22 May 2012

EMA/HMPC/337067/2011
Committee on Herbal Medicinal Products (HMPC)

Assessment report on Tilia cordata Miller, Tilia

platyphyllos Scop., Tilia x vulgaris Heyne or their
mixtures, flos

Based on Article 16d(1), Article 16f and Article 16h of Directive 2001/83/EC as amended (traditional
use)

Final

Herbal substance(s) (binomial scientific name of Tilia cordata Miller, Tilia platyphyllos Scop., Tilia x
the plant, including plant part) vulgaris Heyne or their mixtures, flos
Herbal preparation(s) a) Comminuted herbal substance

b) Liquid extract (DER 1: 1), extraction

solvent ethanol 25% V/V

c) Tincture (ratio of herbal substance to

extraction solvent 1:5), extraction solvent
ethanol 45% V/V

Pharmaceutical form(s) Comminuted herbal substance as herbal tea for

oral use.

Herbal preparations in liquid dosage forms for oral

use.

Rapporteur Ioanna Chinou

7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom

Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7523 7051
E-mail [email protected] Website www.ema.europa.eu An agency of the European Union

© European Medicines Agency, 2012. Reproduction is authorised provided the source is acknowledged.
Table of contents
Table of contents ................................................................................................................... 2

1. Introduction ....................................................................................................................... 3
1.1. Description of the herbal substance(s), herbal preparation(s) or combinations thereof .. 3
1.2. Information about products on the market in the Member States ............................... 6
1.3. Search and assessment methodology ................................................................... 10
2. Historical data on medicinal use ...................................................................................... 10
2.1. Information on period of medicinal use in the Community ....................................... 10
2.2. Information on traditional/current indications and specified substances/preparations .. 11
2.3. Specified strength/posology/route of administration/duration of use for relevant
preparations and indications ....................................................................................... 12
3. Non-Clinical Data ............................................................................................................. 13
3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal
preparation(s) and relevant constituents thereof ........................................................... 13
3.2. Overview of available pharmacokinetic data regarding the herbal substance(s), herbal
preparation(s) and relevant constituents thereof ........................................................... 15
3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal
preparation(s) and constituents thereof ....................................................................... 15
3.4. Overall conclusions on non-clinical data ................................................................ 16
4. Clinical Data ..................................................................................................................... 17
4.1. Clinical Pharmacology ......................................................................................... 17
4.1.1. Overview of pharmacodynamic data regarding the herbal substance(s)/preparation(s)
including data on relevant constituents ........................................................................ 17
4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s)
including data on relevant constituents ........................................................................ 17
4.2. Clinical Efficacy .................................................................................................. 17
4.2.1. Dose response studies...................................................................................... 17
4.2.2. Clinical studies (case studies and clinical trials) ................................................... 17
4.2.3. Clinical studies in special populations (e.g. elderly and children) ............................ 18
4.3. Overall conclusions on clinical pharmacology and efficacy ........................................ 18
5. Clinical Safety/Pharmacovigilance ................................................................................... 18
5.1. Overview of toxicological/safety data from clinical trials in humans ........................... 18
5.2. Patient exposure ................................................................................................ 18
5.3. Adverse events and serious adverse events and deaths .......................................... 18
5.4. Laboratory findings ............................................................................................. 19
5.5. Safety in special populations and situations ........................................................... 19
5.6. Overall conclusions on clinical safety ..................................................................... 20
6. Overall conclusions .......................................................................................................... 20

Annex .................................................................................................................................. 20

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1. Introduction

1.1. Description of the herbal substance(s), herbal preparation(s) or

combinations thereof

• Herbal substance(s)

Tilia flos (lime flower) consists of the whole dried inflorescence of Tilia cordata Miller, of Tilia
platyphyllos Scop., of Tilia x vulgaris Heyne or a mixture of these (European Pharmacopoeia 2008).

Lime tree (Linden) is a tall deciduous tree native throughout Europe as far north as 65o in latitude,
which can grow to heights approaching to 30 metres. It is found in the wild and purposely planted in
gardens. It is also cultivated in Europe and North America while the material of commerce originates
mainly from Balkan countries such as Bulgaria, Romania, former Yugoslavia, Turkey and in part from
China. Lime tree bark is smooth and grey and its leaves are heart-shaped. The 5-petalated, yellow
white flowers are collected in full bloom, dried and preserved under low-moisture conditions
(Blumenthal et al. 1998).

All the above-referred species are preferred because the tannin and mucilage content in their flowers
produce more favourable teas and extracts (Blumenthal et al. 1998).

Tilia has a faint aromatic odour and a faint sweet and mucilaginous taste (European Pharmacopoeia
2008).

Lime flower’s inflorescence is yellowish-green. The main axis of the inflorescence bears a linguiform
bract, membranous, yellowish-green, practically glabrous, the central vein of which is joined for up to
about half of its length with the peduncle. The inflorescence usually consists of 2 - 7 flowers,
occasionally up to 16. The sepals are detached easily from the perianth; they are up to 6 mm long,
their abaxial surface is usually glabrous, their adaxial surface and their borders are strongly pubescent.
The 5 spatule, thin petals are yellowish-white, up to 8 mm long. They show fine venation and their
borders only are sometimes covered with isolated trichomes. The numerous stamens are free and
usually constitute 5 groups. The superior ovary has a pistil with a somewhat 5-lobate stigma.
(European Pharmacopoeia 2008)

Lime flower comprises of the dried inflorescence of Tilia cordata Miller, of Tilia platyphyllos Scop., of
Tilia x vulgaris Heyne (fam. Tiliaceae), or a mixture of these and is used in herbal medicine.
(VIth Hungarian Pharmacopoeia 1970; British Herbal Pharmacopoeia (BHP) 1976; Bradley 1992;
Blaschek et al. 2010; PDR for Herbal Medicines 2007).

