Professional Documents
Culture Documents
VALERIAN
Individual volumes in this series provide both industry and academia with in-depth coverage of
one major medicinal or aromatic plant of industrial importance.
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CONTENTS
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Amsteldijk 166
ix
Contributors
xi
1079 LH Amsterdam
Anthony C. Dweck
1st Floor
The Netherlands
Vll
21
Peter]. Houghton
3
55
Josef Hb'1%1
4
Cultivation of Valerian
77
Jeno Berndth
101
Vaieriana Products
129
The illustration on the cover is taken from the Bloemle^ing uit het Cruydt-boeck van Rfmbert
Dodoens, edited by Dr A. Schierbeek, De Hofstad, The Hague, 1941. This is a compilation
of Herbarius oft Cruydt-hoeck by Rembertus Dodonaeus, Plantijnsche Druckerije van
Balthasar Moretus, Antwerp, 1644. We have tried to find the copyright holder of the
compilation but were not successful, please contact the publisher in case of any copyright
queries.
139
Many industries are involved such as forestry, agriculture, chemical, food, flavour,
beverage, pharmaceutical, cosmetic and fragrance. The plant raw materials are roots,
rhizomes, bulbs, leaves, stems, barks, wood, flowers, fruits and seeds. These yield gums,
resins, essential (volatile) oils, fixed oils, waxes, juices, extracts and spices for medicinal
and aromatic purposes. All these commodities are traded world-wide. A dealer's market
report for an item may say "Drought in the country of origin has forced up prices".
Natural products do not mean safe products and account of this has to be taken by
the above industries, which are subject to regulation. For example, a number of plants
which are approved for use in medicine must not be used in cosmetic products.
The assessment of safe to use starts with the harvested plant material which has to
comply with an official monograph. This may require absence of, or prescribed limits
of, radioactive material, heavy metals, aflatoxins, pesticide residue, as well as the required
level of active principle. This analytical control is costly and tends to exclude small
batches of plant material. Large scale contracted mechanised cultivation with designated
seed or plantlets is now preferable.
Today, plant selection is not only for the yield of active principle, but for the plants
ability to overcome disease, climatic stress and the hazards caused by mankind. Such
methods as in vitro fertilisation, meristem cultures and somatic embryogenesis are used.
The transfer of sections of DNA is giving rise to controversy in the case of some enduses of the plant material.
Some suppliers of plant raw material are now able to certify that they are supplying
organically-farmed medicinal plants, herbs and spices. The Economic Union directive
(CVO/EU No 2092/91) details the specifications for the obligatory quality controls
to be carried out at all stages of production and processing of organic products.
Fascinating plant folklore and ethnopharmacology leads to medicinal potential.
Examples are the muscle relaxants based on the arrow poison, curare, from species of
Chondrodendron, and the antimalarials derived from species of Cinchona and Artemisia.
The methods of detection of pharmacological activity have become increasingly reliable
and specific, frequently involving enzymes in bioassays and avoiding the use of laboratory
animals. By using bioassay linked fractionation of crude plant juices or extracts,
compounds can be specifically targeted which, for example, inhibit blood platelet
aggregation, or have antitumour, or antiviral, or any other required activity. With the
assistance of robotic devices, all the members of a genus may be readily screened.
However, the plant material must be fully authenticated by a specialist.
viii
The medicinal traditions of ancient civilisations such as those of China and India
have a large armamentarium of plants in their pharmacopoeias which are used throughout
South East Asia. A similar situation exists in Africa and South America. Thus, a very
PREFACE
In the comparative backwater of the Cotswolds, some doctors still preferred the
older remedies so my father often made up a large bottle of Potassium Bromide and
Valerian Mixture which was prescribed as a tranquillizer or sedative. This entailed the
use of Valerian Infusion, an alcoholic extract of Vakriana officinalis roots, with its distinctive
and penetrating smell. Many find the odour repulsive but I, either through environmental
high percentage of the world's population relies on medicinal and aromatic plants for
their medicine. Western medicine is also responding. Already in Germany all medical
practitioners have to pass an examination in phytotherapy before being allowed to practise.
It is noticeable that throughout Europe and the USA, medical, pharmacy and health
The business of dietary supplements in the Western World has expanded from the
Health Store to the pharmacy. Alternative medicine includes plant based products.
Appropriate measures to ensure the quality, safety and efficacy of these either already
exist or are being answered by greater legislative control by such bodies as the Food and
Drug Administration of the USA and the recently created European Agency for the
Evaluation of Medicinal Products, based in London.
In the USA, the Dietary Supplement and Health Education Act of 1994 recognised
the class of phytotherapeutic agents derived from medicinal and aromatic plants.
Furthermore, under public pressure, the US Congress set up an Office of Alternative
Medicine and this office in 1994 assisted the filing of several Investigational New Drug
(IND) applications, required for clinical trials of some Chinese herbal preparations.
The significance of these applications was that each Chinese preparation involved several
plants and yet was handled as a single IND. A demonstration of the contribution to
efficacy, of each ingredient of each plant, was not required. This was a major step
forward towards more sensible regulations in regard to phytomedicines.
My thanks are due to the staff of Harwood Academic Publishers who have made
this series possible and especially to the volume editors and their chapter contributors
for the authoritative information.
Roland Hardman
chemical entities.
At the same time, the benzodiazepines such as Valium and Iibrium were being
introduced and used for much the same CNS depressant ends by those with a more
modern inclination. Within ten years Valerian seemed to have disappeared, along with
many other vegetable drugs, from mainstream pharmacy and its monograph was dropped
from the 1973 British Pharmacopoeia.
This shift in medication did not occur to such a great extent in some other European
countries such as Germany where herbal medication was still widely practised by general
practitioners and so, in these countries, Valerian and other drugs were still used.
Consequently, with the incorporation of European Pharmacopoeia monographs into
the British Pharmacopoeia from 1980 onwards, Valerian once more featured in the
entries.
The renaissance of the status of Valerian was also carried by the high annual erowth
estimated at about 10% in most developed countries, in consumer preference for plantbased self-medication. This interest in phytotherapeutic agents, or 'herbal remedies',
has occurred since about 1980 and has directed renewed clinical and scientific attention
towards such products and their plant sources. There is increasing realisation that the
traditional use of these materials often has a scientific basis but also that they may
provide new leads for 'conventional' pharmaceuticals.
In time I learnt that the Valerian plant Vakriana officinalis, known to me as a British
wild flower and as a substance in my father's pharmacy, was one menber of a genus of
plants used throughout the world in most traditional medical systems for much the
same purpose. The therapeutic efficacy of extracts of V. officinalis, together with other
Vakriana species, in providing sedation, has been proven by many pharmacological and
clinical experiments. Such extracts were extensively used during the two world wars for
treatment of the condition known somewhat euphemistically as 'shell shock'. However,
in common with many other phytotherapeutic agents, the chemical basis for this activity
remained largely a mystery since no 'active ingredient' could be clearly identified. This
hampered wider clinical usage since efficacy could not be guaranteed on the basis of
chemical analysis.
The development since 1960 of more refined separation techniques and spectroscopic
CONTRIBUTORS
methods of structural elucidation, followed closely by tests for biological activity using
small amounts and much more specific targets such as receptors, has resulted in a
considerable amount of research on Vaieriana. New types of chemical constituents
have been discovered in this genus and the basis of their mode of action has to some
extent been elucidated. It should be emphasised, however, that the story still awaits
completion and, every year, several research papers appear in scientific journals dealing
with different aspects of Vaieriana species.
Vaieriana is a good example of the problematic and beneficial aspects of the use of
plant materials as pharmaceutical agents. Issues such as variation in chemical content
Jeno Bernath
Josef Holzl
Production
3550 Marburg
Industry
Germany
Peter J. Houghton
H-1502 Hungary
R. Bos
Manresa Road
UK
JJ.C. Scheffer
9713 AW Groningen
The Netherlands
Division of Pharmacognosy
Leiden/Amsterdam Center for Drug
Anthony C. Dweck
Leiden University
Research (LACDR)
Research Director
Gorlaeus Laboratories
PO Box 9502
2300 RA Leiden
The Netherlands
H J. Woerdenbag
UK
Richard Foss
Agros Associates
Antonius Deusinglaan 2
9713 AW Groningen
The Netherlands
Aylsham
1.
AN INTRODUCTION TO VALERIAN
Research Director, Peter Black Medicare, Peter Black Cosmetics <& Toiletries
Southern Distribution Centre, White Horse Business Park,
Aintree Avenue, Trowbridge, Wilts. BA14 OXB
CONTENTS
INTRODUCTION
The Importance Of Valerian And Vaieriana
The Smell
The Name
Vaieriana species
Related plants of importance
Non-related plants with similar trivial names
Language of flowers
Saintly assignations
Vaieriana In History
Cosmetic Uses
Bathing
Topical application
Food Uses
Effect of Vaieriana On Animals
AN INTRODUCTION TO VALERIAN
ANTHONY C. DWECK
INTRODUCTION
A distinctive smell often pervaded pharmacies in Great Britain and several other countries
before the advent of the modern benzodiazepine tranquillisers and similar drugs. This
odour was due to the extracts of a drug, called in English 'Valerian', which was
incorporated in a mixture with potassium bromide prescribed for patients needing a
relief from over-excitement of the central nervous system (CNS). Valerian commonly
used in northern European medicine is derived from the underground organs of Vakriana
offmnalis L, a member of the Valerianaceae. This plant is steeped in history and related
species are used in traditional medicine in many other parts of the world. The original
use of V. ojficinatis as a perfume or perhaps even as a source of food was totally different
to its modern use in orthodox and herbal medicine as a sedative and calming agent. The
stresses of late twentieth century industrial society have resulted in an increase of use
and interest in alternative sedatives to those used in orthodox medicine. Many of the
products intended for self-treatment of mild stress contain Valerian crude drug or extracts.
The additional aspect of its being a drug still prescribed by some orthodox practitioners
as well as phytotherapists mean that a large amount of this group of crude drugs are
grown, processed and used each year. The most important commercial species are
Voffirinalis, V. wallichii (syn. V.jatamansii), V. fauriei and V. edulis and it is these species
which are dealt with in this book.
A few comprehensive reviews dealing with the history, constituents and activity of
Valeriana have been published in recent years (Houghton, 1988, 1994; Hobbs, 1994;
Jasperson-Squibb,l 990). Valeriana species have been used for many years and the history
of their use, or the reported ethnobotany, often seems implausible and the style and
description of the writing is sometimes quaint and seems amusing. However, it is often
startling to discover, that in reviewing the data retrospectively one finds an 'Old Wives
Tale' that has been given scientific proof. Galen, who by luck or by judgement, intimated
that Valerian was a sedative, might have been somewhat bemused to learn that his findings
took another fourteen centuries to be rediscovered.
Figure 1
vile smelling (Saunders, 1976). Another (Heinerman, 1988) even describes the smell as
'unwashed underwear". Fresh valerian root smells like ancient leather but, when dried,
it is nearer to stale perspiration (Bremness,1988).
However, this dislike of the smell was not the case in the years up to and including
the 16th century, when most reports make no adverse comments on the odour of the
plant.
In the East the smell was liked immensely and used as a perfume in bathing.
Today the oil of valerian is used as a component of many blended perfume oils, where
it can impart a leathery' note to a fragrance. Valerian is not a recognised aromatherapy
oil, and yet there is a growing body of evidence to show that the odour of valerian alone
is sufficient to have a sedative effect (Balacs,1992).
The intense smell can be a problem and contaminate equipment, but the odour may
The Smell
The smell has been described as being that of "torn" cats (Hooper, 1984), as dirty socks
(Keville, 1991), as warm and camphorous (Hutchens, 1992), as a strong penetrating,
disagreeable odour with a camphorous, bitter taste (British Pharmaceutical Codex 1923).
Others say it is nauseous and unpleasant (Baraicli Levy, 1991) and it is for this reason
that one of its old names was 'Phu' (Hobbs, 1994), a name interpreted from the
explanation of disgust with the strong smell of long-dried valerian root. He also likens
the odour to well-seasoned dirty socks, while another author goes as far to describe it as
be removed from a scale pan or from the hands by rubbing with sodium bicarbonate
(Murrison,l 935). It is now known that the major part of the odour is due to the isovaleric
acid released by enzyme hydrolysis from some of the compounds present in the plant.
The Name
There are a number of explanations for the origin of the name but no universallyaccepted etymology as yet exists. It might be from the Latin 'valere' meaning courage,
which one might need to drink the infusion. Another source suggests from the Latin
ANTHONY C. DWECK
AN INTRODUCTION TO VALERIAN
Table 1 continued
Species name
Synonyms
Common names
V. acutiloba Rydb.
V dioica
V. adscendens Turcz.
V. agrimonifolia Killip
V. alliariifolia Troitzky
V. alpestris Stev.
V. alternifolia Ledeb
V. ojficinalis L
V. amphilopbis Graebn.
V. amurensis P. Smirn.
ex Kom..
V. angustifolia Tausch
V.officinalis
V, ari^onica A.Gray
Arizona Valerian
V. armeriifolia Schltdl.
V, aschersoniana Graebn.
Aretiastrum aschersonianum
ex Weberbauer
Graebn.
V. asplenifolia Killip
V baltana Graebn.
Figure 2
V. bambusicaulis Killip
V. candolleana Gardner
Clustered Valerian
V. capitata Pall
V. celtica L.
Nardus celtica
Celtic Nard
V. cephalantha Schlecht.
(Coombes,1985). The name valerian is also thought by some to be derived from the
V. chaerophylla Pers
latinised form of the Old High German 'Baldrian' whose origin is uncertain.
V. chaerophylloides Sm.
V. dematitis Kunth
V. dematoides Graebn.
Vakriana is the major genus of the Valerianaceae, a family represented in all the temperate
and sub-tropical areas of the world. Bentham and Hooker (1954) describe the
Valerianaceae as being herbs with opposite leaves and no stipules. The flowers are in
terminal corymbs or panicles and are usually small and numerous. The calyx is above
V. condamoana Graebn.
V, connata Ruiz & Pav
V. connata var. nutans
Graebn
V. convallarioides
(Schmale) B.B. Larsen
the ovary and forms a small, sometimes toothed, border which is scarcely noticeable at
K coreana Briq.
the time of flowering but afterwards unrolls into a feathery pappus. The corolla is
V. cornucopiae L.
usually monopetalous, tubular at the base with five spreading lobes.. There are less
K costata Schmale
stamens than lobes of the corolla. The fruit is small, dry and seed-like with a single seed
suspended from the top of the cell but also frequently one or two imperfect or abortive
empty cells. The genus Vakriana is characterised by perennials having three stamens and
no spurs on the slightly swollen base of the corolla. The fruit is crowned by a feathery
pappus.
Phyllactis convallarioides
Schmale
African Valerian
V. dioica L.
V. acutiloba
Marsh Valerian
K phu
Phu
ANTHONY C. DWECK
Table 1 continued
Species name
AN INTRODUCTION TO VALERIAN
Common names
V. dipsacoides Graebn.
Table 1 continued
Species name
V. ledoides Graebn.
V. linearifolia Killip
V. locusta L.
V. grisiana Wedd.
Common Corn Salad, Lamb's
V. eiatior Graebn.
Lettuce
V. longifolia Kunth
V. exaltata Mikan
V, excelsa Poiret
V. lyrataM. Vahl
V.jauriei Briq.
V. exscapa Griseb.
English: Japanese Valerian, Kisso
Japanese: Kanokosou, Kissoukon
V.friasana Schmale
V. g/obifera Vets.
V. lyrata Ball
V. lyrata Graebn
V. macbridei Killip
V. malvacea Graebn.
V. globiflora Ruiz & Pav.
V. mathewsii Briq.
V. globularioides Graebn.
K dipsacoides Graebn.
V. decussata Ruiz & Pav.
V. globularis Graebn
V. melanocarpa Killip
V. grisiana Wedd.
V. grisiana Killip
V. merxmuelleri Seitz
V. hadros Graebn.
V. maxima Killip
V. globularis A. Gray
V. mexicana DC
Centranthus ruber
V. hardwickii Wall.
V.sorbifolia H.B.K.
V. herrerae Killip
V. hirsutissima Killip
V. macbridei Killip
EG. Mey.
V. hirtella Kunth
V. hispida (Wedd.) Hoeck
V. microphylla Kunth
V. niphobia Briq.
V. microphylla Graebn
V. micropterina Wedd
V. bortensis ~Lam.
1/. humboldtii Hook. & Arn.
Common names
V. montana Bieb
V. humboldtii Briq.
V. nigricans Graebn.
V. matbewsii.Briq.
. V. niphobia Briq.
Aretiastrum imbricatum
V. alpestris
V. nitida Kreyer
(Killip) Killip
V. nivalis Wedd.
K interrupta interrupta
V. obtusifolia DC.
var. interrupta
V. ocddentalis
Small-flower Valerian
K interrupta interrupta
V. ofjicinalis'L..
V.obovata
Graebn
V. interrupta var.
interrupta Ball
V. interrupta eiatior
(Graebn.) Killip
Graebn
K interrupta var.
var. interrupta
V. isoetifolia Killip
K italica
Kjasminoides Briq.
V7.jatamansii Jones
V. wallichii DC
V. kilimandascharia Engl.
V. laciniata Ruiz & Pav
Astrephia chaerophylloides
(Sm.) DC.
valerian
r
AN INTRODUCTION TO VALERIAN
ANTHONY C. DWECK
Table 1 continued
Species name
Table 1 continued
Common names
Spedes name
French: Valeriane
V. quadrangularis Kunth
K radicata Graebn.
V. lyrataM. Vahl
B alderbrackenwur2el,
V. remota Ball
Baldrianwurzel
V. renifolia Killip
Italian: Valeriana
V. repens Host.
V. procurrens Wallr.
Spanish: Valeriane
V. rhi^antha A. Gray
Killip
Dutch: Valeriaan
Welsh: Llysiau Cadwgan
V. offidnalis L., subsp.collina
Pers.
Wallr.Nyman
V. romanana Graebn.
V. condamoana Graebn.
V. offidnalis L. subsp.
V, rufescens Killip
V. rumicoides Wedd.
sambudfolia
V. salina Pleigel
(Mik.f.) Celak
V. offidnalis var. latifolia
Common names
V. sambudfolia Mikan.
V. saxatilis L.
V. angustifolia
V. offidnalis var.
V. scandens L.
Florida Valerian
Mikami, Syme
V. scouleri
Scouler's Valerian
Valerian
V. sitchensis Bong.
Sitra Valerian
Pacific Valerian
V. oligodonta Killip
V. pkctritoides var.
plectritoides Graebn.
K oxyrioides Graebn.
V. lyrataM. Vahl
Belonanthus spathulatus
V. pardoana Graebn.
V, parvula Killip
Schmale
V. paudflora Michx.
Large-flower Valerian
V. sphaerocephala Graebn.
V. stolonifera Czern.
V. interrupta Ruiz &
V. supina L.
V. pentjellii Killip
V. sylvatica Banks
V.phuL.
V. sylvestris Grosch.
V. offidnalis L.
Pbyllactis tenuifolia
Wedd.
V. pimpinelloides Graebn.
V. tessendorffiana Graebn.
(Graebn.) Killip
K texana
V. thalictroides Graebn.
V. plectritoides Graebn.
V. tiliifolia Troitzky
V. tricbomanes Graebn.
plectritoides Killip
Three-leaved valerian
V. tripteris L.
Phyllactis pratensis
V. tuberosa L.
V. urtidfolia Kunth
V. variabilis Graebn.
V. punctata F. Meyer
V. verrucosa Schmale
V. pycnantba A. Gray
V. pyrenaica L.
Guadalupe Valerian
V. tomentosa Kunth
V. plectritoides
K procurrens Wallr.
V. pygmaea Graebn.
V. dioica
Nardus montana
Valeriane
V. versifolia Briigger
V. globularis A. Gray
V. wallichii DC
r
10
ANTHONY C. DWECK
Table 1 continued
Species name
AN INTRODUCTION TO VALERIAN
Table 2
11
Continued
Synonyms
Common names
Plant species
Common name
V.jatamansi Jone s
Ayurveda: Tagar
V. spica Vahl
Sinhalese: Kattakumanjal,
Thuwarda
Valerianella radiata
Valerianella stenocarpa
Hasti,Jimha, Kalanusakara,
Valerianella umbilicaia
Kalanusariva, Kalanusarya,
V. weberbaueri Graebn.
Table 3
Plant species
Common name
American Valerian
Correll(Orchidaceae)
Table 2
Plant species
Common name
Long-spurred Valerian
Garden Heliotrope
Nardostacbysjatamansi DC.=
English: Spikenard
Sinhalese: Jatamansa
Valeriana Species
The number of species of valerian is fairly large and is listed in Table 1 together with
synonyms and common names where applicable.
Although this book is concerned with the genus Valeriana it is important to realise that
medicinal, cosmetic and food materials. A list of the most important of these is given in
Table 2.
As with all plants that share common names, there is always the possibility that people
will become confused and use the incorrect plant, trusting in the vernacular name alone.
The list shown in Table 3 is a compilation of the most commonly reported errors and
mistakes.
12
ANTHONY C. DWECK
This aspect of the information concerning Valerian begins with all the strange and
mystical beliefs that surround it and a collection of anecdotes and folk lore that might
otherwise be difficult to find assembled in one place.
Valerian] a In Folklore
Miscellaneous beliefs
The following section is a short list of miscellaneous statements that have been collected
over the years. They are given without comment, because science has a wonderful knack
of occasionally proving or giving respectability to even the most unlikely of events.
A young woman who carries a sprig of valerian is never said to lack ardent
lovers.
It was said to inspire love and so was used as an ingredient in love philtres. It
was also cited as an aphrodisiac (Gordon,1980). It has also been said that
valerian increases psychic perception (Howard,1987).
It protects a person from thunder and lightening, and was used both for and
against witchcraft (Gordon,1980).
Hanging the herb in the house was reputed to prevent the husband and wife
from bickering (Law, 1973).
AN INTRODUCTION TO VALERIAN
13
Chamomile:
Pink Clover:
Individual plants could be combined with a wide diversity of others in order to build up
a quite a comprehensive message, and thus it became customary to present bouquets of
flowers instead of writing letters or notes, and for this purpose hundreds of flowers
had designated meanings.
There can be few who do not know the symbolic meaning of the red rose. However,
be tempered with caution, for a yellow rose means 'misplaced affection' or "I love
another"! In the book Language of Flowers (Anon: 1968), valerian is said to mean an
Saintly assignation
At more or less the same time that the astrologers were assigning all the plants to planetary
influences, there were others who were dedicating the plants to various saints. Valerian
is dedicated to St. Bernard (Gordon, 1980).
1/akriana In History
much restlessness and severe cases of delusion. It is said that Adolf Hitler
was a valerian addict and regularly took large and excessive doses (Bairacli
In a concise history of valerian, Hobbs (1994) pointed out that the early uses of valerian
Levy, 1991).
were in the most part for its bitter and aromatic qualities. Related plants, especially
spikenard derived from Nardostachysjatamansii, are mentioned in the Bible.
Planetary influences
There was a time when almost everything was considered to come under the influence
of the planets and astral bodies. The astrologers and mystics assigned the futures of
the people and the future of the world according to the positioning of those stars and
heavenly configurations. Trees, precious stones and even plants came under the influence
of the firmament. According to Law (1973) valerian is under the influence of Uranus,
however, Culpeper (Potterton, D. (ed) 1983) and Gordon (1980) say that the plant is
under the influence of Mercury.
Language of flowers
In medieval times, the art of writing was limited to only a few, and even then it was more
common to write in Latin than in the common tongue. In the Middle Ages there
While the king sitteth at his table, my spikenard sendeth forth the smell
thereof. Song of Solomon I v.12
ANTHONY C. DWECK
AN INTRODUCTION TO VALERIAN
The Greek physician and pharmacist, Galen (131-201 A.D.), was probably the first to
were starting to describe the uses of valerian in a way that would almost be accepted
allude to the sedative qualities of valerian. However, it was not until the end of the 16th.
today.
14
century that this use was truly recognised. The virtues of Setwall (the common name at
that time for Valerian) were described by Gerard (1597) as follows:The dry root is put into counterpoysons and medicines preservative against
the pestilence, as are treacles, mithridates, and such like: whereupon it hath
been had (and is to this day among the poore people of our Northerne parts)
in such veneration amongst them, that no broths, pottage or physicall meats
are worth any thing, if Setwall were not at an end: whereupon some women
Poet or other hath made these verses.
