Cannabidiol and clobazam: Elucidating interactions to improve epilepsy treatment
Lyndsey Anderson was awarded the 2020 Epilepsia Prize for Basic Science Research for her article, “Coadministered cannabidiol and clobazam: Preclinical evidence for both pharmacodynamic and pharmacokinetic interactions,” Lyndsey L. Anderson, Nathan L. Absalom, Sarah V. Abelev, Ivan K. Low, Peter T. Doohan, Lewis J. Martin, Mary Chebib, Iain S. McGregor, Jonathon C. Arnold, Epilepsia. Vol 60(11): 2224-2234. DOI: 10.1111/epi.16355.
Good science often starts with skepticism. Such was the case for Lyndsey Anderson, who joined the University of Sydney’s Lambert Initiative for Cannabinoid Therapeutics to establish a screening program for cannabinoids as potential epilepsy treatments.
Lyndsey Anderson, PhD
But Anderson wasn’t convinced that epilepsy’s shining-star cannabinoid, cannabidiol (CBD), had inherent anti-seizure activity. She remembered attending an epilepsy meeting and seeing a presentation on CBD, back when the compound was in clinical trials for Dravet Syndrome and Lennox-Gastaut Syndrome, two severe forms of epilepsy that are often drug resistant. (The US Food and Drug Administration later approved Epidiolex, a CBD oral solution, to treat both syndromes.)
“Clobazam is a common treatment for Dravet syndrome, and I thought that CBD was interacting with clobazam and not doing anything itself to stop seizures,” Anderson said. “And here I am working for a cannabinoid research group.”
Anderson’s supervisor, Jonathon Arnold, suggested she design a study to test her hypothesis. The results showed a pharmacokinetic interaction between CBD and clobazam, just as Anderson had suspected.
But they also found more than that.
Combination treatment with CBD and clobazam produced a greater anti-seizure effect than did either treatment alone, but the effect was observed only with a higher, anticonvulsant dose of CBD. A lower dose initiated the pharmacokinetic interaction but did not boost anti-seizure activity.
The group also found a novel interaction between CBD and clobazam at GABA receptors. GABA is a prime target for anti-seizure medications; its activation reduces activity. Both compounds alone activated GABA, but the combination produced a more potent activation than either compound by itself.
CBD improves survival
In the mouse model of Dravet Syndrome, adding CBD to clobazam didn’t reduce seizure frequency—but it did significantly improve survival. The group isn’t sure why—CBD “hits a lot of targets,” notes Anderson—but “that was an exciting finding,” she said.
“This work provides evidence that there is a pharmacokinetic interaction between CBD and clobazam, and it appears they work in concert to reduce seizures. Many thought that wasn’t necessarily occurring,” said Arnold. “Given that CBD has already gone through clinical trials, some didn’t exactly see the benefit of this type of study, but I think there’s still a role for this type of reverse translation research.”
Anderson and colleagues now are focused on seeking out other components of cannabis that might have anticonvulsant effects. “A lot of parents have turned to cannabis extracts for their kids with Dravet,” said Arnold. “And a lot of them are seeing results—which begs the question whether there’s more to this than just CBD. We’re systematically testing compounds one by one to see if they have anticonvulsant potential.”
Joining the Lambert Initiative
Growing up in Wisconsin with thoughts of becoming a pharmacist, Anderson never expected to find herself in Australia, researching potential new therapies for epilepsy. During graduate school at Vanderbilt University, USA, Anderson joined the lab of Alfred George, Jr. She had been working on a cardiac project, but George suggested research involving an epilepsy mouse model. “So I sort of stumbled into the field, and the more I learned about it, the more I enjoyed it,” she said.
During Anderson’s postdoc at Northwestern University in the United States, she developed a pharmacologic screening platform in a mouse model of Dravet Syndrome. As her time at Northwestern was winding down, she saw the job opening at The Lambert Initiative and decided to apply.
The Lambert Initiative was founded in 2015 through a $33.7 million donation to the University of Sydney by Barry and Joy Lambert, whose granddaughter has Dravet Syndrome. “They wanted to unlock why medicinal cannabis was so effective,” said Arnold, who is deputy academic director at the initiative, as well as an associate professor of pharmacology. “I had seen that there was this great mouse model for Dravet Syndrome, the Scn1a knockout model. The challenge was to implement it in the lab.”
Reaching the beach
When Arnold saw Anderson’s application, he knew she had the skill set that The Lambert Initiative needed. His strategy for recruitment: As soon as Anderson got off the plane in Sydney, Arnold and a graduate student took her straight to the beach for a coffee by the ocean.
“We were really lucky that she applied, and it became readily apparent that she was more than what we hoped for,” said Arnold. “She’s such a hard worker, very organized and systematic, a great problem solver. We would not be doing this research without her.”
Anderson also competes in Ironman triathlons and trained to be a surf lifesaver (volunteer lifeguard) on Sydney’s Bondi Beach, which can attract 30,000 people on a busy weekend day.
