Modafinil is generally well-tolerated; common side effects includeheadache,nausea,anxiety, andinsomnia.[19][20] Rare but serious adverse effects include severe skin reactions such asStevens-Johnson syndrome.[21] Modafinil is contraindicated during pregnancy due to increased risk of birth defects.[22]
Modafinil is used off-label as acognitive enhancer or "smart drug" by students and professionals seeking improved focus.[23][24] Research on cognitive effects in non-sleep-deprived individuals has yielded mixed results.[25][18] The drug is banned in competitive sports by theWorld Anti-Doping Agency.[26]
Developed in France in the 1970s by neurophysiologistMichel Jouvet, modafinil was approved for medical use in France in 1994 and in the United States in 1998.[9][7][27] Generic versions became available in the US in 2012.[28]
Narcolepsy causes a strong urge to sleep during the day and can include symptoms likecataplexy (sudden muscle weakness),sleep paralysis (inability to move or speak while falling asleep or waking up), andhallucinations. Narcolepsy is linked to a lack of the brain chemicalhypocretin (orexin), primarily produced in thehypothalamus.[32][33] Modafinil is not a cure for narcolepsy, but it can help manage the symptoms. While modafinil is used to treat excessive sleepiness, it may also help reduce the frequency and severity of cataplexy attacks in some people. Modafinil is approved for management of narcolepsy with or without cataplexy. However, it is not specifically approved for the treatment of cataplexy.[34][35]
Modafinil is also prescribed forshift work sleep disorder, a condition affecting people who work rotating or night shifts and experience excessive sleepiness during work hours and difficulty sleeping during the day.[7] The recommended dose for this indication is200 mg taken approximately one hour before the start of the work shift.[7] In a 12-week randomized controlled trial, modafinil significantly improved nighttime wakefulness as measured bysleep latency testing, reduced attention lapses, and lowered the rate of accidents or near-accidents during the commute home from work.[36] However, residual sleepiness remained substantial even with treatment, and modafinil did not fully normalize alertness to daytime levels.[36][37] A separate trial found that modafinil also improved patient functioning and mental health-related quality of life in shift workers.[38] ACochrane review concluded that modafinil andarmodafinil increase alertness and reduce sleepiness in shift workers to some extent, but noted that evidence remains limited and the drugs are associated with adverse events including headache and nausea.[39]
Both the American Academy of Sleep Medicine and European guidelines strongly recommend modafinil as a first-line treatment for narcolepsy.[16][44] In France, modafinil is the first-line pharmacological treatment for excessive daytime sleepiness in narcolepsy, with methylphenidate designated as second-line.[15][45]
Fatigue is a common and often debilitating symptom experienced by people with MS.[46][47]
Reviews and meta-analyses of controlled trials have found that modafinil has modest effectiveness in managing MS-related fatigue, though improvements in fatigue severity scores have not consistently reached statistical significance.[48][49] Optimal dosing and treatment schedules are not well established.[49][50] Clinical assessments have found that adverse events were common.[48][51] The AmericanNational Multiple Sclerosis Society states that modafinil can be used off-label to alleviate fatigue associated with MS.[52]
Modafinil is occasionally prescribedoff-label for individuals with attention deficit hyperactivity disorder (ADHD).[53][54][55] It has not consistently shown efficacy in treating adult ADHD,[56] especially when compared to other treatments such aslisdexamfetamine.[57][58] In children, modafinil shows efficacy for ADHD symptoms in clinical trials, though it is less effective than first-line treatments such as methylphenidate and amphetamines.[59][60]
Modafinil is used off-label as anadjunctive treatment for the acute depressive phase of bipolar disorder.[62][63][64] Meta-analyses have found that add-on modafinil and armodafinil are more effective than placebo for treatment response and remission, with low rates of mood switching to mania, but the effect sizes are small and the quality of evidence is low.[65][66][67] Modafinil may also have cognitive benefits in people with bipolar disorder who are in remission.[56]
Military forces in several countries, including France, the United States, and the United Kingdom, have used modafinil as an alternative toamphetamines for managing fatigue during combat operations and extended missions.[68][69][70][71] The US Air Force approved modafinil for specific missions as a fatigue countermeasure.[72] Modafinil is also available to astronauts aboard theInternational Space Station for fatigue management.[73]
