Cannabis in epilepsy: From clinical practice to basic research focusing on the possible role of cannabidivarin.

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“Cannabidivarin (CBDV) and cannabidiol (CBD) have recently emerged among cannabinoids for their potential antiepileptic properties, as shown in several animal models.

We report the case of a patient affected by symptomatic partial epilepsy who used cannabis as self-medication after the failure of countless pharmacological/surgical treatments.

After cannabis administration, a dramatic clinical improvement, in terms of both decrease in seizure frequency and recovery of cognitive functions, was observed, which might parallel high CBDV plasma concentrations.

Our patient’s electroclinical improvement supports the hypothesis that cannabis could actually represent an effective, well-tolerated antiepileptic drug.

Moreover, the experimental data suggest that CBDV may greatly contribute to cannabis anticonvulsant effect through its possible GABAergic action.”

https://www.ncbi.nlm.nih.gov/pubmed/29588939

https://onlinelibrary.wiley.com/doi/abs/10.1002/epi4.12015

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Pharmacological characterization of the cannabinoid receptor 2 agonist, β-caryophyllene on seizure models in mice.

Seizure - European Journal of Epilepsy Home

“Activation of CB1 receptors, produces anticonvulsant effect accompanied by memory disturbance both in animal seizure tests and in patients with epilepsy.

Few reports considered the role of CB2 receptor on seizure susceptibility and cognitive functions. The aim of the present study was to explore the effect of a selective CB2 receptor agonist β-caryophyllene (BCP) in models of seizures and cognition in mice.

CONCLUSION:

Our results suggest that the CB2 receptor agonists might be clinically useful as an adjunct treatment against seizure spread and status epilepticus and concomitant oxidative stress, neurotoxicity and cognitive impairments.”

https://www.ncbi.nlm.nih.gov/pubmed/29547827

http://www.seizure-journal.com/article/S1059-1311(17)30611-8/fulltext

“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.”  http://www.ncbi.nlm.nih.gov/pubmed/23138934

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Cannabis as an anticonvulsant

BMJ Journals“There are records of the cannabis plant being used for medicinal purposes in ancient times, and in the 19th century it was used as an effective anti-epileptic drug (AED) in children.

However, because of its abuse potential, most countries imposed laws restricting its cultivation and use, and this has greatly inhibited research into possible therapeutic uses.

Things are now changing, and cannabis derivatives are now used legally to treat, for example, pain, nausea and spasticity.

The plant contains over 100 biologically active compounds, and recently it has been possible to isolate these and identify the neurochemical mechanisms by which some of them operate: one in particular, cannabidiol”

https://www.ncbi.nlm.nih.gov/pubmed/29449212

http://adc.bmj.com/content/early/2018/02/15/archdischild-2018-314921

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Cannabis for paediatric epilepsy: challenges and conundrums.

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“Research is expanding for the use of cannabidiol as an anticonvulsant drug. The mechanism of cannabidiol in paediatric epilepsy is unclear but is thought to play a role in modulation of synaptic transmission. Evidence for its efficacy in treating epilepsy is limited but growing, with a single pharmaceutical company-funded randomised double-blind controlled trial in children with Dravet syndrome. Progress towards the use of medicinal cannabinoids incorporates a complex interplay of social influences and political and legal reform. Access to unregistered but available cannabidiol in Australia outside of clinical trials and compassionate access schemes is state dependent and will require Therapeutic Goods Administration approval, although the cost may be prohibitive. Further clinical trials are needed to clearly define efficacy and safety, particularly long term.”

https://www.ncbi.nlm.nih.gov/pubmed/29438649

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Do Cannabinoids Confer Neuroprotection Against Epilepsy? An Overview.

Cannabinoid-based medications provide not only relief for specific symptoms, but also arrest or delay of disease progression in patients with pain, multiple sclerosis, and other conditions. Although they also seem to hold potential as anticonvulsant agents, evidence of their efficacy in epilepsy is supported by several evidences.

The data reviewed herein lend support to the notion that the endocannabinoid signalling system plays a key modulation role in the activities subserved by the hippocampus, which is directly or indirectly affected in epilepsy patients.

