH are the predominant metabolites.{{cite journal | vauthors = Aizpurua-Olaizola O, Zarandona I, Ortiz L, Navarro P, Etxebarria N, Usobiaga A | title = Simultaneous quantification of major cannabinoids and metabolites in human urine and plasma by HPLC-MS/MS and enzyme-alkaline hydrolysis | journal = Drug Testing and Analysis | volume = 9 | issue = 4 | pages = 626–33 | date = April 2017 | pmid = 27341312 | doi = 10.1002/dta.1998 | s2cid = 27488987 | url = https://figshare.com/articles/journal_contribution/5028359 | access-date = 2022-12-02 | archive-date = 2023-01-05 | archive-url = https://web.archive.org/web/20230105025824/https://figshare.com/articles/journal_contribution/Simultaneous_quantification_of_major_cannabinoids_and_metabolites_in_human_urine_and_plasma_by_HPLC-MS_MS_and_enzymealkaline_hydrolysis/5028359 | url-status = live }}

More than 55% of THC is excreted in the feces and approximately 20% in the urine. The main metabolite in urine is the ester of glucuronic acid and 11-OH-THC and free THC-COOH. In the feces, mainly 11-OH-THC was detected.{{cite journal | vauthors = Huestis MA | title = Pharmacokinetics and Metabolism of the Plant Cannabinoids, Δ⁹-Tetrahydrocannabinol, Cannabidiol and Cannabinol | journal = Handbook of Experimental Pharmacology | volume = 168 | issue = 168 | pages = 657–90 | year = 2005 | pmid = 16596792 | doi = 10.1007/3-540-26573-2_23 | isbn = 978-3-540-22565-2}}

Estimates of the elimination half-life of THC are variable. THC was reported to have a fast initial half-life of 6{{nbsp}}minutes and a long terminal half-life of 22{{nbsp}}hours in a population pharmacokinetic study. Conversely, the Food and Drug Administration label for dronabinol reports an initial half-life of 4{{nbsp}}hours and a terminal half-life of 25 to 36{{nbsp}}hours. Many studies report an elimination half-life of THC in the range of 20 to 30{{nbsp}}hours. 11-Hydroxy-THC appears to have a similar terminal half-life to that of THC, for instance 12 to 36{{nbsp}}hours relative to 25 to 36{{nbsp}}hours in one study. The elimination half-life of THC is longer in heavy users. This may be due to slow redistribution from deep compartments such as fatty tissues, where THC accumulates with regular use.

THC is a molecule that combines polyketides (derived from acetyl CoA) and terpenoids (derived from isoprenylpyrophosphate). It is hydrophobic with very low solubility in water, but good solubility in many organic solvents.{{cite journal | vauthors = Garrett ER, Hunt CA | title = Physiochemical properties, solubility, and protein binding of delta9-tetrahydrocannabinol | journal = Journal of Pharmaceutical Sciences | volume = 63 | issue = 7 | pages = 1056–64 | date = July 1974 | pmid = 4853640 | doi = 10.1002/jps.2600630705 }} As a phytochemical, THC is assumed to be involved in the plant's evolutionary adaptation against insect predation, ultraviolet light, and environmental stress.{{cite journal |vauthors=Pate DW |year=1994 |title=Chemical ecology of Cannabis |journal=Journal of the International Hemp Association |volume=2 |issue=29 |pages=32–37 |url=http://www.internationalhempassociation.org/jiha/iha01201.html |access-date=2017-12-09 |archive-date=2018-12-21 |archive-url=https://web.archive.org/web/20181221001352/http://www.internationalhempassociation.org/jiha/iha01201.html |url-status=live }}{{cite journal|doi=10.1007/BF02904200 |title=Possible role of ultraviolet radiation in evolution of Cannabis chemotypes |year=1983 | vauthors = Pate DW |journal=Economic Botany |volume=37 |issue=4 |pages=396–405|bibcode=1983EcBot..37..396P |s2cid=35727682 }}{{cite journal | vauthors = Lydon J, Teramura AH, Coffman CB | title = UV-B radiation effects on photosynthesis, growth and cannabinoid production of two Cannabis sativa chemotypes | journal = Photochemistry and Photobiology | volume = 46 | issue = 2 | pages = 201–06 | date = August 1987 | pmid = 3628508 | doi = 10.1111/j.1751-1097.1987.tb04757.x | url = https://zenodo.org/record/1230776 | s2cid = 7938905 | access-date = 2019-07-04 | archive-date = 2020-06-27 | archive-url = https://web.archive.org/web/20200627065313/https://zenodo.org/record/1230776 | url-status = live }}

