Marihuana has been used for over 2 centuries. Its major psychoactive constituent, delta-9-tetrahydrocannabinol (THC) was isolated in 1964 and first used to control nausea and vomiting during chemotherapy in the 1970s. THC has cardiovascular, pulmonary and endocrinological effects as well as actions on the central nervous system. Alterations in mood, memory, motor coordination, cognitive ability, sensorium, spatial- and self-perception are commonly experienced. The precise antiemetic mechanism is unknown. THC and nabilone act at a number of sites within the central nervous system. Cannabinoids have also been shown to inhibit prostaglandin synthesis in vitro. In controlled clinical trials, THC is superior to placebo and prochlorperazine in antiemetic effectiveness. Effectiveness of THC correlates to a 'high' experienced by the patient. A variety of chemotherapy regimens respond to THC including high-dose methotrexate and the doxorubicin, cyclophosphamide, fluorouracil combination. Cisplatin is more resistant. Side effects are generally well tolerated but may limit THC use in the elderly or when high doses are administered. Nabilone, a synthetic cannabinoid, is also an effective antiemetic which is more active than prochlorperazine in preventing chemotherapy-induced emesis, including cisplatin-containing regimens. Side effects are similar to THC and may be dose-limiting. Levonantradol, another synthetic cannabinoid, is an effective antiemetic. It may provide more flexibility in the outpatient setting since it can be administered orally or intramuscularly. Most side effects are mild except for dysphoria which may be dose-limiting.

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OBJECTIVE: To quantify the antiemetic efficacy and adverse effects of cannabis used for sickness induced by chemotherapy. DESIGN: Systematic review.

DATA SOURCES: Systematic search (Medline, Embase, Cochrane library, bibliographies), any language, to August 2000.

STUDIES: 30 randomised comparisons of cannabis with placebo or antiemetics from which dichotomous data on efficacy and harm were available (1366 patients). Oral nabilone, oral dronabinol (tetrahydrocannabinol), and intramuscular levonantradol were tested. No cannabis was smoked. Follow up lasted 24 hours.

RESULTS: Cannabinoids were more effective antiemetics than prochlorperazine, metoclopramide, chlorpromazine, thiethylperazine, haloperidol, domperidone, or alizapride: relative risk 1.38 (95% confidence interval 1.18 to 1.62), number needed to treat 6 for complete control of nausea; 1.28 (1.08 to 1.51), NNT 8 for complete control of vomiting. Cannabinoids were not more effective in patients receiving very low or very high emetogenic chemotherapy. In crossover trials, patients preferred cannabinoids for future chemotherapy cycles: 2.39 (2.05 to 2.78), NNT 3. Some potentially beneficial side effects occurred more often with cannabinoids: "high" 10.6 (6.86 to 16.5), NNT 3; sedation or drowsiness 1.66 (1.46 to 1.89), NNT 5; euphoria 12.5 (3.00 to 52.1), NNT 7. Harmful side effects also occurred more often with cannabinoids: dizziness 2.97 (2.31 to 3.83), NNT 3; dysphoria or depression 8.06 (3.38 to 19.2), NNT 8; hallucinations 6.10 (2.41 to 15.4), NNT 17; paranoia 8.58 (6.38 to 11.5), NNT 20; and arterial hypotension 2.23 (1.75 to 2.83), NNT 7. Patients given cannabinoids were more likely to withdraw due to side effects 4.67 (3.07 to 7.09), NNT 11.

CONCLUSIONS: In selected patients, the cannabinoids tested in these trials may be useful as mood enhancing adjuvants for controlling chemotherapy related sickness. Potentially serious adverse effects, even when taken short term orally or intramuscularly, are likely to limit their widespread use.

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No abstract available

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Eighty evaluable patients receiving chemotherapy were entered on a random prospective double-blind study to evaluate the effectiveness of nabilone, a synthetic cannabinoid, compared to prochlorperazine. Most of these patients received cisplatin, a drug that universally produces severe nausea and vomiting, as part of a combination chemotherapy regimen. The patients served as their own controls, receiving either nabilone or prochlorperazine during two consecutive treatment courses with the identical chemotherapy. Side effects consisting of hypotension and lethargy were more pronounced with nabilone. Toxicity, in general, did not preclude antiemetic treatment and in no way interfered with chemotherapy. Sixty patients (75 per cent) reported nabilone to be more effective than prochlorperazine for relief of nausea and vomiting. Of these 60 patients, 46 required further chemotherapy and continued taking nabilone as the antiemetic of choice.

