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Swinburne University of Technology 1
Prof Con Stough
Centre for Human Psychopharmacology
Cognitive Enhancers
August 2015
Thanks to Prof Andrew Scholey
Collaborator on most of my
studies in this area
Provided slides for Ginseng
and Curcumin studies
What is Cognition?
Cog enhancers for:
Children
University students
Middle aged
Older
Dementia
Part a: Centre for Human Psychopharmacology
Swinburne University
ERA 4/5 Ranking Psychology 2012; 5/5 expected 2015
Top 400 Universities
30,000 students
2,500 Staff
$250M Recent
Investment in ResearchKey collaborators (national)
Peter Howe (UniSA)
Kevin Croft (UWA)
Stephen Myers (Southern Cross)
Denis Chang (UWS)
Frank Rosenfedlt (Alfred Hospital)
International collaborators from:
US
UK
Europe
Netherlands
Canada
China
Directors
Andrew Scholey Con Stough
Head of Aging Studies
Andrew Pipingas
Clinical Trials Co-ordinator
Tinette Goh
Senior Researchers
Richard Silberstein David Crewther
Jerome Sarris (w/Melb Uni) [psychiatry/naturopathy]
Post-docs
Luke Downey [recreational drugs, driving]
Helen MacPherson [coQ10]
David White [neuroimaging]
Matt Pase [cardiovascular/cognitive health]
Research Nurse Bioassay technician
Rosamund McIllaith Shaku Gondalia
PhDs
Anastasia Oussokhova [glucoreg herbs]
Christina Kure [heart and brain health]
Vanessa Bilog [anti-oxidants]
Liz Harris [vitamins & mood]
Renee Rowsell [vitamins/neuroimaging]
Chris Neale [bacopa/neuroimaging]
Rita Brien [cannabis performance]
Isabelle Bauer [fish oils]
Rachel Gold [fish oils]
Matt Pase [heart-brain axis]
Sarah Benson [alcohol/caffeine]
Naomi Perry [phytoestrogens/mood/aggression]
Michaela Pascoe [fish oils/neuroimaging]
Karen Nolidin [genetics/cognition/supplementation]
James Kean [fish oil/ADHD]
Sarah Catchlove [neuroimaging]
Kate Cox [curcumn neurocognition]
Roy Hardman [ageing, wellbeing interventions]
Greg kennedy [brain-heart ageing]
Research Assistants
Amy Gibbs Rebecca King Justine Lomas
Karen Savage Kate Cox Greg Kennedy
Sarah Catchlove Barbara Camfield Laila Hugrass
Michelle Lamblin Alyse Brown Nina Riddell Alexis
Hedrick Riccarda Peters
Adjuncts
Keith Wesnes (UK)
Jeroen Schmitt (switzerland)
Andy Parrott (Wales)
Joris Verster (Netherlands)
Mark Wetherell (UK)
Phil Swann (Australia)
Andrea Zangara (Spain)
Swinburne University of Technology 2
CHP collaborator network
neurobrands
Optimal mental performance
6-10 11 -15 16-20 21-30 31-40 41-50 51-60 60 plus6-10 11 -15 16-20 21-30 31-40 41-50 51-60 60 plus
RT
(se
c)
2000
2200
2400
2600
2800
3000
3200
3400
3600
MENTAL
ABILITY
MENTAL PERFORMANCE
optimizing cognitive performance
PLANT EXTRACTS• Ginkgo biloba• Panax ginseng*• Ginseng quinquefolius*• Ginkgo-ginseng combination• Melissa officinalis*• Salvia officinalis*• Salvia lavandulaefolia*• Valerian• Guaraná*• Ginkgo-phosphatidylserine*• Cocoa polyphenols*• Bacopa monnieri*• Pycnogenol*• Enzogenol*• EGCG• Soy isoflavones• Curcumin*
OTHERS
• oxygen*
• glucose
• aromatherapy oils
• caffeine
• theanine
• water
• chewing gum*
• alcohol [low dose]
• DHA
• multivitamins
• MedDi
CHP capabilities cognitive testing
mood assessment
stress evaluation
brain imaging EEG
fMRI
MEG
TMS
biomarkers cardiovascular
metabolites
inflammation
oxidative stress
etc.
field testing internet
mobile phones
genetics
MRI & MEG
Different strategies for different
ages
Part b: What is cognition?
