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The motivation for individuals to purchase and consume dietary supplements is not always driven by the desire to supplement the normal diet. The reported main motivators for using dietary supplements most commonly include overall health improvement and maintenance, with use heavily dependent on age, gender, socioeconomic status, health insurance, and lifestyle.
Individuals who take daily supplements more often self-initiate their use versus consult with a medical professional. The danger in self-prescribing daily supplements is possible drug-nutrient interactions (i.e., contraindications) that impact absorption, efficacy, and clearance of medications. What’s more, there is little information available on product packaging about the safety risks associated with high doses of supplements taken with medications or co-administered with other dietary supplements. Despite this fact, supplement use is steadily increasing with the central goal of prolonging health.
Unbeknownst to the health-conscious consumer, supplements can pose serious potential health risks when haphazardly combined (i.e., “vitamin-mineral” interactions). People may inadvertently over-supplement with one vitamin or mineral and provoke a deficiency in another. In some cases, there is evidence of a synergistic effect when combining certain micronutrients. Vitamin-mineral interactions are important to explore, understand, and know.
What are vitamin-mineral interactions?
Although many adults turn to supplements for general health support, there is evidence that supplements are consumed to compensate for a lack of certain micronutrients in the diet. The most common micronutrients of concern are iron, zinc, vitamin A, folate, vitamin B12, and calcium. As such, individuals may seek out single-nutrient supplements to fill in the gaps in their diet.
Vitamins and minerals interact with one another at a chemical and biophysiological level in the body, and each has important roles that facilitate normal functioning. Vitamin-mineral, vitamin-vitamin, and mineral-mineral interactions commonly occur with single-nutrient supplements. While micronutrients can be integral to optimal nutrition status and their sufficiency supports normal physiological function, supplementary vitamins and minerals must not contribute to toxic accrual in the body.
Bioavailability of vitamin and mineral supplements
Individuals can consume sufficient dietary sources of vitamins and minerals and still experience micronutrient deficiencies. Reasons for this nutrient gap include poor bioavailability resulting in disrupted absorption or perhaps food processing that affects the utilization of micronutrients. The bioavailability of nutrients largely depends on the health status of the individual. In poor states of health, absorption of nutrients declines, and malnutrition can worsen micronutrient deficiencies. However, some vitamin and mineral combinations may enhance overall immune function, even in poor states of health.
Antagonistic vs. synergistic interactions
Combinations of micronutrients may have a synergistic effect, which results in a health benefit. Increased absorption and bioavailability of nutrients can occur when combining certain micronutrients and help prevent deficiencies. Synergistic interactions may also indirectly become effective strategies for preventing or overcoming diseases caused by deficiencies.
However, not all interactions produce a beneficial effect. Certain combinations of supplements may become harmful to health (i.e., antagonistic). Supplements taken in non-physiological doses (i.e., amounts that exceed recommended daily amounts) are absorbed differently than physiologic doses. In some cases, high doses of nutrients are absorbed more like drugs in that they exert a stronger effect on the body and alter absorption of other nutrients. While combinations of some micronutrients may be beneficial, high doses of single-nutrient supplements, especially in combination with other supplements, may increase the bioavailability of the nutrient in a harmful way. A U-shaped curve can be observed for single-nutrient supplementation, wherein a benefit is demonstrated within a specific range. Outside this range, individuals are either deficient or have toxic levels of a nutrient, with both scenarios causing harm to health.
Antagonistic Interactions
Vitamin D and magnesium
Vitamin D supplementation may provoke a magnesium deficiency. Vitamin D helps the body absorb minerals, such as calcium, magnesium, copper, zinc, iron, and selenium. Similarly, it increases the absorption and accumulation of lead, arsenic, cobalt, aluminum, cadmium, and strontium. For this reason, it is important to consider the effects of excess vitamin D and its effect on the accumulation of toxic metals that could counterproductively decrease vitamin D in the body.
Vitamin D levels are reportedly inadequate around the globe despite its many benefits to health, including lowered risk of all-cause mortality, bone health, normal parathyroid hormone levels, and immune system support. As such, individuals with inadequate levels of vitamin D may turn to supplementation to boost their levels. Supplementing with vitamin D may prevent the development of osteoporosis, parathyroid hormone issues, osteoarthritis, multiple sclerosis, hypertension, and some cancers. However, excess vitamin D supplementation can provoke a magnesium deficiency, which is further aggravated by toxic metal accumulation.