Common names: European Lime, basswood, Linden tree.

Synonym(s)

Tilia cordata Miller = Tilia officinarum Crantz, Tilia officinarum Crantz subsp. officinarum pro parte, Tilia
ulmifolia Scop., Tilia parvifolia Ehrh. ex Hoffm., Small-leaved Lime

Tilia platyphyllos Scop. = Tilia officinarum Crantz, Tilia officinarum Crantz subsp. officinarum pro parte,
Large-leaved Lime

Tilia x vulgaris Heyne, a hybrid of the above = Tilia x europaea auct. non L.

Chemical constituents according to existing references (BHP 1976; Bradley 1992; Barnes et al. 2007;
Duke 1985; Review of Natural Products 2005; WHO 2010):

− Acids - Caffeic acid, chlorogenic acid and p-coumaric acid

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 − Amino acids - Alanine, cysteine, cystine, isoleucine, leucine, phenylalanine and serine

− Carbohydrates - Mucilage polysaccharides (3%). Five fractions identified yielding arabinose,

galactose, rhamnose, with lesser amounts of glucose, mannose, and xylose; galacturonic and
glucuronic acids (Kram & Franz 1985; Yakovlev 1985)

− Flavonoids - Kaempferol, quercetin, myricetin and their glycosides (mainly Kaempferol-3-O-β-

D-(6″-E-p-coumaroyl)-glucopyranoside – tiliroside ) (Nowak 2003)

− Volatile oil - (0.02% to 0.1%) Many components including alkanes, phenolic alcohols and
esters, and terpenes including citral, citronellal, citronellol, eugenol, limonene, nerol, α-pinene
and terpineol (monoterpenes), and farnesol (sesquiterpene) (Fitsiou et al. 2007; Rǎdulescu &
Oprea 2008; Ahmadi & Mirza 1999; WHO 2010)

− Other constituents - Saponin (unspecified), tannin (condensed) and tocopherol (phytosterol).

The ratio of tannins to mucilage appears to be important in determining the flavour of teas prepared
from lime flowers. Those teas with a high (2% or greater) tannin level and low mucilage content
produce the more flavourful teas. Flowers from Tilia cordata and Tilia platyphyllos contain relatively
more tannin than mucilage (Blumenthal et al. 2000). More than 2 dozen additional minor compounds
have been identified in the wood, flowers and fruits of lime. The fragrant components of the flowers
degrade rapidly under conditions of high moisture (Blaschek et al. 2010; PDR for Herbal Medicines
2007; Review of Natural Products 2005).

The herbal substance should contain not less than 15% water-soluble extractive (BHP 1976), while the
Pharmacopoeia of Hungary (VIth Hungarian Pharmacopoeia 1970) requires not less than 18% water-
soluble extractive.

Macroscopic and microscopic tests are used for detecting common adulterations with other species
(mainly Tilia tomentosa = Tilia argentea). According to the European Pharmacopoeia (2008), a
maximum of 2% of foreign matter can be determined on 30 g. There are no inflorescences with a bract
bearing at the abaxial face stellate, five to eight-rayed trichomes and flowers having an apparent
double corolla by transformation of five stamens into petal-like staminoids and having a pistil which is
not lobular nor indented. Hexamerous flowers occur only occasionally (Tilia americana L., Tilia
tomentosa Moench).

• Herbal preparation(s)

a) Comminuted herbal substance

b) Liquid extract (DER 1:1), extraction solvent ethanol 25% V/V

c) Tincture (ratio of herbal substance to extraction solvent 1:5), extraction solvent ethanol 45%
V/V

• 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.

There are several combinations registered in the European Union (EU):

- herbal tea containing Plantaginis folium(25%), Althaeae radix (20%), Cynosbati fructus sine
semine (20%), Liquiritiae radix (15%), Serpylli herba (15%), Tiliae flos (5%) (Czech
Republic)

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 - herbal tea containing Foeniculi dulcis fructus (15%), Sambuci nigrae flos (25%), Tiliae flos
(25%), Plantaginis folium (20%), Liquiritiae radix (15%) (Czech Republic)

- herbal tea containing Tiliae flos & Salicis cortex (Germany)

- herbal tea containing Tiliae flos, Thymi herba & Anisi fructus, Thymi herba, Foeniculi amari
fructus, Lichen islandicus (Germany)

- herbal tea containing Tiliae flos, Farfarae folium and Melissae folium (Poland) (Muszyński
1954)

This assessment report refers only to Tiliae flos.

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1.2. Information about products on the market in the Member States

Member State Regulatory Status (products, indications)

Austria TU
Herbal tea, since 1994
Posology
For oral use in adults and adolescents over 12 years
1 - 2 times daily a cup of fresh prepared infusion (2-4 g herbal substance)
Indication The traditional indication is: for the relief of early symptoms of common
cold

Bulgaria No authorised herbal medicinal products containing Tilia flos as a single drug
preparation are on the market
Cyprus No authorised herbal medicinal products containing Tilia flos as a single drug
preparation are on the market
TU
Herbal tea, since 2000
Posology:
1. for oral use
Adults: 1.5 g/250 ml of boiling water 2 - 3 times daily
Adolescents/children 4 - 12 years of age: 1.5 g/250 ml of boiling water 2 times
daily
Children 1 - years of age: 1.5 g/250 ml boiling water once daily

Indication: Traditionally used as an adjuvant for treatment of catarrhs of upper

respiratory tract and cold associated with dry, irritating cough
Contraindication: Hypersensitivity to the herbal substance/ Special warning: If
dyspnoea, fever or purulent sputum occurs, a doctor should be consulted
Czech Republic
immediately.

