Marrubium – White horehound (Marrubii herba)
|Latin name of the genus:||Marrubium|
|Latin name of herbal substance:||Marrubii herba|
|Botanical name of plant:||Marrubium vulgare l.|
|English common name of herbal substance:||White horehound|
Latin name of the genus: Marrubium
Latin name of herbal substance: Marrubii herba
Botanical name of plant: Marrubium vulgare L.
English common name of herbal substance: White horehound
- 1. Introduction
- 2. Historical data on medicinal use
- 3. Non-Clinical Data
- 3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
- 3.2. Overview of available pharmacokinetic data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
- 3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof
- 3.4. Overall conclusions on non-clinical data
- 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
- 4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
- 4.2. Clinical Efficacy
- 4.2.1. Dose response studies
- 4.2.2. Clinical studies (case studies and clinical trials)
- 4.2.3. Clinical studies in special populations (e.g. elderly and children)
- 4.3. Overall conclusions on clinical pharmacology and efficacy
- 5. Clinical Safety/Pharmacovigilance
- 6. Overall conclusions
1.1. Description of the herbal substance(s), herbal preparation(s) or combinations thereof
Marrubium vulgare L., herba
Definition of the herbal substance
Diverse national monographs for White Horehound have been replaced by the monograph published in the European Pharmacopoeia 5th ed. 2005 (5.1) and the current European Pharmacopoeia 7th edition 2011 (7.0) (01/2008:1835 corrected 6.0) White Horehound – Marrubii herba. The definition of Marrubii herba is “Whole or fragmented dried flowering aerial plants of Marrubium vulgare L. Content: minimum 0.7% marrubiin (C20H20O4; M: 332.4) (dried drug).” Characters: bitter taste.
Material of commerce is usually supplied in the cut or crushed form. It is obtained mainly from European countries and
The species Marrubium vulgare L., Lamiaceae is known under the synonyms: Marrubium album GILB.,
Marrubium germanicum SCHRANK, Marrubium lanatum KUNTH, and Prasium marrubium E.H.L. Krause; it is described as herba Marrubii, herba Marrubii albi, herba Marrubii vulgaris and herba prasii (Blaschek et al., 2006).
In European countries, Marrubium vulgare is known by the following common names: German: Weißes Andornkraut, Gemeiner Andorn,
Adulteration and confusion
Confusion with Ballota nigra L., Nepeta cataria L., Stachy germanicus L., Marrubium incantum DESR or
Marrubium remotum KIT is possible (Blaschek et al., 2006).
Berger (1954) reports that, on the market, Marrubii nigri herba is also a traditionally used herbal substance, which consists of the herb of Marrubium peregrinum L.
The current Natural Health Products Ingredients Database of Health Canada contains a monograph “Black Horehound” (Health Canada, 2008).
Nagy & Svajdlenka (1998) determined the chemical composition of the essential oils obtained from the flowering aerial parts of M. vulgare L. and M. peregrinum L. There were some similarities in chemical composition between both oil samples, but the amounts of corresponding components were quite different. Most of determined constituents were sesquiterpenes. Some specific substances were present in both oils up to 20% of content. It was concluded that the composition difference may cause an important change in the biological activities of both oils.
The HMPC monograph concerns only Marrubium vulgare L.
Principal constituents of the herbal substance
According to Blaschek et al. (2006) the principal constituents of the herbal substance are:
−traces of essential oil
−tannins (up to 7%) and hydroxylcynamic
−flavonoids: flavone and flavonol glycosides and their respective aglycones (e.g. apigenin, luteolin, quercetin, chrysoeriol, vicenin II, vitexin) lactoylflavones,
−minerals, in particular potassium salts
For the bitter taste the furanic labdane dipertene marrubiin is responsible. Up to 4 mg of furanic labdane deterpenes per g fresh weight were found, most in young leaves and buds. Depending on the vegetation period or the extracting conditions, the extracts contain marrubiin,
Information about products on the market in the Member States
According to the information provided by the National Competent Authorities in the overview of the marketed products, the following herbal substances have been on the European market:
Herbal preparations which have been reported to be marketed under
−expressed juice from fresh Marrubii herba
Herbal preparations which have been reported to be marketed under traditional use:
−liquid extract from Marrubii herba (DER
−powdered herbal substance
posology: 3 times daily
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.
According to the overview of the marketed products, in Austria and Hungary, Marrubii herba is used in combination with other herbal substances/herbal preparations. No detailed information about the combination substances and indications is available.
In the Czech Republic, combination preparations and tea preparations of Marrubium vulgare are on the market. They are used as adjuvant therapy in mild gastrointestinal disorders, loss of appetite and mild functional biliary tract disorders. The main combination substances are Menthae piperitae herba, Rhei radix, Agrimoniae herba, Boldi folium, Taraxaci radix cum herba, Frangulae cortex, Matricariae flos, Menthae piperitae herba, Absinthii herba, Gentianae radix, Angelicae radix, Calami radix, Tormentillae radix, Myrrha, Zedoariae radix, Myristicae semen, Macis, Juglandis fructus cortex, Theriak sine opium (Angelicae radix, Valerianae radix, Cinnamomi cortex, Zedoariae radix, Cardamomi fructus, Myrrha).
