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

Alessandra Morano1 Epilepsy Unit, Department of Human Neurosciences, “Sapienza” University of Rome, Rome, Italy

Martina Fanella1 Epilepsy Unit, Department of Human Neurosciences, “Sapienza” University of Rome, Rome, Italy

Mariarita Albini1 Epilepsy Unit, Department of Human Neurosciences, “Sapienza” University of Rome, Rome, Italy

Pierangelo Cifelli2 Department of Physiology and Pharmacology, Pasteur Institute-Cenci Bolognetti Foundation, University of Rome Sapienza, Rome, Italy;3 IRCCS “Neuromed”, Pozzilli, IS, Italy

Eleonora Palma2 Department of Physiology and Pharmacology, Pasteur Institute-Cenci Bolognetti Foundation, University of Rome Sapienza, Rome, Italy

Anna Teresa Giallonardo1 Epilepsy Unit, Department of Human Neurosciences, “Sapienza” University of Rome, Rome, Italy

Carlo Di Bonaventura1 Epilepsy Unit, Department of Human Neurosciences, “Sapienza” University of Rome, Rome, ItalyCorrespondence[email protected]

https://orcid.org/0000-0003-1890-5409

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Figures & data

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.

Table 1 Interactions Between CBD and Other AEDs

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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.

Table 2 AEs Reported in the Open-Label Extension Study (Interim Analysis)

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

Table 1 Interactions Between CBD and Other AEDs

Table 2 AEs Reported in the Open-Label Extension Study (Interim Analysis)

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

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Table 1 Interactions Between CBD and Other AEDs

Table 2 AEs Reported in the Open-Label Extension Study (Interim Analysis)

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