Access to plant (phyto) medicines to prevent or treat illnesses or health conditions both acute and chronic, is an ethical obligation. Many factors impact on this, including their costs and affordability, their quality and availability in efficacious dosage forms, and how they are regulated

Termed Complementary Medicines in Australia, Herbal Medicinal Products in Europe, Botanical Drugs in the U.S.A, and Natural Health Products (NHP’s) in Aotearoa New Zealand and Canada, the products themselves are all used in some way to support human and animal health. How the population of each country regards and uses them, and what checks and balances governments decide to put on their safety and accessibility, is influenced by relevant legislation.

Plant medicines are however, a complex and diverse group of products. In practice, many countries have more than one regulatory agency (generally that responsible for foods, plus that responsible for medicines), involved in overseeing their compliance to what is often a rather confusing legislative framework.

NHP Regulations In Aotearoa New Zealand

In Aotearoa New Zealand, successive governments have struggled for more than 25 years to develop suitable new legislation to replace the hopelessly outdated 1981 Medicines Act, and bring regulations of medicines and NHP’s into the 21^st century⁽¹⁾.  

The Australia New Zealand Therapeutic Products Agency (ANZTPA) was an attempt initiated by the New Zealand and Australian governments in 1996 to develop a joint trans-Tasman scheme for regulating therapeutic products. Government officials and industry representatives worked for eleven years on the detail of this new agency until 2007, when the New Zealand government postponed further legislation.

The next attempt was the Natural Health and Supplementary Products (NHSP) Bill, on which the government worked from 2011 until dropping it at the end of 2017.

The Therapeutic Products Bill was the third attempt to regulate all medicines and medical devices as well as NHP’s, and was introduced by the current government in November 2022. In July of this year it passed its third reading in the House, and subsequently became the Therapeutic Products Act (2023). Regulations as provided for in the Act are now being developed, and need to be in place by September 2026⁽²⁾.

Regulatory Challenges

The huge plethora and diversity of brands and product types, digital marketing, ongoing incorporation of new technologies and supply chain disruptions, are driving constant changes in the availability of products in the marketplace.

The important issue of sustainability of some medicinal plants used as raw materials, is largely left to companies themselves to commit to, and voluntarily opt into secondary regulatory agencies such as the Union for Ethical Biotrade, EcoCert, Rainforest Alliance, FairWild and B-Corp.

Many medicinal plants are also foods, and well known culinary foods and spices such as beetroot, garlic, ginger and turmeric are incorporated into capsule and tablet dosage forms. Whether something is in fact a food or ‘dietary supplement’, or is actually ‘medicinal’, is a 6 million dollar question which extracts different answers depending on who is asked.

Many companies in the industry have leveraged this situation to their advantage, and the terms ‘dietary supplement’ or ‘food supplement’ are widely used as descriptive terms when selling products. Most plant-based NHP’s are safe and fulfill a nutritive or functional dietary need when taken in small doses as a supplement to the diet. Food regulations, while having some obligations on manufacturers and sponsors, also tend to have a lower regulatory bar and thus cost, than those for medicines.

Language however, and the terminology used to describe something can greatly influence one’s perception. By referring to most NHP’s as supplements rather than as pharmacologically active medicines, their perceived ability in the eyes of many to produce tangible health improvements, is somewhat compromised. In many ways it fosters an impression that NHP’s are pawns, rather than knights or rooks, kings or queens. As such their status or ‘mana’ (a Māori word that signifies the presence or intrinsic influence or power of something), is lessened.

Personally, since training in medical herbalism after several years working as a pharmacist, I’ve always regarded well manufactured and properly used plant extracts as medicines. The name of the company I founded 25 years ago, and the title of this blog, extols this principle.

Taking the right approach is a minefield for regulators though, and it is impossible to please everyone. Many parameters require consideration when trying to distinguish between a food or dietary supplement and a medicine. They include the product potency, therapeutic claims made for it, the medical condition(s) or intended application, the presence or absence of a qualified practitioner’s oversight, and the manufacturing standards and pharmacovigilance systems in place.

In practice, a more tiered and evolved approach to classification of NHP’s, to include categories apart from dietary supplements and medicines alone, would have much merit.

While alcohol is alcohol regardless of the form it is presented in, low alcohol beer and gin are poles apart, in terms of their alcohol content. Their accessibility, packaging, effects on the user and thus safety, therefore also vary significantly. The same enormous diversity exists in strength, efficacy and safety of many NHP’s being produced and sold today.  Logically therefore, as with drug-based medicines, it is appropriate that certain products should only be able to be prescribed, by suitably trained and registered practitioners⁽³⁾.

Appraising traditional preparations versus modern pharmaceutical manufacturing methods for their relative risks, and ensuring evidence is sufficient to support therapeutic claims, are other challenging areas. For this and other regulatory tasks, adequate knowledge and training in NHP’s is an important capability need for the regulator. A well resourced regulator in budgetary and human expertise terms, and one built upon principles of good science, public safety, consultation and accountability, is therefore essential.

Prevention better than a cure

A more preventative and self help approach to personal health is critical to reduce the dual burden on governments and future taxpayers of aging populations and increasing resource needs of mainstream healthcare systems. Evidence suggests a vast number of plants can either enhance our resistance to and reduce our risks of a wide range of illnesses, or reduce our dependence on drug and hospital treatments. However, to utilise them as prophylactic and safe selfcare interventions, research, education, and a regulatory environment that facilitates this, needs to continue.

Additionally though, there is in fact a growing recognition of the ability of plant derived medicines to provide efficacious treatments for a whole host of serious illnesses and diseases for which conventional medicine is struggling to make more headway.  

Treatment of serious conditions

The incorporation of medicinal plants into mainstream healthcare including for serious conditions such as sepsis, post-stroke and kidney failure, has been a part of Chinese medicine for a long time^(4-6). Also in Japan, Germany and other countries, parenteral products are manufactured from plant extracts and licenced with regulatory authorities for the treatment of specific conditions.

Results from a recent clinical trial in China have put the potential role of phytotherapy for the treatment of sepsis into the spotlight, with a significant reduction in mortality being reported following administration of a polyherbal parenteral preparation⁽⁷⁾.  Sepsis is a seriously dysregulated host response to infection, and more than 19 million cases of severe sepsis occur globally each year, leading to at least 5 million deaths⁽⁸⁾.

The study was a multicentre, randomized double-blind, placebo-controlled trial conducted in intensive care units at 45 sites in China. It included 1817 randomized patients aged 18 to 75 years with sepsis present for less than 48 hours, nearly half of whom had septic shock. Patients received either an intravenous infusion of the herbal preparation at a dose of 100 mL or volume-matched saline placebo every twelve hours for five days, alongside usual hospital care in either an ICU or medical ward. The primary outcome was 28-day all-cause mortality.

Of the 1760 patients who completed the trial, the 28-day mortality rate was significantly lower in the treatment than in the control group. Within the herbal and conventionally treated group, 165 of 878 patients (18.8%) had died, whereas in the control group who received conventional treatment alone, 230 of 882 patients (26.1%) had died after 28 days. The incidence of adverse events was very similar in both groups^{(7, 9)}.

With plant extracts containing multiple phytochemicals including some which may impede absorption, achieving adequate bioavailability from their oral administration can sometimes be a challenge, just as it is for some drugs.  Parenteral dosage forms are often life-saving in modern medicine, as intravenous or intramuscular injections can achieve much higher plasma and tissue levels, and thus enable better, faster and a more protracted efficacy to be achieved.

However, as every pharmacist knows, parenteral medicines need to be manufactured using a high level of Good Manufacturing Practice (GMP) standards, far greater than those in place for dietary or food supplements, to avoid serious adverse events or treatment failure that may result in death.

Leveraging the potential of phytotherapy

Studies such as this one, highlight the potential contribution of medicinal plants to modern healthcare, as being a whole lot more than that of ‘dietary supplements’ alone.

It is encouraging to see that in some countries of the world, companies, clinicians, governments and regulators have for some time now been actively embracing and researching new potential applications for their traditional plant medicines, including their parenteral (injectable) use for serious or difficult to treat conditions.

Incorporating these and other medicinal plants into current treatment protocols for serious and expensive to treat conditions such as acute infections, sepsis, diabetes, cancer and mental unwellness, is an ambitious aspiration, but an essential one. Additionally for most of these applications, adequate regulatory oversight and adherence to medicine-manufacturing standards, will also be required.

The current New Zealand government has now passed legislation to replace our hopelessly outdated 1981 Medicines Act, which was no easy task. However, many challenges exist with preparation of the subsequent regulations. These include providing a regulatory model that continues to allow self-selected NHP’s both as a safe self-help intervention, but also recognizes and fosters greater research into their potential applications for the prophylaxis or treatment of more serious conditions, and extends the clinical reach of our many highly trained NHP practitioners.

References:

1. Rasmussen PL, NZ Politicians continue to let the Natural Health Products Industry and Practitioners Down. www.herbblurb.com Jun 19, 2020.
2. https://www.health.govt.nz/our-work/regulation-health-and-disability-system/therapeutic-products-regulatory-regime
3. Rasmussen PL, Statutory regulation of medical herbalists and naturopaths: an essential step towards a more cost and outcome beneficial future healthcare system. www.herbblurb.com 26 April, 2019.
4. Cheng C, Yu X. Research Progress in Chinese Herbal Medicines for Treatment of Sepsis: Pharmacological Action, Phytochemistry, and Pharmacokinetics. Int J Mol Sci. 2021;22(20):11078. 
5. Zhang L, Yang L, Shergis J, et al. Chinese herbal medicine for diabetic kidney disease: a systematic review and meta-analysis of randomised placebo-controlled trials. BMJ Open. 2019;9(4):e025653.
6. Wei M, Wang D, Kang D, et al. Overview of Cochrane reviews on Chinese herbal medicine for stroke. Integr Med Res. 2020;9(1):5-9.
7. Liu S, Yao C, Xie J, et al. Effect of an Herbal-Based Injection on 28-Day Mortality in Patients With Sepsis: The EXIT-SEP Randomized Clinical Trial. JAMA Intern Med. 2023;183(7):647-655.
8. Fleischmann C, Scherag A, Adhikari NK, et al. Assessment of Global Incidence and Mortality of Hospital-treated Sepsis. Current Estimates and Limitations. Am J Respir Crit Care Med. 2016;193(3):259-272
9. Rasmussen PL, Chinese parenteral phytomedicine reduces mortality from sepsis. Pharmacy Today, October 2023. ISSN 1170-1927

Introduction

Many of our native plant medicines have the ability to help in the management of conditions affecting the gastrointestinal tract⁽¹⁾. While these have diverse actions and undoubtedly act on many levels concomitantly to prevent and treat such conditions, their direct effects on the gut microbiome, are likely to be contributory.

The gut microbiome is an intricate and dynamic ecosystem of microbes that is strongly influenced by our environment, diet and genes, and altering it can significantly influence our predisposition to and outcomes from many illnesses. While these extend way beyond gastrointestinal conditions alone^(2,3), the association between modulation of the gut microbiome and digestive health, is of particular interest.

Furthermore, it is these intestinal microbiota that play an important role in both the activation and metabolism of medicinal plant phytochemicals themselves, just as they break down proteins, carbohydrates and fats in foods, to simpler and bioavailable molecules. A diverse and healthy microbiome is thus conducive to ensuring optimal processing and bioavailability of medicinally active phytochemicals, and thus achieving favourable clinical outcomes in phytotherapy.

Probiotics (live microorganisms that when administered in adequate amounts confer a health benefit) are now highly regarded, but we’re also increasingly learning about the important role of prebiotics, in feeding and selectively promoting probiotic growth and human health. These include plant foods such as psyllium, onion, asparagus, garlic, kumara, chicory, Jerusalem artichoke, bananas, beetroot and oats, which provide complex carbohydrates such as inulin and other beneficial fibres to support a healthy gut microbiota and immune system.  Additionally, there seem to be positive contributions made by other specific primary or secondary components of many plants and mushrooms, to the microbiome community and subsequently to health outcomes.

Native plants and the microbiome

Regular ingestion of various herbal teas including green, kuding and baical skullcap teas can exert beneficial effects on the gut microbiota, including an increased number of unique bacterial genera, and changes in the relative abundances of particular species^(4-6). Catechins and insoluble fibre contribute to these benefits, and exert a prebiotic-like effect on gut microbiota⁽⁷⁾. Supplementation with certain tannins has also been found to increase the diversity and abundance of butyrate-producing and probiotic bacteria and metabolism of amino acids⁽⁸⁾. In fact the antioxidant and disease preventative properties of many polyphenolic rich plants, may correlate to some extent with their effects on gut bacterial species⁽⁹⁾.

While research is required, many native plants from Aotearoa New Zealand are very rich in a diverse range of polyphenolic compounds and are likely to also produce similar benefits. While tannins and other larger ones of these have poor oral bioavailability, they can nevertheless facilitate significant changes in the abundance of bacterial species associated with a wide range of health outcomes. The hydrolysis of tannins and flavonoids by gut microbiota is also being increasingly recognised as producing smaller, bioavailable and bioactive metabolites, with many health benefits^{(10, 11)}.

Controlling infections

Antibiotics are widely used to eradicate unwanted bacteria, yet they are generally not very selective, and often produce serious negative impacts on beneficial bacteria and the gut microbiome⁽¹²⁾. Plants with a narrower spectrum of antimicrobial activity and when carefully combined, have the ability to provide a more targeted action, and thus reduced adverse events⁽¹³⁾.   They should therefore be used more as first line treatments for many types of infection, and more research into this as well as their combined use with antibiotics, is urgently needed.

The microbiota is also involved in reducing and preventing colonization by enteric pathogens through the process of competitive exclusion and the production of antimicrobial substances. Plants that enhance this production of bacteriostatic and bactericidal substances by the microbiota, are therefore potential interventions to deal with some pathological infections⁽¹⁴⁾.

Mānuka (Leptospermum scoparium), Kānuka (Kunzea ericoides), Harakeke (Phormium tenax), Horopito (Pseudowintera colorata), Tanekaha (Phyllocladus trichomanoides), Rewarewa (Knightia excelsa) Totara (Podocarpus totara, Rimu (Dacrydium cupressinum) and Pukatea (Laurelia novae-zelandiae), all exhibit good activity against specific pathogens. 

Animal studies are increasingly showing the microbiome to have a positive impact not only on gut physiology, but also the immune system of the host. Part of the mechanism of Echinacea purpurea’s immunomodulatory effects may involve its influences on the gut microbiota, as shown by improvement in immunosuppressed ducks in conjunction with increased abundance of beneficial intestinal bacteria⁽¹⁵⁾.

Antibacterial and antifungal actions are prominent activities of many native plants, and traditional uses for gastrointestinal tract infections, were once common. Tannin rich native species such as Mānuka can treat dysentery and diarrhoea, and most tannins also have intrinsic antibacterial properties. The powerful astringent and antimicrobial effects produced by infusions and hydroethanolic liquid extracts of Mānuka’s leaves and stems, make it a useful component of a treatment for gastrointestinal infections.

In its living state, Mānuka itself has around 200 different bacteria within its leaves, stems and roots, that make up a rich community of endophytes (microorganisms that live within and near plants, in a symbiotic relationship). Several of these bacteria themselves produce antifungal or antibacterial compounds as part of their competitive survival⁽¹⁶⁾. Ingestion of preparations made from its leaves and stems will deliver a range of phytochemicals with the potential to modulate the gut microbiome, and thus provide digestive system benefits. The often symbiotic relationships between endophytes and plants, and those between microbes and humans, appear to have much in common.

