Echinacea

Echinacea is a term used to refer to a genus of purple cone flowers (belonging to the family Asteraceae) wth 9 known species,^[1] the most common being purpurea and two other commonly used species being angustifolia and pallida. Echinacea is said to have a fiery and pungent taste^[2] and has historical usage in north american medicine (for the alleviation of pain and the promotion of healing of snake bites, burns, cough, sore throats, and toothache^[2]).

Echinacea is most commonly used as a herbal immunostimulant and for the purposes of fighting respiratory ailments and and flu symptoms,^[1] and appears to be one of the more popular supplements used in US, Australia, and becoming more popular in North Africa, South America, and China in general (data derived from conference presentations cited via here^[3]). It is used for purposes such as cold and general sickness prevention,^[4] sometimes used in cancer patients alongside chemotherapy or after remission,^[5][6][7] and sometimes by athletes for both lung health and attenuated exercise-induced immunosuppression.^[8][9]

The German Monograph issued by the E Commission (book, cited via here^[1]) recommends alcoholic extracts from the root of Echinacea pallida or juices pressed from the leaves and stems.

Echinacea is a highly popular 'immunostimulant' herb taken for the common cold, and the term 'echinacea' refers to a plant genera with a few species all being used commonly (purpurea, angustifolia, and pallida)

Echinacea (purpurea unless otherwise specified) tends to contain:

The alklymaide content (35.9mcg/g in Echinaforce^[10] and up to 2.108mg/g of the dry weight of echinacea purpurea^[11]) of:

• Dodeca-2E,4E,8Z,10Z-tetraenoic acid and Dodeca-2E,4E,8Z,10E-tetraenoic acid (pair of structurally related isomers^[10] totalling 1.44+/-1.00mg/g dry weight^[11]) as well as both Dodeca-2E,4E,8Z-trienoic acid (0.10+/-0.11mg/g) and Dodeca-2E,4E-dienoic acid (0.06+/-0.05mg/g) being the most well known three alkylamides^[10]
• Undeca-2E,4E-diene-8,10-diynoic acid isobutylamide(purpurea^[12] and atrorubens^[13]) as well as its isomer Undeca-2E,4Z-diene-8,10-diynoic acid isobutylamide (0.21+/-0.15mg/g dry weight^[11])
• Undeca-2Z,4E-diene-8,10-diynoic acid 2-methylbutylamide (purpurea^[14] at 0.07+/-0.05mg/g dry weight^[11]) and undeca-2Z,4E-diene-8,10-diynoic acid isobutylamide (0.57+/-0.26mg/g dry weight^[11])
• Dodeca-2E,4Z,10Z-trien-8-ynoic acid isobutylamide(purpurea^[12] and angustifolia ^[15][16])
• Dodeca-2Z,4E,10Z-trien-8-ynoic acid isobutylamide (purpurea^[12] and angustifolia ^[17])
• Dodeca-2E,4E-diene-8,10-diynoic acid isobutylamide (purpurea^[12] and achilles^[12]), its isomer Dodeca-2E,4Z-diene-8,10-diynoic acid isobutylamide(0.42+/-0.19mg/g dry weight),^[11] Dodeca-2Z,4E-diene-8,10-diynoic acid isobutylamide (0.16+/-0.09mg/g dry weight^[11])
• Dodeca-2E,4E-diene-8,10-diynoic acid 2-methylbutylamide (0.25+/-0.12mg/g dry weight^[11]), dodeca-2Z,4E-diene-8,10-diynoic acid 2-methylbutylamide (unquantifiably low^[11]), and dodeca-2E,4Z-diene-8,10-diynoic acid 2-methylbutylamide (0.04+/-0.03mg/g dry weight^[11])
• Pentadeca-8Z-ene-11,13-diyn-2-one (0.64+/-0.34mg/g dry weight), pentadeca-2E,9Z-diene-12,14-diynoic acid isobutylamide (1.04+/-0.67mg/g dry weight), and pentadeca-8Z,13Z-dien-11-yn-2-one (4.77+/-2.08mg/g dry weight) in pallida only^[11]
• The isomer mixture of pentadeca-8Z,11Z,13E-trien-2-one and pentadeca-8Z,11E,13Z-trien-2-one totalling 1.18+/-0.67mg/g (pallida only)^[11]

A large amount of alkylamides (structure of the group) which are mostly either isobutylamides or methylbutylamides (subclassifications). Many of these structures exist in isomer pairs, where the only structural difference is an E or Z designation on a double bond. The exact 'active' molecule, or whether synergism between isomers causative of effects, are not known although the entire class of alkylamides appears to be the molecules causative of echinacea's effects

With other phytochemicals of:

