“Nanoparticles and nano-delivery systems are constantly being refined and developed for biomedical applications such as imaging, gene therapy, and targeted delivery of drugs. Nanoparticles deliver beneficial effects by both release of their cargo and by liberation of their constitutive structural components. The N-acylethanolamines linoleoyl ethanolamide (LEA) and oleoyl ethanolamide (OEA) both exhibit endocannabinoid-like activity. Here, we report on their ability to form nanoparticles that when conjugated with tissue-specific molecules, are capable of localizing to specific areas of the body and reducing inflammation. The facilitation of pharmacological effects by endocannabinoids at targeted sites provides a novel biocompatible drug delivery system and a therapeutic approach to the treatment, patient management and quality of life, in conditions such as arthritis, epilepsy, and cancer.”
“Background: Epilepsy is one of the most common brain disorder and, despite the possible use of several therapeutic options, many patients continue to have seizures for their entire lifespan and they need new therapeutic approaches. In the last years the interest on the non-psychoactive compounds present in Cannabis sativa has massively increased, and cannabidiol (CBD) has been shown to be effective in the treatment of different types of neurological disorders and neurodegenerative diseases such as epilepsy, ischemia, multiple sclerosis and Alzheimer’s Disease.
Methods: We investigated the effects of the selected cannabinoids, Δ9-tetrahydrocannabinol (THC), CBD and cannabigerol (CBG) in rat organotypic hippocampal slices exposed to kainate, an in vitro seizure model. Cell death in the cornu Ammonis 3 (CA3) hippocampal subregion was quantified by propidium iodide fluorescence. Morphological analysis and tissue organization were examined by immunohistochemistry and confocal microscopy and microglia activation and polarization was evaluated using flow cytometry and morphology analysis .
Results: When present in the incubation medium, cannabidiol reduced dose-dependent CA3 injury induced by kainate. Conversely, incubation with THC exacerbated hippocampal damage. The neuroprotective effects of cannabidiol were blocked by TRPV1, TRPV2, 5-HT1A, and PPARγ antagonists. Confocal microscopy confirmed that CBD but not THC had a significant protective effect against neuronal damage and tissue disorganization caused by kainate. Cannabidiol incubation significantly block the microglia activation from the M0 to M1 phenotype observed in the kainate in-vitro seizure model, pushing toward a transition from M0 to M2 .
Conclusions: Our results suggest that CBD mitigated neuronal damage induced by kainate and blocked the transition from the M0 to the M1 phenotype.”
“Background: The treatment of epilepsy during early life poses unique challenges-first-line therapies leave many individuals with poorly controlled seizures. In response to the pharmaco-resistance of current first-line anti-seizure drugs (ASDs) during early life, new therapies have emerged. One such therapy is cannabidiol (CBD). While well studied in adult models of epilepsy, it is poorly studied in immature animals. Here we assessed the efficacy of CBD in immature rodent models of the epilepsies.
Methods: Pups were pre-treated with CBD (1, 10, 50, 100, 200 mg/kg) and assessed for anticonvulsant efficacy using two well-established anti-seizure screening models: the pentylenetetrazole (PTZ) and maximal electroshock (MES) models. We assessed drug efficacy in postnatal day (P)7 and P21 rats.
Results: In the PTZ model, CBD delayed seizure onset in adolescent but not neonatal rats. By contrast, higher doses of CBD reduced seizure duration in both neonatal and adolescent rats in the MES model. The effects of CBD in both models were modest but consistent.
Conclusion: Efficacy of CBD increased in older as compared to younger animals, producing an age-, model-, and dose-dependent suppression of seizures. These data suggest neonatal seizures (modeled by P7 treatment) may be less responsive to CBD. They also suggest preferential efficacy against tonic seizures as compared to partial motor seizures.”
“Presently there is no drug therapy for curing epilepsy. Despite many advancements in epilepsy research, nearly 30% of people with epilepsy remain refractory to current antiseizure medications (ASM).
Cannabidiol (CBD) has recently been approved as an ASM for pediatric refractory seizures, but it has not been widely tested for adult epileptogenesis and focal onset seizures.
In this study, we investigated the efficacy of the FDA-approved CBD in controlling epileptogenesis and complex focal onset seizures using the mouse kindling model of human temporal lobe epilepsy. We also tested combination regimens of CBD with other ASMs.
The two primary outcome measures were disease modification and suppression of generalized seizures.
In the epileptogenesis study, CBD had a striking effect in attenuating kindling development, with a dose-dependent decrease in behavioral and electrographic seizure activity.
In the retention study, mice previously treated with CBD had significantly reduced overall seizure burden, suggesting disease modification.
