Cannabidiol significantly reduces seizures in patients with severe form of epilepsy
Study looked at two doses of cannabis-derived medication's effectiveness in Lennox-Gastaut syndrome
May 16, 2018
Science Daily/NYU Langone Health / NYU School of Medicine
Cannabidiol (CBD), a compound derived from the cannabis plant that does not produce a "high" and has been an increasing focus of medical research, was shown in a new large-scale, randomized, controlled trial to significantly reduce the number of dangerous seizures in patients with a severe form of epilepsy called Lennox-Gastaut syndrome.
In the new study comparing two doses of CBD to a placebo, the researchers reported a 41.9 percent reduction in "drop seizures" -- a type of seizure that results in severe loss of muscle control and balance -- in patients taking a 20 mg/kg/d CBD regimen, a 37.2 percent reduction in those on a 10 mg/kg/d CBD regimen, and a 17.2 percent reduction in a group given a placebo.
The phase III trial was led by principal investigator and study first co-author Orrin Devinsky, MD, a professor of neurology, neurosurgery, and psychiatry at NYU School of Medicine and director of NYU Langone's Comprehensive Epilepsy Center, and was published online May 17 in The New England Journal of Medicine.
"This new study adds rigorous evidence of cannabidiol's effectiveness in reducing seizure burden in a severe form of epilepsy and, importantly, is the first study of its kind to offer more information on proper dosing," says Dr. Devinsky. "These are real medications with real side effects, and as providers we need to know all we can about a potential treatment in order to provide safe and effective care to our patients."
The study included an investigational liquid, oral formulation of CBD called Epidiolex. The product is manufactured by GW Pharmaceuticals, which operates in the U.S. as Greenwich Biosciences; GW Pharmaceuticals funded the clinical trial.
Safety of Two CBD Doses Studied
Lennox-Gastaut syndrome is a rare and severe form of epilepsy characterized by frequent drop seizures and severe cognitive impairment. Six medications are approved to treat seizures in patients with the syndrome, but disabling seizures occur in most patients despite these treatments.
Researchers enrolled 225 patients (age 2 to 55) with Lennox-Gastaut syndrome across 30 international sites in a randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of two doses of CBD: Seventy-six patients received 20 mg/kg/d CBD, 73 received 10 mg/kg/d CBD, and 76 were given a placebo. All medications were divided into two doses per day for 14 weeks. The number of seizures were monitored beginning four weeks prior to the study for baseline assessment, then tracked throughout the 14-week study period and afterwards for a four-week safety check.
Side effects occurred in 94 per of patients in the 20 mg CBD group, 84 percent in the 10 mg CBD group, and 72 percent of those taking placebo. Side effects were generally reported as mild or moderate in severity and those that occurred in more than 10 percent of patients included: sleepiness, decreased appetite, diarrhea, upper respiratory infection, fever, vomiting, nasopharyngitis, and status epilepticus. Fourteen patients taking CBD experienced dose-related, elevated liver enzymes that were reversible. Seven participants from the CBD group withdrew from the trial due to side effects compared to one participant in the placebo group.
"This landmark study provides data and evidence that Epidiolex can be an effective and safe treatment for seizures seen in patients with Lennox Gastaut Syndrome, a very difficult to control epilepsy syndrome," adds study co-first author, Anup Patel, MD, chief of Neurology at Nationwide Children's Hospital.
A study led by Dr. Devinsky published in last May's New England Journal of Medicine showed a 39 percent drop in seizure frequency in patients with a different rare form of epilepsy, Dravet syndrome. Those findings represented the first large-scale, randomized clinical trial for the compound. Open label CBD studies led by Dr. Devinsky also have shown positive results for treatment-resistant epilepsies.
In April, a U.S. Food and Drug Administration advisory panel unanimously voted to recommend approval of a new drug application for Epidiolex cannabidiol oral solution, following a meeting where researchers, including Dr. Devinsky, presented their findings. The FDA will decide whether to approve the medication in late June.
