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

{{short description|Group of four possible stereoisomers found in various plants: a.o., absinthe and mint}}

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 470609541

| Name = Thujone

| ImageFile =

| ImageFileL1 = (-)-alpha-Thujon.svg

| ImageFileR1 = (+)-beta-Thujon.svg

| ImageFile2 = (−)-α-thujone-from-xtal-3D-bs-17.png

| ImageSize2 = 100px

| ImageCaption2 = [[Ball-and-stick model]] of (−)-α-thujone<ref>{{ cite journal | title = Absolute Configuration of Small Molecules by Co-Crystallization | first1 = Clemens | last1 = Richert | first2 = Felix | last2 = Krupp | first3 = Wolfgang | last3 = Frey | journal = [[Angewandte Chemie|Angew. Chem. Int. Ed.]] | year = 2020 | volume = 59 | issue = 37 | pages = 15875–15879 | doi = 10.1002/anie.202004992 | pmid = 32441841 | pmc = 7540501 | doi-access = free }}</ref>

| IUPACName = α: (1''S'',4''R'',5''R'')-4-Methyl-1-(propan-2-yl)bicyclo[3.1.0]hexan-3-one<br>β: (1''S'',4''S'',5''R'')-4-methyl-1-propan-2-ylbicyclo[3.1.0]hexan-3-one

| OtherNames = Bicyclo[3.1.0]hexan-3-one, 4-methyl-1-(1-methylethyl)-, [1''S''-(1α,4α,5α)]-<br> α-Thujone <br> β-Thujone <br>Thujone, ''cis''<br> 3-Thujanone, (1''S'',4''R'',5''R'')-(−)-<br> Thujon<br> 3-Thujanone, (−)-<br> ''l''-Thujone; 4-Methyl-1-(1-methylethyl)bicyclo[3.1.0]hexan-3-one-, (1S,4R,5R)-<br> 3-Thujone; ''cis''-Thujone<br>(''Z'')-Thujone<br> (−)-Thujone; Bicyclo(3.1.0)hexan-3-one, 4-methyl-1-(1-methylethyl)-, (1''S'',4''R'',5''R'')-<br> NSC 93742<br> 1-isopropyl-4-methylbicyclo[3.1.0]hexan-3-one

| SystematicName =

| Section1 = {{Chembox Identifiers

| CASNo = 76231-76-0

| CASNo_Comment = (α,β-thujone)

| CASNo1_Ref = {{cascite|correct|CAS}}

| CASNo1 = 546-80-5

| CASNo1_Comment = (α-thujone)

| CASNo2_Ref = {{cascite|correct|CAS}}

| CASNo2 = 471-15-8

| CASNo2_Comment = (β-thujone)

| IUPHAR_ligand = 5344

| PubChem = 261491

| Beilstein = 4660369

| ChEMBL = 1444078

| EINECS = 214-405-7

| KEGG = C09906

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 86HK1QRJ4K

| UNII_Comment = (α,β-thujone)

| UNII1 = R0SQ9G0DU5

| UNII1_Ref = {{fdacite|correct|FDA}}

| UNII1_Comment = (α-thujone)

| UNII2 = 8ZI5R3T54Q

| UNII2_Comment = (β-thujone)

| UNII2_Ref = {{fdacite|correct|FDA}}

| PubChem1 = 11027

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID_Comment = (α-thujone)

| ChemSpiderID1_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID1 = 82583

| ChemSpiderID1_Comment = (β-thujone)

| ChEBI_Ref = {{ebicite|correct|EBI}}

| SMILES_Comment = (α-thujone)

| SMILES1 = C[C@@H]([C@@H](C2)[C@]2([C@@H](C)C)C1)C1=O

| SMILES1_Comment = (β-thujone)

