The mechanisms through which kappa opioid receptor (KOR) agonists generate psychotomimetic effects are largely unclear, despite the fact that manipulation of this receptor has sparked interest for therapeutic applications. The neuropharmacological effects of salvinorin-A, a highly selective KOR agonist, were investigated by the researchers for a study. Following acute salvinorin-A injection, changes in multimodal electroencephalography, single-photon emission computed tomography, and subjective effects were documented. The research consisted of 2 sub-studies that used a double-blind, crossover, randomized, placebo-controlled design.

While patients were under the influence of salvinorin-A, electroencephalography measurements revealed a significant rise in delta and gamma waves and a decrease in alpha waves. Significant reductions in regional cerebral blood flow were found in numerous areas of the frontal, temporal, parietal, and occipital cortices using single-photon emission computed tomography. Significant increases in regional cerebral blood flow were found in various areas of the medial temporal lobe, including the amygdala, hippocampus gyrus, and cerebellum. The pattern of subjective effects caused by salvinorin-A was comparable to that seen with other psychotomimetic agents, but with a clearly dissociative character. There were no reports of dysphoric effects.

The salvinorin-A–mediated KOR agonism resulted in severe psychotomimetic effects as well as a widespread reduction in cerebral blood flow and electrical activity in the cerebral cortex.