1. Syst Rev. 2018 Jul

Cannabis for pediatric epilepsy: protocol for a living systematic review.

Elliott J(1)(2), DeJean D(3), Clifford T(4)(5), Coyle D(4), Potter B(4), Skidmore
B(6), Alexander C(6), Repetski AE(7), McCoy B(8)(9), Wells GA(4)(10).

Author information: 
(1)School of Epidemiology and Public Health, University of Ottawa, 600 Peter
Morand Crescent, Ottawa, K1G 5Z3, Canada. Esta dirección de correo electrónico está siendo protegida contra los robots de spam. Necesita tener JavaScript habilitado para poder verlo..
(2)Cardiovascular Research Methods Centre, University of Ottawa Heart Institute, 
40 Ruskin Street, Ottawa, K1Y4W7, Canada. Esta dirección de correo electrónico está siendo protegida contra los robots de spam. Necesita tener JavaScript habilitado para poder verlo..
(3)Centre for Health Law, Policy and Ethics, University of Ottawa, 57
Louis-Pasteur Private, Ottawa, K1N 6N5, Canada.
(4)School of Epidemiology and Public Health, University of Ottawa, 600 Peter
Morand Crescent, Ottawa, K1G 5Z3, Canada.
(5)CADTH, 865 Carling Avenue, Ottawa, QEQ 5Q5, Canada.
(6), Ottawa, Canada.
(7), Toronto, Canada.
(8)Department of Paediatrics, University of Toronto, Toronto, Canada.
(9)Division of Neurology, The Hospital for Sick Children Toronto, Toronto, ON,
Canada.
(10)Cardiovascular Research Methods Centre, University of Ottawa Heart Institute,
40 Ruskin Street, Ottawa, K1Y4W7, Canada.

BACKGROUND: Pediatric epilepsy, including treatment-resistant forms, has a major 
effect on the quality of life, morbidity, and mortality of affected children.
Interest has been growing in the use of medical cannabis as a treatment for
pediatric epilepsy, yet there has been no comprehensive review of the benefits
and harms of cannabis use in this population. In this systematic review, we will 
search for, synthesize, and assess the published and gray literature in order to 
provide usable and relevant information to parents, clinicians, and policy
makers.
METHODS: We will perform a living systematic review of studies involving the use 
of cannabis to treat pediatric epilepsy. We will search the published and gray
literature for studies involving children with any type of epilepsy taking any
form of cannabis. Studies will be selected for inclusion by two independent
reviewers. The primary outcome is seizure freedom. Secondary outcomes are seizure
frequency, quality of life (child, caregiver), quality and quantity of sleep,
status epilepticus, tonic-clonic seizures, death (all-cause, sudden unexpected
death in epilepsy), gastrointestinal adverse events (diarrhea, vomiting), and
visits to the emergency room. The quality of each included study will be
assessed. If data are sufficient in quantity and sufficiently similar, we will
conduct pairwise random-effects meta-analysis. We will repeat the literature
search every 6 months to identify studies published after the previous search
date. Sequential meta-analysis will be performed as necessary to update the
review findings.
DISCUSSION: Our review aims to provide a comprehensive and up-to-date summary of 
the available evidence to inform decisions about the use of cannabis in children 
with treatment-resistant epilepsy. The results of this review will be of use to
parents, clinicians, and policy makers as they navigate this rapidly evolving
area.
SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018084755.



2. BMC Pediatr. 2018 Jul

The protocol for the Cannabidiol in children with refractory epileptic
encephalopathy (CARE-E) study: a phase 1 dosage escalation study.

Reithmeier D(1)(2), Tang-Wai R(1)(3)(4), Seifert B(1)(5), Lyon AW(1)(6), Alcorn
J(1)(2), Acton B(1)(7)(8), Corley S(1)(9), Prosser-Loose E(1)(10), Mousseau
DD(1)(11), Lim HJ(1)(12), Tellez-Zenteno J(1)(13), Huh L(14), Leung E(15),
Carmant L(16), Huntsman RJ(17)(18).

