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 (and cannot be rendered as a
salt), but rather is a
terpenoid.[3] It also differs in subjective experience, compared to other hallucinogens, and has been described as
dissociative.[4]
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.[5]
Salvinorin A was first described and named in 1982 by Alfredo Ortega and colleagues in Mexico. They used a combination of
spectroscopy and
x-ray crystallography to determine the chemical structure of the compound, which was shown to have a
bicyclicditerpene structure.[6] Around the same time, Leander Julián Valdés III independently isolated the molecule as part of his PhD research, published in 1983.[7] Valdés named the chemical divinorin, and also isolated an
analog that he named divinorin B. The naming was subsequently corrected to salvinorin A and B after the work was published in 1984.[8] Valdés later isolated salvinorin C.[9]
Pharmacology
Salvinorin A is a trans-neoclerodane
diterpenoid with the
chemical formula C23H28O8.[10] Unlike other known opioid-receptor ligands, salvinorin A is not an
alkaloid, as it does not contain a
basicnitrogenatom.[3][11] Salvinorin A has no action at the
5-HT2Aserotonin receptor, the principal molecular target responsible for the actions of 'classical' psychedelics such as
LSD and
mescaline.[5][11] Salvinorin A has also been shown to have effect on cannabinoid CB1 receptors.[12] It significantly increases prolactin and inconsistently increases cortisol.[13] It causes dysphoria by stopping release of dopamine in the
striatum.[14] Salvinorin A increases activity of
DAT while decreasing activity of
SERT.[14]
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 (Ki = 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] It has been reported that the effects of salvinorin A in mice are blocked by κ-opioid
receptor antagonists.[21] In addition, salvinorin A has recently been found to act as a
D2 receptorpartial agonist, with an
affinity of 5–10 nM, an
intrinsic activity of 40–60%, and an
EC50 of 48 nM.[22] This suggests that the D2 receptor may also play an important role in its effects.[22] Salvinorin A shows atypical properties as an agonist of the KOR relative to other KOR agonists.[23] For instance, it is 40-fold less potent in promoting internalization (
receptor downregulation) of the human KOR relative to the prototypical KOR agonist
U-50488.[citation needed]
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
exogenousacetylcholine.[24] 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.[25]
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.[27]
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[33]), 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.[34] 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.[33]
Similar to many plant-derived psychoactive compounds, salvinorin A is excreted via
peltate glandular
trichomes, which reside external to the
epidermis.[35][36]
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,[37] then revised using 24 steps to yield salvinorin A in 0.15% yield.[38] An approach to the trans-decalin ring system of salvinorin A used an intramolecular
Diels-Alder reaction/
Tsuji allylation strategy,[39] 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.[40]
Salvinorin A is one of several structurally related salvinorins found in the Salvia divinorum plant. Salvinorin A is the only naturally occurring salvinorin that is known to be psychoactive.[41] Salvinorin A can be synthesized from salvinorin B by
acetylation, and de-
acetylated salvinorin A becomes analog to salvinorin B.[42]
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.[43][44][45][46]
Salvinorin B has been detected in S. potentillifolia and S. adenocaulon, however these species do not contain a measureable amount of salvinorin A.[50]
Salvinorin A is not scheduled at the federal level in the
United States.[51] 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]
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."[52]
Australia
Salvinorin A is considered a Schedule 9 prohibited substance in Australia under the
Poisons Standard (October 2015).[53] 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.[53]
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.[54]
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