PHYTOTHERAPY RESEARCH

Phytother. Res. 20, 1023–1035 (2006)

Published online 14 August POTENTIAL
2006 in Wiley InterScience
MEDICINAL PLANTS FOR CNS DISORDERS 1023
(www.interscience.wiley.com) DOI: 10.1002/ptr.1970

REVIEW ARTICLE
Potential Medicinal Plants for CNS Disorders:
an Overview

Vikas Kumar*
Department of Pharmaceutical Sciences, Texas Tech University, Health Sciences Center, School of Pharmacy, Amarillo, TX
79106, USA

Although very few drugs are currently approved by regulatory authorities for treating multi-factorial ailments
and disorders of cognition such as Alzheimer’s disease, certain plant-derived agents, including, for example,
galantamine and rivastigmine (a semi-synthetic derivative of physostigmine) are finding an application
in modern medicine. However, in Ayurveda, the Indian traditional system of medicine which is more than
5000 years old, selected plants have long been classified as ‘medhya rasayanas’, from the Sanskrit words
‘medhya’, meaning intellect or cognition, and ‘rasayana’, meaning ‘rejuvenation’. These plants are used both
in herbal and conventional medicine and offer benefits that pharmaceutical drugs lack. In the present article,
an attempt has been made to review the most important medicinal plants, including Ginkgo biloba, St John’s
wort, Kava-kava, Valerian, Bacopa monniera and Convolvulus pluricaulis, which are widely used for their
reputed effectiveness in CNS disorders. Copyright © 2006 John Wiley & Sons, Ltd.

Keywords: medicinal plants; Alzheimer’s disease; depression; anxiety; stress; CNS disorders.

psychotherapeutics based on acquired knowledge from

INTRODUCTION
Herbs, which have always been the principal form of
medicine in developing countries, are once again
becoming popular throughout the developing and
developed world. Statistics show that more and more
people in Europe, North America and Australia are
consulting trained herbal professionals and using
the plant medicines that their grandparents or great-
grandparents took. Sparreboom et al. (2004) indicated
that interest in the use of herbal products has grown
dramatically in the Western word. Ayurveda-based drug
discovery uses ‘reverse pharmacology’, in which drug
candidates are first identified based on large-scale
use in the population, then validated in clinical trials.
Experts say that this approach can cut the time for
drug discovery from 12 years to 5 years or less, and
for a fraction of the usual cost (Padma, 2005).
All critical analysis on commercial and other infor-
mation available on traditionally known CNS active
herbal remedies indicate that the most popular amongst
such remedies are those which are clinically and
preclinically the most well studied ones, and which are
also recommended for therapeutic purposes by the
health authorities of many Western and other coun-
tries outside the USA. Although the clinical efficacy of
several such herbal extract based remedies have been
revealed repeatedly by proper clinical trials conducted
during the past three decades, reports of concentrated
efforts to develop structurally and functionally novel
* Correspondence address: Pharmacology Laboratory, Department
of Pharmaceutics, Institute of Technology, Banaras Hindu Univerity,
Varanasi-221 005, UP, India.
E-mail(s): neuropharmacologist@rediffmail.com, vikask@bhu.ac.in
Copyright © 2006 John Wiley & Sons, Ltd.
Copyright © 2006 John Wiley & Sons, Ltd.
herbal remedies continue to be rare. The fact that the
vast majorities of currently available psychoactive drugs
are not natural products or are not derived from
bioactive constituents of medicinal plants seems to be a
reflection of such a situation. This is not, however, the
situation in many other therapeutic areas where exam-
ples of drugs derived from secondary plant metabolites
and their derivatives, or conceived from pharmacolog-
ical knowledge gained from studies of herbal remedies,
are abundant. In a systematic analysis published during
1997 it was assessed that 157 of 520 drugs (30%)
approved by Food and Drug Administration (FDA) in
the USA during 1983–94 (11 years) were natural prod-
ucts or their derivatives (Cragg et al., 1997). This report
revealed in addition, that when focused efforts were
made to discover natural products for clinical use, the
success level rose dramatically. Thus during the same
period, 61% of anticancer agents approved were natu-
ral products or their derivatives. In the absence of
targeted programs for natural products, there was no
success. Thus, there were no analgesics, antidepressants,
anxiolytics or other CNS active drugs derived from
natural products which were approved during the 11
year time period analysed.
Our current analysis indicates that the situation
has not changed much during more recent years.
Although identification of hits and leads from second-
ary plant metabolites continue to be a major goal of
many drug discovery projects, most such efforts do
not concentrate on the search for agents potentially
useful for the treatment of CNS disorders. In addition,
the comparatively few reports on neuronal function
modulating activities of herbal extracts and their active
constituents that do appear regularly are, in general,
not subsequently evaluated adequately in terms of their
potential for identifying structurally or functionally
Received
Phytother. Res. 3 October(2006)
20, 1023–1035 2005
Accepted
DOI:1310.1002/ptr
June 2006
1024 V. KUMAR
novel CNS active drugs. The main goals of such reports
continue to be the evaluation of traditionally known
CNS active herbal remedies in terms of our current
understanding of brain functions, or to identify their
active constituents. In general, the main goal of these
reports has been to generate more evidence based
knowledge justifying their traditionally known thera-
peutic uses.
In view of the fact that the clinical efficacy of several
psychoactive herbal extract based remedies has been
demonstrated repeatedly in properly controlled clinical
trials, their efficacy can not be easily interpreted in terms
of current concepts of psychopharmacology, they
deserve proper attention as readily available sources
for structurally and functionally novel classes of CNS
active drugs. This communication summarizes our
current knowledge of the major bioactivities and clini-
cal efficacy of some currently popular CNS active herbal
remedies, which could stimulate interest in evaluating
these herbs as potential sources for structurally and
functionally novel CNS active drug leads or hits.
