DELTA9-TETRAHYDROCANNABINOL

Absorption

Dronabinol is almost completely absorbed (90 to 95%) after a single oral dose. Due to the combined effects of first-pass hepatic metabolism and high lipid solubility, only 10 to 20% of the administered dose reaches systemic circulation. Relative bioavailability data from healthy male and female subjects suggest that a dose of 4.2 mg of SYNDROS provides comparable systemic exposure (Cmax and AUC) to a 5 mg dronabinol capsule, under fasted conditions, with the Cmax and AUCinf of 1.9 ± 1.3 ng/mL and 3.8 ± 1.8 ng.h/mL respectively. The concentrations of both dronabinol and its major active metabolite (11-hydroxy-delta-9-THC) peak at approximately 0.5 to 4 hours after oral dosing with SYNDROS and decline over several days. The mean inter- and intra-subject variability in dronabinol pharmacokinetics (Cmax and AUCinf) was approximately 66% and 47% and 67% and 14%, respectively, following the administration of SYNDROS to healthy subjects.

Description

Tetrahydrocannabinol (THC) is the main active compound in marijuana. It comes from the plant Cannabis sativa (cannabis), which is a dioecious (monoecious varieties do exist) annual herb naturally found in many tropic and temperate regions of the world. Many varieties of cannabis exist, and two related species (Cannabis indica and Cannabis ruderalia) are main sources of THC. Cannabis sativa is also known as hemp, although this name is not unique to the species; its stem is a source of fiber that has been used throughout history for hundreds of applications including rope, twine, paper, and cloth. Hemp seeds are edible and high in protein. The seeds are also a source of fatty oil that can be used for food, cosmetics, medicines, and as a fuel source. Cannabis contains chemicals called cannabinoids; of the 60 cannabinoids found in Cannabis, one is THC, , which is the psychoactive ingredient in marijuana. Marijuana is produced from the leaves and fl owers of cannabis, and hashish is a resin collected from the female fl owers. The THC content, which determines the effect of cannabis drugs, varies with plant structure, variety, and preparation. Buds and fl owers specifically cultivated for drug use have greater THC content than leaves. THC content may vary from a few tenths of a percent to more than 10%, but good quality marijuana has a THC content of approximately 10%, and good hashish and hashish oils generally have THC contents between 30% and 80%.

Chemical properties

Thick Brown Oil

Originator

Unimed (USA)

History

THC was first isolated from hashish in 1964 by Raphael Mechoulam (1930–) and Yehiel Gaoni at the Weizmann Institute. In the early 1990s, the specific brain receptors affected by THC were identified. These receptors are activated by a cannabinoid neurotransmitter called arachidonylethanolamide, known as anandamide. Anandamide was named by Mechoulam using ananda, which is the Sanskrit word for ecstasy. Anandamide is thought to be associated with memory, pain, depression, and appetite. THC is able to attach to and activate anandamide receptors. These receptors are actually called THC receptors rather than anandamide receptors because researchers discovered that THC attaches to these receptors before anandamide was discovered. The areas of the brain with the most THC receptors are the cerebellum, the cerebral cortex, and the limbic system. This is why marijuana affects thinking, memory, sensory perception, and coordination.

The Uses of DELTA9-TETRAHYDROCANNABINOL

It is the principal active constituent of cannabis. Agonist at CB1 and CB2 cannabinoid receptors. Antiemetic; appetite stimulant. Controlled substance (hallucinogen).

The Uses of DELTA9-TETRAHYDROCANNABINOL

Δ9-Tetrahydrocannabinol (Δ9-THC) is a natural psychoactive compound found in plants of the genus Cannabis. This cannabinoid (CB) binds with high affinity to both the central CB1 receptor (Ki = 41 nM) and the peripheral CB2 receptor (Ki = 36 nM). Δ9-THC, working primarily through these receptors, has diverse effects on perception, cognition, pain sensitivity, body temperature, the immune system, fetal development, and more. This product is intended for forensic and research purposes.[Cayman Chemical]

The Uses of DELTA9-TETRAHYDROCANNABINOL

Medical marijuana remains a controversial topic, but synthetic THC, dronabinol, marketedunder the trade name Marinol, has been available by prescription since 1986. Th edronabinol analog nabilone is another THC prescription drug marketed under the nameCesamet. Marinol and Cesamet, taken as capsules, have Food Drug Administration approvalas an antinausea agent and appetite stimulant (for AIDS patients), but they are also prescribedfor depression and muscle spasms. In 2005, Canada was the first country to approve Sativex,a cannabis spray that relieves pain in people with multiple sclerosis.

