Ann's NOTE: It is important to remember that your patients have seen reports indicating that 106,000 deaths occurred in U.S. hospitals in one year, as a result of adverse drug reactions. Lazarou,J et al. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 1998;279:1200-1205
This study also estimated 700,000 patients were injured and 1.5 million were admitted to hospitals due to prescription drug-induced conditions. YOU MUST ACKNOWLEDGE THIS REALITY WHEN SPEAKING TO PATIENTS ABOUT HERBS.
Concurrent use of herbs may mimic, magnify, or oppose the effect of drugs.
Plausible cases of herb-drug interactions include: bleeding when warfarin
is combined with ginkgo (Ginkgo biloba), garlic (Allium sativum), dong quai
(Angelica sinensis), or danshen (Salvia miltiorrhiza);
syndrome in patients who mix St John's wort (Hypericum perforatum) with
serotonin-reuptake inhibitors; decreased bioavailability of digoxin,
theophylline, cyclosporin, and phenprocoumon when these drugs are combined
with St John's wort;
induction of mania in depressed patients who mix
antidepressants and Panax ginseng; exacerbation of extrapyramidal effects
with neuroleptic drugs and betel nut (Areca catechu);
increased risk of
hypertension when tricyclic antidepressants are combined with yohimbine
potentiation of oral and topical corticosteroids
by liquorice (Glycyrrhiza glabra); decreased blood concentrations of
prednisolone when taken with the Chinese herbal product xaio chai hu tang
and decreased concentrations of phenytoin when combined
with the Ayurvedic syrup shankhapushpi. Anthranoid-containing plants
(including senna [Cassia senna] and cascara [Rhamnus purshiana]) and
soluble fibres (including guar gum and psyllium) can decrease the
absorption of drugs
. Many reports of herb-drug interactions are sketchy and
lack laboratory analysis of suspect preparations. Health-care practitioners
should caution patients against mixing herbs and pharmaceutical drugs.
"Poisons and medicines are oftentimes the same substances given with
Peter Mere Latham (1789-1875)
Many medicinal herbs and pharmaceutical drugs are therapeutic at one dose
and toxic at another.
Interactions between herbs and drugs may increase or
decrease the pharmacological or toxicological effects of either component.
Synergistic therapeutic effects may complicate the dosing of long-term
medications--eg, herbs traditionally used to decrease glucose
concentrations in diabetes1 could theoretically precipitate hypoglycaemia
if taken in combination with conventional drugs.
Eleutherococcus senticosis (Siberian ginseng)
Herbal medicines are ubiquitous: the dearth of reports of adverse events
and interactions probably reflects a combination of under-reporting and the
benign nature of most herbs used.
Experimental data in the field of
herb-drug interactions are limited, case reports scarce, and case series
rare. This lack of data is also true of drug-drug interactions: published
clinical studies are mainly case reports (controlled trials are scarce,
since the random assignment of patients to trials that examine unintended
effects is not ethical). The true prevalence of drug interactions is
substantial but unknown. One study of 1000 elderly people admitted to a
hospital from the emergency department found that 538 patients were exposed
to 1087 drug-drug interactions; 30 patients experienced adverse effects as
a consequence of these interactions.2
In clinical practice, polypharmacy is
common, and to the mixture physicians prescribe, patients add various
over-the-counter medications, vitamins, herbs, and foods. All ingested
substances have the potential to interact.
Source and extent of review
Sources for this review include MEDLINE 1966-98 (searched under MeSH terms
"drug interactions" combined with "herbal medicine", "traditional
medicine", "Chinese traditional medicine", "African traditional medicine",
"Ayurvedic medicine", "Oriental traditional medicine", "Unani medicine",
and "Arabic medicine"); EMBASE 1994-99 (searched under the same terms);
reference dredging; and my own files on the subject.
Many reports of herb-induced interactions lack crucial documentation on
temporal relations and concomitant drug use. Perhaps the most serious
problem encountered in analysing such reports is the consistent absence of
any effort (beyond that of reading the label) to establish a positive
identification of the herb involved, and to exclude the effect of
contaminants or adulterants.
Unless noted otherwise, the reports mentioned
herein did not include chemical analyses.
