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14 Modafinil Uses, Dangers & Comparison to Stimulants

Written by Helen Quach, BS (Biochemistry) | Last updated:
Jonathan Ritter
Medically reviewed by
Jonathan Ritter, PharmD, PhD (Pharmacology) | Written by Helen Quach, BS (Biochemistry) | Last updated:

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Diagram

Modafinil is an FDA-regulated drug that is available by prescription for the treatment of daytime sleepiness (narcolepsy) and fatigue. It 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. Read on to find out more information about modafinil.

Disclaimer: By writing this post, we are not recommending this drug. Some of our readers who were already taking the drug requested that we commission a post on it, and we are simply providing information that is available in the clinical and scientific literature. Please discuss your medications with your doctor.

What is Modafinil?

Modafinil is a wakefulness-promoting drug used to treat the symptoms of narcolepsy (daytime sleepiness) and fatigue. In the US, it is an FDA-regulated substance and can be only obtained through a prescription. However, it has been widely used off-label as a cognitive enhancer.

Modafinil is capable of improving a wide range of functions, such as wakefulness, attention, memory, athletic performance, and reaction time.

Modafinil is banned in most sports events as a doping agent, while it still remains popular among competitive workplaces and universities.

Its mechanism of action is complex acting on dopamine, serotonin, norepinephrine, 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 [1].

This drug produces reliable stimulatory effects, and it has significantly less abuse potential than other stimulants such as amphetamines [2, 3].

Modafinil is only available via prescription [4].

Modafinil is also used by astronauts to combat fatigue, improve focus, and help adjust circadian rhythm in an artificial lighting environment [5].

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 [6, 7, 8, 9].

Modafinil Mechanism Of Action

1) 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 [10, 11].

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 [12, 13, 14, 15].

In animal studies, modafinil partially activated the dopamine D2 receptor and promoted wakefulness by significantly increasing dopamine in the brain (nucleus accumbens) [16, 17].

Modafinil’s actions on the dopamine receptor might be responsible for its effects on motivation, confidence, and task enjoyment [18, 19].

2) May Increase Serotonin

Modafinil mildly increases serotonin in certain regions of the brain (frontal cortex, amygdala, and dorsal raphe) [2021].

Modafinil has also shown synergistic actions with SSRIs (selective serotonin reuptake inhibitors) increasing the amount of serotonin in the brain [212223].

Despite promising animal and cell studies, a human trial (double-blind randomized controlled trial) 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 [24].

3) May Increase Norepinephrine

Modafinil occupies the norepinephrine transporter (NET), which leads to an increase of norepinephrine in the brain (hypothalamus and prefrontal cortex) [25, 26, 27].

However, even when the receptors for norepinephrine were blocked, modafinil’s stimulatory properties were not reduced, as modafinil was still able to promote wakefulness [28].

4) May Increase Histamine Release Through Orexin

Modafinil increases histamine release by acting on orexin-releasing neurons, as reported by multiple animal studies [29, 30, 31, 32, 29].

Orexin is a neurotransmitter that increases arousal and wakefulness. Modafinil’s effect on orexin might contribute to its stimulatory effects [33].

Histamine is also involved in the mechanisms of the wake-sleep cycle. Modafinil’s effects on histamine levels might contribute to its wakefulness-promotion properties [34, 35].

5) May Increase Glutamate And Decreases GABA

Modafinil increases glutamate (excitatory) and decreases GABA (inhibitory) in different regions of the brain. Some of these studies showed conflicting results and region-specific effects; therefore, the exact mechanism is not yet conclusive [36, 37, 38, 39, 40, 41].

Uses of Modafinil

1) Fatigue

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 [42].

However, repeated doses of modafinil were unable to prevent deterioration of cognitive performance over a longer period of sleep deprivation [42].

In a placebo-controlled trial with 41 participants under conditions of 64-hour sleep deprivation, 300 mg modafinil significantly improved cognitive function compared to placebo, while amphetamine (20 mg) and modafinil scored similarly in respect to mood, fatigue, and cognition [43].

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 [43].

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 double-blind randomized controlled trial on 278 people [44].

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 double-blind randomized controlled trial of 209 people [45].

One of the symptoms of Parkinson’s disease (PD) is excessive daytime sleepiness. Modafinil reduced daytime sleepiness in two double-blind randomized controlled trials on a total of 36 PD patients [46, 47].

Modafinil helped reduce the sleepiness induced by a genetic disorder that causes the progressive loss and weakening of muscles (myotonic dystrophy) in three double-blind randomized controlled trials on 68 total people [48, 49, 50].

Either alone or in combination with other medications, modafinil helped reduce sleepiness and fatigue in people with major and bipolar depression in four double-blind randomized controlled trials on a total of 587 people and two observational studies on a total of 52 people [51, 52, 24, 53, 54, 55].

In an observational study of 11 people on opioid medication, modafinil reduced sleepiness without disrupting sleep pattern. Similarly, people on antipsychotics saw a reduction in sleepiness and fatigue after taking modafinil [56, 57].

However, in two double-blind randomized controlled trials on a total of 61 people found no differences between modafinil and placebo in reducing sleepiness [58, 59].

3) Addiction

Three studies (randomized controlled trials of 83, 30, and 65 participants respectively) showed that 200 to 400 mg of modafinil significantly reduced alcohol and cocaine addictions [60, 61, 62].

Also, modafinil (200 mg) reduced gambling desire in 20 pathological gamblers in another (double-blind randomized controlled trial) study [63].

