Effects Of Modafinil Research Articles

Chest Tightness and Palpitations Associated With Modafinil and Consumption of Free Glutamate

Back to table of contents Previous article Next article Letters to the EditorFull AccessChest Tightness and Palpitations Associated With Modafinil and Consumption of Free GlutamatePETER T. MORGAN M.D., Ph.D.ROBERT T. MALISON M.D.,PETER T. MORGAN M.D., Ph.D.Search for more papers by this authorROBERT T. MALISON M.D.Search for more papers by this author,Published Online:1 Apr 2008https://doi.org/10.1176/appi.ajp.2007.07040717AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Nausea and anxiety are common side effects of modafinil. Palpitations are common at higher doses when increased dosing is not performed (1) , but a lower dose of 400 mg without increase has been tolerated in cocaine-dependent subjects (2) . We report the case of a possible interaction between modafinil and the consumption of free glutamate. “Mr. B,” a 40-year-old African American man with a 16-year history of cocaine use, was participating in an inpatient research study. He had no significant medical history, was not receiving any medication, was abstinent from cocaine use for 6 days, and had unremarkable physical and laboratory examinations. On days 1 and 2 of the study, he received modafinil, 400 mg, at 7:30 a.m. He reported mild anxiety (1 on a 0- to 3-point scale), mild nausea, and a strong but not fast heartbeat (pulse: 68–82; blood pressure:120–140/80–90), which began 30 to 60 minutes after dosing on both days. These symptoms resolved within 8 hours, and on day 2, at 9:00 p.m., he rated his anxiety and nausea as 0. From approximately 10:30 to 11:00 p.m. on day 2, he ate a large meal of take-out food, including substantial soy sauce and other free-glutamate containing foods, with a total free-glutamate content estimated at 3 to 7 grams of monosodium glutamate equivalent (3 , 4) or approximately 10 times the typical Western daily consumption (4 , 5) . According to his own recollection as well as that of his wife, he had eaten similarly from the same restaurant at least three times during the past year without incident and had no known sensitivity to monosodium glutamate. Thirty minutes after he finished eating, he reported sleeplessness, chest tightness, nausea (moderate), anxiety (moderate), and a pounding but not fast heartbeat, and he appeared severely anxious and in significant distress to the staff. His vital signs were unremarkable (blood pressure:136/84; pulse 84). He was transferred to the emergency department for evaluation. All symptoms subsided within 2 hours, with no electrocardiogram changes or cardiac-enzyme elevation. The patient returned to the research unit with a diagnosis of palpitations. Modafinil, 200 mg daily, was started 30 hours later and increased to 400 mg without incident after 2 days. In our patient, the symptoms reported on the second night included the side effects he experienced earlier in the day, and in retrospect, he described them as “the same but much more intense.” The timing, however, was consistent with the spike in plasma glutamate after a glutamate-rich meal (6) and not with modafinil pharmacokinetics (4) . Although in preclinical models modafinil does not increase glutamate synthesis (7) , it increases brain glutamate (8) , suggesting that an interaction between modafinil and the consumption of free glutamate could have caused the incident reported in our case. New Haven, Conn.Supported by the National Center for Research Resources (PTM; K12RR17594), the National Institute on Drug Abuse (RTM; R01DA011744), and the Connecticut Department of Mental Health and Addiction Services.The authors report no competing interests.This letter (doi: 10.1176/appi.ajp.2007.07040717) was accepted for publication in August 2007.

Sleep architecture of the melanin‐concentrating hormone receptor 1‐knockout mice

Growing amounts of data indicate involvement of the posterior hypothalamus in the regulation of sleep, especially paradoxical sleep (PS). Accordingly, we previously showed that the melanin-concentrating hormone (MCH)-producing neurons of the rat hypothalamus are selectively activated during a PS rebound. In addition, intracerebroventricular infusion of MCH increases total sleep duration, suggesting a new role for MCH in sleep regulation. To determine whether activation of the MCH system promotes sleep, we studied spontaneous sleep and its homeostatic regulation in mice with deletion of the MCH-receptor 1 gene (MCH-R1-/- vs. MCH-R1+/+) and their behavioural response to modafinil, a powerful antinarcoleptic drug. Here, we show that the lack of functional MCH-R1 results in a hypersomniac-like phenotype, both in basal conditions and after total sleep deprivation, compared to wild-type mice. Further, we found that modafinil was less potent at inducing wakefulness in MCH-R1-/- than in MCH-R1+/+ mice. We report for the first time that animals with genetically inactivated MCH signaling exhibit altered vigilance state architecture and sleep homeostasis. This study also suggests that the MCH system may modulate central pathways involved in the wake-promoting effect of modafinil.

