Introduction
Echinacea purpurea (L.) Moench, Echinacea angustifolia DC., and Echinacea pallida (Nutt.) Nutt. (Asteraceae) are frequently used as medicinal plants for the prevention
and treatment of the common cold, influenza, and upper respiratory tract infection.
The aerial parts of E. purpurea are used, as well as the whole plant including the roots from all three species.
Polysaccharides, glycoproteins, caffeic acid derivatives and alkamides have been considered
as the constituents being most relevant for activity [1]. Polysaccharides, glycoproteins and caffeic acid derivatives have been shown to
have immunomodulatory effects. However, the question of bioavailability is still not
solved. Recent investigations have demonstrated that at least alkamides are detectable
in human blood in reasonable concentrations after oral application of Echinacea preparations. Alkamides possess a structural similarity with anandamide, an endogenous
ligand of cannabinoid receptors, and in fact it was shown that they also bind to cannabinoid
receptors and trigger effects on cytokines [2]. Besides asking for evidence on their efficacy, there is an increasing interest
for safety of these preparations. Therefore we have systematically reviewed the available
literature for evidence on drug interactions, contraindications, adverse events, duration
of safe use, and data on safety of use in pregnant and nursing women and have assessed
the safety and tolerability profile of corresponding Echinacea preparations.
Cautions from the Committee on Herbal Medicinal Products (HMPC) [3], [4], [5], [6], [7] have been critically evaluated, especially the use in children below 12 years of
age, duration of use, contraindications like allergic diathesis or in case of immunosuppression
and hematologic systemic diseases and special warnings that autoimmune diseases can
be triggered. Many of these warnings are based only on the theoretical possibility
that the immune-mediated inflammatory mechanism of diseases like autoimmune disease,
tuberculosis, multiple sclerosis and human immunodeficiency virus infection, can be
exacerbated by the immunostimulatory properties of Echinacea
[3], [4], [5], [6], [7], [8].
Therefore, this review shall help to make evidence based decisions about the advice
safe use of Echinacea preparations.
Pharmacodynamic interactions
One study in healthy mice reported that a commercially prepared powder extract of
the root of E. purpurea (0.45 mg/mouse/day) and melatonin (0.0142 mg/mouse/day) administered together, but
not alone, had a detrimental effect on the levels of mature granulocytes in both,
bone marrow and spleen [9], [10]. A potentially positive interaction between E purpurea and the anticonvulsant medication phenytoin (Epanutin®, Phenhydan®, Zentropil®, Dilantin®)
has been reported in mice. Phenytoin has a documented teratogenic activity. Most notably,
phenytoin is known to increase the risk of cleft palate development if taken in pregnancy.
Its use in pregnancy has also been reported to be associated with an increased risk
of heart malformations. The increased incidence of cleft palate reportedly can be
reduced by the stimulation of the maternal immune system. These led researchers to
investigate the use of ethanolic (70 %) extract of E. purpurea dried aerial parts with phenytoin in relationship to the incidence of cleft palate
in mice. The incidence of cleft palate with phenytoin alone, phenytoin with the immune
modulator levamisole, or phenytoin plus E. purpurea extract (360 mg i. p.) was 16 %, 5.3 % and 3.2 %, respectively, showing that both
levamisole and Echinacea decreased the incidence of cleft palate [11]. It is unknown whether the observed effects have any clinical relevance.
In a recently published clinical study by Abdul et al., the pharmacodynamic and pharmacokinetic
interactions of either Echinacea (1275 mg four times daily containing a mixture of 600 mg of E. angustifolia roots and 675 mg of E. purpurea root; standardized to contain 5.75 mg of total alkamides per tablet) or policosanol
(10 mg tablet twice daily) with warfarin in healthy subjects have been investigated.
The apparent clearance of (S)-warfarin was significantly higher during a concomitant
treatment with Echinacea, but this did not lead to a clinically significant change in an INR (International
Normalised Ratio) measurement. No evidence of any apparent effect of CYP2C9 interaction
has been found. Neither Echinacea nor policosanol significantly affected warafarin pharmacodynamics, platelet aggregation
or baseline clotting status in healthy subjects [12].
Although details of drug administration, species, and type of extract are not stated,
it is worth to mention a first report on a possible interaction between Echinacea and etoposide, a CYP3A4 substrate [13]. A 61-year-old man newly diagnosed with cell lung cancer began concurrent chemoradiation
with cisplatin and etoposide. He was admitted to the hospital on day 8 of his first
cycle and found to be thrombocytopenic. His platelet count reached a nadir of 16 × 10(3)/L,
requiring platelet transfusion support. Upon admission, it was discovered that he
was taking vitamin B12, vitamin E, vitamin D, vitamin C, Echinacea (not characterized) and “vitamin B17” (laetrile-apricots kernel), which were discontinued.
He received his next cycle of chemotherapy without taking herbal products and vitamins
and with the addition of pegfilgrastim. As the patient also stopped taking laetrile
and his other vitamins after cycle 1, a potential interaction between laetrile and
etoposide or cisplatin cannot be fully excluded. The authors of the report concluded
that since the exact preparation of Echinacea and corresponding plant extract constituents was unkown, the interaction remains
equivocal. However, it has been written that cautions should be exercised in patients
receiving chemotherapy including CYP3A4 substrates (antracyclines, etoposide, vinca
alcaloids, taxanes) while taking Echinacea
[3], [13].
Pharmacokinetic interactions
The vast majority of reported interactions are of pharmacokinetic nature, resulting
in changes in biotransformation of the affected drug through inhibition or induction
of drug metabolizing enzymes. A number of in vitro and in vivo studies suggest a potential for herb-drug interaction between different uncharacterized
Echinacea extracts and the cytochrome P450 family of drug metabolizing enzymes (CYP 3A4, 2D6,
1 A2 and 2C9) [14], [15], [16], [17]. But only the recently published pharmacokinetic drug interaction studies determined
the influence of chemically characterized Echinacea preparations on CYP3A and CYP2D6, with four conducted in human [18], [19], [20], [21] and seven in vitro studies [22], [23], [24], [25], [26], [27].
In a recently performed clinical study on the activity of human CYP2D6, no significant
inhibition was detected after the application of E. purpurea softgel capsules (Gaia Herbs, Inc., Brevard, NC, USA, 267 mg extract, three times
daily) standardized to contain 2.2 mg alkamides per capsule [18]. Penzak et al. investigated the influence of standardized E. purpurea fresh plant liquid extract 8 : 1 (250 mg) softgel capsules with 500 mg (two 250 mg
capsules) 3 times/day for 28 days on the pharmacokinetics of lopinavir (400 mg)/ritonavir
(100 mg) twice/day and on CYP3A and p-glycoprotein activity by using the probe substrates
midazolam (8 mg) and fexofenadine (120 mg) as single doses, respectively. The concentrated
extract from freshly harvested E. purpurea plants contained standardized amounts of alkamides 0.25 mg/mL, polysaccharides 25.5 mg/mL
and cichoric acid 2.5 mg/mL. The 13 volunteers received for 14 days E. purpurea in combination with lopinavir-ritonavir and for 14 days E. purpurea alone. Neither lopinavir nor ritonavir pharmacokinetics were significantly altered
by 14 days of E. purpurea co-administration [21]. More recently, interactions between etravirine (a nonnucleoside reverse transcriptase
inhibitor of HIV) and darunavir (protease inhibitor) with capsules containing E. purpurea root extract at a dosage of 500 mg every 6 h from days 1 to 14 has been investigated
in HIV infected patients. Etravirine and darunavir undergo extensive metabolism by
the hepatic CYP3A4 isoform. Similar to lopinavir studied by Penzak et al., no significant
interaction has been found with darunavir [19]. Also no significant treatment effects were observed for any of the primary pharmacokinetic
parameters after administration of etravirine with or without E. purpurea
[20].
