Tetrahydrocannabinol

Tetrahydrocannabinol (THC) is one of at least 113 cannabinoids identified in cannabis. THC is the principal psychoactive constituent of cannabis. With chemical name (−)-trans-Δ⁹-tetrahydrocannabinol, the term THC also refers to cannabinoid isomers.

Like most pharmacologically-active secondary metabolites of plants, THC is a lipid found in cannabis,[9] assumed to be involved in the plant's self-defense, putatively against insect predation, ultraviolet light, and environmental stress.[10][11][12]

THC, along with its double bond isomers and their stereoisomers[13], 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.[14] 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[15] under the Controlled Substances Act for having "no accepted medical use" and "lack of accepted safety". However, dronabinol is a synthetic form of THC approved by the FDA as an appetite stimulant for people with AIDS and antiemetic for people receiving chemotherapy.[16] The pharmaceutical formulation dronabinol is an oily resin provided in capsules available by prescription in the United States, Canada, Germany, and New Zealand.

Tetrahydrocannabinol
INN: dronabinol
THC
Delta-9-tetrahydrocannabinol-from-tosylate-xtal-3D-balls
Clinical data
Trade namesMarinol
Synonyms(6aR,10aR)-delta-9-tetrahydrocannabinol, (−)-trans-Δ⁹-tetrahydrocannabinol
License data
Pregnancy
category
  • US: C (Risk not ruled out)
Dependence
liability
8–10% (Relatively low risk of tolerance)[1]
Routes of
administration
Oral, local/topical, transdermal, sublingual, inhaled
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
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
ChEBI
ChEMBL
Chemical and physical data
FormulaC21H30O2
Molar mass314.469 g·mol−1
3D model (JSmol)
Specific rotation−152° (ethanol)
Boiling point155-157°C @ 0.05mmHg,[7] 157-160°C @ 0.05mmHg[8]
Solubility in water0.0028,[6] (23 °C) mg/mL (20 °C)
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Medical uses

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.[17][18] Nabiximols (as Sativex) is available as a prescription drug in Canada.[19]

Pharmacology

Mechanism of action

The actions of THC result from its partial agonist activity at the cannabinoid receptor CB1 (Ki = 10 nM[20]), located mainly in the central nervous system, and the CB2 receptor (Ki = 24 nM[20]), mainly expressed in cells of the immune system.[21] The psychoactive effects of THC are primarily mediated by the activation of cannabinoid receptors, which result in a decrease in the concentration of the second messenger molecule cAMP through inhibition of adenylate cyclase.[22]

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). 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 efficacy and affinity. In populations of low cannabinoid receptor density, THC may act to antagonize endogenous agonists that possess greater receptor efficacy.[23] THC is a lipophilic molecule[24] and may bind non-specifically to a variety of entities in the brain and body, such as adipose tissue (fat).[25][26]

THC, similarly to cannabidiol, albeit less potently, is a positive allosteric modulator of the μ- and δ-opioid receptors.[27]

Due to its partial agonistic activity, THC appears to result in greater downregulation of cannabinoid receptors than endocannabinoids, further limiting its efficacy over other cannabinoids. While tolerance may limit the maximal effects of certain drugs, evidence suggests that tolerance develops irregularly for different effects with greater resistance for primary over side-effects, and may actually serve to enhance the drug's therapeutic window.[23] However, this form of tolerance appears to be irregular throughout mouse brain areas. THC, as well as other cannabinoids that contain a phenol group, possesses mild antioxidant activity sufficient to protect neurons against oxidative stress, such as that produced by glutamate-induced excitotoxicity.[21]

Pharmacokinetics

THC is metabolized mainly to 11-OH-THC by the body. This metabolite is still psychoactive and is further oxidized to 11-nor-9-carboxy-THC (THC-COOH). In humans and animals, more than 100 metabolites could be identified, but 11-OH-THC and THC-COOH are the dominating metabolites.[28] Metabolism occurs mainly in the liver by cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP3A4.[29] More than 55% of THC is excreted in the feces and ≈20% in the urine. The main metabolite in urine is the ester of glucuronic acid and THC-COOH and free THC-COOH. In the feces, mainly 11-OH-THC was detected.[30]

