Modafinil (INN, USAN, BAN, JAN) is a wakefulness-promoting agent (or eugeroic) used for treatment of disorders such as narcolepsy, shift work sleep disorder, and excessive daytime sleepiness associated with obstructive sleep apnea. It has also seen widespread off-label use as a purported cognition-enhancing agent. In English-speaking countries it is sold under the brand names Alertec, Modavigil, and Provigil. In the United States modafinil is classified as a schedule IV controlled substance and restricted in availability and usage, due to concerns about possible addiction potential. In most other countries it is a prescription drug but not otherwise legally restricted. In some countries, for example Egypt, it is sold over the counter under the brand name Bravamax.
(R)-(−)-modafinil (armodafinil; top)
|Trade names||Provigil, others (see below)|
|Psychological: Very low
|Very low to low|
|Bioavailability||Not determined due to the aqueous insolubility|
|Metabolism||Hepatic (primarily via amide hydrolysis; CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5 involved |
|Biological half-life||15 hours (R-enantiomer),
4 hours (S-enantiomer)
|Chemical and physical data|
|Molar mass||273.35 g/mol|
|3D model (Jmol)|
|(what is this?)|
Although the mechanism of action of modafinil was initially unknown, it now appears that the drug acts as a selective, relatively weak, atypical dopamine reuptake inhibitor. However, it appears that other additional mechanisms may also be at play.
Modafinil is a wakefulness-promoting agent (or eugeroic) used for treatment of narcolepsy, shift work sleep disorder, and excessive daytime sleepiness associated with obstructive sleep apnea.
Because of the risk for development of skin or hypersensitivity reactions and serious adverse psychiatric reactions, the European Medicines Agency has recommended that new patient prescriptions should only be to treat sleepiness associated with narcolepsy.
Off-label use for fatigueEdit
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 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.
Military and astronautsEdit
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.
In the United States military, modafinil has been approved for use on certain Air Force missions, and it is being investigated for other uses. As of November 2012, modafinil is the only drug approved by the Air Force as a "go pill" for fatigue management. The use of dextroamphetamine (a.k.a., Dexedrine) is no longer approved.
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.
Allergy and hypersensitivity are the only contraindications of the drug, but literature distributed by Cephalon advises that it is important to consult a physician before using it, as problems may arise for people who are sensitive to constituents of the tablets, people with cirrhosis (which may impair the metabolism of the drug), and people with various cardiovascular problems.
According to documentation distributed by Teva Pharmaceuticals, one-third of participants in clinical trials reported experiencing headaches; 11% reported nausea; other negative side-effects such as nervousness, diarrhea, insomnia, anxiety, dizziness, and gastrointestinal problems were reported by fewer than 10% of participants.
Rare occurrences have been reported of more serious adverse effects, including severe skin rashes and other symptoms that are probably allergy-related. From the date of initial marketing, December 1998, to January 30, 2007, the US Food and Drug Administration received six cases of severe cutaneous adverse reactions associated with modafinil, including erythema multiforme (EM), Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and DRESS syndrome, 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 experiences. 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 TEN, DRESS syndrome, and SJS.
The long term safety and effectiveness of modafinil have not been determined.
Addiction and dependence potentialEdit
The addiction and dependence liabilities of modafinil are very low. It shares biochemical mechanisms with addictive stimulant drugs, and some studies have reported it to have similar mood-elevating properties, although to a lesser degree. Monkeys will self-administer modafinil if they have previously been trained to self-administer cocaine. Although modafinil does not produce reinforcing effects in mice at doses that are equivalent to those used therapeutically in humans, it does do so at higher doses. In accordance, although very rare, case reports of modafinil abuse exist. As such, modafinil is classified by the United States FDA as a schedule IV controlled substance, a category for drugs with valid medical uses and low but significant addiction potential.
Psychological dependence upon modafinil has only been noted in case reports involving daily overdoses on modafinil for an extended period of time. Reported withdrawal symptoms include anhedonia, lethargy, anxiety, and insomnia.
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 1000–3400 mg/kg. Intravenous LD50 for dogs is 300 mg/kg. Clinical trials on humans involving taking up to 1200 mg/day for 7–21 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).