"While the news gives hope for a new treatment option to the epilepsy community, more research remains imperative to better determine the effects of CBD and other similar cannabis-derived compounds on other forms of the disease and in more dosing regimens," says Dr. Devinsky.
https://www.sciencedaily.com/releases/2018/05/180516172255.htm
Medical marijuana liquid extract may bring hope for children with severe epilepsy
April 13, 2015
Science Daily/American Academy of Neurology (AAN)
A medicinal liquid form of marijuana may show promise as a treatment for children with severe epilepsy that is not responding to other treatments, according to a study released today that will be presented at the American Academy of Neurology's 67th Annual Meeting in Washington, DC, April 18 to 25, 2015.
The study involved 213 people, ranging from toddlers to adults, with a median age of 11 who had severe epilepsy that did not respond to other treatments. Participants had Dravet syndrome and Lennox-Gastaut syndrome, epilepsy types that can lead to intellectual disability and lifelong seizures, as well as 10 other types of severe epilepsy.
The participants were given the drug cannabidiol, a component of marijuana that does not include the psychoactive part of the plant that creates a "high." The drug is a liquid taken daily by mouth. Participants all knew they were receiving the drug in the open-label study, which was designed to determine whether the drug was safe and tolerated well.
Researchers also measured the number of seizures participants had while taking the drug. For the 137 people who completed the 12-week study, the number of seizures decreased by an average of 54 percent from the beginning of the study to the end. Among the 23 people with Dravet syndrome who finished the study, the number of convulsive seizures had gone down by 53 percent by the end of the study. For the 11 people with Lennox-Gastaut syndrome who finished the study, there was a 55 percent reduction in the number of atonic seizures, which cause a sudden loss of muscle tone.
A total of 12 people, or 6 percent, stopped taking the drug due to side effects. Side effects that occurred in more than 10 percent of participants included drowsiness (21 percent), diarrhea (17 percent), tiredness (17 percent) and decreased appetite (16 percent).
Study author Orrin Devinsky, MD, of New York University Langone Comprehensive Epilepsy Center and a Fellow of the American Academy of Neurology, said that these are early findings and larger, placebo-controlled, double-blind trials are needed to measure the effectiveness of the drug.
"So far there have been few formal studies on this marijuana extract," Devinsky said. "These results are of great interest, especially for the children and their parents who have been searching for an answer for these debilitating seizures."
https://www.sciencedaily.com/releases/2015/04/150413183743.htm
Cannabis-based medicine may reduce seizures for children with difficult-to-treat epilepsy
April 30, 2019
Science Daily/American Academy of Neurology
Taking a pharmaceutical formulation of cannabidiol, a cannabis-based medicine, cut seizures nearly in half for children with a rare and severe type of epilepsy called Dravet syndrome, according to a phase 3 study released today that will be presented at the American Academy of Neurology's 71st Annual Meeting in Philadelphia, May 4 to 10, 2019. Dravet syndrome, which starts in infancy, can lead to intellectual disability and frequent, prolonged seizures. Cannabidiol is derived from marijuana that does not include the psychoactive part of the plant that creates a "high."
"It's exciting to be able to offer another alternative for children with this debilitating form of epilepsy and their families," said study author Ian Miller, MD, of Nicklaus Children's Hospital, formerly Miami Children's Hospital, in Florida. "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."
The study involved 199 children with an average age of 9 who were divided into three groups. One group received 20 milligrams per kilogram (mg/kg) per day of cannabidiol, the second group received 10 mg/kg per day and the third group received a placebo.
Seizures were recorded for four weeks before the treatments were started to establish a baseline. Then the participants received the treatment for 14 weeks. By the end of the study, seizures with convulsions had decreased for those taking the high dose of the drug by 46 percent and by 49 percent for those taking the lower dose of the drug, compared to 27 percent for those taking the placebo.
Total seizures reduced by 47 percent for those in the high dose group, by 56 percent for those in the lower dose group and by 30 percent for those in the placebo group. In the high dose group, 49 percent of the participants had their seizures cut in half or more, compared to 44 percent in the low dose group and 26 percent in the placebo group.
All of the groups reported side effects, with 90 percent of the high dose group, 88 percent of the low dose group and 89 percent of the placebo group. The most common side effects were decreased appetite, diarrhea, sleepiness, fever and fatigue. About 25 percent of those in the high dose group had serious side effects, compared to 20 percent of those in the low dose group and 15 percent of those in the placebo group. Only participants in the high dose group stopped taking the drug due to side effects; that number was 7 percent.
