Part II: Essential Nutrients
Fortunately, nearly all major vegetarian advocacy and support organizations and authors of books on vegetarian nutrition are now emphasizing the danger of frank B12 deficiency, especially in vegetarians, and the need for a supplement. The sole serious holdout on this front is John McDougall, who continues[i] to downplay the risks of B12 deficiency associated with vegan diets, recommending supplementation only to long-term (>3 y) adherents or pregnant and lactating women, pointing to the production of B12 by colonic bacteria (despite the fact that nearly none of that B12 is produced in parts of the GI tract where it could be absorb), and at least recently[ii] promoting the illusory availability of B12 from seaweed, even after it was known that its presence was being detected because of compounds in the same cobalt-containing chemical group as the vitamin (corrinoids), picked up in nutritional analysis by the standard USP assay method because of their structural similarity to the vitamin, but lacking in bioactivity to mammals.[iii]
There are absolutely no natural, plant-based foods that contain vitamin B12. The long, tenaciously clung-to belief that there are, arises from two sources of error. The first is fecal contamination. The colonic bacteria do produce B12, but unfortunately, we absorb almost none of it: they’re making the stuff for their own use and not ours, and they live much further down in the GI tract than the major site for B12 absorption (the distal ileum), so it passes through us – and, sometimes, traces of it remain on crops where it’s been used as fertilizer. The other source of the myth of vegan B12 is that some vegan organisms (eg, many cyanobacteria (such as Spirulina ), many bacteria (including the ones used to ferment tempeh), and some seaweeds) produce various kinds of “pseudo-B12” that carry out some of the same functions as B12 for them but are useless for mammals; unfortunately, because they’re actually close chemical relatives of B12 (corrinoids), their structural similarity to the vitamin tricks the standard USP method of food analysis, leading to erroneous reporting of its presence.[iv]
Because of this, nonsupplementing vegans are often deficient in B12,[v] and despite the vitamin’s presence in eggs and dairy products, even ovolacto vegetarians’ functional B12 status tends to be poor (eg, ([vi],[vii],[viii],[ix],[x],[xi],[xii])). The main concern with such subclinical deficiency is the elevation in plasma homocysteine, a risk factor for coronary artery disease (CAD). McDougall discounts such ‘mere’ laboratory findings, and misleadingly suggests that B12 deficiency only becomes a concern when the most frank and severe of deficiency develops, complete with neurological dysfunction, but that condition represents a late and acutely dangerous stage of the disease, which is necessarily preceded by a long-term, progressive loss of the critical metabolic functions of B12. The epidemiological association of elevated homocysteine alone renders McDougall’s dismissal of ‘mere’ clinical laboratory findings irresponsible at best— especially now that a study has been completed specifically linking such mild deficiency in B12 to CAD in a predominantly vegetarian population.[xiii] There is also at least a theoretical concern that such long-term subacute deficiencies might lead to a loss of the regulation of genes by modification of methyl groups derived from B12, resulting in an elevated risk of cancer and possibly other cellular malfunction; a study investigating this possibility found such an association, but it was put into doubt by adjustment for confounding factors.[xiv]
Some vegetarian foods already contain B12 through fortification; examples include Red Star nutritional yeast, marmite, and some fortified breakfast cereals. If these foods are real staples of your diet that you eat nearly every day, and they (combined with the rest of your diet) are enough to keep you, on a representative average day, significantly over the new RDA, then that may cover your needs, but that clearly won’t be sufficient if you only eat them occasionally or as snacks or condiments, it would be irresponsible to pretend that an occasional, irregular dose will avert a long-term, subchronic deficiency.
Therefore, while B12 should be tracked in your dietary software as with all other nutrients (the IOM RDA is 2.4 micrograms for adults, except for slightly higher needs for pregnant and lactating women and some older individuals), it is prudent for all vegetarians to take a B12 supplement. A basic, common cyanocobalamin supplement is fine. Ideally, this would begin done immediately upon taking up a vegetarian diet, in which case an RDA-level dose would be quite adequate, although a somewhat higher dose may be required in older people or others with low stomach acid production due to lower absorption. [xv] However, long-term vegetarians (and especially vegans) will likely have spent several years progressively depleting the stores in their livers, and unfortunately, research (conducted in older women) suggests that just jumping back up to RDA levels under such conditions is insufficient to restore healthy B12 metabolism.[xvi]
Whatever you diet and supplement regimen, you will want to determine your actual, functional B12 status, and not just your intake levels. Fortunately, there are two very reliable and well-established tests: homocysteine and methylmalonic acid. Your lab’s reference range should do for methylmalonic acid targets. The optimal level for homocysteine remains a subject of some uncertainty, but the cutoff for increased risk of cardiovascular disease appears to be approximately 9-10 micromoles per Liter.[xvii]
Milligram-for-milligram, iron absorption from vegetarian diets is only about half of that from meat-based ones, and in some strict and traditional vegetarian diets may dip to less than one-third, for several reasons.[xviii] The iron in plant foods is much less bioavailable than the heme iron that predominates in meat; meat itself actually increases nonheme iron absorption, so that a mixed omnivorous meal increases the absorption of the plant-based iron; and because vegetarian diets tend to be higher in phytic acid and other inhibitors of iron absorption. Therefore, has long been a concern that vegetarians might be at risk for iron-deficiency anemia.
Counterbalancing this reduced bioavailability is the fact that absolute iron levels in self-selected Western vegetarian diets tend to be significantly higher than those in omnivorous diets. Additionally, studies show that the body does adapt over time to reduced intake of readily-absorbed iron by actively increasing absorption and retention.[xix],[xx]
Tests performed in free-living vegetarians have generally found that while iron status does tend to be lower in vegetarians than in omnivores, the prevalence of actual iron deficiency is no higher in most Western vegetarian populations than in their omnivorous neighbors. The main exceptions to this generalization has been in Asian immigrant communities and macrobiotic dieters,[xxi],[xxii] due in part to their high intake of phytic acid-rich foods such as brown rice and unleavened chapattis, and possibly high-tannin teas.
And there is an upside to getting most of your iron in the highly-bound forms that predominate in vegetarian diets, and to the resulting historical tendency toward low-normal iron status in Western vegetarians: by reducing the formation of lipid hydroperoxides by free radical reactions catalyzed by the breakdown of heme iron in the gut,[xxiii] and the age-related increase in non-heme iron body burden,[xxiv] it may contribute substantially to the lower rate of cardiovascular mortality and possibly other diseases in ‘average’ vegetarians.
However, you certainly don’t want this favorably-low iron status to slide into iron-deficiency anemia, as it certainly can. Indeeed, ironically, many of today’s more health-conscious vegetarians may be actively compromising their iron status as an unintended consequence of trying to further improve their diets with ‘superfoods.’ Well-known inhibitors of iron absorption in “health foods” (and pseudo-health foods) include phytic acid (present at high levels in unleavened whole grains), fiber, and complex polyphenols (‘tannins’) present in red wine, cocoa (and especially high-flavanol raw and undutched cacao), and a variety of novel ‘antioxidant superfoods’ like açai and goji berries.[xxv]
Bioavailability of nonheme iron can bee boosted through the intake of organic acids in ‘acid-ash’ foods such as fruits (especially citrus) and most vegetables; by increasing vitamin C intake at meals; by sprouting, soaking, and fermenting seeds, grains, and legumes; and by avoiding the intake of absorption-inhibiting foods at mealtime, such as cocoa and black tea.
With so many factors playing into an individual vegetarian’s functional iron status, it can be difficult to know with confidence that you are getting all the iron you need for long-term health. An important first step is to track your intake of iron with your nutrition software, bearing in mind that because of the lower bioavailability of vegan iron, the RDA indicated by default in such software will not be enough to reliably meet your functional needs. For this reason, the IOM has set an RDA for iron intake in vegetarians of 15 mg for men and postmenopausal women, 32 mg for younger adult women, and a whopping 50 mg for pregnant and lactating women, instead of the 8, 18, and 27 mg (respectively) for the general population.xviii Fortunately, iron is again one of the relatively few nutrients for which well-established markers of functional status exist. While a panel of iron markers can be useful in some cases, a blood test for ferritin (using the lab’s reference range, and remembering the likely advantages of low-normal ferritin) should reliably establish your iron status.
If your levels are low, a supplement is in order in the short term, along with any engineering of your diet that you can do to correct the underlying deficiency. Despite health-food-store hype, there’s little evidence to support the superiority of iron amino acid chelates or other ‘special’ forms over more common iron sulfates or gluconate; after the first month, however, if you haven’t clearly recovered after dietary tweaks and supplementation, a more long-term supplement is required, and you may want to switch to iron protein succinylate (available as IronSorb from Jarrow or Iron Protein Plus from the Life Extension Foundation), which seems to take longer to initially restore iron status but does a better job of maintaining it long-term and as is less likely to cause constipation or other GI problems.[xxvi]
This mineral is a much more difficult challenge than iron for vegetarians. Vegetarian foods contain relatively little zinc, and the zinc that exists is largely bound up by phytic acid; moreover, the nonheme iron in which our diets are so rich inhibits absorption. All told, the IOM has made a rough estimate that the requirement for dietary zinc may be half again as high in vegetarians as the 11 mg RDA for omnovores.xviii Compounding this problem, healthier vegetarian diets, rich in vegetables, are ipso facto high in copper, which competes with zinc for absorption and for the binding sites of enzymes that require it as a cofactor.[xxvii],[xxviii] (If it’s any perverse consolation, omnivores face the exact reverse challenge with high intake of bioavailable zinc and low intake of copper, often exacerbated by imbalances in dietary supplementats, which often contain several times the RDA for zinc and little or no copperxxvii,xxviii,[xxix]).
While full-blown zinc deficiency has not been found to be any more widespread in vegetarians than in the rest of the population, we don’t yet really understand zinc needs in omnivores well, and the long-term health impacts of marginal deficiency are even less well-understood. Certainly, vegetarians’ intakes, blood levels, and tissue concentrations do tend to be lower, and unfortunately, there is no reliable test for actual, functional zinc status, despite what your alternative health practitioner may tell you,xviii so it is difficult to know for sure that you’re getting enough. I can tell you this from personal experience: some years back, I suffered with definite zinc deficiency evidenced in (among other things) white spots and deep crosswise indentations (Beau's lines) in my fingernails, despite getting a little more than the RDA in my diet; the primary reason was almost certainly the high (but innocuous-sounding) 4 milligrams of copper and nonheme iron in my high-vegetable diet, combined with getting almost all of my zinc from plant foods.
