Modafinil, an atypical CNS stimulant?

Modafinil is a central nervous system stimulant approved for the treatment of narcolepsy and sleep disorders. Due to its wide range of biochemical actions, modafinil has been explored for other potential therapeutic uses. Indeed, it has shown promise as a therapy for cognitive disfunction resulting from neurologic disorders like ADHD, and as a smart drug in non-medical settings. The mechanism(s) of actions underlying the therapeutic efficacy of this agent remains largely elusive. Modafinil is known to inhibit the dopamine transporter, thus decreasing dopamine reuptake following neuronal release, an effect shared by addictive psychostimulants. However, modafinil is unique in that only a few cases of dependence on this drug have been reported, as compared to other psychostimulants. Moreover, modafinil has been tested, with some success, as a potential therapeutic agent to combat psychostimulant and other substance use disorders. Modafinil has additional, but less understood, actions on other neurotransmitter systems (GABA, glutamate, serotonin, norepinephrine, etc.). These interactions, together with its ability to activate selected brain regions, are likely one of the keys to understand its unique pharmacology and therapeutic activity as a CNS stimulant. In this chapter, we outline the pharmacokinetics and pharmacodynamics of modafinil that suggest it has an "atypical" CNS stimulant profile. We also highlight the current approved and off label uses of modafinil, including its beneficial effects as a treatment for sleep disorders, cognitive functions, and substance use disorders.

Dual DAT and sigma receptor inhibitors attenuate cocaine effects on nucleus accumbens dopamine dynamics in rats.

Psychostimulant use disorders (PSUD) are prevalent; however, no FDA-approved medications have been made available for treatment. Previous studies have shown that dual inhibitors of the dopamine transporter (DAT) and sigma receptors significantly reduce the behavioral/reinforcing effects of cocaine, which have been associated with stimulation of extracellular dopamine (DA) levels resulting from DAT inhibition. Here, we employ microdialysis and fast scan cyclic voltammetry (FSCV) procedures to investigate the effects of dual inhibitors of DAT and sigma receptors in combination with cocaine on nucleus accumbens shell (NAS) DA dynamics in naïve male Sprague Dawley rats. In microdialysis studies, administration of rimcazole (3, 10 mg/kg; i.p.) or its structural analog SH 3-24 (1, 3 mg/kg; i.p.), compounds that are dual inhibitors of DAT and sigma receptors, significantly reduced NAS DA efflux stimulated by increasing doses of cocaine (0.1, 0.3, 1.0 mg/kg; i.v.). Using the same experimental conditions, in FSCV tests, we show that rimcazole pretreatments attenuated cocaine-induced stimulation of evoked NAS DA release but produced no additional effect on DA clearance rate. Under the same conditions, JJC8-091, a modafinil analog and dual inhibitor of DAT and sigma receptors, similarly attenuated cocaine-induced stimulation of evoked NAS DA release but produced no additional effect on DA clearance rate. Our results provide the neurochemical groundwork towards understanding actions of dual inhibitors of DAT and sigma receptors on DA dynamics that likely mediate the behavioral effects of psychostimulants like cocaine.

Selenium alleviates modafinil-induced neurobehavioral toxicity in rat via PI3K/Akt/mTOR/GSK3B signaling pathway and suppression of oxidative stress and apoptosis: in vivo and in silico study.

