a systematic review of valerian as a sleep aid: safe …...sleep medicine reviews (2007) 11,...

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CLINICAL REVIEW

A systematic review of valerian as a sleep aid:Safe but not effective

Diana M. Taibia,�, Carol A. Landisb, Heidi Petryc, Michael V. Vitiellod

aWomen’s Health Nursing Research Training Grant, Department of Family and Child Nursing, University ofWashington, Box 357262, Seattle, WA 98195-7262, USAbBiobehavioral Nursing and Health Systems, University of Washington, Box 357266, Seattle,WA 98195-7266, USAcUniversity of Washington Bothell, 18115 Campus Way NE, Box 358532, Bothell, WA 98011, USAdPsychiatry and Behavioral Sciences, Psychology and Biobehavioral Nursing and Health Systems, Universityof Washington, Box 356560, Seattle, WA 98195-6560, USA

KEYWORDSValerian;Sleep;Complementarytherapies;Herbal therapies;Insomnia

ee front matter & 2007mrv.2007.03.002

ng author. Tel.: +1 2066656.ess: [email protected]

Summary Valerian is an herb that is widely available in a variety of commercialpreparations and is commonly used as a sleep aid. A recent systematic review andmeta-analysis of valerian concluded that evidence in support of the effectiveness ofthe herb was inconclusive. Therefore, in an effort to more closely examine this issue,a systematic review was conducted to examine the evidence on the efficacy ofvalerian as a sleep aid with specific attention to the type of preparations tested andthe characteristics of the subjects studied. A comprehensive search of studiesinvestigating valerian was conducted through computerized databases and handsearches of reference lists. Standardized forms were used to summarize findings andstandardized criteria were used to assess study quality. Out of 592 articles initiallyidentified, a total of 36 articles describing 37 separate studies met criteria forreview: 29 controlled trials evaluated for both efficacy and safety, and eight open-label trials evaluated for safety only. Most studies found no significant differencesbetween valerian and placebo either in healthy individuals or in persons with generalsleep disturbance or insomnia. None of the most recent studies, which were also themost methodologically rigorous, found significant effects of valerian on sleep.Overall, the evidence, while supporting that valerian is a safe herb associated withonly rare adverse events, does not support the clinical efficacy of valerian as a sleepaid for insomnia.& 2007 Published by Elsevier Ltd.

Published by Elsevier Ltd.

543 3906;

ton.edu (D.M. Taibi).

Introduction

Approximately one-third of the adults in the UnitedStates report symptoms of insomnia; including

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D.M. Taibi et al.210

difficulty falling and/or remaining asleep at night.1

Herbal therapies are commonly used for chronicsymptoms of disturbed sleep. According to a recentsurvey, approximately 1.6 million Americans usecomplementary and alternative medical (CAM)therapies to treat their sleep disturbance.2 Valerianis among the top-selling herbals in the US and ismarketed as a promoter of restful sleep. In 2005,valerian was the 13th top-selling herb in US withestimated sales totaling $3.4 million.3

A previous systematic review4 and a recent meta-analysis5 both concluded that effects of valerian onsleep were promising, but inconclusive. Previousreviews have discussed various types of valerianproducts without specific attention to importantdifferences in source species and in preparationtechniques used (e.g., ethanol and water versusextractions with water alone). Because the chemi-cal constituents in valerian products vary depend-ing on species and extraction methods,6,7 failureto evaluate the evidence based on the type ofproduct used may have obscured an accurateassessment of valerian effects on sleep. The speciesused most commonly is Valeriana officinalis,although V. edulis (Mexican valerian) and V. wall-ichii (Indian valerian) are also used therapeutically.In general, extractions are prepared by soaking thedried root and rhizome (the underground portion ofthe stem) of valerian in a solution (called amenstruum), then centrifuging or drying the mix-ture to extract and concentrate plant constituents.The solutions used are typically: water alone,ethanol and water, or methanol and water. Theratio of alcohol to water affects the proportion ofconstituents obtained. According to the AmericanHerbal Pharmacopeia, extraction of valerenic acidsrequires at least 30% alcohol, whereas extraction ofvalepotriates requires 70% alcohol.7 The influenceof extraction on the physiological effects ofvalerian remains unknown because the relativecontributions of constituents responsible for to theplant’s sedative effects have not been determined,and effects may depend on synergy of variouscompounds (e.g., valerenic acids, amino acids,valepotriates).8

In this review, we evaluate the research evidenceon valerian as a sleep aid taking into account thetypes of products used. In addition, we consideredwhether the subjects in these studies were healthy,complained of general sleep disturbance, or metdiagnostic criteria for insomnia: Diagnostic andStatistical Manual of Mental Disorders (DSM-III/IV);International Classification of Diseases (ICD-9/10);or International Classification of Sleep Disorders(ICSD). Finally, we make a recommendation aboutits usefulness as a sleep aid and clarify areas in

which further research on valerian effects on sleepmight be useful.

Materials and methods

The search strategy sought to obtain all relevantpublished data-based articles based on the follow-ing general criteria: (1) valerian root was adminis-tered orally, either alone or in combination withhops, lemon balm, or passion flower (herbs com-monly combined with valerian in commercialpreparations); and (2) a subjective or objectivesleep measure (e.g., polysomnography or actigra-phy) was at least one of the study’s primaryoutcomes. A systematic computerized searchof research databases was performed usingthe following keywords (where * is a wildcard):valerian*, valerenic, valepotriate*, and baldrian(‘‘valerian’’ in German). Databases included in thesearch were Pubmed, the Cochrane Central Regis-ter of Controlled Trials, EMBASE, PsychINFO,CINAHL, International Pharmaceutical Abstracts,and Dissertation Abstracts. The search was limitedto human clinical trials in the databases thatallowed this specification (Pubmed, Cochrane,and EMBASE). Reference lists from relevant arti-cles, reviews, and book chapters were hand-searched to identify additional studies. The searchwas not limited by language because numerousstudies have been conducted in Europe, particu-larly in Germany, and reported in German-languagejournals.9 In order to obtain the widest range ofevidence on valerian, included studies were notlimited to randomized clinical trials (RCTs), butonly relevant full reports were evaluated (abstractswere excluded). Additionally, to fully explore theevidence on the sedative effects of valerian,studies of healthy persons without reported sleepdisturbance were included.

Data were extracted onto standardized forms.A quality score based on the likelihood of bias wasgiven to each study using the Jadad scoring system.In this system, studies are scored 0 (poor) to 5(good) based on descriptions of randomization,double-blind methods, and reporting of drop-outs.10 Methodological features were also reviewedusing the criteria of Stevinson and Ernst,4 with theadded criterion that adequate methods of blindingrequired masking of odor as well as appearance.These criteria included reporting of design ele-ments of the study (e.g., randomization andblinding, effect size or power estimates); potentialsources of bias and error (e.g., control of pre-bedtime variables); and measures to mask the

ARTICLE IN PRESS

Valerian as a sleep aid 211

strong, distinctive odor unique to valerian. Studieswere only assigned a point in the Jadad score foradequate description of blinding if both odor andappearance were addressed.

Results

Study characteristics and valerian productsused

The computerized search yielded 592 article titlesthat were reviewed for relevance (see Fig. 1); 527articles were excluded based on a review of theabstracts and 29 were excluded based on a reviewof the full text. These 556 articles were excludedfor the following reasons: the articles (a) were notclinical studies (418 articles); (b) did not assesssleep as a primary outcome (65); (c) tested multi-ple herbs (other than hops, lemon balm, or passionflower) (6); (d) did not test an oral preparation ofvalerian (2); (e) were pediatric studies (2); (f) werenot related to valerian at all (55); (g) wereabstracts or incomplete reports (6); or (h) used astudy design that did not permit assessment ofvalerian effects (2).

Thirty-six articles describing 37 studies of valer-ian (one article reported two studies)11 for sleep inadults met criteria for inclusion in the review.Seventeen studies were published in German.12–28

The German was translated into English and dataextraction was checked against the articles inthe original language by one of the co-authors(H, Petry), whose first language is German.

There was pronounced heterogeneity of studydesign, especially in regard to: sample inclusion and

Initial search: 592 titles

Excluded: 556 from abstract or title- 527 from full article- 29

Not clinical trial- 418 Not addressing sleep- 65 Unrelated to valerian- 55 Not full report- 6 Multiple herbs- 6 Not oral administration- 2 Excessively biased- 2 Pediatric- 2

Included: 36 (describing 37 studies)

Trials: 28 (describing 29 trials)

Ethanolic- 8 Aqueous- 6 (7 trials) Valepotriate- 5 Combination- 9

Open-label: 8

Figure 1 Search results.

exclusion criteria; duration of treatment; prepara-tion used (valerian species and extraction meth-ods); dose given; dose timing (multiple daily dosesversus bedtime only); and outcomes measured.Of the 37 included studies, 29 were clinical trialsand 8 were open-label studies of clinical use.In the 29 clinical trials (see Table 1), thefollowing preparations were tested: (a) valerianmono-preparations (without other herbs, 20 stu-dies)11,13,17,21,25–27,29–39; (b) valerian with hops(6 studies),15,22,24,40,41 of which one also investi-gated a mono-preparation39; (c) valerian withlemon balm (3 studies)16,23,42; and (d) valerian withboth hops and lemon balm (1 study).43 Eight openlabel trials tested: (a) valerian alone (1 study)44;(b) with hops (2 studies)19,45; (c) with hops andlemon balm (3 studies)14,18,28; and (d) with hops andpassion flower (2 studies).12,20 Open-label trials arediscussed in regard to the safety and tolerability ofthe herb(s) but not for efficacy.

