A double-blind, placebo-controlled investigation of the efficacy of modafinil for sustaining the alertness and performance of aviators: a helicopter simulator study The cognitive-enhancing properties of modafinil are limited in non-sleep-deprived middle-aged volunteers Behavioral and subjective effects of d-amphetamine and modafinil in healthy adults. Effect of Pharmacological Enhancement on the Cognitive and Clinical Psychomotor Performance of Sleep-Deprived Doctors: A Randomized Controlled Trial The effect of modafinil on counter-regulatory and cognitive responses to hypoglycaemia Effects of modafinil on working memory processes in humans Cognitive performance following modafinil versus placebo in sleep-deprived emergency physicians: a double-blind randomized crossover study. Does Modafinil Enhance Cognitive Performance in Young Volunteers Who Are Not Sleep-Deprived? Modafinil activates cortical and subcortical sites in the sleep-deprived state. Effect of Modafinil on Learning and Task-Related Brain Activity in Methamphetamine-Dependent and Healthy Individuals Modafinil for daytime somnolence in Parkinson’s disease: double blind, placebo controlled parallel trial Self-monitoring cognitive performance during sleep deprivation: effects of modafinil, d-amphetamine and placebo. Modafinil affects mood, but not cognitive function, in healthy young volunteers. Modulatory Effects of Modafinil on Neural Circuits Regulating Emotion and Cognition Maintaining alertness and performance during sleep deprivation: modafinil versus caffeine Acute modafinil effects on attention and inhibitory control in methamphetamine-dependent humans. Functional magnetic resonance imaging neuroactivation studies in normal subjects and subjects with the narcoleptic syndrome. Actions of modafinil. Modafinil-induced hippocampal activation in narcolepsy Modafinil treatment for fatigue associated with fibromyalgia. Interest of modafinil, a new psychostimulant, during a sixty‐hour sleep deprivation experiment Modafinil Increases the Latency of Response in the Hayling Sentence Completion Test in Healthy Volunteers: A Randomised Controlled Trial The effects of caffeine, dextroamphetamine, and modafinil on humor appreciation during sleep deprivation. A placebo-controlled evaluation of adjunctive modafinil in the treatment of bipolar depression.
Abstract . Rationale : In 1998 , the FDA approved modafinil for treating  excessive daytime sleepiness in narcoleptics , and this has raised questions about the appropriateness of this compound for enhancing alertness in sleep-deprived controls . This study explored the efficacy of modafinil for maintaining the performance of volunteers required to accomplish highly dem and ing tasks despite sleep loss . Objective : The principal objective was to determine whether prophylactic doses of modafinil would attenuate decrements in aviator performance and arousal throughout 2 days and 1 night without sleep . Methods : Six pilots were exposed to two 40-h periods of continuous wakefulness . In one , three 200-mg doses of modafinil were given and in the other , matching placebos were administered . Helicopter simulator flights , resting EEGs , and Profile of Mood States ( POMS ) question naires were evaluated . Results : Modafinil attenuated sleep deprivation effects on four of six flight maneuvers , reduced slow-wave EEG activity , and lessened self-reported problems with mood and alertness in comparison to placebo . The most noticeable benefits occurred between 0330 and 1130 hours , when the combined impact of sleep loss and the circadian trough was most severe . The most frequently observed drug side effects were vertigo , nausea , and dizziness . These could have been related to : 1 ) the motion-based testing , 2 ) the use of a simulator rather than an actual aircraft ( i.e. , " simulator sickness " ) , and /or 3 ) the administration of more than 400 mg modafinil . Conclusions : Modafinil is a promising countermeasure for  sleep loss in normals ; however , additional studies aim ed at reducing side effects are needed before it should be used in aviators 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 Modafinil is indicated for the management of excessive daytime sleepiness ; however , recent studies have examined a broad range of potential uses . Given that clinical uses of modafinil may be exp and ing , this study compared modafinil and d-amphetamine effects on subjective and performance measures . Across 11 sessions , 11 healthy adults were tested after oral doses of placebo ( 5 sessions ) , modafinil ( 1.75 mg/kg , 3.50 mg/kg , or 7.00 mg/kg ) , and d-amphetamine ( 0.035 mg/kg , 0.070 mg/kg , 0.140 mg/kg ) under double-blind , r and omized conditions . Assessment s of cognitive performance and subjective effects were completed before drug administration , 30 min after drug administration , and at hourly intervals after drug administration for 5 hr . Modafinil increased ratings on the Amphetamine and Morphine Benzedrine Group scales of the Addiction Research Center Inventory ( ARCI ) and increased ratings on the Vigor and Total Positive scales of the Profile of Mood States .  