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Examine.comResearch Digest
Kamal Patel ◆ 5 Year Anniversary Edition
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Table of Contents05 Something fishy: How a component of fish oil may counteract
the effects of some chemotherapy
Fish oil isn’t necessarily benign ... it turns out that certain fatty acids mightpartially negate chemotherapy
13 The study that didn’t end the low-fat/low-carb diet “wars”A recent metabolic ward study set the low-carb world on fire, and producedmany inaccurate media headlines disparaging low-carb diets. We cover thestudy and its implications, detail by detail.
24 Investigating vitamin D as a performance enhancerHaving sufficient vitamin D levels has been associated with better musclerecovery. This trial not only looks at the question of causality, but alsoaddresses some potential mechanisms of vitamin D’s benefit for exercise
32 Not-so-safe supplementsStudies have shown that supplement buyers generally trust the supplementsthey buy. That might not be the safest assumption, as dietary supplementsthat are presumed helpful or neutral may sometimes cause serious sideeffects, as quantified by this study.
41 The espresso effect: caffeine and circadian rhythm Your daily rhythms are influenced by “zeitgebers” such as light and exercise.But until now, we haven’t known the exact impact of late-day caffeine intakeon melatonin and circadian rhythms.
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ContributorsResearchers
Margaret WertheimM.S., RD
Alex Leaf M.S(c)
Courtney SilverthornPh.D.
Zach BohannanM.S.
Anders NedergaardPh.D.
Jeff RothschildM.Sc., RD
Greg PalcziewskiPh.D. (c)
Gregory LopezPharm.D.
Pablo Sanchez SoriaPh.D.
Kamal PatelM.B.A., M.P.H.,Ph.D(c)
Editors
Arya SharmaPh.D., M.D.
Natalie MuthM.D., M.P.H., RD
Stephan GuyenetPh.D.
Sarah BallantynePh.D.
Katherine RizzoneM.D.
Spencer NadolskyD.O.
Mark KernPh.D., RD
Gillian MandichPh.D(c)
Adel MoussaPh.D(c)
Reviewers
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Something fishy: How
a component of fishoil may counteractthe effects of some
chemotherapyIncreased Plasma Levels oChemoresistance -Inducing Fatty Acid 16:4(n-3) Afer Consumption
o Fish and Fish Oil
http://oncology.jamanetwork.com/article.aspx?articleid=2212208http://oncology.jamanetwork.com/article.aspx?articleid=2212208http://oncology.jamanetwork.com/article.aspx?articleid=2212208http://oncology.jamanetwork.com/article.aspx?articleid=2212208http://oncology.jamanetwork.com/article.aspx?articleid=2212208http://oncology.jamanetwork.com/article.aspx?articleid=2212208http://oncology.jamanetwork.com/article.aspx?articleid=2212208http://oncology.jamanetwork.com/article.aspx?articleid=2212208http://oncology.jamanetwork.com/article.aspx?articleid=2212208
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IntroductionCancer is an incredibly broad group o diseases char-
acterized by similar eatures, the most notable being
uncontrolled cell growth. Although researchers have
made great strides in understanding the molecular
mechanisms behind various cancers, they are stillworking on creating effective therapies that speci-
cally target these mechanisms. Tis means that many
therapies rely on relatively old- ashioned treatments:
chemo or radiation, which kill the tumor cells aster or
more effectively than they kill normal cells. As might
be expected rom such harsh therapies or such serious
diseases, many o these cancer therapies are associated
with severe side effects.
o address these side effects (and possibly as a result o
new ound interest in their health), many patients turn
to dietary remedies, including a variety o supplements.
Fish oil is one o the most popular choices, and it is
used by an estimated 20% o cancer patients. However,
relatively little work has been done to assess sh oil’s
interactions with common cancer treatments like
chemotherapy.
Fish oil is a common supplement, but its sources and
processing can vary greatly. It can come rom any oily
sh, including eel, herring, and mackerel. Te specic
atty acids components in sh oil can vary, depending
on the species and diet o the source sh. Since the
benets o sh oil supplementation and oily sh con-
sumption have been widely researched or decades,
scientists are now beginning to assess the components
o sh oil in more detail, especially as they pertain to
specic populations or interactions with medications.
Te group who conducted this study was the rst group
to identi y certain atty acids calledplatinum-induced
atty acids (PIFAs) that can induce resistance to chemo-
therapy in mice. Specically, they identied 12S-HH
and 16:4(n-3) as two atty acids that can cause resis-
tance to chemotherapy by altering DNA damage repair
mechanisms. Figure 1 depicts how PIFAs may interact
with macrophages to ultimately induce some level o
chemoresistance. Tis study is a ollow-up to the previ-
ous mouse-based report and aims to examine the sh
oil supplementation habits o cancer patients, as well as
urther clari y the effects o sh oil supplementation on
chemotherapy resistance.
Fish oil supplementation is relatively common in
cancer patients. Te researchers conducting this
study recently identied certain components o sh
oil (especially platinum-induced atty acid 16:4)
that can promote chemotherapy resistance in mice,
so they sought to understand whether these effects
could also be seen in human tumors.
Figure 1: Possible mechanism for PIFA-induced chemoresistance
Reference: Houthuijzen et al. Nat Commun. 2014 Nov.
http://www.ncbi.nlm.nih.gov/pubmed/15856334http://www.ncbi.nlm.nih.gov/pubmed/21907927http://www.ncbi.nlm.nih.gov/pubmed/21907927http://www.ncbi.nlm.nih.gov/pubmed/21907927http://www.ncbi.nlm.nih.gov/pubmed/21907927http://www.ncbi.nlm.nih.gov/pubmed/15856334
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Who and what was studied?Te design o this study is somewhat different than
most clinical studies because it assesses supplemen-
tation habits that could negatively affect li e-saving
therapies. It would be incredibly unethical to treat
chemotherapy patients with sh oil and assess whether
or not their disease progressed, so instead, the study
authors assessed many o the most important aspects o
sh oil’s interaction with chemotherapy without actual-
ly conducting a clinical trial.
As a rst step, the investigators tried to understand
whether consuming sh oil or atty sh actually
increased PIFA levels in healthy volunteers. Tirty
healthy volunteers who had not recently consumed
atty sh or sh oil were given either 10 or 50 milliliterso sh oil rom one o three different brands o com-
mercially available sh oil (six in each group). wenty
other healthy volunteers were ed 100 grams o either
tuna (a relatively lean sh that served as a sort o con-
trol), salmon, smoked mackerel, or cured herring (ve
participants in each group). Blood was collected rom
all participants be ore consumption as well as 1, 2, 4, 6,
8, and 24 hours afer consumption o the sh oil or sh.
How atty acids are namedBASIC FATTY ACID STRUCTUREFatty acids are primarily long chains o carbonand hydrogen atoms strung together at the endo a carboxyl group (COOH), which is why they are
called “acids.” The irst level o complexity amongatty acids is their differences in length. This is whatresearchers are re erencing when they discuss short-chain and medium-chain atty acids.
GETTING TURNED AROUNDThe second level o complexity among atty acids isthe introduction o double bonds between carbonatoms, which produces a “kink” in the atty acid
chain. Saturated ats don’t have any double bonds,monounsaturated ats have one, and polyunsaturat-ed ats have many. An “omega-3 atty acid” or “n-3” isa atty acid with a double bond on the third carbono the chain.
A NUMBERS GAMEThe naming system described above is common,but many scientists rely on a more complete lipidnumber naming convention. For example, the atty
acid discussed in this paper, 16:4(n-3), is a 16-car-bon atty acid chain with our double bonds and adouble bond at the third carbon (making it a type oomega-3 atty acid). A depiction is shown in Figure 2.
GETTING CONFUSEDAside rom the lipid number system, there are alsosystematic names, which ollow organic chemistrynaming conventions and turn out tongue-twisters
like hexadeca-4,7,10,13-tetraenoic acid, which is thechemical name or the 16:4(n-3) acid mentionedabove. Then there’s the “trivial” naming system that
ollows historical names. For example “arachidonicacid” is widely used but doesn’t actually describeany o the eatures o the atty acid.
Figure 2: 16:4(n-3) fatty acid
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All o the supplements were also analyzed separately or
PIFA content.
o assess whether PIFAs could induce chemoresis-
tance in human cancers, the researchers used a mouse
cancer model in which colon cancer cells are implant-
ed under the skin o the mice, so that the researchers
can study the growth o the tumors. Once the tumors
reached a certain size, the researchers treated the mice
with a variety o chemotherapies, as well as a variety o
PIFA sources. Tese mice were either studied or tumor
growth over time or or pharmacodynamic studies
o the levels o chemotherapeutic and PIFA over time.
Similarly, the tumor-bearing mice were also treated
with puried eicosapentaenoic acid (EPA) to assess
whether mice can convert EPA into PIFAs and whether
those resultant PIFAs affected chemotherapy resistance.
