Modafinil (Provigil, Alertec, Modavigil, Modalert, Modiodal, Modafinilo, Carim, Vigia) is an analeptic drug manufactured by Cephalon, and is approved by the U.S. Food and Drug Administration (FDA) for the treatment of narcolepsy, shift work sleep disorder, and excessive daytime sleepiness associated with obstructive sleep apnea. The European Medicines Agency has recommended that in Europe it be prescribed only for narcolepsy.
Despite extensive research into the interaction of modafinil with a large number of neurotransmitter systems, a precise mechanism or set of mechanisms of action remains unclear. It seems that modafinil, like other stimulants, increases the release of monoamines, specifically the catecholamines norepinephrine and dopamine, from the synaptic terminals. However, modafinil also elevates hypothalamic histamine levels, leading some researchers to consider Modafinil a "wakefulness promoting agent" rather than a classic amphetamine-like stimulant. Despite modafinil's histaminergic action, it still partially shares the actions of amphetamine-class stimulants due to its effects on norepinephrine and dopamine.
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 lowers 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."
Modafinil was shown to be an effective treatment for attention deficit hyperactivity disorder (ADHD), Cephalon's own label for Provigil now discourages its use by children for any purpose. Other potentially effective, but unapproved targets include the treatment of depression, bipolar depression, opiate & cocaine dependence, Parkinson's disease, schizophrenia, and disease-related fatigue, as well as fatigue that is the side effect of another medication.
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 and $425 million fines to the U.S. government in 2008 due to its marketing.
Modafinil and its chemical precursor adrafinil were developed by Lafon Laboratories, a French company acquired by Cephalon in 2001. Modafinil is the primary metabolite of adrafinil, and, while its activity is similar, adrafinil requires a higher dose to achieve equipotent effects. Modafinil is a racemic mixture; the active (R)-enantiomer is known as armodafinil (Nuvigil).
Indications
In the United States, modafinil is approved by the
U.S. Food and Drug Administration only for the treatment of
narcolepsy, obstructive
sleep apnea/
hypopnea and shift work sleep disorder. In some countries, it is also approved for
idiopathic hypersomnia (all forms of excessive daytime sleepiness where causes can't be established). 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).
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.
Off-label use
Modafinil is widely used off-label to suppress the need for sleep. It is also used off-label in combating general fatigue unrelated to lack of sleep such as in treating ADHD and as an adjunct to
antidepressants (particularly in individuals with significant residual fatigue).
There is a disagreement 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" One study found that modafinil restored normal levels of learning ability in methamphetamine addicts, but had no effect on non-addicts.
There is also evidence that it has neuroprotective effects.
Modafinil may be also an effective and well-tolerated treatment in patients with seasonal affective disorder/winter depression
Doping agent
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. |date=May 2011}} Modafinil has been shown to prolong exercise time to exhaustion while performing at 85% of VO
2max 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).
Multiple sclerosis
Modafinil is not approved for, but has been used to allay symptoms of the neurological fatigue reported by some with
multiple sclerosis. Patients follow either the standard usage or take a single dose of 200–400 mg at the start of days self-assessed as being potentially excessively fatiguing. 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.
ADHD
In December 2004, Cephalon submitted a supplemental new drug application (sNDA) to market Sparlon, a brand name of tablets containing higher doses of modafinil for the treatment of ADHD in children and adolescents ages 6 through 17. Though studies showed positive effects, the FDA advisory committee voted 12 to 1 against approval, citing concerns about a number of reported cases of skin rash reactions in a 1000-patient trial, including one which was thought to be likely a case of
Stevens-Johnson syndrome. Final rejection occurred in August 2006, although subsequent follow-up indicated that the skin rash reaction was not Stevens-Johnson syndrome.
fibromyalgia,
chronic fatigue syndrome,
myotonic dystrophy,
opioid-induced sleepiness, spastic
cerebral palsy, and
Parkinson's disease. It increases subjective mood and friendliness, at least among shift workers.
It has also been prescribed by some doctors for delayed sleep phase syndrome.
During high-risk, large-scale, and extended law enforcement or homeland security operations, tactical paramedics in Maryland (US) may administer 200 mg of modafinil once daily to law enforcement personnel in order to "enhance alertness / concentration" and "facilitate functioning with limited rest periods."
