Pharmaceutical-grade cannabidiol (CBD) represents the first in a new class of antiseizure medications |
In randomized controlled trials, CBD reduced seizure frequency in patients with Dravet syndrome, Lennox–Gastaut syndrome, and tuberous sclerosis complex |
Open-label studies suggest the effectiveness of CBD treatment in patients with other epileptic conditions than those addressed by regulatory trials |
The most common adverse events associated with CBD include somnolence, decreased appetite, diarrhea, and increased serum aminotransferases |
1 Introduction
2 Methods
3 Results
Epilepsy condition/etiology | Population | Main findings |
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Tuberous sclerosis complex | Randomized, double-blind, placebo-controlled trial Reduction in TSC-associated seizure frequency: 48.6% (CBD25; p < 0.001), 47.5% (CBD50; p = 0.002), 26.5% (placebo); responder rate TSC-associated seizure frequency: 36.0% (CBD25; p = 0.069), 39.7% (CBD50; p = 0.025), 22.4% (placebo); reduction in total seizure frequency: 48% (CBD25; p = 0.001), 48% (CBD50; p = 0.002), 27% (placebo) during 16-week treatment period. Improvement in overall condition on S/CGIC: 69% (CBD25; p = 0.007), 62% (CBD50; p = 0.058), 40% (placebo) Treatment withdrawal: 10.3%. AEs: 88.0% (CBD25), 97.3% (CBD50), 89.5% (placebo); diarrhea: 30.7% (CBD25), 54.8% (CBD50), 25.0% (placebo); decreased appetite: 20.0% (CBD25), 23.3% (CBD50), 11.8% (placebo); somnolence: 13.3% (CBD25), 26.0% (CBD50), 9.2% (placebo); vomiting: 16.0% (CBD25), 17.8% (CBD50), 9.2% (placebo); pyrexia: 18.7% (CBD25), 16.4% (CBD50), 7.9% (placebo); increased transaminases: 12.0% (CBD25), 24.7% (CBD50), 0% (placebo). SAEs: 21.3% (CBD25), 13.7% (CBD50), 2.6% (placebo) [13] Open-label studies Seizure frequency reduction: 58–93% (week 8) [17] Reduction in epileptic spasm frequency: 15.1–98.8% (week 2), 3.7–94.2% (M1), 58.3–100% (M2), 49.1–100% (M3), 80.2–100% (M6), 85.8–100% (M9), 100% (M12) [41] Seizure frequency reduction >50%: 50% (M2), 50% (M3), 38.9% (M6), 50% (M9), and 50% (M12) for all seizure types; 100% (M2), 75% (M3), 100% (M6), 100% (M9), and 100% (M12) for spasms; 75% (M2), 75% (M3), 75% (M6), 75% (M9), and 50% (M12) for atonic seizures; 50% (M2), 66.7% (M3), 50% (M6), 60% (M9), and 100% (M12) for tonic clonic seizures; 38.5% (M2), 53.8% (M3), 30.8% (M6), 53.8% (M9), and 50% (M12) for focal seizures with impairment of consciousness or awareness; 25% (M2), 50% (M3), 50% (M6), 66.7% (M9), and 50% (M12) for focal seizures evolving to bilateral generalized convulsive seizures; 57.1% (M2), 42.9% (M3), 57.1% (M6), 66.7% (M9), and 50% (M12) for tonic seizures [20] Treatment withdrawal: 16.7% [20] Resolution of hypsarrhythmia: 2/2 [41] Cognitive gains 12/14 (85.7%), behavioral improvement 6/9 (66.7%) [20] AEs: 54.2%. Drowsiness 22.9%, diarrhea 14.6%, ataxia 12.5%, agitation 10.4%, irritability 6.3%, lethargy 6.3%, appetite loss 4.2%, poor sleep 4.2%, confusion, vomiting, abdominal pain, mouth sores, increased acne, ankle swelling, sinusitis, mild elevation of transaminases, increased phenytoin level, increased self-stimulation, behavioral difficulties (all 2.1%) [17, 20, 39, 41] | |
Aicardi syndrome | N = 19 [27] | Median decrease in convulsive seizure frequency: 58.3% (week 12), 59.2% (week 48). Responder rate (convulsive seizures): 71% (week 12), 71% (week 48). Mean CBD daily dose: 8.1 ± 2.3 (week 2), 26.7 ± 12.7 (week 12), 32.0 ± 12.3 (week 48) mg/kg |
