Molecular targets of cannabinoids and their derivatives in epilepsy – a review with focus on CBD

BACKGROUND: Drug-resistant epilepsy challenges clinical management, with many patients failing to find relief. Low Glycemic Index Therapy (LGIT) shows promise but lacks clear efficacy data. Clarifying LGIT's effectiveness could ease patient burden and improve seizure management. AIM: To evaluate the efficacy, tolerability, and adverse effects of Low Glycemic Index Therapy (LGIT) as an adjunctive treatment for drug-resistant epilepsy, utilizing a meta-analysis approach. METHODS: We followed a meticulous approach to conducting a meta-analysis on Low Glycemic Index Therapy (LGIT) in drug-resistant epilepsy, leveraging databases such as PubMed, Embase, Scopus, and the Cochrane Library. A total of twelve studies meeting inclusion criteria were identified. Comprehensive search terms and filters were applied to retrieve relevant data. Two independent reviewers meticulously screened titles, abstracts, and full texts, ensuring adherence to predefined criteria. Data extraction encompassed study characteristics, participant demographics, intervention details, and outcomes, including seizure frequency, %reduction, and adverse events. Quality assessment utilized established tools like the Cochrane Risk of Bias tool and the Newcastle-Ottawa Scale. Statistical analyses incorporated mean differences, risk ratios, and sensitivity/subgroup analyses. Ethical considerations were upheld, and reporting followed PRISMA guidelines. Limitations, including potential biases and heterogeneity, were acknowledged, with sensitivity analyses conducted to enhance findings' validity. This systematic methodology ensures a comprehensive evaluation of LGIT's efficacy, tolerability, and adverse effects in drug-resistant epilepsy patients. RESULTS: Variations in adverse effects and compliance further highlight heterogeneous responses to LGIT. Despite promising results, limitations include study design variability and short follow-up durations, potentially affecting generalizability and long-term outcomes assessment. Mean and risk differences across twelve studies investigating Low Glycemic Index Therapy (LGIT) in drug-resistant epilepsy showed significant reductions in seizure frequency were observed with LGIT compared to control groups (mean difference: -1.97 [-3.48, -0.47], Z = 2.56, p = 0.01). Heterogeneity analysis revealed substantial variability (Tau² = 2.04, Chi² = 49.89, df = 3, I² = 86%). Funnel plots further underscored LGIT's efficacy, with a mean difference of 4.80 [1.98, 7.61] favoring experimental interventions. However, heterogeneity remained considerable (Tau² = 6.20, Chi² = 7.14, df = 4, I² = 63%). Risk differences favored LGIT but were not statistically significant (total: -0.11 [-0.35, 0.13], Z = 0.89, p = 0.37). CONCLUSIONS: Diverse study designs and participant cohorts provide insights into LGIT's efficacy, tolerability, and adverse effects. Notably, LGIT consistently reduces seizure frequency across studies, as evidenced by significant results in multiple investigations.

Drug-resistant epilepsy (DRE) affects >25 million people worldwide and is often associated with neuroinflammation. Increasing evidence links deficiency or malfunctioning of the enzyme phosphoglycerate dehydrogenase (PHGDH), which converts 3-phosphoglycerate to generate serine and the neurotransmitter glycine, with (drug-resistant) epilepsy. Moreover, PHGDH, which is primarily expressed in astrocytes within the brain, has been identified as a critical enzyme in driving macrophage polarization toward an anti-inflammatory state. Hence, PHGDH activators may be beneficial for treating DRE by exhibiting both antiseizure and anti-inflammatory activity. The objective of this study was to identify such PHGDH activators. We screened a drug repurposing library for PHGDH activators and assessed their antiseizure and anti-inflammatory properties using various zebrafish and mouse epilepsy models and explored the mechanistic consequences of activating PHGDH in a cell line, in astrocytes, and in zebrafish heads. Finally, we assessed the efficacy of clioquinol as add-on treatment in three severe DRE patients in a clinical open pilot proof-of-concept study. We identified haloquinolines from a drug repurposing library as potent activators of PHGDH. The most promising haloquinoline clioquinol can increase the catalytic activity of PHGDH up to 2.5-fold, thereby increasing de novo glycine biosynthesis and resulting in reduced glutamate levels. Moreover, we show that clioquinol has PHGDH-dependent antiseizure activity as well as anti-inflammatory properties invivo using various zebrafish and mouse epilepsy models. Finally, we demonstrate the efficacy of clioquinol as add-on treatment in severe DRE patients; two patients showed a 37%-47% reduction in seizure frequency, and all three patients noted a positive impact on quality of life and seizure severity. Increasing activity of PHGDH is a promising new approach to treat DRE.

