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PHYTOTHERAPY RESEARCH Phytother. Res. 20, 519–530 (2006) Published online 20 April BIOACTIVITY 2006 in Wiley InterScience OF CHAMOMILE (MATRICARIA RECUTITA L.) (www.interscience.wiley.com) DOI: 10.1002/ptr.1900

in Wiley InterScience OF CHAMOMILE ( MATRICARIA RECUTITA L.) (www.interscience.wiley.com) DOI : 10.1002/ptr.1900 519
519
519

REVIEW ARTICLE

A Review of the Bioactivity and Potential Health Benefits of Chamomile Tea (Matricaria recutita L.)

Diane L. McKay* and Jeffrey B. Blumberg

USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA 02111, USA

Chamomile (Matricaria recutita L., Chamomilla recutita L., Matricaria chamomilla) is one of the most popular single ingredient herbal teas, or tisanes. Chamomile tea, brewed from dried flower heads, has been used traditionally for medicinal purposes. Evidence-based information regarding the bioactivity of this herb is presented. The main constituents of the flowers include several phenolic compounds, primarily the flavonoids apigenin, quercetin, patuletin, luteolin and their glucosides. The principal components of the essential oil extracted from the flowers are the terpenoids ααααα-bisabolol and its oxides and azulenes, including chamazulene. Chamomile has moderate antioxidant and antimicrobial activities, and significant antiplatelet activity in vitro. Animal model studies indicate potent antiinflammatory action, some antimutagenic and cholesterol-lowering activities, as well as antispasmotic and anxiolytic effects. However, human studies are limited, and clinical trials examining the purported sedative properties of chamomile tea are absent. Adverse reactions to chamo- mile, consumed as a tisane or applied topically, have been reported among those with allergies to other plants in the daisy family, i.e. Asteraceae or Compositae. Copyright © 2006 John Wiley & Sons, Ltd.

Keywords: Matricaria recutita; Chamomilla recutita; chamomile; herbal tea; tisane; apigenin.

INTRODUCTION

While there is an extensive literature suggesting health benefits associated with drinking teas prepared with Camilla sinensis (i.e. black, green and oolong teas) (McKay and Blumberg, 2002), evidence-based infor- mation regarding the effects of most herbal teas, or tisanes, is quite limited. One of the most commonly consumed single ingredient herbal teas is chamomile, prepared with dried flowers from Matricaria recutita L. This is a review of the available scientific literature re- lated closely or directly to the bioactivity and potential health benefits of chamomile tea. Like many other herbal preparations used in traditional cultures, the therapeutic uses and purported health benefits of chamomile are based largely on folklore rather than on scientific substantiation. Information regarding the phytochemical content, in vitro experiments, animal models and human studies available in the recent sci- entific literature is presented.

* Correspondence to: Diane L. McKay, Antioxidants Research Labora- tory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA 02111, USA. E-mail: diane.mckay@tufts.edu Contract/grant sponsor: U.S. Department of Agriculture (USDA) Agri- cultural Research Service; contract/grant number: 58-1950-001 Contract/grant sponsor: Hain Celestial Group (Boulder, CO).

Copyright © 2006 John Wiley & Sons, Ltd.

Copyright © 2006 John Wiley & Sons, Ltd.

NOMENCLATURE

Chamomilla recutita L. (synonymous with Matricaria recutita L. Rauschert, and Matricaria chamomilla) is an annual herbaceous plant indigenous to Europe and Western Asia that has been naturalized in Australia, Britain and the USA. Also known as German chamo- mile, Hungarian chamomile, mayweed, sweet false chamomile or wild chamomile, the plant is cultivated in Germany, Hungary, Russia and other southern and eastern European countries for the flower heads. Infu- sions and essential oils from fresh or dried flower heads have aromatic, flavoring and coloring properties. Both are used in a number of commercial products including soaps, detergents, perfumes, lotions, ointments, hair products, baked goods, confections, alcoholic beverages and herbal teas.

NUTRIENT AND PHYTOCHEMICAL CONSTITUTENTS

Over 120 constituents have been identified in chamo- mile flowers (Mann and Staba, 1986). Amino acids, polysaccharides and fatty acids are present in the muci- lage, which makes up approximately 10% of the flower head. The yield of the volatile or essential oil from the flowers is 0.4–2.0%. The main constituents of the oil include the terpenoids α-bisabolol and its oxides (78%) and azulenes, including chamazulene (1–15%) (Matos et al., 1993; Mimica-Dukic et al., 1993; Stanev et al.,

Phytother. Received Res. 20, 15 519–530 February (2006) 2006

Accepted 23 DOI: February 10.1002/ptr 2006

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D. L. MCKAY AND J. B. BLUMBERG

1996; Pino et al., 2000; Pino et al., 2002). Chamazulene is an artifactual component, formed under high tem- perature and/or acidic conditions from matricin (prochamazulene), which is present in fresh flower heads. The formation of chamzulene can be minimized with CO 2 extraction (Reverchon and Senatore, 1994). Farnesene (12–28%), spathulenol and spiroethers, in- cluding the cis/trans-en-yn-dicycloethers (8–20%), are also present in the volatile oil (Lis-Balchin et al., 1998; Maday et al., 1999; Weglarz and Roslon, 2002). Teas brewed from chamomile contain 10–15% of the essen- tial oil available in the flower. Qualitative and quanti- tative differences in the essential oil of chamomile are not markedly affected by growing conditions (e.g. fertilizer rate, irrigation, pesticide application), but can vary significantly between growing regions, in cul- tivated versus wild plant populations, and with differ- ent processing conditions (Salamon and Honcariv, 1994; Povh et al., 2001; Szoke et al., 2003). Wild and cultivated populations of chamomile also differ with respect to mineral content. Wild growing chamomile contains a wider variety of mineral elements, while cultivated types have higher ratios of K/Na and Ca/Mg (Maday et al., 2000). Whole plants contain about 36 µg/g Mn (Laila, 1988). The dissolution of most min- erals present in chamomile tea is in the range 10–26%, with K, Ca, and Mg present in the highest concentra- tions (Maday et al., 2000). Several flavonoids and other phenolic compounds have been identified in various parts of the chamo- mile flower head, i.e. ligulate flowers, tubular flowers and receptacles. Apigenin (16.8%), quercetin (9.9%), patuletin (6.5%), luteolin (1.9%) and their glucosides are the major flavonoids present in the total flower, although their relative concentrations vary within the different flower parts (Mann and Staba, 1986; Mulinacci et al., 2000; Barene et al., 2003). For example, apigenin is more highly concentrated in the ligulate flowers (68%) than in the tubular flowers (0.9%) or receptacles (0.8%), while quercetin is lowest in the ligulate flowers (2.1%) and higher tubular flowers (12.4%) and receptacles (10.0%). Mulinacci et al. (2000) reported the presence of large amounts (39.1%) of the cinnamic acid deriva- tives ferulic and caffeic acid, as well as other unidenti- fied phenolic derivatives (25.8% of the total flower). The coumarins herniarin and umbelliferone (in a ratio of 1:5) make up approximately 0.1% of the total constituents (Kotov et al., 1991; Ahmad and Misra, 1997). These compounds, as well as the flavonoids and phenolics, are soluble in hot water, and the amounts obtained from frequent consumption of infusions or teas are not negligible (Ceska et al., 1992; Mulinacci et al., 2000).

