CONTINUING PROFESSIONAL DEVELOPMENT

HERBAL THERAPEUTICS

(10) HERBAL INTERACTIONS

By Jo Barnes, PhD, MRPharmS, Linda A. Anderson, PhD, FRPharmS, and J. David Phillipson, DSc, FRPharmS

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The last in a series on the therapeutic use of European herbal medicines in various disorders,
this article focuses on unwanted herbal interactions

identify gaps in your

knowledge
1. Name two groups of people who need special
consideration before using herbal products.
2. List two herbal interactions.
3. What information is required for a yellow card report?
This article relates to the Royal Pharmaceutical Societys
core competencies of drug-related interactions and evidence-based practice (see Medicines, ethics and practice
a guide for pharmacists, number 26, June 2002, pp1056).
You should consider how it will be of value to your practice.

erbal medicines, or herbal medicinal products (HMPs),

are popular in the United Kingdom. Over-the-counter
(OTC) HMPs are not only used for general well-being
and to prevent or treat common minor ailments, but they
are also used by individuals with serious chronic disease. Users also
include pregnant and breastfeeding women, children and the elderly.
As with conventional medicines, it is reasonable to expect that
interactions between HMPs and medicines, other HMPs, alcohol or
foods can occur. Some consumers of HMPs may already be taking,
or may begin to take, conventional OTC or prescribed medicines.
Concurrent use of HMPs and conventional medicines will not
always lead to a clinically relevant herb-drug interaction, but the
potential for this should not be ignored. As the health care professional most likely to interact with consumers of OTC HMPs, pharmacists have roles to play in advising on and monitoring the
concurrent use of herbal and conventional medicines, and in reporting suspected herbal interactions.

EXTENT OF CONCURRENT USE OF

CONVENTIONAL MEDICINES

HMPS AND

Several studies have provided some relevant data on the extent of

use of HMPs by patients taking conventional medicines, but the
incidence of herb-drug interactions has not been explored. One survey of 1,539 adults in the United States found that 44 per cent of
respondents regularly took prescribed medicines, and almost a fifth
of these were also using herbal or high-dose vitamin preparations.1
In 2001, preliminary data from a pilot study of 164 herbal medicine users identified in health-food stores and pharmacies in the
UK, indicated that 59 per cent had taken HMPs and conventional
medicines concurrently in the previous year.2 The conventional
medicines taken included drugs acting on the central nervous
system (eg, lofepramine, paroxetine, metoclopramide, sumatriptan,

Dr Barnes is a lecturer in phytopharmacy at the centre for pharmacognosy

and phytotherapy at the School of Pharmacy, University of London, Dr
Anderson is principal pharmaceutical officer at the Medicines
Control Agency and Professor Phillipson is emeritus professor at
the centre for pharmacognosy and phytotherapy, School of Pharmacy,
University of London. The views expressed are those of the authors and do not
represent the views of the Medicines Control Agency

118

identify
evaluate

record

plan

act

trifluoperazine), antidiabetics, steroids, thyroxine, anti-asthmatics,

cough and cold remedies and drugs acting on the cardiovascular system (eg, atenolol, diltiazem, enalapril, simvastatin, spironolactone
and warfarin), as well as antibacterial agents.
In a study at a memory disorders clinic in Canada, 195 older
patients (and usually their care-providers) were interviewed.
Ninety-seven per cent were using at least one prescription medicine
and 17 per cent (n = 33) were using at least one natural health product (NHPs, defined as herbal medicines, minerals or dietary supplements), mainly Ginkgo biloba (n=22; 67 per cent).3 Although the
precise proportion of concurrent users of prescribed medicines and
NHPs was not given, of the 33 NHP users, nine were deemed by the
researchers to be at risk of a herb-drug interaction, on the basis of
information documented in the medical literature. In eight cases,
the potential interaction related to the use of Ginkgo biloba with
aspirin.
The findings of this study are limited for several reasons: only
small numbers of patients attending one specialised clinic were
involved, no information on formulation and dosage of either the
herbal or the prescribed medicines used was reported, there could
have been problems with information recall and only potential, not
actual, interactions were explored.
Concerns about the concurrent use of herbal and conventional
medicines are amplified when considered together with the general
lack of professional involvement in individuals decisions regarding
the use of HMPs and the lack of disclosure of their use to health care
professionals, even when problems arise.4

