Rationale and Preclinical

Several features of the pharmacology of certain cannabinoids suggest that they may be candidates for investigation as anti-epileptic drugs. 

A series of validated laboratory experiments have shown that certain cannabinoids can modulate neurotransmission[i], can reduce neuro-inflammation[ii], and can affect oxidative stress[iii]. There is a cumulative anti-convulsant effect from certain cannabinoids due to their ability to simultaneously modulate a number of endogenous systems to attenuate and/or prevent epileptic neuronal hyperexcitability[iv]. These include ion channel control[v], inflammation[vi] and endocannabinoid system modulation[vii].

Several channels influence epileptogenesis (the process by which a normal brain develops epilepsy) including both ligand-gated and voltage-gated ion channels[viii]. It is the former to which a proportion of the actions of plant cannabinoids can be attributed, for example through modulation of transient receptor potential (TRP) channels (differentially activated, repressed and desensitized by different plant cannabinoids) as well as agonism and antagonism of G-protein coupled receptors, including orphan receptors[ix]. Additionally it is now recognized that there is a role for inflammation in epilepsy[x]. Some cannabinoids possess anti-inflammatories properties including inhibition of pro-inflammatory cytokine release and modulation of glialcell/neuronal interactions. Furthermore they modulate oxidative stress and production of toxic nitric oxide[xi]. Research shows that other than THC, plant cannabinoids have little or no affinity for the cannabinoid receptors, and do not share the unwanted psychoactivity that goes along with stimulation of the CB1 receptor in particular[xii].

Finally it is possible that certain cannabinoids may possess disease modifying potential through regulation of epilepsy related genes, as well as up-regulation of endogenous anti-convulsant neuropeptides and/or compensatory systems.

The precise mechanism of action of the anti-epileptic cannabinoids is a subject of intensive ongoing research at GW Pharmaceuticals.

 

CBD Pharmacology

The epilepsy relevant pharmacology of CBD can be summarized with: inhibition of neutrophil and microglial migration[xiii], anti-inflammatory effects in conventional animal models[xiv]; inhibition of adenosine uptake and indirect agonism of the neuroprotective and anti-inflammatory A2a receptor[xv]; other neuroprotective effects (TNF inhibition and anti-oxidant activity)[xvi]; antipsychotic activity[xvii]; agonism at the orphan receptor GPR55[xviii]; Desensitizer of TRP channels[xix]; anticonvulsant activity in all laboratory models tested[xx]; ion channel modulation[xxi]; ; and perturbation of the negative effects of THC (opposes euphoric, cognitive and psychotropic effects) via one or more of the above mechanisms[xxii].

 

 

It should be noted that CBD has negligible binding at the CB1 receptor, and so shares neither the pharmacology of CB1 agonists such as THC nor that of CB1 antagonists such as Rimonabant[xxiii]. CBD’s mechanism for treating seizures is not fully understood but is believed to involve a combination of beneficial effects stacking upon one another (polypharmacology)[xxiv]. Preclinical models suggest a broad role for CBD in generalized and absence seizures,.

 

GW CBD Research in Epilepsy

In November 2013, GW received Orphan Drug Designation for Epidiolex for the treatment of Dravet syndrome. With advice from pediatric epilepsy specialists, GW has proposed an investigational plan to the FDA for Epidiolex in Dravet syndrome and expect to hold a pre-IND meeting in the near future. Following this, GW expects to submit an IND to the FDA and commence clinical development in 2014.

We have conducted pre-clinical research of CBD in epilepsy for several years and have reported significant anti-epileptiform and anticonvulsant activity using a variety of in vitro and in vivo models[xxv]. This research has shown the ability of CBD to treat seizures in acute models of epilepsy with significantly fewer motor side effects than existing anti-epileptic drugs[xxvi].

Our cannabinoid research compounds were screened using a validated multi-electrode array technique in electrically discharging 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. In these models, 100µM of CBD decreased epileptiform amplitude and duration of local field potential (LFP) events,  as well as burst frequency in a region- specific fashion[xxvii].