GINKGO BILOBA
Since early pharmacological studies revealed that
Ginkgo biloba leaf specific flavonoids modulated the
contractile functions of vascular smooth muscles,
efforts were subsequently made to obtain a well stand-
ardized extract enriched in flavonoids. This extract is
now often referred to as EGb 761, and until the 1990s,
almost all preclinical and clinical studies reported in
the literature were conducted with this extract only.
It was soon realized though that flavonoids can not
be the sole therapy relevant bioactive constituents and
that its clinical efficacy or pharmacological activity
is not easily interpretable in terms of its effects on blood
vessels only. During the 1980s, based on the results of
extensive studies made in several German and French
laboratories, it was suggested that the structurally unique
and Ginkgo biloba specific terpenic lactones, i.e.
bilobalide and ginkgolides, could be the CNS function
modulating components, and that it could be, pharmaco-
logically, a novel type of so-called ‘noo-tropic’ agent
with cognitive function modulating as well as neuro-
protective properties. Preclinical and clinical efficacy
data generated during these efforts, eventually led the
German and French health authorities to accept EGb
761, and some other analogous Ginkgo extracts (EGbs),
as a phytotherapeutic drug which could also be
prescribed by registered medicinal practitioners. More
recent preclinical and clinical studies have continued
to add further evidence in support of the conviction
that Ginkgo leaf extracts are useful remedies for cop-
ing with several age-related mental health problems
of the elderly, including those associated with AD.
Although, during the past two decades, Ginkgo extracts
have remained the most well studied herbal remedies
commercialized to date in the Western world, many
questions concerning active constituents and their modes
of actions can not yet be answered with certainty.
In any case, it seems certain now that their pharmaco-
logical activity profiles, active constituents and their
modes of actions are certainly not like those of any
known CNS active drug. Since describing all the
Copyright © 2006 John Wiley & Sons, Ltd.
published information on such extracts is beyond the
scope of this review, in the following an attempt will
be made to summarize only those potentially useful
for obtaining novel structurally and functionally novel
CNS active drugs based on our current knowledge on
Ginkgo extracts and their active constituents. Several
reviews and monographs (Boonkaew and Camper, 2005;
Nakanishi, 2005; Gertz and Kiefer, 2004; Sierpina et al.,
2003; Zimmermann et al., 2002; Z’Brun, 1995; Carrigan,
1995; Kleijnen and Knipschild, 1992; Warburton, 1988;
Boralle et al., 1988; Michel and Hosford, 1988) can be
consulted for more detailed information.
Some researchers showed that bilobalide, a consti-
tuent of Ginkgo biloba was successful in inhibiting
phospholipid breakdown and choline release under
hypoxic conditions (Klein et al., 1997). This group
has further established that bilobalide also inhibited
glutamatergic excitotoxic membrane breakdown both
in vitro and in vivo, an effect which may be beneficial
in the treatment of brain hypoxia and/or neuronal
hyperactivity (Weichel et al., 1999). Recently, a similar
group has also showed that bilobalide inhibited an
NMDA-induced chloride flux through glycine/GABA-
operated channels, thereby preventing NMDA-induced
breakdown of membrane phospholipids (Klein et al.,
2003). This effect is expected to contribute to the
neuroprotective effects of Ginkgo biloba extracts.
Chatterjee et al. (2003) demonstrated that ginkgolides
A, B, C and J were also effective blockers of glycine-
activated chloride channels in the hippocampal
neurons of rat, whereas Kondratskaya et al. (2004a)
pointed out that Ginkgolide B preferentially blocks
chloride channels formed by heteromeric glycine
receptors in hippocampal pyramidal neurons of rat.
In our laboratory, other studies are in progress to
investigate bilobalide and its mechanism of action
focused on its neuroprotective effects.
Dementia of the Alzheimer’s type (DAT), together
with vascular dementia, is the most important indica-
tion for Ginkgo biloba extract (EGb). The therapeutic
efficacy of this extract is founded on its neuroprotective,
metabolic and rheological effects. In addition to these
mechanisms – which also form the basis of the activity
of the older synthetic nootropics – the hypothesis that
DAT is due to a ‘cholinergic deficit’ at central synapses
has led, over the past decade, to the development of a
new group of drugs for this indication, the cholinesterase
(ChE) inhibitors. Thus nowadays, EGb is competing,
on the synthetic side, with the ChE inhibitors tacrine,
donepezil, rivastigmine and galantamine. In addition,
the benefits of treatment were rapidly reversed after
ending the administration of ChE inhibitors, which did
not occur to the same extent with EGb (Schulz, 2003a).
Adverse drug reactions were more than ten times more
common with the ChE inhibitors and the treatment
costs about five times higher than with EGb. Given the
limited therapeutic options for DAT, treatment with
EGb still appears to be the method of choice compared
with the ChE inhibitors (Schulz, 2003a). A few another
studies also confirmed the role of Ginkgo biloba or its
isolated constituents in dementia and other memory
disorders (Pan, 2005; Haan and Horr, 2004; Yao et al.,
2004; Lee et al., 2004; Kurz and Van Baelen, 2004; Evans
et al., 2004; Williams et al., 2004; Colciaghi et al., 2004;
Gertz and Kiefer, 2004; Kanowski and Hoerr, 2003;
Stackman et al., 2003; Smith and Luo, 2003; Ahlemeyer
Phytother. Res. 20, 1023–1035 (2006)
DOI: 10.1002/ptr
 POTENTIAL MEDICINAL PLANTS FOR CNS DISORDERS
and Krieglstein, 2003a; 2003b; Le Bars, 2003; Muller
and Chatterjee, 2003; Andrieu et al., 2003; Birks et al.,
2002; Nathan et al., 2002; Mix and Crews, 2002; Gasser
and Gasser, 2001; Wettstein, 2000; van Dongen et al.,
2000; Bastianetto et al., 2000).
