Herbal Medicines: Toxicity October 14, 2009

Posted by dranthonylim in Medical / Surgical.
Tags: Herbal, toxicity
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Herbal Toxicity

Richard T. Tovar, MD, FACEP, FACMT

Renee M. Petzel, PharmD

PII S0011-5029(09)00066-2

Introduction

In the USA, the popularity of using dietary supplements has been documented to escalate yearly. Since the passage of the US Dietary Supplement Health and Education Act of 1994, numerous studies have supported this increase. [1] , [2] , [3] One study reported an increase of 380% in use of botanicals and dietary supplements in the USA during a 10-year period in the 1990s.[1] In other areas of the world, dietary supplements and herbal medicines have been used for centuries. In the USA the definition of a dietary supplement is as follows: “the Food and Drug Administration (FDA) defines a dietary supplement to be a product (other than tobacco) that is intended to supplement the diet that bears or contains one or more of the following dietary ingredients: a vitamin, a mineral, an herb or other botanical, an amino acid, a dietary substance for use by man to supplement the diet by increasing the total daily intake, or a concentrate, metabolite, constituent, extract, or combination of these ingredients.” [4] , [5]

This article limits itself to the review of herbal toxicity only. The Herb Society of America defines an herb as “(an entity with) more than one definition. Botanists describe an herb as a small, seed bearing plant with fleshy, rather than woody, parts (from which we get the term ‘herbaceous’) . … the term refers to a far wider range of plants. In addition to herbaceous perennials, herbs include trees, shrubs, annuals, vines, and more primitive plants, such as ferns, mosses, algae, lichens, and fungi.”[6] Herbs in modern society are valued for their flavor, fragrance, medicinal and healthful qualities, economic and industrial uses, pesticidal properties, and colorizing materials (dyes).

The history of the use of herbs as medication is as old as history itself. Some authors state that the first recorded use of herbs for medical treatment began over 4000 years ago.[7] The origin of this type of medical treatment began in China and India. Traditional Chinese medicine centers on interactions between the body and the environment. The patient’s tongue, iris, and pulse are examined, and a diagnosis is made. A mixture of treatments, including herbs, acupuncture, and massage, is then prescribed.

Traditional Indian medicine has dated back to 3000 BC. One form of traditional Indian medicine is called Ayurvedic. This type of medicine places a heavy emphasis on the use of herbs as treatments. An example of the types of herbal products can be seen in Table 1.

TABLE 1   —  Herbal products from different cultures[8]

Type of Herbal Medication Natural Sources Origins

Ayervidic P, A, M India

Chinese P, A, M China

Indusynunic P, A, M Pakistan

Islamic P, A, M Middle East

Kampo P, A, M Japan

Korean P, A, M Korea

Other Oriental P, A, M Other Asian countries

Aromatherapy P European

Herbalism P European

Homeopathy P European

Botanicals P European

P, medicinal plants; M, minerals; A, animal sources.

In the United States herbal therapy began more recently, along with the founding of the country. A combination of European, Chinese, Ayurvedic, and other unconventional treatments influenced the use of herbs to the present day.

The US Dietary Supplement Health and Education Act of 1994 establishes an herb as a food, and as the regulatory body, the FDA has the burden of proof to show that an herb possesses a significant risk to the public.[9] This is in direct contrast to regulation of the pharmaceutical industry, in which the burden of proof of both safety and efficacy is on the sponsoring drug company. An example of an herbal ban by the FDA is any herb containing Ephedra, a sympathomimetic, which was banned in February of 2004. Besides the FDA determination that Ephedra-containing herbal products were a cause of toxicity, the American Association of Poison Center’s Toxic Exposure Surveillance System analyzed Ephedra use from 1993 to 2002. The Toxic Exposure Surveillance System database substantiated the findings by the FDA and supported the Ephedra ban.[10] A more recent federal law, the Public Health and Security and Bioterrorism Preparedness and Response Act of 2002, requires the FDA to protect the food sources in the USA. Because all dietary supplements are considered food, the food must be registered with the FDA per the above act of 2002.[11] The FDA has actually banned very few substances, most notably Ephedra, as above. Instead, the FDA has placed several herbal products in the “warning and Safety Information” area of the Dietary Supplements Section 11. A current list of supplements is seen in Table 2. Furthermore, when a manufacturer of an herbal product makes a claim that alleges a treatment or positive effect on a bodily structure or function, the FDA may require that the supplement has a cautionary statement. This cautionary statement, which is marked on the herbal product, contains the following wording: “this statement has not been evaluated by the FDA. This product is not intended to diagnose, treat, cure or prevent, any disease.” In this way the FDA attempts to warn the consumer of claims that are either not proved or disproved by science.

TABLE 2   —  FDA herbal product public warnings

Supplement Toxicity

Androstenedione Testosterone-like effect

Anthrax Infectious complications, including sepsis and multiorgan disfunction

Aristocholic acid Nephropathy

Comfrey Liver toxicity

Ephedrine alkaloids Sympathomimetic toxicity

Kava Liver toxicity

Lipokinetics Liver toxicity

Liqiang 4 Hypoglycemia interaction with glyburide

PC SPES and SPES Contains warfarin or alprazolam

Red yeast rice Contains lovastatin

St John’s wort Decrease indinavir plasma concentration

Tiractricol Thyroid hormone like effect

While the FDA establishes herbs as a type of food, some in the public do not have a similar viewpoint. Several articles have reviewed the public’s perception of herbs as medications for illness. [12] , [13] Various studies maintain that anywhere from 3% to 90% of the United States population use herbs for medicinal purposes. What is unclear is whether the use of herbs medically is a regular or episodic use phenomenon. Several studies reported that less than 40% of United States patients using herbal products discussed the use of these products with a physician. [1] , [14]

A recently published study in the Journal of the American Medical Association assessed older Americans’ use of medications and dietary supplements. This study found that nearly 1 of 8 older Americans were using at least 5 dietary supplements. Women were more likely to concurrently use prescription medications and dietary supplements. Use of dietary supplements in both men and women was found to be higher than in previously reported studies.[15]

Furthermore, the World Health Organization estimates that 80% of the world’s population uses herbs as their primary method for health care needs.[12] Conventional medical science has many requirements for a drug to be used in the daily practice of medicine. Herbal medicine does not have the same philosophy about the use of herbal products, as seen in Table 3.

TABLE 3   —  Differences between orthodox and herbal products used in medical care[8]

Properties Herbal Products Orthodox Pharmaceuticals

Active ingredients Often unknown Known

Availability of pure compound Rare Yes

Availability of raw material Limited Yes

Quality of raw material Variable Good

Stability of preparation Variable Good

Mechanism of action Often unknown Usually known

Toxicologic tests Usually not available in animal testing Mandatory

Empiric data Very important Often meaningless

Specific adverse events Rate through experience Frequent

Tolerance of therapy Usually good Limited

Therapeutic window Wide Usually narrow

Suitability for chronic use Often well tested Not yet tested for new drugs

Placebo controls Difficult but possible Achievable

Controlled clinical trials Usually not available Mandatory

The United States government does not regulate standards for concentration of ingredients or recommended daily doses of herbal products. This leads to variation in products that are available in the USA. Other countries’ regulation and acceptance of dietary supplements are different from that of the FDA in the USA. For example, in Germany, the government has national regulation of herbal products, outlined in the German Commission E monographs. These monographs are considered by some as a therapeutic guide of herbal products that evaluates safety and efficacy based on numerous references. The monographs were translated into English and imported to the USA by the American Botanical Council. Although it is used by some in the medical field, caution should exist as the monographs’ contents have been subject to criticism. Health care professionals may find sound data lacking to support claims in the monographs and doses of herbal products are often vague or unavailable in the USA.

Epidemiology

The traditional medical practitioner must realize that, while those in herbal medicine insist that herbs are just natural drugs, there are numerous differences between conventional pharmacotherapy and herbal substances.[3] First, herbal medicines may involve the use of the whole plant. These unpurified substances may contain several active ingredients. Therefore, 2 samples of an herbal drug may contain different drug concentrations. Herbal medicine practitioners counter any possible alleged toxicity by stating that the use of whole herb plants causes “buffering,” which may reduce the amount of isolated drug in a whole plant preparation. The technique of buffering may or may not reduce toxicity and desired effect. Variations also exist depending on growing and harvesting conditions. Different parts of plants may contain different concentrations of active ingredients, which may lead to varying therapeutic activity. Different formulations (eg, capsule, extract, or tea) can also have varying amounts of active ingredients. Dosing instructions for 1 formulation may be very different from another formulation.[16] A second difference is 1 of combining of herbal medications. The herbal medicine proponent states that this practice may actually provide a synergy for treatment and effect. Toxic effects from interactions or increased effect may result from this practice. Conventional pharmacotherapy actually discourages polypharmacy to avoid toxic interactions if at all possible. A third and final difference is that the effects of herbal medicine may be erroneously attributed to an herb, when in fact it is due to “contaminants,” such as conventional medications. An example of this is disease processes, such as inflammation. These symptoms may be treated with nonsteroidal anti-inflammatory “contaminants” intentionally or unintentionally placed in an herbal product.

Medical studies of the lay population’s use of herbs center on many perceptions: herbal use is natural, safe, inexpensive, and effective; use is preferred over conventional medicines in chronic disease processes (for example, AIDS); and use of herbals is a cultural preference. [17] , [18] There is even the introduction of the terms “remedies” and “treatments” of herbal use by western medical providers in various medical publications. [17] , [18] , [19] , [20] A further challenge is whether a patient will divulge to his or her medical provider the concurrent use of herbal products with western medicine treatments. The patient whom is most likely to use herbal products on a regular basis is the 1 with a chronic or recurrent debilitating illness, such as AIDS, diabetes, allergies, asthma, behavioral or developmental problems, cancer, cystic fibrosis, arthritis, and progressive neurological disease. One study estimated that only 30% of chronically ill patients reveal their use of herbal products with their health care provider.[21] Even patients who do report their use of herbal products to health care providers may not be able to accurately describe what they are taking or what dose they are taking. Concentrations of individual products can vary greatly. Dosing may vary based on whether the formulation is a extract, tablet, capsule, etc.[16]

There are many types of cultural herbal medical delivery systems in the USA. The more common delivery systems used in the USA include traditional Chinese medicine, Ayurvedic (traditional herbal medicine from India), and Mexican herbal medicine. Just as there are many herbs used in the practice of herbal medicine, there are countless forms of the practice of herbal medicine. Also, some consumers of herbs do not consult herbal medicine practitioners, choosing to use herbs on their own. This behavior is further made confusing because the medical literature may mislabel different types of herbal medicine practice. An example of this is calling all herbal medical practice “Asian,” which could mean Chinese, Ayurvedic, Japanese, or other Eastern herbal medical practice. Furthermore, numerous articles have been written describing either the resistance of patients to admit to herb use or the common misbelief that herbs are not medicines. Both of these behaviors may lead to adverse effects and serious toxicities.

There are numerous methods in which herbs may cause toxicity to humans. All types of general toxicity will be covered in this article. The general areas of herbal toxicity that will be covered include direct toxicity, drug-herb interactions, and herbal adulterant toxicity. Due to the restrictions on the FDA, 1 of the main problems in assessing both herbal efficacy and toxicity is 1 of actual presence and concentration of the herb in question. Makers of herbs are not required to be specific on the concentrations of the ingredients of the herb or herbal mixtures. At present, the medical literature continues to be plagued with lack of reliable documentary evidence of harm. One author therefore recommends that “potential” herbal toxicities be highlighted and reported due to the lack of solid toxicologic information at present.[7] The same authors have proposed a classification of herbal toxicity, used mainly for herb-drug interactions[7]:

Confirmed: toxicity described by numerous reports, with a rechallenge of the herb resulting in similar observed effects.

