Tag: health

Medicine Security in Unsettled Times

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Medicinal plants in history

Health workforce shortages. Lengthening waiting lists. Hospital cost over-runs. Type 2 Diabetes, the hidden epidemic. Pandemic viruses.  Antibiotic resistance. Aging populations. Increasing meth use. There’s certainly more than a few nightmares for health policy analysts and decision makers to grapple with, when determining how to best allocate government health spending.

Apart from needing food and shelter, being able to resist the many life-threatening and injurious events and diseases that living on Planet Earth entails, has always been essential for our survival as a species. Thus in addition to having food security (access to sufficient healthy and nutritious food), the adequate supply of affordable and efficacious medicines, is a fundamental requirement to ensure good health and survival of human populations.

Humans have traditionally relied largely upon plants and fungi for medicines, and history shows they have served us well. However, despite the development of chemical drugs occurring only just over a hundred years ago, we often fail to acknowledge how the supply chain of medicinal plants, has greatly influenced the course of human history to date.

During the second world war, Cinchona officinalis (Peruvian bark) for instance, from which the valuable antimalarial drug quinine derives, was sourced almost exclusively from Java in Indonesia. However, after the Japanese invasion in 1942 and the capture by Nazis of processing facilities in the Netherlands, allied forces experienced a critical shortage of antimalarial drugs, which subsequently limited their operations in the southwest Pacific. Concerted efforts were therefore made to establish Cinchona cultivation in other locations, and new plantations in south America were developed(1).

Trade in black pepper, cinnamon and many other spices from India, China and south east Asia to Europe, were key contributors to the accumulation of wealth in early ancient cities such as Constantinople, Alexandria, Damascus and Venice.  Europeans fought the Crusades in large part to maintain a portal to the valuable spice trade. The Opium Wars between China, Britain and France in the mid 19th century, arose from China’s attempts to suppress the large European controlled trade of opium to China at that time.

These and many other examples, are reminders about how plants with powerful pharmacological properties have been important to humans. And how our access to them through either trade barriers and/or insufficient local production, can become seriously restricted.

Pandemic lessons

A key realisation that emerged early during the Covid-19 pandemic, was that despite years of well-funded research and development, drugs don’t provide all the answers when treating or preventing disease. A vaccine was developed and distribution commenced in near record time, but this still took many months and had many limitations. Distribution was delayed particularly to poorer countries, and a large percentage of the world’s population resorted as they always have done, to traditional plant medicines instead.

The pandemic also exposed the failure and cluster risks of modern global medicine supply chains. As levels of demand surged, enormous pressures were placed on already stretched supply chains, and widespread supply bottlenecks appeared.  During the Covid-19 lockdown in February 2022, pharmacy and supermarket shelves in Aotearoa NZ were virtually cleared of analgesics as people stockpiled. China’s zero-Covid policy during the pandemic prompted the closures of its many production facilities. India, which obtains most of its active pharmaceutical ingredients (API’s) from China, feared an imminent shortage of these critical raw materials, and thus promptly halted its exports of many medicinal products.  

Since the pandemic, shortages have occurred in supplies of widely used drugs such as the antidepressant fluoxetine, oestradiol patches used for menopause, and paracetamol. Similar shortfalls have happened in many other countries. The forthcoming withdrawal of the U.S. from the World Health Organisation, also doesn’t bode well for future international collaboration or worldwide medicine security.

Antibiotic resistance, is another ticking timebomb already responsible for over a million deaths a year globally, and placing a growing burden on health budgets. Rates of antimicrobial resistance are increasing in Aotearoa New Zealand and globally, including to last-line carbapenem antibiotics usually reserved for severe infections(2). It is a serious problem directly related to their overusage. Resistance to commonly used disinfectants and sanitizing agents, is also of increasing concern(3-5). Reducing their usage through increased utilization of plant derived medicines to help control infection, is a highly recommendable and evidence-based strategy.

Medicine shortfalls

Economic pressures, subsidisation policies and looser regulatory provisions in low-wage countries, have led to vital parts of medicine manufacturing being relocated to Asian countries over the past couple of decades. Historically also, global supplies of medicinal plants have largely derived from countries with low labour costs.

Most of the world’s pharmaceutical production, and around 30% of the production of plants for medicines, now takes place in China and India.  The high concentration of drug manufacturing steps in a small number of sites, often concentrated in the same geographical area, makes a supply chain vulnerable(6). Modern supply chain concepts such as just-in-time delivery, mean fewer reserves are maintained throughout the value chain.

The rapidly increasing frequency of so-called extreme weather events, reduced biodiversity, global warming and climate change, will also cause further threats to trade and supply chain security. These and other human factors are having increasingly serious impacts not only on food production and supplies, but also on the health and habitats of medicinal plants, and our ability to access them.

Geopolitical events, including wars or the introduction of trade tariffs, can also impact suddenly and significantly on our ability to access medicines which are manufactured or sourced from far away. With an increasingly unsettled international situation and tensions currently in a number of areas of the world, supply chain risks and strategies to mitigate these, should be high on a government’s agenda.

Medicine supplies – a government priority

Governments around the world have been considering and implementing additional measures to better secure medicine supply for their populations in the future. For a multitude of reasons, the inclusion of phytomedicines and their raw materials in these programmes, is essential.

Much was learned about the phytochemistry and potential medicinal properties of plants native to Aotearoa New Zealand during world war 2, when the government funded research in anticipation of a Japanese naval blockade limiting our imported medicine supply chain.

Cuba shifted to a more traditional and plant medicine based healthcare system following the introduction of a U.S. embargo in 1961. It now has some of the best health outcomes in the world, and its population’s average life expectancy is the same as that in the U.S. This has been achieved through an emphasis on prevention and education, universal coverage and access to treatment, within a highly proactive and well resourced primary healthcare system. Cuba’s spending per capita on health, is only a fraction of that allocated in the U.S., and less than half that spent in Aotearoa New Zealand (7).

Need for a Natural Health Agency

Healthy plant based foods and efficacious phytomedicines are powerful tools when building resilience to geopolitical or natural events which disrupt medicine supplies, and contribute greatly to better medicine security.

Aotearoa New Zealand is one of the best food and beverage producing countries in the world, with an ability to grow a wide range of foods and medicinal plants. From blueberries to kiwifruit, green tea to ginkgo, ginseng to saffron, numerous plants seem to have special characteristics and world leading levels of active phytochemicals, when grown here.

This capability together with a hard working and adaptable farming community, smart scientists and an innovative culture, provides the key criteria needed to further establish and promote a robust and export driven natural health product industry here. This could become a major contributor to our economy, as a sustainable, value added and profitable industry well aligned with our intrinsic and unique strengths as a country, and employ and retain both highly skilled and less skilled workforces. A scaled up commercial medicinal plant cultivation and processing industry would also help to mitigate risks from being over dependent on dairy and meat exports, and enable more self-sufficiency and medicine security, at the same time.

A New Zealand Space Agency was established in 2016, to be the lead government agency for space policy, regulation and sector development. This supports the ventures of companies such as Rocket Lab and Elon Musk’s SpaceX, and a NZ Space and Advanced Aviation Strategy 2024 to 2030 sets out the steps being taken to catalyse the sector’s growth.

