Modulatory Effects of Modafinil on Neural Circuits Regulating Emotion and Cognition The cognitive-enhancing properties of modafinil are limited in non-sleep-deprived middle-aged volunteers Modafinil modulates anterior cingulate function in chronic schizophrenia. Modafinil Improves Cognition and Attentional Set Shifting in Patients with Chronic Schizophrenia Effects of Modafinil on Emotional Processing in First Episode Psychosis Cognitive enhancing effects of modafinil in healthy volunteers Modafinil Alters Intrinsic Functional Connectivity of the Right Posterior Insula: A Pharmacological Resting State fMRI Study Benefits of adjunct modafinil in an open-label, pilot study in patients with schizophrenia Modafinil treatment for fatigue associated with fibromyalgia. Effects of Modafinil on Wakefulness and Executive Function in Patients With Narcolepsy Experiencing Late-Day Sleepiness The effects of modafinil and cognitive behavior therapy on sleep continuity in patients with primary insomnia. Modafinil activates cortical and subcortical sites in the sleep-deprived state. The Effects of Modafinil, Caffeine, and Dextroamphetamine on Judgments of Simple Versus Complex Emotional Expressions Following Sleep Deprivation The effects of caffeine, dextroamphetamine, and modafinil on humor appreciation during sleep deprivation. Effects of modafinil on cognitive functions in first episode psychosis Effects of modafinil on working memory processes in humans Effect of Modafinil on Learning and Task-Related Brain Activity in Methamphetamine-Dependent and Healthy Individuals Modafinil improves alertness, vigilance, and executive function during simulated night shifts. Modafinil for attentional and psychomotor dysfunction in advanced cancer: a double-blind, randomised, cross-over trial The effect of modafinil on counter-regulatory and cognitive responses to hypoglycaemia Cerebral blood flow changes in man by wake-promoting drug, modafinil: a randomized double blind study. Modafinil for clozapine-treated schizophrenia patients: a double-blind, placebo-controlled pilot trial. Influence of modafinil on somatosensory input processing in the human brain-stem
Modafinil differs from other arousal-enhancing agents in chemical structure , neurochemical profile , and behavioral effects . Most functional neuroimaging studies to date examined the effect of modafinil only on information processing underlying executive cognition , but cognitive enhancers in general have been shown to have pronounced effects on emotional behavior , too . We examined the effect of modafinil on neural circuits underlying affective processing and cognitive functions . Healthy volunteers were enrolled in this double-blinded placebo-controlled trial ( 100 mg/day for 7 days ) . They underwent BOLD fMRI while performing an emotion information-processing task that activates the amygdala and two prefrontally dependent cognitive tasks — a working memory ( WM ) task and a variable attentional control ( VAC ) task . A clinical assessment that included measurement of blood pressure , heart rate , the Hamilton anxiety scale , and the profile of mood state ( POMS ) question naire was also performed on each test day . BOLD fMRI revealed significantly decreased amygdala reactivity to fearful stimuli on modafinil compared with the placebo condition . During executive cognition tasks , a WM task and a VAC task , modafinil reduced BOLD signal in the prefrontal cortex and anterior cingulate . Although not statistically significant , there were trends for reduced anxiety , for decreased fatigue-inertia and increased vigor-activity , as well as decreased anger-hostility on modafinil . Modafinil in low doses has a unique physiologic profile compared with stimulant drugs : it enhances the efficiency of prefrontal cortical cognitive information processing , while dampening reactivity to threatening stimuli in the amygdala , a brain region implicated in anxiety Modafinil is a selective wakefulness-promoting agent that has been shown to enhance cognitive performance under conditions of sleep deprivation but which has equivocal effects in normal young volunteers . In a double-blind parallel group design study , 45 non-sleep-deprived middle-aged volunteers ( 20 men and 25 women , aged 50 - 67 years ) were r and omly allocated to receive two capsules containing placebo , 100 or 200 mg modafinil , and 3 h later they completed  100 mm visual analogue scales of mood and bodily symptoms  , before and after an extensive battery of cognitive tests [ pen and paper and the Cambridge Neuropsychological Test Automated Battery ( CANTAB ) ] . There were no significant treatment-associated changes in ratings of mood or bodily symptoms and no significant effects on most of the cognitive tests used in this study . The group treated with modafinil ( 200 mg ) was significantly faster in a simple colour naming of dots and also significantly better in a test of constructional ability ( Clock Drawing Test ) compared with the placebo group . However , subjects in the 200-mg group also made significantly