Francis Brinker, ND 

Introduction

Circa 1900, the reputation of Echinacea was built on the use of high-alcohol extracts of Echinacea angustifolia roots applied topically for wounds, infections, and poisonous bites and stings and administered internally for acute infections now known to be bacterial. Beginning in the mid-20th century, when European clinical research on low-alcohol fresh plant extracts of Echinacea purpurea established their usefulness in treating the common cold, the perception of Echinacea root extracts was transformed based on their generic relationship. The proclivity of modern botanical use for evidence-associated applications has led to widespread confusion regarding the differences between these distinct botanical species and their preparations.

Original Eclectic Preparations and Official Recognition

Meyer of Nebraska was the first to produce a commercial extract of Echinacea. Although combined with hops and wormwood in his Meyer’s Blood Purifier for internal use, he used the tincture of the root by itself for local applications.¹ Meyer and King² in the Eclectic Medical Journal in 1887 described their use of the root for 16 years as an “alterative” and antiseptic, claiming that its tincture was effective internally and externally for treatment of boils, carbuncles, ulcers of the throat and extremities, hemorrhoids, and wasp and bee stings. In 613 cases of rattlesnake poisoning treated in humans and animals, recoveries occurred after 2 to 12 hours.

Circa 1900, most eclectic physicians were using Lloyd Brothers Pharmacists’ Echinacea extracts, following years of study by Lloyd.¹ After privately supplying a tincture of the root of E angustifolia to eclectic investigators beginning in 1890, the Lloyd Brothers in 1894 introduced their commercial Specific Medicine Echinacea to the medical profession.^3,4 Lloyd determined that the characteristic acrid principles of the dried root that produced a tingling and numbness of the tongue required a high–alcohol concentration for extraction.¹ By 1906, the use of Echinacea as an external and internal remedy had extended to conventionally trained physicians. It was also being used by them for the treatment of infected wounds, septicemia, and bites and stings of poisonous insects.⁵

The Lloyd Brothers manufactured various Echinacea preparations. Their Specific Medicine Echinacea with 65% alcohol had the same drug strength as a fluid extract (1:1), but its production involved a proprietary process.⁶ Other Lloyd Brothers preparations included Echafolta, a refined preparation free of sugars and coloring matter and made with 92% alcohol. Considered equivalent to Specific Medicine Echinacea, Echafolta was a preferable choice in surgical cases, for which greater cleanliness was desired.^1,6 By 1922, a small quantity of tincture of iodine had been added to Echafolta, at which time it became reserved for external use only.⁷ Echafolta Cream provided the active principles in a bland petrolatum base.⁸ It was used as a soothing dressing locally and as an adjunct to internal medication and surgical measures.^1,6 A nonalcoholic extract of Echinacea for hypodermic use was given the trade name Subculoyd Echinacea.⁴ While occasionally specifying tincture, fluid extract, Specific Medicine Echinacea, Echafolta, or Subculoyd Echinacea, most physician reports of E angustifolia root extracts refer to whatever preparation was used simply as Echinacea.

The Lloyd Brothers emphasized the quality of their product:

Echinacea is made from the carefully selected, prime, dried, cured, and assayed root of E. angustifolia. The quality of but few drugs is more influenced by conditions prevailing in different localities and by treatment during drying, than is Echinacea.… Prime drug from favored geographic regions may be ruined by careless or faulty manipulation.… The famous Lloyd process permits the extraction of delicate and complex botanical therapeutic principles without harm.^8(p)

Their ongoing laboratory research led to the statement in 1923 that “the therapeutic importance of the acrid constituent emphasized in our former literature constitutes but a part of its qualities, being most pronouncedly supported by less sensible constituents.”^3(p)

American Medical Association Condemnation vs Acceptance by Physicians and the National Formulary

In 1909, a report by the Council on Pharmacy and Chemistry in the Journal of the American Medical Association condemned Meyer’s “absurd” claims and those “made on no better basis than that of clinical trials by unknown men who have not otherwise achieved any general reputation as acute, discriminating and reliable observers.”^9(p1836) They declared that “Echinacea is deemed unworthy of further consideration until more reliable evidence is presented in its favor.”^9(p)

Ellingwood, the eclectic materia medica professor at Bennett Medical College, Chicago, Illinois, responded to the Council on Pharmacy and Chemistry:

