Herbal Supplements

Physicians closely monitor patients taking prescription medications that alter bleeding, because the effects of these medications are known. Unfortunately, patient use of OTC medications that alter bleeding, including the use of dietary supplements, is not supervised as closely, especially since many patients do not report taking these medications. In fact, use of any form of alternative medicine is not disclosed to health care providers over 60% of the time.17

A study in England documented that a significant number of patients may be co-ingesting herbal medicines with warfarin. One thousand three hundred and sixty patients from 35 different medical practices were surveyed about the use of garlic, ginseng, ginkgo biloba, feverfew, ginger, and St. John’s wort. One hundred and nineteen patients (8.8% of the respondents) reported taking one or more of these herbs. When asked if they had discussed their herbal use with any health care professional, 92.2% reported that they had not. The authors concluded that all general practitioners prescribing warfarin should always ask about the use of herbal medications. They also added that there are risks involved with any herbal preparations, and charged that physicians, as well as their patients, share a joint responsibility to discuss potential herb-drug interactions.94 Dental professionals are also well positioned to help patients understand the vital nature of this type of disclosure along with responsible product use.

Both the desired and adverse effects caused by prescription medicines are predictable, as they are manufactured and tested according to exacting standards. The effects of herbal phytotherapies, including adverse reactions, are hard to foresee. The FDA does not regulate herbal product manufacturing, nor is safety testing required, so it is challenging to find documented safety and efficacy information. However, the popularity of these products has dictated the need for further study to gain a better understanding of how herbs affect the body, and significant improvements in both herbal manufacturing and research have occurred in recent years.

Unlike prescription drugs, individual herbal preparations are often a mixture of more than one active ingredient. Thus, it is difficult to determine which or how many constituents of the herbal product are pharmacologically important. In addition, comparable herbal products vary in formulation, and their undefined composition makes analysis of the active constituents extremely complex.95 This further confounds the understanding and utility of findings gleaned from research studies about the effects of herbal drugs.

Ciocon and colleagues have stated “that certain herbals have been associated with increased risk of bleeding by inhibiting platelet function, platelet aggregation and thromboxane synthesis, thrombin and thromboplastin mechanisms, and by those which contain coumarin-like effects, and salicylate-like effects.”96 They propose a mnemonic of a “Few G’s” to help health professionals remember a list of herbs that are known to alter bleeding. The Few G’s include feverfew, plus ginkgo biloba, ginger, garlic and ginseng. They add that when the “g” is followed by a vowel (eg, ginkgo), the herb is associated with this adverse effect. When an herb that starts with the letter “g” is followed by a consonant (eg, green tea), there is not a concern for bleeding.96 This mnemonic can also be used to remember the herbs that are most likely to interact with anticoagulant and antiplatelet agents.

It is important to note that other herbal products have been implicated in causing adverse bleeding effects as well (Table II).29 However, this article will focus on 5 herbs that are widely used and have some scientific evidence to support the effects described here.

Garlic Allium sativum
Recommended Dosage for general use: Extract, aged: 4 ml daily; Fresh: 4 g daily; Oil: 10 mg daily

Garlic is a perennial bulb with reported uses as an antilipidemic, antimicrobial, anti-asthmatic and anti-inflammatory. The bulb contains aliin and degradation products such as allicin, polysulfides, ajoenes, mercaptanes, thioglycosides, thiosulfinates, adenosine, and selenium.97 The primary chemical components that have been implicated in bleeding include volatile oil and ajoene. The antiplatelet effect of garlic has been demonstrated by studying some of its pure isolated components on human platelet aggregation. Ajoene apparently functions as the chemical component responsible for these effects.98 Ajoene is an unsaturated sulfoxide disulfide and is a component of allicin, a sulfinyl compound that gives garlic its strong odor and flavor. Like aspirin, the effect of ajoene appears to be irreversible, which lasts for the life of the platelet, and may potentiate the effect of other platelet inhibitors.20 Several sulfur-containing compounds isolated from garlic have also demonstrated significant inhibition of human platelet aggregation.99