Other information on relevant combination products:

1. Herbal tea containing Plantaginis folium(25%), Althaeae radix (20%), Cynosbati
fructus sine semine (20%), Liquiritiae radix (15%), Serpylli herba (15%), Tiliae
flos (5%) – on the market since 1995 – for oral use, adjuvant for treatment of
catarrhs of upper respiratory tract associated with dry cough
2. Herbal tea containing Foeniculi dulcis fructus (15%), Sambuci nigrae flos
(25%), Tiliae flos (25%), Plantaginis folium (20%), Liquiritiae radix (15%) – on
the market since 1997 – for oral use – indications: for treatment of common
cold associated with elevated temperature; inflammations of oral cavity and
upper respiratory tract; diaphoretic effect

No authorised herbal medicinal products containing Tilia flos as a single drug

Denmark
preparation are on the market
No authorised herbal medicinal products containing Tilia flos as a single drug
Estonia
preparation are on the market
Finland No authorised herbal medicinal products containing Tilia flos as a single drug
preparation are on the market

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France Only in combination

WEU
9 Herbal teas since 1976
Posology:
for oral use in adults and adolescents over 12 years
1 - 2 times daily a cup of fresh prepared infusion (2 - 4 g herbal substance)
or
1 - 2 cups very hot as “sweat infusion” before going to bed.

Germany
Indications: Used as a diaphoretic in feverish colds
2 authorised combination products
1. herbal tea containing Tiliae flos & Salicis cortex
2. herbal tea containing Tiliae flos, Thymi herba & Anisi fructus, Thymi herba,
Foeniculi amari fructus, Lichen islandicus
single active ingredient: 9 herbal teas
combination products: 11 herbal teas

Greece No authorised herbal medicinal products containing Tilia flos as a single drug
preparation are on the market

TU
Can be found in registered products only in combinations, but it can be bought as
herbal substance in pharmacies and used according to the literature
Herbal tea (Augustin et al. 1948)

Posology:
(VIth Hungarian Pharmacopoeia 1967; English version 1970)
Hungary
For oral use as an infusion
Usual single dose 0.5-1 g
Usual daily dose 2.5-5 g

Indication:
to promote sweating in the case of common cold, chronic coughing and catarrh

Lithuania TU
Herbal tea, since 1995

Posology:
Children older then 2 years, adolescents and adults
Single dose
1.5-2 g of comminuted herbal substance for infusion.
Daily dose
4-6 g of comminuted herbal substance for infusion

Indication:
Traditional herbal medicinal product used as expectorant in dry cough associated
with cold and to promote perspiration in case of fever

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Netherlands No authorised herbal medicinal products containing Tilia flos as a single drug
preparation are on the market

Norway No authorised herbal medicinal products containing Tilia flos as a single drug
preparation are on the market

Poland Herbal tea, since 1991

Posology:
for oral use in adults and adolescents over 12 years

Indication:
Mild antipyretic and diaphoretic agent in common cold and in cough
Hypersensitivity reactions (i.e. urticaria)

Portugal No authorised herbal medicinal products containing Tilia flos as a single drug
preparation are on the market

Slovakia No authorised herbal medicinal products containing Tilia flos as a single drug
preparation are on the market

Slovenia No authorised herbal medicinal products containing Tilia flos as a single drug
preparation are on the market

Only combination products containing Tiliae flos are registered

Spain

No authorised herbal medicinal products containing Tilia flos as a single drug

Sweden preparation are on the market

United Kingdom Only combination products containing Tilia flos are registered

Regulatory status overview

Member State Regulatory Status Comments

Austria MA TRAD Other TRAD Other Specify: Herbal tea as the only
active ingredient since
1994

Belgium MA TRAD Other TRAD Other Specify: Multi-component herbal

teas since 1962

Bulgaria MA TRAD Other TRAD Other Specify: No products registered

Cyprus MA TRAD Other TRAD Other Specify: No products registered

Czech Republic MA TRAD Other TRAD Other Specify: One herbal tea, since
2000

Denmark MA TRAD Other TRAD Other Specify: No products registered

Estonia MA TRAD Other TRAD Other Specify: No products registered

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Member State Regulatory Status Comments

Finland MA TRAD Other TRAD Other Specify: No products registered

France MA TRAD Other TRAD Other Specify: Only in combination

products

Germany MA TRAD Other TRAD Other Specify: Herbal tea since 1976

Greece MA TRAD Other TRAD Other Specify: No products on the

market

Hungary MA TRAD Other TRAD Other Specify: Only in combinations

Iceland MA TRAD Other TRAD Other Specify: Not known

Ireland MA TRAD Other TRAD Other Specify: Not known

Italy MA TRAD Other TRAD Other Specify: Not known

Latvia MA TRAD Other TRAD Other Specify: Not known

Liechtenstein MA TRAD Other TRAD Other Specify: Not known

Lithuania MA TRAD Other TRAD Other Specify: Herbal tea since 1995

Luxemburg MA TRAD Other TRAD Other Specify: Not known

Malta MA TRAD Other TRAD Other Specify: Not known

The Netherlands MA TRAD Other TRAD Other Specify: No products registered

Norway MA TRAD Other TRAD Other Specify: No products registered

Poland MA TRAD Other TRAD Other Specify: Herbal tea since 1991

Portugal MA TRAD Other TRAD Other Specify: No products registered

Romania MA TRAD Other TRAD Other Specify: Not known

Slovak Republic MA TRAD Other TRAD Other Specify: No products registered

Slovenia MA TRAD Other TRAD Other Specify: No products registered

Spain MA TRAD Other TRAD Other Specify: Only combination

products are registered
Tilia flos can be freely
sold as food

Sweden MA TRAD Other TRAD Other Specify: No products registered

United Kingdom MA TRAD Other TRAD Other Specify: Only combination

products containing Tilia
flos are registered

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.

