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HerbalEGram: BlackCohoshClinicalTrialNotRepresentativeofPreviousResearchShowingPositiveResults

AmericanBotanicalCouncilClarifiesRecentClinicalTrial

(Austin,TX.December21,2006)Arecently-publishedclinicaltrialtestingthepopularherbblackcohoshisinconsistentwiththepositiveoutcomesfortreatingmenopausesymptomsseeninthemajorityofpublishedclinicaltrials,saystheAmericanBotanicalCouncil.1“Themedicalliteraturecontainsmanycontrolledanduncontrolledtrialsthatsupporttheefficacyofthetwoleadingblackcohoshpreparationsfortreatingmenopausesymptoms,”saidMarkBlumenthal,founderandexecutivedirectorofABC,theleadingherbalnonprofitresearchandeducationorganization. Numerousherbexpertscautionedthatthistrialmustbeseenincontextoftheentirebodyofclinicalresearchonblackcohosh.AccordingtoMaryHardy,MD,aphysicianinLosAngeleswhohasbeenresearchingherbaldietarysupplementsforoveradecade,andanexpertonblackcohoshclinicaltrials,“Thisstudyshouldnotbeconsideredthedefinitivestudyonblackcohosh.Theseresultsshouldbeplacedinthecontextofalloftheblackcohoshtrials--manyofwhichhaveshownefficacyforothercommerciallyavailableproducts.”GailMahady,PhD,anassistantprofessorofpharmacognosyattheUniversityofIllinois,said,“Since2003therehavebeenabout10clinicalstudiesonblackcohoshpublishedandallwerepositive.”Dr.Mahady,oneoftheprincipalauthorsoftheblackcohoshmonographfortheWorldHealthOrganization,hasreviewedthesetrialsinseveraljournalpublications.2,3Sheadded,“Thus,onenegativestudydoesnotneutralizealloftheother10positivetrials.”Theyear-longtrialdidnotshowanysignificantbenefitinreducinghotflashesornightsweatsfortwodifferentblackcohoshpreparations--oneablackcohoshextractandtheotherblackcohoshwithotherherbsadded--oracombinationoftheblackcohosh/herbalmixturewithanenhancedsoydiet.(Theauthorsacknowledgedthatitwasdifficulttoensurecomplianceoftheaddedsoydietforanentireyear.)Onegroupofwomeninthetrialusedconventionalhormonereplacementtherapy(HRT)butthistreatmentwasterminatedafterresearchersinanothertrialonHRTdiscoveredadversecardiovascularandcancereffectsassociatedwiththeconventionalhormonesin2002.CalledtheHerbalAlternativesforMenopauseTrial(HALT),thestudy,publishedintheAnnalsofInternalMedicineonDecember19,wasaone-year,randomized,double-blind,placebo-controlled,5-armtrial.ResearchersattheCenterforHealthStudiesinSeattleassigned351womenaged45to55tooneof5differentgroups(arms): (1)ablackcohoshextract(CimiPure®,producedbyPureWorldInc.ofHackensack,NJ),(2)amulti-herbpillwithblackcohoshand9otheringredients*(Progyne,Progena,Albuquerque,NM),(3)thesamemulti-herbpillpluscounselingtoensuretheincreasedconsumptionofdietarysoy,(4)conventionalhormonereplacement therapy(estrogenwithorwithoutprogestin;thiswasterminatedbeforetheotherarmswhentheWomen’sHealthInitiativetrialswereprematurelyhaltedin2002duetoobservationsthatHRTactuallyincreasedtheincidenceofcardiovasculardiseaseandcancer),(5)aplacebo(dummypill).TheleadresearcherwasKatherineM.Newton,PhD,oftheGroupHealthCenterforHealthStudies,Seattle,andtheUniversityofWashington,andcolleagues.ThetrialwasfundedbytheNationalInstituteonAging(NIA)andNCCAM.Criteriaforinclusionofthewomeninthistrialconsistedofatleast2ormorevasomotorsymptomsperday(e.g.,hotflashes,nightsweats,etc.).Althoughthisstudyappearstobethelongestplacebo-controlledtrialonblackcohoshandoneofthelargest,therearestillsomepotentiallyseriouslimitations,whichthetrialauthorshaveacknowledged.Bydividingthetotalnumberofwomeninto5groups(arms)totest4differenttherapies(includingHRT)againstplacebo,thenumberofwomenineachgroupdropstoapointwherethestatisticalsignificanceoftheoutcomes(whetherpositiveornegative)aregreatlydiminished.Theauthorswrote,“Thestudywastoosmalltodetectsmallchangesinsymptomfrequency(lessthan1.5hotflashesperday).”1Dr.Hardyalsonotedthat“despitetherelativelylargenumberofparticipants,thecomplexdesign(5arms)meansthateachgrouphadrelativelyfewparticipantsandthusthestudywasnotpoweredtofindanybutlargeeffects.”Thetrialhadsetacriteriaforinclusionataminimumof2hotflashesperday,arelativelylowlevelatwhichreductionsaremoredifficulttoproduceand/ormonitorinatriallikethis(althoughtheactualmedianlevelwasactually6).InacorrespondingeditorialCarolM.Magione,MD,MSPHoftheDavidGeffenSchoolofMedicineinLosAngeleswrote,“Blackcohoshisnoteffective.”-basicallyrelyingonthistrialasthesolearbiteroftheefficacyofblackcohosh.4Dr.Mangione’sconclusioncontrastswithotherrandomizedcontrolledtrials(RCTs)thathaveshownmeasurableefficacyforthetwomostwell-researchedblackcohoshpreparations(e.g.,Remifemin®andKlimadynon®,bothfromGermany).Atleast15clinicaltrialsattesttotheefficacyofRemifemin(SchaperandBruemmer,Salzgitter,Germany,importedbyEnzymaticTherapy,GreenBay,WI)and6dosoforKlimadynon®(Bionorica,Neumarkt,Germany,importedbyBionoricaUSA,Eugene,OR).Severalexpertsnotedthatsomeinformationonthistrialhasbeenpublishedpreviously.AccordingtoDr.Hardy,“Thisisthesecondtimedatafromthistrialhasbeenreportedinthemedicalliterature,socaremustbetakennottocountthisstudytwiceinlookingatthewholebodyofliterature.”

Referringtotherelativelylargeplaceboresponseinthistrial(about30%ofthewomenonplaceboreportedbeneficialeffects,Dr.Hardystatedthat“Researchinmenopausaltreatments,besidesestrogen,areoftenconfoundedbyverylargeplaceboeffects.”DanielFabricant,PhD,Vice-presidentofScientificAffairsattheNaturalProductsAssociationwithadoctorateinPharmacognosyfromtheUniversityofIllinois,whichisalsoconductinganNCCAM-fundedgrantonthesameblackcohoshextract,saidinanemailtoABC,"Thebodyofclinicalevidenceonblackcohoshpreparationsspansmorethan3,000subjectsand50yearsusingtheherbalextractforrelieffromclimacteric(menopausal)/vasomotorsymptoms.Theweightoftheevidencefromthosestudieshasbeenoverwhelminglypositive.”Dr.Fabricantalsonotedthatapotentiallysignificantflawinthetrialisthelackofdataonsecondarytrialoutcomesinthisarticle:“vaginalcytology;serumlipids(totalcholesterol,HDLandLDLcholesterol,triglycerides);bonemineraldensity(hipandspinedualenergyx-rayabsorptiometryscan);glucosemetabolism(insulin,fastingbloodglucose);andcoagulationfactors(fibrinogen,PAI-1)wouldallprovidevaluableinformationregardingboththebotanicalsandtherisksthathavebeenseenwithconjugatedequineestrogens(CEE)inpreviousstudies.”AnotherquestionaboutthestudywasraisedbyFrancisBrinker,ND,oftheUniversityofArizonaProgramforIntegrativeWellnessandauthorofseveralhighly-regardedreferencebooksonherbalmedicine,includingHerbContraindications&DrugInteractions3ded.Dr.Brinkerstates,“Idonothaveaproblemwithacknowledgingthenegativeoutcome,butIrejecttheextrapolationoftheresultstoallformsofblackcohoshproducts.Themoremedical(andherbal)mindsarechallengedonthissortoflazyassumption,thesoonerthey'llrecognizelegitimatedistinctionsamongvariousherbalpreparationsandtheireffects.Notallproductsfromthesameherbarecreatedequal,soweshouldn'tblame,say,PeterCohoshforthefailingsofPaulCohosh(orrewardPeterforPaul'ssuccess),unlessthereissomegoodevidenceforbioequivalency”--theabilitytoshowthatonepreparationhasthesamephysiologicaleffectasanother.Thathasnotbeendemonstratedinthistrial,soitisnotpossibletoextendtheresultsofthistrialtootherclinicallytestedblackcohoshproducts.Dr.Brinkeralsocommentedthattheextractstudiedinthistrialwasadailydoseof160mgofa70%ethanolicextract,whereasthepositivestudieswithRemifemintabletsused40mgdailyofa40%isopropanolicextractinanamountequivalentto40mgoftheherbalmaterial.EckehardLiske,PhD,internationalmedicaldirectoratSchaper&Bruemmer,theGermancompanythatmanufacturersandmarketsRemifemin,themostclinically-researchedblackcohoshproduct,observedthattheblackcohoshproductusedinthistrialdidnotappeartohavemetstabilitytestingthatshouldhavebeenrequiredofanyherbalsubstancethatwasbeingemployedfora12-monthtrial.“Thistypeofpackagingdoesnotprotectthestudymedicationaswellasablisterpackaging,”hewrote.Thiswasacknowledgedbythetrialauthorsintheirwritingthattheywerenotabletodetectseveralcharacteristic[chemical]markersubstances.Thus,thisabsenceofblisteredmedication,accordingtoDr.Liske,suggestsapossibleinstabilityofthestudymedication(i.e.,theblackcohoshextractmayhavedegradedinsomemannerovertime).FrediKronenberg,PhD,professorofclinicalphysiologyatColumbiaUniversityCollegeofPhysiciansandSurgeons,anexpertinmenopause,andauthorofareviewpaperoncomplementaryandalternativeapproachestomenopausalsymptoms,5cautionsthatinscienceonemustlookatthewholebodyofresearchinafield.“Thisstudy,”shesaid,“mustbeconsideredinthecontextoftheotherstudiesoveryearsofresearchonblackcohosh,themajorityofwhichhavepositiveoutcomes.Thisstudyhasanegativeoutcomeonhotflashfrequency.Buteachstudyusesslightlydifferentpopulationsofwomen,someonlypostmenopausalwomen,some,likethisstudy,examiningbothmenopausalandperi-menopausalwomen.Halfofthewomeninthisstudywereperi-menopausal-withestrogenlevelsstillfluctuatingandthusimpactinghotflashes.Whiletheinvestigatorsdidcontrolforthisintheiranalysis,itpointsoutthechallengesforinterpretingresultsacrossstudies.”Dr.Kronenberg,whoisalsoaTrusteeofABC,continued,“Ofcriticalimportancewhenreviewingblackcohoshstudiesisthatweknowlittleabouthowthedifferentextractiontechniquesofblackcohoshpreparationsandresultingformulationsmayimpacthotflashphysiology.Theextractinthisstudywasanethanolicextract.Therehavebeenpositivestudieswithbothethanolicandisopropanolicblackcohoshextracts.Weareinaphaseofpoorlyfundedresearch,sowemustaccumulatetheresultsofmanyrelativelysmallstudiessincewedonothaveanylargestudiesunderwayatthistime.Themediadoesadisservicetothepublicbyusingcatchyheadlinesandnottakingthetimeforthein-depthanalysissoneededinreportingonwhatarecomplexissues.”Insum,Dr.Fabricantemphasized,“Thisnewstudyshouldnotbecalledconclusivebyanystretch.”

