Valerian For Anxiety Disorders (Review)

Valerian for anxiety disorders (Review)
Miyasaka LS, Atallah N, Soares B
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2009, Issue 1 http://www.thecochranelibrary.com
Valerian for anxiety disorders (Review) Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.1. Comparison 1 Valerian vs placebo, Outcome 1 Reduction in anxiety symptoms (HAM-A). . Analysis 1.2. Comparison 1 Valerian vs placebo, Outcome 2 Reduction in anxiety symptoms (STAI-T). . Analysis 1.3. Comparison 1 Valerian vs placebo, Outcome 3 Side effects. . . . . . . . . . . . Analysis 1.4. Comparison 1 Valerian vs placebo, Outcome 4 Overall dropout. . . . . . . . . . . Analysis 2.1. Comparison 2 Valerian vs diazepam, Outcome 1 Reduction in anxiety symptoms (HAM-A). Analysis 2.2. Comparison 2 Valerian vs diazepam, Outcome 2 Reduction in anxiety symptoms (STAI-T). Analysis 2.3. Comparison 2 Valerian vs diazepam, Outcome 3 Side effects. . . . . . . . . . . . Analysis 2.4. Comparison 2 Valerian vs diazepam, Outcome 4 Overall dropout. . . . . . . . . . WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1 2 2 3 3 5 6 6 6 6 8 11 12 12 13 13 14 14 15 15 15 16 16 16 16 17
[Intervention Review]
Valerian for anxiety disorders

