Modafinil is a prescription wakefulness-promoting drug, sold in the US as Provigil and as generics. The FDA first approved it in 1998 to improve wakefulness in adults with excessive sleepiness caused by narcolepsy, obstructive sleep apnea (OSA) or shift work disorder (Provigil label).
Outside medicine it is best known as a “smart drug” used by students, professionals and some athletes to stay alert or think faster. The most important fact for that use: meta-analyses of placebo-controlled trials in healthy, rested adults find only a small average effect on cognition. Modafinil is also a Schedule IV controlled substance in the US and is prohibited in competition by the World Anti-Doping Agency (WADA).
This page summarizes what the FDA label, clinical trials, meta-analyses and regulators report. It is for education only and is not medical advice.
| Property | Detail |
|---|---|
| Drug class | Wakefulness-promoting agent; acts on the dopamine transporter |
| Brands / approval | Provigil (Cephalon/Teva), FDA approved 1998; generics |
| Route | Oral tablet |
| Strengths | 100 mg and 200 mg |
| Labeled dose | 200 mg once daily (morning for narcolepsy/OSA; ≈1 h before the shift for shift work disorder) |
| Half-life (label) | Effective half-life ≈15 h after multiple doses |
| Key warning | Serious rash, including Stevens-Johnson syndrome |
| US status | Prescription only; Schedule IV controlled substance |
| WADA status | Prohibited in competition; S6.A non-Specified stimulant |
What it is
Chemically, modafinil is 2-[(diphenylmethyl)sulfinyl]acetamide, formula C₁₅H₁₅NO₂S, molecular weight 273.35 (Provigil label). It is a racemic mixture: a 1:1 blend of two mirror-image forms, R-modafinil and S-modafinil. The R-form is sold on its own as armodafinil (Nuvigil). Adrafinil is a separate, related compound that WADA lists by name alongside modafinil.
The label describes three related products:
| Compound | Relationship | Notes from the Provigil label |
|---|---|---|
| Modafinil | Racemic mixture (R + S) | The drug covered on this page |
| Armodafinil | R-enantiomer of modafinil | Allergy to either drug is a contraindication to both |
| Modafinil acid, modafinil sulfone | Main metabolites | Do not appear to drive the wake-promoting effect |
Mechanism
The label states plainly that the mechanism by which modafinil promotes wakefulness “is unknown.” What is known:
- Dopamine transporter. In vitro, modafinil binds the dopamine transporter (DAT) and blocks dopamine reuptake. In mice bred without DAT, modafinil lost its wake-promoting effect.
- Not a dopamine receptor agonist. It does not act directly on dopamine receptors, and some of its animal effects differ from amphetamine (for example, haloperidol did not block its wake-promoting effect in rats).
- Adrenergic input. The α1-blocker prazosin can blunt modafinil-induced wakefulness.
A PET imaging study in 10 healthy men confirmed the DAT action in people. Oral modafinil at 200 or 400 mg occupied about 54% of DAT in the caudate and 47% in the putamen, and raised extracellular dopamine, including in the nucleus accumbens, a brain region tied to reward (Volkow et al., JAMA 2009). The authors noted that this is the same signal seen with drugs that carry abuse potential.
Pharmacokinetics
From the Provigil label (DailyMed):
| Parameter | Value |
|---|---|
| Time to peak | 2–4 h (about 1 h later with food; total absorption unchanged) |
| Effective half-life (multiple doses) | ≈15 h |
| R- vs S-enantiomer | R-modafinil half-life ≈3× that of S-modafinil; R makes up ≈90% of the trough level |
| Steady state | 2–4 days of daily dosing |
| Volume of distribution | ≈0.9 L/kg |
| Plasma protein binding | ≈60%, mainly albumin |
| Elimination | ≈90% metabolized in the liver; under 10% excreted unchanged; metabolites leave in the urine |
| Modafinil sulfone half-life | ≈40 h (accumulates with repeated dosing) |
Modafinil is broken down by several routes, including hydrolytic deamidation, S-oxidation, ring hydroxylation and glucuronide conjugation. The label notes that the fastest pathway does not involve CYP enzymes, and CYP3A is only partly involved. Modafinil also induces CYP3A4 itself, which is the basis of its most important drug interactions.
Special populations:
- Severe liver impairment. In 9 patients with cirrhosis, clearance fell by about 60% and steady-state levels doubled. The label halves the dose.
- Older adults. In 12 patients with a mean age of 82, plasma levels were about twice those in younger people. The label advises considering a lower dose.
