|Trade names||Alertec, Modavigil, Modiodal, Provigil, Modalert|
|Licence data||US Daily Med:|
|Bioavailability||Not determined due to the aqueous insolubility|
|Metabolism||Hepatic (via CYP1A2, CYP3A4, and CYP2B6)|
|Molecular mass||273.35 g/mol|
|(what is this?)|
Modafinil is a wakefulness-promoting agent (or eugeroic) that is approved by the United States' Food and Drug Administration (FDA) for treatment of wakefulness disorders such as narcolepsy, shift work sleep disorder, and excessive daytime sleepiness associated with obstructive sleep apnea. In English-speaking countries it is sold under the brand names: Alertec (CA), Modavigil (AU, NZ), and Provigil (IE, ZA, UK, US).
- 1 Medical uses
- 2 Military and law enforcement
- 3 Adverse effects
- 4 Measurement in body fluids
- 5 Pharmacology
- 6 History
- 7 Patent protection and antitrust litigation
- 8 Legal status
- 9 Availability
- 10 See also
- 11 References
- 12 Further reading
- 13 External links
In 1998, modafinil was approved by the U.S. Food and Drug Administration for the treatment of narcolepsy and in 2003 for shift work sleep disorder and obstructive sleep apnea/hypopnea even though caffeine and amphetamine were shown to be more wakefulness promoting on the Stanford Sleepiness Test Score than modafinil. EEG studies indicate caffeine, amphetamine, and modafinil to all be theta wave reducing but only modafinil to be Alpha wave promoting during wakefulness as well as theta wave increasing during sleep.
Approval for attention deficit hyperactivity disorder (ADHD) in children was rejected in 2006 due primarily to two cases of skin rash, one severe, suspected to have been erythema multiforme or Stevens–Johnson syndrome, among 933 subjects receiving the drug. Cephalon's own label for Provigil now discourages its use by children for any purpose. In some countries, it is also approved for other hypersomnias, like idiopathic hypersomnia. The usual prescribed dosage for these disorders is 200 mg once a day (less commonly, 100 to 400 mg/day in one or two doses). Modafinil has also been linked in many articles to increasing concentration.
For conditions other than shift work sleep disorder, modafinil is normally taken in one dose in the morning or in two doses in the morning and at midday. It is generally not recommended to take modafinil after noon: modafinil is a relatively long-acting drug with a half-life of 15 hours, and taking it during the later part of the day carries a risk of sleep disturbances.[unreliable medical source?]
Because of the risk for development of skin or hypersensitivity reactions and neuropsychiatric disorders, the European Medicines Agency has recommended that new patient prescriptions should only be to treat sleepiness associated with narcolepsy. Because any serious side effects will usually appear within the first twelve weeks, the guidance does not require patients already receiving treatment to stop taking the drug.
Other potentially effective, but unapproved uses include the treatment of depression, bipolar depression, opiate and cocaine dependence, Parkinson's disease, schizophrenia, and disease-related fatigue, as well as fatigue that is the side effect of another medication.
A randomized double-blind study of modafinil showed that normal healthy volunteers between the ages of 30-44 showed general improvement in alertness as well as mood. In the three-day study, counterbalanced, randomized, crossover, inpatient trial of modafinil 400 mg was administered as well as a placebo to the control group. The conclusion demonstrated that modafinil may have general mood-elevating effects in particular for the adjunctive use in treatment-resistant depression.
Modafinil was shown to be an effective treatment for ADHD with a more favorable overall side effect profile to approved treatments, but it did not receive FDA approval due to concerns over the unusually high rate of 2 non-fatal cases of Stevens–Johnson syndrome out of 933 children.[further explanation needed]
There is disagreement to whether the cognitive effects modafinil showed in healthy non-sleep-deprived people are sufficient to consider it to be a cognitive enhancer. The researchers agree that modafinil improves some aspects of working memory, such as digit span, digit manipulation and pattern recognition memory, but the results related to spatial memory, executive function and attention are equivocal. Some of the positive effects of modafinil may be limited to "lower-performing" individuals. One study found that modafinil restored normal levels of learning ability in methamphetamine addicts, but had no effect on non-addicts.
In the 1980s, modafinil was used by French students. Recently modafinil has become popular in performance-enhancing use by university students and corporate executives in the United Kingdom. Some students obtain the drug through illicit means (diversion of prescribed medication), whilst others obtain it through online pharmacies.
Modafinil is also used off-label to treat sedation and fatigue in many conditions, including depression, fibromyalgia, chronic fatigue syndrome, myotonic dystrophy, opioid-induced sleepiness, spastic cerebral palsy, and Parkinson's disease. Modafinil has been shown to improve excessive daytime somnolence and fatigue in primary biliary cirrhosis.
It has been reported to reduce jet lag and increase subjective mood and friendliness among shift workers. It is also prescribed by sleep physicians for delayed sleep phase syndrome, which causes excessive daytime somnolence when the natural (delayed) diurnal rhythm is replaced by a socially determined earlier or forward shifted sleep schedule. The resultant wakefulness and neuro-behavioural impairments are comparable to those of travel-associated jet lag and persist as long as the forward shifted sleep schedule is maintained. A similar phenomenon commonly experienced by students and workers with varying sleep schedules during the week is often referred to as "social jet lag" and has been implicated in metabolic disorders and obesity.
Modafinil used alone has been reported to be effective in a subgroup of individuals with depersonalization disorder; the subgroup of people with depersonalization disorder most likely to respond are those who have attentional impairments, under-arousal, and hypersomnia. However, clinical trials have not been conducted. Dr. Evan Torch calls a combination of an SSRI and modafinil "the hidden pearl that can really help depersonalization disorder."
Modafinil has also found off-label use with the neurological fatigue reported by some with multiple sclerosis. In 2000, Cephalon conducted a study to evaluate modafinil as a potential treatment for MS-related fatigue. A group of 72 people with MS of varying degrees of severity tested two different doses of modafinil and an inactive placebo over nine weeks. Fatigue levels were self-evaluated on standardized scales. Participants taking a lower dose of modafinil reported feeling less fatigued and there was a statistically significant difference in fatigue scores for the lower dose versus the placebo. The higher dose of modafinil was not reported to be significantly more effective.
Modafinil is under investigation as a possible method to treat cocaine dependence, for several reasons involving biochemical mechanisms of the two drugs, as well as the observation that clinical effects of modafinil are largely opposite to symptoms of cocaine withdrawal.
The pilot 8-week double-blind study of modafinil for cocaine dependence (2004) produced inconclusive results. The number of cocaine-positive urine samples was significantly lower in the modafinil group as compared to the placebo group in the middle of the trial, but by the end of the 8 weeks the difference stopped being significant. Even before the treatment began, the modafinil group had lower cocaine consumption further confounding the results. As compared to placebo, modafinil did not reduce cocaine craving or self-reported cocaine use, and the physicians ratings were only insignificantly better. Dan Umanoff, of the National Association for the Advancement and Advocacy of Addicts, criticized the authors of the study for leaving the negative results out of the discussion part and the abstract of the article.
A later double-blind study of modafinil in people seeking treatment for cocaine dependence found no statistically significant effect on the rate of change in percentage of cocaine non-use days, but noted a significant improvement in some secondary outcomes such as the maximum number of consecutive non-use days for cocaine.
Post-chemotherapy cognitive impairment
Modafinil has been used off-label in trials with people with symptoms of post-chemotherapy cognitive impairment, also known as "chemobrain", but in 2011 it was found to be no better than placebo. As of 2011 there was no evidence to support using it to reduce fatigue in palliative care.
Studies on modafinil (even those on healthy weight individuals) indicate that it has an appetite reducing/weight loss effect. All studies on modafinil in the Medline database that are for one month or longer which report weight changes find that modafinil users experience weight loss compared to placebo. In 2008, one small-scale study on individuals performing simulated shift work quantified the effect as an 18% decrease in total caloric intake on 200 mg/day, and a 38% decrease on 400 mg/day.
However, the prescribing information for Provigil notes that "There were no clinically significant differences in body weight change in patients treated with Provigil compared to placebo-treated patients in the placebo-controlled clinical trials."
