Aliment Pharmacol Ther 2002; 16: 1689–1699.
Systematic review: herbal medicinal products
for non-ulcer dyspepsia
J. THOMPSON COON & E. ERNST
Department of Complementary Medicine, School of Sport and Health Sciences, University of Exeter, Exeter, UK
Accepted for publication 14 June 2002
SUMMARY
Background: Non-ulcer dyspepsia is predominantly a
self-managed condition, although it accounts for a
significant number of general practitioner consultations
and hospital referrals. Herbal medicinal products are
often used for the relief of dyspeptic symptoms.
Aims: To critically assess the evidence for and against
herbal medicinal products for the treatment of non-
ulcer dyspepsia.
Methods: Systematic searches were performed in six
electronic databases and the reference lists located were
checked for further relevant publications. No language
restrictions were imposed. Experts in the field and
manufacturers of identified herbal extracts were also
contacted. All randomized clinical trials of herbal
INTRODUCTION
Dyspepsia is a common complaint; in a recent UK
survey, 40% of adult responders reported one or more
dyspeptic symptoms in the past year. Of all new patients
consulting UK general practitioners each year, 3.3%
suffer from dyspeptic symptoms; 60% of them will have
no clinically significant abnormalities on investigation
and will be diagnosed with non-ulcer dyspepsia.1 The
majority of patients experience dyspeptic symptoms of
short duration and mild severity, and are therefore self-
managed,2 with less than half of dyspepsia sufferers
Correspondence to: Dr J. Thompson Coon, Department of Complementary
Medicine, School of Sport and Health Sciences, University of Exeter, 25
Victoria Park Road, Exeter EX2 4NT, UK.
E-mail: J.Thompson-Coon@exeter.ac.uk

2002 Blackwell Science Ltd
doi:10.1046/j.0269-2813.2002.01339.
medicinal products administered as supplements to
human subjects were included.
Results: Seventeen randomized clinical trials were
identified, nine of which involved peppermint and
caraway as constituents of combination preparations.
Symptoms were reduced by all treatments (60–95% of
patients reported improvements in symptoms). The
mechanism of any anti-dyspeptic action is difficult to
define, as the causes of non-ulcer dyspepsia are unclear.
There appear to be few adverse effects associated with
these remedies, although, in many cases, comprehen-
sive safety data were not available.
Conclusions: There are several herbal medicinal products
with anti-dyspeptic activity and encouraging safety
profiles. Further research is warranted to establish their
therapeutic value in the treatment of non-ulcer dyspepsia.
seeking medical care for their complaints in the USA
and Europe.3, 4
Herbal medicine is becoming increasingly popular,
particularly for benign, chronic conditions that are self-
managed, such as non-ulcer dyspepsia. Recent surveys
suggest that the prevalence of use of herbal medicine in
the USA is between 12% and 17%,5 with total retail
sales of herbal dietary supplements of $4000 million in
2000.6 The European Scientific Co-operative on Phyto-
therapy definition of a herbal medicinal product is Ôany
medicinal product containing as active ingredients only
plants, parts of plants or plant materials or combina-
tions thereof, whether in the crude or processed stateÕ.
Standard reference texts suggest that several herbal
medicinal products are promoted for non-ulcer dyspep-
sia7–9 (Table 1). It is therefore vital to establish both the
1689
1690 J. THOMPSON COON & E. ERNST

Table 1. Herbal medicinal products commonly recommended for the treatment of dyspepsia

Angelica* Angelica archangelica Ginger* Zingiber officinale

Anise Pimpinella anisum Horsetail Equisetum arvense
Artichoke* Cynara scolymus Haronga Harungana madagascariensis
Bitter orange peel Citrus aurantium Horehound Marrubium vulgare
Blessed thistle Cnicus benedictus Juniper Juniper communis
Bogbean Menyanthes trifoliata Lemon balm* Melissa officinalis
Boldo* Peumus boldus Meadowsweet Filipendula ulmaria
Caraway* Carum carvi Milk thistle* Silybum marianum
Cardamom Elettaria cardamomum Mistletoe Viscum album
Centuary Centaurium minus Oregon grape Mahonia aquifolium
Chicory Cichorium intybus Peach Prunus persica
Cinchona Cinchona pubescens Peppermint* Mentha piperita
Cinnamon Cinnamomum verum Radish Raphanus sativus
Cloves Syzygium aromaticum Rosemary Rosemarinus officinalis
Coriander Coriandrum sativum Sage Salvia officinalis
Dandelion Taraxacum officinale Sandy everlasting Helichrysum arenarium
Devil’s claw Harpagophytum procumbens St John’s wort Hypericum perforatum
Dill Anethum graveolens Star anise Illicium verum
Elecampane Inula helenium Thyme Thymus vulgaris
Fenugreek Trigonella foenum-graecum Turmeric* Curcuma longa
Galangal Alpinia officinarium Wormwood Artemisia absinthium
Gentian* Gentiana lutea Yarrow Achillea millefolium

* Herbal medicinal products discussed in this review.

efficacy of these supplements in relieving dyspeptic
symptoms and their relative safety. This review is an
attempt to systematically evaluate the evidence from
randomized clinical trials for the efficacy of herbal
medicinal products for non-ulcer dyspepsia.
MATERIALS AND METHODS
in Table 1. Further relevant papers were located by
hand-searching the reference lists of all papers. In
addition, experts in the field and manufacturers of
relevant herbal products were contacted to provide
published and unpublished material. Finally, our own
extensive files were hand-searched for further relevant
publications.

