Modafinil: Difference between revisions

{{Use mdy dates|date=October 2015}}

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 417919748

| image = Modafinil enantiomers.svg

| width = 185

| caption = (''R'')-(−)-modafinil ({{w|armodafinil}}; top)<br />(''S'')-(+)-modafinil (bottom)

<!--Clinical data-->

| IUPAC_name = 2-[(diphenylmethyl)sulfinul]acetamide

| tradename = Provigil, others (see below)

| Drugs.com = {{drugs.com|monograph|modafinil}}

| licence_US = Modafinil

| MedlinePlus = a602016

| pregnancy_AU = B3

| pregnancy_US = C

| legal_AU = S4

| legal_CA = <!-- Schedule F not a CA schedule name -->

| legal_UK = POM

| legal_US = Schedule IV

| dependency_liability = [[Psychological dependence|Psychological]]: Very low<ref name="Withdrawal case reports">Case reports:<br />{{•}}{{cite journal | vauthors = Krishnan R, Chary KV | title = A rare case modafinil dependence | journal = Journal of Pharmacology & Pharmacotherapeutics | volume = 6 | issue = 1 | pages = 49–50 | date = March 2015 | pmid = 25709356 | pmc = 4319252 | doi = 10.4103/0976-500X.149149 | quote = 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)].&nbsp;... 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. }}<br />{{•}}{{cite journal | vauthors = Kate N, Grover S, Ghormode D | title = Dependence on supratherapeutic doses of modafinil: a case report | journal = The Primary Care Companion for CNS Disorders | volume = 14 | issue = 5 | year = 2012 | pmid = 23469316 | pmc = 3583757 | doi = 10.4088/PCC.11l01333 }}</ref><br />[[Physical dependence|Physical]]: Negligible<!--withdrawal from ~10x max therapeutic dosage involves "fine tremors"--><ref name="Withdrawal case reports" />

| addiction_liability = Very low to low<ref name="Addiction liability review">{{cite journal | vauthors = Mignot EJ | title = A practical guide to the therapy of narcolepsy and hypersomnia syndromes | journal = Neurotherapeutics | volume = 9 | issue = 4 | pages = 739–52 | date = Oct 2012 | pmid = 23065655 | pmc = 3480574 | doi = 10.1007/s13311-012-0150-9 | quote = 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. }}</ref>

| routes_of_administration = Oral ([[Tablet (pharmacy)|tablets]])

<!--Pharmacokinetic data-->

| bioavailability = Not determined due to the aqueous insolubility

| protein_bound = 62%

| metabolism = Hepatic (primarily via amide [[hydrolysis]];<ref name="pmid12537513">{{cite journal | vauthors = Robertson P, Hellriegel ET | title = Clinical pharmacokinetic profile of modafinil | journal = Clinical Pharmacokinetics | volume = 42 | issue = 2 | pages = 123–37 | year = 2003 | pmid = 12537513 | doi = 10.2165/00003088-200342020-00002 }}</ref> [[CYP1A2]], [[CYP2B6]], [[CYP2C9]], [[CYP2C19]], [[CYP3A4]], [[CYP3A5]] involved <ref name="pmid10820139">{{cite journal | vauthors = Robertson P, DeCory HH, Madan A, Parkinson A | title = In vitro inhibition and induction of human hepatic cytochrome P450 enzymes by modafinil | journal = Drug Metabolism and Disposition | volume = 28 | issue = 6 | pages = 664–71 | date = Jun 2000 | pmid = 10820139 | doi = }}</ref>

| elimination_half-life = 15 hours (''R''-enantiomer),<br />4 hours (''S''-enantiomer)<ref name="nuvigil.com">[http://www.nuvigil.com/PDF/Full_Prescribing_Information.pdf Nuvigil Prescribing Information]</ref>

| excretion = Urine (80%)

<!--Identifiers-->

| IUPHAR_ligand = 7555

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 68693-11-8

| ATC_prefix = N06

| ATC_suffix = BA07

| PubChem = 4236

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB00745

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 4088

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = R3UK8X3U3D

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = D01832

| ChEBI_Ref = {{ebicite|correct|EBI}}

| ChEBI = 31859

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 1373

| synonyms = CRL-40476; Diphenylmethylsulfinylacetamide

<!--Chemical data-->

| C=15 | H=15 | N=1 | O=2 | S=1

| molecular_weight = 273.35 g/mol

| smiles = O=S(C(c1ccccc1)c2ccccc2)CC(=O)N

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 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)

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = YFGHCGITMMYXAQ-UHFFFAOYSA-N

}}

'''Modafinil''' <!--([[International Nonproprietary Name|INN]]<ref>{{cite journal|title=International Nonproprietary Names for Pharmaceutical Substances. Recommended International Nonproprietary Names (Rec. INN): List 27|journal=WHO Drug Information|date=1987|volume=1|issue=4|page=7|url=http://www.who.int/medicines/publications/druginformation/innlists/RL27.pdf|accessdate=18 August 2016}}</ref>)--> is a [[eugeroic]] used for treatment of disorders such as [[narcolepsy]], [[shift work sleep disorder]], and [[excessive daytime sleepiness]] associated with [[obstructive sleep apnea]].<ref name="fda_label"/> It has also seen widespread [[off-label use]] as a purported [[nootropic]]. In English-speaking countries it is sold under the brand names '''Alertec''', '''Modavigil''', and '''Provigil'''. In the United States modafinil is classified as a [[Controlled Substances Act|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 acts as an atypical, selective, and weak [[dopamine reuptake inhibitor]] which indirectly activates the release of [[orexin]] [[neuropeptide]]s and [[histamine]] from the [[lateral hypothalamus]] and [[tuberomammillary nucleus]], respectively, by unknown mechanisms, all of which contribute to heightened arousal.<ref name="Stahl's Essential Psychopharmacology - Modafinil">{{cite book | vauthors=Stahl SM | title=Prescriber's Guide: Stahl's Essential Psychopharmacology | date=March 2017 | publisher=Cambridge University Press | location=Cambridge, United Kingdom | isbn=9781108228749 | pages=491–495 | edition=6th | chapter=Modafinil | accessdate=5 August 2017 }}</ref><ref name="pmid19300566">{{cite journal | vauthors = Gerrard P, Malcolm R | title = Mechanisms of modafinil: A review of current research | journal = Neuropsychiatric Disease and Treatment | volume = 3 | issue = 3 | pages = 349–64 | date = June 2007 | pmid = 19300566 | pmc = 2654794 | doi = | url = }}</ref><ref name="pmid22640618">{{cite journal | vauthors = Ishizuka T, Murotani T, Yamatodani A | title = Action of modafinil through histaminergic and orexinergic neurons | journal = Vitamins and Hormones | volume = 89 | issue = | pages = 259–278 | date = 2012 | pmid = 22640618 | doi = 10.1016/B978-0-12-394623-2.00014-7 | url = }}</ref>

{{TOC limit|3}}

== Uses ==

===Medical===

Modafinil is a [[eugeroic]] used for treatment of [[narcolepsy]], [[shift work sleep disorder]], and [[excessive daytime sleepiness]] associated with [[obstructive sleep apnea]].<ref name="fda_label">{{cite web |url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020717s037s038lbl.pdf | title=Provigil Prescribing Information |date=January 2015 |website=United States Food and Drug Administration |publisher=Teva Pharmaceuticals USA, Inc.|accessdate=July 18, 2015}}</ref><ref name=SleepAcademy2007>{{cite journal | vauthors = Morgenthaler TI, Lee-Chiong T, Alessi C, Friedman L, Aurora RN, Boehlecke B, Brown T, Chesson AL, Kapur V, Maganti R, Owens J, Pancer J, Swick TJ, Zak R | title = Practice parameters for the clinical evaluation and treatment of circadian rhythm sleep disorders. An American Academy of Sleep Medicine report | journal = Sleep | volume = 30 | issue = 11 | pages = 1445–59 | date = Nov 2007 | pmid = 18041479 | pmc = 2082098 | doi = }}</ref><ref name="pmid23385698">{{cite journal | vauthors = Zee PC, Attarian H, Videnovic A | title = Circadian rhythm abnormalities | journal = Continuum | volume = 19 | issue = 1 Sleep Disorders | pages = 132–47 | date = Feb 2013 | pmid = 23385698 | pmc = 3654533 | doi = 10.1212/01.CON.0000427209.21177.aa }}</ref><ref name=2015MetaRev>{{cite journal | vauthors = Battleday RM, Brem AK | title = Modafinil for cognitive neuroenhancement in healthy non-sleep-deprived subjects: A systematic review | journal = European Neuropsychopharmacology | volume = 25 | issue = 11 | pages = 1865–81 | date = Nov 2015 | pmid = 26381811 | doi = 10.1016/j.euroneuro.2015.07.028 | url = http://www.europeanneuropsychopharmacology.com/article/S0924-977X%2815%2900249-7/pdf }}</ref>

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.<ref>European Medicines Agency January 27, 2011 [http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Modafinil_31/WC500099177.pdf Questions and answers on the review of medicines containing Modafinil]</ref>

===Off-label use for fatigue===

Modafinil has also found off-label use with the [[neurological fatigue]] reported by some with [[multiple sclerosis]].<ref>{{cite news |url=https://www.theguardian.com/lifeandstyle/2013/may/03/brain-enhancing-drugs-mj-hyland |title=The drugs do work: my life on brain enhancers &#124; Life and style |publisher=The Guardian |date= May 3, 2013|accessdate=December 31, 2013 |location=London |first=MJ |last=Hyland | name-list-format = vanc }}</ref> In 2000, Cephalon conducted a study to evaluate modafinil as a potential treatment for MS-related fatigue. A group of 72 people with MS of varying degrees of severity tested two different doses of modafinil and an inactive placebo over nine weeks. Fatigue levels were self-evaluated on standardized scales. Participants taking a lower dose of modafinil reported feeling less fatigued and there was a statistically significant difference in fatigue scores for the lower dose versus the placebo. The higher dose of modafinil was not reported to be significantly more effective.<ref name="MS">{{cite journal | vauthors = Rammohan KW, Rosenberg JH, Lynn DJ, Blumenfeld AM, Pollak CP, Nagaraja HN | title = Efficacy and safety of modafinil (Provigil) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 72 | issue = 2 | pages = 179–83 | date = Feb 2002 | pmid = 11796766 | pmc = 1737733 | doi = 10.1136/jnnp.72.2.179 }}</ref><ref name="pmid21252034">{{cite journal | vauthors = Frost J, Okun S, Vaughan T, Heywood J, Wicks P | title = Patient-reported outcomes as a source of evidence in off-label prescribing: analysis of data from PatientsLikeMe | journal = Journal of Medical Internet Research | volume = 13 | issue = 1 | pages = e6 | year = 2011 | pmid = 21252034 | pmc = 3221356 | doi = 10.2196/jmir.1643 }}</ref>