In experimental studies, the appetite reducing effect of modafinil appears to be similar to that of substituted amphetamines, but, unlike substituted amphetamines, the dose of modafinil that is effective at decreasing food intake does not significantly increase heart rate. Also, an article published in the Annals of Clinical Psychiatry, presented the case of a 280 pound patient (BMI=35.52) who lost 40 pounds over the course of a year on modafinil (to 30.44 BMI). After three years, his weight stabilized at a 50 pound weight loss (29.59 BMI). The authors conclude that placebo controlled studies should be conducted on using modafinil as a weight loss agent. Conversely, a US patent (#6,455,588) on using modafinil as an appetite stimulating agent has been filed by Cephalon in 2000.
Modafinil has received some publicity in the past when several athletes (such as sprinter Kelli White in 2004, cyclist David Clinger and basketball player Diana Taurasi in 2010) were discovered allegedly using it as a performance-enhancing doping agent. (Taurasi and another player, Monique Coker, tested at the same lab, were later cleared.) It is not clear how widespread this practice is. The BALCO scandal brought to light an as-yet unsubstantiated (but widely published) account of Major League Baseball's all-time leading home-run hitter Barry Bonds' supplemental chemical regimen that included modafinil in addition to anabolic steroids and human growth hormone. Modafinil has been shown to prolong exercise time to exhaustion while performing at 85% of VO2max and also reduces the perception of effort required to maintain this threshold. Modafinil was added to the World Anti-Doping Agency "Prohibited List" in 2004 as a prohibited stimulant (see Modafinil Legal Status).
Military and law enforcement
Militaries of several countries are known to have expressed interest in modafinil as an alternative to amphetamine—the drug traditionally employed in combat situations where troops face sleep deprivation, such as during lengthy missions. The French government indicated that the Foreign Legion used modafinil during certain covert operations. The United Kingdom's Ministry of Defence commissioned research into modafinil from QinetiQ and spent £300,000 on one investigation. In 2011, the Indian Air Force announced that modafinil was included in contingency plans. The Indian Armed Forces Medical Services is researching its use.
In the United States military, modafinil has been approved for use on certain Air Force missions, and it is being investigated for other uses. One study of helicopter pilots suggested that 600 mg of modafinil given in three doses can be used to keep pilots alert and maintain their accuracy at pre-deprivation levels for 40 hours without sleep; however, significant levels of nausea and vertigo were observed. A second helicopter study found modafinil was comparable to dextroamphetamine and was well-tolerated. Another study of fighter pilots showed that modafinil given in three divided 100 mg doses sustained the flight control accuracy of sleep-deprived F-117 pilots to within about 27 percent of baseline levels for 37 hours, without any considerable side effects. In an 88-hour sleep loss study of simulated military grounds operations, 400 mg/day doses were mildly helpful at maintaining alertness and performance of subjects compared to placebo, but the researchers concluded that this dose was not high enough to compensate for most of the effects of complete sleep loss. In law enforcement, tactical paramedics in Maryland (US) may administer 200 mg of modafinil once daily in order to "enhance alertness / concentration" and "facilitate functioning with limited rest periods."
The Canadian Medical Association Journal also reports that modafinil is used by astronauts on long-term missions aboard the International Space Station. Modafinil is "available to crew to optimize performance while fatigued" and helps with the disruptions in circadian rhythms and with the reduced quality of sleep astronauts experience. Modafinil is a prescription drug in Canada
Contraindications and warnings
Literature distributed by maker Cephalon advises that it is important to consult a physician before using modafinil, particularly for those with:
- Hypersensitivity to the drug or other constituents of the tablets (such as lactose or lactose monohydrate), or
- Previous cardiovascular problems, particularly while using other stimulants, or
- Cirrhosis, or
- Cardiac conditions, particularly:
- Modafinil can make certain types of birth control pills less effective, which could result in an unplanned pregnancy.
Although a nootropic, Modafinil is less likely than its parent drug, adrafinil, to cause side effects such as stomach pain, skin irritation, anxiety, and (with prolonged use) elevated liver enzymes. The patient should be aware that placebo-controlled clinical trials cannot be used to predict the frequency of adverse experiences in the course of usual medical practice, where patient characteristics and other factors may differ from those occurring during clinical studies. Patient control group's reported effects during clinical trials include:
- Headache (~34%)
- Nausea (~11%)
- Nervousness (~7%)
- Diarrhea (~6%)
- Insomnia (~5%)
- Anxiety (~5%)
- Dizziness (~5%)
- Dyspepsia (~5%)
- Dry Mouth (~4%)
- Anorexia (~4%)
- Flu Syndrome (~4%)
- Chest Pain (~3%)
- Depression (~2%)
- Chills (~1%)
- Neck Rigidity (~1%)
Serious side effects include:
- Serious rash
- Serious allergic reaction involving the liver or blood cells
- Mouth sores
- Blistering or peeling skin
- Swelling of the face, eyes, lips, tongue, legs, or throat
- Trouble swallowing or breathing
- Shortness of breath
In 2007, the FDA ordered Cephalon to modify the Provigil leaflet in bold-face print of several serious and potentially fatal conditions attributed to modafinil use, including toxic epidermal necrolysis (TEN), DRESS syndrome, and Stevens-Johnson syndrome (SJS).
The long term safety and effectiveness of modafinil have not been determined.
In mice and rats, the median lethal dose (LD50) of modafinil is approximately or slightly greater than 1250 mg/kg. Oral LD50 values reported for rats range from 1000 mg/kg to 3400 mg/kg. Intravenous LD50 for dogs is 300 mg/kg. Clinical trials on humans involving taking up to 1200 mg/day for 7 to 21 days and known incidents of acute one-time overdoses up to 4500 mg did not appear to cause life-threatening effects, although a number of adverse experiences were observed, including excitation or agitation, insomnia, anxiety, irritability, aggressiveness, confusion, nervousness, tremor, palpitations, sleep disturbances, nausea, and diarrhea. As of 2004, the FDA is not aware of any fatal overdoses involving modafinil alone (as opposed to multiple drugs, including modafinil). Consequently, oral LD50 of modafinil in humans is not known exactly. However, it appears to be higher than oral LD50 of caffeine. Bastuji and Jouvet describe a suicide attempt using 4500 mg of modafinil; the patient survived with no long-term effects but temporary nervousness, nausea, and insomnia. A similar incident involving a suicide attempt by a 15-year-old female using 5000 mg of the drug (102 mg/kg) was observed in 2008 in Israel; the patient experienced severe headache, nausea, abdominal pain, dyskinesia, insomnia, and mild tachycardia, but no cardiovascular distress or abnormalities in liver and kidney function, and recovered in a few days without any apparent long-term effects.
Modafinil may induce severe dermatologic reactions requiring hospitalization. From the date of initial marketing, December 1998, to January 30, 2007, FDA received six cases of severe cutaneous adverse reactions associated with modafinil, including erythema multiforme (EM), SJS, TEN, and DRESS involving adult and pediatric patients. The FDA issued a relevant alert. In the same alert, the FDA also noted that angioedema and multi-organ hypersensitivity reactions have also been reported in postmarketing experience.
A National Institute on Alcohol Abuse and Alcoholism (NIAAA) study highlighted "the need for heightened awareness for potential abuse of and dependence on modafinil in vulnerable populations" due to the drug's effect on dopamine in the brain's reward center. However, the synergistic actions of modafinil on both catecholaminergic and histaminergic pathways lower abuse potential as compared to traditional stimulant drugs while maintaining the effectiveness of the drug as a wakefulness-promoting agent. Studies have suggested that modafinil "has limited potential for large-scale abuse" and "does not possess an addictive potential in naive individuals."
Measurement in body fluids
Modafinil and/or its major metabolite, modafinilic acid, may be quantified in plasma, serum or urine to monitor dosage in those receiving the drug therapeutically, to confirm a diagnosis of poisoning in hospitalized patients or to assist in the forensic investigation of a vehicular traffic violation. Instrumental techniques involving gas or liquid chromatography are usually employed for these purposes. As of 2011, it is not specifically tested for by common drug screens (with the exception of anti-doping screens) and is unlikely to cause false positives for other chemically-unrelated drugs such as substituted amphetamines.
