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Report from a Survey of Parents Regarding the Use of Cannabidiol (Medicinal cannabis) in Mexican Children with Refractory Epilepsy

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Structured online surveys were used to explore the experiences of the parents of children with refractory epilepsy using medicinal cannabis in Mexico during September 2016. The surveys, which were completed in full, were reviewed, and 53 cases of children aged between 9 months and 18 years were identified. Of these, 43 cases (82%) were from Mexico and 10 (18%) were from Latin American countries. Of the 43 Mexican cases, the diagnoses were as follows: 20 cases (47%) had Lennox-Gastaut syndrome (LGS); 13 cases (30%) had unspecified refractory epilepsy (URE); 8 cases (19%) had West syndrome (WS); 1 case (2%) had Doose syndrome (DS); and 1 case (2%) had Ohtahara syndrome (OS). In total, 47.1% of cases had previously been treated with 9 or more anticonvulsant therapies. The parents reported a decrease in convulsions when cannabidiol was used in 81.3% of the cases; a moderate to significant decrease occurred in 51% of cases, and 16% of cases were free from seizure. The number of antiepileptic drugs being used was reduced in 9/43 (20.9%) cases. No serious adverse effects were reported, with only some mild adverse effects, such as increased appetite or changes in sleep patterns, reported in 42% of cases.
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Research Article
Report from a Survey of Parents Regarding the Use of
Cannabidiol (Medicinal cannabis) in Mexican Children with
Refractory Epilepsy
Carlos G. Aguirre-Velázquez
Instituto Tecnol ´
ogico de Estudios Superiores de Monterrey, Campus Salud, Avenida Morones Prieto 3000 Pte.,
Col. Los Doctores, 64710 Monterrey, NL, Mexico
Correspondence should be addressed to Carlos G. Aguirre-Vel´
azquez; drcaguirre@hotmail.com
Received 26 October 2016; Revised 14 December 2016; Accepted 15 December 2016; Published 14 March 2017
Academic Editor: Vincenzo Di Lazzaro
Copyright ©  Carlos G. Aguirre-Vel´
azquez. is is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
Structured online surveys were used to explore the experiences of the parents of children with refractory epilepsy using medicinal
cannabis in Mexico during September . e surveys, which were completed in full, were reviewed, and  cases of children aged
between  months and  years were identied. Of these,  cases (%) were from Mexico and  (%) were from Latin American
countries. Of the  Mexican cases, the diagnoses were as follows:  cases (%) had Lennox-Gastaut syndrome (LGS);  cases
(%) had unspecied refractory epilepsy (URE);  cases (%) had West syndrome (WS);  case (%) had Doose syndrome (DS);
and  case (%) had Ohtahara syndrome (OS). In total, .% of cases had previously been treated with  or more anticonvulsant
therapies. e parents reported a decrease in convulsions when cannabidiol was used in .% of the cases; a moderate to signicant
decrease occurred in % of cases, and % of cases were free from seizure. e number of antiepileptic drugs being used was reduced
in / (.%) cases. No serious adverse eects were reported, with only some mild adverse eects, such as increased appetite or
changes in sleep patterns, reported in % of cases.
1. Introduction
Epilepsy is a common and chronic neurological disorder,
which frequently requires the use of polypharmacy. It has
been calculated that over  million people worldwide
suerfromepilepsy,with%ofthesepatientsresiding
in developing countries such as Mexico. Nearly . million
new cases of epilepsy are diagnosed every year according to
the World Health Organization, “Mental health, Neurology,
Epilepsy” []. About –% of patients have refractory
epilepsy (RE), which is dened as a failure to respond to
 antiepileptic drugs according to the new denition of
refractoriness proposed by the International League Against
Epilepsy (ILAE) Agreement in  []. In Mexico, the
prevalence rate reported by the Programa Prioritario de
Epilepsia [Epilepsy Priority Programme] centers is –/
inhabitants []. us, it is estimated that there are . million
patients with epilepsy in Mexico, with % of patients
receiving inadequate treatment while % of patients have
RE. Some studies carried out in Mexico have reported a
prevalence of between . and %, with Lennox-Gastaut
syndrome presenting in % of childhood epilepsy cases [].
