, Volume 177, Issue 1–2, pp 161–169 | Cite as

Effects of modafinil on working memory processes in humans

  • Ulrich MüllerEmail author
  • Nikolai Steffenhagen
  • Ralf Regenthal
  • Peter Bublak
Original Investigation



Modafinil is a well-tolerated psychostimulant drug with low addictive potential that is used to treat patients with narcolepsy or attention deficit disorders and to enhance vigilance in sleep-deprived military personal. So far, understanding of the cognitive enhancing effects of modafinil and the relevant neurobiological mechanisms are incomplete.


The aim of this study was to investigate the effects of modafinil on working memory processes in humans and how they are related to noradrenergic stimulation of the prefrontal cortex.


Sixteen healthy volunteers (aged 20–29 years) received either modafinil 200 mg or placebo using a double blind crossover design. Two computerized working memory tasks were administered, a numeric manipulation task that requires short-term maintenance of digit-sequences and different degrees of manipulation as well as delayed matching task that assesses maintenance of visuo-spatial information over varying delay lengths. The battery was supplemented by standardized paper pencil tasks of attentional functions.


Modafinil significantly reduced error rates in the long delay condition of the visuo-spatial task and in the manipulation conditions, but not in the maintenance condition of the numeric task. Analyses of reaction times showed no speed-accuracy trade-off. Attentional control tasks (letter cancellation, trail-making, catch trials) were not affected by modafinil.


In healthy volunteers without sleep deprivation modafinil has subtle stimulating effects on maintenance and manipulation processes in relatively difficult and monotonous working memory tasks, especially in lower performing subjects. Overlapping attentional and working memory processes have to be considered when studying the noradrenergic modulation of the prefrontal cortex.


Human Modafinil Noradrenaline Prefrontal Working memory 



The authors are indebted to Dr. Luke Clark and an anonymous reviewer for comments on an earlier version of this paper, to Sandra Brattge and Bettina Johst for programming the delayed matching task, to Anke Pitzmaus for laboratory assistance and to all volunteers for participation. The study was supported by the Max Planck Society and the Alexander von Humboldt-Foundation (Feodor Lynen-Fellowship awarded to U.M.).


