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Artemisia (Absinthii herba)

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Authorisation details
Latin name of the genus: Artemisia
Latin name of herbal substance: Absinthii herba
Botanical name of plant: Artemisia absinthium L.
English common name of herbal substance: Wormwood
Status: F: Final positive opinion adopted
Date added to the inventory: 23/11/2005
Date added to priority list: 23/11/2005
Outcome of European Assessment: Community herbal monograph
Additional Information:





Product Characteristics
COMMUNITY HERBAL MONOGRAPH ON ARTEMISIA ABSINTHIUM L., HERBA
1. N AME OF THE MEDICINAL PRODUCT
To be specified for the individual finished product.
2. Q UALITATIVE AND QUANTITATIVE COMPOSITION 1 , 2
Well-established use
Traditional use
With regard to the registration application of
Article 16d(1) of Directive 2001/83/EC as
amended
Artemisia absinthium L., herba (wormwood herb)
i) Herbal substance
Not applicable.
ii) Herbal preparations
- Comminuted herbal substance
- Expressed juice from the fresh herb (1:0.5-0.9)
- Tincture (1:5, ethanol 70% v/v)
3. PHARMACEUTICAL FORM
Well-established use
Traditional use
Herbal preparation in solid or liquid dosage forms
or as herbal tea for oral use.
The pharmaceutical form should be described by
the European Pharmacopoeia full standard term.
1 The material complies with the Eur. Ph. monograph (01/2008:1380corrected 6.0).
2 The declaration of the active substance(s) for an individual finished product should be in accordance with
relevant herbal quality guidance
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4. C LINICAL PARTICULARS
4.1. Therapeutic indications
Well-established use
Traditional use
a) Traditional herbal medicinal product used in
temporary loss of appetite.
b) Traditional herbal medicinal product used in
mild dyspeptic/gastrointestinal disorders.
The product is a traditional herbal medicinal
product for use in specified indications
exclusively based upon long-standing use.
4.2. Posology and method of administration
Well-established use
Traditional use
Posology
Adults, elderly
Indication a)
Daily dose
Herbal tea: 2-3 g of the comminuted herbal
substance, divided in two to three single doses.
Expressed juice: 10 ml, divided in two single
doses.
Tincture: equivalent to 2-3 g herbal substance,
divided in two to three single doses.
To be taken 30 minutes before meals.
Indication b)
Daily dose
Herbal tea: 2-3 g of the comminuted herbal
substance, divided in two to three single doses.
Comminuted herbal substance in tablets: 2.28 g
herbal substance, divided in three single doses.
Expressed juice: 10 ml, divided in two single
doses.
Tincture: equivalent to 2-3 g herbal substance,
divided in two to three single doses.
To be taken after meals.
For tea preparation, pour 150 ml of boiling water
over 1 g of comminuted herbal substance. Steep
for 10 minutes.
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Indications a) and b)
The intake of thujone should not exceed
3.0 mg/day.
The use in children and adolescents under 18
years of age is not recommended (see section 4.4
‘Special warnings and precautions for use’).
Duration of use
Indication a) and b)
Not to be used for more than 2 weeks.
If the symptoms persist during the use of the
medicinal product, a doctor or a qualified health
care practitioner should be consulted.
Method of administration
Oral use.
4.3. Contraindications
Well-established use
Traditional use
Hypersensitivity to the active substance(s) and to
other plants of the Asteraceae (Compositae)
family.
Obstruction of the bile duct, cholangitis or liver
disease.
4.4. Special warnings and precautions for use
Well-established use
Traditional use
Patients with gallstones and any other biliary
disorders should consult a doctor before using
Absinthii herba preparations.
The intake of Absinthii herba preparations might
influence the effect of medicinal products acting
via GABA receptor, even if not seen clinically.
The use in children and adolescents under
18 years of age has not been established due to
lack of adequate data.
For tinctures containing ethanol, the appropriate
labelling for ethanol, taken from the ‘Guideline
on excipients in the label and package leaflet of
medicinal products for human use’, must be
included.
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4.5. Interactions with other medicinal products and other forms of interaction
Well-established use
Traditional use
None reported.
4.6. Pregnancy and lactation
Well-established use
Traditional use
There are no or limited data from use during
pregnancy and lactation.
The use should be avoided during pregnancy and
lactation (see section 5.3 ‘Preclinical safety
data’).
4.7. Effects on ability to drive and use machines
Well-established use
Traditional use
May impair ability to drive and use machines.
Affected patients should not drive or operate
machinery.
4.8. Undesirable effects
Well-established use
Traditional use
None known.
If adverse reactions occur, a doctor or a qualified
health care practitioner should be consulted.
4.9. Overdose
Well-established use
Traditional use
No case of overdose has been reported.
5. PHARMACOLOGICAL PROPERTIES
5.1. Pharmacodynamic properties
Well-established use
Traditional use
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended.
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5.2. Pharmacokinetic properties
Well-established use
Traditional use
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended.
5.3. Preclinical safety data
Well-established use
Traditional use
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended, unless
necessary for the safe use of the product.
Thujone is reported to be neurotoxic and
chemotypes with low content of thujone should
be preferred.
Tests on reproductive toxicity have been
performed with a dry ethanolic extract of
Absinthii herba administered orally to pregnant
rats. Results showed reduced sites of
implantations and a reduced rate of born pups.
Thujone is known for its uterus stimulating
activity.
A daily intake of 3.0 mg/person is acceptable for
a maximum duration of use of 2 weeks.
Tests on genotoxicity, carcinogenicity and
reproductive toxicity have not been performed
with preparations of Absinthii herba covered by
this monograph.
6. PHARMACEUTICAL PARTICULARS
Well-established use
Traditional use
Not applicable.
7. DATE OF COMPILATION / LAST REVISION
16 July 2009
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Assessment Report
TABLE OF CONTENTS
I.
REGULATORY STATUS OVERVIEW
........................................................................................ 3
II.
ASSESSMENT REPORT
................................................................................................................. 5
II.1
I NTRODUCTION
II.1.1
............................................................................................................................... 6
Description of the herbal substance(s), herbal preparation(s) or combinations thereof
...... 6
Information on period of medicinal use in the Community regarding the specified
indication
II.2
II.1.2
............................................................................................................................................... 8
N ON -C LINICAL D ATA
II.2.1
.................................................................................................................... 9
Pharmacology
....................................................................................................................... 9
Overview of available data regarding the herbal substance(s), herbal preparation(s)
and relevant constituents thereof
II.2.1.2
....................................................................................................... 9
Assessor’s overall conclusions on pharmacology
....................................................... 13
II.2.2
Pharmacokinetics
................................................................................................................ 13
Overview of available data regarding the herbal substance(s), herbal preparation(s)
and relevant constituents thereof
II.2.2.2
..................................................................................................... 13
Assessor’s overall conclusions on pharmacokinetics
.................................................. 14
II.2.3
Toxicology
........................................................................................................................... 14
Overview of available data regarding the herbal substance(s)/herbal preparation(s) and
constituents thereof
II.2.3.2
.......................................................................................................................... 14
Assessor’s overall conclusions on toxicology
............................................................. 17
II.3
C L INICAL D ATA
II.3.1
........................................................................................................................... 18
Clinical Pharmacology
........................................................................................................ 18
II.3.1.1
Pharmacodynamics
...................................................................................................... 18
II.3.1.2
Pharmacokinetics
......................................................................................................... 19
II.3.2
Clinical Efficacy
.................................................................................................................. 20
II.3.2.1
Dose response studies
.................................................................................................. 20
II.3.2.2
Clinical studies (case studies and clinical trials)
......................................................... 20
II.3.2.3
Clinical studies in special populations (e.g. elderly and children)
.............................. 21
II.3.2.4
Traditional use
............................................................................................................. 21
II.3.2.5
Assessor’s overall conclusions on clinical efficacy
.................................................... 22
II.3.3
Clinical Safety/Pharmacovigilance
..................................................................................... 23
II.3.3.1
Patient exposure
.......................................................................................................... 23
II.3.3.2
Adverse events
............................................................................................................ 23
II.3.3.3
Serious adverse events and deaths
............................................................................... 23
II.3.3.4
Laboratory findings
..................................................................................................... 23
II.3.3.5
Safety in special populations and situations
................................................................ 23
II.3.3.6
Assessor’s overall conclusions on clinical safety
........................................................ 25
II.4
A SSESSOR S O VERALL C ONCLUSIONS
......................................................................................... 26
III.
ANNEXES
III.1
....................................................................................................................................... 26
C OMMUNITY H ERBAL M ONOGRAPH ON ARTEMISIA ABSINTHIUM L ., HERBA
................................ 26
III.2
L ITERATURE R EFERENCES
