Tetrahydrocannabinol
60920
224980174
2008-07-11T08:17:15Z
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4928500
Reverting possible vandalism by [[Special:Contributions/65.87.57.192|65.87.57.192]] to version by Joyous!. False positive? [[User:ClueBot/FalsePositives|Report it]]. Thanks, [[User:ClueBot]]. (437682) (Bot)
{{mergefrom|Dronabinol| Talk:tetrahydrocannabinol#Merge proposal |date=July 2008 }}
{{redirect|THC}}
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{{Drugbox
| IUPAC_name = (−)-(6a''R'',10a''R'')-6,6,9-trimethyl-<br />3-pentyl-6a,7,8,10a-tetrahydro-<br />6''H''-benzo[''c'']chromen-1-ol
| image = Tetrahydrocannabinol.svg
| width = 200
| imagename =
| drug_name = Δ<sup>9</sup>-tetrahydrocannabinol
| CAS_number = 1972-08-3
| CAS_supplemental =
| ATC_prefix = A04
| ATC_suffix = AD10
| ATC_supplemental =
| PubChem = 16078
| DrugBank =
| chemical_formula =
| C=21 | H=30 | O=2
| molecular_weight = 314.45
| smiles = C1=C(CC[C@@H]3[C@@H]1C2=C(C=C(C=C2OC3(C)C)CCCCC)O[H])C
| synonyms = Dronabinol
| density =
| melting_point =
| melting_high =
| melting_notes =
| boiling_point = 200
| boiling_notes = 0.02mmHg
| solubility = 2.8 mg/L (23 °C)
| specific_rotation = -152° (ethanol)
| sec_combustion =
| bioavailability = 10-35% (inhalation), 6-20% (oral)<ref name="pmid12648025">{{cite journal |author=Grotenhermen F |title=Pharmacokinetics and pharmacodynamics of cannabinoids |journal=Clin Pharmacokinet |volume=42 |issue=4 |pages=327–60 |year=2003 |pmid=12648025 | doi = 10.2165/00003088-200342040-00003}}</ref>
| protein_bound = 95-99%<ref name="pmid12648025">{{cite journal |author=Grotenhermen F |title=Pharmacokinetics and pharmacodynamics of cannabinoids |journal=Clin Pharmacokinet |volume=42 |issue=4 |pages=327–60 |year=2003 |pmid=12648025 | doi = 10.2165/00003088-200342040-00003}}</ref>
| metabolism = mostly hepatic by CYP2C<ref name="pmid12648025">{{cite journal |author=Grotenhermen F |title=Pharmacokinetics and pharmacodynamics of cannabinoids |journal=Clin Pharmacokinet |volume=42 |issue=4 |pages=327–60 |year=2003 |pmid=12648025 | doi = 10.2165/00003088-200342040-00003}}</ref>
| elimination_half-life = 1.6-59 hours <ref name="pmid12648025">{{cite journal |author=Grotenhermen F |title=Pharmacokinetics and pharmacodynamics of cannabinoids |journal=Clin Pharmacokinet |volume=42 |issue=4 |pages=327–60 |year=2003 |pmid=12648025 | doi = 10.2165/00003088-200342040-00003}}</ref>
| excretion = 65-80% (feces), 20-35% (urine) as acid metabolites<ref name="pmid12648025">{{cite journal |author=Grotenhermen F |title=Pharmacokinetics and pharmacodynamics of cannabinoids |journal=Clin Pharmacokinet |volume=42 |issue=4 |pages=327–60 |year=2003 |pmid=12648025 | doi = 10.2165/00003088-200342040-00003}}</ref>
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| pregnancy_US = <!-- A / B / C / D / X -->
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| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->
| legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C -->
| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->
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[[Image:Thc.pdb.gif|thumb|3D rendering of the THC molecule.]]
