CBD Epidiolex Fails to Improve Life Quality in Dravet Children in Study

Article published by Dravet Syndrom News

Management of Functional Seizures and Functi Six months of treatment with the oral cannabidiol (CBD) solution Epidiolex among children and adolescents with Dravet syndrome or Lennox-Gastaut syndrome (LGS) was not associated with improvements in caregiver-reported quality of life or adaptive behaviors.

That’s according to a small Korean study — though researchers noted that the ability to identify such improvements may have been hampered by the clinical severity of the included patients. These children had treatment-resistant seizures, significant developmental delays, and intellectual disability.

“The relationship between CBD and [quality of life] needs to be investigated in larger patient populations,” the researchers wrote.

“CBD has been found to be an efficacious antiseizure drug for patients with Lennox-Gastaut syndrome and Dravet syndrome, but it did not improve [quality of life] in pediatric patients with treatment-resistant epilepsy in our study,” the team wrote.

The study, “Effects of Cannabidiol on Adaptive behavior and Quality of Life in Pediatric Patients With Treatment-Resistant Epilepsy,” was published in the Journal of Clinical Neurology.

Cannabidiol, also called CBD, is the major non-psychoactive component of the cannabis plant, and has received considerable recent attention for its therapeutic properties.

Epilepsy Research News: April 2022

This month in Epilepsy Research News, we highlight an interesting study of 39 products containing cannabidiol (CBD), such as beverages and oils, which found that the majority were inaccurately labeled. Next, we share the announcement of the first FDA-approved drug, Ztalmy®, to treat seizures for CDLK5 deficiency disorder (CDD), a rare epilepsy caused by mutations in the CDKL5 gene, in children two years of age and older.

In pediatrics news, we share a study that found that pediatric patients with drug-resistant epilepsy that received vagus nerve stimulation and antiseizure medications (ASMs), had lower hospital costs compared to those using ASM alone. Additionally, another study found that assessing the number of days that children are minimally impacted by seizures may be a more appropriate method of evaluating severe childhood epilepsies than measuring seizure frequency alone when determining a patient’s quality of life.

Switching gears, we report on the development of a system that uses specialized sound waves to release medication into specific areas of the brain to stop seizure activity. Finally, a group of researchers reports the development of an animal model of post-traumatic epilepsy (PTE) that has spontaneous seizures after traumatic brain injury as well as behavioral disturbances which can occur in people with PTE.

Summaries of the above mentioned information follow below.

Inaccuracy of Non-Prescription Cannabidiol (CBD) Product Labeling: An analysis of 39 products containing CBD (a non-intoxicating substance found in the cannabis sativa plant) finds that most of these products were inaccurately labeled, and in fact, may contain measurable amounts of THC (an intoxicating substance found in cannabis sativa). The study analyzed the contents of CBD-infused beverages, oils, and other products, including chocolate bars, honey, coconut oil, transdermal patches, and more. Of these products, only 15.4 percent were accurately labeled. Unreliable labeling raises concerns about potential exposure to unwanted substances like THC and inconsistent exposure to CBD if used for medicinal purposes. Learn more

FDA Approves Ztalmy® (Ganaxolone) for CDLK5 Deficiency Disorder (CDD): The FDA has approved a new therapy to treat seizures for CDD, a rare epilepsy caused by mutations in the CDKL5 gene. The drug, Ztalmy (ganaxolone), manufactured by Marinus Pharmaceuticals, is now approved to treat seizures associated with CDD in patients 2 years of age and older. This medication is the first FDA-approved treatment specifically for CDD. It is expected to be available for patients in July 2022. Learn more

Vagus Nerve Stimulation (VNS) Lowers Costs of Care for Children with Uncontrolled Epilepsy: A new study examined a population of pediatric patients with drug-resistant epilepsy and found that the patients who received VNS, when used with antiseizure medications (ASM), had lower hospital costs compared to the use of ASMs alone. Vagus nerve stimulators are implantable devices that send mild electrical pulses to the brain by stimulating the vagus nerve.  The researchers note that these results are important because they show lower costs to the health care system following VNS surgery. Learn more