Physical and chemical properties

Discovery and structure identification

In 1940, cannabidiol was isolated and identified from Cannabis sativa,[31] and THC was isolated and described for its structure and synthesis in 1964.[32][33]

Solubility

As with many aromatic terpenoids, THC has a very low solubility in water, but good solubility in most organic solvents, specifically lipids and alcohols.[6]

Total synthesis

A total synthesis of the compound 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.[34]

Biosynthesis

THC-COOH biosynthesis v2
Biosynthesis of THCA

In the Cannabis plant, THC occurs mainly as tetrahydrocannabinolic acid (THCA, 2-COOH-THC, THC-COOH). Geranyl pyrophosphate and olivetolic acid react, catalysed by an enzyme to produce cannabigerolic acid,[35] 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.[36][37]

Detection in body fluids

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.[38][39][40]

History

THC was first isolated in 1964 by Raphael Mechoulam and Yechiel Gaoni at the Weizmann Institute of Science in Israel.[32][41][42]

At its 33rd meeting, 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 potential.[43]

Society and culture

Comparisons with medical cannabis

Female cannabis plants contain at least 113 cannabinoids,[44] including cannabidiol (CBD), thought to be the major anticonvulsant that helps people with multiple sclerosis;[45] and cannabichromene (CBC), an anti-inflammatory which may contribute to the pain-killing effect of cannabis.[46]

Regulation in Canada

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.[19]

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 regulated sources of cannabis for researchers until August 2016 when licenses were provided to growers for supplies of medical marijuana.[47] Although cannabis is legalized for medical uses in half 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.[48]

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.[49] A 2015 review confirmed that medical marijuana was effective for treating spasticity and chronic pain, but caused numerous short-lasting adverse events, such as euphoria and dizziness.[50]

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.[49][50]
  • 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.[49]
  • 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[49]

Neurodegenerative disorders

  • Huntington disease. No reliable conclusions 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[49]
  • Parkinson's disease. Based on a single study, oral CBD extract was rated probably ineffective in treating levodopa-induced dyskinesia in Parkinson's disease.[49]
  • 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.[51]

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.[49]
  • Cervical dystonia. Insufficient data was available to assess the effectiveness of oral cannabis extract of THC in treating cervical dystonia.[49]
  • Epilepsy. Data was considered insufficient to judge the utility of cannabis products in reducing seizure frequency or severity.[49]

See also

References

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External links

11-Hydroxy-THC

11-Hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC), usually referred to as 11-hydroxy-THC, is the main active metabolite of tetrahydrocannabinol (THC), which is formed in the body after decarboxylated cannabis is consumed.Fresh cannabis contains tetrahydrocannabinolic acid (THCA), which is converted into THC after heating and then metabolized by the body into 11-hydroxy-THC and then into 11-nor-9-carboxy-THC; both compounds can be glucuronidated and mainly excreted into urine. Both compounds, along with THC, are assayed in blood tests.

11-Nor-9-carboxy-THC

11-Nor-9-carboxy-Δ9-tetrahydrocannabinol (11-COOH-THC or THC-COOH), often referred to as 11-nor-9-carboxy-THC or THC-11-oic acid, is the main secondary metabolite of tetrahydrocannabinol (THC), which is formed in the body after cannabis is consumed.

