International Journal of Cardiology 98 (2005) 1 14

www.elsevier.com/locate/ijcard

Review

Cardiovascular pharmacotherapy and herbal medicines:

the risk of drug interaction
Angelo A. Izzo a,*, Giulia Di Carlo a, Francesca Borrelli a, Edzard Ernst b
b

a
Department of Experimental Pharmacology, University of Naples Federico II, via D. Montesano 49, 80131 Naples, Italy
Complementary Medicine, Penninsula Medical School, Universities of Exeter and Plymouth, 25 Victoria Park Road, EX2 4NT, UK

Received 18 April 2003; received in revised form 10 June 2003; accepted 14 June 2003
Available online 21 February 2004

Abstract
Use of herbal medicines among patients under cardiovascular pharmacotherapy is widespread. In this paper, we have reviewed the
literature to determine the possible interactions between herbal medicines and cardiovascular drugs. The Medline database was searched for
clinical articles published between January 1996 and February 2003. Forty-three case reports and eight clinical trials were identified.
Warfarin was the most common cardiovascular drug involved. It was found to interact with boldo, curbicin, fenugreek, garlic, danshen,
devils claw, don quai, ginkgo, papaya, lycium, mango, PC-SPES (resulting in over-anticoagulation) and with ginseng, green tea, soy and St.
Johns wort (causing decreased anticoagulant effect). Gum guar, St. Johns wort, Siberian ginseng and wheat bran were found to decrease
plasma digoxin concentration; aspirin interactions include spontaneous hyphema when associated with ginkgo and increased bioavailability if
combined with tamarind. Decreased plasma concentration of simvastatin or lovastatin was observed after co-administration with St. Johns
wort and wheat bran, respectively. Other adverse events include hypertension after co-administration of ginkgo and a diuretic thiazide,
hypokalemia after liquorice and antihypertensives and anticoagulation after phenprocoumon and St. Johns wort. Interaction between herbal
medicine and cardiovascular drugs is a potentially important safety issue. Patients taking anticoagulants are at the highest risk.
D 2004 Elsevier Ireland Ltd. All rights reserved.
Keywords: Cardiovascular pharmacotherapy; Herbal medicines; Drug interaction

1. Introduction
Interest in alternative medicine including plant-derived medications is growing. Self-administration of herbal
medicines is among the most popular of alternative therapies
[1,2]. In the US, the market for herbal medicinal products
(usually sold as food supplements or nutraceuticals)
amounted to US$590.9 million [3]. These sales figures
relate only to food stores, drug stores and mass market
and would obviously be larger if buying clubs, convenience
stores, natural food markets, multilevel marketing companies, health professionals, mail or Internet order had been
considered. The relevance of alternative therapies for cardiovascular medicine is highlighted by the recent workshop
on the use of herbal medicines in cardiovascular, lung and
blood research sponsored by the US National Heart, Lung,
and Blood Institute [4].

* Corresponding author. Tel.: +39-81-678439; fax: +39-81-678403.

E-mail address: aaizzo@unina.it (A.A. Izzo).
0167-5273/$ - see front matter D 2004 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.ijcard.2003.06.039

In view of the increasing use of herbal remedies by the

general public and subsequent interest by the authorities, it
is imperative to promote credible research on the safety of
herbal products including the possibility of interactions with
concurrent cardiovascular pharmacotherapy. Providing accurate and clinically relevant advice to patients regarding
the possibility of herb drug interactions is a challenge for
healthcare practitioners.
Because all herbal medicines are mixtures of more than
one active ingredient, they obviously increase the likelihood
of herb drug interactions [5]. Moreover, the majority of
people who use herbal products do not reveal this to their
physician or pharmacist [2]. This increases the likelihood
that herb drug interactions are not identified and resolved
in a timely manner. Nevertheless, recent data indicate that
potentially serious interactions exist between some common
herbal remedies and widely used conventional pharmaceuticals [6 16], including those used in the therapy of cardiovascular diseases [17 20].
In this article, we review the existing clinical data on
suspected interactions between herbal medicine and con-

Table 1
Clinical interactions between herbal medicines and conventional cardiovascular drugs
Herbal
medicine

Interaction with cardiac drugs

Digoxin
Gum guar

Result of
interaction

Possible
mechanism

Pharmacological
comment

Clinical
comment

No. of cases

Comment on report
reliability

Ref

Decreased
plasma digoxin
concentration

Reduced absorption

Guar gum reduces

gastric emptying,
which result in a
transient delayed
digoxin absorption.
Digoxin is a substrate
of P-glycoprotein
which is induced by
St. Johns wort.
Siberian ginseng
inhibits the
metabolism of
hexobarbital
in mice.

Similar amount
of digoxin was
found in 24-h urine
whether given with
or without guar gum.
St. Johns wort may
reduce efficacy of
digoxin and make a
patient a nonresponder.
The patient was
asymptomatic for
digoxin toxicity
despite a level of
2.5 ng/l.

Not applicablea

[27]

Not applicablea

[28]

[29]

Bran contains fibers

which can trap
digoxin.

Digoxin levels
were still within
the therapeutic range.

The report is well

documented; the level
of digoxin decreased
upon dechallenge and
increased upon
rechallenge.
Not applicablea

This interaction is
surprising as Ginkgo
is a peripheral
vasodilatator.
Some antihypertensive
drugs induce
hypokalemia; liquorice
has mineralcorticoid
effects which may
cause potassium
excretion.

