Thujone

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Thujone
(-)-alpha-Thujon.svg
(−)-α-Thujone
(+)-beta-Thujon.svg
(+)-β-Thujone
(-)-a-thujone-from-xtal-3D-bs-17.png
Ball-and-stick model of (−)-α-thujone [1]
Names
IUPAC names
α: (1S,4R,5R)-4-Methyl-1-(propan-2-yl)bicyclo[3.1.0]hexan-3-one
β: (1S,4S,5R)-4-methyl-1-propan-2-ylbicyclo[3.1.0]hexan-3-one
Other names
Bicyclo[3.1.0]hexan-3-one, 4-methyl-1-(1-methylethyl)-, [1S-(1α,4α,5α)]-
α-Thujone
β-Thujone
Thujone, cis
3-Thujanone, (1S,4R,5R)-(-)-
Thujon
3-Thujanone, (-)-
l-Thujone; 4-Methyl-1-(1-methylethyl)bicyclo[3.1.0]hexan-3-one-, (1S,4R,5R)-
3-Thujone; cis-Thujone
(Z)-Thujone
(-)-Thujone; Bicyclo(3.1.0)hexan-3-one, 4-methyl-1-(1-methylethyl)-, (1S,4R,5R)-
NSC 93742
1-isopropyl-4-methylbicyclo[3.1.0]hexan-3-one
Identifiers
3D model (JSmol)
4660369
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.013.096 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 214-405-7
KEGG
PubChem CID
UNII
  • InChI=1S/C10H16O/c1-6(2)10-4-8(10)7(3)9(11)5-10/h6-8H,4-5H2,1-3H3/t7-,8-,10+/m1/s1 Yes check.svgY
    Key: USMNOWBWPHYOEA-MRTMQBJTSA-N Yes check.svgY
  • InChI=1/C10H16O/c1-6(2)10-4-8(10)7(3)9(11)5-10/h6-8H,4-5H2,1-3H3/t7-,8-,10+/m1/s1
    Key: USMNOWBWPHYOEA-MRTMQBJTBZ
  • InChI=1S/C10H16O/c1-6(2)10-4-8(10)7(3)9(11)5-10/h6-8H,4-5H2,1-3H3/t7-,8-,10+/m1/s1
    Key: USMNOWBWPHYOEA-MRTMQBJTSA-N
  • (α-thujone):O=C1[C@H](C)[C@@H]2[C@](C(C)C)(C1)C2
  • (β-thujone):C[C@@H]([C@@H](C2)[C@]2([C@@H](C)C)C1)C1=O
Properties
C10H16O
Molar mass 152.237 g·mol−1
Density 0.92 g/cm3 (β-thujone); 0.9116 g/cm3 (α-thujone)
Melting point <25 °C
Boiling point 203 °C (397 °F; 476 K)(alpha,beta-thujone)
407 mg/L
Hazards
GHS labelling:
GHS-pictogram-exclam.svg
Warning
H302
P264, P270, P301+P312, P330, P501
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)
Infobox references

Thujone ( /ˈθuːdʒoʊn/ ( Loudspeaker.svg listen ) [2] ) is a ketone and a monoterpene that occurs predominantly in two diastereomeric (epimeric) forms: (−)-α-thujone and (+)-β-thujone. [3] [4]

Contents

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. Thujone acts on GABA as an antagonist (opposite to the effects of alcohol). As a competitive antagonist of GABA, thujone alone is considered to be convulsant, [5] though by interfering with the inhibitory transmitter GABA, it may convey stimulating, mood-elevating effects at low doses. It is also used in perfumery as a component of several essential oils.

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, [6] in Salvia officinalis .