In Denmark, there has only been one combination product with Marrubii herba on the market (licensed in January 1997 and withdrawn in June 1999). It was used against coughing and catarrh in upper respiratory passages for short periods. The combination substances were Liquiritiae radix, Thymi herba, Hederae helicis folium and Pimpinellae radix.
In Poland, the herbal substance is only available in 2 combination products. The average number of combination substances is 3 to 5. In one product, the combination substances are Menthae piperitae folium, Matricariae flos, Frangulae cortex and Rhei radix. It is used in the indication for mild digestive complaints (feeling of fullness, meteorism) and in lack of appetite. Another product contains an extractum compositum fluidum (1:2), extraction solvent: water, of Millefolii herba, Marrubii herba, Melissae folium, Foeniculi fructus (3/2/3/2). It is used in children in lack of appetite.
In Slovak Republic, the herbal substance is only available in combination products. The average number of combination substances is 3 to 5. The main combination substances are Agrimoniae herba, Inulae radix, Rhei radix and Rubi idaei folium. It is used in the indication biliary disorders, as mild laxans and for reduction of meteorism and cramps.
Extracts of M. vulgare herba are also used for flavouring beverages and candies (Vincenzi, 1995). In the USA it is generally recognized as safe (CFR, 2012) and the Council of Europe permitted Marrubii herba as flavouring category N2 (Bradley, 1992).
This assessment report supports the Community herbal monograph, which refers exclusively to Marrubii herba as a single active substance. With respect to the overall evaluation of the existing data on efficacy, the monograph addresses only the traditional use.
Regulatory status overview
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.
1.2. Search and assessment methodology
A literature search was performed in April 2012 using the common databases of the DIMDI database information system (e.g. MEDLINE, EMBASE, SciSearch, Cochrane Library). The search term was “marrubium”. The literature list of 280 articles was examined. Additional hand searches were performed in books on herbal medicines and plant monographs in the BfArM own library. The bibliographies of included trials and other relevant reviews were searched to identify further potential trials.
In the list of references, the references supporting the assessment report are listed first and secondly references used but not introduced into the assessment report.
2. Historical data on medicinal use
2.1. Information on period of medicinal use in the Community
Marrubii herba is included in pharmacopoeias and standard text books of phytotherapy since many decades. Benedum et al. (2006) describes old references on medicinal use of Marrubii herba such as Dioskurides (“… it is given to patients suffering from … cough … also purges away the mucus from the chest”, Hildegard von Bingen (“… against cough”), Matthiolus (“… helps against cough …”) and Tabernaemontanus (“… purifies chest and lungs from coarse mucus…”). Gilg et al. (1927) describe Marrubii herba for the use in pulmonary diseases. Madaus (1938) notes that Marrubii herba is mentioned since Paracelsus as “preparation for the lung” and from Lonicerus as “emenagogum, expectorans and diureticum”. In the old phytotherapeutic book of Dragendorff (1898), ‘herba Marrubii’ is listed for medical use in catarrhs. ‘Herba Marrubii albi’ is also noted as phytotherapeutic drug in Merck´s Index of 1910. The old textbook ‘Potter’s Cyclopaedia of Botanical Drugs and Preparations’ (1941) describes Horehound as: “Bitter tonic, expectorant and diuretic. Is perhaps the most popular of herbal pectoral remedies. It is exceedingly valuable in coughs, colds, and pulmonary affections. It has a pleasant taste and makes a nice tonic. In many parts it is brewed and sold as Horehound Ale, making an appetising and healthful beverage”. The old Belgian literature “Materia Medica Vegetabilis” (Steinmetz, 1954) describes the use as follow: “White Horehound herb is indicated for the use in form of a decoction boiled into a thin syrup, with honey against coughs, hoarseness of long standing and bronchitis. It is expectorant, diuretic, carminative and stimulant. It is also used against diarrhoea, piles and jaundice”.
Literature reports suggest that Marrubium vulgare, herba is traditionally used also in a number of countries outside of Europe. Haq et al. (2010) describe the use for cough, catarrh, emetic, hysteria, rheumatism in Pakistan. De Souza et al. (1998), de Oliveira et al. (2011) and
The following list shows examples of pharmacopoeias and standard text books with monographs of White Horehound.
−British Herbal Compendium (Bradley 1992)
−Martindale, The Extra Pharmacopoeia 1967
−British Herbal Pharmacopoeia (BHP) 1976, 1983, 1990, 1996
−British Pharmaceutical Codex 1934
−Österreichisches Arzneibuch (ÖAB) – Pharmacopoeia Austriaca 1960, 1981, 1990
−Pharmacopée Française 1989
−DAC 1995, 1997, 2003
−Kommission E (German Commission E) 1990
−Blaschek et al. 2006
Based on pharmacopoeias and standard text books of phytotherapy for Marrubii herba, the requirement for a period of at least 30 years of medicinal use, from Directive 2004/24/EC, for qualification as a traditional herbal medicinal product, is fulfilled.
