Anti-inflammatory activity

In research conducted in the 1950s and 1960s, butcher’s broom extract demonstrated activity against experimental paw inflammation and peritonitis in vivo.⁸

Saponin constituents isolated from butcher’s broom displayed anti-inflammatory activity on rat paw oedema, but did not influence capillary fragility. A strong vasoconstrictor activity was observed on isolated blood vessels and the ruscogenins also decreased capillary permeability in a rabbit model.⁹ However, the ruscogenins failed to inhibit hyaluronidase activity in vitro, but did exhibit a remarkable anti-elastase activity.¹⁰ An in vivo study in mice found that ruscogenin significantly suppressed zymosin A-evoked leukocyte migration, possibly through an anti-adhesive activity via inhibition of the NF-kappaB pathway.¹¹

Venotonic activity

In an experimental microcirculation model, butcher’s broom extract caused constriction in venules, but not arterioles, after intravenous administration.¹² The inhibitory effect of butcher’s broom extract on histamine-induced microvascular permeability was attributed to the blocking of calcium and a selective activation of alpha1-adrenoceptors (and to a lesser extent alpha2-receptors).^12–14 Butcher’s broom extract potentiated the activity of norepinephrine (noradrenaline) released at nerve endings.¹⁵ The vasoconstriction is independent of the endothelium and, as indicated above, is mediated by the activation of smooth muscle adrenergic receptors, but not by endothelin receptors.¹⁶ This adrenergic action of butcher’s broom extract enhances venous return.¹⁷

The venoconstriction induced by butcher’s broom in isolated vessels was increased by heat.^12,18 This effect of temperature on the response to butcher’s broom resembled that noted during partial alpha1-adrenergic activation.¹⁹ A venotonic effect was also observed in diabetic animals, and treatment with butcher’s broom extract combination reversed an experimentally impaired venoarteriolar reflex (which is a hallmark of diabetic microangiopathy).²⁰

Studies utilising isolated human veins indicated that butcher’s broom extract caused dose-dependent contractions in leg veins from patients with primary varicosity. Varicose tributaries were more sensitive to the contractile effects of butcher’s broom extract than segments of the greater saphenous vein removed from the same patient. Contractions following butcher’s broom exposure were independent of the endothelium and mediated by the activation of adrenergic receptors on the smooth muscle, but not endothelin-A.²¹

Butcher’s broom extract increased the cyclic AMP concentration in isolated human varicose veins, but did not affect cyclic GMP levels. In the presence of the extract, the ratios of 6-ketoprostaglandin-F_1a to thromboxane B₂ in varicose veins were rendered identical to normal vein tissue. (Segments of vein were obtained from patients who had undergone surgery.)²² Contractions initiated by butcher’s broom extract were enhanced following chronic exposure to progesterone, an effect that could be reversed by oestrogen. These contractions were mediated by an adrenergic and a non-adrenergic component. The adrenergic component was enhanced by progesterone and decreased by oestrogen.²³

A venoconstrictive activity of a butcher’s broom cream under orthostatic conditions was demonstrated by ultrasonography in a randomised, double blind study involving 18 healthy volunteers. Within 2.5 h of applying a quantity of butcher’s broom cream containing 64 to 96 mg of extract, the diameter of the femoral vein decreased by an average of 1.25 mm, compared with a diameter increase of 0.5 mm for the placebo cream (p<0.05).²⁴

As noted earlier, the mechanism of action of the combination of butcher’s broom extract and hesperidin methylchalcone in the treatment of venous diseases is thought to involve an increase in venous tone (by butcher’s broom extract) and protection of capillary integrity (by hesperidin methylchalcone). In a double blind study involving 20 healthy volunteers, the efficacy of the individual agents, their combination and a placebo were assessed. Butcher’s broom decreased venous capacity (p<0.01), reduced the blood pool in the lower leg under orthostatic conditions and decreased tissue volume in the foot and ankle (p<0.01). Hesperidin methylchalcone lowered the capillary filtration rate (p<0.01) and increased the blood pool (due to dehydration of the lower leg tissue). Blood volume after use of the combination was between the values for butcher’s broom and hesperidin methylchalcone alone, and effects on other parameters corresponded to those obtained for the individual substances.²⁵ Some of the 20 volunteers administered the butcher’s broom extract combination showed a significantly reduced venous capacity, whereas others developed an increase in venous storage ability.

Haemorheological and haemostasis parameters

The influence of combined treatment with butcher’s broom extract (450 mg/day containing 11.16 mg ruscogenin) and hesperidin methylchalcone (450 mg/day) on fibrinolytic activity of the vein wall was investigated ex vivo in patients with venous insufficiency.²⁶ Patients received treatment for 14 days in a double blind, placebo-controlled design: 10 were given active treatment and 10 were given placebo. The fibrinolytic activity of the intima of the greater saphenous vein was significantly increased in the active group (p<0.01). Activity in the adventitia layer also showed a significant increase after an incubation time of 60 minutes (p<0.05). These results suggest that the combination might reduce the risk of venous thrombosis in patients with varicose veins.

The effect of an extract of butcher’s broom on haemorheological parameters was also investigated under double blind, placebo-controlled conditions.²⁷ Forty-five participants took part in the clinical trial. There were 20 volunteers who acted as a normal, untreated control group, 13 patients with venous insufficiency who received oral doses of butcher’s broom extract (amount not specified) and another 12 patients who were given a placebo. Venous blood samples were collected before and after 30 days of treatment, each time before and after 10 minutes of venous stasis induced by a hyperpressure of 10 mmHg. Results demonstrated that butcher’s broom treatment was accompanied by a significant improvement in several rheological parameters under these conditions of venous stasis, including a decrease in plasma viscosity (p<0.01), a reduction in red cell deformability (p<0.001), a reduction in red cell aggregation (p<0.01), an increase in red cell aggregation time (p<0.01) and a reduction in the red cell disaggregation shear rate (p<0.05).

Anti-oedema activity

Oral administration of the butcher’s broom extract combination inhibited histamine-induced plasma exudation in hamsters with mild diabetes, without affecting blood glucose.²⁸ In addition to reducing experimentally induced capillary permeability, a combination of butcher’s broom extract, hesperidin methylchalcone, methylesculetin and ascorbic acid decreased experimentally induced hyperaemia, UV erythema and dextran or carrageenin local oedemas after either oral dosing or intraperitoneal injection.²⁹

The anti-oedematous effect of a combination containing butcher’s broom extract and hesperidin methylchalcone was tested in a randomised, double blind study using water plethysmography.³⁰ Forty patients with permanent oedema caused by chronic venous insufficiency were treated for 15 days orally with 450 mg butcher’s broom extract and 450 mg hesperidin methylchalcone (n=20) or placebo (n=20). After placebo, the oedema volume caused by orthostatic stress increased slightly (16.3 mL). However, in patients receiving active treatment the extent of the provoked venous oedema was significantly reduced (53.4 mL, p<0.01).

Other activity

Butcher’s broom extract inhibited the activation of endothelial cells induced by hypoxia (which mimics venous blood stasis), as evidenced by its effect on several parameters. Hesperidin methylchalcone was also able to inhibit the hypoxia-induced decrease in ATP content.³¹ Butcher’s broom extract combination and each of its components demonstrated a dose-dependent protection against hypoxia in endothelial cells in vitro. A synergistic effect between the components was observed.³²

Chronic venous insufficiency/varicose veins

More than 30 clinical trials over the past 30 years have demonstrated the benefit of the butcher’s broom extract combination in the management of chronic venous insufficiency. A recent meta-analysis included 20 placebo-controlled, randomised, double blind studies, five studies randomised against a comparison treatment and six single-arm surveillance studies.³⁷ (Several of the individual studies included in this meta-analysis are also reviewed below.) In total there was information from 10 246 patients. On a 4-point symptom severity scale, the butcher’s broom extract combination significantly reduced pain severity (0.44 ± 0.12), cramps (0.26 ± 0.08), heaviness (0.53 ± 0.11) and paraesthesia (0.29 ± 0.10) compared with placebo. There was also a significant reduction in venous capacity of 0.7 ± 0.19 mL/100 mL. Reductions in the severity of oedema and decreases in calf and ankle circumference did not achieve statistical significance. The authors concluded that their analysis was a strong and objective demonstration of the clinical efficacy of the butcher’s broom extract combination in chronic venous insufficiency.

