COMMUNITY HERBAL MONOGRAPH ON
SALVIA OFFICINALIS
L., FOLIUM
To be specified for the individual finished product.
Well-established use
Traditional use
With regard to the registration application of
Article 16d(1) of Directive 2001/83/EC as
amended
Salvia officinalis
L., folium; Salviae officinalis
folium (sage leaf)
i)
Herbal substance
Not applicable
ii)
Herbal preparations
Comminuted herbal substance
Liquid extract (1:1), extraction solvent ethanol
70% V/V
Dry extract (4-7:1), extraction solvent: water
Liquid extract (1:3.5-5), extraction solvent:
ethanol 31.5% V/V
Liquid extract (1:4-5) extraction solvent:
ethanol 50% V/V
Liquid extract (1:7.2), extraction solvent:
liquor wine : ethanol 96% V/V
(38.25:61.75 m/m)
Tincture (1:10), extraction solvent: ethanol
70% V/V
1
The material complies with the Eur. Ph. monograph (ref.: 01/2008:1370).
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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Well-established use
Traditional use
Comminuted herbal substance as herbal tea for
oral use.
Comminuted herbal substance (for preparation of
an infusion) for oromucosal and cutaneous use.
Herbal preparations in solid or liquid dosage
forms for oral use.
Liquid or semi-solid preparations for oromucosal
use.
The pharmaceutical form should be described by
the European Pharmacopoeia full standard term.
4.1.
Therapeutic indications
Well-established use
Traditional use
a)
Traditional herbal medicinal product for
symptomatic treatment of mild dyspeptic,
complaints such as heartburn and bloating.
b)
Traditional herbal medicinal product for relief
of excessive sweating.
c)
Traditional herbal medicinal product for the
symptomatic treatment of inflammations in
the mouth or the throat.
d)
Traditional herbal medicinal product for relief
of minor skin inflammations.
The product is a traditional herbal medicinal
product for use in specified indications
exclusively based upon long-standing use.
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4.2.
Posology and method of administration
Well-established use
Traditional use
Posology
Adults, elderly
Indication a)
Comminuted herbal substance for tea preparation:
1-2 g herbal substance in boiling water three
times daily .
Dry extract: 320 mg divided in 3-4 doses.
Liquid extract (1:7.2): 20 drops three times daily.
Liquid extract (1:3.5-5): 10 drops three times
daily in some liquid.
Tincture: ethanol 70% V/V 2-3 ml three times
daily.
Indication b)
Comminuted herbal substance for tea preparation:
2 g herbal substance in 160 ml boiling water.
Liquid extract (1:3.5-5): 10-20 drops dissolved in
liquid three times daily, for night sweat
1 hour directly before bedtime: 30 drops in liquid.
Liquid extract (1:4-5): 50 drops (=2 ml)
three times daily.
Indication c)
Comminuted herbal substance as an infusion:
2.5 g herbal substance in 100 ml boiling water.
The infusion is used for gargle.
Gel 20% liquid extract (1:1), 250 mg of gel up to
5 times daily on affected regions and massage
gently.
Liquid extract (1:3.5-5): 15 drops three times
daily in warm water for gargle.
Liquid extract (1:7.2): 3 spoons (15 ml) in a glass
of water, rinse or gargle.
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Tincture: 1-2 spoons (5-10 ml) in a glass of water,
rinse or gargle, undiluted tincture is applied
locally on the affected regions.
Indication d)
Comminuted herbal substance as an infusion:
2.5 g herbal substance in 100 ml boiling water
2-4 times daily. The infusion is applied
cutaneously.
Indications a), b) and c)
The intake of thujone should not exceed
5.0 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
Indications a) and b)
Oral use.
Sage preparations should not be taken for more
than 2 weeks.
Indication c)
Oromucosal use.
Sage preparations should not be taken for more
than 1 week.
Indication d)
Cutaneous use.
The average duration of use is 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.
Oromucosal use.
Cutaneous use.
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4.3.
Contraindications
Well-established use
Traditional use
Hypersensitivity to the active substance(s).
4.4.
Special warnings and precautions for use
Well-established use
Traditional use
The use in children and adolescents under
18 years of age is not recommended because data
are not sufficient and medical advice should be
sought.
For extracts 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.
4.5.
Interactions with other medicinal products and other forms of interaction
Well-established use
Traditional use
None reported.
The intake of Salviae folium preparations might
influence the effect of medicinal products acting
via GABA receptor (e.g. barbiturates,
benzodiazepines), even if not seen clinically.
Therefore the concomitant use with such
medicinal products is not recommended.
4.6.
Pregnancy and lactation
Well-established use
Traditional use
Safety during pregnancy and lactation has not
been established.
In the absence of sufficient data, the use during
pregnancy and lactation is not recommended.
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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.
Well-established use
Traditional use
Overdose has been reported with a sense of heat,
tachycardia, vertigo and epileptic form
convulsions (seizures) after intake corresponding
to more than 15 g of sage leaves.
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.
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.
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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.
A daily intake of 5.0 mg/person is acceptable for
a maximum duration of use of 2 weeks.
Tests on reproductive toxicity genotoxicity and
carcinogenicity have not been performed with
preparations of Salviae officinalis folium covered
by this monograph.
Well-established use
Traditional use
Not applicable.
12 November 2009
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Assessment Report
TABLE OF CONTENTS
I.
II.
ASSESSMENT REPORT................................................................................................................. 4
II.1 I
NTRODUCTION
............................................................................................................................... 5
II.1.1
Description of the herbal substance(s), herbal preparation(s) or combinations thereof ........ 5
II.1.2
Specified products on the market in the European Member States ......................................... 7
II.1.3
Search and assessment methodology....................................................................................... 8
II.2 H
ISTORICAL DATA ON MEDICINAL USE
.......................................................................................... 9
II.2.1
Information on period of medicinal use in the Community ..................................................... 9
II.2.2
Information on traditional/current indications and specified substances/preparations ......... 9
II.2.3
Specified strength/posology/route of administration/duration of use for relevant preparations
and indications ...................................................................................................................................... 9
HERBAL PREPARATION
(
S
)
AND RELEVANT CONSTITUENTS THEREOF
.......................................... 12
II.3.1
Composition........................................................................................................................... 12
II.3.2
Non-clinical pharmacology ................................................................................................... 15
preparation(s) and relevant constituents thereof ................................................................................ 19
preparation(s) and constituents thereof .............................................................................................. 20
II.3.5
Overall conclusions on non-clinical data.............................................................................. 23
II.4 C
LINICAL
D
ATA
........................................................................................................................... 24
II.4.1
Clinical Pharmacology .......................................................................................................... 24
II.4.2
Clinical Efficacy .................................................................................................................... 28
II.4.3
Overall conclusions on clinical pharmacology and efficacy ................................................. 32
II.5 C
LINICAL
S
AFETY
/P
HARMACOVIGILANCE
................................................................................... 32
II.5.1
Overview of toxicological/safety data from clinical trials in humans ................................... 32
II.5.2
Patient exposure .................................................................................................................... 32
II.5.3
Adverse events and serious adverse events and deaths ......................................................... 33
II.5.4
Laboratory findings ............................................................................................................... 33
II.5.5
Safety in special populations and situations.......................................................................... 33
II.5.6
Overall conclusions on clinical safety ................................................................................... 37
II.6 O
VERALL
C
ONCLUSIONS
.............................................................................................................. 38
III.
ANNEXES........................................................................................................................................ 39
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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
Austria
MA
TRAD
Other TRAD
Other Specify:
Belgium
MA
TRAD
Other TRAD
Other Specify:
Only combinations
Bulgaria
MA
TRAD
Other TRAD
Other Specify:
Only combinations
Cyprus
MA
TRAD
Other TRAD
Other Specify:
No reply
Czech Republic
MA
TRAD
Other TRAD
Other Specify:
Denmark
MA
TRAD
Other TRAD
Other Specify:
Estonia
MA
TRAD
Other TRAD
Other Specify:
Finland
MA
TRAD
Other TRAD
Other Specify:
No MA
France
MA
TRAD
Other TRAD
Other Specify:
No reply
Germany
MA
TRAD
Other TRAD
Other Specify:
Greece
MA
TRAD
Other TRAD
Other Specify:
No reply
Hungary
MA
TRAD
Other TRAD
Other Specify:
Iceland
MA
TRAD
Other TRAD
Other Specify:
No MA
Ireland
MA
TRAD
Other TRAD
Other Specify:
No reply
Italy
MA
TRAD
Other TRAD
Other Specify: Only combination
Latvia
MA
TRAD
Other TRAD
Other Specify:
Only combinations
Liechtenstein
MA
TRAD
Other TRAD
Other Specify:
No reply
Lithuania
MA
TRAD
Other TRAD
Other Specify:
No reply
Luxemburg
MA
TRAD
Other TRAD
Other Specify:
No MA
Malta
MA
TRAD
Other TRAD
Other Specify: No MA
The Netherlands
MA
TRAD
Other TRAD
Other Specify:
No MA
Norway
MA
TRAD
Other TRAD
Other Specify:
Poland
MA
TRAD
Other TRAD
Other Specify:
Portugal
MA
TRAD
Other TRAD
Other Specify:
No MA
Romania
MA
TRAD
Other TRAD
Other Specify:
Slovak Republic
MA
TRAD
Other TRAD
Other Specify:
No MA
Slovenia
MA
TRAD
Other TRAD
Other Specify:
Spain
MA
TRAD
Other TRAD
Other Specify:
Only combinations
Sweden
MA
TRAD
Other TRAD
Other Specify:
Only combination
United Kingdom
MA
TRAD
Other TRAD
Other Specify: Only combinations
1
This regulatory overview is not legally binding and does not necessarily reflect the legal status of the products in
the MSs concerned.
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II.
ASSESSMENT REPORT
SALVIA OFFICINALIS
L., FOLIUM
and
SALVIA OFFICINALIS
L., AETHEROLEUM
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)
Salvia officinalis
L., folium ;
[
Salvia officinalis
L., aetheroleum]
Herbal preparation(s)
Comminuted herbal substance.
Liquid extract (1:1), ethanol 70% V/V
Dry extract (4-7:1), extraction solvent: water
Liquid extract (1:3.5-5), extraction solvent:
ethanol 31.5% V/V
Liquid extract (1:4-5) extraction solvent: ethanol
50% V/V
Liquid extract (1:7.2), extraction solvent: liquor
wine : ethanol 96% V/V (38.25 : 61.75 m/m)
Tincture (1:10) extraction solvent: ethanol
70% V/V
Pharmaceutical forms
Herbal substance as herbal tea for oral and topical
use.
Herbal preparations in liquid or solid dosage
forms for oral use.
Liquid or semi-solid preparations for oromucosal
use.
Rapporteur
Gro Anita Fossum
Assessors
Karl Egil Malterud
Anne-Cecilie Østensvig
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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):
Sage leaf consists of the whole or cut dried leaves of
Salvia officinalis
L. It contains not less than 15 ml/kg
of essential oil for the whole drug and minimum 10 ml/kg of essential oil for the cut drug, both calculated
with reference to the anhydrous drug. Sage leaf oil is rich in thujone (Ph. Eur., 2008).
Sage tincture produced from 1 part of comminuted sage leaf and 10 parts of ethanol (70% V/V) is a
separate monograph in the European Pharmacopoeia. The tincture produced from sage leaf should contain
minimum 0.1% m/m essential oil. The European Pharmacopoeia also has a monograph on three-lobed
sage leaf from
Salvia fructicosa
Mill (Ph. Eur., 2008).
The essential oil has a very variable composition depending on the source, time of harvesting and other
factors (Bradley, 2006). Principal components of the essential oil, in addition to thujone, are cineol and
camphor. In addition, the leaves contain tannins, diterpene bitter principles, triterpenes, steroids, flavones,
and flavonoid glycosides (Blumenthal et al., 2000).
Herbal preparation(s):
Comminuted herbal substance.
Liquid extract (1:1), ethanol 70% V/V
Dry extract (4-7:1), extraction solvent: water
Liquid extract (1:3.5-5), extraction solvent: ethanol 31.5% V/V
Liquid extract (1:4-5) extraction solvent: ethanol 50% V/V
Liquid extract (1:7.2), extraction solvent: liquor wine : ethanol 96% V/V (38.25 : 61.75 m/m)
Tincture (1:10), extraction solvent: ethanol 70% V/V
Combinations of herbal substance(s) and/or herbal preparation(s)
Salvia officinalis
L. is used in
combinations with many other herbal substances/herbal preparations. Combination products in member
states consists of
Salvia officinalis
L. in combination with:
Bellidis flos Foeniculi fructus
Cardui mariae herba
Melissae folium
Herba Viola arvensis Thymi herba
Carvi fructus
Coriandri fructus
Fructus juniperi Menthae piperitae
folium
Berberidis radix
Alchemillae acutifoliae
herba
Folium juglandis
Chelidonii herba
Millefolii herba
Hyperici herba
Betulae folium
Curcumae xanthorizae
rhizoma
Chamomillae
anthodium
Foeniculi fructus
Tiliae flos
Melissae herba
Graminis rhizoma
Salicis cortex
Sambuci flos
Urticae folium
Equseti herba
Urticae radix
Chamomillae flos
Agrimoniae herba
Rosmarini folium
Uvae ursi folium
Anisi fructus
Frangulae cortex
Millefolli herba
Taraxaci radix cum
herba
Cichorii radix
Cucurbitae semen
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This monograph refers exclusively to products containing only
Salvia officinalis
L..
Vitamin(s):
Not applicable
Mineral(s):
The contents of sodium, potassium, magnesium, calcium, iron, manganese, zinc and copper have been
determined in dry sage leaves, and the kinetics of extraction of these metals have been studied with cold
water, hot water, 0.05 M and 0.01 M citric acid solutions, 0.1 M ascorbic acid and 70% ethanol by Zimna
et al., (1984). The leaves have been found to be very rich in iron and magnesium especially. The total
contents of the eight elements were determined in a commercial specimen of sage leaves and in sage
leaves collected in the Garden of Medicinal Plants at the Medical Academy in Gdansk in Poland.
