Community herbal monograph on
Juniperus communis
L.,
pseudo-fructus
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
Juniperus communis
L., pseudo-fructus (juniper
berry)
i) Herbal substance
As defined in the Ph. Eur. monograph.
ii) Herbal preparations
a)
Comminuted herbal substance
b)
Liquid extract (DER 1:1) with 25% ethanol v/v
c)
Tincture (ratio of herbal substance to
extraction solvent 1:5), extraction solvent
ethanol 45% v/v
d)
Soft extract (DER 1.7-1.8:1), extraction
solvent water
Well-established use
Traditional use
Herbal substance or comminuted herbal substance
as herbal tea for oral use.
Herbal substance or herbal preparations in solid or
liquid dosage forms for oral use.
The pharmaceutical form should be described by
the European Pharmacopoeia full standard term.
1
The material complies with the Ph. Eur. monograph (ref. 01/2008:1532).
2
The declaration of the active substance(s) for an individual finished product should be in accordance with relevant herbal
quality guidance.
Community herbal monograph on Juniperus communis L., pseudo-fructus
EMA/HMPC/441929/2008
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4.1.
Therapeutic indications
Well-established use
Traditional use
Indication 1)
Traditional herbal medicinal product to increase
the amount of urine to achieve flushing of the
urinary tract as an adjuvant in minor urinary tract
complaints.
Indication 2)
Traditional herbal medicinal product for
symptomatic relief of digestive disorders such as
dyspepsia and flatulence.
The product is a traditional herbal medicinal
product for use in specified indications exclusively
based upon long-standing use.
4.2.
Posology and method of administration
Well-established use
Traditional use
Posology
Adults and elderly
i) Herbal substance
Indication 1)
Cone berries:
To start on day 1 with 5 cone berries, increasing
the number every day by 1 cone berry (well
chewed) up to 15 cone berries, then decrease the
number (1 per day less) to 5 cone berries. So the
duration of the therapy is 21 days, the maximum
daily dose being 15 cone berries.
ii) Herbal preparations
Indications 1) and 2)
Herbal tea:
2 g of the crushed or comminuted herbal
substance in boiling water as a herbal infusion, 2-
3 times daily
Liquid extract: 2-4 ml 3 times daily
Tincture : 1-2 ml 3 times daily
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Well-established use
Traditional use
Indication 1)
Soft extract: 0.57 g once daily
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
If the symptoms persist longer than 2 weeks
during the use of the medicinal product, a doctor
or a qualified health care practitioner should be
consulted.
Method of administration
Oral use.
Indication 1)
For preparations other than tea preparations,
ensure appropriate fluid intake.
4.3.
Contraindications
Well-established use
Traditional use
Hypersensitivity to the active substance(s).
Severe renal disease including infectious
interstitial nephritis, pyelitis and pyelonephritis.
Indication 1)
Conditions where reduced fluid intake is
recommended (e.g. severe cardiac diseases).
4.4.
Special warnings and precautions for use
Well-established use
Traditional use
The use in children and adolescents under 18
years of age has not been established due to lack
of adequate data.
If the symptoms worsen during the use of the
medicinal product, a doctor or a qualified health
care practitioner should be consulted.
For preparations containing ethanol, the
appropriate labelling for ethanol, taken from the
‘Guideline on excipients in the label and package
Community herbal monograph on Juniperus communis L., pseudo-fructus
EMA/HMPC/441929/2008
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Well-established use
Traditional use
leaflet of medicinal products for human use’, must
be included.
Indication 1)
Appropriate fluid intake is recommended.
If complaints or symptoms such as fever, dysuria,
spasms or blood in the urine occur during the use
of the medicinal product, a doctor or a qualified
health care professional should be consulted.
Concomitant treatment with synthetic diuretics is
not recommended.
4.5.
Interactions with other medicinal products and other forms of
interaction
Well-established use
Traditional use
None reported.
4.6.
Pregnancy and lactation
Well-established use
Traditional use
Safety during pregnancy and lactation has not
been established. In the absence of sufficient
data, the use during pregnancy and lactation is
not recommended.
4.7.
Effects on ability to drive and use machines
Well-established use
Traditional use
No studies on the effect on the ability to drive and
use machines have been performed.
4.8.
Undesirable effects
Well-established use
Traditional use
Allergic skin reactions have been reported. The
frequency is not known.
If other adverse reactions not mentioned above
occur, a doctor or a qualified health care
practitioner should be consulted.
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Well-established use
Traditional use
In case of prolonged use and overdose, urine will
smell of violets. There may be renal irritation and
pain in and near the kidney, strong diuresis,
albuminuria, haematuria, purplish urine,
gastrointestinal upsets, accelerated heartbeat and
blood pressure. Rarely symptoms of central
stimulation like convulsions occur as well as
metrorrhagia and abortion.
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.
There is limited evidence from preclinical studies
that juniper may influence glucose levels in
diabetes.
5.2.
Pharmacokinetic properties
Well-established use
Traditional use
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended.
5.3.
Preclinical safety data
Well-established use
Traditional use
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended, unless
necessary for the safe use of the product.
Adequate tests on reproductive toxicity,
genotoxicity and carcinogenicity have not been
performed.
Well-established use
Traditional use
Not applicable.
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12 November 2009
Community herbal monograph on Juniperus communis L., pseudo-fructus
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Assessment Report
Table of contents
Table of contents
................................................................................................................... 2
1. Introduction....................................................................................................................... 3
Not applicable. .........................................................................................................
4
1.3. Search and assessment methodology....................................................................
7
2. Historical data on medicinal use ........................................................................................ 7
2.1. Information on period of medicinal use in the Community ........................................
7
preparations and indications.......................................................................................
9
3. Non-Clinical Data ............................................................................................................. 10
preparation(s) and relevant constituents thereof ......................................................... 1
0
preparation(s) and relevant constituents thereof ......................................................... 1
6
preparation(s) and constituents thereof ..................................................................... 1
6
4. Clinical Data ..................................................................................................................... 17
4.1. Clinical Pharmacology ....................................................................................... 1
7
including data on relevant constituents ...................................................................... 1
7
including data on relevant constituents ...................................................................... 1
7
4.2. Clinical Efficacy ................................................................................................ 1
8
4.2.1. Dose response studies.................................................................................... 1
8
4.2.2. Clinical studies (case studies and clinical trials).................................................. 1
8
4.2.3. Clinical studies in special populations (e.g. elderly and children)........................... 1
8
4.3. Overall conclusions on clinical pharmacology and efficacy ...................................... 1
8
5. Clinical Safety/Pharmacovigilance................................................................................... 18
5.1. Overview of toxicological/safety data from clinical trials in humans.......................... 1
8
5.2. Patient exposure .............................................................................................. 1
8
5.3. Adverse events and serious adverse events and deaths ......................................... 1
9
5.4. Laboratory findings .......................................................................................... 1
9
5.5. Safety in special populations and situations ......................................................... 2
0
5.6. Overall conclusions on clinical safety ................................................................... 2
0
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L., pseudo-fructus
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1.
