ReviewTherapeutic effects of cannabinoids in animal models of seizures, epilepsy, epileptogenesis, and epilepsy-related neuroprotection
Introduction
In order to understand the justification for modern, preclinical investigations of the effects of cannabinoids in animal models of epilepsy and its associated symptoms and features, some appreciation of the historical, anecdotal use of marijuana (cannabis) in convulsive disorders is required. There is general consensus that the origins of marijuana use in the treatment of convulsions lie in reports from the Middle East that were ascribed to the scholar al-Mayusi [1] in 1100 and the historian Ibn al-Badri in 1464 [2]. It was not until 1649 that Nicholas Culpeper translated the Pharmacopoeia Londonensis from Latin into English, and suggested marijuana as a treatment of “inflammation of the head” [3]. Thereafter, there appears to be no further mention of this therapeutic use of marijuana until its introduction to Western medicine in the 19th century by William O′Shaughnessy. Here, alongside other reports from the same period describing the control seizures with marijuana extracts [4], [5], [6], O′Shaughnessy described successful treatment of infantile seizures with a cannabis tincture [7]. Similarly, J. R. Reynolds described marijuana as ‘the most useful agent with which I am acquainted’ in the treatment of ‘attacks or violent convulsions … (and) …may be stopped with a full dose of hemp’ [6] while William Gowers commented that ‘Cannabis indica…is sometimes, although not very frequently, useful. It is of small value as an adjunct to the bromide, but is sometimes of considerable service given separately’ [8].
Despite these admittedly anecdotal reports of efficacy in convulsive episodes, only very limited investigation of the anti-convulsant effects of marijuana were undertaken in animal models prior to the 1980s [9], [10]. Arguably, it was the isolation, identification, and subsequent synthesis of the two most abundant cannabinoids derived from marijuana, Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), in the 1960s [11], [12] which has driven modern studies of their pharmacological effects in a variety of models of central nervous system disease, including those of epilepsy, seizures, epileptogenesis, and epilepsy-related neuroprotection reviewed here. Recent reports of positive effects in properly controlled human clinical trials of CBD in the treatment resistant epilepsies have provided the first definite evidence of clinical efficacy for one plant cannabinoid in epilepsy. Given the pivotal nature of these clinical findings, critical review of the preclinical literature associated with this topic is warranted and addressed herein.
Section snippets
Methods
To identify effects of cannabinoids in pre-clinical animal models of seizures, epilepsy, epileptogenesis, and neuroprotection, we searched for peer-reviewed, primary literature using a PubMed search. Results were obtained using the keywords “CB1R,” “CB2R,” “cannabinoid”, “cannabidiol”, “THC”/“Tetrahydrocannabinol”, “anandamide”, “2-AG”, “FAAH”/“Fatty acid amide hydrolase”, and “MAG lipase” plus the terms “seizures,” “epilepsy,” “epileptogenesis,” and “neuroprotection.” We excluded primarily in
Pre-clinical models of seizures and epileptogenesis
Early studies from the 1970s–1980s demonstrated that plant cannabinoids (‘phytocannabinoids’) derived from cannabis exerted anti-convulsant effects in both acute animal models of seizures [14], [15], [16], [17], [18] and chronic models of epileptogenesis [19], [20], [21], [22], [23]. These studies initiated clinical and scientific inquiry into mechanisms mediating potential anti-seizure effects of cannabinoids, albeit using unstandardized animal models and variable routes of cannabinoid
Conclusion
In conclusion, we find that the evidence describing the effects of major plant cannabinoids that do not act as CBR ligands, most notably cannabidiol and cannabidavarin, exerts consistently beneficial therapeutic effects in preclinical models of seizures, epilepsy, epileptogenesis, and neuroprotection, consistent with emerging human clinical trial results. This recent clinical validation of the predictive nature of the preclinical models used to study these phytocannabinoids and the continued
Conflict of interest
The authors do not have any conflict of interests to declare.
References (132)
- et al.
