Until the summer of 2002, the pharmacological action of Salvia divinorum was entirely unknown. The chemical had been tested on 43 known bioreceptors with no significant inhibition (Siebert 1994; Sage Student 2002). In August 2002, Roth et al. published their findings that Salvinorin A is a potent kappa-opioid receptor agonist (Roth 2002). Because most other visionary drugs work on the serotonin (specifically the 5-HT-2a receptor) system, earlier attempts to characterize salvinorin A's action failed. By using cloned cells which expressed a variety of neurotransmitter receptor types, bathing them in a solution with salvinorin A in it, and then using radio-labeled chemicals known to bind to the given receptor, they were able to see if the salvinorin kept the other chemical from 'sticking'. Because the binding 'affinity' for the radio-labeled ligands was known, the amount the salvinorin blocked it produced a numerical value which then could be used to rate how much salvinorin stuck to the receptor. Dr Roth's lab is one of the most active in doing this type of neuropharmalogical receptor screening and more info about this type of work can be found at http://pdsp.cwru.edu/nimh/5ht.html.

Interestingly, the kappa opioid receptor was previously known for its ability to cause strange psychoactive effects which have been called 'hallucinogenic'. Pharmaceutical companies looking for novel analgesics investigated kappa-opioid agonists and discovered that they caused unwanted side effects in humans which made them unuseable as pain medications.

In 2001, Walsh et al. published a comparison between enadoline (a kappa opioid agonist) with two other opiate agonists and discovered that enadoline caused hallucinogenic (what they call 'psychotomimetic') effects:

Enadoline significantly increased measures of sedation, confusion and dizziness, produced visual distortions and feelings of depersonalization, and increased urinary output. The highest dose (160 µg/70 kg) was not tolerated and led to psychotomimetic effects. (Walsh 2001)

A much earlier paper, Pfeiffer et al, 1986, found that kappa opioid agonists can cause interesting psychoactive effects not expected from the opioid system: "kappa opiate receptors seem to mediate psychotomimetic effects." (Pfeiffer 1986)

There has also been some speculation that kappa-opioid agonists could reduce the effects of other stimulants and has been looked at to try to reduce self-administration of cocaine, but the one paper on this topic failed to find any reduction in the amount of cocaine used when enadoline was pre-administered. (Walsh 2001a)

This research also suggests the possibility of specific kappa-opioid antagonists acting as 'anti-psychotics' or having other interesting psychoactive effects. As Roth writes in his 2002 paper about salvinorin A, "because the KOR has long been recognized as a target for psychotomimetic agents, KOR antagonists may represent a novel class of psychotherapeutic compounds. Our results also suggest that the KORydynorphin peptide system functions to modulate human perception." (Roth 2002)

Since salvinorin has now been discovered to be a kappa-opioid agonist and is known for its unusual psychedelic effects, this suggests some interesting future research around the issue of whether naltrexone (general opioid antagonist) would reduce or eliminate effects from salvinorin, whether the other kappa-opioid agonists such as enadoline cause effects similar to salvinorin, and many other related questions.