Lincoln Sakiara Miyasaka1 , lvaro N Atallah2 , Bernardo Soares1
1
Brazilian Cochrane Centre, So Paulo, Brazil. 2 Brazilian Cochrane Centre, Universidade Federal de So Paulo / Escola Paulista de Medicina, So Paulo, Brazil Contact address: Lincoln Sakiara Miyasaka, Brazilian Cochrane Centre, Universidade Federal de So Paulo, Rua de Pedro Toledo 598, Vila Clementino, So 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 N, Soares B. Valerian for anxiety disorders. Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD004515. DOI: 10.1002/14651858.CD004515.pub2. Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ABSTRACT Background Anxiety disorders are very common mental health problems in the general population and in primary care settings. Herbal medicines are 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 (CCDANCTR-Studies and CCDANCTR-References) searched on 04/08/2006, MEDLINE, Lilacs. References of all identied studies were inspected for additional studies. First authors of each included study, manufacturers of valerian products, and experts in the eld were 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 in which 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 using Cochrane Handbook criteria. For dichotomous outcomes, relative risk (RR) was calculated, and for continuous outcomes, the weighted mean difference (WMD) was calculated, with their respective 95% condence intervals.
Valerian for anxiety disorders (Review) Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 1
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 signicant differences between the valerian and placebo groups in HAM-A total scores, or in somatic and psychic factor scores. Similarly, there were no signicant differences in HAM-A scores between the valerian and diazepam groups, although based on STAI-Trait scores, signicantly greater symptom improvement was indicated in the diazepam group. There were no signicant 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 insufcient evidence to draw any conclusions about the efcacy or safety of valerian compared with placebo or diazepam for anxiety disorders. RCTs involving larger samples and comparing valerian with placebo or other interventions used to treat of anxiety disorders, such as antidepressants, are needed.
PLAIN LANGUAGE SUMMARY 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 side effects. Valerian is a phytotherapeutic medication frequently used for insomnia. The aim of this study was to investigate the efcacy and safety of valerian for anxiety disorders. Only one study was identied, involving 36 patients and comparing valerian with placebo and diazepam. This study found no signicant 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, additional studies with larger numbers of patients are necessary before drawing conclusions about the effectiveness and safety of valerian as a treatment option for anxiety disorders.
BACKGROUND
Anxiety disorders are a very common mental health problem in the general population and in the primary care setting. In the US National Comorbidity Survey Kessler 1994 found a one year prevalence for anxiety disorders of 17% and a lifetime prevalence of almost 25%. Using the Composite International Diagnostic Interview (CIDI) in 1996-99, Bijl 1998 included 7076 people in 90 municipalities in the Netherlands, and detected a prevalence rate for anxiety of 19.3% in the general population. In Brazil, the prevalence of anxiety was reported at 12.1% in Brasilia, 6.9% in So Paulo and 5.4% in Porto Alegre (Almeida-Filho 1997). One study has found a marked reduction in quality of life and psychosocial functioning in people with anxiety disorders (Mendlowicz 2000). Although anxiety is a treatable disorder, it is often not diagnosed and treated properly. The majority of patients suffering from anxiety consult their general practitioner, and often their complaint presents as a physical symptom, such as headache, palpitations, breathing difculties or chest pain (Walley 1994). Anxiety may be
associated with physical disorders such as diabetes, arthritis and cancer, or it may be the primary symptom of a specic psychiatric disorder such as generalized anxiety disorder, post-traumatic stress disorder, panic or obsessive compulsive disorder. Benzodiazepines are effective in short -term treatment but their overuse may cause dependence (Priest 1988). Psychotherapy is effective and is commonly used to treat anxiety (Borkovec 1987; Borkovec 1993; Taylor 1978; Taylor 1988). A systematic review on psychological therapies for generalised anxiety disorder has been conducted and is expected to be published soon in The Cochrane Library (Hunot 2006). Another systematic review has found that cognitive behavioural therapies and pharmacological treatments including buspirone, trazodone, imipramine and ritanserin significantly improved anxiety (Gould 1997). However, psychotherapy may be an unrealistic option in public health settings in many countries as it is costly and time consuming, and although pharmacological treatments are effective, they may be limited by their side effects and cost. Herbal medicines are in popular usage world2
wide, and could be considered as a treatment option for anxiety disorders if shown to be effective and secure. A systematic review on the effectiveness of kava kava showed its superiority as compared with placebo (Pittler 2002). No systematic review on valerian for anxiety has yet been conducted. Valerian is one of the most popularly used herbal medicines for insomnia (Donath 2000) and is also used for anxiety. It is used in the 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). Hydroalcoholic and aqueous extracts of valerian roots have shown afnity for the GABA-A receptor in the brains of rats (Mennini 1993). In another experiment, valerian oil injected intraperitoneally showed central depressive and muscle relaxation activity in mice (Hendriks 1981). Valepotriates are the most active principle of valerian, but are very labile and unlikely to be present in the nished preparations. In rats there is evidence of inhibition of motor activity, inhibition of aggressivity, prolongation of anaesthesia by hexobarbital (Petkov 1974), but with better motor coordination (Von Eickstedt 1969). In humans, valerian does not seem to potentiate the effect of alcohol, but demonstrates a positive action in tests of concentration and efciency (Mayer 1974), and has been successful in the treatment of insomnia and tension (Schmidt-Voigt 1986, Vorbach 1996, Leathwood 1985, Donath 2000; Stevinson 2000; Ziegler 2002). Although valerian has been used for a long time for treating anxiety disorders its efcacy and side effects are not yet fully established. This review aimed to examine the effectiveness and safety of anxiety disorders.
stress disorder), according to DSM-III or DSM-IV diagnostic criteria (APA 1987, APA 1994), irrespective of gender and ethnic background. Studies in which anxiety was a secondary symptom of a different disorder (for example, depression or any other psychiatric diagnoses) were excluded. Types of interventions Valerian (also called valepotriates or valerian extract), any dose, regime, or method of administration. Trials where valerian was used 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 outcome Effectiveness, measured using clinical outcome measures such as Hamilton Anxiety Scale (HAM-A) (Hamilton 1959) and other scales 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
OBJECTIVES
To investigate the effectiveness and safety of valerian for treating anxiety disorders.
METHODS
Criteria for considering studies for this review Search methods for identication of studies
Types of studies Randomised and quasi-randomised controlled trials. Electronic databases The Cochrane Collaboration Depression, Anxiety and Neurosis Cochrane Controlled Trials Register was searched using the following strategy CCDANCTR-Studies - searched on 04/08/2006 Intervention = valerian CCDANCTR-References - searched on 04/08/2006 Freetext = valerian* OR valepotriate. Lilacs (2005) and MEDLINE (2005) were searched using standard phrases for controlled trials and for anxiety disorders associated to valerian OR valepotriate.
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Types of participants People aged 16 and over, with a primary diagnosis of anxiety disorders or anxiety neurosis or chronic anxiety status, or any other disorder in which anxiety was the primary symptom (generalised anxiety disorder, panic disorder, obsessive compulsive disorder, social phobia, agoraphobia, other types of phobia, post-traumatic
There were no restrictions related to language or date of publication of the studies. Handsearches The references of all identied studies were inspected for additional studies. Personal communication The rst author of each included study was contacted for information regarding unpublished trials and additional data when necessary. The manufacturers of valerian products in Brazil and experts in the eld were also contacted for information regarding unpublished trials.
Data collection and analysis

