Posted on 12th Jul 2009 @ 4:59 AM

pg. 1 ADVANCES in orthomolecular research
Call it the supplement paradox.
A huge body of careful, prospective scientific research into
the relationship between peoples’ lifestyles and their longterm
health has confirmed, again and again, that eating a
diet rich in fruits and vegetables will lead you to a longer
life, and lower your risk of chronic disease.
The most obvious thing about such diets is that they’re rich in
essential vitamins and minerals. And yet time and time
again, controlled clinical trials of nutritional
supplementation with vitamin and minerals – including key
antioxidant nutrients like “vitamin E,” vitamin C, and
beta-carotene – has failed to protect people from killer
diseases.
Whether it’s “vitamin E” against heart disease,1 or betacarotene
against cancer,2-4 or antioxidant “cocktails” against
atherosclerosis5 or death from any cause,6,7 again and again
the results have come back negative. Either there’s no effect
at all … or the results are too ambiguous to pin your hopes
on … or there’s been a suggestion that the people taking
their assigned pills were worse off than people taking the
placebo stand-ins.
It’s a pretty sad record.
How can this be? Before the results of these trials came in,
many health-conscious people had their faith in their
multivitamins boosted by the simple fact that these trials had
even managed to get off the ground in the face of extreme
skepticism from much of the medical establishment. Now
those skeptics feel justified in their condescension – and the
forces that oppose health freedom have been given
ammunition in their anti-supplement attacks.
The reaction from most supplement companies has been
disappointing. Many companies are in the business for no
other reason than to make a quick buck, and have chosen to
simply ignore these trials, hoping that the unsettling results
will not reach the ears of their customers and cut off access
to a reliable cash cow. Other companies are sincere in their
belief in the value of supplementation – but they base this
belief on blind faith, playing hear no evil, see no evil when
large-scale, carefully-controlled, rigorous clinical studies fail
to confirm a pre-established credo. Such companies have
failed to respond to the latest discoveries in the rapidlyaccelerating
field of nutritional science, continuing instead to
design their products based on accepted health-food-store
dogmas.
Health-conscious people can’t afford to be blinded by
wishful thinking, or to rely on formulas based on outmoded
theories and fuzzy-headed, pseudoscientific notions. The
fact is that the conventional wisdom underlying ‘basic’
nutritional supplementation has been disproved. If we
are to gain the benefits that we expect from our
supplement programs, we have to be ready to listen to what
science is actually saying today instead of what it suggested
twenty years ago.We will have to clear the ground, looking
at the science with our old blinders removed, questioning our
assumptions, turning over the graves of the ‘authorities’ of
yesteryear, and laying the foundation for a genuinely new
approach to nutritional supplementation.
Latest Science in
Vitamin & Mineral
Principles In Formulating The
Optimal Multi
Nutritional supplementation with
“vitamin E,” vitamin C,
and beta-carotene –
has failed to protect
people from killer diseases
But where to begin? With what we already know. We know
that healthy diets support longer, healthier life. And we know
that supplements based on old-school thinking do not. Once
we accept these two facts, the way forward becomes clear:
compare the contents of a health-promoting diet to typical
multivitamin/multinutrient products, and see what’s so
fundamentally different between the two. And once you
start looking, the contrast is so sharp that it strikes you like
a barrel of ice water. Multivitamin supplements which should
have been designed to be, in effect, super-concentrated
versions of an optimal diet are revealed instead to be gross
caricatures of those diets, distorting and unbalancing the real
picture of preventive nutrition.
Let’s see where previous products have gone wrong … and
how we can get it right for the future.
First, Do No Harm
The most extreme disconnect between health-giving foods
and badly-designed pills, is cases where a multivitamin not
only doesn’t protect the health of its users, but actively harms
them. We are accustomed to thinking of nutritional
supplements as fundamentally safe; and certainly, no
multivitamin has ever caused the kind of killer toxicity we
see from some xenobiotic drugs (except in cases of
overdose resulting from sloppy manufacturing, or from
accidental or intentional swallowing of too many pills). But
there’s now strong evidence that nearly all multivitamin
products contain one or more nutrient overdoses or
imbalances extreme enough to cause real, long-term
damage to the health of those swallowing them.
One well-documented, crippling result of long-term, chronic
supplement overdose is the association between excessive
preformed vitamin A (retinol/retinyl esters) and the loss
of bone health. It’s long been known, from animal studies,
that getting too much vitamin A is bad for the skeletal
system. In recent years, these findings have been confirmed
in humans. Several large, well-designed population studies
(and a few smaller and less rigorous ones) have now
reported that men and women with the highest intake8,9
or serum levels10,11 of retinol are at the greatest risk of
suffering a fracture; taking in the most retinol also
associates with having the lowest bone mineral density
(BMD).8,12-14 (It’s important to understand that this refers to
preformed vitamin A: beta-carotene and other ‘provitamin
A’ carotenoids have not been associated with loss of
bone health).
Frighteningly, the amount of preformed vitamin A which
these studies have found to put consumers at risk of broken
bones is right in the ballpark found in many – and perhaps
most – multivitamins: “just” 1.5 milligrams (5000 IU) in one
study,8 and a similar 6 600 IU in another9 is enough to
roughly double your risk of a fracture. It’s extremely
unlikely that you’d get dosages like these from food – you’d
have to spend all day gorging on liver, eggs, and fortified
milk – but it’s all too easy to exceed the safety limit if you’re
taking the kind of multivitamin designed around an
unthinking ‘more is better’ paradigm. And indeed, nearly no
one in these studies would have reached the extreme levels
of intake associated with increased fracture risk if it were
not for the badly thought-out supplements they were letting
into their systems.
But this doesn’t mean that you should avoid all intake of
retinol, or depend entirely on carotenoids to get your
vitamin A. The rate of conversion of “provitamin A”
carotenoids into retinol varies nearly ninefold from person to
person,15 and can be altered by age, genes, body weight,
and alpha-tocopherol intake. Remember that retinol is an
absolutely essential nutrient – and in fact, one of its most
important functions in the body is in normal skeletal
metabolism! Indeed, some of the same studies that
reported the impairment of bone health caused by years of
retinol overdose have found that people with the lowest
vitamin A levels11 or intake12 also suffer an elevated
fracture risk11 and lower BMD.12 It appears that the ideal
retinol intake – from diet and supplements combined – is in
the ballpark of 2000 IU.