........................................................................................................... 26
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II.2.1.1
II.2.2.1
II.2.3.1
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I. REGULATORY STATUS OVERVIEW 1
MA: Marketing Authorisation;
TRAD: Traditional Use Registration;
Other TRAD: Other national Traditional systems of registration;
Other: If known, it should be specified or otherwise add ’Not Known’
Member State
Regulatory Status
Comments 2
Austria
MA
TRAD
Other TRAD
Other Specify: combinations
Belgium
MA
TRAD
Other TRAD
Other Specify: no response
Bulgaria
MA
TRAD
Other TRAD
Other Specify: no products
Cyprus
MA
TRAD
Other TRAD
Other Specify: no response
Czech Republic
MA
TRAD
Other TRAD
Other Specify: since 1996 and
combinations
Denmark
MA
TRAD
Other TRAD
Other Specify: combinations
Estonia
MA
TRAD
Other TRAD
Other Specify: since 1999 and
combinations
Finland
MA
TRAD
Other TRAD
Other Specify: no products
France
MA
TRAD
Other TRAD
Other Specify: no products
Germany
MA
TRAD
Other TRAD
Other Specify: since 1976 and
combinations
Greece
MA
TRAD
Other TRAD
Other Specify: no products
Hungary
MA
TRAD
Other TRAD
Other Specify: combinations
Iceland
MA
TRAD
Other TRAD
Other Specify: no products
Ireland
MA
TRAD
Other TRAD
Other Specify: no products
Italy
MA
TRAD
Other TRAD
Other Specify: no products
Latvia
MA
TRAD
Other TRAD
Other Specify: since 1993 and
combinations
Liechtenstein
MA
TRAD
Other TRAD
Other Specify: no response
Lithuania
MA
TRAD
Other TRAD
Other Specify: no response
Luxemburg
MA
TRAD
Other TRAD
Other Specify: no response
Malta
MA
TRAD
Other TRAD
Other Specify: no response
The Netherlands
MA
TRAD
Other TRAD
Other Specify: no products
Norway
MA
TRAD
Other TRAD
Other Specify: no response
Poland
MA
TRAD
Other TRAD
Other Specify: since 1978
Portugal
MA
TRAD
Other TRAD
Other Specify: no products
Romania
MA
TRAD
Other TRAD
Other Specify: since 2004 and
combinations
Slovak Republic
MA
TRAD
Other TRAD
Other Specify: combinations
1 This regulatory overview is not legally binding and does not necessarily reflect the legal status of the products in
the MSs concerned.
2 Not mandatory field
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Member State
Regulatory Status
Comments 2
Slovenia
MA
TRAD
Other TRAD
Other Specify: combinations
Spain
MA
TRAD
Other TRAD
Other Specify: food supplement
Sweden
MA
TRAD
Other TRAD
Other Specify: no products
United Kingdom
MA
TRAD
Other TRAD
Other Specify: no products
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II.
ASSESSMENT REPORT
BASED ON ARTICLE 10A OF DIRECTIVE 2001/83/EC AS AMENDED
(WELL-ESTABLISHED USE)
BASED ON ARTICLE 16D(1) AND ARTICLE 16F AND 16H OF DIRECTIVE 2001/83/EC AS
AMENDED
(TRADITIONAL USE)
Herbal substance(s) (binomial scientific name of
the plant, including plant part)
Artemisia absinthium L.; basal leaves or slightly
leafy, flowering tops, or mixture of these dried,
whole or cut organs.
Herbal preparation(s)
a) comminuted herbal substance
b) expressed juice from fresh Absinthii herba
(1 : 0.5 - 0.9)
c) tincture from Absinthii herba (1:5) ethanol
70% (v/v)
Pharmaceutical forms
Herbal preparation in solid or liquid dosage forms
for oral use or as herbal tea for oral use.
The pharmaceutical form should be described by
the European Pharmacopoeia full standard term
Rapporteur
Germany
Assessor
Dr. Jacqueline Koch
Phone +49 228 207 5980
Fax: +49 228 207 5395
email: jkoch@bfarm.de
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II.1
I NTRODUCTION
II.1.1
Description of the herbal substance(s), herbal preparation(s) or combinations thereof
Herbal substance(s) 3 :
Absinthii herba [European Pharmacopoeia]
Basal leaves or slightly leafy, flowering tops, or mixture of these dried, whole or cut organs of
Artemisia absinthium L. Content: minimum 2 ml/kg of essential oil (dried drug); bitterness value:
minimum 10,000
Synonyms: German- Magenkraut, Wermutkraut; Engl- Wormwood; French- Absinthe, Armoise amère;
Polish- Ziele piolunu; Romanian- Iarbă de pelin.
Artemisia absinthium is a species of wormwood, native to temperate regions of Europe, Asia and northern
Africa. It grows naturally on uncultivated, arid ground, on rocky slopes and wastelands; it can also be
cultivated in dry soil.
The time of harvesting is important for the quality and the composition of the constituents. Metabolism
processes change over the flowering period and ripenening of the fruit, e.g. during the flowering period
the concentration of bitter constituents increases. [H ÄNSEL & S TICHER 2007].
Absinthii herba is used medically with a very long tradition, but it is also used as an ingredient in the
liquor absinthe. In the beginning of the 19th century many countries banned the use of absinthe. Since
1988 the European Union permits a maximum thujone level of 5 mg/kg in alcoholic beverages with less
than 25% volume of alcohol, 10 mg/kg in alcoholic beverages with more than 25% volume of alcohol, and
35 mg/kg in alcohol labelled as bitters. The use and sale of absinthe in the member states is permitted
within this framework [88/388/EEC 1988].
Constituents: [H AGER ROM 2006, W ICHTL 2002, H ÄNSEL & S TICHER 2007]
Volatile oil:
Content: 0.2-1.5%. The composition depends on the plant provenance, the different chemotypes, and
seasonal variations. The 4 main components described are: α-thujone, (Z)-epoxyocimene, trans-
sabinylacetat and chrysanthenylacetat [C ARNAT et al. 1992, H AGER ROM 2006].
”pure”-chemotype:
α -Thujone is typical for plants grown in areas below 1,000 m a.s.l.. (Z)-epoxy-ocimene is the main
component in plants grown in Europe at altitudes higher 1,000 m a.s.l.. In France, there are different
chemotypes with trans-sabinyl-acetate and chrysanthenyl-acetate as main components, while plants from
eastern Europe are mostly mixed types [C HIALVA et al. 1983].
Further volatile oil components are sequiterpenes like α-bisabolol, β-curcumen and spathulenol
[W ICHTL 2002].
3 According to the ‘Procedure for the preparation of Community monographs for traditional herbal medicinal
products’ (EMEA/HMPC/182320/2005 Rev.2) and the ‘Procedure for the preparation of Community
monographs for herbal medicinal products with well-established medicinal use ( EMEA/HMPC/182352/2005
Rev.2)
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“mixed”-chemotype:
(Z)-epoxy-ocimene+chrysanthenyl-acetate+thujone-chemotype: cis-chrysanthyl-acetate ~ 40%, cis-
epoxyocimene ~ 30%, furthermore linalool, cis-chrysanthenol, cis-ocimene, trans-epoxy-ocimene
[A RINO et al. 1999a] cis-chrysanthenol-chemotype (growing in Auvergne): cis-chrysanthenol ~
70%, α-thujone ~ 8% (in november); cis-chrysanthenol ~ 20%, α-thujone ~ 50% (in August)
[A RINO et al. 1999b, C ARNAT et al. 1992]
(Z)-epoxy-ocimene+β-thujone-chemotype (growing in Croatia): β-thujone 14-43%, Z-epoxy-
ocimene 6-38% [J UTEAU et al. 2003]
(Z)-epoxy-ocimene+chrysanthenyl-acetate-chemotype (growing in France): (Z)-epoxy-ocimene 25-
65%, chrysanthenylacetat 15-50% (no α-thujone was detected in any sample) [J UTEAU 2003, A RINO
et al. 1999c]
β-thujone-sabinyl-acetate-chemotype : β-thujone, sabinyl-acetate [C HIALVA et al. 1983]
Bitter constituents : 0.15–0.4%; the most bitter constituents belong to the structure of sesquiterpenlactones
as absinthin (max. 0.28% in the drug), anabsinthin, artabsin (0.04 to 0.16% in the fresh drug) und matricin
(0.007% in the drug) [H AGER ROM 2006, H ÄNSEL & S TICHER 2007]
Other constituents: flavonoids (such as quercetin, rutin), caffeic acids, chlorogenic acid, syringic acid,
salicylic acid, vanillic acid, carotenoids, coumarins, homo-diterpen peroxides, thiophene [H AGER ROM
2006, H ÄNSEL & S TICHER 2007, T OSI et al. 1991, C ANADANOVIC -B RUNET et al. 2005].
Extraction yields:
The extraction method modifies the content of thujone in the preparation as much as the variable amount
of thujone in the starting material. T EGTMEIER & H ARNISCHFEGER [1994] examined the thujone content
of different preparations of A. absinthium .
Table 1:Influence of the extraction procedure on the thujone concentration in the extracts of A. absinthium
[essential oil content: 0.5% (m/v); thujone content in the essential oil: 4.8% (m/v)]; thujone yield
in % [thujone content in extract/actual thujone content]
(mean ± SD; n=6) [T EGTMEIER & H ARNISCHFEGER 1994]
method of extraction extraction solvent thujone yield
percolation (72 h; room temperature) purified cold water not detected
ethanol 30% (v/v)
not detected
ethanol 90% (v/v)
75.0%
digestion (30 min; 80°C)
ethanol 30% (v/v)
70.8%
Distillation
purified water
100.0%
G AMBELUNGHE & M ELAI [2002] examined two ethanolic preparations. The first preparation (macerating
A. absinthium for 30 days with ethanol 20%) contained 0.2 mg/l β-thujone, whereas the other sample
(macerating A. absinthium for 6 months with ethanol 95%) contained 62 mg/l β-thujone. α-Thujone was
not found in any sample.
N IESEL [1992] examined the extraction rates for different herbal substances referring to their contents of
essential oil (tea preparation with boiling water). For peppermint leaves it was shown that 20-25% of the
essential oil could be found in the preparation after 10 min. For fennel fruits anethole recovery rates of
25-35% were found after 10 min. Assuming similar physico-chemical characteristics for the essential oil
of A. absinthium, a 35% transition rate into a tea preparation (boiling water) is estimated.
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Herbal preparation(s) 4 :
i) comminuted herbal substance
ii) expressed juice from fresh Absinthii herba (1:0.5-0.9)
iii) tincture (1:5); extraction solvent: ethanol 70% (v/v)
Combinations of herbal substance(s) and/or herbal preparation(s) 4 :
Absinthii herba is used in combinations with many other herbal substances / herbal preparations. The
main combination substances such as Gentianae radix, Angelicae radix, Curcuma rhizoma, Millefolii
herba, Taraxaci radix, Menthae piperitae herba, Levistici herba, Liquiritiae radix and Foeniculus
fructus exhibit bitter and/or aromatic properties and are usually used for dyspeptic or choleretic
complaints.
This monograph refers exclusively to Absinthii herba.
Vitamin(s) 5 : not applicable
Mineral(s): not applicable
II.1.2
Information on period of medicinal use in the Community regarding the specified
indication
The following herbal substances and herbal preparations have been on the European market for a period of
30 years and were proposed for the monograph on traditional use.
i)
comminuted herbal substance
iii)
tincture (1:5) extraction solvent: ethanol 70% (v/v)
Posology and indications of the traditional herbal substance and preparations of Absinthii herba:
comminuted herbal substance in tablets
Indication: For the symptomatic treatment of dyspeptic complaints such as minor
gastro-intestinal spasms, repletion and flatulence
Posology: 3 times daily 4 coated tablets with 190 mg herb
Single dose: corresponding to 760 mg herbal substance
Daily dose: corresponding to 2.28 g herbal substance
comminuted herbal substance for tea preparation
Poland →
Indication:
lack of appetite, dyspepsia
Posology:
oral use, 1.0 g 2-3 times daily
Spain →
Indication:
appetizer (loss of appetite); dyspepsia
Posology:
oral use, 2-3 cups/daily
4 According to the ‘Guideline on the clinical assessment of fixed combinations of herbal substances/herbal
preparations’ (EMEA/HMPC/166326/2005)
5 Only applicable to traditional use
EMEA 2009
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ii)
expressed juice (1:0.5-0.9)
 