They that will have their heale,
15
This is under the influence of Mercury. Dioscorides saith, That the Garden
Valerian hath a warming faculty, and that being dried and given to drink it
The roots of Valeriana dioica are said to be sometimes mingled with those of the officinal
provokes urine, and helps the stranguary. The decoction thereof taken, doth
plant; but the adulteration is attended with no serious consequences; as, though much
the like also, and takes away pains of the sides, provokes women's courses,
and is used in antidotes. Pliny saith, That the powder of the root given in
drink, or the decoction thereof taken, helps all stoppings and stranglings in
any part of the body, whether they proceed of pains in the chest or sides, and
takes them away. The root of Valerian boiled with liquorice, raisins, and
anniseed, is singularly good for those that are short-winded, and for those
that are troubled with the cough, and helps to open the passages, and to
expectorate phlegm easily. It is given to those that are bitten or stung by any
venemous creature, being boiled in wine. It is of a special virtue against the
plague, the decoction thereof being drank, and the roots being used to smell
to. It helps to expel the wind in the belly. The green herb takes away the
By 1923, there was the first indication (British Pharmaceutical Codex: 1923)
that the action of valerian could also act through an odorous pathway. The
action of valerian rhizome is virtually that of its volatile oil, the valerianic
esters of which have no stimulating action on the physical functions and the
circulation, as was formerly believed, although they possess the usual car
minative action of the volatile oils. The action of such malodorous sub
stances as valerian is generally attributed to the mental effect produced by
their unpleasant odour and taste. Valerian is used as a carminative and
antispasmodic in hysteria and similar nervous manifestations.
pains and prickings there, stays rheum and thin distillation, and being boiled
Valerian has been prescribed (Howard, 1987) as the perfect herbal tranquilliser, and was
in white wine, and a drop thereof put into the eyes, takes away the dimness
used for this purpose in the First World War to treat soldiers suffering from shell shock
of the sight, or any pin or web therein. It is of excellent property to heal any
(Howard, 1987).
inward sores or wounds, and also for outward hurts or wounds, and drawing
away splinters or thorns out of the flesh.
During the Second World War there was a shortage of the dried rhizome and roots of
Valeriana officinalis, collected in the autumn and a special dispensation was printed in the
Valerian was first used therapeutically as a sedative by the English doctor John Hill in
1941 edition of Martindale: "As a war emergency measure, when valerian isprescribed or demanded,
the middle of the 18th century. About a hundred years later this medical plant was
Indian valerian may be dispensed or supplied." The description of the uses read as follows:
described by Christoph Wilhelm Hufeland (1762 - 1836), the founder of the electric
medical school and doctor to many important people, as the "best medicine for the
Given in hysterical and neurotic conditions as a sedative. Its action has been
nerves". The medical drug valerian was chemically analysed already in the 19th century,
the volatile oil in particular being the object of various investigations. By the end of the
century the pharmaceutical texts (Dispensatory of the United States of America: 1883)
ANTHONY C. DWECK
16
AN INTRODUCTION TO VALERIAN
Topical application
Another source (Weiss, 1986) says that the three main areas of use for valerian are for
nervous excitement, nervous sleeplessness, and nervous palpitations.
17
has been
mentioned (Leung, 1980) and also the use of valerian for treating sores and pimples. It
is said (Bremness, 1988) that the use of a lotion is good for the treatment of acne and
skin rashes.
A report of the Council of Europe (1989) on the intended cosmetic effect
ailments of the hair. The roots are also used for improving the complexion, increasing
the lustre of the eye and promoting the growth and increasing the blackness of the hair.
Food Uses
A considerable amount of work has been carried out to determine the compounds
Valeriana and related species are used as minor food plants in some areas. They might
responsible for this activity and to elucidate their pharmacological effects. Extracts
not be to the taste of everyone, however, throughout history, there are reports of the
and their constituents have been shown to exert smooth muscle relaxant, sedative,
plant being used as a source of food. Valeriana cornucopiae linn, or African Valerian, is a
native of the Mediterranean region and provides a salad plant. Valerian edulis Nutt. or
chapter 3.
Tobacco Root, is the principle edible root amongst the Indians who inhabit the upper
waters and streams on the western side of the Rocky Mountains (Hedrick, 1972). In
Medicinal Uses Of Valeriana In Other Cultures
another text Saunders (1976) refers to it as another staple of some tribes, occurring in
perpendicular root is vile smelling and ill tasting, but long steaming makes it palatable, at
are supposed to possess stimulant and antispasmodic properties. They are used in the
least to the Indians. Fremont speaks well of it in his journal, under the Snake name
damp grounds from the Great Lakes to Oregon and British Colombia. Its deep,
kooyah, though his associate Preuss could not stay in the same tent with it, much less
consumption, diseases of the eye, itch, boils, swellings, diseases of the head, hiccough,
eat it.
etc. Also mentioned is Vakriana wallichii DC. Mem., where the root is used as one of
the ingredients in the preparation of snake bite cures. It is also used for liver, kidney
particularly in France and the related Centranthus ruber (L.) DC. is eaten as a salad
(Mabey, 1972) in southern Italy and France. The young leaves of this plant are sometimes
In Chinese medicine (Leung and Foster: 1996), both common and Indian valerian as
boiled with butter as greens, or eaten raw in salads, though they can be rather bitter used
Smirn. ex Kom., and V. hardmckiiWa\l. are similarly used. In addition, they are use in
Vaierianeiia eriocarpa Desv. or Italian Corn Salad, is much used in Europe as a substitute
difficulties, bruises and sores etc., among others, generally as a decoction or alcoholic
for lettuce in the spring, and when grown in rich soil as a substitute for spinach. Vaierianeiia
infusion. Valeriana sylvatica was found in the medicine bag of Canadian Indian warriors
locusta or Lamb's Lettuce, Common Corn Salad, is an original European species, native
East, Caucasus, Northern Africa and North America. According to some it is a spring
Cosmetic Uses
salad vegetable with a pleasant, slightly nutty flavour. It contains about 60 mg of vitamin
Bathing
Lamb's Lettuce is used only fresh in mixed and potato salads, in herb soups and omelettes.
Valerian has been used for perfume baths in the East (Graves,
C, and a large amount of phosphorous, calcium, iron, saccharides, proteins, fats etc.
soothing herb bath (Weiss, 1986) or as a vapour bath (Hutchens, 1992). According to
another source (Bremness, 1991) a decoction is used as a facial wash.
Vaierianeiia olitoria Pollich, commonly Lamb's Lettuce or Corn Salad, one of the widest
European examples of a valerian salad herb.
18
AN INTRODUCTION TO VALERIAN
ANTHONY C. DWECK
There are frequent references to animals and their reaction to valerian. It is said that cats
are known to be attracted by valerian, which can cause a state of ecstasy in them (Weiss,
Blackmore, 1982) to name but a few. It is also said (Graves, 1990) that the male is more
affected by the plant than the female and that cats are so fond of the herb that they will
The root also excites rats and that the famous Pied Piper of Hamlyn may not have
been such a great flute player, but more of a success because of the valerian root that he
carried in his pockets! (Keville, 1991), a thought echoed by other authors (Howard,
1987; Ceres: 1984).
Gypsies use the herb to quieten unfriendly dogs, and horses are also attracted by the
smell of valerian (Conway,1975).
Finally, it is said (Bremness, 1988) that the whole plant stimulates growth of nearby
vegetables by stimulating phosphorus and earthworm activity, since the roots also attract
the worms.
19
Jaspersen-Squib, R (1978). Sedatifs a base de plantes. Schwei^. Apoth. Ztg., 118, 503-508.
Jayaweera, D.M.A. (1982). Medicinal Plants used in Ceylon, Part 5. National Science Council of Sri
Lanka, Colombo.
Keville, K. (1991) The Illustrated Herb Encyclopaedia. Grange Books, London.
Lanska, D. (1992) The Illustrated Guide to Edible Plants. Chancellor Press, London.
Law, D. (1973) The Concise Herbal Encyclopaedia. John Bartholomew and Son Ltd, London.
Leung, A.Y (1980) Encyclopedia Of Common Natural Ingredients Used In Food,Drugs And Cosmetics.
John Wiley, Chichester.
Leung, A.Y. and Foster, S. (1996) Encyclopedia of Common Natural Ingredients used in food,
drugs and cosmetics. 2nd edition. John Wiley, Chichester.
Mabey, R. (1972) Foodfor Free. Collins, London.
Martindale. The Extra Pharmacopoeia. 29th. Edition. 1989. The Pharmaceutical Press, London.
REFERENCES
Anon. (1992) The Language of Flowers. 13th impression Penguin Books Ltd, London.
Bairacli Lev}; J.de. (1991) The illustrated herbal handbook for everyone. 4th edition. Faber and Faber,
London.
Bremness, L. (1988) The Complete Hook Of Herbs. CLB (Colour Library Books) Dorling Kindersley,
London.
British Herbal Pharmacopoeia. (1983) B.H.M.A., Bournemouth, UK.
British Pharmaceutical Codex (1923) The Pharmaceutical Press, London.
Ceres (1984) The Healing Power ofHerbal'Teas, Thorsons, London.
Conway, D. (1975) The Magic of Herbs. Jonathon Cape, London.
Coombes, A.J. (1985) Dictionary Of Plant Names. Hamlyn, London.
Council of Europe (1989) Plant Preparations Used As Ingredients Of Cosmetic Products. 1st Edition.
Gerard, J. (1597) Gerard's Herbal, ed. Marcus Woodward. Studio editions. (1990), London.
Gordon, L. (1980) A Country Herbal. Webb and Bower Ltd., London.
Graves, G. Medicinal Plants - 1990 Bracken Books, London.
Hedrick, UP. (editor). (1972) Sturtevant's Edible Plants of the World. Dover editions, New York.
Heinerman, J. (1988) Heinerman's Encyclopedia of Fruits, Vegetables and Herbs. Parker Publishing
Company, New York.
Hobbs, C. (1994). Valerian - the relaxing and sleep herb. Botanica Press, Capitola, California, USA.
Martindak The Extra Pharmacopoeia. 22nd edition. 1941. The Pharmaceutical Press, London.
Murrison, R.G. Pharm.]., (1935) 106.
Newall, C.A., Anderson, L.A. and Phillipson, J.D. (1996) Herbal Medicines - a guidefor health-care
professionals. The Pharmaceutical Press. London.
Phelps Brown, O. (1993) The Complete Herbalist. Newcastle Publishing (Van Nuys, California).
Potterton, D. (ed). (1983) Culpeper's Colour Herbal. W Foulsham, London.
Saunders, C. F. (1976) Edible and Useful Wild Plants of the United States and Canada. Dover Books,
New York.
Spoerke, D.G. (1990) Herbal Medications. Woodbridge Press, Santa Barbara, California.
Weiss, R.E (1986) Herbal Medicine. The Bath Press, Bath, UK.
2.
CONTENTS
INTRODUCTION
TERPENOIDS
Constituents Of The Volatile Oils
Monoterpenes
Sesquiterpenes
Valepotriates
Naturally-occurring compounds
NITROGENOUS COMPOUNDS
Alkaloids
Amino Acids
PHENYLPROPANOIDS
INTRODUCTION
It is important to know the structure and reactions of the chemical compounds present
in a crude drug, particularly those which contribute to its biological activity. Such
knowledge arises, not only because of the innate curiosity of human beings, but also
because it facilitates authentication of unknown material and also provides markers for
quantitative evaluation.
21
PETER J HOUGHTON
22
A farther benefit which may follow such knowledge is the introduction of a new
chemical entity which may form the basis for designing semisynthetic drugs with the
same activity but improved characteristics compared with the original molecule. The
23
+ AcCoA
AcetylCoenzymeA (AcCoA)-
first two of these principles has been applied to some extent to Valerian but as yet only
a little progress has been made regarding the third approach (Thies, Seitz and Moddelmog,
1984).
It is also important to know what compounds, other than those shown to be active,
might be present in an active fraction since they may exercise a preservative role, improve
bioavailability or solubility- or act as a synergist of the major active substances present.
The medicinal importance of Valeriana species prompted initial chemical investigation
quite early in the nineteenth century but little progress was made in determining the
structure of the compounds present until the improvement in separation techniques
and the introduction of spectroscopic methods of structural elucidation in the last half
HOH2C
CO
COOH
COOH
CoA
Mevalonic acid
Phosphorylation
of the twentieth century. In hindsight it is not difficult to see why individual compounds
were not isolated earlier since extracts and oils obtained from this genus have now been
shown to consist of a complex mixture of closely-related substances, many of which
CH3
QH3
The traditional Northwestern European drug Valerian, the dried underground parts
of V. officinalisy has a distinctive smell, which many people find abhorrent, and this is
due to isovaleric acid 1 which is formed by enzymatic hydrolysis of some of the
constituents during storage. Isovaleric acid was first isolated from Valeriana in 1963
(Schmeltz et al.) and multiples of its branched 5 carbon skeleton, called an isoprenoid,
can be discerned in most of the important chemical compounds which have been isolated
PPOH2C
PPOH2C
Dimethylallylpyrophosphate
Isopentenyl pyrophosphate
(DMAPP)
(IPP)
from Valeriana and related plants. In these compounds the carbon skeleton consists of
2 or 3 of these units, joined in a variety of ways, to form monoterpenoids and
sesquiterpenoids respectively.
Such compounds are found as the major constituents of the volatile oils and also as
less volatile constituents found in the cytoplasm of plant tissues.
The alkaloids found in this plant are also biogenetically related to the terpenoids and
similarities in the carbon skeleton are evident.
Geranyl pyrophosphate
MONOTERPENES
This chapter will deal with the skeletal types and individual constituents found in
Valeriana species with some emphasis on patterns of qualitative and quantitative variation
and also on structure-activity relationships.
TERPENOIDS
The terpenoids arise as products of the mevalonate pathway and consist of multiples
of branched 5-carbon units. The pathway is sometimes called the isoprenoid pathway
since the branched 5-C unit has the isoprene skeleton. A 10-C unit is called a 'terpene'
and the different types of structure are consequently designated monoterpenes,
SESQUITERPENES
Farnesyl
pyrophosphate
CH/
atoms respectively.
CH3
An outline of the mevalonate pathway for the biogenesis of mono- and sesqui
terpenoids is shown in Figure 1.
Figure 1
Table 1
25
PETER J HOUGHTON
24
CH,
Acetyl
2 R=H
Isovaleryl
Borneo!
CH3
a-Acetoxylsovaleryl
3R=
~OC
CO-
P-Acetoxyisovaleryl
5 Camphene
CO-
CO-
Cr
4R=
3-Methylcrotonyl
Y-Acetoxycaproyl
p-Methyllsovaleryl
6 a- Pinene
7p-Pinene
a-lsovaleroyloxyisovaleryl
CH3
CH3
CO-
CH;
CH,
p-Hydroxy Isovaleryl
CH3
9 1-8 Cineol
Figure 2
10 Camphor
side-chains are often found in plants as a complex mixture known as a volatile oil. As
the name implies, these oils have an appreciable vapour pressure, especially in highly
humid conditions and in general are lipophilic rather than hydrophilic. They are often
stored in specialised organs and many play an important role in the survival strategy of
plant species.
Most of the analysis of the volatile oil of Valeriana species has been performed on
steam distilled oil but a recent study descibes the headspace analysis by linked gas
as components of ordinary cytoplasm. Such types of terpenoids are not been reported
present in Valeriana. However, in this genus, the terpenoids are often esterified with one
greater interest and importance as far as chemotaxonomy and biological activity are
concerned.
26
PETER J HOUGHTON
Table 2
27
Species
V. alliarifolia
Borneol 2
Reference
Bos.?/al. (1984)
Bornyl acetate 4
V. dioica
Borneol 2
Bornyl acetate 4
V.fauriei Briq.
12 Valerane ring
Rucker (1979)
13 Kessanerlng
Camphene 5 (16)
CC-pinene 6 (7)
p-pinene 7 (6)
V. officinaBs L.
Borneol 2
Bornyl isovalerate 3
Bornyl acetate 4
Camphene 5
Camphor 10
l-8cineol9
15 Valeranone
Myrcene 8
Camphene 12 (19)
Camphene 5
(syn. V.jatamansiiJones)
Ct-pinene 6
CH3
CH3
Myrcene 8 (3)
(3-cymene 11
Monoterpenes
R1
OH
17
OH
18
Kessyl-2-ol
Kessyl-6-ol
OAc OAc
20
OAc
23
22 Cyclokessyl acetate
Kessyl glycol
OH
19
21
In most samples of oil of V. officinalis examined, major constituents are borneol 2 and
its isovaleric and acetyl esters 3, 4 (Stoll, 1957, Titz,1983) and the acetate was also a
major compound detected in the headspace analysis of the stored roots (Nikiforov
R
OH
H
OAc
H, Olv
Kessyl Isovalerate*
Figure 3
etal., 1994).
The two ring systems unique to the Valerianaceae are the valerenal type 12 and the
kessane type 13. Another important ring found in the family is the an elemane type 14
of which valeranone 15 is an important constituent. This compound was first isolated
from oil of nard,derived from Nardostachysjatamansii DC( a genus related to Valeriana).
This oil has long been prized as a perfume in the Middle East and is mentioned in the
Bible.
The kessane group of sesquiterpenes were the first to be characterised when Ukida
(1944) isolated kessyl glycol 16 during an investigation of the oil from the roots of the
Japanese plant V. officinalisvar. latifolia Miq., now known as V.fauriei Briq. Subsequent
studies resulted in the isolation of other alcohols 17,18 and corresponding acetates
19-21 from the same plant (Hikino, 1963). All the kessyl derivates exert some sedative
activity and the diacetate 19 was shown to be the most potent of compounds 16-21
28
PETER J HOUGHTON
29
QH3h
i Ch3
Oh
CH3
ch
CH3
36 Cryptofaurinol
R1
24
CHO
25
COOH
26
COOH
OH
27
COOH
OAc
28
CH2OH
29
CH2OAC H
30
CH2OIV
31
38
37 Maaliol
Maallenoxlde
CH2OH
R=CH2OOCC4H9
R1 = H
32
CH3
R=CH2OOCC5Hn
R1 = H
40
Kanokonol
CH3
CH3
41
Figure 5
33
34
R = Ac
R = lv
Elemol
Figure 4
resulted in the isolation of two sesquiterpenes having a new ring structure and these
were named valerenal 24 and valerenic acid 25 respectively Several representatives of
this type of structure 24-34 have since been isolated from other Valeriana species (see
(Hikino, 1980). Recent studies have shown that Ct-kessyl alcohol (kessyl-2-ol) 17 kessanol
(kessyl-6-ol) 18 and cyclokessyl actate 22 have antidepressant activity whereas the glycol
16 and its diacetate 19 do not possess this activity (Oshima et al, 1995) The kessane
sesquiterpenes have also been isolated from V. offidnalis (Hazelhoff et al, 1979) and
V.wallicbii, the latter including the novel isovalerate ester 23 (Bos et al, 1992).
Table 2) but valerenic acid 24 has so far not been found in any species other than V.
offidnalis and its presence is used as an identification test for V. offidnalis in the European
Pharmacopeia (1985). Valerenic acid 24 has also been shown to make a substantial
contribution to the sedative and spasmolytic activity of the oil and extracts of V. offidnalis
(Hendriks etal, 1981). The isolation of the related compound (-)-pacifigorgiol 35 (Bos
et al, 1986) is of interest as it is the optical isomer of a compound isolated from a coral.
PETER j HOUGHTON
30
31
CH3
CH2
43
42 Faurinone
Fauronyl acetate
48 p-Farnesene
49
1,4,9 Cadinatriene
HO
50 T^Cadinene
44
45
Patchouli alcohol
Nardol
CH3
CH3
CH3
51
46 a- Curcumene
Figure 6
47
Xanthrorizol
52 p-Elemene
(J-Bisabolene
The third major group of sesquiterpenes found in Valeriana have an elemane ring
structure and both hydrocarbons and oxygenated compounds are found, the latter type
exhibiting the more pronounced pharmacological effects. Valeranone 15 was first isolated
from Nardostachysjatamansii DC ( Govindachari eta/., 1958) and has subsequently been
detected in the oil of V. offidnalis (Hendriks et al, 1981), V.fauriei (Hikino eta/., 1968)
and V wallkhii (Navayanan <?/al, 1964). Related compounds are cryptofaurinol36 found
in V. offidnalis , maaliol 37, maalienoxide 38 and cryptomeridiol 39 from V. wallkhii
Qoshi etal> 1968) and kanokonol 40 from V. fauriei (Oshima et al, 1995). The open A
ring compound elemol 41 is found in V. offidnalis (Stoll et al, 1957). Two related
compounds faurinone 42 and fauronyl acetate 43 possess a 5-membered A ring instead
of the 6-membered ring characteristic of the elemane type.
Figure 7
Patchouli alcohol 44 has been found in the oil of V. edulis, V. offidnalis and V. wallkhii
and in the last named species it forms the major component of the volatile oil.. The
related compound nardol 45 has also been detected in V.fauriei (Hikino et al, 1963).
In addition to these oxygenated compounds some hydrocarbon sesquiterpenes have
p-elemene 52, the patchoulenes 53, 54, guajene 55 and Ct-copaene 56.
33
PETER JHOUGHTON
32
Table 3
CH3
V. alliarifolia
Bos etaL,\9U
Kessane 13
V. celtica ssp, norica
HYDROCARBONS
Bicchi*/^, 1983
(XPatchoulene 52
pPatchoulene 53
OXYGENATED COMPOUNDS
Patchouli alcohol 44
53
a-Patchoulene
54
Valerenic acid 25
(3- Patchoulene
Valerenyl acetate 29
V. edulis
HYDROCARBONS
1,4,9-Cadinatriene 49
CCCopaene 56
(5Elemene 52
aGuajene 55
aPatchoulene 52
pPatchoulene 53
OXYGENATED COMPOUNDS
Patchouli alcohol 44
V.fauriei
55
Guajene
56
OXYGENATED COMPOUNDS
Ukida (1944);
Kessane 13
Hikino^^/., (1963,1980);
Faurinone 42
Kanokonol 40
Valeranone 15
a-Copaene
Kessyl glycol 16
Kessyl-2-ol 17
Figure 8
Kessyl-6-ol 18
Kessyl diacetate 19
Kessyl -2-acetate 20
Kessyl-6-acetate 21
Cyclokessyl acetate 22
V. officinalis
HYDROCARBONS
p-Bisabolene 47
aCurcumene 46
OXYGENATED COMPOUNDS
Valerenic acid derivatives 24-34 (see Table)
Faurinone 42
(-)-Pacifigorgiol 35
Cryptofaurinol 36
It is important to realise that the total amount, the constituents present and the proportion
of each constituent in a volatile oil derived from a particular species varies considerably.
This variation may be due to environmental factors such as climate and soil. Studies
Valeranone 15
Patchouli alcohol 44
Kessyl alcohol 18
have shown that oil content in some plants varies greatly throughout the growing season
and even on a diurnal basis and so variation may be due to the time of collection. The
composition of the volatile oil also varies according to the part of the plant from which
it is distilled but this is not of much concern with Valeriana since the total underground
V.phu
OXYGENATED COMPOUNDS
Patchouli alcohol 44
Valerenal 24 isomers
34
PETER J HOUGHTON
Table 3
V. wallichii DC
35
continued
HYDROCARBONS
The valepotriates
OtCurcumene 46
The valepotriates were first isolated in 1966 from V. wallichii (Thies, 1966) and from
Centranthus rubera member of a related genus of the Valerianaceae (Mannenstatter eta/.,
pFarnesene 48
CX-Patchoulene 53
1966). the isolation of these substances aroused considerable interest since they provided
some answer to the discrepancy often observed between a high measured sedative/
p-Patchoulene 54
OXYGENATED COMPOUNDS
Cryptomeridiol 39
tranquillising effect of Valerian extracts which could not be explained only on the basis
Kanokonol 40
Maaliol 37
The term 'Valepotriate' arises from the part-acronym of Valeriana epoxy triester.
The monoterpene skeleton of the valepotriates is essentially the same as that of the
Maalienoxide 38
Xanthrorizol 51
Patchouli alcohol 44
widely throughout tie more highly-evolved dicotyledons, but the valepotriates are unusual
since, in most cases, no sugar residue is attached and also one or more ester side chains
are present. The hydrolysis of these ester bonds and release of the free acids on storage
makes a large contribution to the characteristic odour of dried Valeriana species.
The first three valepotriates isolated were obtained from V. wallichii and were named
Table 4
Species
Reference
V. edulis
<0.02
V.fauriei
6.5-8.0
Rucker, 1979
V. officinaiis
0.4 - 2.0
K wallichii DC
0.09-0.9
0.5-3.0
valtrate 57 , acevaltrate 58 and didrovaltrate 59 (Thies, 1966). The 'didro' series lacks the
5-6 double bond present in the corresponding compounds. The first valepotriates isolated
all contained an 8-epoxy group and this has been shown to possess alkylating properties
Concern about the alkylating property of the epoxide group prompted the search for
valepotriates where it was absent and several types of such compounds 77-88 have now
been isolated (Holzl eta/., 1976; Finner etal, 1984; Koch and Holzl, 1985). The largest
group of these are known as valtrate hydrines 80-88.
The valepotriates first isolated contained no sugars but valepotriate glycosides 89-93
parts are the only parts used and the oil occurs mainly in the endodermis cells of the
roots. The yields of steam-distilled oil from various Valeriana species is shown in Table 4.
