1. Echinacea: Myth and Reality A Personal Journey
Kerry Bone Co-Founder and Director Research & Development, MediHerb Associate Professor, University of New England, Armidale

2. The Echinacea Confusion
A multitude of products using different species, different plant parts and different manufacturing methods
A lack of consensus over what phytochemicals in Echinacea are responsible for its immune activity
A rudimentary understanding of its exact mode of action on the immune system
Perhaps not any longer!

3. Historical Perspective
Information about the therapeutic value of Echinacea first came from Native American tribes
Their use of Echinacea was then adopted by the Eclectics
By 1921 Echinacea (specifically the root of E. angustifolia) was by far the most popular treatment prescribed by Eclectic physicians
Wagner H. Z Phytother 1996; 17(2): 79-95

4. Historical Perspective
The Eclectics were responsible for Echinacea’s reputation as an immune herb and they used the root extracted in a high percentage of alcohol (lipophilic extracts or tinctures)
They felt that the tingling (due to alkylamides) was the indicator of good quality
In Europe during the 1930s the German herbalist Madaus introduced E. purpurea tops as a stabilised fresh juice
Bauer R, Wagner H. In Wagner H, Farnsworth NR eds. Economic and Medicinal Plant Research, Vol 5, Academic Press, London, 1991

5. Early Encounters with Echinacea: Real or Not?
As a student at the Jackas clinic, Melbourne 1976
As a herbal student, Tunbridge Wells, UK 1982
At a US herbal trade show, 1987
Real Echinacea gives you “asthma”, 1988

6. Learning the Power of Real Echinacea
The Eclectic writings in King’s Dispensatory and Ellingwood, early 1990s
Teaching Echinacea to undergraduates and student feedback, early 1990s
Feedback from patients and learning the power of prevention, early 1990s

7. Surprising Echinacea “Myths”
International herbal conference, Munich, 1995
Reading about polysaccharides, 1990s
Reading about autoimmune disease, Commission E, 1990s

8. Defining the Challenge
Selling the traditional approach to sceptics, 1999
Realising the research that needed to be undertaken, 1999
What is active must be bioavailable, what is bioavailable must be active: the model of undertaking all quality research on herbs
But clinical proof is paramount!

9. What is likely to be absorbed
What is likely to be absorbed? Permeability measurement using Caco-2 model
Living human colon cancer cells are grown on plastic filter support
Herbal extract placed on top of cells and allowed to permeate
Samples taken from above and below cell layer
Analyse by LC/MS
Measure how much has been transported

10. Echinacea Bioavailability – Caco-2 of Major Components20 40 60 80
100
Time (minutes)
% Uptake
Diene alkylamide
Monoene alkylamide
Cichoric Acid
Matthias A, Blanchfield JT, Penman KG et al, J Clin Pharm Ther, 2004; 29: 7-13

11. Pharmacokinetics Study Design: 11 healthy individuals
Age: 18 to 26 years
BMI: 19 to 30
Blood samples taken over 12 hours
Dose:
4 Echinacea Premium tablets

12. What Compounds Were Found in Bloodstream
No caffeic acid conjugates
No caffeic acid conjugate degradation products
No isobutylamide degradation products
The only compounds identified in human plasma were alkylamides from the
Echinacea ingested, at approximately the same ratio as the initial medication
Matthias A, Addison RS, Penman KG, Bone KM et al. Life Sciences 2005; 77:

13. Liver First Pass Metabolism
The pharmacokinetic study suggested that alkylamides were being degraded by the liver on first pass after absorption in the GIT
When liver decomposition of alkylamides was investigated a surprising fact was found
Some alkylamides in E. angustifolia are degraded at a slower rate and protect other alkylamides (found in E. angustifolia and E. purpurea) from degrading

14. Enhancing Bioavailability
2-ene protects the 2,4-diene
increasing amounts of 2-ene alkylamide gives less degradation of the 2,4-diene
Matthias A, Gillam EMJ, Penman KG, Bone KM et al. Chem Biol Interact 2005; 155: 62-70

15. Echinacea - Liquid vs Solid Dose Pharmacokinetics
Matthias A, Addison RS, Agnew L, Bone KM et al, Phytomedicine 2007; 14(9):

16. ICMPR Phoenix 2004
Alkylamides have a potent effect on the TNF synthesis in human monocytes (Gertsch)
Two independent researchers reported the binding of alkylamides to the cannabinoid receptors (Bauer and Gertsch)
Blocking with anti-CB2 polyclonal antibody and the specific antagonist SR inhibited the TNF mRNA induction
Gertsch J, Schoop R, Kuenzle U et al. Int Congress on Natural Products Research, Phoenix, Arizona USA, July 31-August 4, 2004, Lecture O:9
Woelkart K, Xu W, Makriyannis A, Bauer R et al.. Int Congress on Natural Products Research, Phoenix, Arizona USA, July 31-August 4, 2004, Poster P:342

17. Cannabinoid Receptors
CB1 receptors are highly localised in the central nervous system (CNS) and are believed to primarily modulate behaviour
CB2 receptors predominate in immune tissues outside the CNS, especially the spleen, and are believed to modulate immune function
Echinacea alkylamides mainly bind to CB2 receptors
Ralevic V. Cannabinoid modulation of peripheral autonomic and sensory neurotransmission. Eur J Pharmacol 2003; 472(1-2): 1-21

18. Alkylamides and Anandamide
Anandamide: an endogenous cannabinoid
Z,Z tetraene alkylamide from Echinacea

19. A New Insight Into Echinacea
Taken together, these developments presented at the Phoenix conference (including the pharmacokinetic research) suggest the hypothesis that the alkylamides are largely responsible for the systemic immune effects of Echinacea lipophilic tinctures and that this immune modulating activity is (at least in part) due to the interaction of alkylamides with cannabinoid receptors, specifically CB2.

