Does medicinal cannabis work in epilepsy? This is a complex question that depends on what is meant by ‘medicinal cannabis’ and even what is meant by ‘epilepsy’.
While there has been a lot of research on the role of cannabinoids in epilepsy in recent years, the only clinical trials to date have focused on CBD treatment in children with rare, severe epilepsies such as Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS); and Tuberous Sclerosis Complex (TSC) - a rare genetic condition that typically causes seizures to occur.
So we need to break the question down into a number of different components.
Efficacy of CBD in LGS, DS and TSC
This is where we have the strongest evidence to support the use of cannabinoids in epilepsy.
A number of randomised, double-blind, placebo-controlled clinical trials (known as RCTs, the most comprehensive and reliable type of intervention study) provided the evidence that led to the licensing of Epidyolex in the US and Europe for Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) in patients over two years old and in conjunction with clobazam (Frisium). This type of trial was also conducted for Tuberous Sclerosis Complex (TSC). These type of trials involve giving a set of participants the medication itself and another set of participants a substance or treatment which is designed to have no effect (the placebo). The findings from each group are then compared and contrasted to see if there has been in improvement in the condition of those who have received the medication. It should be noted that the findings of these studies cannot be taken to mean that other non-pharmaceutical CBD products will deliver similar results.
A summary of these RCTs are below (numbers and percentages have been rounded), alongside other relevant studies.
- In one 14-week RCT of 120 patients with drug-resistant seizures in Dravet syndrome taking one or more Antis-Seizure Medications(ASMs), Epidyolex at a dose of 20mg per kg resulted in a decrease in median monthly seizure frequency from 12 to 6, compared to a decrease from 15 to 14 with the participants taking a placebo. 43% of patients on Epidyolex had at least a 50% reduction in seizure frequency compared to 27% taking a placebo. 5% of patients on Epidyolex became seizure-free compared to 0% on a placebo. Read the full study by visiting the New England Journal of Medicine website.
- In another 14-week study of 171 patients with treatment-resistant LGS, those on 20mg/kg pf Epidyolex experienced a 44% reduction in seizure frequency compared to 22% in the placebo group Read the full study by visiting the Lancet medical journal website.
- Another study included patients with LGS who were assigned to two different dose groups (20mg/kg and 10mg/kg) as well as a placebo. Those in the 20mg/kg group experienced a 42% reduction in drop-seizure frequency compared to 37% in the 10mg group, and 17% in the placebo group. 39% of those on 20mg/kg and 36% of those on 10mg/kg had at least a 50% reduction in drop seizure frequency compared to 14% in the placebo group. 5% of those taking Epidyolex were free of drop seizures. Read the full study by visiting the New England Journal of Medicine website.
- In an open-label (meaning doctors and patients know that they are receiving treatment, not a placebo) extension of the LGS trials above published in 2019, the median reduction in drop seizure frequency ranged from 48% to 60% after week 48. Median reduction in monthly total seizure frequency ranged from 48% to 57%. 81% of patients/families reported an improvement in the patient’s overall condition. Read the full study by visiting the National Library of Medicine website.
- Full data from the above open-label study was published in August 2021. The study found that sustained reductions in drop and total seizure frequency were observed for up to 156 weeks. Median reductions from baseline ranged between 48%–71% for drop seizures and 48%–68% for total seizures. Adverse events occurred in 96% of patients. Most were were mild (20%) or moderate (48%) but 12% of patients had to discontinue treatment due to side effects. Common side effects were convulsion (39%), diarrhea (38%), pyrexia (34%), and somnolence (29%). 87% of patients/caregivers reported improvement in the patient's overall condition. The mean dose in the trial was 24 mg/kg/day. The authors concluded that "This OLE demonstrates the sustained long-term benefits of Epidiolex/Epidyolex, the regulated and highly purified formulation of plant-based CBD, as a treatment for patients with LGS". Read the full study by visiting the Wiley Online Library website.
- A 2021 analysis of data from two of the above RCTs of patients with LGS found that treatment effect (meaning efficacy and side effects) of CBD may occur within 1 week of starting treatment. It also found that side effects of CBD resolved within 4 weeks in 40% of cases. Read the full study by visiting the Wiley Online Library website.