Potential: 1 or more reports demonstrating observed toxicity with a “sound theoretical” basis for support.

Theoretic: theoretic basis without confirmatory clinical reports.

Unlikely: no observed toxicity

Single report: single reports of potential herbal drug interactions or toxicity are regarded as “not able to be evaluated for toxicity,” until further studies or reports are forthcoming.

When reviewing case reports or summaries of herbal toxicity, the reader is encouraged to keep the above classification. A further problem is that most published information on herbal toxicity is not located in the current medical literature. Instead, it is located in the nutritional and nursing literature, although this is becoming better as time progresses.[21]

One set of authors has published a study that uses modern cell biological, biochemical, in vivo, and in vitro techniques to determine actual cell toxicity.[22] The authors apply herbal products in different concentrations and at different times in the life cycle of the plant. While a preliminary study, this type of herbal toxicity study involving cell cultures holds much promise. In the future, more scientific studies may provide a better understanding of mechanism of action and pharmacokinetics. Increased scientific knowledge may allow for expanded usage, or more specific dosing for herbal products.

Effects of Herbs on Laboratory Tests

Before the discussion of direct and indirect toxicity of herbal preparations on the patient is undertaken, a discussion of specific herbs on laboratory tests should be undertaken. These effects may not cause direct toxicity to the patient, but if misinterpreted, may result in unnecessary treatments of the patient based on erroneous laboratory values, resulting in unintended morbidity. The main effect of some specific herbal preparations on laboratory values lies in the phenomenon of direct assay interference.[23] Several specific Chinese herbal medications interfere with the therapeutic drug monitoring of digoxin. The most common method of serum digoxin levels is via the use of the immunoassay. Either monoclonal or polyclonal antibodies are directed toward digoxin in the patient’s serum and then quantitated via this immunologic reaction. The polyclonal immunologic methods that include fluorescence polarization immunoassay (rabbit polyclonal antibody) and MEIA (microparticle enzyme immunoassay) are more susceptible to interference by Chinese herbal medications than the monoclonal methods.[24] Specifically, the substance Chan Su is derived from the skin glands of Chinese toads (Bufo melanostictus and Bufo gargarizans). Bufo toads are also indigenous to the southwestern US and some parts of Europe (Bufo alvarius, Bufo marinus, and Bufo vulgaris) and can cause similar effects as Chinese toads. Several toxins (collectively known as Bufotoxins or bufadienolides) are structurally similar to digoxin (cardiac glycoside chemical structure). Not only do the Bufotoxins have a similar chemical structure to digoxin, but they have a similar clinical effect. Because of the similar structure of cardiac glycosides and bufadienolides, patients ingesting bufadienolides will have a digoxin level, although this level does not correlate with outcome. Bufadienolides may elevate a patient’s digoxin level if the patient is concurrently taking digoxin. A patient who is not currently taking digoxin but has ingested some form of bufadienolides may have a detectable digoxin level as well. Bufadienolides have a digoxin-like immunoreactive substance, which is detected in the serum as digoxin and causes the elevation in the level.

Ginseng contains ginsenosides, which are also structurally similar to cardiac glycosides. Panax ginseng is not believed to have any of the cardiac effects of other glycosides. Ginsenosides can interfere with measurement of serum digoxin concentrations depending on the assay method. [25] , [26] , [27] Other herbs can actually simulate a falsely lower digoxin level, causing an unsuspecting clinician to increase the usual daily dose, resulting in iatrogenic toxicity. [28] , [29] , [30] , [31] Table 4 is a summary of the herbal products that cause laboratory interference with digoxin assays.

TABLE 4   —  Herbal products causing laboratory interference with digoxin[24]

Herb Interference Tests Affected

Chan Su High FPIA, MEIA, Roche Beckman, turbidimetric (Bayer) assay. No effect: Bayer CLIA assay

Lu-Shen-Wan High to moderate FPIA, MEIA, Roche Beckman, turbidimetric (Bayer) assay. No effect: Bayer CLIA assay

Siberian ginseng Moderate Falsely elevated serum digoxin (FPIA), falsely decreased (MEIA). No interference: turbidimetric (Bayer) assay, emit, Roche/Beckman scans

Asian ginseng Moderate Falsely elevated serum digoxin (FPIA), falsely decreased (MEIA). No interference: turbidimetric (Bayer) assay, emit, Roche/Beckman scans

Dan Shen Moderate Falsely elevated serum digoxin (FPIA), falsely decreased (MEIA). No interference: turbidimetric (Bayer) assay, emit, Roche/Beckman scans

FPIA, fluorescence polarization immunoassay; MEIA, microparticle enzyme immunoassay; CLIA, chemiluminescent immunoassay.

Factors Influencing or Complicating Herbal Toxicity

Before one can identify an herbal product as toxic, researchers as well as front-line clinicians must attempt to identify that the herb is in fact the culprit. The clinician must obtain the following in the workup of alleged herbal toxicity: 1. Detailed patient medical history; 2. History of where herbs were purchased/obtained, type of use (ingested, smoked, brewed, etc), dose, and frequency of use; 3. Actual samples, prescriptions, or packaging (visual identification), if possible; 4. Laboratory identification (local state laboratory of hygiene, etc); 5. Laboratory identification of herbal product should be “identical” to the product used by the patient.

Once the herbal product is identified, other potential contributory issues must be identified to assess herbal product: presence of contaminants, incomplete processing, drug-herb interactions, coexisting diseases, direct toxicity (dose/duration), improper herb identification, and preparation method.[32]

Reports of herbal products with contaminants or adulterants are common in the medical literature. One author reported an adulteration rate of 23.7% rate in 2609 traditional Chinese herbs.[33] In this study, the most common adulterants included caffeine, indomethacin, acetaminophen, hydrochlorothiazide, prednisone, and many others. Another study found sporadic cases of ginkgo biloba that was contaminated with colchicine. Contamination of ginkgo with colchicine was later found to be uncommon; however, patients are still at risk and could experience toxicity from this contaminant. [34] , [35] Other studies observed that not only did some herbal remedies include pharmaceutical products but heavy metals also.[36] One clinical hint to the medical provider as to adulterant herbal toxicity can be obtained from the actual claim that the herbal manufacturer makes. For example, if the herbal product claims to have positive health effects for blood sugar regulation, search for oral hypoglycemic (most commonly sulfonylurea drugs) medications. Patients exposed to herbal products that are contaminated are also at risk for drug-contaminant adverse effects and toxicity. Prescription medications the patient is taking may interact with the contaminant. Contaminated or adulterated herbal products have a much higher rate of morbidity or mortality as compared to nonadulterated herbs.[37]

One common industry procedure is to detoxify herbs by soaking or heating the herbs in water, or cleaning or dissecting parts of the plant that may contain a higher concentration of herbal chemical. One author maintains that some toxic reactions to herbs result from incomplete or improper herb processing.[32] With easy access to the Internet available in the USA and Eastern Europe some patients may be inclined to attempt to make herbal preparations on their own. Many Web sites offer instructions on how to make different preparations of herbal products. [38] , [39] This can also be dangerous as precise measurement of dosage ingested cannot be ascertained nor the quality with which the herbal products are prepared.

A second area of concern is the contamination or adulteration of herbal products with heavy metals. This observation is further complicated when some herbal products intentionally contain heavy metals as essential ingredients. One example of heavy metal use in herbal products is the review by Koh and Woo in 2000.[40] The review included 58 references in traditional Chinese medications from 1990 to 1997. The heavy metals found included the following: lead, mercury, cadmium, arsenic, and thallium. Other studies have found excessive concentrations of essential trace metals, including K, Na, Mg, Ca, Fe, Cu, Zn, Mn, Co, Cr, Ni, and Mo.[40]

Finally, there have been reports of the presence of pesticide contamination in the herbal plant products.[8] It is unknown if there were any negative medical consequences due to these exposures. Theoretically, patients are at risk for adverse effects or toxicity from ingestion of products with pesticide contamination. Organophosphate pesticides can cause multisystem organ failure in severe cases.

Direct Herbal Toxicity

Cardiac Toxicity

Numerous herbal products have been documented to have negative effects on the cardiovascular system. Some of the more common herbal products are listed below.

Licorice (Glycyrrhiza glabra) can be used for inflammation of the upper respiratory tract and gastric and duodenal ulcers. The main ingredient of licorice is saponin glycoside glycyrrhizin and glycyrrhetinic acid.[41] Licorice is thought to block metabolism of prostaglandins E and F2α, which cause cytoprotective effects on the gastric mucosa. Prolonged use of this product (weeks to months) may cause suppression of the renin-aldosterone system, resulting in sodium and water retention, hypokalemia, hypertension, cardiac arrythmias, and myopathy. While studies have recorded individuals taking 200-600 mg of glycyrrhizin daily, adverse effects have been observed at 100 mg daily. [42] , [43] It is not recommended that licorice be used for more than 4-6 weeks without supervision of a healthcare professional. Adverse effects are more likely in higher doses (greater than 600 mg/d) and when licorice is taken for prolonged periods.

Ma Huang (Ephedra sinica) is an ephedrine-containing herbal medical product. There have been over 140 reports to the FDA of serious adverse events from 1997 to 1999. Ten of these events resulted in death and 13 resulted in permanent disability because of its sympathomimetic effects.[44] Patients can experience hypertension, myocardial infarction, seizure, stroke, and psychosis.[45] The ephedrine alkaloids in dietary supplements may be found in many plant species, including but not limited to, Ephedra sinica Staf (also known as Ma Huang, Ephedra, Chinese Ephedra), Ephedra equisetina Bunge, Ephedra intermedia var tibetica Stapf, Ephedra distachya L, Sida cordifolia L, Pinellia ternate. Some patients use Ephedra as a weight loss agent. Other uses include treatment of bronchospasm and asthma, treatment of allergies, and recreational drug use.[33] Ephedra is 1 of 2 herbal products prohibited for importation into the USA by the FDA.[46] The second is the Aristolochia species discussed in the renal toxicity section. Some argue that harmful side effects only occur in patients using excessive doses or for a prolonged period. However, there are multiple case reports of adverse effects associated with what is considered lower doses (20-60 mg of alkaloids) of Ephedra.[47] One study found that patients taking 32 mg Ephedra were 3 times as likely to have a hemorrhagic stroke.[48] Although products containing Ephedra have been banned by the FDA, these products can still be purchased via the Internet, putting patients at risk for serious adverse effects.

