DR CHAITHANYAMALALUR is SHIRA

INTRODUCTION
Cognition & cognitive enhancers

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SCOPE OF COGNITIVE ENHANCERS

In health & disease

ETHICAL ISSUES
Treating -vs- Doping
INTRODUCTION
Cognition & cognitive enhancers.

LUHAT IS COGNITION?

Mental process involved in gaining knowledge and comprehension

THINKING KNOWING
REMEMBERING JUDGING

In simple terms:
brain process of acquiring and exploiting knowledge
COGNITIVE
ENHANCER

A neuro-active substance that

elevates individual's cognitive
abilities in a meaningful & sustained
way

NOOTROPIC

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02 i GENERAL APPROACHES
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Enhancing neurotransmission

® (Increased neuronal metabolism: stimulation

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|mprovement of cerebral functions -

memory
NEUROSCIENCE _
LEARNING MEMORY

raul ela ately Implicit memory

Involves information about how

to perform something, it’s
recalled unconsciously

Knowledge of facts - what we know

about places, things and people—and
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Habituation
Sensitization

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LEARNING MEMORY

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Encoding new information

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Frontal lobe

Archiving & retrieval

PROCESS
~ MEMORY
FORMATION

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lasts for seconds or minutes

NMS TM 0) Ce eRe Me Mal Bay

lasts for days to weeks

LONG-TERM MEMORY
once stored, can be recalled up to
Nene mii) ce] Waele

BTM UT Cape eum Te pT siCunl Meer reese itu

change which is called - Synaptic

PROCESS
of MEMORY
FORMATION

Mitogen-activated protein kinases

CAMP response element-binding protein

synapse-specific structural changes

CELLULAR MECHANISMS
~ NEURO-DEGENERATION

Mis-folded, aggregated proteins

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Excito-toxicity

Neuronal injury resulting from excessive glutamate activity in the brain

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MoA — acute stroke and head trauma

CO esti ities

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ROS — ONA damage, peroxidation of membrane lipids and neuronal death
- s« « @ &© & & © @&

COGNITIVE ENHANCERS
Classification and Mech. of action

* Cognitive metabolic enhancers

* Nootropic vitamins
* Nootropic nutirents
RACETAIMS

Piracetam
Aniracetam
Oxiracetam
Pramiracetam
Phenylpiracetam
Nefiracetam
Coluracetam
= PIRACETAM

MECHANISM OF ACTION USE

¢@ 7 ACh activity in the brain * off-label ADHD

treatment
¢ 4 glutamate activity via
AMPA and NMDA receptors

¢ ~ improve membrane
permeability of neurons >
enhances overall neuronal
function
MECHANISM OF ACTION

¢@ derivative of Piracetam
¢ 5x more potent

¢ also stimulates AMPA receptor:

learning & memory encoding
processes

¢ activate D2 and D3 Dopamine

receptors & 5-HT(2a) receptor
involved in Serotonin processing

USE

* effective as an anti-
anxiety and anti-
depression treatment
MECHANISM OF ACTION
¢ Piracetam analogue (30x)

¢ influences both Glutamate and

ACh receptors

¢ ‘ reuptake at ACh receptor sites

as Well as increasing the
efficiency of nerve impulse
channels in the hippocampus >
central role in memory formation
as well as recall

¢@ mental clarity and

¢ also improving critical

thinking skills

@ speed of information
MECHANISM OF ACTION

¢ Not racetam, but similar MoA

¢ 1000 X

¢ high affinity for ACh, AMPA and

NDMA receptors: relate to short-
term and long-term memory

¢ also activates D2 an D3 receptors

& selective Serotonin receptors

¢d Nerve Growth Factor -

maintenance and repair of healthy
brain cells

¢ investigated as a possible
treatment for Alzheimer’s

od Age-Related Memory Loss

¢ depression & anxiety
OS() NEFIRACETAM
MECHANISM OF ACTION USE
¢ Potentiates excitatory ¢ treat apathy and improve
neurotransmission > prolonging motivation in post-stroke
the opening of calcium channels patients
¢ bindsto N-AChr: communication 4 Anti-amnesia effects
in GABAerge, Cholinergic,
monoaminergic and glutamatergic ¢ powerful anxiolytic
successful in the
d ;
¢ highly cytoprotective treatment of clinical
Choline
Alpha-GPC
Citicoline
Centrophenoxine
Choline
citrate/bitartarate
DMAE

