Thujone

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Thujone
(−)-α-Thujone
(+)-β-Thujone

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 Edit this at Wikidata
EC Number
  • 214-405-7
IUPHAR/BPS
KEGG
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 checkY
    Key: USMNOWBWPHYOEA-MRTMQBJTSA-N checkY
  • 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:
GHS07: Exclamation mark
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).
☒N verify (what is checkY☒N ?)

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

Though it is best known as a

(GABA) as an antagonist (opposite to the effects of alcohol, which is an agonist of GABA). As a competitive antagonist of GABA, thujone alone is considered to be convulsant,[8]
though by interfering with the inhibitory transmitter GABA, it may convey stimulating, mood-elevating effects at low doses. It is also found 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,[9] in Salvia officinalis.

  • (−)-α-thujone
    (−)-α-thujone
  • (+)-α-thujone
    (+)-α-thujone
  • (+)-β-thujone
    (+)-β-thujone
  • (−)-β-thujone
    (−)-β-thujone

Sources

Thujone is found in a number of plants, such as

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

The reactions that generate the thujone skeleton in sabinene from GPP are mediated by the enzyme sabinene synthase which has GPP as its substrate.[10] 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).[10]

The conversion of GPP to alpha-terpinyl cation.
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

From

common garden sage (Salvia officinalis), thujone is formed from the (+)-cis-sabinol intermediate (9-2).[13]

Proposed synthesis of thujone from sabinene
Proposed synthesis of thujone from sabinene

Pharmacology

Research-grade thujone

Based on studies that looked only at molecular shape, for many years thujone was thought to act similarly to

GABAA receptor antagonist[16] 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.[17] This interaction with the GABAA receptor is specific to alpha-thujone.[18] Thujone is also a 5-HT3 antagonist.[19][20]

The

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, α-thujone is metabolized quickly in the liver in mice.[17] 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.[5]

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 alleged 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.[8][21]

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,[22] 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 [6][23] 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.[24] 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.[25]

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 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.[18] In light of modern evidence, these conclusions are questionable, as they are based on a poor understanding of other compounds and diseases,[26] and clouded by Magnan's belief that alcohol and absinthe were degenerating the French race.[27]

After absinthe was banned, research dropped off until the 1970s, when the British scientific journal

psychoactive substance found in cannabis, and hypothesized it would act the same way on the brain, sparking the myth that thujone was a cannabinoid.[14][28]

More recently, following European Council Directive No. 88/388/EEC (1988) allowing certain levels of thujone in foodstuffs in the EU,[29] 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:[30][31]

  • 0.5 mg/kg in food prepared with
    sage
    and non alcoholic beverages
  • 10 mg/kg in alcoholic beverages not prepared with Artemisia species
  • 25 mg/kg in food prepared with
    sage
  • 35 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.

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.[35]

Absinthe offered for sale in the United States must be thujone-free by the same standard that applies to other beverages containing Artemisia,[34] 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.

See also

  • Piołunówka – Polish alcoholic preparation with thujone content higher than in absinthe

References

  1. 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. PMID 10552494
    .
  4. .
  5. ^ .
  6. ^ a b Absinthe Myths Finally Laid To Rest
  7. ^ Chemical Composition of Vintage Preban Absinthe with Special Reference to Thujone, Fenchone, Pinocamphone, Methanol, Copper, and Antimony Concentrations
  8. ^
    PMID 10781032
    .
  9. .
  10. ^ .
  11. .
  12. .
  13. .
  14. ^ p. 152
  15. .
  16. .
  17. ^ .
  18. ^ .
  19. .
  20. ^ Modulation of Ionotropic GABA Receptors by Natural Products of Plant Origin
  21. PMID 15841280
    .
  22. ^ Absinthism: a fictitious 19th-century syndrome with present impact, Padosch et al. Retrieved Oct. 28, 2006.
  23. ^ Chemical Composition of Vintage Preban Absinthe with Special Reference to Thujone, Fenchone, Pinocamphone, Methanol, Copper, and Antimony Concentrations
  24. ^ Thujone—Cause of absinthism? Lachenmeier, Emmert et al. Retrieved Oct. 28, 2006.
  25. ^ Determination of α-/β-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.
  26. .
  27. Pg. 101-105
  28. .
  29. ^ European Council Directive No. 88/388/EEC, 22 June 1988.
  30. ^ Regulation (EC) No 1334/2008 of the European Parliament and Council of 16 December 2008, European Commission.
  31. ^ Opinion of the Scientific Committee on Food on Thujone Scientific Committee on Food (2003) Retrieved Oct 28, 2006.
  32. PMID 22069686
    .
  33. ^ 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.
  34. ^ a b 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
  35. ^ Substances generally recognized as safe. Archived 2005-11-30 at the Wayback Machine Food and Drug Administration (2003). Retrieved Oct 28, 2006.

Further reading

External links