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| Section2 = {{Chembox Properties

| C=10 | H=16 | O=1

| Appearance =

| Density = 0.92 g/cm³ (β-thujone); 0.9116 g/cm³ (α-thujone)

| MeltingPt = <25 °C

| BoilingPtC = 203

| BoilingPt_notes = (alpha,beta-thujone)

| Solubility = 407 mg/L

| Section3 = {{Chembox Hazards

| GHSPictograms = {{GHS07}}

| GHSSignalWord = Warning

| HPhrases = {{H-phrases|302}}

| PPhrases = {{P-phrases|264|270|301+312|330|501}}

| MainHazards =

| FlashPt =

| AutoignitionPt =

}}

| Section4 =

| Section5 =

| Section6 =

{{inline audio}}

'''Thujone''' ({{IPAc-en|audio=En-thujone.ogg|'|θ|uː|dʒ|oʊ|n}}<ref>Derived from the Ancient Greek θυία, ''thuj(a)'', a kind of [[Cedrus|cedar]] + -ωνη, ''-one'', feminine patronymic for a chemical relative of [[acetone]]</ref>) is a [[ketone]] and a [[terpene|monoterpene]] that occurs predominantly in two [[diastereomer]]ic ([[epimer]]ic) forms: '''(−)-α-thujone''' and '''(+)-β-thujone'''.<ref>{{cite journal |vauthors=Perry NB, Anderson RE, Brennan NJ, Douglas MH, Heaney AJ, McGimpsey JA, Smallfield BM | title = Essential Oils from Dalmatian Sage (''Salvia officinalis'' L.): Variations among Individuals, Plant Parts, Seasons, and Sites | journal = [[Journal of Agricultural and Food Chemistry|J. Agric. Food Chem.]] | volume = 47 | issue = 5 | pages = 2048–2054 | year = 1999 | pmid = 10552494 | doi = 10.1021/jf981170m }}</ref><ref>{{ cite journal | journal = [[Helvetica Chimica Acta|Helv. Chim. Acta]] | year = 1997 | volume = 80 | issue = 3 | pages = 623–639 | title = Palladium-Catalysed Intramolecular Cyclisations of Olefinic Propargylic Carbonates and application to the diastereoselective synthesis of enantiomerically pure (−)-α-thujone |vauthors=Oppolzer W, Pimm A, Stammen B, Hume WE | doi = 10.1002/hlca.19970800302 | doi-access = free }}</ref>

Though it is best known as a [[chemical compound]] in the spirit [[absinthe]], it is unlikely to be responsible for absinthe's alleged stimulant and psychoactive effects due to the small quantities present.<ref name="pmid15536765">{{cite journal |vauthors=Dettling A, Grass H, Schuff A, Skopp G, Strohbeck-Kuehner P, Haffner HT | title = Absinthe: attention performance and mood under the influence of thujone | journal = J. Stud. Alcohol | volume = 65 | issue = 5 | pages = 573–81 | year = 2004 | pmid = 15536765 | doi = 10.15288/jsa.2004.65.573| url = http://www.jsad.com/jsad/article/Absinthe_Attention_Performance_and_Mood_under_the_Influence_of_Thujone/1040.html }}</ref><ref name="acs">[http://pubs.acs.org/cen/email/html/cen_86_i18_8618sci2.html Absinthe Myths Finally Laid To Rest]</ref><ref>[http://www.thujone.info/thujone-absinthe-39.html Chemical Composition of Vintage Preban Absinthe with Special Reference to Thujone, Fenchone, Pinocamphone, Methanol, Copper, and Antimony Concentrations]</ref>

Thujone acts on the [[GABAA receptor|GABA_A receptor]] as an antagonist. As a competitive antagonist of GABA_A receptor, thujone alone is considered to be [[convulsant]],<ref name=":0">{{Cite journal|last=Olsen|first=Richard W.|date=2000-04-25|title=Absinthe and γ-aminobutyric acid receptors|pmc=34311|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=9|pages=4417–4418|issn=0027-8424|pmid=10781032|doi=10.1073/pnas.97.9.4417|bibcode=2000PNAS...97.4417O|doi-access=free}}</ref> though by interfering with the inhibitory transmitter GABA, it may convey stimulating, mood-elevating effects at low doses.{{Citation needed|date=March 2024}} It is also found in perfumery as a component of several essential oils.{{Citation needed|date=March 2024}}

