Category Archives: Epilepsy

Cannabidiol Anticonvulsant Effect Is Mediated by the PI3Kγ Pathway

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Neuropharmacology“The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/Akt)/mechanistic target of rapamycin (mTOR) signaling pathway has been associated with several pathologies in the central nervous system (CNS), including epilepsy. There is evidence supporting the hypothesis that the PI3Kγ signaling pathway may mediate the powerful anticonvulsant properties associated with the cannabinoidergic system.

This work aims to investigate if the anticonvulsant and neuroprotective effects of cannabidiol (CBD) are mediated by PI3Kγ.

CDB increased latency and reduced the severity of pilocarpine-induced behavioral seizures, as well as prevented postictal changes, such as neurodegeneration, microgliosis and astrocytosis, in WT animals, but not in PI3Kγ-/-. CBD in vivo effects were abolished by pharmacological inhibition of cannabinoid receptor or mTOR. In vitro, PI3Kγ inhibition or deficiency also changed CBD protection observed in glutamate-induced cell death assay. Thus, we suggest that the modulation of PI3K/mTOR signaling pathway is involved in the anticonvulsant and neuroprotective effects of CBD.

These findings are important not only for the elucidation of the mechanisms of action of CBD, which are currently poorly understood, but also to allow the prediction of therapeutic and side effects, ensuring efficacy and safety in the treatment of patients with epilepsy.”

https://pubmed.ncbi.nlm.nih.gov/32574650/

“CBD is anticonvulsant in a model of pilocarpine-induced behavioral seizures. CB1 receptor mediates the effects of CBD. PI3Kγ pathway mediates the anticonvulsant neuroprotective effects of CBD.”

https://www.sciencedirect.com/science/article/abs/pii/S0028390820302240?via%3Dihub

Current Application of Cannabidiol (CBD) in the Management and Treatment of Neurological Disorders

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SpringerLink“Cannabidiol (CBD), which is nonintoxicating pharmacologically relevant constituents of Cannabis, demonstrates several beneficial effects. It has been found to have antioxidative, anti-inflammatory, and neuroprotective effects. As the medicinal use of CBD is gaining popularity for treatment of various disorders, the recent flare-up of largely unproven and unregulated cannabis-based preparations on medical therapeutics may have its greatest impact in the field of neurology. Currently, as lot of clinical trials are underway, CBD demonstrates remarkable potential to become a supplemental therapy in various neurological conditions. It has shown promise in the treatment of neurological disorders such as anxiety, chronic pain, trigeminal neuralgia, epilepsy, and essential tremors as well as psychiatric disorders. While recent FDA-approved prescription drugs have demonstrated safety, efficacy, and consistency enough for regulatory approval in spasticity in multiple sclerosis (MS) and in Dravet and Lennox-Gastaut Syndromes (LGS), many therapeutic challenges still remain. In the current review, the authors have shed light on the application of CBD in the management and treatment of various neurological disorders.”

https://pubmed.ncbi.nlm.nih.gov/32556748/

https://link.springer.com/article/10.1007%2Fs10072-020-04514-2

Plant Derived Versus Synthetic Cannabidiol: Wishes and Commitment of Epilepsy Patients

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 cannabidiol | www.thctotalhealthcare.com“A special component of cannabis, cannabidiol (CBD), is currently in the focus of epilepsy treatment and research. In this context, we investigated patients’ expectations and preferences pertaining to plant-derived versus synthetic formulation of cannabidiol, as well as their willingness to get this treatment.

Methods: One hundred and four of 153 patients with different forms of epilepsy (54 % female, mean age 40 ± 16 yrs.) responded to the survey. The survey consisted of 8 questions addressing expectations of and concerns towards CBD treatment, preferences of plant-derived versus synthetic CBD, estimated monthly costs, and willingness to buy CBD at one’s own expense.