• Caffeic acid^[3]
• Echinacoside (6.9mcg/g in Echinaforce^[10]), a triglycoside (glucose bound to two rhamnose molecules) with two caffeic acid molecules attached, found at 0.88+/-0.54mg/g in purpurea and 0.71+/-0.73mg/g pallida^[11]
• Cichoric acid, a tartaric acid molecule with two bound caffeic acid molecules (313.8mcg/g in Echinaforce^[10] with 2.87+/-0.96mg/g dry weight of purpurea and 0.27+/-0.17mg/g in pallida^[11], increased to 13.6+/-3.9mg/g in an 80% ethanolic extract of purpurea^[3])
• Cynarine (quinic acid bound to two caffeic acid molecules)
• Chlorogenic Acid (40.2mcg/g in Echinaforce^[10]) at 0.06+/-0.05mg/g in purpurea and not detected in pallida^[11]
• Caftaric acid (264.4mcg/g in Echinaforce^[10])^[11] at 0.15+/-0.06 in purpurea and 0.04+/-0.02 in pallida^[11]
• 9,9′-diisovaleroxy nitidanin (Neolignan)^[12]
• 2, 3-di-O-isoferuloyltartaric acid^[18]
• 2-O-caffeoyl-3-O-isoferuloyltartaric^[18]
• 1β-hydroxy-4(15),5E,10(14)-germacratriene (sequesterpene)^[12]
• Quercetin, the 3-O-rhamnosyl-(1→6)-galactoside glycoside, and Rutin^[19]
• Kaempferol as 3-O-rhamnosyl-(1→6)-galactoside^[19]
• Hypoxanthine^[19]

The other molecules in echinacea are mostly related to caffeic acid (small phenolic molecule common in the plant kingdom) or structures consisting of caffeic acid and either sugars or other small phenolics (tartaric and quinic acid). These are not thought to underlie the effects of echinacea although they are present in supplements

Most of the above molecules are somewhat lipophilic, present in high quantities in 50-80% ethanolic extracts relative to water extracts.^[3][14] Similar to most plants, echinacea bioactives vary depending on season and growing conditions.^[11]

Echinacea also contains a carbohydrate (polysaccharide) content that is immunostimulatory in vitro and in some animal models, with a potency slightly less than that of astragalus membranaceus (25-50mcg/mL) but comparable to that of wolfberry and kelp (Laminaria japonica).^[20] The polysaccharides have shown immunopotentiating potential when given alongside a vaccine in animals^[20] and has been noted to work with the flu vaccination^[21] (data is not unanimous, as one study noted that in their model echinacea was ineffective^[22]).

When comparing species of echinacea against one other, pallida appears to have a lesser overall alkylamide content than purpurea although the latter is comparable to angustifolia.^[23] pallida appears to be comparatively high in ketoalkene and ketoalkyne structures rather than alkylamides, which are more related to cancer cytotoxicity than immunity.^[24] Echinacoside (a caffeic acid glycoside) which sometimes appears to be in large quantities in pallida but not purpurea (sometimes^[25] but not always so,^[11] it does not have inherent immunostimulating properties^[26]), and is an chemical indicator of species alongside cichoric acid (high in purpurea);^[25] although angustifolia and purpurea are somewhat interchangeable, pallida does not appear to be.

There appears to be a component of Braun-type lipoproteins^[27] (also seen in Spirulina) that are causative of the majority (85-98%) of the immunostimulating properties associated with echinacea in vitro^[27][28] and removal of these Braun-type lipoproteins and any lipopolysaccharide (LPS) content abolishes the monocyte stimulating activity (via NF-kB activation) of echinacea.^[27] It should be noted that some alkylamides are also active in this regard, and although LPS contamination appears to be a significant confound it may not be solely responsible (endotoxin free echinacea has also been implicated in immunostimulation^[29])

Bacterial and LPS content in echinacea may underlie a good deal of (but not all) of macrophage stimulation from echinacea supplementation

Basic drying of echinacea (in processing after harvest) is associated with losses of bioactive molecules with chicoric acid being most susceptable to loss,^[30][31] alkylamides have been implicated in this loss^[30] although they are not lost as reliably (sometimes no loss is detected).^[32] Chicoric acid has also been noted to be lost at storage conditions of 40°C when in the dried root, but in powder form the major alkylamide isomer pair appears unstable;^[33] although only after heating processes (as the fresh plant at 20°C storage does not show alkylamide loss^[34]) both chicoric acid and the alkylamide isomer pair are stable at -20°C^[33] and 5°C when stored in the dark.^[34]

High pressure pasteurization (HPP) of echinacea to remove bacterial contamination (Escherichia coli (E. coli) and Listeria monocytogenes^[35]) does not significantly influence the content of phenolics (chicoric, caftaric, and chlorogenic acid) with the alkylamide content also similarly unaffected.^[36] This is thought to be due to HPP preserving hydrogen bonds which are normally broken during heating processes or drying.^[37]

