Stimulant Modafinil Research Articles

Surface plasmon resonance (EC-SPR) sensor based on molecularly imprinted strategy for the determination of stimulant modafinil in saliva samples

A highly sensitive and selective molecularly imprinted polymer-based electrochemical-surface plasmon resonance (MIP-based EC-SPR) sensor was developed for the determination of modafinil in saliva samples. The optimal MIPpy film was synthesized using a modafinil concentration of 1 mM and a constant potential electropolymerization method. The fabricated sensor exhibited a wide linear range (0.1 μM to 10 μM), low detection limits (LOD: 50 nM, LOQ: 170 nM), and high selectivity towards modafinil, with selectivity coefficients of 8.5, 6.2, and 12.7 for adrafinil, armodafinil, and caffeine, respectively. The sensor also demonstrated excellent reproducibility (RSD: 4.2 %) and long-term stability (92 % response after one month). Furthermore, the applicability of the sensor in real samples was validated using spiked saliva samples, with recovery values ranging from 94.7 % to 103.5 %. These results highlight the potential of the MIP-based EC-SPR sensor as a powerful tool for the rapid, sensitive, and selective detection of modafinil in complex biological matrices.

Modafinil Alleviates Rotenone-Induced Neurochemical changes and Striatal Neurodegeneration via Inhibiting Oxidative Stress and Neuroinflammation

Objectives of study are around investigation the effect of the central nervous system stimulant modafinil on brain striatum neurodegeneration caused by subcutaneous (s.c.) rotenone administration in rats, further, the possible modulation by modafinil on L-dopa effect on oxidative stress, inflammation and nigrostriatal cell damage. Seven groups of Male albino mice received dimethyl sulfoxides.c., rotenone (1.5 mg/kg, s.c., 3 times per week), rotenone/L-dopa (25 mg/kg, p.o., daily), rotenone/modafinil (0.1, 0.2 and 0.3 mg/kg respectively, p.o., daily), rotenone/L-dopa/modafinil (0.2 mg/kg, p.o. daily). The treatment was continued for 2 weeks. Mice were tested for behavioral changes 24h after the end of treatments.Mice were evaluated for brain biochemical markers of oxidative stress (lipid peroxidation, reduced glutathione, and nitric oxide), pro-inflammatory factors (tumor necrosis factor-α, interlukin-1beta) and dopamine level. Histopathologic examination and the expression of the anti-apoptotic protein caspase-3 were also performed. Rotenone significantly elevated oxidative stress and pro-inflammation, decreased dopamine, induced substantianigra damage with caspase-3-mediated apoptosis respectly to the control levels. Results of modafinil or its combination with L-dopa may have potential therapeutic effect in Parkinson’s disease by decreasing pro-inflammation and oxidative stress, increasing dopamine, preventing the development of neuronal damage and reducing caspase-3 expression in the striatum.

More on Maternal Modafinil During Pregnancy

As the number of young women treated with the stimulant modafinil (Provigil) has grown, a registry established by the manufacturer has indicated

Neuroepigenetics of arousal: Gamma oscillations in the pedunculopontine nucleus.

Four major discoveries on the function of the pedunculopontine nucleus (PPN) have significantly advanced our understanding of the role of arousal in neurodegenerative disorders. The first was the finding that stimulation of the PPN-induced controlled locomotion on a treadmill in decerebrate animals, the second was the revelation of electrical coupling in the PPN and other arousal and sleep-wake control regions, the third was the determination of intrinsic gamma band oscillations in PPN neurons, and the last was the discovery of gene transcription resulting from the manifestation of gamma activity in the PPN. These discoveries have led to novel therapies such as PPN deep brain stimulation (DBS) for Parkinson's disease (PD), identified the mechanism of action of the stimulant modafinil, determined the presence of separate mechanisms underlying gamma activity during waking versus REM sleep, and revealed the presence of gene transcription during the manifestation of gamma band oscillations. These discoveries set the stage for additional major advances in the treatment of a number of disorders.

Dorsal Striatum Dopamine Levels Fluctuate Across the Sleep-Wake Cycle and Respond to Salient Stimuli in Mice.

