CBD may alleviate seizures, benefit behaviors in people with neurodevelopmental conditions

September 18, 2019

Science Daily/University of North Carolina Health Care

A marijuana plant extract, also known as cannabidiol (CBD), is being commonly used to improve anxiety, sleep problems, pain, and many other neurological conditions. Now UNC School of Medicine researchers show it may alleviate seizures and normalize brain rhythms in Angelman syndrome, a rare neurodevelopmental condition.

Published in the Journal of Clinical Investigation, the research conducted using Angelman syndrome animal models shows that CBD could benefit kids and adults with this serious condition, which is characterized by intellectual disability, lack of speech, brain rhythm dysfunction, and deleterious and often drug-resistant epilepsy.

"There is an unmet need for better treatments for kids with Angelman syndrome to help them live fuller lives and to aid their families and caregivers," said Ben Philpot, PhD, Kenan Distinguished Professor of Cell Biology and Physiology and associate director of the UNC Neuroscience Center. "Our results show CBD could help the medical community safely meet this need."

CBD, which is a major phytocannabinoid constituent of cannabis, has already shown to have anti-epileptic, anti-anxiety, and anti-psychotic effects. And in 2018, the FDA approved CBD for the treatment of seizures associated with two rare forms of epilepsy, but little is known about the potential anti-seizure and behavioral effects of CBD on Angelman symptom.

The Philpot lab is a leader in the creation of genetically modified mouse models of neurodevelopmental disorders, and they use these models to identify new treatments for various diseases, such as Rett, Pitt-Hopkins, and Angelman syndromes.

In experiments led by first author Bin Gu, PhD, a postdoctoral fellow in the Philpot lab, the UNC-Chapel Hill researchers systematically tested the beneficial effects of CBD on seizures, motor deficits, and brain activity abnormalities -- as measured by EEG -- in mice that genetically model Angelman syndrome, with the expectation that this information could guide eventual clinical use.

The researchers found that a single injection of CBD substantially lessened seizure severity in mice when the seizures were experimentally triggered by elevated body temperature or loud sounds. A typical anti-convulsant dose of CBD (100 mg/kg) caused mild sedation in mice but had little effect on motor coordination or balance. CBD also restored the normal brain rhythms which are commonly impaired in Angelman syndrome.

"We're confident our study provides the preclinical framework necessary to better guide the rational development of CBD as a therapy to help lessen seizures associated with Angelman syndrome and other neurodevelopmental disorders," Gu said.

Philpot and Gu added that patients and families should always seek advice from their physician before taking any CBD products, and that a human clinical trial is needed to fully understand its efficacy and safety.

https://www.sciencedaily.com/releases/2019/09/190918105631.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

Cannabis-based compound may reduce seizures in children with epilepsy

December 5, 2018

Science Daily/Wiley

A recent analysis of published studies indicates that the use of cannabinoids for the treatment of epilepsy in children looks promising.

Interest has been growing in the use of cannabinoids -- the active chemicals in cannabis or marijuana -- for the treatment of epilepsy in children. A recent Epilepsia analysis of relevant published studies indicates that this strategy looks promising.

The analysis included four randomized controlled trials and 19 non-randomized studies, primarily involving cannabidiol, a particular type of cannabinoid that does not have psychoactive effects.

Among randomized controlled trials involving children with severe forms of epilepsy, there was no statistically significant difference between cannabidiol and placebo in terms of freedom from seizures, sleep disruption, or vomiting. There was a statistically significant reduction in the median frequency of monthly seizures with cannabidiol compared with placebo and an increase in number of participants with at least a 50 percent reduction in seizures.

"Although we saw no significant difference in the number of children who became completely seizure free, we that found a significant number of these children achieved a 50 percent or more reduction in seizures. Any reduction in seizures has a striking impact on the lives of these children and their families," said lead author Jesse Elliott, of the University of Ottawa, in Canada. "Research in this area is active, and we expect a dramatic increase in the number of studies over the next few years."

https://www.sciencedaily.com/releases/2018/12/181205093644.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

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

Medicinal oil reduces debilitating epileptic seizures associated with Glut1 deficiency, trial shows

August 11, 2014

Science Daily/UT Southwestern Medical Center

A rare metabolic disease that caused hundreds of seizures daily for a 6-year-old is now significantly under control as part of a clinical trial that uses a medicinal oil for treatment. Within hours, treatment with an edible oil dramatically reduced the number of seizures for then-4-year-old.

