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Willow

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Background & General Info

Willows are a group of deciduous trees belonging to the genus Salix, which thrive primarily on moist soils in cold and temperate regions (and thus are absent or uncommon in the tropics) and generate copious amounts of watery bark sap. They are well known for their tough wood and huge, fibrous, often stoloniferous roots. The genus Salix comprises roughly 400 to 500 species that are chiefly distributed across the northern regions of North America and Europe and in the mountains of China and that are either wide-ranging, such as Salix nigra and Salix caroliniana, or localized, such as Salix floridana. [1]

Willows are woody plants that grow rapidly. Currently, willows are at the forefront not only as a key source of biomass, which is an exceptional alternative energy source, but also as a renewable and carbon dioxide-neutral energy source. Willow biomass can be utilized efficiently to produce electricity by co-firing it with coal and can be burned directly or converted to gas or liquid fuel. [2]

Willow forest assemblages are also exceedingly valued in the southwestern United States for their wildlife habitat, biodiversity, and watershed protection, although stream diversions, groundwater pumping, and extended drought have threatened them greatly and have led to the decline of willow forests.



Botany

Willows are generally distinguishable by their alternate, narrow, pointed leaves with yellow-green top and white bottom and with short stalk, although some species are known to have fatter and more rounded leaves. The leaves are also usually elongated and deciduous, with serrated edges in some species. Their fruits contain a tiny dark seed enclosed in a cottony tuft, and winter buds hug the twig and are covered by a single cap-like scale. As winter approaches and temperatures drastically drop, the yellow to green twigs die back to where the wood is hard and tough enough. [3]

During early spring, male and female willow flowers appear as slim, cylindrical flower clusters, or catkins, on different plants. Both the male and female flowers possess no calyx or corolla and consist basically of stamens or an ovary, respectively. [4]

History & Traditional Use

Perhaps the ultimate culprit of willow’s medicinal popularity is its being a source of salicylates, including salicin and salicylic acid, which can be derived from the bark and leaves of willow and poplar trees. Such molecules have been determined by several studies to exhibit phytotherapeutic and chemotherapeutic activities as analgesic drugs.

Since the earliest times during the prosperous period of the ancient Sumerians and Egyptians and of Hippocrates, Celsus, Pliny the Elder, Dioscorides, and Galen, willow and its natural products have been used as remedies for pain, fever, and inflammation. During the Middle Ages, Hildegard of Bingen and Henrik Harpestreng advised these remedies for fever and rheumatism, but it was only when the first “clinical trial” was reported by Edward Stone in 1763 on a successful treatment of malarial fever using the willow bark did willow capture the attention of the medical community. In 1829, the French pharmacist Pierre Joseph Leroux isolated salicin, and salicylic acid was first synthesized from salicin (salicoside) by Raffaelle Piria. [5] In 1876, T. MacLagan, and S. Stricker and L. Riess described the antirheumatic effect of salicin and salicylic acid, respectively. Although acetylsalicylic acid was already synthesized by Charles Gerhardt in 1853 and Felix Hoffmann in the Bayer Laboratories in 1897, the mechanism of analgesic action of acetylsalicylic acid (aspirin) by inhibition of prostaglandin synthesis was explained only in 1971 by John Vane. [6]

General Herbal Uses

Numerous traditional treatments incorporate willow species parts as remedy. Willow leaves have long been used in folk medicine as an antirheumatic, analgesic, and antipyretic herbal medicine. Nevertheless, being the source of salicylic acid (aspirin) stored in large quantities just under its tree bark is what makes willow truly prominent. Modern technology can now however offer aspirin in synthesized form in vitro, which is free of impurities and co-metabolites. It has been used to reduce blood pressure, to thin blood by reducing the platelet count, and to treat headaches. [7]

Due to their anti-inflammatory and analgesic properties, willow bark extracts have become broadly used in sports performance and weight loss products, but to date, no evaluative tests and studies have been conducted in humans that specifically and straightforwardly certify beneficial effects. [8]



Constituents/Active Components

Salicin is regarded as the major constituent of willow bark extract, which, when metabolized, turns into salicylic acid in vivo and plays an important role in the willow bark extract’s anti-inflammatory and analgesic effects Although willow bark extracts are generally standardized to salicin, other active components in the extract including other salicylates, polyphenols, and flavonoids are also responsible for the extracts’ therapeutic actions and biological activities. Moreover, the willow bark is specified to contain not less than 1.5% of total salicylic alcohol derivatives. [9]

