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Cannabidiol in the Treatment of Epilepsy
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Anecdotal reports addressing the successful seizure treatment of severe epilepsies with cannabidiol (CBD) have increased both public interest and academic research. Placebo-controlled, randomized, controlled trials proved the efficacy of pharmaceutical-grade CBD in epilepsy treatment, thus leading to pharmaceutical-grade CBD approval by the US Food and Drug Administration and the European Medicines Agency for the treatment of seizures in Dravet syndrome and Lennox–Gastaut syndrome as well as for tuberous complex syndrome by the Food and Drug Administration only. However, the CBD market is confusing because an array of products of different origins, purity, and concentration is available. Additionally, the results from the pivotal studies with plant-derived, pharmaceutical-grade CBD cannot simply be transferred to other epilepsy types or CBD of any origin. Because of the high demands and expectations that patients with epilepsy and their caregivers have regarding CBD, information outlining the proven facts and potential risks is essential. The aim of this article is to thoroughly review available research data and practical recommendations to provide the treating physician with the necessary information for counseling patients with epilepsy.
|Cannabidiol is an increasingly demanded, quite expensive treatment option for drug-resistant epilepsy.|
|Efficacy was shown for selected epileptic encephalopathies such as Dravet syndrome and Lennox–Gastaut syndrome as well as tuberous sclerosis complex; other forms of epilepsy are currently investigated.|
|There is growing evidence of a positive influence of cannabidiol on behavior and cognition.|
Epilepsy is clinically defined as a syndrome of recurrent unprovoked seizures, or as one seizure with evidence of an increased risk of seizure recurrence of > 60% over the next 10 years . With a prevalence of 0.5–1%, epilepsy is one of the most common neurological diseases. Up to 30% of patients with epilepsy do not achieve seizure freedom with two appropriately chosen antiseizure drugs, hence, have to be considered as drug resistant. Unfortunately, recently developed new-generation antiseizure drugs have not resulted in a significantly higher rate of seizure-free patients, even though the tolerability and interaction profile of newer antiseizure drugs is, generally, more favorable [2, 3]. Seizures, as well as the side effects from antiseizure drugs, co-morbidities, and social consequences of seizures lead to a significant loss in the quality of life for those affected. Therefore, the search for new therapies is still a major challenge for patients and physicians.
Cannabidiol (CBD) is one of the major components of the Cannabis sativa plant. This phytocannabinoid was isolated in the 1940s and thoroughly studied thereafter . Cannabidiol is not only used as a food supplement or for general well-being purposes, in fact, it is under investigation for a board variety of disorders, for example, mood disorders, anxiety, pain, or epilepsy [4, 5]. Cannabidiol can be synthesized (synthetic CBD) as well as extracted from C. sativa (plant derived). For different formulas [with different tetrahydrocannabidiol (THC) co-content], CBD-rich cannabis to purified CBD, to highly purified pharmaceutical-grade CBD (with THC content lower than 0.2%) are available.
First Cannabidiol Treatment in Epilepsy
Since the last century, the anticonvulsant effects of cannabis have been anecdotally described in small studies of patients with refractory epilepsies . However, the effect of medical cannabis on seizures and epilepsies is, in general, inconsistent. The scientific work-up of the phytocannabinoid CBD has shown promising anticonvulsant effects in different animal models [7, 8]. The mechanism of action of CBD is still not fully understood. However, modulation of intracellular Ca2 + mobilization (by GPR55 and TRPV1) as well as modulation of adenosine-mediated signal pathways seem to play an essential role .
Over the past few years, the interest in using CBD for general well-being as well as a treatment option for different diseases has risen. This deluge of personal experiences and reports has inspired patients with epilepsy and their families to try CBD for seizure control. A famous report detailed the treatment course of a 5-year-old girl with Dravet syndrome (DS) who experienced up to 50 bilateral tonic-clonic seizures per month. She experienced a > 90% reduction in seizures with CBD-rich cannabis treatment. This attracted immense attention and raised the interest in treating patients with epilepsy with CBD . Because of a massive amount of media reporting and the expectations and wishes of severely affected patients with epilepsy, the demand for medical cannabis and CBD treatment increased dramatically . In the USA, because of the legal restrictions of cannabis and its compounds, some families even moved to other states with easier access to medical cannabis and CBD to receive this treatment for their children with epilepsy .
