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Wikipedia

Modafinil

January 29, 2023

Modafinil, sold under the brand name Provigil among others, is a central nervous system (CNS) stimulant medication used to treat sleepiness due to narcolepsy, shift work sleep disorder, and obstructive sleep apnea.[3][9] While it has seen off-label use as a purported cognitive enhancer to improve wakefulness in animal and human studies, the research on its effectiveness for this use is not conclusive.[10][11][12][13] Modafinil is taken by mouth.[3]

Modafinil
Clinical data
Trade namesProvigil, Alertec, Modavigil, others
Other namesCRL-40476; Diphenylmethyl-sulfinylacetamide
AHFS/Drugs.comMonograph
MedlinePlusa602016
License data
  • US FDA: Modafinil
Pregnancy
category
  • AU: D
Dependence
liability		Relatively low
Addiction
liability		Very low to low[1][2]
Routes of
administration		By mouth[3]
Drug classCNS stimulant
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityNot determined due to its aqueous insolubility
Protein binding62.3%
MetabolismLiver (primarily via amide hydrolysis;[7] CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5 involved [8]
Elimination half-life15 hours (armodafinil),
4 hours (esmodafinil)[6]
ExcretionUrine (80%)
Identifiers
  • 2-(diphenylmethanesulfinyl)acetamide
CAS Number
  • 68693-11-8 Y
PubChem CID
  • 4236
IUPHAR/BPS
  • 7555
DrugBank
  • DB00745 Y
ChemSpider
  • 4088 Y
UNII
  • R3UK8X3U3D
KEGG
  • D01832 Y
ChEBI
  • CHEBI:31859 Y
ChEMBL
  • ChEMBL1373 Y
CompTox Dashboard (EPA)
  • DTXSID0023329
ECHA InfoCard100.168.719
Chemical and physical data
FormulaC15H15NO2S
Molar mass273.35 g·mol−1
3D model (JSmol)
  • Interactive image
  • O=S(C(c1ccccc1)c2ccccc2)CC(=O)N
  • InChI=1S/C15H15NO2S/c16-14(17)11-19(18)15(12-7-3-1-4-8-12)13-9-5-2-6-10-13/h1-10,15H,11H2,(H2,16,17) Y
  • Key:YFGHCGITMMYXAQ-UHFFFAOYSA-N Y
  (verify)

Modafinil’s side effects include headaches, anxiety, excessive adrenal gland overproduction, and nausea. Serious side effects in high doses include delusions, unfounded beliefs, paranoia, irrational thought, and transient depression, possibly due to its effects on dopamine receptors in the brain, as well as allergic reactions. The amount of medication used should be adjusted in those with kidney problems, as this medication has markedly increased side effects during renal insufficiency.[14]

It is not recommended in those with an arrhythmia, significant hypertension, or left ventricular hypertrophy.[14] Modafinil appears to work by acting on dopamine and modulating the areas of the brain involved with the sleep cycle.[3]

Originally developed in the 1970s by French neuroscientist Michel Jouvet and Lafon Laboratories, Modafinil has been prescribed in France since 1994,[15] and was approved for medical use in the United States in 1998.[9] In the United States it is classified as a schedule IV controlled substance, although its classification has been called into question.[16] In the United Kingdom it is a prescription only medication.[14] It is available as a generic medication.[14] In 2020, modafinil was the 302nd most commonly prescribed medication in the United States, with just over 1,000,000 prescriptions.[17]

Usage

Uses

Medical

Modafinil is not considered to be a classical psychostimulant, but rather is classified as a eugeroic (wakefulness-promoting drug).

Sleep disorders

Modafinil is used primarily for treatment of narcolepsy, shift work sleep disorder, and excessive daytime sleepiness associated with obstructive sleep apnea.[9][12][18][19] For obstructive sleep apnea, it is recommended that continuous positive airway pressure (CPAP) be appropriately used before considering starting modafinil to help with daytime sleepiness.[3] Because of the risk for development of skin or hypersensitivity reactions and serious adverse psychiatric reactions, the European Medicines Agency has recommended that new patient prescriptions should be only to treat sleepiness associated with narcolepsy.[20]

Fatigue

Modafinil is suggested for helping with multiple sclerosis (MS) fatigue by the UK National Institute for Health and Care Excellence (NICE)[21] and by MS NGOs.[22][23]

Occupational

See also: List of drugs used by militaries

Of French origin, Modafinil was fielded to military personnel in the Air Force, Foreign Legion and Marine infantry during the 1st Gulf War. Being more efficient than its parent drug adrafinil, it was deemed combat-worthy by French Ministry of Defense in 1989 and subsequently administered to personnel by their officers under the name Virgyl, in order to improve a unit's operational tempo. The test took place before the introduction of modafinil as medication, and the personnel involved were not informed of the product's nature.[24]

Since then, armed forces of several countries including the United States, the United Kingdom, India and France, have expressed interest in modafinil as an alternative to amphetamine—the drug traditionally employed in combat situations or lengthy missions where troops face sleep deprivation. The French government indicated that the Foreign Legion used modafinil during certain covert operations.[25] The United Kingdom's Ministry of Defence commissioned research into modafinil[26] from QinetiQ and spent £300,000 on one investigation.[27] In 2011, the Indian Air Force announced that modafinil was included in contingency plans.[28]

In the United States military, modafinil has been approved for use on certain Air Force missions, and it is being investigated for other uses.[29] As of November 2012, modafinil is the only drug approved by the Air Force as a "go pill" for fatigue management (replacing prior use of amphetamine-based medications such as dextroamphetamine).[30] It is also used in various Special Forces.

The Canadian Medical Association Journal also reports that modafinil is used by astronauts on long-term missions aboard the International Space Station. Modafinil is "available to crew to optimize performance while fatigued" and helps with the disruptions in circadian rhythms and with the reduced quality of sleep astronauts experience.[31]

Nootropic

Modafinil has been used non-medically as a "smart drug" by students, office workers, soldiers and transhumanists.[32][33][34][35][36] As a 'smart drug' it allegedly increases mental focus and helps evade sleep, properties that attract students, professionals in the corporate and tech fields, air-force personnel, surgeons, truck drivers and call-center workers.[37][38]

Treatment of cocaine addiction

Modafinil binds to the dopamine transporter (DAT) in an occluded conformation, differently than drugs like cocaine and cocaine-like drugs.[39][40][41] Subjects pre-treated with modafinil report experiencing less euphoria from cocaine administration.[40] Modafinil does not potentiate self-administration of cocaine in pretreated Sprague-Dawley rats.[42]

The mechanism by which modafinil inhibits cocaine self-administration is likely more complex than the simple observation that modafinil occupies the DAT, as drugs like methylphenidate (a dopamine re-uptake inhibitor) do not reduce cocaine self-administration.[39][43]

Available forms

 
Modafinil tablets – Modalert 200

Modafinil is available in the form of 100 and 200 mg oral tablets.[9] It is also available as the (R)-enantiomer, armodafinil, and as a prodrug of modafinil, adrafinil.[44]

Drug tolerance

Large-scale clinical studies have found no evidence of fading impact over time (tolerance) with modafinil at therapeutic doses even with prolonged use (for forty weeks and as long as three years).[45][46][47]

Contraindications

Modafinil is contraindicated in people with known hypersensitivity to modafinil or armodafinil.[48] Modafinil is not approved for use in children for any medical conditions, in whom there is a higher risk of rare but serious dermatological toxicity.[49][50][51]

Adverse effects

The incidence of adverse effects are reported as the following: less than 10% of users report having a headache, nausea, and decreased appetite. Between 5% to 10% of users may be affected with anxiety, insomnia, dizziness, diarrhea, and rhinitis.[52] Modafinil-associated psychiatric reactions have occurred in those with and without a pre-existing psychiatric history.[53] No clinically significant changes in body weight have been observed with modafinil in clinical trials,[54] although decreased appetite and weight loss have been reported with modafinil in children and adolescents probably due to the much higher modafinil exposure in these individuals based on body weight (i.e., mg/kg doses).[55]

Rare occurrences have been reported of more serious adverse effects, including severe skin rashes and other symptoms that are probably allergy-related. From the date of initial marketing, December 1998, to January 30, 2007, the US Food and Drug Administration received six cases of severe cutaneous adverse reactions associated with modafinil, including erythema multiforme (EM), Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and DRESS syndrome, involving adult and pediatric patients. The FDA issued a relevant alert. In the same alert, the FDA also noted that angioedema and multi-organ hypersensitivity reactions have also been reported in postmarketing experiences.[56] In 2007, the FDA ordered Cephalon to modify the Provigil leaflet in bold-face print of several serious and potentially fatal conditions attributed to modafinil use, including TEN, DRESS syndrome, and SJS.