In its current efforts to improve economic and wellbeing outcomes for Aotearoa New Zealand, it would be refreshing to see the government also implement the establishment of a Natural Health Agency. This could develop much needed new regulations for the sector, facilitate more research and development to support its growth, and improve patient access to evidence-based plant medicine treatments within primary health care. Expenditure on imported drug medicines would be reduced, and rural communities and our environment benefit through establishing new medicinal plant crops and related processing ventures.  

The natural health products sector is a complex but highly promising one for Aotearoa New Zealand, and a strategic, well integrated and coordinated bipartisan programme resourced over several years and insulated from our three year election cycles, would be an excellent use of limited government funds, in these changing times.

And it should lead to more resilience and medicine security, when the next pandemic or serious geopolitical event pulls the carpet out from our currently largely imported medicine supply chain.

References:

  1. Shanks GD. Historical Review: Problematic Malaria Prophylaxis with Quinine. Am J Trop Med Hyg. 2016 Aug 3;95(2):269-72. doi: 10.4269/ajtmh.16-0138.
  2. Ministry of Health , Manatū Hauora. Growing risk of antimicrobial resistance infection in New Zealand, 18 Nov 2024. https://www.health.govt.nz/news/growing-risk-of-antimicrobial-resistance-infection-in-new-zealand#:~:text=’Resistant%20strains%20of%20bacteria%20and
  3. Van den Poel B, Saegeman V, Schuermans A. Increasing usage of chlorhexidine in health care settings: blessing or curse? A narrative review of the risk of chlorhexidine resistance and the implications for infection prevention and control. Eur J Clin Microbiol Infect Dis. 2022 Mar;41(3):349-362.
  4. Kampf G. Acquired resistance to chlorhexidine – is it time to establish an ‘antiseptic stewardship’ initiative? J Hosp Infect. 2016 Nov;94(3):213-227. 
  5. Fernandes ÂR, Rodrigues AG, Cobrado L. Effect of prolonged exposure to disinfectants in the antimicrobial resistance profile of relevant micro-organisms: a systematic review. J Hosp Infect. 2024 Sep;151:45-59. 
  6. OECD Health Policy Studies. Securing Medical Supply Chains in a Post-Pandemic World. OECD Health Policy Studies, OECD Publishing, Paris. ISSN 2024-319X (online)
  7. M, Sarvestani MA. A Review on the Approach to Herbal Medicine in Cuban Healthcare System. Hispanic Health Care International. 2024;0(0). doi:10.1177/15404153241291747
  8. https://herbblurb.com/2019/06/21/why-new-zealand-grown-herbs-are-best/

Cinchona seedlings growing in Washington DC, USA, in November 1943 taken from Mindanao in the Philippines to re-establish quinine production in the Americas.

US Army Photograph, now in the public domain.

An introduced botanical paradise seen on holiday in Aotearoa New Zealand

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Achillea millefolium (Yarrow) was the first familiar medicinal plant to proudly show itself to me on the 1st day of a recent six day campervan trip from Christchurch to the west coast of Te Waipounamu (the South Island), of Aotearoa New Zealand. Growing and flowering prolifically along the roadside and beyond as we ventured inland towards Arthurs Pass, I wished I could have stayed another night in the campsite, and had the chance to harvest a decent batch.

Yarrow is a great plant to have nearby. So also apparently thought the Greek warrior Achilles, who is said to have applied its leaves and flowers topically to the sword and arrow wounds of his soldiers after battle, to close and heal their wounds. It is widely utilized in the traditional medicine of cultures from Europe to Asia to north America for numerous health conditions. They include spasmodic digestive and gynaecological complaints, and as a febrifuge and antimicrobial for fevers and infections(1). Relief from period pain was reported after drinking three cups of yarrow tea daily on days one to three of the menstrual cycle, in a clinical trial with 91 students aged 19-23(2).

Eschscholztia californica was a pretty poppy that called out with its bright yellow and orange flowers, in many roadside and dry gravelly patches throughout our journey. Related botanically to its opium-producing cousin, also seen in a couple of places thanks to the early Chinese goldminers of central Otago, Californian poppy is now a popular remedy for anxiety, insomnia and mild pain. My application of it however, has mainly been in patients withdrawing from substance dependency(3).

The amount of St John’s Wort (Hypericum perforatum) thriving in numerous locations in the Hawea, Wanaka and Queenstown districts and in other areas throughout our journey, was quite eye opening. I first wildcrafted and grew Hypericum as a student in the UK, and have dispensed it extensively within herbal formulations over the past 30 years.  A powerful antidepressant, antimicrobial and anti-inflammatory, with a multitude of applications both topically and internally.   

Mullein (Verbascum thapsus) was another one, appearing unexpectantly upon rounding many corners on sloping, dry hillbanks, with its distinctive upright stems poking towards the sky. As an invasive plant in many pastures and fields of rural New Zealand, with a rich content of polysaccharide hydrocolloids and other expectorant and anti-inflammatory phytochemicals, its long historical use as a lung tonic and for the management of upper respiratory tract infections, warrants more attention. While it’s a lot of work to harvest and dry the large lightweight leaves, it makes a great cough formula ingredient. The flowers and roots, also have established medicinal properties(4).

And then the rosehips. Through Lindis Pass into the upper Waitaki Valley as well as at the start of Arthurs Pass, fields and fields of them, dominated many parts of the landscape. Rosehips (Rosa canina) are probably best known for their vitamin C content, and in the 1940’s, locals from Otago and Southland wildcrafted the hips and sold them to the Greggs factory in Dunedin to manufacture syrups and powder forms. Rosehips were similarly wildcrafted in Britain during World War Two, and its syrup given to children and troops to prevent scurvy. 

Several clinical trials have reported efficacy of rosehip powder or extracts for the symptomatic treatment of osteoarthritis(5-7). Inhibitory effects against both cyclo-oxygenase 1 and 2 (COX-1 and COX-2) enzymes may contribute to these benefits(8, 9 ). Other traditional indications are for kidney stones, UTI’s and digestive ailments, and its oil is a popular application for skin health. Rosehips have antioxidant, anti-inflammatory, anti-obesity, anti-cancer, hepatoprotective, nephroprotective, cardioprotective, anti-aging, anti H. pylori, neuroprotective and antinociceptive activities(10).

Finally, heading back into Canterbury, the presence of Elder trees (Sambucus nigra), made themselves known upon the landscape. I made many batches of wine using Elder berries or flowers I wildcrafted when living in the U.K. many years ago, although it is a less common albeit somewhat invasive species here and prefers the cooler south rather than north island.  

Elder flowers are a great decongestant, and its berries rich in antioxidant anthocyanins and other anti-inflammatory polyphenols and vitamin C (11). Global demand greatly outstripped supply during the Covid-19 pandemic, due to its alleged antiviral properties (12, 13).

Many other established or invasive medicinal plants were seen during our journey, though most of these didn’t cry out so much to me.  It was the ones that I don’t see as much in the north island where I live, that served to remind me of the enormous geographical and botanical diversity that is characteristic of the Aotearoa New Zealand landscape.

And of course the extent and variety of our own native species was absolutely awe-inspiring, as it has been every time I’ve travelled on the west coast. The dominance of rātā (Metrosideros robusta) with its beautiful red flowers blanketing out in so many locations from within the dominant native beech forests (Nothofagus spp), was truly stunning.

We live in a country where there are bountiful supplies of medicinal plants. From many perspectives including those based upon invasive plant and land management, biodiversity, sustainability, economics and ultimately health outcomes, we should use more of them.

