valerian for anxiety disorders (review)

Valerian for anxiety disorders (Review)

Miyasaka LS, Atallah ÁN, Soares B

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2009, Issue 1

http://www.thecochranelibrary.com

Valerian for anxiety disorders (Review)

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Analysis 1.1. Comparison 1 Valerian vs placebo, Outcome 1 Reduction in anxiety symptoms (HAM-A). . . . . . 12Analysis 1.2. Comparison 1 Valerian vs placebo, Outcome 2 Reduction in anxiety symptoms (STAI-T). . . . . . 12Analysis 1.3. Comparison 1 Valerian vs placebo, Outcome 3 Side effects. . . . . . . . . . . . . . . . 13Analysis 1.4. Comparison 1 Valerian vs placebo, Outcome 4 Overall dropout. . . . . . . . . . . . . . . 13Analysis 2.1. Comparison 2 Valerian vs diazepam, Outcome 1 Reduction in anxiety symptoms (HAM-A). . . . . 14Analysis 2.2. Comparison 2 Valerian vs diazepam, Outcome 2 Reduction in anxiety symptoms (STAI-T). . . . . 14Analysis 2.3. Comparison 2 Valerian vs diazepam, Outcome 3 Side effects. . . . . . . . . . . . . . . . 15Analysis 2.4. Comparison 2 Valerian vs diazepam, Outcome 4 Overall dropout. . . . . . . . . . . . . . 15

15WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .16HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .16CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .16DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .16SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .17INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iValerian for anxiety disorders (Review)

[Intervention Review]

Valerian for anxiety disorders

Lincoln Sakiara Miyasaka1 , Álvaro N Atallah2, Bernardo Soares1

1Brazilian Cochrane Centre, São Paulo, Brazil. 2Brazilian Cochrane Centre, Universidade Federal de São Paulo / Escola Paulista deMedicina, São Paulo, Brazil

Contact address: Lincoln Sakiara Miyasaka, Brazilian Cochrane Centre, Universidade Federal de São Paulo, Rua de Pedro Toledo 598,Vila Clementino, São Paulo, SP, 04039-001, Brazil. lincoln.miyasaka@terra.com.br.

Editorial group: Cochrane Depression, Anxiety and Neurosis Group.Publication status and date: Edited (no change to conclusions), published in Issue 1, 2009.Review content assessed as up-to-date: 20 August 2006.

Citation: Miyasaka LS, Atallah ÁN, Soares B. Valerian for anxiety disorders. Cochrane Database of Systematic Reviews 2006, Issue 4.Art. No.: CD004515. DOI: 10.1002/14651858.CD004515.pub2.

A B S T R A C T

Background

Anxiety disorders are very common mental health problems in the general population and in primary care settings. Herbal medicinesare popular and used worldwide and might be considered as a treatment option for anxiety if shown to be effective and safe.

Objectives

To investigate the effectiveness and safety of valerian for treating anxiety disorders.

Search strategy

Electronic searches: The Cochrane Collaboration Depression, Anxiety and Neurosis Cochrane Controlled Trials Register (CC-DANCTR-Studies and CCDANCTR-References) searched on 04/08/2006, MEDLINE, Lilacs. References of all identified studieswere inspected for additional studies. First authors of each included study, manufacturers of valerian products, and experts in the fieldwere contacted for information regarding unpublished trials.

Selection criteria

Randomised controlled trials (RCTs) and quasi-randomised trials of valerian extract of any dose, regime, or method of administration,for people with any primary diagnosis of general anxiety disorder, anxiety neurosis, chronic anxiety status, or any other disorder inwhich anxiety is the primary symptom (panic disorder, obsessive compulsive disorder, social phobia, agoraphobia, other types of phobia,postraumatic stress disorder). Effectiveness was measured using clinical outcome measures and other scales for anxiety symptoms.

Data collection and analysis

Two review authors independently applied inclusion criteria, extracted and entered data, and performed the trial quality assessments.Where disagreements occurred, the third review author was consulted. Methodological quality of included trials was assessed usingCochrane Handbook criteria. For dichotomous outcomes, relative risk (RR) was calculated, and for continuous outcomes, the weightedmean difference (WMD) was calculated, with their respective 95% confidence intervals.

1Valerian for anxiety disorders (Review)

Main results

One RCT involving 36 patients with generalised anxiety disorder was eligible for inclusion. This was a 4 week pilot study of valerian,diazepam and placebo. There were no significant differences between the valerian and placebo groups in HAM-A total scores, or insomatic and psychic factor scores. Similarly, there were no significant differences in HAM-A scores between the valerian and diazepamgroups, although based on STAI-Trait scores, significantly greater symptom improvement was indicated in the diazepam group. Therewere no significant differences between the three groups in the number of patients reporting side effects or in dropout rates.

