In a series of articles published online May 22 in Epilepsia, experts in the field weigh in on the past, present, and future role of cannabis in the treatment of this disease.
“Rarely in recent memory has there been such interest and public discussion about the potential use of marijuana and one of its active substances cannabidiol (CBD) in the treatment of various neurological conditions,” especially refractory seizures and catastrophic epilepsies, the Epilepsia editorial team, Gary Mathern and Astrid Nehlig, co-editors in chief, and Michael Sperling, associate editor, in an opening editorial.
In his piece, Edward Maa, chief, Comprehensive Epilepsy Program, Denver Health and Hospitals, Colorado, described the heart-breaking case of Charlotte Figi, whose first seizure occurred at the age of 3 months and who was later diagnosed with Dravet syndrome.
Charlotte did not respond to many antiseizure medications or to the ketogenic diet, was experiencing up to 50 generalized tonic-clonic (GTC) seizures a day, and had substantial cognitive and motor delays.
Then she tried CBD, the major nonpsychoactive component of cannabis; the major psychoactive component is A-tetrahydrocannabinol or THC. While THC works mainly on the CB1 receptors of the endocanninoid system, CBD’s mechanism of anticonvulsant action is unknown. However, according to some experts, a likely mechanism is its ability to bind to the GPR55 receptor, which influences calcium activity.
From a baseline frequency of at least 300 convulsions per week, within 3 months of taking a high concentration of a CBD extract, administered sublingually, Charlotte had a greater than 90% reduction in GTC seizures and had been weaned from her other antiepileptic drugs, Dr. Maa reported.
Then, at 20 months after starting to take what is dubbed “Charlottes’ Web,” Charlotte had only 2 to 3 nocturnal GTC seizures a month, was feeding and drinking orally and on her own, sleeping soundly through the night, and walking and talking again, said Dr. Maa. He added that her autistic behaviors, such as self-injury and aggressiveness, have improved.
Cannabis sativa, one of the compounds derived from the marijuana plant (the other is C indica), has a long history of medicinal use, dating back to 4000 BC, when it was a treatment for convulsions, rheumatism, and pain in China. But Dr. Maa noted that since then, there have been conflicting reports on the efficacy of cannabis in treating seizures, probably due to the complexity of the plant itself.
“Cannabis sativa has 489 known constituents, only 70 of which are cannabinoids, with the remainder including potentially neuroactive substances, such as terpenes, hydrocarbons, ketones, aldehydes, and other small hydrophobic compounds capable of crossing the blood-brain barrier.”
In addition, he said, the mode of administration probably affects bioavailability and neuroactivity. For example, smoked and vaporized cannabis requires heat, which may alter the putative antiepileptic substances, while ingested cannabis must survive the acidic environment of the stomach and first-pass metabolism.
Although there’s growing excitement over Epidiolex, the pharmaceutical-grade CBD plant extract being developed by GW Pharma, access to the clinical trial sites is difficult and many families don’t want to wait the “countless years” for approval, said Dr. Maa.
Some are moving to states where cannabis has been legalized, including Colorado, a state that gave him the “green light” to use the Charlotte’s Web extract. Some desperate parents are apparently trying to extract whole plant compounds themselves.
Confirm or Disprove
Amid the emotional turmoil of families and the challenges of using medical marijuana as a potential epilepsy therapy, Dr. Maa called for calm and “a thoughtful and thorough pharmacologic and clinical investigation” into cannabis and its constituent compounds to “confirm or disprove” its safety and potential efficacy.
“Growers and regulators must satisfy concerns about consistency, quality, and safety before medical cannabis will ever gain legitimacy as a mainstream therapeutic option,” he writes. “Investigations involving children with catastrophic epilepsy syndromes require well-conceived, double-blinded placebo protocols.”
In an invited article on the topic, Orrin Devinsky, professor, neurology, neurosurgery and psychiatry, and director, Comprehensive Epilepsy Center, NYU Langone Medical Center, New York, and his coauthors reviewed the history of cannabis and its derivatives in the treatment of epilepsy and the clinical pharmacology of its neuroactive components.
Dr. Orrin Devinsky
They also summarized research into the potential of cannabinoids in other neurologic and psychiatric disorders, including psychosis, anxiety disorders, and addictive behavior, and discussed avenues for future clinical trials.