Koromiko (Hebe stricta) is another effective remedy used for diarrhoea and dysentery among Māori and European settlers, including by New Zealand soldiers during the Second World War. Rebalancing of different microbial species within the gut, is probably involved in its antidiarrhoeal and anti-inflammatory properties.

Intestinal mucosa tonics

Damage to the integrity of the intestinal biofilm can result in alteration in intestinal permeability, a condition widely described asleaky gut. When this occurs, the immune system can become weak or dysregulated, making conditions such as irritable bowel syndrome or inflammatory bowel disease more likely⁽¹⁷⁾. Ulcerative colitis, Crohns and irritable bowel syndrome are all associated with enhanced secretion of proinflammatory cytokines, poor maintenance of the epithelial barrier, and gut dysbiosis^{(18, 19)}.

Kawakawa (Piper excelsum) is a plant widely used for gastrointestinal inflammation and has many pronounced digestive system benefits^{(20, 21)}. As with other Piperaceae species, influences on gastrointestinal absorption and gut permeability, and vascular barrier protective effects have been shown for Kawakawa and some of its amide constituents, including pellitorine, piperine and piperdardine^{(22, 23)}.  Lignans are also prominent constituents, and given other lignans are known to interact with gut microbiota, microbiomal modulations through these phytochemicals within Kawakawa, may also take place.

Other plants with broad-ranging effects on the digestive system, are Horopito (Pseudowintera colorata) and Akeake (Dodonaea viscosa). Both plants exhibit astringent, anti-inflammatory and some antimicrobial properties which probably impact population levels of some microbiome species in a negative manner, and others in a potentially facilitatory manner. An Indian variety of Dodonaea viscosa has been shown to be gastroprotective in animal studies⁽²⁴⁾, suggesting a potentially useful role in the management of peptic ulcers⁽²⁵⁾.

Polysaccharides

These are another type of secondary metabolite whose oral bioavailability is limited, but are increasingly being recognized for the complex interactions they have with microbes within the gut. These include modulation of the gut microbiota composition itself, metabolism of polysaccharides to short chain fatty acids, and polysaccharide-induced modulation of the production of gut microbiota metabolites such as trimethylamine, tryptophan and lipopolysaccharides⁽²⁶⁾. The widely used Psyllium husk (Plantago ovata), increases faecal water content and improves constipation while increasing populations of butyrate-producing microbiota⁽²⁷⁾. Amelioration of antibiotic-associated diarrhoea has been associated with  a prebiotic effect of polysaccharides from the medicinal fungus Hoelen (Poria cocos)⁽²⁸⁾.

Hoheria (Hoheria populnea), is a native tree whose various different organs are all rich in polysaccharides.  Like Slippery Elm and other polysaccharide hydrocolloid rich plants, Hoheria can help reduce symptoms of dyspepsia or gastritis when taken either as an infusion or hydroethanolic liquid extract. As with many other polysaccharide-rich plants or medicinal fungi, beneficial effects on the gut microbiome, also seem likely.

Bitters

Medical herbalists are generally taught that it is the stimulatory effects of bitter-tasting plants on every component of the gastrointestinal system, which accounts for their many beneficial and tonic like actions on digestive processes and thus overall health. We now also know that activation of bitter receptors is involved in the regulation of appetite, insulin sensitivity, airway innate immunity, and other physiological processes. The ability of bitter tasting plants and their inclusion in the diet or regular herbal tonics to positively influence the gut microbiome community, is being increasingly revealed^(29-31).

Native plants such as Kohekohe (Dysoxylum spectabile) and Tanekaha make excellent bitter substitutes to classical European bitters such as Gentian and Wormwood.  These are also likely to have complex but beneficial actions on the gut microbiome.

Summary

Humans have a wide variation in the makeup of their gut microbiome.  This potentially results in variations in microbial metabolism of many phytochemicals, and thus the resulting therapeutic activities of medicinal plants. The relationships between plants and microbes works in both directions though, and there are a multitude of ways in which the ingestion of many plants can produce health benefits through influencing the functions of these bacteria found without our gastrointestinal tract.

While we are only just starting to understand elements of the complex human gut microbiome, it seems certain to provide innovative targets for the incorporation of plants native to Aotearoa New Zealand, to help prevent and treat several gastrointestinal conditions.

References:

1. Rasmussen PL. Treating digestive conditions using New Zealand native plants. Phytomed seminar, October 2009.
2. Miyauchi E, Shimokawa C, Steimle A, Desai MS, Ohno H. The impact of the gut microbiome on extra-intestinal autoimmune diseases. Nat Rev Immunol. 2023;23(1):9-23
3. Sasso JM, Ammar RM, Tenchov R, et al. Gut Microbiome-Brain Alliance: A Landscape View into Mental and Gastrointestinal Health and Disorders. ACS Chem Neurosci. 2023;14(10):1717-1763.
4. Morishima, S., Kawada, Y., Fukushima, Y., Takagi, T., Naito, Y., & Inoue, R. (2023). A randomized, double-blinded study evaluating effect of matcha green tea on human fecal microbiota. Journal of clinical biochemistry and nutrition, 72(2), 165–170.
5. Vamanu E, Dinu LD, Pelinescu DR, Gatea F. Therapeutic Properties of Edible Mushrooms and Herbal Teas in Gut Microbiota Modulation. Microorganisms. 2021;9(6):1262. 
6. Shen J, Li P , Liu S , et al. The chemopreventive effects of Huangqin-tea against AOM-induced preneoplastic colonic aberrant crypt foci in rats and omics analysis [published correction appears in Food Funct. 2021 Mar 15;12(5):2336-2337.
7. Thumann, T. A., Pferschy-Wenzig, E. M., Aziz-Kalbhenn, H., Ammar, R. M., Rabini, S., Moissl-Eichinger, C., & Bauer, R. (2020). Application of an in vitro digestion model to study the metabolic profile changes of an herbal extract combination by UHPLC-HRMS. Phytomedicine : international journal of phytotherapy and phytopharmacology, 71, 153221.
8. Correa PS, Mendes LW, Lemos LN, et al. Tannin supplementation modulates the composition and function of ruminal microbiome in lambs infected with gastrointestinal nematodes. FEMS Microbiol Ecol. 2020;96(3):fiaa024.
9. Morisette A, Kropp C, Songpadith JP, et al. Blueberry proanthocyanidins and anthocyanins improve metabolic health through a gut microbiota-dependent mechanism in diet-induced obese mice. Am J Physiol Endocrinol Metab. 2020;318(6):E965-E980.
10. Sallam IE, Abdelwareth A, Attia H, et al. Effect of Gut Microbiota Biotransformation on Dietary Tannins and Human Health Implications. Microorganisms. 2021;9(5):965.
11. Marín L, Miguélez EM, Villar CJ, Lombó F. Bioavailability of dietary polyphenols and gut microbiota metabolism: antimicrobial properties. Biomed Res Int. 2015;2015:905215.
12. Patangia DV, Anthony Ryan C, Dempsey E, Paul Ross R, Stanton C. Impact of antibiotics on the human microbiome and consequences for host health. Microbiologyopen. 2022;11(1):e1260.
13. Chou, S., Zhang, S., Guo, H., Chang, Y. F., Zhao, W., & Mou, X. (2022). Targeted Antimicrobial Agents as Potential Tools for Modulating the Gut Microbiome. Frontiers in microbiology, 13, 879207.
14. Clavijo, V., & Flórez, M. J. V. (2018). The gastrointestinal microbiome and its association with the control of pathogens in broiler chicken production: A review. Poultry science, 97(3), 1006–1021.
15. Lin R, Zhi C, Su Y, et al. Effect of Echinacea on gut microbiota of immunosuppressed ducks. Front Microbiol. 2023;13:1091116
16. Wicaksono WA, Jones EE, Monk J, Ridgway HJ. The Bacterial Signature of Leptospermum scoparium (Mānuka) Reveals Core and Accessory Communities with Bioactive Properties. PLoS One. 2016;11(9):e0163717.
17. Fukui H. Increased Intestinal Permeability and Decreased Barrier Function: Does It Really Influence the Risk of Inflammation?. Inflamm Intest Dis. 2016;1(3):135-145.
18. Wu X, Chen H, Gao X, Gao H, He Q, Li G, Yao J, Liu Z. Natural Herbal Remedy Wumei Decoction Ameliorates Intestinal Mucosal Inflammation by Inhibiting Th1/Th17 Cell Differentiation and Maintaining Microbial Homeostasis. Inflamm Bowel Dis. 2022 Jul 1;28(7):1061-1071.
19. Aldars-García L, Chaparro M, Gisbert JP. Systematic Review: The Gut Microbiome and Its Potential Clinical Application in Inflammatory Bowel Disease. Microorganisms. 2021;9(5):977.
20. Rasmussen, P.L., Kawakawa: a monograph. Phytonews, published by Phytomed Medicinal Herbs Ltd, 7, 1-7, Sept 2000. ISSN 1175-0251
21. Rasmussen, P.L., Kawakawa: a promising New Zealand native plant. Pharmacy Today, August 2021. ISSN 1170-1927
22. Lee W, Ku SK, Min BW, et al. Vascular barrier protective effects of pellitorine in LPS-induced inflammation in vitro and in vivo. Fitoterapia. 2014;92:177-187.
23. Obst K, Lieder B, Reichelt KV, et al. Sensory active piperine analogues from Macropiper excelsum and their effects on intestinal nutrient uptake in Caco-2 cells. Phytochemistry. 2017;135:181-190.
24. Arun M, Asha VV. Gastroprotective effect of Dodonaea viscosa on various experimental ulcer models. J Ethnopharmacol. 2008;118(3):460-465.
25. Rasmussen PL, NZ Native Plants: Part 2. Webinar, by Phytomed Medicinal Herbs Ltd, October 2018.
26. Zhang D, Liu J, Cheng H, et al. Interactions between polysaccharides and gut microbiota: A metabolomic and microbial review. Food Res Int. 2022;160:111653.
27. Jalanka J, Major G, Murray K, et al. The Effect of Psyllium Husk on Intestinal Microbiota in Constipated Patients and Healthy Controls. Int J Mol Sci. 2019;20(2):433.
28. Xu H, Wang S, Jiang Y, et al. Poria cocos Polysaccharide Ameliorated Antibiotic-Associated Diarrhea in Mice via Regulating the Homeostasis of the Gut Microbiota and Intestinal Mucosal Barrier. Int J Mol Sci. 2023;24(2):1423. 
29. Xiong X, Cheng Z, Wu F, et al. Berberine in the treatment of ulcerative colitis: A possible pathway through Tuft cells. Biomed Pharmacother. 2021;134:111129.
30. Zhao, A., Jeffery, E. H., & Miller, M. J. (2022). Is Bitterness Only a Taste? The Expanding Area of Health Benefits of Brassica Vegetables and Potential for Bitter Taste Receptors to Support Health Benefits. Nutrients, 14(7), 1434
31. Ye JH, Fang QT, Zeng L, et al. A comprehensive review of matcha: production, food application, potential health benefits, and gastrointestinal fate of main phenolics [published online ahead of print, 2023 Apr 3]. Crit Rev Food Sci Nutr. 2023;1-22.

Plants are incredibly clever organisms in having evolved over millions of years and survived predatory pressures, severe climatic events and ecological stressors, largely through their ability to produce and utilise chemicals. These compounds, known as phytochemicals or secondary metabolites, are the essence of phytopharmacology, the medicinal actions of plants.

We as humans are fortunate in being able to also benefit from this foresight by plants, as many of these secondary metabolites help to protect against and treat disease and ill health in humans, as well as slow down our aging processes.

Many drugs or single chemical entities with pharmacological activities have been developed from plants, and we know that individual phytochemicals such as morphine, atropine and digoxin are very potent medicines.  Also how these and most if not all other ‘active’ phytochemicals initiate their actions through modulating receptors and numerous physiological processes throughout our bodies.

However, for the majority of plants used medicinally, there exists little scientific knowledge about their phytochemistry, and what so-called ‘active constituents’, contribute to their therapeutic properties. There are exceptions to this, particularly those plants which have achieved high levels of usage or attracted significant research interest. For some of these, we now have an understanding from traditional knowledge as well as science, that most and probably all phytomedicines contain more than one or even numerous active constituents present. Also that within each individual plant some form of natural synergy between phytochemicals takes place in relation to bioactivity, pharmacokinetic and/or safety profiles.

Purification of many plant constituents often leads to a reduced intestinal absorption after oral administration. The presence of co-existing constituents including primary (carbohydrates, lipids, amino acids etc) and other secondary metabolites can often promote gastrointestinal absorption of pharmacologically active constituents by improving solubility, modulating the gut microbiome, increasing enterocyte membrane permeability, inhibiting liver metabolism, or promoting the formation of active metabolites⁽¹⁾.  

Drug discovery and bioprospecting is often about trying to separate a plant’s phytochemistry in to pieces, in an attempt to unmask a single ‘active constituent’, and subsequently purify and synthesise it or a chemically related potent derivative. In fact the published and undoubtedly much unpublished research field is littered with instances in which despite scientists doing their utmost to split medicinal plant extracts into different fractions, and from there work hard to further narrow down and finally identify the ‘active constituent’, it remains as elusive as the Holy Grail.

A recent study into the cytotoxicity and antimicrobial activities of Echinacea purpurea for example, which attempted to identify key active compounds, found the highest antimicrobial activity was shown by dichloromethane, ethyl acetate, and acetone extracts of the herb, whereas dichloromethane and n-hexane extracts showed the highest cytotoxic activity⁽²⁾. These extracts were therefore fractionated, and the obtained fractions also assessed for potency as cytotoxics. However, and to the perplexity of the researchers, when the cytotoxicity and bioactivity of these purified fractions was compared to those of the original ‘crude’ extracts, the original extracts were still superior, and showed greater bioactivity. This indicated the existence of a possible synergistic effect of different compounds in the whole extracts⁽²⁾.

Such findings are in fact commonplace in phytomedicine research. Of note is that despite what surely must have been billions of dollars of expenditure by pharmaceutical company researchers to date into identifying the active antidepressant constituent within the highly acclaimed plant St Johns Wort (Hypericum perforatum), it has yet to be revealed. 

Standardised extracts:

There are therefore many potential pitfalls with placing too much emphasis on individual phytochemicals when appraising the therapeutic properties of plant medicines, and the boundary between what is a natural or ‘whole extract’ rather than single chemical entity-based medicine, is often a shifting one. Risks include the usually unknown efficacy consequences of not having other types of secondary metabolites or facilitatory ‘team players’ present as occurs in nature, possible safety concerns, and erring excessively down a slippery slope towards the product becoming more like a drug rather than a herbal medicine.  As with other forms of medicine, there are also instances where commercial interests or poor science has highlighed specific phytochemicals as being essential for good clinical outcomes, with little evidence provided.

Despite these cautionary comments, it is often the relative richness or content of particular phytochemicals in a batch of herbal medicine, that largely determines whether the treatment is effective or not, and it can therefore be an important indicator of quality.

Echinacea

Traditional use of both Echinacea purpurea and Echinacea angustifolia is based upon the root, yet when products based upon these north American native plants (and in particular E. purpurea) began to be commercialized, the principle plant part utilized by some companies, became the whole plant or flowering aerial parts.

Alkylamides (alkamides) on the other hand, are now regarded as the major bioavailable and active components in oral forms of Echinacea(^3,4,5), and highest levels of these are found in the traditionally used root, and not the cheaper flowering tops^(6,7,8). Alkylamide-enriched extracts also show the strongest anti-inflammatory activity^(9,10) and have the ability to both dampen down an over-activated immune system in certain situations, as well as enhance its infection prophylactic ability, in others ^{(11, 12)}.

