Developed in the 1970s, modafinil is known as a eugeroic, or “wakefulness-promoting agent.”
In the United States, it is classified as a schedule IV controlled substance, a category reserved for drugs with valid medical uses and low (but significant) addiction potential. In 2017, it was the 328th most prescribed medication in the US, with over 900,000 prescriptions. It is widely available on the Internet, which accounts for its accelerating non-medical use for performance enhancement.
In this article, we will explore what modafinil is and take a closer look at rodent studies that investigate its wide-ranging behavioral effects.
Modafinil, known by the brand name Provigil in the United States, was approved by the FDA in 1998 for treating daytime sleepiness associated with narcolepsy, obstructive sleep apnea, and shift work sleep disorder. It is widely used off-label as a “smart drug” to boost alertness and combat drowsiness.
On this front, modafinil is commonly used by transportation workers and emergency services personnel to promote arousal. The US Air Force, astronauts on the International Space Station (ISS), and military personnel have also used modafinil to manage fatigue on prolonged missions. Professional athletes have allegedly used modafinil as a performance enhancer, which led to its subsequent ban by the World Anti-Doping Agency in 2004.
Starting in 2002, there was an explosive growth of modafinil-related research investigating the drug’s effects on a number of different conditions. In general, modafinil may be helpful in treating conditions that are associated with excessive sleepiness, somnolence, and fatigue. This includes, but is not limited to:
- Attention Deficit Hyperactivity Disorder (ADHD)
- Parkinson’s disease
- Cerebral palsy
- Multiple sclerosis
- Amyotrophic Lateral Sclerosis (ALS)
- Chronic fatigue syndrome
- Jet lag sleep disorder
- Human Immunodeficiency Virus (HIV) infection
In addition, modafinil has shown efficacy for psychiatric conditions such as depression, bipolar, schizophrenia, and autism. As of this writing, almost 2000 articles are listed on Pubmed evaluating its use for conditions like these.
Unlike amphetamines, modafinil is reported to have little peripheral side effects in therapeutic dose ranges. Moreover, it has never been shown to develop tolerance or withdrawal. It has comparatively few side effects compared to traditional stimulants.
In approximately 5-10% of users, the side effect profile includes headache, nausea, decreased appetite, anxiety, insomnia, dizziness, diarrhea, and rhinitis. Serious side effects and allergic reactions have been reported, such as anaphylaxis and severe skin rashes like Stevens-Johnson syndrome. In some individuals with a history of psychosis, hallucinations have been reported at high doses. Modafinil is not currently approved for use in children for any medical condition.
In the United States and Europe, modafinil is available in 100 mg and 200 mg tablets. Following oral administration, peak plasma concentrations are reached in 2-4 hours and elimination half-life is 13-14 hours. As for toxicity, overdoses have been reported but no deaths. The LD-50 (median lethal dose) in mice and rats is approximately 1250 mg/kg.
Modafinil’s Mechanism of Action
Many psychostimulants, such as amphetamine and methylphenidate, inhibit the dopamine active transporter which causes an increase in extracellular dopamine levels. However, modafinil’s mechanism of action appears to differ, as it shows only weak (yet selective) action as a dopamine reuptake inhibitor.
In human Positron Emission Tomography (PET) studies, 200 and 300mg of modafinil lead to 51.4% and 56.9% dopamine active transporter (DAT) occupancy in the striatum, including the nucleus accumbens, a key region of the mesolimbic dopamine reward circuitry. Similar interactions with the DAT have been found in rodents. In DAT-knockout mice, modafinil does not produce wakefulness-enhancing effects, unlike what is seen with their wildtype littermates.
Its action as a weak DAT inhibitor has been found to indirectly activate the release of orexin neuropeptides and histamine from the tuberomammillary nucleus and lateral hypothalamus, both of which may account for its arousal-enhancing properties.
Overall, the mechanism of action of modafinil is not fully understood and its brain targets are a matter of ongoing debate. Researchers have yet to hone in on a single site of action or locate major receptor binding. It appears to stimulate multiple neurochemical systems, including GABA, glutamate, histamine, norepinephrine, serotonin, dopamine, and orexin (also known as hypocretin). Studies have also demonstrated that it upregulates energy metabolism through metabolic-activating effects, namely, increasing the energetic pool of phosphocreatine in the cortex.
