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

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

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

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

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

Digestive Aid

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

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

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

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

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

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

Nausea and vomiting

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

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

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

Obesity management?

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

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

Summary:

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

References:

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  19. Zaghlool SS, Shehata BA, Abo-Seif AA, Abd El-Latif HA. Protective effects of ginger and marshmallow extracts on indomethacin-induced peptic ulcer in rats. J Nat Sci Biol Med. 2015 Jul-Dec;6(2):421-8. doi: 10.4103/0976-9668.160026. PMID: 26283843; PMCID: PMC4518423.
  20. Sistani Karampour N, Arzi A, Rezaie A, Pashmforoosh M, Kordi F. Gastroprotective Effect of Zingerone on Ethanol-Induced Gastric Ulcers in Rats. Medicina (Kaunas). 2019 Mar 11;55(3):64. doi: 10.3390/medicina5
  21. Yamahara J, Mochizuki M, Rong HQ, Matsuda H, Fujimura H. The anti-ulcer effect in rats of ginger constituents. J Ethnopharmacol. 1988 Jul-Aug;23(2-3):299-304. doi: 10.1016/0378-8741(88)90009-8. PMID: 3193792.
  22. al-Yahya MA, Rafatullah S, Mossa JS, Ageel AM, Parmar NS, Tariq M. Gastroprotective activity of ginger zingiber officinale rosc., in albino rats. Am J Chin Med. 1989;17(1-2):51-6. doi: 10.1142/S0192415X89000097. PMID: 2589236.
  23. Nanjundaiah SM, Annaiah HN, Dharmesh SM. Gastroprotective Effect of Ginger Rhizome (Zingiber officinale) Extract: Role of Gallic Acid and Cinnamic Acid in H(+), K(+)-ATPase/H. pylori Inhibition and Anti-Oxidative Mechanism. Evid Based Complement Alternat Med. 2011;2011:249487. doi: 10.1093/ecam/nep060. Epub 2011 Jun 23. PMID: 19570992; PMCID: PMC3136331.
  24. Shin JK, Park JH, Kim KS, Kang TH, Kim HS. Antiulcer Activity of Steamed Ginger Extract against Ethanol/HCl-Induced Gastric Mucosal Injury in Rats. Molecules. 2020 Oct 13;25(20):4663. doi: 10.3390/molecules25204663. PMID: 33066164; PMCID: PMC7587366.
  25. Mahady GB, Pendland SL, Yun GS, Lu ZZ, Stoia A. Ginger (Zingiber officinale Roscoe) and the gingerols inhibit the growth of Cag A+ strains of Helicobacter pylori. Anticancer Res. 2003 Sep-Oct;23(5A):3699-702. PMID: 14666666; PMCID: PMC3761965.
  26. Haniadka R, Saldanha E, Sunita V, Palatty PL, Fayad R, Baliga MS. A review of the gastroprotective effects of ginger (Zingiber officinale Roscoe). Food Funct. 2013 Jun;4(6):845-55. doi: 10.1039/c3fo30337c. Epub 2013 Apr 24. PMID: 23612703.
  27. Ghayur MN, Gilani AH, Ahmed T, Khalid A, Nawaz SA, Agbedahunsi JM, Choudhary MI, Houghton PJ. Muscarinic, Ca(++) antagonist and specific butyrylcholinesterase inhibitory activity of dried ginger extract might explain its use in dementia. J Pharm Pharmacol. 2008 Oct;60(10):1375-83. doi: 10.1211/jpp/60.10.0014. PMID: 18812031.
  28. Riyazi A, Hensel A, Bauer K, Geissler N, Schaaf S, Verspohl EJ. The effect of the volatile oil from ginger rhizomes (Zingiber officinale), its fractions and isolated compounds on the 5-HT3 receptor complex and the serotoninergic system of the rat ileum. Planta Med. 2007 Apr;73(4):355-62. doi: 10.1055/s-2007-967171. PMID: 17511060.
  29. Grzanna R, Lindmark L, Frondoza CG. Ginger–an herbal medicinal product with broad anti-inflammatory actions. J Med Food. 2005 Summer;8(2):125-32. doi: 10.1089/jmf.2005.8.125. PMID: 16117603.
  30. Lantz RC, Chen GJ, Sarihan M, Sólyom AM, Jolad SD, Timmermann BN. The effect of extracts from ginger rhizome on inflammatory mediator production. Phytomedicine. 2007 Feb;14(2-3):123-8. doi: 10.1016/j.phymed.2006.03.003. Epub 2006 May 18. PMID: 16709450.
