Impact of Climate Change and Human Interventions on a Popular South African Medicinal Plant

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.

Herbal medicine for post-Covid fatigue and recovery

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.
  10. Damiano RF, Guedes BF, de Rocca CC, et al. Cognitive decline following acute viral infections: literature review and projections for post-COVID-19. Eur Arch Psychiatry Clin Neurosci. 2022;272(1):139-154.
  11. Alkodaymi MS, Omrani OA, Fawzy NA, et al. Prevalence of post-acute COVID-19 syndrome symptoms at different follow-up periods: a systematic review and meta-analysis. Clin Microbiol Infect. 2022;28(5):657-666.
  12. Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med. 1994;121(12):953-959.
  13. Heyll U, Wachauf P, Senger V, Diewitz M. Definitionen des “Chronic Fatigue Syndrome” (CFS) [Definition of “chronic fatigue syndrome” (CFS)]. Med Klin (Munich). 1997;92(4):221-227.
  14. Mawle AC. Chronic fatigue syndrome. Immunol Invest. 1997;26(1-2):269-273.
  15. Moldofsky H, Patcai J. Chronic widespread musculoskeletal pain, fatigue, depression and disordered sleep in chronic post-SARS syndrome; a case-controlled study. BMC Neurol. 2011;11:37. doi: 10.1186/1471-2377-11-37
  16. Poenaru S, Abdallah SJ, Corrales-Medina V, Cowan J. COVID-19 and post-infectious myalgic encephalomyelitis/chronic fatigue syndrome: a narrative review. Ther Adv Infect Dis. 2021;8:20499361211009385.
  17. Hickie I, Davenport T, Wakefield D, et al. Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study. BMJ. 2006;333(7568):575.
  18. Vanderheiden A, Klein RS. Neuroinflammation and COVID-19. Curr Opin Neurobiol. 2022;76:102608.
  19. Ismail II, Salama S. Association of CNS demyelination and COVID-19 infection: an updated systematic review. J Neurol. 2022;269(2):541-576.
  20. Rasmussen PL, Culinary herbs and spices to know about, in infectious times. www.herbblurb.com 20 March 2020.
  21. Rasmussen PL, Echinacea in the time of a pandemic. www.herbblurb.com 30 October 2020.
  22. Rasmussen PL, Propolis – amazing stuff made by bees from nature. www.herbblurb.com 9 April 2021
  23. Rasmussen PL, Omicron – the latest Covid-19 chapter. www.herbblurb.com 29 Jan 2022.
  24. Jeon, S. R., Kang, J. W., Ang, L., Lee, H. W., Lee, M. S., & Kim, T. H. (2022). Complementary and alternative medicine (CAM) interventions for COVID-19: An overview of systematic reviews. Integrative medicine research11(3), 100842.
  25. Ang L, Song E, Hu XY, Lee HW, Chen Y, Lee MS. Herbal Medicine Intervention for the Treatment of COVID-19: A Living Systematic Review and Cumulative Meta-Analysis. Front Pharmacol. 2022;13:906764. Published 2022 Jun 20.
  26. Prajapati SK, Malaiya A, Mishra G, et al. An exhaustive comprehension of the role of herbal medicines in Pre- and Post-COVID manifestations. J Ethnopharmacol. 2022;296:115420.
  27. Barton DL, Liu H, Dakhil SR, et al. Wisconsin Ginseng (Panax quinquefolius) to improve cancer-related fatigue: a randomized, double-blind trial, N07C2. J Natl Cancer Inst. 2013;105(16):1230-1238.
  28. Kim JW, Han SW, Cho JY, et al. Korean red ginseng for cancer-related fatigue in colorectal cancer patients with chemotherapy: A randomised phase III trial. Eur J Cancer. 2020;130:51-62
  29. Devpura G, Tomar BS, Nathiya D, et al. Randomized placebo-controlled pilot clinical trial on the efficacy of ayurvedic treatment regime on COVID-19 positive patients. Phytomedicine. 2021;84:153494.
  30. Patil VS, Hupparage VB, Malgi AP, Deshpande SH, Patil SA, Mallapur SP. Dual inhibition of COVID-19 spike glycoprotein and main protease 3CLpro by Withanone from Withania somniferaChin Herb Med. 2021;13(3):359-369.
  31. Qi JH, Dong FX, Wang K, et al. Feasibility analysis and mechanism exploration of Rhei Radix et Rhizome-Schisandrae Sphenantherae Fructus (RS) against COVID-19. J Med Microbiol. 2022;71(5):10.
  32. Kushwaha PP, Singh AK, Prajapati KS, Shuaib M, Gupta S, Kumar S. Phytochemicals present in Indian ginseng possess potential to inhibit SARS-CoV-2 virulence: A molecular docking and MD simulation study. Microb Pathog. 2021;157:104954.
  33. Karosanidze I, Kiladze U, Kirtadze N, et al. Efficacy of Adaptogens in Patients with Long COVID-19: A Randomized, Quadruple-Blind, Placebo-Controlled Trial. Pharmaceuticals (Basel). 2022;15(3):345.
  34. Li XT, Li HC, Li CB, Dou DQ, Gao MB. Protective effects on mitochondria and anti-aging activity of polysaccharides from cultivated fruiting bodies of Cordyceps militaris. Am J Chin Med. 2010;38(6):1093-1106.
  35. Bai X, Tan TY, Li YX, et al. The protective effect of cordyceps sinensis extract on cerebral ischemic injury via modulating the mitochondrial respiratory chain and inhibiting the mitochondrial apoptotic pathway. Biomed Pharmacother. 2020;124:109834.
  36. Song J, Wang Y, Teng M, et al. Studies on the Antifatigue Activities of Cordyceps militaris Fruit Body Extract in Mouse Model. Evid Based Complement Alternat Med. 2015;2015:174616.
  37. Zhao H, Zhang Q, Zhao L, Huang X, Wang J, Kang X. Spore Powder of Ganoderma lucidum Improves Cancer-Related Fatigue in Breast Cancer Patients Undergoing Endocrine Therapy: A Pilot Clinical Trial. Evid Based Complement Alternat Med. 2012;2012:809614.
  38. Jan JT, Cheng TR, Juang YP, et al. Identification of existing pharmaceuticals and herbal medicines as inhibitors of SARS-CoV-2 infection. Proc Natl Acad Sci U S A. 2021;118(5):e2021579118.
  39. Yeh H, Vo DNK, Lin ZH, et al. GMI, a protein from Ganoderma microsporum, induces ACE2 degradation to alleviate infection of SARS-CoV-2 Spike-pseudotyped virus. Phytomedicine. 2022;103:154215.
  40. Jędrejko KJ, Lazur J, Muszyńska B. Cordyceps militaris: An Overview of Its Chemical Constituents in Relation to Biological Activity. Foods. 2021;10(11):2634.
  41. Verma AK. Cordycepin: a bioactive metabolite of Cordyceps militaris and polyadenylation inhibitor with therapeutic potential against COVID-19. J Biomol Struct Dyn. 2022;40(8):3745-3752.
  42. Elhusseiny SM, El-Mahdy TS, Awad MF, et al. Proteome Analysis and In Vitro Antiviral, Anticancer and Antioxidant Capacities of the Aqueous Extracts of Lentinula edodes and Pleurotus ostreatus Edible Mushrooms. Molecules. 2021;26(15):4623.
  43. Shahzad F, Anderson D, Najafzadeh M. The Antiviral, Anti-Inflammatory Effects of Natural Medicinal Herbs and Mushrooms and SARS-CoV-2 Infection. Nutrients. 2020;12(9):2573.
  44. Rahman MA, Rahman MS, Bashir NMB, et al. Rationalization of Mushroom-Based Preventive and Therapeutic Approaches to COVID-19: Review. Int J Med Mushrooms. 2021;23(5):1-11
  45. El Dine RS, El Halawany AM, Ma CM, Hattori M. Inhibition of the dimerization and active site of HIV-1 protease by secondary metabolites from the Vietnamese mushroom Ganoderma colossum. J Nat Prod. 2009;72(11):2019-2023.
  46. Zhu Q, Bang TH, Ohnuki K, Sawai T, Sawai K, Shimizu K. Inhibition of neuraminidase by Ganoderma triterpenoids and implications for neuraminidase inhibitor design. Sci Rep. 2015;5:13194. 
  47. Sillapachaiyaporn C, Chuchawankul S. HIV-1 protease and reverse transcriptase inhibition by tiger milk mushroom (Lignosus rhinocerus) sclerotium extracts: In vitro and in silico studies. J Tradit Complement Med. 2019;10(4):396-404. 
  48. Zhang CC, Yin X, Cao CY, Wei J, Zhang Q, Gao JM. Chemical constituents from Hericium erinaceus and their ability to stimulate NGF-mediated neurite outgrowth on PC12 cells. Bioorg Med Chem Lett. 2015;25(22):5078-5082.
  49. Nagano M, Shimizu K, Kondo R, et al. Reduction of depression and anxiety by 4 weeks Hericium erinaceus intake. Biomed Res. 2010;31(4):231-237. 
  50. Chong PS, Fung ML, Wong KH, Lim LW. Therapeutic Potential of Hericium erinaceus for Depressive Disorder. Int J Mol Sci. 2019;21(1):163.
  51. Vigna L, Morelli F, Agnelli GM, et al. Hericium erinaceus Improves Mood and Sleep Disorders in Patients Affected by Overweight or Obesity: Could Circulating Pro-BDNF and BDNF Be Potential Biomarkers?. Evid Based Complement Alternat Med. 2019;2019:7861297.

Medicines from the Sea – so much more than Weeds

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 GracilariaGigartina 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 crispusPorphyra 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.

