The following is drawn from Nutritional Influences on Illness by Melvyn Werbach, M.D.Third Line Press, 1996. Please consult this book for references for the following information.

1. Beta-carotene: High dosage of vitamin can cause orange discoloration of the skin but pro-vitamin beta-carotene supplementation has not been noted to have significant adverse effects.

2. Biotin: Ethanol inhibits the intestinal transport of biotin and decreases plasma levels.

3. Calcium: Usually no adverse effects at customary supplemental doses. A calcium:phosphorus ratio above 2:1 related to excess calcium results in reduced bone strength and interferes with vitamin k absorption/and or synthesis. Intake over 2 gms may cause primary hyperparathyroidism.

Calcium retention in the body does not necessarily occur with supplementation secondary to limited absorption and increased urinary excretion. Calcium is better absorbed with a light meal than when taken alone. Calcium citrate may be better absorbed than other forms, and calcium citrate-malate may be even better absorbed due to 6 times the solubility of calcium citrate or calcium malate. In the presence of achlorhydria, calcium citrate is absorbed 10 times better than calcium carbonate.

Caffeine increases calcium excretion and fatty acids and fiber may decrease intestinal absorption. There was a negative experimental study with soluble fibers regarding its effect on decreasing calcium absorption. Iron, zinc, lactose, sugar, vitamin D and licorice may enhance calcium absorption whereas magnesium may decrease absorption. Protein and sodium may increase calcium urinary excretion.

4. Carnitine: Supplementation with D, L carnitine (not L-carnitine) has been associated with myasthenia-like syndrome in-patients with renal impairment. With L-carnitine, 41% of patients developed GI side effects and 11% had a body odor. No patient discontinued the nutrient due to side effects and a decrease in dosage reduced or eliminated them. Vitamin C may increase urinary excretion of carnitine.

5. Chromium: Calcium carbonate may reduce chromium absorption and sugar may increase urinary excretion.

6. Copper: Alcohol may aggravate copper deficiency and iron, vitamin B6, vitamin C, and zinc may decrease GI absorption. Molybdenum may increase urinary excretion.

7. Essential fatty acids: Omega 6 fatty acids cannot accumulate in cell membranes if the supply of omega 3 fatty acids is too low. Vitamin E prevents peroxidation of polyunsaturated fatty acids and is recommended with essential fatty acid supplementation.

8. Evening Primrose oil: May exacerbate temporal lobe epilepsy and mania.

9. Folate: 5-10mg/day appears to be well-tolerated in non-pregnant subjects; if used during pregnancy, some studies suggest ensuring adequate zinc intake. Higher dosages may exacerbate psychotic behavior, cause GI side effects, sleep disturbance, malaise and irritability. Occasionally seizures may be induced in drug-controlled epileptics. Will cure the anemia of pernicious anemia but the neuropathology will progress. High dose may decrease vitamin B12 levels so joint supplementation is indicated. Vitamin B12 deficiency induces a functional folate deficiency

10. Germanium: Long-term ingestion of germanium dioxide may be nephrotoxic

11. L-Glutamine: Megadoses (at least 1 gm/day) may cause mania.

12. Guar Gum: May adversely affect food absorption

13. Iron: Supplementation is indicated only for deficiency. Subclinical excess may contribute to a wide variety of diseases. GI side effects are common with iron supplementation. On the other hand, absorption is best on an empty stomach. Ferrous iron is 1 and ½ to 15 times better absorbed than ferric iron. Excessive calcium supplementation can reduce iron absorption. Cobalt competes with iron for absorption. Coffee, tea, milk, soy, tannins, zinc and manganese may reduce iron absorption while protein and particularly vitamin C enhances it. Absorption may be impaired with hypochlorhydria. Vitamin A deficiency impairs iron mobilization and utilization in the body. By enhancing the absorption of calcium(which competes with iron for absorption), vitamin D may decrease iron absorption

