While modafinil is used as acognitive enhancer, or "smart drug", among healthy individuals seeking improved focus and productivity,[17][18] its use outside medical supervision raises concerns regarding potential misuse or abuse.[3][7][19] Research on the cognitive enhancement effects of modafinil in non-sleep deprived individuals has yielded mixed results, with some studies suggesting modest improvements in attention andexecutive functions, while others show no significant benefits or a decline in cognitive functions at high doses.[20][21]
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.[25][26] Modafinil is not a cure for narcolepsy, but it can help manage the symptoms. While modafinil is primarily 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.[27][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.[19] 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.[27][33]
As of 2024,[update] both the French and the American Academy of Sleep Medicine strongly recommend modafinil as the first-choice treatment for narcolepsy.[34] In Europe, modafinil is considered one of the primary drugs recommended for treating narcolepsy according to the guidelines.[35]
Fatigue is a common and often debilitating symptom experienced by people with MS.[36][37]
When modafinil is prescribed for fatigue, some people with MS may experience increased energy levels, reduced feelings of tiredness, improved cognitive function, and better quality of life.[38][failed verification –see discussion] Two reviews concluded that modafinil has minor effectiveness in managing fatigue in people with MS,[38][39] and optimal dosing and treatment schedules are not well established.[39][40] Clinical assessments have found that adverse events were common.[38][41] The AmericanNational Multiple Sclerosis Society states that modafinil can be used off-label to alleviate fatigue associated with MS.[42]
Modafinil is occasionally prescribedoff-label for individuals with attention deficit hyperactivity disorder (ADHD).[43][44][45] It has not consistently shown efficacy in treating adult ADHD,[46] especially when compared to other treatments such aslisdexamfetamine.[47][48] In children, modafinil is more effective than placebo for treating ADHD symptoms.[49][50]
Given its approved status in the US to treat narcolepsy, physicians can also prescribe modafinil for off-label uses, such as treating ADHD in both children and adults.[51][52][53]
The Canadian Network for Mood and Anxiety Treatments (CANMAT) suggests modafinil as a second-line treament for comorbid ADHD andbipolar disorder, after first-linepsychostimulants and the antidepressantbupropion.[54]
Modafinil is used off-label as anadjunctive treatment (i.e., in combination therapy) for the acute depressive phase in bipolar disorder.[55][56][57][58] The depressive phase ofbipolar disorder may feature excessive sleepiness and fatigue. Adjunctive treatment with modafinil can be used as an augmentation for the main treatment to increase its effect and is safe and effective, especially for people who do not respond well to standard antidepressants.[59][60][46] Modafinil does not significantly increase the risk of mood switch to mania or suicide attempts in people with bipolar disorder.[61][59] Modafinil may also have cognitive benefits in people with bipolar disorder who are in a remission state.[62][63][46]
Whereas modafinil and armodafinil are approved for narcolepsy, they have been repurposed asadjunctive treatments to alleviate symptoms of acute depressive phase in people with bipolar disorder.[64] Drug repurposing in psychiatry is a strategy for discovering new uses for drugs that have already been approved or tested in clinical trials for other illnesses. As such, drug repurposing is a rapid, cost-effective, and reduced-risk strategy for the development of new treatment options for psychiatric disorders.[64] 2021meta-analysis concluded that add-on modafinil and armodafinil were more effective than placebo on response to treatment, clinical remission, and reduction in depressive symptoms, with only minor side effects, but the effect sizes are small and the quality of evidence is therefore low, limiting the clinical relevance of the evidence.[64][65] Very low rates of mood swing (a change in mood from one extreme to another)[61][66] have been observed with modafinil and armodafinil in depressive phase of bipolar disorder.[57][67]
Modafinil was used during theGulf War by theFrench Foreign Legion,[68] theUS Air Force,[69][70] andUS Marines[71] to enhance "operational tempo" (a term that denotes the speed and intensity at which military operations or activities are executed), aiming to optimize the overall performance and efficiency of the units.[70][72][73]
