(+)-Thujone (1)
is a widely occurring natural product found in the essential oils of two Artemisia species, Artemisia absinthium and Artemisia pontica. Wormwood oil, the oil obtained from Artemisia absinthium, is used as a counterirritant in Absorbine Jr.® and Vicks Vaporub®[3]. The French liquor absinthe was once prepared from wormwood leaves as well as several other herbs. Absinthe, however, was banned early in this century due to its toxicity. Thujone, one of the ingredients in the liquor, has been shown to cause of brain damage, and it is believed to be the compound responsible for the 1915 ban of the once highly popular drink in France.
Thujone is a monoterpene, or a class of natural products containing ten carbons, found in many different plants and flowers. Monoterpenes are derived from the coupling of two isoprenoid units, which are made from isopentylpyrophosphate, a precursor in the biosynthesis of cholesterol. These compounds are usually fragrance oils or low melting solids and are used commerically as aroma or flavoring agents. Thujone is structurally related to menthol (2),
which is an old natural remedy for various ailments. Menthol contains a cyclohexane, or 6-membered, ring in its structure as well as an exocyclic isopropyl group. (+)-Thujone also contains a cyclohexane ring as well as the exocyclic isopropyl group. The essential difference is the presence of an additional 3-membered ring in (+)-thujone. This new ring results from an additional carbon-carbon bond between two of the members of the cyclohexane ring. The biosynthesis of these compounds is thought to derive from the same intermediate. The distinctive peppermint odor of menthol is found in Noxema medicated cream, Solarcaine®, and Ben-Gay®, as well as many other over the counter products [3].
The more notable use of (+)-thujone was in absinthe, a green liquor once very popular in the last quarter of the 19th century and the beginning of this century. The psychological effects of absinthe were believed to be different than other alcoholic beverages. The liquor was believed to enhance the activity of the brain, develop new ideas, expand imagination, and act as an aphrodisiac [4]. As a result, the drink became very popular, especially with artists and writers such as de Maupassant, Toulouse Lautrec, Degas, Gaugin, Manet, and Oscar Wilde [5]. Perhaps the most notable drinker was the troubled painter Vincent Van Gogh. During the last two years of his life, Van Gogh experienced fits of hallucinations and convulsions before his eventual suicide. His condition appears to have been worsened by his addiction to absinthe [6].
Absinthe drinkers were reported to have experienced a double action intoxication [5]. This intoxication combined the separate effects of alcohol and thujone. The alcohol produced a sedative effect in absinthe drinkers while the thujone is reported to have caused hallucinations (both visual and auditory) as well as excitation. The only proven effect of thujone, however, is its toxicity to the brain. The toxicity of thujone in the brain is believed to result from its structural similarity to tetrahydrocannibinol, or THC (3)
, the active compound in marijuana. Cannabis has been used for centuries for medicinal purposes and has great therapeutic potential[8]. Thujone and THC have similar shapes, and it is believed that they interact with the same biological receptor to produce their similar psychological effects [9]. The similarities between the molecules include gem dimethyl groups and a similar carbon framework. It is also believed that the hydroxyl group of THC and the carbonyl of thujone may interact at the same site. Modeling studies show a good degree of overlap (4)(thujone in green; carbonyl oxygen in magenta).
Tremendous progress has been made recently in characterizing cannabinoid receptors, both centrally and peripherally [8]. It would be interesting to reevaluate (+)-thujone at these new receptor populations. (+)-Thujone is a potential cannabinoid ligand and might lead to the development of a new drug.