New Zealand’s Health System under Stress

An article in the New Zealand Herald nearly a month ago painted a somewhat concerning picture of New Zealand’s health system, following a review of Covid-19 recovery plans by all 20 District Health Boards filed prior to the current delta variant outbreak(1).

At that time more than 15,700 people were waiting longer than four months (the maximum time someone should wait under official guidelines), for a first appointment with a specialist. Another 13,500 had been accepted for treatment but were waiting longer than the four months target.

Our health system has been catching up after many appointments and surgical procedures were put on hold during last year’s lockdowns. On the positive side, these figures showed a reduction of nearly 14,000 patients waiting for appointments and treatment, from when we emerged from level 2 lockdown last year. However, progress had been slower than expected, with some District Health Boards struggling to meet their proposed reduction in waiting list numbers. Reasons for this were increased demand, the complexity of procedures, industrial action, and workforce shortages. Many services were already under severe stress, before the emergence of Covid-19.

Compounding this situation, there is a shortage of General Practitioners (GP’s) in several areas, and GP’s nationwide are calling out for increased primary care funding resources and less pressure.  Having a patient every 15 minutes and a full waiting room, is hardly conducive to being able to provide much in the way of educating and motivating a patient to undergo lifestyle or dietary changes that could have a major benefit on their disease outcomes.

And all this, was the situation before the need for NZ to again go into a level 4 lockdown 10 days ago, due to emergence of the more transmissible delta strain of Covid-19 within our population.

The economic burden of chronic illnesses

A huge component of the NZ government’s $20 billion expenditure annually on health, goes into the treatment and management of chronic conditions such as diabetes mellitus, obesity, cardiovascular disease, depression and anxiety. More than 250,000 people in NZ have diabetes mellitus, predominantly type 2. Management of this and its long term secondary outcomes such as leg ulcers, cardiovascular disease, neurological problems such as retinopathy and blindness, and kidney failure, draws heavily on health system resources and invariably requires increasingly intense treatments. The contribution to the pathology of type 2 diabetes, and economic burden that physical inactivity and obesity alone place on health care resources, is also being increasingly recognized(2). This situation is set to worsen further still, with the prevalence of childhood obesity also increasing at a phenomenal rate(3)

In all likelihood there will additionally be a future potential impact of so-called ‘Long Covid’ – chronic health ailments that can be long-lasting and very debilitating (thus expensive to manage) as a result of the secondary and residual effects of Covid-19 on some patients following recovery from the acute infection itself.  Some have projected these long term sequealae which include damage to organs such as the brain and heart, could produce a second public health crisis on the heels of the pandemic itself(4).

Pharmac’s budget was increased to $1.1 billion in the last budget, through many more drugs remain on its wishlist and on those of many New Zealanders that are yet to be approved for funding. Given the impact of our aging population, the continued increase in drug costs and effects of the pandemic on their supply chains, our reliance on a drug-based treatment system for so many chronic conditions, cannot continue to grow as it has done in the recent past. The many inequities within our society in terms of health service access, also need further addressing.

What can medical herbalists and naturopaths do?

I’ve written about this before(5,6), but in life repetition and relitigation is often necessary.

Limited understanding of natural medicines including herbal medicines by politicians and regulators, and lack of statutory regulation of natural health practitioners such as medical herbalists, is currently contributing to reduced accessibility to these medicines, resulting in adverse health and financial costs to society. Given the seriousness of the Covid-19 pandemic, and that it’s starting to look like we may be dealing with it for many years to come, this failure to optimize health outcomes for our population, should be urgently addressed.

Hospitalisation is costly, and in many locations in NZ hospital capacity is limited and already under stress. As an alternative to hospitalisation, home-based secondary prevention programmes for patients with many different types of chronic diseases, are being increasingly shown to provide improved patient as well as cost-benefit outcomes(7, 8, 9).  A recent meta-analysis of studies comparing outcomes in patients with chronic conditions who received “hospital-at-home” visits from a nurse or physician, versus those who received the usual in-hospital care, provides promising data. Those visited at home had a lower risk of long-term care admission than the hospital care group, and lower rates of depression and anxiety than those who remained in hospital(9). There is no reason why other health professionals such as medical herbalists, naturopaths, nutritionists or counsellors could not also achieve useful (and cost-effective) outcomes if patient access to their services was better facilitated.

Some types of interventions

New Zealand Public health researchers have shown cost savings and favourable cost effectiveness ratios for various interventions modelled by the Burden of Disease Epidemiology, Equity and Cost-Effectiveness Programme (BODE3) Programme(10).Not surprisingly,obesity and inactivity have been identified as major factors. They have recommended dietary changes and taxes on junk food and soft drinks, limits on junk food marketing to children, banning sugary drinks in schools, upgraded food labelling regulations, and improvements in walking and cycling infrastructure, as being likely to have the greatest and more lasting health impacts(11).

Herbal medicine treatments aimed at preventing some of the long term neurological and cardiovascular sequelae of poorly controlled diabetes and metabolic syndrome, or helping in the management of conditions such as anxiety disorders or depression, would also be worth evaluating from a cost versus benefit perspective. The cost to the taxpayer in terms such as number of Quality Adjusted Life Years (QALY) achieved through health sector interventions, a metric used also by Pharmac in determining drug-funding decisions, should also be properly researched for specific herbal treatments and practitioner interventions. 

Potential patient as well as pharmaco-economic benefits from adjunctive herbal treatments alongside conventional medical treatment, are now apparent for a large and growing number of common medical conditions. They include infectious disease, leg ulcers, wound healing, and even recovery after a heart failure or stroke.

Insomnia is a very common complaint in today’s world, and as Ive written about previously, there are many herbal medicines that can help(12). A 2011 study by NZ economists calculated a total net benefit of treating someone with insomnia to be $482, consisting of avoidance of $627 in related health costs, less an average cost of treatment of $145. Applied to the at risk population of NZ at the time, annual savings of nearly $22 million were estimated through treatment using a range of different practitioner or other interventions(13).

Herbs such as Japanese Honeysuckle (Lonicera japonica), gymnema, fenugreek, cinnamon, ginkgo and ginger, can produce useful actions in type 2 diabetes including helping to prevent some of the long term neurological and cardiovascular sequelae seen in poorly controlled diabetic patients. Hawthorn, Dan Shen (Salvia miltiorrhiza), Tienchi ginseng (Panax notoginseng), pomegranate and others, can help in the management of various cardiovascular conditions, though concomitant drug medication should be considered, and practitioner supervision is advisable.

New Zealand’s mental health statistics are amongst the worst in the world and rising. Greater resourcing of treatment options is required, and while more money was allocated in the last budget to mental health services, with rates of anxiety, depression and suicide showing no signs of abating anytime soon, a paradigm shift in thinking, would probably help more patients.

Herbal medicines have some relevant unique pharmacological actions and produce improvement in a great deal of mentally distressed people, with herbs such as St Johns Wort, withania (Ashwagandha) and kava being safer and often more accessible, than other interventions(14). And again, a skilled medical herbalist or naturopathic practitioner undertaking a comprehensive interview and history taking, and providing lifestyle and other advice in addition to individualized herbal treatments, should help reduce the need for psychiatric input and institution and drug-based care.

Freeing up healthcare resources for other needs!

I have the utmost respect for virtually all health professions and practices, and am very grateful to be able to access specific services and treatments for different health conditions and concerns, when needed. This is the hallmark of a good public health system, which has been an expectation for several generations now, in countries such as New Zealand.

However, the government simply cannot afford to continue to spend ever-increasing percentages of our GDP on Health (this rose from 5.6% of our GDP in 2005 to 6.5% in 2020), and when issues such as viral pandemics or natural disasters trigger a sudden surge in demand for health care resources, there needs to be some spare capacity in the system. One of the best ways we can enable this, is to focus more on reducing the burden on our limited health care resources that chronic conditions such as diabetes, cardiovascular disease, and mental health conditions, are currently causing. Medical herbalists and naturopaths who have undergone 3 or 4 year training to obtain degree qualifications, and the plant-based interventions which have prophylactic or useful adjunctive properties that they prescribe, are a greatly under-utilised resource.

From an evidence-based perspective considering phytomedicinal treatment options alone, the cost versus efficacy ratio is already compelling to subsidise certain plant-based interventions as alternatives or adjuncts to conventional treatments, for many patients with chronic health conditions. Adding to the benefits of such herbal interventions alone, is the ability of properly trained natural health practitioners to undertake a comprehensive assessment of patients, form a good rapport with them, and provide dietary and lifestyle advice to help slow down disease progression and lessen the need for further and often expensive and limited, mainstream health care interventions. And as an increasing amount of evidence is now informing us, that can only be a good thing in a world that a certain clever virus, is changing so much.

References:

  1. Jones, Nicholas, The New Zealand Herald, Health system failing to cope. August 2, 2021.
  2. Colditz GA. Economic costs of obesity. Am J Clin Nutr. 1992 Feb;55(2 Suppl):503S-507S. doi: 10.1093/ajcn/55.2.503s. PMID: 1733119.
  3. Nga VT, Dung VNT, Chu DT, Tien NLB, Van Thanh V, Ngoc VTN, Hoan LN, Phuong NT, Pham VH, Tao Y, Linh NP, Show PL, Do DL. School education and childhood obesity: A systemic review. Diabetes Metab Syndr. 2019 Jul-Aug;13(4):2495-2501. doi: 10.1016/j.dsx.2019.07.014. Epub 2019 Jul 8. PMID: 31405667.
  4. Rando HM, Bennett TD, Byrd JB, et al. Challenges in defining Long COVID: Striking differences across literature, Electronic Health Records, and patient-reported information. Preprint. medRxiv. 2021;2021.03.20.21253896. Published 2021 Mar 26. doi:10.1101/2021.03.20.21253896
  5. Rasmussen PL, Statutory regulation of medical herbalists and naturopaths: an essential step towards a more cost and outcome beneficial future healthcare system. www.herbblurb.com 26 April, 2019.
  6. Rasmussen PL, Herbal Medicine can help reduce high demands on Hospitals. www.herbblurb.com 31 March, 2017.
  7. McClure T, Haykowsky MJ, Schopflocher D, Hsu ZY, Clark AM. Home-based secondary prevention programs for patients with coronary artery disease: a meta-analysis of effects on anxiety. J Cardiopulm Rehabil Prev. 2013 Mar-Apr;33(2):59-67. doi: 10.1097/HCR.0b013e3182828f71. PMID: 23426558.
  8. Clark AM, Haykowsky M, Kryworuchko J, MacClure T, Scott J, DesMeules M, Luo W, Liang Y, McAlister FA. A meta-analysis of randomized control trials of home-based secondary prevention programs for coronary artery disease. Eur J Cardiovasc Prev Rehabil. 2010 Jun;17(3):261-70. doi: 10.1097/HJR.0b013e32833090ef. PMID: 20560165.
  9. Arsenault-Lapierre G, Henein M, Gaid D, Le Berre M, Gore G, Vedel I. Hospital-at-Home Interventions vs In-Hospital Stay for Patients With Chronic Disease Who Present to the Emergency Department: A Systematic Review and Meta-analysis. JAMA Netw Open. 2021;4(6):e2111568. Published 2021 Jun 1. doi:10.1001/jamanetworkopen.2021.11568.
  10. Wilson N, Davies A, Brewer N, Nghiem N, Cobiac L, Blakely T. Can cost-effectiveness results be combined into a coherent league table? Case study from one high-income country. Popul Health Metr. 2019;17(1):10. Published 2019 Aug 5. doi:10.1186/s12963-019-0192-x
  11. Wilson N et al, BODE3 Interactive League Table – Public Health Expert, University of Otago, New Zealand
  12. Rasmussen PL, Overcoming insomnia: drug versus herbal solutions. www.herbblurb.com Oct 20, 2018.
  13. Scott GW, Scott HM, O’Keeffe KM, Gander PH. Insomnia – treatment pathways, costs and quality of life. Cost Eff Resour Alloc. 2011;9:10. Published 2011 Jun 21. doi:10.1186/1478-7547-9-10
  14. Rasmussen PL, New Zealand’s woeful mental health statistics for young people. www.herbblurb.com Aug 23, 2019.

SARS-CoV-2 – the Coronavirus that is changing the World

Covid-19 resurgence

While New Zealand has been one of the most successful countries in the world at not letting Covid-19 (SARS-CoV-2) become a rampant infection throughout its communities, the global impact of this pandemic remains extremely high.  Given how difficult an elimination strategy has been to execute, and the economic consequences of lockdowns, many countries are now in the process of developing and implementing policies that are based upon learning to live with rather than eliminate it.

The last 18 months have seen a whirlwind of change as this clever virus has caused so many deaths and disrupted so many lives. Over the next year or two we will undoubtedly continue to see further new developments, including the emergence of new variants and increased rates of vaccination, but also further increases in our understanding about how to best deal with the virus in different scenarios.

Recent experiences of our cousins over the ditch in Australia, highlight just how easy it is to tilt from living life largely as we used to, to being back in lockdown, as the more infectious delta variant runs through communities. New South Wales has just recorded 163 cases in the last 24 hours, its highest number of new cases since the latest outbreak began. Other nearby countries such as Fiji, are presently faring much worse, with 918 new cases and 15 more deaths confirmed in the 24 hours to 22nd July.

Apart from being more infectious, studies suggest the delta variant can also produce a much higher viral load within the respiratory system than the original strain of the virus. This combination of a higher viral load and more efficient transmission, makes this variant particularly worrisome.

While vaccination rates are increasing, supply shortfalls and differing levels of prophylactic efficacy, are concerns. Additionally, the duration of immune memory and thus protective immunity after contracting a Covid-19 infection, or after vaccination, are still unknowns that will take years to gather reliable data on(1). All of this and more, highlights just how challenging the battle against this virus is, and that its impact on our lives will continue for a long time yet.

Developing Immunity:

New Zealand modelling has estimated that to ensure herd immunity, an overall vaccination rate of around 83 percent using the Pfizer vaccine will be required. With the more contagious delta variant however, a vaccination rate of 97%, is likely to be needed(2).

Discussing the pros and cons of vaccination is not the purpose of this article. But what now seems clear, is that achieving these levels of vaccination in our population, is very unlikely to happen.  While most New Zealanders will probably opt for vaccination particularly as the global situation remains dire, I cant see more than 70% of the population being vaccinated anytime soon. The conclusion now being reached by epidemiologists and microbiologists is that in addition to relying heavily on vaccination, we’ll probably need to maintain and add a mix of other measures in order to achieve an acceptable level of population immunity. Ongoing border restrictions, mask wearing, social distancing and the need for differing levels of lockdown in the coming months or more, seems unavoidable. In addition to such measures, a focus on individual immunity and treatment interventions should an infection arise, is also important.

Plants have enormous potential to help optimise immunity in humans, and a healthy vegetable and fruit rich diet, is linked with favourable influences on the gut microbiome and immune function. Their complex phytochemistry including diverse polyphenolic molecules and fibre, and vitamins such as vitamin C, contribute to the healthy functioning of these bodily defence systems.

The use of herbal medicines or supplementation of the diet with immune enhancing herbs and spices for at least 14 days during periods of community outbreaks, is a recommendable component of a Covid-19 management strategy. Culinary herbs and spices such as ginger, blackseed and holy basil show potential as antiviral agents and immunity enhancers against viral infections, while others such as horseradish, cinnamon thyme, oregano and garlic, may be useful to help prevent or treat secondary bacterial infections that can contribute to patients becoming seriously unwell(3).

Variations in death rates from Covid-19 in different countries, may in fact partly relate to differences in diet. Associations have been suggested between several countries with low Covid-19 death rates, and traditional diets which incorporate large quantities of certain spices, or fermented vegetables (such as cassava in Africa, cabbage and other cruciferous vegetables in Germany and Korea)(4, 5).  

