Vitamin B6 and B12

by Jessica Slavik, Advanced Case Study student

Vitamin B6 and B12 are both water soluble vitamins in the B complex. They both are important co-factors in many of our body’s metabolic processes. They are often taken together, and work synergistically, along with other B vitamins and especially folic acid, but they each have their own unique functions, sources, contraindications and interactions, so I will describe each individually.

B6

Vitamin B6 or pyroxidine is the generic name for 6 compounds that have the biological activity of pyridoxine. They all convert in the liver to pyridoxal 5’-phosphate (PLP) which is the active form. B6 is stable in heat and acid media, but unstable in alkaline solution and light. It cannot be synthesized by the human body, so dietary intake is necessary. It is present in a wide range of foods. It is absorbed by passive diffusion in the small intestine and then bound to albumin in the blood where it is transported to the liver for conversion or excretion through the urine. B6 as a cofactor plays an important role in more than a 100 different enzyme reactions. Some of the different activities it plays a part in are metabolism of protein, glucose and lipids, synthesis of neurotransmitters (seratonin, dopamine, epinephrine, norepinephrine, GABA), maintaining normal levels of homocysteine (Hcy), immune function, hemoglobin formation, histamine synthesis, and gene expression. B6 can also modify the activity of several major hormones (estrogen and testosterone, eg.) by binding to the receptor sites and lowering their effects through competitive inhibition.

Deficiency

A deficiency of isolated B6 is uncommon, it usually occurs with a deficiency in other B complex vitamins at the same time. Deficiency becomes more obvious as it progresses, with severe deficiency showing symptoms such as microcytic anemia, dermatitis, scaling on lips and cracks at corners of mouth, glossitis (swollen tongue), depression, confusion, weakened immunity, and neuropathy. Mild or borderline deficiency may have no noticeable symptoms for months or years. Some risk factors for deficiency are: impaired renal function, malabsorption diseases like Crohn’s or UC, autoimmune disorders, alcohol dependence, liver disease, hyperthyroid, HIV, type 1 diabetes, and chronic fatigue. In addition, several medications can cause a deficiency, which I will describe later. In the U.S. some sources say that most people consume enough B6 in their diets, an average of 1.5 mg per day, (U.S. Dept of Health and Human Services) with 11% of supplement users and 24% without supplement, showing low plasma levels of PLP. Another source (Treasure/Stargrove) says that 90% of women and 71% of men have diets low in B6, which may be partially attributed to the milling and processing of
grains, which removes 40-90% of B6, and to exposure to medications and pollutants.

Recommended Intake

The Recommended Dietary Amounts (RDA) for Vitamin B6 are for adults 14 years and over 1.3 mg to 1.7 mg per day, increasing with age, 1.9 mg if pregnant, and 2.0 mg if lactating. The Upper Limit (UL) is 100 mg per day.

Food Sources

B6 can be found in a wide variety of food sources, the highest being organ meats, turkey, tuna, spinach, bananas, lentils, and potatoes. It is also found in pork, poultry, milk, egg yolks, corn, legumes, grains, brewer’s yeast, green vegetables, avocados, cantaloupes, carrots, molasses, nuts, peas and non-citrus fruit. Cooking, storing or processing foods destroys a

portion of B6. Freezing destroys 20%, canning 54% and milling 40-90%. B6 found in vegetables is considered the most stable.

Supplements

B6 supplements come in multivitamins, B-complex vitamins, or as a single vitamin. The most common forms are pyroxidine hydrochloride and pyridoxal 5’-phosphate (PLP). The hydrochloride is the most common in conventional medicine, it has efficient blood transport and can cross the blood brain barrier. Many nutritional therapists now recommend PLP which is the activated form. It is more effective if the patient has impaired conversion from liver disease or a zinc or magnesium deficiency. Supplements can found in many forms: oral, sublingual, nasal sprays or by injection (prescription only). Donald Yance recommends only using naturized B vitamins (Grow Company), which are grown on a single celled fungus or yeast rather than chemically synthesized. He says that naturized B6 is 2.54 x more absorbed into the blood than standard USP vitamins which may also contain toxic by-products. (B6 is made with petroleum ester and hydrochloric acid with formaldehyde.) Dosing of naturized B6 is much lower, at 5-10 mg per day.

Suggested dosage ranges widely, depending on the source as well as the purpose. Standard medicine uses B6 supplementation only when there are signs of deficiency, recommending a dose of 10-40 mg per day, but nutritional therapists have been using B6 therapeutically for decades, reporting good results, in doses from 50-200 mg per day, occasionally up to 500 mg per day for short periods, claiming that while the UL is 100 mg per day, no evidence of damage has been seen under 200 mg, with most cases of toxicity at over 1000 mg per day. Using 100-200 mg per day for longer than 2 months should be done under supervision and discontinued if any neurological effects occur. No more than 100 should be

taken during pregnancy or lactation as B6 crosses into the placenta and breastmilk. Supplements are usually not recommended for kids under 12.

