Pharmacological Toxicological Effects 51 Insomnia

Several studies have examined the effects of valerian on sleep (10-15).

Donath and colleagues performed a randomized, double-blind, placebo-controlled, cross-over study assessing the short-term (single dose) and long-term (14-day multiple dosage) effects of valerian extract on sleep structure and sleep quality. There were significant differences between valerian and placebo for parameters describing slow-wave sleep (SWS) and shorter sleep latency, with very low adverse events. Leathwood and colleagues demonstrated valerian's effect on sleep quality (11). A freeze-dried aqueous extract of valerian root (Rhizoma Valeriana officinalis [L.]) 400 mg was compared to two Hova® (valerian 60 mg and hop flower extract 30 mg per tablet) tablets and placebo (finely ground brown sugar) in this crossover study involving 128 volunteers. Study participants took the study medication 1 hour before retiring, and filled out a questionnaire the following morning. This was repeated on nonconsecutive nights, such that each of the three treatments, identified only by a code number, was administered in random order three times to each patient. Valerian caused a significant improvement in subjectively evaluated sleep quality and a significant decrease in perceived sleep latency. The self-reported improvement in sleep quality was especially notable in smokers, those patients who considered themselves poor or irregular sleepers, and those who reported having difficulty falling asleep on a prestudy questionnaire. Hova® did not demonstrate any beneficial effect, but it was reported to cause a "hangover effect" the next morning. Because subjective sleep questionnaires may not correlate with sleep electroencephalogram (EEG) results, a parallel EEG sleep study was performed comparing valerian to placebo in 10 young men. There was not a statistically significant difference between valerian and placebo in this small study. The authors hypothesized that the results of this experiment might have differed from the questionnaire-assessed study because of small sample size and differences in study populations. The larger study involved young and older individuals, men and women, and good and poor sleepers, whereas the EEG study involved young men with no reported sleep abnormalities. Rather than place more credence on the objective study, the investigators concluded that the questionnaire provides a more sensitive means of detecting mild sedative effects.

A double-blind, placebo-controlled study (12) was performed in eight volunteers recruited from among the research staff at Nestle Products and their families who reported that they "usually have problems getting to sleep." Sleep latency was measured using an activity monitor and questionnaire. The investigators documented a small (7 minute) but statistically significant decrease in sleep latency with 450 mg of an extract of valerian (V. officinalis [L.]). No further improvement was demonstrated with a 900-mg valerian dose; however, patients receiving the higher dose were more likely to feel sleepy the next morning. Sleep quality, sleep latency, and sleep depth also improved according to a nine-point subjective rating scale. However, the appropriateness of the statistical analysis used to interpret the results of the subjective portion of the study is unclear.

A more objective double-blind, placebo-controlled trial (13) evaluated the effect of 450- and 900-mg doses of an aqueous valerian extract (V. officinalis [L.]) on two groups of healthy, young (21-44 years of age) volunteers at home and in a laboratory setting. The effect of valerian on sleep was measured using a questionnaire and night-time motor activity recordings in both settings. The effects of valerian on the volunteers in the sleep laboratory were also measured using polysomnography and spectral analysis of the sleep EEG. Both groups demonstrated the mild hypnotic effects of valerian; however, the benefits of valerian were statistically significant only under home conditions.

Another double-blind, placebo-controlled crossover study (14) evaluated Valerina Natt®, a preparation equivalent to 400 mg of valerian root composed mainly of sesquiterpenes from V. officinalis [L.], on subjective sleep quality assessed using a three-point rating scale. Study subjects were 27 consecutive patients seen in a medical clinic for evaluation of sleep difficulty and fatigue who were willing to participate in the investigation. Statistically significant improvement in sleep quality was noted with the valerian preparation. Valerian was rated as better than placebo by 21 subjects, two rated the preparations equally, and four preferred placebo. No adverse effects were reported. Although some study subjects had experienced nightmares when using conventional hypnotics, nightmares were not reported in the study.

The effects of repeated doses (three tablets three times daily) for 8 days of Valdispert Forte® (135 mg of dried extract of V. officinalis [L.]) in 14 elderly women with sleeping difficulties was assessed using polysomnography in a particularly well-designed study (15). Inclusion criteria were well defined: sleep latency longer than 30 minutes, more than three nocturnal awakenings per night with inability to go back to sleep within 5 minutes, and total sleep time less than 5 hours. Subjects could not have medical, psychological, or weight-related causes of sleep difficulty, and had to have normal health status for their age. Sedatives, hypnotics, and other central nervous system (CNS)-active drugs were discontinued 2 weeks prior to the study, and drug screening for morphine, benzodiazepines, barbiturates, and amphetamine was done prior to study commencement. Results showed an increase in SWS, and a decrease in sleep stage 1. There was no effect on rapid eye movement (REM) sleep, sleep latency, time awake after sleep onset, or self-rated sleep quality.