Some studies suggest significant increases in cognitive abilities, while others indicate mild to nonexistent cognitive improvements.[62][37] In some cases, it has been associated with impairments in certain cognitive functions.[25][18][79] It has been shown that a positive impact on cognitive abilities is more noticeable on sleep-deprived individuals.[80] Therefore, in people who are not sleep-deprived, the potential of modafinil as a cognitive enhancer may be limited.[81]
The regulation of modafinil as adoping agent has been controversial in the sporting world, with high-profile cases attracting press coverage since several prominent American athletes tested positive for the substance. Some athletes who used modafinil protested that the drug was not on the prohibited list at the time of their offenses.[82] However, theWorld Anti-Doping Agency (WADA) maintains that modafinil was related to already-banned substances. The Agency added modafinil to its list of prohibited substances on August 3, 2004, ten days before the start of the2004 Summer Olympics.[26]
Several athletes across track and field, cycling, basketball, and rowing have tested positive for modafinil and faced sanctions, with some cases resulting in stripped medals and bans.[83][84][85]
TheBALCO scandal brought to light an unsubstantiated (but widely published) account of Major League Baseball's all-time leading home-run hitterBarry Bonds' supplemental chemical regimen that included modafinil in addition toanabolic steroids andhuman growth hormone.[86]
Modafinil is commercially available in100 mg and200 mg oral tablet forms.[7] Additionally, it is offered as the (R)-enantiomer, known asarmodafinil, and as aprodrug namedadrafinil.[87]
This modest dopaminergic effect is accompanied by broader downstream activation of arousal-related neurotransmitter systems. Modafinil increases noradrenergic tone in wakefulness-promoting nuclei and indirectly engages hypothalamic orexin and histamine pathways, which together help stabilize the sleep–wake regulatory network and support sustained alertness.[95][93] Although modafinil interacts with multiple neurotransmitter systems, its exact mode of action at the molecular level remains uncertain.[93][96]
At the level of neural circuits, modafinil enhances glutamatergic excitatory transmission and reduces GABAergic inhibitory output within cortical and thalamic pathways, shifting network activity toward excitation and cortical activation while exerting minimal direct effects on classical monoamine receptors.[9] Taken together, these actions, including weak DAT inhibition combined with secondary catecholaminergic, orexinergic, glutamatergic, and GABAergic modulation, are thought to underlie modafinil's ability to promote wakefulness and cognitive function with a lower risk of euphoria and abuse than traditional amphetamine-like psychostimulants.[17][95][9]
From laboratory research, modafinil has little to no affinity forserotonin ornorepinephrine transporters and does not directly interact with these systems.[20][17] However, studies have shown that elevated concentrations of norepinephrine and serotonin can occur as an indirect effect following modafinil administration due to increased extracellular dopamine activity.[17][20] Unlike traditional psychostimulant drugs,[29] such ascocaine oramphetamine, modafinil shows low potential for causing euphoria due to differences in how it interacts with dopamine transporters at a cellular level.[93][17][96]
In addition to its influence ondopaminergic pathways, modafinil may impact other neurotransmitter systems, such asorexin (hypocretin).[17] Orexin neurons are involved in promoting wakefulness and regulating arousal states. Modafinil may increase signaling within hypothalamic orexin pathways, potentially contributing to its wake-promoting effects.[20][17]
Cmax (peak levels) occurs approximately 2 to 3 hours after modafinil administration.[10] Food slows the absorption of modafinil but does not affect the totalarea under the curve (AUC).In vitro measurements indicate that 60% of modafinil is bound toplasma proteins at clinical concentrations of the drug. This percentage changes very little when the concentration of modafinil is varied.[97]
Renal excretion of unchanged modafinil accounts for less than 10% of an oral dose; the remainder is metabolized or excreted through feces.[10]
The two major circulatingmetabolites of modafinil aremodafinil acid andmodafinil sulfone. Both of these metabolites have been described as inactive, and neither appears to contribute to the wakefulness-promoting effects of modafinil.[8][98] However, modafinil sulfone does appear to possessanticonvulsant effects, a property that it shares with modafinil.[8][99]
Elimination half-life is in the range of 10 to 12 hours,[10][97] with individual variation depending on sex,[100] cytochrome P450genotypes, liver function, and renal function. Modafinil is metabolized mainly in the liver,[10] and its inactive metabolites are excreted in the urine. Urinary excretion of the unchanged drug is usually less than 10% but can range from 0% to as high as 18.7%, depending on the factors mentioned.[97]