CDKL5 deficiency | Seizure frequency reduction: 100% (week 8) [17] Median decrease in convulsive seizure frequency: 40.8% (week 12), 59.7% (week 48). Responder rate (convulsive seizures): 41% (week 12), 53% (week 48) [27] Responder rate 1/5, increased seizure frequency 2/5 (any seizure types; 8–36 months) [30] Increased seizure frequency: (any seizure types): 2/5 [30] AEs: 4/5. Drowsiness, weight loss, sleepiness, diarrhea, loose stools, agitation. Treatment withdrawal: 4/5 (at 5–23 months) [30] Mean CBD daily dose: 8.3 ± 2.6 (week 2), 18.2 ± 7.0 (week 12), 26.2 ± 10.1 (week 48) mg/kg [27] | |
Doose syndrome | Seizure frequency reduction: 54–100% (week 8). AEs: 50% (drowsiness) [17] | |
Dup15q syndrome | Seizure frequency reduction: 26% (week 8) [17] Median decrease in convulsive seizure frequency: 25.0% (week 12), 38.4% (week 48). Convulsive seizures responder rate: 38% (week 12), 38% (week 48) [27] | |
Epilepsy with myoclonic absences | N = 5 [30] | Responder rate 2/5, seizure freedom 2/5, increased seizure frequency: 2/5 (any seizure types; 5–53 months) Treatment withdrawal: 3/5 (at 5–6 months) AEs: 5/5; decreased appetite/food aversion, weight loss, elevated transaminases, loose stools, lethargy |
Sturge–Weber syndrome | N = 5 [21] | Seizure frequency reduction: 10–90% (week 14), 12–100% (at most recent visit – week 6–60). Treatment withdrawal for lack of efficacy: 2/5 (at week 9 and 38) AEs: 5/5; temporary increased seizures (3/5), behavioral issues (2/5), increased transaminases (1/5), tiredness (1/5) All patients reported improvements in quality of life; subjective improvements in motor, speech, and cognitive abilities, level of alertness, vocalization or communication, mood and behavior also reported. CBD daily dose: 5–25 mg/kg |
SYNGAP1 developmental and epileptic encephalopathy | N = 3 [53] | Seizure frequency reduction: 0–85% (M2), 80-95% (M9). Responder rate: 2/3 (M2), 3/3 (M9) AEs: 1/3 (sleep disorder). Slight increase in transaminases (1/3) EEG improvement in background activity and interictal anomalies Caregivers evaluated as much improved the status of their children. Maximum CBD daily dose: 10–23 mg/kg |
Epilepsy of infancy with migrating focal seizures | Reduction in seizure frequency >90 at M6, with seizure-free periods; improvement in alertness [16] CBD discontinued after 6 months for inefficacy [30] Overall seizure frequency change −12% to +20% during 24-week treatment period; increase in motor arrest seizures with clinically meaningful reduction in seizure intensity, reduction in generalized clonic seizures, reduction/increase in asymmetric tonic seizures [40] | |
SCN8A epileptic encephalopathy | N = 1 [30] | CBD dose reduced for side effects and discontinued after 25 months for inefficacy AEs: drowsiness, somnolence |
Infantile/epileptic spasms | Day 15: freedom of clinical spasms 0/9; resolution of hypsarrhythmia 0/9; improvement at CGIC 7/9; improvement at PGIC 6/9; AEs 5/9 (55.6%); diarrhea 2/9 (22.2%), upper respiratory tract infection 2/9 (22.2%), somnolence 1/9 (11.1%); serious AEs 1/9 (11.1%) [14] Freedom of clinical spasms: 1/8 (day 29), 2/6 (day 43), 1/4 (day 127), 1/3 (day 211), 1/2 (day 295), 3/7 (day 379). Resolution of hypsarrhythmia: 1/8 (day 29), 0/6 (day 43), 1/4 (day 127), 0/3 (day 211), 1/2 (day 295), 3/7 (day 379). Freedom of clinical spasms and resolution of hypsarrhythmia: 1/8 (day 29), 0/6 (day 43), 0/4 (day 127), 0/3 (day 211), 1/2 (day 295), 3/7 (day 379). Improvement at