But remember that, because of government-mandated
fortification, a single serving of low-fat milk or yogurt
contains between about 500 and 750 IU of vitamin A,
and a standard 85g (3 oz) slice of liver contains an
astounding 22 000 IU!
Men and women with the
of are at the r
of suffering a
So it’s very easy to overshoot your safe vitamin A intake if
your supplement contains more than 1000 IU of retinol. The
goal of supplementation should be to put you into that
happy medium where bone health is optimized; supporting
the balance of the diet instead of overbalancing it with
levels you’d never get from well-chosen foods.
Another source of long-term health theft resulting from
sloppily-designed supplements is overbalanced zinc-tocopper
ratios. The body’s metabolism of these two minerals
is inextricably intertwined because of their similar atomic
structure: they resemble each other so closely that they can
compete with one another for absorption and transport, and
interfere with one another’s binding to enzymes, if one is
present in excess. Getting too much of either nutrient creates
a functional deficiency of the other. So keeping the two
minerals in proper balance is important if you’re going to
reap the health benefits of either – or even to avoid doing
yourself damage.
pg. 3 ADVANCES in orthomolecular research
fig 1. Retinol intake and bone mineral density in the elderly. Modified
from reference 54.
Both animal and human evidence suggests that, for optimal
utilization of both minerals, the balance between zinc and
copper should be about ten-to-one.16 But most supplement
formulators seem to have been dazzled by the exciting
research which documents the importance of getting
adequate zinc in your diet – so much so, that they’ve
ignored the crucial place of copper in the equation. As a
result, it’s common for multivitamins to include very high
doses of zinc, but little or no copper, so that many –
perhaps most – multivitamin and multimineral formulas
contain potentially harmful zinc-to-copper imbalances.
Such imbalances are more than just a theoretical concern. In
a series of human studies, using a ratio between zinc and
copper of 23.5-to-one (and sometimes lower) – common
zinc-to-copper ratios, found in many multivitamins –
resulted in wide-ranging metabolic disturbances,
including reduced levels of the copper-based antioxidants
enzymes cytosolic superoxide dismutase and
ceruloplasmin, high total and LDL (“bad”) cholesterol,
reductions in the body’s levels of enkephalins (natural painkilling
molecules), and abnormal cardiac function (including
rhythm disturbances and even heart attacks)!16-18
And these are just the metabolic derangements observed
over the course of a few weeks or months. Over years of
functional copper deficiency created by excessive zinc
intake, it seems inescapable that other problems known to
result from ‘simple’ copper deficiency – such as impaired
bone metabolism, poor glucose control, and increased
levels of Advanced Glycation Endproducts (AGE) – would
also manifest themselves.
The most bitterly ironic twist in the black comedy of zincmad
pill design has only recently appeared. Many men
take zinc supplements to support the health of their
prostates, because of some evidence suggests that low zinc
levels are associated with prostate cancer and other
prostate disorders.19 But a large new study,20 which tracked
the health habits of nearly 50 000 American male health
professionals for 14 years, found that extreme zinc oversupplementation
was associated with a more than
doubled risk of developing advanced prostate cancer,
especially if continued for more than 10 years.
All of this has lead to alarm amongst researchers who have
devoted their academic careers to documenting the
importance of copper in human health. Dr. Leslie M. Klevay,
for instance, has warned of the “hazards of zinc
supplements.”17 But the problem is not zinc supplements, but
the excessive zinc dosages, and/or unbalanced zinc-tocopper
ratios, found in far too many multivitamins. A
properly-designed core nutritional program will work to
ensure optimal intake of both nutrients – individually, and in
balance.
Yet another example of “megadose mania,” for which the
evidence is disturbing if not yet conclusive, is the probable
neurological damage caused by excessive manganese
supplementation. It’s well-established that workers in
industries where inhaling manganese is common (such as
manganese miners and welders) are at greater risk for
neurological syndromes resembling Parkinson’s disease,
and animal studies clearly show that excessive manganese
intake leads to neurological damage.21 Furthermore, in a
study that compared the level of manganese present in the
drinking water in different communities with the rates of
neurological symptoms amongst their residents,22 it was
found that neurological symptoms were more common
amongst the elderly in high-manganese areas. (Another
study, however, did not report an association23).
But the best evidence that manganese oversupplementation
really is an issue worthy of our concern is
a study which compared the manganese intake from diet
and supplements of people with Parkinson’s disease with
those of people without the disease.24 The study found that
people with high dietary intake of manganese are about
70% more likely to fall prey to this neurological disorder
– and that the risk was further increased among people who
also consumed manganese-containing supplements, or who
also had a very high intake of iron.
It’s not clear exactly how much manganese is too much, in
large part because of the different bioavailabilities and
distribution in the body of manganese coming from fumes,
water, food, and supplements. And it’s hard to detect the
early symptoms of manganese excess, because they are so
nonspecific: loss of appetite, impaired reproduction,
anemia, and retarded growth in children.
A review of the evidence by the National Academy of
Sciences’ Institute of Medicine found that the lowest level of
total manganese intake at which suggestions of harm could
be documented was at manganese intake from diet of 15
milligrams; they cautiously suggest that the safe upper limit
of manganese consumption from all sources is 11 mg.25When
you consider that unusually manganese-rich diets can
contain between 6.325 and 826 milligrams of the mineral, the
idea of adding an additional five, ten, or even more
milligrams of manganese in the form of a badly-thoughtout
multivitamin becomes an increasingly bad notion – yet
such dosages are common.
Again, this doesn’t mean that you should treat manganese
like a nutritional pariah, or a toxin like lead or cadmium.
Manganese is an essential nutrient, needed for healthy skin,
bone, and cartilage, for maintaining glucose tolerance, and
for the formation of the mitochondrial form of the
antioxidant enzyme superoxide dismutase (SOD). But the
bottom line is that there’s no good evidence that getting
more than a few milligrams of manganese makes you any
healthier, and there is some pretty suggestive research
indicating that a very high intake could ultimately do you
harm. It seems clear that supplements should contain enough
manganese to ensure that you aren’t deficient, but not much
more: a couple of milligrams is safe, and will meet your
nutritional needs.
Nutritional Bait-And-Switch
But the problems with multivitamins extend into subtler
territories than frank overdose. Another is using the wrong
molecule. When studies show that people whose diets are
chock-full of some key nutrient are protected against a
ravaging disease, you’d think that it’d be a no-brainer to
create supplements which contain that same nutrient. Far too
often, however, supplement companies have cheated
health-conscious consumers by substituting counterfeit
versions of these molecules for the real thing – versions
with fundamentally different effects on the body.
