A preclinical model of THC edibles that produces high-dose cannabimimetic responses

Abstract

AbstractBackgroundNo preclinical approach enables the study of voluntary oral consumption of high dose Δ9-tetrahydrocannabinol (THC) and its intoxicating effects, mainly owing to the aversive response of rodents to THC that limits intake. Here we developed a palatable THC formulation and an optimized access paradigm in mice.MethodsTHC was formulated in chocolate gelatin (THC-E-gel). Adult male and female mice were allowedad libitumaccess for 2 h. Cannabimimetic responses (hypolocomotion, analgesia, and hypothermia) were measured following access. Levels of THC and its metabolites were measured in blood and brain samples. Acoustic startle responses were measured to investigate THC-induced psychotomimetic behavior.ResultsAccess to high-dose THC-E-gel (≈30 mg/kg over 2 h) resulted in robust consumption and CB1receptor-dependent behavioral responses. High-dose THC-E-gel consumption resulted in parallel accumulation of THC and its psychoactive metabolite 11-OH-THC in brain, a profile that contrasts with the known rapid decline in brain 11-OH-THC levels following intraperitoneal THC injections. High-dose THC-E-gel consumption increased the acoustic startle response preferentially in males, and this psychotomimetic response was remarkably different from the response triggered by intraperitoneal contingent administration of THC. Comparing cannabimimetic responses elicited by intraperitoneal versus oral administration enabled us to model a “predicted dose” of THC that triggers these responses.ConclusionVoluntary consumption of high-dose THC-E-gel triggered equivalent cannabimimetic responses in male and female mice but an increased acoustic startle response preferentially in males. These findings indicate that THC-E-gel offers a robust preclinical consumption model to study cannabimimetic responses in mice, including sex-dependent psychotomimetic responses.