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[http://cougar.eb.com/soundc11/t/tetrah06.wav '''Tetrahydrocannabinol'''], also known as '''THC''', '''Δ<sup>9</sup>-THC''', '''Δ<sup>9</sup>-tetrahydrocannabinol'''
(delta-9-tetrahydrocannabinol), '''Δ<sup>1</sup>-tetrahydrocannabinol''' (using an older numbering scheme), or [[dronabinol]], is the main [[psychoactive substance]] found in the [[Cannabis]] plant. It was isolated by [[Raphael Mechoulam]], [[Yechiel Gaoni]], and [[Habib Edery]] from the [[Weizmann Institute of Science]] in [[Rehovot]], [[Israel]] in [[1964]].<ref>{{cite journal
| last = Gaoni | first = Yechiel
| coauthors = Raphael Mechoulam
| title = Isolation, structure and partial synthesis of an active constituent of hashish
| journal = Journal of the American Chemical Society
| volume = 86
| issue = 8
| pages = 1646–1647
| date = 1964
| url = http://pubs.acs.org/cgi-bin/searchRedirect.cgi/jacsat/1964/86/i08/pdf/ja01062a046.pdf
| doi = 10.1021/ja01062a046
| accessdate = 2008-05-31}}</ref> <ref>[http://matters.ecnp.nl/number11/interview2.shtml Interview with the winner of the first ECNP Lifetime Achievement Award: Raphael Mechoulam, Israel] February 2007</ref> <ref>[http://chemicalheritage.org/pubs/ch-v25n2-articles/feature_cannabinoids.html Cannabinoids: A Secret History] by Tom Geller, Chemical Heritage Newsmagazine, 25 (2), Summer 2007.</ref> In pure form, it is a glassy solid when cold, and becomes [[viscous]] and sticky if warmed. An [[aromatic]] [[terpenoid]], THC has a very low [[solubility]] in water, but good solubility in most organic [[solvent]]s such as [[butane]] or [[hexane]]. As is the case with [[nicotine]] and [[caffeine]], the role of THC in [[Cannabis]], it seems, is to protect the plant from [[herbivore]]s. THC also possesses high [[Ultraviolet|UV-B]] (280-315 nm) absorption properties and it seems likely that this protects the seed buds from potentially harmful radiation. THC is also a [[neuroprotective]] [[antioxidant]].<ref name="antioxidant 1998">[http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=20965 Cannabidiol and (−)Δ9-tetrahydrocannabinol are neuroprotective antioxidants], A. J. Hampson, M. Grimaldi, J. Axelrod, and D. Wink, Proc Natl Acad Sci U S A. 1998 July 7; 95(14): 8268–8273.</ref>
== Pharmacology ==
The [[pharmacology|pharmacological]] actions of THC result from its binding to the [[cannabinoid receptor]] [[Cannabinoid receptor type 1|CB<sub>1</sub>]], located in the [[central nervous system]]. The presence of these specialized receptors in the [[brain]] implied to researchers that [[endogenous]] [[cannabinoids]] are manufactured by the body, so the search began for a substance normally manufactured in the brain that binds to these receptors, the so-called natural [[ligand]] or [[agonist]], leading to the eventual discovery of [[anandamide]], 2-arachidonyl glyceride ([[2-AG]]), and other related compounds known as [[endocannabinoid]]s. This story resembles the discovery of the endogenous [[opiates]] ([[endorphins]], [[enkephalins]], and [[dynorphin]]), after the realization that [[morphine]] and other opiates bind to specific receptors in the brain. In addition, it has been shown that cannabinoids, through an unknown mechanism, activate endogenous opioid pathways via the μ<sub>1</sub> [[opioid receptor]], precipitating a [[dopamine]] release in the [[nucleus accumbens]]. The effects of the drug can be suppressed by the CB1 [[cannabinoid receptor]] antagonist [[rimonabant]] (SR141716A) as well as [[opioid receptor]] antagonists (opioid blockers) [[naloxone]] and [[naloxonazine]].<ref name="Lupica 2004">Lupica CR, Riegel AC, Hoffman AF. [http://www.nature.com/bjp/journal/v143/n2/full/0705931a.html "Marijuana and cannabinoid regulation of brain reward circuits."] ''British Journal of Pharmacology''. 2004 Sep;'''143'''(2):227-34. PMID 15313883. {{doi|10.1038/sj.bjp.0705931}}</ref>
The mechanism of endocannabinoid synaptic transmission is believed to occur as follows: first, transmission of the excitatory neurotransmitter [[glutamate]] causes an influx of [[calcium]] ions into the [[post-synaptic]] neuron. Through a mechanism not yet fully understood, the presence of calcium post-synaptically induces the production of endocannabinoids in the post-synaptic neuron. These endocannabinoids (such as anandamide) are released into the synaptic cleft, where binding occurs at cannabinoid receptors present on pre-synaptic neurons, where they modulate neurotransmission. Thus, this form of neurotransmission is termed [[retrograde signaling|retrograde transmission]], as the signal is carried in the opposite direction of orthodox propagation, which previously was thought to be exclusively one way.