Modafinil is also used off-label to treat sedation and fatigue in many conditions, including [[major depressive disorder|depression]],<ref name="Dep1">{{cite journal | vauthors = Menza MA, Kaufman KR, Castellanos A | title = Modafinil augmentation of antidepressant treatment in depression | journal = The Journal of Clinical Psychiatry | volume = 61 | issue = 5 | pages = 378–81 | date = May 2000 | pmid = 10847314 | doi = 10.4088/JCP.v61n0510 }}</ref><ref name="Dep2">{{cite journal | vauthors = DeBattista C, Lembke A, Solvason HB, Ghebremichael R, Poirier J | title = A prospective trial of modafinil as an adjunctive treatment of major depression | journal = Journal of Clinical Psychopharmacology | volume = 24 | issue = 1 | pages = 87–90 | date = Feb 2004 | pmid = 14709953 | doi = 10.1097/01.jcp.0000104910.75206.b9 }}</ref> [[fibromyalgia]], [[chronic fatigue syndrome]], [[myotonic dystrophy]],<ref name="Dyst">{{cite journal | vauthors = MacDonald JR, Hill JD, Tarnopolsky MA | title = Modafinil reduces excessive somnolence and enhances mood in patients with myotonic dystrophy | journal = Neurology | volume = 59 | issue = 12 | pages = 1876–80 | date = Dec 2002 | pmid = 12499477 | doi = 10.1212/01.WNL.0000037481.08283.51 }}</ref> [[opioid]]-induced sleepiness,<ref name="Opioid">{{cite journal | vauthors = Webster L, Andrews M, Stoddard G | title = Modafinil treatment of opioid-induced sedation | journal = Pain Medicine | volume = 4 | issue = 2 | pages = 135–40 | date = Jun 2003 | pmid = 12873263 | doi = 10.1046/j.1526-4637.2003.03014.x }}</ref> spastic [[cerebral palsy]],<ref name="SCP">{{cite journal | vauthors = Hurst DL, Lajara-Nanson W | title = Use of modafinil in spastic cerebral palsy | journal = Journal of Child Neurology | volume = 17 | issue = 3 | pages = 169–72 | date = Mar 2002 | pmid = 12026230 | doi = 10.1177/088307380201700303 }}</ref> and [[Parkinson's disease]].<ref name="Park">{{cite journal | vauthors = Nieves AV, Lang AE | title = Treatment of excessive daytime sleepiness in patients with Parkinson's disease with modafinil | journal = Clinical Neuropharmacology | volume = 25 | issue = 2 | pages = 111–4 | year = 2002 | pmid = 11981239 | doi = 10.1097/00002826-200203000-00010 }}</ref> Modafinil has been shown to improve excessive daytime somnolence and fatigue in [[primary biliary cirrhosis]].<ref name="Bonaventure">{{cite journal | vauthors = Bonaventure P, Letavic M, Dugovic C, Wilson S, Aluisio L, Pudiak C, Lord B, Mazur C, Kamme F, Nishino S, Carruthers N, Lovenberg T | title = Histamine H3 receptor antagonists: from target identification to drug leads | journal = Biochemical Pharmacology | volume = 73 | issue = 8 | pages = 1084–96 | date = Apr 2007 | pmid = 17129577 | doi = 10.1016/j.bcp.2006.10.031 }}</ref>

====Military and astronauts====

{{See also|List of drugs used by militaries}}

Militaries of several countries are known to have expressed interest in modafinil as an alternative to [[amphetamine]]—the drug traditionally employed in combat situations where troops face [[sleep deprivation]], such as during lengthy missions. The [[France|French]] government indicated that the [[French Foreign Legion|Foreign Legion]] used modafinil during certain covert operations.{{citation needed|date=January 2016}} The [[United Kingdom]]'s [[Ministry of Defence (United Kingdom)|Ministry of Defence]] commissioned research into modafinil<ref>{{cite news |author=Wheeler B |url=http://news.bbc.co.uk/1/hi/uk_politics/6083840.stm |title=BBC report on MoD research into modafinil |publisher=BBC News |date=October 26, 2006 |accessdate=July 4, 2012}}</ref> from [[Qinetiq|QinetiQ]] and spent £300,000 on one investigation.<ref>{{cite news |url=http://www.scotsman.com/news/health/mod-s-secret-pep-pill-to-keep-forces-awake-1-1387967 |title=MoD's secret pep pill to keep forces awake |newspaper=The Scotsman |date=February 27, 2005 |accessdate=December 31, 2013}}</ref> In 2011, the [[Indian Air Force]] announced that modafinil was included in contingency plans.<ref>{{cite web |url=http://www.punemirror.in/article/2/201102162011021606331644587714a65/Pilot-pill-project.html |title=Pilot pill project |work=News – City |publisher=PuneMirror |date=February 16, 2011 |accessdate=July 4, 2012}}</ref>

In the [[United States]] military, modafinil has been approved for use on certain [[United States Air Force|Air Force]] missions, and it is being investigated for other uses.<ref name="urlwww.dtic.mil">{{cite web |url=http://www.hep.afrl.af.mil/HEPF/Policy/modafinil.pdf |title=Modafinil and management of aircrew fatigue |author1=Taylor GP, Jr |author2=Keys RE |date=December 1, 2003 |format=PDF |work= |publisher=United States Department of the Air Force |accessdate=September 18, 2009}}</ref> As of November 2012, modafinil is the only drug approved by the Air Force as a "go pill" for fatigue management.<ref name=AF48>[http://static.e-publishing.af.mil/production/1/afsoc/publication/afsoci48-101/afsoci48-101.pdf Air Force Special Operations Command Instruction 48–101] (sects. 1.7.4), U.S. Air Force Special Operations Command, November 30, 2012.</ref> The use of [[dextroamphetamine]] (a.k.a., Dexedrine) is no longer approved.<ref name=AF48/>

The [[Canadian Medical Association Journal]] also reports that modafinil is used by [[astronaut]]s 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 rhythm]]s and with the reduced quality of sleep astronauts experience.<ref name="pmid19487390">{{cite journal | vauthors = Thirsk R, Kuipers A, Mukai C, Williams D | title = The space-flight environment: the International Space Station and beyond | journal = Cmaj | volume = 180 | issue = 12 | pages = 1216–20 | date = Jun 2009 | pmid = 19487390 | pmc = 2691437 | doi = 10.1503/cmaj.081125 }}</ref>

Allergy and hypersensitivity are the only contraindications of the drug,<ref>{{cite web|url=http://www.medmerits.com/index.php/article/modafinil/P4|title=Modafinil - Contraindications|publisher=}}</ref> 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|date=January 2016}}

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.<ref>{{cite web |url=http://www.tevausa.com/assets/base/products/pi/Modafinil_PI.pdf |format=PDF |title=Modafinil Information Page |publisher=[[Teva Pharmaceuticals]] |date=February 1, 2012}}</ref>

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.<ref>{{cite web |title=Modafinil (marketed as Provigil): Serious Skin Reactions |publisher=Food and Drug Administration |year=2007 |url=http://www.fda.gov/cder/dsn/2007_fall/postmarketing.htm#modafinil}}</ref> 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.<ref>{{cite journal | vauthors = Banerjee D, Vitiello MV, Grunstein RR | title = Pharmacotherapy for excessive daytime sleepiness | journal = Sleep Medicine Reviews | volume = 8 | issue = 5 | pages = 339–54 | date = Oct 2004 | pmid = 15336235 | doi = 10.1016/j.smrv.2004.03.002 }}</ref>

Modafinil may have an adverse effect on [[Hormonal contraception|hormonal contraceptives]] for up to a month after discontinuation.<ref>{{cite web |url=http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a602016.html |title=MedlinePlus Drug Information: Modafinil |publisher=[[National Institutes of Health|NIH]] |date=July 1, 2005 |accessdate=July 21, 2007 |archiveurl=https://web.archive.org/web/20070610045952/http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a602016.html |archivedate=June 10, 2007}}</ref>

===Addiction and dependence potential===

The [[addiction]] and [[drug dependence|dependence]] liabilities of modafinil are very low.<ref name="Withdrawal case reports" /><ref name="Addiction liability review" /><ref name="Modafinil" /> 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.<ref name="Modafinil"/> Monkeys will self-administer modafinil if they have previously been trained to self-administer cocaine.<ref name="Modafinil">{{cite web|title=Provigil: Prescribing information|url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020717s037s038lbl.pdf|website=United States Food and Drug Administration|publisher=Cephalon, Inc|accessdate=August 16, 2015|date=January 2015}}</ref> 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.<ref name="BernardiBroccoli2015">{{cite journal | vauthors = Bernardi RE, Broccoli L, Spanagel R, Hansson AC | title = Sex differences in dopamine binding and modafinil conditioned place preference in mice | journal = Drug and Alcohol Dependence | volume = 155 | pages = 37–44 | date = Oct 2015 | pmid = 26342627 | doi = 10.1016/j.drugalcdep.2015.08.016 }}</ref><ref name="NguyenTian2011">{{cite journal | vauthors = Nguyen TL, Tian YH, You IJ, Lee SY, Jang CG | title = Modafinil-induced conditioned place preference via dopaminergic system in mice | journal = Synapse | volume = 65 | issue = 8 | pages = 733–41 | date = Aug 2011 | pmid = 21157933 | doi = 10.1002/syn.20892 }}</ref> In accordance, although very rare, [[case report]]s of modafinil abuse exist.<ref name="CharyKrishnan2015">{{cite journal | vauthors = Krishnan R, Chary KV | title = A rare case modafinil dependence | journal = Journal of Pharmacology & Pharmacotherapeutics | volume = 6 | issue = 1 | pages = 49–50 | year = 2015 | pmid = 25709356 | doi = 10.4103/0976-500X.149149 | pmc=4319252}}</ref><ref name="Cengiz MeteŞenormancı2015">{{cite journal | vauthors = Cengiz Mete M, Şenormancı Ö, Saraçlı Ö, Atasoy N, Atik L | title = Compulsive modafinil use in a patient with a history of alcohol use disorder | journal = General Hospital Psychiatry | volume = 37 | issue = 2 | pages = e7-8 | year = 2015 | pmid = 25655923 | doi = 10.1016/j.genhosppsych.2015.01.001 }}</ref> As such, modafinil is classified by the United States FDA as a [[Controlled Substances Act#Schedule IV controlled substances|schedule IV controlled substance]], a category for drugs with valid medical uses and low but significant addiction potential.<ref name="Addiction liability review" /><ref name=Ballon>{{cite journal | vauthors = Ballon JS, Feifel D | title = A systematic review of modafinil: Potential clinical uses and mechanisms of action | journal = The Journal of Clinical Psychiatry | volume = 67 | issue = 4 | pages = 554–66 | date = Apr 2006 | pmid = 16669720 | doi = 10.4088/jcp.v67n0406 }}</ref>

[[Psychological dependence]] upon modafinil has only been noted in [[case report]]s involving daily overdoses on modafinil for an extended period of time.<ref name="Withdrawal case reports" /> Reported [[Drug withdrawal|withdrawal symptoms]] include [[anhedonia]], [[lethargy]], anxiety, and insomnia.<ref name="Withdrawal case reports" />

===Tolerance===

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).<ref name="pmid16737742">{{cite journal | vauthors = Nasr S, Wendt B, Steiner K | title = Absence of mood switch with and tolerance to modafinil: a replication study from a large private practice | journal = J Affect Disord | volume = 95 | issue = 1–3 | pages = 111–4 | year = 2006 | pmid = 16737742 | doi = 10.1016/j.jad.2006.01.010 | url = }}</ref><ref name="pmid10828434">{{cite journal | vauthors = Mitler MM, Harsh J, Hirshkowitz M, Guilleminault C | title = Long-term efficacy and safety of modafinil (PROVIGIL((R))) for the treatment of excessive daytime sleepiness associated with narcolepsy | journal = Sleep Med. | volume = 1 | issue = 3 | pages = 231–243 | year = 2000 | pmid = 10828434 | doi = 10.1016/s1389-9457(00)00031-9| url = }}</ref><ref name="pmid9450772">{{cite journal | vauthors = | title = Randomized trial of modafinil for the treatment of pathological somnolence in narcolepsy. US Modafinil in Narcolepsy Multicenter Study Group | journal = Ann. Neurol. | volume = 43 | issue = 1 | pages = 88–97 | year = 1998 | pmid = 9450772 | doi = 10.1002/ana.410430115 | url = }}</ref>

==Overdose==

In mice and rats, the [[median lethal dose]] (LD₅₀) of modafinil is approximately or slightly greater than 1250&nbsp;mg/kg. Oral LD₅₀ values reported for rats range from 1000–3400&nbsp;mg/kg. Intravenous LD₅₀ for dogs is 300&nbsp;mg/kg. Clinical trials on humans involving taking up to 1200&nbsp;mg/day for 7–21&nbsp;days and known incidents of acute one-time overdoses up to 4500&nbsp;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.<ref name="fda_label"/> As of 2004, the FDA is not aware of any fatal overdoses involving modafinil alone (as opposed to multiple drugs, including modafinil).<ref name="fda_label"/>

==Interactions==

Coadministration with modafinil alongside [[opioid]]s 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 [[enzyme inducer|inducer]] of the [[CYP3A4]] [[enzyme]]s. If not monitored closely, reduced efficacy or withdrawal symptoms can occur.{{Medical citation needed|date=October 2015}}

==Pharmacology==

===Pharmacodynamics===

{{As of|2017|post=,}} the therapeutic [[mechanism of action]] of modafinil for narcolepsy and sleep-wake disorders remains unknown.<ref name="Stahl's Essential Psychopharmacology - Modafinil" /><ref name="pmid19300566" /><ref>{{cite journal | vauthors = Minzenberg MJ, Carter CS | title = Modafinil: a review of neurochemical actions and effects on cognition | journal = Neuropsychopharmacology | volume = 33 | issue = 7 | pages = 1477–1502 | date = Jun 2008 | pmid = 17712350 | doi = 10.1038/sj.npp.1301534 }}</ref>

