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. 2023 Jan:187:106600.
doi: 10.1016/j.phrs.2022.106600. Epub 2022 Dec 5.

Nasal accumulation and metabolism of Δ9-tetrahydrocannabinol following aerosol ('vaping') administration in an adolescent rat model

Alexa Torrens  1 , Christina M Ruiz  2 , Maricela X Martinez  2 , Alex Mabou Tagne  1 , Pritam Roy  3 , Dakota Grimes  1 , Faizy Ahmed  1 , Valeria Lallai  2 , Victoria Inshishian  2 , Malia Bautista  2 , Yen-Chu Chen  2 , Marilyn A Huestis  4 , Aditi Das  3 , Christie D Fowler  2 , Stephen V Mahler  2 , Daniele Piomelli  5
Affiliations

Nasal accumulation and metabolism of Δ9-tetrahydrocannabinol following aerosol ('vaping') administration in an adolescent rat model

Alexa Torrens et al. Pharmacol Res. 2023 Jan.

Abstract

Passive aerosol exposure to Δ9-tetrahydrocannabinol (THC) in laboratory animals results in faster onset of action and less extensive liver metabolism compared to most other administration routes and might thus provide an ecologically relevant model of human cannabis inhalation. Previous studies have, however, overlooked the possibility that rodents, as obligate nose breathers, may accumulate aerosolized THC in the nasal cavity, from where the drug might directly diffuse to the brain. To test this, we administered THC (ten 5-s puffs of 100 mg/mL of THC) to adolescent (31-day-old) Sprague-Dawley rats of both sexes. We used liquid chromatography/tandem mass spectrometry to quantify the drug and its first-pass metabolites - 11-hydroxy-Δ9-THC (11-OH-THC) and 11-nor-9-carboxy-Δ9-THC (11-COOH-THC) - in nasal mucosa, lungs, plasma, and brain (olfactory bulb and cerebellum) at various time points after exposure. Apparent maximal THC concentration and area under the curve were ∼5 times higher in nasal mucosa than in lungs and 50-80 times higher than in plasma. Concentrations of 11-OH-THC were also greater in nasal mucosa and lungs than other tissues, whereas 11-COOH-THC was consistently undetectable. Experiments with microsomal preparations confirmed local metabolism of THC into 11-OH-THC (not 11-COOH-THC) in nasal mucosa and lungs. Finally, whole-body exposure to THC deposited substantial amounts of THC (∼150 mg/g) on fur but suppressed post-exposure grooming in rats of both sexes. The results indicate that THC absorption and metabolism in nasal mucosa and lungs, but probably not gastrointestinal tract, contribute to the pharmacological effects of aerosolized THC in male and female rats.

Keywords: Cannabis; Metabolism, vaping; Nasal mucosa, lungs; Pharmacokinetics.

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Conflict of interest statement

Declaration of Competing Interest No competing interests exist.

Figures

Figure 1.
Figure 1.
THC concentrations in nasal mucosa, lungs, and plasma of adolescent male rats (A) and female rats (B) after passive exposure to a THC aerosol (100 mg/mL, ■•) or intraperitoneal administration (5 mg/kg, ■•). Tissues were collected 5 min after a 30-min aerosol exposure or 35 min after intraperitoneal injection. Bars represent mean ± SEM, n = 3–4 animals. ***P < 0.001, ****P < 0.0001, significant difference compared to aerosol administration, two-way ANOVA.
Figure 2.
Figure 2.
Concentrations of THC in nasal mucosa (A), lungs (B), plasma (C), olfactory bulb (D) and cerebellum (E) of adolescent male (■) and female (•) rats after passive exposure to a THC aerosol (100 mg/mL). The exposure lasted 30 min and tissues were collected 5, 15 and 60 min later. Symbols represent mean ± SEM, n = 3–4 animals. **P < 0.01, significant sex-difference, two-way ANOVA.
Figure 3.
Figure 3.
Concentrations of 11-OH-THC in nasal mucosa (A), lungs (B), plasma (C), olfactory bulb (D) and cerebellum (E) of adolescent male (■) and female (•) rats after passive exposure to a THC aerosol (100 mg/mL). The exposure lasted 30 min and tissues were collected 5, 15 and 60 min later. Symbols represent mean ± SEM, n = 3–4. *P < 0.05, **P < 0.01, significant sex-difference, two-way ANOVA.
Figure 4.
Figure 4.
Rate of production of 11-OH-THC from THC in nasal mucosa and lung microsomes from naïve adolescent male (■) and female (•) rats. 11-COOH-THC was below the limit of detection in both tissues. Data are shown as pmol/min/mg of protein. Bars represent mean ± SEM, n = 4. **P < 0.01, significant difference compared to nasal mucosa, two-way ANOVA.
Figure 5.
Figure 5.
Concentrations of THC (top) and 11-OH-THC (bottom) in nasal mucosa (A, C) or lungs, plasma, olfactory bulb, and cerebellum (B, D) of adolescent male (■) and female (•) rats after intranasal infusion of THC (5 mg/kg). To match the aerosol exposure protocol, tissues were collected 35 min after administration. Symbols represent mean ± SEM, n = 4.
Figure 6.
Figure 6.
THC deposits on the fur of adolescent male (■) and female (•) rats after passive exposure to THC aerosol. Fur was collected 60 min after removal of the animals from the aerosol chambers. Data are shown as pmol/g of fur. Bars represent mean ± SEM, n = 4.
Figure 7:
Figure 7:
Impacts of vehicle or THC vapor on grooming behavior of the head (unfilled symbols) or body (filled symbols) of adolescent male (■) and female (•) rats after exposure to the chamber/vacuum only (naïve), vehicle vapor (VEH), or THC vapor (100mg/ml). Bars represent mean ± SEM, n = 3 animals. *P < 0.05, ***P < 0.001, ****P < 0.0001, two-way ANOVA, not all statistics are shown for clarity.
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