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An Evidence-Based Systematic Review of Elderberry and Elderflower ( Sambucus nigra ) by the Natural Standard Research Collaboration

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Abstract

ABSTRACT An evidence-based systematic review of elderberry and elderflower (Sambucus nigra) by the Natural Standard Research Collaboration consolidates the safety and efficacy data available in the scientific literature using a validated, reproducible grading rationale. This article includes written and statistical analysis of clinical trials, plus a compilation of expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing.
Journal of Dietary Supplements, 11(1):80–120, 2014
C
2014 by Informa Healthcare USA, Inc.
Available online at www.informahealthcare.com/jds
DOI: 10.3109/19390211.2013.859852
ARTICLE
An Evidence-Based Systematic Review of
Elderberry and Elderower (Sambucus nigra)by
the Natural Standard Research Collaboration
Catherine Ulbricht, PharmD1, Ethan Basch, MD, MPhil2, Lisa Cheung, PharmD3,
Harley Goldberg, DO4, Paul Hammerness, MD5, Richard Isaac6,KartaPurkh
Singh Khalsa, DN-C, RH7, Aviva Romm, BSc, CPM, RH (AHG)8, Idalia Rychlik,
PharmD9, Minney Varghese, BS10, Wendy Weissner, BA6, Regina C. Windsor,
MPH6, & Jayme Wortley, PharmD11
1Massachusetts General Hospital, Boston, MA, USA, 2Memorial Sloan-Kettering
Cancer Center, 1275 York Avenue, New York, NY 10065, USA, 3University of Rhode
Island, 45 Upper College Road, Kingston, RI 02881, USA, 4Kaiser Permanente,
Oakland, CA, USA, 5Harvard Medical School, 25 Shattuck St, Boston, MA, 6Natural
Standard Research Collaboration, Somerville, MA, 7Bastyr University, 14500 Juanita
Drive Northeast, Kenmore, WA 98028-4966, USA, 8American Herbalists Guild, Canton,
GA, USA, 9Massachusetts College of Pharmacy, 179 Longwood Ave, Boston, MA 02115,
USA, 10Northeastern University, 360 Huntington Ave, Boston, MA, 11East Tennessee
State University, Gatton College of Pharmacy, 807 University Pkwy, Johnson City, TN
ABSTRACT. An evidence-based systematic review of elderberry and elderower
(Sambucus nigra) by the Natural Standard Research Collaboration consolidates the
safety and efcacy data available in the scientic literature using a validated, repro-
ducible grading rationale. This article includes written and statistical analysis of clinical
trials, plus a compilation of expert opinion, folkloric precedent, history, pharmacology,
kinetics/dynamics, interactions, adverse effects, toxicology, and dosing.
KEYWORDS. Adverse effects, dosing, elder, elderberry, elderower, evidence-based,
interactions, pharmacodynamics, pharmacology, pharmacokinetics, Sambucus nigra,
systematic review
SYSTEMATIC AGGREGATION, ANALYSIS, AND REVIEW
OF THE LITERATURE
Search Strategy
To prepare this Natural Standard review, electronic searches were conducted
in several databases (including AMED, CANCERLIT, CINAHL, CISCOM, the
Address correspondence to: Catherine Ulbricht, PharmD, Massachusetts General Hospital, Harvard Media-
cal School, Boston, MA, USA (E-mail: ulbricht@naturalstandard.com).
80
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An Evidence-Based Systematic Review of Elderberry and Elderower 81
Cochrane Library, EMBASE, HerbMed, International Pharmaceutical Abstracts,
Medline, and NAPRALERT) from inception to July 2013. Search terms included
the common name(s), scientic name(s), and all listed synonyms. Hand searches
were conducted of 20 additional journals (not indexed in common databases),
and of bibliographies from 50 selected secondary references. No restrictions were
placed on language or quality of publications. Researchers in the eld of comple-
mentary and alternative medicine (CAM) were consulted for access to additional
references or ongoing research.
Selection Criteria
All literature was collected pertaining to efcacy in humans (regardless of study
design, quality, or language), dosing, precautions, adverse effects, use in pregnancy/
lactation, interactions, alteration of laboratory assays, and mechanism of action (in
vitro, animal research, human data). Standardized inclusion/exclusion criteria were
utilized for selection.
Data Analysis
Data extraction and analysis were performed by healthcare professionals conduct-
ing clinical work and/or research at academic centers, using standardized instru-
ments that pertained to each review section (dening inclusion/exclusion criteria
and analytic techniques, including validated measures of study quality). Data were
veried by a second reviewer.
Review Process
A blinded review was conducted by multidisciplinary research-clinical faculty at
major academic centers with expertise in epidemiology and biostatistics, pharma-
cology, toxicology, CAM research, and clinical practice. In cases of editorial dis-
agreement, a three-member panel of the Editorial Board addressed conicts and
consulted experts when applicable. Authors of studies were contacted when clari-
cation was required.
Natural Standard Systematic Review (www.naturalstandard.com)
Copyright ©2014.
Synonyms/Common Names/Related Substances
Almindelig hyld (Danish), alpha-amyrenone, alpha-amyrin, anthocyanins, bac-
cae, baises de sureau (French), battree, beta-sitosterol, betulin, black berried
alder, black elder, black elderberry, boor tree, bountry, boure tree, busine
(Russian), Caprifoliaceae (family), cyanidin-3-glucoside, cyanidin-3-glucoside
monoglucuronide, cyanidin-3-sambubioside, devil’s eye, elderberry, elderberry
anthocyanins, elderberry bark agglutinin, elderberry juice, ellanwood, ellhorn,
European alder, European elder, European elder fruit, European elderberry,
European elderower, frau holloe, German elder, Holunderbeeren (German),
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82 Ulbricht et al.
Holunderbl ¨
uten (German), hyperoside, inking elder, lady elder, mucilage, nigrin
b, N-phenylpropenoyl--amino acid amides, old gal, old lady, oleanolic acid, pe-
onidin monoglucuronide, peonidin-3-glucoside, peonidin-3-sambubioside, pipe
tree, plastocyanin, quercetin, RubiniR(elderberry extract), rutin, Sambreo, Sam-
buci os, Sambuci fructus, Sambucipunct sambucus, sambuco (Italian), Sambu-
cus sieboldiana (Japanese red elder), schwarzer Holunder (German), sambun-
igrin, sieboldin-b, suco (Spanish), sureau noir (French), sweet elder, tannins,
tetrameric, tree of doom, yakori bengestro.
Selected combination products: OptiBerry IH141 (contains wild blueberry,
strawberry, cranberry, wild bilberry, elderberry, raspberry extracts), SinupretR
(contains Sambucus nigra owers, gentian root, verbena, cowslip ower, and sor-
rel), SambucolRActive Defense (contains elderberry extract, vitamin C, zinc
Echinacea angustifolia,Echinacea purpurea, and propolis); SambucolRImmune
System (contains elderberry, Echinacea angustifolia root, Echinacea purpurea,
propolis, vitamin C, zinc); SambucolRfor Kids (contains elderberry, Echinacea
purpurea,Echinacea angustifolia root, propolis). A phytotherapeutic compound
contained Pimpinella anisum,Foeniculum vulgare,Sambucus nigra,andCassia
angustifolia.
Note: Several species of Sambucus produce elderberries. Most scientic litera-
ture pertains to Sambucus nigra. Other species with similar chemical components
include the American elder or common elder (Sambucus canadensis), antelope
brush (Sambucus tridentata), blue elderberry (Sambucus caerulea), danewort
(Sambucus ebulus), dwarf elder (Sambucus ebulus), red-fruited elder (Sambu-
cus pubens,Sambucus racemosa), and Sambucus formosana. American elder (S.
canadensis) and European elder (S. nigra) are often discussed simultaneously
in the literature, since they have many of the same uses and contain common
constituents.
Note: This review does not include Sambucus nigra agglutinin (SNA) afnity
chromatography.
CLINICAL BOTTOM LINE/EFFECTIVENESS
Brief Background
Several species of Sambucus produce elderberries. Most research and publica-
tions refer to Sambucus nigra. Other species with similar chemical components
include the American elder or common elder (Sambucus canadensis), antelope
brush (Sambucus tridentata), blue elderberry (Sambucus caerulea), danewort
(Sambucus ebulus), dwarf elder (Sambucus ebulus), red-fruited elder (Sambu-
cus pubens,Sambucus racemosa), and Sambucus formosana. American elder (S.
canadensis) and European elder (S. nigra) are often discussed simultaneously in
the literature, because they have many of the same uses and contain common
constituents.
According to secondary sources, European elder grows up to 30 ft tall and is na-
tive to Europe, but has been naturalized to the Americas. Historically, the owers
and leaves have been used for pain relief, swelling, inammation, and diuresis
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An Evidence-Based Systematic Review of Elderberry and Elderower 83
(urine production), and as a diaphoretic or expectorant. The leaves have been
used externally for sitz baths. The bark, when aged, has been used as a diuretic,
laxative, or emetic (to induce vomiting). The berries have been used traditionally
in food as avoring and in the preparation of elderberry wine and pies.
According to secondary sources, the owers and berries (blue and black only) are
used most often medicinally. They contain avonoids, which have been found pre-
clinically to possess a variety of biochemical and pharmacological actions, includ-
ing antioxidant and immunologic properties that have shown benet in treating
inuenza, bacterial sinusitis, and bronchitis. Although it has been hypothesized
to be benecial, denitive evidence from well-conducted human clinical trials is
currently lacking regarding the use of elder, especially as monotherapy.
The bark, leaves, seeds, and raw or unripe fruit contain the cyanogenic glycoside
sambunigrin, which is potentially toxic.
Scientic Evidence
Influenza B
Bacterial sinusitis C
Bronchitis C
Cardiovascular disease risk C
Constipation C
Gingivitis C
Hyperlipidemia C
Obesity C
Natural Standard Evidence-Based Validated Grading RationaleTM
Grades reect the level of available scientic evidence in support of the efcacy
of a given therapy for a specic indication.
Expert opinion and historic/folkloric precedent are not included in this assess-
ment and are reected in a separate section of each review (“Expert Opinion
and Historic/Folkloric Precedent”).
Evidence of harm is considered separately; the below grades apply only to evi-
dence of benet.
Level of Evidence Grade Criteria
A (strong scientific
evidence)
Statistically significant evidence of benefit from >2 properly randomized
trials (RCTs), OR evidence from one properly conducted RCT AND one
properly conducted meta-analysis, OR evidence from multiple RCTs with
a clear majority of the properly conducted trials showing statistically
significant evidence of benefit AND with supporting evidence in basic
science, animal studies, or theory.
B (good scientific
evidence)
Statistically significant evidence of benefit from 1 to 2 properly randomized
trials, OR evidence of benefit from >1 properly conducted meta-analysis
OR evidence of benefit from >1 cohort/case–control/nonrandomized
trials AND with supporting evidence in basic science, animal studies, or
theory.
(Continued on next page)
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84 Ulbricht et al.
(Continued)
Level of Evidence Grade Criteria
C (unclear or conflicting
scientific evidence)
Evidence of benefit from >1 small RCT(s) without adequate size, power,
statistical significance, or quality of design by objective criteria,OR
conflicting evidence from multiple RCTs without a clear majority of the
properly conducted trials showing evidence of benefit or ineffectiveness,
OR evidence of benefit from >1 cohort/case–control/nonrandomized
trials AND without supporting evidence in basic science, animal studies,
or theory, OR evidence of efficacy only from basic science, animal
studies, or theory.
D (fair negative scientific
evidence)
Statistically significant negative evidence (i.e., lack of evidence of benefit)
from cohort/case–control/nonrandomized trials, AND evidence in basic
science, animal studies, or theory suggesting a lack of benefit.
F (strong negative
scientific evidence)
Statistically significant negative evidence (i.e., lack of evidence of benefit)
from >1 properly randomized adequately powered trial(s) of high-quality
design by objective criteria.
Lack of evidenceUnable to evaluate efficacy due to lack of adequate available human data.
Objective criteria are derived from validated instruments for evaluating study quality, including the five-point scale
developed by Jadad et al., in which a score below 4 is considered to indicate lesser quality methodologically (Jadad
AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ. Assessing the quality of reports of
randomized clinical trials: is blinding necessary? Controlled Clinical Trials 1996; 17[1]:1–12).
Listed separately in the “Historical or Theoretical Uses That Lack Sufficient Evidence” section.
Historical or Theoretical Uses That Lack Sufcient Evidence
Alzheimer’s disease, angiogenesis (antiangiogenic) (Bagchi, Sen, Bagchi, &
Atalay, 2004; Roy et al., 2002), anti-inammatory (Harokopakis, Albzreh, Haase,
Scannapieco & Hajishengallis, 2006; Mascolo et al., 1987), antioxidant (Cao &
Prior, 1999; Kaack & Austed, 1998), antispasmodic, asthma, astringent, blood
pressure control (Chrubasik et al., 2008; Hasani-Ranjbar, Nayebi, Larijani, &
Abdollahi, 2009), blood vessel disorders, burns, cancer (de Benito et al., 1998;
Lukash et al., 1997), circulatory stimulant, colds (Roxas & Jurenka, 2007), colic,
cough suppressant, diabetes, diaphoretic (Zakay-Rones et al., 1995), diuretic
(Beaux, Fleurentin, & Mortier, 1999), edema, epilepsy, fever, avoring, fra-
grance, gastrointestinal disorders, gout, hair dye, hay fever, headache, Helicobac-
ter pylori, herpes simplex virus, HIV (Konlee, 1998), immune stimulant (Barak,
Halperin, & Kalickman, 2001), insomnia, joint swelling, kidney disease, laryngi-
tis, liver disease, measles, migraines, mosquito repellant, nerve pain, osteoporosis,
psoriasis, respiratory distress, sedative, skin infections, skin irritation (chang),
stress reduction, syphilis, toothache, ulcerative colitis, vomiting.
Expert Opinion and Historic/Folkloric Precedent
According to an ethnobotanical survey, Sambucus nigra is one of the plants most
commonly used for medicinal purposes (Jaric et al., 2007). Historically, the leaves
have been considered to relieve pain and promote healing when applied as a
poultice. Native Americans used elder for infections, coughs, and skin conditions.
Elderower has been used as an insect repellent. When mixed with sage, lemon
juice, vinegar, and honey, elder has been used as a gargle for coughs, head colds,
laryngitis, u-like symptoms, and shortness of breath. It has been used on the skin
as an astringent in rheumatism and for swelling or inammation. When mixed
with peppermint and honey, hot elder has been used to induce diaphoresis to
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An Evidence-Based Systematic Review of Elderberry and Elderower 85
treat colds. Ancient Egyptians used elder owers to improve complexion and
heal burns.
According to secondary sources, elder extracts are used as avoring in foods and
beverages, and in perfumes, hair dyes, scented ointments, skin lotions, and insect
repellent. Elder has also been used in wine, pies, and lemonade.
Elderower has approval status by the German Commission E for colds. The
bark, leaves, and berries of the plant are lacking approval by the World Health
Organization (WHO), the European Scientic Cooperative on Phytotherapy
(ESCOP), and the German Commission E for any use (Akerreta, Cavero, &
Calvo, 2007).
Marz et al. published a review of the evidence regarding the use of SinupretR
for sinusitis (Marz, Ismail, & Popp, 1999). The authors cited preclinical reports
of secretolytic, anti-inammatory, immunomodulatory, and antiviral effects. They
also noted human research suggesting a favorable safety prole and efcacy when
combination products containing elder, such as SinupretR, were added to antibi-
otics and conventional decongestant drugs.
Sambucus canadensis L., or elderower, used as a avoring or seasoning, is on
the U.S. Food and Drug Administration (FDA) Generally Recognized as Safe
(GRAS) list. Other species of elderberry are not listed on the FDA GRAS list.
Brief Safety Summary
Likely safe: According to secondary sources, when cooked berries are consumed
in amounts usually found in foods. According to secondary sources, owers are
believed to be safe for use in food, provided that hydrogen cyanide (HCN) lev-
els are below 25 ppm. Short-term use of elder owers has not been associated
with adverse effects in the available literature. Marz et al. reported a favorable
safety and efcacy prole when combination products containing elder, such as
SinupretR, were added to antibiotics and conventional decongestant medications
(Marz et al., 1999).