The results were :
Sodium (Na) 91 ppm
Potassium (K) 14.9 g/kg
Magnesium (Mg) 4.1 g/kg
Calcium (Ca) 10.1 g/kg
Iron (Fe) 885 ppm
Manganese (Mn) 52.7 ppm
Zink (Zn) 145 ppm
Copper (Cu) 6.9 ppm
(ppm = parts per million. 1 ppm = 0.0001%)
Zimna et al. (1984) also specified the quantities of the metals present in a decoction prepared under usual
conditions: a glass (= 250 ml) of hot water poured onto 10 g of dried leaves and set aside for
30 minutes. According to Zimna et al. (1984) the decoction contains about:
Sodium (Na) 1 mg
Potassium (K) 190 mg
Magnesium (Mg) 32 mg
Calcium (Ca) 57 mg
Iron (Fe) 0.05 mg
Manganese (Mn) 0.6 mg
Zink (Zn)
0.16 mg
Copper (Cu)
0.02 mg
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II.1.2
Specified products on the market in the European Member States
European Member State
Specified products on the market
Austria
1. Dry extract (4-7:1), extraction solvent: water, capsules
1 capsule contains 150 mg extract corresponding to 0.6 g
Leaves, min. 2.5% rosmarinic acid
2. Liquid extract 1:1, extraction solvent ethanol 70%
3. Herbal substance as herbal tea (oral use, oromucosal use)
4. Liquid extract, extraction solvent water, min 0.2% rosmarinic acid
Estonia
Herbal substance, as herbal tea (oral use)
Germany
1.
Dry extract (4-7:1), extraction solvent: water
(oral use, oromucosal use)
2.
Liquid extract (1:7.2),extraction solvent: liquor wine : ethanol 96%
V/V (38.25 : 61:75 m/m) (oral use, oromucosal use)
3.
Dry extract (4-7:1), extraction solvent: water (oral use)
4.
Liquid extract (1:3.5-5), extraction solvent: ethanol 31.5% V/V
5.
Liquid extract (1:1), extraction solvent: ethanol 70% V/V
(oromucosal gel)
6.
Liquid extract (1:4-5) extraction solvent: ethanol 50% V/V
7.
Herbal substance, cut
8.
Liquid extract (1:7.2), extraction solvent: liquor wine : ethanol 96%
V/V (38.25 : 61:75 m/m)
Hungary
1.
Liquid extract (1:1), extraction solvent: ethanol 20% (V/V) (cutanous
use)
2.
2) Liquid extract (1:1), ethanol
70% V/V , (oromucosal gel)
Latvia
1) Herbal substance (oromucosal use)
Norway
1)
Dry extract (4-7:1), extraction solvent: water (capsules)
1 capsule contains 150 mg extract corresponding to 0.6 g
leaves
Poland
1.
Herbal substance (oral use, oromucosal use, cutanous use)
2.
Liquid extract (1:1), extraction solvent: ethanol 70% V/V ,
(oromucosal use)
3.
Tinctura Salviae - (1:5), extraction solvent – ethanol 70% (v/v)
(oromucosal use)
4.
Salviae unguentum - Salviae folii extractum (cutaneous use)
Romania
1. Herbal substance (oral use, oromucosal use)
Slovenia
1. Dry extract (4.5-6.5:1), extraction solvent: water, lozenge
1.
Herbal substance (for tea preparation)
2.
Herbal substance (capsules)
3.
Tincture (1:10) extraction solvent: ethanol
55 % V/V
Sweden
1. Dry extract (4-7:1), extraction solvent: water, capsules
1 capsule contains 150 mg extract corresponding to 0.6 g leaves
Brand names have been deleted. This table is based on information provided by the National Competent
Authorities.
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Spain
II.1.3 Search and assessment methodology
Databases assessed (date, search terms) and other sources used
The following electronic databases were searched on 16
th
of June 2008 with the search term “
Salvia
officinalis
,
Salvia officinalis folium
OR Garden Sage OR Dalmatian Sage OR True Sage”.
Results:
PubMed
:
Salvia officinalis:
239 references
Salvia officinalis
folium
:
4 references (No case report of safety concern)
Garden Sage:
10 references (No case report of safety concern)
Dalmatian Sage:
3 references (One case report of safety concern)
True Sage:
25 references (No case report of safety concern)
Toxline
:
Salvia officinalis
: 101 references
Salvia officinalis
folium: 3 references (No case report of safety concern)
Garden Sage
: 7 references (No case report of safety concern)
Dalmatian Sage
: 10 references (One case report of safety concern )
True Sage
: 4 references (No case report of safety concern)
Scifinder
:
Salvia officinalis:
3430 references
Salvia officinalis
folium
:
37 references (No case report of safety concern when phrase
“toxicity” and “safety” were combined)
Garden Sage:
2045 references (Several case reports of safety concern -animal studies)
Dalmatian Sage:
78 references (No case report of safety concern when phrase “toxicity”
and “safety” were combined)
True Sage:
388 references (No case report of safety concern when phrase “toxicity”
and “safety” were combined)
Assessors comment: Since this database covers both chemical abstracts and Medline, some references may
be cited twice
The Cochrane Library
:
Salvia officinalis:
4 references
Salvia officinalis
folium
:
1 reference
Garden Sage:
0 references
Dalmatian Sage:
0 references
True Sage
: 5 references
This report is based on a scientific review of the scientific and traditional literature referring to
Salvia officinalis
L.
Available handbooks have been searched for relevant references and information. Bibliographic searches
have been done after the same procedure as described for the bibliographic review of safety data.
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II.2
H
ISTORICAL DATA ON MEDICINAL USE
II.2.1
Information on period of medicinal use in the Community
Salvia officinalis
L. is a perennial plant (subshrub), native to the Mediterranean region, especially in the
area of the Adriatic Sea and is cultivated to some extent in different European countries. The material of
commerce originates from south eastern European countries (Blumenthal et al., 2000).
Sage leaf was mentioned in the writings of Hippocrates, Paracelsus, Hildegard von Bingen, and Lonicerus,
Bock and Matthiolus (Madaus, 1938). Its cultivation in northern Europe dates back to medieval times, and
it was introduced to North America during the 17th century. Sage was used in ancient Egyptian, Greek
and Roman medicines. Ancient Egyptians used it as a fertility drug. The Greeks used it to stop bleeding of
wounds and to clean ulcers and sores, towards hoarseness and cough, enhancing memory functions, for
gargles to treat sore mouths and throats.
Its uses in traditional Greek medicine spread to India, where the dried leaf (Salbia-sefakuss in Hindi) and
fluid extract are used in traditional Indian Ayurvedic, Siddha, and Unani medicines (Blumenthal et al.,
2000).
Sage is well known for carminative, antispasmodic, antiseptic, astringent and antihidrotic properties.
Pharmacognostical handbooks describe that traditionally, sage has been used to treat flatulent dyspepsia,
pharyngitis, uvulitis, stomatitis, gingivitis, glossitis (internally or as a gargle/mouthwash), hyperhydrosis,
and galactorrhoea (Barnes et al., 2007). The herbals of Gerard, Culpeper and Hill credit sage with the
ability to enhance memory. The German Commission E approved the internal use of sage for dyspeptic
symptoms and excessive perspiration, and the external use for inflammation of mucous membranes of
mouth and throat.
II.2.2
Information on traditional/current indications and specified substances/preparations
II.2.3
Specified strength/posology/route of administration/duration of use for relevant
preparations and indications
The following herbal substances and herbal preparations have been on the European market for a period
of 30 years and are proposed for the monograph on traditional use:
a)
Comminuted herbal substance.
b)
Liquid extract (1:1), ethanol 70% V/V
c)
Dry extract (4-7:1), extraction solvent: water
d)
Liquid extract (1:3.5-5), extraction solvent: ethanol 31.5% V/V
e)
Liquid extract (1:4-5) extraction solvent: ethanol 50% V/V
f)
Liquid extract (1:7.2), extraction solvent: liquor wine : ethanol 96% V/V (38.25 : 61:75 m/m)
g)
Tincture (1:10), extraction solvent: ethanol 70% V/V
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Posology and indications for traditional herbal substance and preparations of
Salvia officinalis
L. folium
Herbal
substance/
Herbal
preparations
Indication
Posology
Single dose
Daily dose
On the market
a) Comminuted
herbal
substance
For
symptomatic
treatment of
mild dyspeptic
complaints
such as
heartburn and
bloating
For oral use as
a tea
preparation.
1-3 g
3 times daily
1-3 g
3-9 g
Since 1976 in
Germany,
reported as well-
established use
For oral use as
a tea
preparation
1-1.5 g
2-3 times daily
1 - 1.5 g
2-5 g
Since 1978 in
Spain, reported
as traditional use
For treatment
of minor skin
inflammations
For topical use
as an infusion
or decoction in
compresses:
2 spoons of
herbal
substance in
one glass of
water
2 spoons
2 spoons
Since 1978 in
Poland, reported
as traditional use
For relief of
excessive
sweating
For oral use as
a tea
preparation
2 g in 160 ml
water
2 g
2 g
Since 1976 in
Germany,
reported as well-
established use
For
symptomatic
treatment of
inflammations
in the mouth or
the throat
For
oromucosal
use as a tea
preparation
2.5 g in 100 ml
water for
gargle
2.5 g
2.5 g
Since 1976 in
Germany
reported as well-
established use
b) Liquid
extract (1:1),
ethanol
70% V/V
For
symptomatic
treatment of
inflammations
in the mouth or
the throat
For
oromucosal
use 250 mg
(pea-sized
amount) of gel
up to
5 times daily
on affected
regions,
massage gently
250 mg
1250 mg
Since 1976 in
Germany
reported as well-
established use
c) Dry extract
(4-7:1),
extraction
solvent: water
For
symptomatic
treatment of
mild dyspeptic
complaints
For oral use
320 mg
divided in 3-4
doses
80-106 mg
320 mg
Since 1976 in
Germany,
reported as well-
established use
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d) Liquid
extract
(1:3.5-5),
extraction
solvent:
ethanol
31.5% V/V
such as
heartburn and
bloating
For
symptomatic
treatment of
mild dyspeptic
complaints
such as
heartburn and
bloating
For oral use 10
drops
3 times daily in
some liquid
10 drops
30 drops
Since 1976 in
Germany,
reported as well-
established use
For relief of
excessive
sweating
For oral use
10-20 drops
dissolved in
liquid 3 times
daily.
For night
sweat 30
drops in liquid
1 hour or
directly before
bedtime
10-20 drops
30-60 drops
Since 1976 in
Germany,
reported as well-
established use
30 drops
30 drops
e) Liquid
extract (1:4-5)
extraction
solvent:
ethanol
50% V/V
For relief of
excessive
sweating
For oral use 50
drops (= 2 ml)
3 times daily
50 drops
150 drops
Since 1976 in
Germany,
reported as well-
established use
f) Liquid
extract (1:7.2),
extraction
solvent: liquor
wine : ethanol
96% V/V
(38.25 : 61.75
m/m)
For
symptomatic
treatment of
mild dyspeptic
complaints
such as
heartburn and
bloating
For oral use 20
drops 3 times
daily
20 drops
60 drops
Since 1976 in
Germany,
reported as both
traditional and
well-established
use
For
symptomatic
treatment of
inflammations
in the mouth or
the throat
For
oromucosal
use 3 spoons
(15 ml) in a
glass of water,
rinse or gargle
Since 1976 in
Germany,
reported as well-
established use
g)Tincture
(1:10): ethanol
70% V/V
For
symptomatic
treatment of
mild dyspeptic
complaints
such as
heartburn and
bloating
For oral use 2-
3 ml three
times daily
2-3 ml
6-9 ml
Ph. Eur
monograph
Deutsches
Arzneibuch 6.
Ausgabe 1926.
Spiritus dilutus
is Ethanol 68-
69% (V/V) = 60-
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For
symptomatic
treatment of
inflammations
in the mouth or
the throat
For
oromucosal
use 3 spoons
(15 ml) in a
glass of water,
rinse or gargle
61% (m/m).
German
Pharmacopeias
(Ergänzungsbuch
zum Deutschen
Arzneibuch (Erg.
B. 6. Stuttgart
1956, 1958.)
Assessors comment:
There is a lack of safety and toxicity data for the long-term effects, hence limitations in the duration of use
are recommended.
