By Kerry Bone, BSc (hons.), Dip. Phyto

The most well-known herbal support for the immune system is echinacea.

But many patients and practitioners are confused as to the best way to use this herb. There are many echinacea products available which differ according to the plant species (E. angustifolia, E. purpurea, E. pallida or combinations of these), plant part (root, leaves, seeds or combinations of these), quality markers (alkylamides, polysaccharides, or caffeic acid conjugates such as cichoric acid) and dosage.

Underlying this diversity of preparations was a lack of consensus over what phytochemicals are responsible for echinacea’s immune activity and only a rudimentary understanding of the exact mode of action of this herb on immune function. However, recent research has provided some answers to these key questions. In particular, the alkylamides, the unique and characteristic phytochemicals found mostly in the roots of E. angustifolia and E. purpurea have been shown to be the best choice as markers of immune activity. This research validates the traditional preparations prized by 19^th century herbalists.

Historical Context

Before discussing the new research developments for echinacea, its use as an immune herb needs to be understood in its historical context. Information about the therapeutic value of echinacea first came from Native American tribes. Their use of echinacea root was then adopted by the Eclectics, a group of doctors who were prominent around the late 19^th and early 20^th centuries in the U.S. By 1921, echinacea (specifically the root of E. angustifolia) was by far the most popular treatment prescribed by Eclectic physicians.¹ The Eclectics used echinacea for about 50 years and accumulated extensive clinical experience in its use. The best sources of such uses are King’s American Dispensatory² and Ellingwood’s American Materia Medica.³

What also is important to note is that echinacea’s reputation as an immune herb came from the solid traditional data generated by the Eclectics on only one form of echinacea: a fluid extract of the dried root of Echinacea angustifolia extracted in a high percentage of alcohol. We can call this a “traditional echinacea extract” and, because it was extracted in a high percentage of alcohol, the term “lipophilic extract” (fat-loving) also is relevant. In particular, the Eclectics defined good- quality echinacea root “as imparting a persistent tingling sensation,” which is a clear reference to alkylamide levels as a quality indicator.²

In Europe during the 1930s, the German herbalist Madaus used E. purpurea, as he was more successful at growing this species. His interest in homeopathy led him to use the stabilized juice of fresh E. purpurea tops. This remains the most popular form of echinacea in Germany today (and contains very low levels of alkylamides). We can call this style of product a “hydrophilic extract” (water-loving) of echinacea.

Naturally, German scientists were interested to investigate how these new hydrophilic extracts of echinacea might work in the body and undertook a search for active components. Polysaccharides possessing immunological activity were isolated from the aerial parts of E. purpurea.⁴ Some clinicians and scientists then mistakenly applied this research to the very different lipophilic or traditional echinacea preparations, and came to the conclusion that they were therapeutically inferior because of their low or absent content of polysaccharides. (The low levels of polysaccharides in traditional echinacea extracts are due to the low starting levels in the root and the fact that high levels of alcohol do not effectively extract these water-loving molecules.)

However, many herbal clinicians remained unconvinced. A key aspect of modern phytotherapy is a respect for traditionally generated knowledge, and this suggested that a lipophilic extract of E. angustifolia root was the preferred form. Some felt that the concept of polysaccharides failed to explain what was unique about echinacea and expressed concerns about the low oral bioavailability of these large, polar compounds.⁵ So, what was clearly needed was a different understanding of echinacea, especially of the phytochemicals important for the activity of traditional echinacea products and their mode of action on the immune system.

Some of the confusion about echinacea use has arisen from misinterpretation or overemphasis of the polysaccharide research. Statements such as: “Echinacea will not be immunologically active if given as an ethanolic extract,” or “Echinacea is a T-cell activator” or “Echinacea is contraindicated in AIDS,” have all arisen from an overly enthusiastic interpretation of the pharmacological literature pertaining to echinacea polysaccharides. It is worthwhile to first examine what the pharmacological studies on echinacea polysaccharides really say and then to consider the relevance, if any, of these to the normal use of echinacea.

