Antiemetic and motor-depressive actions of CP55,940: cannabinoid CB1 receptor characterization, distribution, and G-protein activation.
Abstract
“Dibenzopyran (Delta(9)-tetrahydrocannabinol) and aminoalkylindole [R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrolol[1,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl) methanone mesylate; (WIN55,212-2)] cannabinoids suppress vomiting produced by cisplatin via cannabinoid CB(1) receptors. This study investigates the antiemetic potential of the “nonclassical” cannabinoid CP55,940 [1alpha,2beta-(R)-5alpha]-(-)-5-(1,1-dimethyl)-2-[5-hydroxy-2-(3-hydroxypropyl) cyclohexyl-phenol] against cisplatin-induced vomiting and assesses the presence and functionality of cannabinoid CB(1) receptors in the least shrew (Cryptotis parva) brain. CP55,940 (0.025-0.3 mg/kg) reduced both the frequency of cisplatin-induced emesis (ID(50)=0.025 mg/kg) and the percentage of shrews vomiting (ID(50)=0.09 mg/kg). CP55,940 also suppressed shrew motor behaviors (ID(50)=0.06- 0.21 mg/kg) at such doses. The antiemetic and motor-suppressant actions of CP55,940 were countered by SR141716A [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide], indicating both effects are cannabinoid CB(1) receptor-mediated. Autoradiographic studies with [3H]-SR141716A and [35S]-GTPgammaS binding revealed that the distribution of the cannabinoid CB(1) receptor and its activation pattern are similar to rodent brain and significant levels are present in brain loci (e.g., nucleus tractus solitarius (NTS)) that control emesis. The affinity rank order of structurally diverse cannabinoid ligands for cannabinoid CB(1) receptor in shrew brain is similar to rodent brain: HU-210=CP55,940=SR141716A>/=WIN55,212-2>/=delta-9-tetrahydrocannabinol>methanandamide=HU-211=cannabidiol=2-arachidonoylglycerol. This affinity order is also similar and is highly correlated to the cannabinoid EC(50) potency rank order for GTPgammaS stimulation except WIN55,212-2 and delta-9-tetrahydrocannabinol potency order were reversed. The affinity and the potency rank order of tested cannabinoids were significantly correlated with their antiemetic ID(50) potency order against cisplatin-induced vomiting (CP55,940>WIN55,212-2=delta-9-tetrahydrocannabinol) as well as emesis produced by 2-arachidonoylglycerol or SR141716A (CP55,940>WIN55,212-2>delta-9-tetrahydrocannabinol).”
Antiemetic efficacy of levonantradol compared to delta-9-tetrahydrocannabinol for chemotherapy-induced nausea and vomiting.
Abstract
“The antiemetic efficacy of im levonantradol, a synthetic cannabinoid, given at a dose of 1 mg every 4 hours, was compared to oral delta-9-tetrahydrocannabinol (THC) given at a dose of 15 mg every 4 hours in a double-blind crossover study. Twenty-six patients receiving emetogenic cancer chemotherapy were evaluated. For each drug, 28% of treated patients had no nausea. The median number of emetic episodes with levonantradol was 2.0 versus 3.0 for THC (P = 0.06). Side effects occurred in 91.7% and 97.3% of levonantradol and THC patients, respectively, with drowsiness and dizziness most commonly seen. Side effects were generally well-tolerated, with only 13.9% of levonantradol and 21.6% of THC patients discontinuing treatment because of side effects. Levonantradol appears to be at least as effective an antiemetic as THC and is the only cannabinoid available for parenteral use.”
Levonantradol for the treatment of chemotherapy-induced nausea and vomiting.
Abstract
“Twenty patients with cancer previously unresponsive to antiemetic treatment of chemotherapy-induced nausea and vomiting were treated with the new tetrahydrocannabinoid Levonantradol. 15 patients experienced substantial relief and 10 of them preferred the drug for further courses. These observations suggest that Levonantradol can be beneficial to patients refractory to conventional antiemetic therapy.”
Delta-9-tetrahydrocannabinol in cancer chemotherapy: research problems and issues.
Abstract
“A critical review of the literature assessing the antiemetic efficacy of delta-9-tetrahydrocannabinol (THC) in patients receiving cancer chemotherapy showed considerable inconsistency in results. The equivocal nature of these results partly reflects the difficulty of doing research on antiemetic therapies, but also can be attributed to differences in the adequacy and nature of the research designs, procedures, and assessment instruments that have been used. Several factors were also identified that are seldom studied but may be important in determining whether THC will be effective: patient variables, such as chemotherapy regimen and age; pharmacologic variables, such as drug tolerance, dose, schedule, toxicity, route of administration, and drug interactions; and environmental variables associated with administration setting. The need to differentiate pharmacologically induced from conditioned nausea and vomiting was also pointed out. We believe that THC does have antiemetic efficacy, but the lack of controlled research does not allow precise knowledge of its true effectiveness and toxicity. Well-controlled trials are needed to help answer some of these questions.”
