a n
a chol a b
a Brain Sciences Institute, Swinburne University, Hawth
b Laguna Beach, CA, USA
a r t i c l e i n f o
Article history:
Received 17 August 2010
Received in revised form 28 January 2011
pb .001) for the Ceretrophin™ group. Improvements in APM scores could be attributed to the
Intelligence 39 (2011) 100–107
Contents lists available at ScienceDirect
Inte ligactive intervention over the placebo, indicating that the treatment improved general
intelligence. Implications for improving our understanding of the biological basis of
intelligence and pharmacologically improving human cognition are discussed.
© 2011 Elsevier Inc. All rights reserved.
1. Introduction
There are many pharmacologically active substances
preliminary animal work, and a few have been subjected to
carefully controlled human clinical trials. The use of nootropic
or cognitive enhancing substances whether they be naturallyavailable that claim to enhance cognitive
as learning and memory. Many of these
subjected to scientific analysis, some have
⁎ Corresponding author at: Brain Sciences Institute, S
Technology, PO Box 218 Hawthorn Victoria, Australia, 3
8167; fax: +61 3 9214 5230.
E-mail address: cstough@swin.edu.au (C. Stough).
0160-2896/$ – see front matter © 2011 Elsevier Inc.
doi:10.1016/j.intell.2011.01.003found: F (1, 57)=7.279, p=0.009, partial η2=.113, with paired samples t-tests revealing a
significant improvement in mean APM score from baseline to retest (week 4) (t(34)=−4.045,Alpha-lipoic acid
Rhodiola Rosea, raven progressive matricesey , Josh Reynolds
orn, Victoria, Australia
a b s t r a c t
Cognitive enhancing substances such as amphetamine and modafinil have become popular in
recent years to improve acute cognitive performance particularly in environments in which
enhanced cognition or intelligence is required. Nutraceutical nootropics, which are natural
substances that have the ability to bring about acute or chronic changes in cognition have also
been gaining popularity in a range of settings and applications including the workplace, driving
and in the amelioration of age related cognitive decline. Huperzine A, Vinpocetine, Acetyl-
L-carnitine, Rhodiola Rosea and Alpha-lipoic Acid are popular nutritional supplements that
have shown promising benefits in improving a range of biological (e.g., blood flow, anti-
inflammatory, anti-oxidant, and direct neurotransmitter effects) and cognitive processes from
in vitro, animal and human clinical research. We report here the first human randomized
clinical trial for cognition in which we administer a combination of Huperzine A, Vinpocetine,
Acetyl-L-carnitine, R. Rosea and Alpha-lipoic acid (called Ceretrophin) vs placebo. Sixty
participants (40 females and 20 males, with a mean age of 45.4 years, SD=12.6) completed
either the odd or even items from the Raven Advanced Progressive Matrices (APM) at baseline
and the opposite odd or even items at week 4 after consuming either the combination
nootropic or placebo. A significant study visit (time)×treatment condition interaction wasAccepted 31 January 2011
Available online 15 March 2011
Keywords:
Intelligence
Huperzine A
Vinpocetine
Acetyl-L-carnitineAndrea Zangara , Andrew S
Con Stough a,⁎, David Camfield a, Christina Kure a, Joanne Tarasuik a, Luke Downey a, Jenny Lloyd a,Improving general intelligence with
pharmacological interventionfunctioning such
have not been
been subjected to
winburne University o
122. Tel.: +61 3 9214
All rights reserved.lfutrient-based
enceoccurring or synthesized is increasing in western societies
as the pressures to achieve and to enhance individual levels
of intelligence increases (Sahakian & Morein-Zamir, 2007).
Despite this trend, there is little research scientifically
examining the efficacy of these substances and particularly
the mechanisms by which they exert their claimed effect.
The term nootropic was first coined by Giurgen (1973)
who used it to propose a class of pharmacologically active

101C. Stough et al. / Intelligence 39 (2011) 100–107substances that improve cognition or intelligence without
side-effects and which should protect the brain from damage.
Therefore it may be better to describe common pharmaceu-
ticals (such as modafinil and amphetamines) that improve
cognition as cognitive enhancers and refer to nutraceuticals
or natural medicines that improve cognition as nootropics.
Most cognitive enhancers or nootropics work acutely to im-
prove the functioning of a narrow range of neural processes
such as is the case with specific neurotransmitter systems
thatmay underpin narrow elements of cognition. Examples of
acute cognitive enhancers that have been subjected to
research are: modafinil (Turner et al., 2003), Ginkgo Biloba
(Kennedy, Scholey, & Wesnes, 2000), amphetamines (Silber,
Papafotiou, Croft, Ogden, et al., 2005; Silber, Papafotiou, Croft,
& Stough, 2005), Ginseng (Scholey et al., 2010) and
Schizandra Chinesis (Panossian & Wikman, 2008).
