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Modafinil is an FDA-regulated drug that is available by prescription for the treatment of daytime sleepiness and fatigue. It reliably promotes wakefulness and alertness and has been used (illicitly, off-label use) as a nootropic (cognitive enhancer) in highly competitive environments such as workplaces and universities.
What cognitive enhancements does modafinil provide that it attracts popular illicit use? What are the mechanisms and how does it compare to other stimulants such amphetamines or caffeine? Does modafinil have risks?
What is Modafinil?
Modafinil is a reliable wakefulness-promoting substance used for the treatment of sleepiness (narcolepsy) and fatigue. In the US, it is an FDA-regulated substance and can be only obtainable under prescription. However, it has been widely used off-label as a cognitive enhancer.
Modafinil is capable of improving a wide range of cognitive functions, such as wakefulness, ADHD, memory, athletic performance, and reaction time.
Modafinil is banned in most sports events as a doping agent, while popular among competitive workplaces and universities.
Its mechanisms of action are complex acting on serotonin, norepinephrine, dopamine, histamine, orexin, glutamate, and GABA receptors.
Modafinil produces fewer side effects, abuse potential, and euphoria than amphetamines while showing similar levels of cognitive stimulation.
Modafinil usually provides a mood and wakefulness boost, from individual reports published online, and might even reduce brain fog.
However, its usage on the developing brain (during youth or adolescence) might have an impact on brain plasticity and other unclear long-term consequences.
Modafinil is an FDA-approved stimulant used for chronic fatigue, excessive daytime sleepiness (narcolepsy), obstructive cessation of breathing (apnea) during sleep, and shift work disorders [R].
Modafinil is classified by the FDA as only available under prescription [R].
Modafinil is also used by astronauts to combat fatigue, improve focus, and help adjust circadian rhythm in an artificial lighting environment [R].
Many reliable survey studies have found that modafinil is often illicitly used and popular within competitive work or study environments. Some studies showed that up to 1 in 5 students had used a stimulant to improve their focus and attention [R, R, R, R].
Uses of Modafinil
Modafinil improved attention in well-rested individuals, while maintaining wakefulness, memory, and executive functions in sleep-deprived individuals compared to placebo, as shown by a meta-analysis of human studies [R].
However, repeated doses of modafinil were unable to prevent deterioration of cognitive performance over a longer period of sleep deprivation [R].
In a trial with 41 participants under conditions of 64-hour sleep deprivation, 300 mg modafinil significantly improved cognitive capabilities compared to placebo, while amphetamine (20 mg) and modafinil scored similarly in mood, fatigue level, and cognitive tests [R].
Also, this study showed that even after 64 hours of sleep deprivation, participants under the influence of modafinil reported almost the same fatigue and mood levels as the participants had when they were well rested [R].
2) Excessive Sleepiness
Shift-work sleep disorder is a circadian rhythm disturbance that frequently occurs in people who have to work during a time when they would typically be sleeping. It is characterized by excessive sleepiness during working hours and insomnia during sleeping hours.
Modafinil improved different sleep and life quality parameters of shift workers in a DB-RCT on 278 people [R].
Modafinil helped shift workers fall asleep, increased attention span during night shifts, and reduced the number of accidents driving home from work. However, it had no effect on the number of sleep episodes during work, the number of accidents at work, and caffeine intake in a DB-RCT of 209 people [R].
Either alone or in combination with other medications, modafinil helped reduce sleepiness and fatigue in people with major and bipolar depression in four DB-RCT on 587 people and two observational studies on 52 people [R, R, R, R, R, R].
In an observational study of 11 people on opioid medication, modafinil reduced sleepiness without disrupting the sleep pattern. Similarly, a few people on antipsychotics reduced their sleepiness and fatigue after taking modafinil [R, R].
Also, modafinil (200 mg) reduced gambling desire in 20 pathological gamblers as shown by another (DB-RCT) study [R].
In a study (DB-RCT) of 248 adolescents, 170-425 mg modafinil significantly improved ADHD symptoms at school and home compared to placebo, as evaluated by clinicians, teachers, and parents [R].
A recent meta-analysis of 5 studies (DB-RCT) of 927 participants (adolescents) showed that modafinil significantly improved symptoms of ADHD as compared to placebo [R].
5) Processing Speed
In a study (DB-RCT) of 16 healthy volunteers, 200 mg modafinil significantly reduced the number of errors in several difficult performance tasks (such as visuospatial maintenance tasks) [R].
