Echinacea and Immune Health

In times of health crisis, plants have frequently been relied upon to support human health and well-being. Medicinal herbs such as Echinacea, whose reputation as an immune enhancer have made it one of the most widely used herbal medicines in the world, speak to the growing global interest in supporting immunity naturally.

Commonly known as purple coneflower, Echinacea’s distinctively shaped flowerheads are observed in all three species used for their medicinal properties including, E. angustifolia (narrow-leafed), E. purpurea (broad-leafed), and E. pallida. All are members of the Daisy (Asteraceae) family but can be distinguished by their chemical composition, biological activities, and ethnobotanical applications.

Some of the earliest available information on the use of Echinacea comes from Native American tribes who used all parts (tops, leaves, and roots) of mainly E. angustifolia and E. purpurea for treating wounds and as an antidote against snakebite, stings, and other poisons. For symptoms associated with the common cold, ground roots of Echinacea were also chewed or prepared as infusions or tinctures to help reduce cough and sore throat.₁

Later introduced to European settlers, Echinacea was adopted by the Eclectics (a prominent group of North American Physicians during the late 19th and early 20th centuries), and by the 1920’s, the root of Echinacea was considered one of their most popular plant preparations. Eclectic texts refer to Echinacea as an “alterative, lymphatic, and/or blood purifier”, indicated in cancer, infection, states of weakened or suppressed immunity (e.g. allergies and autoimmune disease), and other chronic inflammatory conditions.₂

Based on over a century of such traditional uses, the potential applications for Echinacea as immune support becomes much broader than a short-term ”booster” acting solely to suppress symptoms of infection and/or enhance innate immune responses. Indeed, capable of speeding recovery and enhancing resistance to infection, research findings over the past few decades have demonstrated much more about Echinacea’s ability to support immunity in myriad ways through immunomodulatory, anti-viral, anti-inflammatory, and antioxidant effects.

Mechanisms of Action: How Does Echinacea Enhance Immunity?

Like most medicinal herbs, Echinacea’s mechanistic effects are not yet completely understood. However, a growing understanding of the phytochemicals involved and their actions on the immune system continue to be revealed, with a consistent theme amongst current research showing it to be a powerful anti-inflammatory, antioxidant, and modulator of immune function.

Early experimental studies with Echinacea demonstrated activation of innate immune responses, with studies in animals showing increases in macrophages, phagocytosis, cytokine production (e.g. TNF-α, IL-1, IFN-y), activation of natural killer cells (NK), and proliferation of T cells._3,4 Studies in humans would later confirm similar effects, including enhancement of phagocytosis and white blood cells counts in both healthy and immunocompromised participants._5,6 Such effects appear to enhance immunity by reducing response time and providing more direct clearance of a pathogen, while having an overall effect of lessening the severity of infection due to improved immune surveillance.₇ Echinacea has also been shown to ameliorate mucosal immune suppression and inhibit several viral respiratory pathogens as well as fungi, bacteria, and parasites in experimental models.₈

Beyond stimulating innate immune activity, certain Echinacea preparations and its compounds have been shown to exert significant immunomodulatory activity, influencing adaptive immune cells and inducing transcriptional changes to activate immunomodulatory pathways that contribute to anti-inflammatory effects.₉ Immunomodulators can be classified as compounds capable of interacting with the immune system to either up- or down-regulate specific aspects of the host response.₁₀ Thus, they can either activate or suppress innate and adaptive immune mechanisms and provide a greater ability to tolerate harm or damage caused by pathogens. These qualities are consistent with Echinacea’s role in protecting the immune system when the body encounters a challenge (such as infection) by modulating immune activities. In fact, recent findings have demonstrated that when immune cells are overstimulated, exposure to Echinacea can reduce the magnitude of the immune response and potential over-reaction to the threat through the inhibition of pro-inflammatory cytokines and signaling pathway and enhancement of heat shock proteins in vivo._11-13

Echinacea’s Active Constituents

Much debate has occurred over which phytochemicals in Echinacea are responsible for its immune effects, in part due to substantial differences in the chemical composition between species, parts used (i.e. root and/or aerial), geographical location, growing conditions, time of harvest, and post-harvest handling and processing (e.g. storage, drying, and solvent/extraction procedure).₁₄ For example, the average total concentration of alkylamides found in the root of E. purpurea was found to be about 20 times higher than that in the young tops, while the roots of E. angustifolia contained higher levels overall and appear nearly absent from E. pallida._15,16

As is often true with herbal medicine, there is very likely a synergy that results from a combination of Echinacea’s constituents, however the three most-studied groups with potential effects upon the immune system include the caffeic acid derivatives (e.g. echinacoside, chiroric acid), lipophilic components (mainly alkylamides and polyacetylenes) and water-soluble polysaccharides.

