Objective: To review evidence on effectiveness of cannabis and cannabinoids as adjunctive treatments for treatment-resistant epilepsy.
Methods: A systematic search of Medline, Embase, PsycINFO and EBM Reviews. Outcomes were (1) achievement of complete seizure freedom, (2) seizure reduction 50% or more and (3) improved quality of life. Tolerability and safety were assessed by study withdrawals, adverse events (AEs) and serious adverse events (SAEs).
Results: Five randomised controlled trials (RCTs) and 17 observational studies were identified. Cannabidiol (CBD) was more effective than placebo at achieving seizure freedom (RR 6.42, 95% CI 1.53-26.90, 3 RCTs, 306 patients, moderate to high quality evidence). CBD 20mg/kg/day was more effective than placebo at reducing seizure frequency by 50% or more (RR 1.74, 95% CI 1.24-2.44, 2 RCTs, 291 patients, high quality evidence). Pooled across 14 of 17 observational studies, 56% (95%CI 40-72) of patients reported reductions in seizures of 50% or more. In 7 observational paediatric studies 13% were estimated to be seizure-free (PE 13%, 95% CI 4-21). Ten observational studies reported improved quality of life in paediatric and adult samples (PE 38%, 95% CI 28-48). In RCTs 14% of patients withdrew because of treatment-related AEs.
Significance: In patients with paediatric-onset drug-resistant epilepsy pharmaceutical grade CBD products reduce seizure frequency. All studies examined CBD as an adjuvant treatment in addition to standard antiepileptic drugs. More RCTs are needed to better inform consumers of the potential benefits and risks of CBD and other cannabinoid products.
Keywords: epilepsy, cannabis, cannabinoids, Dravet syndrome, Lennox-Gastaut syndrome, seizures, cannabidiol
The International League Against Epilepsy (ILAE) defines epilepsy as a disease of the brain diagnosis of which requires a) at least two unprovoked seizures occurring more than 24 hours apart; b) one unprovoked seizure and the probability of further seizures, occurring over the next ten years; or c) the diagnosis of an epilepsy syndrome . Between 70-80% of patients with new onset epilepsy achieve complete seizure control using antiepileptic drugs such as clobazam, valproate or carbamazepine . 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 anti-epileptic drugs (AEDs) schedules (as either monotherapies or in combination) to achieve seizure freedom  – 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 occurring cannabinoids (phytocannabinoids) have anticonvulsant effects which are mediated by the endocannabinoid system . Cannabidiol and cannabidivarin have shown anti-seizure effects in both in vivo and in vitro models. In contrast to tetrahydrocannabinol (THC), cannabidiol does not produce euphoric or intrusive psychoactive side effects when used to treat seizures . Cannabinoids have been proposed as an adjunctive treatment for epilepsy  and parents of children with epilepsy report using CBD products [8-10]. There are a number of Phase III human trials underway of cannabidiol (CBD) as an adjunctive therapy for treatment resistant paediatric and adult epilepsies [11, 12].
Recently Israel, the Netherlands, Germany, and Canada have legislated to allow the use of cannabinoids 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 synthesised evidence from randomised-controlled trials (RCTs) and observational studies.
This review was conducted according to PRISMA guidelines (see PRISMA checklist in Supplementary Materials 1). The search strategy and data extraction process is briefly summarised here; methodology is detailed in full in the study protocol (Prospero registration number CRD42017055412; see Supplementary Materials 2).
Data sources and search strategy
To find individual studies on the use of cannabinoids to treat epilepsy, databases Medline, Embase, PsycINFO, and EBM Reviews-Cochrane Central Register of Controlled Trials were searched in November, 2016. The databases were searched with the terms below (and their corresponding subject headings in each database where specialised thesauri existed). Searches were limited to studies published from 1980 to November 22, 2016. The Medline search is reproduced in Supplementary Materials 3.
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
7. 5 and 6
3) Types of studies: Experimental and epidemiological study designs including randomised controlled trials (RCTs), non-randomised controlled trials (non-RCT), quasi-experimental, before and after studies, prospective and retrospective cohort studies, case control studies, analytical cross sectional studies, self-report surveys and case reports.
Reviews of mechanisms of cannabinoid systems, commentary articles and review articles were not included in the review.
Two reviewers independently examined titles and abstracts in Covidence. Relevant 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.
We considered the primary and secondary outcomes suggested by Gloss and Vickrey . The primary outcome was the proportion of patients achieving complete seizure freedom. Secondary outcomes included a) responder rate – proportion of patients who experienced a 50% or greater reduction in seizure frequency; b) quality of life; c) withdrawal from the study due to adverse events or other reasons; d) adverse events.