Possibly unsafe: Elderberry products should be used under the direction of a
qualied healthcare provider, due to the risk of cyanide toxicity, especially from
elder bark, root, leaves, or juice (Anonymous, 1984; Kunitz, Melton, Updyke
et al., (1984)). According to secondary sources, the berries must be cooked suf-
ciently to avoid the risk of nausea or vomiting or cyanide toxicity. When used in
patients with arrhythmias or cardiovascular disease, due to the potential of tachy-
cardia from cyanide poisoning (Anonymous, 1984; Kunitz et al., 1984). When used
in patients on blood pressure medications, due to the potential of blood pressure
lowering, according to human research (Chrubasik et al., 2008; Hasani-Ranjbar,
Nayebi, Larijani, & Abdollahi, 2009). When used in patients on chemotherapy
agents, due to the potential of increased adverse effects (de Benito et al., 1998;
Lukash et al., 1997). When used in patients with CNS disorders, due to the poten-
tial for CNS depression from cyanide poisoning (Anonymous, 1984; Kunitz et al.,
1984). When used in patients with dermatological conditions, due to the potential
for application site reactions from patches, according to human research (Grbic,
Wexler, Celenti, Altman, & Saffer, 2011). When used in patients with diabetes or
those taking antidiabetic agents, due to stimulation of glucose metabolism and
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86 Ulbricht et al.
promotion of insulin secretion from beta cells in vitro (Gray, Abdel-Wahab, &
Flatt, 2000). When used in patients with diarrhea or conditions causing diarrhea,
due to the potential of laxative effects, according to human research (Picon et al.,
2010). When used in patients taking diuretics, due to the diuretic properties of
elder, according to animal research (Beaux, Fleurentin, & Mortier, 1999). When
used in patients with eating disorders or those who are underweight, due to the
potential for anorexia or decreased mean body mass, according to human re-
search (Chrubasik et al., 2008; Grbic et al., 2011; Hasani-Ranjbar et al., 2009).
When used in patients who are female, due to the potential for dysmenorrhea,
according to human research (Grbic et al., 2011). When used in patients with gas-
trointestinal disorders, due to the potential for gastrointestinal distress or upset,
diarrhea, nausea, vomiting, abdominal cramps, and dyspepsia (Anonymous, 1984;
Grbic et al., 2011; Kunitz et al., 1984; Tsui, Dennehy, & Tsourounis, 2001). When
used in patients with hypokalemia, due to the potential for decreased potassium,
according to human research (Picon et al., 2010). When used in patients with mi-
graines, due to the potential for headache, according to human research (Grbic
et al., 2011). When used in patients with muscle pain, due to the potential for
backaches, according to human research (Grbic et al., 2011). When used in pa-
tients with respiratory disorders, due to the potential for respiratory depression
from cyanide poisoning (Anonymous, 1984; Kunitz, et al., 1984) or coughing, ac-
cording to human research (Grbic et al., 2011). When used in patients taking
theophylline, due to the potential to inhibit xanthine oxidase and affect levels,
according to secondary sources.
Likely unsafe: according to secondary sources, when the bark, roots, leaves, and
unripe berries of the elder plant are consumed, due to the risk of cyanide poi-
soning. With known allergy or hypersensitivity to elder, as well as plants in the
Caprifoliaceae (honeysuckle) family, according to secondary sources.
DOSING/TOXICOLOGY
General
Doses may be based on those most commonly used in available trials or on histor-
ical practice. However, with natural products it is often not clear what the optimal
doses are to balance efcacy and safety. Preparation of products may vary from
manufacturer to manufacturer, and from batch to batch within one manufacturer.
Because it is often not clear what the active component(s) of a product is, stan-
dardization may not be possible, and the clinical effects of different brands may
not be comparable.
Standardization
According to secondary sources, dried elderower is often standardized to con-
tain at least 0.8% total avonoids calculated as isoquercitrin. Dried ower prepa-
rations often contain at least 25% water-soluble extract.
The standardized elderberry product SambucolRis a 38% standardized black
elderberry extract containing three avonoids. For children, SambucolRis a 19%
standardized black elderberry juice (Zakay-Rones et al., 1995).
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An Evidence-Based Systematic Review of Elderberry and Elderower 87
According to secondary sources, SambucolRActive DefenseTM contains a 38%
standardized black elderberry extract, plus vitamin C, zinc, propolis, and a pro-
prietary blend of Echinacea angustifolia and Echinacea purpurea.
The standardized elderberry product Sinupret R(QuanterraRSinus Defense) is
an herbal mixture containing 18 mg of os Sambucus nigra (elderower), 18 mg
of herba Verbenae off. (vervain wort), 6 mg of radix Gentianae luteae (gentian
root), 18 mg of os Primulae veris cum calycibus (cowslip owers with calyx),
and 18 mg of herba Rumicis acetosae (sorrel) (Neubauer & M¨
arz, 1994).
Dosing
Adult (age 18)
Oral.
General: according to secondary sources, a dose of 3–5 g of dried elder owers
steeped in one cup of boiling water for 10–15 min has been taken by mouth three
times daily. Be aware of possible toxicity.
Cardiovascular disease risk: patients received two capsules (500 mg) of elder-
berry extract (containing 125 mg of anthocyanin (cyanidin-3-glucoside), equiva-
lent to anthocyanin levels measured in 25 g of elderberries, 140 g of blackberries,
and 100 g of blueberries) twice daily (in the morning and at night) for 12 weeks
(Curtis et al., 2009).
Hyperlipidemia: patients were given 400 mg of spray-dried powder capsules con-
taining 10% anthocyanins three times daily equivalent to 5 mL of elderberry juice
for two weeks (Mulleder, Murkovic, & Pfannhauser, 2002). Patients were given
spray-dried elderberry juice containing 120–4,000 mg of anthocyanins daily for
2–3 weeks (Vlachojannis, Cameron, & Chrubasik, 2010).
Inuenza: Patients received 175 mg of proprietary elderberry extract lozenge four
times daily for two days (Kong, 2009). Patients were given 15 mL of elderberry
syrup four times daily for ve days for inuenza symptoms in another clinical trial
by the same author group (Zakay-Rones, Thom, Wollan, & Wadstein, 2004).
Topical
General: according to secondary sources, cream has been prepared by taking sev-
eral handfuls of fresh elder owers, mixing in liqueed petroleum jelly, simmering
for 40 min, ltering, and allowing the formula to solidify. This has been applied
to the hands at bedtime.
Children (age <18).
Insufcient available evidence.
Toxicology.
The bark, root, and leaves of S. nigra contain the cyanogenic glycoside sambuni-
grin, which is potentially toxic, and contact may lead to cyanide poisoning. Flow-
ers may be used in food provided hydrogen cyanide (HCN) levels are below
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88 Ulbricht et al.
25 ppm. Puried galactose-specic lectin from S. nigra owers at 2 mg/mL pos-
sesses mutagenic activity (Lukash et al., 1997).
Overdose: according to secondary sources, Ipecac (within 30 min) has been rec-
ommended following ingestion of elder leaves, roots, bark, or unripe fruit. Acti-
vated charcoal with cathartic may be used, although cathartics may be inadvisable
if diarrhea has developed. Emesis and gastric lavage are recommended in cases
of cyanide toxicity. Amyl nitrate, sodium nitrate, and sodium thiosulfate may also
be used.
At a dose of 3 g/kg, S. nigra extract did not modify the growth rate of rats (Mascolo
et al., 1987).
ADVERSE EFFECTS/PRECAUTIONS/CONTRAINDICATIONS
Allergy
According to secondary sources, avoid in individuals with known allergy or hyper-
sensitivity to elder, as well as plants in the Caprifoliaceae (honeysuckle) family.
Elderberry allergy elicited by 33 kDa allergen, present in pollen, ower, and berry
extracts with signicant homology to ribosomal inactivating proteins, has been
observed (Forster-Waldl et al., 2003).
According to secondary sources, there are anecdotal reports of allergies in chil-
dren playing with toys made from fresh elder stems. In theory, according to in
vitro research, lectins from Sambucus nigra may have the ability to stimulate cy-
tokine release and induce type 1 hypersensitivity (Haas et al., 1999).
In human research, three patients reported application site reaction during use
of a combination transmucosal herbal periodontal patch (THPP) (Grbic et al.,
2011).
Adverse Effects
General: the bark, root, and leaves of S. nigra contain the cyanogenic glycoside
sambunigrin, which is potentially toxic, and contact may lead to cyanide poison-
ing (Anonymous, 1984; Kunitz et al., 1984). Elderberry products should be used
under the direction of a qualied healthcare provider, due to the risk of cyanide
toxicity, especially from elder bark, root, leaves, or juice (Anonymous, 1984;
Kunitz et al., 1984). According to secondary sources, the berries must be cooked
to prevent nausea or cyanide toxicity.
Cardiovascular: cyanide poisoning from bark, root, leaves, or juice may lead to
toxicity (Anonymous, 1984; Kunitz et al., 1984), including tachycardia.
Dermatologic: in human research, three patients reported application site reac-
tion during use of a combination THPP (Grbic, Wexler, Celenti, Altman, & Saf-
fer, 2011).
Endocrine: in vitro research (Gray et al., 2000) refuted earlier research
(Swanston-Flatt, Day, Flatt, Gould, & Bailey, 1989) and reported stimulation of
glucose metabolism and promotion of insulin secretion from beta cells.
Gastrointestinal: there are reports of gastrointestinal distress, diarrhea, vomit-
ing, abdominal cramps, and weakness after drinking elderberry juice made from
crushed leaves, stems, and uncooked elderberries (Anonymous, 1984; Kunitz
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An Evidence-Based Systematic Review of Elderberry and Elderower 89
et al., 1984; Tsui et al., 2001). According to secondary sources, elder may also
possess laxative effects. According to secondary sources, the combination for-
mula SinupretR, which contains elder in combination with gentian root, sorrel,
verbena, and cowslip ower, is anecdotally said to be well tolerated, although in-
frequent cases of gastrointestinal upset have been reported. In human research,
dyspepsia (N=1), nausea (N=1), nausea and/or vomiting (N=1), taste per-
version (N=6), and pharyngitis (N=1) were reported during use of a combina-
tion THPP (Grbic et al., 2011). In human research, patients using a mouthwash
containing S. nigra reported teeth staining and discoloration (N=3) and mouth
sensitivity (N=1) (Samuels, Grbic, Saffer, Wexler, & Williams, 2012).
Genitourinary: in human research, a patient reported dysmenorrhea during use
of a combination THPP (Grbic et al., 2011).
Musculoskeletal: in human research, backache (N=1), anorexia (N=1), and ac-
cidental injury (N=3) were reported during use of a combination THPP (Grbic
et al., 2011).
Neurologic/CNS: cyanide poisoning from bark, root, leaves, or juice may lead to
toxicity (Anonymous, 1984; Kunitz et al., 1984), including CNS and respiratory
depression, and weakness. Three patients reported headaches during use of a
combination THPP (Grbic et al., 2011).
Renal: in theory, high-dose or long-term use of elder owers may have diuretic
effects (Beaux et al., 1999).
Respiratory: a patient reported increased coughing during use of a combination
THPP (Grbic et al., 2011).
Precautions/Warnings/Contraindications
Elderberry products should be used under the direction of a qualied health-
care provider, due to the risk of cyanide toxicity, including from elder bark, root,
leaves, uncooked berries, or juice (Anonymous, 1984; Kunitz et al., 1984).
Use cautiously in patients with arrhythmias or cardiovascular disease, due to the
potential of tachycardia from cyanide poisoning (Anonymous, 1984; Kunitz et al.,
1984).
Use cautiously in patients on blood pressure medications, due to the potential of
blood pressure lowering, according to human research (Chrubasik et al., 2008;
Hasani-Ranjbar et al., 2009).
Use cautiously in patients on chemotherapy agents, due to the potential of in-
creased adverse effects (de Benito et al., 1998; Lukash et al., 1997).
Use cautiously in patients with CNS disorders, due to the potential for CNS de-
pression from cyanide poisoning (Anonymous, 1984; Kunitz et al., 1984).
Use cautiously in patients with dermatological conditions, due to the potential
for application site reactions from patches, according to human research (Grbic
et al., 2011).
Use cautiously in patients with diabetes or those taking antidiabetic agents, due
to stimulation of glucose metabolism and promotion of insulin secretion from
beta cells in vitro (Gray et al., 2000).
Use cautiously in patients with diarrhea or conditions causing diarrhea, due to
the potential of laxative effects, according to human research (Picon et al., 2010).
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90 Ulbricht et al.
Use cautiously in patients taking diuretics, due to the diuretic properties of elder,
according to animal research (Beaux, Fleurentin, & Mortier, 1999).
Use cautiously in patients with eating disorders or those who are underweight,
due to the potential for anorexia or decreased mean body mass, according to
human research (Chrubasik et al., 2008; Grbic et al., 2011; Hasani-Ranjbar et al.,
2009).
Use cautiously in patients who are female, due to the potential for dysmenorrhea,
according to human research (Grbic et al., 2011).
Use cautiously in patients with gastrointestinal disorders, due to the potential for
gastrointestinal distress or upset, diarrhea, nausea, vomiting, abdominal cramps,
and dyspepsia (Anonymous, 1984; Grbic et al., 2011; Kunitz et al., 1984; Tsui et al.,
2001).
Use cautiously in patients with hypokalemia, due to the potential for decreased
potassium, according to human research (Picon et al., 2010).
Use cautiously in patients with migraines, due to the potential for headache, ac-
cording to human research (Grbic et al., 2011).
Use cautiously in patients with muscle pain, due to the potential for backaches,
according to human research (Grbic et al., 2011).
Use cautiously in patients with respiratory disorders, due to the potential for
respiratory depression from cyanide poisoning (Anonymous, 1984; Kunitz et al.,
1984) or coughing, according to human research (Grbic et al., 2011).
Use cautiously in patients taking theophylline, due to the potential to inhibit xan-
thine oxidase and affect levels, according to secondary sources.
Avoid in individuals with known allergy or hypersensitivity to elder, as well
as plants in the Caprifoliaceae (honeysuckle) family, according to secondary
sources.
Pregnancy & Lactation
There is a lack of sufcient data on the use of elderberry during pregnancy or lac-
tation. One study reported gastrointestinal discomfort in pregnant women taking
elderberry (Tsui et al., 2001). A surveillance study of the multi-ingredient prod-
uct SinupretRin pregnant women reported no excess teratogenicity compared
to controls not using SinupretR(Ismail, Wiesel, Marz, & Queisser-Luft, 2003).
Information on elder’s effects on lactation is lacking in the National Institute of
Health’s Lactation and Toxicology Database (LactMed).
INTERACTIONS
Elder/Drug Interactions
Antibiotics: in human research, concurrent use of doxycycline with Quanterra R
Sinus Defense or SinupretRhas been shown to synergistically improve outcomes
in patients with acute bacterial sinusitis (Neubauer & Mrz, 1994).
Antidiabetic agents: in vitro research (Gray et al., 2000) refuted earlier research
(Swanston-Flatt et al., 1989) and reported stimulation of glucose metabolism and
promotion of insulin secretion from beta cells.
Antihypertensive agents: in human research, elderberry improved blood pressure
(Chrubasik et al., 2008; Hasani-Ranjbar et al., 2009).
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An Evidence-Based Systematic Review of Elderberry and Elderower 91
Anti-inammatory agents: anti-inammatory properties have been demon-
strated in animal studies using elder owers (Mascolo et al., 1987). S. nigra is
reported to modulate the inammatory cytokines IL-1 and TNF-alpha in vitro
(Mascolo et al., 1987; Yesilada et al., 1997); increase human basophil secretion of
IL-4, IL-13, and histamine (Haas et al., 1999); alter function of human neutrophils
(Timoshenko & Cherenkevich, 1995); and inhibit macrophage release of proin-
ammatory cytokines and nuclear transcription factor-kB and phosphatidylinos-
itol 3-kinase in vitro (Harokopakis et al., 2006).
Antilipemics: in human research, elderberry juice reduced postprandial lipid lev-
els (Vlachojannis, Cameron, & Chrubasik, 2010). In human research, elderberry
juice decreased cholesterol concentrations and had minor effect on other serum
lipids (Mulleder et al., 2002).
Antineoplastic agents: preclinical research reports that elder may increase the ef-
fects and possible adverse effects of some cancer chemotherapies, including alky-
lating agents (de Benito et al., 1998; Lukash et al., 1997). In vitro, S. nigra inhibited
nuclear protein transport in neuroblastoma cells (Emig, Schmalz, Shakibaei, &
Buchner, 1995).
Antiobesity agents: in human research, an S. nigra (elderberry)-containing prod-
uct decreased mean body weight (Chrubasik et al., 2008; Hasani-Ranjbar et al.,
2009).
Antivirals: in laboratory, animal, and human research, elder had antiviral effects
(Kong, 2009; Konlee, 1998; Serkedjieva et al., 1990; Vlachojannis et al., 2010;
Zakay-Rones et al., 1995).
Caffeine: according to secondary sources, the avonoid quercetin, which is found
in elder, has been reported to inhibit xanthine oxidase and may affect caffeine
levels.
