Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Salvinorin A: Difference between pages

{{short description|Chemical compound}}

{{cs1 config|name-list-style=vanc}}

{{Infobox drug

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 464386432

| IUPAC_name = methyl (2''S'',4a''R'',6a''R'',7''R'',9''S'',10a''S'',10b''R'')-9-(acetyloxy)-2-(furan-3-yl)-6a,10b-dimethyl-4,10-dioxo-dodecahydro-1''H''-naphtho[2,1-c]pyran-7-carboxylate

| image = Salvinorin A structure.svg

| width = 180

| image2 = Salvinorin A ball and stick model.png

| pregnancy_category =

| legal_AU = S9

| legal_BR = F2

| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-07-24 |title=RDC Nº 804 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 804 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-804-de-24-de-julho-de-2023-498447451 |url-status=live |archive-url=https://web.archive.org/web/20230827163149/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-804-de-24-de-julho-de-2023-498447451 |archive-date=2023-08-27 |access-date=2023-08-27 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=2023-07-25}}</ref>

| legal_CA = Schedule IV

| legal_UK = PSA

| bioavailability =

| protein_bound =

| elimination_half-life =

| excretion =

| CAS_number_Ref = {{cascite|changed|??}}

| CAS_number = 83729-01-5

| ATC_suffix =

| ChEBI_Ref = {{ebicite|changed|EBI}}

| ChEBI = 67900

| KEGG_Ref = {{keggcite|changed|kegg}}

| KEGG = C20196

| UNII_Ref = {{fdacite|changed|FDA}}

| UNII = T56W91NG6J

| C=23 | H=28 | O=8

<!--Physical data-->

| melting_point = 238

| melting_high = 240

| melting_notes = (also reported 242–244 °C)<ref>{{citation |url=https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=128563#x27 |title=salvinorin A |publisher=PubChem |access-date=2012-11-23}}</ref>

| density =

| solubility = 25.07 mg/L at 25 °C (water, est)

| specific_rotation = [α]_D = -45.3° at 22 °C/ (c = 8.530 CHCl₃); [α]_D = -41° at 25 °C (c = 1 in CHCl₃)

'''Salvinorin A''' is the main active [[psychotropic]] molecule in ''[[Salvia divinorum]]''. Salvinorin&nbsp;A is considered a [[dissociative]] [[hallucinogen]].<ref name="fp">{{cite journal | vauthors = Butelman ER, Kreek MJ | title = Salvinorin A, a kappa-opioid receptor agonist hallucinogen: pharmacology and potential template for novel pharmacotherapeutic agents in neuropsychiatric disorders | journal = Frontiers in Pharmacology | volume = 6 | pages = 190 | year = 2015 | pmid = 26441647 | pmc = 4561799 | doi = 10.3389/fphar.2015.00190 | doi-access = free }}</ref><ref name="NCBI">{{cite journal | vauthors = MacLean KA, Johnson MW, Reissig CJ, Prisinzano TE, Griffiths RR | title = Dose-related effects of salvinorin A in humans: dissociative, hallucinogenic, and memory effects | journal = Psychopharmacology | volume = 226 | issue = 2 | pages = 381–392 | date = March 2013 | pmid = 23135605 | pmc = 3581702 | doi = 10.1007/s00213-012-2912-9 }}</ref>

It is structurally distinct from other naturally occurring [[hallucinogen]]s (such as [[N,N-dimethyltryptamine|DMT]], [[psilocybin]], and [[mescaline]]) because it contains no [[nitrogen]] atoms; hence, it is not an [[alkaloid]] (and cannot be rendered as a [[Salt (chemistry)|salt]]), but rather is a [[terpenoid]].<ref name=fp/> It also differs in subjective experience, compared to other hallucinogens, and has been described as [[dissociative]].<ref name="NCBI" />

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.<ref name=Roth2002/>

Salvinorin A is found with several other structurally related [[salvinorin]]s. Salvinorin is a ''trans''-[[neoclerodane]] [[diterpenoid]]. It acts as a [[kappa opioid receptor]] [[agonist]] and is the first known compound acting on this [[receptor (biochemistry)|receptor]] that is not an [[alkaloid]].<ref name=Roth2002/>

== History ==

Salvinorin&nbsp;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 [[bicyclic]] [[diterpene]] structure.<ref name=Ortega1982/> Around the same time, Leander Julián Valdés III independently isolated the molecule as part of his PhD research, published in 1983.<ref name=Valdes1983/> Valdés named the chemical ''divinorin'', and also isolated an [[structural analog|analog]] that he named divinorin&nbsp;B. The naming was subsequently corrected to salvinorin&nbsp;A and B after the work was published in 1984.<ref name=Valdes1984/> Valdés later isolated salvinorin&nbsp;C.<ref name=Valdes2001/>

