Salvinorin A

Pharmacokinetics

Salvinorin A is effectively deactivated by the gastrointestinal system, so alternative routes of administration must be used for better absorption. It is absorbed by oral mucosa.^[15] It has a half-life of around 8 minutes in non-human primates.^[16]

Potency and selectivity

Salvinorin A is active at doses as low as 200 μg.^[10][17][18] Synthetic chemicals, such as LSD (active at 20–30 μg doses), can be more potent.^[19] Research has shown that salvinorin A is a potent κ-opioid receptor (KOR) agonist (K_i = 2.4 nM, EC₅₀ = 1.8 nM).^[10] It has a high affinity for the receptor, indicated by the low dissociation constant of 1.0 nanomolar (nM).^[20] In addition, salvinorin A has been found to act as a D₂ receptor partial agonist, with an affinity of 5–10 nM, an intrinsic activity of 40–60%, and an EC₅₀ of 48 nM.^[21] This suggests that the D₂ receptor may also play an important role in its effects.^[21]

Salvinorin A shows atypical properties as an agonist of the KOR relative to other KOR agonists.^[22]

Effect on intestinal motility

Salvinorin A is capable of inhibiting excess intestinal motility (e.g. diarrhea), through its potent κ-opioid-activating effects. 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.^[23] 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.^[24]

Solubility

Salvinorin A is soluble in organic solvents such as ethanol and acetone, but not especially so in water.^[25]

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.^[26]

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, consistent with the common plastidial localization of diterpenoid metabolism.^[31]

Terpenoids are biosynthesized from two 5-carbon precursors, isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). The NMR and MS study by Zjawiony suggested that the biosynthesis of salvinorin A proceeds via the 1-deoxy-d-xylulose-5-phosphate pathway. In the deoxyxylulose phosphate pathway, D-glyceraldehyde 3-phosphate and pyruvate, the intermediates of the glycolysis, are converted into 1-deoxy-D-xylulose 5-phosphate via decarboxylation. Subsequent reduction with NADPH generates 2C-methyl-D-erythritol 2,4-cyclodiphosphate, via the intermediates 4-diphosphocytidyl-2-C-methyl-D-erythritol and 4-diphosphocytidyl-2c-methyl-d-erythritol-2-phosphate, which then lead to IPP and DMAPP.

Subsequent addition of three 5-carbon IPP units to a single 5-carbon DMAPP unit generates the 20-carbon central precursor, geranylgeranyl diphosphate (GGPP). Bicyclization of GGPP by the class II diterpene synthase, ent-clerodienyl diphosphate synthase (SdCPS2^[32]), 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.^[33] 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.^[32]

Similar to many plant-derived psychoactive compounds, salvinorin A is excreted via peltate glandular trichomes, which reside external to the epidermis.^[34][35]

Chemical synthesis

A total asymmetric synthesis of salvinorin A, which relies on a transannular Michael reaction cascade to construct the ring system, was achieved as a 4.5% overall yield over 30 steps,^[36] then revised using 24 steps to yield salvinorin A in 0.15% yield.^[37] An approach to the trans-decalin ring system of salvinorin A used an intramolecular Diels-Alder reaction/Tsuji allylation strategy,^[38] and a total synthesis of salvinorin A was achieved using the intramolecular Diels-Alder / Tsuji allylation approach, combined with an asymmetric late-stage addition of the furan moiety.^[39]

United States

Salvinorin A is not scheduled at the federal level in the United States.^[50] 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.^{[citation needed]}

Australia

Salvinorin A is considered a Schedule 9 prohibited substance in Australia under the Poisons Standard (October 2015).^[52] 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.^[52]

Sweden

Sveriges riksdags health ministry Statens folkhälsoinstitut classified salvinorin A (and Salvia divinorum) as "health hazard" under the act Lagen om förbud mot vissa hälsofarliga varor (translated Act on the Prohibition of Certain Goods Dangerous to Health) as of April 1, 2006, in their regulation SFS 2006:167 listed as "salvinorin A", making it illegal to sell or possess.^[53]