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Sleep Medicine Reviews (2007) 11, 209–230

www.elsevier.com/locate/smrv CLINICAL REVIEW A systematic review of as a aid: Safe but not effective

Diana M. Taibia,Ã, Carol A. Landisb, Heidi Petryc, Michael V. Vitiellod aWomen’s Health Nursing Research Training Grant, Department of Family and Child Nursing, University of Washington, Box 357262, Seattle, WA 98195-7262, USA bBiobehavioral Nursing and Health Systems, University of Washington, Box 357266, Seattle, WA 98195-7266, USA cUniversity of Washington Bothell, 18115 Campus Way NE, Box 358532, Bothell, WA 98011, USA dPsychiatry and Behavioral Sciences, and Biobehavioral Nursing and Health Systems, University of Washington, Box 356560, Seattle, WA 98195-6560, USA

KEYWORDS Summary Valerian is an that is widely available in a variety of commercial Valerian; preparations and is commonly used as a sleep aid. A recent systematic review and Sleep; meta-analysis of valerian concluded that evidence in support of the effectiveness of Complementary the herb was inconclusive. Therefore, in an effort to more closely examine this issue, therapies; a systematic review was conducted to examine the evidence on the efficacy of Herbal therapies; valerian as a sleep aid with specific attention to the type of preparations tested and the characteristics of the subjects studied. A comprehensive search of studies investigating valerian was conducted through computerized databases and hand searches of reference lists. Standardized forms were used to summarize findings and standardized criteria were used to assess study quality. Out of 592 articles initially identified, a total of 36 articles describing 37 separate studies met criteria for review: 29 controlled trials evaluated for both efficacy and safety, and eight open- label trials evaluated for safety only. Most studies found no significant differences between valerian and either in healthy individuals or in persons with general sleep disturbance or insomnia. None of the most recent studies, which were also the most methodologically rigorous, found significant effects of valerian on sleep. Overall, the evidence, while supporting that valerian is a safe herb associated with only rare adverse events, does not support the clinical efficacy of valerian as a sleep aid for insomnia. & 2007 Published by Elsevier Ltd.

Introduction ÃCorresponding author. Tel.: +1 206 543 3906; fax: +1 206 543 6656. Approximately one-third of the adults in the United E-mail address: [email protected] (D.M. Taibi). States report symptoms of insomnia; including

1087-0792/$ - see front matter & 2007 Published by Elsevier Ltd. doi:10.1016/j.smrv.2007.03.002 ARTICLE IN PRESS

210 D.M. Taibi et al. difficulty falling and/or remaining asleep at night.1 which further research on valerian effects on sleep Herbal therapies are commonly used for chronic might be useful. symptoms of disturbed sleep. According to a recent survey, approximately 1.6 million Americans use complementary and alternative medical (CAM) therapies to treat their sleep disturbance.2 Valerian Materials and methods is among the top-selling herbals in the US and is marketed as a promoter of restful sleep. In 2005, The search strategy sought to obtain all relevant valerian was the 13th top-selling herb in US with published data-based articles based on the follow- estimated sales totaling $3.4 million.3 ing general criteria: (1) valerian root was adminis- A previous systematic review4 and a recent meta- tered orally, either alone or in combination with analysis5 both concluded that effects of valerian on hops, lemon balm, or passion flower ( com- sleep were promising, but inconclusive. Previous monly combined with valerian in commercial reviews have discussed various types of valerian preparations); and (2) a subjective or objective products without specific attention to important sleep measure (e.g., or actigra- differences in source species and in preparation phy) was at least one of the study’s primary techniques used (e.g., and water versus outcomes. A systematic computerized search extractions with water alone). Because the chemi- of research databases was performed using cal constituents in valerian products vary depend- the following keywords (where * is a wildcard): ing on species and extraction methods,6,7 failure valerian*, valerenic, valepotriate*, and baldrian to evaluate the evidence based on the type of (‘‘valerian’’ in German). Databases included in the product used may have obscured an accurate search were Pubmed, the Cochrane Central Regis- assessment of valerian effects on sleep. The species ter of Controlled Trials, EMBASE, PsychINFO, used most commonly is Valeriana officinalis, CINAHL, International Pharmaceutical Abstracts, although V. edulis (Mexican valerian) and V. wall- and Dissertation Abstracts. The search was limited ichii (Indian valerian) are also used therapeutically. to clinical trials in the databases that In general, extractions are prepared by soaking the allowed this specification (Pubmed, Cochrane, dried root and rhizome (the underground portion of and EMBASE). Reference lists from relevant arti- the stem) of valerian in a solution (called a cles, reviews, and book chapters were hand- menstruum), then centrifuging or drying the mix- searched to identify additional studies. The search ture to extract and concentrate plant constituents. was not limited by language because numerous The solutions used are typically: water alone, studies have been conducted in Europe, particu- ethanol and water, or and water. The larly in Germany, and reported in German-language ratio of to water affects the proportion of journals.9 In order to obtain the widest range of constituents obtained. According to the American evidence on valerian, included studies were not Herbal Pharmacopeia, extraction of valerenic acids limited to randomized clinical trials (RCTs), but requires at least 30% alcohol, whereas extraction of only relevant full reports were evaluated (abstracts valepotriates requires 70% alcohol.7 The influence were excluded). Additionally, to fully explore the of extraction on the physiological effects of evidence on the effects of valerian, valerian remains unknown because the relative studies of healthy persons without reported sleep contributions of constituents responsible for to the disturbance were included. plant’s sedative effects have not been determined, Data were extracted onto standardized forms. and effects may depend on synergy of various A quality score based on the likelihood of bias was compounds (e.g., valerenic acids, amino acids, given to each study using the Jadad scoring system. valepotriates).8 In this system, studies are scored 0 (poor) to 5 In this review, we evaluate the research evidence (good) based on descriptions of randomization, on valerian as a sleep aid taking into account the double-blind methods, and reporting of drop- types of products used. In addition, we considered outs.10 Methodological features were also reviewed whether the subjects in these studies were healthy, using the criteria of Stevinson and Ernst,4 with the complained of general sleep disturbance, or met added criterion that adequate methods of blinding diagnostic criteria for insomnia: Diagnostic and required masking of odor as well as appearance. Statistical Manual of Mental Disorders (DSM-III/IV); These criteria included reporting of design ele- International Classification of (ICD-9/10); ments of the study (e.g., randomization and or International Classification of Sleep Disorders blinding, effect size or power estimates); potential (ICSD). Finally, we make a recommendation about sources of bias and error (e.g., control of pre- its usefulness as a sleep aid and clarify areas in variables); and measures to mask the ARTICLE IN PRESS

Valerian as a sleep aid 211 strong, distinctive odor unique to valerian. Studies exclusion criteria; duration of treatment; prepara- were only assigned a point in the Jadad score for tion used (valerian species and extraction meth- adequate description of blinding if both odor and ods); dose given; dose timing (multiple daily doses appearance were addressed. versus bedtime only); and outcomes measured. Of the 37 included studies, 29 were clinical trials and 8 were open-label studies of clinical use. In the 29 clinical trials (see Table 1), the Results following preparations were tested: (a) valerian mono-preparations (without other herbs, 20 stu- Study characteristics and valerian products dies)11,13,17,21,25–27,29–39; (b) valerian with hops used (6 studies),15,22,24,40,41 of which one also investi- gated a mono-preparation39; (c) valerian with 16,23,42 The computerized search yielded 592 article titles lemon balm (3 studies) ; and (d) valerian with 43 that were reviewed for relevance (see Fig. 1); 527 both hops and lemon balm (1 study). Eight open 44 articles were excluded based on a review of the label trials tested: (a) valerian alone (1 study) ; 19,45 abstracts and 29 were excluded based on a review (b) with hops (2 studies) ; (c) with hops and 14,18,28 of the full text. These 556 articles were excluded lemon balm (3 studies) ; and (d) with hops and 12,20 for the following reasons: the articles (a) were not passion flower (2 studies). Open-label trials are clinical studies (418 articles); (b) did not assess discussed in regard to the safety and tolerability of sleep as a primary outcome (65); (c) tested multi- the herb(s) but not for efficacy. ple herbs (other than hops, lemon balm, or passion In this review, studies are grouped by extraction flower) (6); (d) did not test an oral preparation of type to allow for comparison of effects among valerian (2); (e) were pediatric studies (2); (f) were preparations that are most likely to contain similar not related to valerian at all (55); (g) were proportions of the various active constituents of abstracts or incomplete reports (6); or (h) used a valerian. study design that did not permit assessment of valerian effects (2). Thirty-six articles describing 37 studies of valer- Ethanolic valerian extracts ian (one article reported two studies)11 for sleep in adults met criteria for inclusion in the review. Eight studies investigated ethanolic-aqueous Seventeen studies were published in German.12–28 V. officinalis extracts (see Table 2). All of these 34 The German was translated into English and data studies except one tested valerian in persons who extraction was checked against the articles in reported at least mild sleep disturbance, and most the original language by one of the co-authors studies based inclusion on clinical diagnostic (H, Petry), whose first language is German. criteria for insomnia. Although some of the studies There was pronounced heterogeneity of study reported the proportions of the sample with design, especially in regard to: sample inclusion and different types of insomnia symptoms (e.g., , sleep maintenance, or both), none of the studies analyzed the outcomes based on the