Introduction
1.1.
Description of the herbal substance(s), herbal preparation(s) or
combinations thereof
Herbal substance(s)
The herbal substance is mentioned in the DAB 10, ÖAB 90, Ph. Fr. X, Ph. Helv. VII, British Herbal
Pharmacopoeia 1983 and the European Pharmacopoeia 6.0. It is described as ‘dried ripe cone berry of
Juniperus communis
L.’. The plant part is described as Juniperi pseudo-fructus. The English name is
Common Juniper. Juniper belongs to the family of the Cupressaceae and the class of the
Gymnosperma (Ph. Eur. 2008).
The plant has its origin in Northern Europe and mountain areas. The herbal substance is imported
among others from Italy, from the countries on the Adriatic coast and from Albania. Leaves are
needles occurring with three on the branches. The berry-like fruits are open on the apex with a
triradiate mark and depression which indicate the sutures of the three scales. They are violet to black-
brown, often bluish pruinose and up to 10 mm in diameter. There are usually three, very hard, oblong,
triangular seeds (Bruneton, 1999; Wichtl, 1994).
There are 4 subspecies of
Juniperus communis
occurring in Europe: ssp.
alpine
(NEILR.) CELAK; ssp.
communis
; ssp.
hemisphaerica
(J. et C. PRESL), ssp.
nana
(Willd.) Syme (Hänsel
et al.
1993).
Adulteration is occasionally observed with fruits of other
Juniperus
species. Fruits from
Juniperus
oxycedrus
L. (cade- or prickly-jumper) are brown-red and larger than genuine juniper berries.
Juniperus sabina
L. (savine) has almost black fruits with a diameter of only 5-8 mm (Wichtl, 2002).
Other species of Juniper mentioned in literature are
Juniperus oxycedrus
,
Juniperus phoenicea
and
Juniperus virginiana
. Their oils are used only as fragrance ingredients in cosmetics (Anonymous,
2001).
Composition of the cone berries has been described by Hänsel
et al.
(1993), Schilcher & Heil (1994),
Bruneton (1999), Barnes
et al.
(2007), Duke (1988), in the ESCOP monograph (ESCOP, 2003), Martin
et al.
(2006) The cone berries contain between 0.5 and 3.42 % of essential oil. The content of
essential oil may vary depending on the origin of the herbal substance (Banthorpe
et al.
1973).
The ESCOP monograph refers to cone berries from Greek plant material as containing high levels of
essential oil. The cone berries may not contain less than 10 ml/kg of essential oil. The amount of
essential oil can be up to 3%. The essential oil of Juniper cone berries contains about 105 constituents
(ESCOP, 2003).
The following constituents were identified in Juniperi pseudo-fructus:
Monoterpenes (about 58% of the essential oil); the essential oil contains mainly α-pinene
(20%), limonene (8.7%), myrcene (8.5%) and β-pinene, myrcene, sabinene, 1,4-cineol,
camphene, Δ³-carene, terpinen-4-ol, terpinolene, 4-terpineol, β-elemene-7-ol
Sesquiterpenes:
-cadinene, α-cadinene, β-cadinene
Diterpenic acids: isocommunic acid; labdane diterpenes
C
12
terpenoid: geijerone
Tannins: proanthocyanidines (condensed), gallocatechin and epigallocatechin
Flavonoids: amentoflavone, quercitin, isoquercitrin, apigenin and various glucosides
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Juniperus communis
L., pseudo-fructus
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Invert sugar (30%); glucose + fructose (about 30%) and pectin
Organic acids: malic acid, ascorbic acid, glucuronic acid
Lignan: desoxypodophyllotoxin
Cerin
Resins
Juniper
in: an amorphous substance isolated from decoctions (most probably a complex of
sugars and tannins)
There is no consensus about the possible role of sugars, salts and saponins in the cone berries. The
content of the cone berries varies with the origin and the ripening.
Herbal preparation(s)
See above.
Combinations of herbal substance(s) and/or herbal preparation(s) including a description of
vitamin(s) and/or mineral(s) as ingredients of traditional combination herbal medicinal products
assessed, where applicable.
Not applicable.
1.2.
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L., pseudo-fructus
EMA/HMPC/441930/2008
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Information about products on the market in the Member States
Country Specifications
Classification
Austria Juniper cone berries
It is recommended to start on day 1 with 5 cone berries ,
increasing the number every day by 1 cone berry (well
chewed) up to 15 cone berries, then decrease the number
(1 per day less) until 5 cone berries. So the duration of
the therapy is 21 days, the maximum daily dose 15 cone
berries.
Traditional use
Denmark 1.
Salus herbal tea nr. 23 – a combination of Fructus
carvi, aetheroleum eucalypti oil and fennel oil) Juniperi
pseudo-fructus (11%) and Folium uvae ursi, folium
betulae,
solidago
, equiseti herba and java tea leaf.
2.
Salus tea – a combination of fructus Juniperi (12%)
and birch leaf and horsetail (equisetum).
Authorised preparations
Estonia
All products containing
Juniper cone berries are
classified as non medical
products.
Finland No authorised preparations on the market
Germany Juniperi communis pseudo-fructus (1.7-1.8:1)
extraction solvent: water.
Pharmaceutical form: syrup for oral use in adults,
Posology: once daily 2 g syrup (100 g syrup contains 28.5
g extract) [that means 0.57 g extract daily = ~ 1 g
Juniperi pseudo-fructus]; traditionally used to support the
elimination function of the kidney
WEU > 1976
Italy
Last mixed preparation withdrawn from the market in
2008 (lozenges and syrup in case of respiratory tract
affections) (mixed combinations)
No authorised preparation
Romania Liquid extract from Juniperi pseudo-fructus (2:10)
Solvent: ethanol 70 % V/V: oral drops
Dose: 3 times 10-15 drops daily, for maximum 4 weeks
Warning: renal impairment
Comminuted herbal substance for herbal tea
Daily dose: 2.5 g
Warning: renal impairment
Traditional use: on the market
since 08/2006 as a diuretic
Traditional use: on the market
since 2004 as a diuretic
These products are not
traditional herbal medicinal
products since they are not on
the market for 30 years (or
15/15).
