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.
Epilepsy is one of the most common non-communicable neurological diseases. Its incidence is 50.4 per 100,000 people per year and is more common in low to middle-income countries, i.e., 81.7 per 100,000 people per year [1,2].
About one-third of the patients suffering from epilepsy have drug-resistant epilepsy.
A patient is said to have drug-resistant epilepsy if their seizures cannot be controlled even after using the appropriate dose of at least two antiepileptic medications.
Drug-resistant epilepsy is associated with reduced quality of life, serious psychosocial consequences, and cognitive problems [3,4].
Therefore, a lot of research is being conducted to find the treatment of drug-resistant epilepsy.
Cannabis sativa is a plant that has been used to treat epilepsy, pain and anorexia since ancient times.
It has more than 80 phytocannabinoids, most abundant among which are delta-9-tetrahydrocannabinol (THC) and Cannabidiol (CBD) [5].
The role of THC predominant preparations came into play in the 19th century and since the last couple of years, clinical trials on less controversial CBD started [6].
More recently trials on Propyl analog of CBD, Cannabidivarin (CBDV), have also started.
The reason for developing and preferring CBD and CBDV as an anticonvulsant drug is because THC has many psychiatric side effects [7].
Although CBD is the most studied molecule for the treatment of epilepsy its mechanism of action is not fully understood until now [8,9]
Discussion
About one-third of epileptic patients do not respond well to the conventional antiepileptic drugs [5].
Moreover, there are many side effects associated with them such as osteomalacia and anemia.
This demands a need for an antiepileptic drug in the market with better efficacy and lesser adverse effects.
For centuries, CBD is considered by the general populace to have anticonvulsants properties.
However, these substances could not find a place in the current prescription regimen to treat seizures because of the two main reasons.
First, no sufficient number of trials have been done which could prove their efficacy in treating or preventing seizure episodes.
Second, there are concerns about their safety in the long-run.
oreover, there are many side effects associated with them such as osteomalacia and anemia.
This demands a need for an antiepileptic drug in the market with better efficacy and lesser adverse effects.
For centuries, CBD is considered by the general populace to have anticonvulsants properties.
However, these substances could not find a place in the current prescription regimen to treat seizures because of the two main reasons.
First, no sufficient number of trials have been done which could prove their efficacy in treating or preventing seizure episodes.
Second, there are concerns about their safety in the long-run.
Endocannabinoids (cannabinoids synthesized normally within the central nervous system (CNS)) have a role in decreasing the release of excitatory neurotransmitter in CNS, hence preventing from seizures [15].
They act on CB1 and CB2 receptors with former being expressed by central and peripheral neurons, while the latter are mainly expressed by immune cells but are also found in the brain cells [16].
An old thought of CB1 receptors being the only ones involved into neuronal activity regulation has been challenged by a recent experimental study on rats, which concluded that loss of both types of receptors will result into a spontaneous and more severe form of seizures than the loss of CB1 receptors alone [17].
This formulates that the development of potential drugs enhancing the activity of these receptors could be used as a therapeutic means for seizure disorders.
Cannabis is extracted from the Cannabis Sativa plant, which has more THC than CBD. THC is psychoactive while CBD has little to no psycho-activity.
Also, CBD has more antiepileptic properties, thus drawing attention to the preparations with more CBD to THC proportion [18].
Lesser adverse effects with CBD could be there because CBD has a weak activity at CB1 and CB2 receptors. CBD instead works by other mechanisms such as transient receptor potential (TRP) cation channels resulting in a decrease in the presynaptic release of glutamate [8,19].
In 1977, in an experiment conducted on rats, it was postulated that the anticonvulsant effects of CBD could be compared with those of phenytoin, and protective effects to decrease relapses were comparable to phenobarbital.
Short-term analysis has also shown that CBD is a safe drug in humans with no psychotropic activity, no changes on clinical and laboratory examination, and no effects on EEG and ECG [11].
