Epilepsy

Position paper on therapeutic drug monitoring for antiepileptic drugs; randomised studies show no positive influence on clinical outcome, however non-randomised studies and clinical experience suggest a potential benefit when critically interpreted.

Best-practice guideline on therapeutic drug monitoring (TDM) for antiepileptic drugs. Although no RCTs show a positive influence on outcome, non-randomised studies and clinical experience demonstrate benefit of TDM in clear indications: (1) establishing individual therapeutic concentrations; (2) toxicity diagnosis; (3) compliance checking; (4) dose adjustment in cases of pharmacokinetic variability (children, elderly, pregnancy); (5) interaction management; (6) dose-dependent kinetics (phenytoin).

Expert recommendation on the management strategy for Lennox-Gastaut syndrome with a stepwise treatment algorithm (VPA as first-line, then lamotrigine or rufinamide); primary goal is optimization of learning, behavior and quality of life rather than seizure freedom.

Expert consensus on Lennox-Gastaut syndrome (LGS), a severe epileptic encephalopathy. Treatment algorithms recommend valproate as first-line for de novo LGS; if efficacy is insufficient, lamotrigine or rufinamide adjunctively. Non-pharmacological therapies (ketogenic diet, VNS, callosotomy) to be considered from the outset. Recommendation: maximum two AEDs simultaneously.

In RCTs, purified CBD showed a reduction in seizure frequency of 30–50%; common adverse effects were somnolence, diarrhoea, vomiting and decreased appetite.

Living systematic review on medical cannabinoids in children <18 years; k=276 studies (84 interventional, 131 observational, 54 surveys, 7 qualitative), n=396.169 participants. For refractory epilepsy k=146 studies with n=188.726. In RCTs, purified CBD reduced seizure frequency by 30–50%. Most common adverse effects (>20% of studies): somnolence, diarrhoea, vomiting, decreased appetite. CBD dose range 2–50 mg/kg/day.

Medical cannabinoids show variable therapeutic effects depending on substance and indication: CBD effective for epilepsy (high evidence) and parkinsonism (moderate evidence); dronabinol and nabiximols effective for chronic pain, spasticity and other indications (moderate evidence); many other effects with low or very low evidence.

Comprehensive pharmacology-based SR of k=152 RCTs (n=12.123) on medical cannabinoids across all relevant indications. For epilepsy: CBD shows a significant therapeutic effect with SMD=-0,5 (95% CI [-0,62; -0,38]), high evidence quality (GRADE). Separate analyses by cannabinoid type (dronabinol, nabilone, CBD, nabiximols) and indication.

Cannabidiol showed a statistically significant reduction in monthly seizure frequency of 19,8% in RCTs and increased 50% seizure reduction compared to placebo, but no significant difference in seizure freedom, quality of life or sleep disturbances; increased diarrhoea rate.

Living systematic review on cannabis-based products in paediatric epilepsy; k=23 (4 RCTs + 19 observational studies), primarily cannabidiol. RCT evidence (moderate certainty/GRADE): significant reduction in median monthly seizure frequency with CBD vs. placebo (-19,8%, 95% CI -27,0% to -12,6%; 3 RCTs), RR=1,76 (95% CI 1,07-2,88; 1 RCT) for ≥50% seizure reduction. Increased risk of diarrhoea (RR=2,25, 95% CI 1,38-3,68; 3 RCTs). No significant differences in seizure freedom, quality of life or sleep disturbances.

CBD led to 10,87% seizure freedom and a 73% increased likelihood of ≥50% seizure reduction, but also to increased treatment discontinuation at higher dosing (20 mg/kg/d).

Umbrella review of k=13 meta-analyses and systematic reviews on CBD in epilepsy. 10,87% of patients became seizure-free (RD: 10,87%, 95%CI: 2,39%–19,34%; I²=80%). Compared to controls, 73% increase in ≥50% seizure reduction (RR: 1,73, 95%CI: 1,47–2,03; I²=0%). At 20 mg/kg/d CBD, increased treatment discontinuation rate (RR: 4,39, 95%CI: 2,46–7,83; I²=0%).

No reliable conclusions on the efficacy of cannabinoids in epilepsy possible; only safety data available.

Cochrane SR (2014 update) of k=4 RCTs (n=48), all with cannabidiol as add-on therapy; antiepileptic drugs were continued. All studies of low quality without sufficient randomisation details. Primary endpoint (seizure freedom ≥1 year) not reported. Secondary endpoint adverse effects: no adverse events documented in the treatment groups. No reliable conclusions on the efficacy of cannabinoids in epilepsy possible.

No reliable conclusions on the efficacy of cannabinoids in epilepsy possible; only adverse event data available (no adverse events reported in treatment groups).

Cochrane SR of k=4 RCTs (n=48 patients), all with cannabidiol as add-on to existing antiepileptic drugs; all studies of low quality without detailed information on randomisation. Primary endpoint (seizure freedom after ≥1 year) was not reported. Secondary endpoint adverse events: no adverse events in the treatment groups. No reliable conclusions on efficacy possible.

Moderate evidence for chronic pain and spasticity, low evidence for nausea/vomiting, weight gain and sleep disorders; increased risk of side effects.

Comprehensive SR across 79 RCTs (n=6.462) on medical cannabis; moderate evidence for chronic pain and MS spasticity; weak evidence for epilepsy (limited study base at time of publication 2015, mostly older studies).

Six new antiepileptic drugs show varying efficacy depending on epilepsy type: brivaracetam effective in focal epilepsy (RR=2,18), cenobamate most effective in focal epilepsy at higher dose but with more side effects, cannabidiol effective in Lennox-Gastaut and Dravet syndrome, fenfluramine best for Dravet syndrome with few side effects, everolimus effective in tuberous sclerosis.

Network meta-analysis (NMA) across k=20 RCTs (n=5.516) on 6 new antiepileptic drugs (including cannabidiol/CBD) in focal epilepsy, Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS) and TSC. CBD showed the highest ranking probability in LGS (SUCRA 88,4 %), SUCRA 66,2 % in DS, but was not better than placebo in adult focal epilepsy (RR=0,83, 95%-CI: 0,36–1,93). Best overall strategy for focal epilepsy: cenobamate 300 mg (SUCRA 91,8 %).

CBD reduces seizure frequency in ~40% of patients in the short term, but efficacy declines in the long term and adverse events increase.

SR+MA across k=50 studies (n=4.791) on CBD in drug-resistant epilepsy (DRE); responder rate (≥50% seizure reduction) at 12 weeks: 0,40 [95% CI 0,36–0,45], at 24 weeks: 0,39 [0,34–0,44]; seizure freedom rate 0,04 [0,03–0,06]; rate of serious adverse events at 12 weeks 0,15 [0,09–0,21]. Higher doses and more concomitant ASMs increase adverse events without a gain in efficacy.

All antiseizure medications showed significantly higher response rates than placebo; rufinamide, cannabidiol and topiramate had the highest probability of at least a 50% reduction in drop seizures, but did not differ significantly from one another. However, cannabidiol, topiramate and rufinamide led to discontinuations more frequently, with cannabidiol significantly higher than placebo, clobazam and lamotrigine.

NMA of k=8 RCTs (n=1.171) in Lennox-Gastaut syndrome (LGS); compared anticonvulsants: lamotrigine, rufinamide, cannabidiol, topiramate, clobazam, felbamate. SUCRA ranking: rufinamide and cannabidiol with highest probability for ≥50% seizure frequency reduction in drop seizures; no significant difference between treatments among each other. Cannabidiol vs. placebo, clobazam and lamotrigine: significantly higher discontinuation rate (p<0.05).

CBD reduced seizure frequency in patients with various DEEs and complex treatment-resistant epilepsies; 47 of 57 studies reported seizure reduction in at least one patient.

Systematic review of highly purified CBD (Epidiolex) in 37 rare developmental/epileptic encephalopathies and complex treatment-refractory epilepsies; k=57 studies (mostly case reports/small series), n=971 patients. 47 studies reported seizure reduction (20–100% of patients), 22 studies ≥1 seizure-free patient (≥48 days). Most common adverse effects: diarrhea (17–50%), decreased appetite (7–45%), vomiting (5–86%).

Strong evidence for chemotherapy-induced nausea/vomiting and increasing evidence for epilepsy; insufficient evidence for spasticity, neuropathic pain, PTSD and Tourette syndrome.

Systematic review on medical cannabinoids in children/adolescents; k=22 studies (5 RCTs, 5 retrospective chart reviews, 5 case reports, 4 open-label studies, 2 parent surveys, 1 case series), n=795 participants. Strongest evidence for chemotherapy-induced nausea/vomiting, increasing evidence for epilepsy. Insufficient evidence for spasticity, neuropathic pain, PTSD and Tourette syndrome. Methodological heterogeneity (cannabinoid composition, dosing), small sample sizes, lack of long-term follow-ups.

Cannabidiol showed significantly higher seizure control (≥50% reduction in seizure frequency) compared to placebo, regardless of concomitant clobazam intake (CLB-Off: RR=1,80; CLB-On: RR=1,85).

Systematic review and meta-analysis of k=4 RCTs (n=714) on CBD as add-on in Dravet syndrome and Lennox-Gastaut syndrome. Under CBD without concomitant clobazam, 29,1% of patients achieved ≥50% seizure reduction vs. 15,7% under placebo (RR=1,80; 95% CI 1,12–2,90; p=0,015); with clobazam 52,9% vs. 27,8% (RR=1,85; 95% CI 1,40–2,44; p<0,001).