Cardiovascular agents: in human research, cyanide poisoning from bark, root,
leaves, or juice may lead to toxicity (Anonymous, 1984; Kunitz, Melton, Updyke,
et al., 1984), including tachycardia.
Decongestants: according to secondary sources, according to preliminary re-
search in patients, increased benets may be seen when elder is used in com-
bination with decongestants, such as oxymetazoline (AfrinR) and antibiotics.
Dental agents: in human research, an S. nigra-containing mouthwash decreased
the gingival index score (Samuels, Grbic, Saffer, Wexler, & Williams, 2012)
Diuretics: according to animal research, elder may possess diuretic properties and
should be used cautiously with drugs that increase urination (Beaux, Fleurentin,
& Mortier, 1999).
Electrolyte modulators: in human research, an S. nigra-containing product pro-
duced a small reduction in potassium during treatment; however, the study did
claim that there were no signicant differences and whether these effects were
from the combination product (Picon et al., 2010).
Gastrointestinal agents: in human research, there are reports of gastrointesti-
nal distress, diarrhea, vomiting, abdominal cramps, and weakness after drink-
ing elderberry juice made from crushed leaves, stems, and uncooked elderberries
(Anonymous, 1984; Kunitz et al., 1984; Tsui et al., 2001). According to secondary
sources, elder may also possess laxative effects and should be used cautiously
with other laxatives.
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92 Ulbricht et al.
HIV agents: in human research, SambucolRdecreased viral load (Konlee, 1998).
Laxatives: according to secondary studies, elder may possess laxative effects and
should be used cautiously with other laxatives. In human research, an S. nigra-
containing product decreased colonic transit time (CTT) and increased daily
evacuations (Picon et al., 2010).
Methylxanthines: according to secondary studies, the avonoid quercetin, which
is found in elder, has been reported to inhibit xanthine oxidase and may affect
caffeine and theophylline levels.
Neurologic agents: in human research, cyanide poisoning from bark, root, leaves,
or juice may lead to toxicity (Anonymous, 1984; Kunitz et al., 1984), including
CNS and respiratory depression, and weakness.
Vascular endothelial growth factor (VEGF) inhibitors: n vitro, OptiBerry IH141
inhibited TNF-alpha-induced VEGF (Bagchi, Sen, Bagchi, & Atalay, 2004).
Elder/Herb/Supplement Interactions
Antibacterials: in human research, concurrent use of doxycycline with
QuanterraRSinus Defense or SinupretRhas been shown to synergistically im-
prove outcomes in patients with acute bacterial sinusitis (Neubauer & Mrz, 1994).
Additional supporting evidence in this area is limited.
Anti-inammatory herbs: anti-inammatory properties have been demonstrated
in in vitro and animal studies using elder owers (Haas et al., 1999; Harokopakis
et al., 2006; Mascolo et al., 1987; Timoshenko & Cherenkevich, 1995; Yesilada
et al., 1997).
Antilipemics: in human research, anthocyanidin reduced postprandial lipid levels
(Vlachojannis et al., 2010). In human research, elderberry juice decreased choles-
terol concentrations and had minor effect on other serum lipids (Mulleder et al.,
2002).
Antineoplastic herbs: preclinical research reports that elder may increase the ef-
fects and possible adverse effects of some cancer chemotherapies, including alky-
lating agents (de Benito et al., 1998; Lukash et al., 1997). In vitro, S. nigra inhibited
nuclear protein transport in neuroblastoma cells (Emig et al., 1995).
Antiobesity herbs: in human research, an S. nigra (elderberry)-containing prod-
uct decreased mean body weight (Chrubasik et al., 2008; Hasani-Ranjbar et al.,
2009).
Antioxidants: elder preparations may exert antioxidant activity, and increased
effects may be seen when elder is used in combination with other antioxidants,
according to laboratory research (Cao & Prior, 1999; Kaack & Austed, 1998).
Antivirals: in laboratory, animal, and human research, elder had antiviral effects
(Kong, 2009; Konlee, 1998; Serkedjieva et al., 1990; Vlachojannis et al., 2010;
Zakay-Rones et al., 1995).
Caffeine: according to secondary sources, the avonoid quercetin, which is found
in elder, has been reported to inhibit xanthine oxidase and may affect caffeine
levels.
Cardiovascular agents: in human research, cyanide poisoning from bark, root,
leaves, or juice may lead to toxicity (Anonymous, 1984; Kunitz et al., 1984), in-
cluding tachycardia.
Decongestants: in theory, increased benets may be seen when elder is used in
combination with decongestants.
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An Evidence-Based Systematic Review of Elderberry and Elderower 93
Dental agents: in human research, an S. nigra-containing mouthwash decreased
the gingival index score (Samuels et al., 2012).
Diuretics: elder may possess diuretic effects and should be used cautiously with
other agents that increase urination (Beaux et al., 1999).
Electrolyte supplements: in human research, an S. nigra-containing product re-
ported a small reduction in potassium during treatment; however, the study did
claim that there were no signicant differences and whether these effects were
from the combination product (Picon et al., 2010).
Gastrointestinal agents: in human research, there are reports of gastrointesti-
nal distress, diarrhea, vomiting, abdominal cramps, and weakness after drink-
ing elderberry juice made from crushed leaves, stems, and uncooked elderberries
(Anonymous, 1984; Kunitz et al., 1984; Tsui et al., 2001). According to secondary
sources, elder may also possess laxative effects and should be used cautiously
with other laxatives.
Hypoglycemics: in vitro research (Gray et al., 2000) refuted earlier research
(Swanston-Flatt et al., 1989) and reported stimulation of glucose metabolism and
promotion of insulin secretion from beta cells.
Hypotensives: in human research, elderberry improved blood pressure
(Chrubasik et al., 2008; Hasani-Ranjbar et al., 2009).
Laxatives: according to secondary sources, elder may possess laxative effects and
should be used cautiously with other laxatives in human research, an S. nigra-
containing product decreased CTT and increased daily evacuations (Picon et al.,
2010).
Neurologic agents: in human research, cyanide poisoning from bark, root, leaves,
or juice may lead to toxicity (Anonymous, 1984; Kunitz et al., 1984), including
CNS and respiratory depression, and weakness.
Elder/Food Interactions
Anthocyanin-rich foods: certain foods rich in anthocyanin may increase effects
of elder (Curtis et al., 2009). These include raspberries, blueberries, red grapes,
plums, radishes, and red cabbage, as well as products with these ingredients
(Curtis et al., 2009).
Sucrose: ingestion of sucrose concomitantly with elderberry has been seen to re-
duce the excretion of anthocyanins found in elder (Mulleder et al., 2002).
Elder/Lab Interactions
Bilirubin: in human research, elderberry (anthocyanins) produced signicant
change in plasma bilirubin, but the clinical impact was minimal, as the bilirubin
levels were still within normal physiological levels (Curtis et al., 2009).
Blood glucose: in vitro research (Gray et al., 2000) refuted earlier research
(Swanston-Flatt et al., 1989) and reported stimulation of glucose metabolism and
promotion of insulin secretion from beta cells.
Blood pressure: in human research, elderberry improved blood pressure
(Chrubasik et al., 2008; Hasani-Ranjbar et al., 2009).
Cholesterol: in human research, elderberry juice reported reduced postprandial
lipid levels (Vlachojannis et al., 2010). In human research, elderberry juice de-
creased cholesterol concentrations and had minor effect on other serum lipids
(Mulleder et al., 2002).
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94 Ulbricht et al.
Colonic transit time (CTT): in human research, an S. nigra-containing product
decreased CTT (Picon et al., 2010).
Electrolytes: in human research, an S. nigra-containing product reported a small
reduction in potassium during treatment; however, the study did claim that there
were no signicant differences and whether these effects were from the combi-
nation product (Picon et al., 2010).
Elder/Nutrient Depletion:
Glucose: in vitro research (Gray et al., 2000) refuted earlier research (Swanston-
Flatt et al., 1989) and reported stimulation of glucose metabolism and promotion
of insulin secretion from beta cells.
Lipids: in human research, elderberry juice reported reduced postprandial lipid
levels (Vlachojannis et al., 2010). In human research, elderberry juice decreased
cholesterol concentrations and had minor effect on other serum lipids (Mulleder
et al., 2002).
MECHANISM OF ACTION
Pharmacology
Constituents: there are multiple chemical and biochemical studies of chemical
constituents in S. nigra. The bark contains alpha-amyrenone, alpha-amyrin, be-
tulin, oleanolic acid, and beta-sitosterol (Lawrie, McLean & Paton, 1964), as well
as nigrin b, a lectin similar to ricin, and other type 2 ribosome inactivating pro-
teins (RIPs) that are less toxic to cells and animals (Battelli et al., 1997). The
owers and leaves contain avonoids, including quercetin (up to 3%), rutin, hy-
peroside (Davidek, 1961), and anthocyanins (Mulleder et al., 2002), as well as
essential oils (responsible for the muscat aroma characteristic of elder owers)
(Toulemonde & Richard, 1983), mucilage, tannins (3%), organic acids, glycoside
(0.042% by weight), plastocyanin (Scawen, Ramshaw, Brown, & Boulter, 1974),
and sambunigrin (0.042% by weight). High amounts of N-phenylpropenoyl--
amino acid amides were found in the owers of Sambucus nigra (Hensel et al.,
2007).
The fruit contains the protein Sambucus nigra agglutinin Ivf (SNAIVf), which is
homologous to type 2 RIP (van Damme, Roy, Barre, Rouge et al., 1997), while
the bark contains a novel type 2 RIP (SNLRP), consisting of an A-chain with N-
glycosidase activity and a B-chain devoid of carbohydrate-binding activity nor-
mally present (van Damme, Barre, Rouge, van Leuven, & Peumans, 1997; van
Damme, Roy, Barre, Citores et al., 1997). Two additional RIPs were further iden-
tied in bark (SNAI and SNAI’) (van Damme, Roy, Barre, Citores et al., 1997),
demonstrating the complexity of type 2 RIP and lectin mixture in S. nigra.The
lectin isolated from bark is tetrameric with two distinct subunits and is rich in glu-
tamine, glutamic acid, valine, and leucine (Broekaert, Nsimba-Lubaki, Peeters,
& Peumans, 1984). The fruit type 2 RIP lectin is 10 amino acids longer than the
bark lectin (Peumans, 1998). Elder RIPs with N-glycosidase activity are reported
to inhibit protein synthesis in rabbits, but not in plants (de Benito et al., 1998).
Quercetin is also present in elder and has been shown to be a potent inhibitor of
xanthine oxidase (Chang, Lee, Lu, & Chiang 1993). S. nigra has been shown to
bind heavy metals (Coupe, Taylor, & Roberts, 1995).
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An Evidence-Based Systematic Review of Elderberry and Elderower 95
According to secondary sources, additional elderberry constituents include
cyanidin-3-glucoside and cyanidin-3-sambubioside, as well as four metabolites:
peonidin-3-glucoside, peonidin-3-sambubioside, peonidin monoglucuronide, and
cyanidin-3-glucoside monoglucuronide.
Experimental assays: the lectin of S. nigra has been used in multiple experi-
mental clinical assays, due to its carbohydrate binding properties and its ability
to precipitate highly sialylated glycoproteins (Shibuya et al., 1987), including
the use of S. nigra agglutinin binding to identify pregnant women at risk for
preterm delivery (by detecting bronectin in cervicovaginal secretions using a
glycoprotein lectin immunoabsorbent assay) (Hampel, Kottgen, Dudenhausen,
& Kottgen, 1999); distinguishing normal from stone-forming kidneys (using
N-acetylneuraminic acid:calcium binding ratios) (Hofbauer et al, 1998); ex-
amining colorectal carcinoma by examining rates of colonic mucin sialylation
(by comparing alpha 2,6-linked sialic acid vs. sialyl-Tn antigen) (Murayama
et al., 1997); evaluating ulcerative colitis by monitoring differences in sialylation
in Asian vs. European colitis patients (McMahon et al., 1997); examining
increased beta-galactoside alpha 2,6-sialyltransferase activity (by detection of
dioxigenin-conjugated S. nigra agglutinin) (Dall’Olio & Trere, 1993); evaluating
SNA levels in women with breast and ovarian cancer (Goodarzi & Turner, 1995);
glycohistochemically identifying microglial cells from Alzheimer’s disease sam-
ples (Zambenedetti, Giordano, & Zatta, 1998); measuring decreased sialylation
of glycoproteins in nasal glands of patients with sinusitis (Ueno et al., 1997);
monitoring elevated serum sialic acids associated with increased cardiovascular
mortality (Crook, Goldman, Dalziel, Madden, & McKenna, 1997); and enriching
stem cell samples and depleting T cells in bone marrow harvests (Mumcuoglu,
Manor, & Slavin, 1986).
Anti-inammatory effects:S. nigra is reported to modulate the inammatory
cytokines IL-1 and TNF-alpha in vitro (Mascolo et al., 1987; Yesilada et al.,
1997); increase human basophil secretion of IL-4, IL-13, and histamine (Haas
et al., 1999); alter function of human neutrophils (Timoshenko and Cherenkevich,
1995); and inhibit macrophage release of proinammatory cytokines and nuclear
transcription factor-kB and phosphatidylinositol 3-kinase in vitro (Harokopakis,
Albzreh, Haase, Scannapieco, & Hajishengallis, 2006).
Antioxidant effects: elderberries contain avonoids (avone, avanone,
isoavone derivatives, and anthocyanins), which are reported to possess antioxi-
dant activity and to protect against oxidative stressors, such as hydrogen peroxide,
2-amidinopropane, dihydrochloride (AAPH), ferrous sulfate, and ascorbic acid
(Abuja, Murkovic, & Pfannhauser, 1998; Middleton & Kandaswami, 1992;
Murkovic, Adam, & Pfannhauser, 2000; Youdim, Martin, & Joseph, 2000).
Antiproliferative effects: in vitro, S. nigra agglutinin has been reported to inhibit
nuclear protein transport in neuroblastoma cells, suggesting a functional signi-
cance of sialylation (Emig et al., 1995).
Antiviral effects: in laboratory and animal research, S. nigra had antiviral ef-
fects by inhibiting inuenza virus types A and B and herpes simplex-1 virus
(Serkedjieva et al., 1990), reducing hemagglutination of red blood cells, and in-
hibiting replication of several strains of inuenza A and B (Zakay-Rones et al.,
1995). A case report exists of an HIV-positive woman, taking no HIV drugs, who
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96 Ulbricht et al.
experienced a viral load drop from 17,000 to 4,000 after ingestion of Sambucol R
with olive leaf extract (Konlee, 1998). The report also included a placebo con-
trolled, double-blind study of SambucolRassociated with a rapid recovery from
inuenza and inhibited replications of nine other strains of the u virus by el-
derberry. The mechanism is believed to be rendering viruses nonfunctional by
staining and coating them. According to a review, in vitro and animal research
reported that elderberry fruit (Sambuci fructus) had an effect on inuenza,
other viral infections, and increased antibody titers (Vlachojannis, Cameron, &
Chrubasik, 2010). Human studies reported the efcacy of elderberry extract for
u-like symptoms (Kong, 2009).
Blood pressure effects: in human research, an S. nigra (elderberry)-containing
product improved blood pressure (Chrubasik et al., 2008; Hasani-Ranjbar,
Nayebi, Larijani, & Abdollahi, 2009); however, details are lacking on whether
these results were due to a decrease in mean body weight.
Cardioprotective effects: in human research, elderberry (anthocyanins) lacked
cardioprotective benet in cardiovascular disease (CVD) after 12 weeks
(Curtis et al., 2009). Signicant changes in plasma levels of inammatory
biomarkers, vascular measures (including platelet reactivity, endothelin-1, blood
pressure, and pulse), and concentrations of total cholesterol, high-density
lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), triglyc-
erides, and glucose, as well as renal and hepatic function, were lacking.
Diuretic effects: in animal research, diuretic effects and sodium excretion were as-
sociated with an extract of S. nigra owers (Beaux, Fleurentin, & Mortier, 1999).
Electrolyte effects: in human research, an S. nigra-containing product reported
a small reduction in potassium during treatment, however, the study did claim
that there were no signicant differences and whether these effects were from
the combination product (Picon et al., 2010). The effects of S. nigra alone are
unclear.
Gingival effects: in human research, an S. nigra-containing mouthwash demon-
strated a minimal, nonsignicant decrease in gingival index scores (Samuels,
Grbic, Saffer, Wexler, & Williams, 2012).
Glucose/insulin metabolism: in vitro research (Gray, Abdel-Wahab, & Flatt,
2000) refuted earlier research (Swanston-Flatt et al., 1989) and reported stimu-
lation of glucose metabolism and promotion of insulin secretion from beta cells.
