Cat's Claw Cat's claw (Uncaria tomentosa) is a South American plant used for treating gastrointestinal (GI) complaints and as an immune-system stimulant.[5] While no drug interactions involving cat's claw have been reported, in vitro research suggests that cat's claw might inhibit CYP3A4.[17] Theoretically, cat's claw might prolong the half-life and increase the serum levels of drugs metabolized by CYP3A4, including protease inhibitors, nonnucleoside reverse-transcriptase inhibitors (NNRTIs), cyclosporine, some benzodiazepines, and many others.[18-20] It is important to keep in mind that interactions demonstrated in vitro may not be observed in vivo. In part, this potential discrepancy may be due to poor bioavailability of the inhibitory substances in vitro or failure to attain sufficient concentrations at the site of drug metabolism (e.g., hepatocytes). Chamomile Chamomile (Matricaria recutita), a relative of the ragweed and the chrysanthemum, is used to treat GI complaints.[5] Laboratory evidence suggests that chamomile might inhibit CYP3A4, potentially decreasing the metabolism, increasing the serum concentration, and increasing the risk of toxicity of drugs such as calcium-channel blockers, cisapride, lovastatin, and simvastatin.[17] However, this interaction has not been reported in humans. Chamomile might have an additive effect when combined with sedative drugs and natural products, such as alcohol, benzodiazepines, catnip (Nepeta cataria), kava (Piper methysticum), lemon balm (Melissa officinalis), and valerian (Valeriana officinalis).[5] Coenzyme Q10 Coenzyme Q10 (also known as ubiquinone or ubidecarenone) is used for congestive heart failure and other cardiovascular disorders.[5] It can reduce the anticoagulant effect of warfarin. There have been two case reports describing decreased International Normalized Ratios (INRs) when coenzyme Q10 was added to warfarin therapy on which patients had been stable.[21,22] In animals, coenzyme Q10 antagonizes the anticoagulant effects of warfarin.[23] Coenzyme Q10 is structurally related to men-aquinone (vitamin K2), suggesting a pharmacodynamic interaction with warfarin.[21,23] Dong Quai Dong quai (Angelica sinesis), a botanical long used in traditional Chinese medicine, is a popular dietary supplement used to treat menopausal symptoms.[5] One case report describes a woman with a stable, therapeutic INR on warfarin whose INR doubled after she began taking dong quai for menopausal symptoms.[24] In vitro evidence suggests that sodium ferulate, a component of dong quai, might inhibit cyclooxygenase activity and platelet aggregation.[25] Dong quai also contains psoralen and bergapten, known photosensitizers. [26] These compounds, when combined with drugs such as sulfa and quinolone antimicrobials or with natural products such as St. John's wort, could theoretically increase the risk of phototoxicity. Echinacea Echinacea (Echinacea angustifolia, Echinacea pallida, Echinacea purpura), a relative of the ragweed plant, is used to treat the common cold and influenza.[5] Evidence obtained in vitro suggests that echinacea inhibits CYP3A4.[17] Concurrent use of echinacea and drugs like alprazolam, calcium-channel blockers, and protease inhibitors could potentially increase serum drug levels and adverse effects.[18,19] Theoretically, a person who treats a cold by taking echinacea and drinking grapefruit juice, which also inhibits CYP3A4, could be at even greater risk for toxicity from CYP3A4-metabolized drugs. However, there have been no reports of an interaction between echinacea and drugs metabolized by CYP3A4. Echinacea's immunomodulating effects make the product contraindicated in patients receiving immunosuppressive therapy. Ephedra Ephedra has nonselective adrenergic agonist activity due to its chief constituents, ephedrine and pseudoephedrine. Ephedra is referred to by a wide variety of common names, including desert herb, ephedrae herba, joint fir, ma huang, popotillo, sea grape, teamster's tea, and yellow horse.[5] Taking advantage of the stimulatory pharmacologic effects, the natural products industry incorporates ephedra into a vast array of formulations for asthma, weight loss, "energy," sexual enhancement, and euphoria. In addition to the pharmacodynamic interactions discussed above, ephedra could interact with noncardioselective É¿-blocking agents, resulting in unopposed Éø-receptor stimulation and increased pressor effects. [27] Patients undergoing anesthesia should be warned to discontinue any ephedrine-containing products before surgery to avoid a potential interaction with general anesthetic agents, which could produce arrhythmias. [28] Pharmacodynamic interactions between monoamine oxidase inhibitors and ephedra may result in severe hypertension. A near-fatal reaction was reported in a 28-year-old woman who took a product that contained ephedrine, caffeine, and theophylline within 24 hours after discontinuing phenelzine treatment.[29] Garlic Garlic (Allium sativum) is used for hyperlipemia, hypertension, and other cardiovascular indications.