Interpreting negative research – a practitioner toolkit for clinical success

Interpreting Nutrition Research:
A practitioner toolkit for clinical
success

Today’s talk objectives:
• To gain a deep understanding of why nutrition
research often fails to produce expected results
• To understand how to critically review nutrition
research to determine which nutrients really work –
with a focus on brain health
• Understand how failures in research methods help us
to be better clinicians
• Learn how to use this information to ensure success
with your clinical protocols

Part 1:
Why fish oils fail
(according to the research headlines)

Alarming headlines, but
DO FISH OILS REALLY FAIL?
“Do fish oils REALLY keep the brain
young? Study finds 'no evidence' that
omega-3 supplements slow mental
decline”
“Is your omega-3 fish oil
supplement any good - or a load
of old codswallop?”
“Omega-3 supplements do little to
protect you from heart diseases,
says new study”
“The benefits of omega-3
seem fishy”
“Experts cast doubt
on omega-3”
“Insufficient evidence to support
omega-3 as a treatment for depression”
– Cochrane review
“Fish oils are no benefit
for diabetes”

Inconsistencies arising from dietary intervention studies give mixed results and create confusing
messages (Von Schacky 2015; Harris 2015)
 Poor heterogeneity in study designs, background diets, endpoint definitions, and baseline fish or
omega−3 fatty acid intakes cloud meta-analysis outcomes
 Patients recruited regardless of their baseline levels and treated with fixed doses
 Recent RCTs (virtually all of which have been conducted in European or North American cohorts
[low dietary fish intakes]) use relatively low doses (376–850 mg EPA & DHA) which at least partly
explains their failure
 CVD secondary-prevention populations - include many individuals who are already taking multiple
heart medications such as statins, aspirin, and ACE inhibitors, which may obscure the effect of
omega-3 fatty acids
 The inter-individual variability in response to a fixed dose of EPA + DHA has been found to be large,
i.e. to vary up to a factor of 13
 Not all ‘fish oils’ are the same - addressing quality/concentration and purity
 Study design to incorporate use of biomarkers?

Omega-3 dosing – ‘one size fits all?’
 Effects of a single dose of EPA & DHA (3.4 g) taken with
breakfast on the Omega-3 index (n =20)
(Harris et al., 2013)
 40 individuals with a baseline omega-3 index <5%
(black bar) and post treatment (white bar) after a 6-
week intervention with omega-3 EPA & DHA (0·5 g/d)
• The mean omega-3 index increased from 4·37% to
6·80% and inter-individual variability in response was
high (varied by a factor of up to 13 inter-individually)
(Kohler et al. 2010)

We are all biochemically unique – our needs for, production of and
response to omega-3 differs considerably:
Many factors influence how we utilise omega-3 in supplement form, i.e.
o Omega-3 baseline levels
o Body weight, age, gender, etc
 Supplement digestibility/bioavailability [rTG, EE, phospholipids]
 Understanding the dose-response effects of EPA and DHA and ‘condition related’
requirements
o EPA vs DHA – no longer viable to address them simply as ‘omega-3’
 Tissue concentrations of these omega-3 fatty acids may be critical to achieving biological
effects
Increasing omega-3 intake is not the same as increasing omega-3 levels!

The EPA/DHA dilemma
 Although EPA and DHA are both long-chain polyunsaturated fatty acids (PUFAs), the
molecules are often reported to produce biochemical and physiological responses that are
qualitatively and quantitatively different from each other
 The kinetics of EPA and DHA differ between different cell types
 The marked differences between the effects of EPA and DHA indicate that it is an over-
simplification to generalise the effects of omega-3 PUFA on cell function
 It is the EPA in excess of DHA that is the active component in fish oil [treating depression]
Verlengia et al., 2004; Martins 2009; Sublette et al., 2011; Russell & Burgin-Maunder 2012

EPA and DHA utilisation differences
 High DHA intake reduces delta-6-desaturase activity
 Studies often report no increase in DHA levels with pure EPA
supplementation – DHA saturation?
 In some cases [depression/neurodevelopmental disorders] high
DHA supplementation has been shown to worsen health outcomes
 12 week intervention with 1.8 g omega-3 (1.2g EPA + 0.6g
DHA) in young healthy males aged 18-25
 During the washout period, EPA and DHA levels decreased
back to baseline levels, with EPA levels rapidly returned to
baseline levels within 2 weeks of stopping fish oil
supplementation, while serum DHA returned to baseline
levels only by the end of the washout period
Suggests high EPA requirements
Roke & Mutch 2014
Time (weeks)