TYPES OF INTERACTIONS
It is beyond the scope of this article to discuss in detail the mechanisms of drug interactions and pharmacists are encouraged to consult standard reference texts, such as Stockleys drug interactions,5
for this information. Although some interactions are unique, as with
conventional drug interactions, herbal interactions usually can be
classified as pharmacokinetic (when the absorption, distribution,
metabolism or excretion of one substance is affected by another, ie,
an HMP can affect the pharmacokinetics of a drug and vice versa)
and pharmacodynamic (when one substance changes the effects of
another at its site of action).5 And like conventional medicines, the
pharmacokinetics of HMPs and, hence, their potential for pharmacokinetic interactions, are influenced by factors, such as age,
genetics and cigarette smoking.6

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CONTINUING PROFESSIONAL DEVELOPMENT

Pharmacists are encouraged to report suspected herbal interactions using the yellow card system

Sometimes herbal interactions can be beneficial. Indeed, one of

the basic tenets of herbal medicine is that interactions occur
between the different constituents of a herb, or a combination of
herbs, either to increase desired effects or reduce unwanted effects
or both, but this is not the focus of this article.

HERB-DRUG INTERACTIONS
The potential for interactions between herbal and conventional
medicines has been recognised for some time, although wider
awareness has arisen only recently. Generally, information on herbdrug interactions, particularly in the clinical setting, is still limited
there are a number of case reports, but little formal clinical investigation.
Many case reports have been summarised and evaluated for
their quality and importance.4,5,7 Some well-known examples are
discussed here, but pharmacists are encouraged to consult reference
texts for further guidance on specific herbal interactions.4,5 Readers
might also want to look back at some of the interactions discussed
during this series.
Concerning the potential for herbal interactions, it is important
to consider the variability that exists in the constituent profile of
different marketed HMPs containing the same herbal ingredient, as
well as the pharmaceutical quality (including the possibility of contamination) of unlicensed HMPs. The suggestion that evidence for
safety (and efficacy) should be considered to be extract- or productspecific and extrapolated only to those products which are pharmaceutically equivalent and bioequivalent was raised at the start of this
series (PJ, 8 June 2002, pp8046).
Pharmacokinetic interactions There is an increasing amount of in
vitro research into potential herb-drug pharmacokinetic interactions, particularly studies exploring the effects of specific herbal
ingredients and constituents on cytochrome P450 (CYP) drug
metabolising enzymes in human liver microsomes. For example,
such studies have found that:
z Silibinin (the major constituent of silymarin present in milk
thistle, Silybum marianum) inhibits CYP3A4 and CYP2C9
activities in vitro
z Constituents of garlic (Allium sativum) inhibit the activity of
various CYP isoforms, including CYP3A4 in vitro
z Peppermint oil and menthol (a constituent of peppermint oil)
inhibit CYP3A4 activity in vitro
These types of study are essential because pharmacokinetic
interactions are hard to predict but, in drawing conclusions from
them, it is important to consider the clinical relevance of any findings and that individuals vary in their response to drugs, including
herbal medicines.
Pharmacodynamic interactions The potential for pharmacodynamic interactions can, to some extent, be predicted if the phytochemical constituents of a herb and their pharmacology, together
with the pharmacology of the drug(s) used concurrently, are known.
Phytochemical and pharmacological data for many herbal ingredi25 January 2003

ents have been summarised, and from these, lists of potential herbdrug interactions have been drawn up. Table 1 (p120) shows selected
examples of potential pharmacodynamic herb-drug interactions for
several popular herbs and conventional medicines compiled on this
basis (see Reference 4, pp497500, for further examples).4 St Johns
wort is discussed separately below. Such lists are intended to be used
as guidance in the absence of research in herb-drug interactions, and
inclusion in a list does not mean that a clinically important herbdrug interaction will necessarily occur.
St Johns wort Probably the most comprehensive information available in terms of herb-drug interactions relates to interactions
between St Johns wort (Hypericum perforatum), a medicinal plant
used for symptomatic relief in mild-to-moderate depression, and
certain prescribed medicines. Pharmacokinetic interactions with
St Johns wort, leading to a loss of or reduction in the therapeutic
activity of the following medicines may occur:
z
z
z
z

Anticonvulsants (carbamazepine, phenobarbital, phenytoin)

