Salvinorin A
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🧬 Receptor activity
| Target | Action | Affinity | Source | |
|---|---|---|---|---|
| Kappa-type opioid receptor | — | Ki 0.75 nM | CHEMBL | TargetKappa-type opioid receptor Action— AffinityKi 0.75 nM SourceCHEMBL |
| Unchecked | — | Ki 458 nM | CHEMBL | TargetUnchecked Action— AffinityKi 458 nM SourceCHEMBL |
| Mu-type opioid receptor | — | Ki 1000 nM | CHEMBL | TargetMu-type opioid receptor Action— AffinityKi 1000 nM SourceCHEMBL |
| Delta-type opioid receptor | — | Ki 1000 nM | CHEMBL | TargetDelta-type opioid receptor Action— AffinityKi 1000 nM SourceCHEMBL |
Mechanism of action
Salvinorin A, the primary psychoactive derivative of the hallucinogenic herb Salvia divinorum, is a potent and highly selective kappa-opioid receptor (KOR) agonist. Several recent studies, however, have suggested endocannabinoid system mediation of some of its effects. This study represents a systematic examination of this hypothesis. Salvinorin A was isolated from S. divinorum and was evaluated in a battery of in vitro and in vivo procedures designed to detect cannabinoid activity, including CB(1) receptor radioligand and [(35)S]GTPgammaS binding, calcium flux assay, in vivo cannabinoid screening tests, and drug discrimination. Salvinorin A did not bind to nor activate CB(1) receptors. In vivo salvinorin A produced pronounced hypolocomotion and antinociception (and to a lesser extent, hypothermia). These effects were blocked by the selective KOR antagonist, JDTic, but not by the CB(1) receptor antagonist rimonabant. Interestingly, however, rimonabant attenuated KOR activation stimulated by U69,593 in a [(35)S]GTPgammaS assay. Salvinorin A did not substitute for Delta(9)-tetrahydrocannabinol (THC) in mice trained to discriminate THC. These findings suggest that similarities in the pharmacological effects of salvinorin A and those of cannabinoids are mediated by its activation of KOR rather than by any direct action of salvinorin A on the endocannabinoid system. Further, the results suggest that rimonabant reversal of salvinorin A effects in previous studies may be explained in part by rimonabant attenuation of KOR activation.
Salvinorin A (SalA), a selective kappa-opioid receptor (KOR) agonist, produces dysphoria and pro-depressant like effects. These actions have been attributed to inhibition of striatal dopamine release. The dopamine transporter (DAT) regulates dopamine transmission via uptake of released neurotransmitter. KORs are apposed to DAT in dopamine nerve terminals suggesting an additional target by which SalA modulates dopamine transmission. SalA produced a concentration-dependent, nor-binaltorphimine (BNI)- and pertussis toxin-sensitive increase of ASP(+) accumulation in EM4 cells coexpressing myc-KOR and YFP-DAT, using live cell imaging and the fluorescent monoamine transporter substrate, trans 4-(4-(dimethylamino)-styryl)-N-methylpyridinium) (ASP(+)). Other KOR agonists also increased DAT activity that was abolished by BNI pretreatment. While SalA increased DAT activity, SalA treatment decreased serotonin transporter (SERT) activity and had no effect on norepinephrine transporter (NET) activity. In striatum, SalA increased the Vmax for DAT mediated DA transport and DAT surface expression. SalA up-regulation of DAT function is mediated by KOR activation and the KOR-linked extracellular signal regulated kinase-1/2 (ERK1/2) pathway. Co-immunoprecipitation and BRET studies revealed that DAT and KOR exist in a complex. In live cells, DAT and KOR exhibited robust FRET signals under basal conditions. SalA exposure caused a rapid and significant increase of the FRET signal. This suggests that the formation of KOR and DAT complexes is promoted in response to KOR activation. Together, these data suggest that enhanced DA transport and decreased DA release resulting in decreased dopamine signaling may contribute to the dysphoric and pro-depressant like effects of SalA and other KOR agonists.
Pharmacokinetics
Half-life
... Salvinorin A /has a/ half-life approximately 8 min in non-human primates ... .
Absorption
Salvinorin A (SA) is a highly selective kappa opioid receptor agonist and the putative psychoactive compound in Salvia divinorum (SD), an increasingly abused hallucinogenic plant. The objectives of this study were to characterize the physiological and subjective effects of SA versus placebo and measure drug and metabolite levels. Sublingual SA doses up to 4 mg were administered in dimethyl sulfoxide/polyethylene glycol 400 solution to eight SD-experienced subjects using a placebo-controlled ascending-dose design. No dose of SA produced significantly greater physiological or subjective effects than placebo. Furthermore, effects did not resemble reported "typical" effects of smoked SD. SA was detectable in plasma and urine, but was, in most cases, below the reliable limit of quantification (0.5 ng/mL). Our results suggest that the sublingual bioavailability of SA is low. Higher doses, alternate formulations, or alternate routes of administration will be necessary to study the effects of SA in humans.
Salvinorin A is a kappa opioid agonist and the principal psychoactive constituent of the Salvia divinorum plant, which has been used for hallucinogenic effects. Previous research on salvinorin A pharmacokinetics likely underestimated plasma levels typically resulting from the doses administered due to inefficient vaporization and not collecting samples during peak drug effects. Six healthy adults inhaled a single high dose of vaporized salvinorin A (n = 4, 21 ug/kg; n = 2, 18 ug/kg). Participant- and monitor-rated effects were assessed every 2 min for 60 min post-inhalation. Blood samples were collected at 13 time points up to 90 min post-inhalation. Drug levels peaked at 2 min and then rapidly decreased. Drug levels were significantly, positively correlated with participant and monitor drug effect ratings. Significant elevations in prolactin were observed beginning 5 min post-inhalation and peaking at 15 min post-inhalation. Cortisol showed inconsistent increases across participants. Hormonal responses were not well correlated with drug levels. This is the first study to demonstrate a direct relationship between changes in plasma levels of salvinorin A and drug effects in humans. The results confirm the efficacy of an inhalation technique for salvinorin A.
The diterpene salvinorin A from Salvia divinorum (Epling and Jativa-M), in doses of 200-500 ug produces effects which are subjectively identical to those experienced when the whole herb is ingested. Salvinorin A is effectively deactivated by the gastrointestinal system, so alternative routes of absorption must be used to maintain its activity. Traditionally the herb is consumed either by chewing the fresh leaves or by drinking the juices of freshly crushed leaves. The effects of the herb when consumed this way depend on absorption of salvinorin A through the oral mucosa before the herb is swallowed.
Metabolism
Salvinorin A’s chemical structure suggests that it may be a substrate of CYP450 (oxidative metabolism), UGT (hydrolysis) or carboxylesterases (ChEs) (hydrolysis). In addition, as observed for CYP1A1, CPY2C18 and CYP2E1, Salvinorin A metabolism via UGTB27 appears to be saturable at higher concentrations.
External links
Fact-sheets from PsychonautWiki. Harm-reduction reference only — not medical advice.