Cannabidiol (Epidiolex)
cannabidiol — plant-derived purified cannabinoid antiseizure medication
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Seizures associated with Lennox-Gastaut syndrome (LGS) | ≥1 year of age | Adjunctive | FDA Approved |
| Seizures associated with Dravet syndrome (DS) | ≥1 year of age | Adjunctive | FDA Approved |
| Seizures associated with tuberous sclerosis complex (TSC) | ≥1 year of age | Adjunctive | FDA Approved |
Cannabidiol was the first plant-derived, pharmaceutical-grade cannabinoid approved by the FDA. The initial approval in June 2018 covered LGS and DS in patients 2 years and older. The TSC indication was added in 2020, and the age range was subsequently expanded to patients 1 year of age and older based on additional clinical data. Epidiolex was initially classified as Schedule V but was fully descheduled by the DEA in April 2020 after data confirmed negligible abuse potential. It remains the only FDA-approved prescription cannabidiol product and should not be confused with unregulated over-the-counter CBD products, which lack the same manufacturing controls and clinical evidence.
Other treatment-resistant epilepsy syndromes: Open-label data and expanded access programs suggest benefit in CDKL5 deficiency, Aicardi syndrome, and other refractory epilepsies, but no controlled trial evidence supports these uses. Evidence quality: Low.
Anxiety disorders: Preliminary clinical trials in adults show anxiolytic effects at single doses of 300–600 mg; no FDA-approved indication exists. Evidence quality: Low.
Dosing
Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| LGS or DS — adjunctive therapy | 2.5 mg/kg BID (5 mg/kg/day) | 5 mg/kg BID (10 mg/kg/day) | 10 mg/kg BID (20 mg/kg/day) | Increase to 10 mg/kg/day after 1 week; further increases in weekly increments of 5 mg/kg/day 20 mg/kg/day gives modestly greater efficacy but more adverse effects |
| TSC — adjunctive therapy | 2.5 mg/kg BID (5 mg/kg/day) | 12.5 mg/kg BID (25 mg/kg/day) | 12.5 mg/kg BID (25 mg/kg/day) | Increase weekly by 2.5 mg/kg BID (5 mg/kg/day) to target; faster titration every other day if clinically warranted Doses below 25 mg/kg/day not studied for TSC efficacy |
| Moderate hepatic impairment (Child-Pugh B) | 1.25 mg/kg BID (2.5 mg/kg/day) | LGS/DS: 2.5–5 mg/kg BID; TSC: 6.25 mg/kg BID | LGS/DS: 10 mg/kg/day; TSC: 12.5 mg/kg/day | All doses halved vs normal; slower titration may be needed AUC 2.5–5.2-fold higher vs healthy controls |
| Severe hepatic impairment (Child-Pugh C) | 0.5 mg/kg BID (1 mg/kg/day) | LGS/DS: 1–2 mg/kg BID; TSC: 2.5 mg/kg BID | LGS/DS: 4 mg/kg/day; TSC: 5 mg/kg/day | Doses reduced to approximately one-fifth of normal Consider not initiating if evidence of significant liver injury at baseline |
| Concomitant strong CYP3A4/2C19 inducers (e.g., rifampin) | Standard starting dose | Up to 2-fold increase based on response | Up to 2x standard max | Rifampin reduces CBD AUC by ~32% and active metabolite 7-OH-CBD by ~63% Adjust based on clinical response and tolerability |
Cannabidiol absorption is highly food-dependent: a high-fat meal increases Cmax 5-fold and AUC 4-fold compared to the fasted state. Even low-fat meals and milk produce 3-fold increases. This variability can lead to unpredictable efficacy and toxicity. Advise patients and caregivers to dose Epidiolex consistently with respect to meals at every administration to minimize pharmacokinetic fluctuations. The PI does not mandate fed or fasted administration, but consistency is critical.
Serum transaminases (ALT and AST) and total bilirubin must be obtained in all patients before starting Epidiolex, due to the risk of hepatocellular injury. Do not initiate in patients with baseline ALT >3x ULN with bilirubin >2x ULN without prior evaluation.