Dispelling the Polysaccharide Myth

Two immunostimulatory polysaccharides (PSI and PSII) were isolated from the aerial parts of E. purpurea in the 1980s.⁴ Studies showed PSI to be a 4-O-methyl glucurono-arabinoxylan (that is, mainly composed of glucuronic acid and the sugars arabinose and xylose), while PSII was shown to be an acidic arabinorhamnogalactan (mainly composed of the sugars arabinose, rhamnose and galactose).⁴

However, most of the studies on echinacea polysaccharides have been on those derived from tissue cultures of E. purpurea that yielded two fucogalactoxyloglucans and an arabinogalactan (AG).⁴ Tissue cultures are artificially cultured plant cells. As expected, the structure of the tissue culture polysaccharides differed from those of the aerial parts of the naturally grown plant since cells in culture possess only primary cell wall components.⁴

Echinacea polysaccharides (EPS; a protein-free, highly enriched polysaccharide mixture from the aerial parts of E. purpurea) seem to preferentially stimulate the mononuclear immune system in vitro.⁴ EPS stimulated both peritoneal and bone marrow macrophages to behave cytotoxically in vitro.⁴ In a second experiment, it was shown that EPS stimulated bone marrow macrophages to release interleukin 1 (IL-1), although it was much less potent than endotoxin in this respect.⁴

Subsequent research was mainly on either an acid arabinogalactan (AG) or an industrially prepared polysaccharide mixture (EPAG), both isolated from tissue cultures of E. purpurea.⁴ AG induced a dose-dependent release of tumor necrosis factor α (TNF α) from peritoneal macrophages in vitro.⁴ When bone marrow macrophages were used in vitro, a dose-dependent release of interferon β₂ (IL-6) also was found.⁴ There also is indirect evidence that EPAG stimulates TNF α from peritoneal macrophages in vitro.⁴ The effect of echinacea arabinogalactan from tissue cultures (AG or EPAG) is strikingly selective for macrophages in vitro.⁴

EPAG given by intravenous injection to mice at the very high dose (relative to levels in echinacea) of 10 mg/kg caused a protective effect against Candida albicans infection.⁶ Other similar tests have been performed with positive results.

It is worthwhile at this point to examine some of the erroneous conclusions about the use of echinacea which have been drawn from this research on polysaccharides. In vitro effects observed on isolated cells are not necessarily translatable to whole organisms. In other words, there are biological mechanisms in the whole organism that can modify the effects observed in in vitro models. In particular, gastrointestinal breakdown, poor absorption and poor tissue mobility of polysaccharides would suggest there are many significant unknowns in the translation of in vitro findings to effects in a living organism after oral dosage.

Polysaccharides are very large molecules that are destroyed in the colon by bacterial activity.⁷ Research on acemannan from aloe vera juice shows that polysaccharide absorption through the gut is only about 1 percent.⁸ In order to achieve immunologically active doses, a daily dose of about 600 mL of aloe vera juice, which is rich in polysaccharides, must be consumed.This implies that the relatively low quantity of polysaccharides in E. purpurea tops (let alone root preparations) will not be absorbed in levels sufficient to achieve the concentrations used in the in vitro studies. Perhaps the polysaccharides may act directly on gut tissue, e.g., Peyer’s patches, but even then it is doubtful they would be present in pharmacologically significant quantities in most Echinacea preparations. Moreover, such effects would not explain the activity of echinacea on bone marrow (see explanation later in this paper).

A recent clinical trial (in fact the only one published to date on echinacea polysaccharides) failed to show marked effects on immune function. In an open, prospective study with matched historical controls, a polysaccharide fraction isolated from Echinacea purpurea cell cultures was tested to see if it could counter the undesired immune side effects of cancer chemotherapy.⁹ Fifteen patients with advanced gastric cancer undergoing palliative chemotherapy with a range of cytotoxic drugs also received daily intravenous injections of 2 mg of a polysaccharide fraction from echinacea. While the polysaccharide treatment did appear to increase white cell counts, there were no clinically relevant effects on phagocytic activity or lymphocyte subpopulations.