Coadministration with modafinil alongside opioids such as hydrocodone, oxycodone, and fentanyl, as well as various other drugs, may experience a drop in plasma concentrations. The reasoning behind this action is because modafinil is an inducer of the CYP3A4 enzymes. If not monitored closely, reduced efficacy or withdrawal symptoms can occur.[medical citation needed]
Dopamine transporter blockerEdit
Initially, the mechanism of action of modafinil was unknown. Research found that modafinil elevates histamine levels in the hypothalamus in animals. The locus of the monoamine action of modafinil was also the target of studies, with effects identified on dopamine in the striatum and, in particular, nucleus accumbens, norepinephrine in the hypothalamus and ventrolateral preoptic nucleus, and serotonin in the amygdala and frontal cortex. 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 affect only the dopamine transporter (DAT), acting as a dopamine reuptake inhibitor (DRI) with an IC50 value of 4 μM. Subsequently, it was determined that modafinil binds to the same site on the DAT as cocaine, but in a different manner. In accordance, modafinil increases locomotor activity and extracellular dopamine concentrations in animals in a manner similar to the selective DRI vanoxerine (GBR-12909), and also inhibits methamphetamine-induced dopamine release (a common property of DRIs, since DAT transport facilitates methamphetamine's access to its intracellular targets). As such, "modafinil is an exceptionally weak, but apparently very selective, [DAT] inhibitor". In addition to animal research, a human positron emission tomography (PET) imaging study found that 200 mg and 300 mg doses of modafinil resulted in DAT occupancy of 51.4% and 56.9%, respectively, which was described as "close to that of methylphenidate". Another human PET imaging study similarly found that modafinil occupied the DAT and also determined that it significantly elevated extracellular levels of dopamine in the brain, including in the nucleus accumbens.
Modafinil has been described as an "atypical" DAT inhibitor, and shows a profile of effects that is very different from those of other dopaminergic stimulants. For instance, modafinil produces wakefulness reportedly without the need for compensatory sleep, and shows a relatively low, if any, potential for abuse. Aside from modafinil, examples of other atypical DAT inhibitors include vanoxerine and benztropine, which have a relatively low abuse potential similarly to modafinil. These drugs appear to interact molecularly with the DAT in a distinct way relative to "conventional" DAT blockers such as cocaine and methylphenidate.
Against the hypothesis that modafinil exerts its effects by acting as a DRI, tyrosine hydroxylase inhibitors (which deplete dopamine) fail to block the effects of modafinil in animals. In addition, modafinil fails to reverse reserpine-induced akinesia, whereas dextroamphetamine, a dopamine releasing agent (DRA), is able to do so. Moreover, one of the first published structure-activity relationship studies of modafinil found in 2012 that DAT inhibition did not correlate with wakefulness-promoting effects in animals among modafinil analogues, and a variety of analogues without any significant inhibition of the DAT still produced wakefulness-promoting effects. Furthermore, "[the] neurochemical effects [of modafinil] and anatomical pattern of brain area activation differ from typical psychostimulants and are consistent with its beneficial effects on cognitive performance processes such as attention, learning, and memory", and a study found that modafinil-induced increased locomotor activity in animals was dependent on histamine release and could be abolished by depletion of neuronal histamine, whereas those of methylphenidate were not and could not be. As such, although it is established that modafinil is a clinically significant DRI, its full pharmacology remains unclear and may be more complex than this single property (i.e., may also include DAT-independent actions, such as "activation of the orexin system").
In any case, there is nonetheless a good deal of evidence to indicate that modafinil is producing at least a portion of its wakefulness-promoting effects by acting as a DRI, or at least via activation of the dopaminergic system. In support of modafinil acting as a dopaminergic agent, its wakefulness-promoting effects are abolished in DAT knockout mice (although it is important to note that DAT knockout mice show D1 and D2 receptor and norepinephrine compensatory abnormalities, which might confound this finding), reduced by both D1 and D2 receptor antagonists (although conflicting reports exist), and completely blocked by simultaneous inactivation of both D1 and D2 receptors. In accordance, modafinil shows full stimulus generalization to other DAT inhibitors including cocaine, methylphenidate, and vanoxerine, and discrimination is blocked by administration of both ecopipam (SCH-39166), a D1 receptor antagonist, and haloperidol, a D2 receptor antagonist. Partial substitution was seen with the DRA dextroamphetamine and the D2 receptor agonist PNU-91356A, as well as with nicotine (which indirectly elevates dopamine levels through activation of nicotinic acetylcholine receptors).
Modafinil may possess yet an additional mechanism of action. Both modafinil and its metabolite, modafinil sulfone, possess anticonvulsant properties in animals, and modafinil sulfone is nearly as potent as modafinil in producing this effect. However, modafinil sulfone lacks any wakefulness-promoting effects in animals, indicating that a distinct mechanism may be at play in the anticonvulsant effects of both compounds.
