What makes provigil work

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Blockade of the noradrenaline carrier increases extracellular dopamine concentrations in the prefrontal cortex: evidence that dopamine is taken up in vivo by noradrenergic terminals.

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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 8 : 85— Brain regional substrates for the actions of the novel wake-promoting agent modafinil in the rat: comparison with amphetamine. Neuroscience 87 : — Differential patterns of regional c-Fos induction in the rat brain by amphetamine and the novel wakefulness-promoting agent modafinil.

Neurosci Lett : 95— Modafinil and unconstrained motor activity in schizophrenia: double-blind crossover placebo-controlled trial. Br J Psychiatry : — A multicenter, placebo-controlled study of modafinil augmentation in partial responders to selective serotonin reuptake inhibitors with persistent fatigue and sleepiness. J Clin Psychiatry 66 : 85— The antinarcoleptic drug modafinil increases glutamate release in thalamic areas and hippocampus.

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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 GABAA receptor blockade. Neuropsychopharmacology 20 : — Modafinil enhances the increase of extracellular serotonin levels induced by the antidepressant drugs fluoxetine and imipramine: a dual probe microdialysis study in awake rat. Synapse New York, NY 55 : — Amplification of cortical serotonin release: a further neurochemical action of the vigilance-promoting drug modafinil.

Neuropharmacology 39 : — 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 68 : — Modafinil does not affect serotonin efflux from rat frontal cortex synaptosomes: comparison with known serotonergic drugs. 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.

Neurosci Lett : 5—8. Effect of modafinil on cerebral blood flow of anaesthetised rats. Comparison with amphetamine. Exp Brain Res : — Evidence for a protective action of the vigilance promoting drug modafinil on the MPTP-induced degeneration of the nigrostriatal dopamine neurons in the black mouse: an immunocytochemical and biochemical analysis.

Exp Brain Res 88 : — Effect of the wake-promoting agent modafinil on sleep-promoting neurons from the ventrolateral preoptic nucleus: an in vitro pharmacologic study. Sleep 27 : 19— Presynaptic regulation of recurrent excitation by D1 receptors in prefrontal circuits. Inhibitory effects of trace amines on rat midbrain dopaminergic neurons. Neuropharmacology 46 : — Cognitive performance following modafinil versus placebo in sleep-deprived emergency physicians: a double-blind randomized crossover study.

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J Clin Pharmacol 41 : — Steady-state pharmacokinetics and tolerability of modafinil administered alone or in combination with dextroamphetamine in healthy volunteers. J Clin Pharmacol 42 : — Awakening properties of modafinil: effect on nocturnal activity in monkeys Macaca mulatta after acute and repeated administration.

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Comparison of modafinil and clonidine on arousal and autonomic functions in human volunteers. Impact of modafinil on prefrontal executive function in schizophrenia.

Modafinil increases histamine release in the anterior hypothalamus of rats. Jasinski DR An evaluation of the abuse potential of modafinil using methylphenidate as a reference. J Psychopharmacol 14 : 53— Loss of autoreceptor functions in mice lacking the dopamine transporter. Nat Neurosci 2 : — The noradrenaline-dopamine interaction in the rat medial prefrontal cortex studied by multi-probe microdialysis.

Modafinil inhibits rat midbrain dopaminergic neurons through D2-like receptors. Neuropharmacology 52 : — Effects of mammillary bodies and mediodorsal thalamic lesions on the acquisition and retention of a learning set in mice: paradoxical effect of the intersession interval. Behav Brain Res 67 : 51— Noradrenergic innervation of monkey prefrontal cortex: a dopamine-beta-hydroxylase immunohistochemical study.

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Role of catecholamines in the modafinil and amphetamine induced wakefulness, a comparative pharmacological study in the cat. Modafinil reduces excessive somnolence and enhances mood in patients with myotonic dystrophy.

Neurology 59 : — Modafinil occupies dopamine and norepinephrine transporters in vivo and modulates the transporters and trace amine activity in vitro. Modafinil and cocaine interactions. Am J Drug Alcohol Abuse 32 : — Dopamine decreases the calcium-activated afterhyperpolarization in hippocampal CA1 pyramidal cells.

