Introduction 

CBD, or cannabidiol, is one of the many potent compounds found in the Cannabis sativa. You may know this plant as hemp; which can cause a ‘high’ when ingested through smoking, inhalation or when mixed with food. 

Indeed, Cannabis sativa can cause you to get high but this is due to the presence of another active ingredient, THC (Δ9-tetrahydrocannabinol), not CBD (Δ9-tetrahydrocannabinol).

CBD is non-intoxicating and can block the effect of THC in the body. These characteristics have made CBD of medical importance and research; CBD extracted from the Cannabis plants has been approved as an anti-seizure medication in some childhood seizure disorders such as epilepsy syndromes.^1,2  

Epilepsy is a significant neurological disorder in the world and significantly affects individuals living in developing countries. It  is a chronic condition of the brain and is commonly characterised by recurrent episodes of seizures. 

In the brain of individuals with epilepsy, groups of brain cells fire multiple electric signals; Seizures result from this misfiring, so much so that the brain is confused and cannot identify which signals to attend to and which not to.

People suffering from this condition may exhibit varying of symptoms and this is dependent on which part of the brain the firing starts in and how far in the brain it spreads.

Epilepsy is not communicable and seizure must occurred at least twice or more in an individual before it is termed epilepsy.

Symptoms can be temporary during the episode and can progress to more severe or permanent conditions.

Temporary symptoms may include loss of consciousness and awareness of one's environment, abnormal movement,  hearing impairment, disturbances vision and taste, mood disturbance and cognitive function.

Some other  serious issues may arise from physical impacts of seizures, such fractures or bruising. It could also lead to psychological issues for the individual such as anxiety and depression. They are also more prone to premature death than individuals without epilepsy.

However, with proper management, it can reduce seizure frequency, stop seizures entirely and prevent physical problems associated with it.³

Current Epilepsy Treatments 

Common traditional anti-epileptic drugs

According to standard guidelines, antiepileptic drugs are prescribed based on the knowledge of the particular type of epilepsy. This is determined by the origin of the epilepsy in the brain and the part of the body it affects. It is described as either focal, originating from only one side of the brain and affecting just one side of the body,or generalised seizures; arising as a result of firing from cells in both hemispheres of the brain at the same time, generalised seizures may also start from a point and then spread.⁴  

Examples of these drugs include:

• Carbamazepine 
• Oxcarbazepine 
• Phenytoin 
• Valproate
• Lamotrigine 
• Levetiracetam
• Topiramate 
• Clobazam

Challenges faced by patients with treatment-resistant Epilepsy

Resistance to these medications has been observed in a number of people with epilepsy.⁵ Although in this context, resistance is not due to misuse but unresponsiveness to the drugs.⁶    

According to the international league against epilepsy (ILAE), drug/ treatment resistant epilepsy is defined as failure to achieve sustained freedom from seizures even after adequate trials of two tolerated, appropriately chosen and used antiepileptic drug schedules (whether as monotherapies or in combination).⁶ 

Drug resistant epilepsy manifests as uncontrolled seizures, alterations in chemical processes within the brain and nervous system, as well as cognitive decline and impaired mental and social functions. 

Other unique comorbidities associated with these symptoms may also manifest, when an Individuals experiences all these, they are at higher risk of suicide and sudden death. Hence, there are more cases of death among patients with treatment-resistant epilepsy.⁶

Role of CBD in Epilepsy Management

The US Food and Drug agency (FDA) as well as the European Medicine Agency (EMA) have approved the use of CBD as a medication to support other anti-epilepsy therapies and this is because CBD has been identified to have definite anti-seizure properties.⁷

CBD is not psychoactive and does not cause intoxication, this is due its lack of affinity for the receptors that other cannabinoids would normally act on. Instead, it acts on other molecular targets which are involved in the regulation of seizures and epilepsy.⁸

One of these targets is called Transient Receptor Potential Vanilloid-1(TRPV1); TRPV1 causes release of an enzyme which excites excitation of neurons leading to seizures. Low doses of CBD inhibit this pathway, thus preventing epilepsy.⁹ 

Another target are the channels that control the amount of Calcium ion,Ca²⁺ in neurons; Increase in the intracellular concentration of Ca²⁺ lead to increased excitability of neurons.  An example of these channels are the T-Type Ca²⁺ channels; CBD inactivates these channels and prevents epilepsy.

