salvia, a sacred story telling - nexira.com white paper cognivia nexira.pdf · 1 nexira -...
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During all his life, human
needs to integrate
information, adapt his
behavior to situation and
people, and acquire
knowledge and skills.
Those processes are achieved by brain using
specific tools, known as cognitive functions.
There are six cognitive functions which are
deeply interconnected, interdependent and
cannot work alone to achieve an intellectual
task.
These six cognitive functions are divided into
two levels:
Low-level cognitive processes:
Gnosis allows to recognize and identify
what our senses feel (e.g. sight, hearing, taste,
sense of smell and touch).
Praxis coordinates different part of our
body to perform a motor task (for example to
run, to draw, to dress, to cook, etc.)
Language is a cognitive function which
implicates comprehension and expression. It
includes both types of support: oral and
written (e.g. listen, discuss, read and write).
High-level cognitive processes:
Attention can be selective (to be focused on
only one thing e.g. phone call in a middle of
open plan office), sustained (to be focused for
a long time e.g. attend to a lesson) or divided
(to be focused on different things in the same
time e.g. attend to a lesson and write notes).
Memory can be divided in two groups:
The working memory implicates both short
term memory and manipulation to achieve a
mental task, such as mental calculation. Short
term memory has a restricted capacity. During
a short period of time, it stores data, used for
instant interpretation.
The long-term memory allows to save data
and recall them after a period of time. For
example, remind mother’s birthday, last diner
composition, etc.
Executive function is probably the most
complex and also the most interdependent
with other cognitive functions. It describes
adaptation (such as behavior) when you are
facing to a new or unknown situation, in
opposite with used and regular situation.
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Many intellectual tasks require
executive function: to plan, to
determine a strategy, to
change our mind, to adapt
ourselves, to work in a team, to
inhibit instinctive reaction, self-monitoring,
etc. For example, how to find a new road the
morning on the way to work, when an accident
happens.
All cognitive functions work in combination
with other(s), in a coordinate manner. More
specifically, Attention, Working memory and
Long-term memory are deeply connected to
achieve an intellectual task (as well as
Executive function).
Nowadays, information are going faster than
ever. We are constantly solicited by an
uninterrupted flow of data that we have to
integrate, treat and memorize. Our cognitive
functions, and likely more high-level processes,
are endlessly recruited and challenged.
In this context, try to extend Long-term
memory (and the recall process), improve or
facilitate Attention and Working memory, is an
interesting approach to adapt and perform in
modern life.
Who is concerned by cognitive
performance?
For healthy persons, exercising and having a
balanced nutrition helps to remain healthy.
However, having a healthy lifestyle could be
challenging. This is why consumers turn to
supplements market.
With the number of people over 60 expected
to double between 2000 and 2050 (WHO,
2017), concerns over cognitive health is
growing worldwide. Dementia is the first fear
in older adults who are a huge audience for
cognitive health products. However, their
cognitive disorders, if classified in age-related
decline, are out of the field of supplements.
In our fast moving society, a growing demand
exists from active people who want to remain
mentally performant and competitive. They
are concerned of their memory in the office or
their concentration on the sports pitch.
Supplements supporting cognitive health can
benefit to all people, from millennials to baby
boomers. Sports people use them to remain
concentrate while practicing. Older people
want to stay mentally sharp (for 94% of adults
over 50 years old, staying mentally sharp is
“everything they need” (AAARP, 2011)). 20%
young people, such as students, are using
psychic tonics to enhance apprenticeship
during exams (Passeport Santé, 2016). Finally,
working persons consume cognitive
supplements to help them staying active and
performant.