====Dopamine transporter blocker====

Research found that modafinil elevates [[histamine]] levels in the [[hypothalamus]] in animals.<ref name="IshizukaMurakami2008">{{cite journal|last1=Ishizuka|first1=Tomoko|last2=Murakami|first2=Masahiro|last3=Yamatodani|first3=Atsushi|title=Involvement of central histaminergic systems in modafinil-induced but not methylphenidate-induced increases in locomotor activity in rats|journal=European Journal of Pharmacology|volume=578|issue=2–3|year=2008|pages=209–215|issn=0014-2999|doi=10.1016/j.ejphar.2007.09.009|pmid=17920581}}</ref> 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]],<ref name="pmid17477916">{{cite journal | vauthors = Dopheide MM, Morgan RE, Rodvelt KR, Schachtman TR, Miller DK | title = Modafinil evokes striatal [(3)H]dopamine release and alters the subjective properties of stimulants | journal = European Journal of Pharmacology | volume = 568 | issue = 1–3 | pages = 112–23 | date = Jul 2007 | pmid = 17477916 | doi = 10.1016/j.ejphar.2007.03.044 }}</ref><ref name="pmid17098298">{{cite journal | vauthors = Murillo-Rodríguez E, Haro R, Palomero-Rivero M, Millán-Aldaco D, Drucker-Colín R | title = Modafinil enhances extracellular levels of dopamine in the nucleus accumbens and increases wakefulness in rats | journal = Behavioural Brain Research | volume = 176 | issue = 2 | pages = 353–7 | date = Jan 2007 | pmid = 17098298 | doi = 10.1016/j.bbr.2006.10.016 }}</ref> [[norepinephrine]] in the [[hypothalamus]] and [[ventrolateral preoptic nucleus]],<ref name="de Saint Hilaire_2001">{{cite journal | vauthors = de Saint Hilaire Z, Orosco M, Rouch C, Blanc G, Nicolaidis S | title = Variations in extracellular monoamines in the prefrontal cortex and medial hypothalamus after modafinil administration: a microdialysis study in rats | journal = NeuroReport | volume = 12 | issue = 16 | pages = 3533–7 | date = Nov 2001 | pmid = 11733706 | doi = 10.1097/00001756-200111160-00032 }}</ref><ref name="pmid14998233">{{cite journal | vauthors = Gallopin T, Luppi PH, Rambert FA, Frydman A, Fort P | title = Effect of the wake-promoting agent modafinil on sleep-promoting neurons from the ventrolateral preoptic nucleus: an in vitro pharmacologic study | journal = Sleep | volume = 27 | issue = 1 | pages = 19–25 | date = Feb 2004 | pmid = 14998233 | doi = }}</ref> and [[serotonin]] in the [[amygdala]] and [[frontal cortex]].<ref name="Ferraro_2002">{{cite journal | vauthors = Ferraro L, Fuxe K, Tanganelli S, Tomasini MC, Rambert FA, Antonelli T | title = Differential enhancement of dialysate serotonin levels in distinct brain regions of the awake rat by modafinil: possible relevance for wakefulness and depression | journal = Journal of Neuroscience Research | volume = 68 | issue = 1 | pages = 107–12 | date = Apr 2002 | pmid = 11933055 | doi = 10.1002/jnr.10196 }}</ref> Modafinil was screened at a large panel of [[receptor (biochemistry)|receptor]]s and [[membrane transport protein|transporter]]s in an attempt to elucidate its pharmacology.<ref name="ZolkowskaJain2009">{{cite journal | vauthors = Zolkowska D, Jain R, Rothman RB, Partilla JS, Roth BL, Setola V, Prisinzano TE, Baumann MH | title = Evidence for the involvement of dopamine transporters in behavioral stimulant effects of modafinil | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 329 | issue = 2 | pages = 738–46 | date = May 2009 | pmid = 19197004 | doi = 10.1124/jpet.108.146142 | pmc=2672878}}</ref> 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|IC₅₀]] value of 4&nbsp;μM.<ref name="ZolkowskaJain2009" /> Subsequently, it was determined that modafinil binds to the same site on the DAT as [[cocaine]], but in a different manner.<ref name="FedericiLatagliata2013">{{cite journal|last1=Federici|first1=M.|last2=Latagliata|first2=E.C.|last3=Rizzo|first3=F.R.|last4=Ledonne|first4=A.|last5=Gu|first5=H.H.|last6=Romigi|first6=A.|last7=Nisticò|first7=R.|last8=Puglisi-Allegra|first8=S.|last9=Mercuri|first9=N.B.|title=Electrophysiological and amperometric evidence that modafinil blocks the dopamine uptake transporter to induce behavioral activation|journal=Neuroscience|volume=252|year=2013|pages=118–124|issn=0306-4522|doi=10.1016/j.neuroscience.2013.07.071|pmid=23933217}}</ref><ref name="Okunola-BakareCao2014">{{cite journal|last1=Okunola-Bakare|first1=Oluyomi M.|last2=Cao|first2=Jianjing|last3=Kopajtic|first3=Theresa|last4=Katz|first4=Jonathan L.|last5=Loland|first5=Claus J.|last6=Shi|first6=Lei|last7=Newman|first7=Amy Hauck|title=Elucidation of Structural Elements for Selectivity across Monoamine Transporters: Novel 2-[(Diphenylmethyl)sulfinyl]acetamide (Modafinil) Analogues|journal=Journal of Medicinal Chemistry|volume=57|issue=3|year=2014|pages=1000–1013|issn=0022-2623|doi=10.1021/jm401754x|pmid=24494745|pmc=3954497}}</ref> In accordance, modafinil increases [[hyperactivity|locomotor activity]] and extracellular dopamine concentrations in animals in a manner similar to the selective DRI [[vanoxerine]] (GBR-12909),<ref name="Young2009">{{cite journal|last1=Young|first1=J. W.|title=Dopamine D1 and D2 Receptor Family Contributions to Modafinil-Induced Wakefulness|journal=Journal of Neuroscience|volume=29|issue=9|year=2009|pages=2663–2665|issn=0270-6474|doi=10.1523/JNEUROSCI.5843-08.2009|pmid=19261860|pmc=2697968}}</ref> 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".<ref name="Wisor2013">{{cite journal | vauthors = Wisor J | title = Modafinil as a catecholaminergic agent: empirical evidence and unanswered questions | journal = Frontiers in Neurology | volume = 4 | pages = 139 | year = 2013 | pmid = 24109471 | doi = 10.3389/fneur.2013.00139 | pmc=3791559}}</ref> In addition to animal research, a human [[positron emission tomography]] (PET) imaging study found that 200&nbsp;mg and 300&nbsp;mg doses of modafinil resulted in DAT occupancy of 51.4% and 56.9%, respectively, which was described as "close to that of [[methylphenidate]]".<ref name="KimTateno2014">{{cite journal | vauthors = Kim W, Tateno A, Arakawa R, Sakayori T, Ikeda Y, Suzuki H, Okubo Y | title = In vivo activity of modafinil on dopamine transporter measured with positron emission tomography and [¹⁸F]FE-PE2I | journal = The International Journal of Neuropsychopharmacology | volume = 17 | issue = 5 | pages = 697–703 | date = May 2014 | pmid = 24451483 | doi = 10.1017/S1461145713001612 }}</ref> 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]].<ref name="VolkowFowler2009">{{cite journal | vauthors = Volkow ND, Fowler JS, Logan J, Alexoff D, Zhu W, Telang F, Wang GJ, Jayne M, Hooker JM, Wong C, Hubbard B, Carter P, Warner D, King P, Shea C, Xu Y, Muench L, Apelskog-Torres K | title = Effects of modafinil on dopamine and dopamine transporters in the male human brain: clinical implications | journal = JAMA | volume = 301 | issue = 11 | pages = 1148–54 | date = Mar 2009 | pmid = 19293415 | doi = 10.1001/jama.2009.351 | pmc=2696807}}</ref>

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.<ref name="ReithBlough2015">{{cite journal | vauthors = Reith ME, Blough BE, Hong WC, Jones KT, Schmitt KC, Baumann MH, Partilla JS, Rothman RB, Katz JL | title = Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter | journal = Drug and Alcohol Dependence | volume = 147 | pages = 1–19 | date = Feb 2015 | pmid = 25548026 | doi = 10.1016/j.drugalcdep.2014.12.005 | pmc=4297708}}</ref><ref name="QuisenberryBaker2015">{{cite journal | vauthors = Quisenberry AJ, Baker LE | title = Dopaminergic mediation of the discriminative stimulus functions of modafinil in rats | journal = Psychopharmacology | volume = 232 | issue = 24 | pages = 4411–9 | date = Dec 2015 | pmid = 26374456 | doi = 10.1007/s00213-015-4065-0 }}</ref> For instance, modafinil produces wakefulness reportedly without the need for compensatory sleep, and shows a relatively low, if any,<ref name="MereuBonci2013" /> potential for abuse.<ref name="Wisor2013" /><ref name="ReithBlough2015" /><ref name="QuisenberryBaker2015" /> Aside from modafinil, examples of other atypical DAT inhibitors include vanoxerine and [[benztropine]], which have a relatively low abuse potential similarly to modafinil.<ref name="ReithBlough2015" /> These drugs appear to interact molecularly with the DAT in a distinct way relative to "conventional" DAT blockers such as cocaine and methylphenidate.<ref name="Okunola-BakareCao2014" /><ref name="ReithBlough2015" />

====DAT-independent actions====

Against the hypothesis that modafinil exerts its effects by acting as a DRI, [[tyrosine hydroxylase]] [[enzyme inhibitor|inhibitor]]s (which deplete dopamine) fail to block the effects of modafinil in animals.<ref name="StickgoldWalker2010">{{cite book|author1=Robert Stickgold|author2=Matthew P. Walker|title=The Neuroscience of Sleep|url=https://books.google.com/books?id=E15ToNvBLcQC&pg=PA191|date=22 May 2010|publisher=Academic Press|isbn=978-0-12-375722-7|pages=191–}}</ref> In addition, modafinil fails to reverse [[reserpine]]-induced [[akinesia]], whereas [[dextroamphetamine]], a [[dopamine releasing agent]] (DRA), is able to do so.<ref name="pmid8998404">{{cite journal | vauthors = Simon P, Hémet C, Ramassamy C, Costentin J | title = Non-amphetaminic mechanism of stimulant locomotor effect of modafinil in mice | journal = Eur Neuropsychopharmacol | volume = 5 | issue = 4 | pages = 509–14 | year = 1995 | pmid = 8998404 | doi = 10.1016/0924-977x(95)00041-m| url = }}</ref> 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.<ref name="DunnHostetler2012">{{cite journal|last1=Dunn|first1=Derek|last2=Hostetler|first2=Greg|last3=Iqbal|first3=Mohamed|last4=Marcy|first4=Val R.|last5=Lin|first5=Yin Guo|last6=Jones|first6=Bruce|last7=Aimone|first7=Lisa D.|last8=Gruner|first8=John|last9=Ator|first9=Mark A.|last10=Bacon|first10=Edward R.|last11=Chatterjee|first11=Sankar|title=Wake promoting agents: Search for next generation modafinil, lessons learned: Part III|journal=Bioorganic & Medicinal Chemistry Letters|volume=22|issue=11|year=2012|pages=3751–3753|issn=0960-894X|doi=10.1016/j.bmcl.2012.04.031|pmid=22546675}}</ref> 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",<ref name="MereuBonci2013">{{cite journal|last1=Mereu|first1=Maddalena|last2=Bonci|first2=Antonello|last3=Newman|first3=Amy Hauck|last4=Tanda|first4=Gianluigi|title=The neurobiology of modafinil as an enhancer of cognitive performance and a potential treatment for substance use disorders|journal=Psychopharmacology|volume=229|issue=3|year=2013|pages=415–434|issn=0033-3158|doi=10.1007/s00213-013-3232-4|pmid=23934211}}</ref> 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.<ref name="IshizukaMurakami2008" /> 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").<ref name="FedericiLatagliata2013" /><ref name="MereuBonci2013" />

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 receptor|D₁]] and [[D2 receptor|D₂ receptor]] [[receptor antagonist|antagonist]]s (although conflicting reports exist),<ref name="pmid8998404" /> and completely blocked by simultaneous inactivation of both D₁ and D₂ receptors.<ref name="Wisor2013" /> 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.<ref name="QuisenberryBaker2015" /> 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 receptor]]s).<ref name="QuisenberryBaker2015" />

