Studies of cognitive performance with modafinil have shown mixed results. Some studies, however, show clear improvement in a number of tasks, including digit span and spatial planning. Other studies, meanwhile, show no effects on vigilance or attentional processing.
One study that used blood-oxygen-level-dependent functional magnetic resonance imaging (fMRI) found that modafinil improved performance on a task requiring executive control, and reduced error rates in a task involving WM and cognitive flexibility.
Modafinil is a stimulant
Modafinil 200 Australia improves alertness and wakefulness in non-sleep-deprived healthy humans. However, there is less consensus about its effect on cognitive performance. For example, it does not consistently improve pattern recognition memory, digit span recall or spatial planning tasks (as measured by SSRT). Moreover, it has no clear effects on arithmetic or reasoning performance.
However, it does appear to have some benefits on working memory tasks such as maintenance and manipulation (distracted shifting) and delayed matching. Modafinil also increases performance in a series of prefrontal-dependent attention tasks and reduces amygdala reactivity during emotional information processing.
The vigilance-promoting effects of modafinil are mediated by elevations in extracellular monoamines and inhibition of NMDA receptors. The former is a consequence of activation of a and b adrenergic receptors, while the latter involves inhibition of striato-pallidal GABA release (Ferraro et al, 1998). It has been suggested that the monoamine elevations are responsible for the vigilance-promoting effect of modafinil.
Modafinil has also been shown to improve cognitive function in psychiatric patients, including schizophrenia. In a double-blind, placebo controlled trial of sleep-deprived emergency physicians, 200 mg/day modafinil improved performance on digit span and trended toward improvements in delayed visual recognition memory and a version of the Tower of London task. It has also been shown to improve a prefrontal-dependent test of executive control, the Stroop interference task, in patients with major depression.
Modafinil is a hypnotic
Modafinil is known to enhance working memory in rats by increasing the duration of the retention phase, but it does not affect the initial response speed (Ward et al, 2004). It also increases performance on a delayed nonmatching to position task and a serial reversal discrimination task.
The cognitive-enhancing effects of Modalert 200 Australia are accompanied by a dose-dependent decrease in the content of GABA in the cortex, medial preoptic area and posterior hypothalamus (Ferraro et al, 1999, 1996), striatum and globus pallidus (Ferraro et al, 1998, 1997), hippocampus and nucleus accumbens (Ferraro et al, 1997a, b), and at high doses, thalamus, substantia nigra, and nucleus accumbens.
Modafinil can also improve cognition in sleep-deprived subjects, although the effect is not as great as that of amphetamine or methylphenidate. A single-dose of modafinil improved errors on the Wisconsin Card Sort Test and interference on the Stroop task compared with placebo, but it had no effect on arithmetic performance (Wesensten, 2005).
Modafinil is thought to modulate cognitive function by acting as an inhibitor of monoamine uptake. It does not interact with DARPP-32, a key component of the dopamine transporter system, and is less potent than either cocaine or amphetamine at inhibiting reuptake of monoamines into neurons. It also has lower binding affinity for the D1 dopamine uptake site in rat brain.
Modafinil is a central nervous system depressant
Modafinil’s effects on cognition are thought to be mediated through changes in central neurotransmitter systems. It does not appear to directly affect acetylcholine synthesis (Blandina et al, 2004), histamine release (Salanon-Moulin et al, 1994), basal or K+-evoked glutamate uptake (Antonelli et al, 1995) or NMDA receptors in the prefrontal cortex of rats (Tanganelli et al, 1992). Modafinil has also been shown to enhance the activity of glutamate synthase in cultured cortical neurons in a sleep-deprived state (Randall et al, 2004).
Several studies have reported that modafinil improves cognitive performance in non-sleep-deprived adults. In one double-blind, placebo-controlled fMRI study, modafinil improved performance in an N-back task. In another, modafinil improved spatial planning and decision-making but not digit span or visual recognition memory. The researchers found that the effect was dose-dependent.
In addition, a series of animal studies have also shown that modafinil improves working memory performance in a delay-dependent manner. It does this without affecting exploratory behavior or reducing the speed-accuracy trade-off in the sequential alternation task. It also improves vigilance in a simulated driving test, but does not affect perceptual, arithmetic or reasoning performance.
Unlike some other stimulants, modafinil has a low potential for abuse. This is probably due to its unique pharmacodynamic profile and its physical properties, which make it difficult to snort or swallow. It is also insoluble in water and unstable at high temperatures, which minimizes its availability by intravenous administration.
Modafinil is a central nervous system stimulant
The use of drugs to enhance cognition is increasing in popularity, especially among adolescents and young adults. The most common cognitive enhancers are psychostimulants (methylphenidate, MPH), wakefulness-promoting agents (modafinil), and glutamate activators.
These drugs are thought to improve cognition by enhancing dopamine, glutamate, and norepinephrine neurotransmitters. However, there are some risks associated with their use. Non-medical use of stimulants may increase the risk of drug abuse. There is also a concern that they may interfere with normal brain function and lead to addiction.
In studies of human cognition, modafinil has been shown to improve working memory and episodic memory in healthy subjects. It has also been found to improve attention and mental performance in patients with narcolepsy and depression. Its clinical efficacy in these conditions is correlated with the modulation of frontal cortical activity, which correlates with improved performances on tests of executive control and vigilance.
The mechanism by which modafinil enhances cognitive functions is complex. It appears to affect GABA synthesis and uptake, but not the basal or K+-evoked release or uptake of glutamate. In addition, it increases the rate of spontaneous alternation as a measure of working memory in mice without affecting exploratory or anxiety-related activity (Pierard et al, 2006).
It also does not appear to directly affect acetylcholine levels in the hypothalamus, but increases the effect of histamine on a NMDA receptor (Blancoottini et al, 2000). It also increases the increase in dialysate serotonin concentration caused by fluoxetine and imipramine in prefrontal cortical slices in a concentration-dependent manner.