"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.
https://www.sciencedaily.com/releases/2019/04/190430164219.htm
Cannabidiol significantly reduces seizures in patients with severe form of epilepsy
Study looked at two doses of cannabis-derived medication's effectiveness in Lennox-Gastaut syndrome
May 16, 2018
Science Daily/NYU Langone Health / NYU School of Medicine
Cannabidiol (CBD), a compound derived from the cannabis plant that does not produce a "high" and has been an increasing focus of medical research, was shown in a new large-scale, randomized, controlled trial to significantly reduce the number of dangerous seizures in patients with a severe form of epilepsy called Lennox-Gastaut syndrome.
In the new study comparing two doses of CBD to a placebo, the researchers reported a 41.9 percent reduction in "drop seizures" -- a type of seizure that results in severe loss of muscle control and balance -- in patients taking a 20 mg/kg/d CBD regimen, a 37.2 percent reduction in those on a 10 mg/kg/d CBD regimen, and a 17.2 percent reduction in a group given a placebo.
The phase III trial was led by principal investigator and study first co-author Orrin Devinsky, MD, a professor of neurology, neurosurgery, and psychiatry at NYU School of Medicine and director of NYU Langone's Comprehensive Epilepsy Center, and was published online May 17 in The New England Journal of Medicine.
"This new study adds rigorous evidence of cannabidiol's effectiveness in reducing seizure burden in a severe form of epilepsy and, importantly, is the first study of its kind to offer more information on proper dosing," says Dr. Devinsky. "These are real medications with real side effects, and as providers we need to know all we can about a potential treatment in order to provide safe and effective care to our patients."
The study included an investigational liquid, oral formulation of CBD called Epidiolex. The product is manufactured by GW Pharmaceuticals, which operates in the U.S. as Greenwich Biosciences; GW Pharmaceuticals funded the clinical trial.
Safety of Two CBD Doses Studied
Lennox-Gastaut syndrome is a rare and severe form of epilepsy characterized by frequent drop seizures and severe cognitive impairment. Six medications are approved to treat seizures in patients with the syndrome, but disabling seizures occur in most patients despite these treatments.
Researchers enrolled 225 patients (age 2 to 55) with Lennox-Gastaut syndrome across 30 international sites in a randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of two doses of CBD: Seventy-six patients received 20 mg/kg/d CBD, 73 received 10 mg/kg/d CBD, and 76 were given a placebo. All medications were divided into two doses per day for 14 weeks. The number of seizures were monitored beginning four weeks prior to the study for baseline assessment, then tracked throughout the 14-week study period and afterwards for a four-week safety check.
Side effects occurred in 94 per of patients in the 20 mg CBD group, 84 percent in the 10 mg CBD group, and 72 percent of those taking placebo. Side effects were generally reported as mild or moderate in severity and those that occurred in more than 10 percent of patients included: sleepiness, decreased appetite, diarrhea, upper respiratory infection, fever, vomiting, nasopharyngitis, and status epilepticus. Fourteen patients taking CBD experienced dose-related, elevated liver enzymes that were reversible. Seven participants from the CBD group withdrew from the trial due to side effects compared to one participant in the placebo group.
"This landmark study provides data and evidence that Epidiolex can be an effective and safe treatment for seizures seen in patients with Lennox Gastaut Syndrome, a very difficult to control epilepsy syndrome," adds study co-first author, Anup Patel, MD, chief of Neurology at Nationwide Children's Hospital.
A study led by Dr. Devinsky published in last May's New England Journal of Medicine showed a 39 percent drop in seizure frequency in patients with a different rare form of epilepsy, Dravet syndrome. Those findings represented the first large-scale, randomized clinical trial for the compound. Open label CBD studies led by Dr. Devinsky also have shown positive results for treatment-resistant epilepsies.
In April, a U.S. Food and Drug Administration advisory panel unanimously voted to recommend approval of a new drug application for Epidiolex cannabidiol oral solution, following a meeting where researchers, including Dr. Devinsky, presented their findings. The FDA will decide whether to approve the medication in late June.