If confirmed, the
interaction is
potentially dangerous.

The report contains

inadequate information.

[31]

Serum potassium
levels should be
monitored closely
in patients who are
predisposed to
cardiac arrhythmias
and who are
concurrently treated
with digitalis
glycosides.

The report contains

inadequate information.

[32]

Digoxin

St. Johns
wort

Decreased
plasma digoxin
concentration

Induction
of P-glycoprotein

Digoxin

Siberian
ginseng

Increased
plasma digoxin
concentration

Digoxin

Wheat bran

Decreased
plasma digoxin
concentration

Some component
of Siberian ginseng
might impair digoxin
elimination or
interfere with the
digoxin assay.
Reduced absorption

Interactions with antihypertensive drugs

Diuretic thiazide
Ginkgo
Increase in blood
pressure

Antihypertensives

Liquorice

Hypokalemia

Not known

Additive effect
on potassium
excretion

[30]

A.A. Izzo et al. / International Journal of Cardiology 98 (2005) 114

Conventional
drug

Interactions with antiplatet drugs

Aspirin
Ginkgo

Aspirin

Tamarind

Additive
inhibition
of platelet
aggregation

Ginkgolides from
ginkgo have
antiplatelet activity
and are PAF receptor
antagonists.

Increased
bioavailability
of aspirin

Not known

Increased
anticoagulant
effect

Additive effect
on coagulation
mechanisms

Both boldo and

fenugreek contain
anticoagulant
coumarins.
Vitamin E contained
in curbicin can
antagonize the
effect of vitamin
K on coagulation.
In addition to its
antiplatelet activity,
danshen decreases
warfarin elimination
in rats.

Warfarin

Curbicin

Increased
anticoagulant
effect

Additive effect
on coagulation
mechanisms

Warfarin

Danshen

Increased
anticoagulant
effect

Warfarin

Devils claw

Increased
anticoagulant
effect, purpura

Additive effect
on coagulation
mechanisms
and/or increased
plasma warfarin
concentration
Unknown

Warfarin

Dong quai

Increased
anticoagulant
effect

Additive effect
on coagulation
mechanisms

Dong quai contains

anticoagulant
coumarins.

Warfarin

Garlic

Increased
anticoagulant
effect; increase
in clotting time

Additive effect
on coagulation
mechanisms

Garlic has antiplatelet

activity.

In contrast to NSAIDs,
devils claw does not
affect platelet function.

Spontaneous bleeding
from the iris into
the anterior chamber
of the eye is a rare
problem.

The report provides some

evidence for interaction.
However, ginkgo taken
on its own has been
suspected to cause
brain hemorrhage.
Not applicablea

[33]

Uncertain

Risk of bleeding;
given the narrow
therapeutic index of
warfarin, vigilance
is needed.
Cases of coagulation
disorders related to
vitamin E have
been reported.

Interaction confirmed
by rechallenge

[35]

[36]

Risk of bleeding;
given the narrow
therapeutic index
of warfarin, vigilance
is needed.

Although neither of
the two patients has
been re-exposed to
curbicin, the causal
relation is quite strong.
Reports provide
reliable evidence for
an interaction.

Risk of bleeding;
given the narrow
therapeutic index
of warfarin, vigilance
is needed.
Risk of bleeding;
given the narrow
therapeutic index of
warfarin, vigilance
is needed.
Garlic treatment has
been associated
with bleeding even in
the absence of
warfarin or other
anticoagulant
treatment.

The report contains

inadequate
information.

[31]

Reports provide
reliable evidence
for an interaction.

[40,41]

The report contains

inadequate
information.

[42]

[34]

[37 39]

A.A. Izzo et al. / International Journal of Cardiology 98 (2005) 114

Interactions with anticoagulants

Warfarin
Boldo/
Fenugreek

Spontaneous
hyphema

(continued on next page)

Table 1 (continued)
Conventional
drug

Herbal
medicine

Interactions with anticoagulants

Warfarin
Ginkgo

Possible
mechanism

Pharmacological
comment

Clinical
comment

No. of cases

Comment on report
reliability

Ref

Intracerebral
hemorrhage

Additive effect
on coagulation
mechanisms

Ginkgolides from
ginkgo have antiplatelet
activity and are PAF
receptor antagonists.

The report contains

reasonable documentation
of interactions.

[43]

Antiplatelet activity
of ginseng has been
reported but would
not seem to explain
this case of decreased
anticoagulation;
a pharmacokinetic study
in rats did not reveal a
significant interaction
between warfarin and
ginseng.
Warfarin produces
anticoagulation
by inhibiting
production of the
vitamin-K dependent
clotting factors.
Green tea contains
vitamin K and
thus antagonize the
effect of warfarin.
The weak inhibition
of Lycium on
hepatic enzyme
could not explain
such interaction.
Mango contains high
amounts of vitamin
A and human studies
have shown that
vitamin A (retinol)
inhibits CYP2C19
enzymes.

Spontaneous bilateral
subdural haematomas
associated with
long-term ginkgo
ingestion have been
reported (even in the
absence of
anticoagulants).
Potential seriousness
of thrombotic
complications

The report is well

documented;
however, the patient
took several other drugs
concomitantly.

