ARTICLE IN BRIEF
THE CANNABIDIOL oil was derived from a substance in the cannabis plant and does not contain the psychoactive component of cannabis, tetrahydrocannabinol.
Several animal studies, as well as open-label and placebo-controlled trials have shown the potential that cannabidiol can have on reducing seizures, but still more research is needed to understand the safe and optimal dosing, and the effect of the cannabidiol on levels of antiepileptic drugs.
HOUSTON—Several animal studies and both randomized and open-label studies have found that cannabidiol oil (CBD) shows promise in treating seizure disorders, but questions remain about proper dosages to apply, the potential for adverse effects, and the drug-drug interactions with other antiepileptic drugs (AEDS), according to several abstracts that were presented here in December at the annual meeting of the American Epilepsy Society.
In one abstracts, study authors reported that the extract appeared to affect blood levels of other AEDs, potentially affecting seizure control.
“We need scientific evidence that we can take back to our patients,” said Jacqueline A. French, MD, FAAN, professor of neurology and director of translational research and clinical trials in epilepsy at the New York University Comprehensive Epilepsy Center and an investigator in the double-blind clinical study testing CBD oil in patients with Lennox Gastaut syndrome“. The study shows that there are benefits and risks. This is not a miracle drug but one that could benefit patients with epilepsy.”
DR. JOSEPH I. SIRVEN: “These studies are further proof that the concept of medical cannabis has moved from a fringe concept to that of a serious science. Cannabidiol is being treated like all medications that have been investigated for potential approval as an anti-epileptic drug.”
DR. TYLER GASTON: “This is a new potential antiepileptic drug, and if levels of other antiepileptic medicines are changing, that is very important information. We just don't know if all of the interactions noted will become clinically significant interactions. A perception exists that CBD is natural and safe, but this is why formal studies need to be done.”
DR. JACQUELINE A. FRENCH: “We need scientific evidence that we can take back to our patients.”
Developed by GW Pharmaceuticals, the CBD drug, Epidiolex, was derived from a substance in the cannabidiol plant and does not contain the psychoactive component of cannabis, tetrahydrocannabinol.
LENNOX-GASTAUT SYNDROME
CBD reduced the frequency of drop seizures in patients with Lennox-Gastaut syndrome by 44 percent compared to 22 percent in those on a placebo dose, according to results from the first multicenter double-blind study in patients with this severe form of childhood-onset epilepsy characterized by frequent seizures and moderate to severe intellectual impairment.
The multicenter study, led by Elizabeth Thiele, MD, PhD, director of the pediatric epilepsy program and the Carol and James Herscot Center for Tuberous Sclerosis Complex and professor of neurology at Harvard Medical School, enrolled 171 children and adults, ranging in age from 2 to 55 years old, from the US, Poland, and the Netherlands. Participants had all taken at least six AEDs to control their seizures; at the time of the enrollment, they were taking on average three different AEDs. They had at least two drop seizures a week but the median drop seizure frequency over a 28-day period was 74.
Half received CBD and the others, a placebo dose. The patients randomized to the CBD arm received a pharmaceutical formulation of 100 mg/mL in oral solution at a dose of 20 mg/kg per day or matched placebo. There was a two-week dose escalation phase at the start of the study.
The primary endpoint was a reduction in drop seizure frequency over the 14-week treatment period. During the study, 14 CBD patients and one on placebo dropped out.
Those taking CBD showed a significant percent reduction in monthly drop seizure frequency (44 percent versus 22 percent, p=0.0135.) The benefit emerged during the first month and continued throughout the 14-week period. Three of the 86 CBD patients had no drop seizures during the maintenance phase of the study, according to the scientists.
The side effects were significant, however, with 86 percent of the CBD patients and 69 percent of those on placebo reporting symptoms. Seventy-eight percent of the symptoms were mild to moderate, the researchers said. More than 10 percent of patients in either group had diarrhea, vomiting, decreased appetite, somnolence and pyrexia.
CBD SIDE EFFECTS: LENNOX-GASTAUT SYNDROME AND DRAVET SYNDROME
DRAVET SYNDROME
In another study, scientists studied the safety and pharmacokinetics of several different CBD doses in 34 DS patients ranging in age from 4 to 10 years old. They were randomized to receive one of three CBD doses or a placebo that was added to their antiseizure regimen, which included on average three AEDs. Almost one in five reported somnolence compared to 14 percent in the placebo group and pyrexia (22 percent), decreased appetite (19 percent), and sedation (15 percent) in only those taking CBD.
