Antiemetic drugs cannabinoids

A9-Tetrahydrocannabinol is the major psychoactive cannabinoid in marijuana (Cannabis sativa). Its synthetic form, dronabinol, became available in the U.S. in 1985 as an antiemetic for patients receiving emetogenic chemotherapy. However, it is seldom used as a first-line antiemetic because of its psychoactive effects, and its use is usually limited to patients who have a low tolerance or minimal response to other antiemetic drugs (see Chapter 18). 

Vincent BJ, McQuiston DJ, Einhorn LH, Nagy CM, Brames MJ. (1983). Review of cannabinoids and their antiemetic effectiveness. Drugs. 25(suppl 1) 52-62. 

The resin secreted by Cannabis indica and Cannabis sativa, varieties of hemp, is known variously as marijuana, hashish or bhang and is abused as a hallucinogenic drug. It appears however to have some beneficial properties and is currently under test as an antiemetic in cancer therapy. The secretion contains a number of interrelated oxygen heterocycles, some of which are shown in Scheme 281, which attempts to indicate their biosynthetic relationships (70MI22401). The cannabinoids are probably derived from a monoterpene unit based on p-menthane and 5-n-pentylresorcinol (olivetol), acting the part of a polyketide. 2,2-Dimethylchromene biosynthesis also requires the intervention of an isoprene fragment. 

In our 1987 review, we summarized the research and clinical experience in this area [1], Surprisingly, in spite of the enormous public interest in medical marijuana and countless articles in the daily press and magazines focused predominantly on this aspect of marijuana use, little progress has been reported on the antiemetic activity of cannabinoids in the last decade. Plasse et al. have reviewed the clinical experience gained over 7 years with dronabinol (d9-THC) in antiemetic treatment [117]. With doses of 7 mg/m2 or below, complete response was noted in 36% of the patients, 32% showed partial response and 32% showed no response. However, 65% displayed drowsiness and dizziness and 12% had dysphoric effects. Combination treatment of dronabinol with prochlorperazine (a dopamine receptor blocker widely used as an antipsychotic drug with antiemetic effects) was more effective than each drug alone [118]. 

Cannabis is one of the oldest and most widely used drugs in the world. In different Western countries the possible therapeutic use of cannabinoids as antiemetics in patients with cancer or in patients with multiple sclerosis has become an issue, because of the prohibition of cannabis, and has polarized opinion about the seriousness of its adverse effects (1,2). 

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. 

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. 

Very few other cannabinoids have been tested (or at least reported) in animals. A-Methyllevonantradol (cf. 9) and nabilone (39) have been compared in the cat model [151]. Both cannabinoids showed dose-dependent antiemetic activity at the 20-100 mg/kg dose levels, A-methyllevonantradol being ca. 5-times more active than nabilone. The latter drug had previously been shown to suppress in the cat emesis induced by apomorphine, deslanoside and the anticancer drugs l,3-bis(2-chlorethyl)-l-nitrosourea (BCNU) and cisplatin, but not nicotine. At the doses tested (25-100/ig/kg), nabilone produced behavioural disturbances, from mild ataxia and display of pleasure at 25 /ig/kg to severe locomotor disturbance, catatonic behaviour and vocalization at 100 /ig/kg. 

Several other synthetic cannabinoids have reached the clinical stage. Levonantradol (9), which was discussed above, is, in addition to being an analgetic, also a potent antiemetic [169-171], It is the only cannabinoid available for parenteral use. This is of considerable clinical importance, as oral administration is certainly not efficient in patients who are already vomiting. It appears to be slightly more effective than THC however, because of the pronounced side-effects, it will probably not be introduced as a drug on the market. 

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