== Pharmacology ==

Salvinorin A is a ''trans''-neoclerodane [[terpenoid|diterpenoid]] with the [[chemical formula]] C₂₃H₂₈O₈.<ref name=Prisinzano2005/> Unlike other known opioid-receptor ligands, salvinorin A is not an [[alkaloid]], as it does not contain a [[Base (chemistry)|basic]] [[nitrogen]] [[atom]].<ref name=fp/><ref name=Harding2006/> Salvinorin A has no action at the [[5-HT2A receptor|5-HT_2A]] [[serotonin receptor]], the principal molecular target responsible for the actions of 'classical' psychedelics such as [[LSD]] and [[mescaline]].<ref name=Roth2002/><ref name=Harding2006/> Salvinorin A has also been shown to have effect on cannabinoid CB1 receptors.<ref>{{Cite web|url=https://pubchem.ncbi.nlm.nih.gov/compound/128563|title=Salvinorin A|website=pubchem.ncbi.nlm.nih.gov}}</ref> It significantly increases prolactin and inconsistently increases cortisol.<ref>{{cite journal | vauthors = Johnson MW, MacLean KA, Caspers MJ, Prisinzano TE, Griffiths RR | title = Time course of pharmacokinetic and hormonal effects of inhaled high-dose salvinorin A in humans | journal = Journal of Psychopharmacology | volume = 30 | issue = 4 | pages = 323–329 | date = April 2016 | pmid = 26880225 | pmc = 5289219 | doi = 10.1177/0269881116629125 }}</ref> It causes dysphoria by stopping release of dopamine in the [[striatum]].<ref name="pmc4188751">{{cite journal | vauthors = Kivell B, Uzelac Z, Sundaramurthy S, Rajamanickam J, Ewald A, Chefer V, Jaligam V, Bolan E, Simonson B, Annamalai B, Mannangatti P, Prisinzano TE, Gomes I, Devi LA, Jayanthi LD, Sitte HH, Ramamoorthy S, Shippenberg TS | display-authors = 6 | title = Salvinorin A regulates dopamine transporter function via a kappa opioid receptor and ERK1/2-dependent mechanism | journal = Neuropharmacology | volume = 86 | pages = 228–240 | date = November 2014 | pmid = 25107591 | pmc = 4188751 | doi = 10.1016/j.neuropharm.2014.07.016 }}</ref> Salvinorin A increases activity of [[Dopamine transporter|DAT]] while decreasing activity of [[Serotonin transporter|SERT]].<ref name="pmc4188751" />

=== 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.<ref>{{cite journal | vauthors = Siebert DJ | title = Salvia divinorum and salvinorin A: new pharmacologic findings | journal = Journal of Ethnopharmacology | volume = 43 | issue = 1 | pages = 53–56 | date = June 1994 | pmid = 7526076 | doi = 10.1016/0378-8741(94)90116-3 }}</ref>

It has a half-life of around 8 minutes in non-human primates.<ref>{{cite journal | vauthors = Placzek MS, Van de Bittner GC, Wey HY, Lukas SE, Hooker JM | title = Immediate and Persistent Effects of Salvinorin A on the Kappa Opioid Receptor in Rodents, Monitored In Vivo with PET | journal = Neuropsychopharmacology | volume = 40 | issue = 13 | pages = 2865–2872 | date = December 2015 | pmid = 26058662 | pmc = 4864638 | doi = 10.1038/npp.2015.159 }}</ref>

=== Potency and selectivity ===

Salvinorin A is active at doses as low as 200&nbsp;[[microgram|µg]].<ref name=Prisinzano2005/><ref name=Imanshahidi2006/><ref name="Marushia2002p11">

{{Cite journal| vauthors = Marushia R | year=2002| title=''Salvia divinorum'': The Botany, Ethnobotany, Biochemistry and Future of a Mexican Mint| journal=Ethnobotany| url=http://www.cyjack.com/Cognition/Salvia.pdf|access-date=2006-12-23 |archive-url=https://web.archive.org/web/20071007165306/http://www.cyjack.com/Cognition/Salvia.pdf |archive-date=October 7, 2007 }}</ref> Synthetic chemicals, such as [[Lysergic acid diethylamide|LSD]] (active at 20–30&nbsp;µg doses), can be more [[potency (pharmacology)|potent]].<ref name=Greiner1958/> Research has shown that salvinorin&nbsp;A is a potent [[kappa-opioid receptor|κ-opioid receptor]] (KOR) [[agonist]] (K_i = 2.4 nM, EC₅₀ = 1.8 nM).<ref name=Prisinzano2005/> It has a high affinity for the receptor, indicated by the low [[dissociation constant]] of 1.0&nbsp;nanomolar (nM).<ref name=Lee2005b/> It has been reported that the effects of salvinorin&nbsp;A in mice are blocked by κ-opioid [[receptor antagonist]]s.<ref name=Zhang2005/> In addition, salvinorin&nbsp;A has recently been found to act as a [[D2 receptor|D₂ receptor]] [[partial agonist]], with an [[affinity (pharmacology)|affinity]] of 5–10&nbsp;nM, an [[intrinsic activity]] of 40–60%, and an [[EC50|EC₅₀]] of 48&nbsp;nM.<ref name=Seeman2009/> This suggests that the D₂ receptor may also play an important role in its effects.<ref name=Seeman2009/> Salvinorin A shows atypical properties as an agonist of the KOR relative to other KOR agonists.<ref name="Dwoskin2014">{{cite book|author=Linda P. Dwoskin|title=Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse|url=https://books.google.com/books?id=b3UpAgAAQBAJ&pg=PA483|date=29 January 2014|publisher=Elsevier Science|isbn=978-0-12-420177-4|pages=483–}}</ref> 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|date=July 2018}}

