Can scientists mimic the benefits of CBD without using cannabis?
A team of researchers has uncovered a mechanism by which CBD prevents severe epileptic seizures.
To some, this conjures a distinct sought-after “high” caused by the psychoactive compound THC. To others, it evokes the thought of a remedy for insomnia or anxiety. The primary compound behind these effects is cannabidiol (CBD). Both THC and CBD are found in the leaves and flowers of the cannabis plant. But there’s another potential application for CBD: as a medicine for serious neurological disorders.
In June 2018, the FDA approved Epidiolex, the first and only prescription CBD, for the treatment of severe seizures. Back then, scientists were unclear on how CBD brings about these changes in the brain. Today, they largely still are – but researchers are gradually uncovering the mechanisms behind CBD’s medicinal effects.
In a recent study published in Nature Communications, a team from Princeton, Tsinghua, and Harvard University reported that they had identified two different binding sites CBD uses to inhibit voltage-gated sodium (NaV) channels in the brain.
NaV channels play a crucial role in initiating brain neuron firing. When they malfunction, often due to mutations, those neurons fire irregularly. In some cases, this results in a seizure. CBD prevents neuron dysfunction by binding to NaV channels.
According to Bruce Bean, professor of neurobiology at Harvard and an author of the study, it was previously known that CBD could help epilepsy by inhibiting the NaV channels, but “the binding sites for CBD on the channels were not known.” The team used cryo-electron microscopy, or cryo-EM, to capture a high-resolution image of CBD bound to NaV channels. Though cryo-EM was first developed in the 1970s, it has rapidly grown in popularity because it allows researchers to obtain detailed images of biomolecules, which was not possible with traditional techniques.
One of the two binding sites identified in the paper helps to explain why CBD can reduce the activity of sodium channels and abnormal electrical activity without completely blocking brain function. This is key for CBD’s use in treating epilepsy since it can prevent abnormal firing without disrupting normal firing.
Though there are other treatments for epilepsy, CBD addresses a crucial gap in current practice. Dravet syndrome, a severe form of epilepsy that begins in the first year of life, cannot be treated with sodium channel blockers that are often used to treat other forms of epilepsy. Epidiolex was the first drug approved to treat Dravet syndrome, along with Lennox-Gastaut syndrome and tuberous sclerosis complex, another severe form of epilepsy and a genetic disorder that can cause seizures.
Jill Crittenden, a scientific researcher and advisor at the McGovern Institute who is not connected to this study, has previously studied cannabis-activated receptors in the brain. “The findings on epilepsy are just phenomenal,” she states. “It’s hard science based on clinical trials1. [CBD] really does make a difference that nothing else does in the lives of these kids. They'll have multiple severe seizures every day. It's just devastating.”
Cannabis research is limited, however, by federal restrictions, despite the increased legalization at the state level. This poses a direct challenge to the drug regimen Bean and his colleagues are investigating. At high concentrations, CBD has effects on the nervous system that are still not completely understood. Bean argues that researchers need to learn more about those.
According to Bean, the CBD dosage for children with epilepsy is about 700 mg. In comparison, the dosage for consumer products, such as gummies, is around 20 mg. When trying to extract such high amounts of CBD from the cannabis plant, it is challenging to avoid contamination with the psychoactive component THC. “It's not so much that contamination is so high that it really interferes with people. But it means that they're always struggling with the federal legalization, because if you have more than a certain amount of psychoactive cannabis, then it's an illegal compound. They're always balancing that.”
The discovery of these specific binding sites opens an opportunity to create a synthetic compound that can bind to those same sites without contamination from THC. Synthetic compounds might also be developed that can avoid side effects of the current medications, which include sleep problems, liver damage, weight loss, and digestive issues. “There's a lot in this paper about new techniques and discoveries that could lead to designing smarter drugs,” Crittenden says. Many mothers of children with severe epilepsy were drivers of cannabinoid research and legalization. “Those are some of the heroes of our society – people who really drive change because they want to see better health outcomes for the people in their lives.”
1 Long-term safety and efficacy of add-on cannabidiol in patients with Lennox-Gastaut syndrome: Results of a long-term open-label extension trial - PubMed (nih.gov)