CGIC: 7/9 (day 29), 6/9 (day 43), 4/9 (day 127), 3/9 (day 211), 3/9 (day 295), 6/9 (day 379); improvement at PGIC: 4/9 (day 29), 5/9 (day 43), 4/9 (day 127), 1/9 (day 211), 1/9 (day 295), 4/8 (day 379). AEs (day 417): 7/9 (77.8%); SAEs (day 417): 2/9 (22.2%) [15] Change in epileptic spasm frequency: −100% to 10.6% (week 2), −96.0% to 10.6% % (M1), −100 to 9.6% (M2), −100 to 12.3% (M3), −100 to −29.8% (M6), −100 to −76.2% (M9), −100 to −42.4% (M12). Resolution of hypsarrhythmia: 3/6. Improvement in cognitive and developmental motor skills: 2/6 [41]. Maximum CBD daily dose: 40 mg/kg [14, 15] | |
Focal cortical dysplasia | N = 2 [49] | Seizure frequency reduction from 70 to 100%, seizure freedom in 1/2 after receiving a stable dosage of CBD for at least 2 weeks. CBD daily dose: 15–20 mg/kg |
Cerebral dysgenesis | Change in seizure frequency: −74% to 99% (week 8); increase in seizure frequency: 2/3 [17] Reduction in epileptic spasm frequency: 100% (week 2), 92.5% (M1), 82.5% (M2), 60% (M3), 67.5% (M6), 85% (M9), 85% (M12) and resolution of hypsarrhythmia [41] AEs: 4/4. Drowsiness (3/4), ataxia and urinary retention (1/4) [17] | |
Lissencephaly | N = 1 [17] | Seizure frequency reduction: 94% (week 8). AEs: none |
Tumor-related epilepsy | Seizure frequency reduction on-study 58–94% (month 2–11) in 2/3 Seizure frequency reduction from 57 to 86% after receiving a stable dosage of CBD for at least 2 weeks [49] | |
Febrile infection-related epilepsy syndrome | N = 7 [19] | Resolution of status epilepticus in 1 out of 2 patients treated in the acute phase Mean seizure frequency reduction in 5 patients treated in the chronic phase: 90.9% (week 4) and 65.3% (week 48) for all seizure types, 99.6% (week 4) and 62.3% (week 48) for focal motor seizures, 75% (week 4) and 73% (week 48) for generalized tonic-clonic seizures, 99.6% (week 4) and 62.4% (week 48) for focal seizures with impaired consciousness AEs: dizziness (2/7), decreased appetite and weight loss (1/7), nausea/vomiting (1/7). CBD daily dose: 15–25 mg/kg |
Super refractory status epilepticus | N = 1 [31] N = 1 [45] | Clinical seizure freedom achieved on day 12, clinical and subclinical seizure freedom demonstrated on day 64; sequential discontinuation of phenobarbital, midazolam, perampanel, and dose-reduction of lacosamide [31] Reduction of frequency in clinical seizures (from 10 to 0–3 episodes per hour) and midazolam drip successfully weaned off [45] |
Rett syndrome | N = 1 [30] | CBD dose reduced for side effects and discontinued after 6 months for inefficacy. AEs: agitation, insomnia, leg cramping |
Refractory generalized epilepsy | ||
Refractory focal epilepsy | Focal epilepsy (vasculitis). Seizure frequency reduction >50%: 1/1 at 40 months; AE: none [30] Focal epilepsy (unknown etiology). Seizure frequency reduction >50%: 0/1; treatment withdrawal 1/1 (at 5 months); AE: diarrhea [30] Focal epilepsy (encephalitis; n = 2): change in seizure frequency −53.9 to −42.9% after receiving a stable dosage of CBD for at least 2 weeks [49]. CBD daily dose: 25 mg/kg [49] Multifocal epilepsy (unknown etiology; n = 1): change in seizure frequency −100% after receiving a stable dosage of CBD for at least 2 weeks [49]. CBD daily dose: 25 mg/kg [49] |
Study, year | Population | Efficacy | Tolerability/safety | Other |