Serious childhood epilepsies are characterized by fre-
quent convulsions, delayed neurological development, and
a deterioration in the quality of life of the child, in these
cases,whichdonotrespondtoconventionaltreatments.
Childhood epilepsies beginning in the rst few years of life
are frequently characterized by seizures that are resistant to
available treatments, including antiepileptic drugs (AEDs),
ketogenic diet, high doses of steroids, and surgery []. When
indicated treatments fail to control their child’s seizures,
some parents turn to alternative treatments. One of these
alternative treatments is cannabidiol-enriched cannabis. e
cannabis plant contains approximately  cannabinoids, of
which cannabidiol and Δ-tetrahydrocannabinol (THC) are
the two most abundant [, ]. Families oen look for
alternative treatments to bridge the gap between the need
for eective treatments and the adverse eects and high
Hindawi
Neurology Research International
Volume 2017, Article ID 2985729, 5 pages
https://doi.org/10.1155/2017/2985729
Neurology Research International
costs of conventional treatments. erefore, these patients
receive multiple combinations of various antiepileptic drugs;
for many of these patients there are no benecial treatment
options.
Over the last decade, interest has emerged in the use of
Cannabis sativa in home-made products to treat various types
of childhood epilepsy, and anecdotal evidence of its success
has spread via digital media according to Gupta []. From the
international point of view, Epilepsy of the ILAE dedicated
part of June issue  to the theme “Cannabis and Medical
Marijuana for Epilepsy,” which is a support for those who are
“interested in working on the subject,” according to Mathern
et al. [].
Gradually medical studies regarding the use of these
products have also been published. Gloss and Vickrey []
conducted a systematic review of four articles reporting on
the use of C. sativa and concluded that studies in animals
have provided sucient justication for testing in humans;
however, there is still no consistent evidence regarding its
eectiveness and safety. Porter and Jacobson [] carried out
an observational study of  children with RE aged between 
and  years in Stanford University via a survey using social
media. e results of that survey showed that  out of 
parents (%) reported a reduced frequency of seizures with
C. sativa. Other eects reported were as follows: improve-
ment in mood (%), increased state of alertness (%),
improved sleep (%), and a reduction in self-stimulating
behaviors (%). e only adverse eects reported were
somnolence (%) and fatigue (%). In another survey of
 parents of children with RE, due to Lennox-Gastaut
and infantile spasms, Hussain et al. [] reported similar
improvements over an average treatment time of . months
using an average dose of . mg/kg/day of cannabidiol (CBD).
Devinsky et al. [] recently published the results of an
open multicenter prospective clinical trial, approved by the
FDA, using a pharmaceutical product (Epidiolex)whichis
cannabinoid based, that is, % CBD. ere was an average
reduction in motor seizures of .% in the  children
studied,andanadequatesafetyproleforCBDwasnoted.
A bioethics review was recently carried into the use
of CBD in the Epilepsy Clinic of the Hospital General de
M´
exico, CDMX [Mexico General Hospital]. is gave rise to
three proposals regarding its position and oered important
points for consideration in the well-practiced debate on the
legalization of cannabis use. One of the proposals suggests
that, from a neuroethical point of view, the use of CBD
is justied in cases of RE or catastrophic cases, based
on international laws safeguarding human life and dignity
(Kalkach-Aparicio et al. []).
We present the rst observational study on the medicinal
use of CBD (Medicinal cannabis) in children with RE in
Mexico.
2. Materials and Methods
An online survey was used to explore the experience of
parents administering CBD to children with RE in Mex-
ico. To this end, an online commercial soware program
was used (http://www.e-encuesta.com) and a license was
obtained which provided options for designing an unlimited
number of questions of dierent types (open, closed, and
multiple choice), as well as using lters in a packet of up to
 e-mail invitations. e system gathered the responses
and automatically produced a report using basic statistical
analyses. e information was securely stored according to
the guidelines of Amazon Web Services.
