Modafinil: A Review of Neurochemical Actions and Effects on Cognition

Imaging Research Center, Davis School of Medicine, UC-Davis Health System, University of California, Sacramento, CA 95817, USA.
Neuropsychopharmacology (Impact Factor: 7.05). 07/2008; 33(7):1477-502. DOI: 10.1038/sj.npp.1301534
Source: PubMed


Modafinil (2-[(Diphenylmethyl) sulfinyl] acetamide, Provigil) is an FDA-approved medication with wake-promoting properties. Pre-clinical studies of modafinil suggest a complex profile of neurochemical and behavioral effects, distinct from those of amphetamine. In addition, modafinil shows initial promise for a variety of off-label indications in psychiatry, including treatment-resistant depression, attention-deficit/hyperactivity disorder, and schizophrenia. Cognitive dysfunction may be a particularly important emerging treatment target for modafinil, across these and other neuropsychiatric disorders. We aimed to comprehensively review the empirical literature on neurochemical actions of modafinil, and effects on cognition in animal models, healthy adult humans, and clinical populations. We searched PubMed with the search term 'modafinil' and reviewed all English-language articles for neurochemical, neurophysiological, cognitive, or information-processing experimental measures. We additionally summarized the pharmacokinetic profile of modafinil and clinical efficacy in psychiatric patients. Modafinil exhibits robust effects on catecholamines, serotonin, glutamate, gamma amino-butyric acid, orexin, and histamine systems in the brain. Many of these effects may be secondary to catecholamine effects, with some selectivity for cortical over subcortical sites of action. In addition, modafinil (at well-tolerated doses) improves function in several cognitive domains, including working memory and episodic memory, and other processes dependent on prefrontal cortex and cognitive control. These effects are observed in rodents, healthy adults, and across several psychiatric disorders. Furthermore, modafinil appears to be well-tolerated, with a low rate of adverse events and a low liability to abuse. Modafinil has a number of neurochemical actions in the brain, which may be related to primary effects on catecholaminergic systems. These effects are in general advantageous for cognitive processes. Overall, modafinil is an excellent candidate agent for remediation of cognitive dysfunction in neuropsychiatric disorders.

