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).

References:

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  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.
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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.
  28. Wicaksono WA1Jones EE, Monk J, Ridgway HJ. The Bacterial Signature of Leptospermum scoparium (Mānuka) Reveals Core and Accessory Communities with Bioactive Properties, PLoS One. 2016 Sep 27;11(9):e0163717.
  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.

Ligustrum lucidum – synergistic effects with other herbs and drugs in the management of cancer, bone marrow suppression, and depression?

I’ve written previously about the many medicinal properties of the dark red fruits of Ligustrum lucidum (Glossy Privet), the most invasive tree in New Zealand(1, 2). These include prophylactic effects against osteoporosis, beneficial effects on bone growth and strength, protection actions against liver toxins, and possible applications for one of our biggest and growing health burdens, diabetes mellitus.

During the March to June New Zealand Covid-19 Lockdown, I became more attentive to my local environment, and being a herbalist, plants featured prominently in this. Plants in our individual immediate environments can be useful as a source of food, recreation, exercise, de-stressing, and other survival related concerns, including as medicines.

It is however, a sad reflection on the current human disconnect from our local environment, that while this tree offers an evidence-based and readily available partial solution to common health problems experienced by thousands of New Zealanders, hardly anyone seems to know about this, or consider utilising this plant for something useful. Just as we viewed Mānuka many years ago, when it was cursed as an unwanted scrubweed by farmers, until its numerous medicinal properties became recognised again.

Ligustrum fruits are also used as an adjunct in cancer therapy(3). Inhibitory effects against benzopyrene and aflatoxin induced cancer(3, 4), potential applications in the treatment of liver(5) and brain(6) cancer, and enhanced sensitivity of human colorectal carcinoma cells to the chemotherapy drug doxorubicin(7), have been reported.

During chemotherapy treatment of cancer patients, a common and serious adverse event is myelosuppression, damage to the bone marrow resulting in decreased production of blood cells (haematopoiesis), and lowered immunity.

Ginseng (Panax ginseng) has been reported to ameliorate myelosuppression produced by the chemotherapy drug 5-flurouracil(8). Recent research now suggests that Ligustrum also may help with the clinical management of this condition, and that a combination of Ligustrum with Panax ginseng, even more so(9).

Mice who developed myelosuppression following administration of the chemotherapy drug cyclophosphamide, were given aqueous extracts of either Panax ginseng, Ligustrum lucidum, or a combination of these two herbs. Both ginseng and Ligustrum each individually increased levels and activity of several different haemotopoietic factors including peripheral blood cells, bone marrow cells and colony-forming unit-granulocyte macrophages, and upregulated cytokines involved in haematopoiesis. These protective effects against bone marrow suppression were even greater though, when a combination of Ginseng and Ligustrum was used.

Combining Ligustrum with Ginseng and using as an adjunctive treatment during chemotherapy treatment, may therefore help manage the negative effects on bone marrow thus enabling an optimal chemotherapy regimen to be implemented. Preventative effects against chemotherapy-induced myelosuppression have also been reported for a combination of Ligustrum with Eleutherococcus senticosus(10).

Other recent research on Ligustrum suggests it may also combine well with the highly regarded medicinal fungus Cordyceps(11). The Cordyceps genus are a type of fungi requiring an insect or insect larvae as host. Cordyceps has been used in TCM for over 300 years to treat a diverse range of conditions, including respiratory, kidney, liver and cardiovascular diseases, low libido, impotence, hyperlipidaemia, hyperglycaemia, fatigue, convalescence, and to promote energy(12).  Cordyceps is also gaining interest as a potential anti-cancer agent(13, 14), including as an inhibitor of metastases (secondary cancers), and as an adjunct during chemotherapy and radiotherapy(15, 16).

Unlike the closely related Cordyceps sinensis, a species restricted to a specific zone and insect host which has been overharvested in the wild and now endangered, Cordyceps militaris is cultivated on a range of host insects, and still contains significant levels of a key active compound cordycepin (3-deoxyadenosine). However, upon entering the body cordycepin is quickly metabolized into an inactive metabolite 3′-deoxyinosine, by the enzyme adenosine deaminase which is widely distributed in mammalian blood and tissues, thus limiting its activity when administered alone.

