By Hanako Darby

On those warm Summer days, many of your taste buds will be very familiar with the sweet tones of cordials and wines produced from the flowers and berries of Elder (Sambucus nigra L.). But you may be surprised to know that aside from their exploitation in the food, beverage and cosmetic industries, they carry health-promoting properties that have been harnessed into antiviral dietary supplements across the world. Elderberries have long been used as a remedy for the common cold and flu, and pharmacologically active polyphenolic compounds are thought to be responsible for this activity. Furthermore, elderflower has emerging antidiabetic potential, however in each case more preclinical and clinical studies are necessary before Elder can be considered for use as a medicine.

Introduction

Over 30 species of the genus Sambucus L. exist as part of the Adoxaceae family (formerly the Caprifoliaceae family). ‘Sambucus’ was supposedly derived from the Greek word ‘Sambuca’ – a string instrument made from Elder wood, not the notorious Italian liqueur you may be thinking of! ‘Elder’ stems from the Anglo-saxon word ‘aeld’ meaning fire, as the hollow stems were used as bellows to build a fire (Amidon, 2013).

The most abundant species is Sambucus nigra L., commonly known as Elder, Elderberry, Black elder, European elder, European elderberry and European black elderberry. It is native to Europe, North Africa and North America, and has spread to many other parts of the world such as East Asia (Młynarczyk, Walkowiak-Tomczak and Łysiak, 2018).

Elder is a tree-like deciduous shrub that can grow up to 9 meters in height, and produces large umbels of small, white, flat-topped, aromatic flowers (Bown, 2013). In late summer, they ripen into clusters of drooping, shiny, dark purple berries. Not to get confused with other European species such as Sambucus ebulus L. (Dwarf Elder), whose height rarely reaches 2 meters (Shokrzadeh and Saeedi Saravi, 2010), and Sambucus racemosa L. (Red Elder), which develops red berries (Grieve, n.d. b). The former prefers growth in semi-shade lands, whilst the latter thrives in wetlands in both low and high altitudes (Bown, 2013). Elder favours nitrogen and phosphate-rich soils, and is usually located around open fields or woodlands in shady, moist areas. Plants reach full maturity at 3-4 years, and berry yields can depend on growth conditions, location and cultivar choice (Młynarczyk, Walkowiak-Tomczak and Łysiak, 2018).

Currently elderberry extracts are sold commercially as immune-boosting nutritional supplements that protect against the winter colds and influenza; one such well-known, trademarked product is known as Sambucol (Zakay-Rones et al., 2004). Aside from being used in fragrances, elderflower extract is known for being a natural emollient (skin-conditioning and soothing), therefore it is used mainly in facial moisturisers, creams and lotions, whilst the fruit extracts have astringent properties that are used in moisturisers as well as cleansers (Ewg.org, n.d. a; Ewg.org, n.d. b).

History and Traditional Use

Renown by the ‘Father of Medicine’, Hippocrates, as a “medicine chest”, knowledge of Elder (in particular the berries) extends all the way back to 400 BCE as a multifunctional medicinal plant against numerous ailments. Ingestion of the berries led to a “healthy life”, and treated diarrhoea and brain conditions to name a few (Jones, 2016). Following his footsteps, both Dioscorides and Pliny elaborated on the diuretic (increased urine production) benefits of Elder, and further listed their non-therapeutic purposes. These included using the dark berry juice as a black hair dye, and the stems as popguns for children.     

Many myths and folklore associated Elder with both death and magic. Not only did Judas hang himself on an Elder tree after betraying Jesus, a dryad known as the ‘Elder-tree Mother’ occupied the trees and haunted those who cut them down (Grieve, n.d. a). In this day and age, Elder is popularly remembered as the source of the almighty Elder Wand used by the fictional character Harry Potter to defeat Voldemort (Barrie Kavasch, 2013), although unfortunately there is no clinical evidence to support such grave power.

In 16^th century, Martin Blochwich, a German physician, detailed the use of every plant part of Elder in folk medicine as both external and internal treatments against more than 30 distinct diseases ranging from toothache and constipation, to epilepsy and arthritis (Blochwitz, 1655). Nowadays only the flowers and fruit are traditionally known to carry medicinal properties in Europe, mainly as a symptomatic treatment against respiratory ailments, but also to promote diuresis, induce perspiration and reduce inflammation (Apps.who.int, 2004; Sidor and Gramza-Michałowska, 2015; Vlachojannis, Cameron and Chrubasik, 2010).