Modafinil induces the cytochrome P450 enzymes CYP1A2, CYP3A4, and CYP2B6, as well as inhibiting CYP2C9 and CYP2C19 in vitro. It may also induce P-glycoprotein (Pgp), which may affect drugs transported by Pgp, such as digoxin. The bioavailability of modafinil is greater than 80% of the administered dose. In vitro measurements indicate that 60% of modafinil is bound to plasma proteins at clinical concentrations of the drug. This percentage actually changes very little when the concentration is varied. Cmax (peak levels) occurs approximately 2–3 hours after administration. Food slows absorption, but does not affect the total AUC[clarification needed](AUC - area under the curve - meaning, food may slow absorption, but the total amount of the chemical will be absorbed with or without food). Half-life is generally in the 10–12 hour range, subject to differences in CYP genotypes, liver function and renal function. It is metabolized in the liver, and its inactive metabolite is excreted in the urine. Urinary excretion of the unchanged drug ranges from 0% to as high as 18.7%, depending on various factors.
Modafinil's efficacy in improving vigor and well-being in sleep deprivation subjects is dependent on COMT status. Research suggests that individuals with the Val/Val genotype experience a great improvement in their cognitive function, while those with the Met/Met genotype experience very little improvement.
Despite extensive research into the interaction of modafinil with a large number of neurotransmitter systems, its precise mechanism or mechanisms of action remain unclear. Modafinil elevates hypothalamic histamine levels, leading some researchers to consider modafinil a "wakefulness-promoting agent" rather than a classic amphetamine-like stimulant. Modafinil seems to inhibit the reuptake action of the dopamine transporter, thus leading to an increase in extracellular and thus synaptic concentrations of dopamine.
The locus of the monoamine action of modafinil has also been the target of studies, identifying effects on dopamine in the striatum and nucleus accumbens, norepinephrine in the hypothalamus and ventrolateral preoptic nucleus, and serotonin in the amygdala and frontal cortex.
A considered mechanism of action involves brain peptides called orexins, also known as hypocretins. Orexin neurons are found in the hypothalamus but project to many different parts of the brain, including several areas that regulate wakefulness. Activation of these neurons increases dopamine and norepinephrine in these areas, and excites histaminergic tuberomammillary neurons increasing histamine levels there. It has been shown in rats that modafinil increases histamine release in the brain, and this may be a possible mechanism of action in humans. There are two orexin receptors, namely orexin receptor 1 (OX1/hcrt1) and orexin receptor 2 (OX2/hcrt2). Animals with defective orexin systems exhibit signs and symptoms similar to narcolepsy, for treatment of which modafinil is FDA-approved. Modafinil seems to activate these orexin neurons in animal models, which would be expected to promote wakefulness. However, modafinil is also able to promote wakefulness with similar efficacy to amphetamine in dogs with complete loss-of-function mutations in orexin receptor 2, suggesting that orexin activation is not required for these effects of modafinil. Additionally, a study of orexin-knockout mice found that not only did modafinil promote wakefulness in these mice, but that it did so even more effectively than in wild-type mice.
Modafinil's substantial, but incomplete, independence from both monoaminergic systems and those of the orexin peptides has proven difficult to explain, in contrast to the better-understood mechanisms of stimulants such as cocaine or substituted amphetamines. Alternative mechanisms of action that have been proposed include the activation of glutamatergic circuits while inhibiting GABAergic neurotransmission. Enhanced electrotonic coupling by enhancing the effectiveness of direct gap junctions between neurons has also been suggested by several studies. Most neurons are separated by synapses, and communication between cells is accomplished via release and diffusion of neurotransmitters. However, some neurons are directly connected to one another via gap junctions, and it is proposed that modafinil influences the effectiveness of these connections. Modafinil increased activity via this mechanism in the thalamocortical loop, which is critical in organizing sensory input and modulating global brain activity. Administration of the gap junction blocker mefloquine abolished this effect, providing good evidence that this result was a consequence of improved electrical coupling. The calmodulin kinase II (CaMKII) inhibitor, KN-93, abolishes modafinil's enhancement of electrotonic coupling. Modafinil's effect is mediated, at least in part, by a CaMKII-dependent exocytosis of gap junctions between GABAergic interneurons and possibly even glutamatergic pyramidal cells. Additionally modafinil has pro electrotonic effects on specific populations of neurons in two sites in the reticular activating system. These sites, the subcoeruleus nucleus and the pedunculopontine nucleus, are thought to enhance arousal via cholinergic inputs to the thalamus.
Looking more closely at electrotonic coupling, gap junctions permit the diffusion of current across linked cells and result in higher resistance to action potential induction since excitatory post-synaptic potentials must diffuse across a greater membrane area. This means, however, that when action potentials do arise in coupled cell populations, the entire populations tend to fire in a synchronized manner. Thus enhanced electrotonic coupling results in lower tonic activity of the coupled cells while increasing rhythmicity. Agreeing with data implicating catecholaminergic mechanisms, modafinil increases phasic activity in the locus coeruleus (the source for CNS norepinephrine) while reducing tonic activity with respect to interconnections with the prefrontal cortex. This implies an increased signal-to-noise ratio in the circuits connecting the two regions. Greater neuronal coupling theoretically could enhance gamma band rhythmicity, a potential explanation for modafinil's nootropic effects. Modafinil's beneficial effects on working memory and motor networks are suggestive of heightened gamma band activity.
Administration of modafinil enhances arousal-specific P13 evoked potentials in a gap-junction dependent manner which provides a direct link between electrotonic coupling and wakefulness. Tying into inconclusive effects on monoamine systems, enhanced electrotonic coupling is thought to reduce activity in localized populations of GABAergic neurons whose normal function is to reduce neurotransmitter release in other cells. For example, dopamine release in the nucleus accumbens has been demonstrated to be the result of decreased GABAergic tone. Thus, while modafinil's unique stimulant profile features interactions with monoamine systems, these may very well be downstream events secondary to effects on specific, electrotonically-coupled populations of GABAergic interneurons. It is likely that modafinil's exact pharmacology will feature the interaction of direct effects on electrotonic coupling and various receptor-mediated events.
Recently, modafinil was screened at a large panel of receptors and transporters in an attempt to elucidate its pharmacology. Of the sites tested, it was found to significantly act only on the dopamine transporter (DAT), inhibiting the reuptake of dopamine with an IC50 value of 4 μM. Accordingly, it increases locomotor activity and extracellular dopamine concentrations in a manner similar to the selective dopamine reuptake inhibitor vanoxerine, and also blocks methamphetamine-induced dopamine release. As a result, it appears that modafinil exerts its effects by acting as a weak dopamine reuptake inhibitor, though it cannot be ruled out that other mechanisms may also be at play. On account of its action as a dopamine reuptake inhibitor and lack of abuse potential, modafinil was suggested as a treatment for methamphetamine addiction by the authors of the study.
The (R)-enantiomer of modafinil, known as armodafinil, has also recently been found to act as a D2 receptor partial agonist, with a Ki of 16 nM, an intrinsic activity of 48%, and an EC50 of 120 nM, in rat striatal tissue. The (S)-enantiomer is inactive with respect to the D2 receptor (Ki > 10,000).
Modafinil was originally developed in France by neurophysiologist and emeritus experimental medicine professor Michel Jouvet and Lafon Laboratories. Modafinil originated with the late 1970s invention of a series of benzhydryl sulfinyl compounds, including adrafinil, which was first offered as an experimental treatment for narcolepsy in France in 1986. Modafinil is the primary metabolite of adrafinil, lacking the polar -OH group on its terminal amide, and has similar activity to the parent drug but is much more widely used. It has been prescribed in France since 1994 under the name Modiodal, and in the US since 1998 as Provigil. It was approved for use in the UK in December 2002. Modafinil is marketed in the US by Cephalon Inc., who originally leased the rights from Lafon, but eventually purchased the company in 2001.
Cephalon began to market the R-enantiomer armodafinil of modafinil in the U.S. in 2007. After protracted patent litigation and negotiations (see below), generic versions of modafinil became available in the U.S. in 2012.
Patent protection and antitrust litigation
U.S. Patent 4,927,855 was issued to Laboratoire L. Lafon on May 22, 1990, covering the chemical compound modafinil. After receiving an interim term extension of 1066 days and pediatric exclusivity of six months, it expired on October 22, 2010. On October 6, 1994, Cephalon filed an additional patent, covering modafinil in the form of particles of defined size. That patent, U.S. Patent 5,618,845 was issued on April 8, 1997, but was reissued in 2002 as RE 37,516, which surrendered the 5618845 patent. With pediatric exclusivity, this patent was due to expire on April 6, 2015.