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In a previous study on the antiemetic effect of nabilone (N) in patients with lung cancer receiving chemotherapy (CT), we found that N was only moderately effective and that its side effects limited its use, especially in elderly outpatients. We, therefore, performed a new study of N in combination with dexamethasone (DXM), a potent antiemetic in itself, to evaluate whether the addition of DXM to N would improve the antiemetic effect and/or reduce the side effects. Forty patients with lung cancer were enrolled in the study. A randomized, third-party-blinded, crossover design was used. Study drugs were given during two consecutive, identical CT cycles. N was given at a fixed dosage regimen of 2 mg b.i.d. The initial dose was administered the evening before CT, the second dose at 0.5 h before CT, and the third dose in the evening 12 h after CT. DXM, 8 mg, or placebo was given orally with the first dose of N. The subsequent doses (either 10 mg DXM or saline) were given intravenously 0.5 h before CT and at 2 and 6 h after the start of CT. The CT regimens given included the following drugs in various combinations: cisplatin, cyclophosphamide, adriamycin, etoposide (VP-16), vincristine, and vindesine. The combination of N and DXM was significantly superior to N alone in the reduction of vomiting episodes, both in subgroups of patients receiving cisplatin and in those receiving other CT combinations. There was no statistically significant difference between the treatments with regard to the patients' assessments of the severity of nausea or effects on appetite. Approximately half the patients (63% with N plus DXM versus 47% with N) reported no side effects. The frequency and severity of central nervous system adverse reactions, mainly vertigo, were similar in both treatment groups. The fall in blood pressure was significantly greater after N alone. Two thirds of the patients preferred N plus DXM. Thus, the addition of DXM to N enhanced the therapeutic yield of N, and we recommend DXM as an adjunct to N, when the use of steroids is not contraindicated. The optimal dose and schedule of DXM was not investigated in our study; a higher dose of DXM might increase the clinical benefit of the drug combination tested.

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An anti-emetic drug, nabilone, a synthetic cannabinoid, has been compared with prochlorperazine in 24 lung cancer patients receiving cancer chemotherapy. Each of the drugs studied was given orally every 12 hours, starting the night before chemotherapy, during one of two consecutive identical chemotherapy cycles in accordance with a double-blind cross-over random order assignment. Single doses were 2 mg of nabilone, or 15 mg of prochlorperazine. The chemotherapeutic regimens given included the following drugs in various combinations: cis-platinum, vincristine, cyclophosphamide, adriamycin, vindesine, and etoposide (VP16). Nabilone was significantly superior to prochlorperazine in the reduction of vomiting episodes. Side effects, mainly vertigo, were evident in nearly half of the patients after nabilone, and three patients were withdrawn from the study due to decreased coordination and hallucinations after nabilone. Side effects from prochlorperazine were limited to mild drowsiness in one patient. Two-thirds of the patients preferred nabilone to prochlorperazine. We conclude that nabilone is a moderately effective anti-emetic drug, but that the unpredictability of its side effects call for careful patient information, especially with elderly outpatients. We recommend that at least after the first dose of nabilone, the patient should be kept under close observation during 4 hours

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The antiemetic effect of oral nabilone, a synthetic cannabinoid, given at a dose of 2 mg every 12 hours was compared to oral slow-release capsules of prochlorperazine given at a dose of 10 mg every 12 hours by a double-blind crossover method in 37 patients receiving cancer chemotherapy. Patients received one of the following as the primary emetic stimulus: high-dose cis-dichlorodiammineplatinum(II) (DDP), low-dose DDP, mechlorethamine, streptozotocin, actinomycin D, or DTIC. Although results varied according to strength of emetic stimulus received, both nabilone and prochlorperazine appeared to produce antiemetic effects. Eighteen of the 37 patients achieved a complete or partial elimination of symptoms: seven with nabilone alone, three with prochlorperazine alone, and eight with each drug. Nabilone appeared to be the more effective antiemetic for patients who received chemotherapy agents other than high dose DDP; it was equivalent to prochlorperazine for those who did receive high-dose DDP. Side effects from prochlorperazine were limited to mild drowsiness occurring among 35% of the patients. The side effects from nabilone were drowsiness and dizziness which occurred frequently and were dose-limiting in 25% of patients.

