Category Archives: Epilepsy

Clinically Meaningful Reduction in Drop Seizures in Patients with Lennox-Gastaut Syndrome Treated with Cannabidiol: Post Hoc Analysis of Phase 3 Clinical Trials

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“Background and objective: In clinical trials of patients with Lennox-Gastaut syndrome (LGS), a ≥ 50% reduction in drop seizure frequency is generally accepted as a key endpoint. However, smaller reductions (< 50%) may yet be impactful for patients in real-world settings. This exploratory analysis evaluated the threshold for a clinically important response in drop seizures that is associated with the Caregiver Global Impression of Change (CGIC) scale score in patients with LGS treated with cannabidiol (CBD) oral solution and assessed the suitability of CGIC as an anchor for meaningful change.

Methods: This exploratory post hoc analysis included patients with LGS (N = 215, age 2-55 years) receiving CBD (Epidiolex® [USA]/Epidyolex® [EU]; 100 mg/mL oral solution) in two phase 3 randomized placebo-controlled trials (NCT02224690, April-October 2015, and NCT02224560, June- December 2015). Reduction in drop seizures (involving sudden loss of muscle tone) was anchored to CGIC scores of “slightly improved” or better or “much improved” or better, to determine the threshold at which seizure reduction can be considered clinically meaningful to patients. Spearman’s correlation indicated suitability of anchors (absolute value ≥ 0.30 deemed appropriate).

Results: In the 215 patients receiving CBD with a CGIC score recorded, CGIC was “slightly improved” or better in 60% of patients, and “much improved” or better in 31% after 14 weeks of treatment. With a CGIC rating of “slightly improved” or better, the best threshold for a clinically important response in drop seizure reduction was – 30.6% (57.7% of patients). Mean and median percentage reductions in drop seizures were – 46.9% and – 58.6%, respectively. Using “much improved” or better, the best threshold was – 49.6% (40.5% of patients). Mean and median percentage reductions in drop seizures were – 57.6% and – 66.0%, respectively. Spearman’s correlation was 0.47.

Conclusion: Anchoring to CGIC of “slightly improved” or better, the threshold for a clinically meaningful reduction in drop seizure frequency was 31%, suggesting that a 50% cutoff may overlook patients with meaningful improvements in their overall condition, as perceived by their caregivers. CGIC scores, although potentially less nuanced than other standardized clinical assessments, were appropriate anchors to determine thresholds. This exploratory analysis may help contextualize clinical trial data to better understand potential patient benefit attained by reductions in drop seizure frequency observed in real-world settings that are < 50%.”

https://pubmed.ncbi.nlm.nih.gov/40775196/

https://link.springer.com/article/10.1007/s40263-025-01201-8

Cannabidiol reduces synaptic strength and neuronal firing in layer V pyramidal neurons of the human cortex with drug-resistant epilepsy

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“The use of cannabidiol (CBD) as an alternative pharmacological approach for the symptomatic management of epilepsy has gained attention due to its potential efficacy, particularly in drug-resistant cases of epilepsy.

Although multiple studies have described that CBD reduces neuronal hyperexcitability, the mechanistic basis of CBD remains a topic of ongoing research. In this study, we provide an electrophysiological portrayal of CBD’s effects on the glutamatergic transmission and intrinsic excitability of layer V pyramidal neurons of the human neocortex resected from drug-resistant epilepsy patients.

The perfusion of CBD transiently depressed the field excitatory potential amplitude elicited in layer I/II and recorded in layer V without altering the paired-pulse ratio, suggesting a postsynaptic locus of action for CBD. Cortical slices perfused with 4-aminopyridine exhibited an increased number of spontaneous synaptic events that were abolished in the presence of CBD.

At the cellular level, whole-cell patch-clamp recordings showed that CBD decreased the excitability of layer V pyramidal neurons, as evidenced by changes in the somatic input resistance, the membrane time constant, the hyperpolarization-induced “sag” conductance, the rheobase current needed to elicit an action potential, and the firing discharge in response to depolarizing current steps.

Consistent with the last observation, CBD decreased the amplitude of the TTX-sensitive inward currents without altering the kinetics of the macroscopic outwardly directed currents. CBD washout restored the passive and active electrophysiological properties of pyramidal neurons.