14. L-lysine: May increase cholesterol and triglyceride levels.

15. Magnesium: Magnesium citrate is more soluble and bioavailable than magnesium oxide. Iron, calcium, fat, manganese and phosphorus decrease intestinal absorption while vitamin D increases absorption. Vitamin D though enhances calcium absorption more, and tissue calcium may displace magnesium enhancing a functional deficiency. Alcohol, caffeine, sugar, potassium and sodium increase urinary excretion. Folic acid may increase the metabolic need for magnesium by inducing glycolytic enzyme activity requiring magnesium and high protein diets as well as sugar also require increased magnesium. High dose riboflavin may increase the risk of magnesium deficiency. Vitamin B6 and magnesium deficiencies are similar and supplementation with one or the other is helpful. Vitamin B6 increases cell membrane transfer and utilization of magnesium.

16. Manganese: Calcium and copper impair plasma uptake of manganese while zinc may increase plasma levels. Iron may accelerate the development of manganese deficiency.

17. Phosphorus: Caffeine increases urinary excretion and calcium increases fecal excretion. If the calcium: phosphorus ratio is above 2:1 secondary to increased calcium, bone strength is reduced and vitamin K synthesis and/or absorption is impaired with internal bleeding. Vitamin D enhances phosphorus absorption.

18. Potassium: Caffeine increases urinary excretion and potassium deficiency may be refractory to treatment in the presence of magnesium deficiency.

19. Selenium: Organic selenium (L-Selenomethionine) is rapidly and completely absorbed while inorganic selenium (selenite and selenate) is less well absorbed and retained. Inorganic selenium is ineffective in various in vitro experiments against selenium deficiency and can interact with glutathione to form free radicals.

20. Niacin: A flush occurs due to histamine release from mast cells, 20 minutes after ingestion lasting up to 1 to 1 and ½ hours. This usually lessens after 3 days and may disappear at higher doses. Decrease by taking niacin with meals, raising dosage slowly, or taking 300mg aspirin 15 - 30 minutes before ingestion of niacin. Can raise uric acid levels by competing with uric acid for renal excretion. Gouty symptoms or uric acid stone formation is rare though. Can see deterioration in oral glucose tolerance. Hepatic toxicity is rare but may occur with doses over 3 gm/day. Can see with sustained-release niacin, which can also cause bleeding with a prolonged thrombin time and lactic acidosis with nausea and vomiting. Other side effects reported with niacin include pruritus, hyperpigmentation, rash, acanthosis nigricans, nausea, diarrhea, aggravation of peptic ulcers, hypotension and atrial fibrillation.

21. Niacinamide: Common side effect is sedation and large doses may cause hepatic toxicity.

22. Omega-3 fatty acids (fish oil, flaxseed oil, borage oil, evening prinjcose oil): Supplementation may require additional vitamin E to prevent increased membrane peroxidation and immune suppression. A temporary thrombocytopenia may occur. In insulin-dependent diabetics, total cholesterol, HDL2 and LDL may increase. In type 2 diabetics, a reversible metabolic deterioration may occur. In general, plasma fasting glucose and triacylglycerol levels may increase insulin activity decrease, and several indices of cell-mediated immunity decrease.

23. Phenylalanine: Supplementation may cause anxiety, headaches and hypertension. Should be avoided by people with phenylketonuria and pregnant or lactating women.

24. Quercetin: Although has been shown to be mutagenic to mammalian cells in vitro, this has not been confirmed in vitro and only one in vivo study showed this activity. This study showed an increase in bladder cancer in a mouse strain known to have an extremely high rate of spontaneous bladder cancer. Recent research suggests a tumor suppressor effect.

25. Selenium: Toxic dosages may be associated with hair loss, thickened fragile fingernails, muscle discomfort, dermatitis, nausea, garlic breath odor, fatigue and suppression of phagocytic and natural killer cell function. The selenite form generates free radicals by interacting with glutathione in the presence of oxygen. This form should not be used although sodium selenate is less likely to be toxic due to more rapid excretion in the urine than selenite. An adequate ascorbic acid status is important for selenium metabolism. Vitamin E and selenium have closely related mechanisms of action and a deficiency of one can be treated with either nutrient.