  1. Arnsten AFT (1998) Catecholamine modulation of prefrontal cortical cognitive function. Trends Cognit Sci 2:436–447CrossRefGoogle Scholar
  2. Arnsten AFT, Robbins TW (2002) Neurochemical modulation of prefrontal function in humans and animals. In: Stuss DT, Knight RT (eds) Principles of frontal lobe function. Oxford University, New York, pp 51–84Google Scholar
  3. Aston-Jones G, Rajkowski J, Cohen J (1999) Role of locus coeruleus in attention and behavioral flexibility. Biol Psychiatry 46:1309–1320PubMedGoogle Scholar
  4. Baranski JV, Pigeau RA (1997) Self-monitoring cognitive performance during sleep deprivation: effects of modafinil, d-amphetamine and placebo. J Sleep Res 6:84–91PubMedGoogle Scholar
  5. Baranski JV, Cian C, Esquivie D, Pigeau RA, Raphel C (1998) Modafinil during 64 hr of sleep deprivation: dose-related effects on fatigue, alertness, and cognitive performance. Mol Psychol 10:173–193Google Scholar
  6. Barde LH, Thompson-Schill SL (2002) Models of functional organization of the lateral prefrontal cortex in verbal working memory: evidence in favor of the process model. J Cognit Neurosci 14:1054–1063CrossRefPubMedGoogle Scholar
  7. Becker PM, Schwartz JR, Feldman NT, Hughes RJ (2004) Effect of modafinil on fatigue, mood, and health-related quality of life in patients with narcolepsy. Psychopharmacology 171:133–139CrossRefPubMedGoogle Scholar
  8. Bensimon G, Benoit D, Lacomblez L, Weiller E et al. (1991) Antagonism by modafinil of the psychomotor and cognitive impairment induced by sleep-deprivation in 12 healthy volunteers. Eur Psychiatry 6:93–97Google Scholar
  9. Béracochéa D, Cagnard B, Célérier A, le Merrer J, Pérès M, Piérard C (2001) First evidence of a delay-dependent working memory-enhancing effect of modafinil in mice. Neuroreport 12:375–378CrossRefPubMedGoogle Scholar
  10. Bublak P, Schubert T, Matthes-von Cramon G, von Cramon Y (2000) Differential demands on working memory for guiding a simple action sequence: evidence from closed-head-injured subjects. J Clin Exp Neuropsychol 22:176–190CrossRefPubMedGoogle Scholar
  11. Bublak P, Müller U, Grön G, Reuter M, von Cramon DY (2002) Difficult manipulation of working memory information is impaired in Parkinson’s disease and related to working memory capacity. Neuropsychology 16:577–590CrossRefPubMedGoogle Scholar
  12. Buguet A, Moroz DE, Radomski MW (2003) Modafinil: medical considerations for use in sustained operations. Aviat Space Environ Med 74:659–663PubMedGoogle Scholar
  13. Burnat P, Robles F, Do B (1998) High-performance liquid chromatographic determination of modafinil and its two metabolites in human plasma using solid-phase extraction. J Chromatogr B 706:295–304CrossRefGoogle Scholar
  14. Caldwell JA Jr, Caldwell JL, Smythe NK III, Hall KK (2000) A double-blind, placebo-controlled investigation of the efficacy of modafinil for sustaining the alertness and performance of aviators: a helicopter simulator study. Psychopharmacology 150:272–282CrossRefPubMedGoogle Scholar
  15. Coull JT, Middleton HC, Robbins TW, Sahakian BJ (1995) Contrasting effects of clonidine and diazepam on tests of working memory and planning. Psychopharmacology 120:311–321PubMedGoogle Scholar
  16. DeBattista C, Doghramji K, Menza MA, Rosenthal MH, Fieve RR, Modafinil in Depression Study Group (2003) Adjunct modafinil for the short-term treatment of fatigue and sleepiness in patients with major depressive disorder: a preliminary double-blind, placebo-controlled study. J Clin Psychiatry 64:1057–1064PubMedGoogle Scholar
  17. Duteil J, Rambert FA, Pessonnier J, Hermant JF, Gombert R, Assous E (1990) Central alpha1-adrenergic stimulation in relation to the behaviour stimulating effect of modafinil; studies with experimental animals. Eur J Pharmacol 180:49–58PubMedGoogle Scholar
