Modafinil

Modafinil is the most widely used pharmaceutical nootropic in the world, prescribed for narcolepsy and sleep disorders but used off-label by millions of healthy individuals for cognitive enhancement. Originally developed by the French pharmaceutical company Lafon Laboratories in the 1970s (as adrafinil, which was later refined to modafinil), it was approved by the FDA in 1998 under the brand name Provigil.

What makes modafinil unique among stimulants is its mechanism of action. Unlike amphetamines which flood the brain with dopamine through vesicle release, modafinil weakly inhibits the dopamine transporter while primarily acting on the orexin/hypocretin wakefulness system and histamine pathways. This produces sustained alertness and focus for 10-15 hours without the euphoria, jitteriness, or crash associated with traditional stimulants. The abuse potential is correspondingly low — it is Schedule IV (compared to Schedule II for amphetamines).

The most important practical consideration with modafinil is its 12-15 hour half-life. Taking it after noon virtually guarantees insomnia. The 100 mg dose is often sufficient and produces fewer side effects than the standard 200 mg dose. Many experienced users find that 50-100 mg provides 80% of the cognitive benefits with significantly less anxiety and appetite suppression.

Standard: 100-200 mg once in the morning. For shift work: 200 mg 1 hour before the shift. Start with 100 mg to assess sensitivity. Do not take after noon due to the very long half-life.

Modafinil's exact mechanism is not fully understood but involves multiple neurotransmitter systems. It inhibits the dopamine transporter (DAT) with moderate affinity, weakly increasing synaptic dopamine levels without causing vesicular depletion. Modafinil activates orexin/hypocretin neurons in the lateral hypothalamus—the brain's master wakefulness system—which project to histaminergic tuberomammillary nuclei, noradrenergic locus coeruleus, and cholinergic basal forebrain. This increases histamine release (promoting cortical arousal via H1 receptors), elevates norepinephrine in the prefrontal cortex (enhancing attention and executive function), and modulates serotonin (5-HT) transmission. Unlike amphetamines, it does not cause significant vesicular catecholamine release or reverse monoamine transporters, which explains its lower abuse potential and lack of typical stimulant crash.