On December 24, 2002, anticipating the expiration of exclusive marketing rights, generic drug manufacturers Mylan, Teva, Barr, and Ranbaxy applied to the FDA to market a generic form of modafinil. At least one withdrew its application after early opposition by Cephalon based on the '516 patent. There is some question as to whether a particle size patent is sufficient protection against the manufacture of generics. Pertinent questions include whether modafinil may be modified or manufactured to avoid the granularities specified in the new Cephalon patent, and whether patenting particle size is invalid because particles of appropriate sizes are likely to be obvious to practitioners skilled in the art. However, under United States patent law, a patent is entitled to a legal presumption of validity, meaning that in order to invalidate the patent, much more than "pertinent questions" are required.
As of October 31, 2011, U.S. Reissue Patent No. RE 37,516 has been declared invalid and unenforceable. The District Court for the Eastern District of Pennsylvania ruled that RE 37,516 was invalid because it: (1) was on sale more than one year prior to the date of the application in violation of 35 U.S.C. section 102(b); (2) was actually invented by someone else (the French company Laboratoire L. Lafon); (3) was obvious at the time the invention was made to a person having ordinary skill in the art under 35 U.S.C. section 103(a); and (4) failed the written description requirement of 35 U.S.C. section 112. The patent was also found to be unenforceable due to Cephalon's inequitable conduct during patent prosecution.
Cephalon made an agreement with four major generics manufacturers Teva, Barr Pharmaceuticals, Ranbaxy Laboratories, and Watson Pharmaceuticals between 2005 and 2006 to delay sales of generic modafinil in the US until April 2012 by these companies in exchange for upfront and royalty payments. Litigation arising from these agreements is still pending including an FTC suit filed in April 2008. Apotex received regulatory approval in Canada despite a suit from Cephalon's marketing partner in Canada, Shire Pharmaceuticals. Cephalon has sued Apotex in the US to prevent it from releasing a genericized armodafinil (Nuvigil). Cephalon's 2011 attempt to merge with Teva was approved by the FTC under a number of conditions, including granting generic US rights to another company; ultimately, Par Pharmaceutical acquired the US modafinil rights as well as some others.
Modafinil is currently[update] classified as a Schedule IV controlled substance under United States federal law; it is illegal to import by anyone other than a DEA-registered importer without a prescription. However, one may legally bring modafinil into the United States in person from a foreign country, provided that he or she has a prescription for it, and the drug is properly declared at the border crossing. U.S. residents are limited to 50 dosage units (i.e., pills). Under the US Food and Drug Act, drug companies are not allowed to market their drugs for off-label uses (conditions other than those officially approved by the FDA); Cephalon was reprimanded in 2002 by the FDA because its promotional materials were found to be "false, lacking in fair balance, or otherwise misleading". Cephalon pled guilty to a criminal violation and paid several fines, including $50 million and $425 million fines to the U.S. government in 2008.
The following countries do not classify modafinil as a controlled substance:
- Canada (not listed in the Controlled Drugs and Substances Act, but it is a Schedule F prescription drug, so it is subject to seizure by Canada Border Services Agency)
- Mexico (Not listed as a controlled substance, in the National Health Law)
- United Kingdom (not listed in the Misuse of Drugs Act and is available without legal restrictions by prescription)
- Australia (listed as a Schedule 4 prescription drug)
- In Germany the classification has been changed from controlled substance (BtM) to prescription drug (RP) effective March 1, 2008.
- In India, generic retailing as Modalert is available from Sun Pharmaceuticals; Indian firms are not required to respect patents filed before 1995.
Currently, use of modafinil is controversial in the sporting world, with high-profile cases attracting press coverage since several prominent American athletes have tested positive for the substance (see modafinil as a doping agent). Some athletes who were found to have used modafinil protested that the drug was not on the prohibited list at the time of their offenses. However, the World Anti-Doping Agency (WADA) maintains that it was related to already banned substances. The Agency added modafinil to its list of prohibited substances on August 3, 2004, ten days before the start of the 2004 Summer Olympics.
Modafinil is sold under a wide variety of brand names worldwide, including:
- Alertec - Canada, Ecuador
- BravaMax - Egypt, Morocco
- Carim - El Salvador, Guatemala, Honduras, Colombia, Ecuador, Uruguay
- Provake - India (also Modalert, Modapro, Modafil, Modvigil, Modatec)
- Modasomil Austria, Switzerland
- Modavigil - Australia, New Zealand
- Modiodal - Mexico, Philippines, Spain, France, Denmark, Iceland, Greece, Cyprus, Netherlands, Portugal, Sweden, Norway, Turkey, Japan, Iran
- Modiwake - Turkey
- Provigil - Belgium, Ireland, Italy, South Korea, United Kingdom, United States, South Africa, Israel, Finland
- Resotyl - Chile (also Mentix, Alertex, Zalux)
- Stavigile - Brazil
- Vigia - Colombia
- Vigicer - Argentina
- Vigil - Germany
- V-Zac - Pakistan
- "Modafinil: The Pharmacology of Vigilance | Socraticism". Socraticism.wordpress.com. December 21, 2008. Retrieved December 31, 2013.
- Engber TM, Koury EJ, Dennis SA, Miller MS, Contreras PC, Bhat RV (January 1998). "Differential patterns of regional c-Fos induction in the rat brain by amphetamine and the novel wakefulness-promoting agent modafinil". Neurosci. Lett. 241 (2-3): 95–8. PMID 9507929.
- Erman MK, Rosenberg R (2007). "Modafinil for excessive sleepiness associated with chronic shift work sleep disorder: effects on patient functioning and health-related quality of life". Prim Care Companion J Clin Psychiatry 9 (3): 188–94. doi:10.4088/PCC.v09n0304. PMC 1911168. PMID 17632651.
- Czeisler CA, Walsh JK, Roth T, Hughes RJ, Wright KP, Kingsbury L, Arora S, Schwartz JR, Niebler GE, Dinges DF (August 2005). "Modafinil for excessive sleepiness associated with shift-work sleep disorder". N. Engl. J. Med. 353 (5): 476–86. doi:10.1056/NEJMoa041292. PMID 16079371.
- "PROVIGIL® (modafinil) – Home". Cephalon, Inc.
- Healy, Melissa (May 2, 2013). "Use of wake-up drug modafinil takes off, spurred by untested uses - Los Angeles Times". LA Times. Retrieved December 31, 2013.
- Kesselheim AS, Myers JA, Solomon DH, Winkelmayer WC, Levin R, Avorn J (February 21, 2012). Alessi-Severini, Silvia, ed. "The prevalence and cost of unapproved uses of top-selling orphan drugs". PLoS ONE 7 (2): e31894. doi:10.1371/journal.pone.0031894. PMC 3283698. PMID 22363762.
- "www.fda.gov". Retrieved August 7, 2010.
- "Modafinil ( Provigil )". Retrieved August 7, 2010.
- Rugino T (June 2007). "A review of modafinil film-coated tablets for attention-deficit/hyperactivity disorder in children and adolescents". Neuropsychiatr Dis Treat 3 (3): 293–301. PMC 2654790. PMID 19300563.
- Mechcatie, Elizabeth (2006). "FDA cites Stevens-Johnson in modafinil's ADHD rejection | Clinical Psychiatry News | Find Articles at BNET". Clinical Psychiatry News. Retrieved August 7, 2010.
- Biederman J, Pliszka SR (March 2008). "Modafinil improves symptoms of attention-deficit/hyperactivity disorder across subtypes in children and adolescents". J. Pediatr. 152 (3): 394–9. doi:10.1016/j.jpeds.2007.07.052. PMID 18280848.
- "Provigil (modafinil)". (U.S.) National Multiple Sclerosis Society. Retrieved December 31, 2013.[unreliable medical source?]
- "Use of Cephalon's Provigil could be limited in Europe". Reuters. July 22, 2010.
