Nevertheless, future research endeavors may wish to investigate if there is a physiologic reason for the relative lack of effect of modafinil in these patient populations.
Although only one study with significant limitations tested the effects of modafinil on humor appreciation Killgore et al , this topic deserves particular attention, because humor appreciation is a very complex neural task requiring frontal lobe function and integrative information processing between numerous cortical and subcortical brain regions Shammi and Stuss ; Goel and Dolan ; Mobbs et al ; Moran et al This test compared the effects of modafinil to caffeine and amphetamine in not only humor appreciation, but also PVT performance and Stanford Sleepiness Test Score.
While the modafinil group had only the second best PVT scores and the worst Stanford Sleepiness Test scores, they had the best humor appreciation scores. The results of this study combined with studies of the brain regions mediating humor Shammi and Stuss ; Goel and Dolan ; Mobbs et al ; Moran et al provide further support to the idea that modafinil improves whole-brain function.
We found only two neuroimaging studies examining the effects of modafinil Ellis et al ; Spence et al both of which used BOLD fMRI to observe event-related circulatory changes in the brain. Notably, the study involving schizophrenic subjects measured event related changes in a working memory task, while the study comparing narcoleptic and normal subjects measured event-related changes during sensory stimulation.
In contrast to this, the stimulant amphetamine simply increases blood flow changes in cortical activation Uftring et al In fact many of these studies provide evidence to the contrary, showing that modafinil does not act on the extracellular targets that would be most plausible in mediating the effects of modafinil in the diseases and conditions studied.
There are, however, a few studies that investigate effects of modafinil on processes that are possibly or even likely intracellularly mediated, and in each of these studies an effect due to modafinil is found Pierard et al ; Antonelli et al ; Ferraro et al , ; Jenner et al ; Xiao et al Though an extracellular mechanism of action cannot be ruled out, these studies taken together suggest that perhaps modafinil targets an intracellular protein or receptor rather than an extracellular site. A number of plausible but uninvestigated sites of action for modafinil, both intracellular and extracellular, remain to be studied to explain its stimulant effects and its neuroprotective effects.
Altered depolarization requirements of neurons via changes in sodium homeostasis, or enhanced calcium influx could explain increased neurotransmitter release which is calcium dependent when a neuron is stimulated. It is also worth noting that while modafinil is chiefly thought of as a stimulant, it has clearly demonstrated both wake-promoting and neuroprotective effects in preclinical studies, yet no previous papers to our knowledge have reported any attempt to integrate these findings or to find a common site of action that could mediate both of these effects.
It has been suspected for a long time, and it is generally agreed now that cellular mitochondria, calcium homeostasis, and oxidative stress play important roles in neurodegeneration. Research also suggests that oxidative stress and neural metabolic function, such as the availability of high energy metabolic substrates including creatine, are important mediators of arousal state and cognitive functions McMorris et al A report showing that reactive oxygen species increased adenosine levels and induced slow-wave sleep suggests that sleep may function in part to allow the reactive oxygen species scavenging system to restore neurochemical redox states Ikeda et al There has also been research showing that neurons of the neocortex and substantia nigra have ATP-sensitive potassium channels K ATP -channels that suppress neuron firing and neurotransmitter release in states of reduced ATP or elevated H 2 O 2.
K ATP -channel activity also appears to be increased by extracellular adenosine via adenosine A1 receptor stimulation Heurteaux et al Therefore, enhanced mitochondrial ATP production, reduced production of H 2 O 2 , or reduced reactive oxygen species production would be expected to increase neurotransmitter release upon neuron stimulation via reduction in K ATP -channel activity. Any mechanism involving improved mitochondrial function or free-radical scavenging could, therefore, explain how modafinil enhances neurocognitive function and bolsters serotonin release without stimulating serotonin release on its own Ferraro et al , , While no antioxidant or mitochondrial effects of modafinil have been reported in the context of its ability to promote wakefulness or enhance neurotransmitter release, it has been shown that modafinil does have an antioxidant effect that appears to mediate its neuroprotective actions in MPTP-induced neurodegeneration Xiao et al It is likely that modafinil both enhances cellular metabolism and reduces free-radicals in neurons Pierard et al ; Xiao et al Reduction in brain oxidation or an increase in cortical creatine could promote vigilance Ikeda et al ; McMorris et al , and each effect can increase neurotransmitter release by reducing inhibitory K ATP -channel activity.
