Cannabinoids in Epilepsy: A New Era of Treatments

In a groundbreaking announcement, a Food and Drug Administration (FDA) advisory panel gave their unanimous recommendation in April 2018 for the approval of Epidiolex, a cannabis-derived product shown to be effective for the treatment of two forms of treatment-resistant childhood epilepsies: Lennox-Gastaut Syndrome and Dravet Syndrome.

If the FDA takes the advisory panel's recommendation and provides final approval, Epidiolex would be the first FDA-approved cannabidiol product available within the United States. Unlike medical marijuana, which is the medical use of unprocessed plant species such as Cannabis sativa or Cannabis indica, Epidiolex consists of purified cannabidiol (CBD), a key medicinal component of the marijuana plant.

Cannabidiol is one of at least 85 active cannabinoids identified within the Cannabis plant that contribute to marijuana's pharmacological activity. Unlike THC, the most well-known cannabinoid found in marijuana or cannabis, CBD does not produce a "high" or the characteristic effects of smoking marijuana like mood and memory changes or increased appetite.

Although it is only one of the many pharmacologically active compounds that have been identified within cannabis plants, CBD accounts for up to 40% of the Cannabis plant's extract and binds to a wide variety of physiological targets of the endocannabinoid system within the human body. The exact medical implications of its use are currently being investigated, however CBD has shown promise as a therapeutic and pharmaceutical drug target in many conditions. Beyond its anticonvulsant effects, CBD has also shown promise as an analgesic, muscle relaxant, anxiolytic, antipsychotic and has shown neuroprotective, anti-inflammatory, and antioxidant activity, among other investigated uses.

CBD's exact place within medical practice is still currently hotly debated as the body of evidence grows and legislation changes to reflect its wide-spread use. Public and medical opinion have changed significantly with regards to its usefulness in a number of medical conditions ranging from anxiety to epilepsy. As public opinion has changed, legislation has also slowly caught up with the wave of growing evidence that supports its medical use.

Prior to the FDA's most recent recommendation, Epidiolex had been granted Orphan Drug and Fast Track status by the FDA due to the rare nature of Lennox-Gastaut and Dravet syndrome and because of a lack of effective therapies for their treatment. According to the FDA, Fast Track designation is given to "facilitate the development, and expedite the review of drugs to treat serious conditions and fill an unmet medical need."

The panel's Epidiolex recommendation came secondary to the release of results from Phase 3 clinical trials that demonstrated clinically significant reductions in the number of seizures suffered by children with Lennox-Gastaut Syndrome (LGS) and Dravet Syndrome (DS). Notably, up to 43% of some patients using Epidiolex observed a 50% decrease in the number of seizures they experienced in a 28 day period. These are groundbreaking results for children living with a life-threatening condition that, up until now, was largely untreatable.

In their report, the panel stated that "Although the review is still ongoing, the risk-benefit profile established by the data in the application appears to support approval of cannabidiol for the treatment of seizures associated with LGS and DS.".

Lennox-Gastaut and Dravet syndrome are two rare forms of severe epilepsy that typically appear in early childhood in the form of repeated, uncontrollable seizures that range from unnoticeable "absence" seizures to the full-body effects of tonic-clonic seizures. If left untreated, which often occurs due to a current lack of effective therapies, long term exposure to the detrimental effects of repeated seizures often leads to developmental delays, brain malformations, traumatic brain injuries, and an increased risk of SUDEP (sudden unexplained death in epilepsy).

While the exact mechanism of action of Epidiolex for the management of epilepsy is still uncertain, CBD has been shown to have a vast number of pharmacological targets. This is largely due to its activity within the endocannabinoid system of the body, which includes a group of lipid proteins, enzymes, and receptors that are involved in many physiological processes. Through its effect on neurotransmitter release, the endocannabinoid system regulates cognition, pain sensation, appetite, memory, sleep, immune function, and mood among many others. These effects are largely mediated through the cannabinoid receptors 1 and 2 (CB1 and CB2) of the endocannabinoid system.

CBD's primary mechanism of action within the endocannabinoid system is through negative allosteric modulation of the cannabinoid CB1 receptor, the most abundant G-Protein Coupled Receptor (GPCR) in the body. Its anti-epileptic mechanism of action is less clear, however.

There are currently four identified cannabinoids with potential for use as anti-epileptics: Cannabidiol (CBD), Cannabidivarin (CBDV),
Tetrahydrocannabivarin (THCV), and Δ9-tetrahydrocannabinolic acid. While their full therapeutic potential continues to be investigated, there have been promising results from animal and human models as well as clinical trials.

The anti-seizure activity of CBD and CBDV, the most well-studied of the anti-epileptic cannabinoids, is thought to be modulated by their effects on transient receptor potential cation channel subfamily V member 1 (TRPV1). Also known as the capsaicin receptor, TRPV1 is part of a large family of ion channels that are involved in the onset and progression of several types of epilepsy. CBD and CBDV have been shown to dose-dependently activate and then desensitize TRPV1 as well as TRPV2 and TRPA1 channels. Desensitization of these ion channels is a potential mechanism by which these molecules cause a reduction in the neuronal hyperexcitability that contributes to epileptic activity and seizures.

Cannabidivarin (CBDV) is being actively developed by GW Pharmaceuticals as the experimental compound GWP42006 as it has "shown the ability to treat seizures in pre-clinical models of epilepsy with significantly fewer side effects than currently approved anti-epileptic drugs". Unfortunately, as of February 2018, GW Pharmaceuticals announced that their Phase 2a placebo-controlled study of CBDV for focal seizure did not reach its primary endpoints. However, they will continue to study its use in epilepsy and are expanding their investigations to include its potential use in Autism Spectrum Disorder, Rett syndrome and Fragile X among others.

The US has been slow to formally recognize the evidence behind cannabis products, however CBD has been available in Canada since 2005 in combination with THC as the Health Canada approved product Sativex, which is approved for symptomatic relief of neuropathic pain and spasticity in Multiple Sclerosis and treatment of moderate-to-severe pain in adults with advanced cancer.

While Epidiolex is the first CBD-based product available on the US market, THC derivatives have been approved for several years for the treatment of Multiple Sclerosis, anorexia associated with AIDS, and nausea and vomiting from chemotherapy. Although cannabis in its natural plant form is currently used "off-label" for the management of these and many other medical conditions, THC is currently commercially available by prescription in synthetic form as Nabilone or as purified isomer as Dronabinol.

If approved by the FDA panel, use of Epidiolex and other cannabinoids for the treatment of resistant forms of epilepsy could mark a new era of treatment for patients who have long-awaited its arrival.

Addendum: As of June 25, 2018 Epidiolex was approved by the FDA and has become the first CBD-based product available on the US market. Along with praising the strong clinical evidence supporting Epidiolex's use, the FDA stated that "prescribers can have confidence in the drug’s uniform strength and consistent delivery that support appropriate dosing needed for treating patients with these complex and serious epilepsy syndromes."