Effect of Cannabidiol on Drop Seizures in the Lennox-Gastaut Syndrome.

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“Cannabidiol has been used for treatment-resistant seizures in patients with severe early-onset epilepsy.

We investigated the efficacy and safety of cannabidiol added to a regimen of conventional antiepileptic medication to treat drop seizures in patients with the Lennox-Gastaut syndrome, a severe developmental epileptic encephalopathy.

Among children and adults with the Lennox-Gastaut syndrome, the addition of cannabidiol at a dose of 10 mg or 20 mg per kilogram per day to a conventional antiepileptic regimen resulted in greater reductions in the frequency of drop seizures than placebo.”

https://www.ncbi.nlm.nih.gov/pubmed/29768152

https://www.nejm.org/doi/10.1056/NEJMoa1714631

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Reefer to the Rescue: The Dope on Cannabidiol as a Multi-Symptom Panacea for Dravet Syndrome

American Epilepsy Society

“Dravet syndrome (DS) is a debilitating developmental disorder typified by severe seizures and delayed onset of psychomotor deficits.

In addition to increasing the risk for sudden unexpected death in epilepsy (SUDEP), the medically refractory status epilepticus in DS can be life-threatening, which makes it crucial to identify drugs to reduce seizures.

The quest for a viable drug to limit seizures in DS has intersected with the recent excitement over the potential use of cannabinoids as antiepileptic agents, leading to extensive anecdotal reports of the potential for cannabinoids to limit seizures in DS

Cannabinoids are active derivatives of the marijuana plant, Cannabis sativa.

The study reveals a strong preclinical basis for the use of CBD in DS. They find that CBD pre-treatment reduces both duration and severity of thermally-induced behavioral seizures.

In conclusion, Kaplan and colleagues provide the first preclinical demonstration that CBD may help alleviate seizures in a mouse model of DS validating the translational potential of CBD in patients with DS.

The demonstration that CBD improves deficits in social interactions in DS launches an exciting therapeutic possibility of alleviating behavioral impairments that persist beyond the seizures and pave the way for mechanistic studies that could positively impact treatment of autism spectrum disorders.”

http://epilepsycurrents.org/doi/10.5698/1535-7597.18.2.118?code=amep-site

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Antiepileptogenic Effect of Subchronic Palmitoylethanolamide Treatment in a Mouse Model of Acute Epilepsy.

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“Research on the antiepileptic effects of (endo-)cannabinoids has remarkably progressed in the years following the discovery of fundamental role of the endocannabinoid (eCB) system in controlling neural excitability. Moreover, an increasing number of well-documented cases of epilepsy patients exhibiting multi-drug resistance report beneficial effects of cannabis use.

Pre-clinical and clinical research has increasingly focused on the antiepileptic effectiveness of exogenous administration of cannabinoids and/or pharmacologically induced increase of eCBs such as anandamide (also known as arachidonoylethanolamide [AEA]). Concomitant research has uncovered the contribution of neuroinflammatory processes and peripheral immunity to the onset and progression of epilepsy.

Accordingly, modulation of inflammatory pathways such as cyclooxygenase-2 (COX-2) was pursued as alternative therapeutic strategy for epilepsy. Palmitoylethanolamide (PEA) is an endogenous fatty acid amide related to the centrally and peripherally present eCB AEA, and is a naturally occurring nutrient that has long been recognized for its analgesic and anti-inflammatory properties.

Neuroprotective and anti-hyperalgesic properties of PEA were evidenced in neurodegenerative diseases, and antiepileptic effects in pentylenetetrazol (PTZ), maximal electroshock (MES) and amygdaloid kindling models of epileptic seizures. Moreover, numerous clinical trials in chronic pain revealed that PEA treatment is devoid of addiction potential, dose limiting side effects and psychoactive effects, rendering PEA an appealing candidate as antiepileptic compound or adjuvant.