 
 
Germany → Indication:
loss of appetite, dyspeptic complaints such as
minor gastrointestinal spasms, repletion, flatulence,
spasmodic functional disorders of the biliary tract
Posology:
(as appetizer: 30 min before meals; all other indications
1 cup of tea after meals)
expressed juice (1:0.5-0.9)
Indication: loss of appetite, dyspeptic complaints such as minor gastrointestinal
spasms, repletion, flatulence
Posology:
2 x daily 5 ml liquid containing 100% expressed juice
tincture (1:5); extraction solvent: ethanol 70% (v/v)
Indication: loss of appetite, dyspeptic complaints such as minor gastrointestinal
spasms, repletion, flatulence
Posology: 3 x daily, single dose amount corresponding to 1 g herbal substance
Single dose: corresponding to approx. 1 g herbal substance
Daily dose: corresponding to approx. 3 g herbal substance
II.2
N ON -C LINICAL D ATA
II.2.1
Pharmacology
II.2.1.1
Overview of available data regarding the herbal substance(s), herbal preparation(s) and
relevant constituents thereof
Herbal substance/Herbal preparations:
in vitro studies:
The free-radical scavenging activity using the stable 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical
and the reactive hydroxyl radical formed in the Fenton reaction was tested with different extracts
(successive extraction with MeOH 70%, petroleum ether, chloroform, ethyl acetate, n-butanol and water)
of A. absinthium (ESR spectroscopy). The total phenolic and flavonoid contents in the plant were 25.6 and
13.06 mg/g, respectively. The following order of antiradical activity was found: ethyl acetate > methanol
> n-butanol > chloroform > petroleum ether > remaining water extracts. A concentration of 0.5 mg/ml of
the ethyl acetate extract reduced all DPPH radical molecules, while for the methanol extract a
concentration of 2 mg/ml led to the 100% antiradical effect. At this high concentration (2 mg/ml) the
antiradical effects of n-butanol, chloroform and petroleum ether extract were 96.06%, 84.82% and
78.26%, respectively. The remaining water extract possessed an antiradical activity of 16.67% in the
concentration of 2 mg/ml. For the antioxidant activity the above described order was proven, too. A
concentration of 0.25 mg/ml of the ethyl acetate extract inhibited completely the formation of hydroxyl
radicals. In this concentration, the methanol extract produced a scavenging effect of 74.65% while for the
n-butanol (57.24%), chloroform (27.95%) and petroleum ether (16.64%) extracts only low scavenging
effects were observed. The remaining water extract exhibited a high scavenging effect (95.68%) only in a
high concentration (3.25 mg/ml) [C ANADANOVIC -B RUNET et al. 2005].
EMEA 2009
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oral use, 1.5 g 2 times daily
 
 
 