The above clinical research reveals the fundamental flaw behind attempts to explain the activity of echinacea in terms of polysaccharides. In the trial, the polysaccharides were administered by injection because their oral bioavailability is uncertain. If the trial scientists had believed that the polysaccharides were orally active, then they would have administered them this way.

Alkylamides Are Bioavailable

It can be concluded from both traditional use and clinical studies that echinacea acts on the immune system at various sites in the body. Hence, for echinacea to exert this influence, it seems reasonable to suggest that the active phytochemicals must be absorbed in significant quantities in the bloodstream. Accordingly, both test tube (in vitro) and clinical (pharmacokinetic) research was initiated to understand which of the key phytochemicals in a lipophilic extract of echinacea root were absorbed. In contrast to the polysaccharides, alkylamides were found to be highly bioavailable.

A particular strain of human colon cells (Caco-2) can be grown in a test tube to form a tight layer of single cells (a monolayer). This can serve as a model of absorption by the human digestive tract. The test components are placed on one side of the monolayer and after a period of time, anything that has been transported across to the other side of the monolayer is sampled and measured. Research using an echinacea extract made from the roots of E. angustifolia and E. purpurea found that all the alkylamides were transported across the Caco-2 monolayer, but the caffeic acid derivates were not transported.^10,11 Hence, results from this model indicate that only the alkylamides in traditional echinacea extracts are likely to be absorbed (and hence bioavailable to the immune system).

These results from the Caco-2 model were then confirmed in a human pharmacokinetic study. Volunteers took four tablets of a commercial echinacea root preparation with a meal and the levels of any detectable echinacea phytochemicals were measured in their blood. Only alkylamides could be detected in the blood after taking this preparation. There were no caffeic acid conjugates found and no degradation products of either these or the alkylamides.¹²

The Importance of Liver Metabolism

As previously noted, only alkylamides were found in human plasma after ingestion of echinacea root tablets, but the levels were quite variable and first-pass liver metabolism was suspected to be influencing this observation. (First-pass metabolism is the rapid degradation by the liver as the products from digestion first pass through the liver on their way to the general circulation.) The alkylamides mainly found in E. purpurea were rapidly degraded by human liver microsomes. In contrast, the alkylamides mainly found in E. angustifolia were much more slowly degraded. Interestingly, it was discovered that the latter type of alkylamide actually slowed down the rate of degradation of the former type of alkylamide. This protective effect of the E. angustifolia alkylamide is a highly novel finding, and it was deduced that the presence of only relatively small proportions of this compound would result in a product with enhanced bioavailability. This is a strong justification for the combination of E. angustifolia root with E. purpurea root.¹³

Liquid Extracts Versus Tablets

One question that often is asked is whether herbs work better as liquid extracts or tablets. Well-made tablets likely work just as well as liquids because they are made using extracts (not the powdered herb) and are formulated to pharmaceutical standards to ensure rapid disintegration. This was verified in a clinical study that compared equivalent doses of a commercial echinacea product in liquid or in tablet form. The total amount of alkylamides absorbed into the bloodstream was essentially the same for both products.¹⁴ To the author’s knowledge, this is the first study of this kind (comparing the bioavailability of equivalent doses of an herbal liquid extract against a tablet) ever undertaken.

Immune Activity of Alkylamides

Research has established that alkylamides are the only phytochemicals that are bioavailable from traditional lipophilic extracts of echinacea root. In addition, combining E. angustifolia with E. purpurea will enhance the alkylamide bioavailability.