Furthermore, in order to harmonize with similar indications in other monographs, the duration of use is
limited as followed:
Oromucosal use: Not more than 1 week
Oral use: Not more than 2 weeks
II.3
O
VERVIEW OF AVAILABLE PHARMACOLOGICAL DATA REGARDING THE HERBAL
SUBSTANCE
(
S
),
HERBAL PREPARATION
(
S
)
AND RELEVANT CONSTITUENTS THEREOF
II.3.1
Composition
Constituents:
(Bradley, 2006)
Essential oil
Up to 3%
Monoterpenoids
-α-thujone
-β-thujone
-camphor
-1,8-cineole
(10-60%)
(4-36% )
(5-20%)
(1-15%)
Sesquiterpenes
-α-humulene
-β-caryophyllene
-viridiflorol
Hydroxycinnamic
acid derivates
About 3.5%
Caffeic acid dimer
-rosmarinic
acid
(up to 3.3%)
Caffeic acid trimers
-melitric acid A
-methyl
melitrate A
-sagecoumarin
-salvianolic
acid K
Caffeic acid tetramer
-sagerinic acid
6-feruloyl-glucose
A polyalcohol derivate of
6-feruloyl-glucose
Three hydroxycinnamic
esters of disaccharides
-1-caffeoyl-
(6`-apiosyl)-
glucoside
-free caffeic acid
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Phenolic
diterpenes
Tricyclic diterpene
↓
(which readily auto-
oxidises to)
↓
Lactones
-
carnosic acid
-carnosol
(0.35%)
Phenolic diterpenes with
lactone structures
-rosmanol
-epirosmanol
-7-methoxy-
rosmanol
-galdosol
-safficinolide
-sagequinone
methide A
Sageone
Methyl carnosate
Triterpenes
Pentacyclic triterpene
acids
- ursolic acid
-oleanolic acid
(up to 3.5%)
(up to 0.4%)
Triterpene alcohols
-α-amyrin
-β-amyrin
(0.18%)
(0.10%)
Flavonoids
About 1.1%
Flavones
and
their
-
luteolin
, its
→7-glucoside
→7-glucuronide,
→3`-glucuronide
→7- methyl ether
-
6-hydroxyluteolin
,
its
→7-glucoside
→ 7-glucuronide
-
6 methoxyluteolin
,
its
→7-methyl ether
-
apigenin,
its
→7-glucoside
→ 7-methyl ether
(= genkwanin)
-6-methoxy-
apigenin
(= hispidulin
)
its
→7-methyl ether
(=cirsimaritin)
-vicenin-2
(= apigenin 6,8-di-
C-glucoside)
-5-methoxy-
salvigenin.
glycosides
Phenolic
glycosides
A diverse range
-
picein
(4-hydroxy
acetophenone
glucoside)
-
4-hydroxy-
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acetophenone-
4-(6-apiosyl)-
glucoside
-
cis-p-coumaric
acid 4-(2-apiosyl)-
glucoside
-trans-p-coumaric
acid 4-(2-apiosyl)-
glucoside --
-isolariciresinol 3-
glucoside
-1-hydroxy-
pinoresinol 1-
glucoside
-caffeoyl-fructosyl
glucoside-caffeoyl-
apiosyl
glucoside
-others
Polysaccharides
Polysaccharides
Arabinogalactans
High-MW pectin
Glucuronoxylan-related
polysaccharides
Other
constituents
Benzoic acid derivates
-p-hydroxybenzoic
acid
-gentisic acid
-syringic acid
Phytosterols
-β-sitosterol
-stigmasterol
(0.001%)
Some constituents mentioned in other handbooks are borneol, bornyl acetate
,
isorosmanol (Wichtl, 2004),
linalyl acetate, chlorogenic-, ellagic-, ferulic- and gallic phenolic acids (Newall et al., 1996), linalool,
α-pinene, camphene, limonene (Blumenthal et al., 2000), cirsiliol (Harborne et al., 1996), menthol and
thymol (Grzunov et al., 1984).
Numerous articles concerning the compositions of
Salvia officinalis
L. and
Salvia fructicosa
Miller have
been published regarding the composition of the essential oil. The considerable variation found may be
due to the quality of the plant material (influence of harvest time, different chemical types, use of
fertilizers etc.) as well as to the methods used for analysis. Essential oil obtained by steam distillation is
influenced to some extent by pH-value of the water used and duration of the steam distillation.
The boiling temperature (corresponding to the ion content of the water) and the degree of grinding have a
significant effect on the result (Länger et al., 1996, with reference to Iconomou et al., 1982).
An analysis of 50 randomly chosen leaves of a commercial sample of sage leaf showed an considerable
inhomogeneity, some leaves showing more 1,8-cineole than thujone and camphor. These inhomogeneities
can be explained by intra-individual differences in the production of essential oil.
From the top to the base of an individual plant, the relative contents of α-thujone and β-thujone decrease,
while the amounts of camphor, α-pinene, camphene and borneol increase. However, the sum of the
contents of α-thujone, β-thujone and camphor remains nearly constant (Länger et al., 1996).
In a study on the relationship of camphor biosynthesis to leaf development in sage, a plot of leaf pair
surface area and camphor content as a function of time, clearly indicated that the increase in camphor
content closely paralleled leaf expansion. Examination of the second and third leaf pairs as they expanded
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provided similar results, although the levels of camphor were generally higher from beginning to end,
reaching approximately 0.7 mg/leaf pair on full expansion (Croteau et al., 1980).
An excess of the (1
R
, 4
R
)-enantiomer (
d
-camphor) characterizes the essential oils of sage (50-70% for
Salvia officinalis
L.) (EFSA, 2008), accessible at
e
).
According to information from handbooks,
Salvia officinalis
L.,
folium is often used as an infusion in
dosages ranging from 1 to 9 g daily. As pointed out by Bradley, 2006, sage contains up to 3% essential oil.
The essential oil consists of 10-60% α-thujone, 4-36% β-thujone and 5-20% camphor. Using the results
from the study of Länger et al; 1996 (with reference to Diploma thesis by Harrer, 1993), for the daily
dosage of sage leaf (1-9 g), the amount of thujone and camphor can be calculated as follows:
Amount of
Salvia
officinalis
folium daily
(between 1-9 g)
Amount of
essential
oil
(up to 3%)
Amount
of β-
thujone
(between
4-36%)
Amount of
α -thujone
(between
10-60%)
Total
amount of
thujone (α-
and β)
extracted
from 150 ml
hot water
(17.6%)
Amount of
camphor
(between
5-20%)
Total amount
of camphor
extracted
from 150 ml
hot water
(35.4%)
1g
3% =
30 mg
4% =
1.2 mg
10% =
3 mg
17.6% =
0.7 mg
5% =
1,5 mg
35.4 % =
0.53 mg
36% =
10.8 mg
60% =
18 mg
17.6% =
5.0 mg
20% =
6 mg
35.4% =
2.1 mg
9g
3% =
270 mg
4% =
10.8 mg
10% =
27.0 mg
17.6% =
6.7 mg
5%
=
35.4% =
4.77 mg
13.5mg
36% =
97.2 mg
60% =
162 mg
17.6% =
45.6 mg
20% =
54 mg
35.4% =
19.1 mg
These results show that the amount extracted varies according to the wide range of thujone-and camphor
content in the essential oil. In 1 g and 9 g sage leaf containing 3% essential oil, the extraction amount of
thujone will theoretically vary between 0.7-5.0 mg, and 6.7-45.6 mg with an extraction efficiency of
17.6%.
Assessor’s comment:
Based on these calculations and data from one unpublished study, we have limited the posology to 6 g
Salvia officinalis
L.,
folium daily, a lower daily dose than used traditionally.
II.3.2
Non-clinical pharmacology
Antibacterial, fungistatic ,antiseptic and virustatic effects
Sage oil has antimicrobial properties, attributed principally to the presence of thujones (Bradley, 2006;
Newall et al., 1996).
Inhibitory activity of the oil against Gram-positive and Gram-negative bacteria and against a range of
fungi has been demonstrated, such as
Escherichia coli, Shigella sonnei, Salmonella
species,
Klebsiella
ozanae
(Gram-negative),
Bacillus subtilis
(Gram-positive), and fungi-species like
Candida albicans,
C. krusei, C.pseudotropicalis, Torulopsis glabrata, Cryptococcus neoformans.
No activity was observed
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versus
Pseudomonas aeruginosa
(Bradley, 2006). Wichtl, 2004, also mentions antimicrobial activity
against
Aspergillus flavus
.
Microencapsulation of the oil into gelatin-acacia capsules introduced a lag-time with respect to the
antibacterial activity and inhibited the antifungal activity (Newall et al., 1996; Barnes et al., 2002).
Horiuchi et al. (2007) found that crude extract from
Salvia officinalis
L. leaves showed antimicrobial
activity against vancomycin-resistant enterococci (VRE).
The effective compound was identified as oleanolic acid. Also ursolic acid showed antimicrobial activity
against VRE. The minimum inhibitory concentrations (MICs) of oleanolic acid and ursolic acid were
8 and 4 µg/ml, respectively. These two compounds also showed antimicrobial activity against
Streptococcus pneumonia
and methicillin-resistant
Staphylococcus aureus
(MRSA), and they showed
bactericidal activity against VRE at least for 48 hours when added at concentrations that were two-times
higher than their MICs. Neither compound showed antimicrobial activity against Gram-negative bacteria
tested (
E. coli, P. aeruginosa, S. marcescens
) and
Candida albicans
. The antimicrobial activity of
oleanolic acid or ursolic acid is not so strong as compared with antimicrobial drugs that are in clinical use,
although oleanolic acid and ursolic acid showed fairly high activity.
From a study by Viuda-Martos et al. (2008) on the effectiveness of the essentials oils from oregano
(
Origanum vulgare
), thyme (
Thymus
vulgaris
), rosemary (
Rosmarinus officinalis
), sage (
Salvia
officinalis
), cumin (
Cuminum cyminum
) and clove (
Syzygium aromaticum
) on the growth of some bacteria
commonly used in the food industry, it could be concluded that these essential oils possess
in vitro
,
antibacterial activity against
Lactobacillus curvatus
,
Lactobacillus sakei, Staphylococcus carnosus,
Staphylococcus xylosus, Enterobacter. gergoviae and Enterobacter amnigenus
. The effects of thyme,
rosemary and sage essential oils are dose-dependent.
The antibacterial efficiency of essential oils is diminished when they are added to more complex materials
(such as food products).This must be taken into account when essential oils are applied as antibacterials in
foods.
An aqueous and a 50%-ethanolic extract of sage leaf exhibited strong inhibitory effects on the
collagenolytic activity of
Porphyromonas gingivalis
. Aerial parts of sage contain diterpenes with antiviral
activity against vesicular stomatitis virus (ESCOP, 2003). The effect against vesicular stomatitis virus is
also mentioned by Bradley (2006) and the effective diterpenes are identified as safficinolide and sagone.
The antiviral action has been attributed to the essential oil according to Wichtl (2004).
Antioxidant effects
In a study performed by Chang et al. 1977, a decrease in the rate of formation of peroxides was used as a
measurement of the antioxidant activity of rosemary and sage extracts. The antioxidant activity of the
purified antioxidant prepared from sage was shown to be comparable to that of rosemary. It appeared that
the rosemary extract is as effective as the commercial antioxidant Tenox VI (Tenox VI is a mixture of
BHA (butylated hydroxyanisole), BHT (butylated hydroxytoluene), propyl galate, and citric acid) when
used in animal fat and is superior to Tenox VI in vegetable oils. The antioxidants also appeared to be able
to improve the flavour stability of soybean oil, as well as the flavour stability of potato chips.
The antioxidant activity of six isolated compounds (1-
O
-(2,3,4-trihydroxy-3-methyl) butyl-6-
O
-feruloyl-
β
-
D-glucopyranoside, ethyl
β
-D-glucopyranosyl tuberonate,
p
-hydroxybenzoic acid, (-)-hydroxyjasmonic
acid, caffeic acid, and 4-hydroxyacetophenone 4-
O
-[5-
O
-(3,5-dimethoxy-4-hydroxybenzoyl)-
β
-D-
apiofrunosyl]-(1f2)-
β
-D-glucopyranoside; all isolated from the
n
-butanol-soluble fraction of sage leaf
extracts was tested in a study by Wang et al. (2000). At the concentration of 30
µ
M, all of the compounds
showed DPPH (radical 2,2-diphenylpicryhydrazyl) radical scavenging activity. Caffeic acid was the most
active compound. According to Bradley (2006) the antioxidant activity is attributable to
hydroxycinnamic acid derivates, notably rosmarinic acid. The antioxidant activity of the carnosol and
carnosic acid is also mentioned by EFSA (2008).
The antioxidant activity of eight aromatic herbs was assessed by the b-carotene bleaching test (diffusion
and spectrophotometric methods) by Dapkevicius et al. (1998). Thyme and sage acetone oleoresins
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showed high antioxidant activity in the tests performed and were regarded as promising sources of natural
antioxidants.
Lipid peroxidation in both enzyme-dependent and enzyme-independent test systems was inhibited more
effectively by a dry 50%-methanolic extract from aerial parts of sage leaf than by α-tocopheryl acid
succinate (as a positive control).The antioxidant activity was attributed mainly to phenolic compounds,
rosmarinic acid being the main contributor due to its high concentration in the main extract (Bradley,
2006).
Two phenolic glycosides isolated from sage leaf, 6-O-caffeoyl-β-D-fructofuranosyl-(2→1)-α-D-
glucopyranoside and 1-O-caffeoyl-β-D-apiofuranosyl-(1→ 6)-β-D-Glucopyranoside, were found to have
moderate antioxidant activity in the DPPH and metmyoglobin test (ESCOP 2003)
Aqueous methanolic extracts of 9 spices were investigated for their phenolic compounds composition and
antioxidant properties, amongst them
Salvia officinalis
L. The extract of sage (not specified to only
concern folium
)
showed in the applied
in vitro
test system
better antioxidant properties than ascorbic acid
which was used as a control (Muchuweti et al., 2007).
To study the phytosterol components of
Salvia officinalis
L. infusion (sage tea) and its antioxidant and
hypocholesterolemic function, rats were divided into 4 groups; normal control group I. Group II, in which
animals were fed on normal diet and received sage tea in a dose of 35 mg/kg bw/day. Group III, where rats
were maintained on high cholesterol diet for 4 wk. Group IV, in which rats were maintained on high
cholesterol diet while receiving sage tea in a dose of 35 mg/kg bw/day for 4 wk. Blood plasma
transaminases, cholesterol, triglycerides, LDL, and lipid peroxides, liver GSH, and its related enzymes,
glutathione-S-transferase (GST) and glutathione reductase (GR) activities were measured to study
biosafety of sage and its protective effect against hypercholesterolemia. Treatment with sage tea resulted
in a significant decrease in total cholesterol, triglycerides, LDL, and lipid peroxides of rats maintained on
high cholesterol diet, (Group IV) compared to group III. The present study showed no toxicity to the liver
and no adverse effects on growth parameters in rats. It also showed positive effects on the antioxidant
status of the liver, mainly the GSH, GST, and GR activities of the rat livers. It was concluded that,
phytosterols (β -sitosterol and stigmasterol) in sage tea act as an antioxidant and exert protective effect
against hypercholesterolemia (El-Desouki et al., 2007).
