“Objective: Cannabidiol (CBD) is approved for treatment of Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS), and tuberous sclerosis complex (TSC). Several studies suggest anti-seizure effects also beyond these three epilepsy syndromes.

Methods: In a retrospective multi-center study, we analyzed the efficacy and tolerability of CBD in patients with epilepsy at 16 epilepsy centers.

Results: The study cohort comprised 311 patients with epilepsy with a median age of 11.3 (0-72) years (235 children and adolescents, 76 adults). Therapy with CBD was off-label in 91.3% of cases due to age, epilepsy subtype, lack of adjunct therapy with clobazam, and/or higher dose applied. CBD titration regimens were slower than recommended, with good tolerability of higher doses particularly in children. Of all patients, 36.9% experienced a reduction in seizure frequency of >50%, independent of their epilepsy subtype or clobazam co-medication. The median observation period was 15.8 months. About one third of all patients discontinued therapy within the observation period due to adverse effects or lack of efficacy. Adverse effects were reported frequently (46.9%).

Significance: Our study highlights that CBD has an anti-seizure effect comparable to other anti-seizure medications with a positive safety profile independent of the epilepsy subtype. Comedication with clobazam was not associated with a better outcome. Higher doses to achieve seizure frequency reduction were safe, particularly in children. These findings call for further trials for an extended approval of CBD for other epilepsy subtypes and for children < 2 years of age.”

https://pubmed.ncbi.nlm.nih.gov/36693811/

https://onlinelibrary.wiley.com/doi/10.1002/epi4.12699

“Objective: Cannabidiol (CBD) expanded access program (EAP), initiated in 2014, provided add-on CBD to patients with treatment-resistant epilepsy (TRE) at 35 US epilepsy centers. Prior publications reported results through December 2016; herein, we present efficacy and safety results through January 2019.

Methods: Patients received plant-derived highly purified CBD (Epidiolex®; 100 mg/mL oral solution), increasing from 2-10 mg/kg/d to tolerance or maximum 25-50 mg/kg/d dose, depending on the study site. Efficacy endpoints included percentage change from baseline in median monthly convulsive and total seizure frequency and ≥50%, ≥75%, and 100% responder rates across 12-week visit windows for up to 192 weeks. Adverse events (AEs) were documented at each visit.

Results: Of 892 patients in the safety analysis set, 322 (36%) withdrew; lack of efficacy (19%) and AEs (7%) were the most commonly reported primary reasons for withdrawal. Median (range) age was 11.8 years (0-74.5), and patients were taking a median (range) 3 (0-10) antiseizure medications (ASMs) at baseline; most common ASMs were clobazam (47%), levetiracetam (34%), and valproate (28%). Median top CBD dose was 25 mg/kg/d; median exposure duration was 694 days. Median percentage reduction from baseline ranged from 50%-67% for convulsive seizures and 46%-66% for total seizures. Convulsive seizure responder rates (≥50%, ≥75%, and 100% reduction) ranged from 51%-59%, 33%-42%, and 11%-17% of patients across visit windows, respectively. AEs were reported in 88% of patients and serious AEs in 41%; 8% withdrew because of an AE. There were 20 deaths during the study deemed unrelated to treatment by the investigator. Most common AEs (≥20% of patients) were diarrhea (33%), seizure (24%), and somnolence (23%).

Significance: Add-on CBD was associated with sustained seizure reduction up to 192 weeks with an acceptable safety profile and can be used for long-term treatment of TREs.”

https://pubmed.ncbi.nlm.nih.gov/36537757/

https://onlinelibrary.wiley.com/doi/10.1111/epi.17496

“Objective: The objective of this systematic review with meta-analysis was to evaluate the efficacy, safety, and short- and long-term tolerability of cannabidiol (CBD), as an adjunct treatment, in children and adults with Dravet syndrome (SD), Lennox-Gataut syndrome (LGS), or tuberous sclerosis complex (TSC), with inadequate control of seizures.

Methods: This systematic review was conducted through a search for scientific evidence in the Mediline/PubMed, Central Cochrane, and ClinicalTrials.gov databases until April 2022. Selected randomized clinical trials (RCTs) that presented the outcomes: reduction in the frequency of seizures and total seizures (all types), number of patients with a response greater than or equal to 50%, change in caregiver global impression of change (CGIC) (improvement ≥1 category on the initial scale), adverse events (AEs), and tolerability to treatment. This review followed Preferred Reporting Items for Systematic reviews and Meta-Analyses.

Results: Notably, six RCTs were included, with a total of 1,034 patients with SD, LGS, and TSC, of which 3 were open-label extension RCTs. The meta-analysis of the studies showed that the use of CBD as compared with placebo, in patients with convulsive seizures refractory to the use of medications, reduces the frequency of seizures by 33%; increases the number of patients with a reduction ≥50% in the frequency of seizures by 20%; increases the number of patients with absence of seizures by 3%; improves the clinical impression evaluated by the caregiver or patient (S/CGIC) in 21%; increases total AEs by 12%; increases serious AE by 16%; increases the risk of treatment abandonment by 12%; and increases the number of patients with transaminase elevation (≥3 times the referral) by 15%.