Based on the research, the following guidelines appear to be the best available rules of thumb. First, vegetarians should aim for a dietary intake of at least 17 mg of zinc a day, rather than the 11 mg of the standard IOM RDA. Second, this should be compared to one’s copper intake: total zinc intake from diet and supplements should be roughly ten times higher,xxviii although the absolute level should probably not exceed 50 milligrams. Third, vegetarians should look to improve zinc bioavailability by reducing the level of phytic acid in the diet, by the aforementioned means of soaking, germinating, or fermenting foods high in phytic acid.
A fallible but sometimes-useful test of zinc functional status can be done using zinc sulfate solution: one of the effects of zinc deficiency is insensitivity to bitter taste, so if you don’t find a few swishes of the stuff to be foul, you’re very likely deficient.
If you find you need a supplement (as I do), then the same lack of reliable markers for zinc status make it difficult to say with confidence the best form or protocol. Most, [xxx],[xxxi] but not all[xxxii] studies find that taking zinc on an empty stomach boosts its absorption, but this may be due to an inherent depressing effect of food on plasma levels, masking true bioavailability. It’s still probably the best way to go, unless doing so upsets your stomach; in that case, you can still improve absorption by taking it at least 15 minutes after finishing eating, and you can experiment with slowly increasing the interval between food and pill. Similarly, most (but not all[xxxiii]) studies have found that zinc citrate is at least as well-absorbed as the expensive health-food-store favorites, such as picolinate,[xxxiv],[xxxv] and while a few studies have reported that zinc monomethionate is more bioavailable than other forms on some measures,[xxxvi],[xxxvii] most studies find equal or greater bioavailability from common zinc sulfate.[xxxviii],[xxxix],[xl],[xli],[xlii],[xliii],[xliv],[xlv],[xlvi] In the absence of a clear answer to these questions, I see no reason to spend the extra money on a ‘premium’ supplement.
Omega-3 Fatty Acids
While many fats are casually referred to as “essential fatty acids,” only two such nutrients actually qualify as essential. One is alpha-linolenic acid (ALA), the root of the omega-3 family that also includes the eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), found primarily in some fatty fish). The other is linoleic acid, the root of the omega-6 group. Other “essential” fatty acids either aren’t strictly necessary at all, or can be made from other fatty acids in the diet.
Studies consistently find that vegetarians have lower levels of omega-3 fatty acids than omnivores – and there’s good reason to think that most omnivores aren’t getting enough omega-3 fatty acids for their long-term health. While frank deficiency has not been noted in vegetarians, the negative impact of having marginal omega-3 status on cardiovascular and brain has become increasingly clear over the course of the last few decades. And low intakes amongst vegetarians could potentially be compounded by high intake of the other family of essential fatty acids, omega-6, in which vegetarian diets tend to be plentiful, because the two nutrients compete with one another for the same enzymes to metabolize them into their longer-chain forms, which are required for these nutrients to carry out some of their biological functions. I believe that marginal omega-3 intake in vegetarians and especially vegans has been a major reason for the surprisingly minimal long-term health benefits associated with eating a fundamentally healthy-looking plant-centered diet.
Fortunately, awareness of this problem is widespread amongst vegetarians: omega-3s are amongst the most widely-touted nutrients of the last decade. Dean Ornish now recommends that his patients take fish oil supplements and enjoy an occasional fish meal; most vegetarian advocacy groups recommend plant-based sources such as canola, flax, and hemp oils, and unhydrogenated soybean oil. The sole holdout is John McDougall, who continues to begrudge the evidence that fat in any form – beyond the amounts necessary to avoid gross neurological disorder – could possibly be health-promoting,[xlvii] preferring instead to exaggerate the potential risks of mercury and PCBs in fish oil (which are present in some fatty fish but almost nonexistent in supplements), cholesterol (a trivial concern), and that “omega-3 fats … can promote obesity … are also known to suppress the immune system and increase risk of bleeding and are suspected of promoting human cancers.”[xlviii]
The evidence supporting the health benefits of a somewhat higher intake of omega-3s is strong, although both the magnitude of the benefits, and the amount of omega-3 intake required to reap them, are uncertain[xlix],[l],[li] and generally exaggerated by supplement companies and vendors of high-omega-3 health foods, such as flax and hemp oils and chia seeds.
Moreover, it is widely asserted, even by qualified experts in omega-3 nutrition and metabolism, that the relatively low conversion of the short-chain alpha-linolenic acid in most vegetarian foods into the long-chain EPA and especially DHA means that it will be very difficult to meet one’s needs from plant sources alone. This seems unlikely, on several grounds. Epidemiology suggests that the level of risk reduction in cardiovascular death and disease from high-ALA diets is as great as that for diets high in fatty fish; the large Lyon Diet Heart Study, in which subjects adopted dietary changes centered on a decrease in saturated fat and an increase in monounsaturated and omega-3 fatty acids achieved by replacing butter with a canola oil-based margarine, led to reductions in cardiovascular and total mortality at least as impressive as in other trials centered on fish and fish oil;[lii] and a head-to-head clinical trial of fish oil (two capsules three times a day, providing1.08 g EPA and 0.72 g DHA) versus ALA from mustard oil (ALA 2.9 g/day), in a largely vegetarian population, yielded roughly equivalent benefits.[liii] This is all the more remarkable, since mustard oil contains erucic acid, the controversial monounsaturated fat that was purged from rapeseed oil to make low-erucic canola oil due to concerns about cardiac abnormalities in rats and monkeys fed high-erucic acid diets from weaning (but not reproduced in animals introduced to the fat in adulthood),[liv] and less ambiguous problems with elevated LDL (“bad”) cholesterol and triglycerides, which tended to counteract the benefits of the ALA in studies in largely vegetarian Indians.[lv]
The IOM did not find the evidence to be strong enough to make a solid RDA for essential fatty acids, instead noting a presumed “Adequte Intake” based on levels in typical American diets, granted the absence of frank deficiency in the general population: 1.6 grams of ALA daily for men, and 1.1 g for women, along with 17 g of LA daily for young men and 12 g a day for young women. IOM suggests this intake “can provide the beneficial health effects associated with the consumption of n-3 fatty acids.”l Other countries’ nutrition panels have made similar or slightly higher recommendations, though not nearly so high as those made by companies trying to sell you health foods and supplements:
Canada recommends a total n–3 fatty acid intake of 1.2–1.6 g/d … but does not distinguish between individual n–3 fatty acids. The United Kingdom … recommends that 1% of energy be from ALA and 0.5% be from EPA and DHA combined. The Committee on Medical Aspects of Food Policy, which includes the United Kingdom, recommends that the combined intake of EPA and DHA be 0.2 g/d. Australia has recommended that there be moderate increases in sources of n–3 fatty acids from plant foods (ALA) and fish (EPA and DHA). Lastly, the North Atlantic Treaty Organization Advance Workshop on n–3 and n–6 Fatty Acids recommended that the combined intake of EPA and DHA be 0.27% of energy or 0.8 g/d.xlix
Similarly, the an expert report from the World Health Organization and Food and Agriculture Organization (WHO/FAO) recommended an intake of 1-2% of Calories from omega-3 fatty acids and 5-8% of Calories from omega-6; at 2000 Calories a day, this would be 2.2-4.4 g of omega-3 and 11-18 g of omega-6.[lvi]
Unfortunately, there aren’t reliable bloodtests for omega-3 status. Some attempts have been made by looking at plasma highly-unsaturated fatty acid levels, based on cross-cultural comparisons, but these don’t really give us information about the long-term effects of a given ratio in individuals, or of the connections between different diets, plasma levels, and tissue concentrations, since no one has actually tracked individuals over time to compare diet, plasma levels, and health outcomes. So we’re left with making evidence-based inferences from available data.
Looking over the judgements of expert panels and evidence of intakes and outcomes from epidemiology and clinical trials, and bearing in mind that most vegetarians will get very little of the long-chain omega-3 fatty acids, and because of I suggest targeting the high end of the more favorable range, for at least 4.5 grams of ALA daily – and, contrary to some expert panels, I recommend this as a floor rather than as a percentage of Calories, with more rather than less if you’re eating a low-Calorie diet and are still losing weight, as a higher amount of EFAs are likely to be burned for energy rather than used to support metabolic activity.
It’s a good idea to track your omega-6 intake, too, although vegetarian diets tend to be quite rich in these EFAs, except in extreme low-fat diets; expert panels and official recommendations tend to suggest a ratio of omega-6 to omega-3 of between 4:1 and 2:1.
Indeed, the use of so-called “balanced” fatty acid health foods, such as Udo’s Choice oil and hemp oil, which contain a good ratio when considered in isolation, will tend to lead to an unbalanced ratio when integrated as part of the whole diet containing nuts, seeds, avocado, and cooking oil. (Of course, an exception might well occur in extreme low-fat dieting, for whom such supplements might work very well).
Instead, expeller-pressed, cold-processed, minimally-refined canola and flax oils, will work well for most people, helping them boost omega-3 intake while leaving room for omega-6 from other sources. Such oils should be kept in the refrigerator to protect the omega-3s from peroxidation and from propagating their damage throughout the oil (and, eventually, your circulating lipoproteins and cellular membranes). In fact, flax oil is probably best kept in the freezer for maximum protection, which provides the added bonus that it acquires a viscosity similar to molasses that actually makes it easier to pour into measuring spoons without spilling it everywhere.
Additionally, there are now ways for vegetarians to get the longer-chain varieties too. Flax-fed hens can produce eggs enriched in EPA and DHA, acceptable in an ovolacto diet, and totally vegan, microalgal-derived supplements are available that provide not only DHA (which has been available for some years), but now EPA as well.[lvii],[lviii] On the other hand, I recommend that you avoid the use of softgel flax oil or “Omega-3-6-9” type supplements, as the elevated temperatures and oxygen exposure during encapsulation, followed by being left at room temperature on a shelf, will certainly lead to peroxidation.
