Chapter 21 in the book ìBehavioral Neurology in the Elderlyî, edited by J. Leon-Carrion and M. Giannini. Published June 2001 by CRC Press LLC, Boca Raton, FL.

21 Vitamin, Mineral,

Antioxidant, and

Herbal Supplements:

Facts and Fictions

Victor Herbert

21.1 IntroductionÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖ.425

21.2 Free RadicalsÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖ...426

21.3 AntioxidantsÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖ426

21.4 Vitamin SupplementsÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖ..427

21.5 Vitamin EÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖ427

21.6 β-Carotene and Vitamin AÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖ..428

21.7 Vitamin DÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖ...429

21.8 Vitamin CÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖ...429

21.9 CalciumÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖ..430

21.10 ChromiumÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖ430

21.11 SeleniumÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖ..430

21.12 Multivitamin PreparationsÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖ...430

21.13 DietÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖ..431

21.14 PGA and Crystalline Vitamin B₁₂ÖÖÖÖÖÖÖÖÖÖÖÖ...431

21.15 Herbs as SupplementsÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖ..434

ReferencesÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖÖ..435-9

21.1 INTRODUCTION

The history of dietary supplements (vitamins, minerals, antioxidants, herbs, etc.) is the history of science (facts: evidence-based delineation of efficacy: safety ratios) vs. snake oil (fictions: deceptions by omission of adverse facts) (Herbert 1980; Barrett & Herbert 1994; Barrett & Herbert, 1999; Herbert & Barrett, 1999). The first snake oil nutrition salesman was the snake in the Garden of Eden, who convinced Eve to get Adam to eat that apple, promising it would give him wisdom, but deceiving by omitting the adverse fact that eating it would result in Adam & Eve being expelled forever from the Garden of Eden.

Deception by omission of adverse facts, and the use of deceptive and misleading ìbuzz wordsî has remained the hallmark of snake oil salesmen down through the ages. They remain today the basis for the sale to the public of billions of dollars annually of unneeded, unnecessary, and often worthless to harmful dietary supplements.

A table summarizing then-known harms from supplements of fiber, omega-3 fatty acids, vitamin A, β-carotene, vitamin C, vitamin E, iron, lecithin, niacin, and selenium was published by Herbert and Kasdan (1994) and Herbert and Subak-Sharpe (1995). Todayís leading deceptive, misleading, and often just plain false ìbuzz wordsî such as ìdietary supplementî (to describe a product which adds a nutrient to a diet which already has it in adequate quantity) ìnaturalî (when used to describe factory-produced synthetics), ìvitaminî (when used to characterize non-vitamins such as coenzyme Q10, laetrile [îvitamin B₁₈"] and ìvitamin B₁₅" [Herbert, 1988]), ìantioxidantî (used to benignly characterize redox agents), ìnutraceuticalî (to describe a food supplement), ìfunctional foodî (to describe a food to which a nutraceutical has been added) (Kolata, 1999), ìpotentî (a benign description for a high dose), ìpotentizeî (the homeopathís descriptor for ìdilutedî), ìsuccussedî (the homeopathís descriptor for ìshakenî). By using these delusional descriptors, sellers can charge more for a homeopathic remedy 100-fold diluted 30 times and shaken each of those 30 times (30X) than for one that has been diluted and shaken only 10 times (10X). Both the 10X and the 30X are essentially water containing no active agent. One hundred-fold dilution, 30 times repeated, yields a product diluted so far past Avogadroís number that there would be about a molecule of active agent in a container more than thirty billion times the size of the Earth (see chapter on ìThe Ultimate Fakeî in Reference 5).

21.2 FREE RADICALS

Free radicals are the price we pay for breathing. We breathe in oxygen and urinate out water, which requires the generation of free radicals along the way. Moderate amounts of free radicals are essential for normal cell metabolism. Excesses are harmful. Slight excesses are prevented from doing harm by various body proteins and enzymes, such as superoxide dismutase. Superoxide dismutase pills are a fraud; as proteins, they are destroyed by gastric and pancreatic proteases and are not absorbed.

21.3 ANTIOXIDANTS

Most Americans, including physicians, have been gulled by an avalanche of media promotions and supplement-industry-funded peer-reviewed papers⁵ into believing that if a supplement is labeled ìantioxidant,î it is good for you. Nothing could be further from the truth.⁴⁰

ìAntioxidantî is a shorthand ìbuzzwordî for ìredox agent.î All ìantioxidantî supplements are in fact redox agents, antioxidant in some circumstances (mainly in dietary reference intake or DRI,^20,21 and lower amounts).³⁴ As naturally present in an`y fruit, fruit juice, vegetable, or grain, they are balanced by over 150 other phyto (plant) chemicals, at least a dozen of which are also redox agents. Thus, one absorbs over 150 phytochemicals, which balance each other out to produce a redox potential close to zero, preventing prooxidant harm. No such protective balance exists in ìantioxidantî supplements.

21.4 VITAMIN SUPPLEMENTS

With the exception of vitamin B₁₂, which is factory biosynthesized, vitamin supplements currently produced in the United States are factory chemically synthesized, whereas some of those produced in Europe are biosynthesized.⁷¹ Chemical synthesis produces racemic (D,L) product (i.e. two mirror-image molecules, facing each other), one of which is natural (i.e. the form found in bacteria and plants, and nutrient in humans), and the other of which is synthetic, not found in nature, and may have harmful properties.^34,34a,71 Representing racemic vitamins, amino acids, and sugars as ìnaturalî is false advertising. Biosynthesis is carried out by fermentation, using live microorganisms or their enzymes, and produces only the natural form, which is the D-form for vitamins and sugars, and the L-form for amino acids.