Nonmedical use of modafinil (MOD) led to increased rates of overdose toxicity, road accidents, addiction, withdrawal, suicide, and mental illnesses. The current study aims to determine the probable MOD brain toxicity and elucidate the possible role of selenium (Se) in ameliorating the neurotoxicity in rat models. Fifty-four male Albino rats were randomly assigned into nine groups. The groups were G1 (control negative), G2 (Se0.1), G3 (Se0.2), G4 (MOD300), G5 (MOD600), G6 (Se0.1 + MOD300), G7 (Se0.2 + MOD300), G8 (Se0.1 + MOD600), and G9 (Se0.2 + MOD600). After finishing the experiment, blood and brain tissue were harvested for biochemical and histological investigation. Neurobehavior parameters were assessed. Tissue neurotransmitter levels and oxidative stress markers were assessed. Gene expression of PI3K/Akt/mTOR-GSK3B, orexin, and orexin receptor2 was measured by qRT-PCR. Histological and immunohistochemistry assessments, as well as molecular docking, were carried out. MOD-induced neurobehavioral toxicity exhibited by behavioral and cognitive function impairments, which are associated with decreased antioxidant activities, increased MDA levels, and decreases in neurotransmitter levels. Brain levels of mRNA expression of PI3K, Akt, and mTOR were decreased, while GS3K, orexin, and orexin receptors were significantly elevated. These disturbances were confirmed by histopathological brain changes with increased silver and Bax immunostaining and decreased crystal violet levels. MOD induced neurotoxic effects in a dose-dependent manner. Compared with the MOD groups, SE coadministration significantly attenuates MOD-induced toxic changes. Docking study shows the protective role of Se as an apoptosis inhibitor and inflammation inhibitor. In conclusion, Se could be used as a biologically effective antioxidant compound to protect from MOD neurobehavioral toxicity in Wistar rats by reversing behavioral alterations, inflammation, apoptosis, and oxidative injury.

Recovery Mimicking “Ideal” CPAP Adherence Does Not Improve Wakefulness or Cognition in Chronic Murine Models of OSA: Effect of Wake-Promoting Agents

Introduction: Obstructive sleep apnea (OSA) is a chronic condition characterized by intermittent hypoxia (IH) and sleep fragmentation (SF). OSA can induce excessive daytime sleepiness (EDS) and is associated with impaired cognition and anxiety. Solriamfetol (SOL) and modafinil (MOD) are widely used wake-promoting agents in OSA patients with EDS. Methods: Male C57Bl/6J mice were exposed to SF along with sleep controls (SC) or to IH and room air (RA) controls during the light (inactive) phase for 4 and 16 weeks, respectively. Both IH and SF exposures were then discontinued to mimic “ideal” continuous positive airway pressure (CPAP) adherence. All groups were then randomly assigned to receive once daily intraperitoneal injections of SOL, MOD, or vehicle (VEH) for 6 days. Sleep/wake activity was assessed along with tests of explicit memory, anxiety and depression were performed before and after treatments. Results: IH and SF exposures increased sleep percentage in the dark phase and reduced wake bouts lengths (i.e., EDS), and induced cognitive deficits and impulsivity in mice. Both SOL and MOD treatments effectively mitigated EDS when combined with recovery, while recovery alone did not improve EDS over the 6-day period. Furthermore, improvements explicit memory emerged only after SOL. Conclusion: Chronic IH and SF induce EDS in young adult mice that is not ameliorated by recovery except when combined with either SOL or MOD. SOL, but not MOD, significantly improves IH-induced cognitive deficits. Thus, SOL emerges as a viable adjuvant medication for residual EDS in OSA along with its positive impact on cognition. (AU)

Open-label placebo treatment does not enhance cognitive abilities in healthy volunteers.

The use of so-called 'smart drugs' such as modafinil to improve cognitive performance has recently attracted considerable attention. However, their side effects have limited user enthusiasm. Open-label placebo (OLP) treatment, i.e., inert treatments that are openly disclosed to individuals as having no active pharmacological ingredient, has been shown to improve various medical symptoms and conditions, including those related to cognitive performance. OLP treatment could therefore be an exciting alternative to pharmacological cognitive enhancers. Here, we used a randomized-controlled design to investigate the effect of a 21-day OLP treatment on several sub-domains of cognitive performance in N = 78 healthy volunteers. Subjective and objective measures of cognitive performance as well as different measures of well-being were obtained before and after the treatment period. Using a combination of classic Frequentist and Bayesian analysis approaches showed no additional benefit from OLP treatment in any of the subjective or objective measures of cognitive performance. Our study thus highlights possible limitations of OLP treatment in boosting cognitive performance in healthy volunteers. These findings are discussed in the light of expectancy-value considerations that may determine OLP efficacy.

Recovery Mimicking "Ideal" CPAP Adherence Does Not Improve Wakefulness or Cognition in Chronic Murine Models of OSA: Effect of Wake-Promoting Agents.