Sources

Thujone is found in a number of plants, such as arborvitae (genus Thuja, hence the derivation of the name), Nootka cypress, some junipers, mugwort, oregano, common sage, tansy, and 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. [7] Quantitative 13CNMR spectroscopic analysis has demonstrated that the isoprene units used to form thujone in plants are derived from the methylerythritol phosphate pathway (MEP). [8]

The reactions that generate the thujane skeleton in sabinene from GPP are mediated by the enzyme sabinene synthase which has GPP as its substrate. [7] 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). [7]

The conversion of GPP to alpha-terpinyl cation. The-conversion-of-gpp-to-alpha-terpinyl-cation.png
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, 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 (8).

The conversion of alpha-terpinyl cation to (+)-sabinene The-conversion-of-alpha-terpinyl-cation-to-sabinene.png
The conversion of alpha-terpinyl cation to (+)-sabinene

From (+)-sabinene (8), the proposed biosynthetic route to generate thujone follows a three-step pathway: (+)-sabinene is first oxidized to an isomer of (+)-sabinol (9-1,2) by a 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). [9] 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 common garden sage ( Salvia officinalis ), thujone is formed from the (+)-cis-sabinol intermediate (9-2). [10]

Proposed synthesis of thujone from sabinene Proposed-synthesis-of-thujone-from-sabinene.png
Proposed synthesis of thujone from sabinene

Pharmacology

Research-grade thujone Thujone by Danny S. - 001.jpg
Research-grade thujone

Based on studies that looked only at molecular shape, for many years thujone was thought to act similarly to THC on the cannabinoid receptors; [11] however, this has since been proven false. [12] Thujone is a GABAA receptor antagonist [13] and more specifically, a GABAA receptor competitive antagonist. By inhibiting GABA receptor activation, neurons may fire more easily, which can cause muscle spasms and convulsions. [14] This interaction with the GABAA receptor is specific to alpha-thujone. [15] Thujone is also a 5-HT3 antagonist. [16] [17]

The median lethal dose, or LD50, of alpha-thujone, the more active of the two isomers, in mice, is around 45 mg/kg, with 0% mortality rate at 30 mg/kg and 100% at 60 mg/kg. Mice exposed to the higher dose have convulsions that lead to death within 1 minute. From 30 to 45 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, alpha-thujone is metabolized quickly in the liver in mice. [14] Pretreatment with GABA positive allosteric modulators like diazepam, phenobarbital, or 1 g/kg of ethanol protects against a lethal dose of 100 mg/kg.[ citation needed ]

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. [18]

Thujone is reported[ by whom? ] 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 arborvitae (Thuja occidentalis) are used in herbal medicine, mainly for their immune-system stimulating effects[ citation needed ]. Side effects from the essential oil of this plant include anxiety, sleeplessness, and convulsions, which confirms the central nervous system effects of thujone. [5] [19]

In absinthe

Thujone is most famous for being a compound in the spirit absinthe. In the past, absinthe was thought to contain up to 260–350 mg/l thujone, [20] 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 (GC-MS) found that the bottles had between 0.5 and 48.3 mg/l and averaged 25.4 mg/l [21] [22] A 2005 study recreated three 1899 high-wormwood recipes and tested with GC-MS, and found that the highest contained 4.3 mg/l thujone. [23] 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. [24]

History

The compound was discovered after absinthe became popular in the mid-19th century. Dr. Valentin Magnan, who studied alcoholism, tested pure wormwood oil on animals and discovered it caused 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 hallucinations. The seizures are caused by the (+)-α-thujone interacting with the GABA receptors, causing epileptic activity. [15] In light of modern evidence, these conclusions are questionable, as they are based on a poor understanding of other compounds and diseases, [25] and clouded by Magnan's belief that alcohol and absinthe were degenerating the French race. [26]

After absinthe was banned, research dropped off until the 1970s, when the British scientific journal Nature published an article comparing the molecular shape of thujone to tetrahydrocannabinol (THC), the primary psychoactive substance found in cannabis, and hypothesized it would act the same way on the brain, sparking the myth that thujone was a cannabinoid. [11] [27]