Authors’ conclusions

Since only one small study is currently available, there is insufficient evidence to draw any conclusions about the efficacy or safety ofvalerian compared with placebo or diazepam for anxiety disorders. RCTs involving larger samples and comparing valerian with placeboor other interventions used to treat of anxiety disorders, such as antidepressants, are needed.

P L A I N L A N G U A G E S U M M A R Y

Valerian for anxiety disorders

Anxiety disorders are a very common mental health problem in the community. Most of the medications used to treat anxiety have sideeffects. Valerian is a phytotherapeutic medication frequently used for insomnia. The aim of this study was to investigate the efficacy andsafety of valerian for anxiety disorders. Only one study was identified, involving 36 patients and comparing valerian with placebo anddiazepam. This study found no significant differences in effectiveness between valerian and placebo, or between valerian and diazepam,for clinician-rated anxiety symptoms, and that both valerian and diazepam were equally well tolerated by patients. However, additionalstudies with larger numbers of patients are necessary before drawing conclusions about the effectiveness and safety of valerian as atreatment option for anxiety disorders.

B A C K G R O U N D

Anxiety disorders are a very common mental health problem inthe general population and in the primary care setting. In theUS National Comorbidity Survey Kessler 1994 found a one yearprevalence for anxiety disorders of 17% and a lifetime prevalenceof almost 25%. Using the Composite International Diagnostic In-terview (CIDI) in 1996-99, Bijl 1998 included 7076 people in 90municipalities in the Netherlands, and detected a prevalence ratefor anxiety of 19.3% in the general population. In Brazil, the preva-lence of anxiety was reported at 12.1% in Brasilia, 6.9% in SãoPaulo and 5.4% in Porto Alegre (Almeida-Filho 1997). One studyhas found a marked reduction in quality of life and psychosocialfunctioning in people with anxiety disorders (Mendlowicz 2000).

Although anxiety is a treatable disorder, it is often not diagnosedand treated properly. The majority of patients suffering from anx-iety consult their general practitioner, and often their complaintpresents as a physical symptom, such as headache, palpitations,breathing difficulties or chest pain (Walley 1994). Anxiety may be

associated with physical disorders such as diabetes, arthritis andcancer, or it may be the primary symptom of a specific psychiatricdisorder such as generalized anxiety disorder, post-traumatic stressdisorder, panic or obsessive compulsive disorder.

Benzodiazepines are effective in short -term treatment but theiroveruse may cause dependence (Priest 1988). Psychotherapy is ef-fective and is commonly used to treat anxiety (Borkovec 1987;Borkovec 1993; Taylor 1978; Taylor 1988). A systematic review onpsychological therapies for generalised anxiety disorder has beenconducted and is expected to be published soon in The CochraneLibrary (Hunot 2006). Another systematic review has found thatcognitive behavioural therapies and pharmacological treatmentsincluding buspirone, trazodone, imipramine and ritanserin signif-icantly improved anxiety (Gould 1997). However, psychotherapymay be an unrealistic option in public health settings in manycountries as it is costly and time consuming, and although phar-macological treatments are effective, they may be limited by theirside effects and cost. Herbal medicines are in popular usage world-

wide, and could be considered as a treatment option for anxietydisorders if shown to be effective and secure. A systematic reviewon the effectiveness of kava kava showed its superiority as com-pared with placebo (Pittler 2002). No systematic review on vale-rian for anxiety has yet been conducted.

Valerian is one of the most popularly used herbal medicines forinsomnia (Donath 2000) and is also used for anxiety. It is used inthe form of a dried herb (0.5-2.0g taken 3-4 times a day), extract(0.5-2.0 ml) or tincture (2-4 ml) (BHMA 1992). Hydroalcoholicand aqueous extracts of valerian roots have shown affinity for theGABA-A receptor in the brains of rats (Mennini 1993). In anotherexperiment, valerian oil injected intraperitoneally showed centraldepressive and muscle relaxation activity in mice (Hendriks 1981).Valepotriates are the most active principle of valerian, but are verylabile and unlikely to be present in the finished preparations. Inrats there is evidence of inhibition of motor activity, inhibition ofaggressivity, prolongation of anaesthesia by hexobarbital (Petkov1974), but with better motor coordination (Von Eickstedt 1969).In humans, valerian does not seem to potentiate the effect of al-cohol, but demonstrates a positive action in tests of concentra-tion and efficiency (Mayer 1974), and has been successful in thetreatment of insomnia and tension (Schmidt-Voigt 1986, Vorbach1996, Leathwood 1985, Donath 2000; Stevinson 2000; Ziegler2002). Although valerian has been used for a long time for treat-ing anxiety disorders its efficacy and side effects are not yet fullyestablished. This review aimed to examine the effectiveness andsafety of anxiety disorders.

O B J E C T I V E S

To investigate the effectiveness and safety of valerian for treatinganxiety disorders.