IN VITRO STUDIES

Antioxidant capacity. Several laboratories have exam- ined the antioxidant potential of chamomile. With the ferric reducing ability of plasma (FRAP) assay, Dragland et al. (2003) determined that the antioxidant capacity of chamomile was relatively low (<18 mmol/ 100 g) in comparison with a selection of other medici- nal and culinary herbs. The mean value of the chamo- mile varieties tested (17.7 mmol/100 g) was higher than

Copyright © 2006 John Wiley & Sons, Ltd.

coriander (3.3 mmol/100 g), but much lower than pep- permint (78.5 mmol/100 g) and oregano (137.5 mmol/ 100 g, the highest value obtained). Lee and Shibamoto (2002) reported the activity of a dichloromethane extract of a steam-distilled solution of dried chamomile (20 g/L water) using two different assay systems. In the aldehyde/carboxylic acid assay, with BHT and α- tocopherol as the standards, the highest dose (500 µg/ mL) of the chamomile extract inhibited hexanal oxidation by 50% over a 40 day period. All the herb and spice plant extracts examined in this experiment exhibited dose-dependent inhibitory activity between concentration (10–500 µg/mL) and antioxidant activity. Compared with chamomile, the inhibition activities of thyme and basil were higher (100%), lavender and cinnamon were lower (5–6%) and rosemary was com- parable (59%) in this assay system. In a conjugated diene assay measuring the inhibition of hydroperoxide formation from methyl linoleate (without initiators or metal catalysts), the trend of inhibition for all herbs and spices was similar to that of the hexanal oxidation. At the highest concentration (200 µg/mL), chamomile exhibited 31% inhibition of conjugated diene formation. Several commercially available essential oils of chamomile were tested by Lis-Balchin et al. (1998) with an agar plate-based method where the essential oils were added to plates containing β-carotene and linoleic acid, then incubated at 45 °C until the background color was bleached. The antioxidant values were reported as the intensity of retained color, and the diameter of the color retention zone. Although not an ideal assay for the assessment of antioxidant activity due to its intra- assay variability, a small difference between the activi- ties of the two German oils (diameter: 10.5 vs 13.6; color intensity: very modest vs. modest) and a greater differ- ence between German and Roman oils (diameter: 0) were observed. Al-Ismail and Talal (2003) studied the antioxidant effect of water and alcohol extracts of chamomile flowers on long-term storage of anhydrous butter fat. Both extracts showed a moderate effect in controlling hydrolytic rancidity, measured by peroxide value and free fatty acids, but the antioxidant effect of the water extract was reported to be significantly higher than the alcohol extract. No other studies measuring the direct antioxidant potential of aqueous chamomile infusions have been reported. Chamazulene extracted from chamomile was shown to inhibit Fe 2+ /ascorbate-induced lipid peroxidation, measured with the thiobarbituric acid reactive sub- stances (TBARS) assay, in a concentration and time- dependent manner (50% inhibition with 18 µM after 45 min incubation) (Rekka et al., 1996). In the same study, chamazulene (25 mM) was also shown to inhibit the autoxidation of dimethyl sulfoxide (DMSO) (33 mM) by 76%, and had a weak capacity to interact with 1,1-diphenyl-2-picrylhydrazyl (DPPH). In a different study of chamomile extracts, McAnlis et al. (1997) tested quercetin and apigenin, along with kaempferol, myricetin and rutin for their effects on the oxidative modification of LDL using both Cu 2+ - and 2, 2-azobis(2- amindinopropane) dihydrochloride (AAPH)-induced oxidation. Quercetin was the most potent inhibitor of Cu 2+ -mediated LDL oxidation, and apigenin was the least. At 0.5 µmol/L, quercetin increased the Cu 2+ -induced oxidation lag time by 64.3 ± 5.6 min.

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At the same concentration, quercetin increased the AAPH-induced lag phase by 58.3 ± 3.1 min and decreased the rate of propagation from 1.2 ± 0.1 to 0.8 ± 0.1 abs units/min. Conversely, apigenin (0.1– 5.0 µmol/L) added to LDL reduced lag time and increased the rate of propagation in response to AAPH, suggesting a possible pro-oxidant effect. The stati- stical significance of the changes described in this study was not reported.

Antimicrobial activity. Essential oils extracted from chamomile have exhibited some antimicrobial activity against certain species of bacteria, fungi and viruses in vitro. German chamomile oils (Matricaria chamomilla) were slightly more effective against 25 different gram- positive and gram-negative bacteria and 20 strains of Listeria monocytogenes than oil from Roman ‘chamo- mile’ (Chamaemelum nobile), but neither was as effec- tive as Moroccan ‘chamomile’ (Ormensis multicaulis) (Lis-Balchin et al., 1998). At best, the efficacy of these oils (10 µL) was low (8–56%) when compared with other plant essential oils used in this experiment, e.g. bay leaf (100%), clove (96%), cinnamon (96%), thyme (56–100%). However, the antifungal activities of the German chamomile oils against Aspergillus niger, A. ochraceus and Fusarium culmorum were, on average, higher than the other two ‘chamomile’ oils (63– 75% inhibition). Soliman and Badeaa (2002) also re- ported the antifungal activities of M. chamomilla oil against two additional Aspergillus strains (A. flavus, A. parasiticus) and F. moniliforme. In this experiment, the highest concentration of chamomile oil used (3000 ppm) exhibited the highest inhibition against these micro- organisms (91–95%); however, the oils of thyme and cinnamon were more effective at lower concentrations (500 ppm). Esters and lactones from German chamo- mile showed activity against Mycobacterium tuberculo- sis and M. avium (Lu et al., 1998), and an ethanol extract of German chamomile inhibited the growth of both herpes and polio virus (Aggag and Yousef, 1972; Vilagines et al., 1985). Al-Ismail and Talal (2003) reported that, in general, aqueous extracts of chamo- mile were more effective against molds and yeast, while alcohol extracts showed higher activities against bacteria.