"While the news gives hope for a new treatment option to the epilepsy community, more research remains imperative to better determine the effects of CBD and other similar cannabis-derived compounds on other forms of the disease and in more dosing regimens," says Dr. Devinsky.
https://www.sciencedaily.com/releases/2018/05/180516172255.htm
Cannabis-based medicine may cut seizures in half for those with tough-to-treat epilepsy
April 18, 2017
Science Daily/American Academy of Neurology
Taking cannabidiol may cut seizures in half for some children and adults with Lennox-Gastaut syndrome (LGS), a severe form of epilepsy, according to new information released today from a large scale controlled clinical study that will be presented at the American Academy of Neurology's 69th Annual Meeting in Boston, April 22 to 28, 2017. Cannabidiol is a molecule from the cannabis plant that does not have the psychoactive properties that create a "high."
Nearly 40 percent of people with LGS, which starts in childhood, had at least a 50 percent reduction in drop seizures when taking a liquid form of cannabidiol compared to 15 percent taking a placebo.
When someone has a drop seizure, their muscle tone changes, causing them to collapse. Children and adults with LGS have multiple kinds of seizures, including drop seizures and tonic-clonic seizures, which involve loss of consciousness and full-body convulsions. The seizures are hard to control and usually do not respond well to medications. Intellectual development is usually impaired in people with LGS.
Although the drop seizures of LGS are often very brief, they frequently lead to injury and trips to the hospital emergency room, so any reduction in drop seizure frequency is a benefit.
"Our study found that cannabidiol shows great promise in that it may reduce seizures that are otherwise difficult to control," said study author Anup Patel, MD, of Nationwide Children's Hospital and The Ohio State University College of Medicine in Columbus and a member of the American Academy of Neurology.
For the randomized, double-blind, placebo-controlled study, researchers followed 225 people with an average age of 16 for 14 weeks. The participants had an average of 85 drop seizures per month, had already tried an average of six epilepsy drugs that did not work for them and were taking an average of three epilepsy drugs during the study.
Participants were given either a higher dose of 20 mg/kg daily cannabidiol, a lower dose of 10 mg/kg daily cannabidiol or placebo as an add-on to their current medications for 14 weeks.
Those taking the higher dose had a 42 percent reduction in drop seizures overall, and for 40 percent, their seizures were reduced by half or more.
Those taking the lower dose had a 37 percent reduction in drop seizures overall, and for 36 percent, seizures were reduced by half or more.
Those taking the placebo had a 17 percent reduction in drop seizures, and for 15 percent, seizures were reduced by half or more.
There were side effects for 94 percent of those taking the higher dose, 84 percent of those taking the lower dose and 72 percent of those taking placebo, but most side effects were reported as mild to moderate. The two most common were decreased appetite and sleepiness.
Those receiving cannabidiol were up to 2.6 times more likely to say their overall condition had improved than those receiving the placebo, with up to 66 percent reporting improvement compared to 44 percent of those receiving the placebo.
"Our results suggest that cannabidiol may be effective for those with Lennox-Gastaut syndrome in treating drop seizures," said Patel. "This is important because this kind of epilepsy is incredibly difficult to treat. While there were more side effects for those taking cannabidiol, they were mostly well-tolerated. I believe that it may become an important new treatment option for these patients."
There is currently a plan to submit a New Drug Application to the FDA later this year.
https://www.sciencedaily.com/releases/2017/04/170418161907.htm
Cannabidiol reduces seizures in children with severe epilepsy
May 26, 2017
Science Daily/Ann & Robert H. Lurie Children's Hospital of Chicago
Children with Dravet syndrome, a severe form of epilepsy, had fewer seizures after taking a daily oral solution of the cannabis compound called cannabidiol, which does not have the psychoactive properties of marijuana, results from a double-blind, placebo-controlled trial reveal.
Results from a double-blind, placebo-controlled trial published in The New England Journal of Medicine revealed that children with Dravet syndrome, a severe form of epilepsy, had fewer seizures after taking a daily oral solution of the cannabis compound called cannabidiol, which does not have the psychoactive properties of marijuana. Over a 14-week treatment with cannabidiol, convulsive seizures dropped from a monthly average of 12.4 to 5.9. In comparison, seizures in the placebo group decreased from a monthly average of 14.9 to 14.1. During the study, seizures stopped completely in 5 percent of patients taking cannabidiol.
