Salvinorin A

Salvinorin A is active at doses as low as 200 μg. It has only been administered to humans in a few studies, one showing that its effects peaked at about 2minutes, that its subjective effects may overlap with those of serotonergic psychedelics, and that it temporarily impairs recall and recognition memory. ==Interactions==

Naltrexone, a non-selective opioid receptor antagonist including of the κ-opioid receptor (KOR), blocks the hallucinogenic and physiological effects of salvinorin A in humans. Conversely, the serotonin 5-HT2A receptor antagonist ketanserin was ineffective. ==Pharmacology==

Pharmacodynamics Research has shown that salvinorin A is a potent κ-opioid receptor (KOR) agonist (Ki = 2.4 nM, EC50 = 1.8 nM). In addition to its KOR agonism, salvinorin A has been found to act as a dopamine D2 receptor partial agonist, with an affinity of 5–10 nM, an intrinsic activity of 40–60%, and an EC50 of 48 nM. It significantly increases prolactin and inconsistently increases cortisol. It causes dysphoria by stopping release of dopamine in the striatum. Salvinorin A increases activity of DAT while decreasing activity of SERT. It has a half-life of around 8 minutes in non-human primates. ==Chemistry==

Salvinorin A is a trans-neoclerodane diterpenoid with the chemical formula C23H28O8. Chemical synthesis The chemical synthesis of salvinorin A has been described. Detection in urine Researchers found that humans who smoked 580 μg of the pure drug had urine salvinorin A concentrations of 2.4–10.9 μg/L during the first hour; the levels fell below the detection limit by 1.5 hours after smoking. Research has produced a number of semi-synthetic compounds. Most derivatives are selective kappa opioid agonists as with salvinorin A, although some are even more potent, with the most potent compound salvinorin B ethoxymethyl ether being ten times stronger than salvinorin A. Some derivatives, such as herkinorin, reduce kappa opioid action and instead act as mu opioid agonists. Salvinorin B methoxymethyl ether is seven times more potent than salvinorin A at KOPr in GTP-γS assays. ==Natural occurrence==

Salvinorin A occurs naturally in several Salvia species: • S. divinorum (0.89 mg/g to 3.70 mg/g). • S. recognita (212.9 μg/g). Salvinorin B has been detected in S. potentillifolia and S. adenocaulon, however these species do not contain a measureable amount of salvinorin A.), produces a labdanyl diphosphate carbocation, which is subsequently rearranged through a sequence of 1,2-hydride and methyl shifts to form the ent-clerodienyl diphosphate intermediate. SdCPS2 catalyzes the first committed reaction in the biosynthesis of salvinorin A by producing its characteristic clerodane scaffold. A series of oxygenation, acylation and methylation reactions is then required to complete the biosynthesis of salvinorin A. Similar to many plant-derived psychoactive compounds, salvinorin A is excreted via peltate glandular trichomes, which reside external to the epidermis. ==History==

Salvia divinorum has been used as an entheogen by the Mazatec people of Mexico for hundreds of years. Subsequently, other researchers, including Blas Pablo Reko and Robert J. Weitlaner, also described the plant and its use in the 1940s and 1950s. Arturo Gómez-Pompa classified the plant as belonging to the genus Salvia in 1957, but was unable to completely identify it at the time due to absence of flowering material. Finally, Robert Gordon Wasson and Albert Hofmann collected flowering specimens of the plant in the early 1960s and sent them to Carl Epling, the leading expert on the Salvia genus of the time, who defined the plant as a new species named Salvia divinorum in 1962. SalvinorinA was isolated from Salvia divinorum and identified by Alfredo Ortega and colleagues in 1982. D. M. Turner published his book Salvinorin: The Psychedelic Essence of Salvia Divinorum, further describing salvinorin A's hallucinogenic effects in humans, in 1996. SalvinorinA was identified as a highly selective and potent κ-opioid receptor (KOR) agonist by Bryan L. Roth and colleagues in 2002. Dennis McKenna has shared that he identified salvinorin A as an extremely high-affinity KOR ligand while working at Shaman Pharmaceuticals in the early 1990s, but did not publish his findings as he could not believe how potent it was and thought that his results were erroneous. Roland Griffiths and colleagues and other researchers characterized the effects of salvinorin A in humans in formal clinical studies in the 2010s. Griffiths and colleagues further showed that salvinorin A's hallucinogenic and other effects in humans were blocked by the KOR antagonist naltrexone in 2016. ==Society and culture==

Legal status Salvinorin A is sometimes regulated together with its host, Salvia divinorum, due to its psychoactive and analgesic effects. United States Salvinorin A is not scheduled at the federal level in the United States. Its molecular structure is unlike any Schedule I or II drug, so possession or sales is unlikely to be prosecuted under the Federal Analogue Act. Florida "Salvinorin A" is a Schedule I controlled substance in the state of Florida making it illegal to buy, sell, or possess in Florida. There is an exception however for "any drug product approved by the United States Food and Drug Administration which contains salvinorin A or its isomers, esters, ethers, salts, and salts of isomers, esters, and ethers, if the existence of such isomers, esters, ethers, and salts is possible within the specific chemical designation." Australia Salvinorin A is considered a Schedule 9 prohibited substance in Australia under the Poisons Standard (October 2015). A Schedule 9 substance is a substance which may be abused or misused, the manufacture, possession, sale or use of which should be prohibited by law except when required for medical or scientific research, or for analytical, teaching or training purposes with approval of Commonwealth and/or State or Territory Health Authorities. Salvinorin A has been screened for its possible use as a structural "scaffold" in medicinal chemistry in developing new drugs for treating psychiatric diseases such as cocaine dependence. ==See also==