In the present study, we aimed at assessing antiepileptic properties of PEA in a mouse model of acute epileptic seizures induced by systemic administration of kainic acid (KA).

Here, we demonstrate that subchronic administration of PEA significantly alleviates seizure intensity, promotes neuroprotection and induces modulation of the plasma and hippocampal eCB and eiC levels in systemic KA-injected mice.”

https://www.ncbi.nlm.nih.gov/pubmed/29593494

https://www.frontiersin.org/articles/10.3389/fnmol.2018.00067/full

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

 Epilepsia Open banner

“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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Cannabidiol exerts antiepileptic effects by restoring hippocampal interneuron functions in a temporal lobe epilepsy model.

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“A non-psychoactive phytocannabinoid, cannabidiol (CBD), shows promising results as an effective potential antiepileptic drug in some forms of refractory epilepsy.

In an attempt to understand the mechanisms by which CBD exerts its anti-seizure effects, we investigated the effects of CBD at synaptic connections, and the intrinsic membrane properties of hippocampal CA1 pyramidal cells and two major inhibitory interneurons: fast spiking, parvalbumin -expressing (PV) and adapting, cholecystokinin-expressing (CCK) interneurons.

CONCLUSIONS & IMPLICATIONS:

In conclusion, our data suggest CBD restores excitability and morphological impairment in epileptic models to pre-epilepsy control levels through multiple mechanisms to restore normal network function.”

https://www.ncbi.nlm.nih.gov/pubmed/29574880

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.14202

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Prospects of Cannabidiol for Easing Status Epilepticus-Induced Epileptogenesis and Related Comorbidities.

Molecular Neurobiology

“The hippocampus is one of the most susceptible regions in the brain to be distraught with status epilepticus (SE) induced injury. SE can occur from numerous causes and is more frequent in children and the elderly population.

Administration of a combination of antiepileptic drugs can abolish acute seizures in most instances of SE but cannot prevent the morbidity typically seen in survivors of SE such as cognitive and mood impairments and spontaneous recurrent seizures. This is primarily due to the inefficiency of antiepileptic drugs to modify the evolution of SE-induced initial precipitating injury into a series of epileptogenic changes followed by a state of chronic epilepsy.

Chronic epilepsy is typified by spontaneous recurrent seizures, cognitive dysfunction, and depression, which are associated with persistent inflammation, significantly waned neurogenesis, and abnormal synaptic reorganization. Thus, alternative approaches that are efficient not only for curtailing SE-induced initial brain injury, neuroinflammation, aberrant neurogenesis, and abnormal synaptic reorganization but also for thwarting or restraining the progression of SE into a chronic epileptic state are needed.

In this review, we confer the promise of cannabidiol, an active ingredient of Cannabis sativa, for preventing or easing SE-induced neurodegeneration, neuroinflammation, cognitive and mood impairments, and the spontaneous recurrent seizures.”

https://www.ncbi.nlm.nih.gov/pubmed/29372545

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Cannabidiol reduced frequency of convulsive seizures in drug resistant Dravet syndrome.

BMJ Journals

“Study design

Design: Multinational double-blinded placebo-controlled trial. Patients randomised in 1:1 ratio to receive cannabidiol or placebo, in addition to stable antiepileptic treatment regime.

Study question

Setting: Twenty-three centres in Europe and USA.

 Patients: Patients aged 2 years to 18 years with established diagnosis of Dravet syndrome having at least four convulsive seizures during the 28-day baseline period despite regular antiepileptic medication.

Intervention: Adjunctive cannabidiol or placebo oral solution at 20 mg per kilogram of body weight per day.

Primary outcome: Percentage change in median frequency of convulsive seizures per month.

Follow-up period: Outcome measured over a 14-week treatment period in comparison to a 4-week baseline period.

Patient follow-up: One hundred and eight (90%) completed the trial: 85% (52/61) in the cannabidiol group and …”

http://ep.bmj.com/content/early/2017/09/22/archdischild-2017-313700

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An Overview on Medicinal Chemistry of Synthetic and Natural Derivatives of Cannabidiol.

