Among all the components produced in Echinacea plants, alkamides are the major lipophilic constituents and can be found in high concentrations in their roots and in lower concentrations in their aerial parts. The root bark and secondary roots of E. Angustifolia contained the highest concentrations of alkamides (Woelkart & Bauer, 2007).

Biological function

Echinacea preparations are known to be antibacterial and antioxidant, but it is difficult to point to a specific compound to explain these effects. In the case of alkamides, they show structural similarity with anandamide and it has been found that they bind significantly to CB2 receptors. The interaction of alkamides with CB2 receptors might explain the immunomodulatory properties of Echinacea. In fact, recent studies have found that Echinacea preparations containing alkamides can modulate pro-inflammatory cytokines in different ways. Also, other studies showed that alkamides possess stimulatory effects on phagocytosis (Woelkart & Bauer, 2007).

Pharmacokinetic studies

After oral administration of 2.5-mL of a 60% ethanolic extract from the roots of E. Angustifolia, 6 alkamides were detected in 11 participants sample, with a tmax of 30 minutes and a Cmax of 0.96ng/ml to 10.88ng/ml (Woelkart, Koidl, et al., 2005).

Echinacea preparations containing 3800mg of (95%) E. Purpurea herba (Drug extract ratio; DER = 1:12) and 200mg (5%) E. Purpurea radix (DER = 1:11), equivalent to 142mg of the alkamides dodeca-2E,4E,8Z,10E/Z-tetraenoic acid isobutylamides, were administered to 8 participants, showing a tmax of 68 minutes and a Cmax of 22ng/ml of these alkamides (Woelkart et al., 2008).

After oral administration of 10mg of E. Angustifolia extract, equivalent to 1mg of dodeca-2E,4E,8Z,10E/Z-tetraenoic acid isobutylamides, reported tmax was 42 minutes and Cmax 7.75mg/ml (Dall’Acqua et al., 2015).

In a receptor binding study, two alkamides showed CB2 binding K_i values of 57nm and 60nm (compared to 36 and 218 of THC and anandamide) (Raduner et al., 2006).

Clinical relevance

Echinacea preparations are mainly used for the treatment of common colds, but the results of clinical studies are not clear yet. Other medical conditions like anxiety, cancer, lung infections and COVID-19 are being investigated. Due to its immunomodulatory effects, any medical condition related to the immune system can be a therapeutic target of Echinacea.

Echinacea preparations are sometimes mixed with other ingredients, mostly with other medicinal plants, like Hydrastis Canadensis, Thujaoccidentalis, or Baptisia tinctoria (Naser et al., 2005). However, dosages are difficult to calculate, since preparations are made with extractions of different parts of the plant and from different species, making it difficult to calculate the concentration of alkamides and other compounds used in folk medicine. The only dosage reference  we have right now comes from clinical trials, and these studies also use different preparations for different conditions. For example, studies used from 40mg/day to 4000 mg/day of Echinacea Extract for prevention and treatment of common colds, for up to four months. Other studies used extracts containing from 0.25mg to 480mg of different types of alkamides.

Common cold, Lung infection and COVID-19

Most of the studies investigating the therapeutic properties of Echinacea against common cold found that Echinacea extracts (2400mg/day to 4000mg/day) can shorten the duration (33%) or decrease the severity of symptoms of the common cold, but results are not always consistent (Catanzaro et al., 2018; Karsch-Völk et al., 2015; Naser et al., 2005; Rondanelli et al., 2018; Woelkart & Bauer, 2007).

Echinacea preparations, particularly E. Purpurea, have been suggested to be an important antiviral agent to be useful in COVID-19 by modulating virus entry, internalization and replication. Also, it could reduce sever symptoms of COVID-19 like coughing, dyspnea or muscle pain. Hence, it could be a reasonably possible candidate for targeting infection, immunity, inflammation and symptomatology of COVID-19. The immunomodulatory, anti-inflammatory and antiviral effects might be mediated by CB2 and PPARγ receptors (Brendler et al., 2020; Hensel et al., 2020; Keflie & Biesalski, 2021; Mesri et al., 2021; Nagoor Meeran et al., 2021).

Cancer

Echinacea preparations and its compounds showed anticancer activity in several in vitro studies and it has been associated with good prognosis in patients who used it together with other supplements. Some authors suggest that the pro-apoptotic effects of Echinacea are mediated by the CB2 (Bright-Gbebry et al., 2011; Driggins et al., 2004; Goey et al., 2013; Hosami et al., 2021; Huntimer et al., 2006; Ma et al., 2011; McGrowder et al., 2020).