In this review, studies are grouped by extractiontype to allow for comparison of effects amongpreparations that are most likely to contain similarproportions of the various active constituents ofvalerian.

Ethanolic valerian extracts

Eight studies investigated ethanolic-aqueousV. officinalis extracts (see Table 2). All of thesestudies except one34 tested valerian in persons whoreported at least mild sleep disturbance, and moststudies based inclusion on clinical diagnosticcriteria for insomnia. Although some of the studiesreported the proportions of the sample withdifferent types of insomnia symptoms (e.g., sleeponset, sleep maintenance, or both), none ofthe studies analyzed the outcomes based on thespecific insomnia symptom. Compared to theliterature on other types of valerian preparations,studies of ethanolic extracts used the most rigorousstandards for recruiting participants with primaryinsomnia (see Table 1). However, only three studiesreported excluding persons with other primarysleep disturbances (e.g., sleep apnea, periodiclimb movement disorder, restless legs).13,33,34

The commercial preparation of valerian mostcommonly studied is LI 156 (Sedoniums), anethanolic extraction of V. officinalis (70% ethanolused for extraction). All six studies of this producttested 300–600mg prior to bedtime (see Table 2).Only two of these studies measured polysomno-graphic (PSG) sleep outcomes.30,33 In a double-blind randomized crossover trial, Diaper andHindmarch30 compared two doses (300 and

ARTICLE IN PRESS

Table

1Sample

charac

teristicsof

valerian

stud

ies.

Stud

y,ye

arSample

size

Slee

pco

ndition

Age

Female

Exclusions

Other

slee

pdisorder

Med

ical

cond

itions

Psych

iatric

problems

Med

ication

affecting

slee

p

Etha

nolicV.

officina

lisex

tracts

Vorbac

het

al.1

7(199

6)12

1(61va

lerian

,60

place

bo)

Insomnia,

V:47

.2711

V:62

%+

++(nouse

within14

day

s)ICD-10criteria

P:47

.6711

.1P:55

%

Kuhlman

net

al.3

4(199

9)10

2(51va

lerian

,51

place

bo)

Insomnia,

V*:

40.878.7

V:51

%+

++

ICD-10criteria

P*:

42.379.0

P:65

%Don

athet

al.3

3(200

0)16

Insomnia,

All,Med

ian:

49All:75

%+

++

+ICSD

criteria

(ran

ge:22

–55

)(14day

s)Dorn1

3(200

0)75

(39va

lerian

,36

oxazep

am)

Insomnia,

V:50

.6712

.4V:

77%

++

++

ICD-10criteria

O:53

.9712

.0O:61

%(4

wee

ks)

Zieg

leret

al.3

2(200

2)18

6(93va

lerian

,93

oxazep

am)

Insomnia,

V:54

.2712

.3V:

73%

++

+ICD-10criteria

O:50

.6712

.6P:61

%(past3

mon

ths)

(4wee

ks)

Cox

eter

etal.3

1(200

3)21

Diagn

osed

insomnia

All:54

715

All:54

%+

++

Jaco

bset

al.2

9(200

3)39

1(135

valerian

,12

1ka

vaka

va,

135place

bo)

Reporteddifficu

lty

withslee

pon

setor

mainten

ance

within2

wee

ks

V:42

.7710

V:79

%Anx

iety

required,

dep

ression

allowed

+K:41

.1710

K:80

%P:40

.5710

P:88

%

Diaper

andHindmarch

30

(200

4)16

Mildslee

pco

mplaints

All:55

.97

4.7

V:62

%+

P:55

%

Aqu

eous

V.officina

lisex

tracts

Leathw

oodet

al.4

6(198

2);

Leathw

oodan

dCha

uffard

39

(198

2/19

83)

166

Gen

eral

voluntee

rs(noslee

pproblem

required)

NR

NR


ARTICLE IN PRESS

Leathw

oodet

al.4

6(198

2);

Leathw

oodan

dCha

uffard

39

(198

2/19

83)

10Gen

eral

voluntee

rs(noslee

pproblem

required)

All:29

73.2

All:0%

Kam

m-Koh

let

al.2

1(198

4)78

(39va

lerian

,39

place

bo)

Elder

homeresiden

ts,

beh

avioralslee

pdisturban

cerequired

V:70

.674.4

V:76

%Beh

avioral

disturban

cerequired

+

P:69

.473.9

P:74

%Balderer

andBorbely1

1

(198

5)10

Hea

lthy,no

slee

pdisturban

ceAll:32

.5(ran

ge:

22–44

)All:50

%

Balderer

andBorbely1

1

(198

5)8

Hea

lthy,no

slee

pdisturban

ceAll:22

.6(ran

ge:

21–26

)All:50

%

Leathw

oodan

dCha

uffard

38

(198

5)8

Slee

pon

setproblems

All:45

(SDNR)

All:37

%

Schu

lzet

al.3

7(199

4)14

Elderly,insomnia

All:61

.67

6.5

All:10

0%+

++(14day

s)

High-va

lepo

triate

prep

arations

Jansen

27(197

7)15

0(74va

lerian

,76

place

bo)

Not

spec

ified

,elder

homeresiden

tsV:

78.4

V:61

%(ran

ge62

–89

)P:51

%P:78

.8(67–

89)

Gessner

etal.2

6(198

3)20

(11va

lerian

,9place

bo)

Diagn

osed

slee

pdisturban

ceAll,rang

e:19

–68

All:57

%+

Gessner

andKlasser

25(198

4)11

Slee

pdisturban

cean

dge

neralne

rvou

sco

nditions

All:26

.1(ran

ge:

20–38

)All:45

%+

Herrera-Arellan

oet

al.3

6(200

1)20

Insomnia,

All:45

77.8

All:70

%+

DSM

-III-Rcriteria

Poya

reset

al.3

5(200

2)19

patients,

18co

ntrols

Insomnia,

All:43

.3710

.6All:80

%+

+Re

quired

DSM

-IVcriteria,

chronicBZD

use;

healthyco

ntrols

+BZD

use-

withd

rawn

Com

bina

tion

prep

arations:va

lerian

andho

psMuller-Limmroth

and

Ehrenstein

22(197

7)12

Self-rep

ortedslee

pdisturban

ceAll,rang

e:22

–27

All:50

%

Roden

bec

ket

al.2

4(198

8)15

(8va

lerian

,7place

bo)

Insomnia,

V:45

.4711

.6,

NR

++

ICSD

criteria

P:47

.6712

.5Schm

itzan

dJackel

15(198

8)46

(23va

lerian

,23

bromazep

am)

Insomnia,

All:50

.3713

.6All:80

%+

+DSM

-IVcriteria

Fussel

etal.4

1(200

0)30

Mildto

mod

erate

insomnia

All*:

57.678.1

A:70

%+

+

Morin

etal.4

0(200

5)18

4(59va

lerian

,65

place

bo,

60diphe

nhyd

ramine)

Mildinsomnia,

V:43

.9710

.5V:

59%

++

++

DSM

-IVor

P:45

.2710

.2P:60

%ICSD

criteria

D:43

.879.7

D:60

%


ARTICLE IN PRESS

Table

1(con

tinu

ed)

Stud

y,ye

arSample

size

Slee

pco

ndition

Age

Female

Exclusions

Other

slee

pdisorder

Med

ical

cond

itions

Psych

iatric

problems

Med

ication

affecting

slee

p

Com

bina

tion

prep

arations:va

lerian

andlemon

balm

Lind

ahlan

dLind

wall43

(198

9)27

Slee

pdisturban

cean

dfatigu

eAll:54

(ran

ge25

–68

)All:30

%

Dressinget

al.2

3(199

2)20

Not

spec

ified

,he

althy

All:37

.275.9

All:50

%+

+

Dressinget

al.1

6(199

6)49

(25va

lerian

,24

place

bo)

Insomnia,

DSM

-IIIor

ICD-10criteria

V:59

.0(ran

ge31

.2–86

.8)

V:26

%+

++

+

P:54

.2(ran

ge22

.1–81

.4)

P:29

%

Cerny

andSchm

id42(199

9)98

(66va

lerian

,32

place

bo)

Noreportedslee

pproblems

V:33

.4712

.5V:

42%

++

+P:34

.8711

.7P:37

%

*Mea

n7SD

calculated

from

inform

ationgive

nin

thearticle.

