Category Archives: Epilepsy

Comparison of various doses of oral cannabidiol for treating refractory epilepsy indications: a network meta-analysis

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“Aim: To evaluate the comparative efficacy and safety of various doses of oral cannabidiol (CBD) in treating refractory epilepsy indications, thus providing more informative evidence for clinical decision-making.

Methods: A literature search of PubMed, Embase, the Cochrane library, and Web of Science (WoS) was performed to retrieve relevant randomized controlled trials (RCTs) that compared different doses of oral CBD with placebo or each other in refractory epilepsy indications. The search was limited from the inception of each database to January 3, 2023. Relative risk [RR] with a 95% confidence interval [CI] was used to express results. STATA/SE 14 was employed for network meta-analysis.

Results: Six RCTs involving 972 patients were included in the final data analysis. Network meta-analysis showed that, CBD10 (10 mg/kg/day) (RR: 1.77, 95%CI: 1.28 to 2.44), CBD20 (20 mg/kg/day) (RR: 1.91, 95%CI: 1.49 to 2.46), CBD25 (25 mg/kg/day) (RR: 1.61, 95%CI: 0.96 to 2.70), and CBD50 (50 mg/kg/day) (RR: 1.78, 95%CI: 1.07 to 2.94) were associated with higher antiseizure efficacy although the pooled result for CBD25 was only close to significant. In addition, in terms of the risk of treatment-emergent adverse events (TEAEs), the difference between different doses is not significant. However, CBD20 ranked first in terms of antiseizure efficacy, followed by CBD50, CBD10, and CBD25. For TEAEs, CBD25 ranked first, followed by CBD10, CBD50, CBD5, and CBD20.

Conclusion: For refractory indications, CBD20 may be optimal option for antiseizure efficacy; however, CBD25 may be best for TEAEs. Therefore, an appropriate dose of oral CBD should be selected based on the actual situation. Due to the limitations of eligible studies and the limited sample size, more studies are needed in the future to validate our findings.”

https://pubmed.ncbi.nlm.nih.gov/38994494/

https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2024.1243597/full

Effectiveness of Highly Purified Cannabidiol in Refractory and Super-Refractory Status Epilepticus: A Case Series

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“Introduction: Refractory and super-refractory status epilepticus are medical emergencies that must be promptly treated in consideration of their high mortality and morbidity rate. Nevertheless, the available evidence of effective treatment of these conditions is scarce. Among novel antiseizure medications (ASMs), highly purified cannabidiol (hpCBD) has shown noteworthy efficacy in reducing seizures in Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and Tuberous Sclerosis Complex (TSC).

Case presentation: Here, we present two cases of effective use of hpCBD in both refractory and super- refractory status epilepticus. The administration of the nasogastric tube permitted the resolution of status epilepticus without adverse events. At 6-month follow-up, both patients were on hpCBD treatment, which continued to be efficacious for treating seizures.

Conclusion: According to our experience, hpCBD should be taken into consideration as an add-on therapy of RSE and SRSE while also considering the possibility of maintaining this treatment during the follow-up of patients. However, more studies and real-world experiences are needed to better understand its effectiveness in this setting and the interaction with other ASMs.”

https://pubmed.ncbi.nlm.nih.gov/38910424/

https://www.eurekaselect.com/article/141195

The Use of Compounds Derived from Cannabis sativa in the Treatment of Epilepsy, Painful Conditions, and Neuropsychiatric and Neurodegenerative Disorders

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“Neurological disorders present a wide range of symptoms and challenges in diagnosis and treatment. Cannabis sativa, with its diverse chemical composition, offers potential therapeutic benefits due to its anticonvulsive, analgesic, anti-inflammatory, and neuroprotective properties.

Beyond cannabinoids, cannabis contains terpenes and polyphenols, which synergistically enhance its pharmacological effects. Various administration routes, including vaporization, oral ingestion, sublingual, and rectal, provide flexibility in treatment delivery.

This review shows the therapeutic efficacy of cannabis in managing neurological disorders such as epilepsy, neurodegenerative diseases, neurodevelopmental disorders, psychiatric disorders, and painful pathologies.