In addition to the naturally occurring (−)-α-thujone and (+)-β-thujone, two other forms are possible: '''(+)-α-thujone''' and '''(−)-β-thujone'''. In 2016, they were found in nature as well,<ref name="williams2016">{{cite journal |last1=Williams |first1=Jack D. |last2=Yazarians |first2=Jessica A. |last3=Almeyda |first3=Chelcie C. |last4=Anderson |first4=Kristin A. |last5=Boyce |first5=Gregory R. |title=Detection of the Previously Unobserved Stereoisomers of Thujone in the Essential Oil and Consumable Products of Sage (Salvia officinalis L.) Using Headspace Solid-Phase Microextraction–Gas Chromatography–Mass Spectrometry |journal=Journal of Agricultural and Food Chemistry |date=23 May 2016 |volume=64 |issue=21 |pages=4319–4326 |doi=10.1021/acs.jafc.6b01065|pmid=27181395 }}</ref> in ''[[Salvia officinalis]]''.'''

<gallery>

File:(-)-alpha-Thujon.svg|(−)-α-thujone

File:Alpha-(+)-Thujon.svg|(+)-α-thujone

File:Beta-(+)-Thujon.svg|(+)-β-thujone

File:Beta-(-)-Thujon.svg|(−)-β-thujone

</gallery>

== Sources ==

Thujone is found in a number of plants, such as [[Thuja|arborvitae]] (genus ''Thuja'', hence the derivation of the name), [[Callitropsis nootkatensis|Nootka cypress]], some [[juniper]]s, [[mugwort]], [[oregano]], [[common sage]], [[tansy]], and [[Artemisia (plant)|wormwood]], most notably grand wormwood (''[[Artemisia absinthium]]''), usually as a mix of isomers in a 1:2 ratio. It is also found in various species of ''[[Mentha]]'' (mint).

== Biosynthesis ==

The biosynthesis of thujone is similar to the synthesis of other monoterpenes and begins with the formation of [[geranyl diphosphate]] (GPP) from [[dimethylallyl pyrophosphate]] (DMAPP) and [[isopentenyl diphosphate]] (IPP), catalyzed by the enzyme geranyl diphosphate synthase.<ref name=Dewick2008>{{cite book |last=Dewick |first=Paul M |date=2009 |title=Medicinal natural products: a biosynthetic approach |url=https://archive.org/details/medicinalnatural00dewi_880 |url-access=limited |edition=3rd |publisher=John Wiley & Sons Ltd |pages=[https://archive.org/details/medicinalnatural00dewi_880/page/n201 195]–197 |isbn=978-0-470-74167-2 }}</ref> Quantitative [[Carbon-13 nuclear magnetic resonance|¹³C NMR]] spectroscopic analysis has demonstrated that the [[Isoprene rule|isoprene units]] used to form thujone in plants are derived from the [[MEP pathway|methylerythritol phosphate pathway]] (MEP).<ref>{{cite journal |last1=Umlauf |first1=Dirk |last2=Zapp |first2=Josef |date=September 2004 |title=Biosynthesis of the irregular monoterpene artemisia ketone, the sesquiterpene germacrene D and other isoprenoids in ''Tanacetum vulgare'' L. (Asteraceae) |journal=Phytochemistry |volume=65 |issue=17 |pages=2463–2470 |doi=10.1016/j.phytochem.2004.08.019 |pmid=15381410|bibcode=2004PChem..65.2463U }}</ref>