Identification of clinical trials Inclusion ⁄ exclusion criteria

In order to identify clinical trials involving herbal
extracts used in the treatment of non-ulcer dyspepsia,
systematic literature searches were conducted in the
following electronic databases: Medline (Via Pubmed),
Embase, CINAHL, Amed (Alternative and Allied Medi-
cine Database, British Library Medical Information
Centre), The Cochrane Library (Issue 2, 2001) and
CISCOM (Research Council for Complementary Medi-
cine, London, UK) (all from their inception to September
2001). The search terms used were: non-ulcer dys-
pepsia, functional dyspepsia, dyspepsia, reizmagen,
idiopathic dyspepsia, phytomedicine, herbal medicine,
botanical medicine, complementary medicine, phyto-
therapy, pfefferminzöl, kummelöl, celandine, Chelidonium
majus, fennel, Foeniculum vulgare, banana, Musapep,
capsaicin, Iberogast, Enteroplant, Lomatol and all terms
Only randomized clinical trials of herbal remedies
administered as supplements to patients with a diagno-
sis of non-ulcer dyspepsia were included. These could be
placebo controlled or equivalent trials. All retrieved
data, including uncontrolled trials, case reports, pre-
clinical and observational studies, were reviewed for
safety information and possible mechanisms of action.
No language restrictions were imposed.
Data extraction and quality assessment
All articles were read in full. Data relating to sample
size, diagnosis of patients, intervention and control,
treatment duration, primary outcome measures and
results were extracted by the first author and validated
by the second author. The methodological quality of

2002 Blackwell Science Ltd, Aliment Pharmacol Ther 16, 1689–1699

 HERBAL MEDICINAL PRODUCTS IN NON-ULCER DYSPEPSIA 1691

each randomized clinical trial was assessed using
the scoring system of Jadad et al.10 This scale ranges
from 0 (poorest) to 5 (highest) and assesses methods of
randomization and blinding and the description of
withdrawals and dropouts.
RESULTS
Seventeen randomized controlled trials of herbal medi-
cinal products for non-ulcer dyspepsia were identified.
All trials stated that included patients had been
diagnosed with non-ulcer or functional dyspepsia.
However, details of the diagnostic tests performed (e.g.
ultrasonography, oesophago-gastroduodenoscopy) were
provided in only 11 of the trials.11–21 Four trials were of
monopreparations (Table 2) and involved turmeric
(Curcuma longa), greater celandine (Chelidonium majus),
banana and Emblica officinalis. The remaining 13 trials
were of combination products (Table 3), including nine
in which peppermint (Mentha piperitae) and caraway
(Carum carvi) were constituent ingredients. For each
herb, possible active constituents and mechanisms of
action, where known, are shown in Table 4.
Clinical trials of monopreparations
Greater celandine (Chelidonium majus). Ritter et al.
conducted a 6-week, placebo-controlled, double-blind,
randomized trial using a standardized celandine extract
in 60 patients with functional epigastric complaints and
cramp-like pains in the region of the biliary and
gastrointestinal tracts.22 After 6 weeks of treatment,
patients treated with the celandine extract reported
fewer gastrointestinal symptoms compared with the
placebo group (P ¼ 0.003). The symptoms that showed
most improvement were stomach pains, bilious com-
plaints, flatulence, nausea and sensation of fullness.
Eight patients reported adverse events during the study,
five whilst receiving placebo (insomnia, urticaria and
sleepiness) and three whilst receiving celandine extract
(dry mouth and insomnia).
In an open clinical trial of greater celandine treatment,
six patients reported adverse events (diarrhoea, 3;
nausea, 2; tiredness, 1).40 A case series of 10 cases of
acute hepatitis following treatment with greater celan-
dine extracts was identified.41 Where available, liver
biopsy specimens were consistent with drug-induced
damage, and other possible causes of liver disease were
excluded by laboratory tests and imaging procedures.
Discontinuation of greater celandine resulted in rapid
recovery, with liver enzyme levels returning to normal
within 2–6 months. One patient was unintentionally
re-challenged, resulting in a second episode of hep-
atic inflammation. A further case series describes
two patients investigated for abdominal pain, who were
prescribed celandine extract (Panchelidon, two capsules
t.d.s. and one capsule b.d.), and presented 2 and
4 months later with scleral jaundice and elevated
transaminase levels. On cessation of therapy, the liver
enzymes returned to normal and the patients recovered
without sequelae. The patients were not re-chal-
lenged.42 A single case report of contact dermatitis in