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1.3. Search and assessment methodology

Search terms: Tilia cordata Miller, Tilia platyphyllos Scop. Tilia x vulgaris Heyne, flowers, Tiliae flos.
Tilia sp., tiliroside,
Databases: Pubmed, Medline, HealLink, scopus.
Libraries: University of Athens, Laboratory of Pharmacognosy and Chemistry of Natural Products of the
University of Athens.

2. Historical data on medicinal use

2.1. Information on period of medicinal use in the Community

Since the middle ages, the lime flowers have been used as a diaphoretic to promote perspiration. In
addition, the flowers have been used traditionally as tranquiliser and to treat headaches, indigestion
and diarrhoea. Infusions of the flowers make a pleasant-tasting tea. Traditionally lime flowers were
added to baths to quell hysteria and steeped as a tea to relieve anxiety-related indigestion, heart
palpitation and vomiting (Blumenthal et al. 1998; 2000). Several sources report the lore that lime
flowers were once believed to be so effective in treating epilepsy that one could be cured simply by
sitting beneath the tree. Sugar is obtained from the sap of the tree and the seed oil resembles olive oil.
In Greek mythology, “Philyra”, a nymph, was transformed into a lime tree after begging the gods not
to leave her among the mortals (Barnes et al. 2007; Duke et al.1985; Review of Natural Products
2005; BHP 1976).

The lime flowers are referred in the VIth Hungarian Pharmacopoeia (1967; English version 1970) with
the following posology: usual single dose: 0.5 - 1 g and usual daily dose: 2.5 - 5 g. In the Hungarian
book by Augustin et al. 1948, it is mentioned that the lime flowers are used in the form of infusion for
promoting sweating in the case of common cold, chronic coughing and catarrh and they are even used
for preparing candies to relieve cough.

Tiliae flos can be found also in the first edition of the Czechoslovak Pharmacopoeia (Československý
lékopis) published in 1947, as well as in the current version of Czech Pharmacopoeia (Český lékopis
2009, suppl. 2010).

Moreover the monograph of Tiliae flos has been defined in details in the Polish Pharmacopoeia of 1970
(Farmakopea Polska 1970), while, also in Poland, Inflorescentia Tiliae (Ożarowski et al. 1978) has been
known to stimulate secretory and excretory functions - diuretic, gastric fluid, bile flow, transpiration
and skin perspiration. It was for oral use as an infusion, as a supportive mean in fever states with sore
throat and bronchitis. These infusions have been used also in nervousness, states of nervous tension
and even in hysteria or hypochondria.

In Germany, lime flower is approved in the Commission E monographs (Blumenthal et al. 1998), and
the tea form is official in the German Standard Licence monographs, and it was also official in the
pharmacopoeia of the former German Democratic Republic (Blumenthal et al. 1998). It is used as a
component of common cold and antitussive preparations and also as an urological and sedative drug.

In German paediatric medicine, it is used as a diaphoretic component of an influenza tea for children
comprised of lime flower, willow bark, meadowsweet flower, chamomile flower and bitter orange peel.
It is also a primary component of “Schweisstreibender Tee” (diaphoretic tea) composed of lime flower,
peppermint leaf, meadowsweet flower and bitter orange. In Switzerland, a comparable diaphoretic tea
is known, composed of lime flower, elder flower, mint leaves and jaborandi leaf (Blumenthal et al.
1998). There is a strong experience available, particularly in the German market, on the use of lime
flower preparations, especially the herbal tea, in children of almost all age groups (Peter 1963;
Kooperation Phytopharmaka 2002; Bühring et al. 2008; Schilcher 1992; Schilcher & Dorsch 2006).

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Medicinal Use

The Commission E approved lime flower for colds and cold-related coughs (Blumenthal et al. 1998;
2000). Lime flower is stated to possess sedative, antispasmodic, diaphoretic, hypotensive, emollient,
diuretic and mild astringent properties. Traditionally it has been used for migraine, hysteria,
arteriosclerotic hypertension, feverish colds, and specifically for raised arterial pressure associated with
arteriosclerosis and nervous tension (Barnes et al. 2007).

Bradley (1992) indicates its use for upper respiratory catarrh, common colds, irritable coughs,
hypertension and restlessness.

The German Standard Licence indicates lime flowers infusion for alleviation of cough irritation due to
catarrh of the respiratory tract and for feverish colds for which a sweat treatment is desired.

Tilia cordata has been used in other sedative effects therapies include relief of sinus headache and
migraines, insomnia, stress and panic disorders. It has been used also to treat nervous palpitations
and has been also reported to lower high blood pressure caused by stress and nervous tension
(Blumenthal et al. 1998).

Food Use

Lime flower is listed by the Council of Europe as a natural source of food flavouring (category N2). This
category indicates that lime flower can be added to foodstuffs in small quantities, with a possible
limitation of an active principle (as yet unspecified) in the final product. Previously, lime flower has
been listed as GRAS (Generally Recognised As Safe) (Barnes et al. 2007).

Conclusion

For Tilia flos a period of at least 30 years of medicinal use as requested by Directive 2004/24/EC for
qualification as a traditional herbal medicinal product is easily fulfilled. The evidence on traditional
medicinal use is confirmed by a large number of publications providing consistent information.

2.2. Information on traditional/current indications and specified

substances/preparations

According to the overview of the European market, the herbal preparation (a) fulfils the criteria for at
least 30 years of medicinal use in the EU, while the herbal preparations (b) and (c) were found in
literature references, and the period of their use is longer than 30 years (BHP 1976).