Not a single member was engaged in active medical practice or was in a position to observe the action of drugs in the influence they exercise in the cure of disease.… In view of the fact that 20,000 physicians of the United States are using this remedy with success; and in view of the fact that there is a perfect agreement concerning the observations made by these reliable and trustworthy practitioners, …it seems strange indeed that this half dozen or more men should say that because of the scrutiny (or lack of scrutiny) that had been made, the remedy is deemed unworthy of further consideration.^10(p)

Clinicians remained enthusiastic about the usefulness and efficacy of Echinacea after the condemnation published in the Journal of the American Medical Association. A survey was sent by Lloyd to more than 30 000 physicians who had graduated from all types of medical schools, asking them to indicate which botanical drugs they used in their practices. More than 10 000 responded, and Echinacea ranked eleventh (listed by 5065 physicians) in importance among all botanical drugs, as published in 1912 in the Journal of the American Pharmaceutical Association.¹¹

In 1916, the fourth edition of the National Formulary¹² established E angustifolia dried roots and its fluid extract as official remedies. In testing the manufacture of a standard Echinacea fluid extract in 1911 for inclusion in the National Formulary, it was concluded that menstruums with less than 67% ethanol did not adequately extract from the dried root those pungent principles responsible for the tingling sensation in the mouth.¹³

Early Scientific Assessments of E angustifolia Root Extracts

The first major clinical research performed with E angustifolia was conducted from 1913 to 1916 by von Unruh, a US Army lieutenant. He used the nonalcoholic injectable medications Subculoyd Echinacea and Inula Compound (1.0 and 1.33 mL, respectively, intramuscularly or intravenously) in the treatment of patients with tuberculosis. Among 150 patients, he described 100% recovery in those with incipient pulmonary disease, 50% arrest in those with moderately advanced disease, but no success in those with advanced disease.^14,15 In microscopic research involving more than 500 differential and cell counts over longer than 4 years, he found that injected Echinacea extract raised the opsonic index, increased the phagocytic power of leucocytes, improved leukopenia and hyperleukocytosis, and normalized the percentage of mature neutrophils.¹⁵

Couch and Giltner subsequently tested the major Echinacea products in animals.¹⁶ Performing injections in small numbers of guinea pigs, they used bacterial toxins to experimentally induce tetanus and botulism, rattlesnake venom to simulate snakebites, and live bacteria to cause tuberculosis, dourine, anthrax, and septicemia. Control animals were untreated or were administered the same alcohol content as in the extracts. Echinacea preparations (Specific Medicine Echinacea, Subculoyd Inula and Echinacea, or Echinacea fluid extract National Formulary 4) were administered before or after the pathologic injections. The induced diseases were interpreted as essentially the same in the control and treated animals. The authors concluded that Echinacea was not of value in the treatment of diseases produced by microorganisms or biologic toxins.^17,18

A 1921 editorial review of these findings that was published in the Journal of the American Medical Association noted, “Of course, it will be retorted that the negative results on laboratory animals need not necessarily apply to sick human beings, and that subtle potent effects are not always discovered by research workers…. Scientific medicine of today, however, asks for evidence that can be demonstrated by the pharmacologist or can be appreciated and accepted by the critical clinician as well as the quack.”^16(p). It was argued that the Echinacea fluid extract used in the experiment should be removed from the National Formulary.¹⁶

A critical review of this laboratory research by Beal,¹⁹ director of pharmaceutical research at the University of Illinois, Urbana, and former editor of the American Pharmaceutical Association Journal, was also published in 1921. He noted that the experiments were too few to be conclusive and that the results were not interpreted from a clinical perspective. Three times the minimum fatal dose of tetanus was administered to 19 animals receiving Specific Medicine Echinacea; 10 times the minimum fatal dose of botulinus was administered. The septicemia and dourine produced by Bacillus bovisepticus and Trypanosoma equiperdum, respectively, were species that were unassociated with human pathologic conditions. In the tuberculosis experiments, the mean weight loss in control animals was 129% that of the treated animals, which survived 36% longer. Of the animals injected with rattlesnake venom, the 3 controls died, while 1 of 6 Echinacea-treated guinea pigs survived.¹⁹

Responses of Clinical Empiricists

The Lloyd Brothers, as a courtesy to Couch and Giltner^17,18 and in fairness to all concerned, publicized their experimental results and suspended advertisements of Echinacea preparations for 1 year, despite the fact that Echinacea products were their best-selling botanicals from 1885 to 1921. Following publication of the negative laboratory research, the Lloyd Brothers recorded their best sales ever of Echinacea extracts by even larger margins over other botanicals in 1921. In 1922, Echinacea sales increased again, almost 25% above 1921 sales and more than 3 times greater than sales of the next plant drug (Chionanthus) among their 239 different plant remedies!³

