Introduction

Canabidiol (CBD) is a non -psychoactive compound obtained from the ancient medicinal plant (Cannabis sativa) with antiepileptic properties.¹ CBD is a first new class of antiepileptic medications approved for use by FDA and EMA  in 2018 and  2019 respectively. Initially it was considered as an add-on to antiepileptic medications for patients two years of age and older diagnosed with Lennox- Gaustaut Syndrome (LGS) or Dravet Syndrome (DS) and drug resistant epilepsy.² CBD has recently been found beneficial for tubeorus sclerosis complex (TSC) another form of Epilepsy.¹ Recent data suggest that CBD may have antiseizure properties in a broad range of epilepsy syndromes and etiologies, such as CDKL5 deficiency disorder, Aicardi syndrome, Dup15q syndrome, Doose syndrome, SYNGAP1 encephalopathy, and epilepsy with myoclonic absences.³

Studies have shown that cannabidiol (CBD) is an effective seizure frequency reducing agent in drug resistant epilepsy such as LGS, DS and TSC in children and adolescents.¹ CBD has demonstrated efficacy with an acceptable safety profile in patients with LGS or DS.⁴. The findings from recent literature and clinical trials indicate that CBD possesses independent anti-epileptic properties.⁶

Epilepsy is a chronic neurological disorder characterized by exorbitant stimulation of neurotransmitters and recurring seizures. Seizures are sudden bursts of electrical activity in the brain. These seizures can vary in intensity and duration, often leading to a range of symptoms including loss of consciousness, convulsions, or unusual sensations. Comprehensive management plans often include a combination of antiepileptic medications, lifestyle adjustments, and sometimes, surgical interventions to help control seizures and improve the quality of life for those affected.

Antiepileptic Medications (AEMs) are used in the management  of epilepsy, AEMs include carbamazepine, phenobarbital, phenytoin, primidone, and valproate (first generation), lamotrigine, levetiracetam, gabapentin,clobazam, eslicarbazepine acetate, ezogabine/retigabine, felbamate,  lacosamide,  oxcarbazepine, perampanel, pregabalin, rufinamide, tiagabine, topiramate, vigabatrin, and zonisamide and topiramate ( 2nd generation, )eslicarbazepine acetate and perampanel (3rd generation).⁷ After a first medication fails, alternatives include monotherapy or dual therapy based on the reasons for failure.^8,9 Recent developments include vigabatrin for disease modification in TSC, fenfluramine for DS and LGS with strong efficacy and safety data, and cenobamate, a novel sodium channel inactivator for adult partial onset epilepsy. Additionally, rescue therapies now include better-tolerated benzodiazepines like nasal midazolam and valium. Several AEMs, notably CLB, valproate (VPA), and stiripentol (STP), are commonly used in the first- and second-line treatment of LGS and DS.⁴ AEMs vary in efficacy against different seizure types, necessitating individualized treatment based on factors like epilepsy syndrome, side effects, and drug interactions. While AEMs primarily provide symptomatic relief, ongoing research aims to develop disease-modifying therapies. It is important to note that no AEM can completely cure epilepsy, and about 30% of patients experience drug-resistant seizures.¹⁰

Most anti-epileptic regimens have often employed drug combinations when there is no response to monotherapy in people with refractory epilepsy and elderly.⁹

Pharmacology of CBD and AEMs

The anti-epileptic mechanisms of CBD is thought to include direct influence on the ECS in which CBD has been shown to reduce neuronal excitability degeneration and antagonistic action on G-protein orphan receptors(GPR55) as well as vanilloid receptors the transient receptor potential cation channel modulating intracellular calcium ions levels. Additionally, the inhibition of adenosine reuptake, positive allosteric modulation of GABAA AND glycine receptors are also taken into account.¹

Metabolism: primarily in the liver via cytochrome P450 enzymes (CYP3A4, CYP2C19).

Based on Mechanism of Action, AEMs are classified as follows:

• Sodium Channel Blockers: Drugs like phenytoin, carbamazepine, and lamotrigine work by blocking voltage-gated sodium channels, reducing neuronal excitability¹⁰ 
• Calcium Channel Modulators: Ethosuximide and gabapentin target voltage-activated calcium channels, which are crucial in controlling seizure activity¹⁰
• GABA Potentiators: Barbiturates and benzodiazepines enhance GABAergic inhibition, a major inhibitory neurotransmitter pathway in the brain¹⁰
• Glutamate Inhibitors: Felbamate and perampanel reduce excitatory neurotransmission by inhibiting glutamate receptors¹⁰

Clinical evidence of CBD-AEM interactions

The complex mechanism of actions of AEMs and CBD provide the basis for the positive and adverse effects when they are used concurrently for managing epilepsy.