This is the only supplement for which I can unambiguously tell you that you need a supplement. It has long been suggested that vegetarians (and especially vegans) would suffer vitamin D deficiencies, since the main dietary sources are fatty fish and fortified dairy products – but the underlying assumption was that most omnivores would be OK, as they could meet the RDA from a ‘healthy diet.’
It’s now become clear, however, that even the most recent IOM RDA for vitamin D is set far too low for optimal health. Based on a mixture of functional tests (the amount of vitamin D required to consistently prevent the rise in parathyroid hormone (PTH) that occurs when the body begins to draw down calcium stores out of bone, and to optimize calcium absorption), epidemiology, and clinical trials, it appears that long-term bone health requires serum levels of the vitamin D metabolite 25-hydroxyvitamin D3 (25(OH)D3 – the primary circulating form of vitamin D) of 30 to 40 nanograms per milliliter (or, equivalently, 75-100 nanomoles per liter)[lix] – far more than the 20 ng/mL (50 nmol/L) at which actual deficiency is diagnosed.
Except for people running around half-naked at midday at low latitudes (ie, people who are Damned Fools about skin cancer), almost no one can meet these needs from diet and sun exposure on a year-round basis. In one study, 26 healthy men who had just spent their summer doing outdoor work all day (landscapers, construction workers, farmers, and outdoor recs and sports coaches and enthusiasts) were assayed at the end of the summer and again in the last days of winter; while all had quite high 25(OH)D3 after basking in the summer sun (roughly equivalent to spending those months indoors but taking 2800 IU of vitamin D3 a day), when they came back in February or March, their average 25(OH)D still on the cusp of the optimal range (74 nmol/L) – but well over half of them (15 men) were beneath the 75 nmol/L threshold, including 3 subjects having slid into frank deficiency at 50 nmol/L or below, which for most people will require a supplemental intake of 800-1000 IU of vitamin D a day.[lx],[lxi] This dose is now endorsed by (among others) the Canadian Cancer Society,[lxii] the Canadian Dermatology Association, [lxiii]and several informal expert panels convened since the last IOM report, and should be considered the real “RDA” until the next such report is issued.
Sun exposure carries a risk of skin cancer, and is an inconsistent and unreliable source (indeed, a useless one for most of the year at latitudes higher than 37 degrees); properly-designed sun lamps are reliable, but inconvenient, and their long-term net health benefits are unproven. Moreover, people with dark skin, who cover themselves with clothes or sunscreen, or to some extent the biologically aged, all suffer considerable reductions in their vitamin D synthesis from these sources. By contrast, dietary supplements of 800-1000 IU of vitamin D a day raise levels of 25(OH)D3 to what appears to be the basic metabolic requirement for long-term health in most people, are proven to reduce fracture risk, and emerging results from randomized, controlled clinical trials are further documenting reductions in cancer risk[lxiv] and even total mortality.[lxv] No matter what your diet or lifestyle, there is simply no good reason to do anything else but take the darned pill.
Vitamin D3 (cholecalciferol) has long been favored as the superior source of vitamin D, as opposed to the vitamin D2 (ergocalciferol) long used in supplements and still generally used to fortify dairy because of cost. On the other hand, some older studies, and one recent and well-performed one,[lxvi] do suggest that D2 is, over a relatively short term, just as effective as D3, but it is still uncertain to what degree specific formulation factors (tablet vs softgel, dissolution medium, etc) are required to gain this benefit, and the weight of evidence still favors D3. Unfortunately, vitamin D3 still comes almost entirely from animal sources, either immediately (eg, cod liver oil) or remotely (cholesterol derived from lanolin in sheep’s wool), and vegan purists may reject even the shearing of sheep to avoid cancer, fractures, and death, so it’s reassuring that vitamin D may meet their needs (and certainly will, at sufficient dose). Cod liver oil should, in any case, be scrupulously avoided, as the amount of supplement needed to get sufficient vitamin D comes mixed in with enough preformed vitamin A (retinol) to put one at substantially increased risk of fracture, probably (ironically) from vitamin D antagonism.[lxvii]
There’s also some evidence that the reasonable-sounding notion that vitamin D – like most fat-soluble vitamins – needs to be taken with fat may be unwarranted. A recent study found that a single, very high dose of vitamin D2 was just as well-absorbed whether it was mixed in with whole milk, skim milk, or corn oil on toast, and that 12 weeks’ consumption of 1000 IU of vitamin D3 in orange juice did a quite adequate job of elevating serum 25(OH)D3 and keeping PTH levels down.[lxviii] Unfortunately, the study did not include the definitive protocol of a direct comparison of the now-known-to-be-adequate dose (1000 IU) used in the orange juice with the same amount in high- and low-fat dairy or similar beverages for the same period; and, vitamin D predissolved in orange juice may not react in the same way as a softgel sitting bathed in the stuff in your tummy. Until more is known, I’d continue to suggest taking your supplement with a fat-containing meal when convenient – but not sweating it if you occasionally find yourself with a fistful of pills and a luncheon in the Esselstyn household.
Another point is dosing frequency. I’ve never understood why some people have a problem taking their pills regularly, and if you’re reading this article, you’re probably not one of them anyway – but if you are, or if you miss a dose, or if you’d just prefer not to take a daily pill, it’s quite clear from clinical trials that, thanks to nontoxic storage in the liver, it’s absolutely fine to take an irregular, very high-dose supplement instead of a daily one containing what ought to be the Recommended “Daily” Allowance
(again, 800-1000 IU). Some studies have even had success with an annual injection of in the elderly. The liver and fat tissues just eke the stuff out on demand.
I’ve already released the feline of clichéd lore from my securely-fastened satchel: a functional test does exist, and it’s a widely-available and reliable. Again, you’ll want to target a 25(OH)D3 serum level of 30 to 40 nanograms per milliliter (or, equivalently, 75-100 nanomoles per liter), and adjust your dose accordingly and re-test if need be. Obviously, your level in the summer is likely to be substantially higher than your winter level, so boost up your dose seasonally if it seems already marginal in the fall.
It’s likely that people who don’t spend much time in the sun, or who have dark skin, and to some extent the older, will need substantially more than the 800-1000 IU starting dose now recommended by a consensus of researchers; for instance, only 60% of a group of 280 postmenopausal black women in the Long Island area achieved such levels after 2 years’ supplementation with 800 IU a day, and calculations suggested that to do so would require a dose of 2800 IU/d for those with levels already over 45 nmol/L and a whopping 4000 IU/d for those beneath this threshold.[lxix]
Fortunately, despite earlier fears, vitamin D has a very wide margin of safety: levels of the vitamin and its active metabolite appear to be well-regulated physiologically and doses in the range just discussed similarly appear to be quite safe. However, that can only be said if what’s on the label is in the pill. This is much more of an issue with vitamin D than with many other supplements, as the quantities equivalent to those required are just a few dozen micrograms, and it’s comparatively easy to screw up, as rare but alarming reports of overdose reveal. You should certainly buy from a well-established and reputable company, and to seriously consider one that is a branch of a pharmaceutical company. Alternatively, I you might choose a reputable but supplement-only company whose manufacturing facilities are officially licensed by FDA (not just claiming to be under “FDA GMPs,” which don’t actually exist in law at present) for over-the-counter drug compounding; or, third, one from Canada, where the supplement industry is better-regulated (again, I want to disclose my former employment, and ongoing relationship, with an innovative Canadian supplement company. Additionally, I would in general recommend softgels rather than tablets or capsules, as predissolved vitamin D is easier to manage, and softgel encapsulation requires a relatively sophisticated operation compared with two-piece gelcap (or VegiCap) encapsulation.
In practice, while ovolacto vegetarians actually tend to have higher calcium intakes than the general population, the intakes of many vegans are fairly consistently below the RDA. Therefore, the average vegan (and at least some ovolacto vegetarians, and indeed many omnivores) should take steps, through diet and supplementation, to boost their intake.
Now, before I get everyone’s collective back up, let me say up front: yes, the RDA for calcium is almost certainly more than you actually require for the health of your bones. But then again, so is the RDA for almost every other nutrient in terms of its relevant health outcomes. Remember, that’s the way the RDA is designed: not to meet the minimum requirement for ‘the average person,’ but to reflect the bellcurve of very individual nutritional needs, meeting the requirements of 97.5% of the population. That means that while some people will indeed need the full RDA for their long-term health, a few will need more – and most people will need less!
In IOM jargon, the RDA (Recommended Daily Allowance) is almost always set significantly higher than the EAR (Estimated Average Requirement). That’s as true for calcium as it is for vitamin C or iodine. No, wait: it’s worse for calcium than it is for most nutrients, because as the IOM themselves admit, we just don’t have the kind of data we would need to set a really reliable EAR or RDA, because the kind of long-term, rigorous studies that might answer the questions the IOM has set itself in terms of bone health have never been done. At the risk of annoying a few copyright lawyers, let me quote at some length from the report:
Ideally, the optimal calcium intake for skeletal health would be defined as that which leads to the fewest osteoporotic fractures later in life. Attaining this information would require prospective determination of the influence of different increments in calcium intake on fracture rates in young and older subjects with a wide range of usual calcium intakes. Such studies are not available, would require that large numbers of subjects be studied for many years, and would be prohibitively expensive.
Several observational studies of calcium intake and fracture risk are available ... Among these, no consistent association has been demonstrated between reported calcium intake over periods of up to 10 years and risk of fracture in peri- and postmenopausal women. [lxx]
Yes, there it is: the smoking gun! The very data that the RDA’s harshest vegetarian critics harp on continuously (usually emphasizing a high-quality1997 report from the Nurses Health study[lxxi] (which, by the way, they misrepresent, pretending that it showed an increase in fracture rate because of a widely-ranging statistical phenomenon called the ‘confidence interval’)), openly stated (“buried,” conspiracy theorists will claim) in black and white in the IOM expert panel’s report. But as they go on to say,
This is not surprising because osteoporosis results from complex interactions among genetic, dietary, and other environmental factors and has a long latency period. From a methodologic perspective, calcium intake may be underestimated by some survey methods and overestimated by others. [Indeed, as we’ve seen, reported intakes of food in general – and thus, its constituent nutrients – are almost uniformly higher than those reported, as part of the general tendency to underreport food intake. –MR]. … In addition, the influence of confounding factors such as frequency of falls and physical activity may vary over time. For these reasons observational studies cannot be used effectively to determine an Estimated Average Requirement (EAR) for calcium.lxx
Moreover, the actual range of dietary calcium intake in Western omnivorous populations are biased high almost across the board, leaving little room for real comparisons. Therefore, the IOM were stuck with starting from a mere Adequate Intake (AI) – again, the amount taken to cover frank deficiency, for the simple reason that it’s the amount consumed in the general population, and the general population doesn’t show signs of calcium deficiency. How this worked out to develop the RDA is also set out in the report: based on the Continuing Survey of Food Intakes by Individuals (CSFII) for 1994-1996, “the median calcium intake for men, aged 31 through 50 years, is 857 mg (21.4 mmol)/day and their seventy-fifth percentile of intake is 1,112 mg (27.8 mmol)/day. Their AI of 1,000 mg (25 mmol)/day falls between the median and seventy-fifth percentile of calcium intake” – and the RDA, designed to give assurance that nearly all of us will be getting enough, is therefore set higher still.lxx Similar calculations were built up for women, from a median intake of 606 mg and a greater concern for fracture risk, as observed in the population.