Anxiety

Echinacea preparations showed a reduction in anxiety scores in both animal and clinical studies (20mg to 40mg of E. Angustifolia extract per day during one week). Authors suggest these effects could be mediated by CB2. (Haller et al., 2010; Haller et al., 2013, 2020; Sarris et al., 2013).

Skin conditions

A specific Echinacea extract shows great potential in alleviating cutaneous symptoms of Atopic Eczema by exerting anti-inflammatory actions and restoring the epidermal lipid barrier. The authors suggest these effects could be mediated by CB2 (Oláh et al., 2017).

Endocannabinoid System

Alkamides are known to modulate the endocannabinoid system by targeting its receptors like CB1, CB2 or PPAR-γ, which can lead to modulatory effects on the immune system, including its inflammation processes.

Alkamides bind to the cannabinoid CB1 receptor, and inhibit the enzyme fatty acid amide hydrolase (FAAH), which degrades the endocannabinoid anandamide, and the inhibition of which increases anandamide levels in the brain (Gertsch, 2008; Woelkart et al., 2005). Also, purified Echinacea alkamides showed that their effects on the CB1 receptor are complex. Some alkamides may be neutral with respect to CB1 activation but others may also exert inverse agonist, partial agonist or antagonist effects (Hohmann et al., 2011).

Alkamides are capable of activating CB2, so they have been suggested to play a role as potential anti-inflammatory and immune-modulatory principles. Alkamides exert pleiotropic effects modulating the endocannabinoid system by simultaneously targeting the CB2 receptor, endocannabinoid transport and degradation (Chicca et al., 2009). In fact, a study shows that Alkamides, anandamide, and SR144528 potently inhibited lipopolysaccharide-induced inflammation in human whole blood. These properties exerted modulatory effects on cytokine expression, and these effects are related to CB2 binding (Raduner et al., 2006). In another study, Alkamides modulated expression of tumor necrosis factor-α (TNF-α) mRNA in human macrophages and monocytes via CB₂ receptor (Gertsch et al., 2004).

Alkamides also modulate PPAR- γ, which leads to cytokine inhibition (Spelman et al., 2009).

Cannabinoid synergies

In a study evaluating the anticancer properties of both Echinacea and Cannabis extracts, authors found pro-apoptotic effects of both extracts and suggest a possible regulatory role of CB2 (Hosami et al., 2021). Since cannabinoids show therapeutic potential to treat conditions that might be treated with Echinacea (eg. cancer and anxiety) and since Echinacea components can regulate the endocannabinoid system, it would be interesting to see if components from both plants can interact to achieve more effective treatments.

NIH health claims

• Taking echinacea might slightly reduce your chances of catching a cold. Echinacea has not been shown to shorten the length of a cold

References

Barth, A., Hovhannisyan, A., Jamalyan, K., & Narimanyan, M. (2015). Antitussive effect of a fixed combination of Justicia adhatoda, Echinacea purpurea and Eleutherococcus senticosus extracts in patients with acute upper respiratory tract infection: A comparative, randomized, double-blind, placebo-controlled study. Phytomedicine: International Journal of Phytotherapy and Phytopharmacology, 22(13), 1195–1200. https://doi.org/10.1016/j.phymed.2015.10.001

Brendler, T., Al-Harrasi, A., Bauer, R., Gafner, S., Hardy, M. L., Heinrich, M., Hosseinzadeh, H., Izzo, A. A., Michaelis, M., Nassiri-Asl, M., Panossian, A., Wasser, S. P., & Williamson, E. M. (2020). Botanical drugs and supplements affecting the immune response in the time of COVID-19: Implications for research and clinical practice. Phytotherapy Research: PTR. https://doi.org/10.1002/ptr.7008

Bright-Gbebry, M., Makambi, K. H., Rohan, J. P., Llanos, A. A., Rosenberg, L., Palmer, J. R., & Adams-Campbell, L. L. (2011). Use of multivitamins, folic acid and herbal supplements among breast cancer survivors: The black women’s health study. BMC Complementary and Alternative Medicine, 11, 30. https://doi.org/10.1186/1472-6882-11-30

