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

Salvinorin A, the psychoactive component of the mint plant Salvia divinorum, is a uniquely potent agonist at kappa-opioid receptors. Positron emission tomography (PET) studies in 6 adult female baboons showed extremely rapid brain uptake, reaching a peak of 3.3% of the total administered dose within 40 seconds and clearing with a half-life of 8 minutes. The compound distributed throughout the brain, with highest concentration in the cerebellum and notable concentration in the visual cortex, which may account for visual hallucinations when smoked. Naloxone did not reduce overall concentration or alter regional distribution. The rapid brain kinetics match the brief time-course of visual hallucinations, and effects may occur at less than 10 micrograms in the human brain, emphasizing its remarkable potency.

Study at a glance

Abstract

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.