COMMUNITY HERBAL MONOGRAPH ON
VALERIANA OFFICINALIS
L., RADIX
1
2
Well-established use
Traditional use
With regard to the marketing authorisation
application of Article 10a of Directive
2001/83/EC as amended
With regard to the registration application of
Article 16d(1) of Directive 2001/83/EC as
amended
Valeriana officinalis
L., radix (valerian root)
Valeriana officinalis
L., radix (valerian root)
•
Herbal substance
not covered
•
Herbal substance
- dried valerian root
•
Herbal preparations
-
extracts prepared with ethanol/water
(ethanol 40 -70 % (V/V))
•
Herbal preparations
-
dry extracts prepared with water
-
valerian tincture
-
expressed juice from fresh root
-
valerian root oil
Well-established use
Traditional use
Herbal preparation in solid or liquid dosage forms
for oral use.
The pharmaceutical form should be described by
the European Pharmacopoeia full standard term.
Herbal substance or herbal preparation in solid or
liquid dosage forms for oral use.
The pharmaceutical form should be described by
the European Pharmacopoeia full standard term.
4.
C
LINICAL
P
ARTICULARS
4.1.
Therapeutic indications
Well-established use
Traditional use
Herbal medicinal product for the relief of mild
nervous tension and sleep disorders.
Traditional herbal medicinal product for relief of
mild symptoms of mental stress and to aid sleep.
The product is a traditional herbal medicinal
product for use in specified indications
exclusively based on long-standing use.
1
The material complies with the Ph. Eur. monographs.
2
The declaration of the active substance(s) should be in accordance with relevant herbal quality guidance.
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4.2.
Posology and method of administration
Well-established use
Traditional use
Posology
Oral use
Posology
Oral use
Adolescents over 12 years of age, adults, elderly
Adolescents over 12 years of age, adults, elderly
Single dose:
-
extracts prepared with ethanol/water (ethanol
max. 40 - 70 % V/V) equivalent to 2 to 3 g of
the herbal substance
For relief of mild nervous tension up to 3 times
daily.
For relief of sleep disorders, a single dose half to
one hour before bedtime with an earlier dose
during the evening if necessary.
Single dose:
-
0.3 to 1 g dried valerian root (e.g. as
powdered herbal substance)
-
1 to 3 g dried valerian root for preparation of
a tea
-
dry extracts prepared with water
corresponding to 1 to 3 g of the herbal
substance
-
valerian tincture corresponding to 0.3 to 1 g
of the herbal substance
-
15 ml of expressed juice
-
15 mg of valerian root oil
Maximum daily dose: 4 single doses.
Method of administration
No special advice.
For relief of mild symptoms of mental stress up to
3 times daily.
To aid sleep, a single dose half to one hour before
bedtime with an earlier dose during the evening if
necessary.
Duration of use
Because of its gradual onset of efficacy valerian
root is not suitable for acute interventional
treatment of mild nervous tension or sleep
disorders. To achieve an optimal treatment effect,
continued use over 2 – 4 weeks is recommended.
Maximum daily dose: 4 single doses
Method of administration
No special advice.
If symptoms persist or worsen after 2 weeks of
continued use, a doctor should be consulted.
Duration of use
If symptoms persist during the use of the
medicinal product, a doctor or a qualified health
care practitioner should be consulted.
4.3.
Contraindications
Well-established use
Traditional use
Patients with known hypersensitivity to the active
substance should not use valerian root
preparations.
Patients with known hypersensitivity to the active
substance should not use valerian root and its
preparations.
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4.4.
Special warnings and precautions for use
Well-established use
Traditional use
The use of this product is not recommended in
children below the age of 12 years.
The use of this product is not recommended in
children below the age of 12 years.
For valerian preparations containing ethanol the
appropriate labelling for ethanol, taken from the
For valerian tincture the appropriate labelling for
ethanol, taken from the guideline
3
on excipients,
must be included.
4.5.
Interaction with other medicinal products and other forms of interaction
Well-established use
Traditional use
Only limited data on pharmacological interactions
with other medicinal products are available.
Clinically relevant interaction with drugs
metabolised by the CYP 2D6, CYP 3A4/5, CYP
1A2 or CYP 2E1 pathway has not been observed.
Combination with synthetic sedatives requires
medical diagnosis and supervision.
Only limited data on pharmacological interactions
with other medicinal products are available.
Clinically relevant interaction with drugs
metabolised by the CYP 2D6, CYP 3A4/5, CYP
1A2 or CYP 2E1 pathway has not been observed.
Combination with synthetic sedatives is not
recommended.
4.6.
Pregnancy and lactation
Well-established use
Traditional use
Safety during pregnancy and lactation has not
been established. As a precautionary measure,
because of lack of data, use during pregnancy and
lactation is not recommended.
Safety during pregnancy and lactation has not
been established. As a precautionary measure,
because of lack of data, use during pregnancy and
lactation is not recommended.
4.7.
Effects on ability to drive and use machines
Well-established use
Traditional use
May impair ability to drive and use machines.
Affected patients should not drive or operate
machinery.
May impair ability to drive and use machines.
Affected patients should not drive or operate
machinery.
4.8.
Undesirable effects
Well-established use
Traditional use
Gastrointestinal symptoms (e.g. nausea,
abdominal cramps) may occur after ingestion of
valerian root preparations. The frequency is not
known.
If other adverse reactions not mentioned above
occur, a doctor or a pharmacist should be
consulted.
Gastrointestinal symptoms (e.g. nausea,
abdominal cramps) may occur after ingestion of
valerian root preparations. The frequency is not
known.
If other adverse reactions not mentioned above
occur, a doctor or a qualified health care
practitioner should be consulted.
3
‘Guideline on excipients in the label and package leaflet of medicinal products for human use’ (Notice to Applicants,
Volume 3B)
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4.9. Overdose
Well-established use
Traditional use
Valerian root at a dose of approximately 20 g
caused benign symptoms (fatigue, abdominal
cramp, chest tightness, lightheadedness, hand
tremor and mydriasis), which disappeared within
24 hours. If symptoms arise, treatment should be
supportive.
Valerian root at a dose of approximately 20 g
caused benign symptoms (fatigue, abdominal
cramp, chest tightness, lightheadedness, hand
tremor and mydriasis), which disappeared within
24 hours. If symptoms arise, treatment should be
supportive.
5.1
Pharmacodynamic properties
Well-established use
Traditional use
Pharmacotherapeutic group: Hypnotics and
sedatives, ATC code: N05C M09
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended.
The sedative effects of preparations of valerian
root, which have long been recognised
empirically, have been confirmed in preclinical
tests and controlled clinical studies. Orally
administered dry extracts of valerian root prepared
with ethanol/water (ethanol max. 70 % (V/V)) in
the recommended dosage have been shown to
improve sleep latency and sleep quality. These
effects cannot be attributed with certainty to any
known constituents. Several mechanisms of action
possibly contributing to the clinical effect have
been identified for diverse constituents of valerian
root (sesquiterpenoids, lignans, flavonoids) and
include interactions with the GABA-system,
agonism at the A1 adenosine receptor and binding
to the 5-HT1A receptor.
5.2
Pharmacokinetic properties
Well-established use
Traditional use
No data available.
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended.
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Well-established use
Traditional use
Extracts with ethanol and the essential oil of
valerian root have shown low toxicity in rodents
during acute tests and from repeated dose toxicity
over periods of 4 – 8 weeks.
Tests on reproductive toxicity, genotoxicity and
carcinogenicity have not been performed.
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended, unless
necessary for the safe use of the product.
Tests on reproductive toxicity, genotoxicity and
carcinogenicity have not been performed.
6.
P
HARMACEUTICAL PARTICULARS
Well-established use
Traditional use
Not applicable.
Not applicable.
7.
D
ATE OF
C
OMPILATION
/
LAST REVISION
26 October 2006
4
Where valerian root is used as powder, the total exposure to valepotriates and degradation products such as
baldrinals should not exceed the maximum exposure with herbal tea (prepared infusion). Alkylating and
cytotoxic properties of valepotriates and baldrinals are normally not relevant for finished products because
valepotriates decompose rapidly and only traces of valepotriates or their degradation products such as baldrinals
are found. Where the applicant cannot demonstrate that the total exposure to valepotriates with the finished
product does not exceed the maximum exposure with herbal tea, he has to provide data on determination of the
threshold of toxicological concern compatible with the safe use of the preparation.
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Assessment Report
T
ABLE OF CONTENTS
II
NON-CLINICAL STUDIES ................................................................................................................... 3
II.1
P
HARMACODYNAMICS
............................................................................................................................ 3
II.1.1
Isolated substances ....................................................................................................................... 3
II.1.2
Aqueous and aqueous-ethanolic valerian root extracts ................................................................ 4
II.1.3
Conclusion .................................................................................................................................... 6
II.2
T
OXICOLOGY
.......................................................................................................................................... 6
II.2.1
Acute Toxicity ............................................................................................................................... 6
II.2.2
Sub-acute/Chronic Toxicity .......................................................................................................... 7
II.2.3
Reproductive Toxicity ................................................................................................................... 7
II.2.4
Mutagenicity/Carcinogenicity....................................................................................................... 7
II.2.5
Conclusion .................................................................................................................................... 8
III
CLINICAL PHARMACOLOGY ...........................................................................................................8
III.1
P
HARMACODYNAMICS
............................................................................................................................ 8
III.1.1
EEG trials ..................................................................................................................................... 8
III.1.2
Volunteer trials in stress situations............................................................................................. 10
III.2
S
AFETY
S
TUDIES
.................................................................................................................................. 10
Conclusion.................................................................................................................................................... 11
III.3
P
HARMACOKINETICS
&
BIOAVAILABILITY
........................................................................................... 11
III.3.1
Pharmacokinetics........................................................................................................................ 11
III.3.2
Bioavailability............................................................................................................................. 11
III.4
I
NTERACTIONS
...................................................................................................................................... 12
III.4.1
Pharmacodynamic interactions .................................................................................................. 12
III.4.2
Pharmacokinetic interactions ..................................................................................................... 12
Conclusion.................................................................................................................................................... 12
IV
CLINICAL EXPERIENCE .................................................................................................................. 12
IV.1
E
FFICACY
............................................................................................................................................. 12
IV.1.1
Dose-Finding Trials.................................................................................................................... 12
IV.1 2
Controlled Clinical Trials........................................................................................................... 13
IV.2
TOLERABILITY .............................................................................................................................. 17
IV.3
TRADITIONAL USE........................................................................................................................ 18
IV.3.1
Europe ........................................................................................................................................ 18
IV.3.2
Asia ............................................................................................................................................. 21
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I
INTRODUCTION
This assessment report reviews scientific data available on Valerianae radix (
Valeriana officinalis
L.).