Anti-platelet activity. Chamomile was reported by Pierre et al. (2005) to be one of only three herbs (of the 28 aqueous extracts tested) to exhibit significant anti- platelet activity in vitro. Nettle and alfalfa were the other two. Chamomile inhibited platelet aggregation induced by ADP (60%) and collagen (84%), as well as whole blood aggregation induced by collagen (30%) compared with controls (p < 0.05). Although none of the three herbs were able to inhibit arachidonic acid or thrombin-induced platelet aggregation, chamomile and alfalfa strongly inhibited thromboxane B2 synthesis induced by either ADP or collagen. However, unlike alfalfa and nettle, chamomile did not significantly in- crease cGMP levels in platelets.

Apigenin – chemopreventive potential. Chamomile is one of the richest natural sources of apigenin (840 mg/ 100 g in contrast to 9 mg/100 g present in peppermint), a flavone that is extracted from the ligules for commer- cial use. Apigenin has an effect on a number of cellular

Copyright © 2006 John Wiley & Sons, Ltd.

processes including cell cycle progression (Sato et al., 1994; Lepley et al., 1996; Lepley and Pelling, 1997; Reiners et al., 1999), cell signaling enzymes, pathways and gene expression (Kuo et al., 1994; Huang et al., 1996; Lin et al., 1997; Uda et al., 1997; Kanda et al., 1998), the regulation of cell membrane transport (Morita et al., 1990; Illek and Fischer, 1998; Lenne- Gouverneur et al., 1999; Niisato et al., 1999; Avallone et al., 2000), gap junctional intracellular communica- tion (Chaumontet et al., 1994; Chaumontet et al., 1997), cytokine production and the inflammatory response (Gerritsen et al., 1995; Smolinski and Pestka, 2003). Evidence supporting the potential mechanisms involved in these processes supports a potential role of chamo- mile in chemoprevention (as an inhibitor of cell prolif- eration and oncogene expression), on neuronal activity and as an antiinflammatory agent. In studies of cell cycle progression, flow-cytometric analyses showed that apigenin was able to arrest rat neuronal cells (Sato et al., 1994), mouse skin cells (Lepley et al., 1996), human HL-60 cells (Lepley et al., 1996) and human diploid fibroblasts (HDF) (Lepley and Pelling, 1997) in the G2/M phase in a dose- dependent and reversible (when apigenin was removed from the culture) fashion. Lepley and Pelling (1997) were also able to demonstrate an apigenin-induced arrest of HDF in the G0/G1 phase using cells syn- chronized in G0 and replated in medium containing 10–70 µM apigenin; at the lowest concentration, apigenin reduced the percentage of cells in the S phase by 20% compared with control cultures. Apigenin can inhibit selected enzymes involved in intracellular signaling cascades and suppress the expres- sion of proto-oncogenes, actions which suggest its potential as a potential anti-cancer agent. Apigenin is an effective mitogen-activated protein (MAP) kinase inhibitor (Kuo and Yang, 1995; Kanda et al., 1998). In mouse hepatoma cells apigenin was a more effective inducer of quinone reductase activity (50% increase at 20 µM) than catechin and epicatechin (0% increase at 0–100 µM) but not quercetin (100% increase at 13 µM) (Uda et al., 1997). Human cytochrome P450 3A4 was inhibited 50% (IC 50 ) with a commercially available ethanol extract of chamomile diluted to 1–2% of full strength (Budzinski et al., 2000). In a more recent experiment, Ganzera et al. (2006) found that crude chamomile essential oil (4.97 µg/mL), and its compo- nents cis-spiroether (6.13 µM), trans-spiroether (7.14 µM) and chamazulene (7.58 µM), were also potent inhibitors of the 3A4 isoform. At 10 µM apigenin was able to in- hibit protein kinase C activity (50%) in mouse fibroblast cells by competing with adenosine triphosphate (ATP) (Huang et al., 1996). It also reduced the level of 12- O-tetradecanoyl-phorbol-13-acetate (TPA)-stimulated phosphorylation of cellular proteins, and could suppress TPA-induced expression of the oncogenes C-JUN and C-FOS (Huang et al., 1996; Lin et al., 1997). Other stud- ies have shown that apigenin could inhibit tyrosine kinases (Kuo et al., 1994) and, in the case of prostate cancer cells, it could reduce hyperphosphorylation (Lee et al., 1998; Gupta et al., 2002), downregulate NF-kappa B/p65, AR protein expression and decrease both intra- cellular and secreted forms of PSA (Gupta et al., 2002). In estrogen-dependent MCF-7 cells, 10 µM apigenin inhibited estradiol (E2)-induced DNA synthesis (Wang and Kurzer, 1998) and, in a different strain of steroid

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D. L. MCKAY AND J. B. BLUMBERG

hormone receptor-positive breast carcinoma cells, acted as a weak progestin (Rosenberg et al., 1998). In a subsequent experiment, Rosenberg Zand et al. (2001) found that a 200 ng/mL ethanol extract of commerci- ally available chamomile gel capsules exhibited both weak estrogenic and progestational activity, but not androgenic activity in their tissue culture screening assay. The effects of apigenin on nuclear receptor levels were demonstrated by Seagart et al. (2000). Using human keratinocytes, apigenin potently inhibited vita- min D receptor (VDR) mRNA and protein expression without changing the half-life of VDR mRNA. Con- currently, retinoid X receptor (RXR) α was down- regulated, p21(WAFI) was upregulated and c-myc mRNA decreased dramatically. The antimutagenic activity of apigenin has been as- certained with the Salmonella typhimurium assay and in Chinese hamster ovary cells. Mutagenesis induced with 2-aminoanthracene, benzo[a]pyrene, 1-nitropyrene (1-NP) or 1,6-dinitropyrene (1,6-DNP) were effectively inhibited 43–62% in the presence of apigenin (Birt et al., 1986; Kuo et al., 1992). Kuo et al. (1992) also observed a significant and dose-dependent reduction in the frequency of sister chromatid exchanges (SCE). At 0–100 µM, apigenin did not prevent the in vitro production of photoproducts in salmon sperm DNA, suggesting that it is not effective in preventing DNA damage due to ultraviolet light (UVA/B) (Birt et al.,

1997).

The biological effects of many flavonoids are due to their interaction with the cellular plasma membrane (Lenne-Gouverneur et al., 1999). In cultured bovine adrenal chromaffin cells, apigenin had a moderate ef- fect on stimulating tyrosine uptake, whereas quercetin had no significant effect (Morita et al., 1990). Apigenin also had a stimulatory effect on a bumetanide-sensitive Na + /K + /2Cl cotransporter in a renal epithelial cell line (Niisato et al., 1999). Apigenin and quercetin both stimulated Cl currents in a dose-dependent manner in transepithelial experiments using Calu-3 cells (Illek and Fischer, 1998). In cultured rat cerebellar granule cells, apigenin reduced γ-aminobutyric acid (GABA)- activated Cl currents in a dose dependent manner (Avallone et al., 2000). In rat epithelial cells, 10–25 µM apigenin enhanced gap junction (GJ) intercellular com- munication and prevented the inhibition induced by a tumor promoter, whereas other flavonoids such as catechin (present in green and black tea) at 50 µM did not (Chaumontet et al., 1994; Chaumontet et al., 1997). In tumor cell lines, apigenin upregulated GJ function and dye transfer in tumors expressing GJ nearly 4-fold, but was inactive in a GJ-negative tumor cell line (Touraine et al., 1998).

