Approximately one-third of epilepsy patients do not become seizure free with antiseizure medications (ASMs). This treatment gap motivates research for new therapeutic options such as cannabidiol (CBD). CBD differs from other cannabis derivatives because of its consistent efficacy and lack of a psychoactive effect. CBD can be recommended as adjunctive therapy in patients with Dravet and Lennox-Gastaut syndromes. The most common adverse effects (AEs) are drowsiness, reduced appetite, diarrhea and vomiting. Transaminase elevation is the most common AE that leads to CBD discontinuation. Coadministration with valproate may increase the risk of hepatotoxicity. The combination of CBD and clobazam may increase both the effectiveness and the risk of AEs associated with these drugs. The most striking gaps in knowledge are the efficacy and optimal dose of cannabidiol for adults with focal epilepsies, thelong-term safety of CBD use and strategies to improve access to CBD for people living with epilepsy. Children with drug-resistant epilepsy may find relief with the help of medical cannabis oil that contains both CBD and lose dose THC. The oil, which contains 95% CBD and 5% THC, can reduce or prevent epileptic seizures in those with epileptic encephalopathy.
Cannabidiol in the Treatment of Epilepsy: A Focused Review of Evidence and Gaps
Approximately one third of epilepsy patients do not become seizure free with antiseizure medications. This treatment gap motivates research for new therapeutic options, such as cannabidiol (CBD). CBD differs from other cannabis derivatives because of its consistent efficacy and lack of a psychoactive effect. CBD can be recommended as adjunctive therapy in patients with Dravet and Lennox-Gastaut syndromes. The most common adverse effects (AEs) are drowsiness, reduced appetite, diarrhea, and vomiting. Transaminase elevation is the most common AE that leads to CBD discontinuation. Coadministration with valproate may increase the risk of hepatotoxicity. The combination of CBD and clobazam may increase both the effectiveness and the risk of AEs associated with these drugs. The most striking gaps in knowledge are the efficacy and optimal dose of CBD for adults with focal epilepsies, the long-term safety of CBD use, and strategies to improve access to CBD for people living with epilepsy.
Epilepsy can be a therapeutic challenge. Despite the growing number of antiseizure medications (ASMs), approximately one third of patients with epilepsy have persistent seizures (1). Surgical treatment, although still underused, may be an alternative in up to 25% of these cases (2). Therefore, many patients are not seizure free. This treatment gap motivates research on new ASMs, such as cannabidiol (CBD).
The medical use of marijuana has gained considerable interest in the press in the last two decades. Three reasons for this are (a) the appeal of being a “natural” alternative treatment (3); (b) the discovery of a complex cell-signaling system responsive to cannabis, the endocannabinoid system (4); and (c) prominent public cases, such as Charlotte Figi in the United States (5).
Cochrane and American Academy of Neurology reviews determined that there was no scientific evidence to support the use of cannabis for epilepsy in 2014 (6, 7). At that time, there were only four placebo-controlled studies on cannabinoid use in epilepsy (8–11). All studies show inadequate power and methodological problems, but despite this, there has been an increasing use of CBD for the treatment of epilepsy (12).
Cannabinoids are obtained from different species of cannabis. Tetrahydrocannabinol (THC) and cannabidiol (CBD) are two of the most prominent cannabinoids found in the Cannabis plant (3). THC is responsible for the psychoactive effects of marijuana, but studies on its effects on epilepsy have shown conflicting results (13–16). THC binds to type 1 cannabinoid receptors (CB1) present in the basal ganglia, cerebellum, hippocampus, hypothalamus, and limbic system. Anandamide and 2-arachidonoylglycerol are endogenous cannabinoid agents that act on presynaptic CB1 and cause a reduction in excitatory activity. As THC is a partial agonist, this could explain the proconvulsant effect.
CBD is a cannabinoid that lacks psychoactive effects. It has a more consistent antiepileptic efficacy than THC (17, 18). CBD does not activate cannabinoid receptors. It does, however, interact with several other signaling systems. Transient receptor potential vanilloid type 1 (TRPV1)-mediated signaling may be the most relevant pathway in the anticonvulsant effect of CBD (19–21).
Evidence on Effectiveness
In 2016, Dr. Orrin Devinsky presented an open-label study with 214 pharmacoresistant child-onset epilepsy patients who received CBD. Dravet (20%) and Lennox-Gastaut (19%) syndromes were the most frequent causes. The initial dose of 5 mg/kg/day was increased up to a maximum dose of 50 mg/kg/day if tolerated. The median monthly frequency of motor seizures was 30.0 at baseline and was reduced to 15.8 over the 12-week treatment period (22).
