JICNAR○| Journal of the International
Child Neurology Association
A peer reviewed open access e-journal in Child Neurology
Cannabis and related products in the treatment of epilepsy
1
J. Helen Cross
1UCL Great Ormond Street Institute of Child Health, Great Ormond Street Hospital for Children NHS
Foundation Trust, London, and Young Epilepsy, Lingfield UK
Email Address: J. Helen Cross (h.cross@ucl.ac.uk)
Corresponding author: Professor JH Cross; Email: h.cross@ucl.ac.uk
Received: 05 July 2018
Accepted: 30 May 2019
Abstract
There has been much heightened interest recently in the possible use of cannabinoid products in the treatment of complex
epilepsies. Although systematic studies have now been performed and reported showing the benefit of cannabidiol (CBD)
as Epidiolex (GW Pharma) in the treatment of Dravet and Lennox-Gastaut syndromes, there remains considerable confu-
sion regarding the role of hemp oils and other products (CBD with tetrahydrocannabinol) for which there is no consistent,
quality-assured product or evidence base for use. There is also a great deal of debate as to whether the psychoactive com-
ponent, tetrahydrocannabinol (THC), is required for optimal effect, with no sound evidence base for support. The current
position is that data has been acquired for Epidiolex, and a licence for use granted by the Federal Drug Administration,
with data submitted to the European Medicines Authority. Other products with greater THC content have been reported
to be beneficial although only in open-label studies, with results that could be considered little different to the randomised
controlled trials with cannabidiol alone. Although benefit in certain specific complex epilepsies has been demonstrated
with CBD, the requirement or not for some THC for added benefit remains under debate and as yet unproven.
Kewords: Cannabis, cannabinoids, cannabidiol, epilepsy, childhood.
© Cross JH.; licensee JICNA
her daughter who had frequent seizures as a result of Dravet
INTRODUCTION
syndrome, a complex developmental epileptic encephalopa-
thy with early onset. At the time of the trial she was ex-
There has been much recent discussion with regard to
periencing nearly 50 convulsive seizures/day - by using the
the use of cannabis-related products in the treatment of
cannabidiol-rich product this decreased to two to three noc-
epilepsy, with stories of effectiveness highlighted in the me-
turnal convulsions/month [1] Subsequent social media and
dia, and the issue being discussed by the governments of
internet reports led to the belief that this must be a miracle
Australia, the Netherlands and the United Kingdom. Heart-
treatment, specifically for Dravet syndrome.
wrenching stories and possible miracle cures are being re-
ported widely. But what is the evidence?
Many parents therefore sought to utilise a similar extract,
either producing it themselves, or sourcing it from produc-
ers in those states in the United States (US) where the prod-
uct was legal, as well as other countries. As a result, Col-
HISTORY
orado became a significant source of the product, and a
Cannabis-related products have long been used in every-
Facebook survey was subsequently generated, the results of
day life, as well as being used as recreational drugs. Mer-
which were published: 19 families reported, showing a pos-
its have also long been claimed in the treatment of vari-
itive effect against seizures in >80%, as well as improved
ous medical conditions. In 2014, attention was brought to
sleep pattern, alertness and mood. Some negative effects
the potential utilisation of these products in the treatment
were reported, not least in fatigue, drowsiness and loss of
of epilepsy through an internet report of a mother in Col-
appetite [2]. While acknowledging the bias towards report-
orado who had researched the possible benefits - she had
ing about those who had experienced a positive effect, and
worked with a Colorado-based medical marijuana group to
the perception of cannabinoid products as ‘natural’, families
extract a cannabidiol-enriched oil that could be utilised for
have continued to seek what they see as the ‘miracle’ treat-
1
Cross J.H. - JICNA 2019, 1(1)
ment.
route of administration, maximum recommended daily
dose, packaging, shelf life, or stability. With fluctuations
in the relative components of the products, and no infor-
mation in dosing, it may not be regarded as safe practice
CANNABINOID PRODUCTS
to prescribe or endorse such products for utilisation. The
The two major neuroactive components in cannabis are the
Medicines and Healthcare Products Regulatory Agency in
psychoactive compound D9 - tetrahydrocannabinol (THC)
the UK examined this issue and released a position state-
and the non-psychoactive cannabidiol (see figure 1).
ment in 2016 ‘products containing cannabidiol (CBD) used
for medical purposes are a medicine. Medicinal products
must have a product licence
(marketing authorisation)
before they can be legally sold, supplied or advertised in
the UK, unless exempt. Licensed medicinal products have
to meet safety, quality and efficacy standards to protect
public health’
Aside from the policing of such use, this proved impossible.