M E T H O D S

Criteria for considering studies for this review

Types of studies

Randomised and quasi-randomised controlled trials.

Types of participants

People aged 16 and over, with a primary diagnosis of anxiety dis-orders or anxiety neurosis or chronic anxiety status, or any otherdisorder in which anxiety was the primary symptom (generalisedanxiety disorder, panic disorder, obsessive compulsive disorder, so-cial phobia, agoraphobia, other types of phobia, post-traumatic

stress disorder), according to DSM-III or DSM-IV diagnostic cri-teria (APA 1987, APA 1994), irrespective of gender and ethnicbackground.Studies in which anxiety was a secondary symptom of a differentdisorder (for example, depression or any other psychiatric diag-noses) were excluded.

Types of interventions

Valerian (also called valepotriates or valerian extract), any dose,regime, or method of administration. Trials where valerian wasused in combination with another drug were not included.Control: placebo, other drugs, psychotherapy, or no intervention.Planned comparisons:(i) valerian versus placebo(ii) valerian versus other drugs(iii) valerian versus psychotherapy(iv) valerian versus no intervention

Types of outcome measures

Primary outcomeEffectiveness, measured using clinical outcome measures such asHamilton Anxiety Scale (HAM-A) (Hamilton 1959) and otherscales for anxiety symptoms:(a) improvement in anxiety (continuous outcome)(b) absence of treatment response (dichotomous outcome)Secondary outcomes(a) Acceptability of treatment :- number of participants reporting side effects- number of participants dropping out due to side effects(b) Side effects(c) Total number of drop-outs(d) Suicide attempts(e) Use/misuse of substances(f ) Use of health services(g) Death(h) Quality of life

Search methods for identification of studies

Electronic databasesThe Cochrane Collaboration Depression, Anxiety and NeurosisCochrane Controlled Trials Register was searched using the fol-lowing strategyCCDANCTR-Studies - searched on 04/08/2006Intervention = valerianCCDANCTR-References - searched on 04/08/2006Freetext = valerian* OR valepotriate.Lilacs (2005) and MEDLINE (2005) were searched using standardphrases for ’controlled trials’ and for ’anxiety disorders’ associatedto ’valerian OR valepotriate’.

There were no restrictions related to language or date of publica-tion of the studies.HandsearchesThe references of all identified studies were inspected for additionalstudies.Personal communicationThe first author of each included study was contacted for informa-tion regarding unpublished trials and additional data when neces-sary. The manufacturers of valerian products in Brazil and expertsin the field were also contacted for information regarding unpub-lished trials.

Data collection and analysis

Selection of trialsTwo review authors (LSM and BGOS) independently selected thetrials found through the search strategy, extracted the data, as-sessed trial quality, and analysed results. Where any disagreementsoccurred, the third review author (ANA) was consulted, and ifconsensus was not yet reached, data were not included in the re-view until the author of the trial was able to provide clarificationon the question posed.Data extractionReview authors screened the abstracts of all publications obtainedby the search strategy and considered eligible in fulfilling the in-clusion criteria. Data concerning participant characteristics, in-tervention details and outcome measures from the included stud-ies were extracted independently using a standard extraction formwith the following items:(a) General information: published or not, title, authors, contactaddress, country, resource, publication idiom, publication year,duplication of publishing, sponsor.(b) Characteristics of the study: design, length, whether ran-domised and method, allocation procedure, blinding (patients,administrator care and outcome appraiser), allocation check.(c) Intervention: placebo inclusion, intervention and controls(dose, route of administration and duration).(d) Patients: inclusion and exclusion criteria, total number of ran-domised and analysed subjects, sex, age, basic characteristics, di-agnostic criteria, length of disease and similarity of groups on thebasic characteristics (including any co-morbidity), assessment oncomplications, sub-groups.(e) Outcomes: Those specified in the section on ’Types of out-comes’, any other outcome assessed, other events, extension of at-tendance, and quality of related outcomes.(f ) Results: outcomes and evaluation time (including the evaluativemeasure), where necessary converted to the measurement of theeffects specified below; intention to treat analysis.Quality assessmentMethodological quality of the trials included in this review wasassessed using the criteria described in the Cochrane Handbook (Clarke 2000). The Cochrane Handbook criteria are based on the