This research poses the question as to whether alkylamides have any effect on the immune system. This can be answered in part by test tube research to investigate such activity. The key findings of preliminary studies are that echinacea alkylamides do not activate the immune system in the absence of any immunological challenge. Echinacea alkylamides tended to modulate the immune responses of macrophages and T-cells, toning down the response in the face of a strong stimulus, thus helping the immune system to operate more efficiently.^15,16

CB2 Receptors

A significant recent discovery, first presented at a major international conference in 2004, was the observation by two separate research teams that some of the immune effects of echinacea may be mediated by the interaction of echinacea alkylamides with cannabinoid receptors. Gertsch found that an in vitro immune-modulating effect of a lipophilic echinacea extract (and individual alkylamides) on monocytes/macrophages could be neutralized by the presence of agents which block CB2 cannabinoid receptors.¹⁷ Bauer, in collaboration with U.S. scientists, found that alkylamides from echinacea bind to both CB1 and CB2 cannabinoid receptors.¹⁸ In particular, certain alkylamides exhibited selectivity for the CB2 receptors.

Taken together, these developments (the pharmacokinetic trials and the CB2 receptor studies) first presented at the conference suggest the hypothesis that the alkylamides largely are responsible for the systemic immune effects of echinacea lipophilic extracts. This immune-modulating activity is (at least in part) due to the interaction of alkylamides with cannabinoid receptors, specifically CB2.

CB1 receptors are highly localized in the central nervous system (CNS) and are believed to primarily modulate behavior, while CB2 receptors predominate in immune tissues outside the CNS, especially the spleen, and are believed to modulate immune function.¹⁹ Cannabinoid receptors are remarkably preserved across the animal kingdom, which suggests they play an important developmental and physiological role.^20,21 Much of the immune activity of the cannabinoid system appears to be mediated by the cytokine network. Cytokines include the interleukins (IL-3, IL-6, etc.), tumor necrosis factor alpha (TNFα) and the interferons (IF

The Swiss team led by Gertsch has followed on from this groundbreaking research and shown that certain echinacea alkylamides bind strongly to CB2 receptors.²² In addition, they have shown that alkylamides also exert additional effects on immune cells which are independent of CB2.²² Their research has been particularly insightful into one aspect of the mode of action of echinacea alkylamides.²³ A lipophilic extract of Echinacea purpurea strongly stimulated TNFα mRNA synthesis in peripheral monocytes, but not TNFα protein production. In other words, the echinacea-induced new TNFα transcripts (mRNA) were not translated into TNFα itself. When monocytes are treated with LPS (lipopolysaccharide or endotoxin, a powerful stimulator of the immune system), TNFα protein production is substantially increased. However, co-incubation of monocytes with lipopolysaccharide (LPS) and echinacea root extract resulted in a strong inhibition of this effect of LPS. Investigation over a longer time span revealed that the lipophilic echinacea extract, via interaction with CB2 receptors, modulated and prolonged TNFα production following immune stimulation

The results of this study suggest echinacea works more as a modulator or facilitator of the immune response, rather than as an immune stimulant. In resting monocytes, it prepares them for a quicker immune response by inducing TNFα mRNA. However, in overstimulated monocytes (as in the case of LPS), it first reduces and then extends their response in terms of TNFα production. In particular, these key findings challenge the mythology that traditional echinacea extracts will “overstimulate and wear out” the immune system if taken continuously.

Echinacea and Innate Immunity

In an extraordinarily titled paper, “Echinacea: A Miracle Herb Against Aging and Cancer?” Dr. Sandra Miller reviewed her research on echinacea, specifically Echinacea purpurea root.²⁴ Dr. Miller’s interest in echinacea was triggered by her team’s research on the drug indomethacin, which is a cyclo-oxygenase inhibitor that reduces the endogenous suppressors of natural killer (NK) cells, namely the prostaglandins.^25,26 The drug resulted in statistically significant increases in NK cell numbers and function in leukemic mice. This led to the search for a safe agent without dangerous side effects that might function in the same way.

The observation that alkylamides in echinacea can inhibit prostaglandin production in vitro,²⁷ and the general reputation of echinacea as an immune herb, led to the investigation of the potential of echinacea in NK cell enhancement using in vivo laboratory models.