- Severe kidney failure. Modafinil levels were not significantly changed, but exposure to the inactive metabolite modafinil acid rose 9-fold.
Approved medical use
The current US label covers adults with excessive sleepiness associated with:
- narcolepsy;
- obstructive sleep apnea (OSA) — for the sleepiness only, not the airway obstruction. CPAP should be used as fully as possible before and during treatment;
- shift work disorder (SWD).
The labeled dose is 200 mg once daily. The label notes that 400 mg/day was well tolerated but gave no consistent extra benefit over 200 mg. Modafinil is not approved for children; a 6-week trial in 165 children with narcolepsy found no significant benefit over placebo.
Pivotal trials
Efficacy was shown in placebo-controlled trials using the Maintenance of Wakefulness Test (MWT, how long a person can stay awake in a quiet, dark room) or the Multiple Sleep Latency Test (MSLT, how quickly a person falls asleep). Change in minutes from baseline at the final visit, from the label:
| Trial | Test | Modafinil 200 mg | Modafinil 400 mg | Placebo |
|---|---|---|---|---|
| Narcolepsy I (9 weeks) | MWT | +2.3 min | +2.3 min | −0.7 min |
| Narcolepsy II (9 weeks) | MWT | +2.2 min | +2.0 min | −0.7 min |
| OSA (12 weeks, n = 327) | MWT | +1.6 min | +1.5 min | −1.1 min |
| SWD (12 weeks, n = 209) | MSLT | +1.7 min | not tested | +0.3 min |
The two narcolepsy trials enrolled 558 patients in total. In a second, 4-week OSA trial (n = 157) of 400 mg/day, the Epworth Sleepiness Scale fell by 4.6 points on modafinil vs 2.0 on placebo. On a clinician-rated global impression scale, 58–74% of patients on modafinil were rated improved, vs 36–38% on placebo.
Europe: narrowed to narcolepsy only
The EU took a stricter view. After a review prompted by psychiatric, skin and cardiovascular safety signals, the European Medicines Agency’s committee (CHMP) concluded in 2010 that benefits outweighed risks only in narcolepsy. It found the evidence in OSA, shift work disorder and idiopathic hypersomnia insufficient, and those indications were removed; the European Commission decision followed on 27 January 2011 (EMA modafinil referral).
What the research shows in healthy people
Most non-medical use is by healthy people seeking better focus or memory. That use has been studied in many small, mostly single-dose, placebo-controlled trials.
Meta-analyses in rested adults
| Review | Studies | Population | Main result |
|---|---|---|---|
| Kredlow et al., J Clin Psychopharmacol 2019 | 19 placebo-controlled trials, single dose | Non-sleep-deprived adults | Overall g = 0.10 (95% CI 0.05–0.15); no difference between cognitive domains or between 100 and 200 mg |
| Roberts et al., Eur Neuropsychopharmacol 2020 | 14 modafinil studies (64 effect sizes) | Healthy, non-sleep-deprived adults | Overall SMD = 0.12; memory updating SMD = 0.28 |
| Repantis et al., Pharmacol Res 2010 | Randomized trials, systematic review with meta-analysis | Rested and sleep-deprived healthy adults | Improved attention in rested people; larger benefits on wakefulness, memory and executive function when sleep-deprived |
An effect size around 0.1 is small: it means the average person on modafinil scored only slightly better than the average person on placebo, and the two groups overlap heavily. Kredlow and colleagues concluded that the evidence shows “only limited potential” outside sleep-deprived populations. Roberts and colleagues noted that the perception of these drugs as effective cognitive enhancers “is not supported by the evidence so far.”
Individual trials and narrative reviews
The often-cited Cambridge trial gave 60 healthy young men a single dose of placebo, 100 mg or 200 mg modafinil (Turner et al., Psychopharmacology 2003). Modafinil improved digit span, visual pattern recognition memory, spatial planning and stop-signal reaction time (a measure of impulse control). It had no significant effect on spatial working memory, sustained attention or attentional set-shifting, and participants slowed down on some tasks. The effects were not clearly dose-dependent.
A systematic review of studies from 1990 to 2014 found that modafinil fairly consistently improved executive function, but only about half of the studies showed gains in attention or learning and memory, and a few reported worse divergent (creative) thinking (Battleday and Brem, Eur Neuropsychopharmacol 2015). The authors argued that more complex tasks show more consistent benefits than basic tests.