Garlic oil exerts its effects on the arachidonic acid pathway (Figure 1). Garlic interrupts the synthesis of thromboxane, and stimulates the synthesis of prostacyclin. By reducing thromboxane and increasing prostacyclin, garlic decreases platelet aggregation and increases bleeding. Further, garlic inhibits platelet aggregation in a dose-dependent fashion. Case reports support that both dietary garlic and garlic supplements demonstrate these effects.100 Further, the constituents of garlic, particularly alliin/allicin, also inhibit the production and/or release of chemical mediators such as platelet-aggregating factor and adenosine, which decreases platelet function.101 Interestingly, many herbalists feel that the best quality, most consistent, and strongest source of allium sativum is the natural garlic clove itself.

Harenberg and colleagues (1988) studied the effects of dried garlic intake on blood coagulation, fibrinolysis, platelet aggregation, serum cholesterol levels and blood pressure in 20 patients with hyperlipoproteinemia. During a 4-week study period, subjects received 600 mg (200 mg bid) of dried garlic in a sugar-coated pill. After 4 weeks of garlic use, both fibrinogen and fibrinopeptide A levels significantly decreased by 10%. Streptokinase-activated plasminogen and fibrinopeptide B beta 15-42 significantly increased by 10%. Serum cholesterol levels significantly decreased by 10%, and both systolic and diastolic blood pressure decreased.102

In another in vivo study, 6 subjects were given 5.0 g of crushed garlic bulbs daily for a 3-week study period. Fasting blood samples were taken at baseline and at weekly intervals to assess the level of serum triglycerides. Results showed that the addition of garlic in the diet resulted in significantly lower levels of serum triglycerides and an increase in blood fibrinolytic activity by the end of the second and third weeks.103

Case reports in the literature also suggest that ingesting garlic while taking warfarin (Coumadin®) may result in over-anticoagulation. One case report documented that the INR of a previously stabilized patient on warfarin had more than doubled and that hematuria occurred 8 weeks after commencement of ingesting 3 garlic tablets a day.97 Izzo and Ernst (2001) cite 2 case reports suggesting that the concomitant use of warfarin and garlic resulted in an increased INR.95 It is evident that this popular herb has the potential to cause adverse bleeding effects.

Ginkgo Ginkgo biloba
Recommended Dosage for general use: Standardized extract: 40 mg tid

Ginkgo is a tree native to Asia and is now also found in the United States. The primary use of ginkgo is to prevent decreased cerebral functioning and peripheral vascular insufficiency associated with Alzheimer’s disease or age-related dementia. Other reported uses are summarized in Table III.

Components of ginkgo include flavonoids (ginkgo-flavones) and terpenoids (ginkgolides and bilobalide). The ginkgo leaf is processed and often standardized to 24% ginkgo flavonglycosides and 6% trilactones (terpene lactones). The primary chemical component that has been implicated in bleeding is the terpene ginkgolides. Ginkgolides, a terpene lactone, are potent and specific platelet activating factor (PAF) antagonists. Their effects are long lived and are rapidly established after oral dosing.104 Ginkgolide B, one component of ginkgo, inhibits platelet activating factor by displacing it from its receptor binding site, resulting in reduced platelet aggregation.105 In laboratory tests, ginkgo increases prothrombin time (PT), and blood salicylate levels, and may decrease platelet activity.106

Ginkgo holds particular interest to the baby boomer and geriatric populations as its cerebral and vascular benefits continue to be researched. Whereas earlier and better known research focused on older and cognitively impaired individuals, a recent review in Herbalgram provided a comprehensive report of its successes with “healthy and cognitively intact adults.” Both short- and long-term studies resulted in positive benefits of ginkgo in the improvement of processes such as memory, attention, and speed of processing.107

Case reports document dangerous bleeding episodes following the regular use of ginkgo: intracranial bleeding (4 cases), spontaneous hyphema (hemorrhage within the anterior chamber of the eye) (1 case), and postoperative bleeding after cholecystectomy (1 case).96 One of these reports occurred when a 70-year-old man presented with bleeding from the iris into the anterior chamber of the eye just 1 week after beginning a self-prescribed regimen of a concentrated ginkgo extract twice daily. He was also taking 325 mg of aspirin daily and had done so for 3 years. It is interesting to note that when he discontinued taking the ginkgo, but not the aspirin, the bleeding resolved. There was no recurrence of bleeding 3 months later.108