A study published after this meta-analysis examined the activity of butcher’s broom extract alone. In a well-designed multicentre, double blind, randomised, placebo-controlled trial, 166 women suffering from chronic venous insufficiency received either butcher’s broom extract (72 to 75 mg/day of a 15 to 20:1 extract) or a placebo for 12 weeks.³⁸ Analysis of the 148 women who completed the trial revealed the herbal treatment significantly reduced leg volume, ankle and leg circumferences (all p<0.001) and subjective symptoms such as heavy tired legs (p=0.0022). Tolerability of both treatments was assessed as good to very good. The authors concluded that butcher’s broom was a safe and effective treatment for patients suffering chronic venous insufficiency.

Significant decreases in the venous diameter of deep veins (for example p=0.02 for the common femoral vein), a significant increase in flow parameters in these veins (p=0.05) and a non-significant decrease in the flow parameters in superficial veins was observed when 12 patients with primary varicose vein disease were treated with butcher’s broom extract combination and assessed in the standing position.³⁹ Measurements were taken using ultrasonography at baseline, 2 h after the intake of the combination on the first day of the study and at the end of the 7-day study period. (Most of the above venotonic outcomes occurred at the 2-h measurement.) In terms of the primary endpoint (venous diameter of the greater saphenous vein in the supine position after 7 treatment days), the study failed to demonstrate a significant effect. (Two hours was assumed to be the time of the peak concentration of the herbal treatment.)

During a 2-month treatment with butcher’s broom extract combination, a significant decrease or regression of clinical symptoms and a reduction in ankle circumference was observed.⁴⁰ This randomised, double blind, placebo-controlled trial involved 60 patients with uncomplicated chronic venous insufficiency. Clinical symptoms that were significantly reduced included heavy legs (p<0.01 at 30 and 60 days), tired legs (p<0.01 at 30 and 60 days), sensation of evening oedema (p<0.01 at 30 and 60 days, p<0.05 at 15 days), pain (p<0.01 at 30 and 60 days), pruritus (p<0.01 at 60 days) and cramp (p<0.05 at 30 and 60 days). The reduction in average ankle circumference for the treatment group compared with placebo was significant at the end of the trial (p<0.05). Global assessment of efficacy in the 30 patients in the butcher’s broom group showed an excellent result in 15 patients, good in 13 and satisfactory in two. Of the 30 patients receiving placebo, results were rated as excellent in four, good in 17, satisfactory in eight and insufficient in one. The tolerability of butcher’s broom extract combination was found to be similar to the placebo.

In a double blind, placebo-controlled, crossover trial, 40 patients with chronic venous disorders of the lower limbs evaluated butcher’s broom extract combination.⁴¹ The trial involved two treatment periods of 2 months, with an interim washout phase of 15 days. During active treatment, patients received capsules each day containing butcher’s broom extract (99 mg), hesperidin (450 mg) and ascorbic acid (300 mg). An overall tendency for improvement occurred that was more distinct during active treatment than during placebo treatment. Pruritus and plethysmographic parameters changed significantly with active treatment compared to placebo (p<0.01 or p<0.05, depending on the parameter). Tolerability was deemed to be excellent.

A significant improvement in venous tone (p<0.05) was measured after 2 weeks in a randomised, double blind, placebo-controlled trial involving 50 patients with varicose veins.⁴² Active treatment consisted of the butcher’s broom extract combination. To assess venous function, venous capacity, venous distensibility and expelled blood volume were measured by plethysmography. The authors suggested that, despite the improvements observed, the treatment period was probably too short to obtain a full therapeutic effect since not all parameters achieved statistical significance.

In patients with post-thrombotic syndrome, the median blood velocity in the femoral vein increased by 24% on the diseased side 2 h after the oral administration of butcher’s broom extract combination.⁴³ The ratio of the middle arterial inflow to venous outflow velocities showed a favourable decrease of 40% after medication (p<0.05). Measurements were conducted using ultrasound and the study was an open design, with results compared against baseline.

In a double blind, placebo-controlled trial involving 100 patients, butcher’s broom extract combination for a period of 1 to 3 months improved the following symptoms: heavy and painful legs, nocturnal cramps, oedema of the lower limbs.⁴⁴ The overall improvement was significant, as measured by global assessment (p<0.05).

A clinical trial comparing the therapeutic efficacy of butcher’s broom extract combination with micronised diosmin found the two treatments produced similar effects by the conclusion of the trial (2 months).⁴⁵ The onset of action for the butcher’s broom extract combination appeared to be earlier, since benefits were observed at 15 days.

In a randomised, multicentre study, butcher’s broom extract combination was more effective than hydroxyethyl rutoside after 90 days of treatment for chronic venous insufficiency.^46,47 More rapid and complete regression of symptoms occurred for the butcher’s broom group (p<0.01). A significant reduction in the affected limb size was observed in both groups, but only persisted for 90 days with the butcher’s broom extract combination (p<0.01).

Several other double blind, placebo-controlled or comparative trials published in the 1980s or early 1990s demonstrated significant clinical benefit for the butcher’s broom extract combination in the management of chronic venous insufficiency.^48–51 Similarly, a group of more recent open label trials from Mexico and South America have shown positive clinical outcomes in patients with chronic venous disorders.^52–55

The safety and efficacy of the butcher’s broom extract combination was evaluated in a multicentre surveillance study involving 886 cases.⁵⁶ After 30 and 60 days of treatment, the number of patients reporting mild and absent symptoms (pain, cramping, paraesthesia, heaviness) was substantially increased. Tolerance was rated as excellent for 85.4% of patients and side effects were reported in 5.6%. These were essentially minor digestive troubles or transient problems that did not necessitate the cessation of treatment except in three cases.

Topical and oral use during pregnancy

A significant reduction in the dilatation of the femoral vein (p<0.05) in pregnancy was observed in an uncontrolled study in 18 women that assessed the use of a butcher’s broom cream.⁵⁷ Similar beneficial results were also observed in an earlier study.⁵⁸

A therapeutic trial involving 20 pregnant women (21 to 24 weeks) found that the oral use of butcher’s broom extract combination improved symptoms of venous insufficiency and was innocuous to the fetus, as assessed by the usual clinical and ultrasonographic criteria of pregnancy surveillance, including umbilical artery flow and the state of the infant and placenta following birth.⁵⁹ In a much larger earlier study, the efficacy and tolerability of the butcher’s broom extract combination were assessed in an uncontrolled multicentre clinical trial.⁶⁰ The product was administered for 2 months to 214 women who presented with chronic venous insufficiency as a result of their pregnancy. Symptoms (including pain, cramps and paraesthesia) and signs (such as varices and oedema) were significantly improved compared to baseline at 30 and 60 days of treatment (no p values were provided). Tolerability was rated as excellent, with only nine patients reporting mild gastrointestinal or skin reactions. No information regarding pregnancy outcomes was provided.

