Matricaria Oil – Matricariae aetheroleum (Matricaria recutita L.)
|Latin name of the genus:||Matricariae aetheroleum|
|Latin name of herbal substance:||Matricaria recutita l.|
|Botanical name of plant:||Herbalref.com|
|English common name of herbal substance:||Matricaria oil|
Latin name of the genus: Matricariae aetheroleum
Botanical name of plant: Matricaria recutita L.
English common name of herbal substance: Matricaria Oil
1.1. Description of the herbal substance(s), herbal preparation(s) or combinations thereof
•Herbal substance(s), Herbal preparation(s)
Matricaria flower do not only have a long tradition in Europe. Herbal preparations derived from it are used worldwide and it is belonging to the most popular medicinal plants of the world. Accordingly, matricaria flower has been included into collections of monographs. The most important amongst them are:
−European Pharmacopeia (Ph. Eur. 8.0)
−German Kommission E monographs (1984)
−British Pharmacopeia (2008)
−British Herbal Pharmacopeia (1983)
−ESCOP Monographs (2003)
−WHO Monographs (1999)
−United States Pharmacopeia 29 / NF24 (2006)
The botany of matricaria and the phytochemical characterisation of the essential oil was reviewed (Carle and Gomaa 1992a; Blaschek et al. 2011). The herbal substance consists of the dried capitula with yellow tubular florets, surrounded by a ring of white ligulate florets, which are often found on their own. The sharply conical receptacle of the inflorescence is hollow and has no paleaceous scales.
Definitions in the European Pharmacopoeia:
Matricaria flower, Matricariae flos, monograph (Ph. Eur. 01/2008:0404)
Dried capitula of Matricaria recutita L. (syn. Chamomilla recutita (L.) Rauschert). Content:
–blue essential oil: minimum 4 ml/kg (dried drug)
Other names: English: German Chamomile, French: Chamomille allemande, Fleur de chamomile, German: Kamillenblüten
Synonym: Chamomillae anthodium
Matricaria oil, Matricariae aetheroleum, monograph (Ph. Eur. 01/2008:1836)
Blue essential oil obtained by steam distillation from the fresh or dried
Matricaria liquid extract, Matricariae extractum fluidum, monograph (Ph. Eur. 01/2008: 1544)
Liquid extract produced from Matricaria flower (Ph. Eur. 01/2008:0404)
Content: minimum 0.30% of blue residual oil
The extract is produced using a mixture of 2.5 volumes of a 10% (m/m) solution of ammonia (NH3), 47.5 volumes of water and 50 volumes of ethanol (96%(V/V)).
Main characteristic constituents of matricaria flowers
•essential oil (0.3 – 1.9%): proazulenes like matricin and matricarin, which are at least partially converted during steam distillation into azulenes like chamazulene (further details see below)
•flavonoids (up to 6%) such as
•sesquiterpene lactones such as matricin
•spiroethers (cis- and trans
Major constituents of the essential oil
(Blaschek et al. 2011; Wichtl and Bauer 2009; Barnes et al. 2007; ESCOP 2003; Sticher et al. 2015; Mann and Staba 1986; Mulinacci et al. 2000; Barene et al. 2003; Matos et al. 1993;
Herbal teas prepared from matricaria flowers are mainly containing flavonoids and their glycosides, mucilaginous constituents and only minor amounts of constituents of essential oil (about 10 to 15% depending on conditions of herbal tea preparations). The coumarines herniarin and umbelliferone are also soluble in hot water, especially matricin is extracted in concentrations which are pharmaceutically relevant (Schilcher 1987; Mulinacci et al. 2000).
Cultivars and different proveniences of matricaria flowers vary substantially with respect to the composition of constituents. The monograph on matricaria oil (Ph. Eur. 1836) differentiates between matricaria oils rich in bisabololoxides and those rich in
•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 two groups of combination products on the European Market. The first one is combination products, containing different parts of Matricaria recutita L. adding information to the traditional use of Matricaria recutita L. in special pharmaceutical forms and to the safety of these products. Secondarily there are lots of combinations on the European Market, which are combining different plants, adding additional information for the safety of the traditional use of Matricariae flos, essential oils and fluid extracts especially in children. Data concerning the efficacy of these products are excluded here, but those supporting the safety of use are integrated into the assessment, they are specified separately.
1.2. Search and assessment methodology
Sources for this assessment report include DIMDI (Deutsches Institut für Medizinische Dokumentation und
Camomilla commune, Manzanilla común, Manzanilla de Aragón, Manzanilla ordinaria. Terms for the constituents of assumed therapeutic activity and the specific diseases or conditions derived from its traditional use and current indications, supplemented with those expected from
2. Data on medicinal use
2.1.Information about products on the market
Information about products on the market in the EU/EEA Member
Matricaria recutita L. is one of the most popular medicinal plants in Europe. Accordingly a number of herbal medicinal products with herbal preparations of matricaria flowers have been authorised in Member States of the EU. There was also a herbal medicinal product with Matricaria oil as active substance, which is suitable to demonstrate a tradition of medicinal use for more than 30 years. The following table is giving an overview.
Information on medicinal products marketed in the EU/EEA
Table 1: Overview of data obtained from marketed medicinal products
This overview is not exhaustive. It is provided for information only and reflects the situation at the time when it was established.
2.2. Information on documented medicinal use and historical data from literature
Since ancient times traditional use of herbal preparations from matricaria have been reported. Benedum et al. (2006) summarised historical references including Hieronymus Bock (Kreutterbuch 1539), Leonhard Fuchs (New Kreüterbuch 1543) Pietro Andrea Matthiolus (Compendium de plantis omnibus de quibus scripsit suis in commentariis in Dioscoridem editis1571), A. Lonicerus (Vollständiges Kräuterbuch 1737) and Tabernaemontanus (New Kreüterbuch 1613). Dioscurides mentioned the medical use as well. In conclusion there is a consistency in literature for cutaneous use for wound healing, oral treatment of aphthae and internal use for gastrointestinal complaints and spasmolytic activity.
