A new study has revealed the role of the endocannabinoid system in treating seizures, in a rare form of epilepsy known as Dravet syndrome.

Researchers at the University of Sydney’s Lambert Initiative for Cannabinoid Therapeutics, investigated the impact of the endocannabinoid system (ECS) in Dravet syndrome – a rare form of intractable childhood epilepsy. 

The study found that alterations in the ECS, as a result of boosting cannabinoid activation with drugs, had an anticonvulsant effect, reducing seizures brought on by the condition.

These results suggest that drugs focused on enhancing the ECS with cannabinoids, could be developed to treat Dravet syndrome and other intractable epilepsies.

“Many in the community suggest that cannabis may yield its therapeutic properties by correcting deficiencies in the ECS,” Professor Jonathan Arnold, principal investigator of the study, told Cannabis Health.

“Given that cannabis and CBD are being used to treat intractable epilepsies like Dravet syndrome, we decided to explore whether deficiencies in the ECS occur in a mouse model of Dravet syndrome and whether boosting endocannabinoid signalling has anti-seizure effects.”

The endocannabinoid system & seizures

The ECS is a naturally occurring signalling system that exists in the body, to control normal physiological functions, and is sensitive to the effects of plant cannabinoids including THC and CBD. 

The team investigated whether boosting endocannabinoid signalling had anti-seizure effects by using one drug that increased endocannabinoid concentrations and another drug that made the CB1 cannabinoid receptor more sensitive to activation. 

Prof Arnold continued: “We found evidence that the gene for the cannabinoid CB1 receptor might be influencing the severity of how Dravet syndrome presents. While 80 per cent of children with Dravet syndrome have a mutation in the SCN1A gene, not all those who have the mutation exhibit the devastating seizure symptoms observed in the condition. This suggests that there are other genes (genetic modifiers) that influence how severe the symptoms are.

“We found that mice who were susceptible to seizures had lower levels of the cannabinoid CB1 receptor gene than mice that were seizure-resistant, which is consistent with the gene for the CB1 receptor being a potential genetic modifier.”

While the drugs had anti-seizure effects against one type of seizures, they also observed that overstimulating the endocannabinoid system with high doses could also trigger seizures. 

This occurs when a tolerance to a particular treatment is built up through repeated dosing and the individual experiences reduced drug effects as the body adapts to the drug, Prof Arnold explained.

Calls for more research

Further studies should explore the role of the ECS in intractable, childhood epilepsies, he said, and drugs focused on boosting cannabinoid activity in the ECS could provide new hope for treating the condition.

“Our results suggest that human studies should further explore whether ECS deficiencies are involved in intractable, childhood epilepsies such as Dravet syndrome. Specifically, it would be of interest to explore the cannabinoid CB1 receptor gene as a genetic modifier in Dravet syndrome,” Prof Arnold concluded.

“Our results suggest that pharmacologically boosting the endocannabinoid system might be examined as a new means to treat Dravet syndrome. However, we also found a potential liability of this strategy, where overstimulating the endocannabinoid system could make things worse.”

Researchers examining the effects of CBGA on Dravet Syndrome report that it may have a ‘modest’ effect on seizures.

Researchers at the University of Sydney have been examining the potential of three cannabinoids to treat Dravet syndrome.

This new study explored whether CBGA, or its precursor olivetolic acid could have better brain penetration and help to control seizures.

While CBGA shows promise in helping to reduce the frequency of seizures, it is limited due to its poor brain penetration abilities and also, its chemical instability.

Researchers aimed to discover if a more stable version of CBGA (CBGA methyl ester) could offer more success.

The results showed that the more stable version of CBGA had limited brain penetration at 13 per cent. This was notably superior in relation to CBGA at two per cent. While the olivetolic acid also showed poor brain penetration at one per cent, it did have a modest anticonvulsant effect.

What is CBGA?

CBGA is the precursor to many cannabinoids including CBD and THC. It is thought to help some diseases such as colon cancer, metabolic disease and cardiovascular disease. It is a non-intoxicating cannabinoid much like CBD, however, it is present in cannabis at much lower levels than CBD making it harder to extract.

Earlier this year, in another study, the same researchers revealed that CBGA may be more effective than CBD in reducing seizures. They also examined  cannabidivarinic acid (CBDVA), cannabigerovarinic acid (CBGVA). CBGA in particular “may contribute to the effects of cannabis-based products in childhood epilepsy” noted the researchers and were found to potentially have ‘anticonvulsant properties.”

Speaking with Cannabis Health about the previous study, Dr Anderson explained that more research is needed to explain how the different cannabinoids work together.

“We don’t know how they work together yet,” she said.