  31. Tóth B, Lantos T, Hegyi P, Viola R, Vasas A, Benkő R, Gyöngyi Z, Vincze Á, Csécsei P, Mikó A, Hegyi D, Szentesi A, Matuz M, Csupor D. Ginger (Zingiber officinale): An alternative for the prevention of postoperative nausea and vomiting. A meta-analysis. Phytomedicine. 2018 Nov 15;50:8-18. doi: 10.1016/j.phymed.2018.09.007. Epub 2018 Sep 5. PMID: 30466995.
  32. Matthews A, Haas DM, O’Mathúna DP, Dowswell T. Interventions for nausea and vomiting in early pregnancy. Cochrane Database Syst Rev. 2015 Sep 8;2015(9):CD007575. doi: 10.1002/14651858.CD007575.pub4. PMID: 26348534; PMCID: PMC7196889.
  33. Stanisiere J, Mousset PY, Lafay S. How Safe Is Ginger Rhizome for Decreasing Nausea and Vomiting in Women during Early Pregnancy? Foods. 2018 Apr 1;7(4):50. doi: 10.3390/foods7040050. PMID: 29614764; PMCID: PMC5920415.
  34. Kiuchi F, Shibuya M, Sankawa U. Inhibitors of prostaglandin biosynthesis from ginger. Chem Pharm Bull (Tokyo). 1982 Feb;30(2):754-7. doi: 10.1248/cpb.30.754. PMID: 7094159.
  35. Saneei Totmaj A, Emamat H, Jarrahi F, Zarrati M. The effect of ginger (Zingiber officinale) on chemotherapy-induced nausea and vomiting in breast cancer patients: A systematic literature review of randomized controlled trials. Phytother Res. 2019 Aug;33(8):1957-1965. doi: 10.1002/ptr.6377. Epub 2019 Jun 21. PMID: 31225678.
  36. Borges DO, Freitas KABDS, Minicucci EM, Popim RC. Benefits of ginger in the control of chemotherapy-induced nausea and vomiting. Rev Bras Enferm. 2020 Mar 30;73(2):e20180903. English, Portuguese. doi: 10.1590/0034-7167-2018-0903. PMID: 32236378.
  37. Crichton M, Marshall S, Marx W, McCarthy AL, Isenring E. Efficacy of Ginger (Zingiber officinale) in Ameliorating Chemotherapy-Induced Nausea and Vomiting and Chemotherapy-Related Outcomes: A Systematic Review Update and Meta-Analysis. J Acad Nutr Diet. 2019 Dec;119(12):2055-2068. doi: 10.1016/j.jand.2019.06.009. Epub 2019 Sep 10. PMID: 31519467.
  38. Yamahara J, Mochizuki M, Rong HQ, Matsuda H, Fujimura H. The anti-ulcer effect in rats of ginger constituents. J Ethnopharmacol. 1988 Jul-Aug;23(2-3):299-304. doi: 10.1016/0378-8741(88)90009-8. PMID: 3193792.
  39. Tramontin NDS, Luciano TF, Marques SO, de Souza CT, Muller AP. Ginger and avocado as nutraceuticals for obesity and its comorbidities. Phytother Res. 2020 Jun;34(6):1282-1290. doi: 10.1002/ptr.6619. Epub 2020 Jan 27. PMID: 31989713.
  40. Seo SH, Fang F, Kang I. Ginger (Zingiber officinale) Attenuates Obesity and Adipose Tissue Remodeling in High-Fat Diet-Fed C57BL/6 Mice. Int J Environ Res Public Health. 2021 Jan 13;18(2):631. doi: 10.3390/ijerph18020631. PMID: 33451038; PMCID: PMC7828532.
  41. Wang J, Wang P, Li D, Hu X, Chen F. Beneficial effects of ginger on prevention of obesity through modulation of gut microbiota in mice. Eur J Nutr. 2020 Mar;59(2):699-718. doi: 10.1007/s00394-019-01938-1. Epub 2019 Mar 11. PMID: 30859364.
  42. Wang J, Chen Y, Hu X, Feng F, Cai L, Chen F. Assessing the Effects of Ginger Extract on Polyphenol Profiles and the Subsequent Impact on the Fecal Microbiota by Simulating Digestion and Fermentation In Vitro. Nutrients. 2020 Oct 19;12(10):3194. doi: 10.3390/nu12103194. PMID: 33086593; PMCID: PMC7650818.
  43. Rasmussen PL, Ginger for weight loss. Phytonews 22, ISSN 1175-0251. Published by Phytomed Medicinal Herbs Ltd, Auckland, July 2005.
  44. Ebrahimzadeh Attari V, Malek Mahdavi A, Javadivala Z, Mahluji S, Zununi Vahed S, Ostadrahimi A. A systematic review of the anti-obesity and weight lowering effect of ginger (Zingiber officinale Roscoe) and its mechanisms of action. Phytother Res. 2018 Apr;32(4):577-585. doi: 10.1002/ptr.5986. Epub 2017 Nov 29. PMID: 29193411.
  45. Ebrahimzadeh Attari V, Ostadrahimi A, Asghari Jafarabadi M, Mehralizadeh S, Mahluji S. Changes of serum adipocytokines and body weight following Zingiber officinale supplementation in obese women: a RCT. Eur J Nutr. 2016 Sep;55(6):2129-36. doi: 10.1007/s00394-015-1027-6. Epub 2015 Aug 29. PMID: 26318445.
  46. Park SH, Jung SJ, Choi EK, Ha KC, Baek HI, Park YK, Han KH, Jeong SY, Oh JH, Cha YS, Park BH, Chae SW. The effects of steamed ginger ethanolic extract on weight and body fat loss: a randomized, double-blind, placebo-controlled clinical trial. Food Sci Biotechnol. 2019 Oct 11;29(2):265-273. doi: 10.1007/s10068-019-00649-x. PMID: 32064135; PMCID: PMC6992804.
Zingiber officinale

