|Systematic (IUPAC) name|
|Legal status||Controlled (S8) (AU) Schedule II (CA) (CA) Schedule I and III (US)|
|Routes||orally, smoked (or vaporized)|
|Bioavailability||10–35% (inhalation), 6–20% (oral)|
|Metabolism||mostly hepatic by CYP2C|
|Half-life||1.6–59 h, 25–36 h (orally administered dronabinol)|
|Excretion||65–80% (feces), 20–35% (urine) as acid metabolites|
|Boiling point||157 °C (315 °F) |
|Solubility in water||0.0028 (23 °C) mg/mL (20 °C)|
|Spec. rot||-152° (ethanol)|
| (what is this?)
Tetrahydrocannabinol (pron.: // tet-rə-HY-drə-kə-NAB-i-nawl or pron.: // tet-rə-HY-drə-kə-NAB-i-nol; THC), also known as delta-9-tetrahydrocannabinol (Δ9-THC), is the principal psychoactive constituent (or cannabinoid) of the cannabis plant. First isolated in 1964, in its pure form, by Israeli scientists Raphael Mechoulam, Yechiel Gaoni and colleagues at the Hebrew University of Jerusalem, it is a glassy solid when cold, and becomes viscous and sticky if warmed. A pharmaceutical formulation of THC, known by its INN dronabinol, is available by prescription in the U.S. and Canada under the brand name Marinol. An aromatic terpenoid, THC has a very low solubility in water, but good solubility in most organic solvents, specifically lipids and alcohols.
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.
The pharmacological actions of THC result from its partial agonist activity at the cannabinoid receptor CB1, located mainly in the central nervous system, and the CB2 receptor, mainly expressed in cells of the immune system. The psychoactive effects of THC are primarily mediated by its activation of CB1G-protein coupled 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 receptors in the brain and body, such as adipose tissue. For a review of the mechanisms behind endocannabinoid synaptic transmission, see the endocannabinoid system.
THC has mild to moderate analgesic effects, and cannabis can be used to treat pain by altering transmitter release on dorsal root ganglion of the spinal cord and in the periaqueductal gray. Other effects include relaxation, alteration of visual, auditory, and olfactory senses, fatigue, and appetite stimulation. THC has marked antiemetic properties, and may also reduce aggression in certain subjects.
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. However, this form of tolerance appears to be irregular throughout mouse brain areas and warrants future research.
THC, as well as other cannabinoids that contain a phenol group, possesses mild antioxidant activity sufficient to protect neurons against oxidative stress, such as that produced by glutamate-induced excitotoxicity.
Appetite and taste 
It has long been known that, in humans, cannabis increases appetite and consumption of food. 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 prior to consuming a meal. After chyme is passed into the duodenum, signaling hormones such as cholecystokinin and leptin are released, causing reduction in gastric emptying and transmission of satiety signals to the hypothalamus. Cannabinoid activity is reduced through the satiety signals induced by leptin release.
Based on the connection between palatable food and stimulation of dopamine (DA) transmission in the shell of the nucleus accumbens (NAc), it has been suggested that cannabis does not only stimulate taste, but possibly the hedonic value of food. A taste-reactivity paradigm in mice was used to investigate the influence of THC on DA release in the NAc upon application of sucrose or quinine solutions. THC application was found to enhance DA release in the NAc from sucrose, but not quinine, in a dose-dependent manner. This effect was enhanced with sweeter solution, which correlated with an increase the researchers' hedonic-behavior assessment as well. The mechanism behind this effect was elucidated by application of rimonabant, a CB1 receptor inverse agonist, known to reduce intake of food or sweet solutions. However, the same DA enhancement effect was not found upon repeated application of sucrose, suggesting that the DA response undergoes habituation. The inconsistency between DA habituation and enduring appetite observed after THC application suggests that cannabis-induced appetite stimulation is not only mediated by enhanced pleasure from platable food, but through THC stimulation of another appetitive response as well.
The effects of the drug can be suppressed by the CB1 receptor antagonist rimonabant (SR141716A) as well as opioid receptor antagonists (opioid blockers) naloxone and naloxonazine. The α7 nicotinic receptor antagonist methyllycaconitine can block self-administration of THC in rates comparable to the effects of varenicline on nicotine administration.
