Introduction

Epilepsy is a chronic neurological disorder resulting from recurrent unprovoked seizures due to unusual electrical activity in the brain. It can affect more than 50 million people worldwide.¹ Repeated seizures can eventually disturb neurons, which may result in cognitive decline or behavioural changes. Cannabidiol (CBD), a non-psychoactive compound derived from the plant Cannabis Sativa, is a promising therapy for epilepsy, especially the treatment-resistant types, such as Dravet syndrome. In contrast to tetrahydrocannabinol (THC), CBD does not cause intoxication and has been found to have potential effects on reducing seizure frequency and severity.²

Apart from any conceivable role CBD could play in the regulation of seizure, it may have other neuroprotective effects. Neuroprotection refers to the properties of neurons to protect against injury sustained. It is crucial in the management of epilepsy since this could minimise the devastating long-term impacts of recurrent seizures on the brain.³ CBD’s ability to reduce inflammation and oxidative stress helps avert deterioration of brain function, consequently improving quality of life.

Mechanisms of CBD in the brain 

Neuroprotection is of particular importance in epilepsy, as seizures are recurrent and therefore make the brain inherently susceptible to injury. Cumulative neuronal damage is the result of repeated seizures due to abnormal electrical activity. These changes lead to increased susceptibility of the brain to cell death, inflammation, oxidative stress, and neurodegeneration with effects on memory, cognition, and general functions of the brain.⁴

There are two body receptors where cannabidiol interacts with the endocannabinoid system –majorly, especially CB1 and CB2 – influencing activities like inflammation, pain, and neuronal activity. CB1 receptors are predominantly found in the central nervous system, and influence neurotransmitter release whereas CB2 receptors are distributed through the immune system.⁵ Interaction through these receptors helps in neuronal stability and minimises the damage caused to cells, hence CBD is considered to be one such neuroprotective agent.

One mechanism by which CBD exerts neuroprotection involves the regulation of neurotransmitter release, such as glutamate.⁶ Overactivation of glutamate release is associated with excitotoxicity – the process by which overstimulation of neurons triggers cell death. By reducing glutamate release, CBD can prevent excitotoxic damage to neurons, which plays a crucial role in decreasing seizure-induced neurodegeneration.

Another cause of neurodegeneration in epilepsy is due to inflammation, because the brain resorts to overactive inflammation responses following frequent seizures. Such an overly inflammatory response hurts neuronal tissue. CBD has been shown to possibly decrease inflammation; thus, it may protect neurons and also decrease frequency and severity in seizures. 

CBD as an Anticonvulsant

CBD was documented to have strong anticonvulsant effects in different models, and thus it represents a potential for the reduction of the frequency and severity of seizures in epilepsy, especially in drug-resistant cases. In the models of acute seizures such as pentylenetetrazol (PTZ), maximal electroshock (MES), and pilocarpine-induced seizures, CBD administration reduces the latency and severity/duration of the seizures in dose-dependent manner. For instance, in MES, CBD showed prophylactic effects against generalised tonic-clonic seizures in adult mice at about 80 mg/kg,  while also enhancing the effectiveness of some ASMs such as topiramate and oxcarbazepine. In addition, studies performed on animals suggest a positive effect in seizure models associated with genetic disorders, for instance, Dravet Syndrome. Whereas treatment by CBD enhanced levels of seizure thresholds as well as decreased severity in young mice.^7,8

The dose-response relationship for CBD's anticonvulsant activity varies widely, with effective dose ranging from 3 mg/kg up to 200 mg/kg, depending upon the model of seizure and the age of animals. This further suggests that CBD is a complex multitarget molecule showing activity in various neurotransmitter systems, such as enhancing GABAergic signaling and blocking glutamate release, which directly affects epileptiform activity.