A range of cannabidiol-containing products have been
utilised for different medical conditions in countries where
THC content is not restricted. These are galenical oils
prepared by pharmacists following medical prescription le-
gal in several European countries such as the Netherlands,
Italy and Germany. Such products may be prescribed by
registered physicians. Dutch-produced Bedrocan varieties
are frequently used for the preparation of galenic CBD-
based oils. More recently, Epidiolex, a liquid formulation of
Figure 1 Structure of cannabinoids
pure plant-derived cannabidiol, or CBD, <0.1% THC (GW
Pharma), has been evaluated for treating a number of rare
childhood-onset epilepsy disorders. It is produced in a con-
The role of ‘medical’ marijuana has been much debated
sistent quality-assured way to pharmaceutical standard, so
for the treatment of many different conditions. Individuals
there is a reliability to the content and stability. It is reg-
who use cannabis for recreational use have reported many
istered as a pharmaceutical, to be assessed in appropriate
benefits. However, the level of THC in the whole plant
clinical trials, and data is to be submitted to the appropri-
means that the drug has remained Schedule 1 in many
ate regulatory authorities for licence. The FDA approved a
countries, and is indeed illegal for any recreational or
licence for the product for use in certain complex childhood
medical use without special licence. There is also great
epilepsies in June 2018; the European Medicines Authority
concern about utilising a product rich in THC within a
(EMA) are currently assessing the medication and are due
specifically paediatric population; some in vitro studies
to report early 2019.
have suggested THC can be proconvulsant, and follow-up
More recently, after full review, legislation in the UK has
studies evaluating users of cannabis have demonstrated
been changed so that physicians can prescribe cannabis-
limitation in performance in neuropsychological tests in
based medicines when it has been agreed that their patients
those who start using the drug under the age of 15 years,
could benefit from this treatment, with further guidance
compared to those starting at an older age [3]. The relative
for children with epilepsy provided by the British Paedi-
amount of THC in a product may determine whether it
may be deemed ‘legal’ for purchase and utilisation. In the
United Kingdom (UK), CBD extract containing < 0.2%
Epidiolex is the only product for which there is evidence
THC has previously been considered legal. This would
and a safety base, and evidence with regard to prescribing
include the ‘hemp oils’ or CBD extract oils, available for
information.
purchase over the internet or from health food shops as
nutritional products. These are however not produced
to pharmaceutical standard. Studies have demonstrated
that such products do not contain consistent amounts of
CANNABINOIDS AND EPILEPSY
the relative CBD and THC components [4], and there is
therefore limited reliability despite the product information
given. No analytical controls are mandatory, there is no
legal protection or guarantee about the composition and
SCIENTIFIC DATA
quality, and there is no obligatory testing or basic regula-
tory framework to determine indication area, daily dosage,
2
Cross J.H. - JICNA 2019, 1(1)
PRECLINICAL TRIALS
signs were included, including randomised controlled tri-
als (RCTs), non-RCTs, quasi-experimental, before and after
Despite the long history of the use of cannabis-related prod-
studies, prospective and retrospective cohort studies, case-
ucts, the endocannabinoid system was not described until
control studies, analytical cross-sectional studies, self-report
the 1980s/90s. Cannabidiol was isolated as early as 1940,
surveys and case reports. This included six randomised con-
and its structure elucidated in 1963, with THC isolated in
trolled trials; the three outlined in the previous Cochrane
1964. The ensuing interest focused on the psychoactive
review, and three new RCTs reporting on utilisation of Epid-
component of this compound. The anticonvulsant effects of
iolex as produced by GW Pharma in Dravet syndrome and
CBD, THC and other cannabinoids have been compared us-
Lennox Gastaut syndrome (LGS). Of the 30 observational
ing a variety of standard seizure models [5]Despite the long
studies, six were open-label intervention trials, 10 were case
history of the use of cannabis-related products, the endo-
studies, eight were self-report surveys, five were retrospec-
cannabinoid system was not described until the 1980s/90s.
