White willow

White Willow (Salix alba L.) — Encyclopedic Reference

1. Identity: Botanical Classification, Common Names, and Natural Source

White willow is a deciduous tree belonging to the genus Salix of the family Salicaceae. Scientifically known as Salix alba, it is a deciduous tree native to Europe and western Asia. The genus is large: there are about 500 species of Salix called willow, mainly found in Europe and North America. From a medicinal standpoint, multiple species are relevant. The species of medical interest include Salix alba, S. nigra, and S. purpurea, but S. daphnoides and S. fragilis along with S. purpurea contain the greatest yield of salicylate precursors.

The official pharmacopoeial definition of the herbal drug is precise: according to the European Pharmacopoeia (01/2005:1583), the herbal substance is the whole or fragmented dried bark of young branches or whole dried pieces of current-year twigs of various species of the genus Salix, including S. purpurea L., S. daphnoides Vill., and S. fragilis L. The drug contains not less than 1.5% of total salicylic derivatives, expressed as salicin. By this herbal monograph definition, the herbal drug consists of the whole or fragmented dried bark of young branches or whole dried pieces of current-year twigs of various species of the genus Salix.

Common names in commerce and traditional use include white willow bark, European willow, and Salicis cortex (the Latin pharmacopoeial name). The medicinal part is exclusively the bark of young branches; leaves and roots are not part of the official monograph preparation. The extract is primarily obtained from the inner bark, which contains natural salicin and other phenolic compounds responsible for its analgesic and anti-inflammatory properties.

2. Traditional and Historical Use

2.1 Ancient Near East and Egypt

The fascinating history of aspirin actually dates back more than 3,500 years, when willow bark was used as a painkiller and antipyretic by Sumerians and Egyptians, and then by great physicians from ancient Greece and Rome. Documentation suggests that civilizations such as the Sumerians and Egyptians were aware of the bark's medicinal benefits, and Salix alba was specifically utilized for its health-promoting properties.

2.2 Ancient Greece and Rome

The seminal Greek physician Hippocrates reportedly prescribed willow bark and leaves for fever and the pain of childbirth. Hippocrates, often called the father of medicine, was known for prescribing the use of willow bark to alleviate fevers and pain. This practice extended into the works of Dioscorides, a Greek physician, pharmacologist, and botanist of the 1st century CE, who similarly promoted the use of willow in treatment. Other cultures soaked willow leaves and applied them topically for use as a painkiller.

2.3 Indigenous North American Use

Historical accounts and archaeological evidence indicate that Indigenous Peoples in North America really did use willow bark to treat aches, pains, and fevers long before 18th-century cleric Edward Stone introduced willow bark as a medicine in England. Native American tribes throughout North America used various willow species for pain relief, fever reduction, and as an anti-inflammatory agent. The Cherokee, Iroquois, and other Eastern Woodlands tribes prepared willow bark decoctions for headaches, arthritis, and general pain relief, while Pacific Northwest tribes used it for wounds and skin conditions.

2.4 Traditional Chinese Medicine

In Traditional Chinese Medicine (TCM), willow bark was used to "cool" the body and combat headache symptoms, particularly those linked to excess heat or an overactive inflammatory response.

2.5 Early Modern European Use and the Discovery of Salicin

It was not until 1763 that the Reverend Edward Stone of the Royal Society of London conducted one of the first clinical studies on the effects of willow-bark powder by treating patients suffering from ague (a fever thought to be caused by malaria). On April 25, 1763, Stone wrote to George Parker, second earl of Macclesfield and president of the Royal Society, describing the use of dried willow bark as a remedy for fevers and agues. Stone gave powdered willow bark over several years to about 50 people complaining of agues or fevers, with success in many of them.

Approximately 100 years later, the Scottish physician Thomas MacLagan studied the effects of willow powder on patients suffering from acute rheumatism, demonstrating that it could relieve fever and joint inflammation. In 1828, Joseph Buchner, professor of pharmacy at Munich University, Germany, succeeded in extracting the active ingredient from willow, producing bitter-tasting yellow crystals that he named salicin. In 1853, French chemist Charles Frédéric Gerhardt determined the chemical structure of salicylic acid and chemically synthesized acetylsalicylic acid. In 1898, salicin was converted to acetylsalicylic acid and sold as Aspirin by the Bayer company.

2.6 Traditional Preparations

Historically, the most common preparations involved direct chewing of the bark or decoction (prolonged boiling in water). Technically, raw willow bark is edible, and it has been historically chewed for natural relief; however, it is extremely bitter and tough to digest, making it less practical. Preparation methods such as brewing it into a tea, creating a decoction, or using tinctures and capsules are much more effective and easier on the stomach. The extract is available in various forms including hydroalcoholic or aqueous extracts, dried preparations, or as tinctures or solutions.