Also Ramos et al. showed a DPPH reduction caused by a hydroalcoholic extract ( A. absinthium from
Cuba) with an IC 50 of 121 µg/ml [R AMOS et al. 2003].
To evaluate human CNS cholinergic receptor binding activity, investigations with an ethanolic extract
(80% EtOH) of leaves from A. absinthium were carried out. Human cerebral cortical cell membranes were
used to prove the activity of the ethanolic extract to displace (N)-nicotine and (n)-scopolamine from
nicotinergic and muscarinic receptors. The assay of the extract as dilution series resulted in a (n)-nicotine
displacement curve resembling the dose-dependant sigmoidal displacement curves typical for
carbamylcholine chloride and choline chloride (both known nicotinergic ligands) and indicating the
presence of nicotine-like material in the extract. The IC 50 value was calculated as 4.1 mg plant/ml while
the choline content was measured with 1.3 x 10 -4 M [W AKE et al. 2000].
For the evaluation of NGF-potentiating activities, methanol, ethyl acetate and aqueous extracts of A.
absinthium from Paraguay were examined for their effects on the NGF-mediated neurite outgrowth from
PC12D cells. At a concentration of 30 µg/ml all three extracts markedly enhanced the neurite outhgrowth
induced by NGF from PC12D cells (50.53%, 41.53% and 51.43%, respectively) [L I & O HIZUMI 2004].
An aqueous crude extract of A. absinthium was used to analyze effects on the osmotic stability of human
erythrocytes. The extract protected human erythrocytes against hypotonic shock. It was discussed that the
flavonoids might be responsible for this effect which might lead to an exacerbation of the van der Waals
contacts inside the lipid layer of the membrane [ DE F REITAS et al. 2008].
In a growth inhibitory assay, aqueous and ethanolic extracts of A. absinthium were tested for their effect
against Naegleria fowleri . Both extracts inhibited strongly the growth of N. fowleri . A sesquiterpene
lactone fraction was prepared from the ethanolic extracts. For this fraction a LD 50 value of 31.9 µg/ml was
obtained in the test system. For artemisin (from A. annua ) the IC 50 was reported with 5 g/ml. Therefore it
was postulated, that the sesquiterpene lactone fraction of A. absinthium may contain artemisin or a
compound with similar activity [M ENDIOLA et al. 1999].
Hernandez et al. prepared an aqueous extract as well as a sesquiterpene lactone fraction from A.
absinthium and tested them in a growth inhibition test against Plasmodium falciparum . In the aqueous
extract the maximum percentage of inhibition of growth (89.9%) was observed at the dilution 1:35. The
LD 50 value of the sesquiterpene lactone fraction was 31.4 µg/ml [H ERNANDEZ et al. 1990].
in vivo studies:
Different semi-pure extracts from A. absinthium from Pakistan were tested for their antiulcer effects on
acetylsalicylic acid induced ulcers in rats. The effects on volume of gastric juice, acid output, peptic
activity and mucin activity were studied. The air-dried powdered plant material was extracted with ethanol
(95% EtOH) and the extract was concentrated. The crude extract was defatted with hexane. The defatted
material was then extracted successively with chloroform and carbon tetrachloride. The fraction finally
obtained was dissolved in methanol and then the colouring matter was removed. The remaining extract
was separated into five purified/semi-purified fractions by chromatography on silica gel.
The ulcerated rats were given the fractions orally at a dose of 5 mg/kg 3 h prior and 3 h after treatment
with acetylsalicylic acid (200 mg/kg) for three days. On the fourth day the rats were operated (pylorus
ligation) and gastric juice was collected for a period of 4 h. Thereafter the animals were killed and the
stomach was removed. The average numbers of ulcers per stomach were recorded and the inhibition of
ulcer formation calculated in percent. Acid output, peptic activity and mucin activity were also
determined.
Phytochemical analysis of the fractions showed the absence of alkaloids and anthraquinones but indicated
the presence of glycosidic sugars and saponins.
Significant antiulcer effects have been observed. Fractions I and II reduced the ulcer index by 65% and
44%, respectively. The other fractions decreased it by 33%, 11% and 27%. Also fractions I and II showed
a decrease (40% and 33%, respectively). Fractions I, II and III also decreased significantly the volumes of
gastric juice (~1/3). Furthermore, for fraction II a decrease in peptic activity was observed. After treatment
EMEA 2009
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with acetylsalicylic acid a decrease in total hexoses in the gastric juice was recorded in the controls. In
fractions I and II (together with acetylsalicylic acid) the amount of total hexoses within the carbohydrates
corresponded to the controls but the amount of fucose increased. Also, the amount of total protein in the
gastric juice increased after treatment with fractions I and II. Fraction I caused a significant change in the
performance of rats in the swimming test (increased duration of swimming). During all studies, injurious
or toxic effects were not observed and no lethal effects occurred with dosages up to 10 mg/kg.
Subsequently no LD 50 could be determined [S HAFI et al. 2004].
An i.v. injection of decoctions of Absinthii herba (equal to 5 g herbal substance) caused a threefold
increase of bile secretion in dogs [K REITMAIR 1951].
Dried aerial parts of A. absinthium were extracted with methanol (80% MeOH) and tested for their
hepatoprotective activity . The dry extract was administered in various experiments to mice or rats with a
concentration of 500 mg/kg. Based on the yield of the dry extract (8%) this is equivalent to 6.25 g herbal
substance/kg.
The aqueous-methanolic extract protected against both acetaminophen- and CCl 4 -induced liver injuries
when administered prophylactically to rats and against lethal doses of acetaminophen in mice. Because the
plant extract led to a prolongation of phenobarbital sleeping time in mice, it was speculated that the plant
extract might contain inhibitors of microsomal drug metabolizing enzymes which cause hepatoprotection.
Furthermore it was assumed, that the compound sesartemin might be responsible for the observed effects.
Calcium channel blocking activities were also discussed. In some experiments a curative effect against
acetaminophen-caused liver damage was found. This effect was attributed to the content of flavonoids,
ascorbic acid, carotenoids, tannins and lignans. The treatment with the plant extract did not reveal any
symptoms of acute toxicity [G ILANI & J ANBAZ 1995].
A. absinthium leaves (fresh, stored frozen after collection) were extracted with organic solvents of
different polarities and tested as repellents against host-seeking nymphs of Ixodes ricinus . The ethyl
acetate extract had a repellent activity of 78.1%, while the hexane and methanol extracts had ~ 60% and
45% repellency, respectively. The main volatile detected in the ethyl acetate (myrtenyl acetate; 77.8%)
was also the main component of the methanol extract (77.1%) [J AENSON et al. 2005].
An ethanolic extract (90% EtOH) from dried aerial parts of A. absinthium was fractionated into hexane-
soluble and chloroform-soluble portions. The chloroform-soluble fraction was further separated into
chloroform- and water-soluble fractions. All three extract fractions were dried and used to examine the
oral antipyretic activity in rabbits (Himalayan strain). Pyresis was induced by subcutaneous yeast
infections. After sixteen hours test substances were administered via a gastric tube (150 mg/kg). The
mean temperature was determined 90, 180 and 270 min after application of the test substance. Aspirin was
used as the reference antipyretic agent (150 mg/kg). An antipyretic activity was observed for all three
extracts. The strongest effect was obtained with the hexane-soluble fraction (comparable to aspirin). No
toxicity (single-dose toxicity) was observed in dosages up to 1600 mg/kg. The possible antipyretic
constituent was identified as 24ζ-ethylcholesta-7,22-dien-3β-ol [K HATTAK et al. 1985, I KRAM et al. 1987].
For the screening of antimalarial effects leaves of A. absinthium were dried and extracted with ethanol
(95% EtOH). The extract was dried, dissolved in deionised water, filtered and the filtrate was concentrated
to dryness. Swiss albino mice were infected with 1x 10 7 parasitized ( Plasmodium berghei ) blood cells
from a donor mouse. The ethanolic extract was given orally, subcutaneously or intra-peritoneally and the
water soluble ethanolic extract was given orally. On day 4 the percentage suppression of parasitaemia was
calculated in relation to the control. The highest suppression (96%) was observed with the ethanolic
extract given orally in a concentration of 74 mg/kg; even 37 mg/kg led to a suppression of 80% [Z AFAR
1990].
Essential oil:
Freshly extracted essential oil from air-dried leaves of A. absinthium in a 1:1000 dilution showed
antibacterial activity against S. aureus , a penicillin resistant strain of S. aureus (H57), K. pneumoniae and
P. aeroginosa . No activity was observed against S. thyphi , E. coli , C. albicans , C. utilis or A. niger [K AUL
et al.1976].
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The essential oil of French A. absinthium showed antimicrobial activity against C. albicans and S.
cerevisiae var. chevaleri (growth inhibitor concentration for 50% of the microorganisms: 0.1 and
0.05 mg/ml, respectively), while no activity could be found against E. coli , S. aureus and E. hirae
[J UTEAU et al. 2003]. The essential oil of a carvone-rich chemotype of A. absinthium had no microbial
activity against S. aureus [K ARWOWSKA et al. 1997].
The anti-listerial activity of the essential oil from A. absinthium was studied and the minimal inhibitory
concentration was given with 1:1280 [F IROUZI et al. 1998].
Dried plant samples of A. absinthium were extracted with CHCl 3 and tested for their antifungal (hyphal
growth inhibition) and antibacterial (disk diffusion method) activity. The dose of 20 µl essential oil was
found to be fungicide against the tested 34 agricultural pathogenic fungal species. The essential oil
showed only a weak antibacterial activity against 13 of the 64 tested strains from plant, food and clinical
origin (600, 900 and 1200 µg/disk) [K ORDALI et al. 2005].
The freshly extracted essential oil from air dried leaves of A. absinthium was tested for its insecticidal
activity. The essential oil was toxic to house flies in concentrations of 10% (mortality rate 3.3%), 15%
(mortality rate 6.6%) and 20% (mortality rate 20%) [K AUL et al. 1978].
The essential oil of A. absinthium (hydrodestillation method) was found to be toxic to adults of Sitophilus
granarius (Coleoptera). The concentration of 9 µl oil/l air caused a mortality rate of 86.7% after 48 h
(53.3% and 73.3% after 12 and 24 h, respectively). Chamazulene (17.8%), nuciferol butanoate (8.2%),
nuciferol propionate (5.1%) and caryophyllen oxide (4.3%) were the main constituents of the essential oil.
The compounds 1,8-cineole (1.5% of the essential oil) and terpinen-4-ol (1.8% of the essential oil), were
found to be more toxic against S. granarius adults, in comparison to the whole oil [K ORDALI et al. 2006,
K ALEMBA et al. 1993]. In addition it was found that the essential oil was strongly toxic to Rhizopertha
dominca (lesser grain borer) and mildly toxic to Tribolium confusum (darkling grain beetle) [K ALEMBA et
al. 1993].
Essential oils of A. absinthium were extracted by three methods (microwave assisted process, distillation
in water and direct steam distillation) and tested for their relative toxicity as contact ascaricides to the two
spotted spider mite, Tetranychus urticae . The LC 50 from the oil obtained by direct steam distillation was
significantly lower (0.04 mg/cm 2 ) than that of the microwave assisted process and distillation in water
(both 0.13 mg/cm 2 ). Chromatographic analysis indicated that a sesquiterpene (C 15 H 24 ) present in the
direct steam distillation oil (absent in the two other oils) might enhance the toxicity [C HIASSON et al.
2001].
Thujone
The structure of a 3-thujone and its ∆ -enol was compared with (-)-∆ -THC and it was suggested that the
3-thujone or the ∆ thujone-enol and THC (or
3,4
9
3,4
their biologically active metabolites) share a common
receptor in the CNS [D EL C ASTILLO et al. 1975].
It was reported that in the hot-plate test (-)-3-isothujone was found to be codein-like and equipotent with
(-)-∆ 9 -THC, while (±)-3-isothujone was half as active and (+)-3-thujone was inactive (s.c., mice). Even
though an antinociceptive action was observed, it could not be
(-)-3-isothujone acts at the same site in the CNS as THC [R ICE & W ILSON 1976].
Following the suggestion that thujone binds to the cannabinoid receptor it was demonstrated that thujone
exhibits only a weak affinity for cannabinoid receptors (CB 1 and CB 2 ) and fails to elicit typical
cannabinoid receptor-mediated responses in rodents at doses as high as 30 mg/kg. The maximum
attainable intake of thujone was estimated with 1 mg/ml (calculated for a 70 kg human, 200 ml alcoholic
absinthe and a thujone concentration of 2.4 mM in the alcohol solution). Therefore a direct, low-affinity
interaction of thujone and related compounds with cannabinoid receptors in the brain as the primar
mechanism of action in absinthe intoxication was not considered likely [M ESCHLER & H OWLETT 1999].
The mechanisms of α-thujone neurotoxicity in rats, mice and a Drosophila strain were investigated. The
observations establish that α-thujone is a rapidly acting modulator of the GABA-gated chloride channel.
distinguished whether
y
EMEA 2009
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The effect appears to be due to the parent compound, while metabolism leads to detoxification [H ÖLD et
al. 2000a].
Other compounds
Orally administered absinthin increased the amount of gastric juice and free HCL while this was not
observed after gavage administration [K REITMAIR 1951].
A tetramethoxy-hydroxyflavone (p7F) isolated from Korean dried A. absinthium was investigated to
determine whether it had an inhibitory effect on inflammatory mediators via suppression of NF-κB. The
compound did not decrease cell viability of RAW 264.7 cells (macrophages) up to the highest tested
oncentration of 200 µg/ml. The p7F suppressed the expression of COX-2 and iNOS and the production
f NO and PGE 2 in RAW 164.7 cells treated with LPS and it decreased efficiently the LPS-induced
F-κB activation [L EE et al. 2004].
II.2.1.2 Assessor’s overall conclusions on pharmacology
It is long known that the bitter constituents stimulate
secretion of gastric juice and bile, thereby promoting appetite and digestion. Additionally, more recent
studies show that taste receptors (bitter taste) could not only be found in the lingual epithelium but also in
the gastrointestinal tract of animals [Rozengurt 2006].
These new findings support literature data which describe the use of Absinthii herba - not only in form of
the herbal tea or hydroalcoh
of mild dyspeptic/gastrointestinal disorders/complaints. The indication ‘lack of appetite’ should be
restricted to fluid preparations only. For this indication, both the tradition of use (more than 30 years) and
the plausibility are proven.
O
h
the gustatory nerves in the mouth and increase the
olic preparations, but also in form of the powdered herbal drug - for the relief
ther possible pharmacodynamic actions such as antimicrobial, anthelmintic, antipyretic, analgesic and
epatoprotective properties are also described.
II.2.2
Pharmacokinetics
I
I.2.2.1
Overview of available data regarding the herbal substance(s), herbal preparation(s) and
eof
Herbal sub
stance/Herbal Preparations:
No data available.
Thujone:
After oral administration of a mixture of α- and β-thujone (ratio 9:2) at a dose level of about
650-800 mg/kg bw to male rabbits, two neutral urinary metabolites were identified as
3-β-hydroxy-α-thujane and 3-β-hydroxy-β-thujane. This indicated a stereo-specific reduction in spite of
the different configurations of the meth
α-Thujone was rapidly metabolised by mouse liver microsomes forming 7-hydroxy-α-thujone as the major
metabolite with five minor products (4-hydroxy-α-thujone, 4-hydroxy-β-thujone, two other hydroxy-
thujones and 7,8-dehydro-α-thujone).
Incubation of α-thujone with rabbit (but not mouse) liver cytosol led to the reduction products, thujol and
neothujol, in low yield [H ÖLD et al. 2000a,b].
yl group [I SHIDA et al. 1989].
EMEA 2009
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c
o
N
relevant constituents ther
 
 
 