Echinacea (Purple coneflower) is one of the most promising immune enhancers from both a traditional as well as evidence-based perspective, and has pronounced anti-inflammatory and immunomodulatory effects. Its immunomodulatory mode of action, whereby it enhances the immune system when taken in the absence of infection, but may reduce excessive and possibly damaging inflammation (the ‘cytokine storm’) during a viral infection, is of particular interest. These properties suggest both a useful prophylactic effect of Echinacea against unwanted viruses, but also a potential usefulness during upper respiratory tract viral infections(6).

While a Cochrane review found Vitamin C supplementation of at least 200mg per day to be associated with a 7.7% reduction in the duration of colds in adults(7), a recent clinical trial which investigated the effects of 8 grams a day of vitamin C or its combination with zinc on recovery from Covid-19 infection, was stopped early due to disappointing results(8). The methodology of this trial and rationale for its early termination, has however been challenged(9).

Vitamin D deficiency has been revealed as a significant risk factor for acute respiratory distress syndrome, heart failure and sepsis, as well as in critically ill Covid-19 patients(10, 11).  Apart from addressing any deficiency as a prophylactic measure, supplementation and restoration to normal range of vitamin D in patients with Covid-19, has been reported to reduce inflammation and improve their immunologic state during antiviral drug treatment(12, 13).

Addressing weight loss when obesity is an issue, is also advisable. A retrospective study in China reported that 88% of non-survivors of Covid-19 with cardiovascular disease had a body mass index (BMI) over 25, as opposed to 18% in the survivor group(14). Similarly a study involving 124 hospitalised Covid-19 patients in France observed that patients with a BMI over 35 were 7 times more at risk of requiring invasive mechanical ventilation during their ICU stay than patients with a BMI less than 25(15)..

Some recent findings:

Despite all the grim news of late, there’s actually been a fair amount of encouraging research undertaken over the past year into plant-derived medicines and their influences on this cunning virus. Much of this has taken place in countries where the pandemic’s impact has been severe, and in others where traditional and plant-based medicines have for many years now been a focus of government health policies and research funding.

Herbal medicines can work well when combined appropriately with drug and other conventional therapies, and this is also the case with Covid-19 patients. In China, incorporation of traditional Chinese herbal treatments into the management of patients with Covid-19 has achieved additional benefits to those seen through drug-based treatment alone(16-20). Similar experiences have been reported through the use of traditional herbal medicines in India and other countries(21-23).

Another example of this is propolis, the resinous substance that bees produce from plant pollens, to help protect their hives. Propolis is full of powerful phytochemicals including many with antiviral properties, and results from a clinical trial involving patients hospitalized with Covid-19 in Brazil, are encouraging. Propolis administration alongside the various conventional drugs and treatments given to seriously ill Covid-19 patients, lead to a much faster recovery time and halving of the median duration of hospital stay, from  12 to 6 days(24, 25). The extent of kidney damage was also reduced in patients given propolis.

Separate clinical trials are also planned or underway in Iran into the use of ginger(26) or pomegranate juice(27) alongside standard hospital treatment for Covid-19, which will measure both inflammatory markers and clinical outcomes. In Saudi Arabia a trial is underway into adjunctive use of the popular middle eastern spice blackseed (Nigella sativa, or black cumin)(28). Several Nigella components have shown promise in in vitro studies as anti-viral agents(29-32).

Extracts of the medicinal fungus Ganoderma lucidum (Reishi), and the wild and culinary herbs Perilla frutescens (Perilla) and Mentha haplocalyx (Mint), have all recently been found to reduce the viral load in animal studies(33). Reishi exhibits antiviral activities also against herpes simplex, dengue fever, hepatitis B, and HIV (34). A combination of Reishi with another medicinal mushroom Lions Mane (Hericium erinaceus), significantly reduced bacteraemia and increased the survival in mice with pneumococcal sepsis(35). As with many other medicinal herbs, these mushroom extracts may exhibit preventive or therapeutic effects against severe bronchial infections and lung inflammation, that feature in severe Covid-19 infections.

In India, the highly regarded immunomodulatory and anti-inflammatory medicinal herb Andrographis paniculata, is being further researched by local scientists. Synergy has been shown between andrographolide and its other phytochemicals, in effects on upper respiratory tract infections and the ability to significantly decrease the production of pro-inflammatory cytokines in viral infections(36). Andrographolide seems to bind with crucial proteins to block the TNF-induced NFkB1 signaling pathway which contributes to the cytokine storm in Covid-19 patients(37). It also seems to inhibit the main protease and other key targets of the virus responsible for replication, transcription and host cell recognition(38, 39).

Sumac is the name given to many different species of Rhus, medicinal flowering plants that are endemic in temperate and tropical regions, including China (Rhus chinensis), the Middle east, and North America. Traditional uses in multiple countries include for antiviral, antimicrobial, antibacterial, antioxidant, and wound-healing properties. Molecular docking and drug-likeness studies have revealed potential protease inhibitory properties for various polyphenolic constituents of Rhus chinensis(40). Other Sumac extracts also exhibit organ-protective properties of relevance to Covid-19 pathology, and may also be useful during infections(41).

In South America, the highly regarded medicinal tree Cats Claw (Uncaria tomentosa), has also been reported to contain compounds which inhibit the virus’s main protease(42, 43). A hydroethanolic extract of its stem bark, also inhibited the virus(44).

Desperate times lead to desperate measures however, and in some instances there have been exaggerated claims of efficacy with little evidence basis, for the use of particular plant medicines in treating symptoms of Covid-19 infection.

What is evident from the many studies either completed or underway in numerous countries of the world, is that planning and funding for research into specific locally available plants and dietary interventions, seems to be paying dividends. In most cases, targeted investigations into relevant traditional and historical uses of some highly regarded local species, including the application of molecular docking and other modern research technologies, combined with the incorporation of learnings to date about how this virus replicates and causes harm, is proving to be a worthwhile approach.

References:

  1. Sette A, Crotty S. Adaptive immunity to SARS-CoV-2 and COVID-19. Cell. 2021;184(4):861-880. doi:10.1016/j.cell.2021.01.007.
  2. A COVID-19 vaccination model for Aotearoa New Zealand (tepunahamatatini.ac.nz)
  3. Rasmussen PL, Culinary herbs and spices to know about, in infectious times. www.herbblurb.com Mar 20, 2020.
  4. Bousquet J, Czarlewski W, Zuberbier T, Mullol J, Blain H, Cristol JP, De La Torre R, Le Moing V, Pizarro Lozano N, Bedbrook A, Agache I, Akdis CA, Canonica GW, Cruz AA, Fiocchi A, Fonseca JA, Fonseca S, Gemicioğlu B, Haahtela T, Iaccarino G, Ivancevich JC, Jutel M, Klimek L, Kuna P, Larenas-Linnemann DE, Melén E, Okamoto Y, Papadopoulos NG, Pfaar O, Reynes J, Rolland Y, Rouadi PW, Samolinski B, Sheikh A, Toppila-Salmi S, Valiulis A, Choi HJ, Kim HJ, Anto JM. Spices to Control COVID-19 Symptoms: Yes, but Not Only…. Int Arch Allergy Immunol. 2021;182(6):489-495. doi: 10.1159/000513538. Epub 2020 Dec 22. PMID: 33352565; PMCID: PMC7900475.
  5. Bousquet J, Anto JM, Czarlewski W, Haahtela T, Fonseca SC, Iaccarino G, Blain H, Vidal A, Sheikh A, Akdis CA, Zuberbier T; ARIA group. Cabbage and fermented vegetables: From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19. Allergy. 2021 Mar;76(3):735-750. doi: 10.1111/all.14549. Epub 2020 Sep 15. PMID: 32762135; PMCID: PMC7436771.
  6. Rasmussen PL, Echinacea in the time of a pandemic. www.herbblurb.com Oct 20, 2020.
  7. Hemilä H, Chalker E. Vitamin C for preventing and treating the common cold. Cochrane Database Syst Rev. 2013 Jan 31;2013(1):CD000980. doi: 10.1002/14651858.CD000980.pub4. PMID: 23440782; PMCID: PMC8078152.
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  13. Annweiler G, Corvaisier M, Gautier J, Dubée V, Legrand E, Sacco G, Annweiler C. Vitamin D Supplementation Associated to Better Survival in Hospitalized Frail Elderly COVID-19 Patients: The GERIA-COVID Quasi-Experimental Study. Nutrients. 2020 Nov 2;12(11):3377. doi: 10.3390/nu12113377. PMID: 33147894; PMCID: PMC7693938.
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  23. Aldwihi LA, Khan SI, Alamri FF, AlRuthia Y, Alqahtani F, Fantoukh OI, Assiri A, Almohammed OA. Patients’ Behavior Regarding Dietary or Herbal Supplements before and during COVID-19 in Saudi Arabia. Int J Environ Res Public Health. 2021 May 11;18(10):5086. doi: 10.3390/ijerph18105086. PMID: 34064950; PMCID: PMC8151200.
  24. Silveira MAD, De Jong D, Berretta AA, et al. Efficacy of Brazilian green propolis (EPP-AF®) as an adjunct treatment for hospitalized COVID-19 patients: A randomized, controlled clinical trial. Biomed Pharmacother. 2021;138:111526. doi:10.1016/j.biopha.2021.111526.
  25. Rasmussen PL, Propolis: amazing stuff made by bees from nature. www.herbblurb.com Apr 9, 2021.
  26. Safa O, Hassaniazad M, Farashahinejad M, Davoodian P, Dadvand H, Hassanipour S, Fathalipour M. Effects of Ginger on clinical manifestations and paraclinical features of patients with Severe Acute Respiratory Syndrome due to COVID-19: A structured summary of a study protocol for a randomized controlled trial. Trials. 2020 Oct 9;21(1):841. doi: 10.1186/s13063-020-04765-6. PMID: 33036662; PMCID: PMC7545374.
  27. Yousefi M, Sadriirani M, PourMahmoudi A, Mahmoodi S, Samimi B, Hosseinikia M, Saeedinezhad Z, Panahande SB. Effects of pomegranate juice (Punica Granatum) on inflammatory biomarkers and complete blood count in patients with COVID-19: a structured summary of a study protocol for a randomized clinical trial. Trials. 2021 Apr 2;22(1):246. doi: 10.1186/s13063-021-05194-9. PMID: 33810808; PMCID: PMC8017515.
  28. Koshak AE, Koshak EA, Mobeireek AF, Badawi MA, Wali SO, Malibary HM, Atwah AF, Alhamdan MM, Almalki RA, Madani TA. Nigella sativa supplementation to treat symptomatic mild COVID-19: A structured summary of a protocol for a randomised, controlled, clinical trial. Trials. 2020 Aug 8;21(1):703. doi: 10.1186/s13063-020-04647-x. PMID: 32771034; PMCID: PMC7414256.
  29. Koshak DAE, Koshak PEA. Nigella sativa L as a potential phytotherapy for coronavirus disease 2019: A mini review of in silico studies. Curr Ther Res Clin Exp. 2020;93:100602. doi: 10.1016/j.curtheres.2020.100602. Epub 2020 Aug 25. PMID: 32863400; PMCID: PMC744515.
  30. Siddiqui S, Upadhyay S, Ahmad R, Gupta A, Srivastava A, Trivedi A, Husain I, Ahmad B, Ahamed M, Khan MA. Virtual screening of phytoconstituents from miracle herb nigella sativa targeting nucleocapsid protein and papain-like protease of SARS-CoV-2 for COVID-19 treatment. J Biomol Struct Dyn. 2020 Dec 8:1-21. doi: 10.1080/07391102.2020.1852117. Epub ahead of print. PMID: 33289456; PMCID: PMC7738213.
  31. Maideen NMP. Prophetic Medicine-Nigella Sativa (Black cumin seeds) – Potential herb for COVID-19? J Pharmacopuncture. 2020 Jun 30;23(2):62-70. doi: 10.3831/KPI.2020.23.010. Erratum in: J Pharmacopuncture. 2020 Sep 30;23(3):179. PMID: 32685234; PMCID: PMC7338708.
  32. Ahmad S, Abbasi HW, Shahid S, Gul S, Abbasi SW. Molecular docking, simulation and MM-PBSA studies of nigella sativa compounds: a computational quest to identify potential natural antiviral for COVID-19 treatment. J Biomol Struct Dyn. 2021 Aug;39(12):4225-4233. doi: 10.1080/07391102.2020.1775129. Epub 2020 Jun 12. PMID: 32462996; PMCID: PMC7298883.
  33. Jan JT, Cheng TR, Juang YP, Ma HH, Wu YT, Yang WB, Cheng CW, Chen X, Chou TH, Shie JJ, Cheng WC, Chein RJ, Mao SS, Liang PH, Ma C, Hung SC, Wong CH. Identification of existing pharmaceuticals and herbal medicines as inhibitors of SARS-CoV-2 infection. Proc Natl Acad Sci U S A. 2021 Feb 2;118(5):e2021579118. doi: 10.1073/pnas.2021579118. PMID: 33452205; PMCID: PMC7865145.
  34. Rai MK, Gaikwad S, Nagaonkar D, dos Santos CA. Current Advances in the Antimicrobial Potential of Species of Genus Ganoderma (Higher Basidiomycetes) against Human Pathogenic Microorganisms (Review). Int J Med Mushrooms. 2015;17(10):921-32. doi: 10.1615/intjmedmushrooms.v17.i10.20. PMID: 26756184.
  35. Hetland G, Johnson E, Bernardshaw SV, Grinde B. Can medicinal mushrooms have prophylactic or therapeutic effect against COVID-19 and its pneumonic superinfection and complicating inflammation? Scand J Immunol. 2021 Jan;93(1):e12937. doi: 10.1111/sji.12937. Epub 2020 Jul 29. PMID: 32657436; PMCID: PMC7404338.
  36. Banerjee S, Kar A, Mukherjee PK, Haldar PK, Sharma N, Katiyar CK. Immunoprotective potential of Ayurvedic herb Kalmegh (Andrographis paniculata) against respiratory viral infections – LC-MS/MS and network pharmacology analysis. Phytochem Anal. 2021 Jul;32(4):629-639. doi: 10.1002/pca.3011. Epub 2020 Nov 9. PMID: 33167083.
  37. Rehan M, Ahmed F, Howladar SM, Refai MY, Baeissa HM, Zughaibi TA, Kedwa KM, Jamal MS. A Computational Approach Identified Andrographolide as a Potential Drug for Suppressing COVID-19-Induced Cytokine Storm. Front Immunol. 2021 Jun 24;12:648250. doi: 10.3389/fimmu.2021.648250. PMID: 34248936; PMCID: PMC8264290.
  38. Murugan NA, Pandian CJ, Jeyakanthan J. Computational investigation on Andrographis paniculata phytochemicals to evaluate their potency against SARS-CoV-2 in comparison to known antiviral compounds in drug trials. J Biomol Struct Dyn. 2021 Aug;39(12):4415-4426. doi: 10.1080/07391102.2020.1777901. Epub 2020 Jun 16. PMID: 32543978.
  39. Enmozhi SK, Raja K, Sebastine I, Joseph J. Andrographolide as a potential inhibitor of SARS-CoV-2 main protease: an in silico approach. J Biomol Struct Dyn. 2021 Jun;39(9):3092-3098. doi: 10.1080/07391102.2020.1760136. Epub 2020 May 5. PMID: 32329419; PMCID: PMC7212536.
  40. Sherif YE, Gabr SA, Hosny NM, Alghadir AH, Alansari R. Phytochemicals of Rhus spp. as Potential Inhibitors of the SARS-CoV-2 Main Protease: Molecular Docking and Drug-Likeness Study. Evid Based Complement Alternat Med. 2021;2021:8814890. Published 2021 Feb 27. doi:10.1155/2021/8814890
  41. Korkmaz H. Could Sumac Be Effective on COVID-19 Treatment? J Med Food. 2021 Jun;24(6):563-568. doi: 10.1089/jmf.2020.0104. Epub 2020 Aug 18. PMID: 32816615.
  42. Yepes-Pérez AF, Herrera-Calderon O, Sánchez-Aparicio JE, Tiessler-Sala L, Maréchal JD, Cardona-G W. Investigating Potential Inhibitory Effect of Uncaria tomentosa (Cat’s Claw) against the Main Protease 3CLpro of SARS-CoV-2 by Molecular Modeling. Evid Based Complement Alternat Med. 2020 Sep 30;2020:4932572. doi: 10.1155/2020/4932572. PMID: 33029165; PMCID: PMC7532411.
  43. Yepes-Pérez AF, Herrera-Calderon O, Quintero-Saumeth J. Uncaria tomentosa (cat’s claw): a promising herbal medicine against SARS-CoV-2/ACE-2 junction and SARS-CoV-2 spike protein based on molecular modeling. J Biomol Struct Dyn. 2020 Oct 29:1-17. doi: 10.1080/07391102.2020.1837676. Epub ahead of print. PMID: 33118480; PMCID: PMC7657399.
  44. Yepes-Perez AF, Herrera-Calderón O, Oliveros CA, Flórez-Álvarez L, Zapata-Cardona MI, Yepes L, Aguilar-Jimenez W, Rugeles MT, Zapata W. The Hydroalcoholic Extract of Uncaria tomentosa (Cat’s Claw) Inhibits the Infection of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) In Vitro. Evid Based Complement Alternat Med. 2021 Feb 24;2021:6679761. doi: 10.1155/2021/6679761. PMID: 33680061; PMCID: PMC7929665.

