Introduction

Epilepsy is a clinical syndrome of recurrent unprovoked seizures. There is an increased risk of individuals experiencing a follow-up seizure over the next ten years. The prevalence rate of epilepsy is 0.5 to 1%, although it is considered to be one of the most common neurological conditions. Around a third of epileptic patients are drug resistant as they do not achieve complete seizure freedom. This is due to anti-seizure drugs having a weakened effect on the patient.

There have been advancements in new generation anti-seizure drugs, however, they have not resulted in a high rate of seizure-free patients. This is despite the new drugs holding a more supportive tolerability and interaction profile. Individuals who are epileptic can face major life consequences, such as seizures, the side effects from anti-seizure drugs, comorbidities, as well as the social consequences from seizures. These can lead to a loss in quality of life, therefore, the search for innovative therapies continues to be a major challenge for clinicians and patients.            

Various treatments have been considered for managing epilepsy, including cannabidiol (CBD). CBD is a major component of the Cannabis sativa plant. This plant-based medicine (phytocannabinoid) was first isolated in the 1940s and thoroughly studied over the years. CBD has been utilised for many uses such as a food supplement, general well-being purposes, and a wide variety of disorders (mood disorders, pain, anxiety and epilepsy). CBD can be synthesised or directly extracted from the Cannabis sativa plant. Different formulations of tetrahydrocannabinol (THC) can be made, particularly to conform to pharmaceutical standards (0.2% or lower).¹

Epilepsy and comorbid mood and behavioural disorders

Epilepsy is a very common neurological condition that can affect any age group. Clinical manifestations include seizures, cognitive disturbances, and comorbid psychiatric disorders (which can be further subdivided into mood and anxiety disorders). Around 30% of individuals with epilepsy experience these second-hand side effects due to epilepsy. Mood and anxiety disorders are a familiar psychiatric comorbidity. The root cause of mood disorders in epilepsy varies from genetics, psychosocial factors, and neurobiological factors. The WHO Mental Health Action Plan 2013-2030 has highlighted that epilepsy and mood disorders represent a global mental health issue. Epileptic patients can experience mood disorders and different levels. 

• Managing epileptic symptoms is affected due to the increased risk of treatment-resistant epilepsy. And an increased incidence of iatrogenic psychiatric and non-psychiatric events (which have associations with antiseizure medications)      
• There are associations with an increased risk of premature mortality. This is a result of the higher occurrence of suicide and death (associated with external factors) 
• Costs are increased for patients, families, and society due to greater usage of medical services  
• Alongside treatment-resistant focal epilepsy, depressive symptoms are one of the causes of epileptic patients experiencing a poor quality of life (in comparison to seizure frequency and severity)       
• Mood disorders can have a negative impact on individuals' seizure control, specifically in advantaged socioeconomic situations

Pharmacological treatment of MD in epilepsy

The major obstacle in treating mood disorders in epilepsy is the failure to recognise them. For this reason, the current evidence in the management of psychiatric comorbidities in epilepsy is insufficient. Experts treat epilepsy and primary mood disorders by utilising the same protocols to achieve symptom remission. In 2021, recommendations were issued by the Task Force of the International League Against Epilepsy (ILAE) in collaboration with the executive and the International Bureau for Epilepsy (IBE) for treating mood disorders.  

Selective serotonin reuptake inhibitors (SSRIs)

• For treating mild depression, psychological interventions are recommended as a priority treatment. Whereas if medication is needed, SSRIs are regarded first. SSRIs are used to treat moderate to severe depressive episodes. SNRIs (such as venlafaxine) are only considered when symptoms are not alleviated by an SSRI
• If symptoms of mood disorders and anxiety persist even after optimal doses of two trials (SSRI and SNRI), the patient must be referred to a psychiatric service. This is because symptoms from a mood disorder and anxiety are likely to be unmanageable. Where mood stabilising agents, including atypical antipsychotic drugs (aripiprazole, quetiapine or risperidone)  

Treatment with antidepressants must be maintained for a minimum of six months following the last depressive episode. Where patients have a history of previous episodes, treatment is recommended to be prolonged to nine months. Whereas in severe cases, it should continue for a longer period in cases of residual symptomatology to ensure symptoms have diminished.   

Research has shown epileptic patients with mood disorders respond positively to pharmacotherapy and cognitive behavioural therapy (CBT) in comparison to primary mood disorders. One example is a randomised controlled study to treat mood disorders in people with epilepsy, which compared the safety and efficacy of sertraline vs CBT. The remission rate achieved was up to two-thirds of people randomised to both therapies.

A common misconception is that antidepressant medications are safe in people with epilepsy if prescribed at a therapeutic dose. However, evidence has shown that most cases of seizures associated with antidepressants are seen in the setting of an overdose. Patients with mood and anxiety disorders who had participated in multicenter randomised double blind placebo-controlled trials of numerous medications (including SSRIs, SNRIs, and tricyclic antidepressants (TCAs)). Results portrayed that seizures were significantly lower amongst patients randomised to these antidepressants than to the placebo. These findings also support the bidirectional relationship between mood disorders and epilepsy, where people with mood disorders are likely to develop epilepsy. 