26. Thiamine: Side effects from oral supplementation is rare although nervousness, itching, flushing, shortness of breath, tachycardia, a heat sensation and perfuse perspiration have been reported. IM or parenteral injections have caused generalized urticaria, facial edema, dyspnea, cyanosis, wheezing and anaphylactic shock. Magnesium is necessary for the conversion of thiamine to its biologically active form, thiamine pyrophosphate.

27. Vitamin A: Although the most common vitamin toxicity, the worldwide incidence is estimated to be only 200 cases annually. Doses of 25,000 - 50,000 IU/day for several months can produce toxic effects especially in individuals with compromised liver function related to drugs, viral hepatitis or protein-energy malnutrition. Symptoms of chronic toxicity include fatigue, malaise, headaches, abdominal discomfort, constipation, insomnia, restlessness, night sweats, alopecia, brittle nails, irregular menses, emotional lability, mouth fissures, dry, scaly, rough, yellowish skin, superficial retinal hemorrhages, exopthalmos, peripheral edema and increased intracranial pressure with associated symptoms of headaches, nausea and vomiting. Hypervitaminosis A is often associate with hypercalcemia, hypercalciuria and calcium deposition in soft tissues. Megadoses may cause hyperplasia of liver and spleen with abnormalities on liver biopsy. In young children, premature epiphyseal closure may occur with abnormal bone growth. Unusually high dosages have been associated with 5 reported cases of birth defects but a clear causal relationship has not been established. Elevated retinol levels may provoke attacks of gouty arthritis. In most cases, toxicity symptoms are relieved, with cessation of intake, within a few days or a week with eventual full recovery except for bony changes or cirrhosis. Megadoses appear reasonably safe in the treatment of cancer despite the potential for side effects.

Absorption may be significantly impaired with vitamin E deficiency and zinc deficiency impairs the conversion of retinol (the ingested form of vitamin A) into retinaldehyde, the first usable breakdown product. Zinc is crucial in the enzyme alcohol dehydrogenase, which catalyzes this conversion. Zinc deficiency also reduces the synthesis of retinol-binding protein necessary for the release of vitamin A into the blood.

28. Vitamin B6: Supplementation may cause a sensory neuropathy with doses as low as 200mg/day over three years. This is thought related to the higher dosages exceeding the liver's ability to convert the pyridoxine to the active coenzyme pyridoxal-5-phosphate with resulting possible neurotoxicity of high levels of pyridoxine or a binding site competition with the active form, pyridoxal-5-phosphate, resulting in a relative deficiency of the active form. There is an inconclusive report of a variety of neurologic symptoms occurring in a cohort of women with pre-menstrual syndrome that stopped with discontinuation of vitamin B6.

Memory may be impaired with doses of 100mg/day or more. An acniform eruption or worsening of acne vulgaris may occur with supplementation. Magnesium and B6 deficiency produce comparable clinical disorders and a deficiency of one nutrient may be treated with either nutrient in the conditions that have been studied.

29. Vitamin B12: Supplementation may cause an acniform eruption or exacerbate acne vulgaris. Oral or sublingual administration apparently produces negligible blood levels compared to IM injection. High doses of folic acid may reduce B12 levels.

30. Vitamin C: Diarrhea is the main side effect of high dosages. Dosages over 6gm/day may increase urinary oxalate excretion, which may be contraindicated in renal insufficiency and in calcium oxalate stone-formers. Vitamin C enhances iron absorption and is contraindicated in cases of iron overload. Sudden discontinuation of high dosages can cause rebound scurvy so that supplementation should be tapered gradually over several days to weeks. Vitamin C enhances aluminum absorption and should not be taken with aluminum-containing substances especially in the presence of renal insufficiency.