From information on the use in Germany since 1976, in Hungary since 1948 (Augustin et al. 1948), in
Czechoslovakia/Czech Republic since 1947:

a) Comminuted herbal substance for herbal tea preparation

From the literature (BHP 1976; Augustin et al. 1948; Bradley 1992; Blumenthal et al. 1998; Barnes et
al. 2007; PDR 2007):

b) Liquid extract (DER 1 : 1) extraction solvent ethanol 25% (V/V)

c) Tincture (ratio of herbal substance to extraction solvent: 1 : 5), extraction solvent ethanol 45%
V/V)

Indications approved in the Member states:

Herbal medicinal product used as a diaphoretic in feverish colds (Germany, Poland).

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Traditionally is used as an adjuvant for treatment of catarrhs of the upper respiratory tract and cold
associated with dry, irritating cough (Czech Republic).

The traditional indication is: for the relief of early symptoms of common cold (Austria).

Traditionally used to promote sweating in the case of common cold, chronic coughing and catarrh and
to relieve coughing (Hungary).

Traditional herbal medicinal product used as expectorant in dry cough associated with cold and to
promote perspiration in case of fever (Lithuania).

Traditional herbal medicinal product used in states of nervous tension (Poland) (Ożarowski et al.
1978).

The following indications are proposed for the Community herbal monograph:

1. Traditional herbal medicinal product used for the relief of symptoms of common cold.

2. Traditional herbal medicinal product for the relief of mild symptoms of mental stress.

2.3. Specified strength/posology/route of administration/duration of use

for relevant preparations and indications

The following posologies have been recorded for lime flower:

a) Comminuted herbal substance

Single dose: 1.5 g, daily dose 3 - 6 g (Český lékopis 2009, supp. 2010)

1.5 g in 150 ml of boiled water 2 - 4 times daily (Blumenthal et al. 1998)

single dose: 0.5 - 1 g, usual daily dose: 2.5 - 5 g (Hungarian Pharmacopoeia 1970)

b) Liquid extract (1 : 1 in 25% alcohol) 2 - 4 ml daily (BHP 1976)

c) Tincture (1 : 5 in 45% alcohol) 1 - 2 ml daily (BHP 1976)

Based on literature data and information from the Member States, the following posology and duration
of use are proposed for the Community herbal monograph:

Posology

Adolescents, adults and elderly

Indication 1) and indication 2)

a) Comminuted herbal substance

Herbal tea: 1.5 g of the comminuted herbal substance in 150 ml of boiling water as a herbal
infusion 2 – 4 times daily
Daily dose: 3 – 6 g

b) Liquid extract.
Single dose: 2 ml, 1 - 2 times daily
Daily dose: 2 - 4 ml

c) Tincture
Single dose: 1 ml, 1 - 2 times daily
Daily dose: 1 - 2 ml

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Children between 4 and 12 years of age

Indication 1)

a) Comminuted herbal substance

Herbal tea: 1 g of the comminuted herbal substance in 150 ml of boiling water as a herbal infusion
2 – 4 times daily
Daily dose: 2 - 4 g

Duration of use

Indication 1)

The therapy should start at first signs of common cold. If the symptoms persist longer than 1 week
during the use of the medicinal product, a doctor or a qualified health care practitioner should be
consulted.

Indication 2)

If the symptoms persist during the use of the medicinal product, a doctor or a qualified health care
practitioner should be consulted.

3. Non-Clinical Data

3.1. Overview of available pharmacological data regarding the herbal

substance(s), herbal preparation(s) and relevant constituents thereof

In vitro and animal studies

Differential cell growth effects on lymphocytes

The antiproliferative action of aqueous, dichloromethane and ethanol extracts obtained from Tilia
cordata Miller, flowers on tumoral (BW 5147 lymphoma) and normal lymphocytes was described. All
extracts showed a selective action on tumoral cells, inducing apoptosis. In the case of normal T cells
these extracts suppressed mitogen-induced proliferation without affecting viability, suggesting a
suppressive but not cytotoxic effect. These effects were clearly concentration-dependent. A coumarin
(scopoletin), the main component in the dichloromethane extract presented antiproliferative action on
BW 5147 cells, suggesting that it may be at least partly responsible for the activity displayed by this
extract (Barreiro et al. 2006).

Anxiolytic and sedative activity

The aqueous extract of Tilia cordata flowers showed in vitro stimulatory effects on lymphocyte
proliferation (maximum stimulatory concentration: 20 μg/ml). This effect was mimicked by Ro 5-4864,
an agonist of the peripheral benzodiazepine receptor, and by Pk 11195, an agonist/antagonist of the
same receptor. These results suggest that Tilia extract could exert its stimulatory effect by acting as an
agonist of the peripheral benzodiazepine receptor (Anesini et al. 1999).

Lime flower’s sedative effects have been reported as significant upon inhalation of Tilia sp. oil in mice
(Blumenthal et al. 1998).

Antispasmodic – spasmogenic activity

In vitro, lime’s seeds water extracts of Tilia platyphylla and Tilia vulgaris have been reported to exhibit
antispasmodic activity followed by a spasmogenic effect on rat duodenum (Lanza & Steinmetz 1986).

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The activity of selected constituents of lime flower (flavonoids and phenolic acids) was inhibited by
atropine and papaverine, and reinforced by acetylcholine. The diaphoretic and antispasmodic
properties claimed for lime flower have been attributed to p-coumaric acid and the flavonoids (Lanza &
Steinmetz 1986; Al-Essa et al. 2007).

The effects of the ethanol extract of Tilia cordata Miller were studied in vitro using intestinal smooth
muscle cells of guinea pigs dispersed by collagenase. The extract induced a dose-dependent
contraction of the dispersed smooth muscle cells. The obtained data indicated a direct effect of the Tilia
cordata extract on the intestinal smooth muscle cells. In addition, the contractions induced by the
extract were inhibited by atropine. These observations indicate an involvement of some active
constituents, with cholinergic properties, found in the alcohol extract to induce contraction of the
intestinal smooth muscle cells via activation of the muscarinic receptors (Al-Essa et al. 2007).