This report takes into account the ‘Core Data for Valerianae radix’ prepared by the EMEA ad hoc
Working Group on Herbal Medicinal Products in 1998. Since, several clinical and preclinical trials
have been published that supplement valuable information on clinical efficacy and possible modes of
action of the herbal substance. This information is reflected in the Community herbal monograph.
This report focusses on findings with aqueous and aqueous-ethanolic extracts since clinical experience
has been collected mainly with these types of extracts, and they were used in most non-clinical and
clinical trials.
Other long-used preparations like the dried herbal substance
1
, herbal tea, aqueous-methanolic extracts,
expressed juice from fresh root and valerian root oil are discussed under the chapter ‘Traditional use’.
Use of extraction solvents such as dichloromethane and other highly lipophilic solvents may result in
substantial differences in the extract composition. No information on comparability of highly
lipophilic extracts to conventional valerian roots extracts with respect to constituents and/or biological
response and clinical effects is available. For this reason, there is no rational basis for discussion of
these kinds of extracts in this report.
The extracts used in the trials are specified in the comments as far as possible. Unfortunately, in many
publications correct specifications of solvent and drug-extract ratio (DER) are missing. In these cases
no details can be given, if the extract could not be identified otherwise.
II
NON-CLINICAL STUDIES
Dependent on the extraction technique, valerian root extracts contain differing amounts of
monoterpenes (such as bornyl esters, camphene and pinenes), sesquiterpenes (including valerenal and
valeranone), and less volatile sesquiterpene carboxylic acids (valerenic acid and derivatives), amino-
acids like gamma-aminobutyric acid, glutamine and arginine, alkaloids, flavonoids and lignans
(Haensel et al., 1999, Hoelzl, 1998). Valepotriates (nonglycosidic iridoid esters) may be present in the
root, but are unstable and unlikely to be present in finished products. The constituents of the volatile
oil are very variable due to population differences in genetics and to environmental factors such as
sowing method and harvest time.
Among the components listed above, no single or main active ingredient has been identified for
valerian root. Various trials with isolated constituents could not fully explain the observed
pharmacological activities of valerian root in total. A possible synergistic action of several
components is assumed. The whole extract of valerian root must therefore be considered as the active
ingredient.
II.1
Pharmacodynamics
II.1.1 Isolated substances
•
Sesquiterpenoids
Hydroxyvalerenic acid and acetoxyvalerenic acid weakly inhibited the catabolism of GABA at
synaptic junctions of the CNS
in vitro
(Riedel et al., 1982). Due to the high concentrations of both
compounds needed to achieve this effect, the data probably have no clinical relevance.
The intraperitoneal application of sesquiterpenoid compounds like valerenic acid, valerenal and
valeranone isolated from the essential oil of valerian root revealed a sedative and muscle relaxant
acitivity. In addition, valerenic acid and valeranone were found to prolong the barbiturate induced
sleeping time (Hendriks et al., 1981, 1985, Rücker et al., 1978, Torrent et al., 1972, Haensel et al.,
1
The herbal substance shall comply with the European Pharmacopoeia monograph: Valerianae radix (ref.
01/2005:0453).
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1994). Valerenic acid caused an inhibitory effect on muscimol-sensitive NTS neurons
in vitro
which was mediated via GABA
A
-receptors (Yuan et al., 2004).
•
Lignans
The lignan hydroxypinoresinol, recently found in valerian root, showed a high affinity with IC
50
of
2.5 µmol/L for the 5-HT
1A
receptor, which plays a role in sleep induction and anxiety reactions.
Affinity for GABA
A
-, benzodiazepine- and µ-opiate-receptors was distinctly lower (Hoelzl 1998,
Bodesheim et al., 1997). The kind of action at the receptor (agonistic/antagonistic activity) was not
investigated.
An olivil derivate was found to be a potent partial agonist at A
1
adenosine receptors
in vitro
(Schumacher et al., 2002). Agonistic activity was also shown for valerian root extract (methanol 45
%, Mueller et al., 2002). Activation of this receptor type has a sedative effect while antagonists like
caffeine have a stimulant effect.
•
Flavonoids
Marder et al. (2002) isolated 6-methylapigenin and hesperidin from
Valeriana officinalis
.
6-methylapigenin, which is a ligand for the benzodiazepine binding site of the GABA
A
receptor
according to Wasowski et al. (2002), produced anxiolytic-like effects in the plus-maze test at a
dose of 1 mg/kg i.p. but was devoid of sedative properties. Hesperidin 2 mg/kg i.p. increased the
thiopental sleeping time in mice; this effect was markedly potentiated when hesperidin and 6-
methylapigenin were combined.
The same authors discovered sleep-enhancing properties for linarin (Fernandez et al., 2004).
Linarin at doses of 4 and 7 mg/kg i.p. showed a sedative effect and with 7 mg/kg i.p. a prolonged
thiopental sleeping-time in mice. The combination of low doses of linarin (5 mg/kg) and valerenic
acid (5 mg/kg) led to a striking increase of thiopental sleeping time while the single administration
of each compound in this dosage had no effect at all.
•
Valepotriates
The valepotriates, mainly occurring in freshly harvested roots, are very unstable compounds due to
their unstable epoxide structure and decompose under different conditions (alkali, acids, storage)
into baldrinal and its derivatives, valerianic and isovalerianic acid, and undefined polymers. Dried
valerian root has therefore a characteristic malodorous aroma, partly due to the content of
isovalerianic acid (Hänsel et al., 1999). Since valepotriates are rapidly degraded during storage and
their oral bioavailability seems to be very low (Wagner et al., 1980),
in vitro
and
in vivo
effects
observed with isolated valepotriates, their degradation products or with valerian root extracts
containing valepotriates
in vitro
or
in vivo
, must be disregarded in the assessment of valerian root
extracts (they are mentioned for the purpose of completeness). Similarly the baldrinals, the
decomposition products of valepotriates, are either not detected or detected only in small quantities.
II.1.2 Aqueous and aqueous-ethanolic valerian root extracts
•
Interaction with neurotransmitter receptors in vitro
Due to the essential inhibitory functions of GABA, the interest has focused on possible interactions
of valerian root with the GABA
A
-messenger system.
-
Both aqueous-ethanolic (extraction solvent ethanol 60%) and total aqueous extract as well as the
aqueous fraction derived from the aqueous-ethanolic extract showed low (IC 50 – 1000 times
lower than IC of GABA) affinity for the GABA
A
receptor
in vitro
. The chemical nature of the
compounds responsible for this activity could not be correlated with sesquiterpenes or
valepotriates (Mennini et al., 1993).
-
An aqueous-ethanolic valerian root extract caused an inhibitory effect on muscimol-sensitive
NTS neurons
in vitro
which was mediated via GABA
A
-receptors (Yuan et al., 2004).
-
Aqueous and ethanolic (extraction with absolute ethanol, dry extract diluted with water) extracts
of valerian root
showed
in vitro
an interaction with the GABA
A
-receptor by displacing [³H]
muscimol from synaptic membranes from rat brain cortices (Cavadas et al., 1995). For valerenic
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acid no effect was shown. The authors, as well as Yuan et al., concluded that this interaction
could be caused by the content of GABA in the extracts.
Further evidence for this conclusion comes from other investigations:
-
An aqueous extract inhibited the uptake and induced the Ca
2+
-dependent release of [³H] GABA
possibly due to a homoexchange mechanism since the extract contained 5 mM GABA, which
proved to be sufficient to induce this effect (Santos et al., 1994 a, b). GABA was shown to be
absent in an ethanolic extract, correspondingly this extract did not significantly affect GABA
release.
The high content of GABA in certain valerian root extracts cannot explain pharmacodynamic
effects
in vivo
since it does not readily cross the blood-brain barrier. High concentrations of
glutamine in aqueous extracts lead to the speculation that GABA-synthesis
in vivo
may be
enhanced due to increased disposal of glutamine in the nerve terminals. In view of the lack of data
indicating a central nervous effect of exogenous glutamine, the unclear bioavailability of glutamine
in valerian root extract and the fact that glutamine is the most abundant amino acid found in the
body while the content in the extract is only 2 g/l, the clinical relevance of this assumption must be
judged critically.
Still, there are data pointing to interaction with the GABA-system via other mechanisms:
-
In other experiments by the group of Santos (Santos 1994 c, Ferreira et al., 1996), the effect of
different valerian root extracts on the uptake and release of GABA in synaptosomes isolated
from rat brain cortex was investigated. While an aqueous and an aqueous-ethanolic extract
inhibited the uptake and stimulated the release of [
3
H]-GABA, possibly by reversal of the
GABA carrier, this effect was not observed for an ethanolic extract.