Modafinil exhibits sex-specific pharmacokinetic differences.[100] It demonstrates higherbioavailability in women compared to men. The mean Cmax is higher in women than in men,5.2 mg/L vs.4.2 mg/L (p < 0.05), following a single200 mg oral dose of modafinil.[100] This difference persists even after adjusting for body weight (0.88 ml/min/kg vs.0.72 ml/min/kg).[100] The clearance of modafinil is 30% higher in men than in women, and plasma concentrations after a single dose are significantly higher in women than in men. These sex-specific pharmacokinetic differences may have implications for the efficacy and safety of modafinil.[100]
Modafinil is generally well-tolerated but can have potential risks and side effects. Common adverse effects of modafinil, experienced by less than 10% of users, includeheadaches,nausea, andreduced appetite.[19][101][20]Anxiety,insomnia,dizziness,diarrhea, andrhinitis (nasal congestion) are also reported in 5% to 10% of users.[20] Psychiatric reactions have occurred in individuals with and without a preexisting psychiatric history.[102]Urinary retention (difficulty emptying the bladder) andparesthesia (tingling or numbness) have also been reported.[103]
Modafinil can cause a slight increase inaminotransferase enzymes, indicative of liver function, but there is no evidence of serious liver damage when levels are within reference ranges.[104]
Rare but serious adverse effects include severe skin rashes and allergy-related symptoms. Between December 1998 and January 2007, the FDA received reports of six cases of severe cutaneous adverse reactions, includingerythema multiforme (target-shaped skin lesions),Stevens–Johnson syndrome,toxic epidermal necrolysis (widespread skin peeling), andDRESS syndrome (a drug reaction involving rash and organ inflammation). The FDA has issued alerts regarding these risks and also noted reports of angioedema and multi-organ hypersensitivity reactions inpostmarketing surveillance.[21][105] In 2007, the FDA requiredCephalon, the manufacturer of Provigil, to modify the Provigil leaflet to include warnings about these serious conditions. The long-term safety and effectiveness of modafinil have not been conclusively established.[106]
The FDA does not endorse modafinil for children's medical conditions due to an increased risk of rare but serious dermatological toxicity, manifested asStevens–Johnson syndrome which is a type of severe skin reaction.[107][8][108] However, in Europe, modafinil may be prescribed for treating narcolepsy in children.[44]
Modafinil is contraindicated for individuals with knownhypersensitivity (allergic reaction) to either modafinil or armodafinil.[7][12]
Modafinil is also contraindicated in certain cardiac conditions, including uncontrolled moderate to severehypertension,arrhythmia,cor pulmonale,[112][113] and in cases with signs of CNS stimulant-inducedmitral valve prolapse orleft ventricular hypertrophy.[114][115] These contraindications arise because modafinil elicits sympathomedullary activation, producing notable increases in heart rate and blood pressure that can worsen pre-existing cardiovascular conditions.[116][117]
Clinical research has not demonstrateddrug tolerance, a reduction in wakefulness-promoting andanti-fatigue effects, as a common outcome, even with therapeutic use extending up to 40 weeks.[69][119][106] However, long-term use can lead to tolerance in some individuals, necessitating higher doses to maintain efficacy.[18] People with current or past substance addictions and those with a family history of addiction are at higher risk.[18][44][120] The underlying mechanisms, which may involvedopamine andnorepinephrine pathways, are not fully understood.[18][44][120] Tolerance appears more likely with off-label use for cognitive enhancement than with therapeutic use for narcolepsy, where effectiveness does not usually diminish with prolonged treatment.[18][44][120]
Although classified as acentral nervous system (CNS) stimulant, the addiction anddependence liabilities of modafinil are considered low.[7][2][31][121] The exact mechanisms of action of modafinil are not known,[93] and it is believed that pharmacological profile of modafinil is different from that of the classical stimulants such ascocaine oramphetamine.[12] Although modafinil shares biochemical mechanisms with stimulant drugs, it is less likely to havemood-elevating properties.[7] The similarities in effects withcaffeine are not clearly established.[12][122] Unlike other stimulants, modafinil does not induce a strong subjectivefeeling of pleasure or reward oreuphoria, which contributes to its lower abuse potential.[18] Albeit to a lower degree than classical stimulants, modafinil still can produce psychoactive, euphoric, and subjective effects typical for abused stimulants.[7][3]
Despite initial assessments of low abuse potential, emerging evidence suggests modafinil acts on the same neurobiological mechanisms as other addictive stimulants, warranting caution when prescribing.[81] Modafinil scores lower than amphetamine on standardized abuse-potential assessments, suggesting reduced propensity for abuse.[123]