Collectively, these experiments demonstrate that CBD decreases the neuronal excitability of human cortical neurons from patients with drug-resistant epilepsy.”

https://pubmed.ncbi.nlm.nih.gov/40766754/

“Within this framework, cannabidiol (CBD), a non-euphoric compound derived from the Cannabis plant, is a drug approved by multiple regulatory agencies for treating drug-resistant seizures associated with epileptic encephalopathies, such as tuberous sclerosis complex and the Dravet and Lennox–Gastaut syndromes.”

“Although our findings may be considered modest, they provide direct evidence of CBD’s modulatory actions on the electrophysiological parameters underlying the neuronal hyperexcitability associated with epilepsy. More importantly, our results reinforce clinical observations reporting CBD’s positive effects in treating patients with DRE.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1627465/full

Efficacy and safety of cannabidiol in a single-center pediatric drug-resistant epilepsy cohort: a retrospective study

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“Background: Pharmacoresistance to conventional antiseizure medications has been described in approximately 30% of the pediatric epileptic patients, making pharmacological management particularly challenging for physicians. Currently, cannabidiol (CBD) is approved as an adjunctive therapy in combination with clobazam for Dravet Syndrome (DS), Lennox-Gastaut Syndrome (LGS), and as adjunctive treatment for Tuberous Sclerosis Complex (TSC). Studies on drug-resistant epilepsy (DRE) suggested that CBD antiepileptic properties may benefit a wider range of pharmacoresistant epilepsy syndromes.

Objective: Our observational, retrospective, monocentric study aimed to evaluate the effect and safety of CBD in a real-world pediatric cohort with DRE.

Methods: We recruited 15 pediatric patients (7 females, 8 males; mean age: 12.33 ± 4.37 years) affected by pharmacoresistant epilepsy treated with CBD as adjunctive therapy. Inclusion criteria required a diagnosis of DRE, initiation of CBD treatment before 18 years of age, and at least 6 months period of follow-up after CBD initiation. Clinical, demographic, and instrumental data were retrospectively extracted from the medical records and caregivers’ reports. Based on seizure reduction, patients were stratified into “responders” (>50%), “partial responders” (30-50%), and “non-responders” (<30%) groups.

Results: CBD was used as an add-on therapy in 8/15 patients on-label (for DS, LGS, and TSC) and in 7/15 off-label. The maximum dose of CBD administered was 21 mg/kg/day, with an average dose of 16.5 mg/kg/day. 11/15 patients showed a reduction in seizure frequency: 7 were responders (2/7 seizure-free) and 5 were partial responders. Additionally, 11/15 patients showed improved social and environmental participation, as assessed using the Clinical Global Impression scale. Interestingly, brain magnetic resonance imaging revealed structural abnormalities in 5/15 patients, with 6/15 showing malformations of cortical development (4/6 responders, including 1 seizure-free).

Conclusion: CBD demonstrated a good safety and tolerability profile and appeared to be a promising therapeutic option for the management of DRE. It offers a valuable alternative for seizure control and has a positive impact on social interaction, with overall improvement in the quality of life for patients and their caregivers.”

https://pubmed.ncbi.nlm.nih.gov/40740850/

“In conclusion, CBD may represent a promising therapeutic option capable of enhancing the clinical management of DRE. Indeed, it offers a valuable alternative for seizure treatment and positively impacts social interaction and quality of life for the patients and their caregivers.”

https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2025.1616480/full

Use of cannabidiol for off-label treatment of patients with refractory focal, genetic generalised and other epilepsies

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“Background: In randomized controlled trials, add-on cannabidiol (CBD) has been shown to reduce seizure frequency in patients with Lennox-Gastaut syndrome, Dravet syndrome and Tuberous sclerosis complex. Real-world studies provide insights into the drug’s profile in other off-label indications. This study evaluated factors predicting efficacy, retention, and tolerability of add-on CBD used for off-label treatment in clinical practice for patients with refractory focal-onset, genetic generalised, and other unclassified epilepsies.

Methods: A retrospective cohort study recruiting all patients who had started CBD between 2019 and 2023 for off-label treatment at six German epilepsy centres. Data on baseline and follow-up were obtained from patients’ medical records.

