Investigational Cannabinoids in Seizure Disorders, what have we learned thus far ?
Dejana Ružić Zečević, Ziyad Tantoush, Marko Folić, Goran Babić, Milan Radovanović and Slobodan M. Janković
may 2018, 23 pages
Introduction : Anticonvulsant activity of cannabinoid attracted much attention in the last decade. Cannabinoids that are currently investigated with intention to become drugs for treatment of epilepsy are cannabidiol, cannabidivarin, Δ9-tetrahydrocannabivarin and Δ9-tetrahydrocannabinolic acid.
Areas covered : Topic of this review are results of pre-clinical and clinical studies with investigational cannabinoids. Relevant literature was searched for in MEDLINE, SCOPUS, EBSCO, GOOGLE SCHOLAR and SCINDEX databases.
Expert opinion : Pre-clinical studies confirmed anticonvulsant activity of cannabidiol and cannabidivarin in a variety of epilepsy models. While results of clinical trials with cannabidivarin are still awaited, cannabidiol showed clear therapeutic benefit and good safety in patients with therapy resistant seizures associated with Dravet syndrome and in patients with Lennox-Gastaut syndrome having drop seizures. However, full therapeutic potential of cannabinoids in treatment-resistant epilepsy has yet to be investigated in near future.
Key Words : cannabidiol; cannabidivarin; treatment-resistant epilepsy; Dravet syndrome; Lennox-Gastaut syndrome
Cannabinoids are terpenophenolic compounds found in hashish (resin separated from flowers of female plants), leaves, and flower buds of the herb Cannabis sativa L . They are synthetized in acidic form, but under the influence of light or heat carboxyl groups are rapidly lost and neutral forms could be found in the plant material. The most abundant and biologically active natural cannabinoids are Δ9-tetrahydrocannabinol, cannabigerol, cannabichromene and cannabidiol [1, 2]. There are also several hundreds of synthetic cannabinoids, mostly designed for illicit use, which bind for the same receptors as natural ones, but with different affinity and intrinsic efficacy . Endogenous cannabinoids were also discovered, being derivatives of arachidonic acid, N-arachidonylethanolamide (anandamide) and 2-arachidonylglycerol, and acting on the same receptors as plant-derived compounds .
Only two types of receptors for cannabinoids are well established to date, CB1 and CB2, both belonging to the G-protein coupled receptors superfamily, although several others were proposed [4, 5]. CB1 receptors are mostly present at nerve terminals (both in central and peripheral nervous system), mediating inhibition of neurotransmitter release, while CB2 receptors could be found on immune cells, being involved in regulation of cytokine release . However, cannabinoids have other binding sites which do not involve CB1/CB2 receptors, but several voltage- or ligand-gated channels and transient potential receptor class channels which are being modulated by these compounds .
There is a plethora of cannabinoid pharmacological effects, which could be found in almost every human organ or tissue . Cannabinoids influence memory, cognition, sense of satisfaction, body movement, appetite, sense of pain and perception in general; they exhibit antiemetic, sedative, both anticonvulsant and pro convulsive action , and at periphery stimulation of heart, accelerated wound healing, liver-protective and immunosuppressant actions could be observed. Anticonvulsant action of cannabinoids has attracted much attention recently, and cannabinoid receptors are seen as molecular targets for development of promising anticonvulsants that could help to decrease burden of drug-resistant epilepsy .