The wakefulness-promoting drug Modafinil improves cognition in psychiatric populations and is being increasingly used off-label for cognitive enhancement. This raises questions about its safety and ethical considerations.

Modafinil 200mg Online produces domain-specific attentional improvements in humans without hyperarousal, unlike the more selective DAT inhibitors, and also increases cognition in mice by modulating adrenergic receptor activity and serotonergic (5HT) signaling.

Cognitive Enhancement

Cognitive dysfunction is a core feature of many neuropsychiatric disorders such as schizophrenia and ADHD. It is also a major unmet need for novel pharmacotherapies. Modafinil has already been shown to improve cognitive deficits in these disorders by enhancing arousal and activity. A number of studies have also found that modafinil enhances cognition in healthy individuals who are not sleep-deprived.

For example, a randomized placebo-controlled study of a single dose of 200 mg modafinil among healthy adults improved performance on the digit span test and a delayed matching task. This suggests improvement in working memory capacity and inhibition of pre-potent responses. A similar study of shift workers undergoing simulated night-shift work found that a 4-day regimen of modafinil reduced errors on the WCST and a version of the Hayling sentence completion task, which requires cognitive control and is associated with activation of dorsolateral PFC and anterior cingulate cortex (Hart et al, 2006).

Other studies have found that modafinil improves performance on the visual discrimination learning task in animals. This is a measure of cognitive set-shifting, which is thought to be modulated by ascending DA systems.

Memory Enhancement

Several studies have shown that modafinil improves cognitive function in healthy individuals (without sleep deprivation). These studies report improvements in working memory, episodic memory and processes requiring cognitive control. These effects may be related to modafinil’s ability to enhance dopamine uptake and release in the frontal cortex.

Moreover, a recent study of shift workers found that modafinil significantly improved performance on the Psychomotor Vigilance Test and reduced lapses of attention compared to placebo. The authors concluded that modafinil is the first well-validated pharmaceutical nootropic that improves cognition independently of its known effects on sleep disorders.

Research in animal models also suggests that modafinil can enhance memory, and improve tasks that involve cognitive control. For example, oral doses of modafinil enhance a delay-dependent improvement in visual discrimination learning in rats. Modafinil (Waklert 150 mg) also increases the rate of conditioned stimulus responses in rhesus monkeys performing an oculomotor delayed-response task, and does so without altering exploratory or anxiety-related activity. Modafinil also induces a dose-dependent enhancement in the rate of spontaneous alternation in a sequential alternation task in mice, but does so without affecting exploration or anxiety-related activity.

Attention Enhancement

In non-sleep-deprived healthy adults, modafinil enhances performance on tasks that require cognitive control. For example, digit span, visual recognition memory, spatial planning tasks (such as a version of the Tower of London), and the California Verbal Learning Test show enhancements. There are also improvements in delayed matching tasks and a measure of attentional set-shifting, the ability to shift attention between different aspects of a target object. Modafinil improves the ability to process contextual cues and inhibit pre-potent responses in these tasks.

Modafinil has been shown to improve performance in psychiatric patients as well. In a double-blind, placebo controlled study of schizophrenic patients with stable chronic schizophrenia, modafinil significantly improved performance on a number-span task and trends toward improvement on a delayed visual recognition memory test and the Tower of London. In addition, modafinil significantly decreased extradimensional shift errors in a visual sustained attention task.

Another study of narcolepsy patients found that modafinil treatment compared to placebo significantly improved performance on the Pauli Test, a measure of attentional deficits associated with narcolepsy. The effect was correlated with changes in activity in frontal and anterior cingulate cortex during the task.

Focus Enhancement

While studies show that modafinil enhances cognition in sleep-deprived subjects, its effects on healthy individuals with no history of sleep deprivation are less clear. However, a few trials have shown that modafinil can improve performance on complex cognitive tasks in non-narcoleptic subjects who are not under any stress (e.g., fMRI studies of working memory performance and a digit symbol task), suggesting that the drug may have cognitive-enhancing properties that extend beyond its benefits in patients with narcolepsy.

For example, a placebo-controlled study of shift workers performing simulated night-shift work found that a 4-day course of modafinil 200 mg significantly reduced errors on the Hayling Sentence Completion Test and a version of the WCST compared with placebo (Hart et al, 2006). Modafinil also shortened the duration of lapses on the Karolinska Sleepiness Scale in these patients, but not the number of lapses or latency.

In addition, a series of double-blind, placebo-controlled fMRI studies have shown that modafinil significantly reduces errors on the WCST and increases activation of the dorsolateral prefrontal cortex and anterior cingulate cortex during intermediate working memory loads in healthy participants who are not sleep deprived (N-back task) (Thomas and Kwong, 2006). This suggests that modulation of central neurotransmitter systems is key to cognitive enhancement by modafinil.

Concentration Enhancement

While modafinil is approved as a treatment for sleep disorders, it is also used off-label to promote cognitive enhancement in healthy people. This reflects the fact that many neuropsychiatric conditions, such as ADHD and schizophrenia, are associated with core disabling cognitive dysfunction. The recent emphasis placed on cognition in these disorders and the established effects of modafinil on arousal and activity have led to an emerging literature examining its pro-cognitive effects.

In a placebo-controlled study of shift work sleep disorder, patients receiving 200 mg of modafinil were found to have improved performance on tasks such as letter-number span and delayed matching-to-sample. They also exhibited reduced slowed latencies on the Tower of London and visual recognition memory tasks, relative to placebo-treated patients.

In addition, no evidence of sedation was observed in the modafinil group, despite the use of several sleep-inducing agents in the control group. Moreover, in this study, no patient reported the use of prescription hypnotics on the days following nights off, whereas one of the 108 patients in the placebo group did. These findings suggest that modafinil may be the first well-validated pharmaceutical nootropic agent to improve cognitive performance in healthy individuals, independent of its known effects on sleep disordered populations.