Varicose ulcers

In a randomised, double blind trial, 23 patients with venous leg ulcers were treated over a period of 6 weeks with six capsules daily of the butcher’s broom extract combination (n=12) or a placebo (n=11).⁶¹ The treatment was in addition to basic ulcer therapy. In the placebo group five patients did not show any improvement or healing of the ulcer during the observation period, whereas in 11 of 12 patients treated with the active combination the ulcer area was markedly reduced (p<0.001). Parallel to the change in the ulcer size, venous haemodynamics were improved and venous drainage increased significantly (p<0.05). The results showed that this additional therapy favourably affects the healing rate of venous ulcers.

Lymphoedema

Fifty-seven patients with secondary lymphoedema of the upper limb after previous treatment for breast cancer participated in a double blind, placebo-controlled trial of butcher’s broom extract combination for a period of 3 months. All patients also underwent manual lymphatic drainage twice a week for at least 1 month. A significant reduction in the volume of arm oedema (12.9%, p<0.01) was observed in the treatment group compared with placebo. Decreased oedema was more marked in the forearm compared to the upper arm, where there was increased fat deposition.⁶²

Haemorrhoids

The efficacy of butcher’s broom extract combination for the treatment of acute attacks of haemorrhoids was investigated in an open label multicentre study.⁶³ One hundred and twenty-four patients were treated for 1 week. The treatment protocol was six capsules of the combination daily for the first 3 days, then four capsules daily. Each capsule contained 150 mg of butcher’s broom extract, 150 mg of hesperidin methylchalcone and 100 mg of ascorbic acid. Parameters studied were painful symptoms (discomfort, sensation of heaviness, burning, pruritus, tenesmus), accompanying symptoms (rectal bleeding, altered intestinal motility, abdominal pains), local signs (prolapse, congestive state, inflammation), overall severity score of symptoms and clinical efficacy and safety. Analysis of results demonstrated a statistically significant decrease in all scores between day 0 and day 7. The main results were: an average decrease of 4.9 points in painful symptoms (p=0.0001 compared against baseline), a decrease of 1.3 points in the assessment of accompanying symptoms (p=0.0001), a decrease of 3.6 points in local signs (p=0.0001) and a decrease of 9.8 points in the overall severity score of the symptoms (p=0.0001). Sixty-nine per cent of the patients rated the efficacy of the treatment as good or excellent (>75% for the physicians’ rating).

Premenstrual syndrome

In a randomised, double blind trial, 40 women suffering premenstrual syndrome received either butcher’s broom extract combination (n=20) or an identical placebo (n=20) for 90 days.⁶⁴ Mastalgia (p<0.02), menstrual pain (p<0.05) and mood (p<0.05) were significantly improved in the treatment group compared with placebo.

Orthostatic hypotension

It has been postulated that butcher’s broom may counter the blood pooling in the lower limbs associated with orthostatic hypotension by virtue of its vasoconstrictive and venotonic properties.⁶⁵

Diabetic retinopathy

The effects of a combination of buckwheat leaf (1.5 g/day) and troxerutin (90 mg/day) or butcher’s broom extract (75 mg/day) on ophthalmological and biochemical parameters in patients with non-proliferative diabetic retinopathy were compared with that of the synthetic rutin derivative troxerutin (1 g/day).⁶⁶ During the study period of 3 months, 60 diabetic patients were divided into three equal groups: group I received troxerutin, group II received butcher’s broom and group III received buckwheat plus troxerutin. The amplitude of oscillating potentials decreased in patients receiving only the troxerutin, and increased in group II and III patients. Regression of changes in the fundus of the eye was demonstrated in 23.1% to 27.8% of all treated patients; however, deterioration in 5.6% of patients in group I, 3.3% of those in group III and none in group II was also observed. Troxerutin seemed to be less effective than the herbs, especially when oscillating potentials were considered.

Anti-inflammatory activity

Chamazulene inhibited the formation of leukotriene B4 in intact neutrophils in a dose-dependent manner and blocked the chemical peroxidation of arachidonic acid. Matricine did not show these effects, even at higher concentrations. Matricine had no effect on cyclo-oxygenase (COX) and 12-lipoxygenase activities in human platelets.¹⁷ However, other in vitro studies have determined that at least part of the anti-inflammatory activity of chamomile extracts is due to constituents that inhibit the formation of 5-lipoxygenase and COX, and have antioxidant activity. Bisabolol and apigenin appear to be responsible for this.¹⁸

An aqueous chamomile extract inhibited the release of prostaglandin E₂ from lipopolysaccharide (LPS)-activated macrophages in vitro. The activity was due to a dose-dependent inhibition of COX-2 activity. Chamomile reduced COX-2 mRNA and protein expression, without affecting COX-1 expression or activity. The species was not defined, but is likely to be Matricaria recutita.¹⁹ Apigenin also inhibited COX-2 and nitric oxide synthase (NOS) activity in LPS-activated macrophages.²⁰

In terms of a possible influence on cytokine activity, apigenin inhibited LPS-induced interleukin-6 production in macrophages. Oral pretreatment (50 mg/kg) inhibited LPS-induced interleukin-6 and tumour necrosis factor-alpha production in mice.²¹

Oral intake of matricine demonstrated anti-inflammatory activity in the carrageenan test on rat paw.²² Matricine was nearly as effective as (–)-alpha-bisabolol up to 3 h after oral administration. Chamazulene was significantly less active than both these compounds.²³ Matricine, together with most of the components in chamomile oil but especially bisabolol, demonstrated anti-inflammatory activity when tested topically on skin.²⁴

(–)-alpha-Bisabolol demonstrated anti-inflammatory activity in a number of experimental inflammatory models: rat paw oedema, adjuvant arthritis of the rat, ultraviolet erythema of the guinea pig and yeast fever in rats.²⁵cis-En-yn-dicycloether inhibited the development of dextran-induced oedema in rats.²⁶ Several polysaccharides in chamomile have demonstrated anti-inflammatory activity when applied topically.²⁷

The anti-inflammatory activity of an aqueous-alcoholic extract of fresh chamomile, an aqueous-alcoholic extract of dried chamomile, the essential oil and isolated components of the essential oil were investigated by topical administration using croton oil-induced dermatitis in mouse ear. The extract prepared from dried flowers showed a mild but significant anti-inflammatory activity (24%), but the extract based on fresh chamomile was more active (32%) and equalled the activity of the reference drug, benzydamine. The essential oil solution did not show any significant inhibition of oedema. The anti-inflammatory activity of apigenin was 10 times higher than matricine, which was 10 times higher than chamazulene. The differences in anti-inflammatory activity of the various preparations might be attributable to the varying concentrations of matricine.²⁸

An aqueous-alcoholic extract of dried chamomile demonstrated a significant reduction of oedema (23.4%) compared with controls after topical administration to mice in the croton oil ear test. The non-steroidal anti-inflammatory agent benzydamine produced a similar reduction at a dose corresponding to twice its usual clinical dose. Hydrocortisone was the most active agent (56.4%).²⁹ Anti-inflammatory effects were demonstrated for topical administration of standardised chamomile extract, the flavone fraction and isolated flavones (apigenin, luteolin and quercetin) in the same model. The lipophilic flavone fraction demonstrated stronger activity than the total chamomile extract, and the action of apigenin was superior to the reference drugs indomethacin and phenylbutazone.³⁰

The anti-inflammatory efficacies of topical compounds were measured directly and objectively on the skin of healthy volunteers using the Tesafilm stripping technique. Three pharmaceutical formulations were investigated: a chamomile cream, its cream base and a hydrocortisone ointment. Chamomile cream exhibited 70% of the activity of the hydrocortisone ointment.³¹ Experimentally induced toxic contact dermatitis was topically treated with a chamomile ointment and compared with ointment base and 1% hydrocortisone acetate. The chamomile ointment demonstrated a superior soothing effect in comparison to the cortisone cream on human skin.³²

Spasmolytic activity

Chamomile extract and some of its constituents demonstrated a dose-dependent spasmolytic effect on isolated guinea pig ileum. (–)-alpha-Bisabolol, bisabolol oxides A and B and chamomile oil showed a papaverine-like antispasmodic activity, with the essential oil showing the lowest effect. The cis-en-yn-dicycloether component also showed activity, although it was not dose dependent. The flavones apigenin, luteolin, patuletin and quercetin demonstrated marked antispasmodic effects, with apigenin significantly more potent than the other flavones, but less active than papaverine. The coumarins only demonstrated a weak effect.³³ Freeze-dried, ethanol-free extract of chamomile completely blocked slow wave activity in isolated mouse small intestine.³⁴ Inhibition of cAMP phosphodiesterase was a likely mechanism for the spasmolytic activity.³⁵

Spasmolytic activity has also been observed following oral administration of apigenin.³⁶cis-En-yn-dicycloether demonstrated a more pronounced antispasmodic effect than papaverine on isolated guinea pig and rabbit intestine.²⁶ Chamomile extract (25 mL/L)³⁷ and chamomile oil (0.2 mL diluted in 400 mL methanol)³⁸ inhibited acetylcholine- and histamine-induced contractions in guinea pig ileum in vitro.