21.5 VITAMIN E

Vitamin E supplements are promoted as antioxidant and immune enhancing. This ignores the fact that immune enhancement may do more harm than good.⁴¹ It also ignores that the vitamin E in plants is 80% γ-tocopherol and only 20% α-tocopherol. The only form in nearly all supplements is α-tocopherol. It blocks cell uptake of γ-tocopherol, thereby promoting rather than retarding NOx free radical damage, such as in the substantia nigra in Parkinsonism, and in Alzheimerís, where NO_xfree radicals are generated from NO (nitric oxide).⁴¹ The experimental use of vitamin E supplements to retard progression of Alzheimer disease has so far not shown value in a New York City group,⁷ but has been associated with hemorrhagic strokes in two patients with Alzheimer disease in a Syracuse (New York) group.⁸⁶ As Amesís group¹² published, γ-tocopherol binds and thereby inactivates both NO_x and oxygen free radicals whereas α-tocopherol only acts against oxygen free radicals. To make matters worse, α-tocopherol supplements prevent cell uptake of food γ-tocopherol, with the result that the cells take up no γ-tocopherol and therefore have no protection against NO_x free radicals. Christen et al.¹² suggest that the solution to the problem is to add γ-tocopherol to α-tocopherol supplements. Herbert⁴¹ suggests that the solution to a harmful pill is not taking it in the first place, rather than adding its antidote. The primary food source for vitamin E is liquid oil from grains; the usual diet provides about 15 IU/day. Stephens et al.⁸⁷ found that in patients with angioscopically proven coronary atherosclerosis, taking 400 or 800 IU of α-tocopherol daily for a median of 510 days (range 3 to 981) led to a statistically significant reduction in the incidence of nonfatal myocardial infarction. However, the incidence of cardiovascular death and all-cause mortality was slightly higher in the patients who took α-tocopherol than in those who took placebo. In a placebo-controlled, prospective study of 27,271 Finnish male smokers aged 50-69, Virtamo et al.⁹¹ found that supplementation with 50 mg daily of α-tocopherol had only marginal effect on the incidence of fatal coronary heart disease and no influence on nonfatal myocardial infarction. Steiner⁸⁵ had found that, in vivo, as little as 50 mg daily of supplement α-tocopherol effectively inhibits platelet adhesion, which would be protective against vascular occlusions (such as heart attacks), but promotional of vascular hemorrhages (such as fatal hemorrhagic strokes). Indeed, this proved to be the case in the Finnish study.⁹¹ Alpha-tocopherol may be a more potent platelet adhesion inhibitor (and general cell adhesion inhibitor) than ìγ-tocopherol.î Additionally, supplements of vitamin E higher than 800 IU can also cause severe bleeding via antagonizing the action of vitamin K.

Of the two vitamin E over-the-counter compounds most commonly purchased, the biological potency of RRR-α-tocopherol (the natural form) is twice that of all-rac-α-tocopherol (the synthetic racemic [D,L] form).⁶¹ Horwitt, the worldís leading authority on, and proponent of, vitamin E has stated, ìVery high levels of antioxidants in blood and tissue may make them prooxidants. A number of reports have shown that the tocopherols can inhibit platelet adhesion and aggregation....My position on health claims on labels is that they should be absent or stated very conservativelyî (cited in Reference 56).

21.6 β-Carotene and Vitamin A:

Primary food sources for carotenoids are dark colored fruits and vegetables. Primary food sources for preformed vitamin A are meats, fish oil, fish, and vitamin A-fortified dairy products.

The Virtamo et al. study,⁹¹ of 27,271 Finnish men, randomly assigned the men to receive vitamin E (50 mg), β-carotene (20 mg), both agents, or placebo daily for 5 to 8 years (median 6.1 years). They found that supplementation with β-carotene has no primary preventive effect on major coronary events.

β-carotene and other carotenoids in the vitamin A family are all redox agents, and epidemiologic studies have found that higher levels of carotenoids in the diet and higher serum levels of carotenoids are associated with a lower incidence of cardiovascular disease and cancer. High serum β-carotene is merely a marker for high total carotenoid ingestion, and not an indicator of value of β-carotene against disease.^37,40,43 In fact, the latest research^1,2 suggests that the reason above-DRI (Daily Reference Intake) supplements of β-carotene increase lung cancer rates among smokers is that smoke (and the high oxygen levels in lung cells) converts the supplemental β-carotene stored in the lungs to oxidized metabolites, which destroy retinoic acid, a tumor suppressor, and increase a protein that activates cell division, thereby promoting precancerous lesions.

It is now generally agreed among non-supplement-industry-funded health scientists, such as those at Harvard, Mount Sinai, The University of Helsinki, The National Cancer Institute, and the FDA, that no one should take carotene supplements.^37,40-44,91

The carotenoids protective against macular degeneration appear to be lutein and its isomer, both normally present in high concentrations in the macula. It was recently discovered² that proteins associated with 3-carotenoids are light-harvesting complexes (LHCs), which capture light for photosynthesis in higher plants. One wonders if there is a similar carotenoid-dependent LHC in the human retina, which needs lycopene and zeaxanthin.

This vitamin is made in human skin adequately exposed to sunlight²⁰ A recent unpublished study in the nursing home of The Bronx VA Medical Center indicates vitamin D deficiency in elderly not exposed to sunlight is prevented by having them sit every day for 30 minutes at a round table, playing cards, with their sleeves rolled up to the elbow and an ultraviolet lamp hanging above the table. In that 30 minutes daily, they make enough vitamin D in their exposed skin to sustain normal blood vitamin D levels round-the-clock.

