Modafinil

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Modafinil is the most well-known wakefulness-promoting drug that has recently gained popularity as a cognitive enhancer. While it possesses some stimulant properties, it does not typically produce the euphoric effects (“rush”) classical psychostimulants are known for, which is why it is often classified as an eugeroic (wakefulness-promoting) substance rather than psychostimulant.

In many countries, it is primarily prescribed for treating narcolepsy, often as first-line choice treatment. It’s also commonly used in treating the symptoms of work shift sleep disorder and excessive daytime sleepiness caused by obstructive sleep apnea. Off-label applications of modafinil include major depression (especially in patients with residual tiredness or fatigue), acute depression in people with bipolar disorder and ADHD due to its lower abuse potential than psychostimulants such as methylphenidate and amphetamines and superior side-effect profile over amphetamines.

Modafinil is a racemic compound, a mixture of with two enantiomers with distinct pharmacokinetics, armodafinil ((R)-modafinil) and esmodafinil ((S)-modafinil). The mechanisms of action of modafinil are not yet fully understood. Generally, it is thought to exert a complex neurochemical profile – it appears to have multiple effects on the catecholamine systems in the brain. Modafinil acts as an atypical, selective, and weak dopamine reuptake inhibitor that indirectly prevents noradrenaline reuptake, leading to elevation in extracellular concentrations of serotonin, glutamate, histamine, and orexin, and reducing concentrations of GABA (gamma-amino-butrytic acid).

There is increasing evidence that supports the view that modafinil can improve cognitive function in healthy, non-sleep-deprived individuals, in particular executive function, working and episodic memory. Studies show that modafinil might enhance not only performance on highly demanding cognitive assignments, but also cognitive flexibility and task enjoyment, planning and decision making, attention (including sustained attention performance), inhibitory control and processing speed.