Table 2. Randomized clinical trials of monopreparations of herbal remedies used in the treatment of non-ulcer dyspepsia

Treatment Improvement
duration in symptoms Jadad
Reference n Diagnosis Treatment (weeks) (%) score

Ritter et al.22 60 Functional epigastric Std celandine extract 6 Celandine 60 3

complaints (6 tablets ⁄ day) or placebo Placebo 26.7
Thamlikitkul et al.23 116 Acid dyspepsia, Turmeric (2 g ⁄ day), 1 Turmeric 87 3
flatulent dyspepsia flatulence (8 capsules ⁄ day) Flatulence 83
or atonic dyspepsia or placebo Placebo 53
Arora and Sharma11 46 Non-ulcer dyspepsia Banana powder 8 Banana 1
(8 capsules ⁄ day) powder 75
or no treatment No treatment 20
Chawla et al.12 38 Peptic ulcer (10) and Amalaki (9 g ⁄ day) or gel 4 Both treatments 1
non-ulcer dyspepsia (28) antacids (30 mL every 3 h) produced a
significant
reduction in
symptom scores

2002 Blackwell Science Ltd, Aliment Pharmacol Ther 16, 1689–1699

 Table 3. Randomized clinical trials of combination preparations of herbal remedies used in the treatment of non-ulcer dyspepsia
1692

Treatment Improvement in Jadad

Reference n Diagnosis Treatment duration (weeks) symptoms (%) score

Tatsuta and Iishi13 42 Chronic idiopathic TJ-43* (7.5 g ⁄ day) 1 Significant reductions in 1
dyspepsia or placebo symptom scores compared
with placebo and baseline
Chen24 100 Non-ulcer dyspepsia Shenxiahewining or an 3 Shenxiahewining 92 1
un-named control drug Control 20
(15 capsules ⁄ day)
May et al.14 96 Functional dyspepsia Peppermint & caraway oils 4 Peppermint ⁄ caraway 67 5
(180 & 100 mg ⁄ day) or placebo Placebo 21
May et al.15 45 Non-ulcer dyspepsia Peppermint & caraway oils 4 Peppermint ⁄ caraway 94.7 3
(270 & 150 mg ⁄ day) or placebo Placebo 55
Freise and Kohler16 223 Non-ulcer dyspepsia Enteric-coated peppermint & 4 Enteric-coated peppermint ⁄ 3
caraway oils (270 & 150 mg ⁄ day) caraway 90 Enteric soluble
J. THOMPSON COON & E. ERNST

or enteric soluble peppermint & peppermint ⁄ caraway 90

caraway oils (108 & 60 mg ⁄ day)
Madisch et al.17 120 Functional dyspepsia Peppermint & caraway oils 4 Peppermint ⁄ caraway 78.6 2
(180 & 100 mg ⁄ day) or cisapride Cisapride 70.9
(30 mg ⁄ day)
Madisch et al.18 60 Functional dyspepsia Iberogast , Iberogast 4 Significant improvements in 4
without bitter candy tuft symptom scores after both herbal
(60 drops ⁄ day) or placebo preparations compared with placebo
Nicolay19 94 Functional Iberogast or metaclopramide 2 Iberogast 52.6à 2
gastroenteropathy (60 drops ⁄ day) Metaclopramide 56.4à
Holtmann et al.25 120 Functional dyspepsia Iberogast (no details of dose 8 Iberogast 68.4 2
provided) or placebo Placebo 35.1
Rosch26 183 Functional dyspepsia Iberogast (60 drops ⁄ day) or 4 Improvements in symptom scores 2
cisapride (30 mg ⁄ day) or placebo after both Iberogast and cisapride
compared with baseline
Westphal et al.20 60 Functional dyspepsia Peppermint, caraway, wormwood 2 Significant improvements in 3
& fennel (75 drops ⁄ day) or gastrospasmspain, nausea,
metaclopramide heartburn and compared with
metaclopramide
Stadelmann et al.21 46 Functional dyspepsia Peppermint oil and ginger 4 Peppermint ⁄ ginger 74 3
extract (180 & 25 mg ⁄ day) Placebo 30
or placebo
Borgia et al.27 359 Mild to moderate Boldo & cascara, rhubarb & gentian, 2 Improvements in loss of appetite, 2
functional disorders of boldo, cascara, rhubarb & gentian dyspepsia and constipation compared
the gastrointestinal tract or placebo with baseline and placebo

* TJ-43 contains spray-dried aqueous extracts of Atractylodis lanceae rhizoma, Ginseng radix, Pinelliae tuber, Hoelen, Zizyphi fructus, Aurantii nobilis pericarpium, Glycyrrhizae radix and Zingiberis
rhizoma.
  Iberogast contains peppermint leaves, caraway fruit, bitter candy tuft fruit, licorice root, lemon balm leaves, angelica root, celandine herbs, milk thistle fruit and chamomile flowers.