Effects on Exploratory Behavior
In 2011, Young and colleagues investigated the dose-dependent effects of modafinil on exploratory behavior using mice. They found that modafinil (32, 64, and 128 mg/kg) significantly enhanced spontaneous activity, rearing (specific exploration), and the smoothness of locomotor paths in C57BL/6J and 129/SJ mice.
Using dopamine receptor knockout mice (DRD1-4 mutant mice), the researchers found that DRD1 receptors played a primary role in producing modafinil’s effects on spontaneous exploration, while DRD4 receptors mediated modafinil’s effects on specific exploration. The researchers suggest that modafinil’s effects on exploratory behavior could be the result of increased synaptic dopamine and secondary actions mediated by DRD1 and DRD4 receptors.
Effects on Locomotor Activity
Modafinil has been found to increase histamine release from the anterior hypothalamus in rats, a mechanism that may in part underlie its arousal-promoting effects. Histamine release from this region is highly correlated with locomotor activity, particularly in the dark period for rats when their activity is highest. With this in mind, a 2008 study by Ishizuka et al. examined modafinil’s effects on locomotor activity in rats within their home cage. To investigate the contribution of histaminergic systems, the researchers measured hypothalamic histamine release using in vivo microdialysis.
Ishizuka and colleagues found that both 75 and 150 mg/kg of modafinil significantly increased locomotor activity and histamine release. The behavioral effects of 150 mg/kg of modafinil were found to be similar to 3 mg/kg of methylphenidate. To further parse out the effects of histamine on locomotor activity, the researchers administered α-fluoromethylhistidine (an irreversible inhibitor of histamine synthesis) to deplete neuronal histamine in the rats. They found that this completely extinguished the locomotor activity-enhancing effects of modafinil, while having no effect on methylphenidate stimulation. In conclusion, they suggest the enhancement of locomotor activity by modafinil, but not methylphenidate, is intimately involved with central histaminergic systems.
In a 2014 rat study, Ornell et al. examined the behavioral effects of modafinil in an open field test. The researchers administered 75, 150, and 300 mg/kg of modafinil and evaluated locomotor activity in the Open Field at varying time points.
The researchers found that only the 300 mg/kg dose of modafinil increased locomotor activity 1 and 3 hours after administration, with increased visits to the center of the open field 1 hour after administration. However, 3 hours after modafinil administration, all of the modafinil doses increased visits to the center of the Open Field. In summary, the researchers note that high dose modafinil (300mg /kg) induces hyperactivity in the Open Field. In addition, modafinil produces anxiolytic effects across all doses, as seen by increased visits to the center of the Open Field.
Effects on Memory
In this section, we will overview modafinil’s effects on working memory in healthy, chronically-stressed, and sleep-deprived mice. Both stress and sleep deprivation are well known to negatively impact working memory performance in humans and other animals. These mice models offer insight into how modafinil interacts with conditions that humans are commonly subjected to when taking modafinil.
Effects on Working Memory in Healthy Mice
Beracochea et al. examined the effects of modafinil on working memory in C57BL/6 mice in a sequential alternation task. The researchers administered a pretest injection of varying doses of modafinil (8 mg/kg, 32mg/kg, and 64 mg/kg) and assessed its effects on delayed spontaneous alternation rates.
They found that 64 mg/kg, but not 8 mg/kg or 32 mg/kg, significantly increased alternation scores when compared to controls. Specifically, the researchers found that 64 mg/kg produced a delay-dependent enhancement in working memory performance by increasing alternation rates mainly at long (60s and 180s) intertrial intervals. In conclusion, the researchers state that modafinil produces a dose- and delay-dependent enhancement of working memory. These effects did not extend to exploratory or anxiety-related activity as measured in a four hole-board apparatus.
Effects on Working Memory in Chronically-Stressed Mice
Modafinil may enhance psychomotor performance and memory in part by increasing glucocorticoid secretion through the adrenal cortex. Glucocorticoids (such as cortisol in humans and corticosterone in rodents) play an important role in mediating learning and memory processes.
Pierard and colleagues examined the dose-effect relationship of modafinil on working memory and psychomotor performance, alongside measurements of plasma corticosterone in chronically-stressed mice. Researchers administered a control or modafinil (8, 16, or 32 mg/kg) after or without chronic stress. The rats were stressed via immobilization in a Plexiglass tube under high light exposure for 15 min/day over 14 consecutive days. Memory performance was evaluated by spontaneous alternation in a T-maze.
The researchers observed that optimal working memory performance was produced from the 16 mg/kg dose under non-stress conditions. Both the 16mg/kg and 32 mg/kg doses of modafinil significantly increased corticosterone levels. However, working memory performance and plasma corticosterone levels appeared to be uncorrelated.