It may be prudent to store processed echinacea products in cool and dark areas to avoid loss of alkylamides and phenolics (Note: inside a bottle of pills is already dark, temperature is the only factor to be concerned with at this stage)

Echinaforce is a hydroalcoholic extract of echinacea purpurea consisting of the herb and roots in a 95:5 ratio;^[10][38] one study has detected that Caffeic acid, cynarin and polysaccharide are not detectable in Echinaforice.^[10] Echinaforce appears to be free of endotoxin (lipopolysaccharide) content.^[39][40] Despite the insignificant concentration of endotoxins such as LPS (which are highly correlated with macrophage stimulation from echinacea products^[27][28]) Echinaforce has at least once been connected to reduced cold symptoms.^[29]

Echinaforce is a standardized product of echinacea which appears to be free of endotoxin (LPS) contamination, with a higher than normal concentration of some alkylamides and no detectable cyanarin or caffeic acid. Although there does not appear to be variability associated with the effects of it, there is probably not enough evidence to conclude that it is more reliable

Echinaguard and Echinacin, common branded names, have been found to not be significantly different from trial using basic plant extracts (without brand name) as assessed by one meta-analysis able to do a subgroup analysis on brands.^[41]

Echinaguard and Echinacin are two common brand names which do not have enough evidence to support their usage as better than the basic plant extract of either echinacea purpurea or angustifolia; essentially they are interchangeable

In isolated Caco-2 cells, there does not appear to be significant uptake of the caffeic acid derivatives of echinacea (caftaric acid, echinacoside, cichoric acid) while alkylamides have a time-dependent uptake; the degree of uptake varied slightly over 90 minutes depending on the alkylamide in question and varied between 100% ((2E,4Z)-N-isobutylundeca-2,4-diene-8,10-diynamide) and 20% (, (2E,9Z)-N-(2-methylbutyl)pentadeca-2,9-diene-12,14-diynamide).^[42] Overall, more than 50% of total alklyamides are absorbed within 90 minutes, and the major alkylamide of echinacea ((2E,4E,8Z,10Z)-N-isobutyldodeca-2,4,8,10-tetraenamide) appears to be absorbed to around 74+/-22%.^[42] The transport of alkylamides has been confirmed when derived from other echinacea species,^[43] and coingestion of multiple alkylamides has the potential for increasing the bioavailability of others (via sacrificial P450 metabolism).^[44][45]

Alkylamides appear to be absorbed, with the degree of absorption varying depending on the alkylamide in question. Other molecules in echinacea do not appear to be well absorbed

Following oral administration of echinacea, the circulating concentration of the main alkylamide isomer pair (dodeca-2E,4E,8Z,10E/Z-tetraenoic acid isobutylamides) has been detected at 10.88ng/mL following ingestion of 2.5mL of echinacea tincture (60% ethanolic extract from echinacea angustifolia; oral dose of alkylamides not given but a 77:1 concentration for the production was noted) with a T_max (time to peak serum levels) being in between 10-30 minutes.^[46] Other alkylamides were detected in serum at a similar T_max including the undeca-2E/Z-ene-8,10-diynoic acid-isobutylamides isomer pair (1.87ng/mL), dodeca-2E,4Z-diene-8,10-diynoic acid-isobutylamide (1.54ng/mL), dodeca-2E-ene-8,10-diynic acid-isobutylamide (0.96ng/mL), and dodeca-2E,4E,8Z-trienoic acid-isobutylamide (2.1ng/mL), while dodeca-2E,4E-dienoic acid-isobutylamide was not detected (limit of detection being 3pg/mL).^[46]

Comparison of tablets versus tinctures has noted a more rapid absorption and higher C_max associted with tincture (0.40ng/mL at 30 minutes) relative to capsules (0.12ng/mL at 45 minutes) although this study also failed to note any significant differences on measured immune parameters.^[39] Another study using tablets has noted slower pharamcokinetic parameters with a T_max of 2.3 hours, when measuring total alkylamides the serum level was 336+/-131ng/mL after acute ingestion of 625mg purpurea and 600mg angustifolia.^[47]

Studies that assess interindividual variability note a large degree of variation, with a sample of three person varying C_max values between 0.012-0.181ng/mL (main isomer pair following 20 drops of tincture as Echinaforce)^[48]

Alkylamides can be detected in serum following oral ingestion of echinacea supplements, and absorption seems quite rapid. Circulating levels of alklyamides are all in the low nanomolar range. Both tinctures as well as capsules appear to increase serum levels, although tinctures may be faster absorbed possibly due to buccal absorption (through the mouth into the blood)

