Monograph Sambucus nigra

Sambucus nigra(Elderberry)Introduction

Samhtuus nigra, or European elder, is a tall iree-Iikeshrub, native to Europe. Asia, and North Africa, and naturalizedin the United States. Various parts of the elder have long beenused in traditional medicine as a diaphoretic, diuretic, astrin-gent, laxative, and emetic. The berries were used traditionallyas a food to make elderberry wine and pies, and as a flavoringor dye. Currently, extracts of the berries are used primarily as

antiviral agents for colds, influenza, and Herpes virus infection. Research has also demonstrated Sambucus nigrahas immune-moduiating. antioxidant. and insulin-stimulating properties.

Description1 he Sambticus nigra plant is a member of the Caprifoliaccae or honeysuckle family, and can be found

growing in shady, moist areas in Europe. Asia. North Africa, and North America. It tolerates relatively poor soilconditions and is often found growing as part of the underbrush in forests. The naturalized plant in North America isknown as Sambucus nigra ssp canadensis. Sambucus canadensis. or North American elderberry. The tree-like shrubhas light brown or gray stippled bark and narrow, dark green, serrated leaves. In early summer. Sambucus nigrablooms with large clusters of small, fragrant, creamy-white (lowers that develop into shiny, purplish-black berriesby late summer and early fal!.'-^ Historically, the leaves, bark, flowers, and berries have all been used medicinally,but most of the clinicai studies have been conducted on the therapeutic uses and properties of the elderberry.

Active ConstituentsThe fruit oi Sambucus nigra (elderberries) contains several constituents responsible for pharmacological

activity. Among these are the flavonoids quercetin and rutin. anthocyanins identified as cyanidin-3-glucoside andcyantdin-3-sambubioside.' the hemagglutinin protein Sambucus nigra agglutinin III (SNA-Ill)/ cyanogenic glyco-sides including sambunigrin,*^" viburnic acid, and vitamins A and C.-

PharmacokineticsDue lo limiicd research, the pharmacokinetics of many constituents of Sambucus nigra are not completely

understood. Available research has focused on the absorption and urinary excretion of the anthocyanin constituents.Historically, researchers were uncertain whether anthocyanins were absorbed unless they were first hydrolyzed inthe gastrointestinal tract. Recently, however, several small pharmacokinetic studies of elderberry extract in heallhyvolunteers demonstrated elderberry anthcKyanins are indeed absorbed and excreted in an intact form.

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Within four hours of consuming 12 g elder-berry extract containing 720 mg total anthocyanins.the two major anthocyanins in elderberry extractwere identified in the urine of four elderly women.^ Asecond similar study involving 16 healthy volunteersconfirmed the presence of the same two anthocyaninsin the urine of study subjects after oral administra-tion of elderberry extract.' In another study involv-ing six healthy volunteers, a single oral dose of 30mL elderberry extract (147.3 mg total anthocyanins)resulted in a rapid urinary excretion rate of intact an-thocyanins with only 0.37 percent of the original dosebeing present in the urine at seven hours post-inges-tion/ One study investigated the absorption ot elder-berry anthocyanins in a single male subject given 25g elderberry extract (1.5 g total anthocyanins): high-performance liquid ehromatography (HPLC) analysisdetected two anthocyanin peaks in plasma collected30 minutes post-dose."^ Another study detected antho-cyanins from elderberry in giycoside form in bothplasma and urine four hours after dosing.'"

Mechanisms of ActionAntiviral

While there are several mechanisms respon-sible for the beneficial effects ofSamhucus nigra andextracts of its berries, perhaps the most important andbest studied are the antiviral effects. Mumcuoglu. anIsraeli virologist, was the first to discover elderberryconstituents neutralize the activity of the hemagglu-tinin spikes found on the surface of several viruses.When these hemagglutinin spikes are deactivated theviruses can no longer pierce cell walls or enter the celland replicate." Based on these findings. Sambucol*,a syrup containing 38-percent standardized extract ofblack elderberry, was developed. Numerous studiesusing the Sambucol preparation have shown it to neu-tralize and reduce the infectivity of influenza virusesA and B. ' -" HIV strains and clinical isolates.'*" andHerpes simple.x virus type I (HSV-1) strains and clin-ical isolates.'^ It probably does so in the same man-ner as with influenza viruses, via neutralization of thevirus resulting in redueed infectivity.

