Modafinil

{{See also|Sleep disorder}}

Modafinil, a eugeroic or wakefulness-promoting drug, is primarily used for treating narcolepsy, a sleep disorder characterized by excessive daytime sleepiness and sudden sleep attacks.{{cite journal | vauthors = Maski K, Trotti LM, Kotagal S, Robert Auger R, Rowley JA, Hashmi SD, Watson NF | title = Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine clinical practice guideline | journal = Journal of Clinical Sleep Medicine | volume = 17 | issue = 9 | pages = 1881–1893 | date = September 2021 | pmid = 34743789 | pmc = 8636351 | doi = 10.5664/jcsm.9328 }} Being a central nervous system (CNS) stimulant itself,{{cite journal |vauthors=Cid-Jofré V, Bahamondes T, Zúñiga Correa A, Ahumada Arias I, Reyes-Parada M, Renard GM |title=Psychostimulants and social behaviors |journal=Front Pharmacol |volume=15 |pages=1364630 |date=2024 |pmid=38725665 |pmc=11079219 |doi=10.3389/fphar.2024.1364630|doi-access=free }} modafinil has lower addictive potential than classical stimulants such as amphetamine, cocaine, or methylphenidate,{{cite journal | vauthors = Kim D | title = Practical use and risk of modafinil, a novel waking drug | journal = Environmental Health and Toxicology | volume = 27 | pages = e2012007 | date = 2012 | pmid = 22375280 | pmc = 3286657 | doi = 10.5620/eht.2012.27.e2012007 }}{{cite journal | vauthors = Tanda G, Hersey M, Hempel B, Xi ZX, Newman AH | title = Modafinil and its structural analogs as atypical dopamine uptake inhibitors and potential medications for psychostimulant use disorder | journal = Current Opinion in Pharmacology | volume = 56 | pages = 13–21 | date = February 2021 | pmid = 32927246 | pmc = 8247144 | doi = 10.1016/j.coph.2020.07.007 }}{{cite journal |vauthors= Kakehi S, Tompkins DM |title=A Review of Pharmacologic Neurostimulant Use During Rehabilitation and Recovery After Brain Injury |journal=Ann Pharmacother |volume=55 |issue=10 |pages=1254–1266 |date=October 2021 |pmid=33435717 |doi=10.1177/1060028020983607 |s2cid=231593912 }} but still produces psychoactive and subjective effects typical of classical stimulants.

Narcolepsy causes a strong urge to sleep during the day and can include symptoms like cataplexy (sudden muscle weakness), sleep paralysis (inability to move or speak while falling asleep or waking up), and hallucinations. Narcolepsy is linked to a lack of the brain chemical hypocretin (orexin), primarily produced in the hypothalamus.{{cite journal | vauthors = Barateau L, Pizza F, Plazzi G, Dauvilliers Y | title = Narcolepsy | journal = Journal of Sleep Research | volume = 31 | issue = 4 | pages = e13631 | date = August 2022 | pmid = 35624073 | doi = 10.1111/jsr.13631 | s2cid = 251107306 | hdl = 11380/1280615 | hdl-access = free }}{{cite journal | vauthors = Anderson D | title = Narcolepsy: A clinical review | journal = JAAPA | volume = 34 | issue = 6 | pages = 20–25 | date = June 2021 | pmid = 34031309 | doi = 10.1097/01.JAA.0000750944.46705.36 | s2cid = 241205299 | doi-access = free | title-link = doi }} Modafinil is not a cure for narcolepsy, but it can help manage the symptoms. While modafinil is primarily used to treat excessive sleepiness, it may also help reduce the frequency and severity of cataplexy attacks in some people. Modafinil is approved for management of narcolepsy with or without cataplexy. However, it is not specifically approved for the treatment of cataplexy.{{cite journal |vauthors=Kallweit U, Bassetti CL |title=Pharmacological management of narcolepsy with and without cataplexy |journal=Expert Opin Pharmacother |volume=18 |issue=8 |pages=809–817 |date=June 2017 |pmid=28443381 |doi=10.1080/14656566.2017.1323877 |s2cid=1906751 }}

Modafinil is also prescribed for shift work sleep disorder.

Modafinil performs moderately (but better than armodafinil or solriamfetol){{cite journal |vauthors=Wang Y, Zhang W, Ye H, Xiao Y |title=Excessive daytime sleepiness in obstructive sleep apnea: Indirect treatment comparison of wake-promoting agents in patients adherent/nonadherent to primary OSA therapy |journal=Sleep Med Rev |volume=78 |issue= |pages=101997 |date=August 2024 |pmid=39243682 |doi=10.1016/j.smrv.2024.101997 |url=|doi-access=free }} as a drug to overcome excessive daytime sleepiness caused by obstructive sleep apnea,{{cite journal |vauthors=Neshat SS, Heidari A, Henriquez-Beltran M, Patel K, Colaco B, Arunthari V, Lee Mateus AY, Cheung J, Labarca G |title=Evaluating pharmacological treatments for excessive daytime sleepiness in obstructive sleep apnea: A comprehensive network meta-analysis and systematic review |journal=Sleep Med Rev |volume=76 |issue= |pages=101934 |date=August 2024 |pmid=38754208 |doi=10.1016/j.smrv.2024.101934}} though it is recommended that people with apnea use continuous positive airway pressure (CPAP) therapy, that is a sleep breathing apparatus to prevent apnea, before starting modafinil.{{cite journal | vauthors = Hashemian SM, Farhadi T | title = A review on modafinil: the characteristics, function, and use in critical care | journal = Journal of Drug Assessment | volume = 9 | issue = 1 | pages = 82–86 | date = 2020 | pmid = 32341841 | pmc = 7170336 | doi = 10.1080/21556660.2020.1745209 }}{{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 = 1445–1459 | date = November 2007 | pmid = 18041479 | pmc = 2082098 | doi = 10.1093/sleep/30.11.1445 }} When obstructive sleep apnea is comorbid with narcolepsy, modafinil is an effective drug to reduce the associated excessive daytime sleepiness.{{cite journal |vauthors=Miano S, Kheirandish-Gozal L, De Pieri M |title=Comorbidity of obstructive sleep apnea and narcolepsy: A challenging diagnosis and complex management |journal=Sleep Med X |volume=8 |issue= |pages=100126 |date=December 2024 |pmid=39386319 |doi=10.1016/j.sleepx.2024.100126|pmc=11462365 }}

Modafinil's use varies by region. In the US, it is approved for adult narcolepsy, shift work sleep disorder, and obstructive sleep apnea, but not for children. In the UK and the EU, since 2014, it is approved solely for narcolepsy, including in children (pediatric narcolepsy), with its use for other conditions restricted by the European Medicines Agency.{{cite web | url=https://www.gov.uk/drug-safety-update/modafinil-provigil-now-restricted-to-narcolepsy | title=Modafinil (Provigil): Now restricted to narcolepsy | work=Medicines and Healthcare products Regulatory Agency | access-date=December 2, 2023 | archive-date=December 15, 2023 | archive-url=https://web.archive.org/web/20231215212604/https://www.gov.uk/drug-safety-update/modafinil-provigil-now-restricted-to-narcolepsy | url-status=live }}{{cite web | url=https://www.gov.uk/drug-safety-update/modafinil-restricted-use-recommended | title=Modafinil: Restricted use recommended | publisher=Medicines and Healthcare products Regulatory Agency | access-date=December 2, 2023 | archive-date=December 2, 2023 | archive-url=https://web.archive.org/web/20231202141511/https://www.gov.uk/drug-safety-update/modafinil-restricted-use-recommended | url-status=live }}

{{As of|2024|post=,}} both the French and the American Academy of Sleep Medicine strongly recommend modafinil as the first-choice treatment for narcolepsy.{{cite journal | vauthors = Arnulf I, Thomas R, Roy A, Dauvilliers Y | title = Update on the treatment of idiopathic hypersomnia: Progress, challenges, and expert opinion | journal = Sleep Medicine Reviews | volume = 69 | pages = 101766 | date = June 2023 | pmid = 36921459 | doi = 10.1016/j.smrv.2023.101766 | s2cid = 257214950 | doi-access = free | title-link = doi | url = https://hal.science/hal-04588723/document | access-date = July 13, 2024 | archive-date = August 6, 2024 | archive-url = https://web.archive.org/web/20240806000406/https://hal.science/hal-04588723/document | url-status = live }} In Europe, modafinil is considered one of the primary drugs recommended for treating narcolepsy according to the guidelines.{{cite journal |vauthors=Winter Y, Lang C, Kallweit U, Apel D, Fleischer V, Ellwardt E, Groppa S |title=Pitolisant-supported bridging during drug holidays to deal with tolerance to modafinil in patients with narcolepsy |journal=Sleep Med |volume=112 |pages=116–121 |date=December 2023 |pmid=37839272 |doi=10.1016/j.sleep.2023.10.005 |doi-access=free }}

The UK's National Institute for Health and Care Excellence (NICE), and the US's National Multiple Sclerosis Society, endorsed the off-label use of modafinil to alleviate fatigue associated with MS in 2022.{{cite web | url=https://www.nice.org.uk/guidance/ng220 | title=Multiple sclerosis in adults: Management, Guidance | publisher=The National Institute for Health and Care Excellence (NICE) | date=June 22, 2022 | access-date=September 5, 2022 | archive-date=September 5, 2022 | archive-url=https://web.archive.org/web/20220905191147/https://www.nice.org.uk/guidance/ng220 | url-status=live }}{{cite web |url=https://www.nationalmssociety.org/Treating-MS/Medications/Provigil |title=Provigil |publisher=National Multiple Sclerosis Society |access-date=September 6, 2022 |archive-date=September 5, 2022 |archive-url=https://web.archive.org/web/20220905191147/https://www.nationalmssociety.org/Treating-MS/Medications/Provigil |url-status=live }}

MS-related fatigue is a common and often debilitating symptom experienced by people with multiple sclerosis.{{cite journal |vauthors=Ayache SS, Serratrice N, Abi Lahoud GN, Chalah MA |title=Fatigue in Multiple Sclerosis: A Review of the Exploratory and Therapeutic Potential of Non-Invasive Brain Stimulation |journal=Front Neurol |volume=13 |pages=813965 |date=2022 |pmid=35572947 |pmc=9101483 |doi=10.3389/fneur.2022.813965 |doi-access=free }}{{cite journal |vauthors=Oliva Ramirez A, Keenan A, Kalau O, Worthington E, Cohen L, Singh S |title=Prevalence and burden of multiple sclerosis-related fatigue: a systematic literature review |journal=BMC Neurol |volume=21 |issue=1 |pages=468 |date=December 2021 |pmid=34856949 |pmc=8638268 |doi=10.1186/s12883-021-02396-1 |doi-access=free }} It can significantly impact their daily functioning, quality of life, and ability to perform everyday activities. When prescribed for MS-related fatigue management, modafinil works by promoting wakefulness and increasing alertness without causing drowsiness or disrupting nighttime sleep. People with multiple sclerosis often report increased energy levels, reduced feelings of tiredness, improved cognitive function, and an overall improvement in their quality of life when taking modafinil.{{cite journal |vauthors=Ghazanfar S, Farooq M, Qazi SU, Chaurasia B, Kaunzner U |title=The use of modafinil for the treatment of fatigue in multiple sclerosis: A systematic review and meta-analysis of controlled clinical trials |journal=Brain Behav |volume=14 |issue=7 |pages=e3623 |date=July 2024 |pmid=38988104 |pmc=11237168 |doi=10.1002/brb3.3623 }} While modafinil can provide relief from MS-related fatigue symptoms, it does not treat the underlying cause or cure MS itself.

{{See also|Attention deficit hyperactivity disorder}}

Modafinil is occasionally prescribed off-label for individuals with attention deficit hyperactivity disorder (ADHD).{{cite journal | vauthors = Wilms W, Woźniak-Karczewska M, Corvini PF, Chrzanowski Ł | title = Nootropic drugs: Methylphenidate, modafinil and piracetam - Population use trends, occurrence in the environment, ecotoxicity and removal methods - A review | journal = Chemosphere | volume = 233 | pages = 771–785 | date = October 2019 | pmid = 31200137 | doi = 10.1016/j.chemosphere.2019.06.016 | s2cid = 189861826 | bibcode = 2019Chmsp.233..771W }}{{cite journal | vauthors = Kittel-Schneider S, Quednow BB, Leutritz AL, McNeill RV, Reif A | title = Parental ADHD in pregnancy and the postpartum period - A systematic review | journal = Neuroscience and Biobehavioral Reviews | volume = 124 | pages = 63–77 | date = May 2021 | pmid = 33516734 | doi = 10.1016/j.neubiorev.2021.01.002 | s2cid = 231723198 | url = https://www.zora.uzh.ch/id/eprint/198979/1/Kittel-Schneider_et_al_2021.pdf | access-date = October 19, 2023 | archive-date = October 21, 2023 | archive-url = https://web.archive.org/web/20231021234946/https://www.zora.uzh.ch/id/eprint/198979/1/Kittel-Schneider_et_al_2021.pdf | url-status = live }}{{cite journal | vauthors = Weiergräber M, Ehninger D, Broich K | title = Neuroenhancement and mood enhancement – Physiological and pharmacodynamical background | journal = Medizinische Monatsschrift für Pharmazeuten | volume = 40 | issue = 4 | pages = 154–164 | date = April 2017 | pmid = 29952165 }} It has not consistently shown efficacy in treating adult ADHD,{{cite journal |vauthors=Miskowiak KW, Obel ZK, Guglielmo R, Bonnin CD, Bowie CR, Balanzá-Martínez V, Burdick KE, Carvalho AF, Dols A, Douglas K, Gallagher P, Kessing LV, Lafer B, Lewandowski KE, López-Jaramillo C, Martinez-Aran A, McIntyre RS, Porter RJ, Purdon SE, Schaffer A, Stokes PR, Sumiyoshi T, Torres IJ, Van Rheenen TE, Yatham LN, Young AH, Vieta E, Hasler G |title=Efficacy and safety of established and off-label ADHD drug therapies for cognitive impairment or attention-deficit hyperactivity disorder symptoms in bipolar disorder: A systematic review by the ISBD Targeting Cognition Task Force |journal=Bipolar Disord |volume=26 |issue=3 |pages=216–239 |date=May 2024 |pmid=38433530 |doi=10.1111/bdi.13414|url=https://eprints.ncl.ac.uk/file_store/production/297410/28FECDCD-DACE-49B2-8260-46BED7B5094C.pdf }} especially when compared to other treatments such as lisdexamfetamine.{{cite journal | vauthors = Stuhec M, Lukić P, Locatelli I | title = Efficacy, Acceptability, and Tolerability of Lisdexamfetamine, Mixed Amphetamine Salts, Methylphenidate, and Modafinil in the Treatment of Attention-Deficit Hyperactivity Disorder in Adults: A Systematic Review and Meta-analysis | journal = The Annals of Pharmacotherapy | volume = 53 | issue = 2 | pages = 121–133 | date = February 2019 | pmid = 30117329 | doi = 10.1177/1060028018795703 | s2cid = 52019992 }} In children, modafinil is more effective than placebo for treating ADHD symptoms.{{cite journal | vauthors = Cortese S, Adamo N, Del Giovane C, Mohr-Jensen C, Hayes AJ, Carucci S, Atkinson LZ, Tessari L, Banaschewski T, Coghill D, Hollis C, Simonoff E, Zuddas A, Barbui C, Purgato M, Steinhausen HC, Shokraneh F, Xia J, Cipriani A | title = Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis | journal = The Lancet. Psychiatry | volume = 5 | issue = 9 | pages = 727–738 | date = September 2018 | pmid = 30097390 | pmc = 6109107 | doi = 10.1016/S2215-0366(18)30269-4 }}{{cite journal | vauthors = Rodrigues R, Lai MC, Beswick A, Gorman DA, Anagnostou E, Szatmari P, Anderson KK, Ameis SH | title = Practitioner Review: Pharmacological treatment of attention-deficit/hyperactivity disorder symptoms in children and youth with autism spectrum disorder: a systematic review and meta-analysis | journal = Journal of Child Psychology and Psychiatry, and Allied Disciplines | volume = 62 | issue = 6 | pages = 680–700 | date = June 2021 | pmid = 32845025 | doi = 10.1111/jcpp.13305 | s2cid = 221329069 }}

Given its approved status in the US to treat narcolepsy, physicians can also prescribe modafinil for off-label uses, such as treating ADHD in both children and adults.{{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 = 455–468 | date = April 2006 | pmid = 16623645 | doi = 10.1586/14737175.6.4.455 | s2cid = 24293088 }}{{cite journal | vauthors = Lindsay SE, Gudelsky GA, Heaton PC | title = Use of modafinil for the treatment of attention deficit/hyperactivity disorder | journal = The Annals of Pharmacotherapy | volume = 40 | issue = 10 | pages = 1829–1833 | date = October 2006 | pmid = 16954326 | doi = 10.1345/aph.1H024 | s2cid = 37368284 }}

The Canadian Network for Mood and Anxiety Treatments (CANMAT) suggests modafinil as a second-line treament for comorbid ADHD and bipolar disorder, after first-line psychostimulants and the antidepressant bupropion.{{cite journal | vauthors = Bond DJ, Hadjipavlou G, Lam RW, McIntyre RS, Beaulieu S, Schaffer A, Weiss M | title = The Canadian Network for Mood and Anxiety Treatments (CANMAT) task force recommendations for the management of patients with mood disorders and comorbid attention-deficit/hyperactivity disorder | journal = Annals of Clinical Psychiatry | volume = 24 | issue = 1 | pages = 23–37 | date = February 2012 | pmid = 22303520 }}

