Willow bark safety and efficacy

The use of willow bark extract dates back thousands of years to at least 500 BC when it was used in traditional medicine. Its use as an anti-inflammatory, analgesic and an antipyretic (fever reducing drug) is common practice globally and has been for many years. However, considering its long standing medicinal use there are relatively few human and animal studies to accompany the many anecdotal reports for its use. Today we are going to take a look at the studies that have been made and to try to reach a conclusion about its safety and efficacy.

There have been a few studies conducted that support the use of willow bark supplementation for treating lower back pain, joint pain and osteoarthritis. The anti-inflammatory properties of willow bark are responsible for the improvement of these conditions.

Willow bark extract has also enjoyed increasing popularity as a sports performance supplement and weight loss product, this is presumably due to the anti-inflammatory and analgesic properties, however, no human studies have been published that specifically address this.

In the last few years a number of in vitro and animal studies have explored the anti-inflammatory properties of willow bark extract. The properties of willow bark have been associated with the down regulation of various inflammatory mediators, including, tumor necrosis factor-α (TNF-α) and nuclear factor-kappa B (NF-kB).

Tumor necrosis factor-α is a proinflammatory cytokine (cell signalling protein) which plays a central role in the regulation of immune cells. As part of its role in the immune response, TNF-α is able to induce fever, apoptosis, cachexia, inflammation and can also inhibit tumorigenesis and viral replication and combat sepsis. The dysregulation of TNF-α production has been implicated in a variety of human diseases including Alzheimer’s disease, cancer, major depression, psoriasis, and inflammatory bowel disease (1-5).

Nuclear factor-kappa B is a protein complex and is a master regulator of many inflammatory genes helping to mediate the immune response to pathogens. Unfortunately when this regulation becomes dysfunctional, then the immune response and resulting inflammation becomes excessive and contributes to diseases. As we age NF-kB becomes increasingly deregulated leading to excessive immune responses and chronic inflammation that further drives the aging process and the development of pathology (6).

Whilst the primary active ingridient in willow bark is salicin, the other other salicylates as well as polyphenols, and flavonoids in willow bark have a significant effect as researchers are now discovering. Adverse effects from taking willow bark appear to be quite minimal compared to other non-steroidal anti-inflammatory drugs such as aspirin and ibrobrufen. The main cause for caution in taking willow bark relates to allergic reactions in salicylate-sensitive individuals, but this is no different to taking any medication or supplement. Willow bark extract is standardized for its salicin content ranging from 15%-50% though 25% is generally the middle ground here with less chance of causing irritation.

Willow bark extract is widely used for conditions associated with pain, inflammation, or fever such as joint or knee pain, acute back pain, osteoarthritis, headache, menstrual cramps, tendonitis, flu, fever, and generalized pain (7).

Human clinical studies

In 2009 Vlachojannis et al. conducted a systematic review of the efficacy of willow bark extract on musculoskeletal pain (8). The research team concluded that extracts of willow bark were effective in the treatment of lower back pain. There were three clinical studies included in their review that explored the use of willow bark extract for pain management and involved a total of 415 subjects. We will take a look at each study in the following paragraphs.

The first study in 2000 by Chrubasik et al. examined the ability of willow bark extract to treat chronic lower back pain (9). In the study they enrolled a total of 210 patients who were randomized into placebo, 120 mg and 240 mg salicin test groups for a four week period. The number of patients who were pain free by the last week of the study was 6% for the placebo group, 21% for the 120 mg group and and impressive 39% for the higher dose 240 mg group. Interestingly the higher dose group saw improvement in just one week of treatment. The willow bark was generally well tolerated in the test the groups with only one person suffering adverse reactions.

A second study in 2001 by Schmidt et al. conducted a randomized placebo controlled double-blind study with 78 patients suffering from osteoarthritis (10). The patients received a placebo or 240 mg salicin daily for a total of two weeks. There was a moderate decrease in pain in the salicin group of 14% as determined using the western Ontario – McMaster University osteoarthritis (WOMAC) pain score. The willow bark was well tolerated with no adverse reactions reported in any of the patients.

