Cannabinoid and Epilepsy / Septiembre 2016

Cannabinoid and Epilepsy

1. Curr Pharm Des. 

From cannabis to cannabidiol to treat epilepsy, where are we?

Lippiello P, Balestrini S, Leo A, Coppola A, Citraro R, Elia M, Russo E(1), De Sarro G.

> Author information:

(1)Chair of Pharmacology, Department of Science of Health, School of Medicine, University of Catanzaro, Italy.

BACKGROUND: Several antiepileptic drugs (AEDs), about 25, are currently clinically available for the treatment of patients with epilepsy. Despite this armamentarium and the many recently introduced AEDs, no major advances have been achieved considering the number of drug resistant patients, while many benefits have been indeed obtained for other clinical outcomes (e.g. better tolerability, less interactions). Cannabinoids have long been studied for their potential therapeutical use and more recently phytocannabinoids have been considered a valuable tool for the treatment of several neurological disorders including epilepsy. Among this wide class, the most studied is cannabidiol (CBD) considering its lack of psychotropic effects and its anticonvulsant properties.

OBJECTIVE: Analyse the currently available literature on CBD also in light of other data on phytocannabinoids, reviewing data spanning from the mechanism of action, pharmacokinetic to clinical evidences.

RESULTS: Several preclinical studies have tried to understand the mechanism of action of CBD, which still remains largely not understood CBD has shown significant anticonvulsant effects mainly in acute animal models of seizures; beneficial effects were reported also in animal models of epileptogenesis and chronic models of epilepsy, although not substantial. In contrast, data coming from some studies raise questions on the effects of other cannabinoids and above all marijuana.

CONCLUSIONS: There is indeed sufficient supporting data for clinical development and important antiepileptic effects and the currently ongoing clinical studies will permit the real usefulness of CBD and possibly other cannabinoids. Undoubtedly, several issues also need to be addressed in the next future (e.g. better pharmacokinetic profiling). Finally, shading light on the mechanism of action and the study of other cannabinoids might represent an advantage for future developments.

2. Orrin Devinsky: breaking through treatment-resistant epilepsy.

 Kirby T.

3. Cannabidiol for epilepsy: trying to see through the haze.

Detyniecki K(1), Hirsch LJ(2).

> Author information:

(1)Comprehensive Epilepsy Center, Yale University, New Haven, CT 06520-8018, USA.

(2)Comprehensive Epilepsy Center, Yale University, New Haven, CT 06520-8018, USA.

4. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial.

Devinsky O(1), Marsh E(2), Friedman D(3), Thiele E(4), Laux L(5), Sullivan J(6), Miller I(7), Flamini R(8), Wilfong A(9), Filloux F(10), Wong M(11), Tilton N(6), Bruno P(4), Bluvstein J(3), Hedlund J(3), Kamens R(2), Maclean J(2), Nangia S(5), Singhal NS(6), Wilson CA(10), Patel A(12), Cilio MR(6).

> Author information:

(1)Comprehensive Epilepsy Center, New York University Langone Medical Center, New York, NY, USA. 

(2)Departments of Neurology and Pediatrics, Division of Child Neurology, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

(3)Comprehensive Epilepsy Center, New York University Langone Medical Center, New York, NY, USA.

(4)Massachusettes General Hospital for Children, Boston, MA, USA.

(5)Ann & Robert H Lurie Children's Hospital of Chicago, Chicago, IL, USA.

(6)Departments of Neurology and Pediatrics, Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA, USA.

(7)Miami Children's Hospital, Miami, FL, USA.

(8)Pediatric and Adolescent Neurodevelopmental Associates, Atlanta, GA, USA.

(9)Texas Children's Hospital, Houston, TX, USA.

(10)University of Utah Medical Center and Primary Children's Hospital, Salt Lake City, UT, USA.

(11)Wake Forest School of Medicine, Winston-Salem, NC, USA.

(12)Nationwide Children's Hospital, Columbus, OH, USA.

BACKGROUND: Almost a third of patients with epilepsy have a treatment-resistant form, which is associated with severe morbidity and increased mortality. Cannabis-based treatments for epilepsy have generated much interest, but scientific data are scarce. We aimed to establish whether addition of cannabidiol to existing anti-epileptic regimens would be safe, tolerated, and efficacious in children and young adults with treatment-resistant epilepsy.