evidence of a strong relationship between allocation concealmentand potential for bias in the results (Schulz 1995). The categoriesfor these criteria are as follows:A - Low risk of bias (adequate allocation concealment)B - Moderate risk of bias (unclear allocation concealment)C - High risk of bias (inadequate allocation concealment)For the purpose of analyses in this review, trials were includedif they met criteria A or B. Additionally, a cut-off of two pointson the Jadad scale was used to check the assessment made by theHandbook criteria (Jadad 1996). However, the Jadad scale was notused to exclude trials in this review.Measures of treatment effectDichotomous outcomesDichotomous outcomes were reported for each included trial bycalculating relative risks (RR) with the uncertainty in each resultbeing expressed through 95% confidence intervals (CI), using thefixed effect model. When further studies become available, di-chotomous data from individual trials will be combined in a meta-analysis, with the estimates of RR based on the random effectsmodel, as it takes into account any between study differences, evenif there is no statistically significant heterogeneity, and gives thesame result as the fixed effects model when there is no betweenstudy variance. Where overall results are significant, the numberneeded to treat (NNT) or number needed to harm (NNH) toproduce one outcome will be calculated.Continuous outcomesContinuous outcomes were reported for each included trial ac-cording to the difference between groups in the mean treatment ef-fect and its standard deviation, using the fixed effect model. Whenmultiple outcome measures were described in a single study, forthe purposes of pooling results, a single ’best available’ outcomemeasure was chosen according to the authors’ specification as theprincipal outcome or what was reported first. When further stud-ies become available, continuous outcomes in individual studieswill be combined by calculating the weighted mean difference(WMD) (where the same scale is used to measure an outcome ina comparison) or the standardised mean difference (SMD) (wheredifferent scales are used to measure the same outcome in a com-parison), together with 95%CIs.Information on missing data was clarified through contact withthe authors.Methods for future updates of the reviewThe following methods will be used when further studies are in-cluded in the review:Assessment of heterogeneityHeterogeneity in the results of trials will be assessed both by in-spection of graphical presentations and by calculating a formalChi-square test of heterogeneity, with heterogeneity assumed tobe present when the significance level is smaller than 0.10 (p <0.10).Subgroup analysis and investigation of heterogeneityWhere significant heterogeneity is present, an attempt will be made

to explain the differences based on the clinical characteristics ofthe included studies. Potential sources of heterogeneity may besample differences, diagnostic criteria or differences in medicationdosage.

Sensitivity analysisSensitivity analysis will be performed excluding quasi-randomisedstudies.Assessment of reporting biasA funnel plot will be produced to investigate the possibility ofpublication bias.

R E S U L T S

Description of studies

See: Characteristics of included studies; Characteristics of excludedstudies.Results of the searchThe electronic searches identified one reference in Lilacs, two ref-erences in MEDLINE, and five references in CCDANCTR-Stud-ies. Of the eight studies identified, only one was eligible for inclu-sion in the review (Andreatini 2002).Manufacturers of valerian in Brazil (Nikkho, Solnay Farma, Bar-renne, Fontovit, Pharmaton/Boehringer Ingelhein, Catarinense)were contacted asking for unpublished trials, but no further stud-ies were found.Included studiesThe study by Andreatini 2002 was a pilot study, using a ran-domised controlled design, which compared valepotriates (vale-rian) with diazepam and placebo. The trial duration was fourweeks. The sample consisted of 36 participants with a diagno-sis of generalised anxiety disorder, according to DSM-III criteria.The mean age of the sample was 41 years, and 21 of the partic-ipants were female. The majority of participants presented withsecondary disorders.Andreatini 2002 used a clinician-rated scale, the HAM-A, and aself-report scale, the STAI-Trait, to measure anxiety symptoms.HAM-A scores were reported for the overall total score, togetherwith a psychic factor (including anxious mood, tension, fears, con-centration disturbances) and somatic factor (including insomnia,respiratory and cardiovascular symptoms).Excluded studiesSeven studies were excluded from the review (see also Table ofexcluded studies).The study by Delsignore 1992 was excluded from the review be-cause the results were poorly presented, and could not be re-anal-ysed (SDs were not presented for continuous outcomes). Similarly,the study by Rabezzana 1995 was excluded because SDs were not

shown for continuous outcomes. It has not yet been possible tocontact the authors for further information.The study by Maisenbacher 1992 was excluded because it did notuse an RCT design. McCutcheon 1996 was excluded because ninephytotherapeutic preparations were used. The study by Panijel1985 was excluded because valerian was combined with hypericumfor comparison with diazepam. The study by Bourin 1997 wasexcluded because it used a combination of six extracts. Finally,Cerny 1998 was excluded because healthy volunteers were used.Awaiting assessmentThere are no studies currently awaiting assessment.

Risk of bias in included studies

AllocationThe study by Andreatini 2002 carried out the randomisation pro-cedure using a computer program. Whether the allocation wasconcealed or not was unclear, therefore it was classified as B, inaccordance with Cochrane Handbook criteria.BlindnessThe study by Andreatini 2002 was a double blind RCT. Mainte-nance of the double-blind procedure was tested for patients andresearchers.DropoutsThe overall dropout rate for Andreatini 2002 was 14%, with twodropouts reported for valepotriates (valerian), two for placebo andone for diazepam. Missing data for dropouts was managed throughuse of last observation carried forward (LOCF).