  18. D’Esposito M, Postle BR, Ballard D, Lease J (1999) Maintenance versus manipulation of information held in working memory: an event-related fMRI study. Brain Cognit 41:66–86PubMedGoogle Scholar
  19. Ellis KA, Nathan PJ (2001) The pharmacology of human working memory. Int J Neuropsychopharmacol 4:299–313CrossRefPubMedGoogle Scholar
  20. Ellis CM, Monk C, Simmons A, Lemmens G, Williams SC, Brammer M, Bullmore E, Parkes JD (1999) Functional magnetic resonance imaging neuroactivation studies in normal subjects and subjects with the narcoleptic syndrome: actions of modafinil. J Sleep Res 8:85–93CrossRefPubMedGoogle Scholar
  21. Eysenck MW (1982) Attention and arousal: cognition and performance. Springer, BerlinGoogle Scholar
  22. Ferraro L, Antonelli T, Tanganelli S, O’Connor WT, Perez de la Mora M, Mendez-Franco J, Rambert FA, Fuxe K (1999) The vigilance promoting drug modafinil increases extracellular glutamate levels in the medial preoptic area and the posterior hypothalamus of the conscious rat: prevention by local GABAA receptor blockade. Neuropsychopharmacology 20:346–356CrossRefPubMedGoogle Scholar
  23. Fuster JM (1995) Memory in the cerebral cortex: an empirical approach to neural networks in the human brain and nonhuman primate. MIT Press, CambridgeGoogle Scholar
  24. Glahn DC, Kim J, Cohen MS, Poutanen VP, Therman S, Bava S, Van Erp TG, Manninen M, Huttunen M, Lonnqvist J, Standertskjold-Nordenstam CG, Cannon TD (2002) Maintenance and manipulation in spatial working memory: dissociations in the prefrontal cortex. Neuroimage 17:201–213CrossRefPubMedGoogle Scholar
  25. Goldman-Rakic PS (1996) Regional and cellular fractionation of working memory. Proc Natl Acad Sci USA 93:13473–13480PubMedGoogle Scholar
  26. Gruber O, Bublak P, von Cramon DY (1999) The neural correlates of working memory components: a functional magnetic resonance imaging study at 3 Tesla [abstract]. J Cognit Neurosci 11:32–33Google Scholar
  27. Honey RA, Turner DC, Honey GD, Sharar SR, Kumaran D, Pomarol-Clotet E, McKenna P, Sahakian BJ, Robbins TW, Fletcher PC (2003) Subdissociative dose ketamine produces a deficit in manipulation but not maintenance of the contents of working memory. Neuropsychopharmacology 28:2037–2044PubMedGoogle Scholar
  28. Horvath TL, Peyron C, Diano S, Ivanov A, Aston-Jones G, Kilduff TS, van Den Pol AN (1999) Hypocretin (orexin) activation and synaptic innervation of the locus coeruleus noradrenergic system. J Comp Neurol 415:145–159CrossRefPubMedGoogle Scholar
  29. Högl B, Saletu M, Brandauer E, Glatzl S, Frauscher B, Seppi K, Ulmer H, Wenning G, Poewe W (2002) Modafinil for the treatment of daytime sleepiness in Parkinson’s disease: a double-blind, randomized, crossover, placebo-controlled polygraphic trial. Sleep 25:905–909PubMedGoogle Scholar
  30. Jäkälä P, Riekkinen M, Sirviö J, Koivisto E, Kejonen K, Vanhanen M, Riekkinen P Jr (1999) Guanfacine, but not clonidine, improves planning and working memory performance in humans. Neuropsychopharmacology 20:460–470PubMedGoogle Scholar
  31. Jasinski DR (2000) An evaluation of the abuse potential of modafinil using methylphenidate as a reference. J Psychopharmacol 14:53–60PubMedGoogle Scholar
  32. Lagarde D, Batejat D (1995) Disrupted sleep-wake rhythm and performance: advantages of modafinil. Mol Psychol 7:165–191Google Scholar
  33. Lewis SJ, Cools R, Robbins TW, Dove A, Barker RA, Owen AM (2003a) Using executive heterogeneity to explore the nature of working memory deficits in Parkinson’s disease. Neuropsychologia 41:645–654CrossRefPubMedGoogle Scholar
