Alternative Drug Interactions May Make for Bad Medicine by Carolyn Cosmos The worst interaction I ever saw in an emergency room involving an herbal medicine was an interaction between St. Johnís wort and the anti-depressant Prozac," said an emergency room nurse working at a hospital in the suburbs of Washington, D.C. "A woman had been taking St. Johnís wort for depression. A doctor put her on Prozac, and she was brought in with a very rapid heartbeat, high blood pressure, tremors, a high fever. We sent her to the intensive care unit and she recovered. It was potentially fatal." The nurse, who did not wish to be identified by name, is among many health professionals who worry about the dangers of combining "complementary and alternative medicine," or CAM, with prescription drugs, anesthesia and other standard medical treatments. Because of that concern, medical researchers and health care providers are pouring out papers on prescription interactions with alternative medicines, and increasingly alerting patients to the possible risks of mixing mainstream treatments with "folk remedies"óthe herbal supplements, vitamin preparations and other over-the-counter answers to what ails you. So is this ER horror story a fluke? Or does it poin t to a real and growing problem as more and more of us rely on CAM? Although numbers for how many people rely on CAM in the United States vary greatlyóanywhere from 30 percent to 80 percentóa survey on CAM dietary supplements published in January 2003 in the American Journal of Preventive Medicine found that more than 75 percent of 45,000 people surveyed in Washington state who had some type of medical condition reported taking more supplements, such as vitamins, than those without any medical conditions, suggesting that the public may be using dietary supplements to treat illnesses. How risky is this trend? "From a clinical perspective, the dangers of CAM interacting with prescription medications can be overblown," said Dr. John C. Pan, a professor of obstetrics and gynecology at the George Washington University Medical Center and director of the universityís Center for Integrative Medicine. He added that most of the interaction information is anecdotal or derives from animal studies and other laboratory research alone, but when it comes to what happens in humans, thereís little actual data. Herbals and Bleeding Problems However, Pan said one important, credible CAM concern involves blood thinners or anti-coagulants such as warfarin when they are combined with popular CAM supplements, such as ginkgo or garlic, which have a similar blood thinning effect. Any combination of substances that reduces blood clotting can overly thin out the blood and increase the risk of prolonged bleeding during and after surgery. Alan Agins and other supplement experts agree with Panís approach. Agins, who holds a doctorate in pharmacology and teaches at Brown University Medical School, said of current concerns about prescription drug and CAM interactions, "Most of itís theoretical and we have to take [worries] with a grain of saltóthat is, they could happen." However, if youíre looking for more certainty, Agins agrees that the "biggest potential problem is the risk of herbal effects on anti-coagulants. In that regard, I talk to patients and clinicians about the ëfour Gísíóginkgo, ginger, ginseng and garlic," all of which are associated with blood thinning. Similarly, the main clinical issue with cancer and herbal treatments involves patients preparing for surgery who are "using several alternative therapies that increase bleeding risk," particularly "mega-doses of vitamin E," said Dr. Nagi Kumar, director of the Department of Nutrition at the H. Lee Moffitt Cancer Center and Research Institute at the University of South Florida in Tampa. This E risk can start at 1,000 milligrams a dayónot an uncommon dose. Coenzyme Q10 may also create problems in patients taking anti-coagulants, Kumar said. In connection with possible bleeding problems, other researchers mention preparations of chamomile, cayenne, dong quai, feverfew, fish oil, flaxseed oil, green tea, horse chestnut and St. Johnís wort as potentially harmful. If that isnít enough to give you pause, a December 2002 article in the Journal of Clinical Pharmacy and Therapeutics warns of a potentially increased bleeding risk when common painkillers, such as aspirin, ibuprofen or acetaminophen, are combined with herbal blood thinners or herbals containing coumarin or tamarind, including those already described. The author of the article, Dr. Worku Abebe of the Medical College of Georgia, adds bilberry, fenugreek, meadowsweet, motherwort, red clover, turmeric and willow to these possibly problematic supplements. St. Johnís Wort Another herbal that research seems to underscore caution is St. Johnís wort (hypericum perforatum). Reviews are mixed on the clinical effectiveness of this popular herbal treatment for depression (see The Washington Diplomat, October 2002), but the current science says it may very well help with milder forms of depression while having no effect on the more severe varieties and episodes of the disease. However, Brown Universityís Agins pointed out two potentially serious problems: First, St. Johnís wort interacts with prescription anti-depressantsósuch as the ER scene described above. (Some research suggests it affects brain serotonin levels just as Prozac and related drugs do.) "Equally problematic," Agins told The Washington Diplomat, "one of the active components in St. Johnís