Brett Goerl1, Sarah Watkins2, Cameron Metcalf3, Misty Smith4, Mark Beenhakker5. 1. Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, 22903, USA. Electronic address: bag4ze@virginia.edu. 2. Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, 22903, USA. Electronic address: ssw2na@virginia.edu. 3. Department of Pharmacology and Toxicology, University of Utah College of Pharmacy, Salt Lake City, UT, 84112, USA. Electronic address: cameron.s.metcalf@utah.edu. 4. Department of Pharmacology and Toxicology, University of Utah College of Pharmacy, Salt Lake City, UT, 84112, USA; Oral Biology, Medicine, & Pathology, University of Utah School of Dentistry, Salt Lake City, UT, 84112, USA. Electronic address: misty.smith@pharm.utah.edu. 5. Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, 22903, USA. Electronic address: mpb5y@virginia.edu.
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.
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.
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