Echinacea purpurea at 1600mg (four divided doses of 400mg) in humans has been found to significantly but modestly inhibit CYP2C9 (tolbutamide clearance reduced by 11% on average, 2/12 persons experiencing 25%), inhibited the aromatase enzyme (CYP1A2) as plasma caffeine levels increased 27-30%, and induced CYP3A4 as serum midazolam clearance 42% relative to control.^[49] Oddly, CYP3A4 appeared to be inhibited in the intestines as oral bioavailability of midozolam increased.^[49] A 28 day study using 1600mg echinacea purpurea has failed to note any interaction with CYP3A4, CYP2E1, or CYP2D6^[50] (previous study noted no acute effects on CYP2D6^[49] and a standardized supplement of 801mg echinacea and 6.6mg isobutylamides also failed^[51]) while there was a minor inhibitory effect of echinacea on CYP1A2 that failed to reach significance.^[50]

1500mg echinacea purpurea daily for 14 days in combination with retroviral therapy (for HIV; protease inhibitor/ritonavir combination therapy) failed to note significant inhibition of the CYP3A4 enzyme, but this study is somewhat confounded as ritonavir itself is a CYP3A4 inhibitor and could outcompete echinacea.^[52] Some decline in serum darunavir following exposure to echinacea after 14 days suggests induction of CYP3A4,^[52] although another study in healthy persons given darunavir/ritonavir for 14 days alongside the same dose of echinacea failed to find any influence on circulating levels of these two drugs despite inducing CYP3A4 (midozolam probe).^[53]

2 weeks of pretreatment with a very high dose of echinacea (5100mg conferring 23mg akylamides) noted a small but significant increase in serum (S)-warfarin concentrations (9%, 95% CI of 1-18%)^[54] that does not appear to be clinically relevant according to a review on the topic.^[1] This is indicative of CYP2C9 and CYP3A4 inhibition.^[55]

In regards to P450 enzymes of importance to drug-herb interactions, there appears to be minor inhibition of aromatase (CYP1A2) and some possible relevant interactions with both CYP3A4 (inhibition and induction acutely, over the long term appears to increase enzyme activity) and CYP2C9 (minor inhibition); CYP2D6 does not appear affected

One study using 801mg echinacea purpurea (6.6mg isobutylamides) for 14 days failed to have any significant effect on P-glycoprotein^[1] despite some of the alkylamides showing inhibition in vitro.^[56] Both echinacea pallida and sanguinea have been noted to inhibit P-glycoprotein.^[57]

No significant effect on P-glycoprotein following ingestion of standard echinacea supplementation, although some possible interactions have been noted ex vivo and with other species

Concentrations of 10-25mcg/mL echinacea appear to stimulante TNF-α production in vitro with macrophages and monocytes (25mcg leading to 11-fold induction of TNF-α protein content and 8-fold induction of mRNA); it was not additive with LPS (which inhernetly induced TNF-α) and mediated TNF-α via cAMP-sensitive and CB2-dependent mechanisms (signalling via CB2 dependent on NF-kB, JNK/ATF-2 and CREB-1).^[40] The potency was in the nanomolar concentration range (1µM being effective, EC₅₀ values not determined), with the isomer pair dodeca-2E,4E,8Z,10E-tetraenoic acid(s) and dodeca-2E,4E-dienoic being most active and cichoric acid ineffective.^[40] There appears to be more affinity for CB2 relative to CB1 associated with echinacea alkylamides, and CB2 receptors are more highly expressed on immune cells (whereas CB1 receptors are highly localized on neurons).^[58]

One study suggested that intracellular rises in Ca²⁺ are noted with alkylamides via CB2 receptor activation (HL60 cells)^[59] although a later study noted that this may be due to a CB-independnet mechanism (rise seen in HEK293 which do not express CB2 receptors).^[2]

Binding to and activation of the CB2 receptor (the cannabinoid receptor expressed on immune cells mostly) has been noted with alkylamides in echinacea, while there does appear to be a degree of binding to the CB1 receptor although it is comparatively less

For studies that do report EC₅₀ values, they are highly variable depending on whether an isolated alkylamide is tested or a mixture is with reports ranging from 60nM^[60] to 2-20μM^[61] (30-fold difference in potency). The isomer mixture (dodeca-2E,4E,8Z,10E-tetraenoic acids) displays additive agonistic effects to 9% of the receptor capability at (The reference agonist, arachidonyl-2′-chloroethylamide, activated 47% of the receptor capability) and the neolignan 9,9′-diisovaleroxy nitidanin also activates cannabinoid receptors.^[12] However, a variety of compounds in echinacea appear to have weak inverse agonist properties.^[12]

