title: Cannabis and Endocannabinoid Signaling in Epilepsy.
abstract: 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.
authors.affiliation: Momentum Laboratory of Molecular Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Szigony u. 43, Budapest, 1083, Hungary. katona@koki.hu.
authors.forename: István
authors.initials: I
authors.lastname: Katona
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002185:Cannabidiol / Q000009:adverse effects / Q000627:therapeutic use*; D063386:Cannabinoid Receptor Agonists / Q000009:adverse effects / Q000627:therapeutic use*; D063388:Endocannabinoids / Q000378:metabolism*; D004827:Epilepsy / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D008385:Marijuana Smoking / Q000009:adverse effects; D064086:Medical Marijuana / Q000009:adverse effects / Q000627:therapeutic use*; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D000927:Anticonvulsants; D063386:Cannabinoid Receptor Agonists; D063388:Endocannabinoids; D064086:Medical Marijuana; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D002185:Cannabidiol
keywords: 2-Arachidonoylglycerol; Anticonvulsant; CB1 cannabinoid receptor; Cannabidiol; Cannabis; Diaclyglycerol lipase-α; Epilepsy; GPR55 receptor; Glutamate; Hippocampus; Metabotropic glutamate receptor; Perisynaptic machinery; Seizure; Synapse; Synaptic circuit-breaker; Δ9-tetrahydrocannabinol