21.8 VITAMIN C

Higher intakes of fruits and vegetables, each of which contains over 150 phytochemicals, of which vitamin C is just one, result in high phytochemical levels in the serum, of which one is a high serum vitamin C level. This has been repeatedly associated with less cataract, cancer, coronary artery disease, and higher high-density lipoprotein (HDL) cholesterol concentrations. In fact, the lower incidence results from the sum total of all the phytochemicals absorbed from food, which cancel out any harmful effects from vitamin C alone. No long-term intervention studies showing a definite value of supplement vitamin C alone have been published. However, Podmore et al.⁷⁸ reported that, in a study of 30 healthy adult male volunteers, half given 500 mg daily of a vitamin C supplement, and half given a placebo, for 6 weeks, those given the vitamin C developed oxidative damage in one part of the DNA of their peripheral blood lymphocytes. Their levels of 8-oxoadenine increased by a factor of four, from a norm of 0.05 nmol/mg to 0.2 nmol/mg, reflecting severe prooxidative damage. This DNA harm would probably occur with only 100 mg daily, because a 100 mg vitamin C supplement daily completely saturates all human cells,⁶⁹ and, as Herbert³⁸ pointed out, saturating normal human macrophages with synthetic vitamin C kills them prematurely by releasing too many free radicals all at once from their ingested heme. Levine et al.⁶⁹ found that 200 mg vitamin C daily saturated not only all the cells, but also all the serum. Noting that 200 mg synthetic vitamin C daily could cause excessive menstrual blood loss, they excluded all females from their study. As Herbert pointed out in critiquing their study,³⁸ they also excluded from their study the greater than one-third of all Americans who, for genetic reasons,⁸⁴ can be harmed by 200 mg synthetic vitamin C per day, namely the approximately 30% of African Americans and 12% of non-African Americans who are heterozygous for hemochromatosis; the approximately 1% of Americans who are homozygous for hemochromatosis (for whom vitamin C supplements will sharply accelerate irreversible organ damage and death); the one sixth of Americans who are stone-formers because they are genetically unable to catabolize ascorbate past oxalate; any of the millions of Americans with diabetes mellitus; and the many with hereditary hemolytic anemias (ie, sickle cell anemia, G6PD deficiency, or paroxysmal nocturnal hemoglobinuria), etc.

21.9 CALCIUM

Women are constantly not only daily remodeling bone, but also laying down new bone until approximately age 35, after which it is a holding action of remodeling and very slow, genetically predisposed, loss of bone, accelerated by menopause loss of estrogen, to eventual osteoporosis (for genetic reasons, earlier in whites than in blacks). This process is retarded by adequate calcium, which makes calcium supplements desirable starting at age 35 in women and at age 50 in men (menopause in men starts about 15 years later than in women).

21.10 CHROMIUM

Chromium is an essential nutrient in trace amounts. Grains are a major food source.⁷⁵ A glass of beer a day supplies all the chromium one needs, and its alcohol content raises HDL cholesterol (the ìgood cholesterolî).

21.11 SELENIUM

Clark et al.¹³agreed in essence with the debunking by Herbert⁴⁵ of their suggestion that selenium supplements (as high-selenium yeast) should be taken to protect against cancer. Herbert⁴⁵ pointed out that the Clark study found no reduction by selenium of all-cause morbidity and mortality. Clark et al. disagreed with Kuller,⁶⁷ who presented evidence from the Surveillance, Epidemiology, and End Results (SEER) program that what Clark et al. had actually found was not a reduced incidence of cancer in those taken the selenium supplements, but rather an increased incidence of cancer in the placebo group. However, both the placebo and the yeast-selenium were coated with titanium, to prevent the study subjects from being able to detect a yeast aroma. Titanium is listed as a carcinogen. This author would speculate that yeast selenium may prevent the absorption of titanium. Should this prove true, it would explain why those taking the placebo, with no yeast selenium in it to block titanium absorption, would develop more cancer.

21.12 MULTIVITAMIN PREPARATIONS

Chandra^11a reported (1992), in a study of 96 elderly Newfoundland patients, that those who took such preparations for 12 months showed signs of better immune function and had fewer sick days, which would be expected in Newfoundland, where sick days are usually due to infectious disorders (which immune enhancement fights). However, immune enhancement brings out and maintains latent autoimmune disorders, such as autoimmune hemolytic anemia, rheumatoid arthritis, lupus erythematosis and multiple sclerosis, and a multitude of neoplasms from malignant lymphoma thru thyroid and epithelial cell cancers.⁴¹ In a CDC (Centers for Disease Control) study of a large cohort of Americans, Kim et al.⁶⁵ found that those who took vitamin and mineral supplements fared no better in overall morbidity and mortality than those who did not take supplements. At the Symposium on Prooxidant Effects of Antioxidant Vitamins³⁸ (cited in Kim et al.,⁶⁵p. 1199S), Kim confirmed and extended this finding, indicating that supplements help some, harm others, and have no effect on most, so the bottom line is a wash.

21.13 DIET.

Many substances found in foods may reduce the occurrence of heart disease and malignancy; few are vitamins. Supplementing the diet with vitamins is a totally inadequate substitute for the beneficial effects of a balanced diet rich in grains, fruits and vegetables, and moderate in milk and milk products, which are the main American source of absorbable calcium, and meat and meat products, which are the main American source of absorbable iron (5 times as absorbable as plant iron) and of vitamin B₁₂.

21.14 PGA AND CRYSTALLINE VITAMIN B₁₂

For the health and safety of the elderly, folate (PGA-pteroylglutamic acid) food fortification or supplements must always be accompanied by crystalline vitamin B₁₂.

Holotranscobalamin II* (holo TCII) is a surrogate Schilling test, in that it becomes low within a week after cessation of absorption of food vitamin B₁₂, usually due to gastric atrophy sufficient to stop production of gastric acid and enzymes.^35,58 Flynn et al.¹⁸ found in 171 (139 men, 32 women) healthy elderly Missouri Caucasians (mean age 65) that 49% had low (below 60 pg/ml serum) holotranscobalamin II, meaning they were no longer able to absorb food vitamin B₁₂; 52 (60%) also had vasculotoxically high serum homocysteine (Hcy) (>17.5 nmol/ml). Of these 52, only 7 also had low total serum vitamin B₁₂ (<200 pg/ml). The remaining 31 who had reduced food B₁₂ absorption, as measured by TC < 60 pg/ml, did not yet have high Hcy. All 171 had normal red cell folate (>136 ng/ml) and serum folate >1.6 ng/ml. Flynn et al are conducting a follow-up study with Green and colleagues at University California, Davis^24,50 to determine how much of this gastric atrophy is of the genetically predisposed variety and how much is due to Helicobacter pylori, and how much to both. The data support that, starting at age 50, the elderly should take a daily oral supplement of not less than 25 or more than 100µg of crystalline B_12. This recommendation, and the reasons for it, are embodied in a petition to the FDA by Herbert and Bigaouette.⁵⁴ While the vitamin B₁₂ DRI²¹ of 2.4 µg/day will suffice in the elderly for the years that the gastric atrophy has not yet proceeded to loss of gastric intrinsic factor (IF), once IF is finally lost, physiologic absorption of vitamin B₁₂ ceases and the only mechanism remaining for absorption of oral vitamin B₁₂ is pharmacologic mass action diffusion, which produces absorption of 1% of any oral dose.^16,27,35

