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1 2 3 4 1 Letter to the Editor 5 6 7 8 2 Wormwood (Artemisia absinthium L.) – a curious plant with both 9 10 11 12 3 neurotoxic and neuroprotective properties? 13 14 15 4 16 17 5 Re: "Neuroprotective effect of Artemisia absinthium L. on focal ischemia and 18 19 20 6 reperfusion-induced cerebral injury" by Bora and Sharma (J. Ethnopharmacol 2010;in press) 21 22 7 23 24 8 Dirk W. Lachenmeier* 25 26 27 9 Chemisches und Veterinäruntersuchungsamt (CVUA) Karlsruhe 28 2910 Weissenburger Strasse 3 30 3111 D-76187 Karlsruhe, Germany 32 3312 34 35 3613 * Corresponding author. 37 3814 Tel.: +49-721-926-5434; fax: +49-721-926-5539. 39 4015 E-mail address: [email protected] (D.W. Lachenmeier) 41 4216 43 44 45 4617 47 48 49 5018 51 52 53 5419 55 56 5720 Conflicts of Interest: None declared. 58 59 60 61 62 63 64 1 65 1 2 321 Abstract 4 5 622 The medical use of the wormwood plant Artemisia absinthium L. dates back to at least Roman times, 7 8 923 while during the last century this tradition was seemingly on the decline due to fears of absinthism, a 10 1124 syndrome allegedly caused by the wormwood-flavoured spirit absinthe and more specifically as a result 12 13 1425 of thujone, a monoterpene ketone often present in the essential oil of wormwood. If threshold 15 1626 concentrations are exceeded, thujone does in fact exhibit neurotoxic properties leading to dose- 17 18 1927 dependent tonic-clonic seizures in animals, likely caused by GABA type A receptor modulation. 20 2128 Research has shown that the concentrations of thujone present in absinthe were not sufficient to exceed 22 23 2429 these thresholds, and the marketing of wormwood-flavoured alcoholic beverages has ultimately been 25 2630 reinstated. The declining fears of absinthism may have led to a revival of the medical uses of 27 2831 wormwood, evidenced by several experimental reports, e.g. on the treatment of Crohn's disease. Most 29 30 3132 recently in this journal, neuroprotective properties of wormwood were detected in rats, and the plant 32 3333 was suggested to be possibly beneficial in the treatment of strokes. While these results sound promising 34 35 3634 and worthwhile for further investigation, the well-defined profile of adverse properties of wormwood 37 3835 demands a more cautious interpretation of these results. It remained unclear in the studies, for example, 39 40 4136 if the threshold dose for thujone (e.g. as set by EMEA) would be exceeded during therapeutic usage. 42 4337 Due to the colourful history of wormwood, its application in humans should be preceded by a thorough 44 4538 and careful risk-benefit analysis. 46 47 4839 49 5040 Keywords: Artemisia absinthium L., wormwood, absinthe, thujone, neurotoxicity syndromes, seizures, 51 52 5341 neuroprotectants 54 55 56 57 58 59 60 61 62 63 64 2 65 1 2 342 1. Introduction 4 5 643 The wormwood plant Artemisia absinthium L., which features the monoterpene ketone thujone as its 7 844 possible "active ingredient" is certainly of ethnopharmacological interest. Its documented medical use 9 1045 can be dated back to the Ebers Papyrus, an ancient Egyptian medical document dating from about 1552 11 12 1346 B.C. and the oldest preserved medical document (Anon., 1937). This papyrus is believed to be a copy 14 1547 of the ancient books of Thoth (3500 B.C.). The name “wormwood” is derived from its anthelmintic 16 17 1848 properties, which were recognized by the ancient Egyptians (Padosch et al., 2006). Wormwood, in the 19 2049 context of its bitter taste, is mentioned several times in the bible (Deu 29:18; Pro 5:4; Jer 9:15; Amo 21 22 2350 5:7; Rev 8:11; Lam 3:15). The Greek word apsinthion, meaning "undrinkable", is likely the ancestor of 24 2551 the word absinthe, which is used in French for the plant species as well as for the alcoholic beverage 26 2752 (Padosch et al., 2006). The Greek mathematician and philosopher, Pythagoras of Samos (569-475 28 29 3053 B.C.), recommended wine-soaked wormwood leaves to alleviate labour pains; Hippocrates (~460-377 31 3254 B.C.) used wormwood extracts for the treatment of menstrual pain and rheumatism (Baker, 2001). 