During recent years, several cases of hemorrhage have
been reported to occur in coincidence with the use of
Ginkgo products. Although a clear causality between
Ginkgo intake and bleeding could not be established,
these observations have generally been explained by
the platelet activating factor (PAF)-antagonistic action
of ginkgolides, which represent characteristic constitu-
ents of Ginkgo extracts. A recent study raises serious
doubts that the PAF antagonistic effect of Ginkgolides
could be responsible for bleeding in patients taking EGb
761® (Koch, 2005). Rather it appears more likely that
the reported cases are isolated incidences which have
happened by chance in connection with the administra-
tion of Ginkgo extracts and whose frequencies are
within the statistical variation with which such events
occur. Indeed, it has recently been suggested that
frequently other motivations may be behind the publi-
cation of possible herb–drug interactions and the side
effects of phytomedicine (Ernst, 2003b). Another
recent study indicates that the effects of EGb 761 on
drug metabolizing enzymes are specific for rats and may
not be extrapolated to man (Chatterjee et al., 2005).
Although our current knowledge on the active
constituents and modes of actions of Ginkgo extracts
remain far from being satisfactory, existing preclinical
and clinical evidences available now are in agreement
with the conviction that more than one active constitu-
ent and mode of action is involved in its observed
clinical effects, and that the activity profile of a given
Ginkgo extract can not be predicted by the knowledge
of its already known or proposed bioactive constituents
only. Of the known CNS active constituents of Ginkgo
biloba leaf extracts, bilobalide seems to be unique, not
only structurally, but also pharmacologically. Although
much has been published on the pharmacological prop-
erties of ginkgolides, by far the vast majority of them
deal with their PAF antagonistic activity and that
too with that of ginkgolide B only. Since therapeutic
relevance of modulating PAF-receptor system still
remains controversial, and only a few reports on the
CNS function modulating effects of ginkgolides are
available at present, it is still too early to consider them
as lead molecules for drug discovery purposes. It must
be pointed out, that despite certain structural similari-
ties between ginkgolides and bilobalide, few analogies
between their CNS activity profiles could be detected.
The results of a recently reported structure–activity
study indicate that differences in the existing molecular
space around their common pharmacophore moiety (i.e.
t-butyl substituted cyclo-pentane ring) dictate their
activity profile (Chatterjee et al., 2003). One of the
molecules synthesized and tested to confirm this possi-
bility led to the identification of a structurally and func-
tionally novel molecule (NV-31) with a therapeutically
interesting combination of neuro-protective, memory
enhancing and other CNS function modulating prop-
erties with a broad safety margin. Thus it seems rea-
sonable to suggest that structure–activity studies with
known bioactive Ginkgo constituents could be a suit-
able starting point in the search for urgently needed
novel types of CNS active drugs. The structurally and
Copyright © 2006 John Wiley & Sons, Ltd.
1025
functionally novel pharmacophore moiety identified in
the previously mentioned report could be a starting
point as well.
HYPERICUM PERFORATUM (ST JOHN’S
WORT)
As in the case of Ginkgo biloba, current interest in the
use of Hypericum perforatum (HP) for the treatment
of mental health conditions was also triggered by
extensive efforts made by German physicians during
the 1980s. Soon after it became apparent that HP
extracts could be as useful for the treatment of mild
to moderately depressed patients as imipramine and
that HP extracts were better tolerated by the patients
than many synthetic antidepressants, extensive efforts
were initiated in many German industrial and academic
laboratories. Observations resulting from such efforts
have been chronologically published and mentioned
elsewhere in this review. In addition, more recently
books in the Milestones in Drug Therapy series by
Muller (2005) and Medicinal and Aromatic Plants-
Industrial Profiles series by Ernst (2003a) have summa-
rized nicely our current knowledge on CNS function
modulating effects of HP extracts, and several other
monographs and reviews have appeared (Izzo, 2004;
Muller, 2003; Rodriguez-Landa and Contreras, 2003;
Kumar et al., 2000b; Challem, 2001; Gaster and Holroyd,
2000; Linde et al., 1996; Bombardelli and Morazzoni,
1995). Therefore, in the following some more impor-
tant developments leading to the suggestion that this
herb could be used as a starting point in the search for
novel CNS active drugs are summarized only.
Hyperforin, a prenylated phloroglucinol present
in this plant, has been focused on as being primarily
responsible for the antidepressant activity of HP
(Bhattacharya et al., 1998a; Chatterjee et al., 1998a;
1998b; Biber et al., 1998; Laakmaann et al., 1998; Muller
et al., 1998). Many of the experimental and clinical
studies have confirmed the antidepressant activity of
hyperforin (Treiber et al., 2005; Vitiello et al., 2005;
Zanoli, 2004; Roz and Rehavi, 2004; Eckert et al., 2004;
Butterweck et al., 2003; Verotta, 2003; Zanoli et al.,
2002; Cervo et al., 2002; Marsh and Davies, 2002).