Thus, through any disruption in the positive feedback loop of increased free-radical production and reduced ATP production modafinil could potentially exert its neuroprotective and wake-promoting effects. Simplified sleep circuit. Nat Rev Neurosci , — We would like to thank Dr. Steven LaRowe and Dr. Patrick Mulholland for helpful consultation in the preparation of this manuscript and Evans Jenkins for technical assistance. National Center for Biotechnology Information , U.
Journal List Neuropsychiatr Dis Treat v. Neuropsychiatr Dis Treat. Paul Gerrard 1 and Robert Malcolm 2. Author information Copyright and License information Disclaimer. All rights reserved. This article has been cited by other articles in PMC. Abstract The novel wake-promoting agent modafinil has been in use for the treatment of several sleep disorders for a few years and is now undergoing clinical trials for its use in the treatment of stimulant addiction, but its primary mechanism of action remains elusive.
Keywords: modafinil, sleep, stimulant, neuroprotective, addiction treatment, free radicals. Introduction In a unique drug for the treatment of narcolepsy was approved by the Food and Drug Administration for the narcolepsy armamentarium. Neuroprotective effects of modafinil Pierard et al measured the in vivo cortical pool of glutamate-glutamine, aspartate, inositol, and creatine-phosphocreatine using 2D COSY H-NMR.
Modafinil human neurocognitive studies EEG studies EEG band definitions can vary somewhat among studies, and research indicates that alpha bands vary among individuals and with age.
Delta: 1—4 Hz Theta: 4—7 Hz Alpha: 7. Functional magnetic resonance imaging studies Spence et al examined the acute effects of mg of modafinil on short term memory and cerebral blood flow with fMRI in 17 medication controlled schizophrenic patients using a double-blind, placebo-controlled, crossover design consisting of 2 trial days separated by one week. Table 1 Summary of modafinil effects. Open in a separate window.
Figure 1. Table 2 Neurocognitive improvements useful in the treatment of addiction. Acknowledgments We would like to thank Dr. Adenosinergic modulation of rat basal forebrain neurons during sleep and waking:neuronal recording with microdialysis. J Physiol. Modafinil prevents glutamate cytotoxicity in cultured cortical neurons. Endogenous hydrogen peroxide regulates the excitability of midbrain dopamine neurons via ATP-sensitive potassium channels.
J Neurosci. A systematic review of modafinil: potential clinical uses and mechanisms of action. J Clin Psychiatry. Adenosine and behavioral state control:adenosine increases C-Fos protein and AP-1 binding in basal forebrain neurons. Brain Res Mol Brain Res. Paradoxical sleep deprivation increases the content of glutamate and glutamine in rat cerebral cortex. Am J Physiol Cell Physiol. A double-blind, placebo-controlled investigation of the efficacy of modafinil for sustaining the alertness and performance of aviators:a helicopter simulator study.
Psychopharmacology Berl ; — State-modulation of cortico-cortical connections underlying normal EEG alpha variants. Physiol Behav. Randomized controlled trial of modafinil for the treatment of fatigue in postpolio patients. Muscle Nerve. Distinctive effects of modafinil and d-amphetamine on the homeostatic and circadian modulation of the human waking EEG. Psychopharmacology Berl ; 2 — Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation.
Variations in extracellular mono-amines in the prefrontal cortex and medial hypothalamus after modafinil administration:a microdialysis study in rats. Influence of modafinil on somato-sensory input processing in the human brain-stem. Clin Neurophysiol. EEG alpha power and intelligence. Superoxide activates mitochondrial uncoupling proteins. Modafinil induces wakefulness without intensifying motor activity or subsequent rebound hypersomnolence in the rat. J Pharmacol Exp Ther.
Functional magnetic resonance imaging neuroactivation studies in normal subjects and subjects with the narcoleptic syndrome. Actions of modafinil. J Sleep Res. Brain regional substrates for the actions of the novel wake-promoting agent modafinil in the rat: comparison with amphetamine.
The antinarcoleptic drug modafinil increases glutamate release in thalamic areas and hippocampus. Modafinil:an antinarcoleptic drug with a different neurochemical profile to d-amphetamine and dopamine uptake blockers. Biol Psychiatry. The effects of modafinil on striatal, pallidal and nigral GABA and glutamate release in the conscious rat: evidence for a preferential inhibition of striato-pallidal GABA transmission.
Neurosci Lett. The vigilance promoting drug modafinil increases extracellular glutamate levels in the medial preoptic area and the posterior hypothalamus of the conscious rat: prevention by local GABA A receptor blockade.