Magnesium is an important mineral in its own right and acts as a cofactor for vitamin D in its conversion to its active form. When magnesium is deficient, vitamin D becomes less available, and mood disorders, cardiovascular issues, poor immunity, and increased C-reactive protein may arise. High doses of vitamin D use up magnesium in the body.
Vitamin D and vitamin A
Although supplementation with vitamin A and beta-carotene reduces lung cancer risk, supplementation in current or past smokers may potentiate lung cancer. Individuals who supplemented with vitamin D have a reduced risk of lung cancer mortality. However, individuals who supplemented with vitamin D and vitamin A/beta-carotene have more risk, suggesting a possible interaction between nutrients. While past smokers are often encouraged to minimize exposures to beta-carotene, it would be prudent to consider their vitamin D supplementation if co-supplemented with vitamin A.
Zinc, iron, and calcium
Individuals who are marginally deficient in zinc and supplement with iron and calcium may become significantly deficient in zinc. This is of particular concern because pregnant women are often recommended iron and calcium supplements to support maternal and fetal health.
Calcium has been shown to reduce zinc absorption. A study on rats given iron and calcium supplements became significantly deficient in zinc in just six weeks. Of note, researchers observed a decrease in superoxide dismutase activity with lower levels of zinc, possibly due to its role in activating this enzyme. Additionally, reduced alkaline phosphatase activity may be the result of decreased levels of zinc. These findings were observed when rats were given single nutrients and in combination. Zinc deficiency can eventually lead to reduced serum calcium levels and absorption and increased parathyroid hormone, which may result in bones becoming more brittle and susceptible to fractures.
Zinc and magnesium
Unlike reduced calcium absorption with zinc deficiency, zinc supplementation may inhibit magnesium absorption. In a study looking at magnesium absorption, individuals were given zinc in addition to calcium in doses of 230, 500, or 800 mg per day. Researchers found that zinc supplementation, regardless of the dose of calcium, decreased magnesium absorption.
Zinc, iron, and copper
An important factor in supplementing with single-nutrient mineral supplements is the competition between micronutrients with similar uptake processes. For zinc, iron, and copper, this is especially true. When iron is consumed in excess, the uptake of both copper and zinc is inhibited. When zinc is consumed in excess, it may reduce the uptake of copper, which can affect iron. Even when these minerals are supplemented concurrently in an equal ratio, both iron and copper uptake are inhibited by nearly 40%.
Zinc, iron, and copper are taken up by the same transporter, thus they compete for absorption. However, pathologies of certain diseases may shed more light on how copper might compete with zinc and worsen disease outcomes. For example, individuals with acute heart failure have significantly higher levels of copper compared to zinc, which is significantly lower. Similarly, individuals with recurrent aphthous stomatitis have higher levels of copper compared to zinc. Concerning disease development and management, supplementation with minerals should be carefully managed.
Calcium and magnesium
Calcium supplementation can lead to reduced magnesium absorption, which can contribute to the formation of kidney stones. Low magnesium absorption combined with high calcium absorption is a risk factor for renal calcium kidney stone disease. This situation may be potentiated by the competition of calcium and magnesium for absorption and transport in the intestines.
However, supplementation with magnesium will offset increased calcium. Supplementing with magnesium helps prevent excess calcium absorption while increasing the absorption of magnesium.
Folic acid and zinc
Folic acid supplementation may inhibit zinc absorption, thereby leading to a deficiency in zinc. Folic acid enhances zinc excretion, even when individuals are supplemented with zinc. A possible mechanism to explain this is the binding together of folic acid with zinc, which would reduce the absorbability of zinc.
However, the formation of complexes between folic acid and zinc in the intestine may result in reduced folic acid absorption. When individuals are supplemented with either zinc or folic acid, the transport of folic acid and zinc is significantly reduced, respectively. This finding suggests that zinc and folic acid mutually inhibit each other.
Vitamin B12 and folic acid
Deficiencies in vitamin B12 and folate present similarly. When an individual is clinically deficient in vitamin B12 (i.e. pernicious anemia), they will have suboptimal hematological biomarkers and a range of neurological symptoms. However, subclinical vitamin B12 deficiency, wherein hematological biomarkers appear normal, may lead to a misdiagnosis of folate deficiency, resulting in folic acid supplementation.