In another attempt to assess the value of Echinacea, a postcard questionnaire was sent by the Lloyd Brothers to physicians concerning the use of Echinacea preparations in their clinical practice in 1921. They asked for prominent indications and uses of Echinacea, providing 1 line for the response and 2 additional lines for remarks. Physicians were asked to consider whether they would be willing to use a synthetic or other substitute to replace Echinacea. In 1923, the responses were published.³ This unparalleled document provides ardent empirical consensus verifying prior clinical claims.

In comments received from 701 physicians who used E angustifolia preparations in their practices, 70.3% (493 respondents) advocated its general use in septic conditions, 22.1% (155 respondents) specified its effectiveness in cases of septicemia or blood poisoning, and 14.3% (100 respondents) noted its efficacy for treatment of typhoid fever (Table 1). Use in cases of blood “dyscrasias” by 21.4% (150 respondents) and as an alterative by 11.3% (79 respondents) were cited as other major indications. Lloyd³ noted that neither tetanus nor botulism was mentioned in any of the survey responses, nor had treatment with Echinacea been recommended for these conditions in major eclectic texts, challenging the pertinence of the findings by Couch and Giltner.^17,18 However, a striking feature of the survey results is that most indications mentioned by physicians for E angustifolia root preparations were bacterial infections vs few mentions of viral or fungal infections.³

In the survey³ results, 31.5% stated explicitly (88 respondents) or implicitly (133 respondents) that no substitute for Echinacea would be acceptable, while 1.5% (No. of respondents) indicated that they would use a substitute if it was shown to be equally as effective. The most preferred preparations were Specific Medicine Echinacea internally or locally by 16.1% (113 respondents), Echafolta Cream by 5.7% (40 respondents), injectable Subculoyd Echinacea by 1.0% (7 respondents), and the Echinacea fluid extract by 0.7% (5 respondents). Internal use was specified by 24.1% (169 respondents), local use by 16.4% (115 respondents), and external use by 12.4% (87 respondents). The most common local conditions treated (topically or internally) were poisonous snakebites by 10.6% (74 respondents), bites or stings by insects or spiders by 9.6% (67 respondents), and wounds by 7.7% (54 respondents). In the published survey, a list of responding physicians was provided. They hailed from 41 of 48 states plus Canada, Mexico, and New Zealand.

Clinicians were enthusiastic about Echinacea (Figure). In 1924, it was noted that sales of Echinacea products were 7 times greater than those of any other product made by the Lloyd Brothers.²⁰ To keep the use of Echinacea in context, the Lloyd Brothers described the therapeutic rationale for its application: “Echinacea is a useful aid in the treatment of infection and sepsis, local or systemic.… It is employed as an aid where there is a necessity for agents that possess general antibacterial properties.”^8(p)

 

Medical Use of E angustifolia Root Extracts for Respiratory Infections

It is notable that when E angustifolia was first introduced to clinical medicine in the late 19th century, scant mention was made of its use for treating simple upper respiratory tract infections. In 1898, Felter and Lloyd¹ noted that E angustifolia hydroalcoholic extract contributes much to the cure of catarrh of the nose, nasopharynx, and respiratory tract.

In a 1919 summary by the Lloyd Brothers²¹ of reports from 1000 physicians asked to cite the most important flu remedy following the recent influenza pandemic, Echinacea was not listed among the 9 most useful remedies for influenza or for pneumonia or among the 9 best external applications for either of these conditions. Echinacea was noted in passing by some physicians who listed it when certain remedies were most indicated, for example, “where sepsis is marked, Echafolta or Echinacea becomes most important.”^{21(back cover)}

That same year (1919), when E angustifolia extracts were recommended by Ellingwood²² for catarrhal conditions, it was cited both as an internal and a local medication. In the survey responses from 701 physicians published by Lloyd³ in 1923, ten respondents mentioned influenza as a prominent indication for use of Echinacea, while only 2 specified its use for catarrh and 1 for colds.

The use of Echinacea extracts for treating influenza was discussed in 1929 by Cox,²³ who believed (as is the general consensus today) that early application of good-sized doses from the first day until the body temperature reached normal was the best means of using this remedy. However, even after several days, Echinacea in large doses was still used. In patients with purulent expectoration, the dosing continued until the sputum cleared up. Echinacea angustifolia was prescribed along with appropriate cough preparations until the pulmonary congestion was entirely resolved. Large doses were administered to patients with influenza until the cough subsided.