Anti-inflammatory/ Antiphlogistic activity effects
Chloroform and
n
-hexane dry extracts from sage leaf dose-dependently inhibited in vivo croton oil-
induced ear oedema in mice, chloroform extracts being the more potent with ID
50
values of 106-140
µg/cm
2
. The main component of the chloroform extract and the major contributor to its anti-inflammatory
activity was found to be ursolic acid (ID
50
: 0.14 µM/cm
2
), which had twice the potency of indomethacin
(ID
50
: 0.26 µM /cm
2
) in this test (ESCOP, 2003; Wichtl, 2004).
Oleanolic acid also showed anti-inflammatory activity but was less effective (ID
50
: 0,36 µM/cm
2
)
(ESCOP, 2003).
Rosmarinic acid has been shown to have anti-inflammatory activity (Verweij-van Vught et al., 1987).
In this study, rosmarinic acid acted as an inhibitor of the complement activation when the influence of
rosmarinic acid on the function of porcine and human polymorphonuclear leucocytes was tested.
In a study to determine the effect of topical application (5% in vehicle) of the anti-inflammatory
rosmarinic acid on the progression of plaque induced gingivitis in six Rhesus monkeys, rosmarinic acid
significantly lowered both gingival and plaque indices in comparison with placebo (Van Dyke et al.,
1986).
The antitussive and immunomodulatory activities of pectin and hemicellulose polysaccharides orginated
from sage was shown in a study performed by Sutovska et al. (2007). Sage polysaccharide complex A
significantly decreased the number of the cough efforts (NE) and the intensity of inspiratory and
expiratory cough attacks (IA– and IA+) of mechanically – induced cough reflex from both,
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laryngopharyngeal and tracheobronchial areas of airways, without any side effects in non-anaesthetized
cats. Antitussive activity tests with some classic drugs, narcotic codeine and non-narcotic dropropizine
performed under same experimental conditions demonstrated that antitussive potency of sage
polysaccharide complex two fold exceeded cough suppressive effect of peripheral antitussive agent and
effectiveness only by 13% lower than opioid receptors agonist.
Furthermore, all fractions of isolated polysaccharides possessed ability to increase rat thymocyte
proliferation, which confirmed their immunological property
The immunomodulatory activity of water-soluble polysaccharides isolated from aerial parts of sage is also
mentioned by Bradley (2006).
Carminative, spasmolytic, stimulant and tonic effects on digestion and nervous system
Sage oil had only a relatively weak spasmolytic effect on isolated guinea pig tracheal and ileal smooth
muscle in comparison with oils from other
Labiatae
such as melissa leaf or thyme (Bradley, 2006).
A water-alcohol extract of
Salvia officinalis
L. demonstrated a marked spasmolytic action on the smooth-
muscle contractions caused by four spasmogens (acetylcholine, histamine, serotonin and BaCl
2
) in isolated
segments of guinea-pig ileum. The experiments showed that the extract inhibited by 70-85% the smooth-
muscle contractions, and its spasmolytic effect was of considerable duration. Newall et al. (1996) refer to
the same effect of 60-80% inhibition of contraction induced by the four spasmogens. An initial
spasmogenic action exhibited by low doses of sage oil, has been attributed to the pinene content.
Antispasmodic activity
in vivo
(iv, guinea pig) has been reported for sage oil, which released contraction
of Oddi’s sphincter induced by intravenous morphine.
The spasmolytic effect of the total flavonoid fraction from
Salvia officinalis
L. was considerably weaker.
It caused inhibition of the contractile smooth-muscle responses to the various spasmogens by 30-60%
(Todorov et al., 1984). Pinene, if tested alone in long-strip guinea-pig ileum, shows a weak spasmogenic
action and induces an evident increase of the basal tone. An initial stimulating action, especially at the
lowest doses, is also seen to be the case of linalyl acetate and limonene in sage essence. The constituents
of the essence influence its action in relation to their concentration and a double spasmogenic-spasmolytic
action appears sometimes in the sage essence (Taddei et al., 1988).
The spasmolytic activity of the components of essential oils probably affects the smooth muscle in direct
and indirect ways and modifies the quantity of Ca
2+
(Taddei et al., 1988).
Cholinesterase (ChE) inhibiting properties of
S. officinalis
on mood, anxiety and performance were
studied
by Kennedy et al. (2006). The sage extract exhibited
in vitro
dose dependent ChE-inhibiting
properties, but was a more selective inhibitor of BuChE (butyrylcholinesterase from human serum) than
AChE (acetylcholinesterase from human erythrocytes) (IC
50
: 0.054 mg/ml and 0.365 mg/ml respectively).
Studies on the effect of
Salvia officinalis
L. extracts showed a prolonged latency of the onset of sleep on
hexobarbital anaesthesia in mice (Todorov et al., 1984).
Hypotensive activity in anaesthetized cats and CNS-depressant action (prolonged barbiturate sleep) in
anaesthetized mice have been reported for sage extract and for the essential oil (Newall et al., 1996).
Other effects
Extracts from
Salvia officinalis
L. contain biologically active substances possessing moderate and
prolonged hypotensive action. Applied intravenously and duodenally, aqueous-alcohol extracts caused
moderate but prolonged lowering of the blood pressure in cats (Todorov et al., 1984).
Hypoglycaemic activity
in vivo
has been reported for mixed phytotherapy preparations involving various
Salvia
species including
S. officinalis
. Activity in normoglyaemic, hypoglyaemic and in alloxan-diabetic
rabbits was observed, although no change in insulin concentrations was noted (Newall et al., 1996).
Common sage is said to have mild blood-sugar lowering action but this is unproven (Wichtl, 2004).
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Some of the terpenoids of sage have demonstrated antimutagenic effects (Wichtl, 2004).
In a study by Patenkovic et al. (2009), the antimutagenic effects of
Salvia officinalis
tea have been
estimated by the somatic mutation and recombination test (SMART) on
Drosophila melanogaster.
Methyl
methanesulphonate (MMS) was used as the mutagen and positive control. Several types of treatment were
performed: short acute treatment with sage infusion or MMS, longer (chronic) treatment with sage
solution or MMS, and two combined treatments, i.e. short treatment with sage followed by a longer
treatment with MMS and vice versa. Sage infusion used in the experiments showed antimutagenic effect
by reducing the frequency of mutations induced by MMS. The study do not reveal which components of
sage infusion are of particular antimutagenic potential.
Antimutagenic properties of terpenoid fractions of sage (
Salvia officinalis
) were tested by Vujosevic et al.,
2004, in mammalian system
in vivo.
The ability of sage to decrease the frequency of aberrant cells induced
by a potent mutagen was examined. First, groups of mice were treated with three concentrations of sage
alone and it was established that the frequency of aberrant cells after treatment with a concentration of
25 μL/kg was not significantly different from the negative control (olive oil), while that found after
treatment with the 50 μL/kg concentration differed significantly
Sage used at a concentration of 100 μL/kg was cytotoxic. Mitomycin C (MMC), known as a potent
mutagen, was used for induction of chromosome aberrations. Post-treatment with sage suppressed the
effects of MMC significantly. Both concentrations (25 μL/kg and 50 μL/kg) produced a significant
decrease in the frequency of aberrations relative to MMC alone. The percent of aberrations decreased
with increasing concentrations of sage.
Cirsiliol occurs on the leaf surface on
Salvia officinalis
L. and is a potent and relatively selective inhibitor
of arachidonate 5-lipoxygenase (Harborne et al., 1996 with reference to Matsuura, 1973). It has been
shown that cirsiliol is a potent inhibitor of 5-lipoxygenase of rat basophilic leukaemia cells. It also
inhibited 12-lipoxygenase from bovine platelets and porcine leucocytes, but the inhibitory activity was
less than the one on 5-lipoxygenase (Hirono, 1987).
Results in a study with natural flavonoids on the inhibition of
3
H-Diazepine binding to rat cerebral cortical
synaptosomal membranes, and the anxiolytic, sedative, myorelaxant, anticonvulsant, amnesic and
hypnotic effects of some of them, showed that cirsiliol have sedative and hypnotic effect
in vivo
(Marder
et al., 2002).
A methanolic extract from sage leaf showed affinity to human brain benzodiazepine receptors (from post-
mortem frontal cortex) by competitive displacement of
3
H-flumazenil, a specific benzodiazepine
antagonist. Activity-guided analysis revealed five benzodiazepine receptor-active constituents, of which
three are flavones and two diterpenes. Compared to diazepam (IC
50
: 0,05 µM) the diterpene galdosol (IC
50
: 0.8 µM ) and the flavone hispidulin (IC
50
:1.3 µM ) were the most active; 7- methoxyrosmanol
(IC
50
: 7.2 µM) also exhibited strong affinity, while apigenin (IC
50
: 30 µM) and cirsimaritin (IC
50
:
350 µM) were considerably less active (Bradley, 2006).
II.3.3
Overview of available pharmacokinetic data regarding the herbal substance(s), herbal
preparation(s) and relevant constituents thereof
In vitro experiments
No pharmacokinetic (ADME) studies on extracts of
Salvia officinalis
L. were available.
Extract of
Salvia officinalis
L. from the commercial herbal medicinal product, Nosweat®, was assessed
in
vitro
for its inhibitory potential on isolated human CYP2D6-mediated dextromethorphan metabolism.
IC
50
for
Salvia officinalis
L. were found to be 0.8 mg/ml and the extent of inhibition was higher than 50%.
In this small screening study,
G. biloba
, common valerian and St. John’s wort were suggested as
candidates for clinically significant CYP interactions
in vivo
(Hellum et al., 2007), whereas no conclusions
can be drawn about potential interactions of sage leaf.
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In vivo experiments
Thujone:
In mice treated intraperitoneally with α-thujone, the brain levels of α-thujone and 7-hydroxy-α-thujone
were dose- and time dependent, but α-thujone appeared at much lower levels and was less persistent than
7-hydroxy-α-thujone. The latter compound is less toxic to mice; at 50 mg/kg administered
intraperitoneally, α-thujone was less lethal but 7-hydroxyl-α-thujone and other metabolites were not lethal
(ESCOP, 2003).
α-Thujone is metabolized by cytochrome P450 to form at least three monohydroxylated derivatives, which
are detected by GC-CI-MS in the brain of thujone-treated mice (Hold et al., 2000).
After oral administration to male rabbits of a mixture of α- and β-thujone (ratio 9:2) at a dose
level of about 650-800 mg/kg bw, two neutral urinary metabolites were identified as 3-β-hydroxy-α-
thujane and 3-β-hydroxy-β-thujane indicating that the reduction was stereo-specific in spite of the
different configurations of the methyl group (Scientific Committee on Food, 2003 with reference to Ishida
et al., 1989).
Camphor:
Camphor is easily absorbed in the gastrointestinal tract. In rabbits, orally administered
d
- and
l
-camphor
were shown to be oxidized to 5-
endo
-hydroxycamphor and 3-
endo
hydroxycamphor, the former
predominating in each case. A reduction to borneol was also observed to some extent (EFSA, 2008 with
reference to Robertson and Hussain, 1969).
In dogs, the major hydroxylation products of
d
- and
l
-camphor detected in urine after extraction and
hydrolysis were 5-
endo
and 5-
exo
hydroxycamphor, and probably the
endo
-stereoisomer of
3-hydroxycamphor.
In vitro
studies with liver preparations from rats and rabbits demonstrated these
reactions to occur in liver microsomes. A small amount of 2,5-bornanedione was also formed in liver
microsomes. The 5-keto group of 2,5-bornanedione was reduced in liver cytosol, and there was
interconversion between the
endo
- and the
exo
isomers of 5-hydroxycamphor in the presence of both
microsomes and cytosol, but this interco version could not account for the production of both 5-hydroxy
isomers from camphor in liver microsomes. The 2-keto group of
d
-camphor underwent no detectable
reduction in rat liver preparations;
l
-camphor was reduced to a small extent. However, rabbit liver cytosol
mediated a vigorous stereo specific
endo
-reduction of
d
-camphor to borneol; a small amount (1%) of
isoborneol was also formed (EFSA, 2008 with reference to Leibman and Ortiz, 1973).
II.3.4
Overview of available toxicological data regarding the herbal substance(s)/herbal
preparation(s) and constituents thereof
Acute and repeated dose toxicity
Sage oil:
An experimental study of the toxic properties of commercialized essential oil of sage has revealed that the
convulsant action was of central nervous system origin in unanaesthetized rats. The dose limit from which
the cortical events are subclinical is 0.3 g/kg for sage oil. Above 0.50 g/kg for sage oil, the convulsions
appeared and became lethal above 3.2 g/kg (ESCOP, 2003). The toxicity appeared to be related to the
presence of camphor and thujone in
Salvia officinalis
oil (Millet et al., 1981; Newall et al., 2002).
Acute LD
50
values for sage oil are documented as 2.6 g/kg in rats for oral administration (ESCOP, 2003;
Bradley, 2006) and 5 g/kg in rabbits for intradermal administration (Newall et al., 2002).
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In an 8-week toxicity study with groups of 5 white rats, a daily dose of 250 mg/kg bw
sage oil was well
tolerated when given by oral administration. When the dose was
increased to 500 mg/kg bw/day, some
convulsing was observed. Upon increase to 1000
mg/kg bw/day, most animals died and all animals died
when the level was increased to 1250
mg/kg bw/day (EFSA 2008, with reference to Skramlik, 1959).
The levels of camphor in 25 different commercial sources of sage leaves varied from 7 to 50% (EFSA
2008, with reference to Lawrence, 1998).