A Pet imaging study of the effects of modafinil and topiramate on brain mechanisms underlying cue-induced cocaine craving and dependence in cocaine-dependent and methadone maintained cocaine-dependent patients

A Pet imaging study of the effects of modafinil and topiramate on brain mechanisms underlying cue-induced cocaine craving and dependence in cocaine-dependent and methadone maintained cocaine-dependent patients

The effect of modafinil following acute CPAP withdrawal: a preliminary study

Daytime symptoms resulting from obstructive sleep apnea (OSA) include impaired neurobehavioural performance and increased sleepiness. Continuous positive airway pressure (CPAP) reduces these symptoms. However, even compliant users may temporarily withdraw from CPAP treatment resulting in an immediate return of OSA. It has been hypothesised that these treatment "holidays" may be associated with neurobehavioural decline. Acute administration of a wakefulness promoter during such treatment "holidays" may help maintain neurobehavioural functioning. We examined the effects of 200 mg modafinil on neurobehavioural performance in a placebo-controlled crossover trial including N = 12 OSA patients acutely removed from CPAP. Sleep-wake activity was assessed for four consecutive days on CPAP and one night off CPAP using actigraphy. During the night off, CPAP patients wore a single channel nasal airflow diagnostic device. On the morning after CPAP withdrawal, patients reported to the laboratory and were administered either modafinil (200 mg) or placebo. At 2 h post-administration, patients completed a single simulated drive of approximately 30 min with simultaneous administration of a divided attention task (STISIMtrade mark), critical flicker fusion (CFF) test and subjective sleepiness scales. After a 14-day washout, participants repeated the protocol. CPAP withdrawal was associated with a worsening of sleep efficiency and the movement and fragmentation index (MFI), compared to the on-CPAP nights (all p < or = 0.02). Modafinil did not result in a superior driving simulator performance or CFF responses the morning after CPAP withdrawal but did result in better subjective sleepiness (both p < or = 0.04) compared to placebo. These data do not support the use of modafinil for the maintenance of daytime functioning in patients with OSA who are acutely withdrawn from CPAP.

Modafinil modulates GABA-activated currents in rat hippocampal pyramidal neurons

Modafinil is a well-known psychoactive drug used to treat narcolepsy, hypoglycemia, cerebral ischemia and Parkinson's disease. Previous studies showed that ATP-sensitive potassium channels (K ATP) play a key role in response to cerebral ischemia, hypoglycemia or metabolic inhibition. Modafinil (0.01–1 mM) dose-dependently decreased the GABA-activated currents (I GABA). Pretreatment with the K ATP channel blocker, glibenclamide (10 μM), significantly reduced the decrease of I GABA caused by modafinil. Thus, the inhibitory effect of modafinil on the I GABA is indirect by modulating K ATP channel activation, at least in part mediated by K ATP channel.

Controversies in translational research: drug self-administration.

Laboratory animal and human models of drug self-administration are used to evaluate potential pharmacotherapies for drug abuse, yet the utility of these models in predicting clinically useful medications is variable. The objective of this study was to track how antagonist, agonist, and partial agonist medication approaches influence heroin and cocaine self-administration by rodents, non-human primates, and humans and to compare these results to clinical outcomes. Across species, heroin self-administration was decreased by all three medication approaches, paralleling their demonstrated clinical utility. The heroin data emphasize the importance of assessing a medication's abuse liability preclinically to predict medication abuse and compliance and of considering subject characteristics (e.g., opioid dependence) when interpreting medication effects. For cocaine, the effects of ecopipam, modafinil, and aripiprazole were consistent in the laboratory and clinic, provided that the medications were administered repeatedly before self-administration sessions. Modafinil attenuated cocaine's reinforcing effects in the human laboratory and improved treatment outcome, while ecopipam and aripiprazole increased the reinforcing effects of cocaine and do not appear promising in the clinic. The self-administration model has reliably identified medications to treat opioid dependence, and the recent data with modafinil suggest that the human laboratory model also identifies medications to treat cocaine dependence. There have been numerous false positives when subjective effects are the primary outcome measure, but not when self-administration is the outcome. Factors relevant to the predictive validity of self-administration procedures include medication maintenance and the concurrent assessment of a range of behaviors to determine abuse liability and the specificity of effect.