Armed forces in various countries, including the United States, the United Kingdom, India, and France, have considered modafinil as an alternative to traditionalamphetamines for managing sleep deprivation in combat or extended missions.[74] The US military approved modafinil for specific Air Force missions, replacingamphetamines for fatigue management.[75] The use of modafinil in military contexts without sleep deprivation is not recommended due to inconclusive evidence on its cognitive enhancement benefits and potential risks of adverse effects.[69]
Modafinil is also available to astronauts aboard theInternational Space Station for the management of fatigue caused by circadian dyssynchrony in orbit.[76]
Modafinil has been used non-medically as a "smart drug"[17][18] by various groups, including students,[77][78][79] office workers,transhumanists,[80][81] and professionals in various sectors. Its use is attributed by these individuals to its potential for enhancing attention, cognitive capabilities, andalertness.[82][83]
The effectiveness of modafinil as a cognitive enhancer is still debated. Some studies suggest significant increases in cognitive abilities, while others indicate mild to nonexistent cognitive improvements.[84][85][55][86] In some cases, it has even been associated with impairments in certain cognitive functions.[20][21][87] It has been shown that modafinil's positive impact on cognitive abilities is more noticeable on sleep-deprived individuals.[88] Therefore, in people who are not sleep-deprived, the potential of modafinil as a cognitive enhancer may be limited.[89]
No significant changes in body weight have been observed in clinical trials, although decreased appetite and weight loss have been noted in children and adolescents.[94] 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.[95]
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,Stevens–Johnson syndrome,toxic epidermal necrolysis, andDRESS syndrome. The FDA has issued alerts regarding these risks and also noted reports of angioedema and multi-organ hypersensitivity reactions inpostmarketing surveillance.[96][97] In 2007, the FDA required Cephalon 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.[98]
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.[99][62][100] However, in Europe, modafinil may be prescribed for treating narcolepsy in children.[101]
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.[102]
Modafinil is contraindicated for individuals with knownhypersensitivity to either modafinil or armodafinil.[7][12]
Modafinil is also contraindicated in certain cardiac conditions, including uncontrolled moderate to severehypertension,arrhythmia,cor pulmonale,[107][108] and in cases with signs of CNS stimulant-inducedmitral valve prolapse orleft ventricular hypertrophy.[109][110] The package insert in the United States cautions about using modafinil in people with a documented medical history of left ventricular hypertrophy or those diagnosed with mitral valve prolapse who have previously exhibited symptoms associated with the mitral valve prolapse syndrome while undergoing treatment involving central nervous system stimulants.[111] The reasons why modafinil is contraindicated in certain cardiac conditions are because modafinil affects the autonomic nervous system and, in particular, exerts significant effects on autonomic cardiovascular regulation, leading in some people to notable increases in heart rate and blood pressure. These substantial changes in the autonomic system warrant careful consideration when prescribing modafinil to people with pre-existing cardiovascular conditions.[112] The increase in heart rate and blood pressure can worsen the symptoms of such pre-existing conditions as hypertension, arrhythmia, and cor pulmonale. These changes in the autonomic system induced by modafinil can increase the risk of heart attack, stroke, and heart failure. Modafinil can stimulate the release of norepinephrine and epinephrine, hormones that activate the sympathetic nervous system. This can causevasoconstriction, which is the narrowing of blood vessels, and increase the heart's workload, which is not desired in people with pre-existing heart conditions. In particular, modafinil can worsen the consequences of mitral valve prolapse or left ventricular hypertrophy, which are structural abnormalities of the heart. These can affect the blood flow and oxygen delivery to the heart and other organs.[113]
Extensive clinical research has not demonstrateddrug tolerance as a common adverse effect, even with therapeutic use extending up to 40 weeks.[68][115][98] Drug tolerance in this context is defined as a reduction in response, to wakefulness-promoting andanti-fatigue properties of modafinil.[68]
While modafinil is generally found to be safe and significant adverse effects are rare, including in pediatric narcolepsy cases (sleep disorders in children), there is evidence that long-term usage can lead to tolerance in some individuals.[21] This necessitates higher doses to maintain the same level of cognitive enhancement or relief from sleepiness.[21]
