Can Medical Marijuana Effectively Treat Childhood Epilepsy?

Following media reports of children with epilepsies reportedly deriving benefits from medical marijuana (or cannabis-based medicinal products) accessed abroad, the UK government allowed clinicians to prescribe these products. A review published in Developmental Medicine & Child Neurology explores the science behind cannabis-based medicinal products in pediatric epilepsies and highlights areas that warrant additional research.

The authors also examined the prescribing environment surrounding these products. They found that a lack of quality evidence for efficacy and safety is the major obstacle to prescribing.

They stress that unlicensed cannabis-based medicinal products should not circumvent usual regulatory requirements before being prescribed. And they worry that children with epilepsy are at risk of being used as a “Trojan horse” for the cannabis industry, with widespread acceptance of medicinal cannabis accelerating the wider legalization of marijuana and opening up a highly lucrative commercial market.

Marijuana-Like Brain Substance Calms Seizures but Increases Aftereffects, Study Finds

Summary, full article published in Stanford Medicine News Center

A marijuana-like chemical in the brain, mirroring its plant-based counterpart, packs both ups and downs.

Epileptic seizures trigger the rapid synthesis and release of a substance mimicked by marijuana’s most psychoactive component, Stanford University School of Medicine investigators have learned. This substance is called 2-arachidonoylglycerol, or 2-AG, and has the beneficial effect of damping down seizure intensity.

But there’s a dark side. The similarly rapid breakdown of 2-AG after its release, the researchers found, trips off a cascade of biochemical reactions culminating in blood-vessel constriction in the brain and, in turn, the disorientation and amnesia that typically follow an epileptic seizure.

The Stanford scientists’ findings, reached in collaboration with colleagues at other institutions in the United States, Canada, and China, are described in a study to be published Aug. 4 in Neuron. Ivan Soltesz, PhD, professor of neurosurgery, shares senior authorship with G. Campbell Teskey, PhD, professor of cell biology and anatomy at the University of Calgary in Alberta, Canada. The study’s lead author is Jordan Farrell, PhD, a postdoctoral scholar in Soltesz’s group.

The researchers’ discoveries could guide the development of drugs that both curb seizures’ strength and reduce their aftereffects.

Epilepsy Research News: August 2020

This month’s research news includes two new approaches for developing epilepsy treatments. One is a new antiseizure drug target and the other creates a completely novel type of antiseizure drug based on a vitamin.

Recent studies also broadened our understanding of developmental outcomes in people with epilepsy and possible causes of intellectual delays in some individuals. A research team demonstrated that there is no difference in the developmental or behavioral outcomes of children who have febrile seizures following vaccination compared to children who do not have these seizures. In addition, data from another study shows that two specific genetic mutations which cause the development of epilepsy, as well as intellectual disability affect the same brain protein in the same way.

In addition, research suggests that many people with epilepsy living in rural areas of China could become seizure-free with expanded access to routine neurosurgery. Finally, in the US the FDA has approved Epidiolex® (cannabidiol) oral solution for the treatment of seizures associated with tuberous sclerosis complex (TSC) in patients age 1 and older. Patients and their families can read the full FDA statement here.

Summaries of these research discoveries and news highlights are below.

