“Drug resistance affects 30% of patients with epilepsy. Cannabidiol (CBD) decreases the expression of drug-resistant seizures in specific syndromes. However, it is unknown if CBD prevents the development of drug-resistant condition in epilepsy.

This research was conducted to investigate if subchronic administration of CBD with sodium channel blockers modifies the mortality associated with clonic-tonic seizures and the development of the drug-resistant phenotype induced by subchronic administration of 3-mercaptopropionic acid (3-MP) in rats. These effects were compared with those elicited by antiseizure medications acting on the GABA_A receptors.

Male Wistar rats were used to evaluate CBD combined with different antiseizure medications (phenobarbital, diazepam, valproic acid, lamotrigine and oxcarbazepine) during the repetitive administration of 3-MP. The mortality rate and development of drug-resistant seizures were estimated. Computational experiments explored interactions between CBD and sodium channel blockers in the NaV1.7 receptor.

Subchronic administration of CBD alone did not modify neither the mortality rate nor the development of drug-resistant seizures. CBD combined with phenobarbital or diazepam reduced the mortality rate and prevalence of drug-resistant seizures. In contrast, coadministration of CBD with valproic acid or lamotrigine did not modify neither the mortality rate nor the expression of drug-resistant seizures. Contrariwise, combining CBD with oxcarbazepine at ED₅₀ increases the incidence of drug-resistant seizures. Computational experiments suggested that CBD acting on NaV1.7 interferes with the action of sodium channel blockers and precludes their inhibitory effects.

Our results indicate that repeated administration of CBD with GABAergic antiseizure medications, but not sodium channel blockers, decreases the mortality and prevents the development of the drug-resistant phenotype induced by repeatedly provoked severe seizures.”

https://pubmed.ncbi.nlm.nih.gov/41050418/

“The present study confirms that CBD alone does not modify the mortality rate induced by severe seizures. Our results also support that CBD combined with GABAergic drugs but not with sodium channel blockers reduces the mortality rate during the repetitive induction of clonic-tonic seizures and prevents the development of drug-resistance seizures in a preclinical model.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1644018/full

“Cannabidiol (CBD) decreases seizures in patients with severe pediatric-onset epilepsies including Dravet, Lennox-Gastaut, and Tuberous Sclerosis syndromes. However, the effects of CBD on neuronal activity and circuits remain obscure.

In the mouse hippocampus, we found that CBD causes a GPR55-independent decrease in CA1 pyramidal neuron firing frequency and a GPR55-dependent reduction in CA3 to CA1 hippocampal activity propagation. CBD-mediated decrease in high-frequency activity was mimicked by GPR55 antagonism and prevented by GPR55 deletion and blockade of GABAergic transmission. Dampening high-frequency activity was accompanied by increased recruitment of parvalbumin+ (PV)-INs and reduced recruitment of somatostatin+ (SST)-INs, leveraging the inhibitory subcircuit to limit propagation of hyperactivity. CBD-induced attenuation of high frequency spike propagation was mimicked by pharmacological enhancement and optogenetic engagement of PV-INs. Such increased on-demand recruitment of PV-INs dampened propagation of high-frequency activity to hippocampal CA1 similarly to CBD.

We predict that CBD potentially curbs propagation and perpetuation of seizure activity via these mechanisms.”

https://pubmed.ncbi.nlm.nih.gov/40909733/

https://www.biorxiv.org/content/10.1101/2025.08.26.672420v1

“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

“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

“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

“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

“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