=== 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&nbsp;A on [[ileum|ileal]] tissue has been described as 'prejunctional', as it was able to modify electrically induced contractions, but not those of [[exogenous]] [[acetylcholine]].<ref name=Capasso2006/> A pharmacologically important aspect of the contraction-reducing properties of ingested salvinorin&nbsp;A on gut tissue is that it is only pharmacologically active on inflamed and not normal tissue, thus reducing possible side-effects.<ref name=Capasso2007/>

=== Solubility ===

Salvinorin&nbsp;A is soluble in [[organic solvent]]s such as [[ethanol]] and [[acetone]], but not especially so in water.<ref>{{cite web|title=Salvia divinorum|url=http://www.emcdda.europa.eu/publications/drug-profiles/salvia|publisher=European Monitoring Centre for Drugs and Drug Addiction|access-date=4 September 2014|quote=Salvinorin A is unstable in basic solutions and is soluble in conventional organic solvents, including acetone, acetonitrile, chloroform, dimethyl sulfoxide and methanol, but is essentially insoluble in hexane and water.}}</ref>

=== Detection in urine ===

Researchers found that humans who smoked 580&nbsp;μg of the pure drug had urine salvinorin&nbsp;A concentrations of 2.4–10.9&nbsp;µg/L during the first hour; the levels fell below the [[detection limit]] by 1.5&nbsp;hours after smoking.<ref name=Pichini2005/>

== Research ==

Salvinorin A has only been administered to humans in a few studies, one showing that its effects peaked at about 2 minutes, that its subjective effects may overlap with those of [[serotonergic psychedelics]], and that it temporarily impairs recall and recognition memory.<ref name="NCBI"/> Like most other agonists of kappa opioid receptors, salvinorin A produces [[sedation]], [[psychotomimesis]], [[dysphoria]], [[anhedonia]], and [[depression (mood)|depression]].<ref name=fp/><ref name="Mott2011">{{cite book| vauthors = Mott PL |title=A Literature Review on the Status and Effects of Salvia Divinorum on Cognitive, Affective, and Behavioral Functioning|url=https://books.google.com/books?id=UFp_x7qBPk0C&pg=PA27|date=2 December 2011|publisher=Universal-Publishers|isbn=978-1-61233-777-7|pages=27–}}</ref><ref name="Biller2008">{{cite book| vauthors = Biller J |title=The Interface of Neurology & Internal Medicine|url=https://books.google.com/books?id=SRIvmTVcYBwC&pg=PA681|year=2008|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-7906-7|pages=681–}}</ref> Salvinorin A has been screened for its possible use as a structural "scaffold" in [[medicinal chemistry]] in developing new [[prescription drug|drugs]] for treating [[psychiatry|psychiatric diseases]]<ref name=fp/><ref>{{cite journal | vauthors = Orton E, Liu R | title = Salvinorin A: A Mini Review of Physical and Chemical Properties Affecting Its Translation from Research to Clinical Applications in Humans | journal = Translational Perioperative and Pain Medicine | volume = 1 | issue = 1 | pages = 9–11 | year = 2014 | pmid = 25346937 | pmc = 4208627 }}</ref> such as [[cocaine dependence]].<ref>{{cite book | vauthors = Kivell BM, Ewald AW, Prisinzano TE | title = Salvinorin A analogs and other κ-opioid receptor compounds as treatments for cocaine abuse | chapter = Salvinorin a Analogs and Other Kappa-Opioid Receptor Compounds as Treatments for Cocaine Abuse | series = Advances in Pharmacology | volume = 69 | pages = 481–511 | year = 2014 | pmid = 24484985 | pmc = 4128345 | doi = 10.1016/B978-0-12-420118-7.00012-3 | isbn = 9780124201187 }}</ref>

== Synthesis ==

[[Image:SalvinorinA.jpg|alt=High purity salvinorin extract isolated from dried ''Salvia divinorum'' foliage|thumb|Salvinorin A]]

=== Biosynthesis ===

The biogenic origin of salvinorin&nbsp;A synthesis has been elucidated using [[nuclear magnetic resonance]] and [[Electrospray ionization|ESI]]-[[mass spectrometry|MS]] analysis of incorporated precursors [[Isotopic labeling|labeled]] with stable [[isotopes]] of [[carbon]] ([[carbon-13]] ¹³C) and [[hydrogen]] ([[deuterium]] ²H). It "is biosynthesized via the [[Non-mevalonate pathway|1-deoxy-d-xylulose-5-phosphate pathway]]", rather than the classic [[mevalonate pathway]], consistent with the common plastidial localization of diterpenoid metabolism.<ref name=Kutrzeba2007/>

[[Terpenoid]]s 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.

