What is Absinthe?
 
Absinthe is bight green liquor flavored using an herbal extract.  The drink was popular in the 19th century especially in France within the bohemian crowd.  The drink is green in color due to the chlorophyll.  Due to the drinks very potent nature, it was traditionally diluted with cold water.  The water is added through a perforated spoon containing sugar.  When the water was added to the drink, it goes from the emerald green color to a cloudy white color.  This occurs because the water causes the essential oils from the herbal extract to precipitate out of the alcohol and form a colloidal suspension.
Chronic use of absinthe leads to absinthism(1).  The symptoms for this addiction include epileptic attacks, delirium, and hallucinations.  Due to this and other social considerations, absinthe was banned in many countries during the early part of the 20th century.

A typical recipe for the herbal flavoring extract, attributed to Henri-Louis Pernod, calls for a ground up mixture of aniseed, fennel, hyssop, lemonbalm, angelica, star anise, dittany, juniper, nutmeg, veronica and wormwood.  A steam distillation of this mixture is done.  More wormwood is added to the distillate and then diluted with ethanol to 75% alcohol by volume(2).

The drink, which is supposed to be green in color due to the extracted chlorophyll, in the past was often made more green artificially by the addition of copper sulfate, cupric acetate, turmeric, and aniline green.  Antimony tricholride was also added to aid in the color change when water was added(2).

These additives increased the toxicity of the drink but the more important problem is the extract from wormwood (Artemisia absinthium)(1).  Wormwood  contains the compound absinthin(3), which is responsible for the bitter flavor of the liquor, but the main toxicant in the essential oil is the compound thujone(3).  It is known to be psychoactive and is the main active ingredient in absinthe other than the alcohol.

Thujone

Thujone belongs to the family of monoterpene ketones(4). There are two principle enantiomers found in wormwood, (-)-3-isothujone (a-thujone) and (+)-3-isothujone (b-thujone).  They make up 90% of the wormwood oil╠s weight(1), but a-thujone has a much higher toxicity than b-thujone.  The ratio in nature of a to b-thujone is 1:2(4).  The IUPAC name of thujone is 4-methyl-1-(1-methylethyl)bicyclo[3.1.0]hexan-3-one.








Properties

Thujone is a colorless liquid with a menthol-like smell.  It is insoluble in water but soluble in ethanol, diethyl ether and chloroform.  Thujone is found in other plants including cedar leaf, sage, tansy, thyme, rosemary and thuja (its namesake)(1).  Trace amounts can be found as a flavoring agent in alcoholic beverages such as vermouth (wermuth, German for wormwood), chartreuse, and benedictine(1).  Traces can also be found in Vick╠s VaporubTM, perfumes, and in pest repellants for rodents and mites(4).

Pharmacology

Thujone has been used in herbal medicine and was said to cure digestive problems, worms, menstrual problems, corns, warts, acne, fever, cough, rheumatism, scurvy and dropsy. It is reported to have antinociceptive, insecticidal, and anthelmintic activity(4).  Rice and Wilson found that a-thujone had comparative antinociceptive effects to codeine when injected subcutaneously in rats using the hot plate test (ED50= 6.5 mg/kg)(5).
 
 

Route Species LD50 (mg/kg)
Oral Rat 500
Intravenous Rabbit 0.03
Subcutaneous Mouse
Mouse
Rabbit
2.16
87.50
0.36
Dermal Rabbit 5000
Table 1: Acute Toxicity Data for a-thujone(4)

Other cultures have discovered thujone╠s intoxicating effects.  In West Bengal Artemisia nilagirica (a thujone containing plant) is smoked for its psychoactive effect and the Zuni smoke Artemisia caruhii as an analgesic(1).

Mode of Action

For a while it was hypothesized that thujone and tetrahydrocannabinol had the same site of action.  This was believed to be true because of the similarities in their structures and effects(6).  But in 1997, it was shown that neither thujone nor wormwood binds to the canabinoid receptor(7).  Until recently it wasn╠t known wh at the mode of action for a-thujone was but a recent study done by Hold et al. at Berkeley have found the toxin╠s mode of action(8).

They discovered that a-thujone is a ¤modulator of the g-aminobutyric acid (GABA) type A receptor.(8)Ë  They compared a-thujone toxic effects to that of picrotoxinin, a GABAA receptor antagonist.  It was found that they both had similar toxic effect and the toxicity in both was suppressed by diazepam, phenobarbital and ethanol. They also found that drosophila that had a single point mutation in the GABA receptor that made them resistant to dieldrin were also resistant to a -thujone. a-Thujone was found to be ¤a competitive inhibitor of [3H]EBOB binding, i.e., of the noncompetitive blocker site of the GABA-gated chloride channel.(8)Ë a-Thujone was also found to be a reversible modulator of the GABAA receptor in the dorsal root ganglia neurons.


Figure1.  a-thujone and 7-hydroxy-a-thujone inhibit [3H]EBOB binding to mouse brain membranes (A) IC50 determination for a-thujone and 7-hydroxy-a-thujone (B) [3H]EBOB and with a-thujone(8)

These researchers also found that a-thujone is rapidly metabolized in mice liver with NADPH (cytochrome p450).  The metabolites from its breakdown are 7-hydroxy-a-thujone (major) and other hydroxythujones (minor).  a-Thujone is found to 56 times more potent in a [3H]EBOB binding assay than 7-hydroxy-a-thujone.  7-hydroxy-a-thujone was also found to be less toxic to mice and houseflies.


