Category Archives: Epilepsy

Antiepileptic activity and potential mechanism of full-spectrum hemp extract

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“Epilepsy is the fourth most common neuropsychiatric disorder. Although the approval of Epidiolex has ignited hope for patients, there is still a large gap in the field of anti-seizure research. The effect and underlying mechanism of full-spectrum hemp extract (HE) remains unclear.

Here this study investigated the anti-seizure effect of HE on seizure models. The results showed that HE significantly reduced seizure susceptibility and prolonged seizure latency with better pharmacokinetic performance compared to CBD.

This article then further explored the anti-seizure active components and their possible mechanism in HE. The results indicated that cannabichromene (CBC) and cannabinol (CBN) were involved in the anti-seizure process, especially CBC showed a strong allosteric enhancement effects on CBD binding site of the GABAA receptor, which implied that the GABAA receptor seemed to be the primary anti-epileptic target of HE.

This article not only presents the great potential of HE as a candidate for new anti-epileptic drugs with less psychoactive, but also provides a valuable contribution to subsequent mechanism research and drug development on epilepsy.”

https://pubmed.ncbi.nlm.nih.gov/40166106/

https://www.sciencedirect.com/science/article/pii/S2667325824004552?via%3Dihub

Expanding the therapeutic role of highly purified cannabidiol in monogenic epilepsies: A multicenter real-world study

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“Objective: This real-world, retrospective, multicenter study aims to investigate the effectiveness of highly purified cannabidiol (CBD) in a large cohort of patients with epilepsy of genetic etiology due to an identified monogenic cause. Additionally, we examine the potential relationship between specific genetic subgroups and treatment response.

Methods: This study was conducted across 27 epilepsy centers and included patients with monogenic epileptic disorders (pathogenic or likely pathogenic variants) who were treated with highly purified CBD for at least 3 months.

Results: A total of 266 patients (135 females, 50.8%) with monogenic epilepsies were included with a median age at CBD initiation of 12 years (interquartile range [IQR] = 7-19) and a median follow-up duration of 17 months (IQR = 12-24). Overall, 77 different monogenic epilepsies have been included, with the most common genes being SCN1A (32.3%), TSC2 (13.5%), CDKL5, and MECP2 (4.5% each). The mean seizure reduction at the last follow-up was 38.6%, with 47.5% of patients achieving ≥50% seizure reduction and 7.4% achieving seizure freedom. The Clinical Global Impression scale indicated improvement in 65.8% of patients. The general linear mixed model revealed that a shorter maximum duration of seizure freedom before CBD initiation and a higher degree of intellectual disability were independently associated with lower CBD effectiveness. Conversely, no significant differences in seizure outcome were observed across different epilepsy syndromes (Lennox-Gastaut syndrome, Dravet syndrome, tuberous sclerosis complex epilepsy, and other developmental and epileptic encephalopathy), between approved indications and off-label use, or between concomitant clobazam use or not.

Significance: This study supports CBD as a potential treatment for monogenic epilepsies beyond its licensed indications, demonstrating comparable effectiveness between approved and off-label use and suggesting genetic subgroups with promising treatment responses.”

https://pubmed.ncbi.nlm.nih.gov/40126049/

Cannabidiol Protects Against Neurotoxic Reactive Astrocytes-Induced Neuronal Death in Mouse Model of Epilepsy

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“Reactive astrocytes play a critical role in the initiation and progression of epilepsy, but their molecular subtypes and functional characterization are not fully understood.

In this study, we report the existence of neurotoxic reactive astrocytes, a recently identified subtype, that contribute to neuronal death in the epileptic brain.

In a kainic acid (KA)-induced mouse model of epilepsy, we show that neurotoxic reactive astrocytes are induced by microglia-secreted cytokines, including IL-1α, TNFα, and C1q, and are detectable as early as 7 days post-KA stimulation. These cells exhibit a distinct molecular signature marked by elevated expression of complement 3 and adenosine 2A receptor. Transcriptomics and metabolomics analyses of human brain tissues from temporal lobe epilepsy (TLE) patients and an epileptic mouse model reveal that neurotoxic reactive astrocytes induce neuronal damage through lipid-related mechanisms.

Moreover, our results demonstrate that the anti-seizure medication cannabidiol (CBD) and an adenosine 2A receptor antagonist can both suppress the formation of neurotoxic reactive astrocytes, mitigate gliosis, and reduce neuronal loss in a mouse model of epilepsy. Electrophysiological and behavioral studies indicate that cannabidiol attenuates seizure symptoms and enhances memory capabilities in epileptic mice.

Our findings suggest that neurotoxic reactive astrocytes are formed at an early stage in both the KA-induced mouse model of epilepsy and TLE patients and can contribute to neuronal loss through releasing toxic lipids.