Apigenin – antiinflammatory actions. The therapeutic potential for apigenin as an antiinflammatory agent was demonstrated in vitro with its ability to interfere with leukocyte adhesion and adhesion protein upregula- tion in human endothelial cells (Gerritsen et al., 1995). It also inhibited interleukin-1 (IL-1) α-induced pro- staglandin synthesis, tumor necrosis factor (TNF)- α-induced IL-6 and IL-8 production, and blocked adhesion of leukocytes to cytokine-treated endothelial cells. In murine macrophage cells, 3.7 and 37 µM apigenin significantly inhibited LPS-induced IL-6 pro-

Copyright © 2006 John Wiley & Sons, Ltd.

duction in a dose-dependent manner, but not TNF-α (Smolinski and Pestka, 2003). Other studies using apigenin in cell culture models have also shown that this flavonoid has inhibitory effects on adhesion molecule expression (Panes et al., 1996; Wolle et al., 1996), prostaglandin (PG) E2, cyclooxygenase (COX)- 2 and nitric oxide production (Liang et al., 1999). A different component of chamomile oil chamazulene, but not its precursor matricine, 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 nucleophilic granulocytes by 50%, whereas matricine had no effect up to the highest concentration tested (200 µM). Additionally, 2 µM chamazulene blocked the chemical peroxidation of arachidonic acid in a cell-free system, while 200 µM matricine exhibited a moderate, but non-significant, inhibition. In an experiment exam- ining histamine release from rat mast cells, another chamomile essential oil component, en-yne dicycloether, partly inhibited a protamine sulphate-provoked de- granulation at concentrations >100 µM, whereas neither chamzulene nor α-bisabolol had any distinct effects (Miller et al., 1996). The potential anti-allergenic activity of chamomile has been demonstrated in vitro in human basophils (Middleton and Drzewiecki, 1982). Quercetin and apigenin were the most effective inhibitors of antigen-induced histamine release from basophils among the 22 naturally occurring flavo- noids tested. At 50 µM, quercetin inhibited histamine release by 95.8% and apigenin by 89.4%; by com- parison, the inhibition activity exhibited by catechin was only 5.7%.

ANIMAL MODEL STUDIES

Antiinflammatory actions. A freeze-dried extract of chamomile given to Wistar albino rats suppressed both the inflammatory effect and leukocyte infiltration in- duced by a simultaneous injection of 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 M. recutita flowers for 11 days, scratching behavior induced by the compound 48/80 was sup- pressed in a dose-dependent manner (Kobayashi et al., 2003). In addition, both the ethyl acetate fraction of an ethanol extract and the ethanol extract of a hot water infusion of the German chamomile flower also showed strong inhibition towards 48/80-induced scratching. The inhibitory effects of these chamomile extracts were comparable to the effect elicited with 10 mg/kg of the anti-allergenic agent, oxatomide. In a later experiment, Kobayashi et al. (2005) determined that the antipruritic effects of the ethyl acetate extract, as well as chamomile essential oil, were dose-dependent. The ethyl acetate preparation (300 mg/kg) was also shown to enhance the effects of either antihistamic agent oxatomide or fexofenadine (10 mg/kg) with com- bined administration. In rats pretreated with apigenin (50 mg/kg, p.o.), the upregulation of TNFα-induced intercellular adhesion molecule-1 (ICAM-1) was effec- tively blocked 5 h after treatment with rTNF (Panes et al., 1996). The mechanism involved in this blocking action was suggested to be unrelated to free radical

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scavenging or leukocyte function. Pro-inflammatory cytokine production was inhibited in mice pretreated

those not treated with apigenin developed tumors. A second experiment showed that apigenin also decreased

with

50 mg/kg apigenin for 1 h then injected with stimul-

the incidence of DMBA-induced skin papillomas. The

ant

lipopolysaccharide (LPS) (Smolinski and Pestka,

papilloma incidence 26 weeks post-DMBA for mice

2003). Analysis of serum collected 90 min later showed

treated with 0, 5 and 20 µM apigenin was 93.3%, 58.0%,

lower levels of LPS-induced IL-6 (65%) and TNF-α

and 39.3%, respectively. A tendency to decrease

(76%) in apigenin-treated animals (n = 12) compared

the conversion of papillomas to carcinomas was also

with

those treated with LPS alone (n = 6). Apigenin

observed with apigenin treatment, although there were

also

demonstrated delayed type hypersensitivity in the

no significant differences between the three groups. In

mouse (Gerritsen et al., 1995) and potent antiinfl- ammatory activity in carrageenan-induced rat paw edema (Al-Hindawi et al., 1989; Gerritsen et al.,

a different study, the pretreatment of mouse epidermis with apigenin for 30 min prior to the application of 17 nM TPA inhibited the induction of ornithine decarboxylase

1995).

(ODC) activity by 6 h (Birt et al., 1986) and, in a dose

A lyophilized ethanol extract of dried chamomile administered to Wistar rats (n = 10), at 1.6 g fresh plant/ kg bw (equivalent to 1% of the estimated lethal dose), inhibited paw edema by 41.1% compared with control

response test, 30–90% inhibition of TPA-induced ODC was observed in mice pretreated with 12.5–100 µM apigenin. ODC activity induced with 0.45 J/cm 2 ultra- violet A and B (UVA/B) light was inhibited 25–45%

rats

(n = 35) receiving only carrageenan (Al-Hindawi

in mice treated with 5 µM apigenin for 12 h prior to and

et al., 1989). By comparison, the edema in rats treated with 100 mg/kg acetylsalicylic acid was inhibited by 32.4%. In Swiss mice, the topical application of a chamo-

1 h following UVA/B exposure (Birt et al., 1997). Mouse skin carcinogenesis induced by exposure to 40 J/cm 2 UVB alone over 11 weeks was also attenuated by

mile

extract to the inner surface of the ear reduced

treatment with 10 µM apigenin. Cancer incidence was

edema induced by the application of a 2.5% emulsion of croton oil (Tubaro et al., 1984). In this experiment,

also reduced (52%), and a significant increase in tumor- free survival was observed in apigenin-treated animals.