Dopamine is involved in numerous neurological processes, and its deficiency has been implicated in Parkinson’s disease, whose patients suffer from severe sleep disorders. Destruction of nigrostriatal dopaminergic neurons or dorsal striatum disrupts the sleep–wake cycle. However, whether striatal dopamine levels correlate with vigilance states still remains to be elucidated. Here, we employed an intensity-based genetically encoded dopamine indicator, dLight1.1, to track striatal dopamine levels across the spontaneous sleep–wake cycle and the dopaminergic response to external stimuli. We found that the striatal dLight1.1 signal was at its highest during wakefulness, lower during non-rapid eye movement (non-REM or NREM) sleep, and lowest during REM sleep. Moreover, the striatal dLight1.1 signal increased significantly during NREM sleep-to-wake transitions, while it decreased during wake-to-NREM sleep transitions. Furthermore, different external stimuli, such as sudden door-opening of the home cage or cage-change to a new environment, caused striatal dopamine release, whereas an unexpected auditory tone did not. Finally, despite both modafinil and caffeine being wake-promoting agents that increased wakefulness, modafinil increased striatal dopamine levels while caffeine did not. Taken together, our findings demonstrated that striatal dopamine levels correlated with the spontaneous sleep–wake cycle and responded to specific external stimuli as well as the stimulant modafinil.

A simple method to detect the stimulant modafinil in authentic saliva using a carbon-nanotube screen-printed electrode with adsorptive stripping voltammetry

Electrochemical detection of modafinil, a stimulant banned in sports competitions, is reported for the first time. An electrochemical sensor is developed based on carbon nanotubes screen-printed electrodes (SPE-CNT) with adsorptive stripping wave voltammetry (AdSWV). The proposed electrochemical method is applied to authentic human saliva for modafinil determination (LOD of 2.0 μM) without interference from uric acid or ascorbic acid. The analytical performance of the SPE-CNT with AdSWV for detection of modafinil in authentic saliva samples suggests its possible application as a simple and fast method for doping control.

Modafinil for the treatment of fatigue in lung cancer: results of a placebo-controlled, double-blind, randomized trial.

Fatigue is a distressing symptom occurring in more than 60% of patients with cancer. The CNS stimulants modafinil and methylphenidate are recommended for the treatment of cancer-related fatigue, despite a limited evidence base. We aimed to evaluate the efficacy and tolerability of modafinil in the management of fatigue in patients with non-small-cell lung cancer (NSCLC). Adults with advanced NSCLC and performance status of 0 to 2, who were not treated with chemotherapy or radiotherapy within the last 4 weeks, were randomly assigned to daily modafinil (100 mg on days 1 to 14; 200 mg on days 15 to 28) or matched placebo. The primary outcome was change in Functional Assessment of Chronic Illness Therapy (FACIT) -Fatigue score from baseline to 28 days, adjusted for baseline fatigue and performance status. Secondary outcomes included safety and patient-reported measures of depression, daytime sleepiness, and quality of life. A total of 208 patients were randomly assigned, and 160 patients (modafinil, n = 75; placebo, n = 85) completed questionnaires at both baseline and day 28 and were included in the modified intention-to-treat analysis. FACIT-Fatigue scores improved from baseline to day 28 (mean score change: modafinil, 5.29; 95% CI, 2.57 to 8.02; placebo, 5.09; 95% CI, 2.54 to 7.65), but there was no difference between treatments (0.20; 95% CI, -3.56 to 3.97). There was also no difference between treatments for the secondary outcomes; 47% of the modafinil group and 23% of the placebo group stated that the intervention was not helpful. Modafinil had no effect on cancer-related fatigue and should not be prescribed outside a clinical trial setting. Its use was associated with a clinically significant placebo effect.

Emerging pharmacotherapy for cancer patients with cognitive dysfunction

Advances in the diagnosis and multi-modality treatment of cancer have increased survival rates for many cancer types leading to an increasing load of long-term sequelae of therapy, including that of cognitive dysfunction. The cytotoxic nature of chemotherapeutic agents may also reduce neurogenesis, a key component of the physiology of memory and cognition, with ramifications for the patient’s mood and other cognition disorders. Similarly radiotherapy employed as a therapeutic or prophylactic tool in the treatment of primary or metastatic disease may significantly affect cognition. A number of emerging pharmacotherapies are under investigation for the treatment of cognitive dysfunction experienced by cancer patients. Recent data from clinical trials is reviewed involving the stimulants modafinil and methylphenidate, mood stabiliser lithium, anti-Alzheimer’s drugs memantine and donepezil, as well as other agents which are currently being explored within dementia, animal, and cell culture models to evaluate their use in treating cognitive dysfunction.