S-sambunigrin

CH2OH

^ —HOHO

Immune Modulation via CytokineProduction

Elderberry extracts also have immune-modu-lating activity in healthy individuals as well as in thosewith viral infections or other diseases characterizedby immunosuppression. Production of certain cyto-kines leads to activation of phagocytes and facilitatestheir movement to inflamed tissues.'^ Two studiesusing blood-derived monocytes from healthy donorsdemonstrated the ability of several Sambucol extractsto significantly increase cytokine production. Cyto-kines tested were tumor necrosis factor-alpha (TNF-a). and interleukins (IL) -1(1 -6, and -8.'^ A secondsimilar study also measured monocyte production ofIL-IO when exposed to various Sambucol prepara-tions and confirmed the results of the first study. A1.3- to 6.2-fold increase in cytokine production wasobserved compared to control. A 2.3-fold increase inIL-10 was also observed.'**

AntioxidantElderberries contain several anthocyanin

flavonoids known to possess significant antioxidantproperties. Research has demonstrated low-levelconcentrations (4 mcg/mL) of elderberry anthocya-nins can efficiently regenerate alpha-tocophero! fromalpha-tocopheroxyl radicals in models of copper-me-diated LDL oxidation.'" Since it has been observedthat anthocyanin glycosides are indeed absorbed inhumans,""'" it is likely that supplementing with el-derberry extracts containing anthocyanins providessignificant antioxidant benefit.

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It has been established that endothelial celldysfunction results in changes in the redox status ofcells.-" Based on this premise and previous researchon elderberry's antioxidant potential. Youdin et aldemonstrated elderberry anthocyanin incorporationinto endothelial cells confers increased protectionagainst oxidative stress. Human aortic endothelialcells incorporated elderberry anthocyanins into boththe membrane and cytosol. affording significantlyenhanced resistance to damage from reactive oxygensptecies. The most pronounced affect was seen withprotection against H,O,-induced loss in cell viabil-

Clinical IndicationsViral InfectionsInfluenza

Two randomized, placebo-controlled, dou-ble-blind studies demonstrated the elderberry ex-tract, Sambucol. effectively inhibited both influenzaA and B strains when given orally to patients in thefirst 48 hours of influenza symptoms. In the earlierstudy, 27 individuals experiencing typical early flusymptoms were given Sambucol or placebo daily forthree days - 2 tablespoons (children) or four table-spoons (adults). Patients were followed for six daysand symptoms monitored. Semm from all subjectswas analyzed for antibodies to influenza A and B atthe initial dose and during the convalescent phase. Inthe treatment group, significant improvement in flusymptoms was observed in 93.3 percent of subjectswithin two days after initial dosing, while 91.7 per-cent of the control group demonstrated improvementafter six days. A complete resolution was achieved inthe treatment group in 90 percent of patients after 2-3days, while the placebo group yielded similar resultsafter six days. Of these 27 patients, 23 had laboratoryconfirmation of influenza B.'-

In a second study. 60 patients (ages 18-54years) experiencing early influenza symptoms weregiven 15 mL of Sambucol or placebo syrup fourtimes daily for five days. Symptoms were monitoredfor eight days. In the treatment group, the majority ofpatients reported "pronounced improvement" after anaverage of 3-4 days, while the placebo group required7-8 days to reach the same level.'-^

