Valerian Extract Research Articles

In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes

Phytochemical-mediated modulation of cytochrome P450 (CYP) activity may underlie many herb-drug interactions. Single-time point phenotypic metabolic ratios were used to determine whether long-term supplementation of goldenseal ( Hydrastis canadensis ), black cohosh ( Cimicifuga racemosa ), kava kava ( Piper methysticum ), or valerian ( Valeriana officinalis ) extracts affected CYP1A2, CYP2D6, CYP2E1, or CYP3A4/5 activity. Twelve healthy volunteers (6 women) were randomly assigned to receive goldenseal, black cohosh, kava kava, or valerian for 28 days. For each subject, a 30-day washout period was interposed between each supplementation phase. Probe drug cocktails of midazolam and caffeine, followed 24 hours later by chlorzoxazone and debrisoquin (INN, debrisoquine), were administered before (baseline) and at the end of supplementation. Presupplementation and postsupplementation phenotypic trait measurements were determined for CYP3A4/5, CYP1A2, CYP2E1, and CYP2D6 by use of 1-hydroxymidazolam/midazolam serum ratios (1-hour sample), paraxanthine/caffeine serum ratios (6-hour sample), 6-hydroxychlorzoxazone/chlorzoxazone serum ratios (2-hour sample), and debrisoquin urinary recovery ratios (8-hour collection), respectively. The content of purported "active" phytochemicals was determined for each supplement. Comparisons of presupplementation and postsupplementation phenotypic ratio means revealed significant inhibition (approximately 40%) of CYP2D6 (difference, -0.228; 95% confidence interval [CI], -0.268 to -0.188) and CYP3A4/5 (difference, -1.501; 95% CI, -1.840 to -1.163) activity for goldenseal. Kava produced significant reductions (approximately 40%) in CYP2E1 only (difference, -0.192; 95% CI, -0.325 to -0.060). Black cohosh also exhibited statistically significant inhibition of CYP2D6 (difference, -0.046; 95% CI, -0.085 to -0.007), but the magnitude of the effect (approximately 7%) did not appear to be clinically relevant. No significant changes in phenotypic ratios were observed for valerian. Botanical supplements containing goldenseal strongly inhibited CYP2D6 and CYP3A4/5 activity in vivo, whereas kava inhibited CYP2E1 and black cohosh weakly inhibited CYP2D6. Accordingly, serious adverse interactions may result from the concomitant ingestion of goldenseal supplements and drugs that are CYP2D6 and CYP3A4/5 substrates. Kava kava and black cohosh may interact with CYP2E1 and CYP2D6 substrates, respectively. Valerian appears to be less likely to produce CYP-mediated herb-drug interactions.

Effect of goldenseal, black cohosh, kava kava, and valerian on human cytochrome p450 1A2, 2D6, 2E1, and 3A4 phenotypes

Background Phytochemical-mediated modulation of cytochrome P450 activity may underlie many herb-drug interactions. Single time-point, phenotypic metabolic ratios were used to determine whether supplementation of goldenseal, black cohosh, kava, or valerian extracts affected CYP1A2, CYP2D6, CYP2E1, or CYP3A4 activity. Methods Twelve healthy volunteers were randomly assigned to receive each supplement for 28 days followed by a 30-day washout period. Probe drug cocktails of midazolam, caffeine, chlorzoxazone, and debrisoquine were administered before and at the end of supplementation. Pre- and post-supplementation phenotypic ratios were determined for CYP3A4, CYP1A2, CYP2E1, and CYP2D6 using 1-hydroxymidazolam/midazolam serum ratios (1-hr), paraxanthine/caffeine serum ratios (6-hr), 6-hydroxychlorzoxazone/chlorzoxazone serum ratios (2-hr), and debrisoquine urinary recovery ratios (8-hr), respectively. Results Comparisons of pre- and post-goldenseal phenotypic ratios revealed significant inhibition (~40%) of CYP2D6 and CYP3A4 activity. Black cohosh also inhibited CYP2D6, but the magnitude (~7%) did not appear clinically relevant. No significant changes were observed for kava or valerian. Conclusions Goldenseal strongly inhibited CYP2D6 and CYP3A4 activity. Accordingly, serious adverse interactions may result if goldenseal is ingested with drugs that are CYP2D6 and CYP3A4 substrates. Kava, black cohosh and valerian appear less likely to produce such interactions. Clinical Pharmacology & Therapeutics (2005) 77, P36–P36; doi: 10.1016/j.clpt.2004.12.030