The unique benefits of pure EPA
EPA (unlike DHA) reduces the pro-inflammatory activity of AA in a number of ways
 EPA is an inhibitor of the enzyme delta-5-desaturase that produces AA
 EPA directly displaces AA from cell membranes
 EPA competes with AA for the enzyme PLA2 necessary to release AA from the membrane
phospholipids
 EPA competes with COX and LOX enzymes to prevent the conversion of AA to its
eicosanoids
As such, studies show that EPA plus DHA oils are less effective at reducing inflammation
than pure EPA oils

BUT - does your fish oil deliver?

 Strength/concentration of the active ingredient
within the total oil volume
 Bioavailability of the omega-3 form used
 Accurate ‘dosing’ – as [mg/kg/day] determined
according to the baseline omega-3 index
For an intervention to be successful you need to raise omega-3 levels and reduce the
inflammatory capacity of omega-6 AA
A combination of factors determine omega-3 intervention success:
TG EE rTG PL

The power of rTG omega-3
Dyerberg et al., 2010 graph shows the % increase in serum EPA+DHA content following 2 weeks of EPA
and DHA supplementation Av. 3.3g per day.
 rTG oil delivered biggest increase in serum lipid content in the lowest volume of oil and
lowest total dose of EPA+DHA (all others delivered 200mg EPA + DHA or more)

Importance of oil concentration
 Higher concentrations increase cellular omega-3 levels more than the same
dose provided at a lower concentration
Brunton and Collins 2007

Importance of dose plus concentration
 Higher dose high concentrations from rTG fish oil increase cellular omega-3
levels up to 5x more than krill oil and 3x more than standard fish oil
Laidlaw et al.,
2014
Comparison of
manufacturer-
recommended
dose of rTG, EE
concentrated
fish oils with Krill
oil (PL) and
salmon oil (TG)

 Subjects (n = 35) were randomly assigned to consume one of four products, in random order,
for a 28-day period, followed by a 4-week washout period
 Subsequent testing of the remaining three products, followed by 4-week washout periods,
continued until each subject had consumed each of the products
Laidlaw et al., 2014
A randomised clinical trial to determine the efficacy of manufacturers’ recommended doses of
omega-3 fatty acids from different sources in facilitating cardiovascular disease risk reduction

Part 2 : Nutrition research and the
brain

Brain studies are extremely difficult to conduct
Why??

Focus, attention and cognitive
performance

Omega-3 increases blood flow to the brain supplying oxygen and fuel, essential for
neurotransmitter production and function, memory, learning, cognition, and brain and
neurone cell structure
Benefits restricted to those with sub-optimal omega-3
intake – surprised?!

DHA is for memory and
learning if intake is low
EPA in excess of DHA for
cognitive performance, in
particular attention
Total omega-
3 needed to
be >400mg
‘DHA only’
often resulted
in detrimental
effects to
cognition
Many benefits of DHA
associated with increased
blood flow
>1month intervention needed
for benefits to be seen

Amino Acids. 2000;19(3-4):635-42.
A taurine and caffeine-containing drink stimulates cognitive performance and well-being.
Seidl R1, Peyrl A, Nicham R, Hauser E.
The findings clearly indicate that the mixture of three key ingredients of Red Bull Energy
Drink used in the study (caffeine, taurine, glucuronolactone) have positive effects upon
human mental performance and mood.
Psychopharmacology (Berl). 2001 Nov;158(3):322-8.
An evaluation of a caffeinated taurine drink on mood, memory and information processing
in healthy volunteers without caffeine abstinence.
Warburton DM1, Bersellini E, Sweeney E.
RESULTS:
In both studies, the caffeinated, taurine-containing beverage produced improved attention
and verbal reasoning, in comparison with a sugar-free and the sugar-containing drinks. The
improvement with the verum drink was manifested in terms of both the mean number
correct and the reaction times. Another important finding was the reduction in the variability
of attentional performance between participants.