Repurposed Medications Show Promise in Stimulant Dependence

Back to table of contents Previous article Next article From the ExpertsFull AccessRepurposed Medications Show Promise in Stimulant DependencePublished Online:4 Jan 2013https://doi.org/10.1176/appi.pn.2013.1a12Stimulant dependence is a substance use disorder (SUD) that continues to affect society on many levels. The economic temptation of producing or bringing stimulants or their precursors (methamphetamine and cocaine) across the U.S. border to sell is continuing as certain South American countries now allow full-fledged coca plant cultivation. Containing the flow of illicit drugs within state lines and across U.S. borders is an insurmountable task for any agency, and demand reduction from effective treatments is desperately needed.Stimulant dependence is a substance use disorder (SUD) that continues to affect society on many levels. The economic temptation of producing or bringing stimulants or their precursors (methamphetamine and cocaine) across the U.S. border to sell is continuing as certain South American countries now allow full-fledged coca plant cultivation. Containing the flow of illicit drugs within state lines and across U.S. borders is an insurmountable task for any agency, and demand reduction from effective treatments is desperately needed.Research for these addiction treatments has benefited greatly from neuroimaging studies and “repurposed” medications. Neuroimaging studies have been essential to understanding central deficits and altered neurotransmission linked to stimulant dependence. For example, recent evidence dispels the widely held misconception that stimulant-dependent individuals are more sensitive to these drugs than the average person, and this is why they become dependent. In fact, the opposite is true. They are less sensitive to the positive euphoric effects of stimulants. This also extends to natural rewards such as food. In contrast, these same individuals are often hypersensitive to stress and overly influenced by environmental cues associated with drug taking that can trigger relapse. Environmental cues that control behavior are influenced by usurped memory circuits. SUDs are often accompanied by comorbid negative mood states that may also contribute to continued drug use through self-medication. Neuroimaging has revealed that abnormally low dopaminergic neurotransmission is paired with orbitofrontal hypoactivation in stimulant dependence and limits impulse control, executive functioning, and working memory. Medications that modulate dopamine, glutamate, and norepinephrine (NE) neurotransmission that show promise for impulse control and enhance cognition may also be used to treat stimulant dependence. Doxazosin is a repurposed NE blocker used for hypertension that Newton et al. (2012) recently found blocks cocaine’s positive subjective effects and the feeling “likely to use cocaine” in cocaine-dependent volunteers after a cocaine infusion. An outpatient clinical trial is presently examining this medication for decreasing cocaine use. Another repurposed medication, the angiotensin-converting enzyme inhibitor and antihypertensive perindopril blocks the cardiovascular and positive subjective effects of methamphetamine. The commonly prescribed antidepressant bupropion has also shown some efficacy in decreasing methamphetamine use in moderate users. Rivastigmine, used in the treatment of dementia, significantly decreased “likely to use methamphetamine” in dependent volunteers. Finally, the atypical stimulant modafinil, used to treat narcolepsy, blocks cocaine’s positive subjective effects and has decreased cocaine use in a select subpopulation.Psychiatric addiction research has benefited from repurposing a wide range of medications. The science behind using these medications is based on understanding from neuroimaging of damaged and reinforcing human neural circuits due to addictive stimulants. For the most part, the development of effective treatments for this pernicious disorder appears promising. ■References are posted at http://www.psychnews.org/update/experts_2_32.html.Thomas Kosten, M.D., is the J.H. Waggoner Professor of Psychiatry, Pharmacology and Neuroscience, vice chair for psychiatry, and codirector of the Institute for Clinical and Translational Research at Baylor College of Medicine. Colin Haile, M.D., Ph.D., is an assistant professor at Baylor College of Medicine, Menninger Department of Psychiatry and Michael E. DeBakey VA Medical Center. He and Kosten are the coauthors of "Cocaine and Methamphetamine Dependence: Advances in Treatment" from American Psychiatric Publishing. APA members may purchase the book at a discount at http://www.appi.org/SearchCenter/Pages/SearchDetail.aspx?ItemId=62407. ISSUES NewArchived

The Role of Nucleus Accumbens Core/Shell in Sleep-Wake Regulation and their Involvement in Modafinil-Induced Arousal

BackgroundWe have previously shown that modafinil promotes wakefulness via dopamine receptor D1 and D2 receptors; however, the locus where dopamine acts has not been identified. We proposed that the nucleus accumbens (NAc) that receives the ventral tegmental area dopamine inputs play an important role not only in reward and addiction but also in sleep-wake cycle and in mediating modafinil-induced arousal.Methodology/Principal FindingsIn the present study, we further explored the role of NAc in sleep-wake cycle and sleep homeostasis by ablating the NAc core and shell, respectively, and examined arousal response following modafinil administration. We found that discrete NAc core and shell lesions produced 26.5% and 17.4% increase in total wakefulness per day, respectively, with sleep fragmentation and a reduced sleep rebound after a 6-hr sleep deprivation compared to control. Finally, NAc core but not shell lesions eliminated arousal effects of modafinil.Conclusions/SignificanceThese results indicate that the NAc regulates sleep-wake behavior and mediates arousal effects of the midbrain dopamine system and stimulant modafinil.