Differential involvement of anterior and posterior cingulate cortices in spatial discriminative learning in a T-maze in mice. Behav Brain Res 44 : — Modafinil binds to the dopamine uptake carrier site with low affinity. Sleep 17 : — Canine cataplexy is preferentially controlled by adrenergic mechanisms: evidence using monoamine selective uptake inhibitors and release enhancers.

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Effects of modafinil on working memory processes in humans. D1 receptor in interneurons of macaque prefrontal cortex: distribution and subcellular localization. J Neurosci 18 : — Modafinil enhances extracellular levels of dopamine in the nucleus accumbens and increases wakefulness in rats.

Behav Brain Res : — Modafinil: preclinical, clinical, and post-marketing surveillance—a review of abuse liability issues. However, amphetamine has an adverse rebounding effect that causes depression or anxiety when the intended effects wear off [ 22 ].

As a clinical medication, amphetamine is used to treat traumatic brain injury, chronic fatigue syndrome, attention deficit hyperactivity disorder ADHD , and hypnolesy [ 8 , 23 , 24 ]. It is also illegally prescribed as a mood enhancer or as a waking drug for daily life.

Amphetamine is widely used for its comparative effectiveness and lasting duration, but when abused it becomes a highly addictive narcotic of rapid toleration rate and increasing dependence [ 25 ]. Caffeine, a methylxantine derivative, has been used as a psychoactive drug for a long period of time.

For healthy adults, the halflife of caffeine is 5 hours and it can be extended up to 11 hours for pregnant women or women taking birth control pills [ 26 ]. Caffeine acts as an antagonist of adenosin receptors [ 27 , 28 ]. Pharmaceutically, caffeine is a stimulant of metabolism and the central nervous system but is also used as a lifestyle drug and a clinical drug to decrease physical fatigue and maintain alertness. Caffeine capsules brighten the mood for those with accumulated fatigue due to lack of sleep and enhance concentration and task performance.

In daily life, caffeine is included in food or drinks to help to improve alertness and to recover from fatigue [ 29 ]. Medically, it is sold as a pill [ 8 , 19 , 24 ]. The effectiveness and duration of caffeine are not as great as amphetamine.

A novel class of psychostimulants is eugeroics under which modafinil, adrafinil, and ampakine are categorized. Eugeroic means good arousal; that is, eugeroics show no sign of common side effects of traditional psychostimulants, such as interference in recovery sleep, psychiatric disturbance, and addiction [ 5 , 30 , 31 ]. Modafinil has been clinically proven as an effective medication in treating narcolepsy, a disabling neurological disorder characterized by permanent and uncontrollable daytime sleepiness.

Orexin, which is a family of wakefulness-promoting and sleep-inhibiting peptides, is involved in inducing narcolepsy [ 32 ].

The orexin neurons are found exclusively in the lateral hypothalamus and the orexin neurons in the hypothalamic area projects to the entire central nervous system [ 33 ]. Orexin neurons may be activated by modafinil. Thus modafinil may induce wakefulness by its action in the anterior hypothalamus [ 34 ].

However, the waking mechanism of modafinil on orexin neurons yet to be fully elucidated. In a cat study, equal doses of amphetamine and methylphenidate increased c-fos gene expression in entire brain region including the caudate, but modafinil induced selectively and prominently the c-fos expression in hypothalamus of the brain [ 35 ]. Modafinil did not bind to most receptors related to sleep and wake cycle and did not inhibit monoamineoxidase or phosphodiesterase activities [ 36 ]. However, some other mechanisms of waking effects were proposed experimentally.

Modafinil activates central alpha 1-adrenergic receptor as an agonist [ 37 ]. The currently proposed mechanism of modafinil suggests that modafinil induces alertness through alpha-adrenergic receptor. However, alpha-adrenergic transmission can not fully explain why the alpha-adrenergic receptors in only a specific part of the brain are activated for enhancing or maintaining wakefulness.

Modafinil inhibits the reuptake of noradrenalin in the noradrenergic nerve endings. Therefore, the noradrenalin signal between sleep-promoting neurons of ventrolateral preoptic nucleus is amplified. Modafinil also amplifies cortical serotonin release [ 40 ]. Amplification of the electro-neurosecretory coupling mechanisms is preferentially involved in serotonin release by modafinil, while via reuptake process does not relate to serotonin release.