Serotonin is another compound that causes excitation and has been associated with epilepsy. CBD has been observed to bind strongly with serotonin receptors and block them.⁸

An indirect mechanism of CBD as an adjunct therapy is its effect on a particular enzyme present in the liver, Cytochrome P450 which is responsible for the metabolism of drugs. CBD inhibits cytochrome P450 and its effect is seen when CBD is used in combination with Clobazam.⁸

Clinical Evidence 

Specific types of epilepsy are defined by distinguishing forms of seizures, these are referred to as epilepsy syndrome. Epilepsy syndromes are important because they give the physician an insight to the specific treatment regimen appropriate for different epilepsy manifestations. This is also important and utilised in the study of the efficacy of CBD in the treatment of treatment-resistant epilepsy.¹⁰

The most common treatment resistant epilepsy syndromes are Dravet syndrome (DS), Sturge-Weber Syndrome (SWS), Tuberous Sclerosis Complex (TSC) and West Syndrome (WS) and Lennox-Gastaut syndrome (LGS).⁸

Studies were carried out to assess the characteristics of Epidiolex, a brand of CBD in these syndromes.  Two of these trials will be discussed:

A series of clinicals trials tested how efficacious and safe it is to use this drug multiple times in children and adults with DS. To evaluate this, it was confirmed that the participants have been using their anti epilepsy drugs for at least a month prior to the test and continued during the trial. The children were grouped based on the dose of CBD administered and the last group was given placebo; a drug a substance made to resemble the drug but without active ingredients but rather, just makes you think you are using the medication.

From the results, a greater percentage of decreased seizures was observed among participants that were given CBD than for those that were given placebo. This proved that CBD is efficacious in the treatment of DS and also used for a long period of time.⁸

Similar trials were carried out for efficacy and safety of CBD as an adjunct therapy in CBD and the result showed that it is important to use CBD for a long time in order to achieve a reduction in frequency of seizures and it is also dependent on the dose used.⁸ 

Safety and Side Effects

Common Adverse Effects

No-serious adverse effects (AEs) include:

• Anaemia
• Gut-related  issues (diarrhoea, flatulence, constipation, gastroesophageal reflux disease, nausea)
• Nervous system disorders (somnolence, sedation, psychomotor hyperactivity, seizure, ataxia) 
• Vomiting
• Loss of appetite
• Drowsiness
• Sedation
• Dizziness
• Dermatitis

Other Serious Adverse effects that may occur include:

• Apnoea 
• Skin eruption 
• Thrombophlebitis 
• Seizure
• Status epilepticus
• Convulsion

Potential drug interactions with traditional Antiepilepsy drugs

From the clinical trials carried out, some interactions have been recorded when CBD is used concomitantly with Clobazam as well as with Valproate.⁸

AEs particularly somnolence were observed in almost all participants who used clobazam concomitantly. Some schools of thought still permit concomitant usage in refractory cases since the adverse effects are not serious but this would demand close monitoring.

In the case of Valproate, liver function test during concomitant use showed a greater damage when compared with participants who stopped valproate along the line in the trial. Thus valproate has been established to cause reversible liver damage, hence concomitant use is not advised at all.⁸  

Regulatory Status

Currently, FDA has approved Epidiolex for use as an adjunct only in Dravet Syndrome (DS) and Lennox-Gastaut syndrome (LGS) in patients that are two years and above although it has been used off-label for other conditions.¹¹  

Although CBD has shown remarkable indications for efficacy as an adjunct to therapy in treatment-resistant epilepsy, many aspects concerning other characteristics have not been clearly understood and established. Areas such as other drug-drug interactions, interaction with food, long term efficacy and safety outcomes in pregnancy are still vague and would need further research.¹¹

Conclusion

I have been able to make you see that including Cannabidiol (CBD)  in your treatment regimen for epilepsy which has proven resistant to medications; it may improve outcomes and reduce how often you experience a seizure.  Anyways, It is important to identify the kind of epilepsy in order to specifically choose the best anti epilepsy drugs and to also define the optimal dose of CBD.

Some not-too-serious adverse effects such as anaemia may occur with CBD as well as some other serious ones including convulsion. It is important to monitor closely for adverse effects as well as interaction with other traditional antiepileptic drugs in concomitant use such as clobazam and valproate.

Other research is ongoing to test the use of CBD in other epilepsy syndromes as well as its use as an antiepileptic drug.