Site specificity and species differences in metabolism of the thujone diastereo-isomers were observed in
mouse, rat and human liver microsomes and also in rats and mice in vivo . 2-hydroxylation was observed
only in mice where the conjugated metabolite was a major urinary metabolite. 4-hydroxylation of α- and
β-thujones is another major pathway and 4-hydroxy thujone is the major urinary metabolite in rats.
7-hydroxylation is another important pathway of metabolism but the conjugated product is a minor urinary
etabolite except for β-thujone in the mouse. Site specificity in glucuronidation favours conjugation of
the other three hydroxy thujones.
as urinary metabolites, respectively
ÖLD et al. 2001].
II.2.2.2
Assessor’s overall conclusions on pharmacokinetics
Limited data are available on pharmacokinetics. For the herbal substance or the herbal preparation no data
are available; therefore no
th
Experimental data from anim
the animal species. The
detoxification of thujone.
conclusion can be drawn. For thujone and even absinthin more data exist, but
ese are not transferable to the herbal substance or herbal preparations.
als indicate that the metabolism of thujone differs strongly in dependence of
CYP system (Cytochrome P450) seems to be involved in the metabolic
I
I.2.3
Toxicology
II.2.3.1
Overview of available dat
constituent
s thereof
a regarding the herbal substance(s)/herbal preparation(s) and
Herbal substa
nce/Herbal preparations:
single dose toxicity:
The LD 50 of an extract of A. absinthium (not specified) was given with 1 mg/kg in rats (i.p.)
[H AGER ROM 2006].
rep
eat dose toxicity:
In a 13-week repeated dose toxicity study Wistar Hannover (GALAS) rats were given water
(ad libitum) containing 0, 0.125, 0.5 or 2% extract from A. absinthium (not defined). The
corresponding amount of extract/day was calculated with 1.27 g/kg/day (males) and 2.06 g/kg/day
(females) for the 2% preparation.
All rats survived the end of the study, and no changes in body weight, haematological parameters
and histopathological examinations were observed. In serum biochemical examinations, levels of
total protein, albumin, blood urea nitrogen, Na und Cl were slightly but significantly increased in
males of the 2% group. Because there were no other changes in other related parameters, these
changes were cons
significantly increased in both sexes of the 2% group. However, since there were no increases in
their absolute weights and no histopathological treatment related changes were observed in the
liver, these changes were not interpreted as
[Muto et al. 2003].
Chronic administration of an essence of Absinthii herba (not specified) caused epilepsy with
consecutively stupor in dogs [Kreitmair 1951].
idered to be of no toxicological significance. Relative liver weights were
toxicological effects. Other effects were not seen
rep
roductive and developmental studies:
Antifertility studies were carried out in Wistar albino rats of proven fertility. Antifertility activity of
an ethanolic dry extract (50% EtOH) of leaves of A. absinthium was assessed in terms of
anti-ovulatory, anti-implantation or abortifacient effects in comparison with vehicle treated controls.
EMEA 2009
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m
the (2R)-hydroxy- and 4-hydroxythujone glucuronides rather than
7,8- and 4,10-dehydro metabolites have been identified in vitro and
[H
 
 
 