More recently, following European Council Directive No. 88/388/EEC (1988) allowing certain levels of thujone in foodstuffs in the EU, [28] 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: [29] [30]

United States

In the United States, the addition of pure thujone to foods is not permitted. [31] Foods or beverages that contain Artemisia species, white cedar, oak moss, tansy, or yarrow, must be thujone-free, [32] which in practice means that they contain less than 10 mg/l thujone. [33] Other herbs that contain thujone have no restrictions. For example, 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. [34]

Absinthe offered for sale in the United States must be thujone-free by the same standard that applies to other beverages containing Artemisia, [33] 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 mg/kg thujone; Quebec allows 15 mg per kg;[ citation needed ] Manitoba allows 6–8 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 L. The individual liquor boards must approve each product before it may be sold on shelves.

Chemical spectra of α-thujone

1H NMR (500 MHz, CDCl3)

δ [ppm] = 2.54 (ddd, J = 18.8, 2.3, 1.1 Hz, 1H, H-2), 2.21 (q, J = 7.2 Hz, 1H, H-4), 2.07 (d, J = 18.8 Hz, 1H, H-2'), 1.36 (hept, J = 6.8 Hz, 1H, H-7), 1.15 (d, J = 7.5 Hz, 3H, H-9), 1.08 (dd, J = 8.1, 4.0 Hz, 1H, H-5), 1.00 (d, J = 6.8 Hz, 3H, H-8), 0.95 (d, J = 6.8 Hz, 3H, H-8') 0.76 (ddd, J = 8.1, 5.6, 2.5 Hz, 1H, H-6), 0.12 (dd, J = 5.6, 4.1 Hz, 1H, H-6'). [35]

13C NMR (91 MHz, CDCl3)

δ [ppm] = 221.7 (C=O, C-3), 47.5 (CH, C-4), 39.9 (CH2, C-2), 33.1 (CH, C-7), 29.8 (C, C-1), 25.7 (CH, C-5), 20.1 (CH3, C-8), 19.9 (CH3, C-8') 18.9 (CH3, C-9), 18.4 (CH2, C-6). [35]

Mass spectrometry

m/z: 81(100), 110(96.58), 109(59.88), 95(58.97), 67(57.37). [36] The www.webbook.nist.gov website lists the m/z ratios for Thujone as: 110(100), 81(~89), 95(~71); 67(~69), 109(~44).

IR

cm−1: 3020, 2961, 1733, 1602, 1455, 1219, 1096, 1014. [37]

See also

Related Research Articles

<i>Thuja</i> Genus of conifers

Thuja is a genus of coniferous trees or shrubs in the Cupressaceae. There are five species in the genus, two native to North America and three native to eastern Asia. The genus is monophyletic and sister to Thujopsis. Members are commonly known as arborvitaes, thujas or cedars.

<i>gamma</i>-Aminobutyric acid Main inhibitory neurotransmitter in the mammalian brain

gamma-Aminobutyric acid, or γ-aminobutyric acid, or GABA, is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system.

<i>Artemisia absinthium</i> Species of plant

Artemisia absinthium is a moderately poisonous species of Artemisia native to temperate regions of Eurasia and North Africa, and widely naturalized in Canada and the northern United States. It is grown as an ornamental plant and is used as an ingredient in the spirit absinthe and some other alcoholic beverages.

GABA<sub>A</sub> receptor Ionotropic receptor and ligand-gated ion channel

The GABAA receptor (GABAAR) is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Upon opening, the GABAA receptor is selectively permeable to chloride ions (Cl−) and, to a lesser extent, bicarbonate ions (HCO3−). Depending on the membrane potential and the ionic concentration difference, this can result in ionic fluxes across the pore. For instance, under physiological conditions Cl− will flow inside the cell if the membrane potential is higher than the equilibrium potential (also known as the reversal potential) for chloride ions if the receptor is activated. This causes an inhibitory effect on neurotransmission by diminishing the chance of a successful action potential occurring at the postsynaptic cell. The reversal potential of the GABAA-mediated inhibitory postsynaptic potential (IPSP) in normal solution is −70 mV, contrasting the GABAB IPSP (-100 mV).

