Phytotherapy Review & Commentaryby Kerry Bone, FNIMH, FNHAA

P.O. Box 713 • Warwick QLD 4370, Australia+61 7 4661 0700 • Fax +61 7 46610788 • www. mediherb.com

FNIMH = Fellow, National Institute of Medical Herbalists (UK)FNHAA = Fellow, National Herbalists Association of Australia

The Best in Phytotherapy in 2004:Solving the Echinacea Puzzle

The most well-known herbal productfor infections is

Echinacea. But recently Echinacea has suffered from well-publicized problems with poor product quality and ineffectiveclinical trials. Perhaps most important of all, the Echinaceamarket at the retail level has become crowded and generic,with a prevalence of cheap but poor quality products. Theissue is compounded by the many different Echinaceaproducts available in the marketplace such as:• The juice of Echinacea purpurea tops either stabilized with

alcohol or spray-dried to a powder.• Fresh or dried whole plant, seed or aerial part

preparations of.B. angustifolia, E. purpurea orE. pallida(either extracted with various percentages of alcohol or,sometimes in the case of dried herb, filled directly intocapsules).

• Fresh or dried preparations from the roots of E.angustifolia, E. purpurea or E. pallida (processed asabove).

• Mixtures of any ofthe above.Underlying this diversity of preparations is a lack of

consensus over what phytochemicals are responsible forEchinacea's immune activity and only a rudimentaryunderstanding ofthe exact mode of action ofthis herb on theimmune system. Perhaps not any longer!

Historical ContextBefore discussing some exciting new research

developments for Echinacea, its use as an immune herb needsto be understood in its bistorical context. Information aboutthe therapeutic value of Echinacea first came from NativeAmerican tribes. Their use of Echinacea was then adoptedby the Eclectics, a group of doctors who were prominentaround the late 19th and early 20th centuries in the UnitedStates. By 1921 Echinacea (specifically the root of £.angustifolia) was by far the most popular treatmentprescribed by Eclectic physicians.' The Eclectics usedEchinacea for about 50 years, which is a relatively short timein the context of traditional use. However, given that theEclectic use of Echinacea was hased on tribal knowledge andthat they accumulated extensive clinical experience in its use,their traditional use data are of a high quality. The bestsources of such data are King's American Dispensatory^ andEUingwood.^

The extensive range of conditions for which Echinacea wasprescribed is listed in these texts and are summarized in Table1. It is clear from this table that the limitations on Echinacea

use suggested by modern writers are not supported. Theconditions in the table are mainly Infections andenvenomations of various kinds (which clearly attest toEchinacea's influence on the immune system).

Table 1: Eclectic Uses of Echinacea^ ̂

AbscessesAlopeciaAnthraxAppendicitisBedsoresBee stingBoilsCancerCarbunclesChicken poxCholeraChronic bronchitisChronic glandular indurationsChronic malariaChronic ulcerationsDiabetes mellitusDiphtheriaDysenteryEczemaEmphesemaEpidemic influenzaErysipelasExophthalmic goiterFeversGangreneGonorrheaImpetigoImpotenceIntestinal indigestionLeg ulcersLeukorrheaMalaria

Mastitis, acute and chronicMeaslesMeningitisNasal catarrhPsoriasisPuerperal infectionPulmonary gangrenePurulent salpingitisQuinsyRabiesRenal hemorrhageRespiratory catarrhScarlet feverScorpion stingSeptic injuriesSepticemiaSmallpoxSnake biteSpider biteSyphilis and syphilitic nodulesTetanusIbnsillitisTubercular abscessesTubercular phthisisTyphoid feverTyphoid pneumoniaUlcerative stomatitisUrethral infectionVulvitisWasp stingWounds