D2 receptor partial agonistEdit
The (R)-(−)-enantiomer of modafinil, known as armodafinil, was also subsequently found to act as a D2High 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. Modafinil has been found to directly inhibit the firing of midbrain dopaminergic neurons in the ventral tegmental area and substantia nigra of rats via activation of D2 receptors.
Modafinil's efficacy in improving vigor and well-being in sleep deprivation subjects is dependent on catechol-O-methyl transferase (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 allele experience very little improvement.
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.
The two major circulating metabolites of modafinil are modafinil acid (CRL-40467) and modafinil sulfone (CRL-41056). Both of these metabolites have been described as inactive, and neither appear to contribute to the wakefulness-promoting effects of modafinil. However, modafinil sulfone does appear to possess anticonvulsant effects, and this is a property that it shares with modafinil.
Measurement in body fluidsEdit
Modafinil and/or its major metabolite, modafinil 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 (except for anti-doping screens) and is unlikely to cause false positives for other chemically-unrelated drugs such as substituted amphetamines.
Reagent testing can be used to screen for the presence of modafinil in samples.
|Modafinil||Yellow/Orange > Brown||Darkening Orange||Deep orange/red|
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.
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.
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 litigationEdit
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 expired 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 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.
Society and cultureEdit
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 (e.g., pills). Under the US Pure 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 pleaded 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:
- Australia (listed as a Schedule 4 prescription drug)
- 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)
- In Finland and Sweden modafinil is a prescription drug but not listed as a controlled substance.
- 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.
- Mexico (Not listed as a controlled substance, in the National Health Law)
- South Africa Schedule V
- United Kingdom (not listed in Misuse of Drugs Act so possession not illegal, but prescription required) 
Modafinil is sold under a wide variety of brand names worldwide, including Alertec, Alertex, Altasomil, Aspendos, Forcilin, Intensit, Mentix, Modafinil, Modafinilo, Modanil, Modasomil, Modavigil, Modiodal, Modiwake, Movigil, Provigil, Resotyl, Stavigile, Vigia, Vigicer, Vigil, Vigimax, and Zalux.
The regulation of modafinil as a doping agent has been controversial in the sporting world, with high-profile cases attracting press coverage since several prominent American athletes have tested positive for the substance. 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 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, and rower Timothy Grant in 2015) 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).
Modafinil has been used non-medically as a "smart drug" by students, office workers, soldiers and transhumanists. It is often compared to the fictional smart drug NZT-48 depicted in Limitless and sometimes called "the 'Limitless' pill".
Double-blind randomized controlled trials have demonstrated the efficacy and tolerability of modafinil in pediatric ADHD, however there are risks of serious side effects such as skin reactions and modafinil is not recommended for use in children.:7 In the United States, it was originally pending marketing as Sparlon for pediatric ADHD, but approval was denied by the FDA due to major concerns over the occurrence of Stevens-Johnson Syndrome in clinical trials.
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."
It has been studied for 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 other 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 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 the maximum number of consecutive non-use days for cocaine and reduced craving.
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.
Delayed sleep phase syndromeEdit
Modafinil has been studied as a possible treatment 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.
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 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. Modafinil reduces the symptoms of attention-deficit hyperactivity disorder and improves working and episodic memory.
Researchers from the University of Oxford and Harvard Medical School evaluated all research papers on cognitive enhancement with modafinil from January 1990 to December 2014 and found 24 studies dealing with benefits that include planning, decision making, flexibility, learning, memory and creativity associated with taking modafinil. The reviewers state that while only limited information is available on the effects of long-term use the drug appeared safe in the short term, with few side effects and no addictive qualities.
In March 2017 a study by researchers throughout Germany and Sweden led by psychiatrist Klaus Lieb at the University of Mainz found that modafinil improved the chess players' performances by an average of 15 percent.
Post-chemotherapy cognitive impairmentEdit
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 2015 it had been studied for use in multiple sclerosis associated fatigue, but the resulting evidence was weak and inconclusive.
Modafinil has been evaluated alone and in combination with scopolamine as an anti-motion sickness medication. It did not help by itself, but appeared to help in combination with scopolamine, acting to reduce symptoms of drowsiness associated with scopolamine.
