Valerian

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

Common Name(s): Valerian , baldrian , radix valerianae , Indian valerian ( V. wallichii ), red valerian ( C. ruber )

Clinical Overview

Uses of Valerian

Valerian has been used for the treatment of restlessness and sleep disorders. However, some of the studies were carried out in healthy volunteers and most of the studies using patients with sleep disorders were small in design.

Valerian Dosing

Valerian root (fresh or dried) has been used at doses of 2 to 3 g given 1 to 3 times/day for nervousness or as an antispasmodic, and at bedtime for insomnia. Several types of extracts have been tested; an aqueous extract has shown activity in sleep studies at doses of 270 to 900 mg, while an ethanolic extract has been recommended at 600 mg for sleep. Combinations with extracts of hops (eg, ReDormin , Ze 91019 ) or with lemon balm ( EuVegal Forte ) are quite common as sleep aids. The valerian extract dose in combination products is 320 to 500 mg. Lipophilic extracts such as Baldrian-Dispert have fallen into disuse because of toxicity concerns and failure to identify their active principles. 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9

Contraindications

Contraindications have not yet been identified.

Pregnancy/Lactation

Documented adverse effects. Avoid use.

Valerian Interactions

None well documented.

Valerian Adverse Reactions

Studies have generally found valerian to have fewer side effects than positive control drugs (eg, diazepam).

Toxicology

Valerian has been classified as GRAS (generally recognized as safe) in the United States for food use.

Botany

Members of the genus Valeriana are herbaceous perennials widely distributed in the temperate regions of North America, Europe, and Asia. Of approximately 200 known species, the Eurasian V. officinalis is most often cultivated for medicinal use. The dried rhizome contains a volatile oil with a distinctive, unpleasant odor. 10 The fresh herb has no appreciable smell; however, drying liberates the odiferous constituent isovaleric acid. 1

History

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. Approximately 50 tons of valerian are sold each year in France. 1

Chemistry

Three distinct classes of compounds have been associated with the sedative properties of valerian: 1) mono- and sesquiterpenes, 2) iridoid triesters (valepotriates), and 3) pyridine alkaloids. The composition of the volatile oil varies markedly between cultivars and species, as does the amount and relative proportion of valepotriates, making chemical standardization difficult but highly desirable.

The most important sesquiterpenes include valerenic acid and its congeners, although in the Japanese 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 rather 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 has been found to contain substantial quantities of gamma-aminobutyric acid (GABA); however, it is doubtful whether GABA penetrates the blood-brain barrier with oral administration. 11

Many analytical high performance liquid chromatographic (HPLC) methods have been developed for the sesquiterpenes and valepotriates. 12 The seasonal variation in valerenic acids and valepotriates has been studied. 13 Tissue culture of valerian species has focused on production of valepotriates. 14

Valerian Uses and Pharmacology

There is substantial debate over which constituents are responsible for the sedative activity of valerian. Human studies have documented valerian's effectiveness as a sleep aid. However, some of the studies were carried out in healthy volunteers and most of the studies using patients with sleep disorders were small in design.

Aqueous and hydroalcoholic extracts of valerian induce release of [ ³ H]GABA from synaptosomal preparations, which has been interpreted as an effect on the GABA transporter. The in vitro effect was correlated with the content of GABA in the extract. Thus GABA may be responsible for some of the peripheral effects of valerian, while glutamine, another free amino acid in the extract, can cross the blood-brain barrier and be metabolized to GABA in situ, thereby producing central sedation. 11

An ethanol extract containing no valepotriates antagonized picrotoxin convulsions in mice but had no effect on metrazol- or harman-induced convulsions. The same extract prolonged barbiturate sleeping time, but did not affect spontaneous motility, pain perception, or body temperature. The effects were traced to valerenic acid. 15 A commercial aqueous alkaline extract of valerian ( Valdispert ), standardized on valerenic acid given orally to mice, reduced spontaneous motility and increased barbiturate sleeping time, but had no effect on metrazol-induced convulsions. 16 Cerebral metabolism was examined in rats by using a positron emission tomography (PET) scan. An effect consistent with a GABAergic mechanism was reported with the methylene chloride extract of valerian; however, valepotriates and valerenic acids were not responsible for the effect. The active compounds were not identified. 17