Results: A total of 108 patients (mean age 27.3; median 36; range 1.4-68 years, 56 male) were treated with CBD. At three months, 42 (38.9% considering all 108 patients that started CBD) reported at least a 50% reduction in seizures, including 28 patients (25.9%) with a 50-74% reduction, and 14 (13%) with a reduction of 75-99%. Among those 48 patients experiencing tonic-clonic seizures (TCS), at least 50% response was reported by 45.8%, and eight (16.7%) patients were free of TCS. Sex, age, epilepsy syndrome, concomitant clobazam (CLB) use, and the number of concomitant or previous ASMs were not predictive of response. Mean seizure days per month significantly decreased from a mean of 16.8 (median: 13.5) to 14.5 (median 10, p = 0.002). The probability of patients remaining on CBD treatment was 85.2% (n = 92/108, 16 discontinuations) at three months, 73.5% at six months and 61.1% at twelve months; retention was better in children or adolescents compared to adults (log-rank p = 0.014). Using the CGI-C for overall impression, 69 (63.0%) patients were rated as very much, much, or minimally improved; for behaviour, 60 (55.6%) reported within this range of improvement. TEAEs were reported in 41 (38%) patients. The most frequent were diarrhoea (n = 15), sedation (n = 13), and nausea and vomiting (n = 7).

Conclusions: Our results suggest CBD to be an effective ASM, with 50% responder rates similar to those observed in regulatory trials for other ASMs licensed in focal epilepsies. Its off-label use in refractory focal-onset, genetic generalised, and other unclassified epilepsies seems to be safe and well-tolerated.”

https://pubmed.ncbi.nlm.nih.gov/40696489/

“In conclusion, our analysis demonstrates that CBD can achieve favourable responder rates in clinical practice, along with good tolerability, among patients with drug-refractory focal-onset epilepsy, genetic generalised epilepsy, and other epilepsy syndromes.”

https://neurolrespract.biomedcentral.com/articles/10.1186/s42466-025-00408-w

Cannabidiol-Loaded Nanostructured Lipid Carriers for Nose to Brain Delivery: An Effective Therapeutic Approach against Epilepsy

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“The presence of first-pass metabolism and the obstacle of the blood-brain barrier may reduce the effectiveness of oral antiepileptic medications. Nasal drug delivery has been considered a promising selective route to the brain for drugs with low aqueous solubility in the treatment of CNS disease.

The purpose of our study was to improve the bioavailability as well as brain targetability of cannabidiol (CBD) by encapsulating it in nanostructured lipid carriers (NLCs) and delivering the formulation via the nasal route.

CBD-NLCs were effectively prepared with the appropriate particle sizes and polydispersity index for the nasal route (77.71 nm± 0.79 and 0.23 ± 0.00, respectively). These particles demonstrated a high entrapment efficiency and drug loading of 99.24% ± 0.07 and 8.73% ± 0.56 w/w, respectively. According to the FTIR, XRD, and DSC data, CBD was either in the amorphous state or distributed molecularly in the lipid matrix.

The absorption of CBD-NLCs in the nasal cavity was significantly superior to pure CBD (the rate constants were 9.02 ± 1.64 and 2.10 ± 0.25 μg/min, respectively). Compared to the intravenous administration of CBD, CBD-NLCs showed a drug targeting efficiency of 277.82% after nasal administration, indicating a more efficient brain targeting. In a rat model where seizure activity was induced by PTZ, intranasal administration of CBD-NLCs significantly prolonged seizure latency and decreased the Racine score.

All of the results suggest CBD-NLCs administered intranasally might be a promising alternative to traditional epilepsy treatments.”

https://pubmed.ncbi.nlm.nih.gov/40693913/

https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.5c00452

A multicenter study on the use of purified cannabidiol for children with treatment-resistant developmental and epileptic encephalopathies

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“Objective: This descriptive, real-world, multicenter study aimed to evaluate the efficacy, safety, and tolerability of purified cannabidiol (CBD) as an add-on therapy in children with treatment-resistant developmental and epileptic encephalopathies (DEE).

Methods: Children aged 0.5 to 16 years who met the International League against Epilepsy (ILAE) criteria for drug-resistant DEE and were treated with purified CBD at 10 different centers between March 2021 and December 2024 were included.

Results: A total of 551 patients were enrolled. The mean age at CBD initiation was 8.5 years (SD 5 years; range 0.5-18). Median follow-up duration was 22 months (range 13-32). Etiologies were structural in 249 (45 %), genetic in 160 (28.8 %), immune-mediated in five (0.9 %), infectious in three (0.5 %), and unknown in 134 (24.3 %). After 12-32 months of follow-up, 279 patients (50.6 %) had a > 50 % reduction in seizure frequency, including 78 (14.2 %) who became seizure-free. A reduction of < 50 % was observed in 106 (19.1 %), and 34 (6.2 %) experienced no change. Adverse events occurred in 32.7 %, mostly mild and transient, improving with dose adjustments. At the last visit, 389 patients (70.6 %) continued CBD, with 173 (31.4 %) maintaining a > 50 % reduction in seizures and 56 (10.2 %) remaining seizure-free.

