Epigraph Vol. 22 Issue 3, Special Journal Prizes issue

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.

Watch a recording of the June 17 Journal Prize Symposium on YouTube

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
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.”