In a fully-kindled seizure study, CBD produced rapid and atypical U-shaped dose-dependent protection against generalized seizures (ED50, 52 mg/kg, i.p.).
In a time-course study, CBD showed a maximal protective effect within 1 h of injection, and it declined within 4 h with a biphasic response.
In the combination study, CBD produced synergistic/ additive protection when given with midazolam and ganaxolone, but not with tiagabine, indicating its strong potential as an adjunct ASM. Finally, the protective effects of CBD were not associated with motor and functional impairments.
These preclinical findings demonstrate the potential of adjunct CBD for controlling adult complex focal onset seizure conditions.”
“CBD has strong antiseizure activity in the adult kindling model of epilepsy.. It has a disease-modifying effect by reducing the overall seizure burden.”
“Novel and effective antiseizure medications are needed to treat refractory and rare forms of epilepsy.
Cannabinoids, which are obtained from the cannabis plant, have a long history of medical use, including for neurologic conditions. In 2018, the US Food and Drug Administration approved the first phytocannabinoid, cannabidiol (CBD, Epidiolex®), which is now indicated for severe seizures associated with three rare forms of developmental and epileptic encephalopathy: Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex.
Compelling evidence supports the efficacy of CBD in experimental models and patients with epilepsy. In randomized clinical trials, highly-purified CBD has demonstrated efficacy with an acceptable safety profile in children and adults with difficult-to-treat seizures. Although the underlying antiseizure mechanisms of CBD in humans have not yet been elucidated, the identification of novel antiseizure targets of CBD preclinically indicates multimodal mechanisms that include non-cannabinoid pathways.
In addition to antiseizure effects, CBD possesses strong anti-inflammatory and neuroprotective activities, which might contribute to protective effects in epilepsy and other conditions. This article provides a succinct overview of therapeutic approaches and clinical foundations of CBD, emphasizing the clinical utility of CBD for the treatment of seizures associated with refractory and rare epilepsies.
CBD has shown to be a safe and effective antiseizure medicine, demonstrating a broad spectrum of efficacy across multiple seizure types, including those associated with severe epilepsies with childhood onset.
Despite such promise, there are many perils with CBD that hampers its widespread use, including limited understanding of pharmacodynamics, limited exposure-response relationship, limited information for seizure freedom with continued use, complex pharmacokinetics with drug interactions, risk of adverse effects, and lack of expert therapeutic guidelines. These scientific issues need to be resolved by further investigations, which would decide the unique role of CBD in the management of refractory epilepsy.”
“Antiseizure medications (ASMs) are the mainstay for the treatment of seizure disorders. However, about one-third of people with epilepsy remain refractory to current ASMs.
Cannabidiol (CBD) has recently been approved as ASM for three refractory seizure indications in children and adults. In this study, we evaluated the overall clinical potential of oral CBD to treat refractory epilepsy in patients with Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS), and tuberous sclerosis complex (TSC) through a systematic review and meta-analysis. A comprehensive search of databases was conducted, including randomized controlled trials (RCTs) assessing the effect of CBD in epilepsy patients. The review was conducted as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The review focused on RCTs involving patients receiving highly purified oral CBD (Epidiolex, 10 to 50 mg/kg/day) for up to 14 weeks. A subgroup analysis by syndrome and CBD with or without clobazam was conducted.
The key outcomes were reduction in seizure frequency, adverse events, and interactions with clobazam as co-therapy. Odds ratio (OR) with 95% confidence interval (CI) were estimated. Of 1183 articles screened, we included 6 RCTs meeting our eligibility criteria. All studies were considered to have a low risk of bias. In the pooled analysis, CBD treatment was found to be significantly efficacious compared to placebo (OR = 2.45, 95% CI =1.81-3.32, p < 0.01). Subgroup analysis by syndrome demonstrated the odds of ≥50% reduction in seizures with CBD treatment in patients with DS (OR = 2.26, 95% CI:1.38-3.70), LGS (OR = 2.98, 95% CI:1.83-4.85) and TSC (OR = 1.99, 95% CI = 1.06-3.76). Compared with placebo, CBD was associated with increased adverse events (OR = 1.81, 95% CI = 1.33-2.46) such as diarrhea, somnolence, and sedation, and any serious adverse events (OR = 2.86, 95% CI = 1.63-5.05). Other factors, including dosage and clobazam co-therapy, were significantly associated with a greater effect on seizure control and side effects of CBD.
In conclusion, the study shows that CBD is highly efficacious both as standalone and adjunct therapy with clobazam for controlling seizures in DS, LGS, and TSC conditions while limiting side effects. Further pharmacodynamic investigation of CBD actions, drug interaction assessment, and therapeutic management guidelines are warranted.”