Initial search: specific insomnia symptom. Compared to the 592 titles literature on other types of valerian preparations, studies of ethanolic extracts used the most rigorous standards for recruiting participants with primary insomnia (see Table 1). However, only three studies Excluded: 556 Included: 36 from abstract or title- 527 (describing 37 studies) reported excluding persons with other primary from full article- 29 sleep disturbances (e.g., , periodic limb movement disorder, restless legs).13,33,34 The commercial preparation of valerian most s Not clinical trial- 418 Trials: 28 commonly studied is LI 156 (Sedonium ), an Not addressing sleep- 65 (describing 29 trials) ethanolic extraction of V. officinalis (70% ethanol Unrelated to valerian- 55 Ethanolic- 8 Not full report- 6 Aqueous- 6 (7 trials) used for extraction). All six studies of this product Multiple herbs- 6 Valepotriate- 5 tested 300–600 mg prior to bedtime (see Table 2). Not oral administration- 2 Combination- 9 Excessively biased- 2 Only two of these studies measured polysomno- Pediatric- 2 Open-label: 8 graphic (PSG) sleep outcomes.30,33 In a double- blind randomized crossover trial, Diaper and Figure 1 Search results. Hindmarch30 compared two doses (300 and ARTICLE IN PRESS

212 D.M. Taibi et al. within 14 days) affecting sleep + (4 weeks) Psychiatric problems required, allowed months) Medical conditions Other P: 55% 4.7 V: 62% + 55) (14 days) – 8.7 V: 51% + + + 9.0 P: 65% 12.0 O: 61% (4 weeks) 12.6 P: 61% (past 3 10 K: 80% 11.1 P: 55% 10 P: 88% 12.4 V: 77% + + + + 11 V: 62% + + + (no use 12.3 V: 73% + + + 10 V: 79% 7 15 All: 54% + + + 7 7 7 7 7 7 7 7 7 7 7 7 NR NR V: 42.7 P: 40.5 K: 41.1 Insomnia, V: 50.6 Insomnia, V: 47.2 Insomnia,ICD-10 criteria P*: 42.3 V*: 40.8 (no sleep problem required) Insomnia, V: 54.2 Reported difficulty with sleep onset or maintenance within 2 weeks ICSD criteria (range: 22 ICD-10 criteria O: 53.9 ICD-10 criteria P: 47.6 ICD-10 criteria O: 50.6 36 ) 60 placebo) 51 placebo) 16166 Mild sleep complaints All: 55.9 General volunteers 93 oxazepam) 121 kava, 135 placebo) 39 30 (1982); (1999) 102 (51 valerian, 46 (1996) 121 (61 valerian, (2003) 21 Diagnosed insomnia All: 54 34 (2000) 16 Insomnia, All, Median: 49 All: 75% + + + + (2002) 186 (93 valerian, (2003) 391 (135 valerian, 17 31 33 32 29 Sample characteristics of valerian studies. (2000) 75 (39 valerian, 13 Aqueous V. officinalis extracts Leathwood et al. Jacobs et al. Donath et al. Leathwood and Chauffard Ethanolic V. officinalis extracts Vorbach et al. Table 1 Study, year Sample size Sleep condition Age Female Exclusions (2004) (1982/1983) Dorn Ziegler et al. Kuhlmann et al. Coxeter et al. Diaper and Hindmarch ARTICLE IN PRESS

Valerian as a sleep aid 213 + withdrawn disturbance required + BZD use- All: 50% All: 50% All: 45% + 27 All: 50% 68 All: 57% + – – 6.5 All: 100% + + + (14 days) 89) 8.1 A: 70% + + – 10.6 All: 80% + + Required 13.6 All: 80% + + 89) P: 51% – 9.7 D: 60% 7 12.5 3.9 P: 74% 10.2 P: 60% 11.6, NR + + 4.4 V: 76% Behavioral 10.5 V: 59% + + + + 7 7.8 All: 70% + 3.2 All: 0% 7 7 7 7 7 7 7 7 7 7 7 44) 26) 38) – – – All: 29 All: 32.5 (range: 22 All: 22.6 (range: 21 V: 78.4(range 62 P: 78.8 (67 V: 61% All, range: 22 All*: 57.6 All, range: 19 V: 70.6 All: 26.1 (range: 20 P: 69.4 Insomnia, All: 43.3 Insomnia, V: 45.4 (no sleep problem required) disturbance disturbance Not specified, elder home residents disturbance insomnia Diagnosed sleep disturbance Elder home residents, behavioral sleep disturbance required Insomnia, All: 50.3 Mild insomnia, V: 43.9 DSM-IV criteria, chronic BZD use; healthy controls and general nervous conditions ICSD criteria P: 47.6 DSM-III-R criteria DSM-IV criteria DSM-IV orICSD criteria D: P: 43.8 45.2 18 controls 7 placebo) 20 Insomnia, All: 45 1010 General volunteers 88 Healthy, no sleep Healthy, no sleep Sleep onset problems All: 45 (SD NR) All: 37% 76 placebo) 12 Self-reported sleep 9 placebo) 39 placebo) 23 ) 65 placebo, 60 ) 39 38 (1984) 11 Sleep disturbance (1988) 46 (23 valerian, 11 11 (1984) 78 (39 valerian, 25 (1982); (1988) 15 (8 valerian, 15 `ly `ly 21 46 24 (1983) 20 (11 valerian, (2002) 19 patients, (1994) 14 Elderly, insomnia All: 61.6 (2000) 30 Mild to moderate (2005) 184 (59 valerian, 26 35 (1977) 37 41 40 22 (1977) 150 (74 valerian, (2001) 27 36 ¨ller-Limmroth and ¨ssel et al. Balderer and Borbe Leathwood and Chauffard Gessner et al. High-valepotriate preparations Jansen Herrera-Arellano et al. Leathwood and Chauffard Leathwood et al. (1982/1983) (1985) (1985) (1985) Schulz et al. Kamm-Kohl et al. Rodenbeck et al. Morin et al. Gessner and Klasser Combination preparations: valerian andMu hops Ehrenstein Schmitz and Jackel Poyares et al. Balderer and Borbe Fu ARTICLE IN PRESS

