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Review evidence for cannabinoids as adjunctive treatments for treatment-resistant epilepsy. Systematic search of Medline, Embase and PsycINFO was conducted in October 2017. Outcomes were: 50%+ seizure reduction, complete seizure freedom; improved quality of life (QoL). Tolerability/safety were assessed by study withdrawals, adverse events (AEs) and serious adverse events (SAEs). Analyses were conducted in Stata V.15.0. 36 studies were identified: 6 randomised controlled trials (RCTs), 30 observational studies. Mean age of participants was 16.1 years (range 0.5–55 years). Cannabidiol (CBD) 20 mg/kg/day was more effective than placebo at reducing seizure frequency by 50%+(relative risk (RR) 1.74, 95% CI 1.24 to 2.43, 2 RCTs, 291 patients, low Grades of Recommendation, Assessment, Development and Evaluation (GRADE) rating). The number needed to treat for one person using CBD to experience 50%+ seizure reduction was 8 (95% CI 6 to 17). CBD was more effective than placebo at achieving complete seizure freedom (RR 6.17, 95% CI 1.50 to 25.32, 3 RCTs, 306 patients, low GRADE rating), and improving QoL (RR 1.73, 95% CI 1.33 to 2.26), however increased risk of AEs (RR 1.24, 95% CI 1.13 to 1.36) and SAEs (RR 2.55, 95% CI 1.48 to 4.38). Pooled across 17 observational studies, 48.5% (95% CI 39.0% to 58.1%) of patients reported 50%+ reductions in seizures; in 14 observational studies 8.5% (95% CI 3.8% to 14.5%) were seizure-free. Twelve observational studies reported improved QoL (55.8%, 95% CI 40.5 to 70.6); 50.6% (95% CI 31.7 to 69.4) AEs and 2.2% (95% CI 0 to 7.9) SAEs. Pharmaceutical-grade CBD as adjuvant treatment in paediatric-onset drug-resistant epilepsy may reduce seizure frequency. Existing RCT evidence is mostly in paediatric samples with rare and severe epilepsy syndromes; RCTs examining other syndromes and cannabinoids are needed. PROSPERO registration number CRD42017055412.
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StockingsE, etal. J Neurol Neurosurg Psychiatry 2018;0:1–13. doi:10.1136/jnnp-2017-317168
REVIEW
Evidence for cannabis and cannabinoids for
epilepsy: a systematic review of controlled and
observationalevidence
Emily Stockings,1 Dino Zagic,1 Gabrielle Campbell,1 Megan Weier,1 Wayne D Hall,2,3
Suzanne Nielsen,1 Geoffrey K Herkes,4 Michael Farrell,1 Louisa Degenhardt1
Epilepsy
To cite: StockingsE, ZagicD,
CampbellG, etal. J Neurol
Neurosurg Psychiatry Epub
ahead of print: [please
include Day Month Year].
doi:10.1136/jnnp-2017-
317168
Additional material is
published online only. To view,
please visit the journal online
(http:// dx. doi. org/ 10. 1136/
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1National Drug and Alcohol
Research Centre, UNSW Sydney,
Sydney, New South Wales,
Australia
2Centre for Youth Substance
Abuse Research, University
of Queensland, Brisbane,
Queensland, Australia
3National Addiction Centre,
Kings College London, London,
England
4Department of Neurology,
Royal North Shore Hospital,
Sydney, New South Wales,
Australia
Correspondence to
Dr Emily Stockings, National
Drug and Alcohol Research
Centre, UNSW Sydney, Sydney,
NSW 2052, Australia; e.
stockings@ unsw. edu. au
Received 29 August 2017
Revised 12 December 2017
Accepted 16 December 2017
ABSTRACT
Review evidence for cannabinoids as adjunctive
treatments for treatment-resistant epilepsy. Systematic
search of Medline, Embase and PsycINFO was
conducted in October 2017. Outcomes were: 50%+
seizure reduction, complete seizure freedom; improved
quality of life (QoL). Tolerability/safety were assessed
by study withdrawals, adverse events (AEs) and serious
adverse events (SAEs). Analyses were conducted in
Stata V.15.0. 36 studies were identified: 6 randomised
controlled trials (RCTs), 30 observational studies. Mean
age of participants was 16.1 years (range 0.5–55 years).
Cannabidiol (CBD) 20 mg/kg/day was more effective than
placebo at reducing seizure frequency by 50%+(relative
risk (RR) 1.74, 95% CI 1.24 to 2.43, 2 RCTs, 291
patients, low Grades of Recommendation, Assessment,
Development and Evaluation (GRADE) rating). The
number needed to treat for one person using CBD to
experience 50%+ seizure reduction was 8 (95% CI 6 to
17). CBD was more effective than placebo at achieving
complete seizure freedom (RR 6.17, 95% CI 1.50 to
25.32, 3 RCTs, 306 patients, low GRADE rating), and
improving QoL (RR 1.73, 95% CI 1.33 to 2.26), however
increased risk of AEs (RR 1.24, 95% CI 1.13 to 1.36) and
SAEs (RR 2.55, 95% CI 1.48 to 4.38). Pooled across 17
observational studies, 48.5% (95% CI 39.0% to 58.1%)
of patients reported 50%+ reductions in seizures; in 14
observational studies 8.5% (95% CI 3.8% to 14.5%)
were seizure-free. Twelve observational studies reported
improved QoL (55.8%, 95% CI 40.5 to 70.6); 50.6%
(95% CI 31.7 to 69.4) AEs and 2.2% (95% CI 0 to 7.9)
SAEs. Pharmaceutical-grade CBD as adjuvant treatment
in paediatric-onset drug-resistant epilepsy may reduce
seizure frequency. Existing RCT evidence is mostly
in paediatric samples with rare and severe epilepsy
syndromes; RCTs examining other syndromes and
cannabinoids are needed.
PROSPERO registration number CRD42017055412.
BACKGROUND
The International League Against Epilepsy (ILAE)
defines epilepsy as a disease of the brain, diag-
nosis of which requires: (a) at least two unpro-
voked seizures occurring >24 hours apart; (b) one
unprovoked seizure and a probability for further
seizures of at least 60%, occurring over the next 10
years or (c) the diagnosis of an epilepsy syndrome.1
Between 70% and 80% of patients with new-onset
epilepsy achieve complete seizure control using
antiepileptic drugs such as valproate or carbamaz-
epine.2 In 20%–30% who are drug-resistant,3 4
there is great interest in investigating novel agents
to reduce seizure frequency and severity. For the
purposes of this review, the ILAE’s definition of
drug-resistant epilepsy—the failure of adequate
trials of two tolerated and appropriately chosen
and used antiepileptic drugs (AEDs) schedules (as
either monotherapies or in combination) to achieve
seizure freedom5—is used. For the 30% of patients
who experience drug-resistant epilepsy, the efficacy
of alternative and adjunctive therapies is likely to be
of great interest.
Preclinical studies suggest that naturally occur-
ring cannabinoids (phytocannabinoids) have anti-
convulsant effects which are mediated by the
endocannabinoid system.6 Cannabidiol (CBD)
and cannabidivarin have shown antiseizure effects
in both in vivo and in vitro models. In contrast
to tetrahydrocannabinol (THC), CBD does not
produce euphoric or intrusive psychoactive side
effects when used to treat seizures.7 Cannabinoids
have been proposed as an adjunctive treatment
for epilepsy7 and parents of children with epilepsy
report using CBD products.8–10 There are a number
of phase III human trials underway of CBD as an
adjunctive therapy for treatment resistant paedi-
atric and adult epilepsies.11 12
Recently Israel, the Netherlands, Germany and
Canada have legislated to allow the use of cannabi-
noids for medicinal purposes. In Australia, Federal
and state legislation that allows doctors to prescribe
cannabinoids is being implemented. Systematic
reviews are required to synthesise the evidence
for individual conditions for which cannabinoids
may be used to inform clinical practice and patient
guidance.
This review considers evidence on the safety and
efficacy of cannabinoids as adjunctive treatments
for drug-resistant epilepsy. As previous reviews
noted a lack of controlled studies,13 14 we synthe-
sised evidence from randomised controlled trials
(RCTs) and observational studies.
METHOD
This review was conducted according to
the Preferred Reporting Items for Systematic
Review and Meta-Analysis (PRISMA) guidelines
(see PRISMA checklist in online supplementary
materials 1). The search strategy and data extraction
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Epilepsy
process are briefly summarised here; methodology is detailed
in full in the study protocol (Prospero registration number
CRD42017055412; see online supplementary materials 2)
Please note that there is considerable material documenting both
the methods and the results of this review in the online supple-
mentary materials, which we recommend reviewing.
Data sources and search strategy
To identify individual studies examining cannabinoids to
treat epilepsy, the electronic databases Medline, Embase and
PsycINFO, and the clinical trials registries: clinicaltrials. gov, the
EU clinical trials register (www. clinic altr ials regi ster . eu) and the
Australian and New Zealand Clinical Trials Registry (ANZCTR,
www. anzctr. org. au) were searched in October 2017 using terms
shown in box 1 (corresponding subject headings in each data-
base were used where specialised thesauri existed). We addition-
ally searched reference lists of systematic reviews identified as
relevant. Searches were limited to studies published from 1980
to 9 October 2017 on human subjects, in any language. The
Medline search is provided in online supplementary materials 4.
Inclusion and exclusion criteria
Studies were included in the review if they administered plant-
based and pharmaceutical cannabinoids to prevent or treat
epilepsy and epileptic seizures in participants of any age, with
any type of epilepsy or seizure. We included all experimental
and epidemiological study designs including RCTs, non-RCTs,
quasi-experimental, before and after studies, prospective and
retrospective cohort studies, case-control studies, analytical
cross-sectional studies, self-report surveys and case reports.
Studies were excluded from the review if they were reviews
of mechanisms of cannabinoid systems, commentary and review
articles.
Study screening
Two reviewers independently examined titles and abstracts in
the web-based systematic review program, Covidence.15 Rele-
vant articles were obtained in full, and assessed for inclusion
independently by two reviewers. Inter-reviewer disagreement on
inclusion was discussed with an aim to reach consensus. A third
reviewer was consulted when consensus could not be reached by
the two initial reviewers.
Outcomes
We considered primary and secondary outcomes suggested
by the International League Against Epilepsy’s Commission
on Outcome Measurement.16 17 The primary outcome was
the proportion of patients who experienced a 50% or greater
reduction in seizure frequency. Secondary outcomes included
the proportion of patients achieving complete seizure freedom;
quality of life indicators (including changes in mood, behaviour,
sleep, attention, speech and cognitive, social and motor skills);
withdrawal from the study (due to adverse events (AEs) or other
reasons) and AEs.
Assessment of risk of bias
Methodological quality ratings for risk of bias in RCTs were
determined using the Cochrane Collaboration risk of bias tool.18
RCTs were judged to have an overall low risk of bias if they
had six to eight risk domains rated as having a low risk of bias,
unclear risk if four or more domains were judged as being unclear
and high risk if three or more domains were judged as being
high risk. Observational or case study reports were evaluated
using risk of bias in non-randomised studies - of interventions
(ROBINS-I) tool for assessing risk of bias in non-randomised
studies of interventions.19 Overall risk of bias was determined
by the most serious risk of bias allocated to that study across the
tool. Any disagreements were resolved through discussion, or
with the input of a third reviewer.
Grading of evidence
An evidence grade was given to each reported study, based on
the Grades of Recommendation, Assessment, Development and
Evaluation (GRADE) tool.18 Randomised, double-blind place-
bo-controlled trials were considered to be of the highest quality,
but ratings could be downgraded where there were instances of
bias or poor design. Single case studies or self-report studies were
considered to be of very low quality. We additionally conducted
a GRADE assessment using GRADEPro (https:// gradepro. org/)
for each reported pooled estimate to evaluate the risk of bias,
inconsistency, indirectness, imprecision and publication bias,
resulting in an overall GRADE rating for each outcome. GRADE
assessments were conducted independently by two reviewers
with disagreements resolved via consensus with a third reviewer.