Modafinil enhances the efficiency and cognitive information processing of a region of the brain responsible for higher cognitive function (prefrontal cortex) [R].
However, in a DB-RCT of 39 men playing chess games, modafinil caused the players to be slower and take a longer time per chess move [R].
Multiple studies (60, 17, and 64 participants) have shown that modafinil improved working memory, even in healthy humans. Modafinil, at 100, 200, and 250 mg, showed significantly better results in memory tasks such as delayed verbal recall, digit span, and visual pattern recognition [R, R, R].
7) Task Enjoyment and Motivation
In a placebo-controlled study of 64 participants, 200 mg modafinil significantly increased task enjoyment, well-being, and attention compared to placebo [R].
Another study on 41 healthy people under 64-hour sleep deprivation conditions noted that modafinil produced overconfidence and overestimation of one’s cognitive abilities [R].
8) Athletic Performance
A DB-RCT of 60 men showed that high-dose (200 mg) modafinil offers the most significant improvement in reaction time compared to low-dose (100 mg). Modafinil also improved performance on cognitively demanding tasks [R].
Reaction time and cognitive functioning are key elements in athletic performance. Doping with modafinil offers an advantage in almost every sport, and such cases have been reported in sprinting [R, R].
Hence, modafinil has been prohibited as a stimulant by the WADA (World Anti-Doping Agency) since 2004.
9) Obstructive Sleep Breathing Cessation
Obstructive sleep breathing cessation is the blockage of the upper airways while sleeping, which is associated with poor-quality sleeping, excessive daytime sleepiness, high blood pressure, and increased risk of cardiovascular diseases and stroke [R, R].
However, modafinil only improved alertness but not sleepiness, quality of life, or cognitive performance in a DB-RCT on 32 people [R].
10) Cognitive Issues
Human studies have shown that modafinil reduces reactivity to threatening stimuli in the amygdala, a brain region involved in anxiety [R].
Although not statistically significant, there were trends for reduced anxiety, as well as decreased anger-hostility on modafinil [R].
Another study on 30 adolescents showed modafinil increased aggression, stress, and anxiety at 100 mg, but not in 200 mg group paradoxically. In fact, the 200 mg group showed a reduction in anxiety [R].
12) Emotional Processing
13) Schizophrenia Symptoms
Animal and Cell Studies
The following studies were only conducted on animal models or cell lines.
14) Neuron Communication
Modafinil’s protection of dopamine-releasing neurons seen in animal studies has shown promise in treating Parkinson’s disease [R].
In a cell-based study (cortical astrocytes), modafinil improved the communication between these cells (gap junctional communication), which may play a role in modafinil’s stimulatory effects [R].
A similar cell-based study noted modafinil improved communication (electrical coupling) between neurons (cortical) [R].
In multiple cell studies, modafinil prevented the damage or death of neurons due to overactivation of receptors by glutamate (excitatory neurotransmitter) and degeneration of dopamine-releasing neurons [R, R, R].
Modafinil Mechanisms Of Action
1) Modafinil Increases Serotonin
Despite promising animal and cell studies, a human trial (DB-RCT) that co-administered modafinil and SSRIs for major depressive disorder (MDD) with fatigue and sleepiness failed to show their synergistic actions for the treatment of depression [R].
2) Modafinil Increases Norepinephrine
However, even when the receptors for norepinephrine were blocked, modafinil’s stimulatory properties were not reduced, as modafinil was still able to promote wakefulness [R].
3) Modafinil Increases Dopamine
Modafinil, although at a low potency, blocks the dopamine transporter (DAT), which increases dopamine. Although this is the same mechanism of cocaine, modafinil’s activities on the transporter are unique and significantly more soothing [R, R].
Interestingly, modafinil’s “atypical” properties at inhibiting DAT might be responsible for its low abuse potential. In fact, due to these properties, modafinil is being researched as a drug for dopamine-acting substance (such as cocaine) withdrawal [R, R, R, R].
4) Modafinil Increases Histamine Release Through Orexin
5) Modafinil Increases Glutamate And Decreases GABA
Modafinil increases glutamate (excitatory) and decreases GABA (inhibitory) in different regions of the brain [R, R, R, R, R, R]. Some of these studies showed conflicting results and region-specific effects; therefore, the exact mechanism is not yet conclusive.