AboutBlackCohoshBlackcohosh,alsoknownbyeitheritsscientificnames(ActaearacemosaandCimicifugaracemosa)isamemberofthebuttercupfamily(Ranunculaceae)andisnativetotheEasternUnitedStates.Therootsandrhizomes(lateralroots)oftheherbhavealonghistoryoftraditionalusebynativeAmericantribestodealwithgenitourinarycomplaintsinwomen.Anisopropanolicextractofblackcohosh(Remifemin®)hasbeenusedinGermanclinicalpracticesincethemid-1950swithsafeandeffectiveresults,andblackcohoshpreparationshavebeenapprovedbytheGermangovernmentassafeandeffectivenonprescriptionmedicationsfortreatmentofmenopausalsymptoms.6Inthepastfewyearsblackcohoshhasbecomeincreasinglypopularasthemostwidely-usednaturalalternativetohormonereplacementtherapy(HRT).Theherb’spopularitywithmiddle-agedwomenandgynecologistsgrewsignificantlyafterthesummerof2002whenalarge-scalegovernment-sponsoredclinicaltrialonHRTwashaltedprematurelyafterevidencethatHRTwasresponsibleforanincreaseincancerandcardiovasculardiseaseinmenopausalwomen.Blackcohoshpreparationsrankedeighthofallsingle-herbsupplementssoldinmainstreamretailoutletsin2005,accordingtodatafromInformationResourcesinChicagoasreportedinthenewissueofHerbalGram(#71),ABC’squarterlyjournal.7*Ingredientsin:Progyne:Blackcohosh,alfalfa(Medicagosativa),boroncitrate,chastetree(Vitexagnus-castus),dongquai(Angelicasinensis),falseunicornroot(Chaemeliriumluteum),licoriceroot(Glycyrrhizaglabra),oatstraw(Avenasativa),pomegranate(Punicagranatum),“Siberianginseng”(Eleutherococcussenticosus)

References1.      NewtonKM, ReedSD,LacroixAZ,GrothausLC,EhrlichK,GultinanJ.Treatmentofvasomotorsymptomsofmenopausewithblackcohosh,multibotanicals,soy,hormonetherapyorplacebo:Arandomizedtrial.AnnInternMed2006;145:869-879.2.      MahadyGB,DoyleB,LocklearT,CotlerS,Guzman-HartmanG,KrishnarajR.Blackcohosh(Actaearacemosa)forthemitigationofmenopausalsymptoms:recentdevelopmentsinclinicalsafetyandefficacy.Women’sHealth2006;2;773-783.3.      MahadyGB.Blackcohosh(Actaea/Cimicifugaracemosa):reviewoftheclinicaldataforsafetyandefficacyinmenopausalsymptoms.TreatEndocrinol.2005;4(3):177-184.4.      MangioneCM.Arandomizedtrialofalternativemedicinesforvasomotorsymptomsofmenopause[editorial].AnnInternMed2006;145:924-925.5.      KronenbergF,Fugh-BermanA.Complementaryandalternativemedicineformenopausalsymptoms:Areviewofrandomizedcontrolledtrials.AnnInternMed.2002;137:805-813.6.      BlumethalM,BusseWR,GoldbergA,GruenwaldG,HallT,RigginsCW,RisterRS(eds.).KleinS,RisterRS(trans.).TheCompleteGermanCommissionEMonographs-TherapeuticGuidetoHerbalMedicines.Boston:IntegrativeMedicineCommunications;Austin:AmericanBotanicalCouncil,1998.7.      BlumenthalM,FerrierGKL,CavaliereC.TotalsalesofherbalsupplementsintheUnitedStatesshowsteadygrowth.HerbalGram.2006;71:64-66.