THC and CBD blood and brain concentrations following daily administration to adolescent primates

• Published in: Drug and alcohol dependence Vol. 213; p. 108129
• Main Authors: Withey, S.L., Bergman, J., Huestis, M.A., George, S.R., Madras, B.K.
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.08.2020; Elsevier Science Ltd
• Subjects: 11-OH-THC, THC-COOH; Accumulation; Adolescent monkeys; Adolescents; Blood; Blood levels; Brain; Cannabidiol; Cannabinoids; Cannabis; CBD; CBD blood; CBD brain; Cerebellum; Cognitive ability; Cortex; Disruption; Dosage; Euphoria; Marijuana; Metabolites; Monkeys; Occipital lobe; Pharmacokinetics; Pharmacology; Primates; Teenagers; Tetrahydrocannabinol; THC; THC blood; THC brain; THC metabolites; CBD; CBD brain; Cannabidiol; THC; CBD blood; Adolescent monkeys; Cannabis; THC blood; 11-OH-THC, THC-COOH; Marijuana; THC brain; Pharmacokinetics; THC metabolites
• ISSN: 0376-8716; 1879-0046; 1879-0046
• DOI: 10.1016/j.drugalcdep.2020.108129

•Adolescent primates dosed daily show stable THC, CBD blood levels for 4 months.•Pharmacokinetic tolerance does not develop to THC or CBD.•CBD did not modulate THC pharmacokinetics during daily dosing.•THC concentrations in brain were higher than blood 24 h after the final daily dose.•Prolonged presence of THC in brain may contribute to persistent behavioral disruption. Cannabis availability with high concentrations of Δ-9-tetrahydrocannabinol (THC) and a range of THC to cannabidiol (CBD) ratios has increased in parallel with a rise in daily cannabis consumption by adolescents. Unanswered questions in adolescents include: 1) whether THC blood concentrations and THC metabolites remain stable or change with prolonged daily dosing, 2) whether CBD modulates THC pharmacokinetic properties and alters THC accumulation in brain, 3) whether blood THC levels reflect brain concentrations. In adolescent squirrel monkeys (Saimiri boliviensis), we determined whether a four-month regimen of daily THC (1 mg/kg) or CBD (3 mg/kg) + THC (1 mg/kg) administration (IM) affects THC, THC metabolites, and CBD concentrations in blood or brain. Blood THC concentrations, THC metabolites and CBD remained stable during chronic treatment. 24 h after the final THC or CBD + THC injection, blood THC and CBD concentrations remained relatively high (THC: 6.0–11 ng/mL; CBD: 9.7−19 ng/mL). THC concentrations in cerebellum and occipital cortex were approximately twice those in blood 24 h after the last dose and did not significantly differ in subjects given THC or CBD + THC. In adolescent monkeys, blood levels of THC, its metabolites or CBD remain stable after daily dosing for four months. Our model suggests that any pharmacological interactions between CBD and THC are unlikely to result from CBD modulation of THC pharmacokinetics. Finally, detection of relatively high brain THC concentrations 24 h after the final dose of THC suggests that the prolonged actions of THC may contribute to persistent cognitive and psychomotor disruption after THC- or cannabis-induced euphoria wane.