2002 Blackwell Science Ltd, Aliment Pharmacol Ther 16, 1689–1699

à Percentage of patients symptom-free.
 HERBAL MEDICINAL PRODUCTS IN NON-ULCER DYSPEPSIA 1693

Table 4. Possible active constituents and proposed mechanisms of action

Herb Possible active constituents Proposed mechanisms of action

Greater celandine Approximately 20 alkaloids with biological activity Animal experiments suggest a direct anti-spasmolytic
including chelidonine, sanginarine and chelerythrine, action on smooth muscle and a stimulation of bile
flavonoids and phenolic acids28 flow28
Turmeric Volatile oil composed mainly of turmerone and Increased bile formation and secretion, promotion of
zingiberene and phenolic compounds (curcuminoids) gall-bladder contraction, the volatile oil acts as a
of which curcumin is the most abundant29 carminative improving digestion, some components
may also be anti-spasmodic23, 29
Banana A flavonoid with anti-ulcerogenic activity has been Not known
isolated from unripe banana pulp30
Emblica officinalis Not known Not known
Liu-Jun-Zi-Tang Not known Increased gastric emptying,13, 31 increased plasma
levels of somatostatin and gastrin,32 promotion of
gastric adaptive relaxation33
Shenxiahewining Not known Not known
Peppermint Menthol and menthone34 Inhibition of smooth muscle contractions due to direct
interaction between peppermint oil and smooth muscle
calcium channels35, 36
Caraway Not known Inhibition of smooth muscle contraction37
Boldo Alkaloids, e.g. boldine, essential oils, volatile oils, Boldine acts as a smooth muscle relaxant in vitro by
flavonol glycosides, resin and tannins directly interfering with the cholinergic mechanism
involved in contraction38 and may cause gall-bladder
contraction increasing bile secretion39
Gentian Bitter substances, e.g. gentiopicroside Stimulates salivary and gastric secretions via
a reflex activity7

a 64-year-old woman who used greater celandine juice
to treat warts was also identified;43 whether this is
relevant to the oral administration of celandine tablets
is not clear.
Turmeric (Curcuma longa). One randomized, double-
blind, multicentre clinical trial conducted in Thailand
was located, in which 116 patients (diagnosed with acid
dyspepsia, flatulent dyspepsia or atonic dyspepsia)
received capsules of turmeric (2 g ⁄ day), placebo or a
combination treatment known as flatulence (cascara
dry extract, nux vomica extract, asofoetida tincture,
capsicum powder, ginger powder and diastase) for
7 days.23 Significantly more patients (P ¼ 0.003)
reported an overall favourable outcome (resolution or
improvement of symptoms) following treatment with
turmeric (33 patients) than placebo (20 patients),
although there was no significant difference in outcome
between those patients treated with turmeric and those
treated with flatulence. Twenty-eight patients experi-
enced adverse events: nine in the turmeric group
(nausea, diarrhoea, headache, tiredness and sleepiness),
nine in the flatulence group (nausea, vomiting, diar-
rhoea, throat discomfort, headache and flatulence) and
10 in the placebo group (nausea, diarrhoea, pruritis,
headache, constipation, anorexia and tiredness). All the
side-effects were described as mild and self-limited.
Banana (Musa sapientum). A prospective, randomized,
open study of 46 consecutive patients diagnosed with
non-ulcer dyspepsia was conducted in India.11 Twenty-
two patients received banana powder (Musapep) cap-
sules for 8 weeks; 24 patients acted as controls and
were not given any additional treatment. Gastrointes-
tinal symptoms were partly or completely relieved in
three-quarters of patients treated with banana powder
and in one-fifth of untreated control patients
(P < 0.05). One patient suffered generalized itching
during treatment with banana powder.
Emblica officinalis. One randomized clinical trial was
identified in which 38 patients (10 with peptic ulcer and
28 with non-ulcer dyspepsia) were treated with Amal-
aki (the pericarp of the dried fruits of Emblica officinalis)
or gel antacids for 4 weeks.12 All patients were advised
to follow a bland diet and to avoid smoking, alcohol,
coffee and all other drugs for the duration of the study.
Both treatments produced a significant reduction in