Chamomile extract showed moderate inhibitory activity in experimentally induced hyperperistalsis. The inhibition (56%) was greater than that of the control drug loperamide (34% at doses of 10 mg/kg). Rats were treated orally with the methanol extract of the aerial parts (5:1, 300 mg/kg).³⁹

Sedative and CNS activity

Several fractions from the aqueous extract of chamomile, including apigenin, have demonstrated significant affinity for the central benzodiazepine receptor in vitro. Apigenin also demonstrated clear antianxiety activity (10 mg/kg) and slight sedative activity without muscle relaxant effects after intraperitoneal administration in mice.⁴⁰ However, a later study in rats found that apigenin (doses from 0.5 to 10 mg/kg, ip) did not demonstrate antianxiety activity. In vitro investigations suggest that any sedative effect demonstrated in vivo for apigenin (by injection), is not mediated by benzodiazepine receptors.⁴¹ Fractions isolated from the methanol extract of chamomile were able to selectively bind to both central and peripheral benzodiazepine receptors in vitro. The displacing activity on radiolabelled muscimol binding observed for several of the fractions was found to be due to the presence of GABA in micromolar concentrations. The identity of other active compounds was not established. However, some of the fractions not containing GABA produced a statistically significant reduction of locomotor activity in rats after intracerebroventricular injection.¹² Chamomile extract significantly inhibited GAD (glutamic acid decarboxylase) activity in vitro (brain homogenate). GAD is a rate-limiting enzyme that determines GABA levels in normal nervous tissues, such as the brain.⁴²

Oral administration of chamomile extract (300 mg/kg) caused a significant shortening in sleep latency in rats. Flumazenil (a benzodiazepine receptor antagonist) at a dose that caused no obvious effect when used alone showed a significant antagonistic effect on the shortening of sleep latency induced by the chamomile extract.⁴³

A dried preparation of a chamomile infusion demonstrated a depressive effect on the CNS after intraperitoneal administration in mice. A dose-dependent decrease of basal locomotor activity was observed (90 to 360 mg/kg) without involving motor coordination and muscle relaxation. A significant sleeping-time potentiating effect was only observed at the two highest doses (160 and 320 mg/kg).⁴⁴ Inhalation of chamomile oil vapour decreased stress-induced increases in plasma ACTH (adrenocorticotropic hormone) in ovariectomised rats, compared with placebo. The plasma ACTH level decreased further when diazepam was administered with chamomile oil vapour, and the decrease was blocked by flumazenil. This suggests that chamomile oil may have an effect on GABA ergic systems in rat brain and perhaps an activity similar to benzodiazepine agonists.⁴⁵

A series of clinical tests in Japan found that an increase in mental activity was observed just after eating warmed chamomile jelly. There was also a decrease in heart rate and an increase in ‘pleasantness’ and good mood. Compared with control nights, eating the warmed jelly improved aspects of sleep in men and women. Skin temperature increased more when drinking chamomile tea than when drinking hot water.^46–48 No exact details of dosage were provided in these studies.

The effect of olfactory stimulation on fluency, vividness of imagery and associated mood was studied with 22 volunteers after exposure to either chamomile oil or placebo. Participants were asked to visualise positive and negative images after exposure to one oil then the other. Chamomile oil did not affect the vividness of imagery ratings, but significantly prolonged the time taken for participants to visualise both positive and negative phrases, suggesting a sedative effect. Negative mood ratings following negative phrase presentation were less extreme after chamomile (p=0.042). Overall mood rating was significantly higher (mean=+1) after chamomile compared with placebo (mean=0) (p=0.001).⁴⁹

Co-administration of extract of Matricaria chamomilla (25 mg/kg) with morphine (both by ip injection) greatly reduced the development of morphine dependence in rats. Administration of chamomile extract before induction of withdrawal syndrome by naloxone injection inhibited the expression of abstinence syndrome in morphine-dependent animals.⁵⁰ Pretreatment with an aqueous-methanolic extract of chamomile (200 mg/kg, ip) increased the latency of seizure onset in experimentally induced seizure in mice.⁵¹

Antiulcer activity

Chamomile extract demonstrated antipeptic activity in vitro.⁵² (–)-alpha-Bisabolol inhibited the occurrence of ulceration induced by indomethacin, stress or ethanol in rats. A decrease in healing time of ulcers was also observed. A standardised chamomile extract also demonstrated ulcer-protective activity.⁵³ Oral administration of (–)-alpha-bisabolol demonstrated a significant protective effect (p<0.05) against gastric toxicity produced by acetylsalicylic acid in rats.⁵⁴ Several more recent studies have confirmed that an aqueous-ethanolic extract of chamomile and alpha-bisabolol can reduce experimentally induced gastric lesions.^55–57 The mechanism of gastroprotection may involve a reduction in oxidation (chamomile extract, alpha-bisabolol),^55,57 and activation of ATP-sensitive potassium channels (alpha-bisabolol).⁵⁶

In an interesting series of experiments, the antiulcerogenic activity of chamomile in rats was compared with a number of other herbs.⁵⁸ A liquid aqueous-ethanolic extract of chamomile demonstrated a dose-dependent protection (2.5, 5 and 10 mL/kg, oral) against indomethacin-induced ulcers, but was not as active as many of the other herbs, including licorice and caraway. However, chamomile extract (10 mL/kg, oral) was the most potent herb at decreasing gastric acidity and acid output. It also significantly increased gastric mucin content, activity shared with licorice, St Mary’s thistle and caraway.

Antimicrobial activity

Antimicrobial activity has been demonstrated for (–)-alpha-bisabolol in vitro⁵⁹ and chamomile oil (<0.05%, v/v) against Staphylococcus aureus, Bacillus subtilis and Candida albicans⁶⁰ and for herniarin in the presence of near UV light. Chamomile extracts demonstrated similar activity against Escherichia.⁶¹ The growth of Staphylococcus aureus, Streptococcus mutans, group B Streptococcus and Streptococcus salivarius was completely inhibited by chamomile extract at 10 mg/mL. The extract showed strong antibacterial activity against Bacillus megatherium and Leptospira icterohaemorrhagiae. The effective concentration of each component (alpha-bisabolol, bisabolol oxides, dicycloethers and chamazulene) was much lower when the component was in combination with the others, as in the natural extract, indicating a possible synergistic effect.⁶²

The antibacterial activity of chamomile against Helicobacter pylori was tested in vitro. Activity ranged from no activity (infusion,⁶³ aqueous-ethanolic extract standardised for alpha-bisabolol,⁶⁴ methanol extract⁶⁵) to some activity (olive oil extract,⁶⁶ essential oil,⁶⁷ concentrated aqueous-methanolic extract⁶⁸). Test methods varied, making comparison difficult. The methanol extract was described as having no activity (MIC greater than 100 μg/mL). In comparison, the MIC of amoxicillin was 0.002 to 0.06 μg/mL.⁶⁵ The MIC₉₀ of chamomile olive oil extract (1:10) was 125 mg/mL (no standard comparison),⁶⁶ while the MIC for the essential oil was 36 to 70 μg/mL (in comparison, the MIC of amoxicillin was 0.02 μg/mL).⁶⁷ (The minimum inhibitory concentration (MIC) is the lowest concentration at which there is no visible bacterial growth. MIC₉₀ is the minimum concentration at which 90% of the bacterial growth is inhibited.)