Effects of interventions

As described above, only one study was included in the review(Andreatini 2002), a double-blind randomised controlled trialcomparing valepotriates (valerian) with diazepam and placebo.1. VALERIAN vs PLACEBO

EffectivenessBased on the HAM-A scale overall score at post-treatment, no sig-nificant difference in symptom reduction was noted between vale-rian and placebo (WMD -1.40, 95%CI -7.93 to 5.13). Similarly,no significant differences in symptom reduction were noted be-tween valerian and placebo for the HAM-A somatic factor (WMD0.40, 95% CI -3.12 to 3.92), for the HAM-A psychic factor(WMD -1.80, 95% CI -6.22 to 2.62) or for STAI-Trait meanscores (WMD 0.70, 95% CI -9.93, 11.33).Side effectsNo side effects were reported by any patients in the valerian group,and were reported by one person in the placebo group. The pa-tient’s complaint was somnolence.Dropout

There was no significant difference in dropout rate between vale-rian and placebo groups.2. VALERIAN vs DIAZEPAMEffectivenessBased on the HAM-A scale total score at post-treatment, no signif-icant difference in symptom reduction was noted between valerianand diazepam (WMD 0.40, 95% CI -6.22 to 7.02). Similarly, nosignificant differences in symptom reduction were noted betweenvalerian and diazepam for the HAM-A somatic factor (WMD -0.20, 95% CI -2.93 to 2.53) or for the HAM-A psychic factor(WMD 0.60, 95% CI -3.82 to 5.02). The diazepam group hadsignificantly lower STAI-Trait mean scores at post-treatment thanthe valerian group (WMD 11.40, 95% CI 1.90, 20.90).Side effectsNo side effects were reported by patients in the valerian group, andwere reported by one person in the diazepam group. The patient’scomplaint was somnolence.DropoutThere was no significant difference in dropout rate between thevalerian and diazepam groups.

D I S C U S S I O N

Only one small pilot study with 36 patients was eligible for in-clusion in this review (Andreatini 2002). This study comparedthe efficacy of valerian with placebo and with diazepam, and eachgroup consisted of 12 patients. The reduction in clinician-ratedanxiety symptoms at post-treatment, based on the HAM-A scale,was similar for the three groups. Diazepam appeared to be superior

to valerian in reducing self-report anxiety symptoms, based on theSTAI-Trait scale. Side effect profiles were similar for valerian anddiazepam.

In view of the lack of available data, on the basis of the currentevidence, it is unclear whether or not valerian is effective and safewhen compared with placebo, or when compared with diazepam,in the treatment of anxiety disorders. Further efforts will be madeto obtain missing data from studies that are currently unable tocontribute to the review (Delsignore 1992, Rabezzana 1995).

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

Since only one study is included in this review, there is insufficientevidence to draw any conclusions on the efficacy or safety of vale-rian in comparison to placebo or diazepam for anxiety disorders.

Implications for research

Randomised controlled trials are needed involving larger samplesand comparing valerian to placebo and other available interven-tions, such as antidepressants, for the treatment of anxiety disor-ders.

A C K N O W L E D G E M E N T S

The staff of the Brazilian Cochrane Centre for their interest insolving daily doubts, and facilitating access to Cochrane data.

R E F E R E N C E S

References to studies included in this review

Andreatini 2002 {published data only}

Andreatini R, Sartori VA, Seabra MLV, Leite JR. Effect ofvalepotriates (valerian extract) in Generalised Anxiety Disorder: arandomised placebo-controlled pilot study. Phytotherapy Research

2002;16:650–4.

References to studies excluded from this review

Bourin 1997 {published data only}

Bourin M, Bougerol T, Guitton B, Broutin E. A combination ofplant extracts in the treatment of outpatients with adjustmentdisorder with anxious mood: controlled study versus placebo.Fundamental and Clinical Pharmacology 1997;11(2):127–32.

Cerny 1998 {published data only}∗ Cerny A, Schmid K. Tolerability and efficacy of valerian/lemonbalm in healthy volunteers ( a double-blind placebo controlledmulticentre study). Fitoterapia 1999;70:221–8.

Delsignore 1992 {published data only}∗ Delsignore R, Orlando S, Costi D, Baroni MC, Butturini U.Clinical comparative evaluation of a stabilized valeriana extract andplacebo [Avaliação clinica comparativa com placebo de um extratoestabilizado de valeriana]. A Folha Medica 1992;104(5):191–196.

Maisenbacher 1992 {published data only}∗ Maisenbacher J, Podzuweit H. Valerian and Melissa - MildPsychopharmaceuticals. Therapiewoche 1992;42(37):2140–2144.

McCutcheon 1996 {published data only}∗ McCutcheon LE. Treatment of anxiety with a homeopathicremedy. Journal of Applied Nutrition 1996;48(1,2):1–5.

Panijel 1985 {published data only}

Panijel M. Treatment of moderately severe anxiety states.Therapiewoche 1985;41:4659–68.