more total errors in the Intra/Extradimensional Set Shift ( ID/ED ) task than both the other groups . Thus , this study found limited evidence of cognitive-enhancing properties of modafinil in healthy middle-aged volunteers BACKGROUND Schizophrenia is associated with widespread cognitive deficits that have an impact on social function . Modafinil promotes wakefulness and is reported to enhance cognition . AIMS To study the acute effects of modafinil administration upon brain activity and cognitive performance in people with chronic schizophrenia . METHOD In a r and omised double-blind placebo-controlled crossover design , 19 patients received either modafinil ( 100 mg ) or placebo prior to undertaking a working memory task with functional magnetic resonance imaging . RESULTS Seventeen patients completed the study and another underwent acute relapse 4 days post-drug . Modafinil administration was associated with significantly greater activation in the anterior cingulate cortex during the working memory task . The anterior cingulate cortex signal correlated with cognitive performance , although only a subset of patients exhibited ' enhancement ' . CONCLUSIONS Modafinil modulates anterior cingulate cortex function in chronic schizophrenia but its beneficial cognitive effects may be restricted to a subset of patients requiring further characterisation Modafinil , a novel cognitive enhancer , selectively improves neuropsychological task performance in healthy volunteers and adult patients with attention deficit hyperactivity disorder ( ADHD ) . It has been argued that persistent cognitive deficits in patients with schizophrenia are responsible for the failure of many patients to rehabilitate socially even when psychotic symptoms are in remission . The present study examined the potential of modafinil as a cognitive enhancer in schizophrenia . Twenty chronic patients with a diagnosis of schizophrenia were entered into a double-blind , r and omized , placebo-controlled crossover study using a 200 mg dose of modafinil . Modafinil had some cognitive enhancing properties in schizophrenia similar to those observed in healthy adults and adult patients with ADHD . Improvement was seen on short-term verbal memory span , with trends towards improved visual memory and spatial planning . This was accompanied by slowed response latency on the spatial planning task . No effect on stop-signal performance was seen . Importantly , significant improvement in attentional set shifting was seen , despite no effect of modafinil on this task being seen in healthy volunteers or ADHD patients . Modafinil may have potential as an important therapy for cognitive impairment in patients with schizophrenia , particularly because of its beneficial effects on attentional set shifting BACKGROUND Emotional impairments are important determinants of functional outcome in psychosis , and current treatments are not particularly effective . Modafinil is a wake-promoting drug that has been shown to improve emotion discrimination in healthy individuals and attention and executive function in schizophrenia . We aim ed to establish whether modafinil might have a role in the adjuvant treatment of emotional impairments in the first episode of psychosis , when therapeutic endeavor is arguably most vital . METHODS Forty patients with a first episode of psychosis participated in a r and omized , double-blind , placebo-controlled crossover design study testing the effects of a single dose of 200 mg modafinil on neuropsychological performance . Emotional functions were evaluated with the  emotional face recognition test  , the  affective go-no go task  , and the  reward and punishment learning test . Visual analogue scales were used throughout the study to assess subjective mood changes . RESULTS Modafinil significantly improved the recognition of sad facial expressions ( z = 2.98 , p = .003 ) . In contrast , there was no effect of modafinil on subjective mood ratings , on tasks measuring emotional sensitivity to reward or punishment , or on interference of emotional valence on cognitive function , as measured by the affective go-no go task . CONCLUSIONS Modafinil improves the analysis of emotional face expressions . This might enhance social function in people with a first episode of psychosis Abstract Rationale . Modafinil , a novel wake-promoting agent , has been shown to have a similar clinical profile to that of conventional stimulants such as methylpheni date . We were therefore interested in assessing whether modafinil , with its unique pharmacological mode of action , might offer similar potential as a cognitive enhancer , without the side effects commonly experienced with amphetamine-like drugs . Objectives . The main aim of this study was to evaluate the cognitive enhancing potential of this novel agent using a comprehensive battery of neuropsychological tests . Methods . Sixty healthy young adult male volunteers received either a single oral dose of placebo , or 100 mg or 200 mg modafinil prior to performing a variety of tasks design ed to test