The researchers also reported efficacy data on 120 patients enrolled in a multicenter double-blind placebo-controlled study: 43 percent of the patients on CBD had more than a 50 percent reduction in convulsive seizures compared to 27 percent of those on a placebo. Three of the patients on CBD achieved convulsive and total seizure freedom during the treatment period and four others during the maintenance phase of the study. By comparison, no one in the placebo arm met this outcome.
DR. ADAM L. HARTMAN: “Even though we do not fully understand the antiseizure mechanism of CBD, it might be a reasonable option for some patients. Determining which patients might benefit most would be very helpful. As with any treatment, there needs to be a thoughtful consideration of potential benefits and risks.”
“These placebo-controlled studies demonstrate that Epidiolex provides clinically meaningful reductions in seizure frequency together with an acceptable safety and tolerability profile,” said Orrin Devinsky, MD, FAAN, director of the New York University Langone Medical Center's Comprehensive Epilepsy Center and a principal investigator of the Dravet syndrome trial.
IMPORTANT DRUG-DRUG INTERACTIONS
Cannabidiol oil can interact with AEDs, altering their blood levels and potentially leading to adverse events, according to researchers at the University of Alabama at Birmingham.
“This is a new potential antiepileptic drug, and if levels of other antiepileptic medicines are changing, that is very important information,” said Tyler Gaston, MD, an instructor in neurology at University of Alabama at Birmingham, who presented the findings at the meeting. “We just don't know if all of the interactions noted will become clinically significant interactions. A perception exists that CBD is natural and safe, but this is why formal studies need to be done.”
Ultimately, the team will be correlating this data with reported side effects. “The study emphasizes the importance of monitoring AED levels during treatment with CBD,” said Dr. Gaston. The findings are part of a larger open-label treatment study led by UAB's Jerzy Szaflarski, MD, PhD, professor of neurology and director of the epilepsy center, and E. Martina Bebin, MD, professor of neurology. The state provided funding following passage of Carly's Law in 2015 that allowed the university to conduct the study. Parent groups led the way for the passage of the bill.
DR. CYNTHIA HARDEN: “These studies change the conversation with our patients who ask us about taking CBD, which is perceived by the public to be natural and safe since it is derived from marijuana. They point out that with medicalization and concentration of the active compound, the risks and benefits of CBD use for epilepsy patients become clearer. Therefore, CBD effectiveness must be considered with the same scrutiny and caution as with any pharmaceutical anti-seizure medication under development.”
The scientists enrolled 39 adults and 42 children, all of whom were prescribed Epidiolex, a CBD oil manufactured by GW Pharmaceuticals. These patients continued to have seizures despite trying at least four AEDs. At the time of the study, they were taking an average of two AEDs. They kept daily seizure diaries, and every two weeks they traveled to the hospital for blood tests, including blood counts, liver function tests, and measurements of drug levels for each medication they were taking.
The CBD dose was titrated, starting at 5 mg/kg per day and increased to tolerability and seizure control every two weeks by 5 mg/kg per day up to a maximum of 50 mg/kg per day. The researchers had baseline data of blood levels for the AEDs the participants were taking; throughout the study the investigators adjusted the doses if they thought that there were drug-drug interactions.
Dr. Gaston said clobazam and valproate doses were frequently adjusted because of increasing sedation and/or alterations in liver function tests. The scientists looked for changes in serum levels of 19 AEDs as the dose of CBD was increased.
Serum levels of topiramate (p<0.01), rufinamide (p<0.01), and desmethyclobazam (p<0.01), an active metabolite of clobazam, were increased. The researchers also found decreased levels of clobazam (p<0.01) as the dose of CBD increased in children and adults. They also observed a significant increase in serum levels of zonisamide (p=0.02) and eslicarbazepine (p=0.04) as the CBD dose was increased in the adults only. In addition, increased reports of sedation were seen in adults with higher desmethylclobazam levels.
In other data presented at the meeting the team reported that the frequency and severity of seizures improved in the majority of patients, but not all. A few patients worsened, said Dr. Szaflarski, who added that more research is needed, including determining why and how CBD helps some people with epilepsy. Children appeared to have greater benefits in seizure frequency and severity than adults in the study, the researchers reported.
Daniel Friedman, MD, an epileptologist and clinical neurophysiologist at the New York University Comprehensive Epilepsy Center, who was not involved with the research, said the study confirms that CBD can interact with AEDs. “We knew about the changing levels of the clobazam metabolite but there were other drugs that would not have been predicted to change.”