Modafinil increases histamine release significantly in the anterior hypothalamus. However, modafinil did not induce histamine release in the orexin knockout mice [ 41 , 42 ]. That is, increase of histamine release by modafinil requires orexinergic transmission. It has been known that modafinil may not be involved in dopamine release in the brain including the nuclear accumbens [ 37 , 43 ], although it seems that modafinil interacts with multiple molecular targets in the brain.

However, in a recent research, addictive potential of modafinil has been reported [ 44 , 45 ]. There is substantial evidence that modafinil, just like other addictive drugs, is sensitive to dopamine signaling in the brain [ 30 , 45 - 47 ]. Modafinil preempts dopamine transporter DAT and norepinephrine transporters in a living primate brain [ 44 ]. It inhibits dopamine reuptake through DAT [ 48 , 49 ].

Therefore modafinil administration increases extracellular levels of dopamine in the brain [ 50 - 52 ], and wake-promoting actions are absent in the DAT-knock-out mice [ 50 ].

Modafinil blocks DAT and causes an increase of dopamine in the animals and human brain including the nucleus accumbens, thus inducing the same response as other waking drugs [ 45 , 49 , 52 ]. An increase of dopamine in the nucleus accumbens may be connected to drug abuse.

The results of the experiment mentioned above are insufficient for a definitive evidence of addiction, since the main focus of those experiments was not addiction. However, these results lead to the possibility of addiction and have set the basis of prohibition on long-term medication of modafinil. Fatigue is a usual symptom among cancer patients, which degrades their quality of life. Depression in cancer patients may also come with tiredness. In regard to treatment of cancer-related fatigue, methylphenidate has long been studied to be very effective, despite its side effects [ 9 , 53 ].

Modafinil was also well-tolerated and effective against fatigue in cancer patients when self-administrated for four weeks [ 10 ]. The mood and quality of life of those patients were improved. Modafinil has been applied effectively to treat fatigue associated with depression, amyotropic lateral sclerosis, and multiple sclerosis [ 11 , 54 ]. Modafinil is effective in lowering the elevated fatigue level of cancer or multiple sclerosis patients, but positive effects in cognitive dysfunction associated with diseases are still controversial [ 54 , 55 ].

Fatigue is a significant problem in a combat environment. Combat fatigue come mainly from sleep deprivation caused by extended duty periods, unpredictable work hours, circadian disruption, fear, anxiety, and many more.

Combat fatigue by continuous sleep deprivation or sleep disorder can be mitigated by medication. Modafinil along with the traditional psychostimulants, such as amphetamines and cocaine, has alertness-enhancing effect and mitigate the accumulated fatigue in combat environment [ 13 , 14 , 27 ]. The effectiveness of caffeine, modafinil, and amphetamine has been directly compared in a few studies, and the doses of equal effectiveness in enhancing alertness and vigilance for each of these three compounds were specified [ 22 , 27 , 56 ].

Administration of a single dose of caffeine mg, modafinil mg, dextroamphetamine 20 mg, or placebo after 44 hours of continuous wakefulness restored psychomotor vigilance effectively compared to placebo in healthy adults [ 27 ]. The duration of this effect was longest for dextroamphetamine and shortest for caffeine. At above doses, caffeine turned out to have the most "subjectively reported side effects", followed by dextroamphetamine.

Dextroamphetamine was the only stimulant that had adverse effects on subsequent recovery sleep. Modafinil did not show significant, subjectively-reported side-effects nor subsequent recovery sleep compared to placebo. The effectiveness of these three stimulants is arranged in Table 1. Modafinil group was not significantly different from placebo group in adverse effects.

Modafinil is generally tolerated, and has few reported cases of adverse events. Modafinil improves task performance when medicated to people with normal living patterns. It is also more effective than amphetamine [ 57 ]. Modafinil may become a lifestyle drug without a restriction for narcoleptic patients.