{{See also|Conversion of CBD to THC}}

The preparation of THC was reported in 1965. that procedure called for the intramolecular alkyl lithium attack on a starting carbonyl to form the fused rings, and a tosyl chloride mediated formation of the ether.{{cite journal | vauthors = Mechoulam R, Gaoni Y | title = A Total Synthesis of Dl-Delta-1-Tetrahydrocannabinol, the Active Constituent of Hashish | journal = Journal of the American Chemical Society | volume = 87 | issue = 14 | pages = 3273–75 | date = July 1965 | pmid = 14324315 | doi = 10.1021/ja01092a065 | bibcode = 1965JAChS..87.3273M }}{{third-party inline|date=March 2017}}

{{also|THC production by yeast}}

In the Cannabis plant, THC occurs mainly as tetrahydrocannabinolic acid (THCA, 2-COOH-THC). Geranyl pyrophosphate and olivetolic acid react, catalysed by an enzyme to produce cannabigerolic acid,{{cite journal | vauthors = Fellermeier M, Zenk MH | title = Prenylation of olivetolate by a hemp transferase yields cannabigerolic acid, the precursor of tetrahydrocannabinol | journal = FEBS Letters | volume = 427 | issue = 2 | pages = 283–85 | date = May 1998 | pmid = 9607329 | doi = 10.1016/S0014-5793(98)00450-5 | doi-access = free | bibcode = 1998FEBSL.427..283F }} which is cyclized by the enzyme THC acid synthase to give THCA. Over time, or when heated, THCA is decarboxylated, producing THC. The pathway for THCA biosynthesis is similar to that which produces the bitter acid humulone in hops.{{cite journal | vauthors = Marks MD, Tian L, Wenger JP, Omburo SN, Soto-Fuentes W, He J, Gang DR, Weiblen GD, Dixon RA | title = Identification of candidate genes affecting Delta9-tetrahydrocannabinol biosynthesis in Cannabis sativa | journal = Journal of Experimental Botany | volume = 60 | issue = 13 | pages = 3715–26 | year = 2009 | pmid = 19581347 | pmc = 2736886 | doi = 10.1093/jxb/erp210 }}{{cite journal | vauthors = Baker PB, Taylor BJ, Gough TA | title = The tetrahydrocannabinol and tetrahydrocannabinolic acid content of cannabis products | journal = The Journal of Pharmacy and Pharmacology | volume = 33 | issue = 6 | pages = 369–72 | date = June 1981 | pmid = 6115009 | doi = 10.1111/j.2042-7158.1981.tb13806.x | s2cid = 30412893 }} It can also be produced in genetically modified yeast.{{cite journal | vauthors = Luo X, Reiter MA, d'Espaux L, Wong J, Denby CM, Lechner A, Zhang Y, Grzybowski AT, Harth S, Lin W, Lee H, Yu C, Shin J, Deng K, Benites VT, Wang G, Baidoo EE, Chen Y, Dev I, Petzold CJ, Keasling JD | title = Complete biosynthesis of cannabinoids and their unnatural analogues in yeast | journal = Nature | volume = 567 | issue = 7746 | pages = 123–26 | date = March 2019 | pmid = 30814733 | doi = 10.1038/s41586-019-0978-9 | bibcode = 2019Natur.567..123L | s2cid = 71147445 | url = https://backend.orbit.dtu.dk/ws/files/240436196/qt3fn1m6p5_noSplash_be06dd7b6fdfa004bec17ec4fed2cabd.pdf | access-date = 2021-12-30 | archive-date = 2022-01-14 | archive-url = https://web.archive.org/web/20220114042915/https://backend.orbit.dtu.dk/ws/files/240436196/qt3fn1m6p5_noSplash_be06dd7b6fdfa004bec17ec4fed2cabd.pdf | url-status = live }}