An aqueous-ethanolic extract of chamomile, standardised for alpha-bisabolol, inhibited the growth of Campylobacter jejuni by approximately 100% at both 1:25 and 1:100 dilutions. The IC₅₀ (for dry weight of herb) against the bacteria was 2 mg/mL. In comparison, the IC₅₀ for gentamicin was 0.08 μg/mL. (IC₅₀ is the concentration of a compound needed to reduce the growth of an organism by 50%.⁶⁴)

Quorum sensing is a process of intercellular communication among bacterial cells, which occurs with the use of signalling molecules. Inhibition of quorum sensing may reduce infections. Chamomile essential oil was ineffective in inhibiting quorum sensing of two sensor strains in vitro.⁶⁹

Chamomile essential oil demonstrated significant virucidal activity towards herpes simplex virus type 2 (HSV-2) in vitro with an IC₅₀ of 1.5 μg/mL.⁷⁰ The oil was also active against an acyclovir-sensitive HSV-1 strain and against acyclovir-resistant clinical HSV-1 isolates.⁷¹ Chamomile essential oil affected the viruses by interrupting the adsorption of virus onto the host cell.^70,71

Bisabolol (500 and 1000 μg/mL) achieved 100% inhibition of Leishmania infantum promastigote in vitro.⁷²

Wound healing, itching

Aqueous extract of chamomile (120 mg/kg/day) in the drinking water of rats resulted in an increased rate of wound contraction, increased wound-breaking strength and hydroxyproline content, and improved histology of experimentally induced wounds.⁷³ Topical application of chamomile extract accelerated the healing of burns and incisions in rats.^74,75 A chamomile ointment was effective in the treatment of oral mucositis in a hamster model. The ointment contained a fluid extract of chamomile (10%) and tincture of myrrh.⁷⁶ The same preparation promoted faster wound healing of tongue lesions compared with topical corticosteroids in rats.⁷⁷

The wound-healing activity of chamomile is closely linked to its anti-inflammatory activity. (–)-alpha-Bisabolol promotes granulation and tissue regeneration.⁵⁹ Application of chamomile extract altered the metabolism of guinea pig skin cells, indicating possible stimulation of cellular regeneration and inhibition of inflammation.⁷⁸ Extracts of chamomile showed moderate activity in stimulating proliferation and migration of fibroblasts in vitro.⁷⁹

The impact of oral administration of chamomile in reducing experimentally induced itch was investigated in mice. A diet containing 30% (w/w) of dried, powdered chamomile for 11 days reduced itch by about 30%, which was not significant. Of the other extracts tested, significant inhibition of itch occurred for an ethyl acetate extract (dosage adjusted to 30% (w/w) of dried chamomile). Removal of water-soluble substances from the ethanol extract appeared to significantly enhance its antipruritic activity.⁸⁰ In the same model, oral administration of ethyl acetate extract of chamomile extract (25:1, 300 mg/kg) combined with antihistamines was more effective for the suppression of scratching behaviour in mice than administration of antihistamines alone. At least part of the antipruritic activity was due to the essential oil, present at approximately 30% in the extract.⁸¹ Topical application of chamomile essential oil (3% oil, 70 μL, daily for six times per week) alleviated some altered immune parameters in mice with experimentally induced atopic dermatitis. The elevation in serum immunoglobulin E (IgE), IgG1 and histamine were significantly reduced compared with control groups. Scratching frequency was significantly lower than in either control group (saline, jojoba oil).⁸²

Other activity

Chamazulene and (–)-alpha-bisabolol, within the concentration range 10−9 to 10−5 M, demonstrated very little influence on histamine release in isolated rat mast cells. At concentrations higher than 10−5 M they stimulated histamine release. En-yn-dicycloether exhibited a moderate stimulating effect at concentrations lower than 10−4 M and a strong inhibiting effect on histamine release at higher concentrations.⁸³

Extracts and infusion (species undefined) of chamomile have shown antioxidant activity in vitro. The activity was moderate compared with other herbs.^84,85 Chamazulene inhibited membrane lipid peroxidation in vitro in a concentration- and time-dependent manner. It also demonstrated hydroxyl radical scavenging activity.⁸⁶ Chamomile may protect against global cerebral ischaemia/reperfusion-induced brain injury in rats. Oral administration of methanol extract decreased lipid peroxidation and increased superoxide dismutase, catalase, glutathione and total thiol levels compared with the untreated group. Cerebral infarction area was also significantly reduced in chamomile-treated groups. The activity was dose-dependent (100 to 300 mg/kg body weight, 9.3:1 extract).⁸⁷

Chamomile extract strongly stimulated the proliferation of lymphocytes, as determined by the mixed lymphocyte reaction, an in vitro stimulatory system involving T cell activation.⁸⁸

Diets containing chamomile flower (1.5% and 7%), several chamomile oils (0.2% to 0.35%) or guaiazulene (0.2%) stimulated liver regeneration in rats.⁸⁹ Intragastric administration of a mixture of flavonoids of chamomile normalised sphingolipid metabolism in the liver of old rats. (An increase in sphingolipid turnover in the liver is associated with elevation of free radical production and state of chronic inflammation in old age.) Animals were fed 160 mg/kg of a mixture consisting of apigenin, luteolin, apigenin-7-glucoside, luteolin-7-glucoside, isorhamnetin and quercetin.⁹⁰ The same mixture and dosage normalised the elevated ceramide content in carbon tetrachloride-damaged livers of rats via neutral sphingomyelinase inhibition and ceramidase activation. Alterations in sphingolipid turnover induced by administration of the flavonoids coincided with the stabilisation of the damaged hepatocyte membranes.⁹¹ This mixture (40 to 80 mg/kg) induced a dose-dependent increase in bile flow and bile acid secretion in adult and old rats. Cholesterol bile secretion was increased and hepatic lipid content reduced in old rats, but not in adult rats.⁹²

In a long-term feeding test, the hot water extract of chamomile (500 mg/kg/day) significantly suppressed blood glucose levels in streptozotocin-induced diabetic rats. The hypoglycaemic effect of chamomile was independent of the inhibition of intestinal alpha-glycosidases, but depended on the inhibition of hepatic glycogen phosphorylase. Chamomile extract also showed strong inhibition against aldose reductase in vitro.⁹³ In the same model, oral administration of an aqueous-ethanolic extract of the aerial parts of chamomile reduced hyperglycaemia and oxidative stress in a dose-dependent manner. Significant results were obtained for daily dosages of 280 and 560 mg/kg (dried herb equivalent). Histological investigation indicated that treatment with chamomile protected the majority of the pancreatic islet cells, in comparison with the control group.⁹⁴

