Evidence Based This post has 88 references
4.4 /5
13

All About Modafinil: Official Uses, Mechanisms, Side-Effects + More

Written by Puya Yazdi, MD | Last updated:
Jonathan Ritter
Matt Carland
Medically reviewed by
Jonathan Ritter, PharmD, PhD (Pharmacology), Matt Carland, PhD (Neuroscience) | Written by Puya Yazdi, MD | Last updated:

SelfHacked has the strictest sourcing guidelines in the health industry and we almost exclusively link to medically peer-reviewed studies, usually on PubMed. We believe that the most accurate information is found directly in the scientific source.

We are dedicated to providing the most scientifically valid, unbiased, and comprehensive information on any given topic.

Our team comprises of trained MDs, PhDs, pharmacists, qualified scientists, and certified health and wellness specialists.

All of our content is written by scientists and people with a strong science background.

Our science team is put through the strictest vetting process in the health industry and we often reject applicants who have written articles for many of the largest health websites that are deemed trustworthy. Our science team must pass long technical science tests, difficult logical reasoning and reading comprehension tests. They are continually monitored by our internal peer-review process and if we see anyone making material science errors, we don't let them write for us again.

Our goal is to not have a single piece of inaccurate information on this website. If you feel that any of our content is inaccurate, out-of-date, or otherwise questionable, please leave a comment or contact us at [email protected]

Note that each number in parentheses [1, 2, 3, etc.] is a clickable link to peer-reviewed scientific studies. A plus sign next to the number “[1+, 2+, etc...]” means that the information is found within the full scientific study rather than the abstract.

Diagram
//

Modafinil is an FDA-regulated drug that is available by prescription for the treatment of narcolepsy and several other fatigue- or sleep-related disorders. As a stimulant drug, it generally promotes wakefulness and alertness — but it is also illegally abused as a “cognitive enhancer” in highly-competitive environments, such as workplaces and universities. Read on to learn more about this drug, its mechanisms, official medical uses, side-effects and more!

Disclaimer: This post is not a recommendation or endorsement for modafinil. This medication is only FDA-approved for the treatment of certain specific medical disorders, and can only be taken by prescription and with oversight from a licensed medical professional. We have written this post for informational purposes only, and our goal is solely to inform people about the science behind modafinil’s effects, mechanisms, current medical uses, and potential risks.

What is Modafinil?

Modafinil is a wakefulness-promoting stimulant medication that is most commonly used to treat the symptoms of sleep/wakefulness disorders.

For example, modafinil has been FDA-approved for the treatment of chronic fatigue, excessive daytime sleepiness (narcolepsy), obstructive sleep apnea, and shift-work sleep disorder [1].

In the US, modafinil is an FDA-regulated substance, and can be only legally obtained and used by a doctor’s prescription.

Unfortunately, many people also obtain and abuse modafinil illegally, in part due to widespread claims or beliefs that it can enhance cognition, boost mood, increase physical energy (e.g. for athletic training), or alleviate the symptoms of “brain fog” [2].

Although the evidence for these various “enhancement” effects is generally quite weak, illegal abuse of modafinil continues to be increasingly widespread among professionals and students. For example, many reliable survey studies have reported that as much as 20% of university students have illegally abused modafinil or other stimulants (such as Adderall and other amphetamines) in order to “improve their focus” or “enhance their attention” [3, 4, 5, 6].

Modafinil abuse is also widespread among athletes, which has led to it being officially banned for use by professional athletes by the World Anti-Doping Agency (WADA) [7].

When it comes to the legitimate medical use of modafinil, it is generally believed to produce relatively fewer side-effects, and have relatively lower potential for abuse and addiction, compared to other psychostimulant medications — and this is one of the reasons that modafinil has been officially FDA-approved for the treatment of certain medical conditions [8, 9].

However, there are still some legitimate reasons to be cautious or skeptical. For one, there is still considerable risk of addiction and drug dependence when modafinil is taken illegally — which is, unfortunately, more widespread than it ideally should be. Additionally, there are also some concerns about its potential negative long-term effects: for example, some early studies have raised concerns that long-term use of modafinil may impair certain cognitive processes (such as brain plasticity) — especially in young (adolescent) users.

Modafinil Mechanisms Of Action

Modafinil’s mechanisms of action are quite complex, and are not yet fully known for certain. However, a variety of early evidence suggests that it may act on dopamine, serotonin, norepinephrine, histamine, orexin, glutamate, and GABA receptors.