Conclusions: This study supports the use of purified CBD as an effective, safe, and well-tolerated treatment option for children with drug-resistant DEEs of diverse etiologies.”

https://pubmed.ncbi.nlm.nih.gov/40669175/

https://www.epilepsybehavior.com/article/S1525-5050(25)00330-0/abstract

Retrospective Multicenter Chart Review Study of Adjunctive Cannabidiol for Seizures Associated with Lennox-Gastaut Syndrome, Dravet Syndrome and Tuberous Sclerosis Complex

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“Introduction: Effectiveness and tolerability of plant-derived highly purified cannabidiol (CBD) in patients with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), or tuberous sclerosis complex (TSC)-associated epilepsy in clinical practice in Germany were evaluated.

Methods: This multicenter, retrospective, chart review study analyzed patients with LGS, DS, or TSC-associated epilepsy receiving ≥ 1 dose of adjunctive CBD (Epidyolex® 100 mg/mL oral solution). Treatment characteristics, seizure outcomes, physician-rated Clinical Global Impression of Change (CGI-C), treatment retention rates, and adverse events (AEs) were analyzed ≤ 12 months.

Results: Among 202 patients identified (159 LGS; 34 DS; 9 TSC), median (interquartile range; range) age was 18.0 (7.9-32.0; 0.3-72.0) years, and median (range) number of prior and concomitant antiseizure medications was 6 (1-24) and 3 (1-7), respectively. Median target CBD dose was 11.1 mg/kg/day (17.6, 15.2, and 9.9 mg/kg/day in the < 6, 6-17, and ≥ 18 years subgroups, respectively). Responder rates (≥ 50% seizure reduction) for total seizures at 3 (n = 194) and 12 (n = 168) months were 43.3% (37.0-50.0% across ages) and 44.0% (37.0-52.5% across ages), respectively, and for generalized tonic-clonic seizures 54.3% (n = 94) (50.0-66.7% across ages) and 47.7% (n = 88) (37.8-66.7% across ages), respectively. Median (range) number of seizure days per month significantly decreased from 30 (0.3-30) to 18 (0-30) in the 3 months before the last 3 months of CBD treatment (p < 0.001). Any improvement in CGI-C was observed in 62% of patients. Of those with available data at 3 and 12 months, 89.6% and 67.1% remained on CBD, respectively. Retention was similar across age groups. AEs reported in ≥ 5% of patients were sedation and diarrhea.

Conclusions: In patients with LGS, DS, or TSC-associated epilepsy, adjunctive CBD was associated with a reduction in seizure frequency across age groups. CBD demonstrated tolerability consistent with its known profile, and 67% of patients remained on treatment at 12 months.”

https://pubmed.ncbi.nlm.nih.gov/40650804/

https://link.springer.com/article/10.1007/s40120-025-00788-w

Dysregulation of the Cannabinoid System in Childhood Epilepsy: From Mechanisms to Therapy

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“Epilepsy affects over 12 million children worldwide, with approximately 30% classified as having drug-resistant epilepsy (DRE), often accompanied by neuropsychiatric comorbidities that severely impact quality of life.

The endocannabinoid system (ECS) functions as a multifaceted neuromodulatory network regulating neuronal excitability, synaptic plasticity, and immune homeostasis from early life through adolescence and into aging. In pediatric epilepsies, alterations in ECS components, particularly CB1 receptor expression and endocannabinoid levels, reveal disorder-specific vulnerabilities and therapeutic opportunities.

Cannabidiol (CBD), a non-psychoactive compound from Cannabis sativa, has shown strong preclinical and clinical efficacy in treating DRE and is approved for Dravet syndrome, Lennox-Gastaut syndrome, and Tuberous Sclerosis Complex. Other ECS-based strategies, such as the use of CB1 receptor-positive allosteric modulators, can selectively enhance endogenous cannabinoid signaling where and when it is active, potentially reducing seizures in conditions like Dravet and absence epilepsy. Similarly, FAAH and MAGL inhibitors may help restore ECS tone without directly activating CB1 receptors.

