Tetrahydrocannabinol ( THC) is a cannabinoid found in cannabis.
Medical uses
THC, referred to as
dronabinol in the pharmaceutical context, is approved in the United States as a capsule or solution to relieve chemotherapy-induced nausea and vomiting and HIV/AIDS-induced anorexia.
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.[Multiple Sclerosis Trust. October 2014 Sativex (nabiximols) – factsheet ] Nabiximols (as Sativex) is available as a prescription drug in Canada.
Side effects
of THC include red eyes,
Xerostomia,
sedation, short-term memory impairment, difficulty concentrating,
ataxia, increased appetite,
anxiety,
paranoia,
psychosis (i.e.,
Hallucination,
Delusion), decreased motivation, and time dilation, among others.
Chronic usage of THC may result in cannabinoid hyperemesis syndrome (CHS), a condition characterized by cyclic nausea, vomiting, and abdominal pain that may persist for months to years after discontinuation.
Overdose
The median lethal dose of THC in humans is not fully known as there is conflicting evidence. A 1972 study gave up to 90 mg/kg of THC to dogs and monkeys without any lethal effects. Some rats died within 72 hours after a dose of up to 36 mg/kg.
A 2014 case study based on the toxicology reports and relative testimony in two separate cases gave the median lethal dose in humans at 30 mg/kg (2.1 grams THC for a person who weighs 70 kg; 154 lb; 11 stone), observing
cardiovascular death in the one otherwise healthy subject of the two cases studied.
A different 1972 study gave the median lethal dose for intravenous THC in mice and rats at 30–40 mg/kg.
A 2020 fact sheet published by the U.S. Drug Enforcement Administration stated that "no deaths from overdose of marijuana have been reported."
Interactions
Formal
drug interaction studies with THC have not been conducted and are limited.
The elimination half-life of the
barbiturate pentobarbital has been found to increase by four hours when concomitantly administered with oral THC.
Pharmacology
Mechanism of action
The actions of Δ
9-THC result from its
partial agonist activity at the cannabinoid receptor CB
1 (K
i = 40.7 nM
), located mainly in the central nervous system, and the CB
2 receptor (K
i = 36 nM
), mainly expressed in cells of the
immune system.
The psychoactive effects of THC are primarily mediated by the activation of (mostly G-coupled) 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
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 . 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.
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.
Pharmacokinetics
Absorption
With oral administration of a single dose, THC is almost completely absorbed by the gastrointestinal tract.
However, due to first-pass metabolism in the
liver and the high
lipid solubility of THC, only about 5 to 20% reaches circulation.
Following oral administration, concentrations of THC and its major active metabolite 11-hydroxy-THC (11-OH-THC) peak after 0.5 to 4hours, with median time to peak of 1.0 to 2.5hours at different doses.
In some cases, peak levels may not occur for as long as 6hours.
Concentrations of THC and 11-hydroxy-THC in the circulation are approximately equal with oral administration.
There is a slight increase in dose proportionality in terms of peak and area-under-the-curve levels of THC with increasing oral doses over a range of 2.5 to 10mg.
A high-fat meal delays time to peak concentrations of oral THC by 4hours on average and increases area-under-the-curve exposure by 2.9-fold, but peak concentrations are not significantly altered.
A high-fat meal additionally increases absorption of THC via the
lymphatic system and allows it to bypass first-pass metabolism.
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.
The bioavailability of THC when smoking or inhaling is approximately 25%, with a range of 2% to 56% (although most commonly between 10 and 35%).
Transdermal administration of THC is limited by its extreme hydrophobicity.
Distribution
The volume of distribution of THC is large and is approximately 10L/kg (range 4–14L/kg), which is due to its high lipid solubility.
The plasma protein binding of THC and its
is approximately 95 to 99%, with THC bound mainly to
and to a lesser extent albumin.
THC is rapidly distributed into well-vascularized organs such as
lung,
heart,
brain, and
liver, and is subsequently equilibrated into less vascularized tissue.
It is extensively distributed into and sequestered by
adipose tissue due to its high lipid solubility, from which it is slowly released.
THC is able to cross the
placenta and is excreted in human
breast milk.