People with current or past substance addictions and those with a family history of addiction are particularly at risk for developing tolerance.[21][101][116]
The mechanisms driving tolerance to modafinil, which may involve its impact ondopamine andnorepinephrine levels in the brain, are not fully understood.[21][101][116]
Repeated administration of modafinil for off-label use, such as increasedalertness and cognitive-enhancing effects in sleep deprivation, can lead to drug tolerance, which means that the effectiveness of the drug may decrease over time. Still, modafinil therapy as aeugeroic agent to treat narcolepsy does not typically lead to drug tolerance, i.e., the effectiveness does not usually decrease on prolonged use, although individual responses may vary.[21][101][116]
Despite being aCNS stimulant, the addiction anddependence liabilities of modafinil are considered low.[7][2][24][117] The exact mechanisms of action of modafinil are not known,[118] 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][119] Unlike other stimulants, modafinil does not induce a strong subjectivefeeling of pleasure or reward, which is commonly associated witheuphoria, an intense feeling of well-being.[21] Euphoria may be an indicator of a drug's potential to be abused. Substance abuse is a compulsive and excessive use of the substance despite adverse consequences.[120] In comparison to classical stimulants, modafinil exhibits a low propensity for abuse, as it lacks significantly expressed pleasurable or euphoric effects.[21] Albeit to a lower degree than classical stimulants, modafinil still can produce psychoactive, euphoric, and subjective effects typical for abused stimulants.[7][3]
Modafinil was not observed to promote overuse or misuse, even in people who have a history of cocaine addiction.[121] Despite the initial belief that modafinil carried no abuse potential, emerging evidence suggests that it works at the same neurobiological mechanisms as other addictive stimulants. Consequently, there exists a potential risk of modafinil abuse, necessitating prudent consideration and caution when prescribing or using this medication.[89] Modafinil exhibits a lower response on the amphetamine scale of the addiction research center inventory, suggesting reduced propensity for abuse compared to amphetamine.[122]
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.[125] Neurological complications, such as seizures, tremors,dystonia, anddyskinesia, may arise from modafinil's interaction with various neurotransmitter systems.[125]
Allergic reactions such as rash,angioedema,anaphylaxis, andStevens–Johnson syndrome may rarely be triggered by an immunological response to modafinil or its metabolites.[126][127] Cardiovascular complications like hypertension,tachycardia, chest pain, andarrhythmias may also be observed due to modafinil's sympathomimetic action.[125]
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.[128][129] 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][130]
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, orhemodialysis may be used.[125] There is no specific antidote for modafinil overdose.[130][131][132] 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.[130]
Some of the drugs that frequently interact with modafinil includearipiprazole (an antipsychotic),amphetamine (including its enantiomers and salts; stimulants),aspirin, and others.[133]
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.[104][134] For instance, it was observed that induction of CYP3A4 by modafinil affects metabolism of the followingmedications andendogenous substances:[138]
opioids, such asmethadone,hydrocodone,oxycodone, orfentanyl – modafinil may result in a drop in opioid plasma concentrations because of faster clearance of opioids by CYP3A4. If the patient is not monitored closely, reduced efficacy or withdrawal symptoms can occur.[138]
steroid hormones, such asestradiol,progesterone orcortisol. Modafinil may have an adverse effect onhormonal contraceptives (such asbirth control pills,patches, etc.) for up to a month after discontinuation.[139] Both modafinil and armodafinil in the United States and the United Kingdom come with package inserts that highlight the interaction between these medications and hormonal birth control.[104] Modafinil may induce cytochrome P450 enzymes that are involved in the clearance of steroid hormones taken as hormonal contraceptives, reducing their effectiveness, which may lead to pregnancy despite taking the birth control medication. Besides steroid hormones, modafinil may affectpituitary gland hormones. In a 2006 study, a single dose of modafinil200 mg caused a decrease in bloodprolactin levels, although it did not affecthuman growth hormone orthyroid-stimulating hormone.[84][140] Since modafinil induces the activity of the CYP3A4 enzyme involved incortisol clearance,[141] 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.[142]