Hepatic effects: in human research, elderberry (anthocyanins) lacked signi-
cant effects on levels of alanine aminotransferase (ALT), alkaline phosphatase
(ALP), gamma-glutamyl transferase (GGT), and albumin; however, a signicant
change in plasma bilirubin was measured, but the clinical impact was minimal,
as the bilirubin levels were still within normal physiological levels (Curtis et al.,
2009).
Laxative effects: in human research, an S. nigra-containing product decreased
CTT and increased daily evacuations in patients with chronic constipation (Picon
et al., 2010). The effects of S. nigra alone are unclear.
Lipid-lowering effects: in human research, elderberry juice reduced postpran-
dial lipid levels (Vlachojannis et al., 2010). In human research, elderberry juice
decreased cholesterol concentrations and had minor effect on serum lipids
(Mulleder et al., 2002).
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An Evidence-Based Systematic Review of Elderberry and Elderower 97
Renal effects: in human research, elderberry (anthocyanins) lacked signicant
effects on urea and creatinine (Curtis et al., 2009).
Vascular effects: in vitro, the multi-ingredient product OptiBerry IH141 has been
shown to possess antiangiogenic properties via inhibition of H2O2- and TNF-
alpha-induced VEGF (Bagchi et al., 2004). In another study, elderberry extracts
were associated with signicantly impaired angiogenesis in human dermal mi-
crovascular endothelial cells (Roy et al., 2002).
Weight loss effects: in human research, an S. nigra (elderberry)-containing prod-
uct decreased mean body weight (Chrubasik et al., 2008; Hasani-Ranjbar et al.,
2009).
Pharmacodynamics/Kinetics
Absorption: anthocyanins, which are potent avonoid antioxidants found in el-
der, are not absorbed in their unchanged glycosylated forms in humans (Milbury
et al., 2002). The maximum concentration of anthocyanins found in blood af-
ter injection of a highly concentrated solution was 35 mg/mL at 1 hr, followed
by a quick decay (Murkovic et al., 2000). In human research, 4 hr after the con-
sumption, the two major anthocyanins in elderberry extract, cyanidin-3-glucoside
and cyanidin-3-sambubioside (including the metabolites peonidin-3-glucoside,
peonidin-3-sambubioside, peonidin monoglucuronide, and cyanidin-3-glucoside
monoglucuronide) were detected in urine (Wu, Cao, & Prior, 2002).
Metabolism: in human research, total elderberry extract anthocyanins demon-
strated a low excretion of 554 ±90 mcg (mean ±SD, n=4) (0.077% of intake/4h,
wt/wt) (Wu, Cao, & Prior, 2002).
Elimination: the elimination of plasma anthocyanins appears to follow rst-order
kinetics, and most anthocyanin compounds are excreted in urine within 4 hr after
ingestion (Milbury et al., 2002). After ingestion of about 30 mL of elderberry ex-
tract (147.3 mg of total anthocyanins), the t1/2 was 1.74 hr (Bitsch, Janssen, Netzel,
Strass, & Frank, 2004). The urinary excretion rate of intact anthocyanins was fast
and appeared to be monoexponential, with high variability.
HISTORY
According to secondary sources, legend states that Judas Iscariot was hanged
from an elder tree and that the cross on which Jesus was hanged was made of
elder. Traditionally, elder was used to ward off evil inuences, witches, spirits,
and death in England and Russia. Knots made from elder twigs were sometimes
carried as charms to protect from rheumatism in England. The Serbs considered
elder to be good luck.
Sambucus nigra is a still commonly gathered in Poland (Luczaj & Szymanski,
2007) and Italy (Guarrera, 2005) for its food and medical uses.
Inhabitants of the South-Slavic diaspora of Mundimitar (Montemitro) (southern
Italy) use elderberry tree (S. nigra) for treating erysipelas in pigs (di Tizio, Luczaj,
Quave, Redzic, & Pieroni, 2012).
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EVIDENCE TABLE
Quality of Study: Magnitude of Number of Patients
Statistically 0–2 =poor Benefit (how Absolute Needed to
Condition Study Author, Significant 3–4 =good strong is the Risk Treat for
Treated Type Year NResults? 5 =excellent effect?) Reduction One Outcome Comments
Influenza Systematic
review
Vlachojannis, 2010 Three trials NA NA NA NA NA Improvements were seen in patients after
three to five days of treatment with
Sambucol Ror anthocyanidin.
Influenza Randomized,
double-blind,
placebo
controlled trial
Kong, 2009 64 Yes 4 Large 28 4 After 24 hr of treatment, symptoms of
fever, headache, muscle aches, and
nasal congestion were significant (p<
.0001). Coughing and mucus discharge
lacked significance. Improvement in all
symptoms was seen at 48 hr in 28% of
patients taking elderberry vs. placebo.
Influenza Randomized
double-blind,
placebo
controlled trial
Zakay-Rones,
1995
27 Yes 3 Large 53 2 Improved symptoms after three days in the
elderberry group vs. six days in controls.
Intent-to-treat analysis was lacking (40
subjects initially randomized).
Influenza Randomized,
double-blind,
placebo
controlled trial
Zakay-Rones,
2004
60 Yes 2 NA NA NA Symptoms were relieved on average four
days earlier, and use of rescue
medication was significantly less than
placebo group. Intent-to-treat analysis
was lacking, and there was a small
sample.
Bacterial
sinusitis
Systematic
review and
meta-analysis
Melzer, 2006 Four trials,
900
patients
Yes NA Medium NA NA BNO-101 (Sinupret R) had a favorable
risk-benefit ratio when used as an
add-on to antibacterial treatment;
incidence of adverse events was similar
to placebo.
Bacterial
sinusitis
Randomized,
double-blind,
placebo
controlled trial
Neubauer, 1994 160 Yes 4 Medium 28 4 Improved X-rays and symptoms after two
weeks with herbal combination
Sinupret Rvs. placebo; all subjects
received antibiotics and decongestants.
Bacterial
sinusitis
Randomized,
double-blind,
placebo
controlled trial
Richstein, 1980 31 Yes 2 Unclear Unclear Unclear Lack of clear description of analysis
precludes ability to calculate ARR and
NNT.
98
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Cardiovascular
disease risk
Randomized,
double-bind,
placebo
controlled,
parallel trial
Curtis, 2009 57 No 4 NA NA NA Most outcome measures lacked
significance vs. placebo. Anthocyanin
supplementation was safe but lacked
additional cardioprotective benefits after
12 weeks of therapy in healthy,
postmenopausal women.
Constipation Randomized,
single-blind,
placebo
controlled
crossover trial
Picon, 2010 20 Yes 2 Medium NA NA Patients taking a combination product
containing 5.0 g of Sambucus nigra
(sabugueiro) flower, had statistical
improvements in colonic transit time of
62.9%.
Gingivitis Phase II,
randomized,
double-blind,
placebo
controlled,
crossover trial
Grbic, 2011 53 Yes 4 Small NA NA A transmucosal herbal periodontal patch
(THPP) significantly decreased gingival
index scores at days 4 and 15.
Gingivitis Randomized,
double-blind,
placebo
controlled trial
Samuels, 2012 62 Yes 3 Large NA NA HM-302 was the only active treatment to
demonstrate a significantly better
change in gingival index score and
percent change.
Hyperlipidemia Systematic
review
Vlachojannis, 2010 Three trials NA NA NA NA NA A study in the systematic review reported a
reduction in postprandial lipid levels in
individuals taking 4,000 mg of
anthocyanidin daily (p-value unclear).
Hyperlipidemia Randomized,
placebo
controlled trial
M¨
ulleder, 2004 34 No 2 NA NA NA Two weeks was too short to determine
benefit. Patients were not blinded.
Obesity Systemic review Hasani-Ranjbar,
2009
One trial NA NA NA NA NA Elderberry reported significant
improvement in weight loss, blood
pressure, and quality of life.
99
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100 Ulbricht et al.
Explanation of columns in Natural Standard Evidence Table
12345678910
Condition Study
Design
Author,
Year
NStatistically
Signi-
cant?
Quality of
Study
0–2 =poor
3–4 =
good 5 =
excellent
Magnitude
of
Benet
Absolute
Risk Re-
duction
Number
Needed
to Treat
Comments
Condition
Refers to the medical condition or disease targeted by a therapy.
Study Design
Common types include:
Randomized controlled trial (RCT): an experimental trial in which participants
are assigned randomly to receive either an intervention being tested or placebo.
Note that Natural Standard denes RCTs as being placebo-controlled, while
studies using active controls are classied as equivalence trials (see below). In
RCTs, participants and researchers are often blinded (i.e., unaware of group
assignments), although unblinded and quasi-blinded RCTs are also often per-
formed. True random allocation to trial arms, proper blinding, and sufcient sam-
ple size are the basis for an adequate RCT.
Equivalence trial: an RCT which compares two active agents. Equivalence trials
often compare new treatments to usual (standard) care and may not include a
placebo arm.
Before and after comparison: a study that reports only the change in outcome in
each group of a study and does not report between-group comparisons. This is a
common error in studies that claim to be RCTs.
Case series: a description of a group of patients with a condition, treatment, or
outcome (e.g., 20 patients with migraine headache underwent acupuncture and
17 reported feeling better afterward). Case series are considered weak evidence
of efcacy.
Case–control study: a study in which patients with a certain outcome are selected
and compared to similar patients (without the outcome) to see if certain risk
factors/predictors are more common in patients with that outcome. This study
design is not common in the complementary and alternative medicine literature.
Cohort study: a study which assembles a group of patients with certain baseline
characteristics (for example, use of a drug), and follows them forward in time for
outcomes. This study design is not common in the complementary and alternative
medicine literature.
Meta-analysis: a pooling of multiple trials to increase statistical power (often
used to pool data from a number of RCTs with small sample sizes, none which
demonstrates signicance alone but in aggregate can achieve signicance). Mul-
tiple difculties are encountered when designing/reviewing these analyses; in
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An Evidence-Based Systematic Review of Elderberry and Elderower 101
particular, outcomes measures or therapies may differ from study to study, hin-
dering direct comparison.
Review: an author’s description of his or her opinion based on personal, nonsys-
tematic review of the evidence.
Systematic review: a review conducted according to pre-specied criteria in an
attempt to limit bias from the investigators. Systematic reviews often include a
meta-analysis of data from the included studies.
Author, year
Identies the study being described in a row of the table.
N
The total number of subjects included in a study (treatment group plus placebo
group). Some studies recruit a larger number of subjects initially, but do not use
them all because they do not meet the study’s entry criteria. In this case, it is
the second, smaller number that qualies as N.Nincludes all subjects that are
part of a study at the start date, even if they drop out, are lost to follow-up, or are
deemed unsuitable for analysis by the authors. Trials with a large number of drop-
outs that are not included in the analysis are considered to be weaker evidence
for efcacy. For systematic reviews, the number of studies included is reported.
For meta-analyses, the number of total subjects included in the analysis or the
number of studies may be reported.
Statistically signicant?
Results are noted as being statistically signicant if a study’s authors report sta-
tistical signicance, or if quantitative evidence of signicance is present (such as
p-values). P=pending verication.
Quality of study
A numerical score between 0 and 5 is assigned as a rough measure of study design/
reporting quality (0 being weakest and 5 being strongest). This number is based
on a well-established, validated scale developed by Jadad et al. (Jadad AR, Moore
RA, Carroll D, et al. Assessing the quality of reports of randomized clinical tri-
als: is blinding necessary? Controlled Clinical Trials 1996;17[1]:1–12). This calcu-
lation does not account for all study elements that may be used to assess quality
(other aspects of study design/reporting are addressed in the “Evidence Discus-
sion” sections of reviews).
A Jadad score is calculated using the seven items in the table below. The rst
ve items are indications of good quality, and each counts as one point toward
an overall quality score. The nal two items indicate poor quality, and a point is
subtracted for each if its criteria are met. The range of possible scores is 0 to 5.
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102 Ulbricht et al.
Jadad score calculation
Item Score
Was the study described as randomized (this includes words such as randomly,
random, and randomization)?
0/1
Was the method used to generate the sequence of randomization described and
appropriate (table of random numbers, computer-generated, etc)?
0/1
Was the study described as double blind? 0/1
Was the method of double blinding described and appropriate (identical placebo,
active placebo, dummy, etc.)?
0/1
Was there a description of withdrawals and dropouts? 0/1
Deduct one point if the method used to generate the sequence of randomization was
described and it was inappropriate (patients were allocated alternately, or according
to date of birth, hospital number, etc).
0/1
Deduct one point if the study was described as double blind but the method of blinding
was inappropriate (e.g., comparison of tablet vs. injection with no double dummy).
0/1
Magnitude of Benet
This summarizes how strong a benet is: small, medium, large, or none. If results
are not statistically signicant “NA” for “not applicable” is entered. In order to
be consistent in dening small, medium, and large benets across different stud-
ies and reviews, Natural Standard denes the magnitude of benet in terms of
the standard deviation (SD) of the outcome measure. Specically, the benet is
considered:
Large: if >1SD
Medium: if 0.5 to 0.9 SD
Small: if 0.2 to 0.4 SD.
In many cases, studies do not report the SD of change of the outcome measure.
However, the change in the SD of the outcome measure (also known as effect
size) can be calculated, and is derived by subtracting the mean (or mean dif-
ference) in the placebo/control group from the mean (or mean difference) in the
treatment group, and dividing that quantity by the pooled SD (effect size =[mean
treatment mean placebo]/SDp).
Absolute Risk Reduction
This describes the difference between the percent of people in the control/
placebo group experiencing a specic outcome (control event rate), and the per-
cent of people in the experimental/therapy group experiencing that same out-
come (experimental event rate). Mathematically, absolute risk reduction (ARR)
equals experimental event rate minus control event rate. ARR is better able to
discriminate between large and small treatment effects than relative risk reduc-
tion (RRR), a calculation that is often cited in studies ([control event rate ex-
perimental event rate]/control event rate). Many studies do not include adequate
data to calculate the ARR, in which cases “NA” is entered into this column. P=
pending verication.
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An Evidence-Based Systematic Review of Elderberry and Elderower 103
Number Needed to Treat
This is the number of patients who would need to use the therapy under inves-
tigation, for the period of time described in the study, in order for one person
to experience the specied benet. It is calculated by dividing the absolute risk
reduction into 1 (1/ARR). P=pending verication.
Comments
When appropriate, this brief section may comment on design aws (inadequately
described subjects, lack of blinding, brief follow-up, not intention-to treat, etc.),
notable study design elements (crossover, etc.), dosing, and/or specics of study
group/subgroups (age, gender, etc). More detailed description of studies is found
in the “Evidence Discussion” section that follows the “Evidence Table” in Natu-
ral Standard reviews.
EVIDENCE DISCUSSION
Note
Due to the common use and study of elder in combination products, meta-
analyses, systematic reviews, and randomized controlled trials of elder in com-
bination products are included in the Evidence Table. Nonrandomized studies of
elder as a monotherapy, as well as elder in combination products, are not included
in the Evidence Table, but are briey discussed in the Evidence Discussion.
Inuenza
Summary: in laboratory and animal research, S. nigra had antiviral effects by in-
hibiting inuenza virus types A and B and herpes simplex-1 virus (Serkedjieva,
Manolova, Zgorniak-Nowosielska et al., 1990), reducing hemagglutination of red
blood cells, and inhibiting replication of several strains of inuenza A and B
(Zakay-Rones et al., 1995). An available study reported that elderberry juice may
improve u-like symptoms, such as fever, fatigue, headache, sore throat, cough,
and aches, in less than half the time that it normally takes to recover from the u
(Zakay-Rones et al., 1995). However, the study was small and had design aws,
and it should be noted that the berries must be cooked to prevent nausea or
cyanide toxicity. In another study, patients taking elderberry for 48 hr had a sig-
nicant eradication of all investigated symptoms such as cough, fever, headache,
mucus discharge, muscle aches, or nasal congestion (Kong, 2009). It remains un-
clear whether there is any benet from elder for this condition. Additional re-
search with further well-designed clinical trials is needed in this area before a
rm conclusion may be reached. Elder should not be used in the place of other
more proven therapies, and patients are advised to discuss inuenza vaccination
with their primary healthcare provider.