Grading of evidence
As the review contained both RCTs, and studies using non-randomised methods, two versions of the standard risk of bias tool was used . Methodological quality ratings for risk of bias in RCTs were determined using the Cochrane risk of bias tool . Studies were judged to have an overall low risk of bias if they had 6-8 factors with low risk of bias, and high risk if 3 or more aspects of bias were judged as being high risk. Observational or case study reports were evaluated using an adapted version of the Cochrane risk of bias tool specific to observational or non-RCTs . 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. Details of risk of bias assessments are found in the Supplementary Tables 6.1.3 and 6.2.3.
An evidence grade was given to each reported study, based on the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) scale . Randomised, double-blind placebo-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 study or self-report studies were considered to be of very low quality.
Full text studies considered eligible by two reviewers were assessed for quality by one reviewer and quality ratings checked by a second reviewer.
Data were extracted from studies using a standardised data extraction tool in Microsoft Excel. The data extracted from studies included specific details about the intervention, populations, study methods and outcomes of significance to the review question and specific objectives. Data extraction tools were piloted and reviewed by the authors before being finalised (see Supplementary Materials 4 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 adverse and serious adverse events. Accordingly, we extracted whether studies identified their participants as having drug-resistant epilepsies participants, in line with the ILAE definition , 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 Supplementary Materials 5 for a summary of this definition). Paediatric epilepsies were defined as those occurring in persons between the ages of 0 and 18 years of age. We also extracted concurrent AEDs reported by the participants.
All reported adverse events (AEs) were included in the review. Serious adverse events (SAEs) were also identified (such as status epilepticus, decreased appetite, lethargy and pneumonias) and checked with clinical experts. There were instances where these SAEs were reported in non-randomised studies but not identified as SAEs; we extracted them as SAEs.
Pooled relative risk (RR) estimates were calculated using bivariate data extracted from the studies. The “metan” command uses inverse-variance weighting to calculate random effects pooled summary estimates and their confidence limits, true effect differences between studies and study heterogeneity . We expected high levels of heterogeneity between studies because of the marked differences between the samples in terms of epilepsy syndromes. We accordingly applied a random effects model to all analyses. Meta-analyses of the proportions reported by observational studies were calculated using the “metaprop” command. The “metaprop” command uses the binomial distribution to model within-study variability, or allowing for Freeman-Tukey double arcsine transformation to stabilise variances .
We conducted sub-analyses of results for: whether the studies only included drug-resistant epilepsy cases; paediatric versus adult or mixed aged samples; and specific epilepsy syndromes (such as Dravet or Lennox-Gastaut syndromes).
Searches identified 370 articles (see Figure 1). An additional eleven poster abstracts were sourced through the American Epilepsy Society conference database  and authors contacted for further details. Three additional papers were published and identified through hand-search by the authors after the initial database search, and two papers were identified via hand-search of systematic review reference lists. After abstract and title screening, 70 articles were selected for full text screening. Of these, 22 met criteria for inclusion in the review (Tables 1 and 2; see Supplementary Materials 6 for full details of study characteristics, and Supplementary Materials 10 for excluded studies).
Figure 1 about here
Of the five randomised trials, three were parallel double-blind placebo-controlled trials [22-24], one was a cross-over study  and one was a randomised placebo-controlled trial with limited details of blinding . Four further studies were open-label intervention trials [11, 12, 27, 28]. Of the remaining studies, five were case-studies [29-33], four were self-report surveys [8, 9, 34, 35], and four were retrospective chart reviews [36-39].
Characteristics of study participants
The RCTs included a total of 330 patients (study range 12-171), all of whom had drug-resistant epilepsy. The non-RCT studies included 979 people with epilepsy (study range 1-214). The epilepsy conditions most commonly included were drug resistant forms of epilepsy: Dravet syndrome, Lennox-Gastaut syndrome and other drug-resistant epilepsy (variously described as uncontrolled epilepsy, treatment-resistant epilepsy and intractable epilepsy). Two RCTs and 12 non-randomised studies included exclusively or primarily patients with paediatric epilepsy, though typically adult studies included young adults.
Cannabinoids used and features of treatment
The RCTs all studied cannabidiol (CBD) with a placebo comparator; CBD was an adjuvant treatment in all cases. The paediatric studies used 20mg CBD/kg/day for 12 weeks; the adult studies used 100mg CBD capsules two or three times per day, with follow-up varying from 2-26 weeks.