THC has mild to moderate [[analgesic]] effects, and [[medical cannabis]] can be used to treat pain. The mechanism for analgesic effects caused directly by THC or other cannabinoid agonists is not fully elucidated. Other effects include relaxation; [[euphoria]]; altered space-time perception; alteration of visual, auditory, and olfactory senses; disorientation; fatigue; and appetite stimulation. The mechanism for appetite stimulation in subjects is believed to result from activity in the gastro-hypothalamic axis. CB1 activity in the hunger centers in the hypothalamus increases the palatability of food when levels of a hunger hormone, [[ghrelin]], increase as food enters the stomach. After chyme is passed into the [[duodenum]], signaling [[hormone]]s such as [[cholecystokinin]] and [[leptin]] are released, causing reduction in gastric emptying and transmission of satiety signals to the hypothalamus, respectively. Cannabinoid activity is reduced through the satiety signals induced by leptin release. It also has [[anti-emetic]] properties, and also may reduce aggression in certain subjects.
THC has an active [[metabolite]], [[11-Hydroxy-THC]], which may also play a role in the analgesic and recreational effects of the [[Cannabis|herb]].
===Toxicity===
{{main|LD50 of THC}}
{{see also|Health issues and effects of cannabis}}
According to the [[Merck Index]], 12th edition, THC has a [[LD50|LD<sub>50</sub>]] value of 1270 [[Milligram|mg]]/[[Kilogram|kg]] (male rats) and 730 mg/kg (female rats) administered orally dissolved in [[sesame oil]].<ref name="Erowid">{{cite web|url=http://www.erowid.org/plants/cannabis/cannabis_chemistry.shtml|title=
Cannabis Chemistry|accessdate=2006-03-20|author=Erowid}}</ref>
The LD<sub>50</sub> value for rats by inhalation of THC is 42 mg/kg of body weight. It is important to note, however, that toxicity in animal models does not necessarily correlate to human toxicity. THC receptor distribution in the rat central nervous system is different from that of humans, meaning that there is the significant possibility that toxicity in humans varies from the published animal LD<sub>50</sub> studies. There has never been a documented fatality from marijuana.<ref name="Walker and Huang">Walker JM, Huang SM. "Cannabinoid analgesia." ''Pharmacology and Therapeutics''. 2002 Aug;'''95'''(2):127-35. PMID 12182960 - "...to date, there are no deaths known to have resulted from overdose of marijuana." (p. 128)</ref> Absorption is limited by serum lipids, which can become saturated with THC, thus the inherent solubility may mitigate toxicity. In order to create a lethal overdose in a human, one would have to consume 1500 pounds in under 15 minutes.<ref>[http://www.druglibrary.org/schaffer/library/mj_overdose.htm] What is the lethal dose of marijuana?</ref>
Studies of the distribution of the cannabinoid receptors in the brain explain why THC's toxicity is so low (i.e., the [[LD50|LD<sub>50</sub>]] of the compound is so large): parts of the brain that control vital functions such as [[Respiration (physiology)|respiration]] do not have many receptors, so they are relatively unaffected even by doses larger than could ever be ingested under any normal conditions.