Synephrine Chemical compound

Synephrine, or, more specifically, p-synephrine, is an alkaloid, occurring naturally in some plants and animals, and also in approved drugs products as its m-substituted analog known as neo-synephrine. p-Synephrine and m-synephrine are known for their longer acting adrenergic effects compared to epinephrine and norepinephrine. This substance is present at very low concentrations in common foodstuffs such as orange juice and other orange products, both of the "sweet" and "bitter" variety. The preparations used in traditional Chinese medicine (TCM), also known as Zhi Shi, are the immature and dried whole oranges from Citrus aurantium. Extracts of the same material or purified synephrine are also marketed in the US, sometimes in combination with caffeine, as a weight-loss-promoting dietary supplement for oral consumption. While the traditional preparations have been in use for millennia as a component of TCM-formulas, synephrine itself is not an approved OTC drug. As a pharmaceutical, m-synephrine (phenylephrine) is still used as a sympathomimetic, mostly by injection for the treatment of emergencies such as shock, and rarely orally for the treatment of bronchial problems associated with asthma and hay-fever.

Mugwort Genus of flowering plants in the daisy family Asteraceae used as herbs

Mugwort is a common name for several species of aromatic flowering plants in the genus Artemisia. In Europe, mugwort most often refers to the species Artemisia vulgaris, or common mugwort. While other species are sometimes referred to by more specific common names, they may be called simply "mugwort" in many contexts.

Allopregnanolone Endogenous inhibitory neurosteroid

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GABA receptor antagonists are drugs that inhibit the action of GABA. In general these drugs produce stimulant and convulsant effects, and are mainly used for counteracting overdoses of sedative drugs.

Absinthe Alcoholic drink

Absinthe is an anise-flavoured spirit derived from several plants, including the flowers and leaves of Artemisia absinthium, together with green anise, sweet fennel, and other medicinal and culinary herbs. Historically described as a highly alcoholic spirit, it is 45–74% ABV or 90–148 proof US. Absinthe traditionally has a natural green color but may also be colorless. It is commonly referred to in historical literature as la fée verte. It is sometimes mistakenly referred to as a liqueur, but is not traditionally bottled with added sugar and is, therefore, classified as a spirit. Absinthe is traditionally bottled at a high level of alcohol by volume, but it is normally diluted with water before being consumed.

Lucid Absinthe Supérieure is the first genuine absinthe made with real Grande Wormwood to be legally available in the United States after the repeal of the 95-year ban.

Etifoxine

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L-838,417

L-838,417 is an anxiolytic drug used in scientific research. It has similar effects to benzodiazepine drugs, but is structurally distinct and so is classed as a nonbenzodiazepine anxiolytic. The compound was developed by Merck, Sharp and Dohme.

Deramciclane

Deramciclane (EGIS-3886) is a non-benzodiazepine-type anxiolytic drug to treat various types of anxiety disorders. Deramciclane is a unique alternative to current anxiolytics on the market because it has a novel chemical structure and target. It acts as an antagonist at the 5-HT2A receptor, as an inverse agonist at the 5-HT2C receptor, and as a GABA reuptake inhibitor. The two serotonin receptors are G protein-coupled receptors and are two of the main excitatory serotonin receptor types. Their excitation has been implicated in anxiety and mood. Deramciclane does not affect CYP3A4 activity in metabolizing other drugs, but it is a weak inhibitor of CYP2D6. Some studies also show the drug to have moderate affinity to dopamine D2 receptors and low affinity to dopamine receptor D1. Researchers are looking for alternatives to benzodiazepines for anxiolytic use because benzodiazepine drugs have sedative and muscle relaxant side effects.

