The use of cannabidiol in patients with Lennox-Gastaut syndrome and Dravet syndrome in the UK Early Access Program: A retrospective chart review study

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“Purpose: To evaluate clinical outcomes from the UK Early Access Program in patients aged 2-17 years with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) treated with plant-derived highly purified cannabidiol (CBD; Epidyolex®; 100 mg/mL oral solution).

Methods: Retrospective chart review of data collected from baseline (1 month before CBD treatment initiation) until 12 months’ treatment, CBD discontinuation, death, or loss to follow up.

Results: At baseline, all 26 patients enrolled (LGS, n = 17; DS, n = 9; male, 73 %; mean [range] age, 11.8 [3.0-17.0] years) experienced motor seizures; 92 % were taking ≥ 1 antiseizure medication. Median (IQR) CBD dosage at 6 months (6 M; n = 12) was 6.0 (2.7) mg/kg/day, and 12 months (12 M; n = 9) 7.3 (2.1) mg/kg/day. Median (IQR) percentage change from baseline for motor seizures was – 56.7 % (60.7) at 6 M (n = 20), and – 60.0 % (53.3) at 12 M (n = 15). Patients experiencing ≥ 50 % and ≥ 75 % reduction in motor seizures were 13/20 (65 %) and 5/20 (25 %) at 6 M, respectively, and 10/15 (67 %) and 6/15 (40 %) at 12 M, respectively. Mean (SD) motor seizure-free days/month were 1.5 (4.3) at baseline (n = 24, missing data n = 2), 2.4 (6.3) at 6 M (n = 18), and 2.7 (5.5) at 12 M (n = 15). At 12 M, CBD retention for patients with follow-up data was 14/19 (74 %), whilst 7/26 (27 %) were lost to follow up. The number of patients reporting ≥ 1 adverse event of special interest (most common: gastrointestinal) was 14/20 (70 %) and 8/15 (53 %) at 6 M and 12 M, respectively.

Conclusion: Results demonstrate a reduction in motor seizures and a safety profile consistent with previous studies.”

https://pubmed.ncbi.nlm.nih.gov/39898301/

“Results on CBD effectiveness and safety are consistent with previous studies.”

https://www.sciencedirect.com/science/article/pii/S2589986424000881?via%3Dihub

The use of cannabidiol as adjunctive therapy in adult patients with drug-resistant epilepsy: a systematic review and meta-analysis

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“Background: Highly purified cannabidiol (CBD), recently approved for various neurological disorders, is explored as a potential therapeutic avenue for drug-resistant epilepsy (DRE) among adult people with epilepsy (PWE) in this systematic review and meta-analysis.

Objectives: To conduct an extensive literature review and meta-analysis of CBD use for DRE in adult PWE.

Design: Systematic review and meta-analysis.

Data sources and methods: We conducted a systematic review of the literature according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and two electronic resources; we searched Ovid MEDLINE and Scopus using appropriate keywords until August 2023. Data were presented as standardized mean difference (SMD) and odds ratio with confidence interval (CI) via random effect. We appraised the risk of bias of the included studies using the Joanna Briggs Institute critical appraisal tool while their strength of evidence with the Oxford Centre for Evidence-Based Medicine (OCEBM) and Grading of Recommendations Assessment Development and Education (GRADE) Levels of Evidence.

Results: We identified 16 studies, 3 of which were randomized controlled trials and 3 prospective cohort studies, while the rest were expanded access programs, deriving a total of 668 participants receiving CBD for seizure control. CBD was used concomitantly with antiseizure medications in all studies. There was a statistically significant seizure reduction in the group receiving CBD therapy compared to the placebo group (SMD: -1.50, 95% CI (-3.47, 0.47), p < 0.01).

Conclusion: The evidence on CBD use in adult patients with DRE demonstrates a moderate level of certainty according to GRADE level and OCEBM level 2. Further prospective studies involving multiple centers are encouraged to study both the efficacy and safety of CBD in adult patients with DRE.”

https://pubmed.ncbi.nlm.nih.gov/39882324/

“Our review has shown that CBD was efficacious as an adjunctive therapy in seizure reduction in adult patients with DRE.”

https://journals.sagepub.com/doi/10.1177/17562864251313914

Update on Cannabidiol in Drug-Resistant Epilepsy

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“Cannabidiol (CBD) has arisen as a promising therapeutic option for children with drug-resistant epilepsy (DRE). CBD has received regulatory nod from different regulatory authorities in the United States, Europe, and India for children with DRE particularly, Dravet syndrome (DS), Lennox Gastaut syndrome (LGS), and Tuberous sclerosis complex (TSC).

Recent clinical trials and observational studies highlight the potential of CBD to lower seizure frequency and provide better quality of life in children affected by these disorders.

The safety profile is generally favorable with minor common adverse events such as somnolence, diarrhea, and gastrointestinal issues. Furthermore, the expense associated with CBD remains a notable concern, especially in low- and middle-income countries such as India, where access to this promising treatment may be constrained. This draws attention to the cost-effective perspective of CBD.

