Cannabidiolic acid exhibits entourage-like improvements of anticonvulsant activity in an acute rat model of seizures

Abstract

Objectives: Cannabidiolic acid (CBDa) is pharmacologically unique from cannabidiol (CBD), but its chemical instability poses challenges for potential clinical utility. Here, we used magnesium ions to stabilize two cannabidiolic acid-enriched hemp extracts (Mg-CBDa and Chylobinoid, the latter of which also contains minor cannabinoid constituents) and compared their anticonvulsant activities with CBD in the maximal electroshock seizure test (MES) in rats.

Methods: Sprague-Dawley rats received intraperitoneal (i.p.) injections of Chylobinoid, Mg-CBDa, or CBD at varying doses at discrete time points. Rats were challenged with a 0.2 s, 60 Hz, 150 mA corneal stimulation and evaluated for resultant hindlimb tonic extension. Dose-response relationships were calculated using Probit analysis and statistical significance was assessed with a two-sample z-test.

Results: Median effective doses (ED₅₀) and 95 % confidence intervals were calculated for each compound and adjusted according to percentage of CBDa (w/w): Chylobinoid: 76.7 (51.7-109.2) mg/kg. Mg-CBDa: 115.4 (98.8-140.9) mg/kg. CBD: 68.8 (56.6-80.0) mg/kg.

Significance: CBDa-enriched hemp extracts exhibited dose-dependent protection in the MES model at doses comparable, but not more effective than, CBD. Chylobinoid was more effective than Mg-CBDa despite lower CBDa content. Test compounds should be compared by sub-chronic dosing in the MES test in order to assess safety and pharmacokinetic profiles. CBDa should be evaluated in pharmacoresistant and chronic animal models of epilepsy.

Keywords: Cannabidiol; Cannabidiolic acid; Cannabis; Entourage effect; Epilepsy; Maximal electroshock seizures.

Fig. 1.. Time of peak effect (TPE) studies for Chylobinoid and Mg-CBDa.

Chylobinoid was administered i.p at a dose of 80 mg/kg and tested at time points of 0.5, 1, 2, and 4 h (N = 6–8 per time point). Mg-CBDa was administered i.p at a dose of 140 mg/kg and tested at time points of 0.5, 1, and 2 h. The TPE for Mg-CBDa and Chylobinoid is 1 h for both compounds.

Fig 2.. Dose-response curve of CBD and Chylobinoid in the rat MES test.

Chylobinoid and CBD were administered i.p. 1 hour and 2 hours prior to stimulation, respectively. Total animals used were N = 48 for Chylobinoid, N = 40 for CBD. The percent of rats protected is shown for each dose, with each point on the graph representing a group of N = 8 animals. ED₅₀’s were calculated per probit analysis to be 102.97 mg/kg (Chylobinoid) and 68.78 mg/kg (CBD). The adjusted graph represents Chylobinoid dose standardized for 74.5% CBDa, with resulting ED₅₀ of 76.61 mg/kg.

Fig 3.. Dose-response curve of CBD and Mg-CBDa in the rat MES test.

Mg-CBDa and CBD were administered i.p. 1 h and 2 h prior to stimulation, respectively. Total animals used were N = 40 for Chylobinoid, N = 40 for CBD. The percent of rats protected is shown for each dose, with each point on the graph representing a group of N = 8 animals. ED₅₀’s were calculated per probit analysis to be 124.34 mg/kg (Mg-CBDa) and 68.78 mg/kg (CBD). The adjusted graph represents Mg-CBDa doses standardized for 92.8% CBDa, with resulting ED₅₀ of 115.39 mg/kg.