Baptisia – a somewhat mysterious phytomedicine

Herbal medicine is full of plants where our historical records of their applications to treat disease and illness are somewhat lacking in content or accuracy. Its also somewhat concerning but also hardly surprising, just how little we really understand about the therapeutic potential and best ways of using, some of the many plants we are taught about or have been made aware of. The fact that much of the knowledge around use of plants as medicines was traditionally transmitted through an oral rather than written form, and that diseases of concern and our understanding of them in the past were different to now, is contributory to this. I remember for example being surprised at how little written information on Echinacea’s traditional use I could find in books on Native Indian Medicine I looked at when travelling in the U.S. many years ago, although we now know it is a brilliant medicine for numerous infectious and inflammatory conditions, for which it was of course also traditionally used.

Wild Indigo

Another North American herb that has always held some mystery to me, is Wild Indigo root (Baptisia tinctoria).  Native to eastern parts of the U.S. and Canada, Baptisia is a Leguminosae family member, and its young shoots were sometimes eaten for greens and used in soups(1) Its root has a somewhat bitter and acrid taste and was a treasured medicine to some native American Indians(2,3).  While having yellow flowers, all parts of Wild Indigo when dried yield a blue dye.  Another species, Baptisia australis, which grew well in my garden years ago, has blue rather than yellow flowers and has been said to be able to be used interchangeably(4), although this claim has not been validated.

Antimicrobial

These indications are reflective of a good antimicrobial phytomedicine. Moderate in vitro activity has been reported for extracts against Staphylococcus aureus(6), and yet surprisingly few other studies into antimicrobial activity or clinical studies appear to have been published on the use of Wild Indigo alone.  Clinical trials involving combinations of Baptisia tinctoria root, Echinacea purpurea root, Echinacea pallida root and Thuja occidentalis reported an improvement in cold symptoms earlier than placebo(7, 8, 9). Enhanced phagocytic activity by leukocytes was also reported for a combination of Baptisia tinctoria, Eupatorium cannabinum and Arnica with Echinacea angustifolia, than that measured for Echinacea alone(10).

The fact that large doses can be emetic, may account for some of this relative paucity of scientific studies into the Wild Indigo’s antimicrobial potential. However, early investigations into its use as a fresh tincture by the Eclectic physicians for typhoid, spurred by the fact that excessive doses can produce fever and other symptoms similar to those of typhoid, appear also to have clouded our view of this phytomedicine.

Large polysaccharide fractions were reported by German researchers in 1985 to show significant immunostimulant activities(11) and enhance production of antibodies against sheep red blood cells(12). A contribution of arabinogalactan proteins extracted from polysaccharides found in Wild Indigo root to its claimed immune-stimulant properties has also been reported(13, 14). These are said to be mediated through a specific antigen-antibody reaction rather than non-specific immune system activation. These effects and reported efficacy using low doses of Wild Indigo root for the treatment of typhoid, has attracted the interest of homoeopathic researchers and product manufacturers(15). However, little published evidence of such effects from low doses in human studies appears to exist, and it would seem this impression of Wild Indigo’s therapeutic properties has perhaps contributed to a blurred understanding of how best to use it, and in what dose.

Typhoid (Salmonella typhi) used to be a serious bacterial infection in much of the world until the development of a vaccine 120 years ago, and still remains a serious infectious bacterial disease in third world countries. Successful management of typhoid fever using antibiotics is also becoming increasingly difficult due to emerging and spreading drug resistance(16). As such, and given the strong historical reputation of Wild Indigo, further research into its relevant activities in the management of this and other infectious diseases seems warranted.

Other applications

Wild Indigo was also sometimes taken in large doses as a purgative. In the 1870’s two chemists Weaver and Greene characterised certain alkaloids including baptisine (baptotoxine), said to be poisonous and likely to contribute to these effects(1). Baptisine was however subsequently shown to be identical with another quinolizidine alkaloid cytisine(17). This is a well-known constituent of various medicinal and somewhat poisonous plants such as the unripe seeds of Laburnum (Cytisus laburnum) and species of Sophora, including those used in traditional Chinese medicine as well as the New Zealand native Kowhai (various Sophora species)(18, 19).

All medicines including plant-derived ones can produce adverse effects, particularly in sensitive individuals or when excessive doses are taken. However, one person’s poison can be another person’s medicine, and while probably contributory to nausea and vomiting when excessive doses of Wild Indigo are taken, cytisine is also used as a medicine. As an alkaloid with nicotinic acetylcholine receptor-agonist properties, it is being increasingly used in small doses for smoking cessation(20). Various clinical trials in New Zealand have in fact found cytisine to have promising potential as an aid to smoking cessation(21, 22, 23, 24).

Case reports of poisoning following ingestion of Wild Indigo mistaken for asparagus have been made, although doses taken were much higher than recommended when used as a medicine (Anderson). As with Wild Indigo poisoning in North America, poisoning due to ingestion of too high a dose of Kowhai (particularly of the high cytisine-containing seeds or aerial parts rather than bark)i, is  not uncommon here in New Zealand(25).  Notably, the effects of such poisoning or overdose are similar to the most frequently reported adverse reactions of cytisine when used as a drug, and include gastrointestinal symptoms that are mostly reported as either mild or moderate in severity(20).

While its content of cytisine and thus tolerance to different doses will vary between individuals, the use of Wild Indigo bark in smoking cessation treatment is potentially indicated.  Analogies to the use of Lobelia inflata, which contains another nicotinic receptor-agonist lobeline, for smoking cessation treatment but invokes emesis in excessive doses (hence its common name ‘Pukeweed’), also spring to mind.  Novel nicotinic partial agonists including cytisine also show potential protective effects in animal studies, against Parkinson’s disease(26), depression and anxiety (27).

True Indigo (Indigofera tinctoria)

Native to southern Asia and now naturalised in many countries, the botanically related True Indigo (Indigofera tinctoria) was one of the original sources of indigo dye. It is also used in traditional medicine, and was used in India to control epileptic seizures. Dose dependent anticonvulsant effects in animal studies have been shown for an ethanolic extract of the whole plant, effects accompanied by increased brain levels of the inhibitory neurotransmitter GABA (gamma amino butyric acid)(28). Protection against the negative immunological effects of noise stress, and stimulation of both adaptive and innate immunity, has also been reported in rats(29).

Anthelmintic activity including inhibition of egg hatching has also been reported against gastrointestinal nematodes in sheep (30). Planting of Indigofera tinctoria has also been shown to help control nematode infestations in the soil(31).

References:

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  2. Hutchens AR. 1973. Indian Herbalogy of North America. Boston, Massachusetts: Shambhala Publications Inc.
  3. Millspaugh CF, American Medicinal Plants, Dover Publications Inc, New York, 1974.
  4. Milton Welch J. The Medical Flora of Kansas. Transactions of the National Eclectic Association. 1882-83, Vol. X. Accessed 18 September 2008.
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  9. Henneicke-von Zepelin HH, Nicken P, Naser B, Kuchernig JC, Brien N, Holtdirk A, Schnitker J, Nolte KU. Non-interventional observational study broadens positive benefit-risk assessment of an immunomodulating herbal remedy in the common cold. Curr Med Res Opin. 2019 Oct;35(10):1711-1719. doi: 10.1080/03007995.2019.1618252. Epub 2019 Jun 17. PMID: 31074674.Anderson MJ, Kurtycz DF, Cline JR. Baptisia poisoning: a new and toxic look-alike in the neighborhood. J Emerg Med. 2015 Jan;48(1):39-42. doi: 10.1016/j.jemermed.2014.09.037. Epub 2014 Nov 6. PMID: 25453859.
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  11. Wagner H, Proksch A, Riess-Maurer I, Vollmar A, Odenthal S, Stuppner H, Jurcic K, Le Turdu M, Fang JN. Immunstimulierend wirkende Polysaccharide (Heteroglykane) aus höheren Pflanzen [Immunostimulating action of polysaccharides (heteroglycans) from higher plants]. Arzneimittelforschung. 1985;35(7):1069-75. German. PMID: 4052142.Mineur YS, Eibl C, Young G, Kochevar C, Papke RL, Gündisch D, Picciotto MR. Cytisine-based nicotinic partial agonists as novel antidepressant compounds. J Pharmacol Exp Ther. 2009 Apr;329(1):377-86. doi: 10.1124/jpet.108.149609. Epub 2009 Jan 22. PMID: 19164465; PMCID: PMC2670591.
  12. Beuscher N, Kopanski L. Stimulation der Immunantwort durch Inhaltsstoffe aus Baptisia tinctoria. (Stimulation of immunity by the contents of Baptisia tinctoria]. Planta Med. 1985 Oct;51(5):381-4. doi: 10.1055/s-2007-969525. PMID: 17342588.
  13. Egert D, Beuscher N. Studies on antigen specifity of immunoreactive arabinogalactan proteins extracted from Baptisia tinctoria and Echinacea purpurea. Planta Med. 1992 Apr;58(2):163-5. doi: 10.1055/s-2006-961420. PMID: 1382301.
  14. Classen B, Thude S, Blaschek W, Wack M, Bodinet C. Immunomodulatory effects of arabinogalactan-proteins from Baptisia and Echinacea. Phytomedicine. 2006 Nov;13(9-10):688-94. doi: 10.1016/j.phymed.2005.10.004. Epub 2005 Nov 14. PMID: 17085292.
  15. Banerji P, Banerji P, Das GC, Islam A, Mishra SK, Mukhopadhyay S. Efficacy of Baptisia tinctoria in the treatment of typhoid: its possible role in inducing antibody formation. J Complement Integr Med. 2012 Jul 2;9:Article 15. doi: 10.1515/1553-3840.1622. PMID: 22850071.
  16. Masuet-Aumatell C, Atouguia J. Typhoid fever infection – Antibiotic resistance and vaccination strategies: A narrative review. Travel Med Infect Dis. 2021 Mar-Apr;40:101946. doi: 10.1016/j.tmaid.2020.101946. Epub 2020 Dec 8. PMID: 33301931.
  17. Plugge PC, Arch. der Pharm. (1891), 229, p. 48.
  18. McDougal OM, Heenan PB, Jaksons P, Sansom CE, Smallfield BM, Perry NB, van Klink JW. Alkaloid variation in New Zealand kōwhai, Sophora species. Phytochemistry. 2015 Oct;118:9-16. doi: 10.1016/j.phytochem.2015.07.019. Epub 2015 Aug 6. PMID: 26253652.
  19. Wang H, Xia C, Chen L, Zhao J, Tao W, Zhang X, Wang J, Gao X, Yong J, Duan JA. Phytochemical Information and Biological Activities of Quinolizidine Alkaloids in Sophora: A Comprehensive Review. Curr Drug Targets. 2019;20(15):1572-1586. doi: 10.2174/1389450120666190618125816. PMID: 31215388.
  20. Tutka P, Vinnikov D, Courtney RJ, Benowitz NL. Cytisine for nicotine addiction treatment: a review of pharmacology, therapeutics and an update of clinical trial evidence for smoking cessation. Addiction. 2019 Nov;114(11):1951-1969. doi: 10.1111/add.14721. Epub 2019 Jul 19. PMID: 31240783.
  21. Walker N, Howe C, Glover M, McRobbie H, Barnes J, Nosa V, Parag V, Bassett B, Bullen C. Cytisine versus nicotine for smoking cessation. N Engl J Med. 2014 Dec 18;371(25):2353-62. doi: 10.1056/NEJMoa1407764. PMID: 25517706.
  22. Walker N, Smith B, Barnes J, Verbiest M, Parag V, Pokhrel S, Wharakura MK, Lees T, Cubillos Gutierrez H, Jones B, Bullen C. Cytisine versus varenicline for smoking cessation in New Zealand indigenous Māori: a randomized controlled trial. Addiction. 2021 Mar 24. doi: 10.1111/add.15489. Epub ahead of print. PMID: 33761149.
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Pomegranate – recent findings

Pomegranate (Punica granatum), was one of the earliest fruits from warmer parts of the world to become popular in Europe. Native to the Middle East, traditional uses include for the treatment of dysentery and diarrhoea. It now seems that the more scientists look, the more they are finding about this famous fruit.  Research findings published over the past year alone, have implications for the management of conditions such as bowel disease, skin conditions, cancer and pain.

Multiple therapeutically active polyphenols are found in the fruits of pomegranate, including anthocyanins and anthocyanidins, flavones, flavonoids and flavonols. The rind or peels, often discarded when juice products are prepared, are also rich in useful phytochemicals and have a high content of hydrolysable ellagitannins such as punicalagin, ellagic acid and punicic acid.


Anticancer properties

Dietary factors are increasingly linked with the risks of certain cancers(1,2,3). While the incidence of prostate cancer in Asian countries is low compared to the West, this incidence increases by as much as 20-fold in Asian immigrants to the United States. Their adoption of a Western diet, a reduced intake of soy, tea, fish, fruits, and vegetables and increased intake of red meat and fat-rich foods, are thought to be largely contributory(4, 5]

Many foods rich in polyphenols have been associated with cancer prevention, effects attributable largely to their antioxidant and free radical scavenging properties.  Pomegranate is one of these, and anti-cancer effects have been measured in vitro for pomegranate fruit extracts using a wide range of different cancer cell lines, including ovarian(6), bladder(7), thyroid(8),  breast(9) and prostate cancer, and multiple myeloma(10).

Flavonoid-rich polyphenol fractions have been reported to exert anti-proliferative, anti-invasive, anti-inflammatory and other anti-cancer actions in breast and prostate cancer cells in vitro and in animal studies(11).  Pomegranate extracts also inhibit the formation of new blood vessels (angiogenesis) by cancer cells(12), and have been shown to have potential to help suppress the final steps of carcinogenesis and metastasis(2, 13, 14).

The state of the gut community of microbes is increasingly linked with a large number of chronic health conditions, and there is growing evidence of an influence of the gut microbiota on mechanisms of prostate cancer initiation and/or progression(15). Changes to the gut microbiome through changes in dietary composition and increased intake of vegetables and polyphenols, may help to modify the risk of prostate cancer through its role in the regulation of chronic inflammation, apoptotic (cell death) processes, cytokines, and hormonal production(15).