Blue cohosh (Caulophyllum thalictroides) is an herbal product often recommended for uterine stimulation, induction of menstruation, epilepsy, hiccups, inflammation of the uterus, and rheumatic conditions and as an antispasmodic.[49] Blue cohosh has sympathomimetic and direct cardiotoxic effects.[50] It is believed to cause coronary vasoconstriction and decrease oxygen flow to the heart, which can lead to morbidity and mortality in the fetus or newborn infant exposed via maternal ingestion. Several other Alkaloid compounds in blue cohosh are thought to be teratogenic, causing congenital malformations. Another compound, N-methylcytosine, contained in blue cohosh, is teratogenic and acts similarly to nicotine. Effects from N-methylcytosine can include hypertension and produce hyperglycemia in the fetus. [49] , [51] Taspine, also found in blue cohosh, is structurally related to morphine. Taspine appears to be cytotoxic and even in low concentrations is lethal to embryos. Several case reports describe adverse effects in infants following maternal use to induce labor. Infants experienced myocardial infarction, congestive heart failure, seizures, and stroke. [49] , [50] Maternal consumption can also lead to adverse effects in the mother, including increased gastrointestinal motility, diarrhea, cramping, angina, hypertension, and hyperglycemia. Midwives use blue cohosh to induce labor; however, because of effects on mothers and fetuses, use during pregnancy is not recommended.[49]

Traditional Chinese medications (TCM) has several substances known to cause direct end-organ toxicity.[52] The plant containing the substance Chinese Beetle (Mylabris phalerata or Ban Mao) contains the toxic substance Cantharidin. One death has been reported with less than 60 mg of the substance. Another TCM, Trepterygium wilfordii Hook f., has been observed to cause hypovolemic shock and cardiac toxicity.[52] Both of these herbs have certain restrictions as to their sale in China and Taiwan.

Another TCM commonly used is aconite (Monkshood, wolfsbane, Fu Tzu). This herb is found in the roots of Aconitum carmichaeli, A. kusnezoffiii, A. balfouri Stapf, and A. szechenyianum Gay. Aconite is traditionally used as a pain reliever for both arthritic and neurologic conditions, including facial paralysis, joint pain, arthritis, gout, finger numbness, inflammation. It is also used for alopecia, for disinfection, and as a cardiac depressant. Topically it is used as a counterirritant, for facial neuralgia, rheumatism, and sciatica.[53] Aconite alkaloids activate sodium channels, which in cardiac tissue can lead to tachyarrhythmias. Hypotension, dizziness, palpitations, and death may occur. Other alkaloids can also cause negative inotropy. Neurologic effects can be observed as well, including paralysis, seizures, coma, delirium, and irritability.[54] Several cases resulting in deaths have been reported.[55] Adverse effects and toxicity can be seen when ingested orally or used topically. Significant systemic toxicity can arise through absorption from the skin. Processed aconite compounds cause toxicity as well. Aconite toxicity is common in Asia.[53] Unlike many of the other herbal products in which toxicity occurs over long periods or with elevated doses, aconite toxicity can develop after 2 or 3 doses. Unfortunately, treatment for aconite toxicity is largely supportive. Cardioversion is thought to be ineffective and there is no antidote available. In some cases, the antiarrhythmic, amiodarone, has been used to treat patients with aconite cardiotoxicity. Charcoal hemoperfusion has also had some success. Recovery of patients may take up to 9 days depending on the severity of toxicity. There is a 5% mortality rate in patients treated for aconite toxicity. [54] , [56] Although Chinese medicine practitioners still use aconite, toxicity is well documented and can even cause death.

Pulmonary Toxicity

An herbal product marketed in the USA as “defat,” the Sabah plant (Sauropus androgynus) has been observed to be associated with pulmonary toxicity. One study described several patients with respiratory disease, possibly related to chronic obstructive pulmonary disease with the chronic consumption of the Sabah plant.[57] Sabah has been promoted as a lipid-reducing, weight loss product. Initial toxic symptoms include insomnia and irritability, followed by respiratory symptoms, including dyspnea, cough, and chest tightness. Symptoms have been observed to resolve with cessation of consumption of the herb. One patient who had lung biopsy performed had the microscopic pathology reveal consistency with bronchiolitis obliterans.[58] The exact toxin contained in the Sabah plant has yet to be elucidated.

Renal Toxicity

Aristolochia can be used as an aphrodisiac, as an anticonvulsant, as an immune stimulant, to promote menstruation, and to treat snake bites. It is also used treat arthritis, gout, rheumatism, eczema, wound treatment, allergic gastrointestinal colic, and gallbladder colic. Aristolochia contains ristolochic acid, which causes renal toxicity and can be carcinogenic. [32] , [59] , [60] , [61] In the USA the FDA has issued several warning letters for both health care professionals and the lay public emphasizing discontinuation of the use of products containing aristolochic acid.[60] These compounds have been observed to cause renal interstitial fibrosis, renal atrophy, and renal tubule damage. [61] , [62] Aristolochic acid damages DNA, causing fibrotic lesions and development of tumors. There have also been reports of bladder, ureter, and/or renal pelvis in patients who experience renal toxicity from aristolochic acid-associated nephropathy.[60] Patients with pre-existing renal disease are at a greater risk to develop toxicity. The toxic renal herb, Aristocholica fang chi, was incorrectly substituted for a nontoxic herb (Stephania tetrandra). Over 1000 women in a Belgian weight loss clinic were exposed to this herbal compound, with approximately 70 of them requiring dialysis or renal transplantation. Furthermore, 18 of these women were also found to have urothelial carcinoma. After reviewing the evidence of aristolochic acid toxicity, the FDA considers all products containing aristolochic acid to be unsafe and adulterated. Along with Ephedra alkaloids, aristolochic acid containing supplements have been banned in the USA. These products have also been banned in many countries in Europe and Japan.

Hematologic Toxicity

While there have been numerous case reports that have alleged negative effects on platelet function and coagulation pathways, there is debate over the clinical significance of these interactions. The debate of clinical significance also extends to those interactions with patients already on conventional anticoagulants.

Ginkgo biloba has recommended indications for the treatment of many different conditions, including Alzheimer’s disease, dementia, cerebral vascular insufficiency, severe claudication, peripheral artery disease, tinnitus, ischemic stroke, and vertigo. Other recommended uses include allergies, arteriosclerosis, asthma, bronchitis, cognitive dysfunction, diabetic retinopathy, glaucoma, genitourinary complaints, hypercholesterolemia, Raynaud’s syndrome, and sexual dysfunction. Ginkgo biloba is interchangeable with ginkgo leaf extract. Originally, only the Ginkgo biloba fruit was used for medicinal purposes; however, now the ginkgo leaf extract is used for the above indications. Ginkgo leaf can be used topically to improve circulation in the skin. Active ingredients in ginkgo include flavonoids, terpenoids, and organic acids. The active ingredients have several theorized mechanisms of action. Ginkgo is believed to have anti-inflammatory effects. Ginkgo loids appear to inhibit platelet-activating factor, which can decrease platelet aggregation and increase cardiac contractility and coronary blood flow. Ginkgo loids decrease glucocorticoid biosynthesis, which may decrease stress and provide neuroprotection and have antimicrobial activity. [43] , [63] It is also theorized that ginkgo may have antioxidant and free radical scavenging properties, which would protect tissues from oxidative stress. Ginkgo flavonoids may also have effects on lipid peroxidation.[63] A review by Bent and coworkers reviewed 15 case reports of adverse effects associated with ginkgo.[64] In 13 of the 15 case reports, patients had risk factors other than ginkgo known to cause an increased risk on spontaneous bleeding (advanced age, medications known to increase bleeding risk, falls, cirrhosis, and previous or present surgery). Only 3 reports published bleeding times, all of which were elevated. Studies on healthy human subjects with a standard ginkgo extract found no significant effect on coagulation, fibrinolysis, or platelet aggregation.[65] Several large-scale trials did not find a significant incidence of bleeding in patients taking ginkgo vs placebo. [66] , [67] One study did find an increase in the incidence of ischemic stroke and transient ischemic attacks in patients taking ginkgo vs placebo.[67] There are reports of bleeding, including intracerebral bleeding that resulted in permanent neurologic damage or death. [68] , [69] , [70] , [71] In cases of less severe bleeding (nose bleeds, etc) associated with ginkgo, once the patient discontinued use of ginkgo, bleeding ceased. Crude ginkgo contains ginkgolic acid, which is toxic and can cause severe allergic reactions.[72] Crude ginkgo should not be used by patients. Ginkgo seeds contain ginkgo toxin, which can cause seizures, difficulty breathing, loss of consciousness, and shock when consuming more than 10 roasted seeds daily. Ginkgo toxin is available in much higher concentrations in ginkgo seeds than in ginkgo leaf extract.[73] Patients with seizure disorders or those that are concurrently taking medications that may lower seizure threshold, who may be at higher risk for the development of seizures, should avoid products that contain ginkgo. Ginkgo leaf extract can also cause allergic skin reactions that resolve after discontinuing ginkgo therapy.[74] There is also a case of Stevens-Johnson syndrome reported in a patient after their second dose of a combination herbal product containing ginkgo leaf extract.[75] Doses vary based on indication and dosage form. Common doses of ginkgo leaf extract range from 120 to 240 mg divided into 2-3 doses daily. To avoid gastrointestinal (GI) side effects, it is recommended to start with a lower dose and titrate as tolerated. [43] , [63] Patients taking ginkgo should make their physician aware of this treatment, especially if they are taking anticoagulant medications or have a seizure disorder.

Garlic is used by patients with dyslipidemia to reduce elevated lipids, for prevention of age-related vascular changes, and to treat mild hypertension. Other reported uses include arthritis, allergies, benign prostatic hypertrophy, bladder, breast, colorectal, gastric, lung, and prostate cancer, earaches, menstrual disorders, and traveler’s diarrhea. Garlic contains high concentrations of thiosulfinate allicin. Garlic is theorized to inhibit 3-hydroxyl-3-methylglutaryl-coenzyme A reductase, which prevents the synthesis of cholesterol. Dose varies based on dosage form ingested. Doses used in clinical trials for dyslipidemia were 600-1200 mg divided into 3 doses daily. Reports of garlic effects on blood coagulation are few. Four case reports observed that there was no laboratory evidence of elevation of coagulation or bleeding time parameters. [43] , [76]

Dong quai (Angelica senensis) contains many pharmacologically active compounds. Its reported uses include dysmenorrheal, premenstrual syndrome, and menopausal symptoms. It is also thought to treat hypertension, infertility, ulcers, anemia, and constipation and can be used for the prevention and treatment of allergy attacks. Topically, combined with other ingredients, it is used for treating premature ejaculation. The active ingredients in dong quai include ferulic acid, ligusticide, nicotinic acid, angelicide, brefeldin A, butylphthalide, and succinic acid. It also contains many other vitamins and minerals and several coumarin-containing compounds. Dong quai also contains bergaptan, safrole, and isosafrole, compounds that can be carcinogenic. It is unclear whether the carcinogenic compounds are present in large enough amounts to cause cancer. Most of the effects of dong quai are believed to come from the ferulic acid and ligusticide components. These compounds are also commonly used to assess the quality of dong quai roots, as the amount of these compounds contained in the root can vary depending on the region in which it is grown. Ferulic acid is thought to have antioxidant, anti-inflammatory, immunostimulant, antiarrhythmic, and antiplatelet effects. Ligusticide has antispasmodic and antiasthmatic effects. Dong quai may also have some estrogenic effects. The dose of dong quai used for menopausal symptoms is 4.5 g of powdered root daily. [77] , [78] One case report of hypertension, headache, vomiting, and weakness was reported in a 32-year-old woman who took the medication for dysmenorrhea.[79] Long-term (>24 weeks) and high-dose use is not recommended.[77] Patients at risk for cancer, especially hormone-sensitive cancers (breast, uterine, and ovarian cancer, endometriosis, and uterine fibroids), should not use dong quai. [80] , [81] Dong quai contains some natural coumarins and has antiplatelet activity. It may increase bleeding risk in patients taking anticoagulation or antiplatelet prescription medications or herbal supplements; therefore, concurrent use is not recommended.[82] The estrogenic effects of dong quai could cause thrombosis. One case described a reported thrombosis in a patient with protein S deficiency and systemic lupus erythematosus who developed retinal vein thrombosis 3 days after taking a combination herbal product that included 100 mg of dong quai. Patients with protein S deficiency who are at risk for thrombosis could be at increased risk if taking dong quai.[77]