Dopamine

According to some preliminary studies, modafinil may act by partially inhibiting the dopamine transporter (DAT), which generally increases dopamine levels. Although this is the same mechanism of action as cocaine, modafinil’s activities on the dopamine transporter are supposedly weaker and milder — more akin to a calming effect than the “stimulant” effects associated with cocaine use [10, 11].

A handful of early animal studies have reported that modafinil also partially activates the dopamine D2 receptor, and may promote wakefulness by stimulating the release of dopamine throughout the brain (particularly in the nucleus accumbens) [12, 13].

Some researchers have proposed that modafinil’s actions on the dopamine receptor might be responsible for some of its reported effects on motivation, confidence, and task enjoyment [14, 15].

Serotonin

Some evidence suggests that modafinil may mildly increase serotonin in certain regions of the brain (such as the prefrontal cortex, amygdala, and dorsal raphe nucleus) [16, 17].

According to a few studies in cells and animals, modafinil has been reported to show synergistic actions when combined with SSRIs (selective serotonin reuptake inhibitors) [17, 18, 19].

However, despite the promising early studies in animals and cells, an actual study in humans (double-blind randomized controlled trial) co-administered modafinil and SSRIs for major depressive disorder (MDD) with fatigue and sleepiness, but failed to observe any synergistic actions for the treatment of depression [20].

Norepinephrine

Findings from a few early animal and cell studies suggest that modafinil may also interact with the norepinephrine transporter (NET), which could lead to an increase of norepinephrine throughout various regions of the brain (such as in the hypothalamus and prefrontal cortex) [21, 22, 23].

However, even when the receptors for norepinephrine were blocked, modafinil’s stimulatory properties were not reduced [24]. This finding suggests that this mechanism is probably not directly related to modafinil’s primary effects — although more research will be needed to find out for sure.

Glutamate and GABA

Modafinil has been reported to stimulate the release of the excitatory neurotransmitter glutamate, while also decreasing the activity of the inhibitory neurotransmitter GABA. However, many of these studies have reported conflicting results and region-specific effects — therefore, the exact mechanism is not yet conclusive, and more research will be needed [25, 26, 27, 28, 29, 30].

Histamine and Orexin

Finally, reports from multiple early studies in animals suggest that modafinil may also increase the release of histamine — possibly by acting on orexin-releasing neurons [31, 32, 33, 34, 31].

Orexin is a neurotransmitter that is believed to play a role in stimulating overall arousal and wakefulness. Based on this, some researchers have speculated that modafinil’s effect on orexin may contribute to its primary stimulatory effects [35].

Histamine is also believed to be involved in the sleep-wake cycle. Modafinil’s effects on histamine levels have therefore also been suggested to contribute to its wakefulness-promotion properties [36, 37].

However, the research on this mechanism is still inconclusive, and more studies will be required to explore these potential effects further.

Approved Medical Uses of Modafinil

1) Narcolepsy

Not only is modafinil FDA-approved for the treatment of narcolepsy, but it is actually the primary medication — or “first-line treatment” — used to treat narcolepsy [38].

2) Excessive Daytime Sleepiness / Shift-Work Sleep Disorder

Modafinil is also the “first-line” (primary) medical treatment for Sleep-work shift disorder [38].

Shift-work sleep disorder is a circadian rhythm disturbance that typically occurs in people who have to work during a time when they would typically be sleeping. It is mainly characterized by excessive sleepiness during working hours, and insomnia during sleeping hours.

According to one double-blind randomized controlled trial on 278 people, modafinil reportedly improved a number of sleep- and quality-of-life-related parameters in shift workers [39].

Similarly, in one double-blind randomized controlled trial (DB-RCT) study of 209 people, modafinil was reported to help shift workers fall asleep, as well as potentially increasing their attention span during night shifts. However, it had no reported effect on the number of sleep episodes during work, the number of accidents at work, or their total amount of caffeine intake [40].

Modafinil reportedly helped reduce the sleepiness induced by a genetic disorder that causes the progressive loss and weakening of muscles (myotonic dystrophy), according to three double-blind randomized controlled trials on 68 total people [41, 42, 43].

According to an observational study of 11 people on opioid medications, modafinil reportedly reduced sleepiness without disrupting the participants’ sleep patterns. Similarly, psychiatric patients currently taking antipsychotic medications reported reductions in overall sleepiness and fatigue after being treated with modafinil [44, 45].

However, in two double-blind randomized controlled trials on a total of 61 people found no differences between modafinil and placebo in reducing sleepiness [46, 47].

