“Objective: Highly purified cannabidiol (CBD) is approved as adjunctive therapy for seizures associated with Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS), and tuberous sclerosis complex (TSC), although its role in other developmental and epileptic encephalopathies (DEEs) remains unexplored. The aim of this study was to assess the real-world use, efficacy, and safety of CBD across a broad cohort of patients with DEEs, including off-label indications.

Methods: In this retrospective study, we evaluated 107 patients with DEEs treated with CBD for ≥3 months between 2020 and 2024. Data on seizure frequency, tolerability, retention, and non-seizure outcomes were collected. Efficacy was defined as ≥50% or ≥75% seizure reduction. Statistical analyses explored predictors of response.

Results: Patients had LGS (55.1%), DS (16.8%), TSC (8.4%), or other DEEs (19.6%), with a genetic etiology in 56.1%. At a median follow-up of 20 months, 69% achieved ≥50% seizure reduction, and 21% achieved ≥75% reduction. Patients with LGS, TSC, and other DEEs showed higher efficacy and retention rates compared to DS. Genetic or unknown etiology was associated with better outcomes (p = 0.011). Combination with valproate was associated with reduced efficacy (p = 0.006), while combination with clobazam had no significant effect on efficacy nor safety. Non-seizure improvements included increased alertness (56%), improved sleep quality (25%), and enhanced motor performance (14%). Adverse events occurred in 33.6%, mostly mild and transient; 9% discontinued due to side effects.

Significances: This study confirms the effectiveness and good tolerability of CBD in a real-world DEE population, including off-label use. These findings support expanding CBD indications and underscore the need for prospective studies targeting both seizure and developmental outcomes.

Plain language summary: This study looked at the use of cannabidiol (CBD), a cannabis-based medicine, in 107 people with severe forms of epilepsy called developmental and epileptic encephalopathies (DEEs). With CBD add-on, about two-thirds of patients had fewer seizures, and some caregivers noticed improvements in alertness, sleep, or movement. Most patients tolerated the treatment well, but some experienced side effects, and a few had to stop taking it. While the results are promising, more research is needed to confirm how effective and safe CBD is for different types of DEEs, especially those not currently approved for treatment with CBD.”

https://pubmed.ncbi.nlm.nih.gov/41165013/

“After a median follow-up of 20 months, CBD was globally effective and safe in 107 patients with LGS, DS, TSC, and other DEEs.”

https://onlinelibrary.wiley.com/doi/10.1002/epi4.70149

“Background: Developmental and epileptic encephalopathies (DEEs) constitute rare epileptic conditions characterized by treatment-resistant seizures, neurodevelopmental delay, and various comorbidities. None of the currently available drugs have proven effective in suppressing epileptiform activity in those conditions.

Objectives: We aimed to assess the efficacy and safety of cannabidiol in children with DEEs through a systematic review.

Methods: We searched MEDLINE, Cochrane Central Register of Controlled Trials, trial registries, and reference lists of included studies. We conducted the last search on March 9, 2024. All study types investigating pharmaceutical cannabidiol in children with DEEs were considered eligible, with no language or date restrictions. Risk of bias was assessed using RoB2 and ROBINS-I V2.

Results: Of the 722 records identified, 14 met the inclusion criteria. The included studies varied in design and involved a total of 682 children. Cannabidiol was administered to a maximum dose of 50mg/kg/day. Almost all studies reported positive outcomes with cannabidiol, leading to a reduction of a 50% or above in seizure frequency in at least 20% of patients included in 11 studies. Adverse events were relatively common across studies and included somnolence, loss of appetite, diarrhea, fatigue, and increased serum aminotransferases. Most of them were mild to moderate and reversible.

Conclusions: Cannabidiol is generally well tolerated and has been shown to effectively reduce seizure frequency in children with DEEs whose seizures are refractory to concomitant antiepileptic medications. Future research should explore the long-term effects of cannabidiol on seizure control, developmental outcomes, and quality of life in this population.”

https://pubmed.ncbi.nlm.nih.gov/41135306/

https://www.seizure-journal.com/article/S1059-1311(25)00269-9/abstract

“In recent years, cannabinoids and their derivatives have been tested for efficacy in epilepsy therapy and related disorders. Many of them may help alleviate ailments associated with seizures. An in-depth study of cannabinoid derivatives and the receptors on which they operate give us a chance for more effective use of these substances in epilepsy therapy.

Many studies point to the beneficial synergy of cannabinoids with chemotherapeutics and the increase in effectiveness of the latter. As a result, both alternatives to drug treatment and support for the pharmacotherapy are being developed.

In this review, we focused on compounds such as Δ9-THC, CBDV, Δ9-THCA, Δ9-THCV, H2CBD and their receptors as well as on CBD’s actions, and the enzymes, ion channels, and transporters engaged in the fundamental causes of epileptic seizures.

Treating epilepsy and drug-resistant epilepsy are the two common medical uses of cannabinoids. We looked at approximately 150 current scientific articles from peer-reviewed journals to explore the molecular effects of cannabinoids in these applications. Our goal was to improve physician awareness of factors influencing treatment decisions and potential adverse reactions to minimize medical errors and optimize patient care.”

https://pubmed.ncbi.nlm.nih.gov/41098593/

“In conclusion, while CBD now stands as a recognized and effective treatment for specific forms of epilepsy, a deeper, integrated understanding of its comprehensive mechanisms, validated efficacy across diverse populations, and long-term safety profile remains essential. Continued collaborative efforts among scientists, clinicians, and policymakers, coupled with stringent critical appraisal of evidence, will be key to unlocking the full and safe potential of cannabinoids in epilepsy therapy.”

https://www.frontierspartnerships.org/journals/acta-biochimica-polonica/articles/10.3389/abp.2025.15251/full

“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