Echinacea, an immune stimulant, may be helpful in treating but not preventing colds.

[LFODPKM ] Letter Key

Latin Name

Echinacea pallida (Nutt.) Nutt, Echinacea purpurea (L.) Moench., Echinacea angustifolia DC.

Family

Compositae/Asteraceae

Other Common Names

Purple coneflower, purple Kansas coneflower, red sunflower, and comb flower

Description

• Echinacea, a decorative plant, has daisy-like flowers (purple, dark pink, sometimes white, yellow, or red) and a prominent central cone; its petals (actually ray flowers) often point earthward.

Part Used

Aerial parts or root

Known Active Constituents

• Caffeic acid derivatives, alkamides, poly-acetylenes (ketoalkenes/ketoalkynes), glyco-proteins, and polysaccharides. Alkylamides are thought to be the most active constituents; it is unclear which alkylamides are most active (also, alkylamides from E. purpurea differ from those of E. angustifolia)(1).
• Cichoric acid, a caffeic acid derivative, may be the most active constituent of fresh squeezed juice preparations, but only traces are present in E. angustifolia roots. Echinacoside, another caffeic acid derivative, is present in the roots of E. angustifolia and E. pallida but is almost absent from E. purpurea roots (1).
• Ketodialkenes and ketodialkynes, present in E. pallida roots, are absent from the roots of E. angustifolia and E. purpurea. Hydrophilic polysaccharides and glycoproteins, prominent in expressed juice and in extracts of aerial parts, are found in lesser concentrations in roots. High molecular weight hydrophilic polysaccharides and glycoproteins may only be bioavailable in parenterally administered preparations (1).

Mechanism/Pharmacokinetics

• Mechanisms of action include stimulation of phagocytosis, activation of macrophage cytotoxicity, and stimulation of tumor necrosis factor-alpha, interleukin-1, and interferon-B2.

[Outline]

• LLatin Name
• FFamily
• OOther Common Names
• DDescription
• PPart Used
• KKnown Active Constituents
• MMechanism/Pharmacokinetics

[CAO ] Letter Key

Clinical Trials

• Prevention of upper respiratory infections (URIs)
  • None of the placebo-controlled randomized controlled trials (RCTs) of echinacea-only products for the prevention of URIs found a benefit. A three-armed trial in 302 subjects (289 were analyzed) compared E. angustifolia root extract to E. purpurea root extract and placebo (2 × 50 drops daily 5 times/week × 12 weeks); there was no difference among groups in the time to occurrence of the first URI or in the proportion of groups that developed URIs (2). Another trial, published twice, tested pressed juice of E. purpurea herb extract (4 mL twice daily for 8 weeks) in 109 subjects and found no benefit on the incidence, duration, or severity of colds or URIs (3,4). The only trial using a rhinovirus challenge found no effect of echinacea (an uncharacterized extract containing 0.16% cichoric acid) on the incidence of experimentally induced infection or colds (5).
• Treatment of URIs
  • Seven randomized, placebo-controlled trials, with a total of 1,354 subjects, found echinacea beneficial for URI treatment in at least one treated group. Tested extracts included: E. pallida root (6,7); pressed juice (8,9); E. purpurea root (10,11); two doses of Echinaforce (containing E. purpurea root 5%, herb 95%) (11); and Echinacea Plus tea, containing E. purpurea herb, E. angustifolia herb, and a dry extract of E. purpurea root in a 6:1 ratio (12). Most formulations (all but two extracts of E. purpurea root) were significantly better than placebo in the primary outcome measures. Most trials examined duration of symptoms; the Hoheisel study (sometimes classified as a prevention trial) administered echinacea at first onset of symptoms and found a significant reduction in proportion of participants who developed a "real cold," as well as shorter duration of symptoms.
• Immune stimulation
  • A systematic review of controlled clinical trials of echinacea products for immune modulation identified 26 controlled clinical trials (18 randomized, 11 double-blind) (13). Nineteen trials examined infection prevention or treatment; four examined side effects of cancer therapies and three trials tested modulation of immune parameters. A beneficial effect was claimed for 30/34 trials; however, studies were methodologically flawed.
  • Echinacea (greater than 0.1 µg/kg) or ginseng extract (10 µg/kg) significantly enhanced natural killer cell function in normal individuals, chronic fatigue syndrome patients, and AIDS patients (14). Both herbs also increased antibody-dependent cellular cytotoxicity of peripheral blood mononuclear cells (from all patient groups) against human herpes virus-6 infected H9 cells.
  • A double-blind study in 24 healthy men found that an ethanolic E. purpurea root extract (30 drops t.i.d. × 5 days) increased phagocytosis by 120%, a significant difference from placebo (which increased phagocytosis by 20%). Phagocytotic activity normalized within 6 days (15).