The Effects of Modafinil, Caffeine, and Dextroamphetamine on Judgments of Simple Versus Complex Emotional Expressions Following Sleep Deprivation

Cognitive abilities such as vigilance, attention, memory, and executive functioning can be degraded 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.

Sex Differences in Cognitive Estimation During Sleep Deprivation: Effects of Stimulant Countermeasures

Stimulant medications restore simple alertness during sleep loss, but it is not clear how they affect complex executive functions, particularly in light of sex differences in cerebral organization. The effectiveness of caffeine, modafinil, dextroamphetamine, or placebo for sustaining performance on the Biber Cognitive Estimation Test (BCET) was compared in 29 men and 25 women following 46 hr of sleep deprivation. Stimulants had differential effects on BCET performance as a function of the sex of the subjects. Women receiving placebo or caffeine scored significantly worse than males, while modafinil and dextroamphetamine were effective at sustaining BCET performance of men andwomen.

Exploring the neuroprotective effects of modafinil in a marmoset Parkinson model with immunohistochemistry, magnetic resonance imaging and spectroscopy

Neuroprotective therapeutics stop or slow down the degeneration process in animal models of Parkinson's disease (PD). Neuronal survival in PD animal models is often measured by immunohistochemistry. However, dynamic changes in the pathology of the brain cannot be explored with this technique. Application of proton magnetic resonance (MR) imaging (MRI) and spectroscopy (MRS) can cover this lacuna as these techniques are non-invasive and can be repeated over time in the same animal. Therefore, the sensitivity of both techniques to measure changes in PD-pathology was explored in an experiment studying the neuroprotective effects of the vigilance enhancer modafinil in a marmoset PD model. Eleven marmoset monkeys were treated with the neurotoxin 1-methyl-1,2,3,6-tetrahydropyridine (MPTP). Six of these 11 animals, simultaneously, received a daily oral dose of modafinil (100 mg/kg) and five received vehicle for 27 days. MR experiments were performed at baseline and 1 and 3.5 weeks after the MPTP intoxication period after which brains were analyzed with immunohistochemistry. Tyrosine hydroxylase immunoreactive (TH-IR) staining of dopamine neurons of the substantia nigra pars compacta confirmed that modafinil was able to partially prevent the MPTP-induced neuronal damage. In MRS, N-acetylaspartate (NAA)/phosphocreatine (tCR) ratios confirmed the protective effect indicating that this is a sensitive measure to detect neuroprotection in the MPTP marmoset model. Furthermore, the number of TH-IR positive neurons and the NAA/tCR ratio were significantly correlated to behavioral observations indicating that the changes measured in the brain are also reflected in the behavior and vice versa.

Placebo and modafinil effect on sleepiness in obstructive sleep apnea

Introduction Previous studies have evaluated the effect of modafinil on residual excessive daytime sleepiness (EDS) in patients with obstructive sleep apnea syndrome (OSAS) under effective CPAP treatment. Even though those trials also used placebo groups, we suppose that the placebo effect might influence the patients' response to modafinil. Methods Twenty sleepy patients with OSAS under CPAP treatment were selected. All of them had Epworth Sleepiness Scale (ESS) > 10. Following baseline evaluation (T1), all subjects were instructed to take placebo for 7 days. After this single-blind placebo phase and second evaluation (T2), patients were randomly allocated to placebo or modafinil treatment for 21 days in a double-blind protocol. Patients underwent a final evaluation (T3) on the last day of drug intake. The evaluations at T1, T2 and T3 consisted of: medical and laboratory examinations, nocturnal polysomnography, ESS, maintenance of wakefulness test (MWT) and complex reaction time (CRT-NY). In addition, in T2 and T3 the change of illness severity scale (CGI-C) and the evaluation of quality of life (SF-36) were applied. Results The comparison between the two groups during the three periods studied, showed the following results: in the modafinil group, ESS score did not change during the initial placebo period, but there was a significant reduction during the modafinil treatment period ( p = 0.0006); in the placebo group a significant reduction occurred during the initial placebo period ( p = 0.05), and no further change was observed in the treatment (placebo) period. A significant difference was found between the two groups after the placebo period (T2) ( p = 0.02). Three patients (33%) of the modafinil group and 9 patients (81%) of the placebo group were classified as placebo-responsive ( X 2: p = 0.039). In the treatment period, reaction time was significantly reduced in the modafinil group compared to the placebo group ( p < 0.02). There was a trend toward improvement in overall clinical condition and also in some domains of SF-36 in the modafinil group. Conclusion In summary, our study confirms that modafinil used adjunctively with CPAP therapy improves subjective daytime sleepiness in patients with OSAS who were regular users of CPAP therapy but still experienced sleepiness. Moreover, it could help in the improvement of objective measures of behavioral alertness and reduce functional impairments. The usefulness of a blinded placebo period for systematic investigation of placebo role in studies based on subjective response is a point that should be considered in this type of drug trial.