Finally, to understand how patients actually use sh oil,
the researchers conducted a survey o over 400 patients,
to which only 118 patients responded. Te question-
naire assessed whether or not patients used nutritional
supplements, which they used, and whether or not they
reported that use to their doctors.
It is difficult to study supplements that may mini-
mize the effectiveness o li esaving therapies. o do
so, the researchers studied whether sh oil or sh
consumption translated into increases in blood PIFA
content in healthy volunteers, whether PIFA inges-
tion induces chemoresistance in a mouse model o
tumor growth, and whether or not cancer patientsuse sh oil supplements.
What were the findings?Te researchers ound signicant levels o 16:4(n-3)
atty acids in all o the commercial sh oils they tested,
so they chose to ocus the rest o their studies on that
specic atty acid. In the mouse study, chemotherapy
controls effectively reduced cancer growth, but the
addition o puried 16:4(n-3) caused the tumors to
grow at a rate comparable to that o tumors rom mice
not treated with chemotherapy at all. Tis effect wasalso seen when mice were treated with sh oil in dos-
es equivalent to about three milliliters, or roughly 2.5
grams, or a human. Tis is about double the dosage
recommended by the American Heart Association,
although even larger doses are ofen taken.
o assess the levels o sh oil required to induce chemo-
resistance, the researchers administered 100, 10, 1, and
0.1 microliters o sh oil to mice and assessed tumor
[...] theaddition o
puri ied 16:4(n-3) caused thetumors togrow at a rate
comparable tothat o tumors
rom mice nottreated with
chemotherapyat all.
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growth. Fish oil supplementation as low as one micro-
liter (again, equivalent to about a three milliliter dose
or humans) showed a signicant reduction in che-
motherapy effectiveness. Finally, when the researchers
administered EPA to mice with tumors and assessed
both their serum 16:4(n-3) content as well as its ability
to induce chemoresistance, they ound both elevated
16:4(n-3) and tumor sizes similar to untreated tumors
in mice that received EPA.
In healthy volunteers, sh oil administration increased
16:4(n-3) levels in participant blood samples or up to
eight hours. It may have increased these levels or even
longer in some cases, but the trial only evaluated up
to eight hours. In the sh studies, participants who ate
mackerel or herring had increased levels o 16:4(n-3),
whereas participants who ate salmon had lower lev-
els, and participants who ate tuna had levels similar to
baseline. As seen in Figure 3, sh oil increased human
blood levels o 16:4(n-3) to a greater degree than did
sh, relative to the amount that existed in the sh or oil
itsel .
Te patient questionnaire revealed that 30% o patients
regularly used nutritional supplements, and 11% reg-
ularly used sh oil or other supplements containing
omega-3 atty acids. Eleven o the 13 patients (85%)
who regularly used these supplements continued to
use them during therapy, but only six o them (55%)
reported their supplementation habits to their doctors.
Fish oil and 16:4(n-3) administration induced tumor
chemoresistance in mouse models. Fish oil adminis-
tration and oily sh consumption increased 16:4(n-3)
blood levels in healthy volunteers. 11% o cancerpatients used sh oil or omega-3 supplements, and
most o these patients used them during chemother-
apy, with only about hal reporting supplementation
to their doctor.
Figure 3: 16:4(n-3) levels in humans - higher thanexpected with fish oil compared to fish
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cancer cells, it also results in off-target effects in other
rapidly dividing tissues, such as intestinal cells. Tis is
why many standard chemotherapeutic agents cause a
variety o gastrointestinal side effects, including vom-
iting and diarrhea. One o the key roles o oncologists
is to control chemotherapy doses to maximize cancer
cell death and minimize side effects. Tere are also a
wide array o supportive therapies available, such as
antiemetics, to help doctors control these side effects.
In many cases, cancer patients also seek out their own
supportive therapies, including supplements, in an
effort to enhance their quality o li e while receiving
cancer treatment.
In most cases, it remains unclear whether supplements
are truly benecial or cancer patients. In some other
cases, there is a clear contraindication or the use o
certain supplements while receiving certain chemo-
therapy agents. One example is St. John’s Wort, which
causes upregulation o enzymes that process a variety o
drugs, including some chemotherapy agents. However,
researchers have only recently begun studying interac-
tions between chemotherapy and supplements, so there
are many other interactions that remain to be discovered.
Tis study represents a kind o “miniature body o evi-
dence” to support the idea that 16:4(n-3) acids ound
in sh oil may reduce the effectiveness o chemother-
apy. Because cancer is such a lethal group o diseases
and because the therapies are already both care ully
calibrated and relatively arduous, it is critical to elimi-
nate any agents or habits that could reduce therapeutic
effectiveness. Although all o the experiments in thisstudy were preliminary, they support the idea that sh
oil supplementation may have a negative impact on
chemotherapy effectiveness, thus indicating that sup-
plementation management may be an important topic
or patients to discuss with a physician.
However, it is worth noting that most chemotherapy
regimens are not continuous, as a result o the side
effects they cause. Generally, chemotherapy is an inter-
mittent treatment in which the patient receives chemodrugs or a certain number o days and then takes a
break rom the treatment in order to recover. Tis was
not really taken into account in the current study, so it
may be acceptable or patients to take sh oil or other
supplements during the times they are not receiving
chemotherapy, but urther study is needed to conrm
this hypothesis.
[...] it may beacceptable or
patients to takeish oil or other
supplementsduring the
times they arenot receivingchemotherapy,but urther
study is neededto con irm thishypothesis.
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The study that didn’t
end the low-fat/low-carb diet “wars”Calorie or Calorie, Dietary Fat
Restriction Results in More Body Fat
Loss than Carbohydrate Restrictionin People with Obesity
http://www.cell.com/cell-metabolism/abstract/S1550-4131(15)00350-2http://www.cell.com/cell-metabolism/abstract/S1550-4131(15)00350-2http://www.cell.com/cell-metabolism/abstract/S1550-4131(15)00350-2http://www.cell.com/cell-metabolism/abstract/S1550-4131(15)00350-2http://www.cell.com/cell-metabolism/abstract/S1550-4131(15)00350-2http://www.cell.com/cell-metabolism/abstract/S1550-4131(15)00350-2http://www.cell.com/cell-metabolism/abstract/S1550-4131(15)00350-2http://www.cell.com/cell-metabolism/abstract/S1550-4131(15)00350-2
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IntroductionSome o you may have already come across our blog
post about this recent blockbuster o a paper published
by Dr. Kevin Hall et al. I you have, stick around or our
extended F.A.Q. section where we tackle the numerous
questions brought up about the study. I you haven’tread the blog, let’s dive right into the trial analysis.
For some, the central dogma behind the hypothetical
superiority o low-carb diets or at loss is the insulin
hypothesis o obesity. Part o this hypothesis states
that by restricting carbohydrates you will see a step-
wise decrease in insulin secretions. Because insulin
plays a part in the regulation o at storage, it has been
theorized that the less insulin secreted the more reeatty acids will be released rom adipose stores lead-
ing to increased at oxidation and rapid at loss. Tese
assumptions have led to the idea that low-carb diets
will induce greater at loss over a low- at diet even when
calories are held constant. Gary aubes, an advocate
o the low-carb approach, posited the ollowing in his
latest book, Why We Get Fat (p. 144-47):
“…any time we try to diet by any of the conventional
[low-fat] methods, and any time we decide to “eat
healthy” as it’s currently dened, we will remove the
most fattening carbohydrates from the diet and some
portion of total carbohydrates as well. And if we lose
fat, this will almost assuredly be the reason why…Tis
is something that even researchers who run clinical
trials testing the effectiveness of different diets rarely
recognize.”
Simply put, aubes suggests that by reducing both
carbs and at in low- at diets it is possible that reduc-
tions in carbohydrate intake could be responsible or
any at loss seen. aubes is correct in that researchers
who run diet trials ofen alter the amount o at and
carbohydrate participates eat, making it impossible
to determine i restricting one will lead to greater at
loss over the other. Previous studies on low- at and
low-carb diets have changed multiple variables simulta-
neously. So even though they end up comparing low- at
and low-carb, they do not specically reduce one mac-
ronutrient or the other rom a baseline diet without
changing other variables. In the present study, Dr. Hall
and his team set out to eliminate that con ounding
variable by subtracting either at or carbs rom the diet
without changing anything else. Tis was done undertightly controlled conditions, to determine i indeed
there is a metabolic at loss advantage to going low-carb.
[...] this was not a ree living low- atvs. low-carb study where researcherseducate groups o volunteers and letthem eat sel -directed low- at or low-carb diets in their own homes to seehow they are.
http://examine.com/blog/really-low-fat-vs-somewhat-lower-carb/http://examine.com/blog/really-low-fat-vs-somewhat-lower-carb/http://www.ncbi.nlm.nih.gov/pubmed/24839118http://lccn.loc.gov/2010034248http://lccn.loc.gov/2010034248http://www.ncbi.nlm.nih.gov/pubmed/24839118http://examine.com/blog/really-low-fat-vs-somewhat-lower-carb/http://examine.com/blog/really-low-fat-vs-somewhat-lower-carb/
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group cut out 828 calories o at and the restricted carb
group cut out 840 calories o carbohydrates. Protein
intake was kept constant throughout. O particular
note was that sugar consumption did not decrease in
the reduced- at group compared to baseline. In act, it
went up rom 152 grams/day to 170 grams/day. It was
important to keep sugar intake up as to not cause any
decreases in insulin secretion, which would have con-
ounded the study results.