Animal/In Vitro

• Immune stimulation
  • Expressed juice of E. purpurea herb (5.0 mg/mL) stimulated phagocytosis in several in vitro assays (a high dose of 12.5 mg, however, reduced phagocytosis) (15). An ethanolic extract of E. purpurea root (5 mg extract t.i.d. × 2 days) tripled phagocytosis in the carbon clearance test in mice (14).
  • In another study, 100 µg of E. purpurea polysaccharides equaled 10 units macrophage-activating factor in stimulating peritoneal and bone marrow macrophages to cytotoxicity against P-815 cells (15).
  • Oral E. purpurea extract for 14 days increased natural killer cell numbers in aging mice (16).
  • Acidic arabinogalactan polysaccharides from E. purpurea activated macrophage cytotoxicity against tumor cells and Leishmania enriettii and stimulated production of tumor necrosis factor-alpha, interleukin-1, and interferon-B2 (17).
  • Another experiment found similar results with concentrations greater than 1 µg; purified polysaccharides had no effect on T lymphocytes but modestly increased proliferation of B lymphocytes (18). The authors mention but do not detail a mouse experiment in which intraperitoneal injection of purified polysaccharides did not affect survival (18).
  • Echinacea-treated rats showed significant augmentation of primary and secondary IgG response to key hole limpet hemocyanin (19).
  • Polysaccharides from E. purpurea cell cultures restored resistance against lethal infections of Listeria monocytogenes and Candida albicans in experimentally immunosuppressed mice (20).
  • Phototoxic effects of E. purpurea root extracts against fungi (including C. albicans and other species of Candida) have been attributed to ketoalkenes and ketoalkynes (21).
  • A polysaccharide and glycoprotein-containing fraction of E. purpurea root showed effects against herpes simplex and influenza viruses; polyacetylenic compounds from E purpurea root have antibacterial activity against Escherichia coli and Pseudomonas aeruginosa (15).
• Antioxidant effects
  • Several polyphenols isolated from echinacea reduced oxygen radical-induced collagen degradation, suggesting that topical echinacea extracts may be useful for preventing ultraviolet radiation-induced photodamage of the skin (22).
  • Methanol extracts of freeze-dried roots of E. angustifolia, E. pallida, and E. purpurea had free radical scavenging effects and suppressed low density lipoprotein (LDL) oxidation (23).
• Wound healing
  • Guinea pig wounds treated with a topical ointment containing 0.15 mL E. purpurea juice were significantly smaller compared with untreated controls (15).

