Research Update articles are produced in order to keep practitioners up to date on impactful research that is relevant to the field of integrative medicine. These articles may contain summaries of recent studies, events, or other industry news that advance current knowledge and standards of care.
The Southwest College of Naturopathic Medicine & Health Sciences (SCNM) hosts its research night event biannually, once in spring and once in autumn. The event highlights discoveries in the field of evidence-based botanical medicine made as a result of the collaboration and hard work of students and faculty. On November 9th, 2021, SCNM’s Fall Research Night showcased presentations ranging from the herbal treatment of bovine mastitis to the use of Echinacea and Artemisia in humans. This research piece will focus on three presentations primarily focused on Echinacea which illuminate the herb’s safety, efficaciousness, and various botanical actions.
Active constituents and drug interaction of Echinacea and pharmaceuticals
The first lecture, presented by Narges Kiyani, PharmD and Susan Trapp, PhD was on the topic of Echinacea and its pharmacognosy indications. This plant belongs to the Asteraceae or daisy family and its common names include purple coneflower, Indian head, and snakeroot. The three most common Echinacea species found in literature reviews and supplement use are Echinacea purpurea (eastern purple coneflower), Echinacea pallida (pale purple coneflower), and Echinacea angustifolia (narrow-leaf coneflower).
The main use of Echinacea is for the treatment of upper respiratory infections, most commonly through oral delivery systems. Though Echinacea is a very popular herb, contradictory and controversial research still remains. This is due in part to the variety of species of Echinacea utilized, the chemical constituents which vary depending on the plant parts used and their extraction solvents, and the limited clinical studies available. The researchers reviewed over 200 studies on this herb in an effort to clarify this confusion with the core goal of improving the quality of products on the market.
This research group described that the main class of compounds in Echinacea is the polyphenolics, which include a major subgroup of caffeic acid derivatives. These include caffeic acid, cichoric acid, and cynarin, each possessing protective actions such as antioxidative, antimutagenic, and anticarcinogenic effects. Another main class is the alkamides, of which over 24 have been identified. Alkamides possess anti-inflammatory and immunomodulatory effects. A specific compound within this class worth mentioning is the compound echinaceae which has a similar structure to anandamide, a compound involved in the endocannabinoid system. Thus, this group proposed that Echinacea may also act as a cannabinoid mimetic. The last major constituent group mentioned in this overview was the polysaccharides which have immune-stimulating effects.
Echinacea chemical constituents vary depending on several factors including the actual plant parts utilized and the extraction methods. The researchers noted that in many Echinacea studies, the plant part used is often described as the “aerial parts,” indicating the utilization of all or some of the above-ground plant parts. However, this is often vaguely specified in research as it fails to denote exactly which aspect of the aerial parts (i.e. flower, stem, and/or leaves) are utilized. Additionally, vagueness in the description of the extraction method contributes to research inconclusivity as some articles fail to disclose the strength of the ethanolic extract used. The most common extraction solvents for Echinacea plant constituents are 50% ethanol, 70% ethanol, 100% ethanol, and aqueous.
The next part of the presentation focused on the mechanism by which Echinacea may cause drug interactions, mainly via inhibition of cytochrome P450 (CYP450) enzymes and induction of transporters. One example that was described was that Echinacea can inhibit CYP2A1 which can lead to increased levels of caffeine in the blood. As CYP450 is a superfamily of enzymes involved in the metabolism of many drugs, the clinical importance of Echinacea’s ability to influence the enzyme is apparent, however, the clinical relevance of Echinacea’s effect on transporters is not yet well understood. An example of this brought up in the presentation was that E. purpurea can induce P-glycoprotein transporters; however, there is no effect on metabolism of digoxin observed in clinical studies.
The next section of the discussion focused on how Echinacea’s potential drug interactions can vary depending on the species, collection time, plant parts utilized, extraction method used, and constituents. An example of this was that the roots of E. angustifolia can inhibit CYP3A4, whereas the aerial parts of Echinacea cannot due to the roots being richer in caffeic acid derivatives. A second example was that the roots of E. purpurea can inhibit both CYP2A6 and CYP2E1 when extracted in high ethanol. However, in low ethanol or with high ethanolic extraction of the aerial parts, this effect may not be observed.
The researchers also studied the potential interactive effect of Echinacea on various drug classes. They found that with immunosuppressive drugs, Echinacea interacts with cyclosporine via inhibition or induction of CYP3A4, CYP3A5, and P-glycoprotein; however, it had no interaction with the drug prednisone. When using antiviral medications, Echinacea was described as safe and well tolerated in patients with human immunodeficiency virus taking the reverse transcriptase inhibitor etravirine. However, it did interact with Tamiflu leading to a possible decrease in the bioavailability of the Tamiflu. One interesting finding was that Echinacea can induce CYP3A4 in some tissues while inhibiting it in others. In reviewing Echinacea’s interactions with chemotherapy, it may cause thrombocytopenia when combined with etoposide despite being safe and well tolerated when combined with the drug docetaxel. There are drugs with which the addition of Echinacea may prove to be beneficial, including azithromycin for the treatment of recurrent tonsillitis, econazole for the treatment of yeast infections, and doxorubicin for the prevention of apoptosis of healthy cells in those undergoing chemotherapy.
The group concluded that Echinacea is primarily indicated for short-term use. The safety and adverse effects of Echinacea was also discussed in this presentation in greater depth, and in essence, the researchers posit that the herb is generally safe and well tolerated. Toxicities and drug interactions do exist, some with severe adverse effects such as thrombocytopenia. Thus, understanding this herb, its plant parts, its constituents, and its pharmacognosy is essential both for optimal efficacy and safety purposes.