[[File:Synthesis of IPP and DMAPP via 1-deoxy-d-xylulose-5-phosphate Pathway.png|thumb|Synthesis of IPP and DMAPP via 1-deoxy-d-xylulose-5-phosphate pathway]]

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<ref name=SdCPS2>{{cite web |url=http://www.ncbi.nlm.nih.gov/nuccore/KX424877.1|title=Salvia divinorum kolavenyl diphosphate synthase (CPS2) mRNA, complete cds|date=December 11, 2016|via=NCBI Nucleotide}}</ref>), produces a labdanyl diphosphate carbocation, which is subsequently rearranged through a sequence of 1,2-hydride and methyl shifts to form the [[Clerodane diterpene|''ent''-clerodienyl diphosphate intermediate]].<ref>{{cite journal | vauthors = Pelot KA, Mitchell R, Kwon M, Hagelthorn LM, Wardman JF, Chiang A, Bohlmann J, Ro DK, Zerbe P | display-authors = 6 | title = Biosynthesis of the psychotropic plant diterpene salvinorin A: Discovery and characterization of the Salvia divinorum clerodienyl diphosphate synthase | journal = The Plant Journal | volume = 89 | issue = 5 | pages = 885–897 | date = March 2017 | pmid = 27865008 | doi = 10.1111/tpj.13427 | doi-access = free }}</ref> 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.<ref name=SdCPS2/>

[[File:Biosynthesis of Salvinorin A.png|thumb|Biosynthesis of salvinorin A]]

Similar to many plant-derived psychoactive compounds, salvinorin&nbsp;A is excreted via [[peltate]] glandular [[trichome]]s, which reside external to the [[Epidermis (botany)|epidermis]].<ref name=Siebert2004/><ref name="urlKunkel2007"/>

=== Chemical synthesis ===

A total [[asymmetric synthesis]] of salvinorin&nbsp;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,<ref name=Scheerer2007/> then revised using 24 steps to yield salvinorin&nbsp;A in 0.15% yield.<ref name=Nozawa2008/> An approach to the ''trans''-decalin ring system of salvinorin&nbsp;A used an intramolecular [[Diels-Alder reaction]]/[[intramolecular Diels-Alder cycloaddition|Tsuji allylation]] strategy,<ref name=Burns2008/> 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.<ref>{{cite journal | vauthors = Line NJ, Burns AC, Butler SC, Casbohm J, Forsyth CJ | title = Total Synthesis of (-)-Salvinorin A | journal = Chemistry: A European Journal | volume = 22 | issue = 50 | pages = 17983–17986 | date = December 2016 | pmid = 27758012 | doi = 10.1002/chem.201604853 }}</ref>

== Associated compounds ==

{{Main|Salvinorin}}

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.<ref name=Munro2003/> Salvinorin&nbsp;A can be synthesized from salvinorin B by [[acetylation]], and de-[[acetyl]]ated salvinorin&nbsp;A becomes analog to salvinorin&nbsp;B.<ref name="lee2005a">{{cite journal | vauthors = Lee DY, Karnati VV, He M, Liu-Chen LY, Kondaveti L, Ma Z, Wang Y, Chen Y, Beguin C, Carlezon WA, Cohen B | display-authors = 6 | title = Synthesis and in vitro pharmacological studies of new C(2) modified salvinorin A analogues | journal = Bioorganic & Medicinal Chemistry Letters | volume = 15 | issue = 16 | pages = 3744–3747 | date = August 2005 | pmid = 15993589 | doi = 10.1016/j.bmcl.2005.05.048 }}</ref>

Research has produced a number of [[semi-synthetic]] compounds. Most derivatives are selective kappa opioid agonists as with salvinorin&nbsp;A, although some are even more potent, with the most potent compound salvinorin&nbsp;B ethoxymethyl ether being ten times stronger than salvinorin&nbsp;A. Some derivatives, such as [[herkinorin]], reduce kappa opioid action and instead act as [[Mu opioid receptor|mu opioid]] agonists.<ref name=Munro2008/><ref name=Holden2007/><ref name=Lee2006/><ref name=Beguin2006/>

The synthetic derivative [[RB-64]] is notable because of its [[functional selectivity]] and potency.<ref name="pmid25320048">{{cite journal | vauthors = White KL, Robinson JE, Zhu H, DiBerto JF, Polepally PR, Zjawiony JK, Nichols DE, Malanga CJ, Roth BL | display-authors = 6 | title = The G protein-biased κ-opioid receptor agonist RB-64 is analgesic with a unique spectrum of activities in vivo | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 352 | issue = 1 | pages = 98–109 | date = January 2015 | pmid = 25320048 | pmc = 4279099 | doi = 10.1124/jpet.114.216820 }}</ref> [[Salvinorin B methoxymethyl ether]] is seven times more potent than salvinorin&nbsp;A at KOPr in GTP-γS assays.<ref>{{cite journal | vauthors = Wang Y, Chen Y, Xu W, Lee DY, Ma Z, Rawls SM, Cowan A, Liu-Chen LY | display-authors = 6 | title = 2-Methoxymethyl-salvinorin B is a potent kappa opioid receptor agonist with longer lasting action in vivo than salvinorin A | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 324 | issue = 3 | pages = 1073–1083 | date = March 2008 | pmid = 18089845 | pmc = 2519046 | doi = 10.1124/jpet.107.132142 }}</ref>