Author information: 
(1)Cannabinoid Research Initiative of Saskatchewan (CRIS), University of
Saskatchewan, Saskatoon, Saskatchewan, Canada.
(2)College of Pharmacy and Nutrition, University of Saskatchewan, Room E3210
Health Sciences 104 Clinic Place, Saskatoon, SK, S7N-2Z4, Canada.
(3)Department of Pediatrics, Division of Child Neurology, Loma Linda University, 
Loma Linda, California, USA.
(4)Division of Pediatric Neurology, Department of Pediatrics, University of
Alberta, 11405-87 Avenue, 4th Floor, Edmonton, AB, T6G-1C9, Canada.
(5)Department of Pharmaceutical Services, Saskatchewan Health Authority,
Saskatoon Health Region, Royal University Hospital, 103 Hospital Drive,
Saskatoon, SK, S7N-0W8, Canada.
(6)Department of Pathology and Laboratory Medicine, Saskatchewan Health
Authority, St. Paul's Hospital, 1702 20th Street West, Saskatoon, SK, S7M-0Z9,
Canada.
(7)Saskatchewan Health Authority and Department of Psychology, University of
Saskatchewan, Saskatoon, Saskatchewan, Canada.
(8)Department of Clinical Health Psychology, Royal University Hospital, 103
Hospital Drive, Saskatoon, SK, S7N 0W8, Canada.
(9)Clinical Trial Support Unit, University of Saskatchewan, Royal University
Hospital, Room 5676, 103 Hospital Drive, Saskatoon, SK, S7N 0W8, Canada.
(10)Department of Pediatrics, University of Saskatchewan, Royal University
Hospital, Room 2665, 103 Hospital Drive, Saskatoon, SK, S7N 0W8, Canada.
(11)Cell Signalling Laboratory, Departments of Psychiatry and Physiology,
University of Saskatchewan, GB41, HSB 107 Wiggins Ave, Saskatoon, SK, S7N 5E5,
Canada.
(12)Department of Community Health and Epidemiology, University of Saskatchewan, 
Room E3222 Health Sciences, 104 Clinic Place, Saskatoon, SK, S7N-2Z4, Canada.
(13)Department of Medicine, Division of Neurology, University of Saskatchewan,
Royal University Hospital, Room 1622, 103 Hospital Drive, Saskatoon, SK, S7N 0W8,
Canada.
(14)Division of Pediatric Neurology, Department of Pediatrics, University of
British Columbia, BC Children's Hospital, Room 2D19, 4480 Oak Street, Vancouver, 
BC, V6H-3V4, Canada.
(15)Division of Pediatric Neurology, Room CE208, Department of Pediatrics 5,
University of Manitoba, Children's Hospital, 840 Sherbrooke Street, Winnipeg, MB,
R3A-1S1, Canada.
(16)Division of Pediatric Neurology, Department of Pediatrics, Centre Hospitalier
Universitaire Sainte-Justine, Universite de Montreal, Room 5-4, 3175 Chemin de la
Cote Ste-Catherine, Montreal, QC, H3T-1C5, Canada.
(17)Cannabinoid Research Initiative of Saskatchewan (CRIS), University of
Saskatchewan, Saskatoon, Saskatchewan, Canada. Esta dirección de correo electrónico está siendo protegida contra los robots de spam. Necesita tener JavaScript habilitado para poder verlo..
(18)Department of Pediatrics, Royal University Hospital, Rm 2744, 103 Hospital
Drive, Saskatoon, SK, S7N 0W8, Canada. Esta dirección de correo electrónico está siendo protegida contra los robots de spam. Necesita tener JavaScript habilitado para poder verlo..

BACKGROUND: Initial studies suggest pharmaceutical grade cannabidiol (CBD) can
reduce the frequency of convulsive seizures and lead to improvements in quality
of life in children affected by epileptic encephalopathies. With limited access
to pharmaceutical CBD, Cannabis extracts in oil are becoming increasingly
available. Physicians show reluctance to recommend Cannabis extracts given the
lack of high quality safety data especially regarding the potential for harm
caused by other cannabinoids, such as Δ9-tetrahydrocannabinol (Δ9-THC). The
primary aims of the study presented in this protocol are (i) To determine whether
CBD enriched Cannabis extract is safe and well-tolerated for pediatric patients
with refractory epilepsy, (ii) To monitor the effects of CBD-enriched Cannabis
extract on the frequency and duration of seizure types and on quality of life.
METHODS: Twenty-eight children with treatment resistant epileptic encephalopathy 
ranging in age from 1 to 10 years will be recruited in four Canadian cities into 
an open-label, dose-escalation phase 1 trial. The primary objectives for the
study are (i) To determine if the CBD-enriched Cannabis herbal extract is safe
and well-tolerated for pediatric patients with treatment resistant epileptic
encephalopathy and (ii) To determine the effect of CBD-enriched Cannabis herbal
extract on the frequency and duration of seizures. Secondary objectives include
(i) To determine if CBD-enriched Cannabis herbal extracts alter steady-state
levels of co-administered anticonvulsant medications. (ii) To assess the relation
between dose escalation and quality of life measures, (iii) To determine the
relation between dose escalation and steady state trough levels of bioactive
cannabinoids. (iv) To determine the relation between dose escalation and
incidence of adverse effects.
DISCUSSION: This paper describes the study design of a phase 1 trial of
CBD-enriched Cannabis herbal extract in children with treatment-resistant
epileptic encephalopathy. This study will provide the first high quality analysis
of safety of CBD-enriched Cannabis herbal extract in pediatric patients in
relation to dosage and pharmacokinetics of the active cannabinoids.
TRIAL REGISTRATION: http://clinicaltrials.gov [Internet]. Bethesda (MD): National
Library of Medicine (US). 2016 Dec 16. Identifier NCT03024827, Cannabidiol in
Children with Refractory Epileptic Encephalopathy: CARE-E; 2017 Jan 19 [cited
2017 Oct]; Available from: http://clinicaltrials.gov/ct2/show/NCT03024827.