Monographs related to efficacy and safety
The Kommission E Monograph Matricariae flos Banz Nr.: 228 from 05.12.1984
The WHO monograph Flos Chamomillae published in WHO Monographs on Selected Medicinal Plants, Volume 1 1999
The ESCOP monograph Matricariae flos published in ESCOP Monographs second edition 2003
Table 2: Overview of historical data
2.3. Overall conclusions on medicinal use
Based on products existing in the market for more than 30 years, corresponding monographs on Matricariae flos and diverse contributions in the scientific literature traditional use is demonstrated for a broad set of herbal preparations of Matricaria recutita, flos and also the Matricaria oil (see table 2.3). The data described in section 2.1 and 2.2 reveal five different indications which were acceptable for a traditional use monograph. The wording in the respective two monographs was adjusted to the wording used for similar indications. For the indication “Traditional herbal medicinal product used for adjuvant therapy of irritations of skin and mucosae in the anal and genital region, after serious conditions have been excluded by a medical doctor”, which is included in both monographs, the exclusion of serious conditions by a medical doctor was regarded necessary to ensure adequate usage.
Table 3: Overview of evidence on period of medicinal use of Matricaria recutita, flos and herbal preparation derived thereof and Matricaria recutita, aetheroleum in the order of the monograph. Matricaria oil is integrated as a1).
Used abbreviations: SD: single dose, DD: daily dose, P: partial bath, F: full bath
Many pharmacological studies have been published regarding preparations of Matricariae flos, Matricaria oil and their constituents. A systematic review of all these studies will not be attempted here, rather a selection of studies with emphasis on studies with relevance for the plausibility of the traditional use of the different preparations and their different methods of administration.
3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
3.1.1. Primary pharmacodynamics
The therapeutic potential of apigenin as an
Chamazulene has also been shown to inhibit the inflammatory process in vitro (Safayhi et al. 1994). At 15 µM chamazulene inhibited the synthesis of leukotriene B4 in stimulated rat peritoneal neutrophilic granulocytes by 50%. In a
Examining histamine release from rat mast cells, the
A freeze dried extract of matricaria (no further information available) given to Wistar rats suppressed both, the inflammatory effect and leucocyte infiltration induced by simultaneously given carrageenan and prostaglandin E1 (Shipochliev et al. 1981).
In mice fed a diet containing 1.2% (w/w) of an ethyl acetate extract of dried Matricaria recutita flower for 11 days, scratching behaviour induced by the compound 48/80 was suppressed in a dose- dependent manner (Kobayashi et al. 2005). The extract was prepared with 350 g dried flowers of Matricaria recutita extracted with 7 l ethyl acetate twice under sonication for 3 hours at 70°C. The extract was filtered and the filtrate was evaporated under reduced pressure and freeze dried (14 g extract). The extract at doses of 100, 300 and 1000 mg/kg was dissolved in a vehicle of 10% ethanol, 10% Tween 80 and 80% physiological saline solution and then orally administered. Scratching
behaviour induced by compound 48/80 was significantly suppressed by the upper two doses (p=0.05) with a
In Swiss mice the topical application of a hydroalcoholic extract of Matricaria recutita (20 g flos to
100 ml ethanol 42% V/V) to the inner surface of the ear reduced oedema induced by the application of a 2.5% emulsion of croton oil (Tubaro et al. 1984). The extract contained: 0.05 mg/ml of
Della Loggia et al. (1990) found that topical treatment with an extract of fresh matricaria containing 51.8 mg/100 g bisabolol, 29.6 mg/100 g matricine, and 5.3 mg/100 g apigenin at a dose equivalent to 750 µg of dry product (n=25) was as effective as the reference drug 0.60 mg benzydamine (n=25) in preventing inflammation in mice subjected to croton oil induced oedema. The benzydamine, fresh matricaria extract and dried matricaria extract (54.6 mg/100 g bisabolol, 16.4 mg/100 g matricine, 6.3 mg/100 g apigenin; n=26) inhibited the inflammatory response by 31.5%, 31.6% and 23.7%, respectively, compared to the control group (n=41).
The antiulcerogenic properties of Matricaria chamomilla hydroalcoholic extract (MCE) on ethanol- induced gastric mucosal injury were investigated by Cemek et al. (2010) in rats. Airdried Matricaria recutita (plant part and status not specified) was pulverised. One hundred grams plant material was extracted with 1 l ethanol 37% in a soxhlet apparatus. The extract was lyophilised. Group 1 (7 rats each) received ethanol, groups
Kobayashi et al. (2005) determined the antipruritic effect of the ethyl acetate extract or essential oil of matricaria flowers after single oral administrations in male ddY mice (12 mice per observation). The essential oil groups (100, 300 and 1000 mg/kg) reduced the scratching behaviour significantly with 300 (p<0.01) and 1000 mg/kg (p<0.001).
Della Loggia et al. (1990) found that topical treatment with matricaria essential oil containing 55.6 mg bisabolol/100 g , 4.7 mg chamazulene/100 g , but no matricine or apigenin at a dose equivalent to 30 μg essential oil showed no effect in preventing inflammation in mice subjected to croton oil induced oedema (6.6% inhibition n=25).
Proinflammatory cytokine production was inhibited in mice treated with 50 mg apigenin/kg for 1 hour then injected with stimulant lipopolysaccharide (LPS) (Smolinski and Pestka 2003). Apigenin inhibited
Panés et al. (1996) injected male
Hempel and Hirschelmann (1998) tested constituents of topical matricaria preparations in inflammations of the mouse ear induced by arachidonic acid, phorbol myristate acetate and oxazolone. Bisabololoxide A and B showed an
In rats, both apigenin and
In vitro pharmacological data for the constituents of Matricaria recutita containing extracts and in vivo data for different extracts (not exactly matching the herbal preparations included in the monograph) as well as constituents thereof showed in several experiments a decrease of the inflammatory reaction documented by controls. These data exist not for all herbal preparations included in the monograph. Furthermore the concentrations/dosages used are relatively high.