As first suggested by Hibbard and Smithells,⁵⁹ confirmed by many others since,⁷⁴ and reviewed by Eskes,¹⁷ about half of newborns with neural tube defects (NTD) can have their NTDs prevented if their mothers take folic acid supplements starting a few months before becoming pregnant. The neural tube forms so early in pregnancy that it may be deformed before a woman knows she is pregnant.^15,76

Folate-preventable NTDs (and some other birth defects)¹⁷ are related to a defect in the genes for 5, 6, 7, 8-tetrahydrofolate reductase, a defect that makes the reductase thermolabile.⁶³The genetic defect is homozygous in 5% of Americans,⁶³including, of course, the elderly, and is overcome by supplying daily above-physiological amounts of folate.⁷³This, plus other considerations^55,81 makes folate supplements in the elderly appropriate. The physiological minimum amount of folate (as synthetic pteroylglutamic acid, PGA) needed orally daily to prevent folate deficiency in healthy non-pregnant adult females with no known genetic defect is only 50 pg.⁴⁵PGA (a synthetic oxidized monoglutamate) is about twice as stable and well absorbed as food folates (reduced folate PGA).^64,83

Spearheaded by the CDCís Godfrey Oakley (1997), folate (PGA) fortification of all fortified grains (breads, cereals, and pastas) to prevent NTDs became U.S. FDA law in January 1998.¹⁹ Supplements containing 400 pg PGA daily were (and are) also heavily promoted (Oakley 1997). PGA, the synthetic oxidized folate monoglutamate, is used because of its shelf-stability,⁸³ a property which Colman et al.¹⁴ has successfully used to fortify grain with PGA in a large study in South Africa more than two decades ago. Synthetic PGA is racemic, and it is possible the human-active isomer given alone would be safer.

A caveat is that when 400 µg of PGA is ingested, it is a little too much to be polyglutamated and reduced to natural forms in the process of absorption, resulting in absorption of some unaltered synthetic PGA, which may act as an antifol.^50,64

If folate fortification (and supplementation) does not also include adding crystalline vitamin B₁₂, millions of elderly (as well as fertile females of black heritage) will be harmed. Fortification with B₁₂ is necessary not only because it is cost effective,³⁵ but also because current screening tests for total serum vitamin B₁₂ have poor positive and negative predictive value,²⁴ and assays for homocysteine and methionine are confounded by a number of variables.²⁴ As Green et al.²⁴ state, ìSome clinical evidence supports the concept that measurements of holo-TCII levels may provide a better index of cobalamin status, but reliable commercial screening assays for holo-TCII are not yet available.î (Ed. note: HoloTC commercial assays are available in Europe from Axis-Shield ASA of Oslo, Norway, and in the United States from ICN Diagnostics at www.icndiagnostics.com).

Fertile females of black African descent rarely have the gene defectfor folate preventable NTD babies, but do have a different gene defect: one for early pernicious anemia (PA), as described in fertile South African Black females,^60,70 and fertile U.S. Afro-American females¹¹reviewed in References 35 and 49). In such women, PGA will mask the hematological damage of their vitamin B₁₂ deficiency, slowing the diagnosis of B₁₂deficiency until well after they develop B₁₂ deficiency neurological damage, some of it irreversible. One such woman⁸ diagnosed at age 33 with PA (with combined system disease), and only sporadically treated, who had serum antibody to intrinsic factor, gave birth at age 40 to a child with temporary vitamin B₁₂deficiency associated with transplacentally acquired antibody to intrinsic factor.

Ever since Combe in the 1820's and Addison in the 1850's first described pernicious anemia (PA), it has been generally recognized that PA is intimately associated with gastric atrophy and is a disease primarily of elderly people. Partly on a genetically predisposed basis and partly due to acquired gastric insults (such as iron deficiency, H. pylori, etc.), gastric atrophy begins in nearly all Americans sometime between ages 50 and 90, and gradually progresses, first with loss of gastric acid and pepsin, causing inability to split B₁₂ from its peptide bonds in food, and then, after a number of years, lossof gastric intrinsic factor, producing inability to absorb crystalline B₁₂ by the efficient physiological mechanism, but still able to absorb about 1% of any oral dose of crystalline B₁₂ by simple mass action diffusion(see Reference 30 for citations).

To take care of those elderly who have lost only gastric acid and pepsin, the DRI²¹ for vitamin B₁₂ states: ìThe RDA (Recommended Dietary Allowance) for adults is 2.4 μg of B₁₂/day. Since 10 to 30 percent of older people (i.e., those over age 50) may be unable to absorb naturally occurring B₁₂ normally, it is advisable for those older than 50 years to meet their RDA mainly by taking foods fortified with (crystalline) B₁₂or a (crystalline) B₁₂ containing supplementî. Intake of 100 μg of vitamin B₁₂ orally daily is able to reduce their hyperhomocysteinemia^20,52 This was easily predictable, since patients with PA absorb by mass action about 1% of any oral dose of crystalline vitamin B_12,³⁹ and only 0.1 μg of cobalamin must be absorbed daily to sustain normality.⁸⁸