Importantly, cannabidiol emerges as a promising therapeutic drug for targeted intervention against neurotoxic reactive astrocytes in adult epilepsy.”

https://pubmed.ncbi.nlm.nih.gov/40099400/

https://onlinelibrary.wiley.com/doi/10.1111/jnc.70038

Ion channels and G protein-coupled receptors: Cannabidiol actions on disorders of excitability and synaptic excitatory-inhibitory ratio

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“Brain excitability is dysfunctional in epilepsy and overlapping neuropsychiatric conditions including autism spectrum disorder (ASD). Epilepsy and ASD are often attributed to malfunctioning coordination between synaptic excitation and inhibition.

Dravet syndrome (DS) is a severe form of epilepsy arising from haploinsufficiency of the SCN1A gene that encodes the voltage-gated sodium channel Nav1.1. A DS mouse model (Scn1a+/-) recapitulated essential features of DS and revealed that sodium current density was profoundly reduced in GABAergic inhibitory interneurons while pyramidal cells were spared, suggesting that DS is an “interneuronopathy.”

Further studies from the Catterall group and others have expanded this picture: DS symptoms, which include recurrent seizures, ataxia, cognitive impairment, ASD, and premature death, could be assigned in part to brain region-specific effects; the Nav1.1 mutations cause dysfunction in some subtypes of interneurons, not others, and are temporally restricted; DS-causing sodium channel mutations were found throughout SCN1A as well as in SCN1B, encoding the β1 subunit.

Interest in therapeutic approaches was sparked by preclinical studies of cannabidiol (CBD) that led to the 2018 US Food and Drug Administration approval for treatment of seizures in patients with DS. Independent evidence showed that CBD antagonized GPR55, a G protein-coupled receptor activated by the lipid signaling molecule lysophosphatidylinositol (LPI).

We summarized evidence from our group and others that CBD has a dual mechanism of action, targeting both ion channels and GPR55. CBD quells an epileptogenic vicious cycle: seizures strengthen LPI-GPR55 signaling while LPI-GPR55 signaling elevates the synaptic excitatory-inhibitory ratio, thereby promoting further seizures.

SIGNIFICANCE STATEMENT: Modern medicine relies on ion channels and G protein-coupled receptors (GPCRs) as key targets. In studies of Dravet syndrome, a devastating genetic disorder with features of epilepsy and autism, William Catterall connected NaV1.1 mutations to deficient excitability of inhibitory neurons. He and his colleagues explored preclinical interventions using cannabidiol (CBD) and clobazam, opening the way to a current understanding of CBD’s therapeutic mechanism. CBD affects both ion channels and GPR55, a GPCR activated by lysophosphatidylinositol, an activity-dependent lipid messenger, readjusting the synaptic excitatory-inhibitory ratio.”

https://pubmed.ncbi.nlm.nih.gov/40048808/

https://molpharm.aspetjournals.org/article/S0026-895X(25)00003-3/fulltext

Case Report: White-Sutton syndrome and cannabidiol, an update on a reported patient with a successful response to off–label therapy

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“White-Sutton syndrome (WSS), associated with POGZ gene mutations, is a rare genetic disorder characterized by a spectrum of phenotypic features, including intellectual disabilities, developmental delays, and epilepsy. A case report described a female patient diagnosed with WSS who experienced seizures resistant to conventional antiseizure medications. Despite various therapeutic attempts, including valproate, topiramate, levetiracetam, clobazam, rufinamide, and vigabatrin, the patient’s seizures persisted.

After initiating an off-label treatment with cannabidiol (CBD), the patient achieved complete remission from seizures. Following significant clinical improvement, CBD therapy was discontinued by the parents against medical advice, leading to seizure recurrence. Upon reinstatement of CBD, the patient once again experienced successful seizure control.

This report emphasizes the need for further investigation into the off-label use of CBD, as an adjunctive therapy in pediatric individuals with drug-resistant epilepsy associated with WSS.

Although CBD shows promise in other epileptic syndromes, this case highlights its potential effectiveness in this specific condition. This manuscript aims to contribute to the understanding of WSS and advocate for further research into novel treatments, particularly the role of CBD in managing epilepsy within this complex clinical context.”

https://pubmed.ncbi.nlm.nih.gov/40051906/

“After numerous antiseizure medications (ASMs), an add-on off-label cannabidiol (CBD) therapy resulted in the patient being seizure-free. CBD, an exogenous compound derived from the cannabis plant devoid of psychoactive properties, has emerged as a prospective adjunctive therapy for refractory pediatric epilepsy and for developmental and epileptic encephalopathies (DEE).

Current evidence indicates that patients with a wide variety of epilepsy disorders and underlying causes may experience a positive response to treatment with a highly purified, plant-derived CBD oil solution, constituting this as a feasible off-label therapeutic alternative in many other rare pediatric epilepsies “

https://www.frontiersin.org/journals/pediatrics/articles/10.3389/fped.2025.1515304/full

Value of cannabidiol as adjunctive treatment for Lennox Gastaut syndrome: cost-effectiveness and budget impact analysis

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“Background: Lennox-Gastaut syndrome (LGS) is a severe encephalopathic disease that leads to a decrease in the quality of life, physical injury, psychosocial impairment, and a significant increase in treatment costs. Cannabidiol (CBD) is approved for the adjunctive treatment of tonic-colonic seizures in LGS. This study aimed to determine the cost-effectiveness of CBD compared to the usual treatment in patients with LGS syndrome.

