Adjunctive Cannabidiol in Patients with Dravet Syndrome: A Systematic Review and Meta-Analysis of Efficacy and Safety.

 “Dravet syndrome (DS) is one of the most severe forms of drug-resistant epilepsy and available interventions fail to control seizures in most patients.

Cannabidiol (CBD) is the first in a new class of antiepileptic drugs with a distinctive chemical structure and mechanism of action.

The aim of this systematic review was to evaluate the efficacy and safety of CBD as adjunctive treatment for seizures in patients with DS using meta-analytical techniques.

CONCLUSIONS:

Adjunctive CBD resulted in a greater reduction in convulsive seizure frequency than placebo and a higher rate of AEs in patients with DS presenting with seizures uncontrolled by concomitant antiepileptic therapy.”

https://www.ncbi.nlm.nih.gov/pubmed/32040850

https://link.springer.com/article/10.1007%2Fs40263-020-00708-6

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Abrupt withdrawal of cannabidiol (CBD): A randomized trial.

Cover image volume 103, Issue “The rationale of this study was to assess occurrence of withdrawal symptoms induced by abrupt cessation of cannabidiol (CBD) after prolonged administration in healthy volunteers.

CONCLUSION:

In healthy volunteers, no evidence of withdrawal syndrome was found with abrupt discontinuation of short-term treatment with CBD.”

https://www.ncbi.nlm.nih.gov/pubmed/32036242

“There was no evidence of a physical withdrawal syndrome after abrupt cessation of CBD.”

https://www.epilepsybehavior.com/article/S1525-5050(19)31116-3/fulltext

Cannabidiol, a safe and non-psychotropic ingredient of the marijuana plant Cannabis sativa” https://www.ncbi.nlm.nih.gov/pubmed/19690824

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Medical Cannabis in Children.

 Logo of rmmj“The use of medical cannabis in children is rapidly growing.

While robust evidence currently exists only for pure cannabidiol (CBD) to treat specific types of refractory epilepsy, in most cases, artisanal strains of CBD-rich medical cannabis are being used to treat children with various types of refractory epilepsy or irritability associated with autism spectrum disorder (ASD).

Other common pediatric disorders that are being considered for cannabis treatment are Tourette syndrome and spasticity.

As recreational cannabis use during youth is associated with serious adverse events and medical cannabis use is believed to have a relatively high placebo effect, decisions to use medical cannabis during childhood and adolescence should be made with caution and based on evidence.

This review summarizes the current evidence for safety, tolerability, and efficacy of medical cannabis in children with epilepsy and in children with ASD. The main risks associated with use of Δ9-tetrahydrocannabinol (THC) and CBD in the pediatric population are described, as well as the debate regarding the use of whole-plant extract to retain a possible “entourage effect” as opposed to pure cannabinoids that are more standardized and reproducible.”

https://www.ncbi.nlm.nih.gov/pubmed/32017680

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Medical Cannabis for Intractable Epilepsy in Childhood: A Review.

 Logo of rmmj“In recent years, cannabis has been gaining increasing interest in both the medical research and clinical fields, with regard to its therapeutic effects in various disorders. One of the major fields of interest is its role as an anticonvulsant for refractory epilepsy, especially in the pediatric population. This paper presents and discusses the current accumulated knowledge regarding artisanal cannabis and Epidiolex®, a United States Food and Drug Administration (FDA)-approved pure cannabidiol (CBD), in epilepsy management in pediatrics, by reviewing the literature and raising debate regarding further research directions.”

https://www.ncbi.nlm.nih.gov/pubmed/32017679

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The anticonvulsant effects of cannabidiol in experimental models of epileptic seizures: from behavior and mechanisms to clinical insights.

Neuroscience & Biobehavioral Reviews“Epilepsy is a neurological disorder characterized by the presence of seizures and neuropsychiatric comorbidities. Despite the number of antiepileptic drugs, one-third of patients did not have their seizures under control, leading to pharmacoresistance epilepsy.