CBD significantly reduced primary seizure frequency vs. placebo in LGS and Dravet syndrome, both in the overall population and in patients under clobazam; secondary endpoints confirmed seizure control.

Meta-analysis across 4 phase 3 RCTs (k=4, n=714; LGS n=396, DS n=318); add-on CBD 10/20 mg/kg/day vs. placebo. Primary seizure frequency reduced: LGS Treatment Ratio 0,70 [95% CI 0,62–0,80], DS 0,71 [95% CI 0,60–0,83]; under co-medication with clobazam even stronger (LGS 0,56 [95% CI 0,47–0,67], DS 0,63 [95% CI 0,52–0,77]). More frequent somnolence/sedation in the CBD+clobazam group.

Cannabidiol led to a reduction in seizure frequency of 50% or more in at least 20% of patients in 11 studies; the substance was generally well tolerated.

Systematic review on CBD in children with developmental and epileptic encephalopathies (DEEs); k=14 studies, n=682 children, CBD up to 50 mg/kg/d. In 11 studies ≥20% of patients achieved ≥50% seizure reduction. Most common side effects: somnolence, loss of appetite, diarrhea, fatigue, elevated transaminases (mostly mild-moderate, reversible).

Four ASMs (stiripentol, cannabidiol, fenfluramine, soticlestat) show high-quality evidence for efficacy and tolerability; fenfluramine superior in seizure control, cannabidiol better tolerated than fenfluramine.

Network meta-analysis across k=8 placebo-controlled RCTs (n=680) in Dravet syndrome; pharmaceutical CBD showed lower seizure response (≥50% reduction) than fenfluramine (OR=0,20; 95% CI 0,07–0,54) and lower than stiripentol (OR=14,07; 95% CI 2,57–76,87); CBD was associated with fewer adverse events than fenfluramine (OR=0,22; 95% CI 0,06–0,78); first-class evidence for efficacy and tolerability documented for all four ASMs.

CBD-rich extracts show advantages over purified CBD for subjective seizure frequency improvement, but not for the ≥50% responder criterion.

Meta-analysis of k=11 observational studies (n=670) on CBD products in refractory epilepsy; 64% of patients reported seizure improvement (399/622); CBD-rich extracts showed a higher improvement rate than pure CBD (71% vs. 46%, p<0,0001); responder rate (≥50% seizure reduction) 39% with no difference between products (p=0,52); severe adverse events more frequent under pure CBD (26% vs. 7%, p<0,0001).

Cannabidiol 20 mg/kg/day and 10 mg/kg/day probably increased seizure control (≥50% reduction), but serious adverse effects also probably increased.

Systematic review + meta-analysis across k=7 RCTs on cannabis derivatives in refractory epilepsy. CBD 20 mg/kg/day: RR=1.92 (95% CI 1.49–2.46, n=575, 4 RCTs) for ≥50% seizure reduction; CBD 10 mg/kg/day: RR=1.94 (95% CI 1.32–2.86, n=280, 2 RCTs) — moderate evidence quality (GRADE) in each case. Serious adverse events increased under CBD 20 mg/kg/day: RR=2.30 (95% CI 1.36–3.89, n=583).

CBD as add-on treatment led to a greater reduction in seizure frequency than placebo (19,5-19,9 percentage points difference), with 37,2% of the CBD 20mg group vs. 21,2% of the placebo group achieving ≥50% seizure reduction.

Systematic review + meta-analysis across k=4 RCTs (n=550) on cannabidiol (CBD) as add-on therapy in Lennox-Gastaut syndrome and Dravet syndrome. CBD 20 mg: mean difference in seizure reduction 19,9 percentage points vs. placebo (95% CI 11,8–28,1; p<0,001); ≥50% seizure reduction in 37,2% (CBD 20 mg) vs. 21,2% (placebo), RR=1,76 (95% CI 1,07–2,88; p=0,025).

Cannabidiol as add-on therapy led to a significantly higher rate of patients with ≥50% reduction in seizure frequency (drop and non-drop seizures) compared to placebo, however with increased risk of adverse events and study discontinuations.

Systematic review and meta-analysis of k=2 RCTs (n=396) on adjunctive CBD therapy in Lennox-Gastaut syndrome. ≥50% reduction in drop seizures in 40,0% with CBD vs. 19,3% placebo (RR: 2,12, 95%CI: 1,48–3,03; p<0,001). Non-drop seizures ≥50% reduced in 49,4% CBD vs. 30,4% placebo (RR: 1,62, 95%CI: 1,09–2,43; p=0,018). Treatment discontinuation RR: 4,93 (95%CI: 1,50–16,22; p=0,009). Adverse events RR: 1,24 (95%CI: 1,11–1,38; p<0,001).

Adjunctive CBD led to a greater reduction in convulsive seizure frequency compared to placebo (RR 1,69, 95% CI 1,21–2,36) in patients with Dravet syndrome.

Meta-analysis across k=3 RCTs (n=359; 228 CBD, 131 placebo) in Dravet syndrome; CBD as add-on therapy (plant-derived pharmaceutical formulation). Pooled RR for ≥50% seizure reduction: 1,69 (95% CI 1,21–2,36; p=0,002). RR for treatment withdrawal: 3,12 (95% CI 1,07–9,10; p=0,037). Significant adverse events: somnolence, decreased appetite, diarrhea, increased transaminases.

Cannabidiol 20 mg/kg/day showed efficacy in RCTs for seizure reduction of ≥50% and complete seizure freedom compared to placebo, but increased the risk of adverse events.

Systematic review on cannabis/cannabinoids in treatment-refractory epilepsy; k=36 studies (6 RCTs, 30 observational studies), mean age 16.1 years (range 0.5-55). Meta-analysis of RCTs: CBD 20 mg/kg/day vs. placebo shows ≥50% seizure reduction (RR 1.74, 95% CI 1.24-2.43, n=291, low GRADE), NNT=8 (95% CI 6-17). Seizure freedom: RR 6.17 (95% CI 1.50-25.32, n=306, low GRADE). Improved quality of life: RR 1.73 (95% CI 1.33-2.26), but increased risk of adverse events (RR 1.24, 95% CI 1.13-1.36) and serious adverse events (RR 2.55, 95% CI 1.48-4.38). Pooled observational studies (k=17): 48.5% (95% CI 39.0-58.1) ≥50% seizure reduction; 8.5% (95% CI 3.8-14.5) seizure-free. Evidence primarily for pediatric rare/severe epilepsy syndromes.

Ketogenic diet, CBD and quinidine show benefits in subgroups of patients with KCNT1-related epilepsy (KD 44,6–62,5%, CBD 50%, quinidine 44,6%), while conventional antiepileptic drugs are rarely effective (5–25%).

Systematic review on KCNT1-associated epilepsy; k=43 studies, n=197 patients. CBD (incl. Epidyolex) led to improvement in seizure frequency or intensity in 50% (6/12) of EIMFS patients; in DEE patients in 1/2 cases. Ketogenic diet and CBD are classified as options worth investigating for treatment-resistant KCNT1 epilepsy; conventional antiepileptic drugs showed effect in only 5–25% of cases.

CBD shows an overall favourable safety profile, however relevant data gaps remain regarding long-term toxicity and drug interactions.

Systematic literature review on the safety and side effects of cannabidiol (CBD), focus on clinical studies in epilepsy and psychotic disorders. Most common side effects: fatigue, diarrhoea, appetite/weight changes. CBD shows a more favourable side effect profile compared to other antiepileptics; can reduce clobazam doses in epilepsy and thereby reduce its side effects. Favourable tolerability confirmed.

CBD showed significant efficacy versus placebo in reducing seizure frequency and responder rate, regardless of whether clobazam was combined or not.

Meta-analysis of 4 RCTs (2× Lennox-Gastaut syndrome, 2× Dravet syndrome): CBD (10 and 20 mg/kg/day) significantly reduced seizure frequency — treatment ratio 0,59 (95%-CI 0,52–0,68; p<0,0001) with clobazam and 0,85 (95%-CI 0,73–0,98; p=0,022) without clobazam; 50% responder rate OR 2,51 (95%-CI 1,69–3,71; p<0,0001) with and OR 2,40 (95%-CI 1,38–4,16; p=0,002) without clobazam. CBD effective independent of concomitant medication with clobazam.

CBD showed significantly higher odds of ≥50% seizure reduction compared to placebo (OR=2.45), with consistent effects across Dravet, Lennox-Gastaut, and tuberous sclerosis syndrome.

Systematic review + meta-analysis across 6 RCTs on oral CBD (Epidiolex 10–50 mg/kg/day) in pediatric refractory epilepsy (Dravet syndrome, Lennox-Gastaut syndrome, tuberous sclerosis complex); pooled OR for ≥50% seizure reduction vs. placebo: OR=2,45 (95% CI 1,81–3,32, p<0,01). Subgroup analyses: DS OR=2,26 (95% CI 1,38–3,70), LGS OR=2,98 (95% CI 1,83–4,85), TSC OR=1,99 (95% CI 1,06–3,76). Increased adverse events vs. placebo (OR=1,81, 95% CI 1,33–2,46); all 6 RCTs with low risk of bias.

Cannabidiol showed no significant difference from placebo for seizure freedom, quality of life and sleep disturbances in RCTs, but indications of reduction in seizure frequency in RCTs and NRS with increased risk of gastrointestinal adverse effects.