[5] In healthy volunteers, garlic significantly reduced plasma saquinavir concentrations. [30] Although the mechanism of this interaction is unknown, garlic supplements probably should be avoided by people taking protease inhibitors and NNRTIs. Although no interactions between garlic and anticoagulants have been reported, garlic is known to inhibit platelet aggregation and has been reported to cause postoperative bleeding and spontaneous spinal epidural hematoma.[31-34] The apparent anticoagulant effect of garlic would lead one to expect an additive effect on the action of warfarin. Ginger Ginger (Zingiber officinale) is used for nausea and arthritis.[5] Although older reports suggested an effect of ginger on platelet aggregation,[35] newer reports indicate no such effect.[36-38] Interactions with warfarin have not been reported. Ginkgo biloba Ginkgo biloba is used for Alzheimer's disease, intermittent claudication, and many other medicinal purposes.[5] Ginkgo leaf extract was associated with coma in a woman with Alzheimer's disease who was also taking trazodone. Flumazenil reversed the coma, suggesting that excess É¡-aminobutyric acid (GABA) activity may have been involved.[5,39] Ginkgo flavonoids appear to have GABA agonist properties and direct activity on benzodiazepine receptors.[40] A theoretical mechanism for this interaction is increased metabolism of trazodone to active GABAergic metabolites, possibly by induction of the CYP3A4 isozyme.[39,41]Ginkgo inhibits platelet aggregation. [42,43] Intracerebral hemorrhage was associated with recent ginkgo use in a patient stabilized on warfarin for five years.[44] Commercial ginkgo extracts inhibit S-warfarin metabolism (via CYP2C9) by human liver microsomes. [45] Ginkgo's inhibition of warfarin metabolism, in addition to its inhibition of platelet adhesion, makes combination therapy with ginkgo and warfarin inappropriate. Furthermore, episodes of subdural hematoma, subarachnoid hemorrhage, and spontaneous hyphema have occurred in patients taking ginkgo alone or with aspirin or ergotamine. [46-50] The combination of ginkgo and anticoagulant drugs or drugs that inhibit platelet adhesion should be avoided. Ginseng Ginseng, including Asian ginseng (Panax ginseng) and American ginseng (Panax quinquefolius), is used in an attempt to improve well-being, enhance the immune system, and boost energy, among a variety of other uses.[5] Both Asian and American ginseng have been shown to reduce blood glucose levels and hemoglobin A1c levels in people with type 2 diabetes mellitus.[51-53] Given concurrently with insulin or oral antidiabetic agents, ginseng may, without careful blood glucose monitoring, result in hypoglycemia. There has been one case report of ginseng decreasing the effect of warfarin in a previously stable patient with a mechanical heart valve. Within two weeks of adding ginseng, the INR dropped to 1.5 from the targeted 3.0-4.0 and returned to 3.3 after ginseng was discontinued.[54] On the other hand, an animal study showed no effect of ginseng on warfarin pharmacokinetics or pharmacodynamics. [55] Until definitive information is published, INRs should be monitored more closely in patients who add ginseng to warfarin therapy. Glucosamine Sulfate Glucosamine sulfate is used alone or in combination with chondroitin for osteoarthritis.[5] A study in 10 people found that an infusion of glucosamine sulfate reduced glucose tolerance. [56] This observation and recent in vitro evidence suggest that glucosamine can increase insulin resistance, resulting in the need for larger doses of oral hypoglycemic agents or insulin in diabetic patients.[57] Patients with diabetes should avoid glucosamine or use it only with medical supervision and monitoring. Goldenseal Goldenseal (Hydrastis canadensis) has a wide variety of uses, none of which are scientifically substantiated. [5] Folklore promotes its use, often in combination with echinacea, to boost the immune system and treat the common cold. Street pharmacologists claim -- erroneously -- that goldenseal masks illicit drugs in the urine.[5] An in vitro study indicated that goldenseal might inhibit CYP3A4, potentially increasing the serum levels of drugs metabolized by this isoenzyme.[17] Goldenseal is often taken with echinacea, which has been shown to inhibit CYP3A4 in vitro.[17] No case reports or clinical studies confirming this interaction have been published. Ipriflavone Ipriflavone is a semisynthetic isoflavone soy derivative used to treat osteoporosis.[5] A case report of increased theophylline levels after the addition of ipriflavone led to laboratory research indicating that ipriflavone, or one of its metabolites, decreases theophylline metabolism through inhibition of CYP1A2.[14,58] Ipriflavone could also elevate the serum levels of other drugs and natural products metabolized by CYP1A2, including caffeine and caffeinecontaining natural products, clozapine, cyclobenzaprine, haloperidol, olanzapine, tacrine, and other drugs.[18-20] Since many of these drugs are likely to be used in older people, ipriflavone use, which occurs primarily among postmenopausal women, should be carefully monitored for drug interactions.According to laboratory data, ipriflavone also competitively inhibits CYP2C9.