HerbalEGram: Volume 14, Issue 3, March 2017

On September 27, 2016, WebMD, a leading online source of health-related information posted a slideshow titled “Herbal Supplements You Shouldn’t Try,” which highlighted potential safety concerns associated with 14 botanical ingredients.¹

The information provided was obtained from eight sources: the Cleveland Clinic²; a Harvard Health Publication on dietary supplement safety³; the Memorial Sloan Kettering Cancer Center⁴; websites of the National Center for Complementary and Integrative Health,⁵ the National Institute of Mental Health,⁶ and the National Kidney Foundation⁷; a highly criticized, error-filled, and discredited paper by Tachjian et al. (2010)⁸; and an out-of-date publication on herb-drug interactions by Cupp from 1999.¹⁰

While the title of the WebMD post implies that the 14 botanical ingredients listed (see Table 1) should never be used, the text about each herb lists potential adverse events and specific limitations for use of these botanicals (e.g., when underlying medical conditions or herb-drug interactions may make such use contraindicated). The title of the slideshow does not accurately reflect the information available regarding herb-drug interactions in this context.

Table 1. Botanicals Mentioned in WebMD Slideshow: Comparing Precautionary Statements*

Botanical	Precautions Listed by WebMD1	Precautions Listed by EMA Community Herbal Monographs and AHPA's Botanical Safety Handbook21,22
Aloe Aloe vera, Xanthorrhoeaceae)	Can cause an abnormal heart rhythm and may lower blood sugar levels in people with diabetes.	Can be safely consumed when used appropriately. Reported adverse events include contact dermatitis and rare cases of Henoch-Schönlein purpura [a disorder of the blood vessels]. No clinically relevant interactions to be expected. As a precautionary measure, other drugs should be taken one hour prior to consumption of Aloe vera leaf gel or several hours after consumption.20
Arnica Arnica montana, Asteraceae)	Oral consumption can raise blood pressure, increase heart rate, and cause shortness of breath. Can result in liver damage, coma, or death.	Cutaneous use only. Allergic reactions such as itching, redness of the skin, and eczema may occur. The frequency is not known. No known interactions with conventional drugs.10
Black Cohosh (Actaea racemosa, Ranunculaceae	May lower blood pressure, especially when consumed in large amounts. Should be avoided in people with liver problems.	Liver toxicity (including hepatitis, jaundice, and disturbances in the liver function tests) is associated with the use of Actaea-containing products. The frequency is not known. Skin reactions (urticaria, itching, and exanthema), facial edema, peripheral edema, and gastrointestinal symptoms (e.g., dyspeptic disorders and diarrhea) have been reported. The frequency is not known.11 No known interactions with conventional drugs.
Ephedra (Ephedra sinica, Ephedraceae)	May increase the chance of heart problems and strokes, and cause a rise in heart rate and blood pressure. Doctors also warn of possibly deadly interactions with many heart medicines. The US Food and Drug Administration [FDA] has banned ephedra as a dietary supplement, but it still can be found in some herbal teas.	Contraindicated in people with anorexia, bulimia, or glaucoma. Not for long-term use. The supervision of a health care practitioner is recommended for people with high blood pressure, heart or thyroid disease, diabetes, or difficulties in urination due to prostate enlargement. Interactions possible with monoamine oxidase (MAO) inhibitors and other prescription drugs.21†
Feverfew (Tanacetum parthenium, Asteraceae	Contains both potassium and phosphorus; people who have kidney disease should be careful with these minerals. May affect blood clotting, so feverfew may be an issue for people with heart disease or blood disorders.	Gastrointestinal disturbances have been reported. The frequency is not known. No known interactions with conventional drugs.21
Garlic (Allium sativum, Amaryllidaceae)	Safe for most people, but garlic can thin the blood, therefore increasing the risk of bleeding in patients taking anticoagulant medications.	Garlic consumption should be avoided seven days before surgery because of the post-operative bleeding risk.  Garlic preparations should be used with caution in patients taking oral anticoagulation therapy and/or anti-platelet therapy because they may increase bleeding times. Concomitant use with the antiretroviral drugs saquinavir and ritonavir is contraindicated because of the risks of decrease in plasma concentration, loss of virological response, and possible resistance to one or more components of the antiretroviral regime.13