A survey was designed which consisted of  questions
in  sections. Informed consent was provided and a con-
dentiality clause was included for personal details, which
required a digital signature from the father or mother as
means of acceptance. e sections were as follows: personal
details, time of evolution and neurological diagnoses, pre-
vious number of conventional anticonvulsants, antiepilep-
tic drugs prior to CBD, total number of seizures in the
month preceding CBD treatment, CBD product, dose and
time of treatment, total number of seizures in the month
following CBD treatment, changes in emotional, cogni-
tive, sleep, and dietary state, side-eects observed during
treatment with CBD, and open feedback on the use of
CBD.
e survey was available for the month of September
 and was presented to parents of patients by a link sent
via e-mail or the Facebook group porGRACE (porGRACE
Association A.C.), which was set up to share information
on the use of medicinal cannabis to treat convulsions in
children. Participation in the survey was voluntary and via
self-selection. e criteria for invitation were as follows: ()
diagnosis of RE, such as Lennox-Gastaut, Dravet, Doose,
or other causes, without symptoms being controlled, and
() current use of medicinal cannabis (cannabidiol alone
or in combination). An automated report of all of the
information was obtained, which removed surveys of people
over the age of , partially answered surveys, or surveys
of individuals who did not meet the ILAE RE criteria. All
completed surveys were printed and individually analyzed.
Microso Excel was used to input data and generate
graphs.
3. Results
, entries were recorded from  completed surveys:
 cases from Mexico and  from other Latin American
countries. e general characteristics of the  Mexican
children are shown in Table .
e most commonly used product was RSHO-X
Cannabidiol (.%), which contains less than .% THC.
Its import has recently been approved by COFEPRIS (gov-
ernment institution equivalent to the US FDA). .% of
individuals use some sort of combination therapy of CBD +
THC (Charlottes web) and .% of individuals use dierent
home-made cannabis extract products containing undened
concentrations of cannabinoids.
e results indicate a decrease in convulsions in .% of
cases, with  cases (%) free from seizure,  cases (%)
showing moderate to signicant improvement, and  cases
(%) showing slight improvement. No change was seen in
 cases (.%), and  cases (.%) showed an exacerbation of
seizures (Table ).
Neurology Research International
T : General characteristics of  Mexican children with RE receiving treatment with CBD.
Surveys / (%)
Age Minimum . months Average: . yrs ±.
Maximum  years
Sex Male  (.%)
Female  (.%)
Evolution
< years  (.%)
– years  (.%)
– years  (.%)
> years  (.%)
Diagnoses
Lennox-Gastaut S.  (%)
West S.  (%)
Doose S.  (%)
Ohtahara S.  (%)
Unspecic R.E.  (%)
 antiepileptic
drugs before CBD
-  (.%)
-  (.%)
-  (.%)
–  (.%)
>  (.%)
 antiepileptic
drugs Aer CBD
-  (.%)
-  (.%)
-  (.%)
–  (.%)
>  (.%)
CBD product
CBD  mg  (%)
CBD  mg  (.%)
CBD + THC  mg  (.%)
CBD + THC  mg  (.%)
Other CBD/THC  (.%)
CBD dose
mg/kg/day
<  (.%)
–.  (.%)
–.  (.%)
–.  (.%)
–  (.%)
Unknown  (.%)
CBD treatment
time in months
<  (.%)
-  (.%)
-  (.%)
-  (.%)
-  (.%)
–  (.%)
>  (%)
e improvements reported by parents were related not
only to the frequency of the seizures, but also to their duration
and intensity (Figure ).
Benets reported by parents in relation to quality of life
indicators for their children were, for example, improvements
in emotional state, attention, communication, sleep patterns,
and diet (Figure ).
No serious adverse eects were reported. In  cases
(%) some mild adverse effects were reported, such
as increased appetite or changes in sleep patterns.
Neurology Research International
T : Responses regarding the monthly frequency of seizures occurring due to the use of CBD.
Categories of improvement % reduction / % cases
General  .%
Free from seizure % %
Signicant –%  .%
Moderate –%  .%
Slight –%  %
Unchanged ±%  .%
Worsening >%  .%
0
10
20
30
40
50
60
70
80
90
100
(%)
Frequency Duration Intensity
Improvement
No change
Exacerbation
F : Eect of treatment with CBD on convulsive seizures.