[44]

Patients receiving
warfarin need
to be routinely
questioned about
their intake of
vitamin K-containing
foods and beverages.

The report is well

documented.

[45]

Risk of bleeding;
given the
narrow therapeutic
index of warfarin,
vigilance is needed.
Risk of bleeding;
given the narrow
therapeutic index
of warfarin,
vigilance is needed.

The report contains

adequate information.

[46]

13

The interaction was

determined as probable
based on the Naranjo
probability scale.
Rechallenge in 2 of the
13 patients confirmed
such interaction.

[47]

Warfarin

Ginseng

Decreased
anticoagulant
effect

Unknown

Warfarin

Green tea

Decreased
anticoagulant
effect

Pharmacological
antagonism

Warfarin

Lycium

Increased
anticoagulant
effect

Unknown

Warfarin

Mango

Increased
anticoagulant
effect

Hepatic enzyme
inhibition

A.A. Izzo et al. / International Journal of Cardiology 98 (2005) 114

Result of
interaction

Warfarin

Papaya

Unknown

Warfarin

PC-SPES

Warfarin

Risk of bleeding;
this interaction is
potentially fatal.
The thromboembolic
side effects of PC-SPES
are potentially fatal;
individuals at risk should
be strongly advised
against using PC-SPES
and warfarin or aspirin.
The decrease in INR
was thought to be
clinically relevant

The report contains

inadequate information.

[31]

The report contains

adequate information.
However, PC-SPES,
administered alone,
can cause transient
severe bleeding diathesis.

[48]

Soy

Decreased
anticoagulant
effect

Not known

Warfarin is metabolised
by CYP 1A2 in the
liver, which is induced
by St. Johns wort.

Although none
of the patients
developed
thromboembolic
complications,
the decrease in
INR was thought
to be clinically
relevant.

Hepatic enzyme
induction

St. Johns wort could

reduce phenprocoum
on plasma levels
throughout hepatic
enzyme induction.

Phenprocoumon
has a narrow
therapeutic window;
possible loss
of activity.

1a

An objective causality
assessment in this case
revealed that INR
decline was in the
range of possible to
probable.
These cases are
reported in a single
publication, which
contains insufficient
information; however,
a clinical study showed
that St. Johns wort
decreased the plasma
concentration of
phenprocoumon (which is
chemically related to
warfarin).
The report provides some
evidence for interaction.
Moreover, a clinical study
confirm such an
interaction.

Warfarin

St. Johns
wort

Decreased
anticoagulant
effect

Hepatic enzyme
induction

Phenprocoumon

St. Johns
wort

Phenprocoumon

Wheat bran

Increased
Quick-Wert
test (indicating
decreased
anticoagulant
effect)
Decreased plasma
level of
phenprocoumon;
increase in the
free plasma
phenprocoumon
fraction

Decreased absorption
can explain the
decreased plasma
level; however, the
mechanism of the
increase of free plasma
phenprocoumon
fraction is unknown.

Bran contains fibers

which can trap
phenprocoumon.

In view of the
different effects
on phenprocoumon
pharmacokinetics,
the clinical
significance is
unpredictable.

Additive effect
on coagulation
mechanisms

PC-SPES contains
anticoagulant
coumarins.

Not applicablea

[50]

[51,52]

[53]

A.A. Izzo et al. / International Journal of Cardiology 98 (2005) 114

Increased
anticoagulant
effect
Increased
anticoagulant
effect

(continued on next page)

Table 1 (continued)
Conventional
drug

Herbal
medicine

Result of
interaction

Lovastatin

Oat bran

Decreased
lovastatin
absorption

Lovastatin

Pectin

Decreased
lovastatin
absorption

Pharmacological
comment

Hepatic enzyme
induction

Simvastatin is
extensively
metabolised by CYP
3A4 in the intestinal
wall and liver, which
are induced by
St. Johns wort.
Bran contains fibers
which can trap digoxin.

Pectin can trap digoxin.

Interaction revealed by a clinical study. Clinical studies are more rigorous than case reports.

Clinical
comment

The decreased
absorption of
lovastatin resulted
to an increase in
LDL levels which
led to the abortion
of the trial. Lovastatin
pharmacokinetics
and LDL returned
normal after bran
discontinuation.
The decreased
absorption of
ovastatin resulted
to an increase in
LDL levels which
led to the abortion
of the trial. Lovastatin
pharmacokinetics
and LDL returned
normal after pectin
discontinuation.

No. of cases

Comment on report
reliability

Ref

Not applicable

[54]

There is a strong evidence

for such interaction.

[55]

Not applicable

[55]

A.A. Izzo et al. / International Journal of Cardiology 98 (2005) 114

Interactions with antilipidaemic drugs

Simvastatin
St. Johns
Decreased
wort
plasma
simvastatin
concentration

Possible
mechanism

A.A. Izzo et al. / International Journal of Cardiology 98 (2005) 114

ventional cardiovascular pharmacotherapy. Its aim is to alert

healthcare professionals to the fact that herbal medicines are
not entirely free of risks for cardiovascular patients.