Valerenic acid inhibits GABA transaminase, the principle enzyme that catabolizes GABA. GABA-T inhibition increases the inhibitory effect of GABA in the CNS, and therefore, can contribute to valerian's sedative properties. 18 Valerenic acid given intraperitoneally had CNS depressant effects in mice, including potentiating barbiturate sleeping time and decreasing spontaneous motor activity and rotorod performance. 19 , 20 The valepotriates, isovaltrate and valtrate, along with valerenone, had antispasmodic effects in isolated guinea pig ileum and other smooth muscle preparations. 21

There is evidence that valerian is effective as a sleep aid and as a mild antianxiety agent, although the effect appears to be weaker in healthy subjects than in poor sleepers. An aqueous extract of the root (400 mg extract) improved sleep quality in a number of subjective parameters in 128 healthy volunteers using a crossover design. 1 Elderly patients with nervous disorders responded positively to a commercial valerian preparation in a placebo-controlled study, as measured by subjective and objective parameters. 22 Sleep latency was decreased in a group of 8 poor sleepers given an aqueous extract of valerian in a double-blind, placebo-controlled study. 2 A sleep laboratory study found minor sedative effects in healthy volunteers. 3 An uncontrolled multicenter study of more than 11,000 patients suffering from sleep-related disorders found subjective improvements in 94% of those treated. 4 Another multicenter trial of the same preparation in a younger study population found progressive symptomatic improvement over 10 days of treatment. 23 Valerian increased slow-wave sleep in a pilot study of poor sleepers. 24 In contrast to previous studies that demonstrated a prompt decrease in symptoms, 1 study found that 2 to 4 weeks was required for improvement in 121 patients with serious insomnia. 25 These studies have been reviewed. 26

Valerian often is combined with other herbs such as hops, St. John's wort, or balm in commercial products. A number of these combinations have been evaluated in clinical studies. A combination of Hypericum perforatum and valerian was evaluated for antidepressant activity in a double-blind study of 93 patients treated for 6 weeks. All psychometric scales showed statistically significant improvement. 27 A second study of the same combination in the treatment of anxiety reached similar positive conclusions. 28 Over a 6-week period, a combination of valerian and Hibiscus syriacus (rose of sharron) was active in 130 depressed patients. 29 A preparation containing valerenic acid sesquiterpenes, but not valepotriates, improved sleep quality in a small crossover study of poor sleepers. 5 Valerian and Melissa officinalis (balm) were effective in combination in a study of 20 poor sleepers. 30 The same combination was tolerated in healthy volunteers and increased their quality of sleep. 6 A complex product made up of 6 herbs ( Ballota , Cola , Crataegus , Passiflora , Paullinia , and Valeriana ) was used to treat generalized anxiety (N = 91), producing progressive decreases in the Hamilton Anxiety Scale that were greater than with placebo. 31

Dosage

Valerian root (fresh or dried) has been used at doses of 2 to 3 g given 1 to 3 times/day for nervousness or as an antispasmodic, and at bedtime for insomnia. Several types of extracts have been tested; an aqueous extract has shown activity in sleep studies at doses of 270 to 900 mg, while an ethanolic extract has been recommended at 600 mg for sleep. Combinations with extracts of hops (eg, ReDormin , Ze 91019 ) or with lemon balm ( EuVegal Forte ) are quite common as sleep aids. The valerian extract dose in combinations is 320 to 500 mg. Lipophilic extracts such as Baldrian-Dispert have fallen into disuse because of toxicity concerns and failure to identify their active principles. 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9

Pregnancy/Lactation

Documented adverse effects. Avoid use.

Interactions

None well documented.

Adverse Reactions

Generally, clinical studies have found valerian to have fewer side effects than positive control drugs such as diazepam, producing little hangover effect when used as a sleep aid. 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. 32 A case of withdrawal after chronic use of valerian has been reported; however, the complex nature of the patient's medical history provides weak support for valerian's role. 33

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.

Toxicology

Concern was raised over the discovery that valepotriates are mutagenic in the Ames assay; however, their poor bioavailability makes them a dubious source of toxicity for patients. 34 Mice receiving doses of valerian more than 1 g/kg by oral and intraperitoneal routes have experienced ataxia, muscle relaxation, and hypothermia. 35

Bibliography

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