Lecithin
Phosphatidylcholine
AChE inhibitors
Galantamine
Huperzine A
GENERAL PRINCIPLES

¢d AChis an excitatory NT

¢ attention, synaptic plasticity,

wakefulness and the reward

system

¢d ‘> cholinergic activity:

improve focus, working
memory, alertness, mental
clarity and performance

1928: Chavany
recovery of cortical function
with cholinergics (hemiplegia)

at first attributed to cerebral

vasodilatation
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¢ water-soluble essential nutrient

¢ structural integrity and signaling

roles for cell membranes

¢ cholinergic neurotransmission
{ACh synthesis)

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¢ treat apathy and improve

motivation in post-stroke
patients

¢@ Anti-amnesia effects

¢ powerful anxiolytic

¢ successful in the treatment

of clinical depression

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ALPHA- GPC
(Alpha Giycerylphosphoryicholine)

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¢@ occurs naturally in the brain, human
breast milk (associated with T1Q in
breast fed babies)
¢ highest bio-availability of Choline

¢@ readily crosses the blood-brain barrier

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¢@ intermediary in the conversion of choline

into phosphatidylcholine in the liver

¢ 7 availability of choline in the brain by

freeing up quantities of choline

¢@ preservation of cardiolipin and

sphingomyelin

@ Citicoline decreases phospholipase

stimulation > less hydroxyl radicals

isis

¢@ approved for treatment in cases

of head trauma, stroke

d neurodegenerative diseases
approved for the treatment of Alzheimer's disease

mild to moderate vascular dementia and Alzheimer's

mild to moderate dementia of the Alzheimer's type and

dementia due to Parkinson's disease

approved for the treatment of Alzheimer's disease

Ai eS) ears

Unifiram
Ampalex (CX-516)
HIMIPA-HINES

GENERAL PRINCIPLES

¢ activate glutamatergic AMPA r: promote

alertness, ‘> attention span and
memory

¢ potential treatment:
Alzheimer's disease,

Parkinson's disease,
schizophrenia,
treatment-resistant
depression,
neurological disorders
such as Attention
Deficit Hyperactivity
Disorder (ADHD)

d¢ ‘ synaptic communication: promote

growth of neurons and the formation of
long term memories

25
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SUNIFIRAM

MECHANISM OF ACTION
¢ Sunifiram activates AMPA-
mediated neurotransmission

¢ It enhances LTP

¢ improves cognitive deficits

via CaM kinase || and protein
kinase C activation

¢ 7 release of ACh in the

cerebral cortex

USE

¢ alleviate symptoms of
ADHD

26
SIMART DRUGS
SIMART DRUGS

GENERAL PRINCIPLES

Smart drugs: interact with natural neurochemicals, such as

hormones, enzymes and neurotransmitters

benefit in cognitive disorders like ADHD, anxiety, Alzheimer’s

and Parkinson's.

PMR es | ener sl eres ae] meat Mala ala emer oe

memory, and focus.

considered separately — they may use stimulatory mechanisms

of action and may carry a greater risk of side effects
MODAFINIL ~!
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MECHANISM OF ACTION

Eugeroic: wakefulness promoting

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CNS to promote wakefulness

~ al-adrenergic receptor agonist

USE

treatment of narcolepsy
ADHD

Shift work sleep disorder

obstructive sleep apnea
potentially useful: depression,
bipolar, opiate and cocaine
dependence, Parkinson's,
schizophrenia and disease-
related fatigue

seasonal affective disorder

Volo ae

Ce

Ca

8] Sl bey

“Modafinil improves some aspects of working

memory, such as digit span, digit manipulation and
pattern recognition memory, but the results
related to spatial memory, executive function and
attention are equivocal”

- Turner OC, Robbins TW, Clark L, Aron AR, Dowson J, Sahakian B!

