Pharmacokinetic and pharmacodynamic profile of high-dose D9-tetrahydrocannabinol in male and female rats.

Abstract

Cannabis products with elevated Δ9-tetrahydrocannabinol (THC) content are prevalent in parts of North America, yet their pharmacokinetic (PK) and pharmacodynamic (PD) properties remain incompletely characterized. We investigated the effects of a single administration of high-dose THC (10 and 30 mg/kg, intraperitoneal, IP) compared with a lower dose (3 mg/kg, IP) in male and female Long Evans rats. Plasma, brain, and white adipose tissue concentrations of THC and its metabolites 11-hydroxy-THC and 11-carboxy-THC were quantified over acute (up to 24 h) and prolonged (14 days) periods. Behavioral endpoints included ingestive behavior, pica, locomotor activity, anxiety-like and stress-coping responses, and nociception. Plasma concentrations of multiple cytokines were also assessed. PK results showed nonlinear disposition with disproportionate increases in maximal concentration at higher doses, greater systemic and tissue exposure in females, and extensive sequestration in adipose tissue. PD effects were also dose- and sex-dependent: suppression of food/water intake and body weight, transient locomotor stimulation in females at low dose and suppression at high doses, increased pica in females at 30 mg/kg, modest anxiety-like shifts, bidirectional stress-coping changes in males, and antinociception primarily in males at 1 hour and 24 hours postdosing. No meaningful changes in proinflammatory or anti-inflammatory cytokines were observed in either sex. The findings indicate that high-dose THC produces nonlinear sex-dependent PK with prolonged central and peripheral retention, alongside distinct acute PD profiles compared with lower doses. SIGNIFICANCE STATEMENT: High-potency cannabis products are common, yet their impact on health remains poorly understood. This study shows that high-dose THC produces nonlinear, sex-dependent distribution and metabolism in rats, with females showing markedly greater systemic exposure, prolonged brain retention, and extensive adipose sequestration, alongside distinct acute pharmacological profiles. These findings show that high-dose THC generates disproportionate systemic and central exposure and distinct acute pharmacological profiles compared with lower doses.