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 in
1964.
[4][5][6] 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.
[7] 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.
[8][9][10]
Dronabinol is the
International Nonproprietary Name (INN) for a pure
isomer of THC, (-)-trans-Δ9-tetrahydrocannabinol, that is, the main isomer in cannabis.
[11] 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.
Pharmacology
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.[
citation needed]
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-arachidonoyl glyceride (
2-AG), and other related compounds known as
endocannabinoids. This is similar to the story of the discovery of 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.
[12]
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.
[13]
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; loss of anxiety;
[14][
unreliable medical source?] anxiety in neurotic individuals or individuals unfamiliar with effects;
[14] disorientation;
[14] 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.[
citation needed] 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. It also has
anti-emetic properties, and also may reduce aggression in certain subjects.[
citation needed]
THC has an active
metabolite,
11-Hydroxy-THC, which may also play a role in the analgesic and recreational effects of
cannabis.[
citation needed]
The α7 nicotinic receptor antagonist
methyllycaconitine can block self-administration of THC in rats comparable to the effects of
varenicline on nicotine administration.
[15]
Two studies indicate that THC also has an anticholinesterase action
[16][17] which may implicate it as a potential treatment for
Alzheimer's and
Myasthenia Gravis.
Toxicity
3D rendering of the THC molecule
A
Cannabis sativa flower coated with
trichomes, which contain more THC than any other part of the plant
See also:
Health issues and effects of cannabis
There has never been a documented human fatality from overdosing on tetrahydrocannabinol or cannabis in its natural form.
[18] However, the synthetic THC pill Marinol was cited by the FDA as being responsible for 4 of the 11,687 deaths from 17 different FDA approved drugs between January 1, 1997 to June 30, 2005.
[19] 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.
[20] According to the
Merck Index, 12th edition, THC has an
LD[SIZE=-1]50[/SIZE] (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.
[21] The LD50 value for rats by inhalation of THC is 42 mg/kg of body weight.
[21]
AnimalAdministrationLD50 [mg/kg]ratoral666
[20]rat (male)oral1270
[21]rat (female)oral730
[21]ratinhalation42
[21]ratintraperitoneal373
[20]ratintravenous29
[20]mouseintravenous42
[20]mouseoral482
[20]mouseintraperitoneal168
[20]monkey (
LDLo)intravenous128
[20]dogoral525
[20]
Research
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.
[4] Research was also published in the
academic journal Science, with "Marijuana chemistry" by
Raphael Mechoulam in June 1970,
[22] followed by "Chemical basis of hashish activity" in August 1970.
[23] 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
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.
[24]
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.
[25] THC and other cannabinoid agonists 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 24 patients showed that the patients taking
dronabinol had a significant reduction in tic severity without serious adverse 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.
Dronabinol's usefulness as a treatment for TS cannot be determined until/unless longer controlled studies on larger samples are undertaken.
[26][27][28]
Research on THC has shown that Cannabinoid receptors are responsible for mediated inhibition of dopamine release in the retina.
[29]
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.
[30]
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.
[31]
THC may also be an effective anti-cancer treatment, with studies showing tumor size reduction in mice conducted in 1975
[32] and 2007,
[33] as well as in a pilot study in humans with
glioblastoma multiforme (a type of brain cancer).
[34]
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.
[35]
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.
[36] In
mice low doses of Δ9-THC reduces the progression of
atherosclerosis.
[37]
Research has also shown that past claims of brain damage from cannabis use fail to hold up to the scientific method.
[38] Instead, recent studies with synthetic cannabinoids show that activation of CB1 receptors can facilitate
neurogenesis,
[39] as well as neuroprotection,
[40] 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.
[41][42] THC is both a CB1 and CB2 agonist.
[43]
Research indicating negative side-effects
Conceivable long-term ill effects of THC on humans are disputed, yet its status as an illegal drug in most countries makes research difficult.[
citation needed]
Some studies claim a variety of negative effects associated with long-term use, including short-term memory loss.
[44][45] Some studies have found little or no difference in MRI scans between user groups and non-using control groups[
citation needed]. Using
positron emission tomography (PET), one study reports altered memory-related brain function (23% better memory for the marijuana users in recalling the end of a list of things to remember, but 19% worse memory for marijuana users in recalling the middle of a list of things to remember) in chronic daily marijuana users.
[46]
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.
[47] Other studies have made similar associations, especially in individuals predisposed to psychosis prior to cannabis use.
[48] A 2005 paper from the
Dunedin study suggested an increased risk in the development of psychosis linked to polymorphisms in the COMT gene.
[49] However, a more recent study cast doubt on the proposed connection between this gene and the effects of cannabis on the development of psychosis.
[50] 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."
[51] 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.
[52]
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.
[53] 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.
[54]
Research from 2007 reported a correlation between cannabis use and increased cognitive function in schizophrenic patients.
[55]
A 2008
National Institutes of Health study of 18 chronic heavy marijuana users with cardiac and cerebral abnormalities (averaging 28g to 272g (1 to 8 oz) weekly) and 24 controls found elevated levels of
apolipoprotein C-III (apoC-III) in the chronic smokers.
[56] 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).
[57] It has been suggested that such effects can be reversed with long term abstinence.
[58] However, the study indicates that they are unsure that the problems were caused by marijuana alone. Furthermore, this correlation might suggest self-medication by individuals with these brain features.
A 2008 study at
Karolinska Institute suggested that young rats treated with
THC received an increased motivation for drug use, heroin in the study, under conditions of stress.
[59][60]
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.
[61] In a similar study from Sweden 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."
[62]
Biosynthesis
Biosynthesis of THC
In the
cannabis plant, THC occurs mainly as tetrahydrocannabinol
carboxylic acid (THC-COOH).
Geranyl pyrophosphate and
olivetolic acid react, catalysed by an
enzyme to produce
cannabigerolic acid,
[63] which is cyclized by the enzyme THC acid
synthase to give THC-COOH. Over time, or when heated, THC-COOH is
decarboxylated producing THC. The pathway for THC-COOH biosynthesis is similar to that which produces the bitter acid
humulone in
hops.
[64]
Metabolism
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.
[65]
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. The concentrations obtained from such analyses can often be helpful in distinguishing active from passive use or prescription from illicit use, the route of administration (oral versus smoking), elapsed time since use and extent or duration of use.
[66][67][68]
Dronabinol
Synthesized THC is known as
dronabinol. It is available as a prescription drug (under Marinol
[69]) 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.
[70]
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.[
citation needed]
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). In addition,
Sativex received European regulatory approval in 2010.[
citation needed]
Comparisons to medical marijuana
Main article:
Medical marijuana
Female cannabis plants contain more than 60 cannabinoids, including
cannabidiol (CBD), thought to be the major
anticonvulsant that helps
multiple sclerosis patients;
[71] and
cannabichromene (CBC), an
anti-inflammatory which may contribute to the
pain-killing effect of cannabis.
[72]
It takes over one hour for Marinol to reach full systemic effect,
[73] compared to minutes for
smoked or
vaporized cannabis.
[74] 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."
[75] United States federal law currently registers dronabinol as a
Schedule III controlled substance, but all other cannabinoids remain
Schedule I, excepting synthetics like
nabilone.[
citation needed]
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 17476-7
. 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).[
citation needed]
An article published in the April–June 1998 issue of the
Journal of Psychoactive Drugs found that "Healthcare professionals have concluded THC Helps if you ingest dangerous mold". The authors state that Marinol has a low potential for abuse.
[76]
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".
[77]
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
