Editing Modafinil (section)

==Drug tolerance==
Extensive clinical research has not demonstrated [[drug tolerance]] as a common adverse effect, even with therapeutic use extending up to 40 weeks.<ref name="pmid30174215">{{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 }}</ref><ref name="billiard-2016-springer">{{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}}</ref><ref name="pmid15336235">{{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 }}</ref> Drug tolerance in this context is defined as a reduction in response, to wakefulness-promoting and [[pro-motivational agent|anti-fatigue]] properties of modafinil.<ref name="pmid30174215"/>

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.<ref name="pmid32341841" /> This necessitates higher doses to maintain the same level of cognitive enhancement or relief from sleepiness.<ref name="pmid32341841" />

People with current or past substance addictions and those with a family history of addiction are particularly at risk for developing tolerance.<ref name="pmid32341841" /><ref name="pmid34173288"/><ref name="pmid33802176"/>

The mechanisms driving tolerance to modafinil, which may involve its impact on [[dopamine]] and [[norepinephrine]] levels in the brain, are not fully understood.<ref name="pmid32341841" /><ref name="pmid34173288"/><ref name="pmid33802176"/>

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.<ref name="pmid32341841" /><ref name="pmid34173288">{{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 }}</ref><ref name="pmid33802176">{{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 }}</ref>