The long term safety and effectiveness of modafinil have not been determined.[57] However, a recent longitudinal study in pediatric patients for narcolepsy for up to 10 years demonstrated that modafinil and armodafinil were safe and effective with the study concluding that use of modafinil and armodafinil significantly improved patient's ability to stay awake and did not exacerbate preexisting psychiatric conditions.[58]

Addiction and dependence

The addiction and dependence liabilities of modafinil are very low.[1][59] It shares biochemical mechanisms with addictive stimulant drugs, and some studies have reported it to have similar mood-elevating properties, although to a lesser degree.[59] It is not clear whether these effects are any more different than the ones from caffeine.[60][61] Modafinil does not appear to produce euphoric effects nor deviations (i.e. abuse) from assigned dosages to the patient.[62]

Modafinil is classified by the United States FDA as a schedule IV controlled substance, a category for drugs with valid medical uses and low addiction potential.[1][63] The International Narcotics Control Board does not consider modafinil a narcotic[64] nor a psychotropic substance.[65] In fact, modafinil may increase abstinence rates in a subgroup of cocaine addicts while modafinil-related discontinuation adverse effects are no different from placebo.[66]

Overdose

In mice and rats, the median lethal dose (LD50) of modafinil is approximately or slightly greater than 1250 mg/kg. Oral LD50 values reported for rats range from 1000 to 3400 mg/kg. Intravenous LD50 for dogs is 300 mg/kg. Clinical trials on humans involving taking up to 1200 mg/day for 7–21 days and known incidents of acute one-time overdoses up to 4500 mg did not appear to cause life-threatening effects, although a number of adverse experiences were observed, including excitation or agitation, insomnia, anxiety, irritability, aggressiveness, confusion, nervousness, tremor, palpitations, sleep disturbances, nausea, and diarrhea.[9] As of 2004, the FDA is not aware of any fatal overdoses involving modafinil alone (as opposed to multiple drugs including modafinil).[9]

Interactions

Coadministration with opioids such as methadone, hydrocodone, oxycodone and fentanyl may result in a drop in opioid plasma concentrations, because modafinil is an inducer of the CYP3A4 enzymes. If not monitored closely, reduced efficacy or withdrawal symptoms can occur.[67] Modafinil may have an adverse effect on hormonal contraceptives for up to a month after discontinuation.[68] In a 2006 study, a single dose of modafinil 200 mg caused a decrease in blood prolactin levels, although it did not affect human growth hormone or thyroid-stimulating hormone.[69][70] Since modafinil can induce the activity of the CYP3A4 enzyme involved in cortisol clearance,[71] modafinil may reduce the bioavailability of hydrocortisone. Therefore, it may be necessary to adjust the steroid substitution dose in subjects receiving CYP3A4-metabolism-inducing drugs such as modafinil.[72] Modafinil is classified as a weak to moderate inducer of CYP3A4.[73][74]

Pharmacology

Pharmacodynamics

Modafinil activity profile
Site Potency Type Species Refs
DAT 1.8–2.6 μM
4.8 μM
6.4 μM
4.0 μM		 Ki
Ki
IC50a
IC50a		 Human
Rat
Human
Rat		 [75][76]
[75]
[77][78]
[75]
NET >10 μM
>92 μM
35.6 μM
136 μM		 Ki
Ki
IC50a
IC50a		 Human
Rat
Human
Rat		 [75][76]
[75]
[77][78]
[75]
SERT >10 μM
46.6 μM
>500 μM
>50 μM		 Ki
Ki
IC50a
IC50a		 Human
Rat
Human
Rat		 [75][76]
[75]
[77][78]
[75]
D2 >10 μM
16 nMb
120 nMb		 Ki
Ki
EC50a		 Human
Rat
Rat		 [75]
[79]
[79]
Footnotes: a = Functional activity, not binding inhibition. b = Armodafinil at D2High. Notes: No activity at a variety of other assessed targets.[75]

Mechanism of action

As of 2017, the precise therapeutic mechanism of action of modafinil for narcolepsy and sleep-wake disorders remains unknown.[80][81] Modafinil acts as an atypical, selective, and weak dopamine reuptake inhibitor and indirectly activates the release of orexin neuropeptides and histamine from the lateral hypothalamus and tuberomammillary nucleus, respectively all of which may contribute to heightened arousal.[80][81][82][83]

Dopamine reuptake inhibitor

Research found that modafinil elevates dopamine levels in the hypothalamus in animals.[84] The locus of the monoamine action of modafinil was also the target of studies, with effects identified on dopamine in the striatum and, in particular, nucleus accumbens,[85][86] norepinephrine in the hypothalamus and ventrolateral preoptic nucleus,[87][88] and serotonin in the amygdala and frontal cortex.[89] Modafinil was screened at a large panel of receptors and transporters in an attempt to elucidate its pharmacology.[75] Of the sites tested, it was found to significantly affect only the dopamine transporter (DAT), acting as a dopamine reuptake inhibitor (DRI) with an IC50 value of 4 μM.[75] Subsequently, it was determined that modafinil binds to the same site on the DAT as cocaine, but in a different manner.[90][91] In accordance, modafinil increases locomotor activity and extracellular dopamine concentrations in animals in a manner similar to the selective DRI vanoxerine (GBR-12909),[92] and also inhibits methamphetamine-induced dopamine release (a common property of DRIs, since DAT transport facilitates methamphetamine's access to its intracellular targets). As such, "modafinil is an exceptionally weak, but apparently very selective, [DAT] inhibitor".[93] In addition to animal research, a human positron emission tomography (PET) imaging study found that 200 mg and 300 mg doses of modafinil resulted in DAT occupancy of 51.4% and 56.9%, respectively, which was described as "close to that of methylphenidate".[94] Another human PET imaging study similarly found that modafinil occupied the DAT and also determined that it significantly elevated extracellular levels of dopamine in the brain, including in the nucleus accumbens.[95]

Modafinil has been described as an "atypical" DAT inhibitor, and shows a profile of effects that is very different from those of other dopaminergic stimulants.[96][97] For instance, modafinil produces wakefulness reportedly without the need for compensatory sleep, and shows relatively low, if any, potential for abuse.[98][93][96][97] Aside from modafinil, examples of other atypical DAT inhibitors include vanoxerine and benztropine, which have a relatively low abuse potential similar to modafinil.[96] These drugs appear to interact molecularly with the DAT in a distinct way relative to "conventional" DAT blockers such as cocaine and methylphenidate.[91][96] Analogues of modafinil with modafinil-like versus cocaine-like dopamine reuptake inhibition and effects have been synthesized.[99]

Dopamine transporter-independent actions

Against the hypothesis that modafinil exerts its effects by acting as a DRI, tyrosine hydroxylase inhibitors (which deplete dopamine) fail to block the effects of modafinil in animals.[100] In addition, modafinil fails to reverse reserpine-induced akinesia, whereas dextroamphetamine, a dopamine releasing agent (DRA), is able to do so.[101] Moreover, one of the first published structure–activity relationship studies of modafinil found in 2012 that DAT inhibition did not correlate with wakefulness-promoting effects in animals among modafinil analogues.[102] Additionally, a variety of analogues without any significant inhibition of the DAT still produced wakefulness-promoting effects.[102] Furthermore, "[the] neurochemical effects [of modafinil] and anatomical pattern of brain area activation differ from typical psychostimulants and are consistent with its beneficial effects on cognitive performance processes such as attention, learning, and memory".[98] Another study found that modafinil-induced increased locomotor activity in animals was dependent on histamine release and could be abolished by depletion of neuronal histamine, whereas those of methylphenidate were not and could not be.[84] Taken together, although it is established that modafinil is a clinically significant DRI, its full pharmacology remains unclear and may be more complex than this single property—as it may also include DAT-independent actions.[90][98] One such action may be activation of the orexin system.[83][90][98]

In any case, there is nonetheless a good deal of evidence to indicate that modafinil is producing at least a portion of its wakefulness-promoting effects by acting as a DRI, or at least via activation of the dopaminergic system. In support of modafinil acting as a dopaminergic agent, its wakefulness-promoting effects are abolished in DAT knockout mice (although DAT knockout mice show D1 and D2 receptor and norepinephrine compensatory abnormalities that might confound this finding), reduced by both D1 and D2 receptor antagonists (although conflicting reports exist),[101] and completely blocked by simultaneous inactivation of both D1 and D2 receptors.[93] In accordance, modafinil shows full stimulus generalization to other DAT inhibitors including cocaine, methylphenidate, and vanoxerine, and discrimination is blocked by administration of both ecopipam (SCH-39166), a D1 receptor antagonist, and haloperidol, a D2 receptor antagonist.[97] Partial substitution was seen with the DRA dextroamphetamine and the D2 receptor agonist PNU-91356A, as well as with nicotine (which indirectly elevates dopamine levels through activation of nicotinic acetylcholine receptors).[97]

Modafinil may possess yet an additional mechanism of action. Both modafinil and its metabolite, modafinil sulfone, possess anticonvulsant properties in animals, and modafinil sulfone is nearly as potent as modafinil in producing this effect.[103] However, modafinil sulfone lacks any wakefulness-promoting effects in animals, indicating that a distinct mechanism may be at play in the anticonvulsant effects of both compounds.[103]

Dopamine D2 receptor partial agonist

Armodafinil, the (R)-enantiomer of modafinil, was also subsequently found to act as a D2High receptor partial agonist,[104] with a Ki of 16 nM, an intrinsic activity of 48%, and an EC50 of 120 nM, in rat striatal tissue.[79] Esmodafinil, the (S)-enantiomer of modafinil, is inactive with respect to the D2 receptor.[79] Modafinil has been found to directly inhibit the firing of midbrain dopaminergic neurons in the ventral tegmental area and substantia nigra of rats via activation of D2 receptors.[105] However, modafinil has also been reported not to interact with the human D2 receptor (Ki = >10 μM).[75]