Pharmacology
Mechanism of Action
The precise mechanisms by which cannabidiol exerts its antiseizure effects in humans remain unknown. Notably, cannabidiol does not appear to act through cannabinoid CB1 or CB2 receptors, distinguishing it from tetrahydrocannabinol (THC) and other psychoactive cannabinoids. Preclinical research suggests multiple potential targets including modulation of intracellular calcium signaling, enhancement of adenosine-mediated signaling through equilibrative nucleoside transporter (ENT1) inhibition, activation of TRPV1 vanilloid receptors, and modulation of GPR55 signaling. The active metabolite 7-OH-CBD also demonstrates anticonvulsant activity in preclinical seizure models, while the major circulating metabolite 7-COOH-CBD (approximately 40-fold higher AUC than the parent) is not pharmacologically active against seizures.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Tmax 2.5–5 h at steady state; less than dose-proportional increase over 5–25 mg/kg/day; high-fat meal increases Cmax 5-fold and AUC 4-fold | Highly lipophilic oral solution in sesame seed oil; food effect is clinically significant — consistent dosing relative to meals is mandatory |
| Distribution | Vd/F 20,963–42,849 L; protein binding >94% | Extremely large apparent Vd reflects high lipophilicity and extensive tissue distribution; highly protein-bound |
| Metabolism | Hepatic and gut metabolism via CYP2C19, CYP3A4, UGT1A7, UGT1A9, UGT2B7; active metabolite 7-OH-CBD (AUC 38% lower than parent); major metabolite 7-COOH-CBD (AUC ~40-fold higher, inactive) | Dual CYP/UGT metabolism creates complex interaction profile; inhibits CYP2C19 (clinically relevant for clobazam) and intestinal P-gp (relevant for everolimus) |
| Elimination | t½ 56–61 h (after 7 days BID dosing); CL/F 1111 L/h; primarily fecal excretion with minor renal clearance | Long half-life supports twice-daily dosing; fecal elimination predominant; no renal dose adjustment studied or recommended |
Side Effects
Adverse reaction data for LGS and DS are from pooled placebo-controlled trials (Studies 1, 2, 3; n = 323 cannabidiol, n = 227 placebo). TSC data are from Study 4 (n = 75 cannabidiol 25 mg/kg/day, n = 76 placebo). Most adverse effects are dose-dependent and more prominent with concomitant valproate or clobazam.
| Adverse Effect | Incidence (10 / 20 mg/kg/day) | Clinical Note |
|---|---|---|
| Somnolence | 23% / 25% vs 8% placebo | Dose-related; markedly higher with concomitant clobazam (46% vs 16% without clobazam); generally improves over time |
| Decreased appetite | 16% / 22% vs 5% placebo | Can lead to weight loss; 16–18% had ≥5% weight decrease at 20 mg/kg/day; monitor growth in pediatric patients |
| Diarrhea | 9% / 20% vs 9% placebo | Dose-related; may be partly related to sesame oil vehicle; usually manageable |
| Transaminases elevated | 8% / 16% vs 3% placebo | ALT >3x ULN in 13% overall; risk substantially higher with concomitant valproate (up to 30% with VPA + clobazam); typically first 2 months |
| Fatigue, malaise, asthenia | 11% / 12% vs 4% placebo | Part of the broader CNS depression spectrum with cannabidiol |
| Rash | 7% / 13% vs 3% placebo | Dose-related; was the most frequent cause of discontinuation in the TSC trial (5%) |
| Insomnia / sleep disorder | 11% / 5% vs 4% placebo | Paradoxically more common at lower dose in trials; clinical significance uncertain |
| Infections (all types) | 41% / 40% vs 31% placebo | Includes viral infections (7–11%), pneumonia (5–8%), and other infections; pneumonia rate higher with concomitant clobazam |
| Adverse Effect | Incidence (20 mg/kg/day LGS/DS) | Clinical Note |
|---|---|---|
| Lethargy | 8% vs 2% placebo | Part of somnolence/sedation cluster; more common with clobazam |