References:

  1. Lordan S, Ross RP, Stanton C. Marine bioactives as functional food ingredients: potential to reduce the incidence of chronic diseases. Mar Drugs. 2011;9(6):1056-1100.
  2. Wu Q, Liu L, Miron A, Klímová B, Wan D, Kuča K. The antioxidant, immunomodulatory, and anti-inflammatory activities of Spirulina: an overview. Arch Toxicol. 2016;90(8):1817-1840.
  3. Hatami E, Ghalishourani SS, Najafgholizadeh A, et al. The effect of spirulina on type 2 diabetes: a systematic review and meta-analysis. J Diabetes Metab Disord. 2021;20(1):883-892.
  4. Donoso A, González-Durán J, Muñoz AA, González PA, Agurto-Muñoz C. “Therapeutic uses of natural astaxanthin: An evidence-based review focused on human clinical trials”. Pharmacol Res. 2021;166:105479.
  5. Ambati RR, Phang SM, Ravi S, Aswathanarayana RG. Astaxanthin: sources, extraction, stability, biological activities and its commercial applications–a review. Mar Drugs. 2014;12(1):128-152.
  6. Kidd P. Astaxanthin, cell membrane nutrient with diverse clinical benefits and anti-aging potential. Altern Med Rev. 2011;16(4):355-364
  7. Lima SGM, Freire MCLC, Oliveira VDS, Solisio C, Converti A, de Lima ÁAN. Astaxanthin Delivery Systems for Skin Application: A Review. Mar Drugs. 2021;19(9):511.
  8. Zhou X, Cao Q, Orfila C, Zhao J, Zhang L. Systematic Review and Meta-Analysis on the Effects of Astaxanthin on Human Skin Ageing. Nutrients. 2021;13(9):2917.
  9. Giannaccare G, Pellegrini M, Senni C, Bernabei F, Scorcia V, Cicero AFG. Clinical Applications of Astaxanthin in the Treatment of Ocular Diseases: Emerging Insights. Mar Drugs. 2020;18(5):239.
  10. Kizawa Y, Sekikawa T, Kageyama M, Tomobe H, Kobashi R, Yamada T. Effects of anthocyanin, astaxanthin, and lutein on eye functions: a randomized, double-blind, placebo-controlled study. J Clin Biochem Nutr. 2021;69(1):77-90
  11. Fitton JH, Stringer DN, Karpiniec SS. Therapies from Fucoidan: An Update. Mar Drugs. 2015;13(9):5920-5946.
  12. Apostolova E, Lukova P, Baldzhieva A, et al. Immunomodulatory and Anti-Inflammatory Effects of Fucoidan: A Review. Polymers (Basel). 2020;12(10):2338
  13. Iliou K, Kikionis S, Ioannou E, Roussis V. Marine Biopolymers as Bioactive Functional Ingredients of Electrospun Nanofibrous Scaffolds for Biomedical Applications. Mar Drugs. 2022;20(5):314.
  14. Xie Y, Gao P, He F, Zhang C. Application of Alginate-Based Hydrogels in Hemostasis. Gels. 2022;8(2):109. 
  15. Premarathna AD, Wijesekera SK, Jayasooriya AP, et al. In vitro and in vivo evaluation of the wound healing properties and safety assessment of two seaweeds (Sargassum ilicifolium and Ulva lactuca). Biochem Biophys Rep. 2021;26:100986. Published 2021 Mar 31. doi:10.1016/j.bbrep.2021.100986
  16. Liberski A, Latif N, Raynaud C, Bollensdorff C, Yacoub M. Alginate for cardiac regeneration: From seaweed to clinical trials. Glob Cardiol Sci Pract. 2016;2016(1):e201604.
  17. Yegappan R, Selvaprithiviraj V, Amirthalingam S, Jayakumar R. Carrageenan based hydrogels for drug delivery, tissue engineering and wound healing. Carbohydr Polym. 2018;198:385-400.
  18. Kang HK, Seo CH, Park Y. Marine peptides and their anti-infective activities. Mar Drugs. 2015;13(1):618-654.
  19. Pérez MJ, Falqué E, Domínguez H. Antimicrobial Action of Compounds from Marine Seaweed. Mar Drugs. 2016;14(3):52
  20. Gomes L, Monteiro P, Cotas J, et al. Seaweeds’ pigments and phenolic compounds with antimicrobial potential. Biomol Concepts. 2022;13(1):89-102.
  21. 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.
  22. Arvinda Swamy ML. Marine algal sources for treating bacterial diseases. Adv Food Nutr Res. 2011;64:71-84
  23. Ardita NF, Mithasari L, Untoro D, Salasia SIO. Potential antimicrobial properties of the Ulva lactuca extract against methicillin-resistant Staphylococcus aureus-infected wounds: A review. Vet World. 2021;14(5):1116-1123
  24. Wei Y, Liu Q, Xu C, Yu J, Zhao L, Guo Q. Damage to the membrane permeability and cell death of vibrio parahaemolyticus caused by phlorotannins with low molecular weight from Sargassum thunbergii. J Aquat Food Product Technol. 2016 Apr 2;25(3):323–33.
  25. Okimura T, Jiang Z, Komatsubara H, Hirasaka K, Oda T. Therapeutic effects of an orally administered edible seaweed-derived polysaccharide preparation, ascophyllan HS, on a Streptococcus pneumoniae infection mouse model. Int J Biol Macromol. 2020;154:1116-1122.
  26. Bhowmick S, Mazumdar A, Moulick A, Adam V. Algal metabolites: an inevitable substitute for antibiotics. Biotechnol Adv. 2020;43(November 2019):107571.
  27. Bogolitsyn K, Dobrodeeva L, Druzhinina A, Ovchinnikov D, Parshina A, Shulgina E. Biological activity of a polyphenolic complex of Arctic brown algae. J Appl Phycology. 2019 Oct;31(5):3341–8.
  28. Lee J-H, Eom S-H, Lee E-H, Jung Y-J, Kim H-J, Jo M-R, et al. In vitro antibacterial and synergistic effect of phlorotannins isolated from edible brown seaweed Eisenia bicyclis against acne-related bacteria. ALGAE. 2014 Mar;29(1):47–55.
  29. Eom SH, Kim DH, Lee SH, et al. In vitro antibacterial activity and synergistic antibiotic effects of phlorotannins isolated from Eisenia bicyclis against methicillin-resistant Staphylococcus aureus. Phytother Res. 2013;27(8):1260-1264. 
  30. Murugaboopathy V, Saravankumar R, Mangaiyarkarasi R, Kengadaran S, Samuel SR, Rajeshkumar S. Efficacy of marine algal extracts against oral pathogens – A systematic review. Indian J Dent Res. 2021;32(4):524-527.
  31. Mišurcová L., Škrovánková S., Samek D., Ambrožová J., Machů L. Health benefits of algal polysaccharides in human nutrition. Adv. Food Nutr. Res. 2012;66:75–145
  32. Besednova NN, Andryukov BG, Zaporozhets TS, et al. Antiviral Effects of Polyphenols from Marine Algae. Biomedicines. 2021;9(2):200.
  33. Geetha Bai R, Tuvikene R. Potential Antiviral Properties of Industrially Important Marine Algal Polysaccharides and Their Significance in Fighting a Future Viral Pandemic. Viruses. 2021;13(9):1817. 
  34. Pagarete A, Ramos AS, Puntervoll P, Allen MJ, Verdelho V. Antiviral Potential of Algal Metabolites-A Comprehensive Review. Mar Drugs. 2021;19(2):94.
  35. Hans N, Malik A, Naik S. Antiviral activity of sulfated polysaccharides from marine algae and its application in combating COVID-19: Mini review. Bioresour Technol Rep. 2021;13:100623
  36. Asif M, Saleem M, Yaseen HS, et al. Potential role of marine species-derived bioactive agents in the management of SARS-CoV-2 infection. Future Microbiol. 2021;16(16):1289-1301
  37. Frediansyah A. The antiviral activity of iota-, kappa-, and lambda-carrageenan against COVID-19: A critical review. Clin Epidemiol Glob Health. 2021;12:100826.
  38. Alsenani F, Tupally KR, Chua ET, et al. Evaluation of microalgae and cyanobacteria as potential sources of antimicrobial compounds. Saudi Pharm J. 2020;28(12):1834-1841.
  39. Lajili S, Deghrigue M, Bel Haj Amor H, Muller CD, Bouraoui A. In vitro immunomodulatory activity and in vivo anti-inflammatory and analgesic potential with gastroprotective effect of the Mediterranean red alga Laurencia obtusa. Pharm Biol. 2016;54(11):2486-2495.
  40. Shu MH, Appleton D, Zandi K, AbuBakar S. Anti-inflammatory, gastroprotective and anti-ulcerogenic effects of red algae Gracilaria changii (Gracilariales, Rhodophyta) extract. BMC Complement Altern Med. 2013;13:61
  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 research15(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
  67. Landrigan PJ, Stegeman JJ, Fleming LE, et al. Human Health and Ocean Pollution. Ann Glob Health. 2020;86(1):151.
  68. Roque BM, Venegas M, Kinley RD, et al. Red seaweed (Asparagopsis taxiformis) supplementation reduces enteric methane by over 80 percent in beef steers. PLoS One. 2021;16(3):e0247820.
  69. https://www.cawthron.org.nz/our-news/opinion-johan-svenson-asparagopsis/

Diabetes mellitus – some useful herbal medicines

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.

MATARIKI – Connecting the Stars, Humans and Nature

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 sciences22(19), 10816.
  2. Mohanraj, R., & Sivasankar, S. (2014). Sweet potato (Ipomoea batatas [L.] Lam)–a valuable medicinal food: a review. Journal of medicinal food17(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 biology305, 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 medicine18(1), 216.

Medicinal Mushrooms – emerging medicines

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.