Swinburne University of Technology 3
Long Term Memory
Short term Memory
Spatial Processes
Vocabulary
Arithmetic
Reasoning
Comprehension
We tried to make it simple but…
Auditory
Processin
g
General
Intelligence
Compre-
hension
Knowledge
Quantitative
Knowledge
Visual
Processing
Short-
term
memory
Reading
and
Writing
Fluid
Reasoning
Language development
Lexical knowledge
Listening ability
General information
Information about culture
Communication ability
Oral production and fluency
Grammatical sensitivity
Foreign language proficiency
Foreign language aptitude
Visualization
Spatial relations
Closure speed
Flexibility of closure
Visual memory
Spatial scanning
Serial perceptual integration
Length estimation
Perceptual illusions
Perceptual alterations
Imagery
Reading decoding
Reading comprehension
Verbal (printed) language
comprehension
Cloze ability
Spelling ability
Writing ability
English usage knowledge
Reading speed
Writing speed
Cognition at its most complex
Long-
term
storage
and
retrieval
Process
-ing
Speed
Decision
Speed/RT
Memory span
Working memory
Associative memory
Meaningful memory
Free recall memory
Ideational fluency
Associational fluency
Expressional fluency
Perceptual speed
Rate of test taking
Numerical facility
Speed of reasoning
Reading speed
Writing speed
Simple RT
Choice RT
Semantic processing
speed
Mental comparison
speed
Inspection Time
Mathematical knowledge
Mathematical achievementGeneral sequential reasoning
Induction
Quantitative reasoning
Piagetian Reasoning
Speed of Reasoning
Phonetic coding
Speech sound discrimination
Resistance to auditory stimulus
distortion
Memory for sound patterns
General sound discrimination
Temporal tracking
Musical discrimination and judgement
Maintaining and judging rhythm
Sound intensity
Sound frequency discrimination
it is more complex..
Age-associated cognitive decline
-General knowledge
-Vocabulary
-Verbal ability
-Timed tasks
-Speed of information
processing
-Recognition memory
-Episodic memory
-Spatial abilities
-Working memory
Part c: Choosing the right natural medicine
Extracts of Ginkgo Biloba
• 122 products on the Australian Register for Therapeutic
Goods (Listed Medicine)
• Supermarkets, pharmacies, naturopaths…
• Appears to be a correlation between quality
and price
Swinburne University of Technology 4
Grow, cultivate, extract-wine?
Blackmores
Flordis
Part e: Evidence for Children & Adolescents
Children with behavioural
problems and cognitive deficits
Improving educational outcomes is more difficult..
Nutrition, breakfast, Omega 3s, cognitive training, EI
Amphetamines & ATS
Widespread belief that
amphetamines improve
intelligence (25% of US Students)
This may support why some people use them
E.g. military, students, children
est 1.5-2.5% of school age children
Medications and prescriptions
amphetamines are prescribed for narcolepsy, obesity,
and attention deficit/hyperactivity disorder.
Prescription names for these medications include
Adderall©
Dexedrine©
DextroStat©
Desoxyn©
Methylphenidate or Ritalin is similar
Used to treat...
Obesity, Parkinson’s disease, Attention deficit
hyperactivity disorder, Narcolepsy (uncontrolled
episodes of sleep)
What about side effects?