214 D.M. Taibi et al. Medication affecting sleep Psychiatric problems Medical conditions Other sleep disorder : ICD, International Classification of Diseases; DSM, Diagnostic and Statistical All: 30% V:26%++++ P: 29% 5.9 All: 50% + + 11.7 P: 37% 12.5 V: 42% + + + 7 7 7 86.8) 81.4) – – 68) – All: 37.2 V: 59.0 (range 31.2 V: 33.4 All: 54 (range 25 P: 54.2 (range 22.1 P: 34.8 Insomnia diagnostic guides healthy Insomnia, DSM-III or ICD-10 criteria No reported sleep problems and 24 placebo) 32 placebo) 27 Sleep disturbance 43 (1999) 98 (66 valerian, ) 42 (1992)(1996) 20 49 (25 valerian, Not specified, 23 16 continued SD calculated from information given in the article. NR, not reported. 7 et al. Manual; ICSD, International Classification of Sleep Disorders. Table 1 ( Study, year Sample(1989) size Sleep condition Age*Mean Female Exclusions Combination preparations: valerian andLindahl lemon and balm Lindwall Cerny and Schmid Dressing et al. ARTICLE IN PRESS

Valerian as a sleep aid 215 1) ¼ 29), 1) 6) 36) ¼ 1), GI 2), ¼ 2), ¼ ¼ ¼ ¼ ¼ 2), oxazepam 3) ¼ ¼ oxazepam (n Withdrawals related to treatment: valerian (n (n effects: valerian (n AE: valerian (n oxazepam (n AE related to valerian: headache (n complaints (n AE differences between treatments not significant, no serious AE Adverse effects Significantly greater incidence of diarrhea with valerian AE differences between treatments not significant AE related to valerian: headache (n morning hangover (n SQ; no significant SQ; no significant m difference between valerian and oxazepam m difference between valerian and oxazepam No significant difference from placebo from placebo Main valerian sleep outcomes from placebo from placebo from placebo sleep questionnaire (VAS ratings) Outcome measures duration 28 nights ISI No significant difference (b) Placebo (b) Oxazepam 10 mg (b) Oxazepam 10 mg (b) Placebo (b) Kava kava, 100 mg, (c) Placebo (a) Valerian 450 mg 7 nights Sleep diaries No significant difference (b) Placebo (b) Placebo Study design Intervention Treatment design* sleep disturbance No PDB, RCT (a) Valerian 600 mg 14 nights VIS-M, VIS-A No significant difference (1996) Yes PDB, RCT (a) Valerian 600 mg 28 nights SF-B No significant difference (2003) Yes PDB, n-of-1 34 (2000) Yes PDB, RCT, C/O (a) Valerian 600 mg 14 nights PSG, sleep diary, (2002) Yes DB, RCT (a) Valerian 600 mg 42 nights SF-B Valerian versus baseline: (2003) Yes PDB, RCT (a) Valerian, 6.4 mg 17 31 33 32 29 Studies of valerian for sleep. (2000) Yes DB, RCT (a) Valerian 600 mg 28 nights SF-B Valerian versus baseline: 13 Coxeter et al. Dorn Ziegler et al. Donath et al. Table 2 Study, year Sample with (1999) Ethanolic extracts Vorbach et al. Jacobs et al. Kuhlmann et al. ARTICLE IN PRESS

216 D.M. Taibi et al. 2), placebo 11), valerian 4), placebo ¼ ¼ ¼ 2) 8) ¼ ¼ (n AE possibly related to treatments: valerian 300 mg (n 600 mg (n (n Not mentioned No residual morning sleepness with 900 mg dose, no other AE No residual sedation Adverse effects Dizziness (4 total): valerian (n No residual sedation No AE occurred Not mentioned SL, both k placebo 4 WASO and SL, both Sleep disturbance, from placebo No significant difference from placebo Valerian versus placebo: greater proportions reported improved SQ and SL Valerian versus placebo:doses Significantly greater SR: No significant difference from placebo from placebo Main valerian sleep outcomes Valerian versus placebo: greater proportions reported improved SL and sleep maintenance Valerian versus placebo: k doses (statistical testing NR) k valerian Valerian versus placebo: PSG: significance NR SR: No significant difference from placebo questionnaire improvement ratings questionnaire quality (VAS) Outcome measures questionnaire rating scales diaries, SF-A, SF- B duration 14 nights Sleep 30 nights 4-point symptom 8 nights PSG, sleep hops – 8; – (b) Placebo (Likert scales) (b) Valerian 600 mg (c) Placebo (c) Placebo (b) Placebo (b) Valerian 400 mg (c) Placebo (b) Valerian 900 mg : (b) Placebo 3x/d (c) Placebo (b) Placebo valepotriates 3x/d 1215 mg on night 1, 405 mg 3x/d days 2 (b) Placebo Study design Intervention Treatment C/O (b) Valerian 900 mg Yes PDB, RCT, C/O (a) Valerian 300 mg 1 night PSG, LSEQ No significant difference NoNo PC, C/O PDB, RCT, C/O (a) Valerian 800 mg (a) 2 Valerian nights 400 mg 3 nights PSG, sleep Yes SQ and SL PDB, RCT, C/O (a) Valerian 450 mg 4 nights Actigraphy, sleep YesNo PDB, CCTNo (a) PDB, Valerian CCT, 90 mg PDB, RCT, C/O (a) Valerian 450 mg (a) Valerian 1 900 mg night 1 night Sleep diary, sleep PSG No significant difference sleep disturbance 11 11 ) `ly `ly 21 46 46 (1994) Yes PDB, RCT (a) Valerian, (2004) 37 (1982/ (1982/ (1985) 30 39 39 38 (1977) No PDB, RCT (a) Valerian, 100 mg continued 27 Balderer and Borbe Aqueous extracts Leathwood et al. Schulz et al. 1983) 1983) Leathwood et al. Kamm-Kohl et al. Leathwood and Chauffard Table 2 ( (1982); Leathwood and Chauffard (1982); Leathwood and Chauffard (1984) (1985) (1985) Diaper and Hindmarch Study, year Sample with Balderer and Borbe Valepotriate preparations Jansen ARTICLE IN PRESS

Valerian as a sleep aid 217 3GI ¼ 2) ¼ 1), blind); PDB: (n ¼ (n bad with V. edulis V. officinalis No hangover symptoms AE with valerian (n complaints) k valerian. No other significant AE differences between treatments m leep quality; SR, self-report; VAS, SL SR: m SL number of k k Stage 4 with WASO, k k SQ and SR: No significant difference from placebo V. edulis awakenings. No significant difference between valerian preparations PSG: 120 mg versus placebo Valerian versus placebo: PSG: SQ Valerian versus placebo: m VAS questionnaires diaries, sleep quality (VAS) A , SF-B 1 night PSG, sleep 15 nights PSG, sleep 9 nights VIS-M, VIS-A, SF- : AE, adverse event; NR, not reported; PSG, polysomnography; SF-A, Gortelmeyer Schlaffragebogen , 120 mg 450 mg 1 night PSG, sleepiness Versus baseline: Dyspepsia (3 total): ,60mg , 240 mg V. officinalis V. edulis V. wallichii V. edulis, V. edulis, V. edulis Outcome measures valepotriates (c) Placebo (b) 450 mg valepotriates (b) 100 mg valepotriates 3x/d (b) Placebo valepotriates (b) Placebo Morgen (a standardized set of visual analog scales of sleep completed in the morning); WASO, wake after sleep onset. – : CCT: controlled clinical trial (non-randomized); C/O: crossover; DB: double-blind (no placebo condition); PC: placebo-controlled (not double- Yes DB, RCT, C/O (a) Yes PDB, RCT, C/O (a) M, Visualanalogskala – 25 (1983) Yes PDB, CCT, C/O, (a) (2002) Yes PDB, RCT (a) 26 35 (2001) 36 Herrera-Arellano et al. Poyares et al. Gessner et al. (1984) visual analog scale; VIS Study design abbreviations A, assesses sleep quality for the past night; SF-B, Gortelmeyer Schlaffragebogen B, assesses sleep quality for the two weeks; SL, sleep latency; SQ, s placebo-controlled double blind; RCT: randomized clinical trial. Gessner and Klasser ARTICLE IN PRESS

