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Phytomedicine, Vol. 8(5), pp. 401–409

http://www.urbanfischer.de/journals/phytomed

Phytomedicine

REVIEW

Synergy and other interactions in phytomedicines

E. M. Williamson

The School of Pharmacy, University of London, London, United Kingdom

Summary

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-

ers.

Key words: synergy, phytomedicine, herbal interactions

Introduction

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

402

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

403

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-

ance.

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:

404

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

follows:

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

quantity

GA:GB

Ginkgolide A

Ginkgolide B

(GA)

(GB)

–––––––

––––––––––––––––

–––––––––––––––––

(µg/ml)

(µg/ml) (µM)

3:1

2.40

1.80

4.41

0.60

1.42

2:1

2.20

1.47

3.60

0.73

1.72

1:1

1.80

0.90

2.21

0.90

2.12

1:2

1.55

0.52

1.27

1.03

2.43

1:3

1.40

0.36

0.88

1.09

2.57

1:10

1.30

0.12

0.29

1.18

2.79

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

405

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

here.

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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