"Seizures in Dravet syndrome are extremely difficult to control and they can be deadly," says study co-author Linda Laux, MD, from Stanley Manne Children's Research Institute at Ann & Robert H. Lurie Children's Hospital of Chicago. "Our results are encouraging, especially considering that we don't have any antiepileptic drugs approved for Dravet syndrome in the U.S."
The study included 120 children and young adults with Dravet syndrome and drug-resistant seizures. They were randomly assigned to receive either cannabidiol or a placebo, in addition to standard antiepileptic treatment.
Adverse events were reported in 93 percent of the patients taking cannabidiol, compared to 75 percent of the patients in the placebo group. The most common side effects were drowsiness, diarrhea and decreased appetite.
"We will need more data to determine the long-term efficacy and safety of cannabidiol for Dravet syndrome," says Laux, who is the Medical Director of the Comprehensive Epilepsy Center at Lurie Children's and Assistant Professor of Pediatrics at Northwestern University Feinberg School of Medicine.
https://www.sciencedaily.com/releases/2017/05/170526085003.htm
Cannabis-based medicine may cut seizures in half for those with tough-to-treat epilepsy
April 18, 2017
Science Daily/American Academy of Neurology
Taking cannabidiol may cut seizures in half for some children and adults with Lennox-Gastaut syndrome (LGS), a severe form of epilepsy, according to new information released today from a large scale controlled clinical study that will be presented at the American Academy of Neurology's 69th Annual Meeting in Boston, April 22 to 28, 2017. Cannabidiol is a molecule from the cannabis plant that does not have the psychoactive properties that create a "high."
Nearly 40 percent of people with LGS, which starts in childhood, had at least a 50 percent reduction in drop seizures when taking a liquid form of cannabidiol compared to 15 percent taking a placebo.
When someone has a drop seizure, their muscle tone changes, causing them to collapse. Children and adults with LGS have multiple kinds of seizures, including drop seizures and tonic-clonic seizures, which involve loss of consciousness and full-body convulsions. The seizures are hard to control and usually do not respond well to medications. Intellectual development is usually impaired in people with LGS.
Although the drop seizures of LGS are often very brief, they frequently lead to injury and trips to the hospital emergency room, so any reduction in drop seizure frequency is a benefit.
"Our study found that cannabidiol shows great promise in that it may reduce seizures that are otherwise difficult to control," said study author Anup Patel, MD, of Nationwide Children's Hospital and The Ohio State University College of Medicine in Columbus and a member of the American Academy of Neurology.
For the randomized, double-blind, placebo-controlled study, researchers followed 225 people with an average age of 16 for 14 weeks. The participants had an average of 85 drop seizures per month, had already tried an average of six epilepsy drugs that did not work for them and were taking an average of three epilepsy drugs during the study.
Participants were given either a higher dose of 20 mg/kg daily cannabidiol, a lower dose of 10 mg/kg daily cannabidiol or placebo as an add-on to their current medications for 14 weeks.
Those taking the higher dose had a 42 percent reduction in drop seizures overall, and for 40 percent, their seizures were reduced by half or more.
Those taking the lower dose had a 37 percent reduction in drop seizures overall, and for 36 percent, seizures were reduced by half or more.
Those taking the placebo had a 17 percent reduction in drop seizures, and for 15 percent, seizures were reduced by half or more.
There were side effects for 94 percent of those taking the higher dose, 84 percent of those taking the lower dose and 72 percent of those taking placebo, but most side effects were reported as mild to moderate. The two most common were decreased appetite and sleepiness.
Those receiving cannabidiol were up to 2.6 times more likely to say their overall condition had improved than those receiving the placebo, with up to 66 percent reporting improvement compared to 44 percent of those receiving the placebo.
"Our results suggest that cannabidiol may be effective for those with Lennox-Gastaut syndrome in treating drop seizures," said Patel. "This is important because this kind of epilepsy is incredibly difficult to treat. While there were more side effects for those taking cannabidiol, they were mostly well-tolerated. I believe that it may become an important new treatment option for these patients."
There is currently a plan to submit a New Drug Application to the FDA later this year.
https://www.sciencedaily.com/releases/2017/04/170418161907.htm
Cannabidiol for treating seizures show promise
Cannabidiol for treating seizures show promise
March 3, 2016
Science Daily/University of Alabama at Birmingham
Researchers have presented the first findings of a large study of cannabidiol for treating seizures.