Subsequently, the anti-convulsant actions of 1, 10 and 100 mg/kg CBD were examined in three different in vivo rodent seizure models. In the PTZ-induced acute, generalized seizure model, 100 mg/kg CBD significantly decreased mortality rate and the incidence of tonic-clonic seizures[xxviii]. In the acute pilocarpine model of temporal lobe seizures all doses of CBD significantly reduced the percentage of animals experiencing the most severe seizures. In this model of partial seizures, 10 and 100 mg/kg CBD significantly decreased the percentage of animals dying as a result of seizures and all doses of CBD also decreased the percentage of animals experiencing the most severe tonic–clonic seizures[xxix].

 

For medical enquiries relating to Epidiolex please email medicaldirector@gwpharm.com

 
 
References

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[ii] Esposito G, Scuderi C, Valenza M, Togna GI, Latina V,De Filippis D, Cipriano M, Carratù MR, Iuvone T, Steardo L.Cannabidiol reduces Ab-induced neuroinflammation andpromotes hippocampal neurogenesis through PPARginvolvement. PLoS ONE 2011; 6: e28668

[iii] Fernández-Ruiz J, Sagredo O, Pazos MR, García C, Pertwee R, Mechoulam R, Martínez-Orgado J.Cannabidiol for neurodegenerative disorders: important new clinical applications for this phytocannabinoid? Br J Clin Pharmacol. 2013 Feb;75(2):323-33.

[iv] Jones NA, Glyn SE, Akiyama S, Hill TD, Hill AJ, Weston SE, Burnett MD, Yamasaki Y, Stephens GJ, Whalley BJ, Williams CM. Cannabidiol exerts anti-convulsant effects in animal models of temporal lobe and partial seizures. Seizure. 2012 Jun;21(5):344-52

[v] Lozovaya N, Min R, Tsintsadze V, Burnashev N. Dual modulation of CNS voltage-gated calcium channels by cannabinoids: Focus on CB1 receptor-independent effects. Cell Calcium. 2009 Sep;46(3):154-62

[vi] Izzo AA, Borrelli F, Capasso R, Di Marzo V, Mechoulam R. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol Sci. 2009 Oct;30(10):515-27.

[vii] De Petrocellis L, Ligresti A, Moriello AS, Allarà M, Bisogno T, Petrosino S, Stott CG, Di Marzo V. Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br J Pharmacol. 2011 Aug;163(7):1479-94.

[viii] Armijo JA, Shushtarian M, Valdizan EM, Cuadrado A, de las Cuevas I, Adín J. Ion channels and epilepsy. Curr Pharm Des. 2005;11(15):1975-2003.

[ix] Izzo AA, Borrelli F, Capasso R, Di Marzo V, Mechoulam R. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol Sci. 2009 Oct;30(10):515-27.

[x] Vezzani A. Inflammation and epilepsy. Epilepsy Curr. 2005 Jan-Feb;5(1):1-6.

[xi] Izzo AA, Borrelli F, Capasso R, Di Marzo V, Mechoulam R. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol Sci. 2009 Oct;30(10):515-27.

[xii] Mechoulam R. Plant cannabinoids: a neglected pharmacological treasure trove. Br J Pharmacol. 2005 December; 146(7): 913–915.

[xiii] Walter L, Franklin A, Witting A,Wade C, Xie Y, Kunos G,Mackie K, Stella N. Nonpsychotropic cannabinoid receptorsregulate microglial cell migration. J Neurosci 2003; 23:1398–405.

[xiv] Izzo AA, Borrelli F, Capasso R, Di Marzo V, Mechoulam R. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol Sci. 2009 Oct;30(10):515-27.

[xv] Carrier EJ, Auchampach JA, Hillard CJ (2006). Inhibition of anequilibrative nucleoside transporter by cannabidiol: a mechanismof cannabinoid immunosuppression. Proc Natl Acad Sci USA 103:7895–7900.