Assessing subjective and psychomotor effects of the herbal medication valerian in healthy volunteers

Valerian is the common name given to the genus Valeriana, an odiferous, herbaceous perennial plant widely distributed in the temperate regions of Asia, Europe, and North America. It is among the most widely used herbal medicines in the world. Numerous clinical studies have demonstrated valerian's ability to improve sleep; however, to the best of our knowledge, no study has systematically assessed subjective and psychomotor/cognitive effects of valerian in young healthy adults across a range of doses. In the present study, we sought to determine whether valerian extract ( Valeriana officinalis) altered mood and/or impaired psychomotor/cognitive performance in young healthy volunteers. We examined the effects of valerian extract (600, 1200, and 1800 mg) and 10 mg diazepam (positive control) compared to placebo in 10 young healthy volunteers. Dependent measures included subjective and psychomotor variables. The valerian extract had no significant effects on any of the dependent measures. Diazepam, though, produced subjective effects as measured by four different rating scales, and impaired psychomotor/cognitive performance. The data suggest that acute administration of valerian does not have mood-altering or psychomotor/cognitive effects in young healthy volunteers.

Neuropharmacological profile of hydroalcohol extract of Valeriana edulis ssp. procera roots in mice.

Valerian is the common name given to the crude drug consisting of the underground organs of the species Valeriana. Valeriana edulis ssp. procera Meyer is the Mexican valerian. The aim of the present work was to elucidate the neuropharmacological profile of a hydroalcohol extract of Valeriana edulis roots at doses of 100, 300 and 1000 mg/kg in several experimental models. A dose-dependent anticonvulsant and anxiolytic-like effect of V. edulis was demonstrated. In addition, the extract decreased rotarod performance and traction force and prolonged the pentobarbital-induced sleeping time at high doses. Concomitant administration of valerian extract and pentobarbital showed a synergistic effect on motor coordination and traction force in mice. The anxiolytic-like effect of V. edulis was compared with diazepam and with diphenhydramine and doxylamine, the latter in order to consider the H(1)-antihistamine effect as another possibility to explain, at least in part, the central nervous system depressant effect of valerian. These results also underlie the medical and industrial use of this species and allowed the conclusion that the extract of V. edulis has central nervous depressant properties similar to, but with some differences to V. of ficinalis, a very well known species.

The Gamma-Aminobutyric Acidergic Effects of Valerian and Valerenic Acid on Rat Brainstem Neuronal Activity

Valerian is a medicinal herb that produces anxiolytic and sedative effects. It was suggested that valerian acts via gamma-aminobutyric acid (GABA)ergic mechanisms. Previous studies showed binding of valerian extract to GABA receptors, but the functional effect of the binding has not been demonstrated. In this study we evaluated the GABAergic effect of valerian extract and one of its major constituents, valerenic acid, on brainstem neuronal activity in an in vitro neonatal rat brainstem preparation. We first observed that muscimol, a GABA(A) receptor agonist, decreased the firing rate in most brainstem neurons in a concentration-related fashion; 30 micro M produced a 38.9% +/- 3.0% (mean +/- SE) inhibition compared with control values (P < 0.01; 50% inhibitory concentration [IC(50)], 2.0 +/- 0.1 microM). This effect was antagonized by bicuculline (10 microM), a GABA(A) antagonist. Then we showed that valerian extract 3 mg/mL induced a 29.6% +/- 5.1% inhibition with an IC(50) of 240 +/- 18.7 microg/mL, whereas 100 microM valerenic acid induced a 22.2% +/- 3.4% inhibition with an IC(50) of 23 +/- 2.6 microM (both P < 0.01). Bicuculline antagonized the inhibitory effects of both the valerian extract and valerenic acid. In addition, pretreatment with valerian extract or valerenic acid decreased the brainstem inhibitory effects produced by muscimol (both P < 0.05), suggesting that these compounds play an important role in the regulation of GABAergic activity. Data from this study suggest that the pharmacological effects of valerian extract and valerenic acid are mediated through modulation of GABA(A) receptor function. Thus, valerian may potentiate the sedative effects of anesthetics and other medications that act on GABA receptors, and presurgical valerian use may cause a valerian-anesthetic interaction. Valerian is an herb used in treating anxiety and insomnia. We observed that the valerian effects are mediated through brain gamma-aminobutyric acid (GABA) receptors in a rat brainstem preparation. Thus, valerian may potentiate the effects of anesthetics that act on GABA receptors, and presurgical valerian use may cause a valerian-anesthetic interaction.