Rhinovirus enhancing effects of E. purpurea root water extracts
The second presentation, delivered by Jeffrey Langland, PhD, continued the discussion on Echinacea, while switching gears to discuss the most common virus in the human population—the rhinovirus. Rhinovirus is the most common cause of the common cold, and interestingly, the presenters added, it can only replicate at 33 to 35°C, explaining why it is typically limited to the nasopharyngeal cavity. Viral plaque assays and aqueous extracts of the root plant part of E. purpurea revealed differences by which Echinacea acts on the rhinovirus compared to vaccinia and herpes simplex virus. More specifically, these experiments presented by the authors revealed that Echinacea amplifies the rhinovirus rather than being antiviral, as it has been shown to be with the vaccinia and herpes simplex viruses.
Several mechanisms of action by which Echinacea may act to amplify rhinovirus were explored. The first investigated its effect with interferon, however, the research suggested that the body’s interferon response is not inhibited by the introduction of the E. purpurea root water extract. The next theory was that perhaps E. purpurea works by way of acting on apoptosis, however, experimentation showed only a slight reduction rate of cell death suggesting that apoptosis is not its main mechanism of action. The next theory explored the possibility that E. purpurea may act on some intracellular part of the replication process, such as by way of increasing viral RNA and/or protein synthesis. This mechanism was confirmed by way of experimentation, demonstrating that Echinacea root water extract targets both viral RNA and protein synthesis.
The findings of this study suggest that E. purpurea should not be recommended for the treatment of rhinovirus infections. Furthermore, this study echoed the sentiments of the first presentation by stressing the importance of understanding the pharmacognosy of this herb, as E. purpurea inhibits replication of some viruses while enhancing the replication of others.
Rhinovirus inhibitory effects of E. purpurea root ethanol extracts and alkamides
The final presentation covered in this article was delivered by Keely Pulchalski, ND and was also on the topic of the rhinovirus and E. purpurea. This presentation focused on describing the inhibitory effect of a 65% ethanolic Echinacea extract and its plant constituents on the rhinovirus.
Similar to the previous presentation, the authors also did a viral plaque assay to explore the potential effects. Each assay well had a single layer of rhinovirus infected cells. The assay acted as the control, with no introduction of E. purpurea ethanol root extract. The remaining wells were each introduced to E. purpurea ethanol root extract, starting at 5 mL, and each subsequent well increased in titration up to 25 mL. Compared to the control, all Echinacea-treated assays demonstrated some level of inhibition; partial inhibition began at 5 mL and full inhibition occurred at 10 mL and with all of the higher titration assays.
Further research then took place to better understand exactly how E. purpurea inhibits the rhinovirus. This included exploring the different plant constituents of E. purpurea extracted with ethanol, which demonstrated that the root was significantly more effective at inhibiting rhinovirus plaque formation as opposed to its stem, leaf, and flower counterparts. The research indicated that E. purpurea inhibited rhinovirus cell attachment, but only partially. Thus, other antiviral mechanisms were concluded to play a role.
Plaque assays of the five most common caffeic phenolic compounds in E. purpurea (echinacoside, caftaric acid, chlorogenic acid, cichoric acid, and dicaffeoylquinic acid) showed a lack of inhibition on the rhinovirus. Finally, the researchers investigated one of the most commonly known aspects of Echinacea, the alkamides, which are well known for their anesthetic effect on the tongue when ingested. Alkamide C demonstrated inhibition of rhinovirus cell attachment as well as the strongest inhibition of rhinovirus amongst the alkamides. Specifically, it demonstrated partial inhibition of replication at 2 μg/mL and full inhibition at 4 μg/mL in the standard plaque assay and an 80% inhibition at 16 μg/mL in the attachment assay.
The main takeaways from this study include that E. purpurea root ethanolic extract inhibits rhinovirus in vitro. However, not all constituents of E. purpurea are strong antivirals as all of the caffeic acid derivatives failed to demonstrate viral inhibition in this experiment. Alkamides, on the other hand, demonstrated antiviral activity, with notably varying degrees amongst them. Specifically, alkamide C leads as the alkamide with strongest antiviral activity against rhinovirus with partial inhibition by way of acting on the attachment or binding phase of the rhinovirus life cycle and full inhibition demonstrated at 4 μg/mL in the standard plaque assay. Future and continued research include investigation of the effects of Echinacea on the other aspects of the rhinovirus life cycle such as endocytosis, uncoating and genome release, translation, replication, assembly, and viral release.
The bottom line
SCNM faculty and students continue to make waves in the research community, with the 2021 Fall SCNM Research Night proving to be no exception. The safety of Echinacea was highlighted, as it proves to be an efficacious herb with a variety of properties that change depending on the plant part(s) and extraction method utilized.
Other groundbreaking presentations displayed at this event included the antiviral activity of Artemisia annua and the investigation of its phytochemistry and pharmacognosy. The topic of cannabinoids in Cannabis sativa extracts, including both their identification and quantification, was brought to the table, and the phytochemistry of Achillea millefolium, commonly known as yarrow, and its use in the treatment of metabolic syndrome was reviewed. Even animal research regarding potential botanicals for the prevention of mastitis in cattle was explored during the convention.
With presentations nothing short of fascinating, the community waits with anticipation for the hosting of the 2022 Spring SCNM Research Night.