(2003). "Cognitive enhancing effects of modafinil in healthy
Volunteers". Psychopharmacology (Berl.) 165 (3): 260-9.
doi:10.1007 /s00213-002-1250-8. PMID 12417966.
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Prodrug of modafinil Narcolepsy

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5

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Indirect dopamine r agonist:

inhibits reuptake

Ss

narcolepsy and shift work sleep

lees

adjuvant therapy for obstructive

sleep apnea

Schizophrenia (neg sym)

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Jet lag
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MECHANISM OF ACTION

Prevents re-uptake of dopamine & NE

Also a SHT1A receptor agonist
Tue em tem inte ae) mall eel ea)

the prefrontal cortex: impulse control,

motivation, and mental clarity

8 )s1 5
ADHD

Off-label: treatment-resistant
eter] OT) (os
depressive disorder
GABHERGICS

GENERAL CONSIDERATIONS

¢ any compounds which interact with GABAergic neurons in the

brain

¢ GABA: natural inhibitory effect on stress responses in the

central nervous system

J
Ho e
PHENIBUT “0H

(B-phenyl-y-aminobutyric acid)

MECHANISM OF ACTION USE

d derivative of GABA ¢ post-traumatic stress
disorder, anxiety, and
d GABA cannot cross BBB insomnia

¢ Phenibut: fully bioavailable

¢ Directly stimulate both GABA-A

and 8 receptors non-selectively

35
DOPAMINERGICS

L-Dopa
Theanine
Suntheanine
Rasagiline
Deprenyl

36
DOPHMINERGICS

GENERAL CONSIDERATIONS

¢ Regulate metabolism and synthesis of dopamine

¢@ are often direct pre-cursors to dopamine

¢ used to treat severe dopamine deficiency disorders like

Parkinson’s disease, schizophrenia, and bipolar disorder

¢@ May also be effective treatments against symptoms of ADHD,

anxiety, and depression

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SULBUTIAMINE —s0, 2 “UA.

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MECHANISM OF ACTION

¢ Synthetic derivative of thiamine

¢ Crosses BBB > thiamine

¢ increases the levels of thiamine and

thiamine phosphate esters in the
brain

¢ improves memory: potentiation of

cholinergic, dopaminergic, and
glutamatergic transmission

USE

¢ Asthenia: chronic
fatigue of cerebral
origin

¢ improves memory in
schizophrenics and AD
x RASAGILINE

oO

MECHANISM OF ACTION

¢ Irreversible inhibitor of monoamine

oxidase >T Dopamine

¢@ neuro-protective and neuro-rescuing

property: effect on the mitochondria
> interferes with and blocks apoptosis
in neurodegenerative disorders

USE

¢@ Monotherapy in Early PD

¢@ Adjunct Therapy in
Advanced PD

¢ ~ treatment of Restless
Legs Syndrome, AD
‘. RASAGILINE

MECHANISM OF ACTION

@ Irreversible inhibitor of
monoamine oxidase > TD

¢@ neuro-protective and neuro-

rescuing property: effect on

the mitochondria — interferes

with and blocks apoptosis in

neurodegenerative disorders

SELEGILINE

USE

¢@ Monotherapy in Early PD

¢@ Adjunct Therapy in
Advanced PD

¢ ~ treatment of Restless
Legs Syndrome, AD
COGNITIVE
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Vinpocetine

ENHANCERS
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ENHANCERS

GENERAL CONSIDERATIONS
~) [Improved circulation to the brain

- “S oxygen consumption of cells > boost metabolism and energy

production
MECHANISM OF ACTION

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ee aCe bier. (s-ia ee).

MUaT CUM sy ate Ui Lael ave] [Lata
acetylcholine
Se

MECHANISM OF ACTION

-» Derived fram the Vinca Minar

(Periwinkle) plant

- “f blood flow to the brain

-: Improve memory capability in

Alzheimer’s disease
MOOTROPIC VITAMINS

Vitamin BI (Thiamine) Low levels: fatigue, depression,

Vitamin B3 (Niacin) and poor memory
Vitamin B5 (Pantothetic Acid)
Vitamin B6 (Pyrodoxine) deficiency can potentially cause
Inositol severe and irreversible damage to

Vitamin B12 (Cobalamin) the brain and nervous system.

