Pharmacokinetics of the potent hallucinogen, salvinorin A in primates parallels the rapid onset and short duration of effects in humans.
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 kappa-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 mug in the human brain, emphasizing its remarkable potency.
Hooker
Jacob M
JM
Medical Department, Brookhaven National Laboratory, Upton, NY 11973, USA. hooker@bnl.gov <hooker@bnl.gov>
Xu
Youwen
Y
Schiffer
Wynne
W
Shea
Colleen
C
Carter
Pauline
P
Fowler
Joanna S
JS
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D045785:Diterpenes, Clerodane / Q000493:pharmacokinetics*; D005260:Female; D006213:Hallucinogens / Q000493:pharmacokinetics*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D010215:Papio; D049268:Positron-Emission Tomography
D002250:Carbon Radioisotopes; D045785:Diterpenes, Clerodane; D006213:Hallucinogens; C090499:salvinorin A