Data extraction
Data were extracted from studies using a standardised data
extraction tool in Microsoft Office Excel 2016. The data
extracted from studies included specific details about the inter-
vention, populations, study methods and outcomes of signif-
icance to the review question and specific objectives. Data
extraction tools were piloted and reviewed by the authors before
being finalised (see online supplementary materials 5 for fields
extracted).
During the review, clinical experts reviewed the extracted data
and gave feedback on the need to define drug-resistant epilepsy,
distinguishing between paediatric and adult epilepsies and
distinguishing between AEs and serious adverse events (SAEs).
Accordingly, we extracted whether studies identified their
participants as having drug-resistant epilepsies, in line with the
ILAE definition,5 namely, the failure of two or more tolerated
and appropriately chosen AEDs, used either in combination
or as monotherapy, to achieve complete seizure freedom (see
online supplementary materials 3 for a summary of this defi-
nition). Paediatric epilepsies were defined as those occurring in
persons between the ages of 0 and 18 years. We also extracted
concurrent AEDs reported by the participants.
All reported AEs, including SAEs and treatment-related adverse
events (TSAEs) were included in the review. We extracted AEs as
being ‘serious’ or ‘treatment-related’ based on authors' report.
Box 1
1. Cannabis or marijuana or cannabinoids or endocannabinoids
or dronabinol or nabilone or marinol or levonantradol or
tetrahydrocannabinol or cesamet or delta-9-THC or delta-9-
tetrahydrocannabinol or nabiximols or sativex pr cannabidiol
2. Therapeutic use or drug therapy or analgesics
3. 1 and 2
4. (medical or medicinal) adj (mari?uana or cannab*) or
‘medical mari?uana’ or ‘medicinal cannabis’
5. 3 or 4
6. Epilepsy
7. 5 and 6
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Epilepsy
Where studies reported multiple points of follow-up data, we
extracted the longest follow-up within each study.
Analysis
All analyses were conducted using Stata V.15.0.20 We expected
high levels of heterogeneity between studies due to differences
in sociodemographic and clinical profiles, thus all outcomes
were analysed using DerSimonian and Laird inverse-variance
random effects meta-analysis.21 For RCTs, the relative risk (RR)
of participants in the treatment groups achieving study outcomes
relative to participants in the comparison group were estimated
using the ‘metan’ command. For observational studies with no
comparison group, the proportion of participants achieving
study outcomes were pooled using the prevalence command,
metaprop’ using the Freeman-Tukey double arcsine transforma-
tion to stabilise variances and prevent exclusion of studies where
proportions approached 0 or 1.20 22 For dichotomous outcomes
from RCTs, we calculated numbers needed to treat (NNT) and
numbers needed to harm (NNH) and their 95% CIs. We used
pooled estimates of relative effect (ie, RRs) to take into account
the event rate in control groups.23 NNT was calculated for the
outcomes 50% or greater reduction in seizures, complete seizure
freedom and quality of life. NNH was calculated for all-cause
AEs, SAEs, TSAEs and study withdrawals due to AEs.
Heterogeneity in all pooled estimates was summarised using
the I2 statistic and was described as being unimportant for values
between 0% and 30%, moderate for 31%–60%, substantial for
61%–75% and considerable for 76%–100%.18
Where sufficient data were available, we conducted subgroup
analyses on the basis of epilepsy type (such as Dravet or
Lennox-Gastaut syndromes); sample age (paediatric vs adult or
mixed aged samples) and overall risk of bias rating.
RESULTS
Searches identified 445 articles (see figure 1). An additional 11
poster abstracts were sourced through the American Epilepsy
Society conference database24 and the authors were contacted for
further details. Three additional papers were published and iden-
tified through hand-search by the authors after the initial data-
base search, and eight papers were identified via hand-searches
of systematic review reference lists. After title and abstract
screening, 91 articles were selected for full-text screening. Of
these, 35 papers (comprising 36 individual studies) met criteria
for inclusion in the review (table 1 and online supplementary
materials 6, table A4; see online supplementary materials 9 for
excluded studies). We additionally identified 10 ongoing studies
that met inclusion criteria but for which results have not yet been
published (see online supplementary materials 10).
Of the six randomised trials, four were parallel double-blind
placebo-controlled trials,25–28 one was a cross-over study29 and
one was a randomised placebo-controlled trial with limited
details of blinding.30 Of the 30 observational studies, 6 were
open-label intervention trials,11 12 31–34 10 were case studies,35–44
8 were self-report surveys,8 9 45–50 5 were retrospective chart
reviews44 51–54 and the design of the remaining study was
unclear.55
Figure 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowchart.
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Epilepsy
Table 1 Study-level summaries of included randomisedcontrolled trials
Study Design Sample Treatment Pharma. grade Outcomes measured Results
Adverse events and serious
adverse events
Bias assessment† /GRADE
assessment
Ames and Crindland30 Randomised clinical
trial
12 adults with frequent seizures not
controlled by anticonvulsant therapy
(drug-resistant epilepsy)
100 mg CBD or placebo sunflower oil 3
times a day for 1 week, then 2 times a
day for 3 weeks
Not stated Seizure reduction - The trial was abandoned before the second stage of the
trial could take place. No significant differences in seizure
frequency were observed between groups.
Reported:
drowsiness
Unclear risk/low
Cunha et al25 Randomised,
double-blind,
placebo-controlled
trial
15 adults (mean age=24; range
14–49; 26.7% male) with secondary
generalisedepilepsy
(drug-resistant epilepsy)
100 mg CBD or placebo glucose capsule,
taken orally 2–3 times per day, for
8–18 weeks
Not stated Reported seizure
improvement; self-reported
subjective improvement
- Four of seven (~57%) patients receiving CBD showed
complete seizure freedom, compared with 1/8 (12.5%)
placebo patients.
- All 7 CBD patients showed some sort of improvement in
seizure frequency, compared with only 2/8 (25%) placebo
patients.
- One CBD patient withdrew from the study, whereas two
patient receiving placebo withdrew.
Somnolence (57.1%)
Painful gastric sensation (14.3%)
High risk/moderate
Devinsky et al26 Randomised,
double-blind,
placebo-controlled
trial
120 children and adolescents (mean
age=9.8; range=2–18; 52% male)
with Dravet syndrome
(drug-resistant epilepsy)
20 mg/kg/day CBD or placebo, taken
orally for 14 weeks, as an adjunctive
treatment
Yes Change in seizure frequency,
caregiver global impression
of change
- Three CBD patients achieved total seizure freedom during
the test period, no placebo patients achieved seizure freedom
(P=0.08).
- Twenty-six CBD patients (~43%) had a >50% reduction in
seizures, compared with 16 patients (~27%) in the placebo
group.
- Thirty-seven caregivers (~62%) judged their child’s overall
condition to be improved in the cannabidiol group, as
compared with 20 (~34%) in the placebo group (P=0.02).
- Nine CBD patients withdrew from the study, 8 of which were
due to adverse events. In comparison, three placebo patients
withdrew, with only one being due to adverse events.
Somnolence (36%)
Diarrhoea (31%)
Decreased appetite (28%)
Fatigue (20%)
Vomiting (15%)
Fever (15%)
Lethargy (13%)
Upper respiratory tract infection
(11%)
Convulsion (11%)
Serious:
Elevated liver aminotransferase
enzymes (20%)
Status epilepticus (4.9%)
Low risk/high
GW Pharmaceuticals 27 Randomised,
double-blind,
placebo-controlled
trial
225 patients (mean age=16;
range=2–55) with
Lennox-Gastaut syndrome
(drug-resistant epilepsy)
i) 10 mg/kg/day CBD for 14 weeks Yes Change in seizure frequency,
change in QoL and caregiver
global impression of change
- Patients randomised to 10 mg/kg/day of CBD achieved
a median reduction in monthly drop seizures of 37%, in
comparison with 17% in those patients in the placebo group
(P=0.0016).
- One patient receiving 10 mg/kg/day CBD withdrew due to
adverse events, as did one placebo patient.
All cause (83.6%)
Serious:
All cause (17.8%)
Unclear risk/high
ii) 20 mg/kg/day CBD for 14 weeks Yes Change in seizure frequency,
change in QoL and caregiver
global impression of change
- Patients taking 20 mg/kg/day of CBD showed a median
reduction in monthly drop seizures of 42%, compared with
17% in the placebo group (P=0.0047).
- Six patients receiving the higher dose (20 mg/kg/day)
withdrew due to adverse events, compared with one placebo
patient.
All cause (93.4%)
Serious:
All cause (17.1%)
Thiele et al28 Randomised,
double-blind,
placebo-controlled
study
171 patients (mean age=15.4;
range=2–45; 51.5% male) with
Lennox-Gastaut syndrome
(drug-resistant epilepsy)
20 mg/kg/day CBD or placebo, taken
daily for 14 weeks, as an adjunctive
treatment
Yes Change in seizure frequency,
caregiver impression of
overall improvement
- Five of 86 CBD patients achieved complete seizure freedom
during the maintenance period, compared with none in the
placebo group.
- Thirty-eight patients (~44%) taking CBD had >50%
decrease in seizures, compared with 20 (~24%) patients
taking placebo.
- Forty-two (~58%) CBD patients were reported (by either
themselves or a caregiver) to have achieved an improvement
in their overall condition, compared with 29 (~34%) placebo
patients.
- Fourteen CBD patients withdrew from the study, compared
with just one patient given placebo.
Diarrhoea (18.6%)
Somnolence (15.1%)
Fever (12.8%)
Decreased appetite (12.8%)
Vomiting (10.5%)
Serious:
All cause (23.3%)
Unclear risk/high
Trembly and Sherman 29 Double-blind,
cross-over, placebo-
controlled add-on
trial
12 adults with incompletely
controlled seizures
(drug-resistant epilepsy)
100 mg CBD or placebo 3 times per day
for 26 weeks
Not stated Monthly seizure episodes - Changes to seizure frequency were not statistically analysed,
but authors report some reduction in seizure frequency for
patients taking CBD.
None reported Unclear risk/moderate
†Bias assessment based on risk of bias for randomised studies.
Studies are presented in alphabetical order; adverse events are reported for participants receiving cannabinoids and experienced by >10% of sample.
CBD,cannabidiol; GRADE,Grades of Recommendation, Assessment, Development and Evaluation; Pharma. grade, pharmaceutical grade cannabinoid product; QoL, quality of life.
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Characteristics of study participants
The RCTs included a total of 555 patients (range: 12–225), all of
whom had drug-resistant epilepsy. The mean age of participants,
where reported, was 16.3 years (range: 2.3–49) and the mean
percentage of males was approximately 48.3% (range: 26.7%–
52%). Two RCTs27 28 examined Lennox-Gastaut syndrome, one26
examined Dravet syndrome and the remaining studies25 29 30
reported on ‘mixed’ epilepsy syndromes.
In comparison, the non-RCT studies included 2865 patients
with drug-resistant epilepsy (range: 1–976), whom had a mean
age of 15 years (range: 0.5–50). The percentage of males was
approximately 48.6% (range: 0%–100%). Nine of the non-RCT
studies examined Dravet syndrome either primarily or as a
subgroup within a larger sample,9 32 35 39 44 46 49 52 53 eight exam-
ined Lennox-Gastaut syndrome,9 32 35 41 46 49 52 53 four studies
examined Doose syndrome,46 49 52 53 the remaining studies exam-
ined mixed epilepsy syndromes8 9 11 12 31–35 37 38 40 42–54 and two
studies36 55 did not specify epilepsy subtype.