Footnotes:a = Functional activity, not binding inhibition.b =Armodafinil at D2High.Notes: No activity at a variety of other assessed targets.[144]
The precisemechanism of action of modafinil for narcolepsy and other sleep disorders remains unclear.[3][118][149][150] Although modafinil may have interactions with neurotransmitter systems, its exact mode of action is not fully understood.[118][151]
From laboratory research, modafinil has little to no affinity forserotonin ornorepinephrine transporters and does not directly interact with these systems.[19][150] 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.[150][19] Unlike traditional psychostimulant drugs,[22] such ascocaine oramphetamine, modafinil shows low potential for causing euphoria due to differences in how it interacts with dopamine transporters at a cellular level.[118][150][151]
In addition to its influence ondopaminergic pathways, modafinil may impact other neurotransmitter systems, such asorexin (hypocretin).[150] 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.[19][150]
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.[152]
Renal excretion of unchanged modafinil usually accounts for less than 10% of an oral dose. This means that when modafinil is taken by mouth, the only approved route of administration, less than 10% of the drug is eliminated from the body through the urine without being metabolized by the liver or other organs. The rest of the drug is either metabolized or excreted through other routes, such as feces or bile.[10]
The two major circulatingmetabolites of modafinil aremodafinil acid (CRL-40467) andmodafinil sulfone (CRL-41056). Both of these metabolites have been described as inactive, and neither appears to contribute to the wakefulness-promoting effects of modafinil.[62][153] However, modafinil sulfone does appear to possessanticonvulsant effects, a property that it shares with modafinil.[62][154]
Elimination half-life is in the range of 10 to 12 hours,[10][152] subject to differences in sex,[104] in 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.[152]
Modafinil exhibits sex-specific pharmacokinetic differences.[104] 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.[104] This difference persists even after adjusting for body weight (0.88 ml/min/kg vs.0.72 ml/min/kg).[104] 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.[104]
Modafinil and/or its major metabolite, modafinil acid, may be quantified in plasma, 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.[156] Instrumental techniques involving gas or liquid chromatography are usually employed for these purposes.[86][157][158] 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.[147][155][159]
Modafinil was developed in France byneurophysiology professorMichel Jouvet and Lafon Laboratories. It is part of a series of benzhydryl sulfinyl compounds, includingadrafinil, initially used as a treatment for narcolepsy in France in 1986.[165] Modafinil, the primary metabolite ofadrafinil,[166] has been prescribed in France since 1994 under the name Modiodal,[165] and in the United States since 1998 as Provigil.[7] Unlike modafinil, adrafinil does not have FDA approval and was withdrawn from the French market in 2011.[167]
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.[171][172]
In Australia, modafinil is considered to be aSchedule 4prescription-only medicine. This means that it is a drug with a perceived low potential for abuse and low risk of dependence; still, the use of Schedule 4 drugs in Australia is restricted to those who have a valid prescription from a medical practitioner; import from abroad is illegal.[175]
In Canada, modafinil is not specifically included in the lists of controlled drugs and substances specified within theControlled Drugs and Substances Act.[176] However, it is classified as a Schedule F prescription drug.[177][178][179] This means that modafinil can only be obtained legally with a valid prescription from a licensed health care practitioner in Canada, and the import of modafinil to Canada from other countries is subject to restrictions: importing prescription drugs without an import permit may result in the seizure of the drugs at the border, the refusal of entry of the drugs into Canada, or prosecution.[180]