Wound healing activity was determined by Nayak et al. 2007, using excision, incision and dead space wound models.
maintained with plain drinking water. Healing was assessed by the rate of wound contraction, period of epithelialisation,
Martins et al. (2009) treated 125 wistar rats in 5 groups with: no drugs (group I), matricaria (commercially in Brazil available matricaria preparation AdMuc; no further specification) (group II), topical triamcinolone acetonide (group III), clobetasole propionate cream (group IV); clobetasole propionate paste (group V). Under anaesthesia traumatic ulcers were applied with a 3 mm circular scalpel. After 1, 3, 5, 7, 14 days each 5 rats were sacrificed to evaluate the grade of wound healing (grade 1 total healing, grade 5 epithelial ulcer and acute inflammatory infiltrate). In the clinical analysis all rats of the matricaria group had healed ulcers at 5 days whereas the other groups reached that status after 14 days. The wound healing in the corticosteroid groups were significantly lower than in the control group. To check the influence of the different tested preparations a viability testing was done with an established cell line of human gingival fibroblasts (FMMI) using MTT reduction. The matricaria replicates (n=8) showed the least viability.
Thirty male Wistar rats
Using isolated guinea pig ileum, Forster et al. demonstrated the effectiveness of an ethanol extract of matricaria (ratio herbal substance:extraction solvent=1:3.5; extraction solvent: ethanol 31% (m/m)) on spasms induced by acetylcholine and histamine. At doses of 2.5 and 10 ml/l the matricaria extract increased the median effective dose (DE50) of acetylcholine and histamine in a
The cyclic nucleotides cAMP and cGMP regulate the smooth muscle tone of the intestinum causing relaxation. Inhibition of phosphodiesterases (PDEs), which catalyse the hydrolysis of cAMP and cGMP to
The antispasmodic effects of different matricaria compounds have been examined in isolated guinea pig ileum. According to
The effect of a herbal combination product (methanolic Matricaria recutita flowers extract, aqueous Foeniculum vulgare fruit extract and aqueous Melissa officinalis aerial parts extract) (no further information available) on upper gastrointestinal transit was investigated in mice in vivo. Reference drug was loperamide (~0.25 mg/mouse). Oral administration of the herbal formulation (0.4-
0.8 ml/mice, corresponding to
Antispamodic effects of extracts and compounds of extracts were described in vitro and in vivo. The clinical relevance of the effects seen in vitro seems to be low. A certain plausibility concerning the antispasmodic effects can be retrieved from that data.
3.1.2. Secondary pharmacodynamics
An ethanolic extract of matricaria inhibited the growth of herpes and polio virus (Aggag and Yousef 1972, Vilaginès et al. 1985).
In general aqueous extracts of matricaria were more effective against moulds and yeast, while alcoholic extracts showed higher activities against bacteria
Antimicrobial activity of the aqueous extract of Matricaria recutita against various microorganisms (Pseudomonas aeruginosa, beta haemolytic streptococci, Enterobacter agglomerans, Escherischia coli,
Staphylococcus aureus) was assessed. These germs were resistant to the extract (Nayak et al. 2007).
Essential oils extracted from matricaria have exhibited some antimicrobial activity against certain species of bacteria, fungi and viruses in vitro. German matricaria oils were slightly more effective against 25 different
against Aspergillus niger, Aspergillus orchraeus and Fusarium culmorum were
Soliman and Badeaa (2002) reported antifungal activities of M. chamomilla oil against Aspergillus flavus and A. parasiticus as well as F. moniliforme. The highest used concentration (3000 ppm) demonstrated the highest inhibition
Effects on the central nervous system
Aqueous extracts of matricaria flowers
Della Loggia et al. (1982) employed a lyophilised aqueous extract of matricaria prepared with 50 g flowers infused for 5 min with 1 l boiling water to study basal motility, exploratory and motor activities of Swiss NOS mice.
360 mg/kg matricaria extract i.p. (n=15) and reached a maximum inhibition of
320 mg/kg i.p. respectively. The matricaria extract administered at 160 and 320 mg/kg i.p. (n=16/group) potentiated
Shinomyia et al. (2005) observed that a matricaria extract, prepared by refluxing water in 1 hour, has
In a study of ovarectomised rats Yamada et al. (1996) found that inhaling the vapour of matricaria oil reduced a
Viola et al. (1995) tested a purified fraction of an aqueous matricaria extract containing apigenin, administered i.p. to examine its effects on anxiolytic, sedative, locomotor, myorelaxant and anticonvulsive activities in mice. At 3 mg/kg, a dose similar to those used for benzodiazepines, apigenin significantly increased the percentage of entries and time spent in the open arms of an elevated plus maze, behaviours indicative of an anxiolytic effect. Doses up to 10 mg/kg produced no changes in spontaneous ambulatory locomotor activity: at 30 and 100 mg/kg there was a 26% and 46% reduction in activity, respectively, and a moderate decrease in the
3 mg/kg diazepam. In mice treated with doses up to 80 mg/kg apigenin no significant anticonvulsant activity was found after challenge with
Avallone et al. (2000) tested different doses of apigenin
Salgueiro et al. (1997) observed that 10 mg/kg apigenin administered to Wistar rats either pre- or
According to Medina et al. (1998) the separation index (ratio between the maximal anxiolytic dose and the minimal sedative dose) for diazepam is 3 while for apigenin is 10. Compounds, other than apigenin, present in extracts of matricaria can also bind benzodiazepine and GABA receptors in the brain and are thought to be responsible for some of the sedative effects; however many of these compounds are unidentified (Avallone et al. 1996).
3.1.3. Safety pharmacology
No information available.
3.1.4. Pharmacodynamic interactions
No information available.
3.2. Overview of available pharmacokinetic data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
Absorption, Distribution, Metabolism, Elimination
There are no data available.
