Tetrahydrocannabinol

Tetrahydrocannabinol (THC) is one of at least 113 cannabinoids identified in cannabis. THC is the principal psychoactive constituent of cannabis. Although the chemical formula for THC (C21H30O2) describes multiple isomers, the term "THC" usually refers to the Delta-9-THC isomer with chemical name (−)-"trans"-Δ⁹-tetrahydrocannabinol. Like most pharmacologically active secondary metabolites of plants, THC is a lipid found in cannabis, assumed to be involved in the plant's evolutionary adaptation, putatively against insect predation, ultraviolet light, and environmental stress.
THC, along with its double bond isomers and their stereoisomers, 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. 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 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. 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 (Δ9-THC), better known to cannabis users simply as THC, is the marijuana plant's primary component for causing psychoactive effects. THC was first discovered and isolated by Bulgarian-born chemist Raphael Mechoulam in Israel in 1964. It was found that, when smoked, tetrahydrocannabinol is absorbed into the bloodstream and travels to the brain, attaching itself to the naturally-occurring endocannabinoid receptors located in the cerebral cortex, cerebellum, and basal ganglia. These are the parts of the brain responsible for thinking, memory, pleasure, coordination and movement.
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. Nabiximols (as Sativex) is available as a prescription drug in Canada. In 2021, Nabiximols was approved for medical use in Ukraine.
Pharmacology.
Mechanism of action.
The actions of THC result from its partial agonist activity at the cannabinoid receptor CB1 (Ki = 10 nM), located mainly in the central nervous system, and the CB2 receptor (Ki = 24 nM), mainly expressed in cells of the immune system. 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. 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 is a lipophilic molecule and may bind non-specifically to a variety of entities in the brain and body, such as adipose tissue (fat). THC, as well as other cannabinoids that contain a phenol group, possess mild antioxidant activity sufficient to protect neurons against oxidative stress, such as that produced by glutamate-induced excitotoxicity.
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.
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 animals, more than 100 metabolites could be identified, but 11-OH-THC and THC-COOH are the dominating metabolites. Metabolism occurs mainly in the liver by cytochrome P450 enzymes CYP2C9, CYP2C19, CYP2D6, and CYP3A4. 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.
Physical and chemical properties.
Discovery and structure identification.
Cannabidiol was isolated and identified from "Cannabis sativa" in 1940, and THC was isolated and its structure elucidated by synthesis in 1964.
Solubility.
As with many aromatic terpenoids, THC has a very low solubility in water, but good solubility in most organic solvents, specifically hydrocarbons and alcohols.
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.
Biosynthesis.
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, 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.
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.
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.
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. Breath sampling as a noninvasive method is in development to detect THC, which is difficult to quantify in breath samples. Scientists and industry are commercializing various types of breath analyzers to monitor THC in breath.
History.
THC was first isolated and elucidated in 1969 by Raphael Mechoulam and Yechiel Gaoni at the Weizmann Institute of Science in Israel.<ref name="doi10.1021/ja01062a046"></ref>
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. 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 and companies that formerly sold forms of THC are lobbying to keep other forms of THC (other than delta-9) legal for commerce. 
Society and culture.
Comparisons with medical cannabis.
Female cannabis plants contain at least 113 cannabinoids, including cannabidiol (CBD), thought to be the major anticonvulsant that helps people with multiple sclerosis; and cannabichromene (CBC), an anti-inflammatory which may contribute to the pain-killing effect of cannabis.
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.
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. 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.
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. 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.