Tuesday, December 26, 2017

Cannabidiol for the treatment of drug-resistant epilepsy in children

Christopher L. Anderson, Victoria F. Evans, Thomas B. DeMarse, Marcelo Febo, Cynthia R. Johnson, Paul R. Carney.  Cannabidiol for the Treatment of Drug-Resistant Epilepsy in Children: Current State of Research.  J Pediatr Neurol 2017; 15(04): 143-150.

The reported effectiveness of these home preparations, especially those with high cannabidiol (CBD) concentrations, has garnered the attention of the medical community. In particular cannabis sativa, known for its lack of a psychoactive effect and high CBD content, has become a target of medical research. The shift in public and political interest to medicinal applications of CBD demands renewed research into its efficacy. Pediatric populations in particular stand to benefit significantly from a better understanding of the safety and efficacy of this novel treatment. This review discusses the current state of CBD research and identifies areas that require further investigation as they pertain to pediatric epilepsy populations. It will especially cover those suffering from refractory epilepsies for which other methods of remediation have not sufficed.

From the article

In August 2013, CBD became nearly a household name when a CNN news article told its readers of the journey of a young 6-year-old girl named Charlotte Figi, who was diagnosed with Dravet's syndrome, a rare form of epilepsy.  By the age of 3, Charlotte was having an average of 300 grand mal seizures (the most severe seizure type) per week and her condition was worsening to the point that physicians were suggesting a medically induced coma to give her battered body a rest. Numerous failed treatment attempts and the reality that there was nothing the hospital could do, Charlotte's parents decided to try a specific strain of marijuana for their daughter. The results were immediate, making Charlotte seizure free after a week of use. The larger scientific community immediately started discussing clinical implications of using CBD to treat epilepsy, with many pharmaceutical companies beginning their own drug development and testing. CBD, being a nonpsychoactive, became the ideal focus of interest for children in particular, due to fewer side effects. Significant examination of CBD for human use quickly began, leading to more critical and sophisticated surveys and studies.

Doubled-blind studies using CBD and a placebo control for epilepsy treatment are few, and of those, the low number of patients involved makes it difficult to provide consistent and sufficient data to prove effectiveness of the drug. Though the obvious conclusion of these smaller studies would be to perform them with a larger patient population and a more long-term treatment plan to better assess safety and efficacy, they give us a snapshot of the possible placebo effect that many federal agencies claim could be a possible explanation for “claimed success” with CBD treatment. One of these studies included 15 patients with generalized epilepsy who were randomly divided into two groups, all of which received a double-blind 200 to 300 mg/kg daily dosage of CBD or placebo along with their current AEDs.  Of the eight who ended up receiving CBD, four were seizure free, three had greater than 50% reduction, and one had no change in activity. Only one of the seven patients in the placebo group noted an improvement in seizure frequency at the end of the trial. Though low in sample size, studies such as this show the importance of using double-blind and placebo controlled studies for CBD research…

A more recent study performed by Devinsky et al used an expanded access program to determine the efficacy and safety of CBD (Epidiolex, GW Pharmaceuticals, Salisbury, United Kingdom) in children and young adults with treatment-resistant epilepsy.  Twenty-three patients, ranging from ages 3 to 26 (10.4 years old average) entered the study with nine diagnosed with Dravet's syndrome, four had Myoclonic-Absence epilepsy, three Lennox-Gastaut syndrome, and the others with generalized epilepsies. All patients underwent a 4-week baseline period when parents and caregivers recorded all seizures and seizure type in a study-provided diary. After baseline data were determined, the patients were then given a purified oil-based extract with a known composition of 98% CBD at a dose of 5 mg/kg/d in addition to their currently used AEDs. Their daily dose was increased by 5 mg/kg/d until a maximum dosage of 25 mg/kg/d was reached. Patients received the CBD treatment for a total of 3 months with seizure data continued to be recorded in provided diaries. All patients enrolled completed the 3 months on the study drug, with 9 (39%) of the 23 patients having a greater than 50% reduction in seizures and a 32% median reduction in seizures across all patients. Four (17%) of the patients were seizure free at the end of the 3 months, with three of the four notably having Dravet's syndrome. It was also noted that of those who entered the study with Dravet's syndrome, 44% (4/9) had a greater than 50% reduction in seizures and a 33% median reduction from baseline, overall. Some notable side effects were also reported, including somnolence (13/23, 57%), fatigue (13/23, 57%), decreased appetite (5/23, 22%), diarrhea (5/23, 22%), and weight loss (2/13, 9%). Because of some of these side effects, the dose of CBD was reduced from 25 to 20 mg/kg/d, which resulted in improvement of these symptoms. It was also significant that five patients had their clobazam dosage reduced due to its potential interaction with the CBD, causing heavy sedation.

Researchers recently published evidence of CBD use as a treatment of refractory epilepsy in tuberous sclerosis complex (TSC).  Using the same drug, Epidiolex, 10 pediatric patients with a definite diagnosis of TSC and refractory epilepsy were treated for 12 months. The safety, efficacy, and changes in behavior and cognition were assessed throughout the study. The results showed an improvement in response rate over time from 50 to 66% of the patients having greater than 50% reduction in seizures after the trial had ended. Parents reported improvements of alertness, verbal communication, cognitive ability, and expression of emotion. It was detailed that more than half of the participants experienced side effects, but most or all were relived after their other AEDs or current CBD does was adjusted. Though this study includes a very small sample size, it suggests that CBD is safe and can be an effective treatment option for children with refractory epilepsy and TSC…

These studies demonstrated the benefits of a clinically conducted, case-controlled trial compared with that of survey or observational collected data, with more directly reported data under known and controlled dosages of CBD. We also see that CBD has a significant effect on seizure activity in this young population. With varying epilepsy disorders and limited controls, this study raises many more questions in regards to what types of neurologic disorders may have an effect on CBD efficacy, shown by the higher response in Dravet's syndrome patients. GW Pharmaceuticals, the producers of Epidiolex, have openly reported success of their CBD-based drug in children with Dravet's and Lennox-Gastaut syndromes. Moving forward they have begun double-blind for the same patient populations to address the FDA's concern over placebo controls as well as smaller studies, looking at other epilepsies including the aforementioned TSC study as well as the efficacy in children with generalized refractory epilepsy…

Though seizure reduction has a significant effect on the patient's quality of life, looking at the other changes and likely improvements that CBD could be causing in social behavior, cognitive function, or motor skills is also important. Improvements or general changes in a patient's lifestyle are important in assessing how effective an AED can be, including CBD. Evaluating these changes while receiving CBD treatment will be an important step in therapeutic testing of the drug. Other clinical trials will need to look at the importance of dosage timing and the effectiveness of CBD in concurrence with other currently prescribed AEDs or any health risks that could be associated with taking these medications together. Examining how the percent of CBD combined with THC or other cannabinoids may work together, how the drug is administered, and at what point in the diseases life are important questions that need to be answered before the true effectiveness of CBD can be measured. With CBD and medical marijuana making a quick entry into medicine and becoming an increasingly significant topic on the political agenda, improved testing techniques, more focused studies on the effectiveness of different forms of CBD, and stronger involvement by clinicians will go a long way in making CBD a more viable option. Combining the promise of this new drug with the sophisticated techniques of clinical trials and laboratory testing can help physicians feel more comfortable about prescribing CBD, and patients about using CBD, while moving this new treatment option forward in the world of medicine.

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