Rabezzana 1995 {published data only}∗ Rabezzana G. Tratamento dei disturbi d’ansia de grado lieve emedio con prodotti a base naturale: valutazione dell“efficacia e

tollerabilità del Sedatol. Riv It Biol Med 1995;15:126–133.

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APA 1987American Psychiatric Association. Diagnostic and statistical manualof mental disorders (DSM-III-R). 3rd Edition. Washington DC:American Psychiatric Association, 1987.

APA 1994American Psychiatric Association. Diagnostic and Statistical Manualof Mental Disorders (DSM-IV). 4th Edition. Washington, DC:American Psychiatric Association, 1994.

BHMA 1992British Herbal Medicine Association. British Herbal Compendium

Vol. 1. Bournemouth: British Herbal Medicine Association, 1992.

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Borkovec 1987Borkovec TD, Mathews AM, Chambers AM, Ebrahimi S, Lytle R,Nelson R, et al.The effects of relaxation training with cognitive ornondirective therapy and the role of relaxation-induced anxiety inthe treatment of generalized anxiety disorder. Journal of Consulting

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Borkovec 1993Borkovec TD, Costello E. Efficacy of applied relaxation andcognitive behavioral therapy in the treatment of generalized anxietydisorder. Journal of Consulting & Clinical Psychology 1993;61(4):611–9.

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Donath 2000Donath F, Quispe S, Diefenbach K, Maurer A, Fietze I, Roots I.Critical evaluation of the effect of valerian extract on sleep structureand sleep quality. Pharmacopsychiatry 2000;33(2):47–53.

Gould 1997Gould RA, Otto MW, Pollack MH, Yap L. Cognitive behaviouraland pharmacological treatment of generalized anxiety disorders:Preliminary meta-analysis. Behavior Therapy 1997;28(2):285–305.

Hamilton 1959Hamilton M. The assessment of anxiety states by rating. BritishJournal of Medical Psychology 1959;32:50–5.

Hendriks 1981Hendriks H, Bos R, Allersma DP, Malingre TM, Koster AS.Pharmacological screening of valerenal and some other componentsof essential oil of Valeriana officinalis. Planta Medica 1981;42(1):62–8.

Hunot 2006Hunot V, Churchill R, Silva de Lima M, Teixeira V. Psychologicaltherapies for generalised anxiety disorder. Cochrane Library 2006,Issue 4.[Art. No.: CD001848. DOI: 10.1002/14651858.CD001848.pub4]

Jadad 1996Jadad AR, Moore RA, Carrol D, Jenkinson C, Reynolds DJ,Gavaghan DJ, et al.Assessing the quality of reports of randomizedclinical trials: is blinding necessary?. Controlled Clinical Trials1996;17(1):1–12.

Kessler 1994Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M,Eshleman S, et al.Lifetime and 12 month prevalence of DSM III-Rpsychiatric disorders in United States. Archives of General Psychiatry1994;51(1):8–19.

Leathwood 1985Leathwood PD, Chauffard F. Aqueous extract of valerian reduceslatency to fall asleep in man. Planta Medica 1985;51(2):144–8.

Mayer 1974Mayer B, Springer E. Psychoexperimental studies on the effect of avalepotriate combination as well as the combined effects ofvaltratum and alcohol [Psyschoexperimentelle untersuchungen zurwirking einer Valepotriatkombination sowie zur Kombiniertenwirkung von Valtratum und Alkohol]. Arzneimittel-Forschung

1974;24(12):2066–70.

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2002;7(11):480–6.∗ Indicates the major publication for the study

C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Andreatini 2002

Methods Allocation: randomised (computer program)Blindness: unclearDesign: parallelDuration: 4 weeksAnalysis: non ITTSão Paulo, Brazil

Participants N=36Diagnosis: GAD (DSM-III-R)Gender: 21 femalesAge: mean of 41 yearsSetting: ambulatoryHistory: most of patients presented an associated clinical disease

Interventions 1. Valerian 81,3 mg/day (N=12)2. Diazepam 6,5 mg/day (N=12)3. Placebo (N=12)

Outcomes HAM-A (LOCF)STAI (LOCF)Side-effectsDropouts

Risk of bias

Item Authors’ judgement Description

Allocation concealment? Unclear B - Unclear

HAM-A - Hamilton Anxiety ScaleLOCF - Last Observartion Carried ForwardSTAI - State-trait Anxiety Inventory

Characteristics of excluded studies [ordered by study ID]

Bourin 1997 Used a combination of six extracts.

Cerny 1998 Allocation: randomisedParticipants: 98 healthy volunteersInterventions: (1) Valeriana/lemon balm; (2) placebo ; 30 daysOutcomes: sleep quality.

Delsignore 1992 Allocation: randomisedParticipants: 40 subjects with minor anxiety symptomatology and emotional tension disturbancesInterventions: (1) Valeriana 50 mg 3x day; (2) placebo 3x day; 21 daysOutcomes: clinical outcomes not available for meta-analysis. Continuous data (HAM-A) without SD.