All the volunteers were crossed-over rom one diet to
the other, as they went through a 2 to 4-week washout
period between the restricted at and restricted carb
diets. Food intake was meticulously monitored. All
subjects were conned to the metabolic ward or the
entirety o the study and were made aware o how crit-
ical it was to consume all ood provided to them. Even
when subjects were visiting with riends and amily,
they sat in a common area under the observation o
research staff to ensure no ood was being passed off.
Daily exercise was also required. Sixty minutes o tread-
mill walking at a sel -selected xed pace was required
everyday that patients were in the metabolic ward.
Multiple measurements were taken over the course
o this trial including cholesterol, appetite hormones,
insulin, cortisol, and body at percentage. Tough a
dual-energy X-ray absorptiometry (DXA) scanner
was employed to assess body at, this method is not
sensitive enough to pick up the small changes in body
at loss that occurred over the duration o this trial.
o get a more sensitive measurement, the changes in
body atness were determined using net at balanceby indirect calorimetry while residing in a metabolic
chamber, in combination with measures o nitrogen
loss in urine. Essentially the difference between dietary
at intake and net at oxidation ( at oxidation minus
de novo lipogenesis) were used to measure overall at
mass loss. Although this method cannot tell us where
the at is being lost rom, a sensible prediction would be
that most would come rom adipose tissue. However, it
is possible that some at could be lost rom the liver or
muscles, which would also be benecial.
A mathematical model o human metabolism was
employed to predict trial outcomes and to help extrapo-
late the 6-day results. Data rom the participant’s results
were plugged into this model to predict how they would
continue to lose weight over the course o 6 months. Dr.
Hall’s model has undergone some extensive validation
and has been shown to be a airly accurate predictor o
weight gain and loss in adults 18 years o age and older.
His research at the National Institute o Health has been
used to create the Body Weight Planner, which you can
explore on their website . A brie instructional video can
be ound here.
It wasimportant to
keep sugarintake up asto not causeany decreases
in insulinsecretion, whichwould havecon ounded the
study results.
http://www.ncbi.nlm.nih.gov/pubmed/21869755http://www.ncbi.nlm.nih.gov/pubmed/21869755http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4060216/http://www.ncbi.nlm.nih.gov/pubmed/19934407http://www.supertracker.usda.gov/bwp/index.htmlhttp://www.supertracker.usda.gov/bwp/index.htmlhttps://youtu.be/_HtmfdTT--Ihttps://youtu.be/_HtmfdTT--Ihttps://youtu.be/_HtmfdTT--Ihttps://youtu.be/_HtmfdTT--Ihttp://www.supertracker.usda.gov/bwp/index.htmlhttp://www.supertracker.usda.gov/bwp/index.htmlhttp://www.ncbi.nlm.nih.gov/pubmed/19934407http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4060216/http://www.ncbi.nlm.nih.gov/pubmed/21869755http://www.ncbi.nlm.nih.gov/pubmed/21869755
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19 healthy subjects with obesity were randomized
and crossed-over into both a restricted at and
restricted carb diet under strict observation in a met-
abolic ward. Indirect calorimetry was used to assess
at mass loss over both 6-day periods participants
were on restricted diets, and a mathematical modelwas used to predict how much weight would be lost
over 6 months.
What were the findings?Te results are summarized in Figure 2. As may have
been expected, the reduced-carb group shifed to pri-
marily oxidizing at as uel, and reached a steady stateafer about 4 days. Te reduced- at group consistently
burned carbs as their main uel source throughout the
trial and saw little reduction in at oxidation. An inter-
esting caveat that popped up was that protein oxidation
was increased in the reduced carbohydrate group, indi-
cating that the higher carb intake o the reduced- at
group may have a slight protein sparing effect. Some
may worry that this increased protein oxidation equates
to muscle tissue being broken down. However, this
may not necessarily be the case as the protein oxidation
could be coming rom the amino acids in the diet. As
most reduced-carbohydrate diets are typically paired
with an increased protein intake, it is unlikely that any
muscle wasting would occur.
One interesting nding was that the reduced- at group
did not experience a major shif in at or carb oxida-
Figure 2: Summary of the study and results
Adapted from: Hall, KD et al. Cell Metab. 2015 Sep.
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tion the way the reduced-carb group did. Within the
reduced-carb group, at oxidation went up 403 calo-
ries (~45g) per day and carb oxidation went down 520
calories (~130g). Tis shif to primarily utilizing at as
energy is a known effect o low-carb diets. One might
speculate that a high carb diet would see an equally
dramatic shif towards burning carbs as the prima-
ry uel, but the reduced- at group saw at oxidation
decreased by only 31 calories (~3.4g) per day and carb
oxidation increase by 44 calories (~11g). It seems that
when aced with a large reduction in dietary at intake
the body keeps trucking along, burning at and carbs at
approximately the same levels.
Overall, the reduced- at diet lead to a at mass loss o
~463 g and the reduced-carb diet saw a at reduction o
~245 g. Te difference in these numbers can possibly be
explained by the stored glycogen the reduced-carb group
would have burned off in the rst 2 to 4 days o the 6-day
diet period, afer which the at mass loss would more
closely match that o the reduced- at group. Te at loss
seen in the reduced- at group occurred even though no
signicant changes in 24-hour insulin secretion were
seen. By contrast, the reduced-carb group saw a 22%reduction in 24-hour insulin secretion. Tis nding
clearly demonstrates that a reduction in dietary carbohy-
drate and insulin is not necessary or losing at mass.
Figure 3 depicts the results rom when the subjects’
data was plugged into the human metabolism model. It
predicted that the reduced- at diet would see about 3
kg (6.6 lbs.) greater at loss afer 6 months, a 40% di -
erence in at loss. O course, this was assuming thatparticipants would adhere 100% to the diet. Real world
diet studies tend to show us that compliance starts to
dwindle afer about the 6-month mark. Additional
simulations were run to see what would happen i carbs
were dropped even lower in the reduced-carb group
with subtracted carb calories being swapped out or at
to keep total calories constant. Te model predicted
that the very low-carbohydrate diet (
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seen in the reduced-carb diet that was not seen in the
reduced- at diet. Tis is suggestive o some more subtle
metabolic changes that occur due to the effect o certain
dietary macronutrient compositions.
Te reduced- at diet group lost more at mass than
then reduced carbohydrate group. Te reduced- at
group did not see any signicant decreases in insu-
lin production, demonstrating that reducing insulin
levels is not necessary or losing at mass. Te math-
ematical model o human metabolism predicted an
advantage to the low- at diet over the course o 6
months, but the differences were minimal and all but
disappeared when a very low- at diet was modeled
against a very low-carb diet.
What does the study reallytell us?Tis study lends more credence to the theory o ener-
gy balance, otherwise known as “calories in, calories
out” (CICO). A common interpretation o CICO is that
there should be ew i any differences between diets o
equal calories on at loss or energy expenditure. Tis
study shows us that while that strict interpretation o
CICO is not 100% correct, it is pretty darn close. Whilethe CICO model holds approximately correct over most
o the macro spectrum, the mathematical model pre-
dicted that it does start to break down a little bit when
looking at macronutrient extremes. As we saw in Dr.
Hall’s 6-month model prediction, the reduced- at group
had a slight advantage over the reduced-carb group.
Tese small differences are about the extent to which
you may see any difference between diets. And as noted
earlier, that advantage all but disappeared when verylow-carb was compared to very low- at diets.
While the study was incredibly rigorous in its design
and execution, the sample size was small. Only 17 o
the 19 recruited individuals completed the entire study.
By metabolic ward study standards, 17 is actually a
pretty large sample size and provided and enough par-
ticipants to ensure small differences in at loss could
Figure 3: Mathematical modelling prediction of diets 6 months out
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be detected. However, because o the small sample
size it may be difficult to extrapolate these results to
the general population. One should also note that the
participants in this study were relatively healthy, so the
results here may not extend to people with health issues.
People with other health issues may also be on various
medications that could alter metabolism, but such peo-
ple were excluded rom this study. Tese actors make
any generalizations rom this study to such populations
very challenging.
While a calorie might not be exactly a calorie, it is
pretty close in terms o its effects on metabolism
during periods o weight loss. Small shifs can occur
depending on the macronutrient composition, butthe end results on equally caloric low-carb and low-
at diets are not strikingly different. Due to the small
sample size and the type o patients recruited to this
study, extrapolation o the results is limited.