| Sedation | 6% vs 1% placebo | Additive with other CNS depressants and alcohol |
| Aggression, anger | 5% vs <1% placebo | Behavioral adverse effect; monitor in pediatric patients |
| Irritability, agitation | 5% vs 2% placebo | May be dose-related or related to underlying epilepsy syndrome |
| Weight decreased | 5% vs 1% placebo | 31% of TSC patients had ≥5% weight loss at 25 mg/kg/day |
| Pneumonia | 5% vs 1% placebo | Risk substantially higher with concomitant clobazam (10–17%); monitor respiratory function |
| Drooling / salivary hypersecretion | 4% vs <1% placebo | More common in younger children |
| Gastroenteritis | 4% vs 1% placebo | GI effects cluster; may relate to sesame oil formulation |
| Vomiting | 17% vs 9% placebo (TSC data; not listed in LGS/DS table) | Primarily a TSC finding at 25 mg/kg/day; not reported above placebo threshold in LGS/DS trials |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Hepatocellular Injury (ALT >3x ULN) | 13% (LGS/DS) / 12% (TSC) vs 1% placebo; ALT >20x ULN in <1% | Typically first 2 months; cases reported up to 18 months | Mandatory LFT monitoring at baseline, 1, 3, 6 months; discontinue if ALT >3x ULN with bilirubin >2x ULN, or ALT >5x ULN sustained; consider VPA/clobazam dose reduction. Postmarketing cholestatic/mixed liver injury also reported |
| Suicidal Behavior and Ideation | AED class effect (RR 1.8 vs placebo) | As early as 1 week after initiation | Monitor for depression, mood changes, suicidal ideation; counsel patients and caregivers |
| Hypersensitivity Reactions | Rare (pruritus, erythema, angioedema reported in clinical trials) | Variable | Discontinue and do not restart; contains sesame seed oil (allergen). Treated with corticosteroids and antihistamines in trials |
| Pneumonia (with clobazam) | 10–17% with clobazam vs 0–4% without clobazam | During treatment | Monitor respiratory status in patients on concomitant clobazam; consider clobazam dose reduction if sedation impairs airway protection |
| Hematologic Abnormalities (Anemia) | New-onset anemia in 30% (LGS/DS) and 38% (TSC) vs 13–15% placebo | During treatment course | Mean Hb decrease –0.37 to –0.42 g/dL; monitor CBC; no effect on RBC indices; clinical significance unclear |
Transaminase elevation is the single most important safety issue with cannabidiol. The risk is dramatically amplified by concomitant valproate: ALT >3x ULN occurred in 30% of patients taking both valproate and clobazam, 21% with valproate alone, versus only 3% without either drug. Higher cannabidiol doses and elevated baseline transaminases further compound the risk. In approximately two-thirds of cases, transaminase elevations resolve with dose reduction of cannabidiol and/or valproate, while in one-third they resolve spontaneously without dose changes. A structured LFT monitoring schedule (baseline, 1, 3, 6 months, then periodically) is mandatory, not optional.
Drug Interactions
Cannabidiol has a broad interaction profile driven by CYP2C19 inhibition, intestinal P-gp inhibition, UGT1A9/UGT2B7 inhibition, and weak CYP1A2 inhibition. CBD itself is a substrate of CYP2C19 and CYP3A4. Of note, cannabidiol does not significantly affect midazolam (CYP3A4 substrate) exposure, suggesting its CYP3A4 inhibitory potential is limited in vivo.
Despite in vitro CYP3A4 substrate status, cannabidiol does not significantly alter midazolam concentrations in vivo. Additionally, itraconazole (potent CYP3A4 inhibitor) and fluconazole (potent CYP2C19 inhibitor) produce only minor, non-clinically meaningful changes in cannabidiol exposure. Valproate exposure is also not significantly changed by cannabidiol, though the hepatotoxicity interaction is pharmacodynamic, not pharmacokinetic.
