INTERACTIONS September 2009 An Evidence-based Systematic Review of Ginseng Interactions by the Natural Standard Research Collaboration
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INTERACTIONS September 2009 An Evidence-based Systematic Review of Ginseng Interactions by the Natural Standard Research Collaboration Authors/Editors: Catherine Ulbricht, PharmD (Massachusetts General Hospital); Ethan Basch, MD (Memorial Sloan-Kettering Cancer Center); Ashley Brigham, PharmD (Northeastern University); J. Kathryn Bryan, BS (Natural Standard Research Collaboration); Dawn Costa, BA, BS (Natural Standard Research Collaboration); Cynthia Dacey, PharmD (Northeastern University); Ivo Foppa, MD, ScD (University of South Carolina); Nicole Giese, MS (Natural Standard Research Collaboration); Ernest B. Hawkins, MS, BSPharm (Health Education Resources); Julie K. Montalbano, PharmD (Massachusetts College of Pharmacy); Shaina Tanguay-Colucci, BS (Natural Standard Research Collaboration);); Minney Varghese, BS (Northeastern University); Mamta Vora, PharmD (Northeastern University); Wendy Weissner, BA (Natural Standard Research Collaboration). Brief background The term ginseng refers to several species of the genus Panax (Latinized from Greek: pan=all and akos=cure) of the Araliaceae family. Although ginseng may also refer to Siberian ginseng (Eleutherococcus senticosus), Siberian ginseng is from another botanical family that differs considerably chemically and pharmacologically. Therefore, Siberian ginseng cannot be considered interchangeable with the Panax ginsengs (1). For more than 2,000 years, the roots of slow-growing perennial Panax plants have been valued in Chinese medicine for their invigorating (2), adaptogenic, and tonic properties (3; 4; 5). The two most commonly used species of ginseng are Asian ginseng (Panax ginseng C.A. Meyer), which is mostly extinct in its natural range, and American ginseng (Panax quinquefolius L.), which is still both harvested from the wild and cultivated. In Western Europe, ginseng is sold as an over-the-counter (OTC) drug. However, in the United States, ginseng is sold as a food additive; thus, it does not need to meet specific safety and efficacy requirements of the U.S. Food and Drug Administration (FDA) in this regard. In 1997, ginseng sales in the United States amounted to more than $300 million annually (6). Because ginseng must be grown for five years before it is harvested, it commands a high price, with top-quality roots easily selling for more than $10,000. In 2006, CV Technologies, Inc. received clearance by the FDA to sell Cold-fX® as a new dietary supplement in the United States. Cold-fX® is a patented natural compound of poly-furanosyl-pyranosyl-
saccharides derived from panax quinquefolius that is claimed to be effective in enhancing cell-mediated (antiviral) immunity (7; 8; 9). Cold-fX® is standardized using proprietary ChemBioPrint technology (US Patent# 6,156,291) (10). Cold-fX® currently has both a prevention and treatment claim that is approved by Health Canada, stating the product "helps reduce the frequency, severity and duration of cold and flu symptoms by boosting the immune system." The predominant pharmacologically active constituents of Panax are ginsenosides (11; 12; 13; 14; 15; 16; 17; 18; 19; 20; 21; 22; 23; 24), at least 25 of which have been identified and are present in variable amounts and ratios to one another, depending on the particular species, variety, and conditions of growth. Panaxosides are also found in American ginseng. Products with a standardized ginsenoside concentration are available (25). Because of the number of herbs sold under the name of ginseng, there can be some confusion for the consumer, since not all are botanically related to Panax ginseng. Red ginseng (steamed, heat-dried root) is said to be slightly stronger and more stimulating in the body than white (dried, unprocessed root), according to Chinese herbalism. Other plants referred to as ginseng include Japanese ginseng (Panax japonicus), Sanchi ginseng (Panax notoginseng or Panax pseudoginseng), Himalayan ginseng (Panax pseudoginseng ssp. Himalaicus), dwarf ginseng (Panax trifolius), California ginseng or spikenard (Aralia californica), dong quai (Angelica sinensis), Indian ginseng or ashwaganda (Withiania somnifea), Brazilian ginseng or suma (Pfaffia paniculata), prince's ginseng (Pseudostellaria heterophylla), white ginseng or sha shen (Adenophora plymorpha), red ginseng or danshen (Salvia miltiorrhiza), purple ginseng or mou shen (Polygonum bistorta), and false ginseng or codonopsis (Codonopsis pilosula). In addition to the botanical naming confusion, there is confusion in the scientific literature about the interchangeability of ginseng names; for example, Cold-fX® is made of poly-furanosyl-pyranosyl- saccharides and is not a ginseng extract, although it is often referred to in this manner. Several other commentaries exist in the primary and secondary literature about the need for precise descriptions of proprietary formulas, combination products, and herbal monotherapies in order to make any use from them (26; 27). In traditional Chinese medicine, shengmai or shenmai (Panax ginseng, Ophiopogon japonicus, and Fructus schisandrae) is one of the more studied ginseng combinations and is used to treat conditions with a weak pulse (e.g. coronary heart diseases and chronic obstruction