The problem, unfortunately, is that we don’t have any better ways to make this assessment. It’s not good enough to point (as too many overzealous advocates of the intrinsic superiority of vegan diets do) to a mixture of extrapolations from a few isolated metabolic factoids, and what I have long termed “cross-cultural crap” but is more formally referred to as “ecological studies:” in this case, the fact that women in traditional Asian societies have both low fracture rates and low calcium intakes. The problem with such analysis is that comparing such data in entire populations at a time misses out all the many variables that factor into such differences across cultures and racial groups, such as (in this case) the small stature of the same Asian women, their differing hip axis length and alignment from Caucasians, their higher level of activity and sun exposure – and the fact that smaller skeletons in smaller bodies necessarily require less calcium to support them. Similarly, the Japanese have a much higher smoking rate than Americans, and also are less likely to die of lung cancer; that doesn’t mean that cigarettes are a boon to lung health. [lxxii]
Unfortunately, what has not been done is a proper, long-term, high-quality prospective epidemiological study or clinical trial of calcium intake in Asian or vegetarian women with habitually low Calcium intake. What evidence is available on this front – from ecological epidemiology and case-control studies within such societies – supports the ability of higher calcium intake among such women to reduce fracture rates and retard the age-related loss of bone.[lxxiii],[lxxiv],[lxxv],[lxxvi] And yes, this still tends to suggest that most such women get away with calcium intake that, although higher than the local average, is still lower than the US RDA – as you would expect it to be.
Similarly, a recent study in the Journal of the American Medical Association (JAMA) found that an intake of 800 mg of calcium a day appeared to be sufficient to maintain calcium metabolism, provided vitamin D status was adequate, based on calcium balance and levels of PTH.[lxxvii] But is this a guarantee of long-term adequacy? And more importantly, is it enough to tell us what you, as an individual, really need just 800 milligrams of calcium to keep your bones strong and your other calcium-requiring metabolic activities going smoothly? No, it does not.
The problem is that we just don’t have a reliable way of determining what’s really needed for an individual. Serum levels of calcium are quite certainly unreliable: calcium is in constant metabolic use for regulating ion channels and other purposes, and when serum levels drop, the body simply leeches more out of the bones. This, indeed, is one of the reasons why real, long-term calcium insufficiency contributes to loss of bone mass and ultimate fracture risk. Similarly, serum levels can be boosted for very unhealthy reasons, such as diet-induced acidosis from eating too many ‘acid ash’ foods (most animal proteins (especially eggs) and grains) along with too few ‘alkali ash’ ones (nearly all fruits and vegetables), which causes the bones to release phosphorus stored up in the bones as part of the acid-buffering response – and in the process, the calcium to which it is bound.
The reason the RDA is so high, then, is not the sinister machinations of the dairy lobby (although the dairy lobby certainly does its best to exaggerate the ‘need’ for its product, and undeniably wields a profound, corrupt, and very negative influence over the form of the ‘Food Pyramid,’ USDA dietary guidelines, and government nutrition programs like the WIC program[lxxviii]). Rather, it’s a mixture of real uncertainty, and the same need to meet the nutritional needs of a wide range of people with individual requirements that is factored in to all the RDAs.
A good 25(OH)D3, reasonable serum calcium ion level, low PTH, and normal urine pH (tested with common litmus paper strips, available at drug stores and many health food stores) can all help to give confidence that your calcium metabolism is likely in order – but they aren’t definitive. Until we get a better way to test functional status or set a better RDA, you’d better make sure you’re getting that 1000 milligrams (or whatever) a day.
Calcium is of course readily available not only from dairy, but from many vegetables, provided they are low in oxalic acid; good sources include bok choi, broccoli, collard greens, okra, turnip greens, and that powerhouse of vegan calcium, kale. By contrast, almost all of the generous-looking calcium supply in spinach, beet greens, amaranth greens (yin tsoi/yin choi), and Swiss chard is tightly bound as oxalates and unavailable for absorption, so remember to discount it out of your nutrition software output. Calcium can also be obtained from fortified foods, of course, but that basically amounts to taking chewable supplement pills rather than real food, which should be your primary source of all nutrients.
The form of calcium that you use really doesn’t matter as much as is widely asserted. The common calcium carbonate used in many supplements is not the best – its bioavailability in people with low stomach acid is poor, and it can interfere with the absorption of other nutrients – but many other forms of calcium are fine. Calcium citrate-malate is the best-absorbed form, but the truth is that you really don’t need to get the highest possible bioavailabilty, so long as your total intake (diet and supplements combined) is adequate. (The exception to this is ossein microcrystalline calcium hydroxyapatite complex (MCHC), a bone-derived supplement which several studies have found to be superior to conventional calcium supplements;[lxxix] ,[lxxx] ,[lxxxi] ,[lxxxii] ,[lxxxiii] ,[lxxxiv],[lxxxv] but for reasons primarily related to its content of intact growth factors and polysaccharides, rather than the chemical form of the calcium; unfortunately, of course, few vegetarians would take such a supplement).
Because calcium is required at relatively high doses, and inhibits the absorption of iron, zinc, and other minerals (but not magnesium, despite what you’ve heardlxx), it’s best to spread your dose throughout the day (again, your ‘dose’ embracing both food and supplements); this also maximizes absorption.
Because some of the richest sources of iodine in the American diet are dairy products, ocean fish, and iodized salt (a quarter teaspoon contains about 95 micrograms), and because many excellent vegan foods (soybeans, and cruciferous vegetables like broccoli, cabbage, mustard greens, and kale) contain compounds called goiterogens that inhibit the thyroid gland’s utilization of the mineral, it’s reasonable to be concerned about iodine levels if you’re vegan. Unfortunately, nutrition software doesn’t track it, because there aren’t enough foods with known iodine levels: deficiency is rare these days in North America, thanks to salt iodization, so testing hasn’t been a big priority.
The positive side to this is that if you’re using iodized table salt or Morton Lite Salt on a daily basis, which contains about 95 micrograms per quarter teaspoon, your iodine needs are probably being met; if not, you may want to take a supplement (say, 100 micrograms). I strongly urge that you not use kelp supplements or other ‘sea vegetables’ as is widely recommended: as I documented in some detail after savaging my own thyroid with regular kombu consumption, levels of iodine in these foods are quite variable and can easily reach toxically high levels.[lxxxvi],[lxxxvii] Additionally, a recent report[lxxxviii] documented toxic levels of arsenic in a sample of eitght commercial kelp supplements; contrary to what was asserted, the arsenic was primarily in its more toxic, inorganic form.[lxxxix] In an industry that is largely still enjoying a Wild West mentality, and with a raw material that is so variable, I would not simply trust the label on either point.
There’s a good chance that you think that I’ve mistakenly put a conditionally-essential nutrient here, or that I’m confused or a flake who will next break into a discussion of laetrile or pangamic acid – or maybe you thought choline was always recognized as a B vitamin and thus an essential nutrient. In fact, it was only in 1998, with the most recent IOM expert panel report for the B vitamins, that the indispensability of choline was recognized.[xc] There was no question that it was physiologically essential: choline is required for the synthesis of components of cell membranes; for transmission of signals taken from the outside of the cell into its heart, and from one nerve cell to the next via the neurotransmitter acetylcholine; for the packing up of cholesterol and fats in the liver for delivery out to the rest of the body and for excretion into the bile (this is why it’s included (with inositol and methionine) in “lipotropic” supplements, which are often mistaken or misrepresented to be weight-loss aids); and as one source of methyl groups to aid in essential biochemical reactions. Human cells deprived of choline in their nutrient baths quickly commit cellular suicide.
No, the question was whether it was nutritionally essential, because the body can synthesize some of its own. Lab animals fed choline-free diets, but with adequate levels of all other essential nutrients, would fail to grow adequately and exhibit kidney, liver, and cognitive dysfunction, but no one had ever clearly observed an equivalent deficiency syndrome in humans, and it wasn’t clear how much choline people were getting in their diets, so there was uncertainty. But after decades of research suggesting that we might still need to get some choline in our diets, a human study was performed by Dr. Steven H Zeisel, later chairman of the Department of Nutrition at the University of North Carolina in Chapel Hill convinced most of the doubters. This study gave otherwise-healthy young men an artificial diet containing all essential nutrients, plus 500 mg of choline. When one group of men had the choline removed from the diet, they suffered progressive rises in liver enzymes, paralleled by a fall in the levels of phosphatidylcholine in their plasma and red blood cells.[xci]
Based on this and later evidence of a real nutritional requirement, but lacking enough detailed information to determine an RDA, the IOM’s 1998 report recognized choline as an essential nutrient in 1998, and based on the amount of choline present in normal, varied diets, determined an Adequate Intake (AI) of 550 mg/day of choline for men and 425 mg/day for women.iA series of later studies confirmed and expanded this finding, and narrowed down the range required to keep people healthy. One particularly important study came out in 2007,[xcii] showing that 23% of healthy men developed muscle or liver damage and/or the beginnings of fatty liver disease when fed the AI – and that while some people’s functional tests could return to normal with as little as 137.5 mg, at least one man appeared to need as much as 825 mg!