Monitoring
-
Hepatic Function (ALT, AST, Bilirubin)
Baseline, 1 mo, 3 mo, 6 mo, then periodically; within 1 mo of dose changes
Routine Most critical monitoring parameter. More frequent monitoring for patients on concomitant valproate or with elevated baseline LFTs. Discontinue if ALT >3x ULN with bilirubin >2x ULN or if ALT >5x ULN is sustained. Also monitor within 1 month of adding/changing hepatotoxic co-medications. Postmarketing: cholestatic and mixed liver injury patterns reported. -
Weight and Growth
Every visit, ongoing
Routine Decreased appetite and weight loss are dose-related (16–31% had ≥5% weight loss in trials). Particularly important in pediatric patients where growth monitoring is essential. -
Complete Blood Count
Baseline, then periodically
Routine New-onset anemia in 30–38% of treated patients vs 13–15% placebo. Mean hemoglobin decrease of 0.37–0.42 g/dL. No effect on RBC indices. In TSC: thrombocytopenia (5%) and eosinophilia (5%) also observed. -
Serum Creatinine
Baseline, then early in treatment
Routine CBD causes ~10% increase in serum creatinine within 2 weeks of initiation (mechanism unknown, not necessarily reflecting true GFR decline). Reversible in healthy adults. -
Mood and Suicidality
Every visit, ongoing
Routine AED class warning. Screen for depression, anxiety, behavioral changes, suicidal ideation at each visit. -
Everolimus Levels
When initiating CBD in patients on everolimus or vice versa
Trigger-based CBD increases everolimus AUC ~2.5-fold via P-gp inhibition. Mandatory TDM; critical in TSC patients already receiving mTOR inhibitor therapy. -
Ammonia
If transaminases elevated, especially with concomitant VPA
Trigger-based Elevated ammonia reported in patients with concurrent transaminase elevations, mostly on VPA/clobazam. Consider VPA/clobazam dose adjustment if ammonia elevated.
Contraindications & Cautions
Absolute Contraindications
- Hypersensitivity to cannabidiol or any ingredient in Epidiolex, including sesame seed oil (vehicle), dehydrated alcohol, strawberry flavor, or sucralose
Relative Contraindications (Specialist Input Recommended)
- Significant baseline liver injury (ALT >3x ULN with bilirubin >2x ULN) — the PI recommends considering not initiating Epidiolex in these patients
- Severe hepatic impairment (Child-Pugh C) — substantially reduced doses required (one-fifth of normal); AUC up to 5.2-fold higher; proceed only if anticipated benefit clearly outweighs risk
- Pregnancy — animal data demonstrate embryofetal mortality (rats), decreased fetal weight (rabbits), and neurobehavioral/reproductive impairment in offspring at clinically relevant exposures. Enroll in the EPIDIOLEX Pregnancy Surveillance Program (1-855-272-7158) and NAAED Pregnancy Registry (1-888-233-2334)
Use with Caution
- Concomitant valproate therapy — dramatically increases hepatotoxicity risk (ALT >3x ULN in up to 30%); intensified LFT schedule required
- Concomitant clobazam therapy — 3-fold increase in active metabolite; increased somnolence (46%), sedation, and pneumonia risk; consider clobazam dose reduction
- Moderate hepatic impairment (Child-Pugh B) — halve all doses; AUC 2.5-fold higher
- Patients on oral P-gp substrates — especially everolimus (2.5-fold AUC increase), sirolimus, tacrolimus, digoxin; TDM required
- Patients with depression or suicidal history — AED class warning applies
- Alcohol use — increases cannabidiol exposure (Cmax +93%, AUC +63%) and potentiates CNS depression
- Sesame allergy — Epidiolex contains sesame seed oil; assess for sesame allergy before prescribing
Antiepileptic drugs, including Epidiolex, increase the risk of suicidal thoughts or behavior. Pooled analysis of 199 placebo-controlled trials of 11 AEDs showed approximately twice the risk (adjusted RR 1.8; 95% CI: 1.2–2.7) in AED-treated patients compared to placebo. Monitor all patients for emergence or worsening of depression, suicidal thoughts, or unusual changes in behavior.
Patient Counselling
Purpose of Therapy
Epidiolex is a prescription cannabidiol oral solution used to reduce the frequency of seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex. It is the only FDA-approved prescription cannabidiol product and is manufactured to pharmaceutical standards, unlike unregulated over-the-counter CBD products. It will not produce a "high" because it contains no THC.
How to Take
Epidiolex is taken twice daily as a liquid measured with the provided oral syringes. It should be taken consistently either with food or without food at every dose, since food dramatically affects how much of the drug is absorbed. An opened bottle must be discarded after 12 weeks. Patients receiving Epidiolex via nasogastric or gastrostomy tube should follow specific flushing instructions provided in the product labeling. Epidiolex contains dehydrated alcohol (7.9% w/v) and sesame seed oil.
Sources
- EPIDIOLEX (cannabidiol) oral solution. Full Prescribing Information. Jazz Pharmaceuticals, Inc. Revised 03/2024. FDA Label Primary regulatory source for all dosing, pharmacokinetic, safety, and interaction data in this monograph.