2002 Blackwell Science Ltd, Aliment Pharmacol Ther 16, 1689–1699

1694 J. THOMPSON COON & E. ERNST
symptom scores (P < 0.01), accompanied by a decrease
in acid output (P < 0.001), compared with baseline,
although comparisons were not made between treat-
ments. Adverse events were reported by four patients
treated with antacids (weakness and pain in the lower
limbs) and three patients treated with Amalaki (loose
motions and vomiting); none were severe enough to
necessitate withdrawal of treatment.
Clinical trials of combination preparations
Liu-Jun-Zi-Tang. Liu-Jun-Zi-Tang is a Chinese herbal
medicine, also known as Rikkunshi-to and TJ-43,
containing spray-dried aqueous extracts of Atractylodis
laneae rhizoma, Ginseng radix, Pinelliae tuber, Hoelen,
Zizyphi fructus, Aurantii nobilis pericarpium, Glycyrrhizae
radix and Zingiberis rhizoma. Forty-two patients with
chronic idiopathic dyspepsia were treated with either
Liu-Jun-Zi-Tang (2.5 g three times daily) or placebo for
7 days.13 Treatment with Liu-Jun-Zi-Tang resulted in a
significantly greater reduction in gastrointestinal symp-
tom scores for epigastric fullness, heartburn, belching
and nausea compared to baseline and compared to
patients treated with placebo (P < 0.05), although
there was no effect on epigastric pain. Compared to
both baseline and placebo treatment, gastric emptying,
measured by the acetaminophen absorption method,
was significantly increased following Liu-Jun-Zi-Tang
treatment (P < 0.01). Details of adverse events were not
provided; however, a case report of drug-induced
pneumonitis due to Liu-Jun-Zi-Tang was identified, in
which a 79-year-old woman was admitted to hospital
with interstitial pneumonia. Following the cessation of
all drugs and the administration of prednisolone, her
symptoms and laboratory data improved. Lymphocyte
stimulation and migration inhibition tests were positive
for Liu-Jun-Zi-Tang.44
Shenxiahewining. Shenxiahewining is a Chinese her-
bal medicine which contains Ginseng radix, Pinelliae
tuber, Coptidis rhizoma, Zingiberis rhizoma exsiccatum
and Glycyrrhizae radix in the ratio 3 : 9 : 3 : 3 : 3. In a
randomized clinical trial performed in China, 100
subjects with non-ulcer dyspepsia were treated with
either shenxiahewining (15 capsules ⁄ day; 0.42 g ⁄ cap-
sule) or an un-named control drug in similar capsules
(15 capsules ⁄ day; 0.42 g ⁄ capsule) for 20 days.
Improvements in symptoms were reported in 92% of
patients treated with the herbal mixture compared

2002 Blackwell Science Ltd, Aliment Pharmacol Ther 16, 1689–1699
with 20% treated with the control medication. No
adverse events were reported for either treatment
group.24
Peppermint and caraway (Mentha piperita and Carum
carvi). Four randomized clinical trials of a fixed
combination of peppermint and caraway oils were
identified, five trials of a combination of peppermint
leaves, caraway fruit, bitter candy tuft (Iberis amara),
licorice root (Glycyrrhiza glabra), lemon balm leaves
(Melissa officinalis), angelica root (Angelicae radix),
celandine herbs (Chelidonium majus), milk thistle fruit
(Silybum marianus) and chamomile flowers (Matricaria
recutita) (Iberogast, Steigerwald Arzneimittelwerk
GmbH, Darmstadt, Germany), one trial of a combina-
tion of extracts of peppermint leaves, caraway fruit,
fennel fruit (Foeniculum vulgare) and wormwood herbs
(Artemisia absinthium) (Lomatol, Lomapharm, Emmer-
thal, Germany), and one trial of a combination of
peppermint oil and ginger extract.
May et al. performed a double-blind, placebo-controlled
trial in 96 out-patients with a diagnosis of functional
dyspepsia, defined as diffuse, unspecific, variable, mod-
erately intense epigastric pain with at least one other
dyspeptic symptom and an absence of organ patholo-
gy.14 Patients received either enteric-coated capsules of
a fixed combination of peppermint and caraway oils
(180 mg ⁄ day peppermint oil and 100 mg ⁄ day cara-
way oil; Enteroplant, Dr Willmar Schwabe GmbH,
Karlsruhe, Germany) or identical placebo capsules for
4 weeks. There were statistically significant differences
in the reduction of pain intensity (40% vs. 22% of the
initial mean value; P < 0.001) and sensation of
pressure, heaviness and fullness (43.5% vs. 22.3% of
the initial mean value; P < 0.001) between the
peppermint ⁄ caraway- and placebo-treated patients,
with an overall median rating of Ômuch improvedÕ for
the peppermint ⁄ caraway group and Ôminimally
improvedÕ for the placebo group (P < 0.001).
A similarly designed study from the same group of
investigators involved 45 patients with non-ulcer
dyspepsia, defined as moderate epigastric pain with
at least one other dyspeptic symptom for the past
14 days.15 A fixed combination of peppermint and
caraway oils (270 mg ⁄ day peppermint oil and
150 mg ⁄ day caraway oil; Enteroplant, Dr Willmar
Schwabe GmbH, Karlsruhe, Germany) or placebo was
administered for 4 weeks. Improvement in pain inten-
sity after 4 weeks of treatment was significantly greater
 HERBAL MEDICINAL PRODUCTS IN NON-ULCER DYSPEPSIA
in the peppermint ⁄ caraway-treated patients than in
those treated with placebo (17 vs. 9; P ¼ 0.015). The
physician also estimated the prognosis and severity of
the disorder on the basis of a Clinical Global Impressions
Scale before and after treatment, and found that 94.7%
of patients in the peppermint ⁄ caraway group showed
improvement compared with only 55% of patients in
the placebo group (P ¼ 0.008).
Two hundred and twenty-three patients with non-
ulcer dyspepsia (defined as dysmotility type or essen-
tial ⁄ idiopathic dyspepsia with irritable bowel syndrome)
were included in a prospective, randomized, double-
blind multicentre trial in which two fixed combinations
of peppermint and caraway oils were compared.16
Patients received either enteric-coated capsules
(270 mg ⁄ day peppermint oil and 150 mg ⁄ day cara-
way oil; Enteroplant, Dr Willmar Schwabe, Karlsruhe,
Germany) or an enteric soluble formulation
(108 mg ⁄ day peppermint oil and 60 mg ⁄ day caraway
oil; Hersteller, Dr Willmar Schwabe, Karlsruhe, Ger-
many) for 4 weeks. The mean baseline measurements of
epigastric pain intensity were 6.1 in the former group
and 5.9 in the latter group [on a visual analogue scale
ranging from 0 (no pain) to 10 (extremely strong pain)].
Statistically significant reductions in pain intensity were
seen in both groups ()3.6 vs. )3.3; P ¼ 0.001).
A double-blind comparative study of a fixed combina-
tion of peppermint and caraway oil and the prokinetic
agent cisapride was performed in 120 out-patients with
functional dyspepsia.17 Inclusion criteria included the
presence of moderate epigastric pain and one other
dyspeptic symptom for at least the past 14 days.
Patients were treated with cisapride (30 mg ⁄ day) or a
peppermint–caraway combination (180 mg ⁄ day pep-
permint oil and 100 mg ⁄ day caraway oil; Enteroplant,
Dr Willmar Schwabe, Karlsruhe, Germany) for 4 weeks.
Both groups showed improvements in epigastric pain
intensity, pain frequency, dyspeptic discomfort (a com-
bined measure of other dyspeptic intestinal and extra-
intestinal symptoms) and Clinical Global Impression,
with no clinically relevant differences between the
effects of the peppermint–caraway combination and
cisapride.
A placebo-controlled, multicentre trial of Iberogast
(Steigerwald Arzneimittelwerk GmbH, Darmstadt,
Germany) was conducted in 60 patients with functional
dyspepsia, in which patients were treated with Ibero-
gast, a similar preparation without extract of bitter
candy tuft or placebo (60 drops ⁄ day) for 4 weeks.18