:File:THC biosynthesis labeled.svg{{clear left}}

{{Further|Removal of cannabis from Schedule I of the Controlled Substances Act}}

Cannabidiol was isolated and identified from Cannabis sativa in 1940 by Roger Adams who was also the first to document the synthesis of THC (both Delta-9-THC and Delta-8-THC) from the acid-based cyclization of CBD in 1942.{{Cite journal |pmid=19312292 |date=1942 | vauthors = Adams R |title=Marihuana: Harvey Lecture, February 19, 1942 |journal=Bulletin of the New York Academy of Medicine |volume=18 |issue=11 |pages=705–730 |pmc=1933888 }}{{Cite journal | vauthors = Adams R, Loewe S, Smith CM, McPhee WD |date=March 1942 |title=Tetrahydrocannabinol Homologs and Analogs with Marihuana Activity. XIII 1 |url=https://pubs.acs.org/doi/abs/10.1021/ja01255a061 |journal=Journal of the American Chemical Society |language=en |volume=64 |issue=3 |pages=694–697 |doi=10.1021/ja01255a061 |bibcode=1942JAChS..64..694A |issn=0002-7863}}{{cite patent | country = US | number = 2419937 | url=https://patents.google.com/patent/US2419937A/en | title=Marihuana active compounds | inventor = Roger A | assign = Individual | gdate = 6 May 1947 }}{{cite journal | doi=10.1021/ja01858a058 | volume=62 | title=Structure of Cannabidiol, a Product Isolated from the Marihuana Extract of Minnesota Wild Hemp. | year=1940 | journal=Journal of the American Chemical Society | pages=196–200 | vauthors = Adams R, Hunt M, Clark JH | issue=1 | bibcode=1940JAChS..62..196A }} THC was first isolated from Cannabis by Raphael Mechoulam and Yehiel Gaoni in 1964.{{cite journal | vauthors = Mechoulam R | title = Marihuana chemistry | journal = Science | volume = 158 | issue = 3936 | pages = 1159–66 | date = June 1970 | pmid = 4910003 | doi = 10.1126/science.168.3936.1159 | bibcode = 1970Sci...168.1159M }}{{cite journal|title=Isolation, structure and partial synthesis of an active constituent of hashish |vauthors=Gaoni Y, Mechoulam R | journal = Journal of the American Chemical Society |year=1964 |volume=86 |issue=8 |pages=1646–47 |doi=10.1021/ja01062a046|bibcode=1964JAChS..86.1646G }}{{cite web |url=http://matters.ecnp.nl/number11/interview2.shtml |title=Interview with the winner of the first ECNP Lifetime Achievement Award: Raphael Mechoulam, Israel |date=February 2007 |archive-url=https://web.archive.org/web/20110430032241/http://matters.ecnp.nl/number11/interview2.shtml |archive-date=2011-04-30 }}{{cite journal| vauthors = Geller T |year=2007 |url=http://chemicalheritage.org/pubs/ch-v25n2-articles/feature_cannabinoids.html |archive-url=https://web.archive.org/web/20080619013348/http://chemicalheritage.org/pubs/ch-v25n2-articles/feature_cannabinoids.html |archive-date=19 June 2008 |title=Cannabinoids: A Secret History |journal=Chemical Heritage Newsmagazine |volume=25 |issue=2}}

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{{Further|Medical cannabis}}

