Moreover, there was no difference among subtypes of epileptic encephalopathies (Dravet and Lennox-Gastaut syndromes), although the data implies that patients from these two genetic-related epileptic syndrome are more sensitive to CBD treatment (Supplementary Table 1). At least 27% of all treated patients showed an “improvement >70%” in seizures frequency (83/311 patients) and the studies varied between 18 and 57% (Table (Table2). 2 ). The “seizure free” endpoint was not used for the analysis because it is not a parameter used by a significant amount of the selected studies. The number of individuals that remained free of seizures was close to 10% in the papers reporting this endpoint, which is a relevant amount for a population that tried several prior anti-epileptic medications without success. The proportion of patients reporting any improvement and “classical” responders was also relatively high for a treatment-resistant population and is slightly above the number of responders commonly observed in studies of registered anti-epileptic drugs (29–31).
However, when the clinical threshold of “reduction of 50% or more in seizure frequency” was evaluated, only 39% of the individuals were considered responders (studies varying between 24 and 74%), and there was no difference (p = 0.52) between treatments with CBD-rich extracts (122/330, 37%) and purified CBD (94/223, 42%). The mean dose, regardless of treatment was 15.0 mg/kg/day of CBD equivalent. The average daily dose reported for purified CBD was 25.3 mg/kg/day, while the average daily dose of CBD equivalent reported for CBD-rich Cannabis extract was merely 6.0 mg/kg/day.
FP gathered data, analyzed results, and wrote the manuscript. LdS and AC helped with data organization and manuscript writing.
The first CBD-based product was just recently registered for the treatment of treatment-resistant epilepsies (27). Meanwhile, the patients are using non-registered hemp extracts and derivative products that are considered “nutritional supplements” with high CBD content and often unknown THC concentration. These products are not considered controlled substances at the production countries and are being distributed in many countries via exceptional import mechanisms.
Positive secondary effects * of treatment with CBD-rich Cannabis extracts and purified CBD described as secondary endpoints in the clinical studies.
The systematic search took place in February/2017 and updated on the 13th of December 2017 using the keywords “child” and “epilepsy” or “Dravet” or “Lennox-Gastaut” or “CDKL5” combined with “Cannabis,” “cannabinoid,” “cannabidiol,” or “CBD” resulting in 199 papers. From these, 138 were duplicates and were removed. The remained 61 records were screened and 42 of these studies were excluded. Nineteen (19) papers were assessed for eligibility and 6 papers were excluded due to lack of observational clinical data (ex: preclinical studies). The qualitative assessment of 13 articles resulted in 11 valid references for analysis, with an average impact factor of 8.1 (ranging from 1.4 to 47.8) (Figure (Figure1 1 ).
The natural source of CBD is a variety of Cannabis plants called “hemp” or “fiber-type Cannabis,” where one can find a high ratio between CBD and THC compounds, sometimes around 30:1 (CBD:THC), with negligible amounts of THC (16, 17). Fiber-type Cannabis are, by definition, Cannabis with < 0.3% THC content, which is not considered controlled substance by the United Nations Office on Drugs and Crime (18). Hemp extracts became an internet buzz (19), with several anecdotal descriptions of therapeutic effects in children with treatment-resistant epilepsies, especially Dravet syndrome, starting to appear since 2013 (11, 20, 21). Preclinical evidence support anti-convulsant properties of CBD [reviewed in Hill et al. (22) and Devinsky et al. (23)]. Furthermore, a number of observational papers suggested good tolerability and therapeutic benefits in seizure control, with patients experiencing low frequency of side effects (6–15). Few randomized control trials in specific diseases have followed (24, 25) and the putative neuronal mechanism of action is still to be established, with the more likely candidates being inhibition of endocannabinoid uptake, allosteric modulation of CB1 receptors, activation of 5-HT1A serotoninergic receptors anti-inflammatory/anti-oxidant effects [reviewed in Bih et al. (26)].