An ethanol extract of chamomile showed weak activity against a cancer cell line in vitro.⁹⁵ In another test, a significant decrease in cell viability was observed in several cancer cell lines for chamomile extracts. Chamomile exposure resulted in differential apoptosis in cancer cells.⁹⁶ Bisabolol oxide A at a concentration of 10 μM inhibited the growth of leukaemia cells in vitro. Combination with 5-fluorouracil further inhibited the growth of leukaemia.⁹⁷ Bisabolol oxide A at 5 to 10 μM did not exert a cytotoxic action on normal non-proliferative cells (rat thymocytes) in a previous study.⁹⁸ Luteolin (5 mg/kg, ip) suppressed prostate tumour growth in mice by inhibiting insulin-like growth factor 1 receptor signalling.⁹⁹ Luteolin inhibited platelet-derived growth factor (PDGF)-induced proliferation by inhibiting PDGF receptor phosphorylation in vascular smooth muscle cells.¹⁰⁰ Bisabolol efficiently and selectively induced apoptosis in malignant tumour cells in vitro by targeting lipid rafts on cell membranes.¹⁰¹

Chamomile extract stimulated osteoblastic cell differentiation and exhibited an anti-oestrogenic effect on breast cancer cells in vitro, without proliferative effects on cervical adenocarcinoma cells.¹⁰² Using an in vitro tissue culture indicator system, chamomile (species undefined) was found to have weak oestrogen agonist activity and weak progestogenic activity.¹⁰³

An aqueous-ethanolic extract of chamomile was superior to 2.5% sodium hypochlorite solution as a cleaning agent to remove the smear layer of teeth. A smear layer is produced by cutting the enamel or dentin in cavity preparation. Extracted, single-rooted teeth were used for this in vitro investigation. Chamomile extract was not better than sodium hypochlorite solution combined with EDTA (ethylenediaminetetraacetic acid), but was more effective than tea tree oil.¹⁰⁴

Eczema, dermatitis and ulceration

Topical application of chamomile preparations helped relieve eczema¹¹⁰ and varicose eczema.¹¹¹ In a survey conducted in the early 1980s, 95% of 2477 general practitioners described good tolerance and therapeutic efficacy for a chamomile cream (containing 2% standardised chamomile extract) in the treatment of eczema.¹¹⁰ The herbal treatment decreased inflammation¹¹¹ and facilitated a reduction in the level of topical corticosteroids used.¹¹⁰

Chamomile cream was compared to steroidal and non-steroidal dermal preparations in the maintenance therapy of hand, forearm and lower leg eczema in an open bilateral comparative trial involving 161 patients. During maintenance therapy over 3 to 4 weeks, the chamomile cream showed similar efficacy to 0.25% hydrocortisone and superior activity to the non-steroidal anti-inflammatory agent (5% bufexamac) and a glucocorticoid preparation (0.75% fluocortin butyl ester).¹¹² After 2 weeks of treatment, a standardised chamomile cream showed mild superiority over 0.5% hydrocortisone cream and marginal improvement compared with placebo in medium-degree atopic eczema. This was a partially blinded, randomised trial carried out as a half-side comparison (one side of the body compared with the other).¹¹³ Eight patients with neurodermatitis in the stage of subacute eczema were treated with ointments containing 1% of a carbon dioxide extract of chamomile or 1% hydrocortisone, in a randomised, double blind trial. Global clinical impression was used to assess the results. Hydrocortisone was significantly more effective than chamomile (p<0.001). Nearly all the patients had been pretreated topically with steroids. In cases of pretreatment with weak or moderately potent steroids, hydrocortisone was much more effective than chamomile, but not in patients pretreated with potent or very potent steroids. The carbon dioxide extract contained constituents similar to the essential oil, with the exception of chamazulene, which was absent.¹¹⁴

In an open, uncontrolled clinical trial, patients with varicose ulcers were treated with a chamomile ointment alone or the ointment and a chamomile wash. The therapeutic response was good at 83% and 78%, respectively.¹¹⁵

Wound healing

Standardised chamomile ointment had similar efficacy to 5% dexpanthenol cream in healing episiotomy wounds in an open, controlled, randomised trial.¹¹⁶ An open, randomised trial compared several procedures for second degree haemorrhoid treatment and found best results in the group receiving application of a standardised chamomile ointment in conjunction with surgical procedures (ligature and anal dilation).¹¹⁷

Chamomile extract demonstrated a statistically significant improvement in wound healing in a double blind, placebo-controlled clinical trial involving 14 patients. The significant decrease in weeping of the wound area and the drying tendency after dermabrasion of tattoos (p<0.05) indicated the therapeutic efficacy of chamomile.¹¹⁸ In a randomised, single blind, controlled trial involving 48 women, chamomile cream was not statistically more effective than almond cream at reducing erythema and moist desquamation acquired after receiving radiotherapy for breast cancer. However, there was a trend to fewer and later appearances of grade 2 reactions for the chamomile treatment.¹¹⁹

A physiotherapist and a medical doctor carried out a small study involving five patients with chronic wounds. The patients were treated with a mixture of chamomile and Lavandula angustifolia essential oils in a grape seed oil carrier base and compared with three controls. One of the controls, who had wounds on his left and right legs, started the study as both a control and a member of the experimental group. Fifty-six days into treatment he discontinued conventional treatment and used essential oils only. The recipients of the essential oils did better than those who only received conventional treatments.¹²⁰

Colostomy patients seeking treatment for a peristomal skin lesions were assigned to one of two treatments: hydrocortisone (1%) ointment applied once a day or chamomile compress in an open label trial involving 72 patients.¹²¹ A chamomile solution was prepared by infusing dried and powdered flowers (6 g) in 150 mL of boiling water for 10 minutes in a closed glass container. The filtered solution was applied to gauze and the compress placed on the wound for 1 hour twice a day. The lesions were evaluated every 3 days for a maximum of 28 days. Lesions healed significantly faster in the chamomile than in the hydrocortisone group (mean time to healing: 8.9 and 14.5 days respectively; p=0.001). Complete healing was achieved in 100% of the chamomile group by day 15, while 76% of the hydrocortisone group achieved complete healing by day 21. Pain intensity and itching were lower in the chamomile group.

Oral inflammation

In an uncontrolled trial involving 36 patients, a chamomile mouthwash provided a cooling and astringent effect in the treatment of chronic oral inflammation, except in the case of glossodynia.¹²² A chamomile preparation was used therapeutically and prophylactically as an oral rinse in the treatment of oral mucositis caused by head and neck irradiation and systemic chemotherapy in an uncontrolled trial. Resolution of mucositis was accelerated by the chamomile rinse and prophylactic use was also favourable.¹²³

In a double blind, placebo-controlled clinical trial involving 164 patients, a chamomile mouthwash did not decrease the incidence of stomatitis resulting from 5-fluoruracil-based chemotherapy. The mouthwash was administered three times per day for 2 weeks.¹²⁴ This may have been too short a period to detect improvement.¹²⁵ A later, randomised trial conducted in Iran found that allopurinol and chamomile mouthwashes were superior to placebo (saline) for the treatment of chemotherapy-induced stomatitis. Both active mouthwashes were equally effective. The chamomile mouthwash was prepared from an infusion (8 g powdered flower per 50 mL water) and filtered.¹²⁶ A case of methotrexate-induced oral mucositis in a patient with rheumatoid arthritis was successfully treated with a chamomile mouthwash. The patient refused standard mouthwash treatment and was instead administered an infusion of Matricaria recutita (8 g dried flower in 1 litre of boiling water). The suggested dosage was 20 mL kept in the mouth or gargled for 1 to 2 minutes and repeated four times daily. By the 13th day the oral mucositis had reduced from grade 3 (oral ulcers, liquid diet only) to grade 2 (oral erythema, ulcers, able to eat solids) and was completely healed within 4 weeks.¹²⁷

Fluid extract of chamomile provided an analgesic effect in patients with aphthous stomatitis and other painful ulcers of the mouth in an open label trial. The analgesic effect was considered excellent by 82% and good by 18% of patients. The efficacy of chamomile was considered excellent in 67% of patients and good in 33%. Pain was assessed using a visual analogue scale and 34 patients were evaluated.¹²⁸