Indian Hypericum perforatum (IHp) extract standard-
ized for hyperforin lacked MAO-A and B inhibitory
activity (Kumar et al., 2001c). Additionally, IHp showed
antidepressant, anxiolytic, antiamnestic, antiinflam-
matory and analgesic and antistress activities in various
animal models (Kumar et al., 1999; 2000a; 2000b; 2000c;
2001a; 2001b; 2002; 2003; Zhang, 2004). Some research-
ers recently found that HP had neuroprotective effects
and diminished cognitive impairment and improved
spatial learning and memory (Trofimiuk et al., 2005;
Silva et al., 2004; Kumar et al., 2003; Widy-Tyszkiewicz
et al., 2002; Kumar et al., 2002; Klusa et al., 2001; Kumar
et al., 2000c). Other studies confirmed that hyperforin
released hippocampal acetylcholine (Kiewert et al., 2004;
Buchholzer et al., 2002) and HP reduced the degrada-
tion rate of acetylcholine (Re et al., 2003). A recent
study from our laboratory indicated that hyperforin may
be a potential neuroprotective agent that blocks activa-
tion of NMDA-type glutamate receptors (Kumar et al.,
2006; Kumar et al., 2005). Further studies testing the
Phytother. Res. 20, 1023–1035 (2006)
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1026 V. KUMAR
possible effect of hyperforin in protein kinase C-
mediated responses and in vivo experiment(s) to
evaluate hyperforin as a potential inhibitor of water
transport are in progress (unpublished).
The current widespread medicinal uses of HP
extracts concentrate mainly on their therapeutic effects
in patients with mild to moderately severe depression,
and that too with hydro-alcoholic extracts only. The
very first report on the efficacy of such an extract
(Daniel, 1935) dates back much earlier than the for-
tuitous discovery of these effects of the synthetic tri-
cyclic antidepressant imipramine or the MAO inhibitor
iproniazide. Interestingly, however, the discovery of
these two synthetic antidepressants during the 1950s
continues to have important impacts on the develop-
ment of modern psychotherapeutics, whereas the simi-
lar clinical efficacy of HP extracts remained unexplored
until the last decades of the past millennium. Only very
recently, some scattered reports on efforts to develop a
hyperforin derivative as an antidepressant as discussed
above or on other possible psychotherapeutic potentials
of hyperforin derivatives or HP extracts have appeared.
In any case, the vast majority of reports on the poten-
tial psychotherapeutic uses of this herb and its CNS
active constituents appearing during the past decade
concentrate around hyperforin only. It can not be over-
emphasized though, that several other therapeutically
interesting CNS-active HP constituents have already
been identified, and that none of the therapeutically
interesting pharmacological properties of HP extracts
can yet be properly explained by their content of the
known bioactive constituents alone. In addition, avail-
able quantitative data on antidepressant like and other
CNS function modulating effects of hyperforin and HP
extracts strongly suggest that, quantitatively, the con-
tribution of hyperforin to the observed antidepressant-
like efficacy of HP extracts must not be a major one.
Indeed, the clinical efficacy of HP extracts almost
devoid of hyperforin has been reported (Käufeler
et al., 2001), and it has been demonstrated also that
hyperforin and HP extracts are more potent cognitive
function modulating agents than antidepressants (Klusa
et al., 2001). Thus, as often suggested in the literature,
the initiation of drug discovery projects based on our
current knowledge on hyperforin seems desirable,
concentrating such efforts for obtaining novel anti-
depressants only seems not very justifiable.
HP has an excellent safety profile clearly superior to
many conventional antidepressants (Stevinson and
Ernst, 2000). The only potentially serious adverse
effects are photosensitization, which is extremely rare,
and the induction of manic symptoms in predisposed
patients (Schulz, 2000). In recent years, multiple case
reports and clinical studies in herb–drug interactions
have been published (Izzo, 2004). In addition, several
preclinical reports have demonstrated that many
bioactive constituents of HP-extracts can modulate the
activities of hepatic drug metabolizing enzymes (Singh,
2005, Muller et al., 2004b; Mills et al., 2004; Fugh-Berman
and Ernst, 2001; Izzo, 2004, and that hyperforin is a
very potent modulator of a therapeutically important
drug transport protein, which is encoded by the multi-
ple drug resistance-gene MDR-1 (Bodo et al., 2003).
There is consistent evidence that clinically relevant drug
interactions may occur when St John’s wort is co-
administered with other drugs, in particular with agents
Copyright © 2006 John Wiley & Sons, Ltd.
predominantly metabolized by CYP3A4 and P-
glycoprotein at the same time (Mannel, 2004; Ernst,
2002; 1999; Drewe, 2000). Through these mechanisms,
HP can decrease the plasma range of prescribed drugs
(such as anticoagulants, oral contraceptives and antivi-
ral drugs), with possible clinically serious consequences
(Ruschitzka et al., 2000; Piscitelli et al., 2000; Yue et al.,
2000). Some evidence indicates that HP and selective
serotonin reuptake inhibitors may lead to serotonin
overload or the serotonin syndrome, particularly in
elderly patients (Ernst, 2002; Ernst, 1999). Although
these reports strongly suggest that co-medications of
some other drugs with HP extracts should be made
with caution, it can not be ignored that many known
psychoactive drugs possess, in addition to other more
serious side effects, potential for drug–drug interaction.
Since all the properly controlled clinical trials of
diverse types of HP extracts in patients with mild to
moderately severe depression have consistently demon-
strated efficacy and a very high safety margin, and
that drug–drug interaction is their only potential side
effect, such extracts can be considered as one of the
safest known psychotherapeutic agents with proven
clinical efficacy according to the modern concept of
‘evidence based medicine’.