== Natural occurrence ==

Salvinorin A occurs naturally in several ''[[Salvia]]'' species:

* ''[[Salvia divinorum|S. divinorum]]'' (0.89&nbsp;mg/g to 3.70&nbsp;mg/g).<ref>{{cite journal | vauthors = Brito-da-Costa AM, Dias-da-Silva D, Gomes NG, Dinis-Oliveira RJ, Madureira-Carvalho Á | title = Pharmacokinetics and Pharmacodynamics of Salvinorin A and ''Salvia divinorum'': Clinical and Forensic Aspects | journal = Pharmaceuticals | volume = 14 | issue = 2 | pages = 116 | date = February 2021 | pmid = 33546518 | pmc = 7913753 | doi = 10.3390/ph14020116 | doi-access = free }}</ref>

* ''[[Salvia recognita|S. recognita]]'' (212.9 μg/g).<ref name=":0" />

* ''[[Salvia absconditiflora|S. cryptantha]]'' (51.5 μg/g).<ref name=":0" />

* ''[[Salvia glutinosa|S. glutinosa]]'' (38.9 μg/g).<ref name=":0">{{cite journal | vauthors = Hatipoglu SD, Yalcinkaya B, Akgoz M, Ozturk T, Goren AC, Topcu G | title = Screening of Hallucinogenic Compounds and Genomic Characterisation of 40 Anatolian Salvia Species | journal = Phytochemical Analysis | volume = 28 | issue = 6 | pages = 541–549 | date = November 2017 | pmid = 28722248 | doi = 10.1002/pca.2703 | bibcode = 2017PChAn..28..541H }}</ref>

[[Salvinorin|Salvinorin B]] has been detected in ''S. potentillifolia'' and ''S. adenocaulon'', however these species do not contain a measureable amount of salvinorin A.<ref name=":0" />

== Legal status ==

{{See also|Legal status of Salvia divinorum}}

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

===United States===

{{see also|Legal status of Salvia divinorum in the United States}}

Salvinorin A is not scheduled at the federal level in the [[United States]].<ref name="Part 1308 — Schedules of Controlled Substances - 1308.11 Schedule I">{{Cite web|url=http://www.deadiversion.usdoj.gov/21cfr/cfr/1308/1308_11.htm|title=21 CFR — Schedules of Controlled Substances §1308.11 Schedule I.|access-date=2014-12-18|archive-date=2009-08-27|archive-url=https://web.archive.org/web/20090827043725/http://www.deadiversion.usdoj.gov/21cfr/cfr/1308/1308_11.htm|url-status=dead}}</ref> 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|date = July 2023}}

====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&nbsp;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."<ref name="Florida Statutes - Chapter 893 - Drug Abuse Prevention and Control">{{Cite web|url=http://leg.state.fl.us/statutes/index.cfm?App_mode=Display_Statute&URL=0800-0899/0893/0893.html|title=Statutes & Constitution :View Statutes : Online Sunshine|website=leg.state.fl.us}}</ref>

===Australia===

Salvinorin A is considered a Schedule 9 prohibited substance in Australia under the [[Standard for the Uniform Scheduling of Medicines and Poisons|Poisons Standard]] (October 2015).<ref name="Poisons Standard">{{cite web | title = Poisons Standard | date = October 2015 | url = https://www.comlaw.gov.au/Details/F2015L01534 | publisher = The Australian Government }}</ref> 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.<ref name="Poisons Standard" />

===Sweden===

[[Riksdag|''Sveriges riksdags'']] health ministry [[:sv:Statens folkhälsoinstitut|''Statens folkhälsoinstitut'']] classified salvinorin&nbsp;A (and ''Salvia divinorum'') as "health hazard" under the act [[:sv:Lagen om förbud mot vissa hälsofarliga varor|''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.<ref>{{cite web|url=http://www.notisum.se/rnp/sls/sfs/20060167.pdf|title=Förordning om ändring i förordningen (1999:58) om förbud mot vissa hälsofarliga varor|trans-title=Ordinance amending the ordinance (1999: 58) on the prohibition of certain dangerous goods|language=Swedish|publisher=Svensk författningssamling|date=2006|access-date=2013-09-25|archive-date=2013-09-29|archive-url=https://web.archive.org/web/20130929062941/http://www.notisum.se/rnp/sls/sfs/20060167.pdf|url-status=dead}}</ref>

== See also ==

* [[Psychoactive drug]]

* [[List of entheogens]]

