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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

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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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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.