{{See also|Bipolar disorder}}

Modafinil is used off-label as an adjunctive treatment (i.e., in combination therapy) for the acute depressive phase in bipolar disorder.{{cite book|chapter=Efficacy of Amphetamines, Methylphenidate, and Modafinil in the Treatment of Mental Disorders|doi=10.1007/978-3-030-62059-2_319|vauthors=Retz W|title=NeuroPsychopharmacotherapy |date=2022 |pages=2465–2486 |isbn=978-3-030-62058-5 }}{{cite journal |vauthors=Dell'Osso B, Ketter TA |title=Use of adjunctive stimulants in adult bipolar depression |journal=Int J Neuropsychopharmacol |volume=16 |issue=1 |pages=55–68 |date=February 2013 |pmid=22717304 |doi=10.1017/S1461145712000326 |hdl=2434/265768 |hdl-access=free }}{{cite journal |vauthors=Shen YC |title=Treatment of acute bipolar depression |journal=Ci Ji Yi Xue Za Zhi |volume=30 |issue=3 |pages=141–147 |date=2018 |pmid=30069121 |pmc=6047324 |doi=10.4103/tcmj.tcmj_71_18 |doi-access=free }} The depressive phase of bipolar disorder may feature excessive sleepiness and fatigue. Adjunctive treatment with modafinil can be used as an augmentation for the main treatment to increase its effect and is safe and effective, especially for people who do not respond well to standard antidepressants.{{cite journal | vauthors = Nunez NA, Singh B, Romo-Nava F, Joseph B, Veldic M, Cuellar-Barboza A, Cabello Arreola A, Vande Voort JL, Croarkin P, Moore KM, Biernacka J, McElroy SL, Frye MA | title = Efficacy and tolerability of adjunctive modafinil/armodafinil in bipolar depression: A meta-analysis of randomized controlled trials | journal = Bipolar Disorders | volume = 22 | issue = 2 | pages = 109–120 | date = March 2020 | pmid = 31643130 | doi = 10.1111/bdi.12859 | doi-access = free | title-link = doi }}{{cite journal | vauthors = Elsayed OH, Ercis M, Pahwa M, Singh B | title = Treatment-Resistant Bipolar Depression: Therapeutic Trends, Challenges and Future Directions | journal = Neuropsychiatric Disease and Treatment | volume = 18 | pages = 2927–2943 | date = 2022 | pmid = 36561896 | pmc = 9767030 | doi = 10.2147/NDT.S273503 | doi-access = free | title-link = doi }} Modafinil does not significantly increase the risk of mood switch to mania or suicide attempts in people with bipolar disorder.{{cite web | url=https://www.proquest.com/openview/017f800499b0259521ea4ef8ccf503a8/1?pq-origsite=gscholar&cbl=5540454 | title=Modafinil in the treatment of selected mental disorders | website=ProQuest | access-date=February 14, 2024 | archive-date=February 14, 2024 | archive-url=https://web.archive.org/web/20240214153327/https://www.proquest.com/openview/017f800499b0259521ea4ef8ccf503a8/1?pq-origsite=gscholar&cbl=5540454 | url-status=live }} Modafinil may also have cognitive benefits in people with bipolar disorder who are in a remission state.{{cite journal |vauthors=Sousa A, Dinis-Oliveira RJ |date=2020 |title=Article commentary: Pharmacokinetic and pharmacodynamic of the cognitive enhancer modafinil: Relevant clinical and forensic aspects |journal=Substance Abuse |volume=41 |issue=2 |pages=155–173 |doi=10.1080/08897077.2019.1700584 |pmid=31951804 |bibcode=2020JPkR...41..155S |s2cid=210709160}}{{cite journal | doi=10.4088/JCP.19r12767 | title=The Potential Procognitive Effects of Modafinil in Major Depressive Disorder | date=2019 | journal=The Journal of Clinical Psychiatry | volume=80 | issue=6 | pmid=31599501 | s2cid=204028869 | vauthors=Vaccarino SR, McInerney SJ, Kennedy SH, Bhat V }}

Whereas modafinil and armodafinil are approved for narcolepsy, they have been repurposed as adjunctive treatments to alleviate symptoms of acute depressive phase in people with bipolar disorder.{{cite journal | vauthors = Bartoli F, Cavaleri D, Bachi B, Moretti F, Riboldi I, Crocamo C, Carrà G | title = Repurposed drugs as adjunctive treatments for mania and bipolar depression: A meta-review and critical appraisal of meta-analyses of randomized placebo-controlled trials | journal = Journal of Psychiatric Research | volume = 143 | pages = 230–238 | date = November 2021 | pmid = 34509090 | doi = 10.1016/j.jpsychires.2021.09.018 | s2cid = 237485915 }} Drug repurposing in psychiatry is a strategy for discovering new uses for drugs that have already been approved or tested in clinical trials for other illnesses. As such, drug repurposing is a rapid, cost-effective, and reduced-risk strategy for the development of new treatment options for psychiatric disorders. 2021 meta-analysis concluded that add-on modafinil and armodafinil were more effective than placebo on response to treatment, clinical remission, and reduction in depressive symptoms, with only minor side effects, but the effect sizes are small and the quality of evidence is therefore low, limiting the clinical relevance of the evidence.{{cite journal | doi=10.1080/14656566.2023.2194488 | title=An update on potential pharmacotherapies for cognitive impairment in bipolar disorder | date=2023 | journal=Expert Opinion on Pharmacotherapy | volume=24 | issue=5 | pages=641–654 | pmid=36946229 | s2cid=257665446 | vauthors=Johnson DE, McIntyre RS, Mansur RB, Rosenblat JD }} Very low rates of mood swing (a change in mood from one extreme to another){{cite journal | vauthors = Salvadore G, Quiroz JA, Machado-Vieira R, Henter ID, Manji HK, Zarate CA | title = The neurobiology of the switch process in bipolar disorder: a review | journal = The Journal of Clinical Psychiatry | volume = 71 | issue = 11 | pages = 1488–1501 | date = November 2010 | pmid = 20492846 | pmc = 3000635 | doi = 10.4088/JCP.09r05259gre }} have been observed with modafinil and armodafinil in depressive phase of bipolar disorder.{{cite journal | vauthors = Perugi G, Vannucchi G, Bedani F, Favaretto E | title = Use of Stimulants in Bipolar Disorder | journal = Current Psychiatry Reports | volume = 19 | issue = 1 | pages = 7 | date = January 2017 | pmid = 28144880 | doi = 10.1007/s11920-017-0758-x | s2cid = 2932701 }}

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

Modafinil was used during the Gulf War by the French Foreign Legion, the US Air Force,{{cite journal | vauthors = Van Puyvelde M, Van Cutsem J, Lacroix E, Pattyn N | title = A State-of-the-Art Review on the Use of Modafinil as a Performance-enhancing Drug in the Context of Military Operationality | journal = Military Medicine | volume = 187 | issue = 1–2 | pages = 52–64 | date = January 2022 | pmid = 34632515 | doi = 10.1093/milmed/usab398 | doi-access = free | title-link = doi }}{{cite journal|vauthors=Brunyé TT, Brou R, Doty TJ|title=A Review of US Army Research Contributing to Cognitive Enhancement in Military Contexts|journal=J Cogn Enhanc|volume=4 |issue= 4|pages=453–468|year=2020|doi=10.1007/s41465-020-00167-3|s2cid=256621326 }} and US Marine{{cite journal | vauthors = Gonzalez J | url = https://www.usni.org/magazines/proceedings/2017/july/go-pills-black-shoes | title = Go Pills for Black Shoes? | journal = U.S. Naval Institute Proceedings | date = July 2017 | volume = 143 | issue = 7/1,373 | access-date = December 3, 2023 | archive-date = December 3, 2023 | archive-url = https://web.archive.org/web/20231203140637/https://www.usni.org/magazines/proceedings/2017/july/go-pills-black-shoes | url-status = live }} infantry to enhance "operational tempo" (a term that denotes the speed and intensity at which military operations or activities are executed), aiming to optimize the overall performance and efficiency of the units.{{cite journal | vauthors = Caldwell JA, Caldwell JL | title = Fatigue in military aviation: an overview of US military-approved pharmacological countermeasures | journal = Aviation, Space, and Environmental Medicine | volume = 76 | issue = 7 Suppl | pages = C39–C51 | date = July 2005 | pmid = 16018329 }}{{cite news | url=https://www.theguardian.com/society/2004/jul/29/health.sciencenews | title=MoD bought thousands of stay awake pills in advance of war in Iraq | newspaper=The Guardian | date=July 29, 2004 | vauthors=Sample I, Evans R | access-date=December 2, 2023 | archive-date=December 2, 2023 | archive-url=https://web.archive.org/web/20231202042216/https://www.theguardian.com/society/2004/jul/29/health.sciencenews | url-status=live }}

Armed forces in various countries, including the United States, the United Kingdom, India, and France, have considered modafinil as an alternative to traditional amphetamines for managing sleep deprivation in combat or extended missions.{{cite magazine|url=https://www.wired.com/2003/11/sleep/|title=It's Wake-Up Time|vauthors=Martin R|date=November 1, 2003|magazine=Wired|access-date=May 23, 2019|issn=1059-1028|archive-date=October 17, 2020|archive-url=https://web.archive.org/web/20201017212750/https://www.wired.com/2003/11/sleep/|url-status=live}} The US military approved modafinil for specific Air Force missions, replacing amphetamines for fatigue management.{{cite web | title = Air Force Special Operations Command Instruction 48–101 | archive-url = https://web.archive.org/web/20180410202141/http://static.e-publishing.af.mil/production/1/afsoc/publication/afi11-202v3_afsocsup/afi11-202v3_afsocsup.pdf | archive-date= April 10, 2018 | quote = (sects. 1.7.4), U.S. Air Force Special Operations Command | date = November 30, 2012 | url = http://static.e-publishing.af.mil/production/1/afsoc/publication/afi11-202v3_afsocsup/afi11-202v3_afsocsup.pdf }} The use of modafinil in military contexts without sleep deprivation is not recommended due to inconclusive evidence on its cognitive enhancement benefits and potential risks of adverse effects.

Modafinil is also available to astronauts aboard the International Space Station for the management of fatigue caused by circadian dyssynchrony in orbit.{{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 = 1216–1220 | date = June 2009 | pmid = 19487390 | pmc = 2691437 | doi = 10.1503/cmaj.081125 }}

Modafinil has been used non-medically as a "smart drug"{{cite news |vauthors=Slotnik DE |title=Smart drugs |newspaper=The Economist |url=https://www.economist.com/leaders/2008/05/22/smart-drugs |access-date=December 3, 2023 |issn=0013-0613 |archive-date=December 3, 2023 |archive-url=https://web.archive.org/web/20231203141554/https://www.economist.com/leaders/2008/05/22/smart-drugs |url-status=live }}{{cite news |vauthors=Slotnik DE |date=October 11, 2017 |title=Michel Jouvet, Who Unlocked REM Sleep's Secrets, Dies at 91 |work=The New York Times |url=https://www.nytimes.com/2017/10/11/obituaries/michel-jouvet-who-unlocked-rem-sleeps-secrets-dies-at-91.html |access-date=December 3, 2023 |issn=0362-4331 |archive-date=December 3, 2023 |archive-url=https://web.archive.org/web/20231203143118/https://www.nytimes.com/2017/10/11/obituaries/michel-jouvet-who-unlocked-rem-sleeps-secrets-dies-at-91.html |url-status=live }} by various groups, including students,{{cite news|vauthors=Cadwalladr C|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|newspaper=The Guardian|date=February 14, 2015|access-date=January 7, 2017|archive-date=August 3, 2020|archive-url=https://web.archive.org/web/20200803132607/https://www.theguardian.com/society/2015/feb/15/students-smart-drugs-higher-grades-adderall-modafinil|url-status=live}}{{cite news |vauthors=Cumming E |date=November 3, 2009 |title=The drug does work |newspaper=The Economist |url=https://www.economist.com/1843/2009/11/03/the-drug-does-work |access-date=December 3, 2023 |issn=0013-0613 |archive-date=December 3, 2023 |archive-url=https://web.archive.org/web/20231203141443/https://www.economist.com/1843/2009/11/03/the-drug-does-work |url-status=live }}{{cite news|date=May 30, 2017 |title=Professors are taking the same 'smart drugs' as students to keep up with workloads |url=https://www.independent.co.uk/news/education/education-news/professor-smart-drugs-modafinil-noopept-students-workloads-university-research-teaching-academic-cambridge-a7763041.html |access-date=January 17, 2023 |website=The Independent |archive-date=December 7, 2022 |archive-url=https://web.archive.org/web/20221207055128/http://www.independent.co.uk/news/education/education-news/professor-smart-drugs-modafinil-noopept-students-workloads-university-research-teaching-academic-cambridge-a7763041.html |url-status=live }} office workers, transhumanists,{{cite magazine|vauthors=Talbot M|title=Brain Gain|url=http://www.newyorker.com/magazine/2009/04/27/brain-gain|magazine=The New Yorker|access-date=April 9, 2017|archive-date=August 19, 2020|archive-url=https://web.archive.org/web/20200819222934/https://www.newyorker.com/magazine/2009/04/27/brain-gain|url-status=live}}{{cite news |title=Towards immortality |date=November 16, 2006 |newspaper=The Economist |url=https://www.economist.com/news/2006/11/16/towards-immortality |access-date=December 3, 2023 |issn=0013-0613 |archive-date=December 3, 2023 |archive-url=https://web.archive.org/web/20231203142303/https://www.economist.com/news/2006/11/16/towards-immortality |url-status=live }} and professionals in various sectors. Its use is attributed by these individuals to its potential for enhancing attention, cognitive capabilities, and alertness.{{cite journal | vauthors = Van Rooyen LR, Gihwala R, Laher AE | title = Stimulant use among prehospital emergency care personnel in Gauteng Province, South Africa | journal = South African Medical Journal = Suid-Afrikaanse Tydskrif vir Geneeskunde | volume = 111 | issue = 6 | pages = 587–590 | date = May 2021 | pmid = 34382572 | doi = 10.7196/SAMJ.2021.v111i6.15465 | s2cid = 236402826 | doi-access = free | title-link = doi | doi-broken-date = November 1, 2024 }}{{cite news |title=Supercharging the brain |newspaper=The Economist |date=September 18, 2004 |url=https://www.economist.com/technology-quarterly/2004/09/18/supercharging-the-brain |access-date=December 3, 2023 |issn=0013-0613 |archive-date=December 3, 2023 |archive-url=https://web.archive.org/web/20231203143124/https://www.economist.com/technology-quarterly/2004/09/18/supercharging-the-brain |url-status=live }}

The effectiveness of modafinil as a cognitive enhancer is still debated. Some studies suggest significant increases in cognitive abilities, while others indicate mild to nonexistent cognitive improvements.{{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 = 260–269 | date = January 2003 | pmid = 12417966 | doi = 10.1007/s00213-002-1250-8 }}{{cite journal |vauthors=Keating GM, Raffin MJ | title=Modafinil: a review of its use in excessive sleepiness associated with obstructive sleep apnoea/hypopnoea syndrome and shift work sleep disorder | journal=CNS Drugs | volume=19 |issue=9 |pages=785–803 |date=2005 |pmid=16142993 |doi=10.2165/00023210-200519090-00005 |s2cid=43733424 }} In some cases, it has even been associated with impairments in certain cognitive functions.{{cite journal | vauthors = Zamanian MY, Karimvandi MN, Nikbakhtzadeh M, Zahedi E, Bokov DO, Kujawska M, Heidari M, Rahmani MR | title = Effects of Modafinil (Provigil) on Memory and Learning in Experimental and Clinical Studies: From Molecular Mechanisms to Behaviour Molecular Mechanisms and Behavioural Effects | journal = Current Molecular Pharmacology | volume = 16 | issue = 4 | pages = 507–516 | date = 2023 | pmid = 36056861 | doi = 10.2174/1874467215666220901122824 | s2cid = 252046371 }}{{cite book | vauthors = Meulen R, Hall W, Mohammed A |title=Rethinking Cognitive Enhancement |date=2017 |publisher=Oxford University Press |isbn=978-0-19-872739-2 |page=116 |url=https://books.google.com/books?id=aAIXDgAAQBAJ&pg=PA116 }} It has been shown that modafinil's positive impact on cognitive abilities is more noticeable on sleep-deprived individuals.{{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 = 1865–1881 | date = November 2015 | pmid = 26381811 | doi = 10.1016/j.euroneuro.2015.07.028 | s2cid = 23319688 }} Therefore, in people who are not sleep-deprived, the potential of modafinil as a cognitive enhancer may be limited.{{cite journal |vauthors=Schifano F, Catalani V, Sharif S, Napoletano F, Corkery JM, Arillotta D, Fergus S, Vento A, Guirguis A |title=Benefits and Harms of 'Smart Drugs' (Nootropics) in Healthy Individuals |journal=Drugs |volume=82 |issue=6 |pages=633–647 |date=April 2022 |pmid=35366192 |doi=10.1007/s40265-022-01701-7 |hdl=2299/25614 |s2cid=247860331 |hdl-access=free }}