The AI was set based on typical, omnivorous North American diets. It was soon realized that vegetarians – and especially vegans – would have a much harder time reaching the AI, because few plant foods contain much choline, and much of the choline in the self-selected omnivorous diets from which the AI was derived came from eggs, along with milk and liver (see the IOM report, and more recently ([xciii])). And the effects of a low choline intake would be compounded by other weak spots in the vegetarian diet. For instance, one of the reasons we need choline in the first place is to transport the conditionally essential nutrient carnitine into our energy-producing mitochondria – but as we’ll see, vegetarians’ intake and plasma levels of this nutrient are also low. Similarly, another metabolic function to which choline can be put is as a source of methyl groups for essential biochemical reactions. One of the nutrients that can make up for any lack of methyl groups in a low-choline diet is the essential amino acid methionine – and vegetarian diets are low in that nutrient, too. So when studies performed in omnivores suggest that 550 mg of choline is probably enough for most, but not all, omnivores when all of these other nutrients are available, there’s reason to think that a vegetarian with the same genes would still be falling behind, because there’s less nutritional slack available from these other nutrients.
Unfortunately, as happens too often, the suggestion that a plant-based diet might have some gaps in it caused knee-jerk responses from many vegetarian advocates, who insisted that typical vegetarian diets just must provide adequate nutrition, and pointed to the presence of choline in a few unusually-rich plant foods (like like whole soy beans, peanuts, and wheat germ (if that counts as a food)) as evidence. The denial in some elements of the vegetarian community went up even further when Dr. Zeisel, who had spent much of his scientific career doing choline research, began prominently warning pregnant and lactating vegetarians to ensure they were getting extra choline to meet the extra requirements imposed by the rapidly-developing brains and nervous systems in their wombs and at their breasts, based on a mixture of animal studies,[xciv],[xcv]human metabolic studies, and a study that found that low choline intake in pregnant women is one factor that contributes to the risk of neural tube defects in their babies.[xcvi] It didn’t help matters that Dr. Zeisel does a significant amount of work on choline nutrition using lab rodents, which raises the hackles of many vegetarians, or that Zeisel and other choline researchers in his department understandably (if unfortunately) have to rely on the American Egg Board and the United Egg Producers’ Egg Nutrition Center for funding to pursue some of their research – organizations with a lot to gain from public attention on choline nutrition. And the politics got even worse when Zeisel was tapped to receive a grant for an entirely worthwhile study to more definitively establish the need for extra choline in pregnant vegan women, because the grant came out of a pool of money that had been put aside by McDonald’s as part of the settlement from the notorious McLibel court case – money that was supposed to go to “vegetarian organizations,” of which his lab clearly is not an instance, although his work is even more important for the health of vegetarians than it is for the rest of the population.
So exactly how much choline even an omnivore needs is quite uncertain, and the level required for a vegetarian even more so. The problem is compounded by the fact that very little data is available on the choline content of foods (although, again, its low levels in most vegetarian foods blunts the potential for missed intake in vegetarians), and that many nutritional software programs don’t even include what information is available; and the importance of assuring adequate intake is emphasized by the fact that some people appear to exhaust their bodies’ choline stores in a matter of days, while others take weeks to run into functional problems,v so that for some people even brief periods of low choline intake could be detrimental.
For now, prudence seems to require that vegetarians err on the side of a generous and definitely supplemented intake of choline, ensuring that dietary (to the extent that it can be known) plus supplemental choline is meaningfully higher than the AI of 550 mg for men and 425 mg/day for women. Functional status is still tricky, but one obvious set of markers is the same panel used to establish signs of deficiency in Zeisel’s depletion-repletion study:iv a fivefold or more increase above normal of the muscle-damage enzyme creatine phosphokinase (CPK), or a one-and-a-half or more times normal reading of the liver enzymes aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT), or lactate dehydrogenase (LD). Fatty liver, unfortunately, requires a harder-to-access MRI of fat deposits in the organ, to which your doctor is unlikely to consent.
It is a common to see the claim (usually from health-food vendors, although too often from sincere but ill-informed vegetarian advocates – including, unfortunately, the obdurate Dr. McDougall[xcvii]) that a given vegan protein source is ‘balanced’ or ‘complete’ because it “contains all of the essential amino acids,” which is a misunderstanding of the very definition of ‘complete’ or ‘balanced’ proteins. In saying that vegetable proteins are ‘incomplete,’ nutritionists mean that the pattern of individual essential amino acids of nearly all individual plant proteins is not well-matched to the needs for these amino acids in the body, making them substantially inferior for supporting growth and tissue maintenance than are animal-sourced ones (see Dr. Howard’s reply to McDougall, and the sections “Protein Quality” and on “Vegetarians” in the relevant IOM report ([xcviii]).
As most vegetarians used to know, these deficits can be partially remediated by combining individual plant proteins so that a relative deficit of one amino acid in one kind of protein relative to the rest – the so-called “limiting amino acid” – is complemented by the relative surplus of that amino acid in another. The classical example of this is legumes and rice or other grains: the former tend to be low in the essential amino acid methionine but relatively high (as plant proteins go) in lysine, while grains exhibit the reverse imbalance. This solution is imperfect, in part because even wellc-combined proteins tend to wind up being low in lysine (and sometimes methionine, too), and also because beyond this question of amino acid balance, the amount of them as a percentage of total protein is also substantially lower in most plant foods.
In researching this article, I wasn’t able to find any hard numbers on how much methionine a typical contemporary Western vegetarian might take in. Because some grain proteins (especially rice and corn) are high in percentage methionine (comparable to beef or egg), at least some vegetarians using rice protein powders or eating a lot of eggs might likely have methionine intakes as high as omnivores.However, between the lower percentage of methionine as a share of protein in legumes, the lower percentage of all essential amino acids out of total protein and Calorie contents of plant proteins generally, and the lower total protein intake in most self-selected vegetarian diets (in one study, [xcix] 40% of vegan women’s food journals indicated they weren’t even getting the RDA), it’s reasonably clear that many vegetarians’ methionine intakes must be lower than those of omnivores.[c]
That may actually be a good thing. Essential as they are to life, all nutrients have toxicities, and there is some evidence that high methionine intake may be bad for you.
For one thing, the body produces low levels of sulfuric acid when the liver metabolizes the sulfur-containing amino acids methionine and its conditionally-essential metabolite cyst(e)ine – ie, they’re “acid-ash,” an idea you’ve likely come across in health food stores, books on ‘cleansing,’ and promotional literature for ‘greens’ supplements – almost always in oversimplified and even distorted form. In brief,[ci] the metabolism of foods releases ions in ways that form acids (in the case of sulfur amino acids, sulfuric) or base (usually bicarbonate), and the balance of these results in a net acidifying or alkalinizing effect on the body’s pH. Because the biochemistry of life can only be carried out within a fairly narrow window close to neutral pH, the body has to neutralize any extra acid or alkali metabolites that it can’t excrete, and the kidneys’ capacity is limited. When the balance tilts too far toward excess diet-derived acid, the body falls back on tapping into the buffering capacity of the phosphate and carbonate reserves in the bone – taking the calcium with which it’s crystallized with it. If this acidifying imbalance persists in the diet over time, the small but continuous drawdown of bone hydroxyapatite, along with a possible excessive activation of bone-breakdown cells (osteoclasts) by the low pH itself, will slowly weaken the bones, while a chronically low systemic pH probably has other negative metabolic health impacts of its own.[cii]
This phenomenon, combined with the higher content of methionine in animal proteins and the higher protein levels in typical omnivorous diets, has long been used to argue that vegetarian diets should be more protective of bone health than omnivorous ones. Yet actual comparisons of real vegetarians and omnivores fail to find an advantage (eg. references [ciii], [civ], ,[cv],[cvi],[cvii],[cviii],[cix], and see earlier studies reviewed in ([cx])).
There are doubtless many factors in this, amongst them the aforementioned lower total protein intake of vegetarians and especially vegans (which – despite the specific acidifying effect of sulfur-containing amino acids, and contrary to the common assertions of vegetarian advocates – is none the less clearly a bone-protective nutrient, especially if most of that protein comes from plant sources and provided that calcium intake is high[cxi]), and the evidence that B12 insufficiency may impair bone health. But acid-alkali balance is also a possible culprit, because the overall mixture of nutrient metabolic substrates in such common vegetarian foods as many grains and cheeses makes them surprisingly powerfully-acidifying relative to their methionine content.xxi,[cxii]
There are other signs that excessive methionine is bad for you. A study in European men found that, while higher protein intake was highly protective against heart attacks and hospitalizations for chest pains, risk rose steadily when methionine inake rose above 1700 mg a day; the effect did not appear to be linked to homocysteine levels.[cxiii] A study in atherosclerosis-prone mice[cxiv] found that excess methionine increased the rate of heart disease, independent of the amino acid’s effect on homocysteine levels. In other rodent models, feeding soy protein vs. higher-methionine casein is protective against kidney disease and cancer, and the latter benefit at least disappears if the soy is topped up with a full ration of extra methionine. And while the effect is uncertain (because it’s confounded by the fact that it leads to impaired growth and low Calorie intake), certainly the face-value reading of a series of experiments going back into the 1980s is that a truly radical reduction in methionine and cysteine intake, corresponding roughly to getting a dangerously-low 263 mg of methionine + cysteine in a 150 pound human (vs. an RDA for humans of 19 mg/kg/d, or 1330 mg for this body mass), dramatically slows down the aging process in rats and mice, keeping the animals young and healthy longer and extending their lifespans.
Should you do anything about this? Certainly, it’s too early to suggest trying radical methionine restriction: there’s no evidence as yet for benefits in normal, healthy people, and even the rodent studies are hard to interpret; moreover, while a few humans are given low-Met diets today for experimental chemotherapy or because of a genetic defect that prevents them from properly detoxifying homocysteine, the regimen can’t be achieved with whole foods: these people wind up eating basically nothing but potatoes, a few vegetables, and a customized super-low-methionine amino acid shake, and its long-term safety in normal, healthy humans is quite unknown.