Measuring Quality of Life in Children with Epilepsy: Researchers have found that assessing the days children are minimally impacted by seizures may be a more appropriate method of evaluating severe childhood epilepsies than measuring seizure frequency alone when determining quality of life. The researchers worked with patient advocacy organizations and developed a questionnaire that was distributed to primary caregivers of children with developmental and epileptic encephalopathies (DEEs), a group of severe epilepsies that often have a genetic basis. The researchers found that quality of life scores were strongly associated with the number of days minimally disrupted by seizures rather than seizure frequency alone, an often-used measure of quality of life. These results suggest the need to re-evaluate how disease severity is measured in DEEs. Learn more

Development of Drug Delivery System to Control Seizures: Researchers have developed a system that uses specialized sound waves to release medication into specific areas of the brain to stop seizure activity. So far, the researchers have tested the system in a laboratory setting but envision creating a device that could be triggered by a person when they have an aura before the onset of a seizure, or automatically by a system that detects seizure activity beginning in the brain, activating the release of the drug to stop the seizure from developing. Though the researchers note that further studies are necessary to determine the utility and safety of the technology in humans, they state that this novel new way of delivering drugs could be an effective solution, and a life-changer for some patients with epilepsy. Learn more

Development of an Animal Model of Post-Traumatic Epilepsy (PTE): A team of researchers have created a novel animal model that has spontaneous recurrent seizures after brain injury, similar to the spontaneous recurrent seizures that occur in humans who develop epilepsy following a traumatic brain injury, a type of epilepsy called PTE. In addition to changes in brain activity, the team also found changes in the animals’ behavior and degeneration of neurons in the brain. The team states that this model provides a vital tool to further understand PTE and can be used to test medical treatments to prevent seizures and other neuropsychiatric conditions in military personnel. Learn more

Non-Prescription CBD Product Labeling Largely Inaccurate, Study Finds

Article published by School of Pharmacy University of Wisconsin-Madison

In 2018, the U.S. Food and Drug Administration approved the first prescription medication derived from cannabis sativa: Epidiolex. Used to treat seizures, Epidiolex is purified formulation of cannabidiol (CBD) and has been proven to significantly lower the frequency of seizures in some patients with devastating epilepsy syndromes such as Lennox Gastaut syndrome, Dravet syndrome and tuberous sclerosis complex.

But for patients who can’t afford a prescription or want to augment an existing antiseizure therapy, can that chocolate bar touting CBD on its label be beneficial? According to a team of researchers from the University of Wisconsin–Madison School of Pharmacy — not likely.

An analysis of 39 CBD products from stores across Southwest Wisconsin, led by fourth-year PharmD student Owen Miller, finds that the majority of these products are inaccurately labeled, and in fact, may contain measurable amounts of THC, which leads to inconsistent and unreliable dosing.

“Some of the companies had what they claimed to have, but a lot of them were either over- or very much under-representing the contents of their product,” says Barry Gidal, professor in the School’s Pharmacy Practice Division, who is the senior author on the publication.

Their study, published in Epilepsy and Behavior, used HPLC, or high performance liquid chromatography, to analyze the contents of 39 CBD-infused beverages, oils, and other miscellaneous products, including chocolate bars, honey, coconut oil, transdermal patches, and more. Although not all products specified CBD levels on their labels, just six — 15.4 percent — were accurately labeled.

Clinical Experts Offer Advice on Prescribing Cannabis Medicines to Patients with Epilepsy

Article published in Medical Xpress

There’s considerable interest in using cannabis-based medications to help treat drug resistant epilepsy, but clinicians have little guidance on how or when to prescribe these products. A working group comprised of pediatric and adult epilepsy specialists, clinical pharmacists, pharmacologists, and cannabis researchers from across Australia recently developed an interim “consensus advise” for prescribers and published it in the British Journal of Clinical Pharmacology.

The document provides an overview of the different cannabis medicines currently available for treating epilepsy in children and adults, with information on dose, drug interactions, toxicity, and type and frequency of symptom and seizure relief. The consensus advice will be updated as new evidence emerges and will provide the structure for a more definitive guideline in the future.