Ciclosporin
Digoxin
Protease inhibitors (indinavir, nelfinavir, ritonavir, saquinavir)
and non-nucleoside reverse transcriptase inhibitors (efavirenz,
nevirapine) indicated for HIV infection
z Oral contraceptives
z Theophylline
z Warfarin
New information from a small (n=5), randomised, non-blinded,
crossover study involving patients with cancer has suggested that the
activity of irinotecan could also be affected by concurrent use of
St Johns wort.8
Results of drug interaction studies have provided some evidence
that the basis for interactions may be the induction of CYP enzymes
(CYP1A2, CYP2C9 and CYP3A4) in the liver and P-glycoprotein (a
transport protein) by St Johns wort constituents.9 Patients already
taking St Johns wort and any of the medicines listed above can experience problems if they stop taking it, because the amount of drug
metabolised could drop and blood concentrations of medicines
could rise, possibly leading to adverse effects. A list of other medicines whose metabolism involves one or more of these CYP
enzymes or P-glycoprotein is available on the Medicines Control
Agency website (w w w.mca.gov.uk). Theoretically, these could also
interact with St Johns wort, but there is no direct evidence of interactions of clinical importance.
The precise mechanism(s) of action responsible for the antidepressant effect of St Johns wort is unclear; effects on serotonergic
systems have been documented in vivo. Pharmacodynamic interactions, namely increased serotonergic effects in patients taking
St Johns wort concurrently with the selective serotonin reuptake
inhibitors (SSRIs) paroxetine and sertraline have been reported.
Other medicines with which St Johns wort could pharmacodynamically interact include other SSRIs, such as fluoxetine, and the
triptans, such as sumatriptan.
Although St Johns wort was previously thought to inhibit
monoamine oxidase, current consensus is that this is not the case

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TABLE 1: SELECTED EXAMPLES OF POTENTIAL PHARMACODYNAMIC HERB-DRUG INTERACTIONS
Therapeutic
category of drugs

Herbal ingredients

Reason for potential

interaction

Nature of potential effect

Anticoagulants

Feverfew, garlic
Ginger
Ginkgo

Inhibit platelet aggregation in vitro

Antiplatelet activity in vitro (conflicting data in humans)
Ginkgolide constituents antagonise PAF, in vitro
and in vivo (humans)
Coumarin constituents
Salicylate constituents

Potentiation

Horse-chestnut
Willow
Anticonvulsants

Willow

Salicylate constituents displacement of phenytoin

from binding sites*

Potentiation*

Antidiabetics

Panax ginseng
Rosemary

Hypoglycaemic activity in vitro and in vivo

Hyperglycaemic activity in vivo

Potentiation
Antagonism

Antidiarrhoeal agents

Aloes, cascara,frangula,
rhubarb, senna
Ispaghula

Hydroxyanthracene constituents with

laxative activity
Bulk laxative

Antagonism

Laxatives

As above

As above

Potentiation

Cardiac glycosides

Devils claw, ginger

Hawthorn

Cardioactive in vivo
Cardioactive in vivo (humans)

Potentiation

Diuretics

Dandelion, elder
Nettle

Diuretic activity in vivo

Diuretic activity, in vivo (humans,
not well established)

Potentiation; increased risk of

hypokalaemia

Hypnotics and
anxiolytics

German chamomile, hops,

passionflower
Valerian

Sedative activity in vivo

Potentiation

Sedative and hypnotic activity in vivo (humans)

Clinically important herb-drug interactions will not necessarily occur, nor occur in every patient taking the named substances
In vivo refers to animal studies unless humans stated specifically
* Current opinion is that there is no clinically significant interaction between phenytoin and aspirin1

and, therefore, the usual precautions for drug and other interactions
with monoamine oxidase inhibitors are not considered necessary
with St Johns wort. There is however, one literature report of a man
who experienced hypertensive crisis after consuming cheese and red
wine, having taken St Johns wort for one week previously (PJ, 29
June 2002, pp90810).
Patients taking the medicines listed above should be advised to
stop taking St Johns wort, although those taking warfarin,
ciclosporin, digoxin, theophylline, anticonvulsants and anti-HIV
medicines should first seek medical advice because dose adjustment
or, in the case of anti-HIV medicines, measurement of viral load,
may be necessary.9
The Royal Pharmaceutical Societys working group on complementary/alternative medicine has produced a fact sheet on St Johns
wort interactions specifically for pharmacists (issued with the PJ in
September 2002 and available on the Societys website,
w w w.rpsgb.org.uk/pdfs/scifactsheetstjwort.pdf). It includes a summary
of reports of suspected interactions between St Johns wort and
conventional medicines received by the MCA and Committee on

action : practice points

1. Identify a patient on your patient medication records who is
taking several medicines. What would you advise if the patient
enquired about taking (a) St Johns wort, and (b) ginkgo?
2. Make a note in your diary to visit the MCA website
(w w w.mca.gov.uk) in six months time to see if there is any
new information about herbal interactions.
3. Go into your local healthfood shop and look at the range of
herbal products available. Consider possible interactions.