==Research==
The original discovery appeared as [http://pubs.acs.org/cgi-bin/abstract.cgi/jacsat/1964/86/i08/f-pdf/f_ja01062a046.pdf "Isolation, structure and partial synthesis of an active constituent of hashish"], published in the [[Journal of the American Chemical Society]] in 1964.<ref>{{cite journal
| last = Gaoni | first = Yechiel
| coauthors = Raphael Mechoulam
| title = Isolation, structure and partial synthesis of an active constituent of hashish
| journal = Journal of the American Chemical Society
| volume = 86
| issue = 8
| pages = 1646–1647
| date = 1964
| url = http://pubs.acs.org/cgi-bin/searchRedirect.cgi/jacsat/1964/86/i08/pdf/ja01062a046.pdf
| doi = 10.1021/ja01062a046
| accessdate = 2008-05-31}}</ref> Research was also published in the [[academic journal]] ''[[Science (journal)|Science]]'', with "Marihuana chemistry" by [[Raphael Mechoulam]] in June 1970,<ref>{{cite journal
| last = Mechoulam | first = Raphael
| title = Marihuana Chemistry
| journal = Science
| volume = 168
| issue = 3936
| pages = 1159–1165
| date = 5 June 1970
| url = http://www.sciencemag.org/cgi/content/citation/168/3936/1159
| doi = 10.1126/science.168.3936.1159
| accessdate = 2008-05-31
| pmid = 4910003}}</ref> followed by [http://www.sciencemag.org/cgi/content/abstract/169/3945/611 "Chemical basis of hashish activity"] in August 1970.<ref>{{cite journal
| last = Mechoulam | first = Raphael
| coauthors = Arnon Shani, Habib Edery, and Yona Grunfeld
| title = Chemical Basis of Hashish Activity
| journal = Science
| volume = 169
| issue = 3945
| pages = 611–612
| date = 7 August 1970
| url = http://www.sciencemag.org/cgi/content/abstract/169/3945/611
| doi = 10.1126/science.169.3945.611
| accessdate = 2008-05-31
| pmid = 4987683}}</ref> In the latter, the team of researchers from [[Hebrew University of Jerusalem|Hebrew University]] Pharmacy School and [[Tel Aviv University]] Medical School experimented on monkeys to isolate the active compounds in [[hashish]]. Their results provided evidence that, except for tetrahydrocannabinol, no other major active compounds were present in hash.
A number of studies indicate that THC may provide medical benefits for [[cancer]] and [[AIDS]] patients by increasing appetite and decreasing nausea. It has been shown to assist some [[glaucoma]] patients by reducing pressure within the eye, and is used in the form of cannabis by a number of [[multiple sclerosis]] patients, who can use it to alleviate [[neuropathic pain]] and [[spasticity]]. The [[National Multiple Sclerosis Society]] is currently supporting research into these uses[http://www.nationalmssociety.org/about-multiple-sclerosis/treatments/complementary--alternative-medicine/marijuana/index.aspx]. New scientific evidence is showing that THC can prevent [[Alzheimer's Disease]] in an [[animal model]] by preventing the inflammation caused by [[microglia]] cells which are activated by binding of [[amyloid]] protein.<ref name="pmid15728830">{{cite journal
|author=Ramírez BG, Blázquez C, Gómez del Pulgar T, Guzmán M, de Ceballos ML
|title=Prevention of Alzheimer's disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation
|journal=J. Neurosci.