This review was limited to the most commonly used medicinal plants, and to
clinical reports (animal studies are cited where relevant). In-vitro
experiments have been excluded, since extrapolation of in-vitro evidence to
clinical effects is difficult.
For example, St John's wort inhibits
monoamine oxidase in vitro; however, in-vivo experiments have shown no such
effects, and there have been no reported cases linking St John's wort with
hypertensive crises associated with monoamine-oxidase inhibitors.3
St John's wort inhibits the uptake of serotonin, norepinephrine, and
dopamine in vitro only at quite high concentrations (concentration to
inhibit uptake by 50% [IC50] 2·4 mg/L, 4·5 mg/L, and 0·9 mg/L,
That anyone could consume enough of this herb to achieve
these concentrations in blood is extremely unlikely. Nevertheless, there
have been six cases of serotonin syndrome caused by mixing of St John's
wort with serotonin-reuptake inhibitors.
The tables summarise the
interactions identified by the search strategy.5-55
Herb and drug(s)Results of interaction
Betel nut (Areca catechu)
Flupenthixol and procyclidineRigidity, bradykinesia, jaw tremor5Betal
contains arecoline, a cholinergic alkaloid.
FluphenazineTremor, stiffness, akithesia5
Prednisone and salbutamolInadequate control of asthma
caused dose-related bronchoconstriction in six asthma patients.6
Chilli pepper (Capsicum spp)
ACE inhibitorCough7Capsaicin depletes substance P.
TheophyllineIncreased absorption and bioavailability8
Danshen (Salvia miltiorrhiza)
WarfarinIncreased INR, prolonged PT/PTT9-11In rats, danshen decreases
elimination of warfarin.12
Danshen is in at least one brand of cigarettes.13
Devil's claw (Harpagophytum procumbens)
Dong quai (Angelica sinensis)
Increased INR15,16 and widespread bruising 16Dong quai contains
Eleuthero or Siberian ginseng (Eleutherococcus senticocus)
DigoxinRaised digoxin concentrations17Herb probably interfered with digoxin
assay (patient had unchanged ECG
despite digoxin concentration of 5·2 nmol/L).
Garlic (Allium sativum)
WarfarinIncreased INR18 Postoperative bleeding,19,20 and spontaneous spinal
epidural haematoma21 have been reported with garlic alone. Whether garlic
prolongs PT is unclear, but it does cause platelet dysfunction.
Ginkgo (Ginkgo biloba)
Spontaneous hyphema22Ginkgolides are potent inhibitors of PAF.23,24
Paracetamol and ergotamine/caffeineBilateral subdural haematoma25May not be
interaction but due to ginkgo alone. Subarachnoid haemorrhage26
and subdural haematoma27 have been reported with the use of ginkgo alone.
Thiazide diureticHypertension18This effect may be an unusual adverse
reaction to the drug or herb; ginkgo
alone has not been associated with hypertension.
Ginseng (Panax spp)
Decreased INR29In rats, concomitantly administered ginseng had no
significant effect on the pharmacokinetics or pharmacodynamics of warfarin.30
PhenelzineHeadache and tremor,31 mania32Patient with mania also ingested
bee pollen, and had previously had unipolar depression.
Increased alcohol clearance33In mice, ginseng increases the activity
of alcohol dehydrogenase and aldehyde dehydrogenase.
Guar gum (Cyamopsis tetragonolobus)
Metformin, phenoxymethylpenicillin,Slows absorption of digoxin,
paracetamol,Guar gum prolongs gastric retention.glibenclamide and
bumetanide; decreases absorption of metformin, phenoxymethylpenicillin, and
some formulations of glibenclamide18
Table 1: Clinical reports of herb-drug interactions (B-G)
Herb and drug(s)
Results of interactionComments
Karela or bitter melon (Momordica charantia)
ChlorpropamideLess glycosuria34Karela decreases glucose concentrations in
Liquorice (Glycyrrhiza glabra)
PrednisoloneGlycyrrhizin decreases plasma clearance, 11ß-dehydrogenase
converts endogenous cortisol to cortisone; orally
increases AUC,36 increases plasma administered glycyrrhizin is metabolised
mainly to glycyrrhetinic acid.36
Hydrocortisone Glycyrrhetinic acid potentiates of cutaneous Glycyrrhetinic
acid is a more potent inhibitor of 5-, 5ß-reductaseand
vasoconstrictor response3811ß-dehydrogenase than is glycyrrhizin.36
Oral contraceptivesHypertension, oedema, hypokalaemia39Oral contraceptive
use may increase sensitivity to glycyrrhizin acid.39
reportedly more sensitive than men to adverse effects of liquorice.40
Papaya (Carica papaya)
Psyllium (Plantago ovata)
LithiumDecreased lithium concentrations41Hydrophilic psyllium may prevent
lithium from ionising.