Evaluation of the Safety of Modafinil for Treatment of Excessive Sleepiness

Modafinil is a wake-promoting agent shown to improve wakefulness in patients with excessive sleepiness (hypersomnolence) associated with shift work sleep disorder, obstructive sleep apnea, or narcolepsy. Safety and tolerability data from 6 randomized, double-blind, placebo-controlled studies were combined to evaluate modafinil across these different patient populations. One thousand five hundred twenty-nine outpatients received modafinil 200, 300, or 400 mg or placebo once daily for up to 12 weeks. Assessments included recording of adverse events and effects of modafinil on blood pressure/heart rate, electrocardiogram intervals, polysomnography, and clinical laboratory parameters. Two hundred seventy-three patients with shift work sleep disorder, 292 with obstructive sleep apnea, and 369 with narcolepsy received modafinil; 567 received placebo. Modafinil was well tolerated versus placebo, with headache (34% vs 23%, respectively), nausea (11% vs 3%), and infection (10% vs 12%) the most common adverse events. Adverse events were similar across all patient groups. Twenty-seven serious adverse events were reported (modafinil, n = 18; placebo, n = 9). In modafinil-treated patients, clinically significant increases in diastolic or systolic blood pressure were infrequent (n = 9 and n = 1, respectively, < 1% of patients). In the studies, 1 patient in the modafinil group and 1 in the placebo group had a clinically significant increase in heart rate. New clinically meaningful electrocardiogram abnormalities were rare with modafinil (n = 2) and placebo (n = 4). Clinically significant abnormalities in mean laboratory parameters were observed in fewer than 1% of modafinil-treated patients at final visit. Modafinil did not affect sleep architecture in any patient population according to polysomnography. Modafinil is well tolerated in the treatment of excessive sleepiness associated with disorders of sleep and wakefulness and does not affect cardiovascular or sleep parameters.

P.8.a.017 The effects of modafinil on driving and self-assessment of driving performance during sleep deprivation

P.8.a.017 The effects of modafinil on driving and self-assessment of driving performance during sleep deprivation

Involvement of central histaminergic systems in modafinil-induced but not methylphenidate-induced increases in locomotor activity in rats

Modafinil is a novel wake-promoting drug used for the treatment of narcolepsy, the mechanism of action of which remains unclear. Previous studies have shown that modafinil produces a different pattern of c-Fos activation in the brain to the classical stimulants amphetamine and methylphenidate. Modafinil, given i.p. to urethane-anesthetized rats, is associated with an increase in histamine release from the anterior hypothalamus, indicating that its behavioral actions may involve histaminergic systems. In the present study, the effects of modafinil on histamine release using in vivo microdialysis and locomotor activity in freely moving rats were examined, and compared with those of the classical psychostimulant methylphenidate. Modafinil (75 and 150 mg/kg, i.p.) increased both histamine release and locomotor activity, significantly. Methylphenidate (3 mg/kg, i.p.) also increased locomotor activity to the same extent as modafinil (150 mg/kg, i.p.) without stimulating histamine release. Depletion of neuronal histamine using α-fluoromethylhistidine abolished the effect of modafinil on locomotor activity in mice but had no effect on methylphenidate-induced locomotion. Examination of the effects of modafinil and methylphenidate on locomotor activity in the dark phase at doses that produced comparable effects in the light phase showed that the effect of modafinil in the dark phase was less than that of methylphenidate, a possible indication that modafinil-induced locomotor activity may be partly related to its wake-promoting actions. These findings suggest that the locomotor effects of modafinil but not of methylphenidate, involve the central histaminergic systems.