Human CYP 450 3A4 was inhibited 50% (IC50) with a commercially available ethanol extract of matricaria diluted to
Ganzera et al. (2006) published an in vitro study on the inhibitory effects of the essential oil of matricaria and its major constituents on human cytochrome P450 enzymes (CYP1A2, CYP2C9, CYP2D6, CYP3A4). Crude essential oil (characterised via GC separation) demonstrated inhibition predominantly
on CYP1A2 (IC50=1.59 μg/ml) followed by CYP3A4 (IC50=4.97 μg/ml). Chamazulene (IC50=4.41 μM),
Maliakal and Wanwimolruk (2001) reported on the effects of herbal teas on hepatic drug metabolising enzymes in rats. Six groups of 5 female Wistar rats each had free access to peppermint, dandelion and matricaria tea (2% w/w of dried flower heads of Matricaria recutita), water as control, green tea extract (0.1%) and aqueous caffeine solution (0.0625%). After 4 weeks of pretreatment different cytochrome isoforms and phase II enzyme activities
From preclinical data in rats an interaction of matricaria containing products resulting in a reduction of CYP 1A2 in rats must be taken into account. However, there is only anecdotal clinical evidence for interactions for a specific group of patients after a renal transplantation.
3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof
3.3.1. Single dose toxicity
No data available.
3.3.2. Repeat dose toxicity
No data available.
Kalantari et al. (2009) studied a matricaria containing preparation (no further details available) from Iran in a
methyl methanesulfonate (MMS: 25 mg/kg, matricaria aetheroleum 250, 500 and 1000 mg/kg) in mouse bone marrow cells. The results indicated a
Anter et al. (2011) evaluated the genotoxic, antigenotoxic, tumoricidal, and apoptotic effect of some major phenols (apigenin, bisabolol, and protocatechuic acid) from two medicinal plants, Matricaria chamomilla and Uncaria tomentosa. The wing spot test of Drosophila melanogaster was used to evaluate the genotoxicity and antigenotoxicity of the three phenols. The human model of
The tests on genotoxicity which are published cannot be used to assess the genotoxic potential of the preparations covered by the monograph. The micronucleus test performed by Kalantari et al. cannot be transferred to any of the preparations of the monograph due to a lack of description of the preparation tested. Furthermore it is to point out that authors themselves classified the preparation as equivocal genotoxic (it is to note, that the test was not guideline conform, e.g. due to a lacking second measurement point). All the other tests were done with isolated substances or with test systems which do not comply with current guidelines.
No data available.
3.3.5. Reproductive and developmental toxicity
No data available.
3.3.6. Local tolerance
No data available.
3.3.7. Other special studies
No data available.
No data available.
3.4. Overall conclusions on
Many pharmacological studies have demonstrated that Matricaria preparations and their constituents display many properties in vivo and in vitro. A systematic review of all these studies was not possible due to the huge amount of published data. Emphasis was put on studies with relevance for the clinical usage. The
Data on pharmacokinetics are limited. From in vitro and in vivo data influence on CYP1A2 seems to be at least conceivable. Further monitoring is necessary in order to draw conclusions on the clinical relevance of these findings.
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
Pharmacodynamic data exist mainly for the cutaneous use.
The antiphlogistic effect of m) liquid extract (DER
After application of a solution of 15% sodium lauryl sulphate for 120 mins the skin of 20 healthy adults
Kerscher (1992) irradiated the skin of 24 probands (age
Korting et al. (1993) showed
The human pharmacological data cover the cutaneous use and support the plausibility of the anti- inflammatory effects of the relevant extracts.
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
See 4.2.2 Generalised Anxiety Disorder (Amsterdam et al. 2009), which is an exploratory dose escalation study. Classical dose response studies are publically not available.
4.2.2. Clinical studies (case studies and clinical trials)
Nasemann and Menzel (1975) treated 29 outpatients and 49
The study supports the antiphlogistic effects of rinsing with liquid extract l), but due to lacking controls does not support the
Carl and Emrich (1991) tested liquid extract l) (DER
The study supports the hypothesis of a prophylactic efficacy of application of liquid extract l) rinsing under polychemotherapy, but cannot be regarded confirmative due to lacking controls. The study is irrelevant for the traditional use because there is no documented medicinal use in this indication for more than 30 years. An antiphlogistic effect of Matricariae flos in oromucosal use is supported.
In a double blind placebo controlled prospective clinical study with two arms, Fidler reported about the prophylactic use of liquid extract l) (DER
The study showed no difference between verum and placebo. The study is possibly negative due to the extreme cooling measures before therapy. It does not support the efficacy regarding the well- established use. The study is irrelevant for the traditional use because the indication is not appropriate. An antiphlogistic effect of Matricariae flos in oromucosal use is supported.
In an open uncontrolled study Troll and
No further criteria were documented. The study documents the use of the inhalation and the use as mouth spray, but is not sufficient to support the efficacy according to well established use of the used preparations.
In an open uncontrolled study 53 patients with sinusitis maxillaris received an operative (n=34 tamponade) or conservative treatment (n=19 irrigation). Steam inhalations were done 2 times per day with 20 ml/1 l hot water l) liquid extract (DER
The study documents the use as inhalation but does not support efficacy for
In an uncontrolled multicentre study 104 ambulant patients with unspecific gastrointestinal complaints (pressure in the stomach; eructation, heartburn; loss of appetite; nausea; vomiting) were treated for 6 weeks with 4 times per day 25 drops of liquid extract l) (DER
better in 84.5%; eructation in 77.5%, heartburn in 81.7%; loss of appetite in 61%; nausea in 88.7%; vomiting in 77.8% (Stiegelmeyer 1978).
Due to lacking controls the study does not support efficacy regarding
Generalised Anxiety disorder (GAD)
In a randomised,
Aroma blinding was achieved by a adding a disk of 1%matricaria oil or neutral oil to the lid of each airtight medication container.