Brinkeborn, R. M., Shah, D. V., & Degenring, F. H. (1999). Echinaforce and other Echinacea fresh plant preparations in the treatment of the common cold. A randomized, placebo controlled, double-blind clinical trial. Phytomedicine: International Journal of Phytotherapy and Phytopharmacology, 6(1), 1–6. https://doi.org/10.1016/S0944-7113(99)80027-0

Catanzaro, M., Corsini, E., Rosini, M., Racchi, M., & Lanni, C. (2018). Immunomodulators Inspired by Nature: A Review on Curcumin and Echinacea. Molecules, 23(11). https://doi.org/10.3390/molecules23112778

Chicca, A., Raduner, S., Pellati, F., Strompen, T., Altmann, K.-H., Schoop, R., & Gertsch, J. (2009). Synergistic immunomopharmacological effects of N-alkylamides in Echinacea purpurea herbal extracts. International Immunopharmacology, 9(7–8), 850–858. https://doi.org/10.1016/j.intimp.2009.03.006

Dall’Acqua, S., Perissutti, B., Grabnar, I., Farra, R., Comar, M., Agostinis, C., Caristi, G., Golob, S., & Voinovich, D. (2015). Pharmacokinetics and immunomodulatory effect of lipophilic Echinacea extract formulated in softgel capsules. European Journal of Pharmaceutics and Biopharmaceutics: Official Journal of Arbeitsgemeinschaft Fur Pharmazeutische Verfahrenstechnik e.V, 97(Pt A), 8–14. https://doi.org/10.1016/j.ejpb.2015.09.021

Driggins, S. N., Myles, E. L., & Gary, T. (2004). The anti-prolific effect of Echinacea Pallida on BT-549 cancer cell line. Cancer Research, 64(7 Supplement), 1010–1010.

Gertsch, Juerg, Schoop, R., Kuenzle, U., & Suter, A. (2004). Echinacea alkylamides modulate TNF-alpha gene expression via cannabinoid receptor CB2 and multiple signal transduction pathways. FEBS Letters, 577(3), 563–569. https://doi.org/10.1016/j.febslet.2004.10.064

Gertsch, Jürg. (2008). Immunomodulatory lipids in plants: Plant fatty acid amides and the human endocannabinoid system. Planta Medica, 74(6), 638–650. https://doi.org/10.1055/s-2008-1034302

Goey, A. K. L., Meijerman, I., Rosing, H., Burgers, J. A., Mergui-Roelvink, M., Keessen, M., Marchetti, S., Beijnen, J. H., & Schellens, J. H. M. (2013). The effect of Echinacea purpurea on the pharmacokinetics of docetaxel. British Journal of Clinical Pharmacology, 76(3), 467–474. https://doi.org/10.1111/bcp.12159

Haller, J., Hohmann, J., & Freund, T. F. (2010). The effect of Echinacea preparations in three laboratory tests of anxiety: Comparison with chlordiazepoxide. Phytotherapy Research: PTR, 24(11), 1605–1613. https://doi.org/10.1002/ptr.3181

Haller, József, Freund, T. F., Pelczer, K. G., Füredi, J., Krecsak, L., & Zámbori, J. (2013). The anxiolytic potential and psychotropic side effects of an echinacea preparation in laboratory animals and healthy volunteers. Phytotherapy Research: PTR, 27(1), 54–61. https://doi.org/10.1002/ptr.4677

Haller, József, Krecsak, L., & Zámbori, J. (2020). Double-blind placebo controlled trial of the anxiolytic effects of a standardized Echinacea extract. Phytotherapy Research: PTR, 34(3), 660–668. https://doi.org/10.1002/ptr.6558

Hensel, A., Bauer, R., Heinrich, M., Spiegler, V., Kayser, O., Hempel, G., & Kraft, K. (2020). Challenges at the Time of COVID-19: Opportunities and Innovations in Antivirals from Nature. Planta Medica, 86(10), 659–664. https://doi.org/10.1055/a-1177-4396

Hohmann, J., Rédei, D., Forgo, P., Szabó, P., Freund, T. F., Haller, J., Bojnik, E., & Benyhe, S. (2011). Alkamides and a neolignan from Echinacea purpurea roots and the interaction of alkamides with G-protein-coupled cannabinoid receptors. Phytochemistry, 72(14–15), 1848–1853. https://doi.org/10.1016/j.phytochem.2011.06.008