References:

  1. Ali SI, Gopalakrishnan B, Venkatesalu V. Pharmacognosy, Phytochemistry and Pharmacological Properties of Achillea millefolium L.: A Review. Phytother Res. 2017 Aug;31(8):1140-116
  2. Jenabi E, Fereidoony B. Effect of Achillea Millefolium on Relief of Primary Dysmenorrhea: A Double-Blind Randomized Clinical Trial. J Pediatr Adolesc Gynecol. 2015 Oct;28(5):402-4.
  3. Rasmussen PL, A Role for Phytotherapy in the Treatment of Benzodiazepine and Opiate Drug Withdrawal; Part 2, Treatment Approaches to Opiate Withdrawal, and Conclusions. Eur J Herbal Med, 1997; 13-10.
  4. Gupta A, Atkinson AN, Pandey AK, Bishayee A. Health-promoting and disease-mitigating potential of Verbascum thapsus L. (common mullein): A review. Phytother Res. 2022 Apr;36(4):1507-1522. 
  5. Rasmussen PL, Rosehip for Osteoarthritis. Phytonews 24, February 2006; published by Phytomed Medicinal Herbs Ltd, Auckland, New Zealand. ISSN 1175-0251.
  6. Christensen R, Bartels EM, Altman RD, Astrup A, Bliddal H. Does the hip powder of Rosa canina (rosehip) reduce pain in osteoarthritis patients?–a meta-analysis of randomized controlled trials. Osteoarthritis Cartilage. 2008 Sep;16(9):965-72. 
  7. Gruenwald J, Uebelhack R, Moré MI. Rosa canina – Rose hip pharmacological ingredients and molecular mechanics counteracting osteoarthritis – A systematic review. Phytomedicine. 2019 Jul;60:152958. 
  8. Jäger AK, Eldeen IM, van Staden J. COX-1 and -2 activity of rose hip. Phytother Res. 2007 Dec;21(12):1251-2. 
  9. Rasmussen PL, Rosehip acts as a cyclo-oxygenase inhibitor. Phytonews 29, June 2008; published by Phytomed Medicinal Herbs Ltd, Auckland, New Zealand. ISSN 1175-0251.
  10. Ayati Z, Amiri MS, Ramezani M, Delshad E, Sahebkar A, Emami SA. Phytochemistry, Traditional Uses and Pharmacological Profile of Rose Hip: A Review. Curr Pharm Des. 2018;24(35):4101-4124.
  11. Stępień AE, Trojniak J, Tabarkiewicz J. Health-Promoting Properties: Anti-Inflammatory and Anticancer Properties of Sambucus nigra L. Flowers and Fruits. Molecules. 2023 Aug 24;28(17):6235.
  12. Wieland LS, Piechotta V, Feinberg T, Ludeman E, Hutton B, Kanji S, Seely D, Garritty C. Elderberry for prevention and treatment of viral respiratory illnesses: a systematic review. BMC Complement Med Ther. 2021 Apr 7;21(1):112.
  13. Boroduske A, Jekabsons K, Riekstina U, Muceniece R, Rostoks N, Nakurte I. Wild Sambucus nigra L. from north-east edge of the species range: A valuable germplasm with inhibitory capacity against SARS-CoV2 S-protein RBD and hACE2 binding in vitro. Ind Crops Prod. 2021 Jul;165:113438.  

Mānuka and other Honeys – exciting recent research

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Honey as a medicine

Honey has been prized both as a food and medicine since the earliest times.(1,2)  Traditional medicine practices from around the world have long valued its therapeutic properties, particularly as a remedy for burns, cataracts, ulcers and wound healing.

All honeys are rich in antioxidant, anti-inflammatory and antimicrobial flavonoids, phenolic acids and other bioactive compounds cleverly extracted and manufactured by bees. These contribute to honey’s anti-inflammatory, antibacterial, antiviral, immunomodulatory and anti-allergic activities.(3-5)

While applications for wound care have become quite well known, clinical trials have also reported beneficial effects of honey intake on cardiovascular and metabolic risk factors, glucose tolerance, mucositis caused by chemo-radiotherapy, and coughs in children.(6,7)

Different types of honey are classified depending on the floral source and/or the geographical regions from which they derive.

Mānuka honey

Mānuka honey is honey made by bees using nectar from flowers of Leptospermum scoparium, a small native tree which grows abundantly throughout Aotearoa New Zealand. Mānuka is an important plant in rongoā Māori and for medical herbalists here, with its bark, foliage and seeds used to compound preparations for wounds, cuts, sores and skin diseases, colds, coughs and gastrointestinal conditions.(8,9) Its essential oil, also has multiple anti-inflammatory, antimicrobial and other bioactivities.(10)

Apart from being a rich source of glucose, fructose and flavonoids such as quercetin and chrysin found in other honeys, Mānuka honey contains unique chemical compounds such as methylglyoxal (MGO), dihydroxyacetone, leptosperin glyoxal, methyl syringate and leptosin.(11)

While once regarded as being inferior to other culinary honeys in terms of its taste profile, interest in the medicinal properties of Mānuka honey began to grow during the 1980’s. Its reputation as a health promoting food grew rapidly, a key catalyst being research in the early 1980’s which showed Mānuka honey to have potent antibacterial activities. 

Antimicrobial properties

These were reported against a wide range of different human pathogens, but antibacterial properties against Staphylococcus aureus and the gut pathogen Helicobacter pylori, attracted particular interest for Mānuka honey.(11-14) With stomach problems being a common human complaint, this research together with anecdotal reports of improvement in various gastrointestinal problems when taking Mānuka honey, lead to increasing demand.

Mānuka honey impregnated dressings have been developed and shown to be effective in wound care and infection management. Successful applications include for diabetic and venous leg ulcers(16-18) and hospital acquired pressure injuries in critically ill children.(19)  These dressings are now being increasingly used by wound care nurse practitioners in Aotearoa New Zealand.

On a global level, much research is ongoing into the antibacterial activities of Mānuka and other honeys.  Numerous scientific papers involving the potential infection control and antimicrobial activities of Mānuka honey have been published over the past year, with several encouraging findings.(20-26)

Research into the use of medical grade Mānuka honey as a post surgical wound application also continues in a number of countries outside of Aotearoa New Zealand, with encouraging findings.(28-30) Applications in oral surgery and dentistry, are also receiving increased attention.(31, 32)

Mānuka honey at low concentrations has been reported to kill multidrug-resistant and extensively drug-resistant clinical strains of Salmonella Typhi.(22)  Saudi Arabian researchers have also reported activity against carbapenem-resistant Enterobacterales.(21)  Medical researchers in Sweden, have found topical Mānuka honey to reduce the bacterial count of Staphylococcus aureus in a comparable way to an intramuscular antibiotic.(33)  They have also advocated potential applications for Mānuka honey as an immediate treatment for war wounds in the field of combat.