* [[Collybolide]]

* [[Nalfurafine]]

* [[Difelikefalin]]

* [[Enadoline]]

== References ==

{{Reflist|colwidth=30em|refs=

<ref name=Beguin2006>{{cite journal | vauthors = Béguin C, Richards MR, Li JG, Wang Y, Xu W, Liu-Chen LY, Carlezon WA, Cohen BM | display-authors = 6 | title = Synthesis and in vitro evaluation of salvinorin A analogues: effect of configuration at C(2) and substitution at C(18) | journal = Bioorganic & Medicinal Chemistry Letters | volume = 16 | issue = 17 | pages = 4679–4685 | date = September 2006 | pmid = 16777411 | doi = 10.1016/j.bmcl.2006.05.093 }}</ref>

<!-- <ref name=Bigham2003>{{cite journal | vauthors = Bigham AK, Munro TA, Rizzacasa MA, Robins-Browne RM | title = Divinatorins A-C, new neoclerodane diterpenoids from the controlled sage Salvia divinorum | journal = Journal of Natural Products | volume = 66 | issue = 9 | pages = 1242–1244 | date = September 2003 | pmid = 14510607 | doi = 10.1021/np030313i | citeseerx = 10.1.1.693.6690 }}</ref> -->

<ref name=Burns2008>{{cite journal | vauthors = Burns AC, Forsyth CJ | title = Intramolecular Diels-Alder/Tsuji allylation assembly of the functionalized trans-decalin of salvinorin A | journal = Organic Letters | volume = 10 | issue = 1 | pages = 97–100 | date = January 2008 | pmid = 18062692 | doi = 10.1021/ol7024058 }}</ref>

<ref name=Capasso2006>{{cite journal | vauthors = Capasso R, Borrelli F, Capasso F, Siebert DJ, Stewart DJ, Zjawiony JK, Izzo AA | title = The hallucinogenic herb Salvia divinorum and its active ingredient salvinorin A inhibit enteric cholinergic transmission in the guinea-pig ileum | journal = Neurogastroenterology and Motility | volume = 18 | issue = 1 | pages = 69–75 | date = January 2006 | pmid = 16371085 | doi = 10.1111/j.1365-2982.2005.00725.x | s2cid = 4498185 }}</ref>

<ref name=Capasso2007>{{cite journal | vauthors = Capasso R, Borrelli F, Zjawiony J, Kutrzeba L, Aviello G, Sarnelli G, Capasso F, Izzo AA | display-authors = 6 | title = The hallucinogenic herb Salvia divinorum and its active ingredient salvinorin A reduce inflammation-induced hypermotility in mice | journal = Neurogastroenterology and Motility | volume = 20 | issue = 2 | pages = 142–148 | date = February 2008 | pmid = 17931335 | doi = 10.1111/j.1365-2982.2007.00994.x | s2cid = 25081755 }}</ref>

<ref name=Greiner1958>{{cite journal | vauthors = Greiner T, Burch NR, Edelberg R | title = Psychopathology and psychophysiology of minimal LSD-25 dosage; a preliminary dosage-response spectrum | journal = A.M.A. Archives of Neurology and Psychiatry | volume = 79 | issue = 2 | pages = 208–210 | date = February 1958 | pmid = 13497365 | doi = 10.1001/archneurpsyc.1958.02340020088016 }}</ref>

<ref name=Harding2006>{{cite journal | vauthors = Harding WW, Schmidt M, Tidgewell K, Kannan P, Holden KG, Gilmour B, Navarro H, Rothman RB, Prisinzano TE | display-authors = 6 | title = Synthetic studies of neoclerodane diterpenes from Salvia divinorum: semisynthesis of salvinicins A and B and other chemical transformations of salvinorin A | journal = Journal of Natural Products | volume = 69 | issue = 1 | pages = 107–112 | date = January 2006 | pmid = 16441078 | pmc = 2544632 | doi = 10.1021/np050398i }}</ref>

<ref name=Holden2007>{{cite journal | vauthors = Holden KG, Tidgewell K, Marquam A, Rothman RB, Navarro H, Prisinzano TE | title = Synthetic studies of neoclerodane diterpenes from Salvia divinorum: exploration of the 1-position | journal = Bioorganic & Medicinal Chemistry Letters | volume = 17 | issue = 22 | pages = 6111–6115 | date = November 2007 | pmid = 17904842 | pmc = 2111044 | doi = 10.1016/j.bmcl.2007.09.050 }}</ref>

<ref name=Imanshahidi2006>{{cite journal | vauthors = Imanshahidi M, Hosseinzadeh H | title = The pharmacological effects of Salvia species on the central nervous system | journal = Phytotherapy Research | volume = 20 | issue = 6 | pages = 427–437 | date = June 2006 | pmid = 16619340 | doi = 10.1002/ptr.1898 | quote = However, when smoked (in a manner similar to free base cocaine), the compound is effective in doses of 200–500&nbsp;μg and produces visions that last from 30 minutes to an hour or two, while doses over 2&nbsp;mg are effective for much longer. At doses greater than 500&nbsp;μg the subject is often no longer aware of their surroundings and may enter an uncontrollable delirium. This compound is the most potent naturally occurring hallucinogen thus far isolated. | s2cid = 35676076 }}</ref>

