Overview

Epilepsy is a long-term neurological condition marked by recurrent and unpredictable seizures resulting from irregular electrical activity in the brain. These seizures can present in multiple ways, impacting motor, sensory, cognitive, or psychological functions, and are categorised based on their origin in the brain, effects on awareness, and motor characteristics. Symptoms may encompass involuntary movements, loss of consciousness, alterations in sensory perception, and atypical behaviors.¹ The disorder is prevalent worldwide, affecting approximately 1% of the population, with a higher incidence in children and the elderly.^1,2,3 

Epilepsy disorder may arise from genetic factors and results in hyperexcitability in the brain.² Seizures can vary significantly, with focal seizures originating in one brain area and generalised seizures affecting the entire brain.^4,5

Both Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) are primary cannabinoids obtained from the medicinal plant Cannabis sativa. Distinct pharmacological effects have been reported for both as a result of their different receptor sites of action. While THC is known to be hallucinogenic, CBD is non-hallucinogenic. Both CBD and THC have shown promise in managing epilepsy, particularly in paediatric cases and where traditional antiepileptic medications are ineffective. However, the psychoactive properties of THC pose a tangible challenge.⁶

The combination of cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) has been explored in clinical studies as a treatment for epilepsy, particularly in cases resistant to conventional anti-epileptic drugs. These studies have shown varying degrees of efficacy and safety, highlighting the potential of cannabinoids as adjunctive therapy for seizure control.

THC, both Δ9-THC and Δ8-THC, has been found effective at higher doses in reducing seizure intensity, although its psychoactive properties limit its use as a standalone treatment.⁶

While CBD and THC have shown promise in managing epilepsy, particularly in paediatric cases, the psychoactive effects of THC and the need for optimal dosing strategies remain a challenge. Additional challenges include the legal and social barriers to accessing cannabinoid-based treatments, the high cost of prescription cannabinoid medications like epidiolex as well as challenges in standardising dosages and formulations.⁶

Pharmacology of CBD and THC

CBD is the first in a new class of antiepileptic medications approved for use by the FDA and EMA  in 2018 and  2019 respectively. CBD directly influences the Endocannabinoid System (ECS) by reducing neuoronal excitability degeneration (loss of the ability ofneurones to respond to stimuli). It operates through multiple mechanisms, including antagonism of the GPR55 receptor (which may help reduce inflammation and pain) and modulation of adenosine levels (which can promote relaxation and protect cells from damage).⁷

At first,  CBD was considered an add-on to an antiepileptic regimen, but it has been found to possess intrinsic antiepileptic properties of its own. CBD has been reportedly used in for patients two years of age and older diagnosed with Lennox-Gaustaut Syndrome (LGS) or Dravet Syndrome (DS) and drug-resistant epilepsy. CBD has recently been found beneficial for tuberous sclerosis complex (TSC) another form of Epilepsy.⁹ Recent data suggest that CBD may have antiseizure properties in a broad range of epilepsy syndromes and causes, such as CDKL5 deficiency disorder, Aicardi syndrome, Dup15q syndrome, Doose syndrome, SYNGAP1 encephalopathy, and epilepsy with myoclonic absences.⁸

CBD is primarily broken down in the liver via cytochrome P450 enzymes (CYP3A4, CYP2C19). CBD's anticonvulsant effects (ability to reduce seizures) are partially mediated by the G-protein-coupled receptor GPR55, and it controls gene expression related to the endocannabinoid system.⁶

THC primarily exerts its effects through the triggering  of cannabinoid receptors CB1 and CB2 in the ECS.  The activation of CB1 receptors is responsible for the psychoactive effects of THC, including perceptual distortions and panic-like effects.^10,11 THC requires higher doses for effectiveness in addition to the psychoactivity which limits its use in epilepsy management.

Efficacy of CBD and THC in epilepsy management

The FDA has approved a pharmaceutical-grade CBD oil marketed as Epidiolex for Dravet syndrome and LGS. Many studies have shown a significant reduction in seizure frequency in children and effectiveness in adolescents having Drug Resistant Epilepsies (DREs).⁹ The potential seizure reduction efficacy of THC  is overshadowed by its psychoactive effects and variability in response, which pose difficulties in dose optimisation of THC.⁶

The safety assessment of CBD and THC combinations has been generally favourable, although some patients may experience adverse effects or an increase in seizure frequency. The variability in response underscores the need for careful patient selection and monitoring.^12,13

Safety and side effects comparison table

Drug Interactions of CBD and THC

Both CBD and THC are metabolised in the liver, primarily involving cytochrome P450 enzymes, hence sharing a common pathway for drug interactions. However, the extent and nature of these interactions vary significantly between CBD and THC. Below are the key aspects of their drug interactions:

Special Populations

Both cannabinoids have poorly characterised pharmacokinetics in special populations, such as pregnant women and those with hepatic impairments, necessitating careful evaluation of potential interactions in these groups.²¹

While both CBD and THC share some metabolic pathways, CBD's stronger inhibitory effects on certain enzymes make its drug interactions more clinically significant, especially at higher doses. Conversely, THC's interactions are less pronounced but still require consideration, particularly in patients taking many drugs concurrently due to comorbid conditions.²¹

Regulatory and Legal Aspects

CBD is approved by the FDA in specific epilepsy syndromes; available in many

countries as a medicinal product. While the legal status varies globally, it is less restrictive than THC. THC is legal only in regions with medical or recreational cannabis laws and requires more stringent controls due to psychoactive and potential abuse concerns.

Numerous hemp-derived products available without a prescription are often mislabeled about their cannabidiol (CBD) levels and could contain delta-9-tetrahydrocannabinol (THC) without adequate notification. Additionally, these products often make unapproved therapeutic claims for conditions not recognised by the FDA, emphasising the laxity of regulation and oversight in the cannabinoid market. There is approximately a 10-40% prevalence of non-medical cannabis use among individuals who are treating epilepsy.¹⁹ Recreational marijuana, which has reportedly been used to treat seizures, should not be confused with medical marijuana, as the former does not contain standardised 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 that can lead to addiction, drug dependency, bullous lung disease, hypersensitivity pneumonitis, and lung cancer. Several non-approved synthetic cannabinoids are available on the market, including MDMB-CHMICA, MDMB-FUBINACA, 5F-ADB, 5F-AMB, and AMPPPCA. Additionally, it mentions the emergence of new synthetic cannabinoids like NNL-1 and URB-754, which have been analytically characterised. These compounds are often found in illegal herbal products and are not detected by standard immunoassays designed for THC metabolites, complicating their identification in biological samples.²⁰

What are the Future Directions of CBD and THC in Epilepsy Management?

In the near future, there is a need for large-scale, randomised controlled trials comparing CBD and THC directly, exploration of long-term safety profiles, particularly for THC and advancement in delivery methods/ innovative formulations like transdermal patches andnanoparticles to enhance efficacy and reduce side effects. 

Summary

The distinct pathways through which THC and CBD operate suggest that their combined use could offer therapeutic benefits by balancing each other's effects. CBD demonstrates stronger evidence and a better safety profile for epilepsy management compared to THC. THC’s role remains limited due to psychoactivity and potential adverse effects. It is crucial to customise therapy based on individual needs, age, and seizure type. There should be continuous research  to maximise the therapeutic potential of CBD and THC.