The booming cognitive market
According to Innova, between 2011 and 2015,
the cognitive market incredibly increased:
+235% on the Supplements category and
+113% on the Food & Beverage category (in
terms of new product launches)! However, on
the Food & Beverage market, cognitive
ingredients still represent a minority with less
than 1% of the NPL. Mainly used in
supplements, cognitive health is a booming
category (11 to 13% of the NPL) and has
reached $2.7 billion in 2015 (Euromonitor
International, 2016)
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Consumers are mainly looking for benefits on
memory (72%): this positioning represents
50% of the sales. Secondly, they seek to
maintain healthy brain functions (59%),
prevent memory loss (57%) and help with
concentration (55%). Finally, focus is seeking
by 48% consumers.
General concern also exists over a lack of sleep,
stress, mood which can affect the cognitive
health.
In the USA, the market for cognitive and brain
supplements is represented by three main
ingredients: fish & animal oils, multivitamins
and Ginkgo biloba (Nutrition Business Journal).
Vegetable products benefit from a more
natural and healthier image than those from
animals. This vegetable trend is true both in
Food & Beverage and in Supplement markets.
On the supplement market, the botanical and
herbal category is growing much faster than
total supplements. In 2016, this category
represents 16% of the new product launches
(Innova, 2016).
Plant-based product is a growing trend in the
supplement industry and begins to appear on
the cognitive category.
According to Innova, in 2016, 4.5% more
botanical and herbal supplements claiming to
promote cognitive health were launched
compared to 2015. This means that consumers’
needs on cognitive plant-based products are
not satisfied yet.
Salvia, a sacred story telling
Sage, or Salvia which means “save” or “heal”
in Latin, belongs to the Lamiaceae family.
Garden Sage is also called the sacred grass: it's
not a surprise that its 900 species are used
throughout the world since time immemorial.
Salvia is considered as one of the oldest
cultivated herbs. Historically, Sage was used in
food and by traditional medicines in Europe
and China. Previously called Salvia salvatrix,
Sage is well-known for its health benefits.
Today, Nexira has chosen the best varieties of
Sages that have a synergistic effect to create a
unique and innovative ingredient.
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What is Cognivia™?
Cognivia™ is a water-dispersible powder,
suitable for numerous dietary supplements
applications.
Cognivia™ is the first organic
ingredient to combine two
species of Sage: Spanish Sage
(Salvia lavandulifolia) and
Garden Sage (Salvia officinalis).
To develop this unique
ingredient, Nexira worked with
different parts of the herb.
First, the essential oil is extracted from Salvia
lavandulifolia. For many years, Nexira has
developed an expertise in micro-encapsulation
with acacia gum. This know-how, applied to
organic Spanish Sage essential oil with
Fibregum™ Bio, insures a protection from
oxidation and drying process. This process also
enhances the powder water dispersibility.
On the other side, the organic Salvia officinalis
provides an aqueous leaf extract.
These two sage species have a synergistic
effect and can help consumers to improve
naturally their cognitive health.
Cognivia™ is a natural and safe ingredient with
a full traceability control.
Cognivia™, an innovative natural & organic
phytoingredient for cognitive performance
Clinical studies with Sage
Most in vivo trials were done using Salvia
officinalis as an aqueous, ethanolic or hydro-
ethanolic extract and sometimes with the
essential oil. It was demonstrated on animal
model that these extracts have two actions.
First, they show an inhibitory activity on
acetylcholine esterase. Secondly, they limit the
noxious effect of oxidative stress. The result is
an improvement of the rodent memory
process. Negative effect of the chemical agents
used to induce amnesia or neurodegeneration
is also limited.
Clinical studies use common and recognized
tests to measure the quality of memory and
cognitive performance:
Immediate word recall: 15 common words
are presented one second each to the
participants. Right after they have to write
down as many words as possible.
Delayed word recall: the participants are
tested 20 minutes after the words have been
presented. Once again they have to write down
as many right words as possible.
Delayed word recognition: the participants
are presented with 15 words from an original
list, plus 15 novel distractor words. They
answer yes or no as to whether each word was
in the original word list. Correctness and speed
are measured.
