Cannabinoids in the treatment of epilepsy – an updated review
Journal of Epileptology, 2019, 27,
Doi : 10.2478/joepi-2019-0004
Introduction : It is estimated that 30% of people with epilepsy continue to have seizures despite treatment. The approval of many new antiseizure drugs during the past two decades has not substantially reduced the proportion of patients with medically refractory disease. Patients need new treatments. Many families choose to try alternative therapy options. An abundance of preclinical evidence and anecdotal human data support the use of cannabinoids in the treatment of epilepsy.
Aim : The present review paper aims to present the current state of knowledge regarding the effectiveness and safety of cannabinoids in the treatment of epilepsy.
Material and methods : This review covers the most relevant and recent papers identified using the Pub- Med database.
Results and discussion : Cannabidiol has shown anticonvulsant activity in many acute animal models of seizures. Recently three well controlled randomized trails focused on the potential usefulness of cannabinoids in the treatment of epilepsy have been published. Based on these publications, the US Food and Drug Administration approved in 2018 a purified, plant-derived cannabinoid for the treatment of seizures in patients with Dravet syndrome and Lennox-Gastaut syndrome.
Conclusion : An abundance of preclinical evidence and anecdotal human data support the use of cannabinoids in the treatment of epilepsy. Recently purified, plant-derived cannabinoid was approved for the treatment of seizures in patients with Dravet syndrome and Lennox-Gastaut. Additional data are needed to determine the long-term efficacy and safety of cannabidiol for severe epilepsy syndromes
Keywords : cannabinoids • epilepsy • treatment
Epilepsy is one of the most common disorders of the nervous system. It is a health problem as well as a social and economic one. Epilepsy affects over 65 million people worldwide (CDC, 2012). Patients who suffer from seizures in spite of the administration of two subsequent, appropriately-selected antiepileptic drugs (AEDs) that are well applied and tolerated, are diagnosed with refractory epilepsy (Kwan et al., 2010). It is estimated that 30% of people with epilepsy continue to have seizures despite treatment (Brodie et al., 2012; Kwan, Brodie, 2000). The approval of many new antiseizure drugs during the past two decades has not substantially reduced the proportion of patients with medically refractory disease (Brodie et al., 2012). The safety and side-effect profile of antiseizure drugs has improved, but side effects related to the central nervous system are common and affect quality of life (Perucca, Gilliam, 2012). Patients need new treatments that control seizures and have fewer side effects. Many families choose to try non-pharmaceutical or alternative therapy options. Cannabis-based treatment for epilepsy has recently received prominent attention in the lay press improvements in seizure control in children with severe epilepsy have been published (Gupta, 2013). An abundance of preclinical evidence and anecdotal human data support the use of cannabinoids in the treatment of epilepsy.
The present review paper aims to present the current state of knowledge regarding the effectiveness and safety of cannabinoids in the treatment of epilepsy in humans.
MATERIAL AND METHOD
This review covers the most relevant recent papers identified using the PubMed database. The search was conducted in June 2019 and included the terms: cannabinoids, epilepsy, treatment, cannabidiol (CBD), tetrahydrocannabinol (THC) It encompasses articles published in English from 2010 to 2019. Randomized controlled trails and reviews was included. Other types of studies were excluded. Also, additional relevant publications were identified within the various references highlighted within the original papers.
RESULTS AND DISCUSSION
THC and CBD
Cannabis has been used by humanity in a variety of medical settings via a range of different formulations for more than 5000 years. The plant Cannabis sativa, commonly known as marijuana, is composed of more than 500 compounds and new components continue to be discovered (Radwan et al., 2009). Although there are many preparations with cannabinoids only some of them are being investigated and developed as anticonvulsants.
These biologically active compounds isolated from the cannabis plant are termed phytocannabinoids. The best studied of these are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) and their metabolites. More recently, trials have begun with Cannabidivarin (CBDV). CBDV has similar molecular structure to CBD but instead of having a pentyl chain, it has a propyl chain. This propyl cannabinoid has slightly different properties than CBD. CBD was isolated in 1940 and its structure was elucidated in 1963, whereas THC was isolated and characterized in 1964 (Mechoulam, Shvo, 1963). In the late 1980s it was found that THC canbind to two G-protein-coupled cell membrane receptors, consequently named the cannabinoid type 1 (CB1) and type 2 (CB2) receptors, to exert its effects. The discovery of cannabinoid receptors in the CNS led to a search for endogenous substances interacting with these receptors.
These endogenous counterparts of phytocannabinoids, are known as endocannabinoids. The most important of which are the arachidonic acid derivatives anandamide (2-arachidonoylethanolamide) and 2-arachidonoyl glycerol (Reddy, Golub 2016). These endocannabinoids are produced on demand during excessive neuronal excitation. Despite overt differences in their chemical structures, phytocannabinoids share three-dimensional aspects of their structure with endocannabinoids (Maccarrone et al., 2017; Chiurchiu et al., 2018). This resemblance is the reason why phytocannabinoids can bind the same targets that are recognised by endocannabinoids. Phytocannabinoids, unlike the endocannabinoids, have terpenophenolic structures because they cannot be synthesised nor hydrolysed by the body. It is important because the biological activity of endocannabinoids is tightly regulated through metabolic control (Iannotti et al., 2016; Maccarrone et al., 2015). THC possible use as an antiepileptic drug (AED) in humans has been hindered by its known psychotropic effects. CBD and CBDV are lacking these complicating properties (Rosenberg et al., 2015). Unlike THC, CBD does not activate CB1 and CB2 receptors.
However, CBD interacts with many other, non-endocannabinoid signaling systems. It is a called “multitarget” drug (Devinsky et al., 2014). The plausible and implausible CBD’s molecular targets as well as the potential pharmacological effects of CBD in neurological disorders including epilepsy has been reviewed elsewhere (Ibeas Bih et al., 2015). It is believed that its anticonvulsant action of cannabidiol is associated with at least some of the following mechanisms: stimulation of 5-HT1a receptors, inhibition of glutamate release, inhibition of noradrenaline, dopamine and adenosine reuptake, stimulation of glycine receptors and stimulation and desensitization of transient receptor potential class channels (ankyrin and vanilloid types, i.e. TRPA1, TRPV1 and TRPV2 receptors ) (Leo et al., 2016). Anticonvulsant effect of CBDV is, similar as CBD, probably related to its agonistic action on TRPA1, TRPV1 and TRPV2, while its inhibitory action on diacylglycerol lipase-α, which synthesizes 2-arachidonoylglycerol, an endocannabinoid, remain yet to be connected to anticonvulsant properties (Hill et al., 2013; Iannotti et al., 2014).