[14] Concomitant use of ipriflavone might increase serum levels and prolong the half-life of drugs such as celecoxib, several nonsteroidal anti-inflammatory drugs, phenytoin, warfarin, and zafirlukast, although no clinical studies or case reports have confirmed this interaction.[18-20] In vitro evidence suggests that isoflavones might inhibit oxidative and conjugative metabolism. Isoflavones might also interact with drug transporters, such as P-glycoprotein and the canalicular multispecific organic anion transporter, which affect drug absorption and biliary excretion.[59] It is inappropriate to combine soy isoflavones (phytoestrogens) with tamoxifen (an antiestrogen) in the prevention or treatment of breast cancer. More research is needed to define the drug interaction risks of taking isoflavone- rich "phytoestrogen" products concurrently with conventional drugs. Melatonin Melatonin is an endogenous hormone used as a supplement to treat jet lag and other sleep disorders.[5] Fluvoxamine significantly increases serum melatonin levels, which may cause excessive drowsiness.[60,61] Fluvoxamine is known to increase endogenous melatonin secretion.[60] When given concurrently with melatonin, fluvoxamine appears to reduce the metabolism of melatonin by inhibiting CYP1A2 or CYP2C9.[60,61] This interaction could be particularly dangerous when melatonin and fluvoxamine are taken with other sedating drugs, such as haloperidol and diazepam, that are also metabolized by CYP1A2 or CYP2C9.Melatonin appears to interact pharmacodynamically with nifedipine. [62] Concurrent melatonin use may reduce the antihypertensive effect of slow-release nifedipine, leading to increased blood pressure and heart rate. Although the exact mechanism of this interaction is unknown, melatonin seems to play a role in cardiovascular regulation.[62] St. John's Wort St. John's wort is marketed as a treatment for mild to moderate depression. It lacks the anticholinergic effects caused by tricyclic antidepressants and the adverse effects on sexual function associated with selective serotonin-reuptake inhibitors (SSRIs).[5] However, the favorable adverse-effect profile is offset by numerous, potentially serious drug interactions.St. John's wort illustrates how results obtained in vitro may not reflect what happens in vivo. St. John's wort has been found to inhibit several CYP isozymes in vitro, including CYP2C9, CYP2D6, and CYP3A4.[17,63,64] In vivo, however, St. John's wort appears to be an enzyme inducer.[8-10,65-67] This mismatch between laboratory and clinical findings may be explained by a constituent of St. John's wort, hyperforin, that affects the production of metabolizing enzymes. Hyperforin appears to bind to a nuclear receptor called the pregnane X receptor, increasing the expression of CYP3A4.[68,69] This activity, which is not observed in vitro, leads to increased CYP3A4 availability and subsequent increased metabolism of drugs acting as substrates for CYP3A4. St. John's wort reduces the serum concentration of amitriptyline, which is a substrate of CYP2C9, CYP2D6, and CYP3A4.[70]Drug interactions with St. John's wort mediated by CYP3A4 could be lethal. In a clinical laboratory study, St. John's wort reduced the area under the concentration-time curve for indinavir by 57% and decreased the extrapolated eight-hour trough by 81%.[9] These effects are believed to be the result of induction of CYP3A4 by St. John's wort. The findings of this study prompted FDA to issue an immediate public health advisory regarding the dangers of the interaction between this herb and protease inhibitors and NNRTIs.[11] People with HIV-associated disease taking St. John's wort risk drug failure and development of viral resistance secondary to subtherapeutic levels of indinavir and other protease inhibitors.St. John's wort has been implicated in multiple cases of dangerously low serum cyclosporine levels and episodes of acute organ rejection in patients with heart, liver, and kidney transplants.[65,67,71,72] The mechanism of this interaction appears to be induction of CYP3A4 and, possibly, induction of the drug transporter P-glycoprotein, which affects the absorption and elimination of many drugs. Although no pregnancies have been reported, St. John's wort has been associated with breakthrough and irregular menstrual bleeding in women taking oral contraceptives.[12] The induction of CYP3A4 might increase the metabolism of estradiols and other corticosteroids that are substrates of the isoenzyme. Women who take St. John's wort concurrently with oral contraceptives should be advised to use other means of birth control.Carbamazepine, a CYP3A4 substrate, was not affected by concurrent St. John's wort ingestion.[73] The explanation for this unexpected finding was that St. John's wort could not further induce CYP3A4 beyond the autoinduction caused by carbamazepine. There have been case reports of serotonin syndrome-like adverse effects when sertraline and St. John's wort were combined.[74,75] These effects may be due to the additive serotonin-promoting effects of both agents. SSRIs and St. John's wort should not be combined. Case reports and a human and laboratory study indicate that St. John's wort reduces serum digoxin levels by 18-25%.