Modafinil is generally well-tolerated but can have potential risks and side effects. Common adverse effects of modafinil, experienced by less than 10% of users, include headaches, nausea, and reduced appetite.{{cite book |title=A worldwide yearly survey of new data in adverse drug reactions |vauthors=Bello NT |publisher=Elsevier |year=2015 |isbn=978-0-444-63525-9 |veditors=Ray SD |series=Side Effects of Drugs Annual |volume=37 |pages=1–13 |chapter=Central Nervous System Stimulants and Drugs That Suppress Appetite |doi=10.1016/bs.seda.2015.08.004 |issn=0378-6080}} Anxiety, insomnia, dizziness, diarrhea, and rhinitis are also reported in 5% to 10% of users. Psychiatric reactions have occurred in individuals with and without a preexisting psychiatric history.{{cite web |date=December 1, 2008 |title=Australian Adverse Drug Reactions Bulletin 2008 |url=https://www.tga.gov.au/publication-issue/australian-adverse-drug-reactions-bulletin-vol-27-no-6#a2 |url-status=live |archive-url=https://web.archive.org/web/20200703041749/https://www.tga.gov.au/publication-issue/australian-adverse-drug-reactions-bulletin-vol-27-no-6#a2 |archive-date=July 3, 2020 |publisher=Australian Adverse Drug Reactions Bulletin}} Urinary retention and paresthesia have also been reported.{{Cite book |last=Ciccone |first=Charles D. |title=Davis's drug guide for rehabilitation professionals |date=2013 |publisher=F.A. Davis |isbn=978-0-8036-2589-1 |location=Philadelphia |language=en |chapter=Modafinil |chapter-url=https://fadavispt.mhmedical.com/content.aspx?bookid=1873§ionid=139018549 |archive-url=https://web.archive.org/web/20240916100601/https://fadavispt.mhmedical.com/content.aspx?bookid=1873§ionid=139018549 |archive-date=2024-09-16 |url-status=live}}

No significant changes in body weight have been observed in clinical trials, although decreased appetite and weight loss have been noted in children and adolescents.{{cite web |date=November 1, 2010 |title=Provigil |url=http://provigil.com/media/PDFs/medication_guide.pdf |url-status=dead |archive-url=https://web.archive.org/web/20160304035819/http://provigil.com/media/PDFs/medication_guide.pdf |archive-date=March 4, 2016 |access-date=December 31, 2013 |work=Medication Guide |publisher=Cephalon, Inc.}} Modafinil can cause a slight increase in aminotransferase enzymes, indicative of liver function, but there is no evidence of serious liver damage when levels are within reference ranges.{{cite book |title=LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. |date=2012 |publisher=National Institute of Diabetes and Digestive and Kidney Diseases |location=Bethesda (MD) |chapter=Modafinil |pmid=31643597 |id={{NCBIBook|NBK548274}}}}

Rare but serious adverse effects include severe skin rashes and allergy-related symptoms. Between December 1998 and January 2007, the FDA received reports of six cases of severe cutaneous adverse reactions, including erythema multiforme, Stevens–Johnson syndrome, toxic epidermal necrolysis, and DRESS syndrome. The FDA has issued alerts regarding these risks and also noted reports of angioedema and multi-organ hypersensitivity reactions in postmarketing surveillance.{{cite web |year=2007 |title=Modafinil (marketed as Provigil): Serious Skin Reactions |url=http://www.fda.gov/cder/dsn/2007_fall/postmarketing.htm#modafinil |url-status=dead |archive-url=https://web.archive.org/web/20090115021301/http://www.fda.gov/cder/dsn/2007_fall/postmarketing.htm#modafinil |archive-date=January 15, 2009 |publisher=U.S. Food and Drug Administration (FDA)}}{{cite news |date=November 6, 2023 |title=Three men hospitalised after taking modafinil or armodafinil to stay awake; drugs were not prescribed |url=https://www.straitstimes.com/singapore/three-men-hospitalised-after-taking-modafinil-or-armodafinil-to-stay-awake-drugs-were-not-prescribed |url-status=live |archive-url=https://web.archive.org/web/20231203191528/https://www.straitstimes.com/singapore/three-men-hospitalised-after-taking-modafinil-or-armodafinil-to-stay-awake-drugs-were-not-prescribed |archive-date=December 3, 2023 |access-date=December 3, 2023 |newspaper=The Straits Times |vauthors=Li TW}} In 2007, the FDA required Cephalon to modify the Provigil leaflet to include warnings about these serious conditions. The long-term safety and effectiveness of modafinil have not been conclusively established.

The FDA does not endorse modafinil for children's medical conditions due to an increased risk of rare but serious dermatological toxicity, manifested as Stevens–Johnson syndrome which is a type of severe skin reaction.{{cite web |date=January 2015 |title=FDA Provigil Drug Safety Data |url=https://www.fda.gov/downloads/Drugs/DrugSafety/UCM231722.pdf |url-status=dead |archive-url=https://web.archive.org/web/20170502094203/https://www.fda.gov/downloads/Drugs/DrugSafety/UCM231722.pdf |archive-date=May 2, 2017 |publisher=U.S. Food and Drug Administration (FDA)}}{{cite journal |vauthors=Rugino T |date=June 2007 |title=A review of modafinil film-coated tablets for attention-deficit/hyperactivity disorder in children and adolescents |journal=Neuropsychiatric Disease and Treatment |volume=3 |issue=3 |pages=293–301 |pmc=2654790 |pmid=19300563}} However, in Europe, modafinil may be prescribed for treating narcolepsy in children.

File:Modafinil 200mg.jpg

Modafinil is commercially available in {{Val|100|u=mg}} and {{Val|200|u=mg}} oral tablet forms. Additionally, it is offered as the (R)-enantiomer, known as armodafinil, and as a prodrug named adrafinil.{{cite book | vauthors = Billiard M, Lubin S | title=Sleep Medicine | chapter=Modafinil: Development and Use of the Compound | publisher=Springer New York | publication-place=New York, NY | year=2015 | doi=10.1007/978-1-4939-2089-1_61 | pages=541–544| isbn=978-1-4939-2088-4 }}

Modafinil is contraindicated during pregnancy and 2 months before getting pregnant. Women who take modafinil should not become pregnant, and, additionally, should be aware that modafinil reduces effectiveness of hormonal contraceptives, increasing chances of getting pregnant.{{cite journal|title=Sleep Medications and Women: a Review of Issues to Consider for Optimizing the Care of Women with Sleep Disorders| vauthors = Krystal A, Attarian H |date=December 2016|journal=Current Sleep Medicine Reports|volume=2|issue=4|pages=218–222|doi=10.1007/s40675-016-0060-1}} Modafinil therapy during pregnancy increases the risk of birth defects,{{cite journal |vauthors=Ghaffari N, Robertson PA |title=Caution in Prescribing Modafinil and Armodafinil to Individuals Who Could Become Pregnant |journal=JAMA Intern Med |volume=181 |issue=2 |pages=277–278 |date=February 2021 |pmid=33074296 |doi=10.1001/jamainternmed.2020.4206 |s2cid=224780160 }}{{cite journal | doi=10.1001/jama.2020.9840 | title=Incidence of Malformations After Early Pregnancy Exposure to Modafinil in Sweden and Norway | date=2020 | journal=JAMA | volume=324 | issue=9 | pages=895–897 | pmid=32870289 | pmc=7489822 | vauthors = Cesta CE, Engeland A, Karlsson P, Kieler H, Reutfors J, Furu K }}{{cite web|url=https://www.gov.uk/drug-safety-update/modafinil-provigil-increased-risk-of-congenital-malformations-if-used-during-pregnancy|title=Modafinil (Provigil): increased risk of congenital malformations if used during pregnancy|date=November 16, 2020|website=GOV.UK|access-date=January 13, 2024|archive-date=January 13, 2024|archive-url=https://web.archive.org/web/20240113182538/https://www.gov.uk/drug-safety-update/modafinil-provigil-increased-risk-of-congenital-malformations-if-used-during-pregnancy|url-status=live}} such as with congenital torticollis, hypospadias, and congenital heart defects.

Modafinil is contraindicated for individuals with known hypersensitivity to either modafinil or armodafinil.

Modafinil is also contraindicated in certain cardiac conditions, including uncontrolled moderate to severe hypertension, arrhythmia, cor pulmonale, and in cases with signs of CNS stimulant-induced mitral valve prolapse or left ventricular hypertrophy.{{cite web | url=https://www.acc.org/latest-in-cardiology/articles/2015/04/28/10/06/the-safety-of-stimulant-medication-use-in-cardiovascular-and-arrhythmia-patients | title=The Safety of Stimulant Medication Use in Cardiovascular and Arrhythmia Patients | access-date=January 29, 2024 | archive-date=January 29, 2024 | archive-url=https://web.archive.org/web/20240129013130/https://www.acc.org/latest-in-cardiology/articles/2015/04/28/10/06/the-safety-of-stimulant-medication-use-in-cardiovascular-and-arrhythmia-patients | url-status=live }}{{cite web | title = Modafinil: Annex III Summary of Product Characteristics, Labelling and Package Leaflet | url = https://www.ema.europa.eu/en/documents/referral/modafinil-annex-iii-summary-product-characteristics-labeling-or-package-leaflet_en.pdf | work = European Medicines Agency | access-date = January 29, 2024 | archive-date = January 29, 2024 | archive-url = https://web.archive.org/web/20240129013129/https://www.ema.europa.eu/en/documents/referral/modafinil-annex-iii-summary-product-characteristics-labeling-or-package-leaflet_en.pdf | url-status = live }} The package insert in the United States cautions about using modafinil in people with a documented medical history of left ventricular hypertrophy or those diagnosed with mitral valve prolapse who have previously exhibited symptoms associated with the mitral valve prolapse syndrome while undergoing treatment involving central nervous system stimulants.{{cite journal |vauthors=Oskooilar N |title=A case of premature ventricular contractions with modafinil |journal=Am J Psychiatry |volume=162 |issue=10 |pages=1983–4 |date=October 2005 |pmid=16199853 |doi=10.1176/appi.ajp.162.10.1983-a }} The reasons why modafinil is contraindicated in certain cardiac conditions are because modafinil affects the autonomic nervous system and, in particular, exerts significant effects on autonomic cardiovascular regulation, leading in some people to notable increases in heart rate and blood pressure. These substantial changes in the autonomic system warrant careful consideration when prescribing modafinil to people with pre-existing cardiovascular conditions.{{cite journal |vauthors=Taneja I, Diedrich A, Black BK, Byrne DW, Paranjape SY, Robertson D |title=Modafinil elicits sympathomedullary activation |journal=Hypertension |volume=45 |issue=4 |pages=612–8 |date=April 2005 |pmid=15753235 |doi=10.1161/01.HYP.0000158267.66763.63 |s2cid=9192971 |citeseerx=10.1.1.521.5289 }} The increase in heart rate and blood pressure can worsen the symptoms of such pre-existing conditions as hypertension, arrhythmia, and cor pulmonale. These changes in the autonomic system induced by modafinil can increase the risk of heart attack, stroke, and heart failure. Modafinil can stimulate the release of norepinephrine and epinephrine, hormones that activate the sympathetic nervous system. This can cause vasoconstriction, which is the narrowing of blood vessels, and increase the heart's workload, which is not desired in people with pre-existing heart conditions. In particular, modafinil can worsen the consequences of mitral valve prolapse or left ventricular hypertrophy, which are structural abnormalities of the heart. These can affect the blood flow and oxygen delivery to the heart and other organs.{{cite journal |vauthors=Hou RH, Freeman C, Langley RW, Szabadi E, Bradshaw CM |title=Does modafinil activate the locus coeruleus in man? Comparison of modafinil and clonidine on arousal and autonomic functions in human volunteers |journal=Psychopharmacology (Berl) |volume=181 |issue=3 |pages=537–49 |date=September 2005 |pmid=15983798 |doi=10.1007/s00213-005-0013-8 |s2cid=10265746 }}

Modafinil is also contraindicated in people with congenital problems like galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.{{cite web | vauthors = Evans K, Tay S | date = September 2020 | title = Shared Care Guideline – Modafinil for narcolepsy (adults) and excessive daytime sleepiness in Parkinson's disease | work = York and Scarborough Medicines Commissioning Committee | url = https://www.yorkandscarboroughformulary.nhs.uk/docs/SC/Modafinil%20shared%20care%20guideline%20v2.pdf | access-date = January 30, 2024 | archive-date = January 30, 2024 | archive-url = https://web.archive.org/web/20240130034658/https://www.yorkandscarboroughformulary.nhs.uk/docs/SC/Modafinil%20shared%20care%20guideline%20v2.pdf | url-status = live }}{{cite web | vauthors = Miller M | veditors = Morgan J | collaboration = Hull & East Riding Prescribing Committee | title = Prescribing Framework for Modafinil for Daytime Hypersomnolence and excessive daytime sleepiness in Parkinsons | url = https://www.hey.nhs.uk/wp/wp-content/uploads/2021/06/modafanil.pdf | location = Northern Lincolnshire, UK | publisher = National Health Service | access-date = December 2, 2023 | archive-date = December 2, 2023 | archive-url = https://web.archive.org/web/20231202001703/https://www.hey.nhs.uk/wp/wp-content/uploads/2021/06/modafanil.pdf | url-status = live }}{{cite web | title = Modafinil for the treatment of adult patients with excessive sleepiness | url = https://gmmmg.nhs.uk/wp-content/uploads/2022/12/GMMMG-Modafinil-primary-care-info-leaflet_Nov-22-approved.pdf | date = November 10, 2022 | publisher = National Health Service, UK | access-date = December 2, 2023 | archive-date = December 2, 2023 | archive-url = https://web.archive.org/web/20231202001703/https://gmmmg.nhs.uk/wp-content/uploads/2022/12/GMMMG-Modafinil-primary-care-info-leaflet_Nov-22-approved.pdf | url-status = live }}

Extensive clinical research has not demonstrated drug tolerance as a common adverse effect, even with therapeutic use extending up to 40 weeks.{{cite journal |vauthors=Billiard M, Broughton R |title=Modafinil: its discovery, the early European and North American experience in the treatment of narcolepsy and idiopathic hypersomnia, and its subsequent use in other medical conditions |journal=Sleep Med |volume=49 |pages=69–72 |date=September 2018 |pmid=30174215 |doi=10.1016/j.sleep.2018.05.027 |s2cid=52143478 }}{{cite book|chapter=Sleep in Narcolepsy and the Effects of Modafinil|vauthors=Billiard M|title=Dopamine and Sleep |doi=10.1007/978-3-319-46437-4_11|date=October 25, 2016|pages=235–253 |publisher=Springer, Cham|isbn=978-3-319-46435-0}}{{cite journal |vauthors=Banerjee D, Vitiello MV, Grunstein RR |title=Pharmacotherapy for excessive daytime sleepiness |journal=Sleep Med Rev |volume=8 |issue=5 |pages=339–54 |date=October 2004 |pmid=15336235 |doi=10.1016/j.smrv.2004.03.002 }} Drug tolerance in this context is defined as a reduction in response, to wakefulness-promoting and anti-fatigue properties of modafinil.

While modafinil is generally found to be safe and significant adverse effects are rare, including in pediatric narcolepsy cases (sleep disorders in children), there is evidence that long-term usage can lead to tolerance in some individuals. This necessitates higher doses to maintain the same level of cognitive enhancement or relief from sleepiness.

People with current or past substance addictions and those with a family history of addiction are particularly at risk for developing tolerance.

The mechanisms driving tolerance to modafinil, which may involve its impact on dopamine and norepinephrine levels in the brain, are not fully understood.

Repeated administration of modafinil for off-label use, such as increased alertness and cognitive-enhancing effects in sleep deprivation, can lead to drug tolerance, which means that the effectiveness of the drug may decrease over time. Still, modafinil therapy as a eugeroic agent to treat narcolepsy does not typically lead to drug tolerance, i.e., the effectiveness does not usually decrease on prolonged use, although individual responses may vary.{{cite journal | vauthors = Bassetti CL, Kallweit U, Vignatelli L, Plazzi G, Lecendreux M, Baldin E, Dolenc-Groselj L, Jennum P, Khatami R, Manconi M, Mayer G, Partinen M, Pollmächer T, Reading P, Santamaria J, Sonka K, Dauvilliers Y, Lammers GJ | title = European guideline and expert statements on the management of narcolepsy in adults and children | journal = Journal of Sleep Research | volume = 30 | issue = 6 | pages = e13387 | date = December 2021 | pmid = 34173288 | doi = 10.1111/jsr.13387 | s2cid = 235648766 | doi-access = free | title-link = doi | hdl = 11380/1251554 | hdl-access = free }}{{cite journal | vauthors = Sharif S, Guirguis A, Fergus S, Schifano F | title = The Use and Impact of Cognitive Enhancers among University Students: A Systematic Review | journal = Brain Sciences | volume = 11 | issue = 3 | page = 355 | date = March 2021 | pmid = 33802176 | pmc = 8000838 | doi = 10.3390/brainsci11030355 | doi-access = free | title-link = doi }}

Despite being a CNS stimulant, the addiction and dependence liabilities of modafinil are considered low.{{cite web|volume=64|issue=17|publisher=Department of Justice|series=Federal register|title=64 FR 4050 - Schedules of Controlled Substances: Placement of Modafinil Into Schedule IV|date=January 27, 1999|vauthors=Sapienza F|url=https://www.govinfo.gov/app/details/FR-1999-01-27/99-1791|access-date=February 5, 2024|archive-date=February 5, 2024|archive-url=https://web.archive.org/web/20240205144036/https://www.govinfo.gov/app/details/FR-1999-01-27/99-1791|url-status=live}}{{cite journal | vauthors = Mignot EJ | title = A practical guide to the therapy of narcolepsy and hypersomnia syndromes | journal = Neurotherapeutics | volume = 9 | issue = 4 | pages = 739–752 | date = October 2012 | pmid = 23065655 | pmc = 3480574 | doi = 10.1007/s13311-012-0150-9 }} The exact mechanisms of action of modafinil are not known, and it is believed that pharmacological profile of modafinil is different from that of the classical stimulants such as cocaine or amphetamine. Although modafinil shares biochemical mechanisms with stimulant drugs, it is less likely to have mood-elevating properties. The similarities in effects with caffeine are not clearly established.{{cite journal|vauthors=Warot D, Corruble E, Payan C, Weil JS, Puech AJ|date=1993|title=Subjective effects of modafinil, a new central adrenergic stimulant in healthy volunteers: a comparison with amphetamine, caffeine, and placebo|journal=European Psychiatry |volume=8|issue=4|pages=201–208|doi=10.1017/S0924933800002923|s2cid=151797528 }} Unlike other stimulants, modafinil does not induce a strong subjective feeling of pleasure or reward, which is commonly associated with euphoria, an intense feeling of well-being. Euphoria may be an indicator of a drug's potential to be abused. Substance abuse is a compulsive and excessive use of the substance despite adverse consequences.{{cite journal |vauthors=de Wit H, Phillips TJ |title=Do initial responses to drugs predict future use or abuse? |journal=Neurosci Biobehav Rev |volume=36 |issue=6 |pages=1565–76 |date=July 2012 |pmid=22542906 |pmc=3372699 |doi=10.1016/j.neubiorev.2012.04.005 }} In comparison to classical stimulants, modafinil exhibits a low propensity for abuse, as it lacks significantly expressed pleasurable or euphoric effects. Albeit to a lower degree than classical stimulants, modafinil still can produce psychoactive, euphoric, and subjective effects typical for abused stimulants.

