Do your supplements mix well with prescription drugs?

By Naveed Saleh, MD, MS, for MDLinx
Published June 12, 2019

Key Takeaways

Supplements, as you may well be aware, are not regulated in the same way that prescription drugs are. Although the FDA requires manufacturers to submit safety data about any new ingredient not sold in the United States in a dietary supplement prior to 1994, the FDA is not authorized to review supplements for safety and efficacy prior to marketing in all other cases. Thus, it’s unclear what the adverse effects of the herbs and nutrients contained in supplements are, and whether these active ingredients may interfere with the actions of other drugs.

The little we know about supplements and their interactions stems from animal studies, case reports, case series, historical contraindications, assumptions from basic pharmacology research, and oft-cited speculative or outdated data. Moreover, randomized, double-blind clinical trials involving supplements are uncommon, and case reports often lack adequate, evidence-based detail.

In addition to the unknowns about the pharmacokinetic properties of supplements, many supplements contain herbs with complex mixtures of ingredients, which depend on factors such as growth, harvesting, processing, and formulation. To boot, these unregulated supplements may also contain various adulterations. Researchers have found, for instance, that a number of Chinese medicines randomly purchased in New York City’s Chinatown contained a variety of undeclared drugs, including promethazine, chlormethiazole, chlorpheniramine, diclofenac, chlordiazepoxide, hydrochlorothiazide, triamterene, diphenhydramine, and sildenafil.

Based on the limited amount of information out there, let’s look at some supplements that likely interact with prescription medications in undesirable ways.

St. John’s wort

Estrogens are metabolized, in part, by cytochrome P450 3A4 (CYP3A4), and inhibitors or inducers of this enzyme can alter estrogen metabolism. St. John’s wort comes from a European flowering shrub and is used to treat mild to moderate depression and symptoms of menopause. It triggers CYP3A4 and interacts with p-glycoprotein, which could lead to increased breakdown of estrogen and other drugs metabolized by this enzyme. Importantly, individuals taking oral contraceptives and St. John’s wort experienced a decrease in estradiol levels in the blood, according to some studies. St. John’s wort is also thought to decrease the efficacy of various other drug types, including certain antidepressants, immunosuppressants, statins, anti-HIV drugs, and chemotherapeutic agents.

Black cohosh

Black cohosh comes from a member of the buttercup family found in North America and is used to treat symptoms of menopause (eg, hot flashes), premenstrual syndrome, and menstrual cramps. Although there are no reported interactions between tamoxifen—a selective estrogen receptor modulator—and black cohosh in clinical trials, this herb may stymie CYP2D6, the enzyme system responsible for the metabolism of tamoxifen, according to some human pharmacokinetic data. However, it remains to be elucidated whether this interaction bears clinical relevance.

Vitamin E

Many foods and medications interfere with the anticoagulant warfarin. Vitamin E is taken to help with Alzheimer’s disease, liver disease, prostate cancer, and preeclampsia. However, some experts have suggested that vitamin E may increase risk of bleeding when taken with warfarin. Furthermore, others have posited that using vitamin E and antiplatelet agents such as aspirin together could inhibit platelet aggregation and lead to an increased risk of bleeding. On a related note, the supplements coenzyme Q10 and ginkgo biloba may also render warfarin and other blood-thinning drugs less effective, according to some researchers. Lastly, in addition to interfering with the effect of anticoagulants, vitamin E could interfere with the drugs metabolized by CYP3A4, such as omeprazole, as well as interfere with anti-tumor antibiotics and alkylating agents.


Athletes take creatine to boost athletic performance and bulk up. Creatine is an amino acid naturally occurring in muscles and the brain. It is found in food sources such as seafood and red meat. The liver, pancreas, and kidneys also make creatine. The creatine found in supplements is produced synthetically. Potentially nephrotoxic drugs, such as nonsteroidal anti-inflammatory drugs (eg, naproxen sodium) and cyclosporine, shouldn’t be mixed with creatine for fear of kidney damage.

Ginkgo biloba

Ginkgo biloba comes from the leaves of the ginkgo tree, one of the oldest living tree species on earth. It has long been used in traditional medicines and, more recently, for the treatment of dementia and claudication. Increased amounts of gingko biloba can lead to seizures and can decrease the efficacy of anticonvulsant drugs. Ginkgo biloba can also decrease the efficacy of antidepressant drugs (eg, fluoxetine) and statins (eg, atorvastatin).

Milk thistle

Native to six of the seven continents, milk thistle—aptly named for the white veins on its leaves—is mainly used for the treatment of liver diseases, such as hepatitis C and cirrhosis, and gallbladder issues. Milk thistle likely interacts with a variety of drugs. For instance, it may increase the concentrations of the hepatitis C drug simeprevir in blood plasma. It may also potentiate the effect of diabetes drugs by further decreasing blood sugar levels. Lastly, milk thistle may reduce the efficacy of the antibiotic metronidazole.

Evening primrose

Evening primrose is native to North America and is used to treat many conditions, including diabetic neuropathy, premenstrual syndrome, and atopic dermatitis. When combined with anticoagulants, however, evening primrose may increase the risk of bleeding. Evening primrose may also slow down the metabolism of anti-HIV drugs, thus increasing concentrations. Evening primrose can also interfere with drugs metabolized by CYP3A4, including lovastatin. Lastly, when combined with phenothiazines, which are used to treat severe psychiatric disorders, seizure threshold could drop.

Many patients believe that supplements in the form of vitamins, minerals, other nutrients, and herbs are more natural or safe than prescription medications. As a physician, it’s imperative to ask all patients about their use of dietary supplements to avoid unnecessary interactions or adverse events. Weigh all substances in your assessment—whether they be prescription, over-the-counter, or dietary supplements.

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