Selection of trials Two review authors (LSM and BGOS) independently selected the trials found through the search strategy, extracted the data, assessed trial quality, and analysed results. Where any disagreements occurred, the third review author (ANA) was consulted, and if consensus was not yet reached, data were not included in the review until the author of the trial was able to provide clarication on the question posed. Data extraction Review authors screened the abstracts of all publications obtained by the search strategy and considered eligible in fullling the inclusion criteria. Data concerning participant characteristics, intervention details and outcome measures from the included studies were extracted independently using a standard extraction form with the following items: (a) General information: published or not, title, authors, contact address, country, resource, publication idiom, publication year, duplication of publishing, sponsor. (b) Characteristics of the study: design, length, whether randomised 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 randomised and analysed subjects, sex, age, basic characteristics, diagnostic criteria, length of disease and similarity of groups on the basic characteristics (including any co-morbidity), assessment on complications, sub-groups. (e) Outcomes: Those specied in the section on Types of outcomes, any other outcome assessed, other events, extension of attendance, and quality of related outcomes. (f ) Results: outcomes and evaluation time (including the evaluative measure), where necessary converted to the measurement of the effects specied below; intention to treat analysis. Quality assessment Methodological quality of the trials included in this review was assessed 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 concealment and potential for bias in the results (Schulz 1995). The categories for 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 included if they met criteria A or B. Additionally, a cut-off of two points on the Jadad scale was used to check the assessment made by the Handbook criteria (Jadad 1996). However, the Jadad scale was not used to exclude trials in this review. Measures of treatment effect Dichotomous outcomes Dichotomous outcomes were reported for each included trial by calculating relative risks (RR) with the uncertainty in each result being expressed through 95% condence intervals (CI), using the xed effect model. When further studies become available, dichotomous data from individual trials will be combined in a metaanalysis, with the estimates of RR based on the random effects model, as it takes into account any between study differences, even if there is no statistically signicant heterogeneity, and gives the same result as the xed effects model when there is no between study variance. Where overall results are signicant, the number needed to treat (NNT) or number needed to harm (NNH) to produce one outcome will be calculated. Continuous outcomes Continuous outcomes were reported for each included trial according to the difference between groups in the mean treatment effect and its standard deviation, using the xed effect model. When multiple outcome measures were described in a single study, for the purposes of pooling results, a single best available outcome measure was chosen according to the authors specication as the principal outcome or what was reported rst. When further studies become available, continuous outcomes in individual studies will be combined by calculating the weighted mean difference (WMD) (where the same scale is used to measure an outcome in a comparison) or the standardised mean difference (SMD) (where different scales are used to measure the same outcome in a comparison), together with 95%CIs. Information on missing data was claried through contact with the authors. Methods for future updates of the review The following methods will be used when further studies are included in the review: Assessment of heterogeneity Heterogeneity in the results of trials will be assessed both by inspection of graphical presentations and by calculating a formal Chi-square test of heterogeneity, with heterogeneity assumed to be present when the signicance level is smaller than 0.10 (p < 0.10). Subgroup analysis and investigation of heterogeneity Where signicant heterogeneity is present, an attempt will be made
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to explain the differences based on the clinical characteristics of the included studies. Potential sources of heterogeneity may be sample differences, diagnostic criteria or differences in medication dosage. Sensitivity analysis Sensitivity analysis will be performed excluding quasi-randomised studies. Assessment of reporting bias A funnel plot will be produced to investigate the possibility of publication bias.
shown for continuous outcomes. It has not yet been possible to contact the authors for further information. The study by Maisenbacher 1992 was excluded because it did not use an RCT design. McCutcheon 1996 was excluded because nine phytotherapeutic preparations were used. The study by Panijel 1985 was excluded because valerian was combined with hypericum for comparison with diazepam. The study by Bourin 1997 was excluded because it used a combination of six extracts. Finally, Cerny 1998 was excluded because healthy volunteers were used. Awaiting assessment There are no studies currently awaiting assessment.
RESULTS
Risk of bias in included studies