Modafinil was not observed to promote overuse or misuse, even in people who have a history of cocaine addiction.{{cite journal | vauthors = O'Brien CP, Dackis CA, Kampman K | title = Does modafinil produce euphoria? | journal = The American Journal of Psychiatry | volume = 163 | issue = 6 | pages = 1109 | date = June 2006 | pmid = 16741217 | doi = 10.1176/ajp.2006.163.6.1109 }} Despite the initial belief that modafinil carried no abuse potential, emerging evidence suggests that it works at the same neurobiological mechanisms as other addictive stimulants. Consequently, there exists a potential risk of modafinil abuse, necessitating prudent consideration and caution when prescribing or using this medication. Modafinil exhibits a lower response on the amphetamine scale of the addiction research center inventory, suggesting reduced propensity for abuse compared to amphetamine.{{cite journal |vauthors=Martins B, Rutland W, De Aquino JP, Kazer BL, Funaro M, Potenza MN, Angarita GA |title=Helpful or Harmful? The Therapeutic Potential of Medications with Varying Degrees of Abuse Liability in the Treatment of Substance Use Disorders |journal=Curr Addict Rep |volume=9 |issue=4 |pages=647–659 |date=2022 |pmid=35990796 |pmc=9376579 |doi=10.1007/s40429-022-00432-9 }}

The US Drug Enforcement Administration has classified modafinil as a Schedule IV controlled substance; the medicine is recognized for having valid medical uses with low addiction potential. The International Narcotics Control Board does not classify it as a narcotic or a psychotropic substance.{{cite web | publisher= International Narcotics Control Board |title=Yellow List: List of Narcotic Drugs Under International Control |series=In accordance with the Single Convention on Narcotic Drugs, 1961 [Protocol of March 25, 1972, amending the Single Convention on Narcotic Drugs, 1961] |date=July 2020 |edition=59th |url=https://www.incb.org/incb/en/narcotic-drugs/Yellowlist/yellow-list.html |access-date=January 12, 2022 |archive-date=January 16, 2022 |archive-url=https://web.archive.org/web/20220116102908/https://www.incb.org/incb/en/narcotic-drugs/Yellowlist/yellow-list.html }}{{cite web | publisher= International Narcotics Control Board |title=Green List: List of Psychotropic Substances Under International Control |series=In accordance with Convention psychotropic substances of 1971 |date=July 2020 |edition=31st |url= https://www.incb.org/incb/en/psychotropics/toolkit.html |access-date=January 12, 2022 |archive-date=January 18, 2022 |archive-url= https://web.archive.org/web/20220118201426/https://www.incb.org/incb/en/psychotropics/toolkit.html |url-status=live }}

An overdose of modafinil can lead to a range of symptoms and complications. Psychiatric symptoms may include psychosis, mania, hallucinations, and suicidal ideation, which can occur even in individuals without a history of mental illness and may persist after discontinuation of the drug.{{cite journal | vauthors = Reinert JP, Dunn RL | title = Management of overdoses of loperamide, gabapentin, and modafinil: a literature review | journal = Expert Review of Clinical Pharmacology | volume = 12 | issue = 9 | pages = 901–908 | date = September 2019 | pmid = 31422705 | doi = 10.1080/17512433.2019.1657830 | s2cid = 201063075 }} Neurological complications, such as seizures, tremors, dystonia, and dyskinesia, may arise from modafinil's interaction with various neurotransmitter systems.

Allergic reactions such as rash, angioedema, anaphylaxis, and Stevens–Johnson syndrome may rarely be triggered by an immunological response to modafinil or its metabolites.{{cite journal | vauthors = Prince V, Philippidou M, Walsh S, Creamer D | title = Stevens-Johnson syndrome induced by modafinil | journal = Clinical and Experimental Dermatology | volume = 43 | issue = 2 | pages = 191–192 | date = March 2018 | pmid = 29028129 | doi = 10.1111/ced.13282 | s2cid = 204987385 }}{{cite journal|doi=10.1007/s40278-018-42202-6 |title=Modafinil overdose |journal=Reactions Weekly |date=2018 |volume=1690 |page=136 |s2cid=195079873 }} Cardiovascular complications like hypertension, tachycardia, chest pain, and arrhythmias may also be observed due to modafinil's sympathomimetic action.

In animal studies, the median lethal dose (LD₅₀) of modafinil varies among species and depends on the route of administration. In mice and rats, the LD₅₀ is approximately {{Val|1250|u=mg/kg}} if administered via an injection, but the oral LD₅₀ for rats is {{Val|3400|u=mg/kg}}.{{cite journal |title=Adrafinil: A Novel Vigilance Promoting Agent|vauthors=Milgram NW, Callahan H, Siwak C|date=September 1999|journal=CNS Drug Reviews|volume=5|issue=3|pages=193–212|doi=10.1111/j.1527-3458.1999.tb00100.x }}{{cite journal | vauthors = Nazarian S, Abdolmaleki Z, Torfeh A, Shirazi Beheshtiha SH | title = Mesenchymal stem cells with modafinil (gold nanoparticles) significantly improves neurological deficits in rats after middle cerebral artery occlusion | journal = Experimental Brain Research | volume = 238 | issue = 11 | pages = 2589–2601 | date = November 2020 | pmid = 32886135 | doi = 10.1007/s00221-020-05913-9 | s2cid = 221495887 }} The LD₅₀ value for humans have not been established. Human clinical trials have involved total daily doses up to {{Val|1200|u=mg/day}} for 7–21 days. Acute one-time total overdoses up to {{Val|4500|u=mg}} have not been life-threatening but resulted in symptoms like agitation, insomnia, tremor, palpitations, and gastrointestinal disturbances.{{cite journal | vauthors = Spiller HA, Hays HL, Aleguas A | title = Overdose of drugs for attention-deficit hyperactivity disorder: clinical presentation, mechanisms of toxicity, and management | journal = CNS Drugs | volume = 27 | issue = 7 | pages = 531–543 | date = July 2013 | pmid = 23757186 | doi = 10.1007/s40263-013-0084-8 }}

The management of modafinil overdose involves supportive care, monitoring of vital signs, and treatment of specific complications. In cases of recent consumption, activated charcoal, gastric lavage, or hemodialysis may be used. There is no specific antidote for modafinil overdose.{{cite journal|doi=10.1007/s40278-018-52897-7|title=Modafinil overdose/misuse/abuse|journal=Reactions Weekly|volume=1723|page=215|year=2018|s2cid=195081462 }}{{cite journal | vauthors = Spiller HA, Borys D, Griffith JR, Klein-Schwartz W, Aleguas A, Sollee D, Anderson DA, Sawyer TS | title = Toxicity from modafinil ingestion | journal = Clinical Toxicology | volume = 47 | issue = 2 | pages = 153–156 | date = February 2009 | pmid = 18787992 | doi = 10.1080/15563650802175595 | s2cid = 12421545 }} The main way to deal with modafinil overdose is supportive care, which includes sedating the patient and stabilizing their blood pressure, and muscle activity in case of manifestations such as agitation or tremor.

Some of the drugs that frequently interact with modafinil include aripiprazole (an antipsychotic), amphetamine (including its enantiomers and salts; stimulants), aspirin, and others.{{cite web | url=https://www.drugs.com/drug-interactions/modafinil.html | title=Modafinil Interactions | work=Drugs.com | date=January 10, 2024 | access-date=February 5, 2024 | archive-date=December 15, 2023 | archive-url=https://web.archive.org/web/20231215212735/https://www.drugs.com/drug-interactions/modafinil.html | url-status=live }}

Modafinil is a weak to moderate inducer of CYP3A4{{cite web | url=https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers | title=Drug Development and Drug Interactions | Table of Substrates, Inhibitors and Inducers | publisher=U.S. Food and Drug Administration (FDA) | date=May 26, 2021 | access-date=April 8, 2022 | archive-date=November 4, 2020 | archive-url=https://web.archive.org/web/20201104173036/https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers | url-status=dead }}{{cite web | url = https://www.uptodate.com/contents/image?imageKey=CARD%2F76992 | title = Cytochrome P450 3A (including 3A4) inhibitors and inducers | work = UpToDate | access-date = April 8, 2022 | archive-date = April 8, 2022 | archive-url = https://web.archive.org/web/20220408220537/https://www.uptodate.com/contents/image?imageKey=CARD%2F76992 | url-status = live }} and a weak inhibitor of CYP2C19, enzymes of the cytochrome P450 group of enzymes. Modafinil also induces or inhibits other cytochrome P450 enzymes. One in vitro study predicts that modafinil may induce the cytochrome P450 enzymes CYP1A2, CYP3A4, and CYP2B6, as well as may inhibit CYP2C9 and CYP2C19. However, other in-vitro studies find no significant inhibition of CYP2C9.{{cite journal | vauthors = Robertson P, Hellriegel ET, Arora S, Nelson M | title = Effect of modafinil at steady state on the single-dose pharmacokinetic profile of warfarin in healthy volunteers | journal = Journal of Clinical Pharmacology | volume = 42 | issue = 2 | pages = 205–214 | date = February 2002 | pmid = 11831544 | doi = 10.1177/00912700222011120 | s2cid = 29223738 }} Modafinil may induce P-glycoprotein, which may affect drugs transported by P-glycoprotein, such as digoxin.{{cite journal | vauthors = Zhu HJ, Wang JS, Donovan JL, Jiang Y, Gibson BB, DeVane CL, Markowitz JS | title = Interactions of attention-deficit/hyperactivity disorder therapeutic agents with the efflux transporter P-glycoprotein | journal = European Journal of Pharmacology | volume = 578 | issue = 2–3 | pages = 148–158 | date = January 2008 | pmid = 17963743 | pmc = 2659508 | doi = 10.1016/j.ejphar.2007.09.035 }}

It was clinically found that modafinil affects pharmacodynamics of drugs which are metabolized by CYP3A4 and other enzymes of the cytochrome P450 family so that interactions of modafinil with these drugs were observed in real people, rather than being predicted in a lab setting. For instance, it was observed that induction of CYP3A4 by modafinil affects metabolism of the following medications and endogenous substances:

• opioids, such as methadone, hydrocodone, oxycodone, or fentanyl – modafinil may result in a drop in opioid plasma concentrations because of faster clearance of opioids by CYP3A4. If the patient is not monitored closely, reduced efficacy or withdrawal symptoms can occur.{{cite web |title=Modafinil drug interactions |url=https://www.drugs.com/drug-interactions/modafinil-index.html |website=Drugs.com |access-date=May 3, 2021 |archive-date=May 3, 2021 |archive-url=https://web.archive.org/web/20210503184406/https://www.drugs.com/drug-interactions/modafinil-index.html |url-status=live }}
• steroid hormones, such as estradiol, progesterone or cortisol. Modafinil may have an adverse effect on hormonal contraceptives (such as birth control pills, patches, etc.) for up to a month after discontinuation.{{cite web |url=https://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a602016.html | work = Medline Plus | publisher = U.S. National Library of Medicine | title = Modafinil |date=July 1, 2005 |access-date=July 21, 2007 |archive-url=https://web.archive.org/web/20070610045952/http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a602016.html |archive-date=June 10, 2007}} Both modafinil and armodafinil in the United States and the United Kingdom come with package inserts that highlight the interaction between these medications and hormonal birth control. Modafinil may induce cytochrome P450 enzymes that are involved in the clearance of steroid hormones taken as hormonal contraceptives, reducing their effectiveness, which may lead to pregnancy despite taking the birth control medication. Besides steroid hormones, modafinil may affect pituitary gland hormones. In a 2006 study, a single dose of modafinil {{Val|200|u=mg}} caused a decrease in blood prolactin levels, although it did not affect human growth hormone or thyroid-stimulating hormone.{{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 = June 2008 | pmid = 17712350 | doi = 10.1038/sj.npp.1301534 | publisher = Springer Science and Business Media LLC | s2cid = 13752498 | doi-access = free | title-link = doi }}{{cite journal | vauthors = Samuels ER, Hou RH, Langley RW, Szabadi E, Bradshaw CM | title = Comparison of pramipexole and modafinil on arousal, autonomic, and endocrine functions in healthy volunteers | journal = Journal of Psychopharmacology | volume = 20 | issue = 6 | pages = 756–770 | date = November 2006 | pmid = 16401653 | doi = 10.1177/0269881106060770 | publisher = SAGE Publications | s2cid = 8033437 }} Since modafinil induces the activity of the CYP3A4 enzyme involved in cortisol clearance,{{cite journal | vauthors = Niwa T, Murayama N, Imagawa Y, Yamazaki H | title = Regioselective hydroxylation of steroid hormones by human cytochromes P450 | journal = Drug Metabolism Reviews | volume = 47 | issue = 2 | pages = 89–110 | date = May 2015 | pmid = 25678418 | doi = 10.3109/03602532.2015.1011658 | publisher = Informa UK Limited | s2cid = 5791536 }} modafinil may reduce the bioavailability of hydrocortisone. Therefore, it may be necessary to adjust the steroid substitution dose in people receiving modafinil, which is a CYP3A4-metabolism-inducing drug.{{cite journal | vauthors = Aquinos BM, García Arabehety J, Canteros TM, de Miguel V, Scibona P, Fainstein-Day P | title = [Adrenal crisis associated with modafinil use] | language = es | journal = Medicina | volume = 81 | issue = 5 | pages = 846–849 | year = 2021 | pmid = 34633961 }}

Hypertensive crises have been reported when armodafinil (one of modafinil's enantiomers) has been taken with monoamine oxidase inhibitors (MAOIs) like tranylcypromine.{{cite journal | vauthors = Kinslow CJ, Shapiro SD, Grunebaum MF, Miller EC | title = Acute hypertensive crisis and severe headache after concurrent use of armodafinil and tranylcypromine: Case report and review of the literature | journal = J Neurol Sci | volume = 393 | issue = | pages = 1–3 | date = October 2018 | pmid = 30077942 | pmc = 6446082 | doi = 10.1016/j.jns.2018.07.023 | url = }}

The precise mechanism of action of modafinil for narcolepsy and other sleep disorders remains unclear.{{cite journal | vauthors = Thorpy MJ, Bogan RK | title = Update on the pharmacologic management of narcolepsy: mechanisms of action and clinical implications | journal = Sleep Medicine | volume = 68 | pages = 97–109 | date = April 2020 | pmid = 32032921 | doi = 10.1016/j.sleep.2019.09.001 | s2cid = 203405397 }}{{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=978-1-108-22874-9 | pages=491–495 | edition=6th | chapter=Modafinil }}{{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 = 349–364 | date = June 2007 | pmid = 19300566 | pmc = 2654794 }} Although modafinil may have interactions with neurotransmitter systems, its exact mode of action is not fully understood.{{cite book | vauthors = Lazarus M, Chen JF, Huang ZL, Urade Y, Fredholm BB | chapter = Adenosine and Sleep | title = Handbook of Experimental Pharmacology | volume = 253 | pages = 359–381 | date = 2019 | pmid = 28646346 | doi = 10.1007/164_2017_36 | isbn = 978-3-030-11270-7 }}

From laboratory research, modafinil has little to no affinity for serotonin or norepinephrine transporters and does not directly interact with these systems. However, studies have shown that elevated concentrations of norepinephrine and serotonin can occur as an indirect effect following modafinil administration due to increased extracellular dopamine activity. Unlike traditional psychostimulant drugs, such as cocaine or amphetamine, modafinil shows low potential for causing euphoria due to differences in how it interacts with dopamine transporters at a cellular level.

In addition to its influence on dopaminergic pathways, modafinil may impact other neurotransmitter systems, such as orexin (hypocretin). Orexin neurons are involved in promoting wakefulness and regulating arousal states. Modafinil may increase signaling within hypothalamic orexin pathways, potentially contributing to its wake-promoting effects.

C_max (peak levels) occurs approximately 2 to 3 hours after modafinil administration. Food slows the absorption of modafinil but does not affect the total area under the curve (AUC). In vitro measurements indicate that 60% of modafinil is bound to plasma proteins at clinical concentrations of the drug. This percentage changes very little when the concentration of modafinil is varied.{{cite book |vauthors=Gilman A, Goodman LS, Hardman JG, Limbird LE |title=Goodman & Gilman's the pharmacological basis of therapeutics |publisher=McGraw-Hill |location=New York |year=2001 |page=1984 |isbn=978-0-07-135469-1 }}

Renal excretion of unchanged modafinil usually accounts for less than 10% of an oral dose. This means that when modafinil is taken by mouth, the only approved route of administration, less than 10% of the drug is eliminated from the body through the urine without being metabolized by the liver or other organs. The rest of the drug is either metabolized or excreted through other routes, such as feces or bile.