Anoverdose of modafinil can lead to a range of symptoms and complications. Psychiatric symptoms may includepsychosis,mania,hallucinations, andsuicidal ideation, which can occur even in individuals without a history of mental illness and may persist after discontinuation of the drug.[127] Neurological complications, such as seizures, tremors,dystonia (involuntary muscle contractions), anddyskinesia (uncontrolled movements), may arise from modafinil's interaction with various neurotransmitter systems.[127]
Allergic reactions such as rash,angioedema (swelling beneath the skin),anaphylaxis (a severe whole-body allergic reaction), andStevens–Johnson syndrome (a serious skin and mucous membrane disorder) may rarely be triggered by an immunological response to modafinil or its metabolites.[128][129] Cardiovascular complications like hypertension,tachycardia (rapid heart rate), chest pain, andarrhythmias may also occur because modafinil stimulates thesympathetic nervous system.[127]
In animal studies, the median lethal dose (LD50) of modafinil varies among species and depends on the route of administration. In mice and rats, the LD50 is approximately1250 mg/kg if administered via an injection, but the oral LD50 for rats is3400 mg/kg.[130][131] The LD50 value for humans have not been established. Human clinical trials have involved total daily doses up to1200 mg/d for 7–21 days. Acute one-time total overdoses up to4500 mg have not been life-threatening but resulted in symptoms likeagitation,insomnia,tremor,palpitations, andgastrointestinal disturbances.[7][132]
The management of modafinil overdose involves supportive care, monitoring of vital signs, and treatment of specific complications. In cases of recent consumption,activated charcoal,gastric lavage (stomach pumping), orhemodialysis (blood filtering) may be used.[127] There is no specific antidote for modafinil overdose.[132][133][134] The main way to deal with modafinil overdose is supportive care, which includes sedating the patient and stabilizing their blood pressure, and muscle activity in case of manifestations such as agitation or tremor.[132]
Some of the drugs that frequently interact with modafinil includearipiprazole (an antipsychotic),amphetamine (including its enantiomers and salts; stimulants), and others.[135]
It was clinically found that modafinil affectspharmacodynamics of drugs which are metabolized by CYP3A4 and other enzymes of the cytochrome P450 family so that interactions of modafinil with these drugs were observed in real people, rather than being predicted in a lab setting.[100][136] For instance, CYP3A4 induction by modafinil can reduce plasma concentrations ofopioids such asmethadone,hydrocodone,oxycodone, andfentanyl, potentially causing reduced efficacy or withdrawal symptoms.[140] Modafinil also affectssteroid hormones, includingestradiol,progesterone, andcortisol, and can reduce the effectiveness ofhormonal contraceptives for up to a month after discontinuation.[141][100][142][143] Since modafinil induces the activity of the CYP3A4 enzyme involved incortisol clearance,[144] modafinil may reduce the bioavailability ofhydrocortisone. Therefore, it may be necessary to adjust the steroid substitution dose in people receiving modafinil, which is a CYP3A4-metabolism-inducing drug.[145]
Modafinil and/or its major metabolite,modafinil acid, may be quantified inPlasma, serum, or urine to monitor dosage in those receiving the drug therapeutically, to confirm a diagnosis of poisoning in hospitalized patients, or to assist in the forensic investigation of a vehicular traffic violation.[148] Instrumental techniques involving gas or liquid chromatography are usually employed for these purposes.[37][149][150] In 2011, modafinil was not tested for by commondrug screens (except for anti-doping screens) and is unlikely to cause false positives for other chemically unrelated drugs such assubstituted amphetamines.[91][147][26]
Modafinil was developed in France byneurophysiology professorMichel Jouvet and Lafon Laboratories in the 1970s. Modafinil is the primarymetabolite ofadrafinil, an earlier compound in the benzhydryl sulfinyl series.[156][27] Modafinil has been prescribed in France since 1994 under the name Modiodal,[27] and in the United States since 1998 as Provigil.[7]
Cephalon introduced armodafinil, the (R)-enantiomer of modafinil, in the United States in 2007. Generic versions of modafinil became available in the US in 2012 after extensive patent litigation.[161][28]
Modafinil's use varies by region. In the US, it is approved for adult narcolepsy, shift work sleep disorder, and obstructive sleep apnea, but not for children.[20] In the UK and the EU, since 2014, it is approved solely for narcolepsy, including in children (pediatric narcolepsy), with its use for other conditions restricted by the European Medicines Agency.[34][162] Modafinil is not approved for use by children in multiple jurisdictions.[1][163][6][7][164]
In 2008, Cephalon, the manufacturer of Provigil, pleaded guilty to a federal criminal charge related to its promotion of off-label uses of Provigil and two other drugs, paying $425 million in fines and settlements.[188]