One example that we’ve previously documented in detail is
lipoic acid: unless they say otherwise, supplement
companies replace R(+)-lipoic acid – the form of this
nutrient produced by the body for its own use – with an
adulterated, 50-50 “racemic mixture” of R(+)-lipoic acid
and the purely artificial S(-)-form of the molecule. Studies
show that the artificial S(-)-lipoic acid is not just less potent
than the natural R(+)-form, but in some cases actually
interferes with, or has the opposite effect of, R(+)-lipoic
acid. (For a review of some of the research on R(+)-lipoic
acid, see “Your Two-Faced Lipoic Acid” in Advances 2(1), or
visit http://www.R-Lipoic.com).
This same problem is common to many keystone nutritional
supplements. One excellent example is beta-carotene. The
studies designed to test the ability of beta-carotene to
prevent cancer and heart disease were based on the very
strong evidence that people whose diets contain more betacarotene
had a lower risk of lung (and other) cancers.27 But
when companies began making beta-carotene supplements,
the form of ‘beta-carotene’ that they produced – and that
was used in nearly all of the trials – was not the same
‘beta-carotene’ that occurs in food.
Beta-carotene from food contains two structural forms
(isomers) of the molecule: all-trans and 9,cis-beta-carotene
(see Figure 1). But the beta-carotene used in nearly all
supplements has been entirely composed of the all-transform
of the molecule.
The difference is important to all of us, not just organic
chemists. Studies have clearly shown that the effects of
natural and synthetic beta-carotene are fundamentally
different. Synthetic beta-carotene has much lower
antioxidant activity;28-30 more alarmingly, studies performed
in human white blood cells have revealed that the synthetic
beta-carotene used in most supplements causes genetic
damage to the cells!31 Natural beta-carotene, by contrast,
does not have this effect.31 So perhaps it’s no surprise that
the studies designed to test the ability of beta-carotene
supplements have actually found that the pills not only fail
to protect users against cancer,2-4 but may actually increase
the cancer risk:2,4 all of these studies used the synthetic, alltrans
form of the molecule.
Another example of molecular mismatch is “vitamin E.”
Numerous studies in the health habits of large populations
have found that the “vitamin E” in food provides protection
against cardiovascular disease (CVD)32-34 and Alzheimer’s
disease.35-37 Yet these same studies have reported that users
of “vitamin E” supplements have not been given protection.32-
37 In fact, a “meta-analysis” study which pooled the results
of 19 high-quality controlled trials found that high-dose
alpha-tocopherol supplements actually increase
mortality in patients with existing cardiovascular disease!1
Scientists now have a very good explanation for this: again,
the “vitamin E” in food is very different from the “vitamin E”
contained in nearly all supplements.
We’re not just talking about the difference between socalled
“natural” “vitamin E” (d-alpha-tocopherol, or more
properly RRR-alpha-tocopherol) and “synthetic” “vitamin E,”
(dl- or all-rac-alpha-tocopherol). The only real difference
between d- and dl-alpha tocopherol is in its strength: it
takes more dl-alpha-tocopherol to get the same effect you
get from d-alpha.38
No, the real distinction between the “vitamin E” you get from
a healthy diet, and the “vitamin E” you’ll find in most pills, is
not one of degree, but of kind. While the “vitamin E” in food
does contain d-alpha-tocopherol, this molecule actually
makes up only a minor fraction of the vitamin E in healthy
diets. “Vitamin E” is not this one molecule, but a complex,
composed of eight distinct molecules – four tocopherols, and
four tocotrienols. And in fact, the single largest amount of
“vitamin E” in healthy diets appears as gamma-tocopherol,
not its alpha cousin.39-43
Again, this isn’t just trivia for biochemistry geeks. The
different members (or “vitamers”) of the E complex have
different functions in the body, just as different B vitamins
do. Recently, the unique properties of gamma-tocopherol,
have become a particular focus of researchers’ attention,44,45
but the unique benefits of the “other” E vitamins are clearly
also important. Some of these unique health properties
were discussed in “There’s No Such Thing as Vitamin E,” in
The Holistic Lifestyle 1(4), and we hope to go into more
detail in a future issue of Advances.
To jump to the punch line, however: these newly-discovered
properties of gamma-tocopherol, tocotrienols, and other
natural E vitamins explain why the “vitamin E” in food
protects against chronic disease where supplements keep
failing.32-37 And indeed, by looking at levels of E vitamers in
the body, the importance of the distinction becomes clear:
high levels of gamma- – and not alpha- – tocopherol is
associated with reduced risk of CVD46-49 and heart attack,50
and that the same is true of prostate cancer.51,52 Likewise,
evidence exists for a selective gamma-tocopherol depletion
in the brains of people with Alzheimer’s
disease.53,54
And the real problem with unbalanced alpha-tocopherol
supplements is not just that they’re missing these other E
vitamers, and therefore fail to provide their unique
benefits. Astoundingly, alpha-tocopherol, at doses typical
of most supplements, actually interferes with the body’s
ability to hold onto and use of the other E complex
members!