There has never been a documented human fatality solely from overdosing on tetrahydrocannabinol or cannabis in its natural form, though the synthetic THC pill "Marinol" was cited by the FDA as being responsible for 4 deaths between January 1, 1997 and June 30, 2005. Information about THC's toxicity is primarily based on results from animal studies. The toxicity depends on the route of administration and the laboratory animal. Absorption is limited by serum lipids, which can become saturated with THC, mitigating toxicity.
The discovery of THC was first described in "Isolation, structure and partial synthesis of an active constituent of hashish", published in the Journal of the American Chemical Society in 1964. Research was also published in the academic journal Science, with "Marijuana chemistry" by Raphael Mechoulam in June 1970, followed by "Chemical basis of hashish activity" in August 1970. In the latter, the team of researchers from 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 hashish.
Studies in humans 
Evidence suggests that THC helps alleviate symptoms suffered both by AIDS patients, and by cancer patients undergoing chemotherapy, by increasing appetite and decreasing nausea. It has also 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 use it to alleviate neuropathic pain and spasticity. The National Multiple Sclerosis Society is currently supporting further research into these uses. Studies in humans have been limited by federal and state laws criminalizing marijuana.
In a 1981 double-blind, placebo-controlled study, oral THC was given to Multiple Sclerosis patients. A decrease in spasticity was shown when compared with placebo. In a 1983 single-blind, placebo-controlled study, decreased tremor occurred in 1/4 of Multiple Sclerosis patients.
Several studies have been conducted with spinal injury patients and THC. Decreased tremor occurred in 2/5 patients in a 1986 double-blind, placebo-controlled crossover study. THC was shown to decrease spasticity and pain in a 1990 double-blind, placebo-controlled study.
Studies in animals and in vitro 
In 2006, researchers from Scripps Research Institute, using both computer modeling and biochemical assays, found THC "may provide an improved therapeutic for Alzheimer's disease" that would treat "both the symptoms and progression" of the disease. THC, they found, inhibits the formation of amyloid plaque (the primary marker for Alheimer's disease). The authors concluded that their research offered "convincing evidence that THC possesses remarkable inhibitory qualities." THC was found to be "considerably more effective" than two of the leading Alzheimer's drugs on the market, donepezil and tacrine.
THC may also be an effective cancer treatment, with studies showing tumor size reduction in mice conducted in 1975 and 2007, as well as in a pilot study in humans with glioblastoma multiforme (a type of brain cancer). THC has also been found to attenuate conditioned retching and sickness, experimentally verifying anecdotal reports that THC alleviates nausea and vomiting when undergoing chemotherapy.
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, of which the onset and frequency were dose related.
Research in rats indicates that THC prevents hydroperoxide-induced oxidative damage as well as or better than other antioxidants in a chemical (Fenton reaction) system and neuronal cultures. In mice low doses of Δ9-THC reduces the progression of atherosclerosis.
Research has also shown that past claims of brain damage from cannabis use fail to hold up to the scientific method. Instead, recent studies with synthetic cannabinoids show that activation of CB1 receptors can facilitate neurogenesis, 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. THC is both a CB1 and CB2 agonist.
Scientific studies indicating side-effects 
Conceivable long-term ill effects of THC on humans are disputed but not improbable, yet 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 and Washington.
Some studies claim a variety of negative effects associated with long-term use, including short-term memory loss. Using positron emission tomography (PET), one study reports altered memory-related brain function (23% better memory for the cannabis users in recalling the end of a list of things to remember, but 19% worse memory for cannabis users in recalling the middle of a list of things to remember) in chronic daily cannabis users.
Some studies have suggested that cannabis users have a greater risk of developing psychosis than non-users. This risk is most pronounced in cases with an existing risk of psychotic disorder. Other studies have made similar associations, especially in individuals predisposed to psychosis prior to cannabis use. A 2005 paper from the Dunedin study suggested an increased risk in the development of psychosis linked to polymorphisms in the COMT gene. However, a more recent study cast doubt on the proposed connection between this gene and the effects of cannabis on the development of psychosis.
A 2008 German review reported that cannabis was a causal factor in some cases of schizophrenia and stressed the need for better education among the public due to increasingly relaxed access to cannabis. Though cannabis use has increased dramatically in several countries over the past few decades, the rates of psychosis and schizophrenia have not generally increased, casting some doubt over whether the drug can cause cases that would not otherwise have occurred.