218 D.M. Taibi et al.

600 mg) of LI 156 to a placebo after one night in a methods (a within-subject repeated crossover de- sample of persons with mild sleep complaints. No sign) to test a high-ethanol (96%) extraction of significant differences were found on PSG or valerian.31 Because this product used an ethanol subjective sleep outcomes (sleep efficiency, sleep concentration over 70% for extraction, the product latency, awakenings, sleep stages, and sleep contained significant amounts of valepotriates quality ratings). Another double-blind randomized (valtrate) as well as valerenic acid. Each partici- crossover study tested 600 mg LI 156 for 14 nights in pant was tested for six one-week periods (three persons with insomnia.33 In the valerian group, valerian, three placebo) in random order. Treat- percent slow wave sleep (SWS, NREM Stages 3 and 4 ment was considered a success or failure within which are considered deep sleep) was increased each individual based on whether the individual compared to baseline. No differences between improved during the weeks of valerian compared to valerian and placebo were found in other PSG the weeks of placebo treatment. The analyses outcomes or subjective sleep quality ratings. showed valerian to be equivalent to placebo The other four double-blinded studies of LI 156 on subjective outcomes of sleep quality, sleep measured only subjective outcomes. Parallel-group latency, awakenings, total sleep time, and morning randomized controlled trials (RCTs) compared refreshment. repeated dosing of valerian versus placebo in In sum, ethanolic extracts of V. officinalis, healthy individuals for 14 days34 or in persons with several of which were investigated using rigorous insomnia for 28 days.17 Subjective sleep quality study designs, have not been shown to significantly ratings improved in the valerian groups of both affect objective30,33 or subjective17,29,31,33,34 sleep studies, but in neither case was sleep significantly outcomes in comparison to placebo in subjects with improved when compared to placebo. Lack of and without insomnia. However, these preparations significance in the healthy sample34 may have have been shown to improve subjective sleep resulted from a ceiling effect. One of these quality ratings in a manner equivalent to benzo- studies,34 as well as two other RCTs,13,32 compared diazepines under the assumption that the benzo- LI 156 (600 mg dose) to (flunitra- diazepines tested were superior to placebo.13,32 zepam and oxazepam). In these studies, the effectiveness of the benzodiazepines was assumed, and comparable effects of valerian and benzodia- Aqueous valerian extracts zepines were presumed to confirm the effective- ness of valerian. Kuhlmann et al.34 reported Seven studies (reported in six publications) inves- reduced subjective sleep latency and increased tigated the effects of aqueous V. officinalis extracts sleep quality ratings with both valerian and (water alone is used for extraction) on sleep (see flunitrazepam compared to placebo after a single Table 2). These studies varied greatly in methodo- night in a sample of healthy persons, but did not logical quality, and several of the trials did not report the statistical significance of these findings. report randomization to treatment procedures. All Two other studies compared valerian and oxazepam of these studies reported using a double-blind for four weeks13 or six weeks32 in persons with design except for one.39 Four of these studies were insomnia. The studies reported significant improve- conducted in general volunteers who were not ment of subjective sleep quality ratings compared required to complain of a sleep disturbance,11,39,46 to baseline with both valerian and oxazepam. one in persons with sleep onset difficulties,38 and Improvement did not significantly differ between two in elderly persons with sleep disturbance.21,37 the treatments, indicating that the effects of None of the studies used insomnia diagnostic valerian were equivalent to oxazepam. criteria as inclusion criteria, and none reported Two studies investigated ethanolic valerian ex- exclusion of persons with primary sleep disorders tracts other than LI 156. In a double-blind RCT, (see Table 1). Only one study excluded medical Jacobs et al.29 compared 28 days of valerian conditions that could contribute to sleep distur- extract (PureWorld Botanicals, 70% ethanolic ex- bance37 and only two excluded concurrent use of tract), kava kava extract, or placebo in persons sleep-altering .21,37 with both sleep disturbance and anxiety. Insomnia Two parallel-group clinical trials investigated a severity index (ISI) scores, subjective sleep latency, commercially available aqueous valerian extract and subjective awakenings were reduced with all (Valdisperts) in elderly individuals with insomnia. three treatments, but the magnitude of improve- In a randomized trial, Schulz et al.37 investigated ment was greatest in the placebo group and neither 405 mg valerian extract or placebo given three of the herbal treatments differed significantly from times a day for eight days to elderly participants placebo. Another double-blind study used n-of-one with sleep onset and sleep maintenance problems. 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Valerian as a sleep aid 219

Objective (PSG) and subjective sleep outcomes In this double-blind crossover trial by Leathwood (sleep efficiency, wake after sleep onset (WASO), and Chauffard38 each of three treatment conditions sleep quality rating) did not differ significantly (450 mg valerian, 900 mg valerian, Dixa S.A., between valerian and placebo after one dose, but Switzerland, or placebo) was given randomly over no statistical comparison of valerian and placebo is 12 weeknights to individuals with difficulty falling reported at the end of treatment (after eight asleep (recruited from the research staff and nights). Another trial of elderly persons with sleep families), with the participants undergoing four disturbances, Kamm-Kohl et al.21 investigated nights per treatment condition. Both doses sig- 90 mg of Valdisperts or placebo three times daily nificantly reduced actigraphic sleep latency com- for 14 days. When asked whether their sleep onset pared to the placebo. Subjective sleep latency and and maintenance difficulties improved, signifi- sleep quality ratings did not differ significantly cantly greater proportions of persons on valerian from the placebo. Morning sleepiness was signifi- reported that these conditions were ‘‘better’’ cantly greater with the 900 mg valerian dose than (versus ‘‘the same or worse’’) after treatment than the placebo, suggesting dose-dependent effects. those on placebo. In sum, studies testing the effects of aqueous Several studies investigated a specific aqueous valerian extracts produced mixed results. In older valerian extract (Dixa S.A., Switzerland) in general persons with sleep disturbance, one study reported volunteers (only one of these studies required sleep that a significant proportion of the sample reported disturbance for enrollment).38 An early randomized ‘‘better’’ sleep,21 whereas another study did not crossover trial by Leathwood and colleagues46 show significant effects on either objective or measured subjective sleep in general volunteers subjective sleep outcomes.37 Short-term supple- (no exclusions noted) with 400 mg aqueous valerian mentation (one to four nights) of valerian was not extract (Dixa S.A., Switzerland) or placebo taken shown to affect PSG11,39 or subjective sleep out- on two nights each in random order (a 400 mg comes11,38,39 in subjects without known sleep valerian/hops extract was also tested, discussed complaints, but valerian did reduce subjective later). A significantly greater proportion of persons sleep latency and WASO with sleep onset insom- rated their sleep quality as ‘‘better than usual’’ and nia.38 The findings of these studies of aqueous sleep latency as ‘‘shorter than usual’’ when given valerian extracts cannot be generalized to persons valerian than when given placebo. Improved sleep diagnosed with insomnia because this type of was more pronounced in the sub-sample of persons product has not been rigorously tested in clinic reporting habitually poor sleep. In a double-blind populations. crossover trial (randomization not reported), Bal- derer and Borbe`ly11 investigated 450 and 900 mg of valerian extract (Dixa S.A., Switzerland) in 10 Valepotriate preparations healthy young persons. One night of valerian significantly decreased subjective sleep latency Five studies investigated valerian extractions stan- and WASO but not sleep quality ratings compared dardized on valepotriate content (see Table 2). This to the placebo. Two studies measured PSG sleep constituent is minimally present in the V. officinalis outcomes. In a small crossover trial, Leathwood and species or extractions from this species. However, colleagues39,46 investigated the effects of two valepotriates are present in significant levels in nights of valerian extract (400 mg, Dixa S.A., other Valeriana species (V. edulis and V. wallichii) Switzerland) on the sleep of 10 young, healthy and are believed to be largely responsible for men. No significant differences between the purported clinical effects of preparations from valerian and placebo were found on PSG sleep these species. The studies of valepotriates varied measures (total sleep time, % sleep stages). In in the products used, samples studied, and timing another crossover trial, Balderer and Borbe`ly11 of administration (e.g., several times/day and/or tested two doses (450 and 900 mg) of the same at bedtime). Information on valerian extraction extract (Dixa S.A., Switzerland) for one night of method was only available from one study.36 As each dose (or placebo) in eight healthy young with the studies of aqueous extracts, none of the persons. Neither PSG nor subjective sleep outcomes studies used insomnia diagnostic criteria for inclu- (sleep latency, awakenings, WASO, time in sleep sion (see Table 2). One study excluded subjects stages) differed significantly between valerian for primary sleep disorders (other than insomnia),35 and the placebo. Finally, one study measured two excluded subjects for co-morbid sleep objective sleep using actigraphs (wrist-worn move- disturbance,25,35 and three excluded subjects for ment detectors that can discriminate waking from current use of sleep-altering medications26,35,36 sleep behavior) in addition to subjective outcomes. (see Table 1). ARTICLE IN PRESS