The notion is supported by a variety of anatomical, electrophysiological, biochemical and pharmacological findings. These data suggest the need for developing novel treatments using compounds that selectively target individual elements of the endocannabinoid signalling system.” https://www.ncbi.nlm.nih.gov/pubmed/29290836

“The data reviewed herein demonstrate that cannabinoids provide neuroprotection against brain excitability. They seem to induce at least partial restoration of neurotransmitter dysfunction, inducing an anticonvulsant effect that may be the biological substrate of the complex neurochemical effects reported in experimental and clinical studies. A large body of data suggests that cannabinoids can be harnessed as antiepileptic agents. Finally, among patients with the Dravet syndrome, cannabidiol resulted in a greater reduction in convulsive-seizure frequency than placebo and was associated with higher rates of adverse events and it might reduce seizure frequency and might have an adequate safety profile in children and young adults with highly treatment-resistant epilepsy.”
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Anticonvulsant Effects of Cannabidiol in Dravet Syndrome

“The Dravet syndrome is a complex childhood epilepsy disorder that is associated with drug-resistant seizures and a high mortality rate. We studied cannabidiol for the treatment of drug-resistant seizures in the Dravet syndrome. Among patients with the Dravet syndrome, cannabidiol resulted in a greater reduction in convulsive-seizure frequency than placebo and was associated with higher rates of adverse events. The importance of this study is that, unlike most other antiseizure medication trials, it assesses a treatment in a specific epilepsy syndrome with a known genetic basis. CBD resulted in a significant decrease of convulsive seizures and seizures of all types in Dravet syndrome, a pharmacoresistant epilepsy known to be associated with high mortality rates.” http://epilepsycurrents.org/doi/10.5698/1535-7597.17.5.281?code=amep-site

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Pharmacological Foundations of Cannabis Chemovars.

“An advanced Mendelian Cannabis breeding program has been developed utilizing chemical markers to maximize the yield of phytocannabinoids and terpenoids with the aim to improve therapeutic efficacy and safety.

Cannabis is often divided into several categories based on cannabinoid content. Type I, Δ9-tetrahydrocannabinol-predominant, is the prevalent offering in both medical and recreational marketplaces. In recent years, the therapeutic benefits of cannabidiol have been better recognized, leading to the promotion of additional chemovars: Type II, Cannabis that contains both Δ9-tetrahydrocannabinol and cannabidiol, and cannabidiol-predominant Type III Cannabis.

While high-Δ9-tetrahydrocannabinol and high-myrcene chemovars dominate markets, these may not be optimal for patients who require distinct chemical profiles to achieve symptomatic relief. Type II Cannabis chemovars that display cannabidiol- and terpenoid-rich profiles have the potential to improve both efficacy and minimize adverse events associated with Δ9-tetrahydrocannabinol exposure. Cannabis samples were analyzed for cannabinoid and terpenoid content, and analytical results are presented via PhytoFacts, a patent-pending method of graphically displaying phytocannabinoid and terpenoid content, as well as scent, taste, and subjective therapeutic effect data.

Examples from the breeding program are highlighted and include Type I, II, and III Cannabis chemovars, those highly potent in terpenoids in general, or single components, for example, limonene, pinene, terpinolene, and linalool. Additionally, it is demonstrated how Type I - III chemovars have been developed with conserved terpenoid proportions. Specific chemovars may produce enhanced analgesia, anti-inflammatory, anticonvulsant, antidepressant, and anti-anxiety effects, while simultaneously reducing sequelae of Δ9-tetrahydrocannabinol such as panic, toxic psychosis, and short-term memory impairment.”

https://www.ncbi.nlm.nih.gov/pubmed/29161743

https://www.thieme-connect.de/DOI/DOI?10.1055/s-0043-122240

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The Role of BK Channels in Antiseizure Action of the CB1 Receptor Agonist ACEA in Maximal Electroshock and Pentylenetetrazole Models of Seizure in Mice.

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“The anticonvulsant effect of cannabinoid compound has been shown in various models of seizure. On the other hand, there are controversial findings about the role of large conductance calcium-activated potassium (BK) channels in the pathogenesis of epilepsy. Also, there is no data regarding the effect of co-administration of cannabinoid type 1 (CB1) receptor agonists and BK channels antagonists in the acute models of seizure in mice.

In this study, the effect of arachidonyl-2′-chloroethylamide (ACEA), a CB1 receptor agonist, and a BK channel antagonist, paxilline, either alone or in combination was investigated.