• L-Theanine + taurine calm and focus the mind via GABA and
dopamine activation
• Caffeine stimulates the brain, increasing energy, alertness and
information processing speed
• L-Theanine + caffeine enhance focus and reduce distractibility

Omega-3
• EPA and DHA are essential for mood-regulating
neurotransmitter production and function
• EPA reduces inflammation, which directly attacks and
degrades serotonin, leading to low mood and depression

Reproducing ‘bad’ science http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD004692.pub4/full

Depression
Sublette 2011 Meta-analysis
http://www.ncbi.nlm.nih.gov/pubmed/21939614

Grosso et
al., 2014
http://ww
w.ncbi.nlm.
nih.gov/pu
bmed/2480
5797

Serotonin
TDO
IDO
IFN-g, TNF-a,
IL-1, IL-6
Kynurenine
Quinolinic acid
NMDA agonist
3-Hydroxykynurenine
+
+
+
KMO
5-HTP
Neuronal damage Depression
Kynurenic acid
NMDA antagonist
NMDA receptor
Tryptophan
Cortisol
IDO
Sleep disturbance
IFN-g, TNF-a,
IL-1, IL-6
+

Serotonin
TDO
IDO
IFN-g, TNF-a,
IL-1, IL-6
Kynurenine
Quinolinic acid
NMDA agonist
3-Hydroxykynurenine
+
+
+
KMO
5-HTP
Kynurenic acid
NMDA antagonist
NMDA receptor
Tryptophan
Cortisol
IDO
Sleep disturbance
IFN-g, TNF-a,
IL-1, IL-6
+
EPA

Serotonin
Kynurenine
Quinolinic acid
NMDA agonist
3-Hydroxykynurenine
KMO
5-HTP
Kynurenic acid
NMDA antagonist
NMDA receptor
Tryptophan
Sleep disturbance
EPA

Serotonin
Kynurenine
Quinolinic acid
NMDA agonist
3-Hydroxykynurenine
KMO
5-HTP
Elevated Mood
Kynurenic acid
NMDA antagonist
NMDA receptor
Tryptophan
Regulated sleep
EPA

EPA and DHA utilisation differences
Roke & Mutch 2014
Time (weeks)
• Half the DHA dose = same enrichment and longer lasting elevation
within the cells of the brain compared with EPA
• Conditions requiring EPA MUST dose with excess EPA at least 3:1

Vitamin D
• acts as a mood stabiliser
• low levels increase risk of anxiety and depression
• Studies show mixed results (in some case worsening) in
managing depression

Should vitamin D supplements be recommended to
prevent chronic diseases? BMJ 2015;
350 doi: http://dx.doi.org/10.1136/bmj.h321
Bottom line:
Do not recommend vitamin D supplements to prevent chronic disease
because clear evidence of benefit does not currently exist and adverse
effects cannot be excluded

‘all studies without flaws demonstrated a statistically significant
improvement in depression with Vitamin D supplements…… the
effect size was comparable to that of anti-depressant medication.’
NB: Only effective in those who are deficient AND dose given must
result in a changed serum Vit D level
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4011048/

BUT almost all studies of omega-3 use to boost
cognitive function have shown little or no
benefits – why?
• Study population
• Dose given
• EPA or DHA
• Cognitive tests chosen
• Duration of intervention time
• Is it already too late?

B vitamins
• B1,2,3 and 5
– support mitochondria of the brain and CNS
– aid detoxification pathways
– reduce inflammation
• B6, B12 and folate in their most active and bioavailable forms
– homocysteine recycling
– elevated levels = significant risk factor for age-related cognitive decline

Brain studies are extremely difficult to conduct
Why??
What's the optimal
length of time for
this intervention
Which nutrients should
be used? Single, isolated
nutrients or blends….
What dose do we
give?
What's the right
population for this study
and intervention?
What else might be affecting
the participants’ brains?

Part 3 : translating this into
successful personalised nutrition
and clinical practice

There are still numerous gaping holes in
research which, for now, prevent firm
conclusions being made.
So - what can we learn from the negative
studies and what we can do in clinic to
ensure therapeutic success?

1: Choosing the right dose for EACH participant
It is increasingly apparent that the right dose for the right person is vital in
ensuring study success.
Before the study even begins we must know each individual participant’s baseline
level of the nutrient being investigated and, where possible, dose according to
pre-determined and validated dosing guidelines.
Translated into a practical clinical setting, testing (genotype and phenotype)
is key to understand biochemical individuality and whether or not your client
actually needs, and will indeed benefit from, a specific nutrient intervention.
Using established dosing guidelines where available - such as that calculated using
the omega-3 index biomarker and body weight – can at least help us to achieve
health-protective levels of a nutrient in our clients, from which we can try to
establish the therapeutic dose.