Systematic review: Vlachojannis et al. conducted a systematic review of 22 stud-
ies to assess the clinical efcacy and pharmacological effects of elderberry fruit
(Sambuci fructus) in disease prevention and treatment (Vlachojannis et al.,
2010). The effects of elderberry were evaluated in 22 articles, including in vitro
and animal studies; however, only three articles assessed the effects of elderberry
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104 Ulbricht et al.
in humans (Murkovic, et al., 2004; Zakay-Rones et al., 2004; Zakay-Rones et al.,
1995). The authors identied relevant studies using CENTRAL, Ovid (MED-
LINE), PubMed, and SilverPlatter databases. The references of the pooled arti-
cles were reviewed to identify additional relevant studies, and a manual review
of literature that was lacking from the electronic databases was conducted. In
a study, participants were administered spray-dried elderberry juice containing
120–4,000 mg of anthocyanins daily for 2–3 weeks. In other studies, participants
were administered SambucolRsyrup containing elderberry, raspberry extract,
honey, glucose, and citric acid. These participants were treated with 4 tbsp. of
SambucolRby mouth daily for 3–5 days. Information on standardization and al-
lergies for these three trials was lacking. For all three studies, adverse effects were
reported to be lacking. Information on toxic effects, dropouts, and interactions
was lacking. Outcome measures included fasting and postprandial levels of total
cholesterol, LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglyc-
erides, as well as clinical symptoms of inuenza or viral upper respiratory tract
infections and antibody titers. A study reported a reduction in postprandial lipid
levels in individuals taking 4,00 0 mg of anthocyanidin daily (p-value was unclear).
Two other studies reported moderate effectiveness of SambucolRin individuals
with inuenza or other viral infections when started within 24 hr of symptom on-
set and taken for 3–5 days. In one of these studies, participants in the SambucolR
treatment group exhibited a signicant symptomatic improvement and increased
antibody titers. In the other study, participants treated with SambucolRshowed
symptom relief four days sooner, as well as a decreased use of rescue medications.
The signicance of these results was unclear from the review. The authors con-
cluded that elderberry fruit has poor-to-moderate effectiveness based on results
from the included studies. Limitations of the review included a lack of informa-
tion on dropouts, standardization, allergies, and interactions, and an overall lack
of statistical values to conrm signicance claims. Further research is needed in
this area. The effect of elder alone is not clear.
Evidence: Kong conducted a randomized, double-blind, placebo controlled trial
to examine the efcacy of a proprietary elderberry extract for the treatment of
u-like symptoms (N=64) (Kong, 2009). Individuals aged 16–60 years and pre-
senting with a minimum of three predesignated u symptoms (coughing, fever,
headache, mucus discharge, muscle aches, or nasal congestion) for 24 hr were
included in this trial. Individuals with known chronic diseases, suspected bacte-
rial infections, concurrent participation in another clinical trial, or recent use of
antiviral therapy, u medication, or inuenza vaccination were excluded from
this trial. Eligible participants were randomly assigned via a computer-generated
randomization code to receive either a 175 mg of a proprietary elderberry extract
lozenge (N=32) or a placebo lozenge (N=32), indistinguishable by appearance,
taste, or composition of nonactive ingredients. Both treatment lozenges were ad-
ministered four times daily for two days and supplied by HerbalScience Singa-
pore Pte. Ltd. Information on standardization was lacking. Adverse events were
reportedly lacking in either group. Information on toxic effects, dropouts, and in-
teractions was lacking. Primary outcome assessed was changed in self-reported
symptom severity on a 0–10 visual analog scale (VAS). After 24 hr of treat-
ment, mean VAS score signicantly improved (lower) in the elderberry group
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An Evidence-Based Systematic Review of Elderberry and Elderower 105
compared to the placebo group for symptoms of fever, headache, muscle
aches, and nasal congestion (p<.0001 for all); however, statistically signicant
between-group differences were lacking for coughing (p=.1556) and mucus dis-
charge (p=.1513). By 48 hr, a statistically signicant between-group improve-
ment in VAS score was seen for all investigated symptoms (p<.0001 for all). In
total, 28% of participants receiving elderberry vs. 0% of participants receiving
placebo demonstrated complete eradication of all symptoms after 48 hr of treat-
ment. Investigators concluded that elderberry extract was effective in attenuating
u symptoms in otherwise healthy individuals. This trial was limited by a lack of
objective outcome measures and a lack of description of dropouts. Also, this trial
was sponsored by HerbalScience Singapore Pte. Ltd., the supplier of both the
active elderberry and placebo lozenges used.
Zakay-Rones et al. conducted a randomized, double-blind, placebo controlled
study of SambucolR(a syrup containing elderberry juice, raspberry extract, glu-
cose, citric acid, and honey) in the treatment of inuenza in otherwise healthy
individuals (children and adults) not previously vaccinated against the u, lo-
cated in an Israeli agricultural community (N=40; Zakay-Rones et al., 1995).
Patients were included who had at least three symptoms (fever, myalgia, nasal
discharge, cough) of less than 24 hr’ duration. Children received 2 tbsp. daily and
adults received 4 tbsp. daily for three days. Age range and mean age were sim-
ilar between groups. An intent-to-treat analysis was lacking, and out of 40 sub-
jects who were initially enrolled and randomized, 13 were disqualied prior to
analysis, due to crossover or protocol violations (ve in the treatment group and
eight in the placebo group). In subjects who were analyzed, convalescent phase
serologies demonstrated higher antibody titers to inuenza B in the group treated
with SambucolR, although statistically signicant changes were lacking and only
demonstrated a trend in favor of the treatment group. Follow-up of symptoms
was adequately recorded over six days, and signicant improvement in symptoms
was observed in 93.3% of treated patients within two days, vs. the control group,
in which it took six days to see improvement in 92.7% of patients (p<.001). A
complete cure was seen within 2–3 days in SambucolR-treated patients (90%),
whereas six days were needed in the placebo group. Although randomization and
blinding were adequately described, this study was limited by the small sample
size, lack of intent-to-treat analysis, and use of inuenza B rather than inuenza
A titer measurement. Results seemed promising. The effect of elder alone is not
clear.
Zakay-Rones et al. conducted a randomized, double-blind, placebo controlled
study of oral elderberry syrup in the treatment of inuenza A and B virus in-
fections during the inuenza season of 1999–2000 in Norway (N=60) (Zakay-
Rones et al., 2004). Patients 18–54 years old with inuenza-like symptoms for 48
hr or less were enrolled. Patients were given 15 mL of elderberry or placebo syrup
four times daily for ve days and recorded their symptoms using a visual analog
scale. An intent-to-treat analysis was lacking. Symptoms were relieved on aver-
age four days earlier, and use of rescue medication was signicantly less in those
receiving elderberry extract compared with placebo. The authors concluded that
elderberry extract seems to offer an efcient, safe, and cost-effective treatment
for inuenza. Although the study was randomized and blinded, this study was
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106 Ulbricht et al.
limited by the small sample size, lack of intent-to-treat analysis, and failure to
report any adverse effects or lack of compliance. Although these results were
positive, additional research is needed in this area before a rm conclusion may
be drawn.
Bacterial Sinusitis
Summary: Elder has been observed to reduce excessive sinus mucus secretion in
laboratory studies (Ueno et al., 1997), and use of elder for bacterial sinusitis has
been the topic of a review (Marz et al., 1999). There is only limited research specif-
ically using elder to treat sinusitis in humans. Combination products containing
elder and other herbs (such as SinupretR) have been reported to have benecial
effects when used with antibiotics to treat sinus infections, although these re-
sults require conrmation with additional research (Ernst, Marz & Sieder, 1997;
Neubauer & Mrz, 1994). Research suggests that herbal preparations containing
elder may result in less swelling of mucus membranes, better drainage, milder
headache, and decreased nasal congestion. Evidence is lacking regarding the ef-
fects of elder when used alone for treatment of this condition, and further well-
designed clinical trials are required before conclusions may be made.
Systematic review and meta-analysis (Sinupret R): Melzer et al. conducted a sys-
tematic review and meta-analysis to assess the effects of BNO-101 (SinupretR)
in the treatment of sinusitis (Melzer, Saller, Schapowal, & Brignoli, 2006). Of
the 22 studies reviewed, six controlled trials on sinusitis were reassessed accord-
ing to predened criteria. Four trials, comprising 900 patients, could be exam-
ined by meta-analysis. After two weeks of treatment, verum was signicantly
superior to placebo (2 RCTs, 159 vs. 160 patients, both add-on to antibacterial
treatment). The benet was based on the patients’ assessment (“cured”: verum =
61.1%, placebo =34.5%), reduction of drain obstruction, headache, and radio-
logical signs (all p<.05). There were no apparent differences between BNO-
101 and ambroxol after two weeks, although results favored BNO-101 in chronic
cases (“cured”: BNO-101 =37.1%, ambroxol =12.5%; p<.05). Individuals us-
ing BNO-101 also had less pyorrhea and headache (p<.05). The authors con-
cluded that BNO-101, combined with standard antibacterial therapy, signicantly
reduced the acute symptoms and signs of sinusitis. In the trials investigated, BNO-
101 had a favorable risk–benet ratio and an incidence of adverse events that was
similar to placebo. The effect of elder alone is not clear.
Evidence (SinupretR): Neubauer and Marz conducted a two-week randomized,
double-blind, placebo-controlled trial to examine the adjunct effects of a com-
bination herbal preparation, SinupretR, on conventional antimicrobials and de-
congestants for the treatment of acute bacterial sinusitis (N=160) (Neubauer &
Marz, 1994). The inclusion criterion for this trial consisted of a conrmed clinical
diagnosis of acute sinusitis associated with plain sinus radiogram opacication.
Individuals with pronounced anatomical nasal septum deviations or those with a
known intolerance of doxycycline were excluded from this trial. All eligible par-
ticipants received antibiotic treatment with Vibramycin R(doxycycline) and de-
congestant treatment with OtrivenR(xylometazoline). Additionally, participants
were randomly assigned via computer program to receive two Sinupret Rtablets
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An Evidence-Based Systematic Review of Elderberry and Elderower 107
(N=81) or identical placebo tablets (N=79) three times daily for two weeks.
Each SinupretRtablet was sugar-coated and contained 6 mg of radix Gentianae
luteae,18mgofosSambuci nigra, 8 mg of os Primulae veris cum calycibus,
18 mg of herba Rumicis acetosae, and 18 mg of herba Verbenae off. Information on
allergies, adverse effects, and toxic effects was lacking. Information on dropouts
was also lacking, although investigators stated that the reasons for missing data in
both groups were unrelated to treatment. Although 10% of subjects used nose-
drops during the study (a protocol violation), this noncompliance was distributed
equally among groups. Investigators also stated that, according to the results
obtained from this trial, possible negative interactions between SinupretRand
conventional therapy were lacking. Primary outcomes investigated were radio-
graphic opacication and self-reported assessment of the therapy. Various clinical
ndings, including mucosa swelling, secretions, patency of the nose, nasal obstruc-
tion, and headache, were assessed as secondary outcomes. Compared to placebo,
radiographic changes in opacication signicantly favored Sinupret Rwhen con-
sidering all observed outcomes (X2 =15.5049; df =5; p=.0084) and when
grouping outcomes based on effect vs. lack of effect (X2 =5.1152; df =1; p=
.02372). Following treatment, the percentage of participants who improved from
opaque or shadowed radiographic ndings to lack of detectable abnormalities
was 64.1% for the treatment group and 36.4% for the placebo group. Similarly for
self-reported assessments, Sinupret Rwas signicantly favored vs. placebo (X2 =
21.45517; df =2; p=.000). Following treatment, the percent of asymptomatic
participants was 60.3% in the treatment group and 25.0% in the placebo group.
With respect to clinical symptoms, a statistically signicant between-group dif-
ference in favor of SinupretRwas seen for mucosa swelling, nasal obstruction,
and headache but was lacking for nasal patency and secretions. Investigators
concluded that the combination herbal therapy SinupretRenhanced the treat-
ment efcacy of conventional antimicrobial and decongestant agents in individ-
uals with acute bacterial sinusitis. Strengths of this trial included the use of both
objective and subjective outcome measures; however, its methodological rigor
was limited by a lack of description regarding dropouts. The use of a combina-
tion product left open the question of elder’s activity as a monotherapy. The short
follow-up period left open the question of longer-term efcacy and safety. Due
to limited descriptions of methods and statistical analysis, additional research is
needed in this area before a rm conclusion may be drawn.
Richstein et al. conducted a double-blind, placebo-controlled study to assess the
efcacy of SinupretRin patients with rhinorrhea and headache (N=31) (Rich-
stein & Mann, 1980). Patients were administered SinupretRor placebo in ei-
ther liquid or tablet form: two SinupretRtablets three times daily, 50 drops of
SinupretRliquid two times daily, or placebo for seven days. Objective and sub-
jective measurements were taken, including measures of symptoms pertaining to
headache, congestion, and changes in radiologic1al ndings. Using a chi-squared
analysis, the authors found that there was a signicant effect in objective (p=
.001) and subjective (p=.025) measurements. The lack of description of clinical
symptom scoring, dropouts, power calculations, use of double dummy, and sta-
tistical analysis made interpretation of these results difcult. The effect of elder
alone is not clear.
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108 Ulbricht et al.
Bronchitis
Summary: reliable human evidence evaluating elder monotherapy as a treatment
for bronchitis is currently lacking. However, elder is an ingredient in the combi-
nation herbal product SinupretR. This proprietary formula has been used histor-
ically in Europe for the treatment of acute bronchitis and bacterial sinusitis. Al-
though studies comparing the combination product to placebo are lacking, there
is initial evidence from a comparison trial of various expectorants vs. SinupretR
in the treatment of acute bronchitis (Ernst et al., 1997). Additional evidence and
well-designed clinical trials are necessary before a rm conclusion may be drawn
regarding the use of sorrel or SinupretRin the management of bronchitis.
Studies of lesser methodological quality (not included in the Evidence Table):
Ernst et al. conducted a comparison trial to evaluate the safety and efcacy of
SinupretRvs. 72 commonly prescribed expectorants, chosen freely by physicians
at the point of care (for example, products containing acetylcysteine, bromhex-
ine, or carbocysteine) (Ernst et al., 1997). The trial was open (nonblinded, non-
randomized) and included 3,187 patients with acute, uncomplicated bronchitis,
1–94 years old. The product was administered for 10 days, and the primary out-
come was improvement in bronchitis-related symptoms. The authors reported
that SinupretRwas superior to the mean improvement seen in the reference
drugs, both in terms of efcacy and adverse effects. However, Sinupret Rwas
not compared to individual expectorants. A subgroup analysis of 535 patients
with bronchitis demonstrated lower efcacy of both Sinupret Rand the reference
expectorants. Further details are lacking. Because SinupretRwas compared to
multiple agents and the study was neither randomized nor blinded, the results
may only be considered preliminary. The effect of elder alone is not clear.
Cardiovascular Disease Risk
Summary: a randomized clinical trial suggested that long-term consumption of
elderberry lacks additional cardioprotective benet in postmenopausal women
(Curtis et al., 2009). Further well-designed clinical trials are required before con-
clusions may be made.
Evidence: Curtis et al. conducted a randomized, double-blind, placebo-
controlled, parallel-designed study to assess the effects of long-term consump-
tion of elderberry (anthocyanins) on cardiovascular disease (CVD) risks in
postmenopausal women (N=57) (Curtis et al., 2009). The authors included
postmenopausal women <70 years of age who lacked menstruation for at least
12 months. Only women with a BMI between 20 and 32 kg/m2were included
in the trial. Women who had taken hormone replacement therapy within the
previous six months or smoked within the previous 12 months were excluded.
Furthermore, women who had a history of diabetes or cardiac, digestive, kidney,
liver, pulmonary, neurologic, thyroid, hematologic, or psychiatric illnesses were
excluded. Those taking anti-inammatory drugs, steroids, antibiotics, vaccines,
or dietary supplements were excluded. Women on weight loss diets or already
participating in a clinical trial within the previous four months were excluded.
Lastly, individuals with anemia, abnormal levels on renal and hepatic tests,
untreated hypertension, or abnormal levels of lipid and glucose were ineligible
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An Evidence-Based Systematic Review of Elderberry and Elderower 109
to participate. Individuals were randomized to receive two capsules of elderberry
or placebo by mouth twice daily (in the morning and at night) for a duration
of 12 weeks. Elderberry extract capsules each contained 125 mg of anthocyanin
(cyanidin-3-glucoside). The daily dose of 500 mg was equivalent to anthocyanin
levels measured in 25 g of elderberries, 140 g of blackberries, and 100 g of
blueberries. Information on allergies was lacking. One participant in the placebo
group reported anal irritation. Information regarding toxic effect was lacking.
Overall, ve participants withdrew from the study (two in the treatment group,
three in the placebo group). One woman in the placebo group discovered a lump
secondary to a routine breast exam and withdrew thereafter. Two individuals
were removed from the study by the researchers due to poor compliance (N=1
in the treatment group) and recurrence of an undisclosed condition (N=1inthe
placebo group). One participant in the placebo group withdrew due to adverse
events, and one individual in the treatment group was lost to follow-up. Inter-
actions with food were minimized by the researchers via enforcement of dietary
restrictions starting seven days prior to the inception and lasting for the 12-week
duration of the study. Participants were to avoid anthocyanin-rich berries, fruits,
and vegetables, including raspberries, blueberries, red grapes, plums, radishes,
and red cabbage, as well as products with these ingredients. Furthermore, the
authors encouraged participants to minimize intake of lower-anthocyanin-yield
products, including black olives, red apples, nectarines, and aubergine (egg-
plant). Any foods that may alter CVD biomarkers, such as tea, oily sh, and
dark chocolate, were restricted. The authors provided a list of freely available
foods as well as guidelines to maintain normal lifestyle and exercise routines.