Maisenbacher 1992 Allocation: not randomisedParticipants: 2395 subjects with acute or subacute psychophysical ill-healthInterventions: (1) Valeriana and Melissa; (2) placebo; 4 weeksOutcomes: clinical outcomes not available for meta-analysis.

McCutcheon 1996 Allocation: randomisedParticipants: 72 subjects with minor anxiety symptomatology and emotional tension disturbancesInterventions: (1) Valeriana and other 8 homeophatic remedies; (2) placebo ; 15 daysOutcomes: . STAI trait and state, Mean, SD.

Panijel 1985 Valerian combined with hypericum for comparison with diazepam.

Rabezzana 1995 Standard deviations were not shown for continuous outcomes.

D A T A A N D A N A L Y S E S

Comparison 1. Valerian vs placebo

Outcome or subgroup titleNo. ofstudies

No. ofparticipants Statistical method Effect size

1 Reduction in anxiety symptoms(HAM-A)

1 Mean Difference (IV, Fixed, 95% CI) Subtotals only

1.1 total score 1 24 Mean Difference (IV, Fixed, 95% CI) -1.40 [-7.93, 5.13]1.2 somatic factor 1 24 Mean Difference (IV, Fixed, 95% CI) 0.40 [-3.12, 3.92]1.3 psychic factor 1 24 Mean Difference (IV, Fixed, 95% CI) -1.80 [-6.22, 2.62]

2 Reduction in anxiety symptoms(STAI-T)

1 24 Mean Difference (IV, Fixed, 95% CI) 0.70 [-9.93, 11.33]

3 Side effects 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only3.1 Somnolence 1 24 Risk Ratio (M-H, Fixed, 95% CI) 0.33 [0.01, 7.45]

4 Overall dropout 1 24 Risk Ratio (M-H, Fixed, 95% CI) 1.0 [0.17, 5.98]

Comparison 2. Valerian vs diazepam

Outcome or subgroup titleNo. ofstudies

No. ofparticipants Statistical method Effect size

1 Reduction in anxiety symptoms(HAM-A)

1 Mean Difference (IV, Fixed, 95% CI) Subtotals only

1.1 total score 1 24 Mean Difference (IV, Fixed, 95% CI) 0.40 [-6.22, 7.02]1.2 somatic factor 1 24 Mean Difference (IV, Fixed, 95% CI) -0.20 [-2.93, 2.53]1.3 psychic factor 1 24 Mean Difference (IV, Fixed, 95% CI) 0.60 [-3.82, 5.02]

2 Reduction in anxiety symptoms(STAI-T)

1 24 Mean Difference (IV, Fixed, 95% CI) 11.40 [1.90, 20.90]

3 Side effects 1 24 Risk Ratio (M-H, Fixed, 95% CI) 0.33 [0.01, 7.45]4 Overall dropout 1 24 Risk Ratio (M-H, Fixed, 95% CI) 1.0 [0.17, 5.98]

Analysis 1.1. Comparison 1 Valerian vs placebo, Outcome 1 Reduction in anxiety symptoms (HAM-A).

Review: Valerian for anxiety disorders

Comparison: 1 Valerian vs placebo

Outcome: 1 Reduction in anxiety symptoms (HAM-A)

Study or subgroup Valerian Placebo Mean Difference Weight Mean Difference

N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

1 total score

Andreatini 2002 12 14.6 (9.8) 12 16 (6.1) 100.0 % -1.40 [ -7.93, 5.13 ]

Subtotal (95% CI) 12 12 100.0 % -1.40 [ -7.93, 5.13 ]Heterogeneity: not applicable

Test for overall effect: Z = 0.42 (P = 0.67)

2 somatic factor

Andreatini 2002 12 4.9 (4.3) 12 4.5 (4.5) 100.0 % 0.40 [ -3.12, 3.92 ]

Subtotal (95% CI) 12 12 100.0 % 0.40 [ -3.12, 3.92 ]Heterogeneity: not applicable

3 psychic factor

Andreatini 2002 12 9.7 (6) 12 11.5 (5) 100.0 % -1.80 [ -6.22, 2.62 ]

Test for subgroup differences: Chi2 = 0.65, df = 2 (P = 0.72), I2 =0.0%

-10 -5 0 5 10

Favours Valerian Favours placebo

Analysis 1.2. Comparison 1 Valerian vs placebo, Outcome 2 Reduction in anxiety symptoms (STAI-T).

Outcome: 2 Reduction in anxiety symptoms (STAI-T)

Study or subgroup Valerian Placebo Mean Difference Weight Mean Difference

Andreatini 2002 12 52.7 (15.3) 12 52 (10.9) 100.0 % 0.70 [ -9.93, 11.33 ]

Total (95% CI) 12 12 100.0 % 0.70 [ -9.93, 11.33 ]Heterogeneity: not applicable

-10 -5 0 5 10

Analysis 1.3. Comparison 1 Valerian vs placebo, Outcome 3 Side effects.