 A clinical trial to compare the use of a medical grade honey with the antifungal drug fluconazole for vaginal thrush is currently underway in the Netherlands, and the results will be interesting.(34)

Honey and Cancer

With rates of cancer increasing steadily as the global population increases and people live longer, research into interventions to help reduce the treatment burden has become more compelling. Interest in potential applications of honey in cancer therapy go back a long way. In fact there are now more than 800 papers and several reviews on honey and cancer in the scientific literature, many with encouraging findings.(35-42)

In vitro antiproliferative and apoptotic effects for honey have been reported against a large number of different cancer cell types. These include bladder cancer, colon, melanoma, breast, cervical, oral, prostate, hepatic and osteosarcoma cancer.  Several different honey types including Mānuka, thyme, gelam and acacia honeys, have shown such activities.(43-50) Relevant activities have also been reported in studies involving rat and mice models of different forms of cancer, including breast, colon, bladder and Ehrlich Ascite carcinoma.(46, 47, 51-54)

Mānuka Honey & cancer

Potential applications of Mānuka preparations in cancer patients, were first reported for a gargle using a mix of mānuka and kānuka essential oils diluted in water, bringing relief to mucositis of the oropharyngeal area as a result of radiation treatment for head and neck cancers.(55)

In vitro research by a number of different researchers has found anti-proliferative effects of Mānuka honey on breast, colorectal, breast and melanoma cell lines. Researchers from United Arab Emirates found that Mānuka honey had potent on all three cancer cell lines in a time- and dose-dependent manner, and was effective at concentrations as low as 0.6% (w/v).(53, 54)

They’ve also found improved survival rates of mice with melanoma when Mānuka honey was administered as an injection, alongside treatment with the chemotherapy drug paclitaxel.(53) Subject to future parenteral product development and human clinical studies, this study suggests exciting potential applications as an adjunct in cancer chemotherapy.  

Enhanced anti-tumour responses against colorectal cancer in mice have been shown following oral administration of Mānuka honey over a four week period.(56) These effects were correlated with immunomodulatory activities and changes in the gut microbiota.

In 2017, Malaysian researchers reported inhibitory effects on tumour development for Mānuka and Tualang honeys in a rat model of breast cancer.(57)  Recently American researchers have also revealed inhibitory effects on human breast cancer progression in preclinical models for Mānuka honey. Mānuka honey reduced the proliferation of MCF-7 breast cancer cells but not that of non-malignant human mammary epithelial cells. Antitumor activity was in a similar range to that exerted by treatment of MCF-7 cells with the oestrogenic antagonist tamoxifen, widely used in the management of breast cancer. (58)

An Italian team has undertaken a considerable amount of research into Mānuka honey’s potential preventive effects against colon cancer. They reported strong inhibitory effects on human colon cancer cells in a dose-dependent manner.(59)  Anti-metastatic impacts on colon cancer stem-like cells, a reduction in the ability of colorectal cancer cells to migrate, and downregulation of pro-angiogenic factors, were revealed as likely mechanisms of Mānuka honey’s activity.(60, 61, 62)

Possible protective effects against prostate cancer cell metastases, have been reported for New Zealand thyme, mānuka and honeydew honeys. Both their phenolic and sugar components, were shown to reduce the cellular adhesion abilities of cancer cells, in this in vitro study.(63)

With these types of cancers having a high risk of metastases, while clinical studies are needed, these anti-metastatic effects of Mānuka honey, offer much promise.

Mechanisms of action

Several potential mechanisms of action are evident for potential preventive effects of Mānuka honey against cancer development. Oxidative stress and increased levels of free radicals is involved in cancer formation, and Mānuka honey is rich in antioxidant phenolic acids and polyphenols with in vitro antiproliferative activity against several types of cancer.(41, 54)

A low immune status is well known to increase the risk of cancer development. Italian research showing an ability of Mānuka honey to modulate the immune system by inducing immunostimulatory and anti-inflammatory effects, could potentially help with chemoprevention.(64)  It’s antimicrobial actions may also be useful, given that chronic infections such as Epstein-Barr virus, human papilloma virus and Helicobacter pylori, are also associated with a higher risk of cancer development.

Possible Chemotherapy adjunct?

Recent research involving an international team of researchers, has provided evidence of sensitising effects of Mānuka honey to chemotherapy  against colon cancer cells.(62) Mānuka honey was associated with downregulation of pro-angiogenic factors, and enhanced the cytotoxicity of 5-fluorouracil. This and other studies by the Italian team suggest a potential of Mānuka honey as an adjunctive intervention to increase the efficacy of this and potentially other anticancer drugs against colon cancer cells.(59, 61, 62)

Protective effects of honey against cisplatin-induced renal toxicity, has been shown both in animals and in patients with cancer.(65)  A recent review found significant evidence for an ability of honey to mitigate toxicity from anticancer chemotherapy toxicity, with multiple mechanisms for this being evident. These included inhibition of oxidative stress and NF-κB-mediated inflammation, the dampening of caspase-dependent apoptosis cascades, and several other potential molecular mechanisms.(42)  

Oral mucositis

Oral mucositis (stomatitis) is a serious complication of cancer chemotherapy resulting in pain, an inability to eat or drink, and often weight loss. It occurs in a large proportion of paediatric patients being treated for cancer, and in patients undergoing treatment with radiotherapy or chemotherapy for head, neck and breast cancers, and is difficult to treat in clinical practice.

At least fifteen clinical trials have now taken place involving Mānuka and several other honey types from around the world as an oral application for oral mucositis, with most finding positive results.(66-69) These include a clinical trial using Mānuka honey in children with leukaemia suffering from chemotherapy-induced oral mucositis.(70)

Summary

Honey is a natural product used since ancient times for its nutritive and therapeutic value.  Despite this extensive history, and a huge body of laboratory data now implicating its usefulness for a large number of serious health conditions in humans, clinical applications have been limited until recently, by there being few human trials, and widespread variability in honey quality.

Research is increasingly providing compelling evidence for preventative as well as potential clinical applications of different types of Mānuka honey, in modern medicine. This research, mostly undertaken outside of Aotearoa New Zealand, suggests exciting therapeutic value particularly in the management of infectious disease and cancer, both highly prevalent and expensive conditions which have a high burden on patients and healthcare systems.

Aotearoa New Zealand was the first country in the world to successfully produce and commercialise grades of honey suitable to be prescribed and sold or dispensed for serious medical conditions. Several other countries are now developing or have already developed their own medical honeys, and are putting these through clinical trials for a range of conditions.

In order to retain and further build Aotearoa New Zealand’s international reputation as a country producing some unique health promoting honeys, significant investment and a world class regulatory environment is needed. Therapeutic claims should be legally possible for products which have achieved clinical trial validation and meet quality standards. Without this, further innovation and product development may be compromised, while other countries forge ahead with developments, in what is certain to continue to be a growing global industry.

Given the extent of the many promising preclinical findings into the potential of Mānuka and other honeys to improve outcomes in cancer patients, more controlled clinical studies are needed. They should involve further work on animal models of cancer, as well as pilot clinical studies using phytochemically characterised types of honey, as an adjunctive treatment in patients receiving chemotherapy or radiotherapy.(9)

While much of the Mānuka honey industry here has gone through difficult times in the aftermath of Covid-19 and challenges in export markets, new and ongoing research suggests there is much more to this treasured local natural product, than just its value as a food.