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.<ref name="pmid15260124">{{cite journal | vauthors = Chatterjie N, Stables JP, Wang H, Alexander GJ | title = Anti-narcoleptic agent modafinil and its sulfone: a novel facile synthesis and potential anti-epileptic activity | journal = Neurochem. Res. | volume = 29 | issue = 8 | pages = 1481–6 | year = 2004 | pmid = 15260124 | doi = 10.1023/b:nere.0000029559.20581.1a| url = }}</ref> 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.<ref name="pmid15260124" />

====D₂ receptor partial agonist====

The (''R'')-(−)-[[enantiomer]] of modafinil, known as [[armodafinil]], was also subsequently found to act as a [[D2 receptor|D₂^High receptor]] [[partial agonist]], with a [[dissociation constant|K_i]] of 16&nbsp;nM, an [[intrinsic activity]] of 48%, and an [[EC50|EC₅₀]] of 120&nbsp;nM, in rat [[striatum|striatal]] tissue.<ref name="pmid19391150">{{cite journal | vauthors = Seeman P, Guan HC, Hirbec H | title = Dopamine D2High receptors stimulated by phencyclidines, lysergic acid diethylamide, salvinorin A, and modafinil | journal = Synapse | volume = 63 | issue = 8 | pages = 698–704 | date = Aug 2009 | pmid = 19391150 | doi = 10.1002/syn.20647 }}</ref> The (''S'')-enantiomer is inactive with respect to the D₂ receptor.<ref name="pmid19391150" /> 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.<ref name="KorotkovaKlyuch2007">{{cite journal|last1=Korotkova|first1=T.M.|last2=Klyuch|first2=B.P.|last3=Ponomarenko|first3=A.A.|last4=Lin|first4=J.S.|last5=Haas|first5=H.L.|last6=Sergeeva|first6=O.A.|title=Modafinil inhibits rat midbrain dopaminergic neurons through D2-like receptors|journal=Neuropharmacology|volume=52|issue=2|year=2007|pages=626–633|issn=0028-3908|doi=10.1016/j.neuropharm.2006.09.005|pmid=17070873}}</ref>

====Miscellaneous====

Modafinil's efficacy in improving vigor and well-being in sleep deprivation subjects is dependent on [[catechol-O-methyl transferase]] (COMT) status.<ref name="pmid19037200">{{cite journal | vauthors = Bodenmann S, Xu S, Luhmann UF, Arand M, Berger W, Jung HH, Landolt HP | title = Pharmacogenetics of modafinil after sleep loss: catechol-O-methyltransferase genotype modulates waking functions but not recovery sleep | journal = Clinical Pharmacology and Therapeutics | volume = 85 | issue = 3 | pages = 296–304 | date = Mar 2009 | pmid = 19037200 | doi = 10.1038/clpt.2008.222 }}</ref> Research suggests that individuals with the [[Rs6265|Val/Val]] [[genotype]] experience a great improvement in their cognitive function, while those with the Met/Met [[allele]] experience very little improvement.<ref name="pmid19037200" />

Modafinil [[enzyme inducer|induces]] the [[cytochrome P450]] enzymes [[CYP1A2]], [[CYP3A4]], and [[CYP2B6]], as well as inhibiting [[CYP2C9]] and [[CYP2C19]] ''[[in vitro]]''.<ref name="pmid10820139"/> It may also induce [[P-glycoprotein]] (Pgp), which may affect drugs transported by Pgp, such as [[digoxin]].{{citation needed|date=May 2013}} The [[bioavailability]] of modafinil is greater than 80% of the administered dose. ''In vitro'' measurements indicate that 60% of modafinil is bound to [[plasma protein]]s at clinical concentrations of the drug. This percentage actually changes very little when the concentration is varied.<ref name="Hardman">{{cite book |vauthors=Gilman A, Goodman LS, Hardman JG, Limbird LE |title=Goodman & Gilman's the pharmacological basis of therapeutics |edition= |language= |publisher=McGraw-Hill |location=New York |year=2001 |origyear= |page=1984 |quote= |isbn=0-07-135469-7 }}</ref> C_max (peak levels) occurs approximately 2–3&nbsp;hours after administration. Food slows absorption, but does not affect the total [[Area under the curve|AUC]]{{clarify|date=August 2014}}(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.<ref name="Hardman"/>

The two major circulating [[metabolite]]s of modafinil are [[modafinil acid]] (CRL-40467) and [[modafinil sulfone]] (CRL-41056).<ref name="SchwertnerKong2005">{{cite journal|last1=Schwertner|first1=Harvey A.|last2=Kong|first2=Suk Bin|title=Determination of modafinil in plasma and urine by reversed phase high-performance liquid-chromatography|journal=Journal of Pharmaceutical and Biomedical Analysis|volume=37|issue=3|year=2005|pages=475–479|issn=0731-7085|doi=10.1016/j.jpba.2004.11.014}}</ref><ref name="RobertsonHellriegel2003">{{cite journal|last1=Robertson|first1=Philmore|last2=Hellriegel|first2=Edward T.|title=Clinical Pharmacokinetic Profile of Modafinil|journal=Clinical Pharmacokinetics|volume=42|issue=2|year=2003|pages=123–137|issn=0312-5963|doi=10.2165/00003088-200342020-00002|pmid=12537513}}</ref> Both of these metabolites have been described as inactive,<ref name="WongWang1998">{{cite journal|last1=Wong|first1=Y. Nancy|last2=Wang|first2=Lixia|last3=Hartman|first3=Linda|last4=Simcoe|first4=Donna|last5=Chen|first5=Yusong|last6=Laughton|first6=Watson|last7=Eldon|first7=Richard|last8=Markland|first8=Colin|last9=Grebow|first9=Peter|title=Comparison of the Single-Dose Pharmacokinetics and Tolerability of Modafinil and Dextroamphetamine Administered Alone or in Combination in Healthy Male Volunteers|journal=The Journal of Clinical Pharmacology|volume=38|issue=10|year=1998|pages=971–978|issn=0091-2700|doi=10.1002/j.1552-4604.1998.tb04395.x}}</ref> and neither appear to contribute to the wakefulness-promoting effects of modafinil.<ref name="SchwertnerKong2005" /><ref name="RobertsonHellriegel2003" /><ref name="Robertson2002">{{cite journal|last1=Robertson|first1=P|title=Effect of modafinil on the pharmacokinetics of ethinyl estradiol and triazolam in healthy volunteers|journal=Clinical Pharmacology & Therapeutics|volume=71|issue=1|year=2002|pages=46–56|issn=0009-9236|doi=10.1067/mcp.2002.121217}}</ref> However, modafinil sulfone does appear to possess anticonvulsant effects, and this is a property that it shares with modafinil.<ref name="pmid15260124" />

{{multiple image

| direction = horizontal

| align = right

| image1 = (R)-(−)-modafinil.svg

| width1 = 220

| caption1 = The (''R'')-(−)-enantiomer of modafinil<ref name="LolandMereu2012" />

| image2 = (S)-(+)-modafinil.svg

| width2 = 220

| caption2 = The ''S''-(+)-enantiomer of modafinil<ref name="LolandMereu2012">{{cite journal | vauthors = Loland CJ, Mereu M, Okunola OM, Cao J, Prisinzano TE, Mazier S, Kopajtic T, Shi L, Katz JL, Tanda G, Newman AH | title = R-modafinil (armodafinil): a unique dopamine uptake inhibitor and potential medication for psychostimulant abuse | journal = Biological Psychiatry | volume = 72 | issue = 5 | pages = 405–413 | date = September 2012 | pmid = 22537794 | pmc = 3413742 | doi = 10.1016/j.biopsych.2012.03.022 | url = }}</ref>

}}

===Measurement 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.<ref name="pmid9549666">{{cite journal | vauthors = Wong YN, King SP, Laughton WB, McCormick GC, Grebow PE | title = Single-dose pharmacokinetics of modafinil and methylphenidate given alone or in combination in healthy male volunteers | journal = Journal of Clinical Pharmacology | volume = 38 | issue = 3 | pages = 276–82 | date = Mar 1998 | pmid = 9549666 | doi = 10.1002/j.1552-4604.1998.tb04425.x }}</ref><ref name="isbn0-9626523-7-7">{{cite book |author=Baselt, Randall C. |title=Disposition of Toxic Drugs and Chemicals in Man |publisher=Biomedical Publications |location=Foster City, CA |year=2008 |isbn=0-9626523-7-7 |pages=1152–1153}}</ref> As of 2011, it is not specifically tested for by common [[Drug test|drug screens]] (except for anti-doping screens) and is unlikely to cause false positives for other chemically-unrelated drugs such as substituted amphetamines.<ref name="urlProvigil in Drug Tests | Modafinil in Drug Tests">{{cite web |url=http://www.provigilweb.org/drugtest.htm |title=Modafinil in Drug Tests |publisher=ProvigilWeb}}</ref>

[[Pill testing|Reagent testing]] can be used to screen for the presence of modafinil in samples.

|Modafinil || Yellow/Orange > Brown<ref name="DesignerTryp"/><ref name="RTUK Modafinil"/> || Darkening Orange<ref name='DesignerTryp'>{{cite journal | vauthors = Spratley TK, Hayes PA, Geer LC, Cooper SD, McKibben TD | title = Analytical Profiles for Five "Designer" Tryptamines | journal = Microgram Journal | volume = 3 | issue = 1–2 | pages = 54–68 | year = 2005 | format=PDF | url = http://www.erowid.org/library/periodicals/microgram/microgram_journal_2005-1.pdf#page=54}}</ref> || Deep orange/red<ref name="RTUK Modafinil">{{cite web | url=http://www.reagent-tests.uk/blog/modafinil-reaction-with-the-froehde-reagent-and-others/ | title=Modafinil reaction with the Froehde reagent and others | publisher=Reagent Tests UK | date=13 December 2015 | accessdate=18 December 2015}}</ref>

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.

<!-- Here is a table; skip past it to edit the text -->

{| class="wikitable mw-collapsible mw-collapsed"

|-

! Pharmacology of modafinil's structural analogs

|- style="text-align: left; style="font-size:smaller"

|

{| class="wikitable sortable"

|+Modafinil analogs and their effects on the central nervous system.<ref name="De RisiFerraro2008">{{cite journal|last1=De Risi|first1=Carmela|last2=Ferraro|first2=Luca|last3=Pollini|first3=Gian P.|last4=Tanganelli|first4=Sergio|last5=Valente|first5=Filippo|last6=Veronese|first6=Augusto C.|title=Efficient synthesis and biological evaluation of two modafinil analogues|journal=Bioorganic & Medicinal Chemistry|volume=16|issue=23|year=2008|pages=9904–9910|issn=0968-0896|doi=10.1016/j.bmc.2008.10.027|pmid=18954992}}</ref>

! Structure

! X₁

! X₂

! NR₁R₂

! Action on CNS

|-

|rowspan=10|[[File:Modafinil analogs 1.svg|250px]]

|-

|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

|}

{| class="wikitable sortable"

|+Thio- & Sulfinylacetamide Modafinil analogs<ref name="Okunola-BakareCao2014"/>

! Structure

! ''X''<br />(di-benzene substitutions)

! ''Y''<br />(CH₂ substitution)

! ''R''<br />(''N''-methyl terminating substitution)

! ''K''_i<nowiki> [</nowiki>SE interval<nowiki>]</nowiki> (''nM'')<br />@ [[Dopamine transporter|DAT]]

! ''K''_i<nowiki> [</nowiki>SE interval<nowiki>]</nowiki> (''nM'')<br />@ [[Serotonin transporter|SERT]]