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Tutin (toxin)

Tutin is a poisonous plant derivative found in New Zealand tutu plants. It acts as a potent antagonist of the glycine receptor, and has powerful convulsant effects. It is used in scientific research into the glycine receptor. It is sometimes associated with outbreaks of toxic honey poisoning when bees feed on honeydew exudate from the sap-sucking passion vine hopper insect, when the vine hoppers have been feeding on the sap of tutu bushes. Toxic honey is a rare event and is more likely to occur when comb honey is eaten directly from a hive that has been harvesting honeydew from passionvine hoppers feeding on tutu plants.

Absinthin Chemical compound

Absinthin is a naturally produced triterpene lactone from the plant Artemisia absinthium (Wormwood). It constitutes one of the most bitter chemical agents responsible for absinthe's distinct taste. The compound shows biological activity and has shown promise as an anti-inflammatory agent, and should not to be confused with thujone, a neurotoxin also found in Artemisia absinthium.

<i>Artemisia herba-alba</i> Species of plant

Artemisia herba-alba, the white wormwood, is a perennial shrub in the genus Artemisia that grows commonly on the dry steppes of the Mediterranean regions in Northern Africa, Western Asia and Southwestern Europe. It is used as an antiseptic and antispasmodic in herbal medicine.

GABA<sub>A</sub> receptor positive allosteric modulator

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Gabapentinoid Calcium channel blockers