Due to various alkylamides having differing effects on cannabinoid receptors (agonistic, antagonistic, or inverse agonistic) and the relative inefficacy overall, it is unlikely that echinacea-derived alkylamides possess neural properties like those seen with marijuana

It is though that echinacea may reduce anxiety (as CB1 receptor activation reduces anxiety^[62] while echinacea has been noted to inhibit fatty acid (FAAH)^[63] which degrades anandamide,^[64] an endogenously produced cannabinoid) and when tested in 22 otherwise healthy adults assessed by the State-Trait Anxiety Inventory (STAI) noted that 40mg of echinacea angustifolia was able to significantly reduce anxiety (20mg ineffective, higher doses not tested) with the average STAI score being reduced from slightly over 120 to 100.^[65] A rat study conducted prior to the human intervention noted that 4-5mg/kg was associated with the best anxiolytic effects (human equivalent of 0.64-0.8mg/kg).^[65]

One study has noted a significant reduction in anxiety associated with very low oral doses of echinacea tablets

As a bell curve was noted with this study, it is unsure if higher doses will have a similar effect; replication of this study would also be prudent

A study assessing an acute dose of echinacea at 350mg failed to find evidence of echinacea altering blood pressure.^[66]

No currently known interactions with blood pressure

The alkylamides in echinacea are known to activate cannabinoid receptors with more affinity for CB2 relative to CB1, with the former being highly expressed on immune cells^[67] and a solution of alkylamides being able to activate CB2 on monocytes and macrophages with an EC₅₀ of less than 1µM^[40] (overall, the EC₅₀ is somwhat variable, between 60nM^[60] and 20µM^[61] possible due to various different ratios of alkylamides and testing conditions).

Secondary to activating the second subset of the cannabinoid receptors (CB2), some alkylamides can induce TNF-α release in macrophages and monocytes.^[40] The release of TNF-α appears to be secondary to NF-kB activation, JNK/ATF-2 and CREB-1 as intermediates, and is additionally cAMP dependent.^[40]

Some potential immunostimulatory effects of echinacea not due to LPS, but secondary to alkylamides, from activation of cannabinoid receptors that increases TNF-α levels. The concentration of which this occurs may be biologically relevant

TNF-α induction has been noted at low concentrations when the alkylamides are fed to rats at 12mcg/kg^[68] and is achieved in isolated macrophages via TLR4 dependent and independent mechanisms.^[69] The activation of macrophages from echinacea alkylamides^[69] is sometimes seen as a modulating effect, since overall NF-kB activation in macrophages treated with both LPS and echinacea is less than that seen with LPS alone.^[70]

One study using endotoxin-free echinacea purpurea has noted a reduction in TNF-α release by 24% from PBMCs taken from persons fed echinacea (4mL of Echinaforce for 3 days, followed by 10mL for 3 days).^[10] This may be related to total bacterial load highly correlating with TNF-α induction.^[28][27][71] The more common endotoxin contaminant known as lipopolysaccharide (LPS) is a proinflammatory reference molecule that induces macrophage activation via the TLR4 receptor.^[72]

When assessing TNF-α induction in vitro, it appears that purpurea is significantly outperformed by pallida, although this study noted a failure of both purpurea and angustifolia to induce TNF-α acutely in PBMCs.^[73]

While alkylamides in echinacea either alternatively activate or suppress macrophages activation while LPS contamination induces macrophages activity via TLR4 (classical activation pathway), the practical effects of orally ingested echinacea on macrophages is unclear. The overall effect could be one where there is a macrophage stimulatory effect without LPS contamination and a controlled stimulation with coincubation of echinacea and LPS (a similar modulatory effect has been seen with Ganoderma Lucidum)

The induction of IL-8, as well as IL-6, appear to hold consistenly when the dose is changed in vitro in leukocytes.^[74]

Endotoxin-free echinacea has been noted to reduce IL-1β secretion from PMBCs while increasing IL-10 by approximately 13%, with weak induction of IFN-γ and IL-8 (cells taken from persons fed 4mL Echinaforce for 3 days and 10mL for another 3 days).^[10] The induction of IL-10 appears to be comparatively higher with pallida and laevigata relative to purpurea when tested in isolated PMBCs,^[73]

In the presence of a mitogen (Phaseolus vulgaris haemagglutinin), echinacea appears to stimulate the lymphocyte proliferation response in mice^[75] which may be general as it has been noted with all common species of echinacea in response to sheep red blood cells (mice);^[76] lymphocyte proliferation has been noted in vitro with alkylamides at 50mcg/mL,^[77] in vivo with a notable increase in CD4+ lymphocytes,^[78] and in vitro by stimulating interferon IFNγ production in anti-CD3-treated murine T-cell cultures.^[79]