Background

Dronabinol (marketed as Marinol) is a synthetic form of delta-9-tetrahydrocannabinol (Δ?-THC), the primary psychoactive component of cannabis (marijuana). THC demonstrates its effects through weak partial agonist activity at Cannabinoid-1 (CB1R) and Cannabinoid-2 (CB2R) receptors, which results in the well-known effects of smoking cannabis such as increased appetite, reduced pain, and changes in emotional and cognitive processes. Due to its evidence as an appetite stimulant and an anti-nauseant, Dronabinol is approved for use in anorexia associated with weight loss in patients with AIDS and for the treatment of nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments .
Tetrahydrocannabinol (THC) and cannabidiol (CBD) are the two most abundant cannabinoids found naturally in the resin of the marijuana plant, both of which are pharmacologically active due to their interaction with cannabinoid receptors that are found throughout the body . While both CBD and THC are used for medicinal purposes, they have different receptor activity, function, and physiological effects. If not provided in their activated form (such as through synthetic forms like Dronabinol or Nabilone), THC and CBD are obtained through conversion from their precursors, tetrahydrocannabinolic acid-A (THCA-A) and cannabidiolic acid (CBDA), through decarboxylation reactions. This can be achieved through heating, smoking, vaporization, or baking of dried unfertilized female cannabis flowers.
From a pharmacological perspective, Cannabis' diverse receptor profile explains its potential application for such a wide variety of medical conditions. Cannabis contains more than 400 different chemical compounds, of which 61 are considered cannabinoids, a class of compounds that act upon endogenous cannabinoid receptors of the body . The endocannabinoid system is widely distributed throughout the central and peripheral nervous system (via the Cannabinoid Receptors CB1 and CB2) and plays a role in many physiological processes such as inflammation, cardiovascular function, learning, pain, memory, stress and emotional regulation, and the sleep/wake cycle among many others . CB1 receptors are found in both the central and peripheral nervous system, and are most abundant in the hippocampus and amygdala, which are the areas of the brain responsible for short-term memory storage and emotional regulation. CB2 receptors are mainly located in the peripheral nervous system and can be found on lymphoid tissue where they are involved in regulation of immune function .

Indications

Dronabinol is indicated for the treatment of anorexia associated with weight loss in patients with AIDS, and nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments.

Definition

ChEBI: A diterpenoid that is 6a,7,8,10a-tetrahydro-6H-benzo[c]chromene substituted at position 1 by a hydroxy group, positions 6, 6 and 9 by methyl groups and at position 3 by a pentyl group. The principal psychoactive constituent f the cannabis plant, it is used for treatment of anorexia associated with AIDS as well as nausea and vomiting associated with cancer chemotherapy.

Manufacturing Process

δ-9-Tetrahydrocannabinol (THC, also known as dronabinol) is the main biologically active component in the Cannabis plant extracted from the resin of Cannabis sativa (marihuana, hashish).
One kg of the fine powdered marijuana plant material [average % of THC was about 5.21%] was macerated with 6 L hexanes (Hexanes GR from EM Sciences) in a percolator (9" in diameter from the top and 20" long, cone shaped) for 24 hours at room temperature and filtered. The macerate was reextracted with 5 L hexanes for another 24 hours. The hexane extracts were combined and evaporated under reduced pressure at low temperature to give 110.7 g residue (11.07% extractives). The % of THC in the hexane extract was 41.21%.
Column Chromatography.
The hexane extract (110.7 g) was mixed with 150 g silica gel (silica gel 60, Art.# 9385-3) and 50 ml hexane. The air dried slurry was transferred to the top of a silica gel column (800 g silica gel 60, particle size 0.04-0.063 mm, from EM Science, Art.# 9385-3). The column was eluted with hexane:ether mixtures in a manner of increasing polarities. Fractions were collected and TLC screened (analytical silica gel plates, developing system: Hexane:Ether (80:20), Visualizing agent: Fast blue). The fractions collected with hexane (3 L) and hexane-ether (95:5, 2 L) were discarded. The following fractions collected with hexane-ether (95:5, 3 L) and hexane-ether (9:1, 5 L) were combined and evaporated to yield 77.2 g of residue. GC analysis of the residue showed THC concentration to be 54.74%.
Fractional Distillation
A portion (30.5 g) of the residue collected above was subjected to fractional distillation under reduced pressure (0.1-0.15 mm/Hg). The temperature was slowly raised to 125°C and the materials collected were kept separate. The temperature was then raised between 140°-160°C where the major fraction was collected (14 g). GC analysis showed >96% THC. Further purification on a silica gel column gives THC with at least 98% purity. An improvement of this process includes the use of high pressure liquid chromatography (HPLC). The preparation of dronabinol and related compounds have employed acidcatalyzed electrophilic condensation of a 5-alkylresorcinol such as 5-npentylresorcinol (commonly known as olivetol) and a menthadienol, followed by cyclization; yield of desired product is about 17-22% (Petrzilka et al., Helv. Chim. Acta, 52, 1102 (1969)).

brand name

Marinol (Unimed).