Fenfluramine has emerged as a promising adjunctive antiseizure medication for treatment-resistant epilepsy syndromes such as Dravet and Lennox-Gastaut. This systematic review synthesized evidence from seven studies, including randomized controlled trials and open-label extensions, evaluating fenfluramine’s efficacy, cardiovascular and metabolic safety, and long-term outcomes across pediatric and adult populations. The findings consistently demonstrated substantial reductions in seizure frequency, particularly for drop and generalized tonic-clonic seizures. Safety monitoring revealed no cases of valvular heart disease or pulmonary arterial hypertension, and treatment-emergent adverse events such as decreased appetite and fatigue were generally mild to moderate. In parallel, selected studies evaluating other commonly used antiseizure medications provided comparative insights into metabolic risks, identifying concerns such as vitamin D deficiency, hyponatremia, and weight fluctuations, alongside mitigation strategies through supplementation and lifestyle interventions. Integrating these data contextualizes fenfluramine’s favorable profile within the broader antiseizure therapy landscape and underscores the importance of individualized risk-benefit assessment. Overall, the evidence supports fenfluramine as an effective and well-tolerated option for drug-resistant epilepsy, while emphasizing the need for systematic metabolic monitoring to optimize long-term care. Future research should prioritize head-to-head comparative trials, standardized cardiovascular and metabolic safety protocols, and long-term real-world studies to strengthen clinical guidance and advance precision therapy in epilepsy management.

Clioquinol as a New Therapy in Epilepsy: From Preclinical Evidence to a Proof-of-Concept Clinical Study Thevissen K, Ny A, Copmans D, Tits J, Kamata K, Gielis E, Longin K, Sourbron J, Thergarajan P, Tan TH, Ali I, Jones NC, O’Brien TJ, Monif M, Semple BD, Germeys C, Frizzi B, Minniti V, Perrone S, Linster CL, Elia I, Van Den Bosch L, Cammue BPA, Voet A, Lagae L, de Witte P. Epilepsia . 2025. doi:10.1111/epi.18536. Online ahead of print Objective: Drug-resistant epilepsy (DRE) affects >25 million people worldwide and is often associated with neuroinflammation. Increasing evidence links deficiency or malfunctioning of the enzyme phosphoglycerate dehydrogenase (PHGDH), which converts 3-phosphoglycerate to generate serine and the neurotransmitter glycine, with (drug-resistant) epilepsy. Moreover, PHGDH, which is primarily expressed in astrocytes within the brain, has been identified as a critical enzyme in driving macrophage polarization toward an anti-inflammatory state. Hence, PHGDH activators may be beneficial for treating DRE by exhibiting both antiseizure and anti-inflammatory activity. The objective of this study was to identify such PHGDH activators. Methods: We screened a drug repurposing library for PHGDH activators and assessed their antiseizure and anti-inflammatory properties using various zebrafish and mouse epilepsy models and explored the mechanistic consequences of activating PHGDH in a cell line, in astrocytes, and in zebrafish heads. Finally, we assessed the efficacy of clioquinol as add-on treatment in three severe DRE patients in a clinical open pilot proof-of-concept study. Results: We identified haloquinolines from a drug repurposing library as potent activators of PHGDH. The most promising haloquinoline clioquinol can increase the catalytic activity of PHGDH up to 2.5-fold, thereby increasing de novo glycine biosynthesis and resulting in reduced glutamate levels. Moreover, we show that clioquinol has PHGDH-dependent antiseizure activity as well as anti-inflammatory properties in vivo using various zebrafish and mouse epilepsy models. Finally, we demonstrate the efficacy of clioquinol as add-on treatment in severe DRE patients; two patients showed a 37%-47% reduction in seizure frequency, and all three patients noted a positive impact on quality of life and seizure severity.