CBD- AEMs interactions can alter the efficacy and toxicity of various agents used in managing epilepsy.¹¹ The clinical interactions have been attributed to shared metabolic pathways of CBD and AEMs culminating as positive with clobazam (enhanced seizure control in some cases) and adverse (increased sedation with clobazam). Rise in liver enzymes or hepatotoxicity has been reported with concomitant valproate use.

Case studies and trials 

• In a study involving patients with epilepsy, CBD co-administration resulted in increased serum levels of clobazam, valproate, felbamate, and topiramate, indicating significant pharmacokinetic interactions¹²
• CBD's effect on the pharmacokinetics of stiripentol and valproate was also evaluated, showing a modest increase in stiripentol exposure but minimal impact on valproate, suggesting variability in interaction strength among different AEDs

In a case series, CBD increased BRV plasma levels by 95% to 280%. While BRV's major metabolic pathway is non-CYP-dependent hydrolysis, the interaction suggests that CBD may influence BRV levels through CYP2C19 inhibition.¹³

Mechanisms of interaction

The neuroprotective capacity (reduction in neuronal excitability) of CBD involves many pathways. These mechanisms include CBD interference with absorption, distribution, Metabolism and excretion (pharmacokinetics) and target sites (pharmacodynamic) activity of AEMs Induction or inhibition of CYP enzymes is a major mechanism that underlies DDIs. (Philip pastalos) CBD interferes with CYP219 that metabolizes Clobazam and valproate. This hindrance increases the concentration of active metabolites and subsequently heightened sedative effect, drowsiness, appetite, and weight loss. The GI effects are directly related to the CBD effect on the ECS, the ECS regulates peristalsis and appetite. Approximately 10% of pediatric and adolescent patients treated with CBD and valproate for LGS, DS or other DREs experience thrombocytopenia which solved after CBD and VPA doses were reduced.¹

CBD is activatedby CYP2C19 and deactivated by CYP3A4 however CBD is an inhibitor of both enzymes. These enzymes are also involved in metabolism of other AEMs hence CBD interference changes the pharmacokinetics of AEMs

Specifically, the plasma levels of  anti-epileptic medication: clobazam is increased. CYP3A4 metabolises CLB to N-CLB which in turn is metabolised to inactive metabolites by CYP2C19, and CBD inhibits CYP2C19. The inhibition of CYP2C19 by CBD leads to a rise in the active  N-CLB concentration. Hence simultaneous use of CLB and CBD increase the frequency of adverse effects experienced by patients, specifically somnolence, sedation and lethargy.^14,4 Another AEM, Valproate elevates the activity of liver enzymes. 

Pharmacodynamic interactions have been seen mostly with co-treatment ofCBD and Valproate.

Pneumonia and rash have been reported with concomitant use of CBD and Clobazam. These interactions result in additive effects on seizure control and sedation in incidence and intensity.¹

Risk factors

There is approximately 10-40% prevalence of NMC use among individuals who are  treating epilepsy. Recreational marijuana which has reportedly been used to treat seizures should not be confused with Medical marijuana as the former does not contain standardized CBD/THC ratios. People using NMC believe it is more natural and safer than standard seizure drugs, There is no substantive evidence to establish the antiepileptic effect of NMC which has a high content of THC. THC is the psychoactive component of cannabis which can lead to addiction, drug dependency, bullous lung disease, hypersensitivity pneumonitis and lung cancer

Safety and monitoring

While the interactions between CBD and antiepileptic medications can enhance therapeutic effects, they also pose a risk of increased side effects due to elevated drug levels. Therefore, careful monitoring and dose adjustments may be necessary to balance efficacy and safety. Additionally, the variability in interaction strength across different AEDs underscores the need for personalized treatment approaches.

Monitoring recommendations

Because of the shared metabolic pathways between CBD and AEMs, regular blood tests for liver function and drug levels are carried out during the course of drug treatment and AEM dosages are adjusted based on interactions.

Summary

There is a heightened interest in the use of CBD as a safe and efficacious agent for the treatment of DREs. The complex mechanism of action and CNS involvement is a predisposing factor for the diverse interactions seen with the co-administration of CBD and other AEMs.There is a bi-directional DDI between CBD and some of these AEMs such as CLB and VPA. Prescribers are expected to start with low CBD doses and titrate slowly. If the clinical situation requires a combination of drugs such as clobazam and CBD,  dose reduction should be considered.

Clinicians should be carefully consider risk-benefit profile when prescribing CBD and other AEMs for concurrent use. The effective management of epilepsy thus necessitates a comprehensive approach to ensure safety and optimal seizure control.