Investigators with the University of Alabama at Birmingham Cannabidiol Program will present the first results drawn from the CBD oil studies underway at UAB and Children's of Alabama. Three abstracts will be presented at the annual meeting of the American Academy of Neurology in Vancouver, Canada.
The abstracts describe results from the first 51 subjects enrolled in the studies. Among other findings, the researchers report that approximately 50 percent of the subjects responded to the CBD oil therapy with overall sustained improvement in seizure control over a six-month period. Seizures declined between 32 and 45 percent in the responders, depending on the CBD dose. Two patients were seizure-free, and nine dropped out due to side effects or lack of efficacy.
UAB launched the studies of CBD oil as a treatment for severe, intractable seizures in April of 2015. The studies, an adult study at UAB and a pediatric study at Children's of Alabama, were authorized by the Alabama Legislature in 2014 by legislation known as Carly's Law.
The studies are designed to test the safety and tolerability of CBD oil in patients with intractable seizures. CBD oil, a derivative of the cannabis plant, is delivered orally as an oily liquid.
"The studies are ongoing, and we have a lot more to learn; but these preliminary findings are encouraging," said Jerzy Szaflarski, M.D., Ph.D., professor in the Department of Neurology, principal investigator of the adult study. "Among our goals was to determine the safety of CBD oil therapy, and it appears that, in many cases, patients tolerate the oil quite well. The evidence of seizure reduction gives us hope that, the more we learn about CBD oil, the better we will be able to tailor this therapy to provide relief for those with severe epilepsy."
The oil used in the studies is produced under stringent requirements of the United States Food and Drug Administration by a licensed pharmaceutical company. It contains only traces of THC, the psychoactive component of marijuana. The process developed by GW Pharmaceuticals guarantees the consistency of the product that is provided to study participants.
"The studies thus far show that the administration of CBD oil is a complex undertaking," said Martina Bebin, M.D., professor of neurology and principal investigator for the pediatric study. "Some patients respond well, but others either have no improvement or experience significant side effects. CBD is not a panacea, and it's not for everyone. But many patients do have a reduction in seizure activity, and we hope our efforts will further define how to best utilize CBD oil for maximum benefit to the appropriate patient population."
Tyler Gaston, M.D., a clinical neurophysiology fellow, led a study of potential interactions between CBD and clobazam, a commonly prescribed anti-epileptic medication. The investigators suspected that CBD treatment might cause an increase in the blood levels of clobazam and its metabolite, N-desmethylclobazam, leading to adverse events including sedation. Seventeen patients in the studies were taking clobazam, and investigators found clear evidence for an interaction, with rising clobazam levels during CBD therapy. This finding highlights the importance of monitoring clobazam and N-desmethylclobazam levels when treating patients with CBD, and the results underscore the importance of the new knowledge gained through the UAB CBD program.
A study headed by Leslie Perry, M.D., also a clinical neurophysiology fellow, looked at the effect of CBD oil therapy on electroencephalography, or EEG. EEG is the standard test to measure electrical activity in the brain. The same cohort of 51 patients received EEG tests prior to beginning CBD therapy and then again after CBD therapy had begun. The investigators report that CBD does not appear to have a negative effect on standard EEG parameters. However, the authors acknowledge that the conclusion is limited by the relatively short duration of both the EEG and the length of time from the tests done prior to beginning CBD therapy and then during therapy.
Another abstract, led by Jane Allendorfer, Ph.D., assistant professor of neurology, will be presented at the annual meeting of the Organization for Human Brain Mapping in Geneva, Switzerland. In her work, she evaluated the effects of CBD treatment on attention circuits in the brain using functional MRI. Eight patients underwent fMRI before treatment with CBD and while taking CBD. Their scanning showed improved activation of brain regions important for attention. The authors conclude that these preliminary results are promising and illustrate the potential of CBD treatment to improve not only seizure control but also cognition in patients with poorly controlled epilepsy.