The two major circulating metabolites of modafinil are modafinil acid (CRL-40467) and modafinil sulfone (CRL-41056). Both of these metabolites have been described as inactive, and neither appears to contribute to the wakefulness-promoting effects of modafinil.{{cite journal | vauthors = Ramachandra B | title = A Critical Review of Properties of Modafinil and Analytical, Bioanalytical Methods for its Determination | journal = Critical Reviews in Analytical Chemistry | volume = 46 | issue = 6 | pages = 482–489 | date = November 2016 | pmid = 26908128 | doi = 10.1080/10408347.2016.1153948 | s2cid = 34069997 }} However, modafinil sulfone does appear to possess anticonvulsant effects, a property that it shares with modafinil.{{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 = Neurochemical Research | volume = 29 | issue = 8 | pages = 1481–1486 | date = August 2004 | pmid = 15260124 | doi = 10.1023/b:nere.0000029559.20581.1a | s2cid = 956077 }}

Elimination half-life is in the range of 10 to 12 hours, subject to differences in sex, in cytochrome P450 genotypes, liver function and renal function. Modafinil is metabolized mainly in the liver, and its inactive metabolites are excreted in the urine. Urinary excretion of the unchanged drug is usually less than 10% but can range from 0% to as high as 18.7%, depending on the factors mentioned.

Modafinil exhibits sex-specific pharmacokinetic differences. It demonstrates higher bioavailability in women compared to men. The mean C_max is higher in women than in men, {{Val|5.2|u=mg/L}} vs. {{Val|4.2|u=mg/L}} (p < 0.05), following a single {{Val|200|u=mg}} oral dose of modafinil. This difference persists even after adjusting for body weight ({{Val|0.88|u=ml/min/kg}} vs. {{Val|0.72|u=ml/min/kg}}). The clearance of modafinil is 30% higher in men than in women, and plasma concentrations after a single dose are significantly higher in women than in men. These sex-specific pharmacokinetic differences may have implications for the efficacy and safety of modafinil.

Modafinil is a racemic mixture of two enantiomers, armodafinil ((R)-modafinil) and esmodafinil ((S)-modafinil).{{cite journal | vauthors = Bogan RK | title = Armodafinil in the treatment of excessive sleepiness | journal = Expert Opinion on Pharmacotherapy | volume = 11 | issue = 6 | pages = 993–1002 | date = April 2010 | pmid = 20307223 | pmc = 3630938 | doi = 10.1517/14656561003705738 }}

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.{{cite journal|url=https://elibrary.ru/item.asp?id=36403188|title=Analytical characteristics and identification of modafinil and adrafinil in the objects of examination|vauthors=Polyakov YS, Mikhniuk ON, Hilkevich TY, Chevtchouk TA, Yurchenko RA, Vinarskiy VA|publisher=State Institute for Advanced Training and Retraining of Customs Authorities of the Republic of Belarus|issn=2413-6158|journal=Судебная экспертиза Беларуси|year=2018|access-date=February 6, 2024|archive-date=September 28, 2020|archive-url=https://web.archive.org/web/20200928001949/https://www.elibrary.ru/item.asp?id=36403188|url-status=live}} Instrumental techniques involving gas or liquid chromatography are usually employed for these purposes.{{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 = 276–282 | date = March 1998 | pmid = 9549666 | doi = 10.1002/j.1552-4604.1998.tb04425.x | s2cid = 26877375 }}{{cite book | vauthors = Baselt RC |title=Disposition of Toxic Drugs and Chemicals in Man |publisher=Biomedical Publications |location=Foster City, CA |year=2008 |isbn=978-0-9626523-7-0 |pages=1152–1153}} In 2011, modafinil was not tested for by common drug screens (except for anti-doping screens) and is unlikely to cause false positives for other chemically unrelated drugs such as substituted amphetamines.

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

{{See also|List of modafinil analogues and derivatives}}

Many derivatives and structural analogs of modafinil have been synthesized.{{cite journal | vauthors = De Risi C, Ferraro L, Pollini GP, Tanganelli S, Valente F, Veronese AC | title = Efficient synthesis and biological evaluation of two modafinil analogues | journal = Bioorganic & Medicinal Chemistry | volume = 16 | issue = 23 | pages = 9904–9910 | date = December 2008 | pmid = 18954992 | doi = 10.1016/j.bmc.2008.10.027 }}{{cite journal | vauthors = Okunola-Bakare OM, Cao J, Kopajtic T, Katz JL, Loland CJ, Shi L, Newman AH | 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 | pages = 1000–1013 | date = February 2014 | pmid = 24494745 | pmc = 3954497 | doi = 10.1021/jm401754x }} Examples include adrafinil, CE-123, fladrafinil (CRL-40941; fluorafinil), flmodafinil (CRL-40940; bisfluoromodafinil, lauflumide), RDS03-94, JJC8-088, modafiendz and modafinil sulfone (CRL-41056).{{cite journal | vauthors = Napoletano F, Schifano F, Corkery JM, Guirguis A, Arillotta D, Zangani C, Vento A | title = The Psychonauts' World of Cognitive Enhancers | journal = Frontiers in Psychiatry | volume = 11 | pages = 546796 | date = 2020 | pmid = 33024436 | pmc = 7516264 | doi = 10.3389/fpsyt.2020.546796 | doi-access = free | title-link = doi }}

Modafinil was developed in France by neurophysiology professor Michel Jouvet and Lafon Laboratories. It is part of a series of benzhydryl sulfinyl compounds, including adrafinil, initially used as a treatment for narcolepsy in France in 1986. Modafinil, the primary metabolite of adrafinil,{{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 = 449–457 | date = July 2002 | pmid = 19810941 | doi = 10.1586/14737175.2.4.449 | s2cid = 32939239 }} has been prescribed in France since 1994 under the name Modiodal, and in the United States since 1998 as Provigil. Unlike modafinil, adrafinil does not have FDA approval and was withdrawn from the French market in 2011.{{cite web | url=https://go.drugbank.com/drugs/DB08925 | title=Adrafinil | publisher=The Governors of the University of Alberta | date=May 14, 2021 | access-date=May 14, 2021 | archive-date=May 16, 2021 | archive-url=https://web.archive.org/web/20210516092402/https://go.drugbank.com/drugs/DB08925 | url-status=live }}

The FDA approved modafinil in 1998 for narcolepsy treatment, and later for shift work sleep disorder and obstructive sleep apnea in 2003.{{cite web | title=Drug Approval Package: Provigil (Modafinil) NDA# 20717 | publisher=U.S. Food and Drug Administration (FDA) | date=September 10, 2001 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/98/020717A_Provigil.cfm | access-date=March 1, 2024 | archive-date=March 1, 2024 | archive-url=https://web.archive.org/web/20240301182513/https://www.accessdata.fda.gov/drugsatfda_docs/nda/98/020717A_Provigil.cfm | url-status=dead }}{{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 | pages = e31894 | date = February 2012 | pmid = 22363762 | pmc = 3283698 | doi = 10.1371/journal.pone.0031894 | veditors = Alessi-Severini S | doi-access = free | title-link = doi | bibcode = 2012PLoSO...731894K }} It was approved in the UK in December 2002. In the United States, modafinil is marketed by Cephalon,{{cite web | url=https://www.thepharmaletter.com/article/cephalon-modafinil | title=Cephalon: Modafinil – Pharmaceutical industry news | date=October 8, 1995 | work=The Pharma Letter | access-date=November 15, 2023 | archive-date=November 15, 2023 | archive-url=https://web.archive.org/web/20231115191229/https://www.thepharmaletter.com/article/cephalon-modafinil | url-status=live }} who acquired the rights from Lafon and purchased the company in 2001.

Cephalon introduced armodafinil, the (R)-enantiomer of modafinil, in the United States in 2007. Generic versions of modafinil became available in the US in 2012 after extensive patent litigation.{{cite journal | vauthors = Gellad WF, Choi P, Mizah M, Good CB, Kesselheim AS | title = Assessing the chiral switch: approval and use of single-enantiomer drugs, 2001 to 2011 | journal = The American Journal of Managed Care | volume = 20 | issue = 3 | pages = e90–e97 | date = March 2014 | pmid = 24773330 }}{{cite web | url=https://www.drugs.com/availability/generic-provigil.html | title=Generic Provigil Availability | publisher=Drugs.com | date=November 2023 | access-date=November 15, 2023 | archive-date=November 15, 2023 | archive-url=https://web.archive.org/web/20231115191917/https://www.drugs.com/availability/generic-provigil.html | url-status=live }}

Modafinil is not approved for use by children in multiple jurisdictions.{{Cite web |url=https://pdf.hres.ca/dpd_pm/00071543.PDF |title=Product monograph including patient medication information Alertec modafinil tablets, 100 mg, oral mfr. std. central nervous system stimulant |access-date=February 28, 2024 |archive-date=February 21, 2024 |archive-url=https://web.archive.org/web/20240221143222/https://pdf.hres.ca/dpd_pm/00071543.PDF |url-status=live }}{{cite web | title=Modafinil | website=European Medicines Agency | date=November 18, 2010 | url=https://www.ema.europa.eu/en/medicines/human/referrals/modafinil | access-date=February 28, 2024 | archive-date=January 20, 2024 | archive-url=https://web.archive.org/web/20240120112003/https://www.ema.europa.eu/en/medicines/human/referrals/modafinil | url-status=live }}

In Australia, modafinil is considered to be a Schedule 4 prescription-only medicine. This means that it is a drug with a perceived low potential for abuse and low risk of dependence; still, the use of Schedule 4 drugs in Australia is restricted to those who have a valid prescription from a medical practitioner; import from abroad is illegal.{{cite web |title=Poisons Standard March 2018 |date=February 28, 2018 |url=https://www.legislation.gov.au/Details/F2018L00168 |access-date=January 20, 2019 |publisher=Legislation.gov.au |archive-date=August 7, 2020 |archive-url=https://web.archive.org/web/20200807113733/https://www.legislation.gov.au/Details/F2018L00168 |url-status=live }}

In Canada, modafinil is not specifically included in the lists of controlled drugs and substances specified within the Controlled Drugs and Substances Act.{{cite news|date=March 26, 2005 |title=Regulations Amending the Food and Drug Regulations (1184 — Modafinil) |newspaper=Canada Gazette |volume=140 |issue=20 |url=http://gazette.gc.ca/archives/p1/2005/2005-03-26/html/reg5-eng.html |archive-url=https://web.archive.org/web/20110706181716/http://gazette.gc.ca/archives/p1/2005/2005-03-26/html/reg5-eng.html |archive-date=July 6, 2011}} However, it is classified as a Schedule F prescription drug.{{Cite web|url=https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/prescription-drug-list/guidance-document.html|title=Guidance Document: Determining Prescription Status for Human and Veterinary Drugs| author = Health Canada|date=May 29, 2013|website=www.canada.ca|access-date=February 8, 2024|archive-date=February 8, 2024|archive-url=https://web.archive.org/web/20240208124250/https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/prescription-drug-list/guidance-document.html|url-status=live}}{{Cite web|url=https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/prescription-drug-list.html|title=The Prescription Drug List| author = Health Canada|date=May 29, 2013|website=www.canada.ca|access-date=February 8, 2024|archive-date=June 28, 2023|archive-url=https://web.archive.org/web/20230628231029/https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/prescription-drug-list.html|url-status=live}}{{Cite web|url=https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/prescription-drug-list/questions-answers.html|title=Questions and Answers - Prescription Drug List| author = Health Canada|date=May 30, 2013|website=www.canada.ca|access-date=February 8, 2024|archive-date=February 8, 2024|archive-url=https://web.archive.org/web/20240208124251/https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/prescription-drug-list/questions-answers.html|url-status=live}} This means that modafinil can only be obtained legally with a valid prescription from a licensed health care practitioner in Canada, and the import of modafinil to Canada from other countries is subject to restrictions: importing prescription drugs without an import permit may result in the seizure of the drugs at the border, the refusal of entry of the drugs into Canada, or prosecution.{{cite web | url=https://www.canada.ca/en/health-canada/services/drugs-health-products/compliance-enforcement/importation-exportation/personal-use-health-products-guidance/document.html | title=Bringing health products into Canada for personal use (GUI-0116) | date=December 23, 2020 | access-date=January 29, 2024 | archive-date=January 29, 2024 | archive-url=https://web.archive.org/web/20240129173522/https://www.canada.ca/en/health-canada/services/drugs-health-products/compliance-enforcement/importation-exportation/personal-use-health-products-guidance/document.html | url-status=live }}

In mainland China, modafinil is strictly controlled like other stimulants such as amphetamines and methylphenidate. It is classified as Class I psychotropic drug. This classification means that modafinil is considered to have a high potential for abuse and dependence, and is therefore subject to strict regulation and control. As a result, modafinil is only available by prescription and cannot be purchased over the counter. In order to obtain a prescription for modafinil, a patient must have a valid medical reason for using the drug, such as narcolepsy or obstructive sleep apnea. Additionally, the prescription must be written by a licensed physician and filled at a licensed pharmacy. The use of modafinil for non-medical purposes, such as with the aim to improve cognitive performance or to stay awake for long periods of time, is strictly prohibited and can result in legal consequences.{{cite web|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 | trans-title = Notice from the Food and Drug Administration, the Ministry of Public Security, and the National Health and Family Planning Commission on publishing the catalog of narcotic drugs and psychotropic drugs | language = zh |publisher=China Food and Drug Administration|url=http://samr.cfda.gov.cn/WS01/CL0844/94735.html |archive-url=https://web.archive.org/web/20181205061404/http://samr.cfda.gov.cn/WS01/CL0844/94735.html|archive-date=December 5, 2018|url-status=dead}}{{cite web|url=http://www.gov.cn/flfg/2007-03/13/content_549406.htm|title=处方管理办法(原卫生部令第53号)| trans-title = Prescription Management Measures (Former Ministry of Health Order No. 53) |website=中国政府网 (China Government Network) |language=zh|access-date=February 8, 2019|archive-date=February 8, 2020|archive-url=https://web.archive.org/web/20200208155424/http://www.gov.cn/flfg/2007-03/13/content_549406.htm|url-status=live}}

In Denmark, modafinil is a prescription drug but not listed as a controlled substance. According to the Danish Medicines Agency, modafinil is approved for use in the treatment of narcolepsy, still, importing modafinil to Denmark is considered illegal without a valid prescription.{{cite web |url=https://www.retsinformation.dk/eli/lta/2020/950 |title=Bekendtgørelse om euforiserende stoffer |date=June 23, 2020 |website=Retsinformation.dk |language=da |trans-title=Narcotics act |access-date=October 7, 2020 |archive-date=November 28, 2020 |archive-url=https://web.archive.org/web/20201128175558/https://www.retsinformation.dk/eli/lta/2020/950 |url-status=live }}{{cite web | url=https://laegemiddelstyrelsen.dk/en/pharmacies/medicines-imported-from-abroad/medicines-for-human-use/are-you-bringing-medicine-into-denmark/ | title=Are you bringing medicine into Denmark? | date=August 13, 2018 | access-date=February 5, 2024 | publisher=Danish Medicines Agency | archive-date=January 26, 2024 | archive-url=https://web.archive.org/web/20240126183328/https://laegemiddelstyrelsen.dk/en/pharmacies/medicines-imported-from-abroad/medicines-for-human-use/are-you-bringing-medicine-into-denmark/ | url-status=live }}{{cite web | url=https://laegemiddelstyrelsen.dk/en/pharmacies/medicines-imported-from-abroad/ | title=Medicines imported from abroad | date=March 16, 2022 | access-date=February 5, 2024 | publisher=Danish Medicines Agency | archive-date=January 26, 2024 | archive-url=https://web.archive.org/web/20240126183315/https://laegemiddelstyrelsen.dk/en/pharmacies/medicines-imported-from-abroad/ | url-status=live }}{{cite web|url=https://www.retsinformation.dk/eli/lta/2011/557|title=BEK nr 557 af 31/05/2011, Indenrigs- og Sundhedsministeriet|date=May 31, 2011|access-date=February 5, 2024|publisher=Civilstyrelsen|archive-date=January 26, 2024|archive-url=https://web.archive.org/web/20240126183312/https://www.retsinformation.dk/eli/lta/2011/557|url-status=live}}

In Finland, modafinil is a prescription drug but not listed as a controlled substance. Finland is a member of the European Union, and it is illegal to import prescription medicine from outside the European Union unless the person has a valid prescription.{{cite web|url=https://www.finlex.fi/fi/lainsaadanto/saadoskokoelma/2009/1095|title=Lääkealan turvallisuus- ja kehittämiskeskuksen päätöslääkeluettelosta|date=2009|website=Finlex.fi|access-date=January 3, 2017|archive-date=August 23, 2020|archive-url=https://web.archive.org/web/20200823111409/https://finlex.fi/fi/laki/alkup/2009/20091095|url-status=live}}{{cite web|url=https://tulli.fi/en/private-persons/ordering-goods-online/prohibited-goods|title=Prohibited goods|publisher=Finnish Customs|access-date=February 5, 2024|archive-date=January 26, 2024|archive-url=https://web.archive.org/web/20240126183313/https://tulli.fi/en/private-persons/ordering-goods-online/prohibited-goods|url-status=live}}{{cite web|url=https://dopinglinkki.fi/en/info-bank/doping-substances/modafinil/|title=Modafinil|date=September 19, 2019|access-date=February 5, 2024|website=Dopinglinkki|publisher=A-klinikkasäätiö|archive-date=January 26, 2024|archive-url=https://web.archive.org/web/20240126183315/https://dopinglinkki.fi/en/info-bank/doping-substances/modafinil/|url-status=live}}

In the Republic of Moldova, modafinil is classified as a psychotropic drug (included in table III list 3 which is the list of psychotropic substances as defined by the Government of Moldova) and is available by prescription.{{cite web | url = https://www.legis.md/cautare/getResults?doc_id=103676&lang=ro | title = Hotărâre Nr. 79 din 23-01-2006 privind aprobarea Listei substanţelor stupefiante, psihotrope şi a plantelor care conţin astfel de substanţe depistate în trafic ilicit, precum şi cantităţile acestora | trans-title = Decision No. 79 of 01-23-2006 regarding the approval of the List of narcotic, psychotropic substances and plants containing such substances detected in illicit traffic, as well as their quantities | language = Romanian | publisher = Moldavian Ministry of Justice | date = January 23, 2006 | access-date = February 5, 2024 | archive-date = April 3, 2023 | archive-url = https://web.archive.org/web/20230403194451/https://www.legis.md/cautare/getResults?doc_id=103676&lang=ro | url-status = live }} Importation of modafinil may be considered illegal and subject to severe penalties, even if you have a prescription.{{cite web | url = https://customs.gov.md/ro/articles/e-bine-sa-stim-1369-ro | title = Serviciul Vamal al Republicii Moldova – E bine să știm! | trans-title = Customs Service of the Republic of Moldova - Good to know! | language = Romanian | work = Customs Service of the Republic of Moldova | access-date = September 4, 2023 | archive-date = September 4, 2023 | archive-url = https://web.archive.org/web/20230904105420/https://customs.gov.md/ro/articles/e-bine-sa-stim-1369-ro | url-status = live }} For example, on June 29, 2017, Moldovan postal officers discovered 60 tablets of Modalert (200 mg modafinil tablets) in a parcel sent from India to a resident in Chișinău, Moldova. The prohibited substance was detected during a routine scan and was seized as illegal. The authorities were notified of the incident and the recipient was charged with criminal penalties.{{cite web|date=June 30, 2007|publisher=curentul.md|vauthors=Parfeni C|url=http://curentul.md/stiri/substante-psihotrope-si-un-pumnal-militar-au-fost-depistate-de-vamesi-in-coletele-postale.html|title=Substanțe psihotrope și un pumnal militar au fost depistate de vameși în coletele poștale|access-date=January 29, 2024|archive-date=January 29, 2024|archive-url=https://web.archive.org/web/20240129202533/http://curentul.md/stiri/substante-psihotrope-si-un-pumnal-militar-au-fost-depistate-de-vamesi-in-coletele-postale.html|url-status=live}}{{cite web| publisher=noi.md| date=June 30, 2017| url=https://noi.md/md/news_id/231399| title=Centrul de Sănătate din Edineţ va fi eficientizat energetic| access-date=January 29, 2024| archive-date=January 29, 2024| archive-url=https://web.archive.org/web/20240129202534/https://noi.md/md/news_id/231399| url-status=live}} In the Transnistria region of Moldova, modafinil is completely prohibited, due to application of the legislation similar to that of Russia where modafinil is completely prohibited and is in the same list as narcotics. Possession or an attempt to bring modafinil to Transnistria potentially leads to imprisonment.