2: What plasma or cellular levels need to be reached in order to have a
clinical effect in this specific area of health?
Whilst there is still no known ‘ideal’ plasma level of each and every nutrient for each and
every condition, the severity of deficiency tells us whether the nutrient in question is
likely to contribute to clinical results and how high we should commence the dose.
Remember - the lower the baseline levels (and the bigger/heavier they are), the more a
person will need to take in order to raise their plasma levels to that associated with
health benefits.
Those with the lowest baseline levels are likely to have the highest level of dysfunction.
Raising their levels closer to ‘ideal’ should help them to notice a tangible benefit to their
health. People with closer-to-adequate plasma levels may still benefit but the scale of
improvement is likely to be smaller and may therefore go unnoticed.
Using current levels and dosing between known therapeutic doses and upper tolerable
limits will help to get quicker positive results.

3: How does the body prioritise which clinical benefit it needs most?
If the client or study participant has more than one condition with high
requirements of this particular nutrient how do we determine how the body
will prioritise distribution?
If you have 3 major organ systems all requiring additional support and you give a
relatively modest dose of a nutrient which is known to contribute to all of these
systems, then perhaps most, or all, of that nutrient gets shuttled to the organ with
the greatest need.
How do we dose correctly if more than one system is crying out for the
nutrient?
We need to look at the body as a whole when designing single nutrient studies for
single clinical benefits to determine if an endogenous competition might be the
reason for our negative outcome!

4: One nutrient alone does not always have the power to significantly
benefit one area of health
This is really key and is the reason humans have evolved to eat food, not
nutrients.
Our organs and systems are extremely complex and it is impossible to isolate
just one nutrient as being ‘most’ important for function.
It is likely that looking at the overall benefits of a combination of nutrients is
much more useful than looking at each nutrient’s impact alone.
The positive research for specific diets, for example the MIND diet in supporting
healthy cognitive ageing and the DASH diet for heart and metabolic health, is
much better established than most isolated nutrients.

5: Choose the right participants for this study and choose what
specific outcome suits them best?
If you want to be sure your client, or participant, will respond it is clear you
need to
a) choose a nutrient that they actually need
b) use a population who require the targeted benefit.
There’s no point in targeting someone with depression knowing it has
inflammatory roots and choosing to give them glucosamine to treat non-
existent joint pain and then expecting their joint pain to improve!
In the AERDS2 study it is clear, for a number of reasons, that both omega-3 and the population
chosen were not ideal for the desired outcomes to be tested. The participants were not
malnourished, poorly educated or financially disadvantaged - all factors known to correlate with
fish consumption and increased risk of brain function decline.

6 and 7: When and for how long is optimal for this intervention?
Understanding what factor, and at which point in the life cycle, has the ability
to impact on long-term health outcomes is vital in determining the likelihood
of positive outcomes from clinical studies.
If the ‘damage’ has already been done, an intervention may only prevent
worsening of symptoms, rather than result in benefits and…
If the intervention is not given for the optimal length of time it may never
reach significance.
The order and length of interventions we choose to use in our day-to-day
clinics will determine if, and to what extent, a client will respond.

Creating a plan of action:
Where do I start?

1. Which symptoms
and systems are of
most concern to you
AND your client?
2. What
strategies
can you
implement?
3. What
impact could
this have?
5. So where
do I start?
4. Does this
change the
benefit
gained or
perceived?

Choosing the right intervention:
Questions you need to ask

Is the intervention you
choose right for the
client?
Is the nutrient right at this
time in their treatment
plan?
What else might be
affecting whether
or not this nutrient
could be effective?
What other
demands might
there be in the
body for this
nutrient?
What are their current
levels of this nutrient?
What other nutrients are needed
to make sure this nutrient can
work in the desired area?
?
Start here:

Planning for success:
factors to consider

• Choose an optimal starting dose
• Limit changes to other factors that could affect positive
outcomes or reduce the likelihood of noticing a benefit
• Make sure the client can be and is committed to compliance
• Don’t overwhelm the system with single nutrient
interventions; optimise the baseline diet and lifestyle and
target systems, not symptoms, initially
• Introduce new nutrients slowly, review regularly, and
routinely stop intake to make sure the nutrients chosen are
individually beneficial and contributing significantly at that
point in the protocol
• Plot it out!

Planning how the whole process of support might look,
including:
what to give and when, relative to the specific organ system and
outcome of greatest concern, from the outset of treatment,
together with recognising the importance of compliance to
certain interventions beyond just a few months,
as well as not being afraid to revisit treatment options at
different times in a treatment plan
is essential to creating a successful support plan.