! ''K''_i<nowiki> [</nowiki>SE interval<nowiki>]</nowiki> (''nM'')<br />@ [[Norepinephrine transporter|NET]]

|-

|Modafinil||H||S=O||H||2600 (2430—2780)||''inactive''||''inactive''

|-

|rowspan=31|[[File:Modafinil analogs 2.svg|250px]]

|-

|H||S||H||12400 (10800—14300)||14500 (11800—17700)||''inactive''<small><br />derived as<br />285000 (117000—690000)</small>

|-

|3,3′-di-Cl||S||H||275 (257—295)||''inactive''<small><br />derived as<br />808000 (706000—924000)</small>||45400 (39600—52000)

|-

|H||S||CH₃||19300 (17900—20800)||''inactive''<small><br />derived as<br />656000 (302000—1420000)</small>||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''<small><br />derived as<br />303000 (267000—344000)</small>||''inactive''<small><br />derived as<br />171000 (88300—332000)</small>

|-

|H||S||''n''-propyl||20700 (20300—21100)||''inactive''<br />derived as<br />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)

|}

|} <!-- End of the table -->

==History==

Modafinil was originally developed in [[France]] by [[Neurophysiology|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,<ref name=Ballas>{{cite journal | vauthors = Ballas CA, Kim D, Baldassano CF, Hoeh N | title = Modafinil: past, present and future | journal = Expert Review of Neurotherapeutics | volume = 2 | issue = 4 | pages = 449–57 | date = Jul 2002 | pmid = 19810941 | doi = 10.1586/14737175.2.4.449 }}</ref> 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]]<ref>{{cite news |url=http://articles.latimes.com/2013/may/02/science/la-sci-stay-awake-drug-modafinil-booming-20130502 |title=Use of wake-up drug modafinil takes off, spurred by untested uses – Los Angeles Times |publisher=LA Times |date=May 2, 2013 |accessdate=December 31, 2013 |first=Melissa |last=Healy | name-list-format = vanc }}</ref> for the treatment of [[narcolepsy]] and in 2003 for [[shift work sleep disorder]] and obstructive [[sleep apnea]]/[[hypopnea]]<ref>{{cite journal | vauthors = Kesselheim AS, Myers JA, Solomon DH, Winkelmayer WC, Levin R, Avorn J |title= The prevalence and cost of unapproved uses of top-selling orphan drugs |journal=PloS One | volume=7 |issue=2 |page=e31894 |date= February 21, 2012 |pmid=22363762 |pmc= 3283698 |doi=10.1371/journal.pone.0031894 | editor1-last= Alessi-Severini |editor1-first= Silvia }}</ref> even though caffeine and amphetamine were shown to be more wakefulness promoting on the Stanford Sleepiness Test Score than modafinil.<ref name="pmid19300566" />

It was approved for use in the UK in December 2002. Modafinil is marketed in the US by [[Cephalon|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 [[#Patent protection and antitrust litigation|below]]), [[generic drug|generic]] versions of modafinil became available in the U.S. in 2012.

===Patent protection and antitrust litigation===

{{US patent|4927855}} was issued to [[Laboratoire L. Lafon]] on May 22, 1990, covering the chemical compound modafinil. After receiving an interim term extension of 1066&nbsp;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, {{US patent|5618845}} 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.<ref>{{cite news |url=http://www.bizjournals.com/philadelphia/stories/2006/03/27/daily13.html |title=Cephalon gets six-month Provigil patent extension |publisher=Philadelphia Business Journal |date=March 28, 2006 |accessdate=July 21, 2007}}</ref><ref>{{cite web |url=http://www.drugpatentwatch.com/ultimate/preview/patent/index.php?query=RE37516 |title=Details for Patent: RE37516}}</ref>

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.<ref>{{cite web |url=http://www.prescriptionaccess.org/lawsuitssettlements/current_lawsuits?id=0024 |title=Prescription Access Litigation (PAL) Project :: Prescription Access Litigation (PAL) Project :: Lawsuits & Settlements :: Current Lawsuits |publisher=Prescriptionaccess.org |accessdate=July 4, 2012}}</ref> 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.<ref>{{cite web |url=http://law.justia.com/cases/federal/district-courts/pennsylvania/paedce/2:2006cv02768/205626/514 |title=Document 514 :: APOTEX, INC. v. CEPHALON, INC. et al |publisher=Pennsylvania Eastern District Court :: US Federal District Courts Cases :: Justia |date=October 31, 2010 |accessdate=July 4, 2012}}</ref> 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.<ref name="url_Justia">{{cite web |url=http://law.justia.com/cases/federal/district-courts/pennsylvania/paedce/2:2006cv02768/205626/513 |title=Document 513 :: APOTEX, INC. v. CEPHALON, INC. et al |date=October 31, 2010 |work= |publisher=Pennsylvania Eastern District Court :: US Federal District Courts Cases :: Justia |accessdate=July 4, 2012}}</ref> The patent was also found to be unenforceable due to Cephalon's inequitable conduct during patent prosecution.<ref name="url_Justia" />

Cephalon made an agreement with four major generics manufacturers [[Teva Pharmaceutical Industries|Teva]], [[Barr Pharmaceuticals]], [[Ranbaxy Laboratories]], and [[Actavis|Watson Pharmaceuticals]] between 2005 and 2006 to [[Reverse payment patent settlement|delay]] sales of generic modafinil in the US until April 2012 by these companies in exchange for upfront and royalty payments.<ref>{{cite web |url=https://www.sec.gov/Archives/edgar/data/873364/000104746909001690/a2190556z10-k.htm |title=Cephalon Inc., SEC 10K 2008 disclosure |pages=9–10 |date=February 23, 2009 |accessdate=August 29, 2009}}</ref> Litigation arising from these agreements is still pending including an FTC suit filed in April 2008.<ref>{{cite news |title=CVS, Rite Aid Sue Cephalon Over Generic Provigil |url=https://www.bloomberg.com/apps/news?pid=20601103&sid=arNEtMSU7D9s |accessdate=August 29, 2009 |publisher=Bloomberg News |date=August 21, 2009}}</ref> [[Apotex]] received regulatory approval in Canada despite a suit from Cephalon's marketing partner in Canada, [[Shire Pharmaceuticals]].<ref>{{cite web |url=http://www.mondaq.com/article.asp?articleid=71906 |title=Canada IP Year in Review 2008 |date=January 1, 2009}}</ref><ref>{{cite web |title=Shire v. Canada |url=http://reports.fja-cmf.gc.ca/eng/2008/2008fc538/2008fc538.html |accessdate=August 29, 2009}}</ref> Cephalon has sued Apotex in the US to prevent it from releasing a genericized armodafinil (Nuvigil).<ref>{{cite web |url=http://www.zacks.com/stock/news/39048/Cephalon+Sues+Apotex |title=Cephalon Sues Apotex |publisher=Zacks.com |date=August 20, 2010 |accessdate=July 4, 2012}}</ref> 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;<ref>"{{cite web |url=http://www.thefreelibrary.com/U.S.+Federal+Trade+Commission+Clears+Teva's+Acquisition+of+Cephalon.-a0268983036 |title=U.S. Federal Trade Commission Clears Teva's Acquisition of Cephalon |publisher=Business Wire |date=October 7, 2011 |quote=Teva will also grant non-exclusive U.S. rights to an undisclosed company to market modafinil tablets, the generic version of Provigil(R), which had annual brand sales in the U.S. of approximately $1.1 billion}}</ref> ultimately, [[Par Pharmaceutical]] acquired the US modafinil rights as well as some others.<ref name="url_Par_Pharmaceutical">{{cite web |url=http://www.prnewswire.com/news-releases/par-pharmaceutical-acquires-three-generic-products-from-teva-pharmaceuticals-132044783.html |title=Par Pharmaceutical Acquires Three Generic Products From Teva Pharmaceuticals |date=October 18, 2011 |work=Press Release |publisher=PRNewswire |accessdate=July 4, 2012}}</ref>

In the United Kingdom, [[Mylan Inc.]] received regulatory approval to sell generic modafinil produced by [[Orchid pharma|Orchid]] in January 2010; Cephalon sued to prevent sale, but lost the patent trial in November.<ref>{{cite news |author=Larson E |title=Cephalon Loses U.K. Bid to Halt Mylan, Orchid Generic-Drug Sales |work= |publisher=bloomberg LP |date=November 19, 2010 |url=https://www.bloomberg.com/news/2010-11-19/cephalon-loses-u-k-bid-to-halt-mylan-orchid-generic-drug-sales.html |archiveurl=https://www.webcitation.org/67Buc3Od8 |archivedate=April 25, 2012 |deadurl=no}}</ref>

==Society and culture==

===Legal status===

==== United States ====

Modafinil is {{As of|2005|alt=currently}} classified as a [[Controlled Substances Act|Schedule IV controlled substance]] under United States federal law; it is illegal to import by anyone other than a [[Drug Enforcement Administration|DEA]]-registered importer without a prescription.<ref>{{cite web |url=http://www.usdoj.gov/dea/illegal_internet.html |publisher=[[United States Drug Enforcement Administration]] |title=Is It Illegal to Obtain Controlled Substances From the Internet? |accessdate=July 21, 2007}}</ref> 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).<ref>{{cite web |url=http://www.deadiversion.usdoj.gov/21cfr/cfr/1301/1301_26.htm |title=USC 201 Section 1301.26 Exemptions from import or export requirements for personal medical use |publisher=[[United States Department of Justice]] |date=March 24, 1997}}</ref> Under the US [[Pure Food and Drug Act]], drug companies are not allowed to market their drugs for [[off-label use]]s (conditions other than those officially approved by the FDA);<ref>{{cite web |publisher=U.S. Food and Drug Administration |title=Prescription Drug Marketing Act of 1987 (PDMA), PL 100-293 |url=http://www.fda.gov/opacom/laws/pdma.html |archiveurl=https://web.archive.org/web/20080223233036/http://www.fda.gov/opacom/laws/pdma.html |archivedate=February 23, 2008}}</ref> Cephalon was reprimanded in 2002 by the FDA because its promotional materials were found to be "false, lacking in fair balance, or otherwise misleading".<ref>{{cite web |url=http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/WarningLettersandNoticeofViolationLetterstoPharmaceuticalCompanies/UCM164556.pdfFDA |title=Letter to Cephalon 01/03/2002 |date=January 3, 2002 |accessdate=July 4, 2012}}</ref> Cephalon pleaded guilty to a criminal violation and paid several fines, including {{nowrap|$50 million}} and {{nowrap|$425 million}} fines to the U.S. government in 2008.<ref>"Cephalon executives have repeatedly said that they do not condone off-label use of Provigil, but in 2002 the company was reprimanded by the FDA for distributing marketing materials that presented the drug as a remedy for tiredness, "decreased activity" and other supposed ailments. In 2008, Cephalon paid $425m and pleaded guilty to a federal criminal charge relating to its promotion of off-label uses for Provigil and two other drugs." http://www.law360.com/articles/127434 {{Verify source|date=June 2012}}</ref><ref>{{cite web |url=http://www.fiercehealthcare.com/story/cephalon-settlement-requires-physician-payments-be-disclosed/2008-09-30 |date=September 30, 2008 |author=Anne Zieger |title=Cephalon settlement requires physician payments to be disclosed |work=Fierce Healthcare}}</ref>

==== China ====

In mainland [[China]], modafinil is strictly controlled like other stimulants, such as [[amphetamines]] and [[methylphenidate]], and not approved for medical use.<ref>{{cite web |url=http://www.sda.gov.cn/WS01/CL0844/94735.html |title=食品药品监管总局　公安部　国家卫生计生委关于公布麻醉药品和精神药品品种目录的通知 |publisher = China Food and Drug Administration |accessdate=Nov 11, 2013}}</ref>

==== Japan ====

In [[Japan]], modafinil is Schedule I psychotropic drug.<ref>http://www.nco.go.jp/dl_data/keitai/keitai_guideh26.pdf</ref><ref>http://www.fukushihoken.metro.tokyo.jp/kenkou/iyaku/sonota/shitei_m/moda.html</ref> There have been reported arrests of people who imported modafinil for personal use.<ref>http://medicallaw.exblog.jp/20422896</ref><ref>http://hayabusa3.2ch.net/test/read.cgi/news/1391949369/</ref>

==== 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.<ref>http://base.consultant.ru/cons/cgi/online.cgi?req=doc;base=LAW;n=142882;fld=134;dst=4294967295;rnd=0.8965571122244;from=141820-563</ref>

==== Other countries ====

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

* Canada (not listed in the [[Controlled Drugs and Substances Act]], but it is a Schedule F prescription drug,<ref>{{cite journal |url=http://gazette.gc.ca/archives/p1/2005/2005-03-26/html/reg5-eng.html#REF1 |title=Regulations Amending the Food and Drug Regulations (1184 — Modafinil) |journal=[[Canada Gazette]] |volume=140 |issue=20 |date=March 26, 2005 |format=– ^{[http://scholar.google.co.uk/scholar?hl=en&lr=&q=intitle%3ARegulations+Amending+the+Food+and+Drug+Regulations+%281184+%E2%80%94+Modafinil%29&as_publication=%5B%5BCanada+Gazette%5D%5D&as_ylo=&as_yhi=&btnG=Search Scholar search]} |author=<!--Staff writer(s); no by-line.--> |archiveurl=https://web.archive.org/web/20110706181716/http://gazette.gc.ca/archives/p1/2005/2005-03-26/html/reg5-eng.html |archivedate=July 6, 2011}}</ref> so it is subject to seizure by [[Canada Border Services Agency]])

