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Phytomedicine, Vol. 8(5), pp. 401–409
© Urban & Fischer Verlag 2001
Synergy and other interactions in phytomedicines
E. M. Williamson
The School of Pharmacy, University of London, London, United Kingdom
Synergistic interactions are of vital importance in phytomedicines, to explain difficulties in always
isolating a single active ingredient, and explain the efficacy of apparently low doses of active con-
stituents in a herbal product. This concept, that a whole or partially purified extract of a plant of-
fers advantages over a single isolated ingredient, also underpins the philosophy of herbal
medicine. Evidence to support the occurrence of synergy in within phytomedicines is now accumu-
lating and is reviewed here. Synergistic interactions are documented for constituents within a total
extract of a single herb, as well as between different herbs in a formulation. Positive and negative
aspects of interactions are discussed together with the methods used to identify and measure syn-
ergy. The evidence is divided into experimental, in vitro instances, as well as clinical examples
where available. Herbs discussed include Ginkgo biloba, Piper methysticum (Kava-Kava), Gly-
cyrrhiza glabra, Hypericum perforatum, Valeriana officinalis, Cannabis sativa, Salix alba and oth-
Key words: synergy, phytomedicine, herbal interactions
Many of the most effective phytomedicines are on the
drug market as whole extracts of plants, and practition-
ers have always believed that synergistic interactions
between the components of individual or mixtures of
herbs are a vital part of their therapeutic efficacy. Until
fairly recently there has been little clinical evidence to
demonstrate conclusively that this is the case, and it
very often it is argued that the dose of supposed active
constituents is too low to exert any therapeutically rele-
vant effect at all. In the absence of clinical proof this
has led sceptics to dismiss these medicines as placebos,
and it is compounded by the fact that there may be re-
sult in a measurable efficacy only after continuous ad-
ministration, which might be due to a cumulative ef-
fect. For this reason long-term therapy is routine, but
this is not a unique property of natural products and is
found in conventional medicines such as the synthetic
antidepressants where several weeks of treatment may
be necessary before a clinical improvement is seen.
The use of drug combinations is also not confined to
herbal products, and for example cancer chemotherapy,
the treatment of HIV and hypertension, routinely em-
ploy drug combinations consisting of two or more indi-
vidual substances. In fact the mechanism of action of
many phytomedicines is still unknown and there are
several instances of a total herb extract showing a
better effect than an equivalent dose of an isolated
compound, for which we have no real rationale. Some
of these will be outlined in this review. Speculation
as to the reason for this, whether it involves synergy,
0944-7113/01/08/05-401 $ 15.00/0
E. M. Williamson
enhanced bioavailability, cumulative effects or simply
the additive properties of the constituents requires fur-
ther research. It will probably involve a thoroughly
new approach, for instance by investigating mecha-
nisms using new molecular biology techniques for the
isolated ingredients individually and in combination,
as has been described by Wagner (1999). In this re-
spect, we are only at the beginning of an interesting
new research field, which should shed light on how
these remedies work, and ultimately result in reduced
side effects and a better therapeutic success.
munosuppressants after transplantation, warfarin as an
anticoagulant and the protease inhibitors used to treat
HIV infection. In addition, herbal products with reput-
ed synergistic activity should not be used if they are
potent herbs used in conditions where the dose is cru-
cial. Foxglove, Digitalis , is not a suitable herbal reme-
dy for congestive heart failure and heart insufficiency
grade I and II according to the NYHY, as the therapeu-
tic index is so low, but hawthorn certainly is because
of its more gentle, cumulative, and probably synergis-
tic, effect.
Positive and negative aspects
of herbal interactions
Differences in the approach
to treatment
In general, synergistic effects are considered to be pos-
itive, with the low doses used perceived as a benefit,
although it is obvious that there may also be negative
aspects. Adverse reactions (ADR’s) tend to be more
apparent with combinations of herbs or interactions
with prescribed synthetic medicines, but clinical mani-
festations of do not seems to be common, which may
be due partly to a lack of reporting of ADR’s for
herbals. Important positive interactions would include
those of Ayurveda, which uses many fixed combina-
tion formulae with “Trikatu” featuring in many of
them. This mixture contains black pepper, Piper
longum , and ginger, Zingiber officinalis and although
an ancient recipe, it is only recently that this combina-
tion has been investigated scientifically and reasons
put forward for its inclusion. Pepper contains the al-
kaloid piperine, which is known to increase the
bioavailability of a number of drugs such as vasicine
(also known as peganine), an antiasthmatic alkaloid
from Adhatoda vesica (Johri et al. 1992). It may be
that this applies much more commonly than has been
previously thought and has implications for nutrition.
