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Modafinil, sold under the brand name Provigil among others, is a wakefulness-promoting drug used for treatment of disorders such as narcolepsy, shift work sleep disorder, idiopathic hypersomnia, and excessive daytime sleepiness associated with obstructive sleep apnea.[6] It has also seen widespread off-label use as a purported cognitive enhancer.[7] In the United States modafinil is classified as a schedule IV controlled substance and restricted in availability and usage, due to concerns about possible addiction potential. In most other countries it is a prescription drug but not otherwise legally restricted.

Modafinil
Modafinil enantiomers.svg
(R)-(−)-modafinil (armodafinil; top)
(S)-(+)-modafinil (bottom)
Clinical data
Trade names Provigil, Alertec, Modavigil, others
Synonyms CRL-40476; Diphenylmethylsulfinylacetamide
AHFS/Drugs.com Monograph
MedlinePlus a602016
License data
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Dependence
liability
Psychological: Very low[1]
Physical: Negligible[1]
Addiction
liability
Very low to low[2]
Routes of
administration
Oral (tablets)
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability Not determined due to the aqueous insolubility
Protein binding 62%
Metabolism Hepatic (primarily via amide hydrolysis;[3] CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5 involved [4]
Biological half-life 15 hours (R-enantiomer),
4 hours (S-enantiomer)[5]
Excretion Urine (80%)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.168.719
Chemical and physical data
Formula C15H15NO2S
Molar mass 273.35 g/mol
3D model (JSmol)
  (verify)

Modafinil acts as an atypical, selective, and weak dopamine reuptake inhibitor which indirectly activates the release of orexin neuropeptides and histamine from the lateral hypothalamus and tuberomammillary nucleus, respectively, by unknown mechanisms, all of which contribute to heightened arousal.[8][9][10]

Contents

UsesEdit

 
Modafinil tablets - Modalert 200

MedicalEdit

Modafinil is a eugeroic used for treatment of narcolepsy, shift work sleep disorder, and excessive daytime sleepiness associated with obstructive sleep apnea.[6][11][12][13]

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 only be to treat sleepiness associated with narcolepsy.[14]

Occupational useEdit

Armed forces of several countries are known to 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.[citation needed] The United Kingdom's Ministry of Defence commissioned research into modafinil[15] from QinetiQ and spent £300,000 on one investigation.[16] In 2011, the Indian Air Force announced that modafinil was included in contingency plans.[17]

In the United States military, modafinil has been approved for use on certain Air Force missions, and it is being investigated for other uses.[18] As of November 2012, modafinil is the only drug approved by the Air Force as a "go pill" for fatigue management.[19] The use of dextroamphetamine is no longer approved.[19]

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.[20]

ContraindicationsEdit

Allergy and hypersensitivity are the only contraindications of the drug,[21] but literature distributed by Cephalon advises that it is important to consult a physician before using it, as problems may arise for people who are sensitive to constituents of the tablets, people with cirrhosis (which may impair the metabolism of the drug), and people with various cardiovascular problems.[citation needed]

Adverse effectsEdit

According to documentation distributed by Teva Pharmaceuticals, one-third of participants in clinical trials reported experiencing headaches; 11% reported nausea; other negative side-effects such as nervousness, diarrhea, insomnia, anxiety, dizziness, and gastrointestinal problems were reported by fewer than 10% of participants.[22]

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.[23] 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.[24]

Modafinil may have an adverse effect on hormonal contraceptives for up to a month after discontinuation.[25]

Addiction and dependence potentialEdit

The addiction and dependence liabilities of modafinil are very low.[1][2][26] 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.[26] Monkeys will self-administer modafinil if they have previously been trained to self-administer cocaine.[26] Although modafinil does not produce reinforcing effects in mice at doses that are equivalent to those used therapeutically in humans, it does do so at higher doses.[27][28] In accordance, although very rare, case reports of modafinil abuse exist.[29][30] As such, modafinil is classified by the United States FDA as a schedule IV controlled substance, a category for drugs with valid medical uses and low but significant addiction potential.[2][31]

Psychological dependence upon modafinil has only been noted in case reports involving daily overdoses on modafinil for an extended period of time.[1] Reported withdrawal symptoms include anhedonia, lethargy, anxiety, and insomnia.[1]

ToleranceEdit

Large-scale clinical studies have found no evidence of tolerance with modafinil at therapeutic dosages even with prolonged use (for 40 weeks and as long as three years).[32][33][34]

Psychiatric reactionsEdit

Modafinil-associated psychiatric reactions have occurred in those with and without a pre-existing psychiatric history.[35]

OverdoseEdit

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 1000–3400 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.[6] As of 2004, the FDA is not aware of any fatal overdoses involving modafinil alone (as opposed to multiple drugs including modafinil).[6]

