Skip to main content
Log in

Anticonvulsant effects of cannabinoids in mice: Drug interactions within cannabinoids and cannabinoid interactions with phenytoin

Psychopharmacologia Aims and scope Submit manuscript

Abstract

The anticonvulsant activity of orally administered δ 9-tetrahydrocannabinol (δ 9-THC), δ 8-THC, cannabidiol (CBD) and cannabinol (CBN) was tested in mice utilizing electroshock and chemoshock methods. In doses tested δ 9-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 δ 9-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 δ 9-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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • 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  • Brown, W. C.: Unpublished observations (1952) cited by Swinyard et al.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)

  • 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 1944

    Google 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 1967

  • 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 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chesher, G.B., Jackson, D.M. Anticonvulsant effects of cannabinoids in mice: Drug interactions within cannabinoids and cannabinoid interactions with phenytoin. Psychopharmacologia 37, 255–264 (1974). https://doi.org/10.1007/BF00421539

Download citation

  • Received:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00421539

Key words

Navigation