No effects on ovulation (no influence of the di-oestrus or oestrus phase of cycle) were seen after
treatment of female rats for 10 days. Pregnant female rats were treated with the dry extract from
days 1 to 7 of pregnancy. On day 10 the numbers of implantation sites in each animal were
recorded. Only 2 out of 6 rats became pregnant and the numbers of born pups per rat were reduced
in comparison to the control. Furthermore pregnant female rats were treated with the dry extract
from days 11 to 13 of pregnancy. All the animals were examined for vaginal bleeding on days 12 to
16 and on day 20; they were killed and the numbers of live and dead foetuses were noted.
A. absinthium (200 mg/kg) significantly reduced the sites of implantations (2 out of 6 rats became
pregnant) and t
1987].
There are no data available on reproductive and developmental studies for aqueous preparations of
he numbers of born pups per rat were reduced in comparison to controls [Rao et al.
A. absinthium .
genotoxicity/carcinog
No studies using herbal preparations of Absinthii herba were located.
enicity:
ial oil
single dose toxicity:
The oral LD 50 of the essential oil of A. absinthium was 0.96 g/kg in rats [Opdyke 1975]. The
minimal dosage which caused spasms in cats was 0.03-0.04 ml for the diluted essential oil (1:20
with ethanol) [Kreitmair 1951].
irritating properties:
The undiluted essential oil was not irritating on the back of hairless mice and slightly irritating to
intact or abraded rabbit skin for 24 h under occlusion [Opdyke 1975].
sensitization:
A 2% preparation in petrolatum produced no sensitization reaction in 25 volunteers (maximization
test) [O
photox
No phototoxic eff
1975].
pdyke 1975].
icity:
ects were reported for undiluted essential oil on hairless mice and swine [Opdyke
Thujo
ne
gle dose toxicity:
The oral LD
sin
50 of a mixture from α- and β-thujone has been reported with 192 mg/kg in rats,
230 mg/kg in mice and 396 mg/kg in guinea pigs [Margaria 1963]. The LD 50 (s.c.) value in mice
was for α-thujone 134 mg/kg and for β-thujone 442 mg/kg [Rice et al. 1976]. The symptoms
associated with acute intoxication are epileptiform convulsions with gene
h
th
lethal effects occurr
Höld et al. [2000a] reported for α-thujone a LD 50 value of 45 mg/kg in mice (i.p.).
ral vasodilation,
ypotension, lower cardiac rhythm and increased respiratory amplitude. In rats, i.p. injections of
ujone induced electro-cortical seizures associated with myoclonic activity. Both convulsant and
ed at similar doses of 0.2 ml/kg bw [Pinto-Scognamiglio 1967, SCF 2002].
rep
eated dose toxicity:
Thujone was administered to rats by gavage at doses of 12.5, 25 or 50 mg/kg/day on five days per
week for 13 weeks. There was an increased lethality of 60% in females and 37% in males at the top
dose level. The NOEL for convulsions in the males was 12.5 mg/kg but no NOEL could be
established in females in this study [Surber 1962].
In a further study, thujone was a
dministered to rats by gavage at doses of 0, 5, 10 or 20 mg/kg/day 6
times per week for 14 weeks. There were 3 deaths in females and 1 in males associated with
EMEA 2009
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essent
convulsions at the top dose level. The NOEL for convulsions was reported to be 10 mg/kg in males
and 5mg/kg in females; no changes were reported in haematologic or histo-pathologic
examinations [Margaria 1963].
α-Thujone and a mixture of α- and β-thujone have been included in the NTP testing programme. In
the 14-day study, α-thujone was administered by gavage to B6C3F1 mice and to Fischer 344 rats at
doses of 0, 1, 3, 10, 30 or 100 mg/kg. In mice, mortality was 4/5 males and 5/5 females in the top
dose group; mortality was not increased in the lower dose groups. The increased mortality was
associated with indications of neurotoxicity (hyperactivity, tremors, tonic seizures). Histological
changes observed only at the top dose level included only mild renal tubular dilatation/focal
degeneration, increased haematopoiesis in spleen, and bone marrow myeloid cell hyperplasia. No
increased mortality occurred in male rats but there was increased mortality (3/5 animals) in females
of the top dose group. As in mice, the increased death rate was associated with
convulsions/seizures.
In the 14-day study on the mixture of α- and β-thujone (detailed composition not available), similar
doses were administered by gavage to mice and rats of the same strains. In mi
level, ther
with any notable gross or histopathological causation. In rats, there was death of 1/5 males in the
highest dose group but gross and histological effects were minimal [SCF 2002].
otoxicity
Negative results have been reported from in vitro mutagenicity tests in Salmonella typhimurium
with α-thujone. The test was performed with the strains TA1535, TA100, TA97 and TA98 with and
without metabolic activation. First toxicity signs were seen in dose units of 100. Negat
have also been reported from in vitro mutagenicity tests in Salmonella typhimurium with a mixture
of α- and β-thujone. The test was performed with the strains TA1535, TA100, TA97 and TA98 with
and without metabolic activ
In-vivo mouse micronucleus test was negative in males and positive in females with a mixture of α-
and β-thujone. The test concentration range was 0-25 mg/kg (males) and 0-50 mg/kg (females),
respectively [NTP 2003].
T
Salmonella typhimurium strain TA100.
damage which indicates some mutagenic activity on the part of thujone (Kim et al. 1992).
ce, at the top dose
e was an increased mortality in males (5/5) and females (2/5), which was not associated
gen
ive results
ation. First toxicity signs were observed in dose units of 333.
hujone was tested at 1.5 and 3% in DMSO for its effect on the mutagenicity of aflatoxin B1 in the
The plates treated with thujone showed evidence of colony
spe
cial studies on mechanisms of toxicity
Several studies on the mechanism of neurotoxicit
T
appear to be due to
Howlett 1999, Höld et al. 2000a].
y of α-thujone suggest a modulation of the GABA
ype A receptor. It is a rapidly acting modulator of the GABA-gated chloride channel. The effects
the parent compound and metabolism leads to detoxification [Meschler &
oth
er biological effects
S
le
in
tudies on primary cultures of chick embryo liver cells indicate that thujone is porphyrogenic,
ading to accumulation of copro- and protoporphyrins. It induces 5-aminolaevulinic acid synthase
this test system [Bonkovsky et al. 1992].
EMEA 2009
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II.2.3.2
Assessor’s overall conclusions on toxicology
There are only limited preclinical safety data for Absinthii herba or preparations thereof.
Also for the essential oil the data are unsatisfactory. The limited toxicological data on thujone and the
quality of the available studies, main
maximum daily intake (MDI).
The results of the single dose toxicity studies show that the LD 50 -data depend strongly on the way of
application and the animal species.
Thujone has a neurotoxic potential and produces convulsions in animals by acting on the central nervous
system. There are several anecdotal and case study reports on the acute effects of thujone-containing
essential oils causing seizures in humans, which indicate that the animal data may be relevant to humans.
However, for the essential oil or thujone, there are no reliable studies on the long-term effects of sub-
convulsive doses on the nervous system and on the liver. Long
studies and reproductive studies are missing for preparations of Absinthii herba, the essential oil and
thujone, respectively. In the latter context, it has been suggested that porphyria may be a consequence of
long-term ingestion of absinthe but this is conjectural [SCF 2002].
Thujone has been evaluated by the Council of Europe which allocated a temporary maximum daily intake
(TMDI) of 10 µg/kg/d based on a NOEL for convulsions of 5 mg/kg in the female rat, dosed by gavage on
6 days per week for 14 weeks, to which a safety factor of 500 was applied [Council of Europe 2007]. The
“temporary acceptable daily intake” is in this context a value for the acceptable daily intake proposed for
guidance when data are sufficient to conclude that use of the substance is safe over the relatively short
period of time required to generate and evaluate further safety d
the use of the substance is safe over a lifetime. A higher-than-normal safety factor is used when
establishing a TMDI. When transferring this TMDI to herbal medicinal products, the daily dosage of
thujone should not exceed 600 µg (= 0.6 mg) for a 60 kg human.
According to the Directive 88/388/EEC 1988 a maximum thujone level of 5 mg/kg in alcoholic beverages
with not more than 25% volume of alcohol and of 35 mg/kg in alcohol labelled as bitters (4
alcohol and more) are allowed. Taking into consideration a daily intake of 4-8 cl (40-80 ml) this amount
corresponds to approximately 0.2-0.4 mg thujone per person (in 25% ethanol v/v) and 1.2-2.4 mg thujone
per person (in bitters), respectively. This is without any restrict
The maximum daily intake (acceptable daily intake for food) is a measure of the amount of a specific
substance that can be ingested (orally) over a lifetime without an appreciable health risk. For a short-term
intake, the limits of thujone may therefore be less restrictive.
Dettling et al. [2004] had
performances, while for the intake of ~1.5 mg thujone/person no such changes were described even
though expected. The authors proposed for safety reasons a limit of 1.5 mg/person in a single dose, were
effects could barely be seen.
At the time of this assessment a daily intake of 3.0 mg/person is considered acceptable for a maximum
duration of use of 2 wee
three single doses. Therefore the single dose (1 mg thujone) is only 2/3 of the amount which was for
safety concerns postulated as the lowest described limit of thujone action. The content of thujone must be
shown for every batch.
The data from reproductive studies suggest that Absinthii herba might influence gravidity. Moreover it
was proven that thujone
Absinthii herba with high content of thujone should be contraindicated during pregnancy and lactation
while aqueous preparations or preparations with a low
p
D
li
ly published in the 1960s, were considered to be insufficient to set an
-term toxicity studies, carcinogenicity
ata, but are insufficient to conclude that
0% volume of
ions for the duration of use.
shown that ~15 mg thujone/person (60 kg) lead to changes in attention
ks. This is due to the fact, that this daily dose is supposed to be taken divided into
stimulates the uterus [B IELENBERG 2002]. Therefore ethanolic preparations of
regnancy and lactation.
ue to the lack of data on mutagenicity, carcinogenicity and reproductive and developmental toxicity, a
st entry for Absinthii herba can not be recommended.
content of thujone are not recommended during
EMEA 2009
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II.3
C LINICAL D ATA
II.3.1
Clinical Pharmacology
II.3.1.1
Pharmacodynamics
I
I.3.1.1.1 Overview of available data regarding the herbal substance(s)/herbal preparation(s)
including data on constituents with known therapeutic activity.
Four healthy test persons (female, age 19-37 years) drank 100 ml of a test solution, which contained an
ethanolic (EtOH 70%) preparation of A. absinthium (corresponds to 0.05 g Absinthii herba) within a time
frame of 5 min. The amount of saliva was measured before and during the drinking. In the collected saliva
the activity of amylase and the amount of hexosamine was measured. The Absinthii herba preparation
caused in all 4 persons an increase in salivation of more than 100%, while the activity of amylase and the
amount of hexosamine were not influenced or decreased. A non-spiced rice dish caused the same increase.
A combination of a non-spiced rice-dish with the Absinthii herba preparation increased the amount of
saliva in an additive manner. Furthermore the authors postulate, also in reference to other publications,
that the action of bitters is more likely to be associated with the gastric juice secretion
b
of the motor activity and directly by inducing hyperemia [Blumberger & Glatzel 1966].
. They claim that
itters may act indirectly (due to sensations of the oral cavity) as activators of the secretion and inhibitors
In a clinical study, a dry ethanolic preparation of A. absinthium (not specified) was administered to
15 patients with hepatic disorders via a duodenal tube. First, the basal secretion was measured for 10 min
before sample administration. In this way also the basis secretion of 22 healthy volunteers was measured
for comparison. The following parameters were measured: volume of duodenal secretion, amount of
bilirubin, cholesterol, lipase
hepatopathy. After the preparation was administered, the duodenal secretion was measured for 100 min
(fractionated in 10 x 10 min).
All parameters were significantly increased when the preparation was given. The stimulation of secretion
of lipase (+163-647%), bi
α-amylase (+22-72%). The increased secretion of bilirubin and cholesterol, lipase and α-amylase was long
lasting [Baumann 1975].
In a further clinical study, 2.5 mg of a dry ethanolic preparation of A. absinthium (not specified) and
10-20 mg of a thujone-free powder of A. absinthium were administered as aqueous solution to 14 (7/7)
healthy test persons via a duodenal tube. The placebo group (8 test persons) received water. First the basal
secretion was measured for 10 min. After administration of preparations/placebo the duodenal secretion
was measured for 40 min (placebo), 100 min (preparation with thujone) and 120 min (preparation without
thujone) in 10 min. intervals. The following parameters were measured: volume of duodenal secretion,
amount of bilirubin, cholesterol, α-amylase an
compared to placebo. The thujone-free preparations had similar of even stronger effects than the thujone-
containing preparation [B AUMANN et al. 1975].
In a double-blind, randomized clinical study an ethanolic preparation of A. absinthium (58.9% m/m) was
administered to 20 healthy test persons (age between 18-35 years) via a duodenal tube. An ethanolic
solution (58.9% m/m) was used as placebo. The basal secretion was measured twice for 10 min before
3 ml verum (100 g verum correspond to 0.65 g A. absinthium ; and ~ 0.02 g Absinthii herba) or 3 ml
placebo were administered. Five min after application the biliary secretion was measured for 60 min
(fractionated in 6 x 10 min). Thereafter
same procedure. The parameters measured were: volume of biliary secretion, amount of protein, trypsin,
chymotrypsine, α-amylase, and lipase.
All parameters were increased (10-20%) after verum application, but due to the variation the changes were
not significant. The highest increase was 10-20 min after application [J AGUSCH 1988].
In a double-blind, randomized clinical study an ethanolic preparation of A. absinthium (58.9% m/m) was
administered to 10 healthy test persons (age between 23-35 years) via
and α-amylase. All parameters were decreased in the patients with
lirubin (+55-170%) and cholesterol (+35-101%) was higher than the increase of
d lipase. All parameters were significantly increased as
, the other preparation was given to the test persons following the
duodenal tube. The procedure was
EMEA 2009
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according to Jagusch 1988. The following parameters were measured: volume and amount of bilirubin,
total cholesterol, HDL-cholesterol, bile acids and alkaline substances.
The parameters volume, bilirubin, total cholesterol and HDL-cholesterol were increased after verum
application but due to the variation the changes were not significant. The highest increase was 10-20 min
fter application. No increase was observed for the amount of bile acids and alkaline substances [K ISTLER
988].
II.3.1.1.2 Assessor’s overall conclusions on pharmacodynamics
Ethanolic preparations from A. absinthium are able to stimulate gastric, intestinal and biliary secretion
probably due to the content of bitter substances and essential oil. The essential oil acts antispasmodic in
small amounts. In high dosages or after longer-lasting intake the essential oil acts as a convulsant poison.
Earlier hypotheses claimed that bitter tasting substances evoke secretory reflexes of the gastrointestinal
tract via taste receptors in the lingual epithelium. The current notion is that
expressed in the gastrointestinal mucosa. It is postulated that activation of bitter taste receptors generate
integrated responses as secretion, motility or absorption [S TERNINI 2007].
In the studies of Jagusch 1988 and Ki
hundred times below the dosage described for medicinal use. This might explain why the observed
moderate effects were not significant.
The long-standing use of aqueous and ethanolic preparations of Absinthii herba , pharmacological studies
and current findings o
o
g
additionally taste receptors are
stler 1988 a dosage (0.02 g herbal substance) was used which is a
f physiological properties justify the use of Absinthii herba for the treatment of loss
f appetite and for the symptomatic treatment of dyspepsia and mild spasmodic disorders of the
astrointestinal tract.
II.3.1.2
Pharmacokinetics
I
I.3.1.2.1 Overview of available data regarding the herbal substance(s)/herbal preparation(s)
including data on constituents with known therapeutic activity.
Within a drinking test two subjects (65 kg body weight) consumed 110 ml absinth with 3.85 mg thujone
(content of absinth 35 mg/l) within 15 min. Blood samples were drawn 15, 30, 60, 90, and 120 m
drinking. The determination of the blood alcohol level was applied via head-space GC and the blood
thujone content was determined via head-space solid-phase micro-extraction (HS-SPME) method.
Blood alcohol concentrations >1 g/l were determined, whereas thujone could not be detected in blood
samples (detection limit 0.34 ng/ml). Conjugates
s
d
in after
of thujone were not determined. The two subjects
howed typical signs of alcoholisation (e.g. staggering, chattiness) while hallucinogenic effects were not
escribed by the two subjects [Kröner et al. 2005].
II.3.1.2.2 Assessor’s overall conclusions on pharmacokinetics
According to the study by Kroener at al. (2005) in both subjects no free thujone could be detected in the
blood samples. First measurements were taken 15 and 30 min after beginning of the drinking. It was not
clear if other time frames could have shown other results. It remains unclear whether the measurement of
unmetabolized thujone in blood is possible at all,
effect in humans. Because of the lipophilic properties of thujone i
th
because no data are known with regard to the first-pass
t is doubtful that noteworthy amounts of
ujone can be detected in human blood samples.
Due to lack of comprehensive data no conclusions can be drawn.
EMEA 2009
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a
1
 