Individuals who are supplemented with folic acid, but are deficient in vitamin B12, may experience worsening symptoms. High doses of folic acid will inadvertently cover up pernicious anemia temporarily. If anemia is not resolved, symptoms will continue and irreversible neurologic damage can occur.
Sodium and calcium
A diet high in sodium is a risk factor for developing osteoporosis, likely due to increased calcium excretion. Possible explanations include increased glomerular filtration rate and sodium and calcium competing for reabsorption in the renal tubule.
Recommendations for supplementing to avoid antagonistic interactions:
Vitamin D:
Multiple minerals:
Folic acid and zinc:
Vitamin B12 and folic acid:
Sodium and calcium:
Vitamin D and calcium
Oftentimes, vitamin D and calcium are combined in supplements due to the belief that this combination optimizes bone health, but current evidence refutes this claim. However, this combination may still produce a favorable health outcome related to bowel health. There is some evidence that, when combined, vitamin D and calcium have an antineoplastic effect in the colon and act together to help reduce the risk of developing colorectal adenomas.
In a randomized, control trial, individuals with higher baseline vitamin D while taking a calcium supplement showed no association with developing colorectal adenomas, whereas individuals with a lower baseline vitamin D only had a reduced risk. Although supplementing with calcium can reduce the risk of colorectal adenomas with lower vitamin D levels, this study suggests that co-supplementing with vitamin D and calcium may further reduce risk.
There is also evidence that this combination may help support normal apoptosis in the colon. Greater consumption of both calcium and vitamin D shows a higher apoptosis score compared to individuals with lower or no supplementation. The effect is less pronounced when calcium and vitamin D are supplemented on their own versus when they are combined.
Vitamin D and vitamin K
Vitamin D and vitamin K are important nutrients involved in calcium metabolism, bone health, and cardiovascular health. In bones, vitamin D enhances the vitamin K-dependent processes that activate bone formation. Vitamin D plays a role in the production of vitamin K-dependent proteins involved in carboxylation, which is an important process for calcification and bone metabolism.
Vitamin D and vitamin K appear to work together in cardiovascular health. Blood vessel wall health is maintained with the combination of supplements compared to vitamin D taken on its own. Further, the addition of vitamin K to a combination of vitamin D and calcium supplements produces less coronary artery calcification. Combined vitamin D and vitamin K may also significantly reduce serum insulin, resolve insulin resistance, improve B-cell function, increase insulin sensitivity, decrease triglycerides, and decrease very low-density lipoprotein (VLDL) cholesterol.
Vitamin A, iron, and zinc
An important component of the synergistic effects of co-supplementation is bioavailability. Iron, zinc, and a combination of both improve the bioavailability of vitamin A. In particular, iron enhances bioavailability most and increases retinol (an active form of vitamin A). Nonetheless, supplementation with single-nutrient zinc and a zinc plus iron supplement will help improve the bioavailability of provitamin A carotenoids (e.g., alpha-carotene, beta-carotene, beta-cryptoxanthin).
Iron, iodine, and selenium
A balance of iron, iodine, and selenium is required for thyroid health. Although iodine is essential for thyroid health, excess iodine consumption can cause thyroiditis. Further, an iron deficiency can worsen and reduce thyroid metabolism because thyroid peroxidase (TPO) is only activated when it binds with iron. TPO is necessary for the production of T4 and T3 from iodine. Glutathione peroxidase (a selenium-dependent reaction) helps clear excess hydrogen peroxide from the iodination process of thyroglobulin to thyroid hormones. Collectively, iron, iodine, and selenium help support normal thyroid function.
Vitamin C and iron
Vitamin C improves iron absorption and metabolism. There is some evidence that the same is potentially true for supplemental vitamin C and iron.
A randomized, control trial evaluated 440 adults with iron deficiency anemia and found that a combination of iron and vitamin C supplement increased hemoglobin levels by an average of 2.00 g/dL, whereas an iron-only supplement showed a mean change of 1.84 g/dL over two weeks. Other studies showed there is no difference between combination or single-nutrient supplementation. It is possible that the processing of vitamin C causes it to become unstable, which may explain why there is evidence that co-supplementation is not more advantageous.
