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Chess Study Revives Debate Over Cognition-Enhancing Drugs

Jeff Lyon

A
placebo-controlled study suggest-
ing that cognition-enhancing drugs
(CEs) can improve a chess players
performance and a related survey indicat-
ing that nearly 10% of ranked German chess
players have taken them during competi-
tion have thrown the spotlight once again on
smart pills, their purported benefits, and
uncharted dangers.
About a decade ago, reports filled
the general and scientific media about
the illicit use of such CEs as methylpheni-
date, a stimulant used to treat attention-
deficit/hyperactivity disorder (ADHD), and
modafinil, a wakefulness agent used to
treat narcolepsy, sleep apnea, and shift
work disorder, by students and others who
were taking them to improve performance
on examinations or in the workplace. There
were stories about the risks and ethics of
such behavior, countered by calls from
some neuroscientists for a more open mind
about the drugs and their positive side. The
field of brain augmentation was even given
a chic new name, cosmetic neurology. because little is known about the drugs chiatry and Psychotherapy at the Univer-
While media attention has since safety and addictive potential over time. sity of Mainz, and his German and Swedish
waned, the underground use of CEs seem- We have no long-term studies in research partners.
ingly has not. A 2013 survey found that healthy people showing that they are safe, After conducting the survey of German
19.9% of the 1105 German surgeons who she said, or whether they are used to surgeons indicating that 1 in 5 have used
responded admitted to having taken a pre- cope with one-off events or are part of a CEs to boost their brainpower, Liebs team
scription or illicit drug to enhance cognition daily routine. We dont know much about turned its attention to the efficacy of such
at least once. Another study found that use patterns. drugs. Could they, for instance, make
61.8% of undergraduates at the University Adding to the muddled picture is the people better at chess?
of Maryland had been offered prescription apparently widespread clinical practice of A group of 39 highly rated male
stimulants for nonmedical purposes, most prescribing CEs off-label, in particular mo- members of the German Chess Federation
of them by friends with prescriptions, and dafinil, which is thought to be among the were enlisted to play more than 3000
31% had used them. most well-tolerated of the drugs. Accord- 15-minute games against computers
And the trend hasnt peaked yet, ing to some reports, the number of pa- matched to their skill levels while taking
noted Barbara Sahakian, DSc, a professor of tients receiving modafinil prescriptions modafinil, methylphenidate, or caffeine.
clinical neuropsychology at the University of for off-label use increased by more than The researchers reported that players tak-
Cambridge who investigates the effective- 15-fold from 2002 to 2009. In the same pe- ing modafinil and methylphenidate won
ness of CEs in treating the cognitive impair- riod, on-label prescribing of the drug in- more games overall, though they pon-
ment associated with certain psychiatric creased by less than 3-fold. dered their moves longer, causing them to
disorders. Across all years, 89% of patients pre- sometimes lose on time.
Sahakian cited more subgroups flock- scribed modafinil did not have an on-label The positive association surprised Lieb.
ing to bootleg CEsacademics facing diagnosis, wrote the authors. Our hypothesis [had been] that its not pos-
publish-or-perish pressure, sleepy physi- sible to enhance subjects who are already
cians rounding at night, business execu- Nonmedical Brain Boosting working at top performance, he said.
tives fighting jet lag in different time zones Covert use of CEs by healthy people to gain The result was disturbing on its own,
and said such widespread nonmedical use by an edge has drawn the interest of Klaus since it implied that the venerable board
those without cognitive deficits worries her Lieb, MD, director of the Department of Psy- game was vulnerable to doping. But then

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legitimizing the nonmedical use of CEs, par-