A comprehensive analysis by Agnolet, Wiese, Verpoorte, and Staerk (2012) of a small set of commercial willow bark extracts by new technology platform identified 16 compounds, such as ampelopsin, taxifolin, 7-O-methyltaxifolin-3'-O-glucoside, and 7-O-methyltaxifolin, which have been reported for the first time in Salix alba bark extract. The analysis also led to the detection of a novel compound, ethyl 1-hydroxy-6-oxocyclohex-2-enecarboxylate. [10] Xylose, glucose, arabinose, galactose, and mannose compose the carbohydrate content of one-year willow wood, with xylose predominating. Willow species containing an abundance of polysaccharides, including cellulose, but the smallest amount of nonhydrolyzable residues are promising for use in the chemical wood-processing industry. The following table presents noteworthy species and their polysaccharide and nonhydrolyzable residue contents: [11]

Willow Compounds

Medicinal/Scientific Research

Pain Relief And Anti-Inflammatory

Willows have been extensively utilized as an herbal medicine for the treatment of pain. The potent analgesic and anti-inflammatory properties of the willow bark have been attributed to the flavonoids and polyphenols that it contains. [12] However, this still requires further research to verify and establish their effectiveness. In recent years, a number of in vitro and animal studies had indicated the association between the anti-inflammatory activity of willow bark extract and the downregulation of inflammatory mediators, in particular tumor necrosis factor-α and nuclear factor-kappa B. [8] Based on a 2009 systematic review on the effectiveness of willow bark in alleviating musculoskeletal pain, confirmatory and exploratory studies demonstrated that administration of willow bark has a dose-dependent analgesic effect in patients with low back pain; the said analgesic activity was deemed not inferior to rofecoxib, a nonsteroidal anti-inflammatory drug. [13]

A randomized double-blind study investigated the effectiveness of willow bark extract for the treatment of low back pain. The study involved 210 patients experiencing chronic low back pain exacerbation who reported a pain rating of 5 or more (out of 10) on the visual analog scale and who then were randomly assigned to the experimental group receiving an oral willow bark extract with either 120 mg (low dose) or 240 mg (high dose) of salicin and to the placebo group, with tramadol as the sole rescue medication. Out of the initial 210 patients, only 191 patients completed the 4-week blinded trial, with 27 (39%) pain-free patients out of 65 receiving high-dose extract, 15 (21%) pain-free patients out of 67 receiving low-dose extract, and 4 (6%) patients out of 59 belonging to the placebo group (p <0.001). It has been noted that after only 1 week of treatment did the response in the high-dose group become apparent and significantly more patients in the placebo group demanded tramadol (p <0.001) during each week of the trial. [14]

A 2016 Cochrane systematic review of randomized controlled trials to determine the efficacy of a variety of herbal medicines for nonspecific low back pain pointed out that white willow bark does seem to alleviate pain more than placebo, but the evidence for this is still of moderate quality at best. [15]

Arthritis

A double-blind, randomized controlled trial that lasted for 2 weeks was conducted by Schmid et al. (2001) to investigate the clinical effectiveness of chemically standardized willow bark extract in treating osteoarthritis. The trial enrolled 78 patients who randomly received either willow bark extract at a dose corresponding to 240 mg salicin/day (experimental group) or placebo (control group). Results revealed a statistically significant difference between the experimental and placebo groups in terms of Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain dimension (d = 6.5 mm, 95% CI = 0.2–12.7 mm, p = 0.047). WOMAC is a self-administered survey commonly used in the evaluation of hip and knee osteoarthritis with respect to pain, stiffness, and physical function, and in this trial, the WOMAC pain scores of patients decreased by 14% from the baseline level after 2 weeks of treatment but increased by 2% in the placebo group. The visual analogue scales supported this as well. Overall, the final assessments demonstrated superiority of the willow bark extract over the placebo, with willow bark extract conclusively exhibiting moderate well-tolerated analgesic effect in osteoarthritis. [16]