Herpes simplexMumcuoglu et al examined the effects of

Sambucol against HSV-I in human dipioid fibro-blasts. Four strains of HSV-1 were utilized - a ref-erence strain, two acyclovir-resistant strains, and astrain isolated from a patient. Viral replication wascompletely inhibited in all four strains, whether thecells were pre-incubated with the extract, simulta-neously incubated with extract, or the extract wasadded 30 minutes after viral adsorption to cells. Thecomplete inhibition of four strains of HSV-I in vitroby elderberry extract warrants further clinical trialsin humans.'"^ A formula of Sambiwus nigra (flowerextract) in combination with Hypericum perforatmnand Saponaria officinalis was also found to inhibitthe replication of HSV-1 in vitro.-

mvSambucol was studied for the potential to

inhibit the infectivity of HIV isolates in CD4-I- celllines, peripheral b!ood lymphocytes, and laboratoryHIV strains. The elderberry extract at two differentdilutions was pre-incubated with HIV virus prior toaddition of the cells. A significant reduction was ob-served in the infectivity of all HIV strains. In patientisolates treated with the extract, no HIV antigen wasdetected at either five or nine days post-incubation.'"*

Anecdotal evidence (six case studies) reportsa combination of elderberry extract and a thymus ex-tract resulted in a reduction in viral load in peoplewith HIV.-'

Conditions Associated with OxidativeStress

Numerous disease states are characterizedby oxidative stress, including cardiovascular dis-ease, cancer, neurodegenerative disease, peripheralvascular disease, autoimmune diseases, and multiplesclerosis. The ability of elderberry extract to pro-vide antioxidant protection via inhibition of LDL-oxidation and scavenging of free radicals makes it apotentially valuable tool in the treatment of diseaseresulting from oxidative stress.''' Elderberry's abilityto incorporate into endothelial cells and potentiallyimprove endothelial function may also indicate a rolein prevention of vascular disease of various kinds.-'

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Sambucus nigra Monograph

Effect on Blood LipidsA randomized, placebo-controlled study of

34 healthy subjects examined the effectiveness oflow-dose, powdered elderberry juice (10% anthocya-nins) versus placebo on lipid parameters. Elderberrywas dosed at 400 mg capsuled powder (equal to 5mL elderberry juice) three times daily for two weeks;patients were instructed to follow a diet containing35-percent fat. Serum was obtained at baseline andat the end of the two-week period. Analysis of re-sults showed a slight, but .statistically insignificant,decrease at two weeks in all lipid parameters of thelow-dose elderberry extract group compared to base-line. Total cholesterol was 199 mg/dL at baselineversus 190 mg/dL at the end of the two-week period.Slight reductions were also reported in triglycerides,and HDL- and LDL-cholesterol.'^ Although improve-ments in lipid values were statistically insignificant,the dosage of elderberry extract was low and it is pos-sible higher dosages might produce a more signifi-cant benefit. In addition, using subjects with normallipid levels may not be as likely to produce significantresults since the lipids are already within the normalrange. Further study on patients with elevated lipidlevels is warranted.

DiabetesIn folk medicine. Sambucus nigra flower

was traditionally suggested as a remedy for diabe-tes.-'' Researchers in Northern Ireland conducted anin vitro study to evaluate the effect on blood sugar. Inthe two-armed study, aqueous extract of elder flowersignificantly increased glucose uptake, glucose oxi-dation, and glycogenesis in rat abdominal muscle. El-der flower extract incubated with rat pancreatic cellsalso had a dose-dependent stimulatory effect on insu-lin secretion. The researchers concluded elder flowerscontain water-soluble constituents capable of directstimulation of insulin secretion and glucose metab-olism.-" Further clinical study is warranted beforeSambucus can be recommended for use in diabetes.

Drug-Botanical InteractionsThere are no confirmed drug interactions

with elderberry extract. However, due to the ability ofSambucus flower extracts to potentiate insulin releasein vitro,-'' patients with diabetes should be advised tomonitor blood sugar closely when using flower ex-tracts.

Side Effects and ToxicityElderberry extracts are generally without side

effects when taken in the suggested dosages.'' Berriesshould be cooked, as the consumption of uncookedberries or juice can result in vomiting and diarrhea.'Certain constituents of the leaves, stems, flowers, androots contain poisonous alkaloids.-^ It has also beenreported that small percentages of the general popula-tion have a type-1 allergy to Samiiuciis nigra as evi-denced by positive-skin prick or RAST

DosageElderberry fruit syrups are often standard-

ized to 30-38 percent elderberry. Powdered extractsare dosed at 500 mg (capsule) 2-3 times daily for 3-4days, or if in liquid form, dosed at one lablespoonful(15 mL) three times daily. In the case of acute viralinfections, course of treatment is generally at leastthree days.'''