tive chart reviews, and in one the design of the remaining
Cannabidiol was isolated as early as 1940, and its structure
study was unclear.
elucidated in 1963, with THC isolated in 1964. The ensuing
interest focused on the psychoactive component of this com-
pound. The anticonvulsant effects of CBD, THC and other
cannabinoids have been compared using a variety of stan-
CANNABIDIOL IN EPILEPSY
dard seizure models [6, 7].
Cannabidiol is the only non-THC phytocannabinoid to
Epidiolex (CBD <0.1% THC, GW Pharma) has been evalu-
have been assessed in preclinical and clinical studies for an-
ated in clinical trials in the treatment of complex epilepsies.
ticonvulsant effects. The anticonvulsant profile of CBD has
Initially, approval from the FDA was achieved for its utilisa-
specifically been demonstrated in acute seizure models, but
tion as an investigational new drug in the open-label treat-
not so convincingly in animal models of chronic epilepsy
ment of children and adults with complex epilepsy across six
[8]. Cannabidivarin (CBDV), the propyl variant of CBD, also
centres in the USA [12]. To qualify for inclusion, individuals
has significant anticonvulsant properties, with and without
had to have intractable early onset epilepsy, be on more than
concomitant anticonvulsant medications (sodium valproate,
three AEDs, not including a ketogenic diet or vagal nerve
ethosuximide, phenobarbitone) [6]. CBDV exerts its effects
stimulation, have a non-progressive disorder, and have no
via the CB1 receptor independent mechanism [9]. CBD and
significant abnormalities on laboratory testing. They would
related compounds may reduce neuronal excitability and
be requested to keep a four-week baseline seizure diary,
neuronal activity, but the exact mechanism through which
would then be initiated on cannabidiol (CBD) 5mg/kg/day,
they exert an anti-epileptic effect is not currently known.
titrated at 2-5mg/kg/day increments until tolerance or a
maximum of 25mg/kg/day. Laboratory investigations were
evaluated at four, eight and 12 weeks. Two hundred and
CLINICAL DATA
fourteen patients were enrolled, with 167 completing for
Clinical use of cannabis-related products in epilepsy has
safety and tolerability analysis, and 137 for efficacy analy-
been scant until recently. A Cochrane review published
sis. Thirty-nine percent experienced >50% seizure reduc-
in
2014 reported four randomised trial reports where
tion over a 12-week period, with 15 seizure-free for the last
cannabidiol was the treatment agent [10]. There was how-
four weeks, and five seizure-free for the whole treatment pe-
ever only a total of 48 patients and all four studies were
riod [12]. Further analysis of those with Dravet syndrome
methodologically flawed. Details of randomisation were not
and LGS showed 49% and 37% responders respectively. Ad-
included in any study report. There was no investigation of
verse events were seen in 79%, most commonly somnolence
whether the control and treatment participant groups were
(25%), decreased appetite and diarrhoea (each 19%). The
the same or different. All four reports were low quality,
overall conclusion of the study was that CBD might reduce
and only dealt with the secondary outcome of adverse ef-
seizure frequency, and might have an adequate safety profile
fects. None of the patients in the treatment groups suffered
in children and young adults with highly treatment-resistant
adverse effects. The authors did not think that any reli-
epilepsy. However, it became clear that through an effect
able conclusions could be drawn regarding the efficacy of
on cytochrome p450 system in the liver, the norclobazam
cannabinoids as a treatment for epilepsy. Cannabidiol had
metabolite of clobazam was dramatically increased when
been safely administered to small numbers of patients gen-
patients were on concomitant treatment [13]. This was sep-
erally for short periods of time, and so the safety of long-
arately reported prior to the results of the full study, where
term cannabidiol treatment could not be reliably assessed.