- European Medicines Agency, EMA/725532/2010 rev. "Questions and answers on the review of medicines containing Modafinil" 27 January 2011 Text
- Fava M, Thase ME, DeBattista C, Doghramji K, Arora S, Hughes RJ (2007). "Modafinil augmentation of selective serotonin reuptake inhibitor therapy in MDD partial responders with persistent fatigue and sleepiness". Ann Clin Psychiatry 19 (3): 153–9. doi:10.1080/10401230701464858. PMID 17729016.
- Frye MA, Grunze H, Suppes T, McElroy SL, Keck PE, Walden J, Leverich GS, Altshuler LL, Nakelsky S, Hwang S, Mintz J, Post RM (August 2007). "A placebo-controlled evaluation of adjunctive modafinil in the treatment of bipolar depression". Am J Psychiatry 164 (8): 1242–9. doi:10.1176/appi.ajp.2007.06060981. PMID 17671288.
- Calabrese JR, Ketter TA, Youakim JM, Tiller JM, Yang R, Frye MA (October 2010). "Adjunctive armodafinil for major depressive episodes associated with bipolar I disorder: a randomized, multicenter, double-blind, placebo-controlled, proof-of-concept study". J Clin Psychiatry 71 (10): 1363–70. doi:10.4088/JCP.09m05900gry. PMID 20673554.
- Tahsili-Fahadan P, Carr GV, Harris GC, Aston-Jones G (October 2010). "Modafinil blocks reinstatement of extinguished opiate-seeking in rats: mediation by a glutamate mechanism". Neuropsychopharmacology 35 (11): 2203–10. doi:10.1038/npp.2010.94. PMC 2939923. PMID 20631691.
- Dackis CA, Kampman KM, Lynch KG, Pettinati HM, O'Brien CP (January 2005). "A double-blind, placebo-controlled trial of modafinil for cocaine dependence". Neuropsychopharmacology 30 (1): 205–11. doi:10.1038/sj.npp.1300600. PMID 15525998.
- van Vliet SA, Vanwersch RA, Jongsma MJ, van der Gugten J, Olivier B, Philippens IH (September 2006). "Neuroprotective effects of modafinil in a marmoset Parkinson model: behavioral and neurochemical aspects". Behav Pharmacol 17 (5–6): 453–62. doi:10.1097/00008877-200609000-00011. PMID 16940766.
- Turner DC, Clark L, Pomarol-Clotet E, McKenna P, Robbins TW, Sahakian BJ (July 2004). "Modafinil improves cognition and attentional set shifting in patients with chronic schizophrenia". Neuropsychopharmacology 29 (7): 1363–73. doi:10.1038/sj.npp.1300457. PMID 15085092.
- Rammohan KW, Rosenberg JH, Lynn DJ, Blumenfeld AM, Pollak CP, Nagaraja HN (February 2002). "Efficacy and safety of modafinil (Provigil®) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study". J. Neurol. Neurosurg. Psychiatr. 72 (2): 179–83. doi:10.1136/jnnp.72.2.179. PMC 1737733. PMID 11796766.
- Rabkin JG, McElhiney MC, Rabkin R, Ferrando SJ (December 2004). "Modafinil treatment for fatigue in HIV+ patients: a pilot study". J Clin Psychiatry 65 (12): 1688–95. doi:10.4088/JCP.v65n1215. PMID 15641875.
- Schwartz TL, Azhar N, Cole K, Hopkins G, Nihalani N, Simionescu M, Husain J, Jones N (September 2004). "An open-label study of adjunctive modafinil in patients with sedation related to serotonergic antidepressant therapy". J Clin Psychiatry 65 (9): 1223–7. doi:10.4088/JCP.v65n0910. PMID 15367049.
- Lundt L (August 2004). "Modafinil treatment in patients with seasonal affective disorder/winter depression: an open-label pilot study". J Affect Disord 81 (2): 173–8. doi:10.1016/S0165-0327(03)00162-9. PMID 15306145.
- Turner DC, Robbins TW, Clark L, Aron AR, Dowson J, Sahakian BJ (2003). "Cognitive enhancing effects of modafinil in healthy volunteers". Psychopharmacology (Berl.) 165 (3): 260–9. doi:10.1007/s00213-002-1250-8. PMID 12417966.
- Randall DC, Viswanath A, Bharania P, Elsabagh SM, Hartley DE, Shneerson JM, File SE (2005). "Does modafinil enhance cognitive performance in young volunteers who are not sleep-deprived?". J Clin Psychopharmacol 25 (2): 175–9. doi:10.1097/01.jcp.0000155816.21467.25. PMID 15738750.
- Baranski JV, Pigeau R, Dinich P, Jacobs I (2004). "Effects of modafinil on cognitive and meta-cognitive performance". Hum Psychopharmacol 19 (5): 323–32. doi:10.1002/hup.596. PMID 15252824.
- Müller U, Steffenhagen N, Regenthal R, Bublak P (2004). "Effects of modafinil on working memory processes in humans". Psychopharmacology (Berl.) 177 (1–2): 161–9. doi:10.1007/s00213-004-1926-3. PMID 15221200.
- Randall DC, Shneerson JM, File SE (2005). "Cognitive effects of modafinil in student volunteers may depend on IQ". Pharmacol. Biochem. Behav. 82 (1): 133–9. doi:10.1016/j.pbb.2005.07.019. PMID 16140369.
- Ghahremani DG, Tabibnia G, Monterosso J, Hellemann G, Poldrack RA, London ED (April 2011). "Effect of modafinil on learning and task-related brain activity in methamphetamine-dependent and healthy individuals". Neuropsychopharmacology 36 (5): 950–9. doi:10.1038/npp.2010.233. PMC 3077264. PMID 21289606.
- Dorozynski A (June 1989). "News: Sleepless pill". BMJ 298 (6687): 1541–1546. doi:10.1136/bmj.298.6687.1541. (registration required (. ))
Professor Jouvet, however, believes that it could benefit children who tend to fall asleep in class, and added: "I have known young girls who didn't stay down in class, who passed their 'bac' and went on to the university thanks to this treatment. I have the impression of having rendered them a very good service.
- Nixey C (April 6, 2010). "Are 'smart drugs' safe for students?". The Guardian (London). Retrieved May 13, 2010.
- Menza MA, Kaufman KR, Castellanos A (May 2000). "Modafinil augmentation of antidepressant treatment in depression". J Clin Psychiatry 61 (5): 378–81. doi:10.4088/JCP.v61n0510. PMID 10847314.
- DeBattista C, Lembke A, Solvason HB, Ghebremichael R, Poirier J (February 2004). "A prospective trial of modafinil as an adjunctive treatment of major depression". J Clin Psychopharmacol 24 (1): 87–90. doi:10.1097/01.jcp.0000104910.75206.b9. PMID 14709953.
- MacDonald JR, Hill JD, Tarnopolsky MA (December 2002). "Modafinil reduces excessive somnolence and enhances mood in patients with myotonic dystrophy". Neurology 59 (12): 1876–80. doi:10.1212/01.WNL.0000037481.08283.51. PMID 12499477.
- Webster L, Andrews M, Stoddard G (June 2003). "Modafinil treatment of opioid-induced sedation". Pain Med 4 (2): 135–40. doi:10.1046/j.1526-4637.2003.03014.x. PMID 12873263.
- Hurst DL, Lajara-Nanson W (March 2002). "Use of modafinil in spastic cerebral palsy". J. Child Neurol. 17 (3): 169–72. doi:10.1177/088307380201700303. PMID 12026230.
- Nieves AV, Lang AE (2002). "Treatment of excessive daytime sleepiness in patients with Parkinson's disease with modafinil". Clin Neuropharmacol 25 (2): 111–4. doi:10.1097/00002826-200203000-00010. PMID 11981239.
- O'Connor, Anahad (June 29, 2004). "Wakefulness Finds a Powerful Ally". New York Times. Retrieved December 31, 2013.
- Hart CL, Haney M, Vosburg SK, Comer SD, Gunderson E, Foltin RW (July 2006). "Modafinil attenuates disruptions in cognitive performance during simulated night-shift work". Neuropsychopharmacology 31 (7): 1526–36. doi:10.1038/sj.npp.1300991. PMID 16395298.