The third study in 2004 by Biegert et al. enrolled one hundred and twenty-seven patients with osteoarthritis also twenty-six patients with rheumatoid arthritis (11). All patients were treated with 240 mg salicin per day for six weeks. However based on the WOMAC score, no significant reduction of pain was observed in the test groups, although no adverse reactions were reported. The reason for the lack of any significant effect compared to the previous two studies is unclear, and the authors of the study provide no explanation. There was also no verification that the willow extract contained 240 mg salicin so we cannot rule out that the willow bark was not of sufficient quality to be effective, certainly it seems strange when compared to the previous two studies.

Since the review by Vlachojannis et al. two additional studies have been conducted and will be discussed here. In 2013 a study by Uehleke et al. a total of four hundred and thirty-six patients suffering from osteoarthritis and/or back pain were treated with a single or combination therapy of willow bark extract and opioids (12). The study authors reported that pain scores were reduced between 33-44% in conjunction with willow bark so it improved the effect of the opioids when combined. There were no reported negative drug impacts during this study.

Finally in 2013 an eight week placebo-controlled, double blind study was conducted by Nieman et al. and involved a total of one hundred patients (13). The patients were aged between fifty and seventy-five years old with a history of joint pain. The participants were divided into a placebo group and a test group which were given a commercial product called Instaflex plus 250 mg of willow bark extract. The Instaflex contained a mixture of glucosamine sulfate, methylsulfonylmethane, ginger root concentrate, Boswellia seratta extract (65% boswellic acid), turmeric root extract, cayenne, and hyaluronic acid.

The authors demonstrated that there was a reduction of joint pain in the test group of 37% vs 16% for the placebo group. Joint stiffness also saw a reduction of 30% vs 12% in the test and placebo group respectively. Patients also reported significant improvement in their ability to perform daily activities. Unfortunately it is impossible to say exactly how much contribution the white willow bark extract had due to the number of other compounds that were present. That said, this study in combination with previous studies and its anecdotal use for centuries as an analgesic and anti-inflammatory, suggests it likely had some level of impact.

For sports and weight loss

Willow bark extract and salicylates have found popularity in sports performance products as well as for weight management supplements in recent years (14). Unfortunately a lack of well designed and controlled studies assessing the effects of will bark extract or salicin on sports and endurance or weight control makes it hard to establish if there is any benefit. It may be a case that any beneficial effects reported by those taking willow bark for sports or weight control may be due to an increased level of pain tolerance as well as a reduction of inflammation. Intense exercise and obesity both create inflammation in the body and willow bark certainly reduces this. Another factor to consider is that pain relief also improves mobility, the ability to exercise and thus increased energy consumption which could lead to weight loss. Until better designed studies are conducted for sports performance and weight control it is not possible to determine if willow bark is useful in this regard.

Animal studies

In 2001 Yuan et al. published a study involving obese mice (15). They demonstrated that salicylates were able to reverse obesity and diet-induced insulin resistance, the results implicate inflammation in the development of insulin resistance and obesity. This study is possibly what gave rise to the popularity of willow bark for weight control products, and indeed a number of commercial weight loss products do include willow bark extract and in particular salicylates.

A 2012 study by Ulrich-Merzenich et al involved rats treated for fourteen days using a standardized willow bark extract or isolated fractions (16). The authors showed that the willow bark extract and the salicyl alcohol-rich fraction were both able to decrease the forced swim test induced immobility time by 35-44%. This test places the rat in a tank of water and measures the level of active (swimming and climbing) or passive (immobility) behavior when rodents are forced to swim in a cylinder from which there is no escape. The rats in this study saw a significant increase to their active behaviour, and the study authors showed that pro-inflammatory interleukin and neurological serotonin were both targets of willow bark extract and the salicyl alcohol fraction.

A 2013 study by Bucolo et al. treated diabetic rats with 150 mg/kg of white willow extract combined with Ginkgo biloba extract, α-lipoic acid (ALA), a red berry extract, and L-carnosine for a period of ten days (17). The study authors demonstrated that the combined extract was able to attenuate diabetes-induced plasma lipid peroxidation by an impressive 50%. It also reduced TNF-α levels in the retina and vascular epidermal growth factor levels, these both play a key role in diabetes. Unfortunately once again, the exact contribution level that willow bark extract played in these changes cannot be determined due to it being used in combination with other compounds.