-
These results were confirmed by Ortiz et al. (1999). They showed that, besides influence on
GABA-release and -uptake, valerian root extracts interact with benzodiazepine binding sites. At
low concentrations, valerian root extracts enhanced [
3
H]-flunitrazepam binding while it was
inhibited at higher extract concentrations. These results may point to at least two different
biological activities interacting with [
3
H]-flunitrazepam binding sites.
-
Another
in vitro
experiment demonstrated the interaction of a hydroalcoholic extract of valerian
root with adenosine receptors, but not with benzodiazepine receptors. However, this extract
contained 1.38 % of valtrate whereas an aqueous extract devoid of valepotriates produced only a
weak effect under similar conditions (Balduini 1989).
•
Animal models
-
Valerian tincture reduced spontaneous motility after intraperitoneal administration of the
valerian tincture in mice (Torrent et al., 1972).
-
Effects on spontaneous motility, thiopental sleeping-time and pentetrazol-induced toxicity were
tested on mice by administering a commercially available aqueous dry valerian root extract
(DER 5 – 6: 1, extraction solvent water). In spontaneous motility tests, doses of 20 and
200 mg/kg diminished the motility moderately, while in control animals 5 mg and 25 mg of
diazepam resulted in substantial reductions in motility shortly after administration. The extract
increased thiopental-induced sleeping time by factors of 1.6 at 2 mg/kg (p < 0.01) and 7.6 at
200 mg/kg (p < 0.01) compared to a factor of 4.7 for chlorpromazine at 4.0 mg/kg. Thus the
extract exhibited dose-related sedative activity in mice, however less pronounced than that of
diazepam or chlorpromazine (Leuschner et al., 1993).
-
An aqueous-ethanolic dry extract (DER 4:1, extraction solvent ethanol 70 % V/V) administered
intraperitoneally to male mice, was assessed for possible neuropharmacological activity. At
doses of up to 100 mg/kg the extract did not produce sedation nor tranquillization, since no
modifications of spontaneous motility, nociception or body temperature and no palpebral ptosis
were observed, whereas diazepam at doses of up to 2 mg/kg clearly reduced spontaneous
motility, lowered body temperature and produced a weak ptosis. However, the extract showed a
significant
of
thiopental-induced
anaesthesia
(p < 0.05)
with
100 mg/kg of extract (Hiller and Zetler, 1996).
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prolongation
-
Cats with implanted electrodes showed no changes in their EEGs following oral administration
of 100 or 250 mg of valerian root extract per kg body weight. The muscle tonus was reduced in
30 – 40 % of the animals (Holm et al., 1980).
-
An aqueous-ethanolic (extraction solvent ethanol 70% V/V) valerian root extract had an
anxiolytic effect in the elevated plus-maze test in male Spraque Dawley rats after oral
administration in the magnitude of ipsapirone, a 5-HT
1A
-receptor agonist (Hiller and Kato,
1996). After single administration of 5, 25 and 100 mg/kg, the extract showed a distinct
anxiolytic-like effect while the observed effect was not significant for 1 mg/kg and lower doses.
Remarkably, a moderate anxiolytic-like effect was maintained during subchronic administration
over 5 days only for low doses of 1 mg/kg. This feature could be interpreted as a bell-shaped
dose-response curve as they are seen for partial agonists. The results of this study deserve to be
highlighted since they were achieved with oral administration of doses comparable to those
given under clinical conditions.
II.1.3 Conclusion
Aqueous and aqueous-ethanolic extracts from valerian root as well as fractions and isolated individual
substances have been investigated in several pharmacological animal models. Since isolated
constituents were used in unphysiological high doses to achieve effects, the clinical relevance of these
investigations may be discussed. On the other hand, Marder et al. (2003) demonstrated a very strong
potentiation of effects by combining flavonoids. These results point to marked synergism; the
observations for single constituents may not reflect their action
in vivo
realistically.
As a whole, the results point to both a sedative and an anxiolytic effect, possibly mediated by different
constituents, which both might contribute to sleep promotion and improvement in nervous state. These
data are consistent with clinical observations. With respect to safety concerns, the prolongation of
thiopental sleeping time by an aqueous extract in a dose dependent manner in mice must be
highlighted. The deduction of a relevant drug interaction of valerian root and barbiturates under
clinical conditions from the cited study is of course questionable. In view of the fact that there is no
information available on experiences with the combination of valerian root
and barbiturates in
humans, a co-medication of valerian root and barbiturates should be avoided for safety reasons as long
as no further data are published.
II.2
Toxicology
Experimental data on the toxicological properties of Valerian root extract and its single compounds are
limited.
For whole extracts or isolated compounds with the exception of valepotriates and their degradation
products in various experiments a low order of toxicity was found as shown below.
II.2.1 Acute Toxicity
-
In acute oral toxicity tests the LD
50
of the sesquiterpene valeranone was greater than 3 g/kg in
both rats and mice which corresponds to low toxicity (Rücker et al., 1978).
-
The LD
50
of essential oil of valerian root, 1,500 mg in rats weighing 100 g, was found to be the
highest of 27 essential oils tested, including for example, peppermint and anise oils (von
Skremlik, 1959).
-
The LD
50
of an ethanolic valerian root extract made from the defatted herbal substance
administered intraperitoneally to mice amounted to 3.3 g/kg, a value, which corresponds to a
low toxicity (Rosecrans et al., 1961).
-
Valerenic acid caused inhibition of spontaneous motility after intraperitoneal administration to
mice at a dose of 50 mg/kg, ataxia and temporary immobility at a dose of 100 mg/kg, muscle
spasms at doses of 150 – 200 mg/kg, and severe convulsions and mortality at a dose of
400 mg/kg (6 of 7 animals
ad exitum
24 hours after administration) (Hendriks et al., 1985).
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II.2.2 Sub-acute/Chronic Toxicity
-
An ethanolic valerian root extract given to rats at a daily dose of 300 mg/kg and 600 mg/kg p.o.
for a period of 30 days did not influence blood pressure, weight of the heart, lungs, liver, spleen,
kidneys, bladder, stomach, intestines or testes, haematological parameters (erythrocytes,
leukocytes including differential blood count, haematocrit, haemoglobin) or biochemical
parameters (blood sugar, urea, SGOT, SGPT and alkaline phosphates). The animals receiving
the higher dose had a slightly higher body weight compared to controls (Fehri et al., 1991).
-
An ethanolic valerian root extract given to rats intraperitoneally at doses of 400 – 600 mg/kg
over a period of 45 days did not result in any significant changes in body weight, blood count or
urine status (Rosecrans et al., 1961).
-
In the rat, a dose of 200 – 225 mg valerian root oil per 100 g body weight was found to be a
tolerable daily dose p.o. over an experimental period of 8 weeks. With higher doses, loss in
body weight, rough and ungroomed coat, apathy and, in some cases, mortality were recorded.
At 250 mg daily, 2/5 of the animals died within 3 weeks (von Skramlik, 1959).
-
The test of a dietary product with undefined quality in mice showed clear effects on nucleic
acid, malondialdehyde and glutathione concentrations in testicular cells and malondialdehyde
and glutathione concentrations in hepatic cells. The concentration used was with ~ 4 g/kg much
higher than the recommended dosage in humans (Al-Majed et al., 2006).
II.2.3 Reproductive Toxicity
There are no published studies on reproductive toxicity of preparations from valerian root. A test of a
dietary supplement in mice revealed the appearance of sperm head morphology abnormalities
(amorphous and triangular head abnormalities). The concentration used was with ~ 4 g/kg much
higher than the recommended dosage in humans. A negative influence on male fertility could not be
proven due to the unclear quality and dosage of the tested product (Al-Majed et al., 2006).
There is no published evidence for fertility impairment due to valerian root preparations or isolated
components. In Australia, valerian root products are classified in category A; this category is
applicable for pharmaceuticals, which have been taken by large numbers of pregnant women and
women of child-bearing age without an increase in malformations or other direct or indirect
teratogenic effects on the foetus being observed (Bos et al., 1998).
Since there are no experimental investigations to date, as stated in the ESCOP- and the WHO-
monograph as well as the core-data on valerian root prepared by the EMEA ad hoc Working Group on
Herbal Medicinal Products, it is recommended that valerian root preparations should not be taken
during pregnancy and lactation; they should not be used without medical advice.
II.2.4 Mutagenicity/Carcinogenicity
A Somatic Mutation and Recombination Test (SMART) in Drosophila melanogaster showed no
genotoxic effects for an infusion of valerian root purchased from a local health food store, raising
questions concerning the quality of the herbal substance in relation to pharmaceutical properties. The
used dose is not specified, the test procedure is not accepted as a standard method for the investigation
of genotoxicity. The data cannot therefore be accepted to show the absence of genotoxic effects of
valerian root (Romero-Jiménez M et al., 2005).
Alkylating, cytotoxic and mutagenic effects have been described for the valepotriates and their
degradation products (Bos et al., 1998, von der Hude, 1986) which are not detectable in valerian root
extracts or are found only in very low amounts.
The test of a dietary product with undefined quality in mice showed weak effects on bone marrow
micronucleus in high doses. The concentration used was with ~ 4 g/kg much higher than the
recommended dosage in humans (Al-Majed et al., 2006).
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II.2.5 Conclusion
Only incomplete experimental data pointing altogether to a low toxicity are available on the
toxicology of valerian root preparations. Safety assessment is thus mainly based on many years of
experience acquired through extensive therapeutic use in man, which indicate valerian root
preparations to be safe. Data on genotoxicity are lacking.