Methods: We developed a lifetime-horizon Markov model to compare the cost-effectiveness of adjunctive CBD versus usual care. Additionally, we performed a budget impact analysis over a 5-year time horizon. The findings were presented as the incremental cost-effectiveness ratio (ICER) for CEA, with a willingness to pay threshold of $18,261 per QALY gained, and as the difference in the overall budget ($) between the scenarios with and without CBD for budget impact assessment.

Results: In the base case scenario, CBD was cost-effective compared with usual care $6573 per QALY. Sensitivity analyses substantiated these results. From a healthcare perspective, there is a 77% probability that CBD is cost-effective at a willingness to pay of $18,261 per quality-adjusted life-year (QALY). Overall, the market access of CBD was associated to an increased budget of about $3,459,846 (+ 33%) in the next 5 years simulated.

Conclusions: Compared to usual care, CBD seems to be cost-effective in LGS patients and sustainable, with less than 34% overall budget increased in the next 5 years. Future studies need to confirm our results in the real word setting and in other countries.”

https://pubmed.ncbi.nlm.nih.gov/40038638/

“Our study demonstrates that CBD is valuable as an add-on therapy for patients with LGS in Iran. At current list prices in Iran and assuming a WTP threshold of $18,261/QALY, CBD is cost-effective for the treatment of LGS. So CBD has a more advantage of efficacy compared with usual care and its incremental BI for health system is relatively acceptable. The present study also provides a reference for stakeholders to judge the value of cannabidiol.”

https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-025-03972-9

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

First case report of effective and safe application of cannabidiol to treat concurrent ALG3-CDG and Lennox-Gastaut Syndrome

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“This study presents the first reported case of a Korean patient with Alpha-1,3-Mannosyltransferase-Congenital Disorder of Glycosylation (ALG3-CDG), characterized by a novel maternally inherited missense mutation and a previously reported paternally inherited nonsense mutation. The patient exhibited typical ALG3-CDG manifestations, including developmental delays, epilepsy, and multisystem involvement, alongside a diagnosis of Lennox-Gastaut Syndrome (LGS).

Cannabidiol therapy, combined with dietary management, led to seizure freedom for over 13 months, significant EEG improvement, and enhanced developmental outcomes.

This case underscores the potential of cannabidiol as a promising treatment strategy for patients with ALG3-CDG and refractory epilepsy, broadening therapeutic perspectives for this rare disorder.”

https://pubmed.ncbi.nlm.nih.gov/39831946/

https://link.springer.com/article/10.1007/s10072-025-08004-1

CBD and the 5-HT1A receptor: A medicinal and pharmacological review

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“Cannabidiol (CBD), a phytocannabinoid, has emerged as a promising candidate for addressing a wide array of symptoms.

It has the ability to bind multiple proteins and receptors, including 5-HT1AR, transient receptor potential vanilloid 1 (TRPV1), and cannabinoid receptors. However, CBD’s pharmacodynamic interaction with 5-HT1AR and its medicinal outcomes are still debated.

This review explores recent literature to elucidate these questions, highlighting the neurotherapeutic outcomes of this pharmacodynamic interaction and proposing a signaling pathway underlying the mechanism by which CBD desensitizes 5-HT1AR signaling.

A comprehensive survey of the literature underscores CBD’s multifaceted neurotherapeutic effects, encompassing antidepressant, anxiolytic, neuroprotective, antipsychotic, antiemetic, anti-allodynic, anti-epileptic, anti-degenerative, and addiction-treating properties, attributable in part to its interactions with 5-HT1AR.

Furthermore, evidence suggests that the pharmacodynamic interaction between CBD and 5-HT1AR is contingent upon dosage. Moreover, we propose that CBD can induce desensitization of 5-HT1AR via both homologous and heterologous mechanisms. Homologous desensitization involves the recruitment of G protein-coupled receptor kinase 2 (GRK2) and β-arrestin, leading to receptor endocytosis. In contrast, heterologous desensitization is mediated by an elevated intracellular calcium level or activation of protein kinases, such as c-Jun N-terminal kinase (JNK), through the activity of other receptors.”

https://pubmed.ncbi.nlm.nih.gov/39778776/

“Cannabis was one of the first inhaled drugs utilized by humans, with evidence of use for gout, rheumatism, and malaria dating to 2737 BCE”

“The concurrent literature revealed that CBD produces several therapeutic effects through its complex pharmacodynamic interactions with 5-HT1AR. Therapeutic applications of CBD, including its anxiolytic, antidepressant, antipsychotic, anti-degenerative, neuroprotective, anti-epileptic, and anti-addictive properties were mediated, at least in part, by its binding to 5-HT1AR.”

https://www.sciencedirect.com/science/article/abs/pii/S0006295225000048?via%3Dihub