A major factor underlying the variation in volatile oil content, particularly the type of
compounds present, is the genotype of the species which is used. Some studies have
carried out in this respect and wild populations of V. officinaiis in the Netherlands have
been shown to comprise three chemical races i.e. phenotypes (Hazelhoff eta/., 1979).
These were identified as Types A, B and C.
Type A contained no kessane derivatives, high amounts of valerenal 24 and moderate
amounts of elemol 41 and valeranone 15.
with the sugar linked through C-l, as found in most iridoids, or through an alcohol
residue at C-4, have since been isolated from V.officina/is and V. wallichii (Thies, 1970;
Taguchi and Endo, 1974; Endo and Taguchi, 1977).
A valepotriate containing a chlorine atom, valechlorine 94, was isolated from V. officinaiis
(Popov etal, 1973) and this is noteworthy since a halogen incorporated into a secondary
metabolite is unusual amongst the flowering plants.
A standard mixture stated to consist of 80% didrovaltrate,15% valtrate and 5%
acevaltrate is marketed in Germany under the name Valmane and is used extensively as
a mild to moderate sedative. Recently sophisticated NMR studies have shown that the
tablets consist of a mixture of six compounds. The presence of valtrate and didrovaltrate
was confirmed but the acevaltrate was shown to be a mixture of l-Ot-acevaltrate and
7-p-acevaltrate whilst the remaining two compounds were novel and had not previously
been reported from any plant (Lin etal, 1991).
PETER J HOUGHTON
36
Olv
CH2OR"
Olv
R1
77Nardostachin
R"
57
Iv
Iv
Ac
58
Aiv
Iv
Ac
1-a-Acevaltrate(T/?/es, 1968a)
60
Iv
Bav
Ac
61
Iv
Ac
Iv
Isovaltrate
62
Iv
Ac
Ac
Diavaltrate
63
Miv
Iv
Ac
64
Iv
Ac
Miv
65
Iv
Ac
Aav
11-Acevaltrate
66
Iv
Aav
Ac
67
Iv
Hiv
Ac
68
Iv
Aic
Ac
69
Cr
Iv
Ac
Seneciovaltrate
70
Iv
Miv
Hiv
71
Iv
Iv
Hiv
72
Iv
Iv
CH2OR"
R'O
(Thies, 1971)
R
R'
R"
78
Iv
Ac
Iv
8,11-DesoxidodidrovaltratefTft'es, 1968a)
79
Miv Ac
Iv
8,11-Desoxidohomodidrovaltrate(es, 1968a)
CH2OR"
HC
R1
R"
R"1
59
Iv
Ac
Iv
Didrovaltrate
(Thies, 1968a)
73
iv
Ac
liv
OH
IVHD valtrate
74
iv
Iv
Ac
Isodidrovaltrate
75
Miv Ac
Iv
Homodidrovaltrate
76
Ac
Aav
Iv
Figure 9
rflY
/ H i
CH2OR'" OR
CH2OR"
(Kucabaetai., 1980)
(Thies, 1968a)
R1
R"
80
Iv
Iv
Iv
Ac
Valtrate hydrine B1
(Holzletal., 1976)
81
Iv
Iv
Ac
Ac
Valtrate hydrine B2
(Holzletal., 1976)
82
Biv
Iv
Iv
83
Iv
Ac
Iv
84
Iv
Iv
Ac
85
Iv
R1"
Ac
Ac
Valtrate hydrine B3
(Holzletal., 1976)
(Finneretai, 1984)
Iv
Iv/Miv
Ac
Iv/Miv Ac
Ac
87
Cr
Iv
Iv
Ac
88
Aav Iv
Iv
Ac
86
Figure 10
37
Table 5
CH2OR"
OR
R
Glucose
R'
R"
Iv
Species
Valepotriates present
Reference
V. ailiarijolia roots
Valtrate 57
V. cardamines
H2OR"
89
39
PETER J HOUGHTON
38
Acevaltrate 58
V. edulis spp.procera
Valtrate 57
roots
Acevaltrate 58
Isovaltrate 61
Valerisodatum
(Thiesetal., 1970)
Didrovaltrate 59
IVHD valtrate 73
90
Iv
Glucose
OH
Kanokoside B
91
Iv
Gentiobiose
OH
Kanokoside D
V.fauriei
Valtrate 57
Acevaltrate 58
IVHD-valtrate 73
V. kilimandasckarica
Valtrate 57
leaf
Isovaltrate 61
Acevaltrate58
CH2OR'
Didrovaltrate 59
IVHD valtrate73 (5.89)
stem
Valtrate 57
Isovaltrate 61
Didrovaltrate 59 (3.17)
CH2OH
flower
Valtrate 57
Isovaltrate 61
Didrovaltrate 59 (3.93)
R'
92
Iv
Glucose
93
Iv
Gentobiose
rhizome
Valtrate 57
Isovaltrate
Acevaltrate 58
Didrovaltrate 59
Figure 11
Acevaltrate 58
Diavaltrate 62
A summary of the valepotriates reported from each species of Vakriana so far investigated
is given in Table 5.
Isovaltrate 61
Nardostachin 77
V. officinalis
Valtrate 57
Acevaltrate 58
Isovaltrate 61
Deacetylisovaltrate 72
Didrovaltrate 59
IVHD-valtrate 73
Valechlorine 94
Valerisodatum 88
Kanokosides A, C,D 91-93
PETERJ HOUGHTON
40
Table 5
Species
Vaiepotriatespresent
Valtrate 57
Reference
Table 6
continued
Cyclodienes
CH2OR"
Acevaltrate 58
V. tbalirtroides
(14.5%)
V. tiliaefolia
V, wallichii leaves
Holzlandjurcic, K (1975)
V. wallichii roots
Valtrate 57
Acevaltrate 58
1966b)
Known compounds
Isovaltrate 61
Didrovaltrate 59
IVHD valtrate 73 (5%)
Valerosidatum 88 (5%)
R1
Valtrate 57
Iv
Iv
R"
Ac
1-a-Acevaltrate 58
Aiv
Iv
Ac
Homovaltrate 63
Miv
Iv
Ac
Isovaltrate 61
Iv
Ac
Iv
Diavaltrate 62
Iv
Ac
Ac
I sodidrovaltrate 74
KuczbaetaL (1980)
Miv
Ac
Iv
Miv
Miv
Ac
Aav
Iv
Ac
Iv
Ac
Ac
production in callus and root differentiated tissue of V. officinalis showed that levels of
Iv
Miv
Hiv
vaiepotriates were formed at least equivalent to those occurring naturally in the root
Iv
Iv
Hiv
Aav
Bav
Ac
Aav
Miv
Ac
Aav
Bav
Ac
Iv
Ac
Hiv
Miv
Ac
Ac
in the parent plant and also six compounds not previously reported (Table 6). Most of
these were of the diene type. Treatment of the culture with colchicine resulted in a
higher yield of vaiepotriates (Becker and Chavadej, 1985).
Hairy root cultures of ]/. officinalis var. sambucifolia have been shown to produce
isovaltrate and IVHD valtrate (Granicher etaL, 1992)
CH2OR"
The vaiepotriates hydrolyse quite rapidly and are not present in significant amounts in
R'O
aqueous or dilute alcoholic extracts after a few days. They are also metabolised in the
gastro-intestinal tract to yield the breakdown products baldrinal 95, homobaldrinal 96,
deacybaldrinal 97 and valtroxal 98 which consist of an unsaturated version of the ring
skeleton (Thies, 1968; Schneider and Willems, 1979; Schneider and Willems 1982). There
is evidence that these compounds are partly responsible for the sedative activity of
some Valeriana samples since they are well-absorbed from the gut and have been shown
to significantly decrease motility of mice (Schneider and Willems, 1982). Homobaldrinal
96 and valtroxal 98 have been shown to possess greater sedative activity than baldrinal
95 and deacylbaldrinal 97 (Wagner 1980; Schneider and Willems, 1982).
Known compounds
R1
R"
R'"
Didrovaltrate 59
Iv
Iv
Ac
Ac
Iv
liv
H
OH
IVHD-Valtrate 72
Ac
Iv
OH
41
PETER JHOUGHTON
42
43
CH2OR"
CH2R
R'O
HO
CH2R"i. OR
94
R'
R"
R"1
Iv
Iv
Ac
Cl
OCH3
ValechlorinefPopoi/efa/., 1973)
CH2OR
99
100
95
96
Ac
Iv
97
101
R= H
Valerianine
R= OH
Actinidine
CH3
98
103 Pyrryl-a-methylketone
Figure 12
Figure 13
CH3
104
Naphthyridylmethylketone
NITROGENOUS COMPOUNDS
alkaloids. The reports of the isolation of the first two compounds does not state the
Alkaloids
nature of the basifying agent so a conclusion cannot be reached as to whether they are
artefacts or not. Valeranine has also been reported from V. wallichii (Bos etal, 1992).
In some medicinal plants alkaloids are the most important secondary metabolites but
this is not the case with Valeriana although alkaloids are present in small amounts. The
methylketone 104 have also been isolated by Cionga (1936) and Janot and his co-workers
presence of alkaloids in this genus has been known since the end of the nineteenth
(1979).
century (Walliczewski, 1891) but it was not until 1967 that two alkaloids 99 and 100 were
All of these compounds are present in small amounts and it is very unlikely that they
isolated from V. offidnahs (Torsell and Wahlberg, 1967). Two further related alkaloids
make a major contribution to the activity of total extracts. 99 has shown choline esterase
valeranine 101 and actinidine 102 have also been isolated from the same species (Francke
structural similarity between these alkaloids and the valepotriates is noticeable and it is
inhibitory properties in vitro but these were not demonstrated in vivo in rabbits (Torsell
and Wahlberg, 1967). Actinidine 102 exhibits antibiotic properties (Buckova et al., 1977;
Johnson and Waller 1971) and the methylketone derivatives have been shown to have a
possible that they may be artefacts since it is well-known that iridoids can incorporate a
45
PETER j HOUGHTON
44
COOH
OH
109
106
105 Tyrosine
NH2"
Glutamine
COOH
COOH
108
107 GABA
Figure 14
Arginine
Amino acids
V. officinalis contains appreciable amounts of amino acids. In one study tyrosine 105,
glutamine 106 and GABA (y-aminobutyric acid) 107 were found to be the major
115 Isoeugenol
113
Eugenol
114
Iv
Eugenol isovalerate
compounds present (Hansel and Schulz, 1981). More recent work by Santos eta/., 1994)
demonstrated the presence of high levels of glutamine 106 (13.4mM) and arginine 108
(25.5mM) with a relatively high concentration of GABA 107 (4.56mM) in aqueous extracts
COOH
COOH
of V. officinalis.
The quantities of GABA and glutamine were considered sufficient to account for the
release of radiolabelled GABA from synaptosomes which was observed when they
were treated with Valerian extract.
PHENYLPROPANOIDS
plants and are formed by the shikimic acid pathway. A characteristic of compounds
formed by this route is the presence of one or more C6(aromatic ring)-C3 units in the
molecule. In Vakriana four types of phenylpropanoids are found as relatively minor
constituents which have not been demonstrated to play a significant role in any
pharmacological effect.
116
Chlorogenic acid
Figure 15
117
118
OH
OH
R1
OH
OCH3
Phenylpropanoids of 'Vakriana
Caffeicacid
Isoferulic acic
r
46
PETER J HOUGHTON
47
a)
b)
c)
the lignans 111 consisting of two units joined through the C3 portions of the molecule
d)
The phenylpropanoids form only a small part of the volatile oil of Valeriana. Eugenol
119
R = OH (+)-1-Hydroxypinoresinol
113 and its isovaleryl ester 114 as well as the isovalerate of isoeugenol 115 have been
120
R = H
Pinoresinol
Phenolic acids
The phenolic acids derived from the shikimate pathway are probably present in most
plant species to some extent either as free compounds or combined with sugars.
Chlorogenic acid 116 and caffeic acid 117 were reported from V. offidnalis a considerable
time ago (Fichter, 1939) and more recently isoferulic acid 118 has been reported (Stoll
OH
121
R = H
126R = OCH3
OH
Apigenin
122 R = H
Acacetin
Diosmetin
Lignans
The first and only report of lignans in Valeriana appeared in 1993 with the isolation of
(+)-hydroxypinoresinol 119 as the major constituent and pinoresinol 120 from
,0H
HO
Y
OH
II
OH
glycosidal forms have been investigated by workers in the former Soviet Union and the
aglycones found are listed in Table 7. V offidnalis have been investigated by Rybal'chenko
and co-workers who isolated luteolin 124, diosmetin 122 and
OCH3
OH
Flavonoids
Flavonoids are present in nearly all flowering plant species and represent a large number
OH
123 Kaempferol
kaemferol 123
(Rybal'chenko et aL, 1976). An unusual compound, linarin isovalerate 126 was isolated
from V. wallichii together with linarin 127 by Thies (1968b).
R = lv
Linarin isovalerate
127
R = H
Linarin
Figure 16
The fatty acids are primary metabolites rather than secondary metabolites but some are
of interest because of their role as essential constituents in the diet and as precursors in
biochemical processes involved with inflammatory conditions and several other disease
states. The seeds of V.offidnalis produce an oil rich in unsaturated fatty acids such as
linoleic acid 128 (Dolya, 1983). The methyl ester of eicosanoic acid 129 has recently
been isolated and quantified in V. wallichii (Pande et aL, 1994).
PETER j HOUGHTON
Table 7
Valeriana species
cardamines
Table 7
Reference
Flavonoid aglyconespresent
'Reference
Fursaetal(1984)
V.palustris
Apigenin 121
Fursa(1983)
Diosmetin 122
Kaempferol 123
Kaempferol 123
Luteolin 124
Luteolin 124
Quercetin 125
Acacetin 126
Quercetin 125
Trzhetsinskii et al (1982)
Apigenin 121
V.spryginii
Apigenin 121
V.tuberosa
Luteolin 124
Acacetin 126
Diosmetin 122
Fursaetal(1984)
Kaempferol 123
Diosmetin 122
Luteolin 124
Kaempferol 123
Quercetin 125
Luteolin 124
Apigenin 121
Acacetin 126
Vjurkestanica
Quercetin 125
exaltata
Rybal'chenkoetal(1976)
Diosmetin 122
Kaempferol 123
Kaempferol 123
Luteolin
Luteolin 124
Quercetin 125
Quercetin 125
Acacetin 126
Apigenin 121
Diosmetin 122
V.fedtschenkoi
Apigenin 121
Quercetin 125
Apigenin 121
Luteolin 124
Diosmetin 122
, eriophylla
continued
Valeriana species
Diosmetin 122
V. chionophila
49
Trzhetsinskii et al (1982)
Apigenin 121
Diosmetin 122
Kaempferol 123
Luteolin 124
Quercetin 125
V.ficariifolii
Acacetin 126
.COOH
Trzhetsinskii etal (1982)
Apigenin 121
Diosmetin 122
Kaempferol 123
Luteolin 124
Quercetin 125
]/,nitida
Apigenin 121
Rybal'chenkoetal(1976)
Diosmetin 122
Kaempferol 123
Luteolin 124
,COOCH3
Quercetin 125
\/,officinalis
Diosmetin 122
Kaempferol 123
Luteolin 124
Figure 17
PETER J HOUGHTON
Bach, K.K., Ghia, F. and Torssell, K.B.G. (1993) Valtrates and Lignans in Vakriana microphylla.
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parts of Valeriana III Composition of Valeriana turkestanica flavonoids. Khim. Proer. Soedin.
98 (CA 95, 21263).
50
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54
PETERJHOUGHTON
Violon, G, Dekegel, D. and Vercruysse, A. (1984) Relation between valepotriate content and
differentiation level in various tissues from Valerianeae./. Nat. Prod. 47, 934-940.
Vomel, A., HolzlJ. and Fucke'l, I. (1984) Ontogenese von Vakriana officinalis L. und V. altiariifolia
3.
Zaitsev, V.G., Fursa, N.S. and Zhukov, VA. (1985) Flavonoids and valepotriates of valerian VIII
JOSEF HOLZL
CONTENTS
INTRODUCTION
THE SEDATIVE EFFECT
Pharmacological Methods Of Detection
Measurement of motility
Electroneurophysiological investigations
The Sokoloff method
Receptor binding studies
Animal studies
Electroneurophysiological investigations
The Sokoloff method
Receptor binding studies
Clinical studies
Alkaloids
Lignans
STUDIES FOR OTHER ACTIVITIES
Spasmolytic Effects
55
JOSEF HOLZL
56
Antifungal Activities
Animal Attractant Properties
57
measurement of the glucoseum sediment in different brain structures, and the procedure
of receptor-binding studies for the tracing of effective substances. Total extracts of
V officinalis and also individual constituents of the plant have been investigated in these
TOXICOLOGY OF VALERIAN
General Considerations
Cytotoxicology of Valepotriates
tests.
Measurement of motility
The measurement of motor activity of rats and mice is a classic experimental model for
CONCLUSION
the investigation of the depressant action of substances on the CNS. There are various
models for the measurement of motility. In a light barrier cage beams of light are
interrupted by movements and these interruptions are registered. In a vibration cage
INTRODUCTION
movement produces vibrations which are registered. In the activity monitor lines of
electric field are set up in the cage; movement causes these to be interrupted and this is
measured as an impulse (Houghton, 1988).
Extracts of various species of Vakriana are used in the traditional medicine of many
parts of the world where they are endemic. The major traditional use is for purposes
which can be classified as tranquillising or sedative but they are also used as gastrointestinal
sedatives, poison antidotes, deodorants and for treating urinary tract disorders (Hobbs,
1989). Species of Vakriana are official in many national pharmacopoeias and are also
used in many proprietary phyto therapeutic preparations sold to promote sleep and reduce
tension.
This chapter deals with the scientific evidence for the reputed activity of Vakriana
and its constituents.
The primary use of Vakriana species and their extracts in pharmacy and phytotherapy is
as a sedative or tranquillizer and to help induce sleep and it is this purpose which is
largely discussed below. The definition of the terms 'sedative' and 'tranquillizer' causes
some confusion and they are often used interchangeably. However, as a general rule, a
sedative causes a reduction in motor activity and mental disturbance often leading to
sleep whilst a tranquillizer reduces mental disturbance without impeding motor function
and mental alertness significantly.
subsequent studies have confirmed these early findings but the identity of the compounds
responsible has been a matter of controversy which has still not been fully resolved.
Pharmacological Methods Of Detection
Many pharmacological test methods are available for investigating the sedative effect of
substances. Methods used in the case of V officinalis included the motility reduction of
laboratory rodents, the lengthening of thiopental sleep, neurophysiological methods
including measurement of the pharmaco-EEG, the desoxyglucose technique with
E/ectronettropbysiological investigations
Electroencephalograph (EEG) output from the brain alters when CNS depressants are
introduced and so the influence of doses of extracts or compounds on different parts
of the brain can be studied by implantation of electrodes in the appropriate areas. The
EEG output is recorded as a pattern of waves of electrical activity which are characteristic
for different parts of the brain and which vary according to psychiatric disease states,
alertness and consciousness.
An extraordinarily elegant method for detecting central neuronal activity was published
during the seventies, the desoxyglucose-technique of Sokoloff etal. (1977). The principle
of this method is to determine quantitively the glucoseum sediment in vivo in different
brain structures by using 14C-labelled 2-desoxy-D-glucose. As the brain satisfies its energy
requirement almost entirely through glucose and the individual brain structures only
assimilate as much glucose as is necessary for their activity, a measure for the neuronal
activity of the respective brain areas can be obtained through the quantitive determination
of the local cerebral glucoseum sediment. These methods can also be used to localise
and quantify the effects of medicinal substances on the brain in vivo. The desoxyglucosetechnique has already proved its worth many times in the determination of the crucial
effect of different medicinal substances.
Receptor-binding studies
In the majority of cases medicines have their effect because of their chemical structure.
This presupposes that a specific structure is present in the organism that recognises the
medical substance. This structure is often a receptor for endogenous hormones,
transmitters or mediating substances for which the medicinal substance works as a
substitute or antagonist.
JOSEF HOLZL
58
Receptors are usually large proteins often localised on the outer surface of the cell
(cell membrane). The chemical fit gives rise to connections and reactions, e.g. to a
59
volatile oil in the Japanese roots and the strong sedative effect of the kessyl derivatives
comprising the bulk of the volatile oil.
deformation, as a result of which an ion channel opens and thus produces an electric
Wagner et al. (1980) showed mat, although the lipid-soluble fraction at lOmg dose
impulse. The contact of the agonist or antagonist frequently leads to the advent of a
gave a 50% reduction in the motility of mice, there was also some activity with the
water-soluble fraction which gave up to 30% reduction in motility at lOOmg dose. Another
Medicinal substances can be either agonists or antagonists; either they trigger a reaction
study in mice showed that intraperitoneal injection also depressed the CNS activity, and
that oral administration had a greatly reduced effect (Veith et al, 1986).
or they produce a receptor blockade. About 40 receptor models are available for the
search for the chemical working principle of a mixture of substances effecting the CNS.
Receptor-binding studies have been developed over the last ten years and are now
valerian root extract (Valdispert) revealed pronounced sedative properties in the mouse
A recent study on the ethanolic extract of the roots of V. offidnalis compared its
neuropharmacological effects with those of diazepam and haloperidol (Hiller and Zetler,
1996). Spontaneous motility, nociception and body temperature were not modified but
Animal studies
Using motility experiments, Gstirmer and Kind (1951) indicated that the activity of the
total extract could not fully be accounted for by the volatile oil content and other work
confirmed these findings (Gstirmer and Kleinbauer, 1958). Stolid/. (1957) were unable
to explain the activity of a sample under investigation in terms of of the bornyl esters
which were the major components of its volatile oil. However, the reality of the sedative
effect of tinctures was demonstrated by reduction of the motility and an alteration of
the reflex responses of mice (Kiesewetter and Muller, 1958).
Work in the United States to identify the active components in a fractionated alcoholic
extract using prolongation of barbital-induced sleeping time and hypotensive effects
was unsuccessful although active fractions were found (Rosecrans et al, 1961).
Lecoq et al. (1963) showed that an extract of V. offidnalis had an encephalic action,
suppressed provoked metachronoses and , in sufficient amounts, neutralised the effects of
alcohol.. Subsequently it was found that the influence of the extract over the effects of
alcohol was more like that of chlorpromazine than hypnotic drugs (Lecoq et al, 1964).
The volatile oil component of Valeriana spp. undoubtedly makes a major contribution
to the sedative activity but there is much evidence that the non-volatile valepotriates
and their metabolites also play a significant part since the isolation of the valepotriates
(Thies, 1966) and the subsequent demonstration of their sedative activity (von Eickstedt,
1969) helped explain the discrepancy between the observed activity of the root tinctures
and the smaller calculated effect based on the volatile oil components present (see below).
However, the total sedative activity of extracts of Valeriana species could not always
anticonvulsant activity against a standard dose of picrotoxin was observed and barbitoneinduced sleeping time was increased.
The psychotropic effects of roots of Japanese valerian,
V offidnalis extract, but kessyl glycol diacetate 1 and diazepam significantly increased
ambulation. Diazepam significantly decreased approach-avoidance conflict in mice in a
water-lick conflict test, but V. offidnalis extract and KGD did not.
By contrast, V.
Prolongation of barbitone-induced sleep was also noted but there was no change in
pain threshold levels and no effect on isolated guinea pig ileum. These results led the
authors to conclude that the extract exhibited neuroleptic properties.
Hkctroneurophysiological investigations
neurophysiological investigation (HoXmetal, 1988). Stray cats were implanted with long-
60
JOSEF HOLZL
in the V. officinalis extract (Santos et al, 1994b). The high levels of glutamine present
and subcortical EEG were apparent in these investigations. The muscular tone was
reduced in 30-40% of the cases. Among the electrically triggered reaction potentials,
GABAergic effect.
the hippocampial response to stimulation of the amygdaloid body was magnified with
the local substances. The increase in amplitude of the amygdalo-hippocampial stimulation
response had similarities with the effects of impramine and kawain among others. These
effects can be ascribed clinically most nearly to the thymoleptic attributes. A sedation is
unlikely, as is a vigilance reduction; the results, on the contrary, point to an improvement
of the sensory and mental functions.
Grusla eta/. (1986) carried out a series of experiments which used the Sokoloff method
to investigate the effect of V. offirina/is extract on glucose consumption in different
areas of the brain. A marked change in the local cerebral glucoseum sediment in contrast
to the control sediment was manifest in particular with 50mg V. officinalis extract per kg.
Significant reductions in the glucose consumption were measurable above all in the
different regions of the cortex, in the region of the limbic system and in the structure
of the rhombencephalon. These results speak for an inhibiting effect on the neuronal
activity and are reconcilable with a sedative effect of V. officinalis. Experiments with
isolated single substances (valtrate 3, didrovaltrate 4, valerenic acid 6, valeranone 7)
resulted, however, in no significant reduction of the glucoseum sediment; so the nature
of the substances responsible for this activity is still not known (Kriegelstein^/^/1986).