Ginger (Zingiber officinale, Zingiberaceae)	Can cause problems with blood clotting, heart rhythms, blood pressure, and blood sugar levels. Avoid in people with gallstones and in those who take blood thinners.	Minor gastrointestinal complaints, particularly stomach upset, eructation, dyspepsia, and nausea have been reported with a frequency of 1-10%. No known interactions with conventional drugs.14
Ginkgo (Ginkgo biloba, Ginkgoaceae)	Can thin the blood and cause bleeding, which is especially risky for those taking blood thinners.	If taken concomitantly with anticoagulants (e.g., phenprocoumon and warfarin) or anti-platelet drugs (e.g., clopidogrel, acetylsalicylic acid, and other non-steroidal anti-inflammatory drugs), their effect may be influenced.15
Ginseng (Panax ginseng, Araliaceae)	May lead to a drop in blood sugar, so it can cause issues for people with diabetes. Should not be taken by patients who have high blood pressure or take blood thinners.	Hypersensitivity reactions (urticaria and itching), insomnia, and gastrointestinal disorders (e.g., stomach discomfort, nausea, vomiting, diarrhea, and constipation) have been reported. The frequency is not known. No known interactions with conventional drugs.16
Goldenseal (Hydrastis canadensis, Ranunculaceae)	Can affect heart rhythm and raise or lower blood pressure. Should be avoided in people with heart problems.	No cases of adverse events have been reported with the use of goldenseal. Goldenseal may slow the metabolism of drug substances influenced by CYP3A4. Such drugs include ciclosporin, tacrolimus, tamoxifen, paclitaxel, ketoconazole, erythromycin, imipramine, sertraline, citalopram, benzodiazepines, lovastatin, simvastatin, sildenafil, indinavir, salmeterol, propranolol, and many others.20
Kava (Piper methysticum, Piperaceae)	May cause liver damage (e.g., hepatitis) and can be dangerous if taken with alcohol or other depressants/sedatives.	Kava has been associated with rare but severe liver injury. Concomitant use of kava and alcohol may produce additive inhibition of cognitive and motor function. Kava may slow the elimination of drug substances for which the metabolism is influenced by CYP2E1. Such drugs include paracetamol, halothane, zopiclone, and others.20
Licorice (Glycyrrhiza glabra, G. inflata, G. uralensis, Fabaceae)	Can raise blood pressure and cause issues with heart rhythms. It also can cause problems for people with kidney disease.	Patients taking licorice medication should not take other licorice-containing products as serious adverse events, such as water retention, hypokalemia, hypertension, and cardiac rhythm disorders, may occur. Licorice medication is not recommended for patients affected by hypertension, kidney diseases, liver or cardiovascular disorders, or hypokalemia, since they are more sensitive to the adverse effects of licorice. Concomitant use with diuretics, cardiac glycosides, corticosteroids, stimulant laxatives, or other medications that may aggravate electrolyte imbalance is not recommended. Licorice root may counteract antihypertensive action of prescribed medications.17
Nettle (Urtica dioica, U. urens, Urticaceae)	To be avoided in people who retain fluid because of heart or kidney problems, and in those who take diuretics.	Gastrointestinal complaints such as nausea, heartburn, feeling of fullness, flatulence, or diarrhea may occur. The frequency is not known. Allergic reactions (e.g., pruritus, rash, and urticaria) may occur. The frequency is not known. No known interactions with conventional drugs.18
St. John's Wort (Hypericum perforatum, Hypericaceae)	Can cause side effects such as headache, nausea, dizziness, and dry mouth, and may increase likeliness to get sunburned. Can cause problems for those who take certain drugs — from heart medicines to antidepressants, birth control pills — and can make chemotherapy less effective.	Gastrointestinal disorders, allergic skin reactions, fatigue, and restlessness may occur. The frequency is not known. Fair-skinned individuals may react with intensified sunburn-like symptoms under intense sunlight. The concomitant use of cyclosporine, tacrolimus for systemic use, amprenavir, indinavir and other protease inhibitors, irinotecan, and warfarin is contraindicated. Special care should be taken with concomitant use of drug substances in which their metabolism is influenced by CYP3A4, CYP2C9, CYP2C19, or P-glycoprotein. Such drugs include amitriptyline, fexofenadine, benzodiazepines, methadone, simvastatin, digoxin, and finasteride.19

* Cautionary statements regarding use during pregnancy and lactation are not listed in this table.