Amplification of cortical serotonin release:a further neurochemical action of the vigilance-promoting drug modafinil. Differential enhancement of dialysate serotonin levels in distinct brain regions of the awake rat by modafinil: possible relevance for wakefulness and depression.
J Neurosci Res. Modafinil enhances the increase of extracellular serotonin levels induced by the antidepressant drugs fluoxetine and imipramine: a dual probe microdialysis study in awake rat. The vigilance promoting drug modafinil decreases GABA release in the medial preoptic area and in the posterior hypothalamus of the awake rat: possible involvement of the serotonergic 5-HT3 receptor. Modafinil does not affect serotonin efflux from rat frontal cortex synaptosomes: comparison with known serotonergic drugs.
Brain Res. Endothelium-derived hyperpolarizing factor synthase cytochrome P 2C9 is a functionally significant source of reactive oxygen species in coronary arteries. Circ Res. Effect of the wake-promoting agent modafinil on sleep-promoting neurons from the ventrolateral preoptic nucleus:an in vitro pharmacologic study [see comment] Sleep.
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Cognitive performance following modafinil versus placebo in sleep-deprived emergency physicians: a double-blind randomized crossover study. Acad Emerg Med. The functional anatomy of humor:segregating cognitive and affective components. Nat Neurosci. When intelligence loses its impact: neural efficiency during reasoning in a familiar area.
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It is usually taken once a day with or without food. If you are taking modafinil to treat shift work sleep disorder, you will probably take it 1 hour before the beginning of your work shift. Take modafinil at the same time every day. Do not change the time of day that you take modafinil without talking to your doctor.
Talk to your doctor if your work shift does not begin at the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand.
Take modafinil exactly as directed. Modafinil may be habit-forming. Do not take a larger dose, take it more often, or take it for a longer period of time than prescribed by your doctor. Modafinil may decrease your sleepiness, but it will not cure your sleep disorder. Continue to take modafinil even if you feel well-rested.
Do not stop taking modafinil without talking to your doctor. Modafinil should not be used in place of getting enough sleep. Follow your doctor's advice about good sleep habits. Continue to use any breathing devices or other treatments that your doctor has prescribed to treat your condition, especially if you have OSAHS. This medication may be prescribed for other uses; ask your doctor or pharmacist for more information. Talk to your doctor about eating grapefruit or drinking grapefruit juice while you are taking this medication.
You should skip the missed dose. Wait until the next time you are supposed to take modafinil, and then take your normal dose. If you take modafinil too late in your waking day, you may find it harder to go to sleep. Do not take a double dose to make up for a missed one. Modafinil may cause other side effects. Call your doctor if you have any unusual problems while taking this medication. Keep this medication in the container it came in, tightly closed, and out of reach of children.
However, it is not uncommon for other groups of people to misuse these drugs as well. For example, 8. Modafinil is supposed to be less addictive than other psychostimulants like amphetamine, but some evidence suggests that dependence and abuse are possible.
Modafinil is sometimes called a "wakefulness-promoting agent. Modafinil affects the hypothalamus, hippocampus, and amygdala which are parts of the brain. Modafinil is a tablet taken by mouth usually once-a-day. However, shift workers who take the drug to promote wakefulness take the drug before their shifts begin.
Modafinil is used to treat problems with sleep, arousal, and wakefulness. Some conditions treated with modafinil include the following:. Modafinil's most common adverse effects include the following:.
Other adverse effects include the following:. Some of these adverse effects are scary and dangerous so be sure to contact your physician if you experience any of them. If you are having suicidal thoughts, contact the National Suicide Prevention Lifeline at for support and assistance from a trained counselor. If you or a loved one are in immediate danger, call For more mental health resources, see our National Helpline Database.
Additionally, some of these adverse effects such as insomnia, restlessness, chest pain, nausea, and confusion may result from overdose with modafinil. If you suspect an overdose, call emergency services or contact a physician immediately. Modafinil isn't for everyone, and before your physician prescribes you this medication, you should inform her of the following:. People who have unstable angina or recently had a heart attack shouldn't be given modafinil.
Furthermore, it's unclear the effect that modafinil has on the seizure threshold. Thus, modafinil should be used with caution in people with epilepsy and other seizure disorders. There are no long-term studies on the effects of modafinil on the brain. A physician must carefully consider whether to prescribe modafinil and weigh the benefit of its stimulant properties with potentially adverse effects.
Although modafinil is probably less addictive than other stimulants like amphetamines and methylphenidate, it still can likely lead to dependence. Please understand that every time a physician makes the decision to prescribe modafinil, this decision is patient specific.
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