Dosage Related Efficacy and Tolerability of Cannabidiol in Children With Treatment-Resistant Epileptic Encephalopathy: Preliminary Results of the CARE-E Study

Abstract

Purpose: There is uncertainty regarding the appropriate dose of Cannabidiol (CBD) for childhood epilepsy. We present the preliminary data of seven participants from the Cannabidiol in Children with Refractory Epileptic Encephalopathy (CARE-E) study. Methods: The study is an open-label, prospective, dose-escalation trial. Participants received escalating doses of a Cannabis Herbal Extract (CHE) preparation of 1:20 Δ⁹-tetrahydrocannabinol (THC): CBD up to 10-12 mg CBD/kg/day. Seizure frequency was monitored in daily logs, participants underwent regular electroencephalograms, and parents filled out modified Quality of Life in Childhood Epilepsy (QOLCE) and Side Effect rating scale questionnaires. Steady-state trough levels (C_{ss, Min}) of selected cannabinoids were quantified. Results: All seven participants tolerated the CHE up to 10-12 mg CBD/kg/day and had improvements in seizure frequency and QOLCE scores. C_{SS, Min} plasma levels for CBD, THC, and cannabichromene (CBC) showed dose-independent pharmacokinetics in all but one participant. C_{SS, Min} CBD levels associated with a >50% reduction in seizures and seizure freedom were lower than those reported previously with purified CBD. In most patients, C_{SS, Min} levels of THC remained lower than what would be expected to cause intoxication. Conclusion: The preliminary data suggest an initial CBD target dose of 5-6 mg/kg/day when a 1:20 THC:CBD CHE is used. Possible non-linear pharmacokinetics of CBD and CBC needs investigation. The reduction in seizure frequency seen suggests improved seizure control when a whole plant CHE is used. Plasma THC levels suggest a low risk of THC intoxication when a 1:20 THC:CBD CHE is used in doses up to 12 mg/kg CBD/kg/day.

Keywords: cannabidiol; cannabinoid plasma levels; cannabis; epileptic encephalopathy; Δ9-tetrahydrocannabinol.

Figure 1

(A) Percentage reduction in daily average seizure frequency as compared to baseline. The value shown at each visit represents the decrease in seizure frequency from baseline during the preceding month. (B) Average percentage reduction in daily average seizure frequency from baseline for all seven participants at each study visit. (C) Average percentage reduction in daily seizure frequency from baseline for all seven participants broken down into seizure type. Data are shown as mean ± s.e.m.

Figure 2

Pooled QOLCE-55 scores and subscores for all seven participants. The values shown at each visit represent the QOLCE-55 total and subscores for the preceding month. Data are mean from seven participants.

Figure 3

Participant minimum steady state (C_SS,Min) plasma concentrations and average plasma C_SS,Min levels for each cannabinoid of cannabidiol (CBD) (A,B), cannabichromene (CBC) (C,D), and Δ⁹-tetrahydrocannabinol (THC) (E,F) analyzed with LC-MS/MS. Values shown represent steady state levels after 1 month on the corresponding dosage of CBD measured just prior to a dose administration. Data are mean ± s.e.m.