Drawing from surveys, patient studies, and clinical trials, it highlights the potential of cannabis in alleviating symptoms, slowing disease progression, and improving overall quality of life for patients. Understanding the diverse therapeutic mechanisms of cannabis can open up possibilities for using this plant for individual patient needs.”

https://pubmed.ncbi.nlm.nih.gov/38891938/

https://www.mdpi.com/1422-0067/25/11/5749


Infant formula as a solid lipid dose form for enhancement of the oral bioavailability of cannabidiol for paediatric patients

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“Cannabinoids can save paediatric patients from harmful psychological conditions caused by epilepsy. However, the limited aqueous solubility of the drug presents a limitation to oral absorption and bioavailability.

Previous studies have shown the enhancement of oral bioavailability for poorly water-soluble drugs using milk or milk-based products like infant formula as a novel lipid-based formulation, due to digestion of the lipids to enhance drug solubility. that is particularly well suited to infants and in low economy settings.

Therefore, this study has investigated the in vitro solubilization enhancement of cannabidiol (CBD) in milk-based products during digestion using synchrotron small angle X-ray scattering, followed by pharmacokinetic studies to determine the relative oral bioavailability. The in vitro results, coupled with in vivo data, demonstrate a two-fold increase in the oral bioavailability of CBD in bovine milk as well as infant formula.

The results of this study indicate the potential for infant formula to be considered as a novel formulation approach for CBD. Further study is encouraged for more drugs with infant formula to strengthen the correlation between the solubilization of drug and their oral bioavailability.”

https://pubmed.ncbi.nlm.nih.gov/38782154/

https://www.sciencedirect.com/science/article/pii/S0378517324004915?via%3Dihub

Use of cannabidiol in the treatment of drug-refractory epilepsy in children and young adults: A systematic review

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“Objectives: Epilepsy poses a significant challenge in pediatric and adolescent populations, impacting not only seizures but also psychological and cognitive comorbidities, leading to higher mortality rates than the general population. Drug-refractory epilepsy, resistant to conventional treatments, affects a range of 7-20% of pediatric patients. The search for alternative therapies has led to exploring the therapeutic potential of Cannabis sativa L. compounds, particularly cannabidiol (CBD). Examine the use of CBD for treating drug-refractory epilepsy in children and young adults, summarizing existing evidence on its efficacy.

Materials and methods: A systematic review, following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, assessed studies from 2018 to 2023, focusing on CBD’s efficacy and safety for treatment-resistant epilepsy in pediatric and juvenile populations. The search spanned seven databases, and the studies underwent rigorous screening and data extraction.

Results: Out of 6351 identified articles, eight were selected for review. The included studies reported positive outcomes, with CBD leading to a reduction in seizure frequency ranging from 50% to complete seizure freedom. Adverse effects were mostly mild and reversible, including drowsiness, diarrhea, and loss of appetite.

Conclusion: The CBD emerges as a promising tool for refractory epilepsy in pediatric patients, showing efficacy in reducing seizure frequency and improving overall quality of life. Despite mild and reversible adverse effects, CBD’s benefits outweigh the risks. However, more research on long-term effects is needed to fully understand its implications.”

https://pubmed.ncbi.nlm.nih.gov/38746511/

“The use of cannabis is a tool for refractory epilepsy when first-line therapies do not have the expected efficacy. The benefits of the crisis are clear, in the reduction and even elimination or blocking of seizures, impacting positively their quality of life such as sleep, behavior, and cognitive functions. There is great efficacy against different types of epileptic seizures, such as tonic, tonic-clonic, epileptic encephalopathy, focal seizures, and generalized seizures, making its use advisable for patients, without forgetting that more information is still required regarding its long-term use. As for the adverse effects, it can be noted that, despite being almost constant, these mainly appear due to the interaction of CBD with the medications used by these patients, although it is clear that none of these adverse effects turned out to be a reason not to stop the treatment that was presented during the different studies.”

https://ruralneuropractice.com/use-of-cannabidiol-in-the-treatment-of-drug-refractory-epilepsy-in-children-and-young-adults-a-systematic-review/

CBD in the Treatment of Epilepsy

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“It has been several years since highly purified cannabidiol (CBD) was registered as a medication that can be used in children of at least 2 years of age to treat different types of seizures related to Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and more recently tuberous sclerosis complex (TSC).

