Tetrahydrocannabinol

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"THC" redirects here. For other uses, see THC (disambiguation).
For the phytocannabinoid homologue of THC, that is much more potent than THC itself, see Tetrahydrocannabiphorol (THCP).
Tetrahydrocannabinol
INN: dronabinol
Clinical data
Trade namesMarinol, Syndros
Other names(6aR,10aR)-delta-9-Tetrahydrocannabinol; (−)-trans-Δ9-Tetrahydrocannabinol; THC
License data
Dependence
liability		Physical: Low
Psychological: Low–moderate
Addiction
liability		Relatively low: 9%
Routes of
administration		Oral, local/topical, transdermal, sublingual, inhaled
Drug classCannabinoid
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability10–35% (inhalation), 6–20% (oral)[3]
Protein binding97–99%[3][4][5]
MetabolismMostly hepatic by CYP2C[3]
Elimination half-life1.6–59 h,[3] 25–36 h (orally administered dronabinol)
Excretion65–80% (feces), 20–35% (urine) as acid metabolites[3]
Identifiers
  • (6aR,10aR)-6,6,9-Trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol
JSmol)
Specific rotation−152° (ethanol)
Boiling point155–157 °C (311–315 °F) 0.05mmHg,[6] 157–160°C @ 0.05mmHg[7]
Solubility in water0.0028 mg/mL (23 °C)[8]
  • CCCCCc1cc(c2c(c1)OC([C@H]3[C@H]2C=C(CC3)C)(C)C)O
  • InChI=1S/C21H30O2/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/h11-13,16-17,22H,5-10H2,1-4H3/t16-,17-/m1/s1 checkY
  • Key:CYQFCXCEBYINGO-IAGOWNOFSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Tetrahydrocannabinol (THC) is a terpenoid found in cannabis.[9] It is the principal psychoactive constituent of cannabis and one of at least 113 total cannabinoids identified on the plant. Its chemical formula C21H30O2 includes compounds,[10] the term THC usually refers to the delta-9-THC isomer with chemical name (−)-trans-Δ9-tetrahydrocannabinol. It is a colorless oil.

Medical uses

Further information: Dronabinol
Not to be confused with Droperidol.

Medical use of cannabis has a long history.[11] 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.[12][13] Nabiximols (as Sativex) is available as a prescription drug in Canada.[14] In 2021, nabiximols was approved for medical use in Ukraine.[15]

Overdose

The

cardiovascular death in the one otherwise healthy subject of the two cases studied.[17] A different 1972 study gave the median lethal dose for intravenous THC in mice and rats at 30–40 mg/kg.[18]

Interactions

Formal

elimination half-life of the barbiturate pentobarbital has been found to increase by 4 hours when concomitantly administered with oral THC.[19]

Pharmacology

See also: Effects of cannabis, Long-term effects of cannabis, and Cannabis in pregnancy

Mechanism of action

For a review of the mechanisms behind endocannabinoid synaptic transmission, see Endocannabinoid system.

The actions of Delta-9-THC result from its

2-AG).[citation needed
]

THC is a

glutamate-induced excitotoxicity.[22]

THC targets receptors in a manner far less selective than endocannabinoid molecules released during

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.[27]

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.[28] 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.

Pharmacokinetics

Absorption

With oral administration of a single dose, THC is almost completely

area-under-the-curve levels of THC with increasing oral doses over a range of 2.5 to 10 mg.[19] A high-fat meal delays time to peak concentrations of oral THC by 4 hours on average and increases area-under-the-curve exposure by 2.9-fold, but peak concentrations are not significantly altered.[19] A high-fat meal additionally increases absorption of THC via the lymphatic system and allows it to bypass first-pass metabolism.[29] 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.[29]

The bioavailability of THC when

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).[20][30] THC is detectable within seconds with inhalation and peak levels of THC occur after 3 to 10 minutes.[3][30] 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.[20][30] Inhalation of THC bypasses the first-pass metabolism that occurs with oral administration.[20] The bioavailability of THC with inhalation is increased in heavy users.[3]

water insolubility.[20] Efficient skin transport can only be obtained with permeation enhancement.[20] Transdermal administration of THC, as with inhalation, avoids the first-pass metabolism that occurs with oral administration.[20]