In the 1980s, modafinil was used by some French students. Recently modafinil has become popular in performance-enhancing use by university students in the United Kingdom. Some students obtain the drug through illicit means (diversion of prescribed medication),
although others obtain it through online pharmacies.
Experimental uses
Cocaine addiction
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.
Weight loss
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 a 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 amphetamines, but, unlike 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.
Primary biliary cirrhosis
Modafinil has been shown to improve excessive daytime somnolence and fatigue in
primary biliary cirrhosis. After two months of treatment significant improvement was observed in symptoms of fatigue using the
Epworth Sleepiness Scale.
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". A University of Rochester study of 68 subjects had significant results. "We knew from previous studies that modafinil does alleviate problems with memory and attention, and were hoping it would do the same for breast-cancer patients experiencing chemo-brain, which it did," related the study's lead author Sadhna Kohli, Ph.D, a research assistant professor at the University of Rochester's James P. Wilmot Cancer Center.
Mood elevation
Modafinil used in a
randomized double-blind study 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 may have an adverse effect on hormonal contraceptives, lasting for a month after cessation of dosage.
Toxicity
In mice and rats, the
median lethal dose (LD
50) of modafinil is approximately or slightly greater than 1250 mg/kg. Oral LD
50 values reported for rats range from 1000 mg/kg to 3400 mg/kg. Intravenous LD
50 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, FDA is not aware of any fatal overdoses involving modafinil alone (as opposed to multiple drugs, including modafinil). 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.
Severe adverse reactions
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),
Stevens-Johnson syndrome (SJS),
toxic epidermal necrolysis (TEN), and
drug rash with eosinophilia and systemic symptoms (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.
Military and astronaut use
Militaries of several countries are known to have expressed interest in Modafinil as an alternative to
amphetamines—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. 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.
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.
Pharmacology
The exact
mechanism of action of Modafinil is unclear, although numerous studies have shown it to increase the levels of various monoamines, namely;
dopamine in the
striatum and
nucleus accumbens,
noradrenaline in the
hypothalamus and
ventrolateral preoptic nucleus, and serotonin in the amygdala and frontal cortex. While the co-administration of a dopamine
antagonist is known to decrease the stimulant effect of
amphetamine, it does not entirely negate the wakefulness-promoting actions of modafinil. Modafinil activates
glutamatergic circuits while inhibiting
GABAergic neurotransmission.
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 receptors for hypocretins, namely hcrt1 and hcrt2. Animal studies have shown that animals with defective orexin systems show signs and symptoms similar to narcolepsy for which Modafinil is FDA approved. Modafinil seems to activate these orexin neurons in animal models, which would be expected to promote wakefulness. However, a study of genetically modified dogs lacking orexin receptors showed that modafinil still promoted wakefulness in these animals, suggesting that orexin activation is not required for the effects of modafinil (reference needed). Additionally, a study looking at orexin-knockout mice, found that not only modafinil promoted wakefulness in these mice but did so even more effectively than in the wild-type mice.
Since modafinil's substantial, but incomplete, independence from both monoaminergic systems and those of the orexin peptides has proven baffling with respect to the better understood mechanisms of stimulants such as cocaine, enhanced electrotonic coupling has been suggested by several studies. Most neurons are separated by synapses, and communication between cells is accomplished via release and diffusion of neurotransmitters. The receptors for these neurotransmitters present an obvious target for drug treatments. However, some neurons are directly connected to one another via gap junctions, and it is proposed that modafinil influences the effectiveness of these connections. In support of this theory, Urbano et al. determined that modafinil increased activity in the thalamocortical loop (critical in organizing sensory input and modulating global brain activity) via enhancements in electrotonic coupling. Administration of the gap junction blocker mefloquine abolished this effect, providing good evidence that this result was a consequence of improved electrical coupling. Further research by the same group also noted the capacity of the calmodulin kinase II (CaMKII) inhibitor, KN-93, to abolish modafinil's enhancement of electrotonic coupling. They came to the conclusion that 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, Garcia-Rill et al. discovered that 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 to 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. 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. 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 produces locomotor activity and extracellular dopamine concentrations in a manner similar to the selective dopamine reuptake inhibitor (DRI) vanoxerine, and also blocks methamphetamine-induced dopamine release. As a result, it appears that modafinil exerts its effects by acting as a weak DRI, though it cannot be ruled out that other mechanisms may also be at play. On account of its action as a DRI 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 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 (Ki > 10,000). Cmax occurs approximately 2–3 hours after administration. Food slows absorption, but does not affect the total AUC. 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. As of 2011, it is not specifically tested for by common drug screens (with the exception of anti-doping screens), and it unlikely to cause false positives for other chemically-unrelated drugs such as amphetamines.