Conclusions: This systematic review, with meta-analysis, supports the use of CBD in the treatment of patients with seizures, originated in DS, LGS, and TSC, who are resistant to the common medications, presenting satisfactory benefits in reducing seizures and tolerable toxicity.”

https://pubmed.ncbi.nlm.nih.gov/36417631/

https://www.scielo.br/j/ramb/a/vh3QpdBkQfXVrdw7nT63bdd/?lang=en

“Objective: To summarize and evaluate clinical experiences with refractory status epilepticus in which cannabidiol (CBD) was utilized for cessation of seizure activity.

Methods: A comprehensive literature review was performed on PubMED, MEDLINE, Scopus, and CINAHL between May – June 2022 with the assistance of a medical reference librarian using the following search terms: “Cannabidiol” [MAJR], “Status Epilepticus” [MAJR], “New-Onset Refractory Status Epilepticus”, and “cannabidiol.” Reports that provided dosing regimens and patient outcomes were included.

Results: Thirty-two articles were screened. Five articles were selected for inclusion in this review and detailed the clinical courses of 11 patients. Five of the 11 patients received CBD during the chronic epilepsy stage, while the remaining 6 received it during a period of acute status epilepticus. Patients were trialed on an average of 9 anti-epileptic drugs prior to CBD administration, after which 9 of the 11 patients experienced a reduction of seizure activity. Dosing of CBD ranged between 5-25 mg/kg/day and was titrated based on patient response to therapy. Adverse effects were relatively benign and were generally limited to gastrointestinal discomfort, reported after seizure cessation.

Conclusions: CBD may provide a potentially efficacious and safe management strategy in refractory status epilepticus, including patients with new-onset refractory status epilepticus and febrile infection-related epilepsy syndrome. A potential for drug-drug interactions between CBD and anti-epileptic drugs warrants judicious monitoring. Additional research is necessary to determine a definitive dosing strategy for this agent.”

https://pubmed.ncbi.nlm.nih.gov/36399869/

“The efficacy and safety of CBD has been demonstrated in Lennox-Gastaut and Darvet Syndromes.”

https://www.seizure-journal.com/article/S1059-1311(22)00260-6/fulltext

“Introduction: Cannabidiol (CBD) has been clinically approved for intractable epilepsies, offering hope that novel anticonvulsants in the phytocannabinoid class might be developed. Looking beyond CBD, we have recently reported that a series of biosynthetic precursor molecules found in cannabis display anticonvulsant properties. However, information on the pharmacological activities of these compounds on CNS drug targets is limited. The current study aimed to fill this knowledge gap by investigating whether anticonvulsant phytocannabinoids affect T-type calcium channels, which are known to modulate neuronal excitability, and may be relevant to the anti-seizure effects of this class of compounds. 

Materials and methods: A fluorescence-based assay was used to screen the ability of the phytocannabinoids to inhibit human T-type calcium channels overexpressed in HEK-293 cells. A subset of compounds was further examined using patch-clamp electrophysiology. Alphascreen technology was used to characterise selected compounds against G-protein coupled-receptor 55 (GPR55) overexpressed in HEK-293 cells, as GPR55 is another target of the phytocannabinoids. 

Results: A single 10 µM concentration screen in the fluorescence-based assay showed that phytocannabinoids inhibited T-type channels with substantial effects on Ca_v3.1 and Ca_v3.2 channels compared to the Ca_v3.3 channel. The anticonvulsant phytocannabinoids cannabigerovarinic acid (CBGVA) and cannabidivarinic acid (CBDVA) had the greatest magnitudes of effect (≥80% inhibition against Ca_v3.1 and Ca_v3.2), so were fully characterized in concentration-response studies. CBGVA and CBDVA had IC₅₀ values of 6 μM and 2 µM on Ca_v3.1 channels; 2 μM and 11 µM on Ca_v3.2 channels, respectively. Biophysical studies at Ca_v3.1 showed that CBGVA caused a hyperpolarisation shift of steady-state inhibition. Both CBGVA and CBDVA had a use-dependent effect and preferentially inhibited Ca_v3.1 current in a slow inactivated state. CBGVA and CBDVA were also shown to antagonise GPR55. 

Conclusion and implications: These findings show that CBGVA and CBDVA inhibit T-type calcium channels and GPR55. These compounds should be further investigated to develop novel therapeutics for treating diseases associated with dysfunctional T-type channel activity.”

https://pubmed.ncbi.nlm.nih.gov/36386164/

“Here we report that the understudied minor phytocannabinoids CBDVA and CBGVA, which are biosynthetic precursor molecules found in the cannabis plant, inhibit both T-type calcium channels and GPR55 receptors in vitro. Our data suggest that these compounds could be further explored for therapeutic potential in disease states which involve these channels or receptors, such as epilepsy, insomnia, pain and gastrointestinal disorders.”

https://www.frontiersin.org/articles/10.3389/fphar.2022.1048259/full

“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.”

https://pubmed.ncbi.nlm.nih.gov/36220975/

https://link.springer.com/article/10.1007/s43440-022-00413-9

“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.”

https://pubmed.ncbi.nlm.nih.gov/36206806/

https://www.sciencedirect.com/science/article/pii/S001448862200262X?via%3Dihub

“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.”

https://pubmed.ncbi.nlm.nih.gov/36206805/

“CBD is effective for all three refractory seizure indications.”

https://www.sciencedirect.com/science/article/abs/pii/S0014488622002631?via%3Dihub

“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.”

https://pubmed.ncbi.nlm.nih.gov/36195689/

https://link.springer.com/article/10.1007/s43440-022-00416-6