Category Archives: Epilepsy

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

Nanoemulsions of Cannabidiol, Δ9-Tetrahydrocannabinol, and Their Combination Similarly Exerted Anticonvulsant and Antioxidant Effects in Mice Treated with Pentyelenetetrazole

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“Background/Objectives: The main biologically active molecules of Cannabis sativa L. are cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC). Both exert anticonvulsant effects when evaluated as single drugs, but their possible interaction as components of C. sativa extracts has been scarcely studied. For this reason, we evaluated CBD and THC, combined or not, in two seizure models in mice, using an improved vehicle formula. 

Methods: Firstly, acute seizures were induced by intraperitoneal (i.p.) pentylenetetrazole (PTZ, 80 mg/kg), and mice received CBD or THC at 1, 3, 6, and 10 mg/kg, or a CBD/THC 1:1 combination at 1.5, 3, and 6 mg/kg, per os (p.o.), one hour before PTZ administration. Secondly, mice received p.o. CBD (10 mg/kg), CBD/THC (1.5, 3, and 6 mg/kg), valproic acid (50 mg/kg), or vehicle (nanoemulsions without CBD or THC), one hour before PTZ (30 mg/kg, i.p.) every other day for 21 days. Behavioral, biochemical, and immunohistochemical analyses were performed to assess the response to PTZ, oxidative stress, and astroglial activation. 

Results: In the acute model, CBD and THC at 3-10 mg/kg, and their combinations, significantly increased latency to generalized seizures and death, and improved survival rates. In the chronic model, similarly to valproic acid, CBD 10 mg/kg and CBD/THC at 1.5 and 3 mg/kg delayed kindling acquisition, while CBD/THC 6 mg/kg had no effect. CBD and CBD/THC treatments reduced oxidative and nitrosative stress and attenuated astrogliosis, as indicated by decreased glial fibrillary acidic protein and GABA transporter 1 expression and increased inwardly rectifying potassium channel 4.1 expression in hippocampal regions. However, no cannabinoid treatment prevented the impairment in novel object recognition and Y maze tests. 

Conclusions: These findings support the potential role of cannabinoids in counteracting seizures, possibly by reducing oxidative stress and astrogliosis. The study also highlights the importance of nanoemulsions as a delivery vehicle to enhance cannabinoid effectiveness while considering the risks associated with direct cannabinoid receptor activation.”

https://pubmed.ncbi.nlm.nih.gov/40573179/

“This study underscores the potential of CBD and THC nanoemulsions in seizure models, highlighting their capacity to reduce convulsions and brain damage. These formulations significantly decreased markers of oxidative and nitrosative stress, enhancing our grasp of their antiseizure mechanisms.”

https://www.mdpi.com/1424-8247/18/6/782

Is highly purified cannabidiol a treatment opportunity for drug-resistant epilepsy in subjects with typical Rett syndrome and CDKL5 deficiency disorder?

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“Objective: This study aimed to evaluate the efficacy and safety of adjunctive, highly purified Cannabidiol (Epidiolex®) in individuals with drug-resistant epilepsy (DRE) due to genetically determined typical Rett Syndrome (RTT) and CDKL5 Deficiency Disorder (CDD).

Methods: We recruited subjects with genetically confirmed typical RTT and CDD with drug-resistant seizures who received add-on treatment with highly purified Cannabidiol (CBD) through a national collaboration group. CBD treatment was titrated from 5 to 20 mg/kg/day; concurrent antiseizure medications (ASMs) could have been adjusted as clinically indicated.

Results: We enrolled 27 subjects (26 females), carrying a MECP2 genetic variant (14 subjects, 51.9%) or a CDKL5 genetic variant (13 subjects, 48.1%). Median age [IRQ] of individuals was 10.5 [7.9, 18.5] years. The median dose of CBD [IRQ] at last follow-up was 15 [11.12, 18.8] mg/kg/day, in association with a mean of 3 ASMs (range 2-4). The median duration of treatment was 14 [8.5, 20] months. Although not reaching a significant statistical effect, CBD reduced the incidence of seizures with respect to the baseline in 18/27 (66.6%) subjects, with 7 (25.9%) showing a seizure reduction >75%, and 11 (40.7%) >50%. The most relevant adverse events were somnolence seen in 3 subjects, irritability/agitation in 2 subjects, loss of appetite in 2 subjects, and insomnia in 1 individual. Caregivers reported an improvement in attention and reactivity in 12 subjects (44.4%), in sleep quality in 5 subjects (18.5%), and in motor aspects in 3 patients (11.1%).