Echinacea’s polysaccharides and caffeic acids have received much attention as its primary immunomodulating components, however much of the research conducted has been in vitro and it remains unclear to what extent these results translate to the human body. Moreover, isolated polysaccharides are unstable in the dried harvested plant and ethanol strengths of 40% or above do not appear to effectively extract them.₁₇ Alkylamides, however, have been shown to be rapidly absorbed and measurable in the plasma of healthy volunteers 20 minutes after oral ingestion (and remain detectable for up to 12 hours), while no caffeic acid conjugates or degradation products or polysaccharides could be identified in the same plasma samples.₁₈

Alkylamides

Over the last decade Echinacea’s alkylamides have revealed themselves to be the most clinically relevant immunomodulating constituents as well as the most bioavailable. They are among the most abundant compounds found in the roots of E. angustifolia and E. purpurea, and more than 30 different types have been identified to date.₁₉ Long known to cause a characteristic tingling in the mouth when ingested, the Eclectic Physicians were well aware of this important sensory effect noting that, “when chewed the root, if of good quality imparts at first a sweetish taste, subsequently becoming acrid and pungent, and finally leaving a persistent tingling sensation, followed by a peculiar numbness of the tongue…”.₂₀

Interestingly, the chemical structure of alkylamides resemble that of the endogenous cannabinoids anandamide & 2-arachidonoylglycerol (2-AG), ligands of cannabinoid (CB) receptors and integral components of the endocannabinoid system, having key roles in immune and inflammatory responses.₂₁ Indeed, the immunomodulatory activities of Echinacea are now primarily attributed to alkylamides’ ability to exert cannabimimetic responses, binding to CB2 receptors in vitro in concentration ranges that are achievable in living organisms._8,22 Such immunomodulatory effects appear to occur from modulation of gene expression, inhibition of inflammatory signaling pathways, and stimulation of regulatory T cells mediated by the activation of CB receptors._8,23-25 In addition, alkylamides from E. angustifolia root have been shown to inhibit the enzyme responsible for the breakdown of endogenous cannabinoids (fatty acid amide hydrolase (FAAH)), potentially prolonging their action at receptor sites.₂₆

Structural differences between alkylamides have been found to predominate within different Echinacea species. Interestingly, one pharmacokinetic study in human microsomes found that the alkylamides in E. angustifolia (2-enes) were more slowly metabolized than those found in E. purpurea (2,4- dienes) and in fact protected against their degradation when used in combination.₂₇ This potential synergy between species provides some clinical rationale for combining E. angustifolia with E. purpurea to result in a product with enhanced bioavailability and therapeutic effects.

Clinical Research and Meta-analyses

Various Echinacea preparations have been studied in a multitude of experimental and clinical studies and reviewed in metanalyses, with variable efficacy reported in the treatment and prevention of upper respiratory tract infections.₂₈

A 2014 Cochrane review investigated the effectiveness of Echinacea preparations compared to placebo for their safety and efficacy in treating and preventing the common cold. Of the 24 controlled trials included with a combined 4631 participants, the overall evidence for clinically relevant treatment effects was considered weak, however the authors suggested that some products could be considered more effective than placebo and acknowledged that the products available under the term Echinacea varied significantly in their composition. Regarding prevention of infection, while most trial findings were inconclusive, a post hoc pooling of results suggest a 10-20 percent relative risk reduction in illness occurrence.₂₉

Another 2015 meta-analysis which included 6 clinical studies with a total of 2458 participants found that the use of Echinacea extracts was associated with a reduced risk of recurrent respiratory infection, with three of the studies demonstrating that the clinical benefits appeared strongest in individuals with higher susceptibility (e.g. stress or immunological weakness). Additionally, complications including pneumonia, otitis media/externa, and tonsillitis/pharyngitis were also less frequent in treatment groups, and increased dosing during acute episodes further enhanced these effects.₃₀

A more recent 2019 meta-analysis assessed the most current evidence regarding safety and efficacy of Echinacea preparations in preventing and treating upper respiratory tract infection and included only randomized double-blind placebo-controlled trials between 1980-2018. While there was no apparent evidence for an effect on the duration of upper respiratory tract infections, the review concluded that Echinacea might have a preventative effect on the incidence of upper respiratory tract infections.₂₈