220 D.M. Taibi et al.

Three studies investigated extracts of V. edulis significantly improved sleep quality ratings in species. Herrera-Arellano and colleagues36 com- persons withdrawing from benzodiazepines35 and pared two types of valerian extracts, V. edulis persons reporting disturbed sleep.25 One of these (high-valepotriate, 450 mg, 62% ethanol extraction) studies also reported reduced awakening versus and V. officinalis (high-valerenic acid, 450 mg, baseline but used no placebo control.36 These information on extraction method not available) findings suggest that valepotriate preparations in a double-blind crossover study of persons with may mildly reduce sleep disturbances. Like aqueous diagnosed insomnia. There were no significant valerian preparations, high-valepotriate prepara- differences between the two species on any PSG tions have not been rigorously tested in persons outcome (sleep latency, sleep efficiency, sleep diagnosed with insomnia and extrapolation from stages), but the overall effects of either prepara- the few studies available suggests such efficacy tion are uncertain because the study did not would be limited. include a placebo group. Two of the studies were placebo-controlled, double-blind crossover trials (Gessner and Klasser; Gessner et al.)25,26 and Valerian combination preparations investigated the effects of V. edulis (Harmonicum Muchs) on sleep in persons with general sleep Many of the valerian products commercially avail- disturbance. In one study26 that assessed only able are combinations with other herbs including subjective sleep outcomes, nine nights of valerian hops, lemon balm, and/or passion flower, all of (standardized to contain 120 mg valepotriates) which purportedly have their own sedating or significantly improved subjective sleep quality tranquilizing effects. It is possible that these ratings and reduced subjective sleep latency combinations produce synergy and thus are more compared to placebo. In the other study, which effective than each of these component herbs assessed the effects of 60 or 120 mg valepotriates alone. Controlled studies have investigated only on PSG outcomes,25 one night of valerian signifi- combinations of valerian with hops and/or lemon cantly reduced Stage 4 sleep in comparison to balm. Most of these studies were in persons with placebo. Neither dose significantly affected other insomnia15,24,40,41 or those with a general com- PSG outcomes. plaint of sleep disturbance,22,43 although three Two other studies tested a preparation standar- studies recruited healthy persons without requiring dized to valepotriate content. One study tested the sleep disturbance.16,23,42 The specificity of exclu- effects of a V. wallichii extract (Valmanes)on sion criteria was thorough in some studies, but not rebound sleep disturbances in persons with insom- in others (see Table 1). Only two of 10 studies nia following gradual cessation of chronic benzo- reported screening for primary sleep disorders diazepine use.35 In this double-blind, placebo- other than insomnia as well as medical conditions controlled RCT, a 100 mg dose of valepotriates affecting sleep, psychiatric problems, and medica- was given three times daily for 15 days. Subjective tions affecting sleep.23,40 Most of the other studies sleep quality ratings improved significantly with screened for some but not all of these criteria, but valerian compared to the placebo. PSG outcomes two studies did not report screening for any of showed reduced WASO. A significant and substantial these criteria. reduction in sleep latency occurred with placebo Six studies investigated valerian–hops combina- but not with valerian. The authors suggested that tions (see Table 3). Three studies investigated the this may have been related to individual differ- effects of the valerian–hops combination ZE 91019 ences in withdrawal from benzodiazepines. In a (Allunas, methanolic-aqueous extract, % alcohol placebo-controlled, double-blind RCT, geriatric proprietary) on sleep. Two of these studies were clinic patients were given 100 mg valepotriates double-blind, placebo-controlled RCTs that com- (species and preparation not reported) three times pared four weeks of ZE 91019 (500 mg valerian/ daily for 30 days.27 When asked to rate whether 120 mg hops24; 374 mg valerian/82 mg hops)40 to their sleep disturbance was better, the same, or placebo in persons with insomnia (ICD or DSM-IV worse, both the valepotriate and placebo groups criteria). In these two studies, neither PSG out- reported improvement. Improvement was greater comes24,40 nor subjective outcomes (sleep effi- in the valepotriate group, but no statistical ciency, sleep latency, ISI scores)40 improved or were comparisons were reported. substantially different between valerian–hops Overall, the literature on valepotriate prepara- and placebo. In a one-group study of persons tions provides limited evidence that valepotriates with mild to moderate insomnia, Fu¨ssel et al.41 may improve sleep, but these studies are highly reported reduced sleep latency and increased varied. Compared to placebo, studies reported sleep efficiency measured by PSG with ZE 91019 ARTICLE IN PRESS

Valerian as a sleep aid 221 1) ¼ 1), ¼ No AE occurred No AE occurred No withdrawal symptoms Stomach complaint: valerian (n bromazepam (n No residual effects, serious AEs, or rebound insomnia No significant group difference in AEs Not mentioned Not mentioned No rebound effects occurred No residual sedation hops SE – m SQ; no SQ m m hops versus hops versus wake, – – k SL, baseline: k Valerian 400 mg versus 4 mg: Greater proportion reported baseline: significant difference between valerian and bromazepam Valerian hops versus diphenhydramine or placebo: no significant difference from placebo from placebo from placebo Main sleep outcomes Adverse effects and placebo No significant difference between valerian 75) ¼ n point scale) sleep questionnaire (ISI); PSG ( Outcome measures questionnaire 1 night Sleep quality (4- 14 nights SF-A, SF-B Valerian 1 night PSG No significant difference 28 nights PSG No significant difference 1 night PSG No significant difference 28 nights Sleep diaries, duration lemon balm lemon balm – – hops hops 400 mg hops 200 mg/ hops 240 mg/ hops 500 mg/ hops lemon balm hops 374 mg/ – – – – – – – – hops 500 mg/120 mg 14 nights PSG Valerian – (b) Valerian 4 mg/375 mg/160 mg 400 mg/375 mg/160 mg (b) Bromazepam 3 mg 45 mg (b) Diphenhydramine 50 mg (c) Placebo Valerian (a) Valerian 400 mg (b) Placebo (b) Placebo 120 mg (b) 0.125 mg (c) Placebo 160 mg/80 mg 82 mg (b) Valerian (c) Placebo post-test Experimental sleep disturbance by traffic noise Study design Intervention Treatment Yes PDB, CCT, C/O, sleep disturbance No PDB, RCT, C/O (a) Valerian 400 mg 3 nights Sleep 39 (1989) Yes DB, RCT, C/O (a) Valerian (1998) Yes DB, RCT (a) Valerian 43 (1982); (1998) Yes PDB, RCT (a) Valerian 15 46 24 (1992) No PDB, RCT, C/O (a) Valerian (2000) Yes One-group, pre- 23 (2005) Yes PDB, RCT (a) Valerian (1977) Studies of valerian combination products for sleep. 41 40 22 Dressing et al. Fussel et al. Valerian and lemon balm Lindahl and Lindwall Morin et al. Leathwood et al. Leathwood and Chauffard Schmitz and Jackel Rodenbeck et al. Table 3 Study, year Sample with (1982/1983) Valerian and Hops Muller-Limmroth and Ehrenstein ARTICLE IN PRESS