3. Key Constituents and Active Compounds

3.1 Salicylate Glycosides (Primary Markers)

Salicylate derivatives are the primary medicinal constituents of willow bark. While small amounts of salicylic acid can be detected in most species, the principal salicylates of S. alba are the phenolic ester glycoside salicortin and glycoside salicin, its acid hydrolysis product. Although salicin is considered the major active constituent, there is research interest in the anticancer activity of polyphenols and flavonoids of willow bark.

The characteristic constituents are derivatives of salicin, mainly salicortin, 2'-O-acetylsalicortin, and/or tremulacin. Other constituents include flavonoids, condensed tannins (8–20%), and catechins. Salicin and its related compounds have been used as a marker of biological activity and quality of willow bark. Other constituents are also used as markers including derivatives of salicin such as salicortin, 2'-O-acetylsalicortin, salicin-7-sulfate, and tremulacin, as well as flavonoids, condensed tannins (8–20%), and catechins. The concentration of salicylates varies significantly between willow species and with the seasons.

3.2 Polyphenols, Flavonoids, and Tannins

Although willow bark extracts are generally standardized to salicin, other compounds in the extracts, including polyphenols, may also play prominent roles in areas such as cosmetology. Proanthocyanidins exhibit various biological activities including antihypertensive, antioxidative, and anti-inflammatory properties. The possible mechanism of anti-inflammatory action of proanthocyanidin dimers B1 and B2 may be connected with the inhibition of transcription of nuclear factor-kappa B (NF-κB). The condensed tannin fraction of willow bark is substantial, representing 8–20% of dry bark weight in the commercially important species.

3.3 Variability in Composition

Standardization to salicin content is important for product comparability, as the concentration of salicylates varies significantly between willow species and with the seasons, but there is only limited variation in phytochemical content between high-salicylate commercial species such as S. purpurea and S. daphnoides. The European Pharmacopoeia sets a minimum of 1.5% total salicylates expressed as salicin for the herbal drug.

4. Mechanisms of Action

4.1 Salicin-to-Salicylic Acid Conversion

Salicin is probably the most active anti-inflammatory compound in willow; it is metabolized to salicylic acid. The genus Salix is traditionally used in folk medicine and represents a valuable source of biologically active compounds, among them salicin, a prodrug for salicylic acid. The latter is oxidized, upon absorption, into salicylic acid, the active drug which inhibits cyclooxygenases (COX I, II). The analgesic actions of willow are typically slow to develop but may last longer than the effects of standard aspirin products.

4.2 Beyond Salicin: Multi-Component Activity

A key finding from pharmacological research is that salicin alone does not fully explain the clinical effects of willow bark extract. The efficacy of willow bark extract in the treatment of painful mobility disorders has been attributed to the content of salicin and its derivatives as pro-drugs of salicylates. However, based on clinical experience and the evidence of experimental pharmacological studies, the fraction of total salicin cannot satisfactorily explain the clinical efficacy of willow bark. In addition, salicins and their metabolites lack the acetylating potential of acetylsalicylic acid (ASA) and must therefore possess a different mechanism of action.

A detailed pharmacological screening of the aqueous willow bark extract STW 33-I addressed the question of the identification of fractions contributing to the overall effect. All in vivo and in vitro models studied pointed to relevant contributions of the fraction of polyphenols and flavonoids. Willow species contain only a low quantity of the prodrug salicin, which is metabolized during absorption into various salicylate derivatives. If calculated as salicylic acid, the daily salicin dose is insufficient to produce analgesia. Salicylic acid concentrations following an analgesic dose of aspirin are an order of magnitude higher.

Flavonoids and polyphenols contribute to the potent willow bark analgesic and anti-inflammatory effect. The multi-component active principle of willow bark provides a broader mechanism of action than aspirin and is devoid of serious adverse events. In contrast to synthetic aspirin, willow bark does not damage the gastrointestinal mucosa.

4.3 COX Inhibition, Cytokine Suppression, and Antioxidant Effects

Willow bark extract inhibits pro-inflammatory cytokines, such as tumor necrosis factor α (TNFα), cyclooxygenase-2 (COX-2), and the nuclear translocation of the transcription factor in proinflammatory activated monocytes, resulting in its anti-inflammatory effect. Willow bark is used to relieve fever, sore throat, headache, and flu, mainly due to the presence of salicin, which is a natural nonselective COX-1 and COX-2 inhibitor.