2. Methods
Systematic literature searches were made using Medline
(via PubMed, from January 1966 to February 2003). The
search terms were herbal medicine, botanical medicine,
phytotherapy, drug interaction, adverse effects, side effects,
adverse drug reaction, safety and toxicity. Recent books on
herb drug interactions or herbalism [21 26] were also
searched for further relevant information. Additional publications were identified by checking all reference lists and
by searching our files. No language restrictions were imposed. All clinical reports on interactions were read and
relevant data were extracted by the first three authors into
predefined tables and validated by the senior author. In vitro
experiments have been excluded.

for digoxin or digitoxin contamination, but none was found.

It is possible that some component of Siberian ginseng
might interfere with digoxin assay.
A double-blind study in 10 healthy volunteers showed
that guar gum reduced serum digoxin concentration during
the early absorption period [27]. This interaction is very
likely due to the ability of guar gum to reduce gastric
emptying [57], which results in a transient delayed digoxin
absorption. Consistently, digoxin levels in 24-h urine were
similar whether subject were given or not guar gum.
A randomized study on 30 geriatric patients showed that
wheat bran (but not ispaghula) reduced digoxin concentration (probably trapped by fiber contained in wheat bran),
although the levels were still within the therapeutic range
[30]. This interaction has no clinical relevant influence on
therapeutic digoxin.

Forty-three case reports (appeared in 21 publications)

and eight clinical studies were located [27 55]. Warfarin
was the most common drug involved (37 cases and 1
clinical trial) [35 50]. Key data from these publications
are summarized in Table 1. Table 2 summarizes chemical
constituents, pharmacological action, clinical evidence and
adverse effects of the herbal medicines interacting with
cardiovascular drugs.

3.1.2. Interaction with antihypertensives

Ginkgo is a peripheral vasodilator [60]. Surprisingly, an
elderly patient was found to have a further increase in blood
pressure after taking ginkgo while receiving a thiazide
diuretic (not specified in the original paper) for hypertension
[31]. There is no rational pharmacological mechanism to
explain this unusual case.
A case of flaccid quadriplegia due to profound hypokalemia has been reported to be due to ingestion of small
amounts of liquorice contained in a laxative preparation
taken in combination with antihypertensive treatment (not
specified in the original paper) [32]. The interaction could
be due to an additive effect of potassium excretion as both
some antihypertensives and liquorice (which possess mineralcorticoid effects) can cause potassium excretion [56,61].

3.1. Interactions with cardiac inotropic drugs

3.2. Interaction with platelet aggregation inhibitor drugs

3.1.1. Digoxin
Digoxin is a cardiac glycoside which originates from the
digitalis (foxglove) plant. As other cardiac glycosides, it can
increase the contractility of the heart muscle and is therefore
used in treating heart failure [56].
A single-blind, placebo-controlled study with two parallel groups showed that St. Johns wort reduced digoxin
through levels after 10 days of co-medication [28]. Intestinal
absorption, distribution and renal excretion of digoxin are
mediated by the multiple-drug-resistance gene product Pglycoprotein, which has been shown to be induced by St.
Johns wort [58,59]. Through this mechanism, St. Johns
wort may reduce efficacy of digoxin and make a patient a
nonresponder, whereas increased toxicity may be anticipated after withdrawal of the herb.
Increased levels of digoxin have been associated with
ingestion of Siberian ginseng [29]. The patient was asymptomatic for digoxin toxicity despite a level of 5.2 ng/l.
Electrocardiogram, potassium level and serum creatine level
were normal. Digoxin levels decreased upon dechallenge
and increased upon rechallenge. The product was analyzed

3.2.1. Aspirin
Aspirin is currently employed in the prophylactic treatment of transient cerebral ischemia, to reduce the incidence
of recurrent myocardial infarction and to decrease mortality in postmyocardial infarction patients. Aspirin blocks
thromboxane A2 synthesis from arachidonic acid in platelets by irreversibly acetylating and thus inhibiting cyclooxygenase, a key enzyme in prostaglandin synthesis. The
aspirin-induced inhibition of thromboxane A2 synthesis
last for the life of the platelet (approximately 7 10 days)
[56].
A case report demonstrated a patient treated with aspirin
for 5 years experienced bleeding of the eye and blurred
vision after self-medication with ginkgo for 1 week [33].
After stopping ginkgo, there was no recurrence of bleeding
over a 3-month follow-up period. The interaction is likely
due to an additive effect on platelet function as ginkgolide B
from ginkgo is a potent PAF receptor antagonist [62].
A clinical study [34] performed on six healthy volunteers
showed that a tamarind extract incorporated in a traditional
meal increased plasma levels of aspirin and salicylic acid

3. Results

A.A. Izzo et al. / International Journal of Cardiology 98 (2005) 114

Table 2
Herbal medicines interacting with cardiovascular pharmacotherapy: source, main constituent(s), main pharmacological action(s), promoted use, clinical
evidence and adverse events
Herbal medicine
(Common name/
Latin name)

Source

Main
constituent(s)

Main
pharmacological
action(s)