0
20
40
60
80
100
Mood Cognition Sleep Appetite
(%)
Improvement
No change
Exacerbation
F : Eects of cannabidiol on quality of life factors.
No adverse effects were reported in  cases (.%;
Table ).
4. Discussion
We believe that the reports from parents who participated
in our survey are encouraging when it comes to the use of
cannabidiol in RE in children. e limitations of this survey
are the self-selected cases and the placebo eect, observed as
% in controlled studies with placebo.
e eectiveness and safety prole of CBD does not vary
greatly from what has been reported by other authors such as
Devinsky et al. [] and Porter and Jacobson [], who report
freedom from seizure in .% and % of cases, respectively,
compared to % of cases in our survey. Reductions in the
frequencyofseizuresofover%,whichisanindicatorof
T : Adverse eects during treatment with CBD.
Adverse e ects/ %
Severe  %
Mild  .%
Increased appetite 
Decreased appetite
Broken sleep
Insomnia 
Constipation 
Flatulence 
Diarrhea 
Tics 
Increase in seizures
None  .%
Some cases presented with several adverse eects.
the eectiveness of an antiepileptic drug, have been reported
by Devinsky et al. (%) and Porter and Jacobson (%)
compared to the % reduction noted in our survey.
With regard to the adverse eects of CBD, these are
similartothosereportedintheliterature[],withthe
exception of fatigue. is is likely due to the limitations in
communication in our cases. While some cases experienced
an increase in convulsive seizures during CBD treatment, no
epileptic state or sudden unexpected death was reported in
the Mexican cases.
Rivera-Olmos and Parra-Bernal in a recent review article
[] commented that preliminary data exist that the use of
CBD in extremely rare childhood epilepsies refractory may
have a therapeutic eect in intractable crises, but controlled
studies based in evidence are still ongoing and have not
been completed. e recommendation is that the use of CBD
in these cases is within a framework of study where the
actual eciency can be determined and security aspects are
monitored.
eseresults,andpublishedfromotherinalargenumber
of patients, are encouraging and have revived interest in
testing these treatment options, despite the legal restrictions
that exist in many countries.
5. Conclusions
is is the rst observational study carried out in Mexico
exploring the use of medicinal cannabis in pediatric RE.
Neurology Research International
e results of this study indicate that, from the viewpoint
of the parents of children with RE, medicinal cannabis is
useful as an “add on” treatment for their children since it
induces a signicant reduction in the frequency, duration,
and intensity of the seizures. It also improved aspects of
the patients’ quality of life in terms of their emotional and
cognitive states, their sleep patterns, and their diet. ere
was an absence of serious adverse eects, with only some
tolerable mild adverse eects experienced with this CBD-
based treatment.
Webelievethattheseresultssupporttheclinicalprotocols
being established in large centers where there are a high num-
ber of epilepsy cases and in epilepsy clinics in our country.
e actual role of CBD in particular, and medicinal cannabis
in general, in epilepsy and other neurological pathologies still
needs to be determined.
Competing Interests
e author of this article declares that they have no conicts
of interest.
Acknowledgments
e author would like to thank Mr. Ra´
ul Elizalde and his wife
Mrs. Mayela Benavides, the parents of Grace, the rst patient
to receive medicinal cannabis in Mexico and founders of
the Association porGRACE A.C., which oers unconditional
support to parents of children with epilepsy. e author thank
them for allowing using the porGRACE Facebook page to
distribute this survey and for covering the costs incurred
in the translation and editing of this research project for
publication. e author also thank Mrs. Alma Reyes V´
azquez
for liaising on their behalf with COFEPRIS, who helped with
the legal procedures to import cannabidiol products (RSHO-
X), thus beneting many Mexican patients.
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... Research studies have explored family attitudes about or experiences with pediatric medical cannabis; 3,22,23 most have focused on treatment types and parent-reported outcomes. [24][25][26][27][28] Data are lacking on family experiences in Canada. In this qualitative study, our objective was to explore family experiences using medical cannabis for children with severe conditions in Canada, to set the stage for further research. ...