Spain
No products on the market registered as medicinal
products
Other preparations can be included with information the
period of use
(Not known, if on the market for 30 years and if they all
have 1 and more indications)
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Regulatory status overview
Member State Regulatory Status
Comments (not
mandatory field)
Austria
MA
TRAD
Other TRAD
Other Specify:
No authorised or
registered preparations
Belgium
MA
TRAD
Other TRAD
Other Specify: No authorised or
registered preparations
Bulgaria
MA
TRAD
Other TRAD
Other Specify: No information
Cyprus
MA
TRAD
Other TRAD
Other Specify: No information
Czech Republic
MA
TRAD
Other TRAD
Other Specify: No authorised or
registered preparations
Denmark
MA
TRAD
Other TRAD
Other Specify:
Mixed preparations with
pseudo-fructus
authorised
Estonia
MA
TRAD
Other TRAD
Other Specify: Only food supplements
Finland
MA
TRAD
Other TRAD
Other Specify: No authorised or
registered preparations
France
MA
TRAD
Other TRAD
Other Specify: No information
Germany
MA
TRAD
Other TRAD
Other Specify:
Pseudo-fructus and
Preparations thereof
authorised
Greece
MA
TRAD
Other TRAD
Other Specify:
No authorised or
registered preparations
Hungary
MA
TRAD
Other TRAD
Other Specify: No information
Iceland
MA
TRAD
Other TRAD
Other Specify: No information
Ireland
MA
TRAD
Other TRAD
Other Specify: No information
Italy
MA
TRAD
Other TRAD
Other Specify: No authorised or
registered preparations
Latvia
MA
TRAD
Other TRAD
Other Specify:
No information
Liechtenstein
MA
TRAD
Other TRAD
Other Specify: No information
Lithuania
MA
TRAD
Other TRAD
Other Specify: No information
Luxemburg
MA
TRAD
Other TRAD
Other Specify: No information
Malta
MA
TRAD
Other TRAD
Other Specify:
No authorised or
registered preparations
The Netherlands
MA
TRAD
Other TRAD
Other Specify: No information
Norway
MA
TRAD
Other TRAD
Other Specify: No information
Poland
MA
TRAD
Other TRAD
Other Specify: No information
Portugal
MA
TRAD
Other TRAD
Other Specify: No authorised or
registered preparations
Romania
MA
TRAD
Other TRAD
Other Specify:
Juniperi pseudo-fructus
as long standing
traditional use
Slovak Republic
MA
TRAD
Other TRAD
Other Specify: No authorised or
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Member State Regulatory Status
Comments (not
mandatory field)
registered preparations
Slovenia
MA
TRAD
Other TRAD
Other Specify:
No authorised or
registered preparations
Spain
MA
TRAD
Other TRAD
Other Specify: No authorised or
registered preparations
Sweden
MA
TRAD
Other TRAD
Other Specify: No authorised or
registered preparations
United Kingdom
MA
TRAD
Other TRAD
Other Specify: No information
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’
This regulatory overview is not legally binding and does not necessarily reflect the legal status of the
products in the MSs concerned.
1.3.
Search and assessment methodology
2.
Historical data on medicinal use
2.1.
Information on period of medicinal use in the Community
Historically, the cone berries were used in a diuretic wine recommended by Cato the Ancient in his
book ‘
De re rustica’
. Leclerc (1966) mentions also case studies in the treatment of rheumatoid arthritis
with a preparation of 8 g essential oil mixed with 4 g diethylether, to be taken in a dose of 10 drops a
day. The famous Oil of Haarlem or ‘Haarlemmer olie’ contains Juniper pseudo-fructus extracts.
Cone berries were traditionally used for dyspepsia (tincture and fluid extract), acute and chronic
cystitis, arteriosclerosis, gout and inflammations. Furthermore, menstruation pain and bleeding,
irritative cough, flu related bronchitis and diabetes are mentioned. Topical use is related to muscle pain
and acute arthritic conditions (Hänsel
et al.
1993; Barnes
et al
. 2007).
Babulka (2000) describes the use of medicinal herbs in Hungary.
Juniperus communis
is reported to be
used for gastro-intestinal complaints, against rheumatic conditions and urinary tract diseases. It is
considered as one of the 50 plant species with a long-standing tradition (at least 100 years).
Schulz (1929 cited by Schilcher & Heil, 1994) mentions the successful use of Juniper berry juice for
treatment of nephritic hydrops. Whereas Klare (1927 cited by Schilcher & Heil, 1994) reports its use in
case of paediatric tuberculosis. The first reports about the diuretic action in humans date from more
than one century ago (Raphael, 1894 and Breitenstein, 1902, both cited by Schilcher & Heil, 1994).
Most probably Raphael used 300 mg essential oil, two times daily during several months. Raphael
considered the essential oil as a whole and not just one group of compounds, more particularly
terpenes.
The German Commission E considered Juniper only for ‘Dyspeptische Beschwerden’ or dyspepsia as a
general complaint (Commission E, 1984).
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In France, Juniperi pseudo-fructus can only claim the following traditional therapeutic indications:
(1) appetite stimulant; (2) renal evacuation of water; (3) diuretic adjuvant in case of minor urinary
complications (Bruneton, 1999). In France, a toxicological dossier must be prepared for tinctures or
extracts with an alcohol strength above 30% (V/V). No toxicological data have to be explicited for
tinctures and extracts with an alcohol strength of 30% or lower (De Smet
et al
. 1993).
According to the ESCOP monograph, Juniper has a widely documented use as a remedy to enhance the
renal elimination of water and for dyspeptic complaints. For these indications, the monograph refers to
handbooks and not to original research (ESCOP, 2003).
Besides for its diuretic action, sometimes Juniper is also used as a urinary antiseptic, an indication
which is disputed. The activity should be mainly limited to water diuresis, mainly due to an irritative
action of terpinen-4-ol on the kidney tissue. More particularly, hyperaemia of the glomeruli should
stimulate the activity of the secretory epithelium (Wichtl, 1994; Barnes
et al
. 2007).
The cone berries are widely used as a flavouring component in spirits (e.g. gin, genever). They play a
traditional culinary role as an ingredient of ‘choucroute’ (France). Juniper is listed by the Council of
Europe as a natural source of food flavouring (fruit N2). Category N2 indicates that the cone berries
can be added to foodstuffs in small quantities, with a possible limitation of an active principle (as yet
unspecified) in the final product (Barnes
et al
. 2007).
The highest average maximum use level reported for the oils is 0.006% in alcoholic beverages and
0.01% for the extract of pseudo-fructus in alcoholic and non alcoholic beverages (Duke, 1988).
In Belgium only
Juniperus sabina
L. cannot be used in food or food supplements. The cone berries of
Juniperus communis
L.,
Juniperus procera
Hochst. and
Juniperus virginiana
L. are allowed as notified
ingredients of food supplements. Also the use of
Juniperus oxycedrus
L. is allowed (Anonymous,
1997).