NR,no

treported.

Insomniadiag

nostic

guides:ICD,Internationa

lClassifica

tion

ofDisea

ses;

DSM

,Diagn

ostican

dStatistica

lMan

ual;ICSD

,Internationa

lClassifica

tion

ofSlee

pDisorders.


ARTICLE IN PRESS

Table

2Stud

iesof

valerian

forslee

p.

Stud

y,ye

arSample

with

slee

pdisturban

ce

Stud

ydesign

Interven

tion

Trea

tmen

tduration

Outco

me

mea

sures

Mainva

lerian

slee

pou

tcom

esAdve

rseeffects

Etha

nolicex

tracts

Vorbac

het

al.1

7(199

6)Yes

PDB,RCT

(a)Va

lerian

600mg

28nigh

tsSF-B

Nosign

ifica

ntdifferenc

efrom

place

boAErelatedto

valerian

:he

adac

he(n¼

2),

morning

hang

over

(n¼

1)(b)Place

bo

Kuhlman

net

al.3

4

(199

9)No

PDB,RCT

(a)Va

lerian

600mg

14nigh

tsVIS-M

,VIS-A

Nosign

ifica

ntdifferenc

efrom

place

boAEdifferenc

esbetwee

ntrea

tmen

tsno

tsign

ifica

nt,no

seriou

sAE

(b)Place

bo

Don

athet

al.3

3(200

0)Yes

PDB,RCT,

C/O

(a)Va

lerian

600mg

14nigh

tsPSG

,slee

pdiary,

slee

pque

stionn

aire

(VASrating

s)

Nosign

ifica

ntdifferenc

efrom

place

boAErelatedto

valerian

:he

adac

he(n¼

1),GI

complaints

(n¼

1)(b)Place

bo

Dorn1

3(200

0)Yes

DB,RCT

(a)Va

lerian

600mg

28nigh

tsSF-B

Valerian

versus

baseline:

mSQ

;no

sign

ifica

ntdifferenc

ebetwee

nva

lerian

andox

azep

am

Withd

rawalsrelatedto

trea

tmen

t:va

lerian

(n¼

2),ox

azep

am(n¼

3)

(b)Oxa

zepam

10mg

Zieg

leret

al.3

2(200

2)Yes

DB,RCT

(a)Va

lerian

600mg

42nigh

tsSF-B

Valerian

versus

baseline:

mSQ

;no

sign

ifica

ntdifferenc

ebetwee

nva

lerian

andox

azep

am

AE:

valerian

(n¼

29),

oxazep

am(n¼

36)

(b)Oxa

zepam

10mg

Han

gove

reffects:

valerian

(n¼

2),

oxazep

am(n¼

6)Cox

eter

etal.3

1(200

3)Yes

PDB,n-of-1

design*

(a)Va

lerian

450mg

7nigh

tsSlee

pdiaries

Nosign

ifica

ntdifferenc

efrom

place

boAEdifferenc

esbetwee

ntrea

tmen

tsno

tsign

ifica

nt(b)Place

bo

Jaco

bset

al.2

9(200

3)Yes

PDB,RCT

(a)Va

lerian

,6.4mg

valerenicac

id28

nigh

tsISI

Nosign

ifica

ntdifferenc

efrom

place

boSign

ifica

ntly

grea

ter

inciden

ceof

diarrhe

awithva

lerian

(b)Kav

aka

va,

100mg,

Kav

alac

tone

s(c)Place

bo


ARTICLE IN PRESS

Table

2(con

tinu

ed)

Stud

y,ye

arSample

with

slee

pdisturban

ce

Stud

ydesign

Interven

tion

Trea

tmen

tduration

Outco

me

mea

sures

Mainva

lerian

slee

pou

tcom

esAdve

rseeffects

Diaper

and

Hindm

arch

30(200

4)Yes

PDB,RCT,

C/O

(a)Va

lerian

300mg

1nigh

tPSG

,LSEQ

Nosign

ifica

ntdifferenc

efrom

place

boAEpossibly

relatedto

trea

tmen

ts:va

lerian

300mg(n¼

11),

valerian

600mg(n¼

4),place

bo(n¼

8)

(b)Va

lerian

600mg

(c)Place

bo

Aqu

eous

extracts

Leathw

oodet

al.4

6

(198

2);Le

athw

oodan

dCha

uffard

39(198

2/19

83)

No

PC,C/O

(a)Va

lerian

800mg

2nigh

tsPSG

,slee

pque

stionn

aire

Nosign

ifica

ntdifferenc

efrom

place

boNot

men

tion

ed(b)Place

bo

Leathw

oodet

al.4

6

(198

2);Le

athw

oodan

dCha

uffard

39(198

2/19

83)

No

PDB,RCT,

C/O

(a)Va

lerian

400mg

3nigh

tsSQ

andSL

improve

men

trating

s

Valerian

versus

place

bo:

grea

terproportion

sreportedim

prove

dSQ

and

SL

Noresidu

alsedation

(b)Va

lerian

–ho

ps

400mg

(c)Place

boKam

m-Koh

let

al.2

1

(198

4)Yes

PDB,CCT

(a)Va

lerian

90mg

3x/d

14nigh

tsSlee

pque

stionn

aire

Valerian

versus

place

bo:

grea

terproportion

sreportedim

prove

dSL

and

slee

pmainten

ance

Dizzine

ss(4

total):

valerian

(n¼

2),place

bo(n¼

2)(b)Place

bo

(Likertscales)

Balderer

andBorbely1

1

(198

5)No

PDB,CCT,

(a)Va

lerian

450mg

1nigh

tSlee

pdiary,slee

pqua

lity

(VAS)

Valerian

versus

place

bo:

kWASO

andSL,both

doses

Noresidu

alsedation

C/O

(b)Va

lerian

900mg

(c)Place

boBalderer

andBorbely1

1

(198

5)No

PDB,RCT,

C/O

(a)Va

lerian

900mg

1nigh

tPSG

Nosign

ifica

ntdifferenc

efrom

place

boNoresidu

alsedation

(b)Place

bo

Leathw

oodan

dCha

uffard

38(198

5)Yes

PDB,RCT,

C/O

(a)Va

lerian

450mg

4nigh

tsActigraph

y,slee

pque

stionn

aire

Valerian

versus

place

bo:

Sign

ifica

ntly

grea

ter

morning

slee

pnesswith

900mgdose,

noothe

rAE

(b)Va

lerian

900mg

Actigraphy

:k

SL,both

doses

(c)Place

boSR

:Nosign

ifica

ntdifferenc

efrom

place

boSchu

lzet

al.3

7(199

4)Yes

PDB,RCT

(a)Va

lerian

,12

15mgon

nigh

t1,

405mg3x

/dday

s2–

8;

8nigh

tsPSG

,slee

pdiaries,SF-A,SF-

B

Valerian

versus

place

bo:

PSG

:sign

ifica

nceNRSR

:Nosign

ifica

ntdifferenc

efrom

place

bo

Not

men

tion

ed

(b)Place

bo

Valepo

triate

prep

arations

Jansen

27(197

7)No

PDB,RCT

(a)Va

lerian

,10

0mg

valepotriates

3x/d

30nigh

ts4-po

intsymptom

rating

scales

kSlee

pdisturban

ce,

valerian

4place

bo(statistical

testingNR)

NoAEoc

curred

(b)Place

bo


ARTICLE IN PRESS

Gessner

etal.2

6(198

3)Yes

PDB,CCT,

C/O

,(a)V.

edulis,24

0mg

valepotriates

9nigh

tsVIS-M

,VIS-A,SF-

A,SF-B

Valerian

versus

place

bo:

mSQ

andk

SLk

bad

dream

swith

valerian

.(b)Place

bo

Noothe

rsign

ifica

ntAE

differenc

esbetwee

ntrea

tmen

tsGessner

andKlasser

25

(198

4)Yes

PDB,RCT,

C/O

(a)V.

edulis,60

mg

valepotriates

1nigh

tPSG

,slee

pque

stionn

aires

PSG

:k

Stag

e4with

120mgve

rsus

place

boNoha

ngov

ersymptoms

(b)V.

edulis,12

0mg

valepotriates

SR:Nosign

ifica

ntdifferenc

efrom

place

bo(c)Place

boHerrera-Arellan

oet

al.3

6(200

1)Yes

DB,RCT,

C/O

(a)V.

edulis,45

0mg

1nigh

tPSG

,slee

pine

ssVe

rsus

baseline:

Dyspep

sia(3

total):

(b)V.

officina

lis

450mg

VAS

V.ed

ulis

knu

mbe

rof

awak

enings.