In a comparative pharmacological study of the standardized extract STW 33-I, on a mg/kg basis, the extract was at least as effective as ASA in reducing inflammatory exudates and in inhibiting leukocytic infiltration, as well as in preventing the rise in cytokines, and was more effective than ASA in suppressing leukotrienes but equally effective in suppressing prostaglandins. On COX-2, STW 33-I was more effective than ASA. The present findings show that STW 33-I significantly raises GSH (reduced glutathione) levels, an effect which helps to limit lipid peroxidation. The extract was more potent than either ASA or celecoxib in this regard.

A clinical study demonstrated that the ingestion of willow bark extract delivering 240 mg salicin (1360 mg extract) in divided doses resulted in an area under the curve equivalent to that expected from an intake of 87 mg acetylsalicylic acid. The bioavailability was 43.3%, peak serum levels were 1.2 mg/L, and both were reached within 2 hours after ingestion. This pharmacokinetic profile — relatively slow absorption and moderate bioavailability — is consistent with the clinical observation that the onset of analgesia with willow bark preparations is typically delayed compared to synthetic aspirin.

5. Scientific Evidence by Area of Use

5.1 Low Back Pain

Low back pain is the best-studied and best-supported clinical indication for willow bark extract. The best-supported use area for willow bark is short-term lower back pain. EMA states that dry willow bark extract can be used for short-term treatment of lower back pain, while NCCIH states that only a small number of studies support willow bark extracts in chronic low-back pain and osteoarthritis.

Key randomized controlled trial (RCT): In a landmark RCT, 210 patients with an exacerbation of chronic low back pain reporting current pain of 5 or more on a visual analog scale were enrolled. They were randomly assigned to receive an oral willow bark extract with either 120 mg (low dose) or 240 mg (high dose) of salicin, or placebo, with tramadol as the sole rescue medication, in a 4-week blinded trial. The principal outcome measure was the proportion of patients who were pain-free without tramadol for at least 5 days during the final week of the study. The numbers of pain-free patients in the last week of treatment were 27 (39%) of 65 in the group receiving high-dose extract, 15 (21%) of 67 in the group receiving low-dose extract, and 4 (6%) of 59 in the placebo group (P <0.001). The response in the high-dose group was evident after only 1 week of treatment.

Systematic review evidence: All studies in the 2009 systematic review investigated ethanolic extracts with daily doses up to 240 mg salicin over periods of up to six weeks. Minor adverse events occurred during treatment. The review provides moderate evidence of effectiveness for the use of ethanolic willow bark extract in low back pain. One confirmatory and two exploratory studies indicate a dose-dependent analgesic effect not inferior to rofecoxib in patients with low back pain.

Cochrane-level evidence: A 2014 Cochrane review of 2 clinical trials involving 261 participants found moderate-quality evidence that daily doses of white willow bark are probably better than placebo for short-term improvements in low-back pain and may reduce the use of rescue medication. The Cochrane evidence summary for herbal medicine for low-back pain reports that standardized Salix alba doses delivering 120 mg or 240 mg salicin/day are probably better than placebo for short-term improvements (moderate-quality evidence in that summary).

Evidence strength assessment: Moderate. The primary RCT is well-designed and shows a statistically significant, dose-dependent effect. However, the total number of trials remains small and study durations are short (4–6 weeks), limiting conclusions about long-term efficacy.

5.2 Osteoarthritis

One study assessed the clinical efficacy of a chemically standardized willow bark extract in the treatment of osteoarthritis. Willow bark extract, in a dose corresponding to 240 mg salicin/day, was compared with placebo in a 2-week, double-blind, randomized controlled trial. The primary outcome measure was the pain dimension of the WOMAC Osteoarthritis Index. A total of 78 patients (39 willow bark extract, 39 placebo) participated. A statistically significant difference between the active treatment and the placebo group was observed in the WOMAC pain dimension; the WOMAC pain score was reduced by 14% from the baseline level after 2 weeks of active treatment, compared with an increase of 2% in the placebo group. Willow bark extract shows a moderate analgesic effect in osteoarthritis.

A 2023 meta-analysis reviewed the evidence more broadly: it included five studies with six RCTs consisting of 329 patients with arthritis. The results showed significant differences in pain relief and improvement in physical status for patients with arthritis between willow bark treatment and placebo groups, and no significant differences in the risk of all adverse events. Owing to potential bias, the certainty and evidence of the findings are still inadequate, and further RCTs are needed to confirm the results.