Female cannabis plants contain at least 113 cannabinoids,{{cite journal | vauthors = Aizpurua-Olaizola O, Soydaner U, Öztürk E, Schibano D, Simsir Y, Navarro P, Etxebarria N, Usobiaga A | title = Evolution of the Cannabinoid and Terpene Content during the Growth of Cannabis sativa Plants from Different Chemotypes | journal = Journal of Natural Products | volume = 79 | issue = 2 | pages = 324–31 | date = February 2016 | pmid = 26836472 | doi = 10.1021/acs.jnatprod.5b00949 | url = https://figshare.com/articles/journal_contribution/5028338 | access-date = 2022-12-02 | archive-date = 2023-01-05 | archive-url = https://web.archive.org/web/20230105025827/https://figshare.com/articles/journal_contribution/Evolution_of_the_Cannabinoid_and_Terpene_Content_during_the_Growth_of_Cannabis_sativa_Plants_from_Different_Chemotypes/5028338 | url-status = live }} including cannabidiol (CBD), thought to be the major anticonvulsant that helps people with multiple sclerosis,{{cite journal | vauthors = Pickens JT | title = Sedative activity of cannabis in relation to its delta'-trans-tetrahydrocannabinol and cannabidiol content | journal = British Journal of Pharmacology | volume = 72 | issue = 4 | pages = 649–56 | date = April 1981 | pmid = 6269680 | pmc = 2071638 | doi = 10.1111/j.1476-5381.1981.tb09145.x }} and cannabichromene (CBC), an anti-inflammatory which may contribute to the pain-killing effect of cannabis.{{cite book | vauthors = Morales P, Hurst DP, Reggio PH | title = Phytocannabinoids | chapter = Molecular Targets of the Phytocannabinoids: A Complex Picture | series = Progress in the Chemistry of Organic Natural Products | volume = 103 | pages = 103–31 | date = 2017 | pmid = 28120232 | pmc = 5345356 | doi = 10.1007/978-3-319-45541-9_4 | isbn = 978-3-319-45539-6 }}

{{Main|Cannabis drug testing}}

THC and its 11-OH-THC and THC-COOH metabolites can be detected and quantified in blood, urine, hair, oral fluid or sweat using a combination of immunoassay and chromatographic techniques as part of a drug use testing program or in a forensic investigation.{{cite journal | vauthors = Schwilke EW, Schwope DM, Karschner EL, Lowe RH, Darwin WD, Kelly DL, Goodwin RS, Gorelick DA, Huestis MA | title = Delta9-tetrahydrocannabinol (THC), 11-hydroxy-THC, and 11-nor-9-carboxy-THC plasma pharmacokinetics during and after continuous high-dose oral THC | journal = Clinical Chemistry | volume = 55 | issue = 12 | pages = 2180–89 | date = December 2009 | pmid = 19833841 | pmc = 3196989 | doi = 10.1373/clinchem.2008.122119 }}{{cite journal | vauthors = Röhrich J, Schimmel I, Zörntlein S, Becker J, Drobnik S, Kaufmann T, Kuntz V, Urban R | title = Concentrations of delta9-tetrahydrocannabinol and 11-nor-9-carboxytetrahydrocannabinol in blood and urine after passive exposure to Cannabis smoke in a coffee shop | journal = Journal of Analytical Toxicology | volume = 34 | issue = 4 | pages = 196–203 | date = May 2010 | pmid = 20465865 | doi = 10.1093/jat/34.4.196 | doi-access = free }}{{cite book| vauthors = Baselt R |title=Disposition of Toxic Drugs and Chemicals in Man |edition=9th |publisher=Biomedical Publications |location=Seal Beach, CA |year=2011 |pages=1644–48}} There is ongoing research to create devices capable of detecting THC in breath.{{cite news | vauthors = Wallace A |title=Testing drivers for cannabis is hard. Here's why |url=https://www.cnn.com/2020/01/02/business/cannabis-breathalyzers-are-coming-to-market/index.html |access-date=26 February 2020 |work=CNN Business |date=January 2, 2020 |archive-date=26 February 2020 |archive-url=https://web.archive.org/web/20200226030155/https://www.cnn.com/2020/01/02/business/cannabis-breathalyzers-are-coming-to-market/index.html |url-status=live }}{{cite journal | vauthors = Mirzaei H, O'Brien A, Tasnim N, Ravishankara A, Tahmooressi H, Hoorfar M | title = Topical review on monitoring tetrahydrocannabinol in breath | journal = Journal of Breath Research | volume = 14 | issue = 3 | pages = 034002 | date = May 2020 | pmid = 31842004 | doi = 10.1088/1752-7163/ab6229 | bibcode = 2020JBR....14c4002M | s2cid = 209388839 }}