The big pictureTe practical implications we can take away romthis study are very limited, but we can surmise that a
reduction in insulin secretion brought about through
low-carb dieting does not seem to con er any metabolic
advantage or at loss. In a way, this is both good and
bad news. Te bad news is that a low-carbohydrate diet
does not appear to possess any super at-blasting prop-
erties which, had that been proven true, would have
been great news to dieters everywhere. I this paper
had shown a signicant advantage to low-carb dietingit very likely would have been a game changer in how
we approach the treatment o obesity and weight loss
research. Te good news is that, because a low-carb is
not necessary or at loss, more eating styles are available
to those trying to lose weight. I you are not someone
who likes low-carb dieting, higher or moderate carbs
diets are a per ectly viable option or weight loss.
Tat isn’t to suggest that low-carb diets should not be
employed i that is your pre erence. Te higher protein
intake that is ofen paired with low-carb diets can help
to increase satiety, causing you to eel less hungry. Many
may nd a reduced-carb diet easier to adhere to than
a reduced- at diet. People who are insulin resistant, a
condition commonly ound among those with pre-di-
abetes or type 2 diabetes, can ofen experience better
I this paperhad showna signi icantadvantage tolow-carb dietingit very likelywould havebeen a gamechanger in howwe approachthe treatmento obesity andweight lossresearch.
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results on a low-carbohydrate eating plan. In a real-
world setting, adherence is king . Even i low-carb diets
had the ability to melt at off your body, i you are not
able to stick with the diet it will not be an asset or your
long-term weight loss goals.
Te act that low-carb diets do not con er a superhu-
man ability to lose at mass is a little disappointing. A
diet that did possess such properties would be a most
welcome nding. However, this study does rein orce
the act that most any diet, be it Mediterranean,
DASH, paleo, or vegetarian, can all work quite effec-
tively or weight loss. It all comes down to personal
pre erence and the ability to stick with the diet in the
long term.
Frequently asked questions– XXL editionTe present study was ull o intricacies and nuances.
In other words, it was ripe or misinterpretation by the
popular media. You may have seen ashy headlines
declaring the superiority o low- at diets and lamentingthe death o low-carb. With so much hyperbole sur-
rounding this study in the news and blogosphere, we’re
bringing you an XXL edition o the F.A.Q. in order to
bust some common myths, misconceptions, and criti-
cisms surrounding this trial.
A 6-day study is not long enough to get intoketosis or to become fat adapted.A lot o people have been commenting on the short
duration o this study. Many argue that it takes up to
1 month to become properly “ at-adapted” or that the
carb content in the reduced-carb diet was not low-carb
enough to induce a state o ketosis. Tis misconception
about at-adaptation likely stems rom those who have
gone low-carb and elt hazy or oggy, commonly known
as the “low-carb u”, or 2 to 4 weeks. While it may
take some time to eel normal again on a low-carb diet,
the body’s energy systems actually make the transi-
tion rom pre erentially burning carbs to pre erentially
burning at rather quickly. Within the reduced-carb
group o this study, it took about 4 days be ore they had
reached maximum at oxidation and we began to see a
leveling off. Tis observation is corroborated by other
trials that show the same quick uel transition. Once the
at oxidation plateau has been achieved, it remains very
constant over the ollowing weeks. Hence, 6 days would
have been sufficient time or subjects to achieve maxi-
mum at oxidation on the reduced-carb diet.
On the criticism that the reduced-carb diet was not
ketogenic, they are correct i you are dening ketogenic
as 50 grams o carbs a day or ewer. But i the argument
is that being in a ketogenic state con ers bonus at burn-
ing abilities, you’d think there might be at least some
suggestion o a dose-response curve as carbs in the diet
decrease. Tis means we should be able to see at loss
increase as carbs in the diet decreased. No such dose
response was observed in this trial. Te mathematical
model employed also indicated that a very low-carb diet
would have similar at loss results to a very low- at diet.
Currently, no metabolic ward study o a ketogenic vs
non-ketogenic diet exists, where calories and protein
are held constant. However, there have been non-met-
abolic ward studies indicating no metabolic advantage
to ketogenic diets . Dr. Hall has just completed (but not
yet published) an 8-week metabolic ward study that will
hope ully shed some more light into this area o research.
Nothing can be gained from this study becauseit does not represent real world conditions.Tis study was not about which diet leads to better
results under real-world conditions. Tere are many
other studies out there that have attempted to address
that question, but as mentioned be ore, a success ul
diet comes down to adherence . Te authors were very
up ront in what this trial was designed to study and its
real-world applications. Te research team planned this
http://www.ncbi.nlm.nih.gov/pubmed/22831182http://www.ncbi.nlm.nih.gov/pubmed/19936157http://www.ncbi.nlm.nih.gov/pmc/articles/PMC292291/http://link.springer.com/chapter/10.1007%2F978-3-642-29056-5_22http://www.ncbi.nlm.nih.gov/pubmed/17684196http://www.ncbi.nlm.nih.gov/pubmed/17684196http://www.ncbi.nlm.nih.gov/pubmed/16685046http://www.ncbi.nlm.nih.gov/pubmed/15601961https://clinicaltrials.gov/ct2/show/NCT01967563http://www.ncbi.nlm.nih.gov/pubmed/19936157http://www.ncbi.nlm.nih.gov/pubmed/19936157https://clinicaltrials.gov/ct2/show/NCT01967563http://www.ncbi.nlm.nih.gov/pubmed/15601961http://www.ncbi.nlm.nih.gov/pubmed/16685046http://www.ncbi.nlm.nih.gov/pubmed/17684196http://www.ncbi.nlm.nih.gov/pubmed/17684196http://link.springer.com/chapter/10.1007%2F978-3-642-29056-5_22http://www.ncbi.nlm.nih.gov/pmc/articles/PMC292291/http://www.ncbi.nlm.nih.gov/pubmed/19936157http://www.ncbi.nlm.nih.gov/pubmed/22831182
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study to look at specic mechanisms o at loss, primar-
ily testing i a reduction in insulin is necessary to lose
body at.
Dr. Hall does have a study in the works that will be
looking into some more real-world diet issues. His
uture trial will be examining some o the changes in
metabolism and the brain that may lead to weight loss,
plateau, and regain.
Te authors even stated the ollowing in their discussion:
“ ranslation of our results to real-world weight-loss
diets for treatment of obesity is limited…. We did
not address whether it would be easier to adhere to
a reduced-fat or a reduced-carbohydrate diet under
free-living conditions. Since diet adherence is likely
the most important determinant of body fat loss, we
suspect that previously observed differences in weight
loss and body fat change during outpatient diet inter-
ventions were primarily due to differences in overall
calorie intake rather than any metabolic advantage of
a low-carbohydrate diet.”
Why were obese but metabolically healthy peopleselected? Wouldn’t having obese people who were meta-
bolically unhealthy have made more sense?
It is possible that a uture study like this may be per-
ormed in those with obesity and metabolic syndrome,
but the additional actors that come with metabolic
dys unction complicate the results o the study. For
example, someone with type 2 diabetes operates under
a different metabolic paradigm than someone without it
due to insulin resistance and potentially decreased pan-creatic unction. Furthermore, many type 2 diabetics
may be taking medications that alter their metabolism
which adds more con ounding variables to the mix
when trying to draw conclusions.
Why were lef-handed people excluded rom the trial?
I you look at the exclusion criteria or this study , you
will indeed nd that those who were lef-handed were
not allowed to participate. While this may seem odd
at rst, it was implemented because neuroimaging
was used on all participants, most likely to be used in
uture publications. Tose who are right-handed tend
to per orm tasks in either the right or lef side o the
brain, whereas lef-handers tend to split that task evenly
across the brain. I you are using neuroimaging to look
at a specic part o the brain, this difference in brain
hemisphere usage in right and lef handers can throw
off your results.
What about the hiccups in the study where people receive
incorrect meals and one woman’s data was not included?
In any clinical trial, mistakes are bound to happen. In
this case, one male and one emale participant received
the wrong meals on the rst day the reduced-carb and
reduced- at diets were administered. Te researchers
opted to keep these data in the nal analysis, as remov-
ing them did not affect the statistical signicance o any
comparisons.
wo o the male participants also dropped out o the
study afer nishing the reduced-carb phase o the trial.
Teir data or the reduced-carb portion was kept in,but obviously they did not contribute any data to the
reduced- at phase.
Curiously, one emale subject saw some unusual
measurements on her DXA scans that prompted the
research team to exclude her data rom that partic-
ular analysis. Tis was because the DXA showed her
at mass had increased on both the reduced-carb and
reduced- at diets despite the act that she had experi-enced weight loss and was in negative energy balance.
Gaining at mass while in substantial negative energy
balance is something that is physiologically impossible,
making it a clear outlier and hence leading to the deci-
sion to exclude those data points.