Ellagitannins are bioactive polyphenols and a principle component of pomegranate peels and other foods such as seeds, nuts and berries with chemopreventive potential against prostate and other cancers. Too large to be absorbed into the bloodstream intact, they are partially hydrolyzed in the gut to ellagic acid. Ellagic acid and its metabolite urolithin A, produced by colonic microflora, have demonstrated significant antioxidant and anticancer effects, including antiproliferative and apoptotic activities(16, 17), and inhibition of angiogenesis(18, 19), in a range of cancer types. 

At least 6 clinical trials involving prostate cancer patients have been undertaken, and while these suggest daily ingestion of sufficiently large doses of pomegranate extracts can produce a significant slowing of PSA increase (20-23), further trials with larger patient numbers and longer treatment durations, are required.

A recent review also supports potential applications to help protect against breast cancer(9). This is supported by a significant number of studies including reports that pomegranate extracts induce cell cycle arrest in the G0/G1 phase, and induce cytotoxicity in a dose- and time-dependent manner.  Inhibitory effects of pomegranate juice on bladder cancer development, have also been reported recently in rats(7). Correction of the expression of pro-inflammatory cytokines and suppression of angiogenesis, were associated with these benefits.

Gastroprotective properties

The traditional uses of pomegranate rinds for the treatment of dysentery and diarrhea, is a reflection of both their tannin content and proven antimicrobial activities, but also suggests potential gastrointestinal protective and anti-inflammatory properties.

Ellagitannins seem to contribute to most of the beneficial analgesic and anti-inflammatory actions of pomegranate in a rat model of inflammatory bowel disease(24). Again, their metabolites ellagic acid and urolithin A, formed by the gut microbiotica following pomegranate consumption, seem to be involved. Urolithin A is increasingly linked not only to protecting against bowel and other cancers, but to having beneficial anti-inflammatory actions of possible relevance to inflammatory bowel conditions such as ulcerative colitis and Crohn’s disease, and other gastrointestinal conditions(25). Protective effects against gastric ulcers have been recently reported in animal studies(26). Anthelminthic activity, thus helping to expel parasitic worms from the gut, is another recently documented application shown against nematodes in sheep(27).

Skin health:

In vitro and animal studies have demonstrated that topical application and oral consumption of pomegranate reduces UVB-induced skin damage from the sun(28). Oral feeding of pomegranate fruit extract to mice protected them from the adverse effects of UVB radiation, by interfering with early stages of photocarcinogenesis(29).

A double-blind, placebo-controlled trial involving female subjects age 20–40s found daily ingestion of an ellagic acid-rich pomegranate extract had an inhibitory effect on skin pigmentation caused by UV irradiation(30). Another trial found protection against UVB irradiation following oral ingestion of pomegranate juice or pomegranate extract, in a group of healthy females aged 30-45 years(28). Influences on the gut or skin microbiome, have again been implicated in these photoprotective effects.

Eczema or dermatitis is a frequent side effect of chemotherapy and radiotherapy treatment in cancer patients, and recent research found pomegranate to promote skin regeneration processes after skin damage induced by 5-fluorouracil(31). This suggests a potential use of pomegranate as an adjuvant during treatment with this and perhaps other chemotherapy drugs. Welsh dental researchers have also recently reported that the peel ellagitannin punicalagin in combination with zinc, may promote anti-inflammatory and fibroblast responses to aid healing of oral cavity wounds(32).

Neuroprotective effects?

Potential neuroprotective effects have been recently reported in animal models of Parkinsons disease(33, 34). A pilot clinical trial also found pomegranate to protect against memory impairment and improve memory retention performance for up to 6 weeks after cardiac surgery(35). As with cancer protective and gastroprotective activities, urolithin A has been implicated in these neuroprotective activities(25, 36).

Preliminary clinical trials recently conducted at Harvard Medical School, have also found supplementation with pomegranate juice by pregnant women may help to protect their fetuses against intrauterine growth restriction, a serious complication with a risk of perinatal death or neurodevelopmental impairment among surviving infants(37, 38).  A pomegranate seed extract has also been reported to protect against tramadol-induced testicular toxicity in animal studies(39). Usage of this painkilling drug is now very common in hospital and community settings around the world, and taking adjunctive pomegranate may help protect against its negative effects on male fertility, particularly during adolescence.

References:

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  13. Rocha A., Wang L., Penichet M., Martins-Green M. Pomegranate juice and specific components inhibit cell and molecular processes critical for metastasis of breast cancer. Breast Cancer Res. Treat. 2012;136:647–658. doi: 10.1007/s10549-012-2264-5.
  14. Ahmadiankia N. Molecular targets of pomegranate (Punica granatum) in preventing cancer metastasis. Iran J Basic Med Sci. 2019;22(9):977-988. doi:10.22038/ijbms.2019.34653.8217Crocetto F, Boccellino M, Barone B, et al. The Crosstalk between Prostate Cancer and Microbiota Inflammation: Nutraceutical Products Are Useful to Balance This Interplay?. Nutrients. 2020;12(9):2648. Published 2020 Aug 31. doi:10.3390/nu12092648.
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  16. Zhao W, Shi F, Guo Z, Zhao J, Song X, Yang H. Metabolite of ellagitannins, urolithin A induces autophagy and inhibits metastasis in human sw620 colorectal cancer cells. Mol Carcinog. 2018;57(2):193-200. doi:10.1002/mc.22746.
  17. Qiu Z, Zhou J, Zhang C, Cheng Y, Hu J, Zheng G. Antiproliferative effect of urolithin A, the ellagic acid-derived colonic metabolite, on hepatocellular carcinoma HepG2.2.15 cells by targeting Lin28a/let-7a axis. Braz J Med Biol Res. 2018;51(7):e7220. doi:10.1590/1414-431×20187220.
  18. Vicinanza R, Zhang Y, Henning SM, Heber D. Pomegranate Juice Metabolites, Ellagic Acid and Urolithin A, Synergistically Inhibit Androgen-Independent Prostate Cancer Cell Growth via Distinct Effects on Cell Cycle Control and Apoptosis. Evid Based Complement Alternat Med. 2013;2013:247504. doi:10.1155/2013/247504.
  19. Ceci C, Lacal PM, Tentori L, De Martino MG, Miano R, Graziani G. Experimental Evidence of the Antitumor, Antimetastatic and Antiangiogenic Activity of Ellagic Acid. Nutrients. 2018 Nov 14;10(11):1756. doi: 10.3390/nu10111756. PMID: 30441769; PMCID: PMC6266224.
  20. Thomas R, Williams M, Sharma H, Chaudry A, Bellamy P. A double-blind, placebo-controlled randomised trial evaluating the effect of a polyphenol-rich whole food supplement on PSA progression in men with prostate cancer–the U.K. NCRN Pomi-T study. Prostate Cancer Prostatic Dis. 2014;17(2):180-186. doi:10.1038/pcan.2014.6.
  21. Paller CJ, Ye X, Wozniak PJ, et al. A randomized phase II study of pomegranate extract for men with rising PSA following initial therapy for localized prostate cancer. Prostate Cancer Prostatic Dis. 2013;16(1):50-55. doi:10.1038/pcan.2012.20.
  22. Paller CJ, Pantuck A, Carducci MA. A review of pomegranate in prostate cancer. Prostate Cancer Prostatic Dis. 2017;20(3):265-270. doi:10.1038/pcan.2017.19.
  23. Freedland SJ, Carducci M, Kroeger N, et al. A double-blind, randomized, neoadjuvant study of the tissue effects of POMx pills in men with prostate cancer before radical prostatectomy. Cancer Prev Res (Phila). 2013;6(10):1120-1127. doi:10.1158/1940-6207.CAPR-12-0423.
  24. Parisio C, Lucarini E, Micheli L, et al. Pomegranate Mesocarp against Colitis-Induced Visceral Pain in Rats: Effects of a Decoction and Its Fractions. Int J Mol Sci. 2020;21(12):4304. Published 2020 Jun 17. doi:10.3390/ijms21124304.
  25. Kujawska M, Jodynis-Liebert J. Potential of the ellagic acid-derived gut microbiota metabolite – Urolithin A in gastrointestinal protection. World J Gastroenterol. 2020 Jun 21;26(23):3170-3181. doi: 10.3748/wjg.v26.i23.3170. PMID: 32684733; PMCID: PMC7336321.
  26. Abd El-Rady NM, Dahpy MA, Ahmed A, et al. Interplay of Biochemical, Genetic, and Immunohistochemical Factors in the Etio-Pathogenesis of Gastric Ulcer in Rats: A Comparative Study of the Effect of Pomegranate Loaded Nanoparticles Versus Pomegranate Peel Extract. Front Physiol. 2021;12:649462. Published 2021 Mar 23. doi:10.3389/fphys.2021.649462
  27. Castagna F, Britti D, Oliverio M, Bosco A, Bonacci S, Iriti G, Ragusa M, Musolino V, Rinaldi L, Palma E, Musella V. In Vitro Anthelminthic Efficacy of Aqueous Pomegranate (Punica granatum L.) Extracts against Gastrointestinal Nematodes of Sheep. Pathogens. 2020 Dec 18;9(12):1063. doi: 10.3390/pathogens9121063. PMID: 33353177; PMCID: PMC7766728.
  28. Henning SM, Yang J, Lee RP, et al. Pomegranate Juice and Extract Consumption Increases the Resistance to UVB-induced Erythema and Changes the Skin Microbiome in Healthy Women: a Randomized Controlled Trial. Sci Rep. 2019;9(1):14528. Published 2019 Oct 10. doi:10.1038/s41598-019-50926-2.
  29. Afaq F, Khan N, Syed DN, Mukhtar H. Oral feeding of pomegranate fruit extract inhibits early biomarkers of UVB radiation-induced carcinogenesis in SKH-1 hairless mouse epidermis. Photochem Photobiol. 2010;86(6):1318–1326. doi: 10.1111/j.1751-1097.2010.00815.x. 
  30. Kasai K, Yoshimura M, Koga T, Arii M, Kawasaki S. Effects of oral administration of ellagic acid-rich pomegranate extract on ultraviolet-induced pigmentation in the human skin. J Nutr Sci Vitaminol (Tokyo). 2006 Oct;52(5):383-8. doi: 10.3177/jnsv.52.383. PMID: 17190110.
  31. Rapa SF, Magliocca G, Pepe G, et al. Protective Effect of Pomegranate on Oxidative Stress and Inflammatory Response Induced by 5-Fluorouracil in Human Keratinocytes. Antioxidants (Basel). 2021;10(2):203. Published 2021 Jan 30. doi:10.3390/antiox10020203
  32. Celiksoy V, Moses RL, Sloan AJ, Moseley R, Heard CM. Evaluation of the In Vitro Oral Wound Healing Effects of Pomegranate (Punica granatum) Rind Extract and Punicalagin, in Combination with Zn (II). Biomolecules. 2020;10(9):1234. Published 2020 Aug 25. doi:10.3390/biom10091234
  33. Kujawska M, Jourdes M, Kurpik M, et al. Neuroprotective Effects of Pomegranate Juice against Parkinson’s Disease and Presence of Ellagitannins-Derived Metabolite-Urolithin A-In the Brain. Int J Mol Sci. 2019;21(1):202. Published 2019 Dec 27. doi:10.3390/ijms21010202
  34. Fathy SM, El-Dash HA, Said NI. Neuroprotective effects of pomegranate (Punica granatum L.) juice and seed extract in paraquat-induced mouse model of Parkinson’s disease. BMC Complement Med Ther. 2021;21(1):130. Published 2021 Apr 26. doi:10.1186/s12906-021-03298-y
  35. Ropacki SA, Patel SM, Hartman RE. Pomegranate Supplementation Protects against Memory Dysfunction after Heart Surgery: A Pilot Study. Evid Based Complement Alternat Med. 2013;2013:932401. doi:10.1155/2013/932401.
  36. Braidy N, et al. Consumption of pomegranates improves synaptic function in a transgenic mice model of Alzheimer’s disease. Oncotarget. 2016;7:64589–64604. doi: 10.18632/oncotarget.10905.
  37. Matthews LG, Smyser CD, Cherkerzian S, Alexopoulos D, Kenley J, Tuuli MG, Nelson DM, Inder TE. Maternal pomegranate juice intake and brain structure and function in infants with intrauterine growth restriction: A randomized controlled pilot study. PLoS One. 2019 Aug 21;14(8):e0219596. doi: 10.1371/journal.pone.0219596. PMID: 31433809; PMCID: PMC6703683.
  38. Ross MM, Cherkerzian S, Mikulis ND, Turner D, Robinson J, Inder TE, Matthews LG. A randomized controlled trial investigating the impact of maternal dietary supplementation with pomegranate juice on brain injury in infants with IUGR. Sci Rep. 2021 Feb 11;11(1):3569. doi: 10.1038/s41598-021-82144-0. PMID: 33574371; PMCID: PMC7878922.
  39. Minisy FM, Shawki HH, El Omri A, Massoud AA, Omara EA, Metwally FG, Badawy MA, Hassan NA, Hassan NS, Oishi H. Pomegranate Seeds Extract Possesses a Protective Effect against Tramadol-Induced Testicular Toxicity in Experimental Rats. Biomed Res Int. 2020 Mar 9;2020:2732958. doi: 10.1155/2020/2732958. PMID: 32219129; PMCID: PMC7085358.

Propolis – amazing stuff made by bees from nature

Propolis is a resinous material collected by bees from plant buds and exudates, mixed with bee enzymes, pollen and wax. The term propolis derives from two Greek words, pro (which means for or in defense of) and polis (which means the city), reflecting its application by bees to help protect the hive. The chemical composition of propolis is directly determined by the geographical location, but polyphenols, phenolic acids, caffeic acid phenethyl ester (CAPE), flavonoids, diterpenes, amino acids, vitamins and minerals are predominant constituents.

“Poplar-type” propolis has the widest spread in the world, in the temperate zones from Europe, Asia, or North America. Different species of Pine (Pinus spp.), Prunus spp., Acacia spp. and also birch (Betula pendula), horsechestnut (Aesculus hippocastanum), and willow (Salix spp) are also important sources of resins for poplar-type propolis(1). New Zealand propolis is usually of the poplar-type, obtained by honey bees largely from exudates of poplar.

Propolis is reported to possess a huge array of biological properties, with more than 270 review papers alone published in the scientific literature. Key actions include antimicrobial, anti-inflammatory, antioxidant, anti-cancer, anti-diabetic as well as cardioprotective and neuroprotective activities. Other potentially useful properties continue to be reported by researchers, on a regular basis.

Antiviral:

Immune modulatory effects have been assigned to propolis for many centuries, with effects on both the cellular and humoral immune responses, including increased antibody production(2, 3).

In the early 1990s, propolis flavonoids were shown to reduce of the infectivity and replication of some herpes virus, adenovirus, rotavirus, and coronavirus strains(4). Potent activity against the herpes simplex type 1 virus has been reported particularly for an ethanolic propolis extract(5). Antiviral activity and a dose-dependent reduction in influenza virus yields in the bronchoalveolar lavage fluids of lungs, and prolonged survival times of influenza infected mice, has been reported following administration of 2 and 10mg/kg doses of propolis three times daily(6). Improved platelet counts and a shortened duration of hospitalization in patients with the Dengue Fever virus, was seen following seven days propolis administration(7).  Enhanced immune responses including lymphocyte proliferation and antibody production after administration of a recombinant HIV-1 vaccine to mice, were recently reported when propolis was used as an adjuvant(8). These and its anti-inflammatory properties, suggest the possibility of using it as an adjuvant to other vaccines(3).

When I reviewed potential phytomedicinal treatment options for COVID-19 early last year, propolis was one of the most compelling agents I evaluated, based upon the published literature at the time. Since then and with research into plant-derived treatments having received increased funding, this view is now further supported by in vitro and clinical studies(9-16).

Brazilian researchers have just published the results of a controlled clinical trial in which propolis was given as an adjunct treatment in hospitalized COVID-19 patients(13). Three groups of 40 patients were assigned to receive standard hospital care plus an oral dose of 400 mg or 800 mg/day of Brazilian green propolis for seven days, or standard care alone. The primary end point was the time to clinical improvement, defined as the length of hospital stay or oxygen therapy dependency duration. Secondary outcomes included acute kidney injury and need for intensive care or vasoactive drugs.