Figure 2. Structures of a-thujone (1S, 4R, 5R-thujone) and its metabolites in the mouse liver microsomal P450 system (8)

Famous Drinkers of Absinthe
 
 
While the use of wormwood can be dated as far back as 1550 B.C.(2), it became ¤the rageË in France starting about 1850.  Its use took hold in the intellectual and artistic comuntities and many famous people, Hemingway, Baudelaire, Picasso, and Degas, drank absinthe(1).  It was thought then that it simulated creativity and acted as an aphrodisiac.  Perhaps the most famous drinker of absinthe was Vincent Van Gogh for it appears that his depression, psychotic behavior and suicide were related to his chronic use of the drink.  Van Gogh suffered from acute intermittent porphyria.  The symptoms of this genetic disorder include attacks of ¤abdominal pain, anxiety, hysteria, delirium, phobias, psychosis, organic disorders, agitation, depression, and altered consciousness fromtiredness to coma.(1)Ë  It has been theorized that the drinking of absinthe may have  triggered these attacks. 

Regulation

Absinthe was banned in the United States in 1912 as part of the Food Inspection Decision 147.  Thujone was banned as a food additive by the Federal Food, Drug and Cosmetics Act of 1972.  In 1975, the Federal Food and Drug Administration designated thujone as an unsafe herb.  But many thujone containing food additives, such as sage and rosemary, have been given Generally Recognized as Safe (GRAS) status by the FDA(4).

In Europe, a limit on the amount of thujone contained in food has been set by the European Community Codex Committee on Food Additives.  The acceptable level is 0.5 ppm (mg/kg) in foods and beverages, 10 ppm in alcoholic drinks above 25% alcohol, 5 ppm in alcoholic drinks less than 25% alcohol, and 35 ppm in bitters(4).

Although absinthe has been banned in the United States, it is still legal in Spain and some other contries in Europe.  The drink also has a "cult" status on the web where absinthe can be ordered and recipes for homemade absinthe can be found.

Other Considerations and Concerns

Thujone has also been found to be volatile enough that it is emitted from plants into the atmosphere.  a and b thujone emissions have been measured near California sagebrush(4).  New concerns as to consumer and worker exposure have lead to new research into its neurotoxicity.

Other Artists and Absinthe
(list from http://itsa.ucsf.edu/~mbagg/roughabsinthefaq.html)

Famous absinthe users include:

    Edouard Manet
    Charles Baudelaire
    Paul Verlaine
    Arthur Rimbaud
    Oscar Wilde
    Ernest Dowson
    Edgar Degas
    Henri de Toulouse-Lautrec
    Vincent Van Gogh
    Adolphe Monticelli
    Paul Gauguin
    Alfred Jarry
    Pablo Picasso
    Ernest Hemingway

Visual artworks inspired by absinthe include:

    Edouard Manet's 1859 The Absinthe Drinker
    Jean-Francois Raffaelli's 1861 Absinthe Drinkers
    Honore Daumier's 1863 Absinthe Lithographs
    Edgar Degas' 1876 L'Absinthe
    Henri de Toulouse-Lautrec 1887 Portrait of Van Gogh
    Vincent Van Gogh's 1887 Still Life with Absinthe
    Henri de Toulouse-Lautrec 1887 Portrait of Van Gogh (pastel)
    Henri de Toulouse-Lautrec 1893 Monsieur Boileau at the Cafe
    Pablo Picasso 1901 Harlequin and his Companion
    Pablo Picasso 1901 The Poet Cornuty
    Pablo Picasso 1901 The Absinthe Drinker
    Pablo Picasso 1902 The Absinthe Drinker
    Pablo Picasso 1911 Glass of Absinthe
    Pablo Picasso 1914 Absinthe Glass

References

1.  Baggott, Matthew.  ¤Absinthe.Ë  1997. http://itsa.ucsf.edu/~mbagg/roughabsinthefaq.html

2.  Arnold, Wilfred Neils.  ¤Absinthe.Ë  Scientific American 260.6 (1989): 3042-4.

3.  Budavari, Susan, ed.  The Merck Index, 12th edition. Whitehouse Station, NJ:  Merck & Co., 1996: p.(a)3,(b)1603.

4.  ¤Summary of Data for Chemical Selection: Alpha-Thujone (546-80-5).Ë http://ntp-server.niehs.nih.gov/htdocs/Chem_Background/ExecSumm/Thujone.html

5.  Rice, K.C; Wilson, R.S.  ¤(-)-3-Isothujone, a small nonnitrogenous molecule with antinociceptive activity in mice.Ë  Journal of Medicinal Chemistry 19.8 (1976): 1054-7.

6.  Del Castillo, J; Anderson, M; Rubottom, GM.  ¤Marijuana, absinthe, and the central nervous system.Ë  Nature 253 (1975): 365-6.

7.  Meschler, J; Marsh, C; Land, B; Howlett.  ¤Failure of the active component of absinthe (Artmisia absinthium) to bind the cannabinoid receptor.Ë  International Cannabinoid Research Society, 1997 Meeting.

8.  Hold, K; Sirisoma, N; Ikeda, T; Narahashi, T; Casida, J: ¤a-Thujone (the active component of absinthe): g-Aminobutyric acid type A receptor modulation and metabolic detoxification.Ë  PNAS 97.8 (2000): 3826-31.

9.  ¤Absinthe & Thujone.Ë  http://www.chem.ox.ac.uk/mom/absinthe/absinthe.html

10.  Prisinazano, Thomas.  ¤Thujone.Ë  1997. http://www.phc.vcu.edu/feature/thuj/thujone.html

11.  Wu, C.  ¤Toxin in absinthe makes neurons run wild.Ë Science News 157.14 (2000): 214.