Omicron – the latest Covid-19 chapter

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 3rd 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:

  1. Kim MK, Lee B, Choi YY, Um J, Lee KS, Sung HK, Kim Y, Park JS, Lee M, Jang HC, Bang JH, Chung KH, Jeon J. Clinical Characteristics of 40 Patients Infected With the SARS-CoV-2 Omicron Variant in Korea. J Korean Med Sci. 2022 Jan 17;37(3):e31. doi: 10.3346/jkms.2022.37.e31. PMID: 35040299; PMCID: PMC8763884.
  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.
  3. Rasmussen PL, New Zealand’s Health System under Stress.  www.herbblurb.com  Aug 27, 2021.
  4. Desai AD, Lavelle M, Boursiquot BC, Wan EY. Long-term complications of COVID-19. Am J Physiol Cell Physiol. 2022 Jan 1;322(1):C1-C11. doi: 10.1152/ajpcell.00375.2021. Epub 2021 Nov 24. PMID: 34817268; PMCID: PMC8721906.
  5. Doria-Rose NA, Shen X, Schmidt SD, O’Dell S, McDanal C, Feng W, Tong J, Eaton A, Maglinao M, Tang H, Manning KE, Edara VV, Lai L, Ellis M, Moore K, Floyd K, Foster SL, Atmar RL, Lyke KE, Zhou T, Wang L, Zhang Y, Gaudinski MR, Black WP, Gordon I, Guech M, Ledgerwood JE, Misasi JN, Widge A, Roberts PC, Beigel J, Korber B, Pajon R, Mascola JR, Suthar MS, Montefiori DC. Booster of mRNA-1273 Strengthens SARS-CoV-2 Omicron Neutralization. medRxiv [Preprint]. 2021 Dec 20:2021.12.15.21267805. doi: 10.1101/2021.12.15.21267805. PMID: 34931200; PMCID: PMC8687471.
  6. Lusvarghi S, Pollett SD, Neerukonda SN, Wang W, Wang R, Vassell R, Epsi NJ, Fries AC, Agan BK, Lindholm DA, Colombo CJ, Mody R, Ewers EC, Lalani T, Ganesan A, Goguet E, Hollis-Perry M, Coggins SAA, Simons MP, Katzelnick LC, Wang G, Tribble DR, Bentley L, Eakin AE, Broder CC, Erlandson KJ, Laing ED, Burgess TH, Mitre E, Weiss CD. SARS-CoV-2 Omicron neutralization by therapeutic antibodies, convalescent sera, and post-mRNA vaccine booster. bioRxiv [Preprint]. 2021 Dec 28:2021.12.22.473880. doi: 10.1101/2021.12.22.473880. PMID: 34981057; PMCID: PMC8722594.
  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.
  17. Rasmussen PL, Culinary herbs and spices to know about, in infectious times.  www.herbblurb.com  Mar 20, 2020.
  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.
  21. Adhikari B, Marasini BP, Rayamajhee B, Bhattarai BR, Lamichhane G, Khadayat K, Adhikari A, Khanal S, Parajuli N. Potential roles of medicinal plants for the treatment of viral diseases focusing on COVID-19: A review. Phytother Res. 2021 Mar;35(3):1298-1312. doi: 10.1002/ptr.6893. Epub 2020 Oct 9. PMID: 33037698; PMCID: PMC7675695.
  22. Aleem A, Akbar Samad AB, Slenker AK. Emerging Variants of SARS-CoV-2 And Novel Therapeutics Against Coronavirus (COVID-19). 2022 Jan 5. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 34033342.
  23. Bhattacharya R, Dev K, Sourirajan A. Antiviral activity of bioactive phytocompounds against coronavirus: An update. J Virol Methods. 2021 Apr;290:114070. doi: 10.1016/j.jviromet.2021.114070. Epub 2021 Jan 23. PMID: 33497729; PMCID: PMC7826042.
  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.
  25. Naik SR, Bharadwaj P, Dingelstad N, Kalyaanamoorthy S, Mandal SC, Ganesan A, Chattopadhyay D, Palit P. Structure-based virtual screening, molecular dynamics and binding affinity calculations of some potential phytocompounds against SARS-CoV-2. J Biomol Struct Dyn. 2021 Mar 8:1-18. doi: 10.1080/07391102.2021.1891969. Epub ahead of print. PMID: 33682632.
  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.
  29. Singh P, Chauhan SS, Pandit S, Sinha M, Gupta S, Gupta A, Parthasarathi R. The dual role of phytochemicals on SARS-CoV-2 inhibition by targeting host and viral proteins. J Tradit Complement Med. 2021 Sep 8. doi: 10.1016/j.jtcme.2021.09.001. Epub ahead of print. PMID: 34513611; PMCID: PMC8424525.
  30. Rasmussen PL, Effects of human pollutants on plants: the case of ribwort.  www.herbblurb.com  Apr 12, 2019.

Ginger – great for so much, including our digestive systems.

The roots and rhizomes of Ginger (Zingiber officinale; Roscoe, Zingiberacae), have been used medicinally for thousands of years.  Originating from southern China and spreading to India and South East Asia, ginger is highly valued and throughout history has had huge economic importance throughout not only for making meals more interesting, but also for its medicinal properties. Dose-dependent antiviral activities of relevance against the current SARS-CoV-2 coronavirus for example, are of great interest at the present time(1-4).

It is a component in a huge percentage of traditional herbal formulations, and like black pepper, became one of the most widely traded spices from Asia via the Silk Road and by sea during the Roman empire and beyond. Its reputation as an aphrodisiac, also made it sought after in Europe. Today it is cultivated in many tropical climates including throughout Asia and Africa, Brazil, Australia, the Caribbean and Polynesia. Many different local varieties and cultivars occur, depending on where it is grown. At least 140 other species are found in the Zingiber genus, some of which have become very invasive in some parts of the world.  

Like all medicinal plants, phytochemical and organoleptic (taste, smell, appearance) parameters of ginger vary depending on the source and post-harvest processing methods used(5). Most known pharmacological properties are largely attributed to polyphenolic compounds known as gingerols in fresh ginger, which dehydrate to become shogaols in dry ginger.

More than 400 scientific papers a year are now being published on ginger’s potential therapeutic properties. Indications include conditions such as digestive upsets, infectious diseases, diabetes mellitus, obesity, inflammatory and degenerative joint conditions, pain and more(6). This article will focus on digestive system applications.

Digestive Aid

Confucius is said to have written as far back as 500 B.C. that he was never without ginger when he ate, and the Greek physician Dioscorides wrote in his famous De Materia Medica of 77 A.D that ginger ‘warms and softens the stomach’(7). Traditional and modern day uses include for ailments such as nausea and vomiting, constipation, belching, bloating, gastritis, epigastric discomfort, gastric ulcerations, and indigestion.

A recurrent feeling of early or prolonged fullness and sometimes pain in the upper digestive tract, known as functional dyspepsia, has been reported to improve following ginger intake(8). This may relate to an accelerating effect on gastric emptying(9).

A recent study using a newly developed animal model of IBS-D (the type of irritable bowel where diarrhoea is a predominant symptom), reported less diarrhoea and other benefits from ginger treatment. Oedema and inflammation in the colons of the IBS-D rats, was also reduced by ginger treatment(10). While a clinical trial involving forty five irritable bowel syndrome (IBS) patients who took 1 or 2 grams of ginger a day failed to find significant benefits, IBS is a difficult and heterogenous condition to treat. Further human trials with greater participant numbers and possibly higher ginger doses, seem warranted(11).  

Diarrhoea and stomach upset are common adverse events of antibiotic usage, and ginger may be a useful adjunct, according to a recent study in rats. Reduced diarrhoea, improved diversity of the gut microbiotica and its faster recovery following antibiotic treatment, plus restoration of intestinal barrier function, was observed following ginger treatment(12). Comparative effects to the drug sulfasalazine have been reported in a rat model of ulcerative colitis(13). A trial involving forty six patients with mild to moderate ulcerative colitis who took ginger for 12 weeks, reported improvements in both disease severity scores and the quality of life(14). Another human trial is planned(15).

Evidence to date also suggests a useful protection against the development of peptic (gastric or duodenal) ulcers, by regular ginger ingestion(38).  Protective effects have been reported against aspirin (16, 17, 18), indomethacin (19) and ethanol (20-23) induced gastric ulcers in rats. Administration of a steamed ginger extract for 14 days also had a marked protective effect against gastric mucosal damage(24). Protection against stress-induced ulcers, and inhibitory activity against Helicobacter pylori, the gut pathogen contributory to peptic ulcers, has also been reported(23, 25, 26). Human trials seem warranted.

Pharmacological actions contributory to ginger’s reputation as a good digestive system tonic, are multiple. They include a spasmolytic activity on smooth muscle(23, 24), antibacterial effects, and diverse anti-inflammatory properties. Many ginger constituents modulate cytokines, chemokines, cyclooxygenase-2, nitric oxide, nuclear factor-κB(NF-κB) and numerous other biochemical pathways involved in both acute and chronic inflammation(27, 28).

Nausea and vomiting

A recent meta-analysis incorporating 10 randomized trials and a total of 918 patients supported the efficacy of ginger in reducing the incidence of post-operative nausea and vomiting, although effects were not statistically significant compared to placebo(27). Underdosing of ginger, was suggested by the authors as accounting for this lack of statistical significance.

A Cochrane Review into the use of ginger products in women with nausea and vomiting in early pregnancy, concluded they may be helpful and three studies supported ginger over placebo(28).  Again however, the evidence of effectiveness was limited and not consistent, hardly surprising given the diversity in study design.  A more recent French review concluded that use of 1 gram of fresh ginger root per day for four days lead to a significant decrease in nausea and vomiting during early pregnancy, and did not reveal any risk for the mother or foetus(29). Personally though, I’ve always regarded the use of large ginger doses near to or during parturition as something that should probably be avoided, due to a theoretical inhibitory effect on prostaglandins involved in labour(30, 34).

A review of nine clinical trials published between 2012 and 2017, recently concluded that ginger may reduce chemotherapy-induced nausea in breast cancer patients(35). Other recent reviews however, while advocated ginger’s benefits as a cheap and accessible therapy, have failed to find statistical confirmation of its effectiveness in the management of nausea and vomiting in cancer patients(36, 37). Cumulatively however, they suggest that further research with stronger study designs, adequate sample sizes, standardized ginger products, and validated outcome measures to confirm efficacy and optimal dosing regimens, are needed.

Obesity management?

Ginger may also have potential uses in the management of obesity(39-44). Several studies have reported weight lowering effects of ginger extract or powder in obese animal models. Korean researchers recently found that supplementation of the diet with 5% ginger significantly ameliorated the body weight gain, hyperglycaemia, hypercholesterolemia, and fatty liver produced as a result of a high fat diet, without altering food intake(40). Ginger also lessened adipocyte hypertrophy and reduced the inflammatory gene expression of adipocytes(40). Similar findings came from another recent study, where obesity preventive effects were accompanied by a healthy modulation of the gut microbiota, and elevation in levels of beneficial short-chain fatty acids (SCFAs)(41, 42).

Two clinical studies have taken place involving 12 weeks of ginger treatment in obese subjects, and while these have reported minor beneficial effects on weight loss and some metabolic features of obesity(44, 46), further and longer term clinical trials, are indicated.