1.week: 1 capsule containing 220 mg Matricaria extract per day
2.week: 2 capsules containing each 220 mg Matricaria extract per day For patients with a reduction of
3.week: 3 capsules containing each 220 mg Matricaria extract per day
4.week: 4 capsules containing each 220 mg Matricaria extract per day
Patients continuing to have a ≥50%/baseline reduction were treated in weeks
The detectable effect size was 0.57 with 80% power (0.68/90%) primary comparisons implemented quasi least squares with
Regression models were used to test the primary hypotheses. Last observation carried forward (LOCF) analysis to examine change in total
The reduction of
The small study of very good quality with a dose escalating design shows a statistically significant clinically relevant reduction of
Nasemann and Menzel (1975) reported in his above mentioned study the use of a liquid extract (DER
The study does not support efficacy according to
In a blind, placebo controlled randomised, monocentric study comparing both sides 72 patients suffering from a moderate atopic dermatitis of both arms received 2 times per day
•Matricariae flos (cream with herbal preparation m)) vs. hydrocortisone cream 0.5%
•Matricariae flos (cream with herbal preparation m)) vs. placebo cream
The authors stated that after a
The study is not suitable to support WEU but supports traditional use on the skin in moderate atopic dermatitis.
Radiation skin reaction in breast cancer patients
The efficacy of a liquid extract (DER
minutes before irradiation and at bed time the randomised preparation was administered above or below the scar. The evaluation took place after 10 Gy and 2 weeks/3 months after the irradiation according to a 4 point Likert scale (0=unchanged; 1=slight reddening; 2=explicit redness; moistening dermatitis). Under treatment with liquid extract m) the grade 1 reaction occurred slightly later. There were 7 patients with grade 2 reactions in the matricaria group compared to 13 patients under almond ointment treatment (Maiche et al. 1991).
The study is too small to support WEU, the indication is not suitable for traditional herbal medicinal products.
Wound healing after proctologic operations
Marti (1977) documented the results of hip baths treated with a product containing herbal preparation l) after sphincterectomy due to anal fissures in 50 patients. The wound healing was normal. No safety concerns were reported.
These data have observational quality and support the plausibility of the traditional use as hip baths.
Fifty patients (28 male, 22 female) suffered from different proctologic diseases (fistulae, perianal thrombosis, marisca) were postoperatively divided in two groups. All received 3 times per day a hip bath with a liquid extract (DER
The study is not suitable for an efficacy assessment according to WEU criteria due to lacking controls, but does support the traditional use in wound healing of superficial wounds
Decubital ulcer/Ulcera crurum
4.3. Clinical studies in special populations (e.g. elderly and children)
Jeschke et al. (2009) reported about the risks of Asteraceae containing extracts in German primary care. Three hundred
The available studies regarding children in internal use are done with different combination products, as
herbal tea (matricaria, vervain, licorice, fennel, balm mint)
standardised extract of matricaria (Matricaria recutita), fennel (Foeniculum vulgare), and lemon balm (Melissa officinalis)
liquid preparation containing apple pectin and matricaria fluid extract standardised to 2.5 g chamazulene/100 g
and are to be used to assess the safety of matricaria containing products in children but may not be used to assess efficacy. There are no clinical studies available concerning the internal use either as inhalation or as oral administration in children.
Aertgeerts (1984) reported on an observational study which included 182 patients who were treated with an ointment (containing liquid extract l)), 2 to 3 times daily, thin layer; fluid, 15 ml/l water for compresses, 5 to 7 ml/l for bath preparation and 15 ml/l water for washings). Twenty four infants (average age 7.5 month) were treated for diaper dermatitis, 123 patients (mean age 65 years) were treated for ulcus cruris and 35 patients (mean age 62 years) were treated for ulcus decubitus. Duration of treatment was varying. Although the design of the study was not suitable for substantial conclusions on efficacy – beside a general tendency on a positive effect – it is remarkable that especially the treatment of infants did only show irritation in two cases possibly due to occlusive conditions. For 22 infants no side effects were observed.
Remme and de Witt (1984) studied the efficacy of liquid extract (DER
patients with ulcera crurum. Seventeen of them suffered from an accompanying eczema. The evaluation followed the survey of the wounds (2 times per week); status documentation (healed, better, unchanged, worsening). The eczema was monitored in cm2 status documentation (healed, better, unchanged, worsening). At the end of treatment there was a global assessment of efficacy (good, sufficient, minor, no). Patients received 4% extract l) as compresses changed 4 times daily or 1 times extract n). Five patients dropped out due to superinfection, 7 patients were healed, 41 were better, 4 were unchanged, 2 worsened.
Peters (1988) observed the efficacy of a a cortisone free local treatment with a Matricariae flos containing ointment. These observational data are too poorly documented to support efficacy, but document the traditional use.
In an open controlled study with 55 children the efficacy of extract m) in treatment of diaper dermatitis was investigated (Viegas et al. 1996). Extract m) cream was applied with every change of diapers, duration of use was two weeks. The result of treatment was analysed by means of a
The study is suitable to demonstrate the cutaneous medicinal use of extract m) cream in children from 2 weeks to 3 years of age.
Stechele (1991) treated 76 infants and toddlers (2/3 in between 1 and 10 months) in several indications (diaper dermatitis, seborrhoic eczema and peroral eczema) with extract m) cream 3 times daily over 8 days. There were no adverse effects observed. The study does not allow any conclusion towards efficacy due to lacking controls.
4.4. Overall conclusions on clinical pharmacology and efficacy
The matricaria containing preparations included in both monographs have been used in Europe for more than 30 years. In section 4 literature data on trials are presented which are not sufficient to conclude for a
Indication 1) Traditional herbal medicinal product used for the symptomatic treatment of minor
Indication 2) Traditional herbal medicinal product used for the relief of symptoms of common cold is supported by the clinical studies (Schmidt 1975, Lauber 1987) – being made to assess the local tolerance of inhalation – (see 5. Clinical safety). The open uncontrolled study of Troll and Patzelt- Wenczler (1990) tested steam inhalation versus mouth spray and is supporting the traditional use of steam inhalation. The observational study of Sauer (1990) supports this use as well for ethanolic extracts in inhalation in the specified posologies for ethanolic extracts.