Even fewer substances have been shown to improve
cognition or intelligence after chronic administration in non-
clinical populations. In contrast to acute cognitive enhancers
they usually exert a gradual biological effect over time on
different neural targets. Instead of a direct change in
neurotransmitter activity they may gradually improve blood
flow to the brain, increase energy metabolism, improve anti-
oxidant defence, provide anti-inflammatory effects, or increase
membrane fluidity usually requiring weeks or longer of
administration. There are several examples of chronic noo-
tropics. Vitamin–mineral supplementation has been shown to
modestly raise the non-verbal intelligence of some groups of
Western schoolchildren (Schoenthaler, Bier, Young, Nichols, &
Jansenns, 2000) and supplementation with creatine (which
plays a pivotal role in brain energy homeostasis) in vegetarians
was shown to produce a significantly positive effect on both
working memory (backward digit span) and intelligence
(Advanced Progressive Matrices; Rae, Digney, McEwan, &
Bates, 2003). Chronic administration of both G. Biloba (e.g.
Stough, Clarke, Lloyd, & Nathan, 2001) the Indian herb Brahmi,
particularly CDRI08 (e.g. Stough, Lloyd, et al., 2001; Stough
et al., 2008) aswell as the pine bark extract Pycnogenol® (Ryan
et al., 2008) have also been shown to improve cognitive
processes in healthy participants.
Pharmacology is an important strategy in understanding the
biological basis of intelligence because it offers the possibility
of understanding more about intelligence at the cellular and
neuronal levels. Although there have been some promising
models describing neural imaging studies of general intelli-
gence which have indicated the role of frontal–parietal net-
works (Deary, Penke, & Johnson, 2010; Jung & Haier, 2007),
these studies are not able to describe processes at the cellular
level that may underpin cognition or intelligence. There have
been several studies that link neurotransmitter activity to
discrete components of cognition or intelligence, such as
dopamine and working memory (Dickinson & Elvevåg, 2009);
or acetylcholine and information processing speed (Stough,
Thompson, Bates, & Nathan, 2001). However, these studies do
not describe more wide-spread cellular influences that have
accumulating long-term effects on the integrity of neuronal
structures.
To date, much of our understanding of the processes
underpinning human cognition at the neuronal level derive
from studies in which age-related changes in the brain have
been characterised (for reviews see Buckner, 2004; Hedden &Gabrieli, 2004). These studies have shown that the integrity
of both white matter and grey matter structures are reliably
correlated with differences in the cognitive ability between
young and old individuals, with the largest age-related
changes observed in the frontal and temporal cortices (Fjell
& Walhovd, 2010). A number of cellular processes have been
implicated in causing impairments to brain function and
cognition, with accumulated damage becoming most notice-
able with advanced age. These processes include oxidative
stress due to free radicals (Halliwell, 1992), chronic systemic
inflammation (Sarkar & Fisher, 2006), and decreased mito-
chondrial efficiency (Kidd, 2005).
As such it is unlikely that one mechanism at the cellular
level will completely contribute to individual differences in
human intelligence. As a consequence strategies in which
combinations of compounds with different cellular mecha-
nisms may be most efficacious in developing nootropic
compounds for chronic consumption. In order to fulfil these
criteria we tested a combination nootropic agent in which
Huperzine, Vinpocetine, Alpha lipoic acid, Acetyl-L-carnitine,
and Rhodiola Rosea were combined. We briefly present
relevant research on the mechanisms and efficacy of each
of these substances. These substances have been selected
because of well validated biological mechanisms which target
processes at the cellular level (such as those described above)
or their solid clinical data showing improvement in cognition
after chronic administration.
1.1. Huperzine A (HupA)
Recent studies have revealed that Huperzine A (HupA)
functionsas apotent reversible inhibitor of Acetylcholinesterase
(Wang & Xi, 2005). There is evidence to suggest that HupA has
better penetration of the blood-brain barrier, higher oral bio-
availability, and longer duration of AChE inhibitory activity
comparedwith thepharmaceutical ChEIs tacrine, donepezil and
rivastigmine (Bai, Tang, & He, 2000). HupA has also been found
to reverse or attenuate cognitive deficits in a broad range of
animal models (Wang, Zhang, & Tang, 2001); and numerous
clinical trials have demonstrated that HupA is effective in
relieving memory deficits associated with the elderly and
Alzheimer's disease (AD) without any serious adverse side
effects (Wang, et al., 2001) and is considered to be safe (Xu et al.,
1995). A recent Cochrane's review of HupA in the treatment of
AD (Li,Wu, Zhou, Liu, & Dong, 2008) concluded that a dosage of
between 0.2 and 0.4 mg per day resulted in significant
improvement to global cognitive function at 6–12 weeks.
1.2. Vinpocetine (VIN)
VIN has been highly researched as a neuroprotective agent
(Dezsi, Kis-Varga, Nagy, Komlodi, & Karpati, 2002; Pereira
et al., 2003; Santos, Duarte, Moreira, & Oliveira, 2000; Vas &
Gulyás, 2005). Due to inhibition of cyclic nucleotide phos-
phodiesterases type 1, VIN causes vasodilation of cerebral
smooth muscle and increases blood flow to the brain
(Hagiwara, Endo, & Hidaka, 1984). In addition to enhancing
cerebral vascular blood flow, VIN has also been found to
increase brain energy metabolism (Gulyás et al., 2002;
Szakács, Veres, & Vereczkey, 2001; Vas & Gulyás, 2005; Vas
et al., 2002) and increase the neuronal uptake of glucose and