Methylphenidate, modafinil, and caffeine for cognitive enhancement in chess: A double-blind, randomised controlled trial
Introduction
Pharmacological cognitive enhancement (CE) is defined as the use of pharmacological substances with the purpose of enhancing cognitive abilities (Bostrom and Sandberg, 2009, Farah et al., 2004, Forlini et al., 2013, Greely et al., 2008, Hildt and Franke, 2013, Smith and Farah, 2011). Substances used with the intention of CE range from over-the-counter substances such as caffeine tablets, prescription drugs such as modafinil or methylphenidate to illegal substances like amphetamines if used for non-medical reasons such as ‘‘speed’’, ecstasy, methamphetamine (crystal meth) or others (de Jongh et al., 2008, Franke et al., 2014, Hildt and Franke, 2013, Mehlman, 2004). Whereas most people intend to avoid CE with stimulants due to safety and legal concerns, CE is practiced by a low, but significant proportion of healthy individuals including students and academics (Dietz et al., 2013, Franke et al., 2011, Franke et al., 2013, Maher, 2008, McCabe et al., 2014, Sahakian and Morein-Zamir, 2015, Sahakian et al., 2015, Wilens et al., 2008), especially in cognitively demanding situations (Burgard et al., 2013).
Methylphenidate is a catecholamine reuptake inhibitor that increases extracellular dopamine in fronto-striatal regions and norepinephrine particularly in frontal regions by binding to the respective transporter and thereby blocking it (Arnsten, 2006, Kuczenski and Segal, 1997, Volkow et al., 2009, Wood et al., 2013). Enhancing effects of methylphenidate have been shown on working memory, memory consolidation, speed of processing, and inhibitory control whereas effects of methylphenidate on attention and vigilance are rather mixed (cf. Caviola and Faber, 2015 for review).
Modafinil is a wakefulness-promoting agent whose precise mechanism of action is unclear up to date (de Jongh et al., 2008, Wood et al., 2013). Similar to methylphenidate, modafinil is assumed to primarily inhibit the reuptake of dopamine and norepinephrine thereby increasing extracellular levels particularly in fronto-striatal networks. In addition, modafinil is believed to exert secondary effects on several neurotransmitters including serotonin, glutamate, GABA etc. (Mereu et al., 2013, Minzenberg and Carter, 2008, Repantis et al., 2010, Wood et al., 2013). Modafinil has been shown to improve attention, wakefulness and vigilance (Caviola and Faber, 2015, de Jongh et al., 2008, Minzenberg and Carter, 2008, Repantis et al., 2010). Mixed results have been reported with respect to effects on mnemonic functions (Caviola and Faber, 2015, de Jongh et al., 2008, Minzenberg and Carter, 2008, Sahakian et al., 2015).
Unlike methylphenidate and modafinil, caffeine does not exert its primary actions on the dopaminergic system, but rather acts as a nonselective antagonist by blocking adenosine receptors, i.e., the A1 and A2A receptor subtypes. It inhibits phosphodiesterase and thus the breakdown of the intracellular second messenger cAMP (Franke and Soyka, 2015, Wood et al., 2013). Assumedly, caffeine stimulates neural activity through higher noradrenaline emission (Caviola and Faber, 2015). Beneficial effects of caffeine have been reported on alertness and sustained attention particularly in simple tasks, encoding, and perceptual as well as response speed whereas findings regarding memnonic functions are rather heterogeneous (Caviola and Faber, 2015, Wood et al., 2013).
The relationship of catecholamine neurotransmitters, the arousal level of the neuronal network and the cognitive performance has repeatedly been suggested as being an inverted U-shape with optimal performance at intermediate catecholamine levels and impaired performance at lower or higher catecholamine levels (de Jongh et al., 2008, Schlosberg, 1954, Wood et al., 2013). Similarly, detrimental effects of high doses of caffeine have been shown whereas beneficial effects of low doses have been reported (Caviola and Faber, 2015). In addition, effects of stimulants on cognitive functions have been shown particularly in individuals with low baseline performance, i.e., individuals with rather poor scores in the assessed function under placebo, or individuals tested after sleep deprivation, which led to the hypothesis that the currently available neuroenhancers are only able to restore basic cognitive functioning to normal levels (de Jongh et al., 2008, Eagle et al., 2007, Hildt and Franke, 2013, Joos et al., 2013, Minzenberg and Carter, 2008, Rubia et al., 2009, Rubia et al., 2011, Schmaal et al., 2013b, Zack and Poulos, 2009). However, due to ceiling effects and/or the inverted U-shape model no performance-enhancing effect should in theory occur in cognitive high-performers (de Jongh et al., 2008; Minzenberg and Carter, 2008; Randall et al., 2005).