Cannabinoids used in the non-RCT studies varied, but CBD was most commonly used; five studies used both CBD and THC extracts. Two low-quality studies examined smoked cannabis (one case study  and one chart review ). Again, cannabinoids were used as adjuvant treatments.
Tables 1 and 2 include the quality assessment ratings for each of the included studies (see also Supplementary Material 6, particularly Tables 6.1.3 and 6.2.3). RCTs or clinical studies included in the review were judged to be at a low  to moderate-to-high [22, 25] or unclear risk of bias [23, 26] (see Supplementary Table 6.1.3). This was largely because of poor randomisation and/or blinding practices in the study methodology, the lack of blinding in open-label trial designs, or lack of detail. Methodological quality was considered to be moderate at most for these studies (see also Table 6.1.1).
Observational studies were judged to be at a higher risk of bias, particularly those with self-reported outcomes on self-selected participant samples (see Supplementary Table 6.2.3). 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 Supplementary Table 6.2.1 for full description of the studies).
Tables 1 and 2 about here
Nine studies reported rates of complete seizure freedom among individuals who given cannabinoids as adjunctive treatments (Table 3; for full details see Supplementary Materials 7, and Table 7.1). These comprised three RCTs, two open label trials, two retrospective chart reviews, one case study and one parent self-report survey.
Of the three RCTs that reported this outcome, one study involved only paediatric patients (N=120) , one included both paediatric and adult patients (N=171) , and one study involved only adult patients (N=15) . The pooled RR from these studies for CBD in achieving complete seizure freedom compared to placebo was 6.42, (95%CI 1.53-26.90, p=0.011, I2= 0.0; total n=306 patients; see Table 3). Sub-analyses indicated that the RR was larger for paediatric compared to adult-only participant groups. The effect was also larger for drug resistant epilepsies compared to epilepsies that were not classified as drug resistant (see Table 3).
Based on 523 patients in non-RCT studies, our pooled estimate was that 10% of patients achieved complete seizure freedom (95%CI 5-16; p<0.001, I2= 71.6). This was higher than the proportion of participants who achieved complete seizure freedom in the two larger, high-quality RCTs (namely 4.9% and 5.8%, see Supplementary Table 6.1.2).
As noted in Table 5, 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.
Table 3 about here
Sixteen studies reported on parents’ or carers’ reports of the proportion of children who experienced 50% or greater reductions in seizure frequency (for full details see Supplementary Materials 7, Table 7.2). These studies consisted of two RCTs, four open-label trials, three retrospective chart studies, four self-report studies and three case reports.
CBD was more likely to produce a greater than 50% reduction in seizures than placebo in two RCTs (RR 1.74, 95%CI 1.24-2.44, n=290 patients, p=0.001, I2=0.0; see Table 3). An estimated 56% of the 780 patients in non-RCTs estimated achieved a 50% or greater reduction in seizures (95%CI 40-72, p<0.001, I2=94.9; see Table 3). The comparable percentages in the two larger, high-quality RCTs were between 42.6%  and 44.2%  (see Supplementary Table 6.1.2).
As noted in Table 5, 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 or high quality studies to assess whether there is a treatment effect of cannabis sativa, CBD:THC combinations, or oral cannabis extracts.
Twelve studies evaluated the effects of cannabinoids on quality of life. Two were RCTs, three were open-label trials, two were retrospective chart reviews, four were case study reports, and one was a self-report survey of parents of children with epilepsy (See Supplementary Materials 7, Table 7.3). Quality of life, as reported by parents/caregivers, was measured in two RCTs [23, 24]. Non-RCTs reported improvements in behaviours, movement, or alertness [12, 30, 31, 33, 35-38]
The pooled RR in those receiving CBD vs placebo of parental reports of overall improvements from two RCTs was 1.73 (95%CI 1.33-2.26, n=274 patients, p<0.001, I2=0.0; see Table 3). A pooled estimate from observational studies of the proportion of patients with improved quality of life when using cannabinoids was 39% (95% CI 29-50, n=213 patients, p<0.001, I2=92.8; see Table 3).
As noted in Table 5, we conclude there is mixed quality evidence that CBD improved patient quality of life when used as an adjunctive treatment. There was very low 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.
Withdrawals are used as an indicator of tolerability and effectiveness of a treatment. Six studies reported on patient withdrawal from treatment – three RCTs, one open-label clinical trial and two retrospective chart reviews (for full details see Supplementary Materials 7, Table 7.4). The study populations were primarily paediatric (n=5 studies, 544 out of 617 patients).