MATURAL NOOTROPICS

Artichoke Extract Hordenine

Ashwagandha Kava Kava
Bacopa Monnieri Kratom

Forskolin Pterostilbene
Grape Seed Extract Rhodiola Rosea
Ginseng St John's Wort
|EUROHORIMONES

DHEA
(Dehydroepiandrosterane)
Vasopressin

Desmopressin

Melatonin

Pregnenolone
[EUROHORIMONES

¢ class of hormones manufactured by neuroendocrine cells

¢ stimulation of cellular growth, stress responses, fight or flight

responses, emotional balancing etc.
¢@ neurohormone produced in human
adrenal glands

¢ commonly used by athletes as a

performance enhancer

@ reduce the visible signs of aging,

and prevents neuronal dysfunction

51
VASOPRESSIN

¢ exerts several nootropic benefits:

¢ better short term memory
¢ heightened metal acuity
¢ deeper memory imprinting

¢@ used as a treatment for memory

issues relating to age, dementia or

Alzheimer’s disease

¢ popular with students

52
¢@ Neurosteroid which is derived from cholesterol
in the adrenal glands, liver, brain, skin, and sex
organs

¢ affects synaptic functioning, neuroprotective,

and enhance myelinization

¢ Improve cognitive and memory functioning

¢ ~ Pregnenolone is also being considered as a

potential treatment for schizophrenia
04

SCOPE OF COGNITIVE ENHANCERS

In health & disease

Alzheimer's
Exam going students Dementia (senile/vascular)
High stressful jobs which TIA, CVA
need complete focus: MR and ADHD in children
neurosurgeons, pilots, Head injury
military personnel Schizophrenia
Artists ocb
Athletes Phobias

Depression
ETHICAL ISSUES

Treating -vs— Doping

Unfair advantage?

Where to draw the line?

Promotes laziness and shortcuts?
Long term effects?

US army 2012 Afghanistan incident

Trans-humanism?

58
CONCLUSION

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REFERENCES

Ingole, S. R., Rajput, S. K., & Sharma, 5S. S, (2008). Cognition enhancers: Current
strategies
and future perspectives. CAIPS, 9(3), 42-48,

Bostrom, N., & Sandberg, 4. (2009). Cognitive enhancement: methods, ethics,

regulatory
challenges. Science and Engineering Ethics, 15(3), 311-341,

Lippincott., Cognitive Enhancers and Neuroprotectants. In: Gualtieri,T., Brain

Injury &
Mental Retardation: Neuropsychiatry & psychopharmacology, 2004; 2nd ed. N¥. Wolters
Kluer. P: 1-37

Insel T., Krystal J., Ehlers M. (2013a). New drug development for cognitive
enhancement
in mental health: challenges and opportunities. Nevropharmocology 64 2-7

Greely, H., Sahakian, B., Harris, J., Kessler, R. C., Gazzaniga, M., Campbell, P,,
& Farah, M.J.

(2008). Towards responsible use of cognitive-enhancing drugs by the

healthy. Nature, 456(7223), P: 702-705.

59
REFERENCES

www.nootriment.com [last accessed on 25.02.2015]

Swerdlow, N. A. (2012), Beyond antipsychotics: pharmacologically-augmented

cognitive
therapies (PACTs) for Schizophrenia Neuropsychopharmocology, 37(1), P: 310.

Lanni, C,, Lenzken, 5. C., Pascale, A., Del Vecchio, |., Racchi, M., Pistoia, F., &
Govoni, 5. (2008),
Cognition enhancers between treating and doping the mind. Pharmacological
Research, 57(3), P: 196-213.

Ressler, K.J., Rothbaum, 8. 0., Tannenbaum, L., Anderson, P., Graap, K., Zimand, E
& Davis, M.
(2004). Cognitive enhancers as adjuncts to psychotherapy: Use of D-cycloserine in
phobic
individuals to facilitate extinctionof fear. Archives of general psychiatry,
61(11), P: 1136-1144,

Stip, E., Chouinard, $., & Boulay, LJ. (2005). On the trail of a cognitive enhancer
for the
treatment of schizophrenia. Progress in Neuro-Psychopharmacology and Biological
Psychiatry, 29(2), P: 219-232.
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