Claus Normann Æ Mathias Berger
Neuroenhancement: status quo and perspectives
j Abstract Neuroenhancement is a pharmacological
attempt to increase cognitive performance in healthy
humans. Strategies to improve learning and memory
aim at plasticity pathways in the brain; phosphodi-
esterase inhibitors such as rolipram and NMDA-
modulating drugs like donepezil and D-cycloserine
have been tested in clinical trials. Modafinil and
methylphenidate are used to increase attention and
vigilance. Other fields of intense research include
mood, social interaction and sexual performance. So
far, all clinical trials of neuroenhancing drugs have
either failed or demonstrated only very limited effi-
cacy. However, the high demand for neuroenhance-
ment and the intense research efforts might come up
with more efficacious drugs in the near future
implying the need for an extended ethical discussion
in society.
j Key words neuroenhancement Æ plasticity Æ
learning Æ cognition Æ modafinil
Introduction
The working and leisure environment of many people
in developed countries is changing dramatically.
Confronted with exponentially increasing computer
performance, fluid intelligence is gaining against
crystallized intelligence. Whereas crystallized intelli-
gence is based on broad knowledge and experience,
fluid intelligence is the ability to find meaning in
confusion and solve new problems. It is the ability to
draw inferences and understand the relationships of
various concepts, independent of acquired knowl-
edge. Fluid intelligence peaks in young adulthood and
then steadily declines [4]. This has increased the de-
mand for pharmacological enhancement of brain
performance.
It has become common practice to modify the
human ‘‘hardware‘‘. The body is shaped and built up
or is changed by surgery. Technical devices aim to
compensate for major disabilities. The deaf learn to
hear by cochlear implants, brain–machine interfaces
control artificial extremities just by the power of the
will [11]. The selection and modification of genes will
allow to prevent or to heal major illnesses. But is it
possible to update the ‘‘brain computer’’, to increase
the capabilities of the human software?
Two psychiatric disorders illustrate how broad the
limits of human performance are. ‘‘Savants’’ are
subjects with special abilities as a feature of their
autistic disorder. Savants demonstrate that circum-
script parts of the fluid intelligence can be increased
excessively. The savant syndrome is commonly ex-
plained as an inability to sort incoming information
by relevance which normally prevents information
overload in order to allow fast and intuitive reactions.
Savants process and store any information within a
certain field irrespective of their relevance. This im-
pairs, however, other aspects of their cognitive per-
formance so that the average IQ of autistic savants is
around 70.
Kim Peek has been the role model for the film
character ‘‘Rain Man’’. He knows the contents of
12,000 books by heart and he is able to store the
contents of a book page within 10 s, scanning each
page by one eye individually. Moreover, he has
superior calculating abilities (http://www.wisconsin-
medicalsociety.org/savant). Other savants can
remember every detail of their life, including every
single meal or rain shower. Stephen Wiltshire, a
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C. Normann (&) Æ M. Berger
Dept. of Psychiatry
University Medical Center
Hauptstraße 5
79100 Freiburg, Germany
Tel.: +49-761/2706501
Fax: +49-761/2706619
E-Mail: Claus.normann@uniklinik-freiburg.de
Eur Arch Psychiatry Clin Neurosci (2008) 258 [Suppl 5]:110–114 DOI 10.1007/s00406-008-5022-2

British artist with autism born in 1974, is able to draw
highly detailed panoramic views of cities after short
round flights (http://www.stephenwiltshire.co.uk).
Another psychiatric disorder demonstrates the
plasticity of brain performance. Bipolar disorder is
characterized by the episodic recurrence of manic and
depressive episodes. In mania, the intellectual pace of
a patient is highly increased; he has racing thoughts
and is sometimes highly creative. Mood is euphoric
and sexuality is lived out excessively. A short time
span later, the same patient might no longer be able to
solve even the most simple cognitive tasks and his
cognition is deteriorated up to pseudodementia
within depression. The patient has major difficulties
to store new information, thinking is slow and the
language production is decreased. Libido is reduced
to a minimum.
Autism with savant syndrome and bipolar disorder
demonstrate that the cognitive and social perfor-
mance of humans can be modified by neurobiological
factors within broad limits. Is it possible to improve
this performance by pharmacological interventions?