According to the information provided by the National Competent Authorities in the overview of the marketed products, qualification as a traditional herbal medicinal product is fulfilled for:
−Expressed juice (DER
−Liquid extract (DER
For the HMPC monograph, additionally preparations with a
−Herbal substance for tea preparation:
−Liquid extract (DER 1:1), extraction solvent ethanol 20% (V/V):
The two preparations liquid extract [(DER
−liquid extract (DER
The powdered herbal substance for oral use in solid dosage forms could also be integrated into the monograph. Tradition is based on the reference given in BHP (herbal substance:
−Powdered herbal substance:
2.2. Information on traditional/current indications and specified substances/preparations
For the herbal substance and preparations thereof the following indications are described in pharmacopoeias and literature:
Respiratory and thoracic disorders:
Further traditional indications:
According to the information provided by the National Competent Authorities in the overview of the marketed products, the following indications are found:
−expressed juice from fresh Marrubii herba
−liquid extract from Marrubii herba
Based on literature and indications for marketed products, the following indications are accepted in the monograph:
a)Traditional herbal medicinal product used as an expectorant in cough associated with cold.
b)Traditional herbal medicinal product for symptomatic treatment of mild dyspeptic complaints such as bloating and flatulence.
c)Traditional herbal medicinal product used in temporary loss of appetite.
2.3. Specified strength/posology/route of administration/duration of use for relevant preparations and indications
Some of the references given in this chapter provide evidence for the
−Herbal substance for tea preparation (comminuted) or for oral use (powdered)
For the monograph the following dosage is recommended:
−Expressed juice (DER
For the monograph the following dosage is recommended:
expressed juice (DER
−Liquid extract (DER
−Liquid extract (DER 1:1), extraction solvent ethanol 20% (V/V)
For the monograph the following dosage was considered:
liquid extract (DER 1:1), extraction solvent: ethanol 20% (V/V):
The two preparations [liquid extract (DER
For this combined preparation, the following dosage is recommended:
Liquid extract (DER
Route of administration
Oral use is the only route of administration for White Horehound herb preparations in the traditional indications discussed in this assessment report.
Duration of use
No information on the duration of use is available. In order to assure safe use as a traditional herbal medicinal product within the scope of the simplified traditional use registration scheme, the duration of use is limited in the context of each respective indication:
Indication 1): Traditional herbal medicinal product used as an expectorant in cough associated with cold: “If the symptoms persist longer than 1 week, a doctor or a qualified health care practitioner should be consulted.”
Indications 2) and 3): Traditional herbal medicinal product for symptomatic treatment of mild dyspeptic complaints such as bloating and flatulence; Traditional herbal medicinal product used in temporary loss of appetite: “If the symptoms persist longer than 2 weeks, a doctor or a qualified health care practitioner should be consulted.”
Method of administration
For the use in the indications 2) and 3), the herbal preparation should be taken ½ hour before the meals (Steinegger & Hänsel, 1968; Hänsel & Haas, 1984; Wichtl, 1984; Wichtl, 2002; Neubeck, 2012).
3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
Schlemper et al. (1996) evaluated the effects of a hydroalcoholic extract of the roots and aerial parts of M. vulgare (DER 1:3, 50% ethanol) in several smooth muscle preparations in vitro (guinea pig ileum, rat duodenum, rat uterus, rat stomach fundus). The results showed that the extract exerts a significant antispasmodic activity which inhibits the action of some neurotransmitters, such as acetylcholine, bradykinin, prostaglandine E2, histamine and oxytocin. The findings suggest a non- competitive inhibitory profile with
De Souza et al. (1998) investigated the possible analgesic effects of a hydroalcoholic extract obtained from M. vulgare in different models of pain in mice. Air dried leaves, stems and roots of M. vulgare were minced and extracted with 50%
Kanyonga et al. (2011) described the effects of a methanolic extract of M. vulgare (200 g powder of the plant was extracted in a Soxhlet apparatus with methanol). The extract was evaporated to dryness to give a yield of 39.2% (DER ~2.5:1). The extract (200 mg/kg, oral) significantly inhibited (35.3%) abdominal constriction in mice in
100 mg/kg dose. In the hind paw oedema induced by prostaglandin E2, the extract at the 200 mg/kg dose showed considerable inhibition
De Oliveira et al. (2011) assessed the gastroprotective properties of the methanol extract (1.5 kg plant material was macerated 7 days with 4 l methanol) and marrubiin obtained from the leaves of M. vulgare. In the model of
In both models, marrubiin (25 mg/kg) produced a significant reduction in all the parameters when compared with the control group. There was also a significant increase in pH (M. vulgare extract at doses of 50 and 100 mg/kg, marrubiin at a dose of 25 mg/kg) and mucus production in the groups treated with M. vulgare extract and marrubiin. These results were seen as indicator that the extract has cytoprotective activity that is correlated, at least in part, with the presence of marrubiin. The data suggest that the gastroprotective effect induced by the M. vulgare extract is slightly related to SHs. On the other hand, the gastroprotection mediated by marrubiin seems to be much more closely related to SHs.