Antimicrobial and antifungal activity

Forty-one plant extracts, known in therapy for other properties, have been tested against nine fungal
species. Lime flower (Tilia cordata) has been documented to possess a range of antifungal activity
(Guerin & Reveillere 1984).

Pancreatic lipase inhibition

Lipids are important components in human nutrition; however, their increased intake contributes to the
development of obesity and can lead to multiple long-term complications. Pancreatic lipase
(triacylglycerol acylhydrolase, EC 3.1.1.3) is a key enzyme for the absorption of dietary triglycerides.
Interference with fat hydrolysis of ingested lipids, therefore inhibition of lipases, decreases fat
absorption. Extracts from 106 species of medicinal plants, vegetables and fruits were screened for
potential lipase inhibitory activity. p-Nitrophenylpalmitate and 5-bromo-4-chloro-3-indoxylpalmitate
were used as substrates in an in vitro test with crude porcine pancreatic lipase. Large-leaved lime (Tilia
platyphyllos) extracts were the most active. Additionally, the activity of selected extracts with removed
polyphenols was measured. The authors concluded that extracts of large-leaved lime are a promising
source for developing functional foods or isolating active compounds (Slanc et al. 2009).

Bioactivities of secondary metabolites from lime flower

Diaphoretic activity

The diaphoretic activity of the flowers of lime is suggested to be caused by quercetin, kaempherol and
p-coumaric acid. Where “sweat cures” would be an advantage, lime tree has been used mainly for
feverish colds and infections. It has been also used to reduce nasal congestion and relieve throat
irritation and cough upon inhalation of Tilia sp. oil in mice (Blumenthal et al. 1998, 2000).

Hepatoprotective activity

Kaempferol-3-O-β-D-(6″-E-p-coumaroyl)-glucopyranoside (tiliroside) has been isolated from many

natural plants sources. This compound showed very interesting pharmacological activities, e.g.,
cytotoxic for human leukaemic cell lines and anti-complement activity. However, there is a lack of data
concerning the presence of this compound in medical plants. In this work, a reproducible and quick
method was elaborated for the separation and determination of tiliroside in methanolic extracts of
selected plants among which Tilia species. The content of tiliroside for various plant materials was
compared (Nowak 2003).

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Antidiabetic activity

A recent study on traditionally used medicinal plants, herbs and spices in Latin America included Tilia
platyphyllos flowers. These were investigated to determine their phenolic profiles, antioxidant activity
and in vitro inhibitory potential against key enzymes relevant for hyperglycaemia and hypertension.
Lime flowers inhibited strongly both the α-glucosidase (exhibited the highest inhibition against α-
glucosidase (~100%) at 2.5 mg of dried sample and its inhibitory activity was high even at lower dose
i.e. 75%, at 0.5 mg of dried sample) and α-amylase enzymes (significant inhibition of porcine
pancreatic α-amylase at the highest evaluated dose (71%) at 25 mg of dried sample); lime flowers
were supposed to have potential for hyperglycaemia and hypertension prevention associated with type
2 diabetes (Ranilla et al. 2010).

Diuretic, sedative and antispasmodic effects

Tilia species are traditional medicinal plants widely used as sedatives and tranquilisers (Zhang 2004).
For this purpose, the infusion of their inflorescences is used to prepare a tea.

In the study by Viola et al., extracts of inflorescences from Tilia tomentosa Moench, one of the species
found in the market, were purified using a benzodiazepine (BZD) binding assay to detect BZD receptor
ligands in the different fractions. One of the ligands was identified as kaempferol, but it had low affinity
(K(i) = 93 μM) for this receptor, and did not produce sedative or anxiolytic effects in mice. On the
other hand, a complex fraction, containing yet unidentified constituents, but probably of a flavonoid
nature, when administered intraperitoneally in mice, had a clear anxiolytic effect in both the elevated
plus-maze and hole board tests, two well-validated pharmacological tests to measure anxiolytic and
sedative compounds. This active fraction had no effect on total and ambulatory locomotor activity. In
conclusion, these results demonstrate the occurrence of active principle(s) like kaempferolin, at least in
Tilia tomentosa while this can be found also in other Tilia species that may explain its
ethnopharmacological use as an anxiolytic (Viola et al. 1994).

In addition, a number of actions have been associated with volatile oils including diuretic, sedative and
antispasmodic effects in mice, which may also account for some of the reputed uses of lime flower
(Tilia cordata) (Taddei et al. 1988; Barnes et al. 2007). Volatile oils are not thought to possess any
true diuretic activity, but to act as a result of certain terpenoid components having an irritant action on
the kidneys during renal excretion.

All these observations of such bioactivities help to account for some of the existing medical effects.

3.2. Overview of available pharmacokinetic data regarding the herbal

substance(s), herbal preparation(s) and relevant constituents thereof

No data on lime flower extracts have been found or reported.

3.3. Overview of available toxicological data regarding the herbal

substance(s)/herbal preparation(s) and constituents thereof

Single-dose and repeated-dose toxicity studies

No data have been found.

Genotoxicity studies

Among six herbal infusions used worldwide (Matricaria chamomilla, Tilia cordata, Mentha piperita,
Mentha pulegium, Uncaria tomentosa and Valeriana officinalis) were assayed for anti-genotoxicity

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using the Somatic Mutation And Recombination Test (SMART) in Drosophila melanogaster. All these
infusions are traditionally used for various medical purposes. Hydrogen peroxide was used as an
oxidative genotoxicant to test the anti-genotoxic potency of the medicinal infusions. None of these
infusions showed a significant genotoxicity, quite the reverse they were able to behave as
desmutagens, detoxifying the mutagen hydrogen peroxide. The phenolic content of such herbal
infusions is argued to be the possible scavenger of reactive oxygen radicals produced by the hydrogen
peroxide (Romero-Jiménez et al. 2005).