The reactions that generate the thujone skeleton in [[sabinene]] from GPP are mediated by the enzyme [[(+)-sabinene synthase|sabinene synthase]] which has GPP as its substrate.<ref name=Dewick2008 /> GPP ('''1''') first isomerizes to linalyl diphosphate (LPP) ('''2''') and neryl diphosphate (NPP) ('''3'''). LPP preferentially forms a delocalized allylic cation-diphosphate ('''4'''). The ion-pair intermediate then cyclizes in an electrophilic addition to yield the α-terpinyl tertiary cation ('''5''').<ref name=Dewick2008 />

[[File:The-conversion-of-gpp-to-alpha-terpinyl-cation.png|center|400px|The conversion of GPP to alpha-terpinyl cation.]]

The α-terpinyl cation ('''5''') then undergoes a 1,2 hydride shift via a [[Wagner-Meerwein rearrangement|Wagner–Meerwein rearrangement]], leading to the formation of the terpinen-4-yl cation ('''6'''). This cation undergoes a second cyclization to form the thujyl cation intermediate ('''7''') before loss of a proton to form the thujone precursor, [[Sabinene|(+)-sabinene]] ('''8''').

[[File:The-conversion-of-alpha-terpinyl-cation-to-sabinene.png|center|700px|The conversion of alpha-terpinyl cation to (+)-sabinene]]

From [[Sabinene|(+)-sabinene]] ('''8'''), the proposed biosynthetic route to generate thujone follows a three-step pathway: (+)-sabinene is first oxidized to an isomer of (+)-sabinol ('''9-1'', ''9-2''') by a [[Cytochrome P450|cytochrome P450 enzyme]], followed by conversion to (+)-sabinone ('''10''') via a [[dehydrogenase]]. Finally, a [[reductase]] mediates the conversion to α-thujone ('''11-1''') and β-thujone ('''11-2''').<ref>{{cite journal |last1=Foster |first1=Adam J. |last2=Hall |first2=Dawn E. |date=Apr 2013 |title=Identification of Genes in ''Thuja plicata'' Foliar Terpenoid Defenses |journal=Plant Physiology |volume=161 |issue=4 |pages=1993–2004 |doi=10.1104/pp.112.206383 |pmc=3613470 |pmid=23388118}}</ref> The isomerism of the (+)-sabinol intermediate varies among thujone-producing plants; for instance, in the [[western redcedar]] (''[[Thuja plicata]]''), thujone is derived exclusively from the (+)-''trans''-sabinol intermediate ('''9-1''') whereas in the [[Garden sage|common garden sage]] (''[[Salvia officinalis]]''), thujone is formed from the (+)-''cis''-sabinol intermediate ('''9-2''').<ref>{{cite journal |last1=Gesell |first1=Andreas |last2=Blaukopf |first2=Markus|date=May 2015 |title=The Gymnosperm Cytochrome P450 CYP750B1 Catalyzes Stereospecific Monoterpene Hydroxylation of (+)-Sabinene in Thujone Biosynthesis in Western Redcedar |journal=Plant Physiology |volume=168 |issue=1 |pages=94–106 |doi=10.1104/pp.15.00315 |pmc=4424034 |pmid=25829465}}</ref>

[[File:Proposed-synthesis-of-thujone-from-sabinene.png|center|700px|Proposed synthesis of thujone from sabinene]]

==Pharmacology==

[[File:Thujone by Danny S. - 001.jpg|thumb|right|Research-grade thujone]]