A 2013 observational study examined the effectiveness and safety of willow bark extract for the alleviation of pain among patients suffering from musculoskeletal disorders and evaluated monotherapy or combination therapy, dosage, and safety during long-term treatment under pragmatic conditions with the aqueous willow bark extract STW 33-I, (Proaktiv®; drug–extract ratio, 16–23:1). This study lasted for over 6 months and involved four hundred and thirty-six patients with rheumatic pain mainly due to osteoarthritis (56.2%) and back pain (59.9%), who were then treated with STW 33-I, followed by comedication with other nonsteroidal anti-inflammatory drugs and opioids. The findings from this study indicated a significant mean reduction from baseline value 58.4±22.6–31.8±22.5 after 24 weeks in the pain intensity scale, even after 3 weeks at the end of the study. The relative reductions of the weekly means of the daily patient self-rated scores of the pain (6-point Likert scales) were between 33% and 44% of the baseline values during the course of the study, and there was good tolerability to treatment, with no relevant drug interactions reported. [17]

The efficacy of willow bark extract in remedying painful mobility disorders such as back pain and arthritis is strongly related to its salicin content, as well as its derivatives. However, according to data from experimental pharmacological studies, salicin cannot entirely and solely elucidate the clinical effectiveness of willow bark, as salicin and its metabolites lack the acetylating potential of acetylsalicylic acid. A comprehensive pharmacological screening of the aqueous willow bark extract STW 33-I identified fractions contributing to the overall effect, and all in vivo and in vitro models studied pointed to applicable contributions of the fraction of polyphenols and flavonoids. [18]

Anticancer

A 2003 study published in the Journal of Biochemistry and Molecular Biology determined the antileukemic activity exerted by the crude water extracts of young developing leaves of willow trees. After incubation in vitro that lasted for a day, the willow leaf extract killed 73.8% of the blasts of acute myeloid leukemia. [19]

El-Shemy, A. Aboul-Enein, K. Aboul-Enein, and Fujita (2007) investigated the effect of an aqueous extract obtained from the young developing leaves of willow (Salix safsaf) trees against human carcinoma cells in vivo and in vitro. In this 2007 study, in vivo Ehrlich ascites carcinoma cells were introduced through injection into the intraperitoneal cavity of mice, and the willow aqueous extract was fed via stomach tube. Results from this study indicated a reduction in tumor growth by the willow extract and a delay in death (for 35 days). A notable lymphoblast destruction (75%) that was significantly higher than the control (7%) occurred after 24-hour incubation of the mononuclear acute lymphoblastic leukemia cells with willow extract. Furthermore, most abnormal cells (75%–80%) among primary cells collected from seven patients with acute lymphoblastic leukemia and thirteen patients with acute myeloid leukemia were killed in vitro by the willow extract, and there were DNA fragmentation patterns within treated cells, inferring targeted cell death by apoptosis. [7]

Enayat et al. (2013) suggested that the powerful anticarcinogenic effects of ethanolic willow bark extract come from the polyphenols and flavonoids it contains. Their study screened the anticancer properties of the ethanolic willow bark extract using HCT-116 and HT29 CRC cell lines. The ethanol extract was acquired from the fresh bark of Salix aegyptiaca, a Middle East willow species. Through analysis of the fractions by tandem mass spectrometry, it was found that catechin, catechol, and salicin were the most abundant constituents of the extract. The findings of this study have fascinatingly showed that the ethanolic willow bark extract had the highest anticancer effect against colon cancer cells tested, as compared with its fractions in ethyl acetate and water. The ethanolic willow bark extract had also strongly decreased the cancer cells’ proliferation, but not of CCD-18Co, a normal colon fibroblast cell line. Cell cycle arrest at G1/S independent of DNA damage in the cancer cells, induction of apoptosis through a p53-dependent pathway, and inhibition of PI3K/Akt and MAP kinase pathways at levels analogous to known commercial inhibitors were also observed. [20] Another similar study reported the inhibition of metastatic potential of colon cancer cell lines HCT-116 and HT-29, as well as their transition from epithelial to mesenchymal phases, by the ethanolic extract of S. aegyptiaca L. bark. Specifically, this 2014 study demonstrated the robust inhibition of anchorage-independent growth, motility, migration, and adhesion of colon cancer cell lines by ethanolic willow bark extract. Such were accompanied by a re-establishment of E-cadherin expression and a decrease in EGFR, SNAI1, SNAI2, and Twist1 and the matrix metalloproteases MMP9 and MMP2, several of which are considered proteins involved in epithelial to mesenchymal transition, which is a critical step in the development of noninvasive tumor cells into malignant, metastatic carcinomas. [21]