Summary:

Ginger became famous and highly sought after because of its efficacy for a range of human health needs, not just as a tasty spice. While perhaps best known for its alleged anti-nausea effects, trials have produced somewhat mixed results, due in large part to the diversity of study designs, product types and doses used. Research in recent years is also increasingly supportive of its long reputation as a remedy for dyspepsia, peptic ulcers and inflammatory conditions of the digestive tract, although there is a need for further human clinical trials in these conditions.  Ginger’s utility as a gastroprotective and anti-inflammatory, and its ability to optimise many aspects of digestive function, certainly make it a spice to take an interest in.

References:

  1. Yadav PK, Jaiswal A, Singh RK. In silico study on spice-derived antiviral phytochemicals against SARS-CoV-2 TMPRSS2 target. J Biomol Struct Dyn. 2021 Aug 24:1-11. doi: 10.1080/07391102.2021.1965658. Epub ahead of print. PMID: 34427179.
  2. Yedjou CG, Njiki S, Enow J, Ikome O, Latinwo L, Long R, Ngnepieba P, Alo RA, Tchounwou PB. Pharmacological Effects of Selected Medicinal Plants and Vitamins Against COVID-19. J Food Nutr (Frisco). 2021 Jun;7(2):202. doi: 10.17303/jfn.2021.7.202. Epub 2021 Jul 12. PMID: 34395868; PMCID: PMC8362927.
  3.  Malekmohammad K, Rafieian-Kopaei M. Mechanistic Aspects of Medicinal Plants and Secondary Metabolites against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Curr Pharm Des. 2021;27(38):3996-4007. doi: 10.2174/1381612827666210705160130. PMID: 34225607.
  4. Nallusamy S, Mannu J, Ravikumar C, Angamuthu K, Nathan B, Nachimuthu K, Ramasamy G, Muthurajan R, Subbarayalu M, Neelakandan K. Exploring Phytochemicals of Traditional Medicinal Plants Exhibiting Inhibitory Activity Against Main Protease, Spike Glycoprotein, RNA-dependent RNA Polymerase and Non-Structural Proteins of SARS-CoV-2 Through Virtual Screening. Front Pharmacol. 2021 Jul 8;12:667704. doi: 10.3389/fphar.2021.667704. PMID: 34305589; PMCID: PMC8295902.
  5. Ginger: Post production management for improved market access. INPhO Food and Agriculture Organisation (FAO), United Nations. 2002. www.fao.org
  6. Rasmussen P. Ginger–Zingiber officinale Roscoe, Zingiberaceae. J Prim Health Care. 2011 Sep 1;3(3):235-6. PMID: 21892429.
  7. The Greek Herbal of Dioscorides (1655/1934) translated by John Goodyer & edited by Robert T. Gunther, 1934.
  8. Hu ML, Rayner CK, Wu KL, Chuah SK, Tai WC, Chou YP, Hu TH. Effect of ginger on gastric motility and symptoms of functional dyspepsia. World Journal of Gastroenterology 2011. 17(1):105-110.
  9. Wu KL, Rayner CK, Chuah SK, Changchien CS, Lu SN, Chiu YC, Chiu KW, Lee CM. Effects of ginger on gastric emptying and motility in healthy humans. Eur J Gastroenterol Hepatol. 2008 May;20(5):436-40. doi: 10.1097/MEG.0b013e3282f4b224. PMID: 18403946.
  10. Zhang C, Huang Y, Li P, Chen X, Liu F, Hou Q. Ginger relieves intestinal hypersensitivity of diarrhea predominant irritable bowel syndrome by inhibiting proinflammatory reaction. BMC Complement Med Ther. 2020 Sep 14;20(1):279. doi: 10.1186/s12906-020-03059-3. PMID: 32928188; PMCID: PMC7489045.
  11. Van Tilburg MA, Palsson OS, Ringel Y, Whitehead WE. Is ginger effective for the treatment of irritable bowel syndrome? A double blind randomized controlled pilot trial. Complement Ther Med. 2014 Feb;22(1):17-20. doi: 10.1016/j.ctim.2013.12.015. Epub 2014 Jan 8. PMID: 24559811; PMCID: PMC3958926.
  12. Ma ZJ , Wang HJ , Ma XJ , Li Y , Yang HJ , Li H , Su JR , Zhang CE , Huang LQ . Modulation of gut microbiota and intestinal barrier function during alleviation of antibiotic-associated diarrhea with Rhizoma Zingiber officinale (Ginger) extract. Food Funct. 2020 Dec 1;11(12):10839-10851. doi: 10.1039/d0fo01536a. Epub 2020 Nov 26. PMID: 33241234.
  13. El-Abhar HS, Hammad LN, Gawad HS. Modulating effect of ginger extract on rats with ulcerative colitis. J Ethnopharmacol. 2008 Aug 13;118(3):367-72. doi: 10.1016/j.jep.2008.04.026. Epub 2008 May 15. PMID: 18571884.
  14. Nikkhah-Bodaghi M, Maleki I, Agah S, Hekmatdoost A. Zingiber officinale and oxidative stress in patients with ulcerative colitis: A randomized, placebo-controlled, clinical trial. Complement Ther Med. 2019 Apr;43:1-6. doi: 10.1016/j.ctim.2018.12.021. Epub 2019 Jan 2. PMID: 30935515.
  15. Shayesteh F, Haidari F, Shayesteh AA, Mohammadi-Asl J, Ahmadi-Angali K. Ginger in patients with active ulcerative colitis: a study protocol for a randomized controlled trial. Trials. 2020 Mar 18;21(1):278. doi: 10.1186/s13063-020-4193-7. PMID: 32183895; PMCID: PMC7079449.
  16. Salah Khalil M. The postulated mechanism of the protective effect of ginger on the aspirin induced gastric ulcer: Histological and immunohistochemical studies. Histol Histopathol. 2015 Jul;30(7):855-64. doi: 10.14670/HH-11-592. Epub 2015 Feb 5. PMID: 25652595.
  17. Khushtar M, Kumar V, Javed K, Bhandari U. Protective Effect of Ginger oil on Aspirin and Pylorus Ligation-Induced Gastric Ulcer model in Rats. Indian J Pharm Sci. 2009 Sep;71(5):554-8. doi: 10.4103/0250-474X.58195. PMID: 20502577; PMCID: PMC2866350.
  18. Wang Z, Hasegawa J, Wang X, Matsuda A, Tokuda T, Miura N, Watanabe T. Protective Effects of Ginger against Aspirin-Induced Gastric Ulcers in Rats. Yonago Acta Med. 2011 Mar;54(1):11-9. Epub 2011 Mar 1. PMID: 24031124; PMCID: PMC3763798.
  19. Zaghlool SS, Shehata BA, Abo-Seif AA, Abd El-Latif HA. Protective effects of ginger and marshmallow extracts on indomethacin-induced peptic ulcer in rats. J Nat Sci Biol Med. 2015 Jul-Dec;6(2):421-8. doi: 10.4103/0976-9668.160026. PMID: 26283843; PMCID: PMC4518423.
  20. Sistani Karampour N, Arzi A, Rezaie A, Pashmforoosh M, Kordi F. Gastroprotective Effect of Zingerone on Ethanol-Induced Gastric Ulcers in Rats. Medicina (Kaunas). 2019 Mar 11;55(3):64. doi: 10.3390/medicina5
  21. Yamahara J, Mochizuki M, Rong HQ, Matsuda H, Fujimura H. The anti-ulcer effect in rats of ginger constituents. J Ethnopharmacol. 1988 Jul-Aug;23(2-3):299-304. doi: 10.1016/0378-8741(88)90009-8. PMID: 3193792.
  22. al-Yahya MA, Rafatullah S, Mossa JS, Ageel AM, Parmar NS, Tariq M. Gastroprotective activity of ginger zingiber officinale rosc., in albino rats. Am J Chin Med. 1989;17(1-2):51-6. doi: 10.1142/S0192415X89000097. PMID: 2589236.
  23. Nanjundaiah SM, Annaiah HN, Dharmesh SM. Gastroprotective Effect of Ginger Rhizome (Zingiber officinale) Extract: Role of Gallic Acid and Cinnamic Acid in H(+), K(+)-ATPase/H. pylori Inhibition and Anti-Oxidative Mechanism. Evid Based Complement Alternat Med. 2011;2011:249487. doi: 10.1093/ecam/nep060. Epub 2011 Jun 23. PMID: 19570992; PMCID: PMC3136331.
  24. Shin JK, Park JH, Kim KS, Kang TH, Kim HS. Antiulcer Activity of Steamed Ginger Extract against Ethanol/HCl-Induced Gastric Mucosal Injury in Rats. Molecules. 2020 Oct 13;25(20):4663. doi: 10.3390/molecules25204663. PMID: 33066164; PMCID: PMC7587366.
  25. Mahady GB, Pendland SL, Yun GS, Lu ZZ, Stoia A. Ginger (Zingiber officinale Roscoe) and the gingerols inhibit the growth of Cag A+ strains of Helicobacter pylori. Anticancer Res. 2003 Sep-Oct;23(5A):3699-702. PMID: 14666666; PMCID: PMC3761965.
  26. Haniadka R, Saldanha E, Sunita V, Palatty PL, Fayad R, Baliga MS. A review of the gastroprotective effects of ginger (Zingiber officinale Roscoe). Food Funct. 2013 Jun;4(6):845-55. doi: 10.1039/c3fo30337c. Epub 2013 Apr 24. PMID: 23612703.
  27. Ghayur MN, Gilani AH, Ahmed T, Khalid A, Nawaz SA, Agbedahunsi JM, Choudhary MI, Houghton PJ. Muscarinic, Ca(++) antagonist and specific butyrylcholinesterase inhibitory activity of dried ginger extract might explain its use in dementia. J Pharm Pharmacol. 2008 Oct;60(10):1375-83. doi: 10.1211/jpp/60.10.0014. PMID: 18812031.
  28. Riyazi A, Hensel A, Bauer K, Geissler N, Schaaf S, Verspohl EJ. The effect of the volatile oil from ginger rhizomes (Zingiber officinale), its fractions and isolated compounds on the 5-HT3 receptor complex and the serotoninergic system of the rat ileum. Planta Med. 2007 Apr;73(4):355-62. doi: 10.1055/s-2007-967171. PMID: 17511060.
  29. Grzanna R, Lindmark L, Frondoza CG. Ginger–an herbal medicinal product with broad anti-inflammatory actions. J Med Food. 2005 Summer;8(2):125-32. doi: 10.1089/jmf.2005.8.125. PMID: 16117603.
  30. Lantz RC, Chen GJ, Sarihan M, Sólyom AM, Jolad SD, Timmermann BN. The effect of extracts from ginger rhizome on inflammatory mediator production. Phytomedicine. 2007 Feb;14(2-3):123-8. doi: 10.1016/j.phymed.2006.03.003. Epub 2006 May 18. PMID: 16709450.
  31. Tóth B, Lantos T, Hegyi P, Viola R, Vasas A, Benkő R, Gyöngyi Z, Vincze Á, Csécsei P, Mikó A, Hegyi D, Szentesi A, Matuz M, Csupor D. Ginger (Zingiber officinale): An alternative for the prevention of postoperative nausea and vomiting. A meta-analysis. Phytomedicine. 2018 Nov 15;50:8-18. doi: 10.1016/j.phymed.2018.09.007. Epub 2018 Sep 5. PMID: 30466995.
  32. Matthews A, Haas DM, O’Mathúna DP, Dowswell T. Interventions for nausea and vomiting in early pregnancy. Cochrane Database Syst Rev. 2015 Sep 8;2015(9):CD007575. doi: 10.1002/14651858.CD007575.pub4. PMID: 26348534; PMCID: PMC7196889.
  33. Stanisiere J, Mousset PY, Lafay S. How Safe Is Ginger Rhizome for Decreasing Nausea and Vomiting in Women during Early Pregnancy? Foods. 2018 Apr 1;7(4):50. doi: 10.3390/foods7040050. PMID: 29614764; PMCID: PMC5920415.
  34. Kiuchi F, Shibuya M, Sankawa U. Inhibitors of prostaglandin biosynthesis from ginger. Chem Pharm Bull (Tokyo). 1982 Feb;30(2):754-7. doi: 10.1248/cpb.30.754. PMID: 7094159.
  35. Saneei Totmaj A, Emamat H, Jarrahi F, Zarrati M. The effect of ginger (Zingiber officinale) on chemotherapy-induced nausea and vomiting in breast cancer patients: A systematic literature review of randomized controlled trials. Phytother Res. 2019 Aug;33(8):1957-1965. doi: 10.1002/ptr.6377. Epub 2019 Jun 21. PMID: 31225678.
  36. Borges DO, Freitas KABDS, Minicucci EM, Popim RC. Benefits of ginger in the control of chemotherapy-induced nausea and vomiting. Rev Bras Enferm. 2020 Mar 30;73(2):e20180903. English, Portuguese. doi: 10.1590/0034-7167-2018-0903. PMID: 32236378.
  37. Crichton M, Marshall S, Marx W, McCarthy AL, Isenring E. Efficacy of Ginger (Zingiber officinale) in Ameliorating Chemotherapy-Induced Nausea and Vomiting and Chemotherapy-Related Outcomes: A Systematic Review Update and Meta-Analysis. J Acad Nutr Diet. 2019 Dec;119(12):2055-2068. doi: 10.1016/j.jand.2019.06.009. Epub 2019 Sep 10. PMID: 31519467.
  38. Yamahara J, Mochizuki M, Rong HQ, Matsuda H, Fujimura H. The anti-ulcer effect in rats of ginger constituents. J Ethnopharmacol. 1988 Jul-Aug;23(2-3):299-304. doi: 10.1016/0378-8741(88)90009-8. PMID: 3193792.
  39. Tramontin NDS, Luciano TF, Marques SO, de Souza CT, Muller AP. Ginger and avocado as nutraceuticals for obesity and its comorbidities. Phytother Res. 2020 Jun;34(6):1282-1290. doi: 10.1002/ptr.6619. Epub 2020 Jan 27. PMID: 31989713.
  40. Seo SH, Fang F, Kang I. Ginger (Zingiber officinale) Attenuates Obesity and Adipose Tissue Remodeling in High-Fat Diet-Fed C57BL/6 Mice. Int J Environ Res Public Health. 2021 Jan 13;18(2):631. doi: 10.3390/ijerph18020631. PMID: 33451038; PMCID: PMC7828532.
  41. Wang J, Wang P, Li D, Hu X, Chen F. Beneficial effects of ginger on prevention of obesity through modulation of gut microbiota in mice. Eur J Nutr. 2020 Mar;59(2):699-718. doi: 10.1007/s00394-019-01938-1. Epub 2019 Mar 11. PMID: 30859364.
  42. Wang J, Chen Y, Hu X, Feng F, Cai L, Chen F. Assessing the Effects of Ginger Extract on Polyphenol Profiles and the Subsequent Impact on the Fecal Microbiota by Simulating Digestion and Fermentation In Vitro. Nutrients. 2020 Oct 19;12(10):3194. doi: 10.3390/nu12103194. PMID: 33086593; PMCID: PMC7650818.
  43. Rasmussen PL, Ginger for weight loss. Phytonews 22, ISSN 1175-0251. Published by Phytomed Medicinal Herbs Ltd, Auckland, July 2005.
  44. Ebrahimzadeh Attari V, Malek Mahdavi A, Javadivala Z, Mahluji S, Zununi Vahed S, Ostadrahimi A. A systematic review of the anti-obesity and weight lowering effect of ginger (Zingiber officinale Roscoe) and its mechanisms of action. Phytother Res. 2018 Apr;32(4):577-585. doi: 10.1002/ptr.5986. Epub 2017 Nov 29. PMID: 29193411.
  45. Ebrahimzadeh Attari V, Ostadrahimi A, Asghari Jafarabadi M, Mehralizadeh S, Mahluji S. Changes of serum adipocytokines and body weight following Zingiber officinale supplementation in obese women: a RCT. Eur J Nutr. 2016 Sep;55(6):2129-36. doi: 10.1007/s00394-015-1027-6. Epub 2015 Aug 29. PMID: 26318445.
  46. Park SH, Jung SJ, Choi EK, Ha KC, Baek HI, Park YK, Han KH, Jeong SY, Oh JH, Cha YS, Park BH, Chae SW. The effects of steamed ginger ethanolic extract on weight and body fat loss: a randomized, double-blind, placebo-controlled clinical trial. Food Sci Biotechnol. 2019 Oct 11;29(2):265-273. doi: 10.1007/s10068-019-00649-x. PMID: 32064135; PMCID: PMC6992804.
Zingiber officinale