Cannabinoids used and features of treatment
The RCTs all studied CBD with a placebo comparator; CBD was
an adjuvant treatment in all cases. The more recent studies that
describe data based on participant weight26–28 reported a CBD
range of 2.5–20 mg/kg/day across a mean treatment length of
14 weeks. Earlier RCTs25 29 30 reported using 100 mg of CBD
administered 2–3 times per day for a treatment period between
8 and 26 weeks.
Cannabinoids used in the non-RCT studies varied, but CBD
was most commonly used (n=159 11 12 31–35 37 41 43 45 46 49 52);
four studies examined a combined CBD:THC extract39 44 54; six
examined cannabis sativa8 36 40 47 48 50; one examined dronab-
inol38 and the remaining studies reported various other canna-
binoid formulations. Cannabinoids were used as an adjuvant
therapy, with a treatment range between 10 days and 7.5 years.
Risk of bias
Table 1 and online supplementary materials 6, table A4 include
the quality assessment ratings for each of the included studies
(see also online supplementary materials 6, figures A1 and A2).
Of the six RCTs included in the review, only one was judged
to be at a low risk of bias,26 one study was judged to be high25
and the remaining four were judged to have an unclear risk of
bias27–30 (see online supplementary materials 6, figures A1 and
A2), primarily due to lack of detail.
Non-randomised trials were mostly judged to be at serious to
critical risk of bias, particularly those with self-reported outcomes
on self-selected participant samples (see online supplementary
materials 6, figure A3). The lack of randomisation, blinding and
control groups in these studies mean that their results can at
most be indicators of clinical experience rather than evidence
for the effectiveness of the product used. Methodological quality
for these studies was typically graded as low or very low (see
online supplementary materials 6, table A4 for full description
of the studies).
Primary outcome: 50% reduction in seizure frequency
Nineteen studies reported the proportion of participants who
experienced 50% or greater reductions in seizure frequency. This
comprised 2 RCTs26 28 and 17 observational studies, including 4
open-label trials,11 31 34 37 3 retrospective chart studies,44 53 54 3
self-report studies,45 46 49 3 case reports39 43 44 and 4 studies of a
general observational design.12 32 52 55
CBD was more likely to produce >50% reduction in seizures
than placebo in two RCTs (RR 1.74, 95% CI 1.24 to 2.43, n=291
patients, mean age: 25.9 years, range: 10–45 years, I2=0%; low
GRADE rating; see table 2 and in online supplementary material
7.1, figure A4). We estimated that the NNT for one person to
achieve a 50% reduction in seizures was 8 (95% CI 6 to 17). Esti-
mates did not differ based on epilepsy type, sample age or study
risk of bias rating (see online supplementary material 7.1, figure
A5–A7). An estimated 48.5% of the 970 patients in 17 observa-
tional studies achieved a 50% or greater reduction in seizures
(95% CI 39.0% to 58.1%, mean age: 8.8 years, range: 6 months
to 46 years, considerable heterogeneity, I2=79.5%; low GRADE
rating; see table 2, supplementary material 8.1, figure B1). This
estimate is comparable to, although larger than the proportion
of responders in the two larger, high-quality RCTs (42.6%26
and 44.2%28). Estimates did not differ by epilepsy type, sample
age or study risk of bias (see online supplementary material 8.1,
figures B2–B5). The pooled estimate for paediatric only samples
(57.7%, 95% CI 39.0% to 75.6%) was somewhat higher than
that for adult, or mixed adult and paediatric samples (36.2%,
95% CI 11.3% to 64.4%); however, these estimates fell within
overlapping bounds of uncertainty (online supplementary mate-
rial 8.1.2a, figure B4).
As noted in table 4, we conclude there is mixed quality
evidence that there may be some treatment effect of CBD as
an adjunctive therapy in achieving 50% or greater reduction in
seizures. There is insufficient evidence from moderate-quality or
high-quality studies to assess whether there is a treatment effect
of Cannabis sativa, CBD:THC combinations or oral cannabis
extracts.
Secondary outcome: complete seizure freedom
Seventeen studies reported rates of complete seizure freedom
among individuals receiving cannabinoids as adjunctive
treatments (see table 2 for full details). This comprised 3
RCTs25 26 28 and 14 observational studies, including 4 self-report
surveys,9 45 46 49 3 open-label trials,11 31 37 2 retrospective chart
reviews,44 54 2 case studies35 44 and 3 studies of a general obser-
vational design.12 52 55
Of the three RCTs that reported data on complete seizure
freedom, one study involved only paediatric patients with
Dravet syndrome (n=120),26 one included both paediatric
and adult patients with Lennox-Gastaut syndrome (n=171)28
and one study involved only adult patients with secondary
generalised epilepsy (n=15),25 all of which were classified as
drug-resistant. The pooled RR from these studies for CBD in
achieving complete seizure freedom compared with placebo was
6.17 (95% CI 1.50 to 25.32, total n=306 participants, mean
age: 16.4 years, range: 2.3–45.1 no heterogeneity, I2=0%; low
GRADE rating; see table 2 and online supplementary material
7.2, figure A8). We estimated that the NNT for one person to
achieve complete seizure freedom was 171 (95% CI 155 to 339).
There were no differences identified in the RR of complete
seizure freedom based on epilepsy type, age group or study
risk of bias (see online supplementary material 7.2, figures A9–
A11); however, each subgroup only contained one study in these
analyses.
The pooled prevalence of participants achieving complete
seizure freedom in the 14 observational studies with no compar-
ison group was 8.5% (95% CI 3.8% to 14.5%, n=944, mean
age: 8.1, range 6 months to 46 years, substantial heteroge-
neity, I2=77.3%; see online supplementary material 8.2, figure
B6, low GRADE rating). This was higher than the proportion
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Epilepsy
Table 2 Meta-analysis of study outcomes of RCTs; non-randomised study pooled estimates as comparison
Endpoints
Subgroup analysis #RCTs
#RCT
participants
RCT pooled relative risk
(95% CI)* I2GRADE (RCTs)
#Non-
RCTs
#Non-RCT
participants
Non-RCT pooled estimate
(95% CI) I2GRADE (non-RCTs)
1. 50% or greater reduction in seizures 2 291 1.74 (1.24to 2.3) 0.0 ⨁⨁◯◯ LOW 17 970 48.5% (39.0to 58.1) 78.2 ⨁⨁◯◯ LOW
Age group
Paediatric 1 120 1.57 (0.94to2.62) ⨁⨁◯◯ LOW 13 370 57.1% (39.2to 74.4) 81.1 ⨁⨁◯◯ LOW
Adult 2 7 24.6% (0.0to 74.1) ⨁⨁◯◯ LOW
Paediatric and adult 1 171 1.88 (1.24to2.43) ⨁⨁◯◯ LOW 4 637 42.7% (38.7to 46.8) 0.0 ⨁⨁◯◯ LOW
Epilepsy type
Dravet syndrome 1 120 1.57 (0.94to2.62) ⨁⨁◯◯ LOW 6 78 46.9% (16.1to 78.7) 79.1 ⨁⨁◯◯ LOW
Lennox-Gastaut syndrome 1 171 1.88 (1.20to 2.95) ⨁⨁◯◯ LOW 4 59 63.8% (32.1to 91.1) 67.0 ⨁⨁◯◯ LOW
Secondary generalised epilepsy
Doose syndrome 3 15 29.4% (0.0to 73.9) ⨁⨁◯◯ LOW
Mixed epilepsy syndromes 7 580 46.9% (38.3to55.6) 64.0 ⨁⨁◯◯ LOW
Tuberous sclerosis complex 1 18 22.2% (9.0to45.2) ⨁⨁◯◯ LOW
Febrile infection-related epilpesy syndrome 1 5 100.0% (56.6to100.0) ⨁⨁◯◯ LOW
Malignant migrating partial seizures 1 1 100.0% (20.7to 100.0) ⨁⨁◯◯ LOW
2. Complete seizure freedom 3 306 6.17 (1.50to25.32) 0.0% ⨁⨁◯◯ LOW 14 944 8.5% (3.8to 14.5) 77.3 ⨁⨁◯◯ LOW
Age group
Paediatric 1 120 6.77 (0.36to128.38) ⨁⨁◯◯ LOW 10 362 15.2% (5.2to28.0) 80.4 ⨁⨁◯◯ LOW
Adult 1 15 4.57 (0.66to31.89) ⨁⨁◯◯ LOW
Paediatric and adult 1 171 10.87 (0.61to 193.64) ⨁⨁◯◯ LOW 4 582 5.5% (2.5to9.5) 59.6 ⨁⨁◯◯ LOW
Epilepsy type
Dravet syndrome 1 120 6.77 (0.36to128.38) ⨁⨁◯◯ LOW 3 48 6.3% (0.0to 41.3) ⨁⨁◯◯ LOW
Lennox-Gastaut syndrome 1 171 10.87 (0.61to 193.64) ⨁⨁◯◯ LOW 2 83 6.4% (1.7to 13.0) ⨁⨁◯◯ LOW
Secondary generalised epilepsy 1 15 4.57 (0.66to31.89)] ⨁⨁◯◯ LOW
Febrile infection-related epilepsy syndrome 1 8 25.0% (7.1to 59.1) ⨁⨁◯◯ LOW
Mixedepilepsy syndromes 8 634 7.6% (2.7to 14.1) 75.6 ⨁⨁◯◯ LOW
Tuberous sclerosis complex 1 18 5.6% (1.0to 25.8) ⨁⨁◯◯ LOW
3. Quality of life 2 274 1.73 (1.33to 2.26) 0.0 ⨁⨁◯◯ LOW 12 440 55.9% (40.5to70.6) 93.9 ◯◯◯ VERY LOW
Age group
Paediatric 1 118 1.79 (1.19to2.69) ⨁⨁◯◯ LOW 8 292 30.1% (16.7to 44.9) 88.9 ◯◯◯ VERY LOW
Adult 2 126 89.3% (75.5to 98.3) 70.8 ◯◯◯ VERY LOW
Paediatric and adult 1 156 1.69 (1.19to2.41) ⨁⨁◯◯ LOW 2 13 89.9% (60.5to 100.0) ◯◯◯ VERY LOW
Epilepsy type *
Dravet syndrome 1 118 1.79 (1.19to 2.69) ⨁⨁◯◯ LOW 2 4 100.0% (84.3to 100.0) 0.0 ◯◯◯ VERY LOW
Lennox-Gastaut syndrome 1 156 1.69 (1.19to 2.41) ⨁⨁◯◯ LOW 1 1 100.0% (48.7to 100.0) ◯◯◯ VERY LOW
Mixedepilepsy syndromes 10 433 44.4% (29.6to 59.5) 95.2 ◯◯◯ VERY LOW
Tuberous sclerosis complex 2 27 66.8% (47.1to 84.2) ◯◯◯ VERY LOW
Malignant migrating partial seizures 1 1 100.0% (21.3to 100.0) ◯◯◯ VERY LOW
*Significant results indicate a greater likelihood of the event in the intervention group relative to controls, and are highlighted bold.
GRADE, Grades of Recommendation, Assessment, Development and Evaluation; RCT, randomised controlled trial.
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of participants who achieved complete seizure freedom in the
two larger, high-quality RCTs (namely 4.9% and 5.8%). There
were no significant differences in the proportion of participants
achieving complete seizure freedom by epilepsy type, participant
age or risk of bias (see online supplementary material 8.2, figures
B7–B10). The pooled estimate for paediatric samples (14.3%,
95% CI 5.2% to 25.9%) was somewhat higher than that for adult
or mixed adult and paediatric samples (4.3%, 95% CI 1.3% to
8.4%); however, these estimates fell within overlapping bounds
of uncertainty (see online supplementary material 8.2.2a, figure
B9).
As noted in table 4, we conclude that there is mixed quality
evidence that the use of CBD as an adjunctive treatment may
help achieve seizure freedom. There is insufficient evidence
to assess whether CBD:THC combinations or oral cannabis
extracts are effective.