InteractionsEdit

Coadministration with modafinil alongside opioids such as hydrocodone, oxycodone, and fentanyl, as well as various other drugs, may experience a drop in plasma concentrations. The reasoning behind this action is because modafinil is an inducer of the CYP3A4 enzymes. If not monitored closely, reduced efficacy or withdrawal symptoms can occur.[medical citation needed]

PharmacologyEdit

PharmacodynamicsEdit

As of 2017, the therapeutic mechanism of action of modafinil for narcolepsy and sleep-wake disorders remains unknown.[8][9]

Dopamine transporter blockerEdit

Research found that modafinil elevates histamine levels in the hypothalamus in animals.[36] 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,[37][38] norepinephrine in the hypothalamus and ventrolateral preoptic nucleus,[39][40] and serotonin in the amygdala and frontal cortex.[41] Modafinil was screened at a large panel of receptors and transporters in an attempt to elucidate its pharmacology.[42] 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.[42] Subsequently, it was determined that modafinil binds to the same site on the DAT as cocaine, but in a different manner.[43][44] In accordance, modafinil increases locomotor activity and extracellular dopamine concentrations in animals in a manner similar to the selective DRI vanoxerine (GBR-12909),[45] 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".[46] 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".[47] 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.[48]

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.[49][50] For instance, modafinil produces wakefulness reportedly without the need for compensatory sleep, and shows a relatively low, if any,[51] potential for abuse.[46][49][50] Aside from modafinil, examples of other atypical DAT inhibitors include vanoxerine and benztropine, which have a relatively low abuse potential similarly to modafinil.[49] These drugs appear to interact molecularly with the DAT in a distinct way relative to "conventional" DAT blockers such as cocaine and methylphenidate.[44][49]

DAT-independent actionsEdit

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.[52] In addition, modafinil fails to reverse reserpine-induced akinesia, whereas dextroamphetamine, a dopamine releasing agent (DRA), is able to do so.[53] 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, and a variety of analogues without any significant inhibition of the DAT still produced wakefulness-promoting effects.[54] 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",[51] and a 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.[36] As such, 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 (i.e., may also include DAT-independent actions, such as "activation of the orexin system").[43][51]

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 it is important to note that DAT knockout mice show D1 and D2 receptor and norepinephrine compensatory abnormalities, which might confound this finding), reduced by both D1 and D2 receptor antagonists (although conflicting reports exist),[53] and completely blocked by simultaneous inactivation of both D1 and D2 receptors.[46] 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.[50] 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).[50]

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.[55] 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.[55]

D2 receptor partial agonistEdit

The (R)-(−)-enantiomer of modafinil, known as armodafinil, was also subsequently found to act as a D2High receptor partial agonist, with a Ki of 16 nM, an intrinsic activity of 48%, and an EC50 of 120 nM, in rat striatal tissue.[56] The (S)-enantiomer is inactive with respect to the D2 receptor.[56] 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.[57]

MiscellaneousEdit

Modafinil's efficacy in improving vigor and well-being in sleep deprivation subjects is dependent on catechol-O-methyl transferase (COMT) status.[58] Research suggests that individuals with the Val/Val genotype experience a great improvement in their cognitive function, while those with the Met/Met allele experience very little improvement.[58]

PharmacokineticsEdit

Modafinil induces the cytochrome P450 enzymes CYP1A2, CYP3A4, and CYP2B6, as well as inhibiting CYP2C9 and CYP2C19 in vitro.[4] It may also induce P-glycoprotein (Pgp), which may affect drugs transported by Pgp, such as digoxin.[citation needed] The bioavailability of modafinil is greater than 80% of the administered dose. In vitro measurements indicate that 60% of modafinil is bound to plasma proteins at clinical concentrations of the drug. This percentage actually changes very little when the concentration is varied.[59] Cmax (peak levels) occurs approximately 2–3 hours after administration. Food slows absorption, but does not affect the total AUC[clarification needed](AUC – area under the curve – meaning, food may slow absorption, but the total amount of the chemical will be absorbed with or without food). Half-life is generally in the 10–12 hour range, 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.[59]

The two major circulating metabolites of modafinil are modafinil acid (CRL-40467) and modafinil sulfone (CRL-41056).[60][3] Both of these metabolites have been described as inactive,[61] and neither appear to contribute to the wakefulness-promoting effects of modafinil.[60][3][62] However, modafinil sulfone does appear to possess anticonvulsant effects, and this is a property that it shares with modafinil.[55]

ChemistryEdit

The (R)-(−)-enantiomer of modafinil[63]
The S-(+)-enantiomer of modafinil[63]

Measurement in body fluidsEdit

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.[64][65] 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.[66]

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[67][68] Darkening Orange[67] Deep orange/red[68]

Structural analogsEdit

Modafinil is a highly researched compound, with many derivatives created and studied, some examples and their differences between dopamine, serotonin & norepinephrine affect is given in bundled table form below.