This anticonvulsant effect is promising but cannot provide consistent outcomes because, irrespective of the dosage and purity, CBD has different methods for administration. There is a chance of desensitisation or side effects at high dosages, while commercial products vary in purity, which can cause varying outcomes. The legality and status of CBD differ in various countries; hence, regulatory barriers provide obstacles in accessing standardised treatments. Although CBD's multitarget effects on neurotransmission, mitochondrial function, and neuroprotection position, it as a valuable adjunctive treatment for refractory epilepsy. Further studies are needed to optimise therapeutic regimens and assess its full effectivenessin specific epilepsy subtypes.⁹

Potential Neuroprotective Benefits of CBD in Epilepsy

CBD has been shown to exhibit promising neuroprotection in epilepsy, reducing neuronal injury and preserve essential areas of the brain. Oxidative stress plays a part in the pathophysiology of epilepsy, as recurrent seizures increase the production of Reactive Oxygen Species (ROS), which lead to neuronal damage and death. CBD has been seen to neutralise oxidative stress by enhancing the antioxidant capacity and lowering the amount of ROS. Since CBD has been shown to modulate mitochondrial function and also inhibit excessive influx of calcium, it has been able to protect neurons from excitotoxicity effects which are common outcomes of prolonged seizure activity.¹⁰

Recently, a new body of evidence also appears to indicate that CBD might enhance neurogenesis, mainly under chronic epilepsy conditions. For instance, CBD activates the PINK1/Parkin pathway,¹¹ ensuring the elimination of malfunctioning mitochondria and supporting the survival of new neurons. This action might support recovery in areas damaged by chronic seizure-induced pathology, such as the dentate gyrus of the hippocampus, where the morphology was critical to preserve original cognitive functions.

More importantly, the interaction of CBD with the endocannabinoid system increases the release of brain-derived neurotrophic factor (BDNF), which is considered the critical protein for neuronal growth and survival. Such a neuroprotective mechanism is particularly important in mitigating cognitive decline due to chronic epilepsy.¹²

These neuroprotective effects position CBD as an exciting therapeutic repositioning for both seizure control and long-term neurological health as a component of the treatment of epilepsy. However, even further clinical research is required to discover these benefits, optimal dosing strategies, as well as long-term impacts on neurogenesis and mitigation of oxidative stress in human patients with epilepsy.¹³

Clinical Implications

The first FDA-approved drug in cannabidiol is Epidiolex. Epidiolex is primarily used for the two rare conditions of epilepsy: Dravet and Lennox-Gastaut syndromes. Clinicals demonstrated the substantial reduction of seizure frequency compared with the placebo and indicated that some patients had their seizures reduced by 50%. Such outcomes emphasise CBD's role as a significant treatment alternative for drug-resistant epilepsy and open another mechanism of action for those resistant to traditional anti-seizure drugs.¹⁴

Although promising, long-term use has some considerations. Among these are side effects including fatigue, diarrhea, and elevation of liver enzymes. Patients should be under close monitoring from their healthcare providers. Additionally, the potential for interaction of this drug with other anti-seizure drugs or treatments suggests that there is a need for careful assessment of each patient on an individual basis. With regard to the different metabolic processing pathways for each drug, CBD may interfere with either the activity or toxicity levels of co-administered treatments.

Another area of potential usefulness may be combining CBD with other neuroprotective therapies. Increasing interest lies in growing preliminary evidence that CBD supplements might enhance the effectiveness of some anti-seizure drugs, combining in a complementary way two therapeutic approaches. Adding CBD with agents for protection against oxidative stress, mitochondrial dysfunction, or inflammation may further result in more robust treatment outcomes. For example, adding CBD along with N-acetylcysteine or mitochondrial wellness-inducing compounds may prove to be a multifaceted approach for seizure-related neuronal damage prevention.¹⁵

Summary

• Epilepsy is a chronic neurological disease affecting over 50 million people worldwide, is characterised by recurrent seizures due to unusual electrical activity in the brain
• Cannabidiol, a major nonpsychoactive compound from Cannabis Sativa, may be effective in treating drug-resistant epilepsy, including Dravet syndrome. The neuroprotective effects of reducing inflammation and oxidative stress may help to decrease seizure frequency and severity
• CBD interacts with CB1 and CB2 receptors in the endocannabinoid system to stabilise neuronal function and avoid excitotoxicity by modulating neurotransmitter release, particularly glutamate
• The only FDA-approved drug so far is Epidiolex, which has been proven effectively to reduce seizures in both Dravet and Lennox-Gastaut syndromes; however, long-term use is of concern with respect to side effects and interactions with other drugs
• Further research is needed on CBD dosing and its treatment outcomes in combination with alternative therapies, along with a comprehensive understanding of the full benefits of CBD in epilepsy management