|volume=25
|issue=8
|pages=1904–13
|year=2005
|pmid=15728830
|doi=10.1523/JNEUROSCI.4540-04.2005
}}</ref>
Research in rats has indicated that THC prevented [[hydroperoxide]]-induced [[oxidative damage]] as well as or better than other [[antioxidant]]s in a chemical ([[Fenton reaction]]) system and [[neuron]]al cultures.<ref name="antioxidant 1998">
Some studies also claim a variety of negative effects associated with constant, long-term use, including short-term memory loss. Other studies have refuted this by evidence of MRIs of long term users showing little or no difference to MRIs of the non-using control group. Although using [[positron emission tomography]] (PET), at least one study claims to have observed altered memory-related brain function in marijuana users. <ref name="Block2002">Block RI, O'Leary DS, Hichwa RD, Augustinack JC, Boles Ponto LL, Ghoneim MM et al. "Effects of frequent marijuana use on memory-related regional cerebral blood flow." ''Pharmacology, Biochemistry and Behavior'' 2002 May;'''72'''(1-2):237-50. PMID 11900794. {{doi|10.1016/S0091-3057(01)00771-7}}</ref> The long-term effects of THC on humans have been disputed because its status as an illegal drug makes research difficult.
Preliminary research on synthetic THC has been conducted on patients with [[Tourette syndrome]], with results suggesting that it may help in reducing nervous tics and urges by a significant degree. Animal studies suggested that [[Marinol]] and nicotine could be used as an effective adjunct to [[neuroleptic]] drugs in treating TS. Research on twelve patients showed that Marinol reduced tics with no significant adverse effects. A six-week controlled study on 24 patients showed the patients taking Marinol had a significant reduction in tic severity without serious adverse effects. Seven patients dropped out or had to be excluded from the study, one due to adverse side-effects. More significant reduction in tic severity was reported with longer treatment. No detrimental effects on cognitive functioning and a trend towards improvement in cognitive functioning were reported during and after treatment. Marinol's usefulness as a treatment for TS cannot be determined until/unless longer controlled studies on larger samples are undertaken.<ref>{{cite journal | author = Müller-Vahl,K.R. Schneider,U. Koblenz,A. Jöbges,M. Kolbe,H. Daldrup,T. Emrich,H.M. | title =Treatment of Tourette's Syndrome with Δ9-Tetrahydrocannabinol (THC): A Randomized Crossover Trial | journal =Pharmacopsychiatry | volume =35 | issue =2 | pages =57–61 | pmid =11951146 | doi =10.1055/s-2002-25028 | year =2002}}</ref><ref>{{cite journal | author =Müller-Vahl KR, Schneider U, Prevedel H, Theloe K, Kolbe H, Daldrup T, Emrich HM. | title =Delta 9-tetrahydrocannabinol (THC) is effective in the treatment of tics in Tourette syndrome: a 6-week randomized trial | journal= J Clin Psychiatry | date = April 2003 | volume =64 | issue =4 | pages =459–65 | pmid =12716250}}</ref><ref>{{cite journal | author = Muller-Vahl KR, Prevedel H, Theloe K, Kolbe H, Emrich HM, Schneider U. | title =Treatment of Tourette syndrome with delta-9-tetrahydrocannabinol (delta 9-THC): no influence on neuropsychological performance | journal = Neuropsychopharmacology | date = February 2003 | volume =28 | issue =2 | pages =384–388 | pmid =12589392 | doi =10.1038/sj.npp.1300047 }}</ref>
Recent research has shown that many adverse side-effects, generally known as the "stoner" stereotype, fail to hold up to the scientific method. Recent studies with synthetic cannabinoids show that activation of CB1 receptors can facilitate neurogeneration, as well as neuroprotection, and can even help prevent natural neural degradation from neurodegenerative diseases such as MS, Parkinson's, and Alzheimer's. This, along with research into the CB2 receptor (throughout the immune system), has given the case for medical marijuana more support. {{Fact|date=February 2008}}