d-Amphetamine increased visual analog ratings of feeling stimulated and liking the drug and increased ratings on the Morphine Benzedrine Group scale of the ARCI . Both medications significantly reduced visual analog scale ratings of feeling sleepy , and modafinil decreased ratings on the ARCI Pentobarbital-Chlorpromazine-Alcohol Group scale . Both medications sustained performance that deteriorated across time on the Sternberg Number Recognition Test . Modafinil also enhanced performance rate on the Digit-Symbol Substitution Task above baseline levels and increased response rate on the Repeated Acquisition of Response Sequences Task . These results suggest that modafinil engenders alerting effects and increases performance in healthy non-sleep-deprived individuals comparable with that of d-amphetamine Objectives : To investigate the effect of modafinil 200 mg on the performance of a cohort of healthy male doctors after 1 night of supervised sleep deprivation . Summary Background Data : Sleep-deprived and fatigued doctors pose a safety risk to themselves and their patients . Yet , because of the around-the-clock nature of medical practice , doctors frequently care for patients after periods of extended wakefulness or during circadian troughs . Studies suggest that a group of substances may be capable of safely and effectively reversing the effects of fatigue . However , little work has been done to investigate their role within our profession . Methods : We conducted a parallel , double-blind , r and omized , and placebo-controlled study to investigate the effect of pharmacological enhancement on performance doctors . Thirty-nine healthy male resident doctors received either lactose placebo ( n = 19 ) or modafinil 200 mg ( n = 20 ) after 1 night of sleep deprivation . A selection of CANTAB neuropsychological tests was used to assess higher cognitive function . Clinical psychomotor performance was assessed using the Minimally Invasive Surgical Trainer Virtual Reality . Assessment s were carried out between 6.00 AM and approximately 8.00 AM . Results : Modafinil improved performance on tests of higher cognitive function ; participants in the modafinil group worked more efficiently when solving working memory ( F 1,38 = 5.24 , P = 0.028 ) and planning ( F 1,38 = 4.34 , P = 0.04 ) problems , were less-impulsive decision makers ( F 1,37 = 6.76 , P = 0.01 ) , and were more able to flexibly redirect their attention ( F 1,38 = 4.64 , P = 0.038 ) . In contrast , no improvement was seen in tests of clinical psychomotor performance . Conclusions : Our results suggest that fatigued doctors might benefit from pharmacological enhancement in situations that require efficient information processing , flexible thinking , and decision making under time pressure . However , no improvement is likely to be seen in the performance of basic procedural tasks 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 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 OBJECTIVES Modafinil has recently been approved for the treatment of shift work sleep disorder , making it potentially available for shift-working emergency physicians . The authors ' objectives were to determine whether modafinil improved cognitive performance of emergency physicians following overnight shifts and to record symptoms and subjective evaluations of the effect of modafinil on the participants . METHODS This was a r and omized , double-blind , placebo-controlled crossover study that followed CONSORT guidelines . Participants were assigned to one of two study groups , with study sessions occurring at least seven weeks apart , and received either modafinil or placebo depending on their r and om allocation . Testing after night shifts included a coding task and an AX version of the Continuous Performance Task , both of which test cognitive function . Participants also completed visual analog scales for three subjective outcomes , and symptoms were elicited . RESULTS Modafinil facilitated performance on long interstimulus-interval AX trials ( F [ 1 , 23 ] = 6.65 , p = 0.1 ) and marginally reduced errors on AY trials in the Continuous Performance Task ( F [ 1 , 23 ] = 3.59 , p = 0.07 ) , suggesting facilitation of sustained attention , cognitive control , and working memory . Additionally , modafinil , compared with placebo , facilitated performance on the coding task at the first session . Subjective data from visual analog scales confirmed that modafinil increased perceived alertness during the simulated patient care sessions but worsened sleep onset when opportunities for sleep