Comfrey – a great herb for bruises, sprains and more

Comfrey is a plant that has been used medicinally for hundreds of years. The variety of names Comfrey is known by – Knitbone, Boneset, Bruisewort – reflect it’s healing properties.  The Greek physician Dioscorides and Roman author Pliny the Elder, both advocated for its benefits in healing broken bones, and in the Middle Ages it was a famous remedy for these. The name Comfrey is a corruption of con firma, alluding to its facilitatory effect on the uniting of bones. The botanical name, Symphytum, is derived from the Greek sympho, meaning ‘to unite’(1).

Other traditional uses for comfrey included for rheumatism and painful joints, bronchial conditions and gastrointestinal disorders such as gastritis and peptic ulcers. It has strongly mucilaginous and thus demulcent and expectorant properties due to its abundant content of fructans and other polysaccharides. It also contains rosmarinic acid and a heterocyclic organic compound called allantoin, which promotes granulation and tissue regeneration and is now an ingredient in many cosmetic products(2, 3). Interestingly, allantoin is also one of many compounds secreted from the roots of plants as a signalling chemical that conveys information on local conditions to other nearby plants(4).

The internal usage of comfrey is now somewhat controversial due to its content of pyrrolizidine alkaloids (PA’s), and most uses are now in the form of topical rather than internal dosage forms. Poultices, pastes, ointments and creams are used as anti-inflammatories in joint inflammations, arthritic swellings, sprains, bruises, contusions, haematomas, phlebitis, mastitis, glandular swellings as well as for the treatment of eczema, psoriasis, ulcers, and poorly healing wounds(5, 6).

Anti-inflammatory

Comfrey contains several compounds with anti-inflammatory effects, and various studies have shown comfrey to have anti-inflammatory properties(7-12).  Phenolic compounds such as globoidnan, rubdoisiin and rosmarinic acid isolated from comfrey roots have antioxidant and anti-inflammatory actions, including inhibiting release of cytokines such as interleukin (IL)-1β, IL-8 and tumor necrosis factor(9-11).

A hydroalcoholic extract of comfrey root reduced development of a pro-inflammatory scenario in primary human endothelial cells, in a dose-dependent manner. Effects included inhibition of interleukin-1 (IL-1) induced expression of pro-inflammatory markers including E-selectin, vascular cell adhesion molecule 1 (VCAM1), intercellular adhesion molecule 1 (ICAM1), and cyclooxygenase-2 (COX-2)(12). Activation of nuclear factor kappa-B (NF-κB), a transcription factor of central importance for the expression of these and other pro-inflammatory genes, was also inhibited(9, 12).

Clinical trials

The topical use of comfrey as an anti-inflammatory and analgesic has now been strongly substantiated by a range of clinical trials over the past 15 years.

The first of these was in 2004, when German researchers undertook a randomised trial involving application of comfrey ointment or a placebo ointment four times daily following acute ankle sprains incurred largely as a result of sporting activity. A more rapid reduction in swelling and pain upon movement, as well as improved joint mobility, occurred following comfrey ointment application over an eight day period (13).

A further trial by the same team which compared comfrey ointment with diclofenac gel, a popular drug treatment for acute ankle sprain, , also found favourable effects(14). A total of 160 patients were included in the randomised study, which was “investigator blind” rather than double-blind, due to the differences in appearance and smell for the comfrey ointment when compared to the diclofenac gel. Patients applied either comfrey or diclofenac four times daily over a seven day period. Treated skin areas were cleaned from every trace of the applied treatment before each patient was seen by the investigator however, making it impossible for the treatment agent to be identified.  As with the earlier trial, patients presented with uncomplicated, acute ankle sprains that had occurred within the previous six hours.