Already in 2007, Raner et al. evaluated the potential of 11 isolated alkamides and
a 33 % and 95 % ethanolic E. purpurea root extract to inhibit cytochrome P450 2E1 in human liver microsomes and from an
in vitro expression system. Extracts of E. purpurea root in 95 % ethanol (2.0 µL of extract in 500 µL reaction) significantly inhibited
the activity (30 %) of cytochrome P450 2E1 in human liver microsomes. No inhibition
was seen when 2 µL of the 33 % ethanolic extract of the E. purpurea roots was used in a 500 µL reaction using human liver microsomes or expressed P450.
The alkamides present in E. purpurea root preparations (undeca-2E/Z,4E-diene-8,10-diynoic acid isobutylamides and dodeca-2E,4E,8Z,10E/Z-tetraenoic acid isobutylamides) showed significant inhibition at concentrations as
low as 25 µM, which corresponds to roughly 6 µg/mL, whereas the caffeic acid derivatives
had no effect [27]. Compared to the measured plasma levels in humans (~ 10 ng/mL) the concentration
needed for in vitro CYP450 2E1 inhibition was about 600 times higher and therefore the relevance of these
results for the in vivo-situation is questionable.
A standardized E. purpurea preparation (Echinaforce®) induced mild inhibition of CYP isoforms, with CYP3A4 being
the most, and CYP2D6 the least sensitive enzyme. In further studies, the Echinacea alkamides were suspected to be responsible for CYP3A4 inhibitory activity [24]. In a more recent approach, a detailed analysis of six commercial Echinacea liquid preparations with emphasis on the metabolomics characterisation of the Echinacea compounds responsible for inhibiting CYP3A4 has been reported by Modarai et al. 2010.
The used preparations were a pressed juice from the aerial parts of E. purpurea (Madaus AG), a tincture from the roots of E. pallida (Salus), and three different tinctures from E. purpurea (with 22 % ethanol from Viridian, with 65 % ethanol from Holland & Barrett, Echinagold®
with 50 % ethanol from a Health Food Shop in Denmark), and a herb/root preparation
from E. purpurea (Echinaforce®, Bioforce). After the separation of each preparation into their ethanol
and water-soluble components, the results directly confirmed the role of alkamides
in the inhibition of CYP3A4. Levels of the alkamides (dodeca-2E,4E,8Z,10E/Z-tetraenoic acid isobutylamides and undeca-2E,4E/Z-diene-8,10-diynoic acid isobutylamides) correlated well with CYP3A4 inhibition [25]. Due to variable and conflicting results in CYP3A4 inhibition between laboratories,
it is now suggested to use multiple CYP3A4 probes in the assessment of CYP3A4 interaction
potentials. Hansen and colleagues compared the CYP3A4 inhibition profiles of E. purpurea (Echinagard®, with final concentrations between 0.24–6360 µg/mL) measured by three
different CYP3A4 substrates and different methodologies. Testosterone metabolism showed
a much lower CYP3A4 inhibition (IC50 5394 µg/mL) compared to the fluorescent substrates BFC (7-benzyloxy-trifluoromethylcoumarin)
and BQ (7-benzyloxyquinoline) (IC50 354 and 452 µg/mL, respectively). The choice of substrate might thus be essential
for the evaluation of the inhibition of CYP3A4 metabolism for some herbs when performing
in vitro studies. The previously described inhibition potential of E. purpurea towards CYP3A4-mediated metabolism was confirmed by the use of three different substrates
[28]. Aside from direct enzymatic inhibition also the transcriptional activity can be
altered by different herbal medicinal products (e.g. induction or inhibition of CYP
expression). Hellum and colleagues found that a commercial pressed juice from the
aerial parts of E. purpurea (Echinagard® – Madaus AG) moderately suppressed CYP3A4 expression in primary human
hepatocytes [22]. In addition, Gorski et al. found that an 8-day course of 400 mg of E. purpurea root preparation administered 4 times daily could cause an induction of CYP3A4 in
intestinal cells, but suppressed hepatic CYP3A4 expression. However, the bioavailability
of midazolam, a CYP3A4 substrate, increased by the same amount, leading to no overall
change in AUC [15]. Kortenkamp et al. (2011) carried out an analysis of the CYP3A4 induction in human
hepatocellular carcinoma HepG2 cells by an E. purpurea herb and root preparation (Echinaforce®, Bioforce), using real-time reverse transcription
polymerase chain reaction (RT-PCR) to determine steady-state mRNA levels. HepG2 cells
were exposed for 96 h to clinically relevant concentrations of the E. purpurea preparation (22, 11.6 and 1.16 µg/mL), or of four Echinacea alkamides (1.62 and 44 nM). Neither Echinaforce® nor the pure alkamides produced
any significant change in the steady-state CYP3A4 mRNA levels [29]. A further study on the rat cytochrome P450 expression level has been carried out
only recently by Mrozikiewicz and colleagues. The potential influence of a standardized
E. purpurea 60 % ethanolic extract of the aerial parts containing 3.7 % m/m polyphenolic compounds
expressed as caffeic acid on the mRNA expression level of major CYP450 enzymes using
an animal model has been investigated. The male Wistar rats were randomly divided
into four groups from A to D (n = 10). Group A was treated once a day with 50 mg/kg
p. o. of E. purpurea ethanolic extract for 3 days, and group B received a standard diet. Group C was treated
with the same extract like group A, 50 mg/kg p. o. once a day, but for 10 days, whereas
group D was used as control for group C. Total RNA was isolated from the rat liver
tissue sixteen hours after the last administration. The authors concluded that the
obtained in vivo data indicated a potent inhibition of the expression of CYP3A1 (41 %, p < 0.05) and
CYP3A2 (25 %, p = 0.001), and an induction of CYP1A1 (80 %, p = 0.01) and CYP2D1 (40 %,
p = 0.007) after the administration of an E. purpurea ethanolic extract [26]. However, nothing has been reported about the important isoform CYP3A4.
In a pharmacokinetic herb-drug interaction study in rats, the effects of different
phytochemically characterized preparations of E. angustifolia, E. purpurea and E. pallida were assessed for its cytochrome P450 (CYP) interaction potential. A total of 216
rats were assigned to the different experimental groups (n = 12) with various dosages,
positive/negative controls (ketoconazole, quinidine, rifampicin) and dodeca-2E,4E,8Z,10E/Z-tetraenoic acid isobutylamides (“tetraenes”). Echinacea preparations were administered for two consecutive weeks. On the last day a CYP cocktail
consisting of theophylline (CYP1A2), tolbutamide (CYP2C), dextromethorphan (CYP2D),
and midazolam (CYP3A) was orally administered before blood sampling. Plasma levels
of substrates and their metabolites were quantified using a validated LC-MS/MS method
[30]. Pharmacokinetic parameters (Cmax and AUClast) were calculated and compared with the blank control group using geometric mean ratios
(GMRs) and its 90 % confidence interval (CI). E. purpurea, E. angustifolia and E. pallida preparations showed significant interactions mainly on CYP1A2 substrate activities.
Co-administration of E. purpurea preparations (60 % ethanolic root extract p < 0.001; CO2-extract p < 0.01; Echinaforce® p < 0.001 and pressed juice p < 0.01) with theophylline
led to a significant increase in the AUClast of the metabolite, 1,3-dimethyluric acid. In addition, the main alkamides of Echinacea (tetraenes) inhibited CYP1A2 with a GMR of 8.65 (7.72–9.68) for the AUClast and 2.96 (2.59–3.39) for Cmax. The pharmacokinetics of dextrorphan (rat CYP2D2 metabolite) were moderately affected.
However, Echinacea formulations showed no significant inhibition on CYP3A and CYP2C activities [3], [31].
