Background: Comparative bioavailability of cannabinoids following their administration by dosing routes has been studied previously, but there are no quantitative reports of distribution of Δ9THC, nor its metabolites, across various brain regions following intranasal (i.n.) administration. The aim of the present study was to determine the time course of Δ9THC transport from nose to brain and to quantify the distribution of Δ9THC and its metabolites in four brain regions.
Methods: Δ9THC was formulated as a lipophilic nano-emulsion and instilled i.n. to three groups of adult mice and euthanized after 2, 4, and 8 h. Brains were dissected into 4 regions. Sensitive analytical methods (HPLC-MS) were utilized to quantify levels of Δ9THC and metabolites in brain regions and peripheral tissues. Data was expressed as mean concentrations (± SEM) of Δ9THC and metabolites in brain regions, blood, plasma, urine, and liver. Two-way analysis of variance was performed followed by post hoc multiple comparisons.
Results: Peak concentrations of Δ9THC were reached at 2 h in the brain (15.9 ng/mg), blood (4.54 μg/mL), and plasma (4.56 μg /mL). The percentage of administered dose of Δ9THC transported to the brain (5.9%) was greater than in blood (1.7%), plasma (1.6%), urine (0.4%), and liver (0.1%). Concentrations of Δ9THC and its THC-COOH metabolite in the liver reached their highest levels at 8 h.
Discussion: The present study is the first to report the uptake and distribution across brain regions of Δ9THC and its principal metabolites following i.n. administration. The systemic bioavailability (absorption into the blood) of intranasal Δ9THC was 1.7% of the administered dose, much lower than that reported by others after oral ingestion (7-10%) and inhalation (20-35%), but those prior studies did not measure the transport of Δ9THC into brain regions. Others have reported Δ9THC in the whole brain following i.n. instillation in a different species (rats) to be twice (5.9%) that following i.p. injections, while metabolites of Δ9THC in rat brain were lower after i.n. administration.
Conclusions: The intranasal route of a Δ9THC nanoformulation is an effective way to deliver cannabinoids to the brain, especially in those who cannot take the medication orally. Going forward, a metered dosing nasal spray will provide accurate and consistent doses.
Keywords: Cannabidiol (CBD); Delta-9-tetrahydrocannabinol (Δ9THC); Intranasal administration; Nanoemulsions; Nanoparticles; Pharmacokinetics.
© 2023. The Author(s).