Indication 3) Traditional herbal medicinal product for the treatment of minor ulcers and inflammations of the mouth and throat. The traditional oromucosal use is supported by open clinical studies by Nasemann and Menzel (1975), Carl and Emrich (1991) and Fidler et al. (1996) in the specified posology.
Indication 4) Traditional herbal medicinal product used for adjuvant therapy of irritations of skin and mucosae in the anal and genital region, after serious conditions have been
excluded by a medical doctor. This indication is supported by an open clinical study (Förster 1987) supporting the use of ethanolic extracts as hip bath after haemorrhoids ligature. In another clinical study Förster explored the different uses as hip bath, cream and ointment after different anal diseases: perianal thrombosis, mariscs and anal fistulae (Förster 1987).
Indication 5) Traditional herbal medicinal product used for the treatment of minor superficial wounds and small boils (furuncles) is supported by open clinical studies (Aertgeerts 1984, Förster 1987). These studies are not sufficient to support WEU, due to lacking controls but cover the traditional plausibility in the relevant posologies.
Posologies defined in the monographs are based on the traditional use of existing products. Taking into account the accepted indications, data from clinical trials and the safety profile described in the following sections a duration of use of one week is justified.
5. Clinical Safety/Pharmacovigilance
5.1. Overview of toxicological/safety data from clinical trials in humans
Lauber reported about the treatment of 12 patients with unspecific bronchial
Chronic obstructive lung disease (COPD)
Ten patients suffering from COPD and 15 healthy probands were treated via inhalation with a liquid extract (DER
Twenty four adult patients (14 female, 10 male) with asthma and
conjunctival test 18 were positive to A. vulgaris, 13 to M. chamomilla. Fifteen were positive in the bronchial test to A.vulgaris, 16 to M. chamomilla. In the oral provocation 13 patients reacted with mild perioral allergy symptoms (pruritus, angioedema of the lips) (de la Torre Morin et al. 2001).
Fourteen patients with a history of allergy either to matricaria or to spices or weeds, and a positive skin prick test/RAST to matricaria were investigated by Reider et al. (2000) for related allergic reactions to food, pollen and others.
Hausen (1996) published data from allergy testing with a Compositae plant mixture. One hundred eighteen of 3,851 tested individuals gave a positive response (3.1%). Further tests with the single species of the mixture revealed a high percentage of reactions to feverfew (70.1%) and lower responses to chrysanthemums (63.6%), tansy (60.8%), matricaria (56.5%), arnica (51.8%), yarrow (51.8%).
Paulsen (2002) resumed in her review regarding contact sensitisation from Compositae containing herbal remedies, that there was no difference between different preparations of Matricaria recutita and that the sensitisation/elicitation risk for dermatitis is low.
Aertgeerts published, that from 123 patients with ulcera crurum, treated with a liquid extract l
Remme and de Witt (1984) studied the efficacy of a liquid extract (DER
In an open uncontrolled trial 512 patients suffering from contact eczema received an epicutaneous test with a liquid extract (DER
Rudzki and Jablonska (2000) published a parallel design with 982 outpatients with known type IV sensitising, of whom 830 received a patch test with 18 contact allergens as well as a liquid extract (DER
Paulsen et al. (2008) tested 8 out of 12
Twenty patients with a known contact allergy to sesquiterpene lactones (SLs) were recalled by Lundh et al. (2006) and patch tested with aqueous extracts of 8 different herbal teas based on Asteraceae plants as well as with parthenolide and other SLs. In 18 of 20 patients with SL allergy, there were positive test reactions to the Asteraceae teas, mainly to those based on matricaria, dandelion and wormwood.
Tea made from matricaria flower was separated by
5.2. Patient exposure
The following table gives an overview of available data on adults, children and pregnant women treated with Matricaria recutita containing products.
Sum: 1,153 pregnant women used predominantly matricaria tea
In summary 2,327 adults and 155 children have been exposed to cutaneous use of Matricaria recutita containing products. For the oral use there are 104 + 28 US adults published. The children published were treated with combination products containing Matricaria recutita among other herbal preparations. They are included here. The publication of Jeschke et al. (2009) covers 817 children treated with
5.3. Adverse events, serious adverse events and deaths
Hypersensitivity reactions including severe allergic reaction (dyspnoea, Quincke’s disease, vascular collapse, anaphylactic shock) following mucosal contact with liquid chamomile preparations have been reported from literature and national pharmacovigilance data bases (see also 4.4, 4.7 and 4.9). The majority of data is referring to herbal preparations of Matricaria recutita, flos. Corresponding sections of the monograph of Matricaria oil have been adapted to this data.
Subiza et al. (1989) reported about an 8 years old boy having suffered from hay fever and asthma caused by a variety of pollen for the past three years. He was under immunotherapy for 2 years. One month after he stopped immunotherapy he had a night episode of coughing, slight dyspnoea and wheezing. His mother tried to relieve the symptoms with a cup of matricaria tea. Several minutes later the patient deteriorated with dyspnoea, loss of consciousness and shock. After medical intervention he could be stabilised. As cause an IgE mediated immunologic reaction potentially cross reacting with the known mugwort allergy could be identified.
Scala (2006) reported on a 20 years old woman with a proven allergy to matricaria, suffered from
A 50 years old metalworker developed acute eczema on forearms and hands, which he tried to clear with compresses and washings with tea from matricaria, roman chamomile and mallow herbs. He was positive tested with roman matricaria extract 1%pet in D2 and D4 and with german matricaria tea D4 and with the combination in both dilutions (Pereira et al. 1997).