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References

  1. ↑ Richert, Clemens; Krupp, Felix; Frey, Wolfgang (2020). "Absolute Configuration of Small Molecules by Co‐Crystallization". Angew. Chem. Int. Ed. 59 (37): 15875–15879. doi: 10.1002/anie.202004992 . PMC   7540501 . PMID   32441841.
  2. ↑ Derived from the Ancient Greek θυία, thuj(a), a kind of cedar + -ωνη, -one, feminine patronymic for a chemical relative of acetone
  3. ↑ Perry NB, Anderson RE, Brennan NJ, Douglas MH, Heaney AJ, McGimpsey JA, Smallfield BM (1999). "Essential Oils from Dalmatian Sage (Salvia officinalis L.): Variations among Individuals, Plant Parts, Seasons, and Sites". J. Agric. Food Chem. 47 (5): 2048–2054. doi:10.1021/jf981170m. PMID   10552494.
  4. ↑ Oppolzer W, Pimm A, Stammen B, Hume WE (1997). "Palladium-Catalysed Intramolecular Cyclisations of Olefinic Propargylic Carbonates and application to the diastereoselective synthesis of enantiomerically pure (−)-α-thujone". Helv. Chim. Acta . 80 (3): 623–639. doi:10.1002/hlca.19970800302.
  5. 1 2 Olsen, Richard W. (2000-04-25). "Absinthe and γ-aminobutyric acid receptors". Proceedings of the National Academy of Sciences of the United States of America. 97 (9): 4417–4418. Bibcode:2000PNAS...97.4417O. doi: 10.1073/pnas.97.9.4417 . ISSN   0027-8424. PMC   34311 . PMID   10781032.
  6. ↑ Williams, Jack D.; Yazarians, Jessica A.; Almeyda, Chelcie C.; Anderson, Kristin A.; Boyce, Gregory R. (23 May 2016). "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 of Agricultural and Food Chemistry. 64 (21): 4319–4326. doi:10.1021/acs.jafc.6b01065. PMID   27181395.
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  8. ↑ Umlauf, Dirk; Zapp, Josef (September 2004). "Biosynthesis of the irregular monoterpene artemisia ketone, the sesquiterpene germacrene D and other isoprenoids in Tanacetum vulgare L. (Asteraceae)". Phytochemistry. 65 (17): 2463–2470. doi:10.1016/j.phytochem.2004.08.019. PMID   15381410.
  9. ↑ Foster, Adam J.; Hall, Dawn E. (Apr 2013). "Identification of Genes in Thuja plicata Foliar Terpenoid Defenses". Plant Physiology. 161 (4): 1993–2004. doi:10.1104/pp.112.206383. PMC   3613470 . PMID   23388118.
  10. ↑ Gesell, Andreas; Blaukopf, Markus (May 2015). "The Gymnosperm Cytochrome P450 CYP750B1 Catalyzes Stereospecific Monoterpene Hydroxylation of (+)-Sabinene in Thujone Biosynthesis in Western Redcedar". Plant Physiology. 168 (1): 94–106. doi:10.1104/pp.15.00315. PMC   4424034 . PMID   25829465.
  11. 1 2 Conrad III, Barnaby; (1988). Absinthe: History in a Bottle. Chronicle Books. ISBN   0-8118-1650-8 p. 152
  12. ↑ Meschler JP, Howlett AC (March 1999). "Thujone exhibits low affinity for cannabinoid receptors but fails to evoke cannabimimetic responses". Pharmacol. Biochem. Behav. 62 (3): 473–80. doi:10.1016/S0091-3057(98)00195-6. PMID   10080239. S2CID   30865036.
  13. ↑ Olsen RW (April 2000). "Absinthe and gamma-aminobutyric acid receptors". Proc. Natl. Acad. Sci. U.S.A. 97 (9): 4417–8. Bibcode:2000PNAS...97.4417O. doi: 10.1073/pnas.97.9.4417 . PMC   34311 . PMID   10781032.
  14. 1 2 Höld KM, Sirisoma NS, Ikeda T, Narahashi T, Casida JE (April 2000). "Alpha-thujone (the active component of absinthe): gamma-aminobutyric acid type A receptor modulation and metabolic detoxification". Proc. Natl. Acad. Sci. U.S.A. 97 (8): 3826–31. Bibcode:2000PNAS...97.3826H. doi: 10.1073/pnas.070042397 . PMC   18101 . PMID   10725394.
  15. 1 2 Höld, Karin M.; Sirisoma, Nilantha S.; Ikeda, Tomoko; Narahashi, Toshio; Casida, John E. (2000-04-11). "α-Thujone (the active component of absinthe): γ-Aminobutyric acid type A receptor modulation and metabolic detoxification". Proceedings of the National Academy of Sciences of the United States of America. 97 (8): 3826–3831. Bibcode:2000PNAS...97.3826H. doi: 10.1073/pnas.070042397 . ISSN   0027-8424. PMC   18101 . PMID   10725394.