memory and attention . A r and omised double-blind , between-subjects design was used . Results . Modafinil significantly enhanced performance on tests of digit span , visual pattern recognition memory , spatial planning and stop-signal reaction time . These performance improvements were complemented by a slowing in latency on three tests : delayed matching to sample , a decision-making task and the spatial planning task . Subjects reported feeling more alert , attentive and energetic on drug . The effects were not clearly dose dependent , except for those seen with the stop-signal paradigm . In contrast to previous findings with methylpheni date , there were no significant effects of drug on spatial memory span , spatial working memory , rapid visual information processing or attentional set-shifting . Additionally , no effects on paired associates learning were identified . Conclusions . These data indicate that modafinil selectively improves neuropsychological task performance . This improvement may be attributable to an enhanced ability to inhibit pre-potent responses . This effect appears to reduce impulsive responding , suggesting that modafinil may be of benefit in the treatment of attention deficit hyperactivity disorder Background Modafinil is employed for the treatment of narcolepsy and has also been , off-label , used to treat cognitive dysfunction in neuropsychiatric disorders . In a previous study , we have reported that single dose administration of modafinil in healthy young subjects enhances fluid reasoning and affects resting state activity in the Fronto Parietal Control ( FPC ) and Dorsal Attention ( DAN ) networks . No changes were found in the Salience Network ( SN ) , a surprising result as the network is involved in the modulation of emotional and fluid reasoning . The insula is crucial hub of the SN and functionally divided in anterior and posterior subregions . Methodology Using a seed-based approach , we have now analyzed effects of modafinil on the functional connectivity ( FC ) of insular subregions . Principal Findings Analysis of FC with resting state fMRI ( rs-FMRI ) revealed increased FC between the right posterior insula and the putamen , the superior frontal gyrus and the anterior cingulate cortex in the modafinil-treated group . Conclusions Modafinil is considered a putative cognitive enhancer . The rs-fMRI modifications that we have found are consistent with the drug cognitive enhancing properties and indicate subregional targets of action . Trial Registration Clinical Trials.gov Patients with schizophrenia experience cognitive impairments associated with hypofunctioning of the frontal cortex . Modafinil , a novel wake-promoting agent , works through the sleep – wake centers of the brain to activate the cortex . This 4-week , open-label , pilot study evaluated adjunct modafinil in patients with schizophrenia or schizoaffective disorder . Eleven patients received once-daily oral doses of modafinil ( 100 mg/day , days 1–14 ; 100 or 200 mg/day , days 15–28 ) in addition to antipsychotic therapy . Modafinil significantly improved patients ' global functioning as assessed by a blinded clinician ( week 2 , P = 0.026 ; week 4 , P = 0.012 ) and the investigator ( week 3 , P = 0.035 ) . Modafinil significantly improved overall clinical condition , with 64 % and 82 % of patients rated as clinical ly improved at week 4 by a blinded clinician and the investigator respectively . Eighty-nine percent of patients considered themselves to be clinical ly improved . Modafinil significantly improved fatigue ( P = 0.025 , week 3 ) and tended to improve cognitive functioning scores . Control of positive symptoms was well maintained . Treatment-emergent adverse events included dry mouth ( n = 2 ) and hallucinations ( n = 2 ) . One patient discontinued the study because of hallucinations that were considered to be possibly related to inadequate antipsychotic therapy . Although preliminary , these results suggest modafinil may be an effective and well-tolerated adjunct treatment that improves global functioning and clinical condition , and reduces fatigue in patients with schizophrenia or schizoaffective disorder . Additional controlled studies are warranted Fatigue , which may occasionally be the chief manifestation , is present in more than 90 % of patients with fibromyalgia . It is a significant cause of morbidity and is quite disabling in its ability to disrupt quality of life . The cause of fatigue is complex , but disturbances in sleep architecture may have a role to play . Modafinil , a nonamphetamine wake-promoting agent and a popular treatment of narcolepsy , displays its antifatigue properties through a potentially central prohistaminergic interplay and may conceptually be postulated to lower fatigue in fibromylagia patients as well . Modafinil , unlike amphetamines , is well tolerated with less peripheral hemodynamic alterations combined with low abuse and tolerance sequelae . It also improves vigilance in sleep-deprived patients . Modafinil has been suggested as a possible treatment of fatigue in multiple sclerosis , parkinsonism , depression , primary biliary cirrhosis among other disorders with some demonstrable benefit . Since fatigue constitutes a significant proportion of the morbidity associated with fibromyalgia , we have conducted a retrospective chart review of 98 patients who have fibromyalgia , were being treated by a rheumatologist and 2 nurse practitioners in a private practice setting , and had been given a prescription for modafinil .  