Both treatments showed a potent effect in reducing the tenderness reaction, but patients treated with comfrey experienced less pain. This was shown by a statistically significant greater AUC (Area Under the Curve) of a graph of the pressure required to cause pain, than that measured in the diclofenac group (p=0.046). After 7 days treatment an overall good or excellent efficacy was recorded by physicians for 78% of patients in the comfrey group compared to 61% in the diclofenac group, while the efficacy reported by patients themselves was 84.2% in the comfrey group, compared to 70.8% in the diclofenac group. Both physician and patient assessments of these differences reached statistical significance. This study provided further validation of the clinical efficacy of comfrey ointment in the treatment of acute sprains as a result of sports injuries, and furthermore implied superior efficacy to what is still one of the most popular drug treatments for such conditions(15).

Another trial compared comfrey ointment to placebo in 120 patients with a mean age of 37, suffering from acute upper or lower back pain. Significant improvements were measured in all outcome measurements, and a rapid onset of action reported (16). Similar benefits were reported in atrial involving a combination of comfrey root extract with methyl nicotinate (17).

Apart from these types of acute injuries, painful and chronic osteoarthritis of the knee, also responded to topical comfrey treatment in a randomised, double-blind, placebo-controlled clinical trial involving 220 patients. Reduced pain, an improvement in knee mobility, and an increase in quality of life, occurred over the three week treatment period. Improvements became more apparent with the duration of comfrey treatment, and adverse events were reported in 7 of the comfrey group, compared with 15 in the placebo group(18).

Muscle pain (myalgia), has also responded to treatment with a cream made from comfrey leaf, in a randomised, double-blind and controlled multicentre study involving 215 patients with muscle pain upon motion(19). Patients who received treatment with a cream containing the equivalent of 25 grams of fresh comfrey herb per 100 grams, experienced much less pain on active motion, pain at rest, and pain on palpation, than in those treated with the reference product which contained only 2.5 grams of fresh comfrey herb per 100 grams.

Reduction in scar formation?

Apart from its benefits in broken bones, bruises and sprains, another traditional applications for which comfrey products are said to be useful, is to facilitate wound healing and reduce scar formation. Research by Brazilian pharmacists reported wound healing properties by various comfrey leaf extract topical formulations, accompanied by a dramatic increase in collagen deposition and reduction in cellular inflammation(20).

Results from a recent German study, provide further support for these applications(21). This used an established in vitro model of human skin cells with the typical strata, for the observation of effects of applied substances on skin regeneration. Damage corresponding to a typical abrasion was created on day 1 by punching an opening into the epidermal fine structure down to the stratum basale, then samples were either untreated (controls) or exposed to comfrey cream on days 2, 3, 5, and 6. Light and electron microscopy then confirmed that application of comfrey cream led to a quicker regeneration of skin cells and to an earlier differentiation of cells towards a normal fine and layered structure. These effects were apparent within 4-7 days.

Comfrey has relatively mild antimicrobial properties compared with many other herbs however, and so should ideally only be applied to abrasions or wounds to help reduce scarring after they have initially healed.

Safety concerns

The ingestion of high doses of certain types of pyrrolizidine alkaloids, such as those found in ragwort and comfrey, has been associated with veno-occlusive disease of the liver, particularly when these are taken over a prolonged period of time. Over the years a small number of cases of human toxicity have been reported, mostly following ingestion of large doses of comfrey over a prolonged period of time(22, 23, 24). This appears to relate to formation of highly reactive compounds during pyrrolizidine alkaloid metabolism in the liver. Comfrey roots contain the highest levels of pyrrolizidine alkaloids, and young leaves contain higher levels than more mature leaves.

While previously comfrey had been used for hundreds of years without reported problems, because of this, it is now generally recommended that the medicinal use is restricted to topical use only, although short term internal use is still sometimes recommended by herbal practitioners. Products containing less than certain levels of pyrrolizidine alkaloids, are also able to be taken internally in Germany and other European countries, without restrictions on the duration of treatment. Internal use of all types of comfrey should however be avoided by those with hepatic disorders, or those taking potentially hepatotoxic medications.   

These safety concerns have recently been rebuttled, however, by at least three separate studies. A German study in which comfrey was fed to chickens as 4% of their diet for 32 days from when they were one day old, revealed no signs of impairment of liver function, mineral homeostasis, bone mineral density or intestinal microanatomy. Pyrrolizidine alkaloid levels were also below the detection limit in liver and breast muscle(25)

Limits placed by some regulatory agencies on pyrrolizidine alkaloid content in topical preparations, have been shown to be an overestimation of any risk (26).  A collection of Australian medical herbalists have alsorecently reviewed this subject, and challenged the evidence base for case reports of safety concerns involving comfrey and its content of unsaturated pyrrolizidine alkaloids(24).

Finally

Aches and pains, sprains and strains, have always afflicted humans just as they have other animals. Taken together with inflammatory joint and muscle conditions which become more common with aging, its hardly surprising that there are multiple drug-based medicines produced to give relief to these painful problems. The fact that various preparations of a common and easily grown plant with thousands of years of history of helping with these types of ailments has had its efficacy validated by several well designed human clinical trials, highlights an impressive natural alternative.

References: 

  1. Grieve M, A Modern Herbal, 1931. Ed CF Leyel, Cape, London.
  2. Thornfeldt C. Cosmeceuticals containing herbs: fact, fiction, and future. Dermatol Surg. 2005 Jul;31(7 Pt 2):873-80; discussion 880. doi: 10.1111/j.1524-4725.2005.31734. PMID: 16029681.
  3. Buszewska-Forajta M, Siluk D, Daghir-Wojtkowiak E, Sejda A, Staśkowiak D, Biernat W, Kaliszan R. Studies of the effect of grasshopper abdominal secretion on wound healing with the use of murine model. J Ethnopharmacol. 2015 Dec 24;176:413-23. doi: 10.1016/j.jep.2015.11.004. Epub 2015 Nov 6. PMID: 26549269.
  4. Wang NQ, Kong CH, Wang P, Meiners SJ. Root exudate signals in plant-plant interactions. Plant Cell Environ. 2021 Apr;44(4):1044-1058. doi: 10.1111/pce.13892. Epub 2020 Oct 7. PMID: 32931018.
  5. Wichtl M, Herbal Drugs and Phytopharmaceuticals. Ed Norman Grainger Bisset, Medpharm Scientific Publishers, CRC Press, Stuttgart, 1994.
  6. Potters Herbal Cyclopaedia, Wren RC. Williamson EM. CW Daniel Co Ltd, Saffron Walden, UK, 2003.
  7. Andres R, Brenneisen R, Clerc JT. Relating antiphlogistic efficacy of dermatics containing extracts of Symphytum officinale to chemical profiles. Planta Medica, 1989; 55:643-644.
  8. Hiermann A, Writzel M. 1988. Antiphlogistic glycopeptide from the roots of Symphytum officinale. Pharm Pharmacol Lett 8:154-157.
  9. Trifan A, Opitz SEW, Josuran R, Grubelnik A, Esslinger N, Peter S, Bräm S, Meier N, Wolfram E. Is comfrey root more than toxic pyrrolizidine alkaloids? Salvianolic acids among antioxidant polyphenols in comfrey (Symphytum officinale L.) roots. Food Chem Toxicol. 2018 Feb;112:178-187. doi: 10.1016/j.fct.2017.12.051. Epub 2017 Dec 28. PMID: 29288756.
  10. Trifan A, Wolfram E, Esslinger N, Grubelnik A, Skalicka-Woźniak K, Minceva M, Luca SV. Globoidnan A, rabdosiin and globoidnan B as new phenolic markers in European-sourced comfrey (Symphytum officinale L.) root samples. Phytochem Anal. 2021 Jul;32(4):482-494. doi: 10.1002/pca.2996. Epub 2020 Oct 5. PMID: 33015885.
  11. Trifan A, Skalicka-Woźniak K, Granica S, Czerwińska ME, Kruk A, Marcourt L, Wolfender JL, Wolfram E, Esslinger N, Grubelnik A, Luca SV. Symphytum officinale L.: Liquid-liquid chromatography isolation of caffeic acid oligomers and evaluation of their influence on pro-inflammatory cytokine release in LPS-stimulated neutrophils. J Ethnopharmacol. 2020 Nov 15;262:113169. doi: 10.1016/j.jep.2020.113169. Epub 2020 Jul 31. PMID: 32739565.
  12. Seigner J, Junker-Samek M, Plaza A, D’Urso G, Masullo M, Piacente S, Holper-Schichl YM, de Martin R. A Symphytum officinale Root Extract Exerts Anti-inflammatory Properties by Affecting Two Distinct Steps of NF-κB Signaling. Front Pharmacol. 2019 Apr 26;10:289. doi: 10.3389/fphar.2019.00289. PMID: 31105555; PMCID: PMC6498879.
  13. Koll R, Buhr M, Dieter R, Pabst H, Predel HG, Petrowicz O, Giannetti B, Klingenburg S, Staiger C. Efficacy and tolerance of a comfrey root extract (Extr. Rad. Symphyti) in the treatment of ankle distorsions: results of a multicenter, randomized, placebo-controlled, double-blind study. Phytomedicine. 2004 Sep;11(6):470-7. doi: 10.1016/j.phymed.2004.02.001. PMID: 15500257.
  14. Predel HG, Giannetti B, Koll R, Bulitta M, Staiger C. Efficacy of a comfrey root extract ointment in comparison to a diclofenac gel in the treatment of ankle distortions: results of an observer-blind, randomized, multicenter study. Phytomedicine. 2005 Nov;12(10):707-14. doi: 10.1016/j.phymed.2005.06.001. PMID: 16323288.
  15. D’Anchise R, Bulitta M, Giannetti B. Comfrey extract ointment in comparison to diclofenac gel in the treatment of acute unilateral ankle sprains (distortions). Arzneimittelforschung. 2007;57(11):712-6. doi: 10.1055/s-0031-1296672. PMID: 18193693.
  16. Giannetti BM, Staiger C, Bulitta M, Predel HG. Efficacy and safety of comfrey root extract ointment in the treatment of acute upper or lower back pain: results of a double-blind, randomised, placebo controlled, multicentre trial. Br J Sports Med. 2010 Jul;44(9):637-41. doi: 10.1136/bjsm.2009.058677. Epub 2009 May 21. PMID: 19460762.
  17. Pabst H, Schaefer A, Staiger C, Junker-Samek M, Predel HG. Combination of comfrey root extract plus methyl nicotinate in patients with conditions of acute upper or low back pain: a multicentre randomised controlled trial. Phytother Res. 2013 Jun;27(6):811-7. doi: 10.1002/ptr.4790. Epub 2012 Aug 8. PMID: 22887778; PMCID: PMC3747459.
  18. Grube B, Grünwald J, Krug L, Staiger C. Efficacy of a comfrey root (Symphyti offic. radix) extract ointment in the treatment of patients with painful osteoarthritis of the knee: results of a double-blind, randomised, bicenter, placebo-controlled trial. Phytomedicine. 2007 Jan;14(1):2-10. doi: 10.1016/j.phymed.2006.11.006. Epub 2006 Dec 13. PMID: 17169543.
  19. Kucera M, Barna M, Horàcek O, Kàlal J, Kucera A, Hladìkova M. Topical symphytum herb concentrate cream against myalgia: a randomized controlled double-blind clinical study. Adv Ther. 2005 Nov-Dec;22(6):681-92. doi: 10.1007/BF02849961. PMID: 16510384.
  20. Araújo LU, Reis PG, Barbosa LC, Saúde-Guimarães DA, Grabe-Guimarães A, Mosqueira VC, Carneiro CM, Silva-Barcellos NM. In vivo wound healing effects of Symphytum officinale L. leaves extract in different topical formulations. Pharmazie. 2012 Apr;67(4):355-60. PMID: 22570943.
  21. Dähnhardt D, Dähnhardt-Pfeiffer S, Groeber-Becker F, Fölster-Holst R, Schmidt M. Epidermal Regeneration Induced by Comfrey Extract: A Study by Light and Electron Microscopy. Skin Pharmacol Physiol. 2020;33(4):189-197. doi: 10.1159/000509121. Epub 2020 Jul 17. PMID: 32683369.
  22. Awang DVC, Comfrey. Revue Pharmaceutique Canadienne, 1987; Feb. 101-104.
  23. Mei N et al, Metabolism, genotoxicity, and cardinogenicity of Comfrey. J Toxicol and Environmental Health, Part B, 2010:13, 509-526. ISSN: 1093-7404.
  24. Avila C, Breakspear I, Hawrelak J, Salmond S, Evans S. A systematic review and quality assessment of case reports of adverse events for borage (Borago officinalis), coltsfoot (Tussilago farfara) and comfrey (Symphytum officinale). Fitoterapia. 2020 Apr;142:104519. doi: 10.1016/j.fitote.2020.104519. Epub 2020 Feb 24. PMID: 32105669.
  25. Oster M, Reyer H, Keiler J, Ball E, Mulvenna C, Muráni E, Ponsuksili S, Wimmers K. Comfrey (Symphytum spp.) as an alternative field crop contributing to closed agricultural cycles in chicken feeding. Sci Total Environ. 2020 Nov 10;742:140490. doi: 10.1016/j.scitotenv.2020.140490. Epub 2020 Jun 27. PMID: 32634689.
  26. Kuchta K, Schmidt M. Safety of medicinal comfrey cream preparations (Symphytum officinale s.l.): The pyrrolizidine alkaloid lycopsamine is poorly absorbed through human skin. Regul Toxicol Pharmacol. 2020 Dec;118:104784. doi: 10.1016/j.yrtph.2020.104784. Epub 2020 Sep 15. PMID: 32941922.