In those elderly people who have lost intrinsic factor secretion, eating 25 μg vitamin B₁₂ will result in absorption of about 0.25 μg and eating 100 μg will result in absorption of about 1 μg. Although the MDR (minimum daily absorbed requirement) to sustain normality is only 0.1 μg,³⁵ when a multivitamin pill containing the RDA for iron, 200mg of vitamin C, and the RDA for B₁₂ and folate dissolves in the stomach, within 30 min (the gastric half-emptying time) the vitamin C and iron destroy about half the B₁₂ and about 20% of the folate³⁶ because of ìvitamin C-driven free radical generation from iron.î³⁶ Worse, the vitamin C and iron convert the B₁₂to anti-B₁₂molecules, which are absorbed with the undestroyed B₁₂ and prevent cell uptake of the undestroyed B₁₂.³⁶ For these reasons, supplements of vitamin B₁₂ should be taken alone, and taken either on wakening or between meals (so as not to attach to the protein in meals and thus become unabsorbable).^36a-c

Kuzminski et al.⁶⁸ reported that 1 mg oral B₁₂ daily was better than 1 mg injections monthly for treating B₁₂ deficiency. This is because daily oral B₁₂ produces a sustained normal serum vitamin B₁₂ level, rather than the roller-coaster serum up-and-down level produced by monthly injections²⁸ Daily to weekly intranasal B₁₂ is also an option, especially for those with disorders producing generalized intestinal malabsorption. Data suggests that 0.1mg (100 μg) of oral vitamin B₁₂ daily will adequately sustain normal serum levels and in fact will prevent gastric atrophy-associated vitamin B₁₂ deficiency from occurring in the first place.^{24,35,36a-c,63}

*As of 1998, the Roman numeral II is no longer used.

21.15 Herbs as supplements

The science of herbs as medicines from natural sources is pharmacognosy, a branch of pharmacology.^4,5,77,89 Herbology is a melange of observation with no controls, anecdote, and misperception of nonspecific coincidence, suggestion, and placebo effect as specific medicinal effect. Herbology is to pharmacognosy what astrology is to astronomy.

To quote Barrett:⁴

ìHerbal or other botanical ingredients include processed or unprocessed plant parts (barks, leaves, flowers, fruits, and stems) as well as extracts and essential oils. They are available as teas, powders, tablets, capsules, and elixirs, and may be marketed as single substances or combined with other herbs, vitamins, minerals, amino acids, or non-nutrient ingredients. The fact that an herb is known to be toxic does not ensure its removal from the marketplace....most published information about herbs is unreliable....with safe and effective medicine available, treatment with herbs rarely makes sense....î .

Barrett⁴ quotes Tyler³⁹ as observing:

ìMore misinformation about the safety and efficacy of herbs is reaching the public currently than at any previous time.... The literature promoting herbs includes pamphlets, magazine articles, and books ranging in quality from cheaply printed flyers to elaborately produced studies in fine bindings with attractive illustrations. Practically all of these writings recommend large numbers of herbs for treatment based on hearsay, folklore, and tradition. The only criterion that seems to be avoided in these publications is scientific evidence. Some writings are so comprehensive and indiscriminate that they seem to recommend everything for anything. Even deadly poisonous herbs are sometimes touted as remedies, based on some outdated report or a misunderstanding of the facts. Particularly insidious is the myth that there is something almost magical about herbal drugs that prevents them, in their natural state, from harming people.î

Hemlock is natural. It has been known at least since Socrates that hemlock is a lethal poison. US Senator Hatchís Dietary Supplement and Heath Education Act (DSHEA) (characterized in the title of a New York Times 1993 editorial as ìThe Snake Oil Supplement Actî), which became law in 1994, decrees that herbs are foods and not drugs.⁵ DSHEA forbids the FDA from protecting the public against the direct marketing of lethal doses of hemlock as a supplement! Brody^9,10 recently reviewed some of the harms from a wide variety of over-the-counter herbs unleashed on the American public by the DSHEA,^9,10 as did Grady.²² At the other end of the scale, one study of 64 ìpureî ginseng products found that 60% of them were so diluted with cheaper herbs as to be worthless.¹⁰

The bottom line is that definitive studies have yet to be done in the United States to show that popular herbs sold in the United States, none of which have any federal controls on content, like St. Johnís wort, ginseng, gingko biloba, kava, saw palmetto, valerian, echinacea, and feverfew, are effective, safe, and do more good than harm. In fact, studies in the United States have shown that almost every brand of any herb sold as a supplement in the United States differs in content, from two little to too much of each active ingredient, from each competing brand. For dietary supplements, the U.S. is still in the age of the Wild West.^3-5,22,36a

References.

1. Anonymous. Why Megadoses of Beta Carotene May Promote Lung Cancer, Food & Nutrition Research Briefs, Agricultural Research Service, U.S. Dept. Of Agriculture, Beltsville, MD, January 1999.

2. Anonymous, A Different Light Trap, Chem Eng. News, 77 (6),1999.

3. Barrett, S, Fad Diagnoses: an epidemic of nonsense in nutrition and ìfringeî medicine,î Nutr. For.,15 (6), 41, 42, 44, 1999. (Comprehensive up-to-date coverage of harms from dietary supplements and herbs can be accessed on Dr. Barrettís web site, available at http://www.quackwatch.com.)

4. Barrett, S, The Herbal Minefield; what we donít know is scaryî. Nutr. For. 16(1) : 5, 1998.

5. Barrett, S, and Herbert V, The Vitamin Pushers: How the ìHealth Foodî Industry Is Selling America a Bill of Goods, Prometheus Books, Amherst, NY, 1994.

6. Barrett S, and Herbert V, Fads, frauds, and quackery in Modern Nutrition in Health and Disease, Shils M.E., Olson J.A., Shike M., and Ross A.C., Eds., Williams & Wilkins, Baltimore, MD, 1999, chap. 109.

7. Brin, M., personal communication, 1999.

8. Bar-Shany S., and Herbert, V., Transplacentally acquired antibody to intrinsic factor with vitamin B₁₂ deficiency, Blood, 30, 777, 1967.

9. Brody, J., Americans gamble on herbs as medicine: with few regulations, no guarantee of quality, New York Times, 9 February, F1, F7, 1999.

10. Brody, J., Natural, ìdrug-freeî herb may have risks of its own, New York Times, 9 February, page F6, 1999.

11. Carmel, R. and Johnson, C.S., Racial patterns in pernicious anemia: early age at onset and increased frequency of intrinsic-factor antibody in black women, N. Engl. J. Med., 298, 647, 1978.

