Examining the Connection Between Modafinil and Positive Emotions
In a small pilot study of emergency department residents and attending physicians, modafinil increased cognitive information processing, and a type of learning that makes tasks seem more pleasurable. Participants tolerated the modafinil dose very well, with only two instances of medication discontinuation due to side effects.
MRI results indicated that modafinil significantly decreased amygdala reactivity to fearful stimuli. During a WM task and a VAC task, modafinil reduced the BOLD signal in the prefrontal cortex and anterior cingulate.
Mood Enhancement
Modafinil Australia is a powerful wakefulness agent and has been shown to improve mood in several studies. For example, a randomized double-blind placebo-controlled study that followed CONSORT guidelines found that modafinil increased mood in patients with attention deficit hyperactivity disorder. In another study, participants with anxiety reported improved mood after a single dose of 200 mg of modafinil, and this effect was sustained for up to eight weeks.
Similarly, in non-sleep-deprived volunteers, modafinil increased certain aspects of cognitive performance and decreased sleepiness in a simulated night shift work trial (Randall DC, Fleck NL, Shneerson JM, File SE, 2005b). However, the positive effects of modafinil on mood were limited to those participants with high IQ scores.
In a 3-week open-label trial of modafinil versus placebo in medication-free narcolepsy patients, the drug was associated with improved performance on the Pauli test, an EEG measure that correlates with frontal and anterior cingulate activity, and reduced errors on the Stroop interference task (Schwartz et al, 2004). The improvement was correlated with modulation of the brain’s alpha 1B-adrenoceptors by modafinil.
Anxiety Reduction
The energizing effects of modafinil are often described as producing euphoric feelings, and many users claim that the drug reduces stress. However, the underlying mechanisms remain unclear.
One possibility is that the drug acts as an agonist of the glutamate system, increasing synaptic release of glutamate onto medial PFC pyramidal cells (which can be blocked by prazosin and not yohimbine) and elevating the concentrations of the metabolites creatine-phosphate and N-acetyl-aspartate in the cerebral cortex (Pierard et al., 1999).
Another possibility is that the drug decreases anxiety. A study of zebrafish, (Danio rerio), using the novel approach test as a measure of anxiety found that modafinil treatment reduced behavior and decreased brain activity associated with anxiety when compared to control fish.
In addition, paired t-test analysis showed that during the face-matching task, bilateral amygdala activation was significantly lower on the Modalert Tablet than on placebo, again with similar task performance.
Similarly, in a study of human subjects, when performing the two-back task, modafinil produced reduced BOLD activity in the PFC and anterior cingulate cortex (peak voxel coordinates x, y, z = (2, 38, 25), Z = 2.91, p=0.04 FWE-corrected within the anterior cingulate ROI) compared to placebo, despite comparable levels of performance.
Mood Stabilization
Mood stabilizers are used to help people with bipolar disorder stay within the balanced mood range, as defined by the two extremes of mania and depression. They can also be used to reduce the severity of manic or depressive episodes and help people enjoy their life more fully. Mood stabilizers work differently for everyone, as each person’s brain is wired in unique ways.
Unlike other stimulants, such as Adderall, modafinil has minimal abuse potential. In addition, it has different effects on central histamine and dopamine systems than dopamine agonists and does not produce cocaine-like discriminative stimulus and reinforcing effect in cocaine-experienced individuals (Malcolm et al, 2006).
The vigilance-promoting effect of modafinil is due to its actions on glutamate. It increases glutamate-glutamine pool size in the brain along with elevations of aspartate and creatine phosphocreatine, but not N-acetyl aspartate or taurine.
In the hypothalamus, it stimulates NE-induced activation of adrenergic arousal regions and enhances synaptic release of glutamate onto medial prefrontal cortex pyramidal cells, an effect that is blocked by prazosin but not by yohimbine (Marek and Aghajanian, 1999). These effects on cognition may be modulated by histamine.
Anxiety Reduction
In addition to improving cognitive performance, modafinil has been shown to reduce anxiety and apathy. It does so by directly binding and inhibiting the dopamine transporter (DAT) and norepinephrine transporter (NET), causing modest but significant elevations in extracellular levels of DA and NE. Additionally, it decreases levels of gamma-aminobutyric acid (GABA) and elevates serotonin (5HT), orexin, and glutamate.
Using the novel approach test in zebrafish (Danio rerio), we administered modafinil at doses of 0, 10, 20, and 40 mg/L for 30 minutes, followed by testing zebrafish in a behavioral experiment assessing anxiety. During the experiment, motion-tracking software measured time spent near the novel object in the arena (thigmotaxis zone), center of the arena, and transition zone. In addition, the amount of time spent immobilized, and distance traveled were measured.
Modafinil significantly reduced the amount of time spent in the thigmotaxis zone and the transition zone, but not in the center zone or immobility. In addition, the amount of time spent moving and meandering was not affected by modafinil. These results suggest that the effect of modafinil on anxiety is related to alterations in the prefrontal cortex.
Mood Stabilization
Mood stabilizing medications help control the highs and lows of mood that are associated with bipolar disorder. These medications are known as anticonvulsants and include lithium (Lithobid), valproic acid (Depakene), carbamazepine (Tegretol, Equetro), and lamotrigine (Lamictal).
Occasionally, an antipsychotic drug may be added to these medications. The most common indication for mood stabilizers is for people with bipolar disorder who are experiencing episodes of mania or depression.
Modafinil can also be used to improve mood for non-psychiatric disorders including chronic fatigue syndrome, narcolepsy, and shift-work sleep disorder.
It improves wakefulness and attention in these conditions by increasing the levels of the neurotransmitter dopamine. This is probably mediated by the actions of NMDA receptors and DA transporters in the brain.
In studies of BD, add-on SGAs appear to confer mood stability superior to MSs alone in the short to medium term, at least for manic/mixed states. However, Li+ remains the cornerstone in the chronic treatment of BD. (73) For adolescent, pregnant/postpartum, and aged patients, SGAs are less likely to be well tolerated than MSs.