“This tells us that some drug-drug interactions will have to be studied more carefully. Many epilepsy patients take multiple drugs to control their seizures. Patients using CBD therapeutically or recreationally need to be aware that it may lead to changes in blood levels of their other medications.”
EXPERTS COMMENT
Several epilepsy experts who were not involved with the CBD trials spoke of the importance of reviewing the new study data. “These studies change the conversation with our patients who ask us about taking CBD, which is perceived by the public to be natural and safe since it is derived from marijuana,” said Cynthia Harden, MD, system director of the clinical epilepsy service at the Icahn School of Medicine at Mount Sinai. “These studies point out that with medicalization and concentration of the active compound, the risks and benefits of CBD use for epilepsy patients become clearer. Therefore, CBD effectiveness must be considered with the same scrutiny and caution as with any pharmaceutical anti-seizure medication under development.”
Joseph I. Sirven, MD, FAAN, professor of neurology and chairman of the department of neurology at the Mayo Clinic in Phoenix, AZ, said: “These studies are further proof that the concept of medical cannabis has moved from a fringe concept to that of a serious science. Cannabidiol is being treated like all medications that have been investigated for potential approval as an anti-epileptic drug.”
“Even though we do not fully understand the antiseizure mechanism of CBD, it might be a reasonable option for some patients,” added Adam L. Hartman, MD, program director in the division of clinical research at the National Institute of Neurological Disorders and Stroke. “Determining which patients might benefit most would be very helpful. As with any treatment, there needs to be a thoughtful consideration of potential benefits and risks.”
NEW SEIZURE MODEL SHOWS CBD WORKS
Scientists at the University of Utah have shown that cannabidiol significantly reduces seizure frequency and burden in a viral infection-induced animal model of limbic epilepsy.
Misty D. Smith, PhD, research assistant professor in pharmacology and toxicology, worked with cannabidiol in an acute seizure model and found that it worked synergistically in combination with levetiracetam to control the frequency of limbic seizures. To expand these findings, she wanted to test the plant-based substance in animals with a chronic seizure disorder.
The Theiler's murine encephalomyelitis virus (TMEV) model has been shown by other investigators at the University of Utah to cause limbic seizures. The TMEV-infected mice also demonstrate histopathologic signs of chronic epilepsy, including neuronal death, gliosis, increased oxidative stress biomarkers, increased expression of multiple inflammatory cytokines, and comorbid behaviors seen in chronic human epilepsy: anxiety and cognitive deficits.
Dr. Smith and her colleagues used the virus to infect the brains of five- to six-week-old C57BL6/J mice. Within three days after the onset of seizures, the investigators began treating groups of TMEV-infected mice every 12 hours for five days with a range of doses of cannabidiol or a vehicle mixture of ethanol, castor oil, and saline. They monitored the animals for seizure activity and frequency four times a day. Animals on the highest dose of cannabidiol had a significant reduction in both seizure frequency and cumulative seizure burden compared to the vehicle-treated animals. The team of researchers administering the treatments and scoring the seizure activity were blinded to the treatment group.
The investigators also wanted to determine if cannabidiol was neuroprotective. They asked: Did the histopathology in the hippocampus of viral-infected mice change in response to the treatment with the 180 mg/kg dose of cannabidiol?
Dr. Smith said that although the subchronic dosing with the 180 mg/kg dose of cannabidiol had significantly reduced the seizure frequency and burden, neuronal loss in the hippocampus was not significantly different than that of the non-treated animals, suggesting that CBD's antiseizure effect was not neuroprotective in the hippocampus.
“The TMEV model is an important tool to study the mechanism(s) underlying epileptogenesis and disease modification by novel AEDs,” said Dr. Smith. “Our goal is to find an optimal dose of CBD that effectively ameliorates seizure activity and/or comorbidities without many of the adverse effects associated with anti-seizure drugs.”
“The findings so far are a green light,” she said, adding that future studies are being designed to test whether CBD reduces any of the other pathologies that they see, including inflammatory changes, anxiety-like behaviors, or cognitive deficits observed in the TMEV-infected mice.
The initial study was funded through the Epilepsy Foundation's Targeted Research Initiative for Research Regarding CBD in Epilepsy.
“This is a helpful study,” said NYU's Dr. Devinsky. “There have now been more than 20 animal species and epilepsy models for which CBD has been found to be effective.”
“It's always hard to know how doses in animals will translate to humans,” added Kimford J. Meador, MD, FAAN, professor of neurology and neurological sciences at Stanford University School of Medicine. “It's hard to scale from mice to humans, but it is an interesting finding.”
—Jamie Talan