V.ed

ulis

(n¼

1),

V.officina

lis(n¼

2)Nosign

ifica

ntdifferenc

ebetwee

nva

lerian

preparations

Poya

reset

al.3

5(200

2)Yes

PDB,RCT

(a)V.

wallich

ii,

100mg

valepotriates

3x/d

15nigh

tsPSG

,slee

pdiaries,slee

pqua

lity

(VAS)

Valerian

versus

place

bo:

PSG

:k

WASO

,m

SLSR

:m

SQ

AEwithva

lerian

(n¼

3GI

complaints)

(b)Place

bo

Stud

yde

sign

abbrev

iation

s:CCT:

controlled

clinical

trial(non

-ran

dom

ized

);C/O

:crossove

r;DB:dou

ble-blind

(noplace

boco

ndition);PC:place

bo-con

trolled(not

dou

ble-blind

);PDB:

place

bo-con

trolleddou

bleblind

;RCT:

rand

omized

clinical

trial.Outcomemea

sures:

AE,

adve

rseev

ent;

NR,no

treported;

PSG

,polysom

nograp

hy;SF-A,Gortelm

eyer

Schlaffrag

ebog

enA,assesses

slee

pqua

lity

forthepastnigh

t;SF-B,Gortelm

eyer

Schlaffrag

ebog

enB,assesses

slee

pqua

lity

forthetw

owee

ks;SL,slee

platenc

y;SQ

,slee

pqua

lity;SR

,self-rep

ort;

VAS,

visual

analog

scale;

VIS

–M,Visua

lana

logska

la–Morge

n(a

stan

dardized

setof

visual

analog

scales

ofslee

pco

mpletedin

themorning

);WASO

,wak

eafterslee

pon

set.


ARTICLE IN PRESS


600mg) of LI 156 to a placebo after one night in asample of persons with mild sleep complaints. Nosignificant differences were found on PSG orsubjective sleep outcomes (sleep efficiency, sleeplatency, awakenings, sleep stages, and sleepquality ratings). Another double-blind randomizedcrossover study tested 600mg LI 156 for 14 nights inpersons with insomnia.33 In the valerian group,percent slow wave sleep (SWS, NREM Stages 3 and 4which are considered deep sleep) was increasedcompared to baseline. No differences betweenvalerian and placebo were found in other PSGoutcomes or subjective sleep quality ratings.

The other four double-blinded studies of LI 156measured only subjective outcomes. Parallel-grouprandomized controlled trials (RCTs) comparedrepeated dosing of valerian versus placebo inhealthy individuals for 14 days34 or in persons withinsomnia for 28 days.17 Subjective sleep qualityratings improved in the valerian groups of bothstudies, but in neither case was sleep significantlyimproved when compared to placebo. Lack ofsignificance in the healthy sample34 may haveresulted from a ceiling effect. One of thesestudies,34 as well as two other RCTs,13,32 comparedLI 156 (600mg dose) to benzodiazepines (flunitra-zepam and oxazepam). In these studies, theeffectiveness of the benzodiazepines was assumed,and comparable effects of valerian and benzodia-zepines were presumed to confirm the effective-ness of valerian. Kuhlmann et al.34 reportedreduced subjective sleep latency and increasedsleep quality ratings with both valerian andflunitrazepam compared to placebo after a singlenight in a sample of healthy persons, but did notreport the statistical significance of these findings.Two other studies compared valerian and oxazepamfor four weeks13 or six weeks32 in persons withinsomnia. The studies reported significant improve-ment of subjective sleep quality ratings comparedto baseline with both valerian and oxazepam.Improvement did not significantly differ betweenthe treatments, indicating that the effects ofvalerian were equivalent to oxazepam.

Two studies investigated ethanolic valerian ex-tracts other than LI 156. In a double-blind RCT,Jacobs et al.29 compared 28 days of valerianextract (PureWorld Botanicals, 70% ethanolic ex-tract), kava kava extract, or placebo in personswith both sleep disturbance and anxiety. Insomniaseverity index (ISI) scores, subjective sleep latency,and subjective awakenings were reduced with allthree treatments, but the magnitude of improve-ment was greatest in the placebo group and neitherof the herbal treatments differed significantly fromplacebo. Another double-blind study used n-of-one

methods (a within-subject repeated crossover de-sign) to test a high-ethanol (96%) extraction ofvalerian.31 Because this product used an ethanolconcentration over 70% for extraction, the productcontained significant amounts of valepotriates(valtrate) as well as valerenic acid. Each partici-pant was tested for six one-week periods (threevalerian, three placebo) in random order. Treat-ment was considered a success or failure withineach individual based on whether the individualimproved during the weeks of valerian compared tothe weeks of placebo treatment. The analysesshowed valerian to be equivalent to placeboon subjective outcomes of sleep quality, sleeplatency, awakenings, total sleep time, and morningrefreshment.

In sum, ethanolic extracts of V. officinalis,several of which were investigated using rigorousstudy designs, have not been shown to significantlyaffect objective30,33 or subjective17,29,31,33,34 sleepoutcomes in comparison to placebo in subjects withand without insomnia. However, these preparationshave been shown to improve subjective sleepquality ratings in a manner equivalent to benzo-diazepines under the assumption that the benzo-diazepines tested were superior to placebo.13,32

Aqueous valerian extracts

Seven studies (reported in six publications) inves-tigated the effects of aqueous V. officinalis extracts(water alone is used for extraction) on sleep (seeTable 2). These studies varied greatly in methodo-logical quality, and several of the trials did notreport randomization to treatment procedures. Allof these studies reported using a double-blinddesign except for one.39 Four of these studies wereconducted in general volunteers who were notrequired to complain of a sleep disturbance,11,39,46

one in persons with sleep onset difficulties,38 andtwo in elderly persons with sleep disturbance.21,37

None of the studies used insomnia diagnosticcriteria as inclusion criteria, and none reportedexclusion of persons with primary sleep disorders(see Table 1). Only one study excluded medicalconditions that could contribute to sleep distur-bance37 and only two excluded concurrent use ofsleep-altering medications.21,37

Two parallel-group clinical trials investigated acommercially available aqueous valerian extract(Valdisperts) in elderly individuals with insomnia.In a randomized trial, Schulz et al.37 investigated405mg valerian extract or placebo given threetimes a day for eight days to elderly participantswith sleep onset and sleep maintenance problems.

ARTICLE IN PRESS


Objective (PSG) and subjective sleep outcomes(sleep efficiency, wake after sleep onset (WASO),sleep quality rating) did not differ significantlybetween valerian and placebo after one dose, butno statistical comparison of valerian and placebo isreported at the end of treatment (after eightnights). Another trial of elderly persons with sleepdisturbances, Kamm-Kohl et al.21 investigated90mg of Valdisperts or placebo three times dailyfor 14 days. When asked whether their sleep onsetand maintenance difficulties improved, signifi-cantly greater proportions of persons on valerianreported that these conditions were ‘‘better’’(versus ‘‘the same or worse’’) after treatment thanthose on placebo.

Several studies investigated a specific aqueousvalerian extract (Dixa S.A., Switzerland) in generalvolunteers (only one of these studies required sleepdisturbance for enrollment).38 An early randomizedcrossover trial by Leathwood and colleagues46

measured subjective sleep in general volunteers(no exclusions noted) with 400mg aqueous valerianextract (Dixa S.A., Switzerland) or placebo takenon two nights each in random order (a 400mgvalerian/hops extract was also tested, discussedlater). A significantly greater proportion of personsrated their sleep quality as ‘‘better than usual’’ andsleep latency as ‘‘shorter than usual’’ when givenvalerian than when given placebo. Improved sleepwas more pronounced in the sub-sample of personsreporting habitually poor sleep. In a double-blindcrossover trial (randomization not reported), Bal-derer and Borbely11 investigated 450 and 900mg ofvalerian extract (Dixa S.A., Switzerland) in 10healthy young persons. One night of valeriansignificantly decreased subjective sleep latencyand WASO but not sleep quality ratings comparedto the placebo. Two studies measured PSG sleepoutcomes. In a small crossover trial, Leathwood andcolleagues39,46 investigated the effects of twonights of valerian extract (400mg, Dixa S.A.,Switzerland) on the sleep of 10 young, healthymen. No significant differences between thevalerian and placebo were found on PSG sleepmeasures (total sleep time, % sleep stages). Inanother crossover trial, Balderer and Borbely11

tested two doses (450 and 900mg) of the sameextract (Dixa S.A., Switzerland) for one night ofeach dose (or placebo) in eight healthy youngpersons. Neither PSG nor subjective sleep outcomes(sleep latency, awakenings, WASO, time in sleepstages) differed significantly between valerianand the placebo. Finally, one study measuredobjective sleep using actigraphs (wrist-worn move-ment detectors that can discriminate waking fromsleep behavior) in addition to subjective outcomes.