* In [[Finland]] and [[Sweden]] modafinil is a prescription drug but not listed as a controlled substance.<ref>{{cite web|url=http://www.finlex.fi/fi/laki/alkup/2009/20091095|title=Lääkealan turvallisuus- ja kehittämiskeskuksen päätöslääkeluettelosta|date=2009|publisher=}}</ref><ref>https://www.fass.se/LIF/product?docType=7&specId=&userType=&nplId=20011005000203&</ref>

* [[Mexico]] (Not listed as a controlled substance, in the National Health Law)<ref>{{cite web |url=http://www.cofepris.gob.mx/pyp/estpsic/es.htm |title=Estupefacientes y Psicotrópicos |trans_title=Narcotic Drugs and Psychotropic Substances |language=Spanish |accessdate=July 21, 2007 |publisher=<!--Comisión Federal para la Protección contra Riesgos Sanitarios-->Federal Commission for Protection against Health Risks |archiveurl=https://web.archive.org/web/20070713135452/http://www.cofepris.gob.mx/pyp/estpsic/es.htm |archivedate=July 13, 2007}}</ref>

* [[South Africa]] Schedule V<ref>{{cite web |url = http://www.saflii.org/za/legis/consol_reg/marsa101o1965rangnr510723.pdf|title = GENERAL REGULATIONS MADE IN TERMS OF THE MEDICINES AND RELATED SUBSTANCES ACT 101 OF 1965, AS AMENDED Government Notice R510 in Government Gazette 24727 dated 10 April 2003. 22A/16/b; states that although import and export is restricted, possession is not illegal providing that a prescription is present.|author = SA Government|date = April 10, 2003|publisher = SAFLII|location = Pretoria|accessdate = Nov 11, 2016}}</ref>

* [[United Kingdom]] (not listed in [[Misuse of Drugs Act 1971|Misuse of Drugs Act]] so possession not illegal, but prescription required) <ref>{{cite web |url = http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con273748.pdf|title = MHRA license for Modafinil in UK|author = MHRA|date = April 3, 2013|publisher = MHRA|location = London|accessdate = April 3, 2013}}</ref>

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.<ref>{{cite web|title=Modafinil - International Brands|url=https://www.drugs.com/international/modafinil.html|publisher=Drugs.com|accessdate=8 January 2017}}</ref>

===Doping agent===

====Sports====

The regulation of modafinil as a [[Doping in sport|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]]<ref>{{cite news |url=http://www.cyclingnews.com/news/clinger-given-lifetime-ban-for-second-doping-infraction |title=Clinger given lifetime ban for second doping infraction |publisher=Cycling News |date=August 14, 2011|accessdate=October 8, 2014}}</ref> and basketball player [[Diana Taurasi]]<ref>{{cite news |url=https://www.washingtonpost.com/wp-dyn/content/article/2010/12/24/AR2010122402993.html |publisher=The Washington Post |title=Taurasi tested positive for modafinil |date=December 25, 2010 |accessdate=December 31, 2013}}</ref> in 2010, and rower Timothy Grant in 2015<ref>{{cite web|url=https://www.theguardian.com/sport/2015/nov/23/british-rowers-handed-two-year-bans-doping-violations-sybren-hoogland-timothy-grant|title=British rowers handed two-year bans for taking banned substances|first=Guardian|last=sport|date=November 23, 2015|publisher=|via=The Guardian}}</ref>) were discovered allegedly using it as a performance-enhancing [[doping (sport)|doping]] agent. (Taurasi and another player, Monique Coker, tested at the same lab, were later cleared.<ref>{{cite web |url=http://sports.espn.go.com/wnba/columns/story?columnist=voepel_mechelle&id=6135920 |author=Voepel M |title=Taurasi: 'I've lost 3 months of my career' |date=February 18, 2011}}</ref>) 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.<ref>{{cite news |title=Bonds Exposed |url=http://sportsillustrated.cnn.com/2006/baseball/mlb/03/06/news.excerpt/1.html |work=Sports Illustrated |accessdate=July 2, 2011 |date=March 7, 2006}}</ref> Modafinil has been shown to prolong exercise time to exhaustion while performing at 85% of VO_2max and also reduces the perception of effort required to maintain this threshold.<ref>{{cite journal | vauthors = Jacobs I, Bell DG | title = Effects of acute modafinil ingestion on exercise time to exhaustion | journal = Medicine and Science in Sports and Exercise | volume = 36 | issue = 6 | pages = 1078–82 | date = Jun 2004 | pmid = 15179180 | doi = 10.1249/01.MSS.0000128146.12004.4F }}</ref> Modafinil was added to the [[World Anti-Doping Agency]] "Prohibited List" in 2004 as a prohibited stimulant (see [[#Legal status|Modafinil Legal Status]]).

====Nootropic====

{{See also|#Cognitive enhancement}}

Modafinil has been used non-medically as a "[[nootropic|smart drug]]" by students, office workers, [[#Military and astronauts|soldiers]] and [[transhumanist]]s.<ref>{{cite web|title=Super Soldiers? Military Drug New Rage|url=http://abcnews.go.com/Technology/Health/story?id=3408266|publisher=ABC News|date=7 December 2008}}</ref><ref>{{cite web|title=Like It or Not, "Smart Drugs" Are Coming to the Office|url=https://hbr.org/2016/05/like-it-or-not-smart-drugs-are-coming-to-the-office|publisher=Harvard Business Review|date=May 2015}}</ref><ref>{{cite web|last1=Cadwalladr|first1=Carole|title=Students used to take drugs to get high. Now they take them to get higher grades|url=https://www.theguardian.com/society/2015/feb/15/students-smart-drugs-higher-grades-adderall-modafinil|publisher=The Guardian|date=14 February 2015}}</ref><ref>{{cite web|last1=Talbot|first1=Margaret|title=Brain Gain|url=http://www.newyorker.com/magazine/2009/04/27/brain-gain|publisher=The New Yorker|accessdate=9 April 2017}}</ref><ref>{{cite web|last1=Plotz|first1=David|title=Medikamente: 100 Milligramm Arbeitswut|url=http://www.zeit.de/2003/35/M-Modafinil/komplettansicht|publisher=Die Zeit|accessdate=9 April 2017|date=21 August 2003}}</ref> It is often compared to the fictional smart drug NZT-48 depicted in ''[[Limitless (film)|Limitless]]'' and sometimes called "the 'Limitless' pill".<ref>{{cite web|title=The 'Limitless Pill' Could Soon Turn Us All into Superhuman Workers|url=https://www.vice.com/en_us/article/could-we-all-soon-be-taking-the-limitless-pill-modafinil-study-drug-britain-universities-working-culture|publisher=Vice|accessdate=9 April 2017|language=en-us}}</ref><ref>{{cite web|title=Why Can't We All Take Modafinil?|url=https://www.vice.com/en_se/article/why-cant-we-all-take-modafinil|publisher=Vice|accessdate=9 April 2017|language=en-us}}</ref><ref>{{cite web|title=Seen At 11: A Real-Life Superhero Pill? Looking Into The 'Limitless' Drug|url=http://newyork.cbslocal.com/2015/11/10/modafinil-limitless-superhero-drug/|accessdate=9 April 2017}}</ref><ref name=cbs41>{{cite web|title=New pill could boost brain function, decision making|url=http://cbs4indy.com/2015/11/10/new-pill-could-boost-brain-function-decision-making/|publisher=CBS 4|accessdate=9 April 2017|date=11 November 2015}}</ref>

==Research==

===ADHD===

Double-blind randomized controlled trials have demonstrated the efficacy and tolerability of modafinil in pediatric ADHD,<ref>{{cite journal|vauthors=Biederman J, Swanson JM, Wigal SB, Boellner SW, Earl CQ, Lopez FA |title=A comparison of once-daily and divided doses of modafinil in children with attention-deficit/hyperactivity disorder: a randomized, double-blind, and placebo-controlled study|journal=The Journal of Clinical Psychiatry |volume=67 |issue=5 |pages=727–35 |date=May 2006|pmid=16841622 |url=http://article.psychiatrist.com/?ContentType=START&ID=10002551|doi=10.4088/JCP.v67n0506}}</ref><ref>{{cite journal|vauthors=Greenhill LL, Biederman J, Boellner SW |title=A randomized, double-blind, placebo-controlled study of modafinil film-coated tablets in children and adolescents with attention-deficit/hyperactivity disorder |journal=Journal of the American Academy of Child and Adolescent Psychiatry |volume=45 |issue=5 |pages=503–11 |date=May 2006 |pmid=16601402 |doi=10.1097/01.chi.0000205709.63571.c9}}</ref> however there are risks of serious side effects such as [[modafinil#Toxicity|skin reactions]] and modafinil is not recommended for use in children.<ref>{{cite web|author=Cephalon, Inc.|date=21 December 2007|format=PDF|url=http://secure.healthlinks.net.au/content/csl/pi.cfm?product=cspmodav11207 |title=Modavigil Product Information |accessdate=2 July 2008 |work=healthlinks.net|publisher=healthlinks.net Pty. Ltd. | archiveurl= https://web.archive.org/web/20080721114706/http://secure.healthlinks.net.au/content/csl/pi.cfm?product=cspmodav11207| archivedate=July 21, 2008}}</ref>{{Rp|7}} In the United States, it was originally pending marketing as Sparlon for pediatric ADHD, but approval was denied by the FDA due to major concerns over the occurrence of [[Stevens-Johnson Syndrome]] in clinical trials.<ref>{{cite journal|author=Kumar R|title=Approved and investigational uses of modafinil : an evidence-based review|journal=Drugs|volume=68|issue=13|pages=1803–39|year=2008|pmid=18729534|doi=10.2165/00003495-200868130-00003|url=}}</ref>

===Depersonalization disorder===

Modafinil used alone has been reported to be effective in a subgroup of individuals with [[depersonalization disorder]];{{Citation needed|date=October 2016}} the subgroup of people with depersonalization disorder most likely to respond are those who have attentional impairments, under-arousal, and [[hypersomnia]]. However, clinical trials have not been conducted.<ref name="isbn0-521-87498-X">{{cite book |author=Mauricio Sierra |title=Depersonalization: A New Look at a Neglected Syndrome |publisher=Cambridge University Press |location=Cambridge, UK |date=August 13, 2009 |page=120 |isbn=0-521-87498-X |url=https://books.google.com/books?id=qOat1nDGZAkC}}</ref> [[Evan Torch|Dr. Evan Torch]] calls a combination of an [[SSRI]] and modafinil "the hidden pearl that can really help depersonalization disorder."<ref>{{Cite book |title=Feeling Unreal: Depersonalization Disorder and the Loss of the Self |year=2006 |page=256 |isbn=978-0-19-517022-1 |vauthors=Simeon D, Abugel J }}</ref>

