Pharmacokinetics of the potent hallucinogen, salvinorin A in primates parallels the rapid onset and short duration of effects in humans

• Published in: NeuroImage (Orlando, Fla.) Fla.), 2008-07, Vol.41 (3), p.1044-1050
• Main Authors: Hooker, Jacob M., Xu, Youwen, Schiffer, Wynne, Shea, Colleen, Carter, Pauline, Fowler, Joanna S.
• Format: Article
• Language: English
• Subjects: Animals; Behavior; Brain - drug effects; Brain - metabolism; Brain research; Carbon; Carbon Radioisotopes - pharmacokinetics; Chromatography; Diterpenes, Clerodane - pharmacokinetics; Drug dosages; Female; Hallucinogens - pharmacokinetics; Humans; Image Processing, Computer-Assisted; Labeling; Papio; Positron-Emission Tomography; Primates; Salvia; Studies
• ISSN: 1053-8119; 1095-9572
• DOI: 10.1016/j.neuroimage.2008.03.003

Salvia divinorum, a mint plant originally used by the Mazatecs of Oaxaca, Mexico in spiritual rituals has gained popularity, in smoked form, as a legal hallucinogen in the United States and Europe. Abuse results in rapid onset and short-lasting effects that include visual hallucinations and motor-function impairment. Salvinorin A, the psychoactive component of S. divinorum, is a uniquely potent agonist at κ-opioid receptors, targets for new therapeutic drugs. We labeled salvinorin A with C-11 by acylation of salvinorin B with [ 11C]-acetyl chloride to study whether its kinetic behavior in the brain parallels its uniquely fast, yet brief physiological effects. Positron emission tomography (PET) studies performed in 6 adult female baboons indicated extremely rapid brain uptake reaching a peak accounting for 3.3% of the total administered dose in 40 s and clearing with a half-life of 8 min. [ 11C]-salvinorin A was distributed throughout the brain with the highest concentration in the cerebellum and a notable concentration in the visual cortex, perhaps accounting for its physiological effects when smoked. Naloxone administration did not reduce the overall concentration of [ 11C]-salvinorin A significantly nor did it change its regional distribution. Peripheral organ kinetics suggested at least two modes of metabolism and excretion occur: through the renal and biliary systems. Our findings have revealed that the exceptionally rapid uptake and brief duration of salvinorin A in the brain match the time-course of visual hallucinations for S. divinorum when smoked. The effects of salvinorin A may occur at < 10 μg in the human brain, emphasizing its remarkable potency.