In mainland China, modafinil is strictly controlled like other stimulants such as amphetamines andmethylphenidate. It is classified as Class I psychotropic drug. This classification means that modafinil is considered to have a high potential for abuse and dependence, and is therefore subject to strict regulation and control. As a result, modafinil is only available by prescription and cannot be purchased over the counter. In order to obtain a prescription for modafinil, a patient must have a valid medical reason for using the drug, such asnarcolepsy orobstructive sleep apnea. Additionally, the prescription must be written by a licensed physician and filled at alicensed pharmacy. The use of modafinil for non-medical purposes, such as with the aim to improve cognitive performance or to stay awake for long periods of time, is strictly prohibited and can result in legal consequences.[181][182]
In Denmark, modafinil is a prescription drug but not listed as a controlled substance. According to theDanish Medicines Agency, modafinil is approved for use in the treatment of narcolepsy; still, importing modafinil to Denmark is considered illegal without a valid prescription.[183][184][185][186]
Finland
In Finland, modafinil is a prescription drug but not listed as acontrolled substance. Finland is a member of the European Union, and it is illegal to import prescription medicine from outside the European Union unless the person has a valid prescription.[187][188][189]
In the Republic of Moldova, modafinil is classified as a psychotropic drug (included in table III list 3 which is the list of psychotropic substances as defined by theGovernment of Moldova)[190] and is available by prescription.[190] Importation of modafinil may be considered illegal and subject to severe penalties, even if you have a prescription.[191] For example, on June 29, 2017,Moldovan postal officers discovered 60 tablets of Modalert (200 mg modafinil tablets) in a parcel sent from India to a resident inChișinău, Moldova. The prohibited substance was detected during a routine scan and was seized as illegal. The authorities were notified of the incident and the recipient was charged with criminal penalties.[192][193] In theTransnistria region of Moldova, modafinil is completely prohibited, due to application of the legislation similar to that of Russia where modafinil is completely prohibited and is in the same list as narcotics. Possession or an attempt to bring modafinil to Transnistria potentially leads to imprisonment.[194]
In Romania, modafinil is classified as a stimulant doping agent and is prohibited in sports competitions.[195] In 2022, laws were passed making its importation or sale a felony, punishable by three to seven years in jail.[196] Simple possession for personal use may result in a fine and confiscation.[196]
In Sweden, modafinil is classified as a schedule IV substance, which means that it is considered to have a low potential for abuse and a low risk of dependence. Still, possession is illegal without a prescription.[197]
In Mexico, modafinil is not listed as a controlled substance, in the National Health Law, and can be purchased in pharmacies without prescription.[199]
In Japan, modafinil is Schedule I psychotropic drug. This means that it is considered to have a high potential for abuse and dependence, and is therefore subject to strict regulations. The use of Schedule I drugs in Japan is generally prohibited, except under certain circumstances, such as for medical purposes. It can only be prescribed by a doctor. It cannot be imported or exported without a permit. It cannot be used while driving or operating machinery.[200][201]Cephalon licensed Alfresa Corporation to produce, andMitsubishi Tanabe Pharma to sell modafinil products under the trade name Modiodal in Japan.[202] There have been arrests of people who imported modafinil for personal use.[203][204]
In Russia, starting from May 18, 2012, modafinil is Schedule II controlled substance. Being classified as a Schedule II controlled substance in Russia means that it is seen as a drug with a high potential for abuse and dependence. This classification imposes strict regulations on the production, distribution, and use of modafinil. Possession of a few modafinil pills can lead to three to ten years imprisonment. Modafinil is not approved for medical use in Russia and cannot be bought even in pharmacies. It also cannot be imported from abroad, even if you have a prescription issued outside Russia.[194][205] There are multiple cases of criminal proceedings initiated against Russian residents who tried to import modafinil by mail from abroad.[206][207]
In South Africa, modafinil is Schedule V substance, which means that it is legal to use modafinil in South Africa, but only with a valid prescription from a licensed medical practitioner.[208]
In the United States, modafinil is classified as aschedule IV controlled substance[2] under US federal law.[7][209] This means that the drug has a low potential for abuse and dependence compared to other controlled substances. However, it still requires a prescription from alicensed healthcare provider to obtain.[209]