3) Obstructive Sleep Apnea

Obstructive sleep apnea is a disorder whose main symptom is the cessation of breathing due to the blockage of the upper respiratory airways during sleeping. This causes numerous problems, such as frequent waking throughout the night, and is in turn associated with dramatically reduced sleep quality, excessive daytime sleepiness, elevated blood pressure (hypertension), and even increased long-term risk of cardiovascular diseases and strokes [48, 49].

According to two double-blind randomized controlled trials on a total of 416 people with obstructive sleep breathing cessation, modafinil reportedly improved daytime wakefulness [50, 51].

However, another double-blind randomized controlled trial (DB-RCT) in 32 people reported that modafinil only improved alertness, but not sleepiness, quality of life, or cognitive performance [52].

Off-Label Uses of Modafinil

Occasionally, doctors will prescribe medications to help treat conditions that fall outside of the official uses approved by the FDA — also known as “off-label” drug use [53]. Usually, this is done because there is actually decent evidence that the drug may help, although this evidence might not be quite strong enough to get full FDA approval (which generally has very strict requirements).

As always, however, always remember that the decision to use medications in this way can only be made by a licensed medical professional.

1) ADHD

Although not especially common, some doctors have been known to prescribe modafinil for treating some of the symptoms of ADHD. While there is some decent evidence that it may be helpful, the available research is not yet strong enough to have met the FDA’s standards for medical approval, and so this remains an “unofficial” use of modafinil.

According to one study (double-blind randomized controlled trial) of 248 adolescents, 170-425mg of modafinil was reported to significantly improve ADHD symptoms both at school and at home (as evaluated by clinicians, teachers, and parents) when compared to placebo [54].

Similarly, a recent meta-analysis of data from 5 studies (double-blind randomized controlled trials) with a total of 927 adolescent participants concluded that modafinil significantly improved symptoms of ADHD compared to placebo [55].

However, while some of this evidence is promising, the fact that many ADHD patients are children and adolescents — combined with potential concerns about the long-term safety of modafinil use in younger people — is one of the major reasons why this particular use of modafinil has not become significantly widespread [1].

2) Alleviating Depression Symptoms

According to four double-blind randomized controlled trials on a total of 587 people, as well as two observational studies on a total of 52 people, modafinil has been reported to help reduce sleepiness and fatigue in people with major and bipolar depression when used either alone or in combination with other medications [56, 57, 20, 58, 59, 60].

Potential Future Medical Applications of Modafinil

The following sections describe some of the research that has been done on the potential medical applications of modafinil. However, these findings are all still very preliminary, and have not strongly established a scientific case for using modafinil for these uses or conditions.

As such, these potential future applications should be considered as having “insufficient evidence” until much more additional research is performed — especially long-term clinical studies in large samples of human patients.

INSUFFICIENT EVIDENCE:

1) Addiction & Substance Abuse Treatment

Three studies (randomized controlled trials of 83, 30, and 65 participants, respectively) have reported that 200-400 mg of modafinil significantly reduced drug cravings in patients with alcohol or cocaine addictions [61, 62, 63].

Similarly, another small-scale double-blind randomized controlled trial (DB-RCT) study has reported that a 200-mg dose of modafinil significantly reduced urges to gamble in a treatment group of 20 pathological gamblers [64].

Interestingly, modafinil’s “atypical” effects at inhibiting the dopamine transporter (DAT) are being researched as a potential treatment for withdrawal from dopamine-acting substances (such as cocaine) [65, 66, 67, 68].

However, a lot more research (including many clinical studies in humans) will be needed to confirm this potential use, and it is not currently part of standard medical practice when treating substance use disorders.

2) Schizophrenia

According to four small-scale DB-RCTs in a total of 83 schizophrenic patients, modafinil reportedly improved fatigue, cognitive performance, or both [69, 46, 70, 71].

However, despite the fact that four studies have reported similar findings, the total number of research subjects is still much too small to come to any solid conclusions about modafinil’s potential for medically treating schizophrenia — and a lot more research will be needed to explore this further.

3) Parkinson’s Disease

According to one preliminary animal study, modafinil was reported to have a potential “neuro-protective” effect on certain populations of dopamine neurons in the brain. Based on this, some researchers have proposed that modafinil may have some future medical potential as a treatment for preventing or treating Parkinson’s disease [72].