222 D.M. Taibi et al. 1) ¼ : AE, 5), placebo (n ¼ significant group difference in AEs No hangover, rebound, or withdrawals. AE: Valerian/lemon balm (n Outcome measures elmeyer Schlaffragebogen B, SL, k Morgen (a standardized set of visual – lemon balm – SQ Valerian versus placebo: No serious AE, no difference. A greater proportion reported SQ improvement versus placebo: m Main sleep outcomes Adverse effects M, Visualanalogskala – VAS, SQ improvement ratings Outcome measures 30 nights Sleep quality 14 nights VIS-M, SF-B Valerian duration lemon balm lemon balm – – (b) placebo 360 mg/240 mg (b) Placebo VAS: No significant 320 mg/160 mg 2x/d Study design Intervention Treatment sleep disturbance : C/O, crossover, DB, double-blind (no placebo condition); PDB, placebo-controlled double blind; RCT, randomized clinical trial. (1999) No PDB, RCT (a) Valerian ) 42 (1996) Yes PDB, RCT (a) Valerian 16 continued Cerny and Schmid Table 3 ( Study design abbreviations Study, year Sample with adverse event; NR, notassesses reported; sleep PSG, quality for polysomnography; theanalog SF-A, two scales Gortelmeyer weeks; of Schlaffragebogen SL, sleep sleep A, completed latency; assesses in SQ, sleep the sleep quality quality; morning). SR, for self-report; the VAS, past visual analog night; scale; SF-B, VIS Gort Dressing et al. ARTICLE IN PRESS

Valerian as a sleep aid 223

(500 mg valerian/120 mg hops) compared to base- of persons with sleep disturbance, a significantly line measurements. greater proportion of participants reported that Two other studies investigated the valerian–hops their sleep quality was ‘‘perfect’’ after one night of combination Hovas (information on extraction a valerian–hops–lemon balm combination (400 mg method not available).15,46 In the previously de- valerian/375 mg hops/160 mg lemon balm, infor- scribed randomized crossover trial by Leathwood mation on extraction method not available; Valeri- and Chauffard,46 three random nights of Hovas ana natts) than a night of hops–lemon balm (400 mg, proportions of valerian/hops not re- alone.43 ported) did not improve sleep in comparison to a In summary, in subjects with insomnia, placebo- placebo in healthy persons. In a double-blind RCT of controlled studies of valerian–hops combinations persons with insomnia, sleep quality ratings im- did not improve PSG or subjective sleep out- proved significantly with both Hovas (200 mg comes,24,40 but a valerian–lemon balm combination valerian/45 mg hops) and the bro- reduced subjective sleep latency and increased mazepam (3 mg).15 The two treatments did not subjective sleep quality.16 A one-group trial significantly differ, although only small improve- of valerian–hops reported improved sleep com- ment was seen with either treatment. Finally, pared to baseline,41 and another trial of in a double-blind controlled clinical trial, Mu¨ller- valerian–hops reported improvement of sleep Limmroth and colleagues22 investigated whether or quality ratings that was similar to improvement not a valerian–hops combination (240 mg valerian/ with a benzodiazepine.15 Neither of the two 400 mg hops, Seda-Kneipps) would attenuate sleep studies of valerian–lemon balm in healthy indivi- disturbances experimentally induced by traffic duals showed significantly improved sleep.16,42 noise. No significant differences were found be- Overall, these findings are similar to results of tween valerian–hops and placebo on the PSG studies of valerian alone. These mixed, but outcomes. predominantly negative, findings concerning the Valerian–lemon balm (also called lemon melissa) effects of valerian combinations on sleep outcomes combinations were investigated in four clinical indicate that combination products are no more trials; two tested the herbal combination in healthy effective than valerian alone; that is to say not persons and two recruited persons with sleep effective at all. disturbance (see Table 3). In a double-blind RCT of healthy persons, 30 nights of a valerian–lemon balm combination (360 mg valerian, 70% ethanol extraction/240 mg lemon balm, 30% methanol Side effects and safety extraction, Songha Nights) had no effect on sleep quality ratings on a 0–100 visual analog scale (VAS) No serious adverse effects occurred in these compared to a placebo.42 However, a significantly reported clinical trials of valerian (see Tables 2 greater proportion of those on valerian–lemon balm and 3). The number of side effects with ethanolic than those on placebo (33% versus 9%) reported valerian extracts did not differ significantly from that their sleep quality was ‘‘better’’ (versus placebo,31,34 and tended to be fewer than benzo- ‘‘unchanged’’ or ‘‘worse’’) even though the VAS diazepines.13,32 Specific side effects reported with ratings did not reflect this change. Another double- ethanolic valerian extracts included headache, blind study of healthy persons investigated the gastrointestinal (GI) complaints, morning ‘‘hang- effects of one night of the valerian–lemon balm over,’’ diarrhea, drowsiness, exaggerated feeling of combination (160 mg valerian, 70% ethanol extrac- well-being, mental dullness, difficulty sleeping, tion/80 mg lemon balm, 30% ethanol extraction; depression, , dizziness, feeling remote, Euvegals).23 In this double-blind crossover study of nausea, and sweating.17,29,30,32,33 Studies of aqu- healthy individuals the herbal combination did not eous extracts reported two cases of dizziness improve PSG-measured sleep efficiency, sleep with valerian21 and one case of nausea possibly latency, or WASO compared to a placebo. The related to valerian.46 Additionally, Leathwood and same research group conducted a 14-day trial of Chauffard38 reported evidence of dose-dependent Euvegals (320 mg valerian, 70% ethanol extrac- hangover effects, with morning sleepiness ratings tion/160 mg lemon balm, 30% ethanol extraction) significantly higher after valerian than placebo for given twice a day in persons with insomnia. The the 900 mg dose but not the 450 mg dose. In the herbal combination significantly improved subjec- clinical trials of valepotriate preparations only five tive sleep quality ratings and reduced subjective participants reported adverse effects, and in all sleep latency compared to the placebo.16 Finally, in cases these were GI (diarrhea, stomach discomfort, a placebo-controlled, double-blind crossover study bitter taste in mouth). ARTICLE IN PRESS

224 D.M. Taibi et al.

Eight open-label clinical studies with sample Quality of the research evidence sizes ranging from 20 to 830 participants investi- gated the tolerability of valerian or valerian The quality of the studies reviewed was rated combination products. In several studies, no ad- using the Jadad scoring criteria for potential verse events occurred,19,20,44 and in another study sources of bias (higher scores ¼ higher quality)10 only three minor events occurred.14 When asked to (see Table 4). The studies of ethanolic extracts rate the tolerability of the herbal products, were conducted most recently and were of the participants (70–90%) rated them as ‘‘good’’ or highest quality; most studies had Jadad scores ‘‘very good’’.12,14,18,20,28 ranging from 3 to 5.13,17,29–32,34 Studies of aqueous extracts and valepotriate-containing extracts were mostly conducted in the 1970s and 1980s, and tended to be of mixed quality; few studies had a Discussion Jadad score X3.21,36,38,46 The studies of highest quality did not find valerian (ethanolic extracts or Evaluation of the effectiveness of valerian as a valerian–hops combination) to be significantly sleep aid is difficult given the considerable varia- superior to placebo for improving outcomes in tion among the studies in duration, design, and insomnia.17,29,31,40 herbal preparation. Originally, we had intended to In a previous systematic review,4 the authors perform a meta-analysis of the literature available evaluated several criteria (e.g., randomization and on valerian, but concluded that such an analysis blinding, power estimates, potential sources of was not appropriate given the variability in the bias) in addition to the Jadad score that were research quality. In particular, evidence on valerian important to the validity of clinical trials of the from both parallel-group and crossover trials should effects of herbs on sleep. None of the studies not be combined in the same meta-analysis because reviewed addressed all of the important trial design inclusion of crossover trials does not account for elements, although the number of elements in- lack of independence of the group data and cluded did increase in the more recent studies increases the risk of Type I error. Other features examined. Few of the studies described the of valerian trials that preclude use of meta-analytic randomization procedures or reported data on procedures are use of different types of products group equivalence, which could bias the findings (species, extraction methods, and herbal combina- if the groups differed on baseline characteristics. tions) and differing characteristics of the samples Perhaps more problematic was the failure to studied (healthy versus insomnia). There is insuffi- calculate sample size, and thus, many studies cient data on specific sleep outcomes to conduct were likely underpowered to detect group differ- separate meta-analyses on the literature divided ences. The majority of studies had sample into categories based on product and sample. sizes between 11 and 21 participants, with only Therefore, to fully evaluate the current state of six studies having moderately large sample sizes the evidence of valerian effects on sleep outcomes, (78–391).17,27,29,32,34,46 Nevertheless, the studies we decided that a descriptive synthesis of the generally used statistical methods that were liberal literature with specific attention to product and in assigning statistical significance to findings (e.g., sample characteristics was most appropriate. paired tests with no alpha rate correction for Issues related to dose and treatment duration multiple testing), which makes the lack of statis- were not emphasized in this review because there tical significance more compelling evidence against are no current standards for an optimal dose or the clear effectiveness of valerian as a sleep aid. recommended treatment duration. Given the lack On the other hand, failure to control pre-bedtime of dose-response studies, it is unclear whether any variables such as use or may have of the studies used an optimal dose, although most allowed these factors to influence sleep outcomes, were consistent with expert recommendations. confounding any potential effects of valerian on Additionally, it is commonly recommended that sleep. at least two weeks of valerian treatment is Of particular methodological concern in the necessary for effects to manifest,8 but this studies reviewed was the considerable failure to recommendation has not been specifically investi- ensure that the placebo (or comparison medica- gated. Although a few placebo-controlled studies tion) and valerian were adequately masked. Valer- of two weeks or longer treatment duration ian has a very distinctive, unpleasant odor. Failure reported significant improvement with valer- to adequately mask the valerian treatment or ian,16,21,35 a greater number found no significant ‘odorize’ the comparison treatment may increase improvement.17,24,29,33,34,40,42 expectations that valerian pills will be effective. ARTICLE IN PRESS