Preclinical studies conducted since 2004 indicate that Echinacea constituents modulate immune mechanisms and there is increasing evidence that lipophilic
Echinacea preparations containing alkamides can suppress stress-related cellular immune responses
[2], [8], [32], [33], [34], [35], [36], [37], in contrast to older literature published, which described only “immunostimulatory”
effects [38], [39], [40], [41], [42], [43]. Therefore, the activity of Echinacea may better be described as “immunomodulatory” rather than immunostimulatory [44]. Warnings against the concomitant use of Echinacea spp. together with immunosuppressive drugs because of the theoretical possibility
of diminished effectiveness and the ingestion in people with inflammatory conditions,
such as asthma, and HIV, therefore remain questionable [45], [46].
The Eclectics, a group of practitioners, who were prominent around the late 19th and
early 20th centuries in the U. S., used Echinacea (especially the root of E. angustifolia) for an extensive range of conditions, including tuberculosis [47]. The use for tuberculosis and disorders related to autoimmunity such as diabetes,
exophthalmic goiter, psoriasis, and renal haemorrhages contrasts with the contraindications
suggested by some recent authors.
Although it is recommended by the authorities that “Echinacea” should be avoided in patients with autoimmune diseases, very few published case reports
exist in this context, moreover they have a limited causal association [48], [49]. The suggestion that Echinacea preparations are contraindicated in autoimmune diseases assumes that the modulation
of any aspect of immune function is deleterious. However, immune function is extraordinarily
complex and a substance that acts largely on phagocytic activity may be safe or even
beneficial in autoimmunity [50], [51], [52], [53], [54]. There were no clinical or laboratory alterations (blood count, electrolytes, liver
and kidney functions) reported after the ingestion of E. angustifolia whole plant dry extract (undefined extraction solvent) over 12 weeks by HIV positive
subjects.
Special warnings and precautions for use
Since the possibility of immune-related adverse consequences has not been ruled out
in atopic individuals, especially this group of patients should use Echinacea spp. with caution and under the supervision of a health care practitioner. The Community
Herbal Monograph stated that atopic patients should consult their doctor before using
Echinacea
[4], [5], [6]. The potential allergenicity of Echinacea has received a fair amount of attention, although some may have not been definitively
associated with the ingested Echinacea preparations [55].
Undesirable effects
Reports of adverse effects within clinical trials, comparing mono-preparations of
Echinacea with placebo since 1996 are summarized in [Table 1]. Most of the adverse events were specified as mild to moderate. However a causal
relationship between Echinacea and the adverse events could not be established. Headache, one of the predominant
mentioned adverse effects, may not accurately reflect adverse events because it is
also a frequent symptom of the common cold.
Table 1 Adverse events reported during administration of Echinacea spp. to human subjects.
|
First author (reference)
|
N
|
Patient population and study design
|
Preparation
|
Adverse events experienced (cases or %)
|
|
Active treatment
|
Placebo
|
|
EA = Echinacea angustifolia; EP = Echinacea purpurea; R = randomized; O = open; DB = double-blind; PC = placebo-controlled
|
|
Parnham; Schöneberger [88]
|
109
|
Patients with more than 3 colds during the previous winter. DB, PC
|
EP pressed juice twice daily for 8 weeks (Echinacin® Liquidum)
|
Gastrointestinal upsets, headache, dizziness and tiredness (11)
|
Gastrointestinal upsets, headache, dizziness and tiredness (7)
|
|
Parnham; Madaus AG [88]
|
47
|
Marathon runners with at least 3 upper airway infections within 6 months. DB, PC
|
EP pressed juice four times a day for a total of 12 weeks (Echinacin® lozenges)
|
No adverse events reported
|
No adverse events reported
|
|
Parnham; Madaus AG [88]
|
38 (n = 79 in total)
|
Prophylaxis of respiratory or urinary tract infections. O
|
EP pressed juice four times a day for 6 weeks (Echinacin® lozenges)
|
Various muscle aches, joint pain, gastrointestinal complaints (e.g. diarrhea, nausea,
gastric discomfort), headache (1–3)
|
Various muscle aches, joint pain, gastrointestinal complaints (e.g. diarrhea, nausea,
gastric discomfort), headache (1–3)
|
|
Parnham; Madaus AG [88]
|
1231
|
Patients with relapsing respiratory and urinary infections. Multicenter study
|
EP pressed juice for 4–6 weeks (1 Echinacin® lozenges 3 times daily)
|
Unpleasant taste (21), nausea/vomiting (6), recurrent infection (5), sore throat (3),
abdominal pain (3), diarrhea (3), difficulty in swallowing (2), other single reports
(19) (not specified whether they received placebo or Echinacin®)
|
|
Schapowal [104]
|
154
|
Patients with acute sore throat. Multicenter, R, DB, compared to chlorhexidine/lidocaine
|
Echinacea/Sage spray (863.3 mg/mL fresh plant extract EP [95 % aerial parts and 5 % roots]
and 430 mg/mL leaves of Salvia officinalis) for 7 days
|
Rash on mucosa (1), burning sensation and dryness of the throat (1), joint pains (1);
adverse event rate of 3.8 %
|
Swelling of the tongue (1), bitter taste in the mouth (1)
|
|
Hill [105]
|
47
|
Healthy volunteers (Effects of EP on aerobic and anaerobic bacteria in the GI tract
has been determined). Comparison with baseline.
|
1000 mg total (two doses of two capsules each) of standardized EP tincture (Echinamide®)
for 10 days
|
Flatulence (1), diarrhea (1), nausea (1)
|
No placebo group
|
|
Vonau [87]
|
50
|
Patients with recurrent genital herpes. DB, PC, cross-over trial
|
Echinaforce® 800 mg of EP extract (95 % aerial parts, 5 % roots) twice daily for 6
month
|
Nausea without vomiting (4), diarrhea (5)
|
Nausea without vomiting (2)
|
|
Melchart [86]
|
99 (EP) and 100 (EA) (n = 289 total)
|
Volunteers without acute illness at time of enrollment. R, DB, PC, three armed
|
Ethanolic EA root liquid extract and EP root extract for 12 weeks (50 drops twice daily, 5 days a week)
|
E. angustifolia
|
E. purpurea
|
Minor gastrointestinal symptoms (6), headache/dizziness (1), allergic symptoms (2),
other symptoms (3)
|
|
Minor gastrointestinal symptoms (9), headache/dizziness (9), allergic symptoms (2),
other symptoms (1)
|
Minor gastrointestinal symptoms (5), headache/dizziness (2), allergic symptoms (2),
other symptoms (4)
|
|
See [106]
|
14
|
HIV patients with or without antiretrovirals
|
EA whole plant dry extract (1000 mg three times daily, undefined type of solvent)
for 12 weeks
|
No adverse events reported
|
|
|
Grimm [107]
|
54 (n = 109 total in trial)
|
Patients with a history of more than 3 colds/respiratory infections in a year. DB,
PC, R
|
EP pressed juice 4 mL twice daily for 8 weeks
|
11 patients with adverse events mainly GI upsets, dizziness and tiredness; 4 patients
dropped out
|
7 patients with adverse events mainly GI upsets, dizziness and tiredness; 3 patients
dropped out
|
|
Brinkeborn [108]
|
181 (n = 246 total in trial)
|
Healthy adult volunteers. DB, PC, R
|
Echinaforce® EP extract (95 % aerial parts, 5 % roots), EP concentrate, EP radix special
prep, two tablets three times daily for not longer than 7 days
|
Echinaforce
|
EP concentrate
|
EP radix special prep.
|
|
|
7 adverse events
|
8 adverse events
|
12 adverse events
|
6 adverse events
|
|
The majority were GI in nature
|
|
Gallo [109]
|
112 women used Echinacea in the first trimester; 17 were exposed in all 3 trimester; (n = 206 total)
|
Pregnant women Prospective case control study
|
Capsules and/or tablets of undefined Echinacea with dosages between 250 to 1000 mg/day; tincture dose varied from 5 to 30 drops
daily; Mostly EA or EP without detailed characterization. Duration 5 to 7 days
|
Comparison with control group suggested no increased risk of major malformations due
to Echinacea ingestion during organogenesis
|
|
Schulten [110]
|
41 (n = 81 total in trial)
|
Patients with the first signs of a cold. DB, PC, R
|
EP pressed juice 5 mL twice daily for 10 days
|
8 adverse events with GI upsets (6)
|
9 adverse events mostly with GI upsets (6)
|
|
Rostock [111]
|
128 (n = 187 total in trial)
|
Breast/colorectal cancer patients. Controlled, open pilot study
|
EP 8 mL or EP pressed juice 24 mL daily for 21 days
|
Number of adverse events were similar in 8 mL group to control and less in 24 mL group.