INTRODUCTION: Obstructive sleep apnea (OSA) is a chronic condition characterized by intermittent hypoxia (IH) and sleep fragmentation (SF). OSA can induce excessive daytime sleepiness (EDS) and is associated with impaired cognition and anxiety. Solriamfetol (SOL) and modafinil (MOD) are widely used wake-promoting agents in OSA patients with EDS. METHODS: Male C57Bl/6J mice were exposed to SF along with sleep controls (SC) or to IH and room air (RA) controls during the light (inactive) phase for 4 and 16 weeks, respectively. Both IH and SF exposures were then discontinued to mimic "ideal" continuous positive airway pressure (CPAP) adherence. All groups were then randomly assigned to receive once daily intraperitoneal injections of SOL, MOD, or vehicle (VEH) for 6 days. Sleep/wake activity was assessed along with tests of explicit memory, anxiety and depression were performed before and after treatments. RESULTS: IH and SF exposures increased sleep percentage in the dark phase and reduced wake bouts lengths (i.e., EDS), and induced cognitive deficits and impulsivity in mice. Both SOL and MOD treatments effectively mitigated EDS when combined with recovery, while recovery alone did not improve EDS over the 6-day period. Furthermore, improvements explicit memory emerged only after SOL. CONCLUSION: Chronic IH and SF induce EDS in young adult mice that is not ameliorated by recovery except when combined with either SOL or MOD. SOL, but not MOD, significantly improves IH-induced cognitive deficits. Thus, SOL emerges as a viable adjuvant medication for residual EDS in OSA along with its positive impact on cognition.

Atomoxetine promotes incentive value of modafinil and sensitizes exploratory behavior.

Substance dependence is a disorder that alters the functioning of the nervous system due to frequent abuse of drugs. The role of dopamine in the addictive effect of psychostimulants is well known; however, the involvement of the noradrenergic system is still unclear and poorly understood, though drugs like cocaine and amphetamines are known to exert significant activity on this system. The drug modafinil (MOD) has no proven addictive effect. It promotes wakefulness by acting mainly on the dopaminergic system and, to a lesser degree, the noradrenergic (NOR) system. Atomoxetine (ATX) is a non-stimulant drug that acts only on the NOR system, enhancing its activity. The aims of the present study were to analyze the effect of co-activating the DA and NOR systems (with MOD and ATX, respectively) on motor activity and exploratory behavior, and to examine the possible emergence of rewarding properties of MOD and an MOD+ATX mixture. Male Wistar rats at postnatal day 60 were treated chronically (16 days) with either monotherapy with 2ATX, 4ATX, or 60MOD mg/kg, two combinations of these substances -60MOD + 2ATX and 60MOD + 4ATX- or a vehicle. The rats co-administered with 60MOD + 4ATX reduced the rearing behavior frequency induced by MOD, but this behavior was sensitized by self-administration of the MOD+ATX mixture after chronic treatment. The rats pre-treated with 60MOD + 4ATX showed higher self-administration of MOD and greater activity on an operant task to obtain the MOD+ATX mixture. In addition, the 60MOD, 2ATX, and 60MOD + 2ATX groups showed sensitization of exploratory behavior after ingesting the mixture. Results suggest that the noradrenergic system enhances the incentive value of MOD and a MOD+ATX mixture, while also playing an important role in the sensitization of exploratory behavior.

Cognitive Rehabilitation for Patients with Schizophrenia: A Narrative Review of Moderating Factors, Strategies, and Outcomes.