In Romania, modafinil is classified as a stimulant doping agent and is prohibited in sports competitions.{{cite web | title = LISTA INTERZISĂ - 2018 | trans-title = Forbidden List - 2018 |work =AGENȚIA NAȚIONALĂ ANTI-DOPING | trans-work = National Anti-Doping Agency | language = Romanian |url=http://anad.gov.ro/web/wp-content/uploads/2017/10/LISTA-2018-web.pdf |archive-date=February 24, 2021 |archive-url=https://web.archive.org/web/20210224105716/http://anad.gov.ro/web/wp-content/uploads/2017/10/LISTA-2018-web.pdf |url-status=dead }} In 2022, laws were passed making its importation or sale a felony, punishable by three to seven years in jail.{{cite web | url=https://legislatie.just.ro/Public/DetaliiDocumentAfis/245003 | title=LEGE 219 26/07/2021 | trans-title = Law 219 26/07/2021 - | work = Portal Legislativ | trans-work = Romanian Legislative Portal| access-date=October 16, 2022 | archive-date=October 16, 2022 | archive-url=https://web.archive.org/web/20221016104753/https://legislatie.just.ro/Public/DetaliiDocumentAfis/245003 | url-status=live | language = Romanian }} Simple possession for personal use may result in a fine and confiscation.

In Sweden, modafinil is classified as a schedule IV substance, which means that it is considered to have a low potential for abuse and a low risk of dependence. Still, possession is illegal without a prescription.{{cite web |title=Läkemedelsverkets föreskrifter (LVFS 2011:10) om förteckningar över narkotika | trans-title = The Swedish Medicines Agency's regulations (LVFS 2011: 10) on lists of drugs | language = sv |url=https://lakemedelsverket.se/upload/lvfs/konsoliderade/LVFS_2011_10_konsoliderad_tom_HSLF-FS_2019_7.pdf |archive-url=https://web.archive.org/web/20190807175859/https://lakemedelsverket.se/upload/lvfs/konsoliderade/LVFS_2011_10_konsoliderad_tom_HSLF-FS_2019_7.pdf |archive-date=August 7, 2019 |url-status=dead }}

In the United Kingdom, it is not listed in Misuse of Drugs Act, so possession is not illegal, but a prescription is required.{{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|access-date = April 3, 2013|archive-date = January 22, 2016|archive-url = https://web.archive.org/web/20160122195257/http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con273748.pdf|url-status = live}}

In Mexico, modafinil is not listed as a controlled substance, in the National Health Law, and can be purchased in pharmacies without prescription.{{cite web |title=Estupefacientes y Psicotrópicos |trans-title=Narcotic Drugs and Psychotropic Substances |language=es |publisher=Federal Commission for Protection against Health Risks |url=http://www.cofepris.gob.mx/pyp/estpsic/es.htm |archive-url=https://web.archive.org/web/20070713135452/http://www.cofepris.gob.mx/pyp/estpsic/es.htm |archive-date=July 13, 2007}}

In Japan, modafinil is Schedule I psychotropic drug. This means that it is considered to have a high potential for abuse and dependence, and is therefore subject to strict regulations. The use of Schedule I drugs in Japan is generally prohibited, except under certain circumstances, such as for medical purposes. It can only be prescribed by a doctor. It cannot be imported or exported without a permit. It cannot be used while driving or operating machinery.{{cite web|url=http://www.ncd.mhlw.go.jp/img/en/total.pdf|title=List of psychotropics|access-date=May 24, 2019|archive-date=July 11, 2019|archive-url=https://web.archive.org/web/20190711014332/http://www.ncd.mhlw.go.jp/img/en/total.pdf|url-status=dead | work = Narcotics Control Department }}{{cite web |url=http://www.fukushihoken.metro.tokyo.jp/kenkou/iyaku/sonota/shitei_m/moda.html |title=モダフィニルの向精神薬への指定 | trans-title = Designation as a psychotropic drug of Modafinyl | language = Japanese |access-date=January 17, 2017 |archive-url=https://web.archive.org/web/20150515002556/http://www.fukushihoken.metro.tokyo.jp/kenkou/iyaku/sonota/shitei_m/moda.html |archive-date=May 15, 2015 |url-status=dead }} Cephalon licensed Alfresa Corporation to produce, and Mitsubishi Tanabe Pharma to sell modafinil products under the trade name Modiodal in Japan.{{cite web|title=医疗用医薬品の添付文书情报-モディオダール锭100mg | trans-title = Attachment of drugs for doctors-Modio Dal 100mg |work = 独立行政法人 医薬品医疗机器総合机 | trans-work = Pharmaceuticals and Medical Devices Agency |url=http://www.info.pmda.go.jp/go/pack/1179047F1022_2_15/ |language=ja|archive-url=https://web.archive.org/web/20190209124042/http://www.info.pmda.go.jp/go/pack/1179047F1022_2_15/|archive-date=February 9, 2019|url-status=dead}} There have been arrests of people who imported modafinil for personal use.{{cite web|url=https://medicallaw.exblog.jp/20422896/|title=モダフィニル密輸で逮捕された歯科医師, ダイエットに使用と供述(報道)| trans-title = Dentist who was arrested for Modafinyl smuggling, usage and confidence (report) | language = ja |website=Medicallaw.exblog.jp|access-date=January 20, 2019|archive-url=https://web.archive.org/web/20190121010916/https://medicallaw.exblog.jp/20422896/|archive-date=January 21, 2019|url-status=dead}}{{cite web|url=https://hayabusa3.5ch.net/test/read.cgi/news/1391949369/|title=向精神薬をインドから密輸入した男を逮捕 | trans-title = Arrested a man who imported psychotropic drugs from India | language = ja |website=Hayabusa3.5ch.net |access-date=January 20, 2019|archive-date=January 21, 2019|archive-url =https://web.archive.org/web/20190121064119/https://hayabusa3.5ch.net/test/read.cgi/news/1391949369/ |url-status=live}}

In Russia, starting from May 18, 2012, modafinil is Schedule II controlled substance. Being classified as a Schedule II controlled substance in Russia means that it is seen as a drug with a high potential for abuse and dependence. This classification imposes strict regulations on the production, distribution, and use of modafinil. Possession of a few modafinil pills can lead to three to ten years imprisonment. Modafinil is not approved for medical use in Russia and cannot be bought even in pharmacies. It also cannot be imported from abroad, even if you have a prescription issued outside Russia.{{cite web |url=http://base.consultant.ru/cons/cgi/online.cgi?req=doc;base=LAW;n=142882;fld=134;dst=4294967295;rnd=0.8965571122244;from=141820-563 |title=Decree of the Government of the Russian Federation of 06.30.1998 N 681 (as amended on 02.26.2013) "On approval of the list of narcotic drugs, psychotropic substances and their precursors subject to control in the Russian Federation" |website=base.consultant.ru |format=PDF |access-date=January 3, 2017 |archive-date=August 28, 2021 |archive-url=https://web.archive.org/web/20210828174157/http://www.consultant.ru/cons/cgi/online.cgi?req=doc&base=LAW&n=142882&fld=134&dst=4294967295&rnd=0.8965571122244&from=141820-563 |url-status=live | language = Russian }}{{cite web |title=Россия начнет производить новый стимулятор на базе модафинила |trans-title=Russia will begin to produce a new stimulator based on modafinil |language=ru |url=https://medvestnik.ru/content/news/Rossiya-gotovitsya-proizvodit-novyi-stimulyator-na-baze-modafinila.html |access-date=December 8, 2023 |website=medvestnik.ru |archive-date=December 8, 2023 |archive-url=https://web.archive.org/web/20231208054906/https://medvestnik.ru/content/news/Rossiya-gotovitsya-proizvodit-novyi-stimulyator-na-baze-modafinila.html |url-status=live }} There are multiple cases of criminal proceedings initiated against Russian residents who tried to import modafinil by mail from abroad.{{cite web |date=February 19, 2020 |title=В Петербурге завели дело из-за полученных по почте таблеток от сонливости |trans-title=In St. Petersburg, a case was started because of the pills received by mail from drowsiness |language=ru |url=https://www.rbc.ru/society/19/02/2020/5e4d28499a79473eeeac6613 |access-date=December 8, 2023 |website=РБК (RBC) |archive-date=December 8, 2023 |archive-url=https://web.archive.org/web/20231208054905/https://www.rbc.ru/society/19/02/2020/5e4d28499a79473eeeac6613 |url-status=live }}{{cite web |date=October 11, 2023 |title="Вместо лечения — тюрьма". Россияне с редкими болезнями оказались в ловушке |trans-title="Instead of treatment - a prison." Russians with rare diseases were trapped |url=https://ria.ru/20231011/son-1901816843.html |access-date=December 8, 2023 |website=РИА Новости (Ria News) |language=ru |archive-date=December 8, 2023 |archive-url=https://web.archive.org/web/20231208054905/https://ria.ru/20231011/son-1901816843.html |url-status=live }}

In South Africa, modafinil is Schedule V substance, which means that it is legal to use modafinil in South Africa, but only with a valid prescription from a licensed medical practitioner.{{cite web|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| url=http://saflii.org/za/legis/consol_reg/marsa101o1965rangnr510723.pdf |archive-url = https://web.archive.org/web/20160422183746/http://saflii.org/za/legis/consol_reg/marsa101o1965rangnr510723.pdf|archive-date = April 22, 2016|url-status = dead}}

In the United States, modafinil is classified as a schedule IV controlled substance under US federal law.{{cite book |title=BNF 74 |date=September 2017 |publisher=Pharmaceutical Press |isbn=978-0-85711-298-9 |page=468 |edition=74}} This means that the drug has a low potential for abuse and dependence compared to other controlled substances. However, it still requires a prescription from a licensed healthcare provider to obtain.

It is illegal to import modafinil to the United States without a Drug Enforcement Administration (DEA)–registered importer and a prescription.{{Cite web |title=Is It Illegal to Obtain Controlled Substances from the Internet? |url=http://www.usdoj.gov/dea/illegal_internet.html |url-status=dead |archive-url=https://web.archive.org/web/20070709032821/http://www.usdoj.gov/dea/illegal_internet.html |archive-date=July 9, 2007 |publisher=United States Drug Enforcement Administration |access-date=July 21, 2007}} Individuals may legally bring modafinil into the US from a foreign country for personal use, limited to 50 dosage units, with a prescription and proper declaration at the border.{{cite web |date=March 24, 1997 |title=USC 201 Section 1301.26 Exemptions from import or export requirements for personal medical use |url-status=dead |archive-url=https://web.archive.org/web/20070203125143/http://www.deadiversion.usdoj.gov/21cfr/cfr/1301/1301_26.htm |archive-date=February 3, 2007 |access-date=January 10, 2007 |publisher=United States Department of Justice|url=http://www.deadiversion.usdoj.gov/21cfr/cfr/1301/1301_26.htm }} Under the Pure Food and Drug Act, marketing drugs for off-label uses is prohibited.{{cite web |title=Prescription Drug Marketing Act of 1987 (PDMA), PL 100-293 |archive-url=https://web.archive.org/web/20080223233036/https://www.fda.gov/opacom/laws/pdma.html |archive-date=February 23, 2008 |publisher=U.S. Food and Drug Administration (FDA) |url=https://www.fda.gov/opacom/laws/pdma.html }} Cephalon, the manufacturer of Provigil, faced legal issues for promoting off-label uses and paid significant fines in 2008.{{cite web |vauthors=Allison J |date=October 9, 2009 |title=Class Action Over Cephalon Off-Label Claims Tossed |url=https://www.law360.com/articles/127434 |publisher=Law360 |quote=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. |access-date=January 12, 2022 |archive-date=April 30, 2022 |archive-url=https://web.archive.org/web/20220430201243/https://www.law360.com/articles/127434 |url-status=live }}

File:Modafinil-generic-aspendos.jpg formulation of modafinil marketed under the Aspendos brand name]]

Modafinil is sold under a variety of brand names worldwide, including Alertec, Alertex, Altasomil, Aspendos, Bravamax, Forcilin, Intensit, Karim, Mentix, Modafinilo, Modalert, Modanil, Modasomil, Modvigil, Modiodal, Modiwake, Movigil, Provigil, Resotyl, Stavigile, Vigia, Vigicer, Vigil, Vigimax, Waklert, and Zalux.{{cite web|title=Modafinil – International Brands|url=https://www.drugs.com/international/modafinil.html|publisher=Drugs.com|access-date=January 8, 2017|archive-date=July 18, 2020|archive-url=https://web.archive.org/web/20200718040144/https://www.drugs.com/international/modafinil.html|url-status=live}}

Originally developed in the 1970s by French neuroscientist Michel Jouvet and Lafon Laboratories, modafinil has been prescribed in France since 1994,{{cite journal|vauthors=Denis F|date=2021|title=Smart drugs et nootropiques|journal=Socio-anthropologie|issue=43|pages=97–110|doi=10.4000/socio-anthropologie.8393|s2cid=237863162|issn=1276-8707|doi-access=free|title-link=doi|volume=43 |url=https://halshs.archives-ouvertes.fr/halshs-03264161/file/DENIS_F%C3%A9lix_2021.pdf|access-date=February 2, 2024|archive-date=January 8, 2022|archive-url=https://web.archive.org/web/20220108000038/https://halshs.archives-ouvertes.fr/halshs-03264161/file/DENIS_F%C3%A9lix_2021.pdf|url-status=live}} and was approved for medical use in the United States in 1998.

