Ballon JS, Feifel D. A systematic review of modafinil: Potential clinical uses and mechanisms of action. J Clin Psychiatry 67: 554-566

Department of Psychiatry, University of California, San Diego, CA, USA.
The Journal of Clinical Psychiatry (Impact Factor: 5.5). 05/2006; 67(4):554-66. DOI: 10.4088/JCP.v67n0406
Source: PubMed


Modafinil is a novel wake-promoting agent that has U.S. Food and Drug Administration approval for narcolepsy and shift work sleep disorder and as adjunctive treatment of obstructive sleep apnea/hypopnea syndrome. Modafinil has a novel mechanism and is theorized to work in a localized manner, utilizing hypocretin, histamine, epinephrine, gamma-aminobutyric acid, and glutamate. It is a well-tolerated medication with low propensity for abuse and is frequently used for off-label indications. The objective of this study was to systematically review the available evidence supporting the clinical use of modafinil.
The search term modafinil OR Provigil was searched on PubMed. Selected articles were mined for further potential sources of data. Abstracts from major scientific conferences were reviewed. Lastly, the manufacturer of modafinil in the United States was asked to provide all publications, abstracts, and unpublished data regarding studies of modafinil.
There have been 33 double-blind, placebo-controlled trials of modafinil. Additionally, numerous smaller studies have been performed, and case reports of modafinil's use abound in the literature.
Modafinil is a promising drug with a large potential for many uses in psychiatry and general medicine. Treating daytime sleepiness is complex, and determining the precise nature of the sleep disorder is vital. Modafinil may be an effective agent in many sleep conditions. To date, the strongest evidence among off-label uses exists for the use of modafinil in attention-deficit disorder, postanesthetic sedation, and cocaine dependence and withdrawal and as an adjunct to antidepressants for depression.

