Safety Issues with Herbal Medicine

Joseph I. Boullata, PharmD, and Angela M. Nace, PharmD, Department of Pharmacy Practice, Temple University School of Pharmacy, and the Drug Information Center, Temple University Hospital, Philadelphia, Pennsylvania.

Pharmacotherapy. 2000;20(3) 

In This Article

Common Herbal Medicines

Available data report intrinsic and extrinsic effects for herbal medicines. These effects are unlikely to be listed on the product packages.

Known by a number of common names, Echinacea purpurea and related species are taken as liquid extracts and tinctures as well as in solid oral dosage forms for short-term immune system stimulation. Products should use above-ground parts of E. purpurea or the roots of E. angustifolia. Allergic reactions can occur and are usually mild, but individuals with a history of asthma, atopy, or allergic rhinitis may experience severe allergic reactions that include dyspnea and anaphylaxis. Other adverse effects are mild and transient tiredness, somnolence, dizziness, headache, gastrointestinal disturbance, and eczema, not significantly different from those with placebo.[92] Flavonoids from this botanical may inhibit cytochrome P450 (CYP) 3A4 activity, but there is little information on interactions with other drugs or nutrients. Echinacea may worsen metabolic control in some diabetic patients and is not recommended in individuals with altered immune function (tuberculosis, human immunodeficiency viral infection, multiple sclerosis, autoimmune diseases) because of altered immunomodulation. Use usually is restricted to 2 weeks for an acute episode and should not exceed 8 weeks as it may lead to immunosuppression. Echinacea should be avoided by patients receiving immunosuppressive therapy.

Taken most often for migraines, this botanical (Tanacetum parthenium ) may suppress prostaglandin and thromboxane production and inhibit serotonin release from platelets. In addition to gastric discomfort, oral ulcers and lip and tongue swelling were reported with use of the leaf and required discontinuation. The mechanism for this effect is unknown. The herb is contraindicated in individuals with an allergy to ragweed or other plants in the daisy family. Nonsteroidal anti-inflammatory drugs may reduce the effect of feverfew, and caution is advised in patients receiving anticoagulants. It is not known whether an interaction exists between feverfew and serotonin agonists used to treat migraines. Few of the North American feverfew products tested contained the proposed minimum content (0.2%) of the predominant active component, parthenolide, with most having less than 0.1%.[93,94]

Besides its use as a food or food additive, garlic (Allium sativum ) is predominantly used clinically for hypertension and hypercholesterolemia. Garlic contains alliin, which is activated by alliinase on crushing or chopping in the absence of heat or acid to form allicin. The reaction may take up to 15 minutes to complete and only then is the active compound heat stable. The activities of garlic are attributed to the constituent allicin, which yields both lipophilic (sulfides, ajoene) and hydrophilic (cysteine) sulfur compounds responsible for pharmacologic effects, with the characteristic odor found in the lipophilic compounds.

Garlic is delivered via oil-filled capsules, encapsulated dried powder, and enteric-coated tablets and capsules; it also is aged in aqueous alcohol. Disintegration and dissolution of these preparations may not be similar.[95] Adverse effects of the extract are limited to a burning sensation in the gastrointestinal tract, nausea, diaphoresis, and lightheadedness; odoriferous skin and breath occur, but odorless preparations may not contain many of the active derivatives of allicin. Contact dermatitis is possible. Pharmacologic doses, especially essential oils, should be avoided by anticoagulated patients due to interference with thromboxane synthesis, possibly by ajoene, decreasing platelet aggregation.[96] A case of morbid spontaneous spinal epidural hematoma was attributed solely to excess garlic ingestion.[97]

The value of commercial garlic products depends on their mode of preparation and yield of active ingredients. For example, allicin is unstable in oil preparations. Dried preparations are considered to contain little if any of the constituents active for garlic's effects, except possibly for freeze-dried garlic in enteric-coated formulations. Patients should avoid taking garlic supplements with prescribed or OTC anti-coagulants due to potential interaction. The products should be taken with food to reduce upset stomach.

Ginkgo biloba and its leaf extracts contain active compounds and have been used to improve circulation and cognition. The extracts are marketed in both liquid and solid forms and appear to be relatively safe. The most common side effects are headache, dizziness, restlessness, nausea, vomiting, diarrhea, and dermal sensitivity. Cross-allergenicity with poison ivy was reported. The allergen ginkgolic acid should be removed by the extraction process. As an inhibitor of platelet-activating factor, ginkgo may alter bleeding times. It also may increase the anticoagulant effect of warfarin and aspirin.