Because of its specific importance to reproduction, and
because a natural diet contains comparatively little of this
specific E vitamin, evolution equipped the body to hang onto
its supplies of alpha-tocopherol – even at the expense of
other E vitamins. As a result, when you flood yourself with
unbalanced alpha-tocopherol supplements, you actually
deplete your body of other E-complex members (see
Figure 3).55-59
It doesn’t take a lot of unbalanced alpha-tocopherol to
drive down your gamma-tocopherol supply: five months of
swallowing just 150 IU of isolated alpha-tocopherol per
day robs your body of 63% of its plasma gammatocopherol
levels, leaving you with lower levels than you
would have had if you were taking no supplement at all.55
And the effect can be long-lasting: after one year of highdose
(1200 IU) alpha-tocopherol supplementation, tissue
gamma-tocopherol levels take two years of “cold turkey” to
recover to the level they were at before supplementation
began.58
And don’t think that the “natural mixed tocopherols” added
in as an afterthought to some “vitamin E” supplements will
make up for this imbalance. These products throw in no more
than 20% as much of the tocopherols other than alphatocopherol,
almost as an afterthought – and they contain no
tocotrienols. But it’s been shown that it takes a lot more of
the “other” E vitamins to make up for the alpha-tocopherol
overdoses found in these pills. For example, if you take 371
milligrams of alpha-tocopherol into your body every day,
you’ll still suffer a 30% loss of gamma-tocopherol in plasma
even if you try to balance it out with more than 400
milligrams of gamma-tocopherol and other E complex
members.59
In fact, careful examination of studies involving the
cholesterol-balancing effects of tocotrienols reveals that the
body needs at least twice as much of the “other” E
vitamins to prevent alpha-tocopherol from canceling out
their benefits.60-62 It should come as no surprise that this ratio
is similar to what’s found in a balanced diet of whole
foods.39-43
Yet another example of the kind of nutritional bait-andswitch
at work in common multivitamin formulations is the
ongoing use of inferior forms of selenium. Extensive
research demonstrates that Se-Methylselenocysteine
(SeMC) is the most effective cancer-fighting form of
selenium available.63-65 (We reviewed the revolution in
selenium cancer research of the last decade in the Spring
2003 issue of Advances). Not surprisingly, foods with known
cancer-fighting powers – such as high-selenium broccoli,
garlic, and onions – contain much of their selenium in this
form, whereas selenomethionine and other common selenium
forms predominate in foods like beef and wheat – foods
which are not particularly noted as being protective against
cancer. Yet most companies continue to put
selenomethionine, selenate, selenite, or selenium yeast into
their pills.
extreme zinc
over-supplementation was
associated with a more than
doubled risk of developing advanced
prostate cancer
ADVANCES in orthomolecular research pg. 6
Figure 2: All-trans and 9,cis-beta-carotene.
Take, again, the difference between menatetrenone (MK-
4, the form of vitamin K2 biosynthesized by mammals) and
phylloquinone (vitamin K1 – the form used in nearly all
supplements). We know that menatetrenone delivers
superior skeletal,66 brain,67 and cardiovascular68,69 health
benefits. Yet supplements continue to use vitamin K1 – or
sometimes bacterial menaquinones (such as
menaquinone-7 (MK-7) – the main bacterial form of K2),
which are not the same molecule (see figure 4).
There’s also the greater bioavailability and stronger
clinical evidence for calcium citrate-malate compared with
other vegetarian calcium sources (regular calcium citrate is
not equivalent!70). And we could go into other examples. But
the point, by now, should be obvious. When evidence
suggests that high intakes of a nutrient found in healthy
foods supports vibrant health, make sure that your
supplement contains the same molecule, and not an
impostor or second-best.
Emerging Essentials
Official government nutrition panels recognize only 13
essential vitamins and 15 essential minerals. But in recent
years, it’s become increasingly clear that a few other
substances are just as indispensable for your health. It was
only recently that chromium was recognized by the Institute
of Medicine to be necessary for your health. But the
evidence is compelling that boron, silicon, lithium, and
vanadium are as necessary to your health as the
“official” essential minerals, such as calcium, magnesium,
or zinc, and that a little-known redox factor called
pyrroloquinoline quinone (PQQ) is being considered as a
vitamin just as essential to your health as vitamin C or
pantothenic acid (vitamin B5).
Boron appears to be an essential to normal brain function,71
a key factor in preserving the health of the skeleton and
joints,72 and has been linked to reduced risk of prostate
cancer;73 recent studies in the homeostatic control of boron
concentration in the body74 and in breast milk75 show that the
body is actively regulating levels, demonstrating its
essentiality in the body, and a failure of this control is
observed in mothers who subsequently undergo premature
labor.75
Silicon has been shown to be essential to normal bone
formation in animal studies,76,77 and epidemiological
studies,78 and preliminary clinical trials79 suggest that it builds
stronger bones in humans, too, apparently through a
cofactor role in collagen synthesis. And vanadium appears
to have a key role in thyroid function, as well as having a
“pharmacological” effect on glucose metabolism at
extremely high doses.80
Perhaps the most remarkable rise of a newly-identified
mineral in recent years has been lithium.81 Although most
people think of this mineral as a “drug” to used treat
bipolar disorder, lithium is a trace mineral found in “hard”
water and food: typical diets contain between 0.650 and
3.1 milligrams of lithium per day, coming mostly from
grains and vegetables.
Animal studies have shown that lithium is an essential
mineral in mammals. Lithium-deficient laboratory rodents
have impaired reproductive function and abnormal lipid
metabolism. When USDA scientists sat down to reformulate
the standard rodent chow used in laboratory experiments in
1997, one of the key changes to the diet was to fortify its
lithium content beyond the amount that occurs naturally in
the elements of the diet.81
Similarly, studies in goats show that lithium-deficient animals
suffer depressed immune systems, chronic inflammation,
splenic atrophy, excessive iron buildup in their tissues, and
calcium deposits in their blood vessels; moreover, the
activity of the enzymes involved in their mitochondrial
energy production is depressed, and they develop “benign”
tumors of the breast, salivary glands, and adrenal glands,
as well as ovarian cysts.81
But the most fascinating research on lithium’s role in health
has come from studies comparing the health of people
living in areas with higher and lower amounts of lithium in
the rain or tap water, and individuals with higher and lower
levels of the mineral in their hair, scalp, and urine. These
studies have found that people living in areas with low
lithium have higher rates of neurosis, schizophrenia,
psychosis, psychiatric ward admissions, homicide,
suicide, forcible sexual assault, burglary, and
runaways.81
Supplement companies have
substituted counterfeit
versions with fundamentally different
effects on the body.
Based on the amount of lithium found in typical diets, and
the amounts known to support brain health when consumed
in the diet and drinking water, nutrition researchers are
now suggesting an ‘RDA’ of lithium in the range of 0.400
to 1 milligram per day.81 Lithium supplements are now
becoming more readily available in the United States;
unfortunately, the Canadian authorities continue to insist that
even nutritional doses of organic lithium is a “drug,” and
threaten fines and imprisonment to anyone making it
available except by prescription.
Plant Protectors
The most consistent finding in all of the science of
epidemiology is that diets rich in fruits and vegetables are
associated with reduced risk of cancer, heart disease, and
age-related disability. Fruits and veggies are the best
source of many vitamins and minerals, of course, but there’s
a lot more in a healthy diet than just these essential
nutrients. For more than half a century, scientists have known
that when experimental animals are fed highly-refined
diets which contain all the protein, essential fats, vitamins,
and minerals known to be essential to their normal growth
and development, they are still more vulnerable to cancer
than animals containing similar levels of all essential
nutrients, but composed primarily of unrefined or semirefined
food sources.82-87 The explanation for this
phenomenon lies mostly in phytochemicals.