The authors point out that the combination of the
Only a few studies can be brought in connection with primary pharmacodynamic effects of M. vulgare. They are not conducted with aqueous extracts nor with ethanolic extracts prepared with ethanol in the strength proposed by the monograph; however even the results with methanolic extracts or with ethanolic extracts (ethanol 50%) can be seen at least as adding some plausibility.
An antispasmodic effect of a hydroalcoholic extract of the roots and aerial parts of Marrubium vulgare was shown by Schlemper et al. (1996) in several smooth muscle preparations in vitro, even though a direct correlation between in vitro and in vivo is not possible. Analgesic effects were shown for a hydroalcoholic extract (DER 1:3) in
The effects of the methanolic extracts seem, at least in terms of the concentration, plausible to be relevant for the aqueous and ethanolic preparations of the monograph.
Gastroprotectice activities were recognised for the methanolic extract while the role of marrubiin has to be discussed, because according to the Ph. Eur. the amount of marrubiin is up to ~1% while the results by De Oliviera et al. were achieved with half the concentration of the extract (would be equivalent of 50%). The dosage of 200 mg/kg oral in mice for the antispasmodic and anti- inflammatory effects equals a HED of 16 mg/kg. For a 60 kg adult, this would mean a single dose of ~1 g extract. According to the yield of extraction, this equals an amount of 2.5 g herbal substance. Even though the interpretation of the results for clinical relevance is limited, at least in the animal testing, the dosage equals the traditional human doses.
Krejci & Zadina (1959) investigated the stimulating effects on bile secretion of marrubiin, marrubiinic acid and its sodium salt in rats. The bile was collected in the duodenum together with the pancreatic juice. Marrubiin failed to stimulate choleresis, while secretion was materially enhanced by marrubiinic acid at doses of
Sahpaz et al. (2002) investigated the chemical composition of a polar extract of M. vulgare to justify the therapeutic uses. The phytochemical analysis of a polar extract led to the isolation of
5 phenylpropanoid esters: 1)
COX activity in vitro
0.69 mM in the range of that of nimesulide. These three compounds did not exhibit any significant inhibition
Stulzer et al. (2006) analyzed marrubiin in a model of microvascular leakage in mice ears. The results obtained for ID50 values (mg/kg, i.p.) and maximal inhibition (%), for the different phlogistic agents used, were: histamine 13.84 mg/kg and 73.7%; bradykinin 18.82 mg/kg and 70.0%; carrageenan 13.61 mg/kg and 63.0%. In addition, marrubiin (100 mg/kg i.p.) significantly inhibited the ovalbumin- induced allergic oedema in actively sensitised animals.
De Jesus et al. (2000) analysed the antinociceptive profile of marrubiin in different models of nociception in mice. The results showed that marrubiin exhibits
(180 µmol/kg), a technique that has a selectivity for
In the formalin test, marrubiin significantly inhibited
inflammatory pain) by i.p. and oral routes. The calculated ID50 values for first and second phases were 6.6
In contrast to marrubiin, acid marrubiin failed to stimulate choleresis in rats after i.v. application. In in vivo experiments in rats choleretic activity of marrubiinic acid was shown. The pharmacokinetics of marrubiin into marrubiinic acid and the concentrations needed for the pharmacological effect is still not examined. Marrubiinic acid may contribute to the pharmacodynamic plausibility, but the clinical relevance is unclear. Furthermore the i.v. administration is not the clinically intended route of administration. Some results suggest that marrubiin interferes with some common mechanisms of phlogistic agents used, but until now it was not possible to determine where it is acting. For some phenylpropanoid esters extracted of M. vulgare and marrubiin,
could be shown in vitro and in vivo, respectively. Results are mostly of low relevance, as they were conducted in vitro or with i.p. administration. Furthermore there is no knowledge about the plasma concentrations of those substances in the clinical situation.
Diaz et al. (1988) tested an aqueous extract (DER 1:10) and an ethanolic extract (no further information) of M. vulgare for antibacterial activity against Bacillus subtilis, Micrococcus luteus and Escherichia coli in disc diffusion method. Both extracts showed no activity.
Keleş et al. (2001) tested the antibacterial action of an ethanolic extract of M. vulgare against
Salmonella enteritis, Salmonella gallinarum, Streptococcus dysgalatiae, Streptococcus agalactiae, Klebsiella pneumoniae, Staphylococcus aureus, E. coli (agar diffusion test). 50 g of dried plant material were extracted with 250 ml of 80% ethanol and evaporated to dryness. The extract of M. vulgare had a minimum inhibitory concentration (MIC) of 4 mg/ml in K. pneumoniae and 1 mg/ml in S. aureus.