One week's use of Ginkgo biloba extract was associated with spontaneous bleeding from the iris into the anterior chamber of the eye.[98] Another report described bilateral subdural hematomas attributed to taking Ginkgo biloba for at least 1.5 years.[99] Taking it for more than 6 months was associated with a subarachnoid hemorrhage in a 61-year-old man.[100] These reports indicate that agents that increase the risk of bleeding should be avoided. It also is advisable for patients with known risk factors for intracranial hemorrhage, such as those with systemic hypertension, diabetes, and amyloid senile plaques, to avoid ginkgo-containing products. An indirect safety issue revolves around replacing a physician's evaluation for serious conditions, such as advanced dementia or stroke, with self-medication with an herbal such as ginkgo. The seeds of this plant, although not purposely marketed, may contaminate products. This is important, as the seeds may contain an epileptogenic substance.

This herbal has found widespread use for a variety of properties. Several products are made from the dried root, such as elixirs, extracts, and tea, as well as capsules and tablets that may differ in terms of content. Several active substances, ginsenosides, each have specific pharmacologic effects that sometimes oppose each other, so the whole root is used in preparations.[101] Ginseng has a number of botanical sources. For example, American ginseng includes Panax quinquefolius, Asian ginseng is designated Panax ginseng, and Sanchi (Tienchi) ginseng contains Panax pseudoginseng. Although it is from the same family of Araliaceae, Siberian ginseng contains Eleutherococcus senticosus and is more correctly referred to as eleuthero, which is an inexpensive substitute for ginseng. Ginseng products and published descriptions rarely report the species, so the following discussion pertains to all Panax sp.

Side effects may include transient nervousness, excitation, insomnia, inability to concentrate, headache, hypertension, epistaxis, and allergies. Three days of ginseng resulted in a case of severe but nonfatal Stevens-Johnson syndrome.[102] A large dose of ethanol-extracted ginseng reportedly led to clinical and angiographic cerebral arteritis.[103] According to one report, high daily doses may cause a syndrome of diarrhea, nervousness, insomnia, rash, depression, and amenorrhea, but this was not confirmed by others.[104,105] Ginseng, when taken with anti-depressants, resulted in mania, which improved with discontinuation of the herb.[106]

Ginseng may produce an estrogen-like effect manifesting as mastalgia and vaginal bleeding, as reported in elderly, postmenopausal women taking a modest oral dosage or with topical application.[107,108,109] It also may induce CYP enzymes, and reportedly interacted with warfarin in a patient with a mechanical heart valve and decreased the international normalized ratio (INR) below therapeutic range within 2 weeks.[39] Thus concurrent anticoagulant and ginseng is best avoided. Taken with phenelzine it may cause insomnia, tremor, headache, and mania.[110] Diuretic resistance was described in a patient taking a ginseng product containing germanium, which is present in some preparations.[111] Siberian ginseng may increase serum digoxin levels, possibly due to assay interference or in vivo conversion of a component; the increase recurred with rechallenge.[37]

Apart from these intrinsic effects, only 25% of ginseng products from a variety of dosage forms evaluated actually contained ginseng.[112] Of 17 oral formulations, 7 (41%) contained no detectable ginsenosides and the remainder contained 0.1-0.7% active constituents. Another report revealed that 12% of ginseng products contained no specific ginsenosides, one contained pharmacologic doses of unlabeled ephedrine, and the others contained between 1.9% and 9% ginsenosides.[113] Due to the high cost of pure ginseng, products may contain scopolamine or reserpine.[114]

Liquid extracts of the herbal were recalled due to unlabeled alcohol levels (up to 24%) after a child purchased a vial of chocolate-mint ginseng in a store's candy section and developed chest pains and heart palpitations.[115,116] Given widespread mislabeling, ingredients not listed in ginseng products may be responsible for therapeutic or adverse effects. Individuals with hypertension, diabetes, psychologic disorders, or insomnia should avoid or cautiously use ginseng.

The anxiolytic effect of kava (Piper methysticum ) is well described. Documented side effects are headache, dizziness, and gastrointestinal discomfort. Localized numbness may occur after oral ingestion. With long-term use or high dosages (300 g/wk) kava may cause dry, scaly skin and discoloration (yellow) of the skin and nails, photosensitivity, and eye redness. Photophobia and diplopia also can occur with excessive consumption. The active pyrones act as muscle relaxants and anticonvulsants. Taking kava with other central nervous system (CNS) depressants, including ethanol, is to be avoided due to significant interactions, such as a comatose state.[3,40] The potential for abuse must be closely evaluated.

