When Liam O'Brien was a toddler, he experienced a sudden seizure—his head jerked and quickly dropped, his parents recall. They took Liam to his pediatrician, who told them to monitor him. Subsequently, Liam exhibited a series of unusual movements: His body would become rigid, an arm or a leg would shoot out, and his head would drop. His mother called a neurologist.

The neurologist suspected Liam had seizures, which was confirmed by a subsequent electroencephalogram (EEG) revealing abnormal electrical activity in his brain. Over the next few years Liam's seizures worsened and were not well controlled by antiepileptic drugs (AEDs). He was diagnosed with symptomatic generalized epilepsy, a type of epilepsy similar to Lennox-Gastaut syndrome, with symptoms such as seizures that are difficult to treat, cognitive and developmental delays, and cerebral palsy.

Maya Adache experienced her first seizure at just 6 months old. Initially it was diagnosed as febrile, which some babies experience when they run a fever. But Maya's seizures continued unabated-often as many as 15 times a day. After multiple tests, she was diagnosed at age 8 with Dravet syndrome, a severe form of epilepsy that typically begins in infancy. Symptoms include frequent, prolonged seizures often triggered by high body temperature (hyperthermia), as well as developmental delay, speech impairment, ataxia, sleep disturbances, and other health problems.

Both Maya and Liam have intractable forms of epilepsy—seizures that are difficult to control using current AEDs. Each tried many different medications. Maya had a right temporal and frontal lobectomy to remove the areas of her brain causing the seizures. But for both children none of the treatments worked.

Trials to the Rescue

After four or five years of unsuccessful efforts to stop their seizures, the children's neurologists suggested Liam and Maya enroll in trials of Epidiolex, a formulation of cannabidiol (CBD)—a type of cannabinoid extracted from marijuana plants—manufactured by GW Pharmaceuticals.

The families were eager to enroll their children. By then, Liam was having 50 to 60 seizures a day. Some were drop seizures, meaning he could fall at any moment and had to wear a helmet to prevent injury. He also could not speak or count.

Maya was still experiencing 10 to 15 seizures a day. She could speak, although not at her age level, and had learned to walk, swim, and ice skate, but she was developmentally delayed and her seizures induced uncontrollable mood swings and behavioral problems.

Marijuana for Some Epilepsies

In three clinical studies, the CBD drug, in combination with other AEDs, showed it was both safe and effective in reducing seizures in patients with Dravet syndrome and Lennox-Gastaut syndrome, says Orrin Devinsky, MD, FAAN, director of the New York University Comprehensive Epilepsy Center and a lead investigator in ongoing trials of Epidiolex. Dr. Devinsky received compensation from GW Pharmaceuticals to appear as an expert witness during the US Food and Drug Administration (FDA) review.

The drug was well tolerated by most children, and the adverse side effects tended to be minimal and transient. Five patients who were also taking the AED clobazam (Onfi) had their clobazam dose reduced because of a sedative effect and potential drug interaction. Patients who experienced diarrhea, weight loss, and decreased appetite had their Epidiolex dose reduced. In combination with some AEDs, especially valproic acid (Depakote), researchers noted elevated liver enzyme levels, which resolved over the course of the trials and didn't result in liver failure in any patients. Nonetheless, doctors are advised to monitor liver enzyme levels in patients prescribed CBD, says Dr. Devinsky.

In June 2018, the FDA approved Epidiolex for the treatment of Dravet and Lennox-Gastaut syndromes. It is the first approved drug to contain a purified extract from the marijuana plant, or cannabis sativa.

Helpful but Not a Cure

The trial results provided the highest level of evidence for CBD's benefit in these childhood epilepsies, says Elaine C. Wirrell, MD, FAAN, director of pediatric epilepsy at Mayo Clinic in Rochester, MN, who considers Epidiolex a useful addition to the array of AEDs already available. Although she has not been compensated by GW Pharmaceuticals, Mayo Clinic has received funding from the company to conduct trials of Epidiolex.

Dr. Wirrell cautions, however, that the drug is neither a panacea nor a cure. The findings from one of the trials, published in the New England Journal of Medicine on May 25, 2017, showed modest benefits in most patients; for approximately 40 percent of them, seizures decreased by at least half, Dr. Wirrell notes. Fewer than 5 percent experienced complete cessation of seizures, and she worries that some parents may have unrealistic expectations.

The drug did not work for every patient, says Shlomo Shinnar, MD, PhD, FAAN, professor of neurology at Montefiore Medical Center and the Albert Einstein College of Medicine in New York and president of the American Epilepsy Society. "But for many it reduced the number of seizures, and in these difficult-to-treat epilepsies this reduction can improve quality of life tremendously," he says. (Dr. Shinnar has no conflicts of interest related to Epidiolex.)