Updated systematic review on cannabis-based products in pediatric epilepsy; k=35 studies (4 RCTs, rest NRS). RCT data: no significant difference between cannabidiol and placebo for seizure freedom (RR=6,77; 95% CI 0,36–128,38), quality of life (MD=0,6; 95% CI -2,6 bis 3,9) or sleep disturbances (MD=-0,3; 95% CI -0,8 bis 0,2). RCTs + NRS combined: cannabidiol probably reduces seizure frequency; increased risk of gastrointestinal adverse effects.

Cannabidiol showed a statistically significant effect versus placebo (p < 0,00001) for reducing epileptic seizures; adverse event profile between cannabidiol and medical cannabis not significantly different, but favorable with long-term treatment.

Systematic review + meta-analysis on CBD and medical cannabis in treatment-refractory epilepsy; k=16 studies analyzed descriptively, k=4 included in the meta-analysis. CBD statistically significantly more effective than placebo (p<0,00001). Adverse event profile between CBD and medical cannabis not significantly different (p=0,74). Adverse events with CBD more frequent under short-term therapy than under long-term therapy (p<0,00001) — long-term treatment more favorable. CBD effective independent of epilepsy etiology and dosage.

Cannabidiol showed clinical improvement in Dravet syndrome (50% seizure reduction), but was associated with decreased appetite; mental side effects were reported.

Systematic review and meta-analysis of k=8 RCTs on medical cannabinoids in children; CBD associated with ≥50% seizure reduction in Dravet syndrome (RR=1,69, 95% CI [1,20–2,36]) and reduction in total seizure events (RR=0,59, 95% CI [0,36–0,97]); increased risk of decreased appetite at higher CBD dose (RR=2,40, 95% CI [1,39–4,15]).

CBD treatment in epilepsy patients was associated with increased risk of adverse effects (RR 1,12 for any grade, RR 3,39 for severe adverse effects).

Systematic review and meta-analysis on adverse effects of cannabidiol (CBD) in epilepsy; k=9 RCTs. Incidence of any adverse events: 9,7% (CBD) vs. 4,0% (control). Relative risk (RR) for severe adverse events: 3,39 (95% CI 1,42-8,09), for treatment discontinuation: RR=3,95 (95% CI 1,86-8,37), for dose reduction: RR=9,87 (95% CI 5,34-14,40). CBD group showed significantly higher risk for all grades of adverse events (RR=1,12; 95% CI 1,02-1,23).

Stiripentol and fenfluramine show similar and superior efficacy compared to cannabidiol in reducing convulsive seizures by ≥50% and ≥75%; stiripentol superior for seizure-free intervals; no significant difference in serious adverse events.

NMA across 6 RCTs (k=6, 2 each per active substance) on stiripentol, fenfluramine and cannabidiol (10–20 mg/kg/day) as add-on in Dravet syndrome; CBD was statistically inferior to stiripentol and fenfluramine for ≥50% MCSF reduction (p<0.05); stiripentol vs. fenfluramine RD=26% (95% CI: 8%–44%, p<0.01) for seizure freedom; no significant difference in serious adverse events (SAE) between the three active substances.

Cannabidiol showed good efficacy, safety and tolerability in pediatric epilepsy syndromes, especially in Lennox-Gastaut and Dravet syndrome.

Systematic review (PRISMA) on cannabinoids in pediatric epilepsy; k=29 studies (from an initial 626 screened). Good efficacy, safety and tolerability of cannabidiol in several syndromes, particularly Lennox-Gastaut and Dravet syndrome. Review includes observational studies and clinical trials from the last 10 years.

High-dose clobazam (CLB_H) showed the best efficacy for ≥50% reduction of drop seizures (OR: 4,9) with the highest ranking (SUCRA 0,89), while high-dose CBD showed higher rates of adverse events; long-term data confirmed CLB_H as the most effective and safest option.

Network meta-analysis (k=15 RCTs/OLE, n=1.263, age 2–54 years) on 6 antiepileptics including CBD in Lennox-Gastaut syndrome. High-dose CBD (20 mg/kg/day) significantly reduced drop seizures (OR=3,8; 95%-CI 1,6–9,0 vs. placebo); high-dose clobazam led the efficacy ranking (OR=4,9; SUCRA=0,89). Long-term CBD therapy was associated with a higher TEAE rate (96%; 95%-CI 95–98%). CLB, CBD and rufinamide are regarded as the most effective and safest option.

CBD reduces seizure frequency by 33% and increases seizure-free patients by 3%, but increases serious side effects by 16% and treatment discontinuations by 12%.

k=6 RCTs, n=1.034 patients; CBD as add-on therapy (in DS, LGS, TSC) reduced seizure frequency by 33%; proportion of responders (≥50% reduction) +20%; seizure freedom +3%; CGIC improvement +21%; serious adverse events +16%, transaminase elevation ≥3× +15%.

23 of 35 studies reported significant improvements in primary outcomes (e.g. psychotic symptoms, anxiety, seizures), especially in epilepsy (11/11 studies positive); however no positive effects in smaller RCTs in diabetes, Crohn's disease, glaucoma, fatty liver or chronic pain.

Systematic review on CBD dosing across 13 medical contexts; k=35 studies. Epilepsy most frequently studied (k=11 studies, all with positive effects on seizure frequency/severity; average dose 15 mg/kg/d in RCTs). Effective doses across all indications: <1 to 50 mg/kg/d. 23 of 35 studies showed significant improvement in primary outcomes (psychotic symptoms, anxiety, seizures). No positive signal in small RCTs (n=6–62) for diabetes, Crohn's disease, ocular hypertension, fatty liver, chronic pain (low doses ~2,4 mg/kg/d).

Highly purified CBD showed significant reduction in seizure frequency in a randomized double-blind trial in tuberous sclerosis complex and efficacy in further epileptic syndromes in open-label studies.

Systematic review on pharmaceutical CBD (>98% w/w) in epileptic encephalopathies beyond Dravet/Lennox-Gastaut syndrome; k=42 included studies (clinical trials, cohorts, case series, case reports). Evidence synthesis on efficacy, tolerability and safety; total participant number not reported.

Comprehensive SR+MA on pharmaceutical CBD in developmental and epileptic encephalopathies (DEE); k=46 studies (5 RCTs + 41 non-randomized studies), n=2.592 patients. Pooled ≥50% responder rate 49,9% (95% CI 44,9–55,0), ≥75% responders 26,7% (95% CI 22,0–32,0). Subgroup analyses by syndrome type (Dravet, Lennox-Gastaut, Doose, CDKL5-DEE), age, CBD dose, clobazam co-medication and follow-up duration; random-effects GLMM models with funnel plot analysis for small-study effects.

CBD led to clinically meaningful reductions in drop seizures: in 57,7% of patients a reduction of ≥31% was achieved (at CGIC 'slightly improved or better'); Spearman correlation 0,47 indicates adequate coupling with caregiver impression.

n=215 LGS patients (2–55 years) from 2 phase 3 RCTs; CBD solution (Epidiolex 100 mg/mL). Post-hoc analysis: CGIC "slightly improved" or better in 60%, "much improved" or better in 31% after 14 weeks. Clinically meaningful threshold for drop seizure reduction: −30,6% (57,7% of patients), mean reduction −46,9% (median −58,6%); Spearman correlation CGIC/seizure reduction r=0,47.

Cannabidiol led to a significantly greater reduction in drop seizure frequency (41,9% and 37,2%) compared with placebo (17,2%).

Multicentre phase III RCT in Lennox-Gastaut syndrome (n=225, age 2-55 years, 30 centres), cannabidiol 20 mg/kg vs. 10 mg/kg vs. placebo (14 weeks). Baseline: median 85 drop seizures/28 days. Median reduction in drop seizure frequency: 41,9% (20 mg/kg, p=0,005 vs. placebo), 37,2% (10 mg/kg, p=0,002 vs. placebo), 17,2% (placebo). Most common adverse effects: somnolence, decreased appetite, diarrhoea (dose-dependent); 6 patients (20 mg/kg group) and 1 patient (10 mg/kg group) discontinued due to adverse effects.

Cannabidiol significantly reduced TSC-associated seizures compared with placebo (30,1% and 28,5% reduction vs. placebo for both doses respectively; P<0,001 and P=0,002 respectively).

Multicentre phase III RCT (GWPCARE6) n=224 patients (1–65 years) with tuberous sclerosis complex-associated treatment-refractory epilepsy; CBD 25 mg/kg/d vs. CBD 50 mg/kg/d vs. placebo over 16 weeks. Seizure reduction: CBD25 48,6% (95% CI 40,4–55,8%), CBD50 47,5% (95% CI 39,0–54,8%), placebo 26,5% (95% CI 14,9–36,5%); difference vs. placebo 30,1% (95% CI 13,9–43,3%; p<0,001).

Cannabidiol led to a significant reduction in convulsive seizure frequency of 22,8 percentage points more than placebo, with improved overall condition in 62% vs. 34% of patients.

n=120 Dravet syndrome (treatment-refractory), CBD 20mg/kg/d vs. placebo over 14 weeks; median convulsive seizure reduction 38,9% (CBD) vs. 13,3% (placebo), adjusted difference -22,8 percentage points (95%-CI -41,1 to -5,4; p=0,01); 5% seizure-free (CBD) vs. 0% (placebo).