References:

  1. Zaidi, M. Z., & Sharma, J. (2019). Honey and its beneficial therapeutic effects: A review. Journal of Pharmacognosy and Phytochemistry, 8(4), 1056-1061.
  2. Nikhat S, Fazil M. History, phytochemistry, experimental pharmacology and clinical uses of honey: A comprehensive review with special reference to Unani medicine. J Ethnopharmacol. 2022 Jan 10;282:114614. 
  3. Aw Yong PY, Islam F, Harith HH, Israf DA, Tan JW, Tham CL. The Potential use of Honey as a Remedy for Allergic Diseases: A Mini Review. Front Pharmacol. 2021 Jan 26;11:599080
  4. Jodidio M, Schwartz RA. Honey therapies for dermatological disorders: more than just a sweet elixir. Int J Dermatol. 2024 Apr;63(4):422-430. 
  5. Khataybeh B, Jaradat Z, Ababneh Q. Anti-bacterial, anti-biofilm and anti-quorum sensing activities of honey: A review. J Ethnopharmacol. 2023 Dec 5;317:116830.
  6. Palma-Morales M, Huertas JR, Rodríguez-Pérez C. A Comprehensive Review of the Effect of Honey on Human Health. Nutrients. 2023 Jul 6;15(13):3056.
  7. Abuelgasim H, Albury C, Lee J. Effectiveness of honey for symptomatic relief in upper respiratory tract infections: a systematic review and meta-analysis. BMJ Evid Based Med. 2021 Apr;26(2):57-64.
  8. Rasmussen PL, Manuka (Leptospermum scoparium) – A Review. Phytonews 1, September 1998, published by Phytomed Medicinal Herbs Ltd, Auckland, New Zealand.    ISSN 1175-0251.
  9. Riley Murdoch, Maori Healing and Herbal, published by Viking Sevenseas, Paraparaumu, New Zealand, 1994
  10. Mathew C, Tesfaye W, Rasmussen P, Peterson GM, Bartholomaeus A, Sharma M, Thomas J. Mānuka Oil-A Review of Antimicrobial and Other Medicinal Properties. Pharmaceuticals (Basel). 2020 Oct 26;13(11):343. 
  11. Wang S, Qiu Y, Zhu F. An updated review of functional ingredients of Manuka honey and their value-added innovations. Food Chem. 2024;440:138060.
  12. Allen KL, Molan PC, Reid GM. A survey of the antibacterial activity of some New Zealand honeys. J Pharm Pharmacol. 1991 Dec;43(12):817-22. 
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ADHD and useful Phytomedicines

On By philrasmIn Anxiety, Mental Health, Plant Medicine, StressLeave a comment

Introduction

ADHD (Attention deficit hyperactivity disorder) is a chronic neuro-behavioural condition characterised by a persistent pattern of inattention, hyperactivity and impulsiveness. It can disrupt education and social development of children and teenagers, and have a huge impact on a person’s life, yet is often undiagnosed.

The DSM (Diagnostic and Statistical Manual of Mental Disorders) describes three subtypes of ADHD. These include: ADHD-Inattentive type (ADHD-I), ADHD-Hyperactive/impulsive (ADHD-H), and ADHD-Combined type (ADHD-C). The presentation can change over time though, and a diagnosis provided at one specific time may differ from that provided at another time in a person’s life.

While reported rates of ADHD are higher than in the past, this is likely to be at least partially due to better recognition of the condition. It is a common condition among young children, and an estimated 50% of these retain ADHD symptoms for the rest of their lives. Research suggests around 5-8 percent of the population has ADHD but only 1-2 percent are diagnosed.  Diagnosis rates have historically been higher in boys than in girls, although rates are now thought to be similar for both genders.

Diagnosis of ADHD can be difficult and there is no diagnostic biological marker. Symptoms should have been present and persistent for a minimum of six months prior to the age of 12, are maladaptive, and cannot be explained by other psychiatric or medical disorders. However, often symptoms may not meet the criteria for a formal diagnosis of ADHD, despite causing significant issues in learning, social and family relationships.  

Symptoms

Impairing levels of inattention, disorganisazion, and/or hyperactivity-impulsivity, are key features of ADHD.  These symptoms are excessive for the age or development level.

In a classroom setting, children with ADHD will often tune out or appear to daydream. They can talk a lot, interrupt others and are unable to wait for their turn. Such children are frequently called out in class or a group or become known as the ‘class clown’, or the subject of bullying. These behaviours can exacerbate difficulties in ‘fitting in’ with peer groups or societal expectations.

While not an anxiety disorder as such, a large proportion of children with ADHD have coexisting psychiatric disorders, including but not limited to depression, bipolar disorder, autism spectrum disorders, eating disorders, and anxiety disorders (1). Adults with ADHD also often have an anxiety or substance use disorder, which can mask ADHD symptoms, sometimes for many years(2). Those with ADHD are also more likely to do dangerous and impulsive things.

Aetiology

Several potentially aetiological factors have been identified. ADHD has a significant familial and genetic predisposition, although the extent of the latter is somewhat contentious. Approximately 30% of children with epilepsy have ADHD .

Environmental contributions such as early childhood exposure to toxic heavy metals (especially lead) or phthalates, have received increased attention in recent years(3-7). Air pollution has also been associated with neurodevelopmental disorders including ADHD(8).

Other studies have associated ADHD with a higher prevalence of smoking, alcohol consumption, and excessive screen time among adolescents(9-11). Dysfunctions have been reported with BDNF (Brain derived neurotrophic factor) metabolism, dopaminergic neurotransmission, and with neurochemical parthways within the prefrontal cortex(12, 13).

However, these associations are complex, and to what extent they are aetiological versus outcome manifestations in those with ADHD, remains debatable.

Increasing greenness exposure or ‘nature medicine’, is likely to help protect against ADHD and other mental health conditions. A large New Zealand study has reported that children who always lived in a rural area after 2 years of age, were significantly less likely to develop ADHD(14 ).  Similar findings were reported in a German study, with residential greenness being protective, but air pollution being a risk factor(15).

Dietary factors may be contributory in some cases. Inattention was negatively correlated with fruit and vegetable consumption and a healthy dietary pattern, in a large population-based Swedish study (16). Some evidence suggests Vitamin D deficiency may be relevant to the pathogenesis of ADHD and autism, and supplementation with this as well as zinc and magnesium, both important cofactors in dopamine metabolism, may be useful(17, 18).

Treatments

The use of stimulant medications and particularly methylphenidate, is the usual treatment for ADHD. Methylphenidate is structurally similar to amphetamines, inhibits the reuptake of dopamine and noradrenaline, and leads to symptom improvement in around seventy percent of patients.  

Dexamphetamine is also occasionally used, as is its prodrug lisdexamfetamine. The selective noradrenaline reuptake inhibitors atomoxetine and viloxazine, are sometimes prescribed. These and alpha-2 adrenergic agonists guanfacine and clonidine, which stimulate noradrenergic neurotransmission in the prefrontal cortex, are occasionally used when stimulants or these drugs are not suitable or tolerated.

Reduced appetite, sleeping difficulties, nausea and abdominal pain are the most common adverse events to stimulant medication. Rare but serious adverse events can include cardiac problems, weight loss, mood fluctuations and psychotic disorders. These can cause concern as treatment can continue from childhood into adolescence and beyond.

Official guidelines discourage the use of medication in children under the age of six, although these are sometimes prescribed by a specialist in severe cases. ‘Off-label’ use of medicines in this age group, is increasingly common. However, few studies have taken place involving the use of ADHD drugs in very young children, and safety and efficacy data is generally lacking. 

Treatment programmes should also include psychological interventions such as counselling or psychotherapy, with patients’ and parents’ preferences and need for such treatment, always considered(19).  It is also often beneficial to not only treat a child, teenager or adult with ADHD, but also offer phytotherapy or other treatment support to their parents, partners or other family members. Adjunctive phytomedicines and sometimes lifestyle and dietary changes, can be very helpful.

