Pharmacokinetics and central accumulation of delta-9-tetrahydrocannabinol (THC) and its bioactive metabolites are influenced by route of administration and sex in rats

Samantha L Baglot,Laurent Brechenmacher,Savannah H M Lightfoot,Gavin N Petrie,Robert J Aukema,Matthew N Hill,Laine M Grace,Ruokun Zhou,Linda Parker,Jong M Rho,Catherine Hume,Stephanie L Borgland,Ryan J Mclaughlin

doi:10.1038/s41598-021-03242-7

Abstract

Up to a third of North Americans report using cannabis in the prior month, most commonly through inhalation. Animal models that reflect human consumption are critical to study the impact of cannabis on brain and behaviour. Most animal studies to date utilize injection of delta-9-tetrahydrocannabinol (THC; primary psychoactive component of cannabis). THC injections produce markedly different physiological and behavioural effects than inhalation, likely due to distinctive pharmacokinetics. The current study directly examined if administration route (injection versus inhalation) alters metabolism and central accumulation of THC and metabolites over time. Adult male and female Sprague–Dawley rats received either an intraperitoneal injection or a 15-min session of inhaled exposure to THC. Blood and brains were collected at 15, 30, 60, 90 and 240-min post-exposure for analysis of THC and metabolites. Despite achieving comparable peak blood THC concentrations in both groups, our results indicate higher initial brain THC concentration following inhalation, whereas injection resulted in dramatically higher 11-OH-THC concentration, a potent THC metabolite, in blood and brain that increased over time. Our results provide evidence of different pharmacokinetic profiles following inhalation versus injection. Accordingly, administration route should be considered during data interpretation, and translational animal work should strongly consider using inhalation models.

Highlights

With recreational use of cannabis recently becoming legal in Canada and some states across the U.S, as well as medicinal use being legal in many other countries, there is a growing need to better understand the effects of cannabis on brain and behaviour
In efforts to make THC injection studies possess more face validity for translatability to humans, these previous studies aimed to produce peak plasma THC concentrations that are comparable to concentrations in human cannabis smokers
Utilizing ‘comparable’ dosages established in previous literature[4,25], as well as through pilot work in our laboratory, we sought to produce similar peak plasma THC concentrations following injection and inhalation that fell within the range produced in humans from cannabis[17,18,19,20,21,23] in order to determine if route of administration influenced metabolism or central accumulation of THC

Summary

Introduction

With recreational use of cannabis recently becoming legal in Canada and some states across the U.S, as well as medicinal use being legal in many other countries, there is a growing need to better understand the effects of cannabis on brain and behaviour. Controlled inhalation (smoking or vaping) of cannabis cigarettes in humans produces peak plasma THC concentrations 10–15-min after initial a dministration[15,17,18,19,20,21,22] with relatively rapid clearance of THC from plasma. Because of individual differences in the number, duration, and spacing of puffs, as well as inhalation volume and hold time, the exact concentration of peak plasma THC in human studies is extremely variable. Peak plasma concentrations of THC range from 60 to 200 ng/mL following inhalation of cannabis flower[17,18,19,20,21,23,24], making animal models that can control dose and timing extremely valuable

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