Additionally, one of the common symptoms of Parkinson’s disease (PD) is excessive daytime sleepiness. According to two small-scale DB-RCT studies in a total of 36 Parkinson’s patients, treatment with modafinil reportedly reduced daytime sleepiness [73, 74].

Nonetheless, while these early findings appear promising, much more research will be needed before modafinil could ever officially become part of the conventional medical treatment for Parkinson’s disease.

Modafinil Side-Effects

Given that modafinil has met FDA approval for certain specific medical uses, the majority of scientific evidence supports the overall safety and effectiveness of modafinil when used as prescribed, and under the supervision of a qualified medical professional.

Nonetheless, like any drug, there is always at least some potential of experiencing adverse side-effects, and so it’s important to be aware of these. If you experience any of the following symptoms occur after taking modafinil, contact your doctor immediately.

The most common severe side-effects of modafinil are elevated heart rate (tachycardia), agitation, dizziness, and anxiety [75].

According to one study of the potential long-term effects of modafinil, most reported adverse side-effects tend to be mild-to-moderate, with headaches, nervousness or anxiety, insomnia, and nausea being the most common symptoms [76].

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 [76].

Although rare, the FDA has published some cases of modafinil-induced Stevens-Johnson syndrome (SJS), an allergic reaction in the skin which can be potentially life-threatening if untreated [77].

Contraindications for Modafinil

Although modafinil has a number of relatively well-supported medical uses when administered by qualified medical professionals, there are a number of factors that doctors may look for that might disqualify someone from receiving modafinil treatment (due to elevated risk of negative side-effects or other adverse reactions).

Some of the contraindications against modafinil use include [38]:

  • Cardiovascular disease: left-ventricular hypertrophy, uncontrolled hypertension, unstable angina, or recent myocardial infarction.
  • Liver and kidney impairments: these concerns are usually manageable by treatment, but generally require that the dose be adjusted.
  • Tic disorders, such as Tourette’s syndrome, which may be worsened by stimulants such as modafinil.
  • Other psychiatric disorders, such as a history of psychosis or mania symptoms.

Modafinil Use During Pregnancy and Breastfeeding

No adequate studies in humans have investigated the safety of modafinil use during pregnancy. Therefore, caution is advised, and the use of modafinil during pregnancy is generally only approved if a qualified medical professional has a specific reason to believe that the potential therapeutic benefits outweigh the potential risks [38].

Similarly, it is currently unknown whether modafinil can be transmitted to an infant through breastmilk, and similar cautions apply to modafinil use by mothers who are nursing [38].

Drug Interactions

Like many drugs, modafinil can interact with the effects of other drugs, which can potentially cause significant health complications.

As always, the best way to minimize the risk of adverse drug interactions is to discuss all treatment options with your doctor, and to make sure that he or she is fully informed about any other medications or supplements you are taking, other pre-existing health conditions, or any other potentially health-related factors that may affect your treatment.

While the full range of modafinil’s potential drug interactions is not yet completely known, a number of early studies have documented potential adverse interactions between modafinil and the following drugs and other compounds [78, 79]:

  • Ethinylestradiol
  • Diazepam
  • Phenytoin
  • Cyclosporin
  • Triazolam

Additionally, some researchers believe that modafinil may interact with certain proteins or enzymes that are involved in the breakdown and removal (metabolism) of many other drugs and compounds. For example, some preliminary evidence suggests that modafinil may inhibit the enzymes CYP2C19 and CYP3A4 [79, 78]. Therefore, the actions of any drugs that require those enzymes to be processed by the body could be altered or negatively influenced during treatment with modafinil.

Tolerance and Dependence

Compared to many other psychostimulant drugs (such as amphetamines), modafinil is generally believed to have relatively lower abuse potential [80].

However, this only means that it is relatively safer than other drugs: it does not mean that modafinil is entirely without risks.

Moreover, the purportedly “lower” abuse potential of modafinil only applies to situations in which it is being taken by prescription and with oversight from a licensed medical professional. Illegal abuse of modafinil (or any psychoactive drug) can significantly increase the risks for developing an addiction, tolerance, and dependence on a substance, and is for this reason highly discouraged.

With that mind, what do we currently know about modafinil’s potential for building physiological tolerance and drug-dependence?

As discussed in the previous sections on the biological mechanisms of modafinil, this drug’s interactions with the dopamine transporter are considered “atypical,” and does not produce some of the psychological effects that cause people to abuse it (such as euphoria). This is believed to be one of the potential reasons why modafinil appears to have relatively lower abuse potential — at least compared to other dopamine-acting drugs (such as amphetamines and cocaine) [65].