Strictly speaking, any biologically-active substance
produced in plants can be called a “phytochemical.” But the
term is most often used to refer to those protective, diseasepreventing
bioactive compounds which – while not
“essential” in the same sense as vitamin C or magnesium –
none the less play a major role in the benefits of a good
diet. In recent years, researchers have made rapid strides
in teasing out the biological effects of these biomolecules –
and every now and then, a phytochemical has been
identified as being crucial to the health-promoting effects of
individual foods, or groups of food, which have been
singled out as especially potent medicines in Nature’s
pharmacy. Each of these discoveries reveals a critical
element of good nutrition that has been missing from
narrowly-defined “multivitamin” formulas.
Figure 3: Unbalanced alpha-tocopherol supplements deplete your body of
gamma-tocopherol. Redrawn from (55).
But there are literally thousands of biologically active
substances in plants: over 5 000 have been identified, many
of them only recently.88 But while some of them are
important contributors to the health of people consuming
them, others are needed by the plant, but are of no value
to us when we eat them – and some of these compounds
(even if found in healthy foods) are known to be toxic.
The research on phytochemicals demands a new approach
to nutritional supplementation. Those bioactive plant
molecules which will help you reach a longer, healthier life
need to be identified and placed on the “A” list for the core
nutritional supplement of tomorrow. But other such
compounds are helpful to only a few people with unique
health concerns, and therefore should not be in a
multinutrient formulation designed to be taken by every
health-conscious person. Still others are of no nutritional
value, and ultimately only of interest to agronomists. And a
few are even harmful. So how do you know which is which?
After decades of research, such an “A” list of
phytochemicals has emerged. The process was long and
painstaking, but its conclusions are proportionally solid. It
began by narrowing down the broad category of “fruits
and vegetables,” and carefully looking at which plant foods
have the most consistent associations with good health. The
conclusion: while there are no doubt health benefits from all
fruits and vegetables, and while any given plant food or
phytochemical may catch a headline here and there, the
most powerful, consistent evidence points to cruciferous
vegetables (such as broccoli, cabbage, and mustard
greens); Allium vegetables (such as garlic and onions);
green, leafy vegetables; citrus fruits, tomatoes, carrots,
and raw vegetables generally, as being especially
powerful in promoting good health.89-96
High-dose alpha-tocopherol
supplements actually mortality
When you flood yourself with
unbalanced alpha-tocopherol
supplements, you actually deplete your
body of other E-complex members
0.15
0.14
0.13
0.12
0.11
0.10
0.09
0.08
0.07
0.06
0.05
0.04
0.03
0.02
Plasma γ- Tocopherol (mg/dl)
-4 0 1 3 7 14 21
28 29 30 31 32
36
Days
SUPPLEMENTATION PERIOD
D-α-tocopherol
pg. 7 ADVANCES in orthomolecular research
Researchers next turned their attention to the question of
why these particular plant foods should be more effective in
keeping you healthy than others. In the case of carrots, the
most likely player is its range of mixed carotenoids,
including lutein and alpha-carotene. But they found that the
other fruits and vegetables contain specific phytochemicals
which are either unique to these foods, or are found in much
higher amounts in these plant foods than in others. And by
exploring these phytochemicals’ effects on the body in
experimental animals and cellular studies, science has
vetted a phytochemical dream team.
The key plant bioactives are the isothiocyanates (most
importantly sulforaphane) and indoles (especially indole-
3-carbinol (I3C)), which appear as glucosinolates in
cruciferous vegetables; the Allium vegetables’ allyl
sulfides (the most potent of which is diallyl disulfide
(DADS)); the limonene and related monoterpenes found in
citrus (and especially citrus peel); the lycopene that comes
overwhelmingly from tomatoes and tomato products; transresveratrol,
found in red wine; green tea’s key polyphenol
EgCG; and chlorophyll, which gives the hue to green, leafy
vegetables. (The importance of raw vegetables probably
comes from the fact that the enzymes which liberate
sulforaphane and I3C from their storage forms are
inactivated by longer, higher-temperature cooking, leading
to reduced bioavailability of these cancer-fighting
nutrients97,98). While it’s currently not possible to put all of
these phytochemicals into a single multivitamin formulation
because of various interactions that make some of the
specific combinations technically impossible or undesirable,
it’s clear that a supplement program designed to closely
mimic an optimal diet must include as many of these phytopowerhouses
as possible.
A review of the scientific literature shows how consistently
the consensus has crystallized around the central
importance of these phytochemical elite.90-96 One can
certainly point to still other substances found in plants which
might have health benefits, but none of them have this
powerful weight of epidemiological, experimental,
mechanistic, and in some cases clinical99-101 evidence to back
them.
So, for instance, test-tube studies on the effects of ellagic
acid on DNA adduct formation are intriguing, but no studies
in the health habits of large human populations show that
people consuming lots of ellagic-acid-rich strawberries or
raspberries are less likely to develop cancer than people
eating other fruits and vegetables. The available results are
intriguing – but not strong enough to justify designating it a
critical phytonutrient which should be a part of every
health-conscious person’s supplement program. (In fact, the
same objection applies to many other polyphenols. For one
of the key reasons underlying many such disconnects, see
For Biochemistry Geeks Only!).
There are also many phytochemicals which have benefits to
people with serious health problems – but that aren’t
necessarily helpful to basically-healthy people looking to
further enhance and protect their health. In many cases,
these phytochemicals come from herbs and other botanicals
which are not a part of the regular, habitual diets of
anyone in the world: they should – and traditionally have
been – regarded as medicines for people with specific health
needs, not healthy foods that contribute to the well-being of
health-conscious people.
Figure 4 : Structural representation of Vit K1 and Vitamin K2.
Silymarin from milk thistle, for instance, is of great benefit
to people with some kinds of liver disease, mostly because
it fights the oxidative stress, membrane damage, and
inflammation of the liver that’s associated with cirrhosis
(scarring) of the organ,124,125 and also perhaps by increasing
the amount of protein-biosynthesis “instructions” coming out
of the tissue’s DNA code.125 All of this gives the cirrhotic liver
the opportunity to heal itself – but there’s no evidence that
healthy people, with undamaged livers, will get “superhealthy”
livers by taking this herb.