OBJECTIVE: Antipsychotic drugs constitute the basis of schizophrenia therapy; however, available pharmaceutical agents lack efficacy for treating the cognitive deficits caused by the illness. The aim of the present work is to present current data regarding cognitive rehabilitation of schizophrenia, providing information and guidance to health professionals. METHOD: A literature search was conducted in the PubMed and Google Scholar Databases from inception up to 1/9/2022. Relevant articles were explored for factors affecting cognitive function, including genetics, psychopathology, time in the course of the illness, and drug therapy. Characteristics and outcome of cognitive rehabilitation programs are briefly presented. RESULTS: A total of 562 relevant articles were retrieved, 39 of which were selected for the review. Factors contributing to a favorable outcome are young age, early phase of disease, symptomatic control of hostility and conceptual disorganization, lack of negative symptoms, management of drug side effects, and cognitive and cortical reserve. Some evidence for a procognitive effect seems to exist for atypical antipsychotics, clozapine, aripiprazole, memantine, modafinil, d-serine, and cycloserine. The Val/Val polymorphism of the COMT gene seems to be associated with worse outcome. Specific remediation strategies include programs such as Cognitive Enhancement Therapy (CET), Cognitive Adaptation Training (CAT), and RehaCom Cognitive Therapy Software, among others, all employing a range of techniques, from paper-and-pencil to computer-assisted, bottom-up, or top-down approaches, and varying neurocognitive targets. CONCLUSION: Cognitive symptoms, closely related to functional impairment, still remain a therapeutic challenge. Cognitive rehabilitation strategies are as yet the only treatment modality offering cognitive improvement to patients who struggle to recover.

Are There Prevalent Sex Differences in Psychostimulant Use Disorder? A Focus on the Potential Therapeutic Efficacy of Atypical Dopamine Uptake Inhibitors.

Psychostimulant use disorders (PSUD) affect a growing number of men and women and exert sizable public health and economic burdens on our global society. Notably, there are some sex differences in the onset of dependence, relapse rates, and treatment success with PSUD observed in preclinical and clinical studies. The subtle sex differences observed in the behavioral aspects of PSUD may be associated with differences in the neurochemistry of the dopaminergic system between sexes. Preclinically, psychostimulants have been shown to increase synaptic dopamine (DA) levels and may downregulate the dopamine transporter (DAT). This effect is greatest in females during the high estradiol phase of the estrous cycle. Interestingly, women have been shown to be more likely to begin drug use at younger ages and report higher levels of desire to use cocaine than males. Even though there is currently no FDA-approved medication, modafinil, a DAT inhibitor approved for use in the treatment of narcolepsy and sleep disorders, has shown promise in the treatment of PSUD among specific populations of affected individuals. In this review, we highlight the therapeutic potential of modafinil and other atypical DAT inhibitors focusing on the lack of sex differences in the actions of these agents.

An FSCV Study on the Effects of Targeted Typical and Atypical DAT Inhibition on Dopamine Dynamics in the Nucleus Accumbens Shell of Male and Female Mice.

Understanding the neurochemistry underlying sex differences in psychostimulant use disorders (PSUD) is essential for developing related therapeutics. Many psychostimulants, like cocaine, inhibit the dopamine transporter (DAT), which is largely thought to account for actions related to their misuse and dependence. Cocaine-like, typical DAT inhibitors preferentially bind DAT in an outward-facing conformation, while atypical DAT inhibitors, like modafinil, prefer a more inward-facing DAT conformation. Modafinil and R-modafinil have emerged as potential therapeutic options for selected populations of individuals affected by PSUD. In addition, analogs of modafinil (JJC8-088 and JJC8-091) with different pharmacological profiles have been explored as potential PSUD medications in preclinical models. In this work, we employ fast scan cyclic voltammetry (FSCV) to probe nucleus accumbens shell (NAS) dopamine (DA) dynamics in C57BL/6 male and female mice. We find that cocaine slowed DA clearance in both male and female mice but produced more robust increases in evoked NAS DA in female mice. R-Modafinil produced mild increases in evoked NAS DA and slowed DA clearance across the sexes. The modafinil analog JJC8-088, a typical DAT inhibitor, produced increases in evoked NAS DA in female and male mice. Finally, JJC8-091, an atypical DAT inhibitor, produced limited increases in evoked NAS DA and slowed DA clearance in both sexes. In this work we begin to tease out how sex differences may alter the effects of DAT targeting and highlight how this may help focus research toward effective treatment options for PSUD.

Not so smart? "Smart" drugs increase the level but decrease the quality of cognitive effort.