Of note is that there are several disparities  in treatment guidelines and the selection and sequencing of various medications  in different countries. Danish guidelines for instance, do not recommend methylphenidate, lisdexamfetamine or atomoxetine as first line treatment options, while German guidelines provide specific drug recommendations tailored to individual comorbidities (1). A greater emphasis on psychotherapy, school and parental support systems and a higher bar before methylphenidate medication is trialed, is applied in some jurisdictions, particularly those where health care expenditure per capita is higher.

Some Useful Phytomedicines

An individualised treatment protocol incorporating plant medicines can offer much to ADHD patients. They can also help children who are resistant to stimulant medications, or those who wish to not take these medicines, or to keep drug dosage needs as low as possible.

Treatment selection depends on the particular type of ADHD, its symptomatology, and of course individual patient needs and wishes.  Given the diverse presentation of ADHD, a range of phytomedicines should be considered. An individualised but ‘trial and error’ approach is recommended, but desirable actions can include neuroprotection, cognition enhancement, anxiolytic and stimulant properties. Any use of other medications or presence of other health conditions should be taken into account.  Addressing other co –existing mental or physical health issues, can in itself often produce significant benefits, and sometimes avoid the need for additional drug-based interventions.

Where restlessness or accompanying anxiety are part of the symptomatology, anxiolytic and relaxant phytomedicines can be useful.  They include Bacopa, Chamomile, Holy basil, Kava, Lavender, Lemon balm, Skullcap, Passionflower, Skullcap, Valerian, Withania and more(20).  Many of these (Ginkgo, Bacopa, Lemon Balm, Valerian, Withania) also have neuroprotective activities and when used appropriately, can help improve cognition and learning outcomes.

Leaves of the Indian plant Bacopa (Bacopa monniera) have been used for anxiolytic and memory enhancing purposes for centuries. As with Ginkgo and Lemon Balm, it is neuroprotective and may help with cognition and attention deficit disorders. It is frequently used in the management of ADHD and autism in children and teenagers.

A recent 14 week Australian clinical trial into Bacopa’s effects in boys with ADHD aged 6-14, found no significant behavioural improvement. However, improvements occurred in their sleep routine and in cognitive flexibility and interpersonal problems(21).  Reduced symptoms of restlessness and improvement in self control, were reported in a smaller open label study in children with ADHD(22).  It is safe in children, although as a liquid its bitter taste can be an issue, particularly as dosage needs tend to be quite high.

Ginkgo (Ginkgo biloba) can be helpful in ADHD or for cognitive deficits in children, and combines very well with other psychoactive phytomedicines such as St Johns wort and anxiolytics. It is also hepatoprotective, and can be helpful when concomitant drug medications which can cause liver or kidney damage, are being taken.

Lemon balm (Melissa officinalis) is another generally safe anxiolytic, and like chamomile is indicated particularly where gastrointestinal upsets or eating disorders are associated with feelings of anxiety(23).  It can also help with cognition in teenagers, though large doses are generally required.

The Chinese medicinal herb Rehmannia (Rehmannia glutinosa) was reported to reduce impulsive and spontaneous behaviour and ameliorate hippocampal neurodevelopmental abnormalities an a rat model of ADHD(24).

Passionflower (Passiflora incarnata), has been shown to help control anxiety in several studies involving adult patients(25) . A combination with St Johns wort and Valerian was reported to reduce nervous agitation in children aged between 6 and 12 years(26)  .  Potential benefits in ADHD and autism, have been reported(27, 28), although larger and better controlled clinical trials are needed.

Kava (Piper methysticum) also has a place in the management of ADHD in some children and adults. Its effectiveness in treating anxiety has been affirmed through several clinical trials and meta-analyses. It may also exhibit a mild antipsychotic effect and be helpful for children with OCD or autism.

Withania (Withania somnifera) is a useful allrounder when it comes to anxiety and stress-associated conditions. As with all adaptogens, it acts on multiple relevant sites of action, neurotransmitter and hormonal systems(29), and is often an effective component of the treatment of ADHD in both young and older people.

St Johns wort (Hypericum perforatum) is our best known clinically effective antidepressant, and I have used it successfully in many hundreds of patients, over the past thirty years. While beyond the scope of this article, concerns about its safety and interactions with other medications, are also often unjustified, this depending on the type of St Johns wort used, and its phytochemical profile(30).

ADHD is now recognised as a common neurodivergent condition, which if not well managed and treated can cause enormous emotional and mental suffering in children, teenagers, adults and their friends and families.

Summary

As with most chronic health conditions, early diagnosis and interventions which are natural and affordable and incorporate a selfcare approach, can produce huge benefits and avoid the need for more serious treatments later on.  While not denying the usefulness of drug medications such as methylphenidate and atomoxetine, it is concerning given the frequency at which these can cause adverse events, that they are being so widely prescribed and relied upon.

If the need for a long term drug prescription can be avoided or drug dosage requirements kept to a minimum through the concomitant use of more natural interventions, then this is a preferred approach. While there is a need for further and larger clinical trials involving phytomedicines in the treatment of ADHD, many medicinal plants exhibit pharmacological actions of benefit to those dealing with this condition, and treatment targeted for each person’s individual clinical presentation, can produce huge benefits.

References:

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  17. Hemamy M, Pahlavani N, Amanollahi A, Islam SMS, McVicar J, Askari G, Malekahmadi M. The effect of vitamin D and magnesium supplementation on the mental health status of attention-deficit hyperactive children: a randomized controlled trial. BMC Pediatr. 2021 Apr 17;21(1):178
  18. Lange KW, Lange KM, Nakamura Y, Reissmann A. Nutrition in the Management of ADHD: A Review of Recent Research. Curr Nutr Rep. 2023 Sep;12(3):383-394.
  19. Schatz NK, Fabiano GA, Cunningham CE, dosReis S, Waschbusch DA, Jerome S, Lupas K, Morris KL. Systematic Review of Patients’ and Parents’ Preferences for ADHD Treatment Options and Processes of Care. Patient. 2015 Dec;8(6):483-97.
  20. https://herbblurb.com/2017/02/03/why-herbs-should-be-the-first-choice-of-treatment-for-acute-anxiety/
  21. Kean JD, Downey LA, Sarris J, Kaufman J, Zangara A, Stough C. Effects of Bacopa monnieri (CDRI 08®) in a population of males exhibiting inattention and hyperactivity aged 6 to 14 years: A randomized, double-blind, placebo-controlled trial. Phytother Res. 2022;36(2):996-1012.
  22. Dave UP, Dingankar SR, Saxena VS, et al. An open-label study to elucidate the effects of standardized Bacopa monnieri extract in the management of symptoms of attention-deficit hyperactivity disorder in children. Adv Mind Body Med. 2014;28(2):10-15.
  23. https://herbblurb.com/2021/01/29/lemon-balm-a-true-tonic-for-stress/
  24. Sun R, Yuan H, Wang J, Zhu K, Xiong Y, Zheng Y, Ni X, Huang M. Rehmanniae Radix Preparata ameliorates behavioral deficits and hippocampal neurodevelopmental abnormalities in ADHD rat model. Front Neurosci. 2024 May 30;18:1402056.
  25. Janda K, Wojtkowska K, Jakubczyk K, Antoniewicz J, Skonieczna-Żydecka K. Passiflora incarnata in Neuropsychiatric Disorders-A Systematic Review. Nutrients. 2020;12(12):3894. 
  26. Trompetter I, Krick B, Weiss G. Herbal triplet in treatment of nervous agitation in children. Wien Med Wochenschr. 2013;163(3-4):52-57. 
  27. Amini F, Amini-Khoei H, Haratizadeh S, et al. Hydroalcoholic extract of Passiflora incarnata improves the autistic-like behavior and neuronal damage in a valproic acid-induced rat model of autism. J Tradit Complement Med. 2023;13(4):315-324.
  28. Golsorkhi H, Qorbani M, Sabbaghzadegan S, Dadmehr M. Herbal medicines in the treatment of children and adolescents with attention-deficit/hyperactivity disorder (ADHD): An updated systematic review of clinical trials. Avicenna J Phytomed. 2023;13(4):338-353.
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Rosemary – a herbal protector