III
CLINICAL PHARMACOLOGY
The treatment of non-organic sleep disturbances with synthetic hypnotics/sedatives like
benzodiazepines and barbiturates is associated with undesirable effects like adaptation, dependency,
hang-over effects, increased sleep apnoea or anterograde amnesia. It induces also undesired changes of
sleep patterns. Antihistamines (e.g. promethazine) may cause palpitations, a dry mouth and other
disturbing undesirable effects. There is obviously a need for better tolerated alternatives to synthetic
sedatives to prevent the manifestation of chronic insomnia. A considerable number of trials underline
that valerian root is such an alternative medication that does not exhibit typical undesirable effects
observed with conventional treatment of sleep and mood disorders.
III.1 Pharmacodynamics
III.1.1 EEG trials
Objective evidence of a mild to moderate sedative or tranquilizing effect of valerian root extract in
man is provided by EEG studies in healthy volunteers and in female subjects with sleep disorders,
although not all results are consistent and they must not be overemphasized for this reason.
•
Healthy volunteers
-
In a placebo-controlled, double-blind study a single administration of 400 mg of an aqueous
valerian root extract (DER 3:1) did not induce significant changes in the objective measures of
sleep (EEG recording in a sleep laboratory) in 10 healthy volunteers (Leathwood and Chauffard,
1982/83). Nevertheless, the results showed tendencies towards a shorter mean sleep latency and
an increased mean latency to first awakening. Lack of significance may be due to the small
number of volunteers.
-
Further sleep EEG investigations were performed with the same aqueous extract. Eight subjects
without major sleep disorders (4 female, 4 male, average age 22.6 years) spent 5 nights in a
sleep laboratory. The first night was without medication, on nights 2 and 3 placebo was
administered, on night 4 900 mg of valerian root extract was administered, and on night
5 placebo was administered again. There was no difference between placebo and valerian root
extract in the sleep EEG. However, in the subjective assessment of quality of sleep, which was
determined by means of a visual analogue scale, the time taken to fall asleep and the time spent
awake during the night were reduced under treatment with the valerian root preparation
(Balderer and Borbely, 1985).
-
In a placebo-controlled, double-blind study of crossover design, the effects of a single dose of
1,200 mg valerian root extract (DER 5 - 7:1, extraction solvent not specified) corresponding to
7.2 g of the herbal substance on the quantitative EEG of 12 healthy subjects (average age: 53.7
± 5.6 years) was compared to that of 1 x 10 mg diazepam, 1 x 1,200 mg lavender extract, 1 x
1,200 mg passion flower extract and 1 x 600 mg Kava kava extract. All substances showed
individual action profiles. Compared to diazepam, an increase in the relative strength of the
theta frequency band was observed for the plant preparations. Under diazepam the power in the
theta frequency band decreased while it increased in the beta band. Valerian root extract
increased power in the delta and theta bands and decreased power in the beta band (Schulz et
al., 1998).
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•
Patients with sleep disturbancies
-
In a double-blind, parallel-group trial (verum: n = 8, placebo: n = 6) in elderly female poor
sleepers (average age: 61.6 ± 6.5 years) the patients took 3 x 405 mg/day of an aqueous-
ethanolic valerian root extract (DER 5 – 6:1). After a 1-day treatment, the total sleeping time
and slow-wave sleep increased significantly, sleep induction time was reduced and quality of
sleep improved. Long-wave sleep (stage 3 and 4) was increased and stage 1 was decreased.
After an 8-day treatment, a percentage reduction in sleep stage 1 from 16.4 % to 11.9 %, an
increase in sleeping phase 3 from 6.5 % to 10.2 %, and an increase in total sleeping phases
3 and 4 from 7.7 % to 12.5 % (p = 0.0273, in each case) occurred under active treatment. Under
placebo, these parameters essentially remained unchanged. REM sleep, sleep latency and time
awake, as well as the subjective quality of sleep (sleep questionnaire SF-A according to
Goertelmeyer, visual analogue scale) did not change under the two medications. The authors
concluded that valerian root has a mild tranquilizing instead of a sedating activity that may
improve sleep quality under certain conditions (Schulz et al., 1994).
-
Donath et al. (2000) performed a placebo-controlled, double-blind crossover study in
16 patients with psychophysiological insomnia (International Classification of Sleep Disorders
ICSD-Code 1.A.1) with intake of 600 mg of an aqueous-ethanolic dry valerian root extract
(DER 3 – 7:1, extraction solvent ethanol 70% V/V), corresponding to 3 g of the herbal
substance/day. The study medication was taken each over a fortnight with a wash-out period of
14 days between the treatment phases. Under both verum and placebo, sleep structure improved
significantly; for the main objective efficacy parameter sleep efficiency no difference could be
stated. On the other hand, subjective sleep latency decreased significantly only after 14 days of
valerian root intake. For valerian root extract a clearly better correlation between objective
improvement and subjective perception could be demonstrated than for placebo. The authors
concluded that drug effects might have been masked by the effects of general interventions
caused by the study design. Valerian root might act by reducing a misperception of sleep and
wake phases. They concluded that valerian root has a mild, delayed effect and could be
recommended for patients with chronic insomnia in combination with additional non-
pharmacological measures but not for patients with acute, reactive sleep disturbances needing
rapid relief.
-
In a placebo-controlled crossover study 24 females suffering from sleep disorders received
10 mg diazepam, placebo, 1,200 mg of a valerian root extract (DER 3 – 7:1, extraction solvent
not specified) or other plant extracts. After intake of valerian root extract the EEG showed an
increase in relative power in the delta and theta frequency. There was no increase in the power
of the beta frequency range after valerian root extract in contrast to diazepam. The subjectively
experienced tiredness increased markedly both after valerian root and diazepam. No absolute
values or significance levels are given in the abstract (Schulz und Jobert, 1995).
-
Diaper and Hindmarch (2004) performed a double-blind placebo-controlled crossover trial in
16 patients (age 50 – 64 years) with mild sleep-disturbancies investigating the effect of a single
dose of placebo, 300 mg or 600 mg of an aqueous-ethanolic valerian root extract (DER 3 – 6:1,
extraction solvent ethanol 70 % V/V) corrresponding to 1.35 or 2.7 g of the herbal substance.
For sleep EEG parameters and several psychometric tests, no group differences were stated;
only a tendency to increased drowsiness with the higher valerian root dose was observed.
Conclusion
Valerian root seems to improve sleep structure with a gradual onset of efficacy rather than to exert a
general sedating effect. After single intake valerian root changed mainly subjective perception of
sleep, while sleep EEG changes were more pronounced after several days of intake. These
observations are in concordance with clinical experiences showing a gradual improvement of
symptoms over 2 – 4 weeks. Valerian root probably exerts its effects in pathological conditions rather
than in healthy volunteers.
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III.1.2 Volunteer trials in stress situations
-
Cropley et al. (2002) performed an open, randomised study comparing the effect of valerian
root, kava-kava and an untreated control group in a pressure situation. 44 students completed
the colour/interference test with increasing speed of presentation before and after one week
intake of 600 mg of an aqueous-ethanolic valerian root extract corresponding to 2.7 g of the
herbal substance, 120 mg kava-kava extract or no medication. Blood pressure and heart rate
were recorded before, during and after the test situation, subjective ratings of pressure before
and during the test were documented on a 7-point scale. The increase of systolic blood pressure
during test completion - with valerian root extract also the increase of heart rate - was
significantly reduced with valerian root extract and kava-kava rhizome extract in contrast to no
change without medication.
Self-reported pressure immediately before and during the test was decreased significantly with
valerian root extract and kava-kava rhizome extract; the decrease of pressure before start of the
test was even more distinct with valerian root extract than with kava-kava rhizome extract. In all
3 groups task performance was improved in the second test.
These results lead to the assumption that valerian root as well as kava-kava rhizome decreases
subjective experience of stress (while cognitive performance is not reduced) which may provide
evidence for the clinically established indication “mild nervous tension”. The significance of the
trial is decreased by potential biases due to the lack of blinding and absence of a placebo-group.
Confirmation of the data in placebo-controlled double-blind trial is desirable.
-
In a double-blind placebo-controlled study the effects of 1 x 100 mg valerian root extract (no
further data) (n = 12) or 1 x 20 mg propanolol (n = 12) or 1 x 100 mg valerian root extract +
20 mg propanolol (n = 12) on a stress situation provoked by a mathematical task were
investigated 90 minutes or 120 minutes after administration in 48 young subjects (age between
19 and 29 years) without health disorders. There was no group difference with regard to
mathematical performance. Under propanolol, the expected reduction in pulse frequency
increase was found in the stress situation; under valerian root a feeling of less marked somatic
activation. The authors concluded that these results pointed to a thymoleptic effect of valerian
root (Kohnen et al., 1988). It is well known that thymoleptic medicinal products may show
anxiolytic properties, which may be differentiated from antidepressive effects. The assumption
of an anxiolytic effect as a major mode of action of valerian root preparations is confirmed by
this trial.
The results of these trials provide supportive information to the indication ‘mild nervous tension´ for
which only limited evidence comes from clinical studies in patients.
III.2 Safety Studies
In view of the assumed sedative effects, several trials with valerian root extracts were undertaken to
investigate a possible influence of valerian root extract on the vigilance:
-
In a double-blind study with 102 subjects (mean age approximately 40 years), in whom a sleep
disorder was excluded, reaction time, attention and co-ordination capacity were determined in
an acute test by means of the Vienna Determination Test on the morning after administration of
600 mg of an aqueous-ethanolic valerian root extract (DER 3 – 6:1, extraction solvent ethanol
70 % V/V), 1 mg flunitrazepam or placebo. Subjective assessment of the quality of sleep was
based on a visual analogue scale. The reduction in reaction time, as an indication of a learning
effect, was significantly smaller with flunitrazepam than in both other groups. No group
differences were observed with regard to attention and co-ordination capacity. The quality of
sleep and the time taken to fall asleep were assessed as improved in all three groups.
