In the past two decades, most research concerning S. divinorum has focused on the psychoactive chemical compounds and its pharmacologic potential. S. divinorum has proven to be unique not only in its botanical significance and ethnopharmacological tradition, but also in its biochemical characteristics. Like many other members of the genus Salvia, S. divinorumcontains unusual terpenoid compounds (Ott 2001).

In 1962, Gordon Wasson and Albert Hofmann collected S. divinorum juice from a leaves given to them in San Jose Tenango from the same flowering plants used as identification by Epling and Jativa.. The juice was preserved in alcohol to be studied, but chemical investigation at the time was unsuccessful. Hofmann concluded that the psychoactive principle must be unstable (Hofmann 1979).

Diaz et al. also studied the mint, but were also had limited success in studying the chemical properties of the plant (Valdes 1994) . S. divinorum’s hallucinogenic components were isolated in 1982 by the research group of Alfredo Ortega, who had also isolated the new compounds salviarin and splendidin from S. splendens (Ott 2001). Ortega et al. isolated a novel trans-neoclerodane diterpene from S. divinorum and determined its structure using X-ray crystallography, but did not study biological activity, or extend the research to investigate the pharmacological applications of the compound. The new compound was named salvinorin (Ortega 1982).

L.J. Valdes has produced a large body of work regarding S. divinorum, both in ethnobotany and chemistry, and was also the first to test salvinorin as a psychoactive principle. In 1984, Valdes et al. isolated the same compound as Ortega et. al. Unaware that the compound had already been characterized and named, the group referred to active compound as divinorumA, and its inactive desacetyl derivative was called divinorum B. The two terms (salvinorin and divinorin) are now applied interchangeably, although salvinorin A and salvinorin B are, officially, the correct names for these molecules (Valdes 1987, 1984). Valdes et. al. tested the biological effects of salvinorin A in mice, and noted that salvinorin had similar effects to mescaline, dramatically reducing animal activity in a manner similar to sedation, but without true sedation since the mice were able to move rapidly for short periods of time. The absolute stereochemistry of the salvinorins was also determined (Koreeda et al. 1990).

While Valdes, Diaz, and Paul had personally tested Salvia divinorum leaves during Mazatec cermonies while conducting ethnobotanical research, Valdes et. al. did not conduct psychonautic human bioassays to determine whether salvinorin A was, in actuality, the visionary principle active in S. divinorum (Ott 1996).

“Basement shamans” (apparently Daniel Siebert and friends) in California were the next group to isolate and test salvinorin as a psychoactive principle (Ott 1996). Siebert soon tested various methods of leaf and salvinorin intake by volunteers to determine site of absorption, effects, and dosage. Siebert found that extended exposure (10 minutes) to the oral mucosa produced psychoactive effects in all volunteers, while quick swallowing and rinsing of leaves produced no effects at all, leading Siebert to conclude that the gastrointestinal system breaks down the psychoactive compound and that leaves must be chewed or held in the mouth to produce hallucinations. Siebert isolated salvinorin A by the same method used by Valdes et al. (1984).

20 volunteers were given capsules of salvinorin A, which produced no effects, reinforcing the hypothesis that salvinorin is inactivated by gastrointestinal absorption. Because salvinorin A is not water soluble, injection was not tested. Inhalation of the vaporized salvinorin A was tested, however, and proved to be the most efficient and dramatic method of salvinorin A intake to produce hallucinations. Threshold effects were usually noted at 200-500 Φg, and hallucinations occurred within 30 seconds, rather than the 10-15 minutes required by oral ingestion (Siebert 1994). With activity apparent at the 200 Φg level, salvinorin A is now the most potent entheogen known thus far, and one of the most potent natural compounds discovered (Valdes 2001, Ott 1996).

Samples of salvinorin A were also submitted to Novascreen for receptor site screening, and was shown not to affect any brain receptor sites affected by most other hallucinogens, suggesting that a unique pathway and receptor site may be present for salvinorin A (Siebert 1994).

Salvinorin A is the first diterpene to be identified as a hallucinogen in humans (Valdes et al 2001). Siebert has also determined and compared levels of salvinorin A found in leaves from several plants grown throughout the United States and Mexico, concluding that leaves may contain a range of .89-3.70 mg/g salvinorin A in dry weight (Siebert 1999). Valdes et al. have further studied the bioactive compounds of Salvia divinorum, and discovered that a third compound exists, salvinorin C, which comprises only about 10% of the bioactive compounds in S. divinorum, but may be even more potent per unit of measure than salvinorin A (Valdes et al 2001).

Salvinorin A, salvinorin B, and salvinorin C bear close resemblance to other neoclerodane diterpenes from Latin American Salvia species, such as salviarin and splendidin. The salvinorins have been the only neoclerodane diterpenes tested for hallucinogenic properties thus far, however, and other similar Salvia compounds should be tested for pychotropic activities (Valdes et al 2001). Great research potential exists in the biochemistry and application of the salvinorin compounds, and related molecules, as hallucinogens, antibiotics, and to discover new neurological pathways and receptor sites.