The Science behind Modafinil and Wakefulness

How Modafinil Works

Modafinil 200mg Tablet, better known as Provigil, is an effective wakefulness agent that has been shown to improve alertness in humans with various sleep disorders. It is used to treat excessive daytime sleepiness in narcolepsy, shift work sleep disorder (inability to fall asleep or stay asleep during scheduled waking hours while on night shifts), and obstructive sleep apnea/hypopnea syndrome (a condition where a person repeatedly stops or gasps for breath during sleep, preventing them from getting enough restful sleep).

Modafinil works by changing the amounts of certain natural substances in the brain that controls sleep and wakefulness. It inhibits DAT and NET, increases extracellular levels of catecholamines (dopamine, norepinephrine, and glutamate), increases orexinergic system activation, and decreases GABA in the brain. It also appears to have a selective impact on cortical rather than subcortical areas of the brain (Thomas and Kwong, 2006).

The effectiveness of modafinil in narcolepsy has been demonstrated in several randomized double-blind placebo-controlled studies by the Narcolepsy Multicenter Study Group (1998, 2000). Modafinil was found to significantly improve subjective and objective measures of alertness in people with narcolepsy compared to placebo. Similarly, it is an effective treatment for shift work sleep disorder and obstructive sleep apnea/hypopnea in conjunction with other treatments such as weight loss, behavioral therapy, and breathing devices. The R-enantiomer of modafinil (armodafinil) has been found to be equally effective at improving alertness compared to the racemic modafinil but is well-tolerated and more rapidly absorbed after administration.

Modafinil’s Mechanisms

Modafinil is a racemic compound that reaches equal plasma concentrations in the R- and S-enantiomers (see Dinges et al, 2006). The R-enantiomer is more selective for the dopamine transporter, reaching higher levels in brain and having more potent wake-promoting effects than the S-enantiomer (Sangal et al, 1999a).

There is evidence that the central histaminergic system may contribute to modafinil’s vigilance-promoting activity. The histamine receptor agonist clonidine blocks modafinil’s effects on working memory in humans. The histamine antagonist yohimbine enhances modafinil’s effects on locus coeruleus-mediated arousal in animal models, and its adrenergic action appears to be responsible for this interaction. Low doses of yohimbine appear to block the inhibitory terminal a2 autoreceptor to augment NE release and thus enhance modafinil’s adrenergic activity, whereas high doses block post-synaptic a2 receptors, attenuating modafinil’s effects on vigilance and activity (Duteil et al, 1990).

Modafinil (Modalert 200 mg) acts as a dopamine agonist by increasing the release of dopamine in the prefrontal cortex, and it reduces dopamine turnover. As a result, it increases DA availability in this area, and has been shown to improve performance on a test of attention and memory under stress in healthy adults (Dinges et al, 2004). In addition, narcolepsy patients who have a long auditory and visual P300 latency showed remediation of their fatigue by 4 weeks of modafinil 100 mg/day (Nagels et al, 2007). Modafinil also has indirect effects on glutamate, with elevations of glutamate-glutamine pools (and reductions of N-acetyl aspartate and creatine-phosphocreatine) in the brains of animals treated with the drug (Ferraro et al, 1999). These changes in neurotransmitter pools may interact with adrenergic mechanisms, as adrenergic stimulation increases NE and thereby promotes the synaptic release of glutamate onto medial PFC pyramidal cells, an effect that is blocked by the a2 antagonist prazosin but not by yohimbine.

Modafinil’s Effects

Modafinil is a powerful wakefulness drug and its effectiveness has been demonstrated in several clinical studies of patients with sleep disorders. In two randomized, double-blind placebo-controlled studies (with a total of 554 patients) conducted by the US Modafinil in Narcolepsy Multicenter Study Group (1998, 2000), modafinil was found to significantly improve subjective and objective measures of alertness compared to placebo.

More recently, a series of small, open-label, non-randomized trials have shown that modafinil is an effective cognitive enhancer in healthy, non-sleep-deprived individuals. These trials generally showed that modafinil improved performance on tasks requiring attention, executive function, and learning, but did not show improvements in divergent creative thinking. Furthermore, these trials did not find that modafinil affected mood or euphoria, and the vast majority of participants had no significant adverse effects.

Modafinil has also been shown to reduce excessive sleepiness in patients with shift-work sleep disorder, and improve vigilance and performance during simulated night-shift work. The R-enantiomer of modafinil (armodafinil) was found to be more efficacious than the racemic form in these trials, suggesting that enantiomers may have different pharmacokinetic properties and behavioral effects.

In addition, a variety of brain imaging studies have demonstrated that modafinil activates the hypothalamic arousal system, increasing levels of norepinephrine and dopamine in the prefrontal cortex of rhesus monkeys performing an oculomotor delayed-response task, and inhibiting the depressant effect of cocaine on this task. In schizophrenic patients, modafinil was shown to increase anterior cingulate activity in the presence of positive symptoms, suggesting that this drug may be useful in the treatment of schizophrenia.

Modafinil’s Side Effects

Modafinil is known for causing a wide range of effects related to waking and cognition, but it is also well-known that the drug has very few side effects when administered in small doses. In fact, it is far less likely to cause jitteriness, excess locomotor activity, or rebound sleepiness than traditional stimulants. Furthermore, it has a lower probability of addiction than other waking drugs. However, it is worth noting that Modafinil increases extracellular levels of dopamine in the nucleus accumbens of the brain by inhibition of DAT, which could potentially lead to drug abuse.

Unlike amphetamine, modafinil does not affect the DA reward system and it has only very moderate effects on the hypothalamic arousal center. In addition, pre-treatment with the NE-selective neurotoxin DSP-4 (which leaves DA neurons intact) does not blunt modafinil-induced waking in rats. The DA autoreceptor agonist quinpirole, on the other hand, does blunt the modafinil effects on waking in these animals.

The majority of studies on modafinil involve people with narcolepsy, and most focus on the drug’s effectiveness in improving wakefulness in sleep-deprived individuals. However, it has received a growing amount of interest for its use among healthy individuals to enhance their cognition and brighten their moods, as well as its potential to mitigate fatigue. These non-narcoleptic users are often incredibly stressed, such as cancer patients or soldiers in war zones, and may require additional arousal in order to accomplish a difficult task.