However, although reports of addiction and withdrawal symptoms are relatively rare for modafinil, a few cases have nonetheless been reported. For example, one medical case report has documented the development of dependence in one patient who took high doses of modafinil for an extended period of time. This patient also experienced a severe withdrawal syndrome after stopping modafinil use, and reported a number of symptoms including fatigue, anxiety, and the loss of the ability to feel pleasure (anhedonia) [81].

Adolescent Usage and Long-Term Consequences

Although modafinil seems to be relatively safe, usage during adolescence might cause permanent consequences [82, 83].

For example, modafinil has shown to stimulate dopamine, glutamate, and norepinephrine: and some researchers have argued that frequent drug-induced stimulation of these pathways during adolescence could cause permanent changes in brain structure — especially in the frontal cortical networks [84].

Additionally, a review study looking at potential damage from various “nootropics” and other stimulant drugs (including modafinil) has reported that frequent activation and alterations of dopamine and glutamate receptors may result in significantly impaired brain plasticity in the long term [85, 86].

The same study also suggested that the adolescent brain is particularly sensitive to the effects of stimulants such as methylphenidate (Ritalin) and modafinil. Therefore, even low doses might result in excessive levels of dopamine and norepinephrine, which could, in turn, result in impaired executive functions and altered circadian rhythm [85].

However, the long-term consequences of modafinil are still unclear, and the evidence is mixed: for example, one 16-week human study of narcolepsy patients taking 300 mg modafinil did not report any major noticeable or significant adverse side-effects [87]. While this might seem to be good news, it should be noted that this study was relatively short, and only lasted 16 weeks — so it’s entirely possible that there are subtler, more long-lasting risks that were not observed by this study design.

Overdose

Just like any drug, overdosing on modafinil can have severe consequences on a person’s health.

However, the risks of overdose are minimal so long as it is only being taken by a doctor’s prescription, and in line with the doctor’s instructions about how to properly use the medication.

Nonetheless, at least one case has been reported, from a patient who intentionally overdosed on modafinil during a suicide attempt. This patient took an especially large dose (>5 grams), and reported a variety of symptoms including [88]:

  • Insomnia
  • Severe headaches
  • Impaired movement (dyskinesia)
  • Moderate heart complications

Fortunately, these symptoms largely seemed to subside within a day or so. Additionally, no long-term damage to vital organs such as the liver or kidney were apparent in this patient [88].

Nonetheless, not much is currently known about the likelihood or potential symptoms of modafinil overdose apart from this single case study — so caution is still highly advised when taking this drug, and care should always be taken to take it only as specifically directed and instructed by your doctor.

About the Author

Puya Yazdi

Puya Yazdi

MD
Dr. Puya Yazdi is a physician-scientist with 14+ years of experience in clinical medicine, life sciences, biotechnology, and nutraceuticals.
As a physician-scientist with expertise in genomics, biotechnology, and nutraceuticals, he has made it his mission to bring precision medicine to the bedside and help transform healthcare in the 21st century.He received his undergraduate education at the University of California at Irvine, a Medical Doctorate from the University of Southern California, and was a Resident Physician at Stanford University. He then proceeded to serve as a Clinical Fellow of The California Institute of Regenerative Medicine at The University of California at Irvine, where he conducted research of stem cells, epigenetics, and genomics. He was also a Medical Director for Cyvex Nutrition before serving as president of Systomic Health, a biotechnology consulting agency, where he served as an expert on genomics and other high-throughput technologies. His previous clients include Allergan, Caladrius Biosciences, and Omega Protein. He has a history of peer-reviewed publications, intellectual property discoveries (patents, etc.), clinical trial design, and a thorough knowledge of the regulatory landscape in biotechnology.He is leading our entire scientific and medical team in order to ensure accuracy and scientific validity of our content and products.

Click here to subscribe

RATE THIS ARTICLE

1 Star2 Stars3 Stars4 Stars5 Stars
(10 votes, average: 4.40 out of 5)
Loading...

FDA Compliance

The information on this website has not been evaluated by the Food & Drug Administration or any other medical body. We do not aim to diagnose, treat, cure or prevent any illness or disease. Information is shared for educational purposes only. You must consult your doctor before acting on any content on this website, especially if you are pregnant, nursing, taking medication, or have a medical condition.

Leave a Reply

Your email address will not be published. Required fields are marked *

This site uses Akismet to reduce spam. Learn how your comment data is processed.