“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.”
“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.”
“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.”
“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.”
“•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.”
“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.”
“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.”
“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.”
“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.”
“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.”
“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.”
“Purpose: Plant-derived highly purified cannabidiol (CBD) reduced the frequency of seizures associated with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) and improved the overall condition of patients in placebo-controlled phase 3 clinical trials. Anecdotal reports also suggest a positive effect on nonseizure outcomes. In this study, we aimed to identify, through a caregiver survey which nonseizure outcomes were most likely to change in these patients.
Methods: The BEhavior, COgnition, and More with Epidiolex® (BECOME) was a 20-minute, cross-sectional, online survey that was developed with extensive input from caregivers, healthcare professionals, and epilepsy researchers, and was based on questions from validated measures and previously published caregiver reports. US-based caregivers (from Jazz Pharmaceuticals patient/caregiver database) of people with LGS or DS who were treated with CBD (Epidiolex®, 100 mg/mL oral solution) for ≥3 months were asked to compare the past month to the period before CBD initiation and rate their impression of changes using symmetrical Likert scales
Results: A total of 498 caregivers (97% parents) of patients with LGS (80%) or DS (20%) completed the survey. Mean (range) age of patients was 16 (1-73) years, and 52% were male. Patients were taking a median CBD dose of 14 mg/kg/d and median 4 concomitant antiseizure medications. A large proportion of respondents reported improvements in ≥1 survey question for all nonseizure-related domains: alertness, cognition, and executive function (85%); emotional functioning (82%); language and communication (79% in nonverbal patients and 74% in verbal); activities of daily living (51%); sleep (51%); and physical functioning (46%). Respondents reported improvements in seizure-related domains, including overall seizure frequency (85%), overall seizure severity (76%), seizure-free days per week for ≥1 seizure type (67%), and seizure freedom during the past month (16%). The majority of respondents who reported reduction in seizure frequency also reported improvements in nonseizure outcomes domains (51-80%). However, improvements in nonseizure outcomes (18-56%) were also reported in patients who either had no change or worsening of seizure frequency.
Conclusions: This survey characterized and quantified caregiver impression of changes in the seizure and nonseizure outcomes in patients taking add-on CBD treatment. Overall, 93% of caregivers reported planning to continue CBD treatment, primarily because of reduced seizure burden but also because of improvements in nonseizure-related outcomes. Despite the limitations that are associated with a retrospective survey-based study design, these results support further evaluation of the effect of CBD treatment on nonseizure outcomes among patients with LGS or DS.”
“Cannabis was used to treat convulsions and other disorders since ancient times. In the last few decades, preclinical animal studies and clinical investigations have established the role of cannabidiol (CBD) in treating epilepsy and seizures and support potential therapeutic benefits for cannabinoids in other neurological and psychiatric disorders. Here, we comprehensively review the role of cannabinoids in epilepsy. We briefly review the diverse physiological processes mediating the central nervous system response to cannabinoids, including D9-THC, cannabidiol, and terpenes. Next, we characterize the anti- and proconvulsive effects of cannabinoids from animal studies of acute seizures and chronic epileptogenesis. We then review the clinical literature on using cannabinoids to treat epilepsy, including anecdotal evidence and case studies as well as the more recent randomized-controlled clinical trials that led to FDA approval of CBD for some types of epilepsy. Overall, we seek to evaluate our current understanding of cannabinoids in epilepsy and focus future research on unanswered questions.”
