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Planta Med 2019; 85(16): 1192-1202
DOI: 10.1055/a-1007-5206
Biological and Pharmacological Activity
Reviews
Georg Thieme Verlag KG Stuttgart · New York

United States Pharmacopeia Safety Review of Willow Bark

Hellen A. Oketch-Rabah
1   U. S. Pharmacopeial Convention, Rockville, MD, USA
,
Robin J. Marles
2   2015 – 2020 United States Pharmacopeia Dietary Supplements Admission Evaluations Joint Standard Setting Subcommittee (DSAE JS3), Rockville, MD, USA
,
Scott A. Jordan
2   2015 – 2020 United States Pharmacopeia Dietary Supplements Admission Evaluations Joint Standard Setting Subcommittee (DSAE JS3), Rockville, MD, USA
,
Tieraona Low Dog
2   2015 – 2020 United States Pharmacopeia Dietary Supplements Admission Evaluations Joint Standard Setting Subcommittee (DSAE JS3), Rockville, MD, USA
› Author Affiliations
Further Information

Publication History

received 08 July 2019
revised 03 September 2019

accepted 18 September 2019

Publication Date:
11 October 2019 (online)

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Abstract

Willow bark (Salix spp.) is an ingredient in some dietary supplements. No serious adverse effects were reported from trials of willow bark extracts delivering 120 – 240 mg salicin (the purported active constituent) daily for up to 8 weeks. All studies involved adults only; none involved special subpopulations such as pregnant or breastfeeding women, or children. The most common adverse effects associated with willow bark are gastrointestinal; a few allergic reactions were also reported. Some publications advise caution when taking willow bark. There is a risk of increased bleeding in vulnerable individuals, salicylates cross the placenta and are eliminated slowly in newborns, some persons are sensitive or allergic to aspirin, and children are at risk of Reye syndrome. Concurrent use with other salicylate-containing medicines increases these risks. Metabolism of 240 mg salicin from willow bark could yield 113 mg of salicylic acid, yet dietary supplement products are not required to be labeled with warnings. In contrast, over-the-counter low-dose aspirin (81 mg strength), which delivers 62 mg salicylic acid, is required by law to include cautions, warnings, and contraindications related to its use in pregnant and nursing women, children, and other vulnerable subpopulations, e.g., those using anticoagulants. In the interest of protecting public health, the United States Pharmacopeia has included a cautionary labeling statement in the United States Pharmacopeia Salix Species monograph as follows: “Dosage forms prepared with this article should bear the following statement: ‘Not for use in children, women who are pregnant or nursing, or by persons with known sensitivity to aspirin.’”

Key words

salix - Salicaceae - willow bark - Reye syndrome - salicin - salicylic acid - salicylates - dietary supplements
 