Under stress conditions, the researchers found that, compared to non-stressed animals, 8mg/kg of modafinil increased working memory performance while the higher doses of 16 mg/kg and 32 mg/kg decreased memory performance. These results indicate that stress lowers the efficiency threshold of modafinil, thereby inducing the most optimal psychomotor performance at low dosages. Concurrent measurements of plasma corticosterone levels revealed that 8 mg/kg lowered corticosterone levels while the higher doses did not affect levels.
Thus, working memory performance appeared to be inversely correlated with plasma corticosterone levels in the stressed condition. In light of this data, the researchers hypothesize that high doses of modafinil could impair performance in humans subjected to stressful conditions (such as seen in sports performance).
Effects on Working Memory in Sleep-Deprived Mice
Given that modafinil is effective in promoting alertness and performance in sleep-disordered patients, modafinil’s efficacy in reversing cognitive impairment due to sleep deprivation has been investigated by a number of researchers.
In one 2007 study, Pierard and colleagues investigated the effects of modafinil on spatial working memory in sleep-deprived mice. The researchers assessed delay-dependent working memory with spontaneous alternation behavior in a T-maze.
To induce sleep deprivation, the researchers used an original total sleep deprivation apparatus validated with EEG recordings. This automated, low-stress apparatus consists of a water box with two platforms that continuously move above and below the surface of the water, forcing the mouse to move back and forth every 10 seconds to avoid water contact.
Firstly, the researchers found that diurnal 10-hour sleep deprivation produces impairments in spatial working memory, seen as reduced alternation rates compared to the non-sleep-deprived control group.
To examine the effects of sleep deprivation on neural activity, they quantified the c-Fos protein in various cerebral zones. Sleep deprivation decreased c-Fos expression in the anterior hypothalamus and supraoptic nucleus, two regions involved in wake-sleep cycle regulation. They also found reduced c-Fos staining in the frontal cortex and hippocampus (involved in memory) and the amygdala (involved in emotions).
The researchers then assessed the effects of modafinil after the 10-hour sleep deprivation period. They found that 64 mg/kg, but not 32 mg/kg, significantly increased alternation rates that were previously impaired by sleep deprivation. Increased spontaneous alternation indicates the rodent better remembered which arm it had last visited. Interestingly, the 64 mg/kg dose of modafinil restored neural activity in the same brain regions previously disrupted by sleep deprivation. The researchers note that the anxiety-like action of modafinil may contribute to the effects on neural activity they observed. In conclusion, modafinil was able to rescue the memory-impairing effects of 10 hours of sleep deprivation and restore normal levels of neural activity in various brain regions affected by sleep deprivation.
Effects on Depression
Depression is one of the most common mental health conditions, with a prevalence of 17% in the population. It is characterized by mood dysfunction, sleep disturbances, impaired cognitive performance, psychomotor changes, and thoughts of suicide. Many of these symptoms originate from reduced dopaminergic function, particularly within the mesocortical and mesolimbic systems. Thus, modafinil may provide relief from depression through its effects on the dopaminergic system, namely, its ability to activate D1 and D2 receptors.
To this end, a 2014 study by Mahmoudi et al. evaluated modafinil’s antidepressant-like effects in a mouse model of depression. In addition, they investigated whether D1 and D2 dopaminergic receptors were responsible for the effects.
In the first portion of the experiment, mice were intraperitoneally administered varying doses of modafinil (50, 75, and 100 mg/kg) and subjected to the Tail Suspension Test (TST) and/or Open Field Test to determine the effective antidepressant dose. The Open Field Test was conducted to rule out psychostimulant effects that could account for reductions in immobility in the TST.
The researchers found 75mg/kg and 100mg/kg of modafinil significantly decreased immobility time, indicating an antidepressant-like effect. However, 100 mg/kg (but not 75 mg/kg) produced significant increases in locomotor activity in the Open Field arena, so its reduction in immobility time in the TST reflects its psychostimulant properties.
Modafinil Exerts Antidepressant Effects via Dopamine D2 Receptors
In the second phase of the experiment, the researchers studied the involvement of the dopaminergic system in modafinil’s antidepressant effects. In this phase, separate groups of mice were pretreated with the D2 receptor antagonist haloperidol (0.2mg/kg), the D2 receptor antagonist sulpiride (50mg/kg), and the D1 receptor antagonist SCH22390 (0.05mg/kg).