The length of hospital stay post-intervention was statistically shorter in both propolis groups than in the control group (lower dose, median 7 days versus 12 days; (95% confidence interval [CI] −6.23 to −0.07; p = 0.049) and higher dose, median 6 days versus 12 days (95% CI −7.00 to −1.09; p = 0.009). A lower rate of acute kidney injury than in the controls (4.8 vs 23.8%) was also reported in the high dose propolis group. No patient discontinued propolis treatment due to adverse events.

While further studies are called for, this study suggests the addition of propolis to standard hospital care procedures could have significant clinical benefits in some COVID-19 patients(13).

Other encouraging reports of late include in vitro inhibition of COVID-19 viral replication by Eqyptian propolis (an activity enhanced by liposomal encapsulation)(9), and inhibition of COVID-19 protease as well as angiotensin-converting enzyme-2 (a receptor for SARS-CoV-2 in the human body), by compounds derived from Indonesian propolis(14, 15). Molecular simulations also suggest that propolis flavonoids may inhibit viral spike fusion in host cells, and viral-host interactions that trigger the cytokine storm(16).

Anti-inflammatory

Hundreds of papers report immunomodulatory and anti-inflammatory activities for different types of propolis, including inhibition of COX-2 and nitric oxide synthesis, reduced levels of inflammatory cytokines, and antioxidant activities(17). A review of six clinical studies involving 406 participants, found a significant reduction in levels of inflammatory markers including serum CRP and TNF-alpha, following propolis intake(18).

In pre-clinical studies, propolis promoted immunoregulation of pro-inflammatory cytokines and exhibited several potential mechanisms to help to reduce the risk of a cytokine storm(10).

As effective anti-inflammatory concentrations of propolis seem significantly lower than antibacterial and antiviral ones, these studies suggest anti-inflammatory properties may be its most important feature(3, 19).

Use as an adjuvant treatment in autoimmune conditions such as asthma has received some clinical trial support (20, 21).

Antibacterial:

The first data published regarding the antibacterial activity of propolis extract dates back to 1980, in which sensitivity of Streptococcus species to propolis extract was reported(22). Since then propolis has been tested on more than 600 strains of bacteria, with encouraging findings(23). Greater activity has been measured against Gram-positive than Gram-negative bacteria, with antimicrobial activity varying depending on the region of the world from which the propolis was sourced.

Many novel antimicrobial compounds have been identified in propolis, several of which can help overcome antimicrobial resistance of multidrug resistant bacteria. Synergistic effect against bacterial strains such as Escherichia coli and Staphylococcus aureus have been reported for combinations with honey or other antibiotics(24).

A clinical trial involving the simultaneous admin of propolis and melatonin in patients with primary sepsis, is currently underway(25).

Dental applications–

The anti-inflammatory, antibacterial and antifungal properties of propolis also have many potential applications in dentistry, as alternatives to current antimicrobial and conventional agents(26-29).  Indications that have been supported by studies including clinical trials, include to heal dental surgical wounds, as an intracanal irrigant, a mouthwash or toothpaste, and for the treatment of periodontitis and gum inflammation, and denture stomatitis(29).

Wound healing:

One of the oldest traditional applications of propolis is its application to disinfect skin and to improve wound healing. Its widespread antimicrobial activities in addition to inhibitory effects on biofilm formation, and anti-inflammatory actions, are undoubtedly largely contributory.  Enhancement in the wound repair abilities of keratinocytes, has also been reported recently(30).

Most in vivo studies undertaken on different wound models suggest beneficial roles of propolis on experimental wound healing(31,32), although products and doses used have been variable.

A review of 5 clinical trials involving the use of propolis mouthwash in cancer therapy-induced oral mucositis, found it to be both effective and safe(33). Post-tonsillectomy pain and wound healing was also significantly improved following use of propolis orally and by gargle, in a Korean clinical trial involving 130 tonsillectomy and adenotonsillectomy patients(34).

A shorter healing time and improved symptom picture was reported for a 0.5% propolis cream compared to acyclovir 5% cream, in a Slovakian trial involving 198 patients with herpes labialis(35).

Mixing different propolis samples collected from different locations in Iraq resulted in superior antimicrobial and wound healing properties than measured in individual propolis(36).

Cancer-protective?

Most diterpenes isolated from propolis possess cytotoxic activities (37 Aminimoghadamfarouj, Nematolahi 2017), and a plethora of in vitro studies have documented cytotoxic effects of many different propolis extracts against various types of cancer. These include head and neck, lung, liver, brain (glioma), pancreas, kidney, prostate, skin (melanoma), breast, oral, esophagus, gastric, colorectal, and bladder cancers(37-42).

Propolis is likely to exhibit chemoprotective or anti-cancer effects due to the presence of phytochemicals with pro-apoptotic, cytotoxic, anti-proliferative, anti-metastatic, anti-invasive, anti-angiogenic and anti-genotoxic or anti-mutagenic properties along with antioxidant, immunomodulatory, and anti-inflammatory functions.

A recent review into evidence-based complementary medicines to support chemotherapy treatment of pancreatic cancer patients, concluded that integrated management offers the best patient outcome, and that propolis was one of 9 most promising natural treatment agents identified(43). Clinical studies are justified, into the use of propolis as an adjuvant alongside standard chemotherapy treatment for the treatment of various cancers(42).

Cardiac health:

A recent review documents numerous potentially useful pharmacological properties of propolis in terms of cardiac health(44). These include anti platelet aggregation, antioxidant and anti-inflammatory activities, which may protect against vascular endothelial and cardiomyocyte dysfunction, and potentially thrombus formation.  Further in vivo studies are however needed to confirm these beneficial effects in the prevention of cardiovascular diseases, and pre-clinical research to assess cardiovascular effects of the different types of propolis, would be useful(17, 45).

Diabetes:

Various animal studies have found improvement in insulin resistance and increased sensitivity to insulin following propolis administration(46). Improvement in glycaemic status and antioxidant enzymes, and reduction in insulin resistance, have been reported following propolis treatment at 1500mg a day for 8 weeks, in type 2 diabetic patients(47).

A recent trial involving 12 months treatment of chronic kidney disease patients with Brazilian green propolis extract at a dose of 500mg/day, reported a significant reduction in proteinuria(48). Another found topical propolis improved healing when used as an adjuvant treatment in the care of diabetic foot wounds(49).

Anti-inflammatory properties of propolis, are likely to contribute to its favourable effects in some diabetic patients, as inflammatory cytokine production in diabetic patients is increased

Other properties

While propolis can be used in these and other conditions, caution should be taken due to some allergic reactions in some patients.

Evidence is also becoming apparent of potentially protective effects against drug-induced nephrotoxicity and various neurological and psychiatric conditions, for both propolis and caffeic acid phenethyl ester(50, 51).

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  20. Khayyal MT, el-Ghazaly MA, el-Khatib AS, Hatem AM, de Vries PJ, el-Shafei S, Khattab MM. A clinical pharmacological study of the potential beneficial effects of a propolis food product as an adjuvant in asthmatic patients. Fundam Clin Pharmacol. 2003 Feb;17(1):93-102. doi: 10.1046/j.1472-8206.2003.00117.x. PMID: 12588635.
  21. Mirsadraee M, Azmoon B, Ghaffari S, Abdolsamadi A, Khazdair MR. Effect of Propolis on moderate persistent asthma: A phase two randomized, double blind, controlled clinical trial. Avicenna J Phytomed. 2021 Jan-Feb;11(1):22-31. PMID: 33628717; PMCID: PMC7885004.
  22. Meresta L., Meresta T. Effect of pH on bactericidal activity of propolis. Bull. Veterina. Inst. Pulawy. 1980;24:21–25.
  23. Przybyłek I, Karpiński TM. Antibacterial Properties of Propolis. Molecules. 2019 May 29;24(11):2047. doi: 10.3390/molecules24112047. PMID: 31146392; PMCID: PMC6600457.
  24. Almuhayawi MS. Propolis as a novel antibacterial agent. Saudi J Biol Sci. 2020 Nov;27(11):3079-3086. doi: 10.1016/j.sjbs.2020.09.016. Epub 2020 Sep 14. PMID: 33100868; PMCID: PMC7569119.
  25. Pahlavani N, Sedaghat A, Bagheri Moghaddam A, Mazloumi Kiapey SS, Gholizadeh Navashenaq J, Jarahi L, Reazvani R, Norouzy A, Nematy M, Safarian M, Ghayour-Mobarhan M. Effects of propolis and melatonin on oxidative stress, inflammation, and clinical status in patients with primary sepsis: Study protocol and review on previous studies. Clin Nutr ESPEN. 2019 Oct;33:125-131. doi: 10.1016/j.clnesp.2019.06.007. Epub 2019 Jul 5. PMID: 31451248.
  26. Bretz WA, Paulino N, Nör JE, Moreira A. The effectiveness of propolis on gingivitis: a randomized controlled trial. J Altern Complement Med. 2014;20(12):943-948. doi:10.1089/acm.2013.0431
  27. Pundir AJ, Vishwanath A, Pundir S, Swati M, Banchhor S, Jabee S. One-stage Full Mouth Disinfection Using 20% Propolis Hydroalcoholic Solution: A Clinico-microbiologic Study. Contemp Clin Dent. 2017;8(3):416-420. doi:10.4103/ccd.ccd_544_17      
  28. Skoskiewicz-Malinowska K, Kaczmarek U, Malicka B, Walczak K, Zietek M. Application of Chitosan and Propolis in Endodontic Treatment: A Review. Mini Rev Med Chem. 2017;17(5):410-434. doi: 10.2174/1389557516666160418122510. PMID: 27087464.
  29. Zulhendri F, Felitti R, Fearnley J, Ravalia M. The use of propolis in dentistry, oral health, and medicine: A review. J Oral Biosci. 2021 Mar;63(1):23-34. doi: 10.1016/j.job.2021.01.001. Epub 2021 Jan 16. PMID: 33465498.
  30. Martinotti S, Pellavio G, Laforenza U, Ranzato E. Propolis Induces AQP3 Expression: A Possible Way of Action in Wound Healing. Molecules. 2019 Apr 19;24(8):1544. doi: 10.3390/molecules24081544. PMID: 31010117; PMCID: PMC6515181.
  31. Abu-Seida AM. Effect of Propolis on Experimental Cutaneous Wound Healing in Dogs. Vet Med Int. 2015;2015:672643. doi: 10.1155/2015/672643. Epub 2015 Dec 13. PMID: 26783495; PMCID: PMC4691486.
  32. Oryan A, Alemzadeh E, Moshiri A. Potential role of propolis in wound healing: Biological properties and therapeutic activities. Biomed Pharmacother. 2018 Feb;98:469-483. doi: 10.1016/j.biopha.2017.12.069. Epub 2017 Dec 27. PMID: 29287194.
  33. Kuo CC, , Wang R-H 2Wang H-H, Li C-H.. Meta-analysis of randomized controlled trials of the efficacy of propolis mouthwash in cancer therapy-induced oral mucositis. Support Care Cancer. 2018 Dec;26(12):4001-4009
  34. Moon JH, Lee MY, Chung YJ, Rhee CK, Lee SJ. Effect of Topical Propolis on Wound Healing Process After Tonsillectomy: Randomized Controlled Study. Clin Exp Otorhinolaryngol. 2018 Jun;11(2):146-150. doi: 10.21053/ceo.2017.00647. Epub 2017 Dec 28. PMID: 29665628; PMCID: PMC5951064.
  35. Jautová J, Zelenková H, Drotarová K, Nejdková A, Grünwaldová B, Hladiková M. Lip creams with propolis special extract GH 2002 0.5% versus aciclovir 5.0% for herpes labialis (vesicular stage) : Randomized, controlled double-blind study. Lippencreme mit 0,5 % Propolis-Spezialextrakt GH 2002 versus 5 % Aciclovir bei Herpes labialis (Bläschenstadium) : Randomisierte, kontrollierte Doppelblindstudie. Wien Med Wochenschr. 2019;169(7-8):193-201. doi:10.1007/s10354-018-0667-6.
  36. Al-Waili N. Mixing two different propolis samples potentiates their antimicrobial activity and wound healing property: A novel approach in wound healing and infection. Vet World. 2018 Aug; 11(8): 1188–1195.
  37. Aminimoghadamfarouj N, Nematollahi A. Propolis Diterpenes as a Remarkable Bio-Source for Drug Discovery Development: A Review. Int J Mol Sci. 2017;18(6):1290. Published 2017 Jun 17. doi:10.3390/ijms18061290
  38. Chen WT, Sun YK, Lu CH, Chao CY. Thermal cycling as a novel thermal therapy to synergistically enhance the anticancer effect of propolis on PANC‑1 cells. Int J Oncol. 2019;55(3):617-628. doi:10.3892/ijo.2019.4844
  39. Asgharpour F, Moghadamnia AA, Zabihi E, et al. Iranian propolis efficiently inhibits growth of oral streptococci and cancer cell lines. BMC Complement Altern Med. 2019;19(1):266. Published 2019 Oct 11. doi:10.1186/s12906-019-2677-3.
  40. Demir S, Aliyazicioglu Y, Turan I, Misir S, Mentese A, Yaman SO, Akbulut K, Kilinc K, Deger O. Antiproliferative and proapoptotic activity of Turkish propolis on human lung cancer cell line. Nutr Cancer. 2016;68(1):165-72. doi: 10.1080/01635581.2016.1115096. Epub 2015 Dec 23. PMID: 26700423.
  41. Zabaiou N, Fouache A, Trousson A, Baron S, Zellagui A, Lahouel M, Lobaccaro JA. Biological properties of propolis extracts: Something new from an ancient product. Chem Phys Lipids. 2017 Oct;207(Pt B):214-222. doi: 10.1016/j.chemphyslip.2017.04.005. Epub 2017 Apr 12. PMID: 28411017.
  42. Chiu HF, Han YC, Shen YC, Golovinskaia O, Venkatakrishnan K, Wang CK. Chemopreventive and Chemotherapeutic Effect of Propolis and Its Constituents: A Mini-review. J Cancer Prev. 2020;25(2):70-78. doi:10.15430/JCP.2020.25.2.70
  43. Jentzsch V et al, Cancers (Basel). 2020 Oct 23;12(11):3096
  44. Silva H, Francisco R, Saraiva A, Francisco S, Carrascosa C, Raposo A. The Cardiovascular Therapeutic Potential of Propolis-A Comprehensive Review. Biology (Basel). 2021;10(1):27. Published 2021 Jan 4. doi:10.3390/biology10010027
  45. Bojić M, Antolić A, Tomičić M, Debeljak Ž, Maleš Ž. Propolis ethanolic extracts reduce adenosine diphosphate induced platelet aggregation determined on whole blood. Nutr J. 2018;17(1):52. Published 2018 May 14. doi:10.1186/s12937-018-0361-y
  46. Pahlavani N, Malekahmadi M, Firouzi S, Rostami D, Sedaghat A, Moghaddam AB, Ferns GA, Navashenaq JG, Reazvani R, Safarian M, Ghayour-Mobarhan M. Molecular and cellular mechanisms of the effects of Propolis in inflammation, oxidative stress and glycemic control in chronic diseases. Nutr Metab (Lond). 2020 Aug 12;17:65. doi: 10.1186/s12986-020-00485-5. PMID: 32817750; PMCID: PMC7425411.
  47. Afsharpour FJavadi M, Hashemipour S, Koushan Y, Haghighian HK. Propolis supplementation improves glycemic and antioxidant status in patients with type 2 diabetes: A randomized, double-blind, placebo-controlled study. Complement Ther Med. 2019 Apr;43:283-288
  48. Silveira MAD, Teles F, Berretta AA, et al. Effects of Brazilian green propolis on proteinuria and renal function in patients with chronic kidney disease: a randomized, double-blind, placebo-controlled trial. BMC Nephrol. 2019;20(1):140. Published 2019 Apr 25. doi:10.1186/s12882-019-1337-7.
  49. Mujica V, Orrego R, Fuentealba R, Leiva E, Zúñiga-Hernández J. Propolis as an Adjuvant in the Healing of Human Diabetic Foot Wounds Receiving Care in the Diagnostic and Treatment Centre from the Regional Hospital of Talca. J Diabetes Res. 2019;2019:2507578. Published 2019 Sep 12. doi:10.1155/2019/2507578
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  51. Menezes da Silveira CCS, Luz DA, da Silva CCS, Prediger RDS, Martins MD, Martins MAT, Fontes-Júnior EA, Maia CSF. Propolis: A useful agent on psychiatric and neurological disorders? A focus on CAPE and pinocembrin components. Med Res Rev. 2021 Mar;41(2):1195-1215. doi: 10.1002/med.21757. Epub 2020 Nov 11. PMID: 33174618.