Therapeutic Function

Appetite stimulant

General Description

Brown amorphous semi-solid, viscous oil or chunky golden yellow solid.

Air & Water Reactions

Slightly soluble in water.

Reactivity Profile

DELTA9-TETRAHYDROCANNABINOLis very unstable to light and high temperatures. DELTA9-TETRAHYDROCANNABINOL should be protected from air during all handling due to its extreme instability. . Flammable and/or toxic gases are generated by the combination of alcohols with alkali metals, nitrides, and strong reducing agents. They react with oxoacids and carboxylic acids to form esters plus water. Oxidizing agents convert them to aldehydes or ketones. Alcohols exhibit both weak acid and weak base behavior. They may initiate the polymerization of isocyanates and epoxides.

Fire Hazard

Flash point data for DELTA9-TETRAHYDROCANNABINOL are not available; however, DELTA9-TETRAHYDROCANNABINOL is probably combustible.

Biological Activity

Cannabinoid receptor agonist (K i values are 5.05 and 3.13 nM for CB 1 and CB 2 receptors respectively; EC 50 values are 6, 0.4 and 8 nM at CB 1 , CB 2 and GPR55 receptors respectively). Major psychoactive constituent of marijuana.

Pharmacokinetics

Dronabinol-induced sympathomimetic activity may result in tachycardia and/or conjunctival injection. Its effects on blood pressure are inconsistent, but subjects have experienced orthostatic hypotension and/or syncope upon abrupt standing.
Dronabinol also demonstrates reversible effects on appetite, mood, cognition, memory, and perception. These phenomena appear to be dose-related, increasing in frequency with higher dosages, and subject to great inter-patient variability. After oral administration, dronabinol capsules have an onset of action of approximately 0.5 to 1 hour and a peak effect at 2 to 4 hours. Duration of action for psychoactive effects is 4 to 6 hours, but the appetite stimulant effect of dronabinol may continue for 24 hours or longer after administration.
Tachyphylaxis and tolerance develop to some of the cardiovascular and CNS pharmacologic effects of dronabinol with chronic use, suggesting an indirect effect on sympathetic neurons. In a study of the pharmacodynamics of chronic dronabinol exposure, healthy male subjects (N = 12) received 12 times the maximum dose for anorexia associated with weight loss in patients with AIDS of dronabinol capsules in divided doses for 16 days. An initial tachycardia induced by dronabinol was replaced successively by normal sinus rhythm and then bradycardia. A decrease in supine blood pressure, made worse by standing, was also observed initially. These subjects developed tolerance to the cardiovascular and subjective adverse CNS effects of dronabinol within 12 days of treatment initiation.
Tachyphylaxis and tolerance do not appear to develop to the appetite stimulant effect of dronabinol. In clinical studies of dronabinol capsules in AIDS patients, at the recommended dosage, the appetite stimulant effect was sustained for up to five months.

Clinical Use

Dronabinol (synthetic △9-THC) i s a n antinauseant approved for the treatment of nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetics. A related cannabinoid, nabilone, was introduced in Canada for his indication in 1982.

Safety Profile

Poison by intraperitoneal and intravenous routes. Moderately toxic by ingestion. Experimental reproductive effects. Questionable carcinogen with experimental tumorigenic and teratogenic data. Human mutation data reported. A hallucinatory drug. When heated to decomposition it emits acrid smoke and irritating fumes. See also CANNABIS.

Metabolism

THC is primarily metabolized in the liver by microsomal hydroxylation and oxidation reactions catalyzed by Cytochrome P450 enzymes. 11-hydroxy-?9-tetrahydrocannabinol (11-OH-THC) is the primary active metabolite, capable of producing psychological and behavioural effects, which is then metabolized into 11-nor-9-carboxy-? 9-tetrahydrocannabinol (THC-COOH), THC's primary inactive metabolite . Dronabinol and its principal active metabolite, 11-OH-delta-9-THC, are present in approximately equal concentrations in plasma. Concentrations of both parent drug and metabolite peak at approximately 0.5 to 4 hours after oral dosing and decline over several days .