Despite this, echinacea juice (leaf) supplementation appears to slightly suppress T-cell levels (6%)^[80] and beyond suppressing T-cell release of IL-2,^[77] TNF-α and IL-1β^[76] there might be reduced antigen uptake from dendritic cells by T-cells.^[19]

Mixed effects observed on T lymphocytes. Although some stimulatory effects are noted, in practical situations there is a very slight suppression of T-cell count without significant alteration of the subpopulations

Dendritic cells are antigen present cells mediating innate and adaptive immunity that play a role in presenting antigens to T-cells for recognization.^[81] Their activation and proliferation, coupled with increased activity of T-cells, leads to greater antigen recognition and adaptive immunity (in response to sickness).^[81]

The basic root extract (polysaccharides, mostly glucitol acetate and mannitol acetate) can increase the content of CD86 and CD54 positive cells in a concentration-dependent manner, increasing from 10% to 25% and 27% (CD86) and from 12% to 30% and 32% (CD54).^[19] The leaf extract appeared to actually reduce content of CD86, CD54, and MHC II relatively, due to a large induction of CD11c+ BMDCs. An induction of CD54 has been noted elsewhere with an ethanolic root extract alongside a general stimulatory effect.^[82]

The leaf extract (more commonly used) is known to concentration-dependently increase CD11c+ BMDCs from 75% in the control to 94% (50mcg/mL) and 100% (150mcg/mL) while the root extract was less effective; due to a reduction in other positive cells (CD86, CD54, MHC II) the relative expression was approximately doubled.^[19] A reduction of CD86 has been noted with the leaf extract elsewhere,^[82]

Differential effects have also been noted on CD83+ cells, being stimulated with a butanolic extract (both stems and roots) and suppressed with an ethyl acetate fraction.^[83]

When assessing antigen uptake by dendritic cells, both the root and leaf extract appear to significantly reduce antigen uptake and acted to inhibit interactions between dendritic cells and CD4+ T cells.^[19] The authors hypothesized (as suppression was noted with both root and leaf extracts, while roots stimulated dendritic cell activity) that this may be due to T-cell suppression (noted elsewhere^[77]).

Although the evidence is a bit unclear, it appears that the polysaccharide fragment may induce dendritic cell activity while the alkylamides (in the leaf extract and more commonly supplemented) may suppress dendritic cell activity; both appear to reduce activity of a dendritic cell and T-cell interaction, which may be due to the effects observed on T-cells

Mechanistically, Cynarin is known to be immunosuppressive^[84] (although the low concentration in echinacea may preclude any efficacy of this ingredient) and extracts of echinacea appear to modulate NF-kB activity in dendritic cells^[85]

The leaf extract has been known to attenuate COX2 induction, with 2-8mcg/mL of the extract (but not root) reducing COX2 induction in a concentration dependent manner in the range of 28-85%; COX1 was unaffected.^[19]

The essential oil of echinacea purpurea has been found to possess anti-inflammatory effects in vivo as assessed by the granulation formation test (28.52%), paw edema (48.51%), and ear edema (44.79% inhibition).^[86]

Extracts of echinacea appear to have anti-inflammatory effects following oral ingestion, but the potency does not appear to be overly remarkable

Increased production of antigen specific immunoglobulins M and G has been noted in rats following ingestion of echinacea (angustifolias were consistently statistically significant).^[87]

May increase the antigen count in the body, which is a possible mechanism for fighting off acute sickness

A systemic review^[88] (assessing several meta-analyses^[41][89][90]) noted that despite fairly well structured studies (average Jadad score^[91] of 3.5) there was poor standardization of test product used (studies more likely than not used echinacea purpurea and more likely than not used the aerial parts, but data is frequency absent).^[88] Despite these potential concerns, previous meta-analyses have concluded a 58% reduced risk of developing cold symptoms (Odds Ratio (OR) 0.42; 95% Confidence Interval (CI) of 0.25-0.71) and 1.4 less cold days on average,^[41] placebo being associated with 55% the risk of colds relative to echinacea (OR 1.55 and 95% CI of 1.02-2.36),^[89] but the Cochrane analysis of randomized blinded trials noted that the large hetereogeneity observed prevented significant benefit from being associated with echinacea.^[90]

One particular meta-analysis^[41] that noted a 58% (95% CI of 29-75%) reduction in cold occurrence and 1.4 days less average cold reduction noted that, while all but one study^[92] had a mean value in the positive range (indicative of less cold occurrence) many studies in isolation crossed the zero point and were statistically insignificant, only reaching significance after pooling.^[41] Another meta-analysis with more restrictive inclusion criteria attempting to do the same failed to find significant benefit associated with echinacea over placebo.^[90]