Assessor’s comments
Preparations made of Juniperi pseudo-fructus mentioned in this assessment report can be considered
as traditional herbal medicinal products as direct and indirect evidence exist that the sources date back
for at least 30 years of medicinal use.
The most frequently cited traditional use of Juniperi pseudo-fructus concerns the renal elimination of
water and dyspepsia. Apart from these indications some other uses are mentioned. They are related to
infections (acute and chronic cystitis), arteriosclerosis, inflammatory conditions (muscles, joints, gout)
and pain (menstruations). Also irritative cough, flu related bronchitis and diabetes are mentioned,
these last indications mostly claimed for mixtures to be inhaled.
There is a lot of discussion about the safe use of Juniperi pseudo-fructus as a diuretic. Some sources
refer to terpenes in the essential oil fraction as being the active substances. Their action should be
based on hyperaemia of the glomeruli which is considered as an irritative action. Experimental
pharmacological and toxicological data will be important in a constructive therapeutic approach.
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2.2.
Information on traditional/current indications and specified
substances/preparations
Use of herbal preparations
* Decoctions and infusions are traditionally used (Hänsel
et al
. 1993)
* Liquid extract with 25% ethanol (DER 1:1 W/V) (Hänsel
et al
. 1993; Barnes
et al
. 2007)
* Tincture with 45% ethanol (DER 1:5 W/V) (ESCOP, 2003; Barnes
et al
. 2007)
* Soft extract with water (DER 1.7-1.8:1 W/V) (since 1976 on the German market).
Although decoctions as well as infusions are traditionally used, most standard sources with information
for therapeutic practice prefer infusions. All secondary sources referring to the liquid extract and the
tincture cite the British Herbal Pharmacopoeia (1983) as a source. Most probably the preparations are
used already more than 30 years in Europe. The British Herbal Pharmacopoeia 1996 contains a
shortened version of Juniper berry and contains information taken from the British Herbal
Pharmacopoeia 1971. As the 1996 edition is a shortened version, no details are given about
preparations. In this edition, the British Herbal Pharmacopoeia 1983 is mentioned as the second
consolidated edition comprising parts 1 (1976), 2 (1979) and 3 (1981). As a consequence, the
information in the 1983 edition is from a date former than 1983.
2.3.
Specified strength/posology/route of administration/duration of use
for relevant preparations and indications
Route of administration
All preparations are used orally.
Posology
The dried herbal substance is used in a dose of 2 g with a maximum dose equivalent to 10 g per day.
According to some authors, this posology corresponds with respectively 20 and 100 mg essential oil
(Hänsel
et al
. 1993; Barnes
et al
. 2007; Ph. Eur. 2008).
In some traditions (Sebastian Kneipp) it is recommended to start on day 1 with 5 cone berries ,
increasing the number every day by 1 cone berry (well chewed) up to 15 cone berries, then decrease
the number (1 per day less) to 5 cone berries. So the duration of the therapy is 21 days, the maximum
daily dose 15 cone berries. In case of therapeutic result the duration should be limited to 3 weeks. It is
not recommended to continue the treatment for more than 2 weeks if the symptoms persist
(Anonymous, 2009).
Preparation of infusion (the concentration may vary according to the method of preparation):
2 to 3 g with 150 ml hot water, infusion time 10 minutes: to be drunk 3 to 4 times a day (Hänsel
et al
. 1993; ESCOP, 2003).
1:20 (W/V) with boiling water: 100 ml 3 times daily (Barnes
et al
. 2007).
The latter is more concentrated and most sources limit the single dose equivalent to 2 g. Therefore an
amount of 2 g 2 to 3 times a day is preferred as recommended dose.
Powder: 2 to 8 g per day (Delfosse, 1998). It is not clear whether the use of powdered pseudo-fructus
can be considered as tradition. Therefore the powdered form has not been taken to the monograph.
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Tincture (1:5 W/V in 45% ethanol): 1-2 ml, 3 times daily (ESCOP, 2003; Barnes
et al
. 2007). As
mentioned earlier there is indirect evidence for more than 30 years of medicinal use of the tincture.
This preparation is taken to the monograph.
Tinctura Juniperi (Codex Français): 5 to 15 g to be enhanced and tapered progressively (Van
Hellemont, 1985). Data about the duration of use are missing. Also the original source is not specified.
This preparation is not included into the monograph.
Liquid extract (1:1 W/V in 25% ethanol): 2-4 ml 3 times daily (Barnes
et al
. 2007). As mentioned
earlier, there is indirect evidence for more than 30 years of medicinal use of the liquid extract. This
preparation is taken to the monograph.
Duration of use
As the duration of use for self medication is concerned, Juniper preparations should not be used for
more than 2 weeks if the symptoms persist or worsen. Traditional use of the pseudo-fructus can be
extended to 3 weeks if the symptoms alleviate (cf. Kneipp). For longer duration of use, medical advice
should be sought.
Assessor’s comments
According to several sources infusions may contain a maximal dose of 10 g cone berries per day. This
dose is subject to some considerations.
As several authors mention the same dose, they may have copied each other.
The approximate weight of 100 cone berries is 16 g (Schilcher & Heil, 1994). A dose of
10 g would correspond to approximately 60 cone berries. This amount seems quite high.
The content of essential oil in cone berries may vary from 0.5 to 3.42%. When the content of essential
oil is high, a daily dose of 10 g corresponds to about 342 mg of essential oil, whereas a maximal daily
dose of 100 mg is recommended according to several sources.
It can be hypothesised that, when making an infusion, the volatile components of Juniper pseudo-
fructus will not be extracted at 100%.
Taking the cone berries as such, a maximum dose of 15 cone berries per day is recommended. By this
way of administration, the cone berries are not taken with water.
As a result of these considerations, for use as an infusion, a maximal dose of 2 g taken 3 times daily
can be considered as a safe margin as, even with a 100% extraction in case of a high content on
essential oil, the amount will be lower than 100 mg per day.
3.
Non-Clinical Data
3.1.
Overview of available pharmacological data regarding the herbal
substance(s), herbal preparation(s) and relevant constituents thereof
Diuretic activity
Although this assessment report is focused on Juniperi pseudo-fructus studies with essential oil are
also included. In several studies, extracts as well as the essential oil were included in the same
experimental setting. As a consequence, it is difficult to separate them.
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L., pseudo-fructus
EMA/HMPC/441930/2008
Page 10/21
SPECIES (references) PREPARATION & INTERVENTION RESULTS
COMMENTS
Rats receiving ADH by
i.p. doses of
p.o.: 5 ml/100g body weight of
Day 1: reduction of diuresis:
These results are
not convincing for
the essential oil.
The activity may
be due to
hydrophilic
substances in the
infusion.
