Medication Guide App

Valerian

Scientific Name(s): Valeriana officinalis L. Family: Valerianaceae . A number of other species have been used medicinally, including Valeriana wallichi DC, Valeriana sambucifolia Mik., and the related Centranthus ruber L.

Common Name(s): Baldrian , cat's love , cat's valerian , garden heliotrope , garden valerian , kesso root , radix valerianae , St. George's herb , valerian fragrant , valerian , vandal root

Uses

The evidence to support the common use of valerian in insomnia remains weak. However, as valerian preparations seem to have a wide margin of safety, further trials for insomnia and anxiety may be warranted.

Dosing

Anxiety: Valeprotriates 150 mg/day in 3 divided doses for 4 weeks has been used in a clinical trial. Other trials used the dried herb 0.5 to 2 g, extract 0.5 to 2 mL, and valerian tincture 2 to 4 mL for anxiety. Insomnia: Valerian extract 400 to 600 mg/day taken 1 hour before bedtime for 2 to 4 weeks has been used in clinical trials. Single-dose studies have consistently found no effect for single doses of valerian in insomnia.

Contraindications

Contraindications have not been identified.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

None well documented.

Adverse Reactions

In general, clinical studies have found valerian to have a wide margin of safety, be devoid of adverse effects, and have fewer adverse reactions than positive control drugs, such as diazepam. Headache and diarrhea have been reported in clinical trials, but hangover is seldom reported.

Toxicology

Valerian has been classified as GRAS (generally recognized as safe) in the United States for food use; extracts and the root oil are used as flavorings in foods and beverages. The observed in vitro cytotoxicity of valepotriate compounds may not be relevant in vivo because of limited absorption.

Botany

Members of the genus Valeriana are herbaceous perennials widely distributed in the temperate regions of North America, Europe, and Asia. The hollow stemmed plant can grow up to 2 m and is branched at the terminal end with opposite leaves and small white or pink flowers. Fruits are oblong, 4-ridged, and single seeded. Of approximately 200 known species, the Eurasian Vakeruaba officinalis is most often cultivated for medicinal use. The dried rhizome used in valerian extracts has numerous rootlets and one or more stolons and contains a volatile oil with a distinctive, unpleasant odor. 1 , 2 , 3 , 4

History

Valerian has been used in Unani, Ayurvedic, and traditional Chinese health systems and for homeopathic uses for cardiotonic and sedative properties, as well as in epilepsy, hysteria, and other conditions. 5 Despite its odor, valerian was considered a perfume in 16th-century Europe. The tincture has been used for its sedative properties for centuries; it is still widely used in France, Germany, and Switzerland as a sleep aid. 6 Other uses attributed to valerian include a digestive aid, emmenagogue, and antiperspirant. 2

Chemistry

Three distinct classes of compounds have been associated with the sedative properties of valerian. These compounds consist of mono- and sesquiterpenes and iridoid triesters (valepotriates). Other compounds identified include flavonoids, triterpenes, lignans, and alkaloids. The composition of the volatile oil varies markedly between cultivars and species, as does the amount and relative proportion of cytotoxic valepotriates, making chemical standardization difficult but highly desirable.

The most important sesquiterpenes include valerenic acid and its congeners, although in Japan, V. officinalis var. latifolia , kessyl alcohols, and esters predominate. Valtrate, acevaltrate, and didrovaltrate are the most important iridoids; European valerian extracts were formerly standardized on these unstable compounds, which have a short shelf life in the tincture.

The alkaloid concentration in roots and rhizomes is low, usually less than 0.2%. The aqueous extract of valerian contains substantial quantities of gamma-aminobutyric acid (GABA); however, it is doubtful whether GABA penetrates the blood-brain barrier.

Many analytical high performance liquid chromatographic methods have been developed for the sesquiterpenes and valepotriates. The seasonal variation in valerenic acids and valepotriates has been studied. Tissue culture of valerian species has focused on the production of valepotriates. 2 , 7 , 8 , 9 , 10 , 11 , 12

Uses and Pharmacology

Several in vitro and animal experiments have attempted to elucidate the mechanism of action for various valerian compounds. Many of these experiments provide contradictory evidence, but most attribute the observed actions of valerian extracts to central actions on GABA, serotonin, and adenosine receptors. The sesquiterpene valerenic acid and its derivatives and the valepotriates are generally thought to be the active constituents; however, wide variations in the composition of commercial preparations make interpretation of clinical data difficult. 9 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22

