Could Cannabidiol be a Treatment Option for Intractable Childhood and Adolescent Epilepsy ?
Chung Mo Koo, Hoon-Chul Kang
Journal of Epilepsy Research, 2017, 7, 16-20.
pISSN 2233-6249 / eISSN 2233-6257
Epilepsy is an important disease that affects brain function, particularly in those under 3 years old. Uncontrolled seizures can affect cognitive function and quality of life. For these reasons, many trials have been conducted to investigate treatments for pediatric epilepsy. Currently, many antiepileptic drugs are available for the treatment of epilepsy, but cases of intractable epilepsy continue to exist. In the past, cannabis has been tested as a potential treatment of intractable epilepsy. Since 2013, 10 epilepsy centers in America have conducted research regarding the efficacy of cannabis to treat epilepsy. Cannabis has many components, including cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC). THC has psychoactive properties exerted through its binding of the cannabinoid receptor (CBR) whereas CBD is a CBR antagonist. The inhibition of epilepsy by CBD may therefore be caused by various mechanisms, although the detailed mechanisms of CBD actions have not yet been well defined. In most studies, trial doses of CBD were 2-5 mg/kg/day. Several such studies have shown that CBD does have efficacy for treatment of epilepsy. Reported adverse effects of CBD were mostly mild, including drowsiness, diarrhea, and decreased appetite. Severe adverse reactions requiring treatment, such as status epilepticus, have also been reported but it is not clear that this is related to CBD. Furthermore, many previous studies have been limited by an open-label or survey design. In future, double-blind, controlled trials are required and the use of CBD to treat other neurological problems should also be investigated.
Key words : Cannabis, Cannabidiol, Epilepsy
Epilepsy impacts the brain, and is associated with cognitive dysfunction and behavior disorder, which can affect quality of life, especially during the developmental period.1-3 Early onset epilepsy, particularly in those less than 3 years old, and uncontrolled seizures are associated with poor cognitive function later in life.4
Currently, more than 20 different antiepileptic drugs (AED) exist for the treatment of epilepsy. However, 30% of patients with epilepsy continue to have seizures.5-7 Many new medications have been approved in the past two decades, but these have not reduced the proportion of patients with intractable epilepsy.5 Recently, cannabis has attracted attention as a potential treatment of epilepsy.7 Cannabis was used to treat epilepsy in Sumeria as early as 1800 BCE.7,8 In the late 19th century, English neurologists also used cannabis for the treatment of epilepsy.9-11 More recently, some states in America have approved medical marijuana for the treatment of epilepsy. Moreover, since 2013, the effects of cannabidiol (CBD) in the treatment of epilepsy have been studied at 10 epilepsy centers using Epidiolex, a purified cannabis containing 99% CBD and less than 0.10% tetrahydrocannabinol (THC). (GW Pharmaceuticals, Sativex, London, UK).
Cannabis contains more than 545 distinct compounds, the most abundant of which are cannabinoids.12 The most important neuroactive components of cannabis are CBD and Δ9-THC. THC binds to G-protein-coupled cell membrane receptors, including the cannabinoid receptor type 1 (CB1R), which is found primarily in the brain, but is also present in peripheral tissues, and the cannabinoid receptor type 2 (CB2R), which is located mainly in immune and hematopoietic cells. THC binds CB1R in inhibitory gamma-aminobutyric acid-ergic and excitatory glutamatergic neurons.13,14 These interactions are the pathways by which cannabis exerts its psychoactive function. However, CBD is an antagonist to CB1R and CB2R.15 Some animal studies show that CB1R antagonists can reduce the threshold of seizures.16 This suggests that CBD has another mechanism by which it can control seizures. Indeed, CBD acts via multiple mechanisms (Fig. 1).7,14,15 These include effects on transient receptor potential ation channels at a low level,17 and antagonistic functions at G-protein-coupled receptor 55, by which it can decrease presynaptic glutamate release.18 However, the mechanisms underlying the anti-epileptic effects of CBD are not well defined.
CBD is metabolized by the liver, and it can inhibit cytochrome P (CYP) 450, especially CYP 2C and CYP 3A, which aids metabolism of several AED.19,20 Therefore, if a patient with epilepsy takes CBD with an enzyme-inducing AED, such as carbamazepine or phenytoin, the AED can reduce serum CBD levels. Whereas, if the patient takes clobazam (CLB) with CBD, CBD can raise the serum level of noroclobazam, the active metabolite of CLB.21 The half-life of CBD in humans is estimated to be between 18 and 32 hours.22
Here, we review recent trials that have investigated the use of CBD as a treatment for epilepsy and highlight key issues for future research.