It is illegal to import modafinil to the United States without aDrug Enforcement Administration (DEA)–registered importer and a prescription.[210] Individuals may legally bring modafinil into the US from a foreign country for personal use, limited to 50 dosage units, with a prescription and proper declaration at the border.[211] Under thePure Food and Drug Act, marketing drugs for off-label uses is prohibited.[212] Cephalon, the manufacturer of Provigil, faced legal issues for promoting off-label uses and paid significant fines in 2008.[213]
Originally developed in the 1970s by French neuroscientist Michel Jouvet and Lafon Laboratories, modafinil has been prescribed in France since 1994,[165][35] and was approved for medical use in the United States in 1998.[7][35]
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.[215][216] 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.[215] The cost of modafinil varied depending on factors such as location and insurance coverage;[215][216][217] still, in 2004, the price of modafinil in the US was around $120 or more per monthly supply.[215] However, the availability of generic versions has increased since then and may have driven down prices.[215][216][217]
In 2020, modafinil was the 302nd most commonly prescribed medication in the United States, with just over 1,000,000 prescriptions.[218]
As of 2024,[update] the global sales figures for modafinil are not known. Still, modafinil sold under the brand name Provigil accounted for over 40% ofCephalon's global turnover for several years, according to the information published in 2020.[219]
Modafinil's patent history involves several key developments. 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.[220] 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.[221]
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.[222] The patent RE 37,516 was declared invalid and unenforceable in 2011.[223]
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.[224]
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.[225] 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.[159]
Several athletes, such as sprinterKelli White in 2003,[226] cyclistDavid Clinger[227] and basketball playerDiana Taurasi[228] in 2010, and rower Timothy Grant in 2015,[229] were accused of using modafinil as a performance-enhancingdoping agent. Taurasi and another player—Monique Coker, tested at the same lab—were later cleared.[230] Kelli White, who tested positive after her 100m victory at the 2003 World Championships in Paris, was stripped of her gold medals.[231] She claimed that she used modafinil to treat narcolepsy, but theInternational Association of Athletics Federations (IAAF) ruled that modafinil was a performance-enhancing drug.[231]
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.[232]
The use of modafinil as a supposed cognitive enhancer may be considered as cheating, unnatural, or risky.[233] 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.[234] 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.[235] Alternately, people in environments likeWall Street trading may not view the use of modafinil as cheating, believing that if modafinil can give them an edge and they are aware of the risks involved, it should not be considered as cheating.[236] 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.[237][238]
Modafinil has been studied in the treatment ofmajor depressive disorder.[239][240][241] In a 2021systematic review and meta-analysis ofrandomized controlled trials ofpsychostimulants for depression, modafinil and other stimulants such asmethylphenidate and amphetamines improved depression in traditional meta-analysis.[241] However, when subjected tonetwork meta-analysis, modafinil and most other stimulants did not significantly improve depression, with only methylphenidate remaining effective.[241] Modafinil and other stimulants likewise did not improvequality of life in the meta-analysis, although there was evidence for reduced fatigue and sleepiness with modafinil and other stimulants.[241] While significant effectiveness of modafinil for depression has been reported by particular trials,[67][240][242] reviews and meta-analyses note that the effectiveness of modafinil for depression is limited, the quality of available evidence is low, and the results are inconclusive.[241][243][244]
Modafinil was considered for the treatment of ADHD because of its lowerabuse potential than conventional psychostimulants[22] like methylphenidate and amphetamines.[52][245] In 2008, an application to market modafinil for pediatric ADHD was submitted to theFood and Drug Administration in the US.[90][46]
However, evidence of modafinil for treatment of adult ADHD is mixed, and a 2016 systematic review of alternative drug therapies for adult ADHD did not recommend its use in this context.[48] In a later largephase 3 clinical trial of modafinil for adult ADHD, modafinil was not effective in improving symptoms, there was also a high rate of side effects (86%) and discontinuation (47%).[246] The poortolerability of modafinil in this study was possibly due to the use of high doses (210–510 mg/d).[246] Another reason for the denial of the approval was due to concerns about rare but serious dermatological toxicity inStevens–Johnson syndrome.[90]
