Tetrahydrocannabinol (pronounced: tɛtrəˌhaɪdrɵkəˈnæbɨnɒl tet-rə-HYE-drə-kə-NAB-i-nol) (THC), also known as delta-9-tetrahydrocannabinol (Δ9-THC), Δ1-THC (using an older chemical nomenclature), or dronabinol, is the main psychoactive substance found in the cannabis plant.
It was first isolated by Raphael Mechoulam, Yechiel Gaoni, and Habib Edery from the Weizmann Institute of Science in Rehovot, Israel in 1964. 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 solvents.
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.
Dronabinol is the International Nonproprietary Name (INN) for a pure isomer of THC, (-)-trans-Δ9-tetrahydrocannabinol, that is, the main isomer 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.
The pharmacological actions of THC result from its binding to the cannabinoid receptor CB1, located mainly in the central nervous system, and the CB2 receptor, mainly present in cells of the immune system. It acts as a partial agonist on both receptors, i.e., it activates them but not to their full extent. The psychoactive effects of THC are mediated by its activation of the CB1 receptor, which is the most abundant G protein-coupled receptor in the brain.
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 endocannabinoids. 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 involving the μ1 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.
The mechanism of endocannabinoid synaptic transmission is thought 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 post-synaptic calcium induces the production of endocannabinoids in the post-synaptic neuron. These endocannabinoids (such as anandamide), then, 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 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 cannabis can be used to treat pain. The mechanism for analgesic effects caused directly by THC or other cannabinoid agonists is not fully understood. Other effects include relaxation; euphoria; altered space-time perception; alteration of visual, auditory, and olfactory senses; anxiety; disorientation; fatigue; and appetite stimulation (colloquially known as "the munchies"). 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 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. 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 cannabis.
There has never been a documented human fatality from overdosing on tetrahydrocannabinol or cannabis. Information about THC's toxicity is derived 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. According to the Merck Index, 12th edition, THC has a LD50 (dose killing half of the research subjects) value of 1270 mg/kg (male rats) and 730 mg/kg (female rats) administered orally dissolved in sesame oil. The LD50 value for rats by inhalation of THC is 42 mg/kg of body weight. One estimate of cannabis's LD50 for humans indicates that about 1500 pounds (680 kilograms) of cannabis would have to be smoked within 14 minutes. This estimate is supported by studies which indicate that the effective dose of THC is at least 1000 times lower than the estimated lethal dose (a "safety ratio" of 1000:1). This is much higher than alcohol (safety ratio of 10), cocaine (15), or heroin (6).
|rat (male)||oral||1270 |
|rat (female)||oral||730 |
|monkey (LDLo)||intravenous||128 |
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 "Marihuana 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.
Research indicating positive medicinal value
Studies in humans
A number of studies show that THC provides medical benefits for cancer and AIDS patients 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.
In August 2009 a phase IV clinical trial by the Hadassah Medical Center in Jerusalem, Israel was started to investigate the effects of THC on post-traumatic stress disorders in women. THC and other cannabinoid agonist have been shown to be beneficial both in open label studies, as well as in laboratory experiments with animals to ameliorate post-traumatic stress disorders.
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. Research on twelve patients showed that Marinol reduced tics with no significant adverse effects. A six-week controlled study on twenty-four patients showed that 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.
Marinol is now a Schedule III medication which allows doctors to prescribe it for off label uses. It is now being prescribed to a small population of patients for ADHD and Depression.
Studies in animals and in vitro
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.
In in-vitro experiments, THC at extremely high concentrations, which could not be reached with commonly-consumed doses, caused inhibition of plaque formation (which are associated with Alzheimer's disease) better than currently-approved drugs.
THC may also be an effective anti-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).
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.
Research indicating negative side-effects
Some studies 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. Using positron emission tomography (PET), one study reports altered memory-related brain function in marijuana users. Conceivable long-term ill effects of THC on humans are disputed. Its status as an illegal drug in most countries makes research difficult.