2002 Blackwell Science Ltd, Aliment Pharmacol Ther 16, 1689–1699
1695
Compared with placebo, both herbal preparations
produced a statistically significant improvement in the
gastrointestinal symptom score after 2 and 4 weeks of
treatment (P < 0.001). There was no difference
between the two herbal preparations, except that
Iberogast appeared to have a more rapid effect on
symptom improvement (P ¼ 0.023), suggesting that
bitter candy tuft is a necessary component of the
mixture.
A single-blind, randomized, comparative study was
conducted involving 94 patients with functional gas-
troenteropathy treated with either Iberogast or meta-
clopramide for 14 days.19 The occurrence of four
symptoms was recorded: feeling of pressure and pain,
sickness and vomiting, eructation and heartburn. After
14 days, there was no significant difference between the
two groups of patients, with approximately 50% of
patients in each group reporting no further symptoms.
On average, symptoms resolved faster in the Iberogast-
treated patients. Seventeen patients withdrew from the
study as a result of treatment failure (metaclopramide,
3; Iberogast, 1), non-compliance with the protocol (12)
and sickness and vomiting (metaclopramide, 1).
Two studies were found which have only been
presented in abstract form to date. The first was a
four-way parallel group study, in which each patient
received treatment for two consecutive 4-week periods;
120 patients with functional dyspepsia were assigned to
one of the following treatment groups: placebo–placebo;
placebo–Iberogast; Iberogast–placebo; and Iberogast–
Iberogast.25 Details of the doses were not provided in the
abstract. After 8 weeks of treatment, 43.3% of patients
treated with Iberogast were symptom-free compared to
only 3.3% of the placebo group (P < 0.001). The
second study had a randomized, double-blind, placebo-
controlled, double dummy design and enrolled 124
patients with functional dyspepsia. After 4 weeks of
treatment with Iberogast (60 drops ⁄ day), cisapride
(30 mg ⁄ day) or placebo, gastrointestinal symptom
scores had decreased in the active treatment groups
(Iberogast, 14.3 to 3.3; cisapride, 14.0 to 3.9). The
results for placebo were not provided. There were no
significant differences between Iberogast and cisapride;
however, both showed significant differences from
baseline (P < 0.001).26 Neither study provided details
of the occurrence of adverse events.
Westphal et al. conducted a comparative, double-blind
study of Lomatol (Lomapharm, Emmerthal, Germany)
in 60 patients with at least one of the following
1696 J. THOMPSON COON & E. ERNST
symptoms: pressure and pain in the upper stomach,
sub- or retrosternal gastrospasms, sensation of reple-
tion, belching, nausea, retching, heartburn and loss of
appetite.20 Patients were treated with the herbal
combination or metaclopramide, a prokinetic used in
the treatment of digestive tract complaints, (25 drops in
lukewarm water three times daily prior to meals) for a
maximum of 14 days. Five symptoms were studied:
pain, nausea, heartburn, retching and gastrospasms.
Compared with metaclopramide, significantly fewer
patients experienced pain, nausea and heartburn after
7 days of treatment with the herbal combination and,
after 14 days, the results were also statistically signifi-
cant for gastrospasms, and two of the secondary
outcome measures: belching and sensation of pressure.
Stadelmann et al. reported a randomized, double-blind,
placebo-controlled study in 46 patients with functional
dyspepsia, who were treated with peppermint oil and
ginger extract (180 mg ⁄ day and 25 mg ⁄ day) or iden-
tical placebo for 4 weeks. At the end of the treatment
period, 74% of patients treated with the herbal combi-
nation reported an improvement in gastrointestinal
symptom scores compared with 30% in the placebo
group (P ¼ 0.012).21
In total, adverse events were reported by 84 of 1046
patients: 26 of these were during peppermint and
caraway treatment; one during treatment with pep-
permint, caraway, fennel and wormwood; 13 during
treatment with peppermint and ginger; 14 during
cisapride treatment; 18 during metaclopramide treat-
ment; two during treatment with Iberogast; and 10
during placebo treatment. The adverse events inclu-
ded heartburn or eructation with a peppermint taste,
diarrhoea, nausea, sickness and vomiting, substernal
burning sensation with severe eructation and nausea,
flatulence and increasing acid taste, hyperventilation
and suspected grand mal with syncope, upper abdom-
inal pain and dizziness, spasm such as abdominal
pains with increased gastrointestinal noise and feeling
of pressure in the upper abdomen, increased stool
evacuation, pasty stools and burning in the rectum,
pain in the neck and shoulder, extreme tiredness,
haemorrhoids, bronchitis and influenza-like symptoms.
Cessation of treatment was necessary in six patients
due to the severity of symptoms. A causal relationship
with the herbal combination was considered possible
in eight patients. No serious adverse events were
reported and no abnormality was detected in laborat-
ory values during or after treatment. A post-marketing