Based on a hypothesis that considered only molecular shape, it was speculated that thujone may act similarly to [[Tetrahydrocannabinol|THC]] on the [[cannabinoid]] receptors,<ref name="thc">[[Barnaby Conrad III|Conrad, Barnaby, III]]; (1988). ''Absinthe: History in a Bottle.'' [[Chronicle Books]]. {{ISBN|0-8118-1650-8}} p. 152</ref> however, thujone failed to evoke a cannabimimetic response in a 1999 investigative study.<ref>{{cite journal |vauthors=Meschler JP, Howlett AC | title = Thujone exhibits low affinity for cannabinoid receptors but fails to evoke cannabimimetic responses | journal = Pharmacol. Biochem. Behav. | volume = 62 | issue = 3 | pages = 473–480 | date = March 1999 | pmid = 10080239 | doi = 10.1016/S0091-3057(98)00195-6 | s2cid = 30865036 }}</ref> Thujone is a [[gamma-aminobutyric acid|GABA_A]] receptor antagonist<ref>{{cite journal | author = Olsen RW | title = Absinthe and gamma-aminobutyric acid receptors | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 97 | issue = 9 | pages = 4417–4418 | date = April 2000 | pmid = 10781032 | pmc = 34311 | doi = 10.1073/pnas.97.9.4417 | bibcode = 2000PNAS...97.4417O | doi-access = free }}</ref> and more specifically, a [[GABAA receptor|GABA_A receptor competitive antagonist]]. By inhibiting GABA receptor activation, neurons may fire more easily, which can cause muscle spasms and convulsions.<ref name="gaba">{{cite journal |vauthors=Höld KM, Sirisoma NS, Ikeda T, Narahashi T, Casida JE | title = Alpha-thujone (the active component of absinthe): gamma-aminobutyric acid type A receptor modulation and metabolic detoxification | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 97 | issue = 8 | pages = 3826–31 | date = April 2000 | pmid = 10725394 | pmc = 18101 | doi = 10.1073/pnas.070042397 | bibcode = 2000PNAS...97.3826H | doi-access = free }}</ref> This interaction with the [[GABAA receptor|GABA_A receptor]] is specific to alpha-thujone.<ref name="ReferenceA">{{Cite journal|last1=Höld|first1=Karin M.|last2=Sirisoma|first2=Nilantha S.|last3=Ikeda|first3=Tomoko|last4=Narahashi|first4=Toshio|last5=Casida|first5=John E.|date=2000-04-11|title=α-Thujone (the active component of absinthe): γ-Aminobutyric acid type A receptor modulation and metabolic detoxification|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=8|pages=3826–3831|doi=10.1073/pnas.070042397|issn=0027-8424|pmid=10725394|pmc=18101|bibcode=2000PNAS...97.3826H|doi-access=free}}</ref> Thujone is also a [[5-HT3 antagonist|5-HT₃ antagonist]].<ref name="5-HT3">{{cite journal|date=Feb 2004|title=Alpha-thujone reduces 5-HT3 receptor activity by an effect on the agonist-reduced desensitization|journal=Neuropharmacology|volume=46|issue=2|pages=192–201|doi=10.1016/j.neuropharm.2003.09.022|pmid=15002407|vauthors=Deiml T, Haseneder R, Zieglgänsberger W, Rammes G, Eisensamer B, Rupprecht R, Hapfelmeier G|s2cid=54346490}}</ref><ref>[http://sydney.edu.au/medicine/pharmacology/adrien-albert/images/pdfs/RefsPDFs/376.pdf Modulation of Ionotropic GABA Receptors by Natural Products of Plant Origin]</ref>

The [[median lethal dose]], or LD₅₀, of α-thujone, the more active of the two isomers, in mice, is around 45&nbsp;mg/kg, with 0% mortality rate at 30&nbsp;mg/kg and 100% at 60&nbsp;mg/kg. Mice exposed to the higher dose have [[convulsions]] that lead to death within 1 minute. From 30 to 45&nbsp;mg/kg, the mice experience muscle spasms in the legs, which progress to general convulsions until death or recovery. These effects are in line with other GABA antagonists. Also, α-thujone is metabolized quickly in the liver in mice.<ref name="gaba" /> Pretreatment with GABA positive allosteric modulators like [[diazepam]], [[phenobarbital]], or 1&nbsp;g/kg of [[ethanol]] protects against a lethal dose of 100&nbsp;mg/kg.{{Citation needed|date=July 2018}}