11a. Chandra, R.K. Taking multivitamins may reduce sick days, Lancet, 340, 1124, 1992.

12. Christen, S., Woodall, A.A., Shigenaga M.K., Southwell-Keely, P.T., Duncan N.W., Ames, B.N., γ-Tocopherol traps mutagenic electrophiles such as NO_x and complements α-tocopherol: physiological implications, Proc. Natl. Acad. Sci.U.S.A., 94, 3217, 1997.

13. Clark, L.C., Combs G.F., Turnbull B.W., and Slate, E.H., Selenium supplementation and cancer rates, JAMA, 277, 881, 1997.

14. Colman, N., Larson, J.V., Barker, M., et al., Prevention of folate deficiency by food fortification. III. Effect in pregnant subjects of varying amounts of added folic acid, Am. J. Clin. Nutr., 28, 465, 1975.

15. Czeizel, A.E., and Dudas, I., Prevention of the first occurrence of neural tube defects by periconceptional vitamin supplementation. N. Engl. J. Med., 327, 1832, 1992.

16. Ellenbogen, L., Herbert, V., and Williams, W.L., Effect of D-sorbitol on absorption of vitamin b₁₂ by pernicious anemia patients, Proc. Soc. Exper. Biol. Med., 99, 257, 1958.

17. Eskes, T.K.A.B., Genetic defects, hyperhomocysteinemia, and neural tube defects, Nutr. Rev., 56, 236, 1998.

18. Flynn, M.A., Herbert, V., Nolph, G.B., and Krause, G., Atherogenesis and the homocysteine-folate-cobalamin triad: do we need standardized analysis? J. Am. Coll. Nutr., 16, 258, 1997.

19. Food and Drug Administration, Food standards: amendment of standards of identity for enriched grain products to require addition of folic acid, Fed. Reg., 61, 878, 1996.

20. Food and Nutrition Board, Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride, National Academy Press, Washington D.C., 1997.

21. Food and Nutrition Board, Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B₆, Folate, Vitamin B₁₂, Pantothenic Acid, Biotin, and Choline, National Academy Press, Washington D.C., 1998.

22. Grady, D., Articles question safety of dietary supplements: use can endanger lives of ailing people, New York Times, 17 September, A23, 1998.

23. Green, R., Screening for vitamin B₁₂ deficiency: caveat emptor, Ann. Int. Med., 124, 509, 1996.

24. Green, R., Miller, J.W., Herbert, V., and Flynn, M.A., Oral vitamin B₁₂ supplementation decreases homocysteine in healthy elderly people with suboptimal vitamin B₁₂ status. FASEB J., February, 1999.

25. Guzik, H.J., Tommasulo, B.C., Mandel, F.S., Kasdan, T.S., and Herbert, V., Prevalence of negative vitamin b₁₂ balance in well- and malnourished frail elderly, J. Amer. Geriat. Soc., 41(10), SA27, 1993.

26. Herbert, V., Cuneen, N., Jaskiel, L., and Kapff, C., Minimal daily adult folate requirements, Arch. Int. Med., 110, 649, 1962.

27. Herbert, V., Estren, S., Brody, E., and Wasserman, L.R., Oral treatment of pernicious anemia, Lancet, 2, 801, 1958.

28. Herbert, V., The Megaloblastic Anemias, Grune & Strattan, New York, 1959.

29. Herbert, V., Nutrition Cultism: Facts and Fictions, George Stickley, Philadelphia, 1980.

30. Herbert, V., Pseudovitamins, in Modern Nutrition in Health and Disease, 7th ed., Shils, M.E., and Young V.R., Eds., Lea & Febiger, Philadelphia, 1988.

31. Herbert, V., Folate and neural tube defects, Nutr. Today, 27 (6), 30, 1992.

32. Herbert, V., Folate deficiency to protect against malaria, N. Engl. J. Med., 328, 1127, 1993.

33. Herbert, V., Vitamin C supplements and disease-counterpoint, J. Am. Coll. Nutr., 14, 2112, 1995.

34. Herbert, V., Chair, Symposium: Prooxidant Effects of Antioxidant Vitamins, J. Nutr., 126 (Suppl), 1197S, 1996.

34a. Herbert, V., Underreporting of dietary supplements to health care providers does great harm. Mayo Clinic Proc., 74, 531, 1999.

35. Herbert, V., Vitamin B₁₂ in Present Knowledge in Nutrition, 7^th ed., Ziegler, E.E., and Filer, L.J., Eds, International Life Sciences institute (ISLI) Press, Washington, D.C.,1996, chap. 20.

36. Herbert V., Anti-hyperhomocysteinemic supplemental folic acid and vitamin b₁₂ are significantly destroyed in gastric juice if co-ingested with supplemental vitamin c and iron, Blood, 88 (10, Suppl. 1), 492a (Abstr. 1957), 1996.

36a. Herbert, V., Vitamin B₁₂ : an overview, in Vitamin B₁₂ Deficiency, Herbert, V., Ed., Round Table Series No. 66, Royal Society of Medicine Press, London, England, 1999.

36b. Herbert, V., Preventing early morbidity and mortality in millions of elderly, and saving $ billions: new evidence that 100µg free vitamin B₁₂ (cobalamin) orally daily from age 50 will prevent gastric atrophy of the elderly from producing subtly progressive B₁₂-deficiency neuropsychiatric dementia and stumbling and later anemia, FASEB J., 14 (4), A292, 2000.

36c. Herbert V. Loss of recent memory (Where in the parking lot is my car? etc.) in persons age >50 is often unrecognized subtle vitamin B₁₂ deficiency, producing inadequate synthesis of new brain cells, but no anemia. FASEB J., 15(5), A59, 2001.

