DE: Dronabinol:Anlage III, Δ9-THC:II, other isomers and their stereochemical variants:I. (Does not apply to THC as part of cannabis, which is regulated separately, seeCannabis (drug))
Tetrahydrocannabinol (THC) is acannabinoid found incannabis.[14] It is the principalpsychoactive constituent ofCannabis and one of at least 113 total cannabinoids identified on the plant. Although thechemical formula for THC (C21H30O2) describes multipleisomers,[15] the termTHC usually refers to the delta-9-THC isomer with chemical name(−)-trans-Δ9-tetrahydrocannabinol. It is a colorless oil.
THC can be administered orally, inhaled, or transdermally, withbioavailability and onset varying by route, and is extensively metabolized in the liver to active and inactive metabolites before being excreted in feces and urine. Side effects includered eyes,dry mouth,drowsiness,memory impairment,anxiety, and, with chronic use,cannabinoid hyperemesis syndrome. While human overdose is rare, THC can interact with other drugs and has a complexpharmacokinetic profile.
THC is classified variably under international and US law, with medical use approved in multiple countries. Research supports its effectiveness for spasticity and central pain in multiple sclerosis, though evidence for otherneurological disorders is limited, and long-term high-dose exposure may carry uncertaintoxicity risks.
Chronic usage of THC may result incannabinoid hyperemesis syndrome (CHS), a condition characterized by cyclic nausea, vomiting, and abdominal pain that may persist for months to years after discontinuation.[21]
Themedian 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.[23] 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), observingcardiovascular death in the one otherwise healthy subject of the two cases studied.[24] A different 1972 study gave the median lethal dose for intravenous THC in mice and rats at 30–40 mg/kg.[25] A 2020 fact sheet published by the USDrug Enforcement Administration stated that "[n]o deaths from overdose of marijuana have been reported."[26]
THC targets receptors in a manner far less selective than endocannabinoid molecules released duringretrograde 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 greaterdownregulation of cannabinoid receptors thanendocannabinoids. 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.[35]
Recently, it has been shown that THC is also a partialautotaxin inhibitor, with an apparent IC50 of 407 ± 67 nM for the ATX-gamma isoform.[36] 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 completelyabsorbed by thegastrointestinal tract.[27] However, due tofirst-pass metabolism in theliver and the highlipid solubility of THC, only about 5 to 20% reaches circulation.[5][27] Following oral administration, concentrations of THC and its majoractive metabolite11-hydroxy-THC (11-OH-THC)peak after 0.5 to 4hours, with median time to peak of 1.0 to 2.5hours at different doses.[27][5] In some cases, peak levels may not occur for as long as 6hours.[5] Concentrations of THC and 11-hydroxy-THC in the circulation are approximately equal with oral administration.[27] There is a slight increase indose proportionality in terms ofpeak andarea-under-the-curve levels of THC with increasing oral doses over a range of 2.5 to 10mg.[27] A high-fat meal delays time to peak concentrations of oral THC by 4hours on average and increases area-under-the-curve exposure by 2.9-fold, but peak concentrations are not significantly altered.[27] A high-fat meal additionally increases absorption of THC via thelymphatic system and allows it to bypass first-pass metabolism.[37] Consequently, a high-fat meal increases levels of 11-hydroxy-THC by only 25% and most of the increase inbioavailability is due to increased levels of THC.[37]
The bioavailability of THC whensmoking orinhaling is approximately 25%, with a range of 2% to 56% (although most commonly between 10 and 35%).[28][38][5] The large range and markedvariability 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).[28][38] THC is detectable within seconds with inhalation and peak levels of THC occur after 3 to 10minutes.[5][38] Smoking or inhaling THC results in greater blood levels of THC and its metabolites and a much fasteronset of action than oral administration of THC.[28][38] Inhalation of THC bypasses the first-pass metabolism that occurs with oral administration.[28] The bioavailability of THC with inhalation is increased in heavy users.[5]
Transdermal administration of THC is limited by its extremewater insolubility.[28] Efficient skin transport can only be obtained with permeation enhancement.[28] Transdermal administration of THC, as with inhalation, avoids the first-pass metabolism that occurs with oral administration.[28]
