Cannabinoids in the Treatment of Epilepsy: Current Status and Future Prospects

Abstract

Cannabidiol (CBD) is one of the prominent phytocannabinoids found in Cannabis sativa, differentiating from Δ⁹-tetrahydrocannabinol (THC) for its non-intoxicating profile and its antianxiety/antipsychotic effects. CBD is a multi-target drug whose anti-convulsant properties are supposed to be independent of endocannabinoid receptor CB₁ and might be related to several underlying mechanisms, such as antagonism on the orphan GPR55 receptor, regulation of adenosine tone, activation of 5HT_1A receptors and modulation of calcium intracellular levels. CBD is a lipophilic compound with low oral bioavailability (6%) due to poor intestinal absorption and high first-pass metabolism. Its exposure parameters are greatly influenced by feeding status (ie, high fat-containing meals). It is mainly metabolized by cytochrome P 450 (CYP) 3A4 and 2C19, which it strongly inhibits. A proprietary formulation of highly purified, plant-derived CBD has been recently licensed as an adjunctive treatment for Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS), while it is being currently investigated in tuberous sclerosis complex. The regulatory agencies' approval was granted based on four pivotal double-blind, placebo-controlled, randomized clinical trials (RCTs) on overall 154 DS patients and 396 LGS ones, receiving CBD 10 or 20 mg/kg/day BID as active treatment. The primary endpoint (reduction in monthly seizure frequency) was met by both CBD doses. Most patients reported adverse events (AEs), generally from mild to moderate and transient, which mainly consisted of somnolence, sedation, decreased appetite, diarrhea and elevation in aminotransferase levels, the last being documented only in subjects on concomitant valproate therapy. The interaction between CBD and clobazam, likely due to CYP2C19 inhibition, might contribute to some AEs, especially somnolence, but also to CBD clinical effectiveness. Cannabidivarin (CBDV), the propyl analogue of CBD, showed anti-convulsant properties in pre-clinical studies, but a plant-derived, purified proprietary formulation of CBDV recently failed the Phase II RCT in patients with uncontrolled focal seizures.

Keywords: cannabidiol; cannabidivarin; drug-resistance; epileptic encephalopathies; phytocannabinoids; tuberous sclerosis complex.

Figure 1

Endocannabinoid-mediated negative feedback in epilepsy: (1) in excitatory synapses, depolarization induces Glutamate (Glut) release into the synaptic cleft, thanks to the increase in intracellular Ca²⁺ levels mediated by the opening of voltage-gated calcium channels (VGCC); (2) in hyperexcitable states, like epileptic seizures, a large amount of neurotransmitter is released from the presynaptic neuron; (3) under basal conditions, Glut binds primarily to intra-synaptic ionotropic receptors (AMPARs); (4) in case of hyperexcitability with Glut “spill over”, group 1 metabotropic Glut receptors (ie, mGlu5Rs) located at pery-synpatic level are activated by ligand binding; (5) mGLU5Rs are anchored together with phospholipase C β (PLCβ) and diacylglycerol lipase α (DGLα) thanks to the scaffolding protein HOMER, forming a sopramolecular complex known as “2-AG signalosome” (illustrated in the smaller panel); (6) mGlu5R activation increases diacyl glycerol (DAG) synthesis by PLCβ and its following conversion into 2-arachydonoyl glycerol (2-AG), catalyzed by DGLα; (7) 2-AG acts as a retrograde messenger and binds pre-synaptic CB₁ (coupled with G_i/o); (8) CB₁ activation inhibits VGCC thus reducing intracellular Ca²⁺ levels; (9) ↓ Ca²⁺ levels determine a decrease in Glut exocytosis. This negative feedback mechanism could be protective against Glut-mediated excitotoxicity in hyperexcitable states.

Figure 2

The figure shows the randomized, double-blind, placebo-controlled trials (followed by ongoing open-label extension studies) performed to evaluate CBD effectiveness and tolerability in DS, LGS and TSC. The percentages shown in the figure indicate the responder rates, ie, the proportion of patients showing >50% seizure reduction (for motor seizures in DS, drop seizures in LGS and convulsive ones in TSC) of CBD 20 mg/kg/day compared with placebo. Abbreviations: DS, Dravet syndrome; LGS, Lennox-Gastaut syndrome; TSC, tuberous sclerosis complex.