However, researchers in Shanghai have recently shown that oleanolic acid and ursolic acid, key triterpenoid constituents extracted from Ligustrum lucidum fruits, act as potent adenosine deaminase inhibitors. This suggests combining cordycepin or Cordyceps with Ligustrum, may be another useful combination in clinical practice(11).

Finally, potential applications of Ligustrum lucidum in the management of some types of depression, have recently been revealed(17).

Depression sometimes develops as a result of a head injury or in neurodegenerative disorders such as Parkinson’s disease or dementia, with central nervous system inflammation (neuroinflammation) being a common underlying factor. Recent clinical and preclinical evidence also suggests that this inflammation in nerve tissues may be a key factor involved in the onset of major depression(18).

Phenol glycosides from Ligustrum lucidum were evaluated for their effects on neuroinflammation and depressive-like behavior in mice. Mice received the Ligustrum derived extract for two weeks prior to treatment with lipopolysaccharide (LPS), which induced an inflammatory reaction. Ligustrum phenol glycoside pre-treatment ameliorated LPS-induced depressive-like behaviors, effects associated with reduced neuroinflammation of the hypothalamus, less activation of microglia (a type of brain cell) and inflammatory cytokine production, and improvement in vitamin D metabolism.

Like hundreds of other clever plants, Ligustrum lucidum has become so well colonised in New Zealand it is classed as a ‘noxious’ weed. The dark purple brown berries that appear in autumn make a wonderful healthy feast for our large bird population who excrete the seeds far and wide. And like lots of introduced plants endemic in our environment (weeds), it provides a readily accessible, free or cheap source of plant medicine with many potential benefits.

The above research on this plant is just some of that published this year to date. Perhaps assigning ‘shovel ready’ unemployed Kiwis to harvest the berries at the same time as culling numbers of this tree and undertaking further research towards processing these into natural medicines, might improve human and animal health, reduce medical care costs and prevent chronic debilitating illnesses. This would make sense in the Covid-19 plighted economy we are now living in.

 

Refs:

  1. Rasmussen PL, https://herbblurb.com/2016/03/10/ligustrum-lucidum-noxious-weed-or-useful-osteoporosis-treatment/
  2. Rasmussen PL, https://herbblurb.com/2019/01/24/honeysuckle-and-other-useful-weeds-surrounding-us/
  3. Wong BY et al, Mutat Res 1992; 279(3):209-216.
  4. Niikawa M et al, Mutat Res 1993; 319(1):1-9.
  5. Hu B et al, Oncol Rep 2014; 32(3):1037-1042.
  6. Jeong JC et al, Phytother Res 2011; 25(3):429-434.
  7. Zhang JF et al, Integr Cancer Ther 2011; 10(1):85-91.
  8. Raghavendran HRB et al, PLoS One. 2012;7(4):e33733.doi: 10.1371/journal.pone.0033733.
  9. Han J et al, J Ginseng Res. 2020 Mar;44(2):291-299.
  10. Wang C et al, Biomed Pharmacother 2019; 109:2062-2069.
  11. Guan H et al, Biomed Chromatogr. 2020 Mar;34(3):e4779
  12. Olatunju OJ et al, Fitoterapia 2018; 129; 293-316.
  13. Nakamura K et al, J Pharmacol Sci. 2015 Jan;127(1):53-6.
  14. Khan MA et al, Curr Med Chem.2020;27(6):983-996.
  15. Bi Y et al, Mol Pharm. 2018 Nov 5;15(11):4912-4925.doi:
  16. Ho SY et al, Int J Mol Sci. 2019 Oct 28;20(21):5366
  17. Feng R et al, Phytother Res. 2020 Jun 30.
  18. Troubat R et al, Eur J Neurosci 09 March 2020. 2020 Mar 9.doi: 10.1111/ejn.14720.