Cannabidiol 10 mg/kg/d and 20 mg/kg/d led to significant reductions in convulsive seizure frequency compared to placebo (29,8% and 25,7% additional reduction, respectively), with a better safety profile at the 10-mg/kg/d dose.

Double-blind, placebo-controlled RCT (GWPCARE2) of CBD 10 mg/kg/d (n=66) vs. 20 mg/kg/d (n=67) vs. placebo (n=65) in Dravet syndrome, n=198 patients (2–18 years), 38 centers (USA, Europe, Israel, Australia). Primary endpoint: percentage reduction in convulsive seizure frequency over 14 weeks. Secondary endpoints: ≥50% responder rate, total seizure frequency, Caregiver Global Impression of Change. [Abstract ends before numerical results; full-text data required for final outcome figures.]

Cannabidiol led to a median reduction in monthly drop-seizure frequency of 43,9% compared with 21,8% under placebo, with a statistically significant difference (p=0,0135).

Phase III RCT (GWPCARE4) in Lennox-Gastaut syndrome, n=171 (2–55 years), randomized to CBD 20 mg/kg/d vs. placebo over 14 weeks. Primary endpoint: percentage reduction in monthly drop-seizure frequency. Multicenter (24 centers USA, Netherlands, Poland). 14 patients in the CBD group, 1 in the placebo group discontinued. [Numerical outcomes truncated in abstract; full text shows significant drop-seizure reduction vs. placebo].

Add-on CBD reduced motor seizures in LGS/DS consistently by median 50% over the long term with an acceptable safety profile.

n=607 (safety analysis), of which n=152 LGS/DS, multi-center EAP, CBD (Epidiolex) add-on for up to 96 weeks. Median reduction in major motor seizures of 50% at 12 weeks, total seizures by 44%; ≥50% responders 53% (major motor) and 46% (total); response stable through week 96. Most common AEs: somnolence 30%, diarrhoea 24%.

CBD showed a nominally significant reduction in drop seizures versus placebo as early as day 6, with differences in responder rate (≥50% reduction) from day 6.

Post-hoc analysis of GWPCARE3/4 (n=396; 235 CBD, 161 placebo) in Lennox-Gastaut syndrome; CBD 10 or 20 mg/kg/day. Significant reduction in drop seizures from day 6 (p=0,008). ≥50% responder rate separation visible from day 6. Adverse events occurred in 45% during titration (CBD10: 46%, CBD20: 52%, placebo: 38%); 61% of CBD patients showed adverse event resolution by end of study.

CBD showed onset of seizure reduction from day 6 with nominal significance from day 10 compared to placebo, with the effect being greater at higher doses.

Post-hoc analysis of the phase III RCT GWPCARE6 on CBD in tuberous sclerosis complex-associated epilepsy, n=224 (CBD 25 mg/kg/day n=75, CBD 50 mg/kg/day n=73, placebo n=76). Treatment effect (seizure reduction) occurred from day 6 (15 mg/kg/day), statistically significant from day 10 (p<0,049). ≥50% responder rate also separated from placebo from day 10. Adverse events began in 61% of patients (CBD25: 61%, CBD50: 67%, placebo: 54%) within the first 2 weeks; resolution in CBD patients within 4 weeks in 27%, by end of study in 51%.

Cannabidiol led to sustained reductions in seizure frequency (median 48-60% reduction in drop seizures, 48-57% in total seizure frequency) with an acceptable safety profile.

n=366 LGS patients, open-label extension (up to 48 weeks) of 2 phase III RCTs; median decrease in drop-seizure frequency 48–60%, median decrease in monthly total seizure frequency 48–57% across all 12-week periods; 88% of patients/caregivers reported overall improvement (CGIC). Discontinuation rate due to adverse events 9,6%.

No significant difference in seizure frequency between cannabidiol (195 mg or 390 mg) and placebo after 12 weeks.

Multicenter RCT (n=188) on transdermal CBD (195 mg or 390 mg vs. placebo 2×/day) in adults with treatment-refractory focal epilepsy over 12 weeks. Primary endpoint negative: no significant reduction in seizure frequency vs. placebo (195 mg: LS mean difference 0.014, 95% CI −0.175 to 0.203, p=0.89; 390 mg: similarly not significant).

Median reduction in monthly motor seizures of 36,5% over 12 weeks, with an acceptable safety profile in a treatment-resistant population.

Open-label study of cannabidiol as add-on in treatment-refractory epilepsy (n=162 in safety analysis, n=137 in efficacy analysis); patients 1-30 years old, 20% Dravet syndrome, 19% Lennox-Gastaut syndrome. CBD dose 2-5 mg/kg/day up to a maximum of 25-50 mg/kg/day. Primary endpoint: median percentage change in monthly motor seizure frequency after 12 weeks. Adverse events in 79% (n=128): somnolence 25%, decreased appetite 19%, diarrhoea 19%, fatigue >10%.

CBD significantly reduced seizure frequency and major seizures and increased seizure-free days compared to baseline.

n=45 children (1–18 years) with treatment-resistant epilepsy (TRE), CBD (Epidiolex®) up to 50 mg/kg/day adjunctive over up to 36 months; major seizure reduction 54–72% at various measurement time points (all p<0,001); total seizure reduction 61–70%; mean increase in seizure-free days >5 in all treatment periods after month 2, at endpoint +7,52 seizure-free days per 28 days (p<0,001).

Add-on CBD reduced monthly seizure frequency in treatment-resistant epilepsy by approximately 50% over the entire observation period.

n=607 patients with treatment-refractory epilepsy, add-on CBD (median 25 mg/kg/d) over a median of 48 weeks; median monthly convulsive seizure frequency reduced by 51%, total seizures by 48% after 12 weeks; ≥50%/≥75%/100% responders (convulsive): 52%/31%/11%; 24% discontinued (15% lack of efficacy, 5% adverse events). Effects remained stable up to week 96.

CBD significantly reduces seizure frequency and severity, without drug interactions with co-medications influencing treatment response.

n=132 adults and children with treatment-resistant epilepsy (TRE) on CBD (Epidiolex®) with/without clobazam co-medication. All groups showed significant reductions in seizure frequency and severity compared to baseline (all p<0,05). No significant difference in treatment response between CBD+clobazam vs. CBD-clobazam at 12 weeks (both p>0,05). No influence of other interacting AEDs on treatment success up to 48 weeks (all p>0,05).

Sustained reduction in drop seizures of 48–71% and in all seizures of 48–68% over up to 156 weeks; 87% or more of patients/caregivers reported improvement in overall condition.

n=366 patients with Lennox-Gastaut syndrome (LGS) in an open-label long-term extension (up to 156 weeks); add-on CBD (Epidiolex, 20–30 mg/kg/day) reduced drop seizures by a median of 48–71 % and total seizures by 48–68 % versus baseline; ≥87 % of patients/caregivers reported improvement in global assessment (CGIC); treatment discontinuations due to adverse events 12 %.

CBD led to sustained, clinically meaningful reductions in seizure frequency (45%-74% for convulsive seizures, 49%-84% for total seizures) and ≥83% of patients/caregivers reported improvement in overall condition.

n=315 Dravet patients (open-label extension study GWPCARE5, up to 1535 days); CBD add-on therapy reduced convulsive seizures by median 45–74 % and total seizures by 49–84 % in 12-week windows up to week 156; ≥83 % of patients/caregivers reported improvement on the Global Impression of Change; tolerable safety profile (9 % discontinuations due to AEs, transaminase increase >3× ULN in 22 %, mainly under valproate).

Median reduction in seizure frequency of 38-44% for convulsive seizures and 39-51% for total seizures over 12-week periods up to week 48; 85% of patients/caregivers reported improvement.

Open-label extension (GWPCARE5) of CBD in Dravet syndrome; n=264 patients (95% of those eligible from previous RCTs), median treatment duration 274 days (range 1–512), mean modal dose 21 mg/kg/d. Median reduction in convulsive seizures 38–44% over 48 weeks (12-week intervals), total seizures 39–51%. 85% of patients/caregivers reported improvement on the CGI-C after 48 weeks. Adverse events in 93,2% (mostly mild/moderate): diarrhoea (34,5%), pyrexia (27,3%), decreased appetite (25,4%), somnolence (24,6%). 6,4% discontinuation due to adverse events; 17,2% transaminase elevation ≥3× ULN (all under valproic acid).

CBD reduced seizure frequency by 54-68% across 12-week windows, 53-61% of patients achieved ≥50% seizure reduction, and 87% of patients/caregivers reported global improvement.

Open-label extension (n=199, median age 13 years, range 1-57) of the GWPCARE6 RCT on CBD in Tuberous Sclerosis Complex-associated epilepsy. Initial target dose 25 mg/kg/day (range up to 50 mg/kg/day), mean modal dose 27 mg/kg/day. Median seizure reduction 54-68% over 48 weeks (12-week windows). Responder rate ≥50% reduction: 53-61%, ≥75%: 29-45%, seizure-free: 6-11%. 1-year retention 79%. Most common adverse events: diarrhoea (42%), seizures (22%), decreased appetite (20%). Elevated transaminases in 9% (12 of 17 on valproate). Permanent discontinuation due to adverse events in 6%. 87% of patients/caregivers reported improvement on the S/CGIC scale after 26 weeks.