Vitamin E has in 1 case report has observed alteration of protime/INR with subsequent ecchymosis and hematuria.[83] Also, there is theoretic support for the alteration of coagulation with herbs that contain coumarin derivatives, such as angelica, aniseed, arnica, chamomile, fenugreek, ginseng, horse chestnut, and red clover. Other herbs that have been alleged to inhibit platelet aggregation include clove, ginger, and licorice. Salicylate-like chemicals are contained in feverfew and meadowsweet and may also effect platelet function.[84]

Willow bark (Salix alba, Salix daphnoides, Salix fragilis, Salix nigra, Salix pentandra, and Salix purpureal) is an herbal used for thousands of years. It is commonly known to be a pain and fever reliever. It is also used for myalgias, osteoarthritis, dysmenorrheal, gouty arthritis, rheumatoid arthritis, gout, common cold, influenza, and weight loss. Willow bark has several different components, including flavonoids, tannins, and salicin. Salicin is considered the main active ingredient as it is metabolized to salicylic acid. The other components of willow bark are thought to have lipoxygenase-inhibiting and antioxidant effects as well as prevent prostaglandin and cytokine release. The effects of willow bark attributed to the salicin compounds include analgesic, anti-inflammatory, antipyretic, and antiplatelet activity.[85] The bioavailability of willow bark is less than that of aspirin due to manufacturing process. A dose of 240 mg salicin, contained in willow bark, is equivalent to 87 mg aspirin.[86] Many of the adverse effects associated with willow bark are similar to salicylates and nonsteroidal anti-inflammatory drugs (NSAIDs), although these effects may be less in patients taking willow bark. Willow bark does have antiplatelet effects; however, there is less effect than in patients taking aspirin. Theoretically, there is still a risk of increased bleeding in patients who are taking willow bark and an anticoagulant/antiplatelet. Patients should avoid willow bark while taking these medications and alert their physician. Patients who are undergoing surgery should stop therapy with willow bark at least 2 weeks before to avoid perioperative bleeding.[87] Patients with allergy to aspirin will also have reactions to willow bark.[88] Usual dosage of salicin recommended for back pain is 120-240 mg, with the higher dose found to be more effective. Up to a week of therapy may be needed before benefit is seen. Willow bark has been used for up to 3 months without adverse effects. [89] , [90]

There are various reports that long-chain unsaturated fatty acids, such as grape seed oil and fish oils, may decrease platelet aggregation.[76] Fish oils contain large amounts of omega-3 fatty acids, specifically eicosapentaenoic acid and docosahexaenoic acid. Fish with high concentrations of omega-3 fatty acids include herring, kipper, mackerel, menhaden, pilchard, salmon, sardine, and trout. Fish oils are used in the treatment of dyslipidemia, coronary heart disease (CHD), and hypertension. Omega-3 fatty acids affect the cyclooxygenase and lipoxygenase pathways by competing with arachidonic acid. The effects seen include decreased platelet aggregation and vasodilation. Omega-3 fatty acids are also thought to prevent increases in blood pressure and to maintain renal function. Affects of omega-3 fatty acids on lipids include decreased secretion of very low-density lipoproteins, increasing very low-density lipoproteins clearance and reduction of triglyceride transport to lower triglyceride levels. For patients who are interested in the prevention of CHD, eating fish high in omega-3 fatty acids is recommended at least twice a week. For patients with diagnosed CHD or dyslipidemia, 2-4 g eicosapentaenoic acid and docosahexaenoic acid should be taken daily. Caution should be exercised in patients at risk for bleeding, especially those taking other anticoagulants. The antithrombotic effects of fish oils could lead to bleeding and use should be monitored by a healthcare professional.[43]

Grape (Vitis vinifera) is used in many different forms as an herbal supplement. Grape seed oil is used to improve wound healing, to prevent dental caries, to treat liver cirrhosis, to prevent cancer, macular degeneration, allergic rhinitis, and diabetes complications, and as a mild laxative. Grape is used to prevent cardiovascular disease, varicose veins, hemorrhoids, atherosclerosis, hypertension, peripheral vascular disease, and myocardial or cerebral infarction. Dried grapes (raisins) can be used as a cough expectorant. Grape leaves can be used for attention deficit-hyperactivity disorder (ADHD), diarrhea, heavy menstrual bleeding, uterine hemorrhage, and canker sores. Infusions of grape leaves can also be used intravaginally as a douche.[91] Grape contains proanthocyanidins, flavonoids, and phenols. Proanthocyanidins give red grapes their color and are contained in higher concentration. Proanthocyanidins provide antioxidant effects. Flavonoids are thought to have antioxidant, vasodilating, anti-lipoperoxidant, and antiplatelet activity. [92] , [93] Grape inhibits liver cytochrome P450 enzyme 2E1 (CYP2E1), which may provide some protective cellular effects in patients who may have drug toxicity. Acetaminophen is metabolized through CYP2E1. Toxicity associated with acetaminophen overdose could theoretically be minimized by the inhibition of CYP2E1. Proanthocyanidins also seem to decrease proliferation of certain cancers, including gastric adenocarcinoma, breast, lung, and prostate cancer. Cancer cell death is also increased in these patient populations.[91] Grape also contains tocopherol, which could theoretically increase bleeding risk, especially in patients also taking anticoagulants, including warfarin. Little evidence is present in the literature documenting increased bleeding risk due to grape or grape compounds used in combination with anticoagulant medications. Grape seed extracts have been used for up to 8 weeks and grape leaf extracts have been used for up to 12 weeks safely. [91] , [94] Grape comes in many different formulations. Grape seed extract compounded as tablets or capsules can be taken in doses of 75-300 mg daily for 3 weeks and then decreased to a maintenance dose of 40-80 mg daily. Doses as high as 720 mg daily have been used. Excessive consumption of grapes or grape compounds can lead to diarrhea because of its laxative properties. Due to concern of increased bleeding risk in patients who are concurrently taking anticoagulant medications, patients should make their health care professionals aware if they are taking grape supplements.[91]

Hepatic Toxicity

Kava kava has been recommended for anxiety, stress, restlessness, ADHD, headaches, epilepsy, respiratory tract infections, and urinary tract infections. It is also used topically for the promotion of wound healing and as an analgesic. The active ingredients that comprise kava kava include kava-lactones or kava pyrones, which contain kawain, dihydrokawain, methysticin, dihydromethysticin, and yangonin. The exact mechanism of kava is unknown. Some theorize that it exerts its effects on the gamma-aminobutyric acid (GABA) receptors. Other reports suggest dopamine antagonism or norepinephrine uptake inhibition. It is not believed that kava kava has any affects on benzodiazepine or opiate receptors (padiyara). Case reports have demonstrated large increases of liver markers with chronic (1-3 months) use of kava kava capsules.[95] Many of these patients experienced liver failure and eventually required liver transplantation. Some of these cases ended in death of the patient. [96] , [97] , [98] One case reported liver toxicity occurring after a single occurrence of alcohol consumption in a patient also taking a kava supplement.[97] The FDA has issued a usage warning discussing severe hepatotoxicity possibly associated with the consumption of kava-containing products.[99] Kava extracts were banned in 2003 in the European Union and Canada. [95] , [99] Extended use and higher doses may contribute to an increase in hepatotoxicity. Patients with pre-existing hepatic disease are also more likely to suffer from toxicity. The dopamine antagonistic effects of kava have been thought to contribute to a parkinsonian-like syndrome. Patients with Parkinson disease should not take supplements containing kava.[100] Doses of 60-120 mg, up to 3 times daily, of kava pyrones are suggested for use for not longer than 1 month. Liver function tests should be monitored while taking kava. Patients should also be discouraged from using other hepatotoxic herbal and prescription medications (acetaminophen, amiodarone, carbamazepine, isoniazid, methotrexate, methyldopa, etc). [43] , [100]

Ma huang was previously discussed under direct cardiovascular toxicity and should be included in herbal products with hepatic toxicity. A case series, focused on several transplant centers, reported 10 patients with hepatotoxicity suspected to be related to ma huang. These patients developed hepatitis with 3 patients progressing to fulminant hepatic failure requiring hepatic transplantation and 1 patient expiring. These patients developed hepatic abnormalities approximately 6 weeks after ingestion of Ephedra products. An idiosyncratic mechanism of hepatic injury has been proposed.[101] Several other case reports have also been published reporting hepatic toxicity related to ma huang/Ephedra products.[102] Both the cardiovascular effects and the possible hepatotoxicity associated with ma huang make it a less than ideal herbal supplement. Its use is not recommended.

Chaparral (Larrea tridentate) is technically not an herb because it has a woody stem. Although it is commonly categorized as an herb, chaparral is actually made from the leaves of the plant and is compounded into tablets or a salve. Chaparral has been used to treat upper respiratory tract infections, infertility, rheumatism, arthritis, diabetes, gallstones, kidney stones, cancer, skin conditions, chicken pox, and snake bites. The active component of chaparral is nordihydroguaiaretic acid (NDGA). NDGA is thought to have antioxidant activity, to inhibit lipoxygenases. It may have anticancer activity and induce apoptosis in tumor cells. Although NDGA has some properties that may be helpful in treating various aliments, it also is thought to cause hepatotoxicity. It inhibits cyclo-oxygenase pathways, which are theorized to allow proinflammatory mediators to cause hepatotoxicity.[103] In the cases reported, patients were typically taking chaparral for at least 2 months before hepatotoxicity developed. Patients developed fatigue, dark urine, jaundice, nausea, diarrhea, and right upper quadrant pain. Most of the patients had resolution of symptoms after discontinuing chaparral. It was found that patients who were rechallenged with chaparral that hepatotoxicity again developed and at a more rapid rate than their initial hepatotoxicity. Some of the patients experienced hepatic failure and required hepatic transplant. The FDA has advised consumers against consumption of products containing chaparral due to concerns about hepatotoxicity; however, it is still available for use in the USA. [103] , [104] , [105] , [106] , [107]

Germander (Teucrium chamaedrys) is used to treat gallbladder conditions, gout, obesity, diabetes mellitus, fever, diarrhea, and stomachaches. Topically it is used as a mouthwash (Germander). Germander contains glycosides, saponins, flavonoids, and furanoneoclerodane diterpenoids. Multiple cases report hepatitis, hepatic cirrhosis, and death in patients taking germander. [108] , [109] Diterpenoids are believed to cause hepatotoxicity. Oxidation of diterpenoids forms an epoxide which depletes glutathione in the liver. The epoxide also causes DNA fragmentation and cell apoptosis. [106] , [108] , [109] It is also theorized that epoxide binding to hepatocytes may cause autoantibody formation, which triggers an immune response leading to cell death.[110] Discontinuation of germander may lead to full resolution of hepatotoxicity. It has been documented in case series that patients rechallenged with germander redevelop hepatitis after reexposure.[13] Use of germander has been banned in France; however, it is still allowed in the USA.