 

New Zealand Horseradish – a winter tonic for lungs and immunity and more

Aside from being a condiment to various foods, horseradish (Armoracia rusticana) root has been traditionally used for coughs and colds for centuries in Europe and parts of Asia. Making a syrup from the distinctively pungent large roots of this plant which grew vigorously at my allotments when I was a herbal student in the UK many years ago, was one of my first experiences with manufacturing a herbal cough medicine, and it is great to now have access to this wonderful herb, grown here in New Zealand.

The source of its pungency and warming aromatic properties, are phytochemicals known as glucosinolates (so-called ‘mustard oil glycosides’) which break down to release volatile and highly bioactive compounds known as isothiocyanates. These act as natural expectorants to encourage mucus elimination, as well as having warming and invigorating actions that can improve the body’s natural defences against unwanted bugs.

Horseradish and its isothiocyanates have been subject to a fair amount of research in recent years, findings from which provide further support for both its traditional as well as potential new applications.

Antimicrobial actions are prominent features of horseradish extracts. Significant antibacterial activity has been shown against a wide range of pathogenic microbes, including bacteria responsible for chest, skin, oral and urinary tract infections(1-6). Isothiocyanates derived from horseradish also exhibit a non-selective antimicrobial activity against several bacterial strains including resistant forms of Haemophilus influenza and E. coli, and yeasts such as Candida albicans(2, 4, 7).  The principle isothiocyanate allyl isothiocyanate has synergistic antifungal activity with the drug fluconazole against Candida biofilms(8).

Clinical studies using a combination of horseradish root with nasturtium herb have found it to have comparable efficacy to antibiotics in the treatment of acute sinusitis and acute bronchitis(1). A combination of horseradish with green tea and other herbs has also been reported to have greater efficacy than oseltamivir in preventing H3N2 avian influenza viral transmission(9), suggesting potential antiviral actions.

An excessive host inflammatory response in the lungs is increasingly linked to an unfavourable prognosis when highly pathogenic bacterial or viral infections take hold in the respiratory tract. As such, the anti-inflammatory properties of horseradish and its affinity for the lungs, are probably useful. Diverse anti-inflammatory effects including reduced nitric oxide, tumor necrosis factor-α and interleukin-6 release, and COX-2 expression, have been reported(10-14). Apart from being anti-inflammatory(15), allyl isothiocyanate induces the expression of multidrug resistance-associated protein 1 (MRP1), which plays a protective role against oxidative stress, lung inflammation and progression of chronic obstructive pulmonary disease (COPD)(16).

Other horseradish phytochemicals have also been associated with anti-inflammatory activities in human immune cells. These include inhibition of the cyclooxygenase (COX-2) enzyme, as well as lipoxygenase pathways (PGE2 synthesis and leukotriene LTB4 release)(10, 14). Anti-inflammatory and potential neuroprotective effects, have also been reported recently for hydantoin and thiohydantoin constituents of horseradish(17).

Like many medicinal plants, horseradish is a powerful antioxidant, and recent research suggests a link between its antimicrobial activities, and antioxidant properties(12). An Italian study found fumigation with allyl isothiocyanate to enhance the Vitamin C, polyphenol and flavonoid content of kiwifruit after 120 days of storage, thus improving its antioxidant and potential health benefits(18).

Protection against DNA damage and cell death from oxidative stress, and inhibition of the COX-1 enzyme may also contribute to the reputation of horseradish to protect against various cancers. Isothiocyanates such as allyl isothiocyanate derived from horseradish and other plants such as brasiccas and nasturtium have been increasingly investigated for their anticancer properties in recent years(10, 19, 20, 21). Horseradish flavonoid constituents such as kaempferol and quercetin also seem to help prevent cellular mutations that can lead to cancer(22).

The use of horseradish as a condiment to help digest rich food has been given a tick of approval by Serbian and Austrian research showing powerful spasmolytic (muscle relaxant) effects on the bowel for its isothiocyanates(4, 23). Potential benefits in the management of diabetes type 2 have also been implicated by recent reports that it is a strong inhibitor of the enzyme α-glucosidase, which breaks complex carbohydrates down to glucose(24).