37. Herbert, V., Shaw, S., Jayatilleke, E., Vitamin C-driven free radical generation from iron, J Nutr., 126 (Suppl. 4), 1213S, 1996. (Note: Figure 3 as printed is incorrect; see Errata containing the correct Figure 3 and correct citation to Ames, 1983, published in J. Nutr., 1746, and Errata adding Herbert, V. to the Ran et al. reference and correcting units of ferritin iron to ng fe/ml of serum, published in J. Nutr.,126, 1902, 1996.

38. Herbert, V., Introduction. American Institute of Nutrition (AIN) Symposium on Prooxidant Effects of Antioxidant Vitamins, J. Nutr., 126 (Suppl. 4), 1197S, 1996.

39. Herbert, V., Anti-hyperhomocysteinemic supplemental folic acid and vitamin B₁₂ are significantly destroyed in gastric juice if co-ingested with supplemental vitamin C and iron, Blood, 88 (10, Suppl. 1), 492a, 1996.

40. Herbert, V., The value of antioxidant supplements vs their natural counterparts, J. Am. Diet. Assoc., 97: 375, 1997.

41. Herbert, V., Destroying immune homeostasis in normal adults with antioxidant supplements.î Am. J. Clin. Nutr., 65, 1901, 1997.

42. Herbert, V., Nutrition status misassessment maims and kills millions, FASEB J., 11(3), A185, 1997.

43. Herbert, V., Genetics determines which supplements are safe (Ex: folate + B₁₂ but not folate alone) and which are unsafe (EX: antioxidants; minerals), in Proc. 16^th International Congress of Nutrition (Abstr.), July 27 - August 1, 1997, Montreal, Canada. Poster presentation.

44. Herbert, V., Fraudulent ìalternativesî and scam ìsupplementsî harm millions and steal $ Billions, J. Invest. Med.,45, 301S, 1997.

45. Herbert, V., Selenium supplements and cancer rates, JAMA, 277, 880, 1997.

46. Herbert, V., The elderly need oral vitamin B₁₂, Am. J. Clin. Nutr., 67, 39, 1998.

47. Herbert, V., A triple hematologic nightmare: grossly underdiagnosing and not treating the most common us genetic disorder (hemochromatosis) and garbaging each year so many tons of good hemochromatosis donor blood as to create donor blood shortages in each of the past 30 years, Am. J. Hematol., 59, 261, 1998.

48. Herbert, V., Relationship of dietary folate and vitamin B₆ with coronary heart disease in women: without vitamin B₁₂ supplements, extra folic acid and vitamin B₆ will do elderly women more harm than good, JAMA, 280, 418, 1998.

49. Herbert, V., Vitamin E supplementation and immune response in elderly patients, JAMA, 279, 505, 1998.

50. Herbert, V., Folic acid, in Modern Nutrition in Health & Disease, 9^th ed., Shils M.E., Olson J.A., Shike M., Ross A.C., Eds., Lea & Febiger, Philadelphia, 1999, chap. 26.

51. Herbert, V. and Spivack M., FDA now approves hemochromatosis blood as normal donor blood. measuring serum iron status as part of routine blood testing will: 1. prevent phenotypic disease in millions; 2. save healthcare $billions; 3. end U.S. biannual blood shortages. J. Invest. Med. 49(2), 241A, 2001; FASEB J., A973, 2001.

52. Herbert, V., To prevent vasculotoxicity from hyperhomocysteinemia, give children vitamin B₆, give fertile females folate, and give all >50 daily oral 25 to 100 μg vitamin B_12.FASEB J., 13(4), A227, 1999.

53. Herbert, V. and Barrett, S., Alternative nutritional therapy claims, Modern Nutrition in Health and Disease, 9th ed., Shils, M.E., Olson J.A., Shike M., Ross, A.C., Eds., Williams & Wilkins, Baltimore, MD, 1999, chap. 110.

54. Herbert, V., Bigaouette, J., Call for endorsement of a petition to the Food and Drug Administration to always add vitamin B₁₂ to any folate fortification or supplement, Am. J. Clin. Nutr., 65, 572, 1997.

55. Herbert, V. and Das, K.S., Folic acid and vitamin B₁₂, in Modern Nutrition in Health and Disease, 8^th ed., Lea & Febiger, Philadelphia, 1994, 402-425.

56. Herbert, V. and Kasdan, T.S., Misleading nutrition claims and their gurus, Nutr. Today, 29 (3), 1994.

57. Herbert, V., Flynn, M.A., Nolph, G.A., and Krause, G., ~50% of healthy American elderly have low serum transcobalamin, diagnosing reduced vitamin B₁₂ absorption; 60% also have high serum homocysteine; none have low red cell folate; all elderly should get 25-100 μg oral free crystalline vitamin B₁₂ daily as food fortificant or supplement, Neth. J. Med. Sci., 52 (Suppl): S8, 1998.

58. Herzlich, B. and Herbert, V., Depletion of serum holotranscobalamin II. An early sign of negative vitamin B₁₂ balance, Lab. Invest., 58 : 332, 1988.

59. Hibbard, E.D. and Smithells, R.W., Folic acid metabolism and human embryopathy, Lancet, 1, 1254, 1965.

60. Hift, W., Moshal, M.G. and Pillay, K., Pernicious anaemia-like syndromes in the non-white population of Natal, S. Afr. Med. J., 21, 915, 1963.

61. Horwitt, M.K., My valedictory on the differences in biological potency between RRR-α-tocopheryl and all-rac-α-tocopheryl acetate, Am. J. Clin. Nutr., 69, 2, 341, 1999.

62. Institute of Medicine, Panel on Folate, other B Vitamins, and Choline, Dietary Reference Intakes: Thiamin, Riboflavin, Vitamin B₆, Folate, Vitamin B₁₂, Pantothemic Acid, Biotin, and Choline, National Academy Press , Washington, DC., 1998.

63. Kang, S.S., Wong, P.W.K. and Malinow, M.R., Homocysteinemia as a risk factor for occlusive vascular disease, Ann. Rev. Nutr., 12, 279, 1992.

64. Kelly, P., McPartlin, J., Goggins, M., Weir, D.G. and Scott, J.M., Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements, Am. J. Clin. Nutr., 65, 1790, 1997.