In this double-blind crossover trial by Leathwoodand Chauffard38 each of three treatment conditions(450mg valerian, 900mg valerian, Dixa S.A.,Switzerland, or placebo) was given randomly over12 weeknights to individuals with difficulty fallingasleep (recruited from the research staff andfamilies), with the participants undergoing fournights per treatment condition. Both doses sig-nificantly reduced actigraphic sleep latency com-pared to the placebo. Subjective sleep latency andsleep quality ratings did not differ significantlyfrom the placebo. Morning sleepiness was signifi-cantly greater with the 900mg valerian dose thanthe placebo, suggesting dose-dependent effects.

In sum, studies testing the effects of aqueousvalerian extracts produced mixed results. In olderpersons with sleep disturbance, one study reportedthat a significant proportion of the sample reported‘‘better’’ sleep,21 whereas another study did notshow significant effects on either objective orsubjective sleep outcomes.37 Short-term supple-mentation (one to four nights) of valerian was notshown to affect PSG11,39 or subjective sleep out-comes11,38,39 in subjects without known sleepcomplaints, but valerian did reduce subjectivesleep latency and WASO with sleep onset insom-nia.38 The findings of these studies of aqueousvalerian extracts cannot be generalized to personsdiagnosed with insomnia because this type ofproduct has not been rigorously tested in clinicpopulations.

Valepotriate preparations

Five studies investigated valerian extractions stan-dardized on valepotriate content (see Table 2). Thisconstituent is minimally present in the V. officinalisspecies or extractions from this species. However,valepotriates are present in significant levels inother Valeriana species (V. edulis and V. wallichii)and are believed to be largely responsible forpurported clinical effects of preparations fromthese species. The studies of valepotriates variedin the products used, samples studied, and timingof administration (e.g., several times/day and/orat bedtime). Information on valerian extractionmethod was only available from one study.36 Aswith the studies of aqueous extracts, none of thestudies used insomnia diagnostic criteria for inclu-sion (see Table 2). One study excluded subjectsfor primary sleep disorders (other than insomnia),35

two excluded subjects for co-morbid sleepdisturbance,25,35 and three excluded subjects forcurrent use of sleep-altering medications26,35,36

(see Table 1).

ARTICLE IN PRESS


Three studies investigated extracts of V. edulisspecies. Herrera-Arellano and colleagues36 com-pared two types of valerian extracts, V. edulis(high-valepotriate, 450mg, 62% ethanol extraction)and V. officinalis (high-valerenic acid, 450mg,information on extraction method not available)in a double-blind crossover study of persons withdiagnosed insomnia. There were no significantdifferences between the two species on any PSGoutcome (sleep latency, sleep efficiency, sleepstages), but the overall effects of either prepara-tion are uncertain because the study did notinclude a placebo group. Two of the studies wereplacebo-controlled, double-blind crossover trials(Gessner and Klasser; Gessner et al.)25,26 andinvestigated the effects of V. edulis (HarmonicumMuchs) on sleep in persons with general sleepdisturbance. In one study26 that assessed onlysubjective sleep outcomes, nine nights of valerian(standardized to contain 120mg valepotriates)significantly improved subjective sleep qualityratings and reduced subjective sleep latencycompared to placebo. In the other study, whichassessed the effects of 60 or 120mg valepotriateson PSG outcomes,25 one night of valerian signifi-cantly reduced Stage 4 sleep in comparison toplacebo. Neither dose significantly affected otherPSG outcomes.

Two other studies tested a preparation standar-dized to valepotriate content. One study tested theeffects of a V. wallichii extract (Valmanes) onrebound sleep disturbances in persons with insom-nia following gradual cessation of chronic benzo-diazepine use.35 In this double-blind, placebo-controlled RCT, a 100mg dose of valepotriateswas given three times daily for 15 days. Subjectivesleep quality ratings improved significantly withvalerian compared to the placebo. PSG outcomesshowed reduced WASO. A significant and substantialreduction in sleep latency occurred with placebobut not with valerian. The authors suggested thatthis may have been related to individual differ-ences in withdrawal from benzodiazepines. In aplacebo-controlled, double-blind RCT, geriatricclinic patients were given 100mg valepotriates(species and preparation not reported) three timesdaily for 30 days.27 When asked to rate whethertheir sleep disturbance was better, the same, orworse, both the valepotriate and placebo groupsreported improvement. Improvement was greaterin the valepotriate group, but no statisticalcomparisons were reported.

Overall, the literature on valepotriate prepara-tions provides limited evidence that valepotriatesmay improve sleep, but these studies are highlyvaried. Compared to placebo, studies reported

significantly improved sleep quality ratings inpersons withdrawing from benzodiazepines35 andpersons reporting disturbed sleep.25 One of thesestudies also reported reduced awakening versusbaseline but used no placebo control.36 Thesefindings suggest that valepotriate preparationsmay mildly reduce sleep disturbances. Like aqueousvalerian preparations, high-valepotriate prepara-tions have not been rigorously tested in personsdiagnosed with insomnia and extrapolation fromthe few studies available suggests such efficacywould be limited.

Valerian combination preparations

Many of the valerian products commercially avail-able are combinations with other herbs includinghops, lemon balm, and/or passion flower, all ofwhich purportedly have their own sedating ortranquilizing effects. It is possible that thesecombinations produce synergy and thus are moreeffective than each of these component herbsalone. Controlled studies have investigated onlycombinations of valerian with hops and/or lemonbalm. Most of these studies were in persons withinsomnia15,24,40,41 or those with a general com-plaint of sleep disturbance,22,43 although threestudies recruited healthy persons without requiringsleep disturbance.16,23,42 The specificity of exclu-sion criteria was thorough in some studies, but notin others (see Table 1). Only two of 10 studiesreported screening for primary sleep disordersother than insomnia as well as medical conditionsaffecting sleep, psychiatric problems, and medica-tions affecting sleep.23,40 Most of the other studiesscreened for some but not all of these criteria, buttwo studies did not report screening for any ofthese criteria.

Six studies investigated valerian–hops combina-tions (see Table 3). Three studies investigated theeffects of the valerian–hops combination ZE 91019(Allunas, methanolic-aqueous extract, % alcoholproprietary) on sleep. Two of these studies weredouble-blind, placebo-controlled RCTs that com-pared four weeks of ZE 91019 (500mg valerian/120mg hops24; 374mg valerian/82mg hops)40 toplacebo in persons with insomnia (ICD or DSM-IVcriteria). In these two studies, neither PSG out-comes24,40 nor subjective outcomes (sleep effi-ciency, sleep latency, ISI scores)40 improved or weresubstantially different between valerian–hopsand placebo. In a one-group study of personswith mild to moderate insomnia, Fussel et al.41

reported reduced sleep latency and increasedsleep efficiency measured by PSG with ZE 91019

ARTICLE IN PRESS

Table

3Stud

iesof

valerian

combinationproduc

tsforslee

p.

Stud

y,ye

arSample

with

slee

pdisturban

ce

Stud

ydesign

Interven

tion

Trea

tmen

tduration

Outco

me

mea

sures

Mainslee

pou

tcom

esAdve

rseeffects

Valerian

andHop

sMuller-Limmroth

and

Ehrenstein

22(197

7)Ye

sPDB,CCT,

C/O

,Ex

perim

ental

slee

pdisturban

ceby

trafficno

ise

(a)Va

lerian

–ho

ps24

0mg/

400mg

1nigh

tPSG

Nosign

ifica

ntdifferenc

efrom

place

bo

Not

men

tion

ed

(b)Place

bo

Leathw

oodet

al.4

6(198

2);

Leathw

oodan

dCha

uffard

39

(198

2/19

83)

No

PDB,RCT,

C/O

(a)Va

lerian

400mg

3nigh

tsSlee

pque

stionn

aire

Nosign

ifica

ntdifferenc

ebetwee

nva

lerian

–ho

ps

andplace

bo

Noresidua

lsedation

(b)Va

lerian

–ho

ps40

0mg

(c)Place

bo

Roden

bec

ket

al.2

4(199

8)Ye

sPDB,RCT

(a)Va

lerian

–ho

ps50

0mg/

120mg

28nigh

tsPSG

Nosign

ifica

ntdifferenc

efrom

place

bo

Not

men

tion

ed

(b)Place

bo

Schm

itzan

dJackel

15(199

8)Ye

sDB,RCT

(a)Va

lerian

–ho

ps20

0mg/

45mg

14nigh

tsSF-A,SF-B

Valerian

–ho

psve

rsus

baseline:

mSQ

;no

sign

ifica

ntdifferenc

ebetwee

nva

lerian

and

bromazep

am

Nowithd

rawal

symptoms

(b)Bromazep

am3mg

Stom

achco

mplaint:

valerian

(n¼

1),

bromazep

am(n¼

1)Fu

ssel

etal.4

1(200

0)Ye

sOne

-group

,pre-

post-test

Valerian

–ho

ps50

0mg/

120mg

14nigh

tsPSG

Valerian

–ho

psve

rsus

baseline:

NoAEoc

curred

kSL,k

wak

e,m

SEMorin

etal.4

0(200

5)Ye

sPDB,RCT

(a)Va

lerian

–ho

ps37

4mg/

82mg

28nigh

tsSlee

pdiaries,

slee

pque

stionn

aire

(ISI);

PSG

(n¼

75)

Valerian

hopsve

rsus

diphe

nhyd

ramineor

place

bo:

nosign

ifica

ntdifferenc

e

Noresidua

leffects,

seriou

sAEs,or

rebou

ndinsomnia

(b)Diphe

nhyd

ramine50

mg

(c)Place

bo

Nosign

ifica

ntgrou

pdifferenc

ein

AEs

Valerian

andlemon

balm

Lind

ahlan

dLind

wall43(198

9)Ye

sDB,RCT,

C/O

(a)Va

lerian

–ho

ps–lemon

balm

400mg/

375mg/

160mg

1nigh

tSlee

pqua

lity

(4-

point

scale)

Valerian

400mgve

rsus

4mg:

NoAEoc

curred

(b)Va

lerian

–ho

ps–lemon

balm

4mg/

375mg/

160mg

Greater

proportion

reportedm

SQDressinget

al.2

3(199

2)No

PDB,RCT,

C/O

(a)Va

lerian

–lemon

balm

160mg/

80mg

1nigh

tPSG

Nosign

ifica

ntdifferenc

efrom

place

bo

Norebou

ndeffects

occu

rred

(b)Triazolam

0.12

5mg

(c)Place

bo


ARTICLE IN PRESS

Table

3(con

tinu

ed)

Stud

y,ye

arSample

with

slee

pdisturban

ce

Stud

ydesign

Interven

tion

Trea

tmen

tduration

Outco

me

mea

sures

Mainslee

pou

tcom

esAdve

rseeffects

Dressinget

al.1

6(199

6)Ye

sPDB,RCT

(a)Va

lerian

–lemon

balm

320mg/

160mg2x

/d14

nigh

tsVIS-M

,SF-B

Valerian

–lemon

balm

versus

place

bo:

kSL,

mSQ

Noha

ngov

er,rebou

nd,

orwithd

rawals.

AE:

Valerian

/lem

onbalm

(n¼

5),place

bo(n¼

1)(b)place

bo

Cerny

andSchm

id42(199

9)No

PDB,RCT

(a)Va

lerian

–lemon

balm

360mg/

240mg

30nigh

tsSlee

pqua

lity

VAS,

SQim

prove

men

trating

s

Valerian

versus

place

bo:

Noseriou

sAE,

nosign

ifica

ntgrou

pdifferenc

ein

AEs

(b)Place

bo

VAS:

Nosign

ifica

ntdifferenc

e.Agrea

terproportion

reportedSQ

improve

men

t

Stud

yde

sign

abbrev

iation

s:C/O

,crossove

r,DB,dou

ble-blind(noplace

boco

ndition);PDB,place

bo-co

ntrolled

dou

bleblind

;RCT,

rand

omized

clinical

trial.Outcomemea

sures:

AE,

adve

rseev

ent;

NR,no

treported;

PSG

,polysom

nograp

hy;SF-A,Gortelm

eyer

Schlaffrag

ebog

enA,assesses

slee

pqua

lity

forthepastnigh

t;SF-B,Gortelm

eyer

Schlaffrag

ebog

enB,

assesses

slee

pqua

lity

forthetw

owee

ks;SL,slee

platenc

y;SQ

,slee

pqua

lity;SR

,self-rep

ort;

VAS,

visual

analog

scale;

VIS

–M,Visua

lana

logska

la–Morge

n(a

stan

dardized

setof

visual

analog

scales

ofslee

pco

mpletedin

themorning

).


ARTICLE IN PRESS


(500mg valerian/120mg hops) compared to base-line measurements.

Two other studies investigated the valerian–hopscombination Hovas (information on extractionmethod not available).15,46 In the previously de-scribed randomized crossover trial by Leathwoodand Chauffard,46 three random nights of Hovas

(400mg, proportions of valerian/hops not re-ported) did not improve sleep in comparison to aplacebo in healthy persons. In a double-blind RCTofpersons with insomnia, sleep quality ratings im-proved significantly with both Hovas (200mgvalerian/45mg hops) and the benzodiazepine bro-mazepam (3mg).15 The two treatments did notsignificantly differ, although only small improve-ment was seen with either treatment. Finally,in a double-blind controlled clinical trial, Muller-Limmroth and colleagues22 investigated whether ornot a valerian–hops combination (240mg valerian/400mg hops, Seda-Kneipps) would attenuate sleepdisturbances experimentally induced by trafficnoise. No significant differences were found be-tween valerian–hops and placebo on the PSGoutcomes.

Valerian–lemon balm (also called lemon melissa)combinations were investigated in four clinicaltrials; two tested the herbal combination in healthypersons and two recruited persons with sleepdisturbance (see Table 3). In a double-blind RCTof healthy persons, 30 nights of a valerian–lemonbalm combination (360mg valerian, 70% ethanolextraction/240mg lemon balm, 30% methanolextraction, Songha Nights) had no effect on sleepquality ratings on a 0–100 visual analog scale (VAS)compared to a placebo.42 However, a significantlygreater proportion of those on valerian–lemon balmthan those on placebo (33% versus 9%) reportedthat their sleep quality was ‘‘better’’ (versus‘‘unchanged’’ or ‘‘worse’’) even though the VASratings did not reflect this change. Another double-blind study of healthy persons investigated theeffects of one night of the valerian–lemon balmcombination (160mg valerian, 70% ethanol extrac-tion/80mg lemon balm, 30% ethanol extraction;Euvegals).23 In this double-blind crossover study ofhealthy individuals the herbal combination did notimprove PSG-measured sleep efficiency, sleeplatency, or WASO compared to a placebo. Thesame research group conducted a 14-day trial ofEuvegals (320mg valerian, 70% ethanol extrac-tion/160mg lemon balm, 30% ethanol extraction)given twice a day in persons with insomnia. Theherbal combination significantly improved subjec-tive sleep quality ratings and reduced subjectivesleep latency compared to the placebo.16 Finally, ina placebo-controlled, double-blind crossover study

of persons with sleep disturbance, a significantlygreater proportion of participants reported thattheir sleep quality was ‘‘perfect’’ after one night ofa valerian–hops–lemon balm combination (400mgvalerian/375mg hops/160mg lemon balm, infor-mation on extraction method not available; Valeri-ana natts) than a night of hops–lemon balmalone.43

In summary, in subjects with insomnia, placebo-controlled studies of valerian–hops combinationsdid not improve PSG or subjective sleep out-comes,24,40 but a valerian–lemon balm combinationreduced subjective sleep latency and increasedsubjective sleep quality.16 A one-group trialof valerian–hops reported improved sleep com-pared to baseline,41 and another trial ofvalerian–hops reported improvement of sleepquality ratings that was similar to improvementwith a benzodiazepine.15 Neither of the twostudies of valerian–lemon balm in healthy indivi-duals showed significantly improved sleep.16,42

Overall, these findings are similar to results ofstudies of valerian alone. These mixed, butpredominantly negative, findings concerning theeffects of valerian combinations on sleep outcomesindicate that combination products are no moreeffective than valerian alone; that is to say noteffective at all.

Side effects and safety

No serious adverse effects occurred in thesereported clinical trials of valerian (see Tables 2and 3). The number of side effects with ethanolicvalerian extracts did not differ significantly fromplacebo,31,34 and tended to be fewer than benzo-diazepines.13,32 Specific side effects reported withethanolic valerian extracts included headache,gastrointestinal (GI) complaints, morning ‘‘hang-over,’’ diarrhea, drowsiness, exaggerated feeling ofwell-being, mental dullness, difficulty sleeping,depression, irritability, dizziness, feeling remote,nausea, and sweating.17,29,30,32,33 Studies of aqu-eous extracts reported two cases of dizzinesswith valerian21 and one case of nausea possiblyrelated to valerian.46 Additionally, Leathwood andChauffard38 reported evidence of dose-dependenthangover effects, with morning sleepiness ratingssignificantly higher after valerian than placebo forthe 900mg dose but not the 450mg dose. In theclinical trials of valepotriate preparations only fiveparticipants reported adverse effects, and in allcases these were GI (diarrhea, stomach discomfort,bitter taste in mouth).