Based on a review of the research conducted in humans, when it comes to infectious disease it appears that Echinacea may have greater overall prophylactic value when given to those who are more susceptible to infection, and/or at the onset of symptom expression.₃₁  Several clinical trials have observed that Echinacea does not appear to substantially alter the course of the common cold, however in some cases those receiving higher doses did experience significant relief of symptoms._32-34 In line with these observations, it is worth noting several clinical trials further highlighting its efficacy in the prevention of infection including:_35,36

• A formula containing the roots of both angustifolia and E. purpurea prevented the common cold in highly stressed medical students in a randomized, double-blind, placebo-controlled trial. By 7 weeks, the Echinacea group had a lower frequency of colds than the placebo group, and by the tenth week the difference was statistically significant
• An alcoholic purpurea extract was studied in children aged 4-12 years for the prevention of viral respiratory tract infection and secondary bacterial complications. Treatment was shown to significantly prevent influenza (3 vs. 20 detections), prevent 32.5 percent of respiratory tract infection episodes, and an observed a reduction of 80.2 percent of associated antibiotic use

In a randomized, double-blind placebo-controlled trial, 175 adults involved in long-haul commercial air travel over a course of 5 weeks participants took Echinacea root extract, (standardized to alkylamide content) or placebo, and were surveyed before, immediately after, and at 4 weeks after travel regarding upper respiratory symptoms and travel-related quality of life. The authors concluded that taking Echinacea before and during travel may have preventive effects against the development of respiratory symptoms, and that dosing, phase of travel, and health status appeared to impact outcomes.₃₁

Study Limitations

As previously mentioned, substantial variations in Echinacea’s phytochemical content and thus clinical properties exist across different preparations, however it is often the case in the literature that they are presented as identical. This makes comparisons and reproducibility of findings difficult considering the fact that differences between the multitude of products using different species, plant parts, extraction procedures, solvents, and manufacturing methods are often ignored. A lack of standardization across preparations, as well as dose-response effects, and distinctions between data obtained with isolated constituents and those from crude extracts (e.g. tincture, tablets or teas) will also have an impact on results. All of this highlights the importance of relying on the highest quality available evidence and comparing standardized preparations for interpreting the most clinical meaningful results.

Safety and Dosage

Of the many different Echinacea preparations available, dosage regimens tested in clinical trials have varied widely. Traditionally Echinacea has been given as a dried root extract of either E. angustifolia or E. purpurea species, with the Eclectic’s preferring a high alcohol percentage extract (60-75% EtOH). Evidence that ethanolic extracts appear to provide superior effects over water extracts (e.g. tea or juices) supports a modern understanding of Echinacea’s pharmacology, as they will likely include a greater presence of lipophilic alkylamides alongside a mixture of polar and other non-polar compounds to achieve synergistic effects.₃₀

Dosing strategies for Echinacea root will differ depending on the clinical situation. Preventative doses or doses for chronic conditions often range from 1-3 g/day or 2-6 ml/day of a 1:2 liquid extract of E. angustifolia dried root, and 1-4 g/day or 3-9 ml/day of 1:2 E. pupurea dried root. When used in combination, a minimum dose of 2.5 g/day would be considered adequate, however doses may be increased (doubled or even tripled) in the short-term for acute conditions.₃₇ This is in line with how Echinacea was employed by the Eclectics, with Ellingwood reporting,

“I am convinced that success in certain cases depends upon the fact that the patient must have at times, a sufficiently large quantity of this remedy in order to produce full anti-toxic effects on the virulent infections. I would therefore emphasize…that it is perfectly safe to give echinacea in massive doses…when the system is overwhelmed with these toxins.₃₈”

Trials of Echinacea preparations for the prevention of upper respiratory tract infection (URTI) have typically involved administration over an 8 or 12 week period, while those for the treatment of URTIs are typically administered over 6 to 10 days.₁₅ It is also noteworthy that there is no clinical evidence to suggest that long-term use has any harmful effects on immune function, and a comparison of the oral bioavailability of Echinacea (extracted in 60% ethanol) and its alkylamides when taken as either liquid or tablets found that both were rapidly absorbed and measurable in human plasma, demonstrating good bioavailability for both forms of administration.₃₉

Adverse Effects  

Echinacea has been reported to have a good safety and tolerability profile in adults and children, with few minor adverse effects associated with continuous ingestion of different preparations for up to 6 months._8,28 Care should be taken when prescribing Echinacea (particularly products made from flowering tops) to patients with known allergy to members of the Daisy family, as allergic reactions are known to occur in those who are susceptible, with reported effects including abdominal pain, angioedema, dyspnea, nausea, pruritus, rash, erythema, and urticaria.₁₅