Antioxidant

Ishikado et al. (2013) provided evidence that supports that willow bark extract could induce antioxidant enzymes and prevent oxidative stress by activating nuclear factor erythroid 2-related factor 2 (Nrf2) independent of salicin. Nrf2 is classified as a redox-sensitive master regulatory transcription factor that contributes to protection against environmental oxidative stress. This study looked into the antioxidative property of willow bark extract in human umbilical vein endothelial cells (HUVECs) and Caenorhabditis elegans, a microscopic, free-living soil roundworm. The results demonstrated that cytotoxicity of HUVECs induced by oxidative stress and the death of C. elegans were prevented by willow bark extract, which dose-dependently increased the mRNA and protein expression levels of Nrf2 target genes, heme oxygenase-1, γ-glutamylcysteine ligase modifier, and catalytic subunits, as well as p62 and intracellular glutathione (GSH) in HUVECs. Moreover, the willow bark extract had boosted the intranuclear expression and DNA binding of Nrf2 and the activity of an antioxidant response element (ARE) reporter plasmid in HUVECs. [9]

Contraindications, Interactions, And Safety

Since the willow bark comprises multiple active components, it has a broader mechanism of action than aspirin and is devoid of serious adverse events. Additionally, the willow bark does not cause injury to the gastrointestinal mucosa, unlike synthetic aspirin, and a willow extract dose with 240 mg salicin results in no major impact on blood clotting. [12]

Vlachojannis, Cameron, and Chrubasik (2009) in a systematic review pointed out minor adverse events occurring during willow bark treatment in some investigative studies. [13] In the study of Chrubasik et al. (2000), one patient suffered from a severe allergic reaction that is likely due to the willow bark extract. [14] No significant adverse events were observed within the fourteen randomized controlled trials included in a 2016 Cochrane systematic review. [15]

At present, still little is published about the bioavailability, absorption, and metabolism of secondary metabolites of willow in humans, and more likely than not, the different groups of compounds present in willow have different pharmacokinetic properties. Patients with known allergy to aspirin must never use willow bark products.

References:

[1] S. Chrubasik, E. Eisenberg, E. Balan, T. Weinberger, R. Luzzati and C. Conradt, "Treatment of low back pain exacerbations with willow bark extract: a randomized double-blind study," American Journal of Medicine, vol. 109, no. 1, p. 9–14, 2000. https://www.ncbi.nlm.nih.gov/pubmed/10936472

[2] J. Vlachojannis, M. Cameron and S. Chrubasik, "A systematic review on the effectiveness of willow bark for musculoskeletal pain," Phytotherapy Research, vol. 23, no. 7, p. 897–900, 2009. https://www.ncbi.nlm.nih.gov/pubmed/19140170

[3] B. Schmid, R. Lüdtke, H. Selbmann, I. Kötter, B. Tschirdewahn, W. Schaffner and L. Heide, "Efficacy and tolerability of a standardized willow bark extract in patients with osteoarthritis: randomized placebo-controlled, double blind clinical trial," Phytotherapy Research, vol. 15, no. 4, p. 344–350, 2001. https://www.ncbi.nlm.nih.gov/pubmed/11406860

[4] S. Norn, H. Permin, P. Kruse and E. Kruse, "From willow bark to acetylsalicylic acid," Dansk Medicinhistorisk Arbog, vol. 37, p. 79–98, 2009. https://www.ncbi.nlm.nih.gov/pubmed/20509453

[5] O. Lafont, "From the willow to aspirin," Revue d'Histoire de la Pharmacie, vol. 55, no. 354, p. 209–216, 2007. https://www.ncbi.nlm.nih.gov/pubmed/18175528

[6] J. Vlachojannis, F. Magora and S. Chrubasik, "Willow species and aspirin: different mechanism of actions," Phytotherapy Research, vol. 25, no. 7, p. 1102–1104, 2011. https://www.ncbi.nlm.nih.gov/pubmed/21226125

[7] S. Zhang and D. D. Fernando, "Structural, histochemical, and protein analysis of male reproductive development in willow," Sexual Plant Reproduction, vol. 18, p. 37–46, 2005. http://link.springer.com/article/10.1007/s00497-005-0249-9