61
could also be metabolised in situ to GABA and thus could contribute to the overall
The same group of workers reported more fully on the interaction of extracts of V.
officinalis on GABAA receptors (Cavadas et al, 1995). [3H] muscimol binding techniques
on rat brain cortices were used and it was found that both aqueous and alcoholic extracts
displaced the muscimol. Both extracts had a similar level of GABA and, when a mixture
of the amino acids was made of the same amounts found in the extracts, it displaced
muscimol in a very similar way Valerenic acid was not seen to have this effect. These
results indicated that GABA present in the extracts was the major component binding
to the receptors but its inability to cross the blood-brain barrier implies that any effect
of the GABA observed in vivo would be peripheral rather than on the CNS.
Clinical Studies
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. In an EEG study on the same preparation the pattern of results tended to
(Santos eta/., 1994a). 50% inhibition was given by l(Ig/mL extract and 100% inhibition
by 8(Ig/mL. GABA previously accumulated in the synaptosomes was also released
independent of calcium ion concentration. A later report showed that the release of
GABA from the synaptosomes stores was probably due to the concentration of GABA
confirm the subjective evaluation (i.e. shorter mean sleep latency, increased mean latency
to first awakening} but the changes did not reach statistical significance.
Another study was carried out with patients who complained of such symptoms as
mental restlessness, delayed onset of sleep, frequent awakening and concentration
JOSEF HOLZL
and there was also no effect on self-rated sleep quality. It was hypothesised that V.
offidnalis extract increases SWS in subjects with low baseline values.
Another multicentre study reported by Orth-Wagner et al. (1995) used a mixture of
extracts from V. offidnalis, Hops (fruits of Humuius lupulus) and Balm {Melissa offidnalis
herb). 225 patients who had trouble falling asleep because of nervous unrest were given
the mixture for two weeks. In over 80% of the subjects significant subjective and objective
improvements in ability' to fall asleep, sleeping time and decrease in anxiety were noted.
62
by observation with semi-quantitive scales throughout the test period. Towards the end
of the test both patient and tester separately gave, on the basis of these observations,
their assessment of the therapy results.
extract reduced perceived sleep latency and wake time after sleep onset. Night-time
motor activity' was enhanced in the middle third of the night and reduced in the last
third. The data suggested a dose-dependent effect. In the sleep laboratory, no significant
differences from placebo were obtained. However, the direction of the changes in the
subjective and objective measures of sleep latency and wake time after sleep onset, as
well as in night-time motor activity, corresponded to that observed under home
conditions. There was no evidence for a change in sleep stages and EEG spectra.
A further study (Schmidt-Voigt,l 986) also showed a success rate of 35 to 66% for an
improved ability to fall asleep. The V. offidnalis preparation was similarly successful in
improving sleep duration. In relation to these studies it should be noted that no better
results were achieved using strong sedatives or psychotherapeutic drugs. It was remarkable
Riicker et al (1978) produced an even higher oral LD of greater than 3 g/kg for
valeranone 7 but the hypotensive effect in rats was found to be fairly weak. In addition
a prolongation of sleep induced by barbiturate was observed. A tranquillising effect
was seen when the electric shock avoidance test was used but valeranone 7 at a dose of
that in these studies the patients reported an early effect of the drug, on average already
after 1.6 to 1.8 days, particularly in cases of mental restlessness. Side effects such as
<?/*/., 1982).
stomach disorders, headaches and itching were noted but occurred only rarely.
Kessane sesquiterpenes
A double blincl test was carried out on a preparation containing primarily sesquiterpenes
(Lindahl and Lindwall, 1989). When compared with placebo it showed a good and
significant effect on poor sleep. 44% reported perfect sleep and 89% reported improved
sleep from the preparation. No side effects were observed.
The effect of acute and repeated treatment with a V. offidnalis extract on objective
and subjective measures of sleep was studied (Schulz et al., 1994). Polysomnography
was conducted in 14 elderly poor sleepers on three nights, at one-week intervals. Subjects
in the V. offidnalis 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
63
The kessane derivatives had been known for some time as chemical curiosities but it
was not until 1973 that tests showed that kessoglycol diacetate 1, a major component of
the oil of V. offidnalis var. latifolia, decreased the motility and prolonged the
hexobarbitone-induced sleeping time in rats (Takamura eta/., 1973). The IJD was high
being greater than 5 g/kg in mice. Subsequent structure-activity studies using several
kessyl sesquiterpenes indicated that the kessyl alcohol 8-acetate 8 was more potent at
prolonging sleep than the 2,8-diacetate 1 but had little effect on the motility of mice
(Takamura et al, 1975a). Butyl analogues prepared synthetically were also found to be
more potent than the acetates (Takamura eta/., 1975b).
T
THE PHARMACOLOGY AND THERAPEUTICS OF VALER1ANA
JOSEF HOLZL
64
65
Valerenic acid 6 was first isolated by Stoll et al (1957) and shown to have a sedative
effect on frogs and a spasmolytic effect on guinea pig gut. No further studies were
performed until Hendriks et al. (1981) investigated several components of the volatile
oil of V. officinalis for various responses indicating sedative activity on groups of mice.
Doses of 50 mg/kg for valerenic acid 6 and valerenal 9 showed significant effects including
decreased motor activity, decreased rotarod performance and ataxia.
1R,R' = OOCCH3 Kessyl glycol diacetate
This work led to a more detailed investigation into the activity' of valerenic acid 6
(Hendriks et al., 1985). Its influence on the rotarod and traction performance of mice
8R = H,R'= OOCCH3
Kessyl 8-acetate
CH2OR
The
profiles for these tests indicated that valerenic acid 6 resembled pentobarbital and is
likely to have a general central depressant activity rather than a muscle relaxant or
neuroleptic effect. Large doses of valerenic acid (>400 mg/kg) caused strong
HO
R
3
10
4
R1
Riedel etal. (1982) showed that valerenic acid 6 inhibited the enzyme system catalysing
R"
Iv
Iv
Ac
Valtrate
11
Ac Baldrinal
Aiv
Iv
Ac
Acevaltrate
12
Iv
Ac
Iv
Isovaltrate
Iv
peripheral bleeding, convulsions and death. Hiller and Zeder (1996) demonstrated that
valerenic acid 6 reduced convulsions induced by picrotoxin.
Homobaldrinal
breakdown of GABA in the brain. The net effect is thus an enhanced level of GABA
which is associated with sedation and a decrease in CNS activity.
Valerenic acid is therefore thought to be an important CNS-depressant constituent
of the oil of those samples of V. officinaliswhich contain large amounts of this type of
sesquiterpene.
Iv
Ac =CH3CO
CO-
Valepotriates
The isolation of the valepotriates (Thies, 1966) led to much interest into their activity'
and this has led to the widespread use in Europe of standardised mixture of valepotriates
Aiv
= CH3
co-
as a mild sedative. The pharmacology of these compounds was first reported by von
Eickstedt and Rahman (1969) although some clinical testing had previously been carried
out(Stocher, 1967).
Several experiments have been carried out using the commercial mixture containing
CH2OOCCH2CH(CH3)2
15% valtrate 3, 80% didrovaltrate 5 and 5% acevaltrate 10. Tests on mice using the
running wheel demonstrated that the valepotriates had a tranquillising effect at doses of
31 mg/kg given orally but this effect was less than that given by 10 mg/kg chlorpromazine.
On the other hand the rotarod test showed an improvement in co-ordination with the
CH3COO
Didrovaltrate
Figure 1
r
THE PHARMACOLOGY AND THERAPEUTICS OF VAJ.ERJANA
JOSEF HOLZL
66
67
showed that the most potent reduction of spontaneous motility was given by valtroxal
13, one of the degradation products of didrovaltrate, rather than didrovaltrate 5 itself
(Veith <?/*/., 1986).
These tests closely identified the sedative activity of Valerianaceous plant extracts
CH3
CH3
with the valepotriates. However it is important to note that a decrease in activity of the
CH3
tincture after a short storage time had been noted in very early work (Macht and Ting,
7 Valeranone
1975). The efficiency of extracts of Valeriana which have been stored for long periods
of time is therefore questionable if valepotriates are the major active components present.
Valerenal
Recent concern about the alkylating potential of the epoxide group has prompted
the investigation of valepotriates that do not contain it.
which lacks the epoxide, was compared with valtrate 3 for its effect on the activity7 of
mice (Holzl and Fink, 1984). Valtrate 3 gave a significant effect in oral dose of 0.5 mg/
CH2OAc
areas of the cortex and sub-cortex of the brain indicated that the valepotriates act on
the amygdaloid body (Holm, 1984). Valtrate 3 and isovaltrate 4 showed similarity to
some antidepressants in being thymoleptic whilst didrovaltrate 5 seemed to inhibit efferent
impulses to the hippocampus in a similar way to the benzodiazepines, thus showing
tranquillising properties.
Other recent work using perfused rat brain has shown that changes in the EEG
pattern were produced in a dose-related fashion by valtrate 3 with a reduction in beta
13
Valtroxal
14
Acetoxyvalthydrine
Figure 2
activity7 and an increase in theta and delta frequencies (Fink et a/., 1984).
Lignans
A newly detected substance, hydroxypinoresinol 15, a lignan, showed the highest binding
at the 5-HT receptor and an insignificant binding at the benzodiazepam receptor when
X^akriana compounds were subjected to receptor-binding studies (Bodesheim eta/, 1995).
Tests on the spontaneous motility of mice showed little extra reduction when the
alcoholic extract of V. officinalis (containing valepotriates) was fortified with more volatile
oil (Wagner et a/., 1980).
sedative action. However, the composition of the oil of V.officina/isis notoriously variable
and, consequendy, so is its activity and it would be unwise to draw too many conclusions
from this work. The same authors compared the effects of the valepotriates and their
decomposition products such as baldrinal 11.
Homobaldrinal 12 was found to have a greater effect on spontaneous motility than
valtrate 3 and isovaltrate 4 at doses of 100 mg/kg given orally. It was therefore postulated
that the hydrolysis products were the most active forms. These compounds seem to be
metabolised quite rapidly in the gut as experiments with didrovaltrate 5 show (Wagner
and Jurcic, 1980).
when injected into mice intraperitone ally (Schneider and Willems, 1982). Recent work
The valepotriates have been shown to exert a spasmolytic effect, first demonstrated
for valtrate 3 and didrovaltrate 5 by Wagner and Jurcic (1979). The commercial mixture
of valepotriates had an effect stronger than the same dose of papaverine but the individual
compounds were less strong even at higher doses. Further investigations by Hazelhoff
et a/. (1982) revealed that valtrate 3, isovaltrate 4 and didrovaltrate 5 probably act as
68
JOSEF HOLZL
69
musculotropic agents. Their action may be due to an influence on the entry of Ca2+ ions
or on their binding to the muscle.
15
Hydroxypinoresinol
The complement system comprises part of the immune system in the body and has
been the subject of investigation for many plant extracts used in traditional medicine.
When the valepotriates were tested all but one showed an inhibitory effect on the
alternative synthesis route in the complement system of the serum (van Meer, 1984).
Didrovaltrate 5 had the greatest activity whereas the decomposition products like baldrinal
11 were less active. This activity indicated a possible use for these compounds in some
auto-immune diseases.
Cholinergic Effects
Little is known about the activity of the alkaloids of V. officinalis which are only minor
constituents. One of the alkaloids 16 isolated by Torsell and Wahlberg (1967) showed a
high degree of cholinesterase activity. This is a derivative of actinidine 17, also found
from Valeriana spp., which has a cholinergic effect.
H,C
Antifungal Activity
Ten valepotriates have been shown to exhibit activity against the plant pathogen fungus
Cladosporium cucumerinum in a bio autographic assay on thin layer chromatography. (Fuzzati
et a/., 1996). Valtrate 3 was active at ljlg and also showed significant inhibition at low
17
Actinidine
18 Nepetalactone
CH2Olv
AcO
Some species of Valeriana are noted for their property of attracting animals, particularly
CH?
19
Olv
Deoxidodidrovaltrate
cats, although rats and animals related to dogs have also been mentioned in this respect.
The alkaloid actinidine 17 has been postulated as the attractant since it also occurs in
Actinidia , another cat-attractant genus (Tucker and Tucker, 1988). Nepetalactone 18 is
found as a minor constituent of the volatile oil of some Valeriana species and this
compound is considered to be the major agent responsible for the characteristic effect
Figure 3
of catnip, Nepeta cataria (Bicchi et a/., 1983). It is also worth noting that isovaleric acid,
JOSEF HOLZL
70
71
responsible for the characteristic odour of stored Vakriana spp., is a component of the
anal gland secretion of some members of the cat family and is associated with mating
marrow early progenitor cells in vitro and the in vivo effect of valtrate 3 on the same type
of cell in mice has subsequently been tested (Braun etal., 1984). In contrast to the in vitro
results no significant effect could be observed when the drug was given orally or
TOXICOLOGY OF VALERIAN
report showed that 50 mg/kg valtrate 3 reduced the ability of the liver to metabolise
14C- methacetin when given intraperitoneally but no significant reduction was observed
General Considerations
Numerous studies have idicated that aqueous and alcoholic extracts of V officinalis have
a high LD
value. A recent case of overdose where the patient had ingested almost 25g
of powdered V. officinalis toot in capsule form demonstrated only mild symptoms (Willey
et aL, 1995). These symptoms included fatigue, abdominal cramps and tremor but all of
them disappeared within 24 hours. Four cases of hepatitis incurred by regular users of
herbal sedatives consisting of a mixture of herbs including V. officinalis has been widely
cited (Macgregor eta/., 1989). The evidence for the V. officinalis being the causative agent
is circumstantial and may be due to the other components present rather than the
These results indicate that in vivo toxicity might not be so great as in vitro tests imply
interest in minimising the potential toxic effects whilst seeking to preserve the use of
Valerianaceous plant as acceptable sedatives.
Although considerable progress has been made in elucidating the chemical basis for the
Comparison of the structure of the valepotriates with the cytotoxic substance 6,20-
observed sedative activity of Vakriana spp., the situation is still far from being completely
epoxylathyrol-3, 5-dibutyrate
total effect being due to a mixture of chemical types with various pharmacological
11 were tested in vitro on isolated liver cell tumours of rats for their cytotoxicity. Valtrate
activities. The constituents seem to act both centrally on the brain and peripherally in
3 was twice as toxic as didrovaltrate 5 and eight times as toxic as baldrinal 11. 24 hours
causing relaxation of smooth muscle. The central action is due, in part, to activity at the
exposure of cells to 33mg valtrate per ml led to their total mortification. In further
plant extract.
cell line for their cytotoxic activity. While 20 mM valtrate 3 led to cell death 48h after
The clinical evidence indicates that Valeriana is a relatively safe substitute for the
incubation, 40% of the cell population survived the dose of didrovaltrate 5 and deoxido-
benzodiazepines as a mild tranquillizer and also that it has potential in aiding onset of
sleep. The large number of commercial preparations available throughout the world
which contain Valeriana spp. or their extracts bear some witness to the reputation and
efficacy of this genus.
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disorders in senium. Med.Welt 35, 1450-1454.
Cavadas, C, Araujo, I., Cotrim, M.D., Amaral, T, Cunha, A.P., Macedo, T. and Fontes Ribiero, C
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on GABAA receptor in rat brain. Ar^neim. Forscb. 45 (II), 753-755.
Chevalier, J. (1907) Pharmacodynamic action of a new alkaloid contained in the roots of fresh
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Krieglstein, J. and Grusla, D. Centrally-acting inhibitory components in Valerian. (1988) Deutsch.
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Ar^neimittel-ForscbungV), 995-997.
Leathwood, P.D., Chauffard, F., Heck, E. and Munoz-Box, R. (1982) Aqueous extract of Valerian
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Godau, P. (1991) Analytik von Inhaltsstoffen aus Valeriana officinalis und deren
pharmakologischen Testung mit RBS. Dissertation, Univ. of Marburg.
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2249-2253.
Gstirmer, F. and Kind, H.H. (1951) Chemical and physiological examination of Valerian
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Gstirmer, F. and Kleinbauer, E. (1958) Zur pharmakologische Priifung der Baldrianwurzel.
Pharma^ie 13, 415-420.
17, 65-72.
Leathwood, PD. and Chauffard, F. (1985) Aqueous extract of valerian reduces latency to fall
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Lecoq, R., Chauchard, P. and Mazoue, H. (1963) Chronaximetric experimental study of the action
of some mineral or vegetable sedatives and the associated effects of ethyl alcohol, with or
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Leuschner,J., Muller, ]. and Rudmann, M. (1993) Characterisation of the central nervous depressant
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JOSEF HOLZL
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74
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75
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4.
CULTIVATION OF VALERIAN
jenO bernAth
CONTENTS
INTRODUCTION
Nutrition
78
jeno bernAth
SELECTION
CULTIVATION OF VALERIAN
Germination
LIGHT
79
DARK
Planting
Care of plants
Harvesting
Seed production
DAYS
1st.
7th.
28th.
Final
1st.
7th.
28th.
Final
INTRODUCTION
Valerian {Vaieriana offidnalis and its related species) is cultivated in many countries of
Europe and Asia. It is cultivated in relatively large areas of Russia, Ukraine, Poland,
Bulgaria, Romania, Hungary, Belgium, France. Other Vaieriana species (e.g. V wallichii,
Vfauriei) are cultivated as well in India, Japan and other countries. In this chapter the
selection of material for cultivation, the factors influencing optimum growth and the
cultivation methods used in the temperate zone are discussed in more detail.
Figure 1
germinated by the end of experiment was greater by 1011 percent, compared with the
dark control. The effectiveness of large-energy illumination and long wavelength
(328 A) laser treatment on seed germination was studied by Kuznechova et ai (1984).
Photoreguiation
The importance of light in germination of valerian has received some attention. Svab
(1978) showed that germination is more intensive under light and at about 20C
temperature. Similar phenomenon has been proved by the data of Dagyte and Morkunas
(1968). They concluded that, under light and room temperature (16 - 18 C), the
germination power of seeds was as high as 34 % and 44 %. In darkness germination
was only 22.2 % and the total number of germinated seeds less than 30 %. The
importance of photoreguiation in germination processes was studied by Berbec (1970)
as well. He confirmed that, while the light increases the germination percent , it has
only a slight effect on the length of period needed for the appearance of the first germ.
However the germination is regulated by the interaction of light and temperature. As is
obvious from the data of Fig. 1., the effectiveness of light is dependent on temperature
conditions.
On the basis of their results the phytochrom system of the seeds was stimulated by 10
minutes treatment of both the large-energy illumination (in 67000 mV/cm2 dose) and
laser treatment (0.3 mV/cm2) and the germination power and the percentage of
germinated seeds became higher. The further development of plants was effected by
these treatments as well, which were manifested in acceleration of development and
higher biomass production.
The distribution of valerian species shows a large ecological diversity. It was proved by
Voroshilov (1959) who analysed the distribution of V. exaltata and V collina species in
both Europe and Asia. These species occur under diverse ecological conditions and
could be the elements of different plant systems. They can grow inside the forests
under low (3-5 Klux) illumination, in margins and clearings in forests and in sunny
places as well, where direct illumination can reach as high as 60-80 Klux intensity. It was
emphasised by Heeger (1956) that the adaptation of valerian species to the different
light conditions is due to the modification of the leaf surface. This modification of leaf
surface is going in parallel with structural changes of plant organs.
jeno bernath
80
CULTIVATION OF VALERIAN
81
The correlation between light and the accumulation level and composition of secondary
It is stated by several authors that the development of valerian is accelerated by dry and
hot climatic conditions and that early flowering is followed by quick ripening. On the
metabolites has been investigated in the case of valerian. The comparison of plant
samples of the same origin taken from natural habitat and cultivated population may
show some differences. Some results were achieved by Sarkany and Baranyai (1958) in
this respect. It seemed to be an overall phenomenon that the essential oil content of
individuals taken from natural habitats was higher. The ecological parameters of natural
habitat and the agrarian condition may differ in many aspects, including that of the light
basis of observation of Dolja (1986), if the temperature increases from 15.7C to 20.221.9 "C before flowering, the time period needed for flowering of V. collina and
V. exaltata becomes much shorter. Similar results were obtained by Konon (1978). He
observed that the flowers are open for 45 days under cold and rainy weather, while
for 2-3 days under dry and hot conditions. This means that the opening of one flower
head may continue over 25 to 35 days. The shorter flowering period - effected by hot
and dry conditions - has an adverse effect on flowering resulting in restricted vitality of
intensity.
Temperature
Thermoregulation
As was mentioned above, the temperature may play an important role in regulation of
It was stated by Heeger (1956) that there is a correlation between the essential oil content
regime only, at about 25 C values. It has been shown by more detailed investigations
by Berbec (1970) that the effect of changing day/night temperature is a more characteristic
of valerian root and the temperature values of the vegetation period. In Germany the
moderate climate seems to be the optimum one: both the warm and the cold weather
has an adverse effect on accumulation of essential oils.
one compared with the constant values. The highest percentage of germination was
obtained in his experiments at 25/15 C day/night rhythm. The germination was relatively
good at low temperature values too, if different day/night regimes (15/5 C) were applied.
However, the germination power of the seeds proved to be dependent on the temperature
conditions existing previously at the time of seed setting and ripening. It was proved in
the long term investigations (Table 1) that a cold and humid climate promoted the
vitality of seeds in this phenophase. The seeds harvested in this climate showed high
germination power, up to 90 % values. As it is obvious from the data too, the seeds
harvested in an optimal year (1962) have a long-lasting biological vitality. The continuous
loss of germination power in this seed material is retarded compared with the commercial
seed samples. Even after three years using this biological valuable seed material, a relatively
good germination of 47 % can be obtained.
Table 1
Effect of climatic conditions existing before ripening on germination percent and life
It is accepted generally that valerian belongs to the group of species with high water
requirement (Heeger, 1956; Svab,1978).Taking into consideration the geographical and
coenological distribution of the species, much more diversity in the water requirement
is expected. Hungarian experiences agree with the data of Auster and Schafer (1958) who
showed that V. exaltata and V. sambucifolia require more humid conditions, while
V. collina prefers warmer habitats, and grows well under relatively dry forests. In
V. exaltata and V. collina the presence of intraspecific adaptation was demonstrated by
Corsi etal. (1984). Individuals of the same species were compared, which were gathered
from Alpine (Apuan) and Mediterranean regions (Trieste). The characteristic features
of the adaptation processes to the dry climate as well as to the humid conditions were
described. The individuals grown on the dry karst form thick leaves with two layers of
Temp.
Water requirement
Precipit.
Number of
After
1 year
2nd
3rd
summer
summer
mm
rainy days
harvest
old
1959
16.9
248.2
27
82.2
63.0
30.2
7.0
1960
15.7
423.7
34
68.0
43.2
18.0
3.8
1961
15.6
147.7
40
78.0
50.0
34.2
9.0
1962
13.7
317.7
55
90.2
89.2
76.4
47.0
1963
17.6
96.6
33
72.0
48.0
36.2
4.6
palisade parenchyma. In contrast the Alpine individuals have a thin leaves with small
epidermal cells and one parenchymatic layer. In parallel with this modification, the vascular
bundles of the stem show a more compact character forming a continuous ring with
increased amount of metaxylem when the plant is grown on karst. The adaptation
ability of individuals to the high water supply was justified in hydroponic experiments
by Gzurjan and Manashjan (1980). The plants affected by continuous water supply
formed a large amount of stomata on the leaf surface and the parenchyma cells become
large and the amount of the vascular bundles increased in both stems and roots. An
optimum water supply - as was proved in hydroponic experiments of Babahanjan (1979) causes an increase in the development of plants and has a favourable effect on dry matter
production. His results showed that the development of plants is quicker by 10 days and
the dry-matter production is higher about 3 times if the water supply is optimum.
jeno bernAth
82
CULTIVATION OF VALERIAN
in plot
experiments by Berbec (1965). The plants were grown in plots on 30, 45, 60 and 75 %
83
essential oil content of roots from 0.73 to 0.68 % while the amount of valepotriates
changed only slightly from 0.63 % to 0.60 %.
water saturation level. However there were large differences in the development of the
In contrast the fatty oil accumulation in the seed can be stimulated by water supply.
plants effected by water supply and their production was evaluated only at the end of
Dolja (1986) established that the characteristic fatty oil content of a population (20.0 -
vegetative growth.
23.7 %) can be increased by irrigation 24.2 28.1 %. However these quantitative changes
at 45 and 60 %
saturation levels in all the three vegetation cycles. Both the higher an lower saturation
levels had an adverse effect on production. However the low water saturation (30 per
accumulation of palmitin, stearin, olein and linolene is increased, while the amount and
the
cent) decreased the root production in every vegetation cycle universally. The advantage
ratio of erucic acid is much higher in seeds ripening on non irrigated plants.
of irrigation was proved under Bulgarian conditions cultivating 'Shipka' cv. as well
(Nedkov and Slavov, 1989). The highest yield was achieved by them, over 3520 kg dry
Soil conditions
It was generalised by Heegcr (1956) that the heavy clay soils are unsuitable for V.officinalis.