Secondary outcome: quality of life
Fourteen studies (comprising 26 individual data points) eval-
uated the effects of cannabinoids on quality of life indicators.
Two were RCTs,26 28 and 12 were observational studies, of
which 4 were retrospective chart reviews,51–54 4 were case study
reports,35 39 41 43 2 were self-report surveys48 49 and 2 were open-
label trials.12 32 Quality of life in the two RCTs26 28 was measured
by parent's/caregiver’s global impression of change. Non-RCTs
reported improvements in mood, social skills, cognitive skills,
behaviour, alertness/attention, speech and language, sleep, appe-
tite and motor skills and reductions in self-stimulation.
The pooled RR of parents/caregivers reporting that the
patients’ overall condition had improved (using the patient
global impression of change measure) in those receiving CBD
versus placebo of 1.73 (95% CI 1.33 to 2.26, n=274 patients,
mean age: 12.6 years, range 2.3–45.1, no heterogeneity, I2=0%;
see table 2, online supplementary material 7.3, figure A12), and
this did not differ on the basis of epilepsy type, sample age or
study risk of bias (online supplementary material 7.3, figures
A13–A15). The NNT for one person receiving CBD to experi-
ence an improvement in parental-reported quality of life was 5
(95% CI 4 to 9).
A pooled estimate from observational studies of the propor-
tion of patients with improved quality of life when using canna-
binoids was 55.8% (95% CI 40.5 to 70.6, n=440 patients, mean
age: 12.7 years, range: 6 months to 50 years, considerable hetero-
geneity, I2=93.9; see online supplementary material 8.3, figure
B11). This included improvements in mood (95.9%, 95% CI
74.1 to 100), cognitive skills (76.1%, 95% CI 53.8 to 93.6),
alertness (54.0%, 95% CI 28.3% to 78.9%) and sleep (50.9%,
95% CI 9.8% to 91.4%; see online supplementary figure B11).
The proportion of participants reporting improvement in quality
of life indicators was higher in samples with Dravet syndrome
(100%, 95% CI 84.3% to 100%) compared with samples with
mixed epilepsy syndromes (44.4%, 95% CI 29.6% to 59.5%);
however, the studies comprising the Dravet syndrome subgroup
were all case series (combined n=5 patients) in which every
patient responded and thus this should be interpreted with
great caution (online supplementary material 8.3.1, figure B12).
Samples comprising adults only reported higher proportions of
participants experiencing improved appetite, mood and sleep
(89.3%, 95% CI 75.5% to 98.3%) compared with paediatric
samples (30.1%, 95% CI 16.7% to 44.9%; see online supple-
mentary material 8.3.2, figure B13). Studies rated as being at
‘serious’ risk of bias (the second highest risk rating) had lower
overall proportions of participants reporting improvement in
quality of life (16.6%, 95% CI 8.4% to 26.3%) compared with
studies at ‘critical risk’ (the highest rating; 65.2%, 95% CI 34.5%
to 91.3%) and studies where risk was unable to be determined
due to lack of information (85.4%, 95% CI 67.5% to 98.0%; see
online supplementary material 8.3.3, figure B14).
As noted in table 4, we conclude there is mixed quality
evidence that CBD improved patient quality of life when used
as an adjunctive treatment. There was very low-quality and
low-quality evidence on the use of Cannabis sativa, oral THC,
CBD:THC combinations and oral cannabis extracts. This was
insufficient to assess their therapeutic usefulness.
Secondary outcome: study withdrawals
Withdrawals are used as an indicator of tolerability and effec-
tiveness of a treatment. Twelve studies reported on patient with-
drawal from treatment—four RCTs25–28 and eight observational
studies, including two open-label trials,11 41 three retrospective
chart reviews44 53 54 and three studies of a general observational
design.12 52 55
In RCTs, there was no difference in the likelihood of study
withdrawal for any reason between patients given CBD and
who received placebo (pooled RR 2.96, 95% CI 0.64 to 13.78,
n=306 patients; mean age: 16.4 years, range: 2.3–49, moderate
heterogeneity, I2=52.2%; see table 3, online supplementary
material 7.4, figure A16). This did not differ on the basis of
epilepsy type, sample age or study risk of bias (see online supple-
mentary material 7.4, figure A17–A19). Based on two RCTs,26 27
patients receiving CBD were more likely to withdraw from the
study due to experiencing AEs (pooled RR 4.87; 95% CI 1.10 to
21.68, n=345, mean age: 11.9, range: 2–55 years, no hetero-
geneity, I2=0%; see online supplementary material 7.4.4, figure
A20), with no difference based on epilepsy type, sample age or
study risk of bias (see online supplementary material 7.4, figures
21–23). The NNH for one person to withdraw from CBD treat-
ment due to AEs was 164 (95% CI 140 to 267).
A pooled estimate of the proportion of participants with-
drawing from the study for any reason in four11 52 53 55
non-RCTs was 28.0% (95% CI 5.2% to 59.5%, n=486, mean
age: 8.7, range: 6 months to 32 years, considerable heteroge-
neity I2=98.0%; see table 3, online supplementary material 8.4,
figure B15). All samples comprised a mix of epilepsy subtypes
(see online supplementary figure B16). Pooled estimates of with-
drawal were higher for paediatric-only samples (47.9%; 95% CI
40.9% to 55.0%) compared with mixed paediatric and adult
samples (15.2%; 95% CI 11.3% to 19.6%; see online supple-
mentary material 8.4.1, figure B17). One study rated as crit-
ical risk of bias (the highest risk category)53 had substantially
higher proportions of participants reporting study withdrawal
(70.6%, 95% CI 61.9% to 78.0%) than studies of lesser risk
(see online supplementary material 8.4.2, figure B18). The
pooled estimate for withdrawals from the study due to AEs in
six studies11 12 41 53–55 was 4.1% (95% CI 0.9% to 8.8%, substan-
tial heterogeneity, I2=72.3%, n=521, mean age: 10, range: 6
months to 32 years; see online supplementary material 8.4.3,
figure B19), and did not differ based on epilepsy type, sample
age or study risk of bias (see online supplementary material 8.4,
figures B20–B22).
Study withdrawals were noted for patients receiving CBD and
oral cannabis extracts (table 3). There is mixed quality evidence,
including from two higher-quality RCTs that patients who
received CBD were more likely to withdraw from treatment.
There is insufficient evidence to draw any conclusions about
withdrawals from oral cannabis extract treatment.
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Table 3 Meta-analysis of study-reported tolerability and safety
Endpoints
Subgroup analysis #RCTs
#RCT
participants
RCT pooled relative risk
(95% CI)* I2GRADE (RCTs)
#Non-
RCTs
#Non-RCT
participants
Non-RCT pooled estimate
(95% CI)† I2GRADE (non-RCTs)
4. Withdrawals 3 306 2.96 (0.64to13.78) 55.2 ⨁⨁◯◯ LOW 4 486 28.0% (5.2to 59.5) 98.0 ◯◯◯ VERY LOW
Age group
Paediatric 1 120 2.90 (0.83to 10.20) ⨁⨁◯◯ LOW 2 194 47.9% (40.9to 55.0) 0.0 ◯◯◯ VERY LOW
Adult 1 15 0.57 (0.06to5.03) ⨁⨁◯◯ LOW
Paediatric and adult 1 171 13.84 (1.86to102.91) ⨁⨁◯◯ LOW 2 292 15.2% (11.3to 19.6) 0.0 ◯◯◯ VERY LOW
Epilepsy type
Dravet syndrome 1 120 2.90 (0.83to10.120) ⨁⨁◯◯ LOW
Lennox-Gastaut syndrome 1 171 13.84 (1.86to102.91) ⨁⨁◯◯ LOW
Secondary generalised epilepsy 1 15 0.57 (0.06to5.03) ⨁⨁◯◯ LOW
5. Withdrawals due to adverse events 3 345 4.87 (1.10to21.68) 0.0 ⨁⨁◯◯ LOW 6 521 4.1% (0.9to 8.8) 72.3 ⨁⨁◯◯ LOW
Age group
Paediatric 1 120 7.74 (1.00to 59.97) ⨁⨁◯◯ LOW 3 211 6.7 (2.2to 12.9) 0.0 ⨁⨁◯◯ LOW
Adult
Paediatric and adult 2 225 2.88 (0.33to 25.53) 0.0 ⨁⨁◯◯ LOW 3 310 2.2% (0.0to 6.8) 0.0 ⨁⨁◯◯ LOW
Epilepsy type
Dravet syndrome 1 120 7.74 (1.00to 59.97) ⨁⨁◯◯ LOW
Lennox-Gastaut syndrome 2 225 2.88 (0.33to 25.53) ⨁⨁◯◯ LOW
Mixed epilepsy syndromes 5 503 3.7% (0.7to 8.4) 75.5 ⨁⨁◯◯ LOW
Tuberous sclerosis complex 1 18 11.1% (3.1to 32.8) ⨁⨁◯◯ LOW
6. Adverse events—all cause 5 531 1.24 (1.13to 1.36) 0.0 ⨁⨁◯◯ LOW 12 651 50.6% (31.7to 69.4) 94.4 ◯◯◯ VERY LOW
Age group
Paediatric 1 120 1.25 (1.06to 1.48) ⨁⨁◯◯ LOW 8 353 47.7% (32.4to 63.3) 82.7 ◯◯◯ VERY LOW
Adult 1 15 5.71 (0.86to 37.91) ⨁⨁◯◯ LOW 3 132 27.6% (4.0to59.8) 0.0 ◯◯◯ VERY LOW
Paediatric and adult 3 396 1.23 (1.10to1.38) 0.0 ⨁⨁◯◯ LOW 2 166 82.8% (75.6to 89.1) 0.0 ◯◯◯ VERY LOW
Epilepsy type
Dravet syndrome 1 120 1.25 (1.06; to 1.48) ⨁⨁◯◯ LOW 1 3 100.0% (43.9to 100.0) ⨁⨁◯◯ LOW
Lennox-Gastaut syndrome 3 396 1.23 (1.10to 1.38) 0.0 ⨁⨁◯◯ LOW 1 1 100.0% (20.7to 100.0) ⨁⨁◯◯ LOW
Secondary generalised epilepsy 1 15 5.71 (0.86to 37.91) ⨁⨁◯◯ LOW
Mixed epilepsy syndromes 4 216 74.3% (41.0to 98.0) 89.1 ⨁⨁◯◯ LOW
Tuberous sclerosis complex 1 18 66.7% (43.7to 83.7) ⨁⨁◯◯ LOW
Specific event
Drowsiness 3 306 2.53 (1.40to 4.57) 7.0 ⨁⨁◯◯ LOW 15 897 22.6% (15.3to 30.7) 84.4 ⨁⨁◯◯ LOW
Diarrhoea 2 291 2.63 (1.45to4.76) 0.0 ⨁⨁◯◯ LOW 9 209 11.3% (2.8to 23.0) 85.2 ⨁⨁◯◯ LOW
Vomiting 2 291 1.25 (0.28to 5.49) 75.3 ⨁⨁◯◯ LOW 7 333 2.6% (0.8to 5.1) 0.0 ⨁⨁◯◯ LOW
Fatigue 1 120 5.80 (1.36to 24.83) ⨁⨁◯◯ LOW
Fever 2 291 1.63 (0.83to 3.21) 0.0 ⨁⨁◯◯ LOW
Upper respiratory tract infection 1 120 1.35 (0.46to 4.03) ⨁⨁◯◯ LOW 4 108 2.1% (0.0to 6.5) 0.0 ⨁⨁◯◯ LOW
Change in appetite 2 291 5.46 (2.18to 13.69) 0.0 ⨁⨁◯◯ LOW 12 613 7.2% (3.1to 12.5) 67.8 ⨁⨁◯◯ LOW
Continued
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Endpoints
Subgroup analysis #RCTs
#RCT
participants
RCT pooled relative risk
(95% CI)* I2GRADE (RCTs)
#Non-
RCTs
#Non-RCT
participants
Non-RCT pooled estimate
(95% CI)† I2GRADE (non-RCTs)
Convulsion 1 120 2.26 (0.61to 8.32) ⨁⨁◯◯ LOW 1 162 11.1% (7.1to16.9) ⨁⨁◯◯ LOW
Lethargy 1 120 2.58 (0.72to 9.26) ⨁⨁◯◯ LOW 4 223 3.6% (0.6to 8.3) 21.6 ⨁⨁◯◯ LOW
Gastrointestinal symptoms 1 15 3.38 (0.16to71.67) ⨁⨁◯◯ LOW 3 268 6.9% (4.0to 10.5) 0.0 ⨁⨁◯◯ LOW
Ataxia 7 94 17.1% (1.1to 41.7) 79.9 ⨁⨁◯◯ LOW
Change in weight 5 340 5.7% (1.6to 11.5) 79.7 ⨁⨁◯◯ LOW
Confusion 2 135 0.6% (0.0to 3.4) 0.0 ⨁⨁◯◯ LOW
Insomnia 6 221 2.6% (0.8to 5.1) 0.0 ⨁⨁◯◯ LOW
7. Serious adverse events 4 516 2.55 (1.48to4.38) 0.0 ⨁⨁◯◯ LOW 7 201 2.2% (0.0to 7.9) 94.2 ⨁⨁◯◯ LOW
Age group
Paediatric 1 120 3.22 (0.93to 11.14) ⨁⨁◯◯ LOW 5 179 3.9% (0.0to 11.4) 64.9 ⨁⨁◯◯ LOW
Adult
Paediatric and adult 3 396 2.40 (1.17to 4.93) 29.6 ⨁⨁◯◯ LOW 2 22 0.0% (0.0to 6.4) ◯◯◯ VERY LOW
Epilepsy type
Dravet syndrome 1 120 3.22 (0.93to 11.14) ⨁⨁◯◯ LOW
Lennox-Gastaut syndrome 3 396 2.40 (1.17to 4.93) 29.6 ⨁⨁◯◯ LOW
Mixed epilepsy syndromes 6 183 2.7% (0.0to 9.5) 56.1 ⨁⨁◯◯ LOW
Tuberous sclerosis complex 1 18 0.0% (0.0to 17.6) ◯◯◯ VERY LOW
Treatment-related serious adverse events 3 396 5.93 (1.38to 25.46) 0.0 ⨁⨁◯◯ LOW 1 162 1.1% (0.6to 1.8) ⨁⨁◯◯ LOW
Specific event†
Status epilepticus 1 120 0.97 (0.20to4.60) ⨁⨁◯◯ LOW 1 162 5.6% (3.0to10.2) ⨁⨁◯◯ LOW
Elevated aminotransferase levels 1 120 11.61 (1.56to 86.48) ⨁⨁◯◯ LOW
Severe diarrhoea 1 162 1.9% (0.6to 5.3) ⨁⨁◯◯ LOW
Appetite loss 1 162 0.6% (0.1to 3.4) ⨁⨁◯◯ LOW
Death 1 162 0.6% (0.1to3.4) ⨁⨁◯◯ LOW
*Significant results indicate a greater likelihood of the event in the intervention group relative to controls, and are highlighted bold.