Download full-text


Available from: Michael Minzenberg,
40 Reads
  • Source
    • "Experiments in a plus-maze discriminative avoidance task conducted with mice revealed that MO exerts a highly dose-dependent aggravation in learning: a high dosage of MO induced memory impairments in mice, 32 mg/kg administered before training impaired memory retrieval, whereas 64 and 128 mg/kg blocked memory consolidation (Fernandes et al., 2013). Throughout the literature very high doses of MO (32–200 mg/kg) were used in rodents for testing its action in various memory paradigms (Minzenberg and Carter, 2008). These doses are not clinically relevant and the reported diverse and contradictory findings may be induced by severe side effects like increased arousal, locomotor activity etc. Psychostimulants like methylphenidate, amphetamines were known to enhance cognition at low doses with no apparent side effects (Wood et al., 2014). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Modafinil (MO) an inhibitor of the dopamine transporter was initially approved to treat narcolepsy, a sleep related disorder in humans. One interesting "side-effect" of this drug, which emerged from preclinical and clinical studies, is the facilitation of cognitive performance. So far, this was primarily shown in appetitive learning paradigms, but it is yet unclear whether MO exerts a more general cognitive enhancement effect. Thus, the aim of the present study in rats was to extend these findings by testing the effects of MO in two aversive paradigms, Pavlovian fear conditioning (FC) and the operant two-way active avoidance (TWA) learning paradigms. We discovered a differential, task-dependent effect of MO. In the FC paradigm MO treated rats showed a dose-dependent enhancement of fear memory compared to vehicle treated rats, indicated by increased context-related freezing. Cue related fear memory remained unaffected. In the TWA paradigm MO induced a significant decrease of avoidance responses compared to vehicle treated animals, while the number of escape reactions during the acquisition of the TWA task remained unaffected. These findings expand the knowledge in the regulation of cognitive abilities and may contribute to the understanding of the contraindicative effects of MO in anxiety related mental disorders.
    Frontiers in Behavioral Neuroscience 09/2015; 9:220. DOI:10.3389/fnbeh.2015.00220 · 3.27 Impact Factor
  • Source
    • "Uncertainty and mental effort may be inextricably linked with pupil diameter if uncertainty triggers phasic activity in the LC - NE system associated with prefrontal cognitive control mechanisms that may help improve the likelihood of correct performance ( Minzenberg and Carter , 2008 ) . The necessity of prefrontal cognitive control mechanisms is conceptually equivalent to earlier characterizations of the need to increase " mental effort " commensurate with cognitive processing load ( Hess and Polt , 1964 ; Kahneman and Beatty , 1966 ; Kahneman , 1973 ; Beatty , 1982 ) . "
    [Show abstract] [Hide abstract]
    ABSTRACT: Pupil diameter has long been used as a metric of cognitive processing. However, recent advances suggest that the cognitive sources of change in pupil size may reflect LC-NE function and the calculation of unexpected uncertainty in decision processes (Aston-Jones and Cohen, 2005; Yu and Dayan, 2005). In the current experiments, we explored the role of uncertainty in attentional selection on task-evoked changes in pupil diameter during visual search. We found that task-evoked changes in pupil diameter were related to uncertainty during attentional selection as measured by reaction time (RT) and performance accuracy (Experiments 1-2). Control analyses demonstrated that the results are unlikely to be due to error monitoring or response uncertainty. Our results suggest that pupil diameter can be used as an implicit metric of uncertainty in ongoing attentional selection requiring effortful control processes.
    Frontiers in Human Neuroscience 08/2015; 9(435):1-14. DOI:10.3389/fnhum.2015.00435 · 3.63 Impact Factor
  • Source
    • "European Neuropsychopharmacology (2014), et al., 2006). While modafinil 0 s neurobiological actions are non-specific, evidence suggests that modafinil blocks DA transporters (Volkow et al., 2009) and elevates dopaminergic transmission (Minzenberg and Carter, 2008). Hence it is plausible that modafinil 0 s effects may be via the DA system, which is consistent with known effects of dopamine on associative learning (Schultz et al., 1997). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Several efforts to develop pharmacological treatments with a beneficial effect on cognition in schizophrenia are underway, while cognitive remediation has shown modest effects on cognitive performance. Our goal was to test if pharmacological augmentation of cognitive training would result in enhancement of training-induced learning. We chose modafinil as the pharmacological augmenting agent, as it is known to have beneficial effects on learning and cognition. 49 participants with chronic schizophrenia were enroled in a double-blind, placebo-controlled study across two sites and were randomised to either modafinil (200mg/day) or placebo. All participants engaged in a cognitive training program for 10 consecutive weekdays. The primary outcome measure was the performance on the trained tasks and secondary outcome measures included MATRICS cognitive battery, proxy measures of everyday functioning and symptom measures. 84% of the participants completed all study visits. Both groups showed significant improvement in the performance of the trained tasks suggesting potential for further learning. Modafinil did not induce differential enhancement on the performance of the trained tasks or any differential enhancement of the neuropsychological and functional measures compared to placebo. Modafinil showed no significant effects on symptom severity. Our study demonstrated that combining pharmacological compounds with cognitive training is acceptable to patients and can be implemented in large double-blind randomised controlled trials. The lack of differential enhancement of training-induced learning raises questions, such as choice and optimal dose of drug, cognitive domains to be trained, type of cognitive training, intervention duration and chronicity of illness that require systematic investigation in future studies. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.
    European Neuropsychopharmacology 03/2015; 25(8). DOI:10.1016/j.euroneuro.2015.03.009 · 4.37 Impact Factor
Show more