arose . CONCLUSIONS Modafinil increased certain aspects of cognitive function and subjectively improved participants ' ability to attend post-night-shift didactic sessions but made it more difficult for participants to fall asleep when opportunities for sleep arose Abstract : In a double-blind , parallel groups study , 60 healthy student volunteers ( 29 men and 31 women , aged 19 - 22 years ) were r and omly allocated to receive placebo , 100 or 200 mg modafinil . Two hours later , in the early evening , they completed an extensive cognitive battery . The 3 groups did not differ in self-ratings of sleepiness or tiredness before the testing session , and there were no treatment-associated changes in these or in mood ratings during the tests . Modafinil was without effect in several tests of reaction time and attention , but the 200-mg group was faster at simple color naming of dots and performed better than placebo in the Rapid Visual Information Processing test of sustained attention . Modafinil was without effect on spatial working memory , but the 100-mg group performed better in the backward part of the digit span test . Modafinil was without effect on verbal short-term memory ( story recall ) , but 100 mg improved digit span forward , and both doses improved pattern recognition , although this was accompanied by a slowing of response latency in the 200-mg group . There were no significant effects of modafinil compared with placebo in tests of long-term memory , executive function , visuospatial and constructional ability , or category fluency . These results suggest that the benefits of modafinil are not clearly dose-related , and those from 100 mg are limited to the span of immediate verbal recall and short-term visual recognition memory , which is insufficient for it to be considered as a cognitive enhancer in non-sleep-deprived individuals 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 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 Background : Excessive daytime somnolence ( EDS ) commonly complicates Parkinson ’s disease ( PD ) . The aetiology of EDS is probably multifactorial but is probably exacerbated by dopaminergic medications . Modafinil is a wake-promoting agent approved for use in narcolepsy , but it is often used to treat a variety of somnolent conditions . Method : A double blind , placebo controlled parallel design trial was conducted to assess the efficacy of modafinil ( 200–400 mg/day ) for the treatment of EDS in PD . The primary efficacy measure was the Epworth Sleepiness ( ES ) scale score . Secondary efficacy points included the Unified Parkinson ’s Disease Rating Scale ( UPDRS ) , the Fatigue Severity Scale , the Hamilton Depression Scale , and the multiple sleep latency test ( MSLT ) . Results : Of a total of 40 subjects ( 29 men , mean ( SD ) age 64.8 ( 11.3 ) years ) , r and omised to modafinil or placebo , 37 completed the study . Modafinil failed to significantly improve ES scores compared with placebo ( 2.7 v 1.5 points improvement , respectively , p = 0.28 ) . MSLT failed to improve with modafinil relative to placebo ( −0.16 v −0.70 , respectively , p = 0.14 ) . UPDRS , global impressions , Fatigue Severity Scale , and Hamilton Depression Scale scores were unchanged . Adverse events were minimal . Conclusion : Modafinil failed to significantly improve EDS in PD compared with placebo . The drug did not alter motor symptoms in PD and was well tolerated Self-monitoring refers to the ability to assess accurately one 's own performance in a specific environment . The present study investigated the effects of the stimulating drugs modafinil ( 300 mg ) and d-amphetamine ( 20 mg ) on the ability to self-monitor cognitive performance during 64 h of sleep deprivation ( SD ) and sustained mental work . Two cognitive tasks were investigated : a visual ( perceptual ) judgement task and a complex mental addition task . Subjects in the placebo  condition displayed marked circadian and SD effects on cognitive task performance but their self-monitoring was substantively undisturbed by SD . Subjects performing under the influence of d-amphetamine likewise displayed highly proficient self-monitoring throughout the SD period . In contrast , modafinil had a disruptive effect on self-monitoring , inducing a reliable ' overconfidence ' effect ( i.e. an overestimation of actual cognitive performance ) , which was particularly marked 2 - 4 h post-dose . Although modafinil has proven to be a safe and effective countermeasure to the effects of extensive SD on cognitive task performance , we encourage a more comprehensive underst and ing of the relation between its subjective and performance enhancing effects before the drug is recommended as a viable fatigue countermeasure Modafinil is a selective wakefulness-promoting agent with beneficial effects in narcolepsy and conditions of sleep