In ''[[in-vitro]]'' experiments, THC at extremely high concentrations, which could not be reached with commonly-consumed doses, caused inhibition of plaque formation, the cause of [[Alzheimer's disease]], better than currently-approved drugs.<ref>{{cite journal |author=Eubanks LM, Rogers CJ, Beuscher AE, ''et al'' |title=A molecular link between the active component of marijuana and Alzheimer's disease pathology |journal=Mol. Pharm. |volume=3 |issue=6 |pages=773–7 |year=2006 |pmid=17140265 |doi=10.1021/mp060066m}}</ref>
THC may also be an effective anti-cancer treatment, with studies showing tumor size reduction in mice conducted in 1975<ref>Munson AE, Harris LS, Friedman MA, Dewey WL, Carchman RA. [http://www.drugpolicycentral.com/bot/pg/cancer/THC_cancer_sep_1975.htm "Anticancer activity of cannabinoids."] Journal of the National Cancer Institute. September 1975;'''55'''(3):597-602. Accessed 2007-10-27.</ref> and 2007<ref>Preet A, Ganju RK, Groopman JE. "Delta(9)-Tetrahydrocannabinol inhibits epithelial growth factor-induced lung cancer cell migration in vitro as well as its growth and metastasis in vivo." ''Oncogene''. 2008 Jan 10;'''27'''(3):339-46. PMID 17621270. {{doi|10.1038/sj.onc.1210641}}</ref>, as well as in a pilot study in humans with [[glioblastoma multiforme]] (a type of brain cancer).<ref>Guzmán M, Duarte MJ, Blázquez C, Ravina J, Rosa MC, Galve-Roperh I et al. "A pilot clinical study of Delta9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme." ''British Journal of Cancer''. 2006 Jul 17;95(2):197-203. PMID 16804518. {{doi|10.1038/sj.bjc.6603236}}</ref>
On July 28, 2007, British medical journal [[The Lancet]] published a study that indicates that cannabis users have, on average, a 41% greater risk of developing [[psychosis]] than non-users. The risk was most pronounced in cases with an existing risk of psychotic disorder, and was said to grow up to 200% for the most-frequent users.<ref>Moore TH, Zammit S, Lingford-Hughes A, Barnes TR, Jones PB, Burke M, Lewis G. "Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review." ''Lancet''. 2007 Jul 28;'''370'''(9584):319-28. PMID 17662880. {{doi|10.1016/S0140-6736(07)61162-3}}</ref> Other studies have revealed similar associations, especially in individuals predisposed to psychosis prior to cannabis use.<ref>Henquet C, Krabbendam L, Spauwen J, Kaplan C, Lieb R, Wittchen HU, van Os J. [http://www.bmj.com/cgi/content/full/330/7481/11 "Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people."] ''BMJ''. 2005 Jan 1;'''330'''(7481):11. PMID 15574485. {{doi|10.1136/bmj.38267.664086.63}}</ref>
Recent research has also shown a correlation between cannabis use and increased cognitive function in schizophrenic patients.<ref>Coulston CM, Perdices M, Tennant CC. "The neuropsychological correlates of cannabis use in schizophrenia: Lifetime abuse/dependence, frequency of use, and recency of use." ''Schizophrenia Research'' (2007); '''96'''(1-3):169-184.</ref>
A two-year study in which rats and mice were force-fed tetrahydrocannabinol dissolved in corn oil showed reduced body mass, enhanced survival rates, and decreased tumor incidences in several sites, mainly organs under hormonal control. It also caused [[testicular atrophy]] and uterine and ovarian hypoplasia, as well as hyperactivity and convulsions immediately after administration.<ref>{{cite journal |author=Chan PC, Sills RC, Braun AG, Haseman JK, Bucher JR |title=Toxicity and carcinogenicity of delta 9-tetrahydrocannabinol in Fischer rats and B6C3F1 mice |journal=Fundamental and applied toxicology : official journal of the Society of Toxicology |volume=30 |issue=1 |pages=109–17 |year=1996 |pmid=8812248 |doi=}}</ref>