Modafinil is a highly researched compound, with many derivatives created and studied, some examples and their differences between dopamine, serotonin & norepinephrine affect is given in bundled table form below.
|Tables containing modafinil analogs & their values: click to|
- Case reports:
• Krishnan R, Chary KV (March 2015). "A rare case modafinil dependence". Journal of Pharmacology & Pharmacotherapeutics. 6 (1): 49–50. PMC . PMID 25709356. doi:10.4103/0976-500X.149149.
He claimed to have symptoms of worsening of lethargy, tremors of hands, anxiety and erratic sleep hours when he skipped modafinil, patient reported a sense of well-being only with the drug and with the above dose [(1200mg/day)]. ... He reported sleep disturbance, increased sense of body warmth, lethargy and low mood during the process of tapering the drug. Low dose of clonazepam was added to reduce the withdrawal symptoms.
• Kate N, Grover S, Ghormode D (2012). "Dependence on supratherapeutic doses of modafinil: a case report". The Primary Care Companion for CNS Disorders. 14 (5). PMC . PMID 23469316. doi:10.4088/PCC.11l01333.
- Mignot EJ (Oct 2012). "A practical guide to the therapy of narcolepsy and hypersomnia syndromes". Neurotherapeutics. 9 (4): 739–52. PMC . PMID 23065655. doi:10.1007/s13311-012-0150-9.
Because of the relatively low risk of addiction, modafinil can be more easily prescribed in patients without a clear, biochemically defined central hypersomnia syndrome, and is also easier to stop, if needed. It is also a schedule IV compound.
- Robertson P, Hellriegel ET (2003). "Clinical pharmacokinetic profile of modafinil". Clinical Pharmacokinetics. 42 (2): 123–37. PMID 12537513. doi:10.2165/00003088-200342020-00002.
- Robertson P, DeCory HH, Madan A, Parkinson A (Jun 2000). "In vitro inhibition and induction of human hepatic cytochrome P450 enzymes by modafinil". Drug Metabolism and Disposition. 28 (6): 664–71. PMID 10820139.
- Nuvigil Prescribing Information
- "International Nonproprietary Names for Pharmaceutical Substances. Recommended International Nonproprietary Names (Rec. INN): List 27" (PDF). WHO Drug Information. 1 (4): 7. 1987. Retrieved 18 August 2016.
- "FDA Approved Labeling Text for Provigil" (PDF). U.S. Food and Drug Administration. January 2015. Retrieved July 18, 2015.
- Morgenthaler TI, Lee-Chiong T, Alessi C, Friedman L, Aurora RN, Boehlecke B, Brown T, Chesson AL, Kapur V, Maganti R, Owens J, Pancer J, Swick TJ, Zak R (Nov 2007). "Practice parameters for the clinical evaluation and treatment of circadian rhythm sleep disorders. An American Academy of Sleep Medicine report". Sleep. 30 (11): 1445–59. PMC . PMID 18041479.
- Zee PC, Attarian H, Videnovic A (Feb 2013). "Circadian rhythm abnormalities". Continuum. 19 (1 Sleep Disorders): 132–47. PMC . PMID 23385698. doi:10.1212/01.CON.0000427209.21177.aa.
- Battleday RM, Brem AK (Nov 2015). "Modafinil for cognitive neuroenhancement in healthy non-sleep-deprived subjects: A systematic review". European Neuropsychopharmacology. 25 (11): 1865–81. PMID 26381811. doi:10.1016/j.euroneuro.2015.07.028.
- European Medicines Agency January 27, 2011 Questions and answers on the review of medicines containing Modafinil
- 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 (Feb 2002). "Efficacy and safety of modafinil (Provigil) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study". Journal of Neurology, Neurosurgery, and Psychiatry. 72 (2): 179–83. PMC . PMID 11796766. doi:10.1136/jnnp.72.2.179.
- 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. PMC . PMID 21252034. doi:10.2196/jmir.1643.
- Menza MA, Kaufman KR, Castellanos A (May 2000). "Modafinil augmentation of antidepressant treatment in depression". The Journal of Clinical Psychiatry. 61 (5): 378–81. PMID 10847314. doi:10.4088/JCP.v61n0510.
- DeBattista C, Lembke A, Solvason HB, Ghebremichael R, Poirier J (Feb 2004). "A prospective trial of modafinil as an adjunctive treatment of major depression". Journal of Clinical Psychopharmacology. 24 (1): 87–90. PMID 14709953. doi:10.1097/01.jcp.0000104910.75206.b9.
- MacDonald JR, Hill JD, Tarnopolsky MA (Dec 2002). "Modafinil reduces excessive somnolence and enhances mood in patients with myotonic dystrophy". Neurology. 59 (12): 1876–80. PMID 12499477. doi:10.1212/01.WNL.0000037481.08283.51.