Some studies have suggested that marijuana 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. 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." Contrastingly, 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 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. Research from 2007 reported a correlation between cannabis use and increased cognitive function in schizophrenic patients.
A 2008 National Institutes of Health study of 18 chronic heavy marijuana users with cardiac and cerebral abnormalities (averaging 78 to 350 marijuana cigarettes per week, or 30 g to 270 g (1 to 9.5 ounces)) 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 fifteen heavy marijuana users (consuming at least five marijuana cigarettes daily for on average twenty years) and sixteen 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. However, the study indicates that they are unsure that the problems were caused by marijuana alone.
A 2009 study found that there was a high prevalence of cannabis in the toxicologic analysis of homicide (22%) and suicide victims (11%) in Australia. In a similar study from Sweden also it was also found that suicide victims had a significant higher use of cannabis, but the authors found that "this was explained by markers of psychological and behavioural problems".
In the cannabis plant THC occurs mainly as tetrahydrocannabinol carboxylic acid (THC-COOH). The enzymatic condensation of geranyl pyrophosphate and olivetolic acid gives cannabigerolic acid, which is cyclized by the enzyme THC acid synthase to give THC-COOH. Heating decarboxylates the acid to THC.
THC is metabolized mainly to 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 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.
Synthetic THC is known as dronabinol. It is available as a prescription drug (under the trade name 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. 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. It is marketed in Canada by GW Pharmaceuticals, being the first cannabis-based prescription drug in the world (in modern times).
Comparisons to medical marijuana
Dronabinol is known to produce mild side effects similar to cannabis. Many scientists believe that dronabinol lacks beneficial properties of cannabis, which contains 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. Others have countered that the effects of all of cannabis's cannabinoids have not been completely studied and are not fully understood.
It takes over one hour for Marinol to reach full systemic effect, compared to 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. This powerful psychoactive effect, however, has led to recreational use of Marinol. 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. 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 cannabis remains Schedule I, except nabilone. Taking a Marinol pill to manage nausea can be ineffective because nausea can cause the pill to be ejected before it is absorbed by the body.
Marinol is also more expensive than medical marijuana, costing for example US$723 for 30 doses at 10 mg online, as of May, 2008.
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.
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, 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. This would put THC in the Convention's least stringently-controlled Schedule.
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- ↑ McPartland, J.M.; Russo, E.B. (2001). "Cannabis and cannabis extracts: greater than the sum of their parts" (PDF). J Cannabis Ther 1 (3-4): 103–132. http://www.omma1998.org/McPartland-Russo-JCANT%201(3-4)-2001.pdf.
- ↑ Pickens JT (1981). "Sedative activity of cannabis in relation to its delta'-trans-tetrahydrocannabinol and cannabidiol content". Br. J. Pharmacol. 72 (4): 649–56.
- ↑ Burns, Tammy L.; Ineck, Joseph R. (2006). "Cannabinoid Analgesia as a Potential New Therapeutic Option in the Treatment of Chronic Pain". The Annals of Pharmacotherapy 40 (2): 251–266. http://www.theannals.com/cgi/content/abstract/40/2/25.
- ↑ http://www.druglibrary.org/schaffer/hemp/medical/marinol1.htm
- ↑ McKim, William A (2002). Drugs and Behavior: An Introduction to Behavioral Pharmacology (5th Edition). Prentice Hall. pp. 400. ISBN 0-13-048118-1.
- ↑ 
- ↑ "Compare Marinol Prices on PharmacyChecker.com". www.pharmacychecker.com. http://www.pharmacychecker.com/Pricing.asp?DrugName=Marinol&DrugId=25680&DrugStrengthId=43149. Retrieved 2008-05-31.
- ↑ Calhoun SR, Galloway GP, Smith DE (1998). "Abuse potential of dronabinol (Marinol)". Journal of psychoactive drugs 30 (2): 187–96.
- ↑ 
- Calhoun SR, Galloway GP, Smith DE (1998). "Abuse potential of dronabinol (Marinol)". J Psychoactive Drugs 30 (2): 187–96.
- 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.
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