Δ⁹-Tetrahydrocannabinol Effects on Respiration and Heart Rate Across Route of Administration in Female and Male Mice

The physiological impact of cannabinoid receptor agonists is of great public health interest due to their increased use in recreational and therapeutic contexts. However, the body of literature on cannabinoid receptor agonists includes multiple confounding variables that complicate comparisons across studies, including route of administration, timeline across which phenotypes are observed, agonist dose, and sex of the study cohort. In this study, we characterized the impact of sex and route of administration on Δ⁹-tetrahydrocannabinol (THC)-induced changes in cardiopulmonary phenotypes in mice. Using noninvasive plethysmography and telemetry, we monitored heart rate and respiration in the same cohort of animals across aerosol, oral gavage, subcutaneous, and intraperitoneal administrations of THC (0-30 mg/kg THC for oral gavage, subcutaneous, and intraperitoneal, and 0-300 mg/ml THC for aerosol). All routes of THC administration altered respiratory minute volume and heart rate, with the direction of effects typically being consistent across dependent measures. THC primarily decreased respiration and heart rate, but females given oral gavage THC showed increased heart rate. Intraperitoneal and subcutaneous THC produced the longest-lasting effects, including THC-induced alterations in physiological parameters for up to 10 h, whereas effects of aerosolized THC were short lived. The fastest onset of effects of THC occurred for aerosolized and intraperitoneal THC. Altogether, the work herein establishes the impact of dosing route on THC-induced heart rate and respiratory alteration in male and female mice. This study highlights important differences in the timeline of cardiopulmonary response to THC following the most common preclinical routes of administration.