===Psychiatric/neurodegenerative disorders===

It has been studied for [[major depressive disorder|depression]],<ref>{{cite journal | vauthors = Fava M, Thase ME, DeBattista C, Doghramji K, Arora S, Hughes RJ | title = Modafinil augmentation of selective serotonin reuptake inhibitor therapy in MDD partial responders with persistent fatigue and sleepiness | journal = Annals of Clinical Psychiatry | volume = 19 | issue = 3 | pages = 153–9 | year = 2007 | pmid = 17729016 | doi = 10.1080/10401230701464858 }}</ref> [[bipolar depression]],<ref name="pmid17671288">{{cite journal | vauthors = Frye MA, Grunze H, Suppes T, McElroy SL, Keck PE, Walden J, Leverich GS, Altshuler LL, Nakelsky S, Hwang S, Mintz J, Post RM | title = A placebo-controlled evaluation of adjunctive modafinil in the treatment of bipolar depression | journal = The American Journal of Psychiatry | volume = 164 | issue = 8 | pages = 1242–9 | date = Aug 2007 | pmid = 17671288 | doi = 10.1176/appi.ajp.2007.06060981 }}</ref><ref name="pmid20673554">{{cite journal | vauthors = Calabrese JR, Ketter TA, Youakim JM, Tiller JM, Yang R, Frye MA | title = Adjunctive armodafinil for major depressive episodes associated with bipolar I disorder: a randomized, multicenter, double-blind, placebo-controlled, proof-of-concept study | journal = The Journal of Clinical Psychiatry | volume = 71 | issue = 10 | pages = 1363–70 | date = Oct 2010 | pmid = 20673554 | doi = 10.4088/JCP.09m05900gry }}</ref> [[opiate]] and [[cocaine dependence]],<ref name="pmid20631691">{{cite journal | vauthors = Tahsili-Fahadan P, Carr GV, Harris GC, Aston-Jones G | title = Modafinil blocks reinstatement of extinguished opiate-seeking in rats: mediation by a glutamate mechanism | journal = Neuropsychopharmacology | volume = 35 | issue = 11 | pages = 2203–10 | date = Oct 2010 | pmid = 20631691 | pmc = 2939923 | doi = 10.1038/npp.2010.94 }}</ref><ref name="pmid15525998"/> [[Parkinson's disease]],<ref>{{cite journal | vauthors = van Vliet SA, Vanwersch RA, Jongsma MJ, van der Gugten J, Olivier B, Philippens IH | title = Neuroprotective effects of modafinil in a marmoset Parkinson model: behavioral and neurochemical aspects | journal = Behavioural Pharmacology | volume = 17 | issue = 5–6 | pages = 453–62 | date = Sep 2006 | pmid = 16940766 | doi = 10.1097/00008877-200609000-00011 | url = http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?an=00008877-200609000-00011 }}</ref> [[schizophrenia]],<ref>{{cite journal | vauthors = Turner DC, Clark L, Pomarol-Clotet E, McKenna P, Robbins TW, Sahakian BJ | title = Modafinil improves cognition and attentional set shifting in patients with chronic schizophrenia | journal = Neuropsychopharmacology | volume = 29 | issue = 7 | pages = 1363–73 | date = Jul 2004 | pmid = 15085092 | doi = 10.1038/sj.npp.1300457 }}</ref> and disease-related [[Fatigue (medical)|fatigue]],<ref>{{cite journal | vauthors = Rammohan KW, Rosenberg JH, Lynn DJ, Blumenfeld AM, Pollak CP, Nagaraja HN | title = Efficacy and safety of modafinil (Provigil) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 72 | issue = 2 | pages = 179–83 | date = Feb 2002 | pmid = 11796766 | pmc = 1737733 | doi = 10.1136/jnnp.72.2.179 | url = http://jnnp.bmj.com/cgi/pmidlookup?view=long&pmid=11796766 }}</ref><ref>{{cite journal | vauthors = Rabkin JG, McElhiney MC, Rabkin R, Ferrando SJ | title = Modafinil treatment for fatigue in HIV+ patients: a pilot study | journal = The Journal of Clinical Psychiatry | volume = 65 | issue = 12 | pages = 1688–95 | date = Dec 2004 | pmid = 15641875 | doi = 10.4088/JCP.v65n1215 | url = http://article.psychiatrist.com/?ContentType=START&ID=10001163 }}</ref> as well as fatigue that is the side effect of other medication.<ref name="pmid15367049">{{cite journal | vauthors = Schwartz TL, Azhar N, Cole K, Hopkins G, Nihalani N, Simionescu M, Husain J, Jones N | title = An open-label study of adjunctive modafinil in patients with sedation related to serotonergic antidepressant therapy | journal = The Journal of Clinical Psychiatry | volume = 65 | issue = 9 | pages = 1223–7 | date = Sep 2004 | pmid = 15367049 | doi = 10.4088/JCP.v65n0910 }}</ref>

Modafinil may also be an effective and well-tolerated treatment in patients with [[seasonal affective disorder]].<ref name="pmid15306145">{{cite journal | vauthors = Lundt L | title = Modafinil treatment in patients with seasonal affective disorder/winter depression: an open-label pilot study | journal = Journal of Affective Disorders | volume = 81 | issue = 2 | pages = 173–8 | date = Aug 2004 | pmid = 15306145 | doi = 10.1016/S0165-0327(03)00162-9 }}</ref>

A [[Randomized controlled trial|randomized]] [[double-blind study]] of modafinil showed that normal healthy volunteers between the ages of 30–44 showed general improvement in alertness as well as mood. In the three-day study, counterbalanced, randomized, crossover, inpatient trial of modafinil 400&nbsp;mg was administered as well as a placebo to the control group. The conclusion demonstrated that modafinil may have general mood-elevating effects in particular for the adjunctive use in [[treatment-resistant depression]].<ref name="Bonaventure"/>

===Cocaine addiction===

Modafinil is under investigation as a possible method to treat [[cocaine dependence]], for several reasons involving biochemical mechanisms of the two drugs, as well as the observation that clinical effects of modafinil are largely opposite to symptoms of cocaine withdrawal.

The pilot 8-week double-blind study of modafinil for cocaine dependence (2004) produced inconclusive results. The number of cocaine-positive urine samples was significantly lower in the modafinil group as compared to the placebo group in the middle of the trial, but by the end of the 8 weeks the difference stopped being significant. Even before the treatment began, the modafinil group had lower cocaine consumption further confounding the results. As compared to placebo, modafinil did not reduce cocaine craving or self-reported cocaine use, and the physicians ratings were only insignificantly better.<ref name="pmid15525998">{{cite journal | vauthors = Dackis CA, Kampman KM, Lynch KG, Pettinati HM, O'Brien CP | title = A double-blind, placebo-controlled trial of modafinil for cocaine dependence | journal = Neuropsychopharmacology | volume = 30 | issue = 1 | pages = 205–11 | date = Jan 2005 | pmid = 15525998 | doi = 10.1038/sj.npp.1300600 }}</ref> Dan Umanoff, of the National Association for the Advancement and Advocacy of Addicts, criticized the authors of the study for leaving the negative results out of the discussion part and the abstract of the article.<ref name="pmid16294193">{{cite journal | vauthors = Umanoff DF | title = Trial of modafinil for cocaine dependence | journal = Neuropsychopharmacology | volume = 30 | issue = 12 | pages = 2298; author reply 2299–300 | date = Dec 2005 | pmid = 16294193 | doi = 10.1038/sj.npp.1300866 }}</ref><ref>{{cite journal |vauthors=Dackis CA, Kampman KM, Lynch KG, Pettinati HM, O'Brien CP |title=Reply: Do Self-Reports Reliably Assess Abstinence in Cocaine-Dependent Patients? |journal=Neuropsychopharmacology |volume=30 |issue=12 |pages=2299–300 |year=2005 |doi=10.1038/sj.npp.1300867}}</ref>

A later double-blind study of modafinil in people seeking treatment for cocaine dependence found no statistically significant effect on the rate of change in percentage of cocaine non-use days, but noted a significant improvement in the maximum number of consecutive non-use days for cocaine and reduced craving.<ref name="pmid19560290">{{cite journal | vauthors = Anderson AL, Reid MS, Li SH, Holmes T, Shemanski L, Slee A, Smith EV, Kahn R, Chiang N, Vocci F, Ciraulo D, Dackis C, Roache JD, Salloum IM, Somoza E, Urschel HC, Elkashef AM | title = Modafinil for the treatment of cocaine dependence | journal = Drug and Alcohol Dependence | volume = 104 | issue = 1–2 | pages = 133–9 | date = Sep 2009 | pmid = 19560290 | pmc = 2818032 | doi = 10.1016/j.drugalcdep.2009.04.015 }}</ref>

===Weight loss===

Studies on modafinil (even those on healthy weight individuals) indicate that it has an appetite reducing/weight loss effect.<ref name="nightshift">{{cite journal | vauthors = Hart CL, Haney M, Vosburg SK, Comer SD, Gunderson E, Foltin RW | title = Modafinil attenuates disruptions in cognitive performance during simulated night-shift work | journal = Neuropsychopharmacology | volume = 31 | issue = 7 | pages = 1526–36 | date = Jul 2006 | pmid = 16395298 | doi = 10.1038/sj.npp.1300991 }}</ref><ref name="Clo"/><ref>{{cite web |url=http://www.psychiatrist.com/pcc/pccpdf/v08n06/v08n0606.pdf |title=Efficacy and Safety of Modafinil Film-Coated Tablets in Children and Adolescents |format=PDF |accessdate=July 4, 2012}}</ref><ref>{{cite journal | vauthors = Vaishnavi S, Gadde K, Alamy S, Zhang W, Connor K, Davidson JR | title = Modafinil for atypical depression: effects of open-label and double-blind discontinuation treatment | journal = Journal of Clinical Psychopharmacology | volume = 26 | issue = 4 | pages = 373–8 | date = Aug 2006 | pmid = 16855454 | doi = 10.1097/01.jcp.0000227700.263.75.39 }}</ref><ref name="ssri">{{cite journal | vauthors = Thase ME, Fava M, DeBattista C, Arora S, Hughes RJ | title = Modafinil augmentation of SSRI therapy in patients with major depressive disorder and excessive sleepiness and fatigue: a 12-week, open-label, extension study | journal = CNS Spectrums | volume = 11 | issue = 2 | pages = 93–102 | date = Feb 2006 | pmid = 16520686 | doi = 10.1017/s1092852900010622}}</ref> All studies on modafinil in the Medline database that are for one month or longer which report weight changes find that modafinil users experience weight loss compared to placebo.<ref>{{cite journal | vauthors = Makris AP, Rush CR, Frederich RC, Kelly TH | title = Wake-promoting agents with different mechanisms of action: comparison of effects of modafinil and amphetamine on food intake and cardiovascular activity | journal = Appetite | volume = 42 | issue = 2 | pages = 185–95 | date = Apr 2004 | pmid = 15010183 | doi = 10.1016/j.appet.2003.11.003 }}</ref> In 2008, one small-scale study on individuals performing simulated shift work quantified the effect as an 18% decrease in total caloric intake on 200&nbsp;mg/day, and a 38% decrease on 400&nbsp;mg/day.<ref name="pmid18573275">{{cite journal | vauthors = Perez GA, Haney M, Foltin RW, Hart CL | title = Modafinil decreases food intake in humans subjected to simulated shift work | journal = Pharmacology, Biochemistry, and Behavior | volume = 90 | issue = 4 | pages = 717–22 | date = Oct 2008 | pmid = 18573275 | doi = 10.1016/j.pbb.2008.05.018 }}</ref>

However, 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."<ref name="urlprovigil.com">{{cite web |url=http://provigil.com/media/PDFs/medication_guide.pdf |title=Provigil |date=November 1, 2010 |work=Medication Guide |publisher=Cephalon, Inc. |accessdate=December 31, 2013}}</ref>

In experimental studies, the appetite reducing effect of modafinil appears to be similar to that of [[substituted amphetamine]]s, but, unlike substituted amphetamines, the dose of modafinil that is effective at decreasing food intake does not significantly increase heart rate. Also, an article published in the ''Annals of Clinical Psychiatry'', presented the case of a 280-pound patient (BMI=35.52) who lost 40 pounds over the course of a year on modafinil (to 30.44 BMI). After three years, his weight stabilized at a 50-pound weight loss (29.59 BMI). The authors conclude that placebo controlled studies should be conducted on using modafinil as a weight loss agent.<ref name="Clo">{{cite journal | vauthors = Henderson DC, Louie PM, Koul P, Namey L, Daley TB, Nguyen DD | title = Modafinil-associated weight loss in a clozapine-treated schizoaffective disorder patient | journal = Annals of Clinical Psychiatry | volume = 17 | issue = 2 | pages = 95–7 | year = 2005 | pmid = 16075662 | doi = 10.1080/10401230590932407 }}</ref> Conversely, a US patent (#6,455,588) on using modafinil as an appetite ''stimulating'' agent has been filed by Cephalon in 2000.

