Review
Volume 355, Number 9198 8 January 2000
   
Herb-drug interactions

Adriane Fugh-Berman

Lancet 2000 (Jan 8); 355 (9198): 134-138


George Washington University School of Medicine and Health Sciences, Department of Health Care Sciences, 2150 Pennsylvania Avenue, NW 2B-417, Washington, DC 20037, USA (A Fugh-Berman MD) (e-mail: fughberman@aol.com)

Source and extent of review
Misidentification, adulteration, and contamination
Counselling of patients about herb-drug interactions
References

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); mild serotonin 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 (Pausinystalia yohimbe); 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 (sho-saiko-to); 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 different intents."

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.


Ginkgo biloba

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 However, 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, respectively).4 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


Table 1: Clinical reports of herb-drug interactions (B-G)
Herb and drug(s) Results of interaction Comments
Betel nut (Areca catechu)
Flupenthixol and procyclidine Rigidity, bradykinesia, jaw tremor5 Betal contains arecoline, a cholinergic alkaloid.
Fluphenazine Tremor, stiffness, akithesia5  
Prednisone and salbutamol Inadequate control of asthma Arecoline challenge caused dose-related bronchoconstriction in six asthma patients.6
Chilli pepper (Capsicum spp)
ACE inhibitor Cough7 Capsaicin depletes substance P.
Theophylline Increased absorption and bioavailability8  
Danshen (Salvia miltiorrhiza)    
Warfarin Increased INR, prolonged PT/PTT9-11 In rats, danshen decreases elimination of warfarin.12 Danshen is in at least one brand of cigarettes.13
Devil's claw (Harpagophytum procumbens)
Warfarin Purpura14  
Dong quai (Angelica sinensis)
Warfarin Increased INR15,16 and widespread bruising16 Dong quai contains coumarins.
Eleuthero or Siberian ginseng (Eleutherococcus senticocus)
Digoxin Raised digoxin concentrations17 Herb probably interfered with digoxin assay (patient had unchanged ECG
    despite digoxin concentration of 5·2 nmol/L).
Garlic (Allium sativum)
Warfarin Increased 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)
Aspirin Spontaneous hyphema22 Ginkgolides are potent inhibitors of PAF.23,24
Paracetamol and ergotamine/caffeine Bilateral subdural haematoma25 May not be interaction but due to ginkgo alone. Subarachnoid haemorrhage26
    and subdural haematoma27 have been reported with the use of ginkgo alone.
Warfarin Intracerebral haemorrhage28  
Thiazide diuretic Hypertension18 This effect may be an unusual adverse reaction to the drug or herb; ginkgo
    alone has not been associated with hypertension.
Ginseng (Panax spp)
Warfarin Decreased INR29 In rats, concomitantly administered ginseng had no significant effect on the pharmacokinetics or pharmacodynamics of warfarin.30
Phenelzine Headache and tremor,31 mania32 Patient with mania also ingested bee pollen, and had previously had unipolar depression.
Alcohol Increased alcohol clearance33 In 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 2: Clinical reports of herb-drug interactions (K-Y)
Herb and drug(s) Results of interaction Comments
Karela or bitter melon (Momordica charantia)
Chlorpropamide Less glycosuria34 Karela decreases glucose concentrations in blood.35
Liquorice (Glycyrrhiza glabra)
Prednisolone Glycyrrhizin 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
  concentrations prednisolone37  
Hydrocortisone Glycyrrhetinic acid potentiates of cutaneous Glycyrrhetinic acid is a more potent inhibitor of 5-, 5ß-reductase and
  vasoconstrictor response38 11ß-dehydrogenase than is glycyrrhizin.36
Oral contraceptives Hypertension, oedema, hypokalaemia39 Oral contraceptive use may increase sensitivity to glycyrrhizin acid.39 Women are
    reportedly more sensitive than men to adverse effects of liquorice.40
Papaya (Carica papaya)
Warfarin Increased INR14  
Psyllium (Plantago ovata)
Lithium Decreased lithium concentrations41 Hydrophilic psyllium may prevent lithium from ionising.
St John's wort (Hypericum perforatum)
Paroxetine Lethargy/incoherence42  
Trazodone Mild serotonin syndrome43 A similar case is described with the use of St John's wort alone.
Sertraline Mild serotonin syndrome44  
Nefazodone Mild serotonin syndrome44  
Theophylline Decreased theophylline concentrations45  
Digoxin Decreased AUC, decreased peak and trough Most, but not all, studies indicate that St John's wort is a potent inhibitor of
  concentrations46 cytochrome P450 isoenzymes47
Phenprocoumon Decreased AUC48  
Cyclosporin Decreased concentrations in serum49  
Combined oral contraceptive (ethinyloestradiol Breakthrough bleeding49  
and desogestrel)    
Saiboku-to (Asian herbal mixture)
Prednisolone Increased prednisolone AUC50 Contains all the same herbs as sho-saiko-to, and Poria cocos,
    Magnolia officinalis, and Perillae frutescens.
Shankhapushpi (Ayurvedic mixed-herb syrup)
Phenytoin Decreased phenytoin concentrations, loss of In rats, multiple coadministered doses (but not single doses) decreased
  seizure control51 plasma phenytoin concentrations; single doses decreased the antiepileptic
    effect of phenytoin.51 Shankhapushpi is used to treat seizures.
Sho-saiko-to or xiao chai hu tang (Asian
herb mixture)
Prednisolone Decreased AUC for prednisolone50 Contains liquorice (Glycyrrhiza glabra), Bupleurum falcatum, Pinellia ternata,
    Scutellaria baicalensis, Zizyphus vulgaris, Panax ginseng, and Zingiber officinale.
Tamarind (Tamarindus indica)
Aspirin Increased bioavailability of aspirin52 Tamarind is used as a food and a medicine.
Valerian (Valeriana officinalis)
Alcohol A mixture of valepotriates reduces adverse  
  effect of alcohol on concentration53  
Yohimbine (Pausinystalia yohimbe)
Tricyclic antidepressants Hypertension54 Yohimbine alone can cause hypertension, but lower doses cause hypertension
    when combined with tricyclic antidepressants. Effect is stronger in hypertensive
    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 concentration/time curve.

 

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 In Hong 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 More 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.


Panax ginseng

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 Non-steroidal 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


Valeriana officinalis

Heavy-metal contamination is not uncommon in Asian herbal products. 24 of 251 Asian patent medicines collected from herbal stores in California, USA, contained lead (at least 1 ppm); 36 products contained arsenic, and 35 contained mercury.62
 

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 further use. 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 drug.65 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.
 

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