Elderberries were predominantly used as a food source and colourant, and are mentioned in popular recipes for pies, jams, juices and alcoholic drinks (Gleńsk et al., 2014; Mikulic-Petkovsek et al., 2015; Silva, Ferreira and Nunes, 2017). Furthermore, infusions of the berries were traditionally used for relief of constipation and respiratory tract infections as well as a diuretic (Silva, Ferreira and Nunes, 2017; Vlachojannis, Cameron and Chrubasik, 2010). Elderflowers were also traditionally processed to make beverages, particularly syrups, and are still made this way in parts of Central and Western Europe (Mikulic-Petkovsek et al., 2015).

Pharmacology: Preclinical and Clinical Data

The major pharmacological activities of the Elder plant, along with their relevant phytochemical constituents are discussed below.

It must be considered that in each of the preclinical and clinical studies, different cultivars of the Elder plant may be used that are grown in different locations and conditions, and processed in a different manner. Thus chemical constituents in preparations may vary, bringing a degree of inconsistency to the results.

It must also be clearly noted that currently there is insufficient evidence for the use of Elder berries and flowers to treat any serious conditions mentioned below. The reader is therefore highly advised NOT to try out the plant as a medicine.

Antioxident:

The antioxidant activities of Elder are mainly attributed to their polyphenolic compounds; a large bioactive chemical class found in the leaves, fruits and flowers (Sidor and Gramza-Michałowska, 2015). Oxidative stress is caused by an imbalance of reactive oxygen species (ROS) and antioxidants. The role of antioxidants is to eliminate excess ROS, which is implicated in a reduction of cellular damage. Thus it has been postulated that life-threatening diseases such as cancers and cardiovascular disease may potentially be prevented or treated (Ray, Huang and Tsuji, 2012).

Subclasses of polyphenols include: flavonoids (such as flavonols and anthocyanins) and phenolic acids. Anthocyanins are predominant in the berries and give the characteristic purple colour to indicate fruit quality, and are used as a safe food colourant (Gleńsk et al., 2014; Młynarczyk, Walkowiak-Tomczak and Łysiak, 2018), as well as carrying potent antioxidant potential. The flowers have a significantly higher polyphenol content than the berries, and evidently have increased neutralizing capacity of ROS (Dawidowicz, Wianowska and Baraniak, 2006; Młynarczyk, Walkowiak-Tomczak and Łysiak, 2018). They contain 2 predominant bioactive flavonoids, namely rutin and quercetin, which may contribute to this activity, however additive or synergistic effects are likely involved (Loizzo et al., 2015; Stoilova et al., 2007).

Elderberry powder reduced ROS production and DNA damage in human colon cells without causing cytotoxicity. It was also discovered that human aortic endothelial cells that had incorporated elderberry anthocyanins possessed increased resistance against ROS damage, leading to increased cell viability. These results may suggest the potential of elderberry in lowering the risk of colon cancer and vascular disease (Olejnik et al., 2016; Youdim, Martin and Joseph, 2000).   

However, a study on 6 healthy human volunteers indicated low bioavailability of anthocyanins in their plasma after ingestion of an elderberry extract, correlating to reduced antioxidant capability in vivo (Frank et al., 2007). Hence further human studies are required to test the antioxidant efficacy of Elder.

Antimcrobial:

As mentioned, Sambucol (containing 38% elderberry extract) is a popular elderberry preparation, with a high flavonoid content that is characteristic of antimicrobial activity. Preclinical and clinical studies have proved its efficacy against influenza A and B, HIV, and Herpes virus (Altmedrev.com, 2005). Despite this, currently only elderflower has approved German Commission E status for use against colds (Chrubasik et al., 2008).

Two clinical trials of moderate significance were carried out using Sambucol. The first included 27 patients with influenza B-like symptoms, and those given Sambucol were treated in 2-3 days compared to 6 days in the placebo group (Zakay-Rones et al., 1995). In the second, 60 patients carrying either influenza A or B participated, and symptomatic relief was achieved 4 days earlier in the Sambucol-treated group (Zakay-Rones et al., 2004). These results are also backed by a study on 10 chimpanzees, which proved the effect of Sambucol both as a prophylactic and treatment against influenza (Burge, Mumcuoglu and Simmons, 1999). However in each case a larger sample is needed (including different high risk groups) to reinforce the existing evidence.