A “hangover” effect was observed in 59.4 % of the test persons under flunitrazepam (p< 0.05
vs. valerian root extract or placebo), 30.3 % under valerian root extract and 32.4 % under
placebo. After a 7-day washout phase, the subjects took 600 mg valerian root extract/day or
placebo over 14 days. No difference between therapies was observed in reaction time, attention
and co-ordination capacity. A slight improvement in quality of sleep was found in the group
treated with valerian root (+7.4 % vs. -4.5 % in the placebo group) (Kuhlmann et al., 1999).
-
In a double-blind trial the authors compared the cognitive and psychomotor effects, in nine
healthy volunteers, of single doses of an aqueous-ethanolic extract (DER 4:1, extraction solvent
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ethanol 70 %) corresponding to 1.6 g or 3.2 g valerian root, 0.25 mg triazolam and placebo
(Hallam et al., 2003). Several cognitive and computer based attentional tasks revealed that
performance was significantly worse with triazolam than with both valerian root doses and
placebo, accompanied by a marked increase in mental sedation. No sedation was observed after
intake of valerian root.
-
Glass et al. (2003) compared acute effects of placebo, valerian root 400 and 800 mg (probably
powdered herbal substance), temazepam 15 and 30 mg, diphenhydramine 50 and 75 mg in
14 elderly volunteers (mean age 71.6 years, range 65 – 89 years). Temazepam and
diphenhydramine dose-dependently caused clear sedation and psychomotor impairment in
connection with drowsiness and fatigue while for both valerian root doses no differences to
placebo were seen.
-
A valerian root extract (no details given) in liquid form was tested with regard to a “hangover”
effect (Phase A) as well as with regard to an acute sedative effect (Phase B) in subjects without
sleeping disorders. To test the “hangover effect” (Phase A), four groups, each with 20 subjects
(age between 20 and 30 years), received 1 x 10 ml = 800 mg of the valerian root preparation
(equivalent to 4 g valerian root) or 1 x 1 mg flunitrazepam or 1 x 600 mg of a valerian root-
combination preparation (sugar coated tablet) or 1 x placebo at a given time of night. Eight
hours after taking the preparation, apparative test diagnostics were performed and subjective
feelings were monitored in the laboratory. A mild “hangover” effect on the morning after
medication was shown with flunitrazepam for two test parameters. While the usual learning
effect occurred under both phytopharmaceuticals and placebo, this effect was not observed
under flunitrazepam. With flunitrazepam, the subjects felt tired, unsteady on their legs,
unconcentrated, less able to perform, sedated and less well than in the other groups. There was
no evidence of a “hangover” effect with the valerian root mono-preparation, the subjects felt
more “active” compared to placebo. The subsequent test for a sedative acute effect (Phase B)
was performed with three groups each with 12 subjects, who took the test one hour after taking
1 x 800 mg of the liquid valerian root mono-preparation or 1 x 600 mg of the combination
preparation or 1 x placebo in the morning. The valerian root mono-preparation led to
measurable decreases in vigilance (more erroneous reactions and fewer correct signal
detections) (p < 0.05 vs. placebo) 1-2 hours after taking the preparation; with regard to the
subjective measures, the subjects had “wobbly legs” and felt less active (p ≤ 0.01 vs. placebo)
(Gerhard et al., 1996).
Conclusion
According to the results described above, high doses of valerian root extract may cause a slight
sedation during the first few hours after ingestion but in contrast to benzodiazepines valerian root does
not reduce vigilance on the next morning when taken in the evening. The corresponding warning (see
section 4.7 Effects on ability to drive and use machinery) is recommended in the Community herbal
monograph as a general precaution for medicinal products negatively influencing vigilance.
Studies on valerian root as single active substance have not addressed synergistic actions with alcohol.
However, data collected for several valerian root combinations, i.e. valerian root and balm
(Albrecht et al., 1995), valerian root and hops (Herberg, 1994 a, Kammerer et al., 1996) and valerian
root and St. John’s wort (Herberg, 1994), allow to conclude that, unlike synthetic benzodiazepine or
barbiturate hypnotics, valerian root does not act synergistically with alcohol.
III.3 Pharmacokinetics & bioavailability
III.3.1 Pharmacokinetics
Data on the pharmacokinetic properties of extracts of valerian root or isolated constituents in man are
not available. Pharmacokinetic data for valepotriates are not relevant for valerian root extracts.
III.3.2 Bioavailability
Data on the bioavailability of extracts or isolated constituents of valerian root are not available.
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III.4 Interactions
III.4.1 Pharmacodynamic interactions
Pharmacodynamic interactions of whole extracts or isolated constituents of valerian root with other
medicinal products, food or alcohol in man have not been observed. For low-dose valerian root extract
(100 mg) and 20 mg propanolol (Kohnen et al., 1988), no interaction could be demonstrated in healthy
volunteers. Further interaction studies in humans are not available. Since nonclinical data point to a
prolongation of barbiturate sleeping time by co-administration of valerian root, the concomitant intake
of synthetic sedatives and valerian root is addressed in the Community herbal monograph under
section 4.5 Interactions with other medicinal products and other forms of interactions.
III.4.2 Pharmacokinetic interactions
While no information on possible interactions of valerian root and its preparations was available up to
2004, results of two trials were published recently:
-
Lefèbre et al. (2004) investigated interactions of several valerian root preparations available on
the US market with CYP 3A4
in vitro
. The data point to a possible inhibition of CYP 3A4-
mediated metabolism and P-glycoprotein ATPase activity that could not be correlated to the
content of certain constituents.
-
The influence of an aqueous-ethanolic valerian root extract on the metabolic activity of CYP
3A4 and CYP 2D6 in humans was investigated in an open crossover trial (Donovan et al.,
2004). Pharmacokinetic parameters after a single intake of 2 mg alprazolam and 30 mg
dextrometorphan (dextrometorphan/dextrorphan ratio) were compared in human volunteers
before and after daily intake of 1,000 mg aqueous-ethanolic valerian root dry extract (no
further details given) over 14 days. The study did not reveal an influence on the CYP 2D6
pathway while for CYP 3A4 a slight inhibition was shown: C
max
of alprazolam increased after
valerian root extract intake from 25 +/- 7 ng/ml to 31 +/- 8 vs (p < 0.05), the AUC at baseline
was 88.9 % of the AUC after valerian root extract intake (n.s.). The authors rated the
magnitude of this moderate increase not as clinically relevant and concluded that valerian root
is unlikely to have clinically relevant effects on the disposition of medications primarily
dependent on the CYP 2D6 or the CYP 3A4 pathways.
-
Gurley et al. (2005) confirmed these results in another open crossover trial in 12 young adults
for intake of 375 mg/d valerian root extract (DER 4:1, extraction solvent not specified by
manufacturer). They found no relevant interaction for CYP 1A2, CYP 2D6, CAP 2E1 and
CYP 3A4/5.
Conclusion
The results of the well-designed trials by Donovan and Gurley are mentioned in the Community herbal
monograph since they give important information on safety of certain co-medications.
IV
CLINICAL EXPERIENCE
IV.1
Efficacy
IV.1.1 Dose-Finding Trials
The dose recommendations of the ESCOP monograph, the German Commission E monograph and the
WHO monograph on valerian root (single doses of 2 – 3 g crude herbal substance (ESCOP: 1 – 3 g)
given once or several times daily according to indication or requirements) are based on broad clinical
experience, on EEG-studies and clinical trials comparing valerian root in the mentioned doses to
placebo or active comparators. Detailed evidence-based statements on minimal effective dose, safe
starting dose, and optimal maintenance dose cannot be made on this basis. The data by Kamm-Kohl
and co-authors (see section ‘nervous tension + insomnia’) demonstrate that even very low doses of
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valerian root may achieve clinically relevant results, but most experience confirms the dose regimen
mentioned above.
Only one dose-finding trial in short-term clinical use of valerian root has been performed, which
showed a dose-dependent effect for the tested doses of 1,300 mg and 2,600 mg valerian root.
-
In a double-blind, randomized crossover trial, 7 patients (age between 33 and 59 years) with
problems getting to sleep took either 450 mg (corresponding to 1,300 mg of the herbal
substance), or 900 mg (corresponding to 2600 mg of the herbal substance) of an aqueous
valerian root extract or placebo before bedtime (Leathwood and Chauffard, 1985). Medication
was taken in a randomized assignment over three periods of 4 days each with a three day pause
in between. During all nights following intake of a test sample, activity was measured by means
of a wrist-worn activity meter. In addition, the subjects filled in a questionnaire in the morning
with a 9-point scale on: time to fall asleep, quality of sleep and depth of sleep. Sleep latency
was decreased significantly with both valerian root extract doses (mean values: placebo = 15.8 ±
5.8 min, 450 mg extract = 9.0 ± 3.9 min, 900 mg extract = 11.4 ± 5.2 min) while total sleep time
and total number of movements remained unchanged. With the higher dose patients felt more
sleepy the next morning than with placebo.
These results were confirmed in a trial in 10 healthy volunteers (age between 24 and 44 years),
who took placebo, 450 or 900 mg of an aqueous valerian root extract corresponding to 1.2 or
2.4 g of the herbal substance in a crossover schedule. Estimated sleep-latency and wake time
after sleep onset were reduced by more than 50 % after the higher dose, while the lower dose
had a somewhat lower effect (Balderer et al., 1985).
-
IV.1 2 Controlled Clinical Trials
Several controlled clinical trials have been performed, mainly in patients with non-organic insomnia,
which confirm a superiority of valerian root versus placebo. In addition, two recent trials must be
highlighted demonstrating that efficacy of valerian root is in the same range as that of low-dose
oxazepam while valerian root is clearly better tolerated.