For many years and still today with some companies, measurements of ‘total phenolics’ in echinacea have been used as an apparent indicator of quality, and by implication therefore, of the immunomodulatory and anti-inflammatory actions for which Echinacea is best known. Given that the assay for total phenolics incorporates a wide range of phytochemicals with a simple or polyphenolic structure, including flavonoids, tannins, cichoric and caftaric acid, and that many of these exhibit poor oral bioavailability and have not been strongly associated with Echinacea’s principle actions, this analytical method appears to have little relevance to the relative quality or potency, of most Echinacea extracts.

The immunomodulatory and anti-inflammatory effects of alkylamides, have been shown to be dose-related in many studies. This fact, combined with traditional use involving doses of up to 30 grams of root in some cases, reinforces the importance of taking adequate amounts of these key tongue-tingling compounds and thus using products that have a guaranteed alkylamide content, wherever possible.

Echinacea extracts have also been shown to modulate endogenous cannabinoid receptors, and alkylamides have again been strongly associated with these effects^(13-14). As with research into the anti-inflammatory properties of Echinacea, recent studies support potential applications for peripheral inflammatory pain such as arthritis and burns, again reflecting the traditional uses of these plants by indigenous north Americans. Other investigations have found Echinacea purpurea root extracts to improve insulin resistance, enhance glucose uptake in adipocytes and activate peroxisome proliferator-activated receptor γ, with alkylamides being contributory^{(15, 16)}.

The complex interactions of bacteria and fungi (endophytes) living symbiotically with Echinacea in its natural state, and their possible modulation of the gut microbiome, is another new area of investigation^{(17, 18)}.

Receptor binding studies involving both crude plant extracts and phytochemically-rich fractions or individual phytochemicals, will continue to reveal more about mechanism(s) of action of our medicinal plants in the future, as well as inform us about ‘new’ (but often simply forgotten), potential applications in clinical practice.

References

1. Zhao, Q., Luan, X., Zheng, M., Tian, X. H., Zhao, J., Zhang, W. D., & Ma, B. L. Synergistic Mechanisms of Constituents in Herbal Extracts during Intestinal Absorption: Focus on Natural Occurring Nanoparticles. Pharmaceutics, 2020;12(2), 128.
2. Coelho, J., Barros, L., Dias, M. I., Finimundy, T. C., Amaral, J. S., Alves, M. J., Calhelha, R. C., Santos, P. F., & Ferreira, I. C. F. R. (2020). Echinacea purpurea (L.) Moench: Chemical Characterization and Bioactivity of Its Extracts and Fractions. Pharmaceuticals (Basel, Switzerland), 13(6), 125.
3. Dietz B, Heilmann J, Bauer R. Absorption of dodeca-2E,4E,8Z,10E/Z-tetraenoic acid isobutylamides after oral application of Echinacea purpurea tincture. Planta Med. 2001;67(9):863-864. 
4. Goel V, Chang C, Slama JV, et al. Alkylamides of Echinacea purpurea stimulate alveolar macrophage function in normal rats. Int Immunopharmacol. 2002;2(2-3):381-38.
5. Jager H, Meinel L, Dietz B, et al. Transport of alkamides from Echinacea species through Caco-2 monolayers. Planta Med. 2002;68(5):469-471.
6. Stevenson LM, Matthias A, Banbury L, et al. Modulation of macrophage immune responses by Echinacea. Molecules. 2005;10(10):1279-1285. 
7. Bauer R, Remiger P. TLC and HPLC Analysis of Alkamides in Echinacea Drugs1,2. Planta Med. 1989;55(4):367-371.Qu L, Chen Y, Wang X, Scalzo R, Davis JM. Patterns of Variation in Alkamides and Cichoric Acid in Roots and Aboveground Parts of Echinacea purpurea (L.) Moench. HortScience. 2005;40(5):1239-1242.
8. Woelkart K, Koidl C, Grisold A, et al. Bioavailability and pharmacokinetics of alkamides from the roots of Echinacea angustifolia in humans. J Clin Pharmacol. 2005;45(6):683-689.
9. Gulledge TV, Collette NM, Mackey E, et al. Mast cell degranulation and calcium influx are inhibited by an Echinacea purpurea extract and the alkylamide dodeca-2E,4E-dienoic acid isobutylamide. J Ethnopharmacol. 2018;212:166-174. 
10. LaLone CA, Rizshsky L, Hammer KD, et al. Endogenous levels of Echinacea alkylamides and ketones are important contributors to the inhibition of prostaglandin E2 and nitric oxide production in cultured macrophages. J Agric Food Chem. 2009;57(19):8820-8830.
11. Vieira SF, Gonçalves VMF, Llaguno CP, et al. On the Bioactivity of Echinacea purpurea Extracts to Modulate the Production of Inflammatory Mediators. Int J Mol Sci. 2022;23(21):13616.
12. Rasmussen PL, Effects of Echinacea on virus induced Cytokines. Phytonews 24, 2006,Feb. Published by Phytomed Medicinal Herbs Ltd, Auckland, New Zealand. ISSN 1175-0251.
13. Liu R, Caram-Salas NL, Li W, Wang L, Arnason JT, Harris CS. Interactions of Echinacea spp. Root Extracts and Alkylamides With the Endocannabinoid System and Peripheral Inflammatory Pain. Front Pharmacol. 2021;12:651292.
14. Gholami M, Amri J, Pazhoohan S, Sadegh M. Anticonvulsive and anti-epileptogenesis effects of Echinacea purpurea root extract, an involvement of CB2 receptor. J Complement Integr Med. 2021;19(4):879-886.
15. Kotowska, D., El-Houri, R. B., Borkowski, K., Petersen, R. K., Fretté, X. C., Wolber, G., Grevsen, K., Christensen, K. B., Christensen, L. P., & Kristiansen, K. (2014). Isomeric C12-alkamides from the roots of Echinacea purpurea improve basal and insulin-dependent glucose uptake in 3T3-L1 adipocytes. Planta medica, 80(18), 1712–1720.
16. Choi, K. M., Kim, W., Hong, J. T., & Yoo, H. S. (2017). Dodeca-2(E),4(E)-dienoic acid isobutylamide enhances glucose uptake in 3T3-L1 cells via activation of Akt signaling. Molecular and cellular biochemistry, 426(1-2), 9–15. 
17. Todd DA, Gulledge TV, Britton ER, et al. Ethanolic Echinacea purpurea Extracts Contain a Mixture of Cytokine-Suppressive and Cytokine-Inducing Compounds, Including Some That Originate from Endophytic Bacteria. PLoS One. 2015;10(5):e0124276. 
18. Maggini, V., Bettini, P. P., Fani, R., Firenzuoli, F., & Bogani, P. (2023). Echinacea purpurea microbiota: bacterial-fungal interactions and the interplay with host and non-host plant species in vitro dual culture. Plant biology (Stuttgart, Germany), 25(2), 246–256.Gerstmeier J, Seegers J, Witt F, et al. Ginkgolic Acid is a Multi-Target Inhibitor of Key Enzymes in Pro-Inflammatory Lipid Mediator Biosynthesis. Front Pharmacol. 2019;10:797.

written by Phil Rasmussen

Introduction

Ensuring the sustainability of medicinal plants and thus their availability to humans to treat illness and disease in the future, is imperative. With the global market for herbs and botanicals continuing to grow, we need to understand where and how they are sourced, before ending up as an ingredient in a ‘dietary supplement’, natural health product or practitioner-prescribed formulation, waiting for us to ingest or apply them.

As most medicinal herbs are currently collected from their natural habitat in the wild (‘wildcrafted’) rather than from cultivated sources, understanding more about what is happening in these natural habitats, and how the health of each species is tracking, is important.  Apart from harvesting practices used for personal use or the medicinal plant trade, factors such as urban sprawl or conversion of natural landscapes to agriculture or forestry, and climate change, can impact on the abundance of plant species.

While various studies have considered each of these factors in isolation in relation to particular species, few have taken a widespread lens and attempted to quantify the contribution of each, in trying to understand and project the impact of humans on the health and population levels of medicinal plants over an extended period of time. 

Natal lily

Clivia miniata, known as Natal lily or bush lily, is a popular plant in its native South Africa and Swaziland, being widely used as a medicine especially by indigenous communities. Clivia is also a highly sought after ornamental plant with attractive and long-lasting flowers, and there are many different cultivars now available through nurseries in many countries.

One of its most popular traditional uses in southern Africa, is as an aid to induce or augment childbirth through an apparent oxytocin-like effect. Effects on uterine contractions have also been shown in animal studies^{(1, 2)}. Other traditional uses include to treat fevers, snake bites, infertility, and urinary tract infections. Phytochemicals with potential anti-diabetic activity have been characterized⁽³⁾, and anticholinesterase effects (implicating potential anti-dementia properties) have been reported for some of its alkaloids⁽⁴⁾. Crude extracts of the roots and leaves also exhibit antiviral activity against poliomyelitis, Coxsackie, Semliki forest, herpes and measles viruses^{(5, 6)}, with an alkaloid lycorine, being contributory. Potential activity against HIV, has also been suggested ⁽⁷⁾.

Under threat

Natal Lily is a highly traded plant in medicine markets in South Africa, and in 2008 it was assessed by the South African National Biodiversity Institute (SANBI) as a “vulnerable” species, after data revealed its population had declined by an estimated 40% over the previous 90 years⁽⁸⁾. The Red List of SANBI in 2016, lists Clivia miniata as in danger of extinction and now rarely occurring in its ecological niches⁽⁹⁾. Furthermore, high volumes in trade, plant scarcities and shortages have been reported by traders in several regional medicinal plant markets.

In order to better understand the response of Clivia miniata to individual and multiple pressures on its survival, a multidisciplinary team of scientists from South Africa, the UK and USA, recently simulated its future range and abundance by modelling the impact of different scenarios of climate change, changes in land cover, and harvesting practices⁽⁷⁾. All pressures were considered in isolation and in combination, to predict future population trends.

Study methods

The effects of climate change, were modelled based upon two scenarios from the Intergovernmental Panel on Climate Change (IPCC). One assumed the increase in global annual greenhouse gas emissions peaked between 2010–2020 and is now declining substantially, resulting in a projected global mean temperature rise of 0.4° to 1.7°C by the end of the century relative to 1850. The other scenario assumed that emissions continue to rise throughout the 21st century and the global mean temperature rises by 2.6° to 4.8°C.

For the influence of changes in land use, they used two different scenarios. One assumed a halt in the expansion of agricultural land and urban areas that has encroached upon Clivia miniata’s habitats, and that farming intensifies in existing agricultural areas only in order to meet future food demand. The other scenario extrapolated from recent trends in land cover change in which cropland and urban land cover gradually replace suitable habitat in proximity to existing locations.

Each of these scenarios was incorporated into a species distribution model and subsequently a metapopulation model, to assess and predict future population densities and extinction risks for the plant over the next 30 years. Habitat suitability was projected for each year between 2015 and 2055, and for each climate scenario used, habitat suitability maps were produced.

Two different harvesting scenarios were used, one based upon the harvest of juvenile plants only (representing the preference of traders for these, which have a lower water content than older plants), and the other which assumed that traders do not discriminate and demand plant material from all life stages equally.

An assumption was also made that harvesting only took place where the plant population size was at least 50 individuals. This relied upon continuation of traditional harvesting practices, in which only a small proportion of the available plant biomass from each location was harvested each time (five plants every second year) to allow time for recovery, and that a minimum population size of 50 plants was set to make harvest viable. This also assumed that smaller populations were more difficult to locate and were therefore visited and harvested less frequently..

Outcomes:

All of the different scenarios used, pointed to continuing declines in suitable habitat and abundance of Clivia miniata by the 2050’s.

Somewhat surprisingly, harvesting in isolation had the least impact, although it is important to note that each scenario was based upon limitations on the number of plants that could be harvested from each population per year. However, harvesting of plants from all stages resulted in a faster decline in abundance than extracting only juvenile plants.  

Each climate change scenario reduced the mean suitable habitat area by around 14%, driven by increasing temperatures and decreasing precipitation. However, not all scenarios caused a consistent decline, with some scenarios leading to an increase in suitable habitat area before a reduction of around 20% (relative to the start of the simulation) by 2050.

Land use change however, caused a substantially higher loss of suitable habitat area with more than 61% relative to the initial conditions. When combined with climate change scenarios, the suitable habitat area declined by 71 to 73%.

While the researchers tried to ascertain whether the interactions between these different pressures on the species were synergistic, additive, or antagonistic, no clear conclusions could be drawn.

Considering pressures independently, the future loss of suitable habitat was mainly driven by land cover change. In many countries including South Africa, conversion from a natural environment to farming for food production or forestry is a significant contributor; in others it is urban drift and increased construction of houses, towns and cities. Once land cover has changed, land is usually permanently lost to the species. This is in line with previous studies that established land cover change as a major threat to biodiversity over the next decades^{(10, 11)} .

Summary

This systematic study by a team of experienced and renowned researchers from South Africa and the UK, found that ongoing inadequate management of populations of Clivia miniata in the wild will have negative consequences on the wellbeing of people relying on it for medicine, and the many others for whom harvesting and trading in it, is a source of income.

While traditional and measured harvesting practices had minimal impact on future populations of the plant, the researchers modeled this on relatively modest and respectful harvest yields. It should be noted that for many at risk species now, harvesting practices are sometimes poorly undertaken and poorly regulated, such as taking plants at all stages of growth, in the case of Clivia miniata. Increasing pressure from land use change, is also likely to further contribute to declines in medicinal plant populations.  

Also, this study focused on a single medicinal plant, known to be relatively hardy and relatively resilient to climate change, but how wild populations of the thousands of other medicinal plants will fare in the face of global warming and increasing human encroachment on their natural environments, remains largely unknown. Much more research, is clearly needed.

A key message from this study is that greater efforts to introduce more cultivation of medicinal plants, are urgently needed.  However, a key comment I noted when reviewing this study, was a statement by the authors that efforts to cultivate had failed to date due to lack of commercial or government institutional support. Without commenting on the relative wealth or funding availability for such agronomy research in South Africa, I suspect that this hurdle is probably a factor in many other countries, particularly those with a relatively low GDP. To me it reiterates the importance of ensuring adequate attention including funding for cultivation trials over several years, in order to achieve the step change we probably need to move from an over-dependence on wildcrafted plants.  Such a change will need a collaborative combination of support and planning by governments or local regional development institutions and communities. Adequate funding and support from both the industry and other stakeholders is required over several years, to research and develop, viable and sustainable cultivation methods.

Finally, while considering the sustainability of an individual species in its native or original habitat is really important, in reviewing this study I realized that I have a couple of plants of Clivia miniata that have flourished in a semi-shady area of my garden for more than 20 years, despite receiving virtually no human attention. This reminded me yet again, that plants that may be increasingly at risk in the natural environment of one country or where they originally evolved, may be much less at risk and potentially even noxious or become ‘weedy’, in others.