Allocation The study by Andreatini 2002 carried out the randomisation procedure using a computer program. Whether the allocation was concealed or not was unclear, therefore it was classied as B, in accordance with Cochrane Handbook criteria. Blindness The study by Andreatini 2002 was a double blind RCT. Maintenance of the double-blind procedure was tested for patients and researchers. Dropouts The overall dropout rate for Andreatini 2002 was 14%, with two dropouts reported for valepotriates (valerian), two for placebo and one for diazepam. Missing data for dropouts was managed through use of last observation carried forward (LOCF).
Description of studies
See: Characteristics of included studies; Characteristics of excluded studies. Results of the search The electronic searches identied one reference in Lilacs, two references in MEDLINE, and ve references in CCDANCTR-Studies. Of the eight studies identied, only one was eligible for inclusion in the review (Andreatini 2002). Manufacturers of valerian in Brazil (Nikkho, Solnay Farma, Barrenne, Fontovit, Pharmaton/Boehringer Ingelhein, Catarinense) were contacted asking for unpublished trials, but no further studies were found. Included studies The study by Andreatini 2002 was a pilot study, using a randomised controlled design, which compared valepotriates (valerian) with diazepam and placebo. The trial duration was four weeks. The sample consisted of 36 participants with a diagnosis of generalised anxiety disorder, according to DSM-III criteria. The mean age of the sample was 41 years, and 21 of the participants were female. The majority of participants presented with secondary disorders. Andreatini 2002 used a clinician-rated scale, the HAM-A, and a self-report scale, the STAI-Trait, to measure anxiety symptoms. HAM-A scores were reported for the overall total score, together with a psychic factor (including anxious mood, tension, fears, concentration disturbances) and somatic factor (including insomnia, respiratory and cardiovascular symptoms). Excluded studies Seven studies were excluded from the review (see also Table of excluded studies). The study by Delsignore 1992 was excluded from the review because the results were poorly presented, and could not be re-analysed (SDs were not presented for continuous outcomes). Similarly, the study by Rabezzana 1995 was excluded because SDs were not
Effects of interventions
As described above, only one study was included in the review (Andreatini 2002), a double-blind randomised controlled trial comparing valepotriates (valerian) with diazepam and placebo. 1. VALERIAN vs PLACEBO Effectiveness Based on the HAM-A scale overall score at post-treatment, no signicant difference in symptom reduction was noted between valerian and placebo (WMD -1.40, 95%CI -7.93 to 5.13). Similarly, no signicant differences in symptom reduction were noted between valerian and placebo for the HAM-A somatic factor (WMD 0.40, 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 mean scores (WMD 0.70, 95% CI -9.93, 11.33). Side effects No side effects were reported by any patients in the valerian group, and were reported by one person in the placebo group. The patients complaint was somnolence. Dropout
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There was no signicant difference in dropout rate between valerian and placebo groups. 2. VALERIAN vs DIAZEPAM Effectiveness Based on the HAM-A scale total score at post-treatment, no significant difference in symptom reduction was noted between valerian and diazepam (WMD 0.40, 95% CI -6.22 to 7.02). Similarly, no signicant differences in symptom reduction were noted between valerian 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 had signicantly lower STAI-Trait mean scores at post-treatment than the valerian group (WMD 11.40, 95% CI 1.90, 20.90). Side effects No side effects were reported by patients in the valerian group, and were reported by one person in the diazepam group. The patients complaint was somnolence. Dropout There was no signicant difference in dropout rate between the valerian and diazepam groups.
to valerian in reducing self-report anxiety symptoms, based on the STAI-Trait scale. Side effect proles were similar for valerian and diazepam. In view of the lack of available data, on the basis of the current evidence, it is unclear whether or not valerian is effective and safe when compared with placebo, or when compared with diazepam, in the treatment of anxiety disorders. Further efforts will be made to obtain missing data from studies that are currently unable to contribute to the review (Delsignore 1992, Rabezzana 1995).
AUTHORS CONCLUSIONS Implications for practice

Since only one study is included in this review, there is insufcient evidence to draw any conclusions on the efcacy or safety of valerian in comparison to placebo or diazepam for anxiety disorders.
Implications for research

Randomised controlled trials are needed involving larger samples and comparing valerian to placebo and other available interventions, such as antidepressants, for the treatment of anxiety disorders.
DISCUSSION
Only one small pilot study with 36 patients was eligible for inclusion in this review (Andreatini 2002). This study compared the efcacy of valerian with placebo and with diazepam, and each group consisted of 12 patients. The reduction in clinician-rated anxiety symptoms at post-treatment, based on the HAM-A scale, was similar for the three groups. Diazepam appeared to be superior
ACKNOWLEDGEMENTS
The staff of the Brazilian Cochrane Centre for their interest in solving daily doubts, and facilitating access to Cochrane data.
REFERENCES
References to studies included in this review

Andreatini 2002 {published data only} Andreatini R, Sartori VA, Seabra MLV, Leite JR. Effect of valepotriates (valerian extract) in Generalised Anxiety Disorder: a randomised placebo-controlled pilot study. Phytotherapy Research 2002;16:6504.
Delsignore 1992 {published data only} Delsignore R, Orlando S, Costi D, Baroni MC, Butturini U. Clinical comparative evaluation of a stabilized valeriana extract and placebo [Avaliao clinica comparativa com placebo de um extrato estabilizado de valeriana]. A Folha Medica 1992;104(5):191196. Maisenbacher 1992 {published data only} Maisenbacher J, Podzuweit H. Valerian and Melissa - Mild Psychopharmaceuticals. Therapiewoche 1992;42(37):21402144. McCutcheon 1996 {published data only} McCutcheon LE. Treatment of anxiety with a homeopathic remedy. Journal of Applied Nutrition 1996;48(1,2):15. Panijel 1985 {published data only} Panijel M. Treatment of moderately severe anxiety states. Therapiewoche 1985;41:465968. Rabezzana 1995 {published data only} Rabezzana G. Tratamento dei disturbi dansia de grado lieve e medio con prodotti a base naturale: valutazione dellefcacia e
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References to studies excluded from this review