Dampening of amygdala activity

Although modafinil enhances the efficiency of prefrontal cortical information processing, there is also some human and mouse evidence to suggest that it conversely reduces amygdala activity (both through direct fMRI observation and anxiety questionnaires).[106][107] The amygdala is highly involved in fear processing, and the dampening of its activity reduces perceptions of fear in response to environmental stress.[108] At least one study has documented a statistically significant reduction in fear response in human subjects given 100 mg of modafinil daily for 7 days.[106] However, another study investigating the acute effects of modafinil on fear processing reported an increase in amygdala responses to fearful faces after administration of 600 mg of modafinil in human subjects.[109]

Modafinil's effects on fear processing are unique from classical psychostimulants such as those based on amphetamine (phenethylamines), which can generate fear and anxiety at high doses.[110]

Other actions

An in vitro study predicts that modafinil may induce the cytochrome P450 enzymes CYP1A2, CYP3A4, and CYP2B6, as well as may inhibit CYP2C9 and CYP2C19.[8] However, an in-vitro studies find no significant inhibition of CYP2C9.[7][111] It may also induce P-glycoprotein, which may affect drugs transported by P-glycoprotein, such as digoxin.[112]

Pharmacokinetics

Cmax (peak levels) occurs approximately 2 to 3 hours after administration. Food slows absorption, but does not affect the total AUC. In vitro measurements indicate that 60% of modafinil is bound to plasma proteins at clinical concentrations of the drug. This percentage changes very little when the concentration of modafinil is varied.[113]

Renal excretion of unchanged modafinil accounts for less than 10% of an oral dose.[7] The two major circulating metabolites of modafinil are modafinil acid (CRL-40467) and modafinil sulfone (CRL-41056).[114][7] Both of these metabolites have been described as inactive,[115] and neither appear to contribute to the wakefulness-promoting effects of modafinil.[114][7][116] However, modafinil sulfone does appear to possess anticonvulsant effects, a property that it shares with modafinil.[103]

Elimination half-life is generally in the range of 10 to 12 hours, subject to differences in CYP genotypes, liver function and renal function. It is metabolized in the liver, and its inactive metabolite is excreted in the urine. Urinary excretion of the unchanged drug ranges from 0% to as high as 18.7%, depending on various factors.[113]

Chemistry

Enantiomers

 
Armodafinil ((R)-(−)-modafinil)
 
Esmodafinil ((S)-(+)-modafinil)

Modafinil is a racemic mixture of two enantiomers, armodafinil ((R)-modafinil) and esmodafinil ((S)-modafinil).[78][117]

Detection in body fluids

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. Instrumental techniques involving gas or liquid chromatography are usually employed for these purposes.[118][119] As of 2011, it is not specifically tested for by common drug screens (except for anti-doping screens) and is unlikely to cause false positives for other chemically unrelated drugs such as substituted amphetamines.[78]

Reagent testing can be used to screen for the presence of modafinil in samples.

Colors produced by modafinil with various reagents
RC Marquis Reagent Liebermann Froehde
Modafinil Yellow/Orange > Brown[120][121] Darkening Orange[120] Deep orange/red[121]

Structural analogues

Many derivatives and structural analogues of modafinil have been synthesized and studied.[99][122][91] Examples of these analogues include adrafinil, CE-123, fladrafinil (CRL-40941; fluorafinil), flmodafinil (CRL-40940; bisfluoromodafinil, lauflumide), and modafinil sulfone (CRL-41056).[123]

History

Modafinil was originally developed in France by neurophysiologist professor Michel Jouvet and Lafon Laboratories. Modafinil originated with the 1970s invention of a series of benzhydryl sulfinyl compounds, including adrafinil, which was first offered as an experimental treatment for narcolepsy in France in 1986.[15] Modafinil is the primary metabolite of adrafinil, lacking the polar -OH group on its terminal amide,[124] and has similar activity to the parent drug but is much more widely used.[citation needed] It has been prescribed in France since 1994 under the name Modiodal,[15] and in the US since 1998 as Provigil.

In 1998, modafinil was approved by the U.S. Food and Drug Administration[125] for the treatment of narcolepsy and in 2003 for shift work sleep disorder and obstructive sleep apnea/hypopnea[126] even though caffeine and amphetamine were shown to be more wakefulness promoting on the Stanford Sleepiness Test Score than modafinil.[81]

It was approved for use in the UK in December 2002. Modafinil is marketed in the United States by Cephalon, who originally leased the rights from Lafon, but eventually purchased the company in 2001.

Cephalon began to market armodafinil, the (R)-enantiomer of modafinil, in the United States in 2007. After protracted patent litigation and negotiations (see below), generic versions of modafinil became available in the US in 2012.

Patent protection and litigation

U.S. Patent 4,927,855 was issued to Laboratoire L. Lafon on May 22, 1990, covering the chemical compound modafinil. After receiving an interim term extension of 1066 days and pediatric exclusivity of six months, it expired on October 22, 2010. On October 6, 1994, Cephalon filed an additional patent, covering modafinil in the form of particles of defined size. That patent, U.S. Patent 5,618,845 was issued on April 8, 1997. It was reissued in 2002 as RE 37,516, which surrendered the 5618845 patent. With pediatric exclusivity, this patent expired on April 6, 2015.[127][128]

On December 24, 2002, anticipating the expiration of exclusive marketing rights, generic drug manufacturers Mylan, Teva, Barr, and Ranbaxy applied to the FDA to market a generic form of modafinil.[129] At least one withdrew its application after early opposition by Cephalon based on the RE 37,516 patent. There is some question of whether a particle size patent is sufficient protection against the manufacture of generics. Pertinent questions include whether modafinil may be modified or manufactured to avoid the granularities specified in the new Cephalon patent, and whether patenting particle size is invalid because particles of appropriate sizes are likely to be obvious to practitioners skilled in the art. However, under United States patent law, a patent is entitled to a legal presumption of validity, meaning that in order to invalidate the patent, much more than "pertinent questions" are required.

As of October 31, 2011, U.S. Reissue Patent No. RE 37,516 has been declared invalid and unenforceable.[130] The District Court for the Eastern District of Pennsylvania ruled that RE 37,516 was invalid because it: (1) was on sale more than one year prior to the date of the application in violation of 35 U.S.C. section 102(b); (2) was actually invented by someone else (the French company Laboratoire L. Lafon); (3) was obvious at the time the invention was made to a person having ordinary skill in the art under 35 U.S.C. section 103(a); and (4) failed the written description requirement of 35 U.S.C. section 112.[131] The patent was also found to be unenforceable due to Cephalon's inequitable conduct during patent prosecution.[131]

Cephalon made an agreement with four major generics manufacturers Teva, Barr Pharmaceuticals, Ranbaxy Laboratories, and Watson Pharmaceuticals between 2005 and 2006 to delay sales of generic modafinil in the US until April 2012 by these companies in exchange for upfront and royalty payments.[132] Litigation arising from these agreements is still pending including an FTC suit filed in April 2008.[133] Apotex received regulatory approval in Canada despite a suit from Cephalon's marketing partner in Canada, Shire Pharmaceuticals.[134][135] Cephalon has sued Apotex in the US to prevent it from releasing a genericized armodafinil (Nuvigil).[136] Cephalon's 2011 attempt to merge with Teva was approved by the FTC under a number of conditions, including granting generic US rights to another company;[137] ultimately, Par Pharmaceutical acquired the US modafinil rights as well as some others.[138]

In the United Kingdom, Mylan Inc. received regulatory approval to sell generic modafinil produced by Orchid in January 2010; Cephalon sued to prevent sale, but lost the patent trial in November.[139]

Society and culture

Brand names

Modafinil is sold under a wide variety of brand names worldwide, including Alertec, Alertex, Altasomil, Aspendos, Forcilin, Intensit, Mentix, Modafinil, Modafinilo, Modalert, Modanil, Modasomil, Modvigil, Modiodal, Modiwake, Movigil, Provigil, Resotyl, Stavigile, Vigia, Vigicer, Vigil, Vigimax, Wakelert and Zalux.[140]

Legal status

Australia

In Australia, modafinil is considered to be a Schedule 4 prescription-only medicine or prescription animal remedy.[141] Schedule 4 is defined as "Substances, the use or supply of which should be by or on the order of persons permitted by State or Territory legislation to prescribe and should be available from a pharmacist on prescription."

Canada

In Canada, modafinil is not listed in the Controlled Drugs and Substances Act, but it is a Schedule F prescription drug,[142] so it is subject to seizure by Canada Border Services Agency.

China

In mainland China, modafinil is strictly controlled like other stimulants, such as amphetamines and methylphenidate. It has been classified as Class I psychotropic drug,[143] meaning that only doctors who have the right to prescribe narcotics and Class I psychotropic drugs (usually through special examination) can prescribe it for no more than three-day use (or seven-day use for control/extend-release products).[144] The first and only modafinil products was approved in November 2017,[145] but its marketing status in mainland China is still unknown.

Japan

In Japan, modafinil is Schedule I psychotropic drug.[146][147] Cephalon has licensed Alfresa Corporation to produce, and Mitsubishi Tanabe Pharma to sell modafinil products under the trade name Modiodal in Japan.[148] Also, there have been reported arrests of people who imported modafinil for personal use.[149][150]

Romania

Modafinil is considered a stimulant doping agent and as such is prohibited in sports competitions, in the same category as steroids.[151] Due to new laws passed in 2022, import into the country or selling is considered a felony and can be punished with jail time from 3 years to 7 years.[152] Simple possession for personal use is still punished with just a fine and confiscation.