METHODS: In this open-label trial, patients (aged 1-30 years) with severe, intractable, childhood-onset, treatment-resistant epilepsy, who were receiving stable doses of antiepileptic drugs before study entry, were enrolled in an expanded-access programme at 11 epilepsy centres across the USA. Patients were given oral cannabidiol at 2-5 mg/kg per day, up-titrated until intolerance or to a maximum dose of 25 mg/kg or 50 mg/kg per day (dependent on study site). The primary objective was to establish the safety and tolerability of cannabidiol and the primary efficacy endpoint was median percentage change in the mean monthly frequency of motor seizures at 12 weeks. The efficacy analysis was by modified intention to treat. Comparisons of the percentage change in frequency of motor seizures were done with a Mann-Whitney U test.

RESULTS: Between Jan 15, 2014, and Jan 15, 2015, 214 patients were enrolled; 162 (76%) patients who had at least 12 weeks of follow-up after the first dose of cannabidiol were included in the safety and tolerability analysis, and 137 (64%) patients were included in the efficacy analysis. In the safety group, 33 (20%) patients had Dravet syndrome and 31 (19%) patients had Lennox-Gastaut syndrome. The remaining patients had intractable epilepsies of different causes and type. Adverse events were reported in 128 (79%) of the 162 patients within the safety group. Adverse events reported in more than 10% of patients were somnolence (n=41 [25%]), decreased appetite (n=31 [19%]), diarrhoea (n=31 [19%]), fatigue (n=21 [13%]), and convulsion (n=18 [11%]). Five (3%) patients discontinued treatment because of an adverse event. Serious adverse events were reported in 48 (30%) patients, including one death-a sudden unexpected death in epilepsy regarded as unrelated to study drug. 20 (12%) patients had severe adverse events possibly related to cannabidiol use, the most common of which was status epilepticus (n=9 [6%]). The median monthly frequency of motor seizures was 30.0 (IQR 11.0-96.0) at baseline and 15.8 (5.6-57.6) over the 12 week treatment period. The median reduction in monthly motor seizures was 36.5% (IQR 0-64.7).

INTERPRETATION: Our findings suggest that cannabidiol might reduce seizure frequency and might have an adequate safety profile in children and young adults with highly treatment-resistant epilepsy. Randomised controlled trials are warranted to characterise the safety profile and true efficacy of this compound.

FUNDING: GW Pharmaceuticals, Epilepsy Therapy Project of the Epilepsy Foundation, Finding A Cure for Epilepsy and Seizures.

Copyright © 2016 Elsevier Ltd. All rights reserved.

5. Neurotoxicology. Cannabidiol, a Cannabis sativa constituent, inhibits cocaine-induced seizures in mice: Possible role of the mTOR pathway and reduction in glutamate release.

Gobira PH(1), Vilela LR(1), Gonçalves BD(1), Santos RP(1), de Oliveira AC(1), Vieira LB(1), Aguiar DC(1), Crippa JA(2), Moreira FA(3).

> Author information:

(1)Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Av. Pres. Antônio Carlos 6627, 31270-901 Belo Horizonte, MG, Brazil.

(2)Department of Neuroscience and Behavior, Ribeirão Preto Medical School, Universidade de São Paulo (USP), Ribeirão Preto, SP, Brazil. 

(3)Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Av. Pres. Antônio Carlos 6627, 31270-901 Belo Horizonte, MG, Brazil.

Cannabidiol (CBD), a major non-psychotomimetic constituent of Cannabis sativa, has therapeutic potential for certain psychiatric and neurological disorders. Studies in laboratory animals and limited human trials indicate that CBD has anticonvulsant and neuroprotective properties. Its effects against cocaine neurotoxicity, however, have remained unclear. Thus, the present study tested the hypothesis that CBD protects against cocaine-induced seizures and investigated the underlying mechanisms. CBD (30 mg/kg) pre-treatment increased the latency and reduced the duration of cocaine (75 mg/kg)-induced seizures in mice. The CB1 receptor antagonist, AM251 (1 and 3mg/kg), and the CB2 receptor antagonist, AM630 (2 and 4 mg/kg), failed to reverse this protective effect, suggesting that alternative mechanisms are involved. Synaptosome studies with the hippocampus of drug-treated animals revealed that cocaine increases glutamate release, whereas CBD induces the opposite effect. Finally, the protective effect of this cannabinoid against cocaine-induced seizure was reversed by rapamycin (1 and 5mg/kg), an inhibitor of the mammalian target of rapamycin (mTOR) intracellular pathway. In conclusion, CBD protects against seizures in a model of cocaine intoxication. These effects possibly occur through activation of mTOR with subsequent reduction in glutamate release. CBD should be further investigated as a strategy for alleviating psychostimulant toxicity.


Copyright © 2015 Elsevier Inc. All rights reserved.