In aggregate, the results of these clinical studies suggest that at doses of approx 450 mg of the aqueous extract, valerian has mild hypnotic effects, possibly by affecting non-REM sleep in patients with reduced SWS. Unlike benzodiazepines, valerian appears not to adversely affect SWS or REM sleep, and does not appear to cause nightmares or hangover. Further well-designed studies are needed to objectively evaluate valerian. Results of animal studies reflect the clinical data. Sedative properties of Valdispert® (dried aqueous extract of V. officinalis [L.]) in mice were documented based on reduced spontaneous movement and an increase in thiopental-induced sleep time; however, these effects were slightly less than those of diazepam and chlorpromazine. No significant anticonvulsant effect was observed (16).

Hendriks and colleagues tested several components of the volatile oil, obtained by steam distillation of V. officinalis [L.], on mice. The essential oil, its hydrocarbon fraction, its oxygen fraction, valeranone, valerenal, valerenic acid, and isoeugenyl-isovalerate were injected intraperitoneally at various doses ranging from 50 to 1600 mg/kg, with three mice receiving each dose. The mice were observed between 15 and 30 minutes postinjection for various symptoms suggestive of CNS stimulation or depression, analgesia, sympatho-mimetic or sympatholytic activity, vasodilation, or vasoconstriction. It was concluded that components of the essential oil, particularly valerenic acid and valerenal, which are present in the oxygen fraction, have a sedative and/ or muscle relaxant effect. The authors (17) tested the effect of intraperitoneal valerenic acid compared to diazepam, chlorpromazine, and pentobarbital on ability to walk on a rotating rod and grip strength in mice. The effects of valerinic acid on spontaneous motor activity and on pentobarbital-induced sleeping time were also assessed. Diazepam, a muscle relaxant, affected the grip test but not the rotarod test, whereas chlorpromazine, a neuroleptic, affected the rotarod test but not the grip test. Valerenic acid, like pentobar-bital, decreased performance in both the rotarod and grip tests. The authors concluded that valerenic acid, like pentobarbital, has general CNS depressant activity. Valerenic acid also decreased spontaneous motor activity and prolonged pentobarbital-induced sleeping time. Dose-response effects of valerenic acid were also observed by the investigators. At a dose of 50 mg/kg, a decrease in spontaneous motor activity occurred. At 100 mg/kg, mice exhibited ataxia, then remained motionless. Muscle spasms occurred at 150-200 mg/kg and convulsions at 400 mg/kg, followed by death in six of seven mice within 24 hours (17).

Sedation is mediated predominantly through the inhibitory neurotrans-mitter GABA. Although the mechanism of action of valerian as a sleep aid is not fully understood, it may involve inhibition of the enzyme that breaks down

GABA. Dihydrovaltrate, hydroxyvalerenic acid, a hydroalcoholic extract containing 0.8% valerenic acid; a lipid extract; an aqueous extract of the hydroalcoholic extract, and another aqueous extract of V. officinalis (L.) were assessed for in vitro binding to rat GABA, benzodiazepine, and barbiturate receptors (18). The results indicated that an interaction of some component of the hydroalcoholic extract, the aqueous extract derived from the hydroalcoholic extract, and the other aqueous extract had affinity for the GABAa receptor. Because hydroxyvalerenic acid (a volatile oil sesquiterpene) and dihydrovaltrate (a valepotriate) did not show any notable activity, the investigators could not identify the specific constituents responsible for this activity. The lipophilic extract derived from the hydroalcoholic extract, as well as dihydrovaltrate, showed affinity for barbiturate receptors, and some affinity for peripheral benzodiazepine receptors.

Other in vitro studies have also yielded results that suggest GABA-me-diated activity; however, the active constituent was unidentified. Cavadas and colleagues verified that valerenic acid (0.1 mmol/L) was not able to displace [3H] muscimol from the GABAA receptor, although both an aqueous and a hydroalcoholic extract were able to do so. The investigators then attempted to identify other compounds in the extracts capable of displacing [3H] muscinol. Both glutamate and glutamine, amino acids present in the aqueous extract, had little inhibitory effect on [3H] muscinol binding. However, glutamine can cross the blood-brain barrier (BBB) and can be taken up by nerve terminals and converted to GABA inside GABA-nergic neurons. Thus, glutamine could be responsible for the sedative effect of the aqueous extract, but not the hydroalcoholic extract, in which it is not present. GABA is found in both extracts, but GABA itself cannot explain the sedative effects of valerian because it is unlikely to cross the BBB in amounts significant enough to cause sedation (19). However, the amount of GABA present in the aqueous extract is sufficient to have effects on peripheral GABA receptors, perhaps resulting in muscle relaxation (20). Another study (21) suggests a different mechanism of action involving inhibition of neuronal GABA uptake and stimulation of GABA release from synaptosomes. These investigators did not attempt to elucidate which constituent of the aqueous extract was responsible for these effects.