Valerian as a sleep aid 225

Of the 28 studies that were trials with a comparison insufficient to exclude the possibility of placebo group, 10 matched treatments on appearance, effects or to conclude that the herb is effective. while seven matched on odor (two described the matching procedures).29,31 Only one study reported the success of the employed masking procedure29 Valerian effects on subjective sleep (see Table 4). In two recently completed studies by outcomes the authors of this review (C.A. Landis and D.M. Taibi, unpublished), researchers used valerian to The research findings to date do not support the confer the odor of valerian on the placebo efficacy of valerian or valerian combinations for capsules. In one study, valerian capsules were improving subjective sleep outcomes. Most of the stored in proximity to the placebo pills. In the evidence of improved sleep with valerian prepara- other study, the placebo was stored in plastic tions is from studies using non-specific outcomes containers that had been ‘‘odorized’’ by containing for clinical trials (i.e. proportion improve- active valerian for a week. Although it is possible ment)21,38,42,43 or studies in which placebo effect that these methods may contaminate the placebo, was not addressed.13,29,32,41 Research evidence of the amount of valerian transferred is likely to be high-quality is available for ethanolic V. officinalis minimal and not clinically effective. In each of extracts, and the findings do not support the these studies, participants were not able to efficacy for the treatment of insomnia. The quality identify which treatment condition they had of research evidence for other valerian products is received, indicating that both masking procedures mixed, but few studies have been conducted with were successful. these products in samples with insomnia. Although The specificity of the sample characteristics, there is some evidence that suggests valerian may including subject inclusion and exclusion criteria improve sleep outcomes, placebo effects cannot be were evaluated (Table 1). Little consideration was ruled out in many of these trials. Therefore, the given to age and gender, although few studies evidence is insufficient to recommend clinical use specifically investigated valerian in older adults. It of valerian for treating disturbed sleep. was evident that many of the studies did not report Recently, Bent and colleagues5 published a meta- exclusion of potentially confounding variables, analysis of subjective sleep quality and sleep including co-morbid insomnia, psychiatric diag- latency outcomes of valerian treatment, conclud- noses, and concurrent use of sleep-altering medi- ing that evidence suggests potential beneficial cations. In particular, a serious omission was the effects of valerian on sleep. In this analysis, the failure to report exclusion of other sleep disorders authors did not consider type of valerian product, (e.g., sleep apnea and ), and they included combination products with as even in several of the high-quality studies. The many as eight other herbs. Two types of sleep findings from studies of ethanolic extracts and quality outcomes have been used in valerian valerian–lemon balm combinations are the most studies: (1) sleep quality improvement—whether reliable in relation to controlling for potential participants rate their sleep as ‘‘improved’’ or ‘‘not confounding variables. Finally, none of the studies improved’’ or (2) sleep quality ratings—e.g., 0–10 of insomnia patients differentiated between types numeric scale, 0 ¼ poor, 10 ¼ excellent. Bent and of insomnia symptoms in the analysis. It is possible colleagues conducted their meta-analysis on sleep that valerian products may have differential effi- quality improvement ratings (‘‘improved versus cacy for sleep initiating versus sleep maintenance ‘‘not improved’’). This analysis favored valerian, symptoms. but inspection of the studies included revealed a publication bias towards small, positive studies. Additionally, in two of the six studies in which sleep quality improvement favored valerian, sleep qual- Evaluation of the effects of valerian on sleep ity ratings showed no significant differences be- tween valerian and placebo.17,42 Therefore, the Only a limited number of studies were available on clinical utility of assessing subjective sleep quality each type of valerian product. Although some of improvement is questionable. Bent et al. reported these studies reported improvement over time, that results for subjective sleep latency were often no direct comparisons of valerian and placebo mixed, and, as discussed in our review, variation groups were reported.27,37,34 Given that several in study quality and lack of control for confounding studies of valerian reported improvement of sleep variables influenced the outcomes of many of the under the placebo condition (e.g.,17,29,33), im- studies. Given the limited scope of outcomes and provement over time in the valerian group is studies considered in the Bent et al. review, the ARTICLE IN PRESS

226 D.M. Taibi et al. Primary ¼ ¼ ¼ p p p Primary sleep outcomes significant NA* Intent-to- treat analyses Validated outcome measures (+) Control of pre- bedtime variables Dropouts reported ++ + ++ Subject inclusion/ exclusion criteria (+) +(+)++ + + (+) ++ +++ + (+) +++(+) + + (+) NA* ++++ + (+) Sample size calculated Compliance checked a statistically significant proportion of the sample improved, but the study did not compare mean scores; : p Success of blinding checked ): +: outcomes significant (versus placebo); (+): only part of main outcomes were significant; NA*: statistical analyses Blinding of odor described Blinding of appearance described Tables 1 and 2 Random procedure described : Studies listed chronologically. +: item was adequately addressed; (+): item was partially addressed; NA: item was not applicable to the study. Score 0 4+ 1 3+ 2 2 3 422 +2 35++(+)++++ ++ 2 3 +3+3+ +2 5++(+)42 45+++ ++35++++++++ +(+)4+(+)+ +++ ++++++ +NA++ + + + ++ + +++ ++ +++ NA (+) + + ++ (+) +++ (+) + + + (+) + + + (+) 1 2 15 42 21 46 46 24 34 16 6 17 37 26 35 Quality, methodological features, and significance of primary outcomes of clinical trials of valerian for sleep. 33 32 29 based on outcomes reported in 37 ( 40 22 30 39 39 (home) (PSG) 38 43 11 11 25 27 36 13 `ly `ly : equivalence of valerian and a benzodiazepine (hypothesis was met if differences were non-significant). ¼ Table 4 Study Jadad Leathwood et al. (lab) Leathwood et al. (home) Gessner et al. Balderer and Borbe Dressing et al. Cerny and Schmid Herrera-Arellano et al. Coxeter et al. Items related to quality Leathwood and Chauffard, outcomes comparing valerian to the placebo were either not done or not reported; + Muller-Limmroth and Ehrentstein Leathwood and Chauffard, Lindahl and Lindwall Vorbach et al. Rodenbeck et al. Kuhlmann et al. Donath et al. Poyares et al. Diaper and Hindmarch Jacobs et al. Morin et al. Jansen Gessner and Klasser Kamm-Kohl et al. Schulz et al. Dressing et al. Schmitz and Jackel Dorn Ziegler et al. Balderer and Borbe Leathwood and Chauffard + ARTICLE IN PRESS