it was also clear that many of the side-effects reported from
A more recent systematic review determined 35 publi-
the CBD could be attributed to increased clobazam metabo-
cations from 36 studies that met inclusion criteria with a
lite levels. Further analysis in the open-label study revealed
further 10 studies yet to be published [11]. Studies were
that 36/70 patients (51%) on clobazam experienced more
included if they administered plant-based and pharmaceu-
than a 50% reduction of seizures, compared to 18/67 (27%)
tical cannabinoids to prevent or treat epilepsy and epileptic
not on clobazam. On multiple logistic regression, clobazam
seizures in participants of any age, with any type of epilepsy
use was the only independent predictor of a >50% reduc-
or seizure. All experimental and epidemiological study de-
tion in motor seizures.
3
Cross J.H. - JICNA 2019, 1(1)
Subsequent randomised controlled trials of CBD vs
42% stiripentol [15]. Although in those where stiripentol
placebo as an add-on treatment of Dravet and LGS have
was taken concomitantly, clobazam metabolites were un-
been published [14, 15, 16]. For the Dravet syndrome study,
likely to have risen further. Subgroup analysis was not pos-
children with a definitive diagnosis of Dravet syndrome (as
sible owing to small numbers [18].
assessed by clinical criteria via the Epilepsy Study Consor-
With regard to LGS, two separate studies of similar
tium), were recruited from 23 centres across the USA and
methodology have been published. In the initial publica-
Europe. A total of 177 children aged two to 18 years were
tion, the study was across 24 sites in the USA, the Nether-
screened, with 120 ultimately randomised to either CBD (up
lands and Poland [14]. One hundred and seventy-one pa-
to 20mg/kg/day) or placebo, having experienced at least
tients with LGS, as verified through criteria by the Epilepsy
four convulsive seizures over the four-week baseline period.
Consortium, were included. Patients who were refractory
The mean age in the CBD group (9.7 years) was not differ-
(i.e., inadequately managed on at least two anti-epileptic
ent from the placebo group (9.8 years). The median num-
drugs, inclusive of previous and current treatments), were
ber of anti-epileptic drugs trialled was four, and the patients
taking one to four anti-epileptic drugs, and who had at
were taking a median of three (range 1-5), most commonly
least two drop seizures per week during the four-week base-
clobazam (65%), valproate (59%), stiripentol (42%), leve-
line period, were eligible. After a four-week screening pe-
tiracetam (28%) and topiramate (26%). In the CBD group,
riod, patients were randomised to receive CBD (N=86), in-
the primary endpoint of convulsive seizure frequency at the
creased to a dose of 20mg/kg/day, or placebo (N=85), and
end of the treatment period decreased by a median -38.9%
received treatment for 14 weeks. The primary endpoint
from the baseline. This was significantly greater than in
was mean percentage reduction in drop seizures frequency
the placebo group (-13.3%, p=0.01)). The responder rate
from baseline. In the CBD group, the monthly frequency of
(>50% reduction in seizures) was 43% in the CBD group
drop seizures decreased by a median of 43.9% from baseline
vs 27% in the placebo group; this did not reach signifi-
over the 14-week treatment period compared to 21.8% in
cance (p=0.08). Adverse events during the treatment pe-
the placebo group; a difference that reached statistical sig-
riod were reported in 93% CBD vs 75% placebo; 89% ad-
nificance. There was also a significant difference between
verse events were mild or moderate. In both groups, the
groups in the reduction of total seizures. With regard to ad-
first occurrence of an adverse event was most commonly
verse events, all-cause adverse events were reported in 86%
reported during the 14 days dose-escalation. Common ad-
of the CBD group and 69% of the placebo group. Those
verse events (>10% frequency) in the CBD group were vom-
occurring in >10% in the CBD group included somnolence
iting, fatigue, pyrexia, upper respiratory tract infection, de-
and diarrhoea. These events led to withdrawal in 12/86 of
creased appetite, convulsion, lethargy, somnolence and di-
the CBD group and 1/85 of the placebo group. In the sec-
arrhoea. In the CBD group, eight patients withdrew from
ond publication, two different doses of CBD were examined,
the trial owing to adverse events, as compared with one in
compared to placebo [16]. A total of 225 patients aged
the placebo group.