Unwanted interactions for example would be the pres-
ence of tannins in a herbal drug, which may hinder the
absorption of proteins and alkaloids, or the induction
of enzymes such as cytochrome P450 which may ac-
celerate drug metabolism resulting in blood levels of
actives too low for a therapeutic effect. This could
have more serious consequences, for example in the
case of St John’s Wort (SJW), Hypericum perforatum -
extract, where interactions with oral contraceptives
have been reported, albeit infrequently. For further re-
ferences negative interactions of herb drugs with syn-
thetic drugs see Ernst et al.1999. However the synthet-
ic drugs involved are usually well known for their po-
tential to interact and patients taking them are warned
not to combine their medication with any other unless
under medical supervision. The most important drugs
from this point of view are cyclosporin used as an im-
As well as with European phytomedicine, Oriental
systems such as traditional Chinese medicine and
Ayurveda generally assume synergy to be taking place,
and it is an intrinsic part of their concept or philosophy
of therapy. Combinations of herbs are normal and may
be either historical formulations, which have been de-
veloped by empirical observation or are put together
for an individual patient. To complicate matters fur-
ther, herbalists use preparations and mixtures which
are not necessarily intended to target a particular
organ, cell tissue or biochemical system , making syn-
ergy even more difficult to identify. The use of phy-
tomedicines has been described as the “herbal shot-
gun” approach, as opposed to the “silver bullet”
method of conventional medicine (Duke and Bogen-
schutz-Godwin 1999) to distinguish the multi-targeted
approach of herbals from the specific enzyme or re-
ceptor target of a synthetic drug. Something as simple
as including a laxative in a preparation for hemo-
rrhoids would fulfil this definition and synergy does
not need to apply in any way at all. There is also the
approach taken by herbalists to skin disorders such as
eczema where the approach differs radically from con-
ventional medicine. In Western medicine, the treat-
ment often involves topical application of corticos-
teroids, which are symptomatically effective but have
inherent disadvantages. In contrast, the Chinese herbal
remedy containing multiple ingredients used to treat
eczema (Sheehan and Atherton 1992) is a good exam-
ple of the herbal approach. However, until the nature
of the interaction is explained and extracts standard-
ised to incorporate what is known, care must be taken.
Further research is therefore paramount to emphasise
the unique qualities of herbal medicines and to ratio-
nalize the therapeutic effect of the complex mixtures
of single drugs or constituents; in addition results can
be extrapolated to other medicines, and can give
lessons in managing disease effectively and with mini-
mal adverse effects.
Synergy and other interactions in phytomedicines
1. Summation of effects: this is when the total effect
of a combination is greater than expected from the
sum of its effects. In effect: E (da,db) = E (da) + E(db),
E = the observed effect, and da and db are the doses
of agents a and b
As it depends on the mechanism of action of each
component, and assumes a linearity of response for
each, it is largely irrelevant when dealing with com-
plex mixtures, it will not be discussed further.
2. Measurement of a fixed dose of one on the dose-
response of another component: This has similar
disadvantages to the “summation of effects” model.
3. Comparison of the effect of a combination with
that of each of its components: This seems very
logical until examined further. It was originally sug-
gested by Gaddum in 1940, ( via Berenbaum 1989),
and says that synergy is deemed present if the effect
of a combination is greater than that of each of
the individual agents – i.e. E(da,db) > E(da), and
E(da,db) > E (db)
This method is independent of any knowledge of
the mechanism of action, and seems logical at first
glance. It is however easily destroyed by looking at
Berenbaum’s example: if two men, working sepa-
rately, can each cut down 10 trees in a day, but to-
gether can cut down only 15, then this would actual-
ly fulfil Gaddum’s mathematical requirements, but
is obviously a nonsense.
4. Isobole method: this is now the method of choice,
and although more complicated, is independent of
the mechanism of action and applies under most
conditions. It also makes no assumptions as to the
behaviour of each agent and is therefore applicable
to multiple component mixtures. An isobole is an
“iso-effect” curve, in which a combination of con-
stituents (da,db) is represented on a graph, the axes
of which are the dose-axes of the individual agents
(Da and Db). If the agents do not interact, the
isobole (the line joining the points representing the
combination to those on the dose axes representing
the individual doses with the same effect as the
combination) will be a straight line. If synergy is oc-
curring, i.e. the effect of the combination is greater
than expected from their individual dose-response
curves, the dose of the combination needed to pro-
duce the same effect will be less than for the sum of
the individual components and the curve is said to
be ‘concave’. The opposite applies for antagonism,
in which the dose of the combination is greater than
expected, and produces a ‘convex’ isobole (Fig 1). It
is quite possible to have synergy at one dose combi-
nation and antagonism at another, with the same
substances and this would give a complicated
isobole with a wave-like or even elliptical appear-
Fig. 1. The Isobole method of identifying synergy. Da and
Db are the individual doses of a and b; da and db are the doses
of a and b in the mixture. The dashed line shows zero inter-
action, i.e. all combination doses to produce this effect if no
interaction occurs. a. Effect of Synergy: the ‘Concave’
Isobole. Synergy is shown by the solid curve. b. Effect of
Antagonism, the ‘Convex’ Isobole. Antagonism is shown by
the solid curve.