•
Non-organic insomnia
-
Ziegler et al. (2002) demonstrated that the efficacy of valerian root extract in non-organic
insomnia is comparable to that of oxazepam: They performed a randomised, double-blind,
multi-center study in 186 patients (age 18 – 73 years, mean 52 +/- 13 years, 125 female,
61 male) with non-organic insomnia (ICD-10, F51.0) who needed a medical treatment.
Over 6 weeks, the patients received once daily in the evening 600 mg of an aqueous-ethanolic
valerian root extract (DER 3 – 6:1, extraction solvent ethanol 70 % V/V) corresponding to
2.7 g of the herbal substance, or 10 mg oxazepam. The study was designed as a non-inferiority-
trial, main efficacy parameter was Goertelmeyer Sleep Questionnaire B (SF-B), item quality of
sleep. The other SF-B items, the Clinical Global Impressions Scale (CGI) and a global rating of
efficacy and tolerability by investigator and patient were chosen as secondary efficacy
parameters. Quality of sleep increased in both groups over the whole treatment period; the one-
sided confidence interval was within the limit for non-inferiority (< 0.2) for the ITT-population
after 2, 4 and 6 weeks of treatment. The other SF-B items (psychic exhaustion in the evening,
feeling of refreshment after sleep, psychosomatic symptoms in the sleep phase, duration of
sleep) showed comparable improvement with confidence intervals < 0.2 as well. 30.4 % of
patients in the valerian root extract group and 23.6 % of patients in the oxazepam group rated
their complaints as ‘very much improved’. However, in the valerian root extract group more
patients did not notice any change (valerian root extract: 13.0 % versus oxazepam: 6.7 %),
while more patients with oxazepam felt at least a minimal improvement (oxazepam: 31.5 %
versus valerian root extract: 19.6 %). Adverse events occurred in 28.4 % of patients treated with
valerian root extract and in 36 % of those, who took oxazepam. Symptoms pointing to possible
“hangover” effects occurred in 6 patients of the oxazepam group versus 2 in the valerian root
extract group.
-
The results of Ziegler are confirmed by another randomised, double-blind trial with the same
comparators in identical dosages which failed to show a difference between valerian root extract
and oxazepam (Dorn, 2000). In this trial, 75 patients, age 52 ± 12 years, with non-organic
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insomnia (ICD-10, F51.0) received oxazepam 10 mg/day or 600 mg of an aqueous-ethanolic
valerian root extract (DER 3 – 6:1, extraction solvent ethanol 70 % V/V) corresponding to
2.7 g of the herbal substance over 4 weeks. The questionnaires included Goertelmeyer SF-B,
well-being scale according to von Zerssen (Bf-S), Hamilton Anxiety Scale (HAMA) and sleep-
rating by the physician. Both groups improved distinctly in all parameters including the HAMA
Scale. The study did not reveal any differences between the treatment groups. In the oxazepam
group patients tended to report more often hang-over symptoms.
-
A placebo controlled, double-blind parallel-group study was carried out in 121 patients
(71 female, 50 male, average age 47 years) suffering from non-organic insomnia according to
ICD-10 (Vorbach et al., 1996). Patients received daily 600 mg of a valerian root extract
(DER 3 – 7:1, extraction solvent ethanol 70 % V/V), corresponding to 3 g of the herbal
substance, or placebo over the course of 28 days as a single dose in the evening. The study
documentation comprised 3 validated questionnaires (sleeping questionnaire B according to
Goertelmeyer, Form B3 (SF-B), von Zerssen’s “Befindlichkeits” Mood Scale (Bf-S), the
Clinical Global Impression (CGI)) and a global rating of efficacy and tolerability by physician
and patient. No main efficacy parameter was defined and the results were clearly rated as
explorative by the authors. The CGI questionnaire improved significantly after 2 weeks; the
difference versus placebo further increased until the end of treatment after 4 weeks. The “self-
rating scale according to von Zerssen”, the “Goertelsmeyer’s sleep questionnaire”, and other
ratings confirmed the positive trend with more pronounced differences between the treatment
groups after 4 weeks than after 2 weeks. The change in status after 28-day treatment with
valerian root extract therapy was given as “very much better” or “much better” in 55.9 % of
cases (placebo 25.9 %). Although no confirmatory statistical evaluations were performed, the
results give quite clear evidence of a therapeutic efficacy of the administered dose of valerian
root
in insomnia.
-
A crossover trial comparing an aqueous valerian root extract (400 mg corresponding to
1,200 mg of the herbal substance), placebo and a combination of valerian root dry extract
(120 mg) + hop strobile dry extract (60 mg) was performed by Leathwood et al. (1982) in
166 volunteers, who were partly poor sleepers. DER for the latter preparation is not given. The
volunteers took one dose of a total of nine doses (three/preparation) on non-consecutive nights
and documented their sleep quality in a questionnaire (not validated). Results were analyzed
only for those volunteers, who completed the trial (n = 128). On the morning after taking the
preparation, time to fall asleep, quality of sleep, natural waking up, dreaming and tiredness in
the morning were recorded by means of a questionnaire. Time to fall asleep was reduced in 37%
of persons taking the valerian root mono-preparation, in 23% under placebo and in 31% under
the combination preparation. The difference between the valerian root mono-preparation and
placebo was statistically significant (p < 0.01). While quality of sleep remained virtually
unchanged in habitually good sleepers with all preparations, in habitually poor or irregular
sleepers the sleep quality was enhanced
and sleep latency was reduced significantly more often
with the valerian root preparation compared to placebo. The combination showed no significant
superiority. The quality of sleep was improved in 43 % of persons with the valerian root mono-
preparation and 25 % with placebo (p < 0.05). No differences in waking up during the night,
dreaming and tiredness in the morning were found between valerian root and placebo. With
regard to the combination preparation, a stronger effect was found for tiredness in the morning,
which was statistically significant compared to both placebo and valerian root mono-
preparation. No significant differences were found for the other parameters.
The interpretation of these data is restricted by the lack of a confirmatory analysis. No detailed
demographic data are given, no validated questionnaires were used in this trial. It is not clear
from the publication whether the medications were taken in a randomised order. Nevertheless,
the results are congruent with those of better designed and reported
trials.
-
A trial conducted in general practices using a series of randomised “n-of-I” trials (Coxeter et al.,
2003) revealed a positive trend, but no significant superiority of valerian root versus placebo
after three weeks of treatment (only 42/86 = 40 % of all randomised patients were included in
the analysis). The daily dosage taken was 450 mg of valerian root extract corresponding to
2 g of the herbal substance (extraction solvent not given). The sleep diary consisted of
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6 outcome variables (latency to sleep, number of night awakenings, total sleep time, quality of
sleep, level of perceived refreshment post-slumber, energy level in the previous day).
•
Nervous tension + insomnia
- In a placebo-controlled, double-blind study, an aqueous valerian root extract (DER 5 - 6:1,
extraction solvent water) and placebo were investigated in 78 hospitalised patients (59 female,
19 male, age between 61 and 79 years) who were suffering from nervous mood and behavioural
disorders. The patients received 3 x 90 mg/day (= 270 mg/day) valerian root extract or placebo
over a period of 14 days. Assessment of the therapeutic effect was performed before and after
treatment using von Zerssen’s Mood Scale (Bf-S) and the Nurses’ Observation Scale for In-
patient Evaluation (NOSIE). In addition, symptoms such as difficulty in falling asleep, problems
in sleeping through the night and rapid exhaustion were assessed on a 4-point scale. The total
score on the Bf-S fell by 10.5 points under active treatment and by 4.5 points under placebo
(p< 0.01, t-test). The total score on the NOSIE scale increased by 22.6 and by 6.8 points under
placebo (p< 0.01, t-test). The symptoms “difficulty in falling asleep” and “difficulty in sleeping
through the night”, which were present in all 78 patients (although no inclusion criterion),
improved significantly under active treatment (p < 0.001 versus placebo in each case); the
symptom of rapid exhaustion, about which 63 patients complained, also showed significant
improvements in favour of the active treatment (p < 0.02, Kamm-Kohl et al., 1984).
- Jacobs et al. (2005) performed a completely internet-based, placebo-controlled randomised trial
in 391 patients comparing kava-kava (daily dose 300 mg of kavalactones), valerian root (daily
6.4 mg of valerenic acids; specification of the extract not available) versus placebo with a
treatment duration of 4 weeks. Anxiety was assessed by the State-Trait Anxiety Inventory
(STAI-State) questionnaire, a validated 20-item measure of anxiety symptoms; insomnia was
assessed by the validated Insomnia Severity Index (ISI). All patient groups improved distinctly
with respect to both symptom complexes, but no differences could be demonstrated between the
groups after 2 and 4 weeks of treatment. Since no details are available on the actual amount of
valerian root taken by the patients, no conclusions can be drawn from these results regarding the
common dose of 2 - 6 g recommended for sleep induction.
•
Review on insomnia
The review of
Stevinson and
Ernst (2000) gave an overview of nine published randomised,
clinical trials summarizing the evidence for valerian as inconclusive and demanding rigorous
trials to determine its efficacy. The following studies that were not included in the review are
included in this assessment report: Coxeter PD et al. (2003); Cropley M et al. (2002); Diaper A
et al.(2004); Donath F et al. (2000); Dorn M (2000) Hallam KT et al. (2003); Ziegler G (2002).
The above-mentioned review evaluates only randomised clinical trials. Valerian root and its
preparations belong to the herbal substances and preparations with well-established medicinal
use, therefore a larger body of evidence is to be assessed. According to Part II.1 of Annex I to
Directive 2001/83/EC as amended on well-established-medicinal use, “…‘bibliographic
reference’ to other sources of evidence (post marketing studies, epidemiological studies, etc.)
and not just data related to tests and trials may serve as a valid proof of safety and efficacy…”.