From Australian Government Website
Swinburne University of Technology 5
Short-Term Effects
High body temperature, Cardiovascular system failure
Hostility or paranoia, Irregular or increased heart rate/ heart beat, Increased diastolic/ systolic blood pressure, Increased activity/ talkativeness, Euphoria, Heightened sense of well-being, Decreased fatigue/ drowsiness, Decreased appetite, Dry mouth, Dilated pupils, Increased respiration, Heightened alertness/ energy, Nausea, Headache, Palpitations, Altered sexual behavior, Tremor/ twitching of small muscles,
Release of social inhibitions, Unrealistic feelings of cleverness, great competence, and power
James Kean
PhD
Lyprinol (150 Children)
Keenmind (100 children)
New Pharmaceutical for Down’s
Syndrome
Safety and efficacy of natural
medicines for ADHD symptoms
An RCT Investigating PCSO-524 , an extract of the New
Zealand Green Lipped Mussel on symptoms of ADHD
Patented extraction technique
Pharmalink NZ processing plant
Batch to batch consistency
Unique Fatty Acids
Swinburne University of Technology 6
Inattention
Careless
schoolwork
mistakes
Poor listening
skills
Avoiding tasks
requiring
sustained
attention
Easily distracted
Forgetful
Hyperactivity
Fidget with
hands or feet
Acts as if driven
by a motor
Talks excessively
Difficulty waiting
turn
Interrupts or
intrudes others
● Aged 6-14 years
● Increased levels of Hyperactivity & Inattention(ADHD Dx & Mx
accepted)
● 150 children around Australia
● 14-week placebo controlled intervention (4-week post follow up)
● Outcomes:
○ Behaviour
○ Cognition
○ Inhibition
○ Mood, EEG changes (brain wave ratio analysis)
An RCT Investigating PCSO-524 , an extract of the New
Zealand Green Lipped Mussel on symptoms of ADHD
Population
● Screened: 351
● Sample: 144
● Final Analysis: 112(incl. 4 Intention to Treat)
● Age: 8.7 + 2.23yrs 6-14 years
● Sex: 124 (m) 20 (f)
● Dropouts: 26 (Majors: Family Issues- 37.5%; Swallow capsules- 29.2%)
● Lost to follow-up: 10
PCSO-524 (Lyprinol) & Symptoms of ADHD
What we found...
PCSO-524 (Lyprinol) & Symptoms of ADHD
Significant improvements:
○ Decreased Hyperactivity
○ Decreased Inattention
○ Decreased Aggression
○ Increased positive mood
○ Increased error recovery
○ Increased recovery speed
○ Sustained recall
○ Increased working memory speed
○ Decreased error response speed
Inattention
Hyperactivity
*
*
Results
Improved attention
Improved mood (vigour subscale)
Improved Recall
Improved Speed of Recall
Improved Working Memory Speed (diagnosed PCSO-524 sample)
Follow-up analysis revealed children taking PCSO-524 became worse following treatment cessation.
Significant increases in hyperactivity & inattention
Swinburne University of Technology 7
Keenmind (CDRI08)
Bacopa
Use has been documented for 3000 years
Chemical investigation of bacopa first published in 1944
by CDRI
Standardised extract of bacopa launched by Indian
Prime Minister in 1996 after 50 years of research
Bacosides thought to be the most important constituent
The Past
50 years of in vitro research in India
Chronic trials
Mechanisms of CDRI08 seemed to map appropriately to
many putative cognitive systems
Excellent animal and in vitro work already conducted in
India
Historical Use
inflammation,
pain,
pyrexia,
epilepsy,
memory
attention behaviour in children
Mechanisms-Indian research
modulate the cholinergic system,Bhattacharya1999
have antioxidant and metal chelating effects Agrawal 1993
anti inflammatory properties Jain 1994
relaxant properties in blood vessels Dar & Channa 1999
anxiolytic Bhattacharya & Ghosal 1998
antidepressant Sairam 2002
Stough, Singh & Zangara (Editors) Special issue of ECAM 2015
on mechanisms of bacopa (10 excellent papers)
Swinburne University of Technology 8
exposureAlzheimer
disease
Bacopa properties
ACh
degenerationabnormal
amyloid
processing
plaques
and
tangles
inflammation
viral
exposure
free radical
damage
Metals
brain
atrophy
nicotine
intake
alcohol
consumption
diet
socio-
economic
status
toxin
exposure
head
trauma
hormonal
status
ApoE
phenotype
ageing RISK
FACTORS
DISEASE
PROCESSES
Alzheimer
disease
head
trauma
ACh
degeneration
ageing ApoE
phenotype
nicotine
intake
socio-
economic
status
alcohol
consumption
inflammation
free radical
damage
abnormal
amyloid
processing
brain
atrophy
plaques
and
tangles
PREVENTIONTREATMENT?