In general, although there is benefit associated with echinacea supplementation for the prevention of colds that is greater than placebo this appears to be highly variable. Meta-analysis of trials is somewhat limited due to large variations seen in trials on echinacea by using different doses, product formulations, and time frames

When isolated studies that use tinctures of echinacea, 2.5mL thrice daily (7.5mL daily, brand Echinaguard) for one week prior to and 5 days after inoculation with the common cold (rhinovirus 39) noted that the rate of cold development occurred in 82% of placebo and only 58% of persons with echinacea;^[93] this trial design has been used with encapsulated echinacea (300mg thrice a day) without effect, although this study used echinacea angustifolia.^[94] Two studies exist using 8mL of a tincture for either 28 days^[95] or 8 weeks^[96] in healthy persons have noted an increase in immunity after exercise and no effect on cold occurrence, respectively. When used prophylactically (daily in prevention of colds) echinacea daily for 4 months appears to be more effective than placebo even at 0.9mL thrice daily (using the brand name Echinaforce).^[97]

In persons already with a cold, children (7.5-10mL daily for 10 days) failed to find benefit with echinacea supplementation when given to children already with a cold^[92] while adults order to take 5mL twice a day for 10 days at the first signs of a cold noted some protective effects associated with supplementation.^[98] One study not located online by cited in meta-analysis^[41] (Braunig and Knick, 1993) has been noted to skew a meta-analysis due to its effect size, where the reduction in cold time reached –3.80 days (95% CI of 3.08-4.52 day reduction) where most other studies noted a day or so reduction.

When looking solely at tincture using studies, the effects appear to be somewhat similar to encapsulated power echinacea (still just as variable as echinacea usage)

A few studies assessing echinacea are confounded with either the inclusion of propolis and Vitamin C,^[99] Thyme and peppermint,^[100] lemongrass and spearmint,^[101] and Vitamin C with rosemary and fennel (not located online, assessed via meta-analysis^[41]); these studies are excluded from the above analysis due to being confounded.

Echinacea appears to be commonly used by athletes for the purpose of preventing exercise-induced immunosuppression^[102] although several reviews note a lack of evidence to support usage.^[103][104]

At least one study noted a low rate of sickness in athletes using echinacea (although limited by no control as well as being open-label)^[105] and another study has noted that the significant reductions in salivary s-IgA (thought to be indicative of immunity suppression from exercise when reduced) were attenuated with echinacea, and although there were no significant differences in frequency of sickness during the 4 week trial the echinacea group reported reduced sickness duration.^[106]

Insufficient evidence to support a role of echinacea supplementation in preventing sickness from exercise-induced immunosuppression

An increase in oxygen carrying capacity of the blood secondary to inducing erythroid growth factors such as the hormone erythropoetin has been noted in animal models^[107] and 8,000mg of echinacea purpurea daily for 28 days is associated with increased erythropoetin levels (in the range of 77-94% increases from weeks 1-3, declining at week 4) without significantly influence RBC count.^[108] This study appears to have been duplicated in Medline.^[109]

Appears to increase erythropoetin levels following oral administration, but this does not appear to be associated with any significant increases in hemoglobin or RBC count

It has been noted that supplementation of echinacea at the equivalent of 3,200mg daily for 30 days (in a study assessing eleutherococcus senticosus and using echinacea as a comparator) trended to increase maximal oxygen consumption (VO² max) in untrained subject (5%) but failed to be significant^[110] while a later study using a much higher dose (8,000mg; 2,000mg four times daily) for 4 weeks in recreationally active men was noted to increase VO² max and decrease the oxygen requirement of exercise without affecting heart rate.^[108]

It was thought that echinacea can increase red blood cell count and thereby increase oxygen carrying capacity and exercise performance, although the study to note improved exercise performance did not detect such an increase in RBC (only an increase in erythropoetin).^[108]

High doses may aid cardiovascular exercise, thought to be secondary to increasing the oxygen carrying capacity of the blood. Requires more evidence to support this position

Echinacea purpurea has been noted to reduce prolactin levels over 15 days in male rats at 100mg/kg, with 30mg/kg being ineffective.^[111]

Relative to other herbs on a dry weight basis, echinacea appears to generally underperform and inhernetly has weak to moderate effects.^{[112][113][114][115][116]}

The anti-oxidant potential of chicoric acid (2R,3R-dicaffeoyl tartaric acid) appears to be comparable to that of rosmarinic acid (caffeic acid bound to 3,4-dihydroxyphenyl lactic acid) on a weight basis,^[117] with the alkylamide being weaker and 24uM being required to be as effective as 1uM rosmarinic acid;^[3] chicoric acid appears to be increased in antioxidative potenty when combined with either alkylamides or polysaccharides from echinacea, and combination of all three outperformed any combination of two agents.^[3]