Pharmacology of modafinil's structural analogs
Modafinil analogs and their effects on the central nervous system.[69]
Structure X1 X2 NR1R2 Action on CNS
 
H H NHCH3 Stimulating
H H NHCH(CH3)2 Stimulating
H H NHC(CH3)3 Stimulating
H H NHCH2CH3 Sedative
H H Piperidine Sedative
H H Morfoline Sedative
4-Cl H NH2 Stimulating
4-F 4-F NH2 Stimulating
4-F H NH2 Stimulating
Thio- & Sulfinylacetamide Modafinil analogs[44]
Structure X
(di-benzene substitutions)
Y
(CH2 substitution)
R
(N-methyl terminating substitution)
Ki [SE interval] (nM)
@ DAT
Ki [SE interval] (nM)
@ SERT
Ki [SE interval] (nM)
@ NET
Modafinil H S=O H 2600 (2430—2780) inactive inactive
 
H S H 12400 (10800—14300) 14500 (11800—17700) inactive
derived as
285000 (117000—690000)
3,3′-di-Cl S H 275 (257—295) inactive
derived as
808000 (706000—924000)
45400 (39600—52000)
H S CH3 19300 (17900—20800) inactive
derived as
656000 (302000—1420000)
27200 (25700—28900)
4,4′-di-Cl S CH3 4130 (3620—4710) 10700 (7310—15700) 9770 (9170—10400)
4,4′-di-Br S CH3 3010 (2770—3260) 5720 (5320—6150) 11000 (9540—12600)
H S allyl 8370 (6680—10500) inactive
derived as
303000 (267000—344000)
inactive
derived as
171000 (88300—332000)
H S n-propyl 20700 (20300—21100) inactive
derived as
419000 (240000—729000)
68000 (53200—86900)
4,4′-di-F S n-propyl 11700 (10300—13200) 44200 (38700—50500) 59700 (51200—69600)
4,4′-di-Cl S n-propyl 1240 (1120—1380) 10100 (8900—11400) 7540 (6830—8330)
4,4′-di-Br S n-propyl 590 (550—632) 8900 (8150—9720) 10600 (9980—11300)
H S cyclopropylmethyl 13600 (11900—15600) 20500 (17500—23900) inactive
4,4′-di-F S cyclopropylmethyl 6700 (5730—7830) 34000 (28800—40200) 57000 (51500—63000)
4,4′-di-Br S cyclopropylmethyl 975 (852—1110) 7030 (6040—8180) inactive
H S n-butyl 23600 (20500—27100) inactive inactive
4,4′-di-F S n-butyl 6400 (5820—7050) 25500 (23300—28000) 56100 (53900—58500)
4,4′-di-Br S n-butyl 722 (659—792) 7090 (6990—8180) 7580 (7210—7970)
H S 3-phenylpropyl 2020 (1990—2050) inactive inactive
4,4′-di-F S 3-phenylpropyl 442 (385—509) 3500 (2950—4160) inactive
4,4′-di-Cl S 3-phenylpropyl 223 (191—260) inactive inactive
4,4′-di-Br S 3-phenylpropyl 238 (202—280) 60700 (58400—63200) 35500 (31700—39800)
H S 4-phenylbutyl 1150 (1020—1290) inactive 7960 (7590—8350)
4,4′-di-Br S 4-phenylbutyl 405 (348—471) inactive inactive
4,4′-di-CH3 S=O H 12700 (12400—13100) inactive inactive
4,4′-di-CF3 S=O H 35400 (34100—36700) not tested not tested
3,3′-di-F S=O H 5930 (4990—7060) inactive inactive
3,3′-di-Cl S=O H 881 (763—1020) inactive inactive
H, 3-Br S=O H 550 (542—557) inactive inactive
H S=O CH3 13100 (12600—13700) inactive inactive
4,4′-di-Br S=O 3-phenylpropyl 1280 (1160—1400) 892 (787—1010) inactive
4,4′-di-Cl S H 2200 (2060—2390) 38800 (36400—41300) 51400 (46000—57500)

HistoryEdit

Modafinil was originally developed in France by neurophysiologist and emeritus experimental medicine professor Michel Jouvet and Lafon Laboratories. Modafinil originated with the late 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. Modafinil is the primary metabolite of adrafinil, lacking the polar -OH group on its terminal amide,[70] and has similar activity to the parent drug but is much more widely used. It has been prescribed in France since 1994 under the name Modiodal, and in the US since 1998 as Provigil.