Bourin 1997 {published data only} Bourin M, Bougerol T, Guitton B, Broutin E. A combination of plant extracts in the treatment of outpatients with adjustment disorder with anxious mood: controlled study versus placebo. Fundamental and Clinical Pharmacology 1997;11(2):12732. Cerny 1998 {published data only} Cerny A, Schmid K. Tolerability and efcacy of valerian/lemon balm in healthy volunteers ( a double-blind placebo controlled multicentre study). Fitoterapia 1999;70:2218.
tollerabilit del Sedatol. Riv It Biol Med 1995;15:126133.
Additional references
Almeida-Filho 1997 Almeida-Filho N, Mari JJ, Coutinho E, Franca JF, Fernandes J, Andreoli SB, et al.Brazilian multicentric study of psychiatric morbidity: Methodological features and prevalence estimates. British Journal of Psychiatry 1997;171:5249. APA 1987 American Psychiatric Association. Diagnostic and statistical manual of mental disorders (DSM-III-R). 3rd Edition. Washington DC: American Psychiatric Association, 1987. APA 1994 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). 4th Edition. Washington, DC: American Psychiatric Association, 1994. BHMA 1992 British Herbal Medicine Association. British Herbal Compendium Vol. 1. Bournemouth: British Herbal Medicine Association, 1992. Bijl 1998 Bijl RV, Ravelli A, van Zessen G. Prevalence of psychiatric disorder in the general population: Results of the Netherland Mental Health Survey and Incidence Study (NEMESIS). Social Psychiatry & Psychiatric Epidemiology 1998;33(12):58795. Borkovec 1987 Borkovec TD, Mathews AM, Chambers AM, Ebrahimi S, Lytle R, Nelson R, et al.The effects of relaxation training with cognitive or nondirective therapy and the role of relaxation-induced anxiety in the treatment of generalized anxiety disorder. Journal of Consulting & Clinical Psychology 1987;55(6):8838. Borkovec 1993 Borkovec TD, Costello E. Efcacy of applied relaxation and cognitive behavioral therapy in the treatment of generalized anxiety disorder. Journal of Consulting & Clinical Psychology 1993;61(4): 6119. Clarke 2000 Clarke M, Oxman AD. Cochrane Collaboration Handbook. Oxford: Update Software, 2000. Donath 2000 Donath F, Quispe S, Diefenbach K, Maurer A, Fietze I, Roots I. Critical evaluation of the effect of valerian extract on sleep structure and sleep quality. Pharmacopsychiatry 2000;33(2):4753. Gould 1997 Gould RA, Otto MW, Pollack MH, Yap L. Cognitive behavioural and pharmacological treatment of generalized anxiety disorders: Preliminary meta-analysis. Behavior Therapy 1997;28(2):285305. Hamilton 1959 Hamilton M. The assessment of anxiety states by rating. British Journal of Medical Psychology 1959;32:505. Hendriks 1981 Hendriks H, Bos R, Allersma DP, Malingre TM, Koster AS. Pharmacological screening of valerenal and some other components of essential oil of Valeriana ofcinalis. Planta Medica 1981;42(1): 628.
Hunot 2006 Hunot V, Churchill R, Silva de Lima M, Teixeira V. Psychological therapies for generalised anxiety disorder. Cochrane Library 2006, Issue 4.[Art. No.: CD001848. DOI: 10.1002/ 14651858.CD001848.pub4] Jadad 1996 Jadad AR, Moore RA, Carrol D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al.Assessing the quality of reports of randomized clinical trials: is blinding necessary?. Controlled Clinical Trials 1996;17(1):112. Kessler 1994 Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S, et al.Lifetime and 12 month prevalence of DSM III-R psychiatric disorders in United States. Archives of General Psychiatry 1994;51(1):819. Leathwood 1985 Leathwood PD, Chauffard F. Aqueous extract of valerian reduces latency to fall asleep in man. Planta Medica 1985;51(2):1448. Mayer 1974 Mayer B, Springer E. Psychoexperimental studies on the effect of a valepotriate combination as well as the combined effects of valtratum and alcohol [Psyschoexperimentelle untersuchungen zur wirking einer Valepotriatkombination sowie zur Kombinierten wirkung von Valtratum und Alkohol]. Arzneimittel-Forschung 1974;24(12):206670. Mendlowicz 2000 Mendlowicz MV, Stein MB. Quality of life in individuals with anxiety disorders. American Journal of Psychiatry 2000;157(6): 66982. Mennini 1993 Mennini T, Bernasconi P, Bombardelli E, Morazzoni P. In vitro study on the interaction of extracts and pure compounds from Valeriana ofcinalis roots with GABA, benzodiazepine and barbiturate receptors in rat brain. Fitoterapia 1993;64(4):291300. Petkov 1974 Petkov VD, Manolov PN, Marekov NL, Popov SS, Handjieva NB. Pharmacological studies on a mixture of valepotrietes isolated from Valeriana ofcinalis. Doklady Bolgarskoi Akademii Nauk 1974;27: 100710. Pittler 2002 Pittler MH, Ernst E. Kava extract for treating anxiety. Cochrane Library 2002, Issue 3. Priest 1988 Priest RG, Montgomery SA, Priest RG, Montgomery SA. Benzodiazepines and dependance: a college statement. Bulletin of the Royal College of Psychiatrists 1988;12:10708. Schmidt-Voigt 1986 Schmidt-Voigt J. Treatment of nervous sleep disorders and unrest with a sedative of purely vegetable origin [Die Behandlung nervoser schfstorungen und innerer unruhe mit einem rein panzlichen sedativum]. Therapiewoche 1986;36(7):6637. Schulz 1995 Schulz KF, Chalmers I, Haves RJ, Altman DG. Empirical evidence of bias: Dimension of methodological quality associated with
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estimates of treatment effects in controlled trials. JAMA 1995;273 (5):40812. Stevinson 2000 Stevinson C, Ernst E. Valerian for insomnia: a systematic review of randomized clinical trials. Sleep Medicine 2000;1(2):919. Taylor 1978 Taylor CB. In: Agras WS editor(s). Relaxation training and related techniques in behavioural modications: Principles and clinical applications. Boston, MA: Little Brown, 1978. Taylor 1988 Taylor CB, Arnow B. The nature and the treatment of anxiety disorders. New York, NY: Free Press, 1988. Von Eickstedt 1969 Von Eickstedt KW, Rahman S. Psychopharmacologic effect of valepotriates [Psychopharmakologische wirkungen von valepotriaten]. Arzneimittel-Forschung 1969;19(3):3169. Vorbach 1996 Vorbach EU, Gortelmeyer R, Bruning J. Therapy of insomnia. The efcacy and tolerability of valerian [Therapie von Insomnien. Wirksamkeit und Vertraglichkeit eines Baldrianpraparats]. Psychopharmakotherapie 1996;3(3):10915. Walley 1994 Walley EJ, Beebe DK, Clark JL. Management of common anxiety disorders. American Family Physician 1994;50(8):174553. Ziegler 2002 Ziegler G, Ploch M, Miettinen-Baumann A, Collet W. Efcacy and tolerability of valerian extract LI 156 compared with oxazepam in the treatment of non-organic insomnia, a randomized double blind comparative clinical study. European Journal of Medical Research 2002;7(11):4806. Indicates the major publication for the study
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]