A further problem of the above mentioned review is that the randomised clinical trials (RCTs)
were not separately evaluated regarding the different herbal preparations used. Most of the
assessed RCTs were performed with aqueous extracts of valerian root with the content
mentioned as mg extract without any information on DER, so that the recalculation of the
amount of herbal substance used is partly impossible without further information.
Many of the older pharmacodynamic and clinical trials included in the review were done with
aqueous extracts of valerian root. Because these data were not convincing to the HMPC, herbal
teas were included in the ‘traditional use’ part of the monograph. Regarding these extracts, this
assessment is concordant with the review of Stevinson and Ernst, 2000. Some
pharmacodynamic trials (i.e. Schulz et al. (1994); Vorbach et al.
(1996); Donath et al. (2000);
Diaper et al. (2004); Dorn (2000); Ziegler
(2002) were also performed using ethanolic extracts
of valerian root supporting the inclusion of these herbal preparations in the "well-established
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use" part of the monograph. Especially the trials published since 2000 are of a better quality,
including GCP compliance.
Conclusion
For the clinical use of valerian root, a substantial body of general evidence is available from
handbooks, expert reports etc. Valerian root has been used for centuries in many countries. Additional
evidence results from several randomised, controlled, double-blind clinical trials, partly with EEG-
recordings. Taking into account these clinical trials, the indication “relief of sleep disorders” is based
All together, the evidence available from literature and from clinical trials with valerian root extracts
in adults confirms that aqueous-ethanolic extracts of valerian root have a clinical effect in sleep
disturbances as assessed by subjective ratings as well as by means of validated psychometric scales
and EEG-recordings. Valerian root may be more efficacious in elder patients, who consider
themselves poor and irregular sleepers. Mild acute sedating effects have been observed in safety trials
and sleep laboratory investigations. There is quite strong evidence both from clinical experience and
sleep-EEG studies that the treatment effect increases during treatment over several weeks. Important
questions remain open concerning for examples optimal dosage and appropriate duration of treatment.
Long-term studies have not been performed. It must be pointed out that there is a general discrepancy
between the typical duration of use of hypnotics as revealed in epidemiological studies and the typical
medication period in clinical trials. No consensus exists that long-term studies should be done with
hypnotic medicinal products, since these would carry a hazard for the patients due to the dependency
risks for most products (Angst et al., 1995).
IV.1.3 Clinical Experience in Children
A drug monitoring trial with an aqueous-ethanolic dry extract (DER 3 – 6:1, extraction solvent
ethanol 70 % V/V) was carried out in 130 children, who suffered from restlessness and/or
difficulty in falling asleep due to nervousness (Hintelmann, 2002). Duration of treatment was at
least 2 weeks, in 97 patients the treatment was continued for more than 4 weeks. 103 children
were in the age group of 6 – 12 years, in this group the mean daily dose was 600 mg
corresponding to 2.7 g of the herbal substance.
starting dose
(mg of herbal
substance)
300 mg
(1,350 mg)
600 mg
(2,700 mg)
900 mg
(4,050 mg)
1,200 mg
(5,400 mg)
n (age 6 – 12
years)
40 (38.9 %)
42 (40.1 %)
12 (11.6 %)
9 (9.4 %)
The dosage was increased in 8.8 % of all cases and reduced in 6.9 %. Efficacy was rated after
2 and 4 weeks. There was a clear tendency towards better ratings after 4 than after 2 weeks.
After 4 weeks, the parents rated efficacy for children with restlessness alone as “good” or “very
good” in 89 % of the cases, for children with difficulties in falling asleep alone in 100 % and for
children with both symptoms in 87 %. Pre-existing accompanying symptoms like
gastrointestinal complaints, tiredness during daytime and fatigue were also improved or
disappeared in a high proportion of patients.
Although the treatment results may be due to a placebo effect in a substantial proportion of
patients, in view of the positive feedback by parents and physicians the treatment can be
considered as a useful alternative to chemically defined compounds in both indications ‘relief of
sleep disorders’ and ‘relief of mild nervous tension’.
2
As referred to in the HMPC ‘Guideline on the assessment of clinical safety and efficacy in the preparation of
Community herbal monographs for well-established and of Community herbal monographs/entries to the
Community list for traditional herbal products/substances/preparations’ (EMEA/HMPC/104613/2005)
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No controlled clinical trials have been performed with valerian root in children, and only limited
experience in drug monitoring trials has been published.
-
Müller SF et al (2006) Phytomedicine (article in press):
In an open multicenter observational study n = 918 children ≤12 years (n = 719 ≥ 6 years) have
been treated with a combination product (coated tablets containing 160 mg valerian root dry
extract (DER 4 – 5:1, extraction solvent ethanol 70% (V/V) + 80 mg lemon balm dry extract
(DER 4 – 6:1, extraction solvent 30% ethanol (V/V)) for 4 weeks ±1 week. 80% of the children
≥ 6 years received the full adult dose without any tolerability problems. The study can be
accepted to support the use of valerian root extract as a single active substance in children
≤ 12 years of age concerning tolerability regarding reduced doses of 2/3 of the adult dose. The
indication of restlessness and sleeping problems covers developmental particularities in
children, due to which data on efficacy in children of the different age groups ≤ 12 years are
necessary.
Conclusion
Although promising results with use of valerian root extracts in children have been published, the data
are still too scarce to justify a general recommendation. A recommendation for use of medicinal
products containing valerian root in children below the age of 12 years should be substantiated by
specific clinical experience. The lack of experience is addressed as a relative contraindication in the
Community herbal monograph. Restlessness and sleep disorders in children of the different age groups
can be common symptoms of specific age dependent diseases/conditions (i.e. attention-
deficit/hyperactivity disorder (ADHD); developing sleep patterns in toddlers, school problems). They
must be differentiated and diagnosed. General recommendations cannot therefore be given and a
treatment should exclusively follow medical advice.
There is no need for clinical trials or specific warnings for adolescents between 12 to 18 years of age
taking into account the excellent tolerability of valerian root and its preparations.
IV.2
OLERABILITY
Approximately 620 patients or subjects received a valerian root extract preparation in the controlled
clinical trials (including human pharmacological studies) listed above.
Valerian root was generally well tolerated while in the same studies chemical substances like
oxazepam, flunitrazepam, temazepam and diphenhydramine showed typical undesirable effects like
drowsiness, fatigue and “hang-over” effects. No typical undesirable effects have been identified for
valerian root by the time this report was adopted by the HMPC.
There is a high exposure to valerian root preparations in the EU Member States: according to data
provided by IMS Health, sales in the EU in 2002 exceeded 50 million units. Nearly 50 % were sold in
Germany. The following adverse events probably linked to the consumption of valerian root have been
reported: gastrointestinal symptoms e.g. nausea, abdominal cramps (unknown frequency).
No unequivocal dependencies have been reported. A case of withdrawal symptoms is reported in a
58-year old man with high-output cardiac failure and delirium, who had had a daily consumption of
2.5 – 10 g valerian root extract over several years. Symptoms improved after application of midazolam
(Garges 1998). Another case was reported in a 41-year old woman, who had taken valerian and
acetaminophen/hydrocodone “regularly” (Wiener et al., 2003). No details on the preparation and the
daily dose are given. In view of the very high consumption of valerian root products worldwide, these
case reports are not considered to be a relevant hint for an abuse risk.
No organ toxicities have been observed in connection with valerian root intake.
One case of acute overdose has been reported. An 18-year old student, who took approximately
18.8 to 23.5 g powdered valerian root (40 to 50 capsules, containing each 470 mg pulverised crude
herbal substance) in a suicide attempt, complained of tiredness, abdominal cramps, tightness in the
breast, tremor in hands and feet and confusion after 30 minutes. Three hours after taking valerian root,
she was admitted to an emergency out-patient department. The examination showed normal physical
findings, apart from a mydriasis and fine hand tremor. ECG, blood count and laboratory parameters
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including liver values were normal. Tetrahydrocannabinol (THC) was detected in the urine. The
patient was treated with active charcoal; the symptoms had completely disappeared after 24 hours. The
authors ascribed the overdose symptoms to taking valerian root, although the positive proof of THC in
the urine could indicate that marihuana abuse also made a contribution. However, THC can often be
detected in urine several weeks after last consuming cannabis; the patient denied using cannabis in the
previous two weeks. The case report shows that valerian root is only slightly toxic and the overdose of
approximately 20 g valerian root did not lead to any severe clinical symptoms (Willey et al., 1995).
IV.3
RADITIONAL USE
Therapeutic use of valerian root and its preparations probably goes back to the ancient Greeks and
Romans who used a valerian-like herb (‚phu‘) for treatment of conditions for which therapists would
use bitter and aromatic roots today. Dioskurides for example (Materia Medica 50 – 70 AD) used the
dry root or its decoct of a plant called ‘phu’ or ‘wild nard’ (not doubtlessly identified as
Valeriana
officinalis
) for warming, as a urinary tract remedy, for menstrual cramps and for liver diseases.
The following compilation is restricted to the use of
Valeriana officinalis
L., radix
.
as monotherapy in
the modern phytotherapeutic tradition going back to the year 1800.
IV.3.1 Europe
•
References
-
Chamisso (1781 – 1831) describes valerian root as antispasmodic, effective against worm
diseases and as strengthening.
Information on preparations and dose recommendations is not available (according to Benedum
et al.).
-
Vietz (1800) recommends valerian root for all spasmodic and convulsive diseases, for epilepsy,
hysteric attacks, worm diseases and against nervous fever.
Information on preparations and dose recommendations is not available (according to Benedum
et al.).
- Hager (1873/74) refers to the use of valerian root for cramps, epilepsy, worm diseases and
hysterical ailments.
Information on preparations and dose recommendations is not available (according to Benedum
et al.).
- Dragendorff (1898) describes the use of the root as antispasmodic, as remedium nervinum and
antihysteric. No details on preparations and dosages are given.