1 case each of elevated liver enzyme levels and leukopenia. 3 cases each of allergic
skin reaction and vertigo. No other serious/potentially serious adverse events.
|
|
Kim [112]
|
24 (n = 48)
|
Healthy female volunteers in each of the 3 groups. DB, PC, R
|
Standardized extract of EP, ultra-purified EP/EA or EA for 4 weeks
|
2 of 48 participants experienced adverse events
|
|
Ultra-purified EP/EA
|
EP group
|
|
|
|
Self-reported anxiety, nervousness and heart palpitation
|
Bilateral arthritic symptoms in wrist, metacarpophalangeal and proximal interphalangeal
joints. Both resolved on discontinuation.
|
|
|
|
Barrett [113]
|
69 (n = 142)
|
Students with common colds at least 2 of 15 cold symptoms for less than 36 hours.
DB, PC, R
|
An encapsulated mixture of EP herb (25 %), root (25 %) and EA root (50 %), 1 g six
times daily on the first day of illness and three times on each subsequent day of
illness for up to 10 days
|
Sleeplessness (1), heartburn (1), nausea (1), stomach ache (1), upset stomach (1)
and bad taste in mouth (3)
|
Stomach ache (3), nausea (1), belching (1), thirst (1) and abdominal pain with diarrhea
(1)
|
|
Lindenmuth [114]
|
48 (n = 95)
|
Employees of a nursing and rehabilitation center with earliest symptoms of a cold.
PC, DB
|
EP aerial parts, EP roots and EA roots in a tea preparation (Echinacea Plus®) with
2 flavoring components (lemon grass leaf and spearmint leaf) 5 to 6 cups on day 1,
titration to 1 cup on day 5
|
There were no negative effects reported by any of the subjects in either group.
|
|
Turner [115]
|
22 (n = 46)
|
Healthy goung adults with a titer of antibody of < 1 : 4 ro thinovirus type 23. R,
PC; DB
|
4 % phenolic extract of a mixture of EP and EA formulated as powder, containing 0.16 %
cichoric acid with almost no echinacoside or alkamides, 1 capsule (900 mg) once a
day for 14 days prior to virus challenge and 5 days after virus challenge
|
One subject was removed due to an unspecified adverse event. No significant side effects
of Echinacea were seen.
|
|
Taylor [80]
|
200 (n = 407)
|
Treatment trial in children between 2 to 11 years. R, PC, DB
|
EP herb in syrup, 7.5 mL/day in children 2 to 5 years and 10 mL/day in those 6 to
11 years up to a max. of 10 days
|
Adverse events in 45.1 % with: stomach ache, diarrhea, drowsiness, headache, “hyper”
behavior, rash and vomiting. Rash was the only side effect that was significantly
more frequent in the Echinacea group compared to placebo (7.1 % versus 2.7 %; p = 0.008).
|
Adverse events in 39.5 % with: stomach ache, diarrhea, drowsiness, headache, “hyper”
behavior, rash and vomiting.
|
|
Sperber [116]
|
24 (n = 46)
|
Prevention trial (experimental virus inoculation with RV-39 after 7 days). R; PC,
DB
|
EP pressed juice, 2.5 mL 3 times daily for 14 days
|
Two participants reported adverse events: Sleeplessness (1), severe oral aphthous
ulcers (1)
|
4 participants in the placebo group reported 6 adverse events, which are not specified.
|
|
Goel [61]
|
59 (n = 128)
|
Healthy adults with at least 2 colds last year. R, PC; DB
|
EP standardized extract (0.25 mg/mL alkamides, 2.5 mg/mL cichoric acid, 25.5 mg/mL
polysaccharides); 10 × 4 mL the first day, then 4 × 4 mL for 6 days
|
Gastrointestinal side effects (nausea, constipation) and heartburn were reported by
13 % (8/59). Again itching, burning sensation and numbness of the tongue were reported
by 13 % (8/59).
|
Gastrointestinal side effects (nausea, constipation) and heartburn were reported by
9 % (6/69). Again itching, burning sensation and numbness of the tongue were reported
by 11 % (8/69).
|
|
Yale [117]
|
63 (n = 128)
|
Adult patients presenting with acute sneezing and nasal discharge for 6 to 24 hours.
R, PC, DB
|
Standardized freeze-dried pressed juice from EP herb, 3 capsules (100 mg) up to a
max of 14 days
|
Nausea (9 %), abdominal pain (4 %), mouth irritation (2 %), bad taste (6 %), headache
(14 %), dizziness (6 %), dry mouth (16 %)
|
Nausea (5 %), mouth irritation (3 %), bad taste (5 %), headache (11 %), dry mouth
(9 %)
|
|
Goel [118]
|
26 (n = 62)
|
Volunteers between 18 and 65 years with 2 or more colds previous year. R, PC, DB
|
EP standardized extract (0.25 mg/mL alkamides, 2.5 mg/mL cichoric acid, 25.5 mg/mL
polysaccharides); 8 × 5 mL the first day, then 3 × 5 mL for 6 days
|
No adverse events reported
|
No adverse events reported
|
|
Turner [119]
|
296 (n = 399)
|
Healthy young adults, serum-neutralizing antibody titer < 1 : 4 to rhinovirus type
39. R; PC; DB
|
60 % and 20 % ethanolic root extract of EA, and a CO2 extract of the roots of EA; 1.5 mL tincture (300 mg Echinacea root) 3 times daily for 7 days before virus challenge and 5 days after challenge
|
5 % of the subjects receiving an Echinacea preparation reported an adverse event. Gastrointestinal side effects were reported
by 12 subjects.
|
4 % of the placebo-treated subjects reported an adverse event. Gastrointestinal side
effects were reported by 4 subjects.
|
|
Hall [120]
|
18 (n = 32)
|
Active, non-smoking adults aged 19 to 46 years. R, PC, DB
|
EP herb 1.2 g in capsules, 8 capsules/day for 4 weeks
|
no adverse events reported
|
no adverse events reported
|
|
OʼNeill [121]
|
28 (n = 58)
|
Healthy adults recruited from hospital personnel
|
EP dried plant extract in capsules, 3 capsules 2 times daily for 8 weeks (300 mg per
capsule)
|
Mild adverse effects were noted by 8 % of the Echinacea group.
|
Mild adverse effects were noted by 7 % of the placebo group.
|
|
Barrett [122]
|
184 (n = 363)
|
Students with common cold symptoms since up to 36 hours. R, PC, DB
|
EP root (675 mg) and EA root (600 mg) standardized tablets, MediHerb (Australia),
2 tablets four times daily on the first day of illness and 1 tablet four times daily
on each subsequent day for up to 4 days
|
Blinded to Echinacea
|
Open-Label Echinacea
|
No Pill
|
Blinded to Placebo
|
|
Bad taste (12 %), diarrhea (10 %), headache (46 %), nausea (16 %), rash (1 %), stomach
upset (15 %)
|
Bad taste (9 %), diarrhea (9 %), headache (48 %), nausea (7 %), rash (2 %), stomach
upset (13 %)
|
Diarrhea (5 %), headache (62 %), nausea (10 %), rash (2 %), stomach upset (16 %)
|
Bad taste (9 %), diarrhea (12 %), headache (49 %), nausea (13 %), rash (1 %), stomach
upset (12 %)
|
|
Jawad [89]
|
325 (n = 673)
|
Healthy adults with 2 or more colds per year. R, PC, DB
|
Alcoholic extraction from freshly harvested EP with 95 % herb and 5 % roots (Echinaforce®),
3 × 0.9 mL per day for illness prevention (2400 mg extract/day), during acute stages
of cold dose was increased to 5 × 0.9 mL per day (4000 mg of extract/day) for 4 months.
|
25 subjects in the Echinaforce group (9 %) experienced 27 drug-related adverse events
(causally related to the study medication). 293 adverse events were reported by 177
subjects treated with Echinaforce. Four adverse events led to discontinuation of treatment.