Prompted by this, studies on CBD in epilepsy were set up. The first prospective data were collected in an observational interventional trial that included 214 children and adolescents with drug-resistant epilepsy of different etiologies. All of them experienced frequent seizures (median about 60 seizures monthly), thus representing a strongly affected group. Cannabidiol was tapered up until intolerance or a maximum of 25 mg/kg/day was achieved. The mean CBD dose was 22.9 mg/kg (safety group) and 22.7 mg/kg (efficacy group), respectively. The median monthly seizure change was − 34.6% for all seizures, − 55% for focal seizures, and − 54.3% for atonic seizures. In contrast, the efficacy for tonic-clonic seizures was worse (− 16%). Responder rates, defined as a reduction of at least 50% of the seizures, were 37% in all seizures, 56% in atonic seizures, 40% in tonic seizures, and 34% in tonic-clonic seizures, thus supporting the idea of CBD having different efficacies in different seizure types. The median reduction and responder rates for motor seizures were higher in the DS patient subgroup (49.8%). In the safety group, 79% of the patients reported adverse events (AEs), and 12% reported drug-related serious AEs. Adverse events led to discontinuation in 3% of the patients. The most common AEs were somnolence (25%), decreased appetite (19%), diarrhea (19%), and fatigue (13%). Six patients experienced thrombocytopenia and 11 had elevated liver enzymes; all of those were taking valproate. This study suggests a reduction in seizure frequency with CBD and an adequate safety profile .
Four randomized, controlled, double-blind studies were carried out in childhood-onset epilepsies: two in Lennox–Gastaut syndrome (LGS) and two in patients with DS. All of them used plant-derived, pharmaceutical-grade CBD from the same company.
Dravet syndrome (severe myoclonic epilepsy of infancy) is a rare, severe, childhood-onset, epileptic encephalopathy. Most patients with DS have a loss-of-function mutation in the voltage-gated sodium channel α1 gene (SCN1A gene); most of them are de novo mutations. Dravet syndrome is characterized by prolonged seizures, often triggered by fever or other quick changes in body temperature. The seizure burden is high with different seizure types such as focal or generalized seizures (absences, tonic atonic, myoclonic, tonic-clonic) and status epilepticus. Psychomotor delay and behavioral disturbances are common. The first randomized, double-blind, placebo-controlled trial of CBD in DS (GWCARE1b) was carried out in 120 children and adolescents using 20 mg/kg/day of CBD. Efficacy was assessed by comparing a 14-week treatment period with a baseline period. The median reduction in convulsive seizures was 38.9% vs 13.3% (adjusted median difference 22.8, p = 0.01). Responder rates were 42.6% vs 27.1% (p = 0.08) for convulsive seizures. For all seizures, the adjusted median difference was 19.2%, being significant (p = 0.03). Adverse events occurred often in the CBD group (93%) as well as in the placebo group (75%), most of the AEs were moderate or mild. Serious AEs were more common in the CBD group (16% vs 5%). Common side effects were somnolence (36% vs 10%), diarrhea (31% vs 10%), decreased appetite (28% vs 5%), and fatigue (20% vs 3%). The withdrawal rate was higher as well (13% vs 2%) . A second double-blind, placebo-controlled, randomized trial investigated 10 and 20 mg/kg/day of CBD (GWPCARE2) in 199 children and adolescents using a similar protocol. Median convulsive seizure reduction was 48.7% in the CBD 10-mg/kg/day group; 45.7% in the 20-mg/kg/day group; and 26.9% in the placebo group. Responder rates were 43.9%, 49.3%, and 26.2%, respectively. Adverse events were common in all groups (87.5%, 89.9%, and 89.2%), 92% of the AEs were judged to be mild or moderate. The most common side effects were decreased appetite, diarrhea, somnolence, pyrexia, and fatigue. A higher incidence of AEs, such as somnolence, rash, and pneumonia, was found when co-medicating with clobazam (CLB). Liver enzyme elevation (more than three times) was found in 12% of the CBD-treated patients, all of them in co-medication with valproate .
Lennox–Gastaut syndrome is an epileptic encephalopathy characterized by severe cognitive impairment, multiple seizures types, and abnormal electroencephalogram patterns with slowing and slow-spike and wave complexes. The incidence is about two per 100,000 and the etiology varies. The seizure burden is high and most of the patients experience drop attacks, which are a major problem because of the injury risk. Two phase III studies were carried out in patients with LGS with a focus on drop seizures. Included were 225 patients in the GWPCARE3 study, randomized to CBD 10 mg/kg/day, CBD 20 mg/kg/day, and placebo groups, all of whom were severely affected with a median frequency of more than 80 per 28 days for drop seizures and higher than 160 for all seizures. About half of the patients took CLB as a co-medication. Over a 14-week treatment period, a significant reduction in drop seizures was found between the 10-mg/kg/day group (37.2%), 20-mg/kg/day group (41.9%), and the placebo group (17.2%) reaching significance; results are significant for all seizures (36.4% vs 38.4% vs 18.5.%), but not for non-drop seizures (61.1% vs 54.6% vs 34.3%). Responder rates for drop seizures were significant (36% vs 39% vs 14%). Adverse events frequently occurred in all groups (84% vs 94% vs 72%), but most of the AEs were rated mild to moderate. Common AEs were somnolence, decreased appetite, and diarrhea; however, the number of patients who withdrew from the study because of AEs was low (1.5%, 7.3%, 1.3%) . A similar study, GWPCARE4, was carried out in 171 patients, 86 in the CBD 20-mg/kg/day group and 85 in the placebo group. The primary endpoint was the mean reduction in drop seizures, which was significant (43.9% vs 21.8%, p = 0.0135). Adverse events occurred often (86% in the CBD group vs 69% in the placebo group) with diarrhea, somnolence, pyrexia, decreased appetite, and vomiting being the most common. Withdrawal from the study because of AEs occurred more frequently in the CBD group (14%) vs 1% in the placebo group .