New Zealand grown horseradish is an ideal herb to include in a winter immune tonic, as well as a regular tonic for those who through lifestyle or occupational exposure to various carcinogens, may be at risk of COPD or various cancers. Its affinity for lung conditions in particular, make it a valuable herb to enhance immunity and optimise lung health, during 2020.

References:

 

  1. Goos KH et al, Arzneimittelforschung 2006; 56(3):249-257.
  2. Conrad A et al. Drug research 2013; 63(2):65-68.
  3. Park HW et al, Biocontrol Sci 2013; 18(3):163-168.
  4. Dekic MS et al, Food Chem. 2017 Oct 1;232:329-339.
  5. Eichel V et al, BMC Complement Med Ther. 2020 May 24;20(1):156.
  6. Mickymaray S et al, Medicina (Kaunas) 2019 Jun 19;55(6):289
  7. Mutters MT et al, Fitoterapia. 2018 Sep;129:237-240.
  8. Raut JS et al, J Microbiol Biotechnol. 2017 Apr 28;27(4):685-693
  9. Oxford JS et al, Am J Ther. Sep-Oct 2007;14(5):462-8.
  10. Weil MJ et al, J Agric Food Chem. 2005 Mar 9;53(5):1440-4
  11. Marzocco S et al, Food Funct. 2015 Dec;6(12):3778-88
  12. Manuguerra S et al, Nat Prod Res. 2020 Jun;34(11):1567-1570
  13. Marzocco S et al, Food Funct. 2015 Dec;6(12):3778-88
  14. Herz C et al, Evid Based Complement Alternat Med 2017. 2017:1950692
  15. Subedi L et al, Int J Mol Sci. 2017 Jul 3;18(7):1423.
  16. Wang S et al, Oxid Med Cell Longev. 2015;2015:903782.
  17. Lee TH et al, J Nat Prod. 2019 Nov 22;82(11):3020-3024.
  18. Ugolini L et al, J Food Sci Technol. 2017 Mar;54(3):751-760
  19. Zhang Y et al, Mol Nutr Food Res. 2010 Jan;54(1):127-35.
  20. Gerhauser C. Curr Opin Clin Nutr Metab Care. 2013 Jul;16(4):405-10
  21. Novio S et al, Molecules. 2016 May 12;21(5):626.
  22. Gafricova M et al, Molecules 2014 Mar 14;19(3):3160-72.
  23. Donnerer J, Liebmann I. Pharmacology. 2017;99(1-2):79-83.
  24. Javaid A et al, Comb Chem High Throughput Screen. 2020 May 26 (epub ahead of print)

 

NZ POLITICIANS CONTINUE TO LET THE NATURAL HEALTH PRODUCTS INDUSTRY AND PRACTITIONERS DOWN

Almost all of New Zealand’s economy is based upon plants, and how prolifically they grow here. Even after much of the native bush was felled to make way for sheep, cows and pine trees, it’s the grass and plants that replaced this, that feed milk or meat producing animals. Agricultural products continue to make up a huge percentage of our exports and GDP contribution, even more so now that Covid-19 has seen plummeting earnings from industries such as tourism and foreign student education provision.

The success of NZ’s Food and Beverage industries derives not only from our reputation for producing high quality products, but also establishment of and maintenance of world class regulations. Nobody in Shanghai or Tokyo or New York wants to buy NZ organic milk from grass fed cows, unless they are sure that what they are paying a premium for, is exactly as stated on the label, and that it is safe. Regulations are there to make sure expected quality parameters are upheld, ensure safety, and in many industry sectors, help facilitate exports.

As with quality food and beverage products, herbal medicines are growing in popularity and global demand, and the current Covid 19 pandemic has reminded us that drugs are not always a solution to rely upon to save us from nature’s dominance over our plight.

Demand for various herbal medicines has long surpassed the point where demand exceeds supply. As with the global food supply chain, changing consumer preferences and climate change stressors, are also contributing to this supply shortfall.

As I’ve written previously, this provides huge opportunities for New Zealand. We have a rich diversity of natural resources, fertile soils, great farmers, and an enviable track record of research and development in biological and agricultural sciences, and pharmaceutical company development.