 

Eclectic Human Research and Decline

Preliminary human research was attempted in 1934, when students at the Eclectic Medical College, Cincinnati, Ohio, volunteered as subjects to study the effects of Echinacea by taking therapeutic doses for 4 days. Specific Medicine Echinacea was administered in water in doses of 2 to 15 minums, derived from 2 to 15 grains (130-975 mg) of the dried root. Blood samples were drawn at baseline and again after each day of use. Increases in total leukocyte counts were apparent, peaking in two-thirds of the subjects after 24 hours and in the remaining one-third after 48 hours.²⁴ The leukocyte increase was mostly neutrophils after 24 hours and mostly lymphocytes after 48 hours. Total and differential counts were normal after 72 hours. These uncontrolled results, crude by modern standards, suggest that Echinacea combats infectious agents acutely, briefly, and indirectly through the blood.

Echinacea angustifolia use diminished after the decline of eclectic medicine in the late 1930s. This was indicated by the dropping of Echinacea fluid extract from the eighth edition of the National Formulary²⁵ in 1946, although the entry of the dried roots was retained in this official text for the last time. In an attempt to identify direct antibacterial activity, German researchers in 1950 isolated the caffeic acid derivative echinacoside from the root; echinacoside demonstrated weak inhibition of streptococcal and Staphylococcus aureus gram-positive bacteria.²⁶

Adoption by Naturopathic Physicians

Echinacea angustifolia was prescribed by naturopathic physicians for local and internal use in accord with the indications established by the eclectics. Echinacea was considered one of naturopathy’s most valuable herbs. In 1936, Specific Medicine Echinacea was recommended by naturopathic physicians as an alterative for septic conditions.²⁷ In such cases, 20 drops of Specific Medicine Echinacea in a little water every 4 hours was suggested for treatment of recurring boils, carbuncles, ulcerations, and lymphangitis. Septic fevers, typhoid fever, and acute nephritis were treated with 20 drops every 2 hours until the crisis passed. This preparation was to be administered internally and applied locally as a wet dressing for snakebites, cuts, wounds, and insect stings.

Twenty years later, the Echinacea fluid extract was again advocated in a naturopathic journal as a treatment for septicemia, as an antiseptic for boils, and locally for swelling.²⁸ A tincture of the fresh root (1 teaspoonful every 2-4 hours) was recommended in patients with diphtheria and puerpural septicemia. It was often combined with other appropriate remedies.^28,29

The Naturae Medicina and Naturopathic Dispensatory in 1953 recommended hydroalcoholic extracts of the dried root of E angustifolia, along with its decoction, as “one of Naturopathy’s most faithful antibiotics and alteratives.”^29(p) Internal use of the tincture or Specific Medicine Echinacea, together with its external application, was again emphasized for insect stings, boils, carbuncles, and certain septicemias. The tincture or decoction was used as a gargle for buccal ulcerations, ulcerative stomatitis, gingivitis, tonsillitis, and pharyngitis and as a retention colonic for ulcerative colitis. In a mixture with glycerin, it was applied on a tampon for eroded cervix and nonspecific vaginitis with leucorrhea.²⁹

Notable natural medicines excluded from the 1953 Naturae Medicina and Naturopathic Dispensatory²⁹ were opiates and antibiotics. The absence of antibiotics is particularly notable because their use had been positively addressed by Bastyr³⁰ in an article in the Journal of the American Naturopathic Association in 1950. He discussed in detail the use of penicillin, steptomycin, aureomycin, bacitracin, polymixin, neomycin, terramycin, and others. These products were considered by Bastyr as appropriate for use on a selective basis, being derived from lower plant life forms according to the taxonomic classifications of that time.

Naturopathic physicians treated many infectious diseases without modern antibiotics. This was primarily because of disruptive effects that their powerful medicines had on symbiotic bacteria in the intestines. Natural methods of destroying germs and stimulating natural immunity were preferentially used.³¹ Bastyr³⁰ had specifically noted the antibacterial efficacy of allicin from garlic (Allium sativum) and extracts of sagebrush (Artemisia tridentata), juniper (Juniperus communis), and buttercups (Ranunculus spp) when prescription antibiotics were inappropriate or if a change of therapy was required.

