Tetrahydrocannabinol (THC) is a cannabinoid found in cannabis.<ref>Template:Cite journal</ref> It is the principal psychoactive constituent of Cannabis and one of at least 113 total cannabinoids identified on the plant. Although the chemical formula for THC (C21H30O2) describes multiple isomers,<ref>Template:Cite web</ref> the term THC usually refers to the delta-9-THC isomer with chemical name (−)-trans-Δ9-tetrahydrocannabinol. It is a colorless oil.
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.<ref name=":0" />
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.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref> A different 1972 study gave the median lethal dose for intravenous THC in mice and rats at 30–40 mg/kg.<ref>Template:Cite journal</ref> A 2020 fact sheet published by the U.S. Drug Enforcement Administration stated that "[n]o deaths from overdose of marijuana have been reported."<ref>Template:Cite web</ref>
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.<ref name="pmid17828291">Template:Cite journal</ref>
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.<ref>Template:Cite journal</ref> 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.<ref name="MarinolLabel2023">Template:Cite web</ref> However, due to first-pass metabolism in the liver and the high lipid solubility of THC, only about 5 to 20% reaches circulation.<ref name="pmid12648025" /><ref name="MarinolLabel2023" /> Following oral administration, concentrations of THC and its major active metabolite11-hydroxy-THC (11-OH-THC) peak after 0.5 to 4Template:Nbsphours, with median time to peak of 1.0 to 2.5Template:Nbsphours at different doses.<ref name="MarinolLabel2023" /><ref name="pmid12648025" /> In some cases, peak levels may not occur for as long as 6Template:Nbsphours.<ref name="pmid12648025" /> Concentrations of THC and 11-hydroxy-THC in the circulation are approximately equal with oral administration.<ref name="MarinolLabel2023" /> 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 10Template:Nbspmg.<ref name="MarinolLabel2023" /> A high-fat meal delays time to peak concentrations of oral THC by 4Template:Nbsphours on average and increases area-under-the-curve exposure by 2.9-fold, but peak concentrations are not significantly altered.<ref name="MarinolLabel2023" /> A high-fat meal additionally increases absorption of THC via the lymphatic system and allows it to bypass first-pass metabolism.<ref name="pmid35523678">Template:Cite journal</ref> 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.<ref name="pmid35523678" />
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%).<ref name="pmid30001569">Template:Cite journal</ref><ref name="pmid31152723">Template:Cite journal</ref><ref name="pmid12648025" /> 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).<ref name="pmid30001569" /><ref name="pmid31152723" /> THC is detectable within seconds with inhalation and peak levels of THC occur after 3 to 10Template:Nbspminutes.<ref name="pmid12648025" /><ref name="pmid31152723" /> 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.<ref name="pmid30001569" /><ref name="pmid31152723" /> Inhalation of THC bypasses the first-pass metabolism that occurs with oral administration.<ref name="pmid30001569" /> The bioavailability of THC with inhalation is increased in heavy users.<ref name="pmid12648025" />
Transdermal administration of THC is limited by its extreme water insolubility.<ref name="pmid30001569" /> Efficient skin transport can only be obtained with permeation enhancement.<ref name="pmid30001569" /> Transdermal administration of THC, as with inhalation, avoids the first-pass metabolism that occurs with oral administration.<ref name="pmid30001569" />
The volume of distribution of THC is large and is approximately 10Template:NbspL/kg (range 4–14Template:NbspL/kg), which is due to its high lipid solubility.<ref name="MarinolLabel2023" /><ref name="pmid30001569" /><ref name="pmid31152723" /> 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.<ref name="MarinolLabel2023" /><ref name="pmid12648025" /> THC is rapidly distributed into well-vascularized organs such as lung, heart, brain, and liver, and is subsequently equilibrated into less vascularized tissue.<ref name="pmid30001569" /><ref name="pmid31152723" /> It is extensively distributed into and sequestered by fat tissue due to its high lipid solubility, from which it is slowly released.<ref name="pmid35523678" /><ref name="pmid30001569" /><ref name="pmid31152723" /> THC is able to cross the placenta and is excreted in human breast milk.<ref name="pmid30001569" /><ref name="pmid12648025" />
The metabolism of THC occurs mainly in the liver by cytochrome P450enzymesCYP2C9, CYP2C19, and CYP3A4.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> CYP2C9 and CYP3A4 are the primary enzymes involving in metabolizing THC.<ref name="MarinolLabel2023" /> Pharmacogenomic research has found that oral THC exposure is 2- to 3-fold greater in people with genetic variants associated with reduced CYP2C9 function.<ref name="MarinolLabel2023" /> When taken orally, THC undergoes extensive first-pass metabolism in the liver, primarily via hydroxylation.<ref name="MarinolLabel2023" /> The principal active metabolite of THC is 11-hydroxy-THC (11-OH-THC), which is formed by CYP2C9 and is psychoactive similarly to THC.<ref name="pmid35523678" /><ref name="pmid30001569" /><ref name="MarinolLabel2023" /> 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.<ref name="pmid35523678" /><ref name="pmid27341312">Template:Cite journal</ref>
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.<ref name="pmid16596792">Template:Cite journal</ref>
Estimates of the elimination half-life of THC are variable.<ref name="pmid30001569" /> THC was reported to have a fast initial half-life of 6Template:Nbspminutes and a long terminal half-life of 22Template:Nbsphours in a population pharmacokinetic study.<ref name="pmid30001569" /><ref name="pmid31152723" /> Conversely, the Food and Drug Administration label for dronabinol reports an initial half-life of 4Template:Nbsphours and a terminal half-life of 25 to 36Template:Nbsphours.<ref name="MarinolLabel2023" /> Many studies report an elimination half-life of THC in the range of 20 to 30Template:Nbsphours.<ref name="pmid12648025" /> 11-Hydroxy-THC appears to have a similar terminal half-life to that of THC, for instance 12 to 36Template:Nbsphours relative to 25 to 36Template:Nbsphours in one study.<ref name="pmid12648025" /> The elimination half-life of THC is longer in heavy users.<ref name="pmid30001569" /> This may be due to slow redistribution from deep compartments such as fatty tissues, where THC accumulates with regular use.<ref name="pmid30001569" />
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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite book</ref> There is ongoing research to create devices capable of detecting THC in breath.<ref name="cnn">Template:Cite news</ref><ref>Template:Cite journal</ref>
THC, along with its double bond isomers and their stereoisomers,<ref>Template:Cite journal</ref> 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.<ref>Template:Cite web</ref> 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<ref>Template:Cite web</ref> 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.<ref name="fda">Template:Cite web</ref>
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.<ref name="ncsl-states">Template:Cite web</ref> 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).<ref name="dea-22">Template:Cite web</ref><ref>Template:Cite web</ref>
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.<ref name=canada2018/>
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.<ref name="MAPS">Template:Cite web</ref> 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.<ref>Template:Cite journal</ref>
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.<ref name="AAN">Template:Cite journal</ref> 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.<ref name="whiting">Template:Cite journal</ref>
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.<ref name="AAN"/><ref name=whiting/>
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.<ref name="AAN"/>
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<ref name="AAN"/>
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<ref name="AAN"/>
Parkinson's disease. Based on a single study, oral CBD extract was rated probably ineffective in treating levodopa-induced dyskinesia in Parkinson's disease.<ref name="AAN"/>
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.<ref>Template:Cite journal</ref>
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.<ref name="AAN"/>
Cervical dystonia. Insufficient data was available to assess the effectiveness of oral cannabis extract of THC in treating cervical dystonia.<ref name="AAN"/>
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.<ref>Template:Cite journal</ref>