wort, hypericum," appears to activate an enzyme "that metabolizes many other classes of drugs." This means it could lower drug levels in your body, reducing or even eliminating them. Medications that may be zapped this way include some benzodiazepine tranquilizers, antibiotics, calcium channel blockers used to treat heart problems and high blood pressure, drugs for high cholesterol and, possibly, oral contraceptives. (No pregnancies have been reported thus far as a result of St. Johnís wort neutralizing an oral contraceptive.) Research examined by Agins and noted by the National Center for Complementary and Alternative Medicine (NCCAM) in an herbal "fact sheet" shows that St. Johnís wort can also interfere with protease inhibitor drugs, such as indinavir, used to control HIV infection. In fact, the U.S. Food and Drug Administration (FDA) has issued a warning about these negative effects on protease inhibitors and other treatments for HIV. Similarly, this botanical can affect anti-cancer or chemotherapy agents such as irinotecan, and, importantly, it interacts with drugs such as cyclosporine that help prevent organ transplant rejections and are used in bone marrow transplants. In addition, patients going into surgery should be aware that the American Society of Anesthesiologists (ASA) warns that St. Johnís wort "may intensify or prolong the effects of some narcotic drugs and anesthetic agents." (ASA cautions that valerian may also prolong anesthesia sedation.) Cardiology Concerns "I was more sympathetic to herbal use a few years ago," said cardiologist David Pearle, a professor of medicine at Georgetown University School of Medicine. Pearle, who is also director of Georgetown Hospitalís Coronary Care Unit, said he respects CAM experts, such as Andrew Weil, and "follows the literature" on herbals and other dietary supplements with interest. Pearle said though that he is currently concerned about blood thinning herbals as well as St. Johnís wort, noting it can "interfere with the metabolism of statin drugs such as Lipitor," which is used to improve cholesterol levels. Pearleís more general worry, however, is that many drugs given for heart failure can be sensitive to interactions with other substances and may be vulnerable to supplement interactions that could go undetected. "A lot of things can upset their balance," he noted, adding that more research and a more systematic look at all interactions is needed, including those involving both standard drugs and CAM therapies. Addressing other matters of the heart, the American Society of Anesthesiologists Web site cautions that anesthesiologists have seen "significant" changes in heart rate or blood pressure in some patients taking herbal supplements, particularly ginseng, which has been associated with high blood pressure and tachycardia, or rapid heartbeat. The ASA also warns patients that ephedra can "dangerously" raise blood pressure and heart rate, and that goldenseal and licorice may affect blood pressure as well. And pharmacology professors Gayle Nicholas Scott of Eastern Virginia Medical School and Gary Elmer of the University of Washington in Seattle warn that melatonin, used to promote sleep, may play a role in cardiovascular regulation and could interact w ith nifedipine, which is used to reduce blood pressure. Cancer Therapies In a recent study conducted by University of South Floridaís Kumar and her Moffitt Cancer Center colleagues, 29 percent of clinic patients who had cancer used CAM nutritional therapies, including vitamins, herbal products and mineral supplements. Other studies have yielded higher rates, with up to 80 percent of breast cancer patients reportedly using dietary supplements. The Moffitt study notes, "Increasing evidence from animal research, observational human studies, and a few clinical trials suggests that some nutrients may indeed help prevent certain cancers or assist in cancer therapies." At least 40 diet-derived substances are being evaluated for anti-cancer properties by mainstream science. The "most promising" include soy, green and black tea, curcumin (found in turmeric and curry), lycopene (found in tomatoes), indole-3-carbinol (found in broccoli and brussels sprouts), vitamins D and E, selenium and calcium. One concern about combinations, Kumar said, centers on the supplement form of soy isoflavones because they add to the effects of tamoxifen treatments for breast cancer and become a risky "co-prescription." And Kumar noted that prostate cancer patients are still using PC-SPES, a combination supplement product, even though the FDA has warned about contamination problems and adverse effects. HIV Therapies HIV-positive patients are avid users of CAM therapies, the University of Marylandís Virna Almuete told a pharmacist conference last June. Almuete, who is also with The Johns Hopkins Hospital in Baltimore, Md., said the figure may be as high as 63 percent of those with HIV. She described potential interaction issues starting with changes in the efficacy of anti-retroviral drugs such as indinavir. In addition to noting concerns about St. Johnís wort, Almuete told the gathering that garlic supplements could affect the drug saquinavir, and that "severe gastrointestinal side effects have been reported" when such supplements were used with ritonavir. In addition, she said there are theoretical concerns about people with HIV infection using echinacea. Pharmacology professors Scott and Elmer agreed that echinacea and garlic as well as St. Johnís wort could affect therapies for HIV, adding