“Background: Cannabidiol (CBD) has been of rapidly growing interest in the epilepsy research field due to its antiseizure properties in preclinical models and patients with pharmacoresistant epilepsy. However, little is known about CBD effects in genetic models of epilepsies. Here we assessed CBD dose-response effects in the Genetically Epilepsy Prone Rats (GEPR-3) strain, which exhibits two types of epileptic seizures, brainstem-dependent generalized tonic-clonic seizures and limbic seizures.
Results: CBD dose-dependently attenuated generalized tonic-clonic seizures in GEPR-3 s; CBD 50 and 100 mg/kg reduced brainstem-dependent seizure severity and duration. In fully kindled GEPR-3 s, CBD 10 mg/kg reduced limbic seizure severity and suppressed limbic seizure expression in 75% of animals.
Conclusions: CBD was effective against brainstem and limbic seizures in the GEPR-3 s. These results support the use of CBD treatment for epilepsies by adding new information about the pharmacological efficacy of CBD in suppressing inherited seizure susceptibility in the GEPR-3 s.”
“Taking into consideration the latest reported beneficial anticolvusant effects of cannabidiol (CBD) and cannabiodiolic acid (CBDA) for clinical applications and the advantages of lipid nano-systems as carriers for targeted brain delivery, the aim of this study was set in direction of in vitro physico-chemical and biopharmaceutical characterization and in vivo evaluation of nanoliposomes and nanostructured lipid carriers loaded with Cannabis sativa extract intended for safe and efficient transport via blood-brain barrier and treatment of epilepsy. These nanoliposomes and nanostructured lipid formulations were characterized with z-average diameter <200 nm, following unimodal particle size distribution, negative values for Z-potential, high drug encapsulation efficiency and prolonged release during 24h (38.84-60.91 %). Prepared formulations showed statistically significant higher antioxidant capacity compared to the extract. The results from in vivo studies of the anticonvulsant activity demonstrated that all formulations significantly elevated the latencies for myoclonic, clonic and tonic seizures and, therefore, could be used in preventing different types of seizures. A distinction in the potential of the nano-systems was noted, which was probably anticipated by the type and the characteristics of the prepared formulations.”
“Epilepsy and neurodevelopmental disorders can arise from pathogenic variants of KCNQ (Kv7) channels. A patient with developmental and epileptic encephalopathy exhibited an in-frame deletion of histidine 260 on Kv7.2. Coexpression of Kv7.2 mutant (mut) subunits with Kv7.3 invoked a decrease in current density, a depolarizing shift in voltage for activation, and a decrease in membrane conductance. Biotinylation revealed an increased level of surface Kv7.2mut compared to Kv7.3 with no change in total membrane protein expression. Super-resolution and FRET imaging confirmed heteromeric channel formation and a higher expression density of Kv7.2mut. Cannabidiol (1 μM) offset the effects of Kv7.2mut by inducing a hyperpolarizing shift in voltage for activation independent of CB1 or CB2 receptors. These data reveal that the ability for cannabidiol to reduce the effects of a pathogenic Kv7.2 variant supports its use as a potential therapeutic to reduce seizure activity.”
“Introduction: The safety and efficacy of a formulation high in cannabidiol (CBD) and low in ∆9-tetrahydrocannabinol (THC) to treat drug-resistant epilepsy have been examined previously in children, but not in adult population. The aim of this study was to evaluate whether CBD-rich oil, as an add-on treatment to conventional antiepileptic drugs, was effective, safe, and well-tolerated in adults with drug-resistant focal epilepsy (DRFE).
Methods: An open-label, prospective cohort, single-center in adult patients with DRFE, were receiving stable doses of antiepileptic drugs (AEDs). A cannabis based-magistral formulation (CBMF) (100 mg/ml CBD and THC <1.9 mg/ml) was administrated 0.1 ml sublingually every 12 hours, up-titrated weekly. The primary outcome was to establish a reduction in seizures frequency >50% at 12 weeks. Adverse-drug reactions monitoring was done. p-value <0.05 was statistically significant.
Results: Between August 2020 and July 2022, 44 (38.6%) patients completed >3 months of follow-up. The median daily dose of CBD was 200 mg, that of THC was 4 mg, and that of CBD per kilogram of weight was 3.7 mg. The median number of seizures per month before CBD treatment was 11, and after CBD treatment was 2.5 (p<0.001). A reduction in seizures >50% at 12 week was achieved in 79.5% of the patients. The median percentage change in seizure frequency per month was 84.1% at 12 weeks. Five patients reported any adverse-drug reactions.
Conclusion: The CBMF is a highly effective and safety therapy to treat adult patients with DRFE. The reduction in seizures frequency is maintained over time.”