Compliance was measured using a food diary for four days. Other information
on interactions was lacking. Levels of anthocyanins and biomarkers for CVD
risk were measured using fasting blood samples. These markers included inam-
matory, lipid, platelet, and glucose levels, as well as measures of hepatic and renal
function using albumin, total bilirubin, alanine aminotransferase (ALT), alkaline
phosphatase (ALP), gamma-glutamyl transferase (GGT), urea, and creatinine.
Blood samples were drawn 1, 2, and 3 hr after the initial bolus. The authors
also measured baseline characteristics such as height, weight, blood pressure,
and pulse. Blood pressure measurements were also taken before and after each
blood draw. Following treatment, a signicantly higher plasma concentration of
anthocyanin metabolites was observed in the treatment group vs. placebo (p=
.02). However, plasma levels of the parent compound (anthocyanin) lacked sig-
nicant between-group differences. Additionally, signicant changes in plasma
levels of the following inammatory biomarkers, vascular measures (including
platelet reactivity, endothelin-1, blood pressure, and pulse), and concentrations
of total cholesterol, high-density lipoprotein cholesterol, LDL-C, triglycerides,
and glucose were lacking. Furthermore, signicant effects of elderberry on renal
and hepatic function, as determined by urea, creatinine, albumin, ALP, ALT,
and GGT, were lacking. A signicant change in plasma bilirubin was measured
between the anthocyanin treatment group and the placebo group (p<.05) after
12 weeks. However, the authors reported that the clinical impact of this differ-
ence was minimal, as the bilirubin levels were still within normal physiological
levels for this population of women. The authors concluded that anthocyanin
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110 Ulbricht et al.
supplementation was safe but lacked additional cardioprotective benets after
12 weeks of therapy in healthy, postmenopausal women. Limitations of this
study included the extensive exclusion data (thus low generalizability of the
results) and a lack of information on adverse and toxic effects. Further research
is needed in this area.
Constipation
Summary: a randomized clinical trial suggests that a combination product con-
taining Sambucus nigra may help treat chronic constipation in as little as two
days (Picon et al., 2010). Signicant results were reported in CTT and daily evac-
uations; however, impact on the quality of life in patients was lacking. Further
well-designed clinical trials are required before conclusions may be made.
Evidence: Picon et al. conducted a randomized, single-blind, placebo-controlled
crossover study to assess the effects of a combination treatment containing
Sambucus nigra L. on constipation (N=20) (Picon et al., 2010). Individuals
aged 18–50 years who experienced chronic constipation (based on American
Gastroenterology Association criteria) were recruited for this study. Participants
were included in the study if they had normal laboratory measurements and
were using appropriate anticonception methods (if they were fertile). Partic-
ipants were excluded from the study if they currently used medications that
could cause constipation, if they had a history of abusing drugs or alcohol, or
if they presented with other diseases that lacked proper control. Participants
were randomized using a computer-generated randomization list to receive
150 mL of tea that was infused with 1 g of the active compound or placebo
tea three times daily for ve days. Following a nine-day wash-out period,
participants were crossed over to the other study arm. Each 15 g portion of the
active compound contained a homogenous blend of the following components:
2gofPimpinella anisum (green anises) fruit, 2.0 g of Foeniculum vulgare
(fennel) fruit, 5.0 g of Sambucus nigra (sabugueiro) ower, and 6.0 g of Cassia
angustifolia (senna) ower. The placebo tea was prepared my adding seven
drops of caramel color plus 10 drops of orange essence to 1,600 mL of boiling
water. According to the investigators, adverse events were lacking. According
to laboratory measurements, treatment with the combination tea resulted in
signicant reduction in serum potassium levels (from 4.5 mEq/L to 3.96 mEq/L,
p<.001). Information regarding dropouts and interactions were lacking. The
primary outcome measure was CTT, which was measured using a radiological
technique 48 hr after the injection of the last treatment for each phase of
the study. Secondary outcome measures included daily symptoms, quality of
life, frequency of adverse events, and use of laxatives during the washout
period. Following treatment, mean CTT was 15.7 hr (95% CI: 11.1–20.2 hr)
for the active treatment group and 42.3 hr (95% CI: 33.5–51.1 hr) for the placebo
group. The mean difference between these two groups was statistically signicant
(26.6 hr, 95% CI: 18.7–34.6 hr), with the treatment group showing an improve-
ment of 62.9%. With regard to the frequency of bowel movements over a 24-hr
time period, 42% of participants in the placebo group and 14% of participants
in the treatment group answered “none”; this between-group difference was
signicant (p<.001). Also, participants in the active treatment group showed
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An Evidence-Based Systematic Review of Elderberry and Elderower 111
a signicant improvement in the perception of bowel function compared to the
placebo group (p=.03). Signicant between-group differences in the use of
laxatives during the washout period or quality of life during treatment phases
were lacking. Limitations of this study include a lack of blinding and lack of
information regarding dropouts. The effect of elder alone is not clear.
Gingivitis
Summary:Sambucus nigra, in combination with other products, has been re-
ported to decrease gingivitis and gingival inammation in human trials (Grbic
et al., 2011). Signicant results were seen four days after treatment. A combina-
tion mouthwash containing Sambucus nigra signicantly decreased gingival index
scores when used three times daily for 14 days (Samuels et al., 2012). It remains
unclear whether there is any benet from elder for this condition. Additional re-
search with further well-designed clinical trials is needed in this area before a rm
conclusion may be reached.
Evidence: Grbic et al. conducted a phase II, randomized, double-blind, placebo-
controlled, crossover study to examine the safety and efcacy of a combina-
tion THPP on gingival inammation (N=53) (Grbic, Wexler, Celenti, Alt-
man & Saffer, 2011). Males and females aged 18–65 years participated in this
study. Inclusion criteria consisted of at least three posterior teeth per maxillary
quadrant and a mean gingival index (GI) score >1 (as per L¨
oe and Silness’s
methodology). Conversely, prospective participants were excluded on the ba-
sis of known allergies to any patch components; concomitant use of antibiotics,
anti-inammatories, or hormonal therapies; existing systemic conditions (e.g., di-
abetes); or evidence of severe periodontal disease, as characterized by 7mm
probing depth on posterior maxillary teeth with the exception of third molars.
Eligible participants were randomly assigned to receive either a THPP patch of
Sambucus nigra,Centella asiatica,andEchinacea purpurea, or a placebo patch
with an identical delivery system but lacking any plant extracts. A total of ve
patches for both treatments were administered over three days. One patch was
administered by the clinical investigator and two by the participants on day 1,
then one patch was administered by the participants on days 2 and 3 each. Infor-
mation on standardization was lacking. Serious adverse events were lacking in
either treatment group. Mild adverse events possibly related to THHP included
accidental injury (N=2), anorexia (N=1), back pain (N=1), increased cough-
ing (N=1), dysmenorrhea (N=1), dyspepsia (N=1), headache (N=3), nau-
sea (N=1), nausea and/or vomiting (N=1), pharyngitis (N=1), reactivity of
the application site (N=3), and taste perversion (N=6). Information on toxic
effects was lacking. Three participants dropped out of the study. Two dropouts
were due to protocol noncompliance, and one was due to an unrelated injury.
Information on interactions was lacking. The primary efcacy outcome investi-
gated was change in GI score. Secondary outcomes included treatment response
(as dened by a minimum one point increase in GI score) and change in beta-
glucuronidase (BG) levels. All efcacy outcomes were evaluated according to
a per-protocol (PP) analysis and reported only for phase 1 of the crossover, as
investigators noted that GI scores lacked a return to baseline during washout.
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112 Ulbricht et al.
Compared to baseline, both THPP and placebo were shown to decrease mean GI
scores; however, a signicantly greater decrease was seen with THPP vs. placebo
at days 4 and 15 (p<.05 for both days). Similarly, signicantly more partici-
pants receiving THPP demonstrated a positive treatment response compared to
those receiving placebo on days 4 (38% vs. 22%, respectively; p=.036) and 15
(p=.014). With regard to gingival enzyme activity, a signicantly larger decrease
in BG level was observed with THPP vs. placebo on days 4 (p=.048) and 8
(p=.04). Investigators concluded that THPP safely and effectively reduced top-
ical gingival inammation. This study was strengthened by the use of both clinical
and laboratory assessments of gingival inammation but was limited by an unsuc-
cessful crossover and a lack of description regarding randomization procedure.
The effect of elder alone is not clear.
Samuels et al. conducted a randomized, double-blind, placebo-controlled trial to
examine the safety and efcacy of a proprietary combination herbal formulation
(HM-302) for the treatment of experimentally induced gingivitis (N=62)
(Samuels et al., 2012). Individuals aged 14–75 years with clinically conrmed
gingivitis were included in this trial. Exclusion criteria consisted of smoking;
comorbid chronic illnesses, including diabetes, heart disease, or inammatory
conditions; concomitant use of anti-inammatory or antibiotic medications; or
evidence of less than 24 teeth or severe periodontitis, as characterized by >5mm
periodontal pockets in more than three areas. Eligible participants were ran-
domly assigned according to the Moses–Oakford algorithm to receive one of four
mouth rinses: (Abuja et al., 1998) HM-302 rinse with extracts from Sambucus
nigra,Centella asiatica,andEchinacea purpurea (Izun Pharmaceuticals Corp.,
Israel; N=15); (Akerreta et al., 2007) a water-based cetylpyridinium chloride
(CPC) rinse (N=14); (Anonymous, 1984) an alcohol-based essential oil (EO)
rinse (ListerineR, Johnson & Johnson; N=17), or; (Bagchi et al., 2004) a water-
based negative control rinse (N=16). All treatment mouth rinses were taken in
15 mL aliquots three times daily for 14 days. All other oral hygiene techniques,
including ossing, use of breath mints, and use of commercial mouth rinses, were
prohibited during this trial. Information on standardization was lacking. HM-302
was reportedly well tolerated and lacked evidence of any serious adverse effects.
Teeth staining and discoloration was the most commonly reported adverse effect
across all treatments, but it lacked a statistically signicant between-group differ-
ence in frequency (N=3 with HM-302). One incidence of mouth sensitivity was
also reported with HM-302. Information regarding toxic effects, dropouts, and
interactions was lacking. The primary outcome assessed was change in gingival
index (GI). Secondary outcomes included change in plaque index (PI) and the
number of bleeding sites. Compared to baseline, HM-302 demonstrated a mini-
mal, nonsignicant decrease in GI score, whereas all other groups demonstrated
an increased (worsening) GI score. Compared to the water control, HM-302 was
the only active treatment to demonstrate a signicantly better change in GI score
(0.213 ±0.23 vs. 0.026 ±0.22 for water vs. HM-302, respectively; p=.007) and
percent change in GI score (31.8 ±37.2 vs. 1.8 0 ±31.8%, respectively; p=.013).
HM-302 also demonstrated the smallest increase (exacerbation) in PI score
from baseline, whereas all other groups demonstrated a statistically signicant
or nearly signicant increase. However, a statistically signicant between-group
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An Evidence-Based Systematic Review of Elderberry and Elderower 113
difference was lacking between HM-302 and the water control with respect to
change in PI score (p=.081) or percent change in GI score (p=0.126) from
baseline. With regard to gingival bleeding, HM-302 demonstrated a minimal
change in the number of bleeding sites from baseline and the highest proportion
of participants with a reduction of bleeding sites post-treatment (i.e., response
rate). Between groups, a statistically signicant difference in change of bleeding
sites from baseline was seen with HM-302 vs. water control (0.2 ±1.07 vs. 9.5 ±
12.3, respectively; p=0.035). Investigators concluded that combination herbal
HM-302 mouth rinse attenuated gingival inammation in otherwise healthy indi-
viduals. Limitations of this trial included a lack of description regarding blinding
procedures and participant dropouts. Also, Izun Pharmaceuticals Corp., the de-
velopers of HM-302 and afliated employer of two study investigators, provided
funding for the statistical analysis of this trial. The effect of elder alone is not
clear.
Studies of lesser methodological quality (not included in the Evidence Table):
Samuels et al. conducted a pilot trial to assess the localized effects of a topical
gingival patch on gingival inammation (N=26) (Samuels, Saffer, Wexler, &
Oberbaum, 2012). Patients were included in the trial if site inammation was
identied on subjects with moderate-to-severe chronic periodontitis. A topical
patch was placed on 22 of 36 identied sites for 24 hr. Reports on adverse effects
were lacking in both groups. The primary outcome assessed was inammation
(measured by neutrophilic activity using gingival crevicular uid (GCF) beta-
glucuronidase (b-glu) levels) and clinical response (measured by gingival index
(GI)). In 17 of 22 sites, GCF b-glu levels signicantly reduced patch placement
(p=.002), compared to 3 of 14 sites in the control group. A signicant reduction
in mean b-glu levels and percent change from baseline were seen during patch
replacement (2.52 ±1.62 and 29.7%, respectively); however; an increase was
seen in the mean b-glu levels and percent change from baseline in the control
group (2.14 ±0.89 and 33%, respectively). Eighteen of 21 sites vs. 7 of 14 sites
had a signicantly better GI response rate at 24 hr (p=.053). Further details are
lacking. The effect of elder alone is not clear.
Hyperlipidemia
Summary: Reliable human evidence evaluating elder monotherapy as a treat-
ment for hyperlipidemia is currently lacking. A randomized control trial reported
that elderberry juice may decrease in serum cholesterol concentrations and in-
crease in LDL stability (Mulleder, Murkovic, & Pfannhauser, 2002). However,
this study was a pilot design of small sample population. It remains unclear
whether there is any benet from elder for this condition. Additional research
is needed in this area before a rm conclusion may be reached.
Systematic review: Vlachojannis et al. conducted a systematic review of 22 stud-
ies to assess the clinical efcacy and pharmacological effects of elderberry fruit
(Sambuci fructus) in disease prevention and treatment (Vlachojannis et al.,
2010). The effects of elderberry were evaluated in 22 articles, including in vitro
and animal studies; however, only three articles assessed the effects of elderberry
in humans (Murkovic et al., 2004; Zakay-Rones et al., 2004; Zakay-Rones et al.,
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114 Ulbricht et al.
1995). The authors identied relevant studies using Central, Ovid (MEDLINE),
PubMed, and SilverPlatter databases. The references of the pooled articles were
reviewed to identify additional relevant studies, and a manual review of litera-
ture that was lacking from the electronic databases was conducted. In a study
assessed, participants were administered spray-dried elderberry juice contain-
ing 120–4,000 mg of anthocyanins daily for 2–3 weeks. In other studies, partic-
ipants were administered SambucolRsyrup containing elderberry, raspberry ex-
tract, honey, glucose, and citric acid. These participants were treated with 4 tbsp.
SambucolRby mouth daily for 3–5 days. Information on standardization and al-
lergies for these three trials was lacking. For all three studies, adverse effects were
reported to be lacking. Information on toxic effects, dropouts, and interactions
was lacking. Outcome measures included fasting and postprandial levels of total
cholesterol, LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglyc-
erides, as well as clinical symptoms of inuenza or viral upper respiratory tract
infections and antibody titers. A study reported a reduction in postprandial lipid
levels in individuals taking 4,00 0 mg of anthocyanidin daily (p-value was unclear).
Two other studies reported moderate effectiveness of SambucolRin individuals
with inuenza or other viral infections when started within 24 hr of symptom on-
set and taken for 3–5 days. In one of these studies, participants in the SambucolR
treatment group exhibited a signicant symptomatic improvement and increased
antibody titers. In the other study, participants treated with SambucolRshowed
symptom relief four days sooner, as well as a decreased use of rescue medications.
The signicance of these results was unclear from the review. The authors con-
cluded that elderberry fruit has poor-to-moderate effectiveness based on results
from the included studies. Limitations of the review included lack of information
on dropouts, standardization, allergies, and interactions, and an overall lack of
statistical values to conrm signicance claims. Further research is needed in this
area. The effect of elder alone is not clear.
Evidence:M¨
ulleder et al. conducted a pilot, randomized, placebo controlled trial
of elderberry juice in the treatment of hyperlipidemia in otherwise healthy indi-
viduals (N=16) (Mulleder et al., 2002). Patients were given 400 mg of spray-dried
powder capsules containing 10% anthocyanins three times daily, equivalent to
5 mL of elderberry juice for two weeks. This was not an intent-to-treat analysis.