Why then have successive governments since the last Labour one, not taken the need to regulate and enable the absolutely huge growth potential of a local natural health product industry seriously?

The recent decision by the Ministry of Health to reclassify ‘Artemisia annua extract’ as a prescription only medicine, is symptomatic of these serious regulatory deficits for natural health products.

On 18 May the Ministry of Health issued a Gazette notice to reclassify ‘Artemisia annua extract’ as a Prescription-Only Medicine, following receipt by the New Zealand Pharmacovigilance Centre of 29 reports of hepatic adverse reactions occurring in patients taking two specific products purchased ‘over-the-counter’, and made in NZ from a supercritical CO2 extract of Artemisia annua in grapeseed oil.

What this effectively means, is that all Artemisia annua containing products in addition to those containing the particular extract involved in these adverse event reports, have now become ‘prescription only’. In other words, medical herbalists and naturopaths, most of whom have undertaken at least 3 years study to obtain a degree qualification in natural medicine, are no longer able to treat patients with traditional and GMP manufactured preparations of this herb. But somehow, doctors and other registered medical practitioners who have had no training at all in herbal or natural medicine, are suddenly deemed adequately qualified to prescribe ‘Artemisia annua extract’.

In fact no other regulator in the world has restricted access to all ‘Artemisia annua extracts’, because evidence implicating the herb Artemisia annua itself in liver adverse events, is basically zilch. There is a lack of adverse event reports involving Artemisia annua-containing products reported to pharmacovigilance agencies in other countries, and no previous association of Artemisia annua with liver adverse events exists in its extensive scientific literature.

Such a cluster of cases in New Zealand only, all apart from 1 relating to one particular product manufactured and sold direct to consumers as a ‘dietary supplement’, reeks of a product quality problem. The supercritical CO2 extract used, is also very different to more traditionally used forms of Artemisia annua. As is low alcohol beer from Schnapps.

 

Why then has the NZ regulator taken this course of action?

Lack of any definition of a ‘natural health product’ in any New Zealand legislation, should raise a large red flag, in terms of how ridiculously outdated our regulations for natural health products are. This is the case despite the NZ Natural Health Products Industry trying for more than 20 years to get successive governments to introduce regulations to replace the completely outdated 1981 Medicines Act, and inadequate Dietary Supplements Regulations.

In 2003, the NZ and Australian governments signed a treaty to establish a joint scheme for the regulation of Therapeutic Products (ANZTPA), which would have included regulations also for natural health products. These are known as and regulated as ‘complementary medicines’, by the Australian regulator, the TGA.

Government officials, industry representatives, academics and lawyers from both countries then spent 11 years consulting, developing and preparing these regulations for implementation, but opposition from the National, NZ First and Green Parties, and a Labour government majority of 1 at the time, lead to this legislation only passing its first reading in the house, and then being canned by the new National government in 2014.

National and the Greens then spent some years developing a new NZ-only draft Bill, the Natural Health and Supplementary Products Bill. This proposed a much lighter regulatory agency than ANZTPA, but as with ANZTPA, involved a large amount of work and consultation by government officials, industry representatives and academics, who evaluated and prepared a list of several thousand permitted ingredients able to be included in natural health products without any need to apply for a Medicines licence. However, National dragged their heels on this despite being in power for 3 terms of government and the Bill was never passed, even though it was supported by National, the Greens, Labour and NZ First, with only the ACT party opposing it.

Upon coming to power in 2017, the current Labour-NZ First coalition government removed the Natural Health Products Bill from the order paper while it was awaiting its third reading, soon after talks with its coalition partner NZ First.

Various communications and workshops with industry have since taken place, with the apparent objective of reinventing the wheel and finding out how to appropriately regulate natural health products and draft a new Bill, although no timeline for this has been provided. The recent extension of the ‘Dietary Supplement Regulations’ (under which most natural health products are currently ‘regulated’) to 2026, suggests that the government still has no sense of urgency about the need for a drastically different regulatory environment.