Warnings and ContraindicationsCurrently there arc no reported adverse ef-

fects in regard to fetal development, pregnancy, orlactation. However, as elderberry is not a well-re-searched botanical, health care practitioners shoulduse caution in recommending it to women who arepregnant or nursing.

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WynianLld.; 1974:174.2. Duke JA. Handbook of MeiHcinal Herbs. Boca

Raton. FL: CRC Pres.s; 1985:423.3. Wu X. Cao G. Prior RL. Absorption and

metabolism of anthocyanins in elderly women afterconsumption of elderberry or blueberry. J Nuir2002; 132:1865-1871.

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4. Mach L. Scherf W. Ammann M, et al. Purificationand partial characterization of a novel lectinfrom eider (Samhucus nigra L.) fruit. Biochem J1991:278:667-671.

5. Jensen SR. Nielsen BJ. Cyanogenic glucosidesin SainbiHii.'i nigra L. Acta Clwm Scand1973:27:266^2662.

6. Buhrmester RA. Ebingerla JE. Seigler DS.Sambunigrin and cyanogenic variabilityin populations of Sambucu.s canadensis L.(Caprifoliaceae). Biochem Svst Ecoi 2000:28:689-695.

7. fViuIIeder U. Murkovie M. Pfannhauser W. Urinaryexcretion of cyanidin glycosides../ BiochemBiophys Methods 2()02;53:61-66.

8. Bitsch I. Janssen M. Netzel M. et al. Bioavailabilityof anthocyanidin-3-glycosides followingconsumption of elderberry extract and blackcurrantjuice. //;/ J Clin Pharmacol Ther 2004;42:293-300.

9. Cao G. Prior RL. Anthocyanins are detected inhuman plasma after oral administration of anelderberry extract. Clin Chem 1999:45:574-576.

10. Mi!bur>' PE. Cao G. Prior RL. Blumberg J.Bioavailability ot elderberry anthocyanins. MechAging Dev 2002:123:997-1006.

11. Personal communication with MadeleineMumeuoglu. MD; January 25, 2005.

12. Zakay-Rones Z. Varsano N. Ziotnik M, et al.hihibition of several strains of influenza virus invitro and reduction of symptoms by an elderberryextract {Sambucus nigra L.) during an outbreakof influenza B Panama. J Altern Complement Med1995;l:361-369.

13. Zakay-Rones Z. Thom E, Wollan T. Wadstein J.Randomized study of the efficacy and safety of oralelderberry extract in the treatment of influenza Aand B virus infections. J Int Med Res 2004;32:132-140.

14. Sahpira-Nahor O. Zakay-Rones Z, MumcuogluM. The effects of Sambucol* -̂ on HIV infection invitro. Ann Israel Congress Microhiol February 6-7,1995.

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23. No authors listed. Anecdotal reports: elderberryextract plus chondroitin and glucosamine sulfateandThy-mate reduces viral load to non-detectablelevels in \0 days. Posii Health New.s 1998:17:7-11.

24. Murkovie M. Abuja PM. Bergmann AR. etal. Effects of elderberry juice on fasting andpostprandial serum lipids and low-densitylipoprotein oxidation in healthy volunteers: arandomized, double-blind, placebo-controlledstudy. Eur J Clin Nutr 2004:58:244-249.

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28. Forster-Waldl E, Marchetti M. Seholl I. et al. Type1 allergy to elderberry (Sambucus nigra) is elicitedby a 33.2 kDa allergen with significant homologyto ribosomal inactivating proteins. Clin Exp Allergv2003:33:1703-1710.

29. Dietary Supplement Information Bureau http://content.nhiondemand.coni/dse/consumer/monoAll-style.asp'.'objlD=I00055&ctype=ds&mtyp=I

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