There was only a statistically insignicant change in cholesterol concentrations
in the elderberry group (from 199 to 190 mg/dL) compared to the placebo group
(from 192 to 196 mg/dL). Elderberry spray-dried extract at a low dose exerted a
minor effect on serum lipids. Higher but nutritionally relevant doses might signif-
icantly reduce postprandial serum lipids. Although randomization and blinding
were adequately described, this study is limited by the small sample size, lack of
intent-to-treat analysis, and use of a low dose of elderberry extract. Additional
research is needed in this area before a rm conclusion may be drawn.
Obesity
Summary: a literature review evaluated a study on the effects of elderberry on
obesity (Hasani-Ranjbar et al., 2009). A signicant difference was seen not only
in body weight, but in blood pressure and quality of life as well (Chrubasik et al.,
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An Evidence-Based Systematic Review of Elderberry and Elderower 115
2008). Further well-designed clinical trials are required before conclusions may
be made.
Systematic review: Hasani-Ranjbar et al. conducted a systematic review of 77
articles to assess the safety and efcacy of herbal medications in the treatment
of obesity (Hasani-Ranjbar et al., 2009). The authors included a variety of an-
tiobesity herbs tested in animals and humans; one study focused on the effects of
Sambucus nigra (elderberry) in humans (Chrubasik et al., 2008). Relevant arti-
cles published prior to December 30, 2008, that assessed the effects of herbal or
plant medicines on obesity in animals or humans were pooled from the PubMed,
Google Scholar, Scopus, IranMedex, and Web of Science databases. Relevant
outcomes included antiobesity effects such as changes in body weight, body fat,
percentage of body fat or adipose tissue, thickness of triceps skin folds, circumfer-
ence of the waist or hips, and changes in appetite or food intake. Studies evaluat-
ing other disease states, such as diabetes, were included if the outcomes matched
those above. Inclusion required the use of a herbal medicine dened as the raw or
rened product of a plant or plant part, including the stems, leaves, owers, buds,
tubers, or roots, used for medicinal purposes. In vitro studies were excluded from
the review, as were letters to the editor, unpublished data, articles without avail-
able abstracts, and review articles. Individuals in the treatment group received a
combination of Sambucus nigra and Asparagus ofcinalis intheformof19mgof
saponin daily. The duration of treatment was unclear. The daily dose of the com-
bination treatment provided 1 mg of anthocyanin, 370 mg of avonol, 150 mg of
hydroxycinnamate from Sambucus nigra, and 19 mg of saponin from Asparagus
ofcinalis. Information regarding allergies, adverse effects toxic effects, dropouts,
and interactions was lacking. Outcomes included mean changes in body weight,
blood pressure, quality of life, and emotional and physical wellness. A signicant
decrease in mean body weight was measured (p-value was unclear). Furthermore,
a signicant improvement in blood pressure values, quality of life, and physical
and emotional wellness was reported (p-values were unclear). The authors con-
cluded that multiple herbal supplements have benecial effects on obese animals
and humans. Specic conclusions regarding the clinical benets of Sambucus ni-
gra were lacking. Limitations of this literature review include lack of informa-
tion regarding the duration of therapy, adverse effects, allergies, interactions, and
dropouts. Further research is needed in this area. The effect of elder alone is not
clear.
BRANDS USED IN CLINICAL TRIALS/THIRD-PARTY TESTING
RubiniRBioFlavonoides Elderberry Extract (Zertikationsnr: IT-CDX 5987) is
a monotherapy derived from elderberries, with no additives from animals or col-
orings, and no preservatives (Youdim et al., 2000).
SambucolR(Razei Bar Industries, Jerusalem, Israel) is a syrup containing elder-
berry juice extract standardized to contain three avonoids, raspberry extract,
glucose, citric acid, and honey (Barak et al., 2001).
SinupretR(QuanterraRSinus Defense) is an herbal mixture of 18 mg of os
Sambucus nigra (elderower), 18 mg of herba Verbenae off. (vervain wort),
6 mg of radix Gentianae luteae (gentian root), 18 mg of os Primulae veris cum
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116 Ulbricht et al.
calycibus (cowslip owers with calyx), and 18 mg of herba Rumicis acetosae (sor-
rel) (Neubauer & Mrz, 1994; Richstein & Mann, 1980).
Declaration of interest: The authors report no conict of interest. The authors
alone are responsible for the content and writing of this paper.
ABOUT THE AUTHORS
Catherine Ulbricht, PharmD, Massachusetts General Hospital, Boston, MA, USA.
Ethan Basch, MD, MPhil, Memorial Sloan-Kettering Cancer Center, 1275 York
Avenue, New York, NY 10065, USA. Lisa Cheung, PharmD, University of Rhode
Island, 45 Upper College Road, Kingston, RI 02881, USA. Harley Goldberg,DO,
Kaiser Permanente, Oakland, CA, USA. Paul Hammerness, MD, Harvard Medi-
cal School, 25 Shattuck St, Boston, MA. Richard Isaac,Wendy Weissner, BA, and
Regina C. Windsor, Natural Standard Research Collaboration, Somerville, MA.
Karta Purkh Singh Khalsa, DN-C, RH, Bastyr University, 14500 Juanita Drive
Northeast, Kenmore, WA 98028-4966, USA. Aviva Romm, BSc, CPM, RH (AHG),
American Herbalists Guild, Canton, GA, USA. Edward Mills, DPH, MSc, Cana-
dian College of Naturopathic Medicine, 1255 Sheppard Avenue East, Toronto M2K
1E2, Canada. Idalia Rychlik, PharmD, Massachusetts College of Pharmacy, 179
Longwood Avenue, Boston, MA 02115, USA. Minney Varghese, BS, Northeastern
University, 360 Huntington Ave, Boston, MA. Jayme Wortley, PharmD, East Ten-
nessee State University, Gatton College of Pharmacy, 807 University Pkwy, Johnson
City, TN.
REFERENCES
Abuja PM, Murkovic M, Pfannhauser W. Antioxidant and prooxidant activities of elder-
berry (Sambucus nigra) extract in low density lipoprotein oxidation. J Agric Food Chem.
1998;46:4091–4096.
Akerreta S, Cavero RY, Calvo MI. First comprehensive contribution to medical ethnobotany of
Western Pyrenees. J Ethnobiol Ethnomed. 2007;3:26.
Anonymous. Leads from the MMWR. Poisoning from elderberry juice. JAMA. 1984;
251(16):2075.
Bagchi D, Sen CK, Bagchi M, Atalay M. Anti-angiogenic, antioxidant, and anti-carcinogenic
properties of a novel anthocyanin-rich berry extract formula. Biochemistry (Mosc).
2004;69(1):75–80, 1.
Barak V, Halperin T, Kalickman I. The effect of Sambucol, a black elderberry-based, natural
product, on the production of human cytokines: I. Inammatory cytokines. Eur Cytokine
Netw. 2001;12(2):290–296.
Battelli MG, Citores L, Buonamici L, Ferreras JM, de Benito FM, et al. Toxicity and cytotoxicity
of nigrin b, a two-chain ribosome-inactivating protein from Sambucus nigra: comparison with
ricin. Arch Toxicol. 1997;71(6):360–364.
Beaux D, Fleurentin J, Mortier F. Effect of extracts of Orthosiphon stamineus Benth, Hieracium
pilosella L., Sambucus nigra L. and Arctostaphylos uva-ursi (L.) Spreng. in rats. Phytother
Res. 1999;13(3):222–225.
Bitsch I, Janssen M, Netzel M, Strass G, Frank T. Bioavailability of anthocyanidin-3-glycosides
following consumption of elderberry extract and blackcurrant juice. Int J Clin Pharmacol
Ther. 2004;42(5):293–300.
J Dietary Suppl Downloaded from informahealthcare.com by University of North Carolina on 04/16/14
For personal use only.
An Evidence-Based Systematic Review of Elderberry and Elderower 117
Broekaert WF, Nsimba-Lubaki M, Peeters B, Peumans WJ. A lectin from elder (Sambucus nigra
L.) bark. Biochem J. 1984;221(1):163–169.
Cao G, Prior RL. Anthocyanins are detected in human plasma after oral administration of an
elderberry extract. Clin Chem. 1999;45(4):574–576.
Chang WS, Lee YJ, Lu FJ, Chiang HC. Inhibitory effects of avonoids on xanthine oxidase.
Anticancer Res. 1993;13:2165–2170.
Chrubasik C, Maier T, Dawid C, Torda T, Schieber A, Hofmann T, et al. An observational study
and quantication of the actives in a supplement with Sambucus nigra and Asparagus ofci-
nalis used for weight reduction. Phytother Res. 2008;22(7):913–918.
Coupe SA, Taylor JE, Roberts JA. Characterisation of an mRNA encoding a metallothionein-like
protein that accumulates during ethylene-promoted abscission of Sambucus nigra L. Leaets
Planta. 1995;197(3):442–447.
Crook JR, Goldman JH, Dalziel M, Madden B, McKenna WJ. Increased ventricular sia-
lylation in patients with heart failure secondary to ischemic heart disease. Clin Cardiol.
1997;20(5):455–458.
Curtis PJ, Kroon PA, Hollands WJ, Walls R, Jenkins G, Kay CD, et al. Cardiovascular dis-
ease risk biomarkers and liver and kidney function are not altered in postmenopausal
women after ingesting an elderberry extract rich in anthocyanins for 12 weeks. J Nutr.
2009;139(12):2266–2271.
Dall’Olio F, Trere D. Expression of alpha 2,6-sialylated sugar chains in normal and neoplastic
colon tissues. Detection by digoxigenin-conjugated Sambucus nigra agglutinin. Eur J His-
tochem. 1993;37(3):257–265.
Davidek J. Isolation of chromatographically pure rutin from owers of elder. Nature.
1961;189(4763):487–488.
de Benito FM, Iglesias R, Ferreras JM, Citores L, Camafeita E, Mendez E, et al. Constitutive
and inducible type 1 ribosome-inactivating proteins (RIPs) in elderberry (Sambucus nigra
L.). FEBS Lett. 1998;428(1–2):75–79.
di Tizio A, Luczaj LJ, Quave CL, Redzic S, Pieroni A. Traditional food and herbal uses of wild
plants in the ancient South-Slavic diaspora of Mundimitar/Montemitro (Southern Italy). J
Ethnobiol Ethnomed. 2012;8:21.
Emig S, Schmalz D, Shakibaei M, Buchner K. The nuclear pore complex protein p62 is
one of several sialic acid-containing proteins of the nuclear envelope. J Biol Chem.
1995;270(23):13787–13793.
Ernst E, Marz RW, Sieder C. [Acute bronchitis: effectiveness of Sinupret. Comparative study
with common expectorants in 3,187 patients]. Fortschr Med. 1997;115(11):52–53.
Forster-Waldl E, Marchetti M, Scholl I, Focke M, Radauer C, Kinaciyan T, et al. Type I allergy
to elderberry (Sambucus nigra) is elicited by a 33.2 kDa allergen with signicant homology to
ribosomal inactivating proteins. Clin Exp Allergy. 2003;33(12):1703–1710.
Goodarzi MT, Turner GA. Decreased branching, increased fucosylation and changed sia-
lylation of alpha-1-proteinase inhibitor in breast and ovarian cancer. Clin Chim Acta.
1995;236(2):161–171.
Gray AM, Abdel-Wahab YH, Flatt PR. The traditional plant treatment, Sambucus nigra (elder),
exhibits insulin-like and insulin-releasing actions in vitro. J Nutr. 2000;130(1):15–20.
Grbic J, Wexler I, Celenti R, Altman J, Saffer A. A phase II trial of a transmucosal herbal patch
for the treatment of gingivitis. J Am Dent Assoc. 2011;142(10):1168–1175.
Guarrera PM. Traditional phytotherapy in Central Italy (Marche, Abruzzo, Latium). Fitoterapia.
2005;76(1):1–25.
Haas H, Falcone FH, Schramm G, Haisch K, Gibbs BF, Klaucke J, et al. Dietary lectins can induce
in vitro release of IL-4 and IL-13 from human basophils. Eur J Immunol. 1999;29(3):918–927.
Hampel DJ, Kottgen B, Dudenhausen JW, Kottgen E. Fetal bronectin as a marker for an immi-
nent (preterm) delivery. A new technique using the glycoprotein lectin immunosorbent assay.
J Immunol Methods. 1999;224(1–2):31–42.
Harokopakis E, Albzreh MH, Haase EM, Scannapieco FA, Hajishengallis G. Inhibition of proin-
ammatory activities of major periodontal pathogens by aqueous extracts from elder ower
(Sambucus nigra). J Periodontol. 2006;77(2):271–279.
J Dietary Suppl Downloaded from informahealthcare.com by University of North Carolina on 04/16/14
For personal use only.
118 Ulbricht et al.
Hasani-Ranjbar S, Nayebi N, Larijani B, Abdollahi M. A systematic review of the efcacy
and safety of herbal medicines used in the treatment of obesity. World J Gastroenterol.
2009;15(25):3073–3085.
Hensel A, Deters AM, Muller G, Stark T, Wittschier N, Hofmann T. Occurrence of N-
phenylpropenoyl-l-amino acid amides in different herbal drugs and their inuence on human
keratinocytes, on human liver cells and on adhesion of Helicobacter pylori to the human stom-
ach. Planta Med. 2007;73(2):142–150.
Hofbauer J, Fang-Kircher S, Steiner G, Wiener H, Susani M, Simak R, et al. N-acetylneuraminic
acids (nana): a potential key in renal calculogenesis. Urol Res. 1998;26(1):49–56.
Ismail C, Wiesel A, Marz RW, Queisser-Luft A. Surveillance study of Sinupret in comparison
with data of the Mainz birth registry. Arch Gynecol. Obstet. 2003;267(4):196–201.
Jaric S, Popovic Z, Macukanovic-Jocic M, Djurdjevic L, Mijatovic M, Karadzic B, et al. An eth-
nobotanical study on the usage of wild medicinal herbs from Kopaonik Mountain (Central
Serbia). J Ethnopharmacol. 2007;111(1):160–175.
Kaack K, Austed T. Interaction of vitamin C and avonoids in elderberry (Sambucus nigra L.)
during juice processing. Plant Foods Hum Nutr. 1998;52(3):187–198.
Kong F. Pilot clinical study on a proprietary elderberry extract: efcacy in addressing inuenza
symptoms. Online J Pharmacol Pharmacokinet. 2009;5:32–43.
Konlee M. A new triple combination therapy. Posit Health News. 1998;(17):12–14.
Kunitz S, Melton RJ, Updyke T, Breedlove D, Werner SB. Poisoning from elderberry juice.
MMWR 1984;33(13):173–174.
Lawrie W, McLean J, Paton AC. Triterpenoids in the bark of elder (Sambucus nigra). Phyto-
chemistry. 1964;3:267–268.
Luczaj L, Szymanski WM. Wild vascular plants gathered for consumption in the Polish country-
side: a review. J Ethnobiol Ethnomed. 2007;3:17.
Lukash LL, Karpova IS, Miroshnichenko OS, Tikhonova TN, Lylo VV, Man’ko VG, et al. The
effect of the lectin from Sambucus nigra inorescences on spontaneous and alkylating agent-
induced mutagenesis in mammalian somatic cells. Tsitol Genet. 1997;31(5):52–60.
Marz RW, Ismail C, Popp MA. Prole and effectiveness of a phytogenic combination preparation
for treatment of sinusitis. Wien Med Wochenschr. 1999;149(8–10):202–208.
Mascolo N, Autore G, Capasso F, Menghini A, Palmira Fasulo M. Biological screening of Italian
medicinal plants for anti-inammatory activity. Phytotherapy Research. 1987;1(1):28–31.
McMahon RF, Warren BF, Jones CJ, Mayberry JF, Probert CS, Coreld AP, et al. South Asians
with ulcerative colitis exhibit altered lectin binding compared with matched European cases.
Histochem J. 1997;29(6):469–477.
Melzer J, Saller R, Schapowal A, Brignoli R. Systematic review of clinical data with BNO-
101 (Sinupret) in the treatment of sinusitis. Forsch Komplement Med. (2006). 2006;13(2):
78–87.
Middleton E Jr, Kandaswami C. Effects of avonoids on immune and inammatory cell func-
tions. Biochem Pharmacol. 1992;43(6):1167–1179.
Milbury PE, Cao G, Prior RL, Blumberg J. Bioavailablility of elderberry anthocyanins. Mech
Ageing Dev. 2002;123(8):997–10 06.
Mulleder U, Murkovic M, Pfannhauser W. Urinary excretion of cyanidin glycosides. J Biochem
Biophys Methods. 2002;53(1–3):61–66.