an ethanol extract of chamomile containing 0.05 mg/

DMSO and DMSO/acetone were found to be appro-

mL

α-bisabolol, 0.45 mg/mL bisabolol oxides, 0.4 mg/

priate and effective vehicles for topical delivery of

mL

apigenin and its glucosides, 0.8 mg/mL en in

apigenin in mouse skin (Li and Birt, 1996; Li et al.,

dicycloethers, and 0.02 mg/mL azulenes was applied to

1996); these beneficial effects against skin cancer

test

animals in doses equivalent to 0.75, 0.25 and 0.08 mg

were not achieved via systemic circulation (Li et al.,

of dried flowers per animal (n = 40/group). Compared

1996). Injections of apigenin in mice bearing tumors

with

control animals (n = 104), mice treated with 0.25 mg

from a mixture of 90% wild type and 10% herpes

of chamomile extract had an 8.5% reduction in edema

simplex virus-thymidine kinase gene-modified MCA38

and

those treated with 0.75 mg had a 23.4% reduction.

adenocarcinoma cells did have an antitumor effect

No

significant changes were observed in mice treated

(Touraine et al., 1998) with a remission in apigenin-

with

the lowest dose used (0.08 mg). The 0.75 mg dose

treated animals of 60–70% compared with 30% in

of chamomile extract induced a reduction similar to

mice treated with the antiviral agent ganciclovir

that

obtained with 0.45 mg benzydamine (26.6%), a non-

alone.

steroidal antiinflammatory agent used as a reference; however, neither treatment reached the level of reduc-

tion attained with 0.15 mg hydrocortisone (56.4%).

Della Loggia et al. (1990) found that topical treatment

with an extract of fresh chamomile 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 edema. The benzydamine, fresh chamomile extract and dried chamo- mile 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 in this model by 31.6%,

31.6% and 23.7%, respectively, compared with the control group (n = 41); however, chamomile essential

oil containing 55.6 mg/100 g bisabolol, 4.7 mg/100 g

chamazulene, but no matricine or apigenin at a dose equivalent to 30 µg essential oil was ineffective (6.6% inhibition; n = 25).

Tumorigenesis. The topical application of chamomile

was also tested for its effectiveness on skin tumori- genesis in mice. Tumorigenesis initiated by 7,12- dimethylbenz(a)anthracene (DMBA) and promoted by

TPA in SENCAR mice was attenuated by the applica-

tion of 20 µM apigenin (Wei et al., 1990). In this experi-

ment, no carcinomas occurred 33 weeks after DMBA initiation in apigenin-treated animals, while 48% of

Copyright © 2006 John Wiley & Sons, Ltd.

Antigenotoxic actions. Chamomile essential oil attenu- ated the genotoxic effects of the mutagenic agents daunorubicin and methyl methane sulfonate (MMS) in mouse bone marrow (Hernandez-Ceruelos et al., 2002). Mice injected with 5, 50 or 500 mg/kg chamomile oil plus 10 mg/kg daunorubicin (n = 5/group) had 25.8%, 75.6% and 75.6% fewer sister chromatid exchanges (SCE) than mice treated with daunorubicin alone. A similar effect was found in mice treated with 250, 500 or 1000 mg/kg chamomile oil plus 25 mg/kg MMS with inhibition of SCE at 24.8%, 45.9% and 62.5%, respec- tively, when compared with the control group treated with MMS alone. No changes in either cellular prolif- eration kinetics or mitotic indices were observed in the chamomile oil/MMS groups; however, a lack of cytotoxic protection against daunorubicin with chamomile oil at the two highest doses was reported.

Hypocholesterolemic effects. An aqueous extract of chamomile was reported to have an effect on serum cholesterol levels in hyperlipidemic Wistar rats (Al- Jubouri et al., 1990). After 10 days, the hyperlipidemic mice treated orally with a 6% aqueous extract of chamo- mile (4 mg/kg) had significantly reduced serum choles- terol compared with control rats; no changes were observed in serum triglyceride levels. The chamomile extract had no effect on the control rats with respect to either cholesterol or triglycerides.

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D. L. MCKAY AND J. B. BLUMBERG

Cardiac effects. In spontaneously beating isolated rat atria, exposure to apigenin had a positive chronotropic effect (Lorenzo et al., 1996). At 0.01–30 µM apigenin increased the atrial rate in a dose-dependent manner and reduced the uptake of radiolabeled noradrenaline.

Gastrointestinal effects. The antispasmodic effects of different chamomile preparations have been examined

in isolated guinea-pig ileum. According to Achterrath-

Tuckermann et al. (1980), compounds contained in both aqueous and oil extracts of the plant are effective antispasmodics in isolated guinea-pig ileum. Compared with papaverine, a smooth muscle relaxing drug, α- bisabolol was 91% as effective on spasms induced with barium chloride, while bisabolol oxides A and

B were 46–50% as effective. Among the flavonoids

tested, apigenin was 3.3 times more potent than papaverine, followed by quercetin, which was 72% as active, patuletin (68%) and luteolin (44%). Using the same model, Forster et al. (1980) demonstrated the effectiveness of an ethanol extract of chamomile on

spasms induced by acetylcholine and histamine. At doses

of 2.5 and 10 mL/L (of a 31% w/w solution), the chamo-

mile extract shifted the dose response curves of both acetylcholine and histamine to the right, reflecting an increase in their median effective dose, when compared with an ethanol control solution. Atropine (7 µg/L) similarly shifted the dose response curves but, unlike chamomile, this antispasmodic drug was unable to de- crease the maximal contraction in response to either acetylcholine or histamine. In rats, both apigenin and α-bisabolol inhibited the development of gastric ulcers induced by indomethacin, stress and alcohol (Szelenyi et al., 1979). In this study, α-bisabolol was also shown to reduce healing times in ulcers induced by either chemical stress or heat coagu- lation. Apigenin, at 12.5–50 mg/kg administered i.p. reduced both small and large intestinal transit time in mice with castor oil-induced diarrhea (Di Carlo et al., 1993). In contrast, catechin, the principal flavonoid in green tea, administered at doses up to 200 mg/kg, had no effect in this experiment.

Hepatic effects. Like green and black teas, chamomile tea can modulate the activity of hepatic cytochrome P450. Maliakal and Wanwimolruk (2001) provided Wistar rats (n = 5) free access to a 2% chamomile tea solution for 4 weeks and found the CYP1A2 isoform activity was 39% lower than a control group given water alone. In a study by Babenko and Shakhova (2006), a prepa- ration containing the chamomile flavonoids apigenin, luteolin, apigenin-7-glucoside, luteolin-7-glucoside, isor- hamnetin and quercetin reduced ceramide levels in the liver of older rats. Ceramide accumulates in several tissues and cells during the aging process, and regulates the biochemical and genetic events that occur with time. The administration of chamomile flavonoids (160 mg/ kg/day) for 7 days reduced the liver ceramide mass and sphingomyelinase activity of older rats (age 27–28 months) down to the levels found in adult rats (24 months).