Andreatini 2002 Methods Allocation: randomised (computer program) Blindness: unclear Design: parallel Duration: 4 weeks Analysis: non ITT So Paulo, Brazil N=36 Diagnosis: GAD (DSM-III-R) Gender: 21 females Age: mean of 41 years Setting: ambulatory History: most of patients presented an associated clinical disease 1. Valerian 81,3 mg/day (N=12) 2. Diazepam 6,5 mg/day (N=12) 3. Placebo (N=12) HAM-A (LOCF) STAI (LOCF) Side-effects Dropouts
Participants
Interventions
Outcomes
Notes Risk of bias Item Allocation concealment? Authors judgement Unclear Description B - Unclear
HAM-A - Hamilton Anxiety Scale LOCF - Last Observartion Carried Forward STAI - State-trait Anxiety Inventory
Characteristics of excluded studies [ordered by study ID]
Bourin 1997 Cerny 1998
Used a combination of six extracts. Allocation: randomised Participants: 98 healthy volunteers Interventions: (1) Valeriana/lemon balm; (2) placebo ; 30 days Outcomes: sleep quality. Allocation: randomised Participants: 40 subjects with minor anxiety symptomatology and emotional tension disturbances Interventions: (1) Valeriana 50 mg 3x day; (2) placebo 3x day; 21 days Outcomes: clinical outcomes not available for meta-analysis. Continuous data (HAM-A) without SD. Allocation: not randomised Participants: 2395 subjects with acute or subacute psychophysical ill-health Interventions: (1) Valeriana and Melissa; (2) placebo; 4 weeks Outcomes: clinical outcomes not available for meta-analysis. Allocation: randomised Participants: 72 subjects with minor anxiety symptomatology and emotional tension disturbances Interventions: (1) Valeriana and other 8 homeophatic remedies; (2) placebo ; 15 days Outcomes: . STAI trait and state, Mean, SD. Valerian combined with hypericum for comparison with diazepam. Standard deviations were not shown for continuous outcomes.
Delsignore 1992
Maisenbacher 1992
McCutcheon 1996
Panijel 1985 Rabezzana 1995
10
DATA AND ANALYSES
Comparison 1. Valerian vs placebo

No. of studies 1 1 1 1 1 1 1 1 24 24 24 24 No. of participants
Outcome or subgroup title 1 Reduction in anxiety symptoms (HAM-A) 1.1 total score 1.2 somatic factor 1.3 psychic factor 2 Reduction in anxiety symptoms (STAI-T) 3 Side effects 3.1 Somnolence 4 Overall dropout
Statistical method Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)
Effect size Subtotals only -1.40 [-7.93, 5.13] 0.40 [-3.12, 3.92] -1.80 [-6.22, 2.62] 0.70 [-9.93, 11.33] Subtotals only 0.33 [0.01, 7.45] 1.0 [0.17, 5.98]
24 24
Comparison 2. Valerian vs diazepam