(1) 10% aqueous infusion of
Juniperus
; or (2) 0.1% aqueous
solution of
Juniper
oil (with 0.2%
of tween 20® solubilizer); or (3)
0.01 solution of terpinen-4-ol; or
control solution of (4) water or
water + 0.2% tween (rats not
receiving ADH)
- 6% /24h with (1) and (2)
0.004 IU/100g
- 30%/24h with (3)
0.04 IU/100g
Day 2 and 3: stimulation of
diuresis:
0.4 IU/100g
(Stanic
et al.
1998)
+ 43-44% with (1)
(P<0.05)
No stimulation with the
other solutions.
Rats
p.o.:
No significant diuresis
Essential oil did not
give a positive
result.
(Schilcher &
Leuschner 1997)
(1)
Juniper
oil 100 mg/kg/day
(2)
Juniper
oil 333 mg/kg/day
Duration: 28 days
Adult rats (Hänsel
et
al.
1993)
Infusions of cone berries:
dissolved in 5 ml water and
administered p.o.
Total urine over a 4 h
period; content of Cl- and
urinary nitrogen enhanced
with variable doses as
compared to controls. With
some doses a lower volume
was excreted (with 8 and
250 mg).
No further
specifications
about the
preparation used.
Doses of 8; 16; 32.5; 65; 125
and 250 mg plant equivalent or
control
Doses not adapted
to animal weight
No indications for
dose dependency
Male rats (Lasheras
et
al.
1986)
All animals received 25 ml/kg
Volume urine excreted after
6 h and excretion of Na+,
K+ and Cl- was not
increased versus controls
Only one dose
tested.
(1) lyophilized water extract of
Juniperus
pseudo-fructus
: 1000
mg/kg p.o.; or
(2) the same volume of water
Rats
s.c. injection
Stimulation of diuresis after
4 / 24 h with
Essential oil less
active than pure
compound
terpinen-4-ol
(Janku
et al.
1957 ;
Janku
et al.
1960)
(1)
Juniper
oil: 1 ml/kg
(2) NaCl solution
(3) 78.4
+
7.1 / 157.6
+
7.1%
(3) Terpinen-4-ol 0.1 ml/kg
(1) 44.0
+
6.9 / 85.3
+
7.6%
(2) 14.3
+
4.1 / 43.8
+
4.6%
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L., pseudo-fructus
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SPECIES (references) PREPARATION & INTERVENTION RESULTS
COMMENTS
Rats
p.o. administration of:
+ 36% diuresis with (1)
A dose dependency
is not clearly
shown as twice or
half of the dose
had less effect.
(Vollmer & Hübner
1937)
(1) aqueous infusion equivalent to
125 mg of
Juniper
; or
+ 119% chloride excretion
with (1)
(2) same volume of water
Rabbits and mice
p.o. administration of:
+ 20% diuresis with (1) in
rabbits
A dose dependency
is not clearly
shown as twice or
half of the dose
had less effect.
(Vollmer & Weidlich
1937)
(1) aqueous infusion equivalent to
750 mg of
Juniper
(rabbits); or
aqueous infusion equivalent to 50
mg of
Juniper
(mice); or
+ 38% diuresis with (1) in
mice
(2) same volume of water
ADH = antidiuretic hormone (vasopressin)
p.o. = peroral
i.p. = intraperitoneal
s.c. = subcutaneous
Hypoglaycemic activity
SPECIES (references) PREPARATIONS &
INTERVENTIONS
RESULTS
COMMENTS
Adult male mice
treated or not with
streptozotocin
200 mg/kg
Dried cone berries of
Juniperus
were homogenized in the solid
food as 6.25% by weight of the
diet.
Basal plasma glucose
significantly lower as
compared to controls
(P < 0.05)
The study dealt
with screening of
several plants and
plant extracts of
which
Juniperus
.
(Swanston-Flatt
et al.
1990)
+ at the same time
Body weight and fluid intake
significantly less lowered as
compared to controls
(P < 0.05)
Juniperus
supplied as infusion: of
1 g per 400 ml boiling water and
during 15 min. This preparation
replaced the drinking water
No influence on food intake.
No influence on residual
plasma insulin by
Juniperus
Duration: 30 days
Adult mice i.p. treated
with streptozotocin
200 mg/kg
Food with powder of cone berries
6.25% and drinking water with
1 g powder/400 ml = intervention
group
Weight loss, drinking
volume and glycaemia:
intervention < control (P <
0.05)
Streptozotocin
used to provoke
hyperglycaemia;
(Hänsel
et al.
1993)
No explainable
mechanism for
hypoglycaemia
Food / drinking water without any
addition = control
Normal rats and
p.o. administered during 24 days:
Significantly lowered
glycaemia in normal and
streptozotocin treated rats
Streptozotocin to
provoke
hyperglycaemia
Streptozotocin
diabetic rats
Normal rats:
Decoction of Juniper:
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Juniperus communis
L., pseudo-fructus
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Page 12/21
SPECIES (references) PREPARATIONS &
INTERVENTIONS
RESULTS
COMMENTS
(Sánchez de Medina
et al.
1994)
250 -500 mg/kg
Effect attributed to
an increase in
peripheral
absorption of
glucose,
independent from
plasma insulin
levels
Streptozotocin rats:
Decoction of Juniper:
125 mg/kg
Streptozotocin
diabetic mice
Juniper preparation
No hypoglycaemic effect
Lack of information
about the
methodology and
results
(Gray & Flatt, 1997)
Sealed dialysis tube
In vitro
diffusion of solution of
glucose and NaCl (0.15 M)
Dialysis of glucose
decreased by 6% after
application of 50 g/l plant
material
No physiological
action. Effect
mainly due to
physicochemical
properties
(Gallagher
et al.
2003)
Measurement of glucose in
external solution
1 g of powdered Juniper cone
berries in 40 ml distilled water,
heated until boiling and infused
during 15 min.
Least active of all
plants applied
i.p. = intraperitoneal
p.o. = peroral
Other activities
SPECIES (references) PREPARATIONS &
INTERVENTIONS
RESULTS
COMMENTS
Rats: carrageenan
used as a pro-
inflammatory agent
p.o. administered:
Reduction of paw oedema:
Only one dose
tested: no dose
response
relationship
investigated
(1) Ethanol extract (80%) of
Juniperus
pseudo-fructus
(1:3)
100 mg/kg
(1) -60 %
(Mascolo
et al.
1987)
(2) -45 %
(1) > (2) : P < 0.01
(2) Indomethacin 5 mg/kg
Male anesthetized
(pentobarbital)
normotensive rats
(Lasheras
et al.