Other Claimed Benefits/Actions

• Urinary tract infections
• Vaginal candidiasis
• Wounds (topical)
• Skin conditions (topical)
• Cancer

[Outline]

• CClinical Trials
  • Prevention of upper respiratory infections (URIs)
  • Treatment of URIs
  • Immune stimulation
• AAnimal/In Vitro
  • Immune stimulation
  • Antioxidant effects
  • Wound healing
• OOther Claimed Benefits/Actions

[APT ] Letter Key

Adverse Reactions

• Four cases of anaphylaxis, 12 cases of acute asthma, and 10 cases of urticaria/angioedema attributed to echinacea were reported to the Australian Adverse Drug Reactions Advisory Committee; 3 of 5 cases evaluated by the reviewers had positive skin prick tests (24).
• With oral products, unpleasant taste is the most common side effect, allergic skin reactions may also occur. Parenteral administration of E. purpurea squeezed sap [Echinacin (R)] may cause shivering, fever, and muscle weakness (25).
• Acute disseminated encephalomyelitis
  • A 49-year-old woman treated with intramuscular injections of a homeopathic product [containing E. angustifolia D2 1.1 mL, lachesis D8 (snake venom) 0.3 mL, and "echinacea comp Hevert inject" 0.3 mL], administered with her own blood, developed numbness and weakness in her arm and was diagnosed with acute disseminated encephalomyelitis (26). Given confounding factors, it is difficult to attribute these effects to echinacea.

Pregnancy/Lactation

• A controlled study compared 206 women who reported gestational use of echinacea to the Motherisk program (112 reported first trimester use) with 206 controls; there were no significant differences between groups for major or minor malformations (27).

Animal Toxicity

• In rats, oral doses of expressed juice of E. purpurea herb (up to 8,000 mg/kg × 4 weeks) caused no pathologic changes on necropsy. LD₅₀ acute dose in rats is >15,000 mg/kg orally and greater than 5,000 mg/kg intravenously; in mice oral LD₅₀ is >30,000 mg/kg and > 10,000 mg/kg intravenously (15).

[Outline]

• AAdverse Reactions
  • Acute disseminated encephalomyelitis
• PPregnancy/Lactation
• TAnimal Toxicity

[C ] Letter Key

Common Dosage Forms

• Echinacea angustifolia root
  • Dried root: 1 g
  • Liquid extract: (1:5 in 45% ethanol) 0.5 to 1 mL t.i.d.
  • Tincture: (1:5 in 45% ethanol) 2 to 5 mL t.i.d.
• Echinacea purpurea herb
  • Juice: 6 to 9 mL expressed juice, or equivalent preparations (daily dose)
  • External: Semisolid preparations containing at least 15% pressed juice
  • Children: Proportion of adult dose by age or body weight
• Echinacea purpurea root
  • 300 mg crude drug t.i.d.
  • Tincture: (1:5, ethanol 55%) 60 drops t.i.d.
• Usually, echinacea is not administered for longer than 8 weeks. For chronic administration, breaks are advised (schedules vary by source and include alternating weeks; 3 out of 4 weeks; 1 month on, 2 weeks off, etc.). No data support one regimen over another.
• Quality note: Extracts of E. purpurea root may be inferior to E. pallida root or E. purpurea herb. Standardized extracts of echinacea are available, but it is unclear to which compound echinacea should be standardized.

[Outline]

• CCommon Dosage Forms
  • Echinacea angustifolia root
  • Echinacea purpurea herb
  • Echinacea purpurea root

Q: Should patients with HIV or autoimmune disease avoid echinacea?

A: Theoretically, stimulation of T cells could encourage viral replication. However, a phase I study, published in a nutraceutical journal, in 14 men with HIV (9 on antiretrovirals) found that E. angustifolia (1,000 mg t.i.d. × 12 weeks) significantly reduced viral load (28). A double-blind placebo-controlled crossover study in HIV-positive patients compared placebo to E. angustifolia (1 g t.i.d. × 16 weeks); preliminary results in 12/61 patients, reported in 1998 as an abstract, revealed marked increase in natural killer (NK)-mediated lysis of HIV-transfected cells only during the treatment period (29).

Even if echinacea is beneficial temporarily, the effects of echinacea are thought to diminish with time. Longer, better studies are needed. I no longer discourage HIV-positive patients from using echinacea, but I do not recommend it either. Concerns that echinacea worsens autoimmune disease are also theoretical; no cases have been reported. Echinacea can cause allergic reactions; I advise atopic and asthmatic patients against taking echinacea.