Black cohosh contains phytosterin, isoferulic acid, fukinolic acid, and triterpene glycosides as active ingredients. It is used for premenstrual discomfort, dysmenorrhea, and symptoms associated with menopause. Hepatoxicity has been described in case reports. The United States Pharmacopeia designated an expert committee to review and evaluate data regarding hepatotoxicity associated with black cohosh. It was determined that a cautionary statement should warn of this association. Regulatory groups from Australia and Europe have also issued warning statements regarding black cohosh induced hepatotoxicity. Black cohosh is available in many different forms. The recommended daily dose is 40-80 mg. Patients should be discouraged from concurrent use of other hepatotoxic herbal products or prescription medications. [43] , [49] , [111]

European mistletoe comes from the family Viscaceae. American mistletoe is also included in the family Viscaceae.[112] European mistletoe is used for hypertension, epilepsy, arteriosclerosis, gout, depression, sleep disorders, headache, amenorrhea, whooping cough, asthma, and diarrhea. It is also used to treat side effects from chemotherapy and radiation therapy and for liver and gallbladder conditions.[113] European mistletoe can also be given as a subcutaneous injection for cancer and degenerative joint disease.[113] Mistletoe is described as a parasitic plant because it grows on trees, including oak, apple, and maple. The composition of mistletoe can vary depending on the type of tree its growing on, weather conditions, and time of year.[114] The active compounds contained in European mistletoe include glycoprotein lectins, viscotoxins, alkaloids, and monoterpene glucosides.[115] The active compounds can be found in the berries, leaf, and stem. Researchers have developed aviscumine, a pure form of mistletoe lectin, through recombinant DNA technology. It is theorized that European mistletoe may act as a biological response modifier to stimulate the immune system and have cytotoxic effects against cancer. European mistletoe causes leukocytosis and increases secretion of interleukin-1, -2, -6, and tumor necrosis factor. [116] , [117] Small amounts of European mistletoe (several berries or leaves) are not considered harmful. Larger doses can cause vomiting, diarrhea, hypotension, seizures, hepatitis, coma, and death.[113] Several case reports have described drug-induced hepatitis in patients taking European mistletoe. Subcutaneous administration of mistletoe can cause chills, fever, headaches, angina, eosinophilia, and anaphylactic reactions.[118] Aviscumine subcutaneous injections can cause fever, nausea, vomiting, pruritus, hypokalemia, and elevated liver function tests.[119] In the USA, interest in mistletoe for the treatment of cancer has recently increased. Mistletoe extracts are used in Europe for the treatment of breast cancer. Currently, there are no mistletoe products approved for use in the USA. Patients should be cautioned in the use of mistletoe as more data are necessary to determine efficacy in cancer treatment.

Pennyroyal oil comes from Mentha pulegium and Hedeoma pulegoides plants and has a minty odor. It is used to treat upper respiratory tract and ear infections, as an abortifacient, and for gallbladder disorders, stomach pains, and weakness. Topically it can be used as an antiseptic, as an insect repellent, for mouth sores, for venomous bites, and as a counterirritant. The main component of pennyroyal is pulegone, which is metabolized in the liver to menthofuran. Menthofuran is directly hepatotoxic, causing cellular necrosis in the centrilobular hepatic tissue. This hepatic injury is similar to the damage caused by acetaminophen toxicity. Pulegone also causes depletion of glutathione stores. The American pennyroyal species is reported to contain 30% less pulegone than the European pennyroyal species.[120] However, small doses have caused serious adverse effects. A dose of 5 mL pennyroyal oil caused coma and seizures, and a dose of 10-15 mL has caused death. Cases have reported patients requiring liver transplant due to pennyroyal oil toxicity. Patients may develop hypoglycemia, elevated liver function tests, hyperammonemia, elevated anion gap metabolic acidosis, GI bleeding, renal failure, mental status changes, and seizures. Most care of pennyroyal toxicity is supportive however because of the mechanism of hepatic injury. N-acetylcysteine is recommended as a possible treatment, to decrease the amount of liver damage. [121] , [122] , [123] , [124]

One well-studied group of herbs, used as teas, that are said to cause a “herbal hepatitis” is that of numerous compounds that contain pyrrolizidine alkaloids (PA). These PAs are a group of approximately 300 chemicals that are contained in various widely used plants.[106] The teas have been promoted as antioxidant/antiaging compounds, as blood purifiers, as sedatives, and for use in the treatment of amenorrhea. The most common adverse effect of these herbal teas is GI upset.[71] Toxicity results from the formation of toxic pyrroles via the hepatic P450 metabolic pathway. The pyrroles alkylate nucleophilic groups on the hepatic cell molecules. This damage causes obstruction of hepatic venous flow. The resulting end-organ injury from pyrrolizidine toxicity is hepatic veno-occlusive disease, which is similar to Budd-Chiari syndrome. [106] , [125] These toxic pyrroles can also be transferred through the placenta, resulting in fetal hepatic toxicity. Infants exposed to PA seem to be most susceptible to toxicity. [73] , [106] Hepatic toxicity can result from as little as 85 mg pyrrolizidine alkaloid.[125] Plant roots contain 10 times more alkaloid than the leaf.[126] Interestingly, mass exposure has occurred to populations of food stuffs via contamination, resulting in hepatotoxicity and death.[127]

Patients exposed to pyrrolizidine alkaloids may acutely experience abdominal pain and vomiting.[125] Physical examination may reveal hepatomegaly, abdominal distention, and ascites. Toxicity may reveal symptoms similar to Reye’s syndrome in children.[127] Biopsy of the liver reveals perivenular congestion, sinusoidal dilation, and occlusion of the terminal venules by connective tissue.[127] This pattern is also seen in Budd-Chiari syndrome, but the course and outcome in Budd-Chiari syndrome is more severe and life-threatening.[127] Some patients are able to undergo hepatic transplantation. It is estimated that death occurs in approximately 20% of patients with acute PA toxicity. A chronic form of PA toxicity has also been reported, which begins with weakness and diarrhea. Patients with chronic toxicity can develop portal hypertension, esophageal varices, encephalopathy, and death.[128] Overall mortality from both acute and chronic is 40%. [129] , [130] Treatment for PA-induced hepatic toxicity is the same as treatment for veno-occlusive liver disease. Most treatment focuses on supportive care: limiting other hepatotoxins, reversing coagulopathy, and reduction of ascites. N-acetylcysteine has not shown any benefit. Some patients receive liver transplants; however, only 30% of patients who receive transplants experience clinical improvement. Table 5 lists pyrrolizidine-containing teas.

TABLE 5   —  Pyrrolizidine-containing teas (as adapted from Kingston)[125]

Herb Common Name Plant Name

Coltsfoot Tussilago farfara

Comfrey Symphytum officinale

Gordolobo Senencio longilobus

Groundsel Senencio vulgaris

Mate Ilex paraguayensis

Tansy ragwort Senencio jacobea

T”u-San-chi Gynura segetum

Endocrine Toxicity

Kelp (also known as bladder wrack, Fucus vesiculosus) is used for thyroid disorders, iodine deficiency, lymphadenoid goiter, obesity, arthritis, bronchitis, emphysema, and anxiety. It is also reportedly used to treat rheumatism, arteriosclerosis, digestive disorders, heartburn, bronchitis, and genitourinary disorders.[131] Bladder wrack contains high amounts of iodine and may also contain heavy metals, such as arsenic and cadmium. Bladder wrack also contains fiber, iron, and vitamin B12. As is common to all herbal preparations, the actual content is variable among different proprietary preparations.[132] Ingestion of more than 150 μg iodine per day can cause hyperthyroidism or exacerbate existing hyperthyroidism.[133] Heavy metal poisoning has also been documented.[134] Bladder wrack is thought to extend the menstrual cycle, increase progesterone, and have antiestrogen effects in premenopausal women.[135]

Licorice was previously mentioned to cause cardiovascular toxicity and has been documented to cause hypokalemic myopathy.[136] The responsible toxin is glycyrrhizic acid, which inhibits the enzyme 11-β-hydroxysteroid dehydrogenase, resulting in low plasma rennin activity, low aldosterone level, and normal cortisol level. The overall state clinically represents pseudohyperaldosteronism.[137]

Aloe (Aloe capensis, Aloe latex, Aloe perfoliata, Aloe vera, Aloe vera barbenoids) has received many positive accolades in the lay press. It has been used and preliminarily studied in wound scarring, psoriasis, and diabetes.[138] It has also been used for inflammatory bowel diseases, fever, osteoarthritis, itching and inflammation, gastroduodenal ulcers, asthma, and radiation-related mucositis. Aloe latex is used for constipation, epilepsy, bleeding, amenorrhea, depression, glaucoma, multiple sclerosis, hemorrhoids, and varicose veins. Topically it is used for burns, sunburn, frostbite, and cold sores. The parts of aloe used to treat various conditions are the gel and latex. The gel is produced by the thin-walled mucilaginous cells in the center of the aloe leaf. The latex is yellow sap or juice produced in the peripheral bundle sheath cells just below the allow leaf skin. Aloe leaf extract can be made with a combination of the gel and latex. Aloe latex contains anthraquinones and free anthraquinones, which can be cleaved in the colon to form anthrones. Anthrones are responsible for the laxative effects of aloe. They irritate mucous membranes, which lead to increased mucous secretion and peristalsis. Anthrones also increase fluid and electrolyte secretion into the lumen. This causes distention. Fluid and electrolyte reabsorption are also inhibited. Usually these effects are seen within 10 hours of aloe ingestion. Aloe latex also causes potassium losses, which paralyze intestinal muscles. Patients who take aloe for constipation for long periods may find that an increased dose is necessary for the same cathartic effects. This can lead to serious adverse effects from electrolyte depletion.[139]

Aloe gel contains mono- and polysaccharides, tannins, sterols, enzymes, amino acids, saponins, salicylic acid, arachidonic acid, lipids, vitamins, and minerals. Aloe gel is believed to inhibit bradykinin, which may cause its pain-relieving effects. It also inhibits histamine, which can decrease itching. Aloe gel is also theorized to inhibit the synthesis of thromboxane A2, which is a potent vasoconstrictor. Inhibition of thromboxane A2 may increase microcirculation and prevent ischemia in wounds. These effects could potentially decrease healing time for burns and frost bite. When aloe is used in combination with silver sulfadiazine, there seems to be synergistic effects on wound healing in comparison to when the products are used alone. Some research also suggests that aloe gel may lower blood glucose levels, which may be useful in diabetic patients. Patients with prolonged use of aloe are more likely to experience adverse effects. Patients can develop diarrhea (with blood), potassium depletion, albuminuria, hematuria, muscle weakness, weight loss, and cardiac effects. Prolonged use of high-dose aloe, greater than 1 g/d, has reportedly caused hemorrhagic gastritis, nephritis, and acute renal failure. Patients are also at greater risk for adverse effects if they are concurrently taking other laxatives or medications affected by electrolyte changes, such as diuretics or cardiac glycosides. Because of the adverse effects related to aloe, the FDA requested safety data from manufacturers. The manufacturers did not feel the expense for the research was acceptable and therefore, in 2002, the FDA required the removal or reformulation of all over-the-counter laxative products containing aloe.[139]

Maternal-Fetal Toxicity

Because herbal medications are considered crude drugs by most conventional medical practitioners, the same cautions that apply to drug use in pregnancy and lactation also apply to the use of herbal products.