Kunduhoglu et al. (2011) showed that the crude ethanolic extract (10 g powdered plant material extracted by Soxhlet extractor, no further information, 100 mg dry extract/ml stock solution) had antimicrobial effect (zone diameters
Kanyonga et al. (2001) studied the in vitro antibacterial activity of a methanolic extract of
M. vulgare (no DER information) at 50, 100, 200, 400 and 600 mg/ml by disc diffusion method. The study revealed that the extract showed a dose dependent effect against B. subtilis, Staphylococcus epidermidis, S. aureus and Candida albicans and moderately effective against Proteus vulgaris and E. coli while ineffective in the case of Pseudomonas aeruginosa.
El Bardai et al. (2001) examined the pharmacological evidence of hypotensive activity of
M. vulgare in spontaneously hypertensive rat (SHR) (210±mm Hg) and normotensive
100 ml water, after lyophilisation the yield was approximately 16% (w/w) (DER ~6.2:1). The rats were given 80 mg extract/kg/day orally, once a day by gavage, for 5 days. The treatment of SHR produced
only a small effect on urine volume at the beginning of the treatment, which vanished after 3 days and had no effect either on electrolytes or on creatinine and urea excretion. It did not affect diuresis and electrolyte excretion significantly in normotensive rats.
Roman Ramos et al. (1992) tested the hypoglycaemic effect of an aqueous extract of
M. vulgare in healthy rabbits with the gastric administration of water (4 ml/kg), tolbutamide (20 mg/kg) or the extract (132 g of the dried plant was boiled in 1 l water; 4 ml/kg). Temporary
hyperglycaemia was induced by s.c. injection of 50% dextrose solution. After 60 min blood glucose was determined every 60 min for a period of 5 h. Both tolbutamide and the extract decreased significantly the hyperglycaemia as compared with control test (water). The extract was not statistically different from 20 mg/kg of tolbutamide.
Novaes et al. (2001) studied the hypoglycaemic effect of M. vulgare on
Boudjelal et al. (2012) conducted a series of in vivo experiments in albino Wistar rats concerning the
VanderJagt et al. (2001) analysed the total antioxidant capacity of aqueous extracts of
M. vulgare (2 g dried plant extracted with 40 ml water) using a
Berrougui et al. (2006) elucidated the properties of a methanolic extract of M. vulgare (40% methanol, no DER information) towards cardiovascular disease by protecting
Yamaguchi et al. (2006) explored the effects of M. vulgare leaves extract on
The interpretation of the results from
The interpretation of clinical relevance of small diuretic effects seen in spontaneously hypertensive rats and antihyperglycaemic effects in rabbits and rats is limited, partially also because of the application way. Furthermore, in the clinical study by
An antioxidative effect of extracts of M. vulgare was shown in vitro. The in vitro tests are no sufficient scientific evidence for a conclusion of a beneficial clinical effect. Furthermore, there is presently no sufficient evidence to suggest an anticancer effect of Marrubii herba.
Effect on vasorelaxant effects
El Bardai et al. (2003a) examined the compounds responsible for the vasorelaxant activity ascribed to the crude aqueous extract of M. vulgare, herba. Marrubii herba (60 g) was extracted with 400 ml distilled water at 90ºC for 15 min. The extract was divided in an aqueous fraction and an cyclohexane fraction.
El Bardai et al. (2003b) investigated the mechanism of the relaxant activity of marrubenol. Marrubenol inhibits contraction of rat arteries by blocking
El Bardai et al. (2004a) described the precise site of interaction on the
Assessing the results of the in vitro studies there is presently no sufficient evidence to acknowledge a vasorelaxant or antioxidant effect of preparations of M. vulgare.
No information available concerning safety pharmacological studies.
Effect on systolic blood pressure/ antihypertensive effects
El Bardai et al. (2001) examined the pharmacological evidence of hypotensive activity of
M. vulgare in SHR rats (210±mm Hg) and normotensive WKY rats (156±mm Hg). The aqueous extract was prepares by boiling 5 g of Marrubii herba in 100 ml water, after lyophilisation the yield was approximately 16% (w/w) (DER ~6.2:1). The rats were given 80 mg extract/kg/day oral, once a day by gavage, for five days. The extract significantly decreased the systolic blood pressure (SBP) in spontaneous hypertensive rat. The hypotensive effect was detectable from day 2 and was maximal at day 4 and 5. At the end of the treatment, the systolic blood pressure remained significantly lower than the
The ex vivo effect of the extract was examined on contractile responses of the aorta. After treatment of SHR, the contractile response of aortic rings to 100 mM KCl solution was depressed by 19±3.4% (n=14, p<0.05). No effect was detected in normotensive rat aorta. The authors concluded that the characteristics of Marrubium actions are reminiscent of the effect of dihydropyridine
El Bardai et al. (2004b) compared the effect of
The administereddose (80 mg extract/kg) corresponds to a HED of 13 mg/kg (= 780 mg for a 60 kg adult = 4.8 g herbal substance). This is within the range of the human therapeutic doses of maximum 6 g herbal substance/day. The administeredsingle dose was higher than the human single dose (up to 2 g herbal substance). In the clinical study by
No information available.