Echinacea – so many new interesting medicinal applications!

Echinacea was highly regarded as a medicine by the indigenous north Americans, who used the roots of both Echinacea purpurea (purple coneflower) and Echinacea angustifolia (narrow-leaved purple coneflower) to treat animal bites and a wide range of infectious and inflammatory conditions(1-3). Early European settlers adopted echinacea as a treatment for wounds, sepsis and glandular inflammation, and it was a preferred treatment for infections by many clinicians until discovery of penicillin in 1928(1-6)

Any plant with such a reputation should be of interest to infectious disease scientists in the world today. With growing worries about antibiotic resistance and highly pathogenic viruses such as SARS-CoV-2 (Covid-19), echinacea is one of a number of medicinal herbs currently receiving more attention from researchers (7, 8).

Ive previously suggested that echinacea’s immunomodulatory and anti-inflammatory actions may offer considerable hope in the ongoing management of this virus (9, 10). Since then a trial involving 100 suspected Covid-19 outpatients, found those who took a combined echinacea and ginger product for 7 days in addition to standard hydroxychloroquine treatment, reported significant improvements in coughing, dyspnoea and muscle pain. A reduced rate of hospitalisation (2%) also occurred in the echinacea and ginger treated group, versus 6% for the drug-only group(11i). While this difference in the need to be hospitalised failed to reach statistical significance, larger well-designed trials are warranted, and are likely underway. Most recently, constituents which exhibit promise as potential inhibitors of the main protease enzyme involved in replication of the SARS-CoV-2 (Covid-19) coronavirus have been identified in Echinacea angustifolia(12).

Apart from research into applications for infectious disease management, there’s also other largely forgotten or new potential applications that some of this research is revealing for Echinacea, a summary of which is below.

Effects on endocannabinoid receptors

Echinacea alkylamides (the main bioavailable active constituents) were first reported in 2004 to bind strongly with endogenous cannabinoid 2 (CB2) receptors(13), which are mainly found on immune cells and unlike CB1 receptors, do not seem to be involved much in the psychoactive effects of cannabinoids. Potential therapeutic uses of cannabinoid receptor agonists include pain management, anxiety, cancer-related symptoms, inflammatory disorders, and epilepsy.

Activation of these endocannabinoid receptors has been associated with various modulatory effects on cytokines by alkylamide-rich Echinacea preparations, such as upregulation of tumour necrosis factor (TNF)-alpha mRNA, and activation of the signalling pathway NF-κB, in human white blood cells(13). The pronounced anti-inflammatory properties of Echinacea and its alkylamides, have also been related at least in part to activation of these CB2 receptors(14, 15)

Anxiolytic

Work by Hungarian researchers in animals and human volunteers, observed anxiolytic (anti-anxiety) effects for high but not low doses of Echinacea angustifolia given for 1 week to healthy volunteers scoring high on a validated anxiety measurement scale(16). A subsequent double blind, placebo controlled trial in 64 participants found the Echinacea angustifolia root preparation performed better than placebo in patients with high baseline anxiety(17).  However, a recent trial in Australia failed to find greater improvements in anxiety in adults with mild-to-moderately severe anxiety compared to the placebo. Some improvements were detected in emotional wellbeing, suggesting potential antidepressant activity, as a secondary outcome. This suggests further trials with greater participant numbers, are warranted(18).

Eczema and hayfever

Contrary to what is sometimes popularly believed, various studies are now suggesting potential applications for alkylamide-rich preparations of Echinacea, in the management of allergic conditions.

European workers have recently reported promising outcomes suggesting echinacea could be an efficacious topical treatment for eczema. Anti-inflammatory effects were shown on human keratinocytes in vitro, and favourable results recorded from Human Repeat Insult Patch testing. These and a clinical study concluded echinacea and various isolated alkylamides showed good potential in alleviating skin symptoms of atopic eczema. Anti-inflammatory actions and restoration of the epidermal lipid barrier, were identified as likely mechanisms of action in echinacea’s benefits in this common chronic inflammatory skin condition(19).

This comes after an earlier study finding that an ethanolic extract of Echinacea purpurea root and one of its isolated alkylamides displays anti-histamine like properties and inhibits the release of histamine and other inflammatory cytokines from mast cells(20, 21). Applications for allergic rhinitis (hayfever) stem from this.

Analgesic

A dose dependent analgesic activity has been reported for both echinacea species in a rodent model of chronic inflammatory pain(22). Again, alkylamides were shown to be key, and modulation of the endogenous endocannabinoid systems a likely mechanism of action. This supports potential applications for peripheral inflammatory pain such as arthritis and burns, which are other traditional uses for echinacea by indigenous North Americans.

A small clinical trial involving a combined ginger and Echinacea angustifolia product taken for 30 days by patients with osteoarthritis of the knee, reported a reduction in pain as well as knee circumference and inflammation(23). These anti-inflammatory and analgesic effects may also be mediated through endocannabinoid receptor modulation, as well as inhibition of the inflammatory enzymes cyclooxygenase -2 (COX-2) and prostaglandin E2 (PGE(2)), by alkylamides(24, 25). These are also mechanisms of action of some anti-inflammatory drugs prescribed for chronic arthritis.

Male fertility?

Possible applications for male reproductive functions have been revealed for Echinacea purpurea through recent research in diabetic rats(26). Echinacea administration for 4 weeks not only improved hyperglycemia and insulin resistance, but also increased sperm motility, protected sperm morphology and had other benefits on related testosterone synthesis pathways.  Levels of superoxide dismutase, catalase, and glutathione antioxidants in sperm were increased, whereas proinflammatory cytokines such as NO, IL-1β, and TNF-α, were decreased by Echinacea treatment. This suggests similar possible outcomes not only in men with diabetes-related fertility issues, but also in non-diabetic men wanting to optimise their fertility. Studies in humans, will hopefully soon be undertaken.

Anticancer effects

In vitro anticancer effects against human lung cancer cells have been reported recently for Echinacea purpurea root extracts, in a time and dose dependent manner(27). Activation of cannabinoid CB2 receptors and enhanced apoptosis (programmed cell death to eliminate unwanted cells) was associated with this activity.  Longevity enhancing and cancer protective actions have previously been reported for Echinacea purpurea in mice(28)In vitro anticancer activity of Echinacea angustifolia, has also been reported and a synergistic in vitro effect with paclitaxel in two different breast cancer cell lines(29). These studies support clinical trials using Echinacea as an adjunct to this and potentially other chemotherapy drugs, to see if such effects can be achieved in clinical practice. Protective effects against gene and plant damage due to mercury poisoning have been revealed by Turkish workers, as a result of which further research will now take place into other possible uses against genotoxic contaminants(30).

Finally, the risk of interactions between Echinacea and other drugs being taken at the same time, is something that requires consideration in many situations and particularly with chronic illnesses where other medication is often prescribed. I’ve reviewed and written about this previously, and at that time found there to be very little evidence of clinically relevant interactions(31). Reassuringly, a recent study which examined the potential of phytochemical constituents of Echinacea purpurea to cause herb-drug interactions via ABCB1 and ABCG2 efflux transporter proteins (a common mechanism of such interactions), failed to find evidence of significant inhibition of these transporters at clinically relevant concentrations(32).