1986)
i.v. administration of a lyophilized
juniper pseudo-fructus extract: 25
mg/kg
Blood pressure enhanced
and later lowered (-27%)
as compared to the initial
values
Results extracted
from a screening
program
Cell cultures
Extract of juniper pseudo-fructus
prepared with hot isopropanol
DNA-replication of HSV-1
lowered in isolated amnion
cells
No cytotoxicity seen
in a range of 1.5 to
7000 ng/ml
(Hänsel
et al.
1993;
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Juniperus communis
L., pseudo-fructus
EMA/HMPC/441930/2008
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SPECIES (references) PREPARATIONS &
INTERVENTIONS
RESULTS
COMMENTS
Barnes
et al.
2007)
Activity may be due
to desoxypodophyl-
lotoxin
Male mice
i.v. administration of a lyophilized
extract of
Juniperus
pseudo-
fructus
:
1.2 g/kg vs. controls
Thermal stimuli:
Results extracted
from a screening
program
(Lasheras
et al.
1986)
analgesic response of
178%
Male rats
Lyophilized extract of
Juniperus
pseudo-fructus
: topical application
of 5 mg in 0.05 ml 0.9% NaCl or
750 mg/kg
Neither local anaesthetic
activity, nor lowering of
spontaneous motoric
activity
Male mice
(Hänsel
et al.
1993)
Gram + and Gram –
bacteria, yeast,
yeast-like fungi,
yeasts and
dermatophytae
Essential oil from Juniper cone
berries, concentrations expressed
as MIC
Gram + / -:
MIC: 8-70% (V/V)
No comparator
tested. The
antibacterial
concentrations vary
considerably. The
highest
concentrations are
nor relevant in a
therapeutic context.
Fungicidal activity against
Candida: MIC:
0.78-2% (V/V)
(Pepeljnjak
et al.
2005)
Dermatophytes MIC:
0.39-10% (V/V)
Microbial organisms
Essential oil distilled from aerial
parts of
J. communis
spp
. alpine
Inhibition zones for
S. aureus
and
E. coli
:
controls <
J. communis <
antibiotics (ciprofloxacine,
penicillin G)
Concentrations
tested are within
acceptable limits.
Staphylococcus
aureus
Escherichia coli
Enterobacter
aerogenes
Pseudomonas
aeruginosa
Concentrations 0.03-2% (V/V) in
agar
(Rossi
et al.
2000)
Gram-negative and
gram-positive
bacteria, fungi and
Candida albicans
Essential oil fractions distilled
from cone berries
Diameter inhibition zone
components (8.75 µg) >
antibiotics (gentamycin,
tetracycline, erythromycin,
vancomycin, clincamycin,
streptomycin, ampicyllin,
penicillin: 6-30 µg)
No comparator for
fungi and Candida
(Glisic
et al.
2007)
Antioxidant activity:
ferric thiocyanate,
thiobarbituric acid
models
Methanol extracts from the
pseudo-fructus
of
Juniperus
communis
L. ssp.
hemisphaerica
vs.
Activity of methanol
extracts:
Approximative
results given as a
histogram
Ferric thiocyanate: > 90%
Antioxidant activity
Butylated hydroxytoluene:
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L., pseudo-fructus
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Page 14/21
SPECIES (references) PREPARATIONS &
INTERVENTIONS
RESULTS
COMMENTS
(Emami
et al.
2007)
Vitamin E and butylated
hydroxytoluene
> 80% vs. positive
controls
with specific sub-
strate.
Concentrations: 0.02%
Antioxidant activity:
Essential oil of fruit
Concentration-response
relationship
Antioxidant activity
with specific sub-
strate: should not be
extrapolated
Difenylpicrylhydrazine
(= DPPH)
* DPPH:
Juniper fruit oil << vitamin
C < quercetin
Desoxyribose
degradation
(Emami
et al.
2007)
* Desoxyribose
Juniper
fruit << quercetin
MCF-7/AZ breast
cancer cells
Aqueous extracts of fruit
Dose-dependent growth
inhibition by extracts:
No positive controls
used
Concentration rate:
0 – 180 µg/ml
(Van Slambrouck
et
al.
2007)
>
60 µg/ml: significant
inhibition (P < 0.05)
Invasion by MCF-7/AZ
cells: significantly inhibited
by Juniper pseudo-fructus
extract (P < 0.05)
Phosphorylation
significantly inhibited by
50 µg/ml
(P < 0.05)
Human blood
platelets
Juniperi communis pseudo-fructus
Inhibition of 12-HETE
biosynthesis (P<0.05) at
100 µg/ml:
Quantification frac-
tionation on Sepha-
dex LH-20 and GC-
MS
(1) Methylene chloride
12(S)-Lipoxygenase
inhibition
(2) Ethyl acetate extract
(1) 66.2
+
4.03%
(Schneider
et al.
2004)
(2) 76.2 + 3.36%
12-HETE = 12-OH-eicosatetraenoic acid
MIC = minimal inhibitory concentration (= no
growth)
HSV-1 = Herpes simplex virus 1
i.v. = intravenous
p.o. = per oral
MCF-7/AZ = mammal carcinoma cell line
vs = versus
Assessor’s overall conclusions on pharmacology
The earliest experimental evidence for a diuretic activity goes back more than 70 years. Rats were
mostly used as subjects. The p.o. way of administration corresponds to traditional use in humans. The
extracts are mostly prepared from whole cone berries, but also the essential oil and terpinen-4-ol are
Assessment report on
Juniperus communis
L., pseudo-fructus
EMA/HMPC/441930/2008
Page 15/21
used. The diuretic activity cannot be characterized as only aquaretic, i.e. increasing the volume of
water excreted by the kidneys, as several authors found also an increased excretion of an organic
component (mainly chloride). In one study, the whole extract of the cone berries seemed to be more
potent as compared to the essential oil, but in this study the rats were pretreated with antidiuretic
hormone. It should be mentioned that the diuretic activity is not always consistent and obtained with
relatively high doses if converted to human conditions (when recalculating the number of berries to be
taken, this leads to more than 100 berries/day). There are no systematic investigations reported about
the possible beneficial consequences of the diuretic activity. Only one study with total extract
intravenously administered to anesthetised normotensive rats mentioned a lowering effect on blood
pressure without any link to increased diuresis.
In contrast with the traditionally claimed indication, there is no experimental evidence for use in
dyspeptic complaints.
Juniper pseudo-fructus preparations had a hypoglycaemic activity in streptozotocin pretreated mice
and rats. It should be taken into account that streptozotocin quickly leads to high glucose levels and
that the results cannot be extrapolated to human diabetic conditions.