Article
Background: Cannabis is legal for recreational and medical use in Canada. Our aim was to explore family experiences using medical cannabis for children with severe conditions in the context of legalization. Methods: We conducted a qualitative study using semistructured interviews between April and July 2019. Participants were parents of children attending BC Children's Hospital oncology or palliative care clinics, recruited through posters, emails or referral. Participants were included if they spoke English and their child used any type of cannabis for medical purposes. Interviews included open-ended questions about the child's cannabis use. Interviews were recorded and transcribed, and thematic analysis was performed using qualitative description. Results: Ten interviews were completed with 9 mothers and 1 mother-father pair. The age range of the children was 22 months to 16 years. The primary reasons for cannabis use were epilepsy (6 children) or chemotherapy management (4 children). Five major themes were identified. 1) Child and family context, and cannabis as a last resort: children were seen as severely ill; parents sought cannabis out of desperation and responsibility to their child. 2) Varied information sources informed decision-making: parents lacked resources from health care providers and sought support from social media, industry and other families. 3) Cannabis as an ambiguous medicine: cannabis was viewed as both a serious drug that doctors should prescribe and as a natural alternative health product, safe to pursue alone. 4) Perceived effects: parents perceived medical benefits with few concerns about adverse effects. 5) Legal and financial challenges: parents were willing to obtain cannabis despite high costs and uncertain legality. Interpretation: Parents of children with severe conditions pursued medical cannabis despite obstacles and needed unbiased information to access alone. Scientific investigation is needed to develop pediatric medical guidelines to inform decisions.
... Other dietary regimens, such as calorie restriction and a gluten-free diet, can also have a positive effect [54]. In the absence of an effect, drugs based on cannabidiol or its synthetic analogues can be prescribed as palliative care, reducing the number of epileptic seizures in about 80% of patients but the frequency of side effects is high-from 42 to 71.4% [55,56]. Drug resistance is not an absolute category. ...
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Introduction Advances in the development of drugs with novel mechanisms of action have not been sufficient to significantly reduce the percentage of patients presenting drug-resistant epilepsy. This lack of satisfactory clinical results has led to the search for more effective treatment alternatives with new mechanisms of action. Development The aim of this study is to examine epidemiological aspects of the use of cannabis-based products for the treatment of epilepsy, with particular emphasis on the main mechanisms of action, indications for use, clinical efficacy, and safety. We conducted a narrative review of articles gathered from the PubMed, EMBASE, and Google Scholar databases and from the reference sections of relevant publications. Conclusions In recent years there has been growing interest in the use of cannabis-based products for the treatment of a wide range of diseases, including epilepsy. The cannabis plant is currently known to contain more than 100 terpenophenolic compounds, known as cannabinoids. The 2 most abundant are delta-9-tetrahydrocannabinol and cannabidiol. Studies of preclinical models of epilepsy have shown that these cannabinoids have anticonvulsant properties, and 100% purified cannabidiol and cannabidiol-enriched cannabis extracts are now being used to treat epilepsy in humans. Several open-label studies and randomised controlled clinical trials have demonstrated the efficacy and safety of these products.
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Neurodevelopmental disorders (NDDs) present symptoms associated with abnormal brain development, onset of which typically occurs during infancy or childhood. Here, we discuss the current knowledge regarding isolated cannabinoids and Cannabis treatment during infancy and adolescence in NDDs. Endogenous and plant-derived cannabinoids target the G-protein-coupled cannabinoid receptors (CB1 and 2). The cannabinoid receptors, endocannabinoids, and their related enzymes constitute the endocannabinoid system (ECS). The ECS is active early in brain development, undergoing neurodevelopment until reaching adolescence, a period associated with increased vulnerability to cannabinoid exposure. The deleterious effects of Cannabis are mostly related to delta-9-tetrahydrocannabinol (Δ⁹-THC), which has psychoactive properties. In contrast, cannabidiol (CBD) is devoid of psychotomimetic effects, being beneficial toward a number of brain functions. The ECS might be involved either in the pathophysiology of NDDs and in protective mechanisms. Cannabinoid exposure can potentially disrupt the neurodevelopmental processes mediated by the ECS. Indeed, cannabinoids have shown to produce both improvements and adverse effects depending on the condition. Cannabis is associated with neurodevelopmental impairments in bipolar disorder and schizophrenia. CBD presents a general safer profile and is effective for some infantile epileptic syndromes and for the most common comorbidities of NDDs such as sleep disorder, anxiety, and seizures. For psychosis, addictive behavior, mood or cognitive disorders, and aggressiveness, the evidence of CBD’s effectiveness is limited. Side effects occur, though severe ones are rare. To provide reliable treatment recommendations, more high-quality clinical trials are required to address the beneficial and adverse effects of cannabinoids in young patients.