Results: The majority (73 %) of the responding epilepsy patients wished to receive plant-derived CBD; 5 % preferred synthetic CBD. Reasons for this choice were botanic origin, lack of chemistry, and the assumption of fewer and less dangerous side effects. Eighty-two percent of the patients estimated the monthly costs of CBD treatment to be below €500. Using the willingness-to-pay approach to assess the commitment of patients, 68 % could imagine buying the drug themselves. Fifty-three percent of these would be willing to pay up to €100, 40 % €100 to €200, and another 7 % €200 to €500 per month.

Conclusion: There is an overwhelming preference towards plant-derived cannabidiol in epilepsy patients, driven by the idea of organic substances being safer and better tolerated than synthetic. The willingness-to-pay approach reflects the high burden and pressure of uncontrolled epilepsy and the expectation of relief. Non-realistic ideas of pricing as well as what patients would be willing and able to pay confirm this perception.”

https://pubmed.ncbi.nlm.nih.gov/32554292/

“Epilepsy patients preferred plant-derived cannabidiol to synthetic cannabidiol.”

https://www.seizure-journal.com/article/S1059-1311(20)30175-8/pdf

Effectiveness of Cannabidiol in a Prospective Cohort of Children With Drug-Resistant Epileptic Encephalopathy in Argentina

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“We report our preliminary findings regarding effectiveness, safety, and tolerability of cannabidiol (CBD) added to antiepileptic therapy in a cohort of children with drug-resistant epileptic encephalopathies (EEs) with a mean follow-up of 8.5 months (range, 3-12 months).

Methods: A prospective cohort study was designed with the aim of assessing the effectiveness, safety, and tolerability of the addition of CBD to standard antiseizure medications (ASMs) in children with drug-resistant EE enrolled at a single center (Neurology Department, Hospital de Pediatría “Juan P. Garrahan”, Buenos Aires, Argentina).

Results: Fifty patients were enrolled between October 2018 and October 2019, 49 of whom had a follow-up of at least 3 months at the time this interim analysis was performed. Mean age at enrollment was 10.5 years (range 2-16). Median age at first seizure was 7 months. Up to the last visit of each patient (follow-up 3-12 months) 39/49 children (80 %) had responded to treatment with a decrease in seizure frequency. Overall, 77.6 % of the patients had a seizure reduction of at least 25 %, 73.5 % had a ≥ 50 % reduction, and 49 % had a ≥ 75 % reduction. Mean monthly seizure frequency was reduced from 959 to 381 (median decrease from 299 to 102, range, 38-1900; median decrease 66 %, p < 0.001). All adverse effects were mild or moderate. The most common adverse effect was drowsiness (in 32 %), usually reversed by adjusting clobazam dose (in 12 children).

Conclusion: In children with drug-resistant EEs, CBD oil as an adjuvant therapy to antiepileptic therapy seems safe, well tolerated, and effective.”

https://pubmed.ncbi.nlm.nih.gov/32544657/

“Cannibidiol showed good effectiveness, with a ≥ 50 % reduction in seizure frequency in 73.5 % of the patients. Good results were obtained in patients with Lennox-Gastaut and Dravet syndromes. In epileptic encephalopathies other than Lennox-Gastaut results were also good. Cannabidiol showed good safety and tolerability as all adverse effects were mild or moderate.”

https://www.seizure-journal.com/article/S1059-1311(20)30167-9/pdf

Does Cannabidiol Have Antiseizure Activity Independent of Its Interactions With Clobazam? An Appraisal of the Evidence From Randomized Controlled Trials

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 Epilepsia“Four pivotal randomized placebo-controlled trials have demonstrated that adjunctive therapy with cannabidiol (CBD) improves seizure control in patients with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS).

Between 47% and 68% of patients allocated to CBD treatment in these trials were receiving clobazam (CLB), which shows complex interactions with CBD resulting, in particular, in a 3.4- to 5-fold increase in plasma concentration of the active metabolite norclobazam. This raises concern as to the role played by these interactions in determining the reduction in seizure frequency in CBD-treated patients, and the question of whether CBD per se has clinically evident antiseizure effects.