Also, the US military has shown interest in modafinil for increasing alertness and helping battle fatigue [ 8 , 13 , 14 ]. Moreover, when medicated to people with fatigue and lethargic reactions as symptoms of depression, modafinil generates a synergy by relieving fatigue as well as depression [ 11 ]. Modafinil has a great potential of becoming a combat-capability-enhancing drug due to its waking, mood-brightening, and fatigue relieving effects [ 2 ]. Elevated lethargy or fatigue under a combat environment or war can be decreased by modafinil, and this can also lead to an enhancement of combat capability through an improvement in vigilance, psychomotor activity, and self-regard.

In early studies, it has been known that modafinil is a well tolerated drug with a low probability of addiction. However, the possibility of addiction in modafinil was reported in recent papers mentioned above [ 44 , 45 ].

Modafinil induced the elevation of dopamine level in the nucleus accumbens, which could lead to drug abuse. Traditional waking drugs elicit dopamine in the nucleus accumbens of the brain. Modafinil increases dopamine in the nucleus accumbens through inhibition of DAT in the animal and human brain as other addictive waking drugs [ 44 , 49 , 52 ].

Classification of modafinil as an addictive is still controversial. Modafinil show possible setbacks of abuse and addiction even though no cases have been reported to date [ 45 ]. The pharmacological mechanism of modafinil must be further elucidated. In general, we believe that sleep helps to build the immune system.

Sleep deprivation induces stress responses and impairs immune functions [ 15 , 16 ]. However, reports for immunomodulating effects of modafinil for keeping wakefulness are quite limited. An investigation for immunomodulation effects of modafinil is a significant step in itself. The disruption of circadian rhythm and sleep control may influence the neuro-immune circuits [ 32 , 33 ]. A waking drug may have effects on neuro-immune circuits.

If someone, who is a non-narcoleptic patient, wants to use modafinil for waking, enhancing their cognition, or brightening his mood, they may already be under a high level of stress, like soldiers in a battle field. It is possible that modafinil seekers already face quite a stressful situation. Stress responses via the hypothalamic-pituitary-adrenal axis start from corticotropin-releasing hormone CRH [ 58 , 59 ].

The waking effect of modafinil is related to CRH [ 60 ]. Modafinil cannot be excluded from investigation for immunomodulatory effects of stress. Serum C-reactive protein level, which indicates the inflammation level of an individual, was increased by a single dose of modafinil, while it reduced host resistance to Listeria monocytogenes infection [ 2 ]. Alertness-enhancing effect of modafinil may affect the autonomic nervous system in the periphery [ 61 , 62 ]. Modafinil increases resting heart rate and blood pressure.

Modafinil elicits plasma and urine norepinephrine and urine epinephrine. Modafinil may induce sympathomedullary activation. Usage of modafinil could be restricted to patients with heart disease because it causes excessive peripheral autonomic activation. A few studies reported that modafinil impairs recovery sleep under sleep deprivation, although alertness-enhancing or cognitive-improving effect of modafinil is significant among sleep-deprived individuals [ 12 , 63 , 64 ].

As modafinil gradually became known for its mood-brightening and memory-enhancing effects along with its waking effect, its usage has clearly increased as it is now medicated to treat memory loss due to dementia, ADHD, jet lag, and fatigue caused by extended work hours or illnesses. It is important to tell your doctor if you become pregnant.

Your doctor may want you to join a pregnancy registry for patients taking this medicine. Serious skin reactions can occur with this medicine. Stop using this medicine and check with your doctor right away if you have blistering, peeling, or loosening of the skin; red skin lesions; severe acne or skin rash; sores or ulcers on the skin; or fever or chills while you are using this medicine.

This medicine may cause you to have a serious type of allergic reaction called anaphylaxis. Anaphylaxis can be life-threatening and requires immediate medical attention. Stop taking this medicine and call your doctor right away if you have a skin rash; itching; hives; hoarseness; trouble breathing; trouble swallowing; or any swelling of your hands, face, or mouth while you are using this medicine. This medicine may cause serious allergic reactions affecting multiple body organs e. Stop using this medicine and check with your doctor right away if you have the following symptoms: chest pain or discomfort, fever and chills, dark urine, headache, rash, stomach pain, unusual tiredness, unusual bleeding or bruising, or yellow eyes or skin.