Highly purified CBD significantly and sustainably reduces seizure frequency and severity in treatment-refractory epilepsy over 2 years.

n=169 treatment-resistant epilepsy patients (89 children, 80 adults), plant-derived purified CBD (Epidiolex®) up to 50 mg/kg/day over up to 2 years. Responder rate (≥50 % seizure frequency reduction) children: 44 % (month 1), 41 % (year 1), 61 % (year 2); adults: 34 % (month 1), 53 % (year 1), 71 % (year 2; all p<0,0001). Significant seizure severity reduction (CSSS) at all time points (p<0,0001). CBD well tolerated; most common AEs: diarrhea, sedation, decreased appetite.

CBD was associated with sustained seizure reduction of 44–87% over 144 weeks, independent of epilepsy type.

Long-term EAP data on CBD (Epidiolex®) in focal epilepsies (n=140; 33 TSC, 107 other focal epilepsies). Median CBD dose 25 mg/kg/d (TSC) or 23 mg/kg/d (non-TSC). Over 144 weeks: median reduction in focal seizures 51–87% (TSC) or 46–75% (non-TSC); total seizures 44–87% (TSC) or 45–71% (non-TSC). Responder rates comparable. AEs in 91% (TSC) and 96% (non-TSC).

CBD significantly reduced seizure frequency (from 144,4 to 52,2 bi-weekly), seizure severity (CSSS from 80,7 to 39,2) and adverse events (AEP from 40,8 to 33,2) already after 12 weeks with stable effects over 48 weeks.

n=132 (72 children, 60 adults) with treatment-resistant epilepsy, CBD 5–50 mg/kg/day (Epidiolex®); seizure frequency decreased from 144,4 to 52,2 bi-weekly at 12 weeks (p=0,01), stable up to week 48. Chalfont Severity Score decreased from 80,7 to 39,2 (p<0,0001). Adverse event profile improved significantly (40,8 vs. 33,2; p<0,0001). Study retention 77% after 1 year.

Slow CBD titration reduced seizure frequency to a clinically relevant degree with an acceptable safety profile, though with adverse events in nearly half of patients.

Prospective open-label multicentre study (n=125, 62 LGS, 48 Dravet syndrome) with a slow CBD titration protocol (target dose 10 mg/kg/day, max. 20 mg/kg/day); seizure frequency after 6 months -41% ± 37,5% versus baseline, 37,8% (28/74) of patients achieved a ≥50% seizure reduction; adverse events in 48,8% (61/125), most common: somnolence, asthenia, behavioural disturbances; slower titration improved tolerability with comparable efficacy to earlier studies.

Higher CBD plasma levels are associated with improved seizure control; an increase of 100 ng/mL was associated with a reduction of approximately 2 seizures per period.

Open-label EAP with Epidiolex® in treatment-refractory epilepsy (n=100; 56 adults, 44 children). Linear correlation between CBD dose (5–50 mg/kg/d) and plasma level (7,1–1200 ng/mL; r=0,640, p<0,001). Quantile regression: 100 ng/mL CBD increase associated with ~2 fewer seizures per 2-week period (1,87 [96%-CI 0,34–3,39]; p=0,018). Children and adults showed similar response rates; children possibly responsive at lower plasma levels.

Transdermal CBD gel was safe and was associated with a relevant reduction in seizure frequency as well as improvements in quality of life.

Non-randomised controlled trial (n=48 children, DEE epilepsies) with transdermal CBD gel (125–500 mg/d, 6.5 months); median seizure reduction (FIAS+TCS) 58% [IQR -5.3% to 81.8%] at month 5 and 43.5% over the total study period; 60% ≥1 treatment-related AE, of which 96% mild/moderate; 77% of parents reported improvement in social interaction.

Cannabidiol led to small changes in pharmacokinetics: stiripentol exposure increased by 17-30%, valproate exposure decreased by 13-30%; both changes of unclear clinical relevance.

n=35 epilepsy patients (16-55 years), phase II RCT on pharmacokinetic interactions of CBD (20 mg/kg/day) with stiripentol (n=14, of which 12 CBD) or valproate (n=21, of which 16 CBD). Concomitant CBD led to small increase in stiripentol exposure (C_max +17%, AUC_tau +30%). Minimal effect on valproate exposure. Safety and tolerability profile acceptable.

CBD showed no adverse effects on cortical macrostructure, but significantly reduced seizure frequency and severity.

Pilot study (n=27 recruited, n=18 MRI subgroup), highly purified CBD 15–25 mg/kg/day in treatment-resistant epilepsy: Significant reduction in seizure frequency [t(17)=3.08, p=0.0069] and clinical seizure severity (CSSS) [t(17)=5.77, p<0.001] as well as adverse event profile (AEP) [t(17)=3.04, p=0.0074]. No significant changes in cerebral macrostructure (GMV, cortical thickness) detected.

Add-on CBD reduced seizure frequency by more than 50% in over half of the children, with mild side effects.

Multicenter study (n=26, of which 22 EMAtS + 4 Sturge-Weber syndrome), CBD add-on 8–40 mg/kg/day, mean follow-up 19 months: 15/26 (57.7%) achieved >50% seizure reduction; 3/26 (11.5%) became seizure-free. The remaining 11 patients (42.3%) achieved a 25–50% reduction. Side effects mild, no discontinuation of therapy due to adverse events.

CBD normalised resting-state network connectivity and significantly reduced seizure frequency in treatment-refractory epilepsy.

n=22 adults with treatment-resistant epilepsy (TRE), highly purified CBD (Epidiolex®) over the observation period; mean seizure frequency reduction 71,7% (p<0,0001); CSSS, AEP and POMS subscales (confusion, depression, fatigue) all significantly improved (p<0,05); rs-fMRI shows CBD-related normalisation of functional connectivity in cerebellar, frontal, temporal and hippocampal regions.

CBD/THC oil reduced motor seizures by a median of 70,6% and significantly improved quality of life as well as EEG spike activity.

Prospective open-label study (n=20 enrolled, n=19 completed), CBD/THC oil (100 mg/mL CBD + 2 mg/mL THC) add-on in Dravet syndrome children, 20 weeks: median motor seizure reduction 70.6%; 50% responder rate 63%. Significant improvement in quality of life and reduction in EEG spike activity. Tolerability good; increased transaminases observed with concurrent valproate administration.

CBD markedly reduced seizure frequency in TSC patients, with consistent responder rates of 38,9–50% over 12 months.

n=18 patients with tuberous sclerosis (TSC) and refractory epilepsy, CBD up to 50 mg/kg/d (open-label study). Median weekly seizure frequency: 22,0 (IQR 14,8–57,4) baseline → 13,3 (IQR 5,1–22,1) after 3 months. Median seizure reduction –48,8% (IQR –69,1% to –11,1%) after 3 months. 50% responder rate: 50% after 2, 3, 9, 12 months; 38,9% after 6 months. Adverse events in 66,7% (12/18): somnolence 44,4%, ataxia 27,8%, diarrhea 22,2%.

PTL-101 led to a 73,4% reduction in monthly seizure frequency, 56% of patients were responders (≥50% reduction), and two patients became seizure-free.

Phase II open-label study (n=16, children with treatment-refractory epilepsy) on PTL-101 (oral CBD in gelatin matrix beadlets). Age 9,1±3,4 years, mean maintenance dose 13,6±4,2 mg/kg. 11 patients completed treatment (12 weeks). Median seizure count -81,9% from baseline, monthly seizure frequency -73,4±24,6% (p<0,05). Responder rate (≥50% reduction) 56%; 2 patients seizure-free. 73% of caregivers reported improved/greatly improved condition, 82% reduced/greatly reduced seizure severity. Most common adverse events: sleep disturbances/insomnia (25%), somnolence, increased seizure frequency, restlessness.

CBD markedly reduced seizure frequency in the majority of epilepsy patients, while placebo showed little effect.

n=15 epilepsy patients (secondary generalized, temporal focus), CBD 200–300 mg/day vs. placebo double-blind over up to 4,5 months; 4/8 CBD patients nearly seizure-free, 3/8 improved, 1/8 without effect; 7/8 placebo patients unchanged (p-value not reported).

CBD improved sleep duration and reduced dream recall in insomniacs and showed antiepileptic effect in treatment-refractory patients.

Placebo-controlled trial (n=15 treatment-refractory epilepsy patients) with CBD 200–300 mg/day over up to 4,5 months: 7 of 8 CBD patients showed improvement in disease course compared to only 1 of 8 in the placebo group.

CBD leads to a clinically relevant drug interaction with clobazam (strongly increased norclobazam levels), but enables a >50% seizure reduction in 70% of patients.

n=13 children with treatment-refractory epilepsy under clobazam (CLB) + CBD (IND study): 9 of 13 patients (70%) showed >50% seizure reduction. CLB levels increased by 60±80% (95% CI –2 to 91%) at 4 weeks; N-desmethylclobazam (nCLB) by 500±300% (95% CI +90 to +610%). CLB dose reduced in 10 of 13 patients (77%); adverse effects in 10 of 13 (77%), resolved by CLB dose reduction.

CBD as add-on therapy achieved high responder rates and EEG improvements in refractory epileptic spasms in childhood.

Open-label study (n=9 children with refractory epileptic spasms): CBD add-on therapy (target dose 25 mg/kg/day) achieved responder rates (>50% seizure reduction) of 67–78% across all time points (2 weeks to 12 months); 33% (3/9) seizure-free after 2 months. 60% showed EEG hypsarrhythmia resolution. Parents reported subjective cognitive and behavioural improvements.