In was proved by the experiment of Corsi et al (1984) that plants grown under different
ecological conditions, parallel with tissue modifications, accumulate different amount
of special compounds. In the case of V. collina the characteristically wide spectrum of
essential oil can be measured in roots taken from Alpine region. Under dry conditions,
especially in plants grown on karst, the spectrum of essential oil components decreases
and 5 of the 25 characteristic essential components present in the Alpine region plants
do not accumulate. However, the profiles of the components accumulated under both
ecological conditions are not the same. Whilst in the oil of Alpine region plants bornyl
acetate (21.7 %) and isobornyl acetate dominate, bornyl isovaltrate is the main component
in the oil from the population grown on the karst.
In the systematic experiments the favourable effect of the continuous water supply
In harmony with this statement the medium loam or sandy loam soils, which have a
medium humus content, are suggested for cultivation by Svab (1978).
The effect of
loam and light sandy soils was compared in three years of plot experiments of Berbec
(1965a). The advantage of a loam soil was obvious, in which the plants developed more
intensively, the number of leaves increased and the plant became 25-30 cm higher. The
higher productivity of these plants was shown by the changes in the root formation and
production. The number of primary roots was higher in loam soil and the total biomass
of roots
production of valerian was also shown by Bernath et al. (1973). Comparing different
soil types of Hungary, the advantage of the sandy (Orbottyan) and loam soils
(Balatonfenyves) were demonstrated in production of root biomass (Table 3.).
did not result in increased essential oil accumulation. On the contrary, in the hydroponic
experiments of Babahanjan (1979), the essential oil content of the root decreased from
0.3 % to 0.19% as an effect of continuous water supply. The experiments of Berbec
Table 3
(1965) led to the same result. As it is shown in Table 2 the increasement of water
saturation level from 30% up to 75 % had on adverse effect on essential oil accumulation.
Soil type
The essential oil content decreased from 0.77 % to 0.57 % and the biological activity
Effect of some Hungarian soil rype on the root production of valerian in average of
Total
of the root extract decreased as well. The relative value of the biological activity decreased
plant
from 408 to 298. Lewkowicz-Mosiej (1984) established the same correlation between
(k)
water and essential oil accumulation; the investigation was also extended to the analysis
of valepotriates. Increasing the water saturation of the soil led to a decrease in the
Table 2
Rootproduction
Root mass
&
279.4
151.6
36.3
1.186
212.4
91.5
8.4
0.756
313.9
137.3
6.0
0.743
396.2
156.6
20.9
0.653
Orbottyan - pH in water 8.0, total salt 0 %, CaCO 0.2 %, hardness number 27,
Water saturation
Rootproduction
Essential
Essential oil
Biological activity
of soil %
&
oil{%)
production (mg)
(relative value)
30
19.2
0.77
0.15
408
45
27.2
0.72
0.19
391
60
28.8
0.69
0.19
333
75
25.8
0.57
0.14
298
Root/ shoot
Budakalasz - pH in water 8.2, total salt 0.02%, CaCO,. 7.7%, hardness number 37,
humus 2.33 %, total nitrogen 0.137 %.
Szarvas - pH in water 8.0, total salt 0.04%, CaCO
10.7 %, hardness
jen6 bernath
84
CULTIVATION OF VALERIAN
85
The root production of individuals was 151.6 g in sandy soil, 156.6 gin loam, while
the actual essential oil content and the number of the cells which are able to accumulate
only 91.5 137.3 g in the other soil types are rich in clay components. The morphological
the oil. In the case of the valepotriates another type of correlation was observed. The
character of the root was affected by the soil type as well. In the sandy and loam soil
accumulation of these substances was more restricted in the soil Szarvas, which was
(Orbottyan, Balatonfenyves) the relative mass of thin roots increased, taking about 20.9
36.3 per cent of total biomass of roots. In the clay soils the ratio of the less valuable
parts of roots decreased showing 6.0 - 8.4 % only. The large amount of thin roots and
ability) reflects on the good adaptation of the species which copes with a lack of nutrients
by intensive differentiation of thin roots.
essential oil content of the roots and the biological activity of the extracts made from
the roots are dependent on the growing conditions, especially on the soil type. 1.08 %
essential oil level was measured
sandy-clay only. In contrast the biological activity of the extract was higher in the roots
grown in the latter soil type. The effect of soil on accumulation of special compounds
was justified by plot experiments (Bernath eta/. 1975).
Evaluating the data shown in Fig. 2 the maximum values of essential oil accumulation
were observed in plants grown in different soil types, especially in clay (Szarvas) and
Nutrition
It was emphasised by Golcz and Kowalewski in 1958 that there are many contradictory
results relating of the nutrient requirement of valerian. From practical purposes the
selection of the soils of high humus and nutrient content are proposed by many authors
(Heeger, 1956, Svab, 1978). The reason for the contradictory results is that the efficacy
of the nutrient supply may depend on many factors. The results of Lewkowicz -Mosiej
(1984) demonstrated that the water saturation level may determine the effect of nutrient
fertilisation: at 80 % water saturation level the activity is significant while at 40 % water
saturation level it is only slight from the same dose of nutrients. The exact reaction
profile of plants to the different nutrients (nitrogen, phosphorous and potassium) can
be characterised in plot experiments (Bernath eta/. 1973). The increase in the degree of
nitrogen supply from 10 mg N pot'week1 to 800 mg N pofVeekA doses resulted in an
optimum type growth in fresh-mass production of plants (Fig. 3.).
sandy (Orbottyan) soils. From the point of view of the root tissue structure the increasing
root surface would result in a potentially higher accumulation but the values show
contradictory results as the essential oil accumulation is independent from the ratio of
FRESH MASS
the rootlets being thicker then 1.5 mm. It does mean that there is no correlation between
ESSENTIAL OIL
-SHOOT
ftt
N2
MJ
N5
PI
P2
PJ
Pi
K2
K3
K5
N supply (mg N pot'week1): (Nl)10 mg, (N2) 50 mg, (N3) 200 mg, (N4) 400 mg, (N5) 800 mg,
P supply (mg P pofVeek"1): (Pl)5 mg, (P2) 25 mg, (P3) 100 mg, (P4) 200 mg, (P5) 400 mg
K supply (mg Kpot'week1): (Kl)5 mg, (K2) 25 mg, (K3) 100 mg, (K4) 200 mg, (K5) 400 mg
Figure 2
The effect of Hungarian soil types on essential oil accumulation of valerian, based
Figure 3
The effect of nitrogen, phosphorous and potassium supply on the shoot and root
CULTIVATION OF VALERIAN
jen6 bernAth
86
However, while the optimum point of shoot production was measured at N4 dose,
the amount of roots reached the maximum value at lower nutrition supply (N2-N3).
SHOOT MASS
The higher nitrogen requirements of the shoot and and relatively smaller requirements
(g)
of root development are well demonstrated by the changes of their ratio. Parallel with
the increasement of nitrogen supply
87
30
decreases from
1.356 to 0.696. The structural characters of the root change at the same time. As an
effect of the increasement of the nitrogen doses the thickness of the roots increases.
The thickness of the roots can be characterised by the dry-mass production of the
roots calculated to the unit surface area of root. Using this calculation
g cm2 value measured at low nutrition increases up to 16.08 g cm'2 at high dose of
nitrogen.
Changes of phosphorus supply result in changes similar to those described for nitrogen
application above. There is only a difference in the rate of shoot and root production,
which shows no characteristic changes.
The potassium supply has a regulatory effect on the structure of the root similar to
nitrogen. An increase results in a restriction in leaf-surface and parallel increasement of
root thickness.
The interaction of nitrogen and phosphorus is demonstrated in Fig. 4a-c.
Unambiguous interaction was found in the case of biomass production of root (a).
Otherwise the shoot production is mainly regulated by nitrogen supply (b) and the
structural changes of the root, characterise by its dry-mass production calculated to the
Figure 4b
unit surface area (c) are regulated by both nitrogen and phosphorus.
ROOT MASS
(g)
Figure 4c
Figure 4a
experiment of Bernath etal (1973) on structural changes of the root, characterised by dry-mass
production calculated to the unit surface area of root.
JEN6 BERNATH
88
CULTIVATION OF VALERIAN
89
There is some information on the calcium requirement of the species. It was mentioned
supply increases the thickness of the roots. In thin roots the relative amount of the
by Heeger (1956) that valerian grows well in lime-soils rich in calcium. This phenomenon
hypodermic layer in which the accumulation of essential oils takes place is relatively
high. In contrast the ratio of hypodermic cells in thick roots is smaller. However, the
that the effectiveness of calcium dosage is dependent on the chemical form of calcium
as well as on the soil-type chosen: CaO in loam and CaCO3in sandy-clay accelerated the
valepotriates some kind of optimum effect was proved by the investigations of Bosetto
growth of roots. Calcium fertilisation also improved the root quality, the utilizable part
et al. (1987). Parallel culture of plants in containers and in a hydroponic system showed
that medium nutrient doses, 150 kg N, 75 kg P2O5 and 75 kg K^O/ha resulted in the
highest root and valepotriate production.
The real connection between the accumulation of special compounds and the nutrient
supply is hardly known (Golcz and Kowalewski, 1958). The reason for the contradictory
results is that the majority of the authors make no distinction between the changes of
the accumulation level and those of production. Lewkowicz - Mosiej (1984) stated that
It has been proved by several investigations carried out in natural habitats that the
the application of nitrogen, phosphorous and potassium may decrease the accumulation
level of the essential oils. However, these changes do not affect the essential oil production
the production of constituents (Titz and Titz,1982: Titz et al. 1983). This variability is
much greater if individuals of the same species are compared taken from deverse
geographical sites and ecological conditions. The reason for the morphological variability
without any changes in accumulation level. In plot experiments the essential oil
accumulation, which was affected by nutrition supply, showed an optimum curve (Bernath
number
eta/. 1975).
V. offidnalis var. latifolia population belonged to the diploid (2n=14) form, which was
which were found in Poland. The majority of the individuals of the local
As shown on Fig. 5., there is no correlation between the accumulation level of the
characterised by high variability in leaf morphology, stem height and time of blossom.
essential oils and the structural changes of the root morphology. Increasing the nutrient
On the basis of the more detailed investigations of 27 natural populations the occurrence
of a tetraploid form (2n=28) was demonstrated. The leaves of the tetraploid individuals
were much wider compared to the diploid ones. There were also differences in the size
of the pollen grains, the diameter being about 46.6 um in tetraploid plants and 42.3 um
in the case of the diploid form. The existence of
chromosome number was determined to be a diploid one (2n=14), while the populations
0.4
0.3
-- 0.2
The close correlation between the number of chromosome and the variability of the
0.1
N3
P3
In contrast to earlier investigations the existence of the octoploid (2n=56) was shown
which reflects the possible autopoidity of the genus. From the results the populations,
determined as V. exaltata, V. collina and V. procurrens} showed a high morphological and
Figure 5
chemical diversity in relation of their chromosome number. The population with higher
polyploidy formed much larger and wider leaves, with more and larger stomata on them.
jenO bernAth
90
91
CULTIVATION OF VALERIAN
The size of the seeds increased as well. Considerable changes were also found in the
1
00
LO
"^t
accumulation of the special plant compounds. The higher chromosome number resulted
in higher accumulations of valepotriates and valerenic acid; the relation of the valerenic
acid content to chromosone number seems to be very strict. While the valerenic acid
p
CM
CM
CM
CM
CM
ON
00
32. 0. 16. 16 38
"1
CM
00
cs
SO
LO
52.
CO
CM
CM
X
Cs
od
cm'
SO
LO
CM
CM
r-
LO
GO
CO
O
r-
63. 0.0
sd so'
sO
CM
X
CM
CM
sO
OO
CM
CD
CM
GO
.t
t>0C
00
LO
CM
^_
CM
CM
o<
r-
OO
CM
CM
CO
OO
CM
G^
OO
OO
sd
GO
CO
CO
OO
II
LO
CO
CO
LTl
CO
TJ"
GO
SO
OO
264
oo
CO
163
so
CM
T-;
sq
^t
go"
content in the root of the diploid and tetraploid forms was as low as 5-32 mg%, in
OO
so
CO
Genotype-phenotype interaction
It was emphasised by Noller (1989) that, in evaluating the variability of the natural
populations of valerian, the modification effect of the ecological conditions has to be
considered. Standardisation of the genetical and ecological interactions is one of the
preconditions to the selection of new cultivars of stable and high productivity. Some
aspects of interaction were proved by Noller (1989) comparing two cultivars 'Polka' and
'Erfurter Breitblattiger Baldrian' under phytotron condition using 5 different temperature
programs. Comparing the two cultivars in a short vegetation cycle there were only
1946% differences in accumulation of valerenic acid. When the vegetation cycle was
extended by three month the differences between cultivars increased up to 52-94%.
However these differences could only be generated under higher temperature regimes.
The accumulation of valerenic acid decreased in both cultivars equally when they were
grown under low temperature regimes.
CO
sO
sO
SO
CO
sd
taxa of diverse polyploidy has been shown by Noller (1989), no evidence was submitted
with regard to populations having identical chromosome number. On the basis of
investigations had been extended to three vegetation cycles, only slight and year dependent
LO
cO
LO
CO
GO
CO
Cs
LO
CO
sO
so
..
r.
Table 5
00
CM
00
CM
OO
CM
LO
-a
v:
"ffl
too
X!
OJ
0
u
OJ
LO
aj
:=!
!J
'o
u
Oh Oh a. a,
<D
r*
Si%e of leaves
Number of leaflets
Valerenic acid
1986
0.13
0.06
-0.36
1987
0.07
0.03
-0.23
-0.24
1988
0.01
0.27
-0.37
-0.32
1986
0.11
-0.14
-0.32
1987
0.26
0.24
0.23
-0.24
1988
-0.04
0.36
0.34
-0.32
1986
-0.06
1987
0.18
-0.01
0.096
-0.09
1988
0.09
-0.29
0.43
-0.17
Valerenale
G
G
Plant height
Year
-)
Rootproduction
Character
"ffl
_C
IT)
Essential oil %
-0.08
0.17
jeno" bernAth
92
Table 6
CULTIVATION OF VALERIAN
Chemical compound
Year
1987
0.65
0.61
0.64
0.03
1988
0.00
0.33
0.75
-0.19
0.76
0.76
0.08
0.18
-0.08
0.06
0.61
0.23
0.33
0.09
Hydroxy-VA (HVA)
1987
Acetoxy-VA (AVA)
1987
1988
1988
Valerenale (VAL)
1987
1988
Acetoxy- VA
reproductive organs, male sterility appeared and biomass production was reduced.
However, from the point of view of plant breeders the increase of both morphological
93
Valeranale
Essential oil %
0.17
-0.22
In
respect of the essential oil the individual values of the original population were near the
mean (0.34 %) with low variability. After self-fertilisation the quantitative distribution
of the essential oils became heterogeneous and values as high as 0.470.54 % were
recorded. These results emphasise the importance of self fertilisation in the selection
of new varieties.
Crossing experiments
Evaluating the data which were shown in the Table 5., it is obvious that the "r" values
are much below the values expected and the variability affected by the condition of the
year is rather high. Only the existence of a negative correlation between the number of
leaflets and accumulation of valerenic acid and valerenal are worth mentioning. The
absence of the correlation between morphological characters and level of active
constituent is emphasised by other publications approaching the subject from ecological
point of view (Bernath et al. 1975).
The existence of correlation between the compounds has been proven by mathema
tical analysis (Table 6.).
theoretical and practical point of view and is not neglected by the considerable influence
of the year which was chosen for the investigation. Based on the existing correlation
the parallel increase of valerenic acid (VA), valerenal (VAL) and hydroxy valerenic acid
(HVA) is expected by the systematic selection. A slight negative correlation was found
between the accumulation of valerenic acid and the accumulation of the essential oil.
The absence of correlation fort valepotriates and essential oils has been mentioned by
other authors (Bernath et al. 1975).
SELECTION
Self fertilisation of the species
The advantage of using self-fertilising lines was mentioned at first by Czabajska (1964)
and Shugaeva (1979). Some years later the result of self-fertilisation using individuals
of 'Kordiola' cultivar was reported by Konon and Novikova (1981). When the vitality
of the inbred lines and the original population were compared the negative effect of
self fertilisation became obvious. While the seed production of the control plants was
as high as 2-15 g, many of the self fertilised plants became sterile and the average seed
production of individuals decreased to 0.20-0.41 g. At the same time the germination
power and the germination percent of the seeds, which were collected from self fertilised
plants was also reduced. The plants which were grown from these seeds showed many
negative characters associated with self-fertilisation; deformations were observed in
pollen donor. When it was used as a pollen donor the valerenic acid content in Fl
generation was 90 mg% or higher in the majority of individuals (85%). In contrast if
the line was used as a mother plant the ratio of individuals accumulating high amount
of valerenic acid decreased to below 42 %.
It was concluded by Noller (1989) that, taking into consideration
the polyploid
46 inbred generations
needed from tetraploid plants. To clear up the additive genetic variance the application
of the "Chain block design" strategy was proposed by Noller and Vomel (1989). Additive
gene effect on 0.02 significance was determined by the German research group in relation
of the VA, VAL accumulation level as well as in production of VA and VAL compounds
(Table 7.).
Cultivars and cultivated populations
The efficacy of the selection of valerian is moderate compared with the large agricultural
crops, even compared with the results that have been achieved in the case of some
other medicinal plants. The selection process has been hindered by many factors. The
Table 7
Chemical character
Production (mglplant)
91.0
3.7
Valerenale (VAL)
84.3
1.2
Significance level
0.001 %
95
CULTIVATION OF VALERIAN
jeno bernAth
94
CULTIVATION
the stabilisation of the characters required. The goal of the selection should be the
stabilisation of different production-biological and chemical characters, which may
Location
correlate to each other negatively. From a selection point of view there are other
Valerian can be cultivated successfully in almost any area of Europe and many parts of
Asia, where the natural precipitation is about 600-700 mm/year. For germination, light
and a moderately high temperature (about 20C) is also required. Valerian prefers
medium loam or sandy loam soils, which have a medium humus content. The root
system grows well in chernozem and peat soils, with a high humus content, but
these ought to be avoided because of the difficulties arising from the adhesion of soil
particles in postharvest processing. The location must be well supplied with moisture
difficulties, which are generated by the advancement of chemical and biological science
discovering new compounds continuously So the goal of the selection has to be modified
from time to time. Taking into consideration the above mentioned facts, four periods in
the selection of valerian can be distinguished.
The first period of the selection of valerian is dated back to the early 1930s. The
selection of the native populations was started by evaluating their morphological and
'Oberlausitzer Schmalblatriger Baldrian' surpass the earlier cultivars in both root and
essential oil production.
The second period of the selection of valerian was connected with the introduction
of "population analysis" begun in the middle of 50s (Eisenhuth 1956). The result of
this period was the registration of the cultivar "Merkator" in Germany. Its root and
essential oil production were about 20 % higher than earlier cultivars. However, this
cultivar had to be propagated vegetatively which was a great disadvantage to its
commercialisation. The results achieved in selection of valerian by Czabajska (1958) at
this time should also be mentioned.
The third period of the selection of valerian started in the early 1970s. The stabilisation
of the production was chosen as the main aim of the selection. The weakness of the
former cultivars became obvious in the course of cultivation. The yield and the quality
of the root showed much more variability than was tolerable to the farmers. The selection
of the resistant materials with high essential oil production had been started. At that
time the isolation of the biologically active valepotriates had a remarkable effect on
further selection process. Well-known varieties introduced in this period were: Anthos'
(East-Germany), 'Samokov' (Bulgarian") and 'Polka' (Polish).
that the idea of the selection process has to be modified to give more attention to the
chemical constituents, especxially for essential oil, valepotriates and valerenic acid.
Furthermore the parallel checking of biomass production as well as the accumulation
of many special compounds (essential oil, valerenic acid, valeranone, cyclopentansesquiterpenes) are suggested by working group of Bos et al. (1986).
....
Valerian can be successfully cultivated after almost any agricultural crop, because it does
not show special requirement with regards to the previous plant (Hornok, 1992).
However, crops with perennial roots like lovage, liquorice, peppermint are not the best
ones to precede cultivation of valerian.
If planting is done in the autumn after the early harvest of the previous crop medium
to deep ploughing is necessary just after harvesting. It is followed by harrowing or
cultivator operation combined with fertiliser supply. The field up to the time of the
planting must be kept clear from weeds. In the case of the spring planting, deep ploughing
is necessary in the previous autumn and the soil has to be prepared for planting in early
spring.
Sowing
Valerian can be propagated both by seeds and vegetatively using root segments (Boros
1980). The vegetative propagation method is applied only in the case of varieties which
are able to develop large amount of stolons. Vegetative propagation may have another
disadvantage. The plants frequently form flower shoots in the first year of cultivation,
which appears to restrict root development. The effectiveness of vegetative propagation
is also dependent on the ecological properties of the cultivation area. According to
Heeger (1956) the optimum yield of root can be obtained at the end of the first vegetation
cycle using vegetative propagation in a moist environment, while only after the second
one if the climate is dry.
The seeds of valerian can be sown at various times of the year and by different
methods. Direct sowing is widely used in the more humid areas (in some districts of
Poland and Ukraine). Catizone et al (1986) proposes the direct sowing in autumn using
50 cm row distance and 3 kg/ha seed dosage. Under Yugoslavian conditions (Kisgeci et
al 1987) the optimum time of direct sowing seems to be later, in October or in the
first half of November, and with higher amount of seed (7-10 kg/ha). Studies by Hotyn
et al (1967) revealed that the time and the form of the direct sowing is determined by
the local climatic conditions. Evaluating the cultivation trials made in Belorussia, Ukraine
and West-Siberian regions the success of the direct sowing is dependent on the ecological
jeno bernAth
CULTIVATION OF VALERIAN
conditions preceding wintering. The plants have to reach the development phase of
3-5 leaves before the cold period which is a precondition of successful wintering. A
special method is applied when valerian is grown together with a second crop. In Russia
barley, rye and oats are often intermixed with valerian. In this case the amount of
propagative material of valerian is decreased by about 20-25 %, and the second crop is
harvested in spring for fresh biomass.
pre-emergent treatment should be done with 2.5 - 3.5 kg/ha Aresin. If the plantation is left
to spring the dosage of Aresin has to be reduced to 2.5 - 3.5 kg/ha. Keeping the plantation
clear of weeds afterwards can be achieved with 2.5 -3.5 kg/ha Patoran or Maloran if the
However in some countries, especially in Hungary, France and Poland nursery sowing
in open-air seedling beds has proved to be the most reliable and economic way of
fungicides.
96
In the case of nursery sowing the procedure has to be started between the end of
June and early August. The seeds should be sown into well-prepared open-air seedling
beds on the surface of the soil using 15-20 cm row distances. According to the literature
(Catizone et al. 1986, Kisgeci etal. 1987) 1-2 g of seeds is required for 1 m2 area. The
seeds are covered afterwards with compost very carefully using no more than 1 mm
layer About 0.5-0.7 kg seed is required to grow seedlings for one hectare cultivation
area and 500-700 m2 nursery surface. One of the preconditions of good development
of seedlings is regular irrigation. The nursery should be slightly shadowed in order to
reduce the water loss through evaporation until the appearance of the first leaves. The
period which is needed for the seedlings to achieve this is about 2.0-2.5 months.
Planting
The seedlings can be planted into the field when they reach the 15-17 cm size at the end
of September (Bernath 1994), or in spring (Perrot and Paris, 1974) using machines. To
allow sufficient time for rooting, the plantation time must be about 1-2 months before
the first frost occurring in the cultivation area, spring planting should be avoided. If it
is necessary, it should be done as early as possible, not later than April. However, using
this cultivation form the yield is generally about 20-25 percent less compared to autumn
culture. If the plantation is cultivated by hand the optimum distance between rows is
30-35 cm and 20-25 cm between individual plants. In the case of mechanised cultivation,
the row distance should be larger, 50 cm at least, with the same placing in the rows.
However the row distance may vary from country to country. Large 60-80 cm row
distances are proposed by Catizone etal. (1986), Perrot etal. (1974) and Heeger (1956),
while 30-40 cm by Kisgeci et al. (1987) and 50 x 25 cm spacing by Racz et al. (1984).
However on the basis of investigation of Berbec (1968) the optimum spacing is about
40 x 40 cm. The difference in spacing may also depend on the various ecological
conditions and the local cultivation methods.
97
Harvesting
Valerian which has been planted in the autumn can be harvested in the next year in
October. The harvest of the spring culture is done in the year of plantation, very rarely
in the next one if the climatic conditions are exceptionally disadvantageous. The optimum
time for root harvest is in the second half of October or first half of November.
Sometimes the root is left in the ground for wintering just prior to the start of vegetation.
This cultivation practice has many disadvantages and may result the decreasement of
the accumulation level of active constituents.
