Cognitive enhancement is often characterized by attempts to increase the performance of cognitive functions, such as attention or memory, in healthy individuals. Defined by Juengst, enhancement is a term used to “characterize interventions designed to improve human form or functioning beyond what is necessary to sustain or restore good health.”1
While humans and other species have consistently made efforts to improve from an evolutionary standpoint, what is relatively new is the impact of medications and technological advances in enhancing such efforts. Although personal enhancements such as cosmetic surgery have gained societal acceptance, interventions such as cognitive enhancement continue to be a matter of significant ethical, philosophical, and sociopolitical debate.
It is important to understand that the use of any currently available pharmaceutical agents to enhance cognition is off-label and is limited by evidence of efficacy.
Psychostimulants. While stimulants are most often used to treat ADHD and narcolepsy, these medications have also been used off-label as an augmentation strategy in depression, to manage fatigue in patients with cancer, and to treat apathy in patients with dementia. Methylphenidate and dextroamphetamine are believed to work by allosteric inhibition of presynaptic dopamine and norepinephrine transporters, thereby preventing neurotransmitter reuptake and resulting in enhanced monoaminergic neurotransmission. In addition, amphetamines result in vesicular release of dopamine.
Methylphenidate and dextroamphetamine have been used successfully in a variety of formulations to manage symptoms of ADHD in children, adolescents, and adults. While effective, stimulants are associated with decreased appetite and weight, insomnia, headache, irritability, and mood changes, as well as palpitations, tachycardia, and substance abuse. Overall, analysis of existing studies provides no consistent evidence for neuroenhancement effects with methylphenidate, although evidence for a positive effect on memory, especially spatial memory, was observed in healthy individuals.2 As a result, based on current evidence, there may be only slight enhancing effects of stimulants in the healthy population, if any, and their use for enhancement may be countered by potential adverse effects.
Modafinil. Modafinil is a wake-promoting agent that has been used for narcolepsy and was researched for use in ADHD. Some studies suggest that nearly 90% of modafinil use is by healthy, non–sleep-deprived individuals such as physicians, academics, and students.3 While the exact mechanism is unknown, modafinil may exert its effect by modulating GABA- and glutamate-mediated neurotransmission, thereby resulting in reuptake inhibition of dopamine and norepinephrine. Modafinil is not approved for use in ADHD because of its potentially life-threatening adverse effects.
Systematic reviews indicate that there is evidence of enhancing effects with modafinil, although such effects are moderate. Repantis and colleagues2 found that modafinil improved attention for well-rested individuals. In individuals who were sleep-deprived, the effects were even more pronounced, especially on wakefulness, memory, and executive functions. Interestingly, Baranski and colleagues3 reported that sleep-deprived individuals who took modafinil overrated their cognitive performance on tests and had an actual “overconfidence” effect.
Medications used for dementia. Cholinesterase inhibitors, especially donepezil, and the NMDA antagonist memantine have also been reviewed. While these medications were well tolerated, no consistent effect on cognitive enhancement was reported.
Dr. Phillips and Dr. Robinson are PGY-3 Residents, and Dr. Madaan is Associate Professor at the University of Virginia Health System, Charlottesville, VA. Drs. Phillips and Robinson report no conflicts of interest concerning the subject matter of this article. Dr. Madaan reports that he has received research support from Pfizer, Forest, Medgenus, Purdue, Sunovion, and Lundbeck; he receives royalties from Taylor & Francis (Routledge).
1. Juengst ET. What does enhancement mean? In: Parens E, ed. Enhancing Human Traits: Ethical and Social Implications. Washington, DC: Georgetown University Press; 1998:29-47.
2. Repantis D, Schlattmann P, Laisney O, Heuser I. Modafinil and methylphenidate for neuroenhancement in healthy individuals: a systematic review. Pharmacol Res. 2010;62:187-206.
3. Baranski JV, Pigeau R, Dinich P, Jacobs I. Effects of modafinil on cognitive and meta-cognitive performance. Hum Psychopharmacol Clin Exp. 2004;19:323-332.
4. Carretti B, Borella E, De Beni R. Does strategic memory training improve the working memory performance of younger and older adults? Exp Psychol. 2007;54:311-320.
5. Holmes J, Gathercole SE, Place M, et al. Working memory deficits can be overcome: impacts of training and medication on working memory in children with ADHD. Appl Cognitive Psych. 2010;24:827-836.
6. Smith PJ, Blumenthal JA, Hoffman BM, et al. Aerobic exercise and neurocognitive performance: a meta-analytic review of randomized controlled trials. Psychosom Med. 2010;72:239-252.
7. Coles K, Tomporowski PD. Effects of acute exercise on executive processing, short-term and long-term memory. J Sports Sci. 2008;26:333-344.
8. Sibley BA, Etnier JL. The relationship between physical activity and cognition in children: a meta-analysis. Pediatr Exer Sci. 2003;15:243-256.
9. Chaddock L, Erickson KI, Prakash RS, et al. A neuroimaging investigation of the association between aerobic fitness, hippocampal volume, and memory performance in preadolescent children. Brain Res. 2010;1358:172-183.
10. Lahl O, Wispel C, Willigens B, Pietrowsky R. An ultra-short episode of sleep is sufficient to promote declarative memory performance. J Sleep Res. 2008;17:3-10.
11. Cai DJ, Mednick SA, Harrison EM, et al. REM, not incubation, improves creativity by priming associative networks. Proc Natl Acad Sci USA. 2009;106:10130-10134.
12. Hodgins HS, Adair KC. Attentional processes and meditation. Conscious Cogn. 2010;19:872-878.
13. Gard T, Hölzel BK, Lazar SW. The potential effects of meditation on age-related cognitive decline: a systematic review. Ann N Y Acad Sci. 2014;1307:89-103.
14. Hariprasad VR, Koparde V, Sivakumar PT, et al. Randomized clinical trial of yoga-based intervention in residents from elderly homes: effects on cognitive function. Indian J Psychiatry. 2013;55:S357-S363.
15. Wan CY, Schlaug G. Music making as a tool for promoting brain plasticity across the life span. Neuroscientist. 2010;16:566-577.
16. Wykes T, Reeder C, Corner J, et al. The effects of neurocognitive remediation on executive processing in patients with schizophrenia. Schizophr Bull. 1999;25:291-307.
17. Gagnon G, Schneider C, Grondin S, Blanchet S. Enhancement of episodic memory in young and healthy adults: a paired-pulse TMS study on encoding and retrieval performance. Neurosci Lett. 2010;488:138-142.
18. Boggio PS, Fregni F, Bermpohl F, et al. Effect of repetitive TMS and fluoxetine on cognitive function in patients with Parkinson’s disease and concurrent depression. Mov Disord. 2005;20:1178-1184.
19. Holtzheimer PE, McDonald WM, Mufti M, et al. Accelerated repetitive transcranial magnetic stimulation for treatment-resistant depression. Depress Anxiety. 2010;27:960-963.
20. Whetstine LM. Cognitive enhancement: treating or cheating? Semin Pediatr Neurol. 2015;22:172-176.