Bacopa research
ECAM, 2015
Keenmind (CDRI08) Summary
Worth trying for behavioural problems in children
particularly if related to cognitive issues
Acute improvement at busy/study time
Highly recommended chronic improvement in adults
and in older people
Keenmind (CDRI08) and Children
Systematic Review
Traditional use
All studies based in India
Most have placebos
Blinding issues
Small samples
PUBMED, SCOPUS, COCHRANE May 2015
Keen et al (In Press)
Search: Bacopa monnieri+child+adolescents
Search: Single extracts and Combination extracts
Search: range of cognitive variables
Results: 36 trials (35 reported safety data)
Results: 4 trials described single extract
Results: Remaining Mentat or combination
Systematic Review: Keen et al
All studies were based in India
Only 2-4 studies tested children with ADHD
Both of these studies showed large improvements
4 single compound studies all showed cognitive
improvements
Nearly all of the other studies showed cognitive
improvements
Cognitive assessments varied considerably
Swinburne University of Technology 9
Single extracts of Bacopa Mentat Formulations
A randomized controlled trial investigating the effects of a special
extract of Bacopa monniera (CDRI08: KeenMind®) on hyperactivity and
inattention in male children and adolescents (Study Trial No.:
ACTRN12612000827831)
James D Kean1, Richard Silberstein1, Justine Lomas1, Antoinette Goh1, Hemant Singh2,
Andrea Zangara1, 2 & Con Stough1*
Part e: Evidence for Students and Adults
Recent acute and acute dose-ranging studies
Dr Luke Downey
National Health &
Medical Research
Council Fellow
Illicit Drugs
Keenmind studies
Cannabis
Swinburne University of Technology 10
Acute Keenmind
Builds upon 2 published studies
RCTs Cross-Over Placebo multi dose acute
RAs, 4th years, 3rd years
Benson et al
Downey et al
Basis of a patent application
Downey et al 2012
24 participants
320mg, 640mg, and placebo (Cross-over)
Cognitive demand battery
Significant changes mainly in 320 but some suggestions
640 may be useful in accuracy
Acute effects of bacopa: preliminary findings
multi-tasking in twenty min blocks (N = 17)
baseline => 1 hr, 2 hr
placebo, 320 mg BM, 640 mg BM
assess
performance: maths, stroop, working memory, tracking
mood: alert, calm, content, anxiety, fatigue
VISUAL
TRACKING
STROOP
WORKING
MEMORY
MATHEMATICAL
PROCESSING
ALERT
1 h 2 h
-15
-10
-5
0
5
10
15 PLACEBO
300 mg BM
600 mg BM
CH
AN
GE
FR
OM
BA
SE
LIN
E
Acute effects of bacopa: mood effects
Swinburne University of Technology 11
CH
AN
GE
FR
OM
BA
SE
LIN
E
MATHS
1 h 2 h
0
20
40
60
80
100
120
140
160
PLACEBO
300 mg BM
600 mg BM
Acute effects of bacopa: performance Acute data
Showing that even single high dose 640mg can
improve:
Attention
Performance
Decrease in anxietyPanax ginseng (Asian ginseng)
Used in Chinese medicine for several millennia as a tonic, restorative and prophylactic agent
Amongst the most widely taken herbal supplement throughout the world –alleviation of fatigue/’pick me up’
Active components are ginsenosides promotes Yang energy (TCM)
anti-fatigue
improves circulation
increases blood supply
revitalises and aids recovery from weakness
stimulates the body
Extract G115 standardised to 4%
EEG confirms central bioactivity
Kennedy, Scholey et al (2003) Pharmacol, Biochem, Behav 75, 701-709
• 360 mg Ginkgo, 200 mg Ginseng, Placebo; 4 h post-dose [N = 15]
Ginkgo
Beta
Alpha
Theta
Ginseng
Delta
P300 LATENCY
FRONTAL L. TEMP R. TEMP PARIETAL OCCIPITAL
msec
320
330
340
350
360PLACEBO GINKGO GINSENG
****
*
*
**
*
Swinburne University of Technology 12
Panax (Asian) ginseng:
cognitive effects
Time1hr 2.5hr 4 hr 6 hr
-80
-60
-40
-20
0
***placebo
200mg
400mg
600mg
Kennedy DO, Scholey AB & Wesnes KA (2001) Nutritional Neuroscience 4, 295-310.