THC, along with its double bond isomers and their stereoisomers,{{cite journal | vauthors = Mazzoccanti G, Ismail OH, D'Acquarica I, Villani C, Manzo C, Wilcox M, Cavazzini A, Gasparrini F | title = Cannabis through the looking glass: chemo- and enantio-selective separation of phytocannabinoids by enantioselective ultra high performance supercritical fluid chromatography | journal = Chemical Communications | volume = 53 | issue = 91 | pages = 12262–65 | date = November 2017 | pmid = 29072720 | doi = 10.1039/C7CC06999E | hdl-access = free | hdl = 11573/1016698 }} is one of only three cannabinoids scheduled by the UN Convention on Psychotropic Substances (the other two are dimethylheptylpyran and parahexyl). It was listed under Schedule I in 1971, but reclassified to Schedule II in 1991 following a recommendation from the WHO. Based on subsequent studies, the WHO has recommended the reclassification to the less-stringent Schedule III.{{cite web|url=https://www.tni.org/en/publication/the-un-drug-control-conventions#box3|title=The UN Drug Control Conventions|date=8 October 2015|access-date=3 December 2015|archive-date=3 February 2018|archive-url=https://web.archive.org/web/20180203181126/https://www.tni.org/en/publication/the-un-drug-control-conventions#box3|url-status=live}} Cannabis as a plant is scheduled by the Single Convention on Narcotic Drugs (Schedule I and IV). It is specifically still listed under Schedule I by US federal law{{cite web |date=1 December 2017 |title=Drug Schedules; Schedule 1 |url=https://www.dea.gov/drug-information/drug-scheduling |archive-date=7 May 2021 |access-date=14 January 2018 |website=United States Drug Enforcement Administration |publisher=US Drug Enforcement Administration, Department of Justice |archive-url=https://web.archive.org/web/20210507061910/https://www.dea.gov/drug-information/drug-scheduling |url-status=live }} under the Controlled Substances Act for having "no accepted medical use" and "lack of accepted safety". However, dronabinol, a pharmaceutical form of THC, has been approved by the FDA as an appetite stimulant for people with AIDS and an antiemetic for people receiving chemotherapy under the trade names Marinol and Syndros.{{cite web|title=Marinol (Dronabinol)|url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/018651s021lbl.pdf|publisher=US Food and Drug Administration|access-date=14 January 2018|date=September 2004|archive-date=10 February 2017|archive-url=https://web.archive.org/web/20170210093236/http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/018651s021lbl.pdf|url-status=live}}

In 2003, the World Health Organization Expert Committee on Drug Dependence recommended transferring THC to Schedule IV of the convention, citing its medical uses and low abuse and addiction potential.{{cite web|url=https://www.who.int/substance_abuse/right_committee/en/index.html |archive-url=https://web.archive.org/web/20050107200642/http://www.who.int/substance_abuse/right_committee/en/index.html |archive-date=January 7, 2005 |title=WHO Expert Committee on Drug Dependence |publisher=World Health Organization |access-date=12 January 2014}} In 2019, the Committee recommended transferring Δ⁹-THC to Schedule I of the Single Convention on Narcotic Drugs of 1961, but its recommendations were rejected by the United Nations Commission on Narcotic Drugs.{{Cite journal | vauthors = Riboulet-Zemouli K, Krawitz MA, Ghehiouèche F |date=2021 |title=History, Science, and Politics of International Cannabis Scheduling, 2015–2021 |url=https://papers.ssrn.com/abstract=3932639 |journal=FAAAT editions |language=en |location=Rochester, NY |ssrn=3932639 |via=SSRN}}

