Tetrahydrocannabinol (THC) is the principal psychoactive constituent of

cannabis ''Cannabis'' () is a genus of flowering plants in the family Cannabaceae. The number of species within the genus is disputed. Three species may be recognized: '' Cannabis sativa'', '' C. indica'', and '' C. ruderalis''. Alternative ...

and one of at least 113 total cannabinoids identified on the plant. Although the

chemical formula In chemistry, a chemical formula is a way of presenting information about the chemical proportions of atoms that constitute a particular chemical compound or molecule, using chemical element symbols, numbers, and sometimes also other symbols, ...

for THC (C₂₁H₃₀O₂) describes multiple

isomers In chemistry, isomers are molecules or polyatomic ions with identical molecular formulae – that is, same number of atoms of each element – but distinct arrangements of atoms in space. Isomerism is existence or possibility of isomers. ...

, the term ''THC'' usually refers to the Delta-9-THC isomer with chemical name (−)-''trans''-Δ⁹-tetrahydrocannabinol. THC is a

lipid Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids in ...

found in

and, like most pharmacologically active secondary metabolites of plants, it is assumed to be involved in the plant's evolutionary adaptation, putatively against insect predation,

ultraviolet light Ultraviolet (UV) is a form of electromagnetic radiation with wavelength from 10 nm (with a corresponding frequency around 30 PHz) to 400 nm (750 THz), shorter than that of visible light, but longer than X-rays. UV radiatio ...

, and

environmental stress Stress, either physiological, biological or psychological, is an organism's response to a stressor such as an environmental condition. Stress is the body's method of reacting to a condition such as a threat, challenge or physical and psyc ...

. THC was first discovered and isolated by Israeli chemist Raphael Mechoulam in Israel in 1964. It was found that, when smoked, THC is absorbed into the bloodstream and travels to the brain, attaching itself to endocannabinoid receptors located in the

cerebral cortex The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. The cerebral cortex mostly consists of the six-layered neocortex, with just 10% consisting o ...

, cerebellum, and

basal ganglia The basal ganglia (BG), or basal nuclei, are a group of subcortical nuclei, of varied origin, in the brains of vertebrates. In humans, and some primates, there are some differences, mainly in the division of the globus pallidus into an ext ...

. These are the parts of the brain responsible for thinking, memory, pleasure, coordination and movement. 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 Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemother ...

under the trade names Marinol and Syndros. The

pharmaceutical formulation Pharmaceutical formulation, in pharmaceutics, is the process in which different chemical substances, including the active drug, are combined to produce a final medicinal product. The word ''formulation'' is often used in a way that includes dosage ...

dronabinol is an oily and viscous

resin In polymer chemistry and materials science, resin is a solid or highly viscous substance of plant or synthetic origin that is typically convertible into polymers. Resins are usually mixtures of organic compounds. This article focuses on nat ...

provided in capsules available by prescription in the United States, Canada, Germany, and New Zealand.

Medical uses

THC is an active ingredient in Nabiximols, a specific extract of ''

Cannabis ''Cannabis'' () is a genus of flowering plants in the family Cannabaceae. The number of species within the genus is disputed. Three species may be recognized: '' Cannabis sativa'', '' C. indica'', and '' C. ruderalis''. Alternative ...

'' that was approved as a botanical drug in the

United Kingdom The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom (UK) or Britain, is a country in Europe, off the north-western coast of the continental mainland. It comprises England, Scotland, Wales and ...

in 2010 as a mouth spray for people with multiple sclerosis to alleviate neuropathic pain, spasticity,

overactive bladder Overactive bladder (OAB) is a condition where there is a frequent feeling of needing to urinate to a degree that it negatively affects a person's life. The frequent need to urinate may occur during the day, at night, or both. If there is loss ...

, and other symptoms. Nabiximols (as Sativex) is available as a prescription drug in Canada. In 2021, Nabiximols was approved for medical use in

Ukraine Ukraine ( uk, Україна, Ukraïna, ) is a country in Eastern Europe. It is the second-largest European country after Russia, which it borders to the east and northeast. Ukraine covers approximately . Prior to the ongoing Russian inva ...

. As of 2022, 37 states, three territories, and the

District of Columbia ) , image_skyline = , image_caption = Clockwise from top left: the Washington Monument and Lincoln Memorial on the National Mall, United States Capitol, Logan Circle (Washington, D.C.), Logan Circle, Jefferson Memoria ...

in the United States allow

medical use of cannabis Medical cannabis, or medical marijuana (MMJ), is cannabis and cannabinoids that are prescribed by physicians for their patients. The use of cannabis as medicine has not been rigorously tested due to production and governmental restriction ...

(in which THC is the primary psychoactive component), with the exception of Idaho, Iowa, Wyoming, Nebraska, Wisconsin, Indiana, Kentucky, Tennessee, Alabama, North Carolina, South Carolina, Georgia, and Florida. As of 2022, the U.S. federal government maintains cannabis as a schedule I controlled substance under law, while dronabinol is classified as Schedule III in capsule form (Marinol) and Schedule II in liquid oral form (Syndros).

Pharmacology

Mechanism of action

The actions of Delta-9-THC result from its

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. They may also be considered ligands which display both agonistic and antagonis ...

activity at the cannabinoid receptor CB₁ (K_i = 40.7 nM), located mainly in the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

, and the CB₂ receptor (K_i = 36 nM), mainly expressed in cells of the

immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...