*
*****
CH
AN
GE
FR
OM
BA
SE
LIN
E
QUALITY OF MEMORY
G115 400 mg
G115 200 mg
G115 400 mg
G115 600 mg
G115 400 mg
G115 200 mg
Un
its
-20
0
20
40
60
Kennedy et al, 2002n=20young
0,1,2.5,4 & 6 h
Kennedy et al, 2001n=20young
0,1,2.5,4 & 6 h
Labadorf et al, 2004n=18
aged 12 to 530,1, 3 & 6 h
Days 0, 7,14,21
Sunram-Lee et al, 2004n=30
aged 18 to 250 & 1.5 h
EFFECTS OF GINSENG (G115) ON QUALITY OF MEMORY
Scores expressed as mean improvements over placebo with 95%
Confidence Intervals
acute effects
chronic effects
Part f: Evidence in the Elderly?
Ageing of the world population
WHO, Dementia Report, 2012
Cognitive Impairment – role of complementary therapies Age-related change in
cognitive function
200
220
240
260
280
300
320
340
360
200
220
240
260
280
300
320
340
360
18-2526-30
31-3536-40 46-50 56-60 66-70 76-80
41-45 51-55 61-65 71-75 81-8518-2526-30
31-3536-40 46-50 56-60 66-70 76-80
41-45 51-55 61-65 71-75 81-8518-2526-30
31-3536-40 46-50 56-60 66-70 76-80
41-45 51-55 61-65 71-75 81-85
~40
msec
msec
%
18-2526-30
31-3536-40 46-50 56-60 66-70 76-80
41-45 51-55 61-65 71-75 81-8518-2526-30
31-3536-40 46-50 56-60 66-70 76-80
41-45 51-55 61-65 71-75 81-8518-2526-30
31-3536-40 46-50 56-60 66-70 76-80
41-45 51-55 61-65 71-75 81-85
~10%
Word Recall Accuracy
18-2526-30
31-3536-40 46-50 56-60 66-70 76-80
41-45 51-55 61-65 71-75 81-8518-2526-30
31-3536-40 46-50 56-60 66-70 76-80
41-45 51-55 61-65 71-75 81-8518-2526-30
31-3536-40 46-50 56-60 66-70 76-80
41-45 51-55 61-65 71-75 81-85
~350
msec
msec
Speed of Word
Recognition
Simple Reaction Time
~100
msec
msecChoice Reaction Time
380
400
420
440
460
480
500
520
540
560
580
600
620
640
660
18-2526-30
31-3536-40 46-50 56-60 66-70 76-80
41-45 51-55 61-65 71-75 81-85380
400
420
440
460
480
500
520
540
560
580
600
620
640
660
18-2526-30
31-3536-40 46-50 56-60 66-70 76-80
41-45 51-55 61-65 71-75 81-8518-2526-30
31-3536-40 46-50 56-60 66-70 76-80
41-45 51-55 61-65 71-75 81-85
600
700
800
900
1000
1100
1200
1300
1400
1500
1600
1700
1800
1900
600
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800
900
1000
1100
1200
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0
10
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60
0
10
20
30
40
50
60
Swinburne University of Technology 13
RecommendationsWhat is curcumin?
Polyphenol found in turmeric (gives its bright yellow colour)
Used as ingredient in food (e.g. curry) also as a food preservative
and natural colour (E100)
Used as a traditional medicines to treat wide variety of conditions
Modern medicine benefits published since the 1930s
Some evidence that more curry => less cognitive decline
Potentiates SSRIs
Enhances memory
and learning
Modulates
neurotranmitter
systems
Antioxidant
Antifungal
Antidepressant
Inhibits aortic
aneurysmsIncreases BDNF
Anti-inflammatory
Why are we interested in curcumin?
