I think the main reason is that the paper opened up an entirely new area of opioid receptor pharmacology. The structure of the novel kappa-opioid receptor agonist salvinorin A is unique and unprecedented. Since then, this area has become extremely active among both medicinal chemists and behavioral pharmacologists.

“I typically recommend to policymakers and others that Salvia divinorum and salvinorin A should be regulated, but that they should not be made Schedule I compounds.”

We discovered that the site of action of an emerging drug of abuse was a single opioid receptor subtype. Essentially, we discovered the receptor responsible for the actions of emerging drugs of abuse—Salvia divinorum and salvinorin A. The Latin name Salvia divinorum, also known as Diviner’s Sage, literally translates to "sage of the seers." The genus name Salvia is derived from the Latin salvare, meaning "to heal" or "to save." The primary psychoactive constituent is a diterpenoid known as salvinorin A.

The active ingredient of the hallucinogenic plant Salvia divinorum (aka the "magic mint") salvinorin A is the most potent naturally occurring hallucinogen, rivaling LSD in potency. Our paper describes the discovery that salvinorin A targets a single receptor type in the brain—the kappa opioid receptor. The results imply that this receptor system is involved in the modulation of human consciousness and emotion.

I’m the Director of the National Institute of Mental Health’s Psychoactive Drug Screening Program (NIMH-PDSP), which was previously located at Case Western Reserve University Medical School where I was a Professor of Biochemistry. In the fall of 2000, I heard about Salvia divinorum’s hallucinogenic properties from an undergraduate who was writing a paper about the plant and who was curious about its mechanism of action.

A quick search on the web disclosed that the molecular target responsible for the actions of S. divinorum and its active ingredient salvinorin A was unknown. We obtained a sample of pure salvinorin A from Daniel Siebert, had it chemically analyzed, and then subjected it to a screen against a large panel of human-cloned brain receptors using the resources of the NIMH-PDSP.

We were surprised to discover that it was a potent and selective kappa opioid receptor agonist, as it did not resemble any known kappa agonist. We sent a sample to Richard Rothman (National Institute of Drug Abuse) who quickly verified the kappa agonist activity and specificity.

The screen actually went surprisingly easy, although I was not convinced that the technician (Karen Baner) had performed the experiments correctly, and I had her repeat the assays several times. Each time she got the same result and, after Richard had replicated the findings, I was convinced that we had discovered something interesting.

We submitted the paper to the Proceedings of the National Academy of Sciences via Track II, and the paper was accepted for publication with only minor changes being necessary. I was gratified to discover, after the paper had been accepted, that my former mentor, Erminio Costa, M.D., the Scientific Director of the Psychiatric Institute at the University of Illinois at Chicago, was the handling Academy member.

There are several main areas of research currently ongoing with regard to salvinorin A. We continue to be interested in the molecular mechanisms responsible for the exquisite selectivity and potency of salvinorin A for the kappa opioid receptor (see Vortherms et. al., JBC, 2007 for example). We have also become interested in discovering the signal transduction pathways responsible for the unique actions of salvinorin A on consciousness.

Salvia divinorum and salvinorin A are emerging hallucinogenic drugs of abuse which are currently unregulated at a Federal level, although several states have begun to regulate the sale and distribution of them. It is likely that at some time in the future the U.S. Government and the Drug Enforcement Agency will schedule Salvia divinorum and salvinorin A.

I typically recommend to policymakers and others that Salvia divinorum and salvinorin A should be regulated, but that they should not be made Schedule I compounds. Placing Salvia divinorum and salvinorin A in Schedule I status would greatly hinder biomedical research into the potential utilities of Salvia divinorum, salvinorin A, and various derivatives.

Currently, many labs are investigating the utility of salvinorin A derivatives for the treatment of a number of diseases including various types of mental illness, drug addiction, chronic pain, and other disorders (see Timothy A. Vortherms and Bryan L. Roth, Molecular Interventions, 2007, for recent review).