What is also important to note is that Echinacea'sreputation as an immune herb came from solid traditionaldata generated by the Eclectics on only one form of Echinacea:a fluid extract of the dried root of Eehinacea angustifoliaextracted in a high percentage of alcohol. We can call this a"traditional Echinacea extract" and, because it is extractedin a high percentage of alcohol, the term "lipophilic extract"(fat loving) is also relevant. In particular, the Eclectics definedgood quality Echinacea root as "imparting a persistenttingling sensation" which is a clear reference to alkylamidelevels as a quaiity indicator.^

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Solving the Echinacea Puzzle

In Europe during the 1930s the German herbalist Madausused E. purpurea as he was more successful at growing thisspecies. His interest in homeopathy led him to use thestabilized juice of fresh E. purpurea tops. This remains themost popular form of Echinacea in Germany today (andcontains very low levels of alkylamides). We can call this styleof product a "hydrophilic extract" (water loving) of Echinacea.

Naturally German scientists were interested to investigatehow these new hydrophilic extracts of Echinacea might workin the body and undertook a search for active components.Polysaccharides possessing immunological activity wereisolated from the aerial parts ofE. purpurea.* Some cliniciansand scientists then mistakenly applied this research to thevery different lipophilic or traditional Echinaceapreparations, and came to the conclusion that they weretherapeutically inferior because of their low or absent contentof polysaccharides. (The low levels of polysaccharides intraditional Echinacea extracts are due to the low startinglevels in the root and the fact that high levels of alcohol donot effectively extract these water-loving molecules.)

However, many phytotherapists remained unconvinced.A key aspect of modern phytotherapy is a respect fortraditionally generated knowledge and this suggested that alipophilic extract of E. angustifolia root was the preferredform. Some felt that the concept of polysaccharides failed toexplain what was unique about Echinacea and expressedconcerns about the low oral bioavailability of such large, polarcompounds.** Because of their important role in primarymetabolism, all plants contain polysaccharides. Moreover, thelevels found in Echinacea preparations are not high whencompared to mushrooms and other accumulators ofpolysaccharides such as Althaea officinalis and Aloe species.It is possible that Echinacea polysaccharides possess someunique and potent pharmacological actions on the immunesystem, but this argument is not helped by research thatshows that many polysaccharides have immunologicalactivity.*

So what was clearly needed was a different understandingof Echinacea, especially ofthe phytochemicals important forthe activity of traditional Echinacea products and their modeof action on the immune system.

New Insight into EchinaceaI believe that these answers came this year, with the

release of a number of exciting developments at theInternational Congress on Natural Products Research heldin Phoenix, Arizona in early August 2004. At this conferenceseveral papers were presented (as posters and oralpresentations) which when combined, provide a new insightinto the possihle mechanism of action of traditional lipophilicextracts of Echinacea. As mentioned before, such extracts areparticularly rich in the phytochemicals known as alkylamides(or alkamides), but also contain the caffeic acid derivatives.(Caffeic acid derivatives include echinacoside and cichoricacid, depending on the species of Echinacea.)

An oral presentation by Dr. Reg Lehmann ofthe MediHerbresearch team (of which I am a part) discussed importantfindings that indicate only the alkylamides (and not the caffeicacid derivatives) were found to be bioavailable using both anin vitro model and observations from a placebo-controlled

pharmacokinetic trial in healthy volunteers.^ In particular,only alkylamides could be detected in the blood plasmasamples from volunteers taking an Echinacea root extract intablet form. No other phytochemicals known to occur inEchinacea root were found in the plasma, despite their beingpresent in the tablets. (If Echinacea is to have systemic effectson the immune system then it is highly likely that thephytochemicals responsible for this must be systemicallyabsorbed.)

These results were supported by an oral presentation byProfessor Rudi Bauer of Karl Franzens University in Austria,whose team investigated the bioavailability of a 60% ethanolicextract of Echinacea angustifolia root in 12 healthyvolunteers.^ The alkylamides were shown to be rapidlyabsorbed after oral ingestion ofthe liquid.