In conclusion, traditional and modern day use experience and a growing body of research, suggests potential benefits to daily prophylactic use of echinacea by those wanting to enhance their immunity, or as an alternative or adjunct to other medications for the management of an increasingly large and diverse range of common health conditions.

References:

  1. Felter, HW & Lloyd, JU. King’s American Dispensatory, 1898.
  2. Smithsonian National Museum of Natural History, http://www.mnh.si.edu/lewisandclark/index.html?loc=/lewisandclark/home.html
  3. Borchardt JK, Native American drug therapy: United States and Canada.  Drug News & Perspectives 2003; 16(3):187-191
  4. Borchers AT, Keen CL, Stern JS, Gershwin ME, Inflammation and native American medicine: the role of botanicals.  American Journal of Clinical Nutrition 2000;72(2):339-347, Aug 2000.
  5. The Lloyd Library and Museum website, www.lloydlibrary.org
  6. Moerman DE. Medicinal plants of North America. Ann Arbor, MI: Museum of Anthropology, University of Michigan, 1986.
  7. Nagoor Meeran MF, Javed H, Sharma C, Goyal SN, Kumar S, Jha NK, Ojha S. Can Echinacea be a potential candidate to target immunity, inflammation, and infection – The trinity of coronavirus disease 2019. Heliyon. 2021 Feb;7(2):e05990. doi: 10.1016/j.heliyon.2021.e05990. Epub 2021 Feb 8. PMID: 33585706; PMCID: PMC7870107.
  8. Aucoin M, Cardozo V, McLaren MD, Garber A, Remy D, Baker J, Gratton A, Kala MA, Monteiro S, Warder C, Perciballi A, Cooley K. A systematic review on the effects of Echinacea supplementation on cytokine levels: Is there a role in COVID-19? Metabol Open. 2021 Jul 29:100115. doi: 10.1016/j.metop.2021.100115. Epub ahead of print. PMID: 34341776; PMCID: PMC8320399.
  9. Rasmussen PL, Optimising immunity to protect against coronaviruses. www.herbblurb.com Feb 4, 2020
  10. Rasmussen PL, Echinacea in the time of a pandemic. www.herbblurb.com Oct 30, 2020
  11. Mesri M, Esmaeili Saber SS, Godazi M, Roustaei Shirdel A, Montazer R, Koohestani HR, Baghcheghi N, Karimy M, Azizi N. The effects of combination of Zingiber officinale and Echinacea on alleviation of clinical symptoms and hospitalization rate of suspected COVID-19 outpatients: a randomized controlled trial. J Complement Integr Med. 2021 Mar 31. doi: 10.1515/jcim-2020-0283. Epub ahead of print. PMID: 33787192
  12. Bharadwaj S, El-Kafrawy SA, Alandijany TA, et al. Structure-Based Identification of Natural Products as SARS-CoV-2 Mpro Antagonist from Echinacea angustifolia Using Computational Approaches. Viruses. 2021;13(2):305. Published 2021 Feb 15. doi:10.3390/v13020305
  13. Gertsch J, Schoop R, Kuenzle U, Suter A. Echinacea alkylamides modulate TNF-alpha gene expression via cannabinoid receptor CB2 and multiple signal transduction pathways. FEBS Lett. 2004 Nov 19;577(3):563-9. doi: 10.1016/j.febslet.2004.10.064. PMID: 15556647.
  14. Raduner S, Bisson W, Abagyan R, Altmann KH, Gertsch J. Self-assembling cannabinomimetics: supramolecular structures of N-alkyl amides. J Nat Prod. 2007 Jun;70(6):1010-5. doi: 10.1021/np060598+. Epub 2007 May 11. PMID: 17497806.
  15. Raduner S, Majewska A, Chen JZ, Xie XQ, Hamon J, Faller B, Altmann KH, Gertsch J. Alkylamides from Echinacea are a new class of cannabinomimetics. Cannabinoid type 2 receptor-dependent and -independent immunomodulatory effects. J Biol Chem. 2006 May 19;281(20):14192-206. doi: 10.1074/jbc.M601074200. Epub 2006 Mar 17. PMID: 16547349.
  16. Haller J, Freund TF, Pelczer KG, Füredi J, Krecsak L, Zámbori J. The anxiolytic potential and psychotropic side effects of an echinacea preparation in laboratory animals and healthy volunteers. Phytother Res. 2013 Jan;27(1):54-61. doi: 10.1002/ptr.4677. Epub 2012 Mar 26. PMID: 22451347.
  17. Haller J, Krecsak L, Zámbori J. Double-blind placebo controlled trial of the anxiolytic effects of a standardized Echinacea extract. Phytother Res. 2020 Mar;34(3):660-668. doi: 10.1002/ptr.6558. Epub 2019 Dec 25. PMID: 31876052.
  18. Lopresti AL, Smith SJ. An investigation into the anxiety-relieving and mood-enhancing effects of Echinacea angustifolia (EP107™): A randomised, double-blind, placebo-controlled study. J Affect Disord. 2021 Oct 1;293:229-237. doi: 10.1016/j.jad.2021.06.054. Epub 2021 Jun 24. PMID: 34217960.
  19. Oláh A, Szabó-Papp J, Soeberdt M, Knie U, Dähnhardt-Pfeiffer S, Abels C, Bíró T. Echinacea purpurea-derived alkylamides exhibit potent anti-inflammatory effects and alleviate clinical symptoms of atopic eczema. J Dermatol Sci. 2017 Oct;88(1):67-77. doi: 10.1016/j.jdermsci.2017.05.015. Epub 2017 May 27. PMID: 28610718.
  20. Gulledge TV, Collette NM, Mackey E, Johnstone SE, Moazami Y, Todd DA, Moeser AJ, Pierce JG, Cech NB, Laster SM. 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 Feb 15;212:166-174. doi: 10.1016/j.jep.2017.10.012. Epub 2017 Oct 14. PMID: 29042288; PMCID: PMC5818717.
  21. Rasmussen PL, Echinacea – a useful herb for allergies. www.herbblurb.com July 14, 2018
  22. 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 Apr 27;12:651292. doi: 10.3389/fphar.2021.651292. PMID: 33986678; PMCID: PMC8111300.
  23. Rondanelli M, Riva A, Morazzoni P, Allegrini P, Faliva MA, Naso M, Miccono A, Peroni G, Degli Agosti I, Perna S. The effect and safety of highly standardized Ginger (Zingiber officinale) and Echinacea (Echinacea angustifolia) extract supplementation on inflammation and chronic pain in NSAIDs poor responders. A pilot study in subjects with knee arthrosis. Nat Prod Res. 2017 Jun;31(11):1309-1313. doi: 10.1080/14786419.2016.1236097. Epub 2016 Oct 13. PMID: 27737573.
  24. Hinz B, Woelkart K, Bauer R. Alkamides from Echinacea inhibit cyclooxygenase-2 activity in human neuroglioma cells. Biochem Biophys Res Commun. 2007 Aug 24;360(2):441-6. doi: 10.1016/j.bbrc.2007.06.073. Epub 2007 Jun 19. PMID: 17599805.
  25. Lalone CA, Huang N, Rizshsky L, Yum MY, Singh N, Hauck C, Nikolau BJ, Wurtele ES, Kohut ML, Murphy PA, Birt DF. Enrichment of Echinacea angustifolia with Bauer alkylamide 11 and Bauer ketone 23 increased anti-inflammatory potential through interference with cox-2 enzyme activity. J Agric Food Chem. 2010 Aug 11;58(15):8573-84. doi: 10.1021/jf1014268. PMID: 20681645; PMCID: PMC3738191.
  26. Mao CF, Sudirman S, Lee CC, Tsou D, Kong ZL. Echinacea purpurea Ethanol Extract Improves Male Reproductive Dysfunction With Streptozotocin-Nicotinamide-Induced Diabetic Rats. Front Vet Sci. 2021 Apr 28;8:651286. doi: 10.3389/fvets.2021.651286. PMID: 33996978; PMCID: PMC8113381.
  27. Hosami F, Manayi A, Salimi V, Khodakhah F, Nourbakhsh M, Nakstad B, Tavakoli-Yaraki M. The pro-apoptosis effects of Echinacea purpurea and Cannabis sativa extracts in human lung cancer cells through caspase-dependent pathway. BMC Complement Med Ther. 2021 Jan 14;21(1):37. doi: 10.1186/s12906-021-03204-6. PMID: 33446187; PMCID: PMC7809807.
  28. Rasmussen PL, Herbs and Cancer. www.herbblurb.com Feb 9, 2018.
  29. Espinosa-Paredes DA, Cornejo-Garrido J, Moreno-Eutimio MA, Martínez-Rodríguez OP, Jaramillo-Flores ME, Ordaz-Pichardo C. Echinacea Angustifolia DC Extract Induces Apoptosis and Cell Cycle Arrest and Synergizes with Paclitaxel in the MDA-MB-231 and MCF-7 Human Breast Cancer Cell Lines. Nutr Cancer. 2020 Sep 22:1-19. doi: 10.1080/01635581.2020.1817956. Epub ahead of print. PMID: 32959676.
  30. Yalçın E, Macar O, Kalefetoğlu Macar T, Çavuşoğlu D, Çavuşoğlu K. Multi-protective role of Echinacea purpurea L. water extract in Allium cepa L. against mercury(II) chloride. Environ Sci Pollut Res Int. 2021 Jul 3:1–9. doi: 10.1007/s11356-021-15097-6. Epub ahead of print. PMID: 34218367; PMCID: PMC8254617.
  31. Rasmussen PL, Recent studies on Echinacea and interactions with drug medication. Phytonews 34, Published by Phytomed Medicinal Herbs Ltd, Auckland, New Zealand. ISSN 1175-0251. July 2010.
  32. Awortwe C, Bruckmueller H, Kaehler M, Cascorbi I. Interaction of Phytocompounds of Echinacea purpurea with ABCB1 and ABCG2 Efflux Transporters. Mol Pharm. 2021 Apr 5;18(4):1622-1633. doi: 10.1021/acs.molpharmaceut.0c01075. Epub 2021 Mar 17. PMID: 33730506.