Promoted use

Clinical
evidence

Adverse events

Boldo/Peumus boldus

Leaves

Boldine

Not expected

Fatty acids,
phytosterols,
flavonoids,
polysaccharides

Indigestion,
constipation,
hepatic ailments
Benign prostatic
hyperplasia

Specific studies
not available

Curbicina/Serenoa repens/
Cucurbita pepo

Choleretic/
cholagogue,
diuretic
Antiandrogenic,
anti-inflammatory

Danshen/Salvia
miltiorrhiza

Roots

Tanshinones,
phenolic
compounds

Vasorelaxant,
anti-ischemic,
antiplatelet;
radical scavenger

Angina, myocardial
infarction, ischemic
diseases

Dong quai/Angelica
sinensis

Roots

Phytoestrogens,
flavonoids,
coumarins

Estrogenic effects,
anti-inflammatory,
vasorelaxant

Devils claw/
Harpagophytum
procumbens

Root, tubers

Harpagoside

Gynecological
disorders,
circulation
conditions
Musculoskeletal
and arthritic pain

Fenugreek/Trigonella
foenum-graecum

Seeds

Alkaloids,
flavonoids,
saponins

Anti-inflammatory,
anti-arrhythmic,
positive inotropic,
negative chronotropic
Antilipidaemic,
Diabetes mellitus,
hypoglycemic,
hypercholesterolemia
cholagogue

Ginseng/Panax
ginseng

Roots

Triterpene
saponins
known as
ginsenosides

Immunomodulatory,
anti-inflammatory,
antitumor,
hypoglycemic

Garlic/Allium
sativum

Bulb

Alliins

Ginkgo/Ginkgo
biloba

Leaves

Ginkgolides,
flavonoids

Antihypertensive,
antidiabetic,
antiplatelet,
antilipidaemic
Increase of
microcirculatory
blood flow,
antiplatelet, free
radical scavenging

Green tea/Camellia
sinensis

Leaves

Polyphenols,
caffeine

Antimutagenic,
antioxidant,
antilipidaemic,
antitumoral, CNS
stimulant

Guar gum/Cyamopsis
tetragonolobus

Seeds

Galactomannan,
lipids, saponins

Antihyperglycemic,
antilipidaemic

Kava/Piper
methysticum

Rhizome

Kavapyrones

Anxiolytic,
anesthetic,
muscle relaxant

Serenoa repens is
effective in the
treatment of benign
prostatic hyperplasia.

Gastrointestinal
complaints,
constipation,
diarrhea,
decreased libido
Effectiveness not
Specific studies
proven. Most studies not available
are neither
placebo-controlled
nor blinded.
No sufficient
Photosensitivity
evidence of
leading to mild
effectiveness
dermatitis,
bleeding
Promising to treat
Gastrointestinal
musculoskeletal
symptoms
and back pain
Promising in
reducing serum
cholesterol levels

Minor
gastrointestinal
symptoms,
allergic reactions
Loss of energy and
Not established
Insomnia, diarrhea,
memory; stress
for any indications
vaginal bleeding,
states; male sexual
mastalgia, possible
dysfunction
cause of
Stevens Johnson
syndrome
Allergic reactions,
Hypercholesterolemia, Small
nausea, heartburn,
prevention of
antihypertensive
flatulence, breath
arteriosclerosis
and antilipidaemic
and body odor
effect
Gastrointestinal
Circulatory disorders Favorable evidence
disturbances,
for the treatment
vomiting, allergic
of intermittent
claudication, tinnitus reactions, pruritus,
headache, dizziness,
and dementia
nose bleeding
(including
Alzheimers
dementia)
Prevention of
Cautiously positive
Insomnia
as anticancer; strong
cancer,
inverse associations
cardiovascular
diseases,
of tea intake with
aortic arteriosclerosis
adjuvant treatment
and cardiovascular
for AIDS
riskb.
Diabetes, obesity,
Small effect
Flatulence, diarrhea,
hypercholesterolemia cholesterol
abdominal
levels; ineffective
distension, nausea,
for obesity
hypoglycemic
symptoms
Stomach
Anxiety insomnia
Well documented
for the treatment
complaints,
of anxiety
restlessness,
mydriasis,
dermatomyositis,
hepatitis

A.A. Izzo et al. / International Journal of Cardiology 98 (2005) 114

Table 2 (continued)
Herbal medicine
(Common name/
Latin name)

Source

Main
constituent(s)

Main
pharmacological
action(s)

Promoted use

Clinical
evidence

Adverse events

Liquorice/Glycyrrhiza
glabra

Roots

Glycyrrhizinic
acid

Gastric ulcer,
catarrhs, cancer
prevention,
inflammation

Liquorice is an
effective anti-ulcer;
however, its use
has declined.

Adverse effect
consistent with
adrenocorticotropic
actions

Mango/Mangifera
indica

Fruits

Vitamins A
and C; fibers

Expectorant,
anti-inflammatory,
anti-ulcer,
aldosterone-like
effects
Analgesic;
anti-inflammatory;
antioxidant; laxative

Specific studies
not available

Not expected

Oat branc/Avena sativa

Seeds

Fibers

Constipation
(also used as a
food and as a
source of vitamins)
Hypercholesterolemia,
prevention of
atherosclerosis

Not expected

Papaya/Carica papaya

Fruits

Papain (enzyme)

Promising in
reducing
cholesterol and
LDL blood levels
Specific studies
not available

Prostate cancer

Lack of
randomized
clinical studies

Reduced libido,
hot flashes,
diarrhea, dyspepsia,
leg cramps,
gynaecomastia,
nipple tenderness,
pulmonary emboli,
vein thrombosis

Pectins-based
home remedies
are useful in the
treatment of
diarrhea.
Not established
for any
indications