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2. Melchart D, Walther E, Linde K et al. Echinacea root extracts for the prevention of upper respiratory tract infections: a double-blind, placebo-controlled randomized trial. Arch Fam Med 1998;7:541–545.
3. Grimm W, Müller H-H. A randomized controlled trial of the effect of fluid extract of Echinacea purpurea on the incidence and severity of colds and respiratory infections. Am J Med 1999;106:138–143.
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5. Turner RB, Riker DK, Gangemi JD. Ineffectiveness of Echinacea for prevention of experimental rhinovirus colds. Antimicrob Agents Chemother 2000;44:1708–1709.
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14. See DM, Broumand N, Sahl L et al. In vitro effects of echinacea and ginseng on natural killer and antibody-dependent cell cytotoxicity in healthy subjects and chronic fatigue syndrome or acquired immunodeficiency syndrome patients. Immunopharmacology 1997;35:229–235.
15. European Scientific Cooperative on Phytotherapy (ESCOP). Echinaceae pallida radix (pale coneflower root), Echinacea purpureae herba (purple coneflower herb), and Echinacea purpureae radix (purple coneflower root), Fascicule 6. Exeter, UK, 1999.
16. Currier NL, Miller SC. Natural killer cells from aging mice treated with extracts from Echinacea purpurea are quantitatively and functionally rejuvenated. Exp Gerontol 2000;35:627–639.
17. Luettig B, Steinmüller C, Gifford GE et al. Macrophage activation by the polysaccharide arabinogalactan isolated from plant cell cultures of Echinacea purpurea. J Natl Cancer Inst 1989;81:669–675.
18. Stimpel M, Proksch A, Wagner H et al. Macrophage activation and induction of macrophage cytotoxicity by purified polysaccharide fractions from the plant Echinacea purpurea. Infect Immun 1984;46:845–849.
19. Rehman J, Dillow JM, Carter SM et al. Increased production of antigen-specific immunoglobulins G and M following in vivo treatment with the medicinal plants Echinacea angustifolia and Hydrastis canadensis. Immunol Lett 1999;68:391–395.
20. Steinmuller C, Roesler J, Grottrup E et al. Polysaccharides isolated from plant cell cultures of echinacea enhance the resistance of immunosuppressed mice against systemic infections with Candida albicans and Listeria monocytogenes. Int J Immunopharmacol 1993;15:605–614.
21. Binns SE, Purgina B, Bergeron C et al. Light-mediated antifungal activity of echinacea extracts. Planta Med 2000;66:241–244.
22. Facino RM, Carini M, Aldini G et al. Echinacoside and caffeoyl conjugates protect collagen from free radical-induced degradation: a potential use of Echinacea extracts in the prevention of skin photodamage. Planta Med 1995;61:510–514.
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25. Parnham MJ. Benefit-risk assessment of the squeezed sap of the purple coneflower (Echinacea purpurea) for long-term oral immunostimulation. Phytomedicine 1996;3:95–102.
26. Schwarz S, Knauth M, Schwab S et al. Acute disseminated encephalomyelitis after parenteral therapy with herbal extracts: a report of two cases. J Neurol Neurosurg Psychiatry 2000;69:516–518.
27. Gallo M, Au W, Koren G. Pregnancy outcome following gestational exposure to echinacea. Arch Int Med 2000;160:3141–3143.
28. See D, Berman S, Justis J et al. Phase I study on the safety of Echinacea angustifolia and its effect on viral load in HIV infected individuals. J Am Nutraceut Assoc 1998;1(ISS1):14–17.
29. Berman S, See DM, See JR et al. Dramatic increase in immune mediated HIV killing activity induced by Echinacea angustifolia. Int Conf AIDS 1998;12:582(abst no 32309).