deprivation . In a double-blind study we examined its effects in 30 healthy , non sleep-deprived students ( 19 men and 11 women , aged 19 - 23 years ) , who were r and omly allocated to placebo , 100 or 200 mg modafinil and 3 h later completed 100 mm visual analogue scales relating to mood and bodily symptoms , before and after an extensive battery of cognitive tests ( pen and paper and CANTAB ) . There were no significant differences between the three treatment groups on any of the cognitive tests used in this study . There was a significant post-treatment change in the factor measuring ' somatic anxiety ' and in individual ratings of ' shaking ' , ' palpitations ' , ' dizziness ' , ' restlessness ' , ' muscular tension ' , ' physical tiredness ' and ' irritability ' , which was mainly due to significantly higher ratings of somatic anxiety in the 100 mg group compared with the other two groups . Further changes in mood were revealed after the stress of cognitive testing , with the 100 mg group showing greater increases in the ' psychological anxiety ' and the ' aggressive mood ' factors ( as measured from the Bond and Lader scales ) 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 Abstract . Rationale : The performance and alertness effects of modafinil were evaluated to determine whether modafinil should replace caffeine for restoring performance and alertness during total sleep deprivation in otherwise healthy adults . Objectives : Study objectives were to determine ( a ) the relative efficacy of three doses of modafinil versus an active control dose of caffeine 600 mg ; ( b ) whether modafinil effects are dose-dependent ; and ( c ) the extent to which both agents maintain performance and alertness during the circadian trough . Methods : Fifty healthy young adults remained awake for 54.5 h ( from 6:30 a.m. day 1 to 1:00 p.m. on day 3 ) and performance and alertness tests were administered bi-hourly from 8:00 a.m. day 1 until 10:00 p.m. day 2 . At 11:55 p.m. on day 2 ( after 41.5 h awake ) , subjects received double blind administration of one of five drug doses : placebo ; modafinil 100 , 200 , or 400 mg ; or caffeine 600 mg ( n=10 per group ) , followed by hourly testing from midnight through 12:00 p.m. on day 3 . Results : Performance and alertness were significantly improved by modafinil 200 and 400 mg relative to placebo , and effects were comparable to those obtained with caffeine 600 mg . Although a trend toward better performance at higher modafinil doses suggested a dose-dependent effect , differences between modafinil doses were not significant . Performance enhancing effects were especially salient during the circadian nadir ( 6:00 a.m. through 10:00 a.m. ) . Few instances of adverse subjective side effects ( nausea , heart pounding ) were reported . Conclusions : Like caffeine , modafinil maintained performance and alertness during the early morning hours , when the combined effects of sleep loss and the circadian trough of performance and alertness trough were manifest . Thus , equivalent performance- and alertness-enhancing effects were obtained with drugs possessing different mechanisms of action . However , modafinil does not appear to offer advantages over caffeine ( which is more readily available and less expensive ) for improving performance and alertness during sleep loss in otherwise normal , healthy adults OBJECTIVE Individuals who are methamphetamine dependent exhibit higher rates of cognitive dysfunction than healthy people who do not use methamphetamine  , and this dysfunction may have a negative effect on the success of behavioral treatments for the disorder . Therefore , a medication that improves cognition , such as modafinil ( Provigil ) , may serve as a useful adjunct to behavioral treatments for methamphetamine dependence . Although cognitive-enhancing effects of modafinil have been reported in several population s , little is known about the effects of modafinil in methamphetamine-dependent individuals . We thus sought to evaluate the effects of modafinil on the cognitive performance of methamphetamine-dependent and healthy individuals . METHOD Seventeen healthy subjects and 24 methamphetamine- dependent subjects participated in this r and omized , double-blind , placebo-controlled , crossover study . Effects of modafinil ( 200 mg , single oral dose ) were assessed on participants ' performance on tests of inhibitory control , working memory , and processing speed/attention . RESULTS Across subjects , modafinil improved performance on a test of sustained attention , with no significant improvement on any other cognitive tests . However , within the methamphetamine-dependent group only , participants with a high baseline frequency of methamphetamine use demonstrated a greater effect of modafinil on tests of inhibitory control and processing speed than those participants