33 34 3555 Pliny the Elder (23-79), a Roman scholar and scientist, also mentioned extracts of wormwood in his 36 3756 opus Historia Naturalis (Pliny the Elder, 1855; Nathan-Maister, 2008). In the Middle Ages, wormwood 38 39 4057 was used as a purge and vermifuge, and it developed towards a “general remedy for all diseases” and 41 4258 was referred to as “a herb of Mars” for its overarching medical powers (Baker, 2001). Wormwood’s 43 44 4559 bitter taste inspired women to apply it to their nipples to encourage the weaning of their babies. In fact, 46 4760 Shakespeare has Juliet’s nurse expound upon this in Romeo and Juliet (Padosch et al., 2006). 48 4961 Whilst wormwood is mentioned in almost all early herbals, the comprehensive section on wormwood 50 51 5262 contained in Rembert Dodoen's herbal "The Stirpium Historiae" printed in 1583 is particularly 53 5463 noteworthy (Nathan-Maister, 2008). The only book exclusively devoted to the subject appears to be the 55 56 5764 "Herba picra, vel de absinthio analecta ad normam & formam academiae naturae curiosorum" 58 5965 published in 1667 (Fehr, 1667). 60 61 6266 63 64 3 65 1 2 367 2. The rise and fall of absinthe 4 5 th 668 In the 18 century, alcoholic decoctions of wormwood and other plants were used as all-purpose 7 th 869 remedies or "cure-alls", but it was not until the beginning of the 19 century that the wormwood- 9 1070 flavoured alcoholic extracts and distillates were seen not only as patent medicines, but also as aperitifs, 11 12 1371 and the large scale production of absinthe began (Nathan-Maister, 2008). During the French occupation 14 1572 of Algeria, absinthe was still used more as medicine than as recreational beverage, and it was given to 16 17 1873 the troops as preventive measure for helminthiasis or fevers, and when mixed with water it was 19 2074 believed to kill germs and fend off dysentery (Padosch et al., 2006; Nathan-Maister, 2008). When the 21 22 2375 returning troops brought with them the taste for the refreshingly bitter drink, absinthe became a hit in 24 2576 bars and bistros all over France, and at the peak years between 1880-1910, absinthe was conceived and 26 2777 marketed purely as an alcoholic beverage (Lanier, 1995; Padosch et al., 2006; Nathan-Maister, 2008). 28 29 3078 The annual per capita consumption of absinthe in France increased fifteen-fold between 1875 and 31 3279 1913. According to an article in The Times (1915), French consumption of pure alcohol in 1876 was 33 34 3580 15,500 hectolitres; it was 10 times that amount in 1908, and in 1913 it had reached the figure of 36 3781 239,492 hectolitres, representing 60 litres per inhabitant. Corresponding to this mass consumption, 38 39 4082 chronic use of absinthe was claimed to produce a syndrome called absinthism, which was characterized 41 4283 by addiction, hyperexcitability, epileptic fits and hallucination (Padosch et al., 2006; Nathan-Maister, 43 44 4584 2008). The definition of absinthism as a particular syndrome separate from alcoholism is directly 46 4785 attributable to the French physician Valentin Magnan (Dowbiggin, 1996; Luauté, 2007; Eadie, 2009). 48 4986 In Magnan's studies on absinthism between 1864 and 1874, he described visual and auditory 50 51 5287 hallucinations accompanied by alterations in consciousness after the consumption of absinthe (Magnan, 53 5488 1864; Magnan, 1874). Wormwood, the major ingredient of absinthe, was quickly pronounced to be the 55 56 5789 culprit. This was predominantly based on animal experiments conducted with pure wormwood extract 58 5990 (Padosch et al., 2006). If injected in its pure form, wormwood extracts and alcohol showed distinctly 60 61 6291 different symptoms (Magnan, 1874; Ott, 1892; Boyce, 1895; Cunningham, 1898; Lesieur, 1907; 63 64 4 65 1 2 392 Ossipow, 1914). These early investigations and the resultant systematic experiments with pure thujone 4 5 693 (see below) have consistently shown that wormwood may act as a strong agent causing seizures in 7 894 animals. The only issue was that the dose-response relationship was largely neglected, as later 9 1095 investigations have shown that the wormwood content in absinthe was so negligible that the "no effect 11 12 1396 level" in animal experiments with additional safety factors would not have been exceeded by even 14 1597 excessive human absinthe ingestion (Lachenmeier et al., 2008). The most plausible hypothesis today is 16 17 1898 that absinthism was just misdiagnosed alcoholism, as ethanol alone can explain all of absinthe’s alleged 19 2099 effects (Strang et al., 1999; Padosch et al., 2006; Lachenmeier et al., 2010). 