Since, in fact, we know virtually nothing about the effects of
these kinds of herbs on otherwise-healthy people; it’s hard
to see the idea of taking these powerful extracts regularly
as anything but an unnecessary gamble with your health.
They do not belong in a core multinutrient formulation,
designed to be taken by everybody, every day, for the rest
of your life.
Your Body’s “Detergent”
While these phytochemicals exert a wide range of
important effects on cellular metabolism, most of them share
the common feature that they modulate the balance of the
ADVANCES in orthomolecular research pg. 8
K1
K2
body’s detoxification enzymes. Your body neutralizes toxic
chemicals and many internal waste products using a twostep
biochemical breakdown process. In phase I
detoxification, ‘procarcinogen’ compounds are first made
more chemically reactive using a group of enzymes known
as the cytochrome P450s or mixed-function oxidases.
Think of phase I detoxification enzymes as “agents
provocateurs,” who infiltrate an enemy group to incite the
more dangerous elements in an organization to show their
cards. It’s then the job of the phase II detoxification system
to play the role of more conventional law enforcement,
“arresting” those fired-up (more reactive) “cellular
terrorists” and “handcuffing” them with molecules
(conjugates) that make them easier to safely excrete
through the urine or the bile.
The danger spot is in the step between, in which the
“activated” procarcinogens are potentially even more
dangerous, until they are “handcuffed” by the phase II
system. This is where many phytochemicals lend a hand.
Broadly, many of the best-documented phytochemicals
increase the activity of the phase II system, while reducing
down the activity of phase I. This slows the overproduction
of activated procarcinogens, and ensures that there is
enough phase II activity to ensure that activated
procarcinogens are all bound up and sent packing.126
But of course, for phase II detoxification to take place, your
phase II enzymes need an adequate supply of the
“handcuffs” (conjugates) that render the procarcinogens
tame. So it’s important to ensure that your diet and
supplement program contains plenty of key conjugation
factors such as acetic acid, glycine, taurine,
trimethylglycine, and sulfur sources such as NAcetylcysteine
(NAC).
Random Dosages
Almost every week, a new study comes out linking a diet rich
in some key nutrient with a longer, healthier life. And when
the popular press reports the story, they put it something like
this: “the people whose diets contained the most of this
nutrient were only two-thirds as likely to get breast cancer”
– or heart attack, or Alzheimer’s disease, or any of the
myriad assaults of “normal” aging. The problem with these
stories is that they rarely tell you how much of the nutrient in
question the people eating those diets were consuming. Too
often, in fact, the medical abstracts of the original scientific
papers don’t give you this information either. If you want to
find out, you have to take a jaunt down to a medical library
and dig up the full-text article.
But few people have the time to take this trouble, especially
granted the wide range of individual ingredients in their
core nutrient formulas, plus their “add-on” supplements. So,
most of us depend on the formulators of these products, not
just to include the right ingredients in their products, but to
include a research-backed dose.
Too often, this just doesn’t happen. In fact, comparing major
research papers to the ingredients lists on typical
supplement bottles, you’ll be forced to wonder if the
designers of such products used a dice roll to determine
their dosages.
Let’s take a couple of examples. There is powerful support
for the ability of the carotenoid lycopene to reduce the risk
of cancer – prostate cancer in particular,92,99,100 but also
cancers at many other sites in the body.92 But how much
lycopene is associated with cancer protection? Studies in
large populations show that high-lycopene diets, rich in
tomato paste and other good sources of the carotenoid,
provide from 13127 or 14,128 through 18,129,130 to as high as
24131 milligrams of lycopene a day. (Earlier studies, which
reported lower intakes (such as 6.5132 or 9133 mg/day) were
using an outdated carotenoid database which neglected
many lycopene-containing foods and which relied on an
obsolete analysis method that low-balled the foods’
carotenoid content134,135).
So a supplement designed to support the protective effects
of high-lycopene diets should also contain these same
established, protective amounts. Instead, nearly no
multinutrient products contain more than 3 milligrams of this
crucial carotenoid – and some contain as little as a tenth of
this paltry amount! To put this into its full, damning
perspective: because tomatoes and tomato products are
consumed even by people eating very poor diets (in the
form of ketchup on their MacGreaseburgers and a little
tomato sauce on the occasional slice of ’za), even the bottom
20% of diets provide lycopene in doses such as 2.3131 to
3.4129 or even as much as 4.4130 or 4.5128 milligrams of
lycopene on an average day!
Where do these senselessly low doses come from? Some
formulators just formulate their products in ignorance,
without bothering to dig into the original research; others
know full well that the measly dose they’re including won’t
do anyone any good, but cynically throw a token quantity
of lycopene into their products for no other reason than to
catch your eye as you scan their labels. Neither is providing
you with anything like the amount of lycopene that the
research says is needed to shield your body from the
ravages of cancer.
pg. 9 ADVANCES in orthomolecular research
Flavonoids of which there are several
thousands are abundant polyphenols in the human diet
and are divided into six main classes:
( ) (e.g. Catechins), (e.g.
Quercetin), (e.g. Luteolin),
(Naringin), (e.g. Genistein) and
(e.g. cyanidin)
Now let’s look at the other – and more disturbing – extreme.
While enthusiasm for beta-carotene has dampened thanks
to the spectacular failures of several large trials, at one
time most ‘premium’ multivitamins contained 25 to 50
milligrams (41 625 to 83 250 IU) of synthetic beta-carotene
in a daily dose; indeed, many antioxidant combination
products still contain such overdoses. (If you’re doublechecking
a supplement label for its carotenoid content,
you’ll want to look for the absolute milligram potency,
because many supplements list IU potencies using old,
outdated conversion factors;25 indeed, the proper way to
make this conversion remains controversial today.136
Milligram potencies are the clearest and best way to get
this information on a label).
We’ve already seen that the use of synthetic beta-carotene
was a disaster in the waiting; however, the use of these
massive amounts of the stuff can only have made things
worse. Because the strong evidence from epidemiological
and experimental studies that beta-carotene protects you
from cancer27 never supported such huge doses – and since
then, animal research has shown that the overkill quantities
of beta-carotene used in too many supplements actually
increase cancer risk when you’re exposed to cigarette
smoke.
Incredible – some would say unconscionable – but true.