† These statements are from the first edition of AHPA’s Botanical Safety Handbook from 1997.²⁰ The second edition²¹ does not feature information about Ephedra sinica since it was banned in the United States in 2004.

There are a number of botanical ingredients on this list that have a long history of safe use and a low risk of adverse side effects. Suggesting that these ingredients should not be consumed defies common sense and — in some instances — guidelines provided by medical associations themselves. A critical evaluation of the statements in this post will be performed below using feverfew, garlic, ginger, and Asian ginseng as examples.

Feverfew

Feverfew is a popular herb used for the prevention of headaches. It is not clear on what basis WebMD chose to include feverfew as an ingredient to avoid for people with kidney disease due to its phosphorus and potassium contents. Both phosphorus and potassium are minerals that are common in plants and occur in most foods, particularly meat and dairy products. The concentrations of potassium and phosphorus in dried, powdered feverfew are listed as 5 mg/g and 22.5 mg/g, respectively.²² For comparison, one medium tomato contains 30 mg of phosphorus and 292 mg of potassium, and a cup of strawberries contains 35 mg of phosphorus and 220 mg of potassium.²³ Patients with kidney disease are unable to properly eliminate phosphorus and potassium and must limit their intake to avoid dangerously high levels of these minerals. Dietary supplements containing crude herbal ingredients are expected to contain some phosphorus and potassium, and therefore the same cautionary statements are applicable for other herbal dietary ingredients in patients with kidney disease.

The use of feverfew is considered generally safe. According to a systematic review from 2015, adverse events observed in clinical studies were overall mild and reversible.²⁴ The most common adverse events were gastrointestinal problems but a wide range of adverse events in the feverfew and placebo groups were reported. In long-term users of feverfew, a high incidence of pains, stiffness in joints and muscles, as well as nervousness, anxiety, and poor sleep was reported. These effects, occurring together with a rebound of migraine symptoms, are said to constitute “post-feverfew syndrome.”

A number of in vitro studies reported that feverfew extracts may inhibit platelet aggregation.^25-27 However, there were no clinically relevant effects observed in a clinical study that evaluated feverfew consumption and its impact on platelet aggregation.²⁸ Other clinical studies also suggest that feverfew does not affect blood pressure, heart rate, body weight, or hematological and biochemical safety parameters.²⁴ Based on the available data, problems with blood clotting related to use of feverfew appear to be more of a theoretical concern rather than an actual problem with clinical relevance.

Garlic

Garlic is widely used as a spice, flavoring, and food product. A United Nations Food and Agriculture Organization (FAO) report in 2011 indicated that the daily per capita consumption worldwide was 567 grams of garlic.²⁹ Garlic is also well known for its long history of use as an herbal remedy. It is taken medicinally for symptoms of the common cold, and is considered safe when consumed appropriately.²⁰ It is also used as adjuvant therapy for the prevention of atherosclerosis.

Garlic’s anticoagulant properties, which the WebMD post mentions as a concern, have been investigated in a number of clinical studies.^30-36 Results from these studies are mixed, but they suggest that garlic has a mild platelet-inhibitory effect. In healthy volunteers, ingestion of 10 grams of garlic per day for two months led to a decrease in clotting time from 5 minutes to 4.1 minutes.³⁷ The literature cited in the WebMD post relies on a number of case reports that have linked garlic intake to a risk of increased bleeding. One case report describes an 87-year-old man who developed a spontaneous postoperative hematoma. The patient had a habit of consuming four cloves of garlic per day.³⁸ In the other two case reports, the ingested amount of garlic was not stated. One report involved a 32-year-old female with prolonged postoperative bleeding,³⁹ and the other described a 72-year-old man who also experienced postoperative bleeding.⁴⁰ Causality between garlic intake and increased coagulation time was not established in any of these case reports.

A report of increased anticoagulant effects of warfarin have been described in two patients taking garlic supplements⁴¹; however, subsequent clinical studies suggest that patients taking warfarin may not need to be placed on a garlic-free diet.^42,43 The potential of garlic to interact with warfarin was investigated in an open-label, randomized, crossover clinical trial. It involved 12 healthy male subjects who received a single dose of 25 mg of warfarin alone or after two weeks of pretreatment with garlic twice per day (one tablet of Garliplex 2000 [Golden Glow Pty Ltd.; Virginia, Queensland, Australia], containing 2000 mg of fresh garlic corresponding to 3.71 mg of allicin). Warfarin concentrations, international normalized ratio (INR), platelet aggregation, and clotting factor activity were measured to assess pharmacokinetic and pharmacodynamic interactions. No significant alterations of warfarin pharmacokinetics or pharmacodynamics were observed after co-administration of garlic.⁴² In another study, 48 patients taking anticoagulant medication with warfarin received either 5 mL of aged garlic extract (Kyolic, provided by Wakunaga; Mission Viejo, California) or placebo for 12 weeks. Bleeding and potential thromboembolic incidents were monitored. No significant differences in adverse events were observed between the garlic treatment group and the placebo groups.⁴³

