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

Abstract

Background: No preclinical approach enables the study of voluntary oral consumption of high dose 9-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. Methods: THC was formulated in chocolate gelatin (THC-E-gel). Adult male and female mice were allowed ad libitum access 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. Results: Access to high-dose THC-E-gel (30 mg/kg over 2 h) resulted in robust consumption and CB1 receptor-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. Conclusion: Voluntary 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.

Oral pre‐ and early postnatal cannabis exposure disinhibits ventral tegmental area dopamine neuron activity but does not influence cocaine preference in offspring in mice

“…Notably these effects were only observed in male mice, consistent with previous work in juvenile male rats (Frau et al, 2019;Traccis et al, 2021). Thus, despite differences in pharmacokinetics of oral versus injected cannabis (Baglot et al, 2021;English et al, 2024;Sallam et al, 2023), different species, and an extended cannabis exposure timeline, disinhibition of dopamine neurons with PPCE is replicated in this voluntary oral model, indicating that this is a robust, sex-specific outcome from prenatal and combined pre-and early postnatal cannabinoid exposure.…”

“…Several models of prenatal, perinatal, and early postnatal cannabis exposure, each with advantages and drawbacks, are described in the literature. Traditionally, animal models have used injection of THC or CB1R agonists, which allows easy control of dose, but does not match human consumption patterns and has a different pharmacokinetic and behavioral profile than vapor (Baglot et al, 2021;Manwell et al, 2014;Moore et al, 2021) or oral administration (English et al, 2024;Sallam et al, 2023).…”

“…Several models of prenatal, perinatal, and early postnatal cannabis exposure, each with advantages and drawbacks, are described in the literature. Traditionally, animal models have used injection of THC or CB1R agonists, which allows easy control of dose, but does not match human consumption patterns and has a different pharmacokinetic and behavioral profile than vapor (Baglot et al., 2021; Manwell et al., 2014; Moore et al., 2021) or oral administration (English et al., 2024; Sallam et al., 2023). Passive vapor exposure has gained popularity recently (Black et al., 2023; Manwell et al., 2014; Moore et al., 2021) and has been used in prenatal models (Baglot et al., 2022; Black et al., 2023; Weimar et al., 2020, 2023), though the dose each animal receives is not as easily controlled as with injections or oral gavage, as how much animals inhale cannot be regulated.…”

“…Therefore, we sought a model of pre‐ and early postnatal cannabis exposure (PPCE), which reduced maternal stress, was administered similar to that of human consumption, and which allowed control over the dose. To this end, we used a model of voluntary oral consumption of a limited quantity of cannabis, as has been used in acute exposure (English et al., 2024). Using tandem liquid chromatography and mass spectrometry, we have characterized the levels of THC, THC‐COOH (main secondary metabolite of THC that is inactive and expelled through urine/fecal matter), and cannabidiol (CBD), a nonpsychoactive constituent found in cannabis, and an increasingly popular supplement (Goodman et al., 2022) in dam plasma and pup brain across the prenatal (gestational day [GD]1–18) and early postnatal (to postnatal day [PD]10) exposure.…”

Neural and behavioral correlates of edible cannabis-induced poisoning: characterizing a novel preclinical model

“…Edible cannabis poisoning may also produce such deficits. While THC exposure via vapor, injection, and gavage induces specific behavioral effects referred to as the cannabis tetrad, which includes catalepsy, hypolocomotion, hypothermia, and anti-nociception [36][37][38], few studies have evaluated similar behavioral effects using edible cannabis [39,40]. Sex differences in sensitivity to the effects of THC [41,42] and its metabolism [43] exist, therefore, it may be worth investigating these differences with respect to edible cannabis poisoning.…”