Cannabis sativa has been used since ancient times in Medicine for the treatment of many diseases, including convulsive seizures.

In this context, Cannabidiol (CBD), a non-psychoactive phytocannabinoid present in Cannabis, has been a promising compound for treating epilepsies due to its anticonvulsant properties in animal models and humans, especially in pharmacoresistant patients. In this review, we summarize evidence of the CBD anticonvulsant activities present in a great diversity of animal models. Special attention was given to behavioral CBD effects and its translation to human epilepsies.

CBD anticonvulsant effects are associated with a great variety of mechanisms of action such as endocannabinoid and calcium signaling. CBD has shown effectiveness in the clinical scenario for epilepsies, but its effects on epilepsy-related comorbidities are scarce even in basic research. More detailed and complex behavioral evaluation about CBD effects on seizures and epilepsy-related comorbidities are required.”

https://www.ncbi.nlm.nih.gov/pubmed/31954723

“CBD presents anticonvulsant behavioral effects in animal models of epilepsy. CBD induces neuroprotection in animal models of epileptic seizures. Multiple mechanisms of action are associated to CBD anticonvulsant effects. Animal models support CBD therapeutic use for epilepsies treatment.”

https://www.sciencedirect.com/science/article/pii/S014976341931067X?via%3Dihub

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Source of cannabinoids: what is available, what is used, and where does it come from?

John Libbey Eurotext“Cannabis sativa L. is an ancient medicinal plant wherefrom over 120 cannabinoids are extracted. In the past two decades, there has been increasing interest in the therapeutic potential of cannabis-based treatments for neurological disorders such as epilepsy, and there is now evidence for the medical use of cannabis and its effectiveness for a wide range of diseases.

Cannabinoid treatments for pain and spasticity in patients with multiple sclerosis (Nabiximols) have been approved in several countries. Cannabidiol (CBD), in contrast to tetra-hydro-cannabidiol (THC), is not a controlled substance in the European Union, and over the years there has been increasing use of CBD-enriched extracts and pure CBD for seizure disorders, particularly in children. No analytical controls are mandatory for CBD-based products and a pronounced variability in CBD concentrations in commercialized CBD oil preparations has been identified.

Randomized controlled trials of plant-derived CBD for treatment of Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) have provided evidence of anti-seizure effects, and in June 2018, CBD was approved by the Food and Drug Administration as an add-on antiepileptic drug for patients two years of age and older with LGS or DS. Medical cannabis, with various ratios of CBD and THC and in different galenic preparations, is licensed in many European countries for several indications, and in July 2019, the European Medicines Agency also granted marketing authorisation for CBD in association with clobazam, for the treatment of seizures associated with LGS or DS.

The purpose of this article is to review the availability of cannabis-based products and cannabinoid-based medicines, together with current regulations regarding indications in Europe (as of July 2019). The lack of approval by the central agencies, as well as social and political influences, have led to significant variation in usage between countries.”

https://www.ncbi.nlm.nih.gov/pubmed/31941643

https://www.jle.com/fr/revues/epd/e-docs/source_of_cannabinoids_what_is_available_what_is_used_and_where_does_it_come_from__316043/article.phtml

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The role of cannabinoids in epilepsy treatment: a critical review of efficacy results from clinical trials.

Image result for Epileptic Disorders journal “CBD was shown to have anti-seizure activity based on in vitro and in vivo models.

However, several reports of small series or case reports of the use of cannabis extracts in epilepsy yielded contradictory results and the efficacy of cannabis use in patients with epilepsy have also been inconclusive.

In 2013, the first Phase 1 trial for a purified form of CBD (Epidiolex/Epidyolex; >99% CBD), developed by GW Pharma, showed some efficacy signals and subsequently, a comprehensive program on the efficacy and tolerability of this compound for the treatment of drug-resistant epilepsies was initiated.