Based on the available data, a recommendation to avoid consumption of garlic seven days prior to surgery is warranted in order to avoid possible bleeding problems. A clinically relevant interaction between garlic and warfarin has not been established.

Ginger

In herbal medicine, ginger root is known for the symptomatic relief of motion sickness, nausea, and for the treatment of mild gastrointestinal complaints, such as spasms, bloating and flatulence. According to the FAO, global production of ginger reached 2.14 million metric tons in 2013.⁴⁴ Minor gastric complaints are known adverse effects from ginger ingestion (Table 1).

The effects of ginger administration on platelet aggregation in humans were discussed in a systematic literature review by Marx et al.⁴⁵ The review included data from eight clinical trials and two observational studies. The clinical studies were generally small (7-36 participants), with the exception of the study by Bordia et al., in which 60 patients participated.⁴⁶ Seven studies used dosages between 3.6-5 g of ginger per day, while one cross-over study had higher amounts (10 g or 40 g per day). The results of the six studies that measured platelet aggregation are conflicting, and only one study reported an inhibitory effect on platelet aggregation at the 3.6-5 g dosage range.⁴⁷ However, a significant inhibition of platelet aggregation was reported in patients with coronary artery disease after receiving a single dose of 10 g.⁴⁶ Conflicting results were also reported in the two clinical studies that measured thromboxane B2 production. Thromboxane B2 is a metabolite of thromboxane A2, which is involved in platelet aggregation.^48,49 Marx et al. also included two observational studies in the systematic review,^50,51 in which people who were prescribed warfarin were asked to report bleeding episodes and factors that could influence these episodes. Ginger consumption was one of the dietary factors that were included in the study, but the results of the two studies were inconclusive.⁴⁵

Based on the available data, the effects of ginger on platelet aggregation are unclear. A clinically relevant blood-thinning effect may be expected at dosages above 5 g,⁴⁵ which is above the recommended adult dosage for gastrointestinal complaints (180 mg of ginger three times per day), or for motion sickness (750 mg half an hour before traveling).¹⁴

The recommendation to avoid ginger in patients with gallstones, as mentioned by the WebMD post, is due to the ability of ginger to increase bile flow, which was observed in rats given acetone ginger extracts or a commercially available spice preparation of ginger.^52,53 It is an area of concern that increased bile flow could detach existing gallstones and therefore possibly obstruct the bile duct, commonly leading to severe pain, nausea, and jaundice. It is recommended to consult with a physician to determine if ginger intake is appropriate for patients with gallstones.²⁰

The blood sugar-lowering effects of ginger have been subject of a small number of clinical trials. Ginger (4 g daily for three months) did not show any effects on blood glucose in patients with coronary artery disease.⁴⁶ However, according to a systematic review that included five clinical studies that evaluated the effects of ginger intake in patients suffering from type 2 diabetes, the ingestion of powdered dry ginger (1,600-3,000 mg daily for 30 days to 12 weeks) resulted in lower fasting blood glucose (-18.7 mg/dL on average) and decreased glycated hemoglobin levels.⁵⁴ This suggests that diabetic patients should be cautious with their ginger intake when taking conventional antidiabetic medications, and monitor blood sugar levels in order to avoid hypoglycemic conditions.

Asian Ginseng

There are a number of different plant species in commerce that are traded as “ginseng.” According to the second edition of the AHPA’s Herbs of Commerce, Asian ginseng (Panax ginseng), Japanese ginseng (Panax japonicus), tienchi or sanchi ginseng (Panax notoginseng), and American ginseng (Panax quinquefolius) each have separate common names to avoid confusion. Additionally, the name “Siberian ginseng” is used commercially for eleuthero (Eleutherococcus senticosus, Araliaceae), and marketers have used the term ginseng for other plants (e.g., “Indian ginseng” as a common name for ashwagandha [Withania somnifera, Solanaceae] and “Peruvian ginseng” for maca [Lepidium meyenii, Brassicaceae]).⁵⁵ The WebMD post does not specify the species of ginseng, and this may mislead the reader into believing that all plant species sold as “ginseng” have the same possible adverse events, contraindications, and interactions. Although the image accompanying the text suggests that the plant in question is Asian ginseng, it is highly unlikely that an interested health care practitioner will be able to identify to which species the article refers based on the picture of a root.