When we turn again to research using the latest carotenoid
database to document the amount of beta-carotene being
consumed by people whose diets are rich in this carotenoid
– diets strongly and consistently associated with lower
cancer risk27 – we see that even the richest diets contain from
as little as 6.8,128 through 8.95129 or 9.8,131 and not more than
11.4127 milligrams of beta-carotene per day. In other words,
the amounts of beta-carotene which, in the diet, is
associated with reduced risk of cancer is only about a third
to one half of the amount used in far too many supplements
– and also in the unsuccessful clinical trials of beta-carotene
to prevent cancer.2-4
And recent studies suggest that this beta-carotene
overdosing isn’t just a matter of wasted money. At these
extreme doses, scientists have observed that the body’s
carcinogen-detoxifying systems become unbalanced137,138
and genes related to the cancer process become
activated.139 One study in ferrets (whose metabolism of
beta-carotene is much more like that of humans than is other
rodents’) compared animals exposed to cigarette smoke
alone to animals exposed to the smoke plus beta-carotene
supplements at one of two doses: one designed to reflect
the levels of beta-carotene present in a diet emphasizing
this nutrient, and the other reflecting the kinds of mega
doses typical of many antioxidant and multivitamin
products.
The results: the “rich-diet” beta-carotene supplement dose
resulted in lower levels of squamous metaplasia
(precancerous lesions) of the lung – but giving the same
animals the equivalent of a 30 milligram (49 950 IU)
synthetic beta-carotene supplement led to the activation of
several pro-cancer genes, and to the animals suffering more
precancerous lung lesions than did those exposed to
cigarette smoke alone!139
Along with the use of synthetic (all-trans-) rather than natural
(9-cis-containing) forms of the molecule, these findings
provide one of the likely reasons for the suggestion of
higher cancer risk in smokers given the equivalent,
unjustifiable doses of beta-carotene in the disastrously
failed clinical trials.2-4,134 And the proof in the pudding has
come from the massive SU.VI.MAX trial. This randomized,
double-blind, placebo-controlled study tested effects of an
antioxidant supplement containing doses that reflect the
amounts found in good diets – including 6 mg of beta
carotene and 120 mg of vitamin C, along with vitamin E,
selenium, and zinc – in 13 017 healthy, middle-aged French
men and women. After following the two groups for 7.5
years, it was found that supplements of beta-carotene and
other antioxidants, at doses typical of good diets,
reduced cancer incidence by 31%, and death from all
causes by 37%– although there was no reduction observed
in the women, apparently linked to fact that the women had
higher levels of antioxidant nutrients to begin with.140
Without hammering the point to death, let’s look at one
more example. It’s important to take all of the B vitamins,
not only because they’re essential nutrients but because they
work as a complex, with their metabolism dependent on one
another and an excess of one sometimes creates a
deficiency of another.141,142 But has it ever occurred to you
how weird it is that so many multivitamins and B-complex
vitamins contain exactly as much thiamin as niacin as
riboflavin, and so on – the same 50 mg or 100 mg for each
and every B vitamin except folic acid, all the way down the
list? Does it physiologically make sense that the body would
optimally use exactly the same amount of half a dozen
different B vitamins, each with its own unique, irreplaceable
functions in the body?
Well, of course, it doesn’t. The numbers used are arbitrary,
with no physiological justification. Someone, years ago,
Science has vetted a phytochemical
dream team: sulforaphane, indole-3-
carbinol (I3C), limonene, lycopene, transresveratrol,
EgCG, and chlorophyll
ADVANCES in orthomolecular research pg. 10
Comparing major research papers
to the ingredients lists on typical
supplement bottles, you ll wonder if the designers used a
dice roll to
determine their dosages.
Those Fickle Flavonoids
With so many phytochemicals showing favorable-looking results in test tube and animal studies, it’s a bit surprising to see how few
have been linked to better health in large population studies or clinical trials. In many cases, it’s likely that this has to do with the
way the body – and in particular, the human body – metabolizes these substances.
Polyphenols (including flavonoids and phenolic acids), in particular, undergo a whole series of complex biotransformations
which make it difficult to predict their effects in the body based on their effects in the test tube. Both the probiotic bacteria in
your intestinal tract, and your body’s own detoxification systems, really “go to town” on polyphenols, so that the original molecule
will go through several cycles of having old conjugates
cleaved and new ones added before it is finally excreted,
creating diverse and largely unpredictable array of
metabolites along the way (see Figure 5).102-104
With most nutrients, you can expect that the effects in
humans will be similar to the effects in experimental
animals. But in the case of flavonoids, this often doesn’t
pan out. Humans metabolize many flavonoids differently –
and often much more heavily – than rodents do,102 so that
extrapolation from rodent studies becomes an extremely
uncertain, speculative exercise.
Some of the metabolites of a given flavonoid will not be
absorbed at all; others will be absorbed, but their
biological activity will be much different from that seen in
test-tube studies using the original, un-metabolized
compound. It’s these metabolites – and not the parent
molecule – that will determine the real effect of flavonoids
in the body: good, bad, or indifferent.102
Let’s take a few examples. The absorption and metabolism
of epigallocatechin gallate (EgCG) in green tea is
well-characterized,105-112 the effects of its metabolites have been explored,113 and there is extensive epidemiological evidence
showing that people consuming high amounts (most consistently, ten servings of Japanese sencha green tea live longer,114 develop
less cancer,114-118 and possibly suffer fewer heart attacks.118, 119 Therefore, we can be confident that there really is value in bringing
EgCG into your diet and supplement program. By contrast, we’re only just beginning to get a handle on what the body does with
apigenin,120 luteolin,121 or the flavonoids in strawberries,122 and there is only very weak evidence to
suggest a specific health benefit in people whose diets contain high amounts of foods rich in these particular polyphenols, as
opposed to other plant foods.
This may also explain why research on the effects of flavonoids as a class in humans has been so conflicting. As one recent review
of the field put it, “Some studies support a protective effect of flavonoid consumption in
cardiovascular disease and cancer, other studies demonstrate no effect, and a few studies suggest potential harm.”123 The
bottom line: with such varying bioavailabilities and biological activities, you can’t really generalize from one polyphenol to
another – and you can’t rely on work in the test tube, or even experimental animals. Human clinical and epidemiological data for
specific foods and food flavonoids must be our touchstone.
Figure 5: Factors Affecting Flavonoid Absorption. Redrawn from (102).
