The Journal of the Arkansas Medical Society Med Journal June 2019 Final - Page 15

mechanisms of action. Preclinical data have shown cannabidiol to have activity against sei- zures in in-vitro and in-vivo models. A Cochrane review in 2012 assessed the safety and efficacy of cannabinoid use in pa- tients with epilepsy. 3 A total of four studies (blinded and unblinded randomized clinical trials) were included in the review; however, all these trials were of low quality with small sample sizes and variations in product, dose, frequency, and duration of treatment. It was de- termined that the efficacy of CBD in the treat- ment of epilepsy could not be confirmed, but a dose of 200-300 mg daily can be administered safely over a short period. Two of these stud- ies were subsequently included in a systematic review by the American Academy of Neurology in 2014 to assess the role of medical marijuana in various neurologic diseases such as multiple sclerosis, epilepsy, and movement disorders. 4 It was concluded that the data were insufficient to support or refute the efficacy of cannabi- noids for reducing seizure frequency. However, the use of cannabinoids, specifically CBD, has increased in response to several anecdotal re- ports of remarkable response in epilepsy, and the perception that a substance or medicine derived from a natural source would be safer. One such report was broadcasted on a CNN special documentary, “Weed.” This special presented a girl named Charlotte Figi, who has Dravet syndrome, a rare and intractable genetic epileptic encephalopathy syndrome associated most commonly with SCN1A mutation. At five years of age, her mother started giving her an oral liquid, high-CBD, low-THC extract (later called Charlotte’s Web) made by the Stanley brothers in Colorado. Charlotte had suffered from very frequent seizures and experienced significant developmental delays and cognitive compromise. She had been treated with several antiepileptic drugs, with little or no improve- ment. In response to treatment with CBD oil, she experienced a >90% reduction in seizure frequency within three months and a remark- able improvement in cognition. 5 This and other similar reports prompted many parents to move their families across the country to gain access to CBD products. Up to 85% reduction in the seizure frequen- cy and increased alertness, better mood, and improved sleep were reported in several papers derived from online surveys and retrospective chart reviews. However, several confounders were present in these open-label retrospective studies; there were high expectations and mo- tivations leading to reporting bias and acting as obstacles to determine the actual efficacy of oral cannabis extracts. Subsequently, the recent in- terest in research in this sphere has led to the completion of several well-controlled studies in epilepsy, using a liquid proprietary oral formula- tion of CBD. Devinski et al. conducted a double- blind, placebo-controlled trial at 23 centers in the U.S. and Europe, with random assignment of 120 children and young adults with the Dravet syndrome and drug-resistant seizures to receive placebo vs. 20 mg/kg/day of CBD. 6 The median frequency of convulsive seizures per month de- creased from 12.4 to 5.9 in response to CBD, compared to a decrease from 14.9 to 14.1 with placebo. A > 50% reduction in convulsive sei- zure frequency was achieved in 43% of the CBD CBD is far from a miracle cure, and it is of paramount importance to have a reasonable expectation of its usefulness as an antiepileptic medication. treated group vs. 27% in the placebo group. The patient’s overall condition improved by at least one category on the seven-category Caregiver Global Impression of Change scale in 62% of the CBD-treated subjects compared to 34% in the placebo group. The frequency of total seizures of all types was significantly reduced in response to CBD (P=0.03), but there was no significant reduction in nonconvulsive seizures. CBD ther- apy rendered seizure freedom in 5% compared to 0% in the placebo group (P=0.08). A major weakness of the trial was the failure to report changes in the plasma concentration of cloba- zam and N-desmethylclobazam (level can in- NUMBER 12 > Continued on page 280. JUNE 2019 • 279