Conversely, research from 2007 reported a correlation between cannabis use and increased cognitive function in schizophrenic patients.
A 2008 National Institutes of Health study of 19 chronic heavy marijuana users with cardiac and cerebral abnormalities (averaging 28g to 272g (1 to 9+ oz) weekly) and 24 controls found elevated levels of apolipoprotein C-III (apoC-III) in the chronic smokers. An increase in apoC-III levels induces the development of hypertriglyceridemia.
A 2008 study by the University of Melbourne of 15 heavy marijuana users (consuming at least 5 marijuana cigarettes daily for on average 20 years) and 16 controls found an average size difference for the smokers in the hippocampus (12 percent smaller) and the amygdala (7 percent smaller). It has been suggested that such effects can be reversed with long term abstinence.
A study of around 1000 people in New Zealand found that starting cannabis below the age of 18, when the brain is undergoing major development, induces a 8 point IQ drop on average. This effect was not fully reverted after stopping cannabis use. However, starting cannabis older seems to be safer.
Opinions and statistical observations indicating side-effects 
A literature review on the subject concluded that "Cannabis use appears to be neither a sufficient nor a necessary cause for psychosis. It is a component cause, part of a complex constellation of factors leading to psychosis." In other words, THC may accelerate symptoms in people already predisposed, but will not create psychosis in the healthy. Likewise, a French review from 2009 came to a conclusion that cannabis use, particularly that before age 15, was a factor in the development of schizophrenic disorders.
A 2009 study found that there was a high prevalence of cannabis in the toxicological analysis of homicide (22%) and suicide victims (11%) in Australia. In a similar study from Sweden it was also found that suicide victims had a significantly higher use of cannabis, but the authors found that "this was explained by markers of psychological and behavioral problems."
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 decarboxylated producing THC. The pathway for THCA biosynthesis is similar to that which produces the bitter acid humulone in hops.
Natural occurrence 
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 humans and 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, 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.
Detection in body fluids 
THC, 11-OH-THC and THC-COOH can be detected and quantitated 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 of a traffic or other criminal offense or suspicious death.
Dronabinol is the INN for a pure isomer of THC, (–)-trans-Δ9-tetrahydrocannabinol, which is the main isomer found in cannabis. It is sold 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. Synthesized THC may be generally referred to as dronabinol. It is available as a prescription drug (under Marinol) in several countries including the United States and Germany. 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 has been approved by the U.S. Food and Drug Administration (FDA) in the treatment of 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 Pharmaceuticals. Cesamet has also received FDA approval and began marketing in the U.S. in 2006; it is a Schedule II drug.
In April 2005, 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 and is a preparation of whole cannabis rather than individual cannabinoids. It is marketed in Canada by GW Pharmaceuticals, being the first cannabis-based prescription drug in the world (in modern times). In addition, Sativex received European regulatory approval in 2010.
Comparisons to medical marijuana 
Female cannabis plants contain more than 60 cannabinoids, including cannabidiol (CBD), thought to be the major anticonvulsant that helps multiple sclerosis patients; 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 patients accustomed to inhaling just enough cannabis smoke to manage symptoms have complained of too-intense intoxication from Marinol's predetermined dosages. Many patients 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.". United States federal law currently registers dronabinol as a Schedule III controlled substance, but all other cannabinoids remain Schedule I, excepting synthetics like nabilone.
Regulatory history 
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 July 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 1045th 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 comprised 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.
See also 
- Cannabis (drug)
- Psychoactive drug
- Medical cannabis
- War on Drugs
- Cannabis rescheduling in the United States
- Health issues and the effects of cannabis
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Further reading 
- Calhoun SR, Galloway GP, Smith DE (1998). "Abuse potential of dronabinol (Marinol)". J Psychoactive Drugs 30 (2): 187–96. doi:10.1080/02791072.1998.10399689. PMID 9692381.
- DEA Moves Marinol To Schedule Three, But Leaves Marijuana in Schedule One. The Magic of Sesame Oil, Richard Cowan, MarijuanaNews.Com.
- Petition to Reschedule Cannabis (Marijuana) per 21 CFR §1308.44(b), Filed October 9, 2002 with the DEA by the Coalition for Rescheduling Cannabis.