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Modern studies about pharmacology and toxicology of thujone
In the 20th century, as a consequence of the description of the bicyclic monoterpene thujone as the main component of wormwood oil, the main focus of scientific studies was changed from the research of wormwood extract to isolated thujone. It must be stressed, however, that besides the Î²-thujone chemotype of the wormwood plant further chemotypes were described, which contain cis-chrysan-thenylacetat, cis-chrysanthenol, cis-expoxyocimene, sabi nylacetate or bornylacetate as principal component [57 63]. In the west alpine area above 1000 m the cis-epoxyo-cimen type is predominat, while the Î²-thujone type rather exists in the lower zones . In wormwood oil from the Tuscany  or the Pyrenees  neither Î±- nor Î²-thujone could be detected. These significant differences in composition of wormwood may also be attributable for the previously described failure of some researchers to replicate the animal experiments of Magnan.
The acute and chronic toxicology of thujone were reviewed in the WHO Food Additives Series 16  and more recently by the Scientific Committee on Food of the European Commission [66 ]. The principal data are sum marized in Table 3. The toxicological evaluations led to the establishment of maximum limits for thujone (35 mg/ l in bitters) by the Codex Alimentarius Commission of the FAO/WHO [ 67], which were adopted by many countries including the European Union  and Switzerland  but not the USA, where manufacture and importation of absinthe is still prohibited [69,70]. It was noted, however, that in the USA consumption and possession remained legal, so that travelers returning to the USA with a bottle or customers buying it from Europe on the internet are not guilty of any crime, though they could have their bot tle confiscated [71 ].
Until today, only little valid data are available concerning the effect of Î±-/Î²-thujone, especially in regard to the influence on the central nervous system after absinthe consumption. In comparison to Î²-thujone, Î±-thujone is believed to be 2.3 fold more toxic . A recent study of Dettling et al. showed that the administration of alcohol containing a high concentration of thujone (100 mg/l) had a negative effect on attention performance [73 ]. When the subjects were under the influence of alcohol or were administered both alcohol and low thujone concentrations (10 mg/l), these effects were not observed. Similarly, it was found that only high concentrations of thujone could temporarily counteract the anxiolytic effect of alcohol.
The interaction of Î±-thujone with Î³-amino butyric acid (GABA) dependent chloride channels can explain its convulsant effects [ 72, 74 - 76]. It was determined that Î±-thu-jone acts like many naturally occurring and synthetic convulsive agents (e.g. picrotoxin) by blocking GABA mediated inhibition. The effect on the brain is excitatory (analeptic). Anxiogenic and possibly alerting effects of GABA antagonists were also noted. However, Olsen commented that in absinthe one is balancing the effect of thujone with the intoxicating, disinhibitory, and depressant effects of ethanol .
Deiml et al. were not addressing the toxicity but instead were researching the 5-HT3 receptor as a potential site of psychotropic actions of Î±-thujone. In homomeric receptors, Î±-thujone enhanced the inherent channel-blocking potency of the natural ligand, 5-HT. In heteromeric receptors, Î±-thujone recruited an additional channel-blocking component of the agonist. The authors could, therefore, prove a reduction of the 5-HT3 receptor activity, but it stayed open if this inhibitory action on serotonergic responses contributes to behavioral effects of thujone [ 77 ].
Interestingly, the activation of human bitter taste receptors by Î±-thujone was recently proven by Behrens et al. and it was found that the receptor is sufficiently sensitive to serve as protection against the ingestion of toxic amounts of this substance . However, it is questiona ble if these findings can be transferred to the ingestion of thujone in alcoholic beverages. Possible receptor interactions between thujone and ethanol as well as differences between sober and inebriated persons must be taken into account.
The sometimes observed porphyrinogenic effect of thujone and other terpenoids is explained with the pathway of metabolization by the hepatic cytochrome P-450 sys tem [46 , 76 , 79]. Under the presumption of relatively high thujone concentrations of 260 mg/l, Bonkovsky et al. speculated that if there is an appreciable hepatic first-pass extraction and if the rate of hepatic metabolism is not unusually rapid, the concentrations in the livers of absinthe drinkers could have been in the 20â200 ÂµM range. Such concentrations would be sufficient to produce porphyric crises in patients with underlying defects in hepatic heme synthesis. An additional effect of ethanol, perhaps acting synergistically, was also anticipated, since ethanol and other short-chain alcohols found in alcoholic beverages are porphyrogenic .
Intoxication due to wormwood or thujone rarely occurs, either due to a misconceived belief in folk remedies or simple ignorance [80 ]. In 1862, Smith described a case of ingestion of about 14 ml of oil of wormwood by a male adult. The patient was insensible, convulsed, the jaw clenched, and foaming at the mouth; tendency to vomit was also present . To our knowledge, there is only one recent clinical case report by Weisbord et al. from the U.S. dealing with obvious acute thujone intoxication . A 31-year-old male had ingested "herbal oil," which he had assumed to be the spirit absinthe and had purchased over the internet from a website that sold essential oils for aromatherapy. Several hours later, the patient became listless, suffered tonic-clonic seizures and finally developed rhabdomyolysis and then acute renal failure. It is tempting to speculate that these symptoms were caused by thujone, however other ingredients of the herbal oil cannot be excluded as the culprit.
Very few data published only in non peer-reviewed literature exist about the pharmacology of thujone. Max pointed out that the typical 2â4 mg of thujone, which were consumed per drink were far below the level at which acute pharmacological effects are observed . This is confirmed by Hinkelbein, who states that by the consumption of absinthe, up to a blood alcohol concentration of 2.5 g/l, approximately 3.5 mg of thujone are ingested (0.005 mg/kg bodyweight) . In this order of magnitude, it is highly improbable that central effects can be caused by thujone.
A pilot drinking study by KrÃ¶ner et al. resulted in high blood alcohol concentration, but as expected no thujone was detected [ 85]. The probands examined did not show any central effect caused by the terpenoids besides the effect of the alcohol. Therefore, the adverse potency of absinthe can be neglected, if the EU limit is obeyed.
The German federal institute for risk assessment holds the view that, even if the legal limit of 35 mg/l is significantly exceeded, the consumer does not ingest health-threaten-ing amounts of thujone. Because of the high alcoholic strength it is advised against a continuous and excessive consumption [86 ].
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