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In the twenty-first century marijuana (Cannabis sativa L.) emerged as a new resource for patient treatment. Despite its millenary use in several cultures, it was only introduced in the West in the nineteenth century as a medicine, remaining so for almost a century, and then disappearing from the pharmacopoeias, after becoming a target of the prohibitionist climate of the early twentieth century. When relatives of patients begin to rediscover cannabis, it returns to the scene taken by special interest. The discovery of the endocannabinoid system produced a breakthrough with the possibility of thinking about cannabis products for several different diseases and disorders, improving the quality of life of patients and relatives. Pharmaceutical industry of cannabis is gaining body in scenarios that have already regulated their use.
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Introduction Hemp ( Cannabis sativa subsp. sativa ), commonly used for industrial purposes, is now being consumed by the public for various health promoting effects. As popularity of hemp research and claims of beneficial effects rises, a systematic collection of current scientific evidence on hemp’s health effects and pharmacological properties is needed to guide future research, clinical, and policy decision making. Objective To provide an overview and identify the present landscape of hemp research topics, trends, and gaps. Methods A systematic search and analysis strategy according to the preferred reporting items for systematic review and meta-analysis-ScR (PRISMA-ScR) checklist on electronic databases including MEDLINE, OVID (OVFT, APC Journal Club, EBM Reviews), Cochrane Library Central and Clinicaltrials.gov was conducted to include and analyse hemp research articles from 2009 to 2019. Results 65 primary articles (18 clinical, 47 pre-clinical) were reviewed. Several randomised controlled trials showed hempseed pills (in Traditional Chinese Medicine formulation MaZiRenWan) improving spontaneous bowel movement in functional constipation. There was also evidence suggesting benefits in cannabis dependence, epilepsy, and anxiety disorders. Pre-clinically, hemp derivatives showed potential anti-oxidative, anti-hypertensive, anti-inflammatory, anti-diabetic, anti-neuroinflammatory, anti-arthritic, anti-acne, and anti-microbial activities. Renal protective effects and estrogenic properties were also exhibited in vitro . Conclusion Current evidence on hemp-specific interventions are still preliminary, with limited high quality clinical evidence for any specific therapeutic indication. This is mainly due to the wide variation in test item formulation, as the multiple variants of this plant differ in their phytochemical and bioactive compounds. Future empirical research should focus on standardising the hemp plant for pharmaceutical use, and uniformity in experimental designs to strengthen the premise of using hemp in medicine.
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In Mexico and the United States of America (USA), a debate was recently opened on the use of some cannabis extracts as anticonvulsive drugs. Given the broad influence that social networks and the media have on the general population, it is worth highlighting the risk to the public of receiving erroneous information and forming opinions that may compromise their health. In light of this context, taxonomic and biochemical properties, the endocannabinoid system and the historical and legal context of cannabis were reviewed in order to provide a clear overview on the physiological and cultural impacts of cannabis extracts. Subsequently, pre-clinical models, clinical trials and ongoing studies evaluating some phytocannabinoids and synthetic cannabinoids as antiepileptic treatment were assessed. The obtained information was then subjected to interdisciplinary scrutiny and discussion. Taking into account that plantation and commercialisation of cannabis have been historically illegal in Mexico, the relative lack of evidence regarding its effects in humans and the ideas arising from the aforementioned, it is understandable that the medical community, as well as the general population, have reservations about its suitability as a treatment. Having developed a clinical neuroethics methodology, an interdisciplinary expert group discussion was coordinated in order to assess the benefits of the medical practice and limit the influence that healthcare professionals’ ethics could have on decision-making. This concluded with three proposals that portray the Hospital General de Mexico Epilepsy Clinic's position, while also contributing important considerations to the mature debate concerning the legalisation of cannabis.