New Drug, New Life

That proved true for Liam O'Brien. After only a week, his seizures stopped altogether, and two years later he has had no breakthrough seizures. He continues to take Epidiolex in combination with clobazam as part of a long-term study. When he began the trial at age 6, he couldn't speak, had terrible balance and trouble walking, and experienced multiple types of seizures every day. Today, he is developing physically and mentally and can ride a bike, speak, and sing.

For Maya Adache, the results were not quite as dramatic. As part of a placebo-controlled study, participants were given either a placebo or Epidiolex for the first four months. Beginning in the fifth month, all participants were given Epidiolex. Although her father has no way of knowing if Maya received a placebo to begin with, he saw no change in her condition at first. Then about halfway through the fifth month, she suddenly stopped having multiple seizures. Since then, she has remained relatively seizure-free. She has occasional absence seizures, in which she stares into space for minutes at a time, and these tend to occur once every two weeks.

With fewer seizures, Maya, now 11, has the energy to exercise and attended her first ice-skating camp this summer. While her father hasn't seen dramatic improvements in her mental and academic development, he has seen a huge improvement in her moods and energy. He's hopeful the academic development will follow.

How Cannabidiol Works

Humans and other mammals naturally produce endocannabinoids, chemicals that interact with cannabinoid receptors in the brain and other parts of the central nervous system, says Barry Gidal, PharmD, professor of pharmacy at the University of Wisconsin School of Pharmacy in Madison, who received compensation from GW Pharmaceuticals to appear as an expert witness during the review process of Epidiolex, the cannabidiol (CBD) manufactured by GW.

Researchers do not fully understand how the endocannabinoid system works, but they know it affects many of the body's systems, including the nervous, cardiovascular, reproductive, endocrine, and immune systems. The marijuana plant has more than 100 cannabinoids, compounds chemically similar to the endocannabinoids our bodies produce. These cannabinoids can interact with receptors in the human nervous system, including those in the brain, and play a part in how neurons communicate with one another, Dr. Gidal says.

Tetrahydrocannabinol (THC) and CBD are two of the most studied compounds. THC is psychotropic and induces the high in people who use marijuana recreationally. CBD, on the other hand, neither is psychotropic nor produces a high. It's a large molecule that interacts with receptors in complex ways, sometimes inhibiting the effects of the body's naturally produced endocannabinoids and sometimes enhancing them, says Dr. Gidal.

In the case of epilepsy, CBD can reduce neural excitability and calm seizing brains in some people. Also, because it works by interacting with the endocannabinoid system, it is unlike other approved AEDs. In the three clinical trials, Epidiolex was used in combination with standard AEDs, including clobazam (Onfi) and valproic acid (Depakote), says Dr. Gidal.

The Future of Cannabinoids

Research into cannabinoids has been limited because marijuana remains illegal in many places. In response to the US Food and Drug Administration (FDA) approval of Epidiolex in June for Dravet syndrome and Lennox-Gastaut syndrome, the US Drug Enforcement Agency has reclassified purified cannabidiol (CBD) as a Schedule V drug, meaning it has verified medical benefits and a relatively low potential for abuse. This may encourage more researchers to study cannabinoids and discover their mechanisms and potential benefits, says Barry Gidal, PharmD, professor of pharmacy at the University of Wisconsin School of Pharmacy in Madison.

Little Data for Other Neurologic Conditions
Because cannabinoids react with receptors in the nervous system, researchers and advocates believe marijuana may be helpful in treating other neurologic conditions, including autism spectrum disorder, Alzheimer's disease, multiple sclerosis (MS), and Parkinson's disease. More than 700 studies are ongoing or recently completed into the effects of cannabinoids, according to the National Institutes of Health database of clinical trials worldwide. These include studies into side effects of recreational marijuana use, efficacy of specific cannabinoids in treating a variety of conditions, and CBD for childhood and other epilepsies.

Many experts say, however, the hype about marijuana for other disorders outstrips the science for now. The data about the safety and efficacy of these compounds are either inadequate or lacking, says Vijayshree Yadav, MD, FAAN, clinical director of the Multiple Sclerosis Center at Oregon Health & Science University in Portland. A 2014 systematic review of medical marijuana by the American Academy of Neurology supports Dr. Yadav's concerns. It revealed little or inadequate evidence that marijuana improved symptoms in Parkinson's disease, Huntington's disease, Tourette's syndrome, or cervical dystonia.

The review found strong evidence that oral cannabis extracts improved patient-reported stiffness and pain in MS. But the same review found no objective improvement in these symptoms when measured by doctors. Besides, Dr. Yadav says, many FDA-approved drugs are available to treat symptoms like pain and muscle stiffness in MS. And doctors already know the profiles of these drugs and their side effects. Physicians can also be confident in the consistency, purity, and potency of the drugs.

Web Extra

For information about dispensary marijuana, read Dispensary Marijuana: An Unknown Entity.