Diagnosis and management of central hypersomnias

Central hypersomnias are diseases manifested in excessive daytime sleepiness (EDS) not caused by disturbed nocturnal sleep or misaligned circadian rhythms. Central hypersomnias includes narcolepsy with and without cataplexy, recurrent hypersomnia, idiopathic hypersomnia, with and without long sleep time, behaviorally induced insufficient sleep syndrome, hypersomnia and narcolepsy due to medical conditions, and finally hypersomnia induced by substance intake. The Epworth Sleepiness Scale is a subjective tool mostly used for EDS assessment, while the Multiple Sleep Latency Test serves as an objective diagnostic method for narcolepsy and idiopathic hypersomnias. As for symptomatic therapy of EDS, the central nervous system stimulants modafinil and methylphenidate seem to work well in most cases and in narcolepsy and Parkinson's disease; sodium oxybate also has notable therapeutic value.

Correction: The Atypical Stimulant and Nootropic Modafinil Interacts with the Dopamine Transporter in a Different Manner than Classical Cocaine-Like Inhibitors

Correction: The Atypical Stimulant and Nootropic Modafinil Interacts with the Dopamine Transporter in a Different Manner than Classical Cocaine-Like Inhibitors

Regulation of Neuronal Activities within REM Sleep-Sign Generators

Regulation of Neuronal Activities within REM Sleep-Sign Generators

Modafinil increases arousal determined by P13 potential amplitude: an effect blocked by gap junction antagonists.

We recorded the effects of administration of the stimulant modafinil on the amplitude of the sleep state-dependent auditory P13 evoked potential in freely moving rats, a measure of arousal thought to be generated by the cholinergic arm of the reticular activating system, specifically the pedunculopontine nucleus (PPN). Groups of rats were implanted for recording auditory evoked responses and the effects on P13 potential amplitude of intracranial injections into the PPN of neuroactive agents determined. The effects of intracranial injections into the PPN of modafinil showed that P13 potential amplitude increased in a dose-dependent manner at doses of 100, 200, and 300 microM. The effect was blocked by pretreatment with either of the gap junction antagonists carbenoxolone (300 microM) or mefloquine (25 microM), which by themselves slightly decreased P13 potential amplitude. These results suggest that modafinil increases arousal levels as determined by the amplitude of the P13 potential, an effect blocked by gap junction antagonists, suggesting that one mechanism by which modafinil increases arousal may be by increasing electrical coupling.

Pharmacogenetics of Modafinil After Sleep Loss: Catechol-O-Methyltransferase Genotype Modulates Waking Functions But Not Recovery Sleep

Sleep loss impairs waking functions and is homeostatically compensated in recovery sleep. The mechanisms underlying the consequences of prolonged wakefulness are unknown. The stimulant modafinil may promote primarily dopaminergic neurotransmission. Catechol-O-methyltransferase (COMT) catalyzes the breakdown of cerebral dopamine. A functional Val158Met polymorphism reduces COMT activity, and Val/Val homozygous individuals presumably have lower dopaminergic signaling in the prefrontal cortex than do Met/Met homozygotes. We quantified the contribution of this polymorphism to the effects of sleep deprivation and modafinil on subjective state, cognitive performance, and recovery sleep in healthy volunteers. Two-time 100 mg modafinil potently improved vigor and well-being, and maintained baseline performance with respect to executive functioning and vigilant attention throughout sleep deprivation in Val/Val genotype subjects but was hardly effective in subjects with the Met/Met genotype. Neither modafinil nor the Val158Met polymorphism affected distinct markers of sleep homeostasis in recovery sleep. In conclusion, dopaminergic mechanisms contribute to impaired waking functions after sleep loss.