†Seeonlinesupplementary materials for full list of reported adverse events.
GRADE, Grades of Recommendation, Assessment, Development and Evaluation; RCT, randomised controlled trial.
Table 3 Continued
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Secondary outcome: AEs
Sixteen studies reported AEs, 4 were RCTs25–28 and 12 were
non-RCTs,11 12 31 32 35 45 48 49 51–54 including 3 self-report
surveys,45 48 49 3 retrospective chart reviews,51 53 54 2 open-label
trials,11 31 1 case study35 and 3 were a general observational
design.12 32 52
A meta-analysis of 516 patients in three RCTs26–28 found that
patients who received CBD had a small but significant increase
in the risk of experiencing any AE compared with those who
received placebo (pooled RR 1.24, 95% CI 1.13 to 1.36, mean
age: 13.7, range: 2–55 years, no heterogeneity, I2=0%; see
table 3, online supplementary material 7.5, figure A24), with
no difference based on epilepsy type, sample age or study risk
of bias (see online supplementary material 7.5, figures A25–
A27). Specific AEs for which participants receiving CBD were
at increased risk included drowsiness (RR 2.53, 95% CI 1.40 to
4.57), diarrhoea (RR 2.63, 95% CI 1.45 to 4.76), fatigue (RR
5.80, 95% CI 1.36 to 24.83) and changes in appetite (RR 5.46,
95% CI 2.18 to 13.69; see online supplementary material 7.5.4,
figure A28). The NNH for one person receiving CBD to experi-
ence any AE was 3 (95% CI 3 to 6).
Pooled estimates of 651 patients in 12 non-RCTs were that
50.6% of patients experienced any AE (95% CI 31.7% to
69.4%, mean age: 12.6, range: 6 months to 50 years, consider-
able heterogeneity, I2=94.4%; see online supplementary mate-
rial 8.5, figure B23). This did not differ based on epilepsy type.
Mixed paediatric and adult samples had significantly higher
proportions of participants reporting any AE (82.8%, 95% CI
75.6% to 89.1%) compared with adult-only and paediatric-only
studies (see online supplementary material 8.5.2, figure B25),
and studies at critical risk of bias (the highest risk level) had
significantly smaller proportions (27.0%, 95% CI 14.2% to
41.9%) than studies at lesser risk (see online supplementary
material 8.5.3, figure B26). The most common specific AEs
included drowsiness (22.6%, 95% CI 15.3% to 30.7%), ataxia
(17.1%, 95% CI 1.1% to 41.7%) and diarrhoea (11.3%, 95% CI
2.8% to 23.0%; see online supplementary material 8.5.4, figure
B27).
Three RCTs26–28 found that patients in the CBD treatment
groups were more likely to experience any SAE event than
patients in placebo conditions (pooled RR 2.55, 95% CI 1.48
to 4.38, n=516, mean age: 14.3, range: 2–55, no heteroge-
neity I2=0.4%, low GRADE rating; see online supplementary
material 7.6, figure A29), with no difference based on epilepsy
type, sample age or study risk of bias (see online supplementary
material 7.6, figures A30–A32). Specific SAEs recorded included
status epilepticus and elevated aminotransferase levels (see
online supplementary material 7.6.4, figure A33) The NNH for
one person using CBD to experience any SAE was calculated to
be 23 (95% CI 18 to 40).
Patients receiving CBD also had increased odds of experi-
encing TSAEs (RR 5.93, 95% CI 1.38 to 25.46, n=396, mean
age: 15.8, range: 2–55 years, no heterogeneity, I2=0%, low
GRADE rating; see online supplementary material 7.6.6, figure
A34), with no difference based on epilepsy type, sample age or
study risk of bias. The NNH for one person to experience a
TSAE was 191 (95% CI 167 to 529).
In the five non-RCT studies12 32 33 45 52 with 201 patients, the
pooled estimate of patients experiencing any SAE were 2.2%
(95% CI 0% to 7.9%, mean age: 9.1 years, range: 6 months
to 31 years, moderate heterogeneity, I2=52.5%, low GRADE
rating) (see online supplementary material 8.6, figure B28). The
percentage of participants experiencing SAEs did not differ by
epilepsy type or sample age; however, studies at critical risk of
bias (the highest risk level) had lower rates of SAEs than studies
at lesser risk (see online supplementary material 8.6, figure B29–
B31). SAEs included pneumonia and thrombophlebitis; however,
these were reported in only one study33 (see online supplemen-
tary material 8.6.4, figure B32). Only one observational study
reported TSAEs,11 with 1.1% (95% CI 0.6% to 1.8%) of partic-
ipants reporting this outcome (n=162, mean age: 10.5, range:
0.9 to 2.62 years, unimportant heterogeneity, I2=22.5%, very
low GRADE rating). Specific TSAEs included status epilepticus,
convulsion, hepatoxicity, pneumonia and death in one case
(see online supplementary material 8.6.5, figure B33).
There is mixed quality evidence, including from three moder-
ate-quality to high-quality RCTs, that patients receiving CBD are
more likely to experience mild-to-moderate AEs (see table 4).
There is insufficient evidence to draw any conclusions on
whether patients receiving Cannabis sativa, oral THC and oral
cannabis extracts were more likely to experience AEs.
Discussion
We synthesised available evidence on the safety and efficacy of
cannabinoids as an adjunctive treatment to conventional AEDs
in treating drug-resistant epilepsy. In many cases, there was qual-
itative evidence that cannabinoids reduced seizure frequency in
some patients, improved other aspects of the patients’ quality
of life and were generally well tolerated with mild-to-moderate
AEs. We can be much more confident about this statement in the
case of children than adults, because the recent, larger, well-con-
ducted RCTs were performed in children and adolescents.
In studies where there was greater experimental control over
the type and dosage of cannabinoid used, there was evidence that
adjuvant use of CBD reduced the frequency of seizures, partic-
ularly in treatment-resistant children and adolescents, and that
patients were more likely to achieve complete seizure freedom.
There was a suggestion that the benefits of adding CBD may be
greater when patients were also using clobazam.11 12 However
because clobazam and CBD are both metabolised in the cyto-
chrome P450 pathway, the pharmacokinetic interactions of these
two drugs still need to be fully determined.56 Further randomised,
double-blind studies with a placebo or active control are needed
to strengthen this conclusion.
Non-RCT evidence was consistent with RCT evidence that
suggested cannabinoids may reduce the frequency of seizures. In
most of these studies, cannabinoid products and dosages were
less well-controlled, and outcomes were based on self-report
(often by parents). These studies provide lower quality evidence
compared with RCTs due to the potential for selection bias in the
study populations, and other weaknesses in study design. There
was also some evidence that studies at very high risk of bias had
higher reported proportions of participants reporting reductions
in seizures and lower proportions reporting AEs. In RCTs, and
most of the non-RCTs, cannabinoids were used as an adjunctive
therapy rather than as a standalone intervention, so at present
there is little evidence to support any recommendation that
cannabinoids can be recommended as a replacement for current
standard AEDs.
Limitations
There are still few well-controlled, randomised and place-
bo-controlled studies on CBD in drug-resistant epilepsy.57 Most
studies in this review were observational and used self-report
data, raising concerns about possible patient selection and
self-reporting bias. This concern especially applies to self-report
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Epilepsy
surveys of parents, most of whom were self-selected and so may
only include the most satisfied users of cannabinoids. They are
unlikely to have included patients who had negative experiences
or received no benefits from using cannabinoids.
The fact that more patients withdrew or experienced AEs
when receiving CBD than placebo indicates the need for clini-
cians and patients to weigh the risks and benefits of adding CBD
to other AED treatment. The most commonly experienced AEs
in patients receiving CBD (drowsiness and dizziness) are similar
to those reported from approved AEDs such as gabapentin and
levetiracetam, and occur at similar rates.58 59
Small numbers of patients (8%–12%) in two RCTs experi-
enced TSAEs.26 28 Studies are needed to assess whether the rate
of these SAEs is similar to that experienced by patients receiving
approved AEDs. Incidence rates of SAEs with clobazam, a
common epilepsy treatment60 61 are similar to the profiles of
cannabinoid SAEs. If cannabinoids are more effective when
combined with clobazam,11 the possibility of increased rates of
SAEs will need to be considered.
Safety issues need to be highlighted when discussing the
results of poorly controlled studies of cannabinoids in epilepsy.