Antiemetic effect of tetrahydrocannabinol. Compared with placebo and prochlorperazine in chemotherapy-associated nausea and emesis.
Abstract
“Fifty-five patients harboring a variety of neoplasms and previously found to have severe nausea or emesis from antitumor drugs were given antiemetic prophylaxis in a double-blind, randomized, crossover fashion. Tetrahydrocannabinol (THC), prochlorperazine, and placebo were compared. Nausea was absent in 40 of 55 patients receiving THC, eight of 55 patients receiving prochlorperazine, and five of 55 in the placebo group.
The antiemetic effect of THC appeared to be more efficacious for cyclophosphamide, fluorouracil, and doxorubicin hydrochloride, and less so for mechlorethamine hydrochloride and the nitrosureas.
Tetrahydrocannabinol appears to offer significant control of nausea in most patients and exceeding by far that provided by prochlorperazine.”
http://www.ncbi.nlm.nih.gov/pubmed/6254456
Amelioration of cancer chemotherapy-induced nausea and vomiting by delta-9-tetrahydrocannabinol.
Abstract
“The antinausea and antivomiting effects of delta-9-tetrahydrocannabinol (THC) in children receiving cancer chemotherapy were compared with those of metoclopramide syrup and prochlorperazine tablets in two double-blind studies. THC was found to be a significantly better antinausea and antivomiting agent… In some patients, THC enhanced appetite during a course of chemotherapy. In two patients, a “high” associated with THC administrationwas reported. Drowsiness was reported significantly more frequently with THC.”
An efficient new cannabinoid antiemetic in pediatric oncology.
Abstract
“Delta-8-tetrahydrocannabinol (delta-8-THC), a cannabinoid with lower psychotropic potency than the main Cannabis constituent, delta-9-tetrahydrocannabinol (delta-9-THC), was administered (18 mg/m2 in edible oil, p.o.) to eight children, aged 3-13 years with various hematologic cancers, treated with different antineoplastic drugs for up to 8 months. The total number of treatments with delta-8-THC so far is 480. The THC treatment started two hours before each antineoplastic treatment and was continued every 6 hrs for 24 hours. Vomiting was completely prevented. The side effects observed were negligible.”
Preliminary efficacy and safety of an oromucosal standardized cannabis extract in chemotherapy-induced nausea and vomiting
“Despite progress in anti-emetic treatment, many patients still suffer from chemotherapy-induced nausea and vomiting (CINV). This is a pilot, randomized, double-blind, placebo-controlled phase II clinical trial designed to evaluate the tolerability, preliminary efficacy, and pharmacokinetics of an acute dose titration of a whole-plant cannabis-based medicine (CBM) containing delta-9-tetrahydrocannabinol and cannabidiol, taken in conjunction with standard therapies in the control of CINV.”
“Compared with placebo, CBM added to standard antiemetic therapy was well tolerated and provided better protection against delayed CINV. These results should be confirmed in a phase III clinical trial.”
“A systematic review of 30 clinical trials involving orally administered synthetic cannabinoids (nabilone and dronabinol) showed that they were superior to dopamine receptor antagonists in preventing CINV. Both are approved by the US Food and Drug Administration for use in CINV refractory to conventional anti-emetic therapy, but some authors have questioned the appropriateness of orally administered cannabinoids due to the variability in their gastrointestinal absorption, low bioavailability, long half-lives and the difficulties for an adequate self titration of the dose.”
“Animal studies suggest that the combined administration of different cannabinoids may enhance some of the therapeutic effects of delta-9-tetrahydrocannabinol (THC). This might explain why some patients preferred marihuana to synthetic cannabinoids in clinical trials.”
Efficacy of Crude Marijuana and Synthetic Delta-9-Tetrahydrocannabinol as Treatment for Chemotherapy-Induced Nausea and Vomiting: A Systematic Literature Review.
Abstract
“Purpose/Objectives: To synthesize the research to determine whether oral delta-9-tetrahydrocannabinol (THC) and smoked marijuana are effective treatments for chemotherapy-induced nausea and vomiting (CINV) and to evaluate side effects and patient preference of these treatments.Data Sources: Original research, review articles, and other published articles in CINAHL(R), MEDLINE(R), and Cochrane Library databases.Data Synthesis: Cannabinoids are effective in controlling CINV, and oral THC and smoked marijuana have similar efficacy. However, smoked marijuana may not be accessible or safe for all patients with cancer. Also, these drugs have a unique side-effect profile that may include alterations in motor control, dizziness, dysphoria, and decreased concentration.Conclusions: This synthesis shows that cannabinoids are more effective than placebo and comparable to antiemetics such as prochlorperazine and ondansetron for CINV.Implications for Nursing: Nurses should feel supported by the literature to recommend oral synthetic THC as a treatment for CINV to their patients and physician colleagues. Nurses should be cognizant of the side-effect profile for this medication and provide appropriate patient education.”