Elsevier

Epilepsy & Behavior

Volume 70, Part B, May 2017, Pages 319-327
Epilepsy & Behavior

Review
Therapeutic effects of cannabinoids in animal models of seizures, epilepsy, epileptogenesis, and epilepsy-related neuroprotection

https://doi.org/10.1016/j.yebeh.2016.11.006Get rights and content

Highlights

  • The endocannabinoid system plays a pivotal role in modifying central synaptic transmission.

  • CB1 agonism generally exerts anti-convulsant, antiepileptic and anti-epileptogenic effects but with several important exceptions.

  • CB1 antagonists can be proconvulsant, but exhibit anti-epileptogenic effects if employed during a precise time window.

  • Cannabidiol (CBD) consistently exerts CB1/CB2R-independent anti-seizure and anti-epileptogenic properties.

  • The cannabinoids’ therapeutic domain in epilepsy includes neuroprotective effects.

Abstract

The isolation and identification of the discrete plant cannabinoids in marijuana revived interest in analyzing historical therapeutic claims made for cannabis in clinical case studies and anecdotes. In particular, sources as old as the 11th and 15th centuries claimed efficacy for crude marijuana extracts in the treatment of convulsive disorders, prompting a particularly active area of preclinical research into the therapeutic potential of plant cannabinoids in epilepsy. Since that time, a large body of literature has accumulated describing the effects of several of the > 100 individual plant cannabinoids in preclinical models of seizures, epilepsy, epileptogenesis, and epilepsy-related neuroprotection.

We surveyed the literature for relevant reports of such plant cannabinoid effects and critically reviewed their findings. We found that acute CB1R agonism in simple models of acute seizures in rodents typically produces anti-convulsant effects whereas CB1R antagonists exert converse effects in the same models. However, when the effects of such ligands are examined in more complex models of epilepsy, epileptogenesis and neuroprotection, a less simplistic narrative emerges. Here, the complex interactions between (i) brain regions involved in a given model, (ii) relative contributions of endocannabinoid signaling to modulation of synaptic transmission in such areas, (iii) multi-target effects, (iv) cannabinoid type 1 and type 2 receptor signaling interactions and, (v) timing, (vi) duration and (vii) localization of ligand administration suggest that there is both anti-epileptic therapeutic potential and a pro-epileptic risk in up- and down-regulation of endocannabinoid signaling in the central nervous system. Factors such receptor desensitization and specific pharmacology of ligands used (e.g. full vs partial agonists and neutral antagonists vs inverse agonists) also appear to play an important role in the effects reported. Furthermore, the effects of several plant cannabinoids, most notably cannabidiol (CBD) and cannabidavarin (CBDV), in models of seizures, epilepsy, epileptogenesis, and neuroprotection are less ambiguous, and consistent with reports of therapeutically beneficial effects of these compounds in clinical studies. However, continued paucity of firm information regarding the therapeutic molecular mechanism of CBD/CBDV highlights the continued need for research in this area in order to identify as yet under-exploited targets for drug development and raise our understanding of treatment-resistant epilepsies.

The recent reporting of positive results for cannabidiol treatment in two Phase III clinical trials in treatment-resistant epilepsies provides pivotal evidence of clinical efficacy for one plant cannabinoid in epilepsy. Moreover, risks and/or benefits associated with the use of unlicensed Δ9-THC containing marijuana extracts in pediatric epilepsies remain poorly understood. Therefore, in light of these paradigm-changing clinical events, the present review's findings aim to drive future drug development for newly-identified targets and indications, identify important limitations of animal models in the investigation of plant cannabinoid effects in the epilepsies, and focuses future research in this area on specific, unanswered questions regarding the complexities of endocannabinoid signaling in epilepsy.

This article is part of a Special Issue titled Cannabinoids and Epilepsy.

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.

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    These authors contributed equally to the work.

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