Bastyr also used E angustifolia root tincture internally for the treatment of septicemia, pyuria, and gangrene.³² He administered it to treat coughs and colds and to boost deficient immune function in many infections. For the treatment of infections, Echinacea was frequently used in combination with other immune-enhancing and antimicrobial botanicals. A fundamental formula used by Bastyr combined extracts of E angustifolia root (4 parts), Hydrastis canadensis rhizome (4 parts), and Phytolacca decandra root (1 part). He also spoke highly of adding Baptisia tinctoria to this formula. He would often combine Echinacea (5 parts) with Baptisia (1 part) for infections and administer 60 drops 3 times daily. He used diluted Echinacea extract topically to treat decubitus ulcers.

A modern E angustifolia fresh root (1:1) 65% ethanol extract (Specific Medicine Echinacea manufactured by the Eclectic Institute using the Lloyd extractor) administered orally to male rats in their drinking water for 6 weeks was recently shown to increase the initial antigen-specific day 0 induction of IgG response after 7 days and subsequent day 10 antigen inductions of IgG on days 14, 21, 24, and 27 in a statistically significant manner compared with controls (range, P = .04 to P = .002).³³ Nonsignificant IgG increases also occurred on days 10, 18, and 32 but not after the third antigen challenge on day 35. Although increases in antigen-specific IgM occurred on all of the aforementioned days, as well as on days 35 and 39, none of these increases were significant compared with to control animals.

Introduction of E purpurea

Other Echinacea species (eg, Echinacea pallida root in the eighth revision of the National Formulary²⁵) were sometimes used as substitutes for E angustifolia.²⁸ Echinacea purpurea had been mentioned by King in his Eclectic Dispensatory (published in 1852) as a folk remedy; at that time, E purpurea was known as Rudbeckia purpurea and was occasionally confused with E angustifolia, although rarely used by the eclectics.¹

Echinacea angustifolia had been introduced into homeopathic practice in Europe in the late 19th century. Because of a severe shortage of this drug in Europe in the 1930s, the German pharmaceutical manufacturer Madaus came to the United States to obtain seeds of E angustifolia; however, the seeds that he bought were actually E purpurea.^34,35 Consequently, Madaus decided to extract the juice from the aboveground part of the blooming E purpurea plant.³⁵ Preserved with 22% alcohol, E purpurea plant juice with cichoric acid and water-soluble arabinoxylan and arabinogalactan polysaccharides is distinct from E angustifolia root extracts in greater than 50% ethanol with echinacoside and is distinguishable from lipophilic alkamides.³⁶ Because E purpurea juice had not previously been used clinically, Madaus experimented with its use. Since then, much European research on Echinacea has used this preparation or similar preparations internally and externally.^34-36

In the 1950s, the Swiss naturopath Vogel³⁷ traveled to America and learned the native uses of E angustifolia from the Sioux in South Dakota. Finding that the related species E purpurea was effective and easier to harvest, he returned with seeds of this species to cultivate in the Swiss “lowlands” at 4500 feet above sea level (1600 m). After 10 years, when these plants had acclimated sufficiently to produce flowers, he began using the tincture of the whole fresh plant to strengthen the immune response to infectious conditions.

In 1989, the German Commission E officially approved the fresh-flowering E purpurea aboveground plant and its preparations for treatment of colds, poor wound healing, and chronic infections of the respiratory and urinary tracts. In 1992, E pallida fresh or dried root was officially recognized by the Commission E for clinical use in influenza-like infections, particularly the 50% alcoholic tincture. However, E purpurea and E angustifolia roots were not approved.³⁸ Echinacea purpurea, E angustifolia, and E pallida roots are distinctive phytochemically (Table 2).³⁶ Ironically, although water extracts of E purpurea roots were potent against influenza virus and although ethanolic fractions and alkamides of E angustifolia root inhibited rhinovirus in vitro, the E pallida root water and ethanolic fractions were ineffective against both.³⁹ European experience and clinical research with the cultivated E purpurea plant has led to its popularization in America.