The research on the use of modafinil for treating individuals with Autism Spectrum Disorder (ASD) who also exhibit ADHD symptoms is currently in its early stages with no results delivered.[247]
Modafinil was studied for the treatment ofstimulant dependence, but the results are mixed and inconclusive.[23][248] Modafinil is not acontrolled substance in some countries, unlike other medications, such asbupropion, which is also used to treatdepression andnicotine dependence.[249] The clinical trials that have tested modafinil as a treatment for stimulant abuse have failed to demonstrate its efficacy and the optimal dose and duration of modafinil treatment remain unclear, and modafinil is not a recommended treatment for stimulant abuse.[249] 2024 reviews found that modafinil was ineffective for treating individuals withamphetamine-type stimulant use disorder[250] ormethamphetamine use disorder[251] from these dependencies.[251][250]
Modafinil and armodafinil were studied as a complement toantipsychotic medications in the treatment ofschizophrenia. They showed no effect on positive symptoms or cognitive performance.[252][253] 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 the condition who are stable, with high negative symptom scores.[253] Among medications demonstrated to be effective for reducing negative symptoms in combination with antipsychotics, modafinil, and armodafinil are among the smallesteffect sizes.[254]
A 2019 review conducted on the potential nootropic effects of modafinil in healthy, non-sleep-deprived individuals revealed the following:[260] a) while studies using basic testing paradigms demonstrated that modafinil enhancesexecutive function, only half of these studies showed improvements in attention, learning, and memory, with a few studies even reporting impairments in divergent creative thinking; b) modafinil displayed small levels of enhancement in attention, executive functions, and learning abilities; c) no substantial side effects or mood changes were observed; d) the available evidence showed limited evidence for modafinil as a cognitive enhancer outside of its use for sleep-deprived populations.
A 2020 review reported that modafinil has a modest effect on memory updating, but the effect is small and may not accurately reflect the perception that it is useful as a cognitive enhancer, as there is insufficient evidence to support such a claim.[261]
General anesthesia is required for manysurgeries, but may cause lingering fatigue, sedation, and/or drowsiness after surgery that lasts for hours to days.[262][263] Inoutpatient surgery thesedation,fatigue, and occasionaldizziness is problematic.[264][265] Modafinil was tested as a potential remedy to alleviate these symptoms.[51] For example, it was expected that modafinil would help people recover quicker from general anesthesia after a short surgery,[90] but the results were uncertain and the inconclusive studies could not reliably verify the expectation.[51] The use of modafinil to relieve post-anesthesia sedation is investigational.[90]
Modafinil is being researched as a potential remedy for excessive daytime sleepiness inmyotonic dystrophy (DM), an inherited condition characterized by progressive muscle loss, weakness, andmyotonia. Myotonia is a condition where muscles cannot relax after they contract.[267] Myotonic dystrophy has two main types: DM1 (Steinert disease) and DM2 (proximal myotonic myopathy). Both types can cause excessive daytime sleepiness. Studies suggest that modafinil may be a promising drug that can reduce both daytime sleepiness and myotonia itself, without significant cardiac conduction effects. These presumed property of modafinil is of particular interest for eventual treatment of people with myotonic dystrophy who often have underlying cardiac issues.[267] Still, modafinil is not approved by the FDA for use in myotonic dystrophy, and the value and role of modafinil in DM remain the subject of debate.[267]
Neuroimaging studies have shown that modafinil increasescerebral blood flow in several brain regions, such as thethalamus,locus coeruleus,limbic system, andinsular cortex;[268] still, observational reports on the use of modafinil in patients with disorders of consciousness have produced mixed results, indicating that its effectiveness may vary among individuals.[268]
A possible link betweeninflammatory processes and depressive disorders[269] has stimulated preliminary research on modafinil for its potential anti-inflammatory effects.[270]
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