Outcome: 3 Side effects

Study or subgroup Valerian Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Somnolence

Andreatini 2002 0/12 1/12 100.0 % 0.33 [ 0.01, 7.45 ]

0.1 0.2 0.5 1 2 5 10

Analysis 1.4. Comparison 1 Valerian vs placebo, Outcome 4 Overall dropout.

Outcome: 4 Overall dropout

Study or subgroup Valerian Placebo Risk Ratio Weight Risk Ratio

Andreatini 2002 2/12 2/12 100.0 % 1.00 [ 0.17, 5.98 ]

Total (95% CI) 12 12 100.0 % 1.00 [ 0.17, 5.98 ]Total events: 2 (Valerian), 2 (Placebo)

Heterogeneity: not applicable

0.1 0.2 0.5 1 2 5 10

Analysis 2.1. Comparison 2 Valerian vs diazepam, Outcome 1 Reduction in anxiety symptoms (HAM-A).

Comparison: 2 Valerian vs diazepam

Outcome: 1 Reduction in anxiety symptoms (HAM-A)

Study or subgroup Valerian Diazepam Mean Difference Weight Mean Difference

1 total score

Andreatini 2002 12 14.6 (9.8) 12 14.2 (6.4) 100.0 % 0.40 [ -6.22, 7.02 ]

2 somatic factor

Andreatini 2002 12 4.9 (4.3) 12 5.1 (2.2) 100.0 % -0.20 [ -2.93, 2.53 ]

3 psychic factor

Andreatini 2002 12 9.7 (6) 12 9.1 (5) 100.0 % 0.60 [ -3.82, 5.02 ]

Test for subgroup differences: Chi2 = 0.10, df = 2 (P = 0.95), I2 =0.0%

-10 -5 0 5 10

Favours Valerian FavoursBenzodiazepin

Analysis 2.2. Comparison 2 Valerian vs diazepam, Outcome 2 Reduction in anxiety symptoms (STAI-T).

Outcome: 2 Reduction in anxiety symptoms (STAI-T)

Study or subgroup Valerian Diazepam Mean Difference Weight Mean Difference

Andreatini 2002 12 52.7 (15.3) 12 41.3 (6.9) 100.0 % 11.40 [ 1.90, 20.90 ]

Total (95% CI) 12 12 100.0 % 11.40 [ 1.90, 20.90 ]Heterogeneity: not applicable

-100 -50 0 50 100

Favours Valerian Favours Benzodiazepi

Analysis 2.3. Comparison 2 Valerian vs diazepam, Outcome 3 Side effects.

Outcome: 3 Side effects

Study or subgroup Valerian Diazepam Risk Ratio Weight Risk Ratio

Andreatini 2002 0/12 1/12 100.0 % 0.33 [ 0.01, 7.45 ]

Total (95% CI) 12 12 100.0 % 0.33 [ 0.01, 7.45 ]Total events: 0 (Valerian), 1 (Diazepam)

0.1 0.2 0.5 1 2 5 10

Analysis 2.4. Comparison 2 Valerian vs diazepam, Outcome 4 Overall dropout.

Outcome: 4 Overall dropout

Study or subgroup Valerian Diazepam Risk Ratio Weight Risk Ratio

Andreatini 2002 2/12 2/12 100.0 % 1.00 [ 0.17, 5.98 ]

Total (95% CI) 12 12 100.0 % 1.00 [ 0.17, 5.98 ]Total events: 2 (Valerian), 2 (Diazepam)

0.1 0.2 0.5 1 2 5 10

W H A T ’ S N E W

Last assessed as up-to-date: 20 August 2006.

6 November 2008 Amended Converted to new review format.

H I S T O R Y

Protocol first published: Issue 4, 2003

Review first published: Issue 4, 2006

21 August 2006 New citation required and conclusions have changed Substantive amendment

C O N T R I B U T I O N S O F A U T H O R S

LSM - protocol writing, searching, trial selection, data extraction, completion of review.

ANA - protocol writing, expertise advice, completion of review.

BGOS - protocol writing, searching, trial selection, data extraction, completion of review.

D E C L A R A T I O N S O F I N T E R E S T

None known.

S O U R C E S O F S U P P O R T

Internal sources

• Brazilian Cochrane Centre, Brazil.

External sources

• No sources of support supplied

I N D E X T E R M S

Medical Subject Headings (MeSH)

∗Phytotherapy; ∗Valerian; Anti-Anxiety Agents [∗therapeutic use]; Anxiety Disorders [∗drug therapy]; Diazepam [therapeutic use];Pilot Projects

MeSH check words

Humans

valerian for anxiety disorders (review)

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