References:

1. Veale DJ, Oliver DW, Arangies NS, Furman KI. Preliminary isolated organ studies using an aqueous extract of Clivia miniata leaves. J Ethnopharmacol. 1989;27(3):341-346.
2. Veale DJ, Oliver DW, Havlik I. The effects of herbal oxytocics on the isolated “stripped” myometrium model. Life Sci. 2000;67(11):1381-1388.
3. Pereira ASP, den Haan H, Peña-García J, Moreno MM, Pérez-Sánchez H, Apostolides Z. Exploring African Medicinal Plants for Potential Anti-Diabetic Compounds with the DIA-DB Inverse Virtual Screening Web Server. Molecules. 2019;24(10):2002.
4. Hirasawa Y, Tanaka T, Hirasawa S, et al. Cliniatines A-C, new Amaryllidaceae alkaloids from Clivia miniata, inhibiting Acetylcholinesterase. J Nat Med. 2022;76(1):171-177. 
5. Ieven M, et al. Planta Med 1979; 36, 311.
6. Ieven M, Vlietinck AJ, Vanden Berghe DA, et al. Plant antiviral agents. III. Isolation of alkaloids from Clivia miniata Regel (Amaryllidaceae). J Nat Prod. 1982;45(5):564-573.
7. Groner VP, Nicholas O, Mabhaudhi T, et al. Climate change, land cover change, and overharvesting threaten a widely used medicinal plant in South Africa. Ecol Appl. 2022;32(4):e2545. doi:10.1002/eap.2545.
8. http://redlist.sanbi.org/species.php?species-2081-5
9. Redlist of South African Plants. 2016. http://redlist.sanbi.org/stats.php
10. Jewitt, D , Goodman P. S, Erasmus B. F. N, O’Connor T. G, and Witkowski E. T. F.. 2015. “Systematic Land‐Cover Change in KwaZulu‐Natal, South Africa: Implications for Biodiversity.” South African Journal of Science 111(9–10): 1–9. 
11. Pereira, H. M. , Leadley P. W., Proença V., Alkemade R., Scharlemann J. P. W., Fernandez‐Manjarrés J. F., Araújo M. B., et al. 2010. “Scenarios for Global Biodiversity in the 21st Century.” Science 330(6010): 1496–501.

written by Phil Rasmussen

Post-viral fatigue is emerging as a frequent problem, with a somewhat alarming proportion of Covid-19 patients experiencing ongoing symptoms and especially fatigue for several weeks or months after recovery from the acute infection.  Due to high rates of infection with the SARS-CoV-2 (Covid-19) as well as influenza and other viruses such as respiratory syncytial virus in Aotearoa New Zealand this year, complaints of a slow or incomplete recovery have been running high.

Exact definitions of ‘Long Covid’ (Post-Covid Syndrome or Post Acute Covid syndrome) remain elusive and continue to be evaluated and debated^{(1, 2)}. The term “Post Covid Conditions” is possibly a better reflection of the diversity of how the delayed recovery syndrome(s) presents in different individuals. However, Long Covid is commonly used to describe signs and symptoms that continue or appear at least four weeks after an acute Covid-19 infection, and that weren’t present beforehand. While most people make a full recovery within twelve weeks, some continue to have symptoms beyond this period^{(3, 4)}. These are hugely variable and still not completely characterised, but fatigue is most common. Other symptoms include ongoing shortness of breath, cough, chest pain, headache, loss of smell, muscle aches and decreased mental and cognitive abilities, including problems with memory and concentration.

Those who have had relatively severe cases of the acute illness or had at least one pre-existing medical condition, seem more likely to develop post-infective syndromes.  Emerging evidence also suggests that gender may also be a factor, with women being more likely than men to experience Long-Covid complications such as fatigue and depression^(5-7). The elderly, Māori and Pasifika people also seem more at risk, given they are at higher risk of contracting serious forms of Covid-19 initially, as are those with type 2 diabetes. Cognitive and cardiovascular complications are also more likely to manifest in these population groups. However, residual Post-Covid symptoms can affect people at all levels of disease severity, even younger adults, children, and those not hospitalized.

Fatigue, brain fog and headaches

Fatigue and ‘brain fog’, headache, cognitive impairment and sleep disturbances, are some of the most disturbing manifestations of long Covid, and can affect the ability to undertake normal daily activities. Apart from anecdotal reports and personal experiences, accumulating data suggests a high prevalence of such prolonged neurological symptoms following an acute Covid-19 infection ^(8-10).

A recent meta-analysis of 68 studies found that 32% of patients experienced fatigue, twelve or more weeks after Covid-19 diagnosis; a meta-analysis of 43 studies found 22% complained of cognitive impairment⁽³⁾. Elevated levels of inflammatory cytokines and other markers, and significant functional impairment, is also seen in a proportion of individuals. While some of these studies may have over-estimated the extent of these symptoms due to the lack of appropriate comparator groups, they paint an alarming picture⁽¹¹⁾.

Long Covid headache can present either through the worsening of a pre-existing primary headache, or, more commonly, as a new intermittent or daily headache starting during the acute infection or soon afterwards. It often accompanies other long Covid symptoms such as loss of the sense of smell. It can be migrainous in type, but is more often a tension-type headache⁽⁹⁾.

Residual symptoms and feelings of fatigue are nothing new when it comes to the post-viral infection period, with long Covid symptoms being similar to those seen in myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS)⁽²⁾. This is a chronic multi-system illness characterized by profound fatigue, sleep disturbances, neurocognitive changes and feeling unwell after exercise which occurs in the absence of any significant clinical or laboratory findings^(12-14). Although not exclusively considered a post-infectious entity, ME/CFS has been associated with several infectious agents including Epstein-Barr Virus, Q fever, influenza, and other coronaviruses^{(15, 16)}.

An Australian study reported prolonged illness characterised by disabling fatigue, musculoskeletal pain, neurocognitive difficulties, and mood disturbance in 12% of Australian patients at 6 months following acute infection with Epstein-Barr virus (glandular fever), Q fever or Ross River virus⁽¹⁷⁾.

Multiple pre-disposing and pathophysiological factors seem to be involved.  The incredibly complex cross talk between numerous components of the nervous system and immune system functions, and the ability of viruses including Covid-19 to cross the blood brain barrier, are undoubtedly contributory.

Given the increase in mental unwellness and anxiety associated with the many impacts of the Covid-19 pandemic over the past nearly three years, accompanying issues such as insomnia, cognitive deficits and fatigue, are to be expected. Prolonged or poorly managed stress, can also lead to burnout, fatigue, and cognitive issues such as poor memory and anxiety or depression.

The role of inflammation including neuroinflammation in the symptomatology of many viral infections and involvement of the gut microbiome to immune functions and chronic inflammatory conditions, are only now starting to be better understood. Just as the so-called ‘cytokine storm’ can cause severe symptoms in acute Covid-19 infections, elevated levels of inflammatory cytokines in the cerebrospinal fluid⁽¹⁸⁾ and the presence of damaging autoantibodies or ongoing dysregulation of the immune system, may lead to chronic inflammation and long term effects on tissues the brain, lungs and heart. An association between Covid-19 infection and demyelination in both the peripheral and central nervous systems, has also been implicated⁽¹⁹⁾.

Management

The presence of ongoing fatigue and poor health following a Covid-19 infection can be very distressing. Social media and the state of the world at times, sometimes also doesn’t help.

However recovery time from many illnesses is often protracted, and adequate rest, good nutrition, and healthy sleep routines, are integral to making a steady recovery. Eating nutritious foods with lots of vegetables, and trying to exercise regularly even if only gentle activities are possible to build up stamina and strength, can really help.  Full recovery will usually take longer if there were pre-existing health challenges such as cardiovascular or respiratory tract conditions, if the person is elderly or their cognition was already somewhat compromised, or they were experiencing a significant amount of stress prior to being infected.

Typical conventional treatment interventions involve the use of analgesics and anti-inflammatories such as paracetamol, ibuprofen and other NSAID’s, as well as vitamin C, lemon and honey. Keeping a daily symptom diary can be helpful for some, to identify which symptoms impact them most, and to monitor how things are progressing.

Herbal Help

While a huge volume of research has taken place and thousands of papers published into the use and potential efficacy of complementary and herbal medicines for the treatment of Covid-19^(20-26) few studies have taken place to date into the potential impacts of natural health product interventions on long Covid symptomatology. This is disappointing given the enormous impact this condition(s) is having on people’s health and its huge potential future healthcare burden, although characterising the syndrome and determining and validating outcome measures in such studies, are challenges for researchers.

There is, however, compelling evidence that various plant based medicines have the potential to greatly help with overcoming the debilitating symptoms of fatigue, headaches and compromised cognitive functions.

Fatigue is of course multi-faceted and broadly defined, which makes understanding its cause(s) especially difficult in conditions such as post-viral syndromes or autoimmune diseases, with their complex pathologies.

Where prolonged or poorly managed stress is likely to have been contributory to sleep disruption and tiredness, anxiolytic, stress insulating and sleep promoting plant medicines can produce marked improvements. Residual damage to the respiratory tract and thus a compromised ability to ensure adequate oxygenation of bodily tissues, may also contribute to ongoing lethargy and constitutional ill health. Addressing this through exercise and bronchial herbal medicines such as Kumerahou, Elecampane, Horseradish and many more, can sometimes help facilitate a return to normal energy levels.

Adaptogens

Adaptogens are a category of medicinal plants that increase the body’s ability to cope with stress, helping to restore balance.  Most if not all adaptogens can play a valuable contribution in a post-viral or convalescence situation where someone has been knocked back by a protracted and debilitating viral infection.

They include well known herbal medicines such as Korean Ginseng (Panax ginseng), American ginseng (Panax quinquefolium), Astragalus (Astragalus membranaceous), Andrographis (Andrographis paniculata), Aswaghandha (Withania somnifera) Bupleurum (Bupleurum falcatum), Eleutherococcus (Eleutherococcus senticosus) and Schisandra (Schisandra chinensis).  Apart from being traditionally used in formulations and treatments taken by the elderly and during convalescence, one of their main indications is for fatigue. In the case of American and Korean ginsengs, clinical trials have shown their potential to help reduce fatigue in cancer patients^{(27, 28)}. A recent clinical trial reported efficacy against Covid-19 infection and reduced levels of inflammatory markers following administration of a product containing Withania and Holy Basil (Ocimum sanctum)⁽²⁹⁾.

Adaptogens have multiple mechanisms of action, such as the ability to increase and modulate innate and adaptive immunity, and exhibit anti-inflammatory actions. Many show direct antiviral actions against a range of viruses, and Withania and Schisandra contain various compounds which act as in vitro protease inhibitors against the SARS-2 coronavirus^(30-32).

A recent clinical trial involving two weeks use of a formulation containing the adaptogens Rhodiola, Eleutherococcus and Schisandra reported improvements in symptoms of fatigue, cognitive function and anxiety, and enabled an increase in daily workout times⁽³²⁾.

Medicinal fungi

Medicinal fungi also possess the ability to act as powerful adaptogens, and most have traditionally been used as tonics to increase energy and physical stamina. The ‘caterpillar fungus’ Cordyceps, one of the most highly sought after natural health products in China, has been termed a mitochondrial adaptogen due to its ability to increase oxygen utilisation and protect mitochondria from adverse events^{(34, 35)}. Its adaptogenic properties and antifatigue activities reported in mice⁽³⁵⁾, together with anti-inflammatory and cardioprotective properties, supports potential benefits as a treatment for Long Covid symptoms such as fatigue. Reishi (Ganoderma lucidum) improved cancer related fatigue in a clinical trial involving breast cancer patients⁽³⁷⁾. Both Reishi^{(38, 39)} and Cordyceps or its active constituent cordycepin^{(40, 41)}, have also shown efficacy in laboratory and animal studies, against the Covid-19 virus.

Like medicinal plants such as Astragalus and Echinacea, medicinal fungi such as Cordyceps, Reishi, Turkey Tail, Shiitake and Maitake exhibit multiple actions on the immune system, and many have pronounced antiviral effects^(42-44). Some of their terpenoid compounds in particular seem to possess anti-inflammatory and antiviral properties, including inhibiting viral enzymes such as neuraminidase and HIV-protease^(45-47).

Finally, the neuroprotective and tonifying effects on nerve cells that seem to be a feature of most medicinal fungi, are highly relevant in the management of post-viral fatigue and cognitive impairment.  Lions Mane (Hericium erinaceus) produces many nurturing effects on the nervous system, showing neuroprotective activity in many animal models, and enhancing Nerve Growth Factor, a neuropeptide involved in regulating nerve cell growth and survival ⁽⁴⁸⁾. Results from clinical trials have also reported improved sleep quality and reduced feelings of depression and anxiety after Lions Mane treatment^(48-50).

Cognition and Headaches

Through addressing the immune dysregulation and nervous system manifestations of Long Covid with some of the targeted herbal treatments already discussed, issues such as a poor memory, a foggy brain and headaches are likely to be at least partially resolved. Adaptogenic plants and medicinal fungi, all have relevant actions in this area, and should generally be part of all Long Covid treatments. Kawakawa as a daily beverage or included in a herbal formulae, can also help with both headaches and other aspects of post-viral recovery.

Where these symptoms are particularly debilitating or distressing, Ginkgo and Bacopa are two phytomedicines for which there is now convincing evidence of their benefits to cognitive function. Improved cognition or relevant neuroprotective effects have also been reported for Cinnamon, Cordyceps, Green tea, Gotu kola, Lemon balm, Lion’s Mane, Nigella, Rosemary, Sage, Turmeric and Valerian.

Apart from the medicinal plants and fungi I’ve already mentioned, there are many others which I’ve discussed in previous blogs^(20-23) that may also assist with overcoming the debilitating symptoms of Long Covid and facilitating a return to good health.

References:

1. Michelen M, Manoharan L, Elkheir N, et al. Characterising long COVID: a living systematic review. BMJ Glob Health. 2021;6(9):e005427.
2. Tirelli U, Taibi R, Chirumbolo S. Post COVID syndrome: a new challenge for medicine. Eur Rev Med Pharmacol Sci. 2021;25(12):4422-4425.
3. Ceban F, Ling S, Lui LMW, et al. Fatigue and cognitive impairment in Post-COVID-19 Syndrome: A systematic review and meta-analysis. Brain Behav Immun. 2022;101:93-135.
4. d’Ettorre G, Gentilini Cacciola E, Santinelli L, et al. Covid-19 sequelae in working age patients: A systematic review. J Med Virol. 2022;94(3):858-868
5. Bucciarelli V, Nasi M, Bianco F, et al. Depression pandemic and cardiovascular risk in the COVID-19 era and long COVID syndrome: Gender makes a difference. Trends Cardiovasc Med. 2022;32(1):12-17.
6. Maglietta G, Diodati F, Puntoni M, et al. Prognostic Factors for Post-COVID-19 Syndrome: A Systematic Review and Meta-Analysis. J Clin Med. 2022;11(6):1541. 
7. López-Sampalo A, Bernal-López MR, Gómez-Huelgas R. Persistent COVID-19 syndrome. A narrative review. Rev Clin Esp (Barc). 2022;222(4):241-250.
8. Stefanou MI, Palaiodimou L, Bakola E, et al. Neurological manifestations of long-COVID syndrome: a narrative review. Ther Adv Chronic Dis. 2022;13:20406223221076890.
9. Tana C, Bentivegna E, Cho SJ, et al. Long COVID headache. J Headache Pain. 2022;23(1):93.
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Seaweeds (otherwise known as algae) are neither plants, animals, bacteria or fungi, but are plant-like organisms that share some morphological and physiological characteristics with plants, and grow in marine environments. Like plants on land they are incredibly diverse and are a valuable source of bioactive compounds with therapeutic and other potential uses.

Seaweeds have long been incorporated into the diet of many traditional coastal communities, and are rich sources of proteins, vitamins, and minerals such as iron and iodine. Practitioners of herbal medicine also recommend or prescribe seaweed preparations for an underactive thyroid, or where mineral deficiencies are perceived.