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Introduction

Rosemary (Rosmarinus officinalis, now known as Salvia Rosmarinus) is a well known plant commonly found in gardens and parks around the world. Its strongly aromatic leaves and prolific flowers are a magnet to bees and other pollinating insects, and its traditional culinary applications are widely embraced.

Medicinal properties of rosemary are of course also substantial, and ancient texts extol many virtues.  In The Physicians of Myddfai, a compilation of medieval recipes written in the 13th century at Myddfai in south Wales, it says of rosemary: “by washing each morning with the decoction and allowing it to dry naturally, the aged will retain a youthful look as long as they live”.

These appealing claims reflect rosemary’s antioxidant actions and multiple influences on cellular degradation and aging processes, and indicate the likely presence of other benefits when taken internally on a regular basis. In fact research is increasingly revealing its protective effects against many negative influences on health.

Protection against environmental toxins

Rosemary’s rich content of triterpene and other phenolic acid constituents such as rosmarinic, olenolic and ursolic acids contribute to its antioxidant and many antimicrobial activities. These help protect meat(1, 2), dairy products(3), fish(4,5) and other foods against spoilage and vegetable oils against oxidation(6). Apart from being a flavour enricher, these are longstanding traditional uses.

Toxic compounds released or deposited within the soil, air or waterways by human activities are now being revealed by more and more science, as having harmful outcomes on living organisms and their environment.

Heavy metals such as cadmium and lead are amongst these, and are widely distributed in the environment as a result of mining and combustion emissions. Rosemary protects against liver damage due to both of these, and against kidney damage from lead exposure(7, 8). Addition of rosemary to fresh water reduces cadmium accumulation in the tissues of freshwater fish, and associated oxidative stress(9). Washing fish in a rosemary solution, has been reported to reduce lead content(10). Applications to remove lead from wastewater, have also been suggested(11).

Such protective actions against toxic environmental contaminants have recently been extended to a remediation ability for rosemary against accumulation of cadmium and lead in a busy urban environment.  Rosemary plants inoculated with a mycorrhizal fungus (Funneliformis mosseae) thrived in cadmium and lead contaminated soils, and mitigated urban traffic pollution in dense traffic conditions(12).

Carnosic acid, another polyphenolic compound found in rosemary, shows a dose-related protective effect against neurotoxicity induced by dieldrin, an organochlorine pesticide implicated in neurological conditions such as Parkinson’s disease(13).

Antispasmodic, anti-histaminic and anti-allergic actions on the respiratory tract, have recently been demonstrated for several rosemary constituents, including rosmarinic, carnosic and ursolic acids, rosmanol and carnosol(14). Airborne environmental pollutants are becoming increasingly linked with a diverse array of chronic health conditions in humans, and these actions are therefore relevant.

Given its many chemopreventive properties against harmful environmental toxins, it is hardly surprising that rosemary constituents such as rosmarinic and carnosic acids have demonstrated effective anti-proliferative properties against various cancers, and are the subject of research to develop new cancer treatments(15, 16). Potential synergistic effects with certain anti-cancer drugs, have also been suggested from in vitro and pre-clinical studies(17).

Reducing harm from lifestyle factors

Many diets and lifestyles in the 21st century are associated with conditions such as liver disorders, weight gain, cardiovascular disease and diabetes type 2. As such, plant-based interventions to help reduce some of the negative health impacts of a poor diet or sedentary lifestyle, and provide an element of prevention against these highly prevalent medical conditions, are of interest.

Many benefits were reported following administration of a rosemary extract to young rats feed a high fat western style diet(18). These included reduced liver fat, liver cholesterol and triglycerides and increased plasma levels of HDL cholesterol.  Rats fed high doses of rosemary extract also had increased fasting plasma concentrations of Glucagon-like peptide-1 (GLP-1), suggesting possible benefits in weight management and diabetes. Modulation of the gut microbiota composition also occured.

Amelioration of the neurotoxic effects of the food flavour enhancer monosodium glutamate, has been reported in animal studies(19).

The various pharmacological effects of rosemary and its key constituents, also  align well with a potential role in the management of metabolic syndrome, a constellation of complex coexisting cardiometabolic risk factors such as hyperglycemia, dyslipidemia, inflammation, abdominal obesity, vascular disorders and hypertension that raise the risk of diabetes mellitus and cardiovascular disease(20). Protection against nephropathy in diabetic rats, and enhancement of the nephroprotective effects of insulin, has been reported following supplementation with rosemary oil(21).

Many studies have now shown hepatoprotective effects for rosemary(22-24). A combination of rosemary with hawthorn protected against alcoholic liver disease, in a rat model(25).

Collectively, these studies suggest protective effects on several common conditions related to obesity, excess alcohol or poor diets.

Protecting male fertility

Declining human fertility is a growing concern in recent decades. While reasons for this are numerous, exposure to airborne pollutants and environmental toxins such as microplastics and nanoplastics and synthetic insecticides, are known contributory factors(26, 27).

Recent research showing that a forty five day pretreatment with rosemary leaf extract alleviated the damaging effects on the adrenal glands and testes following exposure to the synthetic pesticide cypermethrin, are promising. Restoration of spermatogenesis (sperm cell production) was also reported(28). Previous work found co-administration of rosemary with etoposide reduced the extent of testicular injury and DNA damage induced by this antineoplastic drug in male rats(29). These studies suggest a potential by rosemary to guard against infertility, as an outcome of chemotherapy or environmental toxin exposure.