with low baseline use of methamphetamine . CONCLUSIONS Although modafinil produced limited effects across all participants , methamphetamine-dependent participants with a high baseline use of methamphetamine demonstrated significant cognitive improvement on modafinil relative to those with low baseline methamphetamine use . These results add to the findings from a clinical trial that suggested that modafinil may be particularly useful in methamphetamine-dependent subjects who use the drug frequently Functional magnetic resonance imaging ( fMRI ) can be used to detect regional brain responses to changes in sensory stimuli . We have used fMRI to determine the amount of visual and auditory cortical activation in 12 normal subjects and 12 subjects with the narcoleptic syndrome , using a multiplexed visual and auditory stimulation paradigm . In both normal and narcoleptic subjects , mean cortical activation levels during the presentation of periodic visual and auditory stimulation showed no appreciable differences with either age or sex . Normal subjects showed higher levels of visual activation at 10:00 hours than 15:00 hours , with a reverse pattern in narcoleptic subjects ( P = 0.007 ) . The group differences in spatial extent of cortical activation between control and narcoleptic subjects were small and statistically insignificant . The alerting action , and imaging response , to a single oral dose of the sleep-preventing drug modafinil 400 mg were then determined and compared with placebo in both the 12 normal ( 8 given modafinil , 4 placebo ) and 12 narcoleptic subjects ( 8 modafinil , 4 placebo ) . Modafinil caused an increase in self-reported levels of alertness in 7 of 8 narcoleptic subjects , but there was no significant difference between mean pretreatment and post-treatment activation levels as determined by fMRI for either normal or narcoleptic syndrome subjects given modafinil . However , in the modafinil-treated group of 8 normal and 8 narcoleptic subjects , there was a clock time independent correlation between the initial level of activation as determined by the pretreatment scan and the post-treatment change in activation ( visual , P = 0.002 ; and auditory , P = 0.001 ) . No correlation was observed in placebo-treated subjects ( P = 0.99 and 0.77 , respectively ) . Although limited by the small number of subjects , and the lack of an objective measure of alertness , the findings of this study suggest that low cortical activation levels in both normal and narcoleptic subjects are increased following the administration of modafinil . Functional magnetic resonance imaging may be a valuable addition to established studies of attention This study was undertaken to investigate regional metabolic abnormalities and to determine the effects of modafinil in narcoleptics on cerebral glucose metabolism using [ (18)F ] fluorodeoxyglucose positron emission tomography ( FDG PET ) .  Eight narcoleptic patients participated in the study . Two [ (18)F ] FDG PET scans were obtained before and after 2 weeks of modafinil treatment . To identify the effect of modafinil on regional cerebral abnormalities in narcoleptics , pre- and post-treatment PET scans were compared using paired t-statistics with voxel-wised manner . In narcolepsy patients , significant decreases in cerebral glucose metabolism were observed in the midbrain and upper pons , bilateral hypothalamus , posterior thalamus , hippocampus and right parahippocampus as compared with healthy subjects . After treatment , a significant increase in glucose metabolism in the left hippocampus was found in comparison with pre-treatment scan . This study demonstrated that modafinil activates the hippocampus which receives the afferents from hypothalamus , the center of sleep-wake rhythm 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 Summary — Modafinil , a new psychostimulant , was evaluated in eight healthy volunteers subjected to 60 hours of sleep deprivation . During continued wakefulness , vigilance was evaluated by self‐ assessment question naires , analogue visual scales , multiple sleep latency tests ( MSLT ) , sleep logs , and continuous ambulatory electroencephalographic recordings ( EEG ) .  