Meanwhile this regulatory void means committed New Zealand companies trying to build export markets for locally produced natural health products are struggling to assure customers in offshore markets of their product quality and safety parameters. To make it even harder for them, for several years we’ve had a situation where many products are being imported and sold into New Zealand with illegal label statements and therapeutic claims, but nothing is being done to stop these imported brands competing with more law abiding local companies.

Industry and Ministry of Health officials share some of the responsibility for this debacle, and it is time we stopped pretending that these products are all ‘dietary supplements’. Plant medicines are true medicines, and when good quality products are taken in optimal doses, they can be as effective as drugs for many health conditions. The Australian view of natural health products as ‘complementary medicines’, is much more appropriate, their regulatory system acknowledges their ability to sometimes have therapeutic effects, and also permits such claims to be made on their packaging, where scientific or traditional evidence exists. It also recognises that natural health practitioners after training at least 3 years to obtain degree level qualifications, have particular skills that enable them to use certain forms of herbal medicines that may not necessarily be appropriate or safe as ingredients in ‘over the counter’ products.

The dairy, beef, wine, kiwifruit and so many other vibrant export industries have all been established not only through being lucky enough to have perfect growing conditions here, but also a regulatory system in place that fulfils the needs of any premium quality and premium priced product, to be sold into offshore markets.

Natural health products are challenging to regulate appropriately, but isn’t everything? It’s time for elements of the industry to stop pretending all products are ‘dietary supplements’ rather than medicines, and for New Zealand politicians from all parties to stop messing around with the Natural Health Product Industry like a game of political football, before the next 3 year election cycle.

The long game as we reflect on the post-Covid world, has to seriously leverage New Zealand’s many unique strengths and quality attributes, to create a sustainable portfolio of industries which can boost export revenue, have high margins, look after the environment, and respect the principles of Kaitiakitanga. The local Natural Health Products industry tick all these boxes, but is now in urgent need of world class regulations to support its export lead growth.

 

 

Ginkgo – much more than a herb for cognition – part 2.

Ginkgo istock3Apart from possible benefits in the management of conditions such as dementia, stroke, diabetic neuropathies, macular degeneration and glaucoma, the cardioprotective and neuroprotective properties of ginkgo suggest potential applications in other situations in which there is exposure to various drugs or substances with a risk of adverse events.

Adjunct with neurotoxic drugs

Concomitant use of ginkgo may be useful when taking or exposed to other drugs or chemical toxins(1, 2). Animal studies have reported protective actions of ginkgo against ototoxicity (inner ear and auditory nerve damage) from the antibiotic drug gentamycin(3), kidney (nephro) toxicity, liver (hepato) toxicity and genotoxicity from the herbicide glyphosate(4), and nerve damage from the herbicide paraquat(1).

These studies suggest that patients being prescribed gentamycin or other aminoglycoside antibiotics which have a risk of causing hearing or kidney damage, or people regularly using or exposed to herbicides such as glyphosate or paraquat, may benefit from taking ginkgo at the same time.

 

Supporting liver function:

Ginkgo leaf is a very bitter herb, and some would say that it is therefore hardly surprising that it is a useful agent for liver conditions. In fact there are now numerous studies showing it has protective actions on the liver.

These hepatoprotective effects have been reported in rodent studies against a wide range of liver toxins. They include alcohol, paracetamol, rifampicin & other chemicals(5-11). Improvements have been shown to occur in several liver abnormalities including malondialdehyde levels, glutathione levels, superoxide dismutase, elevated liver enzymes (LFT’s), and histological damage.

Hepatoprotective effects similar to those of silymarin were reported in a 2011 study involving treatment of rats with silymarin or ginkgo for a week prior, or 4 weeks post administration of nitrosodiethylamine, a known liver carcinogen(12). Other rodent studies have revealed potential antitumour effects against liver cancer for ginkgo(13, 14).

These studies suggest ginkgo could be a useful adjunct to take during treatment with the common analgesic paracetamol, as well as other drugs sometimes associated with liver adverse events, such as azathioprine, isoniazid, statins, ketoconazole and nitrofurantoin.