A 23 years old woman came with recurrent facial eczema and eczema of the back of her foot. She reacted to colophonium and potassium dichromate in the patch test. A year later she reacted on cobalt and oak moss. Even avoidance did not solve the problem. At 25 she had further recurrences of her facial eczema. Further testing showed reaction to matricaria, sesquiterpenlactones were negative. Roman matricaria was not tested. At last she remembered that the facial eczema eruptions followed the administration of steaming matricaria tea (Rycroft 2003).
antihistamines, volume substitution, etilefrin i.v.) she received an emergency caesarean section. The newborn had a severe asphyxia (Apgar score=0) and died the following day. IgE mediated anaphylaxis triggered during the enema was the reason.
Thien (2001) filed a case report about a 69 years old male, who suffered from an anaphylactic reaction following a matricaria tea enema made to treat a 3 day constipation. Within 5 minutes after the enema he developed flushing and an urticarial rash on the inside of his arms associated with dyspnoea. After an
Benner and Lee (1973) published an anaphylactic reaction after oral ingestion of matricaria tea of a 35 years old atopic female, who had a known ragweed hay fever. After several sips of the tea, she developed abdominal cramps, thickness of her tongue and a tight sensation in her throat. Then angioedema of her lips and eyes developed, diffuse pruritus and a full sensation in her ears. After an
5.4. Laboratory findings
Laboratory data were not published.
5.5. Safety in special populations and situations
5.5.1. Use in children and adolescents
Jeschke et al. (2009) reported about the risks of Asteraceae containing extracts in german primary care. 362 physicians were contacted to participate in an online system to document all prescriptions of Asteraceae containing extracts with the corresponding adverse drug reactions (ADR). One hundred seven physicians agreed to participate, 38 fulfilled the technical requirements, 55% were general practitioners, 45% specialists (23% paediatricians, 11% internal medicine, 11% others). From September
Safety data could only be deduced from clinical studies with combination products.
Only two clinical trials have evaluated the efficacy of matricaria for the treatment of colic in children, and both combined matricaria with other herbs. In a prospective, randomised,
In a prospective,
A combination product (apple pectine and matricaria liquid extract) was investigated in a
In an uncontrolled study 24 infants with diaper rash (11
Fifty five toddlers (31 female, 24 male, age range 2 weeks – 36 months) with diaper rash were treated at every diaper change with extract n) cream. In 2 children a desquamation if the skin, in two children a reddening of the skin was noted (Viegas et al. 1996).
Seventy six infants and toddlers, (2/3 in the age from
Due to the long term use and the lack of safety concerns the publication of KOOP Phytopharmaka (Dorsch et al. 1993) could support to accept the posology published there for herbal tea in children and
adolescents from 4 weeks to 18 years. However, due to general considerations of nutrition and fluid intake of children until an age of 6 months, the monograph displays the use of herbal tea of matricaria starting with the age of 6 months.
5.5.2. Drug Interactions and other forms of interaction
Segal and Pilote (2006) reported on a 70 years old woman, whose medical history included a mitral valve replacement and a previous episode of atrial fibrillation. She was admitted to the hospital with a cough expectoration of yellow sputum. Her medication included warfarin (4 mg 3 day per week; 6 mg 4 day per week) amiodarone, digoxin, synthroid, alendronate metoprolol and a
Nowack and Nowack (2005) reported on 3 cases of patients with cadaveric renal allografts under stable immunosuppression with cyclosporine (metabolised via CYP3A4) and mycophenolate mofetil (MMF)(metabolised via glucuronisation) changing under fluid excess via herbal teas. Two of the case reports were associated with matricaria tea.
Case A: A 48 years old woman having cyclosporine trough levels of
110 mg per day, developed gradually declining trough levels down to 80 μg/l under increasing doses of cyclosporine (2 times 170 mg per day). Comedication was: pravastatin, valsartan, hydrochlorothiazide. The patient reported drinking up to 2 l herbal tea, as recommended by the transplantation unit.
Thüringer 9 Kräuter Tee contained: Mentha piperita, Rubus fruticosus, Matricaria recutita, Melissa officinalis, Coriandrum sativum, Santalum album, Citrus auranticum, Krameria triandra and Pimpinella anisum (no information on the amounts). After 2 weeks of replaced mineral water the trough levels of cyclosporine increased, despite reduced doses (2 times 150 mg per day). A reexposition to the former tea led to decreasing trough levels within 2 weeks.
Case B: A 37 years old Armenian with a cadaveric renal allograft under maintenance immunosuppression with cyclosporine and azathioprin, later replaced with mycophenolate mofetil (MMF) (cyclosporine trough levels of
The case reports are inconsistent. Segal and Pilote argue the coumarin content as relevant for the interaction, which is not relevant for the monograph since the wrong plant parts (leaves) were used to prepare the tea. Nowack and Nowack describe contradictive effects. Case A seems to cover an interaction via CYP3A4, which is induced by a tea containing 9 herbal substances, but does not correspond to the preclinical study from Ganzera et al. (2006) covering the essential oil. Case B might be due to a cancelled inhibition of CYP3A4, which does not correspond to the preclinical data as well as collected for the essential oil by Ganzera et al. Budzinski et al. (2000) demonstrated an inhibition of CYP3A4 through ethanolic standardised Canadian extracts (no specification available). Therefore the following text should be added under interactions:
“For patients after renal transplantation taking high dosages for longer periods (about two months) interactions based on effects on CYP450 have been reported.”
5.5.3. Fertility, pregnancy and lactation
Nordeng and Havnen (2004) reported on the usage of herbal drugs during pregnancy in 400 Norwegian women, 36% (n=144) had used herbal medicinal products during pregnancy. Matricaria was amongst the 10 most commonly used herbal drugs, overall applied by 9% (n=13) of the herbal drugs using women.
In England a questionnaire concerning the use of herbal products was given to 1,037 women, at least 20 weeks pregnant, of which 578 were answered. Three hundred
Cuzzolin et al. (2010) interviewed 392 Italian women regarding their use of herbal products during pregnancy, 48 women used matricaria preparations orally and topically against anxiety, digestive problems and stretch marks. There were no statistically significant effects for any matricaria user. Pregnancy outcome showed no matricaria specific issues. The reported tendency of smaller birth weight for all herbal users could not be addressed towards the herbs used.