However, conflicting results also exist: in one exploratory and one confirmatory study, conflicting results were achieved in participants with osteoarthritis. Three studies with RCT design showed that willow bark extract yielded no significant benefit. According to one group of investigators, although salicin derivatives in the willow bark were metabolized in vivo to salicylic acid, serum salicylate concentration was too low to reach clinical effects.

Evidence strength assessment: Limited to moderate. Some RCTs and one meta-analysis show a positive signal, but the total number of trials is small, results are mixed, and the meta-analysis itself noted inadequate certainty of evidence. Further trials with higher salicin doses and longer durations are needed.

5.3 Rheumatoid Arthritis

No significant effect was seen in a confirmatory study in patients with rheumatoid arthritis, but this study was grossly underpowered. Further studies are required to find out if treatment of osteoarthritis and rheumatoid arthritis requires extract with higher doses than 240 mg salicin per day.

Evidence strength assessment: Insufficient. The single available confirmatory trial was underpowered and showed no effect. No reliable conclusions can be drawn for rheumatoid arthritis.

5.4 Fever and Headache

Willow bark has been used for centuries as a treatment for pain, headache, and inflammatory conditions such as bursitis and tendinitis. The European Medicines Agency (EMA) Committee on Herbal Medicinal Products recognizes willow bark preparations for headache relief in adults under a traditional-use framework, meaning the evidence rests on longstanding safe use rather than robust clinical trial data for headache specifically. Regulatory bodies including the EMA (2017), ESCOP, and Health Canada recognize willow bark for: short-term relief of lower back pain, relief of minor joint pain (due to osteoarthritis), and relief of fever associated with the common cold (all per EMA 2017). Health Canada also recognizes relief of headache (EMA 2017) as a recognized indication. For fever and headache specifically, the regulatory framework is traditional use, not well-established use, reflecting the absence of prospective RCT data for these particular endpoints.

Evidence strength assessment for fever/headache: Traditional use only. Mechanistic plausibility is clear, but no dedicated clinical trials in humans have been conducted for these specific endpoints at the standard of modern RCT methodology.

5.5 Anticancer/Antiproliferative Activity

Willow bark extract has the therapeutic effect of preventing oxidative stress and induces apoptosis in human colon and lung cancer cells. To investigate possible anti-proliferative and pro-apoptotic effects of willow bark, a water extract (STW 33-1) and a polyphenol-rich fraction (fraction E) have been tested using the colon-carcinoma cell line HT-29. Both STW 33-1 and its fraction E showed significant anti-proliferative and pro-apoptotic effects on HT-29 cancer cells. In recent decades, aspirin has become the focus of extensive investigation into antiproliferative and anticancer activities. The historical steps that led to the discovery of aspirin and its antiproliferative and anticancer potential are highlighted in the research literature.

Evidence strength assessment: Preliminary, in vitro only. No human clinical trials have been conducted for cancer endpoints. These findings should be considered hypothesis-generating only.

6. Body Systems and Health Areas

• Musculoskeletal system: The primary evidence-based application. Supported by RCTs and systematic reviews for short-term low back pain and osteoarthritis-associated joint pain.
• Immune and inflammatory system: Anti-inflammatory activity via COX-1/COX-2 inhibition, suppression of TNFα, and NF-κB pathway modulation.
• Thermoregulatory system (antipyretic): Historically documented and officially recognized for fever associated with common cold; no dedicated RCTs.
• Nervous system (headache): Recognized under traditional use by EMA for headache; no dedicated RCTs.
• Antioxidant / oxidative stress: Supported by in vitro and preclinical data; clinical relevance unclear.
• Gastrointestinal (comparative safety): Studies supported the hypothesis that willow bark extract is less prone to cause adverse reactions in the stomach when compared to acetylsalicylic acid.

7. Dosage Forms and Dosages Reported in Studies

Willow is available in various dosage forms, including tablets, capsules, powders, and liquids. Clinical studies and regulatory monographs express dose in terms of milligrams of salicin delivered per day, not raw bark weight alone, because salicin content varies substantially with species and extraction method.

Monograph dosages (ESCOP / EMA): The European Scientific Cooperative on Phytotherapy (ESCOP), which summarizes the use of herbal medicines in Europe, published a monograph on willow bark. The monograph recommends adult doses of various extracts equivalent to a maximum of 240 mg of salicin per day, but a German monograph from 1984 recommends no more than half of that dose.