Delayed picture recognition task: the
participants are presented with the 15 original
pictures, plus 15 distractors. They answer yes
or no as to whether each picture was one of
those presented earlier. Correctness and speed
are measured.
Spatial working memory test: participants
are presented a pictorial representation of a
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house with some of its windows illuminated.
Other presentations of the house are then
presented with only one lighted window. The
participants have to answer as quickly as
possible whether yes or no the window was
already lighted in the original presentation.
Numeric working memory: the participants
are presented five digits. A series of 30 digits
are then presented and the participant have to
answer by yes or no whether the digit was in
the original series.
Digit vigilance task: the participants have to
press “yes” every time a target digit appears
among series of digits on the screen. Accuracy
and speed are measured.
Serial substraction task: the participants
have to count backwards during two minutes
from a given number as fast and accurately as
possible. In this case the numbers they have to
serially substract were either three (3) or seven
(7).
Simple reaction time: the participants have
to press the “yes” button as fast as possible
each time it is presented on a screen.
Stroop color word task: words describing
one of four colors are presented in different
colored fonts. The participants have to click on
color panels corresponding to the color font
and without being confused with the color
written down.
Perceived Alertness : using the Bond-Ladder
mood scale
Five recent clinical studies, using these
cognitive measures, have established the
efficiency of Salvia lavandulifolia essential oil
(E.O.) and Salvia officinalis leaf after only one
intake.
Three studies focus on Salvia lavandulifolia
essential oil:
In 2003, Tildesley and his team established in
two trials that the acute ingestion of 50 µL and
100 µL of Salvia lavandulifolia essential oil
enhanced the memory process of healthy
young adults. 50 µL was the most efficient.
The test used was part of the Cognitive Drug
Research (CDR) computerized assessment
battery. The trials demonstrated an impressive
improvement among young healthy adults in
immediate and delayed word recall at 1 and
2,5h after ingestion.
In 2005, Tildesley and al. went further with a
more exhaustive tailored version of the CDR
using 25 µL and 50 µL of EO. They measured
subjective mood testing and serial subtraction
tasks. Once again they tested healthy young
adults. They confirmed that the essential oil
improved the memory of the participants
starting at 25 µL even though 50 µL is the most
efficient intake.
It appeared that their mental mathematical
skills increased and volunteers felt more alert.
Finally, Kennedy and al. in 2011 used other
batteries of tests: Computerized Mental
Performance Assessment System (COMPASS)
and Cognitive Demand Battery (CDB). The
results confirmed the previous studies
ingesting 50 µL on healthy young adults. The
participants improved their score at the
memory tests and felt more alert.
These studies on Salvia lavandulifolia
essential oil indicate that the effects on
memory come quickly and seem to last during
several hours on alertness and mental skills.
Salvia officinalis leaves, whole dried or
extracted, were also studied:
Kennedy and his team in 2006 demonstrated
that the ingestion of dried leaf increased the
cognitive performance of healthy young
participants using the Defined Intensity
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Stressor Simulation (DISS) computerized
battery. These effects were also confirmed by
participants who felt more alert.
Finally, Scholey et al., in 2008, demonstrated
that the activity of a hydro-ethanolic extract of
S. officinalis was efficient among older
participants (average of 73 years old). Using
several tasks from the CDR they established
that different quantities of leaf extract
increased cognitive performance and improved
the memory of the participants. Thus
demonstrating that S. officinalis turns out to
be efficient for adult young and old.
All those five clinical studies (table1)
demonstrated and confirmed several times the
benefits of Spanish sage essential oil and
Garden sage leaves, on cognitive functions
notably Attention, Working memory, Long-
term (secondary) memory and Executive
function. Those benefits has been highlighted
on young persons, few hours after only one
intake. Those botanical sources represent a
really interesting opportunity for healthy and
active people looking for an improvement of
their cognitive functions.