The ongoing UAB CBD studies currently have 40 children and 39 adults enrolled.
https://www.sciencedaily.com/releases/2016/03/160303204007.htm
Pharmaceutical CBD (cannabidiol) shows promise for children with severe epilepsy
Significant seizure reduction in studies using CBD in combination with AEDs
December 7, 2015
Science Daily/American Epilepsy Society
Around the globe there is high interest in the use of cannabidiol (CBD), a type of cannabinoid, for the treatment of people with epilepsy, especially children who have treatment-resistant forms of the disorder such as Lennox-Gastaut Syndrome (LGS) and Dravet Syndrome (DS). Three studies presented at the American Epilepsy Society's 69th Annual Meeting in Philadelphia highlight emerging efficacy and safety data of Epidiolex, a pharmaceutical liquid formulation of cannabidiol, which is currently undergoing U.S. Food and Drug Administration (FDA) authorized Phase 3 pivotal clinical trials in the United States and across the globe by GW Pharmaceuticals. A fourth study highlights possible interactions of CBD with existing anti-epileptic drugs (AEDs) in animal models of seizures.
The largest CBD study presented efficacy and safety data on GW Pharmaceutical's investigational medicine, Epidiolex (cannabidiol) from open-label Expanded Access programs at 16 sites. The study (abstract 3.034) involves 261 people, predominantly children, who have severe epilepsy that had not responded adequately to other treatments. The average age of the participants was 11. Over the course of 12 weeks, the study participants were given Epidiolex in gradually increasing doses. In all cases, Epidiolex was added to current AED treatment regimes. On average, patients were taking approximately three other AEDs. Participants and their families/caregivers recorded the number of seizures prior to taking CBD and during the 12 weeks of treatment. Clinicians also tested hematologic, liver and kidney function as well as AED levels before treatment and then at four, eight and 12 weeks during the study.
After three months of treatment, the frequency of all seizures was reduced by a median of 45 percent in all participants. Almost half (47%) of the participants in the study experienced a 50 percent or greater reduction in seizures and nine percent of patients were seizure-free. Among specific patient populations, DS patients had a 62 percent reduction in seizures and 13 percent were seizure-free. Patients with LGS experienced a 71 percent reduction in atonic seizures.
Adverse events occurred in more than 10 percent of participants with the most common being somnolence, diarrhea and fatigue and led to discontinuation in 4 percent of patients. Thirty-four percent of participants reported serious adverse events of which 5 percent were considered treatment related including altered liver enzymes (n=4), status epilepticus (n=4), diarrhea (n=4) and others. Twelve percent withdrew from the study for lack of efficacy.
"We are pleased to report these promising data on significant numbers of children," said lead author Orrin Devinsky, M.D., of New York University Langone Medical Center's Comprehensive Epilepsy Center. "These data reinforce and support the safety and efficacy we have shared in previous studies. Most importantly it is providing hope to the children and their families who have been living with debilitating seizures."
However, Devinsky cautions that "these results are from an uncontrolled study. Further study is needed before results can be confirmed. Randomized controlled studies are now underway to help us better understand the effectiveness of the drug. We very much look forward to the results from these studies during 2016," he said.
A related study (abstract 2.296) authored by Michael Oldham, M.D., MPH, formerly at the University of California San Francisco (UCSF) and currently at the University of Louisville, explored the long-term efficacy of Epidiolex. This study followed a subset of the first population (n=25) at UCSF Benioff Children's Hospital San Francisco, with an average age of 9, for one year. The patients took CBD in addition to their regular AED regimen. After 12 months, treatment with CBD resulted in a 50 percent reduction in seizures for 10 participants (40%). One participant with DS remained seizure-free. Twelve of the participants discontinued CBD because the treatment did not work for them. One participant suffered a marked increase in seizure frequency due to CBD.
"The CBD as an add-on therapy reduced seizures by half for a third of the patients in the first 12 weeks of the study," Oldham said. "This substantial improvement was maintained by 40 percent of participants for the entire 12-month period showing strong promise that CBD can be effective in controlling seizures."
A third preclinical study (abstract 3.397) explored the anticonvulsant and tolerability profile of CBD in animal models. Using the Anticonvulsant Screening Program (ASP), the researchers used four well-established acute seizure models and found that CBD exerted significant anticonvulsant effects and was well-tolerated in rodents. This study, provided as a free service by the National Institute of Neurological Disorders and Stroke ASP, was conducted at the University of Utah.