Anxiolytic effect

Both a meta-analysis and systematic review comment on the lack of trials meeting inclusion criteria because of poor methodology, the use of healthy volunteers, and combination therapies. 14 , 23 One small, pilot clinical trial meeting inclusion criteria evaluated the effect of valepotriates 150 mg per day in 3 divided doses over 4 weeks in generalized anxiety disorder. 24 No difference was demonstrated for the standardized valerian extract versus placebo or diazepam 20 mg. 24 Until studies with a larger sample size are conducted, the efficacy of valerian remains unclear. 14 , 23

Another review of clinical trials and in vitro experiments suggests the effect of valerian may be because of anxiolytic action, rather than sedation. 13 This was demonstrated by a laboratory experiment with rodents that found no decrease in spontaneous locomotor activity and no increase in ether-induced anesthesia, but did find a reduction in anxiety using the elevated plus maize test. 25 Older experiments in rodents found conflicting results for spontaneous motor activity. 22 , 26

Insomnia

Single-dose studies have consistently found no effect for a single dose of valerian in improving sleep latency or quality. 27 , 28 , 29

Both a systematic review and a meta-analysis of quality clinical trials found the results inconclusive for valerian use in insomnia. 6 , 30 However, pooled results for the dichotomous outcome of improved sleep quality (improved or not) do find in favor of valerian (relative risk, 1.8; 95% confidence interval, 1.2 to 2.9). 6 Results for sleep latency could not be pooled because of heterogeneity of measures. Issues raised by the reviews include the lack of standardization of the valerian extracts used and possibility of publication bias. 6 , 30 Reviews of older trials not included in the systematic reviews or meta-analysis found valerian to exert an effect similar to the benzodiazepines, but a number of negative trials are also described. 5 , 13

Further randomized clinical trials, published after the meta-analysis, have found no differences for outcome measures for valerian versus placebo in insomnia. 31 , 32 In a large clinical trial, valerian extract 600 mg taken 1 hour before bedtime for 2 weeks demonstrated no difference from placebo for any outcome measure, although a trend towards valerian was found. 31 A small clinical trial found no difference for sleep latency between placebo or valerian extract 500 mg over 4 weeks in nonorganic sleep disorder. 32

Other effects

The valepotriates, isovaltrate, and valtrate, along with valerenone, had antispasmodic effects in isolated guinea pig ileum and other smooth muscle preparations. 33

Valerian had no effect on haloperidol-induced orofacial dyskinesia in rats. 34

Oral administration of valerian root extracts was protective against vasopressin-induced coronary spasms and pressor response in guinea pigs. 7 In the same experiment, bronchial resistance was reduced in both histamine- and antigen-induced bronchospasm. 7

Dosage

A dose of a commercial preparations of valerian extract 600 mg in healthy subjects peaked at 30 minutes to 2 hours, with an elimination half-life of 1.1 ± 0.6 hours, and the marker valerenic acid was in the serum for at least 5 hours after dosing. 35

Anxiety

A clinical trial evaluating valerian as an anxiolytic used valeprotriates 150 mg in 3 divided doses for 4 weeks. 24 Other trials have used valerian dried herb 0.5 to 2 g, extract 0.5 to 2 mL, and tincture 2 to 4 mL. 14

Insomnia

Valerian extract 400 to 600 mg taken 1 hour before bedtime for 2 to 4 weeks has been used in clinical trials evaluating valerian in insomnia. 13 , 31 , 32 A study conducted in children with insomnia (mean age, 11 years) used valerian extract 20 mg/kg body weight at night for 2 weeks. No adverse reactions were noted at this dosage; however, results were inconclusive. 6 , 36 Studies have consistently found no effect for a single dose of valerian in improving sleep latency or quality. 27 , 28 , 29

Valerian extract up to 1,215 mg has been used as a sedative, but clinical trials have not established an optimal dose, and issues of standardization of content and preparation quality have been raised. 6 , 13 Many commercial preparations exist either as valerian alone or in combination with other compounds.

Pregnancy/Lactation

Despite common use without apparent harm during pregnancy, the use of valerian preparations in pregnancy and lactation cannot be supported without evidence of safety. Widespread differences in dosages, duration, and preparations exist, and the stage of pregnancy may be a factor. 37 Valerian is reported in the Complete German Commission E Monographs to stimulate uterine contractions. 38 Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

In vitro studies have suggested valerian inhibits both CYP3A4 metabolism and P-glycoprotein activity, 39 but clinical studies showed no effect of valerian on midazolam, caffeine, chlorzoxazone, debrisoquine, dextromethorphan, or alprazolam levels. 40 A paradoxical lack of potentiation by valerian on the anesthetic isoflurane was demonstrated, while a cumulative effect emerged from the anesthetic in rats when administered with midazolam. 41 Animal studies have also shown potentiation of thiopental and pentobarbital-induced sleep, while no potentiation of the sedative effects of alcohol have been noted. 13 The potential for interactions remains a theoretical possibility.