- Webster L, Andrews M, Stoddard G (Jun 2003). "Modafinil treatment of opioid-induced sedation". Pain Medicine. 4 (2): 135–40. PMID 12873263. doi:10.1046/j.1526-4637.2003.03014.x.
- Hurst DL, Lajara-Nanson W (Mar 2002). "Use of modafinil in spastic cerebral palsy". Journal of Child Neurology. 17 (3): 169–72. PMID 12026230. doi:10.1177/088307380201700303.
- Nieves AV, Lang AE (2002). "Treatment of excessive daytime sleepiness in patients with Parkinson's disease with modafinil". Clinical Neuropharmacology. 25 (2): 111–4. PMID 11981239. doi:10.1097/00002826-200203000-00010.
- 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.
- Air Force Special Operations Command Instruction 48–101 (sects. 1.7.4), U.S. Air Force Special Operations Command, November 30, 2012.
- Thirsk R, Kuipers A, Mukai C, Williams D (Jun 2009). "The space-flight environment: the International Space Station and beyond". Cmaj. 180 (12): 1216–20. PMC . PMID 19487390. doi:10.1503/cmaj.081125.
- "Modafinil - Contraindications".
- "Modafinil Information Page" (PDF). Teva Pharmaceuticals. February 1, 2012.
- "Modafinil (marketed as Provigil): Serious Skin Reactions". Food and Drug Administration. 2007.
- Banerjee D, Vitiello MV, Grunstein RR (Oct 2004). "Pharmacotherapy for excessive daytime sleepiness". Sleep Medicine Reviews. 8 (5): 339–54. PMID 15336235. doi:10.1016/j.smrv.2004.03.002.
- "MedlinePlus Drug Information: Modafinil". NIH. July 1, 2005. Archived from the original on June 10, 2007. Retrieved July 21, 2007.
- "Provigil: Prescribing information" (PDF). United States Food and Drug Administration. Cephalon, Inc. January 2015. Retrieved August 16, 2015.
- Bernardi RE, Broccoli L, Spanagel R, Hansson AC (Oct 2015). "Sex differences in dopamine binding and modafinil conditioned place preference in mice". Drug and Alcohol Dependence. 155: 37–44. PMID 26342627. doi:10.1016/j.drugalcdep.2015.08.016.
- Nguyen TL, Tian YH, You IJ, Lee SY, Jang CG (Aug 2011). "Modafinil-induced conditioned place preference via dopaminergic system in mice". Synapse. 65 (8): 733–41. PMID 21157933. doi:10.1002/syn.20892.
- Krishnan R, Chary KV (2015). "A rare case modafinil dependence". Journal of Pharmacology & Pharmacotherapeutics. 6 (1): 49–50. PMC . PMID 25709356. doi:10.4103/0976-500X.149149.
- Cengiz Mete M, Şenormancı Ö, Saraçlı Ö, Atasoy N, Atik L (2015). "Compulsive modafinil use in a patient with a history of alcohol use disorder". General Hospital Psychiatry. 37 (2): e7–8. PMID 25655923. doi:10.1016/j.genhosppsych.2015.01.001.
- Ballon JS, Feifel D (Apr 2006). "A systematic review of modafinil: Potential clinical uses and mechanisms of action". The Journal of Clinical Psychiatry. 67 (4): 554–66. PMID 16669720. doi:10.4088/jcp.v67n0406.
- Nasr S, Wendt B, Steiner K (2006). "Absence of mood switch with and tolerance to modafinil: a replication study from a large private practice". J Affect Disord. 95 (1–3): 111–4. PMID 16737742. doi:10.1016/j.jad.2006.01.010.
- Mitler MM, Harsh J, Hirshkowitz M, Guilleminault C (2000). "Long-term efficacy and safety of modafinil (PROVIGIL((R))) for the treatment of excessive daytime sleepiness associated with narcolepsy". Sleep Med. 1 (3): 231–243. PMID 10828434. doi:10.1016/s1389-9457(00)00031-9.
- "Randomized trial of modafinil for the treatment of pathological somnolence in narcolepsy. US Modafinil in Narcolepsy Multicenter Study Group". Ann. Neurol. 43 (1): 88–97. 1998. PMID 9450772. doi:10.1002/ana.410430115.