Comfrey – a great herb for bruises, sprains and more

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

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

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

Anti-inflammatory

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

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

Clinical trials

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

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

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

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

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

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

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

Reduction in scar formation?

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

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

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

Safety concerns

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

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

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

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

Finally

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

References: 

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

Echinacea – so many new interesting medicinal applications!

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

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

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

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

Effects on endocannabinoid receptors

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

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

Anxiolytic

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

Eczema and hayfever

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

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

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

Analgesic

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

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

Male fertility?

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

Anticancer effects

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

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

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

References:

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

New Zealand’s Health System under Stress

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

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

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

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

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

The economic burden of chronic illnesses

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

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

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

What can medical herbalists and naturopaths do?

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

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

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

Some types of interventions

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

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

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

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

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

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

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

Freeing up healthcare resources for other needs!

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

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

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

References:

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

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

Covid-19 resurgence

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

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

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

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

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

Developing Immunity:

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

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

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

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

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

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

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

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

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

Some recent findings:

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

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

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

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

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

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

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

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

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

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

References:

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

Baptisia – a somewhat mysterious phytomedicine

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

Wild Indigo

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

Antimicrobial

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

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

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

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

Other applications

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

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

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

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

True Indigo (Indigofera tinctoria)

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

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

References:

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  2. Hutchens AR. 1973. Indian Herbalogy of North America. Boston, Massachusetts: Shambhala Publications Inc.
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  4. Milton Welch J. The Medical Flora of Kansas. Transactions of the National Eclectic Association. 1882-83, Vol. X. Accessed 18 September 2008.
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  9. Henneicke-von Zepelin HH, Nicken P, Naser B, Kuchernig JC, Brien N, Holtdirk A, Schnitker J, Nolte KU. Non-interventional observational study broadens positive benefit-risk assessment of an immunomodulating herbal remedy in the common cold. Curr Med Res Opin. 2019 Oct;35(10):1711-1719. doi: 10.1080/03007995.2019.1618252. Epub 2019 Jun 17. PMID: 31074674.Anderson MJ, Kurtycz DF, Cline JR. Baptisia poisoning: a new and toxic look-alike in the neighborhood. J Emerg Med. 2015 Jan;48(1):39-42. doi: 10.1016/j.jemermed.2014.09.037. Epub 2014 Nov 6. PMID: 25453859.
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  11. Wagner H, Proksch A, Riess-Maurer I, Vollmar A, Odenthal S, Stuppner H, Jurcic K, Le Turdu M, Fang JN. Immunstimulierend wirkende Polysaccharide (Heteroglykane) aus höheren Pflanzen [Immunostimulating action of polysaccharides (heteroglycans) from higher plants]. Arzneimittelforschung. 1985;35(7):1069-75. German. PMID: 4052142.Mineur YS, Eibl C, Young G, Kochevar C, Papke RL, Gündisch D, Picciotto MR. Cytisine-based nicotinic partial agonists as novel antidepressant compounds. J Pharmacol Exp Ther. 2009 Apr;329(1):377-86. doi: 10.1124/jpet.108.149609. Epub 2009 Jan 22. PMID: 19164465; PMCID: PMC2670591.
  12. Beuscher N, Kopanski L. Stimulation der Immunantwort durch Inhaltsstoffe aus Baptisia tinctoria. (Stimulation of immunity by the contents of Baptisia tinctoria]. Planta Med. 1985 Oct;51(5):381-4. doi: 10.1055/s-2007-969525. PMID: 17342588.
  13. Egert D, Beuscher N. Studies on antigen specifity of immunoreactive arabinogalactan proteins extracted from Baptisia tinctoria and Echinacea purpurea. Planta Med. 1992 Apr;58(2):163-5. doi: 10.1055/s-2006-961420. PMID: 1382301.
  14. Classen B, Thude S, Blaschek W, Wack M, Bodinet C. Immunomodulatory effects of arabinogalactan-proteins from Baptisia and Echinacea. Phytomedicine. 2006 Nov;13(9-10):688-94. doi: 10.1016/j.phymed.2005.10.004. Epub 2005 Nov 14. PMID: 17085292.
  15. Banerji P, Banerji P, Das GC, Islam A, Mishra SK, Mukhopadhyay S. Efficacy of Baptisia tinctoria in the treatment of typhoid: its possible role in inducing antibody formation. J Complement Integr Med. 2012 Jul 2;9:Article 15. doi: 10.1515/1553-3840.1622. PMID: 22850071.
  16. Masuet-Aumatell C, Atouguia J. Typhoid fever infection – Antibiotic resistance and vaccination strategies: A narrative review. Travel Med Infect Dis. 2021 Mar-Apr;40:101946. doi: 10.1016/j.tmaid.2020.101946. Epub 2020 Dec 8. PMID: 33301931.
  17. Plugge PC, Arch. der Pharm. (1891), 229, p. 48.
  18. McDougal OM, Heenan PB, Jaksons P, Sansom CE, Smallfield BM, Perry NB, van Klink JW. Alkaloid variation in New Zealand kōwhai, Sophora species. Phytochemistry. 2015 Oct;118:9-16. doi: 10.1016/j.phytochem.2015.07.019. Epub 2015 Aug 6. PMID: 26253652.
  19. Wang H, Xia C, Chen L, Zhao J, Tao W, Zhang X, Wang J, Gao X, Yong J, Duan JA. Phytochemical Information and Biological Activities of Quinolizidine Alkaloids in Sophora: A Comprehensive Review. Curr Drug Targets. 2019;20(15):1572-1586. doi: 10.2174/1389450120666190618125816. PMID: 31215388.
  20. Tutka P, Vinnikov D, Courtney RJ, Benowitz NL. Cytisine for nicotine addiction treatment: a review of pharmacology, therapeutics and an update of clinical trial evidence for smoking cessation. Addiction. 2019 Nov;114(11):1951-1969. doi: 10.1111/add.14721. Epub 2019 Jul 19. PMID: 31240783.
  21. Walker N, Howe C, Glover M, McRobbie H, Barnes J, Nosa V, Parag V, Bassett B, Bullen C. Cytisine versus nicotine for smoking cessation. N Engl J Med. 2014 Dec 18;371(25):2353-62. doi: 10.1056/NEJMoa1407764. PMID: 25517706.
  22. Walker N, Smith B, Barnes J, Verbiest M, Parag V, Pokhrel S, Wharakura MK, Lees T, Cubillos Gutierrez H, Jones B, Bullen C. Cytisine versus varenicline for smoking cessation in New Zealand indigenous Māori: a randomized controlled trial. Addiction. 2021 Mar 24. doi: 10.1111/add.15489. Epub ahead of print. PMID: 33761149.
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  24. Cahill K, Lindson-Hawley N, Thomas KH, Fanshawe TR, Lancaster T. Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev. 2016 May 9;2016(5):CD006103. doi: 10.1002/14651858.CD006103.pub7. PMID: 27158893; PMCID: PMC6464943.
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Pomegranate – recent findings

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

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


Anticancer properties

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

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

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

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

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

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

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

Gastroprotective properties

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

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

Skin health:

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

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

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

Neuroprotective effects?

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

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

References:

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  2. Khan N., Afaq F., Mukhtar H. Cancer Chemoprevention Through Dietary Antioxidants: Progress and Promise. Antioxid. Redox Signal. 2008;10:475–510. doi: 10.1089/ars.2007.1740. 
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  13. Rocha A., Wang L., Penichet M., Martins-Green M. Pomegranate juice and specific components inhibit cell and molecular processes critical for metastasis of breast cancer. Breast Cancer Res. Treat. 2012;136:647–658. doi: 10.1007/s10549-012-2264-5.
  14. Ahmadiankia N. Molecular targets of pomegranate (Punica granatum) in preventing cancer metastasis. Iran J Basic Med Sci. 2019;22(9):977-988. doi:10.22038/ijbms.2019.34653.8217Crocetto F, Boccellino M, Barone B, et al. The Crosstalk between Prostate Cancer and Microbiota Inflammation: Nutraceutical Products Are Useful to Balance This Interplay?. Nutrients. 2020;12(9):2648. Published 2020 Aug 31. doi:10.3390/nu12092648.
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  16. Zhao W, Shi F, Guo Z, Zhao J, Song X, Yang H. Metabolite of ellagitannins, urolithin A induces autophagy and inhibits metastasis in human sw620 colorectal cancer cells. Mol Carcinog. 2018;57(2):193-200. doi:10.1002/mc.22746.
  17. Qiu Z, Zhou J, Zhang C, Cheng Y, Hu J, Zheng G. Antiproliferative effect of urolithin A, the ellagic acid-derived colonic metabolite, on hepatocellular carcinoma HepG2.2.15 cells by targeting Lin28a/let-7a axis. Braz J Med Biol Res. 2018;51(7):e7220. doi:10.1590/1414-431×20187220.
  18. Vicinanza R, Zhang Y, Henning SM, Heber D. Pomegranate Juice Metabolites, Ellagic Acid and Urolithin A, Synergistically Inhibit Androgen-Independent Prostate Cancer Cell Growth via Distinct Effects on Cell Cycle Control and Apoptosis. Evid Based Complement Alternat Med. 2013;2013:247504. doi:10.1155/2013/247504.
  19. Ceci C, Lacal PM, Tentori L, De Martino MG, Miano R, Graziani G. Experimental Evidence of the Antitumor, Antimetastatic and Antiangiogenic Activity of Ellagic Acid. Nutrients. 2018 Nov 14;10(11):1756. doi: 10.3390/nu10111756. PMID: 30441769; PMCID: PMC6266224.
  20. Thomas R, Williams M, Sharma H, Chaudry A, Bellamy P. A double-blind, placebo-controlled randomised trial evaluating the effect of a polyphenol-rich whole food supplement on PSA progression in men with prostate cancer–the U.K. NCRN Pomi-T study. Prostate Cancer Prostatic Dis. 2014;17(2):180-186. doi:10.1038/pcan.2014.6.
  21. Paller CJ, Ye X, Wozniak PJ, et al. A randomized phase II study of pomegranate extract for men with rising PSA following initial therapy for localized prostate cancer. Prostate Cancer Prostatic Dis. 2013;16(1):50-55. doi:10.1038/pcan.2012.20.
  22. Paller CJ, Pantuck A, Carducci MA. A review of pomegranate in prostate cancer. Prostate Cancer Prostatic Dis. 2017;20(3):265-270. doi:10.1038/pcan.2017.19.
  23. Freedland SJ, Carducci M, Kroeger N, et al. A double-blind, randomized, neoadjuvant study of the tissue effects of POMx pills in men with prostate cancer before radical prostatectomy. Cancer Prev Res (Phila). 2013;6(10):1120-1127. doi:10.1158/1940-6207.CAPR-12-0423.
  24. Parisio C, Lucarini E, Micheli L, et al. Pomegranate Mesocarp against Colitis-Induced Visceral Pain in Rats: Effects of a Decoction and Its Fractions. Int J Mol Sci. 2020;21(12):4304. Published 2020 Jun 17. doi:10.3390/ijms21124304.
  25. Kujawska M, Jodynis-Liebert J. Potential of the ellagic acid-derived gut microbiota metabolite – Urolithin A in gastrointestinal protection. World J Gastroenterol. 2020 Jun 21;26(23):3170-3181. doi: 10.3748/wjg.v26.i23.3170. PMID: 32684733; PMCID: PMC7336321.
  26. Abd El-Rady NM, Dahpy MA, Ahmed A, et al. Interplay of Biochemical, Genetic, and Immunohistochemical Factors in the Etio-Pathogenesis of Gastric Ulcer in Rats: A Comparative Study of the Effect of Pomegranate Loaded Nanoparticles Versus Pomegranate Peel Extract. Front Physiol. 2021;12:649462. Published 2021 Mar 23. doi:10.3389/fphys.2021.649462