Hashish. IV. The isolation and structure of cannabinolic cannabidiolic and cannabigerolic acids
Tetrahedron
(1965) - et al.
The absolute configuration of delta-1-tetrahydrocannabinol, the major active constituent of hashish
Tetrahedron Lett.
(1967) - et al.
Molecular targets of cannabidiol in neurological disorders
Neurotherapeutics
(2015) - et al.
Effects of cannabidiol on behavioral seizures caused by convulsant drugs or current in mice
Eur. J. Pharmacol.
(1982) - et al.
Acute antiepileptic effects of 9-tetrahydrocannabinol in rats with kindled seizures
Exp. Neurol.
(1973) - et al.
Effects of marihuana cannabinoids on seizures activity in cobalt-epileptic rats
Pharmacol. Biochem. Behav.
(1982) - et al.
Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors
Biochem. Pharmacol.
(1995) - et al.
2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain
Biochem. Biophys. Res. Commun.
(1995) - et al.
Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action
Trends Neurosci.
(1998) - et al.
Neuronal expression of CB2 cannabinoid receptor mRNAs in the mouse hippocampus
Neuroscience
(2015)
Intracellular trafficking of anandamide: new concepts for signaling
Trends Biochem. Sci.
Molecular characterization of a phospholipase D generating anandamide and its congeners
J. Biol. Chem.
Presynaptic inhibition caused by retrograde signal from metabotropic glutamate to cannabinoid receptors
Neuron
Inhibition of monoacylglycerol lipase mediates a cannabinoid 1-receptor dependent delay of kindling progression in mice
Neurobiol. Dis.
Evidence that 2-arachidonoylglycerol but not N-palmitoylethanolamine or anandamide is the physiological ligand for the cannabinoid CB2 receptor. Comparison of the agonistic activities of various cannabinoid receptor ligands in HL-60 cells
J. Biol. Chem.
Effects of TRPV1 activation on synaptic excitation in the dentate gyrus of a mouse model of temporal lobe epilepsy
Exp. Neurol.
Involvement of transient receptor potential vanilloid type 1 channels in the pro-convulsant effect of anandamide in pentylenetetrazole-induced seizures
Epilepsy Res.
Involvement of TRPV1 channels in the activity of the cannabinoid WIN 55,212-2 in an acute rat model of temporal lobe epilepsy
Epilepsy Res.
Effects of cannabinoids and endocannabinoid hydrolysis inhibition on pentylenetetrazole-induced seizures and electroencephalographic activity in rats
Epilepsy Res.
Attenuation of kainic acid-induced status epilepticus by inhibition of endocannabinoid transport and degradation in guinea pigs
Epilepsy Res.
ABHD6 blockade exerts antiepileptic activity in PTZ-induced seizures and in spontaneous seizures in R6/2 mice
Neuron
Assessment of the role of CB1 receptors in cannabinoid anti-convulsant effects
Eur. J. Pharmacol.
Synthetic cannabinoid WIN 55,212-2 mesylate enhances the protective action of four classical antiepileptic drugs against maximal electroshock-induced seizures in mice
Pharmacol. Biochem. Behav.
Effects of WIN 55,212-2 mesylate on the anti-convulsant action of lamotrigine, oxcarbazepine, pregabalin and topiramate against maximal electroshock-induced seizures in mice
Eur. J. Pharmacol.
Involvement of PPAR receptors in the anti-convulsant effects of a cannabinoid agonist, WIN 55,212-2
Prog. Neuro-Psychopharmacol. Biol. Psychiatry
Effects of WIN 55,212-2 mesylate (a synthetic cannabinoid) on the protective action of clonazepam, ethosuximide, phenobarbital and valproate against pentylenetetrazole-induced clonic seizures in mice
Prog. Neuro-Psychopharmacol. Biol. Psychiatry
Inverse relationship of cannabimimetic (R +)WIN 55, 212 on behavior and seizures threshold during the juvenile period
Pharmacol. Biochem. Behav.