Research Discoveries

  • Novel Target for Antiseizure Drugs: An international study, featuring the work of former CURE grantee Dr. David Henshall, discovered that a small set of molecules called microRNAs, which control gene activity in the brain, are elevated in epilepsy. The team created inhibitors of these microRNAs, and when three of these inhibitors were combined, they were found to stop seizures in laboratory tests. Learn more
  • Novel Antiseizure Drug: Researchers report that a novel vitamin K-based therapy has proved effective in reducing seizures in mouse models of medication-resistant seizures. Learn more
  • Vaccination and Seizures: A study demonstrated that there is no difference in developmental and behavioral outcomes for children who have febrile seizures after vaccination, children who have febrile seizures not associated with vaccination, and children who have never had a seizure. Learn more
  • Intellectual Disability and Epilepsy: Two mutations identified in people with developmental and epileptic brain disease can be traced back to the same brain protein known as TRPM3, which is responsible for sensing heat and pain. Researchers have determined how both mutations independently make the protein overly active and extremely sensitive to stimulation, taking the first step towards unraveling what causes the symptoms in patients with these mutations. Learn more
  • Neurosurgery in China: A study researching the causes and outcomes of epilepsy in people who live in rural China found that at least one million individuals could be candidates for a surgical procedure that may leave them seizure-free. Learn more
  • New Therapy for Tuberous Sclerosis Complex (TSC): The FDA recently approved Epidiolex® (cannabidiol) oral solution for the treatment of seizures associated with TSC in patients 1 year of age and older. Epidiolex had previously been approved for the treatment of seizures associated with two rare and severe forms of epilepsy, Lennox-Gastaut syndrome and Dravet syndrome. Learn more

Join leading epilepsy experts as they discuss the current research landscape during Unite to CURE EpilepsyThis live streamed evening showcasing tenacity, discovery, and hope will also feature inspirational stories from the CURE community and special performers, including Eric Church.

Study Shows that Cannabidiol (Epidiolex®) has Antiseizure Activity Independent of Its Interactions with Clobazam (Onfi®)

Abstract, published in Epilepsia

Four pivotal randomized placebo-controlled trials have demonstrated that “add-on” therapy with cannabidiol (CBD) improves seizure control in patients with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). Between 47% and 68% of patients given CBD treatment in these trials were receiving clobazam (CLB), which shows complex interactions with CBD resulting in an increased in concentration of the active metabolite norclobazam. This raises concern as to the role played by these interactions when evaluating the reduction in seizure frequency in CBD-treated patients, and the question of whether CBD alone has clinically significant antiseizure effects.

This study appraised available evidence on the clinical consequences of the CBD-CLB interaction, focusing on subgroup analyses of seizure outcomes in patients on and off CLB comedication in the pivotal CBD trials. Evaluation of the results of individual trials clearly showed that improvement in seizure control over placebo was greater when CBD was added on to CLB than when it was added on to other medications. However, seizure control was also improved in patients off CLB, and despite the small sample size, the difference vs placebo was statistically significant in one of the two LGS trials.

Stronger evidence for an antiseizure effect of CBD independent of an interaction with CLB comes from analyses of seizure outcomes in the pooled population of LGS and DS patients not receiving CLB comedication. Although these results need to account for methodological limitations, they provide the best clinical evidence to date that CBD exerts therapeutic effects in patients with epilepsy that are independent of its interaction with CLB. Greater antiseizure effects and a greater burden of adverse effects, are observed when CBD is combined with CLB.

Neurologists’ Perspectives on Medical Cannabis for Pediatric Drug-Resistant Epilepsy in Canada

Purpose: To understand the experiences with and perspectives of neurologists about the use of medical cannabis in the treatment of pediatric drug-resistant epilepsy.

Results: The 12 interviewed neurologists generally perceived medical cannabis as a viable treatment option for children with drug-resistant epilepsy; however, participants identified important gaps in the evidence and implications for their practices. Six themes were generated from the content of the interviews: learning about medical cannabis; perceptions about medical cannabis; discussing medical cannabis with parents; experiences with medical cannabis authorization; barriers to authorizing medical cannabis; and the impact of medical cannabis on clinical care. Of note, while some neurologists took on all aspects of the children’s care, including medical cannabis, others referred interested families to non-neurology health care professionals.

Conclusions: Researchers state that these findings highlight the diverse opinions and experiences of neurologists in Canada with medical cannabis for the treatment of drug-resistant epilepsy in children, including with the authorization process and caring for children using medical cannabis. Additional education about medical cannabis may be warranted, to better prepare neurologists to have informed and open conversations with parents about this treatment option and to provide care for children using medical cannabis.