Why did they compare a low- at to a moderate-carb
diet instead o a low- at to low-carb diet?
https://clinicaltrials.gov/ct2/show/NCT02199483http://clinicaltrials.gov/ct2/show/NCT00846040http://www.ncbi.nlm.nih.gov/pubmed/24518415http://www.ncbi.nlm.nih.gov/pubmed/24518415http://www.ncbi.nlm.nih.gov/pubmed/24518415http://www.ncbi.nlm.nih.gov/pubmed/24518415http://clinicaltrials.gov/ct2/show/NCT00846040https://clinicaltrials.gov/ct2/show/NCT02199483
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Te baseline diet was set at 35% at, 15% protein and
50% carbohydrate and about 20% o those total calories
were rom sugar. Tis is believed to represent a typical
American diet composition. Because o this compo-
sition, it was impossible to make subtractions rom
carbs any lower in the low-carb group without having
to add at calories back in while keeping total calories
constant between groups. Te researchers did not want
to do this, as the whole point o the trial design was to
change just one macronutrient level while leaving the
others untouched. Tis is why the macro composition
was askew afer the pre-set number o calories and been
subtracted rom each group.
Tere were too ew participants in the study.
Usually, be ore a trial is conducted, a power calculation
is used to determine how many people may be needed
in the trial to reach adequate statistical power. Tat is
to say, how many people will be needed to ensure that
a statistically signicant difference can be ound in a
study when there is one in reality. Tis method is how
Dr. Hall reached the number 19 or participants needed
in this study. It should be noted that due to the com-
plexities and costs o running a metabolic ward study,19 is actually a large sample size, comparatively.
Why did the reduced- at group experience a greater
drop in asting blood glucose compared to the reduced-
carb group (and other oddities in able 4)?
You would expect the reduced-carb group to have the
greater decrease in endpoints such as asting blood glu-
cose and asting insulin levels. In this case that did not
happen, as the reduced- at group dropped their astingglucose by 7.1 mg/dl and the reduced-carb group only
experienced a 2.69 mg/dl drop. Decreases in asting
insulin were comparable between groups. So what’s
going on in able 4? ry not to read too heavily into the
blood data presented, as they were all exploratory sec-
ondary endpoints o the study. Te p-values were also
uncorrected or multiple comparisons.
Can we see the individual data?
Dr. Hall has said that he will be publishing uture papers
exploring the correlates o individual responses seen in
this study. We look orward to seeing these data too!
What i this restarts the low- at diet trends again? I
loved the 80s!
Please, no more high vs low- at diet shenanigans! Both
dietary approaches are per ectly healthy. Pick what
works best or you in the context o your ood pre er-
ences, environment, and health status.
What should I know?Te most direct takeaway rom this study is that car-
bohydrate restriction and insulin decreases are not
required or at loss. For a more real-world implication,
we can extrapolate that you should pick whichever diet
you can adhere to in the long run. Tis study is not
showing that low-carb diets are ineffective, but rather
demonstrates that both a low-carb and low- at option
may be equally efficacious or those seeking at loss (at
least as ar as your body is concerned). Decreased insulin
in otherwise healthy subjects will not provide an addi-
tional at loss advantage, so do not ret that you must go
low-carb or you will never lose weight ever again. ◆
Te king o all discussion topics: low-carb dieting. odiscuss the topic (actual discussion, not heated opin-
ions!), check out the private ERD Facebook orum.
https://www.facebook.com/groups/examineERD/permalink/892328597521712/https://www.facebook.com/groups/examineERD/permalink/892328597521712/
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IntroductionWhy is Vitamin D such a popular supplement, among
both researchers and the general public? One reason is
that it potentially acts on a broad spectrum o health
and per ormance measurements. Researchers have
examined the effects o this at-soluble vitamin onchronic pain , cystic brosis, multiple sclerosis , and the
risk o cardiovascular disease and mortality (covered
in ERD #7).
Many people are not getting enough o this vitamin.
Recent estimates have indicated that 37.3% o the
world’s population may have an inadequate level o
vitamin D. Te Institute o Medicine has dened blood
concentrations between 30 to 50 nmol/L o vitaminD to generally be considered inadequate. Although
sometimes dened at different cutoff points, risk o
deciency can be characterized by levels lower than
30 nmol/L, while an adequate, healthy range is usually
considered to be between 50 and 125 nmol/L.
We’ll be using units o nmol/L throughout this article,
although many labs report vitamin D levels in ng/mL.
You can see how these two units relate to each other
in Figure 1. One possible downstream effect o these
inadequacies may be a decrease in the body’s ability to
regenerate muscle tissue. Researchers have known since
1985 that there are vitamin D 3 receptors on muscle cells,
and in the past ew years research on vitamin D in the
context o boosting per ormance has become popular.
One intervention trial in well-trained athletes showed
an improvement in sprint times and vertical jump with
supplementation. Further studies have associated higher
vitamin D status with a more rapid recovery o skeletal
muscle strength afer an acute bout o intense exercise.
Te growing body o data showing that vitamin D plays
an important part in the unction o skeletal muscle
suggests this vitamin may be a potential ergogenic
aid. Te act that vitamin D3 is a relatively inexpen-
sive and widely-available supplement makes it all the
more attractive to athletes. Around 56% o athletes
have vitamin D levels o 80 nmol/L or lower, so sup-
plementation could help combat deciency. Although
previous research has indicated vitamin D may help
with improved muscle healing, a causal relationship
has not yet been rmly established. Te study under
review looked urther into this connection to deter-
mine i there is a potential cause-effect relationshipbetween vitamin D and muscle repair, regeneration,
and hypertrophy.
Figure 1: Converting nmol/L to ng/mL
http://www.ncbi.nlm.nih.gov/pubmed/20091647http://www.ncbi.nlm.nih.gov/pubmed/24823922http://www.ncbi.nlm.nih.gov/pubmed/21154396http://www.ncbi.nlm.nih.gov/pubmed/25710567http://www.ncbi.nlm.nih.gov/pubmed/25071593http://www.ncbi.nlm.nih.gov/pubmed/25071593https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/http://www.ncbi.nlm.nih.gov/pubmed/2991224http://www.ncbi.nlm.nih.gov/pubmed/23083379http://www.ncbi.nlm.nih.gov/pubmed/23595134http://www.ncbi.nlm.nih.gov/pubmed/23595134http://www.ncbi.nlm.nih.gov/pubmed/18727936http://www.ncbi.nlm.nih.gov/pubmed/21664245http://www.ncbi.nlm.nih.gov/pubmed/25277808http://www.ncbi.nlm.nih.gov/pubmed/25277808http://www.ncbi.nlm.nih.gov/pubmed/24313936http://www.ncbi.nlm.nih.gov/pubmed/24313936http://www.ncbi.nlm.nih.gov/pubmed/25277808http://www.ncbi.nlm.nih.gov/pubmed/25277808http://www.ncbi.nlm.nih.gov/pubmed/21664245http://www.ncbi.nlm.nih.gov/pubmed/18727936http://www.ncbi.nlm.nih.gov/pubmed/23595134http://www.ncbi.nlm.nih.gov/pubmed/23595134http://www.ncbi.nlm.nih.gov/pubmed/23083379http://www.ncbi.nlm.nih.gov/pubmed/2991224https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/http://www.ncbi.nlm.nih.gov/pubmed/25071593http://www.ncbi.nlm.nih.gov/pubmed/25071593http://www.ncbi.nlm.nih.gov/pubmed/25710567http://www.ncbi.nlm.nih.gov/pubmed/21154396http://www.ncbi.nlm.nih.gov/pubmed/24823922http://www.ncbi.nlm.nih.gov/pubmed/20091647
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Vitamin D plays diverse roles in maintaining health,
and has been investigated or benecial effects on a
host o conditions. A developing line o research has
looked into the roles this vitamin could play in the
context o boosting physical per ormance. Te pres-
ent study investigated vitamin D to determine how itaffects muscle repair, regeneration, and hypertrophy.
Who and what was studied?First, the researchers conducted a double blind, ran-
domized controlled trial in humans (in vivo) to
investigate the effects o vitamin D on the muscle’s
ability to recover rom exercise-induced damage. Teoverall study design is shown in Figure 2.
Second, they extracted isolated muscle cells ( in vitro)rom humans that were vitamin D insufficient and
exposed them to 1,25-dihydroxyvitamin D (1,25(OH)
D), the biologically active orm o vitamin D. Tis was
done to identi y the aspects o muscle cell regeneration
that respond to the supplement. By using a combined invivo/in vitro design, the researchers were able to exam-ine the impact vitamin D had on muscle recovery in
humans while also attempting to determine the cellu-
lar mechanisms through which the effect might occur.
Essentially, the researchers were trying to gure out
how vitamin D affects muscle repair and how it does
what it does.
Researchers recruited twenty young, physically active,
and healthy males or the in vivo study. Baseline
vitamin D status was assessed and participants were
excluded i they had adequate vitamin D concentra-
tions, dened in this study as greater than 75 nmol/L.
All vitamin D blood measurements were analyzed
using an analytical chemistry technique considered the
gold standard or assessing vitamin D levels (LC-MS/
MS). Te average vitamin D status o the cohort was 45
nmol/L. Participants were randomized into the control
or intervention groups and received six weeks o either
supplemental vitamin D3 (4,000 IU/day) or placebo.
