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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.


18/4818

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?

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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


33/4833

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


34/4834

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


35/4835

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.


36/4836

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

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