Therapeutic Trials With Echinacea Extracts for Upper Respiratory Tract Viral Infections

Recent clinical trials of commercial E purpurea fresh plant liquid extracts have been well publicized and consistently demonstrate efficacy against acute upper respiratory tract viral infections. A 2007 meta-analysis⁴⁰ of 14 studies among various Echinacea products evaluated randomized controlled trials that studied 1356 patients for incidence and 1630 patients for duration of the common cold. It showed that the use of these preparations decreased the chance of developing a cold by 58% and reduced the duration by a mean of 1.4 days. The 14 preparations in the meta-analysis included 7 from E purpurea, 4 from a combination of E purpurea and E angustifolia, 1 from E angustifolia only, 1 from E pallida, and 1 from unidentified species. Significant reductions in occurrence and duration of the common cold were observed based on a subgroup analysis limited to 5 E purpurea aerial plant juice investigations.

A contemporary systematic review⁴¹ of randomized controlled trials for the common cold was performed for Echinacea preparations: in 2 prevention trials, 411 subjects received Echinacea products, while 5 trials involved self-treatment (1064 subjects) and 9 trials studied clinically treated upper respiratory tract viral infections (1126 subjects). The review found no benefits for prevention but concluded that preparations based on E purpurea aerial parts may be effective for early treatment of colds. Because other preparations were not biochemically comparable, variations in the studies provided no clear evidence of their efficacy.⁴¹

The single randomized placebo-controlled double-blind study⁴² of E angustifolia performed using 3 noncommercial extracts of 2-year-old fresh roots to prevent or treat colds induced by rhinovirus type 39 in 399 volunteers was possibly the most publicized investigation; this study was funded by the National Institutes of Health, and results were published in the New England Journal of Medicine. These extracts, made with supercritical carbon dioxide, 60% ethanol, or 20% ethanol, produced no tendency toward improvement when used for 1 week after virus exposure. For volunteers treated 1 week before and 1 week after exposure, clinical colds developed in 50% receiving the 20% ethanol extract, in 57% receiving the 60% ethanol extract, in 62% receiving the supercritical carbon dioxide extract, and in 66% receiving placebo. The mean total symptom score was 12.1 for patients receiving the 20% extract, 13.2 for those receiving the 60% ethanol extract, 15.5 for those receiving the supercritical carbon dioxide extract, and 15.1 for those receiving placebo. However, none of the differences were statistically significant compared with placebo.

This study⁴² has been criticized for insufficient dosage (900 mg of root extractives vs recommendations of a daily dose of 3 g by the World Health Organization and the Canadian Natural Health Product Directorate), inadequate validation of species identity, and limitation to 1 of more than 100 subtypes of rhinovirus.⁴³ However, the daily dose in an E pallida study⁴⁴ of 160 patients with flu-like infections was extracted from 900 mg of root, which significantly reduced the illness duration, symptom scores, and clinical scores compared with placebo.

Although 2 authors of the National Institutes of Health study⁴² had previously acknowledged that the geographic location of growing E angustifolia and the time of its harvest affect the chemical composition,⁴⁵ neither of these factors was described in the 2005 study⁴² in characterizing the roots obtained from a German company (and presumably cultivated in Europe). While the supercritical carbon dioxide extract contained 74% alkamides and no polysaccharides or caffeic acid derivatives, the 60% ethanol extract had uncharacteristically high 49% total polysaccharides, 2.3% alkamides, and 0.16% cynarin.⁴² The 20% ethanolic extract with 42% polysaccharides and 0.1% alkamides contained no caffeic acid derivatives. The polysaccharide content was not profiled on the basis of molecular weight but only on relative monosaccharide content, which is of no real value.

The high polysaccharide content of the 60% ethanol extract and the low or 0% content of caffeic acid derivatives (especially echinacoside) in all 3 extracts suggest that the roots used were not equivalent to “wildcrafted” roots traditionally and now used in America. However, even if the lack of efficacy of these experimental E angustifolia root extracts against a single rhinovirus subtype is accepted as legitimate evidence of its clinical effect on the common cold, this application is not representative of the traditional empirical use of this species.

Contraindications and Potential for Drug Interactions

The German Commission E monographs³⁸ for the approved E purpurea herb and E pallida root and for the unapproved E purpurea root, E pallida herb, and E angustifolia herb and root speculate that risks warrant avoidance of use in cases of systemic diseases such as tuberculosis, multiple sclerosis, leukosis, collagenosis, AIDS or human immunodeficiency virus infection, and autoimmune diseases. These contraindications remain controversial. Reactions may occur in allergic individuals, especially when aerial parts are used.⁴⁶