Cannabidiol

Cannabidiol (CBD) is a phytocannabinoid discovered in 1940. It is one of some 113 identified cannabinoids in cannabis plants and accounts for up to 40% of the plant's extract. In 2018, clinical research on cannabidiol included preliminary studies of anxiety, cognition, movement disorders, and pain.Cannabidiol can be taken into the body in multiple ways, including by inhalation of cannabis smoke or vapor, as an aerosol spray into the cheek, and by mouth. It may be supplied as CBD oil containing only CBD as the active ingredient (no included tetrahydrocannabinol [THC] or terpenes), a full-plant CBD-dominant hemp extract oil, capsules, dried cannabis, or as a prescription liquid solution. CBD does not have the same psychoactivity as THC, and may change the effects of THC on the body if both are present. As of 2018, the mechanism of action for its biological effects has not been determined.In the United States, the cannabidiol drug Epidiolex was approved by the Food and Drug Administration in 2018 for treatment of two epilepsy disorders. The side effects of long-term use of the drug include somnolence, decreased appetite, diarrhea, fatigue, malaise, weakness, and sleeping problems. The legality of the sale of CBD varies by jurisdiction.

Cannabinoid

A cannabinoid is one of a class of diverse chemical compounds that acts on cannabinoid receptors, also known as the endocannabinoid system in cells that alter neurotransmitter release in the brain. Ligands for these receptor proteins include the endocannabinoids produced naturally in the body by animals; phytocannabinoids, found in cannabis and some other plants; and synthetic cannabinoids, manufactured artificially. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis. Cannabidiol (CBD) is another major constituent of the plant. There are at least 113 different cannabinoids isolated from cannabis, exhibiting varied effects.Synthetic cannabinoids encompass a variety of distinct chemical classes: the classical cannabinoids structurally related to THC, the nonclassical cannabinoids (cannabimimetics) including the aminoalkylindoles, 1,5-diarylpyrazoles, quinolines, and arylsulfonamides as well as eicosanoids related to endocannabinoids.

Cannabinol

Cannabinol (CBN) is a mildly psychoactive cannabinoid found only in trace amounts in Cannabis, and is mostly found in aged Cannabis. Pharmacologically relevant quantities are formed as a metabolite of tetrahydrocannabinol (THC). CBN acts as a partial agonist at the CB1 receptors, but has a higher affinity to CB2 receptors; however, it has lower affinities relative to THC. Degraded or oxidized cannabis products, such as low-quality baled cannabis and traditionally produced hashish, are high in CBN.Unlike other cannabinoids, CBN does not stem directly from cannabigerol (CBG) or cannabigerolic acid (CBGA), but rather is the degraded product of tetrahydrocannabinolic acid (THCA). If cannabis is exposed to air or ultraviolet light (for example, in sunlight) for a prolonged period of time, THCA will convert to cannabinolic acid (CBNA). CBN is then formed by decarboxylation of CBNA.

Cannabis in Iowa

Cannabis in Iowa state refers to medical cannabis in Iowa. Only cannabidiol (CBD) and 3% or less of delta-9-tetrahydrocannabinol(THC) oil are legal from licensed dispensaries in the state.

In Iowa, possession of even small amounts is a misdemeanor crime, but in contrast with some other states, even repeated arrests for possession, and for any quantity, provided it is personal and not for distribution, are misdemeanors and not felonies. However, CBD oil is permitted for only a limited number of medical conditions.

Cannabis indica

Cannabis indica is an annual plant in the Cannabaceae family. It is a putative species of the genus Cannabis. Whether it and Cannabis sativa are truly separate species is a matter of debate. The Cannabis indica plant is cultivated for many purposes; for example, the plant fibers can be converted into cloth. Cannabis indica produces large amounts of tetrahydrocannabinol (THC). The higher concentrations of THC provide euphoric and intoxicating effects making it popular for use both as a recreational and medicinal drug.