Not expected

d
PC-SPESd/Dendrathema
morofolium/Isatis
indigotica/Glycyrrhiza
glabra/Ganoderma
lucidum/Panax
pseudoginseng/Rabdosia
rubescens/Serenoa
repens/Scutellaria
bacicalensis
Pectinse
fleshy fruits
and storage
roots of many
plantse

Antilipidaemic,
anti-atherosclerotic

Proteolytic,
amylolytic,
lipolytic activity
Polysaccharides, Immunostimulant,
phytosterols, fatty cytotoxic
acids, flavonoids

Indigestion, obesity

Antidiarrheal

Diarrhea

Siberian ginseng/
Eleutherococcus
senticosus

Roots

Eleutherosides

Immunomodulatory,
anti-inflammatory,
antitumor,
hypoglycemic

Loss of energy
and memory;
stress states,
male sexual
dysfunction

Soy/Glycine max

Beans

Phytoestrogens

Hepatoprotective,
anti-osteoporosis

Treatment of
menopausal
symptoms;
prevention of
heart diseases
and cancer

St. Johns wort/

Hypericum
perforatum

Aerial parts

Hypericin,
hyperforin,
flavonoids

Antidepressant,
antiretroviral

Depression

Tamarind/Tamarindus
indica

Fruits

Sugars,
mucilages

Stimulates
intestinal
peristalsis

Constipation
(also used as
a food)

Promising for
treating
menopausal
symptoms;
case-control
studies suggest
a link between
soy phytoestrogen
consumption and
reduced risk of
breast and other
cancers.
Effective for mild
to moderate
depression; not
suited for major
depression
Effective
laxative

Not expected

Diarrhea,
dizziness,
hypertension,
pericardial pain,
tachycardia,
insomnia,
extrasystoles,
headaches
Occasional
gastrointestinal
effects, i.e.
stomach pain,
flatulence, loose
stool and diarrhea

Gastrointestinal
symptoms

Not expected

(continued on next page)

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A.A. Izzo et al. / International Journal of Cardiology 98 (2005) 114

Table 2 (continued)
Herbal medicine
(Common name/
Latin name)

Source

Main
constituent(s)

Main
pharmacological
action(s)

Promoted use

Clinical
evidence

Adverse events

Wheat bran/Triticum
aestivum

Seeds

Indigestible
carbohydrates
(starch, cellulose,
hemicelluloses),
lignin

Stimulates
intestinal
peristalsis

Constipation,
obesity

Ineffective to
treat obesity

Bloating

Data extracted from Refs. [1,21,23].

a
Curbicin contains Serenoa repens (saw palmetto) fruits, Cucurbita pepo (pumpkin) seeds and vitamin E.
b
Data from epidemiological studies.
c
The cholesterol-lowering effect of oat bran is not shared by wheat bran.
d
PC-PCS is a mixture of eight herbal drugs, namely, Dendrathema morofolium (chrysanthemum), Isatis indigotica (dyers woad), Glycyrrhiza glabra
(liquorice), Ganoderma lucidum (reishi), Panax pseudoginseng (san-qui ginseng), Rabdosia rubescens (rubescens), Serenoa repens (saw palmetto) and
Scutellaria bacicalensis (Baikal skullcap).
e
Pectins are biopolymers with molecular weights of 60 000 to 90 000. Their basic structural framework is formed by galacturonic acid molecules. Pectins
are present to some degree in all plant products but are particularly abundant in fleshy fruits and storage roots. Rich commercial sources are sugar beet
fragments, apple residue, orange and lemon waste product and carrots.

(a metabolite of aspirin). The mechanism of such interaction is not known.

3.3. Interaction with anticoagulants
3.3.1. Warfarin
Warfarin owes its action to its ability to antagonize the
cofactor function of vitamin K [56]. Theoretically, increased
anticoagulant effects could be expected when combined
with coumarin-containing herbal medicines (e.g. boldo,
fenugreek and don quai) or with antiplatelet herbs (danshen,
garlic and ginkgo). Conversely, vitamin K-containing herbs
(e.g. green tea) can antagonize the anticoagulant effect of
warfarin [63].
Clinical reports indicate over-anticoagulation when combined to boldo, fenugreek, garlic, danshen, devils claw,
dong quai, ginkgo, papaya, Lycium and mango and decreased anticoagulant effect if co-administered with ginseng, green tea, soy and St. Johns wort [35 50]. Given the
narrow therapeutic index of warfarin, both the effects could
have serious consequences.
A patient treated with warfarin for atrial fibrillation
saw his international normalized ratio (INR) increased
after taking a variety of natural products, including boldo
and fenugreek [35]. When he stopped herbal products, the
INR returned normal after 1 week. The herb drug interaction was observed a second time after both products
were reintroduced a few days later. Both boldo and
fenugreek contain anticoagulant coumarins which, in an
additive or synergistic way, could produce such interaction [64].
Two cases of increased INR were reported after coadministration of curbicin (a preparation containing saw
palmetto, pumpkin and vitamin E) [36]; the INR normalized
after discontinuation of curbicin. No anticoagulant effect has
been found in the literature associated with the two major
components of curbicin. However, vitamin E has been
shown to antagonize the effect of vitamin K and may lead