Anxiety

Fifty-seven outpatients with mild to moderate generalised anxiety disorder were randomised via a double blind design to receive chamomile (Matricaria recutita) extract or placebo for 8 weeks. Treatment was initiated at one capsule per day for the first week and increased to two per day during the second week. Patients with a 50% reduction or less in total Hamilton Anxiety Rating (HAM-A) score (compared with baseline) were increased to three capsules per day during week 3, and then to four per day during week 4. Patients who continued to only have a 50% reduction or less in baseline HAM-A score were increased to five capsules/day during weeks 5 to 8. The chamomile extract (220 mg/capsule, undefined strength) was standardised to contain 1.2% apigenin. There was a significantly greater reduction over time in the mean total HAM-A score for chamomile versus placebo (p=0.047). Secondary outcomes included changes in the Beck Anxiety Inventory, Psychological Well Being and Clinical Global Impression Severity scores and the proportion of patients with 50% reduction or more in baseline HAM-A score. There were no statistically significant differences observed between the groups for any secondary outcome measure. One patient in each treatment group discontinued therapy because of adverse events. The proportion of patients experiencing adverse events was not significantly different between groups (p=0.417).¹²⁹

Gastrointestinal conditions

In an uncontrolled study, 104 patients with non-specific gastrointestinal complaints (probably functional dyspepsia) were treated with an aqueous-ethanolic preparation of chamomile (standardised for alpha-bisabolol and apigenin-7-glucoside) at 25 drops four times a day (in a cup of hot water) for a period of 6 weeks. The following symptoms were assessed: stomach and abdominal pain, burping, fullness, heartburn, loss of appetite, nausea and vomiting. Symptoms completely disappeared in 44.2% of patients. The success rate for single symptoms ranged from 61% for loss of appetite to 84.5% for stomach and abdominal pain and 88.7% for nausea.¹³⁰

In a prospective, double blind, randomised, multicentre, parallel group study, 79 children with acute, non-complicated diarrhoea received either a preparation containing apple pectin and chamomile extract or placebo for 3 days in addition to the usual rehydration and realimentation diet. At the end of treatment, the diarrhoea had stopped significantly more frequently (p<0.05) in the pectin/chamomile group (85%) compared with the placebo group (58%). The pectin/chamomile combination also significantly reduced the duration of diarrhoea by at least 5.2 h (p<0.05). In contrast to placebo, a trend of continuous improvement was observed by parents for the pectin/chamomile group. The parents expressed their satisfaction more frequently (82%) with pectin/chamomile than with placebo (60%).¹³¹ A follow-up trial (also of double blind design) with a larger number of patients found that the combination significantly reduced stool frequency compared with placebo. This multicentre, randomised trial enrolled 255 children aged between 6 months and 6 years with acute diarrhoea. Two hundred and forty-one children were available for final analysis: 121 received the active medication and 120 received placebo. Stool frequency on the third day was significantly lower in the treatment group compared with placebo (decreases of 49% and 36%, respectively; p=0.0012). Each child also received a glucose-electrolyte solution on the first day of treatment.¹³²

The effect of a herbal instant tea preparation containing chamomile, vervain, licorice, fennel and lemon balm on infantile colic was assessed in a prospective, double blind study on babies about 3 weeks old. Tea or placebo up to 150 mL per dose was given to each infant with every episode of colic, but not more than three times a day. After the 7 days of the trial, the colic improvement scores were significantly better in the herbal tea group: 1.7 versus 0.7 for the placebo group (p<0.05). In addition, more babies in the treatment group had their colic eliminated: 57% compared with 26% for placebo (p<0.01).¹³³ A randomised, double blind, placebo-controlled trial showed that colic in infants improved within 1 week of treatment with a combination of chamomile, fennel (Foeniculum vulgare) and lemon balm (Melissa officinalis). The preparation also contained vitamin B1, calcium pantothenate and vitamin B6.¹³⁴ An experimental study found that the activity of the combination in reducing upper gastrointestinal motility was due to the chamomile and lemon balm.¹³⁵

Other activity

Oral administration of chamomile tea during cardiac catheterisation induced a deep sleep in 10 of 12 patients tested, despite the pain and anxiety experienced from the procedure. The chamomile tea had essentially no cardiac effects.¹³⁶

Fifty-five postmenopausal women were randomly assigned to receive tablets containing Matricaria recutita (150 mg/day of an undefined extract) and dong quai (Angelica sinensis, 375 mg/day of an undefined extract) or placebo for a period of 12 weeks. There were significant and dramatic differences observed between the study and control groups in terms of the number and intensity of hot flushes (both p<0.001). In the herbal treatment group, a response was already in evidence by the first month (68% reduction of hot flushes during the day and 74% during the night). There was also a marked alleviation of sleep disturbance and fatigue.¹³⁷

Mean scores improved for Conners’ hyperactivity, inattention and immaturity factors in three young men (14 to 16 years old) diagnosed with attention-deficit hyperactivity disorder who received treatment with chamomile. Two participants received chamomile for 4 weeks and then placebo for 4 weeks; the others received placebo first followed by chamomile. The observed improvement was lower than reported in stimulant trials, but was similar to that found in non-stimulant trials, such as for desipramine.¹³⁸ Treatment with chamomile also led to a slight improvement in irritability and stereotypic behaviour in three male patients with autism. The standardised extract used provided 200 mg/day of alpha-bisabolol.¹³⁹

A randomised, double blind trial found no significant impact on post-operative sore throat and hoarseness for a herbal spray containing standardised chamomile extract administered before intubation, compared with a normal saline spray (placebo). One hundred and sixty-one elective surgery patients were recruited for this study.¹⁴⁰

Sixty outpatients with uncomplicated common cold were randomly assigned to test whether a chamomile inhalation would provide symptomatic relief in an open label, controlled trial. The control group used a solution containing 35% alcohol, while three different treatment groups used increasing doses of an alcoholic extract of chamomile. The steam inhalation was prepared with boiled water cooled to 50°C, with the chamomile extract then added. Patients inhaled slowly and deeply, breathing through the nose and mouth for 10 minutes, with their heads above the container and below a towel. Chamomile reduced symptoms of the common cold in a dose-dependent manner, especially those of the upper and middle respiratory tract. Onset of action was within 15 minutes, the maximum effect was reached between 20 to 30 minutes. The benefit then declined over 2 to 3 h.¹⁴¹

A preliminary study found that use of chamomile baths and a chamomile bladder wash as an adjunct to antibiotic treatment provided a faster alleviation of the symptoms of haemorrhagic cystitis than use of antibiotics alone.¹⁴²

A study in the UK investigated the use of aromatherapy within a healthcare setting for 8058 women in childbirth. A total of 10 essential oils were used, plus carrier oil, and were administered via skin absorption and inhalation. Two essential oils, namely chamomile and clary sage, were effective in alleviating pain.¹⁴³ It is not clear whether the oils were administered individually or in combination. They were described only by common name.

A metabonomic strategy was applied to the study of human biological responses to chamomile tea ingestion. Daily urine samples were collected from 14 volunteers during a 6-week period incorporating a 2-week baseline period, 2 weeks of daily chamomile tea ingestion, and a 2-week post-treatment phase. Although strong intersubject variation in metabolite profiles was observed, a clear differentiation between the samples obtained before and after chamomile ingestion was achieved.¹⁴⁴ It was found that depletion of creatinine and elevation of hippurate, glycine and other molecules in urine were strongly associated with chamomile intake. In addition, the metabolic consequences of chamomile ingestion were prolonged in the 2-week post-dosing period, implying a persistent change of resident gut microflora activities. The clinical significance of these findings is not known.