Before taking off the roots the above ground parts of the plants should be cut using
mobile chaff-cutter machines. After this procedure the roots can be taken up with a
plough from which the steering plate has been removed, or by the help of potato
harvesting machines. In both cases the effectiveness of the operation is largely dependent
on the soil conditions. The roots are usually gathered by hand, put in piles so that the
green parts can be removed and the soil particles shaken out.
The roots are washed with water using basket immersion or a water jet. The material
should be dried at 40-50 C temperature without any delay. Many authors propose
much lower (25-35 C) temperature conditions to avoid the loss of active constituents
(Boros 1980, Catizone etal. 1986). During the drying process and subsequently in storage
valerian should be separated from the other drugs, owing to its strong smell.
The drug of valerian must be stored in confined place, to avoid the contamination by
cats which are often attracted by its smell.
Care of plants
Seed production
After wintering, the plantation has first to be rolled. This is an important action especially if
the root system of the plants has been disarranged as a result of winter frosts. The plantation
requires two or three weedings and hoeings. Because of the high water requirement of the
species (Berbec 1965) irrigation is necessary under more arid conditions to get satisfactory
biomass production. Chemical weed control is also used and, in the case of autumn planting,
Production of seed material for propagation purposes needs special care and technology
because of the continuous ripening and dropping of the seeds which starts after
flowering.
In the small scale production of seeds the flower heads of the plants are used
individually wrapped up in paper sheets or bags at the beginning of flowering. The
98
jeno bernAth
seeds fall down into the bottom of the wrapping. This method is effective, if the weather
conditions are appropriate. Heavy rain makes the paper sheet or bag wet and the seeds
start to germinate or rot and strong winds may harm the paper cover resulting in
considerable losses. The other disadvantage of this method is that the wrapping and
gathering of the seeds is labour-intensive.
CULTIVATION OF VALERIAN
99
In many countries a two stage method is used for producing seeds. In this case the
flowering shoots of plants are cut while green and the the first seeds are starting to
ripen. The shoots are gathered and stored in a dry and covered place having appropriate
air circulation. When the majority of seeds reach the maturity stage they should be
thrashed out. The seed yield depends on climatic conditions and on the methods of
cultivation and harvesting. In these circumstances the yield can vary in a wide range,
Goldblatt, P.Johnson, D.E. (1990) Index toplantchromosome numbers, 1986-1987. Missouri Botanical
11, 271-286.
Evstatieva, L.N., Handjieva, N.V, Popov, S.S., Pashankov, P.I. (1993) A biosystematic study of
Valeriana offidnalis (Valerianaceae) distributed in Bulgaria. Plant Sjstematics and Evolution. 185,
167-179.
Golcz, L., Kowalewski, Z. (1958) Wyniki doswiadczen nawozowycha kozlkiem lekarskim {Valeriana
offidnalis'L.) BiulJnst.RosUnLec^nychych. 4, 107-113.
Garden, 30.
REFERENCES
Auster, F., SchaferJ. {1958) Ar%neipflan%en. 18. ValerianaoffidnalisL. VEB GeorgThieme, Leipzig.
1-44.
Berbec, S. (1965a) Influence of soil humidity on the growth, yield and quality of the raw material
of valerian. Ann. Univ. Mariae Curie-S'klodowska, Lublin-Polonia, 20, 216-231.
Berbec, S. (1965b) Influence of various doses of calcium on the growth, yield and quality of the
raw material of valerian. Ann. Univ. Mariae Curie-Sklodowska, Lxblin-Polonia, 20, 233-249.
Berbec, S. (1970) Some problems from the biology of seed germination of common valerian
{Valeriana offidnalis L.) Ann. Univ, Mariae Curie-Sklodowska, Lublin-Pobnia, 25, 143-152.
Berbec, S. (1968) Influence of spacing and hoeing on the quantity of the yield of valerian
{Valeriana offidnalis L.). Annales Universitatis Mariae Curie-Sklodowska, Lublin, Polonia 23
323-338.
Bernath, J., Foldesi, D., Lassanyi, Zs., Zambo, I. (1975) A tapanyag-ellatottsag es a talajtipus
hatasa a macskagyokerre {Valeriana offidnalis L.ssp. collina (Walr.). II. Az illoolaj es valepotriat
tartalom valtozasa. Herba Hung. 14, 37^6.
Boros, G. (1980) Heil- und Teep/lan^en. Verlag Eugen Ulmer, Stuttgart, 28-29.
Bos, R., Putten, F., Hendriks, K, Mastenbroek, C. (1986) Variation in the essential oil content and
composition in individual plants obtained after breeding experiments with Valeriana offidnalis
strains. Progress in Essential Oil Research. Walter de Gruyter Co., Berlin-New York, 123-130.
Bosetto, M., Fusi, P., Arfaioli, P. (1987) Indagini sull'influenza della fertilizzazione azoto-fosfopotassica sulla resa principio attivo (valepotriati) della Valeriana offidnalis L. Agrocbimica 31
254-264.
Catizone, P., Marotti, M., Toderi, G., Tetenyi. (1986) Coltiva^ione dellepiante medidnali e aromatiche.
Patron Editore, Bologna, 283-287.
Corsi, A., Lokar, L., Pagni, A.M. (1984) Biological and phytochemical aspects of Valeriana offidnalis.
Biochem.Sjst.Ecol. 12, 57-62.
Gzurjan, M.S., Manashjan, K.S. (1980) Osobennosthi stroenia lista i kornia valeriani lekharstevennoi
v ushloviah pktiroi gidroponiki. I%d. Akad. Nauk Arhmanskoi SSK 20, 132-141.
Heeger, E.F (1956) Handbuch desAr^nei und Gewiir%pjlan%enbaues. Deutscher Bauern-Verlag, Berlin,
693-705.
Hotyn, A.A., Gubanov, LA., Kondratenko, P.T., Seberstov, V.V (1967) Lekarstvennie rasthenia SSSR.
Izdatelstva, 'Kolos', 65-74.
Kempf, I. (1986) Grundlagen ^urZuchtung von Valeriana offidnalis L. Baldrian. Justus-Liebig-Universitat,
Gissen, Dissertation, p. 206.
KisgeciJ., Adamovic, D., Kota, E. (1987) Proi^yodnja iiskoriscavanje lekovitog bilja. Nolit, Beograd,
139-143.
Konon, N.T. (1978) Biologia cvetenis i ophilenia valeriani lekharstvennoi v moskovskoi olasthi.
Rast.Rsursi 14, 73-77.
Konon, N.T., Novikova, N.L. (1981) Reakcia valeriani lekh arstvennoi na inbriding. Rast.Resursi,
17, 85-90.
Kuznechova, G.K., Konon, N.T., Sain, S.S., Pomanenko, V.I. (1984) Photostimulatia semian
katharanthusa rozovogo i valeriani lekarsthvenoi predposevnim oblucheniem. KonferendaProblemi
photoenergetiki rastheni ipovishenie urasainosti. Tezis dokladov. (3-5 April, Livov) 160-161.
Lewkowicz-Mosiej, T. (1984) Problemy uprawy kozlka lekarskiego. Wiad.Ziel. 26, 1-2.
Nedkov, N.K., Slavov, S.I. (1989) The effect of irrigation on valerian root yield. Rasteniep'dni.
Nauki. 26, 21-24.
Noller, P. (1989) Untersuchung der Variabilitat von Valerensauren, Valerenal and Valeranon in
Wildpopulationen und Zuchtmaterial von Valeriana offidnalis L. Justus-Liebig-Universitat, Gissen,
Dissertation, p. 165.
Noller, P., Vomel, A. (1989) Breeding experiments as indications for the variance components of
some cyclopentan-sesquiterpenes of Valeriana offidnalis L. XII. Eucarpia Congress, 1989. Vortrag
jurPflan%en%iichtung, 15.
Perrot, E., Paris, R. (1974) Les Plantes Medidnales. Presses Universitaires de France, 237-238.
Racz, G, Racz-Kotilia, E., Laza, A. (1984) Gydgynove'nyismeret, Ceres Konyvkiado, Bukarest,
257-260.
100
JEN6 BERNATH
5.
Titz, W, jurenitsch, J., Gruber, J., Schabus, I., Titz, E., Kubelka, W (1983) Valepotriate und
atherisches 61 morphologisch und chromosomal definierter Typen von Valeriana offidnalis s.l.
Sci.Pharm. 51, 63-87.
Titz, W, Titz, E. (1982) Analyse der Formenmannigfaltigkeit der Valeriana offidnalis - Gruppe in
CONTENTS
INTRODUCTION
Crude drug
Tinctures
Botanical Aspects
Macroscopy
Microscopy
Chemical Tests
Crude drug
Tinctures
101
102
VALERIAN: QUALITY ASSURANCE OF THE CRUDE DRUG AND ITS PREPARATIONS 103
ASSAY PROCEDURES
CH2OR3
CH2OR3
Tincture residue
R9O
R?O
Valepotriates
Spectrophotometry
Titrimetry
Valtrate
Didrovaltrate
TLC
R} = R2 = COCH2CH(CH3)2
Ri = R3 = COCH2CH(CH3)2
GC
R3 = COCH3
R2 = COCH3
HPLC
Is ovaltrate
R! = R3 = COCH2CH(CH3)2
IVHD
R2 = COCH3
R} = COCH(OCOCH2CH(CH3)2)CH(CH3)2
R2 = COCH2CH(CH3)2
R3 = COCH3
Ace valtrate
R! = COCH2C(CH3)2OCOCH3
Baldrinals
R2 = COCH2CH(CH3)2
TLC
R3 = COCH3
HPLC
Figure 1
Essential Oil
GC
GC-MS
INTRODUCTION
The three most important Valeriana species used in herbal medicine in Europe are
Mixed Constituents
TLC
HPLC
valerian). The roots and rhizomes of the three species are all used as mild sedatives, but
show large differences with regard to their constituents. Consequently, phytomedicines
prepared from these species are characterized by different chemical compositions (Hansel
STORAGE CONDITIONS
It is still not fully clear which constituents are to be held responsible for the sedative
action, but the valepotriates (Figure 1) as well as valerenic acid and its derivatives
REGULATORY ASPECTS
Present Situation
Future Developments
divided into two main groups: the diene type (valtrate, isovaltrate and acevaltrate) and
REFERENCES
1992). Quality assurance and quality control of the crude drug and its preparations
should therefore be based on these major groups of secondary metabolites.
VALERIAN: QUALITY ASSURANCE OF THE CRUDE DRUG AND ITS PREPARATIONS 105
H.J. WOERDENBAG ET
104
CH2OR
CHO
COOH
Baldrinal
R= H
R = COCH3
Hydroxyvalerenic acid
R = OH
Homobaldrinal
R = COCH2CH(CH3)2
Figure 2
Figure 3
Hendriks and Bos 1984; Bos et aL, 1986) and V. wallichii (Bos et aL, 1992). In V. edulis
only trace amounts of volatiles are present (Hendriks and Bos 1984; Steinegger and
Hansel 1992; Bos et aL, 1997d). In Table 1 a survey is given of the contents of these
groups of compounds in the three valerian species, as reported in the literature.
All three species are used for the production of solid, oral dosage forms, while from
V. offidnalis also tinctures and a tea are made (Bos et aL, 1996a). Phytomedicines that are
standardized on valepotriates are mostly prepared from V. wallichii and V. edulis^ because
these species are relatively rich in valepotriates (Wichtl 1989).
Another relevant group for analysis is formed by the baldrinals (Figure 3), yellowcoloured decomposition products of the valepotriates. Baldrinal originates from valtrate
and acevaltrate; homobaldrinal from isovaltrate (Steinegger and Hansel 1992; Bos et aL,
1997a). As cytotoxic and mutagenic effects have been described for the baldrinals
(Bounthanth et aL, 1981; Braun eta/., 1986; Von der Hude et aL, 1986; Dieckmann 1988),
their absence in the crude drug and in preparations has to be proved in order to avoid
possible hazardous effects (Bos et aL, 1996a).
At present, there is some discussion about the safety of valepotriates as well. Due to
the reactive epoxy group, valepotriates possess alkylating properties. Cytotoxicity and
Table 1
Contents -based on dry weight- of the major groups of compounds in three valerian
valepotriates (%m/m)
and derivatives
V. offidnalis
0.1-0.5
0.8-1.7
0.5-2.0
K wallichii
absent
1.8-3.5
0.1-2.0
V. edulis
absent
8.0-12.0
"The volatile compounds that are obtained after distillation of the roots of this plant also
include valeric, isovaleric and hydrovaleric acids, as well as several decomposition products
formed upon heating of valepotriates
mutagenicity in in vitro cell systems have been described. The compounds have been
shown to inhibit DNA and protein synthesis in in vitro cultured mammalian cells
(Bounthanth et aL, 1981, 1983, Von der Hude et aL, 1985, 1986; Hansel 1990, 1992;
Keochanthala-Bounthanth et aL, 1990,1993). It is yet unclear to what extent these toxic
effects are relevant for humans after ingestion of valepotriate-containing preparations
(Bos etaL, 1997a). However, more and more preference is given to valerian preparations
that are devoid of the potentially hazardous valepotriates and baldrinals (De Smet and
Vulto 1988; Hansel 1992). Tinctures and teas, prepared from roots and rhizomes of
V. offidnalis, that is officinal in the European Pharmacopoeia 2nd edn, meet this demand
(Hansel and Schulz 1985: Schimmer and Roder 1992; Bos etaL, 1996a).
106
H. J. WOERDENBAG ETAL.
In this chapter analytical aspects related to the medicinally used valerian species are
discussed. Pharmacopoeial aspects are dealt with, and analytical procedures to assay the
different groups of secondary metabolites, as described in the literature, are presented
and discussed.
PHARMACOPOEIAL QUALITY ASSURANCE - IDENTITY
VALERIAN: QUALITY ASSURANCE OF THE CRUDE DRUG AND ITS PREPARATIONS 107
ethanol 70% (v/v). The ethanol content is 63.5-69.0% (v/v). The drug residue is at least
3.0% (m/v) (for assay see under 'Assay procedures (qualitative and quantitative
determinations)').
Introduction
Valepotriates were extracted only with ethanol concentrations above 70% (v/v). This
means that if 70% (v/v) ethanol is used to prepare a valerian tincture, the extraction of
Crude drug
Pharmacopoeial aspects for the crude drug include a definition, and macroscopical and
microscopical description of the crude drug, identity and purity reactions, and an assay
for a quantitative determination.
Valerianae radix or valerian root is listed in the current European Pharmacopoeia, 2nd
edn (1993). Hence, this monograph is also part of, among others, the German
Pharmacopoeia, 'Deutsches Arzneibuch 10', the French Pharmacopoeia, 'Pharmacopee
Francaise X', the British Pharmacopoeia 1993, and the Dutch Pharmacopoeia,
Valerian was included in the second edition of the Indian Pharmacopoeia (1966) and
defined as the dried rhizomes, stolons and roots of Vaieriana wallichii DC. This monograph
is not included in the current third edition. V. edulis has been included in the Mexican
Pharmacopoeia. No monograph on valerian is found in the United States Pharmacopeia,
USP 23 / National Formulary, NF 18 (1995).
Botanical Aspects
Macroscopy
Vaieriana officinalis
The European Pharmacopoeia 2nd edn (1993) describes the morphology of the crude
drug as follows. The rhizome is yellowish-grey to pale greyish-brown, obconical to
Valerian root has a characteristic and penetrating odour, resembling that of valeric
Tinctures
and 10 parts of extraction solvent or 1 part of drug and 5 parts of extraction solvent.
Limits are given for methanol and 2-propanol: not more than 0.05% (v/v) of each of
these alcohols is allowed. It is furthermore stated that a tincture should comply with
limits prescribed for relative density, ethanol content and drug residue, however, without
giving the limits.
According to the Dutch Pharmacopoeia 6th edn, 2nd printing (1966), valerian tincture
is prepared by maceration from 1 part of valerian root and 5 parts of ethanol (70% (v/
v)). The tincture has a brown colour. The relative density of the tincture is 0.897-0.907
(at 20C). The drug residue is at least 2.5% (m/v).
According to the German Pharmacopoeia, 'Deutsches Arzneibuch', DAB 10 (1993),
a valerian tincture is prepared by percolation of 1 part of valerian root with 5 parts of
acid and camphor. The taste is somewhat sweet at first, then spicy and slightly bitter.
Properly dried material has the odour of the fresh essential oil, without a note of valeric
acid. Only poorly dried or old material is characterized by the valeric acid odour.
Vaieriana wallichii
The Indian Pharmacopoeia 2nd edn (1966) describes the macroscopical characters of
the crude drug as follows. Indian valerian consists of dull yellowish-brown rhizomes, 48 cm long and 4 to 10 mm thick, and a very variable amount of roots up to 7 cm long
and 1-2 mm thick. The rhizomes are unbranched and somewhat flattened dorsiventrally.
The upper surface bears leaf scars and the lower surface roots or root scars. The rhizome
breaks with a short fracture, and the horny interior shows a small dark bark, a wellmarked cambium, about 12-15 light-coloured xylem bundles and a dark pith and medullary
rays. Stolons connect the rhizomes, are stout, 1 to 5 mm long and 2 to A mm thick,
yellowish grey in colour, longitudinally wrinkled usually with nodes and internodes and
bearing adventitious roots. Occasionally thin stolons, 1 to 2 mm thick, are found. Roots
are yellowish-brown, 3 to 5 cm long and 1 mm thick. The odour is strong and reminiscent
of isovaleric acid. The taste is bitter and somewhat camphoraceous (Evans 1989).
T
108
K j. WOERDENBAG ETAL.
VALERIAN: QUALITY ASSURANCE OF THE CRUDE DRUG AND ITS PREPARATIONS 109
Vakriana edulis
Microscopy
Vakriana officinalis
The European Pharmacopoeia 2nd edn (1993) describes the microscopical characters
of the crude drug as follows. The transverse section of the root shows small, suberised
epidermal cells, some with root hair. The exodermis consists of one or occasionally two
layers of larger, suberised cells, often containing droplets of essential oil. The outer
cortex comprises two to four layers of resin-containing cells with thin collenchymatous,
sometimes suberised walls. The inner cortex is composed of numerous layers of
polygonal to rounded cells filled with starch. The starch granules are simple or compound.
The simple granules are rounded, 5-15 um in diameter, sometimes showing a cleft or
stellate hilum. The compound granules, with two to six components, are up to 20 \im in
diameter. The endodermis consists of a single layer of suberised, tangentially elongated
cells. The pericycle is continuous and starch-filled. Parenchyma surrounds the phloem
zone. The cambium is frequently indistinct. The vascular bundles form an interrupted
CH2OR3
ORi
The rhizome in transverse section has a different anatomy from the root. Its structure
is complicated by the presence of numerous vascular bundles coming from the roots
and stolons. The epidermis and exodermis are partly replaced by poorly developed
periderm. The central pith is wide and has cavities of various sizes, the larger ones being
separated by plates of partially sclerified tissue.
The powder is light brown and is characterized by numerous fragments of parenchyma
with rounded or elongated cells and containing starch granules as described above. Also
present are cells containing light-brown resin; rectangular sclereids with pitted walls, 515 um thick; xylem, isolated or in non-compact bundles, 10-50 \xm in diameter; some
CH2OR3
CH2OR3
O'
Cyclopenta-[c]-pyrylium salts
Figure 4
It is difficult to see the difference under the microscope between the pulverized
roots of the three valerian species. Thin-layer chromatography, to determine the presence
of valerenic acid, is the best method to prove the identity of V. officinalis (Wichtl 1989).
Vakriana wallichii
followed by about 20 collateral vascular bundles, which in young stolons are separated
Pith wide and lacunar. Root traces are absent. Roots have small central parenchymatous
The Indian Pharmacopoeia 2nd edn (1966) describes the microscopical characters of
the crude drug as follows. The rhizome-cork consists of 4 to 14 layers of lignified
suberised cells, that occasionally contain oil globules. The cortex is parenchymatous and
contains numerous starch grains, oil globules an a yellowish-brown substance. The outer
2 or 3 layers of cortex are collenchymatous and occasional root traces appear as paler
strands. The endodermis is one layered. The pericycle is parenchymatous and within it
12 to 18 collateral vascular bundles, separated by dark medullary rays, are present. The
pith is large, parenchymatous, lacunar and contains starch grains. Starch occurs as single
or occasional compound grains of two components, individual grains being 7 to 30,
mostly 10 to 25 ^.m, in diameter. Calcium oxalate is absent.
Vakriana edulis
No microscopical description is known.
Chemical Tests
Crude drug
The identity test for V. officinalis in the European Pharmacopoeia 2nd edn (1993) consists
of the addition of a mixture of equal volumes of glacial acetic acid (98% (m/m)) and
110
hydrochloric acid (25% (m/v)) to a methylene chloride extract of the freshly powdered
drug and the formation of a blue colour within 15 minutes.
This test shows the presence of valepotriates. Valepotriates are lipophilic compounds
that are extracted from the drug by methylene chloride. With the acetic acid-hydrochloric
acid mixture blue coloured cyclopenta-[c]-pyrylium salts (pseudoazulenes) are formed
VALERIAN: QUALITY ASSURANCE OF THE CRUDE DRUG AND ITS PREPARATIONS 111
After acidification, the sesquiterpene carboxylic acids are extracted with methylene
chloride. This procedure to check the identity of valerian tincture can also be used to
prove its purity, because falsifications are recognized with this procedure. It should be
noticed that hydroxyvaleric acid is not a genuine constituent of V. officinatis; the acid
originates from acetoxyvaleric acid after alkaline hydrolysis.
1 (1975) identity test comprises a TLC identity reaction for a stored mother tincture,
that differs from a freshly prepared mother tincture (see above). Valepotriates are not
This identity reaction, however, is not specific for V. officinatis. The roots of other
Vakriana species, which also contain valepotriates of the diene type, will give a positive
detectable in a stored tincture. Here, constituents of the essential oil are analysed.
The system used consists of silica gel with methylene chloride as the mobile phase.
reaction as well (Hartke and Mutschler 1987). A conclusion about the identity, however,
will be possible after other tests have been carried out. The identity of V. officinatis can
be based on the purity test of the European Pharmacopoeia 2nd edn (1993), using TLC
(see below). In that test the presence of valerenic acid and derivatives, which are
characteristic of V. officinatis, is checked. In addition, HPLC methods are available to
determine the characteristic valepotriate composition of the crude drug, as well as
valerenic acid and its derivatives. These assays, however, are not (yet) included in the
chromatoeram
of the reference solution shows a brown-violet zone of borneol in the
o
lower part and a brown-violet zone of bornyl acetate in the upper part. Related to
bornyl acetate (RRf 1.0), borneol has an RRf of 0.4. In the chromatogram of the test
European Pharmacopoeia.
Tinctures
The German Pharmacopoeia, DAB 10 (1993), determines the identity and purity of
valerian tincture by TLC using silica gel and glacial acetic acid (98% (v/v))-ethyl acetatehexane 0.5:35:65 as the mobile phase. The tincture is treated with aqueous KOH and
washed with methylene chloride. The remaining aqueous layer is acidified and extracted
with methylene chloride to provide the test solution for chromatography. Methanolic
solutions of fluorescein and Sudan red G are used as references. Detection after
development is effected by spraying with anisaldehyde/ sulphuric acid reagent.
The chromatogram of the test solution shows an intense blue zone at about the Rf
solution violet zones with RRf values of 0.3, 0.8 and 1.1 as well as a red zone with an
RRf of 1.6, related to borneol (RRf 1.0) and violet zones with RRf values of 0.8, 1.0, 1.2
and 1.5, related to bornyl acetate (RRf 1.0) are found.
According to the European Pharmacopoeia 2nd edn (1993) the purity of the crude
drug Vaierianae radix is determined by TLC, using silica gel and a mixture of ethyl acetate-
of fluorescein due to hydroxyvalerenic acid and a violet zone at about the Rf of Sudan
red G of valerenic acid. In the upper part of the chromatogram several other faint red
to violet coloured zones are found.
As a test solution the same methylene chloride extract as used for the identity reaction
(see above) is employed and methanolic solutions of aminoazobenzene and Sudan red
G are used as references. Double development is employed and detection is achieved
In a tincture prepared from Vakriana species other than V. officina/is, the zones of
valerenic acid and hydroxyvalerenic acid are absent.
This TLC method is similar to that described by Hansel etal. (1983), with the difference
The chromatogram obtained with the test solution should show in the middle, at an
that these authors used a solution of 1 mg vanillic acid and 2 mg anisaldehyde in methanol
R value between those of the pink zone (Sudan red G) and of the orange zone
(aminoazobenzene) in the chromatogram of the reference solution, a deep-violet zone
(valerenic acid) and sometimes above this zone a greyish-brown zone (valtrate and
isovaltrate). Furthermore, a faint violet zone (acetoxyvalerenic acid) with an Rf value
lower than that of the zone due to aminoazobenzene is seen, as well as grey zones
situated between the zone due to valerenic acid and the starting point, a number of
violet zones of variable intensity in the upper part of the chromatogram, and a mostly
as the reference solution. To valerenic acid an Rf value of 0.4-0.5 (just above anisaldehyde)
was assigned, and to hydroxyvalerenic acid an Rf value of 0.07-0.12 (just below vanillin
acid).