[6,76,77] This interaction is evidently the result of induction of P-glycoprotein. Two weeks of St. John's wort use by eight volunteers increased duodenal expression of P-glycoprotein 1.4-fold.[6] The interactions described in this article are summarized in Tables 1 and 2. Where to Find More Information Pharmacists should be aware of the differences in regulatory control and labeling requirements between drugs and natural products. The DSHEA does not require premarketing studies to identify drug interactions or medical conditions that should preclude use of a dietary supplement. Furthermore, the rules dealing with warnings about drug interactions on dietary supplement product labels are vague. While there are DSHEA requirements for FDA review of labels and Federal Trade Commission review of advertising and promotional materials, a quick look at products in the marketplace indicates that these rules are not being vigorously enforced.[1,81] In view of the less than stringent product information provisions of the DSHEA, pharmacists should consult reliable, independent information sources rather than rely on literature provided by supplement manufacturers.To effectively counsel patients about interactions involving natural products, the pharmacist should be familiar with the most commonly used products and have access to references on more obscure products. Pharmacists must also be aware that natural products may have variable potencies, unidentified components, unproven efficacy, and unknown adverse effects and interactions. To reduce the risk, pharmacists should recommend only those products that are manufactured to high quality-control standards. The United States Pharmacopeial Convention is developing analytical monographs for botanicals, and some have been published in The United States Pharmacopeia, 24th Revision, and The National Formulary, 19th Edition. Purchasing botanicals with USP labeling increases the chances of obtaining a quality product, although manufacturing botanical products to meet analytical standards for marker compounds does not necessarily ensure product efficacy or generic equivalence with products that have shown efficacy. Components other than the marker compound may contribute to the pharmacologic effect, and there may be differences in bioavailability.Natural product information resources should provide objective, complete, referenced information, including data on interactions and adverse effects, to help health care practitioners provide accurate information to consumers. A reference that is regularly updated will provide the most useful information. Some online references offer more frequent updates than printed references, but these may not be easily accessible in all settings. In addition to natural product references, professional journals are a good source of up-to-date information. Increasingly, case reports, review articles, and clinical studies involving natural products are appearing in the conventional medical literature. Several caveats apply, however.Overinterpreting case reports can result in erroneous conclusions. Much of what is "known" about dietary supplement interactions comes from case reports, which can be misleading. For example, it is unclear whether a reported interaction between Siberian ginseng (Eleutherococcus senticosus) and digoxin was the result of inaccurate identification of the herb, interference with the serum digoxin assay, or a true elevation of serum digoxin levels.[79,80] Sensational article titles may attract interest but can lead to faulty assumptions. The entirety of a report, rather than its title, should be considered. For example, a closer look at a case report in Annals of Internal Medicine entitled "Coma from the Health Food Store: Interaction between Kava and Alprazolam" reveals that the patient described was lethargic and disoriented but at no time comatose.[78] While it is reasonable to advise patients about possible additive sedative effects of benzodiazepines and kava on the basis of this case report, warning that the combination may result in coma is unfounded. Although case studies, particularly those that support logical pharmacologic mechanisms, can be useful, the standard for drug interaction information is a carefully conducted clinical laboratory investigation, such as the indinavir-St. John's wort study cited earlier.[9] The best information comes from well-designed controlled studies conducted to verify drug interactions identified through laboratory investigations or case reports. At present, few such studies in a targeted population have been reported. Heightened consumer interest and increased government spending on natural product research should yield more scientifically verified information on interactions and other undesirable effects. Update on Natural Product-Drug Interactions from American Journal of Health-System Pharmacy Gayle Nicholas Scott, Pharm.D., FASCP, BCPS, CGP and Gary W. Elmer, PH.D. 81 citations from Update on Natural Product-Drug Interactions Remember we are NOT Doctors and have NO medical training. This site is like an Encylopedia - there are many pages, many links on many topics. Support our work with any size DONATION - see left side of any page - for how to donate. You can help raise awareness of CAM.