Endophytes – recent developments involving bugs that live inside plants

For centuries, plants have been a valuable source of bioactive compounds and medicinal preparations including herbal (phyto) medicines or drugs, used to prevent and treat a huge and diverse range of human and animal ailments. However, just as the community of microbes (microbiome) found within and on the bodies of animals and humans is now recognised for its discrete but important contribution to health and immunity, microorganisms that live on plants, also seem to play important functions in helping to protect and enable their survival(1).

Endophytes are microorganisms (mostly bacteria and fungi) which reside within plant tissues in leaves, roots, flowers, seeds or stems of plants for at least part of their life cycles, without causing apparent harm to the host plant. They seem to have a neutral or symbiotic and interdependent relationship with their plant hosts, with often mutual benefits. These can include improvement in the plants ability to assimilate nutrients and resist environmental stress or insect infestation, while at the same time providing a home and other support to endophytes which can rely upon the plant metabolism for their propagation and survival. Endophytes have been found in every plant studied to date, with numbers and types found in a particular plant depending upon the host species, host developmental stage, and environmental conditions.

The complexities and inter-dependencies of plant relationships to microbes, are however much more than a fascinating area of research for plant scientists. For many reasons, endophytes are continuing to gain prominence as a potential source of compounds with high therapeutic potential, and their presence (naturally or inoculated) is increasingly been reported to influence the quality and quantity of extracts derived from medicinal plants(2,3). Probably due to their presence in a specialized niche, endophytes are capable of synthesizing diverse types of bioactive molecules (secondary metabolites), just as plants themselves do.

Secondary metabolites include compounds such as alkaloids, peptides, steroids, terpenoids and flavonoids, and help the plant cope with environmental stressors such as drought, predators or infections, and much more. It is these compounds that also often exhibit pharmacological activities of interest, to a human or animal therapeutics domain.

In fact we’ve known about and utilised microbes living in plants for drug development for a long time now, with some well known examples. The first commercialised antibiotic penicillin, was first discovered as a secondary metabolite produced by the endophytic fungus Penicillium notatum, which Fleming noticed had the ability to destroy colonies of the bacterium Staphylococcus aureus. Despite this, only a fraction of endophytic microorganisms have been isolated and investigated for their biological activities.

Endophytes as sources of antibiotics:

Other novel antibiotic types produced by fungi or bacteria living within plants or soil, have since been characterised and commercialised, with tetracyclines and aminoglycosides, being notable examples.

In a world where the emergence of resistance to antimicrobials requires the constant development of new antibiotics, the search for new antimicrobial compounds derived from endophytes, is a key area of research(4, 5). These include secondary metabolites from endophytic actinobacteria(6), and endophytic fungi from macroalgae(7), and a large number of promising compounds have been identified(8).

Mangrove species, which are common and endemic plants in coastal ecosystems, seem to be an ideal source of promising bioactive endophytic compounds(9), due perhaps to their interface between the world of plants, mud, and the sea.  Compounds characterised to date have shown cytotoxic, antibacterial, antifungal, α-glucosidase inhibitory, protein tyrosine phosphatase B inhibitory, and antiviral activities. Antibacterial examples include secondary metabolites produced by the fungus Alternaria spp, an endophyte of the Chinese mangrove species Sonneratia alba, which show broad antimicrobial activity against several multidrug-resistant bacterial strains(10)Phomopsis species of endophytic fungi found in mangroves and various other plants, produce various antibacterial compounds(11), and flavonoid and cinnamic acid compounds made by an endophytic fungus that inhabits Cinnamomum species, show good activity against the tuberculosis bacteria(12). Bacterial communities colonizing different plant parts of Echinacea purpurea, may also contribute to its well-known immune enhancing, and possible antibacterial activities(13).

Among the many different regulators of antibiotic drug resistance, drug transporter molecules which pump or keep the antibiotic(s) out of the bacterial cell, are considered to be key contributors to the development of multidrug resistance. Research is finding, however, that various endophytes can act as novel drug resistance reversal agents, by inhibiting these drug transporters(14).

Disruption of bacterial intercellular communication processes controlling virulence known as quorum-sensing, is also a worthwhile strategy being pursued to help reduce pathogenesis within infectious bacteria. Endophytic microbes provide a plethora of such quorum-sensing inhibitor molecules(15).

Cytotoxics

Bioprospecting and screening of plant endophyte communities has been the source of novel anticancer drugs such as paclitaxel (taxol) first discovered in the bark of the Pacific yew tree, Taxus brevifolia, in 1970(16, 17). A major limitation on the use of taxol as a drug has been its short supply because of the yew tree’s slow growth and extremely low yield of taxol. To meet the large demand for taxol, other production methods have been researched and developed.  

These include the application of semi synthesis, biocatalysis and fermentation by fungi(18, 19). The first endophytic taxol-producing fungus, Taxomyces andreanae, was discovered in T. brevifolia in 1993 (20), and others have subsequently been reported. Since then new techniques in biotechnology, have increased the extraction yield from taxol-producing fungi. These have the potential to increase the efficiency of taxol extraction for a more sustainable production of taxol and related drugs (21)

In addition to being sources of taxol, endophytic fungi from terrestrial, mangrove and marine sources produce other bioactive metabolites that hold promise as potential anticancer agents(22, 23).  Endophytic fungi derived from various seaweeds, have also been found to be good sources of anticancer compounds (24)..

Other applications:

Health depends on the diet, which influences the gut microbiota (and vice versa), and evidence suggests some members of the herbivore gut microbiome derive directly from being common plant microbes(25)

Endophytes produce a wide range of compounds exhibiting anti-inflammatory activities, including against nitric oxide, tumor necrosis factor, and reactive oxygen species (NO, TNF-α, and ROS)(26). Endophytic fungi also appear to be a wealthy pool of potential antimalarial agents, sorely needed due to increasing resistance to currently available antimalarial drugs and insecticides(27).

Apart from being a source of medicines, various applications of plant endophytes in agriculture are suggested. 

In New Zealand, researchers recovered 192 culturable bacteria from the leaves, stems and roots of the New Zealand native mānuka, and found some bacterial isolates to have good activity against two fungal pathogens, as well as the bacterial pathogen Pseudomonas syringae pv. Actinidiae (28). This microbe is responsible for the notorious Psa infection in kiwifruit, suggesting yet another potential use for mānuka in New Zealand agriculture.

Propagules, the reproductive units of mangroves, have recently been found to host beneficial bacteria that enhance the potential of mangrove seedlings establishment, and confer salt tolerance to cereal crops(29). These bacteria may therefore have useful applications, in a world where sea levels are rising.

Increasing the sustainability of future agriculture will required a reduced dependency on use of disease-controlling and often cumulative chemicals such as synthetic fungicides, herbicides and organophosophates pesticides, in order to produce healthy plants and animals, while ensuring our soils remain healthy for future generations. Plants themselves, and the endophytes that they have a cohabitation relationship with, seem like good sources for more natural and less harmful disease control agents.

In the past we used pigs and horses to produce drugs such as insulin and other hormones. Future novel drug discovery as well as the ability to scale up production of known medicinal secondary metabolites found in plants or existing expensive new drugs, would seem to have a fertile spawning ground in the form of the fungi and bacteria that like to live within plants. However, as microbes like to remind us on a regular basis, in doing so, ensuring we respect their evolutionary skills and don’t adversely undermine the interconnectedness of their complex relationships with the rest of nature, will be a critical requirement.

References:

  1. Strobel G, Daisy B, Castillo U, Harper J. Natural products from endophytic microorganisms J Nat Prod. 2004 Feb;67(2):257-68.
  2. Shi M, Huang F, Deng C, Wang Y, Kai G. Bioactivities, biosynthesis and biotechnological production of phenolic acids in Salvia miltiuorrhiza. Crit Rev Food Sci Nutr 2019; 59(6):953-964.
  3. Ding C-H, Wang Q-B, Shenglei Guo S, Wang Z-Y.  The improvement of bioactive secondary metabolites accumulation in Rumex gmelini Turcz through co-culture with endophytic fungi. Braz J Microbiol. Apr-Jun 2018;49(2):362-369.
  4. Martinez-Klimova E, Rodríguez-Peña K, Sánchez S. Endophytes as sources of antibiotics. Biochem Pharmacol. 2017 Jun 15;134:1-17.
  5. Manganyi MC, Collins NA.  Untapped Potentials of Endophytic Fungi: A Review of Novel Bioactive Compounds with Biological Applications. Microorganisms. 2020 Dec 6;8(12):1934.
  6. Dinesh R, Srinivasan V, Sheeja T EAnandaraj M, Srambikkal H.  Endophytic actinobacteria: Diversity, secondary metabolism and mechanisms to unsilence biosynthetic gene clusters. Crit Rev Microbiol. 2017 Sep;43(5):546-566.
  7. Flewelling AJ, Katelyn T Ellsworth  2 Joseph Sanford  3 Erica Forward  4 John A Johnson  5 Christopher A Gray Macroalgal Endophytes from the Atlantic Coast of Canada: A Potential Source of Antibiotic Natural Products? Microorganisms. 2013 Dec 13;1(1):175-187.
  8. Deshmukh SK, Verekar SA, Bhave SV. Endophytic fungi: a reservoir of antibacterials Front Microbiol. 2014; 5: 715.
  9. Ancheeva E, Daletos G, Proksch P. Lead Compounds from Mangrove-Associated Microorganisms Mar Drugs. 2018 Sep 7;16(9):319.
  10. Kjer J, Wray V, Edrada-Ebel R, Ebel R, Pretsch A, Lin W, Proksch P. Xanalteric acids I and II and related phenolic compounds from an endophytic Alternaria sp. isolated from the mangrove plant Sonneratia alba. J Nat Prod. 2009 Nov;72(11):2053-7.
  11. Zhu X-C, Huang G-L, Mei R-Q, Wang B, Xue-Ping Sun X-P Luo Y-PXu J, Zheng C-J.  One new αβ-unsaturated 7-ketone sterol from the mangrove-derived fungus Phomopsis sp.MGF222 Nat Prod Res. 2020 Apr 14;1-7.
  12. Cheng M. J., Wu M. D., Yanai H., Su Y. S., Chen I. S., Yuan G. F., et al. Secondary metabolites from the endophytic fungus Biscogniauxia formosana and their antimycobacterial activity. Phytochem. Lett. 5, 467–472 10.1016 
  13. Haron MH et al, Planta Med 2016; 82(14):1258-1265.
  14. Singh K, Dwivedi GR, Sanket AS, Pati S. Therapeutic Potential of Endophytic Compounds: A Special Reference to Drug Transporter Inhibitors. Curr Top Med Chem. 2019;19(10):754-783.
  15. Mookherjee A, Singh S, Maiti MK Quorum sensing inhibitors: can endophytes be prospective sources? Arch Microbiol. 2018 Mar;200(2):355-369
  16. Kasaei A, Mobini-Dehkordi M, Mahjoubi F, Saffar B. Isolation of Taxol-Producing Endophytic Fungi from Iranian Yew Through Novel Molecular Approach and Their Effects on Human Breast Cancer Cell Line. Curr Microbiol. 2017 Jun;74(6):702-709.
  17. El-Sayed R, Zaki AG, Ahmed AS, Ismaiel AA.  Production of the anticancer drug taxol by the endophytic fungus Epicoccum nigrum TXB502: enhanced production by gamma irradiation mutagenesis and immobilization technique. Appl Microbiol Biotechnol. 2020 Aug;104(16):6991-7003.
  18. Patel RN. Tour de paclitaxel: biocatalysis for semisynthesis. Annu Rev Microbiol. 1998;52:361-95.
  19. Sabzehzari M, Zeinali M, Naghavi MR. Alternative sources and metabolic engineering of Taxol: Advances and future perspectives. Biotechnol Adv. 2020 Nov 1;43:107569.
  20. Stierle A, Strobel TG, Stierle D. Taxol and taxane production by Taxomyces andreanae, an endophytic fungus of Pacific yew, Science. 1993 Apr 9;260(5105):214-6.
  21. Zhou X, Zhu H  Liu L, Juan LinTang K. A review: recent advances and future prospects of taxol-producing endophytic fungi. Appl Microbiol Biotechnol . 2010 May;86(6):1707-17
  22. Uzma F1Mohan CD, Hashem A, Konappa NM, Rangappa S, Kamath PV, Singh BP, Mudili V, Gupta VK, Siddaiah CN, Chowdappa S, Alqarawi AA, Abd Allah EF . Endophytic Fungi-Alternative Sources of Cytotoxic Compounds: A Review. Front Pharmacol. 2018 Apr 26;9:309.
  23. Singh A, Singh DK, Kharwar RN, White JF Gond SK Fungal Endophytes as Efficient Sources of Plant-Derived Bioactive Compounds and Their Prospective Applications in Natural Product Drug Discovery: Insights, Avenues, and Challenges. Microorganisms. 2021 Jan 19;9(1):197.
  24. Teixeira TR, Dos Santos GS, Armstrong L, Colepicolo P, Debonsi HM. Antitumor Potential of Seaweed Derived-Endophytic Fungi. Antibiotics (Basel). 2019 Oct 31;8(4):205.
  25. Martínez-Romero E, Aguirre-Noyola JL, Bustamante-Brito R, González-Román P, Hernández-Oaxaca D, Higareda-Alvear V, Montes-Carreto LM, Martínez-Romero JC, Rosenblueth M, Servín-Garcidueñas LE.  We and herbivores eat endophytes. Microb Biotechnol. 2020 Dec 15.
  26. Pal PP, Shaik AB, Begum AS. Prospective Leads from Endophytic Fungi for Anti-Inflammatory Drug Discovery. Planta Med. 2020 Sep;86(13-14):941-959
  27. Ibrahim SRM, Mohamed GA, Al Haidari RA, El-Kholy AA, Zayed MF. Potential Anti-Malarial Agents from Endophytic Fungi: A Review. Mini Rev Med Chemanti-inflamm. 2018;18(13):1110-1132.
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  29. Soldan R, Mapelli F, Crotti E, Schnell S, Daffonchio D, Marasco R, Fusi M, Borin S, Cardinale M. . Bacterial endophytes of mangrove propagules elicit early establishment of the natural host and promote growth of cereal crops under salt stress. Microbiol Res. Jun-Aug 2019;223-225:33-43.

LEMON BALM – A TRUE TONIC FOR STRESS

Lemon balm (Melissa officinalis) grows really well in my garden, and also in the wild in various locations in New Zealand and other countries. It has a distinctive lemony scent when rubbed, and a plethora of medicinal uses.