Legitimate concerns about combining Echinacea species preparations with pharmaceutical drugs are largely speculative and are based on in vitro research. For example, as a precaution, patients undergoing organ transplantation who take immunosuppressive drugs such as cyclosporine should avoid the use of Echinacea preparations or should consider short-term use.⁴⁶ Echinacea purpurea root extract (oral dose of 1.6 g/day) for 8 days increased the clearance and reduced the bioavailability of intravenous midazolam when this cytochrome P450 (CYP) 3A4 substrate was administered to 12 subjects; the same dose of E purpurea root extract did not alter oral midazolam clearance, suggesting that some extract components inhibit intestinal CYP3A, while other absorbed components induce liver CYP3A.⁴⁷ Echinacea angustifolia root tincture is a potent CYP3A4 inhibitor in vitro, more so than tincture of E purpurea roots.⁴⁸

Most pharmaceuticals, including the macrolide antibiotics clarithromycin and erythromycin, are metabolized by CYP3A4. A theoretical interaction between CYP3A4 substrates and Echinacea root tinctures is limited to in vitro data, but human research suggests otherwise; because of variations in preparations and outcomes, the human research to date is too limited to predict pharmacokinetic or pharmacodynamic interaction outcomes with certainty, and little evidence exists to support significant clinical interactions with medications.⁴⁹

Endangerment and Cultivation

The issue of sustainable harvest of wildcrafted E angustifolia has been raised,⁵⁰ yet it remains abundant in central Kansas, despite more than 100 years (1895-1998) of commercial harvesting and digging booms.⁵¹ Because seeding in November yielded the highest emergence for E angustifolia plants in Nebraska,⁵² harvesting in the autumn and reseeding holes with the dry flower heads is a way to diminish loss from wildcrafting.

Echinacea angustifolia still grows over much of its historical range. Its global conservation status is ranked G4 as apparently secure. In Kansas, where several generations of the same families have dug this species since the early 1900s, tagging pick holes showed a regrowth potential of 36%, and measuring harvest density confirmed that the stands were not significantly diminished; areas that lay fallow for 2 to 3 years after harvesting allow more growth of the small roots and regrowth from remnants of larger harvested roots.⁵³

Cultivation of Echinacea has increased rapidly because of the demand and its great value. Growth of the 3 major medicinal species, E angustifolia, E pallida, and E purpurea, has been the most studied.^54,55 Echinacea purpurea is easy to grow compared with the other 2 commercial species.⁵⁵

Conclusion

The traditional clinical applications of E angustifolia root hydroalcoholic extracts demonstrate their empirical usefulness. Simultaneous internal and local use was believed to increase efficacy. The historical use of E angustifolia to treat serious infectious diseases suggests that an advantage could be gained if it was used to complement conventional antibiotics. However, the positive clinical research on E purpurea fresh plant liquid extracts and E pallida root extract for the treatment of upper respiratory tract viral infections has focused attention almost exclusively on this use. Consequently, the recognition of E angustifolia use for other infectious conditions has diminished.

Although sharing some similarities, selective use of Echinacea species, parts, and their extracts is appropriate for conditions established through empirical tradition (E angustifolia root high-ethanol extracts for sepsis, wounds, and bites) or through modern clinical research (E pallida root 50% ethanol extract for influenza and fresh E purpurea plant low-ethanol extracts for wounds, colds, and chronic respiratory or urinary infections). The safety of Echinacea products is a major advantage, with few theoretical contraindications or individual allergic sensitivities. Echinacea popularity has resulted in regional overharvesting of wild E angustifolia. Nonetheless, commercial cultivation of E purpurea and conscientious wildcrafting can continue to provide a sustainable supply of these important botanical medicines.

 

Ackowledgment

Maggie Heran and her staff at the Lloyd Library and Museum, Cincinnati, Ohio, provided copies of archival material published by the Lloyd Brothers.

 

REFERENCES

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12. Committee on National Formulary. The National Formulary. 4th ed. Washington, DC: American Pharmaceutical Association; 1916.

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14. von Unruh V. Echinacea angustifolia and Inula helenium in the treatment of tuberculosis. Natl Eclectic Med Assoc Q. 1915;7:63-70.

15. von Unruh V. Observations on the laboratory reactions in tests made of echinacea and inula upon tubercle bacilli and other germs. Ellingwood Ther. 1918;12:126-130.

16. Anonymous. Echinacea. J Am Med Assoc. 1921;76:39-40.

17. Couch JF, Giltner T. An experimental study of echinacea therapy. Am J Pharm. 1921;93:227-228.

18. Giltner LT, Couch JF. Echinacea: a reply to Dr. Beal. Am J Pharm. 1921;93:324-329.

19. Beal JH. Comment on the paper by Couch and Giltner on “An experimental study of echinacea therapy.” Am J Pharm. 1921;93:229-232.