The efficacy of pharmaceutical cognitive enhancers in everyday complex tasks remains to be established. Using the knapsack optimization problem as a stylized representation of difficulty in tasks encountered in daily life, we discover that methylphenidate, dextroamphetamine, and modafinil cause knapsack value attained in the task to diminish significantly compared to placebo, even if the chance of finding the optimal solution (~50%) is not reduced significantly. Effort (decision time and number of steps taken to find a solution) increases significantly, but productivity (quality of effort) decreases significantly. At the same time, productivity differences across participants decrease, even reverse, to the extent that above-average performers end up below average and vice versa. The latter can be attributed to increased randomness of solution strategies. Our findings suggest that "smart drugs" increase motivation, but a reduction in quality of effort, crucial to solve complex problems, annuls this effect.

Solriamfetol improves chronic sleep fragmentation-induced increases in sleep propensity and ameliorates explicit memory in male mice.

Obstructive sleep apnea (OSA) is a highly prevalent condition characterized by episodes of partial or complete breath cessation during sleep that induces sleep fragmentation (SF). One of the frequent manifestations of OSA is the presence of excessive daytime sleepiness (EDS) associated with cognitive deficits. Solriamfetol (SOL) and modafinil (MOD) are wake-promoting agents commonly prescribed to improve wakefulness in OSA patients with EDS. This study aimed to assess the effects of SOL and MOD in a murine model of OSA characterized by periodic SF. Male C57Bl/6J mice were exposed to either control sleep (SC) or SF (mimicking OSA) during the light period (06:00 h to 18:00 h) for 4 weeks, which consistently induces sustained excessive sleepiness during the dark phase. Both groups were then randomly assigned to receive once-daily intraperitoneal injections of SOL (200 mg/kg), MOD (200 mg/kg), or vehicle for 1 week while continuing exposures to SF or SC. Sleep/wake activity and sleep propensity were assessed during the dark phase. Novel Object Recognition test, Elevated-Plus Maze Test, and Forced Swim Test were performed before and after treatment. SOL or MOD decreased sleep propensity in SF, but only SOL induced improvements in explicit memory, while MOD exhibited increased anxiety behaviors. Chronic SF, a major hallmark of OSA, induces EDS in young adult mice that is mitigated by both SOL and MOD. SOL, but not MOD, significantly improves SF-induced cognitive deficits. Increased anxiety behaviors are apparent in MOD-treated mice. Further studies aiming to elucidate the beneficial cognitive effects of SOL are warranted.

The Antinarcolepsy Drug Modafinil Reverses Hypoglycemia Unawareness and Normalizes Glucose Sensing of Orexin Neurons in Male Mice.

Perifornical hypothalamus (PFH) orexin glucose-inhibited (GI) neurons that facilitate arousal have been implicated in hypoglycemia awareness. Mice lacking orexin exhibit narcolepsy, and orexin mediates the effect of the antinarcolepsy drug modafinil. Thus, hypoglycemia awareness may require a certain level of arousal for awareness of the sympathetic symptoms of hypoglycemia (e.g., tremors, anxiety). Recurrent hypoglycemia (RH) causes hypoglycemia unawareness. We hypothesize that RH impairs the glucose sensitivity of PFH orexin GI neurons and that modafinil normalizes glucose sensitivity of these neurons and restores hypoglycemia awareness after RH. Using patch-clamp recording, we found that RH enhanced glucose inhibition of PFH orexin GI neurons in male mice, thereby blunting activation of these neurons in low-glucose conditions. We then used a modified conditioned place preference behavioral test to demonstrate that modafinil reversed hypoglycemia unawareness in male mice after RH. Similarly, modafinil restored normal glucose sensitivity to PFH orexin GI neurons. We conclude that impaired glucose sensitivity of PFH orexin GI neurons plays a role in hypoglycemia unawareness and that normalizing their glucose sensitivity after RH is associated with restoration of hypoglycemia awareness. This suggests that the glucose sensitivity of PFH orexin GI neurons is a therapeutic target for preventing hypoglycemia unawareness.

Effects of modafinil and caffeine on night-time vigilance of air force crewmembers: A randomized controlled trial.