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Eight open-label clinical studies with samplesizes ranging from 20 to 830 participants investi-gated the tolerability of valerian or valeriancombination products. In several studies, no ad-verse events occurred,19,20,44 and in another studyonly three minor events occurred.14 When asked torate the tolerability of the herbal products,participants (70–90%) rated them as ‘‘good’’ or‘‘very good’’.12,14,18,20,28

Discussion

Evaluation of the effectiveness of valerian as asleep aid is difficult given the considerable varia-tion among the studies in duration, design, andherbal preparation. Originally, we had intended toperform a meta-analysis of the literature availableon valerian, but concluded that such an analysiswas not appropriate given the variability in theresearch quality. In particular, evidence on valerianfrom both parallel-group and crossover trials shouldnot be combined in the same meta-analysis becauseinclusion of crossover trials does not account forlack of independence of the group data andincreases the risk of Type I error. Other featuresof valerian trials that preclude use of meta-analyticprocedures are use of different types of products(species, extraction methods, and herbal combina-tions) and differing characteristics of the samplesstudied (healthy versus insomnia). There is insuffi-cient data on specific sleep outcomes to conductseparate meta-analyses on the literature dividedinto categories based on product and sample.Therefore, to fully evaluate the current state ofthe evidence of valerian effects on sleep outcomes,we decided that a descriptive synthesis of theliterature with specific attention to product andsample characteristics was most appropriate.

Issues related to dose and treatment durationwere not emphasized in this review because thereare no current standards for an optimal dose orrecommended treatment duration. Given the lackof dose-response studies, it is unclear whether anyof the studies used an optimal dose, although mostwere consistent with expert recommendations.Additionally, it is commonly recommended thatat least two weeks of valerian treatment isnecessary for effects to manifest,8 but thisrecommendation has not been specifically investi-gated. Although a few placebo-controlled studiesof two weeks or longer treatment durationreported significant improvement with valer-ian,16,21,35 a greater number found no significantimprovement.17,24,29,33,34,40,42

Quality of the research evidence

The quality of the studies reviewed was ratedusing the Jadad scoring criteria for potentialsources of bias (higher scores ¼ higher quality)10

(see Table 4). The studies of ethanolic extractswere conducted most recently and were of thehighest quality; most studies had Jadad scoresranging from 3 to 5.13,17,29–32,34 Studies of aqueousextracts and valepotriate-containing extracts weremostly conducted in the 1970s and 1980s, andtended to be of mixed quality; few studies had aJadad score X3.21,36,38,46 The studies of highestquality did not find valerian (ethanolic extracts orvalerian–hops combination) to be significantlysuperior to placebo for improving outcomes ininsomnia.17,29,31,40

In a previous systematic review,4 the authorsevaluated several criteria (e.g., randomization andblinding, power estimates, potential sources ofbias) in addition to the Jadad score that wereimportant to the validity of clinical trials of theeffects of herbs on sleep. None of the studiesreviewed addressed all of the important trial designelements, although the number of elements in-cluded did increase in the more recent studiesexamined. Few of the studies described therandomization procedures or reported data ongroup equivalence, which could bias the findingsif the groups differed on baseline characteristics.Perhaps more problematic was the failure tocalculate sample size, and thus, many studieswere likely underpowered to detect group differ-ences. The majority of studies had samplesizes between 11 and 21 participants, with onlysix studies having moderately large sample sizes(78–391).17,27,29,32,34,46 Nevertheless, the studiesgenerally used statistical methods that were liberalin assigning statistical significance to findings (e.g.,paired tests with no alpha rate correction formultiple testing), which makes the lack of statis-tical significance more compelling evidence againstthe clear effectiveness of valerian as a sleep aid.On the other hand, failure to control pre-bedtimevariables such as caffeine use or exercise may haveallowed these factors to influence sleep outcomes,confounding any potential effects of valerian onsleep.

Of particular methodological concern in thestudies reviewed was the considerable failure toensure that the placebo (or comparison medica-tion) and valerian were adequately masked. Valer-ian has a very distinctive, unpleasant odor. Failureto adequately mask the valerian treatment or‘odorize’ the comparison treatment may increaseexpectations that valerian pills will be effective.

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Of the 28 studies that were trials with a comparisongroup, 10 matched treatments on appearance,while seven matched on odor (two described thematching procedures).29,31 Only one study reportedthe success of the employed masking procedure29

(see Table 4). In two recently completed studies bythe authors of this review (C.A. Landis and D.M.Taibi, unpublished), researchers used valerian toconfer the odor of valerian on the placebocapsules. In one study, valerian capsules werestored in proximity to the placebo pills. In theother study, the placebo was stored in plasticcontainers that had been ‘‘odorized’’ by containingactive valerian for a week. Although it is possiblethat these methods may contaminate the placebo,the amount of valerian transferred is likely to beminimal and not clinically effective. In each ofthese studies, participants were not able toidentify which treatment condition they hadreceived, indicating that both masking procedureswere successful.

The specificity of the sample characteristics,including subject inclusion and exclusion criteriawere evaluated (Table 1). Little consideration wasgiven to age and gender, although few studiesspecifically investigated valerian in older adults. Itwas evident that many of the studies did not reportexclusion of potentially confounding variables,including co-morbid insomnia, psychiatric diag-noses, and concurrent use of sleep-altering medi-cations. In particular, a serious omission was thefailure to report exclusion of other sleep disorders(e.g., sleep apnea and restless legs syndrome),even in several of the high-quality studies. Thefindings from studies of ethanolic extracts andvalerian–lemon balm combinations are the mostreliable in relation to controlling for potentialconfounding variables. Finally, none of the studiesof insomnia patients differentiated between typesof insomnia symptoms in the analysis. It is possiblethat valerian products may have differential effi-cacy for sleep initiating versus sleep maintenancesymptoms.

Evaluation of the effects of valerian on sleep

Only a limited number of studies were available oneach type of valerian product. Although some ofthese studies reported improvement over time,often no direct comparisons of valerian and placebogroups were reported.27,37,34 Given that severalstudies of valerian reported improvement of sleepunder the placebo condition (e.g.,17,29,33), im-provement over time in the valerian group is

insufficient to exclude the possibility of placeboeffects or to conclude that the herb is effective.

Valerian effects on subjective sleepoutcomes

The research findings to date do not support theefficacy of valerian or valerian combinations forimproving subjective sleep outcomes. Most of theevidence of improved sleep with valerian prepara-tions is from studies using non-specific outcomesfor clinical trials (i.e. proportion improve-ment)21,38,42,43 or studies in which placebo effectwas not addressed.13,29,32,41 Research evidence ofhigh-quality is available for ethanolic V. officinalisextracts, and the findings do not support theefficacy for the treatment of insomnia. The qualityof research evidence for other valerian products ismixed, but few studies have been conducted withthese products in samples with insomnia. Althoughthere is some evidence that suggests valerian mayimprove sleep outcomes, placebo effects cannot beruled out in many of these trials. Therefore, theevidence is insufficient to recommend clinical useof valerian for treating disturbed sleep.

Recently, Bent and colleagues5 published a meta-analysis of subjective sleep quality and sleeplatency outcomes of valerian treatment, conclud-ing that evidence suggests potential beneficialeffects of valerian on sleep. In this analysis, theauthors did not consider type of valerian product,and they included combination products with asmany as eight other herbs. Two types of sleepquality outcomes have been used in valerianstudies: (1) sleep quality improvement—whetherparticipants rate their sleep as ‘‘improved’’ or ‘‘notimproved’’ or (2) sleep quality ratings—e.g., 0–10numeric scale, 0 ¼ poor, 10 ¼ excellent. Bent andcolleagues conducted their meta-analysis on sleepquality improvement ratings (‘‘improved versus‘‘not improved’’). This analysis favored valerian,but inspection of the studies included revealed apublication bias towards small, positive studies.Additionally, in two of the six studies in which sleepquality improvement favored valerian, sleep qual-ity ratings showed no significant differences be-tween valerian and placebo.17,42 Therefore, theclinical utility of assessing subjective sleep qualityimprovement is questionable. Bent et al. reportedthat results for subjective sleep latency weremixed, and, as discussed in our review, variationin study quality and lack of control for confoundingvariables influenced the outcomes of many of thestudies. Given the limited scope of outcomes andstudies considered in the Bent et al. review, the

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Table

4Qua

lity,metho

dolog

ical

features,an

dsign

ifica

nceof

primaryou

tcom

esof

clinical

trials

ofva

lerian

forslee

p.