21 22 23100 24 25101 3. The medical use of wormwood - a collateral damage of the absinthe prohibition? 26 27102 In the time of the absinthe prohibition, which lasted from 1915 till 1988 in most European countries 28 29 30103 (Padosch et al., 2006), the medical use and ethnopharmacological research of wormwood was 31 32104 apparently hindered by the demonization of the plant; although the absinthe laws generally regulated 33 34 35105 only the manufacture, importation, distribution and sale of absinthe (i.e. the alcoholic beverage) and not 36 37106 the wormwood herb itself, and did not specifically disallowed the medical use of wormwood. This is 38 39 40107 evidenced, for example, by the lack of published studies researching the potential therapeutic uses and 41 42108 the molecular mechanisms behind the ethnologically known properties of the plant in the years during 43 44 45109 the prohibition. The fear of absinthism in connection with the medical use of wormwood is also still 46 47110 evinced by the recently published monograph of the European Medicines Agency (EMEA, 2009). The 48 49111 EMEA has proposed maximum daily intakes for wormwood based on the presence of its constituent 50 51 52112 thujone. The daily intake of 3.0 mg/person is seen as acceptable for a maximum duration of two weeks. 53 54113 It is striking that the EMEA rationale for establishing such a limit is based on a study regading the 55 56 57114 attention performance and mood under the influence of thujone and alcohol (Dettling et al., 2004). The 58 59115 results of this study, in which the group given high thujone concentrations (in combination with 60 61 62116 alcohol) demonstrated changes in attention performance, were also used to postulate the requirement of 63 64 5 65 1 2 1173 a warning label that states "patients should not drive or operate machinery after intake of Absinthii 4 5 1186 herba preparations" (EMEA, 2009). 7 1198 Throughout history, very few anecdotal reports have been published concerning the toxicity associated 9 10120 with Artemsia overdose in humans (Smith, 1862; Smith, 1863; Robinson, 1889; Weisbord et al., 1997). 11 12 13121 The adverse properties of the thujone contained in wormwood cannot, however, be directly dismissed. 14 15122 The major effect reported in humans as well as in experimental animals was neurotoxicity manifested 16 17 18123 by epileptiform convulsions (Keith, 1931; Sampson and Fernandez, 1939; Wenzel and Ross, 1957; 19 20124 Pinto-Scognamiglio, 1967; Millet et al., 1979; Steinmetz et al., 1980; Millet et al., 1981), which had 21 22 23125 been thought to be due to -aminobutyric acid type A (GABAA) receptor modulation of thujone (Höld 24 25126 et al., 2000). Several animal experiments conducted with pure thujone have confirmed its properties to 26 27 28127 cause dose-dependent tonic-clonic seizures. Besides two short-term animal experiments conducted in 29 30128 the 1960s with rats (Surber, 1962; Margaria, 1963; SCF, 2003), the two most recent chronic long-term 31 32129 studies with rats and mice are notable (NTP, 2009). The no-effect levels (NOEL) were in the range 33 34 35130 between 5 and 12.5 mg/kg bodyweight/day (SCF, 2003). As previously mentioned, the consumption of 36 37131 absinthe was unable to reach the NOEL (Lachenmeier et al., 2008). Currently, it is relatively unclear 38 39 40132 how much thujone is present in medically used wormwood preparations. Wide variations are expected 41 42133 due to the natural thujone variation in wormwood (0-71% thujone in the essential oil of wormwood, see 43 44 45134 review in Lachenmeier and Nathan-Maister (2007)) as well as the amount extracted during preparation, 46 47135 e.g. infusion of wormwood tea. Thujone is less soluble in water than in ethanol, and according to 48 49 50136 Tegtmeier and Harnischfeger (1994), only 8% of thujone is recovered in water compared to extraction 51 52137 in 90% vol ethanol. However, there is a complete lack of data in the literature regarding the actual 53 54138 