The use of seaweeds or algae extracts in human health is nothing new, with agar (from algae such as Gracilaria, Gigartina and Gelidium) being used as a gelling agent and growth medium in microbiology, and extracts from Chondrus crispus (Irish Moss) used to thicken suspensions and syrups, and as a popular cough remedy. In recent decades, marine algae have attracted increased attention as a natural source of ingredients and bioactive constituents for medicines, cosmetics, and dietary supplements⁽¹⁾.

Spirulina and astaxanthin

The blue-green microalgae Spirulina for example, is rich in many vitamin and essential nutrients, beta-carotene and protein, and has antioxidant, anti-inflammatory and anti-diabetic properties^{(2, 3)}. It is now cultivated in both sea and freshwater farms, to meet a large global demand. 

Astaxanthin is a xanthophyll carotenoid found in various species of algae as well as yeast, salmon, trout, krill, shrimp and crayfish. While commercial astaxanthin is mostly from Phaffia yeast, Haematococcus pluvialis (a freshwater green microalgae) is one of the best sources of natural astaxanthin.

It has become increasingly popular as a nutritional supplement in recent years, with in vitro and in vivo studies associating it with health benefits. Its antioxidant, neuroprotective, cardioprotective and antitumoral properties suggest possible applications in the prevention or co-treatment of dementia, Alzheimers, Parkinsons, cardiovascular disease and cancer^(4-6).  Improved skin moisture content and elasticity, has also been reported following oral astaxanthin supplementation, and it is increasingly used in cosmetic formulations^{(7, 8)}. Evidence also suggests its usefulness in the prevention and treatment of eye conditions such as glaucoma, cataracts and uveitis, and to improve visual acuity and eye accommodation^{(4, 9, 10)}.

Polysaccharide complexes known as fucoidans isolated from brown seaweeds have also gained considerable attention lately, through their antioxidant, immunomodulatory, anti-inflammatory, antiobesity, antidiabetic, and anticancer properties^{(11, 12)}.

Wound dressing, drug delivery and scaffolding applications

Because of their high biocompatibility and biodegradability, and other unique physicochemical properties, marine biopolymers are ideal for the development of advanced systems for cell proliferation scaffolds, bioadhesives, release modifiers, and wound dressings⁽¹³⁾.

Alginate dressings are light, highly absorbent fabrics made from seaweed derivatives and fibres, and can stay on the wound bed for days. Research into different species and applications has revealed several new potential applications, for conditions that are currently very difficult to treat^{(14, 15)}.

Alginate is also an ideal building block to promote therapeutic cellular regeneration, and alginate-based hydrogels are an attractive material for the application in cardiac regeneration and valve replacement techniques⁽¹⁶⁾. Carrageenan based hydrogels also have  applications to sustained drug release, in bone and cartilage tissue engineering and in wound healing and antimicrobial formulations⁽¹⁷⁾.

Antimicrobial properties

Apart from their physical attributes making them suitable as wound dressings and drug delivery vehicles, numerous marine algae show direct antimicrobial activities.

A range of seaweed compounds including polysaccharides, fatty acids, phlorotannins, pigments, lectins, alkaloids, terpenoids and halogenated compounds, show antiviral, antiprotozoal, antifungal, and antibacterial properties^(18-20). Much research is underway aimed at the identification and development of bioactive compounds and products that can be used as broad spectrum antibiotics, antibacterial, and antifouling agents^{(20, 21, 22)}.

The green algae sea lettuce (Ulva lactuca) has antibacterial activity including against methicillin-resistant Staph aureus, and shows potential applications in wound preparations⁽²³⁾.

Phlorotannins are a type of tannin occuring as complex polymer mixtures and found only in some seaweeds, and many exhibit good antimicrobial activities. Those from the Atlantic ocean brown seaweed, Fucus vesiculosus, demonstrate bacteriostatic action against Staph. aureus and Strep. pneumoniae^(24-27).   Another weakens resistance mechanisms of acne-related bacteria to antibiotics such as erythromycin and lincomycin⁽²⁸⁾. Compounds from Arame seaweed (Eisenia bicyclis) promote cell membrane damage and reduce expression of methicillin resistance-associated genes in Staph. aureus⁽²⁹⁾.

Regular oral administration of ascophyllan, a sulphated polysaccharide from the edible brown alga Ascophyllum nodosum, before and after bacterial infection resulted in a remarkable increase in survival rate in mice with a severe intranasal Streptococcus pneumoniae infection⁽²⁵⁾.

A recent review of studies using marine algal extracts against oral cariogenic bacteria, identified many as having anti-microbial properties and showing potential for oral hygiene maintenance⁽³⁰⁾.

Polyphenolic compounds and polysaccharides from marine algae also show potential for the discovery and development of new antiviral treatments. In vitro activity has been shown for many sulfated polysaccharides, including carrageenan, agar, ulvan, fucoidan, and alginates. Mechanisms of antiviral actions include blocking the initial entry of the virus or inhibiting its transcription and translation by modulating the immune response of the host cell^(31-35). Many of these agents have anti-inflammatory and immunomodulatory actions that may also be relevant to the management of chronic viral infections or their complications. Several sulfated polysaccharides have been identified as potential antiviral agents against the COVID-19 virus^{(35, 36, 37)}. However, further preclinical and many more clinical studies are still required to establish the roles that seaweed extracts or compounds might have, in the management of viral infections.

Apart from potential applications in human medicine, microalgae and their antimicrobial compounds are also being investigated as biocontrol agents against food and plant pathogens⁽³⁸⁾.

Gastroprotective

The mucilaginous properties of polysaccharides found in many seaweeds can make them useful in the management of digestive conditions such as dyspepsia or peptic ulcers. Anti-inflammatory, anti-ulcerogenic and gastroprotective activities have been reported for algae from different parts of the world^{(39, 40, 41)}. These include the Mediterranean red algae, Laurencia obtusa⁽³⁹⁾, and a Malaysian red algae Gracillaria changii which showed comparable protection to omeprazole against gastric lesions in rats⁽⁴⁰⁾.

Fucoidan has anti-ulcer effects, and can prevent the adhesion of Helicobacter pylori to gastric epithelial cells, and reduce biofilm formation^(42-44).

Neuroprotective potential

Algal metabolites exhibit protective effects against oxidative stress, neuroinflammation, mitochondrial dysfunction, and impaired proteostasis, known factors in many neurological disorders and neurological complications after strokes and brain injuries^{(45, 46)}.

Drugs and substances that inhibit the enzyme cholinesterase (known as cholinesterase inhibitors), are used to alleviate symptoms of dementia and Alzheimer’s disease, and to treat myasthenia gravis and glaucoma.  Research up until 2018 identified and reported 185 marine cholinesterase inhibitor and selected analogue compounds, some of which displayed inhibitory activities comparable or superior to cholinesterase inhibitor drugs in clinical use⁽⁴⁷⁾.

Of these and the many other algal compounds with promising neuroprotective capacity identified to date however, few have had access to clinical trials. Encouragingly though, a marine oligosaccharide, sodium oligomannate, has recently been found to improve cognition in a 36 week Phase 3 clinical trial in patients with mild to moderate Alzheimer’s disease⁽⁴⁸⁾.

Potential applications extend also to the treatment of depression, with favourable results from animal and in vitro studies on some extracts, but human studies are lacking⁽⁴⁹⁾.

Cancer

The search for new anti-cancer drugs is ongoing, and many promising compounds and extracts have been discovered through bioprospecting under the sea^(50-56).

The anti-leukaemic drug cytarabine is derived from arabinose-containing nucleotides from the Caribbean marine sponge Cryptotheca crypta, and the breast cancer drug eribulin, from the Japanese marine sponge Halichondria okadai. New marine-derived substances with anticancer activities are continuously being isolated and tested, with several currently in clinical trials^(57-58).

One such substance is phycocyanin, a biliprotein constituent of Arthrospira platensis with several therapeutic properties, including anti-oxidant, anti-inflammatory, immune-modulatory and anti-cancer activities⁽⁵⁹⁾. Other promising compounds include the leptosins, isolated from the fungus Leptoshaeria spp an endophyte of the macroalgae Sargassum tortile⁽⁵³⁾.

Other potential uses:

Fucoidan and other algae compounds exhibit a range of osteogenic effects, including stimulation of osteoblast activity and mineralisation, as well as suppression of osteoclast resorption. This suggests a potential to assist with bone growth and healing⁽⁶⁰⁾.

Hepatoprotective and endotoxin-protective effects have also been reported for fucoidan, spirulina and other algae extracts^{(63, 64)}.

Red and brown algae are reported to show anti-diabetic activity.  Possible actions include protection against chronic metabolic disease and diabetes mellitus, and complications such as retinopathy, atherosclerosis and nephropathy⁽⁶¹⁾. Red algae species, Chondrus crispus, Porphyra tenera and Schizymenia binderi, produce sulfated polysaccharides known as galactans which have anticoagulant activities^{(13, 65)}.

Alginate has detoxification abilities and potential to chelate metals and reduce cholesterol and blood pressure⁽⁶²⁾.

Safety

Apart from their health benefits, the potential toxicity, mechanisms of action, and interactions of seaweeds with conventional foods, are areas requiring more attention.

Excessive ingestion of many seaweeds can cause high exposure to iodine, which can lead to hyperthyroidism. High salt intake and thus an increased risk of hypertension and hypernatraemia, can also occur through regular ingestion of poorly processed seaweed as a food source.

As with land based plants, some seaweeds are toxic or produce toxic metabolites, and as such, correct species identity is important.  Toxicity might also be due to epiphytic bacteria or harmful algal bloom and absorbed heavy metals from seawater⁽⁶⁶⁾.

Sustainability:

Algae play a crucial role in aquatic ecosystems. A shortage of algae could lead to coastal erosion, loss of biodiversity, lower water quality, and numerous negative effects on the food chain and marine habitats. Similarly intensive and irresponsible aquaculture of algae has the potential to cause water and local environmental pollution, and a decline in wild species populations. The effects of trawling for fish on the entire underwater marine ecosystem, are also still poorly understood.

Worldwide, more than 200 species of marine algae are already being harvested from wild or cultivated sources, and commercially used.

While as a small country with a relatively large sea area Aotearoa New Zealand may seem immune from unsustainable activities, the growing interest and increasingly diverse applications being realised for algae may lead to their overexploitation, unless harvesting is well managed. Ocean pollution is also of growing concern and poses serious threats to human health, with downstream outcomes now only beginning to be understood⁽⁶⁷⁾. Nitrogen and phosphorous runoff from farms as well as climate change factors, contribute to algae “blooms” which can smother and harm other marine species including shellfish, and produce offensive smelling gases during rotting by bacteria.

On the promising side though, possible applications of certain seaweeds such as Asparagopsis spp as food supplements to cows in order to reduce greenhouse gas emissions, are emerging. A red macroalgae Asparagopsis spp. has been shown to cause an 80 percent reduction in methane production by cows⁽⁶⁸⁾. In Aotearoa New Zealand, the Cawthron Institute, seaweed and dairy industry are currently involved in field trials to see if Asparagopsis armata is a viable feed additive to significantly decrease the carbon footprint of cows. While early results are promising, wild seaweed harvest is unlikely to provide a reliable and sustainable supply, meaning that an aquaculture and selective breeding strategy, is likely to be required⁽⁶⁹⁾.

With our country being privileged to have a rich and highly biodiverse marine environment, and seaweeds clearly being an important source of new medicines in the future, a careful and measured approach to research and development and future commercialisation, is critical. Given this, it is good to see the Aotearoa New Zealand government, Cawthron Institute and elements of industry investing significantly into seaweed research, with a National Algae Research Centre being opened at the Cawhron Aquaculture Park in Nelson, in May last year.

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41. Sousa WM, Silva RO, Bezerra FF, et al. Sulfated polysaccharide fraction from marine algae Solieria filiformis: Structural characterization, gastroprotective and antioxidant effects. Carbohydr Polym. 2016;152:140-148.
42. Shibata H., Kimura-Takagi I., Nagaoka M., Hashimoto S., Sawada H., Ueyama S., Yokokura T. Inhibitory effect of cladosiphon fucoidan on the adhesion of helicobacter pylori to human gastric cells. J. Nutr. Sci. Vitaminol. (Tokyo) 1999;45:325–336.
43. Besednova NN, Zaporozhets TS, Somova LM, Kuznetsova TA. Review: prospects for the use of extracts and polysaccharides from marine algae to prevent and treat the diseases caused by Helicobacter pylori. Helicobacter. 2015;20(2):89-97
44. Chua EG, Verbrugghe P, Perkins TT, Tay CY. Fucoidans Disrupt Adherence of Helicobacter pylori to AGS Cells In Vitro. Evid Based Complement Alternat Med. 2015;2015:120981
45. Schepers, M., Martens, N., Tiane, A., Vanbrabant, K., Liu, H. B., Lütjohann, D., Mulder, M., & Vanmierlo, T. (2020). Edible seaweed-derived constituents: an undisclosed source of neuroprotective compounds. Neural regeneration research, 15(5), 790–795.
46. Hannan MA, Dash R, Haque MN, et al. Neuroprotective Potentials of Marine Algae and Their Bioactive Metabolites: Pharmacological Insights and Therapeutic Advances. Mar Drugs. 2020;18(7):347. 
47. Moodie LWK, Sepčić K, Turk T, FrangeŽ R, Svenson J. Natural cholinesterase inhibitors from marine organisms. Nat Prod Rep. 2019;36(8):1053-1092
48. Xiao, S., Chan, P., Wang, T. et al. A 36-week multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial of sodium oligomannate for mild-to-moderate Alzheimer’s dementia. Alzheimer’s research & therapy, 2021;13(1), 62.
49. Subermaniam K, Teoh SL, Yow YY, Tang YQ, Lim LW, Wong KH. Marine algae as emerging therapeutic alternatives for depression: A review. Iran J Basic Med Sci. 2021;24(8):997-1013. 
50. Desamero MJ, Kakuta S, Chambers JK, et al. Orally administered brown seaweed-derived β-glucan effectively restrained development of gastric dysplasia in A4gnt KO mice that spontaneously develop gastric adenocarcinoma. Int Immunopharmacol. 2018;60:211-220.
51. Ruan BF, Ge WW, Lin MX, Li QS. A Review of the Components of Seaweeds as Potential Candidates in Cancer Therapy. Anticancer Agents Med Chem. 2018;18(3):354-366
52. Martínez Andrade KA, Lauritano C, Romano G, Ianora A. Marine Microalgae with Anti-Cancer Properties. Mar Drugs. 2018;16(5):165.
53. Teixeira TR, Santos GSD, Armstrong L, Colepicolo P, Debonsi HM. Antitumor Potential of Seaweed Derived-Endophytic Fungi. Antibiotics (Basel). 2019;8(4):205.
54. Saadaoui I, Rasheed R, Abdulrahman N, et al. Algae-Derived Bioactive Compounds with Anti-Lung Cancer Potential. Mar Drugs. 2020;18(4):197. 
55. Sugumaran A, Pandiyan R, Kandasamy P, et al. Marine biome-derived secondary metabolites, a class of promising antineoplastic agents: A systematic review on their classification, mechanism of action and future perspectives. Sci Total Environ. 2022;836:155445.
56. Ślusarczyk J, Adamska E, Czerwik-Marcinkowska J. Fungi and Algae as Sources of Medicinal and Other Biologically Active Compounds: A Review. Nutrients. 2021;13(9):3178.
57. Jimenez P.C., Wilke D.V., Costa-Lotufo L.V. Marine drugs for cancer: Surfacing biotechnological innovations from the oceans. Clinics. 2018;73:e482s. 
58. Dyshlovoy S.A., Honecker F. Marine compounds and cancer: 2017 updates. Mar. Drugs. 2018;16:41.
59. Braune S, Krüger-Genge A, Kammerer S, Jung F, Küpper JH. Phycocyanin from Arthrospira platensis as Potential Anti-Cancer Drug: Review of In Vitro and In Vivo Studies. Life (Basel). 2021;11(2):91. 
60. Carson MA, Clarke SA. Bioactive Compounds from Marine Organisms: Potential for Bone Growth and Healing. Mar Drugs. 2018;16(9):340. Published 2018 Sep 18.
61. Rayapu L, Chakraborty K, Valluru L. Marine Algae as a Potential Source for Anti-diabetic Compounds – A Brief Review. Curr Pharm Des. 2021;27(6):789-801.
62. Gupta S., Abu-Ghannam N. Recent developments in the application of seaweeds or seaweed extracts as a means for enhancing the safety and quality attributes of foods. Innov. Food Sci. Emerg. Technol. 2011;12:600–609.
63. Altinok-Yipel F, Tekeli IO, Ozsoy SY, Guvenc M, Sayin S, Yipel M. Investigation of hepatoprotective effect of some algae species on carbon tetrachloride-induced liver injury in rats. Arch Physiol Biochem. 2020;126(5):463-467.
64. Kuznetsova TA, Besednova NN, Somova LM, Plekhova NG. Fucoidan extracted from Fucus evanescens prevents endotoxin-induced damage in a mouse model of endotoxemia. Mar Drugs. 2014;12(2):886-898. 
65. Farias WR, Valente AP, Pereira MS, Mourão PA. Structure and anticoagulant activity of sulfated galactans. Isolation of a unique sulfated galactan from the red algae Botryocladia occidentalis and comparison of its anticoagulant action with that of sulfated galactans from invertebrates. J Biol Chem. 2000;275(38):29299-29307
66. Kumar MS, Sharma SA. Toxicological effects of marine seaweeds: a cautious insight for human consumption. Crit Rev Food Sci Nutr. 2021;61(3):500-521
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69. https://www.cawthron.org.nz/our-news/opinion-johan-svenson-asparagopsis/