to increased risk of bleeding, particularly in patients taking

oral anticoagulants [65].
Three case reports have highlighted the possibility of
interaction between warfarin and danshen, resulting in
increased anticoagulant effect [37 39]. The interaction
could have both a pharmacokinetic (changes in plasma
concentration) and a pharmacodynamic (additive effect on
coagulation mechanisms) basis; in fact, animal studies
indicate that danshen, in addition to its antiplatelet effect
[66], increases the absorption and decreases elimination of
warfarin [67].
A review on traditional remedies and food supplements
briefly mentions the case of purpura associated with concomitant use of devils claw and warfarin [31]. Due to the
paucity of information reported, the likelihood of such
interaction cannot be established; possible mechanisms of
such interaction are not known as very little is known about
the metabolism and distribution of devils claw components;
an effect of devils claw on platelet function seems unlikely
as this herbal drug, in contrast to aspirin, does not affect
blood eicosanoids production [68].
Two well-documented case reports indicate over-anticoagulation following co-administration of warfarin and
dong quai [40,41]. Phytochemical analyses have revealed
in dong quai the presence of natural coumarin derivatives
[69], which can decrease coagulation by replacing vitamin
K as the apoenzyme in an enzyme complex; notably,
warfarin is a synthetic coumarin anticoagulant.
Two cases of increased INR were mentioned in patients
taking garlic previously stabilized on warfarin [42]. A
likely mechanism is an additive effect on coagulant mechanisms, as garlic possesses antiplatelet activity [70]. However, garlic treatment has been associated with bleeding
even in the absence of warfarin or other anticoagulant
treatment [71].
A well-documented case report demonstrated that a
patient under pharmacological treatment with warfarin
(5 years) experienced a left parietal hemorrhage after 2

A.A. Izzo et al. / International Journal of Cardiology 98 (2005) 114

months of co-administration with ginkgo [43]. As stated

above, an additive effect on coagulation mechanisms could
be responsible of such interaction [62]. It should be noted
that intracerebral hemorrhage associated with long-term
ginkgo ingestion has been reported, even in the absence of
anticoagulants [72].
A case report of suspected interaction between warfarin
and ginseng has been reported [44]. A decrease of INR was
noted, but because the patient took several other drugs
concomitantly (i.e. diltiazem, nitroglycerin and salsalate),
causality is uncertain. Antiplatelet activity of ginseng has
been previously noted [73], but, of course, this would not
seem to explain such interaction. A pharmacokinetic study
in rats did not reveal a significant interaction between
warfarin and ginseng [74].
A case of inhibition of the effect of warfarin (decreased
INR) by green tea has been reported [45]. The patient,
which received warfarin for thromboembolic prophylaxis,
began drinking 1/2 to 1 gal of green tea per day about 1
week prior to the decreased INR. Green tea can be a
significant source of vitamin K and thus antagonize the
effect of warfarin [75].
An elevated INR was observed in a Chinese woman
previously stabilized on warfarin [46]; this was likely
caused by a concentrated Chinese herbal tea made from
Lycium fruits (three to four glasses daily), a Chinese herb
considered to have a tonic effect on various organs. In vitro
evaluation showed weak inhibition of warfarin metabolism
by CYP2C9 by the tea of Lycium, suggesting that the
observed interaction may be caused by factors other than
the CYP450 system [46].
A single publication reported 13 male patients whose
INR were found increased after mango fruit ingestion [47].
After identification of mango fruit as a possible cause of
supratherapeutic INR, patients were instructed to stop mango ingestion for 2 weeks. The average measured INR in the
13 patients decreased by 17.7% after discontinuation. Rechallenge with mango fruit in 2 of the 13 patients produced
increased INR. Although the exact mechanism for this
interaction is unknown, there are literature reports suggesting that concomitant administration of warfarin and large
doses of vitamin A (mango contains high amounts of
vitamin A) can cause an increased anticoagulant effect
[76]. Vitamin A (retinol) inhibits hepatic human CYP2C19
and this would lead to a moderate increase in warfarin
concentrations and thus higher INRs [77].
Another plant-based remedy which can interact with
warfarin is papaya [31], the fruit of the papaya tree. A case
has been mentioned briefly where the INR of an anticoagulated patient was increased after addition of papaya
extract to his prescribed medication [31]. The pharmacological mechanisms by which papaya may affect coagulation are not known. Nevertheless, this interaction is
potentially fatal. Papaya is contraindicated with warfarin
as it may damage the mucous membranes of the gastrointestinal tract, and the resultant bleeding would be increased.