Dronabinol

The International Nonproprietary Name Dronabinol, sold as trade names Marinol and Syndros, is an appetite stimulant, antiemetic, and sleep apnea reliever. It is approved by the FDA as safe and effective for HIV/AIDS-induced anorexia and chemotherapy-induced nausea and vomiting only.The pharmaceutical formulation, an oily resin in capsules, is available by prescription in the US, Canada, Germany, Australia and New Zealand. Possible exceptions for off label use may be in US states passing laws reserving the right to differ from particular FDA regulations.Dronabinol is the principal psychoactive constituent enantiomer form, (−)-trans-Δ⁹-tetrahydrocannabinol, found in cannabis. Dronabinol does not include the many other tetrahydrocannabinol (THC) isomers of cannabinoid.

Hash oil

Hash oil, also known as honey oil or cannabis oil, is an oleoresin obtained by the extraction of cannabis or hashish. It is a concentrated form of cannabis extracts containing many of its resins and terpenes – in particular, tetrahydrocannabinol (THC), cannabidiol (CBD), and other cannabinoids. There are various extraction methods, most involving a solvent, such as butane or ethanol. Hash oil is usually consumed by smoking, vaporizing or eating. Hash oil may be sold in cartridges used with pen vaporizers. Preparations of hash oil may be solid or colloidal depending on both production method and temperature and are usually identified by their appearance or characteristics. Color most commonly ranges from transparent golden or light brown, to tan or black. Cannabis retailers in California have reported about 40% of their sales are from cannabis oils.Hash oil is an extracted cannabis product that may use any part of the plant, with minimal or no residual solvent. It is generally thought to be indistinct from traditional hashish, according to the 1961 UN Single Convention on Narcotic Drugs (Schedule I and IV), as it is "the separated resin, whether crude or purified, obtained from the cannabis plant".

Hemp oil

Hemp oil (hemp seed oil or hempseed oil) is obtained by pressing hemp seeds. Cold pressed, unrefined hemp oil is dark to clear light green in color, with a nutty flavor. The darker the color, the grassier the flavour. It should not be confused with hash oil, a tetrahydrocannabinol-containing oil made from the Cannabis flower.

Jake Freeman

Thomas Jacob Freeman (born November 5, 1980) is an American hammer thrower. He competed at the 2009 World Outdoor championships.A native of East Greenwich, Rhode Island, Freeman attended Bishop Hendricken High School. He was Track and Field News "High School Athlete of the Year" in 2000.In 2011, Freeman was suspended by the USA Track & Field due a positive test for tetrahydrocannabinol. It was Freeman's second doping violation, having previously tested positive for tetrahydrocannabinol in 2009.

Nabiximols

Nabiximols (USAN, trade name Sativex) is a specific Cannabis extract that was approved in 2010 as a botanical drug in the United Kingdom despite lack of convincing evidence of effectiveness (see below). Nabiximols is sold as a mouth spray intended to alleviate neuropathic pain, spasticity, overactive bladder, and other symptoms of multiple sclerosis; it was developed by the UK company GW Pharmaceuticals. The drug is a pharmaceutical product standardized in composition, formulation, and dose. Its principal active cannabinoid components are the cannabinoids: tetrahydrocannabinol (THC) and cannabidiol (CBD). Each spray delivers a dose of 2.7 mg THC and 2.5 mg CBD.

In May 2003 GW Pharmaceuticals and Bayer entered into an exclusive marketing agreement for GW's cannabis-based medicinal extract product, to be marketed under the brand name Sativex. "Bayer has obtained exclusive rights to market Sativex in the UK. In addition, Bayer has the option for a limited period to negotiate the marketing rights in other countries in European Union and selected other countries around the world."

In April 2011, GW licensed to Novartis the rights to commercialise nabiximols in Asia (excluding China and Japan), Africa and the Middle East (excluding Israel).

O-1125

O-1125 (3-(1,1-dimethylhexyl-6-dimethylcarboxamide)-Δ8-tetrahydrocannabinol) is a research chemical which is a cannabinoid derivative. It has analgesic effects and is used in scientific research. It is a potent CB1 full agonist with a Ki of 1.16 nM.