A larger clinical study has also been conducted using another standardised commercial elderberry extract called Rubini (300mg containing 22% polyphenols). Of the 312 participants, those taking Rubini experienced a shorter cold duration and reduced symptom severity. However results are subjective as they were recorded via a survey system, thus limiting study reliability (Tiralongo, Wee and Lea, 2016). Rubini also demonstrated antimicrobial activities against strains of bacterial and viral pathogens known to infect the upper respiratory tract in humans (Krawitz et al., 2011).

The antimicrobial mechanism of elderberry is still unknown. Some studies have suggested direct effects of flavonoids on the viral particles; binding and thereby blocking host cell penetration and further infection (Roschek et al., 2009; Krawitz et al., 2011). An in vivo study testing antiviral capacity of a concentrated elderberry juice on influenza A-infected mice, showed increased antibody production in their serum to fight off the virions. It was suggested that acidic polysaccharides were responsible for this immunostimulant activity (Kinoshita et al., 2012). Anthocyanins within the extracts also have anti-inflammatory properties, which may have reduced symptoms such as fever and aches.

Anti-Inflammatory:

Proinflammatory cytokines are important molecules released by immune cells (such as macrophages) to trigger the inflammation response, but if excessively released, can cause chronic inflammatory diseases such as atherosclerosis, arthritis and periodontitis (inflammation of tissue surrounding teeth) due to tissue damage. By targeting components of the inflammatory signalling pathway, it would be possible to modulate the production of these cytokines and reduce/inhibit inflammation (Harokopakis et al., 2006).

An in vitro study looking at the anti-inflammatory effects of an aqueous elderflower extract on human and mice macrophages stimulated by periodontal pathogens, showed potent inhibition of proinflammatory cytokine secretion (Harokopakis et al., 2006). Furthermore a clinical study conducted on 50 gingivitis (inflammation of gum) patients showed that a topically applied multi-herb patch containing elderberries exerted a significant reduction on gingival inflammation (Grbic et al., 2011). A similar pilot clinical study using the same herbs in the form of a mouthwash was performed, and again positive results were reported (Samuels et al., 2012).

The long-term effects of a multi-herb preparation “Inflaminat” (containing 165mg elderberries per capsule) were studied on 85 patients suffering asymptomatic atherosclerosis for 2 years. Results concluded a significant reduction in atherosclerotic progression, therefore the preparation has potential to be a prophylactic agent against atherosclerosis. Inflaminat was shown to have similar efficacy to the standard anti-inflammatory drug, Diclofenac. In mouse models of skin inflammation, Inflaminat administration significantly decreased skin thickness within the first day, and a further pilot clinical study demonstrated a reduction in pain intensity and affected areas in patients with arthritis (Kirichenko et al., 2016).

The phytochemicals responsible for the anti-inflammatory effects of Elder are still unknown. One study postulated that a compound known as ursolic acid, belonging to the triterpenoid chemical class, was responsible for such anti-inflammtory activity (Mascolo et al., 1987). Alternatively, elderberry anthocyanins were assumed to have an anti-inflammatory role as anthocyanins of many other berry extracts have previously been involved in such activities (Olejnik et al., 2015).

Antidiabetic:

The use of elderflower as an antidiabetic agent has been reported in folk medicine. Type 2 diabetes is the prevalent form that is often linked to obesity, and develops from the body’s resistance to insulin, leading to high blood sugar levels. Oxidative stress accumulates in tissues as a result, causing chronic inflammation which may instigate diabetic complications. Thus it is necessary to reduce hyperglycemia.

An elderflower extract was shown to selectively inhibit an enzyme involved in the breakdown of carbohydrates to glucose called alpha-glucosidase, consequently lowering blood sugar content (Loizzo et al., 2015). Elderflower has also increased glucose storage in muscle cells in the absence of insulin, reduced fat accumulation in nematode worms, and induced insulin secretion in rat pancreatic cells (Bhattacharya et al., 2013; Gray, Abdel-Wahab and Flatt, 2000).