BACKGROUND: Fatigue remains an important factor in major aviation accidents. Stimulants may counteract fatigue's adverse effects, with modafinil as a promising alternative to caffeine. However, the effect of a single dose of modafinil after a limited period of sleep deprivation remains unknown. AIMS: This study aims to determine the effect of 200 mg modafinil on vigilance during a limited period of sleep deprivation compared to 300 mg caffeine and placebo. METHODS: Thirty-two volunteers of the Royal Netherlands Air Force (RNLAF) were double-blindly administered modafinil, caffeine, and placebo on three non-consecutive trial days after being awake for median 17 h. Afterwards, subjects completed six series of the Vigilance and Tracking test (VigTrack), psychomotor vigilance task (PVT), and Stanford Sleepiness Scale (SSS), yielding six primary endpoints. RESULTS: This study revealed statistically significant effects of caffeine and modafinil compared with placebo on all endpoints, except for VigTrack mean tracking error. PVT results were less impaired 2 h after administration, followed by VigTrack parameters and SSS scores 2 h thereafter. Compared with caffeine, modafinil significantly improved PVT and SSS scores at 8 h after administration. CONCLUSIONS: The present study demonstrates that 200 mg modafinil and 300 mg caffeine significantly decrease the effects of a limited period of sleep deprivation on vigilance compared with placebo. Although PVT parameters already improved 2 h after administration, the most notable effects occurred 2-4 h later. Modafinil seems to be effective longer than caffeine, which is consistent with its longer half-life.

Infant Exposure to Armodafinil Through Human Milk Following Maternal Use of Modafinil.

INTRODUCTION: Narcolepsy, a condition adversely affecting psychological, social, and cognitive function, is more prevalent in females of childbearing age than the general population. Modafinil and armodafinil are central nervous system stimulants approved for treatment of narcolepsy. Infant exposure to these agents through human milk has not been investigated. Poor quality medication safety information during lactation is associated with early cessation of breastfeeding and suboptimal healthcare for the breastfeeding family. MAIN ISSUE: In this case study, we measured the concentration of armodafinil (the most active form of modafinil) in human milk and infant plasma to quantify infant exposure. MANAGEMENT: The participant was a 30-year-old primipara with narcolepsy, taking modafinil (300 mg morning, 100 mg noon) while breastfeeding her 6-week-old infant despite the paucity of safety information. Armodafinil concentrations were measured in eight serial human milk samples collected over a 26-hr period and in single maternal and infant plasma samples using ultra performance liquid chromatography - tandem mass spectrometry. The average concentration of armodafinil in human milk was 1.96 mg/L; the relative infant dose was 4.85%; the theoretical infant dose was 0.294 mg/kg/day. Maternal and infant plasma concentrations of armodafinil were 12.02 mg/L and 0.19 mg/L, respectively. The participant continued to exclusively breastfeed the infant, who had normal growth and development. CONCLUSION: Based on these findings, relatively small amounts of armodafinil pass into human milk, with consequent limited infant exposure. Consideration can be given to the use of modafinil or armodafinil during breastfeeding, provided the infant is monitored. Further studies are needed to confirm these findings.

Effects of Modafinil (Provigil) on Memory and Learning in Experimental and Clinical Studies: From Molecular Mechanisms to Behaviour Molecular Mechanisms and Behavioural Effects.

Modafinil (MOD, 2-diphenyl-methyl-sulphinil-2-acetamide) is a stimulant-like medicine used to treat narcolepsy. Off-label uses include improving cognitive ability in the course of other diseases. This review aims to discuss findings demonstrating the memory and learningenhancing activity of MOD in experimental and clinical studies. We included behavioral evaluations alongside the effects of MOD at the cellular and molecular level. MOD in different animal disease models exerted beneficial effects on induced memory and learning impairment, which in some cases were accompanied by modulation of neurotransmitter pathways or neuroplastic capabilities, reducing oxidative stress, or expression of synaptic proteins. Individuals treated with MOD showed improved memory and learning skills in different conditions. These effects were associated with regulating brain activity in some participants, confirmed by functional magnetic resonance imaging. Presented herein, data support the use of MOD in treating memory and learning deficits in various disease conditions.