In a review by Marcus et al, the recommendation of the use of ginger (Zingiber officinale) as an antiemetic in pregnancy was compared to vitamin B6. Both products were perceived to be equal in efficacy as an antiemetic. However, the review stated that several animal studies concluded that rat embryos exposed to ginger demonstrated an early loss of embryos double that of controls. [140] , [141] Furthermore, some of the compounds in ginger are mutagenic in a bacterial model.[142] The authors of the review did caution that animal studies may not be predictive of human responses. They continue however to observe that ginger compounds are potent inducers of apoptosis in human lymphoma cells. The extrapolation would be the concern over apoptosis in fetal development.[143] Ginger may also alter the estrogen-to-testosterone ratio in the developing embryo.[144] Ginger contains inhibitors of cyclo-oxygenases and 5-lipo-oxygenase, similar to NSAIDs, which might result in fetal or maternal bleeding complications.[145]

Finally, Marcus and Snodgrass, discuss the recommendation by the American College of Gynecology’s classification of ginger as a “nonpharmacologic” treatment for emesis during pregnancy. They caution that ginger being termed nonpharmacologic is scientifically inaccurate and misleading, possibly promoting the idea that herbs are not drugs. Furthermore, they site the recommendation by the Teratology Society to the FDA in that all dietary supplements cannot be assumed to be safe for the embryo or fetus. By inference, this includes ginger, which has not been shown to be safe by “standard scientific methods.”[141] They suggest that the American College of Gynecology practice bulletin regarding nausea and vomiting in pregnancy be revised to recommend that pregnant women not take ginger.

Blue cohosh, which is discussed previously, is used to induce labor in pregnant females. It has sympathomimetic effects and direct cardiac toxicity. Some of the compounds contained in blue cohosh are also teratogenic. Morbidity and mortality have been seen in fetuses and infants through maternal exposure. Its use is not recommended in pregnant women or those who are nursing.

Many of the other herbals previously discussed in this article are also not recommended in females who are pregnant or lactating. In most instances, the concern is fetal exposure via the mother and possible toxicity through exposure. Garlic is safe when used in dietary amounts. Medicinal doses of garlic can have abortifactant effects.[146] In addition to ginkgo’s adverse effects, some of the compounds may have labor-inducing effects. Due to ginkgo’s effects on platelets and coagulation, it is not recommended around delivery because of increased risk of bleeding.[63] St John’s wort, which is discussed in-depth below, may contain teratogenic compounds causing congenital malformations.[147] Dong quai is also suspected to cause musculoskeletal, connective tissue, and eye malformations during the first trimester.[148] Aloe contains anthraquinones, which can be mutagenic and are thought to stimulate menstruation and abortion.[139] Pennyroyal and licorice are also theorized to have abortifacient effects. Licorice has additional effects on estrogens and steroids. Kava contains pyrones that may cause a loss of uterine tone. Herbals are not recommended in breastfeeding females as the active compounds in the herbal products may be ingested by the infant via breast milk.

Other herbs, specific to the Mexican American culture, include peppermint, which has been observed to cause alterations in testosterone, leutinizing hormone, and follicle-stimulating hormones in a rat model.[138] Another herb alleged to cause toxicity is nettle. Nettle is used for its alleged positive effects on osteoarthritis, benign prostatic hypertrophy, and allergic rhinitis. Nettle can, however, have uterine stimulant effects and induce abortion.[149]

Use of most herbal products during pregnancy is cautioned. Not only are pregnant females, their fetuses, and infants at risk of toxicity from the compounds contained in the herbal products but also any adulterants. Exposure to products contaminated with microbes, heavy metals, or pesticides could cause morbidity and mortality. Pregnant and lactating patients considering the use of herbal supplements should consult a health care professional before starting therapy.

Neurological and Psychiatric Toxicity

Direct toxicity by herbal products has been observed to cause cerebral arteritis, coma, confusion, hallucinations, stroke, movement disorders, mood disturbances, and seizures.[150] Multiple herbs have been implicated in a case report fashion, including ginseng, jimson weed, passionflower, kava, nutmeg, and St John’s wort.[150]

Ginseng, from the plant genus Panax, is promoted for a wide range of uses. Ginseng is used for improving respiratory, GI, and central nervous system functions, breast, ovarian, liver, lung, and skin cancer. It is also used for anemia, hyperlipidemia, diabetes, impotence, fever, hangover, rheumatism, convulsions, menopause-related hot flashes, anxiety, depression, chronic fatigue syndrome, loss of appetite, fibromyalgia, insomnia, and to slow the aging process. Topically, Panax ginseng is part of a combination preparation used to treat premature ejaculation. Panax ginseng can also be found in energy drinks, soaps, and cosmetics.[151] Active compounds found in Panax ginseng include ginsenosides, which are also called panaxosides. Other active compounds include pectin, B vitamins, flavonoids, and panaxans. Some of the ginsenosides have conflicting activity. For example, 1 type of ginsenosides may raise blood pressure and be a central nervous system (CNS) stimulant, while another may decrease blood pressure and be a CNS depressant. Ginsenosides also have effects on platelet aggregation and coagulation and have neuroprotectivity. Ginsenosides relax bronchial smooth muscle, which may explain its use in asthmatics.[152]Panax ginseng may also have affected the hypothalamic-pituitary-adrenal axis and increase cortisol levels. This may contribute to its purported use to combat stress. Panax ginseng’s use in cancer is thought to be due to decreased production of tumor necrosis factor, diminished DNA strand breakage, and decreased proliferation of cancer cells and inhibition of formation of induced skin tumors. [153] , [154] Affects of ginseng lead to increases in lipoprotein lipase activity, enhance lipid metabolism, and may lower cholesterol and triglycerides.[155] Panaxans have hypoglycemic effects, which may aid diabetic patients.[156]Panax ginseng is also thought to decrease tissue insulin resistance and possibly directly stimulate insulin release. [157] , [158] The active compounds contained in Panax ginseng come from the root. Variations of each compound can affect the affects seen from different products and formulations.

In the 1970s and 1980s there was discussion of a possible ginseng abuse syndrome associated with long use and higher doses of ginseng. This theory has since been discredited. Patients taking ginseng have been reported to have diarrhea, anxiety, insomnia, nonspecific dermatitis, depression, mania, decreased appetite, amenorrhea, and hypertension.[159] These symptoms have developed in patients with short-term use of ginseng. Patients with psychiatric conditions may be more susceptible to the psychiatric adverse effects associated with Panax ginseng and should avoid its use.[151] Usual doses of ginseng extract are 100 mg twice daily.[44]Panax ginseng therapy is not recommended for more than 3 months. Higher doses are more likely to cause adverse effects.

Valerian, from the family Valerianaceae, is used for insomnia, anxiety, depression and other mood disorders, epilepsy, ADHD, and chronic fatigue syndrome. Valerian is also used for conditions associated with psychological stress, menstrual cramps, and symptoms associated with menopause.[160] The active parts of valerian include the rhizome and the root. The active compounds include valepotriates, baldrinals, volatile oils, monoterpens, flavonoids, and sesquiterpenes. As was mentioned with ginseng, the composition of the active compounds can vary greatly from root to rhizome and also with the different species of valerian. The active compounds are believed to have sedative-hypnotic, anxiolytic, antidepressant, anticonvulsant, and antispasmodic effects. [161] , [162] , [163] Multiple active compounds may be responsible for the activity seen. Sedative-hypnotic effects may arise from valerian’s agonist effects on GABA. Valerian may also directly bind to GABA receptors and stimulate the release and reuptake of GABA. [160] , [164] Some of the valerian flavonoids also bind to the benzodiazepine-binding sites.[165] Valerian is available in many different forms, including extract and teas. Dosing is dependent on indication. For insomnia the recommended dose is 400-900 mg valerian extract orally up to 2 hours before bedtime. Other dosing available is 300-450 mg of valerian extract orally in 3 divided doses. Studies conducted using valerian have found it is safe to use for up to 28 days.[161] A case of valerian overdose has been reported. Fatigue, chest tightness, abdominal cramping, and tremor of hand and foot were seen in a patient after 20 times the recommended valerian dose was ingested.[166] Benzodiazepine-like withdrawal has been noted after discontinuation of valerian therapy.[167] Other adverse effects associated with valerian include headache, excitability, uneasiness, cardiac disturbances, and insomnia. [160] , [161] Adverse effects are more likely seen in patients taking higher doses for prolonged periods. Valerian’s effects on the benzodiazepine receptors may cause a withdrawal syndrome; therefore, abrupt cessation, especially after prolonged therapy, is not recommended. Doses should be tapered gradually, preferably under the care of a physician.

Jimson weed (Datura stamonium) can be used to treat asthma, cough, and pertussis and for diseases of the autonomic nervous system. It is also used to induce hallucinations and euphoria.[168] Jimson weed’s activity comes from belladonna alkaloids, including atropine, L-hyoscyamine, and L-scopolamine. The active compounds are responsible for the anticholinergic effects of jimson weed.[168] Overdose can cause acute anticholinergic toxicity and death. Jimson weed has long been smoked (leaves) or ingested orally (seeds) to obtain its hallucinogenic and euphoric effects. [168] , [169] The seeds contain the highest concentration of belladonna alkaloids. An adult lethal dose is 15-100 g of leaf or 15-25 g of seeds, which is equivalent to 100 mg atropine.[168] Adverse effects of ingestion of jimson weed include dilated pupils, tachycardia, blurred vision, auditory and visual hallucinations, hyperthermia, hypertension, confusion, and seizures. Death in acute toxicity can result from CNS depression, circulatory collapse, and hypotension. Use of jimson weed is not recommended due to possible adverse effects. [168] , [169]

Passionflower (Passiflora incarnate) is used in the treatment of insomnia, anxiety, symptoms of opiate withdrawal, neuralgia, seizures, menopause, ADHD, nervousness, fibromyalgia, and pain relief. Topically, passionflower is used in bath preparations and for hemorrhoids, burns, and inflammation.[170] Passionflower extract is also used for flavoring.[170] The active compounds contained in passionflower are flavonoids (apigenin, luteolin, quercetin, kaempferol, and vitexin), Harman alkaloids (harmine, harmaline, harmalol, Harman, and harming), maltol, and ethyl maltol. [171] , [172] There is controversy about whether passionflower contains a cyanogenic glycoside, gynocardine. The flavonoids and alkaloids contained in passionflower are responsible for its sedative, hypnotic, anxiolytic, analgesic, and antispasmodic effects. [171] , [172] The active compounds may bind to the benzodiazepine receptors, causing anxiolysis without affecting memory or motor skills. Affects may also be seen on the monoamine oxidase system, although more research is needed to confirm this.[173] Passionflower is available as a liquid extract, tablet, tea, tincture, and crude dried parts. Dosing for anxiety is 45 drops of passionflower extract daily or 90 mg daily. [170] , [174] Use for up to 1 month is considered safe. Adverse effects associated using passionflower include dizziness, confusion, sedation, and ataxia.[170] One case report describes a patient who developed severe nausea, vomiting, drowsiness, prolonged QT interval, and episodes of nonsustained ventricular tachycardia. This patient reported taking therapeutic doses of passionflower.[175] Passionflower was approved for use in the USA as an over-the-counter sleep aid and sedative in the 1970s. Since that time it has been removed from the market for lack of safety and efficacy data.[170]