Concerns have been raised about the growing use of modafinil as a "smart drug" or cognitive enhancer among healthy individuals who use it with the aim to improve concentration and memory. In 2003, modafinil sales were skyrocketing, with some experts concerned that it had become a tempting pick-me-up for people looking for an extra edge in a productivity-obsessed society. The cost of modafinil varied depending on factors such as location and insurance coverage; still, in 2004, the price of modafinil in the US was around $120 or more per monthly supply. However, the availability of generic versions has increased since then and may have driven down prices.{{cite news |url=https://www.nytimes.com/2004/06/29/health/wakefulness-finds-a-powerful-ally.html |title=Wakefulness Finds a Powerful Ally|vauthors=O'Connor A|work=The New York Times|date=June 29, 2004 |access-date=December 2, 2023 |archive-date=December 2, 2023 |archive-url=https://web.archive.org/web/20231202005726/https://www.nytimes.com/2004/06/29/health/wakefulness-finds-a-powerful-ally.html|url-status=live}}{{cite news |url=https://www.nytimes.com/2014/07/07/world/europe/european-students-use-of-smart-drugs-is-said-to-rise.html |title=European Students' Use of 'Smart Drugs' is Said to Rise |work=The New York Times |date=July 6, 2014 |vauthors=Petrounin D |access-date=December 2, 2023 |archive-date=December 2, 2023 |archive-url=https://web.archive.org/web/20231202005728/https://www.nytimes.com/2014/07/07/world/europe/european-students-use-of-smart-drugs-is-said-to-rise.html |url-status=live }}{{cite news |url=https://www.nytimes.com/2013/06/20/business/global/eu-fines-drug-companies-for-delaying-generics.html |title=Europe Fines Drug Companies for Delaying Generics |work=The New York Times |date=June 19, 2013 |vauthors=Kanter J |access-date=December 2, 2023 |archive-date=December 2, 2023 |archive-url=https://web.archive.org/web/20231202005731/https://www.nytimes.com/2013/06/20/business/global/eu-fines-drug-companies-for-delaying-generics.html |url-status=live }}

In 2020, modafinil was the 302nd most commonly prescribed medication in the United States, with just over 1,000,000 prescriptions.{{cite web | title = Modafinil – Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Modafinil | access-date = October 7, 2022 | archive-date = June 6, 2023 | archive-url = https://web.archive.org/web/20230606002027/https://clincalc.com/DrugStats/Drugs/Modafinil | url-status = live }}

{{As of|2024|post=,}} the global sales figures for modafinil are not known. Still, modafinil sold under the brand name Provigil accounted for over 40% of Cephalon's global turnover for several years, according to the information published in 2020.{{cite news | url=https://www.cuatrecasas.com/en/global/art/pay-for-delay-ec-fines-teva-cephalon-delaying-entry-generic-version-modafinil-market | title='Pay-For-Delay': The EC fines Teva and Cephalon for delaying the market entry of a generic version of Modafinil | newspaper=Cuatrecasas | access-date=November 16, 2023 | archive-date=November 16, 2023 | archive-url=https://web.archive.org/web/20231116214034/https://www.cuatrecasas.com/en/global/art/pay-for-delay-ec-fines-teva-cephalon-delaying-entry-generic-version-modafinil-market | url-status=live }}

Modafinil's patent history involves several key developments. The original patent, {{US patent|4927855}}, was granted to Laboratoire L. Lafon in 1990, covering the chemical compound of modafinil. This patent expired in 2010.{{cite patent|number=4927855|country=US}} In 1994, Cephalon filed a patent for modafinil in the form of particles of a defined size, represented by {{US patent|5618845}}, which expired in 2015.{{cite magazine|url=http://www.bizjournals.com/philadelphia/stories/2006/03/27/daily13.html |title=Cephalon gets six-month Provigil patent extension |magazine=Philadelphia Business Journal |date=March 28, 2006 |access-date=July 21, 2007 |archive-date=August 4, 2008 |archive-url=https://web.archive.org/web/20080804204005/http://www.bizjournals.com/philadelphia/stories/2006/03/27/daily13.html |url-status=live }}

Following the nearing expiration of marketing rights in 2002, generic manufacturers, including Mylan and Teva, applied for FDA approval to market a generic form of modafinil, leading to legal challenges by Cephalon regarding the particle size patent.{{cite web |url=http://www.drugpatentwatch.com/ultimate/preview/patent/index.php?query=RE37516 |title=Details for Patent: RE37516 |access-date=November 29, 2009 |archive-date=January 1, 2014 |archive-url=https://web.archive.org/web/20140101192226/http://www.drugpatentwatch.com/ultimate/preview/patent/index.php?query=RE37516 |url-status=live }} The patent RE 37,516 was declared invalid and unenforceable in 2011.{{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 |access-date=July 4, 2012 |archive-date=January 1, 2014 |archive-url=https://web.archive.org/web/20140101044356/http://law.justia.com/cases/federal/district-courts/pennsylvania/paedce/2:2006cv02768/205626/514 |url-status=live }}

In addition, Cephalon entered agreements with several generic drug manufacturers to delay the sale of generic modafinil in the US. These agreements were subject to legal scrutiny and antitrust investigations, culminating in a ruling by the Court of Appeals in 2016, which found that the settlements did not violate antitrust laws.{{cite court|court=Court of Appeals, 3rd Circuit|litigants=In re: Modafinil Antitrust Litigation|date=2016}}

The regulation of modafinil as a doping agent has been controversial in the sporting world, with high-profile cases attracting press coverage since several prominent American athletes tested positive for the substance. Some athletes who used modafinil protested that the drug was not on the prohibited list at the time of their offenses.{{cite book | publisher = World Anti-Doping Agency |title=The World Anti-Doping Code: International Standard |chapter=Prohibited List 2018 |chapter-url=https://www.wada-ama.org/sites/default/files/prohibited_list_2018_en.pdf |url=https://www.wada-ama.org/en/content/what-is-prohibited |date=September 5, 2017 |access-date=January 12, 2022 |archive-date=July 3, 2021 |archive-url=https://web.archive.org/web/20210703232308/https://www.wada-ama.org/en/content/what-is-prohibited |url-status=live }} However, the World Anti-Doping Agency (WADA) maintains that modafinil was related to already-banned substances. The Agency added modafinil to its list of prohibited substances on August 3, 2004, ten days before the start of the 2004 Summer Olympics.{{Cite journal|title=Citius, Altius, Fortius—Advanced Mass Spectrometry in Service of Forensic Analysis| vauthors = Grocholska P, Popiel D, Walter M, Biernat M, Cebrat M, Kuczer M, Modzel M, Bąchor R, Kluczyk A |date=August 2022 |journal=Chemosensors |volume=10 |issue=8 |pages=324 |doi=10.3390/chemosensors10080324 |doi-access=free }}

Several athletes, such as sprinter Kelli White in 2003,{{cite news |vauthors=Nazzaro MN |date=August 17, 2013 |title=Out of Track's Doping Scandal, Redemption and Progress |work=The New York Times |url=https://www.nytimes.com/2013/08/18/sports/olympics/out-of-a-doping-scandal-redemption-for-Kelli-White-and-progress-for-track.html |access-date=December 3, 2023 |issn=0362-4331 |archive-date=December 3, 2023 |archive-url=https://web.archive.org/web/20231203143118/https://www.nytimes.com/2013/08/18/sports/olympics/out-of-a-doping-scandal-redemption-for-Kelli-White-and-progress-for-track.html |url-status=live }} cyclist David Clinger{{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 |access-date=October 8, 2014 |archive-date=October 13, 2014 |archive-url=https://web.archive.org/web/20141013173114/http://www.cyclingnews.com/news/clinger-given-lifetime-ban-for-second-doping-infraction |url-status=live }} and basketball player Diana Taurasi{{cite news |url=https://www.washingtonpost.com/wp-dyn/content/article/2010/12/24/AR2010122402993.html |newspaper=The Washington Post |title=Taurasi tested positive for modafinil |date=December 25, 2010 |access-date=December 31, 2013 |archive-date=October 6, 2014 |archive-url=https://web.archive.org/web/20141006091440/http://www.washingtonpost.com/wp-dyn/content/article/2010/12/24/AR2010122402993.html |url-status=live }} in 2010, and rower Timothy Grant in 2015,{{cite news|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|date=November 23, 2015|newspaper=The Guardian|access-date=December 15, 2016|archive-date=July 9, 2020|archive-url=https://web.archive.org/web/20200709214752/https://www.theguardian.com/sport/2015/nov/23/british-rowers-handed-two-year-bans-doping-violations-sybren-hoogland-timothy-grant|url-status=live}} were accused of using modafinil as a performance-enhancing doping agent. Taurasi and another player—Monique Coker, tested at the same lab—were later cleared.{{cite web |url=https://www.espn.com/wnba/columns/story?columnist=voepel_mechelle&id=6135920 |vauthors=Voepel M |title=Taurasi: 'I've lost 3 months of my career' |date=February 18, 2011 |access-date=April 11, 2011 |archive-date=October 6, 2015 |archive-url=https://web.archive.org/web/20151006020737/http://sports.espn.go.com/wnba/columns/story?columnist=voepel_mechelle&id=6135920 |url-status=live }} Kelli White, who tested positive after her 100m victory at the 2003 World Championships in Paris, was stripped of her gold medals.{{cite news|url=http://news.bbc.co.uk/sport2/hi/athletics/world_athletics_2003/3077070.stm|title=White guilty of doping|date=September 9, 2003|via=news.bbc.co.uk|access-date=November 15, 2023|archive-date=November 15, 2023|archive-url=https://web.archive.org/web/20231115164109/http://news.bbc.co.uk/sport2/hi/athletics/world_athletics_2003/3077070.stm|url-status=live}} She claimed that she used modafinil to treat narcolepsy, but the International Association of Athletics Federations (IAAF) ruled that modafinil was a performance-enhancing drug.

The BALCO scandal brought to light an 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.{{cite news|title=Book alleges Bonds's drug use|work=CBC News|url=https://www.cbc.ca/sports/baseball/book-alleges-bonds-s-drug-use-1.605000|date=March 7, 2006|accessdate=January 27, 2024|archive-date=January 27, 2024|archive-url=https://web.archive.org/web/20240127204646/https://www.cbc.ca/sports/baseball/book-alleges-bonds-s-drug-use-1.605000|url-status=live}}

The use of modafinil as a supposed cognitive enhancer may be considered as cheating, unnatural, or risky.{{cite web | vauthors=Macnaughton O | url=https://www.tatler.com/article/the-rise-of-smart-drugs | title=The rise of smart drugs | date=March 16, 2016 | work=Tatler | access-date=November 15, 2023 | archive-date=November 15, 2023 | archive-url=https://web.archive.org/web/20231115162141/https://www.tatler.com/article/the-rise-of-smart-drugs | url-status=live }} The University of Sussex explained that it is a prescription drug and the decision should be made by the doctor on whether to prescribe modafinil to a student.{{cite web | vauthors=Farrell K | url=https://thetab.com/uk/sussex/2017/11/06/asked-sussex-university-modafinil-cheating-22575 | title=We asked Sussex University if Modafinil is cheating | date=November 6, 2017 | work=The Sussex Tab | access-date=November 15, 2023 | archive-date=November 15, 2023 | archive-url=https://web.archive.org/web/20231115162143/https://thetab.com/uk/sussex/2017/11/06/asked-sussex-university-modafinil-cheating-22575 | url-status=live }} As a matter of bioethics, the US President's Council on Bioethics argued that excellence achieved through the use of drugs like modafinil is "cheap" as it obviates the need for hard work and study, and is not fully authentic because the excellence is partly attributable to the drug, not the individual.{{cite journal |doi=10.1080/17449642.2018.1443050 |title=Is the use of modafinil, a pharmacological cognitive enhancer, cheating? |date=2018 |vauthors=Porsdam Mann S, de Lora Deltoro P, Cochrane T, Mitchell C |journal=Ethics and Education |volume=13 |issue=2 |pages=251–267 |s2cid=149138516 |url=https://philpapers.org/archive/PORITU.pdf |access-date=February 2, 2024 |archive-date=February 2, 2024 |archive-url=https://web.archive.org/web/20240202114822/https://philpapers.org/archive/PORITU.pdf |url-status=live }} Alternately, people in environments like Wall Street trading may not view the use of modafinil as cheating, believing that if modafinil can give them an edge and they are aware of the risks involved, it should not be considered as cheating.{{cite magazine|magazine=New York Magazine|url=https://nymag.com/news/intelligencer/modafinil-2013-4/|title=The Real Limitless Drug Isn't Just for Lifehackers Anymore|date=March 29, 2013| vauthors = Robert K |access-date=March 16, 2024|archive-date=December 26, 2023|archive-url=https://web.archive.org/web/20231226213829/https://nymag.com/news/intelligencer/modafinil-2013-4/|url-status=live}} Due to such varying views, modafinil users for narcolepsy may cope with stigma by hiding, denying, or justifying their use, or by seeking support from others who share their views or experiences.{{cite journal | vauthors = Teodorini RD, Rycroft N, Smith-Spark JH | title = The off-prescription use of modafinil: An online survey of perceived risks and benefits | journal = PLOS ONE | volume = 15 | issue = 2 | pages = e0227818 | date = 2020 | pmid = 32023288 | pmc = 7001904 | doi = 10.1371/journal.pone.0227818 | doi-access = free | title-link = doi | bibcode = 2020PLoSO..1527818T }}{{cite journal | vauthors = Kornum BR, Knudsen S, Ollila HM, Pizza F, Jennum PJ, Dauvilliers Y, Overeem S | title = Narcolepsy | journal = Nature Reviews. Disease Primers | volume = 3 | pages = 16100 | date = February 2017 | pmid = 28179647 | doi = 10.1038/nrdp.2016.100 | s2cid = 266008273 | url = http://www.hal.inserm.fr/inserm-01484949/file/nrdp2016100_Primer_1486657828_1.pdf }}{{Dead link|date=March 2024 |bot=InternetArchiveBot |fix-attempted=yes }}

Modafinil has been studied in the treatment of major depressive disorder.{{cite journal | vauthors = Kleeblatt J, Betzler F, Kilarski LL, Bschor T, Köhler S | title = Efficacy of off-label augmentation in unipolar depression: A systematic review of the evidence | journal = European Neuropsychopharmacology | volume = 27 | issue = 5 | pages = 423–441 | date = May 2017 | pmid = 28318897 | doi = 10.1016/j.euroneuro.2017.03.003 | s2cid = 3740987 }}{{cite journal | vauthors = McIntyre RS, Lee Y, Zhou AJ, Rosenblat JD, Peters EM, Lam RW, Kennedy SH, Rong C, Jerrell JM | title = The Efficacy of Psychostimulants in Major Depressive Episodes: A Systematic Review and Meta-Analysis | journal = Journal of Clinical Psychopharmacology | volume = 37 | issue = 4 | pages = 412–418 | date = August 2017 | pmid = 28590365 | doi = 10.1097/JCP.0000000000000723 | s2cid = 27622964 }}{{cite journal | vauthors = Bahji A, Mesbah-Oskui L | title = Comparative efficacy and safety of stimulant-type medications for depression: A systematic review and network meta-analysis | journal = Journal of Affective Disorders | volume = 292 | pages = 416–423 | date = September 2021 | pmid = 34144366 | doi = 10.1016/j.jad.2021.05.119 }} In a 2021 systematic review and meta-analysis of randomized controlled trials of psychostimulants for depression, modafinil and other stimulants such as methylphenidate and amphetamines improved depression in traditional meta-analysis. However, when subjected to network meta-analysis, modafinil and most other stimulants did not significantly improve depression, with only methylphenidate remaining effective. Modafinil and other stimulants likewise did not improve quality of life in the meta-analysis, although there was evidence for reduced fatigue and sleepiness with modafinil and other stimulants. While significant effectiveness of modafinil for depression has been reported by particular trials,{{cite journal | vauthors = Corp SA, Gitlin MJ, Altshuler LL | title = A review of the use of stimulants and stimulant alternatives in treating bipolar depression and major depressive disorder | journal = The Journal of Clinical Psychiatry | volume = 75 | issue = 9 | pages = 1010–1018 | date = September 2014 | pmid = 25295426 | doi = 10.4088/JCP.13r08851 }}{{cite journal | vauthors = Goss AJ, Kaser M, Costafreda SG, Sahakian BJ, Fu CH | title = Modafinil augmentation therapy in unipolar and bipolar depression: a systematic review and meta-analysis of randomized controlled trials | journal = The Journal of Clinical Psychiatry | volume = 74 | issue = 11 | pages = 1101–1107 | date = November 2013 | pmid = 24330897 | doi = 10.4088/JCP.13r08560 }} reviews and meta-analyses note that the effectiveness of modafinil for depression is limited, the quality of available evidence is low, and the results are inconclusive.{{cite journal | vauthors = Malhi GS, Byrow Y, Bassett D, Boyce P, Hopwood M, Lyndon W, Mulder R, Porter R, Singh A, Murray G | title = Stimulants for depression: On the up and up? | journal = The Australian and New Zealand Journal of Psychiatry | volume = 50 | issue = 3 | pages = 203–207 | date = March 2016 | pmid = 26906078 | doi = 10.1177/0004867416634208 | s2cid = 45341424 }}{{cite journal | vauthors = Miskowiak KW, Seeberg I, Jensen MB, Balanzá-Martínez V, Del Mar Bonnin C, Bowie CR, Carvalho AF, Dols A, Douglas K, Gallagher P, Hasler G, Lafer B, Lewandowski KE, López-Jaramillo C, Martinez-Aran A, McIntyre RS, Porter RJ, Purdon SE, Schaffer A, Stokes P, Sumiyoshi T, Torres IJ, Van Rheenen TE, Yatham LN, Young AH, Kessing LV, Burdick KE, Vieta E | title = Randomised controlled cognition trials in remitted patients with mood disorders published between 2015 and 2021: A systematic review by the International Society for Bipolar Disorders Targeting Cognition Task Force | journal = Bipolar Disorders | volume = 24 | issue = 4 | pages = 354–374 | date = June 2022 | pmid = 35174594 | pmc = 9541874 | doi = 10.1111/bdi.13193 }}

====Attention deficit hyperactivity disorder (research)====

Modafinil was considered for the treatment of ADHD because of its lower abuse potential than conventional psychostimulants like methylphenidate and amphetamines.{{cite journal | vauthors = Wang SM, Han C, Lee SJ, Jun TY, Patkar AA, Masand PS, Pae CU | title = Modafinil for the treatment of attention-deficit/hyperactivity disorder: A meta-analysis | journal = Journal of Psychiatric Research | volume = 84 | pages = 292–300 | date = January 2017 | pmid = 27810669 | doi = 10.1016/j.jpsychires.2016.09.034 }} In 2008, an application to market modafinil for pediatric ADHD was submitted to the Food and Drug Administration in the US.{{cite journal | vauthors = Kumar R | title = Approved and Investigational Uses of Modafinil | journal = Drugs | volume = 68 | issue = 13 | pages = 1803–1839 | year = 2008 | pmid = 18729534 | doi = 10.2165/00003495-200868130-00003 | s2cid = 38542387 }}

However, evidence of modafinil for treatment of adult ADHD is mixed, and a 2016 systematic review of alternative drug therapies for adult ADHD did not recommend its use in this context.{{cite journal | vauthors = Buoli M, Serati M, Cahn W | title = Alternative pharmacological strategies for adult ADHD treatment: a systematic review | journal = Expert Review of Neurotherapeutics | volume = 16 | issue = 2 | pages = 131–144 | date = 2016 | pmid = 26693882 | doi = 10.1586/14737175.2016.1135735 | s2cid = 33004517 }} In a later large phase 3 clinical trial of modafinil for adult ADHD, modafinil was not effective in improving symptoms, there was also a high rate of side effects (86%) and discontinuation (47%).{{cite journal | vauthors = Kooij JJ, Bijlenga D, Salerno L, Jaeschke R, Bitter I, Balázs J, Thome J, Dom G, Kasper S, Nunes Filipe C, Stes S, Mohr P, Leppämäki S, Casas M, Bobes J, Mccarthy JM, Richarte V, Kjems Philipsen A, Pehlivanidis A, Niemela A, Styr B, Semerci B, Bolea-Alamanac B, Edvinsson D, Baeyens D, Wynchank D, Sobanski E, Philipsen A, McNicholas F, Caci H, Mihailescu I, Manor I, Dobrescu I, Saito T, Krause J, Fayyad J, Ramos-Quiroga JA, Foeken K, Rad F, Adamou M, Ohlmeier M, Fitzgerald M, Gill M, Lensing M, Motavalli Mukaddes N, Brudkiewicz P, Gustafsson P, Tani P, Oswald P, Carpentier PJ, De Rossi P, Delorme R, Markovska Simoska S, Pallanti S, Young S, Bejerot S, Lehtonen T, Kustow J, Müller-Sedgwick U, Hirvikoski T, Pironti V, Ginsberg Y, Félegyházy Z, Garcia-Portilla MP, Asherson P | title = Updated European Consensus Statement on diagnosis and treatment of adult ADHD | journal = European Psychiatry | volume = 56 | pages = 14–34 | date = February 2019 | pmid = 30453134 | doi = 10.1016/j.eurpsy.2018.11.001 | s2cid = 53714228 | doi-access = free | title-link = doi | hdl = 10651/51910 | hdl-access = free }} The poor tolerability of modafinil in this study was possibly due to the use of high doses ({{Val|210|-|510|u=mg/day}}). Another reason for the denial of the approval was due to concerns about rare but serious dermatological toxicity in Stevens–Johnson syndrome.