Central nervous system effects. Della Loggia et al. (1982) employed a lyophilized aqueous extract of chamomile prepared with 50 g flowers infused for 5 min with 1 L

Copyright © 2006 John Wiley & Sons, Ltd.

boiling water to study basal motility, exploratory and motor activities of Swiss-NOS mice. Long-term motil- ity was reduced 57.1% within 10 min of treatment with 360 mg/kg chamomile i.p. (n = 15) and reached a maximum inhibition of 92.1–97.5%, compared with controls (n = 15) 1.5–2.5 h later; motor coordination was not affected. Short-term motor activity was reduced 90% with a dose of 180 mg/kg i.p. (n = 24). Locomotor activity was reduced by 46.0% and 56.5% and the number of head-dippings reduced by 34.4% and 39.4% with doses of 180 and 320 mg/kg, respectively. Chamo- mile administered at 160 and 320 mg/kg i.p. (n = 16/ group) potentiated hexobarbital-induced sleep in mice by 37.1% and 62.7%, respectively, compared with controls given 100 mg/kg of the barbituate alone. In mice, Viola et al. (1995) tested a purified fraction of an aqueous chamomile extract containing apigenin admin- istered i.p. to examine its effect on anxiolytic, sedative, locomotor, myorelaxant and anticonvulsive activities. At 3 mg/kg, a dose similar to those used for benzodia- zepines (BDZ), apigenin significantly increased the percentage of entries and time spent in the open arms of an elevated plus maze, behaviors indicative of an anxiolytic effect. Doses up to 10 mg/kg produced no changes in spontaneous ambulatory locomotor activity; at 30 and 100 kg/mL, there was a 26% and 46% reduction in activity, respectively, and a moderate decrease in the head-dipping behaviors indicating a mild sedative effect. At 100 mg/kg apigenin had no myorelaxant effect, in contrast to 3 mg/kg of the BDZ diazepam. In mice treated with doses up to 80 mg/kg apigenin, Viola et al. (1995) found no significant anticonvulsant activity after challenge with 50–80 mg/kg of the seizure- inducing pentylenetetrazole (PTZ); however, at 20, 40 and 80 mg/kg apigenin increased the onset time of con- vulsions by approximately 2-fold compared with mice given PTZ alone. Testing doses much lower than em- ployed by Viola et al. (1995), Avallone et al. (2000) found that apigenin did not have a significant anxiolytic effect at 0.5–10 mg/kg. At 1.0 mg/kg the number of entries and time spent in the open arms of an elevated plus maze were higher than the control group, but did not reach statistical significance. Similarly, Avallone et al. (2000) reported that apigenin had no myorelaxant effect up to 50 mg/kg and no effect on picrotoxin- (6 and 8 mg/kg) induced convulsions at 25 and 50 mg/kg, but did significantly reduce the time of latency in the onset of convulsions. Open field tests showed signifi- cant reductions in locomotor activities compared with controls at apigenin doses of 25 and 50 mg/kg, but not at 12.5 mg/kg, indicating a sedative effect at the higher doses, similar to Viola et al. (1995). The lack of effect with the addition of a BDZ agonist to apigenin-treated animals suggests that the sedative properties of apigenin may not be due to a direct effect on BDZ receptors, but to other neurotransmission systems. Salgueiro et al. (1997) observed that 10 mg/kg apigenin administered to Wistar rats either pre- or post- training had no effect on training or test session per- formance of inhibitory avoidance, active avoidance or habituation to an open field, unlike diazepam which had an amnestic effect on animals subjected to the same tests. Also in contrast to diazepam, apigenin had no effect on the tail-flick test, indicating the lack of an analgesic effect. These results also suggest that apigenin

Phytother. Res. 20, 519–530 (2006) DOI: 10.1002/ptr

Significantly reduced crying time compared with placebo. 85% reduction in treatment group vs 49% in placebo group Decreased heart rate and ratings of sadness and depression after drinking tea Diarrhea ended sooner in treatment group (85%) than placebo (58%). Duration was also attenuated Significantly higher colic improvement score compared with placebo. Eliminated colic in 57% of treatment group vs 26% in placebo group Significant decrease in mean brachial artery pressure from baseline

Outcome

Duration

time

time

wk

wk

d

1
3

1

1
1

Standardized herbal mixture (including 71.1 mg/kg/d chamomile) or placebo

Chamomile/apple pectin preparation

serving chamomile tea or placebo

150 mL herbal mixture including

chamomile or placebo

cups chamomile tea

Table 1. Summary of human studies examining the effects of orally ingested chamomile (Matricaria recutita)

(hot water)

or placebo

Dose

2

1

heart disease patients hospitalized

healthy breastfed infants (21–60

acute, non-complicated diarrhea

children (0.5–5.5 years) with

healthy infants (2–8 weeks)

for cardiac catheterization

Young Japanese males

Subjects

weeks)

88

68

79

12

Delivery method

Beverage

Beverage

Beverage

Beverage

Liquid

De la Motte et al., 1997

Nakamura et al., 2002

Weizman et al., 1993

Savino et al., 2005

Gould et al., 1973

Reference

BIOACTIVITY OF CHAMOMILE (MATRICARIA RECUTITA L.)

affects BDZ receptors differently than classical BDZ receptor ligands such as diazepam. In a study of ovarectomized rats, Yamada et al. (1996) found that inhaling the vapor of chamomile oil reduced a stress-induced increase in plasma adrenocorticotropic hormone (ACTH) levels. Diazepam, co-administered with the chamomile oil vapor, further reduced ACTH levels, while flumazenile, a BDZ antagonist blocked the effect of chamomile oil vapor on ACTH. Accord- ing 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 it is 10. Compounds, other than apigenin, present in extracts of chamomile can also bind BDZ and GABA receptors in the brain and are thought to be responsible for some of the sedative effect; however, many of these com- pounds are as yet unidentified (Avallone et al., 1996).

HUMAN STUDIES AND POTENTIAL HEALTH/ THERAPEUTIC APPLICATIONS

In Germany, the chamomile flower is licensed as a standard medicinal tea (infusion) for oral ingestion, for topical application as a rinse or gargle, cream or oint- ment, as a vapor inhalant, and as an additive for sitz or vapor baths. The German E Commission has approved chamomile for internal use to treat GI spasms and inflammatory diseases of the GI tract, and external use for inflammation of the skin, mucous membranes and ano-genital area, bacterial skin diseases (including those of the oral cavity and gums) and respiratory tract inflammation (Blumenthal et al., 1998). The list of the purported benefits and uses of chamomile as a folk remedy or as a complementary and alternative medicine (CAM) therapy include: anodyne, antiallergy, antiinflammatory, anxiolytic, antiseptic, carminative, dermatitis, diuretic, poultice, sedative, spasmolytic, tonic and vulnerary. Studies providing evidence to either support or refute the applicability of chamomile as a treatment for many of these conditions in humans is quite limited (Table 1).