In an interview with Medscape Medical News, Dr. Devinsky described the “major disconnect” in term of the status of medical marijuana in the United States.
“There are states like Colorado where parents are giving their young children medical marijuana with psychoactive THC and dosing it on their own, while the federal government’s Drug Enforcement [Administration] has the nonpsychoactive CBD derived from cannabis plants as a schedule 1 drug, making it extremely difficult for researchers to assess the safety and efficacy of the drug.”
Dr. Devinsky said the medical profession is at “an inflection point” in terms of acceptance of cannabis as a treatment option for epilepsy. “We all agree that there are good data about the effectiveness of CBD and THC in some animal models of epilepsy, but we lack any well-controlled human data about the effectiveness of these compounds or medical marijuana to treat epilepsy.”
He added that while there are good safety data in adults, such data are lacking in children.
“There is still disagreement about whether children with epilepsy should be treated with medical marijuana,” he said. “Some feel that the benefits far outweigh the risks, especially considering that many of FDA [Food and Drug Administration]-approved antiepileptic drugs have disabling side effects — especially when used at high doses in combination. Others feel that the potential toxicity of THC and possibly CBD on the developing nervous system do not warrant use without better data.”
Safety was a theme explored in an essay by Maria Roberta Cilio, professor, neurology and pediatrics and director, Pediatric Epilepsy Research, University of California, San Francisco. She and her colleagues, including Dr. Devinsky, outlined the limited knowledge available on the safety and utility of cannabidiol in epilepsy and noted that the sparse clinical research is due in part to legal restrictions.
Dr. Maria Roberta Cilio
The lack of regulation and standardization in the medical cannabis industry “raises concerns regarding the composition and consistency of the products that are dispensed,” write the authors. Most parents purchase cannabis extracts from a dispensary or a cannabis grower and the preparations may contain different percentages of CBD and THC, as well as other cannabinoids and compounds.
“Their concentration can vary based on the plant clones, weather, soil, and other factors,” they note. “Most importantly, there are no controlled data on the use of these preparations.”
Dr. Cilio stressed the need to consider the negative effects of cannabis in the developing brain. She noted recent research showing that cannabis has adverse effects in children younger than age 15 years, including a risk for psychosis and long-term impairment of executive function.
“We are not talking about an older person who smokes marijuana once, twice, or three times a week; we are talking about a developing brain that is receiving a product, a compound, every single day, day and night, possibly for years,” as a therapy to control seizures, she told Medscape Medical News in an interview.
It’s important, she added, to overcome the common and potentially dangerous belief that treatments derived from natural products are safer or more effective than synthetic ones.
“There is this assumption that because it’s natural and organic, it must be good,” but some products that are derived from plants, such as belladonna and digitalis, can be lethal, Dr. Cilio said.
The only available efficacy data are anecdotal reports, said Dr. Cilio. She cited a recent survey of 19 parents in which 53% reported a greater than 80% reduction in seizure frequency in their children with epilepsy. But the survey was sent to a “very select group” of parents, and not all the ages of the children or their exact diagnosis was known, she said.
However, with CBD’s lack of THC and therefore related risks at younger ages, its safety profile, and its efficacy in preclinical studies, this compound appears to be an “excellent candidate” to evaluate in patients with treatment-resistant epilepsy, said Dr. Cilio.
A “reasonable” development program would obtain initial observations from a dose tolerability and pharmacokinetic study and then include prospective randomized controlled trials in select populations of patients with treatment-resistant epilepsies. Dravet syndrome and Lennox-Gastaut syndrome are attractive because they are orphan disorders in which drug development can be rapid, she said.
Dr. Cilio is involved in a phase 1 open-label study of Epidiolex at 5 centers in the United States. The study aims to enroll a total of 125 children, aged 1 to 18 years, who have intractable epilepsy and in whom at least 2 therapies have failed, although most will have not responded to more therapies that. After 3 months, those who show benefit will continue to be treated for at least a year, said Dr. Cilio.
She said she expects to have some study results by the end of this year.
The Epilepsia editors invite physicians to submit related topics of broad interest to the journal and to participate in an online poll on the issue of cannabis use in epilepsy. Visithttp://surveys.verticalresponse.com/a/show/1539433/4235ab9776/0 to complete the questionnaire, which will be posted on the site until September 1, 2014.