What, then, should one do about methionine intake? The answer of course is to start by checking your software to see how much you’re actually getting. Unfortunately, I know of no nutrition software that comes with built-in data for the RDAs for amino acids, but CRON-O-Meter and some others do let you enter in your own targets; the current RDAs, after a recent wave of research, are somewhat higher for most aminos than the oft-cited FAO values:
Amino Acid RDA for Adults
14 mg/kg/d of histidine
19 mg/kg/d of isoleucine
42 mg/kg/d of leucine
38 mg/kg/d of lysine
19 mg/kg/d of methionine + cysteine combined
33 mg/kg/d of phenylalanine + tyrosine combined
20 mg/kg/d of threonine
5 mg/kg/d of tryptophan
24 mg/kg/d of valine
To calculate your requirements, multiply these values by your mass in kilograms (or your weight in pounds, divided by 2.2 to bring you into at least the 20th century). And while it’s a bit laborious, you can get an idea of the overall quality of your diet’s protein balance can be obtained by targeting similar multiples of the RDAs for all aminos – for instance, roughly 300% of all, including eg. 170% of methionine + 140% of cysteine, for a combined 310% (and similarly for phenylalanine + tyrosine ).[cxv] You may, however, want to accept a reduced ratio of methionine (and cysteine) for the above reasons, which is often the case anyway in vegetarian diets unless you rely on eggs and rice proteins a lot. And based on the results for acute cardiac events, a ceiling of about 1.7 g of methionine seems sensible in any case.
Functional assays, to make sure you aren’t either deficient or overloaded on methioinine, are trickier. Frank deficiency leads to a lot of rather nonspecific symptoms (slow, weak growth of nails and hair; increased risk of liver damage); overdose is unlikely to lead to elevated homocysteine if you aren’t deficient in B12 (which you’re making sure that you’re not – right?). Systemic acidosis can be monitored in your urine with litmus papers, which are available in graded increments covering the a physiological range (such as from pH of 5 to 9 in of 0.5-point intervals); normal physiological pH is very slightly acidic at 6.7. But many factors play into this, including of course how much alkalinizing precursors such as citrate and malate (mostly from vegetables and fruits) you’re getting.
Lysine is much more commonly the limiting amino acid in plant proteins than is methionine, and absolute levels are also low. While intake should be monitored, there’s little reason to fear frank deficiency: the RDA is 38 mg/kg/d (2660 mg/d in a 150 pound adult), and one study reported that lysine intakes in free-living omnivores, ovolacto vegetarians, and vegans were 8300, 5400, and 3700 mg/day, respectively.[cxvi] However, the question of amino acid balancing does remain and should be monitored.
In addition to limiting protein synthesis, a lack of lysine may leave you vulnerable to outbreaks of lipid-enveloped viruses such as those that cause genital and oral herpes. Enveloped viruses in the Herpes group have a high requirement for the amino acid arginine, in particular for proteins required to shuttle the viral DNA into the infected cell’s nucleus to highjack its machinery to reproduce the virus; it’s thought that lysine’s close chemical resemblance to arginine causes it to competes for incorporation into these proteins, slowing their synthesis and thus the replication of the virus. By whatever mechanism, multiple clinical trials in humans show that high-dose (1000-3000 mg in divided doses, preferably taken between meals) of supplemental lysine shortens and may reduce the frequency of outbreaks; the evidence on this has convinced the Canadian government to include it as an approved indication on dietary supplements.[cxvii]
Certainly, you should get the RDA (38 mg/kg/d); additionally, because it shows no evidence of toxicity, and is very well-documented as a suppressor of Herpes simplex (and very plausibly also related viruses with the same vulnerability, such as Herpes zoster (which causes chickenpox and shingles) and cytomegalovirus (with which almost everyone is infected and which rarely causes symptoms, but which may be a major driver of the decline of the immune system with aging[cxviii])), supplementation should be strongly considered in the high end of the clinically-tested range (since vegetarians’ dietary intake will tend to be low). As an added bonus, lysine increases the absorption of calcium, in which vegan diets are sometimes low (although this only applies to lysine taken with the calcium).
While the Health Canada monograph gives no contraindication, caution should be excercised if you are taking antibiotics known as aminoglycosides (gentamicin, neomycin, and others – Google it!) because they may increase the drugs’ toxicity to the kidneys.[cxix]
… And Those Were the Easy ones!
If this all sounds complicated and seat-of-the-pantsish, you’re right: we know quite a bit about human nutrition, but not nearly enough to prescribe down to the iota or give a definitive panel of tests – and vegetarian health remains even less-well-known than that of omnivores. Still, if you’re concerned about your health, and aren’t satisfied with a risk of death the same as your meat-eating cousin Bob, you’re going to have to do some work. The good and bad news is that in the final installment, we’ll be covering even less well-understood “conditionally essential” nutrients: bad news, because the seat of our pants will surely become embarrassingly threadbare; good news, because definitive dietary intakes of such nutrients aren’t as high a priority, and frankly, you can let yourself off the hook about testing and dietary analysis thanks to the sheer depth of the abyss of ignorance that confronts us.
[iii] Herbert V. Vitamin B-12: plant sources, requirements, and assay. Am J Clin Nutr. 1988 Sep;48(3 Suppl):852-8.
[iv] Herbert V. Vitamin B-12: plant sources, requirements, and assay. Am J Clin Nutr. 1988 Sep;48(3 Suppl):852-8.
[v] Elmadfa I, Singer I. Vitamin B-12 and homocysteine status among vegetarians: a
global perspective. Am J Clin Nutr. 2009 Apr 8. [Epub ahead of print]
[vi] Key TJ, Appleby PN, Spencer EA, Travis RC, Roddam AW, Allen NE. Mortality in
British vegetarians: results from the European Prospective Investigation into
Cancer and Nutrition (EPIC-Oxford). Am J Clin Nutr. 2009 Mar 18. doi:10.3945/ajcn.2009.26736L
[vii] Majchrzak D, Singer I, Männer M, Rust P, Genser D, Wagner KH, Elmadfa I. B-vitamin status and concentrations of homocysteine in Austrian omnivores, vegetarians and vegans. Ann Nutr Metab. 2006;50(6):485-91.
[viii] Koebnick C, Hoffmann I, Dagnelie PC, Heins UA, Wickramasinghe SN, Ratnayaka ID, Gruendel S, Lindemans J, Leitzmann C. Long-term ovo-lacto vegetarian diet impairs vitamin B-12 status in pregnant women. J Nutr. 2004 Dec;134(12):3319-26.
[ix] Herrmann W, Schorr H, Obeid R, Geisel J. Vitamin B-12 status, particularly holotranscobalamin II and methylmalonic acid concentrations, and hyperhomocysteinemia in vegetarians. Am J Clin Nutr. 2003 Jul;78(1):131-6.
[x] Krajcovicová-Kudlácková M, Blazícek P, Kopcová J, Béderová A, Babinská K. Homocysteine levels in vegetarians versus omnivores. Ann Nutr Metab. 2000;44(3):135-8.
[xi] Mann NJ, Li D, Sinclair AJ, Dudman NP, Guo XW, Elsworth GR, Wilson AK, Kelly FD. The effect of diet on plasma homocysteine concentrations in healthy male subjects. Eur J Clin Nutr. 1999 Nov;53(11):895-9.
[xii] Mezzano D, Muñoz X, Martínez C, Cuevas A, Panes O, Aranda E, Guasch V, Strobel
P, Muñoz B, Rodríguez S, Pereira J, Leighton F. Vegetarians and cardiovascular risk factors: hemostasis, inflammatory markers and plasma homocysteine. Thromb Haemost. 1999 Jun;81(6):913-7.
[xiii] Kumar J, Garg G, Sundaramoorthy E, Prasad PV, Karthikeyan G, Ramakrishnan L, Ghosh S, Sengupta S. Vitamin B12 deficiency is associated with coronary artery disease in an Indian population. Clin Chem Lab Med. 2009 Mar; 47(3): 334-8.
[xiv] Geisel J, Schorr H, Bodis M, Isber S, Hübner U, Knapp JP, Obeid R, Herrmann W. The vegetarian lifestyle and DNA methylation. Clin Chem Lab Med. 2005;43(10):1164-9.
[xv] Bor MV, Lydeking-Olsen E, Møller J, Nexø E. A daily intake of approximately 6 microg vitamin B-12 appears to saturate all the vitamin B-12-related variables in Danish postmenopausal women. Am J Clin Nutr. 2006 Jan;83(1):52-8.
[xvi] Eussen SJ, de Groot LC, Clarke R, Schneede J, Ueland PM, Hoefnagels WH, van Staveren WA. Oral cyanocobalamin supplementation in older people with vitamin B12 deficiency: a dose-finding trial. Arch Intern Med. 2005 May 23;165(10):1167-72.
[xvii] Malinow MR, Bostom AG, Krauss RM. Homocyst(e)ine, diet, and cardiovascular diseases: a statement for healthcare professionals from the Nutrition Committee, American Heart Association. Circulation. 1999 Jan 5-12;99(1):178-82.
[xviii] Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. 2001; National Academy Press, Washington, DC.
[xix] Hunt JR, Roughead ZK. Adaptation of iron absorption in men consuming diets with high or low iron bioavailability. Am J Clin Nutr. 2000 Jan;71(1):94-102.
[xx] Hunt JR, Roughead ZK. Nonheme-iron absorption, fecal ferritin excretion, and blood indexes of iron status in women consuming controlled lactoovovegetarian diets for 8 wk. Am J Clin Nutr. 1999 May;69(5):944-52.
[xxi] Sanders TA. Vegetarian diets and children. Pediatr Clin North Am. 1995 Aug;42(4):955-65.
[xxii] Craig WJ. Iron status of vegetarians. Am J Clin Nutr. 1994 May;59(5 Suppl):1233S-1237S.
[xxiii] Kanner J, Lapidot T. The stomach as a bioreactor: dietary lipid peroxidation in the gastric fluid and the effects of plant-derived antioxidants. Free Radic Biol Med. 2001 Dec 1;31(11):1388-95.
[xxiv] Xu J, Knutson MD, Carter CS, Leeuwenburgh C. Iron accumulation with age, oxidative stress and functional decline. PLoS ONE. 2008 Aug 6;3(8):e2865.
[xxv] Hurrell RF, Reddy M, Cook JD. Inhibition of non-haem iron absorption in man by polyphenolic-containing beverages. Br J Nutr. 1999 Apr;81(4):289-95.
[xxvi] Köpcke W, Sauerland MC. Meta-analysis of efficacy and tolerability data on iron proteinsuccinylate in patients with iron deficiency anemia of different severity. Arzneimittelforschung. 1995 Nov;45(11):1211-6.