No. of studies 1 1 1 1 1 1 1 24 24 24 24 24 24 No. of participants
Outcome or subgroup title 1 Reduction in anxiety symptoms (HAM-A) 1.1 total score 1.2 somatic factor 1.3 psychic factor 2 Reduction in anxiety symptoms (STAI-T) 3 Side effects 4 Overall dropout
Statistical method Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)
Effect size Subtotals only 0.40 [-6.22, 7.02] -0.20 [-2.93, 2.53] 0.60 [-3.82, 5.02] 11.40 [1.90, 20.90] 0.33 [0.01, 7.45] 1.0 [0.17, 5.98]
11
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 N Mean(SD)
Placebo N Mean(SD)
Mean Difference IV,Fixed,95% CI
Weight
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)

Heterogeneity: not applicable
12
12
100.0 %
-1.40 [ -7.93, 5.13 ]
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 ]
Test for overall effect: Z = 0.22 (P = 0.82) 3 psychic factor Andreatini 2002 12 9.7 (6) 12 11.5 (5) 100.0 % -1.80 [ -6.22, 2.62 ]
Subtotal (95% CI)

12
12
100.0 %
-1.80 [ -6.22, 2.62 ]
Test for overall effect: Z = 0.80 (P = 0.42) Test for subgroup differences: Chi2 = 0.65, df = 2 (P = 0.72), I2 =0.0%
-10
-5
10
Favours Valerian
Favours placebo
Analysis 1.2. Comparison 1 Valerian vs placebo, Outcome 2 Reduction in anxiety symptoms (STAI-T).
Comparison: 1 Valerian vs placebo Outcome: 2 Reduction in anxiety symptoms (STAI-T)
Study or subgroup
Valerian N Mean(SD) 52.7 (15.3)
Placebo N 12 Mean(SD) 52 (10.9)
Weight
Andreatini 2002
12
100.0 %
0.70 [ -9.93, 11.33 ]
Total (95% CI)

12
12
100.0 %
0.70 [ -9.93, 11.33 ]
Test for overall effect: Z = 0.13 (P = 0.90)
-10
-5
10
Favours Valerian
Favours placebo
12
Analysis 1.3. Comparison 1 Valerian vs placebo, Outcome 3 Side effects.

Comparison: 1 Valerian vs placebo Outcome: 3 Side effects
Study or subgroup
Valerian n/N
Placebo n/N
Risk Ratio M-H,Fixed,95% CI
Weight
1 Somnolence Andreatini 2002 0/12 1/12 100.0 % 0.33 [ 0.01, 7.45 ]
0.1 0.2
0.5
10
Favours Valerian
Favours placebo
Analysis 1.4. Comparison 1 Valerian vs placebo, Outcome 4 Overall dropout.

Comparison: 1 Valerian vs placebo Outcome: 4 Overall dropout
Study or subgroup
Valerian n/N
Placebo n/N 2/12
Weight
Andreatini 2002
2/12
100.0 %
1.00 [ 0.17, 5.98 ]
Total (95% CI)

Total events: 2 (Valerian), 2 (Placebo) Heterogeneity: not applicable
12
12
100.0 %
1.00 [ 0.17, 5.98 ]
0.1 0.2
0.5
10
Favours Valerian
Favours placebo
13
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 N Mean(SD)
Diazepam N Mean(SD)
Weight
1 total score Andreatini 2002 12 14.6 (9.8) 12 14.2 (6.4) 100.0 % 0.40 [ -6.22, 7.02 ]
Subtotal (95% CI)

12
12
100.0 %
0.40 [ -6.22, 7.02 ]
Test for overall effect: Z = 0.12 (P = 0.91) 2 somatic factor Andreatini 2002 12 4.9 (4.3) 12 5.1 (2.2) 100.0 % -0.20 [ -2.93, 2.53 ]
Subtotal (95% CI)

12
12
100.0 %
-0.20 [ -2.93, 2.53 ]
Test for overall effect: Z = 0.14 (P = 0.89) 3 psychic factor Andreatini 2002 12 9.7 (6) 12 9.1 (5) 100.0 % 0.60 [ -3.82, 5.02 ]
Subtotal (95% CI)

12
12
100.0 %
0.60 [ -3.82, 5.02 ]
Test for overall effect: Z = 0.27 (P = 0.79) Test for subgroup differences: Chi2 = 0.10, df = 2 (P = 0.95), I2 =0.0%
-10
-5
10
Favours Valerian
FavoursBenzodiazepin
Analysis 2.2. Comparison 2 Valerian vs diazepam, Outcome 2 Reduction in anxiety symptoms (STAI-T).
Comparison: 2 Valerian vs diazepam Outcome: 2 Reduction in anxiety symptoms (STAI-T)
Study or subgroup
Valerian N Mean(SD) 52.7 (15.3)
Diazepam N 12 Mean(SD) 41.3 (6.9)
Weight
Andreatini 2002
12
100.0 %
11.40 [ 1.90, 20.90 ]
Total (95% CI)

12
12
100.0 %
11.40 [ 1.90, 20.90 ]
-100
-50
50
100
Favours Valerian
Favours Benzodiazepi
14
Analysis 2.3. Comparison 2 Valerian vs diazepam, Outcome 3 Side effects.