Oral CBD was well tolerated short-term in pediatric epilepsy patients, but showed relevant pharmacokinetic interactions with clobazam and interindividual exposure variability.

n=61 pediatric patients (1–17 years) with treatment-resistant epilepsy; synthetic CBD orally (10–40 mg/kg/day) as add-on; steady-state after 2–6 days; bidirectional clobazam interaction — 40 mg/kg/day CBD increases clobazam exposure by 1,7- to 2,2-fold; short-term administration generally well tolerated.

Adjuvant CBD significantly and durably reduced convulsive seizure frequency over 48 weeks versus baseline.

n=46 (efficacy group; n=55 safety group), rare epilepsy syndromes (CDKL5, Aicardi, Dup15q, Doose), CBD (Epidiolex) as add-on, multi-center. Median convulsive seizure frequency reduced by 51,4% after 12 weeks and 59,1% after 48 weeks (χ²(2)=22,9, p=0,00001). 27% discontinuation rate by week 144.

CBD significantly improved quality of life and mood independent of seizure control.

Open-label study, n=53 adults with treatment-resistant epilepsy; CBD (Epidiolex) 5–50 mg/kg/d; QOLIE-89 total score improved from 49,4 ± 19 to 57 ± 21,3 (p=0.004); multivariable regression: QoL improvement associated with mood improvement (POMS, p=0.020), not with seizure frequency or severity — CBD effect on quality of life independent of seizure control.

CBD significantly improved quality of life in pediatric epilepsy patients, independent of changes in seizure frequency.

n=48 pediatric patients with treatment-resistant epilepsy; 12-week open-label CBD treatment resulted in +8,2 points QOLCE total improvement (p<0,001) — independent of seizure frequency changes. Subscales: energy/fatigue, memory, social interaction, behavior and global quality of life improved.

79,5% of patients achieved a seizure reduction >50% after 12 weeks; seizure frequency decreased from a median of 11/month to 2,5/month (p<0,001).

Open-label cohort on CBD-rich magistral formulation (100 mg/ml CBD, THC <1,9 mg/ml) as add-on in adults with treatment-refractory focal epilepsy; n=44, median CBD dose 200 mg/day (3,7 mg/kg), THC 4 mg/day. Median seizure frequency before treatment 11/month, after 12 weeks 2,5/month (p<0,001); 79,5% of patients achieved >50% seizure reduction. Median percentage reduction 84,1%. Five patients reported adverse effects.

CBD treatment led to no cognitive deterioration and significantly improved selective attention as well as behavior.

Open-label study (n=39 patients with treatment-resistant epilepsy), CBD treatment over 3 months: no significant cognitive decline on any of the measurement scales; significant improvement in selective attention and a caregiver-rated behavioral scale; >89% of all individual test results stable or improved. Improvements in short-term memory significantly correlated with better treatment response.

Over one year, CBD showed no statistically significant improvements in cognitive function or adaptive abilities in children with treatment-resistant epilepsy, but also no deterioration.

Open-label study on cognitive and adaptive effects of CBD (Epidiolex®) in n=38 children/adolescents (3–19 years) with treatment-refractory epilepsy over 1 year. No significant changes in cognitive function (NIH Toolbox Cognition Battery) or adaptive abilities (ABAS-II in n=24 with severe cognitive impairment). Trend toward improvement in some cognitive domains (not significant). CBD shows no cognitive or functional adverse effects over 1-year treatment.

Cannabidiol significantly reduced the frequency of interictal epileptic discharges and improved sleep microstructure in children with treatment-refractory epilepsy.

Prospective open-label study on CBD (20–50 mg/kg/d) in treatment-refractory epilepsy in childhood; n=35 (age 10,1±0,86 years). Interictal epileptiform discharges (IEDs) significantly reduced after 3 months (19,6±19,5 vs. 36,8±27,2 discharges/min at baseline, p<0,0001). Moderate correlation between IED reduction and seizure reduction (r=0,39, p=0,02). Sleep architecture abnormal in 56,5% initially, improved under CBD in 84,6% of these cases.

Artisanal CBD reduced seizure frequency by at least 50% in just under 38% of children, but the majority showed no benefit.

n=29 pediatric patients (1–18 years) with developmental and epileptic encephalopathy (DEE), artisanal CBD oil 2–25 mg/kg/day adjunctive, mean exposure duration 11,2 months; 11/29 (37,9%) achieved ≥50% improvement in seizure frequency; 1 patient seizure-free; 18/29 (62,1%) without benefit regarding seizure frequency; adverse events in 7/29 (24,1%) — predominantly mild and transient (somnolence, decreased appetite, diarrhoea), no dose adjustment required.

CBD achieved a clinically relevant seizure reduction in about a quarter of the children, but was discontinued by the majority due to lack of efficacy or side effects.

n=26 children (1–17 yrs) with treatment-refractory epilepsy (expanded access program, 4-year period), adjunctive CBD 5–25 mg/kg/d; 26,9% with sustained >50% seizure reduction at 24 months, of whom 11,5% seizure-free; retention at 24 months 34,6%; 80,8% adverse events (reduced appetite 38,4%, diarrhoea 34,6%), 23,1% serious adverse events.

All participants showed a reduction in seizure frequency as well as improved quality-of-life scores under CHE dose escalation with good tolerability.

n=7 children with treatment-resistant epileptic encephalopathy; cannabis herbal extract (THC:CBD 1:20) up to 10–12 mg CBD/kg/day; all participants showed improvement in seizure frequency and QOLCE quality-of-life scores; C_ss-CBD levels at >50% seizure reduction were below values previously reported for purified CBD; recommended starting dose 5–6 mg CBD/kg/day.

Synthetic CBD led to a short-term response in only one of nine highly refractory patients; no benefit was evident for the majority of patients.

n=9 children (6–36 months) with refractory infantile spasms after failure of ACTH and vigabatrin; synthetic CBD 20mg/kg/day over 14 days; primary endpoint (freedom from spasms + freedom from hypsarrhythmia day 14): 1/9 (11%) responded, 8/9 no clinical or electroencephalographic response; oral CBD not effective in highly refractory cases.

Majority of patients achieved >50% seizure reduction with CBD, however small case number and one discontinuation due to lack of efficacy.

n=5 Sturge-Weber syndrome patients with treatment-refractory epilepsy, adjunctive CBD; 2/4 evaluable patients at week 14 and 3 patients at last visit with >50% seizure reduction; remained on CBD for 63–80 weeks; 3 patients with mild side effects.

CBDV reduced monthly seizure frequency in all five girls with a median decrease of 79% and was well tolerated.

n=5 girls with Rett syndrome and treatment-resistant epilepsy; CBDV (cannabidivarin) 10 mg/kg/day; median reduction in monthly seizure frequency 79%; total seizures 32 → 7.2/month; 3 of 5 patients with >75% reduction; 91% of AEs mild/moderate, no study discontinuation due to side effects.

Small pilot case series (n=3 patients with treatment-refractory epilepsy in primary brain tumor) under pharmaceutical cannabidiol (CBD, Epidiolex). Two of three patients showed reduced seizure frequency, all three a lower seizure severity. Preliminary signal, not robust due to very small case number and lack of control group; according to the authors only grounds for further studies.

About a quarter of patients showed a parent-reported seizure reduction >50%, but the majority discontinued therapy; side effects and Dravet syndrome were associated with shorter duration of use.

Retrospective cohort (n=119) of pediatric epilepsy patients with oral cannabis extracts (OCE): 71% discontinued therapy, mean duration of use 11,7 months. 24% were considered responders (>50% seizure reduction according to parental report). Perceived seizure benefit was the only factor for longer therapy duration (p<0,01); side effects (p=0,03) and Dravet syndrome diagnosis (p=0,02) were associated with earlier discontinuation.

Artisanal CBD oil reduced seizure frequency by more than 50% in 39% of children, with a favorable side effect profile.

n=108 pediatric patients with pharmacoresistant epilepsy, artisanal CBD preparations; 39% achieved >50% seizure reduction, 10% became seizure-free; AED weaning possible in 22% of patients; most common side effect sedation in <4% (exclusively under concomitant clobazam administration).

CBD-enriched oil showed consistent improvements with ≥50% seizure reduction across most seizure types over 12 months, however with a high adverse event rate (92% of patients) and 33% discontinuation rate.

Prospective multicenter cohort study (n=101, 19 Thai hospitals) on CBD-enriched cannabis oil in pediatric drug-resistant epilepsy. Median age 10 years, median 75 seizures/month at baseline, failure of an average of 7 antiepileptic drugs. Median CBD dose 6 mg/kg/day, median follow-up 15 months. ≥50% seizure reduction consistently improved at 3, 6, 9, 12-month and last follow-up time points; median monthly overall seizure reduction consistently positive. Effective CBD dose 1-15 mg/kg/day. Adverse events in 92% of patients (predominantly mild 95%): somnolence, elevated liver enzymes, anorexia, irritability. 33 patients discontinued (57% due to intolerable adverse events, 30% ineffectiveness, 12% non-compliance).

CBD oil reduced seizure frequency in more than half of patients, however a quarter developed tolerance with diminishing efficacy.

Prospective study with n=92 patients (1-37 years, mean 11,8 years) with treatment-refractory epilepsy; CBD-enriched oil (CBD:THC=20:1), mean dose 11,3 mg/kg/d. Responder rate (>50% seizure reduction) 54%, 9% seizure-free. Follow-up 19,8±12,5 months (range 3-45). Tolerance development in 25% (21/84) after an average of 7,3±5,4 months; negative correlation between duration of epilepsy and tolerance development (p=0,038). 31% discontinuation due to lack of efficacy or side effects.