Based on three RCT studies, patients given CBD were more likely to withdraw from the study than those who received placebo (pooled RR 3.51, 95%CI 1.48-8.35, n=248 paediatric and n=73 adult patients; p=0.005, I2= 60.0; see Table 3). A pooled estimate of the withdrawal rate among paediatric patients in three non-RCTs was 8% (95%CI 4-12, n=311 patients, p<0.001, I2 = 0.0; see Table 4).
Study withdrawals were noted for patients receiving CBD and oral cannabis extracts (Table 5). 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.
Table 4 about here
Fourteen studies reported on adverse effects. Three were RCTs, four were open label trials, two retrospective chart reviews, two case studies, and three self-report surveys. Thirteen studies included paediatric samples and three included adults.
A meta-analysis of 306 patients in three RCTs found that patients who received CBD had a small increase in the risk of adverse events compared to those who received placebo (pooled RR 1.28, 95%CI 1.13-1.44, n=233 paediatric, n=73 adult patients, p=0.00, I2= 0.0; see Table 4). Pooled estimates of 752 patients in 10 non-RCTs were that 43% of patients experienced an adverse event (95% CI 25-61, p<0.001, I2 = 96.7).
Among the adverse events were: somnolence [11, 12, 22-24, 27, 34, 35, 37, 38], fatigue [11, 28, 35, 38], diarrhoea or other gastrointestinal problems [11, 12, 22-24, 27, 28, 37, 38], agitation [12, 27, 30], change in frequency of seizures or convulsions [11, 24, 37, 38] and weight or appetite increase or decrease [9, 11, 12, 23, 24, 27]. The serious adverse events included: status epilepticus [11, 24, 37], developmental regression and new movement disorders , severe diarrhoea and weight loss , and elevated liver enzymes (liver aminotransferase) .
Two RCTs with a total of 291 patients (n=233 paediatric) reported on the number of serious adverse events (Table 4; for full details see Supplementary Table 5.5). In RCTs, serious adverse events (SAEs) occurred in 16.4% of Dravet syndrome patients who received CBD compared to 5.1% of those who received a placebo . Similarly, SAEs occurred in 23.3% of patients with Lennox-Gastaut syndrome receiving CBD compared to 4.7% of patients receiving placebo . The latter reports did not indicate the type, duration or severity of these SAEs.
Patients in the CBD treatment groups were more likely to experience a serious adverse event than patients in the placebo condition (pooled RR 4.20, 95% CI 1.91-9.25, p<0.001, I2 = 0.0). In the seven non-RCT studies with 557 patients, pooled estimates were that 11% of patients experienced an SAE (95% CI 0-21, p=0.02, I2 = 94.9) (see Table 4). Patients in the CBD treatment groups were also more likely to experience a treatment-related SAE than patients in the placebo condition (pooled RR 9.48, 95% CI 1.79-50.15, p = 0.008, I2 =0.01).
There is mixed quality evidence, including from three moderate to high quality RCTs, that patients receiving CBD are more likely to experience mild to moderate adverse events (see Table 5). 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 adverse events.
Table 5 about here
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 qualitative 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 adverse effects. We can be much more confident about this statement in the case of children than adults, because the recent, larger, well-conducted 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, particularly 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]. 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. 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.
There is still few well-controlled, randomised, and placebo-controlled studies on CBD in drug-resistant epilepsy . 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 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 adverse events when receiving CBD than placebo indicates the need for clinicians and patients to weigh the risks and benefits of adding CBD to other AED treatment. The most commonly experienced adverse events in patients receiving CBD (somnolence and dizziness) are similar to those reported from approved AEDs such as gabapentin and levetiracetam, and occur at similar rates [41, 42].
Small numbers of patients (8-12%) in two RCTs experienced serious treatment-related adverse events [23, 24]. 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 treatment [43, 44] are similar to the profiles of cannabinoid SAEs. If cannabinoids are more effective when combined with clobazam , 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 health care professionals can monitor patients and intervene if they experience adverse effects. 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 cannabidiol reported by parents ranged from 0.5mg/kg/day to 28.6mg/kg/day, and THC dosages ranged from 0 to 0.8mg/kg/day . Well-controlled and well-regulated therapeutic trials are essential to specify the doses required to produce therapeutic effects with a minimum of adverse effects.
A reasonable proportion of patients with paediatric-onset drug-resistant epilepsy may experience a decrease in seizure frequencywhenusingpharmaceutical grade CBD products in additionto AEDs. This conclusion is tempered by a paucity of well-controlled clinical trials. The timely completion and publication of RCTs will provide a better basis for assessing the benefits and risks of cannabinoid products to control 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.
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