2002 Blackwell Science Ltd, Aliment Pharmacol Ther 16, 1689–1699
surveillance study of Iberogast was identified, invol-
ving 2267 patients, in which only one adverse event,
without a causal relationship to Iberogast therapy,
was recorded; 95% of doctors reported the tolerability
to be ÔgoodÕ or Ôvery goodÕ.45 Peppermint oil and
menthol have been reported as causes of allergic
contact dermatitis in fragrances and toothpastes,46–48
contact urticaria has been reported from menthol in
mentholated cigarettes, cough drops, aerosol room
spray and topical medicaments,49 and other rare cases
of skin irritation have also been reported.50, 51
Exacerbation of asthma has been described with the
use of a peppermint-containing toothpaste.52 In a
further case report, two patients who were addicted to
ÔpeppermintsÕ experienced idiopathic atrial fibrillation,
which resolved with the cessation of peppermint
ingestion.53 No further information on the safety of
caraway was located.
Other herbs. One randomized clinical trial was identi-
fied in which herbal combinations containing boldo
(Peumus boldus), cascara (Rhamnus purshianus), gentian
(Gentiana lutea) and rhubarb (Rheum sp.) were evaluat-
ed. All four herbs or placebo were administered to 359
patients with slight or moderate functional disorders of
the gastrointestinal tract for 28 days.27 Compared with
baseline and placebo, the combination of all four herbs
and rhubarb and gentian alone produced statistically
significant improvements in the loss of appetite, dys-
pepsia and constipation (P < 0.001), whereas boldo
and cascara alone only improved symptoms of con-
stipation (P < 0.001). No adverse events were reported
during the trial.
DISCUSSION
Several herbal medicinal products have been identified
for use in the relief of symptoms of non-ulcer dyspepsia;
in all trials, subjects treated with the herbal medicinal
product showed improvements in symptom scores
(results ranging from 60% to 95%) compared with
baseline and ⁄ or placebo or the comparator drug.
Peppermint and caraway have been most extensively
studied, although they have sometimes been adminis-
tered in the presence of other herbal extracts.
There was a large response to placebo (30–55% of
patients showing an improvement in symptoms com-
pared to baseline) reported in five of the 10 placebo-
controlled studies (data were not provided for the
 HERBAL MEDICINAL PRODUCTS IN NON-ULCER DYSPEPSIA
remaining five studies). A large placebo response has
also been noted in clinical trials of conventional
therapies for non-ulcer dyspepsia (13–73%).55 In addi-
tion, an open, non-randomized study designed to assess
the effect of placebo supplementation in patients with
non-ulcer dyspepsia found that 80% of patients reported
an improvement in symptoms, with the improvement
being marked in 47%.54
Due to the episodic nature of non-ulcer dyspepsia,
studies with no placebo arm, in which the herbal
preparation is compared with a comparator drug, e.g.
metaclopramide or cisapride, are difficult to interpret;
although they show similar improvements in symptom
scores for both treatment options, they provide no
measure of the natural progression of symptoms.
A number of weaknesses with the original trials exist.
Of the 17 identified randomized clinical trials of herbal
medicinal products for non-ulcer dyspepsia, only eight
scored three or more points on the scale of Jadad et al.10
The most frequent methodological flaws were single
blind or open studies and incomplete reporting of
methods of randomization, blinding and subject with-
drawals.
Several different methods of scoring symptoms were
used and not all were validated techniques. The
description of patients entered into each trial was
variable; it was not clear whether patients with, for
example, predominantly reflux symptoms were always
excluded or what the Helicobacter pylori status of each
patient was. It is therefore difficult to compare studies or
to extrapolate the data to other patient populations
whose perception of symptom severity may differ.
However, these results compare favourably with those
using conventional treatment approaches for non-ulcer
dyspepsia, which are far from ideal. A meta-analysis of
53 studies published in 1996 concluded that, due to
methodological flaws, there are no proven effective
therapies for the treatment of non-ulcer dyspepsia.55
Antacids appear to provide little relief;56 acid-suppres-
sing agents and prokinetics provide moderate sympto-
matic improvement, with average differences from
placebo of 25%55 and 40%57 in the proportions of
patients showing improvement; the eradication of
H. pylori, although controversial, appears to offer little
benefit.58
Of the 17 trials identified, 13 relate to combination
products containing two or more herbal extracts. It is
unclear which of the herbs contained in these products
is effective or, indeed, if they all play a role in alleviating