Another significant discovery presented at the Congresswas the observation by two separate research teams that theimmune effects of Echinacea may be mediated by theinteraction of Echinacea alkylamides with cannabinoidreceptors. A Swiss research team found that an in vitroimmune-modulating effect of a lipophilic Echinacea extract(and individual alkylamides) on monocytes/macrophagescould be neutralized by the presence of agents which blockCB2 cannabinoid receptors.^ Bauer, in collaboration with USscientists, found that alkylamides from Echinacea bound toboth CBI and CB2 cannabinoid receptors.^" In particular,certain alkylamides exhibited selectivity for CB2 receptors.

Taken together, these developments presented atthe Phoenix conference suggest the hypothesis thatthe alkylamides are largely responsible for thesystemic immune effects of Echinacea lipophilicextracts and that this immune modulating activity is(at least in part) due to the interaction of alkylamideswith cannabinoid receptors, specifically CB2.

Cannabinoid research has undergone a tremendoustransformation in the past 10 to 15 years. This progress wasmade possible by the discovery ofthe cannahinoid receptors.'^There are two cannabinoid receptors, CBI and CB2, whichwere originally found because they were activated by themajor psychoactive component of marijuana (Cannabissativa), delta-9-tetrahydrocannabinol.^^ CBI receptors arehighly localized in the central nervous system (CNS) and arehelieved to primarily modulate hehavior, while CB2 receptorspredominate in immune tissues outside the CNS, especiallythe spleen, and are believed to modulate immune function.'̂

When the cannabinoid receptors were first discovered, theywere classified as orphan receptors, since there were noknown endogenous molecules that stimulated their function.But shortly thereafter two major endogenous cannabinoids(endocannabinoids) were isolated.'̂ These are the arachidonicacid derivatives anandamide and 2-arachidonylglycerol.̂ ^ Infact, the structure of anandamide is strikingly similar to someEchinacea alkylamides (see below).

A tetraene alkylamide from Echinacea

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Cannabinoid receptors are remarkably preserved acrossthe animal kingdom, which suggests they play an importantdevelopmental and physiological role.'*''^ Much ofthe immuneactivity of the cannabinoid system appears to be mediatedby the cytokine network. Cytokines include the interleukins(IL-3, IL-6, etc), tumor necrosis factor alpha fTNFa) and theinterferons (IFN). Specific effects identified thus far foranandamide include:'*^• decreased proliferation in a breast cancer cell line;• increased IL-3 and IL-6 dependent immune cell line

proliferation;• increased IL-6 production in Theiler's virus infected

astrocytes;• decreased interleukins, IFN7 and TNFa in human

peripheral blood mononuclear cells.These effects are similar to some

of those found for Echinaceaalkylamides or for lipophilicEchinacea extracts.

The research of the Swiss teamwas particularly insightful into oneaspect of the mode of action ofEchinacea alkylamides." A lipophilicextract of Echinacea purpureastrongly stimulated TNFa mRNAsynthesis in peripheral monocytes,but not TNFa production. In otherwords, the Echinacea-induced newTNFa transcripts (mRNA) were nottranslated into TNFa itself. Whenmonocytes are treated with LPS(lipopolysaccharide or endotoxin, apowerful stimulator of the immunesystem) TNFa protein production issubstantially increased. However,co-incubation of monocytes with LPSand Echinacea extract resulted in astrong inhibition of this effect ofLPS.

Studies over a longer time-spanrevealed further insights. TNFamRNA was upregulated (around 8-fold) by the Echinacea extract overa time-span of 24 hours, whereas theconstituent protein level (of TNFa)was not changed. However, LPS-stimulated TNFa protein expressionwas potently modulated byEchinacea, resulting in significantinhibition (around 40%) during thefirst 20 hours and a subsequentprolongation of TNFa production.The authors were able to show thatall these effects of Echinacea extracton monocytes were produced by theinteraction of Echinaceaalkylamides with the CB2 receptorson these cells.