In healthy young-adult mice, oral doses of Echinacea purpurea root (0.45 mg per 25 g body weight, similar to human dose rates) stimulated NK cell production by bone marrow in the first seven days, which resulted in significantly higher levels (around 25 percent more) of NK cells in the spleen by two weeks.²⁸ In addition, the “helper” or accessory cells for NK cells, the monocytes, were also around 25 percent more numerous in both the bone marrow and spleens of mice consuming echinacea. The echinacea treatment influenced no other white blood cell counts, and polysaccharides, even by injection, were found to be not responsible for this effect.²⁹

NK cells decline in number and function with age, and this is thought to be one factor behind the increase of various cancers and infections with age. Experiments conducted in healthy, elderly mice found that two weeks of oral doses of echinacea returned NK cell numbers in bone marrow and spleen to the levels of young adults and also resurrected the functional capacity (target cell binding, lysis) of these cells.³⁰

On this result, Dr. Miller writes: “These observations appear to apply uniquely to this herb since we could never rejuvenate the NK cell-mediated component of the immune system in elderly mice by any of the other typical NK cell enhancers.”

As discussed, one of the persistent controversies about echinacea is whether it is safe to be taken consistently for long periods of time. According to Dr. Miller’s findings, the answer, at least in mice, is definitely in the affirmative. Mice were fed Echinacea purpurea root from seven weeks of age to 13 months at the dose previously described.³¹ Long-term use of echinacea was not only not detrimental, but distinctly beneficial. By 13 months of age, 46 percent of the control mice fed the standard chow were still alive, compared to 74 percent of those consuming echinacea. As might be expected from previous experiments, the NK cell levels in the echinacea-fed mice were considerably elevated compared to controls. On this, Miller writes:

“Given that the key immune cells acting as the first line of defence against developing neoplasms in mice and humans are NK cells, it is not difficult to conclude that sustained enhancement of NK cells alone, throughout life, could readily account for the reduced frequency in deaths with advancing age. Spontaneous neoplasms, clinically undetectable, are well known to increase with advancing age in humans and mice. Thus, the logical corollary from this study indicates that chronic daily intake of Echinacea, is clearly not detrimental to the immune system, but rather prophylactic.”

Finally, Miller set out to answer the question of whether echinacea still will be effective once a cancer is in progress. In particular, leukemias and lymphomas are well- known as targets for NK cell attack and are established as the first line of defense against these types of malignancies. Leukemia-induced mice typically died after 3.5 weeks, whereas one-third of mice additionally fed echinacea survived until 3 months after leukemia onset and went on to live a normal lifespan.³²

The Myth About Long-Term Use

On the topic of the supposed detrimental effect of long-term use of echinacea, it should be pointed out that the original concerns arose out of a mistranslation/misunderstanding of German clinical research published in 1989. Jurcic and coworkers tested the effect of an Echinacea purpurea tincture on the phagocytic activity of human granulocytes following intravenous or oral administration.³³ This clinical study has been subjected to considerable misinterpretation or over-interpretation, which has led some writers to suggest that echinacea depletes the immune system when used continuously for periods longer than several days.

The reason behind the misunderstanding was that the test dose of echinacea was only given for the first five days, but phagocytic response was tested for 11 days. A cursory examination of the results might lead to the conclusion that echinacea “wears out” the immune system since phagocytic activity peaks at five days and then begins to fall away. But this was only after the echinacea was stopped and activity only fell back to normal levels. So, the study, in fact, demonstrates that phagocytic activity is higher than normal while echinacea is given and when echinacea is stopped, phagocytic activity remains well above normal for a few days. This suggests that far from causing depletion, there is a residual stimulating effect when echinacea is stopped. Moreover, phagocytic activity only returned to normal; that is, there was no depleting effect found, where activity would drop to less than normal.

Echinacea and Autoimmune Disease

There is considerable controversy over the safety and value of echinacea in autoimmune disease. Given the great variety of disorders that come under this classification, and the associated complexity of immune imbalances, it seems unreasonable to suggest there might be no circumstances when the herb is safe and useful. On the other hand, echinacea might not suit all patients with autoimmune disease. On this point, the few documented cases where it might have been associated with a patient’s deterioration have been taken as proof that it is contraindicated in autoimmune disease. However, this ignores the countless cases where echinacea has been safely prescribed in this context.