Gastrointestinal effects. No clinical trials have exam- ined the gastrointestinal effects of chamomile alone, although three trials have examined its efficacy in com- bination with other components. Weizman et al. (1993) tested the effects of a powdered herbal tea prepara- tion containing extracts of M. chamomilla, vervain (Ver- bena officinalis), licorice (Glycyrrhiza glabra), fennel (Foeniculum vulgare) and balm-mint (Melissa officinalis) as a treatment for infantile colic. In this randomized, double-blind, placebo-controlled trial, 68 healthy term infants (age 2–8 weeks) with colic were given either 150 mL of the herbal tea preparation or a placebo bev- erage containing no herbs for a period of 1 week. For inclusion in the study, colic was defined as unexplained irritability, agitation, fussiness or crying lasting more than 3 h/day, for at least 3 days/week, and continuing for 3 weeks. Exclusion criteria included prematurity, weight gain of <150 g/week, acute or chronic illness, and drug therapy. Parents were instructed to adminis- ter the assigned beverage with each colic episode, but no more than 3 times daily, and to rate any improve- ments observed in their own child. After 7 days, the

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525

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D. L. MCKAY AND J. B. BLUMBERG

colic improvement score was significantly higher in the herbal tea group than in the placebo group (1.7 ± 0.3 vs 0.7 ± 0.5). Among the 33 infants given the herbal tea, colic was eliminated in 19 (57%) compared with 9 of the 35 infants (26%) in the placebo group, although no significant differences with regard to the number of nighttime awakenings were observed. In a randomized, double-blind, placebo-controlled trial, Savino et al. (2005) determined that a standardized herbal prepara- tion containing chamomile (71.1 mg/kg/day), fennel (65.7 mg/kg/day) and balm-mint (38.8 mg/kg/day) ad- ministered daily for 1 week reduced crying time among breastfed colicky infants (n = 41) compared with a placebo (n = 47, p < 0.005). Significant results were attained within 4 days of treatment, and no side effects were observed with this dosage. De la Motte et al. (1997) examined the effects of a chamomile extract and apple pectin preparation in 79 children (age 0.5–5.5 y) with acute, non-complicated diarrhea. In addition to the usual prescription of rehydration and a realimentation diet, the children received either the chamomile/pectin preparation (n = 39) or a placebo (n = 40) for 3 days. The diarrhea ended sooner for more children in the group treated with chamomile and pectin (85%), than in the placebo group (58%). The duration of the diarrhea was also significantly attenuated with the chamomile and pectin treatment by 5.2 h. The effects of a chamomile-containing oral rinse on oral mucositis or stomatitis induced by cancer thera- pies have been examined in one case series and one clinical trial. Carl and Emrich (1991) observed both the prophylactic (n = 66) and therapeutic (n = 32) effects of a chamomile mouthwash in a case series of 98 head and neck cancer patients treated with either radiation or systemic chemotherapy. In the prophylactic group, one of the 20 radiation therapy patients developed grade 3 mucositis in the final week of treatment, while 13 developed intermediate-grade and 6 developed low-grade mucositis. Only 10 of the 46 chemotherapy patients in the prophylactic group developed clini- cally significant mucositis. Of the 32 patients in the therapeutic treatment group (16 radiation, 16 chemo- therapy), all experienced immediate relief from mouth discomfort, and within 1 week nearly all patients had no clinical signs of mucositis. In a double-blind, placebo-controlled clinical trial of 164 chemotherapy patients on their first cycle of 5-fluorouracil (5-FU), in bolus form, Fidler et al. (1996) tested the efficacy of a chamomile mouthwash administered 3 times daily for 2 weeks. In addition, all patients received oral cryotherapy for 30 min with each dose of 5-FU. No differences in stomatitis between the chamomile and placebo mouth- wash groups were detected at the end of the study period. In a review of commonly used medicinal herbs, however, O’Hara et al. (1998) contend that 2 weeks was too short a period to detect discernible differences since mucositis, which is largely a result of immuno- supression, takes weeks to develop.

Topical effects. Several studies have tested the effects of topically applied chamomile preparations on inflam- mation of the skin associated with atopic dermatitis or eczema, radiation therapy and erythema. Aertgeerts et al. (1985) compared the effects of a chamomile- containing cream versus either 0.25% hydrocortisone,

Copyright © 2006 John Wiley & Sons, Ltd.

0.75% fluocortin butyl ester (a glucocorticoid) or 5% bufexamac (a non-steroidal antiinflammatory) in 161 patients presenting with eczema on their hands, fore- arms and lower legs who had been treated initially with 0.1% difluocortolone. During the 3–4 week mainte- nance period, the chamomile cream was reported to be

as effective as 0.25% hydrocortisone and more effective than both the glucocorticoid and non-steroidal antiflam- matory agents. In a 2 week trial, Patzelt-Wenczler and Ponce-Poschl (2000) compared the effects of chamo- mile cream to 0.5% hydrocortisone and a placebo (the vehicle cream) in patients with a medium degree of atopic eczema. The chamomile-treated group showed approximately 50% improvement in pruritis, erythema and desquamation. While the degree of improvement in the hydrocortisone group was mild in comparison, the difference between the effects of the placebo and the chamomile cream were only marginal, making the study inconclusive. Hempel (1999) reported that 1% hydrocortisone was more effective than a chamomile ointment containing 1% CO 2 extract (with no chama- zulene and presumably more matricine) in a study of

80 patients with subacute eczema who were pretreated

with steroids. The difference in the global clinical im- pression rating between the two treatments was, how- ever, smaller in patients pretreated with potent steroids than in those treated with weak steroids. Anderson

et al. (2000) found that massage with blended aro- matherapeutic essential oils, some containing chamo- mile, significantly improved night time disturbance scores and day time irritation scores in 8 children (age 3–7 years) with atopic eczema which was non-respon- sive to conventional therapy. Similar differences were also observed in the control group (n = 8) receiving massage without the essential oils, however, no signifi- cant between-group differences were detected. Chamomile cream proved less effective than 1% hydrocortisone or witch hazel 24 h after inflammation was induced by UV radiation (n = 24) in a study by Korting et al. (1993) where subjects served as their own control. In the same study, erythema induced with cellophane tape stripping of the skin (n = 24) was sig- nificantly reduced with hydrocortisone, but was only less pronounced following chamomile treatment. In a single blind, randomized, placebo-controlled trial of

50 women receiving radiation therapy for breast can-

cer, Maiche et al. (1991) tested the effects of a topical chamomile cream versus an almond oil placebo on

the degree of radiation skin reaction. Each patient served as their own control and both treatments were applied twice daily, once 30 min prior to irradia- tion and again before bed. No significant differences were observed between the two treatments; however, radiation-induced skin reactions in the chamomile- treated areas were less frequent and appeared later. The incidence of severe skin reactions due to radiation in both groups was <10%. Topically applied chamomile preparations have also been examined for their effectiveness in wound care. In a double-blind study of 14 patients with weeping wounds following dermabrasion for tattoo removal, a compress containing chamomile extract significantly decreased the wound area and increased drying of the wound (Glowania et al., 1987). Patients with chronic wounds (n = 5) given a combination of chamomile and lavender essential oils prepared in a grapeseed oil base

Phytother. Res. 20, 519–530 (2006) DOI: 10.1002/ptr

BIOACTIVITY OF CHAMOMILE (MATRICARIA RECUTITA L.)