2002 Blackwell Science Ltd, Aliment Pharmacol Ther 16, 1689–1699
1697
symptoms. Combination preparations are popular in
herbal medicine as many traditional herbalists believe
that synergistic interactions can occur between the
different components, eliciting a larger effect than
would be expected from the individual constituents
alone. There is a limited amount of evidence for such
interactions with some herbs,59 and it may offer some
insight into the mechanism whereby low doses of some
extracts are able to produce beneficial therapeutic
effects. However, there is no such evidence for the
herbs included in this review; much detailed research is
needed to elucidate the role of each individual compo-
nent alone and within combinations.
Smooth muscle relaxation and effects on the gall-
bladder are common to several of the herbs, and may be
important in eliciting the overall effects on symptoms;
however, it is difficult to postulate on and study the
mechanisms by which herbal extracts are able to
alleviate symptoms when the pathophysiology of the
condition is so ill-defined.
The safety profile of these herbs looks encouraging,
with the exception of greater celandine, for which there
have been reports of hepatotoxicity. Many have been
used extensively in traditional medicine and culinary
practices around the world. This supports their relative
safety, but does not demonstrate it beyond reasonable
doubt.60 In particular, the long-term safety for use as
herbal medicines, either alone or in conjunction with
conventional therapies, has not been established. Com-
parative and placebo-controlled trials suggest that
patients experience no more adverse events with these
herbs than with placebo or comparative medications,
although short-term clinical trials are not designed to
detect rare or delayed adverse events. No evidence for
herb–drug interactions with peppermint or caraway
was uncovered; however, there is indirect evidence for
herb–drug interactions with several of the other herbs
contained in the combination preparations.61–63 Fur-
ther research is necessary to elucidate the importance of
these.
To conclude, some of the herbal medicinal products
identified, in particular peppermint and caraway, with
effects of similar or greater magnitude to conventional
therapies and encouraging safety profiles, undoubtedly
warrant further investigation, especially in the light of
the lack of efficacy of conventional therapies for non-
ulcer dyspepsia. A greater understanding of the
pathophysiology of non-ulcer dyspepsia would facili-
tate the improvement of the therapeutic options
1698 J. THOMPSON COON & E. ERNST
available to treat this widespread and debilitating
condition.
ACKNOWLEDGEMENTS
The authors wish to thank Jongbae Park, Barbara
Wider, Katja Schmidt and Francesca Borrelli, Depart-
ment of Complementary Medicine, University of Exeter,
UK, for the translation of papers from Chinese, Italian,
German and French, and Esther Prati, Pharmaton
SA, Lugano, Switzerland, for assistance with locating
relevant articles.
JTC is supported by a research fellowship provided by
Pharmaton SA, Lugano, Switzerland.
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