It is currently less known, however, whether the available substances are effective in enhancing cognitive functions in cognitively high-functioning subjects, i.e. whether they can lead to cognitive hyper-performance similar to physical enhancement in athletics (Hartgens and Kuipers, 2004, Healy et al., 2003). Yet, enhancing effects of stimulants on highly cognitively demanding tasks have been shown in healthy, non sleep-deprived individuals (Battleday and Brem, 2015, Müller et al., 2013, Winder-Rhodes et al., 2010). We thus aimed to assess whether administration of particularly commonly used cognitive enhancers such as methylphenidate and modafinil (e.g., Bisagno et al., 2016; Smith and Farah, 2011; Ragan et al., 2013; Sahakian et al., 2015; Wood et al., 2013) would affect chess performance. In addition, we intended to compare the impact of the above mentioned prescription drugs to one of the most common over-the-counter drug, i.e. caffeine (Ragan et al., 2013, Wood et al., 2013).
We hypothesized that the three substances are able to enhance chess performance in highly skilled tournament chess players if tested at their maximum performance. More specifically, by matching the skill level of the computer to the player׳s initially before the experiment according to the subject׳s Elo (Elo, 1978) or DWZ (German Evaluation Number) rating (both ratings are average estimates based on previous chess players’ tournament performance), we expected an average score of 0.5 for every player in the placebo condition (the achievable scores ranged from 0 to 1: 0=loss, 0.5=draw, 1=win). After drug intake we expected higher average scores (>0.5) as compared to placebo.
Section snippets
Study design and participants
We conducted a phase IV, single-center, randomised, double-blind, placebo-controlled 4×4 crossover trial. All data were collected at the Department of Psychiatry and Psychotherapy, University Medical Center Mainz, Germany. Subjects were recruited with the help of the Hessian Chess Federation (Hessischer Schachbund) using announcements on the internet, in newspapers, and in mailings to members of the German Chess Federation. Announcements included the inclusion and exclusion criteria of the
Randomised participants
Between 14 July 2011 and 27 January 2013, 39 of 40 randomised subjects received all trial medications (methylphenidate, modafinil, caffeine, and placebo) in a randomised order on four different trial days and were all included in the statistical analyses. One subject dropped out before the first trial day due to a car accident after the screening procedure. Baseline demographic and clinical characteristics of the 40 participants who entered the ITT analysis as well as of the 39 participants who
Discussion
This is, at least to our knowledge, the first study showing that modafinil, methylphenidate and caffeine modify complex cognitive performance in a highly demanding task such as playing chess in highly skilled tournament chess players. All three substances significantly increased average reflection time per game as compared to placebo. Consequently more games were lost on time. Only when controlling for game duration or when excluding chess games lost due to time constraints we observed
Contributors
K.L., A.G.F. and H.E.B. designed the clinical trial. A.G.F., K.S., A.A., S.G., K.R., T.R., H.E.B. were responsible for data acquisition. C.R., B.F., C.G. and P.G. analysed the data of the study. K.L., O.T., A.S., P.G., C.R., B.F. and A.G.F. interpreted the results and wrote the manuscript. All authors contributed to and have approved the final manuscript.
Role of the funding source
The study was funded by intramural funds from the University Medical Center Mainz, Department of Psychiatry and Psychotherapy, Mainz, Germany; there was no extramural funding. The internal funding had no influence on the design of the study or the presentation of the manuscript.
Conflict of interest statement
All authors declare to have no competing interests.
Acknowledgements
The authors thank Prof. Ch. Hiemke, Ph.D. and H. Kirchherr as well as Prof. Kühn-Velten, Ph.D. for measuring plasma levels, Nicole Regenfuß (IZKS) for statistical programming, and Prof. Dr. Krämer from the Pharmacy department of the University Medical Center Mainz for the preparation of the study medication.
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