. 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 Camp may refer to: Outdoor accommodation and recreation * Campsite or campground, a recreational outdoor sleeping and eating site * a temporary settlement for nomads * Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...

through inhibition of adenylate cyclase. The presence of these specialized cannabinoid receptors in the

brain A brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as Visual perception, vision. I ...

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 In the biological context of organisms' production of gene products, downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus. The complementary pr ...

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 Cytochrome P450 family 2 subfamily C member 9 (abbreviated CYP2C9) is an enzyme protein. The enzyme is involved in metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, the pro ...

, CYP2C19, CYP2D6, and CYP3A4. More than 55% of THC is excreted in the feces and ≈20% in the

urine Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excreted from the body through the urethra. Cellul ...

. 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 In chemistry, aromaticity is a chemical property of cyclic ( ring-shaped), ''typically'' planar (flat) molecular structures with pi bonds in resonance (those containing delocalized electrons) that gives increased stability compared to satur ...

terpenoids, THC has a very low

solubility In chemistry, solubility is the ability of a substance, the solute, to form a solution with another substance, the solvent. Insolubility is the opposite property, the inability of the solute to form such a solution. The extent of the solubi ...

in water, but good solubility in lipids and most organic

solvent A solvent (s) (from the Latin '' solvō'', "loosen, untie, solve") is a substance that dissolves a solute, resulting in a solution. A solvent is usually a liquid but can also be a solid, a gas, or a supercritical fluid. Water is a solvent for ...

s, specifically

hydrocarbon In organic chemistry, a hydrocarbon is an organic compound consisting entirely of hydrogen and carbon. Hydrocarbons are examples of group 14 hydrides. Hydrocarbons are generally colourless and hydrophobic, and their odors are usually weak or ...

s and alcohols.

Unknown lethal dose

The median lethal dose of THC in humans is not fully known as there is conflicting evidence. 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. A 2014 study gave the median lethal dose in humans at 30 mg/kg (2.1 grams THC for a person who weighs 70kg), observing cardiovascular death in otherwise healthy subjects. A different 1972 study gave the median lethal dose for intravenous THC in mice and rats at 30–40 mg/kg.

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 ''

'' plant, THC occurs mainly as tetrahydrocannabinolic acid (THCA, 2-COOH-THC). Geranyl pyrophosphate and

olivetolic acid Olivetolic acid is an organic compound that is an intermediate in the biosynthetic pathway of the cannabinoids in ''Cannabis sativa''. The ester dimer of olivetolic acid, anziaic acid, is found in lichen A lichen ( , ) is a composite or ...

react, catalysed by an

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...

to produce cannabigerolic acid, which is cyclized by the enzyme THC acid synthase to give THCA. Over time, or when heated, THCA is

decarboxylated Decarboxylation is a chemical reaction that removes a carboxyl group and releases carbon dioxide (CO2). Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain. The reverse process, which is ...

, producing THC. The pathway for THCA biosynthesis is similar to that which produces the bitter acid humulone in hops. It can also be produced in genetically modified

yeast Yeasts are eukaryotic, single-celled microorganisms classified as members of the fungus kingdom. The first yeast originated hundreds of millions of years ago, and at least 1,500 species are currently recognized. They are estimated to constit ...

. :

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 An immunoassay (IA) is a biochemical test that measures the presence or concentration of a macromolecule or a small molecule in a solution through the use of an antibody (usually) or an antigen (sometimes). The molecule detected by the immunoa ...

and

chromatographic In chemical analysis, chromatography is a laboratory technique for the separation of a mixture into its components. The mixture is dissolved in a fluid solvent (gas or liquid) called the ''mobile phase'', which carries it through a system (a ...

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 Law enforcement is the activity of some members of government who act in an organized manner to enforce the law by discovering, deterring, rehabilitating, or punishing people who violate the rules and norms governing that society. The term ...

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 Israel (; he, יִשְׂרָאֵל, ; ar, إِسْرَائِيل, ), officially the State of Israel ( he, מְדִינַת יִשְׂרָאֵל, label=none, translit=Medīnat Yīsrāʾēl; ), is a country in Western Asia. It is situated ...

. In 2003, the

World Health Organization The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level o ...

Expert Committee on Drug Dependence recommended transferring THC to Schedule IV of the Convention, citing its medical uses and low abuse and addiction potential. The

Agriculture Improvement Act of 2018 The 2018 farm bill or Agriculture Improvement Act of 2018 is an enacted United States farm bill that reauthorized $867 billion for many expenditures approved in the prior farm bill (the Agricultural Act of 2014). The bill was passed by the Sena ...

allows any hemp-derived product not exceeding 0.3% Δ-9 THC to be sold legally in the US. Since the law counted only Δ-9 THC, Δ-8 THC was considered legal to sell under the farm bill and is widely available online.

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 Cannabichromene (CBC), also called cannabichrome, cannanbichromene, pentylcannabichromene or cannabinochromene, is an anti-inflammatory which may contribute to the pain-killing effect of cannabis. It is one of the hundreds of cannabinoids found i ...

(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 The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country Continental United States, primarily located in North America. It consists of 50 U.S. state, states, a Washington, D.C., ...

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.

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. * ''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. * ''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

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

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. * '' Cervical dystonia''. Insufficient data was available to assess the effectiveness of oral cannabis extract of THC in treating cervical dystonia.

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.

References

External links

U.S. National Library of Medicine: Drug Information Portal – Tetrahydrocannabinol
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Pharmacodynamics Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or combinations of organisms ...

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