20. CB2 Binding of Alkylamide Isomers
Using alkylamides supplied from Australia it has been found that the tetra-ene isomers vary in terms binding to CB receptors
Isomer Ki CB2 (nM)
ZZ ± 8.5
ZE ± 2985
EZ ± 711
EE >
Matovic N, Matthias A, Gertsch J, Bone KM et al. Org Biomol Chem 2007; 5(1);

21. Echinacea - Prevention of Colds in Student Population
A prevention trial was performed at NCNM in Portland using Echinacea Premium liquid vs tonic formula vs placebo
n=265 students
significant decrease in incidence of winter colds in highly stressed student. (10% in placebo to <3% in Echinacea group after 70 days)
MacIntosh et al, presented at AANP convention, Couer d’Alene Nov 1999

22. Further Clinical Work on Echinacea Root
Echinacea Premium was given at 2 tablets per day for 2 weeks
Agnew LL, Guffogg SP, Matthias A, Bone KM et al. J Clin Pharm Ther 2005; 30(4),

23. Echinacea: A Miracle Herb?
In an extraordinarily entitled paper: “Echinacea: a Miracle Herb against Aging and Cancer?”, Dr Sandra Miller has recently reviewed her research on Echinacea, specifically Echinacea purpurea root1
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 7 days which resulted in significantly higher levels (around 25% more) of NK cells in the spleen by 2 weeks2
1. Miller SC. eCAM 2005; 2(3):
2. Sun LZ-Y, Currier NL, Miller SC. J Altern Complement Med 1999; 5:

24. Echinacea Boosts NK Cells
In addition, the ‘helper’ or accessory cells for NK cells, the monocytes, were also increased by 25%
The Echinacea treatment influenced no other white blood cell counts
Polysaccharides, even by injection, were found to be not responsible for this effect
Dr Miller feels that alkylamides are largely responsible for the effect (personal communication)
This research shifts the focus for Echinacea to innate immunity and emphasises its preventative role
Currier NL, Lejtenyi D, Miller SC. Phytomedicine 2003; 10:

25. Echinacea Reverses Ageing of Innate Immunity
NK cells decline in number and function with age and this is thought to be one factor behind the increase of various cancers with age
Experiments conducted in healthy, elderly mice found that 2 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 cells1
Currier NL, Miller SC. Exp Gerontol 2000; 35:

26. Echinacea Reverses Ageing of Innate Immunity
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….”
Miller SC. eCAM 2005; 2(3):

27. Echinacea is Beneficial if Taken Regularly
One of the persistent controversies about Echinacea is whether it is safe to be taken consistently for long periods of time. According to Miller’s findings the answer, is definitely in the affirmative
Mice were fed Echinacea purpurea root from 7 weeks of age to 13 months at the dose previously described.1 Long-term use of Echinacea was not only not detrimental, but distinctly beneficial – lifespan was significantly extended compared to controls
1. Brousseau M, Miller SC. Biogerontology 2005; 6:

28. Echinacea and Autoimmunity
Mice with autoimmune diabetes did not show adverse effects when fed Echinacea purpurea root1
In a controlled clinical trial, patients with autoimmune uveitis were able to reduce their time on prednisone when given Echinacea purpurea2
1. Delorme D, Miller SC. Autoimmunity 2005; 38(6):
2. Neri PG, Stagni E, Filippello M et al. J Ocul Pharmacol Ther 2006; 22(6):

29. 21st Century Echinacea Myths
Echinacea will give you colon cancer
Echinacea is contraindicated in pregnancy
Echinacea causes liver damage

30. Conclusions The Preferred Preparation
The preferred parts of Echinacea to use are the roots of E. angustifolia combined with E. purpurea
The alkylamides are the important quality marker compounds (even active constituents) and MUST be present in adequate quantities
Doses must be adequate: at least 2.5 g of a root combination per day (temporarily  to ward off infection)
Alkylamides are bioavailable, importantly tablet and liquid preparations are equipotent if appropriately formulated
Alkylamides in E. angustifolia help to inhibit the rapid liver breakdown of alkylamides from E. purpurea

31. Conclusions The Mode of Action
Echinacea root boosts innate immunity with continued use and modulates immune activity during an acute phase response
This latter effect can be partly explained by the interaction of alkylamides with CB2 receptors
Long-term use of Echinacea is in fact not only beneficial, it is necessary for its full immune effects
There is no reason why Echinacea should be contraindicated in autoimmune disease, in fact it may be beneficial

32. Echinacea Research Collaborators
University of Queensland research groups
Prof Istvan Toth
Dr JJ De Voss
Dr E Gillam
Prof R Dickenson and Prof W Hooper
Southern Cross University research groups
A/Prof D Leach
Prof S Meyers
University of New England research group
Prof K Watson
Swiss Federal Institute of Technology
Dr J Gertsch
University of Wisconsin
Dr Bruce Barrett

33. Acknowledgments
A/Prof Reg Lehmann
Dr Anita Matthias
Dr Kerry Penman

34. A Final Thought! To avoid sickness, eat less
To prolong life, worry less……
Chu Hui Weng

35. …… and take Echinacea for both!
A Final Thought!
…… and take Echinacea for both!
Kerry Bone