Patients were involved in this usual practice setting , and the clinicians documented patient encounters in a st and ard medical record format . The charts were review ed by 5 outside psychiatric clinicians from SUNY Upstate Medical University ’s Depression and Anxiety Disorders Research Program . The study team attempted to exclude charts where there may have been other medical comorbidities that may have induced fatigue and also excluded charts where the initiation of modafinil coincided with the initiation of any other off-label fibromyalgia treatment ( i.e. , duloxetine , amytriptyline , tramadol , etc ) . An analog rating scale was created for this chart review as notes had to be read by study clinicians and retrospective assessment s were made regarding any change in fatigue . This simple scale used a method of visual quantitation of subjective symptomatology change with regard to fatigue . This ranged from a level of 1 , indicative of low fatigue , to 10 , as a representative of the diametrically opposite extreme of marked symptom fatigue . The 5 clinician raters were calibrated to 0.8 accuracy to decrease inter-rater reliability bias . Progress notes were also scanned for reported side effects and for reasons why modafinil may have been discontinued . The average age of the patients was 47 years , and the average dose of modafinil was 162 mg/d , with an average duration of treatment spanning 2 years . The average number of concomitant medications was eight . The mean pre and postfatigue analog scale scores were analyzed and significant statistical difference was demonstrated whereby modafinil augmentation lowered patient fatigue levels from 7.2 0.13 ( severe fatigue ) to 4.4 0.18 ( low-moderate fatigue ( P 0.001 ) . The net mean improvement in fatigue as a target symptom was approximately 28 % . There is often little focus on the fatigue that is commonly reported by these patients . Our simple , retrospective study may be the first that focuses on the use of modafinil for alleviating this symptom . In our retrospective chart review , we found a majority of patients to be involved in both polypharmacy regimens and nonpharmacologic treatment ( i.e. , biofeedback ) as well . The timing of modafinil addition and fatigue amelioration suggests that this agent may be able to effectively treat the fatigue associated with fibromyalgia . It is also a well-tolerated drug with a minimum of side effects reported . These observations should encourage the development of prospect i ve controlled studies Objectives : A modafinil daily dosing strategy promotes wakefulness in narcolepsy patients experiencing excessive daytime sleepiness ; however , some patients may continue to experience late-day sleepiness . Excessive sleepiness in narcolepsy is associated with cognitive impairment . Modafinil has improved executive function in other models of excessive sleepiness . This study evaluated the effects of once-daily vs. split doses of modafinil on wakefulness and of combined doses on executive function in narcolepsy patients experiencing late-day sleepiness despite satisfactory modafinil treatment earlier in the day . Methods : After a 2-week washout , 24 patients received 3 weeks of double-blind treatment with modafinil 400-mg once daily ( 7 AM ) plus placebo ( noon ) or modafinil 600-mg split dose ( 400 mg , 7 AM ; 200 mg , noon ) . Assessment s included a Maintenance of Wakefulness Test ( MWT ) for individual regimens and the Wisconsin Card Sort Test ( WCST ) for treatments combined . Results : Modafinil 600-mg split dose was significantly more effective than modafinil 400-mg once daily in improving late-day MWT scores ( 5 PM–7 PM ; P < 0.05 ) . Significant mean ( ± SEM ) reductions from baseline of 8.2 ± 2.7 in the total number of errors and 5.9 ± 1.9 in total percent of errors ( P < 0.05 , both ) were demonstrated for modafinil on the WCST . Modafinil was well tolerated ; adverse events included headache ( n = 1 ) , emotional lability ( n = 1 ) , bronchitis ( n = 1 ) , and accidental injury ( n = 2 ) , with no reports of insomnia . Conclusions : For patients with residual late-day sleepiness associated with narcolepsy , an additional 200-mg dose of modafinil taken at midday was effective in sustaining wakefulness throughout the entire waking day . Treatment with modafinil also significantly improved executive function BACKGROUND Daytime fatigue , if not frank sleepiness , is a common symptom among patients with insomnia , one that is exacerbated during acute treatment with cognitive behavior therapy ( CBT ) . The present study was undertaken