Morning/evening menopausal formula relieves menopausal symptoms: a pilot study.

The purpose of the study was to determine the efficacy of a morning/evening menopause formula (morning capsule contains panax ginseng, black cohosh, soy, and green tea extracts; evening capsule contains black cohosh, soy, kava, hops, and valerian extracts) for relieving menopausal symptoms such as hot flashes and sleep disturbance. Healthy postmenopausal women, between 45 and 65 years of age, were asked to take the menopause formula orally, one capsule of the morning formula every morning and one capsule of the evening formula every evening for 2 months. The Greene Climacteric Scale (GCS) and the Pittsburgh Sleep Quality Index (PSQI) were used to determine the efficacy. Morning/evening menopause formula significantly reduced the number of hot flashes. The reduction in the number of hot flashes was observed as early as at the end of the second week. At the end of the second week, the number of hot flashes was reduced by 47%. The morning/evening menopause formula also significantly reduced the GCS total and subscale scores. At the end of the eighth week, the vasomotor, anxiety, and depression scores of GCS were reduced by 50%, 56%, and 32%, respectively. Furthermore, the morning/evening menopause formula significantly reduced global PSQI score and scores in five components (sleep quality, sleep latency, sleep duration, sleep disturbance, and daytime dysfunction) by 18%-46%. This study suggests that the morning/evening menopausal formula is safe and effective for relieving menopausal symptoms including hot flashes and sleep disturbance.

In vitro study on the genotoxicity of dichloromethane extracts of valerian (DEV) in human endothelial ECV304 cells and the effect of vitamins e and c in attenuating the DEV-induced DNA damages

To study the genotoxicity of valepotriates in vitro, the degree of DNA damage in human endothelial cell line ECV304 treated with 5–60 μg/mL of dichloromethane extracts of valerian (DEV) was analyzed by the Comet assay. No DNA damage was observed in ECV304 cells after culture for 48 h in the presence of 5,10, and 20 μg/mL of DEV. But a moderate degree of DNA damage was observed in the cells treated with 40 or 60 μg/mL of DEV. Quantitative analyses of DNA damage in the presence of antioxidants vitamin E (VE) and vitamin C (VC) were also carried out. The study revealed that both VE and VC exhibited a biphasic effect, reducing DEV-induced DNA damages at low concentrations but increasing them at high concentrations. We concluded that (1) the observed DNA damage in ECV304 cells induced by high concentrations of DEV was mainly through epigenetic mechanisms, i.e., reactive oxygen species mediated oxidative DNA damage (2) at the low doses, DEV did not appear to have any significant genotoxicity in ECV304 cells, and (3) VE and VC, at proper concentrations, can reduce or eliminate the adverse effects derived from high doses of DEV. This study should serve as scientific guidance for clinical therapy of valerian preparation.

Interactions of valerian extracts and a fixed valerian-hop extract combination with adenosine receptors.

