Cannabis and Endocannabinoid Signaling in Epilepsy

Part of the Handbook of Experimental Pharmacology book series (HEP, volume 231)


The antiepileptic potential of Cannabis sativa preparations has been historically recognized. Recent changes in legal restrictions and new well-documented cases reporting remarkably strong beneficial effects have triggered an upsurge in exploiting medical marijuana in patients with refractory epilepsy. Parallel research efforts in the last decade have uncovered the fundamental role of the endogenous cannabinoid system in controlling neuronal network excitability raising hopes for cannabinoid-based therapeutic approaches. However, emerging data show that patient responsiveness varies substantially, and that cannabis administration may sometimes even exacerbate seizures. Qualitative and quantitative chemical variability in cannabis products and personal differences in the etiology of seizures, or in the pathological reorganization of epileptic networks, can all contribute to divergent patient responses. Thus, the consensus view in the neurologist community is that drugs modifying the activity of the endocannabinoid system should first be tested in clinical trials to establish efficacy, safety, dosing, and proper indication in specific forms of epilepsies. To support translation from anecdote-based practice to evidence-based therapy, the present review first introduces current preclinical and clinical efforts for cannabinoid- or endocannabinoid-based epilepsy treatments. Next, recent advances in our knowledge of how endocannabinoid signaling limits abnormal network activity as a central component of the synaptic circuit-breaker system will be reviewed to provide a framework for the underlying neurobiological mechanisms of the beneficial and adverse effects. Finally, accumulating evidence demonstrating robust synapse-specific pathophysiological plasticity of endocannabinoid signaling in epileptic networks will be summarized to gain better understanding of how and when pharmacological interventions may have therapeutic relevance.


2-Arachidonoylglycerol Anticonvulsant Cannabidiol Cannabis CB1 cannabinoid receptor Diaclyglycerol lipase-α Epilepsy Glutamate GPR55 receptor Hippocampus Metabotropic glutamate receptor Perisynaptic machinery Seizure Synapse Synaptic circuit-breaker Δ9-tetrahydrocannabinol 











Drug Enforcement Administration






γ-aminobutyric acid


Monoacylglycerol lipase


Metabotropic glutamate receptor








Transient receptor potential channel


United Kingdom Cannabis Internet Activists


World Health Organization



This work was supported by the Hungarian Academy of Sciences Momentum Program LP-54/2013 and by the Wellcome Trust International Senior Research Fellowship. The author is very grateful to Dr. S. Woodhams for his critical comments on the manuscript; to Mr. B. Barti for his help with artwork; to Profs. R. DeLorenzo, R. Karlócai, D. Rusakov, G. Stephens for permission to modify figures from their original work; and to Profs. T. Freund, Z. Maglóczky, and I. Soltesz for their generous support and advice on his research relevant to the topic of this review over the years.

Conflict of Interest

The author declares no conflict of interest.


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© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Momentum Laboratory of Molecular NeurobiologyInstitute of Experimental Medicine, Hungarian Academy of SciencesBudapestHungary

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