Overview

Epileptic disorder is a chronic neurological condition characterised by recurrent epileptic seizures. These seizures are a result of excessive neuronal excitation (or electrical activity) in the brain, resulting in a sudden burst of energy. This can be caused by anything from genetic mutations and syndromes such as Dravet Syndrome and Lennox-Gastaut Syndrome, to head trauma, drugs, and infection.

Cannabidiol (CBD) ultimately works to reduce the severity and frequency of seizures by modulating and decreasing the amount of neuronal excitation in the brain.

What is CBD oil?

Cannabidiol (CBD) is a phytocannabinoid naturally found in cannabis and hemp. It is non-psychoactive and not to be confused with tetrahydrocannabinol (THC), the psychoactive compound found in the plant.¹ CBD oil has been approved in the United Kingdom as Epidyolex®, for the treatment of seizures in patients two years and older.² It is commonly administered orally, suspended in an oil-based solution. After the medicine is swallowed, it is absorbed into the bloodstream. From here, the CBD in Epidyolex® can travel into the brain by passing the blood-brain barrier, a semi-permeable membrane that lines blood vessels in the brain, acting as a filter to protect the brain. The CBD is then free to elicit its seizure-reducing effects.²

CBD has gained significant traction in the medical world in recent years, due to its promising effects on sleep, anxiety, depression, and epilepsy. But what is actually happening in the brain and body in order for these effects to take place? How exactly does CBD manage to decrease neuronal activity in the brain without any detrimental side effects? To answer this, we must first look at the standard treatment of epilepsy as a whole.

Treating epilepsy

There are two main pathways that can be taken when treating epilepsy:

• Decreasing electrical excitation in the brain: via decreasing the activity of voltage-gated sodium and/or calcium channels, or decreasing the efficacy of excitatory synapses
• Increasing inhibition in the brain: via increasing the efficacy of inhibitory synapses, or increasing potassium channel activity, the channel associated with electrical inhibition of the brain

As previously mentioned, CBD utilises the pathway of decreasing electrical excitation in the brain. It achieves this via multiple mechanisms.

CBD mechanisms of action

Naturally occurring compounds, such as CBD, have many targets in the brain, allowing them to have such a variety of medical uses. For this reason, the exact mechanism of action of CBD in reducing seizures is not yet completely understood.

Current data, supported by clinical studies, suggests three main targets of CBD: the GPR55 receptor, the TRPV1 channel, and the equilibrative nucleoside transporter 1 (ENT-1).³

The GPR55 receptor

This receptor is a type of G protein-coupled receptor found in the brain. It plays a key role in excitability via increased intracellular calcium concentration.³ CBD acts as an antagonist (blocker) of this receptor, leading to a reduction of the neuronal excitability caused by the GPR55 receptor.

TRPV1 channels

The transient receptor potential vanilloid-1 (TRPV1) channel is expressed throughout the central nervous system. Activating TRPV1 leads to neuronal depolarisation, causing increased firing of neurones and synaptic activity. Studies have shown that TRPV1 expression is increased in epilepsy in humans.³ CBD is an agonist (activator) of the TRPV1 receptor, leading to desensitisation of the TRPV1 channel and therefore lowering its activity.³ Lowering the activity of TRPV1 will lead to a decrease in synaptic activity and decreased neuronal excitation, one of the goals of epilepsy treatment. Evidence of CBD's role with these channels was shown in a model of generalised seizures.⁴ The deletion of the TRPV1 gene resulted in a blunted response to CBD, suggesting that TRPV1 is a key target implicated in the seizure-reducing effects of CBD.⁴

ENT-1 transporters

ENT-1 transporters are responsible for the uptake of adenosine, which reduces the amount of adenosine that is readily available. Adenosine modulates neuronal excitability and could be considered the brain's built-in anticonvulsant. CBD enhances adenosine signalling by inhibiting adenosine uptake from ENT-1 receptors, therefore increasing extracellular adenosine availability.³ This leads to increased modulation of neuronal excitability; in other words, neuronal excitability is lowered.

Other proposed targets of CBD

Another proposed target of CBD is GABAA receptors.⁵ CBD is a positive allosteric modulator of GABAA receptors, meaning it increases the activity of the receptors. GABAA receptors are inhibitory, so this increase in activity would subsequently decrease overall brain activity and contribute to a reduction in seizure frequency.

CBD also modulates serotonin levels in the brain and is known to inhibit serotonin reuptake, thereby increasing the levels of available serotonin.⁵ This may also contribute to the anticonvulsive effects of CBD.

Clinical evidence of CBD's effects

In a recent study, CBD reduced the frequency of convulsive seizures in patients with Dravet Syndrome substantially more than in the placebo group.⁶ Five per cent of the patients became seizure-free during the month-long study, with the others experiencing a substantial drop in seizure frequency.⁶

CBD has also been shown to enhance the anticonvulsive properties of other medications, such as clobazam, suggesting there is potential for the combinational therapy of CBD oil alongside other anti-epileptic drugs.⁶ CBD has been proven to increase plasma levels of a clobazam metabolite by an average of 500%.⁶ For this reason, there is some discussion on whether CBD only has substantial effects when combined with other drugs, and what effect it would have when taken solely. More research on this is crucial to understand how these drugs interplay, and no medication should be taken against your doctor's advice.

FAQs

How much CBD is needed to stop seizures?

The dose of CBD oil is completely dependent on body weight. The recommended starting dose is 2.5 mg/kg twice a day. This is likely to be increased to anything up to 10 mg/kg twice a day.² It is important to remember that there is no guarantee that a cannabidiol solution will completely stop the seizures, and the effects vary for each individual. Most clinical trials suggest a reduction in frequency and severity of seizures, rather than a complete cessation. In order to eliminate all seizures, a combination of drugs may be recommended by your neurologist.

What drugs should not be taken with CBD?

CBD can have unwanted interactions with prescribed medications such as opioids, benzodiazepines, antidepressants, antipsychotics, and antihistamines, unless the doses are decreased.⁷ It is important to liaise with your healthcare provider if you are taking any of these medications and are looking to begin taking CBD. Taking CBD alongside the aforementioned drugs can lead to enhancement of their effects, such as drowsiness and fatigue, potentially leading to accidental falls.⁷ Furthermore, some herbal supplements, including St John's wort and melatonin, can also lead to increased fatigue.⁷ Taking CBD with stimulants used to treat attention deficit/hyperactivity disorder (ADHD) can lead to a decreased appetite.⁷

Can the NHS prescribe CBD oil?

Yes, the NHS can prescribe CBD oil for conditions such as Lennox-Gastaut Syndrome and Dravet Syndrome, both of which are severe forms of childhood-onset epilepsy.⁸ It is important to note that only a specialist doctor, such as a consultant neurologist, can prescribe CBD oil, and it will only be considered after all other treatment options have been explored. Your GP can refer you to a specialist if you are concerned, but they cannot prescribe the drug themselves.

Summary

CBD oil holds considerable promise for the future of epilepsy treatment; however, much remains to be discovered surrounding how the compound works. Mechanisms of action with plausible evidence include antagonising the GPR55 receptor, leading to reduced brain excitability; desensitising the TRPV1 channel, also leading to reduced neuronal excitability; and inhibiting ENT-1 transporters, leading to reduced adenosine uptake and more modulated neuronal excitability. Studies are currently investigating whether these characteristics of CBD are achievable by CBD alone, or whether the compound must be taken alongside small doses of other anticonvulsives in order to produce the same seizure-reducing effect.