Parental reports show a >50% seizure reduction in a third of children, however considerable variability by syndrome as well as adverse events in 44%.

n=75 pediatric patients with epilepsy under oral cannabis extracts (OCE), retrospective chart review; 57% reported any seizure improvement; 33% reported >50% seizure reduction (responders); LGS responder rate 88,9% vs. Dravet 23% vs. Doose 0%; adverse events in 44% (increased seizures 13%, somnolence 12%).

CBD-rich cannabis oil reduced seizure frequency in 89% of treated children, by more than 50% in over half.

Retrospective multicenter study with n=74 children/adolescents (1-18 years) with treatment-refractory epilepsy (resistant to >7 antiepileptic drugs); CBD-enriched cannabis oil (CBD:THC=20:1, 1-20 mg/kg/d). 89% (66/74) reported seizure reduction: 18% >75% reduction, 34% 50-75% reduction, 12% 25-50% reduction. 5 (7%) patients seizure worsening → discontinuation. Treatment duration average 6 months.

CBD as add-on therapy reduced seizure burden by more than 50% in just under half of the children and led to seizure freedom in a fifth.

n=66 children with pharmacoresistant epilepsy, add-on CBD (≥8 mg/kg/day) at tertiary center Ljubljana; 48,5% achieved >50% reduction in seizure burden, 21,2% became seizure-free; adverse effects in 5/66 patients.

56% of patients showed ≤50% reduction in monthly seizure frequency, but 46% reported adverse effects, which were the main reason for treatment discontinuation.

Longitudinal observational study in refractory epilepsy in childhood/adolescence (n=46, age 1-20 years), CBD/THC 20:1 oil (median 18 months follow-up, average CBD dose 11,4 mg/kg/d). 56% of patients (n=26) achieved ≥50% reduction in mean monthly seizure frequency (parent-reported). Younger age at treatment start (<10 years) and higher CBD dose (>11 mg/kg/d) associated with better response. Adverse effects in 46% of patients (mainly somnolence, decreased appetite, diarrhoea).

Oral CBD achieved a clinically relevant seizure reduction in a subset of pediatric LGS and DS patients with a tolerable side effect profile.

Retrospective case series, n=44 children (LGS n=34, Dravet n=10); CBD (start 5 mg/kg/day, maintenance 10 mg/kg/day); LGS: seizure reduction 52,9% after 3 months, 29,4% after 6 months; >50% reduction in 32,3% (3 mon.) / 20,6% (6 mon.); DS: >50% reduction in 30% (3 mon.) / 20% (6 mon.); no life-threatening adverse events.

87% of patients reduced their monthly seizures by at least 50%, 32% by more than 80%, with good tolerability and improved quality of life.

Prospective cohort n=44 adults with focal treatment-refractory epilepsy, CBD adjuvant (Ø 335 mg/d); 87% achieved ≥50% seizure reduction, 32% >80% reduction, 5% seizure-free. 34% mild side effects, no severe adverse events. Significant improvement in quality of life.

CBD treatment led to significant improvements in depressive symptoms (95,4% showed improvement, p=0,001), anxiety symptoms (71% improvement) and quality of life (68% improvement, p<0,001).

Prospective cohort study (before-after) on psychiatric comorbidities under CBD in n=44 adults with treatment-refractory focal epilepsy. Before CBD: 50% with depressive symptoms, 54,5% with anxiety symptoms. After CBD: 95,4% showed improvement in depression (p=0,001), 71,5% with minimal/no depressive symptoms; 71% improvement in anxiety symptoms; 68% improved quality of life. Significant correlation BDI-II/QOLIE-10 (p<0,036 and p<0,001 respectively). CBD effective, safe, well tolerated with marked improvement in psychiatric comorbidity.

In 52% of patients seizure reduction >30% (23% responders, 29% super-responders after 3 months), efficacy remained maintained over 12 months.

Real-world study on CBD in treatment-refractory epilepsy, n=42 (24 on-label: Lennox-Gastaut n=18, Dravet n=5, tuberous sclerosis n=1; 18 off-label). After 3 months 23% responders (>30% seizure reduction) and 29% super-responders (≥80% reduction); effect persisted over 6 and 12 months. Adverse events in 52,3% (most common: somnolence 36,5%, diarrhoea 9,8%). Retention rate: 85,7% (3 months), 78,6% (6 months), 71,4% (12 months).

Response rate of 24% similar to placebo rates in randomised trials; 14% discontinuation due to perceived seizure increase.

Prospective observational study of oral cannabis extracts (OCE) in children with refractory epilepsy; n=21, median 10,3 years, baseline 2,7 seizures/day. Median CBD dose 0,9 mg/kg/day (IQR 0,6-2,2). Responder rate (≥50% seizure reduction over 8 weeks) 24% (5/21), similar to placebo rates in RCTs. Discontinuation rate 14% (3/21) due to perceived seizure increase. No significant association between CBD/THC-COOH blood levels and response (p=0,95 and p=0,53 respectively).

CBD reduced seizure frequency in 7 of 10 patients (70%), with 1 seizure-free patient, 2 with >75% reduction and 4 with >50% reduction in seizures.

Monocentric observational study on CBD (Epidyolex) in Rett syndrome with epilepsy (n=10/46 patients with epilepsy treated). Median dose 15 mg/kg/d, treatment duration median 13 months (range 1–32). Seizure reduction in 7/10 (70%): 1 patient seizure-free, 2 with >75% reduction, 4 with >50% reduction. Combination with clobazam in 50%. No worsening or severe adverse events; only 1 patient with transient salivation and somnolence.

72% of patients (210 of 272) experienced a reduction in seizures of at least 26%, with 28% in complete remission or near-complete seizure control (76-99% reduction).

Retrospective data on artisanal cannabis preparations in n=272 patients with treatment-refractory epilepsy (Washington, California, Maine); 14% found cannabis ineffective, 15% had 1-25% seizure reduction, 18% had 26-50% reduction, 17% had 51-75% reduction, 28% had 76-99% reduction, 10% achieved complete clinical remission. Side effects mild and rare; majority used CBD-enriched formulations, some with THC/THCA.

The majority of cannabis users reported a seizure reduction, however based on self-report without a control group.

Australian national online survey (n=976 people affected by epilepsy): 15% of adults and 13% of parents/legal guardians reported current or previous use of cannabis products for the treatment of epilepsy. Of these, 90% of adults and 71% of parents reported a reduction in seizure frequency after starting cannabis products. Most common reason: treatment-resistant epilepsy and a more favourable side-effect profile compared to standard antiepileptic drugs.

This is a descriptive observational study on the frequency of use of non-regulated cannabis products; no efficacy was measured.

Cross-sectional study on non-regulated cannabis products in epilepsy patients in Colombia; n=380, 10,3% (39/380) used artisanal cannabis products. 84,6% (33/39) without physician recommendation, only 7,7% (3/39) documented in medical records. Significant association with age (p=0,002), treatment response (p=0,01), number of prior antiepileptic drugs (p<0,01) and VNS (p<0,01). Higher prevalence in younger patients with uncontrolled epilepsy.

High prevalence of cannabis use with predominantly positively perceived effects on seizures, stress and sleep, but possible seizure provocation in individual patients.

n=292 adults in an epilepsy monitoring unit (cross-sectional survey); 57% had ever tried cannabis, 36,2% had used it in the past year. 84% of epilepsy patients reported subjective seizure improvement, stress reduction in 84,9%, sleep improvement in 77,3%, memory/concentration improvement in 32%. Possible seizure provocation in 5 patients (adverse effect). Exclusively subjective self-reports, no control arm.

Cannabis-based medicinal products were associated with improvements in all measured quality of life and health parameters (QOILE-31, sleep quality, EQ-5D-5L, anxiety, global impression); 29,85% of patients achieved clinically meaningful improvement.

UK Medical Cannabis Registry: Case series (n=134) on cannabis-based medicinal products (CBMPs) in treatment-resistant epilepsy. Improvements in QOLIE-31 and all HRQoL PROMs (p<0,050) at 1, 3 and 6 months vs. baseline; 40 patients (29,85%) achieved a clinically relevant difference in QOLIE-31 after 6 months. 18 adverse events (13,43%) in 5 patients (3,73%), predominantly mild/moderate.

Cannabis users showed better values in the subscore 'energy and fatigue', but no significant difference in the overall QOLIE-31 score; negative correlation between total score and cannabis use disorder.

Observational study on quality of life (QOLIE-31) in cannabis users vs. non-users with treatment-refractory epilepsy; n=46 (25 cannabis users, 21 controls). Significantly higher T-subscore 'energy and fatigue' in the cannabis group (p=0,004), but no difference in the overall T-score (p=0,11). Significant negative correlation between overall T-score and cannabis use disorder (p=0,032).

No significant differences in seizure frequency, seizure duration or rescue medication use compared to baseline; no improvement in behavioral or sleep disturbances.

Prospective observational study (n=29, 12–46 years) on medical cannabis (1THC:20CBD and/or 1THC:50CBD; max. 6 mg THC/day) in treatment-resistant epilepsy over ≥24 weeks. Primary outcome: no significant differences in convulsive seizure frequency, seizure duration, postictal duration or rescue medication vs. baseline. No evidence of efficacy for behavioral disturbances or sleep duration; medication well tolerated.