Another open-label study was performed in patients with pharmacoresistant epilepsy with tuberous sclerosis who received CBD. The initial dose of 5 mg/kg/day was increased by 5 mg/kg/day every week up to a maximum dose of 50 mg/kg/day if tolerated. The median reduction in total weekly seizure frequency was 48.8% after 3 months of treatment (23).
In 2017, the first randomized, double-blinded, placebo-controlled study evaluating high-purity CBD in patients with Dravet syndrome was published (24). The intervention group received a highly pure 100 mg/ml CBD solution. The dose was increased up to 20 mg/kg. The percentage of patients who had at least a 50% reduction in convulsive-seizure frequency was 43% after a 14-week treatment period with CBD. The overall conditions improved by at least one category on the Caregiver Global Impression of Change scale for 62% of patients in the CBD group. Three patients in the CBD group were seizure free. There was no significant reduction in nonconvulsive seizures.
In 2018, a randomized, double-blind, placebo-controlled study was published on patients with Lennox-Gastaut syndrome who used CBD (25). The patients had two or more drop seizures per week and a mean age of 16 years. Favorable outcomes were found in the 10 and 20 mg/kg CBD groups during the treatment period with a median percentage reduction from baseline in the frequency of drop seizures of 37.2 and 41.9% in the 10 and 20 mg/kg CBD groups, respectively.
Secondary outcomes were also significant. Thirty-six percent and 39% of patients had at least a 50% reduction from their baseline in drop-seizure frequency in the CBD groups compared with 14% in the placebo group. Furthermore, compared with the placebo group, a greater percentage of patients had at least a 75% reduction from baseline in drop-seizure frequency (11 and 25% in the CBD groups, 3% with placebo). Some patients became free from drop seizures during the entire maintenance phase in the CBD groups (4% and 7%, 1% in the placebo group).
The estimated median difference in reduction from baseline in the frequency of all seizures was 19.5 (p = 0.002) and 18.8 (p = 0.009) percentage points in the 10 and 20 mg CBD groups, respectively. Additionally, an improvement from baseline in overall condition according to the Patient or Caregiver Global Impression of Change at the last visit was reported in 66 and 57% of 10 and 20 mg CBD-treated patients, respectively, compared to 44% in the placebo group with an odds ratio of 2.57 (p = 0.002) for the 10-mg cannabidiol group vs. the placebo group and 1.83 (p = 0.04) for the 20 mg cannabidiol group.
Another randomized, double-blind, placebo-controlled phase 3 trial investigated the efficacy of CBD as an add-on therapy for drop seizures in patients with treatment-resistant Lennox-Gastaut syndrome. The results confirmed the efficacy of CBD with a median percentage reduction in monthly drop seizure frequency from a baseline of 43.9% in patients treated with 20 mg/kg of CBD compared to 21.8% in the placebo group. Other secondary outcomes were positive, including a greater proportion of patients experiencing a reduction of ≥75% seizures during the treatment period (20% CBD vs. 8% on placebo; p = 0.0273) (26).
A systematic review identified six randomized controlled studies (27). The average age of the participants was 16.1 years (0.5–55 years). At a dose of 20 mg/kg/day, the number needed to treat to one person experiencing 50%+ seizure reduction was 8. CBD was more effective than placebo at achieving complete seizure freedom. In 14 observational studies, 8.5% of patients were seizure free (95% CI, 3.8–14.5%).
Another recent systematic review (28) evaluated the role of concomitant clobazam (CLB) use on the efficacy of CBD in patients with Dravet syndrome and Lennox-Gastaut syndrome and enrolled 714 participants in four trials (429 treated with CBD, 240 with taking concomitant CLB). The percentages of patients not taking CLB who had at least a 50% reduction in seizure frequency during the treatment period were 29.1% with CBD and 15.7% in the placebo group (RR 1.80, p = 0.015); among patients receiving CLB, a 50% reduction in seizure frequency was achieved by 52.9 and 27.8% in the CBD and placebo groups, respectively (RR 1.85, p < 0.001). This study suggests that despite the drug–drug interactions that occur between CBD and CLB, adjunctive treatment with CBD can reduce seizures independent of concomitant CLB, reinforcing that CBD has intrinsic antiseizure activity (28).
Available data indicate that patients cotreated with CBD and CLB have higher response rates, highlighting that both pharmacodynamic and pharmacokinetic interactions may contribute to the efficacy of this combination (29).