Another case is a 61-year-old man who developed subarachnoid hemorrhage after consuming 40 mg of ginkgo 3 or 4 times per day for more than 6 months. No other medication was used. The patient’s bleeding time increased to 6 minutes but normalized to 3 minutes within 4 months after discontinuing the ginkgo.109

A systematic review by Izzo and Ernst discusses 2 case reports documenting that patients taking warfarin and aspirin had experienced severe spontaneous bleeding after self-prescribing ginkgo at recommended doses.95 A fatal intracerebral mass bleeding was reported in a 71-year-old man who had taken ginkgo in conjunction with ibuprofen. He was previously in excellent health. He had been taking ginkgo for 2 ½ years for self-reported dizziness and had added ibuprofen 600 mg daily for osteoarthritis of the hip just 4 weeks prior to his death.110 This is a good example of an otherwise healthy older patient self-medicating with fatal consequences.

A 40-year-old woman was admitted to the hospital with an acute subdural hematoma with no history of head trauma, falls, alcohol abuse, or bleeding disorders. Her hematoma was evacuated via burr holes, yet her blood results, especially the INR, were difficult to stabilize. After treatment and questioning, it was revealed that she had been taking 40 mg of ginkgo twice daily for the past 2 months to “assist her while studying.” Disturbingly, her family continued to give her the herb while in the hospital, stating that they were “just herbs.” Once the herb was discontinued, the blood results returned to normal.97

Clearly, ginkgo has tremendous potential for causing bleeding complications, and with its broad range of claimed benefits, the use of this herb is attractive to many. With a growing geriatric population and baby boomers wishing to preserve cognitive function, it is safe to expect use of this herb to increase.

Ginseng Panax quinquefolius Panax ginseng
Recommended dosage for general use: Capsules: 200-500 mg extract daily; Powdered root: 1-4 g daily; standardized extract: 200-500 mg daily; Tincture: 1-2 ml extract daily (1:1 dilution)

Ginseng is one of the most popular, well-known, and valued herbs worldwide. Panax Ginseng has been used medicinally in Asia for more than 5000 years and, in China, it is more highly valued than gold.111 The Chinese believe that ginseng can fight cancer, slow aging, protect one against heart attack and other sudden illnesses, strengthen digestion, and reduce high blood pressure, among numerous other benefits.112 The Asian population is significant in the United States. According to the US Census 2000, almost 12 million Asians are living in the United States, and the Asian population increased faster than the total population between 1990 and 2000.113 With the increasing interest in both alternative medicine and traditional Chinese medicine, the use of ginseng will continue to be strong by a large segment of the population.

The word Panax is derived from the Greek word for panacea, as the herb is considered a cure-all, ie, good for all parts of the body. In fact, the plant itself resembles a human figure. According to Chinese sages, ginseng replenishes vital energy, increases production of vital body fluids, and promotes health and longevity. This is the concept of a tonic or adaptogen, which our culture has little understanding of.

Standardized ginseng extracts contain 5% ginsenosides, an aglycone chemical component believed to act as a stimulant. Ginsenosides act on the hypothalamus-pituitary-adrenal cortex axis, stimulating the secretion of adrenocorticotropic hormone (ACTH), which increases production of the adrenal hormones (eg, cortisol, sex hormones, aldosterone). Thus, ginseng produces central nervous system (CNS) stimulating effects, estrogen-like effects, and elevates blood pressure.29 Ginseng is also thought to restore and strengthen the body’s immune response, and promotes growth of normal cells.104

The ginsenosides are also believed to have the potential to inhibit platelet-activating factor.106 Ginseng has been reported to inhibit platelet-activating factor (PAF), platelet aggregation, thrombin and thromboplastin, and can cause further bleeding when combined with aspirin, heparin, warfarin, and non-steroidal anti-inflammatory drugs.114,115