  34. Lewis SJ, Dove A, Robbins TW, Barker RA, Owen AM (2003b) Cognitive impairments in early Parkinson’s disease are accompanied by reductions in activity in frontostriatal neural circuitry. J Neurosci 23:6351–6356PubMedGoogle Scholar
  35. Lin JS, Roussel B, Akaoka H, Fort P, Debilly G, Jouvet M (1992) Role of catecholamines in the modafinil and amphetamine induced wakefulness, a comparative pharmacological study in the cat. Brain Res 591:319–326PubMedGoogle Scholar
  36. Mattay VS, Callicott JH, Bertolino A, Heaton I, Frank JA, Coppola R, Berman KF, Goldberg TE, Weinberger DR (2000) Effects of dextroamphetamine on cognitive performance and cortical activation. Neuroimage 12:268–275CrossRefPubMedGoogle Scholar
  37. McClellan KJ, Spencer CM (1998) Modafinil: a review of its pharmacology and clinical efficacy in the management of narcolepsy. CNS Drugs 9:311–324Google Scholar
  38. Mehta MA, Sahakian BJ, McKenna PJ, Robbins TW (1999) Systemic sulpiride in young adult volunteers simulates the profile of cognitive deficits in Parkinson’s disease. Psychopharmacology 146:162–174PubMedGoogle Scholar
  39. Mehta MA, Swainson R, Ogilvie AD, Sahakian J, Robbins TW (2001) Improved short-term spatial memory but impaired reversal learning following the dopamine D(2) agonist bromocriptine in human volunteers. Psychopharmacology 159:10–20PubMedGoogle Scholar
  40. Müller U (2002) Die katecholaminerge Modulation präfrontaler kognitiver Funktionen beim Menschen (MPI Series in Cognitive Neuroscience 26). Max-Planck-Institut für neuropsychologische Forschung, LeipzigGoogle Scholar
  41. Müller U, von Cramon DY, Pollmann S (1998) D1- versus D2-receptor modulation of visuospatial working memory in humans. J Neurosci 18:2720–2728PubMedGoogle Scholar
  42. Müller U, Mottweiler E, Bublak P (2004) Noradrenergic blockade and numeric working memory in humans. J Psychopharmacol (in press)Google Scholar
  43. Nishino S (2003) The hypocretin/orexin system in health and disease. Biol Psychiatry 54:87–95CrossRefPubMedGoogle Scholar
  44. Pigeau R, Naitoh P, Buguet A, McCann C, Baranski J, Taylor M, Thompson M, Mack II (1995) Modafinil, d-amphetamine and placebo during 64 hours of sustained mental work. I. Effects on mood, fatigue, cognitive performance and body temperature. J Sleep Res 4:212–228PubMedGoogle Scholar
  45. Postle BR, Berger JS, D’Esposito M (1999) Functional neuroanatomical double dissociation of mnemonic and executive control processes contributing to working memory performance. Proc Natl Acad Sci USA 96:12959–12964PubMedGoogle Scholar
  46. Rammohan KW, Rosenberg JH, Lynn DJ, Blumenfeld AM, Pollak CP, Nagaraja HN (2002) Efficacy and safety of modafinil (provigil) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study. J Neurol Neurosurg Psychiatry 72:179–183PubMedGoogle Scholar
  47. Randall DC, Shneerson JM, Plaha KK, File SE (2003) Modafinil affects mood, but not cognitive function, in healthy young volunteers. Hum Psychopharmacol Clin Exp 18:163–173CrossRefGoogle Scholar
  48. Robbins TW (1998) Homology in behavioural pharmacology: an approach to animal models of human cognition. Behav Pharmacol 9:509–519PubMedGoogle Scholar
  49. Robbins TW (2000) Chemical neuromodulation of frontal-executive functions in humans and other animals. Exp Brain Res 133:130–138PubMedGoogle Scholar
  50. Robbins TW, James M, Owen AM, Sahakian BJ, Lawrence AD, McInnes L, Rabbitt PM (1998) A study of performance on tests from the CANTAB battery sensitive to frontal lobe dysfunction in a large sample of normal volunteers: implications for theories of executive functioning and cognitive aging. Cambridge neuropsychological test automated battery. J Int Neuropsychol Soc 4:474–490PubMedGoogle Scholar