There is growing evidence from individual cases and experimental models that autoimmune disease is often associated with a defective functioning of some aspect of the immune response, especially involving natural killer (NK) cells. NK cells are part of innate immunity and hence, this aspect of immunity can be deficient in autoimmune disease. In contrast, some aspects of T- and B-cell responses, which form the acquired immune response, usually are overactive in these disorders.

The NK cell deficiencies probably vary across the range of different autoimmune diseases, but also might vary for individual patients expressing a particular disorder. (This latter point might explain why a handful of patients with autoimmune disease do not respond well to echinacea.) For example, patients with systemic lupus erythematosus often are deficient in NK cell function³⁴, and the role of NK cells in inhibiting autoimmunity in general has been well-established from experimental models.^35,36 Natural killer cell dysfunction also is a distinguishing feature of systemic onset juvenile rheumatoid arthritis³⁷ and circulating NK cells are reduced in psoriasis and rheumatoid arthritis.³⁸ A particular focus has been on NKT cells, which are a subset of T-cells that share properties of NK cells and conventional T-cells.³⁹ NKT cells are potent producers of immunoregularity cytokines that can control an overactive immune response. A survey of patients with different autoimmune diseases found around half had reduced numbers of NKT cells.⁴⁰

Given the above, the findings noted previously by Sandra Miller that Echinacea purpurea root boosts NK cell numbers and function in experimental models are particularly relevant. Dr. Miller and colleague Danielle Delorme also have examined the effects of echinacea root consumption in non-obese diabetic (NOD) mice, a model of human type 1 diabetes. NKT cells are believed to be implicated in type 1 diabetes and their functional and/or numerical deficiency is thought to be largely responsible for the development of this disease in NOD mice.⁴¹ When NOD mice were fed echinacea for varying times, there was a substantial and significant increase in NK cell numbers. This was the only type of immune cell influenced by the echinacea in these mice. The authors concluded:

“The observations of the present study have, at least in the animal model of human type 1 diabetes, led to 2 conclusions. First, daily consumption of Echinacea by animals afflicted with this particular autoimmune disease, leads to no negative repercussions, and indeed, may provide all the advantages, in vivo, that consuming this herb does for normal, unafflicted mice (humans). Second, the study may provide evidence for a possible new approach to the treatment of type 1 diabetes. That is, immuno-stimulation only of those cells (NK/NKT) involved in modulating the disease. Echinacea is one such uniquely tailored, immuno-stimulant, whose effect is on NK cells.”

Idiopathic autoimmune uveitis usually is treated by oral corticosteroids. It’s an inflammation of part or all of the uvea, the middle (vascular) tunic of the eye, although it also commonly involves the sclera, cornea and the retina. On the basis of the known interaction of echinacea alkylamides with cannabinoid CB2 receptors, which implies immune- modulating and anti-inflammatory activities, a group of Italian clinicians investigated the safety and efficacy of Echinacea purpurea in this autoimmune disease.⁴² Fifty-one patients with low-grade autoimmune uveitis were treated with conventional therapy, including oral prednisone. In addition, 32 of these patients were given echinacea as an add-on therapy. At the last follow-up, which was nine months later, 87.5 percent of patients receiving echinacea were in clinical remission compared to 82.3 percent of the control group. However, steroid-off time was significantly higher in the echinacea group (indicating that patients receiving echinacea needed less prednisone to induce remission). The authors concluded that the oral intake of echinacea appears safe and effective in the control of low-grade autoimmune uveitis. No patient showed any side effects or aggravation from the use of echinacea for their autoimmune disease.

