Echinacea

Scientific Name(s): Echinacea angustifolia DC, Echinacea purpurea (L.) Moench, and Echinacea pallida (Nutt.) Britton. Family: Asteraceae (sunflowers)

Common Name(s): American coneflower , black Sampson , black Susan , comb flower , echinaceawurzel , hedgehog , igelkopfwurzel , Indian head , Kansas snakeroot , narrow-leaved purple coneflower , purple coneflower , purpursonnenhutkraut , racine d'echininacea , rock-up-hat , roter sonnenhut , scurvy root , snakeroot , sonnenhutwurzel

Uses

There is limited evidence that echinacea is effective in shortening the duration of symptoms of upper respiratory tract infections, but a lack of effectiveness for its use in prevention. Echinacea is hypothesized to be an immunomodulator. There is also interest in its potential use in cancer therapy, but clinical trials are lacking. The variation in available commercial products and lack of consistency in clinical trials make specific recommendations difficult.

Dosing

Many commercial preparations are available containing components derived from different plant parts as well as from different species and varieties. Recommended dosing (all administered 3 times daily) include the following: 300 mg dry powdered extract (standardized to 3.5% echinacoside), 0.25 to 1.25 mL liquid extract (1:1 in 45% alcohol), 1 to 2 mL tincture (1:5 in 45% alcohol), 2 to 3 mL expressed juice of E. purpurea , and 0.5 to 1 g dried root or tea. Echinacea use for more than 8 weeks at a time should be avoided because of the potential for immune suppression. Intravenous (IV) use is not recommended.

Contraindications

Known hypersensitivity to plants of the Asteraceae/Compositae family; any condition in which immune stimulation or suppression would be considered disadvantageous.

Pregnancy/Lactation

Limited clinical evidence, expert opinion, and long-term traditional use suggest that oral echinacea is safe for use during pregnancy at normal dosages. Direct evidence for safety during lactation is lacking. Use with caution.

Interactions

Specific case reports of interactions are lacking, and limited, conflicting data regarding effects on the cytochrome P450 (CYP-450) enzyme system have been published.

Adverse Reactions

Adverse reactions are rare. In clinical trials, adverse reactions caused by echinacea were generally not statistically significant compared with placebo. The most commonly reported reactions were allergy, GI upset, and rash. Individuals with allergy to ragweed or related allergens should use echinacea with caution. A case report of leukopenia, possibly caused by long-term use of echinacea, has been published. Potential immune suppression with long-term use has been suggested.

Toxicology

Little is known about the toxicity of echinacea. Animal studies generally indicate low toxicity.

Botany

There are at least 9 species of Echinacea . 1 Those most commonly used medicinally are E. purpurea , E. pallida , and E. angustifolia . 2 , 3 Echinacea is native to the United States, specifically Kansas, Nebraska, and Missouri. Because of confusion regarding the identification of echinacea species, much of the early European research conducted on this plant, particularly E. angustifolia , may have been conducted on E. pallida . 4 E. angustifolia and E. purpurea are perennial herbs with narrow leaves and stout stems that grow from 90 cm to 1.2 m in height that blossom as a single lavender or purple flower head. When chewed, the plant imparts a pungent taste and causes tingling of the lips and tongue. 1

History

Echinacea is a popular herbal remedy in the United States. The plant was used in traditional medicine by American Indians and quickly adopted by settlers. During the 1800s, claims for the curative properties of the plant ranged from blood purification to treatment of dizziness and rattlesnake bites. During the early part of the 20th century, extracts of the plant were used as anti-infectives; however, the use of these products fell out of favor after the discovery of modern antibiotics. The plant and its extracts continue to be used topically for wound healing and internally to stimulate the immune system. 5 , 6

Chemistry

There is general agreement that no single chemical constituent is responsible for echinacea's biological activity. 3 , 7 Most studies indicate that the lipophilic fraction of the root and leaves contains the most potent immunostimulating components. 7 Many alkamides, predominantly isobutylamides, have been described. 8 Caffeic acid glycosides and esters (eg, echinacoside, cynarin, cichoric acid) are found in the root and aerial parts of the plants, but echinoside is not found in E. purpurea . 3 Polysaccharides have been identified in E. purpurea aerial parts and E. pallida root. 3

The alkamides found in echinacea are available following oral administration, whereas the caffeic acid derivatives are not. 3 The pungent component of the plant is echinacein, an isobutylamide. 9 Depending on the species, the essential oil obtained from the root may be high in unsaturated alkyl ketones or isobutylamides. 4