3.2. Overview of available pharmacokinetic data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
No published data about pharmacokinetics are available.
3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof
Single dose toxicity
Jaouhari et al. (1999) carried out an acute toxicity study of the aqueous extract of M. vulgare on Swiss albino mice. The tested preparation was an infusion prepared of 1 g dried herb in 50 ml distilled water (DER 1:50). The extract was administered orally at a dose of 1 g/kg body weight. Animals were observed 7 days and changes in weight and behaviour were noted. On the eighth day the animals were sacrificed and an
De Oliveira et al. (2011) treated five female rats in an acute toxicity study orally with a single dose of 2,000 mg/kg extract of M. vulgare (1.5 kg plant material was macerated 7 days with 4 l methanol). On a period of 14 day the animals were observed. No changes could be detected in the skin, fur, eyes, mucous membrane (nasal), central nervous system and autonomic nervous system. The data suggest that the toxic dose of the M. vulgare methanolic extract is higher than 2,000 mg/kg. It would be classified in category 5 for toxicity under the criteria of the GHS (Globally Harmonized Classification System for Chemical Substances and Mixtures).
Reproductive and developmental toxicity
Kchouk & Chadli (1962) analysed the reproductive and developmental toxicity of a decoction from
M. vulgare (no DER information) in 2 rats, 2 guinea pigs and 2 mice (approximately 2 ml/kg buccal or s.c.). The results showed a certain abortive activity in rats, whereas its abortive effect in guinea pigs and mice was not convincing. The authors concluded the data do not permit to extrapolate an abortive effect to humans.
3.4. Overall conclusions on
Marrubii herba traditionally has been used as secretolytic drug and as bitter principle (amarum) in dyspeptic complaints and loss of appetite. In literature the expectorant action, possibly caused by stimulation of secretion from the mucous lining of the respiratory tract, is often attributed to marrubiin and the volatile oil. Marrubium vulgare herba has a bitter value of 3,000 (Blaschek et al., 2011). It is considered that Marrubium, as bitter principle, causes an increase of the gastric and biliary secretion and stimulates the appetite via activation of the bitter receptors.
Only a few studies exist which can be brought in connection with primary pharmacodynamic effects of M. vulgare. Antispasmodic,
receptors (Janssen et al., 2011), even though no studies for Marrubium preparations or its components exist. Pharmacodynamic studies which could prove expectorant effects could not be identified.
In in vivo experiments in rats, choleretic activity of marrubiinic acid was shown. The pharmacokinetics of marrubiin into marrubiinic acid and the concentrations needed for the pharmacological effect have not been investigated. Marrubiinic acid may contribute to the pharmacodynamic plausibility, but the clinical relevance is unclear. For some phenylpropanoid esters extracted from M. vulgare and marrubiin,
The effects which are classified as secondary pharmacodynamic effects of herbal preparations and/or isolated compounds
While no conventional studies concerning safety pharmacology were found, two studies in rats suggest a hypotensive effects (in spontaneous hypertensive rats) and antihypertrophic effects in the aorta. From the
No published data about pharmacokinetics are available.
No data from investigations concerning single- and
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
M. vulgare, the plasma glucose level was reduced by 0.64% and cholesterol and triglycerides by 4.16% and 5.78% respectively. The effect produced by the extract from M. vulgare was minimal and contrasts that in the
The treatment evaluated did not produce important modifications of the parameters that measure the renal function. The serum levels of creatinine and urea did not show pathologic alterations at the end of the study. In some patients, the treatment produced only mild and temporary side effects, for which
it was not necessary to interrupt the treatment. In the group of M. vulgare, five side effects occurred: nausea, oral dryness, sialorrhea, dizziness and anorexia, while in the group of C. obtusifolia three side effects were reported: excessive salivary flow, exhaustion and pyrosis.
4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
No human data available.
4.2. Clinical Efficacy
4.2.1. Dose response studies
Dose response studies have not been performed.
4.2.2. Clinical studies (case studies and clinical trials)
Ballero et al. (1998): Ethnopharmacobotanical studies carried out in northern Sardinia have confirmed the use of Marrubium vulgare in the prevention and treatment of asthmatic syndrome. For acute asthma a decoction of M. vulgare was given. For a preventive treatment for asthma a decoction of fresh leaves of M. vulgare together with Cynodon dactylon leaves was administered at spring or all through the year in cases of perennial asthma. The decoction for the prevention of asthmatic fits was administered in one dose (a glass of
4.2.3. Clinical studies in special populations (e.g. elderly and children)
No human data from clinical studies in children or elderly are available. For some marketed preparations, a dosage is recommended for adolescents above 12 years of age. Due to the lack of sufficient data, the use in children under 12 years of age is not recommended. In the absence of safety concerns, a posology is given in the monograph for use in adolescents, adults and elderly.