No severe adverse event was observed with Echinaforce.
|
30 subjects in the placebo group (10 %) experienced 30 drug-related adverse events.
306 adverse events were reported by 172 subjects in the placebo group. Three adverse
events led to discontinuation of treatment. One severe adverse event (glandular fever)
occurred with placebo.
|
|
Tiralongo [123]
|
85 (n = 170)
|
Healthy adults, traveling on intercontinental flights. R, PC, DB
|
112. 5 mg EP root (675 mg dry root) and 150 mg EA root (600 mg dry root) standardized
tablets, days − 14 to − 3 (1 tablet twice a day), days − 2 to + 7 (2 tablets twice
a day), + 8 to + 32 (1 tablet twice a day), + 33 to + 42 (2 tablets twice a day),
+ 43 to + 49 (1 tablet twice a day)
|
Adverse events were reported by only 3 participants.
|
|
Heartburn and diarrhoea. However, the participant who reported heartburn was also
taking aspirin and several other medicines such as sleeping tablets. Tingling and
burning of the tongue and mouth (2)
|
Vomiting and headache
|
Allergic reactions
E. angustifolia (3825 mg whole plant extract) and E. purpurea (150 mg dry root) have been associated with allergic reactions, including one reported
case of anaphylaxis [56], [57]. Skin allergy testing of 84 patients with asthma or allergic rhinitis demonstrated
reactivity to those Echinacea extracts in 16 subjects (19 %) [57].
Huntley et al. analysed a total of 8 case reports of allergic reactions to Echinacea with such typical signs as generalized urticaria, itchy and watery eyes, gastrointestinal
upset, respiratory obstruction, asthma, and a positive reaction to skin prick test
(skin allergy test, SPT), which may or may not resolve with time [45]. A 19-year-old female suffered an acute asthma attack and severely itchy and watery
eyes and a runny nose within 10 minutes of her first ever exposure to an Echinacea-containing tea, with no further characterization of the species and the plant part.
It is necessary to mention that combination products and homeopathic preparations
were excluded from this safety reviwe.
Jeschke et al. [58] published the results of a prospective pharmacovigilance study of Asteraceae extracts,
including Echinacea. The aim of this study was to analyze prescribing patterns and adverse drug reactions
(ADRs) for Asteraceae-containing remedies in Germany. Altogether, 18 830 patients
(58.0 % female, 60.3 % children) received 42 378 Asteraceae-containing remedies. This
included 2672 patients receiving 4605 Echinacea-containing prescriptions with 69 different medications (30 % phytotherapeutic, 60 %
< D4, 10 % > D4). No serious adverse drug reactions were reported. In a subgroup analysis,
considering also non severe adverse drug reactions in 6961 prescriptions for Asteraceae,
11 non-serious adverse reactions were detected (all for homeopathic preparations and
none for phytotherapeutic preparations). This supports the observation that allergic
reactions due to Echinacea products are rather rare and mostly not serious [3], [58].
There is no literature available for the Stevens-Johnson Syndrome, which is mentioned
in the HMPC Monograph as an hypersensitive reaction. But obviously there have been
4 cases reported in the Eudra vigilance database [3].
Thrombocytopenia
Only one adverse event report with thrombocytopenia was identified specifically for
E. pallida. Liatsos et al. [59] reported a case of severe thrombotic thrombocytopenic purpura (TTP) in an otherwise
healthy 32-year-old Caucasian man. Examination revealed hypotension, sinus tachycardia,
mild elevation in temperature, and few diffused petechiae, anemia (Hb = 6.0 g/dL),
severe thrombocytopenia (platelets = 20 000/µL), and microangiopathic-type haemolytic
anemia with fragmented red blood cells, increased indirect bilirubin, and markedly
elevated LDH levels. Bacterial and viral antibodies were negative. The patient was
transfused with red blood cells and fresh frozen plasmas (FFPs) but had a syncope
episode followed by seizures and finally entered status epilepticus which was controlled with general anesthesia and ventilator assistance. He was treated
with large-volume plasmapheresis twice a day, and administration of FFPs. He finally
had an uneventful outcome [59]. Causality has not been evidenced.
Leucopenia and eosinophilia
Kemp and Franco published a case report of leucopenia associated with the long-term
use of an uncharacterized Echinacea product (450 mg tid). A 51-year old woman appeared healthy from all aspects with
the exception that her white cell count had decreased from 5800/µL the preceding year
to 3300/µL (normal range 4000 to 11 000). For the past 8 weeks she had been taking
the undefined Echinacea product (1350 mg of Echinacea per day), Ginkgo biloba L. (Ginkgoaceae; dosage not given), bupropion for depression (300 mg daily), as well
as vitamins-C, -E, -B, and calcium. She suffered from hayfever, but did not take medication
for it. One month after the discontinuation of therapy with Echinacea, her white cell count had increased to 3700/µL. The next year she resumed taking
Echinacea and after two months her white cell count was 2880/µL. Two months after discontinuing
taking Echinacea, her white cell count was 3440/µL and 7 months later arose to 4320/µL. Due to the
fact, that the authors could not find another reason for the leucopenia, they assumed
a relationship to the intake of Echinacea
[60]. Although it is known that the concomitant ingested product, bupropion (Wellbutrin
SR®), releases changes in hematology. While in a study performed by Goel et al., no
significant differences between groups taking E. purpurea (ethanol extraction of various freshly harvested parts) or a placebo after white
blood cell differential count were observed [61]. Furthermore, a case of a patient with eosinophilia of unclear aetiology whose condition
resolved after the discontinuation of “Echinacea” has been reported. The authors felt that this represents an IgE-mediated allergic
process to an uncharacterized used Echinacea preparation [62].
Erythema nodosum
One isolated report describes the case of a 41-year-old man who experienced four episodes
of erythema nodosum after using an undefined Echinacea preparation at each onset of an influenza-like illness. The man had been using Echinacea intermittently for 18 months, as well as loratadine on a basis as required, and St. Johnʼs
wort for the previous 6 months. Each episode of erythema nodosum responded to conventional
treatment, including prednisone. The man was advised to discontinue the treatment
with Echinacea and, after 1 year, he had not experienced any further recurrences. However, the report
does not provide any details (species, plant part, formulation, dosage regimen) of
the Echinacea (or the St. Johnʼs wort) preparation involved and therefore is difficult to interpret.
Causality has not been established [63].
Sjögren syndrome
Logan and Ahmed reported on a 36 year old woman, who ingested St. Johnʼs wort, undefined
Echinacea, and Kava for 2 weeks, a development of severe general muscle weakness, which resolved
under supplementation of NaHCO3 and KCl. The report did not provide any further details of the Echinacea species that was contained in the product, or of the types of preparations, formulations,
dosages and routes of administration of any of the herbal medicines listed. Complaints
of joint stiffness, fatigue, dry mouth and eyes surfaced 6 weeks later. Sjögren syndrome
was diagnosed and a Plaquenil (hydroxychloroquine 200 mg daily) treatment begun. The
abnormalities renal tubular function resulting in hypokalimea and acidification with
muscle weakness, are reported because of the Sjögren syndrome. Problems resolved under
therapy with prednisone and cyclophosphamide, which unterlines the autoimmunogenesis.
This case may represent one example where an autoimmune disease was exacerbated. The
connection between the Echinacea therapy and the undesirable effect has been estimated as possible, but is not conclusive
[49].