Introduction

Diabetes mellitus is a growing problem, particularly type 2 diabetes which used to be termed “late onset” although it is increasingly being seen in younger age groups. This illness is having a large and increasing burden on health care systems around the world including in Aotearoa New Zealand where its incidence in children under 15 years of age has increased by around 5% a year over the last 25 years⁽¹⁾. An estimated 250,000 people in New Zealand now have diabetes, and one in four New Zealanders aged 15 or over have prediabetes, which is where blood glucose levels are higher than normal, but not high enough to be diagnosed as diabetes.  Māori and Pacific populations have around double the prevalence of diabetes than other New Zealanders, and are at least three times more likely to suffer from complications⁽²⁾.

A large percentage of people under the age of 40 years diagnosed with type 2 diabetes are overweight or obese, and so the need to address dietary and lifestyle factors contributing to the development of this disease, is imperative. This can include changes in diet and increased exercise, as well as stress management. Prevention is always preferable to the need to treat a serious chronic illness requiring long term medication.

Medications for type 2 diabetes usually include oral hypoglycaemic drugs such as metformin, and sometimes second line drugs such as empagliflozin which can help reduce renal or cardiovascular complications.  Type 1 diabetes, is treated by intraperitoneal injections of insulin.

Complications of diabetes include a wide range of related symptoms and potential health problems.  It is a major cause of blindness, kidney failure, heart attacks, stroke and amputation of limbs.

While proper diagnosis and management of both Type 1 and Type 2 diabetes is critical and drug medication can be life-saving, dietary changes and appropriately prescribed herbal medicines can also play a useful role. 

Dietary plants

Many plants possess activities of relevance to the prophylaxis or management of Type 2 diabetes and its complications. Epidemiological studies have found diets rich in plant products such as legumes and nuts, berries and vegetables, and the so-called Mediterranean diet, have a lower risk of Type 2 diabetes^(3-5).

Culinary spices such as ginger, turmeric, blackseed and cinnamon, have various actions that may be favourable for diabetic patients. Clinical trials on cinnamon have found it to reduce fasting blood glucose and improve insulin resistance in Type 2 and pre-diabetic patients⁽⁶⁾ . Ginger can reduce elevated levels of inflammatory markers associated with the onset and severity of diabetes^{(7, 8)}. Blackseed (Nigella sativa), a popular culinary space in Mediterranean and many Asian countries, improves the dysfunction seen in the lining (endothelium) of small blood vessels in diabetic patients, as well as kidney, heart and immune functions⁽⁹⁾.

Popular herbal medicines

While these and other plants and spices may help to normalise hyperglycaemia, other objectives in using herbal medicines are more fruitful in diabetic patients. These include the prevention of diabetic complications such as kidney nephropathy, retinopathy, peripheral vascular and cardiovascular disease, and cognitive decline.

One of the common names for the Indian herb Gymnema (Gymnema sylvestre), is ‘Gurmur (or Gudmar)’ in Hindi, which means ‘sugar destroyer’, due to its ability to suppress the sensation of sweetness from eating sweet foods⁽¹⁰⁾. Studies have shown it to reduce blood glucose and elevated cholesterol and triglyceride levels⁽¹¹⁾, and to enhance insulin producing cells in the pancreas in animals^{(11, 12)}.  However claims that its sugar neutralising properties lead to less desire for sweet foods, have not been substantiated⁽¹³⁾.

Other prominent medicinal plants used for diabetes include fenugreek (Trigonella foenum-graecum), bitter melon (Momordica charantia), and turmeric (Curcuma longa).  As with cinnamon, all exhibit a broad range of antioxidant, anti-inflammatory, insulin sensitising or other actions relevant to the development or progression of diabetes and its complications. While some clinical trials have taken place, more large well designed trials and over longer periods of time, are needed.

Prevention of neuropathies and cardiovascular complications

Diabetic nephropathy (deterioration in kidney function) is a serious complication of diabetes, and affects around 30-40% of diabetic patients. It is the leading cause of middle and end-stage chronic kidney disease and accounts for more than 50% of patients entering dialysis or transplant programmes. Like diabetic retinopathy (deterioration in eyesight) it is a serious and debilitating complication of poorly controlled diabetes, and treatment options are expensive and limited.

Many herbal medicines exhibit protective actions against nerve damage and show potential to help prevent such neuropathies.  A recent analysis revealed multiple potentially relevant mechanisms of action for a combination of the Chinese herbs astragalus and dong quai, including inhibition of inflammatory reactions, oxidative stress, glycogen depositions and collagen fibre formation, reduced urinary protein leakages, and improvement in kidney function and other damage caused by high glucose⁽¹⁴⁾.

A number of other neuroprotective and cardioprotective herbal medicines such as green tea, ginkgo, ginseng, withania and rehmannia, may also reduce the risks of diabetic complications such as nephropathy or at least reduce its impact on patients’ lives.

Cardiovascular disease is the leading cause of mortality in people with Type 2 diabetes, and most patients have high blood pressure and an increased risk of heart attack and stroke.  Vascular complications can also lead to claudication and complete peripheral vessel obstruction, resulting in difficult to treat leg ulcers and issues with mobility.

A recent review of 15 randomized controlled trials involving ginkgo as an adjunctive treatment for ischaemic stroke, concluded that it appears to improve neurological function and dependence, at different stages following an ischaemic stroke⁽¹⁵⁾.

A large epidemiological study involving more than 500,000 Chinese adults, recently associated daily green tea consumption with a lower risk of type 2 diabetes and a lower risk of all-cause mortality in patients with existing diabetes. Associations were also made with a lower risk of some diabetic complications⁽¹⁶⁾.

Two common so-called ‘weeds’ which are endemic in our country and which Ive written about previously⁽¹⁷⁾, Japanese honeysuckle (Lonicera japonica) and Chinese privet (Ligustrum lucidum), also possess pharmacological activities of value in the management of diabetes mellitus. Japanese honeysuckle reduces diabetic nephropathy when given to rats, reversing the reduced creatinine clearance, increased blood urea and proteinuria seen when the kidneys are struggling⁽¹⁸⁾. Improvement in diabetic retinopathy, has also been reported in mice⁽¹⁹⁾. Chinese Privet (Ligustrum lucidum), contains flavonoid compounds shown to protect against diabetes-induced osteoporosis in mice⁽²⁰⁾. This is of interest given the frequent coexistence of osteoporosis and increased fracture risk in diabetic patients⁽²¹⁾.

Cognitive decline

The risk of dementia, Alzheimer’s disease, and cognitive decline is higher in people with poor blood sugar control and insulin resistance.  Reduced glucose utilization and deficient energy metabolism also occur early in the course of many patients with Alzheimers’ disease⁽²²⁾.

In addition to improving blood sugar control, plant medicines with the potential ability to reduce nerve cell inflammation within the brain, may provide some benefits in diabetic patients showing signs of cognitive decline. Apart from ginkgo, these include ginseng, blackseed, bacopa, gotu kola, dan shen, lions mane, rosemary and sage.

Diabetic Leg Ulcers

These are common, debilitating and serious complications for diabetic patients. Most don’t heal in a timely fashion and non-healing is associated with complications including infections and sometimes a need for amputation.

While advances have occurred in standard care, more research is critical to identify new and better therapies, particularly given antibiotic resistance and the burden that slow healing ulcers place on the patient and the health care system. Several herbal treatments can be helpful, such as echinacea and horsechestnut, and topical applications such as active manuka honey, which may shorten healing times and lessen the need for antibiotics and hospitalization.

Summary

Diabetes mellitus is a serious and increasingly common condition, and there is a great deal of evidence that plant medicines can help from both preventative as well as management perspectives, particularly with many of its associated complications. However, it is important to also ensure such interventions or adjunctive herbal treatments are prescribed for the particular individual patient, and that the potential for both useful or unwanted interactions with other medications, is taken into account.

While more clinical trials are needed, given the many impacts this illness can have on patients, families and the health care system, even small gains through herbal interventions seem warranted.  These factors and the evidence to date, provides a strong and growing case for more research into specific plants and clinical outcomes.

References:

1. Sjardin, N., Reed, P., Albert, B., Mouat, F., Carter, P. J., Hofman, P., Cutfield, W., Gunn, A., & Jefferies, C. Increasing incidence of type 2 diabetes in New Zealand children <15 years of age in a regional-based diabetes service, Auckland, New Zealand. Journal of paediatrics and child health, 2018; 54(9), 1005–1010.
2. Moore, M. P., & Lunt, H. Diabetes in New Zealand. Diabetes research and clinical practice, 2000; 50 Suppl 2, S65–S71.
3. Schwingshackl L, Hoffmann G, Lampousi AM, et al. Food groups and risk of type 2 diabetes mellitus: a systematic review and meta-analysis of prospective studies. Eur J Epidemiol. 2017;32(5):363-375.
4. McMacken M, Shah S. A plant-based diet for the prevention and treatment of type 2 diabetes. J Geriatr Cardiol. 2017;14(5):342-354.
5. Martín-Peláez S, Fito M, Castaner O. Mediterranean Diet Effects on Type 2 Diabetes Prevention, Disease Progression, and Related Mechanisms. A Review. Nutrients. 2020;12(8):2236.
6. Deyno S, Eneyew K, Seyfe S, et al. Efficacy and safety of cinnamon in type 2 diabetes mellitus and pre-diabetes patients: A meta-analysis and meta-regression. Diabetes Res Clin Pract. 2019;156:107815.
7. Huang FY, Deng T, Meng LX, Ma XL. Dietary ginger as a traditional therapy for blood sugar control in patients with type 2 diabetes mellitus: A systematic review and meta-analysis. Medicine (Baltimore). 2019;98(13):e15054.
8. Mohammad A, Falahi E, Mohd Yusof BN, et al. The effects of the ginger supplements on inflammatory parameters in type 2 diabetes patients: A systematic review and meta-analysis of randomised controlled trials. Clin Nutr ESPEN. 2021;46:66-72.
9. Mahmoodi MR, Mohammadizadeh M. Therapeutic potentials of Nigella sativa preparations and its constituents in the management of diabetes and its complications in experimental animals and patients with diabetes mellitus: A systematic review. Complement Ther Med. 2020;50:102391.
10. Tiwari P, Mishra BN, Sangwan NS. Phytochemical and pharmacological properties of Gymnema sylvestre: an important medicinal plant. Biomed Res Int. 2014;2014:830285.
11. Devangan S, Varghese B, Johny E, Gurram S, Adela R. The effect of Gymnema sylvestre supplementation on glycemic control in type 2 diabetes patients: A systematic review and meta-analysis. Phytother Res. 2021;35(12):6802-6812.
12. Kumar V. H., Nayak I. N., Huilgol S. V., Yendigeri S. M., Narendar K. Antidiabetic and hypolipidemic activity of Gymnema sylvestre in dexamethasone induced insulin resistance in Albino rats. Int. J. Med. Res. Health Sci. 2015; 4 (3), 639–645. 
13. Kashima N, Kimura K, Nishitani N, Yamaoka Endo M, Fukuba Y, Kashima H. Suppression of Oral Sweet Sensations during Consumption of Sweet Food in Humans: Effects on Gastric Emptying Rate, Glycemic Response, Appetite, Food Satisfaction and Desire for Basic Tastes. Nutrients. 2020;12(5):1249.
14. Dong Y, Zhao Q, Wang Y. Network pharmacology-based investigation of potential targets of astragalus membranaceous-angelica sinensis compound acting on diabetic nephropathy. Sci Rep. 2021;11(1):19496
15. Ji H, Zhou X, Wei W, Wu W, Yao S. Ginkgo Biloba extract as an adjunctive treatment for ischemic stroke: A systematic review and meta-analysis of randomized clinical trials. Medicine (Baltimore). 2020 Jan;99(2):e18568.
16. Nie, J., Yu, C., Guo, Y., Pei, P., Chen, L., Pang, Y., Du, H., Yang, L., Chen, Y., Yan, S., Chen, J., Chen, Z., Lv, J., & Li, L. Tea consumption and long-term risk of type 2 diabetes and diabetic complications: a cohort study of 0.5 million Chinese adults. The American journal of clinical nutrition, 2021; 114(1), 194–202.
17. Rasmussen PL, www.herbblurb.com Honeysuckle and other useful weeds surrounding us. Jan 24, 2019.
18. Tzeng TF, Liou SS, Chang CJ, Liu IM. The ethanol extract of Lonicera japonica (Japanese honeysuckle) attenuates diabetic nephropathy by inhibiting p-38 MAPK activity in streptozotocin-induced diabetic rats. Planta Med. 2014;80(2-3):121-129.
19. Zhou L, Zhang T, Lu B, et al. Lonicerae Japonicae Flos attenuates diabetic retinopathy by inhibiting retinal angiogenesis. J Ethnopharmacol. 2016;189:117-125.
20. Feng, R., Ding, F., Mi, X. H., Liu, S. F., Jiang, A. L., Liu, B. H., Lian, Y., Shi, Q., Wang, Y. J., & Zhang, Y.. Protective Effects of Ligustroflavone, an Active Compound from Ligustrum lucidum, on Diabetes-Induced Osteoporosis in Mice: A Potential Candidate as Calcium-Sensing Receptor Antagonist. The American journal of Chinese medicine, 2019; 47(2), 457–476.
21. Paschou, S. A., Dede, A. D., Anagnostis, P. G., Vryonidou, A., Morganstein, D., & Goulis, D. G. Type 2 Diabetes and Osteoporosis: A Guide to Optimal Management. The Journal of clinical endocrinology and metabolism, 2017;102(10), 3621–3634.
22. Nguyen, T. T., Ta, Q., Nguyen, T., Nguyen, T., & Giau, V. V. Type 3 Diabetes and Its Role Implications in Alzheimer’s Disease. International journal of molecular sciences, 2020; 21(9), 3165.