Sleep deprivation
The clearest benefit in healthy people is under sleep loss, which matches the drug’s approved use. Repantis and colleagues found modafinil maintained wakefulness, memory and executive function better than placebo in sleep-deprived people. They also found that repeated doses could not prevent cognitive decline over longer periods of sleep deprivation, while keeping people awake and possibly making them overconfident in their own performance (Repantis et al., Pharmacol Res 2010).
“Limitless pill.” Popular accounts often describe modafinil as a large, general boost to intelligence. The pooled trial data do not support that: average effects in rested adults are small, task-specific and inconsistent between studies.
Side effects and risks
Serious rash, including Stevens-Johnson syndrome
Modafinil has no boxed warning, but serious rash is the first warning on its label (Provigil label):
- In clinical trials in children (under 17), rash leading to discontinuation occurred in about 0.8% (13 of 1,585), including 1 possible case of Stevens-Johnson syndrome (SJS) and 1 multi-organ hypersensitivity reaction. No cases occurred in 380 children on placebo. The median time to rash was 13 days.
- In the pediatric ADHD program, there were 3 serious rashes, including 1 possible SJS, among 933 children exposed.
- Postmarketing reports in adults and children include SJS, toxic epidermal necrolysis (TEN, a severe skin-shedding reaction) and DRESS (drug rash with eosinophilia and systemic symptoms). The label says the reporting rate of SJS and TEN exceeds the general-population background rate of 1–2 cases per million person-years.
- Nearly all serious rashes began 1–5 weeks after starting, but some appeared after months. No factor predicts which rash will become serious.
The label tells prescribers to stop modafinil at the first sign of rash unless it is clearly unrelated to the drug. Related warnings cover angioedema and anaphylaxis, and multi-organ hypersensitivity reactions (fever and rash with involvement of organs such as the heart, liver or blood), including at least one postmarketing death. Skin risk in children was a main reason the EMA advised against pediatric use.
Psychiatric effects
In adult controlled trials, anxiety (1%), nervousness (1%), insomnia, confusion, agitation and depression (each under 1%) led to discontinuation more often than on placebo. Postmarketing reports include mania, delusions, hallucinations, suicidal ideation and aggression. One healthy volunteer developed paranoid delusions and hallucinations on repeated 600 mg doses (three times the labeled dose) combined with sleep deprivation; the symptoms resolved after stopping.
Heart and blood pressure
Average blood pressure did not change in short trials, but more patients on modafinil needed new or increased blood pressure medication: 2.4% vs 0.7% on placebo overall, and 3.4% vs 1.1% in OSA trials. The label does not recommend modafinil in people with left ventricular hypertrophy, or in mitral valve prolapse with prior stimulant-related symptoms, and advises extra monitoring after a recent heart attack or unstable angina.
Common side effects
Adverse reactions in pooled placebo-controlled trials (modafinil n = 934, placebo n = 567):
| Reaction | Modafinil | Placebo |
|---|---|---|
| Headache | 34% | 23% |
| Nausea | 11% | 3% |
| Nervousness | 7% | 3% |
| Anxiety | 5% | 1% |
| Insomnia | 5% | 1% |
| Anorexia (loss of appetite) | 4% | 1% |
| Chest pain | 3% | 1% |
| Hypertension | 3% | 1% |
Headache and anxiety rose with dose. Overall, 8% of patients on modafinil stopped because of side effects, vs 3% on placebo.
Abuse potential
Modafinil is reinforcing in animals (monkeys trained on cocaine self-administer it). In people experienced with drugs of abuse, 200–800 mg produced euphoric and psychoactive effects similar to methylphenidate. The label advises close follow-up of people with a history of stimulant misuse. In one 9-week trial, no withdrawal symptoms were seen over 14 days after stopping, although sleepiness returned in patients with narcolepsy.
Pregnancy
Intrauterine growth restriction and miscarriage have been reported with modafinil and armodafinil, though it is unknown whether the drug caused them. Developmental toxicity occurred in rats and rabbits at exposures similar to human doses. There are no adequate studies in pregnant women.