Promotes wound
healing
Antiparasitic
Enhances
antioxidant
defences
Neuroprotective
Inhibits
acetylcholinesterase
Antiepileptic
Antibacterial
Immune enhancing
Chemoprevenative
Antiangiogenic
Improved efficacy of cancer
therapies and reduced
chemoresistance
Improved endothelial function
Anti-amyloidogenic Inhibits amyloid
aggregation and
promotes
disaggregation
influences DNA &
RNA expression
pro-apoptotic
Increases
neurogenesis
Protective against diabetic
complications and high
glucose effects
Reduces damage by high
alcohol consumption
hypocholesterolemic
Protective against
stress effects
Reduced side effects of
chemotherapy
Radioprotective
Antiviral
Improves
mitochondrial
function/ health
Our trial:
60 x 65-80 year olds randomised to
curcumin or placebo
Chronic Effects = 4 Weeks Treatment
4 weeks of treatment Assessment at Follow-Up
11
12
13
14
15
Placebo Curcumin
Total fatigue
5
6
7
8
9
10
Placebo Curcumin
Physical fatigue
4
5
6
7
8
Placebo Curcumin
Mental fatigue
* **
-15
-10
-5
0
5
10
PlaceboCurcumin
*
Contentedness FatigueCalmness
*
* p < 0.05 , Controlling for Baseline, pre-dose change
*
Chronic Effects: State Mood
Swinburne University of Technology 14
Chronic (4 weeks):
Reduced fatigue, particularly physical fatigue
Produced a resistance to the fatiguing and negative mood
effects of completing a cognitive test battery
Benefited working memory task performance
Reduced total cholesterol and LDL (bad cholesterol)
Curcumin Summary
Studies on Keenmind
Human Trials
Clinical trials-chronic Systematic review (Pase, 2012, JACM)
1. Barbhaiya et al (2008) Journal of Pharmacology and Toxicology
2. Stough et al (2008) Phytotherapy Research
3. Calabrese et al (2008) JACM
4. Roodenrys et al (2002) Neuropsychopharmacology
5. Stough et al (2001) Psychopharmacology
6. Nathan et al (2004) Human Psychopharmacology
7. Morgan & Stevens (2010) JACM
8. Raghav et al. (2006) Age associated memory Imp
Our own systematic review published in 2012
Dr Matthew Pase
NHMRC Fellow
Collaboration between
Swinburne –
Boston University-
Harvard Medical School
(cardiovascular and
cognition)
Swinburne University of Technology 15
Author/
Year
Dosage n Sample Trial
Design
Outcome Measures Results Effect Size Q
/10
Stough et al.
(2001)
KM 300mg daily
BC: min 55%
46
23(B)
23(P)
18-60 yrs 12-week
DB, PC
Full cognitive testing
battery inc: IT, AVLT,
reaction time, digit span
BM significantly improved Speed of visual
information processing (IT), learning rate and
memory consolidation on AVLT
VP & A1: 0.25
L & M1: 0.27
L & M2: 0.52
L & M3: 1.01
8
Nathan et al.
(2001)
KM 300mg single
dose
BC: min 55%
38
18 (B)
20 (P)
18-60 years 0 and 2 hours
DB, PC
No effect on any
measure
No acute effects of BM on a battery of measures N/S 8
Roodenrys et
al. (2002)
KM 300mg (ppts
< 90kg)
400mg (ppts
90kg+)
BC:55%
76
37 (B)
39 (P)
40 – 65
years
0 and 3
months DB,
PC
Cognitive testing battery
including story recall,
word pairs, general
knowledge
Positive effects on retention of new information L & M9 : 0.23 6
Raghav et al.
(2006)
CDRI 250mg
daily
BC: min 55%
40
20 (B)
20 (P)
55+ years
Participants
had AAMI
0 and 12
weeks DB,
PC
WMS Significant improvements on mental controlb,
logical memoryb, paired associate learningb (all
from WMS)
WM & EF: 0.83
L & M7: 1.56
L & M8: 0.12
7
Stough et al.
(2008)
KM 300mg daily
BC: min 55%
62
33 (B)
29 (P)
18-60 years 0 and 90
days DB, PC
CDR Testing Battery Significant Working Memorya and RVIP
improvementsa
WM & EF2: 0.47
VP & A2: 0.309
Calabrese et
al. (2008)
MH 300mg daily
BC: min 50%
44
24 (B)
24 (P)
65+ years 0 and 12
weeks DB,
PC
AVLT, Stroop, DAT,
WAIS letter digit test
Significant AVLTa and Stroopa improvements. L & M4: 0.36
WM & EF3: 0.329
Barbhaiya et
al. (2008)
BM 450mg daily
BC: bacoside A3
> 5% w/w
44
23 (B)
21 (P)
50 – 75
years
MMSE 24+
0, 12 and 24
weeks DB,
PC
Treatment 0
– 12 wks
Cognitive testing battery
@12 weeks treatment
and 24 week follow up.
