In the last few years, both scientists and members of the media alike have turned their focus to medical marijuana and extracts of cannabidiol (CBD), the non-psychoactive cannabinoid that shares a common precursor with the infamous delta-9- THC, as a potential treatment for pediatric epilepsy. Three particularly severe forms of epilepsy have emerged as targets for cannabidiol treatment: Dravet syndrome, Lennox-Gastaut syndrome, and infantile spasms (West syndrome). According UCLA Cannabis Research Initiative researcher and pediatric neurologist Shaun Hussain, these types of epilepsy can produce potentially devastating cognitive impairment—including autism—and available therapies are often ineffective.
Stories of parents with children suffering from seizures who turn to medical marijuana pepper the mainstream press. The New York Times profiled the Siqueira family, who moved to Colorado in pursuit of a hemp oil with low THC and high CBD to treat their daughter, Grace, spurring other parents to do the same. Many parents turn to options such as the Colorado-based Charlotte’s Web, extracted from a strain of marijuana with low THC and high CBD. However, as Buzzfeed News reported, lack of regulation of the medical marijuana industry has let CBD into “our nation’s medicine cabinets by hook or by crook,” with unscrupulous companies hawking products to parents desperate to help their children.
Cannabidiol is a very promising investigational treatment for epilepsy, but we have to remember that its effectiveness and safety are not yet proven. We still have more questions than answers,” stated Hussain, who advocates for more research on cannabis- based compounds for treatment of epilepsy and changed federal regulations on marijuana for research use. Currently, Hussain and his team have just completed a multi-center phase II clinical trial evaluating synthetic CBD in the treatment of children with infantile spasms who had previously failed all FDA-approved treatments, with results forthcoming in publication. This trial is one of the many being launched by pharmaceutical companies and researchers; United Kingdom-based drug developer GW Pharmaceuticals announced in 2016 that they reduced epileptic seizures in a clinical trial with their drug, Epidiolex, a pure extract of CBD.
Many standard treatments for pediatric epilepsy are expensive, high-risk, and simply ineffective in a substantial minority of patients, says Hussain. Hormonal treatments such as intramuscular injection of adrenocorticotropic hormone (ACTH) or oral prednisolone post risk of potentially lethal infection due to their immunosuppressive effects, as well as hypertension, which can lead to heart failure. Vigabitrin, known by the brand name Sabril in the United States, is another option, but has been linked to irreversible vision loss.
Since ancient history, the supposed anticonvulsant effects of cannabis have been well documented in the medical literature. As early as 1800 BCE, Sumerian and Akkadian tablets referenced a plant that is most likely cannabis for various ailments, including nocturnal convulsions. In the 11 th century, Arabic physician al-Mayusi specifically recommended use of cannabis extracts for epilepsy. More recently, 19 th century Victorian physician William O’Shaughnessy reported on a case with an infant with nocturnal convulsant episodes that a “spirituous [hemp] tincture” helped cure. Although the molecular structure of CBD and THC were elucidated in the 1960’s1, the mechanisms by which THC acts within the brain is well characterized while those of CBD remain elusive.
In the case of epilepsy, the cannabinoid receptor system within the brain, specifically cannabinoid receptor 1 (CB1R), where THC and CBD act upon, has been shown to be implicated in seizures in animal models, including that hippocampal CB1R expression is protective against acutely induced seizures. CB1R activity affects clinical seizures by inhibition of adenyl cyclase activity, which in turn by decreasing cAMP induces potassium efflux and decreases calcium reflux. This diminishes neuronal hyperexcitability and may attenuate seizure frequency.2
However, a unifying hypothesis on how exactly CBD affects epilepsy is still elusive due to conflicting research. In vitro, CBD has been shown to have CB1R antagonist properties, but this is unlikely to be the mechanism of action responsible for its anticonvulsant properties.3 CBD has low affinity to cannabinoid receptors (CB1R and CB2R) and may induce anticonvulsant properties via CB1R-independent mechanisms including regulation of cytosolic calcium levels, blocking low voltage calcium channels, member hyperpolarization by agonistic activity on 5HT1A recptors, and the increase of endogenous adenosine levels.4,5
However, these reports of marijuana’s anticonvulsant effects in pre-clinical studies and throughout history are no match for rigorous, evidence based clinical trials. Despite numerous clinical studies over several decades suggesting potential benefit of CBD in the treatment of epilepsy, the overall shortage of well-designed research led the National Academy of Sciences 2017 report on cannabis to proclaim that there is insufficient evidence that cannabinoids are an effective treatment for epilepsy.7 The largest study to date, published in the Lancet Neurology in 2016, where researchers treated 162 epilepsy patients open-label with CBD and monitored them for 12 weeks, reported that this intervention reduced motor seizures at a rate similar to existing drugs.8 However, the study’s major limitations, including a lack of placebo controls, make it difficult to draw solid conclusions about CBD’s efficacy.
Mirroring this, Hussain cautions against the blanket promotion of CBD as a treatment for epilepsy. Instead, he argues that the decision to use CBD should be made on a case-by-case basis, with consideration of the potential benefit as well as potential medical—and even legal—risks. He points out that there are certainly individual cases in which a trial of CBD is quite reasonable, especially when all other reasonable options have been exhausted. On the other hand, any new, exciting drug is subject to bias. In a 2015 survey administered to parents of pediatric epilepsy, Hussain et al. found 85 percent of respondents reported a reduction in seizure frequency, indicating at least a perception of efficacy.9 However, though promising, these results are vulnerable to significant confounding, including selection bias, and Hussain himself says, “They are merely the beginning of a long journey in which we rigorously evaluate the safety and efficacy of CBD.”
When it comes to current clinical use, Hussain believes CBD may be an option when patients have failed to respond to conventional epilepsy treatments, or have significant side effects. However, there are legal and social risks for parents, depending on jurisdiction, as CBD and medical marijuana are still classified as Schedule I controlled substances on a federal level, even as marijuana enjoys quasi-legal status at the statewide level in California. More work needs to be done to understand both the mechanisms of action and clinical profile of CBD, especially given the collective actions of worldwide who turn to unregulated CBD oil and other medical marijuana products in the desperate effort to control their children’s seizures.