65. Kim, I., Williamson, D.F., Byers, T. and Koplan, J.P., Vitamin and mineral supplement use and mortality in a us cohort, Am. J. Publ. Health,83, 546, 1993.

66. Kolata, G., Drug or food? Patients stumble into gray area, The New York Times, 9 February, F6, 1999.

67. Kuller, L.H., Selenium supplementation and cancer rates, JAMA, 277, 880, 1997.

68. Kuzminski, A.M., Del Giacco, E.J., Allen R.H. et. al., Effective treatment of cobalamin deficiency with oral cobalamin, Blood, 92,1191, 1998.

69. Levine, M., Conry-Cantilena, C., Wang, Y., Welch, R.W., Washko, P.W., Dhariwal, K.R., Park, J.B., Lazarev, A., Graumlich, J.F., King, J., Cantilena, L.R., Vitamin C pharmokinetics in healthy volunteers: evidence for a recommended dietary allowance, Proc. Natl. Acad. Sci., USA, 93(8), 3704, 1996.

70. Metz J., Randall T.W. and Kniep C.H., Addisonian pernicious anemia in young bantu females, Br. Med. J., 1, 178, 1961.

71. McCoy, M., Chemical makers try biotech paths, Chem. & Eng. News, June 22 13, 1998.

72. McCully, K.S., Relationship of dietary folate and vitamin B₆ with coronary heart disease in women, JAMA, 280, 419, 1998.

73. Molloy, A.M., Daly, S., Mills, J.L., et al., Thermolabile variant of 5-10 MTHFR associated with low red cell folate: implications for folate intake recommendations, Lancet, 349, 1591, 1997.

74. MRC Vitamin Study Research Group, Prevention of neural tube defects: results of the Medical Research Council Vitamin Study, Lancet, 338, 131, 1991.

75. Nielsen, F.H., Chromium, in Modern Nutrition in Health and Disease, 9th ed., Shils E., Olson J.A., Shike M., Lea & Febiger, Philadelphia, 1999.

76. Oakley, G.P., Jr., Letís increase folic acid folic acid fortification and include vitamin B₁₂, Am. J. Clin. Nutr., 65, 1889, 1997.

77. PDR, PDR (Physiciansí Desk Reference) for Herbal Medicines, Gruenwald J., Ed., Medical Economics Company, NJ, 1998, medical director of a German phytomedicine company. On page iv, it is stated that ìThe publisher has performed no independent verification of the data reported herein....î The book updates the German Commission E reports, and adds hundreds other products sold in the U.S., listing alleged effects and side effects, and some contra-indications.

78. Podmore, I., Griffiths, H., Herbert, K., Mistry, N., Mistry, P., and Lunec, J., Vitamin C exhibits pro-oxidant properties, Nature, 392, 559, 1998.

79. Ran, J.Y., Dou, P., Wang, L.Y., Qin,Y., Jin, S.Y., Li, X.F., and Herbert, V., Correlation of low serum folate and total B₁₂ with high incidence of esophageal carcinoma (EC) in Shanxi, China, Blood, 82 (Suppl. 1), 532a, 1993.

80. Ran, J.Y., Dou, P., Wang, L.Y., Yuan, R.X., Hao, J.M., Zhang, H., Jin, S.Y., Li, P., Qin, Y., and Herbert, V., In a high-frequency esophageal carcinoma (EC) area, folate and B₁₂ deficient subjects with esophageal dysplasia (ED) improve with added folate and B₁₂, Blood, 82 (Suppl. 1), 532a, 1993.

81. Rimm E.B., Willet W.C., Hu F.B., Colditz G.A., Sampson L., Manson J.E., Hennekens C.H., and Stampfer, M., relationship of dietary folate and vitamin B₆with coronary heart disease in women, JAMA, 280, 418, 1998.

82. Russell, R., Mild cobalamin deficiency in older dutch subjects, Am. J. Clin. Nutr., 68, 222, 1998.

83. Seyoum, E., and Selhub, J., Properties of food folates determined by stability and susceptibility to intestinal pteroylpolyglutamate hydrolase action, J. Nutr, 128, 1956, 1998.

84. Simopoulos, A., Herbert, V., and Jacobson, B., Genetic Nutrition: Designing A Diet Based on Your Family Medical History, Macmillan, New York, 1993. (Reprinted in 1995 as a text-unchanged softcover with a new title The Healing Diet: How to reduce your risks and live a healthier life if you have a family history of cancer, heart disease, hypertension, diabetes, alcoholism, obesity, food allergies.)

85. Steiner, M., Vitamin E inhibits blood coagulation, J. Am. Coll. Nutr., 10, 466, 1991.

86. Steiner, J., personal communication, 1999.

87. Stephens, N.G., et al., Vitamin E and mortality. Lancet, 347, 781, 1996.

88. Sullivan, L.W., and Herbert, V., Studies on the minimum daily requirement for vitamin B₁₂ hematopoietic responses to 0.1 microgram of cyanocobalamin or coenzyme B₁₂, and comparison of their relative potency, New Engl. J. Med., 272, 340, 1965.

89. Foster, S. and Tyler, V., Tylerís Honest Herbal, 4th ed., Haworth Press, Binghamton, NY, 1999.

90. Van Asselt, D.Z.B., De Groot, L.C.P.G.M., Van Staveren, W.A., Blom, H.J., Wevers, R.A., Biemond, I., and Hoefnagels, W.H.L., Role of cobalamin intake and atrophic gastritis in mild cobalamin deficiency in older dutch subjects, Am. J. Clin. Nutr., 68, 328, 1998.

91. Virtamo, J., Rapola, J.M., Ripatti, S., Heinonen, O., Taylor, P.R., Albanes, D., and Huttunen, J.K., Effect of vitamin E and beta carotene on the incidence of primary nonfatal myocardial infarction and fatal coronary heart disease, Arch Intern Med, 158, 668, 1998.V.H. CV #817Seville

21 Vitamin, Mineral,

Antioxidant, and

Victor Herbert

CONTENTS