Effectiveness analysis of three-drug combination therapies for refractory focal epilepsy

Expression and cellular distribution of multidrug resistance-related proteins in patients with focal cortical dysplasia

Efficacy and safety of MR-guided laser interstitial thermoablative therapy (MRgLITT) for drug-resistant epilepsy

ObjectiveTo determine the efficacy and safety of clobazam, a benzodiazepine derivative endorsed for adjunctive therapy in drug-resistant epilepsy due to its broad-spectrum efficacy and tolerability profile, as an adjunctive treatment for pediatric patients with drug-resistant epilepsy.MethodsThis was a multicenter, real-world, self-controlled study. Pediatric drug-resistant epilepsy patients receiving clobazam adjunctive treatment at three centers were retrospectively included. The primary outcomes were response rates and seizure-free rates at 6 and 12 months of treatment. The secondary outcomes included retention rates at months 6 and 12 of treatment and adverse events that occurred during the addition of clobazam therapy.ResultsA total of 146 patients were included. The retention rates were 87.67% (128/146) and 81.51% (119/146) at 6 and 12 months, respectively. The response rates were 58.99% (82/139) and 62.41% (83/133), and the seizure-free rates were 36.69% (51/139) and 35.34% (47/133) at 6 and 12 month, respectively. Clobazam has shown good efficacy in patients with epilepsy due to genetic variants (60.42%, 29/48) and its significantly better efficacy for the SCN1A genotype than for other genotypes (P=0.048). The independent factor associated with clinical response was a lower baseline seizure frequency (seizure frequency <1 seizure/day). Adverse reactions occurred in 24 (24/146, 16.64%) patients, with excessive salivation/hypersalivation (4/146, 2.74%) and loss of appetite (4/146, 2.74%) being the most common.ConclusionClobazam adjunctive therapy is effective, safe and well tolerated in pediatric patients with drug-resistant epilepsy.

Efficacy and safety of cannabidiol as add-on therapy in drug-resistant epilepsy, a single center experience

To evaluated the effectiveness and safety of single anti-seizure medication (ASM) when used as adjunctive therapy for drug-resistant focal epilepsy. We conducted a comprehensive search of PubMed, EMbase, and the Cochrane Library from their inception until 12 February, 2025, to identify randomized controlled trials (RCTs) meeting our criteria. The trials were analyzed for their use of ASMs in treating drug-resistant focal epilepsy. Inclusion criteria comprised: 1) Participants aged 12years or older with drug-resistant focal epilepsy; 2) Incorporation of an additional single ASM as an adjunct to the existing antiepileptic treatment regimen; 3) Comparison with placebo or continuation of the original antiepileptic regimen without a new ASM; 4) Primary outcome as a 50% response rate, with safety as a secondary outcome, encompassing dizziness, somnolence, headache, ataxia, diplopia, fatigue, and nausea; and 5) Study design limited to RCTs. The surface under the cumulative ranking curve (SUCRA) was employed to rank the effectiveness and safety of the ASMs. A total of 53 RCTs involving 17 ASMs as adjunctive therapy and placebo were analyzed. Compared to placebo, the following ASMs demonstrated statistically significant effectiveness in achieving a 50% response rate: brivaracetam (RR = 2.07, 95% CI: 1.53-2.81), cenobamate (RR = 2.12, 95% CI: 1.56-2.88), eslicarbazepine acetate (RR = 1.95, 95% CI: 1.41-2.70), gabapentin (RR = 2.30, 95% CI: 1.76-3.02), lacosamide (RR = 2.22, 95% CI: 1.47-3.35), lamotrigine (RR = 1.55, 95% CI: 1.00-2.40), levetiracetam (RR = 2.43, 95% CI: 1.88-3.15), oxcarbazepine (RR = 3.03, 95% CI: 2.08-4.40), perampanel (RR = 1.72, 95% CI: 1.21-2.44), pregabalin (RR = 2.06, 95% CI: 1.70-2.50), rufinamide (RR = 2.28, 95% CI: 1.20-4.31), tiagabine (RR = 4.07, 95% CI: 2.03-8.18), topiramate (RR = 3.10, 95% CI: 2.44-3.95), vigabatrin (RR = 2.34, 95% CI: 1.58-3.46), and zonisamide (RR = 2.40, 95% CI: 1.76-3.27). Based on SUCRA rankings, tiagabine (92.7%) exhibited the most favorable therapeutic outcome, followed by topiramate (87.3%), oxcarbazepine (83%), and levetiracetam (62.8%). The ASMs with the least favorable therapeutic effects were placebo (1.1%), lamotrigine (17.8%), and perampanel (24.7%). The network meta-analysis revealed topiramate, tiagabine, oxcarbazepine, and levetiracetam as the four most effective adjuvant ASM treatments for drug-resistant focal epilepsy. However, it is noteworthy that topiramate and oxcarbazepine were associated with a higher incidence of somnolence. Additionally, comprehensive safety data for tiagabine and levetiracetam are lacking, necessitating further research. Larger studies are required to solidify these findings and better understand the safety profiles of all involved ASMs.