This review aims to explore the pharmacological properties of CBD, its mechanisms of action, and the clinical evidence supporting its use in various pediatric epilepsies, including LGS, DS, and TSC. Additionally, this review sheds light on the current regulatory landscape in India where CBD use is still in its nascent stages, and discusses the challenges and opportunities for integrating CBD into clinical practice.”

https://pubmed.ncbi.nlm.nih.gov/39585547/

https://link.springer.com/article/10.1007/s12098-024-05337-1

Cannabidiol Treatment for Adult Patients with Drug-Resistant Epilepsies: A Real-World Study in a Tertiary Center

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“Background and purpose: Around 30% of patients with epilepsy show drug-resistant epilepsy (DRE). While cannabidiol has demonstrated efficacy as an adjunctive treatment in Dravet syndrome (DS), Lennox-Gastaut Syndrome (LGS), and epilepsy related to tuberous sclerosis complex (TSC), its more global effectiveness in adult patients with DRE apart from these three specific contexts needs to be clarified.

Methods: We conducted a retrospective study at the epilepsy unit of Pitié Salpêtrière Hospital. Patients initiating pharmaceutical cannabidiol treatment and followed for at least 1 year were included. Patients were categorized into “authorized” (LGS, DS, or TSC) and “off-label” groups. Cannabidiol effectiveness and tolerance were compared between groups, and characteristics of responders (patients with >50% reduction in seizure frequency) in the off-label group were examined.

Results: Ninety-one patients, followed by a median duration of 24 months, were included. A total of 35.2% of the patients were in the authorized group. No significant differences were observed in responder rates between groups (31.3% vs. 35.6%, p = 0.85) and retention rates at 1 year (75.0% vs. 74.6%, p = 0.97). Sleepiness was more commonly reported in the authorized group (50.0% vs. 22.0%, p = 0.01), with no other significant differences. Among off-label patients (n = 59), clobazam co-prescription was more prevalent in responders (71.4% vs. 28.9%, p = 0.002).

Conclusion: Our findings suggest that cannabidiol may benefit all adult patients with DRE, particularly those already receiving clobazam. Randomized controlled trials are warranted in off-label patients to validate these observational findings.”

https://pubmed.ncbi.nlm.nih.gov/39501537/

https://onlinelibrary.wiley.com/doi/10.1002/brb3.70122

Cannabinoids and Genetic Epilepsy Models: A Review with Focus on CDKL5 Deficiency Disorder

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“Pediatric genetic epilepsies, such as CDKL5 Deficiency Disorder (CDD), are severely debilitating, with early-onset seizures occurring more than ten times daily in extreme cases. Existing antiseizure drugs frequently prove ineffective, which significantly impacts child development and diminishes the quality of life for patients and caregivers.

The relaxation of cannabis legislation has increased research into potential therapeutic properties of phytocannabinoids such as cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC).

CBD’s antiseizure properties have shown promise, particularly in treating drug-resistant genetic epilepsies associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and Tuberous Sclerosis Complex (TSC). However, specific research on CDD remains limited. Much of the current evidence relies on anecdotal reports of artisanal products lacking accurate data on cannabinoid composition. Utilizing model systems like patient-derived iPSC neurons and brain organoids allows precise dosing and comprehensive exploration of cannabinoids’ pharmacodynamics.

This review explores the potential of CBD, THC, and other trace cannabinoids in treating CDD and focusing on clinical trials and preclinical models to elucidate the cannabinoid’s potential mechanisms of action in disrupted CDD pathways and strengthen the case for further research into their potential as anti-epileptic drugs for CDD. This review offers an updated perspective on cannabinoid’s therapeutic potential for CDD.”

https://pubmed.ncbi.nlm.nih.gov/39409097/

https://www.mdpi.com/1422-0067/25/19/10768

Off-label use of cannabidiol in genetic epileptic and developmental encephalopathies: A case report

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“Developmental Epileptic encephalopathies (DEEs) are severe neurological conditions where cognitive functions appear modulated by both seizure and interictal epileptiform activity.

Cannabidiol (CBD) has been shown to be highly effective in the treatment of drug-resistant seizures in patients with DEEs.

Along with its antiseizure effects, CBD demonstrated clinical beneficial effects in patients’ quality of life, sleep and numerous adaptive behaviors. However, based on the available phase III studies, the indications for this treatment have so far been restricted to Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS) and tuberous sclerosis complex (TSC) by regulatory authorities.

We present the case of a 30-year-old girl with a rare genetic DEE, experiencing relevant seizure frequency reduction together with striking improvement in sleep quality, mood, behavior, language and motor skills after introducing off-label CBD.”

https://pubmed.ncbi.nlm.nih.gov/39040437/

  • “•Cannabidiol exerts also clinical beneficial non-seizure outocomes.
  • •Cannabidiol should be considered in other developmental epileptic encephalopathies.
  • •Cannabidiol presents antiepileptic, neuroprotective and anti-inflammatory effect.”

“Besides its antiseizures effect, CBD might lead to clinical beneficial effects in patients’ quality of life, sleep, cognition and numerous adaptive behaviors. Hopefully, the growing interest in the CBD antiepileptic activity will lead to its use in other developmental and epileptic encephalopathie.”

https://www.sciencedirect.com/science/article/pii/S2589986424000443?via%3Dihub


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

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

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