Clinical Effects on Immune Function

A traditional lipophilic echinacea root preparation has been shown to prevent winter infections when taken regularly. A randomized, double-blind placebo-controlled trial carried out by Dr. Anna Macintosh (National College of Naturopathic Medicine, Portland, Ore.) and co-workers in 1999 demonstrated that an echinacea root liquid and a liquid formula made from three tonic herbs both significantly reduced the incidence of winter colds in students.⁴³ The echinacea liquid consisted of a flavored blend of E. angustifolia and E. purpurea roots (in equal quantities) standardized to contain at least 1 mg/mL of alkylamides.

The trial was conducted on 265 medical students because this group tends to be highly stressed and susceptible to winter infections. The students were assigned to receive either one of the two active formulas or the placebo in late autumn and were followed for 105 days. Three dosage protocols were tested over the length of the trial: high (4 mL twice/day) followed by medium (3 mL twice/day) followed by low (2 mL twice/day). Whereas the incidence of colds remained at about 10 percent of the test population for the placebo group, the incidences for the echinacea and the tonic formula fell to 2 percent and 3 percent at 42 and 70 days, winding back to 4 percent and 8 percent at 105 days, respectively. This reduction in effect at 105 days probably reflects the effect resulting from the reduced dose protocol. The differences between the active liquids and placebo were both at the borderline of statistical significance at 42 days (p = 0.06 to 0.07), and achieved statistical significance at 70 days (p = 0.03). Results at 105 days were not significantly different from placebo (reflecting the low-dose protocol).

There was no significant difference between side effects for the three groups, although there was a slightly greater incidence of digestive upset for the echinacea group. In particular, the echinacea treatment did not increase or aggravate allergies. The authors suggested their study demonstrated that the effective dose for the echinacea root combination as a preventative treatment was approximately 5 mL per day.

To further understand the effects of a traditional echinacea root product at a clinical level, a small study was undertaken to investigate its effects on heat-shock proteins and whole-blood parameters. Healthy volunteers were dosed with two tablets per day of a commercial echinacea preparation for two weeks, with assessment at the beginning and the end of the trial. Positive results were evident, with increased heat-shock protein levels (hsp70) and increased white cell counts within normal physiological limits. (Heat-shock proteins are molecular chaperones that modulate the immune response.)⁴⁴ Further work is planned to evaluate these effects in a much larger study.

This increase in white cell count for echinacea root ties in well with research from the team of Dr. Miller in Canada mentioned previously. This clinical research, together with that of Dr. Miller, implies that echinacea acts mainly on innate immunity and hence, will work best as an infection preventative, as shown in the study by Dr. Macintosh.

Recent research has made a substantial contribution to a new understanding of lipophilic extracts of echinacea. From this research, the following can be concluded:

• Alkylamides must be used as the markers of quality and activity.
• The root of echinacea is the preferred plant part, since it is highest in alkylamides.
• The preferred species of echinacea are E. angustifolia and E. purpurea, since they contain high levels of alkylamides (compared to E. pallida).
• Echinacea must be extracted using an alcohol percentage sufficiently high to efficiently extract the alkylamides.
• Echinacea modulates the immune response, at least in part, by the interaction of the bioavailable alkylamides with CB2 receptors.
• Echinacea root (rich in alkylamides) additionally boosts the white cell count, especially NK cells, which are part of innate immunity.

Long-term use of echinacea is not only safe, but also distinctly beneficial. There is no sound reason why a general contraindication of echinacea in autoimmune disease should exist; in fact, there is evidence to suggest it could be beneficial. The traditional way echinacea was used has been validated by scientific research at the cutting edge of modern immunology.