Concerns have been raised about the growing use of modafinil as a "smart drug" or cognitive enhancer among healthy individuals who use it with the aim to improve concentration and memory.[190][191] In 2003, modafinil sales were skyrocketing, with some experts concerned that it had become a tempting pick-me-up for people looking for an extra edge in a productivity-obsessed society.[190] The cost of modafinil has decreased substantially since generic versions became available in the US in 2012; retail prices for generic modafinil (30 tablets of 200 mg) range from approximately $20 to $45 with discount programs, compared to over $120 per month for brand-name Provigil in 2004.[190][192][190][191][192]
Global sales figures for modafinil have not been publicly disclosed. Modafinil sold under the brand name Provigil accounted for over 40% ofCephalon's global turnover for several years, according to data published in 2020.[193]
The original patent,U.S. patent 4,927,855, was granted to Laboratoire L. Lafon in 1990, covering the chemical compound of modafinil. This patent expired in 2010.[194] In 1994, Cephalon filed a patent for modafinil in the form of particles of a defined size, represented byU.S. patent 5,618,845, which expired in 2015.[195]
Following the nearing expiration of marketing rights in 2002, generic manufacturers, including Mylan and Teva, applied for FDA approval to market a generic form of modafinil, leading to legal challenges by Cephalon regarding the particle size patent.[196] The patent RE 37,516 was declared invalid and unenforceable in 2011.[197]
In addition, Cephalon entered agreements with several generic drug manufacturers to delay the sale of generic modafinil in the US. These agreements were subject to legal scrutiny and antitrust investigations, culminating in a ruling by the Court of Appeals in 2016, which found that the settlements did not violate antitrust laws.[198]
The use of modafinil as a supposed cognitive enhancer may be considered as cheating, unnatural, or risky.[199] TheUniversity of Sussex explained that it is a prescription drug and the decision should be made by thedoctor on whether to prescribe modafinil to a student.[200] As a matter ofbioethics, the USPresident's Council on Bioethics argued that excellence achieved through the use of drugs like modafinil is "cheap" as it obviates the need for hard work and study, and is not fully authentic because the excellence is partly attributable to the drug, not the individual.[201] Alternately, people inWall Street trading may consider it a tool for a competitive edge in a high-intensity environment.[202] Due to such varying views, modafinil users for narcolepsy may cope with stigma by hiding, denying, or justifying their use, or by seeking support from others who share their views or experiences.[203][204]
Modafinil has been studied as an adjunctive treatment formajor depressive disorder.[205][206][207] While some individual trials have reported benefits,[208][209] systematic reviews and meta-analyses have found the evidence limited, the quality of evidence low, and the results inconclusive; modafinil did not significantly improve depression in network meta-analysis, though there was some evidence for reduced fatigue and sleepiness.[206][207][210]
Modafinil was investigated for ADHD because of its lowerabuse potential than conventional psychostimulants,[29][211][212] but evidence for adult ADHD is mixed. A 2016 systematic review did not recommend its use,[58] and a largePhase III trial found modafinil ineffective with a high rate of side effects (86%) and discontinuation (47%), possibly due to high doses (210–510 mg/d).[213] A 2008 FDA application for pediatric ADHD was denied due to concerns about rare but seriousdermatological toxicity.[19]
Modafinil and armodafinil were studied as a complement toantipsychotic medications in the treatment ofschizophrenia. They showed no effect on positive symptoms or cognitive performance.[219][220] A 2015meta-analysis found that modafinil and armodafinil may slightly reduce negative symptoms in people with acute schizophrenia, though they do not appear useful for people with stable schizophrenia who have prominent negative symptoms (such as reduced motivation or social withdrawal).[220] Among medications demonstrated to be effective for reducing negative symptoms in combination with antipsychotics, modafinil, and armodafinil are among the smallesteffect sizes.[221]
Systematic reviews have found limited evidence for modafinil as a cognitive enhancer in healthy, non-sleep-deprived individuals. A 2019 review found small enhancements in attention, executive functions, and learning, but impairments in divergent creative thinking in some studies.[225] A 2020 review reported only a modest effect on memory updating, concluding there is insufficient evidence to support the perception that modafinil is a useful cognitive enhancer.[226]
Modafinil has been investigated for several other conditions with inconclusive or preliminary results. Preliminary research is examining modafinil for excessive daytime sleepiness inmyotonic dystrophy, though it is not approved for this use and results are debated.[227] Modafinil has also been studied fordisorders of consciousness, but observational reports have produced mixed results.[228]
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