- Grady S, Aeschbach D, Wright KP, Czeisler CA (August 2010). "Effect of modafinil on impairments in neurobehavioral performance and learning associated with extended wakefulness and circadian misalignment". Neuropsychopharmacology 35 (9): 1910–20. doi:10.1038/npp.2010.63. PMC 2904872. PMID 20505660.
- Balbo M, Leproult R, Van Cauter E (2010). "Impact of sleep and its disturbances on hypothalamo-pituitary-adrenal axis activity". Int J Endocrinol 2010: 759234. doi:10.1155/2010/759234. PMC 2902103. PMID 20628523.
- Mauricio Sierra (August 13, 2009). Depersonalization: A New Look at a Neglected Syndrome. Cambridge, UK: Cambridge University Press. p. 120. ISBN 0-521-87498-X.
- Simeon D, Abugel J (2006). Feeling Unreal: Depersonalization Disorder and the Loss of the Self. p. 256. ISBN 978-0-19-517022-1.
- Hyland, MJ (May 3, 2013). "The drugs do work: my life on brain enhancers | Life and style". London: The Guardian. Retrieved December 31, 2013.
- Rammohan KW, Rosenberg JH, Lynn DJ, Blumenfeld AM, Pollak CP, Nagaraja HN (February 2002). "Efficacy and safety of modafinil (Provigil) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study". J. Neurol. Neurosurg. Psychiatr. 72 (2): 179–83. doi:10.1136/jnnp.72.2.179. PMC 1737733. PMID 11796766.
- Frost J, Okun S, Vaughan T, Heywood J, Wicks P (2011). "Patient-reported outcomes as a source of evidence in off-label prescribing: analysis of data from PatientsLikeMe". Journal of Medical Internet Research 13 (1): e6. doi:10.2196/jmir.1643. PMC 3221356. PMID 21252034.
- Dackis CA, Kampman KM, Lynch KG, Pettinati HM, O'Brien CP (2005). "A double-blind, placebo-controlled trial of modafinil for cocaine dependence". Neuropsychopharmacology 30 (1): 205–11. doi:10.1038/sj.npp.1300600. PMID 15525998.
- Umanoff DF (2005). "Trial of modafinil for cocaine dependence". Neuropsychopharmacology 30 (12): 2298; author reply 2299–300. doi:10.1038/sj.npp.1300866. PMID 16294193.
- Dackis CA, Kampman KM, Lynch KG, Pettinati HM, O'Brien CP (2005). "Reply: Do Self-Reports Reliably Assess Abstinence in Cocaine-Dependent Patients?". Neuropsychopharmacology 30 (12): 2299–300. doi:10.1038/sj.npp.1300867.
- Anderson AL, Reid MS, Li SH, Holmes T, Shemanski L, Slee A, Smith EV, Kahn R, Chiang N, Vocci F, Ciraulo D, Dackis C, Roache JD, Salloum IM, Somoza E, Urschel HC, Elkashef AM (September 2009). "Modafinil for the treatment of cocaine dependence". Drug Alcohol Depend 104 (1–2): 133–9. doi:10.1016/j.drugalcdep.2009.04.015. PMC 2818032. PMID 19560290.
- Portela MA, Rubiales AS, Centeno C (June 2011). "The use of psychostimulants in cancer patients". Current Opinion in Supportive and Palliative Care 5 (2): 164–8. doi:10.1097/SPC.0b013e3283462ff3. PMID 21532350.
- Peuckmann V, Elsner F, Krumm N, Trottenberg P, Radbruch L (2010). Radbruch, Lukas, ed. "Pharmacological treatments for fatigue associated with palliative care". Cochrane Database Syst Rev (11): CD006788. doi:10.1002/14651858.CD006788.pub2. PMID 21069692.
- Henderson DC, Louie PM, Koul P, Namey L, Daley TB, Nguyen DD (2005). "Modafinil-associated weight loss in a clozapine-treated schizoaffective disorder patient". Ann Clin Psychiatry 17 (2): 95–7. doi:10.1080/10401230590932407. PMID 16075662.
- "Efficacy and Safety of Modafinil Film-Coated Tablets in Children and Adolescents" (PDF). Retrieved July 4, 2012.
- Vaishnavi S, Gadde K, Alamy S, Zhang W, Connor K, Davidson JR (August 2006). "Modafinil for atypical depression: effects of open-label and double-blind discontinuation treatment". J Clin Psychopharmacol 26 (4): 373–8. doi:10.1097/01.jcp.0000227700.263.75.39. PMID 16855454.
- Thase ME, Fava M, DeBattista C, Arora S, Hughes RJ (February 2006). "Modafinil augmentation of SSRI therapy in patients with major depressive disorder and excessive sleepiness and fatigue: a 12-week, open-label, extension study". CNS Spectr 11 (2): 93–102. PMID 16520686.
- Makris AP, Rush CR, Frederich RC, Kelly TH (April 2004). "Wake-promoting agents with different mechanisms of action: comparison of effects of modafinil and amphetamine on food intake and cardiovascular activity". Appetite 42 (2): 185–95. doi:10.1016/j.appet.2003.11.003. PMID 15010183.
- Perez GA, Haney M, Foltin RW, Hart CL (October 2008). "Modafinil decreases food intake in humans subjected to simulated shift work". Pharmacol. Biochem. Behav. 90 (4): 717–22. doi:10.1016/j.pbb.2008.05.018. PMID 18573275.
- "Provigil". Medication Guide. Cephalon, Inc. November 1, 2010. Retrieved December 31, 2013.
- "Clinger given lifetime ban for second doping infraction". Cycling News. August 14, 2011. Retrieved 8 October 2014.
- "Taurasi tested positive for modafinil". The Washington Post. December 25, 2010. Retrieved December 31, 2013.
- Voepel M (February 18, 2011). "Taurasi: 'I've lost 3 months of my career'".
- "Bonds Exposed". Sports Illustrated. March 7, 2006. Retrieved July 2, 2011.
- Jacobs I, Bell DG (2004). "Effects of acute modafinil ingestion on exercise time to exhaustion". Med Sci Sports Exerc 36 (6): 1078–1082. doi:10.1249/01.MSS.0000128146.12004.4F. PMID 15179180.
- Wheeler B (October 26, 2006). "BBC report on MoD research into modafinil". BBC News. Retrieved July 4, 2012.
- "MoD's secret pep pill to keep forces awake". The Scotsman. February 27, 2005. Retrieved December 31, 2013.
- "Pilot pill project". News - City. PuneMirror. February 16, 2011. Retrieved July 4, 2012.
- Taylor GP, Jr, Keys RE (December 1, 2003). "Modafinil and management of aircrew fatigue" (PDF). United States Department of the Air Force. Retrieved September 18, 2009.
- Caldwell JA Jr, Smythe NK III, Caldwell L, Hall KK, Norman DN, Prazinko BF, Estrada A, Johnson PA, Crowley JS, Brock ME (June 1, 1999). "The Effects of Modafinil on Aviator Performance During 40 Hours of Continuous Wakefulness: A UH-60 Helicopter Simulator Study" (PDF). USAARL Report No. 99. U.S. Army Aeromedical Research Laboratory. Retrieved July 4, 2012.
- Estrada A, Kelley AM, Webb CM, Athy JR, Crowley JS (June 2012). "Modafinil as a replacement for dextroamphetamine for sustaining alertness in military helicopter pilots". Aviat Space Environ Med 83 (6): 556–64. doi:10.3357/ASEM.3129.2012. PMID 22764609.
- "The efficacy of Modafinil for sustaining alertness and simulator flight performance in F-117 pilots during 37 hours of continuous wakefulness". United States Air Force Research Laboratory. January 2004.
- Whitmore J, Hickey P, Doan B, Harrison R, Kisner J, Beltran T, McQuade J, Fischer J, Marks F (August 1, 2006). "A double-blind placebo-controlled investigation of the efficacy of modafinil for maintaining alertness and performance in sustained military ground operations" (PDF). United States Air Force Research Laboratory. Retrieved July 4, 2012.
- "The Maryland Medical Protocols for Emergency Medical Services Providers" (PDF). July 1, 2009.
- Thirsk R, Kuipers A, Mukai C, Williams D (June 2009). "The space-flight environment: the International Space Station and beyond". CMAJ 180 (12): 1216–20. doi:10.1503/cmaj.081125. PMC 2691437. PMID 19487390.