Standardized extract doses used in key RCTs:

• In the primary low back pain RCT (210 patients), participants were randomly assigned to receive an oral willow bark extract with either 120 mg (low dose) or 240 mg (high dose) of salicin per day, or placebo, in a 4-week blinded trial.
• In the primary osteoarthritis RCT (78 patients), willow bark extract in a dose corresponding to 240 mg salicin/day was compared with placebo in a 2-week double-blind randomized controlled trial.
• All studies in the 2009 systematic review investigated ethanolic extracts with daily doses up to 240 mg salicin over periods of up to six weeks.

Duration of use: Equivalent to 120–240 mg of total salicin per day. For low back pain and joint pain indications, preparations are not to be used for more than 4 weeks. While some regulatory bodies suggest limiting willow bark use to 4 weeks, clinical studies and surveys have not found evidence of serious adverse events with use up to 8 weeks, even in large patient groups.

Pharmacokinetic note: Ingestion of willow bark extract delivering 240 mg salicin resulted in an area under the curve equivalent to that expected from an intake of 87 mg acetylsalicylic acid, with a bioavailability of 43.3% and peak serum levels of 1.2 mg/L reached within 2 hours. This confirms that standard therapeutic doses of willow bark extract do not achieve plasma salicylate concentrations equivalent to anti-inflammatory doses of synthetic aspirin.

8. Safety Considerations and Drug Interactions

8.1 General Tolerability

In the clinical studies reviewed in the USP Safety Review, no serious adverse events were reported. The most common adverse effects associated with willow bark are gastrointestinal; a few allergic reactions were also reported. Reports from clinical trials primarily document GI discomfort (e.g., nausea, stomachache) as well as dizziness and skin rash.

8.2 Aspirin Allergy and Salicylate Sensitivity

The WHO monograph for Cortex Salicis cautions against the use of willow bark in children under 12 years of age, citing the possibility of Reye syndrome (sudden acute brain and liver damage associated with the use of aspirin). The monograph also contraindicates the use of willow bark in patients with hypersensitivity to other NSAIDs and in people with asthma because of potential severe reactions (acute bronchospasms). This contraindication is maintained in the 2017 review carried out by EMA.

Willow-containing products should be avoided in patients with known hypersensitivity to aspirin, asthma, impaired thrombocyte function, need for vitamin K antagonistic treatment, diabetes, gout, kidney or liver conditions, peptic ulcer disease, and any other medical condition for which aspirin is contraindicated.

8.3 Bleeding Risk and Anticoagulant Interactions

An extract dose with 240 mg salicin had no major impact on blood clotting. However, caution is still warranted with concurrent use of anticoagulant or antiplatelet drugs. The interaction rating for willow bark with anticoagulant/antiplatelet drugs is classified as "Major — Do not take this combination." Concomitant use theoretically might increase the risk of bleeding due to decreased platelet aggregation. Willow bark has antiplatelet effects, but less so than aspirin. Drugs in this category include aspirin, clopidogrel, dalteparin, enoxaparin, heparin, ticlopidine, warfarin, and others. Willow bark may also interact with oral anticoagulants, methotrexate, metoclopramide, phenytoin, probenecid, spironolactone, and valproate. White willow may enhance the anticoagulant effect of warfarin.

8.4 Pregnancy and Lactation

The American Herbal Products Association's (AHPA) Botanical Safety Handbook classifies Salix spp. bark as an herb that can be safely consumed when used appropriately; however, caution is advised because of the risk of increased bleeding and the fact that salicylates cross the placenta and that newborns eliminate them very slowly.

8.5 Case Reports of Serious Events

Several allergic reactions, including one serious case of anaphylaxis, were described in case reports, similar to what patients had experienced with aspirin following ingestion of willow bark extract. At least one case report exists of a woman with G6PD deficiency who experienced life-threatening hemolysis after ingesting a herbal product containing S. caprea. One case of fulminant hepatic failure (FHF) was recently reported in an infant who had been given willow bark and acetaminophen.

8.6 Labeling Gaps Identified in the Literature

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. A published survey of product labels confirms this gap: of 70 products evaluated, only 8.6% listed a warning. The warning regarding aspirin sensitivity was present on 4.3%, Reye's syndrome on 2.9%, and interactions with anticoagulants/"blood thinners" on 4.3%.

8.7 Difference from Aspirin

Many believe that willow is the natural source of aspirin. However, willow species contain only a low quantity of the prodrug salicin, which is metabolized during absorption into various salicylate derivatives. If calculated as salicylic acid, the daily salicin dose is insufficient to produce analgesia. Salicylic acid concentrations following an analgesic dose of aspirin are an order of magnitude higher. Even though salicin in willow bark served as a precursor to aspirin, its medical effect cannot be solely attributed to it.

References

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• NCCIH — Nutritional Approaches for Musculoskeletal Pain: What the Science Says
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