A 2008 study by the [[National Institutes of Health]] suggested that chronic heavy marijuana use might increase risk of heart attack or stroke, as these users showed elevated levels of [[Apolipoprotein C3|apolipoprotein C-III]], a risk factor for cardiovascular disease.<ref>Jayanthi S, Buie S, Moore S, Herning RI, Better W, Wilson NM, et al. "Heavy marijuana users show increased serum apolipoprotein C-III levels: evidence from proteomic analyses." ''Molecular Psychiatry''. 2008 May 13. [Epub ahead of print] PMID 18475272. {{doi|10.1038/mp.2008.50}}</ref> The marijuana users in the study averaged smoking 78 to 350 marijuana cigarettes per week, i.e. between 2 and 9 ounces of marijauana or between $600 and $2700 a week. The study also only measured 18 long term smokers along with 24 others who do not use the drug. <ref>{{cite news|url=http://www.reuters.com/article/healthNews/idUSN1231013620080513|title=Marijuana may up heart attack, stroke risk: study |publisher=Reuters}}</ref><ref>{{cite news|url=http://blog.norml.org/2008/05/13/marijuana-may-up-heart-attack-stroke-risk/|title=Marijuana may up heart attack, stroke risk-if you smoke 2-9 Oz. a week |publisher=NORML.org}}</ref>
A 2008 study by the [[University of Melbourne]] found that daily, long-term marijuana use may be linked to abnormalities in parts of the brain.<ref>{{cite news|url=http://www.ctv.ca/servlet/ArticleNews/story/CTVNews/20080602/marijuana_effects_080602/20080602?hub=Health |title=Long-term marijuana use linked to brain abnormalities |publisher=CBC}}</ref> The daily long-term users consumed at least 5 marijuana cigarettes daily for on average 20 years. Among the 15 heavy marijuana users in the study, the hippocampus volume was 12 percent less and the amygdala volume was 7 percent less than in 16 men who were not marijuana users, the researchers said.<ref>{{cite news|url=http://www.reuters.com/article/latestCrisis/idUSN02271474|title=Heavy marijuana use shrinks brain parts - study |publisher=Reuters}}</ref>
In [[mice]] low doses of Δ<sup>9</sup>-THC reduce the progression of [[atherosclerosis]].<ref name="pmid15815632">{{cite journal
|author=Steffens S, Veillard NR, Arnaud C, ''et al''
|title=Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice
|journal=Nature
|volume=434
|issue=7034
|pages=782–6
|year=2005
|pmid=15815632
|doi=10.1038/nature03389
}}</ref>
==Biosynthesis==
[[Image:THC biosynthesis.png|thumb|Biosynthesis of THC]]
In the [[cannabis]] plant THC occurs mainly as tetrahydrocannabinol carboxylic acid (THC-COOH). The [[enzyme|enzymatic]] condensation of [[geranyl pyrophosphate]] and olivetolic acid gives [[cannabigerol|cannabigerolic acid]] which is cyclized by the enzyme THC acid synthase to give THC-COOH. Heating [[decarboxylation|decarboxylates]] the acid to THC.
==Metabolism==
THC is mainly metabolized to [[11-Hydroxy-THC|11-OH-THC]] (11-hydroxy-THC) by the human 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. Metabolism mainly occurs in the liver by [[cytochrome P450]] enzymes [[CYP2C9]], [[CYP2C19]], and [[CYP3A4]]. More than 55% of THC are 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.<ref name="pmid16596792">{{cite journal
|author=Huestis MA
|title=Pharmacokinetics and metabolism of the plant cannabinoids, Δ<sup>9</sup>-tetrahydrocannabinol, cannabidiol and cannabinol
|journal=Handb Exp Pharmacol
|volume=
|issue=168
|pages=657–90
|year=2005
|pmid=16596792
|doi=
}}</ref>
==Synthetic THC==
Synthetic THC, also known under the substance name ''dronabinol'', is available as a prescription drug (under the trade name [[Marinol]]) in several countries including the [[United States|U.S.]] and [[Germany]]. In the United States, Marinol is a [[Controlled Substances Act#Schedule III drugs|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 [[Removal of cannabis from Schedule I of the Controlled Substances Act#2002 Coalition for Rescheduling Cannabis petition|2002 petition]] has been accepted by the [[Drug Enforcement Administration|DEA]]. As a result of the rescheduling of Marinol from Schedule II to Schedule III, refills are now permitted for this substance. Marinol has been approved by the [[FDA]] in the treatment of [[anorexia (symptom)|anorexia]] in [[AIDS]] patients, as well as for refractory [[nausea]] and [[vomiting]] of patients undergoing [[chemotherapy]], which has raised much controversy as to why natural THC is still a [[schedule I]] drug.