Thevolume of distribution of THC is large and is approximately 10L/kg (range 4–14L/kg), which is due to its high lipid solubility.[27][28][38] Theplasma protein binding of THC and itsmetabolites is approximately 95 to 99%, with THC bound mainly tolipoproteins and to a lesser extentalbumin.[27][5] THC is rapidly distributed into well-vascularized organs such aslung,heart,brain, andliver, and is subsequently equilibrated into less vascularized tissue.[28][38] It is extensively distributed into and sequestered byfat tissue due to its high lipid solubility, from which it is slowly released.[37][28][38] THC is able to cross theplacenta and is excreted in humanbreast milk.[28][5]
More than 55% of THC isexcreted in thefeces and approximately 20% in theurine. The main metabolite in urine is the ester ofglucuronic acid and 11-OH-THC and free THC-COOH. In the feces, mainly 11-OH-THC was detected.[42]
Estimates of theelimination half-life of THC are variable.[28] THC was reported to have a fast initial half-life of 6minutes and a longterminal half-life of 22hours in apopulation pharmacokinetic study.[28][38] Conversely, theFood and Drug Administration label for dronabinol reports an initial half-life of 4hours and a terminal half-life of 25 to 36hours.[27] Many studies report an elimination half-life of THC in the range of 20 to 30hours.[5] 11-Hydroxy-THC appears to have a similar terminal half-life to that of THC, for instance 12 to 36hours relative to 25 to 36hours in one study.[5] The elimination half-life of THC is longer in heavy users.[28] This may be due to slow redistribution from deep compartments such as fatty tissues, where THC accumulates with regular use.[28]
Thepreparation of THC was reported inJACS in 1965. That procedure called for the intramolecular alkyl lithium attack on a startingcarbonyl to form the fused rings, and atosyl chloride mediated formation of the ether.[47]
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 ofimmunoassay andchromatographic techniques as part of a drug use testing program or in a forensic investigation.[63][64][65] There is ongoing research to create devices capable of detecting THC in breath.[66][67]
THC, along with its double bond isomers and theirstereoisomers,[68] is one of only three cannabinoids scheduled by the UNConvention on Psychotropic Substances (the other two aredimethylheptylpyran andparahexyl). It was listed under Schedule I in 1971, but reclassified to Schedule II in 1991 following a recommendation from theWHO. Based on subsequent studies, the WHO has recommended the reclassification to the less-stringent Schedule III.[69] Cannabis as a plant is scheduled by theSingle Convention on Narcotic Drugs (Schedule I and IV). It is specifically still listed under Schedule I by US federal law[70] under theControlled Substances Act for having "no accepted medical use" and "lack of accepted safety". However,dronabinol, a pharmaceutical form of THC, has been approved by theFDA as an appetite stimulant for people withAIDS and anantiemetic for people receivingchemotherapy under the trade names Marinol and Syndros.[71]
As of 2023, 38 states, four territories, and theDistrict of Columbia allowmedical 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.[74] 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).[75][76]
As of October 2018 when recreational use of cannabis waslegalized in Canada, some 220dietary supplements and 19veterinary health products containing not more than 10 parts per million of THC extract were approved with general health claims for treating minor conditions.[19]
In April 2014, theAmerican Academy of Neurology found evidence supporting the effectiveness of the cannabis extracts in treating certain symptoms ofmultiple sclerosis and pain, but there was insufficient evidence to determine effectiveness for treating several other neurological diseases.[77] A 2015 review confirmed that medical marijuana was effective for treating spasticity and chronic pain, but caused numerous short-lastingadverse events, such as dizziness.[78]
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.[77][78] Nabiximols likely effectively reduces the severity of spasticity in the short‐term.[79]
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.[77]
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.[77]
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[77]
Parkinson's disease. Based on a single study, oral CBD extract was rated probably ineffective in treating levodopa-induced dyskinesia in Parkinson's disease.[77]
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.[80]
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.[77]
Cervical dystonia. Insufficient data was available to assess the effectiveness of oral cannabis extract of THC in treating cervical dystonia.[77]
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.[81]
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