Lemon balm was a sacred herb to the ancient Greeks, and widely planted by early beekeepers to keep honeybees happy and well fed with nectar. Its healing properties were increasingly recognised during the Medieval and Renaissance ages, and by the 9th century it was widely planted in monastery gardens. Widespread medicinal uses were described by the Greek and Persian physicians Dioscorides and Avicenna and reiterated by the 17th century English herbalist Nicholas Culpeper, who also described it as ‘an excellent remedy for a cold and moist stomach’, which ‘cheers the heart, refresheth the mind, takes away grief, sorrow and care, instead of which it produces joy and mirth’(1).

Like other members of the lamiaceae (mint) family of plants such as peppermint, basil, rosemary and sage, aerial parts of lemon balm can be a valuable component to the management of nervous dyspepsia and digestive conditions such as bloating and irritable bowel syndrome.  Perhaps more than anything though, its potential applications for nervous system conditions such as anxiety and mood disorders, have been increasingly supported by animal and human clinical studies in recent years.

Administration of a single dose of lemon balm to healthy student volunteers was first reported to improve cognitive performance in a laboratory model of acute stress by British researchers in 2002 (2-6). These and subsequent experiments measured a reduction in the negative effects of stress on mood and improved self ratings of calmness, while not causing any reduction in accuracy whilst undertaking required laboratory tasks. These effects were apparent for up to 6 hours following lemon balm administration.

A pilot trial in which 20 volunteers suffering from mild to moderate anxiety disorders and sleep disturbances took lemon balm for 15 days, found most responded to treatment, with a reduction in anxiety and associated symptoms, and an improvement in sleep(7). While this was an open-label study with no placebo, and clinician contact may have contributed to the symptom improvement observed, it supports further controlled trials with larger patient numbers.

Other clinical studies have expanded our understanding of lemon balm’s relaxant properties. Favourable effects were reported in an Iranian trial in which lemon balm capsules were taken twice daily by young women with premenstrual syndrome over a 3 month period(8). Those who received lemon balm reported a significant reduction in psychosomatic symptoms, anxiety and sleeping disorder, as well as improvements in social functioning difficulties.

Results from two studies involving combinations of lemon balm with other plant extracts, are also of interest. These include a small placebo controlled trial using a combination of lemon balm with the Iranian herb Nepeta menthoides (Ostokhodus) which improved insomnia, depression and anxiety in a group of 67 insomniacs(9). A recent Swiss retrospective study also investigated the effects of a combination product containing lemon balm, valerian, passionflower and butterbur extracts on the prescription pattern of benzodiazepines and other psychoactive drugs in hospitalised psychiatric patients. This found concomitant prescribing of benzodiazepines for anxiety to be lower in patients taking the combination herbal product, although the level of prescribing of hypnotics and antidepressants (including herbal ones), was higher(10).

Anxiety disorders can affect cardiovascular parameters such as the heart rate and blood pressure, and a diagnosis of a cardiovascular medical condition can cause or exacerbate anxiety. Culpeper’s comments and other traditional use information allude to an affinity for the cardiovascular system for lemon balm, and in fact two clinical trials have found favourable outcomes in this regard.

Treatment of a group of 71 volunteers suffering from an abnormal awareness of heartbeat with the equivalent of 5 grams dried lemon balm leaves daily for 14 days, resulted in less frequent and less intense symptoms of heart palpitations (11, 12). Lemon balm treatment also reduced the number of patients with concomitant anxiety and insomnia disorder in this study. Another small trial reported a reduction in symptoms and signs of depression, anxiety, stress and sleep disorder, in a group of patients with chronic but stable angina following an 8 week course of lemon balm treatment(13).

Recent animal studies also provide further interesting data. Adipogenesis and obesity can also accompany chronic stress, and the finding that lemon balm lead to improvements in fasting blood glucose, glucose tolerance, and pancreatic dysfunction in female obese mice, has implications for the potential prevention of visceral obesity and insulin resistance in obese premenopausal women(14).

Another study further evaluated the effects of a hydro-alcoholic extract of lemon balm in a behavioural study in mice(15). Reversal of behaviours reflective of anxiety and helplessness occurred following lemon balm treatment, effects accompanied by enhanced enzymatic antioxidant activities and restoration of serum corticosterone levels previously disrupted by stress.

The mechanism(s) of action of lemon balm’s anxiolytic and possible mood modulating effects, seem to involve the gamma amino butyric acid (GABA) neurotransmission system(16). In vitro studies have reported inhibitory activity against GABA transaminase for lemon balm extracts, an enzyme involved in metabolising this endogenous ‘relaxant’ neurotransmitter.

The collective picture emerging for lemon balm and how it affects our brains and functioning, is that of a uniquely compelling and probably dose-related combination of relaxant as well as cognitive enhancing properties. Possible applications in those with accompanying digestive or cardiovascular conditions or a predisposition to obesity or depression, are also suggested. These attributes together with the various other established and likely health benefits of this easy to grow plant, would seem to make it an ideal daily tonic to help with stress management, in the modern world.

References:

  1. Culpeper, Nicholas. (1653). A Complete Herbal. London, Peter Cole.
  2. Kennedy DO et al,  Pharmacol Biochem Behav. 2002 Jul;72(4):953-64.
  3. Kennedy DO et al. Psychosom Med. Jul-Aug 2004;66(4):607-13
  4. Kennedy DO et al, Neuropsychopharmacology. 2003 Oct;28(10):1871-81.
  5. Rasmussen PL, Phytonews 20, published by Phytomed Medicinal Herbs Ltd, Dec 2004.ISSN 1175-0251.
  6. Rasmussen PL, Phytonews 17, published by Phytomed Medicinal Herbs Ltd, Oct 2003.ISSN 1175-0251.
  7. Cases J et al, Med J Nutrition Metab. 2011 Dec;4(3):211-218.
  8. Heydari N et al, Int J Adolesc Med Health. 2018 Jan 25;31(3):/j/ijamh.2019.31.issue-3/ijamh-
  9. Ranjbar M et al,egr Med Res. 2018 Dec;7(4):328-332 
  10. Keck et al, Phytother Res. 2020 Jun;34(6):1436-1445.
  11. Alijaniha F et cl, J Ethnopharmacol 2015; 164:378-384.
  12. Rasmussen PL, Phytonews 41, published by Phytomed Medicinal Herbs Ltd, Mar 2017.ISSN 1175-0251.
  13. Haybar H et al, Clin Nutr ESPEN. 2018 Aug;26:47-52.
  14. Lee D et al, J Ethnopharmacol. 2020 May 10;253:112646.
  15. Ghazizadeh J et al, Exp Physiol. 2020 Apr;105(4):707-720
  16. Awad R et al, Can J Physiol Pharmacol. 2007 Sep;85(9):933-42

Calendula – a powerful healing herb

Flowers of the English or Pot Marigold (Calendula officinalis), have long been recommended and used for minor cuts, grazes, and slow healing wounds. However despite this popularity, and it being approved by the European Medicines Agency as a traditional medicinal product(1), clinical trials involving calendula have been few and far between until recently. Now though, results from at least 10 clinical trials involving use of topical dosage forms of calendula for a range of clinical conditions, have been published.

Preventive effects against radiation-induced dermatitis were reported by French oncologists in a study involving 254 breast cancer patients in 2004. Only 41% of patients who received calendula ointment treatment after each radiotherapy session subsequently developed acute dermatitis, compared to 63% of those given topical trolamine treatment. Reduced radiation-induced pain, and less frequent interruption of the radiotherapy treatment regimen, were other positive outcomes associated with calendula ointment application(2,3).

A more recent Australian trial involving 81 women undergoing breast cancer radiotherapy compared topical calendula with the standard sorbolene treatment. The prevalence of radiation-induced dermatitis was 53% in the calendula group and 62% in the sorbolene group. While this difference was not statistically significant, the study was underpowered due to less than half the recruitment target of 178 patients, being achieved(4). Use of a calendula mouthwash has also been reported to reduce the intensity of radiation-induced oropharyngeal mucositis in patients with head and neck cancers undergoing radiotherapy(5).

Other trials have evaluated calendula in the management of venous leg ulcers. The first of these compared twice daily application of calendula ointment with saline solution dressings, in a group of 34 patients over a 3 week period(6). After the third week, the total surface of the ulcers decreased by an average of 41.7% in the calendula group, but only 14.5% in the group treated with saline dressings. In four calendula treated patients, complete wound closure was achieved. 

A Brazilian clinical trial evaluated the effectiveness of a spray application of calendula extract on the healing rate of 38 non-healing diabetic leg ulcers(7). Treatment entailed twice daily application of calendula or standard hospital procedure, consisting of the enzyme collagenase, the antibiotic chloramphenicol, and 1% silver sulfadiazine cream for a period of 30 weeks or until ulcers healed.

After 12 weeks of treatment, 39% of wounds treated with calendula were completely closed, but none in the standard treatment control group. After 30 weeks treatment, 72% achieved complete wound closure, compared to only 32% in the control group. Average healing times were 12 weeks in the calendula treatment group, versus 25 weeks in the control group. No adverse events were observed during calendula treatment.

While confirmation of these benefits through a trial involving greater patient numbers is needed, these studies suggest a significant acceleration of venous ulcer healing through twice daily application of topical calendula products.

A shortened duration of caesarian wound healing, has also been recently reported by another Iranian trial involving 72 women, through twice daily application of calendula ointment versus the standard hospital post surgical routine(8). Faster wound healing after episiotomy, has also been reported from an Italian trial recently(9). Women who received calendula ointment compared to standard care benefited from a significantly lower pain level starting from day two after episiotomy, as well as improved wound healing in terms of redness and oedema.

Several mechanisms of action are likely to be responsible for these effects of calendula on wound healing or dermatitis prevention. Beneficial effects on granulation tissue and new tissue formation during acute wound healing have been observed in vitro using human immortalised keratinocytes and human dermal fibroblasts(10). A recent review of calendula’s effects on acute wounds which incorporated 7 animal and 7 clinical studies, reported faster resolution of the inflammation phase and increased production of granulation tissue, in acute wounds treated with calendula(11).

Another traditional application of calendula is for the treatment of fungal infections, and findings from another Iranian trial comparing a 7 day treatment of calendula or clotrimazole cream for the treatment of vaginal candidiasis in a group of 150 women aged 18–45 years, are of interest(12). While a higher rate of negative testing for candidiasis was measured at 10-15 days post treatment in the clotrimazole than in the calendula group (74% vs 49% negative tests for candidiasis), when further testing was undertaken at 30-35 days after treatment, calendula treatment was associated with 77% testing negative for candidiasis, versus only 34% in the clotrimazole group. Signs and symptoms were similar in both groups at 10-15 days post treatment, but significantly less in the calendula group, at the later follow-up. Thus vaginal administration of calendula cream was effective in treating vaginal candidiasis, and while the onset of effect was delayed compared to clotrimazole, a greater and longer term effect was seen following calendula treatment(12)

With antibiotic resistance becoming an increasing problem, not to mention the high and rising costs of wound care management associated with aging populations and the impact of diabetes, investigation into plant-based alternative wound treatment agents, is gaining more research attention.

The orange-yellow flowers of calendula have a convincing reputation for helping to enhance wound healing in traditional herbal medicine. Encouragingly, its potential usefulness in wound care management and fungal infections such as candidiasis, is being increasingly validated by a growing number of clinical studies published in recent years.

References:

  1. https://www.ema.europa.eu/en/medicines/herbal/calendulae-flos.
  2. Pommier P et al, J Clin Oncol. 2004 Apr 15;22(8):1447-53.
  3. Rasmussen PL, Calendula for radiotherapy-induced skin damage. Phytonews 20, published by Phytomed Medicinal Herbs Ltd, Dec 2004.ISSN 1175-0251.
  4. Siddiquee S et al, Australas J Dermatol 2020 Sep 23. doi: 10.1111/ajd.13434. Online ahead of print.
  5. Babaee B et al, Daru. 2013 Mar 7;21(1):18.
  6. Duran V et al, Int J Tissue React. 2005;27(3):101-6.
  7. Buzzi M et al, Ostomy/wound Management 2016; 62(3):8-24.
  8. Jahdi F et al, J Family Med Prim Care. Sep-Oct 2018;7(5):893-897.
  9. De Angelis CD et al,  Matern Fetal Neonatal Med. 2020 May 27;1-5. doi: 10.1080/14767058.2020.1770219. Online ahead of print.
  10. Nicolaus C et al, J Ethnopharmacol. 2017 Jan 20;196:94-103.
  11. Givol O et al,Wound Repair Regen 2019 Sep;27(5):548-561.
  12. Saffari E et al, Women Health Nov-Dec 2017;57(10):1145-1160.

Echinacea in the time of a pandemic

While here in New Zealand we are now very fortunate that very low numbers of new Covid-19 cases are being reported, and the wearing of masks and social distancing practices are starting to seem like a distant memory to many people, much of the world is not so lucky. As our days lengthen and thoughts of a forthcoming summer break brighten our days, the virus continues to wreak havoc and cause huge stress and loss of life, in so many other countries.

Over the next few months those lucky enough to be living in New Zealand will hopefully be able to attend concerts, shows, sports events and festivals again, and these will help facilitate some kind of ‘return to normality’ from our spells in lockdown over autumn and winter. However, the coming summer may become a period of relative respite, because pressure will grow to further reopen our borders, and no public health or border protection system is invincible. Therefore as we prepare for or engage with gatherings involving larger numbers of people where the risk of community transmission is greater, ensuring a healthy immunity over the next few months and then as we move into autumn, remains important.

Evidence of efficacy is often a challenging subject to address with phytomedicines, due to the phytochemical diversity of whole plants and the many different extracts and products to evaluate.  Not to mention the difficulties in accessing funding to undertake clinical trials where large patient numbers and/or lengthy treatment interventions are often required to achieve adequate statistical power.

Pandemics have afflicted the human race throughout our entire history, and plant-based medicines have been a cornerstone of how we dealt with these, way before single active chemical interventions (drugs or vaccines) were conceived. The current Covid-19 pandemic is a reminder that drugs are often unable to protect us against everything that the natural world throws at us.

Significant evidence indicates that a dysregulated innate immune response contributes to the clinical presentation of patients with severe Covid-19 infections(1,2).  

Covid-19 pathology

A meta-analysis of 21 studies, found that biomarkers of inflammation, cardiac and muscle injury, liver and kidney function and coagulation measures were significantly elevated in patients with both severe and fatal Covid-19. In particular, interleukins 6 (IL-6) and 10 (IL-10) and serum ferritin were strong discriminators for severe disease(2).

These elevations in inflammatory cytokines have led to the view that an immunity-mediated “cytokine storm,” is primarily responsible for the toxicity and end-organ damage mediated by Covid-19 infections. The combined effect seems to be promotion of granulocyte infiltration into the lungs, resulting in acute lung injury & sometimes death due to primary respiratory failure. An abnormal immune mechanism and upregulationof genes involved in apoptosis, tissue injury & oxidative damage, can also damage organs such as the heart, kidney and liver, and lead to multiple organ exhaustion and shut down, or residual damage to these post infection recovery.

Attenuation of the peak immune response, either with corticosteroids such as dexamethasone or more specifically targeting of interleukin IL-6 or IL-1β to limit damage to other organs during the early immune response, may benefit some patients(3,4). There are risks with such drug therapy however, as early immune hyperactivity may be a reflection of high viral burden and a much-needed protective antibody response, and our understanding of the how this clever coronavirus influences immune mechanisms at different infection stages in different patients, is still lacking.

Echinacea’s immunomodulatory effects:

In western herbal medicine, one of the most highly regarded phytomedicines from both a traditional as well as evidence-based perspective, is the well known Echinacea (Purple coneflower). Two species are generally used, Echinacea purpurea and Echinacea angustifolia.

A principle application claimed for Echinacea-based products over the last 50 years has been as a prophylactic or treatment for colds and influenza. Several clinical trials have shown beneficial effects of Echinacea in this context, although others have had less favourable outcomes, particularly where product quality or doses used have been suboptimal(5). Few adverse events have been reported, and the risk of interactions is low(6).  But what is the evidence that this phytomedicine can help us during the current global Covid-19 pandemic?