We appraised available evidence on the clinical consequences of the CBD-CLB interaction, focusing on subgroup analyses of seizure outcomes in patients on and off CLB comedication in the pivotal CBD trials, as provided by the European Medicines Agency Public Assessment Report.

Evaluation of the results of individual trials clearly showed that improvement in seizure control over placebo was greater when CBD was added on to CLB than when it was added on to other medications. However, seizure control was also improved in patients off CLB, and despite the small sample size the difference vs placebo was statistically significant for the 10 mg/kg/d dose in one of the two LGS trials.

Stronger evidence for an antiseizure effect of CBD independent of an interaction with CLB emerges from meta-analyses of seizure outcomes in the pooled population of LGS and DS patients not receiving CLB comedication.

Although these results need to be interpreted taking into account methodological limitations, they provide the best clinical evidence to date that CBD exerts therapeutic effects in patients with epilepsy that are independent of its interaction with CLB. Greater antiseizure effects, and a greater burden of adverse effects, are observed when CBD is combined with CLB.”

https://pubmed.ncbi.nlm.nih.gov/32452568/

https://onlinelibrary.wiley.com/doi/abs/10.1111/epi.16542

Investigation of cannabidiol gastro retentive tablets based on regional absorption of cannabinoids in rats.

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European Journal of Pharmaceutics and Biopharmaceutics“The cannabis plant has been widely researched for many therapeutic indications and found to be effective in many chronic conditions such as epilepsy, neuropathic or chronic pain and more. However, biased opinion against compounds of the plant, regulatory as well as compounding challenges have led to very few approved medicinal products. Those formulations which are approved are dosed several times a day, creating an unmet need for controlled release (CR) formulations of cannabinoids. Conventional CR formulations rely on prolonged absorption including the colon. The purpose of this work is to investigate regional absorption of major cannabinoids THC and CBD from the colon and develop a suitable CR formulation. As hypothesized by researchers, THC and CBD have poor absorption from the colon compared to small intestine, suggesting that these compounds have a narrow absorption window. The suggested formulation examined in-vitro was a floating gastro retentive tablet based on egg albumin matrix, gas generating agents and surfactants. In-vivo investigation of CBD containing formulation in the freely moving rat model proved a prolonged absorption phase with a substantial increase in bioavailability compared to CBD solution. The findings of this paper answer a crucial question regarding potential application of CR dosage forms for cannabinoids and shed light on the regional intestinal absorption of these compounds. Ultimately, these results cement the way for future development of cannabinoid gastro retentive dosage forms.”

https://www.ncbi.nlm.nih.gov/pubmed/32422168

https://www.sciencedirect.com/science/article/abs/pii/S0939641120301375?via%3Dihub

Economic Evaluation of Cannabinoid Oil for Dravet Syndrome: A Cost-Utility Analysis.

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SpringerLink “Cannabinoid oils are being increasingly used to treat Dravet syndrome, yet the long-term costs and outcomes of this approach are unknown. Thus, we examined the cost effectiveness of cannabinoid oil as an adjunctive treatment (added to clobazam and valproate), compared with adjunctive stiripentol or with clobazam and valproate alone, for the treatment of Dravet syndrome in children.

METHODS:

We performed a probabilistic cost-utility analysis from the perspective of the Canadian public health care system, comparing cannabinoid oil and stiripentol (both on a background of clobazam and valproate) with clobazam and valproate alone. Costs and quality-adjusted life-years (QALYs) were estimated using a Markov model that followed a cohort of children aged from 5 to 18 years through model states related to seizure frequency. Model inputs were obtained from the literature. The cost effectiveness of adjunctive cannabinoid oil, adjunctive stiripentol, and clobazam/valproate alone was assessed through sequential analysis. The influence of perspective and other assumptions were explored in scenario analyses. All costs are expressed in 2019 Canadian dollars, and costs and QALYs were discounted at a rate of 1.5% per year.

