**7. Conclusion**

other cognitive functions, social interactions, behavior, and global quality of life (QOL). Interestingly, these differences were not correlated to changes in seizure frequency or adverse events. The results suggest that CBD may have beneficial effects on patient QOL, distinct from

Devinsky et al. later performed a double blind, placebo-controlled trial in patients with Dravet syndrome including 120 children and young adults using Epidiolex with a CBD dosage of 20 mg/kg/day. The median frequency of convulsive seizures per month decreased from 12.4 (baseline) to 5.9 with CBD, as compared with a decrease from 14.9 (baseline) to 14.1 with placebo (adjusted median difference between cannabidiol vs. placebo was −22.8% points [CI], −41.1 to −5.4; p = 0.01). The percentage of patients who had at least a 50% reduction in convulsive seizure frequency was 43% with cannabidiol and 27% with placebo (odds ratio, 2.00; 95% CI, 0.93–4.30; p = 0.08). This study shows an overall benefit of CBD over placebo but also

Another trial that assessed the efficacy of Epidiolex in reducing atonic seizures in patients with Lennox-Gastaut syndrome. In this double blind, placebo-controlled trial, a total of 225 patients were enrolled, 76 patients were assigned to a treatment group (20 mg/kg/day CBD) and 76 to the placebo group. The median percent reduction from baseline in monthly atonic seizure frequency during the treatment period was 41.9% in the treatment group vs. 21.8% in the placebo group. As with the other studies assessing Epidiolex, the most common adverse events among the patients in the treatment groups were somnolence, decreased appetite, and diarrhea [69]. A recent systematic review assessed the safety and efficacy of pharmaceutical grade CBD in pediatric onset drug resistant epilepsy with outcome measures including 50% seizure reduction, complete seizure freedom, improved QOL. A total of 36 studies were identified including 6 randomized controlled trials and 30 observational studies. Overall CBD at a dose of 20 mg/kg/day was more effective than placebo in reducing seizure frequency by 50% (Relative Risk 1.74: 1.24–2.43). For one patient to achieve a 50% reduction in seizures the number of patient needed to treat was 8. In pooled data of 17 of the observational studies CBD at 20 mg/ kg/day resulted in 48.5% of patients achieving a 50% reduction in seizures (95% CI: 39.0–58.1%) while pooled data from 14 observational studies showed 8.5% of patients became seizure free (95% CI: 3.8–14.5%). Quality of life improved in 55.8% of patients (95% CI: 40.5–70.6%) while serious adverse events related to treatment with CBD was very low at 2.2% of patients (95% CI: 0.0–7.9%). From this data, the authors concluded that pharmaceutical grade CBD may reduce seizure frequency but other randomized controlled trials examining a more diverse

group of epilepsy syndromes and other cannabinoids was needed [70].

To date, the evidence to support the use of cannabis in adults is minimal. STAR 1 is a phase 2A, randomized, double blind, placebo-controlled study that evaluated the safety and efficacy of synthetic transdermal CBD in adult patients with focal epilepsy. In this study 174 patients were randomized to receive either 195 mg CBD, 390 mg CBD or placebo via a transdermal patch. Patients who completed the 12-week study were able to continue into the 24-month open-label extension STAR 2 study (n = 171). In as of yet published data from these trials there was an increase in efficacy of transdermal CBD over 18 months. Median percentage change in seizure rates was −25% at 3 months, −40% at 6 months, −48% at 9 months, −52% at

its seizure reducing effects [67].

212 Recent Advances in Cannabinoid Research

a large placebo effect in the control group [68].

The cannabinoids found in cannabis appear to offer a unique pharmacological mode of action in the treatment of epilepsy. This, combined with the apparent low risk of serious side effects, makes cannabis and an attractive potential option for patients with treatment resistant epilepsy.

Currently, there is a large public perception that cannabis products are superior to and safer than conventional anti-epileptic medications especially in treating patients with Dravet syndrome and other pediatric onset epileptic encephalopathies. Based on interpretation of the available data, the authors feel that cannabis based therapies show promise in the treatment of children with treatment resistant epilepsies. While the studies to date assessing cannabis based therapies for the treatment of epilepsy have been encouraging, they should be interpreted with caution. At this time, the long-term adverse effects, the indicated epilepsy and seizure types suitable for treatment with cannabis, the dosing of CBD and other cannabinoids, remain unknown. Also, there is minimal data regarding the pharmacokinetics of the cannabinoids especially in children and when used in patients with multiple concomitant medications. Moreover, the existing studies are limited with the majority of them being retrospective and subject to bias, possible placebo effect, and other limitations.

As such, further studies assessing the safety and efficacy of cannabis based therapies in both adults and children are urgently needed. The authors recommend that these studies start with well-designed dose finding studies that include age stratified pharmacokinetic analysis followed by larger scale clinical trials. When faced with physicians that are reluctant to authorize cannabis based products due to a lack of high quality safety and efficacy data, parents who are desperate to help their children are then forced to turn to unregulated suppliers of cannabis. This puts their children at risk of harm and themselves in legal jeopardy.

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