The CNS-depressant component of valerian is still unknown. Thus far, three major constituents of valerian have been identified: the volatile or essential oil, containing sesquiterpenes and monoterpenes, nonglycosidic iridoid esters (valepotriates), and a small number of alkaloids (2). Valepotriates are unstable compounds and are easily hydrolyzed by heat and moisture (22). In addition, valepotriates are not water soluble, and aqueous extracts contain small amounts (22). For example, the aqueous extract used in the study by Balderer and Borbely, described previously (13) was analyzed using thin-layer chromatography, and no valepotriates were detectable. Furthermore, valepotriates are not well absorbed orally (23). Therefore, the likelihood that valepotriates are a major contributor to valerian's effects is questionable. Because of the low amount of alkaloid present in preparations, their contribution is also questionable (24). It is postulated that a combination of volatile oils, valepotriates, and possibly certain water-soluble constituents that have not yet been identified are responsible for valerian's sedative effects (23).

Antidepressant effects of valerian were identified by Oshima and associates using a methanol extract of V. fauriei roots (25). They found a strong antidepressant activity in mice as measured by the forced swimming test. One active component isolated was a-kessyl alcohol, a volatile oil component. At 30 mg/kg intraperitoneally, a-kessyl alcohol exhibited an effect similar to imipramine, a commonly used antidepressant. Kessanol and cyclokessyl acetate, guaiane-type sesquiterpenoids, also exhibited antidepressant activity. Kanokonol, kessyl glycol, and kessyl glycol diacetate, valerane-type sesquiterpenoids, did not exhibit an effect.

A 30% ethanol extract of the Japanese valerian root ("Hokkai-Kisso") extract (4.1 g/kg and 5.7 g/kg) and imipramine (20 mg/kg) also demonstrated statistically significant antidepressant effects compared to placebo as measured by the forced swimming test in rats (26). As in the Oshima study, kessyl glycol diacetate exhibited no antidepressant activity in the forced swimming test. Because the forced swimming test can be affected by stimulants, anti-cholinergics, and antihistamines as well as antidepressants, the effect of the valerian extract on reserpine-induced hypothermia, a test for antidepressant activity and inhibition of neuronal reuptake of monoamines, was measured. Both valerian (11.2 g/kg) and imipramine (20 mg/kg) reversed reserpine-in-duced hypothermia, suggesting that the antidepressant effect of valerian is caused by reuptake of monoamine neurotransmitters, as with conventional antidepressants.

More evidence is needed to evaluate the use of valerian in children. One study using a combination product of valerian root extract and lemon balm leaf extract found that symptoms of dyssomnia or pathological restlessness might decrease in children under age 12 (27).

5.2. Anxiety

A few studies have examined the effects of valerian on anxiety (28-30). Cropley and colleagues investigated whether kava or valerian could moderate physiological stress induced under laboratory conditions in healthy vol unteers. Subject (n = 18-kava, and n = 18-valerian) and comparison group (n = 36) volunteers performed a standardized mental stress task 1 week apart. Cases had their blood pressure, heart rate, and subjective ratings of pressure assessed at rest and during the mental stress task (time 1 = T1). The valerian subjects took a standard dose for 7 days (time 2 = T2). In the valerian group, heart rate reaction to mental stress was found to decline, systolic blood pressure decreased significantly, and subjects reported less pressure during mental stress test tasks at T2 relative to T1. Behavioral performance on the standardized mental stress test task did not change between the groups over the two time points. There were no significant differences in blood pressure, heart rate, or subjective reports of pressure between T1 and T2 in the control group.

Kohnen and Oswald conducted a study on the effects of valerian, propranolol, and combinations on activation, performance, and mood of healthy volunteers under social stressor conditions. The results of this study were equivocal and published over 15 years ago; however, it is mentioned here for historical reference (29).

Andreatini and colleagues examined the effect of valerian extract (valepotriates) using a randomized, parallel, double-blind placebo-controlled pilot study design in patients with generalized anxiety disorder (GAD). After a 2-week wash-out period, 36 patients with GAD as defined by the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised were randomized to one of the following three treatment groups for 4 weeks: valepotriates, mean daily dose of 81.3 mg; diazepam, mean daily dose of 6.5 mg; or placebo. There was a significant reduction in the psychic factor of the Hamilton anxiety scale in the valepotriates group; however, the principal study analysis using between group comparisons on total Hamilton anxiety scale scores found negative results. The conclusion of this study suggests that there may be a potential anxiolytic effect of valepotriates on the psychic symptoms of anxiety, but the total number of subjects per group (n = 12) was very small and results must be viewed as preliminary (30).

5.3. Musculoskeletal Relaxation

Isovaltrate and valtrate (valepotriates) and valeronone, an essential oil component, isolated from V. edulis ssp. procera Meyer (Valeriana "mexicana") caused suppression of rhythmic contractions in guinea pig ileum in vivo at a dose of 20 mg/kg administered intravenously via the jugular vein. The investigators also demonstrated that the same compounds as well as dihydrovaltrate isolated from the same valerian species produced relaxation of carbachol-

stimulated guinea pig ileum preparations in vitro. They concluded that these compounds have a musculotropic action in concentrations from 10-5 to 10-4 M (31).

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