Analysis of Cannabidiol (CBD) and THC in Nonprescription Consumer Products: Implications for Patients and Practitioners

Abstract appeared in PubMed

Purpose: Cannabidiol products remains largely unregulated in the US. Unlike the Rx formulation of CBD [EpidiolexR], little information is available regarding labeling accuracy (does the product contain what the label says it does), lot to lot variability, nor long-term product stability.

Understanding these properties are fundamental if these products are to be used in patients with epilepsy, where product variability of traditional AEDs has been suspected to result in inadequate seizure control.

Therefore, we analyzed commercial CBD products, including oils, aqueous products (i.e., beverages), and various Other products for cannabinoid content vs label claims and stability under United States Pharmacopeia (USP) standards.

Method: Samples were diluted and analyzed by HPLC for CBD, THC, and CBN concentrations in order to assess product label accuracy. Products with <90% of label claim CBD were denoted over-labeled, products with >110% of label claim CBD were denoted under-labeled, and products between 90% and 110% of label claim CBD were denoted appropriately labeled, per USP standards.

Results: Among commercial CBD Oils (n?=?11), mean CBD concentration vs label claim was 91.56% [95% CI, 66.02–117.10%], although 18.18% of oils (n?=?2) made nonspecific label claims of “hemp extract” in lieu of CBD. Among all oils, 36.36% (n?=?4) were appropriately labeled, another 36.4% (n?=?4) of all oils were under-labeled, maximum 128.3% label claim, and finally, 9.09% (n?=?1) of oils were over-labeled. The remaining 18.18% (n?=?2) of oils lacked specific CBD label claims, minimum of 0.3?mg CBD per 1-ml “dose”. THC was detected in 54.55% (n?=?6) of oils with a maximum concentration of 0.2% w/v and a minimum concentration of 0.036% w/v. Cannabinol was detectable in only 9.1% (n?=?1) of products at a concentration of 0.00465% w/v.

Among aqueous products (n?=?21) tested, only 66.67% (n?=?14) gave specific CBD label claims, with mean CBD concentration vs label claim of 59.93% [95% CI, 38.24–81.63%]. Only 7.14% (n?=?1) of aqueous products with a label claim were appropriately labeled, 14.29% (n?=?2) were found to be under-labeled, and 78.57% (n?=?11) over-labeled. THC was detected in 23.81% (n?=?5) of aqueous products tested with a maximum THC concentration of 0.0005% w/v, and a minimum concentration of 0.0002% w/v. Cannabinol was detected in 9.52% (n?=?2) of aqueous products, both at a concentration of 0.0015% w/v.

“Other” products (n?=?7) tested ranged from chocolate bars to transdermal patches. Some 42.86% (n?=?3) gave specific CBD label claims, with mean CBD concentration vs label claim of 67.01% [95% CI, 0.87–133.14%]. Among these three “Other” products with specific label claims, 33% (n?=?1) was appropriately labeled, and 66.67% (n?=?2) were over-labeled, with CBD concentrations vs label claim ranging from a minimum of 39.30% to a maximum of 101.99%.

The remaining 57.14% (n?=?5) of “Other” products tested made nonspecific CBD label claims, denoting CBD content in terms of “full spectrum hemp extract” or “activated cannabinoids”. One such product was labeled with a “40–50-mg CBD” range instead of a single, specific value. Tetrahydrocannabinol was detected in 71.43% (n?=?5) of Other products tested with a maximum concentration of 0.0046% w/w, and a minimum concentration of 0.0008% w/w. Cannabinol was detected in 14.3% (n?=?1) of Other products at a concentration of 0.0001% w/w.

Conclusion: We demonstrate that commercial CBD products, especially aqueous beverages, can show inconsistent labeling, vary largely from their label claims should they make them, and show lot-to-lot variability making dosing unpredictable.