If you think modafinil is not working properly after you have taken it for a few weeks, do not increase the dose. Instead, check with your doctor. If you are using a medicine for birth control such as birth control pills, implants, shots, patches, vaginal rings, or an IUD , it may not work properly while you are taking modafinil.

To keep from getting pregnant, use another form of birth control while you are using this medicine and for one month after your last dose. Other forms of birth control include condoms, diaphragms, or contraceptive foams or jellies. Modafinil may cause some people to feel dizzy, drowsy, have trouble thinking or controlling movements, or trouble seeing clearly. Make sure you know how you react to this medicine before you drive, use machines, or do other jobs that require you to be alert, well-coordinated, or able to think or see well.

Stop using this medicine and check with your doctor right away if you have the following symptoms while taking the medicine: aggressive behavior, anxiety, depression, hallucinations, mania, thoughts of suicide, or other mental problems. If you have been taking this medicine for a long time or in large doses and you think you may have become mentally or physically dependent on it, check with your doctor. Some signs of dependence on modafinil are:. If you have been taking this medicine in large doses or for a long time, do not stop taking it without first checking with your doctor.

Your doctor may want you to gradually reduce the amount you are taking before stopping it completely. Do not take other medicines unless they have been discussed with your doctor.

This includes prescription or nonprescription over-the-counter [OTC] medicines and herbal or vitamin supplements. You should not take Provigil if you have a known allergy or sensitivity to Provigil or any of its ingredients. Let your healthcare provider know if you have a history of high blood pressure or mental health, heart, or liver problems.

Your healthcare provider may need to monitor these underlying conditions while you are taking Provigil. Moreover, Provigil is not approved to treat children for any health condition. Studies of children taking Provigil showed serious side effects, including severe skin rashes and psychiatric or nervous system reactions.

Lastly, Provigil is a controlled substance and may be habit forming or lead to dependence. As a result, Provigil should be used cautiously in people who have a history of substance abuse disorder.

Several medications may interact with Provigil, including:. A similar medication called Nuvigil armodafinil is available to use for improving wakefulness in patients with narcolepsy, obstructive sleep apnea, and shift-work disorder.

Provigil and Nuvigil share a similar chemical structure, availability, dosing once a day , drug interactions, and side effects. However, blood levels of Nuvigil are higher later in the day compared with Provigil, suggesting that Nuvigil may be better at improving wakefulness over the course of a day.

Provigil and Nuvigil both have stimulant-like effects, similar to drugs like Adderall dextroamphetamine-amphetamine and Ritalin methylphenidate. That said, the potential for abuse and dependence is higher for stimulant drugs than for Provigil or Nuvigil.

The FDA approved Provigil to treat excessive daytime sleepiness in patients with narcolepsy, obstructive sleep apnea, and shift work sleep disorder. Dopamine is a chemical involved in arousal attention, mood, motivation, and memory, among other functions. Serious side effects of Provigil are not common but require immediate medical attention and include:. Provigil will not cure your health condition, but it can ease the excessive sleepiness you feel during the day. Taking Provigil will hopefully grant you the time and energy you need to focus on other healthy behaviors in your life, such as engaging in physical activity or connecting with friends or family members.

Keep taking or using your other health-related medications or devices. For instance, do not stop using your CPAP machine for sleep apnea unless your healthcare provider tells you to do so. Also, always tell your healthcare provider if you are taking any new medications or experiencing any bothersome or persistent side effects.

Remember that Provigil can be habit forming, so let your healthcare team know if you think this is becoming a problem for you. In the end, Provigil can be a welcome relief to your daily exhaustion, but it's not a perfect or miracle drug. Scientists are still learning about how it works and its long-term effects. As with any medication, be mindful while taking Provigil and stay in touch with your healthcare team.

Verywell Health's drug information is meant for education purposes only and not intended as a replacement for medical advice, diagnosis, or treatment from a healthcare professional. Consult your doctor before taking any new medication s. IBM Watson Micromedex provides some of the drug content, as indicated on the page.

Tossing and turning night over night can have a big impact on your quality of life. Our free guide can help you get the rest you need. Sign up for our newsletter and get it free. Food and Drug Administration.