[xvi] Mechoulam R, Peters M, Murillo-Rodriguez E, Hanus LO. Cannabidiol--recent advances. Chem Biodivers. 2007 Aug;4(8):1678-92.

[xvii] Zuardi, A.W. (2008) Cannabidiol: from an inactive cannabinoid to adrug with wide spectrum of action. Rev. Bras. Psiquiatr. 30, 271–280

[xviii] Ryberg E, Larsson N, Sjögren S, Hjorth S, Hermansson NO, Leonova J, Elebring T, Nilsson K, Drmota T, Greasley PJ. The orphan receptor GPR55 is a novelcannabinoid receptor. Br. J. Pharmacol. 152, 1092–1101

[xix] De Petrocellis L, Ligresti A, Moriello AS, Allarà M, Bisogno T, Petrosino S, Stott CG, Di Marzo V. Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br J Pharmacol. 2011 Aug;163(7):1479-94.

[xx] Jones NA, Glyn SE, Akiyama S, Hill TD, Hill AJ, Weston SE, Burnett MD, Yamasaki Y, Stephens GJ, Whalley BJ, Williams CM. Cannabidiol exerts anti-convulsant effects in animal models of temporal lobe and partial seizures. Seizure. 2012 Jun;21(5):344-52

[xxi] Fernández-Ruiz J, Sagredo O, Pazos MR, García C, Pertwee R, Mechoulam R, Martínez-Orgado J.Cannabidiol for neurodegenerative disorders: important new clinical applications for this phytocannabinoid? Br J Clin Pharmacol. 2013 Feb;75(2):323-33.

[xxii] Karniol IG, Shirakawa I, Kasinski N, Pfeferman A, Carlini EA. Cannabidiol interferes with the effects of delta 9 - tetrahydrocannabinol in man. Eur J Pharmacol. 1974 Sep;28(1):172-7.

[xxiii] Bisogno T, Hanus L, De Petrocellis L, Tchilibon S, Ponde DE, Brandi I, Moriello AS, Davis JB, Mechoulam R, Di Marzo V. Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol. 2001 Oct;134(4):845-52.

[xxiv] Jones NA, Glyn SE, Akiyama S, Hill TD, Hill AJ, Weston SE, Burnett MD, Yamasaki Y, Stephens GJ, Whalley BJ, Williams CM. Cannabidiol exerts anti-convulsant effects in animal models of temporal lobe and partial seizures. Seizure. 2012 Jun;21(5):344-52

[xxv] Jones NA, Hill AJ, Smith I, Bevan SA, Williams CM, Whalley BJ, Stephens GJ. Cannabidiol displays antiepileptiform and antiseizure propertes in vitro and in vivo. J Pharmacol Exp Ther. 2010 Feb;332(2):569-77.

[xxvi] Jones NA, Glyn SE, Akiyama S, Hill TD, Hill AJ, Weston SE, Burnett MD, Yamasaki Y, Stephens GJ, Whalley BJ, Williams CM. Cannabidiol exerts anti-convulsant effects in animal models of temporal lobe and partial seizures. Seizure. 2012 Jun;21(5):344-52

[xxvii] Jones NA, Hill AJ, Smith I, Bevan SA, Williams CM, Whalley BJ, Stephens GJ. Cannabidiol displays antiepileptiform and antiseizure propertes in vitro and in vivo. J Pharmacol Exp Ther. 2010 Feb;332(2):569-77.

[xxviii] Jones NA, Hill AJ, Smith I, Bevan SA, Williams CM, Whalley BJ, Stephens GJ. Cannabidiol displays antiepileptiform and antiseizure propertes in vitro and in vivo. J Pharmacol Exp Ther. 2010 Feb;332(2):569-77.

[xxix] Jones NA, Glyn SE, Akiyama S, Hill TD, Hill AJ, Weston SE, Burnett MD, Yamasaki Y, Stephens GJ, Whalley BJ, Williams CM. Cannabidiol exerts anti-convulsant effects in animal models of temporal lobe and partial seizures. Seizure. 2012 Jun;21(5):344-52