History
Modafinil originated with the late 1970s invention of a series of benzhydryl sulfinyl compounds, also including
adrafinil, by scientists working with the French pharmaceutical company
Lafon. Adrafinil was first offered as an experimental treatment for narcolepsy in France in 1986. Modafinil is the primary metabolite of adrafinil and has similar activity 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 leased the rights from Lafon. Cephalon eventually purchased Lafon in 2001. In 2005, a petition by a private individual was filed with the FDA requesting over-the-counter sale of modafinil.
Patent protection and antitrust litigation
A was granted to Lafon for modafinil in 1990. The FDA granted modafinil
orphan drug status in 1993. The formulation patent expired on 30 March 2006. The particle size patent was filed by Cephalon , covering pharmaceutical compositions of modafinil, in 1994. That patent, granted in 1997, was reissued in 2002 as RE 37,516, which provides Cephalon with patent protection for certain preparations of the drug in the United States until 2014, which is now apparently extended to April 6, 2015 after Cephalon received a six-month patent extension from the FDA.
Some competing generic pharmaceutical manufacturers applied to the FDA to market a generic form of modafinil in 2006 (the year of patent expiry of the active ingredient). At least one withdrew its application after early opposition by Cephalon based on its new patent on particle sizes (set to expire in 2015). 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. To date, no generic manufacturer has been able to invalidate Cephalon's particle size patent, and, indeed, those that attempted to do so were not successful such that the patent remains in force.
Cephalon made an agreement with four major generics manufacturers Teva, Barr Pharmaceuticals, Ranbaxy Laboratories, and Watson Pharmaceuticals between 2005-2006 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 Nuvigil.
In England, Mylan Inc. received regulatory approval to sell generic Orchid-produced modafinil in January 2010; Cephalon sued to prevent sale, but lost the patent trial in November.
Legal status
Modafinil is 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). Note that
Adrafinil, a drug that is closely related to Modafinil, is currently not classified as a controlled substance, and therefore it is not as severely regulated.
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
United Kingdom (not listed in the Misuse of Drugs Act and is available by prescription without legal restrictions)
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.
Availability
Modafinil is sold under a wide variety of brand names world wide.
Provigil - United States, United Kingdom, Italy, South Korea
Carim - Ecuador, Uruguay, Columbia
Alertec- Canada, Ecuador
Vigil - Germany
Modalert - India
Modavigil - Australia, New Zealand
Vigicer - Canada
Modiadal - Mexico, France, Sweden
Resotyl - Chile
See also
Adrafinil, prodrug to modafinil
Armodafinil, the (−)-(R)-modafinil stereoisomer
Circadian Rhythm Sleep Disorder
CRL-40941
Eugeroic
Orexin-A
Human reliability
Hypopnea syndrome
Narcolepsy
Nootropics
Seasonal affective disorder (SAD)
Shift work sleep disorder (SWSD)
Sleep apnea
Sleep disorder
References
External links
PROVIGIL - official website
*Medication Guide for Patients
*Full Prescribing Information
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
"My experiment with smart drugs" -(essay by Johann Hari; online version of an Evening Standard article)
"Mayo Clinic Proceedings Publishes Study of NUVIGIL in Patients with Shift Work Disorder"
http://abcnews.go.com/GMA/DrJohnson/story?id=128275
U.S. National Library of Medicine: Drug Information Portal - Modafinil
"Judge slams FTC in pay-for-delay generic drug case" -(Reuters)
Category:Nootropics
Category:Stimulants
Category:Anxiogenics
Category:Sulfoxides
Category:Acetamides