Vitamin C is 35% better absorbed when taken as a natural citrus extract containing bioflavonoids along with protein and carbohydrates. Experimental studies show that vitamin C with citrus bioflavonoids is better absorbed and stays in the body longer than the equivalent dose of vitamin C alone.

31. Vitamin D: Excessive intake may cause hypercalcemia, due to increased intestinal absorption of calcium, leading to calcium phosphate deposition in the kidney with nephrocalcinosis and decreased kidney function. Soft tissue calcification in the joints, blood vessels, stomach, lungs and heart may occur.

In the elderly with insufficient light exposure, 25 ug/day of 25-hydroxyvitamin D3 may be effective in maintaining vitamin D nutriture. Vitamin E deficiency inhibits vitamin D metabolism in the liver and kidneys.

32. Vitamin E: A large review revealed an incidence of non-specific side effects of 0.8%, a figure expected in the non-treated population. Doses up to 3200mg/day have not been found to cause adverse effects but it can exacerbate the effects of vitamin K deficiency. This latter effect is responsible for vitamin E's potentiation of coumadin and it may increase the coagulative function of vitamin K. Vitamin E may increase the inhibition of platelet aggregation cause by aspirin.

The most common side effect from high doses is gastrointestinal with nausea, flatulence and diarrhea. Supplementation can exacerbate hypertension. The water miscible form is preferred in patients with cardiovascular disease and diabetes mellitus since the oily form can increase the serum trigylcerides: vitamin E ratio. Vitamin E may reduce insulin requirements and the insulin dosage in diabetics may need to be readjusted. There are reports of megadoses decreasing thyroid homone but this was not confirmed in a double-blind study. Doses of 40,000 IU/day or more may be teratogenic in pregnancy but doses lower than 10,000 IU/day appear to be safe.

Vitamin E succinate may be more effective in preventing free radical damage than alpha tocopherol. Inorganic (ferric) iron oxidizes and inactivates vitamin E in the intestines but the commonly used supplement, ferrous iron, does not. Vitamin E and selenium have similar mechanisms of action and a clinical deficiency of one can be treated with either nutrient. Zinc deficiency can aggravate the effects of vitamin E deficiency.

33. Vitamin K: Excessive doses of calcium, or a calcium: phosphorus ratio over 2:1 due to excess calcium interferes with vitamin K synthesis and/or absorption resulting in internal bleeding. Intake of a large dose of vitamin E may reduce intestinal absorption of vitamin K and antagonize the effect of vitamin K on coagulation at the level of prothrombin formation.

33. Zinc: Doses of 100 - 300mg/day for several weeks can impair immune function and over several months can produce a severe copper deficiency with hypocupremia, anemia and leukopenia as well as a decrease in HDL cholesterol. Concurrent supplementation with 1.0 mg copper/day is recommended. Pharmacologic doses of 100 - 300mg/day may also cause nausea, increased sweating, alcohol intolerance and transient worsening of depression or hallucinations. Supplementation may increase grand mal seizures in epileptics, possibly related to a reduction in blood manganese levels. In epileptics, manganese supplementation should be started before the use of zinc.

Supplementation is best taken separate from meals as eggs, milk, cereal and other foods will decrease its bioavailability. Zinc picolinate is significantly better absorbed than zinc citrate with decreasing absorption of gluconate, orotate and sulfate in that order. A glucose polymer may enhance absorption. Copper, folic acid, iron and phytates (found in vegetable fiber) may decrease zinc absorption. In iron deficiency, zinc absorption is enhanced and Vitamin A and Vitamin B6 enhances absorption as well. Vitamin B6 deficiency may increase zinc absorption while decreasing serum zinc concentrations suggesting less availability for metabolic processes. Vitamin E deficiency reduces plasma zinc concentrations possibly due to a redistribution of zinc for antioxidant activity, membrane stabilization or prostaglandin function. Vitamin E deficiency aggravates the effects of zinc deficiency possibly related to their mutual effects on reducing lipid peroxidation.

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