PIPER METHYSTICUM (KAVA KAVA)
Piper methysticum Forst. (Family Piperaceae) called
kava, continues to occupy a central place in everyday
life in the Polynesian islands concerned. The term ‘kava’
and the variant ‘kawa’ are used for both the plant and
the beverage made from it. The origins of kava usage
in Oceania are not known. The first pharmacological
evaluation of the kava pyrones was published in Lewin’s
admirable monograph but because limited quantities
of pure compounds – methysticin and yongonin – were
at his disposal, his data now are deemed of only histori-
cal significance (Lewin, 1886). A study showed that kava
helped to induce deep sleep that set in lasting from 2 to
10 h. The birds used in the study appeared to be fully
recovered upon awakening (Van Veen, 1938). Many
researchers demonstrated Kava’s effectiveness in anxi-
ety disorders and enhancing sleep quality through
preclinical or placebo-controlled double-blind studies
(Capasso and Sorrentino, 2005; Brown and Gerbarg,
2001; Conner et al., 2001; Witte et al., 2005; Shinomiya
et al., 2005b; Jorm et al., 2004a; 2004b; Barnett et al.,
2001; Cote et al., 2004; Abraham et al., 2004; Geier
and Konstantinowicz, 2004; Feltenstein et al., 2003;
Wheatley, 2001a; 2001b; Singh and Singh, 2002; Ernst,
2002; Smith et al., 2001; Beaubrun and Gray, 2000; Pittler
and Ernst, 2000). Thompson et al. (2004) investigated
the acute effects of the herbal anxiolytic Kava-kava on
emotional reactivity and cognitive performance through
a double-blind randomized placebo-controlled trial
involving healthy volunteers. The results of this study
indicate that the mood-elevating effects of Kava were
most prominent in trait cheerful subjects, indicating that
trait cheerfulness moderated the drug-induced increase
in cheerful mood. Furthermore, Kava improved the
accuracy and the speed of performing the partial
report and the item recognition task, indicative of a
beneficial effect of the phytopharmacon on visual
Phytother. Res. 20, 1023–1035 (2006)
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 POTENTIAL MEDICINAL PLANTS FOR CNS DISORDERS
attention and short-term memory retrieval, respectively.
Thus, unlike conventional benzodiazepine-type anxi-
olytics, which tend to impair cognitive performance and
to increase the occurrence of negative affective states,
Kava is a potent anxiolytic agent, which, additionally,
can facilitate cognitive functioning and can increase
positive affectivity related to exhilaration.
In a 1996 randomized placebo-controlled double-blind
study, two groups of 29 patients were treated with a
standardized special extract made from kava rhizome
or placebo. The dose was 100 mg of dry extract stand-
ardized to 70 mg kava lactones three times daily for
4 weeks. The study concluded that kava was clinically
effective in the reduction of states of anxiety, tension
and excitedness of non-mental origin. No adverse re-
actions were noted (Lehmann et al., 1996). Kava con-
tinues to occupy a central place in South Pacific
communities, and its importance there recently has
increased with a surge of interest in the ethnic culture
and customs of native people. Kava products were sold
in the USA in many health food stores, Polynesian
grocery stores, by mail order and also in mass market
outlets. Because of its reputed lack of addictive proper-
ties, legal availability and claims by various authors (it
induces ‘deep restful sleep and clear, epic-length dreams’
(Tierra, 1990), ‘enhances psychic powers and visions’
(Cunningham, 1991) and ‘relieves insomnia and ner-
vousness’ (Santillos, 1991) and because earlier it has
been recognized by European health authorities as a
relatively safe remedy for anxiety (Blumental et al.,
1998), kava had rapidly gained popularity. The present
interest and widespread use of herbal medicines has
created the possibility of interaction between them and
pharmaceutical drugs if they are used concomitantly.
Before the recent reports of apparent hepatotoxicity
associated with the use of Kava, it was one of the top
10 selling herbal remedies in Europe and North America
(Singh, 2005). This adverse effect had not been pre-
viously encountered with the traditional beverage
prepared as a water infusion in contrast to the com-
mercial products extracted with organic solvents.
Kavalactones, the active principles in kava, are potent
inhibitors of several of the CYP 450 enzymes, sug-
gesting a high potential for causing pharmacokinetic
interactions with drugs and other herbs which are
metabolized by the same CYP 450 enzymes (Singh,
2005; Anke and Ramzan, 2004b; Zou et al., 2004).
Furthermore, some kavalactones have been shown to
possess pharmacological effects, such as blockade of
GABA receptors and sodium and calcium ion chan-
nels, which may lead to pharmacodynamic interac-
tions with other substances which possess similar
pharmacological properties (Singh, 2005). Hu et al.
(2005) showed that Kava enhanced the hypnotic effect
of alcohol in mice, but this was not observed in
humans. The authors further suggested that herbs should
be appropriately labeled to alert consumers to poten-
tial interactions when concomitantly used with drugs,
and to recommend a consultation with their general
practitioners and other medical carers. In fact, hepatic
toxicity from manufactured herbal remedies that con-
tain kava lactones has been reported in Europe, North
America and Australia (Clough et al., 2003). There is
no evidence for serious liver damage in kava-using
populations in Pacific Island societies or in indigenous
Australians who have used aqueous kava extracts. The
Copyright © 2006 John Wiley & Sons, Ltd.
1027
authors also stated that liver function changes in users
of the aqueous kava extracts at moderate levels of con-
sumption appear to be reversible and begin to return
to baseline after 1 to 2 weeks abstinence from kava. No
evidence for irreversible liver damage has been found
(Clough et al., 2003).
Toxicological and clinical studies have shown that
kava extracts are virtually devoid of toxic effects with
the exception of the rare hepatotoxic side effects re-
ported in few patients (Teschke et al., 2003). In recent
years, kava kava has been implicated in a number of
liver failure cases. Ever since this has kept the scientific
world busy. Even though, on closer inspection, the
majority of the case reports are probably not connected
to kava intake, the hepatotoxic effects of kava cannot
generally be ruled out (Anke and Ramzan, 2004a). In
spite of all these hypotheses, there is still no satisfac-
tory answer. In any case, further studies, that might
hopefully restore the reputation of kava, are required.
However, a recommendation has already been made
by Natural Standard Research Collaboration, Cam-
bridge, MA, USA to consolidate and analyse available
reports and to continue postmarket surveillance in an
international repository to prevent duplication and to
promote the collection of thorough details at the time
of each report so that any association with kava is clearly
defined (Ulbricht et al., 2005).