- In 2019, a clinical trial in patients with tuberous sclerosis complex (TSC) found a 49% reduction in seizures in patients taking Epidyolex 25mg/kg per day compared with 24% for a placebo. Read the full press release by visiting the Jazz Pharmaceuticals website.
- A retrospective review published in May 2021 of 54 patient-held seizure diaries and medical records of patients with refractory epilepsy who enrolled in one of the original open-label Epidyolex studies in the US found that CBD maintains efficacy in the long term. The researchers followed up patients at an average of 45.5 months (and up to 60 months in some cases), and found that the percentage of those responding remained similar over time at approx. 42%. CBD was particularly effective for controlling seizures in tuberous sclerosis complex. Read the full study by visiting the Wiley Online Library website.
- A December 2021 study on the long-term efficacy regarding the use of Epidyolex in the treatment of TSC reported positive findings, with a median percentage seizure reduction rate recorded at 54%–68% across a 48 week period. This study was an extension of a previous study - the 2019 study which is referenced above. Read the full study by visiting the Wiley Online Library website.
These results are very positive and show that Epidyolex may result in reduced seizures and improved quality of life for a significant minority of patients with DS, LGS and TSC when used with other medications. For a small minority of patients, seizure freedom may even be possible. A 50% reduction in seizure frequency in 50% of patients is conventionally considered to be the gold standard for an epilepsy medication.
Efficacy of CBD in other epilepsy
Although several studies have taken place investigating the efficacy of CBD in treatment-resistant epilepsy, none of these have been high-quality RCTs like those outlined for Epidyolex above.
While we can say that these studies have generally highlighted promising results, it is important to note that significant weaknesses in the methodologies used in these studies exist so definitive conclusions about the effectiveness of CBD in treatment-resistant epilepsy cannot be drawn based on what is currently known.. These weaknesses include:
- Much of the data is from observational studies, which can be open to bias and to a range of hidden factors influencing results. Other data comes from surveys completed by patients and caregivers, a method that does not produce reliable results.
- Studies are typically ‘single-arm’ meaning that there is no control (placebo) group. In these cases, it is not possible to compare the impact of treatment to ‘doing nothing’.
- Studies typically include small numbers of patients.
- Products used in studies are not standardised meaning they are open to differences in formulation and quality. In addition, dosages vary considerably across studies.
With the above in mind, the following are key findings from a systematic review published in the British Medical Journal in 2018. A systematic review is a type of study that identifies, selects, and evaluates existing published research and analyses the data from all the studies together.
- An estimated 48.5% of the 970 patients in 17 observational studies achieved a 50% or greater reduction in seizures. It appeared that children were more likely to benefit than adults.
- Complete seizure freedom across 14 observational studies was achieved by 8.5% of participants (14% in children; 4% in adults).
- Using a variety of measures, the proportion of patients with improved quality of life when using CBD was 56%. This included improvements in mood, cognitive skills, alertness and sleep.
- 51% of patients experienced an adverse event (side effect). These included drowsiness, ataxia and diarrhoea.
- You can read the full review by visiting the British Medical Journal website
Unfortunately, because of differences in the underlying mechanisms behind LGS/DS/TSC and other types of epilepsy, it is not possible to use the data from the LGS/DS/TSC RCTs to automatically assume that Epidyolex will work as well for other types of epilepsy.
Aside from Epidyolex, no other form of CBD or CBD-and-THC product has yet been proven to be effective in high quality clinical trials. We cannot assume that because Epidyolex (a pharmaceutical grade CBD medication) has had positive outcomes for many people, other forms of CBD products will deliver equally positive results.
More research including randomised clinical trials is badly needed to investigate the efficacy of CBD in treatment-resistant epilepsy.
Safety of CBD
It is not true to say that because cannabis is ‘natural’, CBD-based products will not have any side effects. All treatments have side effects and caution is needed regardless of the drug. If you are taking any cannabis-based product, medical supervision is essential. It is very important that you discuss this with your medical team and that you do not stop taking other prescribed epilepsy medications in favour of CBD.