Significant improvements in digit cancellation
and visual retention @12 week. Comparisons
not between treatment groups but change from
baseline in each group
N/A 9
Morgan &
Stevens
(2010)
BM 300mg daily
BC: 40 – 50%
81
36 (B)
45 (P)
55+ years 0 and 12
weeks
DB, PC
Multiple cognitive
measures: AVLT, CFT,
TMT, MAC-Q
Significant improvements on verbal learning,
memory acquisition and delayed recall AVLT
measures
No significant differences on CFT, TMT or MAC-
Q
L & M4: 0.95
L & M5: 0.53
L & M6: 0.57
10
Stough et al 2001
46 participants ages 18-60 years
(1 and 90 days)
Neuropsychological tests; anxiety
Inspection Time/Reaction Time
Auditory Verbal Learning Test (AVLT)
Digit Span/ Digit Symbol
Trail Making Test/ STAI/POMS
Stough et al (2001)
Psychopharmacology
First international study was by our group …
MS
EC
CH
AN
GE
FR
OM
BA
SE
LIN
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-40
-35
-25
-20
-15
-10
-5
0
5
10
BASELINE 90 DAYSBASELINE 90 DAYS
-30
BASELINE 90 DAYSBASELINE 90 DAYS
-12
-10
-8
-6
-4
-2
0
2
4
6INSPECTION TIME SIMPLE REACTION TIME
placebo
bacopa
***
Stough et al 2001
Results indicated improvement in
information processing, memory
consolidation and reduction in state
anxiety after 90 days of Bacopa
monniera administration (Stough et
al., 2001)
Clinical relevance...
Improvements in Memory consolidation and retrieval
Improvements in cognitive speed
THE two factors underpinning cognitive ageing
Swinburne University of Technology 16
Ginkgo biloba
Many different extractions
Few reputable
The most reputable extraction is termed EGb 761 and
was first patented in Germany in 1972
Subsequent improved patent for EGb 761 was lodged in
1989/1990 (Europe)
EGb 761
In general safety and efficacy of ginkgo biloba extracts
have only been established for extracts which contain 5
ppm ginkgolic acids
In Australia ginkgo biloba extracts are sourced from a
wide variety of regional areas
Some of these have alarming levels of ginkgolic acids
but EGb 761 < 5ppm GAs
Nearly all published scientific work (toxicology,
pharmacology and psychology/psychiatry) have used
extracts with stringent extraction specifications
Over 400 published studies many of these with EGb
761 extraction
Very little is known about other extraction techniques
Ginkgo Research
Animal Studies Suggest
Antioxidant/free radical scavenging properties may
help reduce nervous tissue damage from beta amyloid
plaques
Up regulation of post-synaptic ach (muscarinic)
receptors
Enhance active choline uptake
Blood flow
Improving cognition
Ginkgo EGB761 Stough et al, 2001
30 days treatment Int J of Neuropsychopharmacology
Significant improvements due to EGB761 in healthy
participants, particularly memory and information processing
speed
These are the domains related to cognitive ageing
Swinburne University of Technology 17
How do natural ingredients measure up to pharma?
Modafinil: largest effect size (d):
(visuospatial working memory) = 0.77
Ginseng: largest effect sizes (d):
cognitive (reaction time) = 0.86
mood (mental fatigue) = 1.40
Bacopa: largest effect size (d):
(delayed word recall) = 0.95
Part f: Evidence in Dementia and Cognitive Decline?
Growth of numbers of people with dementia
In Australia:
• 320,000 in 2012
• 1,700 new cases/ week
• All: 1 in 77
• 65+: 1 in 10
• 85+: 3 in 10
• 3rd most common cause of
death
• Expected to triple by 2050
Cognitive Impairment – role of complementary therapies
WHO: Dementia Report , 2012
Access Economics, 2012
What about the evidence for EGB 761 and
Alzheimer’s Dementia?