“We found that CBGA exhibited both anticonvulsant and pro-convulsant effects. CBGA was more potent than CBD against febrile seizures in a mouse model of Dravet syndrome. We also found that a combination of CBGA and clobazam was more effective than either treatment alone. Additionally, we found that CBGA was anticonvulsant in the maximal electroshock acute seizure model, a model for generalised tonic-clonic seizures.”

She added: “CBGA did, however, present some pro-convulsant effects. The frequency of spontaneous seizures in the mouse model of Dravet syndrome was increased with a high dose of CBGA. Also, CBGA was pro-convulsant in the 6-Hz acute seizure model, a model of focal, psychomotor seizures.”

Read more about the previous study here

More research needed

Although CBGA shows promise, Dr Anderson also cautioned that Dravet syndrome patients may still need to proceed with caution.

“Artisanal cannabis-based products are believed to reduce seizures in Dravet syndrome patients,” she said.

“As these oils contain rare cannabinoids like CBGA, it is possible that it contributes to the anticonvulsant effects of these artisanal cannabis oils. However, there were pro-convulsant effects observed with CBGA, suggesting that Dravet syndrome patients may need to proceed with caution. The pro-convulsant liability of CBGA would need to be addressed before it replaced CBD as an anticonvulsant.”

Seizure frequency fell by 86% in children with intractable epilepsy, who were using medical cannabis, a new study has found, prompting further calls for NHS access.

Epileptic seizure frequency fell by an average of 86 per cent among 10 children treated with whole plant medicinal cannabis, reveals a case series, published in the journal, BMJ Paediatrics Open. 

Researchers at Drug Science, the UK charity for drug reform, studied 10 children suffering with intractable epilepsies, to assess the change in monthly seizure frequency and the impact of medicinal cannabis on conventional epilepsy drug use. 

Seizure frequency across all 10 participants reduced by 86 per cent, with investigators reporting no significant adverse effects. One patient showed full remission from seizures.

Participants were also able to reduce their use of anti-epileptic drugs, from an average of seven to one, following treatment with medical cannabis.

The paper follows previous findings from Drug Science, that a child would have a 96 per cent chance of having a significant reduction in seizures were they to be prescribed cannabis.

The children, recruited from lobby group End Our Pain and Medcan Support, were between the ages of one to 13 years, with a range of epilepsies. Three had other concurrent issues, including infantile spasms, learning disabilities, and global developmental delay.

None of them had responded to other treatments, including the only cannabidiol (CBD) product licensed for their condition Epidyolex. 

Parents and carers reported significant improvements in the health and wellbeing of their children, including in sleep, eating, behaviour and cognition after they started to take whole plant medicinal cannabis products. Only a few minor side effects, such as tiredness, were reported. 

“Huge relief” for families

Researcher on the study, Rayyan Zafar, described the impact as “outstanding”, with positive outcomes for the wellbeing of the whole family.

Speaking to Cannabis Health, Zafar, commented: “All the children in our study had a substantial reduction in seizures which was paired with improvements in their behaviour, sleeping patterns, eating and cognitive abilities. 

“The impact it has had was truly outstanding with one patient showing full remission in their seizures. For the families this was obviously a huge relief, allowing them to see a renewed sense of reassurance in their child’s health which also had positive impacts on their own wellbeing.” 

The paper also highlights that those families involved in the study were paying an average of £874 a month to ​​access these medicines through private prescriptions.

Since medical cannabis was legalised in the UK in 2018, only three prescriptions have been issued on the NHS.

Those behind the study believe this data provides evidence to support its introduction into the NHS within current NICE prescribing guidelines. 

“These data provide adequate evidence for the clinical efficacy for whole-plant medical cannabis in this patient group and this data should complement the growing literature to support this as a licensed intervention,” said Zafar.

“We hope we have highlighted the burden of private prescriptions and encourage the NHS to allow for specialist physicians to prescribe these medicines through the NHS where clinically appropriate.”

Growing calls for NHS access

The paper contributes to growing calls from patients, campaigners, doctors and scientists, for medical cannabis to be available more widely on the NHS, particularly for those living with childhood epilepsies.

In light of the increasing pressures facing the NHS, access to medical cannabis could potentially save the healthcare system hundreds of thousands, in costs related to intensive care treatment and conventional anti-epileptic drugs.

Zafar believes allowing doctors to prescribe would be in the “best interest” of both the patients and the NHS.

“Our case series highlights the remarkable and life changing results of this intervention that standard licensed anti-epileptic drugs have not been able to achieve,” he added.

“In the current era with higher demands on the NHS cost saving is of paramount importance. Here we demonstrate how a very difficult to treat and unwell clinical population have managed to regain control of seizures through a relatively inexpensive, safe and effective intervention. The alternative being high costs due to repeated ICU trips and high costs associated with their care. Given this and the external pressures faced by the NHS in the present day, we believe it would be in the best interest of both the patients and the NHS to prescribe these medicines for these patients.”