- Lin JS, Roussel B, Akaoka H, Fort P, Debilly G, Jouvet M (September 25, 1992). "Role of catecholamines in the modafinil and amphetamine induced wakefulness, a comparative pharmacological study in the cat". Brain Research 591 (2): 319–26. doi:10.1016/0006-8993(92)91713-O. PMID 1359924.
- Ballas CA, Kim D, Baldassano CF, Hoeh N (July 2002). "Modafinil: past, present and future". Expert Rev Neurother 2 (4): 449–57. doi:10.1586/14737220.127.116.119. PMID 19810941.
- "Modafinil Information Page" (PDF). Teva Pharmaceuticals. February 1, 2012.
- Banerjee D, Vitiello MV, Grunstein RR (October 2004). "Pharmacotherapy for excessive daytime sleepiness". Sleep Med Rev 8 (5): 339–54. doi:10.1016/j.smrv.2004.03.002. PMID 15336235.
- "MedlinePlus Drug Information: Modafinil". NIH. July 1, 2005. Archived from the original on June 10, 2007. Retrieved July 21, 2007.
- "FDA Approved Labeling Text for Provigil" (PDF). U.S. Food and Drug Administration. January 23, 2004. Retrieved December 31, 2013.
- Bastuji H, Jouvet M (1988). "Successful treatment of idiopathic hypersomnia and narcolepsy with modafinil". Prog. Neuropsychopharmacol. Biol. Psychiatry 12 (5): 695–700. doi:10.1016/0278-5846(88)90014-0. PMID 2906157.
- Neuman G, Shehadeh N, Pillar G (August 2009). "Unsuccessful suicide attempt of a 15 year old adolescent with ingestion of 5000 mg modafinil". J Clin Sleep Med 5 (4): 372–3. PMC 2725258. PMID 19968017.
- "Modafinil (marketed as Provigil): Serious Skin Reactions". FDA. 2007.
- Volkow ND, Fowler JS, Logan J, Alexoff D, Zhu W, Telang F, Wang GJ, Jayne M, Hooker JM, Wong C, Hubbard B, Carter P, Warner D, King P, Shea C, Xu Y, Muench L, Apelskog-Torres K (March 2009). "Effects of modafinil on dopamine and dopamine transporters in the male human brain: clinical implications". JAMA 301 (11): 1148–54. doi:10.1001/jama.2009.351. PMC 2696807. PMID 19293415.
- Myrick H, Malcolm R, Taylor B, LaRowe S (2004). "Modafinil: preclinical, clinical, and post-marketing surveillance--a review of abuse liability issues". Ann Clin Psychiatry 16 (2): 101–9. doi:10.1080/10401230490453743. PMID 15328903.
- Deroche-Gamonet V, Darnaudéry M, Bruins-Slot L, Piat F, Le Moal M, Piazza PV (June 2002). "Study of the addictive potential of modafinil in naive and cocaine-experienced rats". Psychopharmacology (Berl.) 161 (4): 387–95. doi:10.1007/s00213-002-1080-8. PMID 12073166.
- Wong YN, King SP, Laughton WB, McCormick GC, Grebow PE (March 1998). "Single-dose pharmacokinetics of modafinil and methylphenidate given alone or in combination in healthy male volunteers". J Clin Pharmacol 38 (3): 276–82. doi:10.1002/j.1552-4604.1998.tb04425.x. PMID 9549666.
- Baselt, Randall C. (2008). Disposition of Toxic Drugs and Chemicals in Man. Foster City, CA: Biomedical Publications. pp. 1152–1153. ISBN 0-9626523-7-7.
- "Modafinil in Drug Tests". ProvigilWeb.
- Robertson P, DeCory HH, Madan A, Parkinson A (June 2000). "In vitro inhibition and induction of human hepatic cytochrome P450 enzymes by modafinil". Drug Metab. Dispos. 28 (6): 664–71. PMID 10820139.
- Gilman A, Goodman LS, Hardman JG, Limbird LE (2001). Goodman & Gilman's the pharmacological basis of therapeutics. New York: McGraw-Hill. p. 1984. ISBN 0-07-135469-7.
- Bodenmann S, Xu S, Luhmann UF, Arand M, Berger W, Jung HH, Landolt HP (March 2009). "Pharmacogenetics of modafinil after sleep loss: catechol-O-methyltransferase genotype modulates waking functions but not recovery sleep". Clin. Pharmacol. Ther. 85 (3): 296–304. doi:10.1038/clpt.2008.222. PMID 19037200.
- Gerrard P, Malcolm R (June 2007). "Mechanisms of modafinil: A review of current research". Neuropsychiatric Disease and Treatment 3 (3): 349–64. PMC 2654794. PMID 19300566.
- Minzenberg MJ, Carter CS (June 2008). "Modafinil: a review of neurochemical actions and effects on cognition". Neuropsychopharmacology 33 (7): 1477–502. doi:10.1038/sj.npp.1301534. PMID 17712350.
- Ishizuka T, Murakami M, Yamatodani A (January 2008). "Involvement of central histaminergic systems in modafinil-induced but not methylphenidate-induced increases in locomotor activity in rats". Eur. J. Pharmacol. 578 (2–3): 209–15. doi:10.1016/j.ejphar.2007.09.009. PMID 17920581.
- Engber TM, Koury EJ, Dennis SA, Miller MS, Contreras PC, Bhat RV (January 1998). "Differential patterns of regional c-Fos induction in the rat brain by amphetamine and the novel wakefulness-promoting agent modafinil". Neurosci. Lett. 241 (2–3): 95–8. doi:10.1016/S0304-3940(97)00962-2. PMID 9507929.
- Zolkowska D, Jain R, Rothman RB, Partilla JS, Roth BL, Setola V, Prisinzano TE, Baumann MH (May 2009). "Evidence for the involvement of dopamine transporters in behavioral stimulant effects of modafinil". J. Pharmacol. Exp. Ther. 329 (2): 738–46. doi:10.1124/jpet.108.146142. PMC 2672878. PMID 19197004.
- Dopheide MM, Morgan RE, Rodvelt KR, Schachtman TR, Miller DK (July 2007). "Modafinil evokes striatal [(3)H]dopamine release and alters the subjective properties of stimulants". Eur. J. Pharmacol. 568 (1–3): 112–23. doi:10.1016/j.ejphar.2007.03.044. PMID 17477916.
- Murillo-Rodríguez E, Haro R, Palomero-Rivero M, Millán-Aldaco D, Drucker-Colín R (January 2007). "Modafinil enhances extracellular levels of dopamine in the nucleus accumbens and increases wakefulness in rats". Behav. Brain Res. 176 (2): 353–7. doi:10.1016/j.bbr.2006.10.016. PMID 17098298.
- de Saint Hilaire Z, Orosco M, Rouch C, Blanc G, Nicolaidis S (November 2001). "Variations in extracellular monoamines in the prefrontal cortex and medial hypothalamus after modafinil administration: a microdialysis study in rats". NeuroReport 12 (16): 3533–7. doi:10.1097/00001756-200111160-00032. PMID 11733706.
- Gallopin T, Luppi PH, Rambert FA, Frydman A, Fort P (February 2004). "Effect of the wake-promoting agent modafinil on sleep-promoting neurons from the ventrolateral preoptic nucleus: an in vitro pharmacologic study". Sleep 27 (1): 19–25. PMID 14998233.
- Ferraro L, Fuxe K, Tanganelli S, Tomasini MC, Rambert FA, Antonelli T (April 2002). "Differential enhancement of dialysate serotonin levels in distinct brain regions of the awake rat by modafinil: possible relevance for wakefulness and depression". J. Neurosci. Res. 68 (1): 107–12. doi:10.1002/jnr.10196. PMID 11933055.
- Ishizuka T, Sakamoto Y, Sakurai T, Yamatodani A (March 2003). "Modafinil increases histamine release in the anterior hypothalamus of rats". Neurosci. Lett. 339 (2): 143–6. doi:10.1016/S0304-3940(03)00006-5. PMID 12614915.
- Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, Richardson JA, Williams SC, Xiong Y, Kisanuki Y, Fitch TE, Nakazato M, Hammer RE, Saper CB, Yanagisawa M (August 1999). "Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation". Cell 98 (4): 437–51. doi:10.1016/S0092-8674(00)81973-X. PMID 10481909.