  • References

  • 1 European Medicines Agency (EMA)-Committee on Herbal Medicinal Products (HMPC). Assessment report on Salix [various species including S. purpurea L., S. daphnoides Vill., S. fragilis L.], corte. Available at: https://www.ema.europa.eu/en/documents/herbal-report/final-assessment-report-salix-various-species-including-s-purpurea-l-s-daphnoides-vill-s-fragilis-l_en.pdf Accessed: August 19, 2019
    PubMedGoogle Scholar
  • 2 Applequist W. The identification of medicinal plants: a handbook of the morphology of botanicals in commerce. St. Louis: Missouri Botanical Garden Press; 2007
    Google Scholar
  • 3 Wood JN. From plant extract to molecular panacea: a commentary on Stone (1763) ʼAn account of the success of the bark of the willow in the cure of the aguesʼ. Philos Trans R Soc Lond B Biol Sci 2015; 370: 20140317
    CrossrefPubMedGoogle Scholar
  • 4 Mahdi JG. Medicinal potential of willow: A chemical perspective of aspirin discovery. J Saudi Chem Soc 2010; 14: 317-322
    CrossrefPubMedGoogle Scholar
  • 5 Mahdi JG, Mahdi AJ, Bowen ID. The historical analysis of aspirin discovery, its relation to the willow tree and antiproliferative and anticancer potential. Cell Prolif 2006; 39: 147-155
    CrossrefPubMedGoogle Scholar
  • 6 Authorities of the Medical Societies and Colleges. The Pharmacopoeia of the United States of America. Boston, MA: Wells and Lilly; 1820
    Google Scholar
  • 7 Shara M, Stohs SJ. Efficacy and safety of white willow bark (Salix alba) extracts. Phytother Res 2015; 29: 1112-1116
    CrossrefPubMedGoogle Scholar
  • 8 Oketch-Rabah HA, Roe AL, Muldoon-Jacobs K, Giancaspro GI. Challenges and opportunities for improving the safety assessment of botanical dietary supplements: a united states pharmacopeia perspective. Clin Pharmacol Ther 2018; 104: 426-429
    PubMedGoogle Scholar
  • 9 USP. Guideline for the Admission of Dietary Supplement Ingredients to the USP–NF Monograph Development Process. Available at: https://www.usp.org/sites/default/files/usp/document/get-involved/submission-guidelines/guideline-for-the-admission-of-dietary-supplement-ingredients.pdf Accessed: August 19, 2019
    PubMedGoogle Scholar
  • 10 USP. Sample USP-NF monograph. Available at: https://www.uspnf.com/sites/default/files/usp_pdf/EN/USPNF/sample_monograph.pdf Accessed: August 19, 2019
    PubMedGoogle Scholar
  • 11 USP. Reference Standards. Available at: https://www.usp.org/reference-standards Accessed: August 19, 2019
    PubMedGoogle Scholar
  • 12 Bradley PR. British Herbal Compendium, Volume 1. A Handbook of Scientific Information on Widely Used Plant Drugs. Companion to Volume 1 of the British Herbal Pharmacopoeia. Bournemouth, Dorset: British Herbal Medicine Association; 1992
    Google Scholar
  • 13 Wichtl M. Herbal Drugs and Phytopharmaceuticals: A Handbook for Practice on a Scientific Basis. Stuttgart: CRC Press; 2004
    Google Scholar
  • 14 Gawlik-Dziki U, Sugier D, Dziki D, Sugier P. Bioaccessibility in vitro of nutraceuticals from bark of selected Salix species. ScientificWorldJournal 2014; 2014: 782763
    PubMedGoogle Scholar
  • 15 WHO. Cortex Salicis. In: Volume 4 WHO Monographs on Selected Medicinal Plants. Geneva, Switzerland: WHO; 2009
    Google Scholar
  • 16 Förster N, Ulrichs C, Zander M, Kätzel R, Mewis I. Influence of the season on the salicylate and phenolic glycoside contents in the bark of Salix daphnoides, Salix pentandra, and Salix purpurea . J Appl Bot Food Qual 2012; 82: 99-102
    PubMedGoogle Scholar
  • 17 Noleto-Dias C, Ward JL, Bellisai A, Lomax C, Beale MH. Salicin-7-sulfate: A new salicinoid from willow and implications for herbal medicine. Fitoterapia 2018; 127: 166-172
    CrossrefPubMedGoogle Scholar
  • 18 Nahrstedt A, Schmidt M, Jaggi R, Metz J, Khayyal MT. Willow bark extract: the contribution of polyphenols to the overall effect. Wien Med Wochenschr 2007; 157: 348-351
    CrossrefPubMedGoogle Scholar
  • 19 Shao Y. Phytochemischer Atlas der Schweizer Weiden [Diss. Naturwiss.]. ETH Zurich; 1991 Nr. 9532
    PubMedGoogle Scholar
  • 20 Jurgenliemk G, Petereit F, Nahrstedt A. Flavan-3-ols and procyanidins from the bark of Salix purpurea L. Pharmazie 2007; 62: 231-234
    PubMedGoogle Scholar