References:

  1. Gavriil A, Zilelidou E, Papadopoulos AE, et al. Evaluation of antimicrobial activities of plant aqueous extracts against Salmonella Typhimurium and their application to improve safety of pork meat. Sci Rep. 2021;11(1):21971.
  2. Olivas-Méndez P, Chávez-Martínez A, Santellano-Estrada E, et al. Antioxidant and Antimicrobial Activity of Rosemary (Rosmarinus officinalis) and Garlic (Allium sativum) Essential Oils and Chipotle Pepper Oleoresin (Capsicum annum) on Beef Hamburgers. Foods. 2022;11(14):2018.
  3. Gad, A. and Sayd, A. (2015) Antioxidant Properties of Rosemary and Its Potential Uses as Natural Antioxidant in Dairy Products—A Review. Food and Nutrition Sciences, 6, 179-193.
  4. Aala J, Ahmadi M, Golestan L, Shahidi SA, Shariatifar N. Effect of multifactorial free and liposome-coated of bay laurel (Laurus nobilis) and rosemary (Salvia rosmarinus) extracts on the behavior of Listeria monocytogenes and Vibrio parahaemolyticus in silver carp (Hypophthalmichthys molitrix) stored at 4 °C. Environ Res. 2023;216(Pt 2):114478.
  5. Abd El-Fatah RA, Rozan MA, Ziena HM, et al. Improvement of Microbial Quality, Physicochemical Properties, Fatty Acids Profile, and Shelf Life of Basa (Pangasius bocourti) Fillets during Chilling Storage Using Pepsin, Rosemary Oil, and Citric Acid. Foods. 2023;12(22):4170.
  6. Song X, Sui X, Jiang L. Protection Function and Mechanism of Rosemary (Rosmarinus officinalis L.) Extract on the Thermal Oxidative Stability of Vegetable Oils. Foods. 2023;12(11):2177. 
  7. Mężyńska M, Brzóska MM. Review of polyphenol-rich products as potential protective and therapeutic factors against cadmium hepatotoxicity. J Appl Toxicol. 2019;39(1):117-145
  8. Mohamed WA, Abd-Elhakim YM, Farouk SM. Protective effects of ethanolic extract of rosemary against lead-induced hepato-renal damage in rabbits. Exp Toxicol Pathol. 2016;68(8):451-461.
  9. Al-Anazi MS, Virk P, Elobeid M, Siddiqui MI. Ameliorative effects of Rosmarinus officinalis leaf extract and Vitamin C on cadmium-induced oxidative stress in Nile tilapia Oreochromis niloticus. J Environ Biol. 2015;36(6):1401-1408.
  10. Salim A, Hassanin MA, Zohair A. A simple procedure for reducing lead content in fish. Food Chem Toxicol. 2003;41(4):595-597. doi:10.1016/s0278-6915(02)00259-4
  11. Zarrabi A, Ghasemi-Fasaei R. Preparation of green synthesized copper oxide nanoparticles for efficient removal of lead from wastewaters. Int J Phytoremediation. 2022;24(8):855-866.
  12. Alinejad Z, Abtahi SA, Jafarinia M, Yasrebi J. The impact of arbuscular mycorrhizal symbiosis, Funneliformis mosseae, on rosemary phytoremediation ability under urban traffic. Int J Phytoremediation. 2024;26(2):250-262.
  13. Park JA, Kim S, Lee SY, et al. Beneficial effects of carnosic acid on dieldrin-induced dopaminergic neuronal cell death. Neuroreport. 2008;19(13):1301-1304.Atef RM, Abdel Fattah IO, Mahmoud OM, Abdel-Rahman GM, Salem NA. Protective effects of Rosemary extract and/or Fluoxetine on Monosodium Glutamate-induced hippocampal neurotoxicity in rat. Rom J Morphol Embryol. 2021;62(1):169-177.
  14. Farhadi F, Baradaran Rahimi V, Mohamadi N, Askari VR. Effects of rosmarinic acid, carnosic acid, rosmanol, carnosol, and ursolic acid on the pathogenesis of respiratory diseases. Biofactors. 2023;49(3):478-501.
  15. Sirajudeen F, Bou Malhab LJ, Bustanji Y, et al. Exploring the Potential of Rosemary Derived Compounds (Rosmarinic and Carnosic Acids) as Cancer Therapeutics: Current Knowledge and Future Perspectives. Biomol Ther (Seoul). 2024;32(1):38-55.
  16. Bouammali H, Zraibi L, Ziani I, et al. Rosemary as a Potential Source of Natural Antioxidants and Anticancer Agents: A Molecular Docking Study. Plants (Basel). 2023;13(1):89.
  17. Bouzas A, Gómez de Cedrón M, Colmenarejo G, et al. Phenolic diterpenes from Rosemary supercritical extract inhibit non-small cell lung cancer lipid metabolism and synergise with therapeutic drugs in the clinic. Front Oncol. 2022; Nov 9:12:1046369.
  18. Madsen S, Bak SY, Yde CC, et al. Unravelling Effects of Rosemary (Rosmarinus officinalis L.) Extract on Hepatic Fat Accumulation and Plasma Lipid Profile in Rats Fed a High-Fat Western-Style Diet. Metabolites. 2023;13(9):974.
  19. Hassani FV, Shirani K, Hosseinzadeh H. Rosemary (Rosmarinus officinalis) as a potential therapeutic plant in metabolic syndrome: a review. Naunyn Schmiedebergs Arch Pharmacol. 2016;389(9):931-949.
  20. Fareed SA, Yousef EM, Abd El-Moneam SM. Assessment of Effects of Rosemary Essential Oil on the Kidney Pathology of Diabetic Adult Male Albino Rats. Cureus. 2023;
  21. al-Sereiti MR, Abu-Amer KM, Sen P. Pharmacology of rosemary (Rosmarinus officinalis Linn.) and its therapeutic potentials. Indian J Exp Biol. 1999;37(2):124-130.
  22. Hegazy AM, Abdel-Azeem AS, Zeidan HM, Ibrahim KS, Sayed EE. Hypolipidemic and hepatoprotective activities of rosemary and thyme in gentamicin-treated rats. Hum Exp Toxicol. 2018;37(4):420-430.
  23. Guimarães NSS, Ramos VS, Prado-Souza LFL, et al. Rosemary (Rosmarinus officinalis L.) Glycolic Extract Protects Liver Mitochondria from Oxidative Damage and Prevents Acetaminophen-Induced Hepatotoxicity. Antioxidants (Basel). 2023;12(3):628.
  24. Martínez-Rodríguez JL, Gutiérrez-Hernández R, Reyes-Estrada CA, et al. Hepatoprotective, Antihyperlipidemic and Radical Scavenging Activity of Hawthorn (Crataegus oxyacantha) and Rosemary (Rosmarinus officinalis) on Alcoholic Liver Disease. Altern Ther Health Med. 2019;25(4):54-63.
  25. Atef RM, Abdel Fattah IO, Mahmoud OM, Abdel-Rahman GM, Salem NA. Protective effects of Rosemary extract and/or Fluoxetine on Monosodium Glutamate-induced hippocampal neurotoxicity in rat. Rom J Morphol Embryol. 2021;62(1):169-177.
  26. He Y, Yin R. The reproductive and transgenerational toxicity of microplastics and nanoplastics: A threat to mammalian fertility in both sexes. J Appl Toxicol. 2024;44(1):66-85.
  27. Liu J, Dai Y, Li R, Yuan J, Wang Q, Wang L. Does air pollution exposure affect semen quality? Evidence from a systematic review and meta-analysis of 93,996 Chinese men. Front Public Health. 2023;11:1219340.
  28. Ali Hasan S, Al-Rikaby AA. Evaluating the Influence of Rosemary Leaves Extract on Hormonal and Histopathological Alterations in Male Rabbits Exposed to Cypermethrin. Arch Razi Inst. 2023;78(3):797-805.Ramadan KS, Khalil OA, Danial EN, Alnahdi HS, Ayaz NO. Hypoglycemic and hepatoprotective activity of Rosmarinus officinalis extract in diabetic rats. J Physiol Biochem. 2013;69(4):779-783. 
  29. Tousson E, Bayomy MF, Ahmed AA. Rosemary extract modulates fertility potential, DNA fragmentation, injury, KI67 and P53 alterations induced by etoposide in rat testes. Biomed Pharmacother. 2018;98:769-774.