II.3.2
Clinical Efficacy 6
II.3.2.1
Dose response studies
II.3.2.2
Clinical studies (case studies and clinical trials)
In a multi-centre, randomized, double-blind trial 40 patients suffering from Crohn’s disease receiving a
stable dose of steroids at an equivalent of 40 mg or less of prednisone for at least 3 weeks were
administered a product containing A. absinthium (3 x 500 mg/day) or a placebo for 10 weeks. Steroids, 5-
aminosaliciyates (if dose remained constant for at least 4 weeks prior to entering the trial) and/or
azathioprine (stable dose for at least 8 weeks) or methotrexate (stable for at least 6 weeks) were permitted
as concomitant medications. The recruited patients were evaluated with the help of a Crohn’s Disease
Activity Index (CDAI) questionnaire, an Inflammatory Bowel Disease Questionnaire (IBDQ), the 21-item
Hamilton Depression Scale (HAMD) and an 8-item Visual Analogue Scale (VA-Scale) in 2-week
intervals during the first 10 study weeks, and then at week 12, 16 and 20, which were the medication free
observation periods. The initial stable dose of steroids was maintained until week 2, after that a defined
tapering schedule was started so that at the start of week 10 all the patients were free of steroids. At the
end of week 10 the trial medication was also discontinued. The concomitant medications were maintained
at the same dose levels till the end of the observation period that was the end of week 20.
The capsules contained powdered A. absinthium herb and powdered rose-petals, cardamom seeds and
mastic resin while the placebo contained only powdered rose-petals, cardamom seeds and mastic resin.
The powdered A. absinthium used for the product contained 0.2-0.38% absinthin and 0.25-1.52% essential
oil, depending upon the batch.
The patients were 21-75 years old and suffered from Crohn’s Disease 2.7-14.2 years (Crohn’s Disease
verified by coloscopy and histology). The median CDAI was 240-321 in the A. absinthium group and 238-
317 in the placebo group, while median IBDQ was 110-152 in the A. absinthium group and 123-147 in the
placebo group. Patients with serious pathological findings in ECG, liver, kidney and heart functions, or
coexisting organic diseases such as history of cancer, asthma or other autoimmune disease requiring
steroid treatments, were excluded from the trial.
Response to treatment was defined as a decrease in the CDAI score of at least 70 points from the
qualifying score, or a decrease in 30% of CDAI score from the baseline score. For the HAMD total score,
the primary outcome measure was the absolute decrease of the Hamilton total depression score between
baseline and the following treatment weeks. Response was defined as a decrease in total score of >50%
from baseline and remission as a score <10 points.
After week 2 in the placebo group 16 patients (80%) showed CD exacerbation due to reduction in steroid
dose, whereas there were only two (10%) such patients in the group receiving A. absinthium . The
exacerbation of CD symptoms necessitated the re-start of steroids in 11 patients in the placebo and 2 from
the A. absinthium group.
At week 10 13 patients (65%) of the verum group were almost free of CD symptoms and there was no
need to restart the steroid treatment in the follow-up weeks. Five patients from this group tolerated the
reduction of the steroids. Their CDAI scores remained almost unchanged during the first 10 weeks, but
they gradually improved in the following 10 weeks.
Nine patients of the placebo group tolerated the reduction of the steroids (unchanged CDAI score). After
6 weeks the number of patients who showed clinical improvement were significantly higher in the verum
group as compared to the placebo group. This significant difference continued beyond week 10.
There was almost no change in the subjective feelings of illness in self-assessment (VA-scale) of the
patients in the placebo group, whereas in the A. absinthium group the self-assessment evaluation of the
patients indicated significant improvement. HAMD total scores, decreased by an average of 9.8 (SD 5.8)
points for the verum group and by 3.4 (SD 6.6) points for the placebo group. At the end of the acute
6 In case of traditional use the long-standing use and experience should be assessed.
EMEA 2009
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treatment phase (week 10) 70% of the patients of the A. absinthium group and none in the placebo group
showed remission of depressive symptoms. The authors assumed that the efficacy might be due to the
anti-DNA virus properties, but also an immune system modulation caused by
A. absinthium was considered. However, only one subgroup showed response to A. absinthium . It was
striking that A. absinthium had also significant effects on the quality of life and mood [Omer et al. 2007].
Tahir et al. tested A. absinthium (powdered) in 20 patients against amoebiasis. All patients had symptoms
and signs of amoebiasis i.e., abdominal pain and tenderness, loose motion mucous in stool often mixed
with blood and tenesmus and Entamoeba histolytica
suffering from other gastrointestinal, cardiovascular, respiratory, endocrinal, nervous system and sexually
transmitted diseases were excluded from the study.
The powdered herbal substance was administered in the form of a capsule (500 mg). Three capsules every
six hours were given to the patients for a period of fifteen days. The efficacy was assessed weekly in te
of improvement, in termination of the symptoms and signs of disease without the aid of any
the management of this condition. The patients were between 14-65 years old (16 males, 4 females).
After treatment with 6 g A. absinthium /day for 15 days the following results were achieved:
All the patients had abdominal pain and loose motions at the beginning of the treatment. Regarding
abdominal pain the relief in symptoms was recorded as complete in 13 patients and partial in 6 patients,
while the relief in loose motions was noted in 14 (total) and 4 (partly) patients. Seventeen patients had
abdominal tenderness before treatment and relief was noted in 11 (total) and 4 (partly) patients. Blood
stained stool was present in 7 patients before treatment and relief was seen in 6 patients (total), while
mucous stained stool was present in 10 patients before treatment and relief was seen in 8 (total) and 1
(partly) patients. Blood with mucous stained stool was present in 3 patients and in 2 patients a total relief
was achieved. Tenesmus was seen in 13 patients at the beginning and a relief was recorded for 8 (total)
and 2 (partly) patients). The average re
15.34% of the cases showed negligible or no relief. This reflects the fact that amoeba in stool disappeared
in 70% of cases after 15 days treatment.
The autho
p
a
was diagnosed in stool under the microscope. Patients
rms
other drug for
lief in all symptoms was noted in 84.66% of the cases, while
rs report that the amoebicidal, anti-spasmodic, anti-inflammatory, analgesic and astringent
roperties of A. absinthium described in literature might be responsible for the effects observed [T AHIR et
l. 1997].
II.3.2.3
Clin
ical studies in special populations (e.g. elderly and children)
None reported.
II.3.2.4
Traditional use
Artemisia absinthium has a long-standing traditional use for various indications.
Already the Egyptians used A. absinthium (or a closely related species) as an antiseptic, a stimulant and
tonic, and as a remedy for fevers and menstrual pains (Ebers Papyrus). Hippocrates recommended
Absinthii herba as a cure for jaundice. Pliny’s “Historica Naturalis” describes the extract of Absinthii
herba as having a long-standing benefit against gastro-intestinal worms and in Dioscorides’ “De Materia
Medica” it was also fully described. In the Middle Ages, the plant was used to exterminate tapeworm
infestations while leaving the human host uninjured. Paracelsus considered it as a stomachic,
anthelminthic herb which also acts as prophylaxis against sea-sickness. A. absinthium has been known to
aid digestion,
Bingen highlight the treatment of gastro-intestinal complaints with it [M ADAUS 1976, A RNOLD 1989,
H OSE 2002].
During the last decades A. absinthium is used as “amarum aromaticum” to promote the appetite in cases of
gastritis, hypoacidity, and dyspepsia. The plant is also described as a choleretic [BHP 83, H AGER ROM
2006, M ARTINDALE 1989]. An ethnopharmacobotanical study (1977-2000) confirmed that A. absinthium
is used in Central Italy for the treatment of lack of appetite [G UARRERA 2005]. A survey among Hakims
and as an effective treatment for upset stomach. Dioscorides, Galen and Hildegard von
EMEA 2009
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in Pakistan showed that A. absinthium is used against liver diseases, hepatitis, blood purification, jaundice,
diabetes, skin diseases, allergy, scabies, tetanus and as brain tonic [Q URESHI et al. 2002]. In Russia,
Lithuania, Poland and America Absinthii herba was used in folk medicine against dyspeptic complaints
[M ADAUS 1976].
The dried comminuted herbal substance has been described in Pharmacopoeias and Pharmacognosy
handbooks for decades, while the tincture was described in various German Pharmacopoeias [G ERMAN
P HARMACOPOEIA 1872, AB-DDR 1975] and handbooks [DAC 2
H AGER R OM 2006, M ADAUS 1976, S CHULZ & H ÄNSEL
e
The use for more than 30 years could be proven for
- comminuted herbal sub
substance daily) for the treatment of dyspeptic complaints such as minor gastrointestinal spasms,
repletion and flatulence
- comminuted herbal substance for tea preparation 2-3 times daily 1 g (2-3 g herbal substance daily)
for the treatment of loss of appetite, dyspeptic com
repletion and flatulence and functional disorders of the biliary tract (as appetizer 30 min before
meals, all other indications 1 cup of tea after meals)
- expressed juice (1:0.5-0.9) 2 times daily 5 ml for the treatment of loss of appetite, dyspeptic
complaints such as minor gastrointestinal spasms, repletion and flatulence
- tincture (1:5); extraction solvent ethanol 70% (v/v) 3 times daily, each s
stance in tablets 3 times daily 760 mg herbal substance (2.28 g herbal
plaints such as minor gastrointestinal spasms,
ingle dosage equivalent to
1 g herbal substance to improve appetite and stimulate a digestion in cases of hypoacidity and
chronic gastritis [S CHULZE & H ÄNSEL 2004; S CHMID & S CHULTZ 1979].
II.3.2.5
Assessor’s overall conclusions on clinical efficacy
Although A. absinthium has been used to treat loss of appetite, indigestion, biliary disorders, and other
gastrointestinal problem
antiparasitic and anthelmintic agent, there are no published studies evaluating the efficacy for these
indications in humans.
The pharmacodynamic properties (clinical data) support the use of A. absinthium for the treatment of loss
of appetite and for the symptomatic treatment of dyspepsia and mild spasmodic disorders of the
gastrointestinal tract. This is also confirmed by results of another typical bitter drug ( Gentiana lutea ).
G. lutea was tested as a dry extract in isolated rat stomach cells and in a multicentre uncontrolled study
(205 patients). A concentration dependent rise in gastric acid production was observed in rat cells, while
in patients a rapid and dramatic relief of symptoms (constipation, flatulence, appetite loss, vomiting,
heartburn, abdominal pain, nausea) was achieved [G EBHARD
explain why bitters, also when encapsulated, show therapeutic effects; suggesting that the reflex effect via
lingual taste receptors is not the only mechanism of action.
Based on the pharmacological and clinical data and the long-standing use
3
herbal substances/herbal preparations with similar effects after discussion in the M
s, clinical data supporting these uses are lacking. Also for the described use as an
T 1997, W EGENER 1998]. Such findings could
for more than
0 years the following indications are plausible. The wording of the indications was adjusted to other
LWP:
a) Traditional herbal medicinal product used in temporary loss of appetite
b) Traditional herbal medicinal product used for mild dyspeptic/gastrointestinal disorders
According to the discussion concerning the safety of preparations of A. absinthium wit
f thujone, following preparations and rela
comminuted herbal substance for
expressed juice (1:0.5-0.9): 10 ml daily
to be taken 30 min before meals
h respect to their
content o
tea preparation: 2-3 g herbal substance daily
EMEA 2009
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007, H AFFNER & S CHULTZ 1979,
2004; T EUSCHER 1989]. Authorized products with
xpressed juice of A. absinthium are currently on the German market.
a)
ted posologies were agreed on:
 