“Growing up where I did, my ocean experience was minimal, but I went to every extra training session they offered,” said Anderson, who also lives near the beach. “I’ve grown to love it—it was smart of Jono to bring me straight there.”
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CBD Reduces Seizures Associated With Rare Form Of Epilepsy
The children and adults who experience these seizures suffer endlessly.
But their parents, families and loved ones suffer as well.
Standard anti-epileptic drug (AED) therapy typically fails to control these seizures, with many suffering hundreds of seizures in a 24-hour period.
Graciela Elizalde, an eight-year-old girl who suffers Lennox-Gastaut syndrome, has became the first . [+] Mexican citizen to whom a federal judge has allowed the use of a derivative of marijuana for therapeutic purposes and who responded favorably to the drug, is seen on November 12, 2015 in Guadalupe municipality, Nuevo Leon State, Mexico. (Julio Cesar Aguilar/AFP/Getty Images)
These seizures occur as part of a rare disorder known as Lennox-Gastaut Syndrome (LGS), quite treatment-resistant, often developing in young children between the ages of three and five. Its cause is multifactorial, potentially the result of an infection in the central nervous system, a congenital structural abnormality or even a genetic defect. In nearly 30% of cases, there is no identifiable cause.
Children with LGS suffer with many different types of seizures, but one type in particular, drop seizures, are quite disabling. These seizures are short in duration, resulting in the body’s muscles becoming limp, leading to head nodding, falls and potential injuries associated with loss of posture.
However, one potential approach using cannabidiol (CBD), a non-THC and thus non-hallucinogenic form of cannabis–in combination with standard AED–is showing promise.
Results from a phase 3 placebo-controlled study recently presented at the American Academy of Neurology’s (AAN) annual meeting held this week in Boston demonstrated that adding CBD to standard AED therapy reduced seizure frequency in this traditionally treatment-resistant population.
While there were more adverse effects with CBD–mainly increased appetite and somnolence—the medication was well-tolerated by reducing seizure frequency.
The study looked at 225 patients, just under one-third of whom were adults, with a mean age of 16 years. During a baseline period, study participants had experienced eight or more drop seizures during the preceding four-week period, in which at least one AED had not been effective.
Enrolled patients recorded a median of 85 drop seizure events, with a median failure of six AEDs, with patients taking a median of three AEDs.
Patients were randomized to receive CBD (Epidiolex; GW Pharmaceuticals) 20 mg/kg/day, CBD 10 mg/kg/day or placebo. The patients took the CBD for 12 weeks, after going through a two-week titration period.
The aim of the study was to measure the change in drop seizure frequency from baseline.
The study found that compared with placebo (17% reduction in seizures from baseline), both doses of CBD reduced seizure frequency (42% reduction for 20mg/kg dose, P=.0047; 37% for 10 mg/kg dose, P=.0016).
Analysis of the findings revealed that adverse events occurred in 94% of the 20mg/kg CBD group, 84% of the 10mg/kg CBD group and 72% of the placebo group. The majority of these were described as mild to moderate in nature.
Of note, 13 patients had elevated aminotransferase levels, a potential marker for liver abnormalities. However, deeper analysis indicates that 10 patients in this cohort were taking valproic acid, an AED that could cause this elevation.
While Epidiolex has previously been studied in LGS patients with a noted reduction in seizure frequency, researchers in this study went a step further by delivering data on responder rates–indicating a 50% or greater reduction in monthly drop seizures–and from the Caregiver Global Impression of Change (CGI) questionnaire, which indicates whether life actually improved for patients while taking the drug.
These additional results demonstrated that the responder rate was 15% in the placebo group, 36% in 10 mg/kg CBD group (P = .0030) and 40% in the 20 mg/kg group (P = .0006).
Looking at the CGI results, 66% of patients taking the lower dose and 57% taking the higher dose states they had a better quality of life, compared with 44% for placebo.
It’s also important to note that GW Pharmaceuticals was granted orphan drug status from the FDA for Epidiolex for the treatment of Dravet syndrome–another rare seizure disorder–LGS, tuberous sclerosis complex and infantile spasms.
Furthermore, GW was also was granted the FDA’s fast track designation for the treatment of Dravet syndrome as well as orphan designation from the European Medicines Agency for Epidiolex in the treatment of Dravet syndrome and LGS.
Based on this study, CBD appears to be an effective adjunctive therapy in this rare form of treatment-resistant epilepsy, showing the ability to reduce seizure frequency. The only caveats are an elevated rate of adverse effects, without the ability to completely eliminate seizures altogether.
Cannabidiol reduces seizures in kids with severe form of epilepsy, trial shows
Research focused on Dravet syndrome, a rare form of treatment-resistant epilepsy that begins in infancy
A cannabis compound has been proven for the first time to reduce the frequency of seizures in people with a rare, severe form of epilepsy, according to the results of a randomized trial.
