Cannabinoids act on multiple systems and it is understood that cannabinoids interact with many neurotransmitter and neuromodulator systems and important to note that cannabinoids have the ability to interact with all kinds of cellular pathways implicated in a range of diseases. GW is particularly well skilled at exploring these therapeutic prospects.
Cannabinoids act as ligands (a small molecule able to dock onto the binding site of a protein) conferring their ability to modulate a receptor’s behavior and consequently their downstream biological pathways. Although the cannabinoids may have similar structures, they display a remarkably wide array of actions. For example it is known that THC and THCV have very different biological effects.
How does CBD work in epilepsy?
As is the case for many other AEDs, the exact MOA by which CBD produces its anticonvulsant effects is unknown. Cannabidiol is a structurally novel anti-convulsant. Cannabidiol does not exert its anti-convulsant effects through CB1 receptors, nor through voltage-gated sodium channels. CBD may exert a cumulative anti-convulsant effect, modulating a number of endogenous systems including, but not limited to neuronal inhibition (synaptic and extrasynaptic GABA channels), modulation of intracellular calcium (TRPV, VDAC, GPR55), and possible anti-inflammatory effects (adenosine). CBD does not directly bind to, nor activate, CB1 and CB2 receptors at concentrations pharmacologically relevant to its anticonvulsant effect. Among the likely mechanisms of action, modulation of intra-cellular calcium via GPR-55, TRPV, and VDAC is under active investigation in our research laboratories. Additional mechanisms under exploration by our researchers include adenosine modulation, glycine and GABAergic modulation, and serotonin agonism.
GW CBD Pre-clinical Research in Epilepsy
GW has been conducting pre-clinical research of cannabidiol (CBD) in epilepsy since 2007 and has reported significant anti-epileptiform and anticonvulsant activity of CBD using a variety of in vitro and in vivo models. This research has shown the ability of CBD to treat seizures in acute models of seizure with a potentially favourable tolerability profile. Screening for potential anti-epileptic drugs (AEDs) using in vitro models provides network-level information of epileptiform activity which is difficult to investigate under in vivo conditions. Thus, such in vitro models provide informative data for early identification of potential AEDs before their examination in vivo.
Our cannabinoid research compounds were screened using a validated multi-electrode array technique in electrically discharging acute hippocampal brain slices caused by the omission of Mg2+ ions from, or addition of the K+ channel blocker, 4-aminopyridine (4-AP) to the bathing solution (Hill et al., 2010). In these in vitro models, CBD exerted significant anti-epileptiform effects (≥ 10 nM CBD, both models) in both a concentration-related and region-dependent manner (Jones et al., 2010). Overall, data from these in vitro studies demonstrated CBD to have therapeutic potential in the control of epilepsy and provided enough evidence for GW Pharmaceuticals to investigate CBD in well-established in vivo models of seizure.
For AED discovery, in vivo models of seizure are necessary to determine the pre-clinical efficacy of potential AEDs translated from in vitro research. However, with seizure type varying considerably from patient to patient, such anti-epileptiform compounds must be screened against a number of acute in vivo models that target a diverse range of seizure types.
The anticonvulsant actions of 1, 10 and 100 mg/kg CBD were examined in three different chemically-induced in vivo rodent seizure models. In the pentylenetetrazole (PTZ)-induced acute, generalized seizure model, 100 mg/kg CBD significantly decreased mortality rate, seizure severity and the incidence of tonic-clonic seizures (Jones et al., 2010). In the acute pilocarpine model of temporal lobe seizures (indicative of effects against status epilepticus), CBD exhibited modest anticonvulsant effects, significantly lowering the incidence of the most severe seizures (Jones et al., 2012). In the penicillin model of partial seizures, CBD demonstrated significant anticonvulsant effects, lowering the incidence of the most severe seizures (≥ 1 mg/kg) and caused a significant two-fold reduction in the percentage of animals dying as a result of seizures (≥ 10 mg/kg) (Jones et al., 2012).
In an audiogenic model, generalized seizures are initiated in genetically epilepsy-prone rodents via an auditory tome (110-120 dB). Audiogenic seizures were significantly attenuated by CBD (100 and 200 mg/kg), lowering the incidences of the clonic convulsions, as well as non-significantly suppressing tonic convulsions and mortality rate (Jones et al., 2014).
The anticonvulsant profile of CBD was also investigated by the National Institute of Neurological Disorders and Stroke (NINDS) Anticonvulsant Screening Program (ASP) to independently verify and further characterize CBD’s effects on a battery of well-established rodent seizure models. In the ASP program CBD exerted significant anticonvulsant effects in the 6Hz ‘psychomotor’ tests of therapy-resistant partial seizures, the maximal electroshock test of generalized tonic-clonic seizures, and the subcutaneous Metrazole seizure threshold test of clonic forebrain seizures (Jones et al., 2015).
The precise mechanism by which cannabidiol (CBD) exerts its antiepileptic effects is unknown and is under further investigation. However, it is known that CBD does not directly activate CB1 receptors, is not reported to have psychoactive effects and is thus quite distinct from its better known relative, tetrahydrocannabinol (or THC). CBD is also structurally unrelated to other approved anti-epileptic drugs and the anticonvulsant effect of CBD is not thought to be mediated through sodium-dependent mechanisms. As such, CBD represents a potential novel treatment for seizure management. Current research suggests that CBD may exert a cumulative anticonvulsant effect, modulating a number of endogenous systems, which is being studied further.
Molecular targets of cannabidiol in neurological disorders, Bih and Whalley, 2015 Neurotherapeutics, doi: 10.1007/s13311-015-0377-3