Defining and proving synergy
This is difficult, since synergy has a precise mathemat-
ical definition according to the method used to prove it.
There are only a few well-documented instances avail-
able from the literature, and there are several reasons
for this, the main one being the difficulty in methodolo-
gy of proving such effects. To do so would necessitate
the testing of individual constituents and comparing
the activity with an equivalent dose in the mixture. This
is an immense undertaking and prohibitively expensive
in terms of time and money and has therefore rarely
been done, although some recent experiments confirm
its existence and will be described later. We therefore
tend to use the term “polyvalent (synonyms are: mulit-
valent or pleiotropic) action” to denote an improved
and co-operative sort of effect, without necessarily
qualifying it, in an attempt pre-empt some of the criti-
cisms faced. The general understanding of synergy is
that it is an effect seen by a combination of substances
being greater than would have been expected from a
consideration of individual contributions. This can
apply to either an increased therapeutic effect, a re-
duced profile of side effects or, preferably (and logical-
ly), both. Within herbal mixtures, this may be very dif-
ficult to describe accurately as there are present con-
stituents about which we know very little, either chem-
ically, pharmacologically or even quantitatively. An-
tagonism is a much easier concept to define, being a re-
duced effect from that expected, and tends to be more
easily demonstrated regardless of the mathematical
derivation. To briefly summarise the measurement of
synergy, the definitions of Berenbaum (1989) are the
most useful:
E. M. Williamson
Fig. 2. Synergy between ginkgolides A and B measured
using a platelet aggregation test.*
* B Steinke. Chemisch-analytische und Pharmakologische
Untersuchungen von Pflanzlichen PAF-Antagonisten und
Inhibitoren der Thrombozytenaggregation. Thesis, University
of Munich (with permission) (see also Wagner, 1999).
The IC 50 ** values of various Ginkgolide A + B mixtures
obtained by an in vitro induced platelet aggregation test.
the effect should be anticipated, and when activity is
thought to be lost during purification, synergy should
be suspected. This could be the point at which a search
for synergy in particular could be instigated. There are
other reasons for not always isolating or fractionating a
plant extract, and together these may be summarised as
1. Synergism : if synergism is known or suspected to
be present, the mixture is necessary for the thera-
peutic effect. Known examples include Ginkgo
biloba, Artemisia annua, Cannabis sativa and
Kava-Kava, Piper methysticum , but there are proba-
bly many more .
2. Unstable constituents : sometimes the presence of
the whole plant material, which may contain for ex-
ample antioxidants, may “protect” the actives from
decomposition. Examples here would include: vale-
rian, Valeriana spp.; garlic, Allium sativum ; ginger,
Zingiber officinalis ; hops, Humulus lupulus .
3. Unknown active constituents: even if some of the
chemistry is know, the actives may not have been
completely identified. Examples include raspberry
leaf, Rubus idaeus, chasteberry, Vitex agnus castus,
Passiflora, Crataegus and many others
4. A range of actives (which may or may not indicate
synergy): Echinacea spez., Harpagophytum
procumbens, Cynara scolymus, Hypericum perfora-
tum, Glycyrrhiza glabra essential oils and many
others. These may well (and do) have documented
clinical activity and there is little incentive to frac-
tionate, isolate and characterise, and they may be
acting synergistically or additively.
A number of theoretical possibilities have been put
forward but it remains to be seen whether they occur in
clinical practice or not, and it is often not possible to
predict these. Some will appear only after prolonged
administration of the combination, and some with only
high doses
mixture IC 50
Ginkgolide A
Ginkgolide B
(µg/ml) (µM)
(µg/ml) (µM)
n = 2–9
** IC 50 is the concentration causing a 50% inhibition of the
platelet aggregation induced by PAF (platelet activating factor).
