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Cannabinoids and Epilepsy

Investigational cannabinoids in seizure disorders, what have we learned thus far?

Ružić Zečević D(1), Folić M(1), Tantoush Z(1), Radovanović M(1), Babić G(1),
Janković SM(1).

Author information: 
(1)a University of Kragujevac , Faculty of Medical Sciences.

INTRODUCTION: The anticonvulsant activity of cannabinoids attracted much
attention in the last decade. Cannabinoids that are currently investigated with
the intention of making them drugs for the treatment of epilepsy are cannabidiol,
cannabidivarin, Δ9-tetrahydrocannabivarin and Δ9-tetrahydrocannabinolic acid.
Areas covered. In this review, the authors look at the results of pre-clinical
and clinical studies with investigational cannabinoids. Relevant literature was
searched for in MEDLINE, SCOPUS, EBSCO, GOOGLE SCHOLAR and SCINDEX databases.
Expert opinion. Pre-clinical studies confirmed anticonvulsant activity of
cannabidiol and cannabidivarin in a variety of epilepsy models. While the results
of clinical trials with cannabidivarin are still awaited, cannabidiol showed
clear therapeutic benefit and good safety in patients with therapy resistant
seizures associated with Dravet syndrome and in patients with Lennox-Gastaut
syndrome who have drop seizures. However, the full therapeutic potential of
cannabinoids in treatment-resistant epilepsy needs to be investigated in the near
future.



2. 
Endocannabinoid CB1 receptors are involved in antiepileptogenic effect of low
frequency electrical stimulation during perforant path kindling in rats.

Mardani P(1), Oryan S(2), Sarihi A(3), Alaei E(3), Komaki A(3), Mirnajafi-Zadeh
J(4).

Author information: 
(1)Department of Animal Biology, Faculty of Biological Science, Kharazmi
University, Tehran, Iran; Department of Biology, Faculty of Sciences, Payame Noor
University, Iran. Electronic address: Esta dirección de correo electrónico está siendo protegida contra los robots de spam. Necesita tener JavaScript habilitado para poder verlo..
(2)Department of Animal Biology, Faculty of Biological Science, Kharazmi
University, Tehran, Iran.
(3)Neurophysiology Research Center, Hamadan University of Medical Sciences,
Hamadan, Iran.
(4)Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares
University, Tehran, Iran. Electronic address: Esta dirección de correo electrónico está siendo protegida contra los robots de spam. Necesita tener JavaScript habilitado para poder verlo..

INTRODUCTION: Administration of low-frequency electrical stimulation (LFS) at the
kindling site has an antiepileptogenic effect. In the present study, we
investigated the role of cannabinoid receptors type 1 (CB1) in mediating the
inhibitory effects of LFS on the development of perforant path kindled seizures.
METHODS: For seizure generation, rats were kindled by electrical stimulation of
perforant path in semi-rapid kindling manner (12 stimulations per day at 10 min
intervals at afterdischarge threshold intensity).To determine the effect of LFS
(0.1 ms pulse duration at 1 Hz, 800 pulses) on seizure generation, LFS was
applied to the perforant path 5 min after the last kindling stimulation daily.
AM281, a CB1 receptor antagonist, was microinjected into the lateral ventricle
immediately after the last kindling stimulation (before LFS application) at the
doses of 0.5 and 2 μg/μl during kindling procedure. The expression of cannabinoid
receptors in the dentate gyrus was also investigated using immunohistochemistry.
RESULTS: Application of LFS had inhibitory effect on development of kindled
seizures (kindling rate). Microinjection of AM281 (0.5 μg/μl) immediately after
the last kindling stimulation (before LFS application) reduced the inhibitory
effect of LFS on the kindling rate and suppressed the effects of LFS on
potentiation (increasing the magnitude) of both population spike amplitude and
population excitatory postsynaptic potential slope during kindling acquisition.
AM281 pretreatment also prevented the effects of LFS on kindling-induced increase
in early and late paired pulse depression. The higher dose of AM281 (2 μg/μl)
failed to exert the effects observed with its lower dose (0.5 μg/μl). In
addition, there was a decreased CB1 receptors immunostaining in kindled animals
compared to control. However, application of LFS following kindling stimulations 
led to overexpression of CB1 receptors in the dentate gyrus.
CONCLUSION: Obtained results showed that activation of overexpressed cannabinoid 
CB1 receptors by endogenous cannabinoids may have a role in mediating the
inhibitory effect of LFS on perforant path kindled seizures.

Copyright © 2018. Published by Elsevier B.V.



3.
Effect of Cannabidiol on Drop Seizures in the Lennox-Gastaut Syndrome.

Devinsky O(1), Patel AD(1), Cross JH(1), Villanueva V(1), Wirrell EC(1),
Privitera M(1), Greenwood SM(1), Roberts C(1), Checketts D(1), VanLandingham
KE(1), Zuberi SM(1); GWPCARE3 Study Group.

Collaborators: Nabbout R, Bhathal H, Gil-Nagel A, Rodruguez-Uranga J,
Sanchez-Carpintero R, Chin R, Bailey R, Barron T, Clarke D, Crepeau A, Davis R,
Goyal M, Halford J, Kang H, Madan-Cohen J, Mitchell W, Nahouraii R, Park Y, Perry
S, Wechsler R, Weinstock A, Wong M, Dlugos D, French J, Kessler S, Shellhaas R,
Sullivan J, Thio LL.