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Geffrey et al. (2015) [17] | N = 13 | Mean change in seizure frequency (week 8): 51%; >50% decrease in seizure frequency (week 8): 69.2% Increased seizure frequency: 15.4% | AEs: 76.9%. Drowsiness 46.2%, ataxia 15.4%, irritability 15.4%, restless sleep 7.7%, urinary retention 7.7%, tremor 7.7%, loss of appetite 7.7% Treatment withdrawal: 0% | |
Devinsky et al. (2016) [18] | N = 214 | Median reduction in seizure frequency (week 12): 34.6% (all), 55.0% (focal), 54.3% (atonic), 36.5% (tonic), 16% (tonic-clonic); 36.5% (motor) Seizure freedom (week 12): 4% (motor seizures), 2% (all seizures) Responder rates (week 12): 37% (all seizures), 39% (motor seizures) | AEs: 79.0%. AEs reported in >5% of patients: somnolence 25.3%, decreased appetite 19.1%, diarrhea 19.1%, fatigue 13.0%, convulsion 11.1%, increased appetite 8.6%, SE 8.0%, lethargy 7.4%, weight increased 7.4%, weight decreased 6.2%, drug concentration increased 5.6%; elevated liver functions tests 6.8%. SAEs: 12.3% Drug withdrawal because of AEs: 3.1% | Diarrhea or related side effects (e.g., weight loss) more likely if CBD daily dose >15 mg/kg Somnolence more common in patients taking CLB |
Rosenberg et al. (2017) [22] | N = 48 | Median reduction in seizure frequency (week 12): 39.4% Responder rate (week 12): 41.7% | Somnolence, drowsiness, or fatigue: 58.3% | Improvement in patient QOLCE as assessed by caregivers (energy/fatigue, memory, other cognitive functions, control/helplessness, social interactions, behavior and global QOL item sub-scores), not related to changes in seizure frequency or AEs |
Gaston et al. (2017) [23] | N = 81 | Sedation more frequent with higher N-CLB concentrations in adults and transaminase levels significantly higher in participants taking concomitant VPA Sedation resulted in CLB dose decrease, but not discontinuation | Increases in TPM, RUF, and N-CLB and decrease in CLB serum concentrations with increasing CBD dose. Increases in serum concentrations of ZNS and ESL with increasing CBD dose in adults. Except for CLB and N-CLB, all mean concentration changes were within the therapeutic ranges | |
Szaflarski et al. (2018) [26] | N = 607 | Median reduction in seizure frequency (week 12-96): 46–53% (total), 44–51% (convulsive). Responder rate (week 12–96): 48–52% (total), 44–52% (convulsive seizures). Seizure freedom rate (week 12–96): 6–8% (total seizures), 9–13% (convulsive). Seizure frequency increase (week 12–96): 19–25% (total), 20–27% (convulsive). Drug withdrawal for lack of efficacy: 14.7% | AEs: 88.3%; diarrhea 29.2%, somnolence 22.4%, convulsion 16.8%, decreased appetite 12.4%, upper respiratory tract infection 12.4%, vomiting 11.4%, fatigue 10.7%, pyrexia (10.4%), SE 7.4%, pneumonia 6.8%. Increased transaminases: 10% (of which 75% were on VPA). Somnolence more common in patients taking (38%) than not taking (14%) CLB SAEs: 32.8% Drug withdrawal because of AEs: 5.3% | |
Chen et al. (2018) [28] | N = 40 | Seizure frequency not reliably recorded because of disease severity | AEs: 62.5%; somnolence 32.5%, diarrhea 10.0%, anorexia 10.0%, increased seizures 5.0%, vomiting 2.5%, rash 2.5%; increased transaminases 5.0% (all receiving VPA) SAEs: 20.0% Drug withdrawal because of AEs: 5.0% | Improvement at CGIC: 12/40 (30.0%) Improvement at PGIC: 12/40 (30.0%) |
Szaflarski et al. (2018) [29] | N = 132 | Seizure frequency reduction: 63.6% (week 12), sustained with no significant differences at week 24 and week 48 Responder rate: 55.4% (week 12), 51.2% (week 24), 63.9% (week 48) Seizure freedom: 6.2% (week 12), 6.8% (week 24), 3.3% (week 48) | Significant decrease in AEP at week 12 with stable scores thereafter (week 24 and 48) Retention rate: 77% (week 48) | Significant decrease in CSSS scores at 12 weeks and stable thereafter (week 24 and 48) |