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Table 1. Responses From 701 Physicians in 1923 About Liquid Extracts of Echinacea angustifolia Root^a

Variable	No. of Respondents
Indications and Uses
Sepsis (unspecified infections)	493
Septicemia	155
Blood dyscrasias	150
Typhoid fever	100
Poisonous snakebites	74
Insect or spider bites or stings	67
Wounds (infected or not)	54
Sores (recent or old)	35
Suppuration (prevent or treat)	34
Diphtheria	29
Fever (nonspecific)	28
Boils	26
Toxemia	26
Skin diseases	23
Puerperal fever	22
Ulcers (indolent)	22
Sore throat	19
Syphilis	17
Tonsillitis	17
Abscesses	16
Erysipelas	15
Enlarged glands	14
Lacerations	14
Carbuncles	13
Intestinal sepsis	13
Putrefaction	13
Asthenia	12
Inflammatory conditions (local)	11
Influenza	10
Exanthems (rashes, eruptions)	10
Bowel trouble, bruises, burns, dog bites, goiter, indigestion, pneumonia, poisons, postsurgical, pyemia	6-9
After miscarriage or birth, arthritis, burning, cachexia, catarrh, cough, coated tongue (black or dark brown), convalescence, cystitis, dark red tongue, dysentery, eczema, endometritis, fetid breath, gangrene, itching, malarial fever, malignancy, otitis media, pain, painful caries, pellegra, peritonitis, poison ivy, puncture (rusty nail) wound, pyorrhea alveolaris, rabies, rheumatism, scarlet fever, septic stomach, smallpox, streptococcal infection, tuberculosis, uremia	2-5
Acne, anthrax, atonic mucosa, bronchitis (moist), canker, chronic appendicitis, colds, conjunctivitis, epilepsy, epithelioma, felons, gonorrhea, intertrigo, Ludwig angina, meningitis, osteonecrosis, ovarian neuralgia, pelvic inflammation, after escharotics, ptomaine poisoning, pyelitis, ringworm, scrofula, septic vomiting, sinusitis, spotted fever, surface hemorrhage, tetanus, thrush, tumors, uterine cancer, vaccinations	1
Numerous others	19
Effects
Alterative (blood purifier)	79
Antiseptic (used for sepsis)	75
Tonic	12
Increase leucocytosis, stimulant	4
Antizymotic, sedative	3
Antispasmodic, phagocytotic, uterine tonic, vitalizer	1
Applications
Internal	169
Local	115
External	87
Hypodermic	5
Intravenous	1
Preparations
Specific Medicine Echinacea	113
Echafolta	40
Combinations	24
Subculoyd Echinacea	7
Echinacea fluid extract	5
Echafolta Cream	2
Green tincture	2
Homemade tincture	2
Ointment	1
Tolerability
Safe	7
Use for infants or children	7
May upset digestion	2
Repulsive taste	1
Too pungent for children	1

^aFrom survey results by Lloyd.³ The mean duration of prescription of Echinacea angustifolia was at least 27 years based on experience reported by 15 physicians.

 

Table 2. Some Phytochemical Distinctions Between Popular Echinacea Crude Herb Parts³⁶

Major Phytochemical	Echinacea purpurea Aerial Plant	Echinacea purpurea Root	Echinacea angustifolia Root	Echinacea pallida  Root
Hydrophilic
Polysaccharides	Present (eg, arabinoxylans, arabinogalactans)	Present (eg, fructosans, arabinogalactans)	Present (eg, 5.9% inulin)	Present
Glycoproteins	Present	Present	Present	Present
Caffeic acid derivatives	Present (eg, 1.2%-3.1% cichoric acid in flowers)	Present, 0.6%-2.1% (eg, cichoric acid)	Present (eg, 0.3%-1.8% echinacoside, cynarin)	Present (eg, 0.7%-1.0% echinacoside
Flavonoid glycosides	Present, 0.48% (eg, quercetin and kaempferol)	…	…	…
Lipophylic
Alkamides	Present, 0.001%-0.04%	Present, 0.001%-0.04%	Present, 0.01%-0.15%
Ketoalkynes, ketoalkenes	…	…	…	Present
Essential oils	Present, 0.08%-0.32%	Present, ≤0.2%	Present, <0.1%	Present, 0.2%-2.0%