Based on these values, the observed NOAEL of 250 mg sage oil/kg bw/day corresponds to camphor
intakes of 18 and 125 mg/kg bw/day, respectively (EFSA 2008, accessible at:
http://www.efsa.europa.eu/cs/BlobServer/Scientific_Opinion/afc_ej729_camphor_op_en.pdf?ssbinary=tru
e).
Thujone:
α-Thujone, which is more toxic than β-thujone and is present as a higher proportion of the essential oil, is
a convulsant. Its intraperitoneal LD
50
in mice is about 45 mg/kg, while 60 mg/kg causes a tonic convulsion
leading to death within 1 minute (ESCOP, 2003; Bradley, 2006), whereas at 30-45 mg/kg mice either die
or recover (ESCOP, 2003). The mechanism of α-thujone neurotoxicity has been shown to be a modulation
of the γ-aminobutyric acid (GABA) type A receptor (Scientific Committee on Food 2003, with reference
to Meschler & Howlett
,
1999
,
Höld et al.,
2000). Observations suggest that α-thujone acts as a GABA-
gated chloride channel blocker; the poisoning signs are similar to those of picrotoxin (Scientific
Committee on Food 2003, with reference to Hold et al., 2000).
However, α-thujone is rapidly detoxified in mice by conversion to less toxic metabolites (ESCOP, 2003;
Bradley, 2006).
Suggestions that thujone activates the CB1 cannabinoid receptor, based on structural similarities of
thujone enol to tetrahydrocannibinol, have not been supported experimentally (Scientific Committee on
Food 2003, with reference to Meschler &Howlett, 1999).
Subcutaneous LD
50
values in mice were determined as 87.5 mg/kg body weight (bw) for α-thujone and
442.4 mg/kg for β-thujone, thus α-thujone present in a higher proportion of the essential oil, is more toxic
than β-thujone.
The oral LD
50
of α- and β thujone (+) in rats was found to be 192 mg/kg and 500 mg/kg bw, respectively
(Scientific Committee on Food 2003, with reference to Margaria, 1963). In subchronic toxicity tests in
rats, thujone (α + β) given orally to rats at 10 mg/kg daily produced convulsions in only 1 out of 20
animals by the 38
th
day (ESCOP, 2003).
Thujone is much more acutely toxic after parenteral administration and the intravenous LD
50
in the rabbit
is stated to be 0.031 mg/kg bw (Scientific Committee on Food 2003, with reference to NLM, 1997)
In rats, i.p. injections of thujone induced electro-cortical seizures associated with myoclonic activity and
the convulsant and lethal effects occurred at similar doses of 0.2 ml/kg bw. Thujone was administered to
rats by gavage at doses of 12.5, 25 or 50 mg/kg bw/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 (No-Observed
Adverse-Effect Level) for convulsions in the males was 12.5 mg/kg bw but no NOEL could be established
in females in this study (Scientific Committee on Food 2003, with reference to Surber, 1962).
In a further study, thujone was administered to rats by gavage at doses of 0, 5, 10 or 20 mg/kg bw/day 6
times per week for 14 weeks. There were 3 deaths in females and 1 in males associated with convulsions
at the top dose level. The NOEL for convulsions was reported to be 10 mg/kg bw in males and 5 mg/kg
bw in females; no changes were reported in haematologic or histopathologic examinations (Scientific
Committee on Food 2003, with reference to Margaria, 1963).
In a 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 bw. In mice, mortality was 4/5 males and 5/5 females in the top dose
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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 mice, at the top dose level there was
increased mortality in males (5/5) and females (2/5) but not associated 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 (Scientific Committee on Food, 2003).
Consumption of as much as 1 liter of an alcoholic beverage containing 5 mg/l, the maximum permitted
level of thujone in alcoholic beverages with up to 25% alcohol, would result in an intake of about 0.08 mg
thujone/kg bw for a 60 kg adult.
This intake is about 100 times lower than the NOEL derived from a 14 week study in rats (Scientific
Committee on Food, 2003).
Although the toxic effects of thujone are evident, the concentrations found in sage leaves are low
according to calculations made by Länger et al.,1996.
Investigations showed that only 17% of the genuine thujone content could be extracted with hot water
corresponding to 2.5 mg thujone per cup of tea (the most common preparation of sage leaves). A cup of
tea prepared from 3.0 g sage leaves and 150 ml boiling water contained 3.8 mg thujone, which is
approximately only 17% of the thujone present in the herbal substance. Twenty-three per cent of the
cineol and 35% of the camphor present in the herbal substance were extracted (according to e-mail from
Länger with reference to Diploma thesis by Harrer, 1993). The use of chemotypes low in thujone should
be preferred in order to minimize the exposure to thujone.
Genotoxicity
Single
constituents
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. Negative results have also been
reported from in-vitro mutagenicity tests in
Salmonella typhimurium
with a mixture of α- and β-thujone.
The test was done with the strains TA1535, TA100, TA97 and TA98 with and without metabolic
activation. First toxicity signs were seen in dose units of 333.
In-vivo mouse micronucleus test was negative in males and positive in females with a mixture of α- and β-
thujone. Tested concentrations were 0-25 mg/kg (males) and 0-50 mg/kg (females), respectively [NTP
2003].
Thujone was tested at 1.5 and 3% in DMSO (dimethyl sulfoxide) for its effect on the mutagenicity of
aflatoxin B1 in
Salmonella typhimurium
strain TA100. The plates treated with thujone showed evidence of
colony damage which indicates some mutagenic activity on the part of thujone (Kim et al. 1992).
Gomes-Carneiro (1998) investigated the mutagenic potential of six monoterpenoid compounds: two
aldehydes citral and citronellal, a ketone (+-camphor.), an oxide (
1,8
-cineole, also known as eucalyptol),
and two alcohols terpineol and (-)-menthol.
No mutagenic effect was found with (+) camphor, citral, citronellal,
1,8
-cineole, and (-)-menthol.
The results from this study therefore suggest that, with the exception of terpineol, the monoterpenoid
compounds tested are not mutagenic in the Ames test.
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A rosemary extract, and its main active components, carnosic acid and carnosol, were checked for their
potential mutagenicity in the bacterial Ames test. Purified carnosol and carnosic acid were not mutagenic
in the test (EFSA, 2008).
Other studies with rosemary extract and carnosic acid has demonstrated antimutagenic activity in bacteria
(EFSA, 2008 with reference to Minnuni et al., 1972; Santamaria et al., 1987) and in
in vitro
human liver
and bronchial cell models (EFSA 2008, with reference to Offord et al., 1997).
Camphor did not show mutagenic activity in
Salmonella typhimurium
strains TA 1535, TA 1538, TA 98
and TA 100 with and without S9 activation (Anderson and Styles, 1978). No mutagenic effect was found
with
d
,
l
-camphor in strains TA 97a, TA 98, TA 100 and TA 102 with and without metabolic activation
(Gomes-Carneiro et al
.,
1998).
Herbal preparations of Salviae folium
Bradley (2006) and ESCOP (2003) refer to tests on genotoxicity performed with sage leaf tincture and
sage essential oil. In the study by Zani et al. (1991) genotoxic properties of essential oils from different
herbs, including
Salvia officinalis
L. and one of its varieties were tested.
ESCOP (2003) with reference to Schimmer et al., 1994) describe that a sage leaf tincture (Salviae tinctura
German Pharmacop. 6th ed.) at doses up to 200 µl/plate showed no mutagenic activity in the Ames test
using
Salmonella typhimurium
strains TA98 and TA 100 with or without S9 metabolic activation system.
Assessor's comment:
The study with the
essential oil
as published by Zani et al. (1991) cannot be interpreted because of
deficiencies in the performance and analysis of the tests.
Results from tests with the essential oil are not transferable to the herbal substance or other preparations of
Salvia officinalis
L. folium.
The testing of sage leaf tincture by Schimmer et al. 1994 with two strains is not complete (3 strains are
missing).
Based on the available data for the tincture, the requirements for a list entry are not fulfilled.
Reproductive and developmental toxicity:
No studies with
Salvia officinalis
L., neither essential oil nor extracts, were available.
No experimental data on thujone were available (Scientific Committee on Food, 2003)
No adverse effects on foetal growth, viability, or morphological development were reported on camphor
(EFSA 2008, with reference to NTP, 1992b).
Carcinogenity
No studies with
Salvia officinalis
L., either essential oil or extracts, were available.
No oral studies on chronic toxicity or carcinogenicity with camphor are available. In a pulmonary tumour
response test
d
-camphor injected intraperitoneally into strain A/He mice (groups of 15 males and females)
three times a week for 8 weeks in total doses of 3.6 and 18 g/kg bw induced no increase in primary lung
tumours and was not considered by the authors to be carcinogenic for lung (EFSA 2008, with reference to
Stoner et al.,
1973).
II.3.5
Overall conclusions on non-clinical data
Pharmacodynamics
Salvia officinalis
L. and some of its constituents have been investigated in several preclinical studies.
Indication a)
Traditional herbal medicinal product for symptomatic treatment of mild dyspeptic,
complaints such as heartburn and bloating
:
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The indication is supported by the fact that it has been an indication for the traditional use of
Salvia
officinalis
L. for a period of at least 30 years in Europe. Further preclinical studies are necessary to clarify
this effect.
Indication b)
Traditional herbal medicinal product for relief of excessive sweating:
The indication is supported by the fact that it has been an indication for the traditional use of
Salvia
officinalis
L. for a period of at least 30 years in Europe. Further preclinical studies are necessary to clarify
this effect.
Indication c)
Traditional herbal medicinal product for the symptomatic treatment of inflammations in
the mouth or the throat, and minor inflammations of the skin:
Many preclinical studies have been performed investigating the antibacterial and anti-inflammatory
effects of
Salvia officinalis
L. and some of its constituents. Many of these studies show positive results
which support this indication. It is further supported by the fact that it has been an indication for the
traditional use of
Salvia officinalis
L. for a period of at least 30 years in Europe.
Several other preclinical studies on different plausible effects from sage leaf have also been performed,
but further studies are necessary.
Pharmacokinetics
Based on the limited data available on pharmacokinetics for the herbal substance, no conclusion can be
made.
Toxicology
There is a lack of safety and toxicity data for the long-term effects, hence limitations in duration of use is
recommended. The essential oil of
Salvia officinalis
L. contains constituents like thujone and camphor,
which have toxic effects in high doses. Toxicological dose limits have been set based on the available
toxicological data and other studies. The toxic effect appears to be of central nervous origin with
convulsions as the main symptom. Based on existing data it can be concluded that because of the toxic
properties of the essential oil, one should not exceed recommendations concerning time of use and
posology of sage leaf. The duration of human treatment is recommended limited for maximum 2 weeks.
No studies on reproductive toxicity or carcinogenity are available for
Salvia officinalis
L. There is no
suspicion for a carcinogenic potential. Inclusion to the Community list of traditional herbal substances,
preparations and combinations thereof for use in traditional herbal medicinal products can not be
recommended for any preparations.
II.4
C
LINICAL
D
ATA
II.4.1
Clinical Pharmacology
II.4.1.1
Overview of pharmacodynamic data regarding the herbal substance(s)/preparation(s)
including data on relevant constituents
Perspiration-inhibiting/Antihidrotic effect studies
Excessive sweat induced by pilocarpine was inhibited by a dialysate of an aqueous extract of fresh sage. In
an open study, 40 patients were given dried aqueous extract of sage (440 mg, equivalent to 2.6 g herbs)
and 40 were given infusion of sage (4.5 g herb daily). Reduction of sweat (less than 50%) was achieved in
both groups of patients with idiopathic hyperhidriosis (the secretion of an abnormally large amount of
sweat). It should be noted however, that this study did not include a control group (Barnes et al. 2007,
with reference to ESCO 2003).
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Several open studies, carried out mainly in the 1930s on patients or healthy volunteers but also including a
larger study from 1989 (unpublished) on 80 patients with idiopatic hyperhidrosis, supported the long-
standing assumption that sage leaf aqueous extracts have anti-hyperhidrotic activity (Bradley, 2006).
Secretion-promoting effects
In folk medicine, sage is used to promote menstruation (unproven) (Wichtl, 2004).
Healthy people in a tolerance-test were given a 50 % plant substance preparation, Salvia “Teep” forte,
one full teaspoon three times daily; duration of administration not specified. The people who sweat little
experienced a more excessive perspiration, and those with already excessive perspiration experienced a
reduced perspiration and strong need to urinate with increased amount of urine.
When Salvia was used diluted, as in a 10% plant substance preparation, Salvia “Teep” mite, one tablet
three times daily, duration of administration not specified, the inhibitory effect was strong (Madaus,
1938).
Antilactagogue effects
In folk medicine, sage is used to facilitate weaning due to a milk-secretion inhibiting action (Wichtl, 2004;
Madaus 1938).
Memory-enhancing effects and beneficial effects on cognitive performance and mood - studies with sage
extract
In a randomized, double blind, placebo-controlled study, patients aged 65-80 years of age with a diagnosis
of mild to moderate dementia and probably Alzheimer`s disease were treated for 16 weeks with 60
drops/day of either sage leaf liquid extract (1:1, 45% ethanol; n=15) or placebo liquid (n=15). Compared
with the placebo group, patients in the sage leaf group experienced significant benefits in cognitive
function by the end of the treatment, as indicated by improved scores in the Clinical Dementia Rating
(CDR; p‹0.003) and the Alzheimer`s Disease Assessment Scale (ADAS-Cog; p=0.03). Within the
limitations of a fairly small number of patients and short period of follow-up, the results suggested
efficacy of the sage leaf extract in the management of mild to moderate Alzheimer`s disease (Bradley,
2006).