The research on the use of modafinil for treating individuals with Autism Spectrum Disorder (ASD) who also exhibit ADHD symptoms is currently in its early stages with no results delivered.{{cite journal |vauthors=Martins PL, Torquato GC, Dias GA, Leite IB, Gaspar TM, Pinto JP, Macedo DS |title=Effectiveness of pharmacological interventions for managing ADHD symptoms in individuals with autism spectrum disorder: A systematic review and meta-analysis |journal=Prog Neuropsychopharmacol Biol Psychiatry |volume=134 |issue= |pages=111089 |date=August 2024 |pmid=39004333 |doi=10.1016/j.pnpbp.2024.111089 |url=}}

Modafinil was studied for the treatment of stimulant dependence, but the results are mixed and inconclusive.{{cite journal | vauthors = Hersey M, Bacon AK, Bailey LG, Coggiano MA, Newman AH, Leggio L, Tanda G | title = Psychostimulant Use Disorder, an Unmet Therapeutic Goal: Can Modafinil Narrow the Gap? | journal = Frontiers in Neuroscience | volume = 15 | pages = 656475 | date = 2021 | pmid = 34121988 | pmc = 8187604 | doi = 10.3389/fnins.2021.656475 | doi-access = free | title-link = doi }} Modafinil is not a controlled substance in some countries, unlike other medications, such as bupropion, which is also used to treat depression and nicotine dependence.{{cite journal | vauthors = Tardelli VS, Bisaga A, Arcadepani FB, Gerra G, Levin FR, Fidalgo TM | title = Prescription psychostimulants for the treatment of stimulant use disorder: a systematic review and meta-analysis | journal = Psychopharmacology | location = Berlin | volume = 237 | issue = 8 | pages = 2233–2255 | date = August 2020 | pmid = 32601988 | doi = 10.1007/s00213-020-05563-3 | s2cid = 220150476 }} The clinical trials that have tested modafinil as a treatment for stimulant abuse have failed to demonstrate its efficacy and the optimal dose and duration of modafinil treatment remain unclear, and modafinil is not a recommended treatment for stimulant abuse. 2024 reviews found that modafinil was ineffective for treating individuals with amphetamine-type stimulant use disorder or methamphetamine use disorder{{cite journal |vauthors=Yates JR |title=Pharmacological Treatments for Methamphetamine Use Disorder: Current Status and Future Targets |journal=Subst Abuse Rehabil |volume=15 |issue= |pages=125–161 |date=2024 |pmid=39228432 |pmc=11370775 |doi=10.2147/SAR.S431273|doi-access=free }} from these dependencies.{{cite journal | vauthors = Elkrief L, Sharafi H, Bakouni H, McAnulty C, Bastien G, Dubreucq S, Garel N, Trépanier A, Ziegler D, Jutras-Aswad D | title = Efficacy and Safety of Modafinil for Treatment of Amphetamine-Type Stimulant Use Disorder: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials | journal = The Canadian Journal of Psychiatry | date = July 2024 | volume = 69 | issue = 11 | pages = 793–805 | pmid = 39033427 | doi = 10.1177/07067437241262967 | pmc = 11572177 }}

Modafinil and armodafinil were studied as a complement to antipsychotic medications in the treatment of schizophrenia. They showed no effect on positive symptoms or cognitive performance.{{cite journal | vauthors = Kane JM, D'Souza DC, Patkar AA, Youakim JM, Tiller JM, Yang R, Keefe RS | title = Armodafinil as adjunctive therapy in adults with cognitive deficits associated with schizophrenia: a 4-week, double-blind, placebo-controlled study | journal = The Journal of Clinical Psychiatry | volume = 71 | issue = 11 | pages = 1475–1481 | date = November 2010 | pmid = 20816042 | doi = 10.4088/jcp.09m05950gry }} A 2015 meta-analysis found that modafinil and armodafinil may slightly reduce negative symptoms in people with acute schizophrenia, though they do not appear useful for people with the condition who are stable, with high negative symptom scores.{{cite journal | vauthors = Andrade C, Kisely S, Monteiro I, Rao S | title = Antipsychotic augmentation with modafinil or armodafinil for negative symptoms of schizophrenia: systematic review and meta-analysis of randomized controlled trials | journal = Journal of Psychiatric Research | volume = 60 | pages = 14–21 | date = January 2015 | pmid = 25306261 | doi = 10.1016/j.jpsychires.2014.09.013 | url = https://espace.library.uq.edu.au/view/UQ:345290/UQ345290_OA.pdf }} Among medications demonstrated to be effective for reducing negative symptoms in combination with antipsychotics, modafinil, and armodafinil are among the smallest effect sizes.{{cite journal | vauthors = Correll CU, Rubio JM, Inczedy-Farkas G, Birnbaum ML, Kane JM, Leucht S | title = Efficacy of 42 Pharmacologic Cotreatment Strategies Added to Antipsychotic Monotherapy in Schizophrenia: Systematic Overview and Quality Appraisal of the Meta-analytic Evidence | journal = JAMA Psychiatry | volume = 74 | issue = 7 | pages = 675–684 | date = July 2017 | pmid = 28514486 | pmc = 6584320 | doi = 10.1001/jamapsychiatry.2017.0624 }}

Modafinil is researched to determine whether it might improve abstinence in people with cocaine addiction.{{cite journal | vauthors = Sangroula D, Motiwala F, Wagle B, Shah VC, Hagi K, Lippmann S | title = Modafinil Treatment of Cocaine Dependence: A Systematic Review and Meta-Analysis | journal = Substance Use & Misuse | volume = 52 | issue = 10 | pages = 1292–1306 | date = August 2017 | pmid = 28350194 | doi = 10.1080/10826084.2016.1276597 | s2cid = 4775658 }}

Modafinil has been found to reverse tetrabenazine-induced motivational deficits in animals and hence can produce pro-motivational effects.{{cite journal | vauthors = Salamone JD, Correa M | title = The Neurobiology of Activational Aspects of Motivation: Exertion of Effort, Effort-Based Decision Making, and the Role of Dopamine | journal = Annu Rev Psychol | volume = 75 | issue = | pages = 1–32 | date = January 2024 | pmid = 37788571 | doi = 10.1146/annurev-psych-020223-012208 | url = | hdl = 10234/207207 | hdl-access = free }}{{cite journal | vauthors = Salamone JD, Yohn SE, López-Cruz L, San Miguel N, Correa M | title = Activational and effort-related aspects of motivation: neural mechanisms and implications for psychopathology | journal = Brain | volume = 139 | issue = Pt 5 | pages = 1325–1347 | date = May 2016 | pmid = 27189581 | pmc = 5839596 | doi = 10.1093/brain/aww050 | url = }}{{cite journal | vauthors = Yohn SE, Gogoj A, Haque A, Lopez-Cruz L, Haley A, Huxley P, Baskin P, Correa M, Salamone JD | title = Evaluation of the effort-related motivational effects of the novel dopamine uptake inhibitor PRX-14040 | journal = Pharmacol Biochem Behav | volume = 148 | issue = | pages = 84–91 | date = September 2016 | pmid = 27296079 | doi = 10.1016/j.pbb.2016.06.004 | url = }} Novel modafinil analogs with greater potency, including CE-123, CE-158, JJC8-088, MK-26, and RDS03-94, have also been developed and have shown pro-motivational effects in animals.{{cite journal | vauthors = Ecevitoglu A, Meka N, Rotolo RA, Edelstein GA, Srinath S, Beard KR, Carratala-Ros C, Presby RE, Cao J, Okorom A, Newman AH, Correa M, Salamone JD | title = Potential therapeutics for effort-related motivational dysfunction: assessing novel atypical dopamine transport inhibitors | journal = Neuropsychopharmacology | volume = 49 | issue = 8 | pages = 1309–1317 | date = July 2024 | pmid = 38429498 | doi = 10.1038/s41386-024-01826-1 | pmc = 11224370 | pmc-embargo-date = July 1, 2025 | url = }} These agents are of potential interest in the treatment of motivational disorders in humans.

A 2019 review conducted on the potential nootropic effects of modafinil in healthy, non-sleep-deprived individuals revealed the following:{{cite journal | vauthors = Kredlow MA, Keshishian A, Oppenheimer S, Otto MW | title = The Efficacy of Modafinil as a Cognitive Enhancer: A Systematic Review and Meta-Analysis | journal = Journal of Clinical Psychopharmacology | volume = 39 | issue = 5 | pages = 455–461 | date = 2019 | pmid = 31433334 | doi = 10.1097/JCP.0000000000001085 | s2cid = 201119084 }} a) while studies using basic testing paradigms demonstrated that modafinil enhances executive function, only half of these studies showed improvements in attention, learning, and memory, with a few studies even reporting impairments in divergent creative thinking; b) modafinil displayed small levels of enhancement in attention, executive functions, and learning abilities; c) no substantial side effects or mood changes were observed; d) the available evidence showed limited evidence for modafinil as a cognitive enhancer outside of its use for sleep-deprived populations.

A 2020 review reported that modafinil has a modest effect on memory updating, but the effect is small and may not accurately reflect the perception that it is useful as a cognitive enhancer, as there is insufficient evidence to support such a claim.{{cite journal | vauthors = Roberts CA, Jones A, Sumnall H, Gage SH, Montgomery C | title = How effective are pharmaceuticals for cognitive enhancement in healthy adults? A series of meta-analyses of cognitive performance during acute administration of modafinil, methylphenidate and D-amphetamine | journal = European Neuropsychopharmacology | volume = 38 | pages = 40–62 | date = September 2020 | pmid = 32709551 | doi = 10.1016/j.euroneuro.2020.07.002 | url = https://researchonline.ljmu.ac.uk/id/eprint/13268/8/How%20effective%20are%20pharmaceuticals%20for%20cognitive%20enhancement%20in%20healthy%20adults%20A%20series%20of%20meta-analyses%20of%20cognitive%20performance%20during%20acute%20administration%20of%20modafinil%2C%20methylphenidate%20and%20d-amphetamine..pdf | url-status = live | s2cid = 220651670 | archive-url = https://web.archive.org/web/20220220101717/https://researchonline.ljmu.ac.uk/id/eprint/13268/8/How%20effective%20are%20pharmaceuticals%20for%20cognitive%20enhancement%20in%20healthy%20adults%20A%20series%20of%20meta-analyses%20of%20cognitive%20performance%20during%20acute%20administration%20of%20modafinil%2C%20methylphenidate%20and%20d-amphetamine..pdf | archive-date = February 20, 2022 }}

General anesthesia is required for many surgeries, but may cause lingering fatigue, sedation, and/or drowsiness after surgery that lasts for hours to days.{{cite journal| doi=10.1136/sbmj.070256 | title=Anaesthesia: Induction and maintenance of general anesthesia | date=2007 | journal=BMJ | volume=334 | vauthors = Behar JM, Gogalniceanu P, Bromley L }}{{cite journal |vauthors=Vacas S, Cole DJ, Cannesson M |title=Cognitive Decline Associated With Anesthesia and Surgery in Older Patients |journal=JAMA |date=August 2021 |volume=326 |issue=9 |page=863 |pmid=34338712 |pmc=8807795 |doi=10.1001/jama.2021.4773}} In outpatient surgery the sedation, fatigue, and occasional dizziness is problematic.{{cite journal|doi=10.1097/00000542-200211000-00035 |title=Fatigue in Anesthesia |date=2002 |journal=Anesthesiology |volume=97 |issue=5 |pages=1281–1294 |pmid=12411816 | vauthors = Warltier DC, Howard SK, Rosekind MR, Katz JD, Berry AJ }}{{cite journal|doi=10.1097/00000542-200204000-00030 |title=Systematic Review and Analysis of Postdischarge Symptoms after Outpatient Surgery |date=2002 |journal=Anesthesiology |volume=96 |issue=4 |pages=994–1003 |pmid=11964610 | vauthors = Wu CL, Berenholtz SM, Pronovost PJ, Fleisher LA }} Modafinil was tested as a potential remedy to alleviate these symptoms. For example, it was expected that modafinil would help people recover quicker from general anesthesia after a short surgery, but the results were uncertain and the inconclusive studies could not reliably verify the expectation.{{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 = 554–566 | date = April 2006 | pmid = 16669720 | doi = 10.4088/jcp.v67n0406 }} The use of modafinil to relieve post-anesthesia sedation is investigational.

Caution should be exercised in people who have narcolepsy in comorbidity with postural orthostatic tachycardia syndrome (POTS).{{cite journal |vauthors=Raj SR |title=The Postural Tachycardia Syndrome (POTS): pathophysiology, diagnosis & management |journal=Indian Pacing Electrophysiol J |volume=6 |issue=2 |pages=84–99 |date=April 2006 |pmid=16943900 |pmc=1501099}}

Modafinil is being researched as a potential remedy for excessive daytime sleepiness in myotonic dystrophy (DM), an inherited condition characterized by progressive muscle loss, weakness, and myotonia. Myotonia is a condition where muscles cannot relax after they contract.{{cite journal |vauthors=Hoxhaj D, Pascazio A, Maestri M, Ricci G, Fabbrini M, Torresi FB, Siciliano G, Bonanni E |title=Excessive daytime sleepiness in myotonic dystrophy: a narrative review |journal=Front Neurol |volume=15 |issue= |pages=1389949 |date=2024 |pmid=39011358 |pmc=11248093 |doi=10.3389/fneur.2024.1389949|doi-access=free }} Myotonic dystrophy has two main types: DM1 (Steinert disease) and DM2 (proximal myotonic myopathy). Both types can cause excessive daytime sleepiness. Studies suggest that modafinil may be a promising drug that can reduce both daytime sleepiness and myotonia itself, without significant cardiac conduction effects. These presumed property of modafinil is of particular interest for eventual treatment of people with myotonic dystrophy who often have underlying cardiac issues. Still, modafinil is not approved by the FDA for use in myotonic dystrophy, and the value and role of modafinil in DM remain the subject of debate.

Modafinil has been studied for its potential therapeutic effects in patients with disorders of consciousness. Researchers are investigating whether modafinil can stimulate neurotransmitters such as histamine, norepinephrine, serotonin, dopamine, and orexin, and whether modafinil has potential anti-oxidative effects.{{cite journal |vauthors=Barra ME, Solt K, Yu X, Edlow BL |title=Restoring consciousness with pharmacologic therapy: Mechanisms, targets, and future directions |journal=Neurotherapeutics |volume=21 |issue=4 |pages=e00374 |date=July 2024 |pmid=39019729 |pmc=11452330 |doi=10.1016/j.neurot.2024.e00374}}

Disorders of consciousness are states characterized by impaired arousal and awareness. These states include coma, vegetative state/unresponsive wakefulness syndrome (VS/UWS), minimally conscious state (MCS), cognitive motor dissociation, and covert cortical processing. Brain injuries can impair consciousness through neuroanatomic lesions involving the bilateral cerebral hemispheres, rostral brainstem, diencephalon, or basal forebrain.

Neuroimaging studies have shown that modafinil increases cerebral blood flow in several brain regions, such as the thalamus, locus coeruleus, limbic system, and insular cortex; still, observational reports on the use of modafinil in patients with disorders of consciousness have produced mixed results, indicating that its effectiveness may vary among individuals.

A possible link between inflammatory processes and depressive disorders{{cite journal | vauthors = Kohler O, Krogh J, Mors O, Benros ME | title = Inflammation in Depression and the Potential for Anti-Inflammatory Treatment | journal = Current Neuropharmacology | volume = 14 | issue = 7 | pages = 732–742 | date = 2016 | pmid = 27640518 | pmc = 5050394 | doi = 10.2174/1570159x14666151208113700 }} has stimulated preliminary research on modafinil for its potential anti-inflammatory effects.{{cite journal | vauthors = Zager A | title = Modulating the immune response with the wake-promoting drug modafinil: A potential therapeutic approach for inflammatory disorders | journal = Brain, Behavior, and Immunity | volume = 88 | pages = 878–886 | date = August 2020 | pmid = 32311496 | doi = 10.1016/j.bbi.2020.04.038 | s2cid = 215807973 }}

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