Ma huang, ephedra, contains a number of alkaloids, including ephedrine, from various Ephedra sp. Ma huang is not considered a safe herbal.[117] A potent CNS stimulant, these alkaloids were implicated in over 800 reports of adverse effects including nervousness, insomnia, irritability, psychosis, headache, dizziness, seizures, stroke, premature ventricular contraction, hypertension, myocardial infarction, and death.[118] Much of this is owed to the agent's nonselective adrenergic agonist properties. As a result the FDA proposed limits on the use of ephedrine-containing products: a maximum of 8 mg/dose and 24 mg/day for no more than a week, and combined with no products that contain caffeine. Some states reclassified these agents to control availability, but ephedra-containing alkaloids continue to be widely available. Numerous multi-ingredient products marketed for weight loss or energy contain ma huang. The Drug Enforcement Agency proposed that products containing over 2% ephedrine be subject to the Controlled Substances Act. Individuals with cardiovascular or thyroid disease and diabetes should avoid the products altogether, as should those consuming caffeine, theophylline, cardiac glycosides, and monoamine oxidase (MAO) inhibitors.

The most widely used botanical for the treatment of benign prostatic hyperplasia is an extract from the berries of Serenoa repens (Serenoa serrulata), the saw palmetto plant. The extract has estrogenic as well as antiandrogenic properties. The active constituents appear to come from the lipophilic extract. Side effects may be limited to headache and gastrointestinal disturbances (nausea, abdominal pain, constipation, diarrhea) together with possible hormonal actions. Estrogenic activity from numerous organic compounds in an herbal remedy taken for prostate health can induce typical side effects similar to those with pharmacologic doses of estrogen; for example, breast tenderness, loss of libido, and venous thrombosis.[119] There are no documented drug interactions with saw palmetto. Whereas a recent review of randomized, controlled trials suggests symptomatic efficacy similar to finasteride and mild adverse effects comparable with placebo over a short duration, the preparations were not standardized.[120]

One of at least 300 Hypericum sp, Hypericum perforatum, more commonly known as St. John's wort, has gained increased use for managing mild depressive symptoms. It is being studied in at least one large prospective trial for this indication in comparison with a selective serotonin reuptake inhibitor and placebo. It also has been used for viral infections. It contains many active compounds, such as hypericin, hyperforin, and melatonin, with mechanisms that may contribute to a pharmacologic effect.[121,122] As with any mechanism of action attributed to medicinal compounds, these must be tested prospectively with targeted outcomes for validation. Although unlikely to be the sole active component, hypericin content is used as a product marker.

Reported adverse effects are allergic reactions, headache, dizziness, restlessness, fatigue, dry mouth, nausea, vomiting, constipation, and photosensitivity.[3] Overall event rates were estimated to be no different from those with placebo.[123] Photosensitivity, in part due to hypericin, and possible nerve damage manifested as reversible subacute toxic neuropathy were reported.[124] Caution is warranted in combining the herbal with other drugs known to cause photo-sensitivity, and patients should limit sun exposure.

Recent reports described hyperasthesia and a syndrome of dyspnea and hyperventilation with flushing headache, mydriasis, nausea, palpitations, and tremor, as well as significant reductions in cyclosporine levels.[122] A patient with a history of panic disorder taking St. John's wort tincture for 10 days experienced a hypomanic episode that resolved within 2 days of discontinuing the herbal.[125] Until more is known about its mechanism of action it seems prudent to avoid taking it with antidepressant drugs such as MAO inhibitors of either isoform, levodopa, and tryptophan. Also a 2-week washout period between agents is necessary. Given potential MAO inhibition with hypericin, restriction of foods containing tyramine is wise.

The USP-endorsed high-performance liquid chromatography evaluation was performed to analyze hypericin and pseudohypericin in 10 St. John's wort products: 6 liquid extracts, 4 encapsulated products.[126] The results revealed inconsistencies with up to 10-fold differences in levels of the ingredients.

Consumers choosing to use St. John's wort should be instructed to take it with food or divide doses to decrease gastrointestinal symptoms. Closely monitor the INR of individuals also taking warfarin due the potential for an interaction. Safety in children and adolescents has not been well evaluated, and St. John's wort is not recommended in pregnancy due to possible uterotonic activity.[122]

Valerian root (Valeriana officinalis ) is considered a sedative and anxiolytic. Valerian is reported to cause headache, excitability, ataxia, and gastrointestinal complaints. An intentional oral overdose resulted in rapid onset of fatigue, chest tightness, abdominal cramps, lightheadedness, and tremors of the hands and feet.[127] A suggested mechanism of action involves the -aminobutyric acid receptor. A withdrawal syndrome involving cardiac abnormalities and delirium in a hospi-talized patient responded to benzodiazepines.[128] Valerian should be avoided by patients taking benzodiazepines, barbiturates, opiates, and alcohol as their effects may be prolonged. Provide the same precautions regarding alertness as for other sedatives.

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