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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 Elderower (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 elderower
(Sambucus nigra) by the Natural Standard Research Collaboration consolidates the
safety and efcacy data available in the scientic 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, elderower, 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 Elderower 81
Cochrane Library, EMBASE, HerbMed, International Pharmaceutical Abstracts,
Medline, and NAPRALERT) from inception to July 2013. Search terms included
the common name(s), scientic 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 efcacy 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 (dening inclusion/exclusion criteria
and analytic techniques, including validated measures of study quality). Data were
veried 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 conicts 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 elderower, 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 scientic 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) afnity
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, inammation, and diuresis
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An Evidence-Based Systematic Review of Elderberry and Elderower 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 benet in treating
inuenza, bacterial sinusitis, and bronchitis. Although it has been hypothesized
to be benecial, denitive 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.
Scientic 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 reect the level of available scientic evidence in support of the efcacy
of a given therapy for a specic indication.
•Expert opinion and historic/folkloric precedent are not included in this assess-
ment and are reected 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 benet.
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 evidence†Unable 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 Sufcient Evidence
•Alzheimer’s disease, angiogenesis (antiangiogenic) (Bagchi, Sen, Bagchi, &
Atalay, 2004; Roy et al., 2002), anti-inammatory (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 (chang),
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.
Elderower 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 inammation. 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 Elderower 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.
•Elderower 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 Scientic 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-inammatory, immunomodulatory, and antiviral effects. They
also noted human research suggesting a favorable safety prole and efcacy when
combination products containing elder, such as SinupretR, were added to antibi-
otics and conventional decongestant drugs.
•Sambucus canadensis L., or elderower, 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 efcacy prole 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
qualied 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 efcacy 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 elderower 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 Elderower 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 (elderower), 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).
•Inuenza: 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 inuenza 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 liqueed 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).
•Insufcient 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. Puried galactose-specic 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 signicant 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 qualied 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 Elderower 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 qualied 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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•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 sufcient 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 Elderower 91
•Anti-inammatory agents: anti-inammatory properties have been demon-
strated in animal studies using elder owers (Mascolo et al., 1987). S. nigra is
reported to modulate the inammatory 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 benets 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 signicant 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-inammatory herbs: anti-inammatory 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 benets may be seen when elder is used in
combination with decongestants.
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An Evidence-Based Systematic Review of Elderberry and Elderower 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 signicant 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 signicant
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 signicant 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-
tied 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 Elderower 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-inammatory effects:S. nigra is reported to modulate the inammatory
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 proinammatory 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,
isoavone 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 inuenza 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 inuenza 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
inuenza 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 inuenza,
other viral infections, and increased antibody titers (Vlachojannis, Cameron, &
Chrubasik, 2010). Human studies reported the efcacy 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 benet in cardiovascular disease (CVD) after 12 weeks
(Curtis et al., 2009). Signicant changes in plasma levels of inammatory
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 signicant 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, nonsignicant 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 signicant
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 Elderower 97
•Renal effects: in human research, elderberry (anthocyanins) lacked signicant
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 signicantly 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 inuences, 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
Benet
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 denes RCTs as being placebo-controlled, while
studies using active controls are classied 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 sufcient 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 efcacy.
•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 signicance alone but in aggregate can achieve signicance). Mul-
tiple difculties are encountered when designing/reviewing these analyses; in
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An Evidence-Based Systematic Review of Elderberry and Elderower 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-specied 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
•Identies 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 qualies 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 efcacy. 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 signicant?
•Results are noted as being statistically signicant if a study’s authors report sta-
tistical signicance, or if quantitative evidence of signicance is present (such as
p-values). P=pending verication.
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 Benet
•This summarizes how strong a benet is: small, medium, large, or none. If results
are not statistically signicant “NA” for “not applicable” is entered. In order to
be consistent in dening small, medium, and large benets across different stud-
ies and reviews, Natural Standard denes the magnitude of benet in terms of
the standard deviation (SD) of the outcome measure. Specically, the benet 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 specic 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 verication.
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An Evidence-Based Systematic Review of Elderberry and Elderower 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 specied benet. It is calculated by dividing the absolute risk
reduction into 1 (1/ARR). P=pending verication.
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 specics 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 briey discussed in the Evidence Discussion.
Inuenza
•Summary: in laboratory and animal research, S. nigra had antiviral effects by in-
hibiting inuenza 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 inuenza 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-
nicant 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 benet 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 inuenza vaccination
with their primary healthcare provider.