[8] E. Jensen, D. Zahler, B. Patterson and B. Littlefield, "Common Trees of the Pacific Northwest: Willows (Salix)," Oregon State University. http://oregonstate.edu/trees/broadleaf_genera/willow.html

[9] "Willow," Wikipedia. https://en.wikipedia.org/wiki/Willow

[10] G. Argus, "The genus Salix (Salicaceae) in the Southeastern United States," Systematic Botany Monographs, vol. 9, p. 1–170, 1986. https://www.researchgate.net/publication/271688422

[11] H. El-Shemy, A. Aboul-Enein, K. Aboul-Enein and K. Fujita, "Willow leaves' extracts contain anti-tumor agents effective against three cell types," PLoS ONE, vol. 2, no. 1, p. e178, 2007. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1779808/

[12] H. El-Shemy, A. Aboul-Enein, M. Aboul-Enein, S. Issa and K. Fujita, "The effect of willow leaf extracts on human leukemic cells in vitro," Journal of Biochemistry and Molecular Biology, vol. 36, no. 4, p. 387–389, 2003. https://www.ncbi.nlm.nih.gov/pubmed/12895297

[13] M. Shara and S. Stohs, "Efficacy and safety of white willow bark (Salix alba) extracts," Phytotherapy Research, vol. 29, no. 8, p. 1112–1116, 2015. https://www.ncbi.nlm.nih.gov/pubmed/25997859

[14] J. Gagnier, H. Oltean, M. van Tulder, B. Berman, C. Bombardier and C. Robbins, "Herbal medicine for low back pain: A Cochrane review," Spine Journal, vol. 41, no. 2, p. 116–133, 2016. https://www.ncbi.nlm.nih.gov/pubmed/17202897

[15] A. Nahrstedt, M. Schmidt, R. Jäggi, J. Metz and M. Khayyal, "Willow bark extract: the contribution of polyphenols to the overall effect," Wiener Medizinische Wochenschrift, vol. 157, no. 13–14, p. 348–351, 2007. https://www.ncbi.nlm.nih.gov/pubmed/17704985

[16] S. Enayat, M. Ceyhan, A. Başaran, M. Gürsel and S. Banerjee, "Anticarcinogenic effects of the ethanolic extract of Salix aegyptiaca in colon cancer cells: involvement of Akt/PKB and MAPK pathways," Nutrition and Cancer, vol. 65, no. 7, p. 1045–1058, 2013. https://www.ncbi.nlm.nih.gov/pubmed/24168160

[17] S. Enayat and S. Banerjee, "The ethanolic extract of bark from Salix aegyptiaca L. inhibits the metastatic potential and epithelial to mesenchymal transition of colon cancer cell lines," Nutrition and Cancer, vol. 66, no. 6, p. 999–1008, 2014. https://www.ncbi.nlm.nih.gov/pubmed/25175673

[18] B. Uehleke, J. Müller, R. Stange, O. Kelber and J. Melzer, "Willow bark extract STW 33-I in the long-term treatment of outpatients with rheumatic pain mainly osteoarthritis or back pain," Phytomedicine : International Journal of Phytotherapy and Phytopharmacology, vol. 20, no. 11, p. 980–984, 2013. https://www.ncbi.nlm.nih.gov/pubmed/23731658

[19] A. Ishikado, Y. Sono, M. Matsumoto, S. Robida-Stubbs, A. Okuno, et al., "Willow bark extract increases antioxidant enzymes and reduces oxidative stress through activation of Nrf2 in vascular endothelial cells and Caenorhabditis elegans," Free Radical Biology & Medicine, vol. 65, 2013. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3800243/

[20] S. Agnolet, S. Wiese, R. Verpoorte and D. Staerk, "Comprehensive analysis of commercial willow bark extracts by new technology platform: combined use of metabolomics, high-performance liquid chromatography-solid-phase extraction-nuclear magnetic resonance spectroscopy and high-resolution radical scavengin," Journal of Chromatography A, vol. 1262, p. 130–137, 2012. https://www.ncbi.nlm.nih.gov/pubmed/23021634

[21] A. Skrigan, T. Murashkevich, G. Pershina, N. Khorevskaya and S. Pimenova, "The chemical composition of the wood of some species of willow," Chemistry of Natural Compounds, vol. 3, no. 6, p. 328–330, 1967. https://www.researchgate.net/publication/226329907

Article researched and created by Dan Albir for herbs-info.com. © herbs-info.com 2018

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