4) ADHD

In a study (double-blind randomized controlled trial) of 248 adolescents, 170 to 425 mg modafinil significantly improved ADHD symptoms at school and home compared to placebo, as evaluated by clinicians, teachers, and parents [64].

A recent meta-analysis of 5 studies (double-blind randomized controlled trials), with a total of 927 adolescents participants, showed that modafinil significantly improved symptoms of ADHD compared to placebo [65].

5) Processing Speed

In a study (double-blind randomized controlled trial) of 16 healthy volunteers, 200 mg of modafinil significantly reduced the number of errors in several difficult performance tasks (such as visuospatial maintenance tasks) [66].

Modafinil enhances the efficiency and processing of cognitive information in a region of the brain responsible for higher cognitive functions (prefrontal cortex) [67].

However, in a double-blind randomized controlled trial of 39 men playing chess games, modafinil caused the players to be slower and take a longer time per chess move [68].

6) Memory

Multiple studies (in 60, 17, and 64 participants respectively) have shown that modafinil improved working memory, even in healthy humans. Participants that took 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 [69, 70, 71].

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 [19].

Another study on 41 healthy people under 64-hour sleep deprivation conditions noted that modafinil produced overconfidence and overestimation of one’s cognitive abilities [72].

8) Athletic Performance

Modafinil improved reaction time in both healthy and cognitively impaired individuals [69, 73].

A double-blind randomized controlled trial 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 mentally demanding tasks [69].

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 [74, 75].

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 [76, 77].

In two double-blind randomized controlled trial on a total of 416 people with obstructive sleep breathing cessation, modafinil improved daytime wakefulness [78, 79].

However, modafinil only improved alertness but not sleepiness, quality of life, or cognitive performance in a double-blind randomized controlled trial on 32 people [80].

10) Cognitive Issues

Symptoms of multiple sclerosis (MS), such as fatigue and cognitive impairment, have been reduced by modafinil across 4 studies on a total of 122 participants (only two were double-blind randomized controlled trials) [81, 82, 83, 84].

11) Mood

Human studies have shown that modafinil reduces reactivity to threatening stimuli in the amygdala, a brain region involved in anxiety [67].

Although not statistically significant, there were trends for reduced anxiety, as well as decreased anger-hostility on modafinil [67].

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 [85].

12) Emotional Processing

Multiple studies (in 40 and 54 participants) shown modafinil significantly improves emotional processing, such as recognition of facial expressions, as compared to placebo [86, 87, 88].

13) May Improve Schizophrenia Symptoms

In four double-blind randomized controlled trials on a total of 83 people with schizophrenia, modafinil improved fatigue, cognitive performance, or both [89, 58, 90, 91].

14) May Improve Neuron Communication

Modafinil’s protection of dopamine-releasing neurons seen in animal studies has shown promise in treating Parkinson’s disease [92].

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 [93].

A similar cell-based study noted modafinil improved communication (electrical coupling) between neurons (cortical) [94].

In multiple cell studies, modafinil prevented the damage or death of neurons due to overactivation of receptors by glutamate (an excitatory neurotransmitter) and degeneration of dopamine-releasing neurons [95, 96, 97].

Side Effects of Modafinil

The most common severe side effects of modafinil are tachycardia, agitation, dizziness, and anxiety [98].

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 [99].

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 [99].

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 [100].

Overdose and Withdrawal of Modafinil

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 [101].

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 [101].

Although addiction and withdrawal are rare, a case report has been published [102].

Tolerance and Dependence of Modafinil

Modafinil’s low abuse potential has been one of the reasons why it is a popularly used nootropic [103].

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 [12].

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) [102].

Contraindications of Modafinil

The following contraindications are more precautions than strict contraindications [104]:

  • Cardiovascular disease: left-ventricular hypertrophy, uncontrolled hypertension, unstable angina, or recent myocardial infarction.
  • Liver and kidney impairment. The dose should be adjusted.
  • Tic and psychiatric disorders.

Modafinil Use During Pregnancy and Breastfeeding

No adequate studies in humans have looked at modafinil use in pregnancy. Therefore, caution is advised and the potential benefits should outweigh the potential risk to justify modafinil’s use. It is unknown whether modafinil is found in breastmilk [104].

Drug Interactions of Modafinil

It has been shown that modafinil inhibits CYP2C19 and, to a lesser extent, CYP3A4 enzymes, which metabolize many drugs [105].

One study suggested that modafinil may affect the metabolism of drugs by CYP2C19 [106].

Potential interactions of modafinil with ethinylestradiol, diazepam, phenytoin, cyclosporin, and triazolam were reported [106, 105].

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 [107].

Although modafinil seems to be relatively safe, usage during adolescence might cause permanent consequences [108, 109].

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 [110].

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 [111, 112].

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 [111].

Modafinil Compared To Other Common Stimulants

1) 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 [43].

Another placebo-controlled 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 [72].

However, amphetamines are capable of increasing anxiety levels, while modafinil is not, as shown by both animal and human studies [113, 114].

Modafinil has a lower abuse potential than amphetamines, which increase dopamine levels across the brain to a greater extent. For this reason, addiction to prescription amphetamines is common [115, 116, 117].

2) 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 [114].

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 [118].

3) Methylphenidate

Methylphenidate, most popularly sold as Ritalin, is similar to modafinil regarding its cognitive enhancing properties [119].

Although therapeutic doses of methylphenidate no not produce addiction, higher doses could cause euphoria and dependence if used often [120, 121].

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About the Author

Helen Quach

BS (Biochemistry)

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