Significance: CBD resulted effective in reducing seizure frequency in 66.6% of the study sample, regardless of the pathogenic variant; side effects were mild, and caregivers reported an improvement in behavioral and motor features.

Plain language summary: This study explored the use of highly purified Cannabidiol (CBD, Epidiolex®) as an add-on therapy for individuals with drug-resistant epilepsy due to Rett Syndrome (RTT) or CDKL5 Deficiency Disorder (CDD). Twenty-seven participants received CBD alongside their usual ASMs. After a median treatment duration of 14 months, 66.6% experienced fewer seizures, with some showing over 75% reduction. Side effects were generally mild, mainly sleepiness or irritability. Notably, caregivers reported improvements in attention, responsiveness, sleep, and motor function. While results were not statistically significant, they suggest CBD may benefit seizure control and quality of life in RTT and CDD patients.”

https://pubmed.ncbi.nlm.nih.gov/40543048/

“Many caregivers observed positive changes beyond seizure control, including better attention, improved sleep, and enhanced motor function.”

https://onlinelibrary.wiley.com/doi/10.1002/epi4.70078

19 patients report seizure freedom with medical cannabis oil treatment for drug-resistant epilepsy: a case series

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“Purpose: Seizure freedom (SF) is the primary goal of epilepsy treatment. More treatments that produce SF in drug-resistant epilepsy (DRE) are needed. Cannabis-based products for medicinal use (CBPMs) containing cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), administered as oils, have been shown to induce SF in DRE. However, there remains a paucity of published real-world evidence in both pediatrics and adults on SF resulting from CBPM therapy.

Methods: This is a retrospective case series at an outpatient neurology clinic in Toronto, Canada, on patients with DRE who experienced significant SF during CBPM treatment. All patients were treated via the clinic’s stepwise treatment protocol with CBPM oils only. The study describes clinical features of patients and their CBPM-related SF.

Results: We report 19 DRE cases that experienced SF; 15 pediatric, 4 adults. The median cumulative SF duration was 245 days, split between continuous SF periods lasting at least 90 days. Five patients had continuous SF periods lasting ≥ 1 year. Most patients used CBD+THC regimens. Three patients weaned all concomitant ASMs. Adverse events (AEs) were reported by half of the patients.

Conclusion: The results of the study support prioritizing CBPMs in cases of DRE. It also supports research into identifying clinical and biological biomarkers for DRE cases that may achieve SF under CBPM treatment. Lastly, the study supports improving the accessibility of CBPMs, using SF as a primary outcome in future CBPM epilepsy trials, and assessing the role of THC in reducing seizures.”

https://pubmed.ncbi.nlm.nih.gov/40458487/

“A promising treatment for DRE are cannabis-based products for medicinal use (CBPMs) containing variations of cannabinoids, such as cannabidiol (CBD), Δ-9-tetrahydrocannabinol (THC) and other cannabis plant products in an oil formulation.”

“This study reports Real World Evidence from 19 patients with Drug Resistant Epilepsy who experienced Seizure Freedom due to Cannabis based medicinal products therapy. The SF rates observed in this study complement existing literature that reports rates of at least 4%, higher than the 1% observed with established ASMs.”

https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2025.1570531/full

National Multicenter Cohort Study: Adjunctive Cannabidiol-Enriched Cannabis Oil for Pediatric Drug-Resistant Epilepsy Treatment in Thailand

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“Background: Several studies have reported the effectiveness and tolerability of cannabidiol (CBD)-enriched oil adjunctive treatment in children with drug-resistant epilepsy. This is the first multicenter cohort study of medical-grade CBD-enriched drugs in pediatric drug-resistant epilepsy in Thailand.

Methods: A prospective observational study was conducted across 19 Thai government hospitals between 2021 and 2023. The study aimed to assess CBD-enriched adjunctive treatment in pediatric drug-resistant epileptic patients with various etiologies ensuring a follow-up period of at least three months including cases wherein the medication was discontinued before three months.

Results: Of 101 patients, 42% were male with a median age of 10 years, experiencing a seizure frequency of 75 per month, and having failed treatment with an average of seven types of antiseizure medications. The median follow-up duration was 15 months with a median modal CBD dose of 6 mg/kg/day. The ≥50% seizure reduction rate and the median monthly total seizure reduction showed consistent improvement with reductions at three-, six-, nine-, and 12-month and the latest follow-up visits. Most seizure types responded positively to treatment, except for complex motor seizures. The effective CBD dose varied within a range of 1-15 mg/kg/day. Adverse events were reported in 92% of patients, predominantly mild (95%) and including somnolence, increased liver enzymes, anorexia, and irritability. Thirty-three patients discontinued CBD, with 57% due to intolerable adverse events, 30% ineffectiveness, and 12% noncompliance.