<ref name="urlKunkel2007">{{cite web |title=Leaf glandular trichome (''Salvia divinorum'') | vauthors = Kunkel D |publisher=Dennis Kunkel Microscopy, Inc |url=https://www.sciencephoto.com/media/801352/view |year=2007 |access-date=2022-04-04 }}</ref>

<ref name=Kutrzeba2007>{{cite journal | vauthors = Kutrzeba L, Dayan FE, Howell J, Feng J, Giner JL, Zjawiony JK | title = Biosynthesis of salvinorin A proceeds via the deoxyxylulose phosphate pathway | journal = Phytochemistry | volume = 68 | issue = 14 | pages = 1872–1881 | date = July 2007 | pmid = 17574635 | pmc = 2065853 | doi = 10.1016/j.phytochem.2007.04.034 | bibcode = 2007PChem..68.1872K }}</ref>

<!--<ref name=Kutrzeba2009>{{cite journal | vauthors = Kutrzeba LM, Ferreira D, Zjawiony JK | title = Salvinorins J from Salvia divinorum: mutarotation in the neoclerodane system | journal = Journal of Natural Products | volume = 72 | issue = 7 | pages = 1361–1363 | date = July 2009 | pmid = 19473009 | doi = 10.1021/np900181q }}</ref>-->

<ref name=Lee2005b>{{cite journal | vauthors = Lee DY, Ma Z, Liu-Chen LY, Wang Y, Chen Y, Carlezon WA, Cohen B | title = New neoclerodane diterpenoids isolated from the leaves of Salvia divinorum and their binding affinities for human kappa opioid receptors | journal = Bioorganic & Medicinal Chemistry | volume = 13 | issue = 19 | pages = 5635–5639 | date = October 2005 | pmid = 16084728 | doi = 10.1016/j.bmc.2005.05.054 }}</ref>

<ref name=Lee2006>{{cite journal | vauthors = Lee DY, He M, Liu-Chen LY, Wang Y, Li JG, Xu W, Ma Z, Carlezon WA, Cohen B | display-authors = 6 | title = Synthesis and in vitro pharmacological studies of new C(4)-modified salvinorin A analogues | journal = Bioorganic & Medicinal Chemistry Letters | volume = 16 | issue = 21 | pages = 5498–5502 | date = November 2006 | pmid = 16945525 | doi = 10.1016/j.bmcl.2006.08.051 }}</ref>

<ref name=Munro2003>{{cite journal | vauthors = Munro TA, Rizzacasa MA | title = Salvinorins D-F, new neoclerodane diterpenoids from Salvia divinorum, and an improved method for the isolation of salvinorin A | journal = Journal of Natural Products | volume = 66 | issue = 5 | pages = 703–705 | date = May 2003 | pmid = 12762813 | doi = 10.1021/np0205699 }}</ref>

<ref name=Munro2008>{{cite journal | vauthors = Munro TA, Duncan KK, Xu W, Wang Y, Liu-Chen LY, Carlezon WA, Cohen BM, Béguin C | display-authors = 6 | title = Standard protecting groups create potent and selective kappa opioids: salvinorin B alkoxymethyl ethers | journal = Bioorganic & Medicinal Chemistry | volume = 16 | issue = 3 | pages = 1279–1286 | date = February 2008 | pmid = 17981041 | pmc = 2568987 | doi = 10.1016/j.bmc.2007.10.067 }}</ref>

<ref name=Nozawa2008>{{cite journal | vauthors = Nozawa M, Suka Y, Hoshi T, Suzuki T, Hagiwara H | title = Total synthesis of the hallucinogenic neoclerodane diterpenoid salvinorin A | journal = Organic Letters | volume = 10 | issue = 7 | pages = 1365–1368 | date = April 2008 | pmid = 18311991 | doi = 10.1021/ol800101v }}</ref>

<ref name=Ortega1982>{{cite journal | vauthors = Ortega A, Blount JF, Manchard PD |title=Salvinorin, a new ''trans''-neoclerodane diterpene from ''Salvia divinorum'' (Labiatae) |journal=Journal of the Chemical Society, Perkin Transactions 1 |year=1982 |pages=2505–8 |doi=10.1039/P19820002505}}</ref>

<ref name=Pichini2005>{{cite journal | vauthors = Pichini S, Abanades S, Farré M, Pellegrini M, Marchei E, Pacifici R, Torre R, Zuccaro P | display-authors = 6 | title = Quantification of the plant-derived hallucinogen Salvinorin A in conventional and non-conventional biological fluids by gas chromatography/mass spectrometry after Salvia divinorum smoking | journal = Rapid Communications in Mass Spectrometry | volume = 19 | issue = 12 | pages = 1649–1656 | date = 30 June 2005 | pmid = 15915477 | doi = 10.1002/rcm.1970 | bibcode = 2005RCMS...19.1649P }}</ref>