Valerian as a sleep aid 227 preponderance of negative findings was neglected, occurred with high doses of valepotriates, but not and the author’s conclusions that valerian, as it has with low doses.52 It has been suggested that the GI been tested to date, is a promising therapy are tract is at particularly high risk for adverse effects unsupported in the broader context of the litera- of valepotriates because of the chemical degrada- ture reviewed here. tion of these substances in the stomach.8 While GI symptoms were reported in the reviewed studies on high-valepotriate preparations, these symptoms Valerian effects on objective sleep outcomes likely were related to purported muscle-relaxant effects of valepotriates.8 No report was found in Current evidence suggests that the investigated the literature directly linking valepotriates to the valerian preparations do not significantly affect occurrence of serious adverse events in , objective sleep outcomes, although very few but caution in the use of these products is studies have actually recorded sleep. Of the studies warranted until more is known about potential administering V. officinalis mono-preparations, adverse effects. only two of the studies that measured PSG out- There is little evidence on potential herb– comes investigated valerian administration for interactions of valerian. In vitro studies have longer than three days in persons with sleep demonstrated mild to moderate inhibition of the disturbance,33,35 one showed no significant out- drug-metabolizing in the small bowel and comes,33 and the other reported reduced WASO.35 liver that are involved in first-pass drug metabo- Studies of valerian combinations reporting PSG lism.53,54 Although inhibition of these enzymes outcomes after either one night22,23 or 28 days24,40 theoretically increases the risk of excessive levels found no outcomes significant compared to of certain medications in the , an in vivo study placebo. One study of an aqueous valerian extract of humans showed no significant effects of one showed reduced sleep onset latency by wrist valerian preparation on circulating levels of med- actigraphy in persons with sleep onset insomnia.38 ications given to test inhibition.55 Although However, sleep latency was not longer than 30 min evidence indicates that valerian is unlikely to at baseline (15 min) and on average was reduced significantly affect drug , caution may only four to six minutes, providing only weak be advised with medications that are metabolized evidence of valerian sedation. Overall, these by cytochrome P450 enzyme subtype 3A4, and to findings do not support the effectiveness of valerian a lesser extent subtypes 2C19 and 2D6, if the or valerian combinations for improving objective medications have high toxicity and a narrow sleep outcomes. Additionally, when considering therapeutic range (e.g., digoxin). Additionally, that the tested valerian preparations did not synergistic effects of valerian with medications clearly show improved subjective sleep ratings, are potentially problematic. In animal studies, any evidence of improved objective sleep outcomes valerian had been shown to potentiate is of questionable relevance. induced sleeping time.6 Valerian should not be taken with benzodiazepines and other sedating Safety of valerian substances, such as and alcohol, due to the risk of over-sedation. The studies reviewed support the safety of valer- ian. The most common side effects were mild and tended to be either mild neurological symptoms (dizziness, headache, drowsiness) or gastrointest- Conclusion inal (GI) symptoms (nausea, diarrhea). Although valerian has been implicated in a few case reports Although valerian is commonly used in the United of transient liver dysfunction,47,48 no hepatic States and Europe as a sleep aid, current evidence symptoms or changes in liver function were on the efficacy of valerian for improving sleep reported in the research literature reviewed.13,42 outcomes does not support such use. However, Valerian had been shown to cause little to no valerian is an apparently safe herb, with few impairment of performance, especially in compar- reported side effects. Despite the lack of evidence ison to benzodiazepines.30,34,49–51 for efficacy, these products are unlikely to cause Concerns have been raised regarding the safety harm other than perhaps delaying individuals from of ingesting valepotriates. These constituents have seeking the effective treatment for insomnia been shown in vitro to be cytotoxic and to inhibit symptoms. DNA synthesis.8 A recent in vitro study demon- Although current evidence fails to support strated that DNA damage of human epithelial cells efficacy of valerian for relief of insomnia, the ARTICLE IN PRESS

228 D.M. Taibi et al. widely variable and methodologically mixed nature  Future studies should use greater specifica- of the extant literature clearly leaves room for tion of inclusion/exclusion criteria, espe- further clarification. First, it is important to note cially in defining the type of sleep that the source valerian plant material used in most disturbance in the sample. Study methods studies was extracted from dried, rather than should also plan for greater control of fresh, root and rhizome. The concentration of potential sources of bias (see Table 4). certain constituents of valerian varies between  Matching of valerian and placebo odor is fresh and dried products, and study findings on critical to ensure adequate masking and to dried root extracts should not be generalized to reduce potential placebo effects. fresh root preparations. Second, valerian prepara-  Evidence on valerian preparations in tinc- tions were administered in pill form rather than as ture form is lacking. Given that this is a a liquid, which is the preferred method recom- formulation preferred by herbalists, re- mended by herbalists (personal communication search on such preparations may provide Robin DePasquale, January, 2007). No studies were new information on potential effects of found that tested valerian tinctures for sleep; valerian. although one tested cognitive impairment with a syrup.50 This is an important distinction because the presence and availability of active constituents varies between pills and tinctures. Finally, rigorous studies testing different doses of valerian and types Acknowledgments of valerian products in well-defined samples of persons with insomnia are needed. It remains The systematic review and manuscript were possible that valerian may be a useful, mild supported by the National Institutes of Health, treatment for sleep disturbance, but current grant numbers R21-AT-002108, P30-NR04001, and evidence does not support its use, and research is T32-NR07039. The authors thank Robin DiPasquale, needed to determine which products and doses of N.D., R.H.(AHG) for consulting on this article and valerian might be efficacious. Cristina Fuller, Ph.D.(c), for assistance with Portu- guese translation. Practice points References  Current evidence does not support the efficacy of valerian or valerian combina- 1. Ohayon MM. Epidemiology of insomnia: what we know and tions with other herbs for reducing general what we still need to learn. Sleep Med Rev 2002;6(2): sleep disturbance or insomnia symptoms. 97–111.  Valerian has been shown to be a safe 2. Pearson NJ, Johnson LL, Nahin RL. Insomnia, trouble product and is unlikely to cause harm in sleeping, and complementary and alternative medicine: Analysis of the 2002 national health interview survey data. the majority of patients. Healthcare provi- Arch Intern Med 2006;166(16):1775–82. ders should advise patients of potential 3. Blumenthal M, Ferrier GK, Cavaliere C. Total sales of herbal herb–drug interactions (e.g., additive seda- supplements in United States show steady growth. Herbal- Gram 2006;71:64–6. tion, possible alteration of drug metabo- Ã lism). 4. Stevinson C, Ernst E. Valerian for insomnia: a systematic review of randomized clinical trials. Sleep Med 2000;1(2):  Caution should be exercised in the use of 91–9. valerian by patients who have a history of Ã5. Bent S, Padula A, Moore D, Patterson M, Mehling W. liver , those at risk for liver dysfunc- Valerian for sleep: a systematic review and meta-analysis. tion, and taking other herbs linked to liver Am J Med 2006;119(12):1005–12. dysfunction. 6. Bos R, Woerdenbag HJ, DeSmet PAGM, Scheffer JJ. Valeriana species. In: DeSmet PAGM, Keller K, Hansel R, Chandler RF, editors. Adverse effects of herbal . Berlin: Springer; 1997. p. 165–80. 7. Upton R, Graff A, Williamson E, Bevill A, Ertl F, Reich E, Research agenda et al. Valerian root, Valeriana officinalis: analytical quality control, and therapeutic monograph. In: Upton R, editor.  Future studies of valerian should specifically American herbal pharmacopoeia and therapeutic compen- exclude persons with primary sleep distur- dium. Santa Cruz, CA: American Herbal Pharmacopoeia; bances other than insomnia (e.g., restless 1999. legs syndrome, sleep apnea). ÃThe most important references are denoted by an asterisk. ARTICLE IN PRESS

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