Eucalyptus leaf (Eucalyptus globulus, Eucalyptus bicostata, Eucalyptus smithii, Eucalyptus odorata, Eucalyptus polybractea) is used as an expectorant, in the treatment of respiratory tract infections, asthma, osteoarthritis, acne, burns, ringworm, loss of appetite, bladder diseases, gonorrhea, flu, diabetes, neuralgia, and cancer. Eucalyptus oil is used for coughs, bronchitis, sinusitis, asthma, chronic obstructive pulmonary disease, fever, and as an antiseptic and an expectorant. Topically, Eucalyptus oil is used for arthritis, genital herpes, nasal congestion, and insect repellent. Eucalyptus is used as a flavoring agent in foods, as mouthwash, antiseptic, and toothpaste, and as a fragrance component of perfume and cosmetics.[176] The active component of Eucalyptus is eucalyptol. Eucalyptus oil contains between 60% and 90% of eucalyptol. Eucalyptus may exhibit some hypoglycemic effects. It is thought to increase insulin secretion and enhance uptake and metabolism of glucose by muscle.[177] Eucalyptol exhibits analgesic and anti-inflammatory effects by inhibiting the cyclo-oxygenase pathway and blocking the production of arachidonic acid metabolites. Eucalyptol also inhibits cytokines, tumor necrosis factor, interleukins, leukotrienes, and thromboxane, which would decrease inflammation.[178] Some of this activity may be helpful in asthmatic patients.[179] Other components of Eucalyptus can produce toxicity. Cineole will cause seizures in high doses. Hydrocyanic acid is another toxic compound. [176] , [180] In adults, ingestion of 3.5 mL Eucalyptus oil can be fatal. Toxicity can arise from topical exposure as well, especially after prolonged exposure or large amounts of Eucalyptus oil. Toxicity includes agitation, drowsiness, slurred speech, ataxia, muscle weakness, seizures, coma, and death. Children are even more susceptible to toxicity than adults. [176] , [180] , [181] The recommended dose of Eucalyptus oil for the treatment of asthma is 200 mg eucalyptol compound 3 times daily.[179] Eucalyptus has been used safely for up to 12 weeks. Treatment for longer periods is not recommended. Because of the potential for toxicity, patients should be extremely cautious when taking this herbal product. Eucalyptus oil should be kept out of reach of children as toxicity can develop with small doses and can be lethal.[176]

St John’s wort (Hypericum perforatum) is 1 of the most studied herbal products available. Many clinical trials have been conducted to confirm its pharmacologic effects. St John’s wort is used in the treatment of depression, anxiety, seasonal affective disorder, obsessive-compulsive disorder, menopausal symptoms, migraine headache, fibromyalgia, chronic fatigue syndrome, neuralgia, and cancer. Topically St John’s wort is used to treat abrasions, inflammation, burns, wounds, bug bites, hemorrhoids, and neuralgia. Many studies have compared St John’s wort to placebo, low-dose tricyclic antidepressants, and selective serotonin reuptake inhibitors, including fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil). [182] , [183] , [184] , [185] , [186] , [187] , [188] St John’s wort appears to improve mood, decrease anxiety and somatic symptoms, and decrease insomnia related to mild to severe major depression. [182] , [183] , [184] , [185] , [186] , [187] , [188] It appears that short-term response rate to St John’s wort (65%-100%) is higher than long-term response rate (60%-69%).[182] It has been theorized by some that patients with less severe cases of major depression may respond better to treatment with St John’s wort.[189] The American College of Physicians–American Society of Internal Medicine has guidelines for the treatment of depression. These guidelines elude that along with prescription antidepressants, St John’s wort can be considered an option for short-term treatment of mild depression. [190] , [191] Many of the studies have shown St John’s wort to have equivalent effectiveness and tolerability in comparison to prescription antidepressants. However St John’s wort has numerous drug interactions (which are discussed below), which may not make it a first-line choice in some patients, especially those who are on multiple medications.[147] The active compounds in St John’s wort are usually found in the flowers and to a lesser extent the leaves. St John’s wort contains hypericin and hyperforin, which are believed to be the main pharmacologically active compounds.[147] Melatonin is also found in St John’s wort. [147] , [192] Hyperforin and hypericin are theorized to modulate the effects of serotonin, dopamine, and norepinephrine and may inhibit their reuptake. [147] , [193] The effects on neurotransmitters may also cause cortisol stimulation in a dose-dependent manner. [147] , [194] Hyperforin also inhibits synaptosomal uptake of GABA and L-glutamate.[195] It is thought that St John’s wort’s effects on serotonin are responsible for most of its antidepressant activity. Other active components may also contribute to its antidepressant effects. [147] , [196] Hyperforin may have effects on cancer cells by inducing apoptosis.[197] St John’s wort may also have antiviral and antibacterial activity, although further investigation is warranted to confirm these effects.[147] The composition of the active ingredients in St John’s wort vary based on the season and different regions in which it is grown.[198] Exposure to light may also affect the active compounds in St John’s wort.[199]

The dose of St John’s wort used in clinical trials for depression is 300 mg 3 times a day. A standard 0.3% hypericin extract is used.[182] Doses up to 1200 mg have been used.[190] Pediatric dosing used in children over the age of 6 is 300 mg daily of the 0.3% hypericin extract.[200] Adverse effects associated using St John’s wort include vivid dreams, irritability, diarrhea, dry mouth, neuropathy, dizziness, photosensitivity, and hypoglycemia. Cases of serotonin syndrome have been reported with use.[201] Patients may experience extreme anxiety, confusion, nausea, hypertension, and tachycardia. Serotonin syndrome usually develops within 2-3 weeks after starting therapy with St John’s wort. Patients taking other medications or foods that may affect serotonin are at increased risk to develop serotonin syndrome.[202] Withdrawal has occurred in patients who have abruptly stopped taking St John’s wort.[203] Withdrawal symptoms are usually experienced within several days of discontinuation of St John’s wort. Symptoms of withdrawal are not based on dose or duration of therapy. [203] , [204] France banned the use of St John’s wort because of significant drug-herb interactions. The UK, Canada, and Japan are attempting to place warning labels on St John’s wort containing products because of the drug-herb interactions. While St John’s wort appears to have many beneficial effects, it has many drug interactions and can cause serious adverse effects. Patients taking St John’s wort should alert their physician of the use of this herbal product.[147]

Nutmeg (Myristica fragrens) is actually the shelled dried seed from the plant. Nutmeg has been used for diarrhea, nausea, flatulence, insomnia, kidney disease, insomnia, and inducing abortion and as a hallucinogen. Topically nutmeg is used for analgesia, specifically for rheumatism, mouth sores, and toothaches. In foods nutmeg is used as a spice and for flavoring. Nutmeg oil is used as a fragrance in soaps and cosmetics.[205] It as been advertised as an aphrodisiac, narcotic, mood elevator, and hallucinogen for centuries.[125] Nutmeg contains many volatile oils, including myristicin, elemicin, eugenol, isoeugenol, gerinol, pinese, cineole, borneol, and safrole.[206] Many of the effects of these volatile oils contradict each other. For example, some volatile oils cause CNS stimulation and others cause CNS depression. Other effects of the volatile oils contained in nutmeg are convulsant and anticonvulsant activity. Nutmeg can cause hallucinations, euphoria, and delusions. Myristicin and elemicin are metabolized to compounds related to methamphetamines, which may account for this activity. These 2 volatile oils may also have effects on the serotonergic system. High doses of nutmeg cause anticholinergic effects; however, cineole and terpinene have anticholinesterase activity.[206] Adverse effects can be seen when nutmeg is used in doses higher than those used in food. Five to 20 grams of nutmeg powder is equivalent to 1-3 whole seeds. A large dose may be contained in only a few seeds. Ingestion of greater than 5 g of nutmeg produces GI upset within the first 30 minutes. Vivid hallucinations may appear, with a duration of action of up to 3 days.[125] Other adverse effects include tachycardia, hypotension, hypothermia, numbness, disorientation, anxiety, panic, agitation, seizures, shock, coma, and death. Some of the adverse effects are due to anticholinergic activity of nutmeg. Depending on the amount ingested, symptoms may resolve within 2-6 hours but may take up to several days. Chronic use of nutmeg is limited by its concomitant GI upset properties. This herbal product is not recommended for use beyond a culinary spice. As with some of the other herbal products, toxicity can arise from a small amount of nutmeg. It should be kept out of reach of children to avoid fatal toxicity. [205] , [206]

Herb-Drug Interactions

The extent of orthodox drug negative interactions with herbal preparations is not known, but well reported as observational studies in the literature.[52] Most authors believe that the incidence of herb-drug interactions is increasing due to the presence of already existing polypharmacy of conventional drugs in the United States population. Furthermore, the addition of vitamins, herbs, foods, and over-the-counter medications adds to an increased potential for negative interactions. Herb-drug interactions can be considered similar to commonly studied drug-drug interactions. These interactions can be either pharmacodynamic or pharmacokinetic.

Pharmacokinetic interactions can be classified into the following mechanisms: alteration in drug absorption, alteration in drug metabolism (mostly hepatic, by affecting cytochrome oxidase/CYP450 function), alteration in renal clearance, and alterations in plasma protein binding. Pharmacodynamic drug interactions result in additive or synergistic effects on the effector organ sites (especially the cardiac or central nervous system).

Some of the most clinically important and most studied herb-drug interactions affect the CYP450 hepatic drug metabolizing system. Unfortunately, these studies suffer from discrepancies due to the reasons stated in Table 3, even for the same herb and drug. Two common drug-herb interactions are those of St John’s wort and kava. The plant H perforatum, St John’s wort, strongly induces the metabolizing effect of CYP3A, which metabolizes approximately 50% of available United States pharmaceuticals.[76] Case reports describe the stimulation of the CYP3A enzyme by the toxin hyperforin, with concomitant decrease in the levels of indinavir, cyclosporin, estrogens, and amitriptyline along with many other drugs.[207] Other P450 enzymes that may be affected are CYP2E1, 2C9, 2C19, and 1A2. Kava kava (Piper methysticum) liquid extract inhibits several of the CYP 450 enzymes, potentially resulting in elevated serum levels. However, other authors report different levels of decreased enzyme metabolism, again probably due to the differences of herbal preparations used in the respective studies.

P glycoprotein (P-gp) is an intestinal cell membrane transporter. P-gp transports drugs and other substances across cell membranes. P-gp can regulate medication concentrations and bioavailability. Medications and herbal products can effect drug bioavailability by inhibiting or inducing P-gp. St John’s wort has been shown to induce P-gp. Induction of P-gp can prevent absorption of drugs and decrease effects of drugs if they are not able to reach their effector sites. Inhibition of P-gp can increase absorption of drugs and increased effects/toxicity at effector sites. Some of the medications affected by the P-gp transport system are etoposide, paclitaxel, vinblastine, vincristine, ketoconazole, itraconazole, amprenavir, indinavir, nelfinavir, saquinavir, diltiazem, verapamil, corticosteroids, erythromycin, digoxin, cimetidine, ranitidine, fexofenadine, and quin dine. Kava has been shown in vitro to inhibit P-gp, increasing levels of drugs that are substrates of P-gp. However kava has not been shown in humans to cause alterations in P-gp. Patients on medications that are substrates of P-gp and are concurrently taking kava or St John’s wort should be monitored for adverse effects related to this reaction. [100] , [147] , [207] , [208] , [209] , [210] , [211] , [212] , [213]

[TABLE 6] , [TABLE 7] , [TABLE 8] list many herb-drug interactions and herb-CYP 450 interactions, which also affect many drugs. Herb-CYP 450 interactions can occur in 2 different ways. Herbal products can induce CYP 450 enzymes, increasing the metabolism of medications and possibly decreasing efficacy. They can also inhibit CYP 450 enzymes, decreasing the metabolism of medications and possibly increasing effects/toxicity. These tables are not all inclusive but provide many of the most common interactions reported.