Hosami, F., Manayi, A., Salimi, V., Khodakhah, F., Nourbakhsh, M., Nakstad, B., & Tavakoli-Yaraki, M. (2021). The pro-apoptosis effects of Echinacea purpurea and Cannabis sativa extracts in human lung cancer cells through caspase-dependent pathway. BMC Complementary Medicine and Therapies, 21(1), 37. https://doi.org/10.1186/s12906-021-03204-6

Huntimer, E. D., Halaweish, F. T., & Chase, C. C. L. (2006). Proliferative activity of Echinacea angustifolia root extracts on cancer cells: Interference with doxorubicin cytotoxicity. Chemistry & Biodiversity, 3(6), 695–703. https://doi.org/10.1002/cbdv.200690071

Isbaniah, F., Wiyono, W. H., Yunus, F., Setiawati, A., Totzke, U., & Verbruggen, M. A. (2011). Echinacea purpurea along with zinc, selenium and vitamin C to alleviate exacerbations of chronic obstructive pulmonary disease: Results from a randomized controlled trial. Journal of Clinical Pharmacy and Therapeutics, 36(5), 568–576. https://doi.org/10.1111/j.1365-2710.2010.01212.x

Karsch-Völk, M., Barrett, B., & Linde, K. (2015). Echinacea for preventing and treating the common cold. JAMA, 313(6), 618–619. https://doi.org/10.1001/jama.2014.17145

Keflie, T. S., & Biesalski, H. K. (2021). Micronutrients and bioactive substances: Their potential roles in combating COVID-19. Nutrition (Burbank, Los Angeles County, Calif.), 84, 111103. https://doi.org/10.1016/j.nut.2020.111103

Ma, H., Carpenter, C. L., Sullivan-Halley, J., & Bernstein, L. (2011). The roles of herbal remedies in survival and quality of life among long-term breast cancer survivors—Results of a prospective study. BMC Cancer, 11, 222. https://doi.org/10.1186/1471-2407-11-222

McGrowder, D. A., Miller, F. G., Nwokocha, C. R., Anderson, M. S., Wilson-Clarke, C., Vaz, K., Anderson-Jackson, L., & Brown, J. (2020). Medicinal Herbs Used in Traditional Management of Breast Cancer: Mechanisms of Action. Medicines (Basel, Switzerland), 7(8). https://doi.org/10.3390/medicines7080047

Mesri, M., Esmaeili Saber, S. S., Godazi, M., Roustaei Shirdel, A., Montazer, R., Koohestani, H. R., Baghcheghi, N., Karimy, M., & Azizi, N. (2021). The effects of combination of Zingiber officinale and Echinacea on alleviation of clinical symptoms and hospitalization rate of suspected COVID-19 outpatients: A randomized controlled trial. Journal of Complementary & Integrative Medicine. https://doi.org/10.1515/jcim-2020-0283

Nagoor Meeran, M. F., Javed, H., Sharma, C., Goyal, S. N., Kumar, S., Jha, N. K., & Ojha, S. (2021). Can Echinacea be a potential candidate to target immunity, inflammation, and infection—The trinity of coronavirus disease 2019. Heliyon, 7(2), e05990. https://doi.org/10.1016/j.heliyon.2021.e05990

Naser, B., Lund, B., Henneicke-von Zepelin, H. H., Köhler, G., Lehmacher, W., & Scaglione, F. (2005). A randomized, double-blind, placebo-controlled, clinical dose-response trial of an extract of Baptisia, Echinacea and Thuja for the treatment of patients with common cold. Phytomedicine: International Journal of Phytotherapy and Phytopharmacology, 12(10), 715–722. https://doi.org/10.1016/j.phymed.2005.03.002

Notarnicola, A., Maccagnano, G., Tafuri, S., Fiore, A., Pesce, V., & Moretti, B. (2015). Comparison of shock wave therapy and nutraceutical composed of Echinacea angustifolia, alpha lipoic acid, conjugated linoleic acid and quercetin (perinerv) in patients with carpal tunnel syndrome. International Journal of Immunopathology and Pharmacology, 28(2), 256–262. https://doi.org/10.1177/0394632015584501

Oláh, A., Szabó-Papp, J., Soeberdt, M., Knie, U., Dähnhardt-Pfeiffer, S., Abels, C., & Bíró, T. (2017). Echinacea purpurea-derived alkylamides exhibit potent anti-inflammatory effects and alleviate clinical symptoms of atopic eczema. Journal of Dermatological Science, 88(1), 67–77. https://doi.org/10.1016/j.jdermsci.2017.05.015