An analog of dronabinol, [[nabilone]], is available commercially in Canada under the trade name Cesamet, manufactured by Valeant. Cesamet has also received FDA approval and has began marketing in the U.S. as of 2006 and is a [[Controlled Substances Act#Schedule II drugs|Schedule II]] drug.
In April 2005, [[Canada|Canadian]] authorities approved the marketing of [[Sativex]], a mouth spray for [[multiple sclerosis]] patients, who can use it to alleviate [[neuropathic pain]] and [[spasticity]]. Sativex contains tetrahydrocannabinol together with [[cannabidiol]]. It is marketed in [[Canada]] by GW Pharmaceuticals, being the first cannabis-based prescription drug in the world.
== See also ==
* [[Cannabis (drug)]]
* [[Psychoactive drug]]
* [[Cannabinoids]]
** [[HU-210]]
** [[WIN 55,212-2]]
* [[Medical cannabis]]
* [[Dronabinol]]
* [[War on Drugs]]
* [[THC Ministry]]
* [[Cannabis rescheduling in the United States]]
* [[Cannabidiol]], an [[isomer]] of THC
* [[Health issues and the effects of cannabis]]
== References ==
{{reflist|2}}
== External links ==
* [http://www.sciam.com/article.cfm?articleID=000A844E-8FBE-119B-8EA483414B7FFE9F&ref=sciam&chanID=sa004 Marijuana research: Current restrictions on marijuana research are absurd], by the editors of ''[[Scientific American]]'', November 2004
* [http://www.erowid.org/plants/cannabis/cannabis_info2.shtml Compounds found in ''Cannabis Sativa''], Erowid Cannabis Vault
* [http://chemicalheritage.org/pubs/ch-v25n2-articles/feature_cannabinoids_p2.html Cannabinoid Chemistry in "Cannabinoids: A Secret History"] by Tom Geller, Chemical Heritage Newsmagazine, 25 (2), Summer 2007.
* [http://www.eurekalert.org/pub_releases/2005-12/cp-mot121505.php Machinery of the "marijuana munchies"]
* [http://www.erowid.org/plants/cannabis/cannabis_spirit6.shtml Resurrection of the Higher Self] by Matthew Webb
{{ancient anaesthesia-footer}}
{{Cannabinoids}}
[[Category:Cannabinoids]]
[[Category:Amorphous solids]]
[[bs:Tetrahidrokanabinol]]
[[bg:Тетрахидроканабинол]]
[[ca:Tetrahidrocannabinol]]
[[cs:Tetrahydrocannabinol]]
[[cy:Tetrahydrocannabinol]]
[[da:Tetrahydrocannabinol]]
[[de:Tetrahydrocannabinol]]
[[es:Tetrahidrocannabinol]]
[[fr:Tétrahydrocannabinol]]
[[gl:Tetrahidrocannabinol]]
[[hr:Tetrahidrokanabinol]]
[[it:Delta-9-Tetraidrocannabinolo]]
[[he:THC]]
[[lt:Tetrahidrokanabinolis]]
[[hu:Tetrahidrokannabinol]]
[[nl:Tetrahydrocannabinol]]
[[ja:テトラヒドロカンナビノール]]
[[no:Tetrahydrocannabinol]]
[[pl:Tetrahydrokannabinol]]
[[pt:Tetraidrocanabinol]]
[[ro:THC]]
[[ru:Тетрагидроканнабинол]]
[[sk:Tetrahydrokanabinol]]
[[sl:Tetrahidrokanabinol]]
[[sr:Tetrahidrokanabinol]]
[[fi:Tetrahydrokannabinoli]]
[[sv:Tetrahydrocannabinol]]
[[th:เตตร้าไฮโดรแคนนาบินอล]]
[[tr:THC]]
[[uk:Тетрагідроканнабінол]]