thujone content in herbal medicines. As the literature reports only few cases of wormwood intoxication, 55 56 57139 generally due to the accidental or intentional ingestion of very large amounts of wormwood oil, the 58 59140 occasional therapeutic use of wormwood preparations appears to be of rather low likelihood to result in 60 61 62 63 64 6 65 1 2 1413 acute toxic events. For wormwood itself, only short-term toxicity studies are available (a 13-week 4 5 1426 study by Muto et al. (2003) and a six-month study reported by Omer et al. (2007)), both of which failed 7 1438 to show any adverse effects. However, uncertainty remains as the thujone content in the wormwood 9 10144 material used in both toxicity studies was inadequately characterized. In the Muto et al. (2003) study, 11 12 13145 the composition of the wormwood extract was stated to be unknown. In the Omer et al. (2007) study, 14 15146 the thujone content was less than 5 ppm (no exact value stated). The experience from beverage 16 17 18147 production shows that the thujone content in wormwood is highly variable, depending not only on the 19 20148 plant's chemotype, but also on time of harvest, climate and drying conditions (Lachenmeier et al., 21 22 23149 2006). Similar to food producers, manufacturers of herbal wormwood preparations should apply quality 24 25150 control measures to ensure that toxicity studies conducted with low thujone chemotypes of wormwood 26 27151 are representative of the batches actually sold. 28 29 30152 31 32153 4. Comment on modern studies about wormwood 33 34 35154 Regarding the well-known neurotoxic properties of wormwood, the headline of the article by Bora and 36 37155 Sharma (2010) that wormwood has neuroprotective effects on focal ischemia and reperfusion-induced 38 39 40156 cerebral injury was rather surprising. The results, which were based on animal experiments, sound 41 42157 promising and will hopefully lead to a renaissance of research on wormwood aimed at validating the 43 44 45158 ethnological and traditional uses of the plant. Promising results relating to the therapeutic uses of 46 47159 wormwood were also obtained in previous studies on Crohn's disease (Omer et al., 2007; Krebs et al., 48 49160 2010). Wormwood has also exhibited hepatoprotective action (Gilani and Janbaz, 1995). 50 51 52161 Prior to clinical studies in humans, however, the above mentioned adverse properties of wormwood 53 54162 should be more carefully evaluated. The surprising disparity between the neurotoxic and 55 56 57163 neuroprotective effects of the plant was not mentioned in the study of Bora and Sharma (2010). The 58 59164 thujone concentration in the applied wormwood plant extract was not stated in the study, so that it is 60 61 62165 not possible to pass judgment in terms of the exceedance of the NOEL or the EMEA guidelines. It 63 64 7 65 1 2 1663 could very well be the case that thujone was removed during the relatively extended preparation of the 4 5 1676 wormwood extract, which included drying and milling of the plant parts, followed by methanolic 7 1688 Soxhlet extraction, vacuum reduction and freeze drying. Therefore, a limitation of the study is that the 9 10169 neuroprotective effects do not apply to wormwood per se (as could be erroneously deduced from the 11 12 13170 title), but only to the extract prepared in this specific fashion. 14 15171 In conclusion, the risk associated with the occasional medicinal use of wormwood appears to be rather 16 17 18172 low, however, due to its colourful history, the application in humans should be preceded by a careful 19 20173 risk-benefit analysis, especially considering the toxic properties of thujone. 21 22 23174 24 25175 References 26176 27177 Anon., 1937. The Papyrus Ebers: The greatest Egyptian medical document translated by B. 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The New England Journal of Medicine 337, 825-827. 25 26 27280 Wenzel, D.G., Ross, C.R., 1957. Central stimulating properties of some terpenones. Journal of the 28281 American Pharmaceutical Association 46, 77-82. 29282 30283 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 11 65 Graphical Abstract Click here to download high resolution image

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