Therefore, CBD is effective as an adjunctive therapy in the treatment of drug-resistant childhood-onset epilepsy. Nevertheless, current evidence is restricted to rare and severe epileptic syndromes. A summary of CBD effectiveness can be seen in Table 1 and Figure 1 (12).
Table 1. Major studies about CBD in the treatment of epilepsy.
Cannabis dosage studied to reduce seizures in children with severe epilepsy
Summary: Children with drug-resistant epilepsy may find relief with the help of medical cannabis oil that contains both CBD and lose dose THC. The oil, which contains 95% CBD and 5% THC, can reduce or prevent epileptic seizures in those with epileptic encephalopathy.
Source: University of Saskatchewan
Medicinal cannabis oil containing both cannabidiol (CBD) and a small amount of THC can reduce or end seizures in children with severe, drug-resistant epilepsy, a study by the University of Saskatchewan (USask), Canada has found.
Children with severe epilepsy also experienced improvements in their quality of life after taking low doses of the medicinal cannabis oil, according to research published in Frontiers in Neurology.
The study tested the effects of medicinal cannabis oil with 95 percent CBD, a chemical which does not create a high, and 5 percent THC, a substance which can be intoxicating in large enough doses.
Studying an evidence-based scientifically guided dosage regimen, the research team found no evidence of THC intoxication when using CBD-enriched whole plant extracts.
“What makes these results really exciting is it opens up as a treatment option for kids who have failed to respond to traditional medications,” said Dr. Richard Huntsman (M.D), a pediatric neurologist who led the study.
Three of the seven children in the USask study–mainly funded by Saskatchewan’s Jim Pattison Children’s Hospital Foundation–stopped having seizures altogether.
“Some of the improvements in quality of life were really dramatic with some of the children having huge improvements in their ability to communicate with their families. Some of these children started to talk or crawl for the first time. They became more interactive with their families and loved ones,” said Dr. Huntsman.
Several studies have shown that cannabis products containing CBD can be effective in helping to control seizures in children with epileptic encephalopathy, a severe form of epilepsy which begins in childhood. Despite this, many children cannot access these products because there is very little guidance for physicians on which doses to use and some health-care providers are concerned about possible intoxication from THC.
This research found that most of the children had a reduction in seizures with a twice-daily dose of CBD totaling 5-6 milligrams of cannabis extract per kilogram of weight (mg/kg) per day. By the time a CBD dose of 10-12 mg/kg per day was achieved, all children experienced a reduction in their seizures, most by more than 50 percent.
“What is really important is that we have been able to dispel in a scientific manner some of the concerns about how to dose these products and the possibility of them causing a ‘high’ in these children. We did this by slowly increasing the dose of cannabis extract in a very tightly regulated manner. We watched the children very closely for side effects and measured blood levels of CBD and THC,” said Dr. Huntsman,
The children had drug-resistant epilepsy, failing to respond to at least two forms of anti-convulsant medication. They had been prescribed several anti-convulsant medications yet continued to have seizures, with one child experiencing 1,223 in the month leading up to the study.
“We are very proud to support this important pediatric research, which is making such a difference in the lives of children who have severe epilepsy,” said Brynn Boback-Lane, President and CEO of Jim Pattison Children’s Hospital Foundation.
“This groundbreaking study is giving hope and improved health outcomes. It is heartening to have donors that see the value of such important work.”
Allyssa Sanderson’s eight-year-old son Ben from Prince Albert, Sask. was one of the participants in the study. Ben was born without complications but later developed infantile spasms. When Ben was two, he was diagnosed with Lennox-Gastaut syndrome, a severe form of epilepsy.
Studying an evidence-based scientifically guided dosage regimen, the research team found no evidence of THC intoxication when using CBD-enriched whole plant extracts. The image is in the public domain.
Despite trying multiple medications and treatments, Ben’s seizures were unpredictable. He was seizure-free on some days, but on others had 150 seizures a day.
“Ben was very lethargic and would just lay there and have seizures all day. He wasn’t active and didn’t even want to eat. His eyes looked dull, and he didn’t focus on anything. He really looked lifeless,” Allyssa explained. “I knew this trial was a last resort for my son.”
Once Ben started taking CBD, he began showing improvements in his seizure frequency and then became seizure-free during the study.
“I was seeing the change in Ben every single day. I was thankful as I watched his little personality come out. He was back to his silly self that I hadn’t seen in years. He was stronger. I believe this research is one of the greatest things to happen for kids with epilepsy,” Allyssa said.