Sleep and Injuries in Military Personnel With Suggestions for Improving Sleep and Mitigating Effects of Sleep Loss.

Sleep professionals suggest adults should sleep at least seven hours per night and define good sleep quality as 1) sleep onset =15 minutes, 2) one or fewer awakenings per night, 3) awake after sleep onset =20 minutes, and 4) sleep efficiency (ratio of sleep time to time in bed) =85%. This paper focuses on associations between injuries and sleep quality/duration among military personnel and strategies to optimize sleep and mitigate effects of sleep loss. Investigations among military personnel generally used convenience samples who self-reported their injury and sleep quality/quantity. Despite these limitations, data suggest that lower sleep quality or duration is associated with higher risk of musculoskeletal injury (MSI). Possible mechanisms whereby poor sleep quality/duration may influence MSI include hormonal changes increasing muscle catabolism, increases in inflammatory processes affecting post-exercise muscle damage, and effects on new bone formation. Sleep can be optimized by a slightly cool sleeping environment, bedding that maintains a stable thermal microclimate around the body, not using media devices near bedtime or in the sleeping environment, minimizing noise, and having regular bed and awaking times. Sleep loss mitigation strategies include napping (<30 to 90 minutes), sleep banking (extended time in bed), and judicious use of caffeine or modafinil.

Psychostimulants Modafinil, Atomoxetine and Guanfacine Impair Bone Cell Differentiation and MSC Migration.

Attention deficit hyperactivity disorder (ADHD) is one of the most common worldwide mental disorders in children, young and adults. If left untreated, the disorder can continue into adulthood. The abuse of ADHD-related drugs to improve mental performance for studying, working and everyday life is also rising. The potentially high number of subjects with controlled or uncontrolled use of such substances increases the impact of possible side effects. It has been shown before that the early ADHD drug methylphenidate influences bone metabolism negatively. This study focused on the influence of three more recent cognitive enhancers, modafinil, atomoxetine and guanfacine, on the differentiation of mesenchymal stem cells to osteoblasts and on their cell functions, including migration. Human mesenchymal stem cells (hMSCs) were incubated with a therapeutic plasma dosage of modafinil, atomoxetine and guanfacine. Gene expression analyses revealed a high beta-2 adrenoreceptor expression in hMSC, suggesting it as a possible pathway to stimulate action. In bone formation assays, all three cognitive enhancers caused a significant decrease in the mineralized matrix and an early slight reduction of cell viability without triggering apoptosis or necrosis. While there was no effect of the three substances on early differentiation, they showed differing effects on the expression of osterix (OSX), receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) in the later stages of osteoblast development, suggesting alternative modes of action. All three substances significantly inhibited hMSC migration. This effect could be rescued by a selective beta-blocker (Imperial Chemical Industries ICI-118,551) in modafinil and atomoxetine, suggesting mediation via beta-2 receptor stimulation. In conclusion, modafinil, atomoxetine and guanfacine negatively influence hMSC differentiation to bone-forming osteoblasts and cell migration through different intracellular pathways.

Cognitive enhancement: Effects of methylphenidate, modafinil, and caffeine on latent memory and resting state functional connectivity in healthy adults.

Stimulants like methylphenidate, modafinil, and caffeine have repeatedly shown to enhance cognitive processes such as attention and memory. However, brain-functional mechanisms underlying such cognitive enhancing effects of stimulants are still poorly characterized. Here, we utilized behavioral and resting-state fMRI data from a double-blind randomized placebocontrolled study of methylphenidate, modafinil, and caffeine in 48 healthy male adults. The results show that performance in different memory tasks is enhanced, and functional connectivity (FC) specifically between the frontoparietal network (FPN) and default mode network (DMN) is modulated by the stimulants in comparison to placebo. Decreased negative connectivity between right prefrontal and medial parietal but also between medial temporal lobe and visual brain regions predicted stimulant-induced latent memory enhancement. We discuss dopamine's role in attention and memory as well as its ability to modulate FC between large-scale neural networks (e.g., FPN and DMN) as a potential cognitive enhancement mechanism.