In 1998, modafinil was approved by the U.S. Food and Drug Administration[71] for the treatment of narcolepsy and in 2003 for shift work sleep disorder and obstructive sleep apnea/hypopnea[72] even though caffeine and amphetamine were shown to be more wakefulness promoting on the Stanford Sleepiness Test Score than modafinil.[9]

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

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

Patent protection and antitrust litigationEdit

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, but was reissued in 2002 as RE 37,516, which surrendered the 5618845 patent. With pediatric exclusivity, this patent expired on April 6, 2015.[73][74]

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.[75] At least one withdrew its application after early opposition by Cephalon based on the '516 patent. There is some question 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.[76] 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.[77] The patent was also found to be unenforceable due to Cephalon's inequitable conduct during patent prosecution.[77]

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.[78] Litigation arising from these agreements is still pending including an FTC suit filed in April 2008.[79] Apotex received regulatory approval in Canada despite a suit from Cephalon's marketing partner in Canada, Shire Pharmaceuticals.[80][81] Cephalon has sued Apotex in the US to prevent it from releasing a genericized armodafinil (Nuvigil).[82] 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;[83] ultimately, Par Pharmaceutical acquired the US modafinil rights as well as some others.[84]

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.[85]

Society and cultureEdit

Legal statusEdit

United StatesEdit

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.[86] 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).[87] 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);[88] Cephalon was reprimanded in 2002 by the FDA because its promotional materials were found to be "false, lacking in fair balance, or otherwise misleading".[89] 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.[90][91]

ChinaEdit

In mainland China, modafinil is strictly controlled like other stimulants, such as amphetamines and methylphenidate, and not approved for medical use.[92]

JapanEdit

In Japan, modafinil is Schedule I psychotropic drug.[93][94] There have been reported arrests of people who imported modafinil for personal use.[95][96]

RussiaEdit

In Russia modafinil is Schedule II controlled substance like cocaine and morphine. Possession of few modafinil pills can lead to 3–10 years imprisonment.[97]

Other countriesEdit

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

Brand namesEdit

Modafinil is sold under a wide variety of brand names worldwide, including Alertec, Alertex, Altasomil, Aspendos, Forcilin, Intensit, Mentix, Modafinil, Modafinilo, Modanil, Modasomil, Modavigil, Modiodal, Modiwake, Movigil, Provigil, Resotyl, Stavigile, Vigia, Vigicer, Vigil, Vigimax, and Zalux.[104]

Doping agentEdit

SportsEdit

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. 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[105] and basketball player Diana Taurasi[106] in 2010, and rower Timothy Grant in 2015[107]) were discovered allegedly using it as a performance-enhancing doping agent. (Taurasi and another player, Monique Coker, tested at the same lab, were later cleared.[108]) 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.[109] 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.[110] Modafinil was added to the World Anti-Doping Agency "Prohibited List" in 2004 as a prohibited stimulant (see Modafinil Legal Status).

NootropicEdit

Modafinil has been used non-medically as a "smart drug" by students, office workers, soldiers and transhumanists.[111][112][113][114][115] It is often compared to the fictional smart drug NZT-48 depicted in Limitless and sometimes called "the 'Limitless' pill".[116][117][118][119]

ResearchEdit

ADHDEdit

In the United States, an application to market modafinil for pediatric ADHD was submitted to the FDA, but approval was denied due to major concerns over the occurrence of Stevens-Johnson Syndrome in clinical trials.[120]

SchizophreniaEdit

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.[121][122] 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.[122] Among medications demonstrated to be effective for reducing negative symptoms in combination with anti-psychotics, modafinil and armodafinil are among the smallest effect sizes.[123]

Weight lossEdit

The prescribing information for Provigil notes that "There were no clinically significant differences in body weight change in patients treated with Provigil compared to placebo-treated patients in the placebo-controlled clinical trials."[124]

Cognitive enhancementEdit

A 2015 review of clinical studies of possible nootropic effects in healthy people found that there were little to no effects when simple testing methods were used, except for a possible effect on executive function, but in more complex tests, modafinil appeared to also improve executive function, attention, learning, and memory. Some studies found decreases in certain cognitive functions but there was no consistent negative effect. There was generally no effect on mood.[13]

Post-chemotherapy cognitive impairmentEdit

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.[125] As of 2015 it had been studied for use in multiple sclerosis associated fatigue, but the resulting evidence was weak and inconclusive.[126]

See alsoEdit

ReferencesEdit

  1. ^ a b c d e Case reports:
     • Krishnan R, Chary KV (March 2015). "A rare case modafinil dependence". Journal of Pharmacology & Pharmacotherapeutics. 6 (1): 49–50. doi:10.4103/0976-500X.149149. PMC 4319252 . PMID 25709356. He claimed to have symptoms of worsening of lethargy, tremors of hands, anxiety and erratic sleep hours when he skipped modafinil, patient reported a sense of well-being only with the drug and with the above dose [(1200mg/day)]. ... He reported sleep disturbance, increased sense of body warmth, lethargy and low mood during the process of tapering the drug. Low dose of clonazepam was added to reduce the withdrawal symptoms. 
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