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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, 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.[16] The pharmaceutical formulation dronabinol is an oily and viscous resin provided in capsules available by prescription in the United States, Canada, Germany, and New Zealand.


Delta-9-tetrahydrocannabinol, better known to cannabis users simply as THC, is the marijuana plant's primary component for causing psychoactive effects – in other words, the part of the plant responsible for getting you high. THC was first discovered and isolated by Bulgarian-born chemist Raphael Mechoulam in Israel in 1964. It was found that, when you smoke, tetrahydrocannabinol is absorbed into the bloodstream and travels to the brain, attaching itself to the naturally-occurring cannabinoid receptors – known as the endocannabinoid system – located in the cerebral cortex, cerebellum and basal ganglia. These are the parts of the brain responsible for thinking, memory, pleasure, coordination and movement[17]

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.[18][19] Nabiximols (as Sativex) is available as a prescription drug in Canada.[20]

Pharmacology

Mechanism of action

The actions of THC result from its partial agonist activity at the cannabinoid receptor CB1 (Ki = 10 nM[21]), located mainly in the central nervous system, and the CB2 receptor (Ki = 24 nM[21]), mainly expressed in cells of the immune system.[22] 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.[23]

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.[24] THC is a lipophilic molecule[25] and may bind non-specifically to a variety of entities in the brain and body, such as adipose tissue (fat).[26][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.[24] 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.[22]

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, CYP2D6, and CYP3A4.[29][30] 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 11-OH-THC and free THC-COOH. In the feces, mainly 11-OH-THC was detected.[31]

Physical and chemical properties

Discovery and structure identification

Cannabidiol was isolated and identified from Cannabis sativa in 1940,[32] and THC was isolated and its structure elucidated by synthesis in 1964.[33][34]

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.[8]

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.[35][third-party source needed]

Biosynthesis

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,[36] 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.[37][38]

No known lethal dose

The Median lethal dose of THC in humans is not known. A 1972 study gave up to 9000 mg/kg of THC to dogs and monkeys without any lethal effects. Some rats died within 72 hours after a dose of up to 3600 mg/kg.[39]

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.[40][41][42]

Detection in breath

Recreational use of cannabis is legal in many parts of North America, increasing the demand for THC monitoring methods in both personal and law enforcement uses.[43] Breath sampling as a noninvasive method is in development to detect THC, which is difficult to quantify in breath samples.[43] Scientists and industry are commercializing various types of breath analyzers to monitor THC in breath.[44]

History

THC was first isolated and elucidated in 1969 by Raphael Mechoulam and Yechiel Gaoni at the Weizmann Institute of Science in Israel.[33][45][46]

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 and addiction potential.[47] In 2018 the federal farm bill was passed allowing any hemp derived product not exceeding 0.3% Δ-9 THC to be sold legally. Since the law counted only Δ-9 THC, Δ-8 THC was considered legal to sell under the farm bill and was sold online. After August 21st, 2020, all forms of THC were deemed illegal above 0.3% under the CSA (Controlled Substances Act), according to the DEA. The ruling is currently being debated[by whom?] and companies that formerly sold forms of THC are lobbying to keep other forms of THC (other than delta-9) legal for commerce. [48]

Society and culture

Mechanism of action

The actions of THC result from its partial agonist activity at the cannabinoid receptor CB1 (Ki = 10 nM[21]), located mainly in the central nervous system, and the CB2 receptor (Ki = 24 nM[21]), mainly expressed in cells of the immune system.[22] 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.[23]

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.[24] THC is a lipophilic molecule[25] and may bind non-specifically to a variety of entities in the brain and body, such as adipose tissue (fat).[26][27]

Due to its partial agonistic activity, THC appears to result in greater downregulation of cannabinoid receptors than endocannabinoids, further limiting its efficac

The actions of THC result from its partial agonist activity at the cannabinoid receptor CB1 (Ki = 10 nM[21]), located mainly in the central nervous system, and the CB2 receptor (Ki = 24 nM[21]), mainly expressed in cells of the immune system.[22] 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.[23]

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.[24] THC is a lipophilic molecule[25] and may bind non-specifically to a variety of entities in the brain and body, such as adipose tissue (fat).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.[24] THC is a lipophilic molecule[25] and may bind non-specifically to a variety of entities in the brain and body, such as adipose tissue (fat).[26][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.[24] 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.[22]

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, CYP2D6, and CYP3A4.[29][30] 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 11-OH-THC and free THC-COOH. In the feces, mainly 11-OH-THC was detected.[31]

Physical and chemical properties

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

Total synthesis

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,[36] 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.[37][38]

No known lethal dose

The Median lethal dose of THC in humans is not known. A 1972 study gave up to 9000 mg/kg of THC to dogs and monkeys without any lethal effects. Some rats died within 72 hours after a dose of up to 3600 mg/kg.[39]

Detection in body fluids