Plasma and Brain Levels of Δ6-THC and Seven Monooxygenated Metabolites Correlated to the Cataleptic Effect in the Mouse

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Abstract
The brain and plasma levels of unchanged Δ6-tetrahydrocannabinol (Δ6-THC), 7-hydroxy-Δ6-THC, the five side-chain hydroxylated Δ6-THC derivatives and 1α, 2α-epoxyhexahydrocannabinol (EHHC) were correlated to the cataleptic effect in the mouse up to 60 min. after intravenous administration of radiolabelled compounds in the range 1.3 to 12.4mg/kg. All cannabinoids except Δ6-THC and l″-hydroxy-Δ6-THC showed a very good correlation between brain/plasma concentrations and cataleptic effect. 4″-Hydroxy- and l″-hydroxy-Δ6-THC reached the highest concentration in the brain but the most potent cannabinoids were: Δ6-THC, 7-hydroxy-, 3″-hydroxy-Δ6-THC, and EHHC followed by 5″-hydroxy-, 4″-hydroxy-, 2″-hydroxy-, and 1″-hydroxy-Δ6-THC in decreasing order. It was concluded that structural rather than pharmacokinetic features are most important in determining the psychoactivity of the various cannabinoid metabolites of THC.