Russia

In Russia modafinil is Schedule II controlled substance like cocaine and morphine. Possession of few modafinil pills can lead to 3–10 years imprisonment.[153]

Sweden

In Sweden, modafinil is classified as a schedule IV substance and possession is therefore illegal without prescription.[154]

United States

Modafinil is currently classified as a Schedule IV controlled substance under United States federal law; it is illegal to import by anyone other than a DEA-registered importer without a prescription.[155] The Clinton administration issued regulations in 64 FR 4050 effective 27 January 1999 based upon a recommendation of the administration's Assistant Secretary for Health.[156]

However, one may legally bring modafinil into the United States in person from a foreign country, provided that he or she has a prescription for it, and the drug is properly declared at the border crossing. U.S. residents are limited to 50 dosage units (e.g., pills).[157] Under the US Pure Food and Drug Act, drug companies are not allowed to market their drugs for off-label uses (conditions other than those officially approved by the FDA);[158] Cephalon was reprimanded in 2002 by the FDA because its promotional materials were found to be "false, lacking in fair balance, or otherwise misleading".[159] Cephalon pleaded guilty to a criminal violation and paid several fines, including $50 million and $425 million fines to the U.S. government in 2008.[160][161]

Other countries

The following countries do not classify modafinil as a controlled substance:

  • In Finland, modafinil is a prescription drug but not listed as a controlled substance.[162]
  • In Denmark, modafinil is a prescription drug but not listed as a controlled substance.[163]
  • Mexico (Not listed as a controlled substance, in the National Health Law. Can be purchased in pharmacies without prescription.)[164]
  • South Africa Schedule V[165]
  • United Kingdom (not listed in Misuse of Drugs Act so possession not illegal, but prescription required) [166]

Sports use and issues

The regulation of modafinil as a doping agent has been controversial in the sporting world, with high-profile cases attracting press coverage since several prominent American athletes have tested positive for the substance. Some athletes who were found to have used modafinil protested that the drug was not on the prohibited list at the time of their offenses.[167] However, the World Anti-Doping Agency (WADA) maintains that it 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 the 2004 Summer Olympics.

Modafinil has received some publicity in the past when several athletes (such as sprinter Kelli White in 2004, cyclist David Clinger[168] and basketball player Diana Taurasi[169] in 2010, and rower Timothy Grant in 2015[170]) were accused of using it as a performance-enhancing doping agent. Taurasi and another player, Monique Coker, tested at the same lab, were later cleared.[171] It is not clear how widespread this practice is. The BALCO scandal brought to light an as-yet unsubstantiated (but widely published) account of Major League Baseball's all-time leading home-run hitter Barry Bonds' supplemental chemical regimen that included modafinil in addition to anabolic steroids and human growth hormone.[172] Modafinil has been shown to prolong exercise time to exhaustion while performing at 85% of VO2max and also reduces the perception of effort required to maintain this threshold.[173] Modafinil was added to the World Anti-Doping Agency "Prohibited List" in 2004 as a prohibited stimulant (see Modafinil Legal Status).

Research

Psychiatric conditions

Major depression

Modafinil has been studied in the treatment of major depressive disorder.[174][175][176][177][178][179][180][181] In a 2021 systematic review and meta-analysis of randomized controlled trials of psychostimulants for depression, modafinil and other stimulants such as methylphenidate and amphetamines improved depression in traditional meta-analysis.[181] However, when subjected to network meta-analysis, modafinil and most other stimulants did not significantly improve depression, with only methylphenidate remaining effective.[181] Modafinil and other stimulants likewise did not improve quality of life in the meta-analysis, although there was evidence for reduced fatigue and sleepiness with modafinil and other stimulants.[181] While significant effectiveness of modafinil for depression has been reported,[175][177][180] reviews and meta-analyses note that the effectiveness of modafinil for depression is limited, the quality of available evidence is low, and more research is needed.[174][176][178][181]

Bipolar depression

Modafinil and armodafinil have been repurposed as adjunctive treatments for acute depression in people with bipolar disorder.[104] A 2021 meta-analysis found 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 has to be considered low, limiting the clinical relevance of current evidence.[104] Very low rates of mood switch have been observed with modafinil and armodafinil in bipolar disorder.[177]

Attention deficit hyperactivity disorder

Modafinil has been studied and reported to be effective in the treatment of attention deficit hyperactivity disorder (ADHD), with significantly less abuse potential than conventional psychostimulants like methylphenidate and amphetamines.[182][183] In the United States, an application to market modafinil for pediatric ADHD was submitted to the FDA.[55] However, approval was denied due to concerns about rare but serious dermatological toxicity (specifically, the occurrence of Stevens–Johnson syndrome).[55] In any case, modafinil may be used off-label to treat ADHD in both children and adults.[184][182][185] However, evidence of modafinil for treatment of adult ADHD is mixed, and a 2016 systematic review of alternative drug therapies for adult ADHD could not recommend its use in this context.[186] In a large phase 3 clinical trial of modafinil for adult ADHD, modafinil was not effective in improving symptoms and there was a high rate of side effects (86%) and discontinuation (47%).[187] The poor tolerability of modafinil in this study was possibly due to the use of excessively high doses (210–510 mg/day).[187]

Substance dependence

Modafinil has been studied for the treatment of stimulant dependence.[184][55][188][98][66][99][189]

Schizophrenia

Modafinil and armodafinil have been studied as a complement to antipsychotic medications in the treatment of schizophrenia. They have been consistently shown to have no effect on positive symptoms or cognitive performance.[190][191] A 2015 meta-analysis found that modafinil and armodafinil may slightly reduce negative symptoms in people with acute schizophrenia, though it does not appear useful for people with the condition who are stable, with high negative symptom scores.[191] Among medications demonstrated to be effective for reducing negative symptoms in combination with anti-psychotics, modafinil and armodafinil are among the smallest effect sizes.[192]

Cognitive enhancement

A 2015 review of clinical studies of possible nootropic effects in healthy people found: "... whilst most studies employing basic testing paradigms show that modafinil intake enhances executive function, only half show improvements in attention and learning and memory, and a few even report impairments in divergent creative thinking. In contrast, when more complex assessments are used, modafinil appears to consistently engender enhancement of attention, executive functions, and learning. Importantly, we did not observe any preponderances for side effects or mood changes."[12] A 2019 review of studies of a single-dose of modafinil on mental function in healthy, non-sleep deprived people found a statistically significant but small effect and concluded that the drug has limited usefulness as a cognitive enhancer in non-sleep deprived persons.[11] A 2020 review of the cognitive enhancing potential of methylphenidate, d-amphetamine, and modafinil in healthy individuals across various domains found that modafinil has a small, positive effect on memory updating.[193]

Modafinil has been used off-label in trials with people with symptoms of post-chemotherapy cognitive impairment, also known as "chemobrain", but a 2011 review found that it was no better than placebo.[194] As of 2015 it had been studied for use in multiple sclerosis-associated fatigue, but the resulting evidence was weak and inconclusive.[195]

Post-anesthesia sedation

General anesthesia is required for many surgeries, but there may be lingering fatigue, sedation, and/or drowsiness after surgery has ended that lasts for hours to days. In outpatient settings wherein patients are discharged home after surgery, this sedation, fatigue and occasional dizziness is problematic. As of 2006, modafinil had been tested and reported to be effective in one small (N=34) double-blind randomized controlled trial for this use.[184]

Fatigue

Research on using modafinil to reduce multiple sclerosis (MS) fatigue has been inconclusive.[196][197]

Postural orthostatic tachycardia syndrome

However, caution should be exercised in patients who have narcolepsy in comorbidity with postural orthostatic tachycardia syndrome (POTS). Therefore, there are potential warnings for a class of drugs used to treat narcolepsy. Centrally acting stimulants like modafinil are often considered first-line drugs for narcolepsy. However, modafinil stimulation increases POTS-related autonomic dysfunction and results in tachycardia/arrhythmia side effects in patients with cardiovascular risk factors. Sodium oxybate, a metabolite of GABA, is an alternative drug for stimulant-intolerant patients. Therefore, there is a potential for reconsidering the safety and use of stimulants such as modafinil as first-line therapy in patients with cardiac diseases such as POTS and arrhythmias.[198]

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External links

  • for modafinil users
  • "Modafinil". Drug Information Portal. U.S. National Library of Medicine.

