High-Dose Cannabidiol Induced Hypotension after Global Hypoxia-Ischemia in Piglets

Abstract

Background: Cannabidiol (CBD) is considered a promising neuroprotectant after perinatal hypoxia-ischemia (HI). We have previously studied the effects of CBD 1 mg/kg in the early phase after global HI in piglets. In contrast to prior studies, we found no evidence of neuroprotection and hypothesized that higher doses might be required to demonstrate efficacy in this animal model. Objective: To assess the safety and potential neuroprotective effects of high-dose CBD. Methods: Anesthetized newborn piglets underwent global HI by ventilation with 8% O₂ until the point of severe metabolic acidosis (base excess -20 mmol/L) and/or hypotension (mean arterial blood pressure ≤20 mm Hg). Piglets were randomized to intravenous treatment with vehicle (n = 9) or CBD (n = 13). The starting dose, CBD 50 mg/kg, was reduced if adverse effects occurred. The piglets were euthanized 9.5 h after HI and tissue was collected for analysis. Results: CBD 50 mg/kg (n = 4) induced significant hypotension in 2 out of 4 piglets, and 1 out of 4 piglets suffered a fatal cardiac arrest. CBD 25 mg/kg (n = 4) induced significant hypotension in 1 out of 4 piglets, while 10 mg/kg (n = 5) was well tolerated. A significant negative correlation between the plasma concentration of CBD and hypotension during drug infusion was observed (p < 0.005). Neuroprotective effects were evaluated in piglets that did not display significant hypotension (n = 9) and CBD did not alter the degree of neuronal damage as measured by a neuropathology score, levels of the astrocytic marker S100B in CSF, magnetic resonance spectroscopy markers (Lac/NAA and Glu/NAA ratios), or plasma troponin T. Conclusions: High-dose CBD can induce severe hypotension and did not offer neuroprotection in the early phase after global HI in piglets.

A Systematic Review on the Pharmacokinetics of Cannabidiol in Humans

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A systematic review of minor phytocannabinoids with promising neuroprotective potential

“…In a recent systematic review conducted by our group, Millar, Stone, Yates, and O'Sullivan (2018) highlighted discrepancies regarding CBD bioavailability, C max , T max , and half‐life ( t 1/2 ) in humans depending on the route of administration and formulation and whether CBD was dosed in a fed or fasted state. That being said, studies conducted in piglets (Garberg et al, 2017) and rodents (Hammell et al, 2016; Long et al, 2012) have shown a dose‐dependent relationship between CBD administration and brain and plasma concentrations. Limited data extracted by Millar et al (2018) showed that administration of CBD in humans also led to dose‐dependent increases in plasma concentrations, suggesting the same may apply to brain concentrations in man.…”

DHA reduces oxidative stress following hypoxia-ischemia in newborn piglets: a study of lipid peroxidation products in urine and plasma

“…This was to investigate more subtle interactions as the study does not have enough power to finally conclude, and hence the risk for a type II statistical error where we find false negatives and erroneously reject a false null hypothesis, has been present. In paper I we used a one-way ANOVA as had been used in the bilateral project of Garberg et al 99,209 , whereas in paper II and III we used a twoway ANOVA as this was suggested by reviewers in paper II. According to the statistical advice, both analyses can be used, but the strength of the two-way ANOVA is the interaction and the possibility to decipher which of the interventions in a factorial design (therapeutic hypothermia and DHA) have effects.…”