Conclusions: The Thai medical-grade CBD-enriched oil is effective and tolerable for at least 12 months of adjunctive treatment in pediatric drug-resistant epilepsy in Thailand.”

https://pubmed.ncbi.nlm.nih.gov/40460512/

“Cannabidiol (CBD) has emerged as a promising therapeutic option, demonstrating efficacy in reducing seizures in children with drug-resistant epilepsy.”

“In conclusion, the Thai medical grade CBD-enriched oil is effective and well tolerated for at least 12 months of continuous adjunctive treatment in pediatric drug-resistant epilepsy in Thailand even at lower CBD doses than those used in other CBD-purified studies.”

https://www.pedneur.com/article/S0887-8994(25)00111-0/fulltext

Cannabidiol and microRNAs: shared cellular targets and new insights for developing anti-seizure modalities

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“Cannabidiol (CBD) and 9-tetrahydrocannabinol (THC) are the two main components of cannabis that provide its therapeutic benefits.

CBD has been extensively studied for its role in reducing seizures, among its many other uses. While the exact mechanisms by which CBD works to relieve seizures have not yet been fully determined, it is evident that CBD effectively diminishes seizure activity and is now being used as an approved treatment for severe forms of non-responsive epilepsy.

As essential components of several biological processes, microRNAs (miRNAs) are crucial for achieving optimal cellular functioning. During the past few years, there has been an increasing interest in elucidating the functional significance of microRNAs in epilepsy. Yet, there is still considerable ambiguity regarding the precise mechanisms by which miRNAs are involved in seizure disorders and also their direct interaction with CBD.

Herein, we seek to present an overview of the varying mechanisms by which CBD offers therapeutic benefits concerning seizures. Accordingly, we highlighted the shared molecular targets between microRNAs and CBD in alleviating seizure symptoms to shed light on the ways in which new therapeutic and diagnostic modalities could be shaped in the future.”

https://pubmed.ncbi.nlm.nih.gov/40461016/

https://academic.oup.com/jpp/advance-article-abstract/doi/10.1093/jpp/rgaf039/8156016?redirectedFrom=fulltext&login=false

Cannabidiol ameliorates seizures and neuronal damage in ferric chloride-induced posttraumatic epilepsy by targeting TRPV1 channel

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“Ethnopharmacological relevance: Posttraumatic epilepsy (PTE) is an acquired epilepsy caused by traumatic brain injury (TBI). From Mesopotamian civilization to Eastern medical classics, the use of Cannabis for anticonvulsant purposes has spanned three millennia of medical history. As a non-psychoactive plant extract of Cannabis, cannabidiol (CBD) has attracted considerable attention in epilepsy-related treatment. However, whether CBD exhibits an anticonvulsant effect against PTE and its underlying molecular mechanisms remains to be elucidated.

Aim of the study: This study aims to investigate the anticonvulsant and neuroprotective effect of CBD on PTE, as well as its molecular mechanisms.

Methods: Ferric chloride (FeCl3)-induced PTE rat models were constructed in normal rats and brain-localized transient receptor potential vanilloid type 1 (TRPV1) overexpression rats. The anticonvulsant effects of CBD were evaluated by epileptic behavioral scoring and electroencephalogram (EEG) monitoring. The neuroprotective effect was measured by histopathological staining of the brain tissues. Immunofluorescence, western blot, q-PCR and Ca2+ fluorescence intensity detection were employed to investigate the mechanisms of CBD on PTE rats.

Results: CBD significantly reduced the seizure severity and brain damage in FeCl3-induced PTE rat models. Besides, EEG data showed decreased amplitude, total power, and spike wave discharges in PTE rats pretreated with CBD. Moreover, CBD suppressed the phosphorylation of heat shock factor 1 (HSF1) by targeting TRPV1, thereby specifically inhibiting the stress-induced heat shock protein 70 (HSP70) increase in the brain-localized TRPV1 overexpression rats.

Conclusion: CBD exerts an anticonvulsant and neuroprotective effect on PTE rats by regulating the TRPV1/HSF1/HSP70 pathway and may be a potential drug for the prophylactic treatment of PTE.”

https://pubmed.ncbi.nlm.nih.gov/40449694/

“CBD may be a potential drug for the prophylactic treatment of PTE.”

https://www.sciencedirect.com/science/article/abs/pii/S0378874125007597?via%3Dihub