Most if not all traditional cultures including Māori used the stars to guide them not only in navigation, but also as a correlation to the seasonal patterns of fish, plants and other living creatures, and how these impacted on human food and medicine supplies and survival. Maramataka is a traditional Māori practice of using knowledge of the star systems, moon cycles, tides and the environment to determine the appropriate time to carry out particular tasks. Maramataka came to Aotearoa with the first Polynesian migrants around 1000 years ago, and iwi in different parts of the country developed their own maramataka based on their local environment.  It is sometimes called the Māori calendar, but instead of counting days, weeks and months, it is based upon the cycles and phases of the moon.

Here in Aotearoa this year we are having a national holiday for the first time in our history to celebrate an important timeline in this lunar calender, known as Matariki. The Matariki cluster of seven stars (Matariki and her six daughters, known as the Pleiades to Greek astronomers) reappears in our night sky between the end of May and July, and this year it coincides closely with the winter solstice.

Plants have a huge relevance to Matariki and human nutrition, health and survival, and to the wellness of the earth. A key plant for early Māori, was the kumara (Ipomoea batatas, or sweet potato), which originated in south America but was adapted and cultivated as a virtual perennial in the Pacific islands, then further adapted by early Māori to the temperate New Zealand climate and stored successfully during the winter months. This was a major achievement of early Māori agriculture, as this plant provided sustenance and helped ensure winter survival. Little wonder that in centuries gone by, as is still the case with traditional and farming families and close communities today, when the kumara or other important crop was safely harvested, dried and stored, there soon came a time for celebration and a special hangi or sharing of food. Research has since shown kumara to have many potential medicinal applications, including in the treatment of diabetes and hyperlipidaemia⁽¹⁾, cancer^{(2, 3)} and chronic inflammatory conditions such as arthritis⁽⁴⁾.

These traditional ceremonies, celebrations and rituals, many of which involved an admiration and gratitude to the far away stars (regarded as atua, or gods to Māori), are important for many reasons. Not only do they help to foster a closer connection with nature and respect for the sustenance Papatūānuku (the earth mother) provides, but they also foster a stronger sense of community.

While Matariki has different meanings to different iwi and individuals, it should be a time to celebrate harvest, gift and share food, and plan for the year ahead. In north America they have Thanksgiving, in Germany an autumn harvest festival known as Erntedankfest, in China a mid-autumn festival known as the Moon Festival.  These festivals have their own unique traditions, including making offerings to the gods, and preparing a special traditional dish. In all cases, they incorporate the practice of expressing gratitude to the earth, seas and rivers for providing food and sustenance, and celebrating the end of another annual cycle of growing, harvesting and gathering food and medicine from nature.

Finally, an annual seasonal event that relates to the stars and life in Aotearoa New Zealand, and celebrates the richness of the traditional knowledge and pursuits of Māori, is being acknowledged in the diaries of all New Zealanders.

The faster and faster pace of modern living, increasing impact of information technology, artificial intelligence and virtual reality on our daily lives, excessive consumerism and preoccupation with monetary wealth, are factors catalyzing an increasingly alarming disconnection from nature for a growing proportion of the world’s population. The Covid-19 lockdowns resulted in people taking more interest again in their local surroundings, neighbourhoods and communities. Global supply chain disruptions gave and continue to give us a wakeup call as to how over-dependent we are, on goods and medicines produced in far away countries. Matariki this year for me is a time to reflect upon how vulnerable we humans still are to the powers of nature, yet how fruitful nature can be. Regardless of what we’re already pursuing in our busy lives, it is important and necessary to sometimes pause and reflect on how fortunate we are to be living in a small country on a small planet in the cosmos, which still provides bountiful supplies of food and medicine for most of us almost at our very doorsteps.

Unlike how we perhaps tend to approach other European culture-dominated public holidays, Matariki is a time to try and ensure we take proper time out to actually spend time in nature, and celebrate the beautiful land, waterways, plants and creatures that surround us here in Aotearoa. Listening to Te Whenua (the land), noticing what changes are happening around us, and nurturing our local environment.  Looking upwards to the stars, and also behind and to the sides sometimes, not just to the front or to other humans, books or the internet for guidance.

While each of us will have or over time develop our own personal connection to this first ever intrinsically Aotearoan holiday and time of reflection, there is much we can do to help foster a closer relationship with plants and their wellbeing. Making and sharing nutritious and kapai food from kumara, pumpkin, apples or other recent local harvests from our garden or forest, or immersing ourselves for a time in the bush, where the plants talk to us and teach us just by being there. Planting seeds of a native plant, garlic or other food or medicinal species, or nurturing plants already established in our local environment. Harvesting medicines from them and planning to make teas, tinctures, syrups or balms, or preparing and planning for the annual plant calender year ahead, are all activities that align well with the significance of Matariki. And what better time to slow down, reflect and immerse ourselves in these simple but meaningful and powerful pursuits than Matariki this year, after what the world has been through in the last couple of years.

References

1. Naomi, R., Bahari, H., Yazid, M. D., Othman, F., Zakaria, Z. A., & Hussain, M. K. (2021). Potential Effects of Sweet Potato (Ipomoea batatas) in Hyperglycemia and Dyslipidemia-A Systematic Review in Diabetic Retinopathy Context. International journal of molecular sciences, 22(19), 10816.
2. Mohanraj, R., & Sivasankar, S. (2014). Sweet potato (Ipomoea batatas [L.] Lam)–a valuable medicinal food: a review. Journal of medicinal food, 17(7), 733–741.
3. Lin, H. H., Lin, K. H., Wu, K. F., & Chen, Y. C. (2021). Identification of Ipomoea batatas anti-cancer peptide (IbACP)-responsive genes in sweet potato leaves. Plant science : an international journal of experimental plant biology, 305, 110849.
4. Majid, M., Nasir, B., Zahra, S. S., Khan, M. R., Mirza, B., & Haq, I. U. (2018). Ipomoea batatas L. Lam. ameliorates acute and chronic inflammations by suppressing inflammatory mediators, a comprehensive exploration using in vitro and in vivo models. BMC complementary and alternative medicine, 18(1), 216.

Mushrooms are the ‘fruiting bodies’ produced by about 14,000 different species of fungi. They are the part of the fungi we see, but in fact most of the fungi lies below the soil or tissue of the host as a massive network of thread-like cells known as the mycelium. The mushroom is simply a reproductive organ which like the flower of a plant bursts forth to spread its spores, then dies away again.

Mushrooms have been used as foods and medicines for many thousands of years by all if not virtually all traditional cultures around the world. Local knowledge and customs around the gathering and usage of wild mushrooms, based on edible or non-edible (poisonous) species and the customary usage of certain species as medicines, is ingrained into rural communities in every continent. Much of this knowledge is however now being lost, due to migration of rural populations to cities, and the demise of traditional living practices and natural ecosystems⁽¹⁾.

Fungi come in many different shapes, colours and forms, and given their incredible diversity, its hardly surprising that medicinal fungi exhibit a wide spectrum of pharmacological properties. Predominant ones include anti-inflammatory, antioxidant, immunomodulatory, antiviral, antibacterial, osteoprotective, nephroprotective, hepatoprotective, anti-diabetic, cognitive enhancing and anticancer actions⁽²⁾.  This is an impressive repertoire, and underlines their traditional uses to help protect against and treat many different illnesses and health-related conditions.

Medicinal mushrooms have attracted much more research interest in recent years, and this has spurred a lot of product development. Some that have been particularly well researched and achieved high acclaim, are various species used widely for thousands of years in traditional Chinese and Asian medicine.

Active constituents:

These vary depending on the species, but until fairly recently most attention has been on a type of polysaccharide known as the β-glucans. We are now, however, also recognising  the importance of other compounds such as the di- and tri-terpenoids, and the fungal steroidal compound ergosterol. Mushrooms are also rich in various nutrients and other bioactive compounds including alkaloids, lectins, phenolic acids, polyunsaturated fatty acids, vitamins, and minerals. Some also contain reasonable levels of protein, with contents of 5-20% (dried weight), being fairly typical⁽³⁾.

Sourcing:

Medicinal mushrooms were historically taken from the wild from the dead wood of trees or other locations, and this remains the means of gathering in traditional practices. Commercial supplies now though, derive from both wildcrafted and cultivated sources. The latter are cultivated on growth medium such as rice and other grains, and this as well as how they are dried or processed following harvest, can influence their phytochemical makeup and thus medicinal properties. Debate is ongoing for instance, about whether undigested grain can sometimes dilute down the active phytochemicals in a mycelial mass. Other quality control considerations such as the actual part(s) of the fungi used, the need to ensure product authenticity and purity, and the importance of preventing pesticide and heavy metal contamination, also apply⁽⁴⁾.

Reishi (Ganoderma lucidum):

Known as Reishi in Japan and Ling Zhi in China, Reishi is considered a symbol of happiness and a good future, good health and longevity. There are over 2000 papers published on it in the peer-reviewed literature, and more than 400 different bioactive compounds have been characterised. Its inventory of reported pharmacological activities is vast, and includes immunomodulation, anti-atherosclerotic, anti-inflammatory, analgesic, chemo-preventive, antitumour, chemo and radio protective, sleep promoting, antibacterial, antiviral (including anti-HIV), hypolipidemic, anti-fibrotic, hepatoprotective, anti-diabetic, anti-androgenic, anti-angiogenic, antioxidative and radical-scavenging, anti-aging, hypoglycemic, oestrogenic activity and anti-ulcer properties.  Evidence from clinical trials to date suggests it can be a safe and useful adjunct to conventional cancer treatment, although further and larger trials are needed⁽⁵⁾.

Lions Mane (Hericium erinaceous)

Lions mane has been used for centuries throughout China and Japan for general debility and a mood tonic, and for various digestive disorders⁽⁶⁾. Nerve protective (neuroprotective) actions mediated through its antioxidant action as well as perhaps via stimulating Nerve Growth Factor (NGF) have been reported.

A trial involving 30 patients with mild dementia, reported improvements in cognitive function following 16 weeks treatment with 3g Lions Mane per day⁽⁷⁾, and another reported  increased cognitive function in participants aged 50 and over following 12 weeks treatment⁽⁸⁾. A small trial found evidence of anxiolytic and antidepressant effects, after 4 weeks administration to women in Japan^(9).

More trials are underway, to further explore the effects of this beautiful white waterfall-like fungus, on the human psyche.

Other well-known Asian species include Cordyceps militaris (Orange caterpillar fungus), which grows inside caterpillars, consuming the tissue of its host before bursting forth to release its spores.  It is used for respiratory, kidney, liver and cardiovascular diseases, low libido, impotence, hyperlipidaemia, hyperglycaemia and as a tonic for fatigue, convalescence, and to promote energy^{(10, 11, 12)}. Several Chinese clinical trials involving people with varying levels of chronic kidney failure, have also reported an ability to improve kidney function, reduce anaemia, and act as a useful adjunct to the drug cyclosporine, which has a predisposition to cause kidney damage ^{(13, 14, 15)}. 

Shiitake (Lentinula edodes) is rich in antioxidants and has been shown to support healthy immune T-cell function. Maitake (Grifola frondosa) is another popular species with potential applications in neurodegenerative diseases, and whose fruiting body and fungal mycelium have antitumour and immunomodulatory activities⁽¹⁶⁾.

The above has hardly touched the edges of the amount of information now available on these increasingly popular mushroom species, which are being utilised as foods, medicines and natural health products around the world. Given the clever evolutionary nature of fungi and their ability to grow on a range of decaying organic matter and symbiotically with other plant species while producing a diverse array of highly bioactive compounds, it is perhaps a reflection of the circularity of everything in nature that so many of them seem to have a powerful ability to help humans and other animals deal with chronic health conditions often seen with aging, and to live healthier lives.

Future opportunies for Aotearoa

Aotearea New Zealand has a fascinating mix of native, endemic and introduced fungi. Several of our native medicinal fungi are endangered, including Cordyceps robertsii (āwheto) and Hericium novae-zelandiae (pekepekekiore), a cousin of Lion’s Mane. Little research into their medicinal actions has taken place, although University of Auckland researchers have found extracts of Hericium novae-zelandiae to have anti-proliferative effects on three prostate cancer cell lines^{(17, 18)}.

The rich environmental and species diversity of Aotearoa New Zealand and our growing realisation of the medicinal properties of so many fungi, lends itself to the identification, mapping, analysis, bioactivity testing, agronomy work, cultivation, and commercialization of both native and introduced mushroom species. Their potential as foods and medicines, and as facilitators of a more natural biodegradation of waste, warrants much more research into medicinal fungi in Aotearoa’s future.

References:

1. Ramírez-Terrazo A, Adriana Montoya E, Garibay-Orijel R, Caballero-Nieto J, Kong-Luz A, Méndez-Espinoza C. Breaking the paradigms of residual categories and neglectable importance of non-used resources: the “vital” traditional knowledge of non-edible mushrooms and their substantive cultural significance. J Ethnobiol Ethnomed. 2021;17(1):28. Published 2021 Apr 21.
2. Anusiya G, Gowthama Prabu U, Yamini NV, et al. A review of the therapeutic and biological effects of edible and wild mushrooms. Bioengineered. 2021;12(2):11239-11268.
3. Chang S, Buswell J. Medicinal Mushrooms: Past, Present and Future. Adv Biochem Eng Biotechnol. 2022 Feb 27. doi: 10.1007/10_2021_197. Epub ahead of print. PMID: 35220455.
4. Hobbs C. Medicinal Fungi: Chemistry, Activity, and Product Assurance. HerbalGram, Journal of the Americal Botanical Council, 113, Feb-Apr 2017.
5. Jin X, Ruiz Beguerie J, Sze DM, Chan GC. Ganoderma lucidum (Reishi mushroom) for cancer treatment. Cochrane Database Syst Rev. 2016 Apr 5;4(4):CD007731.
6. Wang M, Gao Y, Xu D, Konishi T, Gao Q. Hericium erinaceus (Yamabushitake): a unique resource for developing functional foods and medicines. Food Funct. 2014 Dec;5(12):3055-64.
7. Mori K, Inatomi S, Ouchi K, Azumi Y, Tuchida T. Improving effects of the mushroom Yamabushitake (Hericium erinaceus) on mild cognitive impairment: a double-blind placebo-controlled clinical trial. Phytother Res. 2009 Mar;23(3):367-72.
8. Saitsu Y, Nishide A, Kikushima K, Shimizu K, Ohnuki K. Improvement of cognitive functions by oral intake of Hericium erinaceus. Biomed Res. 2019;40(4):125-131.
9. Nagano M, Shimizu K, Kondo R, Hayashi C, Sato D, Kitagawa K, Ohnuki K. Reduction of depression and anxiety by 4 weeks Hericium erinaceus intake. Biomed Res. 2010 Aug;31(4):231-7.
10. Ashraf SA, Elkhalifa AEO, Siddiqui AJ, Patel M, Awadelkareem AM, Snoussi M, Ashraf MS, Adnan M, Hadi S. Cordycepin for Health and Wellbeing: A Potent Bioactive Metabolite of an Entomopathogenic Cordyceps Medicinal Fungus and Its Nutraceutical and Therapeutic Potential. Molecules. 2020 Jun 12;25(12):2735.
11. Cao C, Yang S, Zhou Z. The potential application of Cordyceps in metabolic-related disorders. Phytother Res. 2020 Feb;34(2):295-305. doi: 10.1002/ptr.6536. Epub 2019 Oct 31. PMID: 31667949.
12. Phull AR, Ahmed M, Park HJ. Cordyceps militaris as a Bio Functional Food Source: Pharmacological Potential, Anti-Inflammatory Actions and Related Molecular Mechanisms. Microorganisms. 2022 Feb 10;10(2):405.
13. Li Y, Xue WJ, Tian PX, Ding XM, Yan H, Pan XM, Feng XS. Clinical application of Cordyceps sinensis on immunosuppressive therapy in renal transplantation. Transplant Proc. 2009 Jun;41(5):1565-9.
14. Luo Y, Yang SK, Zhou X, Wang M, Tang D, Liu FY, Sun L, Xiao L. Use of Ophiocordyceps sinensis (syn. Cordyceps sinensis) combined with angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB) versus ACEI/ARB alone in the treatment of diabetic kidney disease: a meta-analysis. Ren Fail. 2015 May;37(4):614-34.
15. Sun T, Dong W, Jiang G, Yang J, Liu J, Zhao L, Ma P. Cordyceps militaris Improves Chronic Kidney Disease by Affecting TLR4/NF-κB Redox Signaling Pathway. Oxid Med Cell Longev. 2019 Mar 31;2019:7850863.
16. Wu JY, Siu KC, Geng P. Bioactive Ingredients and Medicinal Values of Grifola frondosa (Maitake). Foods. 2021 Jan 5;10(1):95
17. Chen ZG , Bishop KS , Tanambell H , Buchanan P , Smith C , Quek SY . Characterization of the bioactivities of an ethanol extract and some of its constituents from the New Zealand native mushroom Hericium novae-zealandiae. Food Funct. 2019 Oct 16;10(10):6633-6643.
18. Chen ZG, Bishop KS, Tanambell H, Buchanan P, Quek SY. Assessment of In Vitro Bioactivities of Polysaccharides Isolated from HericiumNovae-Zealandiae. Antioxidants (Basel). 2019 Jul 8;8(7):211.