that catís claw, chamomile and goldenseal may also negatively affect protease inhibitors, cyclosporine and other drugs. Mental Health Treatments Scott and Elmer also point to natural product-drug interactions that could affect patients receiving mental health treatments and underscore the likely St. Johnís wort interactions with tranquilizers and anti-depressants. They warn that Kava and ginkgo biloba could create problems with tranquilizers, as can ephedra use in patients taking monoamine oxidase inhibitors for depression. Scott and Elmer added that Ipriflavone, a soy derivative used to treat osteoporosis, could affect the metabolism of certain anti-psychotic drugs, the tranquilizer haloperidol, and the drug tacrine, which is used to treat Alzheimerís disease. Kumar advises that patients taking Nardil (phenelzine sulfate) should avoid mixing it with ginseng. The combination could possibly cause headache, tremors or manic episodes. In general, she cautioned against ginseng for people suffering from anxiety disorders. Looking for any panacea in a bottle can work against improving mental health, warned Dr. James S. Gordon, adjunct professor of psychiatry and family medicine at Georgetown Universityís School of Medicine. Gordon, who is also director of the Center for Mind-Body Medicine in Washington, D.C., and served as chair of the White House Commission on Complementary and Alternative Medicine Policy, noted that a continuum of factors is involved in psychiatric disorders, including hereditary issues and environmental matters, such as family relations: "Any therapy has to take them into account." Mental health patients who wish to incorporate dietary supplements into such a comprehensive treatment should "go to somebody trainedóuse an herbalist," Gordon advised. He said the Center of Mind-Body Medicine uses a wide range of CAM therapies, including yoga and massage to treat psychiatric problems, and does not encourage patients to rely on a single approach. Pan, the director of George Washington Universityís Center for Integrative Medicine, offered several more suggestions for people incorporating supplements into their medical treatments. First, donít overdose yourself. Risks rise with mega-doses of herbal products. And "donít get the cheapest brand," Pan said. People are less likely to run into quality problems or adulterated products if they stick to recognized and standard brands. Pan and other experts emphasize another key point: The less you tell your doctor about the supplements you are taking, the more likely it is you might harm your health through herbal interactions with standard drugs. "Itís important for the consumer to let the doctor know about any CAM therapies," said Pan. "Then the burden is on the physician" to address efficacy, side effects and interactions. Interactions Possible With Dietary Supplements In addition to the supplements associated with bleeding risk noted in the main article, professor Nagi Kumar, nutrition director of the H. Lee Moffitt Cancer Center and Research Institute at the University of South Florida in Tampa, published a study in the centerís Cancer Control Journal warning of the following possible interactions with dietary supplements that may occur in cancer patients: ï Cola nut may strengthen the effects of caffeine and drugs that stimulate the central nervous system. ï Echinacea may counteract immune-suppressant drugs. ï Ephedra interacts with many drugs and may increase stimulant side effects. ï Flaxseed (not flaxseed oil) and red clover have a theoretical potential to affect tamoxifen, raloxifene, estrogen and hormone replacement therapies. ï Goldenseal can interfere with vitamin B absorption. ï Licorice may enhance the action of corticosteroids or work against drugs for high blood pressure. ï PC-SPES, a combination product, may be contaminated with prescription drugs. Itís been associated with deep vein thrombosis and estrogenic activity, and it also may raise blood pressure or interfere with other therapies. ï Saw palmetto can create misleading readings on prostate PSA tests. ï Valerian enhances the effects of sedatives and hypnotic drugs. ï Vitex may affect sex hormones and should not be taken with birth control pills or other hormone therapies. ï In addition, the absorption of some drugs and minerals such as calcium may be reduced by bearberry, black walnut husk, flaxseed, oak bark, raspberry leaves and sheep sorrel. The Moffitt study is described at www.medscape.com/viewarticle/438531. Kumar and her colleagues have also published a book that summarizes the science and evaluates the effectiveness, uses, and safety of a large number of CAM nutritional therapies for cancer and other applications. For more information, please contact the H. Lee Moffitt Cancer Center at (813) 972-4673 or visit www.moffitt.usf.edu. Other resources that are available online include: ï The National Institutes of Healthís (NIH) National Center for Complementary and Alternative Medicine at http://nccam.nih.gov ï The NIH Office of Dietary Supplements at http://dietary-supplements.info.nih.gov/links/links.html ï The National Cancer Instituteís Office of Cancer Complementary and Alternative Medicine at www3.cancer.gov/occam ï The George Washington Universityís Center for Integrative Medicine www.integrativemedicinedc.com ï The Center for Mind-Body Medicine in Washington, D.C., at www.cmbm.org ï The Smith Farm Center for the Healing Arts (Cancer Help Program) at www.smithfarm.com Carolyn Cosmos is a freelance writer in Washington, D.C.