Figure 2: Trial design
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What’s the difference between vitamin D2 and D3 ?
Vitamin D in the diet comes in two orms: D2 and D3. D2 is usually ound in ungi, while D3 isound in animal products.
D2 does not bind well to the human vitamin D receptor, compared to D 3. For that reason,and because it is more easily deactivated and thus remains in an active orm or less time,it is generally considered to be a poorer orm o the supplement.
An overview o vitamin D metabolism is shown in Figure 3. Vitamin D2 and D3 must bothundergo urther enzymatic reactions be ore the body can utilize them. They both travelto the liver, where they are converted into 25-hydroxyvitamin D (25(OH)D), the orm that isusually measured in blood tests or vitamin D. Vitamin D3 is more effective at raising thismeasurement than D 2 is. They are then sent to the kidneys, where the inal conversionstep occurs. 25(OH)D becomes 1,25-dihydroxyvitamin D (1,25(OH)D), the bioactive hor-monal orm o the vitamin.
It is this substance that can interact with the vitamin D receptors ound throughout tissuesin the body. The 1,25(OH)D that is not used by the body gets degraded into inactive orms,with D2 tending to be deactivated more quickly than D 3 .
Figure 3: Vitamin D metabolism
Adapted from: Dahlquist et al. J Int Soc Sports Nutr. 2015 Aug.
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Be ore the participants began their supplement regimen,
baseline muscle recovery measurements were taken.
Participants produced a maximal voluntary contrac-
tion (MVC) in their right leg prior to and ollowing a
series o eccentric exercises. An eccentric contraction
is the portion o the exercise during which a muscle
is lengthening. For example, the eccentric portion o
a bicep curl is when the weight is lowered back down
to the rest at the side, thus lengthening the biceps. Te
eccentric exercises and MVCs were per ormed on
an isokinetic dynamometer, which can measure the
amount o torque being produced. A video o this
machine in action can be viewed here . MVC torque was
then re-measured 24 hours, 48 hours and seven days
ollowing the exercise session. Tis same procedure was
repeated ollowing the six weeks o supplementation.
For the in vitro study, researchers took muscle biopsiesrom the quadriceps o ourteen young male volun-
teers with inadequate levels o vitamin D. Te muscle
cells were cultured and isolated be ore the experiment
began. o induce muscle damage, a pipette was used to
scrape the cells on the culture plate. Once any remain-
ing cell debris had been removed, the muscles cells wereexposed to a low (10 nmol/L) or high (100 nmol/L) dose
o vitamin D3, or a control substance. Tese varying
doses were used to determine i the potential respons-
es in muscle repair are dose dependent. Researchers
observed the cells at zero and 48 hours, as well as seven
and 10 days afer the pipette-induced cell damage.
Tis study was split into two parts: one per ormed on
humans and one on cultured muscle cells. During the
human study, researchers administered exercise tests
be ore and afer a six-week intervention during which
participants either took vitamin D 3 or a placebo. Te
researchers were attempting to determine i vitamin Dplays a role in muscle repair. During the second study,
the cultured muscle cells were given varying doses
o vitamin D 3 to try and determine the mechanisms
through which the vitamin acts on muscle tissue.
What were the findings?Te rst, and perhaps most obvious nding, was thatthere was a signicant increase in serum vitamin D in
the group receiving the supplement. Concentrations
increased by a actor o 2.5, rom an inadequate vitamin
D status o 45 nmol/L to an adequate status o 115 nmo-
l/L. On the other hand, the placebo group’s serum level
actually dropped by 26%, rom 45 nmol/L to 33 nmol/L.
wo exercises were utilized to test muscle recovery. One
where participants produced maximal torque whilemoving their legs at 60 degrees per second and one at
180 degrees per second. Within the vitamin D group,
signicant muscle recovery improvements were seen in
the 60°/second test and, although a positive trend was
observed, no statistically signicant results were record-
The irst, and perhaps most obviousinding, was that there was a signi icant
increase in serum vitamin D in thegroup receiving the supplement.
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ed or the 180°/second test. However, the relationship
between higher serum vitamin D levels and the ability
o the participants to recover their strength afer eccen-
tric exercises (i.e. peak torque) was highly correlated (r 2
= 0.88). No changes in muscle soreness were detected
between groups.
Te in vitro study looked at endpoints like cell migration,which is a key initial step in the muscle repair process.
Both the high and low doses signicantly enhanced cell
migration compared to placebo, but the high dose was
superior. Te high and low doses also improved migra-
tion speed and distance covered, which resulted in more
cells moving into the wounded space to repair the dam-
aged tissue. Interestingly, the high dose o vitamin D3
did not per orm as well as the low dose when it came
to myoblast usion. Myoblasts are cells that use to orm
myotubes. Myotubes are used to produce various mus-
cle groups required to generate orce .
Te low treatment group experienced signicant
improvement in myotube measurements over the con-
trol and high vitamin D 3 treatments. Cells exposed to
the lower dose also saw increased creatine kinase activity,which helps muscles to unction effectively by energizing
creatine. Low doses also showed a trend in being able
to up-regulate certain gene expressions associated with
muscle repair and growth, more so than the high dose.
During the human intervention portion o the trial,
higher vitamin D status was positively correlated with
the ability o muscles to recover quicker rom exer-cise-induced damage, although statistically signicant
differences were only seen in one o the two muscle
recovery tests. When looking at the results o the
muscle cell cultures, the low dose o D 3 appeared to be
the most benecial or muscle ber repair, improved
creatine kinase activity, and up-regulation o gene
expressions involved with muscle tissue growth.
What does the study reallytell us?Tis study illustrates the important role that vitamin
D plays in muscle recovery, repair, and regeneration.
When serum vitamin D status is brought up rom a
level o inadequacy, the unctional recovery o skeletalmuscle occurs more quickly. Te cell cultures tested in
this study provide a deeper understanding o how this
process occurs, namely by illuminating the underlying
mechanisms that heal muscle tissue.
Data presented in the study may also provide insight
into what might occur i supplemental vitamin D is
taken in excess. When tested on the muscle cells, the
higher vitamin D dosage suppressed certain aspects
o the muscle repair process. Myoblast usion, creatine
kinase activity, and certain gene expressions were not
as active as their low dose counterparts by day 10 o the
cell culture observations. It is unclear i these same sup-
pressions would happen in vivo and, i so, what dose
would be needed to bring about these effects.
While the dosage used in this study (4,000 IU/day)demonstrated a positive effect on muscle repair in
people with insufficient levels, it is not known i these
effects would continue to improve, level off, or dissipate
at higher doses. Te sa e upper limit established in the
United States and Canada is presently set at 4,000 IU/
day , but some research suggests that the upper limit
could be as high as 10,000 IU/day . However, a dosage o
1,000-2,000 IU/day should be sufficient or most people.
Te study did have a ew design limitations. A sample
size o 20 participants is airly small, so a larger scale trial
is needed to help veri y the results o this study. Further
studies should include emale participants as well. Also,
the chosen mode o exercise was highly specic and
is not necessarily translatable to everyday activities or
training. Future experiments could employ exercise
modalities that reect more real-world scenarios.
http://www.ncbi.nlm.nih.gov/pubmed/19932206http://www.ncbi.nlm.nih.gov/pubmed/19932206http://www.ncbi.nlm.nih.gov/books/NBK56058/?report=readerhttp://www.ncbi.nlm.nih.gov/books/NBK56058/?report=readerhttp://www.ncbi.nlm.nih.gov/pubmed/22414585http://www.ncbi.nlm.nih.gov/pubmed/22414585http://www.ncbi.nlm.nih.gov/pubmed/22414585http://www.ncbi.nlm.nih.gov/pubmed/22414585http://www.ncbi.nlm.nih.gov/books/NBK56058/?report=readerhttp://www.ncbi.nlm.nih.gov/books/NBK56058/?report=readerhttp://www.ncbi.nlm.nih.gov/pubmed/19932206http://www.ncbi.nlm.nih.gov/pubmed/19932206
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Furthermore, the doses o D 3 the muscle cell cultures
were exposed to was well above what would be seen in
a normal human, making the different doses used in
the in vitro and in vivo studies hard to compare. Te
authors suggest that urther research should look into
estimating the concentration o D 3 that skeletal muscles
are normally exposed to. Tese discoveries would help
researchers design in vitro experiments that are more
relevant to real-world concentrations o vitamin D.
People with inadequate serum vitamin D can increase
intake to ensure adequate levels, which will likely
benet muscle repair and regeneration. In vitro stud-
ies demonstrate that vitamin D is able to enhance
these repair mechanisms. Future testing is needed todetermine i doses higher than 4,000 IU/day will ben-
et or potentially attenuate these mechanisms.