Both pentylenetetrazole (PTZ) and maximal electroshock (MES) acute models of seizure were used to evaluate the protective effects of drugs. Mice were randomly selected in different groups: (i) control group; (ii) groups that received different doses of either paxilline or ACEA; and (iii) groups that received combinations of ACEA and paxillin at different doses. In MES model, prevention of hindlimb tonic extension (HLTE) was considered as protective effect. In PTZ model, the required dose of PTZ (mg/kg) to induce tonic-clonic seizure with loss of righting reflex was considered as seizure threshold. In PTZ model, while administration of ACEA per se (5 and 10 mg/kg) caused protective effect against seizure; however, co-administration of ACEA and ineffective doses of paxilline attenuated the antiseizure effects of paxilline. In MES model, while pretreatment by ACEA showed protective effects against seizure; however, co-administration of paxilline and ACEA caused an antagonistic interaction for their antiseizure properties.

Our results showed a protective effect of ACEA in both PTZ and MES acute models of seizure. This effect was attenuated by co-administration with paxilline, suggesting the involvement of BK channels in antiseizure activity of ACEA.”

https://www.ncbi.nlm.nih.gov/pubmed/28979317

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The potential role of cannabinoids in epilepsy treatment.

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“Epilepsy is one of the world’s oldest recognized and prevalent neurological diseases. It has a great negative impact on patients’ quality of life (QOL) as a consequence of treatment resistant seizures in about 30% of patients together with drugs’ side effects and comorbidities. Therefore, new drugs are needed and cannabinoids, above all cannabidiol, have recently gathered attention.

This review summarizes the scientific data from human and animal studies on the major cannabinoids which have been of interest in the treatment of epilepsy, including drugs acting on the endocannabinoid system.

Despite the fact that cannabis has been used for many purposes over 4 millennia, the development of drugs based on cannabinoids has been very slow. Only recently, research has focused on their potential effects and CBD is the first treatment of this group with clinical evidence of efficacy in children with Dravet syndrome; moreover, other studies are currently ongoing to confirm its effectiveness in patients with epilepsy.

On the other hand, it will be of interest to understand whether drugs acting on the endocannabinoid system will be able to reach the market and prove their known preclinical efficacy also in patients with epilepsy.”

https://www.ncbi.nlm.nih.gov/pubmed/28845714   http://www.tandfonline.com/doi/abs/10.1080/14737175.2017.1373019

 

“The role of cannabinoids and endocannabinoid system in the treatment of epilepsy. Cannabis has been used for thousands of years in the treatment of various diseases. Cannabinoids have been shown in preliminary animal model studies and in studies of patients with epilepsy to have antiepileptic activity. ” https://www.degruyter.com/view/j/joepi.ahead-of-print/joepi-2015-0034/joepi-2015-0034.xml
“Phytocannabinoids produce anticonvulsant effects through the endocannabinoid system, with few adverse effects.”
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Anticonvulsant effect of cannabidiol in the pentylenetetrazole model: Pharmacological mechanisms, electroencephalographic profile, and brain cytokine levels.

“Cannabidiol (CBD), the main nonpsychotomimetic compound from Cannabis sativa, inhibits experimental seizures in animal models and alleviates certain types of intractable epilepsies in patients.

Here we tested the hypothesis that CBD anticonvulsant mechanisms are prevented by cannabinoid (CB1 and CB2) and vanilloid (TRPV1) receptor blockers. We also investigated its effects on electroencephalographic (EEG) activity and hippocampal cytokines in the pentylenetetrazole (PTZ) model.

Pretreatment with CBD (60mg/kg) attenuated seizures induced by intraperitoneal, subcutaneous, and intravenous PTZ administration in mice. The effects were reversed by CB1, CB2, and TRPV1 selective antagonists (AM251, AM630, and SB366791, respectively). Additionally, CBD delayed seizure sensitization resulting from repeated PTZ administration (kindling). This cannabinoid also prevented PTZ-induced EEG activity and interleukin-6 increase in prefrontal cortex.

In conclusion, the robust anticonvulsant effects of CBD may result from multiple pharmacological mechanisms, including facilitation of endocannabinoid signaling and TRPV1 mechanisms. These findings advance our understanding on CBD inhibition of seizures, EEG activity, and cytokine actions, with potential implications for the development of new treatments for certain epileptic syndromes.”

https://www.ncbi.nlm.nih.gov/pubmed/28821005

http://www.epilepsybehavior.com/article/S1525-5050(17)30322-0/fulltext

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