In a randomized, placebo-controlled, double blind, balanced, five-period crossover study the acute effects
on cognitive performance of a standardized extract of
Salvia officinalis
L. in older adults were
investigated. Twenty volunteers (>65 years of age, mean=72.95) received four active doses of extract
(167, 333, 666 and 1332 mg) and a placebo with a 7-day wash-out period between visits. Assessment
involved completion of the Cognitive Drug Research computerized assessment battery. On study days,
treatments were administered immediately following a baseline assessment with further assessment at
1, 2.5, 4 and 6 h post treatment.
Compared with the placebo condition (which exhibited the characteristic performance decline over the
day), the 333-mg dose was associated with significant enhancement of secondary memory performance at
all testing times. Similar effects, although to a lesser extent, were observed with other doses. There also
were significant improvements to accuracy of attention following the 333 mg dose.
In vitro
analysis
confirmed cholinesterase inhibiting properties for the extract.
The overall pattern of results is consistent with a dose-related benefit to processes involved in efficient
stimulus processing and/or memory consolidation rather than retrieval or working memory efficiency
(Scholey et al., 2008).
.
In a double blind, placebo controlled, crossover study, 30 healthy young volunteers (17 males,
13 females; mean age 24 years) were given, on three separate days at 7-day intervals in accordance with a
randomized scheme, different single-dose treatments in identical opaque capsules: 300 mg or 600 mg of
dried sage leaf, or placebo. On each test day, at pre-dose time and at 1 hour and 4 hours post-dose each
participant underwent mood assessment, requiring completion of Bond-Lader mood scales and the State
Trait Anxiety Inventory (STAI) before and after a 20-minute performance on the Defined Intensity Stress
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Simulator (DISS) computerized multitasking battery. The DISS comprises a set of four cognitive and
psychomotor tasks presented concurrently on a split (quartered) screen layout, to which responses had to
be made with an external mouse, giving attention simultaneously to all four tasks while monitoring the
cumulative score (reflecting accuracy and speed of response) in the centre of the screen. The DISS
engenders increases in self-ratings of negative mood, arousal and stress- related physiological responses.
Both doses of sage leaf led to post-dose improved ratings of mood before performing on the DISS, with
the lower dose reducing anxiety and the higher dose increasing “alertness”, “calmness” and
“contentedness” on the Bond-Lader scales. However, the lower dose reduced alertness on the DISS and, as
a result of performing on the DISS, the previously reduced anxiety effect of this dose was abolished. After
the higher dose, task performance on the DISS battery improved at both post-dose sessions, but after the
lower dose task performance decreased. The results indicated that single doses of sage leaf can improve
cognitive performance and mood in healthy young participants, although the lower dose (300 mg)
appeared to fall somewhat below the level required for beneficial effects. It is possible that inhibitor of
cholinesterases by sage leaf (demonstrated only
in
vitro
) could be involved in the mechanism causing
these effects (Kennedy, 2006).
The anticholinesterase activity of several
Salvia
species and their constituents have been investigated in
the search for new drugs for the treatment of Alzheimer`s disease. The inhibition of acetylcholinesterase
in
vitro
by an ethanolic extract of
S. officinalis
. L (2.5 mg/ml) was 68%, and by oils of
S. officinalis
L. and
S.
lavandulaefolia
(0.1 µg/ml) was 52% and 63% respectively. The monoterpenes 1,8-cineole and α-pinene
from the oil have been identified as the inhibitors of acetylcholinesterase (Barnes et al., 2002).
Symptomatic relief of inflammations of the mouth and throat
Hubbert et al., 2006, compared the efficacy and tolerability of a new sage product presented as a pump
spray in a glass flacon against placebo in the treatment of patients with acute viral pharyngitis. The
therapeutically active principle is a sage leaf fluid extract (1:1, extraction solvent ethanol 70% V/V). The
product contains 15% of the extract in an aqueous solution. Placebo was identically composed regarding
ethanol and excipient concentration and contained a pharmacologically inactive amount of 0.3 % sage leaf
extract for appropriate blinding. According to this article there are no similar approved products available
on the European market. No information about any marketing authorization has been submitted from the
member states. Switzerland is therefore assumed to be the first country to market this spray. The Swiss
Agency for Therapeutic Products have the following product information on a spray for similar use
available on their website
www.swissmedic.ch
(retrieved 2008-12-19):
Salviae extractum ethanolicum liquidum 150 mg, DER: 1:1, excipiens
ad solutionem pro 1 g, corresp. ethanolum 19% V/V.
Methods/Study design
: A randomised, double-blind, placebo-controlled, multicentre, parallel group
phase II/III study with adaptive two-stage design and interim analysis. The study participants were in two
study parts. A total of 286 patients with subjective and objective evidence of pharyngitis were
randomized. In the first study part, 122 patients were recruited from 16 doctor’s offices ( n=31 on 30%
spray, n= 31 on the 15% spray, n= 30 on the 5% spray, n= 30 on placebo) over a period of
3 months. During the interim analysis a sample size re-assessment was done, based on the treatment effect
observed in the first study part. Further 80 patients per group were recruited. In the second study part (the
main study), 164 patients were included from 21 doctor’s offices (n= 82 on 15% spray and n= 82 on
placebo) for a time period of 3 months. The treatment duration per patient was 3 days, including one
baseline visit and one final visit at the doctor’s office. All applications of the spray were made up of 3
puffs each, containing 140 μl sage extract per dose. Prior to the first application spontaneous throat pain
was estimated by the patient on a 100 mm visual analog scale (VAS) for baseline value. During the first 2
hours pain intensity was assessed every 15 minutes and documented in the doctor’s office. Thereafter, all
subsequent pain measurements were done accordingly at home in a way explained by the study personnel.
Inclusion criteria:
were male and female patients aged 18 years and older with symptoms of acute
pharyngitis existing for max. 48 hours. Typical signs (spontaneous pain, local inflammation) of
pharyngitis were confirmed by the study physician. All participants had to document their spontaneous
pain intensity on a VAS with a minimum value of 40 mm on a VAS 100 mm.
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Exclusion criteria:
were a positive test on group A β-hemolytic streptococci, concomitant illness
(rhinosinusitis, laryngitis, tracheitis, bronchitis, fever, wounds or other significant changes in the oral
cave), unallowed comedication, other pain situation (dental or tumour pain, requiring the intake of
analgetic medication ), operations in the oropharynx area up to 4 weeks prior to the study, seizures, or any
known hypersensitivity against the study medication. Pregnant, lactating and women of childbearing
potential who were not taking adequate contraceptive precautions were also excluded.
Measurements/Endpoints:
The primary efficacy variable in both study parts was the change of throat
pain intensity documented every 15 minutes within the first 2 hours after the first application as compared
to baseline (using VAS, area under curve (AUC), and pain intensity differences (PID).
The secondary endpoints in both study parts were
- meaningful pain relief (MPR): max. 50% of the baseline value on VAS
- complete pain reduction after first application
- change of throat pain intensity during study treatment (according to patient’s diary)
- number of patients with early treatment discontinuation due to lack of efficacy
- overall efficacy assessment both by the physician and by the patient
- overall safety assessment both by the physician and by the patient
- adverse events (AE)
Results:
The efficacy analysis demonstrated according to Hubbert et al. (2006), that the 15% spray was
significantly superior in throat pain reduction, whereas for the 30% and the 5% preparation results made
superiority over placebo unlikely in the final analysis. It was not possible to show any dose dependency of
the sage spray in the first study part and the authors suggested that a dose-response linearity may not be
present for herbal preparations.
Regarding MPR and complete pain reduction within the first 2 hours after the first application, no
significant superiority could be shown. A ca 44% pain reduction within 2 hours following the first
application was found in both study parts for the 15 % spray, compared to ca 34% pain reduction in the
placebo group. The author’s states that this difference can be contributed to the sage fluid extract itself
since the placebo contained the same amount of alcohol as the 15% spray.
The magnitude of the mean pain reduction of the 15% spray in the second study part was in the same
range as the placebo effect in the first study part on the mm on the VAS. Possible explanations given by
the authors are that “pain” is a very subjective parameter which makes interpretation of such studies
challenging, and that the two collectives were different to some extent. Also a possible contribution from
the placebo-effect itself giving rise to the result of ca 34% is mentioned.
Only minor side effects such as dry pharynx or burning of mild intensity were seen.
Assessors comment : The product used in this study by Hubert et al., 2006, has a concentration of 15%.
This does not correspond to the concentration for similar formulations with a marketing authorisation, i.e.
the gargle, for external use in the Comission E monograph of 2.5-5%. A gargle and a spray are considered
to be different pharmaceutical formulations, and the strength and posology are not equal. According to the
information available there has not been any equivalent products available within the Community for at
least 10 years. The period of time required for establishing a well established medicinal use of herbal
substance/herbal preparation must not be less than one decade from the first systematic and documented
use of that substance as a medicinal product in the Community.
Therefore, this study can not be assessed as documentation for well-established use until the necessary
period of time required is fulfilled.
II.4.1.2
Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s)
including data on relevant constituents
No data available regarding the herbal substance.
Camphor:
In humans admitted to hospital in a state of acute intoxication after ingestion of 6-10 g camphor, camphor
hydroxylated in the positions 3, 5 and 8 (or 9) were identified as major metabolites in the urine; 5- and 8-
(or 9-) hydroxycamphor were subsequently oxidised to the corresponding ketones and carboxylic acids,
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the latter being conjugated with glucuronic acid (EFSA 2008, with reference to Köppel et al
.
,
1982)
(Accessible at:
http://www.efsa.europa.eu/cs/BlobServer/Scientific_Opinion/afc_ej729_camphor_op_en.p
II.4.2
Clinical Efficacy
The following traditional uses, dosages, method and duration of administrations have been recorded for
Salvia officinalis
L.,
folium in the handbooks:
Traditional use
Dosage
Method and Duration
of Administration
Handbook Reference
External
:
Inflammations and
infections of the
mouth and throat
(stomatitis,
gingivitis,
pharyngitis)
Topical use
:
An infusion of 3 g of the
drug in 150 ml of water
as a mouthwash
or gargle
1
Method
:
For oral administration
or topical application
ESCOP Monographs
(2003)
1
Reference source
dated 1988, 2002
2
Reference source
dated 1988
3
Reference source
dated 1988, 2002
4
Reference source
dated 1989
Duration
:
In hyperhidrosis,
treatment for
2-4 weeks is
recommended, using a
aqueous preparation
Oral use:
in hyperhidrosis:
Tincture
:
(1:10) in 55% ethanol,
75 drops daily
2
Infusion
:
1-1.5 g of dried herb in 150
ml of water, once or several
times daily
3
Internal:
Hyperhidrosis
Dry extract
:
160 mg of dry
aqueous extract
corresponding to 880 mg of
drug three times daily
4
Internal
:
Digestive disorders
(dyspepsia,
flatulence, poor
digestion, bloating)
To reduce
excessive
perspiration, e.g. in
the menopause.
As a gentle,
stimulating tonic.
Internal daily dose
:
3-6 g of dried leaf, usually
as an infusion
1
;
liquid extract 1:1 in 45%
ethanol, 2-6 ml
2
Method:
Oral and topical
administration
British Herbal
Compendium, (Bradley,
2006)
1
Reference source
dated 1983, 1985
2
Reference source
dated 1983, 2003
3
Reference source
dated 1985
Duration
:
No information
Topical use
: mouthwashes
and
gargles : 2.5 g of dried leaf
to 100 ml of water as an
infusion
3
External
:
Inflammations of
the mouth or throat
mucosa
(pharyngitis,
tonsillitis,
stomatitis,
gingivitis glossitis)
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External
:
As an
antiphlogistic for
inflammations of
the mouth and
throat and for
gingivitis and
stomatitis
Tea
:
Depending on the
indication:
Method:
Oral and Topical
Administration
Herbal Drugs and
Phytopharmaceuticals
(Wichtl, 2004)
1
Wichtl, dated 2004
2
Wichtl, dated 2004
3
Wichtl, dated 2004
Gargle
:
Pour boiling water over
3 g finely cut dried leaf.
Steep for 10 minutes,
strain
1
Duration
:
No information
Internal
:
For digestive
disturbances,
flatulence,
inflammations of
the intestinal
mucosa.
Diarrhoea
To treat night
sweats:
Prepare the tea like the
previous, but let it cool
before drinking
2
For gastrointestinal
complaints
:
Pour boiling water over
1.5-2 g finely cut
dried leaf. Steep for
5 min, strain
3
1 teaspoon=about
1.5 g
Internal
:
Digestive
complaints with
mild spasms in the
gastrointestinal
tract, feeling of
distension,
flatulence.
Excessive
perspiration.
Unless otherwise
prescribed, drink one cup of
tea infusion 3-4 times daily,
prepared as follows:
Pour 150 ml boiling water
over 1 teaspoonful (about
1.5g) of sage leafs, or over
a corresponding amount in
one or more teabags. Steep
for about
10-15 minutes, strain
1
For use in the mouth and
throat area, rinse or gargle
with the tea infusion
prepared as follows:
Pour 100 ml boiling water
over an exactly measured
1
1
/
2
teaspoonful (about
2.5g) of sage leaves. Steep
for about 10-15 minutes,
strain
2
Method
:
Oral and Topical
Administration
Herbal Drugs and
Phytopharmaceuticals
(Wichtl, 2004) with
reference to The German
Standard License, 1996
1
dated 1996
2
dated 1996
Duration
:
In acute cases that last
longer than one week or
periodically reoccur, it is
recommended to seek
medical advice
External
:
Inflammations of
the oral and
pharyngeal mucosa
Internal
:
Digestive
complaints
Excessive
perspiration.