Side Effects / Safety

Side effects are seen only in supplemental use of B6, not from food intake. Although water soluble and efficiently excreted through the urine, B6 is the only B vitamin with toxicity concerns. Long-term doses over the UL can result in irreversible neurological damage, causing severe and progressive sensory neuropathy with signs starting as numbness and tingling in the extremities. Symptoms of neuropathy have been reported on average after taking high doses (1000 mg) of the supplement for 2.9 years, and usually stop if discontinued as soon as they appear. Other side effects can be sensitivity to sunlight, skin rashes, nausea, vomiting, abdominal pain, loss of appetite, headaches, insomnia, breast tenderness, acne, and increased liver function. Although
not clinically evaluated, it is possible that these adverse effects could be attributed to intake levels that exceed the liver’s ability to convert pyridoxine to PLP, and therefore taking PLP may have fewer side effects.

Therapeutic Uses

B6, along with B12 and folic acid help to reduce levels of homocysteine in the blood. Homocysteine is a sulphur containing amino acid derived from methionine which is part of a chain of metabolic processes which need B complex vitamins to convert it to its next derivatives. High levels of homocysteine are a risk factor for many disorders such as cardiovascular disease, strokes, cognitive decline, lowered immune function and general inflammation. While
there is a lack of clinical trials showing its effectiveness in reducing these risks, nutritional therapists use B6 (and other B vitamins) to treat these conditions. Other conditions that are commonly treated with B6 are PMS, nausea and vomiting in pregnancy (the American Congress of Obstetrics and Gynecology recommends 10-25 mg of B6 3-4 X daily, and if this doesn’t work to then add doxylamine), colo-rectal cancer, chemo-related neuropathy, depression, nerve compression issues like carpal tunnel, arthritis, ADHD, diabetes, kidney stones, acne, asthma, side effects of oral contraceptives, and to counter-effect B6 depleting medications.

Lab Tests

There are no generally accepted lab tests for B6, but here are some ways to test levels: Plasma PLP: less than 30 nmol/L shows deficiency. (symptoms of deficiency may occur even with normal levels) Plasma total B6: less than 40 nmol/L shows deficiency. Urinary 4-pyridoxic acid: less than 3.0 umol per day shows deficiency. Erythrocyte glutamic-pyrnric transaminase index (EGPT): a ratio of greater than 1.25 shows deficiency.

Interactions

Drug:
Several drugs can deplete B6 levels, which can be countered by supplementation without interfering with the drug’s efficacy. These are: methotrexate, theopylline, furosemide, loop diuretics, isoniazid, cycloserine and anti-tuberculars, thiosemicarbazide, oral contraceptives, gentamicin, neonycin, aminogycide antibiotics and haloperidol. High levels of B6 can accelerate the metabolism of levodopa (anti-Parkinson’s) impairing its therapeutic activity. Low doses are fine.

B6 may prevent or mitigate adverse effects and enhance clinical outcomes of anti-convulsants, barbituates, amiodarone, erythropoietin and stimulating agents, and tricyclic antidepressants. B6 may bind to some antibiotics such as tetracycline, hydralazine and penicillamine, lowering the drug’s availability, but not usually to a clinically significant degree.

Nutrient and Herb:

B6 has a synergistic effect with CoQ10. Both decline with age and are associated with cognitive decline and cardiovascular disease. B6 works together with B12 and folic acid to reduce homocysteine levels. Long-term dosing of B6 alone can upset the balance, reducing serum folate levels. B6 may increase bioavailability of oral magnesium, and enhances the absorption of zinc. B6 and ginger administered together can safely and effectively treat nausea and vomiting in pregnancy.

B12

Vitamin B12 is the generic name for a group cobalt containing compounds called cobalamins. Cobalamin is a precursor to the bioactive forms, methylcobalamin and adenosylcobalamin. B12 is a water soluble, red coloured, crystalline substance, which will degrade in dilute acid, alkali, light, and with oxidization. B12 found in food is bound to proteins, and released in the stomach by hydrochloric acid and proteases. It is absorbed in the ilium and is highly dependent on Intrinsic Factor (IF) which is produced by the parietals cell in the stomach lining. The IF binds to B12 enabling transfer across the intestinal mucosa where it enters the bloodstream and makes its way to the liver, where it can be stored for up to 3 years, as well as the kidneys and adrenal glands. It is excreted though the urine. B12 cannot be produced by any plants, fungi or animals. Only bacteria and archaea have the necessary enzymes. B12 was discovered through its relationship with pernicious anemia, an auto-immune disorder in which the parietal cells are destroyed.