Attention performance has been tested with low and high doses of thujone in alcohol. The high dose had a short-term negative effect on attention performance. The lower dose showed no noticeable effect.<ref name="pmid15536765"/>

Thujone is reported{{By whom|date=January 2018}} to be toxic to brain, kidney, and liver cells and could cause convulsions if used in too high a dose. Other thujone-containing plants such as the tree [[Thuja|arborvitae]] (''Thuja occidentalis'') are used in herbal medicine, mainly for their alleged immune-system stimulating effects{{Citation needed|reason=What does it even mean in a medical sense that thujone would "stimulate the immune system"?|date=January 2018}}. Side effects from the [[essential oil]] of this plant include anxiety, sleeplessness, and convulsions, which confirms the central nervous system effects of thujone.<ref name=":0" /><ref>{{cite journal |vauthors=Naser B, Bodinet C, Tegtmeier M, Lindequist U | date = Mar 2005 | title = Thuja occidentalis (Arbor vitae): A Review of its Pharmaceutical, Pharmacological and Clinical Properties | journal = Evidence-Based Complementary and Alternative Medicine | volume = 2 | issue = 1| pages = 69–78 | doi=10.1093/ecam/neh065| pmid = 15841280 | pmc = 1062158 }}</ref>

==In absinthe==

Thujone is most commonly known for being a compound in the spirit [[absinthe]]. In the past, absinthe was thought to contain up to 260–350&nbsp;mg/L thujone,<ref>[http://www.substanceabusepolicy.com/content/1/1/14 Absinthism: a fictitious 19th-century syndrome with present impact], Padosch et al. Retrieved Oct. 28, 2006.</ref> but modern tests have shown this estimate to be far too high. A 2008 study of 13 pre-ban (1895–1910) bottles using [[Gas chromatography–mass spectrometry|gas chromatography–mass spectrometry]] (GC-MS) found that the bottles had between 0.5 and 48.3&nbsp;mg/L and averaged 25.4&nbsp;mg/L <ref name="acs"/><ref>[http://www.thujone.info/thujone-absinthe-39.html Chemical Composition of Vintage Preban Absinthe with Special Reference to Thujone, Fenchone, Pinocamphone, Methanol, Copper, and Antimony Concentrations]</ref> A 2005 study recreated three 1899 high-wormwood recipes and tested with GC–MS, and found that the highest contained 4.3&nbsp;mg/L thujone.<ref>[http://www.thujone.info/thujone-absinthe-3.html Thujone—Cause of absinthism?] Lachenmeier, Emmert et al. Retrieved Oct. 28, 2006.</ref> GC–MS testing is important in this capacity, because [[gas chromatography]] alone may record an inaccurately high reading of thujone as other compounds may interfere with and add to the apparent measured amount.<ref>[http://www.emmert-analytik.de/DLR_100_9_S352-356.pdf Determination of α-/β-Thujone and Related Terpenes in Absinthe using Solid Phase Extraction and Gas Chromatography] {{Webarchive|url=https://web.archive.org/web/20071127195042/http://www.emmert-analytik.de/DLR_100_9_S352-356.pdf |date=2007-11-27 }}, Emmert et al. Retrieved Oct. 28, 2006.</ref>