Cannabidiol (CBD) and Cognition in Epilepsy

Abstract, originally published in Epilepsy & Behavior

Anecdotal reports of the benefits of cannabis and its components in the treatment of epilepsy have been reported for millennia. However, only recently randomized controlled trial data in support of cannabidiol (CBD) became available resulting in its FDA approval for the treatment of seizures and epilepsy. One of the most common and debilitating comorbidities of epilepsy is cognitive impairment. This impairment has a multifactorial etiology including network dysfunction due to seizures, negative cognitive side effects from anti-seizure medications (ASMs), and mood disturbances.

Knowing the effects of a particular ASM (either positive or negative) is vital for providers to counsel patients on expected side effects, and may result in choosing a particular regimen over the other if the patient already suffers from significant cognitive deficits. Unlike most other ASMs and other well-studied cannabinoids such as ?9-tetrahydrocannabinol, CBD has been shown to have additional mechanisms of action (MOA) that result in neuroprotective, anti-inflammatory, anti-oxidant, and neurogenesis effects. These additional MOAs suggest that the use of CBD could lead to other actions including positive effects on cognition that may be independent of seizure control.

This targeted review discusses the currently available data on CBD’s effects on cognition in epilepsy. First, we review the proposed mechanisms by which CBD could exert effects on cognition. Then, we present the pre-clinical/animal data investigating cognitive effects of CBD in seizure/epilepsy models. Finally, we discuss the available human data, including the studies in people with epilepsy that included cognitive evaluations pre- and on-CBD, and studies investigating if CBD has any effects on brain structure or function in areas pertinent to memory and cognitive functions.

Seizure Frequency, Quality of Life, Behavior, Cognition, and Sleep in Pediatric Patients Enrolled in a Prospective, Open-Label Clinical Study with Cannabidiol

Abstract, originally published in Epilepsy & Behavior

Objective: To evaluate the effects of oral pharmacological cannabidiol (CBD) on seizures, side effects, quality of life, behavior, mood, and sleep in children with drug-resistant epilepsy (DRE) during a phase II, prospective, open-label clinical study.

Methods: During a phase II expanded access program (EAP) study to evaluate the safety and efficacy of using cannabidiol (CBD) for the long-term treatment of children with drug-resistant epilepsy, secondary outcome measures were also performed, including quality of life (QOLCE), behavior (aberrant behavior checklist ABC), and sleep (children’s sleep habit questionnaire, CSHQ). Participants between the ages of 2 and 16 years of age with drug-resistant epilepsy (n = 35) were included in this EAP. Primary outcomes included change in parent-recorded seizure frequency relative to baseline, as well as the safety and tolerability over the course of 24 months of CBD treatment. Secondary outcomes observed in the first 12 months included changes in child behavior, and cognitive function, and sleep quality.

Results: The median change in overall seizure frequency decreased from baseline (n = 33) by -61.3% ([n = 33], Inter Quartile Range (IQR): 43-88%) at month 3, -62.9% at month 6 ([n = 29], IQR: 48-92%), -74.7% at month 12 ([n = 29], IQR: 64-96%), and finally -83.7% ([n = 28], IQR: 68-100%) at the conclusion of 24 months of treatment. Seven (20%) of the 35 patients enrolled withdrew from treatment and observation by month 24: 2 failed inclusion criteria at baseline, 4 due to lack of treatment efficacy, and 1 was lost to follow-up. The 12-month recording of secondary measures revealed a significant improvement in Irritability (-39.4%, [n = 28], ABC), Hyperactivity (-45.4%, [n = 28], ABC), Cognition in Quality of Life (+14.2%, [n = 28], QOLCE), Behavioral function (+14.7%, [n = 28], QOLCE), General Health (+14.7%, [n = 28], QOLCE), Sleep duration (-33.9%, [n = 28], CSHQ), Daytime sleepiness (-23.8%, [n = 28], CSHQ), and nocturnal arousals (-36.2%, [n = 28], CSHQ).

Significance: The results of this phase II open-label study demonstrate that pharmacological CBD significantly reduces seizure frequency, and improves quality of life, behavior deficits, and sleep disruption, in children with drug-resistant epilepsy. The results also suggest that CBD is efficacious in controlled seizures over a 2-year period in childhood drug-resistant epilepsy.

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.