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    • "As a nonamphetamine stimulant with low abuse liability, modafinil may be a safe alternative for treatment of fatigue syndrome and psychiatric disorders such as treatmentresistant depression and attention deficit/hyperactivity disorder (Minzenberg and Carter 2008; Swanson et al. 2006). Despite the widespread clinical use of modafinil, the precise mechanisms underlying its therapeutic efficacy are complex and not well understood (for review, see Ballon and Feifel 2006; Minzenberg and Carter 2008). Modafinil is reported to affect many central neurotransmitter systems: dopamine, norepinephrine, 5-hydroxytryptamine, glutamate, GABA, histamine, and orexin. "
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    ABSTRACT: Seizures occur when the excitability of brain circuits is not sufficiently restrained by inhibitory mechanisms. Although modafinil is reported to reduce GABA-activated currents and extracellular GABA levels in the brain, the drug exerts anticonvulsant effects in animal studies. The aim of this study was to determine the effects of modafinil and its metabolites (sulfone and carboxylic acid) on the anticonvulsant action of four classical antiepileptic drugs (AEDs)-carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), and valproate (VPA). Anticonvulsant activity was assessed with the maximal electroshock seizure threshold (MEST) test and MES test in mice. Brain concentrations of AEDs were measured to ascertain any pharmacokinetic contribution to the observed anticonvulsant effects. Intraperitoneal injection of 75 mg kg(-1) of modafinil or its metabolites significantly elevated the threshold for electroconvulsions in mice, whereas 50 mg kg(-1) of each compound enhanced the anticonvulsant activity of CBZ, PHT, and VPA, but not that of PB. A 25-mg kg(-1) dose of modafinil or its sulfone metabolite enhanced anticonvulsant activity of VPA. Modafinil and its metabolites (50 mg kg(-1)) did not alter total brain concentrations of PB and VPA but did elevate CBZ and PHT. Enhancement of anticonvulsant actions of VPA by modafinil in the mouse MES model is a pharmacodynamic effect. Collectively, our data suggest that modafinil may be a safe and beneficial adjunct to the therapeutic effects of AEDs in human patients.
    Psychopharmacology 02/2015; 232(14). DOI:10.1007/s00213-015-3884-3 · 3.88 Impact Factor
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    • "These effects of MD on memory have also been described in psychiatric patients, suggesting that this drug is an excellent candidate agent for treatment of cognitive dysfunction in psychiatric disorders [7] [8] [9]. In addition, clinical research has shown that MD improves symptoms in patients with major depression, bipolar disorder, schizophrenia, and attentiondeficit/hyperactivity disorder (ADHD) [10] [11] [12]. "
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    ABSTRACT: The effects of modafinil (MD) on behavioral and oxidative damage to protein and lipid in the brain of rats were evaluated. Wistar rats were given a single administration by gavage of water or MD (75, 150, or 300 mg/kg). Behavioral parameters were evaluated in open-field apparatus 1, 2, and 3 h after drug administration. Thiobarbituric acid reactive substances (TBARS) and protein carbonyl formation were measured in the brain. MD increased locomotor activity at the highest dose 1 and 3 h after administration. MD administration at the dose of 300 mg/kg increased visits to the center of open-field 1 h after administration; however, 3 h after administration, all administered doses of MD increased visits to the open-field center. MD 300 mg/kg increased lipid damage in the amygdala, hippocampus, and striatum. Besides, MD increased protein damage in the prefrontal cortex, amygdala, and hippocampus; however, this effect varies depending on the dose administered. In contrast, the administration of MD 75 and 300 mg/kg decreased the protein damage in the striatum. This study demonstrated that the MD administration induces behavioral changes, which was depending on the dose used. In addition, the effects of MD on oxidative damage parameters seemed to be in specific brain region and doses.
    Behavioural neurology 11/2014; 2014:917246. DOI:10.1155/2014/917246 · 1.45 Impact Factor
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    • "This raises the important question of whether popular drugs like modafinil, a putative cognitive enhancer that has been recently reported to be used by healthy individuals for cognitive enhancement (Franke et al., 2013; Mohamed & Sahakian, 2012), boosts brain systems associated with creativity performance in the same way it has been reported to affect executive functions and working memory in healthy individuals (Turner et al., 2003). Modafinil is a drug licensed for the treatment of narcolepsy (Ballon & Feifel, 2006). It has been consistently reported to be used by healthy people for cognitive enhancement purposes (Franke et al., 2013; Mohamed, 2014; Mohamed & Sahakian, 2012). "
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    ABSTRACT: Modafinil is a drug licensed for the treatment of narcolepsy and sleep apnea. Recently, modafinil has been reported to be used as a pharmacological cognitive enhancer by healthy individuals with no psychiatric disorders. This paper reports on a study that investigated the effects of modafinil on divergent and convergent thinking tasks of creativity. Sixty-four healthy male (n = 31) and female (n = 33) volunteers participated in a randomized double-blind placebo-controlled parallel group design study. For the convergent thinking tasks, modafinil had no significant main effect on the Group Embedded Figures Task and the Remote Associates Task (RAT). However, a median split analysis showed that modafinil participants low in creativity personality trait had significantly higher RAT scores (Mean [M] = 6.85, SD = 3.39; 95% confidence interval [95% CI]: 5.53–8.2) than those high in creativity personality trait (M = 4.27, SD = 3.0; 95% CI: 2.4–6.0). For the divergent thinking tasks, relative to placebo (M = 1.195, SD = 0.28; 95% CI: 1.0–1.3), modafinil (M = 0.77, SD = 0.37; 95% CI: 0.63–0.92) significantly reduced the performance of flexibility scores and marginally reduced the elaboration scores as measured by the Abbreviated Torrance Test for Adults (ATTA). Overall, participants on modafinil (M = 6.3, SD = 2.6; 95% CI: 5.3–7.4) had significantly lower ATTA scores relative to participants on placebo (M = 9.5, SD = 2.3; 95% CI: 8.6–10.4). These results indicate that modafinil might reduce divergent thinking of creativity in healthy individuals. They suggest that, rather than being a more general cognitive enhancer, modafinil might have negative and subtle effects on creativity. However, the results are from a small-scale trial, which tested a small number of participants. Therefore, the results need to be interpreted with caution. A replication with a large sample of participants is recommended.
    The Journal of creative behavior 09/2014; DOI:10.1002/jocb.73 · 1.10 Impact Factor
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