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

The Anticonvulsant Effects of Different Cannabis Extracts in a Zebrafish Model of Epilepsy

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“Epilepsy is a widespread neurological disorder that remains a critical global public health challenge. While numerous antiepileptic drugs (AEDs) are available, many patients either fail to achieve adequate seizure control or experience significant side effects.

One promising alternative is pure cannabidiol (CBD), but using a whole cannabis extract may be equally effective and preferred for some patients.

In the current study, we employed the pentylenetetrazole (PTZ)-induced hyperactivity model in zebrafish to compare the effects of CBD with various cannabis extracts. We evaluated three cannabis strains, each subjected to three different extraction methods, and benchmarked the results against the commercially available AED valproic acid (VPA).

Our findings revealed that 5.7 µg/mL of CBD and 10 µg/mL of different extracts significantly reduced movement compared to PTZ and VPA. In addition, effective extracts produced effects similar to pure CBD despite containing much lower molecule levels.

These results reinforced and expanded previous evidence supporting the clinical potential of both CBD and whole cannabis extracts for seizure control while suggesting a possible entourage effect. Further research is necessary to determine which patients may benefit more from pure CBD versus those who might prefer whole cannabis extracts.”

https://pubmed.ncbi.nlm.nih.gov/40427547/

“In conclusion, our results validate and extend previous ones concerning the potential clinical effects of both CBD and whole cannabis extracts used for seizure control.”

https://www.mdpi.com/2218-273X/15/5/654

Cannabidiol Pretreatment Reduces Status Epilepticus and Glutamate Uptake Induced by Kainic Acid in Adult Zebrafish

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“Background: Epilepsy is a neurological chronic disorder that affects about 70 million people worldwide. Status epilepticus (SE) are neural disturbances that cause intense glutamatergic excitatory discharges that modulate changes in normal brain physiological activity. Cannabidiol (CBD) is the main nonpsychomimetic compound present in Cannabis sativa and exhibits a wide spectrum of neuroprotective properties. The use of zebrafish (Danio rerio) is regarded as an important alternative animal model for studies on seizures, as it has neuronal mechanisms similar to humans. 

Objective: This study aims to evaluate the effects of CBD on SE induced by kainic acid (KA) in zebrafish. 

Methods: Animals received CBD (5, 10, or 40 mg·L-1 tank water) for 24 h followed by KA administration (5 mg/kg intraperitoneally). The convulsive pattern of alterations was then assessed. After 12 h, cerebral glutamate transport and oxidative stress were also verified. 

Results: CBD at 5 and 40 mg·L-1 induced a significant decrease in the seizure intensity (26.1% and 29.9%) and an increase in the latency to reach SE (from 10.71 min to 17.5 and 25 min), respectively. In addition, CBD administration (40 mg·L-1) attenuated the decrease in cerebral glutamate transport following 12 h KA-induced seizure. The KA-induced seizure was also able to alter the oxidative stress parameters 2′,7′-dichlorofluorescin, and catalase activity. However, CBD (40 mg·L-1) did not influence these markers.

The present study indicates that CBD promotes a neuroprotective response against the epileptic profile in zebrafish. These findings contribute to the understanding of the influence of CBD on the modulation of excitatory/inhibitory disruption on zebrafish seizure.”

https://pubmed.ncbi.nlm.nih.gov/40354278/

https://www.liebertpub.com/doi/10.1089/can.2024.0189

Adjunctive use of cannabidiol in pediatric drug-resistant epilepsy: A retrospective multicenter analysis

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“Background: Epilepsy affects approximately 70 million people globally, with one-third experiencing drug-resistant epilepsy (DRE). Cannabidiol (CBD) has shown promise in reducing seizure frequency for specific epilepsy syndromes, though data for broader etiologies remain limited. The goal of the study is to evaluate the effectiveness of CBD as an adjunct treatment in the reduction of seizure frequency in DRE patients of various etiologies.

Methods: We conducted a retrospective chart review of patients with refractory epilepsy who received a CBD as an adjunct treatment at two tertiary care centers. Seizure frequency at the start of CBD treatment and at a minimum follow-up of 3 months was recorded. Epilepsy diagnosis was categorized into five groups: Focal/Multifocal Epilepsy, Primary Generalized Epilepsy, Lennox-Gastaut Syndrome, Dravet Syndrome, and Other Developmental and Epileptic Encephalopathies.

Results: Among all patients, 49 % achieved a ≤ 25 % reduction in seizures, while 5 % had a 26-50 % reduction, 21 % reached a 51-75 % reduction, 20 % experienced a 76-99 % reduction, and 5 % achieved near seizure freedom. There was a significant reduction in median seizure frequency from 30 at baseline to 8 post-treatment (p = 0.000). Significant reductions in seizure frequency were also observed within each diagnostic category.

Discussion: CBD has proven to be an effective adjunctive treatment for medically refractory epilepsy, showing significant efficacy across various epilepsy etiologies and genetic backgrounds. Its ability to reduce seizure frequency and the burden of anti-seizure medications (ASMs), especially in syndromes that are traditionally difficult to manage, highlights its value as an additional therapeutic option.”

https://pubmed.ncbi.nlm.nih.gov/40288063/

https://www.epilepsybehavior.com/article/S1525-5050(25)00165-9/abstract

Cannabidiol in Drug-Resistant Epilepsy (DRE) in Children: A Retrospective Study

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“Objectives: To describe the effectiveness and tolerability of cannabidiol (CBD) in children with drug-resistant epilepsy (DRE).

Methods: Records of children with DRE who received CBD for at least six months were reviewed. Reduction in seizure frequency [complete (> 90%), partial (30-90%), no response (< 30%)], parent reported adverse effects and discontinuation of CBD, if any, were noted.

Results: Records of 50 children with DRE (Lennox-Gastaut syndrome 32, Dravet syndrome 4, and Tuberous sclerosis complex 2), mean (SD) age 7.8 (4.3) years were reviewed. Complete, partial, and no response to CBD was seen in 10, 18 and 14 children; 8 became seizure-free. Eight children discontinued treatment due to lack of efficacy (n = 4), by increased adverse effects (n = 3) and aggravation of seizures (n = 1). Adverse effects were noted in 22 (44%), none required hospitalization.

Conclusion: Cannabidiol is a useful and safe add-on drug in children with DRE.”

https://pubmed.ncbi.nlm.nih.gov/40261499/

https://link.springer.com/article/10.1007/s13312-025-00075-9