Salvinorin A

Salvinorin A is the main active psychotropic molecule in Salvia divinorum, a Mexican plant which has a long history of use as an entheogen by indigenous Mazatec shamans. Salvinorin A is a hallucinogenic compound with psychedelic/dissociative effects.

It is structurally distinct from other naturally occurring hallucinogens (such as DMT, psilocybin, and mescaline) because it contains no nitrogen atoms, hence it is not an alkaloid.

Salvinorin A can produce psychoactive experiences in humans with a typical duration of action being several minutes to an hour or so, depending on the method of ingestion.

Salvinorin A is found with several other structurally related salvinorins. Salvinorin is a trans-neoclerodane diterpenoid. It acts as a kappa opioid receptor agonist and is the first known compound acting on this receptor that is not an alkaloid. Salvinorin A was isolated in 1982 by Alfredo Ortega in Mexico. Its pharmacological mechanism was elucidated in the laboratory of Bryan L. Roth.

Pharmacology
Salvinorin A is a trans-neoclerodane diterpenoid, chemical formula C23H28O8. Unlike other known opioid-receptor ligands, salvinorin A is not an alkaloid &mdash; it does not contain a basic nitrogen atom. Salvinorin A has no action at the 5-HT2A serotonin receptor, the principal molecular target responsible for the actions of 'classical' psychedelics such as LSD and mescaline.

Potency and selectivity
Salvinorin A "is the most potent naturally occurring hallucinogen." It is active at doses as low as 200 µg. Synthetic chemicals, such as LSD (active at 20–30 µg doses), can be more potent. Research has shown that salvinorin A is a potent κ-opioid receptor agonist. It has been reported that the effects of salvinorin A in mice are blocked by κ-opioid receptor antagonists. This makes it unlikely that another mechanism contributes independently to the compound’s observed effects in mice. However, salvinorin A has recently been found to act as an even more potent D2 receptor partial agonist, with an affinity of 5–10 nM, an intrinsic activity of 40–60%, and an EC50 of 50–90 nM, which is several-fold higher than its EC50 of 235 nM for the κ-opioid receptor. This suggests that the D2 receptor may also play an important role in its effects.

Salvinorin A is unique in that it is the only naturally occurring substance known to induce a visionary state via this mode of action; there are synthetic kappa-opioid agonists, (e.g. enadoline, ketazocine, pentazocine and relatives), which show similar hallucinatory and dissociative effects.

Salvinorin A's potency shouldn't be confused with toxicity. Mice chronically given dosages "many times that of what humans are exposed to" did not show signs of organ damage. However, "further studies should be done on blood pressure effects" and "Pulse pressure did appear to increase with salvinorin A exposure twenty and forty minutes after exposure, however, this increase was not statistically significant" (note that the data shows an increase in Pulse Pressure that was roughly 1.5–2 times the control group's).

Effect on intestinal motility
Salvinorin A is capable of inhibiting excess intestinal motility (e.g. diarrhea), through a combination of k-opioid and cannabinoid (mainly CB1 receptor) receptors in inflamed but not normal gut in vivo. The mechanism of action for Salvinorin A on ileal tissue has been described as 'prejunctional', as it was able to modify electrically induced contractions, but not those of exogenous acetylcholine. A pharmacologically important aspect of the contraction-reducing properties of ingested Salvinorin A on gut tissue is that it is only pharmacologically active on inflamed and not normal tissue, thus reducing possible side-effects.

Solubility
Salvinorin is soluble in organic solvents such as ethanol and acetone, but not especially so in water.

Detection in urine
Humans who smoked 580 micrograms of the pure drug had urine salvinorin A concentrations of 2.4–10.9 µg/L during the first hour, but the levels fell below the detection limit by 1.5 hours after smoking. Analytical measurements may be performed using gas or liquid chromatography-mass spectrometry.

Associated compounds
Many other terpenoids have been isolated from Salvia divinorum, including other salvinorins and related compounds named divinatorins and salvinicins. None of these compounds have shown significant (sub-micromolar) affinity at the kappa-opioid receptor, and there is no evidence that they contribute to the plant's psychoactivity.

Biosynthesis
The biogenic origin of salvinorin A synthesis has been elucidated using nuclear magnetic resonance and ESI-MS analysis of incorporated precursors labeled with stable isotopes of carbon (Carbon-13 13C) and hydrogen (Deuterium 2H). It "is biosynthesized via the 1-deoxy-d-xylulose-5-phosphate pathway," rather than the classic mevalonate pathway typical for plant terpenoids.

Similar to many plant-derived psychoactive compounds, Salvinorin A is excreted via peltate glandular trichomes, which reside external to the epidermis.

Chemical synthesis
A total asymmetric synthesis of salvinorin A, which relies on a transannular Michael reaction cascade to construct the ring system, was achieved in 2007 by Evans and co-workers in 4.5% overall yield over 30 steps. More recently, a synthesis was published by a Japanese group, requiring 24 steps to yield salvinorin A in 0.15% yield.

An approach to the trans-decalin ring system of salvinorin A has been described by Forsyth (et al.) utilizing an intramolecular Diels-Alder reaction/Tsuji allylation strategy.

An attempt at the synthesis of salvinorin A has also been published by a group at RMIT University, adopting a convergent synthesis of a functionalized cyclohexanone with a α,β-unsaturated lactone.

Salvinorins A - F, J
Salvinorin A is one of several structurally related salvinorins found in the Salvia divinorum plant. Salvinorin A can be synthesized from the inactive salvinorin B by acetylation. The des-acetylated analog salvinorin B is devoid of human activity. It was speculated that salvinorin C might be even more potent than salvinorin A, but human tests and receptor binding assays could not confirm this [Ref?]. Salvinorin A seems to be the only active naturally occurring salvinorin.

The newly discovered salvinorin J is most closely related to salvinorin E in structure, with a C-17 secondary alcohol instead of an ketone group.

Semi-synthetic analogues
Research on salvinorin derivatives has produced a number of semi-synthetic compounds, several of which can be conveniently made from Salvinorin B. Most derivatives are selective kappa opioid agonists as with Salvinorin A, although some are even more potent, with the most potent compound 2-ethoxymethyl Salvinorin B being 10x stronger than Salvinorin A. A few derivatives such as herkinorin have reduced kappa opioid action and instead act as mu opioid agonists.


 * 2-Ethoxymethyl Salvinorin B
 * 2-Methoxymethyl Salvinorin B
 * Herkinorin

Legality
Salvinorin A is sometimes regulated together with its host, Salvia divinorum, due to its psychoactive and analgesic effects.