B12 is vital to the metabolism of every cell in the body. It is a coenzyme needed for many functions such as: fat and carbohydrate metabolism, protein synthesis, cell replication, hematopoesis, the conversions of homocysteine, synthesis of DNA and myelin sheaths. B12 is a cofactor in methylation, a vital biochemical process in which a methyl group of atoms (one carbon and three hydrogens) is added to another compound such as homocysteine, to create a new molecule with a new function, such as methionine, an essential amino acid which is involved in a number of biochemical processes including synthesis of neurotransmitters and SAMe. B12 is necessary for the maturation of red blood cells, without it they can grow without dividing, becoming megaloblasts, leading to a condition called megaloblastic anemia.

Deficiency

Symptoms of B12 deficiency include numbness and tingling in the hands, legs and feet, difficulty walking, anemia, swollen, inflamed tongue, jaundice, cognitive difficulty, memory loss, paranoia, hallucinations, mania, weakness and fatigue, lack of appetite, weight loss and depression. Symptoms can come on gradually or suddenly. Untreated, B12 deficiency can cause severe and irreversible damage, especially to the brain and nervous system. Levels only
slightly low can cause symptoms like fatigue, lethargy, depression, poor memory, breathlessness and headaches. The most common cause of deficiency is malabsorption. Some other common risk factors are: Elders- 10-30% of elders experience atrophic gastritis, producing a sub-normal amount of
hydrochloric acid to release B12 from protein. Pernicious Anemia- lack of intrinsic factor. 1% of B12 can be absorbed without IF, so large oral
doses can be an effective treatment. G.I. disorders or intestinal surgery- celiac, Crohn’s, etc…affects absorption in the small intestine. Vegetarian or vegan diets- especially kids born to vegan moms. 40-80% of vegetarians and 80% of vegans are deficient.

Also, pregnant or lactating women, alcoholics, long-term antibiotic therapy, PPIs, H2 blockers, metformin, nicotine, malnourishment, HIV, psychiatric disorders, pancreatic disorder, and tapeworms. While it has not been directly studied, it is recognized that antibiotic use can have a direct effect on B12 levels as well as many other nutrients by reducing absorption and increasing elimination, due to the eradication of healthy gut flora. The use of probiotics afterwards is essential to protect nutritional status. Deficiency can be hard to recognize and is more normal than suspected. Serum levels can look normal even when a significant deficiency is present. In the U.S. deficiency is estimated to be 1.5-15%.

Recommended Intake

The RDA for B12 is 2.4 ug per day for adults over 14, 2.6 ug for pregnancy, and 2.8 for lactation. It is recommended that people over 50 take a supplement. There is no UL (upper limit), with no adverse effects from high doses.

Food Sources

Food sources for B12 include clams, organ meats (esp. liver), lamb, beef, turkey, fish, eggs, crab, oysters, aged cheese, milk, fortified foods and fortified brewer’s or nutritional yeast. B12 is not found in any fruit, vegetable, grains or legumes. B12 is produced by bacteria in the gut, but is not absorbable as it is made in the colon and not the small intestine, but this makes feces a rich source for some animals. 30% is destroyed by cooking.

Supplements

The most common B12 supplements are hydroxycobalamin and cyanocobalamin. Cyanocobalamin contains a ‘safe’ amount of cyanide. Methylcobalamin (the active form) is sometimes used but is more expensive. B12 is produced industrially through a bacterial
fermentation process. B12 comes in many forms, in multivitamins, B-complex, or alone. It can be taken orally, sublingually, in lozenges, pills, lollipops, patches, intra-nasally or by injection. There is no evidence that the sublingual form is absorbed better than oral supplements, but intranasal may be, as it bypasses the digestive system. Unless using injectable (prescription only) B12, the body’s ability to absorb it is limited by the amount of IF you have, but this can be overcome by taking large enough doses (eg. 1 ml) that the 1% you are able to absorb without IF is enough. Injectable B12 is usually used for treating pernicious anemia, severe malabsorption and severe deficiency. B12 is also commonly used to enrich grain based foods like bread and breakfast cereal and pasta, as well as in energy drinks and shots. Supplemental dosage of B12 is recommended at 50-100 ug per day for maintenance and from 100 to 3000 ug per day therapeutically. A clinical trial by Eussen et al showed that the minimum oral dose required to normalize a mild B12 deficiency is 500-600 ug per day, showing that the standard dosing levels may be much too low. It is advisable to give B12 with folic acid so the levels of these two do not become unbalanced. As with B6, Donald Yance recommends taking B12 in a naturized form, which is 2.56 times more absorbed into the blood than the standard USP, and contains no cyanide.