527

did better than those receiving conventional therapy (n = 3) in a study by Hartman and Coetzee (2002). However, a chamomile-extract spray was not effective in relieving post-operative sore throat and hoarseness in a randomized double-blind, placebo-controlled study of 161 elective surgical patients by Kyokong et al. (2002). Among the 80 patients who received 111 mg of chamomile extract spray before intubation, 42 (52.5%) experienced no post-operative sore throat, compared with 41 (50.6%) of the 81 patients who received a saline spray. No significant differences were observed 24 h after the operation in either group.

Inhalation treatments. A hospital-based observational study of 8058 women who gave birth between 1990 and 1998 found that chamomile oil administered via the skin and/or inhalation was effective in alleviating pain during labor and delivery (Burns et al., 2000), although no specific endpoint measurements or statistics regard- ing chamomile were reported. In a study examining the effects of inhaling essential oils on electroencepha- logram (EEG) activity and sensory evaluation in 13 healthy females by Masago et al. (2000), chamomile significantly reduced alpha 1 activity, measured at the parietal and posterior temporal lobes and contributed to reports of a ‘comfortable feeling’. Roberts and Williams (1992) reported on 22 subjects who were asked to visualize positive and negative phrases following in- halation of either chamomile oil or a placebo (crushed green peppers) on two separate occasions. The chamo- mile oil did not affect vividness ratings, but did signifi- cantly increase the time taken for subjects to visualize both positive and negative phrases (latency). The mean response time increased from 3.2 to 3.6 s for the positive images, and from 3.1 to 3.6 s for the negative images. Negative mood ratings following the presenta- tion of negative images were less extreme with chamo- mile exposure compared with placebo (3.0 vs. 3.5 s respectively), and overall mood ratings were shifted in a positive direction. The frequency of judgements was similarly affected, i.e. subjects tended to think more positive than negative images were presented following exposure to chamomile.

Autonomic nervous system effects. Clinical trials on the sedative and anxiolytic properties of chamomile have not been conducted, although the effects of chamomile tea on autonomic nervous system parameters including heart rate, peripheral skin temperature, EEG and mood were examined in young Japanese males. Nakamura et al. (2002) observed a greater heart rate decrease and skin temperature increase after 45 min of ‘calculation work’ when subjects consumed chamomile tea versus a control beverage of hot water. ‘Sadness and depres- sion’, calculated from EEG data using the emotion spec- tral analysis (ESA-16) system, also decreased more after drinking chamomile tea, however, relaxation scores increased after drinking either beverage.

Hemodynamic effects. The hemodynamic effects of chamomile tea were examined in an open study of 12 heart disease patients hospitalized for cardiac catheteri- zation. Gould et al. (1973) observed that patients had a small but significant increase in mean brachial artery pressure (91 to 98 mmHg) 30 min after drinking two cups of chamomile tea (prepared as 2 tea bags in 6 oz

Copyright © 2006 John Wiley & Sons, Ltd.

water). No other significant changes in cardiac function were observed, although 10 of the 12 patients fell into a deep sleep within 10 min of consuming the tea. Epidemiological studies have reported the intake of flavonoids, particularly those present in chamomile (apigenin, quercetin and luteolin), is inversely associ- ated with heart disease risk (Hertog et al., 1993; Hertog et al., 1995; Knekt et al., 1996). However, a 7 day inter- vention study of 18 healthy men and women (mean age 25 ± 8 years) examining the effects of a daily dietary supplement providing 377 ± 10 µmol quercetin (from onions) and 84 ± 6 mg apigenin (from parsley) on plate- let aggregation and other hemostatic variables in vivo found no significant changes on collagen- or ADP- induced platelet aggregation, thromboxane B 2 produc- tion, platelet number, factor VII, plasminogen, PAI-1 activity or fibrinogen concentrations (Janssen et al.,

1998).

ADVERSE REACTIONS/TOXICITY

Severe allergic reactions to chamomile have been re- ported (Subiza et al., 1989; Reider et al., 2000), particu- larly among those who also have allergies to other plants in the daisy family (Asteraceae or Compositae) includ- ing mugwort (Artemisia vulgaris) (De la Torre Morin et al., 2001) and ragweed (Ambrosia trifida) (Subiza et al., 1989). Both oral and topical uses have been re- ported to cause contact dermatitis (Pereira et al., 1997; Rodriguez-Serna et al., 1998; Rycroft, 2003), although the risk of elicitation with Compositae-containing prod- ucts in sensitive individuals is unknown (Paulsen, 2002). Angioedema associated with contact urticaria (Foti et al., 2000) and allergic conjunctivitis (Subiza et al., 1990) has also been reported in patients who applied chamomile tea, either as a compress or rinse, to their eyes. Potential drug interactions with chamomile have been suggested, however, all are based on theoretical postu- lates rather than empirical evidence. Coumarin, a con- stituent of chamomile, may potentiate the effects of warfarin therapy (Miller, 1998; Heck et al., 2000) by acting as a vitamin K antagonist and interfering with the blood coagulation processes. Similarly, coumarin may provide additive blood thinning effects to the antiplatelet or hypoprothrombinemic actions of aspi- rin, other non-steroidal antiinflammatory drugs, and/or acetaminophen when used concomitantly (Abebe, 2002). Due to its mild sedative effect, chamomile also has the potential to increase the CNS depressant effects of other sedative drugs such as opioid analgesics, BDZ or alco- hol and, therefore, a contraindication has been sug- gested in conjunction with these agents (O’Hara et al., 1998; Abebe, 2002; Larzelere and Wiseman, 2002).

Acknowledgements

Research support was provided by the U.S. Department of Agricul- ture (USDA) Agricultural Research Service under Cooperative Agreement No. 58-1950-001 and a grant from the Hain Celestial Group (Boulder, CO). The contents of this publication do not neces- sarily reflect the views or policies of the USDA nor does mention of trade names, commercial products, or organizations imply endorse- ment by the U.S. Government.

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