Gaston et al. (2019) [32] | N = 53 | Seizure count: at enrollment 41.5% (<14 seizures), 30.2% (14–50 seizures), 28.3% (>50 seizures); at 12 months: 62.3% (<14 seizures), 24.5% (14–50 seizures), 13.2% (>50 seizures) | Improvement in AEP scores at 12 months | Significant decrease in CSSS at 12 months Improvement in POMS and QOLIE-89 total scores at 12 months |
Szaflarski et al. (2019) [34] | Median seizure frequency reduction: 54% (at the time of CBD plasma level testing after stable dosage for at least 14 days) Responder rate: 57% (at the time of CBD plasma level testing after stable dosage for at least 14 days) | Diarrhea 30%, sedation 14%, depression and mood issues 7%, nausea/vomiting 3% | Positive linear correlation between CBD dosage and plasma peak concentration Increased CBD concentrations associated with improvement in seizure frequency after adjusting for age | |
Allendorfer et al. (2019) [35] | N = 22 | Median seizure frequency: 71.2% after a median time of 10 weeks and achieving a stable CBD dose for at least 2 weeks | Improvements in seizure severity and mood. CBD reduced right superior frontal gyrus and right insula/ middle frontal gyrus activation related to stimulus conflict resolution and reduced differences in condition-based functional connectivity of the right superior frontal gyrus | |
Martin et al. (2019) [36] | N = 27 | Improvement in seizure severity at 12 months. No statistically significant score changes in cognitive tests. No statistically significant association between changes in cognitive test performance and CBD dose or seizure severity change | ||
Gaston et al. (2019) [37] | N = 132 | Sustained reduction in seizure frequency at 12, 24, and 48 weeks | Improvement in seizure severity as assessed by the CSSS at 12, 24, and 48 weeks No significant differences in seizure frequency and severity reduction between CLB-On and CLB-Off patients and between patients taking and not taking interacting ASMs (rufinamide, eslicarbazepine, zonisamide, topiramate) | |
Savage et al. (2020) [38] | N = 47 | Seizure frequency reduction: 26.8% (CLB-On), 26.2% (CLB-Off) at M2; 58.5% (CLB-On), 49.5% (CLB-Off) at the best point of seizure control within the first year Responder rate: 50.0% (CLB-On), 26.7% (CLB-Off) at M2; 71.9% (CLB-On), 33.3% (CLB-Off) at the best point of seizure control within the first year Seizure freedom: 3.1% (CLB-On), 0% (CLB-Off) at M2; 6.3% (CLB-On), 0% (CLB-Off) at the best point of seizure control within the first year | Most common AEs: diarrhea, somnolence, fatigue; increased serum aminotransferases in patients taking concomitant VPA. Somnolence, ataxia, irritability, and urinary retention were common in the setting of concomitant CLB use and typically resolved after dose adjustments to either CLB or CBD | No significant difference in mean seizure frequency reduction between patients taking and not taking concomitant CLB. There was a significantly greater responder rate for subjects taking CBD and CLB at the point of best seizure control within the first year of treatment No significant difference in mean CBD doses and no correlation between change in N-CLB or CLB levels and change in seizure frequency |