Pregnancy & Lactation

Based on limited human data, Echinacea has not indicated any safety concerns for use during pregnancy, however animal studies have given mixed results and safety has not been conclusively established. Although small quantities of alkylamides are known to be present in breastmilk and passed to the infant during feeding, Echinacea is generally considered compatible with breastfeeding as it may in fact confer health benefits to both mother and child._37,40

Autoimmunity

Concerns surrounding the use of Echinacea in autoimmune disease such as collagen disorders, multiple sclerosis, AIDS, and HIV infections are based around the theory of it acting as an immune stimulant which should be used cautiously in case of causing a potential flare or exacerbation of these conditions. However, definitive data supporting an association with autoimmune exacerbation is lacking, and a more modern understanding of the immunomodulatory role of high quality Echinacea preparations highlights the fact that such concerns are largely theoretical. Although some case reports exist to contraindicate its use entirely would be doing so based on a few isolated events with questionable product preparations, and to ignore discoveries of its potential beneficial applications._41,42

Cytokine storm

Echinacea’s ability to enhance immune function has also been reported to potentially risk activation of the immune system during a cytokine storm, and that it might harmfully enhance the cytokine response during acute respiratory viral infections.

Such concerns are based solely on in vitro studies, and there is currently no evidence that Echinacea root will inappropriately stimulate the cytokine response during an acute viral infection and cause harm in humans. In fact, many clinical studies with Echinacea preparations have been shown to reduce pro-inflammatory cytokines and promote anti-inflammatory cytokines instead, having the potential to diminish the cytokine storm and ameliorate tissue damage in part due to CB2 receptor activation._8,43

“Just because an agent (such as a medicinal plant) facilitates cytokine signaling release in the early stages of an immune response does not necessarily mean it will drive that cytokine response to an excessive level in the later rampant stage of an infection. In other words, improving efficiency does not imply subsequent overproduction. The opposite is more likely to be true.” – Kerry Bone, Medical Herbalist

Interactions with other medications or herbs.

Preclinical studies have demonstrated that co-administration of Echinacea with drugs metabolized by CYP3A or CYP1A2 may affect their elimination via enzyme induction.₄₄ Studies in humans have found that Echinacea root may decrease drug levels of some anti-retroviral drugs, HIV protease inhibitors, and theoretically immunosuppressant medications._45-47 Practitioners should exercise caution and monitor patients appropriately.

Integrative Approaches

Echinacea can be utilized in many holistic immune-boosting protocols. Common myths regarding its activity as a potent immune stimulant or antimicrobial that will “wear out” the immune system if taken over long periods of time are unfounded. Based on the evidence to date, a lipophilic extract of Echinacea root rich in alkylamides can prime the immune response before viral exposure, but then continue to modulate responses once it encounters the threat.

This is in line with traditional uses of Echinacea being used over long periods of time to manage chronic inflammatory, allergic, and autoimmune conditions, and is based on the best available research which has shown that its primary therapeutic role is for infection prevention, particularly in those experiencing stress or a compromised immune response. In this way, combining Echinacea with other immune support essentials at the onset of cold and flu season such as Vitamin A, C, D, Zinc, and probiotics are particularly helpful. Other herbs which combine well with Echinacea in this regard would be adaptogens such as Eleuthero, Ashwagandha, and Panax ginseng, and immunomodulating herbs like Astragalus, Reishi, and Shitake.

Although Echinacea can also potentially be useful as part of a treatment regimen to reduce severity and duration of symptoms or acute viral infections, it should ideally be given at the onset or as early as possible and at sufficiently high doses. Any significant antiviral activity likely follows indirectly from immune enhancement. In such cases it is ideal to consider pairing with other anti-viral herbs such as Licorice, Andrographis, and Holy Basil.

Recommendations for Healthcare Practitioners

Health Care practitioners have a responsibility to their patients to ensure they provide the highest quality available herbal products to ensure treatment protocols are both safe and efficacious. Commercial samples of Echinacea have been shown to vary widely, thus when choosing a product or preparation it is crucial to ensure that:_48,49

• The most medicinal species and plant part are being utilized either alone or in combination (i.e. roots of angustifolia and/or E. purpurea)
• The product has been standardized to the most relevant constituents responsible for immunomodulating effects (i.e. alkylamides) at guaranteed levels for the life of the product, as post-harvesting processes have the potential to enzymatically degrade phytochemicals resulting in significant compositional changes and thus clinical effects

After considering the relevant research and traditional uses, there is no doubt of Echinacea’s importance in the prevention and treatment of infections, but also its potential as an immunomodulator in the management of chronic inflammatory and autoimmune conditions. Although more research is needed to further enhance our understanding of how Echinacea works, insights within the last decade regarding its polyvalent effects and interactions with the endocannabinoid system are promising and filled with therapeutic potential.

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