A dropper adding liquid to an extract in a bottle with cannibals leafs in the background.

XPhyto Therapeutics Epilepsy Treatment Program

XPhyto is pleased to announce significant progress with respect to development of its cannabidiol (CBD) based epilepsy product. Further to the company’s press release, titled “Epilepsy Treatment to be Developed with XPhyto Therapeutics Thin Film Delivery System,” and based on recent positive product development results, XPhyto will be advancing the program to clinical studies immediately.

In the past three months, Vektor Pharma TF GmbH (“Vektor”), the Company’s wholly owned German subsidiary, has completed the initial stage of product development and established a number of critical parameters necessary for an efficient and well-defined dissolvable oral CBD dosage form. The Company is now finalizing the formulation and preparing for European-based clinical studies in Q2 and Q3 of 2020.

XPhyto’s thin film drug delivery system was developed by Vektor, a narcotics manufacturer, importer, and researcher located in the Upper Swabia region of the German state of Baden-Württemberg. Vektor’s previous development work has included narcotics delivery systems for conventional oncology and non-oncology pain treatment, such as Fentanyl, Hydromorphone, and Oxycodone, and more recently, the development of efficient cannabis delivery and dosage systems.

The Company’s CBD-based Epilepsy treatment program is one of several dissolvable oral drug delivery initiatives for 2020. Oral thin film drug delivery is a large and growing international industry which provides an alternative to conventional solid and liquid oral dosage forms. Transparency Market Research estimates that the global market for thin film drug manufacturing will be worth US$15.984 billion by 2024 and rising at a solid 9.0% CAGR between 2019 and 2024. XPhyto’s additional oral thin film drug delivery programs include both cannabinoid and non-cannabinoid products for pain, neurology and infectious disease.

Further to the Company’s press release on March 3, 2020, XPhyto is planning to announce, in due course, an update on its infectious disease programs, particularly as they relate to products relevant to the COVID-19 pandemic.

A dropper adding liquid to an extract in a bottle with cannibals leafs in the background.

Epilepsy and Cannabidiol: A Guide to Treatment

The growing interest in cannabidiol (CBD), specifically a pure form of CBD, as a treatment for epilepsy, among other conditions, is reflected in recent changes in legislation in some countries. Although there has been much speculation about the therapeutic value of cannabis-based products as an anti-seizure treatment for some time, it is only within the last two years that Class I evidence has been available for a pure form of CBD, based on placebo-controlled RCTs for patients with Lennox-Gastaut syndrome and Dravet syndrome.

However, just as we are beginning to understand the significance of CBD as a treatment for epilepsy, in recent years, a broad spectrum of products advertised to contain CBD has emerged on the market. The effects of these products are fundamentally dependent on the purity, preparation, and concentration of CBD and other components, and consensus and standardisation are severely lacking regarding their preparation, composition, usage and effectiveness.

This review aims to provide information to neurologists and epileptologists on the therapeutic value of CBD products, principally a purified form, in routine practice for patients with intractable epilepsy.

A dropper adding liquid to an extract in a bottle with cannibals leafs in the background.

The Other Side of the Leaf: Seizures Associated with Synthetic Cannabinoid Use

There has recently been a marked rise in the medicinal use of cannabis for epilepsy and multiple other conditions. While seizures have been reported in association with synthetic cannabinoids, the clinical features and prognosis have not been studied.

Thirty patients with a history of seizures occurring within 24 h of synthetic cannabinoid use were identified from a first seizure clinic database in Perth, Western Australia between 2011 and 2016. Eight had a prior history of seizures, three related to synthetic cannabinoid use, with an additional three patients having risk factors for seizures. The presenting event was a tonic-clonic seizure in 27 patients (90%). “Kronic” was the synthetic cannabinoid used by 16 patients. Absorption was via smoking in all cases, with seizures occurring within 30 min of inhalation in 14 patients (46%).