Valerenic acid and acetoxyvalerenic acid, that are characteristic of V. officina/is, can be
detected immediately in the tincture. However, a purification step is added to the
procedure. Tinctures that are prepared from Indian or Mexican valerian contain neutral
substances that can disturb the detection of the two acids. The acids are converted into
their corresponding potassium salts. The disturbing neutral compounds can now be
removed from the aqueous phase by extraction with methylene chloride. Acetoxyvalerenic
available as reference substances until recendy, the location of the spots due to these
compounds are related to the location of Sudan red G and aminoazobenzene. Nowadays
112
H. J. WOERDENBAG ETAL.
(iso)valtrate and valerenic acid can be purchased. The purity test is selective for
V-Jonahs.because the presence of valerenic acid and derivatives is checked Harke
and Mutschler 1987). In addition, essential oil components are also separatedTus^g t
The chromatographic tests prescribed to establish identity also serve as a method
whereby impurities, particularly species related to the required Valenanal "an be
HABTl1975)^rTLCameAmdeOPathiC
PharmaCOpOek''Hom6oPatischesAr2neibuch',
rM r i i
,
described as a purity test for Valerianae radix as well as
for a freshly prepared mother tincture. The same test was described in the European
Pharmacopoeia 1st edn (1975). Here, silica gel with a fluorescence indicator (Gf"
used as the stationary phase with hexane-methyl ethylketone 8:2 as the mob k phase
which is double-developed. A methylene chloride extract of the drug is uld or
mother tincture, and solutions of vanillin and amsaldehyde are used ;
S2 ^S
VALERIAN: QUALITY ASSURANCE OF THE CRUDE DRUG AND ITS PREPARATIONS 113
present as well, which are located in the upper half, i.e. above the zone due to valtrate
The essential oil components can be distinguished from the valepotriates by first spraying
the chromatogram with a mixture of glacial acetic acid-hydrochloric acid (25%/l:l.
The essential oil components colour purple to violet, whereas valepotriates yield greengrey (valtrate, acevaltrate), blue-green (isovaleroxyhydroxydidrovaltrate) and blue-grey
Other Tests
Extractives
According to the European Pharmacopoeia 2nd edn (1993) the extractable matter yield
The area corresponcUng to valtrate is now coloured greenish-grey and that correspond
using 96% ethanol for K officinalis should be not less than 15.0% w/w. The Indian
the lower part, a blue area having the same Rf of about 0.3 as the yellow area
The chromatogram obtained for the test solution shows, between the blue area
Pharmacopoeia 2nd edn (1966) uses 60% alcohol for V. wallichiiznd specifies a minimum
In the European Pharmacopoeia 1st edn (1975), this demand was included in the
definition of valerian root. However, the determination of the amount of extractable
matter is not a substitute for an assay, quantitating valepotriate and/or valerenic acid
and its derivatives (Bohme and Hartke 1978). Moreover, after harvesting the fresh roots
are washed. If the washing procedure has taken too long, the roots can leach, resulting
in a lower amount of extractable matter (Hartke and Mutschler 1987).
of
The blue area in the chromatogram obtained for the test solution, having the same R
of about 0.3 as the yellow area corresponding to vanUlm in the chromatogfam obS
to sthlcSyor
V.waWM and V. edufc may contain valepotriate hydnns, yielding violet-blue zones in
the chromatogram that are located immediately under the blue JL mentioned in tne
previous paragraph (Bohme and Hartke 1979). Valepotriate hydnns have the T
V7f T T ' u" ' '' FlJ111LCU LU lne ract tnat> n^t to the valepotriates located in the
halt of the chromatogram, components of the essential o.l of valerian root are
Ash values
According to the European Pharmacopoeia 2nd edn (1993) the sulphated ash should
not be more than 15.0% m/m.
When organic matter is incinerated as such, the residue found will depend of the
temperature used. For instance, alkali chlorides and earth-alkali carbonates are volatile
at certain temperatures. In the presence of sulphuric acid non-volatile sulphates are
ammonium carbonate is added at the end. The sulphated ash is a measure for the total
amount of inorganic matter in the plant material (B6hme and Hartke 1978).
Ash insoluble in hydrochloric acid
The maximum level set by the European Pharmacopoeia 2nd edn (1993) is 7.0%.
The ash insoluble in hydrochloric acid is the residue obtained after extracting the
sulphated ash with hydrochloric acid, calculated with reference to 100 g of drug. Non
volatile, inorganic impurities are determined, such as soil and sand. It is a control of the
114
H. J. WOERDENBAG ET AL.
VALERIAN: QUALITY ASSURANCE OF THE CRUDE DRUG AND ITS PREPARATIONS 115
ASSAY PROCEDURES
with sodium iodide in an ethanolic, acetate-buffered, acetic acid solution and the
As this reaction proceeds very slowly (24 h), Liptak and Verzar-Petri (1980) published
an improved titrimetric method with respect to time. The titration of valepotriates was
The European Pharmacopoeia 2nd edn (1993) requires a minimum of 0.5%v/m for
volatile oil in V. officinalis root. This test is a hydrodisfiliation in a special apparatus
where the distillate is collected in a graduated tube.
performed by opening the epoxide ring with hydrobromic acid using a methylene chloride
extract of the crude drug. This was put in the dark for 1.5 h. Subsequently, the flask was
put on ice and the reaction mixture was rapidly titrated with 0.01 N sodium acetate
solution. Just before the end of the titration 5 ml of a crystalviolet solution was added
as an indicator. The titration was continued until a blue colour appeared.
Tincture residue
The determination of the residue from evaporation of the tincture is described in the
Results of drug residue determinations, obtained in our laboratory for the three
Valeriana species discussed in this chapter: V. officinalis 28-31%, V. wallichii 21-46%,
V. edulis 29-30%.
Valepotriates
Spectrophotometry
The first procedure for a quantitative determination of valepotriates has been described
by Mannestatter etal (1968). They isolated 'Halazuchrom B' (= valtrate) from a valerian
extract, prepared with diethyl ether, after TLC on silica gel with methylene chloridemethyl ethyl ketone 9:1, or after column chromatography separation with hexane. Valtrate
was measured spectrophotometrically at 254 nm.
Valtrate was also converted into a deep-blue coloured product using hydrochloric
acid in methanol ('Halazuchrom-Reaktion') whereafter the absorbance was measured at
610 nm (Mannestatter etal, 1968). The identity reaction for V. officinalis, as described in
the European Pharmacopoeia 2nd edn (1993), is derived from this work.
As only diene valepotriates colour blue with hydrochloric acid, didrovaltrate cannot
(GF /) with double development using hexane-methyl ethyl ketone 8:2 as the mobile
phase. The spots were visualized under UV light (254 nm) and after spraying with
benzidine-hydrochloric acid reagent (0.1% benzidine in hydrochloric acid (25%)-glacial
acetic acid 1:1), followed by 160 min heating at 105C.
Under UV light, the largest zone is found at Rf 0.5-0.6 (equal to anisaldehyde), due to
valtrate. After the reaction with benzidine a series of coloured zones are seen. Valtrate
becomes green-grey and anisaldehyde yellow. In the lower part of the chromatogram a
blue zone is found at Rf 0.2-0.3 (equal to vanillin, yellow). Between the blue zone and
the valtrate zone, two smaller and less intensively coloured zones are visible, due to
didrovaltrate and acevaltrate.
The applied spray reagent was regarded as an improvement as compared with older
reagents. Spraying with 6 N hydrochloric acid (Mannestatter et al, 1967) yielded an
unstable blue colour with valtrate and acevaltrate. Also a mixture of equal volumes of
hydrochloric acid (25%) and glacial acetic acid only coloured the diene valepotriates
(Thies and Funke 1966). Antimony trichloride 22% in chloroform {Thies and Funke
1966; Mannestatter et al, 1967) did not give clear colours in daylight.
Benzidine is a carcinogenic agent; as a substitute, Stahl and Schild (1969) proposed a
solution of 0.1% 2,4-dinitrophenylhydrazine in hydrochloric acid (25%)-glacial acetic
acid 1:1 as a spraying reagent. As a disadvantage, a yellow background was obtained and
the fluorescence was less. As an advantage, the intensity of the colours due to valtrate,
acevaltrate (blue) and didrovaltrate (faint orange) was stronger.
indicator (GF2 J was used. -Hexane-methyl ethyl ketone 8:2 was used as the mobile
phase. The reference solution was the same as applied by Stahl and Schild (1969), or was
composed of reference valepotriates, 20 mg of valtrate, 20 mg of acevaltrate and 20 mg
116
H. J. WOERDENBAG ETAL.
Verzar-Petri etal. (1976) described the first GC method for the determination of valtrate,
acevaltrate and didrovaltrate. In addition, baldrinal could be detected. They used two
different stationary phases: 2% OV-1 and 3% OV-17.
A GC determination of valepotriates has also been described by Graf and Bornkessel
(1978). The substances, extracted by methylene chloride, were first separated using TLC.
The valepotriates were then eluted from their respective zones, and hydrolysed with a
VALERIAN: QUALITY ASSURANCE OF THE CRUDE DRUG AND ITS PREPARATIONS 117
0.5 N methanolic potassium hydroxyde solution in methanol (60 min at 70C). Each
valepotriate yielded isovaleric acid after the alkaline hydrolysis, that was subsequently
extracted with diethyl ether containing propionic acid as the internal standard. Tsovaleric
acid was determined by GC on a Carbowax column.
High-performance liquid chromatography (HPLC)
The first HPLC method for the determination of valepotriates has been published by
Tittel and Wagner (1978) andTittel etal. (1978). They obtained a good separation suitable
for qualitative as well as quantitative purposes from both crude material and preparations.
A silica gel column with a particle size of 10 um (MN-Nucleosil 50, 25 cm x 4 mm i.d.,
or Lichrosorb Si 100, 35 cm x 8 mm) and -hexane-ethyl acetate 20:3 as the eluent were
used. For detection a refractive index detection system and UV detection were applied.
The authors stated that this method was superior to the combined TLCspectrophotometric method using the hydroxylamine-iron(III)chloride reagent (Wagner
etal, 1970), with respect to time consumption, precision and sensitivity. The sequence
of elution was valtrate and isovaltrate, didrovaltrate, acevaltrate.
For the determination of (iso)valtrate another HPLC method has been presented by
Hazelhoff et al, (1979b). A Spherisorb Silica S5W column, 250 mm x 4.6 mm i.d.,
particle size 5 urn (Chrompack, Middelburg, The Netherlands), with 0.8% methanol in
hexane as the mobile phase, and detection at 254 nm were applied.
Van Meer and Labadie (1981) described a straight-phase as well as a reversed-phase
HPLC method for the analysis of valepotriates. The straight- phase column was a 5 urn
Partisil silica column (Chrompack), 25 cm x 3 mm i.d. As eluents -hexane-ethyl acetate
90:10 or 95:5, or -hexane-ethanol 99.5:0.5 were used. The reversed-phase column was
a 5 |xm Spherisorb ODS (Chrompack), 25 cm x 3 mm i.d. Methanol-water 50:50 or
acetonitrile-water 60:40 were the eluents applied. Monoene valepotriates were detected
at 206 nm, diene valepotriates at 256 nm.
Dossaji and Becker (1981) used reversed-phase HPLC with gradient elution for the
determination of the e valepotriates. A Waters \i Bondapak C18 column, 30 cm x 3.9 mm
i.d., was used with a methanol-water mixture as the eluent: A: 20:80 and B: 80:20; initially
85% B, finally 100% B in 5 min. Monoene valepotriates were separated on the same
column, isocratic with methanol-water 80:20. Detection was done at 254 nm (dienes)
and 208 nm (monoenes).
A comparable system was presented by Forster et al. (1984). The authors used an
Altex Ultrasphere-ODS preparative column, 25 cm x 10 mm, particle size 5 um, equipped
with an Altex guard column (45 x 4.6 mm, 30 \xm particles pellicular ODS). Monoenes
were eluted with acetonitrile-water 70:30 and detected at 206 nm. For dienes a gradient
was used of methanol-water mixtures, A: 60:40 and B: 90:10; initially 60% B, finally
90% B in 15 min. Detection of the dienes at 254 nm.
Chavadej etal (1985) applied gradient elution for the monoenes as well as the dienes.
A Iichrospher 100 CH (5 |xm) column (Merck) was used. A 10 min gradient elution was
achieved with methanol-water, A: 40:60 and B: 90:10; starting with 75% B to 95% B.
The dienes were detected at 254 nm and the monoenes at 206 nm. As an internal standard
-pentylbenzene was used.
118
Wtrate and isovaltrate have been analysed in a methylene chloride extract of valerian
on a Lichrosorb RP 18 column (7 jim) using methanol-water 80:20 with 0.5% phosphoric
aad as the eluent. Detection was done at 255 nm. With a flow rate of 2 ml/min isovaltrate
eluted after 6.4 min and valtrate after 7.4 min (Hansel and Schulz 1985).
Gramcher et al. (1992) applied the system of Forster et al. (1984), but with some
modifications. They used a Nucleosil C18 column (25 cm x 4 mm i.d., 5 urn) fitted with
a Nucleosil C18 guard-column (30 x 4 mm i.d., 5 ^m). Pentylbenzene was used as internal
standard. The solvent system was methanol-water 90:10 (pump A) and methanol-water
40:60 (pump B). Elution of the diene type valepotriates was achieved isocratic with 60%
A for 15 min, and a linear gradient to 90% A in 22 min. The monoene valepotriates
were eluted with 60% A for 27 min, followed by a linear gradient to 80% A in 14 min.
Valerenic Acid and Derivatives
Initially, analytical procedures were focussed on the valepotriates as they were considered
to be the main pharmacologically active constituents of valerian. In the 1980s however
the valerenic acids started to attract attention and analytical procedures'for these
For a better detection of acetoxyvalerenic acid in valerian root, Schimmer and Roder
DAB J, (also the procedure described in the European Pharmacopoiea 2nd edn (1993))
with the TLC identity test for valerian tincture as included in the same pharmacopoiea
since acetoxyvalerenic acid could better be determined after conversion into
hydroxyvalerenic acid.
In addition, Schimmer and Roder (1992) obtained a better separation of the zone
due to valerenic acid from the tincture following a second development of the plate
Hansel and Schulz (1982) were the first to describe an HPLC method for the
determination of valerenic, acetoxyvalerenic and hydroxyvalerenic acids, and valerenal
in both the crude drug and tinctures of K offianalis. The co-occurrence of the two
hydroxyvalerenic acid, is confined to V. offianalis and this HPLC method can therefore
be employed to detect adulterations by non-officinal valerian root extractives (V. wallichii
and/or V. edulis).
VALERIAN: QUALITY ASSURANCE OF THE CRUDE DRUG AND ITS PREPARATIONS 119
of root material. The lipophilic acids were separated from the lipophilic neutral
components by treatment with alkali. After acidification of the alkaline aqueous fraction
containing the sesquiterpenoids, they were extracted with chloroform. Tinctures of V.
offianalis were analysed directly, as they were devoid of valepotriates. Biphenyl was used
as an internal standard.
Baldrinals can be assayed using the HPLC method of Bos et al (1996a), simultaneously
with valerenic acid and derivatives and with valepotriates (see below).
Essential Oil
120
VALERIAN: QUALITY ASSURANCE OF THE CRUDE DRUG AND ITS PREPARATIONS 121
H. J. WOERDENBAG ETAL.
The identity of the components was assigned by comparison of their retention indices,
Table 2 Main constituents of the essential oils of V. offidnalis, V. wallichii and V. eduiis roots
and rhizomes with their retention indices (CP Sil 5 column, molecular weight (BP+) and base
peak (bp; 100% of the mass spectrum)) (Bos etal. 1997b,c,d).
relative to C9-C19 //-alkanes, and mass spectra with corresponding data from reference
K offidnalis'
concentration of the components was calculated from the GC peak areas, using the
Component
Retention Index
M+
BP
Borneol
1141
154
95
Bornyl acetate
1262
196
43
Kessane
1505
222
43
Valerianol
1624
222
59
Valeranone
1639
222
41
Cryptofauranol
1644
238
41
Valerenal
1686
218
91
normalization method.
In Table 2 the main constituents of the essential oils of V. offidnalis, V. wallichii and
V. eduiis roots and rhizomes with their retention indices are listed.
Mixed Constituents
In our laboratory the following TLC system is applied in order to prove the identity of
V. offidnalis. An 1:5 70% ethanolic extract of plant material is made and chromatographed
V7. wallichii
Component
compounds and from the literature (Adams 1989; Tucker and Maciarello 1993). The
Retention Index
M+
BP
Borneol
1141
154
95
Bornyl acetate
1264
196
43
69
Detection uses
anisaldehyde/sulphuric acid reagent followed by 5-10 min heating at 105C. The detected
compounds with their respective R values and the colours of the spots are listed in
Table 3.
Maaliol
1541
222
Patchouli alcohol
1625
222
83
Xanthorrizol
1717
218
136
a-Kessyl acetate
1772
280
43
Retention Index
M+
BP
can be detected in one run (Bos et al, 1996a). The procedure can be applied to both
Patchoulene
1423
204
122
Patchouli alcohol
1625
222
83
1/. eduiis
Component
]Based on the principal components of the oil, four chemotypes can be distinguished within the
species V. offidnalis: the valeranone, valerianol, cryptofauranol and valerenal types (Bos et al,
1986). Initially, the valerianol type was called elemol type (Hendriks etal., 1977, Hazelhoff etal,
1979a; Hendriks and Bruins 1980)
In the case of plant material HI0.0 g is ground (1 mm) and extracted with 3 x 30 ml
of methanol during 5 min in an ultrasonic bath (Bransonic 220) at room temperature.
The extracts were filtered into a volumetric flask and the volume was adjusted to
100.0 ml with methanol. This extract was submitted to HPLC analysis as described
below.
Table 3
GC analysis was performed using WCOT fused-silica CP-Sil 5 CB, 25 m x 0.32 mm i.d.;
(precoated channeled glass plates with 250 (J.m silica gel layer; hexane-diethyl ether (6:4); 15 cm;
film thickness, 0.25 |j.m (oven temperature programme, 50-290C at 4C/min; injection
temperature, 250C; detector (FID) temperature, 300C; carrier gas, nitrogen; inlet
pressure, 5 psi; linear gas velocity, 26 cm/s; split ratio, 1:56; injected volume, 1.0 fil.
Compound
GC-MS (El) was performed using the conditions described above, except: column, 25
Colour
Hydroxyvalerenic acid
0.01
Violet
Acetoxyvalerenic acid
Valerenic acid
0.15
Violet
0.38
Violet
Baldrinal
0.47
Yellow
Crypto fauronol
0.65
Purple-violet
m x 0.25 mm i.d.; carrier gas, helium; linear gas velocity, 32 cm/s; split ratio, 1:20. MS
Patchouli alcohol
0.70
Brownish-blue
conditions: ionization energy, 70 eV; ion source temperature, 250C; interface temperature,
Valerenal
0.86
Blue
280C; scan speed, 2 scans/s; mass range, 34-500 amu; injected volume, 1.0 \il
Valeranone
0.89
Yellow
122
Table 4
VALERIAN: QUALITY ASSURANCE OF THE CRUDE DRUG AND ITS PREPARATIONS 123
Reference valerian compounds, separated using the on-line HPLC System (Bos et a/.,
1996a), with their respective retention time, capacity factor and UV maximum.
Compound
Powdered valerian root rapidly loses its essential oil and will no longer comply the
pharmacopoeial standard. In addition, the drying as well as the storage temperature are
Retention
Capacity
UV
time (min)
factor
maximum (nm)
yielding valeric and isovaleric acids. The characteristic odour of these acids points to
Baldrinal
5.00
1.99
424
Hydroxyvalerenic acid
5.39
2.21
220-221
Homobaldrinal
11.14
5.60
424
Acetoxyvalerenic acid
11.79
6.02
220-221
Acevaltrate
19.22
10.44
255
Valerenic acid
20.28
11.07
220-221
Didrovaltrate
20.31
11.09
200
Isovaleroxyhydroxydidrovaltrate
21.16
11.60
200
Isovaltrate
22.14
12.18
decomposed, first yielding baldrinals, that may react further with yet unknown substances
255
Valtrate
22.92
12.64
255
*The capacity factor (k') was calculated using the formula k' = TR-TQ / TQ; TR = retention time
of peak (min) and T = retention time of uracil (void time).
REGULATORY ASPECTS
Present Situation
If phytomedicines such as tinctures, capsules and coated tablets, are analysed using
the HPLC method some modifications are made in the preparation process. Tinctures
are analysed as such, but the content of a capsule is first dissolved in 100.0 ml methanol
and a coated tablet in 5.0 ml methanol. All samples were filtered through a 45 urn
DynaGard HPLC filter (Microgon Inc., Laguna Hills, CA, USA) before injection into
the HPLC apparatus.
HPLC was performed using an Isco HPLC pump 2350, an Isco gradient mixer 2360,
a Kontron autosampler 360, an Isco V4 absorbance detector, a Kontron PC Integration
pack and a Shimadzu SPDM6A-Diode Array Detector (DAD) under the following
conditions. DAD: wavelength, 200-600 nm; band width, 2 nm; spectrum abs. scale
with their respective retention time, capacity factor and UV maximum. Compounds
with about the same retention times could be distinguished by their UV maximum.
For quality control of the crude drug and of phytomedicines prepared from valerian,
monographs of the European Pharmacopoeia 2nd edn (1993) can be used, but additional
analyses are necessary (Woerdenbag 1995).
Between various countries of the European Union and in the United States of America,
large differences exist in the legal position of herbal medicines. Regulations vary
considerably from country to country, and in most European countries and in the USA
the legislation of herbal drugs is much less progressive than for synthetic drugs.
The German health authorities, 'Bundesgesundheitsamt', have set up an expert
committee for the evaluation of herbal drugs, the so-called 'Kommission E\ The findings
of the Kommission E, based on data available from literature, are laid down in a
monograph, in which the balance between usefulness and risk is weighed (Woerdenbag
et at, 1993; Woerdenbag 1995). For valerian a 'Positiv-Monographie' exists, meaning
that the herbal drug has been found to be biologically active, without inducing serious
side-effects (Anonymous 1992). The root is permitted for oral use, and as herbal tea
and tincture (De Smet 1993).
In France and Belgium, herbal remedies are subject to general drug regulations, and
should therefore comply with criteria of efficacy, safety and quality. As compared with
synthetic drugs, a simplified admission procedure is applied, which is based on chemical
and pharmaceutical documentation, as available from the literature. Subterranean parts
of V. officinalis and preparations are permitted for oral use in France. In Belgium
subterranean parts, powder, extract and tincture are permitted as traditional tranquillizer
(De Smet 1993).
STORAGE CONDITIONS
In the United Kingdom, there are no special guidelines for the admission of herbal
remedies to the drug market. To be accepted as a medicinal product, a herbal preparation
According to the European Pharmacopoeia 2nd edn (1993), the crude drug should be
stored in a well-closed container, protected from light.
must comply with the Guidelines on Safety and Efficacy Requirements for Herbal
Medicinal Products. As proofs of safety and efficacy, literature data should be submitted.
124
H. J. WOERDENBAG BTAL.
VALERIAN: QUALITY ASSURANCE OF THE CRUDE DRUG AND ITS PREPARATIONS 125
For acceptance as an approved drug, however, evidence from clinical trials is required.
derivatives, because of their stability. This implies that V. officinalis is the crude material
For this reason, only few phytomedicines, not including valerian, have reached the status
2nd edn (1993) and the "Warenwet' (Food Act) exist for phytomedicines. They do not
have the status of drugs therefore, and may not be called a drug or recommended as
such. In principle, herbal preparations can be sold by anyone in the Netherlands, a
situation which tends to provoke inexpert use (Woerdenbag 1995).
It is clear that there is no unity at all in the European Union, in the field of herbal
drugs. In 1989 the European Scientific Cooperative on Phytotherapy (ESCOP) was
founded. The general aim of ESCOP is to advance the scientific status of phytomedicines
and to assist with harmonization of their regulatory status in European countries. In a
European frame-work, ESCOP prepares monographs for herbal drugs. These
monographs, officially known as SPCs (Summary of Product Characteristics) are offered
to regulatory authorities, the Committee on Proprietary Medicinal Products (CPMP), as
a means of harmonizing the medicinal uses of plant drugs in the European Union and
in a wider European context. An SPC of Vakrianae radix has been submitted to the
CPMP (Krant 1994).
ESCOP defines phytomedicines as follows:
Many of today's widely used herbs were once the subject of official monographs in
The United States Pharmacopeia and The National Formulary, including valerian root
(V. officinalis). No such legal standards exist in the USA today. The Food and Drug
Administration (FDA) has evaluated the safety and efficacy of several herbal medicines.
