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Pharmacological and Therapeutic Properties of Cannabidiol for Epilepsy

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Abstract

Cannabidiol (CBD) is a major active component of the Cannabis plant, which, unlike tetrahydrocannabinol (THC), is devoid of euphoria-inducing properties. During the last 10 years, there has been increasing interest in the use of CBD-enriched products for the treatment of epilepsy. In 2018, an oil-based highly purified liquid formulation of CBD (Epidiolex) derived from Cannabis sativa was approved by the US Food and Drug Administration for the treatment of seizures associated with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). The mechanisms underlying the antiseizure effects of CBD are unclear but may involve, among others, antagonism of G protein-coupled receptor 55 (GPR55), desensitization of transient receptor potential of vanilloid type 1 (TRPV1) channels, and inhibition of adenosine reuptake. CBD has complex and variable pharmacokinetics, with a prominent first-pass effect and a low oral bioavailability that increases fourfold when CBD is taken with a high-fat/high-calorie meal. In four randomized, double-blind, parallel-group, adjunctive-therapy trials, CBD given at doses of 10 and 20 mg/kg/day administered in two divided administrations was found to be superior to placebo in reducing the frequency of drop seizures in patients with LGS and convulsive seizures in patients with DS. Preliminary results from a recently completed controlled trial indicate that efficacy also extends to the treatment of seizures associated with the tuberous sclerosis complex. The most common adverse events that differentiated CBD from placebo in controlled trials included somnolence/sedation, decreased appetite, increases in transaminases, and diarrhea, behavioral changes, skin rashes, fatigue, and sleep disturbances. About one-half of the patients included in the DS and LGS trials were receiving concomitant therapy with clobazam, and in these patients a CBD-induced increase in serum levels of the active metabolite norclobazam may have contributed to improved seizure outcomes and to precipitation of some adverse effects, particularly somnolence.

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Fig. 1

Reproduced from Taylor et al. (2018) [69], with permission

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Authors and Affiliations

  1. Division of Clinical and Experimental Pharmacology, Department of Internal Medicine and Therapeutics, University of Pavia, Via Ferrata 9, 27100, Pavia, Italy

    Valentina Franco & Emilio Perucca

  2. IRCCS Mondino Foundation, Pavia, Italy

    Valentina Franco & Emilio Perucca

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  1. Valentina Franco
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  2. Emilio Perucca
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Correspondence to Emilio Perucca.

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This work was not supported by any funding source.

Conflict of interest

Valentina Franco received consultancy fees from GW Pharma. Emilio Perucca received speaker and/or consultancy fees from Amicus Therapeutics, Biogen, Eisai, GW Pharma, Sanofi, Sun Pharma, Takeda, UCB Pharma and Xenon Pharma.

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Note Added in Proof

On 26 July 2019, the EMA Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion recommending marketing authorisation of GW CBD (Epidyolex™) for use as adjunctive therapy of seizures associated with LGS or DS, in conjunction with clobazam, for patients 2 years of age and older. The European Commission is expected to make a final decision on the marketing authorisation application approximately two months after the CHMP's positive opinion. (http://ir.gwpharm.com/node/10891/pdf. Accessed 28 July 2019).

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Franco, V., Perucca, E. Pharmacological and Therapeutic Properties of Cannabidiol for Epilepsy. Drugs 79, 1435–1454 (2019). https://doi.org/10.1007/s40265-019-01171-4

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