evaluate
How could your learning have been more effective?
What will you do now and how will this be achieved?

120

Safety of Medicines. Information for health care professionals and

patients is also available on the MCA website.
Ginkgo and garlic There are isolated reports of bleeding episodes in
patients taking warfarin or aspirin and who began taking ginkgo, and
several other reports where ginkgo ingestion alone has been associated with bleeding episodes.4,5 Although an interaction or causal
relationship has not been confirmed in these cases, because of their
relevant pharmacological activity, general advice is that ginkgo
extracts should only be used with caution in patients taking anticoagulant and antiplatelet agents.4 Similarly, pharmacists should be aware
of the potential for other herbs with anticoagulant and or antiplatelet
activity to interact with such agents (see Table 1 for examples).
There are also isolated reports of increased international
normalised ratio (INR) in patients taking warfarin and garlic supplements concurrently and in a recent study involving 10 healthy volunteers, the mean area under the curve (concentration of drug in
plasma against time), trough and maximum concentrations of
saquinavir (1,200mg three times daily for four days) decreased by 51,
49 and 54 per cent, respectively, during use of a garlic supplement
(taken twice daily for the previous 20 days).10 Although the study did
not involve individuals with HIV infection, the authors advised
caution if garlic supplements are used concurrently with saquinavir
as the sole protease inhibitor in such patients.
Since October 1996, of the 57 reports of suspected interactions
associated with HMPs received by the MCA (most relate to
St Johns wort) three relate to suspected interactions between garlic
preparations and prescribed medicines. Hypotension and syncope
were associated with use of garlic and lisinopril and increased INR
was associated with use of garlic and warfarin. A need to reduce
warfarin dose (not considered serious) was associated with use of
garlic, echinacea and warfarin. Two further reports describe
suspected herb-herb interactions.

HERB-DISEASE INTERACTIONS
Herbal interactions do not only involve medicines. There is also a
potential for herb-disease interactions where patients with certain

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THE PHARMACISTS ROLE THE YELLOW CARD SCHEME
As part of a professional role in advising on, monitoring for and
reporting herb-drug interactions, pharmacists are encouraged
routinely to ask patients taking conventional medicines about their
use of HMPs (and vice versa) and, where appropriate, to record
use of HMPs on patient medication records or medical notes. As
with all drug interactions, particular attention should be given to:
z Older patients and others with compromised hepatic or renal
function
z Those taking several prescribed medicines
z Those taking medicines with a narrow therapeutic window or
with which serum concentrations are otherwise particularly
important, such as anticoagulants, anticonvulsants, antiinfectives, digitalis glycosides, hypoglycaemic agents and
immunosuppressants.5
In addition, changes that occur during pregnancy, such as
increases in total body water and fat stores, can influence pharmacokinetics. Since several studies have shown that some pregnant women
use HMPs, this patient group also needs special consideration.

conditions use HMPs. For example, potentially, problems could

occur where patients with hypertension ingest herbal ingredients
containing constituents with hypertensive properties, and there may
be a risk of loss of glycaemic control in patients with diabetes who
ingest herbal ingredients containing constituents with hyper- or
hypoglycaemic activity.
Potential herb-disease interactions can, to some extent, be predicted in the same way as can potential pharmacodynamic herbdrug interactions. Lists of herbal ingredients with pharmacological
properties, such as diuretic, hypo- or hypertensive, coagulant or
anticoagulant, sedative, hypo- or hyperglycaemic activity, documented from in vitro and in vivo (animals or humans), have been
compiled.4 Again, such lists are intended to be used as a guide in the
absence of knowledge on herb-disease interactions, and inclusion in a
list does not mean that a clinically important herb-disease interaction
will occur.
Pre-operative use of HMPs The need for patients to discontinue use
of HMPs before undergoing surgery has been proposed on the basis
that there is a potential for interactions to occur with anaesthetics,
anticoagulants and other substances used before, during or after
surgery, as well as direct pharmacological effects of HMPs which
could interfere with, for example, control of anticoagulation and
blood pressure.11