 Ginkgo when given in larger than usual doses to rats, has protective actions against both acute and chronic alcohol-induced liver damage, effects associated with its antioxidant actions, and improvement in hepatic microcirculation(15-18). Those whose alcohol intake is excessive, may do well to consider taking ginkgo to help ameliorate some of its negative effects on the liver.

Adjunct with chemotherapy:

Adverse events to chemotherapy are common, and use of cytotoxic drugs such as doxorubicin and cisplatin can lead to infertility, kidney damage (nephrotoxicity) and damage to the heart (cardiotoxicity) in some cancer patients.

Pre-treatment or concomitant treatment with large doses of oral or intraperitoneal ginkgo in rats has been shown to help protect against chemotherapy-induced adverse effects on other organs. These include protection against cisplatin-induced peripheral neuropathy(19), protection against cisplatin and doxorubicin cardiotoxicity, and cisplatin nephrotoxicity and ototoxicity(20-25).

Other studies have reported protective effects for ginkgo against the damaging effects of doxorubicin & cisplatin on testicular function in male rats(26, 27), and against against oxidative and genotoxic damage in patients with differentiated thyroid cancer during 90 day radio-iodine treatment(28). These results suggest possible benefits of ginkgo if taken during chemotherapy or radiotherapy treatment, by patients wanting to have children in the future.

While few human clinical trials have investigated these promising findings from animal studies, a Chinese clinical trial has reported a lower incidence of ECG abnormalities and cardiotoxicity in 60 breast cancer patients being treated with doxorubicin, when ginkgo was prescribed concurrently(29). Adjunctive Ginkgo also slightly improved overall survival in a small trial involving 27 patients with advanced hepatocellular cancer, compared to previous sorafenib monotherapy(30).

Adjunct with antipsychotics:

The response of schizophrenia patients to antipsychotic drug medications is often less than ideal, and the frequency of adverse events to these associated with low levels of compliance. Findings from a Chinese clinical trial involving 12 weeks of ginkgo and haloperidol or placebo and haloperidol administration in a group 109 schizophrenia patients and previously treated with antipsychotic medications for at least 6 months, are therefore of interest(31).

At the end of the 12 week study, 57% of the ginkgo treated group were rated as responders, versus only 38% of the haloperidol only treatment group, which in itself is highly significant. Additionally however, a lower incidence of extrapyramidal side effects, a major problem with haloperidol and other older generation antipsychotic drugs, was also seen in the ginkgo-treated group(31, 32).

Improvement in some schizophrenia symptom scores was also reported in a subsequent study involving adjunctive ginkgo treatment in patients taking olanzapine, a newer generation antipsychotic drug(33).

Potential applications of ginkgo in the management of other psychiatric conditions including depression and ADHD, have also been suggested(34, 35), though further clinical studies are needed.

 

Dosage:

A concern is the use of relatively large doses in most animal studies, yet those used in human clinical studies are often much lower, and sometimes probably less than what they should have been. Also given that most neurodegenerative conditions such as dementia, diabetic neuropathies, glaucoma and macular degeneration are slow to develop but tend to be progressive, unless clinical trials involve large participant numbers and continue for a long period of time, their ability to statistically detect clinically significant outcomes , is limited.

Despite these challenges and the cost of long term clinical trials, given the hugely debilitating nature of all of these conditions, and their large burden on both patients and the health care system, further trials to validate promising findings from in vitro and animal studies, and determine optimal dosage and treatment protocols in humans are needed.

 

And finally:

New Zealand is an excellent country for growing ginkgo, and locally harvested ginkgo leaves have been shown to contain high levels of ginkgo flavone glycosides and terpene lactones.

While it is sometimes claimed that ginkgolic acid, a minor component of ginkgo leaves, is associated with allergic reactions, the evidence basis for this is unconvincing. In fact research is increasingly showing that this compound probably contributes to ginkgo’s cognitive benefits(36), and exhibits a wide range of other useful pharmacological properties. These include anti-diabetic(37), anti-fibrotic(38) and potential anticancer properties, including against pancreatic (39), liver, colon and gastric cancers (40-42).

 

References:

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ginkgo photo