Adverse Reactions

Valerian has been classified as GRAS in the United States for food use; extracts and the root oil are used as flavorings in foods and beverages. 13

Generally, clinical studies have found that valerian has a wide margin of safety, is devoid of adverse effects, and has fewer adverse reactions than positive control drugs, such as diazepam. Headache and diarrhea have been reported in clinical trials, but hangover is seldom reported. 5 , 6 , 13 , 24 , 30 , 31 , 32

An intentional overdose has been reported, in which 20 times the recommended dose was ingested; the patient experienced mild symptoms that resolved within 24 hours. 42 A case of withdrawal after chronic use of valerian has been reported; however, the complex nature of the patient's medical history provides weak evidence of valerian's role. 43 Farmers growing valerian were evaluated for adverse reactions, with few notable effects observed. 44

Toxicology

Concern was raised following the discovery that valepotriates are mutagenic in the Ames assay; however, their poor bioavailability and hepatic detoxification makes them a dubious source of toxicity for patients. 2 , 45 The cytotoxicity of baldrinal compounds (metabolites of the valepotriates) is higher in vivo than in vitro because they are more readily absorbed, and these metabolites have been detected in commercial preparations. 2

No teratogenicity or overt toxicity of valepotriate compounds was found in rodents in 2 different studies. 2 , 13 , 46 Mice receiving doses of valerian more than 1 g/kg by oral and intraperitoneal routes have experienced ataxia, muscle relaxation, and hypothermia. 47

No evidence of hepatitis was observed following consumption of oral valerian at average dosages of 2.5 g/day for 4 years. 46

