Tetrahydrocannabinol (THC) refers to a psychotropic cannabinoid (dronabinol, trade name Marinol) and is the principal psychoactive constituent of cannabis. Its chemical name is (–)-trans-Δ⁹-tetrahydrocannabinol and the term "THC" is used to refer to isomers as well. The pharmaceutical formulation dronabinol is available by prescription in the U.S, Canada, Germany and New Zealand.
Like most pharmacologically-active secondary metabolites of plants, THC in Cannabis is assumed to be involved in self-defense, perhaps against herbivores. THC also possesses high UV-B (280–315 nm) absorption properties, which, it has been speculated, could protect the plant from harmful UV radiation exposure.
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 passed by the US Congress in 1970.
Dronabinol is the INN for a pure isomer of THC, (–)-trans-Δ⁹-tetrahydrocannabinol, which is the main isomer found in cannabis. It is used to treat anorexia in people with HIV/AIDS as well as for refractory nausea and vomiting in people undergoing chemotherapy. It is safe and effective for these uses.
THC is also 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.
An overdose of dronabinol usually presents with lethargy, decreased motor coordination, slurred speech, and postural hypotension. Non-fatal overdoses have occurred.
A meta analysis of clinical trials conducted using standardized cannabis extracts or THC conducted by the American Academy of Neurology found that of 1619 persons treated with cannabis products (including some treated with smoked cannabis and nabiximols), 6.9% discontinued due to side effects, compared to 2.2% of 1,118 treated with placebo. Detailed information regarding side effects was not available from all trials, but nausea, increased weakness, behavioral or mood changes, suicidal ideation, hallucinations, dizziness, and vasovagal symptoms, fatigue, and feelings of intoxication were each described as side effects in at least two trials. There was a single death rated by the investigator as "possibly related" to treatment. This person had a seizure followed by aspiration pneumonia. The paper does not describe whether this was one of the subjects from the epilepsy trials.), located mainly in the central nervous system, and the CB2 receptor (Ki=24nM 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 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. 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, similarly to cannabidiol, albeit less potently, is a positive allosteric modulator of the μ- and δ-opioid receptors.
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. Metabolism occurs mainly in the liver by cytochrome P450 enzymes CYP2C9, CYP2C19, 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 THC-COOH and free THC-COOH. In the feces, mainly 11-OH-THC was detected.
==Physical and chemical properties==
===Discovery and structure identification=== Early Discovery: Roger Adams isolated and identified cannabidiol from Cannabis sativa, showed its relationship to cannabinol, and tetrahydrocannabinol. THC was later studied by a team of researchers from Hebrew University Pharmacy School, who reported their work in 1964,
Stereoisomers include Δ9-Tetrahydrocannabinol (Δ9-THC) and isomers include Δ6a(10a)-THC, Δ6a-THC, Δ7-THC, Δ8-THC, Δ10-THC and Δ9(11)-THC.
===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.
===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.
=== 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.
== History ==
THC was first isolated in 1964 by Raphael Mechoulam and Yechiel Gaoni at the Weizmann Institute of Science in Israel.
Since at least 1986, the trend has been for THC in general, and especially the Marinol preparation, to be downgraded to less and less stringently-controlled schedules of controlled substances, in the U.S. and throughout the rest of the world.
On May 13, 1986, the Drug Enforcement Administration (DEA) issued a Final Rule and Statement of Policy authorizing the "Rescheduling of Synthetic Dronabinol in Sesame Oil and Encapsulated in Soft Gelatin Capsules From Schedule I to Schedule II" (DEA 51 FR 17476-78). This permitted medical use of Marinol, albeit with the severe restrictions associated with Schedule II status. For instance, refills of Marinol prescriptions were not permitted. At its 10th meeting, on April 29, 1991, the Commission on Narcotic Drugs, in accordance with article 2, paragraphs 5 and 6, of the Convention on Psychotropic Substances, decided that Δ⁹-tetrahydrocannabinol (also referred to as Δ⁹-THC) and its stereochemical variants should be transferred from Schedule I to Schedule II of that Convention. This released Marinol from the restrictions imposed by Article 7 of the Convention (See also United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances).
An article published in the April–June 1998 issue of the Journal of Psychoactive Drugs found that "Healthcare professionals have detected no indication of scrip-chasing or doctor-shopping among the patients for whom they have prescribed dronabinol". The authors state that Marinol has a low potential for abuse.