two to 55 years were enrolled with confirmed LGS as per
In this study, 65% of children with Dravet syndrome were
clinical criteria, from 30 clinical centres, and randomised
taking clobazam. As highlighted above, there is no question
to placebo, 10mg/kg/day CBD or 20mg/kg/day. The me-
that norclobazam levels rise when CBD and clobazam are
dian percent reduction from baseline in drop-seizure fre-
given together, and some of the side-effects, such as som-
quency during the treatment period was 41.9% in the 20mg
nolence, could well be attributed to this. Some may ques-
CBD group, 37.2% in the 10mg CBD group, and 17.2% in
tion whether any of the CBD effects on seizures is the re-
the placebo group (P = 0.005 for the 20mg CBD group vs
sult of such an interaction, or a direct effect of the med-
placebo group, and P = 0.002 for the 10mg CBD group vs
ication itself. Prior to the Dravet study, a pharmacoki-
placebo group). Adverse events were reported in 77 of 82
netic dose-finding study was performed and recently pub-
patients (94%) in the 20mg CBD group, in 56 of 67 patients
lished [17]. Thirty-four children with Dravet syndrome
(84%) in the 10mg CBD group, and in 55 of 76 patients
aged four to 10 years were randomised 4:1 to CBD (5, 10 or
(72%) in the placebo group. The most common adverse
20mg/kg/day) or placebo taken twice a day; 32 completed
events among the patients in the CBD groups were som-
treatment. The double-blind trial comprised a four-week
nolence, decreased appetite, and diarrhoea; these events
baseline, three-week treatment, 10-day taper and four-week
occurred more frequently in the higher-dose group. Six
follow-up. Pharmacokinetic sampling for the measurement
patients in the 20mg CBD group and one patient in the
of CBD, metabolites and anti-epileptic drug levels were per-
10mg CBD group discontinued the trial medication because
formed on the first day of dosing and at the end of treat-
of adverse events and were withdrawn from the trial. El-
ment. CBD did not effect concomitant AED levels, except
evation of serum aminotransferase concentrations was the
for norclobazam. Norclobazam levels increased on all doses
most common adverse event among these patients, occur-
of CBD, but not placebo, and not if there was concomitant
ring in four of the six patients in the 20mg/kg CBD group
stiripentol. Although numbers were small with only four
as well as in the patient in the 10mg/kg CBD group, with
patients taking both clobazam and stiripentol, this suggests
maximum elevations in aspartate aminotransferase or ala-
that stiripentol maximally inhibits CYP2C19. In the Dravet
nine aminotransferase concentrations that were 3.2 to 12.2
trial, 65% of the children were also taking clobazam, and
times the upper limit of the normal range. Further publi-
4
Cross J.H. - JICNA 2019, 1(1)
cations have reported on observational studies in a wider
in-patients-with-focal-seizures-at-the-2018-annual-
range of complex epilepsies, as well as extended follow-up
meeting-of-the-american-academy-of-neurology-aan/).
of the expanded access programme. Observational studies
The question remains open however as to whether the full
have suggested efficacy in epilepsy associated with CDKL5
benefit is obtained from pure CBD, or whether additional
disorder, Aicardi syndrome, Doose syndrome and 15q dele-
benefit may be gained by combining it with THC to some
tion syndrome [19], as well as Febrile Infection Related
extent. A recent case series from Israel reported on the
Epilepsy Syndrome (FIRES)[20], epilepsy associated with
experience of five paediatric epilepsy clinics utilising
tuberous sclerosis[21] and epilepsy associated with Sturge
CBD-enriched medical cannabis with 1% THC [25]. They
Weber syndrome [22]. These data suggest wider efficacy
reported on 74 patients who had previously failed on up
across a range of complex epilepsies beyond the selected
to seven anti-epileptic drug treatments, some of which
groups for the RCTS. Expansion of the open access pro-
included a ketogenic diet and vagal nerve stimulation.