===Delayed sleep phase syndrome===

Modafinil has been studied as a possible treatment for [[delayed sleep phase syndrome]], which causes excessive daytime somnolence when the natural (delayed) diurnal rhythm is replaced by a socially determined earlier or forward shifted sleep schedule.<ref name="pmid20505660">{{cite journal | vauthors = Grady S, Aeschbach D, Wright KP, Czeisler CA | title = Effect of modafinil on impairments in neurobehavioral performance and learning associated with extended wakefulness and circadian misalignment | journal = Neuropsychopharmacology | volume = 35 | issue = 9 | pages = 1910–20 | date = Aug 2010 | pmid = 20505660 | pmc = 2904872 | doi = 10.1038/npp.2010.63 }}</ref>

{{See also|Neuroenhancement|Nootropic|#Nootropic}}

There is disagreement to whether the cognitive effects modafinil showed in healthy non-sleep-deprived people are sufficient to consider it to be a [[cognitive enhancer]].<ref name="pmid12417966">{{cite journal | vauthors = Turner DC, Robbins TW, Clark L, Aron AR, Dowson J, Sahakian BJ | title = Cognitive enhancing effects of modafinil in healthy volunteers | journal = Psychopharmacology | volume = 165 | issue = 3 | pages = 260–9 | date = Jan 2003 | pmid = 12417966 | doi = 10.1007/s00213-002-1250-8 }}</ref><ref name="pmid15738750">{{cite journal | vauthors = Randall DC, Viswanath A, Bharania P, Elsabagh SM, Hartley DE, Shneerson JM, File SE | title = Does modafinil enhance cognitive performance in young volunteers who are not sleep-deprived? | journal = Journal of Clinical Psychopharmacology | volume = 25 | issue = 2 | pages = 175–9 | date = Apr 2005 | pmid = 15738750 | doi = 10.1097/01.jcp.0000155816.21467.25 }}</ref><ref name="pmid15252824">{{cite journal | vauthors = Baranski JV, Pigeau R, Dinich P, Jacobs I | title = Effects of modafinil on cognitive and meta-cognitive performance | journal = Human Psychopharmacology | volume = 19 | issue = 5 | pages = 323–32 | date = Jul 2004 | pmid = 15252824 | doi = 10.1002/hup.596 }}</ref><ref name="pmid26381811">{{cite journal | vauthors = Battleday RM, Brem AK | title = Modafinil for cognitive neuroenhancement in healthy non-sleep-deprived subjects: A systematic review | journal = European Neuropsychopharmacology : the Journal of the European College of Neuropsychopharmacology | volume = 25 | issue = 11 | pages = 1865–81 | year = 2015 | pmid = 26381811 | doi = 10.1016/j.euroneuro.2015.07.028 | lay-summary = http://www.livescience.com/51919-modafil-improves-attention-learning.html | lay-source = Live Science }}</ref> The researchers agree that modafinil improves some aspects of [[working memory]], such as [[memory span|digit span]], digit manipulation and [[Pattern recognition (Physiological Psychology)|pattern recognition]] memory, but the results related to [[spatial memory]], [[executive system|executive function]] and [[attention]] are equivocal.<ref name="pmid12417966"/><ref name="pmid15738750"/><ref name="pmid15252824"/><ref name="pmid15221200">{{cite journal | vauthors = Müller U, Steffenhagen N, Regenthal R, Bublak P | title = Effects of modafinil on working memory processes in humans | journal = Psychopharmacology | volume = 177 | issue = 1–2 | pages = 161–9 | date = Dec 2004 | pmid = 15221200 | doi = 10.1007/s00213-004-1926-3 }}</ref> Some positive effects of modafinil may be limited to "lower-performing" individuals.<ref name="pmid15221200"/><ref name="pmid16140369">{{cite journal | vauthors = Randall DC, Shneerson JM, File SE | title = Cognitive effects of modafinil in student volunteers may depend on IQ | journal = Pharmacology, Biochemistry, and Behavior | volume = 82 | issue = 1 | pages = 133–9 | date = Sep 2005 | pmid = 16140369 | doi = 10.1016/j.pbb.2005.07.019 | url = http://www.erowid.org/references/refs_view.php?A=ShowDocPartFrame&ID=6624&DocPartID=6148 }}</ref> One study found that modafinil restored normal levels of learning ability in [[methamphetamine]] addicts, but had no effect on non-addicts.<ref name="pmid21289606">{{cite journal | vauthors = Ghahremani DG, Tabibnia G, Monterosso J, Hellemann G, Poldrack RA, London ED | title = Effect of modafinil on learning and task-related brain activity in methamphetamine-dependent and healthy individuals | journal = Neuropsychopharmacology | volume = 36 | issue = 5 | pages = 950–9 | date = Apr 2011 | pmid = 21289606 | pmc = 3077264 | doi = 10.1038/npp.2010.233 }}</ref> Modafinil reduces the symptoms of [[attention-deficit hyperactivity disorder]]<ref name="pmid16623645">{{cite journal | vauthors = Turner D | title = A review of the use of modafinil for attention-deficit hyperactivity disorder | journal = Expert Review of Neurotherapeutics | volume = 6 | issue = 4 | pages = 455–68 | year = 2006 | pmid = 16623645 | doi = 10.1586/14737175.6.4.455 }}</ref> and improves working and episodic memory.<ref name="pmid17712350">{{cite journal | vauthors = Minzenberg MJ, Carter CS | title = Modafinil: a review of neurochemical actions and effects on cognition | journal = Neuropsychopharmacology | volume = 33 | issue = 7 | pages = 1477–502 | year = 2008 | pmid = 17712350 | doi = 10.1038/sj.npp.1301534 }}</ref>

Researchers from the [[University of Oxford]] and [[Harvard Medical School]] evaluated all research papers on cognitive enhancement with modafinil from January 1990 to December 2014 and found 24 studies dealing with benefits that include planning, [[decision making]], flexibility, learning, memory and creativity associated with taking modafinil.<ref name=cbs41/><ref>{{cite web|title=Review of ‘smart drug’ shows modafinil does enhance cognition|url=http://www.ox.ac.uk/news/2015-08-20-review-%E2%80%98smart-drug%E2%80%99-shows-modafinil-does-enhance-cognition|publisher=University of Oxford|accessdate=9 April 2017}}</ref><ref>{{cite web|last1=Waugh|first1=Rob|title=‘My brain is ninja level’: New ‘smart drug’ actually makes you cleverer|url=http://metro.co.uk/2015/10/28/my-brain-is-ninja-level-new-smart-drug-actually-makes-you-cleverer-5467361/|publisher=Metro|accessdate=9 April 2017|date=28 October 2015}}</ref><ref>{{cite web|title='Smart drug' taken by one in four students really does boost performance|url=http://www.telegraph.co.uk/news/science/science-news/11812682/Smart-drug-taken-by-one-in-four-students-really-does-boost-performance.html|publisher=The Telegraph|accessdate=9 April 2017|language=en}}</ref> The reviewers state that while only limited information is available on the effects of long-term use the drug appeared safe in the short term, with few side effects and no addictive qualities.<ref>{{cite web|last1=Thomson|first1=Helen|title=Narcolepsy medication modafinil is world's first safe 'smart drug'|url=https://www.theguardian.com/science/2015/aug/20/narcolepsy-medication-modafinil-worlds-first-safe-smart-drug|publisher=The Guardian|accessdate=9 April 2017|date=19 August 2015}}</ref>

In March 2017 a study by researchers throughout Germany and Sweden led by psychiatrist Klaus Lieb at the [[University of Mainz]] found that modafinil improved the [[chess]] players' performances by an average of 15 percent.<ref>{{cite web|title=Cognitive enhancing drugs can improve chess play, scientists show|url=https://www.sciencedaily.com/releases/2017/03/170306091726.htm|publisher=Science Daily|accessdate=9 April 2017}}</ref><ref>{{cite web|title=A new study reveals that certain drugs may make us smarter than we thought|url=http://www.businessinsider.de/modafinil-methylphenidate-nootropic-cognitive-enhancer-chess-study-2017-3|publisher=Business Insider|accessdate=9 April 2017|language=en}}</ref><ref>{{cite web|last1=Hamblin|first1=James|title=On Cognitive Doping in Chess (and Life)|url=https://www.theatlantic.com/health/archive/2017/03/cognitive-enhancement-paradox/519948/|publisher=The Atlantic|accessdate=9 April 2017}}</ref><ref>{{cite web|title=Special Report: New Study Finds Performance-Enhancing Drugs for Chess|url=https://worldchess.com/2017/01/25/special-report-new-study-finds-performance-enhancing-drugs-for-chess/|website=World Chess|accessdate=9 April 2017}}</ref><ref>{{cite journal|last1=Franke|first1=Andreas G.|last2=Gränsmark|first2=Patrik|last3=Agricola|first3=Alexandra|last4=Schühle|first4=Kai|last5=Rommel|first5=Thilo|last6=Sebastian|first6=Alexandra|last7=Balló|first7=Harald E.|last8=Gorbulev|first8=Stanislav|last9=Gerdes|first9=Christer|last10=Frank|first10=Björn|last11=Ruckes|first11=Christian|last12=Tüscher|first12=Oliver|last13=Lieb|first13=Klaus|title=Methylphenidate, modafinil, and caffeine for cognitive enhancement in chess: A double-blind, randomised controlled trial|journal=European Neuropsychopharmacology|date=March 2017|volume=27|issue=3|pages=248–260|doi=10.1016/j.euroneuro.2017.01.006|accessdate=}}</ref>

===Post-chemotherapy cognitive impairment===

Modafinil has been used [[off-label]] in trials with people with symptoms of [[post-chemotherapy cognitive impairment]], also known as "chemobrain", but in 2011 it was found to be no better than placebo.<ref>{{cite journal | vauthors = Portela MA, Rubiales AS, Centeno C | title = The use of psychostimulants in cancer patients | journal = Current Opinion in Supportive and Palliative Care | volume = 5 | issue = 2 | pages = 164–8 | date = Jun 2011 | pmid = 21532350 | doi = 10.1097/SPC.0b013e3283462ff3 }}</ref> As of 2015 it had been studied for use in multiple sclerosis associated fatigue, but the resulting evidence was weak and inconclusive.<ref name=Cochrane2015>{{cite journal | vauthors = Mücke M, Mochamat CH, Peuckmann-Post V, Minton O, Stone P, Radbruch L | title = Pharmacological treatments for fatigue associated with palliative care | journal = The Cochrane Database of Systematic Reviews | volume = 30 | issue =5 | pages = CD006788 | year = 2015 | pmid = 26026155 | doi = 10.1002/14651858.CD006788.pub3 }}</ref>

===Motion sickness===

Modafinil has been evaluated alone and in combination with [[Hyoscine hydrobromide|scopolamine]] as an anti-motion sickness medication. It did not help by itself, but appeared to help in combination with scopolamine, acting to reduce symptoms of drowsiness associated with scopolamine.<ref>{{cite journal|last1=Hoyt|first1=RE|last2=Lawson|first2=BD|last3=McGee|first3=HA|last4=Strompolis|first4=ML|last5=McClellan|first5=MA|title=Modafinil as a potential motion sickness countermeasure.|journal=Aviation, space, and environmental medicine|date=August 2009|volume=80|issue=8|pages=709–15|pmid=19653573|doi=10.3357/asem.2477.2009}}</ref>

==See also==

{{Portal|Pharmacy and Pharmacology}}

* [[Adrafinil]]

* [[Armodafinil]]

* [[Caffeine]]

* [[CRL-40,940]]

* [[CRL-40,941]]

* [[Fluorenol]]

{{clear}}

==References==

{{Reflist|30em}}

==Further reading==

* {{cite journal | vauthors = Minzenberg MJ, Carter CS | title = Modafinil: a review of neurochemical actions and effects on cognition | journal = Neuropsychopharmacology | volume = 33 | issue = 7 | pages = 1477–502 | date = Jun 2008 | pmid = 17712350 | doi = 10.1038/sj.npp.1301534 }}

* {{cite news |title=Stay Awake Pill May Get Wider Approval |url=http://abcnews.go.com/GMA/DrJohnson/story?id=128275 |newspaper=ABC News |date=October 9, 2006}}

==External links==

* [http://www.provigil.com/ PROVIGIL – official website]

** [http://www.provigil.com/pdfs/medication_guide.pdf Medication Guide for Patients]

** [http://www.provigil.com/pdfs/prescribing_info.pdf Full Prescribing Information]

* [http://www.rxlist.com/cgi/generic2/modafinil_pi.htm RxList Patient Information] for modafinil users

* [http://ca.sys-con.com/node/1169081 "Mayo Clinic Proceedings Publishes Study of NUVIGIL in Patients with Shift Work Disorder"]

* [http://druginfo.nlm.nih.gov/drugportal/dpdirect.jsp?name=Modafinil U.S. National Library of Medicine: Drug Information Portal – Modafinil]

[[Category:Anticonvulsants]]