[xxvii] Maret W, Sandstead HH. Zinc requirements and the risks and benefits of zinc supplementation. J Trace Elem Med Biol. 2006;20(1):3-18.
[xxviii] Sandstead HH. Requirements and toxicity of essential trace elements, illustrated by zinc and copper. Am J Clin Nutr. 1995 Mar;61(3 Suppl):621S-624S.
[xxix] Klevay LM. Lack of a recommended dietary allowance for copper may be hazardous to your health. J Am Coll Nutr. 1998 Aug;17(4):322-6.
[xxx] Stargrove MB, Treasure J, McKee DL. Herb, nutrient, and drug interactions: clinical implications and therapeutic strategies. 2007; Elsevier Health Sciences, ISBN 0323029647.
[xxxi] Moser PB, Gunderson CJ. Changes in plasma zinc following the ingestion of a zinc multivitamin-mineral supplement with and without breakfast. Nutr Res. 1983 May-Jun;3(3):279-84.
[xxxii] Nève J, Hanocq M, Peretz A, Khalil FA, Pelen F. Absorption and metabolism of oral zinc gluconate in humans in fasting state, during, and after a meal. Biol Trace Elem Res. 1992 Jan-Mar;32:201-12.
[xxxiii] Barrie SA, Wright JV, Pizzorno JE, Kutter E, Barron PC. Comparative absorption of zinc picolinate, zinc citrate and zinc gluconate in humans. Inflamm Res. 1987 Jun;21(1-2):223-8.
[xxxiv] Schelling JL, Muller-Hess S, Thonney F. Letter: Effect of food on zinc absorption. Lancet. 1973 Oct 27;2(7835):968-9.
[xxxv] Roth HP, Kirchgessner M. Utilization of zinc from picolinic or citric acid complexes in relation to dietary protein source in rats. J Nutr. 1985 Dec;115(12):1641-9.
[xxxvi] Rosado JL, Muñoz EC, López P, Allen LH. Absorption of zinc sulfate, methionine, and polyascorbate in the presence and absence of a plant-based rural Mexican diet. Nutr Res. 1993 Oct;13(10):1141–51.
[xxxvii] Spears JW. Zinc methionine for ruminants: relative bioavailability of zinc in lambs and effects of growth and performance of growing heifers. J Anim Sci. 1989 Mar;67(3):835-43.
[xxxviii] Wagner JJ, Engle TE, Wagner JJ, Lacey JL, Walker G. The Effects of ZinMet Brand Liquid Zinc Methionine on Feedlot Performance and Carcass Merit in Crossbred Yearling Steers. Profess Anim Scientist. 2008 Oct; 24(8):420-9.
[xxxix] Nunnery GA, Vasconcelos JT, Parsons CH, Salyer GB, Defoor PJ, Valdez FR, Galyean ML. Effects of source of supplemental zinc on performance and humoral immunity in beef heifers. J Anim Sci. 2007 Sep;85(9):2304-13.
[xl] van Heugten E, Spears JW, Kegley EB, Ward JD, Qureshi MA. Effects of organic forms of zinc on growth performance, tissue zinc distribution, and immune response of weanling pigs. J Anim Sci. 2003 Aug;81(8):2063-71.
[xli] Mohanna C, Nys Y. Effect of dietary zinc content and sources on the growth, body zinc deposition and retention, zinc excretion and immune response in chickens. Br Poult Sci. 1999 Mar;40(1):108-14.
[xlii] Rojas LX, McDowell LR, Martin FG, Wilkinson NS, Johnson AB, Njeru CA. Relative bioavailability of zinc methionine and two inorganic zinc sources fed to cattle. J Trace Elem Med Biol. 1996 Dec;10(4):205-9.
[xliii] Schell TC, Kornegay ET. Zinc concentration in tissues and performance of weanling pigs fed pharmacological levels of zinc from ZnO, Zn-methionine, Zn-lysine, or ZnSO4. J Anim Sci. 1996 Jul;74(7):1584-93
[xliv] Rojas LX, McDowell LR, Cousins RJ, Martin FG, Wilkinson NS, Johnson AB, Velasquez JB. Relative bioavailability of two organic and two inorganic zinc sources fed to sheep. J Anim Sci. 1995 Apr;73(4):1202-7.
[xlv] Wedekind KJ, Lewis AJ, Giesemann MA, Miller PS. Bioavailability of zinc from inorganic and organic sources for pigs fed corn-soybean meal diets. J Anim Sci. 1994 Oct;72(10):2681-9.
[xlvi] Hill DA, Peo ER Jr, Lewis AJ, Crenshaw JD. Zinc-amino acid complexes for swine. J Anim Sci. 1986 Jul;63(1):121-30.
[xlviii] McDougall J. Optimal diets to prevent heart disease. JAMA. 2003 Mar 26;289(12):1509.
[xlix] Kris-Etherton PM, Taylor DS, Yu-Poth S, Huth P, Moriarty K, Fishell V, Hargrove RL, Zhao G, Etherton TD. Polyunsaturated fatty acids in the food chain in the United States. Am J Clin Nutr. 2000 Jan;71(1 Suppl):179S-88S.
[l] Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (Macronutrients). 2005; Washington, DC: National Academies Press. ISBN-10: 0-309-08525-X
[li] León H, Shibata MC, Sivakumaran S, Dorgan M, Chatterley T, Tsuyuki RT. Effect of fish oil on arrhythmias and mortality: systematic review. BMJ. 2008 Dec 23;337:a2931.
[lii] de Lorgeril M, Salen P, Martin JL, Monjaud I, Delaye J, Mamelle N. Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study. Circulation. 1999 Feb 16;99(6):779-85.
[liii] Singh RB, Niaz MA, Sharma JP, Kumar R, Rastogi V, Moshiri M. Randomized, double-blind, placebo-controlled trial of fish oil and mustard oil in patients with suspected acute myocardial infarction: the Indian experiment of infarct survival-4. Cardiovasc Drugs Ther. 1997 Jul;11(3):485-91.
[liv] Ackman RG, Loew FM. Effects of High Levels of Fats Rich in Erucic Acid (from Rapeseed Oil) or Cetoleic and Cetelaidic Acids (from Partially Hydrogenated Fish Oil) in a Short-Term Study in a Non-Human Primate Species I. Fette, Seifen, Anstrichmittel. 1977 Jan; 70(1):15-24.
[lv] Ghafoorunissa. Requirements of dietary fats to meet nutritional needs & prevent the risk of atherosclerosis: an Indian perspective. Indian J Med Res. 1998 Nov;108:191-202.
[lvi] Joint WHO/FAO Expert Consultation on Diet, Nutrition and the Prevention of Chronic Diseases. Diet, Nutrition and the Prevention of Chronic Diseases. WHO Technical Report Series, No. 916 (TRS 916). 2002; Geneva: World Health Organization. Available online at http://whqlibdoc.who...WHO_TRS_916.pdf . Accessed 2009/05/14.
[lviii] Karabudak E, Kiziltan G, Cigerim N. A comparison of some of the cardiovascular risk factors in vegetarian and omnivorous Turkish females. J Hum Nutr Diet. 2008 Feb;21(1):13-22.
[lix] Holick MF. Vitamin D deficiency. N Engl J Med. 2007 Jul 19;357(3):266-81.
[lx] Barger-Lux MJ, Heaney RP. Effects of above average summer sun exposure on serum 25-hydroxyvitamin D and calcium absorption. J Clin Endocrinol Metab. 2002 Nov;87(11):4952-6.
[lxi] Vieth R, Bischoff-Ferrari H, Boucher BJ, Dawson-Hughes B, Garland CF, Heaney RP, Holick MF, Hollis BW, Lamberg-Allardt C, McGrath JJ, Norman AW, Scragg R, Whiting SJ, Willett WC, Zittermann A. The urgent need to recommend an intake of vitamin D that is effective. Am J Clin Nutr. 2007 Mar;85(3):649-50.
[lxiii] Canadian Dermatology Association. Canadian Dermatology Association Position Statement: Safe and effective way to maintain adequate levels of vitamin D. 2007 May 1. Available online at http://www.dermatolo...atest_news.html . Accessed 2009/05/11.
[lxiv] Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr. 2007 Jun;85(6):1586-91. Erratum in: Am J Clin Nutr. 2008 Mar;87(3):794.
[lxv] Autier P, Gandini S. Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials. Arch Intern Med. 2007 Sep 10;167(16):1730-7.
[lxvi] Holick MF, Biancuzzo RM, Chen TC, Klein EK, Young A, Bibuld D, Reitz R, Salameh W, Ameri A, Tannenbaum AD. Vitamin D2 is as effective as vitamin D3 in maintaining circulating concentrations of 25-hydroxyvitamin D. J Clin Endocrinol Metab. 2008 Mar;93(3):677-81.
[lxvii] Cannell JJ, Vieth R, Willett W, Zasloff M, Hathcock JN, White JH, Tanumihardjo SA, Larson-Meyer DE, Bischoff-Ferrari HA, Lamberg-Allardt CJ, Lappe JM, Norman AW, Zittermann A, Whiting SJ, Grant WB, Hollis BW, Giovannucci E. Cod liver oil, vitamin A toxicity, frequent respiratory infections, and the vitamin D deficiency epidemic. Ann Otol Rhinol Laryngol. 2008 Nov;117(11):864-70.
[lxviii] Tangpricha V, Koutkia P, Rieke SM, Chen TC, Perez AA, Holick MF. Fortification of orange juice with vitamin D: a novel approach for enhancing vitamin D nutritional health. Am J Clin Nutr. 2003 Jun;77(6):1478-83.
[lxix] Talwar SA, Aloia JF, Pollack S, Yeh JK. Dose response to vitamin D supplementation among postmenopausal African American women. Am J Clin Nutr. 2007 Dec;86(6):1657-62.
[lxx] Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. 1997; National Academy Press:Washington, DC.
[lxxi] Feskanich D, Willett WC, Stampfer MJ, Colditz GA. Milk, dietary calcium, and bone fractures in women: a 12-year prospective study. Am J Public Health. 1997 Jun;87(6):992-7.
[lxxii] For more on different kinds of scientific studies and their strengths and weaknesses, please see Rae M. Prospective Epidemiology vs Cross-Cultural Crap. Calorie Restriction Society discussion forum. 2006 Jul 06. Available online at http://www.caloriere...8314#msg-168314 . Accessed 2009/15/13. (By coincidence, this post was a response to a question on this subject by none other than Erin Dame).
