Potential Clinical Benefits of CBD-Rich Cannabis Extracts Over Purified CBD in Treatment-Resistant Epilepsy: Observational Data Meta-analysis

Abstract

Abstract Potential clinical benefits of CBD-rich Cannabis extracts over purified CBD in treatment-resistant epilepsy: observational data meta-analysis Different therapies involving cannabinoid compounds have become popular on the past few years, particularly the use of canabidiol (CBD) based products for the treatment of child refractory epilepsy. In this segment we highlight genetic disorders such as the Dravet Syndrome, which has received a lot of attention in Brazil. Our country has been giving visibility for this issue after the public discussion regarding the patient Anne Fischer, who benefited from a treatment with hemp based products, imported from the United States of America as a nutritional supplement, and still unregistered in Brazil. To this moment there is no cannabinoid based product registered for clinical indication for epilepsy, so patients have at their disposal products considered nutritional supplements, in general produced from a type of Cannabis known as “hemp”, which are commercialized in Brazil through medical prescription. Despite several anecdotal evidences from patients and family members, until now there is no consensus on medical literature over the efficacy and safety of these products. Some observational studies are available on scientific literature, but there is still a scarcity of clinical studies conducted under the logic, rigor and organization necessary for clinical trial dedicated to the register of a pharmaceutical product. The objective of this paper is to describe the analysis of several observational clinical studies available on the literature regarding the treatment of child refractory epilepsy with cannabinoid based products. Beyond attempting to establish the safety and efficacy of such products, when possible, the present analysis also intended to investigate if there is enough evidence between the different aspects of safety and efficacy between CBD enriched extracts compared to purified CBD products. Results: a systematic search for papers in the “PubMed” search system with the words “Dravet”, "Lennox-Gastaut" and "epilepsy" combined with the terms "Cannabis", "cannabinoid" and "child" yielded 30 papers. From those, 24 were not considered for the systematic review, for not having valid content (13), for being opinion only papers (6), showed not clinical data (4) and reported different subjects (1), resulting in 6 valid papers published between 2013 and 2016. One additional study was in press at the moment of the search was added manually (1) resulting in 7 valid references for analysis, with an average impact factor of 5,9 (2,3 to 21,8). Public data from partial reports of controlled randomized studies conducted in order to register a medication (2) were also considered, when appropriated and were mentioned in the text. The categorical data were analyzed by the Fischer test. Overall, the papers analyzed report observational clinical data of 442 patients, treated with CBD rich extracts or purified CBD, with he average daily dose between 1 and 50 mg/kg, with treatment length from 3 to 12 months (average of 6,2 months). A considerable amount of 66% (292/442) of the patients reported improvement in the frequency of convulsive crisis. There were more reports of improvement from patients treated with purified CBD (242/285) than patients treated with purified CBD (68/157), with statistical significance (p<0,0001). Nevertheless, when the standard clinical threshold of a “50% reduction or more in the frequency of convulsive crisis” was applied, only 40% of the individuals are considered respondent, and there were no difference (p=0,57) between the treatments with extract (64/168) and purified CBD (65/157). However, even that both treatments have similar efficacy, the patients treated with CBD enriched extracts reported a lower average dose than purified CBD patients. The average CBD equivalent dose on the extracts was 7,1 mg/kg/day, while the purified CBD was 22,9 mg/kg/day, suggesting that CBD is about 3x more potent in the extract than in its purified form. Looking only at the data relative to genetic originated disorders, there is evidence of a superior efficacy on Dravet Syndrome patients (37/72, p=0,01), but not for Lennox-Gastaut Syndrome (78/188, p=0,18), compared to the number of refractory epilepsy respondents in general (107/305). There is also an advantage of the CBD enriched extracts related to the occurrence of side effects. The report of mild side effects (109/285 vs. 291/346, p<0,0001) and severe (23/285 vs. 77/346, p<0,0001) are more frequent in products containing purified CBD than on CBD enriched extracts. Important to mention that these are the numbers of total reports of side effects, it is not possible to infer which fraction of these numbers are related to the treatment. In conclusion, this meta analysis suggests that treatments using CBD enriched extracts are more potent and have a better profile of adverse effects (but not more efficacy) than p