TABLE 6   —  Direct herbal neurological or psychiatric toxicity (adapted from Ernst[150])

Herb Traditional Use Toxicity

Ginseng CNS effects, GI disorders, asthma, diabetes, cancer Insomnia, mania, euphoria

Valerian Insomnia, anxiety, seizures, depression Benzodiazepine-like withdrawal, insomnia, mania

Jimson weed Asthma, cough, muscle spasm Ataxia, blurred vision, confusion, hallucinations, seizure, coma, death

Passionflower Neuralgia, seizures, hysteria, insomnia, ADHD Nausea, ataxia, confusion, sedation, cardiac abnormalities

Eucalyptus Nasal congestion, respiratory disorders, fever, cough Cyanosis, delirium, GI symptoms, coma

St John’s wort Depression, anxiety, ADHD, migraines, wound healing Serotonin syndrome

Nutmeg Diarrhea, flatulence, insomnia, analgesia Hallucinations, nystagmus, euphoria, anxiety, panic, seizures, coma, death

TABLE 7   —  Common herb-drug interactions [24] , [43] , [45] , [49] , [53] , [59] , [63] , [77] , [87] , [91] , [100] , [104] , [107] , [113] , [120] , [131] , [139] , [146] , [147] , [151] , [160] , [168] , [170] , [176] , [214] , [215] , [216] , [217] , [218] , [219] , [220] , [221]

Herb Drug Action

Aloe, licorice Digoxin, furosemide, hydrochlorothiazide, other thiazide diuretics May cause hypokalemia, altering drug effects

Aloe Stimulant laxatives Increased laxative effect, may cause excessive fluid/electrolyte loss

Aloe, eucalyptus, panax ginseng, ma huang Antidiabetic agents: glimepiride, glyburide, insulin, metformin, pioglitazone, rosiglitazone May potentiate hypoglycemia

Black cohosh Cisplatin May decrease cytotoxic effects on breast cancer cells

Black cohosh, chaparral, comfrey, kava Hepatotoxic drugs: acetaminophen, amiodarone, atorvastatin, azathioprine, carbamazepine, isoniazid, methotrexate, etc May increase risk of developing liver damage

Bladder wrack Hypothyroid drugs: methenamine, methimazole, potassium iodide May potentiate hypothyroid effects

Bladder wrack, dong quai, evening primrose oil, feverfew, garlic ginkgo, ginseng, grape, red clover, saw palmetto, vitamin E, willow bark Anticoagulants/antiplatelets: warfarin, aspirin, clopidogrel, enoxaparin Increased bleeding

Blue cohosh, licorice Antihypertensive drugs: metoprolol, verapamil, diltiazem May cause hypertension leading to decreased efficacy

Blue cohosh Antidiabetic agents: glimepiride, glyburide, insulin, metformin, pioglitazone, rosiglitazone May cause hyperglycemia leading to decreased efficacy

Dong quai Warfarin Increased bleeding

European mistletoe Antihypertensive drugs: metoprolol, verapamil, diltiazem May potentiate hypotensive effects

Evening primrose oil Phenothiazines Increased risk of seizures

Garlic Isoniazid Decreased concentration of isoniazid

Ginger Antidiabetic agents: glimepiride, glyburide, insulin, metformin, pioglitazone, rosiglitazone May increase insulin release causing additive hypoglycemic effects

Ginger Calcium channel blockers: nifedipine, verapamil, diltiazem, felodipine May have effects at calcium channels and potentiate hypotension

Ginkgo Thiazide diuretics Hypertension

Ginkgo Anticonvulsants May reduce effectiveness of anticonvulsants in preventing seizures

Ginkgo Antidiabetic agents: glimepiride, glyburide, insulin, metformin, pioglitazone, rosiglitazone May alter insulin release and metabolism

Echinacea, ginseng, European mistletoe Immunosuppressants: azathioprine, cyclosporine, Mycophenolate, tacrolimus, sirolimus, corticosteroids May interfere with immune suppressing effects

Jimsonweed Amantadine, atropine, phenothiazines, tricyclic antidepressants May increase anticholinergic effects and adverse effects

Kava, passionflower, valerian Benzodiazepines, sedatives, barbiturates, zolpidem May potentiate sedative effects

Kava Levadopa May decrease efficacy

Ma Huang Anticonvulsants May increase risk for seizures

Ma huang Methylxanthines, MAO inhibitors, pseudoephedrine May increase risk for hypertension

Ma huang QT prolonging drugs: amiodarone, dofetilide, ibutilide, procainamide, quinidine, sotalol May increase risk for QT prolongation

Red clover Contraceptive drugs, estrogens, tamoxifen Competitive inhibition, may interfere with binding at estrogen receptors

St John’s wort (SJW) Paroxetine, trazadone, sertraline, nefazodone, triptans, dextromethorphan, MAOIs Lethargy, incoherence, increased risk of serotonin syndrome

SJW Digoxin Decreased digoxin concentration

SJW Statins (simvastatin) No effect on pravastatin, fluvastatin

SJW Nonnucleoside reverse transcriptase inhibitors, protease inhibitors, Irinotecan, imatinib Decreased effects reduced efficacy

Verapamil

Saw palmetto, valerian Contraceptives, estrogens May have antiestrogenic effects antagonizing these medications

Willow bark Salicylates Will have additive effects as willow bark contains salicylates

Vitamin E, passionflower Statins, niacin, Pentobarbital, benzodiazepines, zolpidem, sedatives May blunt effects on HDL cholesterol, may potentiate sedative effects

TABLE 8   —  Common CYP 450—herbal interactions [43] , [45] , [49] , [53] , [59] , [63] , [77] , [87] , [91] , [100] , [104] , [107] , [113] , [120] , [131] , [139] , [146] , [147] , [151] , [160] , [168] , [170] , [176] , [214] , [215] , [216] , [217] , [218] , [219] , [220] , [222]

CYP P450 Enzyme Herbal Product Example Medications Affected*

1A1 Inducer: nutmeg Theophylline

1A2 Inhibitors: Eucalyptus, feverfew, ginkgo, ginseng, kava, red clover inducers: grape, nutmeg, SJW Amitriptyline, clopidogrel, clozapine, cyclobenzapine, diazepam, estrogen/progesterone contraceptives, estradiol, haloperidol, imipramine, naproxen, nortriptyline, ondansetron, propranolol, theophylline, verapamil, warfarin

2B6 Inhibitor: licorice Ketamine, phenobarbital, dexamethasone

2C19 Inhibitors: Eucalyptus, kava, red clover Inducers: ginkgo, ginseng Amitriptyline, carisoprodol, cyclophosphamide, diazepam, lansoprazole, nelfinavir pantoprazole, phenytoin, phenobarbital, warfarin

2C9 Inhibitors: Eucalyptus, feverfew, ginkgo, ginseng, kava, red clover Inducer: licorice, SJW Amitriptyline, glipizide, estrogen/progesterone contraceptives, irbesartan, losartan, NSAIDs, phenytoin, tamoxifen, torsemide, warfarin

2D6 Inhibitors: Black cohosh, ginkgo, ginseng, kava Amitriptyline, clozapine, codeine, desipramine, donepezil, fentanyl, flecainide, fluoxetine, meperidine, methadone, metoprolol, olanzepine, ondansetron, risperidone, tramadol, trazodone, venlafaxine

2E1 Inhibitors: garlic, kava Acetaminophen, ethanol, enflurane, halothane, isoflurane, theophylline

3A4 Inhibitors: Echinacea, Eucalyptus, feverfew, ginseng, kava, licorice, red clover, valerian Inducers: garlic, ginkgo (questionable), ginseng, SJW, vitamin E Alprazolam, amlodipine, clarithromycin, cyclosporine, delavirdine, efavirenz, erythromycin, estrogen/progesterone contraceptives, fexofenadine, itraconazole, ketoconazole, saquinavir, triazolam, verapamil, warfarin

Treatment of Herbal Toxicity

The most difficult part of treating herb-induced toxicity is that of the recognition of involvement of the herbal product. Unfortunately, most medical care of herbal toxicity is supportive.

In 1 review by Haller, 6 major herbal treatments are selected for reference texts, published from 1966 to 2000, with respect to their recommendations for herbal overdose situations. The conclusion was that the herbal reference texts did not contain sufficient or correct recommendations for the medical management of herbal overdose or toxic problems.[76]

Although most treatment of herbal toxicity is supportive, there are several herbals that may be treated with specific therapies. As previously discussed, pennyroyal oil is known to cause hepatotoxicity. The active component of pennyroyal oil causes depletion of glutathione. The metabolism of pennyroyal oil causes hepatotoxic metabolites. The hepatotoxicity seen after ingestion of pennyroyal oil is similar to that caused by acetaminophen. N-acetylcysteine was used in several animal studies to treat pennyroyal oil hepatotoxicity. It has also been used in humans as a pennyroyal oil antidote to decrease damage to the liver. Adverse effects associated with N-acetylcysteine are relatively benign and treatment may reduce hepatotoxicity. The dosing of N-acetylcysteine is the standard dosing used to treat acetaminophen toxicity. Unlike acetaminophen toxicity, levels of pennyroyal oil cannot be obtained to guide antidotal therapy. Duration of therapy with N-acetylcysteine is unknown. N-acetylcysteine therapy should be started empirically in patients with suspected pennyroyal oil toxicity. In combination with supportive care, N-acetylcysteine may provide some benefit in patients with pennyroyal oil toxicity. [121] , [123]

Chan Su (containing bufadienolides) and ginseng (containing ginsenosides) were discussed previously because of their interference with laboratory testing of digoxin levels. Ginsenosides are similar to cardiac glycosides and may increase or decrease a patient’s digoxin level depending on the immunoassay. However, ginsenosides do not cause any of the cardiac effects seen with digoxin. Bufadienolides, by contrast, can have cardiac effects similar to those seen with cardiac glycosides. Patients who ingest Chan Su or other substances that contain bufadienolides will have an elevated digoxin level. [28] , [29] , [30] , [31] Toxicity can develop especially if the patient is concurrently taking digoxin. Treatment of digoxin toxicity includes the use of digoxin-specific antibody fragments (FAB). Digoxin-specific FAB are thought to bind bufadienolides, forming an inactive complex that is excreted through the urine. Elimination of this complex decreases the toxicity associated with bufadienolides. Digoxin levels in patients with bufadienolide toxicity cannot predict outcome. [28] , [29] , [30] , [31] There is no dosing conversion for the use of digoxin-specific FAB in bufadienolide toxicity. Empirically, 10 vials can be given and repeated if necessary. Supportive care and monitoring are also necessary when treating patients with bufadienolide toxicity. [28] , [29] , [30] , [31]

Aconite was discussed previously because of its potential cardiac toxicity. Patients can develop life-threatening ventricular tachycardia. A review by Lin et al identified 17 case reports of aconite toxicity. All patients were given supportive therapy and 4 patients who developed ventricular tachycardia received treatment with charcoal perfusion therapy. All patients fully recovered.[54] Charcoal hemoperfusion should be considered in patients with suspected aconite toxicity.

While the mainstream of USA conventional medical practitioners do not incorporate herbal medicine in their daily practice, it has been estimated that up to 70% of French and German physicians regularly prescribe herbal medical medication, along with more modern therapies.[3]

Whether or not USA conventional medical practitioners use herbal medicine in practice, the public is using over-the-counter herbal products. It should be the responsibility of health care professionals to be aware of herbal products and the effects that they can have on medications. One simple step to minimize adverse effects related to herbal medications is to simply ask patients about use of herbal products. New practitioners should have some knowledge of common herbal products. Health care professionals should educate patients on adverse effects and warning signs associated with herbal products. As more research is completed, more is elucidated about herbal products. These compounds may someday be part of conventional medical practice and it is important to understand their uses, adverse effects, and toxicities.[223]