CBD has been shown to interact with certain anti-epileptic drugs (AEDs) and your doctor may need to adjust your AED dosage accordingly. Studies to date using CBD have in particular highlighted sodium valproate (Epilim) and clobazam (Frisium) in this regard.
The Epidyolex clinical trials found that the drug was well-tolerated and side effects were mild to moderate. The most common side effects included fever, drowsiness, decreased appetite, vomiting, diarrhoea and fatigue. A 2021 retrospective review (open label/ patient-reported) of patients taking Epidyolex for up to 60 months (average 45.5 months) found that CBD was generally well tolerated in the long-term, with drowsiness and diarrhea as the main adverse reactions. The study concluded that "CBD is an effective, safe, and well-tolerated AED for long-term use". You can read this study by visiting the 'Online Wiley Library' website.
It should also be noted that while authorised medicines (including Epidyolex) must legally disclose potential side effects, unauthorised cannabis-based products such as the CBD oil purchased from health food stores are not required to do so. This does not mean side effects do not exist for these products.
Another issue relates to the quality and composition of some CBD oils/products sold online or in health food stores. Non-pharmaceutical CBD is not standardised, and consumers do not have the same legal protections afforded by approved medicines. In one study of 14 commercially available CBD products, nine out of the 14 had CBD concentrations that differed notably from the declared amounts. You can read this study by visiting the 'National Library of Medicine' website.
Another study found that nine out of 46 CBD samples collected from patients contained no cannabinoids at all, while 18 of the 46 contained virtually only THC with little or no CBD. You can read and download this study by visiting the 'Karger' website.
Efficacy and safety of THC
There have been a number of case studies and anecdotal reports in recent years that appear to highlight the benefits of THC in combination with CBD in severe epilepsies like DS and LGS.
Despite these positive reports, there is yet no strong scientific evidence to support the claim that THC-and-CBD is more effective than CBD-only. As with any potential treatment, anecdotal evidence is never sufficient to establish whether or not a treatment has a proven level of efficacy and safety that would justify its widespread use.
In some animal studies, THC was found to have certain anti-convulsant effects, but other studies have shown an opposite pro-convulsant effect. This inconsistency, along with its psychoactive properties and potential for long-term side effects, has meant that THC hasn’t been studied as a realistic treatment option to the same degree as CBD.
In a review of the available evidence published in the Journal of Epilepsy Research in 2017, it was summarised that THC “is generally unsuitable for [epilepsy], not only because evidence for an anti-seizure activity of THC is equivocal and risk of seizure aggravation cannot be excluded, but also because THC is associated with many undesired effects, including addiction liability, psychiatric disorders, cognitive and motor and, possibly, also cardiovascular toxicity. The maturing brain is also more vulnerable to the adverse of effects of marijuana and there is evidence of THC impairing structural and functional connectivity during brain development.” You can read this study by visiting the 'National Library of Medicine' website.
Further research, up to and including randomised clinical trials, are urgently required in order to better understand the benefits and risks of treating epilepsy with THC.
Unanswered questions from existing data
What we know so far is that one form of pharmaceutical grade CBD (Epidyolex) works to reduce seizures by half for about 4 in 10 people with LGS or DS when used together with clobazam (Frisium). However, there are many unanswered questions elsewhere:
- How effective is Epidyolex as a standalone treatment and how does it compare to other AEDs?
- How effective is Epidyolex in treating other forms of epilepsy?
- As most Epidyolex studies have focused on children, how effective will it be for adults with epilepsy?
- How effective and safe are other forms of CBD products (oils, GMP products, etc.) in treating epilepsy, both in adults and children?
- Does the addition of THC to CBD increase the effectiveness of the intervention?
- What are the short- and long-term adverse effects of using THC-containing products to treat epilepsy, particularly in children?
A paper published by the British Paediatric Neurology Association (BPNA) in November 2021 highlights many of the above unanswered questions. You can download this paper by visiting the 'BPN' website. As with any potential treatment, further research in the form of well-regulated clinical trials represents the only safe and objective way to definitively answer these questions.