Phytopharmaceuticals and dietary supplements containing valerian are used as mild sleep-inducing agents. An in vitro radioligand binding assay at A(1) and A(2A) adenosine receptors (ARs) was conducted with a fixed extract combination of valerian and hop (Ze 91019) to investigate a possible mechanism for the pharmacological activity of the extract. Component extracts of valerian and hop were also individually investigated. The fixed combination Ze 91019 as well as the valerian extracts therein exhibited selective affinity to A(1)ARs (K(i) = 0.15-0.37 mg/mL vs [(3)H]CCPA). The same extracts exhibited partial agonist activity at the A(1) adenosine receptor as indicated by a lower degree of stimulation of [35S]GTP gamma S binding in membrane preparations of CHO-hA(1) cells as compared to the full A(1) AR agonist N(6)-cyclopentyladenosine (CPA). In addition valerian extract inhibited cAMP accumulation in CHO-hA(1) cell membranes. The partial agonistic activity at A(1)ARs may thus play a role in the sleep inducing effect of Ze 91019 and the valerian extract therein.

Effects of Valeriana officinalis extracts on [3H]flunitrazepam binding, synaptosomal [3H]GABA uptake, and hippocampal [3H]GABA release.

Extracts of Valeriana officinalis have been used in folkloric medicine for its sedative, hypnotic, tranquilizer and anticonvulsant effects, and may interact with gamma-aminobutyric acid (GABA) and/or benzodiazepine sites. At low concentrations, valerian extracts enhance [3H]flunitrazepam binding (EC50 4.13 x 10(-10) mg/ml). However, this increased [3H]flunitrazepam binding is replaced by an inhibition at higher concentrations (IC50 of 4.82 x 10(-1) mg/ml). These results are consistent with the presence of at least two different biological activities interacting with [3H]flunitrazepam binding sites. Valerian extracts also potentiate K+ or veratridine-stimulated release of radioactivity from hippocampal slices preloaded with [3H]GABA. Finally, inhibition of synaptosomal [3H]GABA uptake by valerian extracts also displays a biphasic interaction with guvacine. The results confirm that valerian extracts have effects on GABA(A) receptors, but can also interact at other presynaptic components of GABAergic neurons.

The quantitative EEG as a screening instrument to identify sedative effects of single doses of plant extracts in comparison with diazepam

Two multiple crossover studies, each involving 12 adult female subjects, were performed to screen for acute sedative effects of eight different plant extracts (Valeriana off., Lavandula off., Passiflora incarnata, Kava-kava, Melissa off., Eschscholzia californica, Hypericum perforatum and Ginkgo biloba). Both studies were placebo-controlled, and a single dose of 10 mg diazepam was used as an active reference drug. All drugs were administered as a single dose. Prior to administration, as well as 2 h and 3 h after administration the EEG was recorded from two leads (F(z)-C(z) and O(z)-T(6)) under vigilance-controlled and resting conditions, for five minutes each. The extend of tiredness was rated by the subjects on a visual analogue scale. The EEG was digitized and stored for later analysis of the absolute and relative power of seven factorially defined frequency bands. Under diazepam the power in the theta frequency band decreased while it increased in the beta band. In contrast, some plant extracts showed an increase of power in the theta frequency band, but no increase in the beta frequency range. Valerian extract, which was administered in both studies, displayed an increase of power in the delta and theta band and a decrease in the beta band. Self-rated tiredness increased under diazepam and under some of the plant extracts but not with placebo. The results show that sedating effects of plant extracts can be identified by quantitative EEG analysis and by self-assessment instruments.

Clinical trials with Phyto-Psychopharmacological agents

Phyto-psychopharmacological agents are extracts of plants with stimulating or calming effects on the central nervous system. Phyto-psycho-pharmacological agents are among the most commonly prescribed herbal medicines in Germany. The efficacy and harmlessness of some of the preparations have been established by high quality clinical trials. Between 1975 and 1992, a total of 34 clinical studies involving some 2326 patients were published on the effects of Ginkgo special extract EGb 761 and LI 1370; to date, 28 clinical trials in 2120 patients have been under-taken with alcoholic extracts of St. John's Wort. The therapeutic efficacy of kava and valerian extracts has been investigated in six and four controlled studies, respectively. In general, a high placebo effect is likely, which is why it is essential to include control groups in these studies. A considerable advantage over synthetic psychopharmacological agents is the low incidence of side effects, which in safety assessment studies is below 3%. The sharp increase in quality standards for clinical trials has meant that only a few preparations have undergone large scale testing programs in accordance with international guidelines. For other phyto-psychopharmacological agents, there is the danger that no further clinical trials will be undertaken due to the excessively high standards now demanded.