11

A 79-year-old man with prostate cancer started treatment

with warfarin after he developed deep vein thrombosis
during treatment with PC-SPES (an anticancer herbal mixture) [48]. PC-SPES therapy was stopped, but when it was
subsequently reinitiated, his INR became more difficult to
maintain in the therapeutic range and his warfarin requirements decreased. HPLC analysis of PC-SPES revealed the
presence of coumarins, which can inhibit vitamin K reductase in a similar manner to warfarin [78].
A 70-year-old man who was stable on warfarin therapy
developed subtherapeutic INR values after ingesting soy
protein in the form of soy milk [50]. The subtherapeutic
INR values could not be explained by factors known to
reduce the INR such as noncompliance, new medication,
other alternative therapies or increased consumption of
vitamin K. INR values returned to therapeutic concentrations within 2 weeks after discontinuation of the soy milk.
The mechanism of such interaction is not known.
Although not all investigations yielded the same results,
most studies agreed that St. Johns wort activate enzymes
of the cytochrome P450 enzyme system, including CYP
1A2 which is responsible of the metabolisation of warfarin
in the liver [79 81]. Probably via this mechanism, St.
Johns wort increased the metabolism of warfarin; such
mechanism could explain the decrease of the seven cases
of INR associated with concomitant use of warfarin and St.
Johns wort reported by the Swedish Medical Product
Agency [50]. Notably, a clinical study [52] showed that
St. Johns wort decreased the plasma concentration of
phenprocoumon, an anticoagulant chemically related to
warfarin (see below).
3.3.2. Phenprocoumon
Phenprocoumon is an anticoagulant chemically related to
warfarin; as it is the case of warfarin, it could potentially
interact with coumarin- or vitamin K-containing herbal
medicines or with antiplatelet herbs [56].
A case report highlighted the possible reduced efficacy of
phenprocoumon if co-administered with St. Johns wort
[51]. The possibility is strengthen by a clinical study which
showed that 11-day medication of St. Johns wort resulted in
a significant decrease of the area under the curve (AUC) of
the free phenprocoumon compared with placebo [51].
Induction of hepatic enzyme by St. Johns wort is a likely
mechanism which could explain such interaction.
A study on seven healthy volunteers showed that ingestion of 35 g wheat bran produced a decreased absorption
rate of phenprocoumon but no decrease in overall bioavailability [53]. In addition, an increase in the free plasma
fraction of phenprocoumon was seen after wheat bran
administration. While the presence of fibers in bran can
easily explain the decreased absorption rate, the increase in
the free plasma fraction cannot be explained by our present
knowledge of wheat bran biological properties. It is noteworthy that the increase in absorption would predict decreased efficacy, while increased free plasma fraction would

12

A.A. Izzo et al. / International Journal of Cardiology 98 (2005) 114

predict increased activity of phenprocoumon; thus, the

clinical significance of such interaction is unpredictable.
3.4. Interaction with antihyperlipidemic drugs
3.4.1. Simvastatin, pravastatin and lovastatin
Simvastatin, pravastatin and lovastatin are inhibitors of
HMG-CoA reductase, the rate-limiting step in cholesterol
synthesis. By inhibiting de novo cholesterol synthesis, they
deplete the intracellular supply of cholesterol [56].
A clinical study showed that repeated St. Johns wort
treatment (14 days) decreased plasma concentrations of
simvastatin but not of pravastatin [54]. Because simvastatin
is extensively metabolised by CYP3A4 in the intestinal wall
and liver (which is induced by St. Johns wort) [79 81], it is
likely that this interaction is partly caused by the enhancement of the CYP3A4-mediated first-pass metabolism of
simvastatin in the small intestine and liver.
A decrease of absorption of lovastatin was observed in
patients who took this lipid-lowering agent concomitantly
with pectin or oat bran [55]. This resulted to an increase in
LDL levels which lead to the abortion of the trial. When
these plant-based preparations were discontinued, lovastatin
pharmacokinetics returned to normal and lipoprotein levels
in plasma normalized as a result. This interaction is likely
due to the ability of pectins or bran fibers to bind or trap
concurrently administered lovastatin.

4. Discussion
Herbal medicines follow modern pharmacological principles. Hence, herb drug interactions are based on the same
pharmacokinetic and pharmacodynamic mechanisms as
drug drug interactions [5]. Herbal medicines may affect
absorption (e.g. guar gum reduces digoxin absorption) [27],
metabolism (e.g. St. Johns wort increases warfarin metabolism, causing decreased anticoagulant effect) [50] or excretion (St. Johns wort increases digoxin renal excretion)
[28] of concurrently administered cardiovascular drugs.
Herb drug interactions that involve distribution mechanisms have not been reported. Moreover, interactions may
be additive or synergetic, whereby the herbal products
potentiate the action of the conventional cardiovascular
drug (e.g. ginkgo potentiates the antiplatelet effect of
aspirin) [33]. Conversely, the herb may be directly antagonistic to the action of the drug (e.g. green tea antagonizes the
anticoagulant effect of warfarin) [45].
Based on the above evidence, there can be little doubt
that interactions between herbal medicines and cardiovascular drugs exist. The real incidence of such interactions is
probably unknown, as is the likelihood that a patient will
have an adverse event when taking two drugs (i.e. herbal
and conventional medicines) with the potential to interact.
Much of the available information about the interaction
between herbal medicines and cardiovascular pharmacother-

apy is gleaned from case reports, although clinical studies

are now also beginning to appear in the literature. Obviously, case reports have to be interpreted with great caution, as
causality is not usually established beyond reasonable
doubt. To establish causality is, of course, a difficult task.
Rechallenge would be the most straightforward clinical test,
but for obvious reasons, this option is not always available.
Hence, even well-documented case reports (and many are
not well documented) can only serve as a critical early
warning system.
In conclusion, interaction between herbal medicine and
cardiovascular drugs is a potentially important safety issue.
Patients under anticoagulant pharmacotherapy are at the
highest risk. Healthcare professionals need to be aware of
potential herb drug interactions and researcher should
strive to fill the numerous gaps in our present understanding
of this problem.

Acknowledgements
This work was supported by the Enrico and Enrica
Sovena Foundation and SESIRCA (Regione Campania,
Italy).

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