  27. Castagna F, Britti D, Oliverio M, Bosco A, Bonacci S, Iriti G, Ragusa M, Musolino V, Rinaldi L, Palma E, Musella V. In Vitro Anthelminthic Efficacy of Aqueous Pomegranate (Punica granatum L.) Extracts against Gastrointestinal Nematodes of Sheep. Pathogens. 2020 Dec 18;9(12):1063. doi: 10.3390/pathogens9121063. PMID: 33353177; PMCID: PMC7766728.
  28. Henning SM, Yang J, Lee RP, et al. Pomegranate Juice and Extract Consumption Increases the Resistance to UVB-induced Erythema and Changes the Skin Microbiome in Healthy Women: a Randomized Controlled Trial. Sci Rep. 2019;9(1):14528. Published 2019 Oct 10. doi:10.1038/s41598-019-50926-2.
  29. Afaq F, Khan N, Syed DN, Mukhtar H. Oral feeding of pomegranate fruit extract inhibits early biomarkers of UVB radiation-induced carcinogenesis in SKH-1 hairless mouse epidermis. Photochem Photobiol. 2010;86(6):1318–1326. doi: 10.1111/j.1751-1097.2010.00815.x. 
  30. Kasai K, Yoshimura M, Koga T, Arii M, Kawasaki S. Effects of oral administration of ellagic acid-rich pomegranate extract on ultraviolet-induced pigmentation in the human skin. J Nutr Sci Vitaminol (Tokyo). 2006 Oct;52(5):383-8. doi: 10.3177/jnsv.52.383. PMID: 17190110.
  31. Rapa SF, Magliocca G, Pepe G, et al. Protective Effect of Pomegranate on Oxidative Stress and Inflammatory Response Induced by 5-Fluorouracil in Human Keratinocytes. Antioxidants (Basel). 2021;10(2):203. Published 2021 Jan 30. doi:10.3390/antiox10020203
  32. Celiksoy V, Moses RL, Sloan AJ, Moseley R, Heard CM. Evaluation of the In Vitro Oral Wound Healing Effects of Pomegranate (Punica granatum) Rind Extract and Punicalagin, in Combination with Zn (II). Biomolecules. 2020;10(9):1234. Published 2020 Aug 25. doi:10.3390/biom10091234
  33. Kujawska M, Jourdes M, Kurpik M, et al. Neuroprotective Effects of Pomegranate Juice against Parkinson’s Disease and Presence of Ellagitannins-Derived Metabolite-Urolithin A-In the Brain. Int J Mol Sci. 2019;21(1):202. Published 2019 Dec 27. doi:10.3390/ijms21010202
  34. Fathy SM, El-Dash HA, Said NI. Neuroprotective effects of pomegranate (Punica granatum L.) juice and seed extract in paraquat-induced mouse model of Parkinson’s disease. BMC Complement Med Ther. 2021;21(1):130. Published 2021 Apr 26. doi:10.1186/s12906-021-03298-y
  35. Ropacki SA, Patel SM, Hartman RE. Pomegranate Supplementation Protects against Memory Dysfunction after Heart Surgery: A Pilot Study. Evid Based Complement Alternat Med. 2013;2013:932401. doi:10.1155/2013/932401.
  36. Braidy N, et al. Consumption of pomegranates improves synaptic function in a transgenic mice model of Alzheimer’s disease. Oncotarget. 2016;7:64589–64604. doi: 10.18632/oncotarget.10905.
  37. Matthews LG, Smyser CD, Cherkerzian S, Alexopoulos D, Kenley J, Tuuli MG, Nelson DM, Inder TE. Maternal pomegranate juice intake and brain structure and function in infants with intrauterine growth restriction: A randomized controlled pilot study. PLoS One. 2019 Aug 21;14(8):e0219596. doi: 10.1371/journal.pone.0219596. PMID: 31433809; PMCID: PMC6703683.
  38. Ross MM, Cherkerzian S, Mikulis ND, Turner D, Robinson J, Inder TE, Matthews LG. A randomized controlled trial investigating the impact of maternal dietary supplementation with pomegranate juice on brain injury in infants with IUGR. Sci Rep. 2021 Feb 11;11(1):3569. doi: 10.1038/s41598-021-82144-0. PMID: 33574371; PMCID: PMC7878922.
  39. Minisy FM, Shawki HH, El Omri A, Massoud AA, Omara EA, Metwally FG, Badawy MA, Hassan NA, Hassan NS, Oishi H. Pomegranate Seeds Extract Possesses a Protective Effect against Tramadol-Induced Testicular Toxicity in Experimental Rats. Biomed Res Int. 2020 Mar 9;2020:2732958. doi: 10.1155/2020/2732958. PMID: 32219129; PMCID: PMC7085358.