Electroencephalography (EEG) showed epileptiform abnormalities in 11%, and neuroimaging revealed epileptogenic lesions in 12%. Nine of 24 patients with follow-up had subsequent seizures, occurring in the setting of further synthetic cannabinoid use in two patients. This seizure recurrence rate is similar to seizures provoked by other acute systemic insults. In conclusion, smoking of some synthetic cannabinoids is associated with seizures, and this may relate to an intrinsic proconvulsant effect.

Study Finds Cannabidiol (Epidiolex®) Effective in Subjects with Refractory Epilepsy with or without Simultaneous Use of Clobazam

OBJECTIVE: To evaluate the efficacy of open-label, highly purified cannabidiol (CBD, Epidiolex®) in treating refractory epilepsy relative to the concomitant use of clobazam (CLB) as well as the clinical implications of changes in CLB and norclobazam (nCLB) levels.

METHODS: Data were examined retrospectively, in patients who either used CBD with concomitant CLB or without concomitant CLB after two months of treatment with CBD and at the point of best seizure control within the first year of treatment with CBD. Responder rates (percentage of subjects with a 50 % or greater reduction in weekly seizures from their baseline) and mean reduction in weekly seizure frequency were calculated and compared between those who concomitantly used CLB and those who did not. The relationship between the change in CLB and nCLB levels and change in mean weekly seizure frequency was also investigated within the group of subjects using concomitant CLB and CBD.

RESULTS: Researchers analyzed data from 47 subjects between the ages of 2.5-51 years. There was no significant difference between the concomitant CLB (n = 32) and no concomitant CLB (n = 15) groups in terms of demographics (age (p = 0.4344), race (p = 1.0000), sex (p = 0.7507)) or most epilepsy characteristics (underlying condition (all p > 0.05), mean baseline seizure frequency (p = 0.6483)). There was only one significant difference between groups regarding seizure types (more subjects with epileptic spasms in concomitant CLB group (p = 0.0413)). Concomitant AED usage was not significantly different in the two groups (all p > 0.05). Mean reduction in weekly seizure frequency was greater at the best point of seizure control within the first year than at two months of treatment with CBD, regardless of concomitant CLB usage (all p > 0.05). There was no significant difference in reduction of mean weekly seizure frequency between those who took concomitant CLB and those who did not at either time point (all p > 0.05). There was a significantly greater responder rate for subjects taking CBD and CLB than those taking CBD without CLB only at the point of best seizure control within the first year of CBD treatment (p = 0.0240). There was no strong, significant correlation between change in nCLB or CLB levels and change in seizure frequency at either time point (all p < 0.22).

SIGNIFICANCE: With or without concomitant clobazam, cannabidiol can be effective in reducing seizure frequency. Changes in norclobazam and clobazam levels do not have a clinically significant correlation with changes in weekly seizure frequency for those taking cannabidiol with clobazam.

A dropper adding liquid to an extract in a bottle with cannibals leafs in the background.

Study Provides Insights on the Effects of Cannabidiol on Severe Form of Epilepsy, LGS

Results from a study published in the British Journal of Clinical Pharmacology may help explain why cannabidiol (CBD)—a chemical component of marijuana with no psychoactive properties—reduces the frequency of seizures in patients with a severe form of epilepsy. The effect may be explained by a drug-drug interaction between cannabidiol and the anti-seizure medication clobazam.

The form of epilepsy examined in the study is called Lennox–Gastaut syndrome. Investigators conducted clinical trial simulations for the effect of 20 mg/kg/day cannabidiol on seizure frequency in patients with this syndrome.

“The effects of cannabidiol on seizure frequency in Lennox-Gastaut patients could be explained entirely through estimated elevations of blood levels of clobazam, which might mean that cannabidiol in itself may not have any, or at best limited, antiepileptic effects,” said senior author Geert Jan Groeneveld, MD, PhD, of the Centre for Human Drug Research, in The Netherlands.