The results of this study suggestthat Echinacea works more as amodulator or facilitator of theimmune response, rather than as animmune st imulant . In resting

Solving the Echinacea Puzzle

monocytes it prepares them for a quicker immune responseby inducing TNFa mRNA. However, in overstimulatedmonocytes (as in the case of LPS) it first reduces and thenextends their response in terms of TNFa production. Inparticular, these key findings challenge the mythology thattraditional Echinacea extracts will "overstimulate and wearout" the immune system if taken continuously. On thecontrary, we now have evidence (also confirmed by theAustralian team) that Echinacea does not stimulate restingimmune cells and moderates the excessive and probablydetrimental response of overstimulated cells, therebyprolonging their effective activity. _

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Solving the Echinacea Puzzle

The Importance of Liver MetabolismThe MediHerb research team also discovered some

interesting factors, which appear to govern the humanbioavailability of Echinacea alkylamides. As stated previously,only alkylamides were found in human plasma afler ingestionof Echinacea tablets, but the levels were quite variable andfirst pass liver metaboiism was suspected as influencing thisobservation. The 2,4-diene alkylamides (predominant in E.purpurea) were found to be rapidly degraded by human livermicrosomes; in contrast the 2-ene alkylamides (predominantin E. angustifolia) were much more slowly degraded. Moreinterestingly, it was discovered that the 2-ene alkylamide,undeca-2E-ene-8,10-diynoic acid isobutylamide, actuallyslowed down the rate of 2,4-diene alkylamide degradation.The protective efFect ofthis major alkylamide is a highly novelfinding and it was deduced that only relatively smallproportions of this compound will result in a product withenhanced bioavailability. This is the first work that supportsthe traditional use of E. angustifolia root preparations, sincethe 2-ene alkylamides are not found in E. purpurea. It alsoshows the value, from a pharmacokinetic perspective, ofcombining the root of E. purpurea with E. angustifolia. Inother words, the alkylamides from E. angustifolia willenhance the bioavailability of those in E. purpurea.

Whole Root Extracts are Still ValidSeveral other research groups are now ofthe opinion that

the alkylamides are the most important compounds for thepharmacological activity of traditional Echinacea extracts.In addition to the above teams, a Canadian group found thatalkylamides at quite low oral doses significantly increase thephagocytic activity as well as the phagocytic index of alveolarmacrophages in normal rats.̂ ** Thus, a previously knownimmune function of Echinacea (increased phagocytic activity)can also be attributed to alkylamides.

Drugs that interact with CB2 receptors are underinvestigation at several research centers, and the temptationwill no doubt be there to isolate the Echinacea alkylamidesas a class of new immune-modulating drugs. However, theother components of an Echinacea extract probably serve arole in stabilizing the alkylamides, which are particularlyprone to oxidation, and possibly have other functions as well.

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Hence the use of whole root extracts is still preferable. Onthe other hand, growing, harvesting, drying and extractiontechniques should be tested and modified if necessary toensure that good levels of alkylamides are maintained intraditional Echinacea products. In addition, the inclusion ofalkylamide levels (per dose or per mL) on the label will providevaluable and clinically relevant quality information.

ConclusionsRecent research findings for traditional lipophilic extracts

of Echinacea root not only provide information on theimportant bioactive components in these preparations (thealkylamides), but also demonstrate that these unusualphytochemicals interact with cannabinoid 2 receptors (whichare at the cutting edge of immune system research). In otherwords, the traditional forms of Echinacea have been validatedby a recent scientific hreakthrough: the discovery of thecannahinoid receptors.

Liver metaholism studies suggest tha t either E.angustifolia extracts or combinations ofE. angustifolia withE. purpurea will provide the most bioavailable preparationsfor Echinacea alkylamides.