As of 2023, 38 states, four territories, and the District of Columbia allow medical use of cannabis (in which THC is the primary psychoactive component), with the exception of Georgia, Idaho, Indiana, Iowa, Kansas, Nebraska, North Carolina, South Carolina, Tennessee, Texas, Wisconsin, and Wyoming.{{cite web|title=State Medical Cannabis Laws|url=http://www.ncsl.org/research/health/state-medical-marijuana-laws.aspx|publisher=National Conference of State Legislatures|date=3 February 2022|access-date=10 December 2022|archive-date=11 December 2018|archive-url=https://web.archive.org/web/20181211125951/http://www.ncsl.org/research/health/state-medical-marijuana-laws.aspx|url-status=live}} As of 2022, the federal government maintains cannabis as a schedule I controlled substance, while dronabinol is classified as Schedule III in capsule form (Marinol) and Schedule II in liquid oral form (Syndros).{{cite web |title=Drug scheduling: Marijuana (Cannabis) |url=https://www.dea.gov/drug-information/drug-scheduling |publisher=US Department of Justice, Drug Enforcement Administration |access-date=10 December 2022 |date=2022 |archive-date=10 December 2022 |archive-url=https://web.archive.org/web/20221210002749/https://www.dea.gov/drug-information/drug-scheduling |url-status=live }}{{cite web |title=Controlled Substances |url=https://www.deadiversion.usdoj.gov/schedules/orangebook/c_cs_alpha.pdf |website=usdoj.gov |access-date=December 11, 2022 |archive-date=April 21, 2021 |archive-url=https://web.archive.org/web/20210421180644/https://www.deadiversion.usdoj.gov/schedules/orangebook/c_cs_alpha.pdf |url-status=live }}

As of October 2018 when recreational use of cannabis was legalized in Canada, some 220 dietary supplements and 19 veterinary health products containing not more than 10 parts per million of THC extract were approved with general health claims for treating minor conditions.

The status of THC as an illegal drug in most countries imposes restrictions on research material supply and funding, such as in the United States where the National Institute on Drug Abuse and Drug Enforcement Administration continue to control the sole federally-legal source of cannabis for researchers. Despite an August 2016 announcement that licenses would be provided to growers for supplies of medical marijuana, no such licenses were ever issued, despite dozens of applications.{{cite web |url=http://www.maps.org/research/mmj/ |title=Medical Marijuana |publisher=Multidisciplinary Association for Psychedelic Studies |access-date=12 January 2014 |archive-date=14 April 2012 |archive-url=https://web.archive.org/web/20120414114518/http://www.maps.org/research/mmj/ |url-status=live }} Although cannabis is legalized for medical uses in more than half of the states of the United States, no products have been approved for federal commerce by the Food and Drug Administration, a status that limits cultivation, manufacture, distribution, clinical research, and therapeutic applications.{{cite journal | vauthors = Mead A | title = The legal status of cannabis (marijuana) and cannabidiol (CBD) under U.S. law | journal = Epilepsy & Behavior | volume = 70 | issue = Pt B | pages = 288–91 | date = May 2017 | pmid = 28169144 | doi = 10.1016/j.yebeh.2016.11.021 | url = http://www.epilepsybehavior.com/article/S1525-5050(16)30585-6/fulltext | doi-access = free | access-date = 2018-01-26 | archive-date = 2022-10-21 | archive-url = https://web.archive.org/web/20221021191845/https://www.epilepsybehavior.com/article/S1525-5050(16)30585-6/fulltext | url-status = live }}

In April 2014, the American Academy of Neurology found evidence supporting the effectiveness of the cannabis extracts in treating certain symptoms of multiple sclerosis and pain, but there was insufficient evidence to determine effectiveness for treating several other neurological diseases.{{cite journal | vauthors = Koppel BS, Brust JC, Fife T, Bronstein J, Youssof S, Gronseth G, Gloss D | title = Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders: report of the Guideline Development Subcommittee of the American Academy of Neurology | journal = Neurology | volume = 82 | issue = 17 | pages = 1556–63 | date = April 2014 | pmid = 24778283 | pmc = 4011465 | doi = 10.1212/WNL.0000000000000363 }} A 2015 review confirmed that medical marijuana was effective for treating spasticity and chronic pain, but caused numerous short-lasting adverse events, such as dizziness.{{cite journal | vauthors = Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Hernandez AV, Keurentjes JC, Lang S, Misso K, Ryder S, Schmidlkofer S, Westwood M, Kleijnen J | title = Cannabinoids for Medical Use: A Systematic Review and Meta-analysis | journal = JAMA | volume = 313 | issue = 24 | pages = 2456–73 | year = 2015 | pmid = 26103030 | doi = 10.1001/jama.2015.6358 | doi-access = free | hdl = 10757/558499 | hdl-access = free }}