RESULTS:

The incremental cost per QALY gained with the use of adjunctive cannabinoid oil, from the health care system perspective, was $32,399 compared with clobazam and valproate. Stiripentol was dominated by cannabinoid oil, producing fewer QALYs at higher costs. At a willingness-to-pay threshold of $50,000, cannabinoid oil was the optimal treatment in 76% of replications. From a societal perspective, cannabinoid oil dominated stiripentol and clobazam/valproate. The interpretation of the results was insensitive to model and input assumptions.

CONCLUSION:

Compared with clobazam/valproate, adjunctive cannabinoid oil may be a cost-effective treatment for Dravet syndrome, if a decision maker is willing to pay at least $32,399 for each QALY gained. The opportunity costs of continuing to fund stiripentol, but not cannabinoid oil, should be considered.”

https://www.ncbi.nlm.nih.gov/pubmed/32406036

https://link.springer.com/article/10.1007%2Fs40273-020-00923-5

Parents’ experiences using medical cannabis for their child.

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Nursing Outlook (@NursingOutlook) | Twitter“Parents across the United States use medical cannabis for their children, often without professional guidance. These parents have become more expert on medical cannabis than most health professionals.

Using a case-study design, this study was conducted to describe the experience of parents using medical cannabis for relief of seizures in their child or dependent.

Themes revealed a complex, multifaceted experience. Many parents report benefit from medical cannabis, and are not hindered by the financial costs or uncertainties. Political and social influences have significant impact on the stigmatization and normalization of cannabis.”

https://www.ncbi.nlm.nih.gov/pubmed/32334826

“Parents across the United States are using cannabis to treat their child’s epilepsy.”

https://www.nursingoutlook.org/article/S0029-6554(19)30195-2/pdf

Novel approaches and current challenges with targeting the endocannabinoid system.

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 Publication Cover“The pathophysiological relevance of the endocannabinoid system has been widely demonstrated in a variety of diseases including cancer, neurological disorders, and metabolic issues. Therefore, targeting the receptors and the endogenous machinery involved in this system can provide a successful therapeutic outcome.

Ligands targeting the canonical cannabinoid receptors, CB1 and CB2, along with inhibitors of the endocannabinoid enzymes have been thoroughly studied in diverse disease models. In fact, phytocannabinoids such as cannabidiol or Δ9-tetrahydrocannabinol are currently on the market for the management of neuropathic pain due to spasticity in multiple sclerosis or seizures in children epilepsy amongst others.

Expert opinion: Even if orthosteric CB1 and CB2 ligands are on the forefront in cannabinoid clinical research, emerging strategies such as allosteric or biased modulation of these receptors along with controlled off-targets effects may increase the therapeutic potential of cannabinoids.”

https://www.ncbi.nlm.nih.gov/pubmed/32336154

“Multi-target approaches could be promising strategies for the treatment of endocannabinoid system-related disorders. The authors believe that phytocannabinoids are at the forefront of future clinical research.”

https://www.tandfonline.com/doi/abs/10.1080/17460441.2020.1752178?journalCode=iedc20

A preliminary study of the effects of cannabidiol (CBD) on brain structure in patients with epilepsy.

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Epilepsy & Behavior Reports“This preliminary study examines whether daily CBD dose of 15-25 mg/kg produces cerebral macrostructure changes and, if present, how they relate to changes in seizure frequency.

In conclusion, short-term exposure to highly purified CBD may not affect cortical macrostructure.”

https://www.ncbi.nlm.nih.gov/pubmed/32322816

“We document no effect of CBD on gray matter volume and cortical thickness.”

https://www.sciencedirect.com/science/article/pii/S258998641930111X?via%3Dihub