January 29, 2023
modafinil, sold, under, brand, name, provigil, among, others, central, nervous, system, stimulant, medication, used, treat, sleepiness, narcolepsy, shift, work, sleep, disorder, obstructive, sleep, apnea, while, seen, label, purported, cognitive, enhancer, imp. Modafinil sold under the brand name Provigil among others is a central nervous system CNS stimulant medication used to treat sleepiness due to narcolepsy shift work sleep disorder and obstructive sleep apnea 3 9 While it has seen off label use as a purported cognitive enhancer to improve wakefulness in animal and human studies the research on its effectiveness for this use is not conclusive 10 11 12 13 Modafinil is taken by mouth 3 ModafinilClinical dataTrade namesProvigil Alertec Modavigil othersOther namesCRL 40476 Diphenylmethyl sulfinylacetamideAHFS Drugs comMonographMedlinePlusa602016License dataUS FDA ModafinilPregnancycategoryAU DDependenceliabilityRelatively lowAddictionliabilityVery low to low 1 2 Routes ofadministrationBy mouth 3 Drug classCNS stimulantATC codeN06BA07 WHO Legal statusLegal statusAU S4 Prescription only CA only 4 UK POM Prescription only US Schedule IV 5 Pharmacokinetic dataBioavailabilityNot determined due to its aqueous insolubilityProtein binding62 3 MetabolismLiver primarily via amide hydrolysis 7 CYP1A2 CYP2B6 CYP2C9 CYP2C19 CYP3A4 CYP3A5 involved 8 Elimination half life15 hours armodafinil 4 hours esmodafinil 6 ExcretionUrine 80 IdentifiersIUPAC name 2 diphenylmethanesulfinyl acetamideCAS Number68693 11 8 YPubChem CID4236IUPHAR BPS7555DrugBankDB00745 YChemSpider4088 YUNIIR3UK8X3U3DKEGGD01832 YChEBICHEBI 31859 YChEMBLChEMBL1373 YCompTox Dashboard EPA DTXSID0023329ECHA InfoCard100 168 719Chemical and physical dataFormulaC 15H 15N O 2SMolar mass273 35 g mol 13D model JSmol Interactive imageSMILES O S C c1ccccc1 c2ccccc2 CC O NInChI InChI 1S C15H15NO2S c16 14 17 11 19 18 15 12 7 3 1 4 8 12 13 9 5 2 6 10 13 h1 10 15H 11H2 H2 16 17 YKey YFGHCGITMMYXAQ UHFFFAOYSA N Y verify Modafinil s side effects include headaches anxiety excessive adrenal gland overproduction and nausea Serious side effects in high doses include delusions unfounded beliefs paranoia irrational thought and transient depression possibly due to its effects on dopamine receptors in the brain as well as allergic reactions The amount of medication used should be adjusted in those with kidney problems as this medication has markedly increased side effects during renal insufficiency 14 It is not recommended in those with an arrhythmia significant hypertension or left ventricular hypertrophy 14 Modafinil appears to work by acting on dopamine and modulating the areas of the brain involved with the sleep cycle 3 Originally developed in the 1970s by French neuroscientist Michel Jouvet and Lafon Laboratories Modafinil has been prescribed in France since 1994 15 and was approved for medical use in the United States in 1998 9 In the United States it is classified as a schedule IV controlled substance although its classification has been called into question 16 In the United Kingdom it is a prescription only medication 14 It is available as a generic medication 14 In 2020 modafinil was the 302nd most commonly prescribed medication in the United States with just over 1 000 000 prescriptions 17 Contents 1 Usage 1 1 Uses 1 1 1 Medical 1 1 1 1 Sleep disorders 1 1 1 2 Fatigue 1 1 2 Occupational 1 1 3 Nootropic 1 1 4 Treatment of cocaine addiction 1 2 Available forms 1 3 Drug tolerance 2 Contraindications 3 Adverse effects 3 1 Addiction and dependence 4 Overdose 5 Interactions 6 Pharmacology 6 1 Pharmacodynamics 6 1 1 Mechanism of action 6 1 2 Dopamine reuptake inhibitor 6 1 3 Dopamine transporter independent actions 6 1 4 Dopamine D2 receptor partial agonist 6 1 4 1 Dampening of amygdala activity 6 1 5 Other actions 6 2 Pharmacokinetics 7 Chemistry 7 1 Enantiomers 7 2 Detection in body fluids 7 3 Structural analogues 8 History 8 1 Patent protection and litigation 9 Society and culture 9 1 Brand names 9 2 Legal status 9 2 1 Australia 9 2 2 Canada 9 2 3 China 9 2 4 Japan 9 2 5 Romania 9 2 6 Russia 9 2 7 Sweden 9 2 8 United States 9 2 9 Other countries 10 Sports use and issues 11 Research 11 1 Psychiatric conditions 11 1 1 Major depression 11 1 2 Bipolar depression 11 1 3 Attention deficit hyperactivity disorder 11 1 4 Substance dependence 11 1 5 Schizophrenia 11 2 Cognitive enhancement 11 3 Post anesthesia sedation 11 4 Fatigue 11 5 Postural orthostatic tachycardia syndrome 12 References 13 External linksUsage EditUses Edit Medical Edit Modafinil is not considered to be a classical psychostimulant but rather is classified as a eugeroic wakefulness promoting drug Sleep disorders Edit Modafinil is used primarily for treatment of narcolepsy shift work sleep disorder and excessive daytime sleepiness associated with obstructive sleep apnea 9 12 18 19 For obstructive sleep apnea it is recommended that continuous positive airway pressure CPAP be appropriately used before considering starting modafinil to help with daytime sleepiness 3 Because of the risk for development of skin or hypersensitivity reactions and serious adverse psychiatric reactions the European Medicines Agency has recommended that new patient prescriptions should be only to treat sleepiness associated with narcolepsy 20 Fatigue Edit Modafinil is suggested for helping with multiple sclerosis MS fatigue by the UK National Institute for Health and Care Excellence NICE 21 and by MS NGOs 22 23 Occupational Edit See also List of drugs used by militaries Of French origin Modafinil was fielded to military personnel in the Air Force Foreign Legion and Marine infantry during the 1st Gulf War Being more efficient than its parent drug adrafinil it was deemed combat worthy by French Ministry of Defense in 1989 and subsequently administered to personnel by their officers under the name Virgyl in order to improve a unit s operational tempo The test took place before the introduction of modafinil as medication and the personnel involved were not informed of the product s nature 24 Since then armed forces of several countries including the United States the United Kingdom India and France have expressed interest in modafinil as an alternative to amphetamine the drug traditionally employed in combat situations or lengthy missions where troops face sleep deprivation The French government indicated that the Foreign Legion used modafinil during certain covert operations 25 The United Kingdom s Ministry of Defence commissioned research into modafinil 26 from QinetiQ and spent 300 000 on one investigation 27 In 2011 the Indian Air Force announced that modafinil was included in contingency plans 28 In the United States military modafinil has been approved for use on certain Air Force missions and it is being investigated for other uses 29 As of November 2012 modafinil is the only drug approved by the Air Force as a go pill for fatigue management replacing prior use of amphetamine based medications such as dextroamphetamine 30 It is also used in various Special Forces The Canadian Medical Association Journal also reports that modafinil is used by astronauts on long term missions aboard the International Space Station Modafinil is available to crew to optimize performance while fatigued and helps with the disruptions in circadian rhythms and with the reduced quality of sleep astronauts experience 31 Nootropic Edit Modafinil has been used non medically as a smart drug by students office workers soldiers and transhumanists 32 33 34 35 36 As a smart drug it allegedly increases mental focus and helps evade sleep properties that attract students professionals in the corporate and tech fields air force personnel surgeons truck drivers and call center workers 37 38 Treatment of cocaine addiction Edit Modafinil binds to the dopamine transporter DAT in an occluded conformation differently than drugs like cocaine and cocaine like drugs 39 40 41 Subjects pre treated with modafinil report experiencing less euphoria from cocaine administration 40 Modafinil does not potentiate self administration of cocaine in pretreated Sprague Dawley rats 42 The mechanism by which modafinil inhibits cocaine self administration is likely more complex than the simple observation that modafinil occupies the DAT as drugs like methylphenidate a dopamine re uptake inhibitor do not reduce cocaine self administration 39 43 Available forms Edit Modafinil tablets Modalert 200 Modafinil is available in the form of 100 and 200 mg oral tablets 9 It is also available as the R enantiomer armodafinil and as a prodrug of modafinil adrafinil 44 Drug tolerance Edit Large scale clinical studies have found no evidence of fading impact over time tolerance with modafinil at therapeutic doses even with prolonged use for forty weeks and as long as three years 45 46 47 Contraindications EditModafinil is contraindicated in people with known hypersensitivity to modafinil or armodafinil 48 Modafinil is not approved for use in children for any medical conditions in whom there is a higher risk of rare but serious dermatological toxicity 49 50 51 Adverse effects EditThe incidence of adverse effects are reported as the following less than 10 of users report having a headache nausea and decreased appetite Between 5 to 10 of users may be affected with anxiety insomnia dizziness diarrhea and rhinitis 52 Modafinil associated psychiatric reactions have occurred in those with and without a pre existing psychiatric history 53 No clinically significant changes in body weight have been observed with modafinil in clinical trials 54 although decreased appetite and weight loss have been reported with modafinil in children and adolescents probably due to the much higher modafinil exposure in these individuals based on body weight i e mg kg doses 55 Rare occurrences have been reported of more serious adverse effects including severe skin rashes and other symptoms that are probably allergy related From the date of initial marketing December 1998 to January 30 2007 the US Food and Drug Administration received six cases of severe cutaneous adverse reactions associated with modafinil including erythema multiforme EM Stevens Johnson syndrome SJS toxic epidermal necrolysis TEN and DRESS syndrome involving adult and pediatric patients The FDA issued a relevant alert In the same alert the FDA also noted that angioedema and multi organ hypersensitivity reactions have also been reported in postmarketing experiences 56 In 2007 the FDA ordered Cephalon to modify the Provigil leaflet in bold face print of several serious and potentially fatal conditions attributed to modafinil use including TEN DRESS syndrome and SJS The long term safety and effectiveness of modafinil have not been determined 57 However a recent longitudinal study in pediatric patients for narcolepsy for up to 10 years demonstrated that modafinil and armodafinil were safe and effective with