Wheatley (2005) demonstrated that Kava-kava is
a well-established hypnotic drug, with a rapid onset
of effect, adequate duration of action and minimal
morning after-effects. However, reports of serious
hepatotoxicity with this preparation have led to it
being banned in most countries worldwide. In his
personal trial (not double-blind) in stress-induced
insomnia, kava and valerian improved sleep and the
ill-effects of stress, and the combination of the two was
even more effective for the control of insomnia. The
author concluded there is a need for longer-term con-
trolled studies.
During the early 1950s some concentrated efforts
were made to evaluate the antiepileptic-like efficacy of
pure methysticine and one of its synthetic analogs,
ethysticine. The results of clinical trials conducted
during these efforts demonstrated their efficacy only
after a very high or near toxic dose, and thus no further
efforts were made to develop it as a drug. However,
later extensive efforts (supported by ADD project of
NIMH, USA) to obtain a therapeutically useful
kavalactone derivative led to the identification of
losigamone as a potential antiepileptic drug (Chatterjee
and Nöldner, 1997). Its efficacy and safety as an
add-on therapy for drug resistant epilepsy have been
demonstrated in several clinical trials, and its pre-
clinical activity profile revealed that in addition to
anticonvulsant activity it possessed a broad range of
therapeutically interesting CNS function modulating
properties. Despite extensive efforts, no definitive
statements can yet be made on its mode of action,
which is also the case for the neuroactive kavalactones
(Chatterjee and Nöldner, 1997). Therefore, it seems
reasonable to suggest that further concentrated
efforts to understand the proper therapeutic use and
mode of actions of kava-lactones, can not only lead
to novel drugs, but also to urgently needed novel
pharmacological targets potentially useful for drug
discovery purposes.
Phytother. Res. 20, 1023–1035 (2006)
DOI: 10.1002/ptr
1028 V. KUMAR
VALERIANA OFFICINALIS
Valeriana officinalis L. (Valerian) is a perennial her-
baceous plant, belonging to the Valerianaceae family.
Etymologically, Valeriana derives from the Latin word
‘Valere’ (well being); ‘officinalis’ is a term indicating
the pharmaceutical use of the plant. Valerian has been
used therapeutically since the Greek and Roman times.
Discorides in the first century AD described its use as
a mild sedative. V. officinalis is a plant widely distrib-
uted in Europe and Asia; nowadays, for medicinal use,
it is largely cultivated in Europe. Complementary thera-
pies are becoming increasingly popular, particularly for
symptoms such as sleep disturbance. The herb valerian
may be useful as a mild sleep aid in the clinical popu-
lation, such as for persons with rheumatoid arthritis
(Taibi et al., 2004).
In Unani, Ayurvedic and Homoeopathic systems of
medicine, it is used as a cardiotonic, sedative, stimulat-
ing, cure for epilepsy, hysteria and convulsive affec-
tions, in increased heart palpitation, in intestinal colic,
for late scanty menses and as an antiseptic. Valerian
has been used in China for over 1000 years for similar
purposes. The essential oils in valerian appear to pro-
vide its sedative activity, while the valepotriates exert a
regulatory effect on the autonomic nervous system.
Although more than 150 constituents have been identi-
fied, none appear to be solely responsible for valerian’s
effects, suggesting that many compounds may act
synergistically (Houghton, 1999; Hendriks et al., 1981).
Despite the well-known sedative properties of
valerian, little information exists on the activity of the
different GABA receptors and their modulatory sites.
The total extract of valerian, as well as the isolated
sesquiterpene alcohols and ketones and valepotriates
were reported to induce a significant displacement of
fluorodiazepam in the guinea-pig brain (Thies and
Funke, 1966). A slight inhibition of 3H-flunitrazepam
binding to benzodiazepine-like immunoreactivity in the
TLC of the extract fractions was observed, thus sug-
gesting that the binding inhibition could be due to in-
terfering substances in the total extract (Medina et al.,
1989). A recent study indicates that valerian and valeric
acid are new partial agonists of the 5-HT (5a) receptor
(Dietz et al., 2005). Another in vitro study showed that
valerian had binding affinity at the melatonin (ML 1
and ML 2) and serotonin (5-HT4e, 5-HT6 and 5-HT7)
receptor subtypes (Abourashed et al., 2004). A few stud-
ies also established valerian’s role through GABA
mediation (Yuan et al., 2004; Santos et al., 1994c).
Schellenberg et al. (2004) indicated in a clinical trial
that valerian extract acts via a central adenosine mecha-
nism which is possibly the reason for its sleep-inducing
and maintaining activity.
The clinical use of valerian as a sedative is well known
and widespread. The drug is used in the composition of
many proprietary medicinal products in the form of its
galenic preparations, mostly as an extract and tincture.
Valerian was used as a sedative in various forms of
nervous disorders, non-severe hysterical conditions,
anxiety, neurasthenia, all cases of nervous sensory or
cerebral erethism, menopausal disturbances, nervous
gastralgia and infantile anorexy. The drug was usually
administered half an hour before meals (Auster and
Schaefer, 1958). The value of past clinical studies is
Copyright © 2006 John Wiley & Sons, Ltd.
limited as they are all relevant to uncontrolled trials,
conducted with a variety of valerian preparations.
Reference is here made for historical reason to the
paper of Schultz and Mueller (1960), where the reports
of different valerian investigators are reviewed. A
double-blind clinical study, comparing a valerian
aqueous extract, placebo and a commercial prepara-
tion containing extracts of valerian and hop flowers,
showed that valerian produced a significant increase in
sleep quality. The improvement in sleep quality was
most notable among people who considered themselves
poor and irregular sleepers (Leathwood et al., 1982;
Leathwood and Chauffard, 1985). Another double-blind
study (Lindahl and Lindwall, 1989) was carried out on
a valerian preparation standardized for sesquiterpenes.