gramme with follow-up up to 96 weeks has shown sustained
Although they reported a positive effect, only 18% reported
efficacy in a wider range of complex epilepsies with 76% re-
>75% reduction in seizures, and 34% reported a 50-75%
tention; treatment-emergent adverse events were similar to
reduction. Although this was an open-label study, these
previous reports with convulsions (9%), status epilepticus
figures appear little different to that seen in the RCTs of
(7%), pneumonia (5%), and vomiting (3%) the most fre-
CBD alone. Similar adverse effects were also reported
quently reported [23].
including somnolence, fatigue, gastrointestinal disturbance
One question remains as to whether seizure outcome is
and irritability, leading to discontinuation in five patients.
the only benefit that may be seen utilising cannabinoid
A further study utilising CBD with 2% THC from Canada
products. Trials are being undertaken in children with de-
reported on open-label use in 20 children with Dravet syn-
velopmental disorders, but without epilepsy. Further in the
drome. The dose ranged from 2-6 mg/kg/day of CBD and
Epidiolex trials, a secondary outcome was reporting on any
0.04-0.32 mg/kg/day of THC. Nineteen patients completed
change seen in the Caregiver Global Impression of Change
20 weeks intervention; one child who died of SUDEP was
(CGIC) scale, assessed on a seven-point Likert-like scale that
excluded from the analysis. As with the RCTs, somnolence,
used three categories of improvement (slightly improved,
anorexia and diarrhoea were the most common adverse
much improved, or very much improved), three categories
events seen, with abnormalities of liver transaminases and
of worsening (slightly worse, much worse, or very much
platelets observed with concomitant valproic acid therapy.
worse), and an option of ‘no change’. In all studies, sig-
Following 20 weeks therapy, 12/20 reported >50% reduc-
nificantly more parents reported an improvement in the
tion of seizures [26], again not dissimilar figures to the
scale in the CBD group as compared to the placebo group
RCTs of CBD.
[14, 15, 16]. In a further reported subset of patients en-
rolled in a prospective, open-label clinical study where they
analysed the caregiver-reported Quality of Life in Childhood
CURRENT POSITION
Epilepsy (QOLCE), results from caregivers of 48 patients in-
dicated an 8.2 ± 9.9-point improvement in overall patient
There is much confusion about different cannabinoid-
QOLCE (p < 0.001) following 12 weeks of CBD. Subscores
related products and their proven role (or not) in the treat-
with improvement included energy/fatigue, memory, con-
ment of epilepsy. Parents and families are often desperate
trol/helplessness, other cognitive functions, social interac-
to leave no stone unturned in the treatment of devastating
tions, behaviour, and global QOL, differences that were not
conditions. News travels fast via the internet and should a
correlated to changes in seizure frequency or adverse events
possible effective treatment be reported, families are under-
[24]. These findings suggest that effects beyond seizure out-
standably keen to pursue this. Further, a product derived
come warrant further evaluation.
from a plant may be perceived to be ‘natural’, particularly
if available as a ‘health’ food. As highlighted above, how-
ever, only the pharmaceutically derived product Epidiolex
STUDIES UTILISING ALTERNATIVE
has been trialled in a systematic way for efficacy and safety.
Hemp oils are not produced in a similar quality-assured way,
PRODUCTS
and content is not consistent. Further, there is no reliable
In the recently published systematic review by Stockings
evidence to indicate an appropriate dose. When children
et al[11], by far the majority of publications reviewed
do not respond to a product, however, there is speculation
were observational and open-label. A preliminary report
thereafter as to why this may not be the case. The ques-
on an RCT using a transdermal CBD gel (Zynerba) in
tion arises as to whether THC content may be required, and
refractory focal epilepsy in adults showed a statistical
consequently tried. Again there is no evidence to support
reduction in seizures with either of two doses compared
this; one also has to question the safety of such a suggestion
to placebo over a 12-week period, although with mean-
while being aware of this as the psychoactive component,
ingful clinical reductions in seizures in the open-label
although further research is warranted. Parental reporting
extension
studies can also be subject to bias; a recent study enrolled 75
announces-twelve-month-zyn002-data-from-star-2-study-
patients of which 57% reported no improvement in seizure
5
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Cross, J. H. (2019). Cannabis and related products in
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