For years, parents have pointed to anecdotal benefits of cannabidiol (CBD), a compound in the marijuana plant that does not produce a high, saying it reduces seizures in treatment-resistant epilepsy.
Now doctors have performed a large-scale randomized trial to show cause and effect, with the findings published in Wednesday's issue of the New England Journal of Medicine.
To conduct the study, the researchers focused on Dravet syndrome, a rare form of epilepsy that begins in infancy and has a high mortality rate. The syndrome is linked to a particular mutation and often resists combinations of up to 10 conventional seizure medications. They enrolled 120 patients who ranged in age from 2.5 to 18 years.
Sixty-one patients were randomly assigned to cannabidiol, and the 59 others to placebo. Neither the researchers nor the families knew who received the medication to prevent bias. All continued to take their existing medications for 12 weeks.
"The message is that cannabidiol does work in reducing convulsing seizures in children with Dravet syndrome," lead author Dr. Orrin Devinksy, who is director of NYU's Langone Comprehensive Epilepsy Center, said in a hospital video.
Marijuana compound and epilepsy
For those in the cannabinoid group, the median number of convulsive seizures per month dropped from 12.4 per month before treatment to 5.9 seizures, the researchers reported.
The placebo group, in comparison, only saw their convulsive seizures fall from 14.9 per month to 14.1.
The study was funded by GW Pharmaceuticals, which also designed and helped run it; one of the company doctors involved also has a related patent pending.
The most common adverse event was drowsiness, reported in 22 patients in the cannabidiol group and six patients in the placebo group. Many of these patients were taking another anti-epileptic medication. Some gastrointestinal effects, such as vomiting and diarrhea, were also reported.
A total of 12 patients quit the study: nine on the drug and three in the placebo group.
'Last hope' for parents
Dr. Mark Ware, who directs the Canadian Consortium for the Investigation of Cannabinoids, says the findings add credibility to the widely held anecdotal view that CBD helps patients with epilepsy.
But he cautioned that the CBD used in the trial is a pharmaceutical grade product, administered under carefully controlled experimental conditions with careful medical supervision.
"It is important to note that not all patients will respond," Ware said in an email.
The McKnight family, of Constance Bay, Ont., has used a combination of high CBD, low THC oil to control seizures in their nine-year-old son, Liam, for four years now. He has Dravet syndrome.
- Ottawa boy forced to rely on homemade cannabis oil to calm 'catastrophic' seizures
Before he started using the oil, Liam was having upward of 80 seizures per day. They left him catatonic, lying on the couch, unable to walk or go to school — despite taking up to 10 anti-seizure medications.
"We were trying everything, and despite everything we were trying, we were losing our battle," his mother, Mandy McKnight, recalls. "The cannabis … was probably our last hope."
Within 24 hours of starting the oil, McKnight says Liam's seizures stopped for 10 days. Though the seizures came back, she estimates the frequency was about 90 per cent less than before.
Liam can now go for weeks without a seizure, although they tend to return when he is sick with an infection.
McKnight says she welcomes the new findings, as it proves what parents like her have been advocating to their medical teams. "Sometimes science doesn't always lead the way — sometimes it has to catch up."
At Toronto's Sick Kids Hospital, neurologist Blathnaid McCoy is conducting a similar study. She and her team have just enrolled their 20th and final participant in a Tilray-sponsored trial of a combination CBD and THC treatment for children with Dravet syndrome.
McCoy noted there is a significant placebo effect when it comes to epilepsy. That's why it's so important that this team was able to show improvements in seizures above placebo.
"If it improves your seizure control, then families will accept a certain amount of side-effects," McCoy said.
McCoy noted that a THC-CBD combination product is what's available in Canada, so it's what patients here are using.
- Researchers studying usage, safety of cannabis oil for children with epilepsy
But, she adds, THC may have some added benefit since it binds directly to cannabinoid receptors. Since little is known about using THC medicinally in children, figuring out the safe dose and limiting side-effects will be key, McCoy said.
Another pediatric epilepsy specialist sees a potential role for cannabis-based treatments in a select group of children with resistant epilepsy, including those with Dravet syndrome.
"To parents I would caution that while cannabidiol is a plant-based product, it appears to have the potential to interact negatively with other antiseizure treatments and cause side-effects," said Dr. Richard Huntsman, a pediatric neurologist at the University of Saskatchewan. He is co-leading a pilot study of highly concentrated CBD oil in children with epilepsy.
Medical supervision is key in part because CBD could affect liver function, said Dr. Danielle Andrade, a neurologist and director of the epilepsy program at Toronto Western Hospital.
Andrade is concerned about misconceptions of using CBD in other types of epilepsy when there is no evidence it works.
"All the patients that were treated, they have very significant learning disability, developmental disability. We don't really know what effects it could cause someone who is higher functioning," Andrade said.
The CBD product used in the study, called Epidiolex, is not approved by regulators or available for sale.