A fourth study, led by Misty D. Smith, Ph.D. at the University of Utah (abstract 1.215), explores how CBD interacts with five different AEDs in animal models of seizure. The study helps determine the effects of CBD in combination with common AEDs, including carbamazepine, valproate, levetiracetam, clobazam and lacosamide. The interactions between these drugs could be additive, meaning the drugs work well together; synergistic, meaning the drugs enhance each other's effects; or antagonistic, which occurs when the combination of drugs seems to reduce overall effectiveness.
Smith used isobolographic analysis of three fixed dose ratio combinations of CBD with each AED in order to rapidly assess the effectiveness of each combination against limbic seizure activity. The study found a significant synergistic interaction of CBD with levetiracetam and significant antagonistic interactions with some of the fixed dose-ratio combinations of CBD with clobazam and CBD with carbamazepine.
"By identifying the synergistic, additive or antagonistic interactions between CBD and other ASDs, we are gaining a better understanding of the nature of these interactions. This will help optimize therapeutic safety and efficacy for CBD going forward," said Smith.
https://www.sciencedaily.com/releases/2015/12/151207145856.htm
Could cannabis active substance curb seizures? Experts weed through evidence
May 22, 2014
Science Daily/Wiley
The therapeutic potential of medical marijuana and pure cannabidiol (CBD), an active substance in the cannabis plant, for neurologic conditions is highly debated. A series of articles published in Epilepsia, a journal of the International League Against Epilepsy (ILAE), examine the potential use of medical marijuana and CBD in treating severe forms of epilepsy such as Dravet syndrome.
In a case study, Dr. Edward Maa, Chief of the Comprehensive Epilepsy Program at Denver Health in Denver, Colo., details one mother's experience of providing medical marijuana to her child with Dravet syndrome. The adjunct therapy, a strain of cannabis high in CBD and tetrahydrocannabinol (THC) known as Charlotte's Web, was given in conjunction with the patient's antiepileptic drug regimen. The child's seizure frequency was reduced from 50 convulsions per day to 2 to 3 nighttime convulsions per month.
"Colorado is "ground zero" of the medical marijuana debate," says Dr. Maa. "As medical professionals it is important that we further the evidence of whether CBD in cannabis is an effective antiepileptic therapy." Currently, 21 states and the District of Columbia (DC) have legalized marijuana for medical purposes according to GOVERNING magazine.
A counter-point article summarizes current scientific evidence of CBD use in epilepsy and other neurological or psychiatric disorders including anxiety, schizophrenia and addiction. Previous studies found that THC, the primary psychoactive substance and CBD the main non-psychoactive ingredient in cannabis, display anticonvulsive properties in animals. However, this research was conducted in acute animal models and data is limited for chronic recurrent seizures. Recent studies claim medical marijuana with high ratios of CBD to THC are more effective in seizure control, but the data was anecdotal and not well controlled.
"While cannabis has been used to treat epilepsy for centuries, data from double-blind randomized, controlled trials of CBD or THC in epilepsy is lacking," explains Dr. Orrin Devinsky, Director of the Comprehensive Epilepsy Center at NYU Langone Medical Center in New York and Saint Barnabas Institute of Neurology and Neurosurgery in New Jersey. "Randomized controlled studies of CBD in targeted epilepsy groups, such as patients with Dravet or Lennox-Gastaut syndromes, are in the planning stages."
Dr. Maria Roberta Cilio, Director of Research in Pediatric Epilepsy of the Comprehensive Epilepsy Center at UCSF Benioff Children's Hospital in San Francisco, agrees, "There is a critical need for new therapies, especially for childhood-onset treatment-resistant epilepsies that impair quality of life and contribute to learning and behavioral disorders. Rigorous investigation of the safety and efficacy of medical marijuana or individual components such as CBD are necessary for patients with epilepsy before any conclusion is made. "
"There is much interest in the therapeutic potential of medical marijuana and CBD in treating epilepsy," say Drs. Gary Mathern and Astrid Nehlig, Editors-in-Chief of Epilepsia. "We would like your perspective on this important issue and ask that patients, clinicians, and medical professionals visit http://surveys.verticalresponse.com/a/show/1539433/ea840f4206/0 to provide feedback on the use of medical marijuana in epilepsy."
https://www.sciencedaily.com/releases/2014/05/140522074747.htm