to assess whether modafinil could be used to reduce daytime fatigue , sleepiness , or both in patients with primary insomnia and whether the pharmacologic augmentation of wakefulness might produce improved sleep by itself or in combination with CBT . METHODS 30 subjects with primary insomnia were enrolled in this study and were r and omly assigned to 1 of 3 treatment conditions : ( 1 ) placebo plus CBT , ( 2 ) 100 mg modafinil plus CBT , or ( 3 ) 100 mg modafinil plus a contact control ( monitor-only condition ) . Subjects were continuously monitored with sleep diaries from study intake until study end ( 10 weeks ) and were evaluated on a weekly basis for changes in sleepiness . RESULTS The mean age of the group was 41.3 years ( SD , 13.4 ) , and 70.4 % of subjects were women . All 3 groups exhibited mean sleep latency and wake after sleep-onset times that were more than 30 minutes in duration . The mean pretreatment sleep profiles did not significantly differ . Modafinil , when administered alone , did not significantly affect the patients ' sleep profiles . A trend , however , was evident for improved sleep latency . Modafinil , as an adjunct to CBT , tended to ( 1 ) reduce daytime sleepiness as measured by the Epworth Sleepiness Scale and ( 2 ) enhance compliance with CBT .  With respect to the latter , subjects in the modafinil plus CBT group more reliably adhered to the prescribed phase delay in bedtime than did the placebo plus CBT group . DISCUSSION These data suggest that modafinil may be used to diminish the negative side effects of CBT ( increased daytime sleepiness ) and may increase subject compliance with therapy . Whether enhanced daytime function mediates the change in adherence and whether reduced sleepiness and enhanced compliance translate to less patient attrition in the clinical setting remain to be evaluated UNLABELLED SUBJECT OBJECTIVES : To assess the effect of the wake-promoting drug modafinil on working memory and brain activation in the executive network , following a single night of sleep deprivation . DESIGN R and omized , placebo-controlled , 4-arm , double-blind evaluation of a single 200-mg dose of modafinil on working memory ( 1- , 2- , and 3-back)-related functional brain activation and performance following overnight sleep deprivation . SETTING General Clinical Research Center , Biomedical Imaging Center . SUBJECTS Eight medication-free men , aged 21 to 35 years . INTERVENTIONS Overnight sleep deprivation , single-dose 200-mg modafinil , functional magnetic resonance imaging MEASUREMENTS AND RESULTS Brain activation patterns and regional signal intensity based on the blood-oxygen level-dependent signal were assessed . The following reaction times were used as measures of performance : ( 1 ) attention in the scanner before functional scanning , ( 2 ) " back " responses during the active-task block , and ( 3 ) attention during the baseline task block . Contrast of activation maps among conditions revealed sleep-deprivation and drug effects , and their interactions . Performance in the deprived state was enhanced by modafinil only at an intermediate ( 2-back ) level of task difficulty and was associated with the recruitment of increased cortical activation volumes . Strong and consistent individual differences in performance were noted on the working memory tasks . CONCLUSIONS Modafinil effectively counters the adverse effects of overnight sleep deprivation on working memory but only when task difficulty is moderate , recruiting extensive areas in the executive network to do so . Interindividual differences in working-memory performance are stable trait characteristics Cognitive abilities such as vigilance , attention , memory , and executive functioning can be de grade d significantly following extended periods of wakefulness . Although much evidence suggests that sleep-loss induced deficits in alertness and vigilance can be reversed or mitigated by stimulants such as caffeine , it is not clear how these compounds may affect other higher level cognitive processes such as emotional perception and judgment . Following 47 h of sleep deprivation , the study examined the effect of three stimulant medications ( modafinil 400 mg , dextroamphetamine 20 mg , caffeine 600 mg ) or placebo on the ability of 54 healthy participants to discriminate and label simple emotional expressions versus complex affect blends ( created by morphing photographs of two different affective facial expressions ) . For simple affective faces , neither sleep loss nor stimulant medications made any difference on the accuracy of judgments . In contrast , for complex emotion blends , all three stimulant medications significantly improved the ability to discriminate subtle aspects of emotion correctly relative to placebo , but did not differ from one another . These findings suggest that all three stimulant medications are effective at restoring some aspects of subtle affective perception STUDY OBJECTIVES Sleep loss consistently impairs performance on measures of alertness , vigilance , and response speed , but its effects on higher-order executive functions are not well delineated . Similarly , whereas deficits in arousal and vigilance can be temporarily countered by the use of several different stimulant medications , it is not clear how these compounds affect complex cognitive processes in sleep-deprived individuals . DESIGN We evaluated the effects of double-blind administration of 3 stimulant medications or placebo on the ability to appreciate humor in visual ( cartoons ) or verbal ( headlines ) stimuli presented on a computer screen following 49.5 hours of sleep deprivation . SETTING In-residence sleep-laboratory facility at the Walter Reed Army Institute of Research . PARTICIPANTS Fifty-four healthy adults ( 29 men , 24 women ) , ranging in age from 18 to 36 years . INTERVENTIONS Each participant was r and omly assigned to 1 of 3 stimulant medication groups , including caffeine , 600 mg , n = 12 ; modafinil , 400 mg , n = 11 ; dextroamphetamine , 20 mg , n = 16 ; or placebo , n = 14 . MEASUREMENTS AND RESULTS Humor appreciation for cartoon stimuli was enhanced by modafinil relative to both placebo and caffeine , but there was no effect of any stimulant medication on the appreciation of verbal humor during sleep loss . In contrast , all 3 stimulants improved psychomotor response speed , whereas only caffeine and dextroamphetamine improved ratings of subjective sleepiness . CONCLUSIONS Findings suggest that , despite similar alerting and vigilance-promoting effects , these 3 compounds have significantly different effects on those highly complex cognitive abilities mediated by the pre-frontal cortex Rationale Cognitive impairments are important determinants of functional outcome in psychosis , which are inadequately treated by antipsychotic medication . Modafinil is a wake-promoting drug that has been shown to improve attention , memory and executive function in the healthy population and in patients with schizophrenia . Objectives We aim ed to establish modafinil ’s role in the adjunctive treatment of cognitive impairments in the first episode of psychosis , a time when symptoms may be more malleable than at chronic stages of the disease . Methods Forty patients with a first episode of psychosis participated in a r and omised , double-blind , placebo-controlled crossover design study assessing the effects of a single dose of 200 mg modafinil on measures of executive functioning , memory , learning , impulsivity and attention . Results Modafinil improved verbal working memory ( d = 0.24 , p = 0.04 ) , spatial working memory errors ( d = 0.30 , p = 0.0004 ) and strategy use ( d = 0.23 , p = 0.03 ) . It also reduced discrimination errors in a task testing impulsivity . Modafinil showed no effect on impulsivity measures , sustained attention , attentional set-shifting , learning or fluency . Conclusions Modafinil selectively enhances working memory in first episode psychosis patients , which could have downstream effects on patients ’ social and occupational functioning Rationale 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 , underst and ing of the cognitive enhancing effects of modafinil and the relevant neurobiological mechanisms are incomplete . Objectives 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 . Methods 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 st and ardized paper pencil tasks of attentional functions . Results 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 . Conclusions 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 study ing the noradrenergic modulation of the prefrontal cortex Methamphetamine (MA)-dependent individuals exhibit deficits in cognition and prefrontal cortical function . Therefore , medications that improve cognition in these subjects may improve the success of therapy for their addiction , especially when cognitive behavioral therapies are used . Modafinil has been shown to improve cognitive performance in neuropsychiatric patients and healthy volunteers . We therefore conducted a r and omized , double-blind , placebo-controlled , cross-over study , using functional magnetic resonance imaging , to examine the effects of modafinil on learning and neural activity related to cognitive function in abstinent , MA-dependent , and healthy control participants .  Modafinil ( 200 mg ) and placebo were administered orally ( one single dose each ) , in counterbalanced fashion , 2 h before each of two testing sessions . Under placebo conditions , MA-dependent participants showed worse learning performance than control participants . Modafinil boosted learning in MA-dependent participants , bringing them to the same performance level as control subjects ; the control group did not show changes in performance with modafinil . After controlling for performance differences , MA-dependent participants showed a greater effect of modafinil on brain activation in bilateral insula/ventrolateral prefrontal cortex and anterior cingulate cortices than control participants . The findings suggest that modafinil improves learning in MA-dependent participants , possibly by enhancing neural function in regions important for learning and cognitive control . These results suggest that modafinil may be a suitable pharmacological adjunct for enhancing the efficiency of cognitive-based therapies for MA dependence STUDY OBJECTIVES To assess the effect of 200 mg of modafinil compared to placebo on alertness , neurobehavioral performance , and executive function during 4 consecutive simulated night shifts . DESIGN Double-blind , r and omized , parallel groups . SETTING Sleep research facility . PARTICIPANTS 32 male and female volunteers between the ages of 18 and 55 years . INTERVENTIONS 200 mg of modafinil or placebo given nightly on the 4 consecutive simulated night shifts . MEASUREMENTS AND RESULTS Subjects were r and omly assigned to 1 of the 2 treatment conditions , following medical , psychiatric , and polysomnographic screening . On 4 consecutive nights , subjects took study drug at 2200 , and then from about 2300 to 0730 participated in a simulated night shift that included the Maintenance of Wakefulness Test , Psychomotor Vigilance Test , Digit Symbol Substitution Test , measures of subjective alertness , and multiple executive-function measures . At 0800 , daytime sleep periods were recorded polysomnographically for 6 to 8 hours . Alertness -- as measured by the MWT , vigilance and reaction time as indexed by Psychomotor Vigilance Test lapses , and slowest 10 % of reaction times-- and 3 executive-function tasks showed significant enhancement with modafinil versus placebo .  Subjective sleepiness at night and some performance measures did not show consistent treatment differences . Daytime sleep showed minimal differences between conditions . CONCLUSIONS The physiologic sleepiness and neurobehavioral deficits that occurred during the hours of a typical night shift were clearly attenuated by modafinil . Modafinil also had beneficial effects on some measures of executive function Cognitive impairment seems to be highly prevalent in patients with advanced cancer .  Modafinil , a novel vigilance and wake-promoting agent , may be an alternative treatment . We wanted to investigate this treatment on attentional and psychomotor dysfunction in cancer patients . 28 cancer patients with a tiredness score of 50 mm or more on a scale of 0 to 10 ( 0=no tiredness , 10=worst possible tiredness ) and Karnofsky Performance Status 40—70 were included . All medications were kept stable during the trial despite short acting opioids for breakthrough pain . On day 1 the patients were r and omly assigned to receive 200 mg Modafinil orally or placebo and on day 4 they crossed-over to the alternative treatment .  Finger Tapping Test ( FTT ) , Trail Making Test ( TMT ) and Edmonton Symptom Assessment System ( ESAS ) were evaluated before tablet intake and again 4 , 5 hours after . FTT for the dominant h and as well as TMT were statistically significantly improved on modafinil ( p-values=0.006 and 0.042 , respectively ) . On ESAS , depression and drowsiness also improved statistically significantly ( p-values=<0.001 and 0.038 , respectively ) . Modafinil in a single dose regimen was significantly superior to placebo regarding two cognitive tests of psychomotor speed and attention . Furthermore subjective scores of depression and drowsiness were significantly improved by modafinil Aims /hypothesisOur hypothesis is that reducing release of the inhibitory neurotransmitter gamma-aminobutyric acid ( GABA ) with modafinil will enhance symptomatic and hormonal responses to hypoglycaemia . Methods Nine healthy men received , in r and om order , two 100-mg doses of modafinil or placebo , followed by an insulin clamp in which plasma glucose was either reduced stepwise to 2.4 mmol/l or was sustained at euglycaemia ( four studies ) . Catecholamines , symptom scores and cognitive function were measured . Results Modafinil had no effect on the measured parameters during euglycaemia . During hypoglycaemia , autonomic symptom scores were significantly higher with modafinil ( increase at lowest plasma glucose concentration 271.3±118.9 vs 211.2±80.4/40 min , p=0.019 ) , and the heart rate response was increased ( 12,928±184 vs 6773±148 bpm/140 min , p=0.016 ) . Deterioration in performance of two cognitive tasks was reduced : Stroop colour – word test ( 613±204 vs 2375±161/65 min , p=0.009 ) and accuracy of a simple reaction task ( 11.3±1.8 vs 9.4±3.7 , p=0.039 ) . Conclusions /interpretationWe conclude that modafinil improves adrenergic sensitivity and some aspects of cognitive function at hypoglycaemia , possibly by reducing neuronal central GABA concentrations To investigate the effects of a wake-promoting drug , modafinil on regional cerebral blood flow ( rCBF ) in healthy volunteers , we performed (99m)Tc-ethylcysteinate dimer single photon emission computed tomography ( SPECT ) before and after modafinil or placebo administration . Twenty-one healthy subjects received single doses of 400 mg modafinil or placebo in a double blind r and omized crossover study design . Administrations of modafinil