Metabolism
The
metabolism of THC occurs mainly in the
liver by cytochrome P450
CYP2C9, CYP2C19, and CYP3A4.
CYP2C9 and CYP3A4 are the primary enzymes involving in metabolizing THC.
research has found that oral THC exposure is 2- to 3-fold greater in people with genetic variants associated with reduced CYP2C9 function.
When taken orally, THC undergoes extensive first-pass metabolism in the liver, primarily via
hydroxylation.
The principal active metabolite of THC is 11-hydroxy-THC (11-OH-THC), which is formed by CYP2C9 and is psychoactive similarly to THC.
This metabolite is further
oxidation to 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.
Elimination
More than 55% of THC is
excretion 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.
Estimates of the elimination half-life of THC are variable.
List of related compounds
|
|
| an analog of THC |
| an analog of THC |
a novel synthetic cannabinoid analog (neocannabinoid) that mimics THC. |
| an analog of THC |
| an analog of THC and dimethylheptylpyran |
| a semi-synthetic derivative of THC |
| a hydrogenated derivative of THC |
| a synthetic derivative of THC |
| the hemisuccinate ester of THC that's water soluble and has rectal bioavailability to reach CNS |
| the acetate ester of THC |
| a water-soluble organophosphate ester derivative |
| a homologue of THC |
| a hexyl homologue of THC |
| a homologue of THC and THCV |
| a homologue of THC |
| the heptyl homologue of THC |
| a homologue of THC |
| an isomer of THC |
| a synthetic isomer of THC |
| a synthetic isomer of THC |
| a synthetic isomer of THC |
| a double bond isomer of THC |
| a positional isomer of THC |
| a minor active metabolite of THC |
| an active metabolite of THC |
| an active metabolite of THC |
| the main active metabolite of THC |
| an active metabolite of THC and a metabolite of the trace cannabinoid hexahydrocannabinol (HHC) |
| the main secondary metabolite of THC |
| the biosynthetic precursor for THC |
| a synthetic prodrug of THC |
Chemistry
THC is a molecule that combines polyketides (derived from
acetyl CoA) and terpenoids (derived from isoprenylpyrophosphate). It is hydrophobic with very low
solubility in water, but good solubility in many
.
As a
phytochemical, THC is assumed to be involved in the plant's evolutionary
adaptation against
predation, ultraviolet light, and environmental stress.
The total synthesis of THC was reported in 1965. that procedure called for the intramolecular alkyl lithium attack on a starting Carbonyl group 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). 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
decarboxylation, 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.
History
Cannabidiol was isolated and identified from
Cannabis sativa in 1940 by
Roger Adams who was also the first to document the synthesis of THC (both Delta-9-THC and Delta-8-THC) from the acid-based cyclization of CBD in 1942.
THC was first isolated from Cannabis by Raphael Mechoulam and
Yehiel Gaoni in 1964.
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
Analgesic effect of 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
immunoassay and
chromatographic techniques as part of a drug use testing program or in a forensic investigation.
There is ongoing research to create devices capable of detecting THC in breath.
Regulation
THC, along with its double bond isomers and their
Stereoisomerism,
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.
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 the United States
As of 2023, 38 states, four territories, and the District of Columbia 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.
As of 2022, the 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).
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
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.
Multiple sclerosis symptoms
-
Spasticity. Based on the results of three high-quality trials and five 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 four high-quality trials and four 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.
See also
-
Cannabinoids
-
Anandamide, 2-Arachidonoylglycerol, endogenous cannabinoid agonists
-
Cannabidiol (CBD)
-
Cannabinol (CBN), a metabolite of THC
-
Delta-8-THC, one of the isomers of THC
-
HU-210, WIN 55,212-2, JWH-133, synthetic cannabinoid agonists (neocannabinoids)
-
Hashish
-
List of investigational analgesics
-
Medical cannabis
-
Dronabinol, the name of THC-based pharmaceutical (INN)
-
Epidiolex (prescription form of purified cannabidiol derived from hemp used for treating some rare neurological diseases)
-
Sativex
-
Effects of cannabis
-
War on Drugs
-
Vaping-associated pulmonary injury
-
Cannabinoid hyperemesis syndrome (CHS)
External links
