Modafinil
Modafinil, sold under the brand name Provigil among others, is a central nervous system stimulant and eugeroic medication used primarily to treat narcolepsy, a sleep disorder characterized by excessive daytime sleepiness and sudden sleep attacks. Modafinil is also approved for stimulating wakefulness in people with sleep apnea and shift work sleep disorder. It is taken by mouth. Modafinil is not approved by the US Food and Drug Administration for use in people under 18 years old.
Common side effects of modafinil include anxiety, insomnia, dizziness, and headache. Modafinil has potential for causing severe allergic reactions, psychiatric effects, hypersensitivity, adverse interactions with prescription drugs, and misuse or abuse. Modafinil may harm the fetus if taken during or two months prior to pregnancy.
While modafinil is used as a cognitive enhancer, or "smart drug", among healthy individuals seeking improved focus and productivity, its use outside medical supervision raises concerns regarding potential misuse or abuse. Research on the cognitive enhancement effects of modafinil in non-sleep deprived individuals has yielded mixed results, with some studies suggesting modest improvements in attention and executive functions, while others show no significant benefits or a decline in cognitive functions at high doses.
The mechanism of action is not fully defined, but is thought to act mainly as an atypical dopamine transporter inhibitor that modestly increases dopamine in cortical and striatal regions without the rapid signaling seen with classical stimulants. This effect is accompanied by activation of noradrenergic, orexin, histamine, glutamate, and GABA systems that together promote stable wakefulness and cortical activation. These combined actions likely explain modafinil’s wake-promoting and cognitive effects with a lower risk of euphoria and abuse than amphetamine-like stimulants.
Uses
Medical
Sleep disorders
Modafinil, a eugeroic or wakefulness-promoting drug, is primarily used for treating narcolepsy, a sleep disorder characterized by excessive daytime sleepiness and sudden sleep attacks. Being a central nervous system stimulant itself, modafinil has lower addictive potential than classical stimulants such as amphetamine, cocaine, or methylphenidate, but still produces psychoactive and subjective effects typical of classical stimulants.Narcolepsy causes a strong urge to sleep during the day and can include symptoms like cataplexy, sleep paralysis, and hallucinations. Narcolepsy is linked to a lack of the brain chemical hypocretin, primarily produced in the hypothalamus. Modafinil is not a cure for narcolepsy, but it can help manage the symptoms. While modafinil is primarily used to treat excessive sleepiness, it may also help reduce the frequency and severity of cataplexy attacks in some people. Modafinil is approved for management of narcolepsy with or without cataplexy. However, it is not specifically approved for the treatment of cataplexy.
Modafinil is also prescribed for shift work sleep disorder.
Modafinil performs moderately as a drug to overcome excessive daytime sleepiness caused by obstructive sleep apnea, though it is recommended that people with apnea use continuous positive airway pressure therapy, that is a sleep breathing apparatus to prevent apnea, before starting modafinil. When obstructive sleep apnea is comorbid with narcolepsy, modafinil is an effective drug to reduce the associated excessive daytime sleepiness.
Modafinil's use varies by region. In the US, it is approved for adult narcolepsy, shift work sleep disorder, and obstructive sleep apnea, but not for children. In the UK and the EU, since 2014, it is approved solely for narcolepsy, including in children, with its use for other conditions restricted by the European Medicines Agency.
both the French and the American Academy of Sleep Medicine strongly recommend modafinil as the first-choice treatment for narcolepsy. In Europe, modafinil is considered one of the primary drugs recommended for treating narcolepsy according to the guidelines.
Multiple sclerosis-related fatigue
Fatigue is a common and often debilitating symptom experienced by people with MS.When modafinil is prescribed for fatigue, some people with MS may experience increased energy levels, reduced feelings of tiredness, improved cognitive function, and better quality of life. Two reviews concluded that modafinil has minor effectiveness in managing fatigue in people with MS, and optimal dosing and treatment schedules are not well established. Clinical assessments have found that adverse events were common. The American National Multiple Sclerosis Society states that modafinil can be used off-label to alleviate fatigue associated with MS.
Attention deficit hyperactivity disorder
Modafinil is occasionally prescribed off-label for individuals with attention deficit hyperactivity disorder. It has not consistently shown efficacy in treating adult ADHD, especially when compared to other treatments such as lisdexamfetamine. In children, modafinil is more effective than placebo for treating ADHD symptoms.Given its approved status in the US to treat narcolepsy, physicians can also prescribe modafinil for off-label uses, such as treating ADHD in both children and adults.