Precise outcome data about the surgical therapy of cerebral cavernous malformation (CCM)-associated epilepsy is scarce regarding different epilepsy types, surgical approach, and outcome. Long-term outcome in patients with CCM-associated epilepsy is analyzed in a large single-center series. Seizure outcome data >24 months was available in 118 patients. The influence of different parameters of preoperative workup and surgical technique was analyzed with regard to seizure outcome. The study cohort comprised 76 patients with drug-resistant epilepsy (DRE), 20 patients with chronic epilepsy that did not meet the definition of DRE, as well as 22 patients with sporadic seizures. Temporal localization of CCMs predisposed to develop DRE. Detailed epileptologic workup was performed in 85 patients; invasive monitoring was done in 23 (37%) of 76 DRE cases. In 84% of DRE cases more extensive resections were performed. Mean follow-up varied between 107 and 137 months for the three groups. Seizure freedom in DRE was 88%, in chronic epilepsy 80%, and in sporadic seizures was 91%. Longer symptom duration was associated with worse seizure outcome. Outcome of patients who underwent invasive monitoring was not worse. The outcome in CCM-associated DRE can be good if more extensive resections are used and if noninvasive and/or invasive presurgical epileptologic workup is used whenever indicated. DRE was considerably more frequent in the temporal lobe, suggesting that temporal localization predisposes development of DRE. Seizure freedom rates were stable over a long period. Surgical therapy of CCM-associated seizures and epilepsy can be successful if different surgical techniques according to presurgical evaluation are realized. To prevent clinical worsening into DRE, surgical intervention in CCM-associated epilepsy may be considered early.

Objectives: Dynamic changes in psychophysiological arousal are directly expressed in the sympathetic innervation of the skin. This activity can be measured as tonic and phasic fluctuations in electrodermal activity [Galvanic Skin Response (GSR)/skin conductance]. Biofeedback training can enable an individual to gain voluntary control over this autonomic response and its central correlates. Theoretically, control of psychophysiological arousal may be harnessed as a therapy for epilepsy, to mitigate pre-ictal states. Evidence is accumulating for the clinical efficacy of GSR biofeedback training in the management of drug resistant epilepsy. In this review, we analyse current evidence of efficacy with GSR biofeedback and evaluate the methodology of each study.Method: We searched published literature pertaining to interventional studies of GSR biofeedback for epilepsy, through MEDLINE and Cochrane databases (1950–2018). Using percentage seizure reduction as an indicator of therapeutic efficacy induced by GSR biofeedback, we used meta-analytic methods to summarize extant findings. We also compare and contrast study design with relevance to the interpretation of outcomes.Results: Out of 21 articles retrieved for GSR/EDA/Skin conductance biofeedback, four studies were identified as interventional trials, involving 99 patients with drug-resistant epilepsy in total. Three of these studies included a control group and a positive therapeutic effect of biofeedback was reported in each of these. The difference in seizure frequency percentage (Biofeedback—Control) was between −54.4 and −74.0% with an overall weighted mean difference of −64.3% (95% CI: −85.4 to −43.2%). The response rates (proportion of patients manifesting >50% reduction in seizure frequency) varied from 45 to 66% across studies.Significance: This timely evaluation highlights the potential value of GSR biofeedback therapy, and informs the optimal study design of larger scale studies that are now required to more definitively establish the utility of this non-invasive, non-pharmacological interventional approach for drug-resistant epilepsy.