- Scammell TE, Estabrooke IV, McCarthy MT, Chemelli RM, Yanagisawa M, Miller MS, Saper CB (November 2000). "Hypothalamic arousal regions are activated during modafinil-induced wakefulness". J. Neurosci. 20 (22): 8620–8. PMID 11069971.
- Wisor JP, Nishino S, Sora I, Uhl GH, Mignot E, Edgar DM (March 2001). "Dopaminergic role in stimulant-induced wakefulness". J. Neurosci. 21 (5): 1787–94. PMID 11222668.
- Willie JT, Renthal W, Chemelli RM, Miller MS, Scammell TE, Yanagisawa M, Sinton CM (2005). "Modafinil more effectively induces wakefulness in orexin-null mice than in wild-type littermates". Neuroscience 130 (4): 983–95. doi:10.1016/j.neuroscience.2004.10.005. PMID 15652995.
- Nardone R, Bergmann J, Lochner P, Caleri F, Kunz A, Staffen W, Tezzon F, Ladurner G, Trinka E, Golaszewski S (October 2010). "Modafinil reverses hypoexcitability of the motor cortex in narcoleptic patients: a TMS study". Sleep Med. 11 (9): 870–5. doi:10.1016/j.sleep.2010.05.007. PMID 20810311.
- Urbano FJ, Leznik E, Llinás RR (July 2007). "Modafinil enhances thalamocortical activity by increasing neuronal electrotonic coupling". Proc. Natl. Acad. Sci. U.S.A. 104 (30): 12554–9. doi:10.1073/pnas.0705087104. PMC 1925036. PMID 17640897.
- Garcia-Rill E, Heister DS, Ye M, Charlesworth A, Hayar A (November 2007). "Electrical coupling: novel mechanism for sleep-wake control". Sleep 30 (11): 1405–14. PMC 2082101. PMID 18041475.
- Siegel J (2008). "Gaps that wake you up". Department of Psychiatry, University of California, Los Angeles.
- Minzenberg MJ, Watrous AJ, Yoon JH, Ursu S, Carter CS (December 2008). "Modafinil shifts human locus coeruleus to low-tonic, high-phasic activity during functional MRI". Science 322 (5908): 1700–2. doi:10.1126/science.1164908. PMID 19074351.
- Minzenberg MJ, Carter CS (June 2008). "Modafinil: a review of neurochemical actions and effects on cognition". Neuropsychopharmacology 33 (7): 1477–502. doi:10.1038/sj.npp.1301534. PMID 17712350.
- Beck P, Odle A, Wallace-Huitt T, Skinner RD, Garcia-Rill E (December 2008). "Modafinil increases arousal determined by P13 potential amplitude: an effect blocked by gap junction antagonists". Sleep 31 (12): 1647–54. PMC 2603487. PMID 19090320.
- Ferraro L, Tanganelli S, O'Connor WT, Antonelli T, Rambert F, Fuxe K (June 1996). "The vigilance promoting drug modafinil increases dopamine release in the rat nucleus accumbens via the involvement of a local GABAergic mechanism". Eur. J. Pharmacol. 306 (1–3): 33–9. doi:10.1016/0014-2999(96)00182-3. PMID 8813612.
- Seeman P, Guan HC, Hirbec H (August 2009). "Dopamine D2High receptors stimulated by phencyclidines, lysergic acid diethylamide, salvinorin A, and modafinil". Synapse 63 (8): 698–704. doi:10.1002/syn.20647. PMID 19391150.
- "Cephalon gets six-month Provigil patent extension". Philadelphia Business Journal. March 28, 2006. Retrieved July 21, 2007.
- "Details for Patent: RE37516".
- "Prescription Access Litigation (PAL) Project :: Prescription Access Litigation (PAL) Project :: Lawsuits & Settlements :: Current Lawsuits". Prescriptionaccess.org. Retrieved July 4, 2012.
- "Document 514 :: APOTEX, INC. v. CEPHALON, INC. et al". Pennsylvania Eastern District Court :: US Federal District Courts Cases :: Justia. November 31, 2010. Retrieved July 4, 2012. Check date values in:
- "Document 513 :: APOTEX, INC. v. CEPHALON, INC. et al". Pennsylvania Eastern District Court :: US Federal District Courts Cases :: Justia. November 31, 2010. Retrieved July 4, 2012. Check date values in:
- "Cephalon Inc., SEC 10K 2008 disclosure". February 23, 2009. pp. 9–10. Retrieved August 29, 2009.
- "CVS, Rite Aid Sue Cephalon Over Generic Provigil". Bloomberg News. August 21, 2009. Retrieved August 29, 2009.
- "Canada IP Year in Review 2008". January 1, 2009.
- "Shire v. Canada". Retrieved August 29, 2009.
- "Cephalon Sues Apotex". Zacks.com. August 20, 2010. Retrieved July 4, 2012.
- ""U.S. Federal Trade Commission Clears Teva's Acquisition of Cephalon". Business Wire. October 7, 2011.
Teva will also grant non-exclusive U.S. rights to an undisclosed company to market modafinil tablets, the generic version of Provigil(R), which had annual brand sales in the U.S. of approximately $1.1 billion
- "Par Pharmaceutical Acquires Three Generic Products From Teva Pharmaceuticals". Press Release. PRNewswire. October 18, 2011. Retrieved July 4, 2012.
- Larson E (November 19, 2010). "Cephalon Loses U.K. Bid to Halt Mylan, Orchid Generic-Drug Sales". bloomberg LP. Archived from the original on April 25, 2012.
- "Is It Illegal to Obtain Controlled Substances From the Internet?". United States Drug Enforcement Administration. Retrieved July 21, 2007.
- "USC 201 Section 1301.26 Exemptions from import or export requirements for personal medical use". United States Department of Justice. March 24, 1997.
- "Prescription Drug Marketing Act of 1987 (PDMA), PL 100-293". U.S. Food and Drug Administration. Archived from the original on February 23, 2008.
- "Letter to Cephalon 01/03/2002". January 3, 2002. Retrieved July 4, 2012.
- "Cephalon executives have repeatedly said that they do not condone off-label use of Provigil, but in 2002 the company was reprimanded by the FDA for distributing marketing materials that presented the drug as a remedy for tiredness, "decreased activity" and other supposed ailments. In 2008, Cephalon paid $425m and pleaded guilty to a federal criminal charge relating to its promotion of off-label uses for Provigil and two other drugs." http://www.law360.com/articles/127434[verification needed]
- Anne Zieger (September 30, 2008). "Cephalon settlement requires physician payments to be disclosed". Fierce Healthcare.
- "Regulations Amending the Food and Drug Regulations (1184 — Modafinil)" (– Scholar search). Canada Gazette 140 (20). March 26, 2005. Archived from the original on July 6, 2011.
- "Estupefacientes y Psicotrópicos" [Narcotic Drugs and Psychotropic Substances] (in Spanish). Federal Commission for Protection against Health Risks. Archived from the original on July 13, 2007. Retrieved July 21, 2007.
- Julia Llewellyn Smith (January 6, 2004). "The 44-hour day". London: The Daily Telegraph. Retrieved December 31, 2013.
- Minzenberg MJ, Carter CS; Carter (June 2008). "Modafinil: a review of neurochemical actions and effects on cognition". Neuropsychopharmacology 33 (7): 1477–502. doi:10.1038/sj.npp.1301534. PMID 17712350.
- "Stay Awake Pill May Get Wider Approval". ABC News. October 9, 2006.
- PROVIGIL - official website
- The New Yorker magazine December 3, 2001 "Eyes Wide Open" — (article about modafinil research by the U.S. military)
- "Brain Gain: The underground world of 'neuroenhancing' drugs" -(article about use of nootropics and other drugs in general)
- "Wake Up, Little Susie" article and reporter's diary on taking modafinil from March 7, 2003 Slate magazine
- "Get ready for 24-hour living" from 18 February 2006 New Scientist
- RxList Patient Information for modafinil users
- "Mayo Clinic Proceedings Publishes Study of NUVIGIL in Patients with Shift Work Disorder"
- U.S. National Library of Medicine: Drug Information Portal - Modafinil