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24. Miller SC. Echinacea: a miracle herb against aging and cancer? Evidence in vivo in mice. eCAM, 2005;2(3):309-314.
25. Christopher FL, Dussault I, Miller SC. Population dynamics of natural killer cells in the spleen and bone marrow of normal and leukemic mice during in vivo exposure to interleukin-2. Immunobiology, 1991;184(1):37-52.
26. Dussault I, Miller SC. Stimulation of natural killer cell numbers but not function in leukemic infant mice: a system primed in infancy allows survival in adulthood. Nat Immun, 1993;12(2):66-78.
27. Muller-Jakic B, Breu W, Probstle A, et al. In vitro inhibition of cyclooxygenase and 5-lipoxygenase by alkamides from Echinacea and Achillea species. Planta Med, 1994;60(1):37-40.
28. Sun LZ-Y, Currier NL, Miller SC. The American coneflower: a prophylactic role involving nonspecific immunity. J Altern Complement Med, 1999;5(5):437-446.
29. Currier NL, Lejtenyi D, Miller SC. Effect over time of in-vivo administration of the polysaccharide arabinogalactan on immune and hemopoietic cell lineages in murine spleen and bone marrow Phytomedicine, 2003;10(2-3)145-153.
30. Currier NL, Miller SC. Natural killer cells from aging mice treated with extracts from Echinacea purpurea are quantitatively and functionally rejuvenated. Exp Gerontol, 2000;35(5):627-639.
31. Brousseau M, Miller SC. Enhancement of natural killer cells and increased survival of aging mice fed daily Echinacea root extract from youth. Biogerontology, 2005;6(3):157-163.
32. Currier NL, Miller SC. Echinacea purpurea and melatonin augment natural-killer cells in leukemic mice and prolong life span. J Altern Complement Med, 2001;7(3):241-251.
33. Jurcic K, Melchart D, Holzmann M, et al. Two studies on the stimulation of the phagocytosis of granulocytes by drug preparations containing extracts of echinacea in healthy volunteers. Zeitschrift fur Phytotherapie, 1989;10:67-70.
34. Green MR, Kennell AS, Larche MJ, et al. Natural killer cell activity in families of patients with systemic lupus erythematosus: demonstration of a killing defect in patients. Clin Exp Immunol, 2005;141(1):165-173.
35. Gombert JM, Herbelin A, Trancrede-Bohin E, et al. Early quantitative and functional deficiency of NK1+-like thymocytes in the NOD mouse. Eur J Immunol, 1996;26(12):2989-2998.
36. Horwitz DA, Gray JD, Ohtsuka K, et al. The immunoregulatory effects of NK cells: the role of TGF-beta and implications for autoimmunity. Immunol Today, 1997;18(11):538-542.
37. Villanueva J, Lee S, Giannini EH, et al. Natural killer cell dysfunction is a distinguishing feature of systemic onset juvenile rheumatoid arthritis and macrophage activation syndrome. Arthritis Res Ther, 2005;7(1):R30-R37.
38. Cameron AL, Kirby B, Griffiths CE. Circulating natural killer cells in psoriasis. Br J Dermatol, 2003;149(1):160-164.
39. Mercer JC, Ragin MJ, August A. Natural killer T cells: rapid responders controlling immunity and disease. Int J Biochem Cell Biol, 2005;37(7):1337-1343.
40. Kojo S, Adachi Y, Keino H, et al. Dysfunction of T cell receptor AV24AJ18+, BV11+ double-negative regulatory natural killer T cells in autoimmune diseases. Arthritis Rheum, 2001;44(5):1127-1138.
41. Delorme D, Miller SC. Dietary consumption of echinacea by mice afflicted with autoimmune (type I) diabetes: effect of consuming the herb on hemopoietic and immune cell dynamics. Autoimmunity, 2005;38(6):453-461.
42. Neri PG, Stagni E, Filippello M, et al. Oral Echinacea purpurea extract in low-grade, steroid-dependent, autoimmune idiopathic uveitis: a pilot study. J Ocul Pharmacol Ther, 2006;22(6):431-436.
43. Macintosh A, et al. “Prevention of Colds by Two Herbal Formulas in a High Stress Population.” Paper presented at the AANP Convention, Coeur d’Alene, November 1999.
44. Agnew LL, Guffogg SP, Matthias A, Bone KM, et al. Echinacea intake induces an immune response through altered expression of leukocyte hsp70, increased white cell counts and improved erythrocyte antioxidant defences. J Clin Pharm Ther, 2005;30(4):363-369.