the study concluding that use of modafinil and armodafinil significantly improved patient s ability to stay awake and did not exacerbate preexisting psychiatric conditions 58 Addiction and dependence Edit The addiction and dependence liabilities of modafinil are very low 1 59 It shares biochemical mechanisms with addictive stimulant drugs and some studies have reported it to have similar mood elevating properties although to a lesser degree 59 It is not clear whether these effects are any more different than the ones from caffeine 60 61 Modafinil does not appear to produce euphoric effects nor deviations i e abuse from assigned dosages to the patient 62 Modafinil is classified by the United States FDA as a schedule IV controlled substance a category for drugs with valid medical uses and low addiction potential 1 63 The International Narcotics Control Board does not consider modafinil a narcotic 64 nor a psychotropic substance 65 In fact modafinil may increase abstinence rates in a subgroup of cocaine addicts while modafinil related discontinuation adverse effects are no different from placebo 66 Overdose EditIn mice and rats the median lethal dose LD50 of modafinil is approximately or slightly greater than 1250 mg kg Oral LD50 values reported for rats range from 1000 to 3400 mg kg Intravenous LD50 for dogs is 300 mg kg Clinical trials on humans involving taking up to 1200 mg day for 7 21 days and known incidents of acute one time overdoses up to 4500 mg did not appear to cause life threatening effects although a number of adverse experiences were observed including excitation or agitation insomnia anxiety irritability aggressiveness confusion nervousness tremor palpitations sleep disturbances nausea and diarrhea 9 As of 2004 the FDA is not aware of any fatal overdoses involving modafinil alone as opposed to multiple drugs including modafinil 9 Interactions EditCoadministration with opioids such as methadone hydrocodone oxycodone and fentanyl may result in a drop in opioid plasma concentrations because modafinil is an inducer of the CYP3A4 enzymes If not monitored closely reduced efficacy or withdrawal symptoms can occur 67 Modafinil may have an adverse effect on hormonal contraceptives for up to a month after discontinuation 68 In a 2006 study a single dose of modafinil 200 mg caused a decrease in blood prolactin levels although it did not affect human growth hormone or thyroid stimulating hormone 69 70 Since modafinil can induce the activity of the CYP3A4 enzyme involved in cortisol clearance 71 modafinil may reduce the bioavailability of hydrocortisone Therefore it may be necessary to adjust the steroid substitution dose in subjects receiving CYP3A4 metabolism inducing drugs such as modafinil 72 Modafinil is classified as a weak to moderate inducer of CYP3A4 73 74 Pharmacology EditPharmacodynamics Edit Modafinil activity profile Site Potency Type Species RefsDAT 1 8 2 6 mM4 8 mM6 4 mM4 0 mM KiKiIC50aIC50a HumanRatHumanRat 75 76 75 77 78 75 NET gt 10 mM gt 92 mM35 6 mM136 mM KiKiIC50aIC50a HumanRatHumanRat 75 76 75 77 78 75 SERT gt 10 mM46 6 mM gt 500 mM gt 50 mM KiKiIC50aIC50a HumanRatHumanRat 75 76 75 77 78 75 D2 gt 10 mM16 nMb120 nMb KiKiEC50a HumanRatRat 75 79 79 Footnotes a Functional activity not binding inhibition b Armodafinil at D2High Notes No activity at a variety of other assessed targets 75 Mechanism of action Edit As of 2017 update the precise therapeutic mechanism of action of modafinil for narcolepsy and sleep wake disorders remains unknown 80 81 Modafinil acts as an atypical selective and weak dopamine reuptake inhibitor and indirectly activates the release of orexin neuropeptides and histamine from the lateral hypothalamus and tuberomammillary nucleus respectively all of which may contribute to heightened arousal 80 81 82 83 Dopamine reuptake inhibitor Edit Research found that modafinil elevates dopamine levels in the hypothalamus in animals 84 The locus of the monoamine action of modafinil was also the target of studies with effects identified on dopamine in the striatum and in particular nucleus accumbens 85 86 norepinephrine in the hypothalamus and ventrolateral preoptic nucleus 87 88 and serotonin in the amygdala and frontal cortex 89 Modafinil was screened at a large panel of receptors and transporters in an attempt to elucidate its pharmacology 75 Of the sites tested it was found to significantly affect only the dopamine transporter DAT acting as a dopamine reuptake inhibitor DRI with an IC50 value of 4 mM 75 Subsequently it was determined that modafinil binds to the same site on the DAT as cocaine but in a different manner 90 91 In accordance modafinil increases locomotor activity and extracellular dopamine concentrations in animals in a manner similar to the selective DRI vanoxerine GBR 12909 92 and also inhibits methamphetamine induced dopamine release a common property of DRIs since DAT transport facilitates methamphetamine s access to its intracellular targets As such modafinil is an exceptionally weak but apparently very selective DAT inhibitor 93 In addition to animal research a human positron emission tomography PET imaging study found that 200 mg and 300 mg doses of modafinil resulted in DAT occupancy of 51 4 and 56 9 respectively which was described as close to that of methylphenidate 94 Another human PET imaging study similarly found that modafinil occupied the DAT and also determined that it significantly elevated extracellular levels of dopamine in the brain including in the nucleus accumbens 95 Modafinil has been described as an atypical DAT inhibitor and shows a profile of effects that is very different from those of other dopaminergic stimulants 96 97 For instance modafinil produces wakefulness reportedly without the need for compensatory sleep and shows relatively low if any potential for abuse 98 93 96 97 Aside from modafinil examples of other atypical DAT inhibitors include vanoxerine and benztropine which have a relatively low abuse potential similar to modafinil 96 These drugs appear to interact molecularly with the DAT in a distinct way relative to conventional DAT blockers such as cocaine and methylphenidate 91 96 Analogues of modafinil with modafinil like versus cocaine like dopamine reuptake inhibition and effects have been synthesized 99 Dopamine transporter independent actions Edit Against the hypothesis that modafinil exerts its effects by acting as a DRI tyrosine hydroxylase inhibitors which deplete dopamine fail to block the effects of modafinil in animals 100 In addition modafinil fails to reverse reserpine induced akinesia whereas dextroamphetamine a dopamine releasing agent DRA is able to do so 101 Moreover one of the first published structure activity relationship studies of modafinil found in 2012 that DAT inhibition did not correlate with wakefulness promoting effects in animals among modafinil analogues 102 Additionally a variety of analogues without any significant inhibition of the DAT still produced wakefulness promoting effects 102 Furthermore the neurochemical effects of modafinil and anatomical pattern of brain area activation differ from typical psychostimulants and are consistent with its beneficial effects on cognitive performance processes such as attention learning and memory 98 Another study found that modafinil induced increased locomotor activity in animals was dependent on histamine release and could be abolished by depletion of neuronal histamine whereas those of methylphenidate were not and could not be 84 Taken together although it is established that modafinil is a clinically significant DRI its full pharmacology remains unclear and may be more complex than this single property as it may also include DAT independent actions 90 98 One such action may be activation of the orexin system 83 90 98 In any case there is nonetheless a good deal of evidence to indicate that modafinil is producing at least a portion of its wakefulness promoting effects by acting as a DRI or at least via activation of the dopaminergic system In support of modafinil acting as a dopaminergic agent its wakefulness promoting effects are abolished in DAT knockout mice although DAT knockout mice show D1 and D2 receptor and norepinephrine compensatory abnormalities that might confound this finding reduced by both D1 and D2 receptor antagonists although conflicting reports exist 101 and completely blocked by simultaneous inactivation of both D1 and D2 receptors 93 In accordance modafinil shows full stimulus generalization to other DAT inhibitors including cocaine methylphenidate and vanoxerine and discrimination is blocked by administration of both ecopipam SCH 39166 a D1 receptor antagonist and haloperidol a D2 receptor antagonist 97 Partial substitution was seen with the DRA dextroamphetamine and the D2 receptor agonist PNU 91356A as well as with nicotine which indirectly elevates dopamine levels through activation of nicotinic acetylcholine receptors 97 Modafinil may possess yet an additional mechanism of action Both modafinil and its metabolite modafinil sulfone possess anticonvulsant properties in animals and modafinil sulfone is nearly as potent as modafinil in producing this effect 103 However modafinil sulfone lacks any wakefulness promoting effects in animals indicating that a distinct mechanism may be at play in the anticonvulsant effects of both compounds 103 Dopamine D2 receptor partial agonist Edit Armodafinil the R enantiomer of modafinil was also subsequently found to act as a D2High receptor partial agonist 104 with a Ki of 16 nM an intrinsic activity of 48 and an EC50 of 120 nM in rat striatal tissue 79 Esmodafinil the S enantiomer of modafinil is inactive with respect to the D2 receptor 79 Modafinil has been found to directly inhibit the firing of midbrain dopaminergic neurons in the ventral tegmental area and substantia nigra of rats via activation of D2 receptors 105 However modafinil has also been reported not to interact with the human D2 receptor Ki gt 10 mM 75 Dampening of amygdala activity Edit Although modafinil enhances the efficiency of prefrontal cortical information processing there is also some human and mouse evidence to suggest that it conversely reduces amygdala activity both through direct fMRI observation and anxiety questionnaires 106 107 The amygdala is highly involved in fear processing and the dampening of its activity reduces perceptions of fear in response to environmental stress 108 At least one study has documented a statistically significant reduction in fear response in human subjects given 100 mg of modafinil daily for 7 days 106 However another study investigating the acute effects of modafinil on fear processing reported an increase in amygdala responses to fearful faces after administration of 600 mg of modafinil in human subjects 109 Modafinil s effects on fear processing are unique from classical psychostimulants such as those based on amphetamine