St John's wort (Hypericum perforatum)
TrazodoneMild serotonin syndrome43A similar case is described with the use
of St John's wort alone.
SertralineMild serotonin syndrome44
NefazodoneMild serotonin syndrome44
TheophyllineDecreased theophylline concentrations45
DigoxinDecreased AUC, decreased peak and troughMost, but not all, studies
indicate that St John's wort is a potent inhibitor of
concentrations46cytochrome P450 isoenzymes47
CyclosporinDecreased concentrations in serum49
Combined oral contraceptive (ethinyloestradiolBreakthrough bleeding49
Saiboku-to (Asian herbal mixture)
PrednisoloneIncreased prednisolone AUC50Contains all the same herbs as
sho-saiko-to, and Poria cocos,
Magnolia officinalis, and Perillae frutescens.
Shankhapushpi (Ayurvedic mixed-herb syrup)
PhenytoinDecreased phenytoin concentrations, loss ofIn rats, multiple
coadministered doses (but not single doses) decreased
seizure control51plasma phenytoin concentrations; single doses decreased
effect of phenytoin.51
Shankhapushpi is used to treat seizures.
Sho-saiko-to or xiao chai hu tang (Asian
PrednisoloneDecreased AUC for prednisolone50 Contains liquorice (Glycyrrhiza
glabra), Bupleurum falcatum, Pinellia ternata,
Scutellaria baicalensis, Zizyphus vulgaris, Panax ginseng, and Zingiber
Tamarind (Tamarindus indica)
AspirinIncreased bioavailability of aspirin52T amarind is used as a food and
Valerian (Valeriana officinalis)
AlcoholA mixture of valepotriates reduces adverse
effect of alcohol on concentration 53
Yohimbine (Pausinystalia yohimbe)
Tricyclic antidepressantsHypertension54 Yohimbine alone can cause
hypertension, but lower doses cause hypertension
when combined with tricyclic antidepressants.
Effect is stronger in
than normotensive individuals.55
ACE=angiotensin-converting enzyme; INR=international normalised ratio;
PT=prothrombin time; PTT=partial thromboplastin time;
ECG=electrocardiogram; PAF=platelet-activating factor; AUC=area under the
Misidentification, adulteration, and contamination
Labelling of herbal products may not accurately reflect their contents, and
adverse events or interactions attributed to specific herbs may actually be
due to misidentified plants, pharmaceutical drugs, or heavy metals.56 For
example, a "Siberian ginseng" (Eleutherococcus senticosus) product
implicated in a case of neonatal androgenisation57 was found on analysis to
be an unrelated species, Chinese silk vine (Periploca sepium).58
Kong, encephalopathy and neuropathy associated with a Chinese herbal
preparation purportedly made from the roots of long-dan-cao (Gentiana
rigescens) turned out to be due to another plant Podophyllum emodi.56
than 48 cases of renal poisoning attributed to fang-ji (Stephania
tetrandra) in a weight-loss preparation were actually caused by
guang-fang-ji (Aristolochia fangchi): aristolochic acid is a known
nephrotoxin.56 The confusion in the latter case seems to have arisen from
the similarity of the names in Chinese.