Finally, in the words of the Swiss research team: "Thefinding that alkylamides are the likely immunomodulatoryprinciples of Echinacea is of great interest for further clinicalstudies with this medicinal plant. We believe that theequivocal outcome of different clinical trials with Echinaceais in part derived from differences in quality of the usedpreparations."^'

References1, Wagner H. Herbal immunostiniulants. Z Phytoiher 1996; 17(2); 79-952, Felter HW, Lloyd JU. King's American Dispensatory, 18th Edn, 3rd revision. First

published 1905, reprinted Eclectic Medical Pubiications. Portland, 1983.3, Etlingwood F. American Materia Medica, Therapeutics and Pharmacognosy. Eclectic

Medical Publications, Portland, 1993.4, Bauer R. Wagner H. In Wagner H, Farnsworth NR eds, Ecoriomic and Medicinal

Plant Research, Vol 5, Academic Press, London, 1991.5, Melchart D, Clemm C, Weber B et al, Polysaccharides isolated from Echinacea

purpurea herba cell cultures to counteract undesired effects of chemotherapy - a pilotstudy, Phytother Res 2002; 16; 138-142

6, Egert D, Beuschner N. Studies on antigen specificity of immunoreactivearabinogalactan proteins extracted from Baptisia tinctoria and Echinacea purpurea,Planta Med 1992; 58<2); 163-165

7, Matthias A. Penman KG, Bone KM et al, Echinacea - what constituents aretherapeutically important? International Congress on Natural Products Research.Phoenix, Arizona USA, July 31-August 4, 2004, Lecture 0;8,

8, WoelkartK, KoidlC,GriaoldAet al. Pharmacokinetics and bioavailability of alkamjdesfrom the roots ot Echinacea anguBtifolia in humans after oral application. InternationalCongress on Natural Products Research, Phoenix, Arizona USA, July 31-August 4,2004, Lecture 0;10.

9, Gertsch J,Schoop R, KuenzleUetal. Alkyiamides from EcAinaceapurpureo potentlymodulate TNF-alpha gene expreaaion; Possible role of cannabinoid receptor CB2,NF-KB, P38, MAPK and JNK pathways. International Congress on Natural ProductsResearch, Phoenix, Arizona USA, July 31-August 4, 2004, Lecture 0:9,

10, Woelkart K, Xu W, Makriyannis Aet al. The endocannabinoid system as a target foralkamides from Echinacea roots. International Congress on Natural ProductsResearch, Phoenix, Arizona USA, July 31-August 4, 2004, Poster P;342,

11, Berdyghev EV, Cannabinoid receptors and the regulatian of immune response, ChemPhys Lipids 2000; ]08( 1-2); 169-190

12, Grotenhermen F, Pharmacology of cannabinoids, Neuro Endocrinol Lett 2004; 25(1-2); 14-23

13, Ralevic V, Cannabinoid modulation of peripheral autoDomic and sensoryneurotransmiasion. Eur J Pharmacol 2Q03\ 472(1 2); 1-21

14, Salzet M. Breton C, Bisogno T et al. Comparative biology of the endocannabinoidsystem possible role in the immune response. Eur J Biochem 2000; 267(16); 4917-4927

15, Fride E, The endocannabinoid-CB receptor system; Importance for development andin pediatric disease, Neuro Endacrinul Lett 2004; 25( 1-2); 24-30

16, Klein TW, Lane B, Newton C et al. The cannabinoid system and cytokine network,Proc Soc Exp Biol Med 2000; 225; 1-8

17, Gertsch J, Schoop R, Kuenzle U et al, Echinacea alkylamides modulate TNF-a geneexpression via cannabinoid receptor CB2 and multiple signal transduction pathways.PEBS Letters 2004 [in pressi

18, Goel V, Chang C, Slama JV et al, Alkylamides of Echinacea purpurea stimulatealveolar macrophage function in normal rats, Irtt Immunopharmacol 2002; 2(2-3);381-387

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