Twenty-five cancer patients with phlebitis from intravenous infusion of antineoplastic chemotherapy were divided into five treatment groups using an open label design.¹⁴⁵ The patients received compresses of chamomile infusion (1.25%, 2.5%, 5.0% or 10.0%) or water (control group) three times a day for 20 minutes each time. Phlebitis (erythema) regression times were significantly shorter for the 1.25%, 2.5% and 5% concentration groups compared with the control group (p<0.001). The average regression time for the 2.5% concentration group was 29.2 h versus 110.4 h for the control group.

Contact allergy and hypersensitivity reactions

Hypersensitivity reactions have been confirmed as the basis for contact dermatitis to chamomile,^170,171 but are relatively rare. Chamomile tea allergy,¹⁷² and contact dermatitis,^173–176 as well as urticaria,¹⁷⁷ including from cosmetics, have been reported.¹⁷⁸ Occasional hypersensitivity reactions, including asthma, to chamomile dust have been reported among tea packers.^179,180 A 20-year-old woman with a proven allergy to chamomile suffered from short-lasting rhinitis when using a chamomile-scented toilet paper. The plant species was not disclosed.¹⁸¹ Contact dermatitis with asthma and rhinitis was reported in a beautician using chamomile in face masks.¹⁸² Recurrent facial dermatitis from drinking German chamomile tea has been reported.¹⁸³

Chamomile was described as a trigger for eczema as early as 1921. However, varying reports of chamomile causing iatrogenic contact dermatitis have been published since. In a 1936 study on 539 patients, 3.1% displayed sensitivity to chamomile on epidermal testing. No occurrences were reported in 260 patients over a period from 1957 to 1963. From 1964 to 1967, 1.3% of 237 patients demonstrated an adverse reaction to external applications containing chamomile. Other authors concluded that chamomile was not a causative factor in their studies of 265 and 240 cases of iatrogenic contact dermatitis. However, a 1967 report indicated that 7.1% of 338 patients demonstrated contact dermatitis from chamomile preparations. It is unknown whether the chamomile preparation was the single identifiable harmful substance.¹⁸⁴

Later studies suggest that genuine contact dermatitis from chamomile has a lower incidence. One clinical investigation was undertaken to clarify possible adverse reactions to chamomile preparations. Among 200 patients, 21 (10.5%) reacted positively on epicutaneous tests to chamomile preparations, though only three patients reacted to chamomile extract. Only one patient had exhibited a clinical contact reaction to a chamomile ointment used previously. Of the other 18 patients, 13 had a provable hypersensitivity to the preservatives and five patients probably to ointment bases and/or other constituents of the preparations. The authors felt that genuine chamomile allergy was not as prevalent as first thought.¹⁸⁵

This conclusion was also supported in a study of 830 patients with contact dermatitis. Only one patient with very high exposure to chamomile tested positive when patch tested with chamomile extract. One hundred and fifty-two patients were tested with chamomile cream and chamomile ointment. Results were negative, even in one patient with oral allergy syndrome and immediate hypersensitivity to many plants, including chamomile.¹⁸⁶

A high (–)-alpha-bisabolol-containing chamomile extract demonstrated negative results in a contact allergy study in 540 patients with eczema. These results suggest that the extract does not contain allergenic components, such as might be found in other chamomile products.¹⁸⁵ However, allergic contact dermatitis to bisabolol has been reported twice in European adults (1995 and 2008). Bisabolol was also regarded as the likely allergen in three children who presented with recalcitrant atopic dermatitis.¹⁸⁷ The coumarin herniarin, which is present in German chamomile, may also be a sensitiser. Among 36 patients with known or suspected Compositae contact allergy who were patch tested, there was one positive and three doubtful positive reactions to herniarin.¹⁸⁸

To investigate Compositae dermatitis, sesquiterpene lactones and ether extracts of five European Compositae plants (Arnica, feverfew, German chamomile, yarrow and tansy) were added to routine patch testing of patients over 1 year; 4.5% of the 686 patients demonstrated Compositae sensitivity. Testing with the individual ingredients of the extract in these 31 Compositae-allergic patients resulted in 75% positive reaction to chamomile.¹⁸⁹ In a later study, patch testing in 190 Danish Compositae-allergic patients found that feverfew caused positive reactions most frequently (81%), followed by tansy (77%), German chamomile (64%), yarrow (41%) and Arnica (23%). A large proportion of the positive reactions to feverfew, tansy and chamomile are likely to be due to chrysanthemum (Dendranthema cultivar) sensitivity, that is they are cross-reactions.¹⁹⁰

Chamomile allergies are also likely to follow previous sensitisation to mugwort (Artemisia vulgaris). Cross-reactivity with mugwort has been confirmed by skin patch tests using chamomile in 21 out of 24 affected individuals. Positive inhalation reactions to chamomile pollen occurred in 16 of these individuals, and positive reactions to oral consumption of chamomile in 13 out of the 24.¹⁹¹

A study of 30 patients with atopic dermatitis found that nine were positive in patch tests to a mix of Compositae or Compositae mix and sesquiterpene lactone mix. Five were positive to chamomile. Among Compositae-sensitive patients, 78.8% had other contact allergies, most often to nickel.¹⁹² When chamomile-sensitive patients were patch tested with a range of preparations, although positive reactions occurred most frequently to the plant, fragrances, emulsifiers and preservatives also tested positive. Avocado oil and witch hazel tincture were unexpectedly detected as sensitisers as well.¹⁹³

Allergic conjunctivitis was observed in seven hay fever sufferers who had used chamomile tea as an eyewash; all cases had positive skin tests to chamomile, but there were no reactions after oral consumption. The pollens were judged to be the sensitising components.¹⁹⁴

The above data suggest that the likelihood of chamomile preparations causing a contact allergy is low, but persons with known sensitivity to other members of the Compositae family should generally avoid contact with chamomile or chamomile products. However, it may be that chamomile is in part a victim of misidentification, as suggested in the Adulteration section above.

Anaphylactic reaction

Severe anaphylaxis occurred in a man 1 h after consuming chamomile tea. Laboratory examination demonstrated a total serum IgE of 123 kU/L, with specific IgE against chamomile (4.94 kU/L, class 3). Skin prick test and labial provocation test with chamomile both showed a strong positive reaction.¹⁹⁵

Two cases of anaphylactic shock associated with the use of chamomile as an enema have been reported (1998 and 2001). The enemas were prepared using an oily extract of chamomile (Matricaria recutita) and tea (species unknown).^196,197 One case of severe anaphylactic reaction was observed in an atopic child after taking chamomile tea for the first time. Mugwort was identified as one of the predisposing allergens.¹⁹⁸

Over a 2-year period, 14 patients with sensitivity to chamomile (as proven by RAST (radioallergoabsorbent test) and/or the skin prick test) were identified in an allergy unit serving approximately 4000 patients/year. Ten of these patients had a positive history of anaphylaxis to chamomile. The most severe symptoms were observed in two women who had received chamomile-containing enemas, in one case an oily extract of chamomile (case mentioned above). Eleven of the 14 patients exhibited positive RAST and skin prick test reactions to mugwort; six patients had a history of a mugwort-celery-spice syndrome and eight were sensitised to birch pollen. Bet v 1 (homologue of birch pollen allergen) and non-carbohydrate high molecular weight proteins were found to be allergens and responsible for cross-reactivity with other foods and pollen.¹⁹⁹

Given the widespread consumption of chamomile tea and the few reported cases of anaphylaxis, this type of reaction is quite rare. Moreover, the use of ethanolic extracts denatures the proteins in chamomile and renders this type of reaction unlikely.

Other reactions

One thousand, four hundred and twenty people completed questionnaires regarding their use of herbal medicines from pharmacies in a north-eastern town in Italy. Two consumers noted an adverse reaction (hypotension, tachycardia) to a product containing chamomile, valerian and Melissa.²⁰⁰ The species of the herbs were not verified.