The addition of pharmaceutical drugs to "herbal" products is a particular
problem with Chinese patent medicines. Of 2609 samples of traditional
Chinese medicines collected from eight hospitals in Taiwan, 23·7% contained
pharmaceutical adulterants, most commonly caffeine, paracetamol,
indomethacin, hydrochlorothiazide, and prednisolone.59
anti-inflammatory drugs and benzodiazepines have been found in many Chinese
patent medicines sold outside Asia; these compounds include Miracle Herb,
Tung Shueh, and Chuifong Toukuwan.60 The latter preparation is notorious:
at different times since 1974, the formulation has contained aminopyrine,
phenylbutazone, indomethacin, hydrochlorothiazide, chlordiazepoxide,
diazepam, corticosteroids, diclofenac, mefenamic acid, and dexamethasone.61
Heavy-metal contamination is not uncommon in Asian herbal products.
251 Asian patent medicines collected from herbal stores in California, USA,
contained lead (at least 1 ppm); 36 products contained arsenic, and 35
Counselling of patients about herb-drug interactions
Use of herbal and dietary supplements is extremely common: in one US survey
of adults who regularly take prescription medication, 18·4% reported the
concurrent use of at least one herbal product or high-dose vitamin (and
61·5% of those who used unconventional therapies did not disclose such use
to their physicians).63 A survey of 515 users of herbal remedies in the UK
found that 26% would consult their general practitioner for a serious
adverse drug reaction associated with a conventional over-the-counter
medicine, but not for a similar reaction to a herbal remedy.64
Patients may not be forthcoming about the use of herbal medicine--even if
it causes severe adverse effects--because they fear censure. Clinicians
must ask patients about their use of herbs in a non-judgmental, relaxed
way: a disapproving manner will ensure only that a patient will conceal
The patient should be treated as a partner in watching out for
adverse reactions or interactions, and should be told about the lack of
information on interactions and the need for open communication about the
use of herbal remedies.
Formulation, brand, dose, and reason for use of
herbs should be documented on the patient's charts and updated regularly.
Any laxative or bulk-forming agents will speed intestinal transit, and thus
may interfere with the absorption of almost any intestinally absorbed
The most popular stimulant laxative herbs are the
anthranoid-containing senna (Cassia senna and C angustifolia) and cascara
sagrada (Rhamnus purshiana). Dried exudate from the aloe vera (Aloe
barbadensis) leaf (not gel) also contains anthranoids and is used as a
laxative. Aloe vera gel, found within the leaves, is used topically for
burns and cuts, and is sometimes recommended by herbalists for internal
ingestion to treat ulcers and other disorders.
The gel (or juice made from
the gel) does not contain anthranoids, but some oral preparations are
contaminated by the laxative leaf.
Less commonly used anthranoid-containing
plants are frangula (Rhamnus frangula), yellow dock (Rumex crispus), and
Chinese rhubarb (Rheum officinale).
Patients with clotting disorders, those awaiting surgery, or those on
anticoagulant therapy should be warned against the concurrent use of
ginkgo, danshen, dong quai, papaya, or garlic.
Although the combined use of
anticoagulants with these herbs should be discouraged, patients who insist
on the combination should have their bleeding times monitored (most of
these herbs interfere with platelet function, not the coagulation cascade,
and thus will not affect prothrombin time, partial thromboplastin time, or
international normalised ratio [INR]).
Many other herbs also contain
anticoagulant substances; as a precaution, patients on warfarin should have
an INR measurement within a week of starting any herbal treatment.
Patients on serotonin-reuptake inhibitors, cyclosporin, digoxin,
phenprocoumon, or any critical chronic medication should avoid St John's
wort; those on phenelzine should avoid ginseng; and those on tricyclic
antidepressants should avoid yohimbine.
Patients taking phenytoin should
avoid Ayurvedic herbal mixtures for seizures. Liquorice (a very common
ingredient in Chinese herb mixtures) may potentiate the action of
corticosteroids, and betel nuts have pronounced cholinergic effects. There
are doubtless many as yet undiscovered interactions.
I thank Dennis Awang and Ted Kaptchuk for helpful comments on the paper.
A Review Article from
Lancet 2000; 355: 134-38
Contact: Adriane Fugh-Berman, MD email@example.com
Ann's NOTE: This demonstrates 1)that herbs do have activity, and 2)nothing here is an indictment on the use of herbs. They should be something we all learn about. And yes, there is a lot to know. Check out the links to herbal information. Also the work of James Duke, PhD and others.
Lancet article-Adriene Fugh-Berman, MD
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