<ref name=Prisinzano2005>{{cite journal | vauthors = Prisinzano TE | title = Psychopharmacology of the hallucinogenic sage Salvia divinorum | journal = Life Sciences | volume = 78 | issue = 5 | pages = 527–531 | date = December 2005 | pmid = 16213533 | doi = 10.1016/j.lfs.2005.09.008 }}</ref>

<ref name=Roth2002>{{cite journal | vauthors = Roth BL, Baner K, Westkaemper R, Siebert D, Rice KC, Steinberg S, Ernsberger P, Rothman RB | display-authors = 6 | title = Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 18 | pages = 11934–11939 | date = September 2002 | pmid = 12192085 | pmc = 129372 | doi = 10.1073/pnas.182234399 | doi-access = free | bibcode = 2002PNAS...9911934R | jstor = 3073142 | author1-link = Bryan Roth }}</ref>

<ref name=Scheerer2007>{{cite journal | vauthors = Scheerer JR, Lawrence JF, Wang GC, Evans DA | title = Asymmetric synthesis of salvinorin A, a potent kappa opioid receptor agonist | journal = Journal of the American Chemical Society | volume = 129 | issue = 29 | pages = 8968–8969 | date = July 2007 | pmid = 17602636 | doi = 10.1021/ja073590a }}</ref>

<ref name=Seeman2009>{{cite journal | vauthors = Seeman P, Guan HC, Hirbec H | title = Dopamine D2High receptors stimulated by phencyclidines, lysergic acid diethylamide, salvinorin A, and modafinil | journal = Synapse | volume = 63 | issue = 8 | pages = 698–704 | date = August 2009 | pmid = 19391150 | doi = 10.1002/syn.20647 | s2cid = 17758902 }}</ref>

<ref name=Siebert2004>{{cite journal | vauthors = Siebert DJ | title = Localization of salvinorin A and related compounds in glandular trichomes of the psychoactive sage, Salvia divinorum | journal = Annals of Botany | volume = 93 | issue = 6 | pages = 763–771 | date = June 2004 | pmid = 15087301 | pmc = 4242294 | doi = 10.1093/aob/mch089 | jstor = 43576030 }}</ref>

<ref name=Valdes1983>{{Cite thesis |degree=PhD |title=The pharmacognosy of ''Salvia divinorum'' (Epling and Jativa-M): An Investigation of Ska Maria Pastora (Mexico) | vauthors = Valdés III LJ |year=1983 |publisher=University of Michigan |id={{ProQuest|303280881}} }}

</ref>

<ref name=Valdes1984>{{cite journal | vauthors = Valdés III LJ, Butler WM, Hatfield GM, Paul AG, Koreeda M |title=Divinorin A, a psychotropic terpenoid, and divinorin B from the hallucinogenic Mexican mint ''Salvia divinorum'' |journal=Journal of Organic Chemistry |year=1984 |volume=49 |pages=4716–20 |doi=10.1021/jo00198a026 |issue=24}}</ref>

<ref name=Valdes2001>{{cite journal | vauthors = Valdés LJ, Chang HM, Visger DC, Koreeda M | title = Salvinorin C, a new neoclerodane diterpene from a bioactive fraction of the hallucinogenic Mexican mint Salvia divinorum | journal = Organic Letters | volume = 3 | issue = 24 | pages = 3935–3937 | date = November 2001 | pmid = 11720573 | doi = 10.1021/ol016820d }}</ref>

<ref name=Zhang2005>{{cite journal | vauthors = Zhang Y, Butelman ER, Schlussman SD, Ho A, Kreek MJ | title = Effects of the plant-derived hallucinogen salvinorin A on basal dopamine levels in the caudate putamen and in a conditioned place aversion assay in mice: agonist actions at kappa opioid receptors | journal = Psychopharmacology | volume = 179 | issue = 3 | pages = 551–558 | date = May 2005 | pmid = 15682306 | doi = 10.1007/s00213-004-2087-0 | s2cid = 4533805 }}</ref>

}}

== Further reading ==

{{refbegin}}

* {{Cite book | vauthors = Baselt RC | year = 2008 | title = Disposition of Toxic Drugs and Chemicals in Man | publisher = Biomedical Publications | edition = 8th | place = Foster City, CA | pages = 1405–6 | isbn = 978-0-9626523-7-0 }}

{{refend}}

{{Hallucinogens}}

{{Dopaminergics}}

{{Opioidergics}}

[[Category:Dissociative drugs]]

[[Category:Entheogens]]

[[Category:Kappa-opioid receptor agonists]]

[[Category:D2-receptor agonists]]

[[Category:Oneirogens]]

[[Category:Terpenes and terpenoids]]

[[Category:3-Furyl compounds]]

[[Category:Acetate esters]]

[[Category:Lactones]]

[[Category:Methyl esters]]

[[Category:Oxygen heterocycles]]

[[Category:Heterocyclic compounds with 3 rings]]