Exanthema
An autoimmune disease supposedly triggered by an unspecified Echinacea supplement has been reported by Lee and Werth. A patient with pre-existing chronic
inflammatory condition started taking Echinacea for the first time in his life at the onset of an upper respiratory tract infection.
Within days the patient developed blisters on body, head and oral mucosa. The authors
also mentioned that the temporal relationship of the patient disease flare with ingestion
of Echinacea is strongly suggestive of a causal relationship. However, the practitioners could
not rule out the possibility that the patient experienced an exacerbation as part
of the natural course of his condition, nor could they dismiss the possibility that
the upper respiratory tract infection contributed to his flare [48]. Furthermore, no further details of the product, including species of Echinacea, plant part, excipients, type of preparation, and dosage were provided. Without verification
that the product implicated did contain Echinacea material and was free of other ingredients or adulterants, this report adds little
to the debate on the safety of use of Echinacea by individuals with autoimmune disorders [48].
Among a total of 64 493 reported adverse reactions submitted to the Swedish Medical
Products Agency, only 778 reports concerned adverse reactions related to the use of
complementary and alternative medicine (CAM) products. 63 (8.1 %) reports concerned
E. purpurea, among them mostly urticaria (11) and exanthema (13) were reported [64].
Acute cholestatic autoimmune hepatitis
In a case report by Kocaman et al. (2008) a 45-year old male patient complained of
fatigue and jaundice of 1-week duration. He told that he had started taking “Echinacea root” (1500 mg/day) after catching a common cold. Physical examination revealed an
icteric patient. Markers for viral hepatitis, ceruloplasmin, iron and ferritin levels,
and alpha 1 antitrypsin level were not remarkable for acute hepatitis. Liver biopsy
revealed an interface hepatitis, prominent cholestasis, and a portal lymphoplasmocytic
and eosinophilic granulocyte infiltration. After admission, the patient stopped taking
the “Echinacea”. One month later, all laboratory values were normalized, except for the anti-smooth
muscle antibody positivity. The authors concluded this first report of an Echinacea-induced acute cholestatic autoimmune hepatitis (ACAH) as a result in a breakdown
of autoimmunity self-control in the liver. Due to the undefined Echinacea preparation used (species, formulation) it is difficult to interpret the connection
between Echinacea and the severe acute hepatitis [65]. In the same year, a case communication reported a patient with autoimmune hepatitis
and hypergammaglobulinemic purpura related to an uncharacterized herbal medicine including
“Echinacea, Combucha, Chinese herbal mixtures, and Kava Kava”. The 57 year old woman, a practitioner
of alternative medicine, was hospitalized with jaundice and weakness. Viral serology
for hepatitis B and C were negative. A liver biopsy demonstrated cirrhosis with severe
piecemeal necrosis, severe intra-acinar necrosis, focal necrosis and cholestasis.
The patient was started on prednisone 60 mg per day with a prompt laboratory improvement
and complete normalization of her liver function. It remains speculative whether the
association between the herbal preparation and the autoimmune hepatitis is causative
or only coincidental. Above all, the connection between the uncharacterized “Echinacea” preparation and the autoimmune hepatitis is questionable [66].
Concerns of potential hepatotoxicity have been raised, although documented cases are
lacking. Miller published that all Echinacea preparations, if used beyond 8 weeks, could cause hepatotoxicity and therefore should
not be used with other known hepatotoxic drugs, such as anabolic steroids, amiodarone,
methotrexate, and ketoconazole [46]. However, the magnitude of this hepatoxicity has been questioned since Echinacea lacks pyrrolizidine alkaloids with a 1,2 unsaturated necine ring associated with
hepatotoxicity. There have also been hepatoprotective effects of Echinacea reported in male rats [67]. Therefore, there is no clear evidence for hepatotoxicity.
Autoimmune diseases like encephalitis disseminate and the Evans Syndrome are undesirable
effects cited in the HMPC monographs with unclear background. There is no literature
available in connection with Echinacea. In the recent update of the European Medicines Agency monograph on E. purpurea, herba recens [4] Evans Syndrome has already been deleted.
Effects on Reproduction and Development
Preclinical data indicate that E. purpurea aerial part or root preparations are unlikely to cause negative reproductive or developmental
effects in laboratory animals. Oral doses up to 2700 mg/kg of Echinacin® did not cause
embryotoxicity in rats or rabbits or affect postnatal development in rats. Studies
looking for gene mutations, malignant transformation, or chromosome aberrations in
bacteria, mouse lymphoma cells, cultured hamster cells, or human lymphocytes have
found no evidence of mutagenicity of Echinacin® [68]. However, Ondrizek et al. reported that very high concentrations of E. purpurea (0.6 mg/mL, plant part undisclosed) applied directly to sperm impaired sperm motility
and they suggested that this may have a negative effect on male fertility. Motility
was inhibited at 24 and 48 h after incubation. They reported similar in vitro results using hamster sperm and oocytes [69], [70]. It is questionable whether these findings are relevant in an in vivo situation.
In 2007, the first study was conducted to evaluate whether pharmaceuticals containing
alcoholic extracts of E. purpurea given to pregnant mice (n = 8) influence angiogenic activity and may then lead to
severe developmental disturbances. They found an increase in the angiogenic activity
of tissue homogenates in the Esberitox® group, containing 3.2 mg of a native dry extract
(30 % ethanol) from Baptisia tinctoria (L.) Vent. (Fabaceae) root, E. purpurea root, E. pallida root and Thuja occidentalis L. (Cupressaceae) herba, and a diminution in case of Immunal forte (1 tablet contains
80 mg dry E. purpurea pressed juice 31–60 : 1). The growth factor concentration was lower in all groups
compared to the control. They concluded that there is some possibility that pharmaceuticals
containing E. purpurea might influence the fetal development in humans also, because they may interfere
with embryonic angiogenesis, and should not be recommended for pregnant women [71].
The vascular endothelial growth factor (VEGF) known as the most powerful angiogenesis
promoter plays a crucial role in organogenesis, liver and pancreas induction, kidney
glomerulus, bone and nervous system development. Moreover, VEGF contributes to the
placentation and cytotrophoblast proliferation during pregnancy. Wasiutynski et al.
(2009) evaluated the effect of the following E. purpurea containing drugs on the angiogenic activity and VEGF concentration of murine sarcoma
L-1 tumors: Immunal forte tablets (1 tablet contains 80 mg dry E. purpurea pressed juice 31–60 : 1; LEK, Slovenia) and Echinapur tablets (no detailed characterization;
Herbapol Poznan). They found that both drugs significantly diminished the VEGF concentration
in L1 sarcoma tumor tissue and they speculated that therefore they may affect the
placenta formation in pregnant women [72], [73].
Perri et al. (2006) conducted a literature review with no specification of Echinacea (species, plant part and extraction method used) of seven electronic databases from
their inception through 2005 and compiled data according to the degree of evidence
for the use, safety, and pharmacology of Echinacea pertaining to pregnancy and lactation [74]. No association with an increased risk for major or minor malformations with a reported
gestational use of Echinacea during organogenesis was found [75], [76], [77]. Capsule and/or tablet formulations of undefined Echinacea were used by 114 (58 %) of the 198 respondents, while 76 (38 %) of the respondents
used tinctures. The dosage of capsules and/or tablets used varied from 250 to 1000 mg/day.
Tincture dose varied from a minimum of 5 to 10 to a maximum of 30 drops per day. Duration
of use also varied but was normally continuous for 5 to 7 days. The different brands
used covered the two species E. angustifolia and E. purpurea without detailed characterization. 112 women (54 %) reported taking the herb in the
first trimester of pregnancy, and 17 (8 %) used Echinacea throughout their pregnancies. No significant differences were noted between the Echinacea and the control groups in the rate of major or minor birth defects, nor were there
any differences in pregnancy outcome, delivery method, maternal weight gain, gestational
age, infant birth weight, or foetal distress. Thirteen miscarriages were documented
in the Echinacea group, compared with seven in the control group [76]. The study has several limitations. The most important is that participants used
a range of different preparations of Echinacea at different dosage regimens. So the study does not provide adequate evidence for
a specific preparation.