Publication Product tested Use level Participants Significant and noticeable effects of Sage
Tildesley and al. 2003
S. lavandulifolia essential oil Or Placebo
50 µL, 100 µL and 150 µL
(1 and 2.5 hours after a single
intake)
Group 1 of 20 young healthy adults (av.: 19 y.o) Group 2 of 24 young healthy adults (av.: 23 y.o)
50 µL was the most efficient intake tested: Immediate word recall score: Grp1: +8 to 13% / Grp2: +12% Delayed word recall score : Grp1: +18%
Tildesley and al. 2005
S. lavandulifolia essential oil Or Placebo
25 or 50 µL (1, 2.5, 4 and 6 hours after a single intake)
24 young healthy adults (av.: 23.2 y.o)
Quality of memory: +8% Secondary memory: +15% Speed of memory: +5 to 6%. Perceived alertness: +11 to 12% Speed of mental calculation: +9 to 15% Accuracy of mental calculation: +26 to 97%
Kennedy and al. 2011
S. lavandulifolia essential oil Or Placebo
50 µL (1 and 4 hours after a single
intake)
Delayed word recall: +22% Simple reaction time: +7% Delayed word recognition: +12% Delayed picture recognition: +7 to 8% Perceived alertness: +5%.
Kennedy and al. 2006
S. officinalis dried leaves Or Placebo
300 or 600 mg (1 and 4 hours after a single
intake)
30 young healthy adults (av.: 24.4 y.o)
600 mg was the most efficient intake tested: Stroop color test: +18% to 36% Perceived alertness: +7 to 11%
Scholey and al. 2008
S. officinalis hydro-ethanolic (70%) extract Or Placebo
167, 333, 666 or 1332 mg
(1, 2.5, 4 and 6 hours after a single intake)
20 older adults (av.: 73 y.o)
333 mg was the most efficient intake tested: Delayed word recognition: +22 to 33% Immediate word recall: +18 to 19% Delayed word recall: +25 to 27%
Table1: Summary of Sage effects on cognitive functions, demonstrated in human studies
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Proprietary study and Cognivia™
benefits
Nexira, in collaboration with Nutribrain
(Adera/INSERM – Bordeaux University –
France) investigated Cognivia™ benefits on
cognitive functions in an in vivo study.
Because of lack of consciousness and language
skills in rodent study, explicit (declarative)
memory is not assessable. Specific models on
mice have been developed to measure
memory function by reducing it into basic
experimental paradigms (Sharma 2010). In
these behavioral paradigms, we can assess
impacts on memory by observation of animal
behavior in response of a two-step process: a
Learning Phase where animal is recording data;
then a Recall Phase (restitution test) where
animal facing to multiple solutions can express
a choice through his behavior and based on
recalled information.
In this study on normal adult mice, we assessed
three ingredients compared to control
conditions:
Cognivia™
Essential oil of Spanish sage (Salvia
lavandulifolia) contained in Cognivia™
Aqueous leaves extract of Garden sage
(Salvia officinalis) contained in
Cognivia™
Single intake:
In this part, we confirmed that a single intake
of Cognivia™ (as well as both sources of sage
individually) has a significant positive impact
on memory in the Y-maze model, 2 hours after
administration. The Y-maze model is more
related to working memory (Sharma 2010).
This observation is in accordance with benefits
observed in clinical studies described above
and regarding both sources of sage included in
Cognivia™.
We can conclude that this association of both
sage remains effective to improve cognitive
function.
Prolonged administration:
In the Morris water maze model, we assessed
administration of our three ingredients during
14 days. The first step is an adaptation to the
environment during 4 days. The learning phase
lasted from the 5th day to the 11th day. It
consists in learning the position of the
submerged platform, ie the localization of the
target quadrant. Then, there are 2 days of
forgetting process, without intervention. The
last step is the restitution test, performed on
the 14th day: the platform is removed and we
observed the mice behavior.
The behavioral paradigm of mice assessed was
the distance travelled in the target quadrant
(where the platform is supposed to be),
compared to the time spent in remaining
quadrants. Higher distance in the target quadrant indicates that the mice haven’t forgotten (or less forgotten) that the platform
is supposed to be there.