Sharma et al. (2019) [42] | N = 18 | Reduction in seizure frequency at ≥10 weeks | Reduction in AEP at ≥10 weeks | Voxel-level paired samples t-tests did not identify significant changes in gray matter volume or cortical thickness |
Ben‑Menachem et al. (2020) 89.1 [43] | N = 35; CBD n = 28, placebo n = 6 | STP arm: AEs: 66.7% (CBD), 0% (placebo), diarrhea 41.7% (CBD), 0% (placebo), fatigue 25.0% (CBD), 0% (placebo), nausea 16.7% (CBD), 0% (placebo), decreased appetite 16.7% (CBD), 0% (placebo), increased transaminases 16.7% (CBD), 0% (placebo) SAEs: 8.3% (CBD), 0% (placebo) VPA arm: AEs: 87.5% (CBD), 25.0% (placebo), diarrhea 68.8% (CBD), 0% (placebo), nausea 12.5% (CBD), 0% (placebo), nasopharyngitis 12.5% (CBD), 0% (placebo). SAEs: 6.3% (CBD), 0% (placebo) | Coadministration of steady-state CBD led to a small increase in exposure to steady-state STP and little effect on VPA exposure | |
McNamara et al. (2020) [46] | N = 87 | Seizure frequency improvement in 50.7% of patients | AEs: sedation 26%, behavior change 15%, thrombocytopenia 10%, agitation 6% | All patients with thrombocytopenia were taking VPA. Thrombocytopenia was reversible |
VanLandingham et al. (2020) [47] | N = 20; CBD = 16, placebo = 4 | Seizure frequency improved in 56.3% of patients in CBD group and 25.0% of patients in placebo group (10-day titration period followed by 21-day maintenance period) | AEs: 81.3% (CBD), 50.0% (placebo). Diarrhea 37.5% (CBD), 25.0% (placebo), nausea 18.8% (CBD), 0% (placebo), vomiting 18.8% (CBD), 0% (placebo), dizziness 12.5% (CBD), 0% (placebo), sedation 12.5% (CBD), 0% (placebo), somnolence 12.5% (CBD), 0% (placebo), dermatitis 12.5% (CBD), 0% (placebo) Increased transaminases: 12.5% CBD SAEs: 6.3% (CBD), 0% (placebo) Treatment withdrawal due to AEs: 12.5% (CBD), 0% (placebo) | No evidence of drug–drug interaction between CBD and CLB; significant drug–drug interaction between CBD and N-CLB |
NCT02564952 [48] | N = 18 | AEs: 94.4%. Diarrhea 44.4%, somnolence 38.9%, dizziness 22.2%, headache 22.2%, vomiting 16.7%, fatigue 11.1%, irritability 11.1%, respiratory tract infection 11.1%, seizure 11.1%, hyponatremia 11.1% SAEs: 11.1% | ||
Thompson et al. (2020) [50] | N = 38 | Improvement in seizure severity at 12 months as assessed by CSSS No significant change in cognitive performance or functional adaptive status at 1 year | ||
Gaston et al. (2020) [51] | N = 20 | Change in seizure frequency −100% to +50%, responder rate 70%, seizure freedom rate 30% after reaching a stable dosage of CBD for more than 2 weeks | No significant changes in modified Sternberg working memory task performance; increased activation in inferior frontal gyrus regions in memory encoding | |
D’Onofrio et al. (2020) [52] | N = 125 | Seizure frequency reduction: 28.6% (M1), 37.4% (M2), 41.0% (all patients, M6), 42.7% (CLB-On, M6), 38.5% (CLB-Off, M6) Seizure responder (M6): 37.8% (all patients), 43.2% (CLB-On patients), 31% (CLB-Off patients) | AEs: 48.8%. Somnolence 20.8%, fatigue 16.0%, behavioral disorders 12.8%, decreased appetite 9.6%, sleep disturbance 5.6%, diarrhea 4.8%, convulsion 0.8%. Increased transaminases: 9.6% (all patients receiving both CLB and VPA and CLB) | AE and efficacy did not differ between CLB-On and CLB-Off patients Improvement at CGIC. No statistical difference in C/PCGI scores between CLB-On and CLB-Off patients |
Cortopassi et al. (2020) [54] | N = 1 | Seizure frequency reduction 50% (M6) | Increase in INR during CBD titration, which required a nearly 20% warfarin dose reduction |