Use in children
Götte and Roschke [78] made an observation in children with recurring infections of the upper respiratory
tract to assess the tolerability and efficacy of an alcohol free pressed juice from
the aerial parts of E. purpurea. The children had to be at least 2 years of age, and the juice was administered over
a period of 11 days with doses adjusted according to age. In more than 95 % of cases
(n = 1322), the physician and parents globally assessed the tolerability as good or
very good [78]. It has been reported in a recently published study by Du et al. that the use of
herbal medicinal products in general is closely associated with younger age between
0 and 17 years, and that two thirds of the preparations used are for the treatment
of coughs and colds [79]. Taylor et al. found an increased risk of rash when children of 2 to 11 years (mean
5.5 years, standard deviation 2.7 years) received an alcohol-free preparation of dried
pressed E. purpurea juice of the aerial parts, compared with those who received a placebo [80]. In this study adverse events were found in 45.1 % of patients receiving Echinacea (and in 39.5 % of patients receiving placebo). The most frequent adverse events were:
stomach ache, diarrhoea, drowsiness, headache, “hyper” behaviour, rash and vomiting.
Rash was the only side effect that was significantly more frequent in the Echinacea group compared to the placebo group (7.1 % versus 2.7 %, respectively). Therefore,
caution is recommended when using this E. purpurea juice preparation in children who have atopy and asthma because they are likely to
be at higher risk for a rash. In a subgroup analysis of the Taylor et al. data it
has been found that children taking Echinacin® juice were significantly less likely
to have another URI compared to children receiving placebo. Use of Echinacea was associated
with a 28 % decreased risk of subsequent URI (p = 0.01) [81]. Moreover, in a study performed by Saunders and colleagues, the safety and tolerability
of an open-label E. purpurea product prepared from the dried, pressed juice of aerial parts (Echinagard®) has
been examined in children. The dose was based on age (2.5 mL three times q day for
children aged 2–5 years, and 5 mL two times per day for children aged 6–12 years)
and administered for 10 days in an open-label trial. No allergic or adverse reaction
occurred and no safety issues arose during this study [82].
Four observational studies regarding the safety of the oral administration of preparations
of the aerial parts of E. purpurea in different dosages for children below the age of 18 were submitted by the German
authority [3]. From the in total 1184 children, two cases of nausea and two generalized exanthema
have been reported, which could be due to an infection as well. Three children dropped
out due to the bad taste of the preparation. Otherwise there were no reports concerning
adverse events even when used more than 10 days [3].
Duration of use
Several authoritative sources (e.g. EMA/HMPC/48 704/2014) have suggested that Echinacea should be used only for limited periods of time (not longer than one week or 10 days),
without giving reasons and references to verify the scientific background. The World
Health Organization (1999) and the European Scientific Cooperative on Phytotherapy
(ESCOP) monographs [83], citing the German Commission E monographs on Echinacea, cautions that internal and external administration of E. pallida and E. purpurea should not exceed 8 weeks, again without rationale. There was no data found supporting
a treatment duration limit for Echinacea
[84]. When addressing the issue of a duration limit for Echinacea preparations, Bone (2004) emphasized the importance of reviewing the traditional
use of Echinacea by the U. S. Eclectic physicians that were active in the late 19th and early 20th
century. Authoritative works published by these physicians, based upon their extensive
clinical experience, indicate that Echinacea was used over a long-term in chronic conditions without side effects [47].
Several studies of long-term (10–24 weeks) oral use of different Echinacea preparations without occurrence of serious adverse effects have been reported [85], [86], [87]. The longest intervention of E. purpurea whole plant dry extract (undefined extraction solvent) studied to date was 800 mg
twice per day for 6 months. The only adverse events reported by these subjects were
nausea without vomiting (n = 4) and diarrhoea (n = 5) [87]. Melchart et al. studied the oral use of an E. purpurea root liquid extract and E. angustifolia root extract for 12 weeks (100 drops daily of a 1 : 11, 30 % ethanolic extract for
5 days a week). No toxicological concerns were reported [86]. Parnham published that no adverse reactions other than aversion to the taste have
been reported after oral administration of Echinacin® (E. purpurea pressed juice) for up to 12 weeks [88]. Recently, Jawad et al. tested the safety and efficacy of E. purpurea (57.3 % m/m alcoholic extraction from freshly harvested 95 % herba and 5 % roots,
Echinaforce®) in a large clinical trial (755 healthy subjects) and investigated its
risk/benefit in a long-term treatment (4 month). In the haematological or biochemical
measures no significant or clinically relevant changes from before to after Echinacea treatment and in comparison to placebo were detected. No abnormalities were found
after the 4-month exposure to Echinacea
[89]. Schapowal reported that a standardized extract of Echinacea purpurea (Echinaforce®) can be recommended for long-term use, also in children, the elderly
as well as those suffering from COPD, asthma patients or smokers, people in whom the
consequences of cold and flu can be severe [90].
Discussion
After review of the available literature, all medicinal species of „Echinacea“, including E. purpurea, E. angustifolia, and E. pallida appear to be quite safe. While the absence of severe drug-related adverse events
does not conclusively prove safety, it is an indication that significant acute toxicological
events are lacking. In a toxicity study by Mengs et al. it has been concluded that
even a lethal dose could not be found [68]. Except for in vitro studies, which claim some cytotoxic effects [70], [91], studies in humans and with experimental animals are reassuring and suggesting a
wide therapeutic window of safety. Oral treatment of rats for 4 weeks at doses up
to 8 g/kg daily of the fresh juice of E. purpurea aerial parts failed to cause any toxicology. Moreover, oral doses up to 2700 mg/kg
of the same preparation did not cause embryotoxicity in rats or rabbits or affect
postnatal development in rats [68]. While Echinacea ingestion during human pregnancy is touted to be safe [74], [76], [77] others are more sceptical, indicating that other members of the family Asteraceae
have distinctly negative effects on human pregnancy [56], [92]. However, the Asteraceae family is very big and plants are quite different in constituents.
Echinacea for example is lacking sesquiterpene lactones. Some caution exists regarding the
use of an E. purpurea extract (0.6 mg/day within Esberitox®, Immunal® or Echinapur®) in the first trimester
of pregnancy based upon testing in mice. The growth factor concentration was lower
in all Echinacea groups compared to the control. Based on animal studies, there is some suspicion
that pharmaceuticals containing alcoholic extracts of E. purpurea and pressed juice of E. purpurea might influence fetal development in humans, because they may interfere with embryonic
angiogenesis, and should therefore only be taken during pregnancy and lactation after
consulting a physician [71], [72], [73], [93]. However, there is no evidence on the possibility that consuming Echinacea may promote spontaneous abortions. This hypothesis arose from only one report. Gallo
et al. found a virtual doubling in the number of spontaneous abortions, i.e., in 13
women consuming two species, E. angustifolia and E. purpurea without a detailed characterization (total: 206), versus 7 in 206 women not consuming
the herb [76]. It is known that, in vivo, Echinacea, given to either normal, healthy adult mice, or to adult leukemic mice, significantly
increases the numbers of natural killer cells [94], [95]. Since, natural killer cells have been implicated in foetus rejection, manifesting
in humans as spontaneous abortion [96], [97], [98], [99] it was speculated that Echinacea may influence abortion. Actually, the results from the human and animal studies of
Echinacea spp. are not sufficient to conclude on the safety in pregnancy [100]. No firm conclusions on the risk of spontaneous abortions and angiogenesis can be
drawn from the animal studies [71], [93]. The small number of test animals and the dubious relation to human conditions make
the results questionable. Furthermore, Perri et al. conducted a literature review
and found no significant differences between the Echinacea group (E. angustifolia and E. purpurea, without detailed characterization) and the control groups in the rate of major or
minor birth defects, nor were there any differences in pregnancy outcome, delivery
method, maternal weight gain, gestational age, infant birth weight, or foetal distress.
