More Evidence That CBD Reduces Seizures
— Two doses show similar efficacy in Dravet syndrome
by Judy George, Senior Staff Writer, MedPage Today April 30, 2019
PHILADELPHIA — Cannabidiol (Epidiolex) as an add-on anticonvulsant treatment cut convulsive seizures nearly in half among children with Dravet syndrome, a dose-ranging phase III placebo-controlled study found.
After 14 weeks, two doses showed similar efficacy, according to Ian Miller, MD, of Nicklaus Children’s Hospital in Miami, and colleagues in an abstract that will be presented at the Emerging Sciences session of the American Academy of Neurology meeting next week.
Convulsive seizures decreased by 46% in children taking 20 mg/kg/day and 49% for children taking 10 mg/kg/day of cannabidiol, compared with 27% for placebo, they reported. Elevated transaminases and certain adverse events were higher in patients taking cannabidiol 20 mg/kg/day, and discontinuations due to adverse events occurred only in that group.
“Based on these results, dose increases above 10 mg/kg per day should be carefully considered based on the effectiveness and safety for each individual,” Miller said in a statement.
“The children in this study had already tried an average of four epilepsy drugs with no success and at the time were taking an average of three additional drugs, so to have this measure of success with cannabidiol is a major victory,” he added.
Dravet syndrome is an infantile-onset developmental and epileptic encephalopathy associated with drug-resistant seizures. Epidiolex is a pharmaceutical formulation of highly purified cannabidiol in an oral solution and was approved by the FDA last year to treat Dravet syndrome and Lennox-Gastaut Syndrome, another rare form of epilepsy.
Cannabidiol is a component of the Cannabis sativa plant that does not cause the intoxication that comes from tetrahydrocannabinol (THC). It is structurally unrelated to other anti-seizure medications and its anticonvulsant mechanism is unknown.
In this multi-center, randomized, double-blind trial (GWPCARE2), researchers studied 199 patients with Dravet syndrome: 67 received cannabidiol 20 mg/kg/day, 67 received cannabidiol 10 mg/kg/day, and 65 received placebo. The primary endpoint was the change in convulsive seizure frequency over a 14-week treatment period, compared with a 4-week baseline.
The mean age of patients was 9 years, and patients were taking a median of three antiepileptic drugs, after having discontinued a median of four drugs.
In both cannabidiol groups, the percentage reduction in convulsive seizures was higher compared with placebo (P=0.0299 for 20 mg/kg/day; P=0.0095 for 10 mg/kg/day). The reduction in total seizures also was higher.
The incidence of adverse events was similar across all groups (90% for the 20-mg dose, 88% for the 10-mg dose, and 89% for placebo) and most commonly included decreased appetite, diarrhea, somnolence, pyrexia, and fatigue. Serious adverse events were reported in 25% of the 20-mg group, 20% of the 10-mg group, and 15% of the placebo group. Only in the 20-mg group did patients discontinue because of serious adverse events (7%).
Elevated transaminases exceeding three times the upper limit of normal occurred in 19% of the 20-mg group and 5% of the 10-mg group, but none had elevations in bilirubin; all were taking concomitant valproate and all elevations resolved. There were no deaths, the researchers reported.
Miller will present detailed findings of this study at the Pennsylvania Convention Center Poster Hall, at 11:45 a.m. ET on Tuesday, May 7. The research adds to an expanding bank of literature about Dravet syndrome and cannabidiol; earlier this year, an open-label extension trial showed that long-term cannabidiol treatment over a median of 274 days had an acceptable safety profile and led to sustained reductions in seizure frequency.
The study was supported by GW Research, operating in the U.S. through its affiliate, Greenwich Biosciences.
Miller disclosed relevant relationships with Insys pharmaceuticals, GW Pharma, the TS Alliance, the DS Foundation, Visualase, NeuroBlate, Zogenix, and Ultragenyx. Co-authors disclosed multiple relevant relationships with industry including Greenwich Biosciences.
Whole-Plant Cannabis Extract Reduces Epileptic Seizures By 86% in Small Study
A small study of children with treatment-resistant epilepsy has found that whole-plant cannabis therapies reduced seizures by 86 percent, according to research published recently by the journal BMJ Paediatrics Open.