The big pictureViews on vitamin D have changed in the past decade. It
was previously mostly viewed as a regulator o calcium
balance, hence aiding in healthy bone ormation. Forexample, rickets, a bone disorder typically ound in
children, is caused by insufficient vitamin D intake and
can be reversed with supplemental vitamin D . However,
research per ormed over the past decade has shown that
many tissues in the body
will respond to and unc-
tion sub-optimally when
exposure to vitamin D is
limited. Studies have iden-tied over 900 genes that
are regulated in part by
vitamin D. Te biologically
active orm o vitamin D
shares some characteristics
with steroids like testos-
terone. Tus, research
looking into these hor-
mone properties has led scientists to investigate vitamin
D as a potential ergogenic aid. Specically, the potential
ability o vitamin D to assist in rapid muscle recovery,
which would be o particular interest to athletes.
Te authors point out that this research has raised new
questions about populations susceptible to muscle
damage and vitamin D inadequacy, such as the elderly.
A more senior population may experience a diminished
capacity to regenerate muscle when vitamin D levels
are not sufficient. Higher levels o supplementation may
aid in reversing some o these processes.
Previous in vitro studies conducted on human cells have shown promise in the use o vitamin D to aid in
muscle recovery times. An animal study, per ormed on
rats, echoed these ndings and demonstrated enhanced
recovery with the supplement. Besides the current
study, one additional study has investigated vitamin D’s
muscle recovery effects in humans. Baker et al. exam-
ined 28 healthy active males with adequate vitamin
D levels. Afer baseline measurements were recorded,
4,000 IU daily o vitamin D or placebo was adminis-
tered or 35 days. Te post-test results showed bothenhanced recovery time and a decrease in biomarkers
o muscle damage in the vitamin D group.
Te combined results o the muscle cell tests, animal
studies, and experiments
per ormed in humans
have built a strong case
or the need to ensure
adequate vitamin D statusor optimal physical per-
ormance. However, the
research looking into sup-
plementation in emales
is lacking, as both o the
two human intervention
trials recruited only t
healthy males.
Studies have
identi ied over900 genes that areregulated in partby vitamin D.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1523417/http://www.ncbi.nlm.nih.gov/pubmed/16002434http://www.ncbi.nlm.nih.gov/pubmed/22982629http://www.ncbi.nlm.nih.gov/pubmed/21673099http://www.ncbi.nlm.nih.gov/pubmed/23260772http://www.ncbi.nlm.nih.gov/pubmed/23260772http://www.ncbi.nlm.nih.gov/pubmed/24313936http://www.ncbi.nlm.nih.gov/pubmed/24313936http://www.ncbi.nlm.nih.gov/pubmed/23260772http://www.ncbi.nlm.nih.gov/pubmed/23260772http://www.ncbi.nlm.nih.gov/pubmed/21673099http://www.ncbi.nlm.nih.gov/pubmed/22982629http://www.ncbi.nlm.nih.gov/pubmed/16002434http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1523417/
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While typically viewed as the vitamin that aids in
bone ormation, vitamin D’s role in the body has
been shown to be wide ranging. An emerging body
o evidence has demonstrated that inadequate levels
o vitamin D can lead to decreases in muscular per-
ormance and increased recovery times. Athletes andthe elderly in particular may want to monitor their
vitamin D status. Future trials should look to inves-
tigate these effects in emales, as the present research
has been conducted solely in healthy, t males.
Frequently asked questionsSupplementation vs. Food vs. Sunlight: How should I get my vitamin D?
Tere are many options to ensure adequate intake o
vitamin D. Vitamin D comes in two avors: D 3, mostly
ound in animals, and D 2, the orm typically seen in
non-animal sources. Certain high vitamin D oods can
be used to help de end against vitamin deciency. Fish
like halibut, salmon, trout, mackerel, and sturgeon are
abundant sources o vitamin D 3. Other good options
may include eggs, certain ortied cereals, and ortieddairy products. Sources o D2 include many varieties o
mushrooms, such as portabella and shiitake, and orti-
ed soymilk.
Sometimes ood may not be enough. In these cases, a
moderate supplemental dose o 1,000 to 2,000 IU/day
o D3 may suffice or most people, although at-risk pop-
ulations such as those who cover their skin extensively
or who have very dark pigmentation could warrant
higher doses. Studies have shown 100 IU o additional
vitamin D per day can be expected to increase levels
by about 2.5 nmol/L on average . So, a person with a
starting vitamin D level o 37 nmol/L would need about
1,500 IU/day to bring levels up to 75 nmol/L. Luckily,
D3 tends to be an inexpensive supplement.
Te last option is to harness the internal production o
vitamin D that occurs afer sun exposure. When the
skin is exposed to ultraviolet B radiation (UVB), it sets
into motion a process that produces biologically active
1,25(OH)D, the orm o vitamin D that’s useable to our
cells. Going outside or ve to twenty minutes, two to
three times a week, with at least 5% o skin exposed can
help generate adequate amounts o D3 . Fifeen min-
utes o UVB exposure during the summer in bathing
suit attire (be ore sunscreen application) can produce
10,000 to 20,000 IU o D3 in light-skinned individuals,
while those with darker skin need much longer expo-
sure times. However, as UV radiation rom the sun or
tanning beds is a known carcinogen that plays a role in
the development o skin cancer (especially in those with
very air skin), limiting exposure o unprotected skin
to sunlight would be prudent or some people. Many
actors can affect these sunlight-driven synthesis rates
though, such as higher altitudes, cloudy climate, thick
ozone layers, and skin pigmentation .
What should I know?Te results o this trial demonstrate that low levels o
vitamin D can easily be elevated to a healthy range via
supplementation, and that this may benet muscle
repair and recovery.
Te next step in progressing this line o research would
be to try and replicate these results using a larger sample
size, while ideally including emale participants. I you
believe you may have low vitamin D, get your 25(OH)D
levels assessed by your doctor be ore adding a D3 sup-
plement, as it can interact with some medications. ◆
Oh Vitamin D, what can’t you do? Te answer: quite a
lot actually … although this particular study was prom-
ising or a subset o the population. o discuss the rich
area in between panaceas and snake oil, head over the
to the ERD Facebook orum.
http://www.ncbi.nlm.nih.gov/pubmed/18525006http://www.ncbi.nlm.nih.gov/pubmed/16443061http://www.ncbi.nlm.nih.gov/pubmed/18525006http://www.ncbi.nlm.nih.gov/pubmed/26288575http://www.ncbi.nlm.nih.gov/pubmed/26288575https://www.facebook.com/groups/examineERD/permalink/934703996617505/https://www.facebook.com/groups/examineERD/permalink/934703996617505/http://www.ncbi.nlm.nih.gov/pubmed/26288575http://www.ncbi.nlm.nih.gov/pubmed/26288575http://www.ncbi.nlm.nih.gov/pubmed/18525006http://www.ncbi.nlm.nih.gov/pubmed/16443061http://www.ncbi.nlm.nih.gov/pubmed/18525006
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Not-so-safesupplements
Emergency Department Visitsor Adverse Events Related to
Dietary Supplements
http://www.ncbi.nlm.nih.gov/pubmed/26465986http://www.ncbi.nlm.nih.gov/pubmed/26465986http://www.ncbi.nlm.nih.gov/pubmed/26465986http://www.ncbi.nlm.nih.gov/pubmed/26465986http://www.ncbi.nlm.nih.gov/pubmed/26465986http://www.ncbi.nlm.nih.gov/pubmed/26465986
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IntroductionDietary supplements are sometimes erroneously per-
ceived as inherently healthy. And because o the way
many supplements are advertised, it’s easy to overlook that
improper administration can lead to adverse outcomes.
Te classication o a supplement is dened in
the United States Dietary Supplement Health and
Education Act o 1994 (DSHEA) as a vitamin, miner-
al, herb or botanical, amino acid, and any concentrate,
metabolite, constituent, or extract o these substances.
In the U.S., the Food and Drug Administration (FDA)
is the governing body that oversees the regulation o
dietary supplements. I a supplement has been report-
ed to be causing serious adverse events or reactions,the FDA has the authority to pull it rom the market.
However, no sa ety testing or FDA approval is required
be ore a company can market their supplement. Te
lack o oversight authority given to the FDA has even
drawn the attention o late night talk shows hosts like
John Oliver, who humorously covered the issue in this
You ube video .
Many adults are using one or more supplements to
address illnesses or symptoms, and to maintain or
improve health . Hal o all U.S. adults have report-
ed using at least one supplement in the past 30 days .
welve percent o college students have reported taking
ve or more supplements a week. Now, more than ever,
there are seemingly endless options to choose rom.
Te number o supplement products currently avail-
able on the market is thought to be in excess o 55,000.
Compare that to the mere 4,000 available in 1994, when
DSHEA was passed.
Furthermore, condence in the sa ety and efficacy o
these supplements is very high despite the lack o rigor-
ous oversight by the FDA. A survey conducted by the
trade association, Council or Responsible Nutrition,
ound that “85% o American adults … are condent in
the sa ety, quality and effectiveness o dietary supple-
ments.” An independent survey has echoed these results,
nding that 67.2% o respondents elt extremely or
somewhat condent in supplement efficacy and 70.8%
elt extremely or somewhat condent about their sa ety.