Clinical Picture for Cognitive Enhancers ticularly modafinil.
Beyond their long-standing use in treating Schizophrenia Modafinil, a US Food and Drug Admin-
ADHD, cognitive enhancers (CEs) are also Although studies of schizophrenia have istration (FDA)approved eugeroic,
being tested in the clinical treatment of implicated dysfunction of the glutamate increases cortical catecholamine levels
the following medical conditions: receptor N-methyl-D-aspartate, efforts while indirectly upregulating cerebral sero-
Neurodegenerative Disorders to treat the disease with CEs that tonin, glutamate, orexin, and histamine
Cognitive enhancers such as modulate glutamate have thus far been
and downregulating -aminobutyric acid
acetylcholinesterase inhibitors, disappointing. However, some experts
note that most of trials have involved (GABA) levels. Its status as a front-runner
which increase the availability of the
older, mostly male patients who are among CEs is based on studies that have
neurotransmitter acetylcholine,
have been tested in mitigating cognitive least likely to benefit. evaluated its effects on people with cogni-
decline in Alzheimer disease, Parkinson Down Syndrome tive difficulties related to mental disorders,
disease, and dementia with Lewy Several studies have shown that as well as other studies performed on medi-
bodies. Acetylcholinesterase inhibitors compounds that target GABAergic cally fit volunteers.
like donepezil and rivastigmine have neurotransmission can improve learning Sahakian, herself, conducted such a trial
shown a modest measure of success. and memory in mouse models of the
on healthy subjects in 2013, finding that the
Major Depression chromosomal disorder by rescuing
drug significantly improved performance
Cognitive enhancers like the serotonin underlying deficits in hippocampal
synaptic plasticity. Human trials are on tests of executive function, including
modulator vortioxetine and the
currently under way to evaluate the working memory and cognitive flexibility.
wakefulness drug modafinil have shown
promise in alleviating the intellectual efficacy of the -aminobutyric acidA Furthermore, it raised the subjects engage-
fog that can accompany major receptor antagonist pentylenetetrazole ment level. As she told JAMA, Modafinil not
depression and sometimes persists in improving the intellectual abilities only improved test performance but task-
even after the mood disorder itself lifts. of patients with Down syndrome
related motivation as well. It didnt make
One recent study suggested that aged 13 to 35 years.
them euphoric. It just made them enjoy the
modafinil improved episodic and Autism
task better.
working memory in remitted patients, Cognition enhancing drug interventions
and a meta-analysis of 3 studies similar to those being tested in Down
Pivotal was a 2015 meta-analysis of 24
concluded that vortioxetine syndrome have been proposed, studies published from 1990 to 2014 that
significantly improved cognition as reduced GABAergic signaling seems examined modafinils impact on healthy,
in depressed patients. to play a role in the pathophysiology nonsleep-deprived humans. The review
of autism as well. concluded that the drug sharpened deci-
sion making and planning and likely
improved attention and learning as well.
the researchers discovered something recently because of an overall downturn in
more. Employing an online survey and a the drug industrys investment in neuro- Safety Concerns
randomized mailed questionnaire, they pharmaceuticals. Theres so much excite- To Sahakian, though, the central question is
polled members of the German Chess Fed- ment about biologics and cancer that a lot less about efficacy than safety, particularly
eration as to their past use of psychoactive of pharmas oxygen is getting sucked into since population-based safety data on any of
substances, including not only modafinil that area. Plus the brain is really hard. There the CEs in healthy people are scarce. What
and methylphenidate, but amphetamines, hasnt been much change in the efficacy [of is known about the drugs action over time
-blockers, ephedrine, and cannabis. Using CEs] in 50 years. is based on their use in the clinic (see Box),
a randomized response technique to guar- where physicians are licensed to prescribe
antee anonymity, they reported that 8.9% Questioning Cognitive Enhancement drugs only to correct medical conditions
of respondents admitted to having used Chatterjee describes himself as on the not to help healthy CEOs deliver presenta-
prescription or illicit drugs at one time or fence about the nonmedical use of CEs by tions to investors. In the former context, ad-
another to improve their chess play. people without cognitive deficits. But some verse effects of CEs must be balanced
The finding troubled some physicians, commentators like Henry Greely, JD, of against therapeutic benefits.
among them Anjan Chatterjee, MD, of the Stanford Universitys Program in Neurosci- For patients with ADHD, for example,
Center for Cognitive Neuroscience at the ence and Society, are unabashed support- the indicated drugs are methylphenidate,
University of Pennsylvania, who has writ- ers. Greely collaborated on a 2008 essay atomoxetine, and a combination of amphet-
ten extensively on the pluses and minuses titled Towards Responsible Use of Cogni- amine and dextroamphetamine. In this clini-
of making CEs more available for nonmedi- tive Enhancing Drugs by the Healthy that cal population, their side effects and ad-
cal use. appeared in Nature. verse events, observed over many years,
Chatterjee found the cheating revela- I have the bias that more cognitive range from nausea and dry mouth to heart
tion disquieting, calling it a symptom of capacity could lead to better societies, attack and stroke. But their use in all but
modern society, where progress and pro- he said. those patients with serious heart problems
ductivity are valued over everything else. One of Greelys collaborators on the is deemed worth the risk.
He said the national conversation 2008 Nature article was Sahakian, who As Sahakian pointed out, however, the
about the ethics of CEs had subsided counts herself as a conditional advocate of cost-benefit equation is murky for the use of

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CEs in healthy young people who are among and drug development. Previous trials of Sharon Straus, MD, MSc, a gerontolo-
the biggest underground users. CEs in the healthy have been small, of gist at the University of Toronto, is wary of
We now know that the frontal lobes are spotty quality, and so varied in approach prescribing CEs for mild cognitive impair-
one of the last parts of the brain to com- and metrics that comparisons are difficult, ment in the elderly because of adverse ef-
plete development, so one has to learn if he noted. But large, systematic trials of fects, including diarrhea, vomiting, fatigue, in-
those under 25 who do not have ADHD efficacy and safety in otherwise healthy somnia, and weight loss that have been noted
should be taking them, she noted. individuals, of the kind designed to elicit among patients with Alzheimer disease.
The potential for developing sub- approval by the FDA, are not feasible at There is no high-quality evidence to
stance use disorder symptoms is of particu- this time. support use of cognitive enhancers in
lar concern for healthy individuals using In the current regulatory climate [the] healthy people, said Straus, who is direc-
amphetamines or modafinil. FDA will not license drugs for use in non- tor of the Knowledge Translation Program at
Prior to her 2013 study, Sahakian medical conditions or to improve perfor- St Michaels Hospital in Toronto. I would ad-
sought permission to follow her healthy mance [among the unimpaired], he said. vise clinicians to avoid their use.
volunteers over an extended period to see Some think a case might at least be She notes that there are alternative
if any adverse outcomes appeared. But made for legitimizing the use of CEs in oth- interventions known to stave off cognitive
the ethics committee wouldnt pass it, erwise healthy seniors who fear losing their decline, including exercise, tobacco cessa-
she said. former mental acuity. tion, and weight loss, though she acknowl-
Longitudinal studies are indeed needed, Lets say you are in your 60s and 70s, edges that they are difficult to implement.
said Lon Schneider, MD, MS, a professor said Sahakian. You dont have dementia, I think people are looking for a magic
of psychiatry, neurology, and gerontol- but youre losing some sharpness. You just bullet.
ogy at the University of Southern California want to get some of your old faculties back. Note: The print version excludes source references.
who advises on clinical trial methodology Is that enhancement? Or is it restoration? Please go online to jama.com.

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