CBD for epilepsy

How does CBD affect epileptic seizures?

Cannabidiol (CBD) acts antiepileptically by modulating multiple neuronal and inflammatory signaling pathways – including influencing calcium channels, adenosine pathways, GABAergic transmission, and inhibiting excitatory glutamate receptors. CBD does not act directly on classical cannabinoid receptors (CB1/CB2) but exerts its effect through a broader molecular network.

CBD acts on epileptic seizures not via CB1/CB2 like THC, but through a multimodal effect on ion channels, neurotransmitters, and inflammatory pathways. This makes it an innovative addition, especially in the form of the approved medicinal product, particularly for therapy-resistant epilepsy Epidiolex®, whose effect is based on a broad molecular target structure supports.

Which types of epilepsy can be treated with CBD?

Cannabidiol (CBD), especially in the form of the approved medicinal product Epidiolex®, is primarily used for the treatment rarer, therapy-resistant forms of epilepsy used. The best scientific evidence exists for the Dravet syndrome, which Lennox-Gastaut Syndrome as well as the Tuberous Sclerosis Complex. Furthermore, there is evidence of efficacy in other difficult-to-treat epilepsies, also in adulthood.

CBD is currently officially approved for three difficult-to-treat forms of epilepsy: Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis. The evidence is based on large-scale, randomized phase III studies with Epidiolex®. For other forms of epilepsy such as West syndrome or focal epilepsies, only observational or experimental evidence before – here the use must be assessed individually and off-label.

What does science say about the effect of CBD on epilepsy?

The scientific evidence for the effect of cannabidiol (CBD) in epilepsy is particularly well established for certain treatment-resistant syndromes such as Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis. Several large, randomized, placebo-controlled studies have shown that CBD – mostly in the form of the drug Epidiolex® – can significantly reduce seizure frequency. The effect is not based on classical cannabinoid receptors but on a multimodal mechanism of action: CBD influences, among others, TRPV1, GPR55, and 5-HT1A receptors, inhibits proinflammatory signaling pathways (e.g., via NF-κB), and enhances the anticonvulsant properties of endogenous messengers such as anandamide. Clinical research shows good tolerability and a low rate of serious side effects, especially compared to other antiepileptic drugs. Nevertheless, CBD is not equally effective for all forms of epilepsy, and outside the approved indications, it is an off-label use whose benefit must be evaluated individually.

Is CBD an alternative to antiepileptics or an add-on?

According to current scientific knowledge, CBD is primarily to be regarded as an add-on treatment – not as a complete substitute for traditional epilepsy medications.

In the large approval studies on Epidiolex® (pure CBD) cannabidiol was used exclusively as concomitant measure used in addition to existing antiepileptic medication – typically in patients with therapy-resistant epilepsythat responded insufficiently to several other medications. It was shown that CBD frequency and severity of epileptic seizures can significantly reduce, especially in Dravet and Lennox-Gastaut syndrome. The therapeutic effect was dose-dependentbut never alone sufficient to achieve complete seizure freedom.

Scientific reviews (e.g., Silvestro et al., 2019) and clinical guidelines emphasize that CBD is currently not recommended as monotherapy is used, but exclusively as a additive therapy option in difficult-to-treat cases. So far, there are no randomized studiesin which classic antiepileptics were completely replaced by CBD.

However, in individual cases, CBD can be a reduction of concomitant medication enable – e.g., by lowering the dose of clobazam, which can reduce side effects. This requires medical supervision, as CBD affects CYP450 enzymes changes the plasma levels of many antiepileptics.

Conclusion: CBD is not an alternative in the sense of a complete replacement of antiepileptics, but rather a meaningful add-on, especially with therapy-resistant childhood epilepsy forms. A complete replacement should only be done within the framework of clinical studies or individual off-label attempts under strict medical supervision.

How safe is the use of CBD in children with epilepsy?

The use of cannabidiol (CBD) in children with epilepsy is considered well tolerated and safe according to current studies – especially within the approved indication with Epidiolex®. In several large randomized controlled trials (e.g., Devinsky et al., 2017; Thiele et al., 2018), the safety of oral CBD at doses between 10 and 20 mg/kg body weight per day in children with Dravet or Lennox-Gastaut syndrome were extensively studied. The most common side effects were drowsiness, diarrhea, decreased appetite, and elevation of liver enzymes (ALT/AST) – the latter especially with simultaneous intake of Valproic acid.

In the approval studies, no relevant impairment of cognitive or neurological development caused by CBD. On the contrary, parents often report a improved alertness, social interaction, and quality of life, even with incomplete seizure control.

Despite this positive record, the use of CBD in children should only under medical supervision occur – especially due to possible interactions with other antiepileptic drugs (e.g., clobazam, topiramate) and the necessity of regular liver function monitoring. Also, long-term data over many years are so far only limited, which is why a careful benefit-risk assessment is indicated.