Two years ago, the parents of Chloe Olivarez watched painfully as their daughter experienced epileptic seizures hundreds of times a day. The seizures, caused by a rare metabolic disease that depleted her brain of needed glucose, left Chloe nearly unresponsive, and slow to develop.

Within hours, treatment with an edible oil dramatically reduced the number of seizures for then-4-year-old Chloe, one of 14 participants in a small UT Southwestern Medical Center clinical trial.

"Immediately we noticed fewer seizures. From the Chloe we knew two years ago to today, this is a completely different child. She has done amazingly well," said Brandi Olivarez, Chloe's mother.

For Chloe and the other trial participants who suffer from the disease called Glut1 deficiency (G1D), seizure frequency declined significantly. Most showed a rapid increase in brain metabolism and improved neuropsychological performance, findings that suggested the oil derived from castor beans called triheptanoin, ameliorated the brain glucose-depletion associated with this genetic disorder, which is often undiagnosed.

"This study paves the way for a medical food designation for triheptanoin, thus significantly expanding therapeutic options for many patients," said Dr. Juan Pascual, Associate Professor of Neurology and Neurotherapeutics, Physiology, and Pediatrics at UT Southwestern and lead author of a study on the findings, published in JAMA Neurology.

For the estimated 38,000 Americans suffering from this disease, the only proven treatment has been a high-fat ketogenic diet, which only works for about two-thirds of patients. In addition, this diet carries long-term risks, such as development of kidney stones and metabolic abnormalities.

Based on the results of this trial, triheptanoin appears to work as efficiently as the ketogenic diet; however, more research needs to be done before the oil is made available as a medical food therapy, researchers said.

"Triheptanoin byproducts produced in the liver and also in the brain refill brain chemicals that we found are preferentially diminished in the disorder, and this effect is precisely what defines a medical food rather than a drug," said Dr. Pascual, who heads UT Southwestern's Rare Brain Disorders Program, maintains an appointment in the Eugene McDermott Center for Human Growth and Development, and holds The Once Upon a Time Foundation Professorship in Pediatric Neurologic Diseases.

The oil, approved for use in research only, is an ingredient in some cosmetic products and is added to butter in some European countries. It is not commercially available in the U.S. for clinical use.

Triheptanoin's success as an experimental treatment for other metabolic diseases, along with preclinical success in G1D mice, led Dr. Pascual and his trial collaborator, Dr. Charles Roe, Clinical Professor of Neurology and Neurotherapeutics, to first conceive the idea and then launch this trial for G1D patients. The 14 pediatric and adult patients in the study consumed varying amounts of the oil, based on their body weight, four times a day. Given the trial's success, Dr. Pascual plans further research to refine the optimal dosage toward the goal of facilitating medical food designation of triheptanoin as a new G1D treatment.

While some trial participants reported mild stomach upset as a side effect, for Chloe the oil has been a miracle medicine without negative effects. Her parents, Brandi and Josh Olivarez of Waco, Texas, continue to be amazed by her progress.

"Before, she was having so many seizures a day that she couldn't even talk. Now she sings all the time, she can eat whatever she wants, and her speech is greatly improved. She still has some learning delays, but has come a long way," said Mrs. Olivarez.

Many Glut1 patients suffer from movement disorders that limit their physical capabilities, but that does not appear to be the case with Chloe. As for the seizures, she still has minor ones occasionally, but they are not debilitating.

"She is now able to run a solid mile without stopping. This would not have been possible without the oil," Mrs. Olivarez said. "Before, she had almost no muscle tone, was lethargic and had a very wide gait due to trying to balance herself while walking, which was very tiring for her."

To better understand this disease, UT Southwestern established a patient-completed registry to track G1D incidence and what treatments work or do not work for those registered.

Study author Dr. Hanzhang Lu, Associate Professor in the Advanced Imaging Research Center and of Psychiatry and Radiology, a TI Scholar in Advanced Imaging Technologies, devised a novel MRI technique used in the trial to measure brain metabolism.

https://www.sciencedaily.com/releases/2014/08/140811165819.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