Tuberous sclerosis complex (TSC) is a rare (1:6000), autosomal, dominant, genetic disease causing benign tumors in different organs (eyes, skin, heart, kidney, lung, and brain). The severity varies widely, but most patients with TSC have epilepsy with different seizure types . After pharmaceutical-grade CBD medication for 3 months, a relevant reduction in the median seizure frequency (48.8%) and responder rates (50%) were shown. The reduction was higher in the group with the CLB co-medication (58.3% vs 33.3%). Adverse events were common (66.7%): drowsiness, ataxia, and diarrhea . A randomized controlled trial for seizures in TSC (GWPCARE6) randomized 224 patients to CBD 25 mg/kg/day, CBD 50 mg/kg/day, and placebo groups. The median reduction of seizure frequency was significantly greater in CBD groups (43.4 and 36.6%) than for placebo groups (20.1%). Adverse events were common (88%, 97%, 90%). Diarrhea (31%, 55%, 25%), somnolence (13%, 26%, 9%), vomiting (10%, 16%, 8%), pyrexia (19%, 16%, 8%), and decreased appetite (20%, 23%, 12%) were the most common . An open-label extension of this study is currently in the recruiting phase.
As a result of the above-mentioned studies, the first plant-derived, purified, pharmaceutical-grade CBD treatment (Epidiolex ® ) was approved for DS and LGS by the US Food and Drug Administration in 2018 and for the same epilepsy entities in combination with CLB by the European Medicines Agency (Epidyolex ® ) in 2019. In 2020, approval for the treatment of patients with TSC with plant-derived, purified, pharmaceutical-grade CBD (Epidiolex ® ) was given by the Food and Drug Administration only for a maintenance dose of 25 mg/kg/day as a higher dose showed a negative risk-for-benefit ratio (see Table Table1 1 for an overview of all studies).
Results of the pivotal studies on plant-derived pharmaceutical-grade cannabidiol (CBD) [Epidiolex ® ]
Treating Epilepsy with CBD Oil
Galveston resident Trysten Pearson, who has epilepsy, experienced his first seizure in 2013 when he was 12 years old. But last summer, his mother Shena Pearson explained, his condition began to deteriorate quickly.
Despite taking a slew of medications, and despite having a device implanted under the skin of his chest that sends electrical impulses to his brain to reduce the number and severity of his seizures, Trysten’s symptoms persisted.
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He often felt nauseous and he’d vomit every few days. Because exercise triggered his seizures, his school stopped allowing him to participate in physical education, leading to weight gain. His grades were dropping and his memory was fading, too.
“Because of these horrific seizures, when I show him photos from when he was younger, his memory is completely lost,” Shena explained. “Sometimes, he looks at a photo from his past, and he just bawls. He says, ‘It’s unfair to me that my history is gone.’”
But this spring, Trysten’s luck finally turned, thanks to a treatment that has become available to him and thousands of other epilepsy patients across the state.
“My life has changed so much,” said Trysten, who turns 17 in July.
Teachers told Shena that Trysten was less distracted at school and that his performance had improved. In his first 30 days on his new treatment, he had just one seizure. He hasn’t felt this well for the past three years.
And it’s all thanks, the Pearsons say, to cannabis.
“I really wanted this medicine to work because of how many times pills have failed me,” said Trysten, who takes drops of the oil orally. “Once I started taking it, I felt so much better. I don’t have seizures.”
For the Pearsons, cannabis was a last resort to relieve Trysten’s epilepsy after years of other treatments failed to provide relief.
They were astounded by how quickly, and how well, the treatment worked.
Across Texas, doctors and patients are now finally able to take advantage of a three-year-old law that makes cannabidiol oil, or CBD oil, available to some epilepsy patients. CBD oil is derived from the cannabis plant, also known as marijuana. CBD oil provides symptom relief without intoxicating effects.