phenethylamines which can generate fear and anxiety at high doses 110 Other actions Edit An in vitro study predicts that modafinil may induce the cytochrome P450 enzymes CYP1A2 CYP3A4 and CYP2B6 as well as may inhibit CYP2C9 and CYP2C19 8 However an in vitro studies find no significant inhibition of CYP2C9 7 111 It may also induce P glycoprotein which may affect drugs transported by P glycoprotein such as digoxin 112 Pharmacokinetics Edit Cmax peak levels occurs approximately 2 to 3 hours after administration Food slows absorption but does not affect the total AUC In vitro measurements indicate that 60 of modafinil is bound to plasma proteins at clinical concentrations of the drug This percentage changes very little when the concentration of modafinil is varied 113 Renal excretion of unchanged modafinil accounts for less than 10 of an oral dose 7 The two major circulating metabolites of modafinil are modafinil acid CRL 40467 and modafinil sulfone CRL 41056 114 7 Both of these metabolites have been described as inactive 115 and neither appear to contribute to the wakefulness promoting effects of modafinil 114 7 116 However modafinil sulfone does appear to possess anticonvulsant effects a property that it shares with modafinil 103 Elimination half life is generally in the range of 10 to 12 hours subject to differences in CYP genotypes liver function and renal function It is metabolized in the liver and its inactive metabolite is excreted in the urine Urinary excretion of the unchanged drug ranges from 0 to as high as 18 7 depending on various factors 113 Chemistry EditEnantiomers Edit Armodafinil R modafinil Esmodafinil S modafinil Modafinil is a racemic mixture of two enantiomers armodafinil R modafinil and esmodafinil S modafinil 78 117 Detection in body fluids Edit 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 Instrumental techniques involving gas or liquid chromatography are usually employed for these purposes 118 119 As of 2011 it is not specifically tested for by common drug screens except for anti doping screens and is unlikely to cause false positives for other chemically unrelated drugs such as substituted amphetamines 78 Reagent testing can be used to screen for the presence of modafinil in samples Colors produced by modafinil with various reagents RC Marquis Reagent Liebermann FroehdeModafinil Yellow Orange gt Brown 120 121 Darkening Orange 120 Deep orange red 121 Structural analogues Edit Many derivatives and structural analogues of modafinil have been synthesized and studied 99 122 91 Examples of these analogues include adrafinil CE 123 fladrafinil CRL 40941 fluorafinil flmodafinil CRL 40940 bisfluoromodafinil lauflumide and modafinil sulfone CRL 41056 123 History EditModafinil was originally developed in France by neurophysiologist professor Michel Jouvet and Lafon Laboratories Modafinil originated with the 1970s invention of a series of benzhydryl sulfinyl compounds including adrafinil which was first offered as an experimental treatment for narcolepsy in France in 1986 15 Modafinil is the primary metabolite of adrafinil lacking the polar OH group on its terminal amide 124 and has similar activity to the parent drug but is much more widely used citation needed It has been prescribed in France since 1994 under the name Modiodal 15 and in the US since 1998 as Provigil In 1998 modafinil was approved by the U S Food and Drug Administration 125 for the treatment of narcolepsy and in 2003 for shift work sleep disorder and obstructive sleep apnea hypopnea 126 even though caffeine and amphetamine were shown to be more wakefulness promoting on the Stanford Sleepiness Test Score than modafinil 81 It was approved for use in the UK in December 2002 Modafinil is marketed in the United States by Cephalon who originally leased the rights from Lafon but eventually purchased the company in 2001 Cephalon began to market armodafinil the R enantiomer of modafinil in the United States in 2007 After protracted patent litigation and negotiations see below generic versions of modafinil became available in the US in 2012 Patent protection and litigation Edit U S Patent 4 927 855 was issued to Laboratoire L Lafon on May 22 1990 covering the chemical compound modafinil After receiving an interim term extension of 1066 days and pediatric exclusivity of six months it expired on October 22 2010 On October 6 1994 Cephalon filed an additional patent covering modafinil in the form of particles of defined size That patent U S Patent 5 618 845 was issued on April 8 1997 It was reissued in 2002 as RE 37 516 which surrendered the 5618845 patent With pediatric exclusivity this patent expired on April 6 2015 127 128 On December 24 2002 anticipating the expiration of exclusive marketing rights generic drug manufacturers Mylan Teva Barr and Ranbaxy applied to the FDA to market a generic form of modafinil 129 At least one withdrew its application after early opposition by Cephalon based on the RE 37 516 patent There is some question of whether a particle size patent is sufficient protection against the manufacture of generics Pertinent questions include whether modafinil may be modified or manufactured to avoid the granularities specified in the new Cephalon patent and whether patenting particle size is invalid because particles of appropriate sizes are likely to be obvious to practitioners skilled in the art However under United States patent law a patent is entitled to a legal presumption of validity meaning that in order to invalidate the patent much more than pertinent questions are required As of October 31 2011 U S Reissue Patent No RE 37 516 has been declared invalid and unenforceable 130 The District Court for the Eastern District of Pennsylvania ruled that RE 37 516 was invalid because it 1 was on sale more than one year prior to the date of the application in violation of 35 U S C section 102 b 2 was actually invented by someone else the French company Laboratoire L Lafon 3 was obvious at the time the invention was made to a person having ordinary skill in the art under 35 U S C section 103 a and 4 failed the written description requirement of 35 U S C section 112 131 The patent was also found to be unenforceable due to Cephalon s inequitable conduct during patent prosecution 131 Cephalon made an agreement with four major generics manufacturers Teva Barr Pharmaceuticals Ranbaxy Laboratories and Watson Pharmaceuticals between 2005 and 2006 to delay sales of generic modafinil in the US until April 2012 by these companies in exchange for upfront and royalty payments 132 Litigation arising from these agreements is still pending including an FTC suit filed in April 2008 133 Apotex received regulatory approval in Canada despite a suit from Cephalon s marketing partner in Canada Shire Pharmaceuticals 134 135 Cephalon has sued Apotex in the US to prevent it from releasing a genericized armodafinil Nuvigil 136 Cephalon s 2011 attempt to merge with Teva was approved by the FTC under a number of conditions including granting generic US rights to another company 137 ultimately Par Pharmaceutical acquired the US modafinil rights as well as some others 138 In the United Kingdom Mylan Inc received regulatory approval to sell generic modafinil produced by Orchid in January 2010 Cephalon sued to prevent sale but lost the patent trial in November 139 Society and culture EditBrand names Edit Modafinil is sold under a wide variety of brand names worldwide including Alertec Alertex Altasomil Aspendos Forcilin Intensit Mentix Modafinil Modafinilo Modalert Modanil Modasomil Modvigil Modiodal Modiwake Movigil Provigil Resotyl Stavigile Vigia Vigicer Vigil Vigimax Wakelert and Zalux 140 Legal status Edit Australia Edit In Australia modafinil is considered to be a Schedule 4 prescription only medicine or prescription animal remedy 141 Schedule 4 is defined as Substances the use or supply of which should be by or on the order of persons permitted by State or Territory legislation to prescribe and should be available from a pharmacist on prescription Canada Edit In Canada modafinil is not listed in the Controlled Drugs and Substances Act but it is a Schedule F prescription drug 142 so it is subject to seizure by Canada Border Services Agency China Edit In mainland China modafinil is strictly controlled like other stimulants such as amphetamines and methylphenidate It has been classified as Class I psychotropic drug 143 meaning that only doctors who have the right to prescribe narcotics and Class I psychotropic drugs usually through special examination can prescribe it for no more than three day use or seven day use for control extend release products 144 The first and only modafinil products was approved in November 2017 145 but its marketing status in mainland China is still unknown Japan Edit In Japan modafinil is Schedule I psychotropic drug 146 147 Cephalon has licensed Alfresa Corporation to produce and Mitsubishi Tanabe Pharma to sell modafinil products under the trade name Modiodal in Japan 148 Also there have been reported arrests of people who imported modafinil for personal use 149 150 Romania Edit Modafinil is considered a stimulant doping agent and as such is prohibited in sports competitions in the same category as steroids 151 Due to new laws passed in 2022 import into the country or selling is considered a felony and can be punished with jail time from 3 years to 7 years 152 Simple possession for personal use is still punished with just a fine and confiscation Russia Edit In Russia modafinil is Schedule II controlled substance like cocaine and morphine Possession of few modafinil pills can lead to 3 10 years imprisonment 153 Sweden Edit In Sweden modafinil is classified as a schedule IV substance and possession is therefore illegal without prescription 154 United States Edit Modafinil is currently update classified as a Schedule IV controlled substance under United States federal law it is illegal to import by anyone other than a DEA registered importer without a prescription 155 The Clinton administration issued regulations in 64 FR 4050 effective 27 January 1999 based upon a recommendation of the administration s Assistant Secretary for Health 156 However one may legally bring modafinil into the United States in person from a foreign country provided that he or she has a prescription for it and the drug is properly declared at the border crossing U S residents are limited to 50 dosage units e g pills 157 Under the US Pure Food and Drug Act drug companies are not allowed to market their drugs for off label uses conditions other than those officially approved by the FDA 158 Cephalon was reprimanded in 2002 by the FDA because its promotional materials were found to be false lacking in fair balance or otherwise misleading 159 Cephalon pleaded guilty to a criminal violation and paid several fines including 50 million and 425 million fines to the U S government in 2008 160 161 Other