Propolis – amazing stuff made by bees from nature

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

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

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

Antiviral:

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

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

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

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

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

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

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

Anti-inflammatory

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

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

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

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

Antibacterial:

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

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

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

Dental applications–

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

Wound healing:

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

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

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

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

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

Cancer-protective?

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

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

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

Cardiac health:

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

Diabetes:

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

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

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

Other properties

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

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

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  21. Mirsadraee M, Azmoon B, Ghaffari S, Abdolsamadi A, Khazdair MR. Effect of Propolis on moderate persistent asthma: A phase two randomized, double blind, controlled clinical trial. Avicenna J Phytomed. 2021 Jan-Feb;11(1):22-31. PMID: 33628717; PMCID: PMC7885004.
  22. Meresta L., Meresta T. Effect of pH on bactericidal activity of propolis. Bull. Veterina. Inst. Pulawy. 1980;24:21–25.
  23. Przybyłek I, Karpiński TM. Antibacterial Properties of Propolis. Molecules. 2019 May 29;24(11):2047. doi: 10.3390/molecules24112047. PMID: 31146392; PMCID: PMC6600457.
  24. Almuhayawi MS. Propolis as a novel antibacterial agent. Saudi J Biol Sci. 2020 Nov;27(11):3079-3086. doi: 10.1016/j.sjbs.2020.09.016. Epub 2020 Sep 14. PMID: 33100868; PMCID: PMC7569119.
  25. Pahlavani N, Sedaghat A, Bagheri Moghaddam A, Mazloumi Kiapey SS, Gholizadeh Navashenaq J, Jarahi L, Reazvani R, Norouzy A, Nematy M, Safarian M, Ghayour-Mobarhan M. Effects of propolis and melatonin on oxidative stress, inflammation, and clinical status in patients with primary sepsis: Study protocol and review on previous studies. Clin Nutr ESPEN. 2019 Oct;33:125-131. doi: 10.1016/j.clnesp.2019.06.007. Epub 2019 Jul 5. PMID: 31451248.
  26. Bretz WA, Paulino N, Nör JE, Moreira A. The effectiveness of propolis on gingivitis: a randomized controlled trial. J Altern Complement Med. 2014;20(12):943-948. doi:10.1089/acm.2013.0431
  27. Pundir AJ, Vishwanath A, Pundir S, Swati M, Banchhor S, Jabee S. One-stage Full Mouth Disinfection Using 20% Propolis Hydroalcoholic Solution: A Clinico-microbiologic Study. Contemp Clin Dent. 2017;8(3):416-420. doi:10.4103/ccd.ccd_544_17      
  28. Skoskiewicz-Malinowska K, Kaczmarek U, Malicka B, Walczak K, Zietek M. Application of Chitosan and Propolis in Endodontic Treatment: A Review. Mini Rev Med Chem. 2017;17(5):410-434. doi: 10.2174/1389557516666160418122510. PMID: 27087464.
  29. Zulhendri F, Felitti R, Fearnley J, Ravalia M. The use of propolis in dentistry, oral health, and medicine: A review. J Oral Biosci. 2021 Mar;63(1):23-34. doi: 10.1016/j.job.2021.01.001. Epub 2021 Jan 16. PMID: 33465498.
  30. Martinotti S, Pellavio G, Laforenza U, Ranzato E. Propolis Induces AQP3 Expression: A Possible Way of Action in Wound Healing. Molecules. 2019 Apr 19;24(8):1544. doi: 10.3390/molecules24081544. PMID: 31010117; PMCID: PMC6515181.
  31. Abu-Seida AM. Effect of Propolis on Experimental Cutaneous Wound Healing in Dogs. Vet Med Int. 2015;2015:672643. doi: 10.1155/2015/672643. Epub 2015 Dec 13. PMID: 26783495; PMCID: PMC4691486.
  32. Oryan A, Alemzadeh E, Moshiri A. Potential role of propolis in wound healing: Biological properties and therapeutic activities. Biomed Pharmacother. 2018 Feb;98:469-483. doi: 10.1016/j.biopha.2017.12.069. Epub 2017 Dec 27. PMID: 29287194.
  33. Kuo CC, , Wang R-H 2Wang H-H, Li C-H.. Meta-analysis of randomized controlled trials of the efficacy of propolis mouthwash in cancer therapy-induced oral mucositis. Support Care Cancer. 2018 Dec;26(12):4001-4009
  34. Moon JH, Lee MY, Chung YJ, Rhee CK, Lee SJ. Effect of Topical Propolis on Wound Healing Process After Tonsillectomy: Randomized Controlled Study. Clin Exp Otorhinolaryngol. 2018 Jun;11(2):146-150. doi: 10.21053/ceo.2017.00647. Epub 2017 Dec 28. PMID: 29665628; PMCID: PMC5951064.
  35. Jautová J, Zelenková H, Drotarová K, Nejdková A, Grünwaldová B, Hladiková M. Lip creams with propolis special extract GH 2002 0.5% versus aciclovir 5.0% for herpes labialis (vesicular stage) : Randomized, controlled double-blind study. Lippencreme mit 0,5 % Propolis-Spezialextrakt GH 2002 versus 5 % Aciclovir bei Herpes labialis (Bläschenstadium) : Randomisierte, kontrollierte Doppelblindstudie. Wien Med Wochenschr. 2019;169(7-8):193-201. doi:10.1007/s10354-018-0667-6.
  36. Al-Waili N. Mixing two different propolis samples potentiates their antimicrobial activity and wound healing property: A novel approach in wound healing and infection. Vet World. 2018 Aug; 11(8): 1188–1195.