Side effects / Safety

No toxicities are reported or suspected with B12 use. Infrequent reactions may be diarrhea, urticaria, itching skin and peripheral vascular thrombosis. Large doses may exacerbate acne symptoms. Injectable B12 may rarely provoke reactions, sometimes severe, which may be related to the cyanide content, or to preservatives such as benzyl alcohol. B12 is safe for pregnant and lactating women, and for kids.

Contras

B12 is contraindicated in hypersensitivity to B12, and in hereditary optic neuropathy (Leber’s disease). Apparent deficiency should not be treated with B12 alone until a folate deficiency is ruled out. Treating B12 related megaloblastic anemia may result in severe hypokalemia (low potassium), which can be fatal, due to cellular potassium requirements as the anemia corrects. Supplement with folate as well and ensure plenty of dietary or supplemental potassium. B12 and folic acid should in general be avoided in cancer, as they may stimulate tumor growth.

Therapeutic Uses

As well as being used to treat deficiency and symptoms of deficiency, B12 can be used as a therapeutic agent for several conditions. Because of its role in the conversion of homocysteine, B12, along with B6 and folic acid are used to treat conditions linked with high levels of Hcy, such as cardiovascular disease, stroke, osteoporosis, dementia and Alzheimer’s. Studies have shown that B12 supplementation has positive results in lowering the risk of stroke and cognitive decline.

Due to its role in energy metabolism, B12 is often promoted as an energy enhancer and booster of athletic performance and endurance, but there is no clinical evidence to support this unless an actual nutritional deficiency is present. Other conditions that may be helped by B12 supplementation are diabetes and related neuropathy, HIV, age-related hearing loss, depression and bipolar disease, schizophrenia, CFS, low immune function, MS, and neuralgia.

Lab Tests

The most common test for B12 is blood serum levels, with levels less than 150 pmol/L showing deficiency, but evidence suggests that serum levels may not accurately reflect cellular levels, often looking normal when anemia and other signs of deficiency are present.

High levels of methylmalonic acid is a more reliable test for B12 deficiency, levels greater than 0.4 micromol/L. High levels of serum Hcy (less than 13 micromol/L) may also show deficiency, but this may also show low B6 or folate. Note: antibiotics, methotrexate and pyrimethamine invalidate B12 and folic acid blood tests.

Interactions

Drugs that deplete B12 are: AZT, cholestyramine, colchine, metformin, Histamine (H2) blockers and PPIs. These drugs all impair absorption from food, but not from supplements. Usually it takes use of a drug for at least 2 years to create a deficiency, but many people may already have low levels to start with. Taking supplemental calcium can reverse B12 malabsorption from metformin use. Drugs that lower folate levels, such as methotrexate, oral contraceptives and anti-convulsants can also contribute to B12 deficiency. Vitamin C supplements may diminish the effectiveness of B12 (if taken orally), so take at least 1 hour apart.

Herbs and B vitamin deficiencies

Herbs reported to be high in Vitamins B6 and B12 are as follows:
(www.herbalhealthreview.com)
B6: alfalfa, oatstraw, catnip, hawthorn berries, licorice, hops
B12: bladderwrack, dandelion, alfalfa, white oak bark

I can’t find any information on the levels of B vitamins in these plants, and there is some debate as to whether vitamin B12 is actually found in any plant, or if it has just been found in bacteria on the plant. Alfalfa is touted by some (Dr. Edward Group, globalhealingcenter.com, Dr. Balch) as the only plant source of the entire B complex, and while this may be debatable, it is certainly a good nutritional tonic to take at the same time as supplements. Other herbal therapies which would be helpful to consider with B vitamin deficiencies would be to treat the root cause of malabsorption issues. In elders with atrophic gastritis bitter herbs before meals would help increase the hydrochloric acid levels needed to release B12. In people with Crohn’s, colitis, UC, celiac and other problems of the intestines, using herbs that will heal and treat their specific conditions will help nutrients of all types be assimilated. Treatment with probiotics and prebiotic herbs would be helpful after antibiotic use to heal gut flora and increase absorption.

Conclusion

From my research I have come to the conclusion that B vitamin deficiency is probably more common than thought in conventional medicine, affected by many things such as low nutritional levels in foods, overuse of antibiotics and other medications, and pollutants. Recommended dosages of supplements may be too low in many cases to counter deficiency, and the therapeutic uses of these vitamins are often overlooked in the medical profession.

Sources

Stargrove and Treasure. “Herb, Nutrient, and Drug Interactions”. Mosby Elselvier, 2008
U.S. Department of Health and Human Services, National Institutes of Health, Office of Dietary
Supplements. www.ods.od.nih.gov
Weil, Andrew. www.drweil.com
Yance, Donald. “Adaptogens in Medical Herbalism” Healing Arts Press, 2013.

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