Results of these trials led to the FDA and EMA approval respectively in 2018 and 2019 for the treatment of seizures associated with two rare epilepsies: Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) in patients two years of age and older.

Thus, CBD became the first FDA-approved purified drug substance derived from cannabis and also the first FDA-approved drug for the treatment of seizures in DS.

We detail the clinical studies using purified CBD (Epidiolex/Epidyolex), including the first open interventional exploratory study and Randomized Control Ttrials for DS and LGS.”

https://www.ncbi.nlm.nih.gov/pubmed/31916540

https://www.jle.com/fr/revues/epd/e-docs/the_role_of_cannabinoids_in_epilepsy_treatment_a_critical_review_of_efficacy_results_from_clinical_trials_316030/article.phtml

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The proposed mechanism of action of CBD in epilepsy.

Image result for Epileptic Disorders journal“Highly purified cannabidiol (CBD) (approved as Epidiolex® in the United States) has demonstrated efficacy with an acceptable safety profile in patients with Lennox-Gastaut or Dravet syndrome in four randomized controlled trials.

While the mechanism of action of CBD underlying the reduction of seizures in humans is unknown, CBD possesses affinity for multiple targets, across a range of target classes, resulting in functional modulation of neuronal excitability, relevant to the pathophysiology of many disease types, including epilepsy.

Here we present the pharmacological data supporting the role of three such targets, namely Transient receptor potential vanilloid-1 (TRPV1), the orphan G protein-coupled receptor-55 (GPR55) and the equilibrative nucleoside transporter 1 (ENT-1).”

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Efficacy and Tolerance of Synthetic Cannabidiol for Treatment of Drug Resistant Epilepsy.

Image result for frontiers in neurology“Controlled and open label trials have demonstrated efficacy of cannabidiol for certain epileptic encephalopathies.

However, plant derived cannabidiol products have been used almost exclusively. Efficacy of synthetically derived cannabidiol has not been studied before.

The objective of this study was to evaluate tolerability and efficacy of synthetic cannabidiol in patients with pharmacoresistant epilepsy.

Efficacy and tolerance in our study of synthetic CBD treatment in pharmacoresistant epilepsy is similar to open label studies using plant derived CBD.

Regarding economic and ecological aspects, synthetic cannabidiol might be a reasonable alternative to plant derived cannabidiol.”

https://www.ncbi.nlm.nih.gov/pubmed/31920934

“Over the last decade, the therapeutic use of cannabidiol (CBD) in intractable epilepsies has increased considerably. Its anticonvulsant properties have been shown in several animal models for acute and chronic epilepsy.

Recent randomized, controlled trials have demonstrated that CBD is superior to placebo in seizure reduction in children with Dravet syndrome and patients with Lennox-Gastaut syndrome. In addition, open label studies indicate that cannabidiol has anticonvulsive properties in a broader range of epilepsy syndromes and etiologies.

In summary, the results of this study provide class III evidence of efficacy and safety of synthetic cannabidiol in children and adults with pharmacoresistant epilepsy. Additional studies investigating efficacy and tolerance of synthetic CBD in larger cohorts are needed.”

https://www.frontiersin.org/articles/10.3389/fneur.2019.01313/full

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Efficacy of cannabidiol in subjects with refractory epilepsy relative to concomitant use of clobazam.

Epilepsy Research“To evaluate the efficacy of open-label, highly purified cannabidiol (CBD, Epidiolex®) in treating refractory epilepsy relative to the concomitant use of clobazam (CLB) as well as the clinical implications of changes in CLB and norclobazam (nCLB) levels.”

“With or without concomitant CLB, CBD may be effective in reducing seizure frequency.”   https://www.sciencedirect.com/science/article/abs/pii/S0920121119303778?via%3Dihub

“With or without concomitant CLB, CBD can be effective in reducing seizure frequency. “

https://www.ncbi.nlm.nih.gov/pubmed/31923763

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