A number of natural products including Echinacea have shown in vitro effects against the SARS-CoV-2 coronavirus responsible for Covid-19(7-9), although these are limited to date, and clinical studies are lacking.

Echinacea is frequently portrayed as an ‘immune stimulant’ herb in the popular media and therefore sometimes claimed to be contraindicated in situations where elements of the immune system are ‘overactivated’. This is a gross simplification of the effects of this phytomedicine, as its widespread traditional use for conditions that are largely inflammatory and autoimmune in nature has been largely overlooked, as have anti-inflammatory properties particularly for its constituent alkylamides and high alkylamide-containing products(10-12).

Studies using different types of Echinacea purpurea on murine dendritic cells (immune cells in mice which play important roles in activating and initiating immune responses) found immunostimulatory, immunosuppressive, and/or anti-inflammatory actions can all be produced, with distinctively different outcomes depending on the plant part and extraction method used(13). Furthermore, different actions appear to occur during uninfected and infected states, suggesting that there is much more to Echinacea than a simple immune stimulant action. These include its influences on cytokine secretion.

Key outcomes when Echinacea is taken by healthy volunteers seem to be increased numbers of circulating white blood cells, monocytes, neutrophils and natural killer (NK) cells, and thus enhancement of the non-specific (innate) immune system. This is thought to improve the body’s ability to maintain immunosurveillance against a variety of potential viral or bacterial pathogens or spontaneous-developing tumours.  Daily administration of Echinacea purpurea root prolonged the life spans of normal mice(14), and Echinacea purpurea had a suppressive effect on spontaneously occurring leukaemia caused by a murine leukaemia virus(15). It has also been reported to have beneficial effects on stress-induced immunosuppression in rodents, by increasing splenocyte proliferation and NK cell activity, while restoring and modulating T lymphocyte subsets and serum cytokine levels(16). These essentially prophylactic effects were largely related to enhancement of immune systems.

Administration of Echinacea during an infection however, is likely to produce somewhat different outcomes, as is shown by various studies(17-19).

Rhinovirus infection in a line of human bronchial epithelial cells was shown to induce or increase the secretion of at least 31 different inflammatory cytokines and chemokines, including the interleukins IL-1β, IL-3, IL-5, IL-6, IL-17, granulocyte-macrophage colony stimulating factor, interferon-gamma (IFN-ﻻ), and tumor necrosis factor (TNF-α).  Echinacea treatment of the infected cells over 48 hours however, reversed this stimulation of inflammatory cytokine and chemokine levels, either partially or completely(17)

Subsequent studies reported that Echinacea purpurea reduced rhinovirus induced secretion of interleukin-6 and interleukin-8 from human bronchial epithelial cells, regardless of whether it was added before or after virus infection(18).

In contrast to the above effects on infected cells, when uninfected cells were treated with Echinacea, cytokine levels were mostly increased, particularly by a root-derived rather than fresh whole plant-derived preparation.

These investigations provide support for an immunomodulatory mode of action for Echinacea, whereby the immune system is enhanced when Echinacea is taken in the absence of infection, but excessive and possibly damaging inflammation during a viral infection may be reduced. This suggests not only a useful prophylactic effect of Echinacea against unwanted viruses, but also a potential usefulness during upper respiratory tract viral infections such as rhinovirus. While much more work needs to be done, these effects could extend also to other highly pathogenic viral infections in which excessive activation of elements of the immune response and a sudden and unregulated increase in the production of pro-inflammatory cytokines, may occur(19,20).

An assessment of human trials involving Echinacea use for up to 4 months, failed to locate any evidence of cytokine storm(21). Furthermore, those which measured changes in cytokine levels in response to Echinacea use, provide results which are largely consistent with a decrease in pro-inflammatory cytokines. While there is currently no research on the therapeutic effects of Echinacea in the management of cytokine storm, this evidence suggests further research is warranted.

Traditional and modern day use experience points to potential benefits and few if any contraindications of daily prophylactic use of Echinacea to further enhance our immunity to contracting infection, beyond advisable public health measures such as social distancing and good hygiene. Additionally, while much is unknown and more research is advocated, this highly regarded phytomedicine could also provide useful anti-inflammatory and immunomodulatory effects as part of the very challenging management of seriously ill patients, where a hyperinflammatory situation seems contributory to worse outcomes.

Secondary bacterial infections:

Secondary or co-existing bacterial infections are a common cause of pneumonia and death in patients with viral infections of the respiratory tract. Viral infections can express bacterial adhesion receptors, and the virus-induced inflammatory response can also disturb the integrity of the physical barrier to bacteria.  The use of prophylactic antibiotics in Covid-19 infected patients has therefore become relatively common. Recent reviews however, suggest the frequency of such secondary bacterial infections may be less than initially thought. These found bacterial co-infection was identified in only 3.5-7% of patients, and secondary bacterial infection in 14% of patients (22,23), While such infections are more common in seriously ill and elderly patients, and antibiotics should of course be used when indicated, not overusing them in an age of increasing antibiotic resistance, is also important. As such, evidence suggesting echinacea may prevent virus-induced bacterial adhesion to cell membranes(24), suggests another potential mechanism of action to improve host resistance against such unwanted secondary infections.

Dietary supplementation with Echinacea purpurea has been reported to improve the final body weight and immune response of non-infected chickens, and reduce the mortality of those infected with E. coli(25)

A recent clinical trial involving 300 children in Eqypt with recurrent tonsillitis, reported fewer tonsillitis attacks and less severe symptoms when Echinacea was taken alongside the antibiotic azithromycin, three times daily for 10 consecutive days every month for 6 consecutive months(26). While the plant part(s) used and phytochemical analysis of the preparation involved was not disclosed in this report, these findings are supported also by the clinical experience of many western medical herbalists, who prescribe concomitant Echinacea in patients receiving antibiotic treatment. Usage of Echinacea as an adjunctive with antibiotics, clearly warrants further clinical trials.

Effects on Stress?

Another unexpected but potentially helpful application of some Echinacea preparations in a stress-invoking pandemic world, is to help alleviate anxiety. Anxiolytic effects have been reported previously for certain Echinacea extracts and products, but clinical evidence has been lacking. However, a recent double blind, placebo controlled trial in which volunteers prone to anxiety took a standardized Echinacea angustifolia root extract twice daily for 7 days, found a decrease of 11 in state anxiety scores after 7 days of Echinacea, compared to only 3 in the placebo group(27).

Echinacea products are being sought after in northern hemisphere countries as second or third waves of the Covid-19 pandemic continue to plague multiple nations.  While clinical studies are sadly lacking and are sorely needed, the many potentially relevant pharmacological properties shown by this highly regarded phytomedicine would seem to go a long way to justify its recent rise in popularity.

,

Refs:

  1. Henry BM et al, Clin Chem Lab Med 2020 Jun 25;58(7):1021-1028
  2. Jamilloux Y et al, Autoimmun Rev. 2020 Jul;19(7):102567
  3. Vardhana SA et al, J Exp Med. 2020 Jun 1; 217(6): e20200678.
  4. Conti P J BiolRegulHomeost Agents. 2020 Mar 14;34(2)
  5. Shah SA et al, Lancet Infect Dis. 2007 Jul;7(7):473-80.
  6. Rasmussen PL, Recent studies on Echinacea and interactions with drug medication. Phytonews 34, July 2010. Published by Phytomed Medicinal Herbs Ltd, Auckland, New Zealand. ISSN 1175-0251.
  7. Signer J et al, Virol J. 2020 Sep 9;17(1):136.
  8. Mani JS et al, Virus Res 2020; Jul 15:284:197989.
  9. Khalifa I et al, J Food Biochem. 2020 Aug 11;e13432.
  10. Clifford LJ et al, Phytomedicine 9(3), 249-254, April 2002.
  11. Rasmussen PL, Evaluation of anti-inflammatory effects of Echinacea purpurea and Hypericum perforatum. Phytonews 14, Dec 2002. Published by Phytomed Medicinal Herbs Ltd, Auckland, New Zealand. ISSN 1175-0251.
  12. Lalone CA et al, J Agric Food Chem. 2010 Aug 11;58(15):8573-84
  13. Benson JM et al, Food Chem Toxicol. 2010 May;48(5):1170-7.
  14. Brouseau M, Miller SC, Biogerontology. 2005;6(3):157-63.
  15. Hayashi I et al, Nihon Rinsho Meneki Gakkai Kaishi. 2001;24(1):10-20.
  16. Park S et al, J Med Food 2018 Mar;21(3):261-268.
  17. Sharma M et al, Phytother Res 2006; 200(2):147-152.
  18. Sharma M et al, Antiviral Res. 2009 Aug;83(2):165-70.
  19. Rasmussen PL, Effects of Echinacea on virus-induced respiratory cytokines. Phytonews 24, Feb 2006, June. Published by Phytomed Medicinal Herbs Ltd, Auckland, New Zealand. ISSN 1175-0251.
  20. Rasmussen PL, Phytotherapy in an Influenza Pandemic: Swine Flu. Phytonews 32, 2009, June. Published by Phytomed Medicinal Herbs Ltd, Auckland, New Zealand. ISSN 1175-0251.
  21. Aucoin M et al, Adv Integr Med 2020; Aug 1. Doi: 10.1016/j.aimed.2020.07.004
  22. Langford BJ et al, Clin Microbiol Infect. 2020 Jul 22;S1198-743X(20)30423-7
  23. Lansbury L et al, J Infect. 2020 Aug;81(2):266-275
  24. Vimalanathan S et al, Virus Res. 2017; 2(233):51-59.
  25. Hashem MA et al, Trop Anim Health Prod. 2020 Jul;52(4):1599-1607.
  26. Osama G Abdel-Naby Awad, Am J Otolaryngol. Jul-Aug 2020;41(4):102344.
  27. Haller J et al, Phytother Res. 2020 Mar;34(3):660-668.

VALERIAN – MORE THAN JUST A SLEEPING AID

Roots of the European and northern Asian herb Valerian (Valeriana officinalis), are well known for their relaxant and anxiolytic properties, and usefulness in the management of insomnia and mild anxiety. Clinical trials into its effects on insomnia and sleep problems including in menopausal women and patients withdrawing from benzodiazepine drugs, have generally reported favourable findings(1-4).

As with all medicinal plants, a single useful application is a far-fetched concept, and Valerian is no different in this. Apart from being pleasing to some cats in a similar way catnip is, another increasingly supported application for this well known herb, is to help support cognitive function.

Conventional sleeping tablets such as triazolam and zopiclone have detrimental effects on cognitive function(5,6), but comparative studies found valerian to show no such negative effects(1, 7). Next day hangover like symptoms and cognitive deficits are relatively frequent adverse events of all drug-based anti-anxiety or sedative agents, so this itself is a significant valerian advantage. However, evidence that valerian may additionally protect against cognitive decline or enhance cognitive functions in other settings, is of interest.

Early indications of cognitive enhancing effects of valerian particularly in the elderly, came from a Korean study in aged mice published in the journal Exp Gerontology(8). Following 3 weeks of valerian root administration (and valerenic acid), improvements occurred in several behavioural parameters indicative of improved cognitive functions, including exploration of new objects, escape latency, and swimming speeds. These effects were accompanied by enhancement in nerve cell differentiation and neuroblast differentiation, and reduced serum levels of corticosterone, in the valerian versus control treated mice. While an animal study, these findings suggest similar cognitive promoting effects in elderly humans.

Since then, at least two human clinical studies have measured changes in cognitive function following valerian administration. These include a study with 39 patients on haemodialysis whose cognitive status improved after taking valerian 60 minutes before bedtime for one month(9). The prevalence of cognitive disorders in kidney failure patients undergoing haemodialysis is twice as high as the general population, and these are often undiagnosed(10).  Neuroprotective properties, as reported for ethanolic extracts of valerian in animal studies, may be contributory to such benefits(11, 12).

Another study explored cognitive dysfunction in 61 patients aged between 30 and 70 years, scheduled for elective coronary artery bypass surgery(13). Patients received either valerian or placebo capsules twice daily for 8 weeks following surgery. Cognitive brain function was evaluated prior to surgery and at 10-day and 2-months following, using the Mini Mental State Examination (MMSE) test. In the valerian treated patient group the mean MMSE score decreased from 27.03 ± 2.02 in the preoperative period to 26.52 ± 1.82 at the 10th day, and then increased to 27.45 ± 1.36 at the 60th day. Conversely in the placebo group, scores reduced from 27.37 ± 1.87 in the preoperative period to 24 ± 1.91 at the 10th day, and rose only slightly to 24.83 ± 1.66 at the 60th day. With post-operative cognitive decline now recognised as a negative outcome in many patients undergoing this increasingly common surgical procedure(14), the finding that valerian may prevent this, has implications for coronary artery bypass as well as potentially other forms of surgery.

Valerian is also used traditionally for digestive or menstrual cramps, and for nervous headaches(15, 16). Prior to the development of early tranquilliser drugs such as barbiturates, or when these weren’t accessible, it was also a valued intervention in the management of some forms of pain.

Support for these historical applications has emerged recently from results of a clinical trial in Iran which investigated the effects of valerian on tension headaches. These present as dull pain, tightness, or pressure around the forehead or back of the head and neck, and are the most common type of headache.

The study included 88 participants with tension-type headache, randomly assigned to take valerian or placebo capsules twice daily after dinner for a month. After this one month treatment, valerian was associated with a significant reduction in the negative impacts of headaches on daily living and disability, and a reduction in the severity score, relative to the placebo group(17).

Finally, as anti-anxiety and sedative drugs can impart clinical improvement in some patients with depression, and potential antidepressant activity has been implicated for valerian in an animal model of depression associated with chronic stress(18, 19), beneficial applications in some patients with depression, are possible. Depression can also be accompanied by cognitive disturbances and a compromised memory. As such, herbs such as ginkgo and valerian for which benefits on associated cognitive function have been shown, may offer additional effects beyond those of antidepressant herbs and drugs, in the management of patients with depressive illness.

Refs:

  1. Dorn M. Forsch Komplementarmed Klass Naturheilkd. 2000 Apr;7(2):79-84
  2. Poyares DR et al, Prog Neuropsychopharmacol Biol Psychiatry. 2002 Apr;26(3):539-45
  3. Ziegler G et al, Eur J Med Res. 2002 Nov 25;7(11):480-6.
  4. Taavoni S et al, Menopause. 2011 Sep;18(9):951-5.
  5. Gunja N. J Med Toxicol. 2013 Jun;9(2):163-71.
  6. Stranks EK et al, J Clin Exp Neuropsychol. 2014;36(7):691-700 
  7. Hallam KT et al, Hum Psychopharmacol. 2003 Dec;18(8):619-25.doi: 10.1002/hup.542.
  8. Nam SM et al, Exp Gerontol. 2013 Nov;48(11):1369-77.
  9. Samaei A et al, BMC Nephrol. 2018 Dec 27;19(1):379
  10. Erken E et al, Clin Nephrol. 2019 May;91(5):275-283
  11. Malva JO et al, Neurotox Res. 2004;6(2):131-40.
  12. De Oliviera DM et al, Neurochem Res. 2009 Feb;34(2):215-20.
  13. Hassani S et al, Psychopharmacology (Berl). 2015 Mar;232(5):843-50.
  14. Ngcobo NN et al, S Afr J Psychiatr. 2020 Jul 9;26:1470.
  15. Rudolf Fritz Weiss, Herbal Medicine, published by Volker Fintelmann 1998
  16. Barker J. The Medicinal Flora of Britain and Northwestern Europe. Winter Press, West Wickham, Kent, UK, 2001. ISBN 1 874581 630
  17. Azizi H et al, Avicenna J Phytomed. May-Jun 2020;10(3):297-304
  18. De Brito APA et al, Front Neurosci 2020; 14:759.
  19. Kandilarov IK et al, Folia Med (Plovdiv) 2018; 60(1):110-116.