- Epidiolex (cannabidiol) Summary of Product Characteristics. GW Pharma (International) B.V. EMA Approved. EMA EPAR European regulatory source for adjunctive indication in LGS and DS; marketed as Epidyolex in the EU.
- Thiele EA, Marsh ED, French JA, et al. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018;391(10125):1085–1096. doi:10.1016/S0140-6736(18)30136-3 Study 1 (GWPCARE4): pivotal phase 3 LGS RCT demonstrating 44% median reduction in drop seizures at 20 mg/kg/day vs 22% placebo.
- Devinsky O, Patel AD, Cross JH, et al. Effect of cannabidiol on drop seizures in the Lennox-Gastaut syndrome. N Engl J Med. 2018;378(20):1888–1897. doi:10.1056/NEJMoa1714631 Study 2 (GWPCARE3): LGS RCT comparing 10 and 20 mg/kg/day with placebo; established efficacy of both dose levels.
- Devinsky O, Cross JH, Laux L, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med. 2017;376(21):2011–2020. doi:10.1056/NEJMoa1611618 Study 3: pivotal DS RCT showing 39% median reduction in convulsive seizures at 20 mg/kg/day vs 13% placebo.
- Thiele EA, Bebin EM, Bhathal H, et al. Add-on cannabidiol treatment for drug-resistant seizures in tuberous sclerosis complex: a placebo-controlled randomized clinical trial. JAMA Neurol. 2021;78(3):285–292. doi:10.1001/jamaneurol.2020.4607 Study 4 (GWPCARE6): pivotal TSC RCT demonstrating 48% estimated mean seizure reduction at 25 mg/kg/day vs 24% placebo.
- Wirrell EC, Laux L, Donner E, et al. Optimizing the diagnosis and management of Dravet syndrome: recommendations from a North American consensus panel. Pediatr Neurol. 2017;68:18–34.e3. doi:10.1016/j.pediatrneurol.2017.01.025 North American consensus recommendations for Dravet syndrome management including role of cannabidiol in treatment algorithms.
- Cross JH, Auvin S, Falip M, et al. Expert opinion on the management of Lennox-Gastaut syndrome: treatment algorithms and practical considerations. Front Neurol. 2017;8:505. doi:10.3389/fneur.2017.00505 Expert consensus on LGS treatment algorithms providing context for where cannabidiol fits among therapeutic options.
- Devinsky O, Cilio MR, Cross H, et al. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia. 2014;55(6):791–802. doi:10.1111/epi.12631 Seminal review of cannabidiol pharmacology covering non-CB receptor targets including TRPV1, GPR55, adenosine reuptake, and intracellular calcium modulation.
- Perucca E, Bialer M, White HS. New GABA-targeting therapies for the treatment of seizures and epilepsy: I. role of GABA as a modulator of seizure activity and recently approved medications acting on the GABA system. CNS Drugs. 2023;37(9):755–779. doi:10.1007/s40263-023-01025-4 Review of recently approved ASMs including cannabidiol, placing its mechanism in context of GABAergic and non-GABAergic pathways.
- Wheless JW, Dlugos D, Miller I, et al. Pharmacokinetics and tolerability of multiple doses of pharmaceutical-grade synthetic cannabidiol in pediatric patients with treatment-resistant epilepsy. CNS Drugs. 2019;33(6):593–604. doi:10.1007/s40263-019-00624-4 Pediatric pharmacokinetic data supporting weight-based dosing in treatment-resistant epilepsy populations.
- Lattanzi S, Brigo F, Trinka E, et al. Efficacy and safety of cannabidiol in epilepsy: a systematic review and meta-analysis. Drugs. 2018;78(17):1791–1804. doi:10.1007/s40265-018-0992-5 Systematic review and meta-analysis of cannabidiol efficacy across pivotal trials, quantifying responder rates and adverse event profiles.
- Gaston TE, Bebin EM, Cutter GR, Liu Y, Szaflarski JP. Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia. 2017;58(9):1586–1592. doi:10.1111/epi.13852 Key study characterizing the clobazam interaction and N-desmethylclobazam level changes with cannabidiol co-administration.
- Devinsky O, Marsh E, Friedman D, et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol. 2016;15(3):270–278. doi:10.1016/S1474-4422(15)00379-8 Early open-label efficacy and safety data from 162 patients with treatment-resistant epilepsy that informed the design of subsequent pivotal trials.