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Nabilone is a cannabinol derivative which has potent central antiemetic effects in animals. We observed that the drug significantly reduced the nausea and vomiting induced by cancer chemotherapy in 10 of 13 patients who were refractory to conventional antiemetics. A dose-response effect was apparent. The drug was generally well-tolerated, although it also had sedative effects. Additionally, dizziness, decreased coordination and postural hypotension were observed in some patients. Euphoric effects of the agent were minimal at antiemetic dosage levels.

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In a randomized, double-blind, crossover trial, nabilone was compared to prochlorperazine for control of cancer chemotherapy-induced emesis in 30 children 3.5 to 17.8 years of age. All subjects received two consecutive identical cycles of chemotherapy with the trial antiemetics given in accordance to a body weight-based dosage schedule beginning eight to 12 hours before treatment. The overall rate of improvement of retching and emesis was 70% during the nabilone and 30% during the prochlorperazine treatment cycles (P = .003, chi 2 test). On completion of the trial, 66% of the children stated that they preferred nabilone, 17% preferred prochlorperazine, and 17% had no preference (P = .015, chi 2 test). Major side effects (dizziness, drowsiness, and mood alteration) were more common (11% v 3%) during the nabilone treatment cycles. CNS side effects appeared to be dose related and were most likely to occur when the nabilone dosage exceeded 60 micrograms/kg/d, but individual tolerance to nabilone varied considerably. Lower dosages of nabilone were associated with equivalent efficacy and no major side effects. Nabilone appears to be a safe, effective, and well-tolerated antiemetic drug for children receiving cancer chemotherapy. Although major side effects may occur at higher dosages, nabilone is preferable to prochlorperazine because of improved efficacy.

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A prospective randomised double blind crossover trial was conducted comparing the new synthetic cannabinoid nabilone with oral domperidone in a group of children receiving repeated identical courses of emetogenic chemotherapy for a variety of malignant diseases. Eighteen of 23 consecutive eligible children, aged 10 months to 17 years, completed the trial. When taking nabilone they experienced significantly fewer vomiting episodes and less nausea, and two thirds expressed a preference for the drug. The most common side effects of treatment with nabilone were somnolence and dizziness, with one patient being disturbed by hallucinations. The results indicate that nabilone is an effective antiemetic for children having chemotherapy, even for young children. It seems to be superior in this respect to domperidone, and although it has a higher incidence of side effects, these are mostly acceptable to patients. It can be recommended as an alternative to conventional antiemetic treatment throughout childhood.

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Cannabinoids - the active components of Cannabis sativa and their derivatives - exert palliative effects in cancer patients by preventing nausea, vomiting and pain and by stimulating appetite. In addition, these compounds have been shown to inhibit the growth of tumour cells in culture and animal models by modulating key cell-signalling pathways. Cannabinoids are usually well tolerated, and do not produce the generalized toxic effects of conventional chemotherapies. So, could cannabinoids be used to develop new anticancer therapies?

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Cannabis occurs naturally in the dried flowering or fruiting tops of the Cannabis sativa plant. Cannabis is most often consumed by smoking marihuana. Cannabinoids are the active compounds extracted from cannabis. Recently, there has been renewed interest in cannabinoids for medicinal purposes. The two proven indications for the use of the synthetic cannabinoid (dronabinol) are chemotherapy-induced nausea and vomiting and AIDS-related anorexia. Other possible effects that may prove beneficial in the oncology population include analgesia, antitumor effect, mood elevation, muscle relaxation, and relief of insomnia. Two types of cannabinoid receptors, CB1 and CB2, have been detected. CB1 receptors are expressed mainly in the central and peripheral nervous system. CB2 receptors are found in certain nonneuronal tissues, particularly in the immune cells. Recent discovery of both the cannabinoid receptors and endocannabinoids has opened a new era in research on the pharmaceutical applications of cannabinoids. The use of cannabinoids should be continued in the areas indicated, and further studies are needed to evaluate other potential uses in clinical oncology.

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