Volunteers with self-reported sleep difficulties were
selected. The study showed significant improvement
in subjective sleep quality, 44% reporting perfect sleep
and 89% reporting improved sleep with the prepara-
tion. Other clinical trials and animal studies also
established the effect of valerian on improving sleep
quality and its role as a sedative (Shinomiya et al., 2005a;
Fernandez et al., 2004; Oliva et al., 2004; Trevena, 2004;
Diaper and Hindmarch, 2004; Hadley and Petry,
2003; Hallam et al., 2003; Ziegler et al., 2002; Cropley
et al., 2002; Poyares et al., 2002; Larzelere and Wiseman,
2002; Andreatini et al., 2002; Krystal and Ressler, 2001;
Wheatley, 2001a; Fussel et al., 2000; Dominguez et al.,
2000; Donath et al., 2000).
Valerian is on the FDA’s Generally Recognized
as Safe (GRAS) list. The results of a recent phase I
clinical study show that valerian is a safe herb with
respect to effects on human male sterility when admin-
istered at dose levels corresponding to approximately
three times the human daily dose (Mkrtchyan et al.,
2005). Many studies reported in this review confirm the
validity of valerian preparations, in spite of the doubts
raised in the past.
BACOPA MONNIERA
Though pharmaceutical companies continue to invest
enormous resources in identifying agents that could
be used to alleviate debilitating disorders and retard
mental deterioration afflicting numerous people around
the world, a source of potentially beneficial agents,
namely phytochemicals, would appear to have signifi-
cant benefits that have yet to be fully exploited (Russo
and Borrelli, 2005). Bacopa monniera (BM) in India is
locally known as Brahmi or Jalanimba (Chopra et al.,
1956). The name Brahmi is derived from the word
‘Brama’, the mythical ‘creator’ in the Hindu pantheon.
Because the brain is the centre for creative activity,
any compound that improves the brain health is
called Brahmi. ‘Brahmi’ which also means ‘bringing
knowledge of the Supreme Reality’ and it has long been
used there medicinally and as an aid to meditation. In
India, BM is largely treasured as a revitalizing herb
that strengthens nervous function and memory.
BM has been used by Ayurvedic medical practition-
ers in India for almost 3000 years and is classified as
a medhyarasayana, a drug used to improve memory
and intellect (medhya). BM has been mentioned in
several ancient Ayurvedic treatises including the Charaka
Phytother. Res. 20, 1023–1035 (2006)
DOI: 10.1002/ptr
 POTENTIAL MEDICINAL PLANTS FOR CNS DISORDERS
Samhita (6th century AD), in which it is recommended
in formulations for the management of a range of
mental conditions including anxiety, poor cognition
and lack of concentration, and the Bhavprakash
Var-Prakarana (16th century AD). In certain parts of
India, Brahmi is believed to be an aphrodisiac; in Sri
Lanka, under the name of Loonooweella, Brahmi is
prescribed for fevers; in the Philippines, it is used as a
diuretic (Uphof, 1968).
The BM extracts and isolated bacosides have been
investigated extensively for their neuropharmacological
effects and their nootropic action or antiamnestic
effect confirmed (Kishore and Singh, 2005; Anbarasi
et al., 2005a; 2005b; 2005c; Jorm et al., 2004; Achliya
et al., 2004; Nathan et al., 2004; Sumathi et al., 2002a;
2002b; Das et al., 2002; Nathan et al., 2001; Kidd, 1999;
Malhotra and Das, 1959; Singh and Dhawan, 1982; Singh
and Dhawan, 1992; Singh and Dhawan, 1997). Singh
et al. (1988) suggested that bacosides induce membrane
dephosphorylation, with a concomitant increase in pro-
tein and RNA turnover in specific brain areas. The other
proposal is that BM enhances protein kinsae activity
in the hippocampus which may also contribute to its
nootropic action (Singh and Dhawan, 1997). Loss of
cholinergic neuronal activity in the hippocampus is the
primary feature of Alzheimer’s disease (Enz et al., 1993).
A team of other researchers reported that a stand-
ardized bacosides-rich extract of BM, reversed the
cognitive deficits induced by intracerebroventricularly
administered colchicines and injection of ibotenic acid
into the nucleus basalis magnocellularis (Bhattacharya
et al., 1999). In the same study, BM also reversed the
depletion of acetylcholine, the reduction in choline
acetylase activity and the decrease in muscarinic
cholinergic receptor binding in the frontal cortex and
hippocampus.
BM extract or bacosides have also shown anxiolytic
effects (Bhattacharya and Ghosal, 1998b; Shankar and
Singh, 2000), antidepressant activity (Sairam et al., 2002),
anticonvulsive action (Shanmugasundaram et al., 1991;
Martis and Rao, 1992; Ganguly and Malhotra, 1967),
antioxidant activity (Singh et al., 2006; Bafna and
Balaraman, 2005; Rohini et al., 2004; Russo et al., 2003a;
2003b; Sumathy et al., 2001; Pawar et al., 2001;
Bhattacharya et al., 2000c; Tripathi et al., 1996) anti-
stress (Rai et al., 2003; Chowdhuri et al., 2002)
and antiulcerogenic activity (Dorababu et al., 2004;
Jain et al., 1994; Rao et al., 2000; Sairam et al., 2001;
Goel et al., 2003). Singh et al. (1996) suggest an involve-
ment of the GABA-ergic system in the mediation of
central nervous system effects of BM.