During this time, 39 randomized clinical trials (RCTs) and 13 meta-analyses on the efficacy and safety of CBD treatment have been published. Each of the meta-analyses had its own criteria for the RCTs’ inclusion and, therefore, slightly different interpretations of the analyzed data.

Each of them contributed in its own way to the understanding of CBD pharmacology, mechanisms of therapeutic action, development of adverse reactions, and drug-drug interactions. Hence, it seemed reasonable to gather the most relevant data in one article and present all the current knowledge on the use of CBD in epilepsy.

The results of the 13 meta-analyses presented herein confirmed the effectiveness and safety of CBD in children and adolescents with DREs. In adults, reliable conclusions cannot be drawn due to insufficient data.”

https://pubmed.ncbi.nlm.nih.gov/38731471/

https://www.mdpi.com/1420-3049/29/9/1981

Direct Inhibition of BK Channels by Cannabidiol, One of the Principal Therapeutic Cannabinoids Derived from Cannabis sativa

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“Cannabidiol (CBD), one of the main Cannabis sativa bioactive compounds, is utilized in the treatment of major epileptic syndromes. Its efficacy can be attributed to a multimodal mechanism of action that includes, as potential targets, several types of ion channels. In the brain, CBD reduces the firing frequency in rat hippocampal neurons, partly prolonging the duration of action potentials, suggesting a potential blockade of voltage-operated K+ channels. We postulate that this effect might involve the inhibition of the large-conductance voltage- and Ca2+-operated K+ channel (BK channel), which plays a role in the neuronal action potential’s repolarization. Thus, we assessed the impact of CBD on the BK channel activity, heterologously expressed in HEK293 cells. Our findings, using the patch-clamp technique, revealed that CBD inhibits BK channel currents in a concentration-dependent manner with an IC50 of 280 nM. The inhibition is through a direct interaction, reducing both the unitary conductance and voltage-dependent activation of the channel. Additionally, the cannabinoid significantly delays channel activation kinetics, indicating stabilization of the closed state. These effects could explain the changes induced by CBD in action potential shape and duration, and they may contribute to the observed anticonvulsant activity of this cannabinoid.”

https://pubmed.ncbi.nlm.nih.gov/38708937/

“Taken together, our findings expand our understanding of the spectrum of ion channels directly modulated by CBD, suggesting a potential multitarget mechanism underlying its therapeutic effects. Finally, the widespread distribution and function of BK channels in human physiology and pathologies broaden the potential therapeutic uses of CBD to other conditions in which this channel is implicated.”

https://pubs.acs.org/doi/10.1021/acs.jnatprod.3c01274

Cannabidiol attenuates seizure susceptibility and behavioural deficits in adult CDKL5R59X knock-in mice

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“Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is caused by a loss-of-function mutation in CDKL5 gene, encoding a serine-threonine kinase highly expressed in the brain. CDD manifests with early-onset epilepsy, autism, motor impairment and severe intellectual disability.

While there are no known treatments for CDD, the use of cannabidiol has recently been introduced into clinical practice for neurodevelopmental disorders. Given the increased clinical utilization of cannabidiol, we examined its efficacy in the CDKL5R59X knock-in (R59X) mice, a CDD model based on a human mutation that exhibits both lifelong seizure susceptibility and behavioural deficits.

We found that cannabidiol pre-treatment rescued the increased seizure susceptibility in response to the chemoconvulsant pentylenetetrazol (PTZ), attenuated working memory and long-term memory impairments, and rescued social deficits in adult R59X mice. To elucidate a potential mechanism, we compared the developmental hippocampal and cortical expression of common endocannabinoid (eCB) targets in R59X mice and their wild-type littermates, including cannabinoid type 1 receptor (CB1R), transient receptor potential vanilloid type 1 (TRPV1) and 2 (TRPV2), G-coupled protein receptor 55 (GPR55) and adenosine receptor 1 (A1R). Many of these eCB targets were developmentally regulated in both R59X and wild-type mice. In addition, adult R59X mice demonstrated significantly decreased expression of CB1R and TRPV1 in the hippocampus, and TRPV2 in the cortex, while TRPV1 was increased in the cortex.