[lxxiii] Yaegashi Y, Onoda T, Tanno K, Kuribayashi T, Sakata K, Orimo H. Association of hip fracture incidence and intake of calcium, magnesium, vitamin D, and vitamin K. Eur J Epidemiol. 2008;23(3):219-25.
[lxxiv] Xu L, Phillips M, D'Este C, Dibley M, Porteous J, Attia J. Diet, activity, and other lifestyle risk factors for forearm fracture in postmenopausal women in China: a case-control study. Menopause. 2006 Jan-Feb;13(1):102-10.
[lxxv] Lau EM, Woo J, Lam V, Hong A. Milk supplementation of the diet of postmenopausal Chinese women on a low calcium intake retards bone loss. J Bone Miner Res. 2001 Sep;16(9):1704-9.
[lxxvi] Lau EM, Suriwongpaisal P, Lee JK, Das De S, Festin MR, Saw SM, Khir A, Torralba T, Sham A, Sambrook P. Risk factors for hip fracture in Asian men and women: the Asian osteoporosis study. J Bone Miner Res. 2001 Mar;16(3):572-80.
[lxxvii] Steingrimsdottir L, Gunnarsson O, Indridason OS, Franzson L, Sigurdsson G.
Relationship between serum parathyroid hormone levels, vitamin D sufficiency, and
calcium intake. JAMA. 2005 Nov 9;294(18):2336-41.
[lxxviii] Nestle M. Food Politics: How the Food Industry Influences Nutrition and Health. 2007; Univ of California Press, ISBN-10: 0520254031.
[lxxix] Albertazzi P, Steel SA, Howarth EM, Purdie DW. Comparison of the effects of two different types of calcium supplementation on markers of bone metabolism in a postmenopausal osteopenic population with low calcium intake: a double-blind placebo-controlled trial. Climacteric. 2004 Mar;7(1):33-40.
[lxxx] Castelo-Branco C, Pons F, Vicente JJ, Sanjuan A, Vanrell JA. Preventing postmenopausal bone loss with ossein-hydroxyapatite compounds. Results of a two-year, prospective trial. J Reprod Med. 1999 Jul; 44(7): 601-5.
[lxxxi] Ruegsegger P, Keller A, Dambacher MA. Comparison of the treatment effects of ossein-hydroxyapatite compound and calcium carbonate in osteoporotic females. Osteoporos Int. 1995 Jan; 5(1): 30-4.
[lxxxii] Ruegsegger P, Dambacher MA. Therapy of osteoporosis with an ossein-hydroxyapatite compound evaluated with quantitative computed tomography. J Bone Miner Res. 1987 Jun; 2(Suppl1): A325.
[lxxxiii] Stellon A, Davies A, Webb A, Williams R. Microcrystalline hydroxyapatite compound in prevention of bone loss in corticosteroid-treated patients with chronic active hepatitis. Postgrad Med J.1985 Sep; 61(719): 791-6.
[lxxxiv] Epstein O, Kato Y, Dick R, Sherlock S. Vitamin D, hydroxyapatite, and calcium gluconate in treatment of cortical bone thinning in postmenopausal women with primary biliary cirrhosis. Am J Clin Nutr 1982 Sep; 36(3): 426-30.
[lxxxv] Durance RA, Parsons V, Atkins CJ, Hamilton EB, Davies C. A trial of calcium supplements (Ossopan) and ashed bone. Clin Trials J. 1973 Nov; 10(3): 67-73.
[lxxxviii] Amster E, Tiwary A, Schenker MB. Case report: potential arsenic toxicosis secondary to herbal kelp supplement. Environ Health Perspect. 2007 Apr;115(4):606-8.
[lxxxix] Schenker MB, Amster E. Arsenic in Herbal Kelp Supplements: Schenker et al. Respond. Environ Health Perspect. 2007 December; 115(12): A576–7.
[xc] Institute of Medicine. Food and Nutrition Board. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, PantothenicAcid, Biotin, and Choline. 1998; National Academy Press: Washington, DC.
[xci] Zeisel SH, Da Costa KA, Franklin PD, Alexander EA, Lamont JT, Sheard NF, Beiser A. Choline, an essential nutrient for humans. FASEB J. 1991 Apr;5(7):2093-8.
[xcii] Fischer LM, daCosta KA, Kwock L, Stewart PW, Lu TS, Stabler SP, Allen RH,
Zeisel SH. Sex and menopausal status influence human dietary requirements for the
nutrient choline. Am J Clin Nutr. 2007 May;85(5):1275-85.
[xciii] Fischer LM, Scearce JA, Mar MH, Patel JR, Blanchard RT, Macintosh BA, Busby MG, Zeisel SH. Ad libitum choline intake in healthy individuals meets or exceeds the proposed adequate intake level. J Nutr. 2005 Apr;135(4):826-9.
[xciv] Zeisel SH. Nutritional importance of choline for brain development. J Am Coll Nutr. 2004 Dec;23(6 Suppl):621S-626S.
[xcv] Li Q, Guo-Ross S, Lewis DV, Turner D, White AM, Wilson WA, Swartzwelder HS. Dietary prenatal choline supplementation alters postnatal hippocampal structure and function. J Neurophysiol. 2004 Apr;91(4):1545-55.
[xcvi] Shaw GM, Carmichael SL, Yang W, Selvin S, Schaffer DM. Periconceptional
dietary intake of choline and betaine and neural tube defects in offspring. Am J
Epidemiol. 2004 Jul 15;160(2):102-9.
[xcvii] McDougall J. Plant foods have a complete amino acid composition. Circulation. 2002 Jun 25;105(25):e197; author reply e197.
[xcviii] Institute of Medicine. Food and Nutrition Board. Dietary Reference Intakes for Energy, Carbohydrates, Fiber, Fat, Protein and Amino Acids (Macronutrients). 2002; National Academy Press: Washington, DC.
[xcix] Haddad EH, Berk LS, Kettering JD, Hubbard RW, Peters WR. Dietary intake and biochemical, hematologic, and immune status of vegans compared with nonvegetarians. Am J Clin Nutr. 1999 Sep;70(3 Suppl):586S-593S.
[c] McCarty MF, Barroso-Aranda J, Contreras F. The low-methionine content of vegan diets may make methionine restriction feasible as a life extension strategy. Med Hypotheses. 2009 Feb;72(2):125-8.
[ci] Remer T. Influence of diet on acid-base balance. Semin Dial. 2000 Jul-Aug;13(4):221-6.
[cii] New SA. Nutrition Society Medal lecture. The role of the skeleton in acid-base homeostasis. Proc Nutr Soc. 2002 May;61(2):151-64.
[ciii] Ho-Pham LT, Nguyen PL, Le TT, Doan TA, Tran NT, Le TA, Nguyen TV. Veganism, bone mineral density, and body composition: a study in Buddhist nuns. Osteoporos Int. 2009 Apr 7. doi: 10.1007/s00198-009-0916-z
[civ] Wang YF, Chiu JS, Chuang MH, Chiu JE, Lin CL. Bone mineral density of vegetarian and non-vegetarian adults in Taiwan. Asia Pac J Clin Nutr. 2008;17(1):101-6.
[cv] Keramat A, Patwardhan B, Larijani B, Chopra A, Mithal A, Chakravarty D, Adibi H, Khosravi A. The assessment of osteoporosis risk factors in Iranian women compared with Indian women. BMC Musculoskelet Disord. 2008 Feb 27;9:28.
[cvi] Thorpe DL, Knutsen SF, Beeson WL, Rajaram S, Fraser GE. Effects of meat consumption and vegetarian diet on risk of wrist fracture over 25 years in a cohort of peri- and postmenopausal women. Public Health Nutr. 2008 Jun;11(6):564-72.
[cvii] Smith AM. Veganism and osteoporosis: a review of the current literature. Int J Nurs Pract. 2006 Oct;12(5):302-6.
[cviii] Fontana L, Shew JL, Holloszy JO, Villareal DT. Low bone mass in subjects on a long-term raw vegetarian diet. Arch Intern Med. 2005 Mar 28;165(6):684-9.
[cix] Dhonukshe-Rutten RA, van Dusseldorp M, Schneede J, de Groot LC, van Staveren WA. Low bone mineral density and bone mineral content are associated with low cobalamin status in adolescents. Eur J Nutr. 2005 Sep;44(6):341-7.
[cx] New SA. Do vegetarians have a normal bone mass? Osteoporos Int. 2004 Sep;15(9):679-88.
[cxi] See a collection of studies and discussion in Rae M. Bones & Protein -- Why the Research Contradiction? Post to CR Society discussion forum. 2009/01/29. Available online at http://www.caloriere...1086#msg-191086 . Accessed 2009/06/10.
[cxii] Remer T, Manz F. Potential renal acid load of foods and its influence on urine pH. J Am Diet Assoc. 1995 Jul;95(7):791-7.
[cxiii] Virtanen JK, Voutilainen S, Rissanen TH, Happonen P, Mursu J, Laukkanen JA, Poulsen H, Lakka TA, Salonen JT. High dietary methionine intake increases the risk of acute coronary events in middle-aged men. Nutr Metab Cardiovasc Dis. 2006 Mar;16(2):113-20.
[cxiv] Troen AM, Lutgens E, Smith DE, Rosenberg IH, Selhub J. The atherogenic effect of excess methionine intake. PNAS. 2003 Dec 9;100(25):15089-94.
[cxv] This actually isn’t quite correct, since the ideal amino acid pattern is not quite the same as the simple balance of RDAs; see Table 10-24 from the IOM report.10 If you’d rather delve into this part of the equation, you could plug in the pattern value instead of the RDAs, and do the same proportional analysis suggested above.
[cxvi] Linder MC. Nutritonal Biochemistry and Metabolism: With Clinical Applications. 2nd Ed. 1991; McGraw-Hill/Appleton & Lange. ISBN-10: 0838570844
[cxviii] Pawelec G, Koch S, Gouttefangeas C, Wikby A. Immunorejuvenation in the elderly. Rejuvenation Res. 2006 Spring;9(1):111-6.
[cxix] Tomblin FA Jr, Lucas KH. Lysine for management of herpes labialis. Am J Health Syst Pharm. 2001 Feb 15;58(4):298-300