or placebo in a subject were separated by a 2-week washout . Brain SPECT was performed twice before and 3 h after modafinil or placebo administration . For statistical parametric mapping analysis , all SPECT images were spatially normalized to the st and ard SPECT template and then smoothed using a 12-mm full width at half-maximum Gaussian kernel . The paired t-test was used to compare pre- versus post-modafinil and pre- versus post-placebo SPECT images . Differences in rCBF between post-modafinil and post-placebo conditions were also tested . Modafinil decreased Epworth and Stanford sleepiness scales whereas placebo did not . The post-modafinil condition was associated with increased rCBF in bilateral thalami and dorsal pons , whereas the post-placebo condition showed increased rCBF in a smaller area of the dorsal pons when compared with the drug naïve baseline condition . Compared with the post-placebo condition , the post-modafinil condition showed higher rCBF in bilateral frontopolar , orbitofrontal , superior frontal , middle frontal gyri , short insular gyri , left cingulate gyrus , left middle/inferior temporal gyri , left parahippocampal gyrus , and left pons . In healthy volunteers , modafinil increased wakefulness and rCBF in the arousal-related systems and in brain areas related to emotion and executive function BACKGROUND Patients with schizophrenia often suffer from cognitive deficits and negative symptoms that are poorly responsive to antipsychotics including clozapine . Clozapine-induced sedation can worsen cognition and impair social and occupational functioning . OBJECTIVES To evaluate the efficacy , tolerability , and safety of modafinil for negative symptoms , cognition , and wakefulness/fatigue in DSM-IV-diagnosed schizophrenia patients treated with clozapine . METHOD A double-blind , placebo-controlled , flexible-dosed 8-week pilot trial was conducted between September 2003 and September 2007 , adding modafinil up to 300 mg/d to stabilized schizophrenia out patients receiving clozapine .  Psychopathology , cognition , and wakefulness/fatigue were assessed with st and ard rating scales . RESULTS Thirty-five patients were r and omly assigned to treatment with study drug and included in the analysis . Modafinil did not reduce negative symptoms or wakefulness/fatigue or improve cognition compared to placebo . Modafinil was well tolerated and did not worsen psychosis . CONCLUSIONS Results of this pilot trial do not support routine use of modafinil to treat negative symptoms , cognitive deficits , or wakefulness/fatigue in patients on clozapine . However , given our limited power to detect a treatment effect and the clear possibility of a type II error , larger trials are needed to resolve or refute a potential therapeutic effect of uncertain magnitude . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00573417 OBJECTIVE Since high frequency oscillations ( HFOs ) evoked by upper limb stimulation are susceptible to arousal fluctuation , we verified whether administration of modafinil , a vigilance promoting drug , modifies such responses at different levels of the somatosensory system . METHODS HFOs were obtained in 6 healthy volunteers by 500 - 700 Hz filtering of right median nerve somatosensory evoked potentials , before and 2 hours after the administration of 100 mg modafinil . Raw data were further su bmi tted to brain electrical source analysis . RESULTS Modafinil significantly increased subcortical HFOs , as well as the strength of a dipolar source at the base of the skull . CONCLUSIONS Our data suggest that modafinil exerts its action also at the level of the brain-stem , where it interferes with the processing of somatosensory ascending inputs
A review of its effects in schizophrenia suggests that modafinil facilitates cognitive functions , with pro-mnemonic effects and problem solving improvements .
The systematic review on the neurochemical modulation of the modafinil suggests that its mnemonic enhancing properties might be the result of glutamatergic and dopaminergic increased neuronal activation in the hippocampus and in the prefrontal cortex respectively .
Other neurotransmitters were also activated by modafinil in various limbic brain areas , suggesting that the drug acts on these brain regions to influence emotional responses .
Modafinil is a central nervous system wake promoting agent used for the treatment of excessive daytime sleeping .
Its vigilance promoting properties and low abuse potential has intrigued the scientific community and has led to use it as a cognitive enhancer , before its neural functions were understood .
Here , we review the effects of modafinil in human cognition and emotion and its specific actions on symptoms in patients with schizophrenia and whether these are consistently effective throughout the literature .
We also performed a systematic review on the effects of modafinil on neurotransmitter signalling in different areas of the brain in order to better underst and the neuromechanisms of its cognitive and emotional enhancing properties .