In clinical trials and non-experimental clinical studies, doctors
and other healthcare professionals can monitor patients and
intervene if they experience AEs. When patients use ‘artisanal’
cannabis products, there is much less control over dosages and
purity of the product, and so more variability in dosing. For
example, in one study, dosages of CBD reported by parents
ranged from 0.5 to 28.6 mg/kg/day, and THC dosages ranged
from 0 to 0.8 mg/kg/day.49 Well-controlled and well-regulated
therapeutic trials are essential to specify the doses required to
produce therapeutic effects with a minimum of AEs. We iden-
tified an additional 10 studies that met inclusion criteria but
for which results were not yet posted. As these results become
available, we hope to see these included in updated reviews13 in
order to improve recommendations on the use of cannabinoids
for treatment-resistant epilepsy.
Conclusions
Few high-quality RCTs have been conducted to date, and those
that currently exist have tested CBD in paediatric samples with
rare and serious forms of drug-resistant epilepsy. Of these existing
studies, a reasonable proportion of patients experienced a decrease
in seizure frequency when using pharmaceutical grade CBD prod-
ucts in addition to AEDs; however, minor AEs were likely and
complete seizure freedom was unlikely. The timely completion
and publication of RCTs will provide a better basis for assessing
the benefits and risks of cannabinoid products to control epilepsy.
Table 4 An overview of the research evidence on cannabis and cannabinoids in the treatment of epilepsy
50% reduction in seizures
n=19 studies (2 RCTs)
Complete seizure
freedom
n=17 studies (3 RCTs)
Quality of life
n=14 studies (2 RCTs)
Withdrawals
n=12 studies (4 RCTs)
Adverse events
n=16 studies (4 RCTs)
Cannabis sativa/extract Two studies (no RCT) No studies Two studies (no RCT) No studies Two studies (no RCT)
Findings Positive effect Positive effect AEs reported by 13%
Evidence GRADE ◯◯◯ VERY LOW ◯◯◯ VERY LOW ◯◯◯ VERY LOW
Risk of bias Serious to critical risk Critical risk Critical risk
Conclusion Insufficient evidence Insufficient evidence Insufficient evidence
CBD 11 studies (2 RCT) 13 studies (3 RCT) 9 studies (2 RCT) 8 studies (3 RCT) 11 studies (4 RCT)
Findings Small effect Positive effect Positive effect Patients more likely to
withdraw from CBD
AEs reported by 11%–
100%
Evidence GRADE ⨁⨁◯◯ LOW ⨁⨁◯◯ LOW ⨁⨁◯◯ LOW ⨁⨁◯◯ LOW ⨁⨁◯◯ LOW
Risk of bias Low to serious risk Low to critical risk Low to critical risk Low to critical risk Low to critical risk
Conclusion Some evidence of effect Some evidence of effect Some evidence of effect Greater likelihood of
withdrawal
Mild-to-moderate AEs
likely
Oral THC No studies No studies No studies No studies One study (no RCT)
Findings AEs reported by 12.5%
Evidence GRADE ◯◯◯ VERY LOW
Risk of bias No information
Conclusion Insufficient evidence
CBD:THC Five studies (no RCTs) Three studies (no RCTs) Two studies (no RCT) Two studies (no RCT) Two studies (no RCT)
Findings Positive effect Small effect Positive effect Withdrawal rate14% AEs reported by 42%
Evidence GRADE ⨁⨁◯◯ LOW ◯◯◯ VERY LOW ◯◯◯ VERY LOW ◯◯◯ VERY LOW ◯◯◯ VERY LOW
Risk of bias Serious to critical risk Serious to critical risk Serious risk Serious risk Serious to critical risk
Conclusion Insufficient evidence Insufficient evidence Insufficient evidence Insufficient evidence Insufficient evidence
Oral cannabis extracts One study (no RCT) One study (no RCT) One study (no RCT) One study (no RCT) No studies
Findings Positive effect Small effect Positive effect Withdrawal rate 15%
Evidence GRADE ◯◯◯ VERY LOW ◯◯◯ VERY LOW ◯◯◯ VERY LOW ◯◯◯ VERY LOW
Risk of bias Critical risk Serious risk Serious risk Serious risk
Conclusion Insufficient evidence Insufficient evidence Insufficient evidence Insufficient evidence
Risk of bias=low to high in randomised trials; low to critical risk in non-randomised studies, no information where information not available.
GRADE ratings:high: we are very confident that the true effect lies close to that of the estimate of the effect; moderate: we are moderately confident in the effect estimate: the
true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different; low quality: our confidence in the effect estimate is limited:
the true effect may be substantially different from the estimate of the effect; very low quality: we have very little confidence in the effect estimate: the true effect is likely to be
substantially different from the estimate of effect.
CBD,cannabidiol; GRADE,Grades of Recommendation, Assessment, Development and Evaluation; RCT, randomised controlled trial; THC, tetrahydrocannabinol,.
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Epilepsy
These results will also provide a better basis for a more rational and
informed clinical use of cannabis-based products and cannabinoids
to treat drug-resistant epilepsy.
Acknowledgements The authors would like to acknowledge Mary Kumvaj
for her assistance with the literature searches, David Clarke for his assistance
with data screening, Rakin Rahman for his assistance with data extraction and
checking and John Lawson for providing comments on an earlier draft of the
manuscript.
Contributors MW, SN and LD devised the search strategy and data extraction
tool, and ES and MW ran the literature searches. ES, DZ, GC and MW screened
studies for inclusion, and extracted study data. DZ and GC conducted GRADE
assessments, and ES resolved conflicts. ES conducted the data analysis. ES, GC, DZ,
MW, WDH and LD wrote the manuscript, and SN, GKH and MF provided substantial
comments on iterations of the draft. All authors approved the final version for
submission.
Funding Funding was received from the Commonwealth Department of Health,
the NSW Government Centre for Medicinal Cannabis Research and Innovation,
the Victorian Department of Health and Human Services and the Queensland
Department of Health. GC, ES, SN and LD are supported by NHMRC research
fellowships (#1119992; #1104600; #1013803 and #1041472). The National Drug
and Alcohol Research Centre at the University of NSW is supported by funding from
the Australian Government under the Substance Misuse Prevention and Service
Improvements Grant Fund.
Competing interests SN, MF and LD have all been investigators on untied
investigator-driven educational grants funded by Reckitt Benckiser. MF and LD
have received an untied educational grant from Mundipharma for postmarketing
surveillance studies of Reformulated OxyContin. SN, MF and LD have been
investigators on untied investigator-driven educational grants funded by Indivior.
WDH provided evidence to parliamentary committees on medical uses of cannabis in
Australia and the UK, and is on the Australian Advisory Council on the Medicinal Use
of Cannabis. MW, WDH, MF and LD have previously published manuscripts on the
topic of therapeutic use of cannabis.
Provenance and peer review Not commissioned; externally peer reviewed.
© Article author(s) (or their employer(s) unless otherwise stated in the text of the
article) 2018. All rights reserved. No commercial use is permitted unless otherwise
expressly granted.
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and observational evidence
epilepsy: a systematic review of controlled
Evidence for cannabis and cannabinoids for
Degenhardt
Hall, Suzanne Nielsen, Geoffrey K Herkes, Michael Farrell and Louisa
Emily Stockings, Dino Zagic, Gabrielle Campbell, Megan Weier, Wayne D
published online March 6, 2018J Neurol Neurosurg Psychiatry
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... CBD significantly reduces motor seizures by 35% in patients with severe, intractable, childhood onset, treatment-resistant epilepsy (Devinsky et al. 2016). Epidiolex, an oral solution mostly containing CBD, is also effective for the treatment of seizures (Stockings et al. 2018;Hess et al. 2016). There is therefore sufficient evidence for the efficacy of CBD against epilepsy, and this CBD could be extracted from hemp. ...
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Background Interest in industrial hemp is increasing steadily, as can be seen by the growing number of countries that have either decriminalized industrial hemp or are contemplating its decriminalization. In line with this trend, Ghana recently decriminalized the cultivation of industrial hemp (the cannabis variety with low Δ9-tetrahydrocannabinol (THC) and high cannabidiol (CBD) content), resulting in the need for research into its benefits to Ghanaians. This article examines cannabis (including industrial hemp) production, facilities for industrial hemp exploitation, and the potential benefits of industrial hemp in Ghana. Main body Indigenous cannabis strains in Ghana have high THC to CBD ratios suggesting the need for the government to purchase foreign hemp seeds, considering that the alternative will require significant research into decreasing the THC to CBD ratio of indigenous cannabis strains. Furthermore, there are several facilities within the country that could be leveraged for the production of medicinal hemp-based drugs, as well as the existence of a number of possible regulatory bodies in the country, suggesting the need for less capital. Research has also shown the potential for treatment of some medical conditions prevalent among Ghanaians using medicinal hemp-based products. These reasons suggest that the most feasible option may be for the government to invest in medicinal hemp. Conclusion Considering the challenges associated with the development of other hemp-based products, the availability of resources in the country for exploitation of medicinal hemp, and the potential benefits of hemp-based drugs to Ghanaians, investing in medicinal hemp may be the best option for the government of Ghana.
... Unfortunately, the availability of CBD has outpaced research on the drug and its effectiveness. While there is scientific evidence regarding the efficacy of prescription CBD for treating Dravet and Lennox-Gastaut syndromes [20][21][22][23][24] and tuberous sclerosis complex [20], the evidence for its effectiveness for other health conditions or outcomes is limited [9,18]. A survey of non-prescription CBD consumers (n = 2409) revealed that many individuals purchase the product for general wellness or recreation (38%), but most use CBD to treat a health condition (62%), such as anxiety, depression, or insomnia [25]. ...
Article
Background: Legislative changes have fueled the global availability of cannabis and cannabis-derived compounds, such as cannabidiol. Little is known about the effectiveness and safety of cannabidiol for treating health conditions other than seizure disorders. Objective: A systematic review of the literature was performed to investigate other health conditions, characteristics of the studied populations, and the effectiveness of cannabidiol in randomized clinical trials. Methods: Seven publication databases were searched from February to March 2021. The inclusion criteria for studies were: (1) utilized a randomized clinical trial design; (2) published in a peer-reviewed journal or thesis/dissertation; (3) published in English; (4) investigated either prescription (i.e., Epidiolex) or non-prescription CBD that was derived from the Cannabis sativa plant with < 3% ∆9-tetrahydrocannabinol; and (5) reported at least one outcome. This review excluded seizure-related disorders as several previous reviews have been done on this topic; it also excluded published protocols, other systematic reviews, or meta-analyses of randomized clinical trials that investigated cannabidiol. Independent reviewing, risk of bias assessment, and data abstraction were performed by two authors. Results: Fifty-eight studies from eight countries were included in this review. Twenty-seven studies (47%) were conducted in healthy populations, 14% were restricted to male individuals (n = 8), and 72% had sample sizes of fewer than 40 participants. Doses of cannabidiol used in these studies ranged from 400 µg to 6000 mg. The effect of cannabidiol on mental health was the most studied topic (53%), which focused mainly on anxiety, psychosis, schizophrenia, and substance use disorders. The remaining studies investigated neurological conditions (19%) and a myriad of other health conditions or outcomes. While cannabidiol appears to be anxiolytic, its effectiveness for other conditions was highly variable. Conclusions: This review highlights the inconsistencies of cannabidiol as a treatment for non-seizure-related health conditions or outcomes. Studies incorporating larger sample sizes in more diverse populations are encouraged. While cannabidiol was generally safe and well tolerated even in high doses among the included studies, clearer dosing guidelines and increased regulation of cannabidiol products are also needed.