pulmonary disease) (28). In various chemical analyses, shenmai has been found to contain up to 39 ginsenosides as well as seven ophioponins (29; 30). In addition, there has been growing interest in using chemical analysis for quality control of shenmai and other herbal combinations (29; 30; 31). Scientific evidence regarding the effect of ginseng on exercise capacity (32; 33; 34; 35), cognitive performance (36; 37; 38; 39), and well-being is available. The substantial number of trials supporting efficacy cannot be ignored. Most negative trials were conducted with small heterogeneous samples and have low statistical power. Future studies of sufficient statistical power and with clearly defined populations and outcomes should aim at resolving the conflicting evidence. There is preliminary evidence of possible benefits from ginseng for a variety of indications, such as immunostimulation (40; 41; 42; 43; 44), type 2 diabetes (45; 46), and coronary artery disease. Although there is a lack of conclusive clinical evidence of Panax ginseng curing cancer, research has continually found tumor inhibition, especially in the promotion and progression phases (2; 17; 18; 19; 49; 50; 51; 52; 53; 54). Further efficacy studies are needed for a final assessment of these indications. Comparative efficacy results to other commonly used therapies may be helpful. The huge popularity of ginseng both in Asia and increasingly in Europe and North America grants this root much scientific scrutiny. Yet, several promising, but less popular indications still need better scientific evaluation. Overall, Panax ginseng appears to be well tolerated, although caution is advised
about concomitant use with some pharmaceuticals, such as warfarin (55; 56), oral hypoglycemic agents, insulin, and phenelzine (25). Ginseng Interactions ACE inhibitors: Based on laboratory study, extracts of Panax ginseng (G115®) may inhibit angiotensin- converting enzyme (ACE) activity, but may not affect nitric oxide (NO) production (57). Alcohol: Based on human trials, Panax ginseng may reduce blood concentration of alcohol (ethanol) and enhance blood alcohol clearance (55; 56; 58; 59). Many tinctures contain high levels of alcohol, and ginseng tinctures may cause nausea or vomiting when taken with metronidazole (Flagyl®) or disulfiram (Antabuse®). Alzheimer's agents: In human study, ginseng constituents or supplements containing ginseng have been shown to improve symptoms of dementia (60; 61; 62). The effects with Alzheimer’s agents are not well understood. Analgesics: There are mixed results regarding the effects of ginseng on opioids. Analgesic effects of opioids have been blocked by ginseng. Panax ginseng potentiates the antinociceptive effects of pentazocine and aspirin (63) and appears to have independent effects based on pharmacological study (64). In mice, ginseng has been shown to inhibit tolerance formation to opioids and psychostimulants (90; 91). Total saponins of Panax notoginseng may possess some agonist activities at opioid-like peptide receptors (121). However, in animal study, ginseng inhibited tolerance formation to opioids (90; 91; 119). Morphine-induced analgesia was shown to be antagonized by ginseng total saponins, which also inhibit the development of analgesic tolerance to, and physical dependence on, morphine in guinea pigs (119). Androgens: Men treated with ginseng have experienced an increase in testosterone and dihydrotestosterone (DHT) concentrations (136). In rats fed with ginseng for 60 days, a significant increase of blood testosterone levels was found, combined with a significantly reduced prostate weight (139). No changes have been observed in some clinical trials (137). Antiarrhythmics: There is mixed results regarding the effects of ginseng on heart rhythm. Shenmai injection (a ginseng-containing formula) may have antiarrhythmic action (65). Based on in vitro study, American ginseng water extract may reversibly block sodium channels (126). However, there is preliminary evidence that ginseng may increase the QTc interval (thus increasing the risk of abnormal heart rhythms). Caution is warranted with antiarrhythmic agents and agents that prolong the QT interval. Anticoagulant and antiplatelets, NSAIDs: Based on in vitro, animal and human study, it is unclear how ginseng may act when used in combination with anticoagulants or antiplatelet agents due to conflicting data. Panax ginseng may inhibit the aggregation of platelets (66; 67), reduce platelet adhesiveness (68), reduce INR (69), prolong PTT (135), and reduce warfarin concentrations and increase clearance (11; 55; 56; 58; 70; 71). However, other study has not found changes in warfarin pharmacokinetics (72; 73). Whether American ginseng interferes with other anticoagulant drugs (such as heparin) or with antiplatelet drugs (clopidogrel, Ticlid®) is not known. Antidepressants: Panax ginseng or Panax quinquefolius may affect MAOI inhibitors (71). Panax ginseng has reportedly lead to mania, headache, tremor, and insomnia when used concomitantly with phenelzine (25; 55; 56; 58; 71; 74; 75; 118). Antidiabetics: Based on clinical trials, ginseng may significantly reduce blood glucose levels (11; 25; 38; 76; 77) and hemoglobin A1c (HbA1c) (77). High intake of American ginseng has resulted in hypoglycemia in both diabetics and non-diabetics (80). Combination use may lead to additive effects.