In 1999, Marinol was rescheduled from Schedule II to III of the Controlled Substances Act, reflecting a finding that THC had a potential for abuse less than that of cocaine and heroin. This rescheduling constituted part of the argument for a 2002 petition for removal of cannabis from Schedule I of the Controlled Substances Act, in which petitioner Jon Gettman noted, "Cannabis is a natural source of dronabinol (THC), the ingredient of Marinol, a Schedule III drug. There are no grounds to schedule cannabis in a more restrictive schedule than Marinol".
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.
== Society and culture == ===Brand names===
Dronabinol is marketed as Marinol, a registered trademark of Solvay Pharmaceuticals. Dronabinol is also marketed, sold, and distributed by PAR Pharmaceutical Companies under the terms of a license and distribution agreement with SVC pharma LP, an affiliate of Rhodes Technologies. Dronabinol is available as a prescription drug (under Marinol) in several countries including the United States, Germany, South Africa and Australia. In the United States, Marinol is a Schedule III drug, available by prescription, considered to be non-narcotic and to have a low risk of physical or mental dependence. Efforts to get cannabis rescheduled as analogous to Marinol have not succeeded thus far, though a 2002 petition has been accepted by the DEA. As a result of the rescheduling of Marinol from Schedule II to Schedule III, refills are now permitted for this substance. Marinol's U.S. Food and Drug Administration (FDA) approvals for medical use has raised much controversy as to why natural THC is considered a schedule I drug.
==== 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.
It takes over one hour for Marinol to reach full systemic effect, compared to seconds or minutes for smoked or vaporized cannabis. Some people accustomed to inhaling just enough cannabis smoke to manage symptoms have complained of too-intense intoxication from Marinol's predetermined dosages. Many people using Marinol have said that Marinol produces a more acute psychedelic effect than cannabis, and it has been speculated that this disparity can be explained by the moderating effect of the many non-THC cannabinoids present in cannabis. For that reason, alternative THC-containing medications based on botanical extracts of the cannabis plant such as nabiximols are being developed. Mark Kleiman, director of the Drug Policy Analysis Program at UCLA's School of Public Affairs said of Marinol, "It wasn't any fun and made the user feel bad, so it could be approved without any fear that it would penetrate the recreational market, and then used as a club with which to beat back the advocates of whole cannabis as a medicine." Mr. Kleiman's opinion notwithstanding, clinical trials comparing the use of cannabis extracts with Marinol in the treatment of cancer cachexia have demonstrated equal efficacy and well-being among subjects in the two treatment arms. United States federal law currently registers dronabinol as a Schedule III controlled substance, but all other cannabinoids remain Schedule I, except synthetics like nabilone.
==Research== Its status as an illegal drug in most countries can make research difficult; for instance in the United States where the National Institute on Drug Abuse was the only legal source of cannabis for researchers until it recently became legalized in Colorado, Washington state, Oregon, Alaska, California, Maine, Massachusetts and Washington D.C.
In April 2014 the American Academy of Neurology published a systematic review of the efficacy and safety of medical marijuana and marijuana-derived products in certain neurological disorders. The review identified 34 studies meeting inclusion criteria, of which 8 were rated as Class I quality. which is a capsule with a standardized Cannabis sativa extract; the cannabis grown in Switzerland and processed in Germany. Each capsule of Cannador contains 2.5 mg Δ⁹- tetrahydrocannabinol and cannabidiols are standardized to a range 0.8–1.8 mg.
===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.
===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. * Epilepsy. Data was considered insufficient to judge the utility of cannabis products in reducing seizure frequency or severity.
== See also ==
* Cannabinoids ** 11-Hydroxy-THC, metabolite of THC ** Anandamide, 2-Arachidonoylglycerol, endogenous cannabinoid agonists ** Cannabidiol (CBD), an isomer of THC ** Cannabinol (CBN), a metabolite of THC ** Dimethylheptylpyran ** Parahexyl ** Tetrahydrocannabinolic acid, the biosynthetic precursor for THC ** HU-210, WIN 55,212-2, JWH-133, synthetic cannabinoid agonists * Medical cannabis * Nabilone * War on Drugs * Effects of cannabis * Cannabinoid hyperemesis syndrome
== References ==
== External links == * [http://druginfo.nlm.nih.gov/drugportal/dpdirect.jsp?name=Tetrahydrocannabinol U.S. National Library of Medicine: Drug Information Portal – Tetrahydrocannabinol]
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