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

Ajeigbe O.; Tran A.; Klein R.; Tagne A.; Avalos H.; Ahmed F.; Piomelli D. · The Journal of pharmacology and experimental therapeutics · 2026

**Background & Methods** This study investigated the pharmacokinetic and pharmacodynamic properties of high-dose Δ9-tetrahydrocannabinol (THC) in male and female Long Evans rats following single intraperitoneal administration. Researchers quantified THC and metabolite concentrations (11-hydroxy-THC, 11-carboxy-THC) in plasma, brain, and adipose tissue over acute (24 hours) and prolonged (14 days) periods, while assessing behavioral endpoints and plasma cytokine levels. **Key Findings** • **Nonlinear pharmacokinetics with sex-dependent differences**: Higher THC doses (10 and 30 mg/kg) produced disproportionately elevated maximal concentrations compared to the 3 mg/kg dose. Females demonstrated significantly greater systemic and tissue exposure than males, with extensive sequestration in white adipose tissue. • **Dose- and sex-dependent behavioral effects**: High-dose THC (30 mg/kg) suppressed food/water intake and body weight across both sexes. Females exhibited transient locomotor stimulation at low dose but suppression at high doses, with increased pica at 30 mg/kg. Males showed bidirectional stress-coping changes and primarily antinociceptive effects at 1 and 24 hours postdosing. • **Minimal inflammatory response**: No meaningful changes in proinflammatory or anti-inflammatory cytokines were observed in either sex across any dose tested. **Dosage & Administration** Intraperitoneal administration of THC at 3 mg/kg (low dose), 10 mg/kg (high dose), and 30 mg/kg (very high dose) in male and female Long Evans rats. **Safety & Adverse Effects** Dose-dependent adverse effects included suppression of food and water intake, body weight reduction, transient locomotor changes (dose- and sex-dependent), increased pica behavior (females at highest dose), and modest anxiety-like behavioral shifts. Antinociceptive effects were observed primarily in males. No cytokine-mediated inflammatory responses were detected. **Evidence Quality** This preclinical animal study provides controlled pharmacokinetic and pharmacodynamic data but is limited to rat models and may not directly translate to human cannabis users. The intraperitoneal route of administration differs from typical human consumption routes (inhalation, oral), potentially affecting metabolic profiles. The study's strength lies in systematic characterization of sex differences and dose-response relationships, though findings require human validation. Published in 2026 in a peer-reviewed pharmacology journal, suggesting current relevance to cannabis research.

More recent cannabis research