Although echinacea appears to be synergistic with itself when it comes to antioxidative properties, it does not appear to have more antioxidative potential in vitro relative to other supplemental herbs

In an ex vivo model of lung function (3-dimensional organotypic model) infected with the common cold, echinacea has been noted to reduce mucus production and to abolish the increase in IL-6 and IL-8 seen with rhinovirus administration without affecting lung structure or histology.^[118]

Oral ingestion of echinacea in mice has been noted to increase the macrophage activity in lung tissue in a dose dependent manner with significant occurring at an alkylamide and polysaccharide intake of 80mcg/kg and 20mg/kg, respectively.^[119] Oral intake of echinacea does not appear to be able to influence viral concentration in lung tissue of animals with the flu despite being noted to lower inflammatory cytokines (IFNγ and IL-10)^[120] and aiding the course of symptoms in mice.^[121]

There appear to be beneficial effects of echinacea supplementation on the lungs and airway, although the practical relevance of this animal data to humans is not certain

When the alkylamide are incubated with oxidized LDL (and exert relatively weak anti-oxidant effects), there appear to be synergistic antioxidant effects when coincubated with either free caffeic acid or a source of caffeic acid (chicoric acid or echinacoside).^[3] This synergism was built off of previous research noting more antioxitive effects with chicoric acid and alkylamides,^[117] and the synergism with alkylamides is also seen with a combination of chicoric acid and the polysaccharides from echinacea.

Coingestion of multiple alkylamides also has the potential for increasing the bioavailability of others (via sacrificial P450 metabolism)^[44][45] which theoretically increases absorption of echinacea alkylamides when consumed in combination relative to in isolation.

In rat studies, induction of mRNA for TNF-α, IL-10, and TGF-β1 are comparable with echinacea (0.75g/kg) and panax ginseng (0.50mg/kg) although some differences were observed at 20 days and no longer present at 40 days.^[122]

A study feeding rats 1% of their feed as either echinacea (purpurea) or ashwagandha (Withania somnifera at 3.6% withanoids and 1.1% alkaloids) for 4 weeks noted that there were no significant differences in any serum immunoglobulin (A, G, M, or E) although both groups appeared to increase levels of immunoglobulins relative to control.^[123]

Echinacea secreted more IFN-γ and IL-2 than ashwagandha and less TNF-α, and this trend persisted after LPS and mitogen stimulation.^[123]

A study feeding rats 1% of their feed as either echinacea (purpurea) or bacopa monnieri (12.8% saponins) for 4 weeks noted Bacopa was able to increase serum IgA and IgG to a higher degree than echinacea (32% and 102% more, respectively) while they performed equally on serum IgM and IgE.^[123]

In response to Concavalin A and LPS, bacopa secreted more IL-6 relative to echinacea while there were no differences in IFN-γ and IL-2.^[123]

Kan Jang capsules are a traditional chinese medicine consisting of Andrographis paniculata and Siberian Ginseng (Eleutherococcus senticosus). In comparison to a brand name called Immunal (Echinacea purpurea 20% ethanolic extract) in children (4-11yrs) with uncomplicated respiratory diseases noted that Kan Jang outperformed echinacea in regards to reducing symptoms associated with upper respiratory tract infection over 10 days of treatment.^[124]

Kan Jang combination tablets have once been noted to outperform echinacea in regards to reducing symptoms assocaited with upper respiratory tract infection, although it should be noted the echinacea is not really too effective in reducing symptoms (being more associated with reduced risk of getting the symptoms instead) and this may have not been an accurate comparison

In general, there do not appear to be clinically significant adverse effects associated with echinacea supplementation^[125] which seem to be related to allergic reaction or rash.^[126] One study looking at supplements which may be related to dry eyes noted that echinacea, as well as both Kava and niacin, were somewhat associated although causation could not be placed.^[127]

Allergy to echinacea appears to be highly correlated with an allergy to ragweed, which can be used as an indicator of possible adverse effects to echinacea.^[128]

In general there are no significant side effects with echinacea, although it is possible to be allergic to the plant genus. Allergies to echinacea appear to be correlated with allergies to ragweed, and thus those with allergies to ragweed may be at higher risk of allergic responses to supplemental echinacea

Ingestion of 5mL of a 40% ethanolic tincture (bioequivalent to 3825mg echinacea angustifolia and 150mg echinacea purpurea) caused immediate flushing, throat burning, urticaria and diarrhea that was successfully treated upon hospital administration and Promethazine which was thought to be assocaited with an allergic reaction to the herb;^[129] other case studies have been reported where patients respond positively to allergic testing at later dates.^[130]

It is possible to be allergic to echinacea supplementation