Unless otherwise
prescribed:
Internal
:
Daily dose, 4-6 g dried
leaf
1
,
0.1- 0,3 g essential oil
2
,
Method
:
Cut dried leaf for
infusion, alcoholic
extracts and distillates
for gargles, rinses and
paints, and for internal
Herbal Drugs and
Phytopharmaceuticals
(Wichtl, 2004) with
reference to The
German Commission
E monograph, 1990)
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External
:
Inflammations of
the oral and
pharyngeal mucosa
2.5-7.5 g tincture (as per
Erg.B.6
)
3
,
1.5-3 g fluidextract
(as per
Erg.B.6
)
4
use and as the pressed
juice of fresh plants
1
Dated 1990
2
Dated 1990
3
Source referred is
Ergänzungsbuch
zum Deutschen
Arzneibuch, 1941
4
Source referred is
Ergänzungsbuch
zum Deutschen
Arzneibuch, 1941
5
Dated 1990
6
Dated 1990
Duration
:
No information
Externally
:
For gargles and rinses: 2.5
g dried leaf or 2-3 drops
essential oil in 100 ml of
water as an infusion or 5 g
alcoholic extract in one
glass water
5
As a paint: Undiluted
alcoholic extract
6
Internal
:
Dyspeptic
symptoms and
excessive
perspiration.
Internal
:
Dried leaf
: 1-3 g, three
times daily
2
Infusion
: 1-3 g in 150 ml
water, three times daily
3
Dry aqueous extract
5.5:1
(w/w): 0.18-0.36 g, three
times daily
4
Fluidextract
: 1.5-3 g
(Erg.B.6)
5
Essential oil
: 0.1-0.3 ml.
7
Succus
: Pressed juice of
fresh plant in 25%
alcoholic
preservation
8
Method
:
Internal or External
Administration
Duration
:
No information
Herbal Medicine
Expanded Comission E
Monographs
(Blumenthal, 2000)
1
Blumenthal dated
2000
2
Blumenthal dated
2000
3
Blumenthal dated
2000
4
Blumenthal dated
2000
5
Source referred is
Ergänzungsbuch
zum Deutschen
Arzneibuch, 1941
6
Blumenthal dated
2000
7
Blumenthal dated
2000
8
Blumenthal dated
2000
9
Blumenthal dated
2000
10
Blumenthal dated
2000
External
:
For inflammations
of the mucous
membranes of nose
and throat.
External
:
Gargle or rinse
: Use warm
infusion.
2.5 g cut leaf in 100 ml
water;
or 2 to 3 drops of essential
oil in 100 ml water; or use
5 ml
of fluidextract diluted in 1
glass water, several
times daily
9
Paint
:
Apply the undiluted
alcoholic fluidextract to the
affected area with a brush
or swab
10
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Internal
:
Flatulent
dyspepsia,
Hyperhidrosis
galactorrhoea
Internal:
Leaf
:
1-4 g as an infusion three
times daily; 4-6 g daily
1
Liquid extract: 1-4 ml (1:1
in 45% alcohol) three times
daily
2
Method
:
Oral administration
Duration
:
No information
Herbal Medicine,
(Barnes et.al., 2002;
2007)
1
Reference source
dated 1983,1998
2
Reference source
dated 1983
3
Reference source
dated 1998
External
:
Gargle, mouthwash
(pharyngitis,
uvulitis, stomatitis,
gingivitis,
glossitis)
External
:
Gargle/ rinses : 2.5 g/100
ml water
3
Internal
:
Regulate
perspiration
(during
menopause,
nightsweat)
Ordinary dose:
Internal
:
Tinctur: 60 drops daily
1
30-
50 drops several times a
day
2
Warm infusion: 2-3
spoonfuls (=3.4-5.1g) of the
leaves
Method
:
Internal and external
administration
Duration
:
No information
Lehrbuch der
Biologischen Heilmittel,
Madaus 1938
1
Source referred to is
Krahn 1896
2
Source referred to is
Hager, year not
specified
Lactation
inhibitation
Gastrointestinal
complaints
External
:
Respiratory
diseases and
inflammations in
mouth and throat
Internal
Tincture (1:10), extraction
solvent: ethanol 70% V/V
tincture (1:10) 2.5-7.5 g
daily, divided in 3 doses.
5-10 g (1-2 spoon) of
tincture, diluted in a glass
of water, for rinsing or
gargling; tincture (1:10)
undiluted, for direct
application on the gum.
Duration
No information
This tinctur and the
ethanol percentage is
specified as a seperate
monograph in Ph. Eur
2008 and the Deutsches
Arzneibuch 6. Ausgabe
1926. Spiritus dilutus is
Ethanol 68-69% (V/V) =
60-61% (m/m).
Information concerning
this tincture is
documented in earlier
German Pharmacopeias
(Ergänzungsbuch zum
Deutschen Arzneibuch
(Erg. B. 6. Stuttgart
1956, 1958
For symptomatic
treatment of mild
dyspeptic
complaints such as
heartburn and
bloating
External
For symptomatic
treatment of
inflammations in
the mouth or the
throat
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II.4.2.1
Dose response studies
There are no dose response studies available
II.4.2.2
Clinical studies (case studies and clinical trials)
Some clinical studies are performed as specified in II.4.1.1
II.4.2.3
Clinical studies in special populations (e.g. elderly and children)
In a randomized clinical study, 15 elderly patients treated with 60 drops/day of sage leaf liquid extract
(1:1.45% ethanol) for 16 weeks experienced slightly more mild gastrointestinal complaints than those
receiving placebo, but the differences were not statistically significant (Bradley, 2006).
The oral use of sage is not recommended in children due to the lack of adequate data, and the presence of
compounds (such as thujone and camphor) with neurotoxic effects. A warning is recommended for the use
in children and adolescents because data are not sufficient and medical advice should be sought when
children have such symptoms.
The recommended dosage for adults and children over 12 years for oral use is supported by use in member
states. There are no studies in adolescents between 12 and 18 years available.
Oromucosal use in children over 4 years is also listed under the reported posologies from the European
Member States.
Background for marketing authorisation for oromucosal use in children:
No clinical studies in children are available, but oromucosal use in children was accepted in one member
state in 2004 in accordance with the national regulations for the described oromucosal posology. A single
dose for oromucosal use was in this safety assessment stated to contain no more than 0.5 mg thujone in
150 ml of water. The absorption is estimated to be negligible and children older than 4 years of age are
considered able to rinse or gargle without swallowing.
II.4.3
Overall conclusions on clinical pharmacology and efficacy
Several clinical studies have been conducted to determine the effectiveness of herbal preparations of
Salvia officinalis
L.
Based on these results it is plausible that sage has effects that support the traditional
indications, however, the clinical data cannot be considered to fulfil the criteria required for “well-
established medicinal use” according to directive 2001/83/EC. According to the information available,
products used in the studies cannot be considered to be corresponding to any of the products available
within the Community for the required time period of at least 10 years. More studies are needed and this is
also mentioned by Barnes et al., 2007. Overall the existing data are not sufficient at present to show
efficacy of sage in a well-established use. However, the data can be accepted for establishing
“
plausibility
” of the traditional use. Sufficient data are available to develop a Community herbal
monograph on the traditional use of sage leaf.
Based on the limited data available on pharmacokinetics for the herbal substance, no conclusion can be
made.
II.5
C
LINICAL
S
AFETY
/P
HARMACOVIGILANCE
II.5.1
Overview of toxicological/safety data from clinical trials in humans
II.5.2
Patient exposure
Products containing
Salvia officinalis
L., folium is widely available. The products have various regulatory
status. A considerable patient/consumer exposure must be anticipated as sage is widely used as a natural
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source of food flavouring (Barnes et al., 2007) and in herbal medicinal products on the market in the
European Member States. .
II.5.3
Adverse events and serious adverse events and deaths
Sage essential oil:
After prolonged use of alcoholic extracts or of the pure essential oil, epileptiform convulsions can occur
(Wichtl, 2004, with reference to The German Commission E monograph, 1990).
Convulsant activity in humans (and animals) has been documented for sage oil. Clinical intoxications
were characterized by tonic-clonic or solely clonic convulsions associated with a comatose state, which
required admission to an intensive care unit Millet et al. 1981).
A case of human poisoning has been documented following ingestion of sage oil for acne.
There are several anecdotal and case study reports of the acute effects of essential oils containing
thujone causing seizures in humans, indicating that the animal data are of relevance to humans. In most
cases, the doses are not well determined but one case was associated with about twelve drops of the
essential oil of sage, which caused a generalized tonic-clonic seizure followed by a postictal coma lasting
for 15 minutes. However, there are no reliable studies of the long-term effects of sub-convulsive doses
either on the nervous system or on the liver (Scientific Committee on Food, 2003).
More than a few drops of the oil can be toxic due to the high thujone content. Thujone is a nervous system
stimulant that may cause convulsions at high doses (
http://extoxnet.orst.edu/newsletters/n42_83.htm
)
.
Sage oil is reported to be a moderate skin irritant and is not recommended for use in aromatherapy (Barnes
et al., 2007; Newall et al., 2002).
Sage leaf herbal tea:
Case Report: A previously healthy 18 month-old female with 3 days of intermittent vomiting and
diarrhoea without fevers, was given a tea made from water and a home-grown herb. Two hours after
drinking the tea, the child developed tonic–clonic contractions of the upper extremities, left eye deviation,
and unresponsiveness that lasted less than 1 min. There was no prior history of convulsions. The child was
evaluated in the ED, where she was afebrile with a normal physical exam, head CT, CBC, and serum
chemistries. She was discharged home, but 18 hours after her initial ingestion, she developed three
subsequent seizures requiring treatment with lorazepam. An EEG the following morning showed some
parietal lobe slowing, interpreted as a possible seizure focus. A sample of the herb was identified by a
botanist as
S. officinalis
L. or sage. Conclusion: Tea made from sage may have kindled convulsions in a
child with a previously unmasked seizure focus (Tong et al., 2003).
Allergic contact dermatitis caused by spices is well documented; however, commercial patch tests are
unavailable. Between October 1991, and August 1992, a series of fifty-five patients with suspected contact
dermatitis were tested at Ochsner Clinic for sensitivity to a group of spices at concentrations of 10 percent
and 25 percent in petrolatum. Concordant patch test results (positive at concentrations of 10 percent and
25 percent) were most common with ginger (seven), nutmeg (five), and oregano (four); the remaining
spices produced zero or one positive responses. Patients exhibiting positive reactions at only one
concentration were more likely to do so at 25 percent: nutmeg (five), ginger and cayenne (four), curry,
cumin, and cinnamon (three), turmeric, coriander, and sage (two), oregano (one), and basil and clove
(zero). Single responses at this level may represent a threshold for detecting true allergy or, as an
alternative, a marginal irritant reaction. Those responding to only 10 percent concentrations generally did
so weakly. Three patients were deemed to have relevant patch test responses to spices (Futrell et al.,
1993).
II.5.4
Laboratory findings
None known concerning
Salvia officinalis
L.
II.5.5
Safety in special populations and situations
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Pregnancy and lactation
: Sage is contra-indicated during pregnancy and lactation (ESCOP 2003, Barnes
et al., 2002, 2007). The volatile oil contains a high proportion of α- and β- thujones, which are known to
be abortifacient and emmenagogic (Barnes et al., 2002, 2007).
The pure essential oil and alcoholic extracts should not be taken during pregnancy (Wichtl 2004, with
reference to the German Commission E monograph), (Blumenthal et al., 2000).
Assessors comment: Safety during pregnancy and lactation has not been established.
In the absence of sufficient data, the use during pregnancy and lactation is not recommended.
Use in children:
No data about
Salvia officinalis
L. are available. Use in children and adolescents under 18 years of age is
not recommended because data are not sufficient and medical advice should be sought.
Camphor:
The American Academy of Pediatrics concluded that although adults recovered from ingestions of as
much of 42 g camphor, the ingestion of 2 g generally produces dangerous effects. In children, ingestions
of 0.7 to 1.0 g of camphor have proven fatal (EFSA 2008, with reference to AAP, 1994). In the pediatric
population, exposure to as little as 500 mg camphor is cited as a cause of mortality. More commonly,
750 to 1000 mg is associated with the development of seizures and death. Currently available products
with 10% camphor contain 500 mg in 5 ml. It is concluded that small doses are dangerous. In children less
than 6 years of age, exposure to 500 mg or more requires rapid triage to the closest health care facility.
According to a recently published case report, a 10-year old boy presented at the emergency room with
symptoms of lethargy, nausea, vomiting and rigors. Approximately 24 hours previously, he had chewed
three over-the-counter cold remedy transdermal patches containing 4.7% (95.4 mg/patch) camphor and
2.6% menthol as active ingredients (EFSA 2008, with reference to Ragucci et
al
.,
2007). On the basis of
an assumed body weight of 30 kg, this would correspond to an
intake of camphor of approximately
10 mg/kg bw.
1000 mg of camphor is a concerning exposure in the child under 6 years of age (Love et al., 2004)
Exposure to camphor should not exceed 2 mg/kg bw on a single day in any age group (EFSA, 2008).
According to the extraction rate of 35.4% for camphor shown in the study of Länger et al., 1996, a toxic
amount for children and adults will theoretically not be reached in a tea-preparation of 1-9 g sage leaf.
Drug interactions:
No drug interactions are documented clinically. However, the potential for preparations
of sage to interact with other medicines administered concurrently, is the basis for giving this
precautionary information about potential interactions. According to the available information, it is given
as a precautionary advice that concomitant use of other GABA-acting medicinal products should be
avoided in thujone containing herbal medicines. The mechanism of neurotoxicity has been ascribed to the
available information regarding α-thujone and its effect on the γ-aminobutyric acid (GABA) type A
receptor. When the nerve impulses are inhibited, neurons fire to easily and it is known that this could
potentially unbalance the brain’s message delivery system causing a seizure or epileptic attack (Hold et al.
2000).
Assessors comment:
Potential for clinically relevant interactions based on the pharmacodynamic properties and in vivo
pharmacokinetic studies of the medicinal product, with a particular emphasis on the interactions, which
result in a recommendation regarding the use of this medicinal product can be useful. This also includes
in vivo
interaction results which are important for extrapolating an effect on a marker (‘probe’) substance
such as α-thujone to other medicinal products having the same pharmacokinetic property as the marker.’