Interactions
Modafinil induces CYP3A4 and inhibits CYP2C19, so it can lower or raise levels of other drugs (Provigil label):
| Interacting drug | Effect | Data from the label |
|---|---|---|
| Hormonal (steroidal) contraceptives | Lower levels; reduced contraceptive effectiveness | Ethinyl estradiol AUC −18%, peak −11% (modafinil 200 then 400 mg/day) |
| Triazolam (CYP3A4 substrate) | Lower levels | Peak −42%, AUC −59% |
| Cyclosporine | Lower levels | One transplant patient’s cyclosporine levels fell 50% after a month of 200 mg/day |
| Midazolam, quetiapine | Lower levels | Shown with armodafinil: oral midazolam −32%, quetiapine ≈−29% |
| CYP2C19 substrates (omeprazole, phenytoin, diazepam, propranolol, clomipramine) | Higher levels | Armodafinil raised omeprazole exposure 40% |
| Tricyclic antidepressants, SSRIs in CYP2D6 poor metabolizers | Higher levels | CYP2C19 becomes their backup pathway |
| Warfarin | Possible change in INR | No change after a single warfarin dose; more frequent INR monitoring advised |
| MAO inhibitors | Caution advised | — |
The contraceptive interaction is the most practically important. The label recommends an alternative or additional method of contraception while taking modafinil and for one month after stopping, including for depot and implantable contraceptives. Strong CYP3A4 inducers (carbamazepine, phenobarbital, rifampin) or inhibitors (ketoconazole, erythromycin) may also change modafinil levels.
Who should not use it
- People with known hypersensitivity to modafinil or armodafinil (the only labeled contraindication).
- Caution is advised in people with a history of psychosis, depression or mania, or with heart disease.
- It is not approved for children or adolescents.
Legal status and anti-doping
- US. Modafinil is listed in Schedule IV of the Controlled Substances Act under stimulants (21 CFR 1308.14). It is legal only with a prescription.
- EU. Authorized for narcolepsy only since the 2011 Commission decision (EMA).
- Sport. The WADA 2026 Prohibited List names modafinil in S6.A, non-Specified stimulants, prohibited in competition (WADA 2026 Prohibited List). The same section also lists adrafinil and the fluorinated analogs flmodafinil and fladrafinil.
Key takeaways
- An approved wakefulness drug, not a general “smart pill.” The FDA label covers excessive sleepiness from narcolepsy, OSA and shift work disorder, at 200 mg once daily; Europe now limits it to narcolepsy.
- Small effects in healthy people. Two meta-analyses found average effects of about 0.10–0.12 standard deviations in rested adults. Benefits are clearer under sleep deprivation, where users may also overrate their own performance.
- Acts on dopamine. Modafinil blocks the dopamine transporter in the human brain, which underlies its Schedule IV status and abuse potential.
- Rash is the key safety signal. Stevens-Johnson syndrome, TEN, DRESS and multi-organ reactions are reported; the label says to stop at the first sign of rash.
- Weakens hormonal contraception. Modafinil induces CYP3A4, lowering ethinyl estradiol levels; backup contraception is advised during use and for one month after.
- Banned in competition. WADA lists it as an S6.A non-Specified stimulant in 2026.
Sources
- Cephalon, LLC (Teva). Provigil (modafinil) tablets, for oral use, C-IV: prescribing information. DailyMed version March 2025. DailyMed.
- Code of Federal Regulations. 21 CFR 1308.14, Schedule IV, paragraph (f) Stimulants. eCFR.
- World Anti-Doping Agency. The 2026 Prohibited List, International Standard. In effect January 1, 2026. WADA.
- European Medicines Agency. Modafinil – referral under Article 31 of Directive 2001/83/EC (CHMP opinion 2010; European Commission decision January 27, 2011). EMA.
- Volkow ND, Fowler JS, Logan J, et al. Effects of modafinil on dopamine and dopamine transporters in the male human brain: clinical implications. JAMA. 2009;301(11):1148–1154. PubMed.
- Kredlow MA, Keshishian A, Oppenheimer S, Otto MW. The efficacy of modafinil as a cognitive enhancer: a systematic review and meta-analysis. J Clin Psychopharmacol. 2019;39(5):455–461. PubMed.
- Roberts CA, Jones A, Sumnall H, Gage SH, Montgomery C. How effective are pharmaceuticals for cognitive enhancement in healthy adults? A series of meta-analyses of cognitive performance during acute administration of modafinil, methylphenidate and D-amphetamine. Eur Neuropsychopharmacol. 2020;38:40–62. PubMed.
- Repantis D, Schlattmann P, Laisney O, Heuser I. Modafinil and methylphenidate for neuroenhancement in healthy individuals: a systematic review. Pharmacol Res. 2010;62(3):187–206. PubMed.
- Battleday RM, Brem AK. Modafinil for cognitive neuroenhancement in healthy non-sleep-deprived subjects: a systematic review. Eur Neuropsychopharmacol. 2015;25(11):1865–1881. PubMed.
- Turner DC, Robbins TW, Clark L, et al. Cognitive enhancing effects of modafinil in healthy volunteers. Psychopharmacology (Berl). 2003;165(3):260–269. PubMed.