4.3. Overall conclusions on clinical pharmacology and efficacy
The traditional use is well documented in literature and different European pharmacopoeias. The efficacy of the medicinal product is plausible on the basis of
–“Traditional herbal medicinal product used as an expectorant in cough associated with cold”,
–“Traditional herbal medicinal product for symptomatic treatment of mild dyspeptic complaints such as bloating and flatulence” and
–“Traditional herbal medicinal product used in temporary loss of appetite”.
Controlled clinical studies required to support a
proof efficacy for acute asthma or as a preventive remedy for asthma. No conclusion for efficacy for specific indications is possible. The results of the study indicate that the use of Marrubium tea can be beneficial in the context of the use as an
Bitter preparations increase saliva and gastric secretion, therefore the efficacy in case of appetite loss can only be assumed in patients with a reduced gastric secretion. In patients with normal appetite, no increase can be expected (Hänsel, 1991; Tyler, 1994; Schilcher et al., 2007).
5. Clinical Safety/Pharmacovigilance
5.1. Overview of toxicological/safety data from clinical trials in humans
See section 4.1.1.
5.2. Patient exposure
Apart from the medicinal use, Marrubium vulgare is also used as food e.g. in candies. There is no information available on the extent of this use.
5.3. Adverse events and serious adverse events and deaths
In phytotherapeutic books such as Bradley (1992), Blumenthal et al. (1998), Blaschek et al. (2006), no adverse events, serious adverse events and deaths are reported.
Carey (1962): In a list of occupational toxicity of cultivated flowers, that relates to the central states of the U.S., Horehound juice is listed as constituent that may induce contact dermatitis.
Case reports in the EU Member States
In the BfArM (Germany) database (28 June 2012), no adverse events are reported. No adverse events have been reported also by the other Member States during the preparation of the monograph.
Published case reports
Jayasekera et al. (2005): A
In the clinical study by
No case reports are available in the databases of the Member States. Mild gastrointestinal reactions are reported within a clinical trial with 21 diabetic patients but are not mentioned in the monograph, because the patients received a
Like all herbal preparations with a traditional use as bitter remedy, Marrubium vulgare products increase the gastric acid secretion. Schilcher et al. (2007) recommend that bitter compounds (amara) with a bitter value over 10,000 should be contraindicated in patients with active peptic ulcer (e.g. Cynarae folium 10,000; Cinchonae cortex ≥12,000; Gentianae radix ≥10,000). As Marrubii herba has a lower bitter value (3,000), given that it shows gastroprotective effects in vivo and as no case reports are available, no absolute contraindication is necessary for this patient group; patients with active peptic ulcer should however consult a doctor before using Marrubii herba preparations.
5.4. Laboratory findings
No laboratory findings in relation to other Marrubium vulgare preparations are available.
5.5. Safety in special populations and situations
Use in children
No clinical studies in children or elderly are available. In the marketed preparations, the dosages are recommended for adolescents above 12 years of age and adults. From the market information provided by the Member States during the preparation of the monograph, it was seen that some Marrubium products seem to be also used in children e.g. for lack of appetite. Due to the lack of sufficient data including dosages, the use is not recommended for children under 12 years of age.
Based on data held at the Uppsala Monitoring Centre of the WHO (World Health Organization) that has the largest database on adverse drug reactions (ADRs), including
In phytotherapeutic books such as Bradley (1992), Blumenthal et al. (1998), Blaschek et al. (2006), interactions with other drugs are not mentioned.
Use in pregnancy and lactation
Ciganda et al. (2003): A descriptive retrospective survey was conducted on the calls received by the Montevideo Poison Centre (Uruguay), between 1986 and1999, concerning the ingestion of herbal infusion with an abortive intend. A total of 86 cases involving 30 different plant species had been identified. Marrubium was used in one case in a
Safety during pregnancy and lactation has not been established. There are no human data on effects of Marrubium vulgare preparations on the foetus. Animal studies (Kchouk & Chadli, 1962) showed a certain abortive activity in rats, whereas its abortive effect in guinea pigs and mice was not convincing.
In view of the absence of sufficient clinical data, the use of M. vulgare products during pregnancy and lactation is not recommended.
According to List et al. (1976), in high dosages Marrubium can cause arrhythmia. No information about the “high dosages” or case reports are given. Theoretically “large amounts” of White Horehound may increase the risk of abnormal heart rhythms and should be avoided by people taking drugs that affect heart rhythm.
Schilcher et al. (2007) reported that “large” dosages of amara can lead to contradictory effects, such as inhibition of appetite and secretolysis, and can cause headache in sensitive patients.