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Delta(9)-tetrahydrocannabinol binds cannabinoid (CB(1) and CB(2)) receptors, which are activated by endogenous compounds (endocannabinoids) and are involved in a wide range of physiopathological processes (e.g. modulation of neurotransmitter release, regulation of pain perception, and of cardiovascular, gastrointestinal and liver functions). The well-known psychotropic effects of Delta(9)-tetra hydrocannabinol, which are mediated by activation of brain CB(1) receptors, have greatly limited its clinical use. However, the plant Cannabis contains many cannabinoids with weak or no psychoactivity that, therapeutically, might be more promising than Delta(9)-tetra hydrocannabinol. Here, we provide an overview of the recent pharmacological advances, novel mechanisms of action, and potential therapeutic applications of such non-psychotropic plant-derived cannabinoids. Special emphasis is given to cannabidiol, the possible applications of which have recently emerged in inflammation, diabetes, cancer, affective and neurodegenerative diseases, and to Delta(9)-tetrahydrocannabivarin, a novel CB(1) antagonist which exerts potentially useful actions in the treatment of epilepsy and obesity.
Article
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.
Article
There is a great need for safe and effective therapies for treatment of infantile spasms (IS) and Lennox-Gastaut syndrome (LGS). Based on anecdotal reports and limited experience in an open-label trial, cannabidiol (CBD) has received tremendous attention as a potential treatment for pediatric epilepsy, especially Dravet syndrome. However, there is scant evidence of specific utility for treatment of IS and LGS. We sought to document the experiences of children with IS and/or LGS who have been treated with CBD-enriched cannabis preparations. We conducted a brief online survey of parents who administered CBD-enriched cannabis preparations for the treatment of their children's epilepsy. We specifically recruited parents of children with IS and LGS and focused on perceived efficacy, dosage, and tolerability. Survey respondents included 117 parents of children with epilepsy (including 53 with IS or LGS) who had administered CBD products to their children. Perceived efficacy and tolerability were similar across etiologic subgroups. Eighty-five percent of all parents reported a reduction in seizure frequency, and 14% reported complete seizure freedom. Epilepsy was characterized as highly refractory with median latency from epilepsy onset to CBD initiation of five years, during which the patient's seizures failed to improve after a median of eight antiseizure medication trials. The median duration and the median dosage of CBD exposure were 6.8months and 4.3mg/kg/day, respectively. Reported side effects were far less common during CBD exposure, with the exception of increased appetite (30%). A high proportion of respondents reported improvement in sleep (53%), alertness (71%), and mood (63%) during CBD therapy. Although this study suggests a potential role for CBD in the treatment of refractory childhood epilepsy including IS and LGS, it does not represent compelling evidence of efficacy or safety. From a methodological standpoint, this study is extraordinarily vulnerable to participation bias and limited by lack of blinded outcome ascertainment. Appropriately controlled clinical trials are essential to establish efficacy and safety. Copyright © 2015 Elsevier Inc. All rights reserved.
Article
Severe childhood epilepsies are characterized by frequent seizures, neurodevelopmental delays, and impaired quality of life. In these treatment-resistant epilepsies, families often seek alternative treatments. This survey explored the use of cannabidiol-enriched cannabis in children with treatment-resistant epilepsy. The survey was presented to parents belonging to a Facebook group dedicated to sharing information about the use of cannabidiol-enriched cannabis to treat their child's seizures. Nineteen responses met the following inclusion criteria for the study: a diagnosis of epilepsy and current use of cannabidiol-enriched cannabis. Thirteen children had Dravet syndrome, four had Doose syndrome, and one each had Lennox-Gastaut syndrome and idiopathic epilepsy. The average number of antiepileptic drugs (AEDs) tried before using cannabidiol-enriched cannabis was 12. Sixteen (84%) of the 19 parents reported a reduction in their child's seizure frequency while taking cannabidiol-enriched cannabis. Of these, two (11%) reported complete seizure freedom, eight (42%) reported a greater than 80% reduction in seizure frequency, and six (32%) reported a 25-60% seizure reduction. Other beneficial effects included increased alertness, better mood, and improved sleep. Side effects included drowsiness and fatigue. Our survey shows that parents are using cannabidiol-enriched cannabis as a treatment for their children with treatment-resistant epilepsy. Because of the increasing number of states that allow access to medical cannabis, its use will likely be a growing concern for the epilepsy community. Safety and tolerability data for cannabidiol-enriched cannabis use among children are not available. Objective measurements of a standardized preparation of pure cannabidiol are needed to determine whether it is safe, well tolerated, and efficacious at controlling seizures in this pediatric population with difficult-to-treat seizures.