While Omicron, the latest Covid-19 variant to emerge is less likely to cause serious illness than its delta predecessor, it’s also a lot more infectious. Given this, and the New Zealand government’s policy change to ‘learning to live with’ this virus rather than wanting to return to lockdowns, the country is probably on the verge of a rapidly spreading outbreak.

We should be thankful that New Zealand avoided the extensive outbreaks of the more virulent delta variant experienced in most other countries, and omicron may even be the ‘beginning of the end’ phase of the global disruption caused by the SARS-CoV-2 virus over the past two and a half years. Most will experience a relatively mild infection, and around 20% of those infected with omicron are likely to be asymptomatic^{(1, 2)}.

Omicron can, however, still produce serious illness particularly in those with underlying health conditions or who are unvaccinated, and due to the likely rapid spread and extent of the outbreak, there are worries it may overwhelm hospitals and other health care services as has occurred overseas. These concerns are heightened due to staff and resource shortages within New Zealand’s mainstream health care system⁽³⁾.

After two years of very low rates of influenza due to social distancing and lockdowns, New Zealand is now also overdue for a flu epidemic, and to my mind the risks of a double whammy of both influenza and omicron hitting us this winter, are relatively high. Together with the highly debilitating nature and protracted recovery time of so-called Long Covid, which can continue or develop long after the initial infection is over⁽⁴⁾, the omicron form of Covid-19 is therefore a virus to try and avoid.

For New Zealanders, avoiding infection with omicron in the coming months, will probably be difficult. This is likely to be the case both for those who are vaccinated and unvaccinated. While vaccination and in particular having had the 3^rd booster Pfizer vaccine is associated with milder symptoms^{(5, 6)}, the level of protection against omicron appears to be less than that against the delta variant^{(7, 8, 9)}.  The duration of the protective action of the current Pfizer booster vaccine, is also as yet unknown.

Vaccination strategy

Researchers in the U.S. who tracked the evolutionary trajectories of vaccine-resistant mutations over time in more than 2.2 million SARS-CoV-2 genomes, have found the occurrence and frequency of vaccine-resistant mutations to correlate strongly with vaccination rates in Europe and America⁽¹⁰⁾. Their data suggests that vaccine-resistant mutations will gradually become one of the main evolutionary tendencies of new variants, particularly in populations with high rates of vaccination.

Despite the good intentions of the Covid-19 Vaccines Global Access (COVAX) scheme for providing vaccines to low-income countries, global vaccine inequities have also worsened with the recent focus on booster vaccines, and huge disparities continue to exist between vaccine access in high versus low income countries^{(11, 12, 13)}. This has ethical and many other implications.

While the development of new generation and multivariant vaccines may have broader spectrums of action and avoid the need for frequent booster immunisations, these factors are cumulatively reasons to reconsider the relative contribution that vaccines will make to the world’s future Covid-19 management strategy^{(14, 15)}.

Herbal approaches to dealing with omicron

Given most of us will need to manage an omicron infection at home, it’s a good time to consider other medicines that may be useful. Official government Covid-19 communications are now encouraging us to stock up on medicines such as paracetamol, ibuprofen and nasal decongestants in preparation for the omicron outbreak.

I’ve previously discussed herbal interventions that may help with either a prophylactic or treatment approach to Covid-19^{(16, 17, 18, 19, 20)}. Since this coronavirus first emerged more than two years ago, there’s also been a huge amount of research into potentially useful herbal medicines, and a lot of encouraging findings published in the scientific literature^{(21, 22, 23, 24, 25)}.

For many years I’ve promoted the benefits of herbs such as Echinacea in helping to both enhance immunity and reduce inflammation in a wide range of infectious conditions (18), provided the appropriate type and dose is used.

There’s a lot we’ve learnt about omicron from other countries in recent weeks. It has several differences to earlier variants of Covid-19, and understanding these and its particular symptomatology and pathology is helpful. A runny nose, headache and fatigue are the most common symptoms, with body ache, muscle ache, cough and fever also being frequently experienced⁽¹⁾.

While omicron has a greater ability than delta to infect us through our upper nasal cavity and mouths, it seems more likely to be confined to the upper nasal passages, throat and sinuses, and somewhat less able to produce a serious infection of the lower respiratory tract or lungs^{(1, 26)}.

As such, the rationale of optimising our body’s own inbuilt defence system at the top end of our respiratory tract, would seem to make particular sense. Providing a local physical barrier to the entry of airborne viruses is how masks work, and inhalations or sprays through the oral or nasal cavities are also often the route of administration of drugs used to treat lung conditions such as asthma or nasal congestion.

Many traditional applications of herbal medicine including Maori Medicine (Rongoā Māori), Ayurvedic, Chinese and European herbal medicine, utilised inhalation through the lungs as a popular method of administration. This pulmonary route of administration through inhalation or sprays, is also widely used to treat conditions such as asthma or sore throats, or as a way to deliver drugs to the general blood circulation and treat other systemic conditions. 

When I researched herbs for the 1996 bird flu and 2009 swine flu pandemics, I formed the view that there is merit in the use of local applications to the upper airways of decongestant, anti-inflammatory and antimicrobial herbs, as part of a strategy to both prevent or treat these other highly virulent respiratory tract viruses. This lead me to subsequently formulate and develop both a throat spray and a lung care spray, each administered as fine sprays through the oral cavity.

These products contain some of our wonderful New Zealand grown herbs such as elecampane, horseradish, thyme and kawakawa, as well as New Zealand propolis. Each of these has specific benefits of relevance to optimising and enhancing our own natural and ‘first line’ upper respiratory tract defence barriers to infection^{(19, 20)}. Their anti-inflammatory, antimicrobial and expectorant actions provide a healthy and natural support for the body’s mucous membranes, immune system and cilia within our respiratory tract whose job is to try to keep unwanted bugs and other nasties out of our lungs.

Elecampane has long been traditionally used for coughs, chest infections, asthma and other lung conditions. Beneficial effects included suppression of pulmonary pathological changes, neutrophil infiltration, pulmonary permeability, and pro-inflammatory cytokine expression^{(27, 28)}. Promising affinity towards both the SARS-CoV-2 viral proteins and host receptors has also been reported for elecampane phytochemicals⁽²⁹⁾, suggesting a potential dual. action to simultaneously improve host immunity while targeting viral proteins to reduce the severity of the infection. Such multiple actions and sites of action, are a key strength of plant derived phytochemicals, particularly given the ability of the viral genome to mutate so rapidly and outpace our ability to develop and distribute effective new vaccines on an ongoing basis.

The common weed ribwort (Plantago lanceolata), can be safely taken as a tea or in herbal products, regarded as a tonic and food for mucous membranes, while having additional expectorant and anti-inflammatory properties⁽³⁰⁾. In sufficiently high doses, it can also act as a wonderful natural decongestant.

Other useful herbs for upper respiratory tract support include peppermint, elderflower and yarrow, all of which are easily grown in our country, and are available in various forms. The warming and sometimes diaphoretic (sweat inducing) properties of these particularly when drunk as dried or fresh herb infusions, and their traditional uses for infections such as colds, influenza and other viral infections, inflammation and fevers for many centuries, make them also worthy of use.

Apart from Echinacea, I’m now making sure I have plenty of these various herbs and products made from them, in my own medicine cabinet at home.  Given omicron’s affinity to affect the upper rather than lower respiratory tract, I think they will be at least as useful as cough syrups for most people who contract this virus. That’s not to say that we wont also need these, as lung infections will still occur.

To summarise, as well as stocking up on drugs such as paracetamol and ibuprofen, coffee, toilet paper and disinfectant, there’s a lot we can do in terms of increasing our intake of certain dietary herbs and spices, and quite a number of different medicinal herbal products out there for which there is compelling evidence that they can help get us through the forthcoming omicron outbreak in Aotearoa.

Based upon their powerful tradition and strong scientific basis, I urge everyone to incorporate effective plant medicine in addition to other measures to help soften the impact of the forthcoming outbreak of the omicron variant of Covid-19, and other potential respiratory tract infections this autumn and winter.

References:

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2. Meo SA, Meo AS, Al-Jassir FF, Klonoff DC. Omicron SARS-CoV-2 new variant: global prevalence and biological and clinical characteristics. Eur Rev Med Pharmacol Sci. 2021 Dec;25(24):8012-8018. doi: 10.26355/eurrev_202112_27652. PMID: 34982465.
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7. Cele S, Jackson L, Khoury DS, Khan K, Moyo-Gwete T, Tegally H, San JE, Cromer D, Scheepers C, Amoako DG, Karim F, Bernstein M, Lustig G, Archary D, Smith M, Ganga Y, Jule Z, Reedoy K, Hwa SH, Giandhari J, Blackburn JM, Gosnell BI, Abdool Karim SS, Hanekom W; NGS-SA; COMMIT-KZN Team, von Gottberg A, Bhiman JN, Lessells RJ, Moosa MS, Davenport MP, de Oliveira T, Moore PL, Sigal A. Omicron extensively but incompletely escapes Pfizer BNT162b2 neutralization. Nature. 2021 Dec 23. doi: 10.1038/s41586-021-04387-1. Epub ahead of print. PMID: 35016196.
8. Malik JA, Ahmed S, Mir A, Shinde M, Bender O, Alshammari F, Ansari M, Anwar S. The SARS-CoV-2 mutations versus vaccine effectiveness: New opportunities to new challenges. J Infect Public Health. 2022 Jan 5;15(2):228-240. doi: 10.1016/j.jiph.2021.12.014. Epub ahead of print. PMID: 35042059; PMCID: PMC8730674.
9. Ai J, Zhang H, Zhang Y, Lin K, Zhang Y, Wu J, Wan Y, Huang Y, Song J, Fu Z, Wang H, Guo J, Jiang N, Fan M, Zhou Y, Zhao Y, Zhang Q, Liu Q, Lv J, Li P, Qiu C, Zhang W. Omicron variant showed lower neutralizing sensitivity than other SARS-CoV-2 variants to immune sera elicited by vaccines after boost. Emerg Microbes Infect. 2022 Dec;11(1):337-343. doi: 10.1080/22221751.2021.2022440. PMID: 34935594; PMCID: PMC8788341.
10. Wang R, Chen J, Wei GW. Mechanisms of SARS-CoV-2 Evolution Revealing Vaccine-Resistant Mutations in Europe and America. J Phys Chem Lett. 2021 Dec 16;12(49):11850-11857. doi: 10.1021/acs.jpclett.1c03380. Epub 2021 Dec 7. PMID: 34873910; PMCID: PMC8672435.
11. Singhal T. The Emergence of Omicron: Challenging Times Are Here Again! Indian J Pediatr. 2022 Jan 13:1–7. doi: 10.1007/s12098-022-04077-4. Epub ahead of print. PMID: 35025038; PMCID: PMC8756165.
12. Van De Pas R, Widdowson MA, Ravinetto R, N Srinivas P, Ochoa TJ, Fofana TO, Van Damme W. COVID-19 vaccine equity: a health systems and policy perspective. Expert Rev Vaccines. 2022 Jan;21(1):25-36. doi: 10.1080/14760584.2022.2004125. Epub 2021 Nov 25. PMID: 34758678; PMCID: PMC8631691.
13. Editorial, Omicron is bad but the global response is worse. Nature 2021 Dec;600(7888):190.
14. Cohen J, Omicron sparks a vaccine strategy debate. Science 2021; Dec 24)374(6575):1544-1545.
15. Haque A, Pant AB. Mitigating Covid-19 in the face of emerging virus variants, breakthrough infections and vaccine hesitancy. J Autoimmun. 2022 Jan 1;127:102792. doi: 10.1016/j.jaut.2021.102792. Epub ahead of print. PMID: 34995958; PMCID: PMC8719928.
16. Rasmussen PL, Optimising Immunity to protect against coronaviruses. www.herbblurb.com  Feb 4, 2020.
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18. Rasmussen PL, Echinacea in the time of a pandemic. www.herbblurb.com  Oct 30, 2020.
19. Rasmussen PL, SARS-CoV-2 – the coronavirus that is changing the world. www.herbblurb.com July 25, 2021.
20. Rasmussen PL, Propolis – amazing stuff made by bees from nature.  www.herbblurb.com  Apr 9, 2021.
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24. Haridas M, Sasidhar V, Nath P, Abhithaj J, Sabu A, Rammanohar P. Compounds of Citrus medica and Zingiber officinale for COVID-19 inhibition: in silico evidence for cues from Ayurveda. Futur J Pharm Sci. 2021;7(1):13. doi: 10.1186/s43094-020-00171-6. Epub 2021 Jan 9. PMID: 33457429; PMCID: PMC7794642.
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26. Kozlov M. Omicron’s feeble attack on the lungs could make it less dangerous. Nature. 2022 Jan;601(7892):177. doi: 10.1038/d41586-022-00007-8. PMID: 34987210.
27. Seca AM, Grigore A, Pinto DC, Silva AM. The genus Inula and their metabolites: from ethnopharmacological to medicinal uses. J Ethnopharmacol. 2014 Jun 11;154(2):286-310. doi: 10.1016/j.jep.2014.04.010. Epub 2014 Apr 19. PMID: 24754913.
28. Gierlikowska B, Gierlikowski W, Bekier K, Skalicka-Woźniak K, Czerwińska ME, Kiss AK. Inula helenium and Grindelia squarrosa as a source of compounds with anti-inflammatory activity in human neutrophils and cultured human respiratory epithelium. J Ethnopharmacol. 2020 Mar 1;249:112311. doi: 10.1016/j.jep.2019.112311. Epub 2019 Oct 20. PMID: 31644941.
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