Long-Term Efficacy and Safety of Cannabidiol (Epidiolex®) in Patients with Treatment-Resistant Epilepsies: 4-Year Results from the Expanded Access Program

Abstract found on PubMed

Objective: Cannabidiol (CBD) expanded access program (EAP), initiated in 2014, provided add-on CBD to patients with treatment-resistant epilepsy (TRE) at 35 US epilepsy centers. Prior publications reported results through December 2016; herein, we present efficacy and safety results through January 2019.

Methods: Patients received plant-derived highly purified CBD (Epidiolex®; 100 mg/mL oral solution), increasing from 2-10 mg/kg/d to tolerance or maximum 25-50 mg/kg/d dose, depending on the study site. Efficacy endpoints included percentage change from baseline in median monthly convulsive and total seizure frequency and ?50%, ?75%, and 100% responder rates across 12-week visit windows for up to 192 weeks. Adverse events (AEs) were documented at each visit.

Results: Of 892 patients in the safety analysis set, 322 (36%) withdrew; lack of efficacy (19%) and AEs (7%) were the most commonly reported primary reasons for withdrawal. Median (range) age was 11.8 years (0-74.5), and patients were taking a median (range) 3 (0-10) antiseizure medications (ASMs) at baseline; most common ASMs were clobazam (47%), levetiracetam (34%), and valproate (28%). Median top CBD dose was 25 mg/kg/d; median exposure duration was 694 days. Median percentage reduction from baseline ranged from 50%-67% for convulsive seizures and 46%-66% for total seizures. Convulsive seizure responder rates (?50%, ?75%, and 100% reduction) ranged from 51%-59%, 33%-42%, and 11%-17% of patients across visit windows, respectively. AEs were reported in 88% of patients and serious AEs in 41%; 8% withdrew because of an AE. There were 20 deaths during the study deemed unrelated to treatment by the investigator. Most common AEs (?20% of patients) were diarrhea (33%), seizure (24%), and somnolence (23%).

Significance: Add-on CBD was associated with sustained seizure reduction up to 192 weeks with an acceptable safety profile and can be used for long-term treatment of treatment-resistant epilepsies.

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.