Anticonvulsant effects of cannabinoids in mice: Drug interactions within cannabinoids and cannabinoid interactions with phenytoin
- 172 Downloads
The anticonvulsant activity of orally administered δ9-tetrahydrocannabinol (δ9-THC), δ8-THC, cannabidiol (CBD) and cannabinol (CBN) was tested in mice utilizing electroshock and chemoshock methods. In doses tested δ9-THC afforded no protection to mice from chemoshock seizures and was effective against electroshock only in high doses (160–200 mg/kg). CBD and CBN (150–200 mg/kg) were without effect in both tests.
An interaction between cannbinoids was apparent when all three were administered simultaneously (each at 50 mg/kg) because this combination produced a significant reduction in the duration of the hind-limb extensor phase of the electroshock seizures.
The administration of δ9-THC significantly potentiated the anticonvulsant effectiveness of phenytoin against electroshock seizures and this effect was further potentiated by the concurrent administration of CBD. Whilst the potentiation of phenytoin by δ9-THC (50 mg/kg) was of the order of 1.5 times, the combination of δ-9THC and CBD (each 50 mg/kg) produced a four-fold potentiation.
Neither within-cannabinoid interaction nor cannabinoid potentiation of phenobarbitone effectiveness could be demonstrated in chemoshock tests.
The mechanism of the cannabinoid facilitation of phenytoin is unknown but it possibly involves activity at central nervous system level rather than being a metabolic interaction. This drug interaction may have potential clinical significance.
Key wordsδ9-Tetrahydrocannabinol Cannabidiol Cannabinol Phenytoin Phenobarbitone Anticonvulsant Drug-Interactions
Unable to display preview. Download preview PDF.
- Anderson, P. F., Jackson, D. M., Chesher, G. B.: The interaction of δ 9-tetrahydrocannabinol and cannabidiol on intestinal motility in mice. J. Pharm. Pharmacol. 26, 136–137 (1974)Google Scholar
- Brown, W. C.: Unpublished observations (1952) cited by Swinyard et al. (1952)Google Scholar
- Carlini, E. A., Leite, J. R., Tannhauser, M., Berardi, A. C.: Cannabinol and Cannabis sativa extract protect mice and rats against convulsive agents. J. Pharm. Pharmacol. 25, 664–665 (1973)Google Scholar
- Chesher, G. B., Jackson, D. M., Starmer, G. A.: Interaction of cannabis and general anaesthetic agents in mice. Brit. J. Pharmacol. (in press) (1974)Google Scholar
- Cohen, G. M., Peterson, D. W., Mannering, G. J.: Interactions of δ 8-tetrahydrocannabinol with the hepatic microsomal drug metabolizing system. Life Sci. 10, 1207–1215 (1971)Google Scholar
- Consroe, P. F., Man, D. P.: Effects of δ 9 and δ 8-tetrahydrocannabinol on experimentally induced seizures. Life Sci. 13, 429–439 (1973)Google Scholar
- Davis, J. P., Ramsey, H.H.: Antiepileptic action of marihuana-active substances. Fed. Proc. 8, 284–285 (1949)Google Scholar
- Dingel, J. V., Miller, K. W., Heath, E. C., Klausner, H. A.: The intracellular localization of δ 9-tetrahydrocannabinol in liver and its effects on drug metabolism in vitro. Biochem. Pharmacol. 22, 949–958 (1973)Google Scholar
- Fujimoto, J. M.: Modification of the effects of δ 9-tetrahydrocannabinol by phenobarbital pretreatment in mice. Toxicol. appl. Pharmacol. 23, 623–634 (1972)Google Scholar
- Garriott, J. C., Forney, R. B., Hughes, F. W., Richards, A. B.: Pharmacologic properties of some cannabis related compounds. Arch. int. Pharmacodyn. 171, 425–434 (1968)Google Scholar
- Gill, E. W., Paton, W. D. M., Pertwee, R. G.: Preliminary experiments on the chemistry and pharmacology of cannabis. Nature (Lond.) 228, 134–136 (1970)Google Scholar
- Goodman, L. S., Greival, M. S., Brown, W. C., Swinyard, E. A.: Comparison of maximal seizures evoked by pentylenetetrazol (Metrazol) and electroshock in mice, and their modification by anticonvulsants. J. Pharmacol. exp. Ther. 108, 168–176 (1953)Google Scholar
- Krantz, J. C., Berger, H. J., Welch, B. L.: Blockade of (−)trans-δ 9-tetrahydrocannabinol depressant effect by cannabinol in mice. Amer. J. Pharm. 143, 149–152 (1971)Google Scholar
- Kubena, R. K., Barry, H.: Interactions of δ 1-tetrahydrocannabinol with barbiturates and amphetamines. J. Pharmacol. exp. Ther. 173, 94–100 (1970)Google Scholar
- Litchfield, J. T., Wilcoxon, F.: A simplified method of evaluating dose-effect experiments. J. Pharmacol. exp. Ther. 96, 99–113 (1949)Google Scholar
- Loewe, S.: Studies on the pharmacology of marihuana. In: The marihuana problems in the city of New York. Ed. by the Mayor's Committee on Marihuana, pp. 149–212. Lancaster, Pa.: The Jaques Catell Press 1944Google Scholar
- Loewe, S., Goodman, L. S.: Anticonvulsant action of marihuana active substances. Fed. Proc. 6, 352 (1947)Google Scholar
- O'Shaughnessy, W. B.: On the preparations of the Indian hemp or guna (cannabis indica): the effects on the animal system in health and their utility in the treatment of tetanus and other convulsive disorders. Trans. Med. Physiol. Soc. Bombay, p. 460 (1842)Google Scholar
- Paton, W. D. M., Pertwee, R. G.: Effect of cannabis and certain of its constituents on pentobarbitone sleeping time and phenazone metabolism. Brit. J. Pharmacol. 44, 250–261 (1972)Google Scholar
- Reynolds, J. R.: Therapeutical uses and toxic effects of cannabis indica. Lancet 1, 637–638 (1890)Google Scholar
- Sofia, R. D., Solomon, T. A., Barry, H.: The anticonvulsant activity of δ 1-tetrahydrocannabinol in mice. Pharmacologist 13, 246 (1971)Google Scholar
- Snedecor, G. W., Cochran, W. G.: Statistical methods. Iowa State University Press 1967Google Scholar
- Swinyard, E. A.: Laboratory assay of clinically effective antiepileptic drugs. J. Amer, pharm. Ass. 38, 201–204 (1949)Google Scholar
- Swinyard, E. A., Brown, W. C., Goodman, L. S.: Comparative assays of antiepileptic drugs in mice and rats. J. Pharmacol. exp. Ther. 106, 319–330 (1952)Google Scholar
- Whittle, B. A.: The use of changes in capillary permeability in mice to distinguish between narcotic and non-narcotic analgesics. Brit. J. Pharmacol. 22, 246–253 (1964)Google Scholar