Besides, having the long half-life (30 hours when given through the intravenous route and 23 hours when given orally) will also be helpful in patient-compliance [20].
Although studies had been conducted on CBD to appreciate its potential antiepileptic effects, many of them, until 2016, were carried out over a short duration of three to four months and remained underpowered with the maximum sample size of 15 patients. In 2016 and 2017, Devinsky et al. did trials to appreciate the effects of CBD on seizures in patients with childhood-onset seizures, especially with Dravet syndrome. More than 100 patient participants were in his studies.
He observed a good antiepileptic effect of CBD with a few adverse effects. Most of them were mild to moderate and included somnolence, decreased appetite, fatigue, diarrhea, and increased convulsions, that showed CBD might also have pro-convulsive properties [5,14].
In some patients, a few abnormalities in the liver function tests were reported, which gradually returned to normal with the continuous use of CBD [14].
Whether CBD per se has anticonvulsant properties or it potentiates the effects of traditional antiepileptic drugs is not yet clear. CBD has been shown to increase the concentration of a few other antiepileptic drugs especially clobazam through its inhibitory action on cytochrome P450 system [21].
Recently, the first time a randomized, controlled, double-blinded multi-center study was done to appreciate the potential effects of CBD in controlling drop seizures in patients with Lennox-Gastaut syndrome (a childhood onset seizure disorder associated with encephalopathy which usually is multi-drug resistant) [22].
A total of 171 patients were randomly divided into a drug or placebo group in 1:1 pattern. There was 43.9% reduction of drop seizures in CBD group patients and 21.8% of the reduction in the patients who were in the placebo group.
Besides drop seizures, the frequency of other types of seizures was also reduced drastically which reflected a wide spectrum of effects of CBD in controlling different types of seizures.
The most common adverse effects (in >10% of cases), though mild to moderate in severity, including somnolence, diarrhea, and decreased appetite were seen in 86% of patients who were in CBD group and 69% of patients who were in the placebo group.
The most serious treatment-related adverse effect occurred was an elevation of liver enzymes (alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyltransferase) in >3% cases but resolved on their own with the continuation of the treatment.
Additional studies on adverse effects of CBD are needed since most of the patients in the studies so far were concomitantly taking other antiepileptics such as valproate and clobazam, which may have confounded the results.
In 2017, an Australian Nationwide survey on medical cannabis use for epilepsy was carried out, which included 976 responders (patients with epilepsy and/or parents/guardians of patients with epilepsy).
It showed that around 15% of patients used cannabis irrespective of their physician’s knowledge to control their multi-drug resistant seizures and to get rid of the adverse effects associated with traditional antiepileptic drugs. Most of them reported an improvement in their seizures [23].
Conclusions
We have reviewed multiple clinical trials on drug-resistant epilepsy and have discussed their results in this review article. There is an increasing interest in developing cannabis preparations for the treatment of drug-resistant epilepsy as they are observed to be more efficacious with less side effect profile. Hence, we encourage research in this area in order to help decrease the morbidity and mortality associated with drug-resistant epilepsy.
Funding: The study was funded by Jim Pattison Children’s Hospital Foundation, the Saskatchewan Health Research Foundation (SHRF), the Durwood Seafoot Estate and the Savoy Foundation.
The research team included neurologists, psychologists, and pharmacologists from USask’s Cannabinoid Research Initiative of Saskatchewan.
Source:
University of Saskatchewan
Media Contacts:
Jennifer Thoma – University of Saskatchewan
Image Source:
The image is in the public domain.
Original Research: Open access
“Dosage Related Efficacy and Tolerability of Cannabidiol in Children With Treatment-Resistant Epileptic Encephalopathy: Preliminary Results of the CARE-E Study”. Dr. Richard Huntsman (M.D) et al.
Frontiers in Neurology. doi:10.3389/fneur.2019.00716