Effects of the atypical stimulant modafinil on a brief gambling episode in pathological gamblers with high vs. low impulsivity

Pathological gambling (PG) is a serious psychiatric disorder afflicting 1-3% of the general population. Experimental evidence indicates shared neurochemical substrates for PG and psychostimulant addiction. Impulsivity characterizes one key subtype of PG. Therefore, medications that ameliorate psychostimulant addiction and impulsive syndromes might also benefit impulsive PG subjects. The atypical stimulant, modafinil reduces cocaine abuse and impulsivity in patients with ADHD. The present study sought to determine if modafinil (200 mg) would reduce the reinforcing effects of slot machine gambling in PG subjects, and if this effect was stronger in high (H-I) vs. low (L-I) impulsivity subjects (N = 20). A placebo-controlled, double-blind, counterbalanced, repeated measures design was employed. Apart from bet size, which declined uniformly in both groups under drug, modafinil had bi-directional effects in the two groups. In H-I subjects, the drug decreased desire to gamble, salience of Gambling words, disinhibition and risky decision-making. In L-I subjects, modafinil increased scores on these indices. Modafinil also differentially affected blood pressure response to the game in the two groups. These findings for modafinil appear to fit well with a growing literature demonstrating bi-directional effects of D2 agonists as a function of trait impulsivity. Impulsivity could critically moderate medication response in PG.

Electrical Coupling: Novel Mechanism for Sleep-Wake Control

Recent evidence suggests that certain anesthetic agents decrease electrical coupling, whereas the stimulant modafinil appears to increase electrical coupling. We investigated the potential role of electrical coupling in 2 reticular activating system sites, the subcoeruleus nucleus and in the pedunculopontine nucleus, which has been implicated in the modulation of arousal via ascending cholinergic activation of intralaminar thalamus and descending activation of the subcoeruleus nucleus to generate some of the signs of rapid eye movement sleep. We used 6- to 30-day-old rat pups to obtain brainstem slices to perform whole-cell patch-clamp recordings. Recordings from single cells revealed the presence of spikelets, manifestations of action potentials in coupled cells, and of dye coupling of neurons in the pedunculopontine nucleus. Recordings in pairs of pedunculopontine nucleus and subcoeruleus nucleus neurons revealed that some of these were electrically coupled with coupling coefficients of approximately 2%. After blockade of fast synaptic transmission, the cholinergic agonist carbachol was found to induce rhythmic activity in pedunculopontine nucleus and subcoeruleus nucleus neurons, an effect eliminated by the gap junction blockers carbenoxolone or mefloquine. The stimulant modafinil was found to decrease resistance in neurons in the pedunculopontine nucleus and subcoeruleus nucleus after fast synaptic blockade, indicating that the effect may be due to increased coupling. The finding of electrical coupling in specific reticular activating system cell groups supports the concept that this underlying process behind specific neurotransmitter interactions modulates ensemble activity across cell populations to promote changes in sleep-wake state.

Les médicaments du sommeil et de la vigilance et leurs indications

This paper is a review of the use of drugs in sleep and wakefulness disorders. Insomnia is more often a symptom than an autonomic disorder. Good knowledge of the clinical facts is required before prescribing hypnotics. Sedative drugs are potentially hypnotics; yet, melatonin is not sedative and may be considered to resynchronise of sleep phases. Stimulant drugs are prescribed in attention disorders; methylphenidate is the more frequently used. Narcolepsy, which is characterized by daytime sleepiness and irresistible episodes of sleep, is treated by an alpha1 noradrenergic stimulant modafinil which has no amphetaminic properties.

Pharmacogenomics in the treatment of narcolepsy.

Narcolepsy is a neurological disorder characterized by excessive daytime sleepiness and cataplexy. Available treatments of narcolepsy include stimulants and antidepressants but the recent discovery of orexin/hypocretin deficiency in narcolepsy opens up new perspectives. Narcolepsy is a complex disorder involving genetic, immune and environmental factors. Although only a strong association is found with the HLA DQB1*0602 gene, other genetic susceptibility factors might be involved. Among these, the functional polymorphism of the catechol-O-methyltransferase (COMT) gene is critically involved in the severity of narcolepsy and in the response to the stimulant modafinil. Other pharmacogenetic targets include the orexinergic, noradrenergic and possibly the serotonergic pathways.

Sleep disorders

Many pharmacologic and nonpharmacologic strategies are available to treat sleep disorders successfully. Conventional stimulants and the new stimulant modafinil have roles to play in the management of narcolepsy and idiopathic hypersomnia. Knowledge of the properties and clinical effects of these drugs allows adequate doses of medications to be used with the goal of attaining as maximal alertness as possible. A range of dopaminergic agents is available to treat restless legs syndrome; other medications such as opiates, benzodiazepines, and anticonvulsants can also be used. Successful use of the dopaminergic agents depends on an understanding of the phenomena of augmentation, rebound, and tolerance. Arousal parasomnias can be treated with behavioral methods such as hypnosis and drug therapy. Clonazepam provides relief of the symptoms in most patients with REM sleep behavior disorder.