No adequate genotoxicity studies carried out on lime flower in the scientific literature.

Carcinogenicity studies

No carcinogenicity studies carried out on lime flower in the scientific literature.

Reproductive and developmental toxicity studies

No reproductive and developmental toxicity studies carried out on lime flower are reported in the
scientific literature.

The safety of lime flower during pregnancy and lactation has not been established. In accordance with
general medical practice, the herbal medicinal products (herbal teas, other finished products) should
not be used during pregnancy and lactation without medical advice.

3.4. Overall conclusions on non-clinical data

Lime flower has officially been recognised since 1947 in the first edition of the Czechoslovak
Pharmacopoeia (Československý lékopis) till the current version of Czech Pharmacopoeia (Český
lékopis 2009, suppl. 2010). Also it has been proposed since 1948 (Augustin et al. 1948) and then
introduced in the VIth edition of the Hungarian Pharmacopoeia in 1970 as an herbal remedy
traditionally used in for the relief of symptoms in common cold (diaphoretic in feverish cold). Lime
flower is in the Polish Pharmacopoeia (Farmakopea Polska 1970). Also according to Ożarowski et al.
(1978), Inflorescentia Tiliae has been known in Poland to stimulate secretory and excretory functions
(diuretic, gastric fluid, bile flow, transpiration, skin perspiration), as supportive treatment in fever
states with sore throat and bronchitis, and in states of nervous tension. It has been also referred in the
BHP (1976).

Based on the above-mentioned data, it is evident that Tiliae flos has been used as a traditional remedy
for a long time and without safety problems for much more than 30 years.

The published data referring to the indications and preparations is limited, but on the basis of existing
data the pharmacological activities (BHP 1976; Madaus 1979; Bradley 1992) support the traditional
use of Tilia cordata, Tilia platyphyllos and Tilia x vulgaris and preparations thereof in the proposed
indications:
1. Traditional herbal medicinal product for the relief of symptoms of common cold
2. Traditional herbal medicinal product used to relieve mild symptoms of mental stress

The efficacy of traditional herbal medicinal products is only plausible but not proven by clinical data.

Although no adequate toxicity data are available, lime flower and lime flower preparations can be
regarded as safe based on the fact that lime flower is listed by the Council of Europe as a natural
source of food flavouring (category N2). Lime flower is listed as Generally Recognised as Safe (GRAS)
by the FDA.

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Nevertheless, the lack of genotoxicity, carcinogenicity as well as reproductive and developmental
toxicity studies does not allow the establishment of a Community list entry.

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

No data available.

4.1.2. Overview of pharmacokinetic data regarding the herbal

substance(s)/preparation(s) including data on relevant constituents

No data available.

4.2. Clinical Efficacy

4.2.1. Dose response studies

No data available.

4.2.2. Clinical studies (case studies and clinical trials)

Antidiabetic activity

A cross-sectional study was conducted by interviewing 310 diabetic patients visiting two medical
centres in Jordan, Jordan University of Science & Technology Medical Centre and Sarih Medical Centre,
between December 2003 and August 2004. It was found that 31% of interviewed patients have used
herbal products (96 patients). The results revealed that the most commonly used herbs by diabetic
patients in Jordan were Trigonella foenumgraecum (22.9%), Lupinus albus (14.6%), Allium sativum
(11.5%), Allium cepa (5.2%), Nigella sativa (7.3%), Zea mays (6.3%), Urtica dioica (8.3%),
Eucalyptus globulus (9.4%), Olea europea (3.1%), Cumminum cyminum (9.4%), Coriandrum sativum
(10.4%), Salvia officinalis (3.1%) and Tilia cordata (1%). The side effects for all the assayed herbs
were reported by 36.5% of the patients and included headache, nausea, dizziness, itching, palpitation
and sweating. Among the patients, 72.9% used the herbs as adjunctive therapy along with their
antidiabetic drugs and 80.2% of the patients informed their physicians about their use. A 79.2% of the
sample confirmed their intention to re-use these herbs as 86.5% of them were satisfied with their
diabetes control. Therefore, it is essential to increase the level of awareness among diabetic patients
and health care providers regarding the efficacy and toxicity of these medicinal herbs (Otoom et al.
2006).

Diaphoretic activity

The diaphoretic action of Tiliae flos was investigated in an open controlled clinical trial in patients with
uncomplicated catarrhal disease. Fifteen patients with catarrhal disease inhaled water vapour from a
preparation made with two sachets of Tiliae flos in 500 ml of water. Inhalation was maintained for 10
minutes at 40–50 ºC. A control group of 15 patients inhaled vapour from coloured water. Fifteen
minutes after inhalation, all patients experienced a certain subjective relief with further improvement
of their condition in the group that had inhaled the preparation of Tiliae flos. In the control group,

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improvement was observed only for the first 120 minutes, and after addition of other symptomatic
treatment. It was suggested that the inhalation of a preparation of Tiliae flos had a kind of diaphoretic
effect. As there was no statistical analysis of the data, an objective assessment of this investigation is
not possible (WHO 2010).

There is a lack of clinical research, except the above-referred references by Otoom et al. 2006, WHO
2010, assessing the effects of lime flower and rigorous randomised controlled clinical trials are
required.

4.2.3. Clinical studies in special populations (e.g. elderly and children)

None reported.

4.3. Overall conclusions on clinical pharmacology and efficacy

Due to the lack of the data, no conclusion can be drawn.

5. Clinical Safety/Pharmacovigilance

5.1. Overview of toxicological/safety data from clinical trials in humans

There is a lack of clinical and non-clinical safety and toxicity data for lime flower and further
investigation of these aspects is needed.