Modafinil ( 200 mg ) or a placebo was given every 8 hours for three days ; the sessions were separated by a 15 day wash out period . Results indicated a satisfactory level of vigilance , both subjective and objective , after the administration of modafinil , characterised by the quasi total absence of microsleep episodes which gradually occurred under placebo conditions . The confirmed wakening potency of modafinil makes this substance suitable for therapeutic use in patients with sleep disorders such as Gelineau 's syndrome and hypersomnia Background Modafinil is a medication licensed for the treatment of narcolepsy . However , it has been reported that healthy individuals without wakefulness disorders are using modafinil off-label to enhance cognitive functioning . Although some studies have reported that modafinil improves cognitive task performance in healthy volunteers , numerous other studies have failed to detect cognitive enhancing effects of modafinil on several well-established neuropsychological tasks . Interestingly , several clinical and pre clinical studies have found that improved cognitive task performance by modafinil is accompanied by slower response times . This observation raises the question as to whether this slowing of response time in healthy volunteers is a necessary and sufficient condition for cognitive enhancement with modafinil . The aim of the current experiment was to explore this question by investigating the effects of modafinil on the Hayling Sentence Completion Test ( HSCT ) . Methodology Sixty-four healthy volunteers received either a single dose ( 200 mg ) of modafinil ( n = 32 ) or placebo ( n = 32 ) in a r and omized , double-blind , placebo-controlled , parallel group study in which the principal outcome measures were response latencies on the response initiation and response inhibition sections of the HSCT . Principal Findings Participants dosed with modafinil had significantly longer mean response latencies on the HSCT for both the response initiation and response inhibition compared to participants dosed with placebo . However , participants in both groups made a similar number of errors on each of these measures , indicating that modafinil did not enhance the accuracy of performance of the task relative to placebo . Conclusions This study demonstrated that administration of single 200 mg doses of modafinil to healthy individuals increased the latency of responses in the performance of the HSCT , a task that is highly sensitive to prefrontal executive function , without enhancing accuracy of performance . This finding may provide important clues to defining the limitations of modafinil as a putative cognitive enhancer . Trial Registration Clinical Trials.gov 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 OBJECTIVE Modafinil is approved by the U.S. Food and Drug Administration for improving wakefulness in patients with excessive sleepiness associated with narcolepsy , obstructive sleep apnea , and shift-work sleep disorder . This study was conducted to evaluate the efficacy and safety of adjunctive modafinil in bipolar depression , which is often characterized by excessive sleepiness and fatigue . METHOD Eighty-five patients with bipolar depression that was inadequately responsive to a mood stabilizer with or without concomitant antidepressant therapy were r and omly assigned to receive adjunctive modafinil ( N=41 ) or placebo ( N=44 ) for 6 weeks . The primary outcome measure was baseline-to-endpoint change in score on the Inventory of Depressive Symptoms -- Clinician Rated ( IDS ) . RESULTS The baseline-to-endpoint change in IDS score was significantly greater in the modafinil group ( mean dose , 177 mg/day ) compared with the placebo group . Improvement in depressive symptoms was significantly greater in the modafinil group by week 2 , and this greater improvement was maintained at weeks 4 , 5 , and 6 . Both the response and remission rates were significantly higher in the modafinil group ( 44 % and 39 % ) compared with the placebo group ( 23 % and 18 % ) . During the 6-week study period , there was no difference between groups in treatment-emergent hypomania or mania ( six patients in the modafinil group and five in the placebo group ) or hospitalization for mania ( one in each group ) . CONCLUSIONS These data suggest that adjunctive modafinil at doses of 100 - 200 mg a day may improve depressive symptoms in patients with bipolar disorder
We found that whilst most studies employing basic testing paradigms show that modafinil intake enhances executive function , only half show improvements in attention and learning and memory , and a few even report impairments in divergent creative thinking .
In contrast , when more complex assessment s are used , modafinil appears to consistently engender enhancement of attention , executive functions , and learning .
Importantly , we did not observe any preponderances for side effects or mood changes .
Modafinil is an FDA -approved eugeroic that directly increases cortical catecholamine levels , indirectly upregulates cerebral serotonin , glutamate , orexin , and histamine levels , and indirectly decreases cerebral gamma-amino-butrytic acid levels .
In addition to its approved use treating excessive somnolence , modafinil is thought to be used widely off-prescription for cognitive enhancement .
However , despite this popularity , there has been little consensus on the extent and nature of the cognitive effects of modafinil in healthy , non-sleep-deprived humans .