There are only a few kinds of “true” ginsengs in the botanical genus Panax. There are other plants that are in the ginseng family, but they are more distantly related to ginseng botanically, such as eleuthero or Siberian Ginseng. These other ginsengs affect the body in similar ways. They are not as powerful as “true” ginsengs, but they are less costly. True ginsengs in the Panax category include: Oriental, Chinese, Korean and American ginseng.112

The effects of ginseng are supported by hundreds of laboratory experiments, but there are very few controlled human studies.112 Two laboratory studies assessed the potential for ginseng to cause bleeding. Chung and colleagues (1987) examined the effect of a ginkgolide mixture (BN 52063) in antagonizing skin and platelet responses to PAF in human subjects. The ginkgolide significantly inhibited PAF-induced platelet aggregation in platelet-rich plasma (p< 0.001). The researchers concluded that the BN 52063 “seems to be an antagonist of PAF in man.”105

There is some research to suggest that Oriental ginseng (Ginsana) may antagonize the anticoagulant effects of warfarin. In 1 case report, the INR of a 47-year-old man who had been receiving warfarin for 9 months (7.5 mg every Tuesday and 5 mg on all other days) to prevent thrombotic complications associated with a mechanical heart valve was stabilized at 3.9 – 4.0. The patient began taking Oriental ginseng, and within 2 weeks, his INR fell to 1.5. The patient denied any other changes in his medication regimen, including the use of other nonprescription or herbal products, diet, alcohol consumption, or other lifestyle factors that may have affected his response to warfarin. The patient’s INR returned to therapeutic level (3.3) 2 weeks after he stopped using ginseng.116

Ginseng possesses a paradoxical effect. Despite ginseng’s anticoagulant potential, it has been noted to decrease the effectiveness of warfarin. Yuan and colleagues (2004) conducted a study with 20 healthy volunteers to assess this potential drug-herb interaction. Subjects had no medical conditions requiring warfarin, nor had they taken warfarin or ginseng. During the 4-week study period, all of the volunteers were given warfarin. During the second week, the researchers randomly assigned each volunteer either a placebo or ginseng, taken in addition to the warfarin. Subjects had their blood clotting times tested using the INR. Results of the study revealed that the subjects taking ginseng had lower blood levels of warfarin, thus compromising anticoagulation.117

As previously stated, ginseng increases the production of adrenal hormones, including the sex hormones, leading to estrogen-like effects. There is a case report of postmenopausal bleeding that was attributed to the use of topical ginseng. A 44-year-old woman used a ginseng face cream from China in the hopes of relieving some post- menopausal symptoms. After using the cream, she experienced 2 episodes of spotting and her follicle-stimulating hormone (FSH) dropped significantly. After one month of discontinuing the product, the bleeding stopped and her FSH returned to previous levels. The authors concluded that ginseng appeared to have an estrogen-like effect on genital tissues.118 With its broad range of claimed benefits from increased physical endurance to improved ability to cope with stress, it seems reasonable to expect that all ginsengs will continue to be a popular choice in an increasingly fast-paced society.

Ginger Zingiber officinale
Recommended dosage for general use: Dried ginger capsules: 1 g/day; Dried root equivalent: 500mg bid-qid; Fluid extract: 0.7-2ml/day (1:2 dilution); Tablets/caps: 500 mg bid-qid; Tincture: 1.7-5 ml/day (1:5 dilution)

Ginger is primarily used to relieve motion and morning sickness, and preliminary research documents its efficacy in decreasing pain and inflammation associated with arthritis and other joint disorders.106 Traditionally, in herbal folklore, ginger is best known for settling upset stomachs. The major constituents of ginger are pungent principles (gingerol, shogaol, zingerone), volatile oils (bisabolene, zingiberene, zingiberol), and proteolytic enzymes. Many people consider ginger to be a root, but it is actually a rhizome. Zingiber comes from the Sanskrit word for ginger, singabera, meaning “shaped like a horn.”119