For clarification and rational evaluation more studies are needed, however, pregnancy
is not necessarily a contraindication and application of Echinacea preparations during pregnancy should be subjected to medical supervision.
Cautions from several authoritative sources (Community Herbal Monographs) are available
and concern especially hypersensitive persons like atopic or immunosuppressed patients,
the duration of use, and children. However, many trademark products containing Echinacea sp. will be defined as dietary supplements and thus not be legally bound to follow
the recommendations in the official plant monographs. E. g., in the latest Monographs
stated from the official European Medicines Agency (EMEA) [3], [4], [5], [6], [7], it has been suggested that the medicinally used Echinacea species should not be used for more than 10 days, but there were no pharmacological,
toxicological and clinical data found supporting a limit of treatment duration for
any “Echinacea” species used in either modern or traditional medical literature. The primary concerns
for these temporal limits appear to be theoretical, including over-stimulation of
the immune system and possible immune depression and immune habituation following
long-term use. However, up to now the limitations are not justified and no substance
classes can be hold responsible for the temporal limits. Long-term use of the pressed
juice of Echinacea purpurea has not shown evidence of a deleterious effect on immune cells. One study reported
that the immune reactivity in mice was greater after 10 weeks of continuous oral doses
of an expressed juice of the aerial parts of Echinacea purpurea than after 2 weeks [85]. Miller et al. reported in a study that the chronic administration of an Echinacea purpurea root extract (0.45 mg daily for 14 months) from puberty until old age in mice resulted
in the preservation of NK cell activity. Natural killer cell activity normally decreases
with age and contributes to an increased mortality. The use of Echinacea purpurea preparations increased the life span of most of the mice and no toxicological concerns
were noted [52]. Moreover, three further long term studies (12–24 weeks) with continuous ingestion
of ethanolic Echinacea purpurea root or whole plant extracts reported no toxicological concerns [86], [87], [88], [89]. Moreover, no significant or clinically relevant changes from before to after the
Echinacea treatment and in comparison to the placebo were detected in haematological or biochemical
measures, after 4-month exposure to an E. purpurea preparation (alcoholic extraction from freshly harvested 95 % herba and 5 % roots)
[89]. There is no firm evidence to conclude the debate on duration limits.
Application of “Echinacea” species and preparations in those taking immunosuppressive drugs has been assumed
as with any immune stimulant. Similarly, those with allergic sensitivities to members
of the plant family Asteraceae, as well as atopic individuals and patients with asthma,
should use Echinacea species with cautions and after consulting a physician. Regardless, very few published
reports exist in this context, and those have limited causal association [48], [49]. The cautions in taking “Echinacea” from atopic patients arise from the common known allergenicity to the pollen proteins
from plants of the sunflower family (Asteraceae). E. purpurea aerial parts products have more potential to elicit allergic reactions in atopic
individuals than do root products. Considering the fact that proteins are very poorly
extracted in ethanol-water mixtures it is also unlikely that an allergy would result
from the fluid extracts and tinctures of Echinacea, even if the aerial parts were used. Proteins that are potentially contained may
be denaturized by alcohol and are unlikely to cause an allergic cross-reactivity [52]. This indicates that the general risk for an allergic reaction to Echinacea is low. However, atopic patients and those with asthma should be informed about such
a possibility before intake of preparations containing Echinacea. The suggestion that “Echinacea” preparations are contraindicated in autoimmune disease assumes that the modulation
of any aspect of immune function is deleterious. However, immune function is extraordinarily
complex and a substance that acts largely on the phagocytic activity may be safe or
even beneficial in autoimmunity [50], [51], [52], [53], [54]. It is known that a stimulation of cytokines may lead to an exacerbation of autoimmune
related inflammation and a majority of autoimmune diseases are thought to be due to
a loss of tolerance to self-antigens and a dysregulation of Th1T-helper cells. Th1
cells produce cytokines IL-2, TNF-α, and IFN-γ. There has been one report indicating that both Th1 cytokine and IFN-γ and T-cell proliferation can be stimulated by E. angustifolia
[101]. Haemolytic anemia (thrombocytopenia, leucopenia and eosinophilia) have been published
only in single cases, mostly with uncharacterized Echinacea preparations and concomitant intake of other drugs or herbal medicinal products,
so that the relevance is not clear. The published data on leucopenia have to be considered
as not relevant for the safety of Echinacea due to reports concerning the occurrence of changes in hematology, like anemia and
pancytopenia after a concomitant ingestion of bupropion (product information Wellbutrin,
PDR, USA). Moreover, the patient showed also low respectively borderline levels of
the white cell counts without Echinacea
[60].
A specific risk in children is not documented and adverse events are very rare, with
no causality. Rash was the only side effect that occured significantly more frequent
after the ingestion of an alcohol-free preparation of the dried pressed juice of the
aerial parts of E. purpurea compared to a placebo (Taylor et al. 2003). Moreover, it has been found that those
children taking the pressed juice from E. purpurea were significantly less likely to have another upper respiratory infection [81]. Risk/benefit results suggest that the use in children can be recommended, but an
intake of any Echinacea preparation in children less than 1 year of age should be discussed with a physician,
because their immune system is not fully developed.
Concerning pharmacokinetic herb-drug interactions, which can result in tremendous
variability (over 10-fold changes) in pharmacokinetics of concomitantly administered
drugs, only the studies published since 2007, present reasonable data. The studies
before have been performed with different and phytochemically insufficient characterized
Echinacea preparations. With the in vivo studies published no significant inhibitions of human CYP2D6 and CYP3A4 isoforms
have been found after the application of standardized E. purpurea preparations (softgel capsules with 267 mg, 3 times daily or fresh plant liquid extract
again in softgel capsules with 500 mg, 3 times daily) [18], [21]. No significant interaction has been found with etravirine, darunavir, and lopinavir-ritonavir,
which undergoes extensive metabolism by the hepatic CYP3A4 isoform [19], [20], [21]. Only a cautious conclusion can been drawn that Echinacea alkamides inhibit CYP2E1 and CYP3A4 in human liver microsomes or enzyme substrates
(supersome assay) [27]. After separating each characterized Echinacea preparation (pressed juices or alcoholic tinctures from E. purpurea and E. pallida) into its ethanol- and water-soluble components, the results directly confirmed the
role of alkamides in the inhibition of CYP3A4 [24], [25]. Controversial results exist on the transcriptional/translational activities with,
e.g., induction or inhibition of CYP3A4 expression. A pressed juice from the aerial
parts of E. purpurea and an E. purpurea root preparation suppressed hepatic CYP3A4 expression [15], [22]. Whereas, Kortenkamp et al. found no significant changes in the steady-state CYP3A4
mRNA levels neither for Echinaforce® nor the pure alkamides [29]. However, herbal products are often marketed as dietary supplements, which have
fewer requirements for testing of pharmacokinetic interaction potential before marketing
compared to registered drugs. Recently the U. S. Department of Health and Human Services,
Food and Drug Administration (FDA) and the European Medicines Agency (EMA) released
“Guidelines on the Investigation of Drug Interactions” [102], [103]. Two pharmacodynamic interaction studies in mice exist about the administration
of an E. purpurea root extract or an ethanolic extract of E. purpurea dried aerial parts. One study found a negative effect on levels of mature granulocytes
after a concomitant ingestion of melatonin [9], [10]. However, a positive interaction has been reported after taking phenytoin at the
same time, with a decrease in the incidence of cleft palate [11]. No evidence of any apparent effect on warfarin pharmacodynamics with platelet aggregation
or baseline clotting status in healthy subjects has been found after concomitant administration
of Echinacea (600 mg E. angustifolia roots and 675 mg E. purpurea roots, four times a day) with (S)-warfarin [12].
A declaration of pharmacodynamic and pharmacokinetic interactions with homeopathic
preparations is not needed.
In conclusion, these data suggest that medicinally used Echinacea spp. have a very good safety profile.