Mumcuoglu M, Manor D, Slavin S. Enrichment for GM-CFU from human bone marrow using
Sambucus nigra agglutinin: potential application to bone marrow transplantation. Exp Hema-
tol. 1986;14(10):946–950.
Murayama T, Zuber C, Seelentag WK, Li WP, Kemmner W, Heitz PU, et al. Colon carcinoma
glycoproteins carrying alpha 2,6-linked sialic acid reactive with Sambucus nigra agglutinin are
not constitutively expressed in normal human colon mucosa and are distinct from sialyl-Tn
antigen. Int J Cancer. 1997;70(5):575–581.
Murkovic M, Abuja PM, Bergmann AR, Zirngast A, Adam U, Winklhofer-Roob BM, et al. Ef-
fects of elderberry juice on fasting and postprandial serum lipids and low-density lipoprotein
oxidation in healthy volunteers: a randomized, double-blind, placebo-controlled study. Eur J
Clin Nutr. 2004;58(2):244–249.
J Dietary Suppl Downloaded from informahealthcare.com by University of North Carolina on 04/16/14
For personal use only.
An Evidence-Based Systematic Review of Elderberry and Elderower 119
Murkovic M, Adam U, Pfannhauser W. Analysis of anthocyane glycosides in human serum. Fre-
senius J Anal Chem. 2000;366(4):379–381.
Neubauer N, M¨
arz RW. Placebo-controlled, randomized double-blind clinical trial with
Sinupret Rsugar coated tablets on the basis of a therapy with antibiotics and decongestant
nasal drops in acute sinusitis. Phytomedicine. 1994;1(3):177–181.
Peumans WJ, Roy S, Barre A, Rouge P, van Leuven F, van Damme EJ. Elderberry (Sambucus ni-
gra) contains truncated Neu5Ac(alpha- 2,6)Gal/GalNAc-binding type 2 ribosome-inactivating
proteins. FEBS Lett. 1998;425(1):35–39.
Picon PD, Picon RV, Costa AF, Sander GB, Amaral KM, Aboy AL, et al. Randomized clin-
ical trial of a phytotherapic compound containing Pimpinella anisum,Foeniculum vulgare,
Sambucus nigra,Cassia augustifolia for chronic constipation. BMC. Complement Altern Med.
2010;10:17.
Richstein A, Mann W. [Treatment of chronic sinusitis with Sinupret]. Ther Ggw. 1980;119(9):
1055–1060.
Roxas M, Jurenka J. Colds and inuenza: a review of diagnosis and conventional, botanical, and
nutritional considerations. Altern Med Rev. 2007;12(1):25–48.
Roy S, Khanna S, Alessio HM, Vider J, Bagchi D, Bagchi M, et al. Anti-angiogenic property of
edible berries. Free Radic Res. 2002;36(9):1023–1031.
Samuels N, Grbic JT, Saffer AJ, Wexler ID, Williams RC. Effect of an herbal mouth rinse in pre-
venting periodontal inammation in an experimental gingivitis model: a pilot study. Compend
Contin Educ Dent. 2012;33(3):204–211.
Samuels N, Saffer A, Wexler ID, Oberbaum M. Localized reduction of gingival inammation
using site-specic therapy with a topical gingival patch. J Clin Dent. 2012;23(2):64–67.
Scawen MD, Ramshaw JA, Brown RH, Boulter D. The amino-acid sequence of plastocyanin
from Sambucus nigra L. (Elder). Eur J Biochem. 1974;44(1):299–303.
Serkedjieva J, Manolova N, Zgorniak-Nowosielska I, et al. Antiviral activity of the infusion (SHS-
174) from owers of Sambucus nigra L., aerial parts of Hypericum perforatum L., roots of
Saponaria ofcinalis L. against inuenza and herpes simplex viruses. Phytotherapy Research.
1990;4(3):97–100.
Shibuya N, Goldstein IJ, Broekaert WF, Nsimba-Lubaki M, Peeters B, Peumans WJ. The el-
derberry (Sambucus nigra L.) bark lectin recognizes the Neu5Ac(alpha 2–6)Gal/GalNAc se-
quence. J Biol Chem. 1987;262(4):1596–1601.
Swanston-Flatt SK, Day C, Flatt PR, Gould BJ, Bailey CJ. Glycaemic effects of traditional Eu-
ropean plant treatments for diabetes. Studies in normal and streptozotocin diabetic mice. Di-
abetes Res. 1989;10(2):69–73.
Timoshenko AV, Cherenkevich SN. [H2O2 generation and human neutrophil aggregation as af-
fected by lectins]. Gematol Transfuziol. 1995;40(4):32–35.
Toulemonde B, Richard HM. Volatile constituents of dry elder (Sambucus nigra L.) owers. J.
Agric Food Chem. 1983;31(2):365–370.
Tsui B, Dennehy CE, Tsourounis C. A survey of dietary supplement use during pregnancy at an
academic medical center. Am J Obstet Gynecol. 2001;185(2):433–437.
Ueno K, Wang ZH, Hanamure Y, Yoshitsugu M, Fukuda K, Furuta S, et al. Reduced sialy-
lation of glycoproteins in nasal glands of patients with chronic sinusitis. Acta Otolaryngol.
1997;117(3):420–423.
van Damme EJ, Barre A, Rouge P, van Leuven F, Peumans WJ. Isolation and molecular cloning
of a novel type 2 ribosome-inactivating protein with an inactive B chain from elderberry (Sam-
bucus nigra) bark. J Biol Chem. 1997;272(13):8353–8360.
van Damme EJ, Roy S, Barre A, Citores L, Mostafapous K, Rouge P, et al. Elderberry (Sambucus
nigra) bark contains two structurally different Neu5Ac(alpha2,6)Gal/GalNAc-binding type 2
ribosome-inactivating proteins. Eur J Biochem. 1997;245(3):648–655.
van Damme EJ, Roy S, Barre A, Rouge P, van Leuven F, Peumans WJ. The major elderberry
(Sambucus nigra) fruit protein is a lectin derived from a truncated type 2 ribosome-inactivating
protein. Plant J. 1997;12(6):1251–1260.
Vlachojannis JE, Cameron M, Chrubasik S. A systematic review on the sambuci fructus effect
and efcacy proles. Phytother Res. 2010;24(1):1–8.
J Dietary Suppl Downloaded from informahealthcare.com by University of North Carolina on 04/16/14
For personal use only.
120 Ulbricht et al.
Wu X, Cao G, Prior RL. Absorption and metabolism of anthocyanins in elderly women after
consumption of elderberry or blueberry. J Nutr. 2002;132(7):1865–1871.
Yesilada E, Ustun O, Sezik E, Takaishi Y, Ono Y, Honda G. Inhibitory effects of Turkish folk
remedies on inammatory cytokines: interleukin-1alpha, interleukin-1beta and tumor necro-
sis factor alpha. J Ethnopharmacol. 1997;58(1):59–73.
Youdim KA, Martin A, Joseph JA. Incorporation of the elderberry anthocyanins by endothelial
cells increases protection against oxidative stress. Free Radic Biol Med. 2000;29(1):51–60.
Zakay-Rones Z, Thom E, Wollan T, Wadstein J. Randomized study of the efcacy and safety of
oral elderberry extract in the treatment of inuenza A and B virus infections. J Int Med Res.
2004;32(2):132–140.
Zakay-Rones Z, Varsano N, Zlotnik M, Manor O, Regev L, Schlesinger M, et al. Inhibition of
several strains of inuenza virus in vitro and reduction of symptoms by an elderberry extract
(Sambucus nigra L.) during an outbreak of inuenza B Panama. J Altern Complement Med.
1995;1(4):361–369.
Zambenedetti P, Giordano R, Zatta P. Histochemical localization of glycoconjugates
on microglial cells in Alzheimer’s disease brain samples by using Abrus precatorius,
Maackia amurensis,Momordica charantia,andSambucus nigra lectins. Exp Neurol.
1998;153(1):167–171.
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... Described as a medicinal plant since ancient times, the black elder (Sambucus nigra) is found in abundance in the spontaneous flora ( Figure 1). Since ancient Egypt, there is evidence of the use of black elder for the treatment of many diseases, in various medicinal formulas, as well as food [7]. Various parts of the plant have been used over the years not only by the population of the Mediterranean basin and surrounding regions [8][9][10] but also by Native Americans [7]. ...
... Since ancient Egypt, there is evidence of the use of black elder for the treatment of many diseases, in various medicinal formulas, as well as food [7]. Various parts of the plant have been used over the years not only by the population of the Mediterranean basin and surrounding regions [8][9][10] but also by Native Americans [7]. In the 5th century BC, data from Hippocrates, Dioscoridis and Pliny described the use of drugs prepared from Sambucus nigra [11]. ...
... Apart from flowers and ripe fruit, all parts of this shrub contain sambunigrin, a poisonous cyanogenic glycoside, so they are no longer used as recognized remedies, except for those obtained from elder flowers and ripe elderberries. Cyanogenic glycosides can be harmful to animals and humans when they are in excess of 0.5 and 3.5 Since ancient Egypt, there is evidence of the use of black elder for the treatment of many diseases, in various medicinal formulas, as well as food [7]. Various parts of the plant have been used over the years not only by the population of the Mediterranean basin and surrounding regions [8][9][10] but also by Native Americans [7]. ...
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In the current context, when more and more unknown pathogens appear, healthy eating and supplementing it with natural products play an increasingly important role in maintaining the health of the body. The European black elder (Sambucus nigra), found in abundance in the spontaneous flora, can provide us, as a raw material, elderberries, which have been known for thousands of years as having nutritional and healing properties. The phytotherapeutic principles found in elderberry fruits give them antiviral, antibacterial and antidiabetic properties, antitumor potential, antioxidant, antidepressant and immune boosting properties, as well as a certain impacts on obesity and metabolic dysfunctions. Polyphenols and lectins give elderberry fruits the ability to inhibit coronaviruses, which is a topic of great interest in our times. This article summarizes the existing data regarding the chemical composition, active principles and biopharmaceutical properties of elderberries, as well as their use.
... Other anthocyanins were also identified, but in smaller quantities: cyanidin-3-sambubioside-5glucoside (16.0-82.6 mg/100 g FW), cyanidin-3,5-diglucoside (7.41-23.29 mg/100 g FW), callistephin (0.3-1.80 mg/100 g FW), and pelargonidin-3-sambubioside (0.025 mg/100 g FW) [41,43]. Besides these compounds, the presence of chrysanthemin monoglucuronide, peonidin monoglucuronide, peonidin-3-sambubioside, and peonidin-3-glucoside was also reported [34,45]. The degree of ripeness of the fruit influences the content of anthocyanins (ripe fruits have a higher content), especially the amount of cyanidin-3-sambubioside-5glucoside, cyanidin-3-sambubioside, and cyanidin-3-glucoside [31]. ...
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Elderberries are appreciated for their antioxidant properties. Sambucus nigra L. is an extremely abundant plant in the wild flora of Romania, but it is underutilized. Elderberry is used in modern and traditional medicine due to the complex chemical composition of the fruit. The content of phenolic compounds is high (516–8974 mg/100 g DW), of which the most abundant are anthocyanins. Phenolic compounds are known for their beneficial effects on the body. Numerous studies have demonstrated the antioxidant capacity, antibacterial, antiviral, antidiabetic, and anticancer properties of the fruit. It is considered that most of the therapeutic properties of elderberries can be correlated with the antioxidant activity they have. S. nigra fruits are also used in the food industry. Some studies have shown that the therapeutic properties of elderberries can also be found in the products obtained from them. Therefore, this review aimed to describe the chemical composition of elderberries and products obtained from them, the positive effects on the body, and the methods by which the bioactive compounds can be extracted from the fruits and analyzed. This manuscript is useful for extraction optimization and characterization in order to valorize new functional foods, food supplements, and also in new pharmaceutical products.
... Immune modulators are the components that can be upregulated or downregulated by the host immune response [ Figure 3]. [26][27][28] dIscussIon Elderberry possesses antiviral effects as a result of its capacity to regulate pro-inflammatory cytokines [3] and has been shown to be effective against a variety of viruses both in vitro and in vivo. [29][30][31][32][33] There has been no published research on the usage of elderberry in COVID-19 patients as of this writing. ...
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Background: The novel severe acute respiratory syndrome coronavirus 2 emerged in 2019. Health-care systems around the world are looking for alternative prevention and treatment remedies. Herbal supplements are popular among consumers as a complementary method to prevent and treat illnesses. One of them is Sambucus nigra. Methods: We searched for related articles in Scopus, Web of Science, PubMed, Google Scholar, and the Directory of Open Access Journals using the following keywords: elderberry, S. nigra, and COVID-19. Results: Elderberry has antiviral properties due to its ability to modulate inflammatory cytokines. The current evidence suggests elderberry is appropriate for the prevention and initial treatment of viral disease. Concerns have been raised that elderberry may overstimulate the immune system, increasing the risk of a cytokine storm. There is not yet enough evidence to support this claim. Conclusions: For COVID-19 patients, further research is required since elderberry may provoke a cytokine storm if administered therapeutically.
... The intake should be cautiously monitored in diabetic patients to promote glucose and insulin metabolism. Some of the side effects that have been reported upon its use include nausea and vomiting, hypokalemia, dehydration, tachycardia, hypotension, and diarrhea [86]. ...
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Infectious diseases have been a threat to human health globally. The relentless efforts and research have enabled us to overcome most of the diseases through the use of antiviral and antibiotic agents discovered and employed. Unfortunately, the microorganisms have the capability to adapt and mutate over time and antibiotic and antiviral resistance ensues. There are many challenges in treating infections such as failure of the microorganisms to respond to the therapeutic agents, which has led to more chronic infections, complications, and preventable loss of life. Thus, a multidisciplinary approach and collaboration is warranted to create more potent, effective, and versatile therapies to prevent and eradicate the old and newly emerging diseases. In the recent past, natural medicine has proven its effectiveness against various illnesses. Most of the pharmaceutical agents currently used can trace their origin to the natural products in one way, shape, or form. The full potential of natural products is yet to be realized, as numerous natural resources have not been explored and analyzed. This merits continuous support in research and analysis of ancient treatment systems to explore their full potential and employ them as an alternative or principal therapy.
... Antiviral activity has been tested against dengue virus serotype-2, influenza, herpes simplex virus type 1, parainfluenza, influenza, and respiratory syncytial virus. However, reports of clinical trials demonstrating the efficacy of elderflower extract do not exist, even though four trials exist that use elderberry extracts [64][65][66]. ...
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... S. nigra has antiviral potential against human immunodeficiency virus (HIV), herpes simplex virus type 1 (HSV1) and influenza (94,95). The effects of S. nigra against influenza have been extensively studied in a specific neighborhood (96). In S. nigra, some biochemical mechanisms have been investigated to elucidate the anti-influenza activities. ...
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... In addition, the aroma composition of elderflowers includes aldehydes, ketones, alcohols, esters, oxides, terpenes and free fatty acids [37]. The bark, leaves, seeds and raw or unripe fruits contain the cyanogenic glycoside sambunigrin, which is potentially toxic because it can release cyanide [23, 38,39]. ...
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The present review summarizes the current knowledge concerning provenance, properties, physiological and therapeutic actions of elderberry and the bioactive molecules present in the plant, with emphasis on their action on female reproduction. Elderberry or black elder (Sambucus nigra L.) attracts attention due to its easy cultivation and high availability of bioactive compounds. Most of the available data concerning black elder’s therapeutic action are focused on its effects such as activation of immune processes and anti-inflammatory processes (cytokine production, etc.) and regulation of hormones and their receptors in cancer cells. The effects of elderberry on reproduction have been poorly investigated so far. Nevertheless, conducted studies so far demonstrate the stimulatory influence of black elder extract and its constituents, such as rutin, anthocyanins and agglutinins, on the viability and steroidogenesis of healthy ovarian cells as well as their ability to promote apoptosis and reduce the viability and proliferation of ovarian cancer cells. Furthermore, the action of black elder extract and its constituent biomolecules, such as anthocyanins and lectins, on embryogenesis and the embryonal estradiol-estradiol receptor system have also been reported. The available information, despite limitations, suggest the applicability of black elder constituents for improvement of reproductive processes in animal biotechnology, animal production and assisted reproduction, as well as for prevention and treatment of reproductive disorders (including cancer) in veterinary and human medicine.
... 52 Evaluation of elder bioactivity is further complicated by the parallel use of flowers and berries in multiple food and botanical preparations and frequent lack of clarity on the exact origin of the extract in the scientific abstracts. It is generally recognized that flowers and not berries were the primary source of the traditional antiviral remedies, 53 also highlighted in Hans Christian Andersen tale Hyldemoer (The Elder-Tree Mother). Earlier it was proposed that certain flower polysaccharides are also responsible for the antiviral properties of elderflower infusions. ...
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