Uses and Pharmacology

Cancer

Root extract from 3 echinacea species ( E. purpurea , E. angustifolia , and E. pallida ) showed concentration- and time-dependent induction of apoptosis in human pancreatic and colon cancer cell lines. 10

Animal data

In mice, the mean survival age was prolonged and thymic lymphoma enlargement suppressed with 8 weeks of echinacea therapy, while other experiments have demonstrated elevated natural killer cell levels and prolonged survival times in leukemic mice. 11 , 12 Dietary supplementation with E. purpurea in rats undergoing experimental irradiation resulted in the mobilization and enhancement of vitamin E–mediated oxidation/reduction pathways, suggesting that echinacea may have potential as a radioprotector. 13 However, another study in rats showed that coadministration of cadmium and echinacea lead to a concentration of cadmium in certain organs and blood. 14 An in vitro study demonstrated that typical constituents of echinacea species applied topically were effective in the prevention and/or treatment of skin damage caused by ultraviolet/ultraviolet B radiation, 15 and another study suggested radioprotection following oral administration of echinacea by radiology technicians. 16

Clinical data

In a trial investigating the effects of an IV-administered polysaccharide fraction of echinacea among patients with advanced gastric cancer, increases in the median number of leukocytes was demonstrated; however, the differences were not considered clinically relevant. 17 Another study involving 23 patients with tumors showed no effect on cytokine or leukocytes after using a preparation of E. angustifolia . 18

Immunomodulation

Many studies investigating immunomodulatory properties have been conducted with different Echinacea species, extracts, and plant parts. However, there is little agreement on which chemical constituents are responsible for activity on the immune system. 3 , 19 , 20 Enhanced macrophage function, stimulation of cytokine production (including certain interleukins and tumor necrosis factor alpha), enhanced natural-killer function, and increased mean circulating total white blood cell counts have all been demonstrated in vitro. 3 , 21 , 22 , 23 , 24 , 25 , 26 , 27

Clinical data

In healthy adults, stimulation of the immune system via the CD69 marker was demonstrated within 24 hours of echinacea ingestion. 28 A study in humans found changes in CD8, T lymphocytes, and natural killer cells, but not in other lymphocyte subpopulations. 29 Another study found that echinacea extract stimulated cell-mediated immunity in humans following a single dose, but repeated daily doses suppressed the immune response. 30 A study in healthy adults found that echinacea attenuated the suppression of exercise-induced mucosal immune response. 31 A consensus statement on the lack of evidence to support the use of echinacea among athletes to maintain immune health has been published. 32

Upper respiratory tract infection

In vitro studies suggest activity of echinacea extracts against some respiratory bacteria and viruses. 33

Animal data

The widespread traditional use of echinacea for the common cold and the availability of clinical trial data make animal data mostly irrelevant. 33

Clinical data
Treatment

A few quality meta-analyses have been published on the effect of echinacea on the management of the common cold. All have emphasized methodological issues within individual clinical trials, such as variations in preparation and dosage used, outcomes measuring high dropout rates, and lack of intention-to-treat analyses, making comparisons difficult. 34 , 35 , 36 Evidence regarding a definitive place in therapy remains weak. In comparing echinacea with placebo, a Cochrane review found an effect in 9 trials, a trend in 1 trial, and no effect in 6 trials. Most of the included trials studied E. purpurea . 35 Other reviews found a trend toward beneficial effects, but variations in trial data make definitive statements about effect difficult. 34 , 37 , 38 , 39 One study evaluated the placebo effect in treating the common cold and found decreased duration and severity of symptoms among a subgroup of participants who believed in echinacea, regardless of whether or not they had received echinacea or placebo. 40 Clinical trials continue to be undertaken with results remaining equivocal. 41 , 42 One clinical study in otitis media suggested an increased risk of disease in echinacea-treated children. 43

Prevention

The analyses of trial data for the prevention of colds are less compelling in their conclusions than those of treatment. However, variations in the delay between appearance of cold symptoms and taking the preparation may add to the difficulty in making comparisons. 44 The Cochrane meta-analysis included data from 3 trials and found no difference between echinacea and placebo. 35 In 2 additional reviews, trial data excluded from the Cochrane meta-analysis showed a trend toward benefit in the prevention of colds. 39 , 44 All reviewers concluded that more rigorous trials are required. 35 , 39 , 44