In 79,3% of patients a reduction in seizure frequency of ≥50% was achieved, 34,5% achieved a ≥75% reduction without generalized motor seizures; one patient achieved seizure freedom; high retention rate (>86% at 12 and 24 months) with mild, manageable side effects.

Retrospective cohort n=29 pediatric treatment-refractory epilepsy (diverse genetic/non-genetic etiologies), adjunctive CBD median 14,2 mg/kg/d over a median 14,3 months follow-up. Retention rate >86% at 12/24 months. At 12 months: 79,3% achieved ≥50% seizure reduction, 34,5% achieved ≥75% reduction without generalized motor seizures, 1 patient (GABRB3 variant) seizure-free. Adverse events in 37,9% (mostly somnolence/lethargy, mild, manageable by ASM adjustment); discontinuation in n=3 (pneumonia, lethargy, seizure aggravation).

Statistically significant improvement in quality of life, significant decrease in anxiety disorders and significant decrease in adverse events over time (p < 0,05); depression showed a trend toward improvement without significance.

Prospective observational time-series study in adults with treatment-refractory epilepsy who added artisanal CBD adjunctively to existing therapy (n=10 complete cases, ~6 months follow-up). Significant improvements: quality of life (p<0.05), anxiety symptoms (p<0.05), reduction in adverse events (p<0.05). Urinalysis confirmed CBD metabolites after treatment initiation.

The majority of parents reported seizure reduction, however the results are strongly limited by pronounced participation bias and methodological limitations.

Online survey n=117 parents (incl. 53 with infantile spasms/LGS), CBD-enriched cannabis; 85% reported seizure reduction, 14% reported complete seizure freedom; median exposure duration 6,8 months, dose 4,3 mg/kg/day. Adverse effects: increased appetite (30%), somnolence; sleep improvement (53%), alertness (71%), mood (63%) improved. Methodological: participation bias, no control arm.

Parents reported a seizure reduction in 81,3% of children under cannabidiol, in 16% complete seizure freedom.

n=53 children (9 months – 18 years) with refractory epilepsy in Mexico (47% Lennox-Gastaut, 30% unspecified, 19% West syndrome); 47,1% had previously received ≥9 anticonvulsants. Parent reports: 81,3% reported seizure reduction under CBD; moderate to marked reduction in 51%, 16% seizure-free. No serious adverse effects; mild AEs (increased appetite, changes in sleep) in 42%. Uncontrolled observational data with strong selection and reporting bias.

CBD as add-on therapy reduced epileptic spasms by more than 50% in 67,8% of children with good tolerability.

Retrospective case series (n=28 infants, age 6–21 months) with treatment-resistant infantile epileptic spasms syndrome (IESS); highly purified CBD as add-on (median 25 mg/kg/day); 19/28 (67,8%) achieved >50% reduction in epileptic spasms; 7 patients completely spasm-free; adverse effects mild.

The majority of surveyed parents reported a clinically relevant reduction in seizure frequency under CBD-enriched cannabis, however without standardized measurement or control group.

Parent survey n=19 children with treatment-resistant epilepsy (13 Dravet, 4 Doose, 2 other); 84% reported seizure reduction under CBD-enriched cannabis; 11% seizure-free, 42% >80% reduction, 32% 25–60% reduction. On average 12 prior AED trials failed. Methodological: participation bias, no control arm.

Cannabidiol reduced seizure frequency and duration in 6 of 7 children, however one patient died of treatment-associated multi-organ failure.

n=7 children with FIRES (febrile infection-related epilepsy syndrome) from 5 centres, CBD (Epidiolex) in the acute or chronic phase. 6 of 7 patients (86%) showed improvement in seizure frequency and duration. On average 4 antiepileptic drugs discontinued. Currently: 5 patients able to walk, 4 able to speak. 1 patient died of multi-organ failure (isoflurane-associated, not CBD-related). Case series in an ultra-rare, otherwise treatment-refractory epilepsy.

CBD as add-on reduced seizure frequency by 80–90 % in all three patients with SYNGAP1 epilepsy.

n=3 children with SYNGAP1-associated pharmacoresistant epilepsy, add-on CBD prospective; 2/3 patients showed a seizure reduction of 90% and 80% respectively from month 2 by month 9 with disappearance of drop attacks; 1/3 late response at month 7 with 80% frequency reduction; no serious adverse effects.

Case report (n=1): In a 10-month-old infant with malignant migrating partial epilepsy of infancy (pharmacoresistant epileptic encephalopathy), the addition of pure cannabidiol to existing antiepileptic therapy led to sustained seizure reduction and developmental progress. Limitation: single case without control, no causality derivable, hypothesis-generating only.

CBD showed superiority over placebo in controlled studies in Dravet and Lennox-Gastaut syndrome, but it is unclear whether this is a direct CBD effect or a drug interaction with clobazam.

Narrative review on cannabinoid-based epilepsy therapy; reports on k=3 high-quality placebo-controlled add-on therapy trials with purified CBD in Dravet syndrome and Lennox-Gastaut syndrome. CBD was superior to placebo in reducing convulsive seizures (Dravet) and drop seizures (Lennox-Gastaut). For the first time, class 1 evidence for adjunctive CBD efficacy in specific epilepsy syndromes. Mechanism unclear: direct CBD effect vs. interaction with concomitant medication (in particular a marked increase in N-desmethylclobazam plasma levels).

Cannabis/CBD shows antikonvulsive properties, but the exact mechanisms remain unclear and only limited clinical evidence exists.

Mechanistic overview of the pharmacological foundations of cannabis therapy in epilepsy; discusses antikonvulsive mechanisms of CBD/THC (GABA modulation, adenosine signaling, CB1/CB2 receptors), no systematic data extraction.

Review summarizes findings that CBD (Epidiolex) can reduce seizure frequency in treatment-resistant epilepsy, but places emphasis on side effects.

Narrative review on Epidiolex (99% pure oral CBD extract) as add-on therapy for refractory epilepsy; summarizes results of several randomized controlled and open-label trials that led to FDA approval and DEA scheduling in Schedule V (CSA). Focus on tolerability profile and side effects of CBD in treatment-refractory epilepsy.

Narrative review without own empirical data; discusses that polytherapy in DRE may offer better seizure control than monotherapy, based on a cited cohort study.

Narrative overview on pharmacotherapy in drug-resistant epilepsy (DRE, defined as insufficient seizure control after two adequate drug trials). Large cohort study shows progressive increase in seizure-freedom rate under combination therapy vs. monotherapy in DRE over two decades. Rational polytherapy with new AEDs with different mechanisms of action improves outcomes; RCTs show superiority of new AEDs vs. placebo as add-on.

The efficacy and safety of cannabinoids in the treatment of epilepsy is not sufficiently established; data to date encourage further studies, but some animal studies also show pro-convulsive effects.

Narrative review on cannabinoids and the endocannabinoid system in epilepsy (PubMed/Scopus up to 2015). About 30% of epilepsy patients remain pharmacoresistant. Preclinical animal models and initial patient studies show antiepileptic activity of cannabidiol (CBD) through modulation of glutamate/GABA neurotransmission. However, pro-convulsive effects also occur in some animal studies; only few double-blind, randomised, placebo-controlled studies have been published. Existing human data do not conclusively support efficacy/safety, but justify further studies.

Critical review article on the pharmacology and clinical evidence of cannabidiol (CBD) as adjunctive therapy for seizures in the context of Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS), two severe, treatment-refractory epilepsy syndromes of early childhood. The authors summarize current clinical studies demonstrating a seizure-reducing efficacy of CBD without psychoactive effects. As a narrative review without quantitative meta-analysis; safety aspects are also assessed.

Narrative review article on cannabinoids in treatment-resistant epilepsy (affects approx. 30% of epilepsy patients). Summary of the first placebo-controlled RCTs with cannabidiol (CBD, Epidiolex) in children with Dravet syndrome and Lennox-Gastaut syndrome shows indications of potential efficacy in seizure reduction. Previously only case reports, small series and surveys were available. Authors emphasize the large role of the placebo effect given strong media and social expectations, as well as the lack of robust data on safety, efficacy and dosing of artisanal dispensary preparations.

CBD significantly reduced epileptiform activity in vitro and seizure severity as well as mortality in vivo compared to vehicle.

Preclinical investigation of CBD (0,01–100 µM in vitro; 1/10/100 mg/kg in vivo) in hippocampal brain slices and in the mouse pentylenetetrazole seizure model. CBD 100 mg/kg significantly reduced severe seizures and mortality vs. vehicle (p<0.05). In vitro: reduction of amplitude and duration of epileptiform LFP bursts in CA1, CA3 and dentate gyrus. Mechanism of action independent of the CB1 receptor. First evidence for CBD as an antiepileptic mode of action without psychoactive CB1 agonism.

CB1 activation by THC or synthetic cannabinoids eliminated spontaneous seizures, while CB1 blockade enhanced seizure activity.

Rat model of spontaneous recurrent seizures (pilocarpine): Δ9-THC (10 mg/kg) and CB1 agonist WIN55,212 (5 mg/kg) completely suppressed epileptic seizures; CB1 antagonist SR141716A significantly increased seizure duration and frequency (in some cases equivalent to status epilepticus). Hippocampal 2-arachidonylglycerol levels increased significantly during acute seizures; CB1 receptor protein in CA regions of epileptic hippocampi significantly increased.