  51. Rugino TA, Copley TC (2001) Effects of modafinil in children with attention-deficit/hyperactivity disorder: an open-label study. J Am Acad Child Adolesc Psychiatry 40:230–235PubMedGoogle Scholar
  52. Scammell TE, Estabrooke IV, McCarthy MT, Chemelli RM, Yanagisawa M, Miller MS, Saper CB (2000) Hypothalamic arousal regions are activated during modafinil-induced wakefulness. J Neurosci 20:8620–8628PubMedGoogle Scholar
  53. Schubert T, Volkmann J, Müller U, Sturm V, Voges J, Freund HJ, Von Cramon DY (2002) Effects of pallidal deep brain stimulation and levodopa treatment on reaction-time performance in Parkinson’s disease. Exp Brain Res 144:8–16CrossRefPubMedGoogle Scholar
  54. Smith A, Nutt D (1996) Noradrenaline and attention lapses. Nature 380:291PubMedGoogle Scholar
  55. Stivalet P, Esquivie D, Barraud PA, Leifflen D, Raphel C (1998) Effects of modafinil on attentional processes during 60 hours of sleep deprivation. Hum Psychopharmacol Clin Exp 13:501–507CrossRefGoogle Scholar
  56. Sutcliffe JG, de Lecea L (2002) The hypocretins: setting the arousal threshold. Nat Rev Neurosci 3:339–349CrossRefPubMedGoogle Scholar
  57. Talbot K, Stradling J, Crosby J, Hilton-Jones D (2003) Reduction in excess daytime sleepiness by modafinil in patients with myotonic dystrophy. Neuromuscul Disord 13:357–364CrossRefPubMedGoogle Scholar
  58. Taylor FB, Russo J (2000) Efficacy of modafinil compared to dextroamphetamine for the treatment of attention deficit hyperactivity disorder in adults. J Child Adolesc Psychopharmacol 10:311–320PubMedGoogle Scholar
  59. Thorpy MJ, Schwartz JR, Kovacevic-Ristanovic R, Hayduk R (2003) Initiating treatment with modafinil for control of excessive daytime sleepiness in patients switching from methylphenidate: an open-label safety study assessing three strategies. Psychopharmacology 167:380–385PubMedGoogle Scholar
  60. Turner DC, Robbins TW, Clark L, Aron AR, Dowson J, Sahakian BJ (2003) Cognitive enhancing effects of modafinil in healthy volunteers. Psychopharmacology 165:260–269PubMedGoogle Scholar
  61. Turner DC, Clark L, Dowson J, Robbins T, Sahakian B (2004) Modafinil improves cognition and response inhibition in adult attention-deficit/hyperactivity disorder. Biol Psychiatry 55:1031–1040CrossRefPubMedGoogle Scholar
  62. US Modafinil in Narcolepsy Multicenter Study Group (2000) Randomized trial of modafinil as a treatment for the excessive daytime somnolence of narcolepsy. Neurology 54:1166–1175PubMedGoogle Scholar
  63. Wesensten NJ, Belenky G, Kautz MA, Thorne DR, Reichardt RM, Balkin TJ (2002) Maintaining alertness and performance during sleep deprivation: modafinil versus caffeine. Psychopharmacology 159:238–247PubMedGoogle Scholar
  64. Wisor JP, Nishino S, Sora I, Uhl GH, Mignot E, Edgar DM (2001) Dopaminergic role in stimulant-induced wakefulness. J Neurosci 21:1787–1794PubMedGoogle Scholar
  65. Wong YN, King SP, Simcoe D, Gorman S, Laughton W, McCormick GC, Grebow P (1999) Open-label, single-dose pharmacokinetic study of modafinil tablets: influence of age and gender in normal subjects. J Clin Pharmacol 39:281–288CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Ulrich Müller
    • 1
    • 2
    Email author
  • Nikolai Steffenhagen
    • 3
  • Ralf Regenthal
    • 4
  • Peter Bublak
    • 5
  1. 1.Department of PsychiatryUniversity of LeipzigLeipzigGermany
  2. 2.Departments of Experimental Psychology & PsychiatryUniversity of CambridgeCambridgeUK
  3. 3.Max-Planck-Institute of Cognitive NeuroscienceLeipzigGermany
  4. 4.Department of Clinical PharmacologyUniversity of LeipzigLeipzigGermany
  5. 5.Department of PsychologyLudwig-Maximilians-UniversitätMünchenGermany

Personalised recommendations