===History===

The compound was discovered after absinthe became popular in the mid-19th century. [[Valentin Magnan]], who studied alcoholism, tested pure wormwood oil on animals and discovered it caused [[Non-epileptic seizure|seizures]] independent from the effects of alcohol. Based on this, absinthe, which contains a small amount of wormwood oil, was assumed to be more dangerous than ordinary alcohol. Eventually, thujone was isolated as the cause of these reactions. Magnan went on to study 250 abusers of alcohol and noted that those who drank absinthe had seizures and [[hallucination]]s. The seizures are caused by the '''(+)-α-thujone''' interacting with the GABA receptors, causing epileptic activity.<ref name="ReferenceA"/> In light of modern evidence, these conclusions are questionable, as they are based on a poor understanding of other compounds and diseases,<ref>{{cite journal|last1=Lachenmeier|first1=Dirk|last2=Nathan-Maister|first2=David|last3=Breaux|first3=Theodore|last4=Luaute|first4=Jean-Pierre|last5=Emmert|first5=Joachim|title=Absinthe, Absinthism and Thujone – New Insight into the Spirit's Impact on Public Health|journal=The Open Addiction Journal|date=2010|volume=3|pages=32–38|doi=10.2174/1874941001003010032|doi-access=free}}</ref> and clouded by Magnan's belief that alcohol and absinthe were degenerating the French race.<ref>[[Barnaby Conrad III|Conrad III, Barnaby]]; (1988). ''Absinthe: History in a Bottle''. [[Chronicle books]]. {{ISBN|0-8118-1650-8}} Pg. 101-105</ref>

After absinthe was banned, research dropped off until the 1970s, when the British scientific journal ''[[Nature (journal)|Nature]]'' published an article comparing the molecular shape of thujone to [[tetrahydrocannabinol]] (THC), the primary [[psychoactive]] substance found in [[cannabis (drug)|cannabis]], and hypothesized it would act the same way on the brain, sparking the myth that thujone was a [[cannabinoid]].<ref name="thc"/><ref>{{cite journal |author1=Del Castillo J. |author2=Anderson M. |author3=Rubottom G.M. | year = 1975 | title = Letters to Nature: Marijuana, absinthe and the central nervous system | journal = Nature | volume = 253 | issue = 5490| pages = 365–366 | doi=10.1038/253365a0|pmid=1110781 |s2cid=4245058 }}</ref>

More recently, following European Council Directive No. 88/388/EEC (1988) allowing certain levels of thujone in foodstuffs in the EU,<ref>[http://eur-lex.europa.eu/legal-content/en/TXT/?uri=CELEX:31988L0388&qid=1467286141813 European Council Directive No. 88/388/EEC, 22 June 1988.]</ref> the studies described above were conducted and found only minute levels of thujone in absinthe.

==Regulations==

===European Union===

Maximum thujone levels in the EU are:<ref name="EU2008">[http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2008:354:0034:0050:en:PDF Regulation (EC) No 1334/2008 of the European Parliament and Council of 16 December 2008], [[European Commission]].</ref><ref>[http://ec.europa.eu/food/fs/sc/scf/out162_en.pdf Opinion of the Scientific Committee on Food on Thujone] Scientific Committee on Food (2003) Retrieved Oct 28, 2006.</ref>

*0.5&nbsp;mg/kg in food prepared with [[Artemisia (genus)|''Artemisia'']] species, excluding those prepared with [[common sage|sage]] and non alcoholic beverages

*10&nbsp;mg/kg in alcoholic beverages not prepared with ''Artemisia'' species

*25&nbsp;mg/kg in food prepared with [[common sage|sage]]