Phenolic acids and flavonoids are thought to be the key antidiabetic agents (Tundis et al., 2018). In one study it was shown that the elderflower flavonoids, quercetin and kaempferol, were responsible for the highest glucose uptake in both human skeletal muscle and liver cells. However contradictory results have been observed in other studies, thus difference in cell type and conditions seem to impact their antidiabetic effects (Ho et al., 2017).

Elderflowers have potential use in the prevention or treatment of type 2 diabetes, but more in vivo and clinical studies must be performed.

Other Effects:

Elder has been known for its laxative properties, and one such multi-herb tea preparation containing 33% elderflowers was taken by patients suffering chronic constipation 3 times/day for 5 days. Positive results were obtained, suggesting potential for the preparation as an alternative non-synthetic treatment (Picon et al., 2010).

Ursolic and oleanolic acid, both triterpenoid compounds found in elderflowers, berries, leaves and bark, may have potential to become new anticancer therapies due to their cytotoxic nature (Inoue and Sato, 1975; Lawrie, Mclean and Paton, 1964; Gleńsk et al., 2014; Gleńsk et al., 2017). Anthocyanins and lectins may also carry apoptotic (programmed cell death) and antiproliferative activities against cancer cells. For example an S. nigra lectin has demonstrated selective apoptosis towards ovarian cancer cells (Chowdhury et al., 2017), and an elderberry anthocyanin-enriched extract was capable of inhibiting proliferation of mouse melanoma cells (Rugina et al., 2017). However much evidence is needed to support this.

Toxicity

Adverse effects of Elder were not witnessed during clinical trials and have not been reported (Porter and Bode, 2017). However, the unripe elderberries and any inadequately heated preparations containing the fruits, leaves, stems, seeds and roots must be treated with caution as high doses may cause gastrointestinal disorders such as nausea and vomiting (Vlachojannis, Cameron and Chrubasik, 2010). Also, depending on the specie of Sambucus the level of toxicity can vary. For example, S. racemosa is much more toxic, therefore one must be careful of misidentification (Barrie Kavasch, 2013).

The major responsible compounds for toxicity are lectins and cyanogenic glycosides (mainly sambunigrin); the former known to carry a risk of allergenicity, and the latter of which could accumulate in the body as free cyanide and subsequent cyanide toxicity (Vlachojannis, Cameron and Chrubasik, 2010). Thermal processing has been found to denature these compounds (Senica et al., 2016), deeming commercial products safe to consume.

Women are advised not to take Elder during pregnancy and breast-feeding due to lack of scientific information. Children are also advised not to make toys out of the stems, and raw berries should be kept out of their reach (Vlachojannis, Cameron and Chrubasik, 2010).

Drug interactions with Elder have not been accounted for, however due to potential insulin stimulating effects of elderflower, diabetic patients taking other drugs should be aware of their blood sugar levels (Altmedrev.com, 2005). Elder is also known to stimulate the immune system, hence should not be used by patients with autoimmune diseases and those taking immunosuppressants (Webmd.com, 2018). If in doubt, a consultation with a healthcare practitioner is always recommended.

Further safety analysis is much required, with emphasis on different risk groups and long-term use of Elder preparations. There is also no guideline on optimal dose range yet for polyphenols, thus one must be wary of toxicity when taking food supplements containing these compounds (Vlachojannis, Cameron and Chrubasik, 2010).

Conclusion

Elder is a historically well-respected medicinal plant, with centuries of traditional therapeutic and culinary uses. These days, research has focused attention on the polyphenol-rich elderberries and flowers that have shown significant antimicrobial, antioxidant and anti-inflammatory activities. One way of increasing these health-promoting properties is by selection of Elder cultivars that yield the highest polyphenol content. Growing evidence is suggesting desirable antidiabetic effects of elderflower which may potentially be capable of treating type 2 diabetes. Preparations of Elder are currently only sold as dietary supplements and have a good safety profile, but with further extensive studies using high quality standardised preparations, they could be used as medicines in the future.

DISCLAIMER: In this essay we do not to advise or recommend herbs for medicinal or health use. This information is intended for educational purposes only and should not be considered as a recommendation or an endorsement of any particular medical or health treatment. The use of any such product should be based on the appropriate advice of a health care professional or based on the information available in the patient information leaflets (i.e. for THR products).

© Hanako Darby 2019. All rights reserved.

Hanako Darby is an MSc Medicinal Natural Products and Phytochemistry student at the UCL School of Pharmacy (2018-2019).

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