In vitro studies

In 2010 Bonaterra et al. explored the anti-inflammatory effects of willow bark extract on lipopolysaccharide-activated human monocytes and differentiated macrophages and compared it to aspirin and diclofenac (18). The study authors showed that willow bark extract demonstrated significant anti-inflammatory action and inhibited pro-inflammatory the factors TNF-α, COX-2 and NF-κB in activated monocytes.
In a 2012 study by Freischmidt et al. examined willow bark extract, and its fractions for its ability to inhibit TNF-α-induced expression of intercellular adhesion molecule-1, a biomarker for inflammation in human endothelial cells (19). The research team concluded that not only salicin derivatives but also catechin and flavonoids contribute to the anti-inflammatory effect of willow bark.

A study by Ishikado et al. in 2012 demonstrated that an extract of willow bark with the salicin removed, was able to induce antioxidant enzymes and reduce oxidative stress (20). This was in both human umbilical vein endothelial cells and Caenorhabditis elegans, a type of roundworm used in research. This study showed the researchers how other compounds in willow bark beyond salicin and its derivatives.work and how they contribute to the effectiveness of willow bark.

Shakibaei et al. conducted a study in 2012 that investigated the anti-inflammatory properties of various plant species and their methods of action, one of the compounds tested was willow bark extract (21). The authors showed that willow bark extract was able to exert anti-inflammatory and anabolic effects on canine articular chondrocytes (cartilage cells). Willow bark was able to inhibit interleukin-1β induced NF-κB activation via down regulation of COX-2 and matrix metalloproteinases.

Willow bark was even compared for its anti-inflammatory activity against the potent polyphenols, quercetin and apigenin, and also against salicylic acid in human acute monocytic leukemia cell line macrophages (22). The 2013 study focused on reducing interleukin-6 and TNF-α, both pro-inflammatory signals, they showed that willow bark extract had a greater anti-inflammatory activity compared to the other compounds tested.

A number of studies have looked at willow bark extract and its anticancer properties. In a 2007 study Hostanska et al. tested willow bark extract and a number of fractions thereof and showed it was able to suppress the growth of human colon and lung cancer cells in vitro (23). Not only that but it was also able to induce apoptosis in these cancer cell types. Interestingly, the salicin-related, flavonoid, and proanthocyanidin fractions also demonstrated similar anti-proliferative activity.

In 2007 El-Shemy et al. studied the anticancer properties of an extract from willow leaves by testing it against three types of carcinoma both in vitro and in vivo (24). Mice with induced cancer given willow extract experienced reduced tumor growth and lived longer. In vitro the extract killed 75-80% of acute leukemia and myeloid leukemia cells harvested from human patients.

The safety of willow bark

As we have already discussed in the general presentation on this website, salicin is chemically similar to salicylic acid and aspirin (acetylsalicylic acid). However, unlike salicylic acid or aspirin it does not appear to be as irritating to the stomach and is generally better tolerated (25).

People who are allergic to aspirin should not use willow bark extract as this could cause an allergic reaction. The most serious adverse effects are anaphylactic reactions in individuals allergic to aspirin and salicylates in general (26-27).

It is also suggested that people with gastritis, stomach ulcers, diabetes, asthma, or hemophilia should avoid willow bark extract. Additionally children and young adults under the age of 18 should not use white willow bark extract due to the potential risk of causing Reye syndrome.

Conclusion

We have compiled the most significant studies for the use of willow bark extract including five human clinical trials and a variety of key studies in murine models and cell cultures. There is no direct evidence to support the use of white willow for weight control or improving sports performance due to the poor design of the studies. It is our hope that more studies will be made to see if willow bark does help with either of these things but until then no conclusion for sports or weight loss can be made.

Willow bark extracts have been used for thousands of years for their anti-inflammatory and analgesic properties. Yet surprisingly there far fewer scientific studies than one might assume for a supplement that has been so widely used medicinally by many cultures. However, the mountain of anecdotal reports about willow bark extract are hard to ignore even with the lower number of studies.

That said the data from these studies is consistent with the anti-inflammatory and analgesic properties of willow bark extract reported anecdotally. The antioxidant and free radical scavenging properties of various polyphenols and flavonoids present in willow bark extracts as catechin and ampelopsin are also well documented. Willow bark extract is generally regarded as safe, and may be a more gentle alternative to aspirin. Given its potent anti-inflammatory action it may be of interest for those considering if for their supplement regime.

References
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