ADVANCES in orthomolecular research pg. 12
plucked these numbers out of thin air – and somehow, they
stuck. The irrationality of these numbers can clearly be seen
in the case of thiamin.
The conventional form of thiamin cannot pass directly across
cell membranes: it requires a special shuttle system to pump
it across the intestinal wall and (later) into the cell. There are
enough “seats” on the shuttles to ensure that you’ll absorb
the small doses typically found in food … but most of a 50
milligram dose gets left waiting at the harbor as the ship
pulls away. And while a small amount of additional
absorption occurs via diffusion into the fluid that bathes the
cells, this adds little to total bioavailability: no
matter how much thiamin you take, you
don’t materially increase plasma levels
beyond what you get from the first
12 milligrams of the dose.143-147
Even greater problems occur in
getting thiamin into the cells to do
its job. While some thiamin crosses the
intestinal wall through diffusion into the
fluid surrounding the cells of the intestinal
tract, the cells themselves (except for red blood cells) cannot
absorb conventional thiamin except through the active
transport system.147,148
The strictness of the limits of this system can be seen when
you bypass the limited intestinal absorption of thiamin by
injecting it directly into the blood. When 5 milligrams are
injected, most of the dose is taken up by the cells, and the
kidneys will excrete only 25% of the original dose. But
increasing the dose does not increase the cellular
absorption. The more thiamin you inject, the more ends up
simply passing out through the urine, and at 100 milligrams
or more, 100% of the additional thiamin is excreted in the
urine.149
There’s certainly no harm to taking this extra thiamin – but
no point to it, either. This is one case where the old skeptic’s
taunt is true: you really are flushing most of that extra
thiamin down the toilet! And the same is true of a lot of
the other B vitamins you’re taking. Doses should be based
on science – not nice, round numbers.
When the Mix Won’t Match
There are plenty of health-promoting substances out there
that you may want to seriously consider taking in
supplemental form, but that you wouldn’t want to have
included in your multivitamin for one reason or another.
Many people, for instance, take supplemental IP6 (inositol
hexaphosphate or “phytate”), a nutrient found in many
plant foods which plenty of evidence suggests is a powerful
nutrient protector against the horrors of cancer.150 And it
would certainly be convenient to get this important
supplement along with your other core nutrients in one
formula. We’ve even seen IP6 included in some multivitamin
and immune-boosting formulas. The problem with doing this
lies in a key chemical property of IP6: its ability to react
with many minerals – including calcium and zinc – to form
tightly-bound, insoluble, un-absorbable complexes. The
result: when you mix IP6 with calcium in your gut, you
lose much of the benefit of both the IP6 and these
minerals!
This problem is even seen in some IP6-
rich grain foods. On the one hand,
bone disorders – including
osteomalacia, rickets, and
osteoporosis – are commonplace
in populations where unleavened
breads and similar foods provide
the bulk of the energy in the
diet;151-153 and on the other hand,
studies show that animals
receiving a diet high in wheat bran
experience two thirds less cancer protection than
animals given the same amount of IP6 in their drinking
water,154 where it doesn’t come in contact with the nutrients in
their food.
The key green tea polyphenol EgCG (epigallocatechin
gallate) is a similar case. Green tea polyphenols inhibit
the absorption of many minerals. The most famous case is
iron: green tea extracts clearly reduce its bioavailability,155
and it’s clear that people who drink a lot of tea and who
have marginal iron status are at higher risk of anemia.156-159
Tea polyphenols may also inhibit absorption of calcium160,161
and zinc,161,162 although the effects appear to be minor and
perhaps transient.
Of course, you may not want to absorb all of the iron in your
diet, particularly if you’re a man or a postmenopausal
woman or eat a high-meat diet. Excess iron levels are
associated with oxidative DNA damage163 and may increase
risk of several age-related diseases, including neurological
disease,24,164 diabetes,165-167 and possibly heart disease.168 But
while most people don’t need an iron supplement, people
who are conscious about their diet – particularly if they
don’t eat much red meat – have little to gain from actively
inhibiting their iron absorption. Overall, it just makes sense
to take your green tea supplements away from meals –
and thus separately from your main nutritional supplement.
The overkill quantities
of beta-carotene
used in too many
supplements actually increase
cancer risk
pg. 13 ADVANCES in orthomolecular research
Get Back to “Basics”
Oftentimes, people become so excited about the potential
of exotic botanicals or emerging orthomolecular compounds
to impact their health, that they pay less attention to the
basic, essential nutrients. Maybe it’s a case of “familiarity
breeding contempt:” we’re so familiar with zinc, copper, or
vitamin C that we neglect to pay them any attention. But you
can’t expect to enjoy optimized health from advanced
supplementation if your body is lacking the basic nutrient
cofactors required for its essential biochemical processes.
And on the flip side, as we’ve seen, it’s all too easy to
mistakenly imbalance yourself on these same nutrients or to
fail to reap their full benefits, if you aren’t paying enough
attention to just what and how much you’re taking.
Instead of just taking your supplements based on “one size
fits all” nutritional formula, it’s worthwhile to take careful
stock of where you’re at, nutritionally, from your diet alone.
If your diet is particularly healthy, you may not need a full
daily dose of a multivitamin formula; and if you have a diet
that is especially strong on a specific nutrient, you may not
need to add on extra nutrition on top of your multi as others
might. Do you drink a lot of milk? Then you probably don’t
need a full 1000 milligrams of calcium from supplements
alone. Are you absolutely addicted to oysters? Your zinc is
likely covered. And so on.
For those wishing to personalize their supplement program
to the greatest possible degree, there are many software
packages available that will actually tell you how much of
the essential nutrients you’re taking in each day. One of the
best is http://www.nutritiondata.com , which is free,
available online, and gives great, user-friendly graphical
output. The time required to plug in the foods you eat every
day for a couple of weeks will be worth it if it tells you
where key deficiencies or imbalances may lie – and where
you can rest on your nutritional laurels.
So the first rule of supplementation is: begin at the
beginning. With this base, you can consider moving up to a
more advanced multinutrient formula, incorporating key
phytochemicals from the “superstar” team identified above,
and then adding in additional, more advanced supplements
such as powerful phytochemicals or cutting-edge
orthomolecules like benfotiamine or extended release
R(+)-Lipoic Acid based on your own priorities and health
concerns. Once you have a well-laid foundation, you can
build up a solid nutritional fortress.
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