Distribution

The volume of distribution of THC is large and is approximately 10 L/kg (range 4–14 L/kg), which is due to its high lipid solubility.[19][20][30] 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.[19][3] THC is rapidly distributed into well-vascularized organs such as lung, heart, brain, and liver, and is subsequently equilibrated into less vascularized tissue.[20][30] It is extensively distributed into and sequestered by fat tissue due to its high lipid solubility, from which it is slowly released.[29][20][30] THC is able to cross the placenta and is excreted in human breast milk.[20][3]

Metabolism

The

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.[29][33]

Elimination

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.[34]

Estimates of the

terminal half-life of 22 hours in a population pharmacokinetic study.[20][30] Conversely, the Food and Drug Administration label for dronabinol reports an initial half-life of 4 hours and a terminal half-life of 25 to 36 hours.[19] Many studies report an elimination half-life of THC in the range of 20 to 30 hours.[3] 11-Hydroxy-THC appears to have a similar terminal half-life to that of THC, for instance 12 to 36 hours relative to 25 to 36 hours in one study.[3] The elimination half-life of THC is longer in heavy users.[20] This may be due to slow redistribution from deep compartments such as fatty tissues, where THC accumulates with regular use.[20]

Chemistry

Solubility

As with many

aromatic terpenoids, THC has a very low solubility in water, but good solubility in lipids and most organic solvents, specifically hydrocarbons and alcohols.[8]

Total synthesis

A

tosyl chloride mediated formation of the ether.[35][third-party source needed
]

Biological function

As a

ultraviolet light, and environmental stress.[36][37][38]

Biosynthesis

In the

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.[40][41] It can also be produced in genetically modified yeast.[42]

Biosynthesis of THC

History

Further information: Removal of cannabis from Schedule I of the Controlled Substances Act

Delta-8-THC) from the acid-based cyclization of CBD in 1942.[43][44][45][46] THC was first isolated from Cannabis by Raphael Mechoulam in 1964.[47][48][49][50]

Society and culture

Comparisons with medical cannabis

Further information: Medical cannabis
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Female cannabis plants contain at least 113 cannabinoids,[51] including cannabidiol (CBD), thought to be the major anticonvulsant that helps people with multiple sclerosis,[52] and cannabichromene (CBC), an anti-inflammatory which may contribute to the pain-killing effect of cannabis.[53]

Drug testing

Main article: 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

chromatographic techniques as part of a drug use testing program or in a forensic investigation.[54][55][56] There is ongoing research to create devices capable of detecting THC in breath.[57][58]

Regulation

THC, along with its double bond isomers and their

AIDS and an antiemetic for people receiving chemotherapy under the trade names Marinol and Syndros.[62]

In 2003, the

Schedule IV of the convention, citing its medical uses and low abuse and addiction potential.[63]

In the United States

As of 2023, 38 states, four territories, and the District of Columbia in the United States 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.[64] As of 2022, the U.S. 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).[65][66]

In Canada

As of October 2018 when recreational use of cannabis was

veterinary health products containing not more than 10 parts per million of THC extract were approved with general health claims for treating minor conditions.[14]

Research

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.[67] 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.[68]

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.[69] 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.[70]

Multiple sclerosis symptoms

  • Spasticity. Based on the results of 3 high quality trials and 5 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.[69][70]
  • Centrally mediated pain and painful spasms. Based on the results of 4 high quality trials and 4 low quality trials, oral cannabis extract was rated as effective, and THC as probably effective in treating central pain and painful spasms.[69]
  • 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[69]

Neurodegenerative disorders

  • 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[69]
  • Parkinson's disease. Based on a single study, oral CBD extract was rated probably ineffective in treating levodopa-induced dyskinesia in Parkinson's disease.[69]
  • 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.[71]

Other neurological disorders

  • 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.[69]
  • Cervical dystonia. Insufficient data was available to assess the effectiveness of oral cannabis extract of THC in treating cervical dystonia.[69]

Potential for toxicity

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.[72]

See also

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External links
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