... This is primarily due to patient preference and also reflects the fact that the entire inflorescence provides greater therapeutic benefits than isolated cannabinoids due to the presence of co-occurring bio-active plant substances such as terpenes (Baram et al., 2019;Nallathambi et al., 2018;Namdar et al., 2019;Russo, 2011). The therapeutic potential of medicinal cannabis has been demonstrated for the treatment of various medical conditions such as sleep disorders, nausea, anorexia, emesis, pain, inflammation, neurodegenerative disorders, epilepsy, and cancer (Bar-Sela et al., 2013;Elliott et al., 2019;Hussain et al., 2015;Machado Rocha et al., 2008;Naftali et al., 2011Naftali et al., , 2013Patsos et al., 2005;Sarfaraz et al., 2008;Schleider et al., 2019;Stockings et al., 2018). A wide variety of specialized metabolites are found in cannabis inflorescences, such as terpenes/terpenoids (>120), cannabinoids (>120), poly-phenolic compounds (~42) and flavonoids (~34) (Andre et al., 2016;Berman et al., 2018;ElSohly, 2007;Hanuš et al., 2016;Jin et al., 2020;Mudge et al., 2019;Radwan et al., 2021;Shapira et al., 2019). ...
Article
Cannabis sativa L. is used to treat a wide variety of medical conditions, in light of its beneficial pharmacological properties of its cannabinoids and terpenes. At present, the quantitative chemical analysis of these active compounds is achieved through the use of laborious, expensive, and time-consuming technologies, such as high-pressure liquid-chromatography- photodiode arrays, mass spectrometer detectors (HPLC-PDA or MS), or gas chromatography-mass spectroscopy (GC-MS). Hence, we aimed to develop a simple, accurate, fast, and cheap technique for the quantification of major cannabinoids and terpenes using Fourier transform near infra-red spectroscopy (FT-NIRS). FT-NIRS was coupled with multivariate classification and regression models, namely partial least square-discriminant analysis (PLS-DA) and partial least squares regression (PLS-R) models. The PLS-DA model yielded an absolute major class separation (high-THC, high-CBD, hybrid, and high-CBG) and perfect class prediction. Using only three latent variables (LVs), the cross-validation and prediction model errors indicated a low probability of over-fitting the data. In addition, the PLS-DA model enabled the classification of chemovars with genetic-chemical similarities. The classification of high-THCA chemovars was more sensitive and more specific than the classifications of the remaining chemovars. The prediction of cannabinoid and terpene concentrations by PLS-R yielded 11 robust models with high predictive capabilities (R²CV and R²pred > 0.8, RPD >2.5 and RPIQ >3, RMSECV/RMSEC ratio <1.2) and additional 15 models whose performance was acceptable for initial screening purposes (R²CV > 0.7 and R²pred < 0.8, RPD >2 and RPIQ <3, 1.2 < RMSECV/RMSEC ratio <2). Our results confirm that there is sufficient information in the FT-NIRS to develop cannabinoid and terpene prediction models and major-cultivar classification models.
... Owing to the relative infancy of cannabinoid medicine, there is only a small set of systematic reviews investigating the use of the three licensed CBMPs for the treatment of chronic pain, MS and treatmentresistant epilepsy (Stockings et al, 2018a;2018b). There is also limited evidence to estimate the effectiveness of these cannabinoids for unlicensed indications, such as appetite and weight loss associated with HIV/ AIDS, Tourette syndrome, anxiety, post-traumatic stress disorder and schizophrenia (National Academies of Science, 2017). ...
Article
Cannabis sativa L has a long history as a medicinal plant, dating back more than two millennia. Preclinical studies using both pharmacological and genetic approaches have increased the understanding of this plant and its importance in providing therapeutic strategies for a variety of conditions. The cannabis plant comprises hundreds of different active compounds with potential therapeutic properties, with cannabinoids being the main class of active compounds. Recent drug development has produced cannabinoid-rich cannabis-based medicinal products, which were legalised in November 2018 in the UK. They are increasingly prescribed for conditions, including multiple sclerosis, epilepsy and chronic pain. This article aims to review the current literature on the therapeutic effects and applications of the two main cannabinoids found in cannabis-based medicinal products.
... Owing to the relative infancy of cannabinoid medicine, there is only a small set of systematic reviews investigating the use of the three licensed CBMPs for the treatment of chronic pain, MS and treatmentresistant epilepsy (Stockings et al, 2018a;2018b). There is also limited evidence to estimate the effectiveness of these cannabinoids for unlicensed indications, such as appetite and weight loss associated with HIV/ AIDS, Tourette syndrome, anxiety, post-traumatic stress disorder and schizophrenia (National Academies of Science, 2017). ...
Article
Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating and neurodegenerative disease of the central nervous system that affects over 100 000 individuals in the UK. The symptoms of MS are heterogenous and correspond to the location of demyelination. However, common symptoms include sensory, motor, cognitive and affective disturbances. While the cornerstone of medical therapy is disease modifying agents, there is an ongoing need to develop symptomatic treatments. Cannabis-based medicinal products (CBMPs), which were partially legalised in the UK in November 2018, have been touted as a potential management option for the associated sequelae of MS. Nabiximols, an oromucosal spray containing cannabidiol and (−)-trans-Δ ⁹ -tetrahydrocannabinol, has been extensively evaluated for the treatment of MS-related spasticity. However, unlicensed CBMP formulations are a novel therapeutic class of medications, of which the clinical effects are less well known. Yet, there are promising indications for the use of CBMP in the symptomatic treatment of MS. This article reviews the literature on efficacy and safety of medical cannabis for people with MS.
... Moreover, a randomized controlled trial demonstrated that CBD significantly reduced the frequency of seizures in children with Dravet syndrome, Lennox-Gastaut syndrome, and other forms of intractable epilepsy (Chu Sin Chung and Kieffer 2013; Ligresti et al. 2016;Nazıroğlu 2015). A recent systematic review identified six randomized controlled studies that reported CBD at a dose of 20 mg/kg/day was more effective than placebo in achieving complete seizure freedom (Stockings et al. 2018). In terms of safety, the adverse effects of CBD are mild and only observed during the first month of use (Silva et al. 2020). ...
Article
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Background In 2019, Thailand legalized cannabidiol (CBD) for intractable epilepsy. The purpose of this study was to collect information regarding the experience and knowledge of CBD use in pediatric epilepsy. To the best of our knowledge, this is the first CBD survey in pediatric epilepsy in Southeast Asia. Method We performed a cross-sectional survey among all parents of pediatric epilepsy patients seen in the Pediatric Neurology Clinic at Phramongkutklao Hospital, Bangkok, Thailand between November 2018 and July 2020. The survey comprised 34 questions that assessed the demographics, knowledge, experiences, and opinions of parents/guardians regarding CBD use. The results were summarized using descriptive statistics. In addition, logistic regression was used to predict the factors for CBD use. Results Overall, 166 respondents (100%) participated in the study. Among the respondents, 9% have experienced using CBD; 56.25% of these reported reduced seizure frequency. CBD products were mostly obtained from folk healers (31.25%) and foreign products (25%). Common adverse effects included headache and nausea (31.5%). The number of anti-seizure medications (OR: 12.28, 95% CI: 1.27–118.8), knowledge of CBD as treatment for epilepsy (OR: 14.7, 95% CI: 1.43–150.87), and knowledge of CBD side effects (OR: 12.73, 95% CI: 2.77–58.43) were factors significantly associated with CBD use. Regarding CBD knowledge, our survey showed 80.72% of the respondents did not know the CBD compound for treating epilepsy, and 89.16% were not aware of CBD side effects. Interestingly, despite a lack of knowledge, 77.11% of the respondents expressed willingness to participate in future CBD trials. Conclusion Our survey highlights that half of the parents of patients who previously used CBD reported reduced seizure frequency; however, none became seizure-free. Additionally, there were gaps in knowledge regarding the use of CBD. These findings suggest that the implementation of cannabidiol knowledge is crucial for both public and healthcare professionals. Survey limitations due to the retrospective nature of the self-report could have resulted in recall bias.
Article
Cannabinoids are commonly identified and quantified using chromatographic based methods. In the present study, fluorescence spectroscopic method coupled with Parallel Factor Analysis (PARAFAC) modeling was developed and validated as a simple and fast alternative technique for identification and quantification of major cannabinoids. A PARAFAC model was built on a set of excitation-emission matrices, yielding an optimal quantitative and qualitative performance using five components, which were identified as (-)-Δ9-trans-tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA), cannabigerolic acid (CBGA), cannabichromenic acid (CBCA) and (-)-Δ9-trans-tetrahydrocannabinol/cannabidiol/cannabigerol (THC/CBD/CBG). The identity of the major acidic components, THCA, CBDA and CBGA was verified by the correlation between PARAFAC model scores and their corresponding concentrations measured by HPLC as well as by the similarity between the excitation-emission spectral loadings of each PARAFAC component and the excitation-emission spectra of pure cannabinoids standards. Moreover, the PARAFAC model scores of each component were plotted against the cannabinoids actual concentrations in the extracts to evaluate the performance of the model for predicting the concentration of each compound. All three major acidic cannabinoids revealed good to excellent linear correlations (R2 > 0.7) between the model scores and measured concentrations according to the model calibration, cross-validation and prediction performance criteria. On the other hand, components 4 and 5 identified as CBCA and THC/CBD/CBG, respectively, revealed weaker linear correlation between the PARAFAC scores to the measured concentrations. These findings pave the way for a more comprehensive assessment of cannabis excitation-emission matrices (EEMs) as a cheaper and fast alternative for commonly used chromatographic-based quantification methods.
Article
Cannabis based products are widely used for various medicinal conditions. Currently, the most common method to identify and quantify cannabinoids are liquid chromatographic methods coupled to UV-VIS or mass spectrometric detectors. As cannabinoids are fluorescent compounds, fluorescent-based detection methods are gaining increasing interest. Consequently, a comprehensive qualitative and quantitative determination of fluorescence characteristics of major cannabinoids is warranted. In the present study we have determined the fluorescent excitation-emission-spectrum of 13 major cannabinoid standards and calculated their molar extinction coefficient (ε) and quantum yield (Φ) values. Furthermore, we examined the correlation between ε and Φ to available physico-chemical substance descriptors, namely, octanol/water partitioning coefficient, molar weight and boiling point. The cannabinoids displayed a characteristic fluorescence excitation (225–400 nm)-emission (300–525 nm) signal. Neutral and acid cannabinoids could be distinguished based on their characteristic excitation-emission spectrum, namely neutral cannabinoids exhibited maximal intensities at 280 nm excitation and 300 nm emission, while acidic cannabinoids displayed maximal intensity at 300 nm excitation and 400 nm emission. Moreover, cannabinoids with overlapping UV spectrum (such as Δ9-trans-tetrahydrocannabinolic acid, cannabidiolic acid and Cannabigerolic acid) were found to have overlapping fluorescence excitation-emission spectrum, due to the same number of conjugated double bonds and the presence or absence of a carboxylic group. The calculated ε and Φ values were found to negatively correlate with each other. The spectral data provided hereby could assist to develop tools for initial screening of extracted samples for the presence of cannabinoids.
Article
Abstrak Penggunaan ganja (Cannabis sativa) sudah dimulai dari zaman dahulu. Hal ini tertuang dalam kitab-kitab pengobatan dari China, India bahkan pada zaman Mesopotamia. Dalam catatan-catatan tersebut, penggunaan ganja (Cannabis sativa) tidak hanya sebagai obat, namun juga sebagai bahan makanan dan alat ritual. Isu yang popular di Indonesia saat ini adalah mengenai legalisasi ganja. Dalam undang-undang narkotika, ganja merupakan narkotika golongan I yang berpotensi sangat tinggi menyebabkan ketergantungan dan tidak digunakan untuk terapi. Namun beberapa lembaga telah mewacanakan agar ganja dapat dilegalkan di Indonesia, selain dinilai memberikan manfaat secara medis juga memiliki potensi ekonomi. Ganja mengandung cannabinoid yang dianggap memiliki manfaat secara medis, yang dalam beberapa negara telah dikembangkan sebagai sediaan obat legal. Dalam hal manfaat ekonomi, ganja memiliki potensi perdagangan yang cukup besar dan dapat dijadikan sebagai komoditas ekspor. Pendekatan dalam penelitian ini menggunakan metode kualitatif dengan menggunakan data kepustakaan berupa buku, peraturan-peraturan, pendapat ahli, serta menelaah berbagai jurnal ilmiah menggunakan Garuda, PubMed, Sciencedirect, dan Wiley. Hasil dari analisa data berupa informasi yang sistematis. Artikel ini dapat menjadi rujukan dalam pengembangan dan pelegalan ganja medis di Indonesia. Kata kunci: Ganja Medis, Pengobatan rasional, Peraturan.