A different substance in the plant, tetrahydrocannabinol, or THC, is responsible for the high associated with cannabis.
In June 2015, Gov. Greg Abbott signed into law the Texas Compassionate Use Act after it passed both chambers of the state legislature by wide, bipartisan margins. But it wasn’t until late 2017 that the state issued full licenses to the only three businesses in Texas that can now legally provide CBD oil to prescribed patients.
Meanwhile, doctors have been slow to sign up for the program as they navigate the new law. As of late June, just 42 physicians across Texas were registered with the state to become CBD oil prescribers, including 12 in Harris County, though not all are prescribing CBD oil at this point. According to the Epilepsy Foundation of Texas, approximately 149,000 Texans have been diagnosed with the form of epilepsy that would make them eligible for the program.
For many who have used CBD oil, the newly available treatment has provided relief when all else failed. About two thirds of epilepsy patients will respond to the first or second medicine they’re given for epilepsy. But once an epilepsy patient has taken two different medicines without relief, the odds that a third medication will work are less than 1 percent, doctors say. That leaves other options, such as special diets, surgeries, device implementation—or CBD oil.
“This can be really beneficial to patients,” said Michael Watkins, M.D., assistant professor of pediatric neurology with McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth). Watkins works at the Pediatric Epilepsy Clinic at UTHealth, where about 20 patients have been prescribed CBD oil. He said the stigma associated with taking medicine derived from cannabis is fading.
“Most people are looking for anything beneficial to prevent their kids from having seizures,” Watkins said.
Doctors, patients and advocates are quick to point out CBD oil isn’t a miracle cure. It doesn’t eradicate epilepsy and it doesn’t help everyone. But for some patients, it can help eliminate or reduce their symptoms, and it may allow them to ease off of other drugs that have serious side effects, including anemia, low platelet levels, liver failure, pancreatitis, allergic reactions and suicidal tendencies.
Before the Texas law took effect, many patients were trying CBD oil on their own by visiting other states or ordering it online, which is a legal gray area. The problem with that, doctors say, is it’s difficult to determine the precise potency of the drug the patient is receiving.
“It’s kind of risky, but these parents and families are desperate for their kids,” said Gretchen Von Allmen, M.D., chief of pediatric epilepsy with McGovern Medical School at UTHealth and a pediatric neurologist at Memorial Hermann-TMC.
Under the state’s compassionate use law, patients’ medicine must contain at least 10 percent CBD oil and no more than 0.5 percent THC. For context, recreational marijuana might measure 20 percent THC. Those restrictions ensure Texas CBD oil makers maximize the compounds that provide symptom relief while minimizing those that can cause side effects or a high (Trysten Pearson, for his part, said he experiences no side effects from CBD oil).
Still, Texas’s CBD law is considered “pretty restrictive” compared to those involving cannabis in other states, said Katharine Neill Harris, Ph.D., a drug policy fellow at Rice University’s Baker Institute for Public Policy.
Texas patients must get two doctors to approve their use of CBD oil. And they are only eligible for a prescription if they have what’s called “intractable” epilepsy—meaning at least two other medications have failed to help them. Harris said she wouldn’t even call Texas’ policy a “medical marijuana” law.
Perhaps the biggest hurdle of all is price. The Pearsons pay $350 per month for Trysten’s CBD oil—a typical amount—and the cost isn’t covered by insurance. That’s unlikely to change, experts say, as long as the federal government views cannabis as a Schedule I drug with no accepted medical use. In May, a federal appeals court sided with the Drug Enforcement Administration, ruling that CBD oil is a Schedule I controlled substance. But in June, the U.S. Food and Drug Administration approved Epidiolex, a CBD oral solution to treat seizures associated with rare and severe forms of epilepsy.
Morris Denton, CEO of Compassionate Cultivation, which provides the CBD oil used by the Pearson family, has launched a discount program with the Epilepsy Foundation Texas to help subsidize CBD oil costs for low-income Texans. So far, the program has served 12 of its approximate 300 customers.
Meanwhile, the Texas law doesn’t permit people with any diagnosis besides intractable epilepsy to use CBD oil, even though some other states allow those with multiple sclerosis, late-stage cancer, Crohn’s disease and other conditions to access CBD oil or medical marijuana. That has frustrated some patients and advocates, but skeptics say more research must be done to evaluate whether and how CBD oil can treat those illnesses.
“Now that the people of Texas are seeing the real impact of this medicine, not just the potential impact, we need to figure out how to get it into other people’s hands that are as deserving as people with intractable epilepsy,” Denton said. “That’s up to the legislature to figure out how to make that happen.”