Research
Reduction in 4 ADAS-COG points is equivalent to
stemming of the progression of dementia by
approximately 6 months
Research
Kanowski, Herrman, Stephan, Wierich & Hörr (1996)
156 patients with mild to moderate dementia
(Alzheimer’s disease and vascular dementia)
24 weeks daily treatment with 240mg EGb 761 or
placebo
Swinburne University of Technology 18
ResearchLe bars, Katz, Berman, Itil, freedman & Shatzberg (1997)
309 patients with mild to severe dementia (Alzheimer’s
disease and vascular dementia)
Multi centre trial
Research
Outcome measures at 12, 26 and 52 weeks of daily
treatment with 120mg EGb 761 or placebo
ResearchModest but noticeable improvements in social and
cognitive functioning of patients with Alzheimer’s
disease and vascular dementia at 26 weeks and 52
weeks
Equivalent to stemming the course of the illness for 6
months(ADAS-cog score reduced by 4 points)
ResearchLe bars, Kieser & Kurtz (2000)
244 patients with mild to severe dementia (Alzheimer’s
disease and vascular dementia)
26 weeks daily treatment with 120mg EGb 761 or
placebo
Research
The placebo group showed a statistically significant worsening in all domains of assessment
The group receiving EGb 761 was considered slightly improved on the cognitive assessment and the daily living and social behaviour
Equivalent to stemming the course of the illness for 6 months (ADAS-cog score reduced by 4 points)
Comparison of EGb 761 with
Cholinesterase Inhibitors
Wettstein (2000)
Compared the results of Kanowski et al (1996) and Le Bars et
al (2000) with research on the efficacy of four
Cholinesterase inhibitors;
— Tacrine (80, 120, 160 mg/day)
— Donepezil (5, 10 mg/day)
— Rivastigmine (1-4, 6-12mg/day)
— Metrifonate (100-180 mg/day)
Swinburne University of Technology 19
Ginkgo biloba for Dementia
Only Tacrine exhibited a high dropout rate due to
adverse reactions
When initial severity of dementia and placebo effect
were accounted for, all treatments were considered
equally effective
Cognitive Impairment – role of complementary therapies
Rainer et al., 2013
• Delay in ADL deterioration by 22.3 months compared to placebo.
• Savings mainly driven by delays in progression towards higher home care subsidies.
Systematic Review
Recent systematic review identified 9 double blind
randomized controlled clinical trials in Alzheimer’s
patients
8 of these found a statistically significant superiority of
EGb 761 to placebo
Recent studies
Herrschaft et al (2012)
Journal of Psychiatric Research
RCT: double blind
240 Mg Egb 761 daily
24 weeks administration
“once-daily dose of 240 mg was safe and resulted in a
significant and clinically relevant improvement in cognition,
psychopathology, functional measures and quality of life of
patients and caregivers”
Preventing Dementia
Different question than treating dementia
Less research and this question is unknown
At the moment we know very little about this question
Safety
Extremely well tolerated even at high doses
Despite long term use in Germany and France there
has never been overdosage reported
Special warnings or precautions according to some
authors do not seem to be required
Swinburne University of Technology 20
Safety-rare and due to poorer extracts
Adverse effects
? Headache
? Gastrointestinal problems (nausea, dyspepsia)
? Sleep disturbance (racing thoughts, intense dreaming)
? Allergic skin reactions
? Bleeding
Responsible Use of Ginkgo
biloba
Safety
Drug Interactions
- Warfarin (left parietal haemorrhage)
Diamond et al., 2013
Amieva et al (2013) PLoS One
3612 non-demented patients
EGB761 (589), Piracetam (149), neither (2874)
20 year duration
MMSE scores for cognitive decline
Less decline in EGB716 group than other groups
EGB761-conclusions
240mg a day may be good for patients with AD
Not enough evidence to indicate a protective effect
Safe, good evidence for improving cognition in the
health and elderly Part g: Summary and Conclusions
Swinburne University of Technology 21
Take home messages!
Not all herbal medicines are equivalent
Not all have been researched
Use high quality herbals which have been subjected to
research
Sadly, price and quality are usually correlated in the
herbal but not pharmaceutical business!
Recommended
Thank You
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