O’Neil, J., Hughes, S., Lourie, A., & Zweifler, J. (2008). Effects of echinacea on the frequency of upper respiratory tract symptoms: A randomized, double-blind, placebo-controlled trial. Annals of Allergy, Asthma & Immunology: Official Publication of the American College of Allergy, Asthma, & Immunology, 100(4), 384–388. https://doi.org/10.1016/S1081-1206(10)60603-5

Raduner, S., Majewska, A., Chen, J.-Z., Xie, X.-Q., Hamon, J., Faller, B., Altmann, K.-H., & Gertsch, J. (2006). Alkylamides from Echinacea are a new class of cannabinomimetics. Cannabinoid type 2 receptor-dependent and -independent immunomodulatory effects. The Journal of Biological Chemistry, 281(20), 14192–14206. https://doi.org/10.1074/jbc.M601074200

Rondanelli, M., Miccono, A., Lamburghini, S., Avanzato, I., Riva, A., Allegrini, P., Faliva, M. A., Peroni, G., Nichetti, M., & Perna, S. (2018). Self-Care for Common Colds: The Pivotal Role of Vitamin D, Vitamin C, Zinc, and Echinacea in Three Main Immune Interactive Clusters (Physical Barriers, Innate and Adaptive Immunity) Involved during an Episode of Common Colds-Practical Advice on Dosages and on the Time to Take These Nutrients/Botanicals in order to Prevent or Treat Common Colds. Evidence-Based Complementary and Alternative Medicine: ECAM, 2018, 5813095. https://doi.org/10.1155/2018/5813095

Ross, S. M. (2016). Echinacea Formula (Echinaforce® Hotdrink): Effects of a Proprietary Echinacea Formula Compared With Oseltamivir in the Early Treatment of Influenza. Holistic Nursing Practice, 30(2), 122–125. https://doi.org/10.1097/HNP.0000000000000144

Sarris, J., McIntyre, E., & Camfield, D. A. (2013). Plant-based medicines for anxiety disorders, part 2: A review of clinical studies with supporting preclinical evidence. CNS Drugs, 27(4), 301–319. https://doi.org/10.1007/s40263-013-0059-9

Schapowal, A., Berger, D., Klein, P., & Suter, A. (2009). Echinacea/sage or chlorhexidine/lidocaine for treating acute sore throats: A randomized double-blind trial. European Journal of Medical Research, 14(9), 406–412. https://doi.org/10.1186/2047-783x-14-9-406

Spelman, K., Iiams-Hauser, K., Cech, N. B., Taylor, E. W., Smirnoff, N., & Wenner, C. A. (2009). Role for PPARgamma in IL-2 inhibition in T cells by Echinacea-derived undeca-2E-ene-8,10-diynoic acid isobutylamide. International Immunopharmacology, 9(11), 1260–1264. https://doi.org/10.1016/j.intimp.2009.08.009

Whitehead, M. T., Martin, T. D., Scheett, T. P., & Webster, M. J. (2012). Running economy and maximal oxygen consumption after 4 weeks of oral Echinacea supplementation. Journal of Strength and Conditioning Research, 26(7), 1928–1933. https://doi.org/10.1519/JSC.0b013e318237e779

Woelkart, K., & Bauer, R. (2007). The role of alkamides as an active principle of echinacea. Planta Medica, 73(7), 615–623. https://doi.org/10.1055/s-2007-981531

Woelkart, K., Dittrich, P., Beubler, E., Pinl, F., Schoop, R., Suter, A., & Bauer, R. (2008). Pharmacokinetics of the main alkamides after administration of three different Echinacea purpurea preparations in humans. Planta Medica, 74(6), 651–656. https://doi.org/10.1055/s-2008-1034284

Woelkart, K., Koidl, C., Grisold, A., Gangemi, J. D., Turner, R. B., Marth, E., & Bauer, R. (2005). Bioavailability and pharmacokinetics of alkamides from the roots of Echinacea angustifolia in humans. Journal of Clinical Pharmacology, 45(6), 683–689. https://doi.org/10.1177/0091270004273493

Woelkart, K., Xu, W., Pei, Y., Makriyannis, A., Picone, R. P., & Bauer, R. (2005). The endocannabinoid system as a target for alkamides from Echinacea angustifolia roots. Planta Medica, 71(8), 701–705. https://doi.org/10.1055/s-2005-871290