- Madaus (1938) recommends the use of the dried root, the powdered herbal substance, tincture
or fresh root: trituration
Dosages according to different therapists cited by the author:
•
powdered herbal substance: 0.5 – 4 g several times/day
•
powdered herbal substance 0.5 – 5 g
•
4.8 g of the herbal substance for cold extract
•
1 – 3 tbl. (each corresponding to 0.125 g fresh valerian root) of trituration ‚Teep‘, for
sleeplessness 2 tbl. in the evening
Recommendations for valerian root as single therapy:
•
For sleeplessness and neurasthenia:
cold extract (1 teaspoon, corresponding to approximately 5 g of the herbal substance, for
24 hours in 1 glass of water, intake in sips over the day, for sleeplessness consumption of the
whole extract in the evening)
•
as enema against worms and cramps in the lower abdomen:
10 – 12 g of the herbal substance as decoct in 250 ml water
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Traditional indications according to several authors cited by Madaus:
•
internal use:
aphrodisiac, diuretic, analgesic, emmenagogue, analeptic, stomachic, carminative. Against
cough, asthma, flatulence, chronic diarrhoea, obstipation, worm infections, anthrax, hysteria,
cramps of the neck muscles and paresis due to acute infectious diseases. For internal injuries.
After severe typhoid or diphteria. Before salvarsan injection as prophylaxis of a salvarsan-
induced shock.
•
external use:
headache, reddened and painful eye, wound healing. Bath against acute rheumatism.
For these indications the root was used in most cases, only exceptionally the leaves. Details on
herbal preparations and dosages are not given.
- Ward (1936) recommends valerian root for use in hysteria, neuralgia and nervous debility.
Preparation/Dosage: an infusion of 1 ounce to 1 pint of boiling water in wineglass doses three or
four times daily.
-
Weiss (1944) emphasizes the following established indications for valerian root:
Nervous agitation, nervous sleeplessness, nervous palpitations.
Preparations and dose recommendations:
•
dried root: tea infusion with two teaspoons / cup
infusion 10.0/15.0, to take in sips
cold maceration with two teaspoons/glass of cold water
•
tinctura valerianae, single dose ½ - 2 teaspoons
•
tinctura valeriana aetherea: to be dosed drop by drop
•
extractum valerianae fluidum (no dose recommendation for single use given)
-
The Hungarian Pharmacopoeia (Edition VI. Volume III. 1967) lists the following valerian root
preparations:
•
tinctura valerianae aethera (1:5, ethanol 70 % and aether 7.5:2.5 m/m), single dose
00 –
500 mg
•
tinctura valerianae spirituosa (1:5, ethanol 70 % V/V), si
•
valerianae rhizoma et radix, single dose 0,5 – 1 g
- The twenty-fifth edition of Martindale’s Extra Pharmacopoeia (1967) recommends the
l wing
ngle dose 200 – 500 mg
fol o uses of herbal preparations made from the dried rhizome
•
valerian extract (B.P.C. 1954). Single dose 60 – 300 mg
•
valerian liquid extract (B.P.C.), DER 1:1, extraction solvent ethanol 60 %.
inglS dose 0.3 – 1 ml.
•
concentrated valerian infusion (B.P.C.), DER 1:5, prepared by percolation with ethanol
(25 %). Single dose 15 – 30 ml.
•
valerian infusion: Dilution of 1 vol. of the concentrated infusion to 8 vol. with water.
•
tinct. valerian. simp. (B.P.C. 1949), DER, prepared by maceration with ethanol (60 %).
Single dose: 4 – 8 ml.
Indications: hysteria and other nervous condition, carminative.
-
The British Herbal Pharmacopoeia (1976) gives the following recommendations:
Indications: Hysterical states, excitability, insomnia, hypochondriasis, migraine, cramp,
intestinal colic, rheumatic pains, dysmenorrhoea
Preparations/Dose recommendations (three time daily)
•
dried rhizome and root: 0.3 – 1 g by infusion or decoction
•
liquid extract 1:1 (60 % ethanol): 0.3 – 1 ml
•
tincture simple 1:8 (60 % ethanol): 4 – 8 ml
•
concentrated infusion 1:5 (25 % ethanol): 2 – 4 ml
-
Hager’s Handbuch (1979) lists the following indications for valerian root:
Mild sedative in nervous exhaustion, sleeplessness, mental overwork, nervous heart ailments,
headache, neurasthenia, hysteria. As antispasmodic for stomach cramps, colics etc.
and roots:
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2
Recommended preparations: dried powdered herbal substance, tincture (extraction solvent
ethanol 60 %), fresh dried herbal substance.
The dose range for the single dose, taken from several pharmacopoeias, is 0.3 – 1 g, for the total
daily dose 2 – 15 g.
- Haffner et al. (1991) recommend the following single doses for the use of valerian root
preparations:
•
herbal substance:
2.5 g
•
extr. fld.
2.0 g
•
extr. (sicc.)
0.5 g
•
tinct.
5.0 g
•
aetheroleum
0.1 g
•
Traditional use in EU countries
Medicinal products containing aqueous and aqueous-ethanolic extracts, which can be assumed as well-
established, combination products and preparations for external use are excluded from the following
listing.
Germany
- Several preparations containing pressed juice of the fresh valerian root were traded in the year
1975 and have been fully registered.
Indications: for nerve calming and sleep disturbances, spasmolytic in general spasmophily,
nervous gastrointestinal disorders, nervous cardiac disorders.
Dose recommendation: 3 x 1 table spoon/day
-
A preparation with valerian root oil for oral use with registration as “traditional remedy” has
been notified in the year 1978.
Indication: Traditionally used for improvement of well-being in stress situations.
Dose recommendation: single dose 15 mg
-
Powdered herbal substance for preparation of a tea (tradition proven in cited literature) is
registered for the indications “restlessness” and “sleep-induction disturbances due to nervous
conditions”.
Dose recommendation: single dose 2.5 g, once or several times daily.
-
Several products containing dry extract with methanol/water (methanol 45 % V/V) have been
registered during the last year. Traditional use for at least 30 years is not proven.
France
The French Competent Authority recommends the following traditional use of valerian root
preparations:
“Traditionally used in symptomatic treatment of neurotonic conditions of adults and children,
particularly in cases of minor sleep disturbances.”
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IV.3.2 Asia
According to Usmanghani (1997, Pakistan), valerian root and rhizomes are used in traditional
formulations to relieve disorders of the spinal cord, ‘nervous debility’, failing reflexes, as hypnotic, for
nervous disorders during menopause, for insomnia due to nervous exhaustion and mental overwork,
against neurosis, hysteria and epilepsy.
Herbal preparations: Only the names of traditional preparations are given.
Dosage: approximately 3 – 5 g (it is not specified whether this is a single or a daily dose)
The authors remark that valerian root is described as harmful for kidney function if taken in large
doses or for long period.
Due to the lack of information, the plausibility of the Pakistanian tradition cannot be rated. Since the
herbal preparations are not common in Europe, no traditional use can be supported in this report vis-à-
vis registration in the EU Member States.
IV.3.3 USA
- Sayre’s Materia Medica (1917) lists valerian root as a ‘gentle nerve stimulant and
antispasmodic’, employed in hysterical disorders.
Preparations:
•
Herbal substance (single dose: 1 – 4 g)
•
Tincturae Valerianae (20 %), single dose 4 – 8 ml
•
Tinctura Valerianae Ammoniata (20 %), single dose 2 – 4 ml
- Culbreth (1927) recommends the use of valerian root in the following indications:
Hysteria, hypochondria, hemicrania, nervous coughs, whooping-cough, diabetes, delirium
tremens, typhoid state, dysmenorrhoea, vertigo, epilepsy, worm convulsions, flatulence, reflex
neuralgia.
Herbal preparations:
•
Tinctura Valerianae, single dose: 2 – 8 ml.
•
Fluidextractum Valerianae (80 % ethanol), single dose: 1 – 4 ml.
Culbreth also mentions unofficial preparations (abstract, extract, infusion, syrup and aqueous
extracts).
Conclusion
For valerian root and some of its preparations, a tradition can be claimed within the EU:
•
Herbal substance
- dried valerian root
•
Herbal preparations
-
dry extracts prepared with water
-
valerian tincture
-
expressed juice from fresh root
-
valerian root oil
Traditional indications comprise a multitude of conditions, which are only in part comprehensible
from a contemporary point of view. Sedative and anxiolytic effects, which have been discussed in
detail above, are well reflected in the common indications for valerian root preparations. Besides that,
spasmolytic and anticonvulsive properties have been demonstrated in several nonclinical
investigations (Ruecker et al., 1978, Hazelhoff et al., 1982, Leuschner et al., 1993, Hiller et al., 1996).
These effects are in congruence with the clinical use for dysmenorrhea and gastrointestinal cramps due
to nervous conditions which has been outlined in most of the references cited above.
For all other indications, a rational basis is lacking; they are not acceptable in view also of the facts
that effective alternatives are available nowadays and that sufficient information on the herbal
preparations and dose recommendations are missing.
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Recommended dose range for traditional valerian root and its traditional preparations (single dose):
Adolescents over 12 years of age, adults, elderly
Single dose:
-
0.3 to 1 g dried valerian root (e.g. as powdered herbal substance)
-
1 to 3 g dried valerian root for preparation of a tea
-
dry extracts prepared with water corresponding to 1 to 3 g of the herbal substance
-
valerian tincture corresponding to 0.3 to 1 g of the herbal substance
-
15 ml of expressed juice
-
15 mg of valerian root oil
For relief of mild symptoms of mental stress up to 3 times daily.
To aid sleep, a single dose half to one hour before bedtime with an earlier dose during the evening if
necessary.
Maximum daily dose: 4 single doses
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Source: European Medicines Agency
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