  • 21 Freischmidt A, Jurgenliemk G, Kraus B, Okpanyi SN, Muller J, Kelber O, Weiser D, Heilmann J. Contribution of flavonoids and catechol to the reduction of ICAM-1 expression in endothelial cells by a standardised Willow bark extract. Phytomedicine 2012; 19: 245-252
    CrossrefPubMedGoogle Scholar
  • 22 United States Pharmacopeia (USP). Salix Species Bark. In: USP42-NF37 . Rockville, MD: United States Pharmacopeia (USP); 2019: 5185
    Google Scholar
  • 23 European Pharmacopoeia (Ph. Eur.). Willow bark (Salicis Cortex), Willow Bark Dry Extract (Salicis Corticis Extracum Siccum). In: 9th Edition 2019 (9.8). European Pharmacopoeia (Ph Eur). Strasbourg, France: The European Directorate for the Quality of Medicines & HealthCare; 2019: 1561-1562
    Google Scholar
  • 24 ESCOP (European Scientific Cooperative on Phytotherapy). ESCOP Monographs: Salicis cortex, Willow Bark, Salix spp. including S. purpurea L., S. daphnoides Vill. and S. fragilis L. 2017. Available at: http://escop.com Accessed: August 19, 2019
    PubMedGoogle Scholar
  • 25 National Institutes of Health (NIH). Dietary Supplement Label Database. In: Version 7.0.7 – May 2019 (5a1ad7d). Bethesda, MD: Office of Dietary Supplements and National Library of Medicine; 2019
    Google Scholar
  • 26 Canada H. Willow Bark Natural Health Product Monograph. October 18, 2013. Available at: http://webprod.hc-sc.gc.ca/nhpid-bdipsn/atReq.do?atid=white.wil.saule.bla&lang=eng Accessed August 23, 2019
    PubMedGoogle Scholar
  • 27 Blumenthal M, Goldberg A, Brinckmann J. Herbal Medicine. Expanded Commission E monographs: Integrative Medicine Communications. Newton, MA: 2000
    Google Scholar
  • 28 United Natural products Alliance (UNPA). Old Dietary Ingredient List. Available at: http://dnndvlduk.cloudapp.net/Portals/0/Documents/News/UNPA_ODI_List%207-23-08.pdf Accessed: August 19, 2019
    PubMedGoogle Scholar
  • 29 Canada H. Natural Health Products Ingredients Database. 2019. Available at: http://webprod.hc-sc.gc.ca/nhpid-bdipsn/search-rechercheReq.do?lang=eng Accessed: August 23, 2019
    PubMedGoogle Scholar
  • 30 Canada H. Licensed Natural Health Products Database. 2019. Available at: https://health-products.canada.ca/lnhpd-bdpsnh/index-eng.jsp Accessed: August 22, 2019
    PubMedGoogle Scholar
  • 31 Government A. Australian Register of Therapeutic Goods. 2019. Available at: https://www.tga.gov.au/artg Accessed: August 22, 2019
    PubMedGoogle Scholar
  • 32 Biegert C, Wagner I, Ludtke R, Kotter I, Lohmuller C, Gunaydin I, Taxis K, Heide L. Efficacy and safety of willow bark extract in the treatment of osteoarthritis and rheumatoid arthritis: results of 2 randomized double-blind controlled trials. J Rheumatol 2004; 31: 2121-2130
    PubMedGoogle Scholar
  • 33 WOMAC. Western Ontario and McMaster Universities Arthritis Index (WOMAC). Available at: https://web.archive.org/web/20180815012621/http://www.womac.org:80/womac/index.htm Accessed: August 19, 2019
    PubMedGoogle Scholar
  • 34 Crichton N. Visual analogue scale (VAS). J Clin Nurs 2001; 10: 706
    PubMedGoogle Scholar
  • 35 Saller R, Melzer J, Felder M, Group SAS. Pain relief with a proprietary extract of Willow Bark in rheumatology. An open trial. Schweizerische Zeitschrift fur GanzheitsMedizin 2008; 20: 156
    PubMedGoogle Scholar
  • 36 Schmidt B, Ludtke R, Selbmann HK, Kotter I, Tschirdewahn B, Schaffner W, Heide L. Efficacy and tolerability of a standardized willow bark extract in patients with osteoarthritis: randomized placebo-controlled, double blind clinical trial. Phytother Res 2001; 15: 344-350
    CrossrefPubMedGoogle Scholar
  • 37 Uehleke B, Muller J, Stange R, Kelber O, Melzer J. Willow bark extract STW 33-I in the long-term treatment of outpatients with rheumatic pain mainly osteoarthritis or back pain. Phytomedicine 2013; 20: 980-984
    CrossrefPubMedGoogle Scholar
  • 38 Beer AM, Wegener T. Willow bark extract (Salicis cortex) for gonarthrosis and coxarthrosis–results of a cohort study with a control group. Phytomedicine 2008; 15: 907-913
    CrossrefPubMedGoogle Scholar
  • 39 Chrubasik S, Künzel O, Black A, Conradt C, Kerschbaumer F. Potential economic impact of using a proprietary willow bark extract in outpatient treatment of low back pain: an open non-randomized study. Phytomedicine 2001; 8: 241-251
    CrossrefPubMedGoogle Scholar
  • 40 Chrubasik S, Eisenberg E, Balan E, Weinberger T, Luzzati R, Conradt C. Treatment of low back pain exacerbations with willow bark extract: a randomized double-blind study. Am J Med 2000; 109: 9-14