Morris water maze is related to working
memory and long-term (reference) memory.
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Graph 1: Morris water maze model: restitution
test after 14 days of intake. Difference of
distance travelled in between the target and
remaining quadrants
After 14 days of intake, Cognivia™ is the only
ingredient to have a significant (p value < 0,01)
positive impact (Graph1). After the same
period of administration, the two Sage sources,
tested individually, haven’t demonstrated any
significant results.
The combination of both sources in Cognivia™
allows a synergistic action responsible of the
improvement of the behavioral paradigm
related to working and long-term memory.
Thanks to these trials results, we concluded
that Cognivia™ represents a specific Sage
based ingredient to improve working and
long-term memory.
Cognivia™ inspired by nature and science:
Clinical studies performed on both sources of Sage included in Cognivia™
Single intake efficacy
(from 1 hour to at least 6 hours after intake)
Improvements of high cognitive level processes
(Attention, Working memory, long-term memory, executive function)
Description of most effective intake in human as proposed in Cognivia™’s recommended level
of use
Proprietary study: in vitro study performed on Cognivia™
Confirmation of single intake efficacy
Demonstration of the specific advantage of Cognivia™ for prolonged intake
Possible claims:
EFSA pending claims on Salvia lanvandulifolia: “Helps maintaining optimal mental well-being,
eg maintaining concentration, attention and memory”
Organic certified
Suitable for young and healthy adults
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Although NEXIRA has used diligent care to ensure that the information provided herein is accurate and up to date, NEXIRA
makes no representation or warranty of the accuracy, reliability, or completeness of the information. This document only
contains scientific and technical information for business to business use. Country or region-specific information should also
be considered when labelling or advertising to final consumers. This publication does not constitute or provide scientific or
medical advice, diagnosis, or treatment and is distributed without warranty of any kind, either expressly or implied. In no
event shall NEXIRA be liable for any damages arising from the reader’s reliance upon, or use of, these materials. The reader
shall be solely responsible for any interpretation or use of the material contained herein.
CDB: Cognitive Demand Battery
CDR: Cognitive Drug Research
COMPASS: Computerized Mental Performance Assessment System
DISS: Defined Intensity Stressor Simulation
EO: Essential Oil
INSERM: Institut National de la Santé Et de la Recherche Médicale
NPD: New Product Development
NPL: New Product Launch
Dinel, A. L., C. Andre, A. Aubert, G. Ferreira, S. Laye, N. Castanon. “Cognitive and emotional alterations are related to hippocampal inflammation in a mouse model of metabolic syndrome”. PLoS One, 2011, 6: e24325. Dinel, A. L., C. Joffre, P. Trifilieff, A. Aubert, A. Foury, P. Le Ruyet, S. Laye. “Inflammation early in life is a vulnerability factor for emotional behavior at adolescence and for lipopolysaccharide-induced spatial memory and neurogenesis alteration at adulthood." J Neuroinflammation, 2014, 11: 155. Eidi M., Eidi A, Bahar M. “Effects of Salvia officinalis L. (sage) leaves on memory retention and its interaction with the cholinergic system in
rats”. Nutrition, 2014, 22, 321–326
El-Kholy, W. M., El-Habibi, E. M., Mousa, A. T. “Oxidative stress in brains of male rats intoxicated with aluminium and the neuromodulating effect of some forms of sage (Salvia officinalis)”. Journal of American Science, 2010, 6(12), 1283-1297. Horvathova, E., A. Srancikova, E. Regendova-Sedlackova, M. Melusova, V. Melus, J. Netriova, Z. Krajcovicova, D. Slamenova, M. Pastorek, K. Kozics. "Enriching the drinking water of rats with extracts of Salvia officinalis and Thymus vulgaris increases their resistance to oxidative stress." Mutagenesis, 2016, 31: 51-59. Jadad, A. R., R. A. Moore, D. Carroll, C. Jenkinson, D. J. Reynolds, D. J. Gavaghan, H. J. McQuay. "Assessing the quality of reports of randomized clinical trials: is blinding necessary?" Control Clin Trials, 1996, 17: 1-12. Kennedy D.O., Pace S., Haskell C., Okello E.J., Milne A., Scholey A.B. “Effects of Cholinesterase Inhibiting Sage (Salvia officinalis) on Mood, Anxiety and Performance on a Psychological Stressor Battery”. Neuropsychopharmacology, 2006, 31, 845–852.