Bibliography

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2. Valerian. In: WHO monographs on selected medicinal plants . Vol 1. Geneva, Switzerland: World Health Organization; 1999:267-276.
3. Leathwood PD , Chauffard F , Heck E , Munoz-Box R . Aqueous extract of valerian root ( Valeriana officinalis L.) improves sleep quality in man . Pharmacol Biochem Behav . 1982;17(1):65-71.
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9. Santos MS , Ferreira F , Faro C , et al. The amount of GABA present in aqueous extracts of valerian is sufficient to account for [ 3 H]GABA release in synaptosomes . Planta Med . 1994;60(5):475-476.
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11. Bos R , Woerdenbag HJ , van Putten FM , Hendriks H , Scheffer JJ . Seasonal variation of the essential oil, valerenic acid and derivatives, and valepotriates in Valeriana officinalis roots and rhizomes, and the selection of plants suitable for phytomedicines . Planta Med . 1998;64(2):143-147.
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15. Dietz BM, Mahady GB, Pauli GF, Farnsworth NR. Valerian extract and valerenic acid are partial agonists of the 5-HT 5a receptor in vitro. Brain Res Mol Brain Res . 2005;138(2):191-197.
16. Ortiz JG, Rassi N, Maldonado PM, González-Cabrera S, Ramos I. Commercial valerian interactions with [ 3 H]flunitrazepam and [ 3 H]MK-801 binding to rat synaptic membranes. Phytother Res . 2006;20(9):794-798.
17. Sichardt K, Vissiennon Z, Koetter U, Brattström A, Nieber K. Modulation of postsynaptic potentials in rat cortical neurons by valerian extracts macerated with different alcohols: involvement of adenosine A 1 - and GABA A -receptors. Phytother Res . 2007;21(10):932-937.
18. Hiller K-O , Zetler G . Neuropharmacological studies on ethanol extracts of Valeriana officinalis L: behavioural and anticonvulsant properties . Phytother Res . 1996;10(2):145-151.
19. Leuschner J , Müller J , Rudmann M . Characterization of the central nervous depressant activity of a commercially available valerian root extract . Arzneimittelforschung . 1993;43(6):638-641.
20. Krieglstein JG , Frusia D . Central depressant constituents in Valeriana . Valepotriate, valerenic acid, valeranone and volatile oil are ineffective afterall . Dtsch Apoth Ztg . 1988;128:2041.
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24. Andreatini R, Sartori VA, Seabra ML, Leite JR. Effect of valepotriates (valerian extract) in generalized anxiety disorder: a randomized placebo-controlled pilot study. Phytother Res . 2002;16(7):650-654.
25. Hattesohl M, Feistel B, Sievers H, Lehnfeld R, Hegger M, Winterhoff H. Extracts of Valeriana officinalis L. s.l. show anxiolytic and antidepressant effects but neither sedative nor myorelaxant properties. Phytomedicine . 2008;15(1-2):2-15.
26. Hendriks H , Bos R , Allersma DP , Malingré TM , Koster AS . Pharmacological screening of valerenal and some other components of essential oil of Valeriana officinalis . Planta Med . 1981;42(1):62-68.
27. 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):47-53.
28. Diaper A, Hindmarch I. A double-blind, placebo-controlled investigation of the effects of two doses of a valerian preparation on the sleep, cognitive and psychomotor function of sleep-disturbed older adults. Phytother Res . 2004;18(10):831-836.
29. Hallam KT, Olver JS, McGrath C, Norman TR. Comparative cognitive and psychomotor effects of single doses of Valeriana officianalis and triazolam in healthy volunteers. Hum Psychopharmacol . 2003;18(8):619-625.
30. Stevinson C, Ernst E. Valerian for insomnia: a systematic review of randomized clinical trials. Sleep Med . 2000;1(2):91-99.
31. Oxman AD, Flottorp S, Håvelsrud K, et al. A televised, web-based randomised trial of an herbal remedy (valerian) for insomnia. PLoS One . 2007;2(10):e1040.
32. Koetter U, Schrader E, Käufeler R, Brattström A. A randomized, double blind, placebo-controlled, prospective clinical study to demonstrate clinical efficacy of a fixed valerian hops extract combination (Ze 91019) in patients suffering from non-organic sleep disorder. Phytother Res . 2007;21(9):847-851.
33. Hazelhoff B , Malingré TM , Meijer DK . Antispasmodic effects of Valeriana compounds: an in-vivo and in-vitro study on the guinea-pig ileum . Arch Int Pharmacodyn Ther . 1982;257(2):274-287.
34. Fachinetto R, Villarinho JG, Wagner C, et al. Valeriana officinalis does not alter the orofacial dyskinesia induced by haloperidol in rats: role of dopamine transporter. Prog Neuropsychopharmacol Biol Psychiatry . 2007;31(7):1478-1486.
35. Anderson GD, Elmer GW, Kantor ED, Templeton IE, Vitiello MV. Pharmacokinetics of valerenic acid after administration of valerian in healthy subjects. Phytother Res . 2005;19(9):801-803.
36. Hrastinger A, Dietz B, Bauer R, Sagraves R, Mahady G. Is there clinical evidence supporting the use of botanical dietary supplements in children? J Pediatr . 2005;146(3):311-317.
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38. Ernst E. Herbal medicinal products during pregnancy: are they safe? BJOG . 2002;109(3):227-235.
39. Hellum BH, Nilsen OG. In vitro inhibition of CYP3A4 metabolism and P-glycoprotein-mediated transport by trade herbal products. Basic Clin Pharmacol Toxicol . 2008;102(5):466-475.
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41. Chaplin RL Jr, Jedynak J, Johnson D, Heiter D, Shovelton L, Garrett N. The effects of valerian on the time course of emergence from general anesthesia in Sprague-Dawley rats ( Rattus norvegicus ). AANA J . 2007;75(6):431-435.
42. Willey LB , Mady SP , Cobaugh DJ , Wax PM . Valerian overdose: a case report . Vet Hum Toxicol . 1995;37(4):364-365.
43. Garges HP , Varia I , Doraiswamy PM . Cardiac complications and delirium associated with valerian root withdrawal . JAMA . 1998;280(18):1566-1567.
44. Skórska C, Golec M, Mackiewicz B, Góra A, Dutkiewicz J. Health effects of exposure to herb dust in valerian growing farmers. Ann Agric Environ Med . 2005;12(2):247-252.
45. von der Hude W , Scheutwinkel-Reich M , Braun R . Bacterial mutagenicity of the tranquilizing constituents of Valerianaceae roots . Mutat Res . 1986;169(1-2):23-27.
46. Yao M, Ritchie HE, Brown-Woodman PD. A developmental toxicity-screening test of valerian. J Ethnopharmacol . 2007;113(2):204-209.
47. Hobbs C . Valerian: a literature review . HerbalGram . 1989;21(1-2):19-34.

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