Cannabinoids and Epilepsy

Abstract

Cannabis has been used for centuries to treat seizures. Recent anecdotal reports, accumulating animal model data, and mechanistic insights have raised interest in cannabis-based antiepileptic therapies. In this study, we review current understanding of the endocannabinoid system, characterize the pro- and anticonvulsive effects of cannabinoids [e.g., Δ9-tetrahydrocannabinol and cannabidiol (CBD)], and highlight scientific evidence from pre-clinical and clinical trials of cannabinoids in epilepsy. These studies suggest that CBD avoids the psychoactive effects of the endocannabinoid system to provide a well-tolerated, promising therapeutic for the treatment of seizures, while whole-plant cannabis can both contribute to and reduce seizures. Finally, we discuss results from a new multicenter, open-label study using CBD in a population with treatment-resistant epilepsy. In all, we seek to evaluate our current understanding of cannabinoids in epilepsy and guide future basic science and clinical studies.

Keywords: Epilepsy; THC; cannabidiol; cannabinoids; cannabis; seizures.

Fig. 1

Biosynthesis, degradation, and signaling of endocannabinoids. (A) Presynaptic cannabinoid type 1 receptor (CB₁R) signaling. (B) Postsynaptic endocannabinoid biosynthesis/signaling. NArPE = N-arachidonoyl phosphatidylethanolamine; DAG = 1-acyl, 2-arachidonoyl diacylglycerol; VGCC = voltage-gated calcium channels; PEA = palmitoylethanolamide; ACPA = arachidonylcyclopropylamide; ACEA = arachidonyl-2'-chloroethylamide; PMSF = phenylmethylsulfonyl fluoride

Fig. 2

Biosynthesis of phytocannabinoids [73]

Fig. 3

Homeostatic changes to hippocampal cannabinoid type 1 receptors (CB₁Rs) in preclinical animal seizure models [, –166]. GABA = γ-aminobutryic acid

Fig. 4

Summary of cannabinoids and preclinical seizure models. (A) Composite data from 175 preclinical seizure models (e.g., maximal electroshock, kainic acid) or discrete experimental designs (e.g., with combined antiseizure medications). Pro-/antiseizure effects are subclassified by given intervention: 1) modulators of the endocannabinoid (eCB) system (e.g., fatty acid amide hydrolase inhibitor URB597); 2) cannabinoid type 1 receptor (CB₁R) agonists (e.g., WIN55212-2); 3) CB₁R antagonists (e.g., SR141716A); 4) Δ⁹-tetrahydrocannabinol (Δ⁹-THC); and 5) cannabidiol (CBD)/cannabidivarin (CBDV). (See Supplementary Material for complete description of preclinical studies.) (B) Summary of preclinical data on cannabinoid interactions with antiseizure medications. Sources indicated in boxes. *Recent evidence from a phase I clinical trial suggests that CBD/CBDV elevates serum concentrations of clobazam and N-desmethylclobazam in human pediatric patients with treatment-resistant epilepsy [292]. ACEA = arachidonyl-2'-chloroethylamide