Author information: 
(1)From New York University Langone Comprehensive Epilepsy Center, New York
(O.D.); Nationwide Children's Hospital and the Ohio State University College of
Medicine, Columbus (A.D.P.), and the University of Cincinnati Medical Center,
Department of Neurology, Cincinnati (M.P.) - all in Ohio; UCL Great Ormond Street
Institute of Child Health, London (J.H.C.), GW Research Ltd., Cambridge (S.M.G., 
C.R., D.C.), and the Royal Hospital for Children and School of Medicine,
University of Glasgow, Glasgow (S.M.Z.) - all in the United Kingdom; Refractory
Epilepsy Unit, Neurology Service, Hospital Universitario y Politécnico La Fe,
Valencia, Spain (V.V.); the Divisions of Child and Adolescent Neurology and
Epilepsy, Department of Neurology, Mayo Clinic, Rochester, MN (E.C.W.); and
Greenwich Biosciences, Carlsbad, CA (K.E.V.).

BACKGROUND: Cannabidiol has been used for treatment-resistant seizures in
patients with severe early-onset epilepsy. We investigated the efficacy and
safety of cannabidiol added to a regimen of conventional antiepileptic medication
to treat drop seizures in patients with the Lennox-Gastaut syndrome, a severe
developmental epileptic encephalopathy.
METHODS: In this double-blind, placebo-controlled trial conducted at 30 clinical 
centers, we randomly assigned patients with the Lennox-Gastaut syndrome (age
range, 2 to 55 years) who had had two or more drop seizures per week during a
28-day baseline period to receive cannabidiol oral solution at a dose of either
20 mg per kilogram of body weight (20-mg cannabidiol group) or 10 mg per kilogram
(10-mg cannabidiol group) or matching placebo, administered in two equally
divided doses daily for 14 weeks. The primary outcome was the percentage change
from baseline in the frequency of drop seizures (average per 28 days) during the 
treatment period.
RESULTS: A total of 225 patients were enrolled; 76 patients were assigned to the 
20-mg cannabidiol group, 73 to the 10-mg cannabidiol group, and 76 to the placebo
group. During the 28-day baseline period, the median number of drop seizures was 
85 in all trial groups combined. The median percent reduction from baseline in
drop-seizure frequency during the treatment period was 41.9% in the 20-mg
cannabidiol group, 37.2% in the 10-mg cannabidiol group, and 17.2% in the placebo
group (P=0.005 for the 20-mg cannabidiol group vs. placebo group, and P=0.002 for
the 10-mg cannabidiol group vs. placebo group). The most common adverse events
among the patients in the cannabidiol groups were somnolence, decreased appetite,
and diarrhea; these events occurred more frequently in the higher-dose group. Six
patients in the 20-mg cannabidiol group and 1 patient in the 10-mg cannabidiol
group discontinued the trial medication because of adverse events and were
withdrawn from the trial. Fourteen patients who received cannabidiol (9%) had
elevated liver aminotransferase concentrations.
CONCLUSIONS: Among children and adults with the Lennox-Gastaut syndrome, the
addition of cannabidiol at a dose of 10 mg or 20 mg per kilogram per day to a
conventional antiepileptic regimen resulted in greater reductions in the
frequency of drop seizures than placebo. Adverse events with cannabidiol included
elevated liver aminotransferase concentrations. (Funded by GW Pharmaceuticals;
GWPCARE3 ClinicalTrials.gov number, NCT02224560 .).



4.
Chronic exposure to cannabidiol induces reproductive toxicity in male Swiss mice.

Carvalho RK(1), Santos ML(1), Souza MR(1), Rocha TL(2), Guimarães FS(3),
Anselmo-Franci JA(4), Mazaro-Costa R(1).

Author information: 
(1)Department of Pharmacology, Laboratory of Physiology and Pharmacology of
Reproduction, Universidade Federal de Goiás, Goiânia, GO, Brazil.
(2)Institute of Tropical Pathology and Public Health, Universidade Federal de
Goiás, Goiânia, GO, Brazil.
(3)Department of Pharmacology, Ribeirão Preto Medical School, Universidade de São
Paulo, Ribeirão Preto, SP, Brazil.
(4)Department of Morphology, Stomatology and Physiology, Dental School of
Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.

Children and adults with frequent and severe episodes of epilepsy that do not
respond to standard treatments (such as carbamazepine, phenytoin and valproate)
have long been prescribed cannabidiol (CBD) as an anticonvulsant drug. However,
the safety of its chronic use in relation to reproduction has not been fully
examined. This study aimed to assess the effects of chronic CBD exposure on the
male reproductive system. CBD was orally administered to 21-day-old male Swiss
mice at doses of 15 and 30 mg kg-1 daily (CBD 15 and 30 groups, respectively),
with a control group receiving sunflower oil, for 34 consecutive days. After a
35 day recovery period, the following parameters were evaluated: weight of
reproductive organs, testosterone concentration, spermatogenesis,
histomorphometry, daily sperm production and its morphology. The CBD 30 group had
a 76% decrease in total circulating testosterone, but it remained within the
physiological normal range (240-1100 ng dl-1 ). CBD treatment induced a
significant increase in the frequency of stages I-IV and V-VI of spermatogenesis,
and a decrease in the frequency of stages VII-VIII and XII. A significant
decrease in the number of Sertoli cells was observed only in the CBD 30 group. In
both CBD groups the number of spermatozoa in the epididymis tail was reduced by
38%, sperm had head abnormalities, and cytoplasmic droplets were observed in the 
medial region of flagellum. These results indicated that chronic CBD exposure was
associated with changes in the male reproductive system, suggesting its
reproductive toxicity.

Copyright © 2018 John Wiley & Sons, Ltd.