Precision targeting of ECS components based on regional expression and syndrome-specific pathophysiology may optimize seizure control and associated comorbidities. Nonetheless, long-term pediatric use must be approached with caution, given the critical role of the ECS in brain development.”

https://pubmed.ncbi.nlm.nih.gov/40650012/

“In conclusion, alterations in the ECS are likely involved in the pathophysiology of childhood epilepsy. Precision targeting of ECS components, considering regional CB1R density, fluctuating eCB levels, and syndrome-specific ECS pathophysiology, may offer a more rational and safer strategy for pediatric epilepsy cases with multifactorial etiologies. “

https://www.mdpi.com/1422-0067/26/13/6234

The DEC2-SCN2A Axis is Essential for the Anticonvulsant Effects of Cannabidiol by Modulating Neuronal Plasticity

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“Impairment of neuronal plasticity is involved in a spectrum of neurological disorders such as epilepsy, yet its regulatory mechanisms remain incompletely understood.

Here, it is reported that the basic helix-loop-helix transcription factor DEC2 serves as a pivotal regulator of both neuronal plasticity and epileptogenesis through its repression of sodium voltage-gated channel alpha subunit 2 (SCN2A). Knockdown of DEC2 in hippocampal neurons elevates intrinsic excitability and synaptic transmission, exacerbating seizure susceptibility and severity. Conversely, overexpression of DEC2 in hippocampus reduces intrinsic excitability and synaptic transmission, ultimately decreasing seizure susceptibility. Mechanistically, DEC2 functions as a transcriptional repressor of Scn2a by directly binding class B E-boxes (CACGTG) in its promoter. Additionally, DEC2 forms complexes with myoblast determination protein 1 (MYOD1) and occupies the CAGCTG E-boxes within the Scn2a promoter; however, this interaction does not affect Scn2a transcription in vivo.

These findings also reveal that cannabidiol (CBD) can modulate the DEC2-SCN2A axis. Notably, CBD predominantly enhances DEC2’s direct transcriptional repression of SCN2A.

In summary, this study identifies DEC2 as a critical regulator of neuronal plasticity in epilepsy progression, suggesting a novel therapeutic pathway for epilepsy treatment.”

https://pubmed.ncbi.nlm.nih.gov/40641288/

https://advanced.onlinelibrary.wiley.com/action/oidcStart?redirectUri=%2Fdoi%2F10.1002%2Fadvs.202416315

Cannabidiol attenuates epileptic phenotype and increases survival in a mouse model of developmental and epileptic encephalopathy type 1

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“Objective: Developmental and epileptic encephalopathy type 1 (DEE1) is a rare drug-resistant pediatric epilepsy caused by trinucleotide repeat expansions in the X-linked ARX gene, leading to elongation of the first polyalanine tract. It presents with early onset tonic seizures or spasms, developmental and cognition delay, and high risk of premature mortality. We evaluated the therapeutic potential of highly purified cannabidiol (CBD) in Arx(GCG)7/Y mice, a genetic DEE1 model that replicates key features of the human condition.

Methods: Arx(GCG)7/Y mice received daily intraperitoneal CBD (100 mg/kg) for 7 days. The epileptic phenotype was evaluated via video monitoring and a scoring matrix. In Arx-DEE1 male cortex, real-time polymerase chain reaction and Western blotting assessed CBD effects on proinflammatory and neuronal markers. Microglial morphology was analyzed by Iba1 immunostaining and Sholl analysis. In vitro patch-clamp recordings tested CBD activity on Arx(GCG)7/Y cortical neurons.

Results: CBD reduced the severity and frequency of spontaneous recurrent seizures and significantly extended the lifespan of epileptic mice. In mutant symptomatic mice, CBD activated peroxisome Pparg expression and the concurrent desensitization/inactivation of TRPV1 channels. Additionally, CBD counteracted the dysregulated expression of the proinflammatory genes Ptgs2, Mmp9, Il12, Cd68, Ccl2, and Irf3, while also restoring normal microglial morphology. Further molecular analysis demonstrated that CBD effectively offsets normal alternative splicing for the presynaptic receptor genes Nrnx1 and Nrnx3. Consistent with this, CBD rescued proper Nrnx1 splicing in mutant cortical neurons after K+-induced depolarization. Finally, we found that CBD reduced neuronal excitability by inducing hyperpolarization, raising the action potential threshold, and reducing the frequency and mean charge of inhibitory postsynaptic currents and the mean charge of excitatory postsynaptic currents.

Significance: These findings represent the first preclinical evidence of CBD efficacy in a murine model of genetic DEE1, identifying CBD-sensitive downstream targets and paving the way to further exploration of CBD effects in this disease for future clinical consideration.”

https://pubmed.ncbi.nlm.nih.gov/40608247/

https://onlinelibrary.wiley.com/doi/10.1111/epi.18522