The 5-min pupillary alertness test is sensitive to modafinil: a placebo controlled study in patients with sleep apnea

The extent of pupillary miosis during 5 min in darkness is a simple, recently introduced alertness test which may become useful in the clinical assessment of normal and pathological sleepiness. In this study, we further validated this test by testing its sensitivity to the effects of modafinil, a non-stimulant, alertness-promoting drug. Twelve unmedicated patients recently diagnosed with obstructive sleep apnea (OSA) after polysomnography, received placebo or modafinil (200 mg), according to a double-blind, cross-over design. The patients' resting pupil diameter (RPD) was sampled over 5 min in darkness before (10:00 A.M.) and after treatment (2:00 P.M.), and their light reflexes were elicited and recorded in darkness with an infrared video pupillometer. We found a circadian miosis at 2:00 P.M. in the placebo treatment condition, which was reversed by modafinil. This effect correlated with modafinil-induced increase in subjective alertness, and it was greater in the most severely affected patients in terms of lowest oxygen saturation, independently of body mass index, age, or apneic episodes during sleep. Modafinil reduced the light reflex amplitude, suggesting an increase in the inhibitory input at the pupilloconstrictor Edinger-Westphal nucleus. These effects of modafinil are best explained via an activation of the hypoxia-sensitive nucleus locus coeruleus. The 5-min pupillary alertness test has promising predictive validity, and it holds promise as a fast and sensitive method for the objective assessment of excessive daytime sleepiness, monitoring of disease progression, and response to treatment.

Non-cholinergic modulation of antisaccade performance: a modafinil-nicotine comparison

The antisaccade task provides a powerful tool with which to investigate the cognitive and neural systems underlying goal-directed behaviour, particularly in situations when the correct behavioural response requires the suppression of a prepotent response. Antisaccade errors (failures to suppress reflexive prosaccades towards sudden-onset targets) are increased in patients with damage to the dorsolateral prefrontal cortex, and in patients with schizophrenia. Nicotine has been found to improve antisaccade performance in patients with schizophrenia and healthy controls. This performance enhancing effect may be due to direct effects on the cholinergic system, but there has been no test of this hypothesis. In a double blind, double dummy, placebo-controlled design, we compared the effect of nicotine and modafinil, a putative indirect noradrenergic agonist, on antisaccade performance in healthy non-smokers. Both compounds reduced latency for correct antisaccades, although neither reduced antisaccade errors. These findings are discussed with reference to the pharmacological route of performance enhancement on the antisaccade task and current models of antisaccade performance.

Modafinil exerts a dose-dependent antiepileptic effect mediated by adrenergic α 1 and histaminergic H 1 receptors in mice

Epilepsy is characterized by neuronal hyperexcitability and hypersynchronization. Disruption of electroencephalographically (EEG) synchronized epileptiform discharges may be a possible therapy for epilepsy. In the present study, to clarify the role of EEG desynchronization on epilepsy, we investigated the effect of modafinil, a potent wake-promoting substance with EEG desynchronization activity, on epilepsy in mice and clarified the receptors involved in the suppression of seizure caused by maximal electroshock (MES) and pentylenetetrazol (PTZ) kindling models. Modafinil given at 22.5, 45, and 90 mg/kg, i.p. significantly decreased the incidence of tonic hindleg extension in MES seizure models, and protected against PTZ-induced convulsive behaviors in a dose-dependent manner. In addition, modafinil at 180 mg/kg exerted an antiepileptic effect in the MES model; however, at the same dosage it increased the seizure stage in the PTZ-kindling model. The antiepileptic effect in both MES and PTZ models was antagonized by the adrenergic α 1 receptor antagonist terazosin, but not by the adrenergic α 2 receptor antagonist yohimbine or by dopaminergic receptor antagonists, SCH-23390 (for D 1 receptors) and haloperidol (for D 2 ones). Pyrilamine, a histaminergic H 1 receptor antagonist, counteracted the antiepileptic action of modafinil in the PTZ induced-kindling model, but not in the MES seizure model. Taken together, the present findings indicate that modafinil exerted its antiepileptic effect via adrenergic α 1 and histaminergic H 1 receptors, and might be of potential use in the treatment of epilepsy.

