Supplement-Drug Interactions: Separating the Signals from the Noise

SAN DIEGO – It is certainly reasonable to be concerned about potential adverse effects and interactions between the drugs you prescribe and the supplements your patients are taking on their own.

But keep in mind that there is very wide variation in the quality of published data on interactions. In fact, many adverse event alerts are based on unverified case reports called in to the Food & Drug Administration or regional adverse events reporting systems. Some of the interactions widely cited in medical textbooks are actually based on very flimsy evidence. Others are all too real.

When it comes to interactions, it is admittedly difficult to distinguish the real from the ridiculous in many cases, which is why Creighton University's Center for Drug Information and Evidence Based Practice ( is an extremely valuable resource for busy physicians.

Creighton’s team of pharmacologists, epidemiologists, and clinical researchers systematically screen tens of thousands of published and unpublished reports, surveys, and regulatory alerts worldwide, in an effort to identify which potential interactions and AE's warrant serious attention.

Speaking at Scripps’ 6th annual Evidence Based Update on Natural Supplements, Phillip Gregory, PharmD, a member of the Creighton team, and editor of the Natural Medicines Comprehensive Database ( ) said that many of the red flags physicians hear of are little more than isolated and unverified case reports. With its limited resources, FDA only investigates a potential adverse event or interaction if there is a cluster of reports that scream for attention.

Based on the best available data, Dr. Gregory and his team have identified a number of significant concerns while exonerating herbs or nutrients that have been unduly vilified. Here are a few of their findings:

Bitter Orange & CV Problems: Bitter Orange, also known as Citrus aurantium and Fructus aurantii, has been used for centuries in traditional Chinese herbal decoctions for digestive problems. Owing to its thermogenic properties, it has recently found its way into weight loss and "energy" supplements, especially following the FDA's ban on Ephedra.

This fruit contains high levels of synephrine, sometimes as much as 30%. If used indiscriminately, it can induce the same adverse effects as Ephedra, including arrhythmias, ischemic stroke, syncope, QT interval prolongation, MI, rhabdomyolysis and ischemic colitis.

At the same time, actual reported problems are rare; in some cases the problems were in people taking Bitter Orange with other stimulants like caffeine and the popular South American herb, Guarana. So it is not entirely fair to demonize Bitter Orange itself, especially if given judiciously by qualified TCM practitioners.

Given the seriousness of these potential side effects, doctors should discourage patients from taking Bitter Orange for weight loss. "The risks outweigh the potential benefits in my mind," Dr. Gregory said. Be aware that some products containing Bitter Orange are promoted as "Ephedra Free," leading consumers to believe they're a safer alternative. While these products may technically be free of Ephedra, they're not necessarily free of Ephedra-like risks.

Glucosamine & Chondroitin Plus Warfarin: Several years ago, there was a widely publicized case report of bleeding and bruising in a patient on warfarin who also took this popular arthritis combo remedy. Since then there have been 40 reports to FDA or WHO of interactions between warfarin and glucosamine alone or glucosamine with chondroitin.

Close examination of the reports, however, show that in most cases people were taking very high doses of glucosamine/chondroitin, in some cases up to 6 times the recommended dose.  "It is probably not a real problem in people who take the recommended doses, but patients taking warfarin should be careful," he said, adding that this message holds for almost anything one adds on top of warfarin.

Glucosamine does have a "heparinoid" structure and could have a mild anticoagulant effect. However, data to support this notion are pretty weak. Another possible explanation is that the supplement somehow modifies gastrointestinal flora, thus altering warfarin pharmacokinetics, but this too is speculation.

Calcium & CV Risk: Last year a large study in the British Medical Journal indicated that older women taking more than 1 g calcium citrate per day had twice the incidence of MI, and significant increases in coronary artery calcification over a 5 year period (Bolland et al. Br Med J. 2008). That’s worrisome, given how many post-menopausal women take calcium to prevent osteoporosis. But Dr. Gregory said the study is crawling with confounding variables and unanswered questions, making it difficult to draw a firm conclusion.

The study gives no data on magnesium levels; since calcium and magnesium are antagonistic, the observed problems may reflect the fact that patients were on "unopposed" calcium. In those with already low baseline magnesium, this could be dangerous. "If the calcium to magnesium ratio exceeds 2:1 it can be problematic. In the US, many people have levels of 6:1," Dr. Gregory noted.

He added that the observed increase in heart problems may also be related to low levels of vitamin D and vitamin K, all of which play a role in calcium metabolism and bone formation.

"This study is an alert, not absolute proof, and the finding has not shown up in other calcium studies. So don’t assume that calcium is causing the problem. Do not dissuade patients from taking calcium, but don't overdo it: 1,200 mg per day is fine." And make sure they are also getting magnesium.

Selenium & Type 2 Diabetes: Selenium has been proposed as a preventive for several different conditions including Alzheimer's disease, prostate cancer (though its merits in this context were challenged by the SELECT trial), and type 2 diabetes. The latter recommendation is based on epidemiological data showing a strong inverse correlation between diabetes and selenium intake.

But secondary analysis of data from the Nutritional Prevention of Cancer Trial shows that people taking 200 mcg of supplemental selenium daily had a significant increase of type 2 diabetes over 8 years (Stranges et al. Ann Intern Med 2007). This unexpected finding was corroborated by the SELECT trial, which also showed a diabetes increase, albeit not statistically significant, in those on selenium alone. However, there was no diabetes increase in the SELECT patients taking selenium plus vitamin E compared with those getting placebos.

What gives?

"When selenium is taken by itself, it may be oxidative rather than anti-oxidative. So taking high doses of selenium or any other independent antioxidant may not be so healthy," hypothesized Dr. Gregory. Though the picture is hardly clear, he advised against recommending selenium alone, especially for individuals prone to insulin resistance and diabetes. "The diabetes finding is a signal. We can't draw definitive conclusions from it, but we do need to be aware of it."


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