Failure to recognise this data has also contributed to the misconception that antidepressant drugs have proconvulsant properties. Potential anticonvulsant effects of SSRIs, SNRIs and TCAs have been suggested in animal models of epilepsy. Still, this effect has yet to be established in double-blind placebo-controlled trials in epilepsy.²

The role of CBD in epilepsy treatment

Over the years, the anticonvulsant effects of cannabis have been described in small studies of patients with unmanageable epilepsies. Contrastingly, the effect of medical cannabis on seizures and epilepsies is inconclusive. Scientific research conducted on the phytocannabinoid CBD has shown promising anticonvulsant effects in different animal models. Although the mechanism of action of CBD is not entirely understood. The modulation of intracellular Ca2+ mobilisation by GPR55, TRPV1, and adenosine-mediated signal pathways seems to perform an essential role. Over recent years, the interest in using CBD for general well-being and as a treatment option for different conditions has increased. The overwhelming anecdotal information, personal experiences, and reports have inspired patients suffering from epilepsy and their families to utilise CBD to manage seizures.                

A report which gained global attention for the treatment course a five-year-old girl received with Dravet syndrome. Prior to the treatment, she experienced around 50 bilateral tonic-clonic seizures in one month. After receiving CBD treatment, seizures were reduced by 90%. This attracted extensive attention, raising interest in treating epileptic patients with CBD. This resulted in greater media reporting, and also affected the expectations and wishes of severely affected patients. This increased the demand dramatically for medical cannabis and CBD treatment to be made available to treat epilepsy. In the United States, due to the cannabis and its compounds to hold legal restrictions, some families made the decision to move to other states in the hope of gaining easier access to medical cannabis and CBD to treat their children with epilepsy.   

This prompted studies on CBD in epilepsy to be conducted. The first set of data was collected in an observational interventional trial. 214 children and adolescents were included who experienced drug-resistant epilepsy of different etiologies. All participants had a history of frequent seizures (median: approximately 60 per month). Which represented a strongly affected group. Cannabidiol was tapered until intolerance or a maximum of 25 mg/kg/day was reached. 

The mean dose for the:

• Safety group was 22.9 mg/kg
• The efficacy group was 22.7 mg/kg

The median monthly seizure change was:

• 34.6% for all seizures
• 55% for focal seizures      
• 54.3% for atonic seizures

Contrastingly, the efficacy rate for the tonic-clonic seizures was worse (-16%). Responder rates were also reduced by approximately 50% of seizures. This supported the connotation that CBD can have differing efficacies in different seizure types.    

• The median reduction and responder rates were higher for motor seizures in the Dravet syndrome patient subgroup (49.8%)
• In the safety group, some patients (79%) reported adverse events, and some (12%) reported drug-related serious adverse events  

Due to the nature of the adverse events, 3% of patients discontinued their participation in the trial. The most common adverse events observed were: 

• Drowsiness (25%)
• Decreased appetite (19%)
• Diarrhoea (19%)
• Fatigue (13%)
• 6 patients experienced thrombocytopenia 
• 11 patients had elevated liver enzymes 

Overall, the research showed a positive insight into treating epilepsy with cannabis and CBD treatment. The study suggested an adequate safety profile and a reduced seizure frequency with CBD.¹     

Pitfalls and challenges

The demand for CBD has risen, particularly due to social media and robust marketing strategies. Due to the overwhelming supply available on the internet and in specialist stores, CBD has become easily purchasable in any preparation and dosage form. It is important to consider that non-pharmaceutical products are not under the same legal investigations as pharmaceutical-grade products, meaning the quality and quantity of CBD remain unknown. Inaccurate labelling, unexpected contents, and under- and overdosing of CBD have been detected in products with specified content. This can have fatal consequences on individuals receiving CBD.        

Self-medication is commonly viewed as a complementary medicine and is generally harmless. Self-medicating with CBD treatment is well known for epileptic patients and is supported by easy access and availability as an over-the-counter medication. Patients are expecting the efficacy of CBD treatment in epilepsy and the additional benefits. For example, relief from other health conditions and general well-being. Acceptance of the adverse events patients may experience is high. This reflects patients' high expectations for symptom relief,  particularly for a supposedly non-harmful and plant-based drug. In the medicinal market, Cannabidiol is a cost-intensive medication. In Germany, depending on the quality, the estimated cost per gram is €100 to €200. Monthly costs for an adult can lead to around €3000, as dosage is dependent on the patient’s body weight. Whereas, the average monthly costs that arise from anticonvulsant therapy are €262 in a German territory centre.¹         

Summary

Cannabidiol is an intriguing but non-economical treatment option for drug-resistant epilepsy. Studies have shown promising results in treating epileptic patients. However, the efficacy in treating epilepsy is generally still under review. Though increased rates of side effects have been reported and withdrawal is rare, there is further evidence of the positive influence of CBD on behaviour, cognition, and mood. The limitations that involve CBD treatment are costs, drug–drug interactions, and emotionally triggered preconceptions. These are reflections from patients and their caregivers about CBD as a cannabis derived option.¹