Other activities include an anti-inflammatory (
in vivo
and
in vitro
) effect, antimicrobial activity towards
some viruses (HSV-1), bacteria (
E. coli
and
S. aureus
) and
Candida albicans
. The antimicrobial and
anti-inflammatory activity may underpin the traditional claim of urinary infections (see comment on
the high concentrations). Most of the experiments were carried out with the essential oil or its
components. However, extrapolation of
in vitro
results to
in vivo
conditions remains difficult, due to the
sometimes high concentrations of oil used and the direct contact with micro-organisms which may
result in cytotoxic rather than antimicrobial effects.
Furthermore antioxidant and antitumoral activity is reported in some experimental
in vitro
models.
Extrapolations of these activities remain speculative.
3.2.
Overview of available pharmacokinetic data regarding the herbal
substance(s), herbal preparation(s) and relevant constituents thereof
No data were found about absorption, distribution, metabolism, elimination and pharmacokinetic
interactions with other medicinal products.
Assessor’s overall conclusions on pharmacokinetics
No data are available. The complex phytochemistry of Juniper cone berries makes it difficult to
conceive any representative pharmacokinetic study.
3.3.
Overview of available toxicological data regarding the herbal
substance(s)/herbal preparation(s) and constituents thereof
Acute toxicity
LD
50
of a lyophilized water extract of Juniper pseudo-fructus in male mice: 3000 mg/kg
intraperitoneally. Juniper is considered as a mild toxic agent (Hänsel
et al
. 1993).
Acute toxicity was tested on 10 Wistar rats of a standardised 80% ethanolic extract of Juniper pseudo-
fructus (2.5 g/kg) during 7 days. No side effects were reported. All animals survived. A dose of 3 g/kg
induced hypothermia and mild diarrhoea in 10-30% of animals (Hänsel
et al
. 1993).
Other sources mention an oral LD
50
of the herbal substance or Juniperi pseudo-fructus: 6.28 g/kg or at
least 5 g/kg in rats (De Smet
et al
. 1993).
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L., pseudo-fructus
EMA/HMPC/441930/2008
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Reproductive and developmental toxicology
Doses of 300 and 500 mg (p.o.) of an of Juniperi communis pseudo-fructus extract (extraction solvent
50% ethanol) was administered to 10 Swiss albino female rats from day 1 to 7 of pregnancy. On day
10 the implantation was controlled by laparotomy. In the 300 mg/kg group 5 out of 10 and in the
500 mg/kg 8 out of 10 animals had no implantation. Another series of doses was administered on day
14, 15 and 16, to the rats which showed implantation. On day 18 the rats were again laparotomized in
order to control abortifacient activity. The number of embryos developing was lower in the intervention
group as compared to the rats receiving vehiculum only: in rats which showed implantation sites
(pregnant), no pups could be delivered.
In another experiment, three of the rats without implants on day 10 were allowed to mate with males
after 2 months of rest. Although mating was successful, no implantations were reported.
Based on the results of the preceding experiments, the investigations concluded that Juniperi
communis pseudo-fructus extract had antifertility and abortifacient effects in rats. This type of
experiment cannot be used to evaluate teratogenicity as the study was not adapted for teratogenicity
(Agrawal
et al
. 1980; Hänsel
et al
. 1993; De Smet
et al
. 1993; ESCOP, 2003; Barnes
et al
. 2007).
Genotoxicity
There are no genotoxicity data available for
Juniperus communis
or preparations thereof. In the tar of
Juniperus oxycedrus
(cade oil) benzpyrenes were found in the nanogram/g range, but this does not
apply to
J. communis
.
According to one source, the chemical composition of
J. communis
oil and
J. communis
pseudo-fructus
extract is considered as similar when genotoxicity is considered (Anonymous, 2001). However, the
difference in composition between the oil and water extracts of Juniperi pseudo-fructus must be taken
into consideration.
Assessor’s overall conclusions on toxicology
There is no serious concern about possible acute toxicity of the Juniperi pseudo-fructus. No data on
carcinogenicity and genotoxicity exist. Incomplete investigations concerning reproductive toxicity point
to antifertility and abortifacient effects of the preparation tested. The antifertility testing cannot be
used to conclude on teratogenicity because the design of the study is not appropriate.
4.
Clinical Data
4.1.
Clinical Pharmacology
4.1.1.
Overview of pharmacodynamic data regarding the herbal
substance(s)/preparation(s) including data on relevant constituents
There are no data available on human pharmacodynamics.
4.1.2.
Overview of pharmacokinetic data regarding the herbal
substance(s)/preparation(s) including data on relevant constituents
There are no data available on human pharmacokinetics.
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4.2.
Clinical Efficacy
4.2.1.
Dose response studies
Not available.
4.2.2.
Clinical studies (case studies and clinical trials)
Not available.
4.2.3.
Clinical studies in special populations (e.g. elderly and children)
Not available.
4.3.
Overall conclusions on clinical pharmacology and efficacy
Not applicable.
5.
Clinical Safety/Pharmacovigilance
5.1.
Overview of toxicological/safety data from clinical trials in humans
Not applicable.
5.2.
Patient exposure
Historically, the cone berries were used in a diuretic wine recommended by Cato the Ancient in his
book ‘
De re rustica’
(Leclerc, 1966). The use of Juniper cone berries can be considered as a century-
long standing practice.
On the other hand, there is a lack of systematically obtained subacute clinical safety and toxicity data
for Juniper, creating the need for safety update reporting. Standard references give contradictory
information, mostly based upon interpretation by the authors and not on clinical data.
Schilcher & Heil are not convinced of the renal toxicity of
Juniperus
oil because quite a lot of sources
may just have copied the doubtful renal side effects (Schilcher & Heil, 1994; ESCOP, 2003).
Nevertheless, the German Commission E only considered dyspepsia as the only therapeutic indication.
The use of essential oil is questioned by some authors (Bruneton, 1999). A quote supported by Duke
(1988): “
…this drug is no longer recommended for various kidney disorders by the medical profession.
Since much safer and more effective diuretic and carminative drugs exist, the use of Juniper in folk
medicine should also be abandoned….”.
The author does not refer to case studies or causality
reporting. Not all German sources limit the use of Juniper. Weiss & Fintelman (1999) consider the cone
berries of
Juniperus communis
as valuable ‘
aquaretica
’. They include the following conditions for
traditional use: unspecific dysuria, sensitive bladder (‘Reizblase’) and prophylaxis of relapsing
urolithiasis and urinary infections.
Juniper berry oil was given GRAS (Generally Recognised as Safe) status by the Flavouring Extract
Manufacturers Association (FEMA) in 1965 and is approved by the U.S. Food and Drug Administration
for food use. Juniper berry was included in the Council of Europe list of substances, spices and
seasonings deemed admissible for use with a possible limitation of the active principle in the final
product (De Smet
et al.
1993).
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5.3.