•Systematic review: Vlachojannis et al. conducted a systematic review of 22 stud-
ies to assess the clinical efcacy 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 identied 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 inuenza 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 inuenza 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 signicant 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 signicance 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 conrm signicance 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 efcacy 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 inuenza 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 signicantly improved (lower) in the elderberry group
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An Evidence-Based Systematic Review of Elderberry and Elderower 105
compared to the placebo group for symptoms of fever, headache, muscle
aches, and nasal congestion (p<.0001 for all); however, statistically signicant
between-group differences were lacking for coughing (p=.1556) and mucus dis-
charge (p=.1513). By 48 hr, a statistically signicant 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 inuenza 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 disqualied 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 inuenza B in the group treated
with SambucolR, although statistically signicant 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 signicant 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 inuenza B rather than inuenza
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 inuenza A and B virus in-
fections during the inuenza season of 1999–2000 in Norway (N=60) (Zakay-
Rones et al., 2004). Patients 18–54 years old with inuenza-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 signicantly less in those
receiving elderberry extract compared with placebo. The authors concluded that
elderberry extract seems to offer an efcient, safe, and cost-effective treatment
for inuenza. 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 benecial
effects when used with antibiotics to treat sinus infections, although these re-
sults require conrmation 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 predened criteria. Four trials, comprising 900 patients, could be exam-
ined by meta-analysis. After two weeks of treatment, verum was signicantly
superior to placebo (2 RCTs, 159 vs. 160 patients, both add-on to antibacterial
treatment). The benet 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, signicantly
reduced the acute symptoms and signs of sinusitis. In the trials investigated, BNO-
101 had a favorable risk–benet 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 conrmed clinical
diagnosis of acute sinusitis associated with plain sinus radiogram opacication.
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 Elderower 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,18mgofosSambuci 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 opacication 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 opacication signicantly 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 signicantly 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 signicant 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 efcacy 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 efcacy 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
efcacy 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 signicant 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 difcult. 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 efcacy 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 efcacy and adverse effects. However, Sinupret Rwas
not compared to individual expectorants. A subgroup analysis of 535 patients
with bronchitis demonstrated lower efcacy 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 benet 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-inammatory 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 Elderower 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 inam-
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 signicantly 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-
nicant between-group differences. Additionally, signicant changes in plasma
levels of the following inammatory 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, signicant effects of elderberry on renal
and hepatic function, as determined by urea, creatinine, albumin, ALP, ALT,
and GGT, were lacking. A signicant 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 benets 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). Signicant 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
signicant 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 signicant
(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
signicant (p<.001). Also, participants in the active treatment group showed
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An Evidence-Based Systematic Review of Elderberry and Elderower 111
a signicant improvement in the perception of bowel function compared to the
placebo group (p=.03). Signicant 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 inammation in human trials (Grbic
et al., 2011). Signicant results were seen four days after treatment. A combina-
tion mouthwash containing Sambucus nigra signicantly decreased gingival index
scores when used three times daily for 14 days (Samuels et al., 2012). It remains
unclear whether there is any benet 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 efcacy of a combina-
tion THPP on gingival inammation (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-inammatories, 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 efcacy outcome investi-
gated was change in GI score. Secondary outcomes included treatment response
(as dened by a minimum one point increase in GI score) and change in beta-
glucuronidase (BG) levels. All efcacy 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 signicantly greater decrease was seen with THPP vs. placebo
at days 4 and 15 (p<.05 for both days). Similarly, signicantly 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 signicantly 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 inammation. This study was strengthened by the use of both clinical
and laboratory assessments of gingival inammation 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 efcacy 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 conrmed
gingivitis were included in this trial. Exclusion criteria consisted of smoking;
comorbid chronic illnesses, including diabetes, heart disease, or inammatory
conditions; concomitant use of anti-inammatory 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 signicant 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, nonsignicant 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 signicantly 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 signicant
or nearly signicant increase. However, a statistically signicant between-group
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An Evidence-Based Systematic Review of Elderberry and Elderower 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 signicant 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 inammation 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 afliated 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 inammation (N=26) (Samuels, Saffer, Wexler, &
Oberbaum, 2012). Patients were included in the trial if site inammation was
identied on subjects with moderate-to-severe chronic periodontitis. A topical
patch was placed on 22 of 36 identied sites for 24 hr. Reports on adverse effects
were lacking in both groups. The primary outcome assessed was inammation
(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 signicantly reduced patch placement
(p=.002), compared to 3 of 14 sites in the control group. A signicant 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 signicantly 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 benet 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 efcacy 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 identied 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 inuenza 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 inuenza 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 signicant 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 signicance 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 conrm signicance 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 insignicant 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 signicant 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 Elderower 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 efcacy 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 dened as the raw or
rened 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 ofcinalis 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
ofcinalis. 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 signicant
decrease in mean body weight was measured (p-value was unclear). Furthermore,
a signicant 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 benecial effects on obese animals
and humans. Specic conclusions regarding the clinical benets 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 (Zertikationsnr: 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 (elderower), 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 conict 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.
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