However, this is an area of controversy because different species of ginseng may have different effects (78) and the experimental data is not consistent in this area (8; 79; 80). In one study of 323 subjects, type 2 diabetes mellitus was diagnosed in two subjects in the ginseng group (1.5%), and they were subsequently withdrawn from the study (8). Antihypertensives: Despite observational evidence suggesting a link between ginseng and the development of hypertension, there has been no long-term scrutiny of its effect on blood pressure. Increases (81), decreases (66; 82), and no changes in blood pressure have been reported in patients taking ginseng (83; 84). Animal study suggests that ginsenosides may have biphasic actions on blood pressure, with initial decreases in blood pressure followed by increases (85; 86). Antilipemics: There are mixed results over whether ginseng reduces lipids. Based on animal and human study, red ginseng powder may reduce plasma total cholesterol, triglyceride, LDL, and non-esterified fatty acid (NEFA), while elevating plasma high-density lipoprotein (HDL)-cholesterol (68; 135). Hepatic cholesterol and triglyceride contents were decreased and phospholipids increased by ginseng administration in high cholesterol diet-fed rats, corresponding to improvement of the fatty liver. However, no effect on plasma lipids was found in a study on type 2 diabetics or erectile dysfunction (77; 137). Antineoplastics: Based on an in vitro study, ginsenosides from Panax ginseng may have antineoplastic activity (87). Based on laboratory and animal study, ginseng preparations may act synergistically with cytotoxic drugs, chemotherapy, and radiation (53; 88; 106; 107). Based on in vitro study, panaxytriol from Panax ginseng may interact synergistically with mitomycin C (120). Based on in vivo animal study, Korean red ginseng may interact synergistically with paclitaxel and attenuate cisplatin-induced nausea and vomiting (49; 88). Antipsychotics: Anecdotal reports have noted a possible interaction between ginseng and antipsychotics (may exaggerate effects), although scientific data is lacking. Examples include haloperidol, chlorpromazine (Thorazine®), fluphenazine (Prolixin®), olanzapine (Zyprexa®), and prochlorperazine (Compazine®). Antiretrovirals: Based on in vitro evidence, kaempferol from ginseng may interact with HIV protease inhibitors by inhibiting the efflux and CYP3A4-mediated metabolism of xenobiotics (89). Based on human laboratory assays, Cold-fX® significantly (p
Caffeine: There is controversy over whether caffeine and other stimulants are safe to take with ginseng. Some experts believe that when taken in the recommended dosages, Asian ginseng is considered safe (11), while others disagree (94). However, in rare cases, ginseng may cause insomnia and headaches and enhance the effects of caffeine. Calcium channel blockers: Based on case reports, ginseng may alter the effects of blood pressure or heart medications, including calcium channel blockers such as nifedipine (Procardia®). Ginseng increased serum levels of nifedipine in healthy volunteers (95). Cardiac glycosides (digoxin): Ginseng may increase or decrease digoxin levels. Based on human study, Korean red ginseng may enhance the effects of digoxin (Lanoxin®) in congestive heart failure (96). However, in a pharmacokinetic study in patients with congestive heart failure taking digoxin, shengmai injection (a Panax ginseng containing formula) lowered serum digoxin levels (108). CNS stimulants: Because it is a non-specific central nervous system stimulant, Panax ginseng may theoretically increase the effects and the side effects (increased heart rate and blood pressure) of prescription and non-prescription drugs that also stimulate the central nervous system (90; 91; 92; 119), such as those used for increasing energy, losing weight, raising mental alertness, or treating colds or asthma. If Panax ginseng or Panax quinquefolius are taken concomitantly, the central nervous system may be over stimulated, possibly resulting in insomnia, irritability, and increased blood pressure (theoretical). Stimulants include amphetamine salts (Adderall®), dextroamphetamine (Dexedrine®), methylphenidate (Concerta®, Methlyn®, Ritalin®), and phentermine (Adipex-P®, Ionamin®). Corticosteroids: Panax ginseng extract may have glucocorticoid-like activities in homeostasis and regulation of immunity, etc. (116). Based on in vitro study, Panax ginseng has a steroid-like effect in vitro, and may have a potentiating effect with hydrocortisone on T cell-mediated immunity (127). Ginseng may stimulate