Extensive clinical research has not demonstrated drug tolerance, defined as a reduction in response, to wakefulness-promoting and anti-fatigue properties of modafinil, even with therapeutic use extending up to 40 weeks.
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.