Facchinetti et al. (2012) interviewed 700 women around labour in 2 university hospitals and one general hospital, 35.7% took matricaria predominantly in oral administration. A correlation (matricaria use and low body weight of the infant) assumed to be relevant, did not show to be statistically significant.
Bishop et al. (2011) reported about the results of an observational
Matricaria was used by 551 women throughout pregnancy (14.6%).
In Canada a questionnaire was submitted to 8,505 women who gave birth to a live born between January 1998 and December 2003 in one of the Quebec´s hospitals. The questionnaire was answered by 3,354 women and 9% of them used herbal products (HP) during pregnancy. Matricaria, green tea, peppermint and flax were the most frequently HP used. Matricaria tea was used by 122 women out of 356 pregnant women (Moussally et al. 2009). From the same data set the researchers performed a case control study regarding premature delivery (<37th week), 623 preterm childbirths were identified, 62 women used HP during pregnancy, one third matricaria. After adjusting to cofounders no relation between the use of matricaria during the last two trimesters of pregnancy and preterm delivery was found.
A questionnaire was answered by 588 Australian pregnant women
The above mentioned studies with large numbers of pregnant women showed no risk for the use of matricaria teas during pregnancy. The specific information on the other preparations of the Matricariae flos monograph is too scarce to recommend a use. The case reports include severe anaphylactic reactions, which is not a pregnancy related risk but could happen to any atopic patient reacting to Asteraceae. For matricaria tea the use in pregnancy and lactation is sufficiently documented to recommend a traditional use, since it is widely used as herbal tea.
Since data regarding the cutaneous use of matricaria containing preparations during lactation are not available the use during pregnancy and lactation is not recommended. Nevertheless, sore nipples are a common problem. Therefore, if applicable (e. g. for herbal tea) the following text should be included under pregnancy and lactation to prevent sensitisation of breastfed babies: “Before nursing the baby the nipples should be cleaned from matricaria containing products to prevent a sensitisation of the baby.”
5.6. Overall conclusions on clinical safety
The clinical safety of Matricaria recutita containing preparations is good. The main risk is a sensitisation in cutaneous use, which is minor. For children there are data from 817 patients with an allerginicity of 0.12% (Jeschke et al. 2009), 3,851 adults having an indication for allergy testing showed a risk of Asteraceae allergy of about 3.1% in adults, 56% thereof were allergic to matricaria (Hausen 1996). This risk is covered by a contraindication in the monograph.
To prevent sensitisation of breastfed babies a note has to be introduced, if appropriate in the section on pregnancy, lactation and fertility:
“Before nursing the baby the nipples should be cleaned from matricaria containing products if applicable to prevent a sensitisation of the baby.”
Other specific risks for children of any age group are not deductible. Pregnant women may use herbal tea, for all other preparations there is a lack of data. Therefore for all other herbal preparations mentioned in the monograph the use during pregnancy and lactation is not recommended.
The drug interaction data are inconclusive from preclinical assessment to case reports. Nevertheless interactions regarding cyclosporine immunosuppression after renal transplants are possible. Therefore a note should be entered in the monograph:
“For patients after renal transplantation taking high dosages for longer periods (about two months) interactions based on effects on CYP450 have been reported.”
6. Overall conclusions
The medicinal use of preparations containing Matricariae flos has been documented for millennia in Europe and all over the world. The multitude of preparations from the different countries of Europe attests to that.
Only one clinical study of good quality according to current standards has been identified (Amsterdam et al. 2009). As the studied indication (generalised anxiety disorder) is not authorised in a medicinal product in the EU since at least 10 years a
Accumulating the vast data from preclinical sources and from the traditional literature as well as from different clinical studies of mostly mediocre quality and from registered or authorised medicinal products in the EU the traditional use of Matricariae flos can be accepted for the following indications for adolescents, adults and elderly. The use in children of different age groups for distinct indications was acceptable for few herbal preparations ( a), e), g), h), k), l), m), o) ), because data were available and safety has been sufficiently demonstrated.
Indication 1: Traditional herbal medicinal product used for the symptomatic treatment of minor gastrointestinal complaints such as bloating and minor spasms
Indication 2: Traditional herbal medicinal product used for the relief of symptoms of common cold
Indication 3: Traditional herbal medicinal product for the treatment of minor ulcers and inflammations of the mouth and throat.
Indication 4: Traditional herbal medicinal product used for adjuvant therapy of irritations of skin and mucosae in the anal and genital region, after serious conditions have been excluded by a medical doctor.
Indication 5: Traditional herbal medicinal product used for the treatment of minor inflammation of the skin (sunburn), superficial wounds and small boils (furuncles).
For Matricariae aetheroleum no sufficient clinical evidence could be identified except observational data from Marti (1977). Based on pharmacological data and medicinal products authorised or registered in the EU the traditional use as bath additive is acceptable for adolescents, adults and elderly in the indication:
Traditional herbal medicinal product used for adjuvant therapy of irritations of skin and mucosae in the anal and genital region, after serious conditions have been excluded by a medical doctor.
Relevant sections of the monograph on Matricaria oil have been aligned to the monograph on Matricariae flos if appropriate.
The main safety issue is sensitisation regarding allergies towards Asteraceae. Jeschke et al. (2009) published data from 1,602 patients where the reported rate of allergies was 0.12%. The labeling is adapted accordingly.
The preclinical data refer to an inhibition of CYP450 3A4, reflected by a clinical case report, where the interaction occurred after an intake of
The use in pregnant women is for the majority of herbal preparations not recommended because absence of sufficient data. Only herbal tea can be recommended in pregnant women and during breast feeding.
Risk Benefit assessment
Since no further risks than allergenicity and sensitisation are noteworthy the benefit risk relation for the traditional use is to be assessed as positive.
A European Union list entry is not established due to lack of sufficient data on genotoxicity.