Stud

yJadad

Score

Ran

dom

proce

dure

described

Blind

ingof

appea

ranc

edescribed

Blind

ingof

odor

described

Successof

blind

ing

chec

ked

Com

plian

cech

ecke

dSample

size

calculated

Subject

inclusion/

exclusion

criteria

Dropou

tsreported

Con

trol

ofpre-

bed

time

variab

les

Validated

outcom

emea

sures

Intent-to-

trea

tan

alyses

Prim

ary

slee

pou

tcom

essign

ifica

nt

Muller-Limmroth

and

Ehrentstein22

1(+)

Jansen

27

3+

NA*

Leathw

oodan

dCha

uffard,3

9

Leathw

oodet

al.4

6

(lab

)

0(+)

Leathw

oodan

dCha

uffard,3

9

Leathw

oodet

al.4

6

(hom

e)

4+

++

+p

Gessner

etal.2

62

++

(+)

Gessner

and

Klasser

25

2(+)

(+)

Kam

m-Koh

let

al.2

13

++p

Balderer

and

Borbely1

1(hom

e)1

++

(+)

Balderer

and

Borbely1

1(PSG

)2

++

+

Leathw

oodan

dCha

uffard

38

4+

++

+(+)

Lind

ahlan

dLind

wall43

2+

(+)

+p

Dressinget

al.1

62

++

Schu

lzet

al.3

72

++

NA*

Dressinget

al.6

3+

++

++

+Vo

rbac

het

al.1

75

++

(+)

++

++

++

Roden

bec

ket

al.2

42

++

Schm

itzan

dJackel

15

3+

++

+¼

Cerny

andSchm

id42

3+

++

Kuhlman

net

al.3

43

++

++

Don

athet

al.3

32

+(+)

Dorn1

35

++

(+)

++

++¼

Herrera-Arellan

oet

al.3

64

+(+)

++

(+)

Poya

reset

al.3

52

++

+(+)

Zieg

leret

al.3

24

+(+)

++

++

++¼

Cox

eter

etal.3

75

++

++

NA

++

NA

Diaper

and

Hindmarch

30

3+

(+)

++

Jaco

bset

al.2

95

++

++

++

++

++

Morin

etal.4

04

+(+)

++

++

++

+

Item

srelatedto

quality:

Stud

ieslisted

chrono

logica

lly.

+:item

was

adeq

uately

addressed

;(+):

item

was

partially

addressed

;NA:item

was

notap

plica

ble

tothestud

y.Prim

ary

outcom

es(based

onou

tcom

esrepo

rted

inTables

1an

d2):+:

outcom

essign

ifica

nt(versusplace

bo);(+):

only

partof

mainou

tcom

esweresign

ifica

nt;NA*:

statistica

lan

alyses

comparingva

lerian

totheplace

bowereeither

notdon

eor

notreported;

+p:astatistica

llysign

ifica

ntpropo

rtionof

thesample

improve

d,but

thestud

ydid

notco

mparemea

nscores;

+¼:eq

uiva

lenc

eof

valerian

andaben

zodiaze

pine(hyp

othe

siswas

met

ifdifferenc

eswereno

n-sign

ifica

nt).


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preponderance of negative findings was neglected,and the author’s conclusions that valerian, as it hasbeen tested to date, is a promising therapy areunsupported in the broader context of the litera-ture reviewed here.

Valerian effects on objective sleep outcomes

Current evidence suggests that the investigatedvalerian preparations do not significantly affectobjective sleep outcomes, although very fewstudies have actually recorded sleep. Of the studiesadministering V. officinalis mono-preparations,only two of the studies that measured PSG out-comes investigated valerian administration forlonger than three days in persons with sleepdisturbance,33,35 one showed no significant out-comes,33 and the other reported reduced WASO.35

Studies of valerian combinations reporting PSGoutcomes after either one night22,23 or 28 days24,40

found no outcomes significant compared toplacebo. One study of an aqueous valerian extractshowed reduced sleep onset latency by wristactigraphy in persons with sleep onset insomnia.38

However, sleep latency was not longer than 30minat baseline (15min) and on average was reducedonly four to six minutes, providing only weakevidence of valerian sedation. Overall, thesefindings do not support the effectiveness of valerianor valerian combinations for improving objectivesleep outcomes. Additionally, when consideringthat the tested valerian preparations did notclearly show improved subjective sleep ratings,any evidence of improved objective sleep outcomesis of questionable relevance.

Safety of valerian

The studies reviewed support the safety of valer-ian. The most common side effects were mild andtended to be either mild neurological symptoms(dizziness, headache, drowsiness) or gastrointest-inal (GI) symptoms (nausea, diarrhea). Althoughvalerian has been implicated in a few case reportsof transient liver dysfunction,47,48 no hepaticsymptoms or changes in liver function werereported in the research literature reviewed.13,42

Valerian had been shown to cause little to noimpairment of performance, especially in compar-ison to benzodiazepines.30,34,49–51

Concerns have been raised regarding the safetyof ingesting valepotriates. These constituents havebeen shown in vitro to be cytotoxic and to inhibitDNA synthesis.8 A recent in vitro study demon-strated that DNA damage of human epithelial cells

occurred with high doses of valepotriates, but notwith low doses.52 It has been suggested that the GItract is at particularly high risk for adverse effectsof valepotriates because of the chemical degrada-tion of these substances in the stomach.8 While GIsymptoms were reported in the reviewed studies onhigh-valepotriate preparations, these symptomslikely were related to purported muscle-relaxanteffects of valepotriates.8 No report was found inthe literature directly linking valepotriates to theoccurrence of serious adverse events in humans,but caution in the use of these products iswarranted until more is known about potentialadverse effects.

There is little evidence on potential herb–druginteractions of valerian. In vitro studies havedemonstrated mild to moderate inhibition of thedrug-metabolizing enzymes in the small bowel andliver that are involved in first-pass drug metabo-lism.53,54 Although inhibition of these enzymestheoretically increases the risk of excessive levelsof certain medications in the blood, an in vivo studyof humans showed no significant effects of onevalerian preparation on circulating levels of med-ications given to test enzyme inhibition.55 Althoughevidence indicates that valerian is unlikely tosignificantly affect drug metabolism, caution maybe advised with medications that are metabolizedby cytochrome P450 enzyme subtype 3A4, and toa lesser extent subtypes 2C19 and 2D6, if themedications have high toxicity and a narrowtherapeutic range (e.g., digoxin). Additionally,synergistic effects of valerian with medicationsare potentially problematic. In animal studies,valerian had been shown to potentiate barbiturateinduced sleeping time.6 Valerian should not betaken with benzodiazepines and other sedatingsubstances, such as antihistamines and alcohol, dueto the risk of over-sedation.

Conclusion

Although valerian is commonly used in the UnitedStates and Europe as a sleep aid, current evidenceon the efficacy of valerian for improving sleepoutcomes does not support such use. However,valerian is an apparently safe herb, with fewreported side effects. Despite the lack of evidencefor efficacy, these products are unlikely to causeharm other than perhaps delaying individuals fromseeking the effective treatment for insomniasymptoms.

Although current evidence fails to supportefficacy of valerian for relief of insomnia, the

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widely variable and methodologically mixed natureof the extant literature clearly leaves room forfurther clarification. First, it is important to notethat the source valerian plant material used in moststudies was extracted from dried, rather thanfresh, root and rhizome. The concentration ofcertain constituents of valerian varies betweenfresh and dried products, and study findings ondried root extracts should not be generalized tofresh root preparations. Second, valerian prepara-tions were administered in pill form rather than asa liquid, which is the preferred method recom-mended by herbalists (personal communicationRobin DePasquale, January, 2007). No studies werefound that tested valerian tinctures for sleep;although one tested cognitive impairment with asyrup.50 This is an important distinction becausethe presence and availability of active constituentsvaries between pills and tinctures. Finally, rigorousstudies testing different doses of valerian and typesof valerian products in well-defined samples ofpersons with insomnia are needed. It remainspossible that valerian may be a useful, mildtreatment for sleep disturbance, but currentevidence does not support its use, and research isneeded to determine which products and doses ofvalerian might be efficacious.

Practice points

� Current evidence does not support theefficacy of valerian or valerian combina-tions with other herbs for reducing generalsleep disturbance or insomnia symptoms.� Valerian has been shown to be a safe

product and is unlikely to cause harm inthe majority of patients. Healthcare provi-ders should advise patients of potentialherb–drug interactions (e.g., additive seda-tion, possible alteration of drug metabo-lism).� Caution should be exercised in the use of

valerian by patients who have a history ofliver disease, those at risk for liver dysfunc-tion, and taking other herbs linked to liverdysfunction.

�The most important references are denoted by an asterisk.

Research agenda

� Future studies of valerian should specificallyexclude persons with primary sleep distur-bances other than insomnia (e.g., restlesslegs syndrome, sleep apnea).

� Future studies should use greater specifica-tion of inclusion/exclusion criteria, espe-cially in defining the type of sleepdisturbance in the sample. Study methodsshould also plan for greater control ofpotential sources of bias (see Table 4).� Matching of valerian and placebo odor is

critical to ensure adequate masking and toreduce potential placebo effects.� Evidence on valerian preparations in tinc-

ture form is lacking. Given that this is aformulation preferred by herbalists, re-search on such preparations may providenew information on potential effects ofvalerian.

Acknowledgments

The systematic review and manuscript weresupported by the National Institutes of Health,grant numbers R21-AT-002108, P30-NR04001, andT32-NR07039. The authors thank Robin DiPasquale,N.D., R.H.(AHG) for consulting on this article andCristina Fuller, Ph.D.(c), for assistance with Portu-guese translation.

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a systematic review of valerian as a sleep aid: safe …...sleep medicine reviews (2007) 11,...

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