Various clinical studies have also been carried out to
establish the efficacy of BM in memory and attention
disorders (Maher et al., 2002; Roodenrys et al., 2002;
Stough et al., 2001; Dave et al., 1993; Sharma et al.,
1987; Singh and Singh, 1980; Ghosh and Kar, 1966;
Mukherjee and Dey, 1966). In view of the positive
results of such clinical trials, BM has been introduced
in the Indian market and in other countries, alone or in
combination with other phytocomplexes, and utilized
in the treatment of memory and attention disorders
(Shukia et al., 1987).
BM has been found to be well tolerated and without
any untoward reaction or side effects in many regula-
tory pharmacological and toxicological studies (Russo
and Borrelli, 2005). The LD50 of aqueous and alcohol
Copyright © 2006 John Wiley & Sons, Ltd.
1029
crude extracts of BM in rats were 1000 mg and 15 g/kg
by the intraperitoneal route, respectively (Martis et al.,
1992). It has been reported that antiepileptic drugs, such
as phenytoin, can result in cognitive impairment (Smith,
1991). Vohora et al. (2000) reported that BM reversed
the phenytoin-induced cognitive impairment when
administered concomitantly with phenytoin which sug-
gests a potential corrective effect of BM extract in
phenytoin-induced cognitive deficits. Diverse studies
indicated that interactions between herbal medicines
and synthetic drugs exist and can have serious conse-
quences (Izzo and Ernst, 2001). Therefore, it is neces-
sary to consider the possibility of BM–drug interaction.
The mechanism of action behind various reported
preclinical studies indicating a cognitive enhancing ef-
fect is still uncertain, as its multiple active constituents
make its pharmacology complex. In light of the many
reports showing important activities of BM extracts or
bacosides, further research is required to ascertain the
findings mentioned in this review.
CONVOLVULUS PLURICAULIS
Convolvulus pluricaulis (CP) is also known as
Shankhpushpi (or shankapushpi), is an herb that has
been used in India for hundreds of years for nervous
disorders such as stress, anxiety and insomnia. It pro-
duces a feeling of peace and calm, reduces stress, anxi-
ety and mental fatigue. Shankhpushpi is a morning-glory
like perennial that grows on the plains of India. It has
been widely used in Ayurvedic medicine to treat ner-
vous disorders, in the same way that kava-kava and
valerian are prescribed by American herbalists. It is
only recently that Shankhpushpi has been brought to
American stores for medicinal use. Herbalists believe
that Shankhpushpi calms the nerves by regulating the
body’s production of the stress hormones, adrenaline
and cortisol.
In Ayurvedic medicine, it is also believed that
Shankhpushpi is an anti-aging remedy called Rasayan.
Even though Ayurvedic practitioners have used
Shankhpushpi for centuries, there is no hard scientific
evidence as to the positive effects of this herb, beside
a few Indian studies performed in the 1970s and
1980s and most of them were published locally. In those
studies, people suffering from anxiety were given
Shankhpushpi for 6 weeks and claimed to have slept
better, have more energy and better concentration. In
one of these studies, published in an Indian Medical
Journal in 1982, researchers gave 28 people diagnosed
with anxiety 50 mg daily of an herbal formula with
shankhpushpi as a primary ingredient. After 6 weeks
of treatment, 91% of the patients had more energy
and 60% to 70% could sleep and concentrate better
(Shaughnessy, 2002). Today this herb is still the pre-
ferred method for reducing symptoms associated with
anxiety, panic attacks, nervousness and insomnia. The
leaves of Shankhpushpi are used to treat chronic
bronchitis and asthma. The root is used for childhood
fever, and the oil stimulates the growth of hair. Using
the whole plant in the form of a decoction with cumin
and milk is used to treat fever, debility, memory loss,
syphilis and scrofula. Ganju et al. (2003) has showed
that Shankhpushpi has immunomodulatory effects.
Phytother. Res. 20, 1023–1035 (2006)
DOI: 10.1002/ptr
1030 V. KUMAR
Another study indicated that CP has an antiulcerogenic
effect due to augmentation of mucosal defensive fac-
tors such as mucin secretion, lifespan of mucosal cells
and glycoproteins rather than on the offensive factors
such as acid-pepsin (Sairam et al., 2001c).
CP shows promise as a safe, effective remedy for
anxiety, but controlled human studies are needed
to establish scientifically its efficacy in various CNS
disorders with special emphasis on memory enhancing
properties. Indurwade and Biyani (2000) found that
shankhpushpi has potent depressive action in mice.
A study indicated that CP has antiepileptic activity
and researchers further investigated the CP interaction
with phenytoin from both pharmacokinetic (serum
levels) and pharmacodynamic (electroshock seizure
prevention) aspects. They advised that clinical combina-
tion of CP with phenytoin should be avoided (Dandekar
et al., 1992).
CONCLUSIONS AND PERSPECTIVES
Although the therapeutic possibilities offered by herbs
for diverse types of CNS disorders have been known to
mankind for centuries, until now little concentrated
effort has been made to define and understand their
most appropriate therapeutic uses, or to exploit them
for identifying and developing CNS active drugs. As
can be inferred from the facts mentioned in the intro-
duction, researchers interested in CNS active drug dis-
covery projects have been, until recently, very negligent
in using existing knowledge on herbal remedies as the
starting point for their endeavours. Such a situation
is surprising because several modern therapeutically
interesting concepts of modern pharmacology, in gen-
eral, and psychopharmacology in particular, could be
conceived through studies and efforts made to better
understand the traditionally known herbal remedies
only. Hereupon studies conducted with reserpine (an
active principle of Raulwolfia serpentina), amphetamine
(a congener of ephedrine, an active component of the
Chinese herbal agent ma huang) and with many other
well known psychoactive secondary plant metabolites
played a crucial role. Thus, although the clinical anti-
psychotic effects of reserpine were described during
the early 1950s, i.e. the same period during which the
therapeutic efficacy of chlorpromazine was first demon-
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Acknowledgements
The author would like to dedicate this article to his PhD mentors Dr
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