The Canadian Network for Mood and Anxiety Treatments suggests modafinil as a second-line treament for comorbid ADHD and bipolar disorder, after first-line psychostimulants and the antidepressant bupropion.
Bipolar disorder
Modafinil is used off-label as an adjunctive treatment for the acute depressive phase in bipolar disorder. The depressive phase of bipolar disorder may feature excessive sleepiness and fatigue. Adjunctive treatment with modafinil can be used as an augmentation for the main treatment to increase its effect and is safe and effective, especially for people who do not respond well to standard antidepressants. Modafinil does not significantly increase the risk of mood switch to mania or suicide attempts in people with bipolar disorder. Modafinil may also have cognitive benefits in people with bipolar disorder who are in a remission state.Whereas modafinil and armodafinil are approved for narcolepsy, they have been repurposed as adjunctive treatments to alleviate symptoms of acute depressive phase in people with bipolar disorder. Drug repurposing in psychiatry is a strategy for discovering new uses for drugs that have already been approved or tested in clinical trials for other illnesses. As such, drug repurposing is a rapid, cost-effective, and reduced-risk strategy for the development of new treatment options for psychiatric disorders. 2021 meta-analysis concluded that add-on modafinil and armodafinil were more effective than placebo on response to treatment, clinical remission, and reduction in depressive symptoms, with only minor side effects, but the effect sizes are small and the quality of evidence is therefore low, limiting the clinical relevance of the evidence. Very low rates of mood swing have been observed with modafinil and armodafinil in depressive phase of bipolar disorder.
Occupational
Modafinil was used during the Gulf War by the French Foreign Legion, the US Air Force, and US Marines to enhance "operational tempo", aiming to optimize the overall performance and efficiency of the units.Armed forces in various countries, including the United States, the United Kingdom, India, and France, have considered modafinil as an alternative to traditional amphetamines for managing sleep deprivation in combat or extended missions. The US military approved modafinil for specific Air Force missions, replacing amphetamines for fatigue management. The use of modafinil in military contexts without sleep deprivation is not recommended due to inconclusive evidence on its cognitive enhancement benefits and potential risks of adverse effects.
Modafinil is also available to astronauts aboard the International Space Station for the management of fatigue caused by circadian dyssynchrony in orbit.
Non-medical
Modafinil has been used non-medically as a "smart drug" by various groups, including students, office workers, and transhumanists.The effectiveness of modafinil as a cognitive enhancer is still debated. Some studies suggest significant increases in cognitive abilities, while others indicate mild to nonexistent cognitive improvements. In some cases, it has been associated with impairments in certain cognitive functions. It has been shown that a positive impact on cognitive abilities is more noticeable on sleep-deprived individuals. Therefore, in people who are not sleep-deprived, the potential of modafinil as a cognitive enhancer may be limited.
Available forms
Modafinil is commercially available in and oral tablet forms. Additionally, it is offered as the -enantiomer, known as armodafinil, and as a prodrug named adrafinil.Adverse effects
Modafinil is generally well-tolerated but can have potential risks and side effects. Common adverse effects of modafinil, experienced by less than 10% of users, include headaches, nausea, and reduced appetite. Anxiety, insomnia, dizziness, diarrhea, and rhinitis are also reported in 5% to 10% of users. Psychiatric reactions have occurred in individuals with and without a preexisting psychiatric history. Urinary retention and paresthesia have also been reported.No significant changes in body weight have been observed in clinical trials, although decreased appetite and weight loss have been noted in children and adolescents. Modafinil can cause a slight increase in aminotransferase enzymes, indicative of liver function, but there is no evidence of serious liver damage when levels are within reference ranges.
Rare but serious adverse effects include severe skin rashes and allergy-related symptoms. Between December 1998 and January 2007, the FDA received reports of six cases of severe cutaneous adverse reactions, including erythema multiforme, Stevens–Johnson syndrome, toxic epidermal necrolysis, and DRESS syndrome. The FDA has issued alerts regarding these risks and also noted reports of angioedema and multi-organ hypersensitivity reactions in postmarketing surveillance. In 2007, the FDA required Cephalon to modify the Provigil leaflet to include warnings about these serious conditions. The long-term safety and effectiveness of modafinil have not been conclusively established.
The FDA does not endorse modafinil for children's medical conditions due to an increased risk of rare but serious dermatological toxicity, manifested as Stevens–Johnson syndrome which is a type of severe skin reaction. However, in Europe, modafinil may be prescribed for treating narcolepsy in children.