Article
Background: Marijuana appears to have anti-epileptic effects in animals. It is not currently known if it is effective in patients with epilepsy. Some states in the United States of America have explicitly approved its use for epilepsy. Objectives: To assess the efficacy of marijuana, or one of marijuana's constituents in the treatment of people with epilepsy. Search methods: We searched the Cochrane Epilepsy Group Specialized Register (May 15, 2012), the Cochrane Central Register of Controlled Trials (CENTRAL issue 4 of 12, The Cochrane Library 2012),MEDLINE (PubMed, searched on May 15, 2012), ISI Web of Knowledge (May 15, 2012), CINAHL (EBSCOhost, May 15, 2012), and ClinicalTrials.gov (May 15, 2012). In addition, we included studies we personally knew about that were not found by the searches, as well as references in the identified studies. Selection criteria: Randomized controlled trials (RCTs), whether blinded or not. Data collection and analysis: Two authors independently selected trials for inclusion and extracted data. The primary outcome investigated was seizure freedom at one year or more, or three times the longest interseizure interval. Secondary outcomes included: responder rate at six months or more, objective quality of life data, and adverse events. Main results: We found four randomized reports which included a total of 48 patients, each of which used cannabidiol as the treatment agent. One report was an abstract, and another was a letter to the editor. Anti-epileptic drugs were continued in all. Details of randomisation were not included in any study. There was no investigation of whether control and treatment groups were the same or different. All the reports were low quality.The four reports only answered the secondary outcome about adverse effects. None of the patients in the treatment groups suffered adverse effects. Authors' conclusions: No reliable conclusions can be drawn at present regarding the efficacy of cannabinoids as a treatment for epilepsy. The dose of 200 to 300 mg daily of cannabidiol was safely administered to small numbers of patients, for generally short periods of time, and so the safety of long term cannabidiol treatment cannot be reliably assessed.
Article
P>To improve patient care and facilitate clinical research, the International League Against Epilepsy (ILAE) appointed a Task Force to formulate a consensus definition of drug resistant epilepsy. The overall framework of the definition has two "hierarchical" levels: Level 1 provides a general scheme to categorize response to each therapeutic intervention, including a minimum dataset of knowledge about the intervention that would be needed; Level 2 provides a core definition of drug resistant epilepsy using a set of essential criteria based on the categorization of response (from Level 1) to trials of antiepileptic drugs. It is proposed as a testable hypothesis that drug resistant epilepsy is defined as failure of adequate trials of two tolerated, appropriately chosen and used antiepileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom. This definition can be further refined when new evidence emerges. The rationale behind the definition and the principles governing its proper use are discussed, and examples to illustrate its application in clinical practice are provided
Article
To improve patient care and facilitate clinical research, the International League Against Epilepsy (ILAE) appointed a Task Force to formulate a consensus definition of drug resistant epilepsy. The overall framework of the definition has two "hierarchical" levels: Level 1 provides a general scheme to categorize response to each therapeutic intervention, including a minimum dataset of knowledge about the intervention that would be needed; Level 2 provides a core definition of drug resistant epilepsy using a set of essential criteria based on the categorization of response (from Level 1) to trials of antiepileptic drugs. It is proposed as a testable hypothesis that drug resistant epilepsy is defined as failure of adequate trials of two tolerated, appropriately chosen and used antiepileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom. This definition can be further refined when new evidence emerges. The rationale behind the definition and the principles governing its proper use are discussed, and examples to illustrate its application in clinical practice are provided.