Vitamin D, vitamin C, and zinc
Vitamin D, vitamin C, and zinc appear to work together to bolster the immune system. Because of their roles in the immune system, they effectively work by increasing the body’s natural defense system. Vitamin C supports cellular function and is involved in collagen production, which creates a physical barrier from foreign invaders that may enter through the skin. Zinc supports B- and T-lymphocyte processes necessary for immune function. Vitamin D plays a role in the permeability of the skin and supports anti-inflammatory processes at the cellular level when fighting infection or illness.
Ultimately, in combination, these micronutrients are necessary for immune function, and symptoms of illness and infections may decline. Most importantly, vitamin D, vitamin C, and zinc support the immune system by improving the epithelial barrier and skin integrity, supporting cells from foreign invaders, and helping produce antibodies.
Vitamin C, vitamin D, and selenium
Baseline health and nutrition status affect how an individual combats illness, especially if immune function is compromised due to micronutrient deficiencies. To enhance the body’s defenses against infections, increase immunity, and combat deficiencies associated with infections, individuals may supplement with vitamin C, vitamin D, and selenium.
As mentioned above, vitamin D helps immune function by supporting a physical barrier against infection and improves anti-inflammatory defenses. Because of the antiviral actions of vitamin C, it has been shown to reduce the risk of mortality with COVID-19 infection. Selenium plays a role in T cell functionality and maturation and the production of antibodies. When combined, vitamin D, vitamin C, and selenium may strengthen the immune system, especially when the consumption of each constituent micronutrient is inadequate in the diet.
Vitamin E and vitamin C
Vitamin C is both an antioxidant and a prooxidant, depending on the dose. When supplementing with vitamin C, potential outcomes include improved baseline antioxidant status and enhanced vitamin E levels. Vitamin C helps prevent vitamin E deficiency and maintains sufficient levels by preventing vitamin E degradation.
Despite the numerous benefits of vitamin C supplementation on vitamin E status, high doses of vitamin C become prooxidant in the body. In this scenario, vitamin E should be co-administered to offset the negative effects of high vitamin C. Together they produce a synergistic effect in support of antioxidant activity.
Vitamin E and selenium
Vitamin E and selenium are potent antioxidants that can be used for the prevention of prostate cancer. The main mechanism of action is apoptosis, which induces the death of cancerous cells. Studies demonstrate that concurrent supplementation is more beneficial than single-nutrient supplementation. When combined, they act together to increase the Bax/Bcl-2 ratio, promoting cell death.
In addition to chemoprevention, vitamin E and selenium may support cardiovascular health in cases of iron overload. By supporting antioxidant activity, both supplements taken together will increase both vitamin E and selenium levels, increase glutathione peroxidase activity, and reduce serum iron. However, there appears to be heterogeneity in reactions to co-supplementing vitamin E and selenium. Age, gender, and health status may indicate the effect of a combined supplement.
Magnesium and vitamin B6
Premenstrual symptoms may be alleviated by taking a combination of magnesium and vitamin B6. Magnesium as a single nutrient was first introduced in premenstrual syndrome (PMS) support due to magnesium deficiency and the effect of magnesium on muscle contraction. Vitamin B6 has been shown to support mood changes related to PMS, including depression, fatigue, and irritability. When combined with vitamin B6, PMS improves more than just magnesium on its own, which suggests a synergistic effect.
Calcium and vitamin B6
Further benefits to PMS are also found with a combination of calcium and vitamin B6. When taken in a combined supplement, PMS symptoms decrease more than when either supplement is taken on its own. Both calcium and vitamin B6 taken independently from one another may help alleviate PMS symptoms, but when combined, the reduction is significant.
Recommendations for supplementing to support synergistic interactions:
Vitamin-mineral interactions can be both helpful and harmful, producing synergistic and antagonistic effects, respectively. Because of bio-individuality and differences in daily diets, lifestyles, living environments, stressors, socioeconomic status, age, and gender, each person may require personalized supplement recommendations to augment their nutrition. Nutrient needs depend on the individual, and careful consideration should be made when consuming supplements. Understanding how supplements may interact with drugs, foods, and other supplements could prevent unwanted health outcomes.
Of course, a food-first approach fosters a sense of well-being. People can take the synergistic approach of increasing fruits, vegetables, whole grains, and functional foods (foods containing phytochemicals) to maintain or improve health and prevent disease.
If you have questions about which foods or supplements can best support your health, talk to your doctor, nutritionist, dietitian, or another member of your healthcare team for personal options based on your individual circumstances.