    CrossrefPubMedGoogle Scholar
  • 41 Manniche C, Asmussen K, Lauritsen B, Vinterberg H, Kreiner S, Jordan A. Low Back Pain Rating scale: validation of a tool for assessment of low back pain. Pain 1994; 57: 317-326
    CrossrefPubMedGoogle Scholar
  • 42 Akao T, Yoshino T, Kobashi K, Hattori M. Evaluation of salicin as an antipyretic prodrug that does not cause gastric injury. Planta Med 2002; 68: 714-718
    Article in Thieme ConnectPubMedGoogle Scholar
  • 43 Meier B, Sticher O, Julkunen-Tiitto R. Pharmaceutical aspects of the use of willows in herbal remedies. Planta Med 1988; 54: 559
    Article in Thieme ConnectPubMedGoogle Scholar
  • 44 Schmid B, Kotter I, Heide L. Pharmacokinetics of salicin after oral administration of a standardised willow bark extract. Eur J Clin Pharmacol 2001; 57: 387-391
    CrossrefPubMedGoogle Scholar
  • 45 Foetsch G, Pfeifer S. Vergleichende Serumspiegeluntersuchung von Salicylsäure nach oraler Applikation von Salicin bzw. Natriumsalicytalat in Ratten. Pharmazie 1990; 45: 535-536
    PubMedGoogle Scholar
  • 46 Higgs GA, Salmon JA, Henderson B, Vane JR. Pharmacokinetics of aspirin and salicylate in relation to inhibition of arachidonate cyclooxygenase and antiinflammatory activity. Proc Natl Acad Sci U S A 1987; 84: 1417-1420
    CrossrefPubMedGoogle Scholar
  • 47 Krivoy N, Pavlotzky E, Chrubasik S, Eisenberg E, Brook G. Effect of salicis cortex extract on human platelet aggregation. Planta Med 2001; 67: 209-212
    Article in Thieme ConnectPubMedGoogle Scholar
  • 48 Shalansky S, Lynd L, Richardson K, Ingaszewski A, Kerr C. Risk of warfarin-related bleeding events and supratherapeutic international normalized ratios associated with complementary and alternative medicine: a longitudinal analysis. Pharmacotherapy 2007; 27: 1237-1247
    CrossrefPubMedGoogle Scholar
  • 49 Gardner Z, McGuffin M. American Herbal Products Associationʼs botanical safety handbook. Boca Raton: CRC Press; 2013
    Google Scholar
  • 50 Jennings A. Link between salicylate and willow bark. Pharm J 2006; 276: 417
    PubMedGoogle Scholar
  • 51 Boullata JI, McDonnell PJ, Oliva CD. Anaphylactic reaction to a dietary supplement containing willow bark. Ann Pharmacother 2003; 37: 832-835
    CrossrefPubMedGoogle Scholar
  • 52 Srivali N, Cheungpasitporn W, Chongnarungsin D, Edmonds LC. White willow bark induced acute respiratory distress syndrome. N Am J Med Sci 2013; 5: 330
    CrossrefPubMedGoogle Scholar
  • 53 Baker S, Thomas PS. Herbal medicine precipitating massive haemolysis. Lancet 1987; 1: 1039-1040
    PubMedGoogle Scholar
  • 54 Colonna P. Aspirin and glucose-6-phosphate dehydrogenase deficiency. Br Med J (Clin Res Ed) 1981; 283: 1189
    PubMedGoogle Scholar
  • 55 Dinakaran D, Bristow E, Armanious H, Garros D, Yap J, Noga M, Sergi C. Co-ingestion of willow bark tea and acetaminophen associated with fatal infantile fulminant liver failure. Pediatr Int 2017; 59: 743-745
    CrossrefPubMedGoogle Scholar
  • 56 German Federal Institute for Risk Assessment (BfR), Unit of Food Toxicology Germany. Matyjaszczyk E, Schumann R. Risk assessment of white willow (Salix alba) in food. EFSA Journal 2018; 16: e16081
    PubMedGoogle Scholar
  • 57 Algreen M, Trapp S, Rein A. Phytoscreening and phytoextraction of heavy metals at Danish polluted sites using willow and poplar trees. Environ Sci Pollut Res Int 2014; 21: 8992-9001
    CrossrefPubMedGoogle Scholar
  • 58 Mleczek M, Rissmann I, Rutkowski P, Kaczmarek Z, Golinski P. Accumulation of selected heavy metals by different genotypes of Salix. Environ Exp Bot 2009; 66: 289-296
    CrossrefPubMedGoogle Scholar
  • 59 Van Slycken S, Witters N, Meiresonne L, Meers E, Ruttens A, Van Peteghem P, Weyens N, Tack FM, Vangronsveld J. Field evaluation of willow under short rotation coppice for phytomanagement of metal-polluted agricultural soils. Int J Phytoremediation 2013; 15: 677-689
    CrossrefPubMedGoogle Scholar
  • 60 Gasser U, Klier B, Kuhn A, Steinhoff B. Current findings on the heavy metal content in herbal drugs. Pharmeur Sci Notes 2009; 1: 37-50
    PubMedGoogle Scholar
  • 61 European Pharmacopoeia (Ph. Eur.) 9.2. Herbal drugs, general monograph 07/2017: 1433. Available at: http://online6.edqm.eu/ep908/ Accessed October 1, 2019
    PubMedGoogle Scholar