b)
comminuted herbal substance in tablets:
comminuted herbal substance for tea preparation: 2-3 g herbal substance daily
expressed juice (1:0.5-0
tincture
to be taken after meals
2.28 g herbal substance daily
.9): 10 ml daily
(1:5); extraction solvent: ethanol 70% (v/v): approx. 2-3 g herbal substance daily
The intake of thujone should not exceed 3.0 mg/day and the duration of intake is restricted to a maximum
of 2 weeks. Chemotypes of A. absinthium with low content of thujone should be preferred.
The published study on the possible reduction in steroid dosages in Crohn’s disease after A. absinthium
intake is well conducted. However, well-established use is defined as well-documented use for a time
frame of minimum 10 years, which is not fulfilled.
b
indication for Absinthii herba can not be supported.
Furthermore the study of Tahir et al. does not fulfill,
esides other deficiencies, the requirements of a well-established use. Therefore a well-established use
II.3.3
Clinical Safety/Ph
armacovigilance
II.3.3.1
Patient exposure
II.3.3.2
Adverse events
A 61 year-old woman was treated with a herbal medicinal product containing 5 plant extracts, including
one preparation from A. absinthium . Some of the other plants of the combination product belong also to
the Asteraceae (Compositae) familiy. After the intake, she complained of soreness and burning of the oral
mucosa and tongue. Slight erythema could be seen in the oral cavity and on the tongue. Blood cou
differential were normal. Patch test with the plant extracts of the herbal medicinal product showed positive
reactions to the extract of A. absinthium as well as to all the other extracts [B AYERL & J UNG 1996].
Undesirable effects for aqueous pr
is
c
nt and
eparations from the herbal substance are not reported. In the literature it
described, that contact with the flowers can provoke a scarlatina-like redness of the skin in very rare
ases [H AUSEN & V IELUF 1997].
II.3.3.3
Serious adverse events and deaths
A 31 year-old man drank 10 ml of the essential oil incidentally. He was found in an agitated, incoherent
and disoriented state. Later on tonic and clonic seizures with decorticate posturing were observed. On the
second day the patient developed moderately intense, bilateral soreness of the leg muscles, followed by
congestive heart failure. Among other changes he developed hyper-natriaemia, hypo
b
a
II.3.3.4 Labor
No data available.
atory findings
II.3.3.5
Safety in special populations and situations
Dettling et al. [2004] investigated if the impact of thujone (absinthe) on attention performance and mood
differs from the one experienced with beverages that contain only alcohol. 22 healthy subjects were tested
using an attention performance test, which was developed for aptitude diagnostics in the area of
EMEA 2009
Page 23/26
kalaemia and hypo-
icarbonataemia. By day 17 (after treatment which included diuretics and sodium restriction) biochemical
bnormalities and blood chemistry had returned to normal [W EISBORD ET AL . 1997].
 
 
 
 
 
 
performance and which is applied in the diagnostics of alcohol and drug-induced effects on visual
orientation performance. Mood was assessed using two questionnaires that test different mood
dimensions: one (Masel Mood test) records the factors vitality, intra-psychic equilibrium, social
extraversion and attentiveness, the other one (general activation –high activation state scale) records state
anxiety and current subjective activation.
The calculated total amount of thujone consumed was 0.28 mg/kg and 0.028 mg/kg for men and
0.24 mg/kg and 0.024 mg/kg for women. The alcohol content was adjusted to 16 g/l in all beverages. The
amount of liquid to be consumed depended on the weight of the subject. It was tried to attain a maximum
blood alcohol concentration of 0.05% (= 0.5‰) for each su
small standard meal; the beverage had to be drunk then within 10 min. All tests were performed before
drinking (T0) and 30 (T1) and 90 min (T2) after drinking.
The results between T0-T1 and T0-T2 revealed no significant alterations in attention performance after the
consumption of alcohol and low thujone concentration. When the subjects were under the influence of the
high thujone concentration, the number of correct reactions in the peripheral field of attention decreased
significantly and the reaction time in both the peripheral and central fields of attention increased
significantly between T0-T1. Furthermore the number of “false alarm” reactions also increased.
The changes in performance after 90 min (T2) revealed results that show a pattern similar to the results
after 30 min but less pronounced (not significant). No significant differences in attention performance
between the three treatments could be found either from T0-T1 or from T0-T2 (ANOVA
t-test). It was assumed that the effects of the high thujone condition are quantitative but not qualitative.
One possible explanation was the theory that the effects of alcohol on attention processing may be an
inverted
attention performance, at low thujone concentrations was explained by alcohol antagonizing the effect of
thujone.
While within the treatment groups the mood state changed either from T0-T1 or from T0-T2, no
significant differences (Friedman rank variance analyses) in the alteration of the tested mood dimensions
could be found when comparing the treatment groups with each other. The most prominent difference was
observed for the parameter “state anxiety”. High thujone concentrations led to a decrease in state anxiety
at T2. This effect was explained with the interaction of thujone with the GABA-receptor. T
e
ro
bject. Before drinking every subject received a
U-shaped function with thujone shifting the dose-effect to the left. The missing alteration in
he antagonistic
ffect of thujone on the GABA-receptor lead to an increase in fear sensations and also a stimulating and
using effect, while ethanol acts as a GABA-enhancer (anxiolytic, sedative and amnesic).
II.3.3.5.1 Intrinsic (including elderly and children) /extrinsic factors
o data available. Use in children and adolescents under 18 years of age is not recommended because data
re not sufficient and medical advice should be sought.
II.3.3.5.2 Drug i
nteractions
No data available.
The action of thujone is explained in the literature by its bin
A
GABA receptor, even if such effects were not s
ding to the GABA receptor. The intake of
bsinthii herba preparations might therefore influence the effect of medicinal products acting via the
een clinically.
II.3.3.5.3 Use in pregnancy and lactation
No data available. Most sources recommend contraindication in pregnancy and lactation due to the uterus
stimulating effects of thujone.
EMEA 2009
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N
a
Tests on reproductive toxicity have only been performed with a dry ethanolic extract of A. absinthium
orally administered to pregnant rats. Results showed significantly reduced sites of implantations and a
reduction in the numbers of born pups per rat.
Safety during pregnancy and lactation has not been established. Because of the amounts of thujone in the
preparations covered by the assessment report, the proposed contraindication was changed into the
sentence “The use should be avoided during pregnancy and lactation.” after discussion in MLWP and
HMPC.
II.3.3.5.4 Overdose
Limited data are available for Absinthii herba. After intake of a concentrated infusion of Absinthii herba a
male developed dizziness, atony, tremor of the legs, lasting uresiaesthesia and burning in the glans penis
[L EWIN 1929] and it is stated that excessive doses of Absinthii herba preparations may cause vomiting,
severe diarrhea, retention of urine or dazed feelings [R OTH ET AL . 1994]. On the other hand it is stated that
after excessive or long lasting intake of Absinthii herba preparations aversions against the intake may
develop. Therefore, acute or chronic intoxications due to Absinthii herba preparations are not suspected
[H ÄNSEL & S TICHER 2007].
Overdosage of alcoholic Absinthii herba preparations or the use of the essential oil may cause CNS
disturbances which can lead to convulsions and ultimately to unconsciousness and death [G ESSNER 1974;
R OTH ET AL . 1994].
Cases with severe intoxications in humans have been reported after consumption of essential oil rich in
thujone [C ENTINI & L AURINI 1987, M ILETT ET AL . 1981]. Convulsions resembling epilepsy have been
reported after the ingestion of isolated thujone [C OBB 1922].
There are no cases of overdose reported concerning herbal tea preparations.
II.3.3.5.5 Drug abuse
No data available.
II.3.3.5.6 Withdrawal and rebound
No data available.
II.3.3.5.7 Effects on ability to drive or operate machinery or impairment of mental ability
No data available.
Attention performance [D ETTLING ET AL . 2004] was changed under the influence of high thujone
concentrations. For safety reasons affected patients should not drive or operate machinery after intake of
Absinthii herba preparations.
II.3.3.6
Assessor’s overall conclusions on clinical safety
Limited data are available. From the study of Dettling et al. [2004] it can be assumed that at least a
concentration of 0.24-0.28 mg thujone/kg might lead to changes in attention performances and mood
conditions (even if not significant). For a 60 kg adult this corresponds to a single dose of 14.4-16.8 mg
thujone per person. For the concentration of 1.44-1.68 mg per person an effect was postulated but not
proven.
EMEA 2009
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The use in children and adolescents is not recommended. The use of Absinthii herba during pregnancy or
lactation should be avoided. Absinthii herba should not be used in cases of obstruction of the bile duct,
cholangitis, or liver disease. Medical advice is needed in cases of gall stones or other biliary disorders.
The intake of Absinthii herba preparations might influence the effect of medicinal products acting via the
GABA receptor. After intake of preparations from Absinthii herba, patients should not drive or operate
machinery for safety reasons. Duration of use should be limited to a maximum of 2 weeks.
II.4
A SSESSOR S O VERALL C ONCLUSIONS
Absinthii herba is well known and derived traditional herbal medicinal products have been used for
centuries in European countries. Sufficient data are available to develop a Community monograph on the
traditional use of Artemisia absinthium L., herba - provided the indications are suitable for self-
medication. The proposed indications are:
a) Traditional herbal medicinal product use in temporary loss of appetite
b) Traditional herbal medicinal product used for mild dyspeptic/gastrointestinal disorders
The pharmacological studies in vitro and in vivo showed stimulating effects on the gastric, intestinal and
biliary secretion.
The intake of thujone should not exceed 3.0 mg/day and the duration of use should be limited to 2 weeks.
Chemotypes of A. absinthium with low content of thujone should be preferred.
Use of Absinthii herba should be avoided during pregnancy and lactation and Absinthii herba should not
be taken in children and adolescent under 18 years of age and in patients with obstruction of the bile duct,
cholangitis or liver disease. The intake of Absinthii herba preparations might influence the effect of
medicinal products acting via the GABA receptor. For safety reasons, patients should not drive or operate
machinery after intake of preparations from Absinthii herba.
Because the minimum required data on mutagenicity (Ames test) are not available for herbal preparations
of Absinthii herba, an inclusion to the Community list of traditional herbal substances and preparations is
not recommended.
III.
ANNEXES
III.1
C OMMUNITY H ERBAL M ONOGRAPH ON ARTEMISIA ABSINTHIUM L ., HERBA
III.2
L ITERATURE R EFERENCES
EMEA 2009
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