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Nexira - [email protected] - www.nexira.com - 170427
Kennedy D.O., Dodd F.L., Robertson B.C., Okello E.J., Reay J.L., Scholey A.B., Haskell C.F. “Monoterpenoid extract of sage (Salvia lavandulaefolia) with cholinesterase inhibiting properties improves cognitive performance and mood in healthy adults”. J Psychopharmacol, 2011, 25, 1088-100. Kishore, S., Anitha, K., Nettem, S., Pratima, K., Shobana, K. “Evaluation of nootropic activity of Salvia officinalis L. extract using different experimental models in rats”. JGTPS, 2014, 5 (4) - 2115–2117 Miroddi, M., M. Navarra, M. C. Quattropani, F. Calapai, S. Gangemi, G. Calapai. "Systematic review of clinical trials assessing pharmacological properties of Salvia species on memory, cognitive impairment and Alzheimer's disease." CNS Neurosci Ther, 2014, 20: 485-495. Morris, R. "Developments of a water-maze procedure for studying spatial learning in the rat." J Neurosci Methods ,1984, 11: 47-60. Perry, N. S., P. J. Houghton, P. Jenner, A. Keith, E. K. Perry. "Salvia lavandulaefolia essential oil inhibits cholinesterase in vivo." Phytomedicine, 2002, 9: 48-51. Perry, N. S., P. J. Houghton, A. Theobald, P. Jenner, E. K. Perry . "In-vitro inhibition of human erythrocyte acetylcholinesterase by Salvia lavandulaefolia essential oil and constituent terpenes." J Pharm Pharmacol, 2000, 52: 895-902. Savelev, S., E. Okello, N. S. Perry, R. M. Wilkins, E. K. Perry. "Synergistic and antagonistic interactions of anticholinesterase terpenoids in Salvia lavandulaefolia essential oil." Pharmacol Biochem Behav, 2003, 75: 661-668. Scholey A.B., Tildesley N.T.J., Ballard C.G., Wesnes K.A., Tasker A., Perry E.K., Kennedy D.O. “An extract of Salvia (sage) with anticholinesterase properties improves memory and attention in healthy older volunteers”. Psychopharmacology, 2008, 198, 127-139. Sharma, S., Rakoczy, S., Brown-Borg, H. “Assessment of spatial memory in mice”. Life sciences, 2010, 87(17), 521-536. Smach, M. A., Hafsa, J., Charfeddine, B., Dridi, H., Limem, K. “Effects of sage extract on memory performance in mice and acetylcholinesterase activity”. Annales Pharmaceutiques Françaises, 2015, Vol. 73, No. 4, pp. 281-288. Tildesley N.T.J., Kennedy D.O., Perry E.K., Ballard C.G., Wesnes K.A., Scholey A.B. Salvia lavandulaefolia (Spanish Sage) enhances memory in healthy young volunteers. Pharmacology Biochemistry and Behavior, 2003, 75, 669-674.
Tildesley, N. T. J., Kennedy, D. O., Perry, E. K., Ballard, C. G., Wesnes, K. A., & Scholey, A. B. “Positive modulation of mood and cognitive performance following administration of acute doses of Salvia lavandulaefolia essential oil to healthy young volunteers”. Physiology & behavior, 2005, 83(5), 699-709.