While the majority o Americans trust in their sup-
plements, more than one-third have not told their
physician about using them. Tere are numerous docu-
mented drug-supplement interactions ranging rom the
mild to the severe. Te herb St. John’s Wort is thought
to be able to reduce symptoms in people with mild to
moderate depression. But this ‘natural’ supplement also
has 200 documented major drug interactions , including
some with common depression medication. However,
no good data currently exists to document how com-
mon adverse events related to dietary supplements may
be. Te authors o the present study have used surveil-
lance data to try and ll this knowledge gap.
Due to DSHEA, supplements remain largely unreg-
ulated by the FDA. But dietary supplements are
becoming ever more popular, as about hal o U.S.
adults report using one or more in the past 30 days.
rust in the sa ety and efficacy o these supplements
also remains high. Te authors o this study aimed
to investigate how many annual adverse events are
caused by improper supplement usage.
Who and what was studied?Te researchers looked at 10 years o data (2004-2013) to
estimate the adverse events associated with dietary sup-plements in the United States rom 63 different hospitals.
Te selection o these hospitals was meant to be nation-
ally representative and included locations that had
24-hour emergency departments. rained patient record
abstractors reviewed the reports rom each hospital to
identi y cases where supplements had been implicated
as the likely source o the adverse event. Tese abstrac-
tors have been trained to analyze and compile medical
in ormation contained in patient records.
http://www.gpo.gov/fdsys/pkg/STATUTE-108/pdf/STATUTE-108-Pg4325.pdfhttp://www.gpo.gov/fdsys/pkg/STATUTE-108/pdf/STATUTE-108-Pg4325.pdfhttp://www.fda.gov/Food/DietarySupplements/QADietarySupplements/default.htm#FDA_rolehttps://youtu.be/WA0wKeokWUUhttps://youtu.be/WA0wKeokWUUhttp://www.ncbi.nlm.nih.gov/pubmed/23381623http://www.ncbi.nlm.nih.gov/pubmed/23381623http://www.ncbi.nlm.nih.gov/pubmed/23381623http://www.ncbi.nlm.nih.gov/pubmed/25466950http://www.gao.gov/assets/660/653113.pdfhttp://web.health.gov/dietsupp/final.pdfhttp://www.crnusa.org/prpdfs/CRNPR12-ConsumerSurvey100412.pdfhttp://www.ncbi.nlm.nih.gov/pubmed/23051046http://www.ncbi.nlm.nih.gov/pubmed/23403846http://www.ncbi.nlm.nih.gov/pubmed/23403846http://examine.com/supplements/Hypericum+perforatum/http://www.drugs.com/drug-interactions/st-john-s-wort.htmlhttp://www.drugs.com/drug-interactions/st-john-s-wort.htmlhttp://examine.com/supplements/Hypericum+perforatum/http://www.ncbi.nlm.nih.gov/pubmed/23403846http://www.ncbi.nlm.nih.gov/pubmed/23403846http://www.ncbi.nlm.nih.gov/pubmed/23051046http://www.crnusa.org/prpdfs/CRNPR12-ConsumerSurvey100412.pdfhttp://web.health.gov/dietsupp/final.pdfhttp://www.gao.gov/assets/660/653113.pdfhttp://www.ncbi.nlm.nih.gov/pubmed/25466950http://www.ncbi.nlm.nih.gov/pubmed/23381623http://www.ncbi.nlm.nih.gov/pubmed/23381623http://www.ncbi.nlm.nih.gov/pubmed/23381623https://youtu.be/WA0wKeokWUUhttps://youtu.be/WA0wKeokWUUhttp://www.fda.gov/Food/DietarySupplements/QADietarySupplements/default.htm#FDA_rolehttp://www.gpo.gov/fdsys/pkg/STATUTE-108/pdf/STATUTE-108-Pg4325.pdfhttp://www.gpo.gov/fdsys/pkg/STATUTE-108/pdf/STATUTE-108-Pg4325.pdf
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Cases were scanned or emergency room visits where
the treating clinician had explicitly ascribed dietary
supplements as the root cause o the medical issue. Tis
included herbal or complementary nutritional products
such as botanicals, microbial additives, and amino acids,
in addition to micronutrients like vitamins and minerals.
Products that may typically be classied as ood were
excluded, like energy drinks and herbal tea beverages.
opical herbal items and homeopathic products were
included in the analysis even though they do not all
under the regulatory denition o dietary supplements.
Adverse events were classied as anything causing
adverse or allergic reactions, excess doses, unsu-
pervised ingestion by children, or other events like
choking. Due to the non-standard death registration
practices among different hospitals, cases involving a
mortality were not included, as were any cases involv-
ing intentional sel -harm, drug abuse, therapeutic
ailures, nonadherence, and withdrawal.
Researchers examined patient records rom 2004 to
2013 rom 63 different hospitals. Cases where the
treating clinician had identied a supplement asthe cause o the medical emergency were extracted
rom the dataset. However, deaths associated with or
caused by supplements were not included, as hospi-
tals differ in their practice o registering mortalities.
What were the findings?Some o the major ndings are summarized in Figure
1. Over 3,600 cases were identied within the prede-
termined 10-year period. Te researchers extrapolated
rom these data that the U.S. experienced an average
Figure 1: Supplement safety by the numbers
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o 23,000 supplement-related emergency department
visits per year, with estimates ranging rom 18,600 to
27,400. O these 23,000 emergency room visits, it was
calculated that about 2,150 (9.4%) o these result in
hospitalization. About 88% o these ER visits were
attributed to a single supplement, as opposed to inter-
actions or mixtures o multiple supplements. Te
average age o patients treated or supplement-related
adverse events was 32 years, and the majority o these
cases were emale.
Figure 2 shows age and supplement category related
results. About a quarter o ER visits involved people
between the ages o 20 to 34, but people older than 65
years old were more likely to have a visit that resulted
in hospitalization. O patients above 65 admitted to the
ER, 16% had to be hospitalized. Surprisingly, one-fh
o supplement-related ER visits were due to accidental
ingestion by children. When the data covering unsuper-
vised ingestion o dietary supplements by children was
not included, the researchers ound that the majority
o ER visits (65.9%) were due to herbal or complemen-
tary nutritional products. Te top ve products in this
category included the ollowing: weight loss (25.5%),
energy (10.0%), sexual enhancement (3.4%), cardiovas-
cular health (3.1%), and sleep, sedation, or anxiolysis
(i.e. anti-anxiety) (2.9%). Multivitamins or unspecied
vitamin products were the biggest contributors to ER
visits under the micronutrient product category.
ER visits also varied according to gender and age.
Weight loss and micronutrient supplements dispro-
portionately landed emales in the ER, while sexual
enhancement and bodybuilding products largely affect-
ed males. Among patients younger than our years old
and adults over 65, micronutrients were the number
one cause o emergency department visits. Tis is in
contrast to the other age groups, where herbal and
complementary nutritional products were the biggest
contributor. In people ages ve to 34, weight loss prod-
ucts or energy products were implicated in more than
50% o ER visits. Weight loss products mostly affected
Figure 2: Summary of which types of supplements lead to ER visits by age
Source: Geller AI et al. N Engl J Med. 2015 Oct.
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patients rom 20 to 34 years o age, while the micro-
nutrients iron, calcium, and potassium mostly affected
those older than 65.
About 23,000 people go to the ER or supplement-re-
lated visits every year. Te biggest contributors tothis are herbal or complementary nutritional prod-
ucts like weight loss and energy supplements, which
largely affect people between the ages o ve to 34.
Females are more likely than males to end up in the
ER due to adverse supplement reactions. Tose over
the age o 65 are most at risk or an ER visit due to
micronutrient supplements such as iron, calcium,
and potassium.
What does the study reallytell us?While 23,000 annual supplement-related emergency vis-
its may sound high, this is less than 5% o pharmaceutical
product-related ER visits. However, these ER admittance
rates do not line up with the marketing that has promot-
ed dietary supplements as undamentally healthy. Tat is,
the general public overwhelmingly perceives these prod-
ucts to be sa e and effective, but the present data does not
support this notion (ERD readers excluded. We think
you are all ahead o the curve on this one).
However, it should also be noted that overall incidences
o supplement-related ER visits have remained con-
stant over time. No signicant changes were detected
between 2004 and 2013 when accounting or popu-
lation increases. Te only increase that occurred was
ER visits associated with micronutrient supplements,
which jumped 42.5%, rom 3,212 to 4,578 cases in this
same time rame.
Unlike their highly regulated pharmaceutical coun-
terparts, there are no legal requirements or dietary
supplements to identi y any potential adverse effects or
major drug interactions on their packaging. Te lack o
adequate warning labels may be a contributing actor
to why histories o dietary supplement usage are rarely
obtained by clinicians . Tis can be due to a combina-
tion o clinicians not asking proper patient screening
questions and to a lack