  37. Aminimoghadamfarouj N, Nematollahi A. Propolis Diterpenes as a Remarkable Bio-Source for Drug Discovery Development: A Review. Int J Mol Sci. 2017;18(6):1290. Published 2017 Jun 17. doi:10.3390/ijms18061290
  38. Chen WT, Sun YK, Lu CH, Chao CY. Thermal cycling as a novel thermal therapy to synergistically enhance the anticancer effect of propolis on PANC‑1 cells. Int J Oncol. 2019;55(3):617-628. doi:10.3892/ijo.2019.4844
  39. Asgharpour F, Moghadamnia AA, Zabihi E, et al. Iranian propolis efficiently inhibits growth of oral streptococci and cancer cell lines. BMC Complement Altern Med. 2019;19(1):266. Published 2019 Oct 11. doi:10.1186/s12906-019-2677-3.
  40. Demir S, Aliyazicioglu Y, Turan I, Misir S, Mentese A, Yaman SO, Akbulut K, Kilinc K, Deger O. Antiproliferative and proapoptotic activity of Turkish propolis on human lung cancer cell line. Nutr Cancer. 2016;68(1):165-72. doi: 10.1080/01635581.2016.1115096. Epub 2015 Dec 23. PMID: 26700423.
  41. Zabaiou N, Fouache A, Trousson A, Baron S, Zellagui A, Lahouel M, Lobaccaro JA. Biological properties of propolis extracts: Something new from an ancient product. Chem Phys Lipids. 2017 Oct;207(Pt B):214-222. doi: 10.1016/j.chemphyslip.2017.04.005. Epub 2017 Apr 12. PMID: 28411017.
  42. Chiu HF, Han YC, Shen YC, Golovinskaia O, Venkatakrishnan K, Wang CK. Chemopreventive and Chemotherapeutic Effect of Propolis and Its Constituents: A Mini-review. J Cancer Prev. 2020;25(2):70-78. doi:10.15430/JCP.2020.25.2.70
  43. Jentzsch V et al, Cancers (Basel). 2020 Oct 23;12(11):3096
  44. Silva H, Francisco R, Saraiva A, Francisco S, Carrascosa C, Raposo A. The Cardiovascular Therapeutic Potential of Propolis-A Comprehensive Review. Biology (Basel). 2021;10(1):27. Published 2021 Jan 4. doi:10.3390/biology10010027
  45. Bojić M, Antolić A, Tomičić M, Debeljak Ž, Maleš Ž. Propolis ethanolic extracts reduce adenosine diphosphate induced platelet aggregation determined on whole blood. Nutr J. 2018;17(1):52. Published 2018 May 14. doi:10.1186/s12937-018-0361-y
  46. Pahlavani N, Malekahmadi M, Firouzi S, Rostami D, Sedaghat A, Moghaddam AB, Ferns GA, Navashenaq JG, Reazvani R, Safarian M, Ghayour-Mobarhan M. Molecular and cellular mechanisms of the effects of Propolis in inflammation, oxidative stress and glycemic control in chronic diseases. Nutr Metab (Lond). 2020 Aug 12;17:65. doi: 10.1186/s12986-020-00485-5. PMID: 32817750; PMCID: PMC7425411.
  47. Afsharpour FJavadi M, Hashemipour S, Koushan Y, Haghighian HK. Propolis supplementation improves glycemic and antioxidant status in patients with type 2 diabetes: A randomized, double-blind, placebo-controlled study. Complement Ther Med. 2019 Apr;43:283-288
  48. Silveira MAD, Teles F, Berretta AA, et al. Effects of Brazilian green propolis on proteinuria and renal function in patients with chronic kidney disease: a randomized, double-blind, placebo-controlled trial. BMC Nephrol. 2019;20(1):140. Published 2019 Apr 25. doi:10.1186/s12882-019-1337-7.
  49. Mujica V, Orrego R, Fuentealba R, Leiva E, Zúñiga-Hernández J. Propolis as an Adjuvant in the Healing of Human Diabetic Foot Wounds Receiving Care in the Diagnostic and Treatment Centre from the Regional Hospital of Talca. J Diabetes Res. 2019;2019:2507578. Published 2019 Sep 12. doi:10.1155/2019/2507578
  50. Farooqui T, Farooqui AA. Beneficial effects of propolis on human health and neurological diseases. Front Biosci (Elite Ed). 2012 Jan 1;4:779-93. doi: 10.2741/418. PMID: 22201913.
  51. Menezes da Silveira CCS, Luz DA, da Silva CCS, Prediger RDS, Martins MD, Martins MAT, Fontes-Júnior EA, Maia CSF. Propolis: A useful agent on psychiatric and neurological disorders? A focus on CAPE and pinocembrin components. Med Res Rev. 2021 Mar;41(2):1195-1215. doi: 10.1002/med.21757. Epub 2020 Nov 11. PMID: 33174618.

Endophytes – recent developments involving bugs that live inside plants

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

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

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

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

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

Endophytes as sources of antibiotics:

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

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

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

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

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

Cytotoxics

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

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

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

Other applications:

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

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

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

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

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

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

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

References:

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

LEMON BALM – A TRUE TONIC FOR STRESS

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

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

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

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

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

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

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

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

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

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

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

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

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

References:

  1. Culpeper, Nicholas. (1653). A Complete Herbal. London, Peter Cole.
  2. Kennedy DO et al,  Pharmacol Biochem Behav. 2002 Jul;72(4):953-64.
  3. Kennedy DO et al. Psychosom Med. Jul-Aug 2004;66(4):607-13
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