Comparison: 2 Valerian vs diazepam Outcome: 3 Side effects
Study or subgroup
Valerian n/N
Diazepam n/N 1/12
Weight
Andreatini 2002
0/12
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) Test for overall effect: Z = 0.69 (P = 0.49)
0.1 0.2
0.5
10
Favours Valerian
Analysis 2.4. Comparison 2 Valerian vs diazepam, Outcome 4 Overall dropout.

Comparison: 2 Valerian vs diazepam Outcome: 4 Overall dropout
Study or subgroup
Valerian n/N
Diazepam n/N 2/12
Weight
Andreatini 2002
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) Test for overall effect: Z = 0.0 (P = 1.0)
0.1 0.2
0.5
10
Favours Valerian
15
WHATS NEW
Last assessed as up-to-date: 20 August 2006.
6 November 2008
Amended
Converted to new review format.
HISTORY
Protocol rst published: Issue 4, 2003 Review rst published: Issue 4, 2006
21 August 2006
New citation required and conclusions have changed
Substantive amendment
CONTRIBUTIONS OF AUTHORS
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.
DECLARATIONS OF INTEREST
None known.
SOURCES OF SUPPORT Internal sources

Brazilian Cochrane Centre, Brazil.
16
External sources
No sources of support supplied
INDEX TERMS Medical Subject Headings (MeSH)
Phytotherapy; Valerian; Anti-Anxiety Agents [ therapeutic use]; Anxiety Disorders [ drug therapy]; Diazepam [therapeutic use]; Pilot Projects
MeSH check words

Humans
17

Valerian For Anxiety Disorders (Review)

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Valerian For Anxiety Disorders (Review)

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Valerian for anxiety disorders (Review)

Miyasaka LS, Atallah N, Soares B

Valerian for anxiety disorders

Data collection and analysis

Risk of bias in included studies

AUTHORS CONCLUSIONS Implications for practice

Implications for research

References to studies included in this review

References to studies excluded from this review

tollerabilit del Sedatol. Riv It Biol Med 1995;15:126133.

Characteristics of included studies [ordered by study ID]

Characteristics of excluded studies [ordered by study ID]

Bourin 1997 Cerny 1998

Panijel 1985 Rabezzana 1995

DATA AND ANALYSES

Comparison 1. Valerian vs placebo

Comparison 2. Valerian vs diazepam

Comparison: 1 Valerian vs placebo Outcome: 1 Reduction in anxiety symptoms (HAM-A)

Mean Difference IV,Fixed,95% CI

Mean Difference IV,Fixed,95% CI

Subtotal (95% CI)

-1.40 [ -7.93, 5.13 ]

Subtotal (95% CI)

0.40 [ -3.12, 3.92 ]

Subtotal (95% CI)

-1.80 [ -6.22, 2.62 ]

Comparison: 1 Valerian vs placebo Outcome: 2 Reduction in anxiety symptoms (STAI-T)

Valerian N Mean(SD) 52.7 (15.3)

Placebo N 12 Mean(SD) 52 (10.9)

Mean Difference IV,Fixed,95% CI

Mean Difference IV,Fixed,95% CI

0.70 [ -9.93, 11.33 ]

Total (95% CI)

0.70 [ -9.93, 11.33 ]

Test for overall effect: Z = 0.13 (P = 0.90)

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

Comparison: 1 Valerian vs placebo Outcome: 3 Side effects

Risk Ratio M-H,Fixed,95% CI

Risk Ratio M-H,Fixed,95% CI

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

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

Comparison: 1 Valerian vs placebo Outcome: 4 Overall dropout

Placebo n/N 2/12

Risk Ratio M-H,Fixed,95% CI

Risk Ratio M-H,Fixed,95% CI

1.00 [ 0.17, 5.98 ]

Total (95% CI)

1.00 [ 0.17, 5.98 ]

Test for overall effect: Z = 0.0 (P = 1.0)

Comparison: 2 Valerian vs diazepam Outcome: 1 Reduction in anxiety symptoms (HAM-A)

Mean Difference IV,Fixed,95% CI

Mean Difference IV,Fixed,95% CI

Subtotal (95% CI)

0.40 [ -6.22, 7.02 ]

Subtotal (95% CI)

-0.20 [ -2.93, 2.53 ]

Subtotal (95% CI)

0.60 [ -3.82, 5.02 ]

Comparison: 2 Valerian vs diazepam Outcome: 2 Reduction in anxiety symptoms (STAI-T)

Valerian N Mean(SD) 52.7 (15.3)

Diazepam N 12 Mean(SD) 41.3 (6.9)

Mean Difference IV,Fixed,95% CI