Valerian root has been granted the status 'Generally Recognized As Safe' (GRAS) (De
Smet 1993; Tyler 1993, 1994).
Note
As of 1 January 1997, the 2nd edition of the European Pharmacopoeia has been replaced
by the 3rd edition. The monograph 'Valerian root' (Valerianae radix) in the current
edition has hardly changed as compared with the former. Therefore, in all cases that is
referred to the 2nd edition of the European Pharmacopoeia, it can also be read as being
Bos, R., Van Putten, F.M.S., Hendriks, H. and Mastenbroek, C. (1986) Variations in the essential
oil content and composition in individual plants obtained after breeding experiments with a
Valeriana officinalis strain. InE.-J. Brunke, {cA), Progress in Essential Oil Research, Walter de Gruyter
& Co., Berlin, p. 123-130.
Bos, R., Woerdenbag, H.J., Hendriks, H. and Malingre, Th.M. (1992) Der indische oder
pakistanische Baldrian. Z. Phytother., 13, 26-34.
Future Developments
Bos, R., Woerdenbag, HJ. and Zwaving, J.H. (1994) Valeriaan en valeriaanpreparaten. Pharm.
In the near future the European Pharmacopoeia Commission is expected to change the
Bos, R., Woerdenbag, H.J., Hendriks, R, Zwaving, J.H., De Smet, P.A.G.M., Tittel, G., Wikstrom,
Bos, R., Woerdenbag, HJ., De Smet, P.A.G.M. and Scheffer, JJ.C. (1997a) I 'akriana species. In
Hansel and Schulz (1985) proposed criteria for the content of valerenic acid and its
derivatives. They recommended that alcoholic extracts of V. officinalis should contain
valerenic acids with a minimum of 120 mg/100 g and aqueous extracts a minimum of
60 mg/100 g.
Bos, R., Woerdenbag, HJ., Hendriks, H., Smit, H.F., Wikstrom, H.V and Scheffer, JJ.C. (1997b)
P.A.G.M. De Smet, K. Keller, R. Hansel, and R.F. Chandler, (eck), Adverse Effects of Herbal
Drugs, Volume 3, Springer-Verlag, Berlin, Heidelberg, p. 165-180.
Composition of the essential oil from roots and rhizomes of Valeriana wallichii DC. Flavour
Fragr.J., 123-131.
Bos, R., Woerdenbag, H.J., Hendriks, H. and Scheffer, JJ.C. (1997c) Composition of the essential
oils from underground parts of Valeriana officinalis L. s.L, and several closely related taxa.
126
H. J. WOERDENBAG ETAL.
Bos, R, Woerdenbag, H.J., Hendriks, H. and Scheffer, JJ.C. (1997d) Essential oil from roots of
Mexican Valeriana species, in preparation.
Bounthanth, C, Richert, L., Beck, J.R, Haag-Berrurier, M. and Anton, R. (1983) The action of
valepotriates on the synthesis of DNA and proteins of cultured hepatoma cells. PlantaMed,
49,138-142.
Braun, R., Dittmar, W, Machut, M. and Wendland, S. (1983) Valepotriate - zur Bestimmung mit
Hilfe von Nitrobenzylpyridin (NBP-Methode). Dtsch.Apoth. Ztg., 123, 2474-2477.
Braun, R., Dieckmann, H., Machut, M., Echarti, C and Maurer, H.R. (1986) Studies on the
effects of baldrinal on hemopoietic cells in vitro, on the metabolic activity of the liver in vivo,
and on the content in proprietry drugs. PlantaMed., 52, 446-450.
Chavadej, S., Becker, H. and Weberling, E (1985) Further investigations of valepotriates in the
Valerianaceae. Pbarm. WeekbL Sd. Ed, 7, 167-168.
De Smet, P.A.G.M. and Vulto, A.G. (1988) Drugs used in non-orthodox medicine. In M.N.G.
Dukes and L. Beely, (eds.), Side Effects of Drugs -Annual 12, Elsevier, Amsterdam, p. 402-415.
De Smet, P.A.G.M. (1993) Legislatory outlook on the safety of herbal remedies. In P.A.G.M. De
Smet, K. Keller, R. Hansel and R.F. Chandler, (eds.) Adverse Effects of Herbal Drugs, Volume 2,
Springer-verlag, Berlin, p. 1-90.
Evans WC. (1989) Trease and Evans' Pharmacognosy, 13th edn., Bailliere Tindall, London, p. 525528.
Forster, W., Becker, H. and Rodriguez, E. (1984) HPLC analysis of valepotriates in the North
American genera Plectritisand Valeriana. PlantaMed, 50, 7-9.
Freytag, W.E. (1983) Bestimmung von Valerensauren und Valerenal neben Valepotriaten in Valeriana
officinalis dutch HPLC. Pbarm. Ztg., 128, 2869-2871.
German Pharmacopoeia, 'Deutsches Arvpeibucti, 10. Auflage (1993), Deutscher Apotheker Verlag,
Stuttgart; Govi-Verlag GmbH, Frankfurt.
Hansel, R., Schulz, J. and Stahl, E. (1983) Priifung der Baldrian-Tinktur auf Identitat. Arch. Pharm.
(Weinheim), 316, 646-647.
Hansel, R. and Schulz, J. (1985) Beitrag zur Qualitatssicherung von Baldrianextrakten. 4. Mitt.
Pharm.lnd, 47, 531-533.
VALERIAN: QUALITY ASSURANCE OF THE CRUDE DRUG AND ITS PREPARATIONS 127
Hendriks, H., Smith, D. and Hazelhoff, B. (1977) Eugenyl isovalerate and isoeugenyl isovalerate
in the essential oil of Valerian root. Photochemistry, 16, 1853-1854.
Hendriks, H. and Bos, R. (1984) Essential oils of some Valerianaceae. Dragoco Rep. (English ed.)
1,3-17.
Houghton, P. (1988) The biological activity of valerian and related plants./. Ethnopharmacol, 22,
121-142.
Mitt.: Der Nachweis einiger Inhaltsstoffe von Kentranthus ruberDC. Pbarm. Zentralhalle, 106,
797-804.
Mannestatter, E., Gerlach, Hand Poethke, W. (1968) Uber die Inhaltsstoffe von Valerianaceen. 3.
Mitt.: Beitrage zur Bestimmung des Halazuchroms B in Valerianaceen-Drogen. Pharm.
Zentralhalle, 107, 261-269.
Morazzoni, P. and Bombardelli, E. (1995) Valeriana offidnalis; traditional use and recent evaluation
of activity. Fitoterapia, 66, 99-112.
Riicker,
G.,
Neugebauer
M.
and
Sharaf
El
Din,
M.
(1981)
Quantitative
128
H. J. WOERDENBAG ETAL.
Steinegger, E. and Hansel, R. (1992) Pharmakognosie, 5th edn. Springer-Verlag, Berlin, p. 162-
6.
163,666-671.
VALERIANA PRODUCTS
Thies, P.W (1968) Die ^Constitution der Valepotriate. Mitteilung iiber die Wirkstoffe des Baldrians.
Tetrahedron, 24, 313-347.
Thies, P.W (1969) Zum chromogenen Verhalten der Valepotriate. Ar^neim.-Forsch., 19, 319-322.
Thies, P.W. and Funke, S. (1966) Nachweis und Isolierung von sedativ wirksamen IsoValeriansauree stern aus Wurzel und Rhizomen von verschiedenen Vakriana- und Kentranthus-
Tittel, G., Chari, V.M. and Wagner, H. (1978) HPLC-Analyse von Vakriana mexicana Extrakten.
PlantaMed., 34, 305-310.
CONTENTS
Titz, W, Jurenitsch, J., Fitzbauer-Busch, E., Wicho, E. and Kubelka, W (1982) Valepotriate und
atherisches Ol, morphologisch und chromosomal defmierter Typen von Vakriana officinalis L.
s.l. I. Vergleich von Valepotriatgehalt und -Zusammensetzung. Set. Pharm., 50, 309-324.
Titz, W, Jurenitsch, J., Gruber, J., Schabus, L., Titz, E. and Kubelka, W. (1983) Valepotriate und
INTRODUCTION
atherisches Ol, morphologisch und chromosomal defmierter Typen von Vakriana officinalis L.
s.l. II. Variation charakteristischer Komponenten des atherischen Ols. Set. Pharm., 51, 63-86.
Tucker, A.O. and Maciarello, M. (eds.) (1993) Mass Spectral'Library of Flavor <&'Fragrance Compounds,
Volume I-XXV11, Department of Agriculture & Natural Resources, Delaware State University,
Dover, Delaware.
Tyler, VE. (1993) The Honest Herbal, 3rd edn, Pharmaceutical Products Press, New York, p. 315317, p. 350-351.
Tyler, VE. (1994) Herbs of Choice, Pharmaceutical Products Press, New York, p. 17-32, 117-119.
Van Meer, J.H., Van der Sluis, WG. and Labadie, R.P. (1977) Onderzoek naar de aanwezigheid
van valepotriaten in valeriaanpreparaten. Pharm. WeekbL, 112, 20-27.
Van Meer, J.H. and Labadie, R.P. (1981) Straight-phase and reversed-phase high-performance
liquid chromatographic separations of valepotriate isomers and homologues. /. Chromatogr.,
Medicinal products
Extracts
Oils
Commercial preparations
Isolated constituents
205, 206-212.
Von der Hude, W, Scheutwinkel-Reich, M. and Braun, R. (1986) Bacterial mutagenicity of the
tranquilizing constituents of Valerianaceae roots. Mutat. Res., 169, 23-27.
Wagner, H., Horhammer L., Holtzl, J. and Schaette, R. (1970) Zur Wertbestimmung der Baldrian-
Wienschierz, HJ. (1978) Erfahrungen bei der Kultivierung von Vakriana wallichii (DC) in der
Bundesrepublik Deutschland. Ada Horticult., 73, 315-321.
Woerdenbag, H.J., De Smet, P.A.G.M. and Scheffer, JJ.C. (1993) Plantaardige geneesmiddelen in
medisch-farmaceutisch perspectief. Pharm. WeekbL, 128, 164177.
Woerdenbag, HJ. (1995) The role and research of phytomedicines in European countries. Ned.
Tijdschr. Fytother., 8, (1), 13-16.
Zwaving, J.H. (1993) Kwaliteitscontrole van natuurlijke grondstoffen door de apotheker en zijn
rol in de voorlichting over plantaardige geneesmiddelen aan de patient. Pharm. Weekbl, 128,
178-184.
Other uses
INTRODUCTION
There are four species of Vakriana that are important articles of commerce either as the
Briq.. Commercial supplies of these four species are mainly obtained from cultivation
but some plants are still collected from the wild. The first three of these are cultivated in
Europe whilst Japanese Valerian is grown and used mainly in the Far East and Indian
Valerian is the species grown and used on the Indian subcontinent. V. officinalis is also
grown commercially in North America. Most of the data available refers to V. officinalis
since this is the species which has received most attention as a commercial crop and is
consequendy utilised in Western society. It should be remembered, however, that a large
trade in these and more local Vakriana species, as with other plants used in traditional
129
2
2
23
Greece
Hungary
Italy
Germany
471
Franco-phone 14
West Africa
193
20
Sedative
Biogal
Valeriana
Dispert, Tintura
Farmades, Valeriana
Functional Baldrian
Baldrian Tinktur,
Perozon Baldrian,
Baltherm Baldrian,
Knufinke Baldrian,
Baldrian, Balsedat,
-a
o
z
o
X
DC
O
T1
Baldrian, Togasan
Beruhigung, Regivkal
Baldrianetten, Visinal
Baldrisedon, Orasedon,
Baldrian-Phyton,
Baldrian Dispert,
Baldrian, Baldrain
Weber und Weber
Recvalysat, Abtei
Baldrian, Baldrianwurzel,
Baldriafur, Sedalint
Sedative
34
Examples
Schuck, Spitzner,
cardiovascular
Number
Valeriane Arkogelules
Valeriane Titrex,
Valeriane Pachant,
Pharmakon, Phoenix,
Sedative,
Fides, Hanosan,
Sedative
peutic uses
Nestmann, Pascoe,
Lehning
58
Tincture
continued
Main manufacturers
Table 1
Monol, Arkopharma
Major thera-
Valeriane Effidose,
Sedative
Valerian Vitaflor,
Valrian, Valdispert
Sedative
Ardeval, Lehning,
Lerius, Orion
antitussive
Sedative
Chrop 1, Santa
18
Powder
Valeria
spasmodic
Analgesis,
Nerviol, Tintura de
Valerian
Valdispert
Dispert, Baldrinetten
Klosterfrau, Baldrian
Baldrian-Drei-Herzbl,
Baldrian Kneipp,
Valerian
Valerian, Vitaglow
Polcopharma Valerian,
Examples
Sedative, anti-
Number
Mepaco
Inquifar, Lafont
Medipharm, Volta
195
Extract
Oil
raw materials
Base
Number of
products
1
27
Country
24
57
Egypt
France
Colombia
Sedative
Sedative
MRF
Vida, Henmann
Finland
Chile
America
Central
Sedative
Hauser, Lyssia
Sedative
Sedative
Rhone Poulenc,
Vitaplex
Smetana, Chepharin-
Sedative
Nora
Leofarm
Tincture
5
4
Brazil
Canada
Belgium
16
Powder
Major thera
peutic uses
Sedative
30
Austria
Oil
Main manufacturers
Centrapharm, Lyssia
10
Australia
13
Extract
raw materials
Base
Number of
products
Argentina
Country
Table 1
5
1
15
Morocco
Netherlands
2
15
4
1
2
25
Taiwan
Tunisia
USA
UK
Venezuela
33
86
Switzerland
Sweden
Base
10
39
Extract
Powder
raw materials
Oil
Number of
products
1
2
Country
Sedative
Pharbita, Daro,
12
Sedative
Nutter
Valeriana, Valeriana
Valeriana, Relaxul
Valeriana Deiters,
Calmettes
Valdispert, Circulin
Valerian Compound
Blackmores Valerian,
Valeriane-2
Valdispert, Extract
Tendo Valeriaan,
Katwyk, Calmolan,
Valerianae, Valeriaan
2
2
Sedative
Sedative
Sedative
Gerard House
Lariviere, Gache
1
2
Antitussive
Pharmavite
gynaecological
Sedative,
Valerianato Pierl
Valerian root
Arkogelules
Sa Saoka Yakuhin
Regivital, Kuenzle,
Valdispert, Baldrisedon,
Baldrian Dispert
Wiedenmamm, Zeller
Sedative
Kuenzle, Dronamia,
Valerecen, Neurol,
Examples
Robins,
Sedative
Number
Kabi Pharmacia
peutic uses
Major thera
Sedative
Sanofi Winthrop
Tincture
continued
Main manufacturers
Table 1
Deiters, Ordesa
Noristan
Examples
Gynaecological,
antacid
Arnet Pharmaceutical
Zyma Farma
Sedative
Portugeas, Roba
Porrugesa
Sedative
Sedative
Soekami-Lefranq
Cardiovascular
Sedative
Franco Mexicana
Spain
1
11
Philippines
Portugal
Sedative, anti-
hypertensive,
cardiovascular
Han Lim, Hae Woi
Zaiseido
Major thera
peutic uses
Tincture
continued
Main manufacturers
Table 1
Powder
South Africa
Pakistan
New Zealand 7
10
Korea
Mexico
2
Oil
raw materials
products
Base Extract
Number of
13
Japan
Country
c
z
X
o
T1
134
VALERIANA PRODUCTS
medicine, occurs within developing countries at a local level and information concerning
this usage is practically impossible to obtain. In these conditions material is more likely
to be obtained from wild plants or from small-scale cultivation. The collection of wild
material has raised concern about the possible extinction of less common species.
Valerian products are marketed and used worldwide (see Table 1) and comprise one
of the best-selling entities of the health food/natural medicine sector in the industrialised
world (Brevoort, 1996). More than two hundred commercial preparations containing
V. officinalis are listed (Martindale, 1996). This chapter presents an overview of the
The price of the volatile oil obtained from Valeriana officinalis has increased in recent
Medicinal products
Production
About 1200 tonnes of V. officinalis roots are estimated to be produced annually in Europe
in the years after 1990. Traditional growing areas include Germany, the Netherlands and
Belgium and these still produce the best quality material. Recently large amounts of this
species have been grown in eastern Europe, particularly in Poland, Bulgaria and Ukraine,
and this has resulted in a surplus of an estimated 800 tonnes. V. officinalis-is also produced
for local consumption in North America (Hobbs, 1989).
V. wallichii originates from the Indian subcontinent and is still grown and used
extensively there but is also now cultivated in China and Germany as a source of
valepotriates (Bos et al, 1992). V edulis is collected and grown in Mexico, its country of
origin, but is also cultivated in Germany, mainly as a source of valepotriates, since it
contains high amounts of these compounds and has large roots.
The steam-distilled oil from V. officinalis is now produced mainly in China and the
annual production is estimated at about 7 tonnes.
Markets
The major market for Valeriana at present in Europe is Germany where the retail sales
value of valerian products is reckoned to be five million US dollars annually. Significant
amounts of Valeriana products are also consumed in Switzerland, France, Austria and
Italy.
Prices
There are two levels of prices for V, officinalis, the price at which the roots are sold by
the growers and that at which they are sold by traders on the commodities market. In
1995 the first price was 2.00-2.50DM (US$ 1.4-1.7) per kg. Trader's selling prices per
kilo varied according to the country where purchased and ranged from 6.5DM (US$4.4)
in UK to 6.75-7.35DM (US$ 4.6-5.0) in France and 7.5-8.0DM (US$ 5.1-5.5) in Germany.
It is expected that prices may be almost halved during the next few years because of the
surplus of roots available.
135
years as cheap European products have been displaced by more expensive material of
Chinese origin. In 1984 the price was US$42 per kilo but in 1993 was quoted at US$150
per kilo.
In some countries, e.g. Germany, the dried root is still sold as a consumer product for
the production of a tea to relieve over-excitement, aid the onset of sleep and for
gastrointestinal disturbances (Bradley, 1992). Careful instructions for correct use and
dosage have to be provided in some countries.
Extracts
The most common galenical preparation, listed in many official formularies and
pharmacopoeias, is a tincture made with 60% ethanol. This may be concentrated to
form a soft extract. However in some modern monographs a tincture made with 70%
ethanol is described (DAB10, 1991). A concentrated infusion, made with 25% ethanol,
has been employed in the UK (BPC, 1963). It is likely that the preparations made with
more concentrated alcohol, when freshly prepared, contain some of the volatile oil
components and also valepotriates thought to be the major active components, although
the latter hydrolyse quickly upon storage.
Many commercial preparations contain dried extracts made from \^aknana species
although the solvent used is not always specified.
Oils
The steam-distilled volatile oil (sometimes called the essential or ethereal oil) from
V. officinalis is included in a few preparations (see Table) but it should be noted that it
plays a much less prominent role than the various solvent extracts employed.
Commercialpreparations
136
VALERIANA PRODUCTS
DAB 10 (1991) Deutsches Ar^neibuch (German Pharmacopeia) 10th edition. Deutscher Apotheker
relaxation or sleep. The most common of these are Passionflower Herb {Passiflora incarnata
L.), Hops (the fruit of Humulus lupulus L.) and Scullcap Herb (Scutellaria laterifolia L.).
The dose of individual herbs in such preparations is not always as high as the that
recommended in semi-official publications such as the British Herbal Pharmacopeia
(1996) or German Kommission E monograph (1990, 1996) and careful selection and
Although the majority of preparations based on Valeriana employ extracts or oils, there
are a few instances where single compounds isolated from these crude extracts are used
or where isolated compounds are combined in a standardised mixture.
The major example of the latter is Valmane which is a mixture of three valepotriates
consisting of didrovaltrate 80%, valtrate 15% and acevaltrate 5%. It is used in several
sedative proprietary preparations widely sold in European countries.
The single isolated constituents used are all obtained from the volatile oil distilled
from the plant material. Valeric acid and isovaleric acid are used as active ingredients in
some sedative products in Austria, Germany and Italy. The monoterpenes pinene and
borneol are obtained from many other sources as well as Valeriana. They are used
extensively in perfumery as well as in pharmaceutical products to relieve nasal congestion
and for topical application as counter-irritants in the treatment of muscular pain. Pinene
and borneol are also used as feedstock substances for the semisynthesis of a wide range
The essential oil of Valeriana officinaks is used to some considerable extent in the perfumery
industry although it is blended in small amounts with other oils because of its strong
odour which many find objectionable.
REFERENCES
Bos, R, Woerdenbag, H.J., Hendriks, H. and Malingre, Th. M. (1992) Der Indische oder
137
INDEX
Acetoxyvalthydrine, 67
Clinical Studies, 61
Adulteration, 124
Complement system, 69
Cosmetic, 11,16
Crossing experiments, 93
Culpeper, 12, 13
Animals, 17,65,70
Anodyne, 15
Anticonvulsant activity, 59
Degradation, 67
Dependence, 12
Desoxyglucose method, 57
Aphrodisiac reputation, 12
Astrology, 12, 13
Diazepam, 59, 65
Didrovaltrate, 35, 36, 38, 39, 40, 41, 44, 60,
Baldrian, 91,94
Baldnnal, 40, 42, 64, 67, 69, 70, 105, 116, 119
116,136
Balm, 62
Benzodiazepam, 67
DNA synthesis, 71
Biogenesis, 22
Dopamine, 69
57,59
cAMP, 58
Camphene, 26
Elemane, 27, 30
Carminative, 15
Catnip, 70
ESCOP, 124
Essential oil, 16, 80, 81, 82, 84, 88, 89, 92, 93,
Cell cultures, 38
Centranthus, 10,17, 35
122,124,136
Chemical races, 34
Chlordiazepoxide, 65
139
140
Fatty acids, 47
Fertilisers, 88
Flavonoids, 46, 47
Floral symbolism, 12
Folklore, 1,11
Isoprenoids, 22
103,105,110,111,112,116,118
Soil, 17, 32, 77, 82, 83, 84, 88, 95, 96, 97,113
Sokoloff, 55, 57, 60
Kawain, 59
a-Pinene, 25, 26
Poison, 56
Spikenard, 13
Prices, 129,134
.83,94,107,
108,112,113,115,122
Light intensity, 80
Lignans, 47
Genotype, 34
Gerard, 13
Sleep-inducing properties, 16
Sleeplessness, 15, 61
Fungi, 69
Galenicals, 135
GABA,44, 60,61,65, 71
Galen, 2, 13
Phenylpropanoids, 44, 47
141
INDEX
INDEX
Markets, 35,123,134,135
Medicinal, 11, 15, 22, 42, 57, 93, 123, 124,
135
Production, 38, 77, 79, 81, 82, 83, 84, 85, 87,
134,135
Productivity, 83,91,94
Melissa offirinalis, 62
Harvesting, 78, 97
Migraine, 15
REM sleep, 62
Trade, 129
Guaiane skeleton, 59
Receptors, 58
119,121
Hippocampus, 67
History, 1, 13
Rheumatic conditions, 16
Monoterpenoids, 22
Morphology, 88, 89, 107
Rotarod test, 65
Saints, 13
V. cornucopiae, 5, 17
Sales, 134
Hepatitis, 70
Root formation, 83
Valeriana spp.
Myrcene, 26
Nepetalactone, 68, 70
5-HT receptor, 67
Hypnotic, 15,58,62
112,114,118,121
Imipramine, 59
Immune system, 69
Patchouli alcohol, 31
Perfume, 2,3, 16,27
43, 56, 58, 59, 60, 61, 63, 65, 67, 71,103,
136
Seeds, 47, 78, 79, 80, 81, 83, 91, 92, 95, 96,
97,98
V. dioica,5,15,26
V. exaltata, 6, 79,81,89
V. fauriei, 2, 6,15, 26, 27,30, 31,33, 39,
47,59,78,129
V. jatamansii, 2, 6
31, 33, 34, 35, 39, 40, 42, 44, 47, 56, 58,
59, 60, 61, 62, 63, 65, 67, 69, 70, 78, 83,
89,102, 103,104,105,106,108,109,
110,111,112,113,114,118,119,121,
123, 124,129,134,135,136
V. procurrens, 8, 89
Shoot production, 87
V. sambucifolia, 9, 81
Skin, 16
V. sylvatica, 9,16
142
INDEX
107, 108,112,113,114,118,119,121,
Valerianella, 10, 17
124,129,134
Valdispert, 59
Valtrate, 35, 36, 38, 39, 40, 41, 44, 59, 60, 65,
67, 69, 70, 71,103, 105,110, 111, 112,
114,115,116,118,136
Valtroxal, 40, 66, 67
61, 65, 67, 69, 70, 71, 82, 85, 88, 89, 91,
93
Volatile oil, 14, 15, 21, 22, 24, 25, 26, 29, 31,
32, 34, 35, 47, 58, 61, 62, 65, 67, 70, 71,
114,135,136
Water requirement, 81
Valerenic acid, 28, 29, 55, 60, 61, 65, 66, 91,
Weed control, 96