Adverse events and serious adverse events and deaths
Most handbooks warn for renal damage when
Juniperus communis
preparations are used for their
aquaretic properties. Although the monograph is conceived for the pseudo-fructus, some reporting on
the essential oil is included as well. This must allow for comparisons with pseudo-fructus starting from
the oil content.
Renal damage has been reported after long-term use (several months). Overdosing with the essential
oil leads to renal damage. Cramp-like pain and bleeding of the uterus has been mentioned (Hänsel
et
al.
1993).
The most detailed study is made by Schilcher & Heil (1994) mentioning that ancient sources do not
warn for renal complications in humans. Massive doses that were much higher than the 400-500 mg
essential oil Raphael (1894, cited by Schilcher & Heil 1994) and Gmeiner (1904, cited by Schilcher &
Heil 1994) tested on themselves. Furthermore, starting from cone berries it will be impossible to reach
massive dose equivalents: the weight of 100 cone berries is 16 g. The weight of a daily dose of
15 cone berries is 2500 mg. With a 1% content of essential oil, the oil equivalent will be 25 mg. There
have been no adverse events mentioned after the use of broiled cone berries, although it must be
specified that this preparation is a residual product of cone berries from which the essential oil has
been removed (Schilcher & Heil, 1994).
According to Semon (1844; cited by Schilcher & Heil 1994),
Juniperus
oil increases the renal circulation
and dose-dependent damage can occur (stranguria, dysuria, hematuria and ischuria). The activity of
Juniperus
oil was formerly compared with terpentine oil. Most probably the findings for terpentine oil
were copied to
Juniperus
oil without factual analysis. Also Potter (1898; cited by Schilcher & Heil,
1994) mentioned
Juniperus
cone berries in his
Materia Medica
: “
…may set up renal irritation, in large
doses producing strangury, priapism, hematuria, suppression of the urine and uremic convulsions…”
, a
wording taken over by the German literature.
Although the volatile oil is reported to be generally non-sensitising and non-phototoxic, dermal
irritation has been recognized with Juniper and positive patch test reactions have been documented.
The latter are attributed to the irritant nature of the Juniper pseudo-fructus extract. Burning,
erythema, inflammation with blisters and oedema have been reported after external application of the
essential oil (Barnes
et al.
2007).
Of 26 patients examined for suspect plant dermatitis, 14 showed positive patch test reactions to
Juniper pseudo-fructus extract (nature of extract not specified) (Mathias
et al.
1979).
Seizures and kidney damage have been reported in individuals who took more than 10 g of Juniper per
day or who took high doses of Juniper for longer than 4 weeks. The way and form of administration is
however not specified. Also the exact dose (“
…more than 10
g…”
) is not mentioned. The same source
recommends a maximal daily dose of 10 g of dried Juniperi pseudo-fructus. However the source is not
scientifically documented, which brings uncertainty about this information
(
http://www.rxlist.com/
Juniper
/supplements.htm
last visit on 2 July 2 2009). If such reactions occur,
they can be caused by contamination of the oil (Schilcher
et al.
2007).
Serious adverse events and deaths
None reported.
5.4.
Laboratory findings
No data are available.
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L., pseudo-fructus
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5.5.
Safety in special populations and situations
Safety in special populations and situations
The use of
Juniperus communis
is contra-indicated in case of inflammation of the kidney, nephritis and
pyelitis (Commission E, 1984; De Smet
et al.
1993; ESCOP, 2003).
Intrinsic (including elderly and children)/extrinsic factors
No data available. Because of the tighter dose margin, a restriction to adults is recommended.
Drug interactions
There is limited evidence from preclinical studies that Juniper may influence glucose levels in diabetes
(ESCOP, 2003; Barnes
et al.
2007).
Use in pregnancy and lactation
There are no data available about use during pregnancy and lactation.
In case of prolonged use and overdose, urine will smell of violets. There may be renal irritation and
pain in and near the kidney, strong diuresis, albuminuria, haematuria, purplish urine, gastrointestinal
upsets, accelerated heartbeat and blood pressure. Rarely symptoms of central stimulation like
convulsions occur as well as metrorrhagia and abortion (Wichtl, 1994; Duke, 1988; Barnes
et al.
2007
).
Drug abuse
No data available.
Withdrawal and rebound
No data available.
Effects on ability to drive or operate machinery or impairment of mental ability
No data available.
5.6.
Overall conclusions on clinical safety
With the use of cone berries serious adverse events are improbable as the amount of substance to be
ingested before problems occur will be high. Issues of safety monitoring are related to:
the preparation: the concentrating effect on the compounds depends upon the solvents and the
way of extraction; as both the cone berries and the essential oil have a possible antioxidant affect,
respecting the original composition is recommended
the patients: apart from preclinical data on reproductive toxicology, little is known about possible
groups at risk and interactions with other medication
it can be expected that the kidney will be the first target organ
6.
Overall conclusions
The traditional use of
Juniperus communis
pseudo-fructus
and preparation thereof should be limited to
the stimulation of renal water excretion and to dyspeptic disorders. The former is sustained by
tradition and by experimental evidence, the latter only by tradition.
Assessment report on
Juniperus communis
L., pseudo-fructus
EMA/HMPC/441930/2008
Page 20/21
There is a need for systematic pharmacovigilance reporting in order to address the issue of subacute
safety when using different preparations of Juniper.
Benefit-risk assessment
Juniper
berries as well as the essential oil are described in the European Pharmacopoeia. The
macroscopic identification of the berries can be done easily. Adulteration and contamination remain
possible: unripe berries should not be used. Essential oil should only be prepared from ripe berries,
without any needles or wood from the tree. Contaminated oil can indeed affect the renal function, so
quality should be proven. However, reports on cases of overdose or prolonged use are vague and of
questionable quality, not meeting the pharmacovigilance criteria. Pharmacokinetics of Juniper
components are not known.
As genotoxicity and carcinogenicity are not studied, a list entry in the ‘Community list of herbal
substances, preparations and combinations thereof for use in traditional herbal medicinal products’
cannot be established.
The therapeutic indications do not relate to life threatening conditions and they are supported by
traditional use evidence. There are more potent conventional medicines with known benefits based on
well-established use. Groups at risk can be defined as constitutional: elderly, pregnant and
breastfeeding mothers and children. There are no reports on drug interactions, but combining Juniper
with diuretic compounds is not recommended. Although there is experimental evidence for a blood
glucose lowering effect, there are no reports on clinical consequences of combining
Juniperus
with
blood glucose lowering medicines. There are no clinical trials on Juniper berries and Juniper oil, but
European tradition goes back to more than 2000 years for both.
Annex
List of references
Assessment report on
Juniperus communis
L., pseudo-fructus
EMA/HMPC/441930/2008
Page 21/21
Source: European Medicines Agency
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