Use of cannabidiol in the treatment of epilepsy: Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex

“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 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.”

Cannabidiol in refractory status epilepticus: A review of clinical experiences

Seizure (journal) - Wikipedia

“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.”

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

The anticonvulsant phytocannabinoids CBGVA and CBDVA inhibit recombinant T-type channels

Frontiers - Crunchbase Company Profile & Funding

“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 Cav3.1 and Cav3.2 channels compared to the Cav3.3 channel. The anticonvulsant phytocannabinoids cannabigerovarinic acid (CBGVA) and cannabidivarinic acid (CBDVA) had the greatest magnitudes of effect (≥80% inhibition against Cav3.1 and Cav3.2), so were fully characterized in concentration-response studies. CBGVA and CBDVA had IC50 values of 6 μM and 2 µM on Cav3.1 channels; 2 μM and 11 µM on Cav3.2 channels, respectively. Biophysical studies at Cav3.1 showed that CBGVA caused a hyperpolarisation shift of steady-state inhibition. Both CBGVA and CBDVA had a use-dependent effect and preferentially inhibited Cav3.1 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.”

“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.”

Preclinical efficacy of cannabidiol for the treatment of early-life seizures


“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.”

Therapeutic and clinical foundations of cannabidiol therapy for difficult-to-treat seizures in children and adults with refractory epilepsies

Experimental Neurology

“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.”

Clinical efficacy and safety of cannabidiol for pediatric refractory epilepsy indications: A systematic review and meta-analysis

Experimental Neurology

“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.”

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

Cannabidiol attenuates generalized tonic-clonic and suppresses limbic seizures in the genetically epilepsy-prone rats (GEPR-3) strain


“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.”

Cannabidiol counters the effects of a dominant-negative pathogenic Kv7.2 variant

iScience journal (@iScience_CP) / Twitter

“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.”

“Control of seizure activity has been increasingly gained through use of cannabinoids, with cannabidiol (CBD) specifically approved for clinical use.”

Cannabis-based magistral formulation is highly effective as an adjuvant treatment in drug-resistant focal epilepsy in adult patients: an open-label prospective cohort study


“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.”

Cannabidiol effect in pentylenetetrazole-induced seizures depends on PI3K


“Background: The phytocannabinoid cannabidiol (CBD) has previously shown to have anticonvulsant effects in preclinical and clinical studies. Recently, CBD has been approved to treat certain types of drug-resistant epileptic syndromes. However, the underlying mechanism of action remains unclear. The phosphatidylinositol 3-kinase (PI3K) signaling pathway has been proposed to modulate seizures and might be recruited by CBD. Thus, we tested the hypothesis that the anticonvulsant effect of CBD involves PI3K in a seizure model induced by pentylenetetrazole (PTZ).

Methods: We employed pharmacological and genetic approaches to inhibit PI3K and quantified its effects on seizure duration, latency, and number.

Results: PI3K genetic ablation increased the duration and number of seizures. CBD inhibited PTZ-induced seizures in mice. Genetic deletion of PI3K or pretreatment with the selective inhibitor LY294002 prevented CBD effects.

Conclusion: Our data strengthen the hypothesis that the CBD anticonvulsant effect requires the PI3K signaling pathway.”