From literature, monographs and databases of the Member States, no case reports on overdose of M. vulgare preparations are available. Therefore, it is stated in the monograph that no case of overdose has been reported.
There are no reports on drug abuse in relation to the medicinal use of M. vulgare preparations.
Withdrawal and rebound
There are no reports on withdrawal and rebound in relation to the medicinal use of M. vulgare preparations.
Effects on ability to drive or operate machinery or impairment of mental ability.
No studies on the ability to drive and use machines have been performed. There are no reports on impairment of mental ability. No conclusions can be drawn on potential concern arising from effects on ability to drive or operate machinery by the known ingredients of Marrubium vulgare.
5.6. Overall conclusions on clinical safety
The safety of use in defined conditions of Marrubium vulgare medicinal products can be derived from the
Limited data of laboratory findings during treatment with a Marrubium vulgare tea suggest that it did not produce important modifications in the plasma glucose level, cholesterol and triglycerides and the parameters that measure the renal function, serum levels of creatinine and urea.
On the basis of information on traditional use, Marrubii herba containing medicinal products prove not to be harmful in the specified conditions of use. The indications are appropriate for use in adolescents
over 12 years of age, in adults and in elderly without the supervision of a medical practitioner for diagnostic purposes or for prescription or monitoring of treatment. The duration of use without medical advice is limited to one week for the first indication and to two weeks for the second and third indications found in the monograph.
M. vulgare preparations are contraindicated in patients with hypersensitivity to the active substance and to other plants of the Lamiaceae (Labiatae) family. Like all herbal preparations with bitter remedy, M. vulgare preparations are contraindicated in patients with obstruction of the bile duct, cholangitis, liver disease and ileus.
Patients with active peptic ulcer, gallstones and any other biliary disorders should consult a doctor before using Marrubii herba preparations.
Due to lack of data, the use is not recommended during pregnancy and lactation.
6. Overall conclusions
Based on the data documented in the assessment report, a Community herbal monograph is established on the traditional uses of several preparations from Marrubium vulgare L., herba. The traditional uses of Marrubium vulgare preparations fulfil the requirement for at least 30 years of medicinal use at a specified strength and specified posology, according to Directive 2001/83/EC as amended. None of the data fulfils the requirements to demonstrate a
Traditional herbal medicinal product used as an expectorant in cough associated with cold.
Traditional herbal medicinal product used for symptomatic treatment of mild dyspeptic complaints such as bloating and flatulence.
Traditional herbal medicinal product used in temporary loss of appetite.
For the use in indications 2) and 3), the herbal preparation should be taken ½ hour before the meals.
The licensing of herbal medicinal product is subject to compliance with the requirements of a European Pharmacopoeia monograph. As an unambiguous macroscopic, microscopic, chemical identification of the herbal material is possible, adulteration/contamination of the herbal substance therefore is not expected.
In the databases of the Member States, no adverse events are reported. Mild gastrointestinal reactions were observed in a clinical study in diabetic patients, however the patients received a
There are no reports on drug interactions, drug abuse, withdrawal and rebound, effects on ability to drive or operate machinery or impairment of mental ability. Limited data of laboratory findings during treatment with a Marrubium vulgare tea suggest that it did not produce important modifications in the plasma glucose level, cholesterol and triglycerides and the parameters that measure the renal function, serum levels of creatinine and urea.
No data from investigations of single- and
The herbal preparations should not be used in patients with hypersensitivity to the active substance and to other plants of the Lamiaceae (Labiatae) family, obstruction of the bile duct, cholangitis, liver disease or ileus. Caution for use is necessary for patients with active peptic ulcer, gallstones and any other biliary disease.
The duration of use is limited because the preparation is intended and designed for use without the supervision of a medical practitioner ( one week for the indication 1) or two weeks for the indications 2) and 3). Due to lack of data, the use is not recommended during pregnancy and lactation. Marketed preparations are used at specified dosages in adults and adolescents above 12 years of age. Therefore the monograph establishes the use in these age groups as well as in elderly in the absence of safety concerns for the latter. Due to the lack of adequate data, the use is not recommended in children under 12 years of age.
There are therapeutic alternatives for the indication 1) from chemical preparations (such as ambroxol) to other herbal preparations (e.g. Thymi herba, Hederae helicis folium).
For the indications 2) and 3), there are therapeutic alternatives like other herbal preparations traditionally used in the context of a bitter remedy (e.g. Absinthii herba, Cichorii radix, Millefolii herba, Taraxaci radix cum herba).
It can be concluded that the
The therapeutic areas for browse search on the EMA website are “Cough and cold” and “Gastrointestinal disorders”.
Because the minimum required data on mutagenicity (AMES test) are not available for herbal preparations of Marrubii herba, an inclusion to the Community list of herbal substances, herbal preparations and combinations thereof for use in traditional herbal medicinal products is not recommended.