The mice pretreated with haloperidol and sulpiride inhibited the antidepressant impact of modafinil by preventing the anti-immobility effect in the TST. On the other hand, the mice pretreated with SCH22390 did not antagonize the antidepressant effects, suggesting that modafinil exerts its antidepressant effects specifically through the activation of the dopamine D2 receptor.
Modafinil May Complement Conventional Antidepressants
In the last phase of the experiment, the researchers evaluated modafinil’s ability to potentiate the sub-effective doses of the conventional antidepressants bupropion (1mg/kg), fluoxetine (1mg/kg), and imipramine (1mg/kg). They found that co-administration of modafinil (50 mg/kg) was able to potentiate the action of these antidepressants by reducing immobility time in TST compared to the antidepressants alone. In conclusion, they state that modafinil may be an effective adjunct therapy in depression by potentiating the action of standard antidepressants.
Effects on Attention
A 2005 study by Waters et al. investigated modafinil’s effects on attentional processes in rats subjected to a 5-Choice Serial Reaction Time Test. Across all doses, ranging from 32-128 mg/kg, modafinil failed to significantly enhance sustained attention, nor was it able to reverse attentional performance deficits induced by pre-treated scopolamine (a drug with anticholinergic effects).
At high doses, modafinil increased premature responses, suggesting it increases impulsivity similar to D-amphetamine under similar task conditions. In summary, the researchers state that modafinil does not appear to improve response control in rodents, instead it facilitates impulsive response. In addition, the researchers conclude that modafinil’s inability to improve performance deficits produced by scopolamine suggests that it does not directly act on the cholinergic system.
In contrast to these findings, human studies have found that modafinil improves attention in doses that don’t produce hyperarousal. Modafinil (200 and 400 mg) appears to improve attention in healthy, non-sleep deprived humans in the 5-Choice Continuous Performance Task and Wisconsin Card Sort Task.
Effects on Addiction
The addictive potential of modafinil is relatively low, despite sharing some of the same biochemical mechanisms with addictive psychostimulants. Through its effects on dopaminergic reward pathways, it may have similar mood-elevating properties to addictive psychostimulants, though to a lesser extent.
Modafinil appears to have rewarding effects at high doses, and animals will self-administer modafinil if previously trained to self-administer more addictive drugs like cocaine.
A 2010 study by Nguyen found that a high dose of 125mg/kg of modafinil produced significant conditioned place preference in mice, mediated through changes in dopamine, glutamate, and GABA receptor binding in various dopaminergic brain regions.
Shuman et al. found that high dose modafinil (75 mg/kg) induced place preference and sensitization in mice, similar to cocaine. On the other hand, a low dose of modafinil (0.75 mg/kg) did not produce conditioned place preference nor did it have any effect on locomotor sensitization.
Interestingly, modafinil may be an effective therapeutic prevention for relapse and addiction to methamphetamine. In 2010, Reichel and colleagues found that modafinil reduced active lever responding in a reinstatement model of methamphetamine relapse.
In a subsequent study, Reichel and colleagues found that chronic modafinil (30 or 100 mg/kg) reduced relapse to a methamphetamine-paired context and decreased methamphetamine-primed reinstatement behaviors. They found only very high doses of modafinil (300mg/kg) had an impact on methamphetamine intake, suggesting that only lower doses have therapeutic potential for methamphetamine addiction.
Modafinil is able to affect behavior and cognition as evidenced by a wide array of studies using various rodent models. The precise mechanism of action is not fully understood, but modafinil appears to interact with numerous neurotransmitter systems and, in particular, enhance locomotion through its effects on the histaminergic system.
Modafinil dose-dependently improves working memory in healthy mice. In addition, it appears to restore working memory performance in chronically stressed at low doses and rescues memory performance and neural activity in sleep-deprived mice at higher doses.
Via its action on the dopaminergic system, modafinil shows antidepressant and anxiolytic effects in the Tail Suspension Test and Open Field Test, respectively.
Similar to traditional psychostimulants, modafinil increases impulsive responses in the 5-Choice Serial Reaction Time Test. These results, however, don’t necessarily translate to the human population, where modafinil (in non-hyperarousal doses) appears to improve measures of sustained attention.
Lastly, modafinil shows low abuse potential but may potentiate drug-seeking behavior in animals pre-exposed to psychostimulants like cocaine. At lower doses, modafinil may prevent methamphetamine reinstatement behavior, which signals therapeutic potential for methamphetamine addiction and relapse.
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