THC-O-phosphate

THC-O-phosphate is a water-soluble organophosphate ester derivative of tetrahydrocannabinol (THC), which functions as a metabolic prodrug for THC itself. It was invented in 1978 in an attempt to get around the poor water solubility of THC and make it easier to inject for the purposes of animal research into its pharmacology and mechanism of action. The main disadvantage of THC phosphate ester is the slow rate of hydrolysis of the ester link, resulting in delayed onset of action and lower potency than the parent drug. Pharmacologically, it parallels the action of psilocybin as a metabolic prodrug for psilocin.

THC phosphate ester is made by reacting THC with phosphoryl chloride using pyridine as a solvent, following by quenching with water to produce THC phosphate ester. In the original research the less active but more stable isomer Δ8-THC was used, but the same reaction scheme could be used to make the phosphate ester of the more active isomer Δ9-THC.

Tetrahydrocannabinol-C4

Tetrahydrocannabinol-C4, also known as THC-C4 and butyl-THC, is a homologue of tetrahydrocannabinol (THC), the active component of cannabis. They are only different by the pentyl side chain being replaced by a butyl side chain. It is unknown whether THC-C4 is an agonist, partial agonist, or antagonist at the cannabinoid receptors. The propyl analog, THCV, is a cannabinoid receptor type 1 and cannabinoid receptor type 2 antagonist, while THC is a CB1 agonist. THC-C4 has rarely been isolated from cannabis samples, but appears to be less commonly present than THC or THCV. It is metabolised in a similar manner to THC. Similarly to THC, it has 7 double bond isomers and 30 stereoisomers.It is not scheduled by Convention on Psychotropic Substances.

Tetrahydrocannabinolic acid

Tetrahydrocannabinolic acid (THCA, 2-COOH-THC; conjugate base tetrahydrocannabinolate) is a precursor of tetrahydrocannabinol (THC), the active component of cannabis.THCA is found in variable quantities in fresh, undried cannabis, but is progressively decarboxylated to THC with drying, and especially under intense heating such as when cannabis is smoked or cooked into cannabis edibles. THCA is often the majority constituent in cannabis resin concentrates, such as hashish and hash oil, when prepared from high-THC cannabis plant material, frequently comprising between 50% and 90% by weight.

Tetrahydrocannabinolic acid synthase

Tetrahydrocannabinolic acid (THCA) synthase (full name Δ1-tetrahydrocannabinolic acid synthase) is an enzyme responsible for catalyzing the formation of THCA from cannabigerolic acid (CBGA). THCA is the direct precursor of tetrahydrocannabinol (THC), the principal psychoactive component of cannabis, which is produced from various strains of Cannabis sativa. Therefore, THCA synthase is considered to be a key enzyme controlling cannabis psychoactivity. Polymorphisms of THCA synthase result in varying levels of THC in Cannabis plants, resulting in "drug-type" and "fiber-type" C. sativa varieties.

Tetrahydrocannabivarin

Tetrahydrocannabivarin (THCV, THV) is a homologue of tetrahydrocannabinol (THC) having a propyl (3-carbon) side chain instead of a pentyl (5-carbon) group on the molecule, which makes it produce very different effects from THC.

Vaporizer (inhalation device)

A vaporizer or vaporiser, colloquially known as a vape, is a device used to vaporize substances for inhalation. Plant substances can be used, commonly cannabis, tobacco, or other herbs or blends. However, they can also be filled with a combination propylene glycol, glycerin, and drugs such as nicotine (e.g. extract from tobacco) or tetrahydrocannabinol as a liquid solution.

Vaporizers contain various forms of extraction chambers including straight bore, venturi, or sequential venturi, and are made of materials such as metal or glass. The extracted vapor may be collected in an inflatable bag, or inhaled directly through a hose or pipe. When used properly, cooler temperatures due to lack of combustion result in significantly more efficient extraction of the ingredients. Hence, the irritating and harmful effects of smoking are heavily reduced, as is its secondhand smoke.

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