Modafinil Compared To Other Common Stimulants
1) Modafinil vs. Amphetamines
As referenced above, in a 60-participant study, modafinil and d-amphetamine produced similar results in improving cognitive function, fatigue, and mood during a 64-hour sleep deprivation [R].
Another study by the same author noted that modafinil produced overconfidence and overestimation of one’s own cognitive abilities. While modafinil disrupted one’s self-monitoring cognitive performance, participants given amphetamine performed accurate self-monitoring throughout the study [R].
While modafinil has much lower abuse potential, amphetamines, on the other hand, increase dopamine levels across the brain to a greater extent. For this reason, addiction to prescription amphetamines is common [R, R, R].
2) Modafinil vs. Caffeine
Modafinil was compared to caffeine, d-amphetamine, and placebo in a 16-volunteer study, which noted that modafinil, similar to caffeine, did not produce euphoria and less self-well-being compared to d-amphetamine. Amphetamine also increased anxiety and blood pressure levels more than caffeine and modafinil [R].
Caffeine was also unable to sustain alertness awareness during sleep-deprivation studies. In a 48-subject study using a placebo, caffeine, modafinil, and d-amphetamine, modafinil scored better than caffeine in improving fatigue [R].
3) Modafinil vs. Methylphenidate
Methylphenidate, most popularly sold as Ritalin, is similar to modafinil regarding its cognitive enhancing properties [R].
Modafinil Drug Interactions
One study suggested that modafinil may affect the metabolism of drugs by CYP2C19 [R].
Modafinil Allergic Reactions And Side Effects
Although rare, the FDA published some cases of modafinil-induced Stevens-Johnson syndrome (SJS), a skin allergy reaction that is potentially life-threatening if not treated [R].
A review study on long-term effects of modafinil reported that all adverse effects were mild to moderate, being the most common headaches, nervousness, insomnia, and nausea [R].
The same review also noted that, at therapeutic doses, modafinil did not elevate the average blood pressure or heart rate compared to placebo in populations at risk for heart disease [R].
The most common severe side effects of modafinil are tachycardia, agitation, dizziness, and anxiety [R].
A case of overdose (unsuccessful suicide attempt) with 5 grams modafinil was reported. Even at a high dosage, modafinil showed no signs of toxicity to vitals, liver, and kidney function [R].
Symptoms of the overdose included insomnia, severe headache, impaired movement (dyskinesia), and a mild heart complication (long QT interval), all of which subsided the next day [R].
Although addiction and withdrawal are rare, a case report has been published [R].
Modafinil Tolerance And Dependence
Modafinil’s low abuse potential has been one of the reasons why it is a popularly used nootropic [R].
As discussed in the dopamine section, modafinil’s interaction with the dopamine transporter is atypical (unlike cocaine) and is thought to be the reason why it does not produce as much euphoric and abuse potential [R].
Although addiction and withdrawal are rare, cases have been reported. Dependence resulted after daily use for an extended period at high dosage. Withdrawal symptoms included fatigue, anxiety, and inability to feel pleasure (anhedonia) [R].
Modafinil Adolescent Usage And Long-Term Consequences
A 16-week human study of sleepy (narcoleptic) patients taking 300 mg modafinil did not notice significant side effects [R].
Modafinil has shown to stimulate dopamine, glutamate, and norepinephrine. Frequent activation of these pathways during adolescence could cause permanent changes in the frontal cortical networks [R].
A review study looking at potential damage from nootropics and stimulants (including modafinil), noted that frequent activation and alterations of dopamine and glutamate receptors could impair brain plasticity in the long term [R, R].
The same study also suggested that the adolescent brain is sensitive to the effects of stimulants such as methylphenidate and modafinil; therefore, even low doses might result in excessive levels of dopamine and norepinephrine. This could result in impaired executive functions and altered circadian rhythm. However, long-term consequences are still unclear [R].
Modafinil Individual Experiences
Modafinil has been hailed to reduce brain fog, and for one user, “felt like me for the first time in years”.
Many users said that modafinil reliably produced cognitive enhancing effects.
Going over the therapeutic dosage is not recommended. One report of a user taking 4,000 mg of modafinil, experienced a severe headache along with dizziness, or what he described as “Worst Experience of My Life!”
Other severe side effects of modafinil are already reported in scientific publications, such as the racing heart (tachycardia). One user was taken to the ER and was given IV beta blockers after IV adenosine failed.
Some Redditors also reported tolerance after daily use.