Pharmepa® RESTORE & MAINTAIN™
The fastest, most effective, clinical omega-3
intervention

‘RESTORE’
pure EPA
‘MAINTAIN’
EPA, DHA and GLA
Minimum 3-6 months
Therapeutic role of Pharmepa®
RESTORE & MAINTAIN™
 AA to EPA ratio
 Inflammatory regulation
 Symptoms of inflammatory illness
 Optimum brain, cell, heart, immune
and CNS function
 Optimum wellbeing
 Omega-3 index
 AA to EPA ratio
 Long-term general and cellular health
 Heart, brain and eye health
 Reduce risk of chronic illness and help
protect against inflammatory disease

Sophie Tully
BSc MSc DipPT
Nutrition Education Manager
sophiet@igennus.com
07908368173
http://igennus.com/professionals/

References
Bays HE, Ballantyne CM, Braeckman RA, Stirtan WG, Soni PN: Icosapent ethyl, a pure ethyl ester of eicosapentaenoic acid: effects on circulating markers of inflammation from the
MARINE and ANCHOR studies. American journal of cardiovascular drugs : drugs, devices, and other interventions 2013, 13:37-46.
Hull MA, Sandell AC, Montgomery AA, Logan RF, Clifford GM, Rees CJ, Loadman PM, Whitham D: A randomized controlled trial of eicosapentaenoic acid and/or aspirin for colorectal
adenoma prevention during colonoscopic surveillance in the NHS Bowel Cancer Screening Programme (The seAFOod Polyp Prevention Trial): study protocol for a randomized
controlled trial. Trials 2013, 14:237.
Flock MR, Skulas-Ray AC, Harris WS, Etherton TD, Fleming JA, Kris-Etherton PM: Determinants of erythrocyte omega-3 fatty acid content in response to fish oil supplementation: a
dose-response randomized controlled trial. Journal of the American Heart Association 2013, 2:e000513.
Harris WS: The omega-3 index: clinical utility for therapeutic intervention. Current cardiology reports 2010, 12:503-508.
Harris WS: Pushing the limits with omega-3 fatty acids. Trends in cardiovascular medicine 2015.
Harris WS, Von Schacky C: The Omega-3 Index: a new risk factor for death from coronary heart disease? Preventive medicine 2004, 39:212-220.
Harris WS, Varvel SA, Pottala JV, Warnick GR, McConnell JP: Comparative effects of an acute dose of fish oil on omega-3 fatty acid levels in red blood cells versus plasma: implications
for clinical utility. Journal of clinical lipidology 2013, 7:433-440.
Kohler A, Bittner D, Low A, von Schacky C: Effects of a convenience drink fortified with n-3 fatty acids on the n-3 index. The British journal of nutrition 2010, 104:729-736.
Martins JG: EPA but not DHA appears to be responsible for the efficacy of omega-3 long chain polyunsaturated fatty acid supplementation in depression: evidence from a meta-
analysis of randomized controlled trials. Journal of the American College of Nutrition 2009, 28:525-542.
Puri BK, Leavitt BR, Hayden MR, Ross CA, Rosenblatt A, Greenamyre JT, Hersch S, Vaddadi KS, Sword A, Horrobin DF, et al: Ethyl-EPA in Huntington disease: a double-blind,
randomized, placebo-controlled trial. Neurology 2005, 65:286-292.
Puri BK, Bydder GM, Counsell SJ, Corridan BJ, Richardson AJ, Hajnal JV, Appel C, McKee HM, Vaddadi KS, Horrobin DF: MRI and neuropsychological improvement in Huntington
disease following ethyl-EPA treatment. Neuroreport 2002, 13:123-126.
Russell FD, Burgin-Maunder CS: Distinguishing health benefits of eicosapentaenoic and docosahexaenoic acids. Marine drugs 2012, 10:2535-2559.
Sublette ME, Ellis SP, Geant AL, Mann JJ: Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. The Journal of clinical psychiatry 2011, 72:1577-
1584.
Surette ME: The science behind dietary omega-3 fatty acids. CMAJ : Canadian Medical Association journal = journal de l'Association medicale Canadienne 2008, 178:177-180.
Verlengia R, Gorjao R, Kanunfre CC, Bordin S, de Lima TM, Martins EF, Newsholme P, Curi R: Effects of EPA and DHA on proliferation, cytokine production, and gene expression in Raji
cells. Lipids 2004, 39:857-864.

Interpreting negative research – a practitioner toolkit for clinical success

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