Cannabinoids, antiemetic action

Cannabinoids Marijuana derivatives, including dronabinol [droe NAB i nol] and nabilone, are effective against moderately emetogenic chemotherapy. However, they are seldom first-line antiemetics because of their serious side effects, including dysphoria, hallucinations, sedation, vertigo, and disorientation. In spite of their psychotropic properties (see p. 105), the antiemetic action of cannabinoids may not involve the brain synthetic cannabinoids having no psychotropic activity, nevertheless are antiemetic. 

The mechanism of cannabinoid antiemetic activity is not well understood. As pointed out above, it does not seem to involve CB, or CB2. Fan has shown that anandamide and some synthetic cannabinoid agonists inhibit the activation of 5-HT3 receptors in rat nodose ganglion neurons [61]. These receptors are known to mediate emetic activity. However, we have found that HU-211 does not bind to 5-HT3 receptors (unpublished observations). Hence, although cannabinoids may act, in part at least, through this serotonin receptor, this mode of action does not account for the total activity. 

Nabilone is a synthetic cannabinoid and has properties similar to tetrahydrocannabinol (the active constituent of marijuana) which has an antiemetic action. It is used to relieve nausea or vomiting caused by cytotoxic drugs. Adverse effects include somnolence, dry mouth, decreased appetite, dizziness, euphoria, dysphoria, postural hypotension, confusion and psychosis. These may be reduced if prochlorperazine is given concomitantly. 

Dronabinol (delta-9-tetrahydrocannabinol marinol) is a naturally occurring cannabinoid that can be synthesized chemically or extracted from the marijuana plant. Cannabis sativa. The antiemetic action of dronabinol probably relates to stimulation of the CBj subtype of cannabinoid receptors on neurons in and around the vomiting center. 

Darmani, N.A. (2002a) Antiemetic action of ACtetrahydrocannabinold and synthetic cannabinoids in chemotherapy-induced nausea and vomiting, in Biology of Marijuana Prom Gene to Behavior, E.S. Onaivi, Ed., pp. 356-389. London, U.K. Taylor and Francis. 

Dronabinol (tetrahydrocannabinol), the active principle from cannabis and synthetic cannabinoids, nabilone and levonantradol are effective in treating nausea and vomiting in cancer chemotherapy. The mode of action is unclear but appears to involve cannabinoid CBi receptors. Cannabinoids have been shown to reduce acetylcholine release in the cortex and hippocampus, and have been suggested to inhibit medullary activity by a cortical action. Inhibition of prostaglandin synthesis and release of endorphins may also be involved in the antiemetic effect. A review of trials of dronabinol, nabilone or levonantradol concluded that while the cannabinoids were superior to placebo or dopamine receptor antagonists in controlling emesis... 

Cannabinoids have antiemetic activity when used alone or in combination with other antiemetics.5 Dronabinol and nabilone are commercially available oral formulations used for preventing and treating refractory CINV.5,10 Dronabinol is also used to treat anorexia and weight loss associated with human immunodeficiency virus (HIV) infection. Cannabinoids are thought to exert their antiemetic effect centrally, although the exact mechanism of action is unknown.1,10 Sedation, euphoria, hypotension, ataxia, dizziness, and vision difficulties can occur with cannabinoids. 

There are two features of the cannabinoids which may ultimately be of therapeutic importance. THC lowers intraocular pressure, which may be of benefit in the treatment of glaucoma. There is also evidence that THC is a moderately effective antiemetic agent. Such a discovery has led to the development of nabilone, a synthetic cannabinoid, as an antiemetic agent, but its use is limited because of the dysphoria, depersonalization, memory disturbance and other effects which are associated with the cannabinoids. Whether the bronchodilator action of THC will ever find therapeutic application in the treatment of asthma remains an open question. 

Darmani NA (2001b) The cannabinoid CBl receptor antagonist SR 141716A reverses the antiemetic and motor depressant actions of WIN 55, 212-2. Eur J Pharmacol 430 49-58... 

Darmani NA, Sim-Selley LJ, Martin BR, Janoyan JJ, Crim JL, Parekh B, Breivogel CS (2003b) Antiemetic and motor-depressive actions of CP55,940 cannabinoid CBl receptor characterization, distribution, and G- protein activation. Eur J Pharmacol 459 83-95... 

Levitt [ 146] has recently commented, somewhat facetiously, that, The use of cannabinoids as cancer chemotherapy antiemetics represents, in essence, using a drug with a relatively undefined mechanism of action to treat the side-effects of other drugs, also with relatively undefined mechanisms of action which are being used to treat cancer, a disease or series of diseases whose precise nature remains enigmatic . This is a situation not unknown in other areas of medicinal research, but apparently not to the extent noted in this field. 

Much of our understanding of the physiology of emesis and nausea is due to Borison and McCarthy, and so is also the little we know on the mode of action of cannabinoids as antiemetics [149-152]. 

Darmani, N. A. (2001) The cannabinoid antagonist/inverse agonist SR 141716A reverses the antiemetic and motor depressant action of WIN 55,212-2 in the least shrew. Ear. J. Pharmacol. 430, 49-58. 

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