adrenocorticotropic hormone (ACTH) and thereby increase plasma cortisol levels (134). It has been suggested that ginseng lowers cortisol levels in diabetics while increasing cortisol levels in non-diabetics (anecdotal). Cytochrome P450 2D6 and 3A4 substrates: Although Panax ginseng has been shown to activate CYP3A4 in vitro, there is a lack of an in vitro correlation with the in vivo effects (98; 99; 100; 101; 102). Based on laboratory study, Panax ginseng may inhibit CYP2D6, but the magnitude of the effect did not appear to be clinically relevant (103). Other laboratory studies demonstrate no effect on CYP450 activity by ginseng preparations or Cold-fX® (104; 105). Diuretics: One case report linked ginseng to furosemide (Lasix®) diuresis resistance (109). Drugs that prolong QT interval: There is preliminary evidence that ginseng may increase the QTc interval (thus increasing the risk of abnormal heart rhythms). Caution is warranted with agents that prolong the QT interval. Drugs that regulate heart rate: Heart rate decreased with the high dose (200mg), but not with the lower dose (100mg) of a ginseng-gingko combination product (66). Theoretically, ginseng may interfere with heart rate regulating agents. Erectile dysfunction drugs (e.g., Viagra®): Theoretically, Panax ginseng may have additive effects when taken concomitantly with sildenafil (Viagra®) (110). Estrogens: There is limited laboratory evidence that ginseng may contain estrogen-like chemicals and may affect medications with estrogen-like or estrogen-blocking properties (19; 111; 112; 113). This has
not been well demonstrated in humans. In a clinical trial in postmenopausal women investigating a herbal mixture, including ginseng, there was no effect on estradiol (130). Additionally, no estrogenic activity was evident in the sample of Panax ginseng extract tested or in a sample of the combination product ArginMax® (114). Gastrointestinal agents: Side effects associated with ginseng use include diarrhea, loss of appetite, nausea, and vomiting (115). Thus, ginseng may interact with effectiveness of gastrointestinal agents. Gonadotropins (LH/FSH): Men treated with ginseng have experienced an increase in luteinizing hormone (LH) and follicle stimulating hormone (FSH) concentrations (136). In a clinical trial in postmenopausal women investigating a herbal mixture, including ginseng, there was no effect on FSH (130). Hepatotoxic drugs: Ginseng is typically considered a hepatoprotective agent, but may interact with hepatotoxic drugs (71). In a case report, a 65 year-old man with nocturia developed jaundice and severe pruritus after two weeks of taking a multi-ingredient product, Prostata®, containing Panax ginseng (117). Conversely, in a clinical trial in postmenopausal women investigating a herbal mixture, including ginseng, there was no effect on liver enzymes (130). Immunomodulators: Based on clinical trials and laboratory study, Cold-fX® has been shown to enhance the immune system (8; 9; 47; 48). Theoretically, ginseng may interfere with immunomodulators. Influenza vaccine: Panax ginseng may increase the efficacy of influenza vaccination (55). Phenytoin: Panax ginseng may affect phenytoin via human liver cytochrome P450 enzyme interaction (71; 122). Photosensitizers: In laboratory study, Panax ginseng acted as a photoprotector in low concentrations and as a photosensitizer in high concentrations (123). Pituitary hormones: Intravenous administration of Panax ginseng in rats showed that the physiological effect of ginseng is not affected by translation, conversion rate, or the chemical structure of hormones from the posterior pituitary (138). Men treated with ginseng have experienced a decrease or no effect in prolactin concentrations (136; 137). Radioprotective drugs: Panax ginseng may offer radioprotective effects in human study (124; 125). Thus, there may be additive effects with ginseng and other radioprotective agents. Sedatives: Ginseng may have stimulant effects (90; 91; 92; 119). Theoretically, ginseng may interfere with sedatives. Sperm count: Men treated with ginseng have experienced an increase in spermatozoon number and improvement of motility (136). Thyroid hormones: In a clinical trial in postmenopausal women investigating a herbal mixture, including ginseng, there was no effect on thyroid stimulating hormone (130). Vasodilators: Ginsenosides Rb1 and Rg1 appear to have vasodilatory effects, possibly mediated by the proportion of nitric acid release (128). Theoretically, ginseng may have an additive effect when used with vasodilators.
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