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“Cannabidiol (CBD) has been traditionally used in Cannabis-based preparation, however historically, it has received far less interest as a single drug than the other components of Cannabis. Currently, CBD generates considerable interest due to its beneficial neuroprotective, antiepileptic, anxiolytic, antipsychotic, and anti-inflammatory properties. Therefore, the CBD scaffold becomes of increasing interest for medicinal chemists. This review provides an overview of the chemical structure of natural and synthetic CBD derivatives including the molecular targets associated with these compounds. A clear identification of their biological targets has been shown to be still very challenging.”  https://www.ncbi.nlm.nih.gov/pubmed/28701957

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Neurological aspects of medical use of cannabidiol.

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“Cannabidiol (CBD) is among the major secondary metabolites of Cannabis devoid of the delta-9-tetra-hydrocannabinol psychoactive effects. It is a resorcinol-based compound with a broad spectrum of potential therapeutic properties, including neuroprotective effects in numerous pathological conditions. CBD neuroprotection is due to its antioxidant and antiinflammatory activi-ties and the modulation of a large number of brain biological targets (receptors, channels) involved in the development and maintenance of neurodegenerative diseases.

OBJECTIVE:

Aim of the present review was to describe the state of art about the pre-clinical research, the potential use and, when existing, the clinical evidence related to CBD in the neurological field.

RESULTS:

Laboratory and clinical studies on the potential role of CBD in Parkinson’s disease (PD), Alzheimer’s disease (AD), multiple sclerosis (MS), Huntington’s disease (HD), amyotrophic lateral sclerosis ALS), cerebral ischemia, were examined.

CONCLUSIONS:

Pre-clinical evidence largely shows that CBD can produce beneficial effects in AD, PD and MS patients, but its employment for these disorders needs further confirmation from well designed clinical studies. CBD pre-clinical demonstration of antiepileptic activity is supported by recent clinical studies in human epileptic subjects resistant to standard antiepileptic drugs showing its potential use in children and young adults affected by refractory epilepsy. Evidence for use of CBD in PD is still not supported by sufficient data whereas only a few studies including a small number of patients are available.”

https://www.ncbi.nlm.nih.gov/pubmed/28412918

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An Australian nationwide survey on medicinal cannabis use for epilepsy: History of antiepileptic drug treatment predicts medicinal cannabis use.

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“Epilepsy Action Australia conducted an Australian nationwide online survey seeking opinions on and experiences with the use of cannabis-based products for the treatment of epilepsy. The survey was promoted via the Epilepsy Action Australia’s main website, on their Facebook page, and by word of mouth. The survey consisted of 39 questions assessing demographics, clinical factors, including diagnosis and seizure types, and experiences with and opinions towards cannabis use in epilepsy. A total of 976 responses met the inclusion criteria.

Results show that 15% of adults with epilepsy and 13% of parents/guardians of children with epilepsy were currently using, or had previously used, cannabis products to treat epilepsy. Of those with a history of cannabis product use, 90% of adults and 71% of parents reported success in reducing seizure frequency after commencing cannabis products. The main reasons for medicinal cannabis use were to manage treatment-resistant epilepsy and to obtain a more favorable side-effect profile compared to standard antiepileptic drugs.

The number of past antiepileptic drugs tried was a significant predictor of medicinal cannabis use in both adults and children with epilepsy. Fifty-six percent of adults with epilepsy and 62% of parents/guardians of children with epilepsy expressed willingness to participate in clinical trials of cannabinoids. This survey provides insight into the use of cannabis products for epilepsy, in particular some of the likely factors influencing use, as well as novel insights into the experiences of and attitudes towards medicinal cannabis in people with epilepsy in the Australian community.”

https://www.ncbi.nlm.nih.gov/pubmed/28238865

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