5.2. Patient exposure

No data available.

5.3. Adverse events and serious adverse events and deaths

Observations of suspected allergy to lime flower pollen (Tilia cordata) have been published several
times and aeroallergen sensitisation due to Tilia cordata is believed to be among the most common
(Loureiro et al. 2005; Krakowiak et al. 2004; Mur et al. 2001).

A case-report of occupational allergy in a 55-year old woman has appeared in the scientific literature.
The woman, a non-smoker, who was working as a cosmetician, had experienced recurrent itching and
erythematous papulovesicular lesions on the backs of her hands for around 18 months, and had had a
history of sneezing, nasal obstruction and watery eyes for some years when she came into contact with
depilatory wax or flowers of Tilia cordata. Clinical examination, as well as routine laboratory
parameters, remained normal. Total immunoglobulin E was 13 084 IU/ml and skin-prick tests showed
positive reactions to common environmental allergens – grass and tree pollens, and to flowers. Specific
immunoglobulin E antibodies for grass and tree pollens were negative. The results of patch tests with
Tilia flowers with a standard series and a series of plant allergens were positive. A bronchial challenge
test was performed in an inhalation chamber for 30 minutes. In the first stage, the patient was
challenged with placebo (potato flour); during the second stage (after 7 days), with depilatory wax
that had been thermally activated, and after 14 days with dried flowers. Following such exposures,
clinical symptoms of rhinoconjunctivitis appeared, and were observed for 48 hours after the
challenges. In addition, increases in eosinophil and basophil proportions in nasal lavage and tear fluids
were observed during the late phase of allergic reaction. A diagnosis of occupational allergy was made
based on the positive results of the allergy tests, analysis of the clinical status and medical history, and
the positive results of specific challenges (WHO 2010; Krakowiak et al. 2004).

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Over a 5-year period, 1790 paediatric outpatients were observed for suspected allergic symptoms and
371 children were given a skin prick test to check for responses to aeroallergens. Aeroallergen
sensitisation due to Tilia cordata was observed in 11.4% of the paediatric patients examined (Loureiro
et al. 2005).

It has been advised that lime flower should be avoided by individuals with an existing cardiac disorder
(Duke 1985), as excessive use may result in cardiac toxicity; however, the scientific basis for this
statement, if any, is not known (Barnes et al. 2007).

5.4. Laboratory findings

No data available.

5.5. Safety in special populations and situations

Special patient population

Available evidence and experience on the use of lime flower preparations, especially the herbal tea, in
children of different age groups can be found in several textbooks e.g. Kooperation Phytopharmaka
2002 or Bühring et al. 2008, where the preparation of a herbal tea from lime flower as well as of two
combination teas for the specific paediatric use is described. Similar recommendations for combination
teas are given by Schilcher (1992) and Schilcher & Dorsch (2006), e.g. a “species diaphoreticae” with
reference to a clinical study of Traisman and Hardy who treated various groups of children suffering
from respiratory infections with different medications and non-medicinal measures. Good results have
been obtained, using lime flower tea without any other medication.

The use for the relief of symptoms of common cold in children under 4 years of age has not been
established due to lack of adequate data.

The use for the relief of mild symptoms of mental stress in children under 12 years of age has not been
established due to lack of adequate data.

Fertility, pregnancy and lactation

No data are available. In the absence of sufficient data and in accordance with general medical
practice, it is recommended not to use herbal medicinal products containing lime flower during
pregnancy and lactation.

No fertility data available.

Overdose

No cases of overdose have been recovered in the scientific literature.

Drug abuse

No information retrieved from the literature search.

Effects on ability to drive or operate machinery or impairment of mental ability

No data retrieved from the literature search.

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Potential for interactions

None reported.

5.6. Overall conclusions on clinical safety

Tiliae flos is intended for use in adolescents, adults and elderly. Tiliae flos can also be used for the
relief of symptoms of common cold in children between 4 and 12 years of age, however the use in
children under 4 years of age for this indication has not been established due to lack of adequate data.

In the absence of sufficient data and in accordance with general medical practice, it is recommended
not to use herbal medicinal products containing Tiliae flos (lime flower) during pregnancy and lactation.

Some cases of allergic reactions have been reported, however the frequency is not known.

No other adverse effects have been reported, showing sufficient safety for the proposed traditional use
of Tiliae flos preparations.

The establishment of a Community list entry is not possible, as there are no available data on
genotoxicity, carcinogenicity, reproductive and developmental toxicity of lime flower extracts.

6. Overall conclusions
The positive effects of lime flower on the relief of symptoms of common cold as well as its activity to
relieve the symptoms of mild nervous tension have been recognised empirically. The traditional use is
recognised as plausible, based on the existing in vitro and in vivo pharmacological data. There is a lack
of controlled clinical studies with preparations containing lime flower.

In conclusion, Tiliae flos and its preparations can be regarded as traditional herbal medicinal products
in the following indications:

− Traditional herbal medicinal product used for the relief of symptoms of common cold

− Traditional herbal medicinal product for the relief of mild symptoms of mental stress.

Based on information from the Member States and on literature data, Tiliae flos can be recommended
for use in adolescents, adults and elderly and can be recommended for use in children between 4 and
12 years of age for the relief of symptoms of common cold.

In the absence of sufficient data and in accordance with general medical practice, it is recommended
not to use herbal medicinal products containing lime flowers during pregnancy and lactation.

Safety data reported above support a safe use at the recommended posology in the proposed
traditional uses, for traditional herbal medicinal products containing Tiliae flos preparations.

As there are no data available on the genotoxicity, carcinogenicity, reproductive and developmental
toxicity of lime flowers and preparations thereof, the establishment of a Community list entry is not
possible due to safety concerns.

Annex

List of references

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