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Recent clinical trials indicate that cannabidiol (CBD) may reduce seizure frequency in pediatric patients with certain forms of treatment-resistant epilepsy. Many of these patients experience significant impairments in quality of life (QOL) in physical, mental, and social dimensions of health. In this study, we measured the caregiver-reported Quality of Life in Childhood Epilepsy (QOLCE) in a subset of patients enrolled in a prospective, open-label clinical study of CBD. Results from caregivers of 48 patients indicated an 8.2 ± 9.9-point improvement in overall patient QOLCE (p < 0.001) following 12 weeks of CBD. Subscores with improvement included energy/fatigue, memory, control/helplessness, other cognitive functions, social interactions, behavior, and global QOL. These differences were not correlated to changes in seizure frequency or adverse events. The results suggest that CBD may have beneficial effects on patient QOL, distinct from its seizure-reducing effects; however, further studies in placebo-controlled, double-blind trials are necessary to confirm this finding.
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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.
Article
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Epilepsy Action Australia conducted an Australian nationwide online survey seeking opinions on and experiences with the use of cannabis-based products for the treatment of epilepsy. The survey was promoted via the Epilepsy Action Australia's main website, on their Facebook page, and by word of mouth. The survey consisted of 39 questions assessing demographics, clinical factors, including diagnosis and seizure types, and experiences with and opinions towards cannabis use in epilepsy. A total of 976 responses met the inclusion criteria. Results show that 15% of adults with epilepsy and 13% of parents/guardians of children with epilepsy were currently using, or had previously used, cannabis products to treat epilepsy. Of those with a history of cannabis product use, 90% of adults and 71% of parents reported success in reducing seizure frequency after commencing cannabis products. The main reasons for medicinal cannabis use were to manage treatment-resistant epilepsy and to obtain a more favorable side-effect profile compared to standard antiepileptic drugs. The number of past antiepileptic drugs tried was a significant predictor of medicinal cannabis use in both adults and children with epilepsy. Fifty-six percent of adults with epilepsy and 62% of parents/guardians of children with epilepsy expressed willingness to participate in clinical trials of cannabinoids. This survey provides insight into the use of cannabis products for epilepsy, in particular some of the likely factors influencing use, as well as novel insights into the experiences of and attitudes towards medicinal cannabis in people with epilepsy in the Australian community.
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Non-randomised studies of the effects of interventions are critical to many areas of healthcare evaluation, but their results may be biased. It is therefore important to understand and appraise their strengths and weaknesses. We developed ROBINS-I ("Risk Of Bias In Non-randomised Studies-of Interventions"), a new tool for evaluating risk of bias in estimates of the comparative effectiveness (harm or benefit) of interventions from studies that did not use randomisation to allocate units (individuals or clusters of individuals) to comparison groups. The tool will be particularly useful to those undertaking systematic reviews that include non-randomised studies.
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 and safety of cannabinoids when used as monotherapy or add-on treatment for people with epilepsy. Search methods: We searched the Cochrane Epilepsy Group Specialized Register (9 September 2013), Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2013, Issue 8), MEDLINE (Ovid) (9 September 2013), ISI Web of Knowledge (9 September 2013), CINAHL (EBSCOhost) (9 September 2013), and ClinicalTrials.gov (9 September 2013). In addition, we included studies we personally knew about that were not found by the searches, as well as searched the 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 the 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 trial reports that 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 studies. Details of randomisation were not included in any study report. There was no investigation of whether the control and treatment participant 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 generally for short periods of time, and so the safety of long term cannabidiol treatment cannot be reliably assessed.
Article
Background: Patients with Lennox-Gastaut syndrome, a rare, severe form of epileptic encephalopathy, are frequently treatment resistant to available medications. No controlled studies have investigated the use of cannabidiol for patients with seizures associated with Lennox-Gastaut syndrome. We therefore assessed the efficacy and safety of cannabidiol as an add-on anticonvulsant therapy in this population of patients. Methods: In this randomised, double-blind, placebo-controlled trial done at 24 clinical sites in the USA, the Netherlands, and Poland, we investigated the efficacy of cannabidiol as add-on therapy for drop seizures in patients with treatment-resistant Lennox-Gastaut syndrome. Eligible patients (aged 2-55 years) had Lennox-Gastaut syndrome, including a history of slow (<3 Hz) spike-and-wave patterns on electroencephalogram, evidence of more than one type of generalised seizure for at least 6 months, at least two drop seizures per week during the 4-week baseline period, and had not responded to treatment with at least two antiepileptic drugs. Patients were randomly assigned (1:1) using an interactive voice response system, stratified by age group, to receive 20 mg/kg oral cannabidiol daily or matched placebo for 14 weeks. All patients, caregivers, investigators, and individuals assessing data were masked to group assignment. The primary endpoint was percentage change from baseline in monthly frequency of drop seizures during the treatment period, analysed in all patients who received at least one dose of study drug and had post-baseline efficacy data. All randomly assigned patients were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02224690. Findings: Between April 28, 2015, and Oct 15, 2015, we randomly assigned 171 patients to receive cannabidiol (n=86) or placebo (n=85). 14 patients in the cannabidiol group and one in the placebo group discontinued study treatment; all randomly assigned patients received at least one dose of study treatment and had post-baseline efficacy data. The median percentage reduction in monthly drop seizure frequency from baseline was 43·9% (IQR -69·6 to -1·9) in the cannibidiol group and 21·8% (IQR -45·7 to 1·7) in the placebo group. The estimated median difference between the treatment groups was -17·21 (95% CI -30·32 to -4·09; p=0·0135) during the 14-week treatment period. Adverse events occurred in 74 (86%) of 86 patients in the cannabidiol group and 59 (69%) of 85 patients in the placebo group; most were mild or moderate. The most common adverse events were diarrhoea, somnolence, pyrexia, decreased appetite, and vomiting. 12 (14%) patients in the cannabidiol group and one (1%) patient in the placebo group withdrew from the study because of adverse events. One patient (1%) died in the cannabidiol group, but this was considered unrelated to treatment. Interpretation: Add-on cannabidiol is efficacious for the treatment of patients with drop seizures associated with Lennox-Gastaut syndrome and is generally well tolerated. The long-term efficacy and safety of cannabidiol is currently being assessed in the open-label extension of this trial. Funding: GW Pharmaceuticals.
Article
Background The Dravet syndrome is a complex childhood epilepsy disorder that is associated with drug-resistant seizures and a high mortality rate. We studied cannabidiol for the treatment of drug-resistant seizures in the Dravet syndrome. Methods In this double-blind, placebo-controlled trial, we randomly assigned 120 children and young adults with the Dravet syndrome and drug-resistant seizures to receive either cannabidiol oral solution at a dose of 20 mg per kilogram of body weight per day or placebo, in addition to standard antiepileptic treatment. The primary end point was the change in convulsive-seizure frequency over a 14-week treatment period, as compared with a 4-week baseline period. Results The median frequency of convulsive seizures per month decreased from 12.4 to 5.9 with cannabidiol, as compared with a decrease from 14.9 to 14.1 with placebo (adjusted median difference between the cannabidiol group and the placebo group in change in seizure frequency, −22.8 percentage points; 95% confidence interval [CI], −41.1 to −5.4; P=0.01). The percentage of patients who had at least a 50% reduction in convulsive-seizure frequency was 43% with cannabidiol and 27% with placebo (odds ratio, 2.00; 95% CI, 0.93 to 4.30; P=0.08). The patient’s overall condition improved by at least one category on the seven-category Caregiver Global Impression of Change scale in 62% of the cannabidiol group as compared with 34% of the placebo group (P=0.02). The frequency of total seizures of all types was significantly reduced with cannabidiol (P=0.03), but there was no significant reduction in nonconvulsive seizures. The percentage of patients who became seizure-free was 5% with cannabidiol and 0% with placebo (P=0.08). Adverse events that occurred more frequently in the cannabidiol group than in the placebo group included diarrhea, vomiting, fatigue, pyrexia, somnolence, and abnormal results on liver-function tests. There were more withdrawals from the trial in the cannabidiol group. Conclusions Among patients with the Dravet syndrome, cannabidiol resulted in a greater reduction in convulsive-seizure frequency than placebo and was associated with higher rates of adverse events. (Funded by GW Pharmaceuticals; ClinicalTrials.gov number, NCT02091375.)
Article
Treatment-resistant epilepsy (TRE) affects 30% of epilepsy patients and is associated with severe morbidity and increased mortality. Cannabis-based therapies have been used to treat epilepsy for millennia, but only in the last few years have we begun to collect data from adequately powered placebo-controlled, randomized trials (RCTs) with cannabidiol (CBD), a cannabis derivative. Previously, information was limited to case reports, small series, and surveys reporting on the use of CBD and diverse medical marijuana (MMJ) preparations containing: tetrahydrocannabinol (THC), CBD, and many other cannabinoids in differing combinations. These RCTs have studied the safety and explored the potential efficacy of CBD use in children with Dravet Syndrome (DS) and Lennox-Gastaut Syndrome (LGS). The role of the placebo response is of paramount importance in studying medical cannabis products given the intense social and traditional media attention, as well as the strong beliefs held by many parents and patients that a natural product is safer and more effective than FDA-approved pharmaceutical agents. We lack valid data on the safety, efficacy, and dosing of artisanal preparations available from dispensaries in the 25 states and District of Columbia with MMJ programs and online sources of CBD and other cannabinoids. On the other hand, open-label studies with 100 mg/ml CBD (Epidiolex®, GW Pharmaceuticals) have provided additional evidence of its efficacy along with an adequate safety profile (including certain drug interactions) in children and young adults with a spectrum of TREs. Further, Phase 3 RCTs with Epidiolex support efficacy and adequate safety profiles for children with DS and LGS at doses of 10- and 20-mg/kg/day. This article is part of a Special Issue titled "Cannabinoids and Epilepsy".
Article
Objective: Oral cannabis extracts (OCEs) are being used in the treatment of epilepsy with increasing rates in the United States following product legalization; however, no studies demonstrate clear efficacy. We evaluated the duration of use of OCEs as a measure of perceived benefit in a cohort of patients with pediatric epilepsy. Methods: Retrospective chart review was performed of children and adolescents who were given OCEs for treatment of epilepsy. Results: Of the 119 patients included in the analysis, 71% terminated use of their OCE product during the study period. The average length of use of OCE was 11.7 months (range 0.3-57 months). Perceived seizure benefit was the only factor associated with longer duration of treatment with OCE (p < 0.01). Relocation to Colorado was associated with perceived benefit of OCEs for seizures (65% vs. 38%, p = 0.01), but was not independently associated with longer OCE use. Factors associated with shorter use included adverse effects (p = 0.03) and a diagnosis of Dravet syndrome (p = 0.02). Twenty-four percent of patients were considered OCE responders, which was defined by a parent's report of a > 50% reduction in seizures while on this therapy. Adverse events (AEs) were reported in 19% of patients, with the most common side effects being somnolence and worsening of seizures. Significance: Parental report of OCE use in refractory pediatric epilepsy suggests that some families perceive benefit from this therapy; however, discontinuation of these products is common. Duration appears to be affected by logical factors, such as perceived benefit and side effect profile. Surprisingly, families of patients with Dravet syndrome terminated use of OCEs more quickly than patients with other epilepsy syndromes. Results from this study highlight the need for rigorous clinical studies to characterize the efficacy and safety of OCEs, which can inform discussions with patients and families.