Improving the effects of ketogenic diet therapy in children with drug-resistant epilepsy

Drug-resistant epilepsy poses very difficult treatment challenges worldwide. Findings regarding the connection between ketogenic diet therapy (KDT) and genetic epilepsy are still unclear. In this meta-analysis we sought to examine the efficacy of KDT for drug-resistant epilepsy in patients with genetic mutations. The data were sourced from studies that reported KDT for epilepsy patients with monogenic etiology and were found in PubMed, Embase, Scopus, Web of Science, Cochrane Library, and 4 Chinese databases from database inception until January 2, 2024. We determined that 50 studies involving a total of 849 patients who were treated with KDT met the eligibility criteria for inclusion. The meta-analysis revealed that the responder rate was 58% (95% CI, 49%-67%, I2 = 389%, P < .01) and the seizure-free rate was 29% (95% CI, 19%-39%, I2 = 86%, P < .01). In 40 reported studies, comprising 615 patients, specific gene mutations and response rates after KDT were mentioned. The highest responder rate, which occurred among patients with mutations in the solute carrier family 2 member 1 gene, SLC2A1 (n = 87), was 96% (95% CI, 91%-100%, I2 = 0%, P = .72), and the lowest, which occurred among patients with mutations of the sodium voltage-gated channel alpha subunit 8 gene, SCN8A (n = 5), was 15% (95% CI, 0%-60%, I2 = 39%, P = .20). In 39 studies, including 405 patients, specific gene mutations and seizure-free rates after KDT were reported. The highest seizure-free rate, which occurred in patients with mutations in SLC2A1 (n = 80), was 67% (95% CI, 49%-86%, I2 = 78%, P < .01), and the lowest seizure-free rates occurred in patients with mutations in the cyclin-dependent kinase-like 5 gene, CDKL5, (n = 40) and those with mutations in the potassium sodium-activated channel subfamily T member 1 gene, KCNT1 (n = 48), who had seizure-free rates of 0% (95% CI, 0%-6%, I2 = 0%, P = 1.00) and 2% (95% CI, 0%-7%, I2 = 0%, P = .82), respectively. The maximum efficacy of KDT, reflected by the responder rate (72%) and seizure-free rate (46%), was achieved at the 6-month follow-up, at which patients showed outcomes superior to those demonstrated at earlier or later assessments. The present meta-analysis revealed the efficacy of KDT in the treatment of genetic epilepsies, particularly in epilepsies associated with SLC2A1 and SCN1A mutations, but KDT had relatively poor efficacy in epilepsies related to CDKL5 and KCNT1 mutations. Notably, compared to other follow-up intervals, at the 6-month post-KDT follow-up interval patients showed the highest overall responder and seizure-free rates. PROSPERO registration No. CRD42024610852.

Drug-resistant epilepsy seems like a different disease compared with easy to control epilepsy, and new strategies are needed to help these patients. Vagus nerve stimulation (VNS) therapy is the most frequently used neurostimulation modality for patients with drug-resistant epilepsy who are not eligible for seizure surgery. In this study, we aimed to evaluate the efficacy and adverse effects of VNS in patients with drug-resistant epilepsy in an open-label, prospective, long-term study in Iran. We selected 48 patients with partial-onset drug-resistant epilepsy. Implantations were performed in the neurosurgery department of Loghman Hospital, Tehran, Iran. Follow-up visits were done on monthly bases for 5years. Forty-four patients completed the study. Mean age of patients was 24.4years. Mean years of epilepsy history was 14years. The mean number of anti-epileptic drugs did not significantly change over five years (p=0.15). There was no exacerbation of epilepsy; however, one patient discontinued his therapy due to unsatisfactory results. Five patient had more than 50%, and 26 patients (59%) had 25-49% reduction in the frequency of monthly seizures persistently. Overall mean frequency of monthly seizures decreased by 57.8, 59.6, 65, 65.9, and 67%, in 1st, 2nd, 3rd, 4th, and 5th years of follow-up, respectively. Most common side effects were as follows: hoarseness (25%) and throat discomfort (10%). We found VNS as a safe and effective therapy for drug-resistant epilepsy, with an approximate long-term decrease in mean seizure frequency of 57.8-67%. Thus, VNS is recommended for suitable patients in developing countries.