These findings support the potential for dysregulation of eCB signalling as a plausible mechanism and therapeutic target in CDD, given the efficacy of cannabidiol to attenuate hyperexcitability and behavioural deficits in this disorder.”

https://pubmed.ncbi.nlm.nih.gov/38654472/

“The current report is the first to show experimental evidence that cannabidiol can mitigate some of the memory and social deficits as well as seizure susceptibility in a well-characterized CDD mouse model. These findings continue to support the emerging clinical observational data that cannabidiol-based compounds have efficacy in CDD patients, especially those in later childhood and adulthood.”

https://onlinelibrary.wiley.com/doi/10.1111/ejn.16350

Cannabidiol Exerts Anticonvulsant Effects Alone and in Combination with Δ9-THC through the 5-HT1A Receptor in the Neocortex of Mice

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“Cannabinoids have shown potential in drug-resistant epilepsy treatment; however, we lack knowledge on which cannabinoid(s) to use, dosing, and their pharmacological targets. This study investigated (i) the anticonvulsant effect of Cannabidiol (CBD) alone and (ii) in combination with Delta-9 Tetrahydrocannabinol (Δ9-THC), as well as (iii) the serotonin (5-HT)1A receptor’s role in CBD’s mechanism of action. Seizure activity, induced by 4-aminopyridine, was measured by extracellular field recordings in cortex layer 2/3 of mouse brain slices. The anticonvulsant effect of 10, 30, and 100 µM CBD alone and combined with Δ9-THC was evaluated. To examine CBD’s mechanism of action, slices were pre-treated with a 5-HT1A receptor antagonist before CBD’s effect was evaluated. An amount of ≥30 µM CBD alone exerted significant anticonvulsant effects while 10 µM CBD did not. However, 10 µM CBD combined with low-dose Δ9-THC (20:3 ratio) displayed significantly greater anticonvulsant effects than either phytocannabinoid alone. Furthermore, blocking 5-HT1A receptors before CBD application significantly abolished CBD’s effects. Thus, our results demonstrate the efficacy of low-dose CBD and Δ9-THC combined and that CBD exerts its effects, at least in part, through 5-HT1A receptors. These results could address drug-resistance while providing insight into CBD’s mechanism of action, laying the groundwork for further testing of cannabinoids as anticonvulsants.”

https://pubmed.ncbi.nlm.nih.gov/38534310/

https://www.mdpi.com/2073-4409/13/6/466

The efficacy and safety of cannabidiol (CBD) in pediatric patients with Dravet Syndrome: a narrative review of clinical trials

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“Background: Dravet Syndrome (DS) is a rare and severe form of childhood epilepsy that is often refractory to conventional antiepileptic drugs. Emerging evidence suggests that Cannabidiol (CBD) offer therapeutic benefits for DS. This review aims to evaluate the efficacy and safety of CBD in pediatric patients with DS based on data from ten clinical trials.

Methods: A review was conducted to identify clinical trials assessing the efficacy and safety of CBD in pediatric patients diagnosed with DS. PubMed, MEDLINE, Scopus, Web of Science, and relevant grey literature were systematically searched for relevant articles up to October 2023, and clinical trials within the last 10 years were included. The search strategy incorporated controlled vocabulary terms and keywords related to “Cannabidiol,” “Dravet Syndrome,” and “pediatric patients.”

Results: The analysis revealed promising efficacy outcomes. Notably, CBD demonstrated substantial reductions in seizure frequency, with some patients achieving seizure freedom. The findings emphasised the consistency of CBD’s efficacy across different patient subgroups. The safety profile of CBD was generally acceptable, with adverse events often being manageable.

Conclusion: This review consolidates evidence from multiple clinical trials, affirming the potential of CBD as a promising treatment option for pediatric patients with DS. While further research is needed to address existing knowledge gaps, CBD’s efficacy and acceptable safety profile make it a valuable addition to the therapeutic tools for DS.”

https://pubmed.ncbi.nlm.nih.gov/38500226/

“This review offers a comprehensive and in-depth analysis of the existing evidence on the efficacy and safety of CBD in pediatric patients diagnosed with DS. The findings, compiled from ten distinct clinical trials, consistently point to the potential of CBD as a valuable therapeutic option for managing DS. Notably, CBD remarkably reduces seizure frequency and enhances the overall quality of life for affected patients.”

https://eurjmedres.biomedcentral.com/articles/10.1186/s40001-024-01788-6