The research on ginger is mixed and limited to a few case reports, small scale in vivo studies and some in vitro studies. In one laboratory test, aqueous ginger extract reduced platelet thromboxane and also inhibited platelet aggregation.120 In a small study of 8 healthy male volunteers, subjects ingested either 2 grams of dried ginger in capsule form or a placebo. Bleeding time, platelet count, thromboelastography, and whole blood platelet aggregometry were performed before, 3 hours, and 24 hours after ingestion. It was concluded that the effect of ginger on thromboxane synthetase activity was dose dependent and only occurs with fresh ginger, and that up to 2 grams of dried ginger is unlikely to cause platelet dysfunction when used therapeutically. Data obtained from case reports and studies with very small sample sizes (eg, N=7) suggest that ginger’s antiplatelet effect exists with raw ginger only. For example, in one case report, an unspecified amount of marmalade with 15% raw ginger was consumed leading to inhibition of platelet aggregation. One week after discontinuing ginger, platelet function was described as spontaneously returning to normal.121 It is important to note that these are very small sample populations, and additional study is needed to further define the effects of ginger on platelet function.

Despite the lack of substantial evidence, ginger continues to be included in published literature reviews that detail the ability of herbal therapies to increase clotting time either alone or together with another herb or prescription drug.96,114,122 Further, as one of the “few G’s,” health care professionals need to be aware of the potential for adverse bleeding events.

St John’s wort Hypericum perforatum L
Recommended Dosage for general use: 300 mg hypericum extract, standardized to 0.3% hypericin, tid

St John’s wort is a popular herb used to manage mild to moderate depression. Depression is a silent health threat and statistics from the NIH indicate the highest risk is among middle-aged adults, aged 45 years to 64 years.123 Depression is considered to be of epidemic proportion among adolescents in the United States, and is more common in women. This herb is one of few herbs with a significant body of research to support its efficacy. Given its popularity and numerous adverse effects, there are significant risks associated with undisclosed usage among patients.

St John’s wort has had a colorful history. Ancient Europeans believed it had magical protective powers against disease and evil. Ancient herbalists from Hippocrates to Dioscorides valued St John’s wort not only for the treatment of “melancholia” and other emotional disorders, but also for burns, wounds (especially those involving nerve injuries), neuralgia or nerve pain, inflammation, ulcers, and more. Today, it is used as an antidepressant. The major constituents of the herb include: hypericin, hyperforin, pseudohypericin, flavonoids, xanthones, and essential oils.

A meta-analysis of 23 randomized European clinical investigations involving a total of 1757 patients concluded that standardized St. John’s wort extract was significantly more effective than placebo and just as effective as standard antidepressant medications in the treatment of mild or moderate depression.119 Since 1998, 7 case reports were received by the Medical Products Agency (MPA) in Sweden that demonstrated a reduced anticoagulant effect of warfarin (decreased INR) associated with the concomitant use of St John’s wort. This is the opposite of the other herbal interactions previously discussed, and is actually more dangerous, as the effect would be to potentially increase clotting. The reduced anticoagulation effect of warfarin is likely caused by induction of the liver enzyme cytochrome P450 2C9, which increases the metabolism of warfarin, thus decreasing its effect.124 None of the patients in these studies developed thromboembolic complications, but the decrease in INR was thought to be clinically significant. The INR returned to target values either after the warfarin dose was increased or the St John’s wort was withdrawn.

The induction reaction of hepatic cytochrome P450 has been attributed to the hypericum extracts from St. John’s wort, which may double the metabolic activity of the liver, and thus reduce the effects of many drugs. 125 For example, use of St John’s wort (900 mg per day of hypericum extract LI160) resulted in a significant decrease of digoxin when compared to placebo in subject taking 0.25 mg of digoxin per day.126 Digoxin is a drug that is used for the treatment of congestive heart failure and various types of arrhythmias.29 It is easy to see that the adverse metabolic effects of this herb can cause many significant complications in patients with heart disease.

The National Center for Complementary and Alternative Medicine is studying the effects of St John’s wort for a wide spectrum of mood disorders. Positive research findings will likely lead to renewed interest in this herbal remedy.