In vitro and other experimental evidence
It is still routine practice for scientists to investigate
and extract medicinal plants with a view to finding the
single chemical entity responsible for the effect, and
this may lead to inconclusive findings. If a combina-
tion of substances is needed for the effect, then the
bioassay-led method of investigation, narrowing activ-
ity down firstly to a fraction and eventually a com-
pound, is doomed to failure, and this has led to the sug-
gestion that the plants are in fact devoid of activity. An
example of this would be with Kigelia pinnata , where
fractionation destroyed the previously noted cytotoxic
effect (Houghton, 2000). Only clinical trials can dispel
these misconceptions, but they are expensive. Instead
Ginkgo biloba
In one of the few published examples, Ginkgo biloba ,
has been assessed using an in vitro platelet aggregation
test. The ginkgolides are known to be PAF antagonists,
which is one of their mechanisms of antiinflammatory
activity, and now a synergistic interaction between
ginkgolides A and B has been shown by Wagner’s
group in Munich. In this case, a positive interaction
was shown by an isobole curve for 50 % inhibition of
Ginkgolide A/B mixtures (Fig 2). The presence of the
other ginkgolides and the ginkgoflavones is also likely
to have an affect on the overall activity and is con-
firmed by the example Wagner quotes. A mixture of
Synergy and other interactions in phytomedicines
ginkgolides A, B and C, at a dose of 100–240mg, can
generate a PAF-antagonizing effect in humans (Chung
et al. 1987). However a dose of 120mg of a standard-
ized Ginkgo extract containing only 6–7mg of
ginkgolides, together with bilobalide and flavonol gly-
cosides, has an equivalent effect (Wagner 1999). The
implications of these results are of course that an isolat-
ed ginkgolide would be less therapeutically effective
than a mixture, despite the fact that ginkgolide B is
known to be a specific PAF antagonist and has been the
subject of many pharmacological experiments. So al-
though a “magic bullet” has been discovered in the
herb, it is still more effective when used as part of the
extract, i.e. the “herbal shotgun” approach is vindicated
Liquorice, Glycyrrhiza glabra
Liquorice provides a number of examples of synergism
between its own constituents, as well as with other
herbs. It has been shown to affect absorption from the
gut in an experiment where blood levels of glycyrrhizin
were found to be lower, due to reduced absorption, when
taken as part of an extract rather than as an isolated com-
pound (Cantelli-Forti et al. 1994). A crude extract of
liquorice inhibits angiogenesis, granuloma formation
and fluid exhudation in a mouse model of inflammation,
as does isoliquiritin and related compounds, whereas
glycyrrhizin and glycyrrhetinic acid tend to promote an-
giogenesis (Kimura et al. 1992). These are obviously
opposing actions within the herb itself, and there is then
the situation where liquorice is added to so many mix-
tures in Chinese medicine as a synergistic agent, both as
a potentiator and detoxifier. These effects are now be-
coming better understood, and it is known that liquorice
potentiates compounds such as paeoniflorin as a neuro-
muscular blocking agent, whilst affecting intestinal ab-
sorption of toxic substances such as the aconite alka-
loids (Miaorong and Jing, 1996). This gives liquorice as
useful role in detoxification and suggests further investi-
gation would be rewarding.
Kava-Kava, Piper methysticum
Kava is a well-known psychoactive herb used in the
South Pacific as a ceremonial drink, sedative and mild
euphoriant. It also has a well-established place in
herbal medicine for the treatment of mild anxiety
states as an alternative to the benzodiazepines
(Schultz et al. 1998). The chemical composition of
kava is well known but the contribution of each to the
overall activity is not, although synergy is implicated
in several ways. The anticonvulsant activity of the
kavalactones yangonin and desmethoxyyangonin was
found to be superior when given with other kava con-
stituents; and in a separate experiment when a recon-
stituted mixture of individual constituents was tested
and related to the activity of the most potent com-
pound (dihydromethysticin) synergy was again indi-
cated. For details of these experiments see Singh and
Blumenthal (1997).
Marihuana, Cannabis sativa
Recent research is confirming the role of cannabis as a
useful therapeutic agent in chronic conditions such as
rheumatoid arthritis, AIDS and multiple sclerosis (MS).
Documented reports of interactions within the single
herb include that of marijuana, Cannabis sativa , where
levels of tetrahydrocannabinol (THC) in the brain can
be elevated by cannabidiol (Zuardi et al. 1982). It has
long been known that THC alone can induce anxiety
Fig. 3. Cannabis extract is a bet-
ter antispastic agent than tetra-
hydrocannabinol at an equivalent
dose (D. Baker and E. Williamson
with permission).
* P < 0.05; ** P < 0.01; *** P<
0.001 compared to baseline
(paired t test); ## P < 0.01 com-
pared to % inhibition in D
Time (mins)
9 THC-
treated mice ( t -test); Results re-
present recordings from 8 animals
12 limbs were analysed per group
(Baker et al., 2000).
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