*35&nbsp;mg/kg in alcoholic beverages prepared with ''Artemisia'' species

===United States===

In the United States, the addition of pure thujone to foods is not permitted.<ref>{{cite journal | journal = Toxins | date = 2010 | volume = 2 | issue = 9 | pages = 2289–2332 | doi = 10.3390/toxins2092289 | pmc = 3153292 | title = Naturally Occurring Food Toxins |author1=Laurie C. Dolan |author2=Ray A. Matulka |author3=George A. Burdock |name-list-style=amp | pmid=22069686| doi-access = free }}</ref> Foods or beverages that contain ''[[Artemisia (plant)|Artemisia]]'' species, [[white cedar]], [[oakmoss]], [[tansy]], or [[yarrow]], must be thujone-free,<ref>[https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=172.510 FDA Regulation 21 CFR 172.510 – Food Additives Permitted for Direct Addition to Food for Human Consumption.] Food and Drug Administration (2003). Retrieved Oct 28, 2006.</ref> which in practice means that they contain less than 10&nbsp;parts per million thujone.<ref name=ttb>[http://www.ttb.gov/industry_circulars/archives/2007/07-05.html Department of the Treasury Alcohol and Tobacco Tax and Trade Bureau Industry Circular 2007-5] {{Webarchive|url=https://web.archive.org/web/20140209141259/http://www.ttb.gov/industry_circulars/archives/2007/07-05.html |date=2014-02-09 }} October 17, 2007. Retrieved May 5, 2009</ref> Other herbs that contain thujone have no restrictions. For example, [[Common sage|sage]] and [[sage oil]] (which can be up to 50% thujone) are on the [[Food and Drug Administration]]'s list of [[generally recognized as safe]] (GRAS) substances.<ref>[http://www.cfsan.fda.gov/~lrd/fcf182.html Substances generally recognized as safe.] {{Webarchive|url=https://web.archive.org/web/20051130204800/http://www.cfsan.fda.gov/~lrd/fcf182.html |date=2005-11-30 }} Food and Drug Administration (2003). Retrieved Oct 28, 2006.</ref>

Absinthe offered for sale in the United States must be thujone-free by the same standard that applies to other beverages containing Artemisia,<ref name =ttb /> so absinthe with small amounts of thujone may be legally imported.

===Canada===

In Canada, liquor laws are the domain of the provincial governments. Alberta, Ontario, and Nova Scotia allow 10&nbsp;mg/kg thujone; Quebec allows 15&nbsp;mg per kg;{{Citation needed|date=April 2007}} Manitoba allows 6–8&nbsp;mg thujone per litre; British Columbia adheres to the same levels as Ontario. However, in Saskatchewan and Quebec, one can purchase any liquor available in the world upon the purchase of a maximum of one case, usually 12 750-ml bottles or 9&nbsp;L. The individual liquor boards must approve each product before it may be sold on shelves.

==See also==

* ''[[Piołunówka]]'' – Polish alcoholic preparation with thujone content higher than in absinthe

==References==

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== Further reading ==

{{refbegin}}

*{{cite journal |vauthors=Lachenmeier DW, Nathan-Maister D, Breaux TA, Sohnius EM, Schoeberl K, Kuballa T | title = Chemical composition of vintage preban absinthe with special reference to thujone, fenchone, pinocamphone, methanol, copper, and antimony concentrations | journal = J. Agric. Food Chem. | volume = 56 | issue = 9 | pages = 3073–81 | date = May 2008 | pmid = 18419128 | doi = 10.1021/jf703568f | doi-access = free }}

{{refend}}

==External links==

*[http://cerncourier.com/cws/article/cern/34928 Absinthe absolved] {{Webarchive|url=https://web.archive.org/web/20120319010636/http://cerncourier.com/cws/article/cern/34928 |date=2012-03-19 }}, ''Cern Courier'', July 8, 2008

*[http://www.wormwoodsociety.org/index.php?option=com_content&task=view&id=1&Itemid=85 The Shaky History of Thujone] – Wormwood Society article on thujone and its history.

{{Commons category|Thujone}}

{{Absinthe}}

{{GABAergics}}

{{Serotonergics}}

{{Convulsants}}

[[Category:Absinthe]]

[[Category:GABAA receptor negative allosteric modulators]]

[[Category:Convulsants]]

[[Category:Monoterpenes]]

[[Category:5-HT3 antagonists]]

[[Category:Ketones]]

[[Category:Perfume ingredients]]

[[Category:Bicyclic compounds]]

[[Category:Cyclopentanes]]

[[Category:Cyclopropanes]]

[[Category:Isopropyl compounds]]

[[Category:Neurotoxins]]

[[Category:Plant toxins]]