The pharmacists role in identifying herb-drug interactions

has been recognised by the MCA and CSM. These organisations
saw pharmacists as a means of disseminating information, for
example, on St Johns wort interactions with prescribed medicines
when this issue emerged. Pharmacists are encouraged to report
suspected ADRs (which include drug interactions) for licensed and
unlicensed HMPs on yellow cards. Pharmacists need only have a
suspicion that an interaction (or ADR) has occurred it is not
necessary to be certain of a causal relationship.
For a yellow card report, the essential items of information are
patient details, reporter details, suspected HMP(s) or drug(s) and
suspected interaction(s) or reaction(s).
Further information, including route, dosage, reason for use,
whether rechallenge occurred and what the outcome was, is welcomed if it is available, although pharmacists should not be
deterred from reporting if information is missing. For HMPs,
useful additional information includes: manufacturers name,
batch number, type of extract, Latin binomial name and plant part
used, particularly where the interacting herb was supplied by a
herbalist.

The minimum period for which HMPs should be discontinued

before surgery will depend on the pharmacokinetics of the particular HMP and factors affecting pharmacokinetics (eg, age) for each
patient. However, with some exceptions, little is known about the
pharmacokinetics of constituents of HMPs.12 For example, on the
basis of what is known about the pharmacokinetics of ginkgo leaf
constituents, treatment should be stopped 24 to 48 hours before
surgery, but preferably earlier.

OTHER PRECAUTIONS
Although not considered to be drug interactions,1 there are also
instances where HMPs could interfere with the results of diagnostic
and biochemical tests. Information in this area is also limited. Interference with dipstick tests for glucose and haemoglobin in urine
associated with cranberry ingestion (possibly related to the ascorbic
acid content) and elevated digoxin concentrations in a patient taking
digoxin and Siberian ginseng (Eleutherococcus senticosus; possibly
because of interference by Siberian ginseng with the digoxin
assay),4,5 have been documented.
ACKNOWLEDGEMENT The authors thank Leigh Henderson,
Medicines Control Agency, for information on numbers of reports
of herbal interactions.

REFERENCES
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2.

3.

4.

5.
6.

Eisenberg DM, Davis RB, Ettner SL, Appel S, Wilkey S, Van

Rompay M et al. Trends in alternative medicine
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Gulian C, Barnes J, Francis S-A. Types and preferred sources
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Dergal JM, Gold JL, Laxer DA, Lee MSW, Binns MA, Lanctt
KL et al. Potential interactions between herbal medicines and
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memory clinic. Drugs Aging 2002;19:87986.
Barnes J, Anderson LA, Phillipson JD. Herbal medicines. A
guide for healthcare professionals. 2nd edition. London:
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Stockley IH (ed). Stockleys Drug Interactions. 6th edition.
London: Pharmaceutical Press, 2002.
De Smet PAGM, Brouwers JRBJ. Pharmacokinetic evaluation of herbal remedies. Basic introduction, applicability,

25 January 2003

current status and regulatory needs. Clinical Pharmacokinetics 1997;32:42736.

7. Fugh-Berman A, Ernst E. Herb-drug interactions. Review
and assessment of report reliability. Br J Clin Pharmacol
2001;52:58795.
8. Mathijssen RH, Verweij J, de Bruijn P, Loos Wj, Sparreboom
A. Effects of St Johns wort on irinotecan metabolism. J Nat
Cancer Inst 2002;94:12479.
9. Henderson L, Yue QY, Bergquist C, Gerden B, Arlett P. St
Johns wort (Hypericum perforatum): drug interactions and
clinical outcomes. Br J Clin Pharmacol 2002;54:34956.
10. Piscitelli SC, Burstein AH, Welden N, Gallicano KD,
Falloon J. The effect of garlic supplements on the pharmacokinetics of saquinavir. Clin Infect Dis 2002;34:2348.
11. Ang-Lee MK, Moss J, Yuan CS. Herbal medicines and perioperative care. JAMA 2001;286:20816.
12. Bhattaram VA, Graefe U, Kohlert C, Veit M, Derendorf H.
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