The Effect of Valerian Extract on Sleep Polygraphy in Poor Sleepers: A Pilot Study

The effect of acute and repeated treatment (seven days) with a valerian extract (Valdispert forte, 405 mg t.i.d.) on objective and subjective measures of sleep was studied. Polysomnography was conducted in 14 elderly poor sleepers on three nights, at one-week intervals (N0, N1, N2). N0 was an adaptation night, N1 and N2 the first and last night under treatment. Six subjects received placebo and eight subjects valerian. Subjects in the valerian group showed an increase in slow-wave sleep (SWS) and a decrease in sleep stage 1. Density of K-complexes was increased under active treatment. There was no effect on sleep onset time or time awake after sleep onset. REM sleep was unaltered. There was also no effect on self-rated sleep quality. We hypothesize that valerian increases SWS in subjects with low baseline values.

Potential Psychotropic Activity of Phlebotropic Drugs: Weak Interactions with Brain Benzodiazepine Receptors

Background: Epidemiological and psychometric studies have provided evidence that some symptoms of venous disease might reflect a psychosomatic rather than organic disorder. Traditionally, plant extracts are prescribed to alleviate such symptoms. Since benzodiazepines (BZ) and BZ-like compounds are present in various plants, we studied potential interactions of ‘phlebotropic’ drugs with BZ receptors. Methods: Six drug preparations used in phlebology and extracts of hop and valerian were tested for neuronal and mitochondrial BZ receptor binding activity in vitro. In addition, plasma samples of volunteers who ingested phlebotropic drugs for 3 weeks were assayed for the presence of BZ-like activity. Results: All phlebotropic drug preparations interacted weakly with central and/or peripheral BZ receptors in vitro. Their diazepam-equivalent concentrations were, however, too low to be of pharmacological relevance. No binding activity was recovered in the blood of volunteers pretreated with phlebotropic drugs. Conclusion: The positive influence of so-called ‘phlebotropic’ drugs on the subjective symptoms of venous disease is not mediated through BZ receptors.

Aqueous extract of valerian reduces latency to fall asleep in man.

A group of 8 volunteers suffering from mild insomnia received a placebo, 450 mg or 900 mg of an aqueous extract of valerian root in a double-blind, repeated measures, random-order design. Subjective sleep ratings were assessed by questionnaire and movements were recorded throughout the night with wrist-worn activity meters. Using the first period of 5 consecutive minutes without movement as a criterion of sleep onset, there was a significant decrease in sleep latency with 450 mg valerian compared to placebo (15.8 ± 2.2 min vs 9.0 ± 1.5 min; paired “t” = 3.37;p < 0.01). The higher dose of valerian produced no further improvement in sleep latency.

Aqueous extract of valerian root ( Valeriana officinalis L.) improves sleep quality in man

The effect of an aqueous extract of valerian ( Valeriana officinalis L.) root on subjectively rated sleep measures was studied on 128 people. Each person received 9 samples to test (3 containing placebo, 3 containing 400 mg valerian extract and 3 containing a proprietary over-the-counter valerian preparation). The samples, identified only by a code number, and presented in random order, were taken on non-consecutive nights. Valerian produced a significant decrease in subjectively evaluated sleep latency scores and a significant improvement in sleep quality; the latter was most notable among people who considered themselves poor or irregular sleepers, smokers, and people who thought they normally had long sleep latencies. Night awakenings, dream recall and somnolence the next morning were relatively unaffected by valerian. With the proprietary valerian-containing preparation, the only change was a significant increase in reports of feeling more sleepy than normal the next morning. Thus the questionnaire, simple to use and non-invasive, provides a sensitive means for detecting the effects of mild sedatives on different aspects of sleep in man. It also allows identification within the test population of the subgroups most affected.