To conduct the study, researchers collected retrospective clinical data from caretakers and clinicians of 10 children with intractable, or drug-resistant, epilepsy. All 10 patients recruited for the study had not responded to CBD products.
When the patients were given a whole-plant cannabis oil containing THC, CBD, and other cannabinoids as well as compounds including terpenes and flavonoids, the frequency of their seizures decreased by nearly 90 percent.
“Seizure frequency across all 10 participants reduced by 86 percent with no significant adverse events,” the authors of the study wrote.
The dosage of cannabis oil was determined by each patient’s physician. On average, the children in the study received about 5mg of THC per day, although they did not get high from the medication. Parents reported results to researchers by phone or via video conference calls. Few adverse effects, including excessive tiredness before exact dosing was determined, were reported to researchers.
“All parents reported that the whole-plant products were well-tolerated and the children showed improvements in their mood, behavior, eating anding as well as substantial improvements in their cognitive [mental] abilities,” said study author Rayyan Zafar, a fellow at the Centre for Psychedelic Research and Neuropsychopharmacology at Imperial College London.
The research also revealed that using the cannabis oil resulted in a dramatic reduction in the number of other medications taken by the patients in the study. At the onset of the research, patients were taking multiple medications daily, a figure which declined significantly after treatment with cannabis oil was begun.
“Participants reduced use of antiepileptic drugs from an average of seven to one following treatment with medical cannabis,” the researchers wrote.
Researchers Support Improved Access to Cannabis Therapies
Although U.K. Home Secretary Sajid Javid (now the Secretary of State for Health and Social Care) announced in 2018 that cannabis medicines would be made available to patients “with an exceptional clinical need,” so far few patients have received a prescription from the National Health Service. The authors of the study “noted significant financial costs of £874 per month to obtain these medicines through private prescriptions” and believe that the data collected on whole-plant cannabis therapies provide evidence to introduce such medications into the NHS under current prescribing guidelines.
“Such a move would be hugely beneficial to the families, who in addition to having the psychological distress of looking after their chronically ill children, have also to cover the crippling financial burden of their medication,” the authors concluded.
Parents Cautioned Against Unsupervised Cannabis Treatment for Seizures
Dr. Kevin Chapman, a neurologist at the Phoenix Children’s Hospital and spokesperson for the American Epilepsy Society, said that more research is needed and warned parents not to try to medicate their children with cannabis from a dispensary, saying “it’s still buyer beware.”
“There isn’t enough evidence to support using these products at this time especially instead of prescribed epilepsy treatments,” Chapman said.
The authors of the study acknowledged that there are risks treating young people with psychoactive compounds, but noted that commonly used medications for epilepsy also have serious side effects. Dr. Peter Grinspoon, a primary care physician at Massachusetts General Hospital in Boston and a board member of the advocacy group Doctors for Cannabis Regulation who was not involved in the study, noted that worries about how cannabis therapies may affect children should be considered in the context of the risks associated with other commonly used medications.
“I’d imagine that any concerns about the use of THC in a pediatric population would be at least in part alleviated by the drop of anti-epileptic drugs, many of which have side effects,” Grinspoon told UPI.
“It is not difficult to understand why there is such a determined parents’ movement in support of access to cannabinoids for pediatric epilepsy,” he added.
The researchers noted that the individual dosage and blend of cannabis oil was tailored to each patient by their doctors and warned against using the medication without proper supervision.
“Medical oversight is important,” Zafar said. “We encourage parents interested in using these medicines for these children to approach clinics and discuss this option with their physician.”
The authors of the research cited several limitations of the study, including using data that was retrospective and relied on caregiver recall, although parents often kept diaries for recording seizures as documentation of their experiences as they occurred. They also noted that the study was not randomized and did not include a placebo group with which to compare results.
Researchers also cited the small sample size of the study as a limitation, but noted that the results were consistent with other research. The authors called for further study into the benefits of whole-plant cannabis products for epilepsy patients who experience seizures.
A report on the research, “Medical cannabis for severe treatment resistant epilepsy in children: a case-series of 10 patients,” was published on December 14 by BMJ Paediatrics Open.