The cognitive effects of modafinil in breast cancer survivors: A randomized clinical trial

9004 Background: Patients receiving treatment for cancer can experience a diminution of their cognitive abilities which can persist for many years after. The present study examined the potential of modafinil as a cognitive enhancer on memory and attention in a randomized clinical trial in breast cancer patients following completion of treatment. Methods: Breast cancer patients who reported a score of = 2 on the Brief Fatigue Inventory (BFI) an average of 22.8 months following completion of chemotherapy were enrolled. In Phase 1, patients received 200mg modafinil open-label once daily for 4 weeks. In Phase 2, patients with a positive response following Phase 1 were randomized either to an additional 4 weeks of modafinil or to placebo. Tests of memory and attention selected from the Cognitive Drug Research (CDR) computerized cognitive assessment were performed at baseline (before modafinil) and after completing Phase 1 and 2. The difference between scores at baseline and scores at Phase 1 and Phase 2, were subjected to a Wilcoxon's signed rank test. Results: Of the 82 women enrolled, 68 completed all 3 CDR assessments in the study (range=33–83 years, median age=54 years). At the end of Phase 1 (week 4), modafinil had a significant effect on the Speed of Memory Index (p=0.0047) and the Digit Vigilance Test (p=0.0014) but showed no significant effect on Quality of Working Memory (p=0.3528) nor on Power of Attention (p=0.8953). At the end of phase 2 (week 8), the group that continued modafinil demonstrated improved Mean Continuity of Attention (p=0.0002) compared with the placebo group and also demonstrated significantly greater improvements in Quality of Episodic Secondary Memory relative to placebo (p&lt;0.005). This improvement was observed at week 4, and was maintained throughout the study. Finally, continued modafinil demonstrated significantly greater improvement in Speed of Memory relative to placebo (p=0.009). Conclusions: Modafinil provides significant improvements in attention and speed of memory for breast cancer patients following their treatment of cancer. Although further study is needed, these findings suggest that modafinil may enhance quality of life in this patient population. Supported by a grant from Cephalon, Inc and NCI Grants U10-CA37420 and R25- CA102618. No significant financial relationships to disclose.

Modafinil for excessive sleepiness associated with chronic shift work sleep disorder: effects on patient functioning and health-related quality of life.

We evaluated the effects of modafinil, a wake-promoting agent, on patient functioning, health-related quality of life, and nighttime and daytime sleep in patients with excessive sleepiness associated with shift work sleep disorder (SWSD). A 12-week, randomized, double-blind, placebo-controlled study was performed at 31 centers in the United States between February 2001 and March 2002. Adults (N = 278) with excessive sleepiness associated with chronic SWSD (International Classification of Sleep Disorders criteria) were randomly assigned to receive modafinil 200 or 300 mg or placebo, 30 to 60 minutes before each night shift. Effects on patient functioning and quality of life were assessed using the Functional Outcomes of Sleep Questionnaire (FOSQ) and the 36-item Short Form Health Survey (SF-36), respectively. Daily patient diaries were used as a sleep log. Modafinil 300 mg significantly improved mean FOSQ total score relative to placebo (2.3-point increase from baseline vs. 1.6 for placebo; p < .05). Both doses of modafinil significantly improved mean SF-36 mental component scores relative to placebo (mean changes from baseline of 3.2, 3.7, and 0.7 points in the modafinil 300-mg, modafinil 200-mg, and placebo groups, respectively; p < .05 for each comparison vs. placebo). Modafinil did not adversely affect sleep when sleep was desired or caffeine use. Modafinil was well tolerated. Headache (21.5%) and nausea (12.4%) were the most common adverse events in modafinil-treated patients. Differences between modafinil and placebo for vital sign measurements, physical examination findings, or electrocardiography results were not clinically meaningful. Modafinil significantly improves functioning and quality of life in patients with SWSD. Modafinil is an effective treatment for excessive sleepiness associated with SWSD.

Smoked Cocaine Self-Administration is Decreased by Modafinil

Modafinil has been reported to reduce cocaine use in a clinical sample of infrequent users (2 days/week), but the effects of modafinil on cocaine self-administration in the laboratory have not been studied. The present study investigated the effects of modafinil maintenance on cocaine self-administration by frequent users (4 days/week) under controlled laboratory conditions. During this 48-day double-blind, crossover design study, the effects of modafinil maintenance (0, 200, and 400 mg/day) on response to smoked cocaine (0, 12, 25, and 50 mg) were examined in nontreatment-seeking cocaine-dependent individuals (n=8). Cocaine significantly increased self-administration, subjective-effect ratings, and cardiovascular measures; modafinil at both doses (200 and 400 mg/day) markedly attenuated these effects. These findings agree with data from previous human laboratory and clinical investigations of modafinil as a potential cocaine abuse treatment medication. Thus, our data support the potential of modafinil as a pharmacotherapy for cocaine dependence.

Modafinil-induced hippocampal activation in narcolepsy

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.