Other uses
Antiviral

Echinacea's in vitro activity against herpes simplex virus, HIV, and influenza has been described for E. purpurea extracts. 33 , 45 , 46 A clinical trial investigating the effect of echinacea on the severity and recurrence of genital herpes found no difference over placebo. Antifungal and antibacterial properties have also been described, but clinical trials are lacking. 3 , 24

Anti-inflammatory

When injected IV in mice or rats, echinacea extract almost completely inhibited carrageenan-induced mice or rat paw edema. Similarly, when the extract was applied topically, it almost completely inhibited the inflammation induced by croton oil applied to the mice or rat ears. 47 Activity of echinacea was slightly less than that of topical indomethacin. Several caffeoyl conjugates isolated from E. angustifolia , including chicoric acid, cynarine, chlorogenic acid, and caftaric acid, demonstrate antihyaluronidase activity. 48 Alkamides from E. angustifolia exhibited cyclooxygenase-2–dependent prostaglandin E 2 inhibition in laboratory experiments. 26 , 46 , 49

Dermatology

Cream and gel echinacea preparations demonstrated skin hydrating and antiwrinkle properties in a small clinical study. 50 Echinacea exhibited in vitro antibacterial activity against clinical strains of Propionibacterium acnes , suggesting a role in the management of acne. 51

Dosage

A major limitation reported in the meta-analyses of available trial data was the lack of standardization of echinacea preparations. Many products lacked active echinacea chemical compounds or were contaminated with other chemical entities. 3 , 34 , 35

Recommended dosing (all administered 3 times daily) includes 300 mg dry powdered extract (standardized to echinacoside 3.5%), 0.25 to 1.25 mL liquid extract (1:1 in alcohol 45%), 1 to 2 mL tincture (1:5 in alcohol 45%), 2 to 3 mL expressed juice of E. purpurea , and 0.5 to 1 g dried root or tea. 52 Safety and tolerability have been studied in children. 43 , 53

Intravenous use of echinacea is not recommended. 13 Echinacea use for more than 8 weeks at a time should be avoided because of the potential for immune suppression. 35 , 52 , 54

Pregnancy/Lactation

A prospective cohort study (N = 206) found no increased risk of fetal malformations with the use of echinacea during the first trimester, 55 but was limited by small sample size, allowance of detection of common malformations only, and lack of standardization of preparations. 3 , 56 Evidence for the safe use of echinacea during pregnancy is lacking; however, the Complete German Commission E Compendium Monographs considers oral echinacea safe for use during pregnancy and lactation in normal recommended dosages. 6 , 52

Interactions

Specific case reports of interactions are lacking, and limited, conflicting data regarding effects on the CYP-450 enzyme system have been published. 3 , 57 , 58 , 59 Studies have shown no clinically important effects of coadministration of echinacea with digoxin, 59 warfarin, 60 darunavir, lopinavir, or ritonavir. 61 , 62 A theoretical interaction with immunosuppressant drugs has been postulated due to immunomodulatory activity described for echinacea. 45

Adverse Reactions

Adverse reactions for echinacea are not commonly reported despite widespread use and are observed as frequently as with placebo in clinical trials. 34 , 45 The most commonly reported are allergic reactions (including a case report of immunoglobulin E–related eosinophilia), GI upset, and rash. Individuals with allergy to ragweed, chrysanthemum, marigold, daisies, or related allergens should use echinacea with caution. 45 , 52 , 63

A case report of leukopenia, possibly caused by long-term use of echinacea, has been published, 54 while a case of reversible acute cholestatic autoimmune hepatitis has been attributed to echinacea consumption. 64 In a trial conducted among patients with advanced gastric cancer, an association with the use of IV E. purpurea extract could not be ruled out in the deaths of 2 patients. 17

Debate exists regarding the appropriateness of echinacea use in patients with autoimmune disorders, and until clarified, echinacea should not be used in any condition in which immune stimulation or suppression would be considered disadvantageous, such as HIV, tuberculosis, multiple sclerosis, and immunosuppressive therapy. 45 , 65

Toxicology

Little is known about the toxicity of echinacea, despite its widespread use. It has been documented in traditional American medicine for more than a century and generally has not been associated with acute or chronic toxicity. 3 Purified echinacea polysaccharide is relatively nontoxic. Toxicity studies found that doses of arabinogalactan as high as 4 g/kg injected intraperitoneally or IV were essentially devoid of toxic effects. 22 High-dose oral and IV administration (ie, several times the normal human therapeutic dose) of the expressed juice of E. purpurea to rodents for 4 weeks demonstrated no acute, subacute, genotoxic, carcinogenic, mutagenic, or other toxic reactions. 66

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