  16. ↑ Deiml T, Haseneder R, Zieglgänsberger W, Rammes G, Eisensamer B, Rupprecht R, Hapfelmeier G (Feb 2004). "Alpha-thujone reduces 5-HT3 receptor activity by an effect on the agonist-reduced desensitization". Neuropharmacology. 46 (2): 192–201. doi:10.1016/j.neuropharm.2003.09.022. PMID   15002407. S2CID   54346490.
  17. ↑ Modulation of Ionotropic GABA Receptors by Natural Products of Plant Origin
  18. ↑ Dettling A, Grass H, Schuff A, Skopp G, Strohbeck-Kuehner P, Haffner HT (2004). "Absinthe: attention performance and mood under the influence of thujone". J. Stud. Alcohol. 65 (5): 573–81. doi:10.15288/jsa.2004.65.573. PMID   15536765.
  19. ↑ Naser B, Bodinet C, Tegtmeier M, Lindequist U (Mar 2005). "Thuja occidentalis (Arbor vitae): A Review of its Pharmaceutical, Pharmacological and Clinical Properties". Evidence-Based Complementary and Alternative Medicine. 2 (1): 69–78. doi:10.1093/ecam/neh065. PMC   1062158 . PMID   15841280.
  20. ↑ Absinthism: a fictitious 19th-century syndrome with present impact, Padosch et al. Retrieved Oct. 28, 2006.
  21. ↑ Absinthe Myths Finally Laid To Rest
  22. ↑ Chemical Composition of Vintage Preban Absinthe with Special Reference to Thujone, Fenchone, Pinocamphone, Methanol, Copper, and Antimony Concentrations
  23. ↑ Thujone—Cause of absinthism? Lachenmeier, Emmert et al. Retrieved Oct. 28, 2006.
  24. ↑ Determination of a-/b-Thujone and Related Terpenes in Absinthe using Solid Phase Extraction and Gas Chromatography Archived 2007-11-27 at the Wayback Machine , Emmert et al. Retrieved Oct. 28, 2006.
  25. ↑ Lachenmeier, Dirk; Nathan-Maister, David; Breaux, Theodore; Luaute, Jean-Pierre; Emmert, Joachim (2010). "Absinthe, Absinthism and Thujone – New Insight into the Spirit's Impact on Public Health" (PDF). The Open Addiction Journal. 3: 32–38. doi: 10.2174/1874941001003010032 . Retrieved 6 July 2016.
  26. ↑ Conrad III, Barnaby; (1988). Absinthe: History in a Bottle. Chronicle books. ISBN   0-8118-1650-8 Pg. 101-105
  27. ↑ Del Castillo J.; Anderson M.; Rubottom G.M. (1975). "Letters to Nature: Marijuana, absinthe and the central nervous system". Nature. 253 (5490): 365–366. doi:10.1038/253365a0. PMID   1110781. S2CID   4245058.
  28. ↑ European Council Directive No. 88/388/EEC, 22 June 1988.
  29. ↑ Regulation (EC) No 1334/2008 of the European Parliament and Council of 16 December 2008, European Commission.
  30. ↑ Opinion of the Scientific Committee on Food on Thujone Scientific Committee on Food (2003) Retrieved Oct 28, 2006.
  31. ↑ Laurie C. Dolan; Ray A. Matulka & George A. Burdock (2010). "Naturally Occurring Food Toxins". Toxins. 2 (9): 2289–2332. doi: 10.3390/toxins2092289 . PMC   3153292 . PMID   22069686.
  32. ↑ 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.
  33. 1 2 Department of the Treasury Alcohol and Tobacco Tax and Trade Bureau Industry Circular 2007-5 Archived 2014-02-09 at the Wayback Machine October 17, 2007. Retrieved May 5, 2009
  34. ↑ Substances generally recognized as safe. Archived 2005-11-30 at the Wayback Machine Food and Drug Administration (2003). Retrieved Oct 28, 2006.
  35. 1 2 Thamm, Irene; Richers, Johannes; Rychlik, Michael; Tiefenbacher, Konrad (2016). "A six-step total synthesis of α-thujone and d6-α-thujone, enabling facile access to isotopically labelled metabolites" (PDF). Chemical Communications. 52 (78): 11701–11703. doi: 10.1039/c6cc05376a . ISSN   1359-7345. PMID   27709180.
  36. ↑ Movafeghi, A.; Djozan, Dj.; Torbati, S. (2010-08-15). "Solid-phase microextraction of volatile organic compounds released from leaves and flowers of Artemisia fragrans, followed by GC and GC/MS analysis". Natural Product Research. 24 (13): 1235–1242. doi:10.1080/14786410903108951. ISSN   1478-6419. PMID   20645210. S2CID   2711713.
  37. ↑ Lightner, David A.; Pak, Chwang Siek; Crist, B.Vincent; Rodgers, Stephen L.; Givens, John W. (January 1985). "The octant rule. XVI1. COnformation and circular dichroism of and 2-methylbicyclo[3.1.0]hexan-3-ones, thujone and isothujone". Tetrahedron. 41 (19): 4321–4330. doi:10.1016/s0040-4020(01)97203-5. ISSN   0040-4020.

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