• Spasticity. Based on the results of three high-quality trials and five of lower quality, oral cannabis extract was rated as effective, and THC as probably effective, for improving people's subjective experience of spasticity. Oral cannabis extract and THC both were rated as possibly effective for improving objective measures of spasticity.
• Centrally mediated pain and painful spasms. Based on the results of four high-quality trials and four low-quality trials, oral cannabis extract was rated as effective, and THC as probably effective in treating central pain and painful spasms.
• Bladder dysfunction. Based on a single high quality study, oral cannabis extract and THC were rated as probably ineffective for controlling bladder complaints in multiple sclerosis

• Huntington disease. No reliable conclusion could be drawn regarding the effectiveness of THC or oral cannabis extract in treating the symptoms of Huntington disease as the available trials were too small to reliably detect any difference
• Parkinson's disease. Based on a single study, oral CBD extract was rated probably ineffective in treating levodopa-induced dyskinesia in Parkinson's disease.
• Alzheimer's disease. A 2009 Cochrane Review found insufficient evidence to conclude whether cannabis products have any utility in the treatment of Alzheimer's disease.{{cite journal | vauthors = Krishnan S, Cairns R, Howard R | title = Cannabinoids for the treatment of dementia | journal = The Cochrane Database of Systematic Reviews | issue = 2 | pages = CD007204 | date = April 2009 | volume = 2009 | pmid = 19370677 | pmc = 7197039 | doi = 10.1002/14651858.CD007204.pub2 | veditors = Krishnan S }}

• Tourette syndrome. The available data was determined to be insufficient to allow reliable conclusions to be drawn regarding the effectiveness of oral cannabis extract or THC in controlling tics.
• Cervical dystonia. Insufficient data was available to assess the effectiveness of oral cannabis extract of THC in treating cervical dystonia.

Preliminary research indicates that prolonged exposure to high doses of THC may interfere with chromosomal stability, which may be hereditary as a factor affecting cell instability and cancer risk. The carcinogenicity of THC in the studied populations of so-called "heavy users" remains dubious due to various confounding variables, most significantly concurrent tobacco use.{{cite journal | vauthors = Reece AS, Hulse GK | title = Chromothripsis and epigenomics complete causality criteria for cannabis- and addiction-connected carcinogenicity, congenital toxicity and heritable genotoxicity | journal = Mutation Research | volume = 789 | pages = 15–25 | date = July 2016 | pmid = 27208973 | doi = 10.1016/j.mrfmmm.2016.05.002 | bibcode = 2016MRFMM.789...15R }}

{{Portal|Cannabis|Chemistry}}

{{Div col|colwidth=30}}

• Cannabinoids
• Anandamide, 2-Arachidonoylglycerol, endogenous cannabinoid agonists
• Cannabidiol (CBD)
• Cannabinol (CBN), a metabolite of THC
• Delta-8-THC, one of the isomers of THC
• HU-210, WIN 55,212-2, JWH-133, synthetic cannabinoid agonists (neocannabinoids)
• Hashish
• List of investigational analgesics
• Medical cannabis
• Dronabinol, the name of THC-based pharmaceutical (INN)
• Epidiolex (prescription form of purified cannabidiol derived from hemp used for treating some rare neurological diseases)
• Sativex
• Effects of cannabis
• War on Drugs
• Vaping-associated pulmonary injury
• Cannabinoid hyperemesis syndrome (CHS)

{{Div col end}}

{{Reflist}}

• [http://druginfo.nlm.nih.gov/drugportal/dpdirect.jsp?name=Tetrahydrocannabinol U.S. National Library of Medicine: Drug Information Portal – Tetrahydrocannabinol]

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