In the following sections, we will describe pharma-
cological methods to improve learning and memory,
attention, mood, communicative skills and sexual
performance in healthy humans.
Learning and memory
The human brain is a plastic organ which can adapt to
changing environmental conditions. Until some years
ago, it has been a dogma in neurobiology that neu-
rons develop early and cannot be replaced in adults.
This view has been changed by the demonstration of
adult neurogenesis in rodents, primates and humans.
In the adult brain, new neurons are generated and
integrated into neuronal networks. However, neuro-
genesis is limited to a distinct part of the brain,
namely the dentate gyrus of the hippocampus, and
could not be detected in cortical regions [7].
Beneath this form of structural plasticity, there are
other forms of functional plasticity. As early as 1949,
Canadian psychologist Donald Hebb postulated that
‘‘when an axon of cell A excites cell B and repeatedly
or persistently takes part in firing it, some growth
process or metabolic change takes place in one or
both cells so that A’s efficiency as one of the cells
firing B is increased.’’ [10]. These theoretical predic-
tions were experimentally confirmed in 1973 when
Bliss and Lomo described long-term synaptic poten-
tiation (LTP) [3]. In LTP, repeated activation of a
synaptic pathway leads to a persistent increase in
synaptic transmission (Fig. 1). In its counterpart,
long-term depression (LTD), transmission is persis-
tently decreased [5, 13, 14].
Long-term synaptic plasticity is an ubiquitous
form of functional brain plasticity. It has been de-
scribed in most brain regions and is regarded as the
neurobiological correlate of learning and memory.
Recent experimental work has consistently shown
that simple behavioral learning induces LTP in the
hippocampus and that learning can be impaired by
inhibition of synaptic plasticity in the hippocampus
[22]. Literally thousands of publications describe the
mechanisms of synaptic plasticity. A complex cascade
of receptors, proteins and ion channels detects the
induction paradigms of synaptic plasticity and con-
verts this information into a persistent modification
of synaptic power. In a late phase of synaptic plas-
ticity, morphological changes follow the functional
alterations; new synapses are generated.
Given their central role for learning and memory,
the mechanism for LTP and LTD are primary targets
for the development of neuroenhancing drugs. Pio-
neers in this field are the Nobel laureates Eric Kandel
and Walter Gilbert. Their research focuses on the
modulation of calcium channels and the CREB pro-
tein. So far, no drugs have been approved for clinical
use to increase learning and memory in healthy hu-
mans; however, some interesting preliminary results
have been published.
Rolipram is a phosphodiesterase inhibitor and in-
creases the intracellular concentration of the regula-
tory protein cAMP response element-binding protein
(CREB). CREB is crucial for LTP and regulates the
transcription of genes which stabilize an increase in
synaptic efficacy. CREB is activated by cyclic adeno-
sine monophosphate (cAMP) which by itself is de-
graded by phosphodiesterase. When CREB is
increased in drosophila by genetic manipulations, the
animals learn the location of food source within a
single trial whereas wildtype flies need ten or more
repeats to learn an identical task [20]. Application of
rolipram has caused a dramatic increase in learning
performance in mice [2]. Several phosphodiesterase
inhibitors are in the early stage of clinical testing in
humans.
Donepezil is approved for the treatment of Alz-
heimer dementia. In a double-blind, placebo-con-
trolled study, Yesavage et al. have tested the efficacy
of this substance in elderly pilots with an average age
of 52 years. They were tested in a flight simulator
before and after a 30-day intake of donepezil. Con-
fronted with complex flight situations, the pilots in
the donepezil group showed a highly significant in-
crease in performance [23].
D-cycloserine is a partial agonist at the N-methyl-D-
aspartate (NMDA) glutamate receptor. The substance
facilitates LTP in brain slices and promotes
fear extinction in behavioural animal experiments. D-
cycloserine is approved in the United States as an
antibiotic drug to treat tuberculosis. In several pla-
cebo-controlled clinical trials, D-cycloserine has been
demonstrated to augment exposition-based psycho-
therapy. In one of the first of these trials, a single dose
of D-cycloserine or placebo was used prior to expo-
sition therapy in a virtual glass elevator in patients
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