countries Edit The following countries do not classify modafinil as a controlled substance In Finland modafinil is a prescription drug but not listed as a controlled substance 162 In Denmark modafinil is a prescription drug but not listed as a controlled substance 163 Mexico Not listed as a controlled substance in the National Health Law Can be purchased in pharmacies without prescription 164 South Africa Schedule V 165 United Kingdom not listed in Misuse of Drugs Act so possession not illegal but prescription required 166 Sports use and issues EditThe regulation of modafinil as a doping agent has been controversial in the sporting world with high profile cases attracting press coverage since several prominent American athletes have tested positive for the substance Some athletes who were found to have used modafinil protested that the drug was not on the prohibited list at the time of their offenses 167 However the World Anti Doping Agency WADA maintains that it 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 the 2004 Summer Olympics Modafinil has received some publicity in the past when several athletes such as sprinter Kelli White in 2004 cyclist David Clinger 168 and basketball player Diana Taurasi 169 in 2010 and rower Timothy Grant in 2015 170 were accused of using it as a performance enhancing doping agent Taurasi and another player Monique Coker tested at the same lab were later cleared 171 It is not clear how widespread this practice is The BALCO scandal brought to light an as yet unsubstantiated but widely published account of Major League Baseball s all time leading home run hitter Barry Bonds supplemental chemical regimen that included modafinil in addition to anabolic steroids and human growth hormone 172 Modafinil has been shown to prolong exercise time to exhaustion while performing at 85 of VO2max and also reduces the perception of effort required to maintain this threshold 173 Modafinil was added to the World Anti Doping Agency Prohibited List in 2004 as a prohibited stimulant see Modafinil Legal Status Research EditPsychiatric conditions Edit Major depression Edit Modafinil has been studied in the treatment of major depressive disorder 174 175 176 177 178 179 180 181 In a 2021 systematic review and meta analysis of randomized controlled trials of psychostimulants for depression modafinil and other stimulants such as methylphenidate and amphetamines improved depression in traditional meta analysis 181 However when subjected to network meta analysis modafinil and most other stimulants did not significantly improve depression with only methylphenidate remaining effective 181 Modafinil and other stimulants likewise did not improve quality of life in the meta analysis although there was evidence for reduced fatigue and sleepiness with modafinil and other stimulants 181 While significant effectiveness of modafinil for depression has been reported 175 177 180 reviews and meta analyses note that the effectiveness of modafinil for depression is limited the quality of available evidence is low and more research is needed 174 176 178 181 Bipolar depression Edit Modafinil and armodafinil have been repurposed as adjunctive treatments for acute depression in people with bipolar disorder 104 A 2021 meta analysis found 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 has to be considered low limiting the clinical relevance of current evidence 104 Very low rates of mood switch have been observed with modafinil and armodafinil in bipolar disorder 177 Attention deficit hyperactivity disorder Edit Modafinil has been studied and reported to be effective in the treatment of attention deficit hyperactivity disorder ADHD with significantly less abuse potential than conventional psychostimulants like methylphenidate and amphetamines 182 183 In the United States an application to market modafinil for pediatric ADHD was submitted to the FDA 55 However approval was denied due to concerns about rare but serious dermatological toxicity specifically the occurrence of Stevens Johnson syndrome 55 In any case modafinil may be used off label to treat ADHD in both children and adults 184 182 185 However evidence of modafinil for treatment of adult ADHD is mixed and a 2016 systematic review of alternative drug therapies for adult ADHD could not recommend its use in this context 186 In a large phase 3 clinical trial of modafinil for adult ADHD modafinil was not effective in improving symptoms and there was a high rate of side effects 86 and discontinuation 47 187 The poor tolerability of modafinil in this study was possibly due to the use of excessively high doses 210 510 mg day 187 Substance dependence Edit Modafinil has been studied for the treatment of stimulant dependence 184 55 188 98 66 99 189 Schizophrenia Edit Modafinil and armodafinil have been studied as a complement to antipsychotic medications in the treatment of schizophrenia They have been consistently shown to have no effect on positive symptoms or cognitive performance 190 191 A 2015 meta analysis found that modafinil and armodafinil may slightly reduce negative symptoms in people with acute schizophrenia though it does not appear useful for people with the condition who are stable with high negative symptom scores 191 Among medications demonstrated to be effective for reducing negative symptoms in combination with anti psychotics modafinil and armodafinil are among the smallest effect sizes 192 Cognitive enhancement Edit A 2015 review of clinical studies of possible nootropic effects in healthy people found whilst most studies employing basic testing paradigms show that modafinil intake enhances executive function only half show improvements in attention and learning and memory and a few even report impairments in divergent creative thinking In contrast when more complex assessments are used modafinil appears to consistently engender enhancement of attention executive functions and learning Importantly we did not observe any preponderances for side effects or mood changes 12 A 2019 review of studies of a single dose of modafinil on mental function in healthy non sleep deprived people found a statistically significant but small effect and concluded that the drug has limited usefulness as a cognitive enhancer in non sleep deprived persons 11 A 2020 review of the cognitive enhancing potential of methylphenidate d amphetamine and modafinil in healthy individuals across various domains found that modafinil has a small positive effect on memory updating 193 Modafinil has been used off label in trials with people with symptoms of post chemotherapy cognitive impairment also known as chemobrain but a 2011 review found that it was no better than placebo 194 As of 2015 it had been studied for use in multiple sclerosis associated fatigue but the resulting evidence was weak and inconclusive 195 Post anesthesia sedation Edit General anesthesia is required for many surgeries but there may be lingering fatigue sedation and or drowsiness after surgery has ended that lasts for hours to days In outpatient settings wherein patients are discharged home after surgery this sedation fatigue and occasional dizziness is problematic As of 2006 modafinil had been tested and reported to be effective in one small N 34 double blind randomized controlled trial for this use 184 Fatigue Edit Research on using modafinil to reduce multiple sclerosis MS fatigue has been inconclusive 196 197 Postural orthostatic tachycardia syndrome Edit However caution should be exercised in patients who have narcolepsy in comorbidity with postural orthostatic tachycardia syndrome POTS Therefore there are potential warnings for a class of drugs used to treat narcolepsy Centrally acting stimulants like modafinil are often considered first line drugs for narcolepsy However modafinil stimulation increases POTS related autonomic dysfunction and results in tachycardia arrhythmia side effects in patients with cardiovascular risk factors Sodium oxybate a metabolite of GABA is an alternative drug for stimulant intolerant patients Therefore there is a potential for reconsidering the safety and use of stimulants such as modafinil as first line therapy in patients with cardiac diseases such as POTS and arrhythmias 198 References Edit a b c Mignot EJ October 2012 A practical guide to the therapy of narcolepsy and hypersomnia syndromes Neurotherapeutics 9 4 739 752 doi 10 1007 s13311 012 0150 9 PMC 3480574 PMID 23065655 Because of the relatively low risk of addiction modafinil can be more easily prescribed in patients without a clear biochemically defined central hypersomnia syndrome and is also easier to stop if needed It is also a schedule IV compound Krishnan R Chary KV 2015 A rare case modafinil dependence Journal of Pharmacology amp 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July 4 2012 Document 514 APOTEX INC v CEPHALON INC et al Pennsylvania Eastern District Court US Federal District Courts Cases Justia October 31 2010 Retrieved July 4 2012 a b Document 513 APOTEX INC v CEPHALON INC et al Pennsylvania Eastern District Court US Federal District Courts Cases Justia October 31 2010 Retrieved July 4 2012 Cephalon Inc SEC 10K 2008 disclosure February 23 2009 pp 9 10 Retrieved August 29 2009 CVS Rite Aid Sue Cephalon Over Generic Provigil Bloomberg News August 21 2009 Retrieved August 29 2009 Canada IP Year in Review 2008 January 1 2009 Shire v Canada Archived from the original on April 24 2010 Retrieved August 29 2009 Cephalon Sues Apotex Zacks com August 20 2010 Archived from the original on March 5 2012 Retrieved July 4 2012 U S Federal Trade Commission Clears Teva s Acquisition of Cephalon Business Wire October 7 2011 Archived from the original on April 18 2016 Retrieved March 11 2013 Teva will also grant non exclusive U S rights to an undisclosed company 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doi 10 1002 14651858 CD006788 pub3 PMC 6483317 PMID 26026155 Kraft GH Bowen J December 2005 Modafinil for fatigue in MS a randomized placebo controlled double blind study Neurology 65 12 1995 1997 doi 10 1212 01 wnl 0000200985 04239 53 PMID 16380634 S2CID 46704293 Nourbakhsh B Revirajan N Morris B Cordano C Creasman J Manguinao M et al January 2021 Safety and efficacy of amantadine modafinil and methylphenidate for fatigue in multiple sclerosis a randomised placebo controlled crossover double blind trial The Lancet Neurology 20 1 38 48 doi 10 1016 S1474 4422 20 30354 9 PMC 7772747 PMID 33242419 Kim H Ayele GM Atalay RT Hussien S Tewoldemedhin B Michael MB Scharf SM July 2022 What Works for One May Not Work for Another A New Warning for Modafinil Cureus 14 7 e27287 doi 10 7759 cureus 27287 PMC 9413809 PMID 36043022 External links EditRxList Patient Information for modafinil users Modafinil Drug Information Portal U S National Library of Medicine Retrieved from https en wikipedia org w 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