3. Sci Rep. 2018 Jul 

Composition and Use of Cannabis Extracts for Childhood Epilepsy in the Australian
Community.

Suraev A(1), Lintzeris N(2)(3), Stuart J(1), Kevin RC(1), Blackburn R(1),
Richards E(1), Arnold JC(1)(4), Ireland C(5), Todd L(5), Allsop DJ(1), McGregor
IS(6).

Author information: 
(1)The Lambert Initiative for Cannabinoid Therapeutics, School of Psychology, The
University of Sydney, Sydney, 2050, Australia.
(2)Addiction Medicine, Central Clinical School, Faculty of Medicine, The
University of Sydney, Sydney, 2006, Australia.
(3)The Langton Centre, Drug and Alcohol Services, South East Sydney Local Health 
District, NSW Health, Surry Hills, 2010, Australia.
(4)Department of Pharmacology, Faculty of Medicine, University of Sydney, Sydney,
NSW, 2006, Australia.
(5)Epilepsy Action Australia, Sydney, Australia.
(6)The Lambert Initiative for Cannabinoid Therapeutics, School of Psychology, The
University of Sydney, Sydney, 2050, Australia. Esta dirección de correo electrónico está siendo protegida contra los robots de spam. Necesita tener JavaScript habilitado para poder verlo..


Recent surveys suggest that many parents are using illicit cannabis extracts in
the hope of managing seizures in their children with epilepsy. In the current
Australian study we conducted semi-structured interviews with families of
children with diverse forms of epilepsy to explore their attitudes towards and
experiences with using cannabis extracts. This included current or previous users
of cannabis extracts to treat their child's seizures (n = 41 families), and
families who had never used (n = 24 families). For those using cannabis, extracts
were analysed for cannabinoid content, with specific comparison of samples rated 
by families as "effective" versus those rated "ineffective". Results showed that 
children given cannabis extracts tended to have more severe epilepsy historically
and had trialled more anticonvulsants than those who had never received cannabis 
extracts. There was high variability in the cannabinoid content and profile of
cannabis extracts rated as "effective", with no clear differences between
extracts perceived as "effective" and "ineffective". Contrary to family's
expectations, most samples contained low concentrations of cannabidiol, while
Δ9-tetrahydrocannabinol was present in nearly every sample. These findings
highlight profound variation in the illicit cannabis extracts being currently
used in Australia and warrant further investigations into the therapeutic value
of cannabinoids in epilepsy.


4. Chem Biol Interact. 2018 Aug

Cannabidiol did not induce teratogenicity or neurotoxicity in exposed zebrafish
embryos.

Valim Brigante TA(1), Abe FR(2), Zuardi AW(3), Hallak JEC(3), Crippa JAS(3), de
Oliveira DP(4).

Author information: 
(1)School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, 
14040-903, Ribeirão Preto, São Paulo, Brazil. Electronic address:
Esta dirección de correo electrónico está siendo protegida contra los robots de spam. Necesita tener JavaScript habilitado para poder verlo..
(2)School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, 
14040-903, Ribeirão Preto, São Paulo, Brazil.
(3)Department of Neuroscience and Behavioral Sciences, Ribeirão Preto Medical
School, University of São Paulo, 14048-900, São Paulo, SP, Brazil; National
Institute of Science and Technology for Translational Medicine (INCT-TM),
Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Brasília,
Brazil.
(4)School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, 
14040-903, Ribeirão Preto, São Paulo, Brazil; National Institute of Science and
Technology for Detection, Toxicological Evaluation and Removal of Emerging and
Radioactive Contaminants (INCT-DATREM), Conselho Nacional de Desenvolvimento
Cientifico e Tecnologico (CNPq), Brasília, Brazil.

Cannabidiol (CBD) is a non-psychotomimetic compound of the Cannabis sativa that
has been used for the treatment of severe epilepsy as well as other diseases of
nervous system. However, toxicity studies of CBD have great relevance to
guarantee the patients safety. In this context, morphological analyses of
zebrafish can contribute to evaluate the teratogenic potential, as well as
evaluation of acetylcholinesterase activity and motor activity of zebrafish are
valuable tools to verify the neurotoxicity potential. In the present work, we use
this methodology to test the toxicity of CBD to zebrafish embryos. No
malformation was observed in morphological analysis of embryos exposed to all
tested concentrations of CBD. Although, twenty per cent of embryos exposed to
maximal dose of CBD (300 μg/L) hatched after 96hpf, while embryos in control
solution had already hatched in this period. Embryos exposed to CBD did not show 
differences in acetylcholinesterase activity, but embryos exposed to CBD
20-300 μg/L were 1.4 up to 1.7-fold more active when compared to the control.
Despite that, at 48 hpf, motor activity returned to control values. Our results
suggest that the effects observed after CBD exposure are intimately related to
CB1 receptor that is present in zebrafish since early stages of development. The 
present work showed early light effects induced by CBD exposure in concentrations
that did not alter biochemical activity.

Copyright © 2018 Elsevier B.V. All rights reserved.