Other sources has also mentioned the hypoglycemic effects (Newall et al., 1996), but due to limited
evidence from preclinical studies of hypoglycemic activity (Barnes et al., 2007) this information is not
included in the monograph.
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Overdose:
Sage oil:
A sense of heat, tachycardia, feelings of vertigo and epileptiform convulsions can occur following
prolonged intake of ethanolic extracts of the drug or volatile oil, or through overdose (corresponding to
more than 15 g of the sage leaves) (Fleming, 1999; Blumenthal et al. 2000; Wichtl, 2004). A case of
human poisoning has been documented following ingestion of sage oil for acne (Barnes et al. 2007 with
reference to Centini et al. 1987).
Not many
Lamiaceae
poisonings are known. The essential oils of
Lamiaceae
can be dangerous when
ingested in large doses. The most noxious are those, like official sage oil (
Salvia officinalis
L.), that
contain monoterpenoid ketones like thujones [(-)-3-isothujone and (+)-3-thujone]. The symptomatology of
this type of intoxication is characterized by epileptiform convulsions, sometimes with cyanosis, and
interrupted by periods of hypotonus and hyporeflexia.
Thujone:
From the study of Dettling et al. (2004), it can be assumed that at least a concentration of 14.4-16.8 mg
thujone per person (60 kg) might lead to changes in attention performances and mood alterations.
Sage can be added to foodstuffs providing the concentration of thujones (α and β) present in the final
product does not exceed current Regulatory Status on Thujone (Scientific Committee on Food, 2003)
European Union:
Annex II of Directive 88/388/EEC (EEC, 1988) on flavourings sets the following maximum levels for
thujone (α and β) in foodstuffs and beverages to which flavourings or other food ingredients with
flavourings properties have been added: 0.5 mg/kg in foodstuffs and beverages
with the exception of
5 mg/kg in alcoholic beverages with not more than 25% volume of alcohol
10 mg/kg in alcoholic beverages with more than 25% volume of alcohol
25 mg/kg in foodstuffs containing preparations based on sage
35 mg/kg in bitters.
Thujone may not be added as such to food.
Thujone is not authorized for use as a flavouring substance in the USA.
Estimates of intakes of thujone have been made in France and the United Kingdom. In France, the mean
and 97.5th percentile daily intakes were estimated to be 15.6 and 44.3 µg/kg bw/day respectively. The
intakes in the United Kingdom were estimated to be somewhat lower at 3.9 and
14.2 µg/kg bw/day respectively. Both estimates were based on the maximum limits proposed by the CoE
(Council of Europe, 2000). The major dietary contribution to thujone intake appeared to derive from sage
and sage-flavoured products, and alcoholic beverages (Scientific Committee on Food, 2003).
Camphor:
Dietary exposure to camphor arises from the consumption of foods flavoured by using either
herbs (e.g. basil, coriander, marjoram, rosemary, sage), their essential oils or the chemically defined
flavouring substance
d
-camphor).
The dietary exposure to camphor was estimated to be 1.5 mg/person/day (Council of Europe, 2001).
Assuming an average body weight of 60 kg, this corresponds to an exposure of 25 μg/kg bw/day
Limits for
d
-camphor, suggested by the Council of Europe were 10 mg/kg in beverages (including
alcoholic drinks), 25 mg/kg in food in general, 100 mg/kg in candies, 140 mg/kg in fresh cheese,
150 mg/kg in sauces and condiments. (EFSA, 2008).
The Scientific Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food
(Panel) have assessed the toxicity risks associated with the exposure to camphor in various food
commodities (EFSA 2008).
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In humans, signs of camphor intoxication include central nervous stimulation, oral and gastric irritation,
nausea and vomiting, excitement, hallucinations, delirium, muscular excitability, tremors, convulsions and
urinary retention (EFSA 2008, with reference to Opdyke, 1978). Locally it can produce irritation of skin,
eyes and mucous membranes of the respiratory tract (EFSA, 2008)
Intoxications from camphor have been frequently reported in literature, mostly involving the accidental
ingestion of camphorated oil (20% camphor in cottonseed oil). For example 20 children aged 1 to 4 years
who became ill after ingestion of 1 to1.5 tablespoons of camphorated oil equivalent to about 3 to 4.5 g
camphor. Most of them had seizures, but recovered (EFSA 2008, with reference to Benz, 1919).
As little as 1 g camphor ingested in 1 teaspoonful of camphorated oil was fatal in a 19-month-old child
(EFSA 2008, with reference to Smith et al., 1954).
“The probable lethal oral bolus dose has been reported to be in the range of 50 to 500 mg/kg bw. No acute
toxicity was reported after doses lower than 2 mg/kg bw and clinically insignificant signs of toxicity may
be seen in sensitive individuals at doses of 5 mg/kg bw and higher, whereas clinically manifest toxicity in
sensitive persons would require doses higher than 30 mg/kg bw.” Although acute exposure estimates via
food for children and adults are about 2-5 times and 6-14 times, respectively, lower than the dose of 2
mg/kg bw, the Panel considered dose-response relationship to be robust and to cover also inter-individual
variability in sensitivity to camphor, and thus “concluded that that it is unlikely that acute effects may
occur in relation to consumption of foods providing less than 2 mg/kg bw in one large portion.”
Limit exposures
Daily doses
2 mg/kg: no acute effects
120 mg/day
5 mg/kg: insignificant effects in sensitive individuals
300 mg/day
30 mg/kg: clinically manifest toxicity in sensitive individuals
1800 mg/day
50-500 mg/kg: a probably lethal oral bolus
3-30 g/day
Assessor’s comment:
Due to variations of thujone and camphor it is difficult to set an exact value on the maximum amount of
sage leaves which could result in a overdose based on the available data.
Drug abuse:
Only experimental use or abuse due to the reputed effects of another species,
Salvia
divinorum
L. (
Lamiaceae
) has been used for centuries by the Mazatecan culture This species has gained
popularity due to its potent hallucinogenic effects (Grundmann et al., 2007).
Withdrawal and rebound:
No reactions reported.
Ability to drive or operate machinery or impairment of mental ability:
No known effects on ability to
drive and use machines (ESCOP, 2003), however according to the study performed by Dettling et al.
(2004) it was shown that attention performance was changed under the influence of high thujone
concentrations.
Thujone:
Dettling et al. (2004), determined if the impacts of thujone (absinthe) on attention performance and mood
were different from those experienced with beverages that contain only alcohol. Twenty-two healthy
subjects were tested using an attention performance test, which was developed for aptitude diagnostics in
the area of 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: the one (Masel Mood test) records the factors vitality, intra-psychic equilibrium, social
extraversion and attentiveness, the other (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
EMA/HMPC/330383/2008
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blood alcohol concentration of 0.05% (= 0.5‰) for each subject. Before drinking every subject received a
small standard meal; the beverage had to be drunk then within 10min. 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 revealed results that show a pattern similar to the results after 30 min
but not so pronounced (not significant anymore). 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 given with the theory that the effects of alcohol on attention processing may be an
inverted U-shaped function and that thujone shifts the dose-effect to the left. The missing alteration in
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. Most prominent difference was
seen for the point “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. The antagonistic effect of
thujone on the GABA-receptor lead to an increase in fear sensations and also have a stimulating and
rousing effect, while ethanol acts as a GABA-enhancer (anxiolytic, sedative and amnesic).
Assessors comment: The study by Dettling et al. (2004) showed that approximately 15 mg thujone/person
(60 kg) leads to changes in the in attention performance, while intake of approximately 1.5 mg
thujone/person gave no such changes in attention performance. Accordingly for safety reasons, 1.5 mg
/person in a single dose is suggested as a limit for thujone content in thujone containing herbal medicinal
products.
Further clinical studies are needed for assessment of effects on ability to drive or operate machinery or
impairment of mental ability, and precautions are included in the monograph.
II.5.6
Overall conclusions on clinical safety
The essential oil of
Salvia officinalis
L. contains constituents like thujone and camphor, which have toxic
effect in high doses. Most studies have been performed
in vivo
in animals, and toxicological dose limits
have been set based on the available toxicological data, case reports and clinical studies. The toxic effect
appears to be of central nervous origin. Maximum apparent doses of rectal or oral preparations regarding
the camphor content of sage leaf are up to about 500 mg/day, which may cause insignificant effects in
sensitive
individuals.
Highest
estimates
of
exposure
via
food
are
0.34 mg/kg bw (adults, about 20 mg/day) and 0.83 mg/kg bw (children).
The camphor content in sage leaf preparations for oral and oromucosal use, are not expected to cause
safety concern if dose recommendations are followed.
The study by Dettling et al. (2004) showed that approximately 15 mg thujone/person (60 kg) leads to
changes in the in attention performance, while intake of approximately 1.5 mg thujone/person gave no
such changes in attention performance. Accordingly for safety reasons, 1.5 mg /person in a single dose is
suggested as a limit for thujone content in thujone containing herbal medicinal products.
The presence of thujone in sage leaf preparations in the monograph is restricted to a daily intake of 5.0
mg/person for a maximum duration of 2 weeks as no data were retrieved for more serious conditions that
could alter the benefit/risk assessment. There is a lack of safety and toxicity data for the long-term effects,
hence limitations in duration of use is recommended.
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During the meetings of the MLWP after the public consultation, the following points led to amendments
in the monograph and the assessment report:
Since this is not a new chemical, but an herbal preparation, a reduced safety factor is accepted based on
the extensive traditional use of a variety of herbal sage leaf preparations covered by the monograph. The
safety data available for assessment are from single constituents, and not from sage leaf as a whole. Even
when acknowledging that thujone containing essential oils are amongst the essential oils associated with
the highest risk, the recommended posology of the preparations covered by the monograph and the
restricted duration of use will provide a sufficient safety margin. An intake of about 0.08 mg thujone/kg
bw for a 60 kg adult are assessed as safe when used occasionally in foodstuff and beverages. This
exposure level is not a recommended daily intake proven safe. However, as serious side effects on the
nervous system and the liver, remains to be shown in clinical studies and in traditional use, we consider
that a precautionary approach is taken with a maximum thujone content of 5.0 mg/day and a duration of
use of maximum 2 weeks.
Products exceeding the recommended maximum thujone limit cannot be recommended for marketing
without supplementary safety studies and a detailed benefit/risk assessment.The MLWP discussion
focused on the lack of adverse drug reactions indicating that thujone could be less neurotoxic than thought
in the past. The potential danger of the substance is possibly overrated because of the problems
encountered with the consumption/misuse of liquors. There are no side effects reported for the Salviae
folium.
The importance of limiting the exposure of thujone must also be seen together with the background intake
of thujone from the use of Sage leaf based spices and other sources of thujone such as alcoholic beverages
based on Absinth.
Preparations with less than 5.0 mg thujone/day
:
Herbal medicinal products complying with the monograph must have a specification showing that the
daily amount of thujone does not exceed the set limit with the approved posology.
Preparations with more than 5.0 mg thujone/day:
These herbal preparations should provide safety studies and a detailed benefit/risk assessment .
The thujone content in sage leaf preparations for oral and oromucosal use, are not expected to cause safety
concern if dose recommendations are followed and the specified maximum limits of thujone are not
exceeded.
Sage leaf can be recognized as safe when used in recommended dosages under specified conditions.
If dose recommendations are followed in relation to camphor and the specified maximum limits of thujone
content are kept, sage leaf should not be a safety concern in adults. However, exposures of children will be
limited to be sure that doses causing significant toxic effects are avoided.
The maximum daily dose of 5.0 mg thujone/day is supposed to be divided according to listed posologies
in the monograph. Therefore the single dose is always lower than the amount postulated as the lowest
described limit of thujone action in the study by Dettling et al., 2004. The content of thujone must be
shown for every batch.
II.6
O
VERALL
C
ONCLUSIONS
There are sufficient data available to develop a Community monograph on the traditional use of sage leaf.
Traditional use has shown that sage leaf can be recognised as safe when used in recommended dosages
under the conditions specified in the monograph.
The clinical data cannot be considered to fulfil the criteria required for “well-established medicinal use”
according to directive 2001/83/EC.
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Traditional medicinal use of sage leaf has been found to fulfil the requirement of medicinal use for at least
30 years (15 years within the Community) according to Directive 2004/24/EC for following indications:
1) Traditional herbal medicinal product for symptomatic treatment of mild dyspeptic complaints such
as heartburn and bloating.
2) Traditional herbal medicinal product for symptomatic treatment of excessive sweating
3) Traditional herbal medicinal product for symptomatic treatment of inflammations in the mouth or
the throat
4) Traditional herbal medicinal product for relief of minor skin inflammations..
Concomitant use of other GABA-acting medicinal products should be avoided. After intake of
preparations from sage leaf patients should not drive or operate machinery for safety reasons.
As minimum required data on mutagenicity (Ames’ test) are not available, an inclusion to the Community
list of traditional herbal substances and preparations can not be recommended.
Sage essential oil is characterised by high levels of thujone. Consumption of sage essential oil in single
ingredient products involves a high risk of exceeding the maximum recommended daily intake of thujone.
Thujone is toxic and may cause seizures at high doses as shown in animal studies and indicated from case
reports. The available clinical and toxicological data on sage essential oil can not be considered adequate
to fulfil the criteria required for developing a Community herbal monograph. For this reason, no
monograph will be made on sage essential oil before supplementary information on clinical and
toxicological data for sage essential oil are considered adequate to fulfil those criteria.
III.
ANNEXES
III.1
III.2
L
ITERATURE
R
EFERENCES
2
According to the ‘Procedure for the preparation of Community monographs for traditional herbal medicinal
products’ (EMEA/HMPC/182320/2005 Rev.2)
3
According to 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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Source: European Medicines Agency
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