CBD is well studied, largely safe, and tolerable in children with difficult-to-treat epilepsy (especially Dravet, LGS, TSC) – provided it is used under controlled medical application. Outside these indications, use is off-label and requires particularly strict medical supervision.

Which CBD preparations are approved for epilepsy?

Epidiolex® is the only cannabidiol (CBD)-containing medicinal product approved in the USA and Europe for the treatment of certain forms of epilepsy. In the USA, Epidiolex® was approved in 2018 for the treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome in patients from two years of age. In 2020, the approval was extended to seizures associated with tuberous sclerosis complex. In Europe, the preparation is marketed under the name Epidyolex® known and is used in combination with clobazam for the treatment of seizures in Lennox-Gastaut syndrome and Dravet syndrome in patients from two years of age.

Regarding the magistral preparation of CBD (CBD active pharmaceutical ingredient) for the treatment of epilepsy, there is currently no specific information about approved products. Magistral preparations are individually made medications prepared in the pharmacy based on a medical prescription for a specific patient. The use of CBD in such preparations generally occurs outside the approved indications (off-label use) and should only be done under strict medical supervision.

Are there differences between isolated CBD and full-spectrum CBD?

Isolated cannabidiol is a highly pure active ingredient (>99 %), the no other cannabinoids, terpenes or flavonoids contains. It is usually produced in pharmaceutical quality (e.g. as an active ingredient in Epidiolex®) and enables a precise dosing without THC content.

• Advantages: High reproducibility, no THC risk (also relevant for drug tests), ideal for THC sensitivity or in children.

• Limitations: In studies, isolated CBD sometimes showed a weaker or less robust effect as cannabinoid-rich extracts – especially at very low doses. It often shows a U-shaped dose-response curve.

Full-spectrum preparations contain, besides CBD, also other naturally occurring cannabinoids (e.g. CBG, CBC, traces of THC), Terpenes and other plant substances. This combination is often referred to as “Entourage effect” discussed – the synergistic effect of several active substances that together act stronger or more stable than isolated.

• Advantages: Possibly stronger overall effect through synergy, especially in chronic pain, inflammation or anxiety disorders.

• Limitations: THC content (also <0.2%) can cause unwanted effects (e.g. sedation, interactions), legally and toxicologically not always clear, harder to standardize.

The clinical evidence for anticonvulsant effect of CBD comes almost exclusively from studies with pure, isolated CBD (Epidiolex®). For full-spectrum CBD there are hardly controlled studies in epilepsy, so here only indirect statements are possible. In epilepsy – especially in childhood – isolated CBD preferred to to avoid interactions and THC effects.

What experiences are there with CBD in treatment-resistant epilepsy?

The experiences with CBD in treatment-resistant epilepsy are overall positive – both from scientific studies as well as from clinical case reports and patient observations. Especially in children with rare, difficult-to-treat forms of epilepsy such as Dravet syndrome, the Lennox-Gastaut syndrome (LGS) and the Tuberous sclerosis complex (TSC) cannabidiol was able to in numerous studies significantly reduce seizure frequency – often despite previous failure of several classic antiepileptics.

How is CBD properly dosed for epilepsy?

The dosage of cannabidiol (CBD) for epilepsy depends on body weight, type of epilepsy, and individual tolerance. In clinical studies and approval recommendations, it is usually started with 2.5 mg/kg body weight twice daily (a total of 5 mg/kg/day) started. If well tolerated, the dose can be gradually increased to maximum 10 mg/kg twice daily (20 mg/kg/day) can be increased. This guideline applies especially to the approved preparation Epidiolex® (Epidyolex in Europe).

Higher doses (>20 mg/kg/day) have been used in studies but are not officially approved and are associated with a higher risk of side effects.

What side effects can occur during CBD therapy?

Cannabidiol (CBD) is generally considered well tolerated, especially compared to classic antiepileptics. Nevertheless, at therapeutically effective doses – especially from 10–20 mg/kg/day – it can cause mild to moderate side effects occur. These usually appear dose-dependent and mainly affect the Gastrointestinal tract, which Central nervous system as well as the Liver function.

CBD is well tolerated in epilepsy, but not free of side effects. The most common effects are mild to moderate, however, require regular monitoring, especially in combination with other antiepileptics such as Valproic acid or ClobazamA structured start of therapy under medical supervision is therefore essential.

Literature & Sources

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• Devinsky, O., Patel, A. D., Cross, J. H., Villanueva, V., Wirrell, E. C., Privitera, M., ... Thiele, E. A. (2018). Effect of cannabidiol on drop seizures in Lennox–Gastaut syndrome. New England Journal of Medicine, 378(20), 1888–1897. DOI: 10.1056/NEJMoa1714631
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