Asian ginseng root is used to boost energy and for symptoms of asthenia such as fatigue and weakness. The usefulness of Asian ginseng as an adjuvant therapy in patients with diabetes has been the subject of a number of clinical trials, and has been evaluated in several systematic reviews.^56-59 Overall, there is evidence to support of mild decrease in fasting plasma glucose levels after Asian ginseng intake in patients with type 2 diabetes; however, no significant differences between treatment and placebo were found for any of the other measured parameters, such as the oral glucose tolerance test (OGTT), the homeostasis model assessment insulin sensitivity index (HOMA-ISI), or hemoglobin A1c (HbA1c).^56,57 In addition, the inclusion of American ginseng in two of the reviews^56,59 and the variability of the treatment (dosage and manufacturing process) make it difficult to make a general statement on the impact of Asian ginseng in diabetic patients. As a precautionary measure, the use of Asian ginseng in people with diabetes is best done under the supervision of a physician, and by appropriately monitoring plasma glucose levels.

Cautionary statements about the concomitant use of Asian ginseng and blood-thinning medications are based on two case reports in which patients using warfarin experienced a decrease in blood clotting.^60,61 In one case, a 47-year-old man had received warfarin to prevent embolic events. Other medications included diltiazem hydrochloride for hypertension, nitroglycerin for chest pain, and the non-steroidal anti-inflammatory drug salsalate (a derivative of salicylic acid) as needed. Four weeks prior to taking the Asian ginseng capsules, his INR was 3.1, but within two weeks after the patient started taking ginseng, his INR declined to 1.5. Asian ginseng use was discontinued, and the INR returned to 3.3 in two weeks.⁶⁰

In the second case report, a 58-year-old man was hospitalized because of an anteroseptal myocardial infarction and diabetic ketoacidosis. Upon arrival, his INR was 1.4. According to the patient’s history, his INR had been stable up to three months prior to the hospital admission. The unsteady INR was attributed to the intake of a commercial “ginseng” preparation that was obtained abroad (no further details on the preparation were given by the authors).⁶¹ Considering the absence of details on this case, the lack of knowledge about the exact product used, and particularly the use of the common name “ginseng” for a number of different plant species,⁵⁵ causality between Asian ginseng intake and the low INR number cannot be established.

Subsequent studies in healthy people with dosages of 1-3 g per day for up to six weeks,^62-64 in patients with cardiac valve replacement⁶⁵ (1 g per day for six weeks) and in ischemic stroke patients⁶⁶ (1.5 g per day for two weeks) did not find any effects of Asian ginseng on the pharmacokinetics and pharmacodynamics of warfarin. Overall, the evidence linking Asian ginseng to a clinically relevant interaction with warfarin is insufficient.⁶⁷

Conclusion

The safety record of most herbal dietary supplement ingredients is excellent. Nevertheless, there are situations in which a dietary supplement is contraindicated or in which clinically relevant interactions are known. It is important for health care practitioners and consumers to understand the adverse event potential of dietary supplement ingredients and to be aware of contraindications and herb-drug interactions. In the digital age, databases such as WebMD play an important role in accessing such information quickly and (one presumes) reliably. WebMD, which is one of the most widely visited databases for consumers, physicians, health care professionals, and others with an interest in health care, has a responsibility to provide information that is thoroughly researched, appropriately vetted (e.g., peer reviewed by experts knowledgeable about the clinical effects and safety of herbs), and unbiased.

The suggestion that patients should not try ingredients like aloe, garlic, ginger, Asian ginseng, or nettle is completely misleading, and may discourage people from appropriately and responsibly using these ingredients as part of their regular diet and health regimens. As shown by the examples of feverfew, garlic, ginger, and Asian ginseng, it is important to consider all the scientific and available therapeutic literature, and evaluate the appropriateness of an ingredient’s use on a case-by-case basis.

—Stefan Gafner, PhD

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