Arachidonyl-2′-chloroethylamide, a highly selective cannabinoid CB1 receptor agonist, enhances the anti-convulsant action of valproate in the mouse maximal electroshock-induced seizures model
Eur. J. Pharmacol.
Effect of arachidonyl-2′-chloroethylamide, a selective cannabinoid CB1 receptor agonist, on the protective action of the various antiepileptic drugs in the mouse maximal electroshock-induced seizures model
Prog. Neuro-Psychopharmacol. Biol. Psychiatry
Effect of ACEA–a selective cannabinoid CB1 receptor agonist on the protective action of different antiepileptic drugs in the mouse pentylenetetrazole-induced seizures model
Prog. Neuro-Psychopharmacol. Biol. Psychiatry
The cannabinoid anti-convulsant effect on pentylenetetrazole-induced seizures is potentiated by ultra-low dose naltrexone in mice
Epilepsy Res.
Involvement of nitrergic system in the anti-convulsant effect of the cannabinoid CB(1) agonist ACEA in the pentylenetetrazole-induced seizures in mice
Epilepsy Res.
The interaction of cannabinoids and opioids on pentylenetetrazole-induced seizures threshold in mice
Neuropharmacology
Cannabinoid type 2 receptors mediate a cell type-specific plasticity in the hippocampus
Neuron
The cannabinoid CB2 receptor-specific agonist AM1241 increases pentylenetetrazole-induced seizures severity in Wistar rats
Epilepsy Res.
Evidence for a physiological role of endocannabinoids in the modulation of seizures threshold and severity
Eur. J. Pharmacol.
Palmitoylethanolamide attenuates PTZ-induced seizures through CB1 and CB2 receptors
Epilepsy Res.
Crucial roles of the endocannabinoid 2-arachidonoylglycerol in the suppression of epileptic seizures
Cell Rep.
Pilocarpine-induced status epilepticus results in mossy fiber sprouting and spontaneous seizures in C57BL/6 and CD-1 mice
Epilepsy Res.
Kindling and status epilepticus models of epilepsy: rewiring the brain
Prog. Neurobiol.
Role of oxidative stress in epileptic seizures
Neurochem. Int.
Pilocapine alters NMDA receptor expression and function in hippocampal neurons: NADPH oxidase and ERK1/2 mechanisms
Neurobiol. Dis.
Long-term disease-modifying effect of the endocannabinoid agonist WIN55,212-2 in a rat model of audiogenic epilepsy
Pharmacol. Rep.
Post-status epilepticus treatment with the cannabinoid agonist WIN 55,212-2 prevents chronic epileptic hippocampal damage in rats
Neurobiol. Dis.
The cannabinoid receptor agonist WIN55.212 reduces consequences of status epilepticus in rats
Neuroscience
The therapeutic use of Cannabis sativa L. in Arabic medicine
J. Cannabis Ther.
History of therapeutic cannabis
A homelie herb: medicinal cannabis in early England
J. Cannabis Ther.
Cannabis indica in convulsions
Report of the Ohio State Medical Committee on Cannabis indica
Cited by (149)
Therapeutic potential of CB<inf>1</inf>R activation by Qingyangshen glycoside M1 for seizure relief
2024, Journal of EthnopharmacologyIn silico exploration of CB2 receptor agonist in the management of neuroinflammatory conditions by pharmacophore modeling
2024, Computational Biology and ChemistryBinding of the monoacylglycerol lipase (MAGL) radiotracer [<sup>3</sup>H]T-401 in the rat brain after status epilepticus
2024, Neurochemistry InternationalAcute toxic hippocampal encephalopathy in heavy cannabis users: A case report
2024, Radiology Case ReportsThe longitudinal effects of cannabidiol on brain temperature in patients with treatment-resistant epilepsy
2024, Epilepsy and BehaviorBuilding evidence on therapeutic efficacy and innovative mechanisms of cannabinoids in neurological disorders
2023, Experimental Neurology
- 1
These authors contributed equally to the work.