- Gerrard P, Malcolm R (Jun 2007). "Mechanisms of modafinil: A review of current research". Neuropsychiatric Disease and Treatment. 3 (3): 349–64. PMC . PMID 19300566.
- Minzenberg MJ, Carter CS (Jun 2008). "Modafinil: a review of neurochemical actions and effects on cognition". Neuropsychopharmacology. 33 (7): 1477–502. PMID 17712350. doi:10.1038/sj.npp.1301534.
- Ishizuka, Tomoko; Murakami, Masahiro; Yamatodani, Atsushi (2008). "Involvement of central histaminergic systems in modafinil-induced but not methylphenidate-induced increases in locomotor activity in rats". European Journal of Pharmacology. 578 (2–3): 209–215. ISSN 0014-2999. PMID 17920581. doi:10.1016/j.ejphar.2007.09.009.
- Dopheide MM, Morgan RE, Rodvelt KR, Schachtman TR, Miller DK (Jul 2007). "Modafinil evokes striatal [(3)H]dopamine release and alters the subjective properties of stimulants". European Journal of Pharmacology. 568 (1–3): 112–23. PMID 17477916. doi:10.1016/j.ejphar.2007.03.044.
- Murillo-Rodríguez E, Haro R, Palomero-Rivero M, Millán-Aldaco D, Drucker-Colín R (Jan 2007). "Modafinil enhances extracellular levels of dopamine in the nucleus accumbens and increases wakefulness in rats". Behavioural Brain Research. 176 (2): 353–7. PMID 17098298. doi:10.1016/j.bbr.2006.10.016.
- de Saint Hilaire Z, Orosco M, Rouch C, Blanc G, Nicolaidis S (Nov 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. PMID 11733706. doi:10.1097/00001756-200111160-00032.
- Gallopin T, Luppi PH, Rambert FA, Frydman A, Fort P (Feb 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 (Apr 2002). "Differential enhancement of dialysate serotonin levels in distinct brain regions of the awake rat by modafinil: possible relevance for wakefulness and depression". Journal of Neuroscience Research. 68 (1): 107–12. PMID 11933055. doi:10.1002/jnr.10196.
- 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". The Journal of Pharmacology and Experimental Therapeutics. 329 (2): 738–46. PMC . PMID 19197004. doi:10.1124/jpet.108.146142.
- Federici, M.; Latagliata, E.C.; Rizzo, F.R.; Ledonne, A.; Gu, H.H.; Romigi, A.; Nisticò, R.; Puglisi-Allegra, S.; Mercuri, N.B. (2013). "Electrophysiological and amperometric evidence that modafinil blocks the dopamine uptake transporter to induce behavioral activation". Neuroscience. 252: 118–124. ISSN 0306-4522. PMID 23933217. doi:10.1016/j.neuroscience.2013.07.071.
- Okunola-Bakare, Oluyomi M.; Cao, Jianjing; Kopajtic, Theresa; Katz, Jonathan L.; Loland, Claus J.; Shi, Lei; Newman, Amy Hauck (2014). "Elucidation of Structural Elements for Selectivity across Monoamine Transporters: Novel 2-[(Diphenylmethyl)sulfinyl]acetamide (Modafinil) Analogues". Journal of Medicinal Chemistry. 57 (3): 1000–1013. ISSN 0022-2623. PMC . PMID 24494745. doi:10.1021/jm401754x.
- Young, J. W. (2009). "Dopamine D1 and D2 Receptor Family Contributions to Modafinil-Induced Wakefulness". Journal of Neuroscience. 29 (9): 2663–2665. ISSN 0270-6474. PMC . PMID 19261860. doi:10.1523/JNEUROSCI.5843-08.2009.
- Wisor J (2013). "Modafinil as a catecholaminergic agent: empirical evidence and unanswered questions". Frontiers in Neurology. 4: 139. PMC . PMID 24109471. doi:10.3389/fneur.2013.00139.
- Kim W, Tateno A, Arakawa R, Sakayori T, Ikeda Y, Suzuki H, Okubo Y (May 2014). "In vivo activity of modafinil on dopamine transporter measured with positron emission tomography and [¹⁸F]FE-PE2I". The International Journal of Neuropsychopharmacology. 17 (5): 697–703. PMID 24451483. doi:10.1017/S1461145713001612.
- 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 (Mar 2009). "Effects of modafinil on dopamine and dopamine transporters in the male human brain: clinical implications". JAMA. 301 (11): 1148–54. PMC . PMID 19293415. doi:10.1001/jama.2009.351.
- Reith ME, Blough BE, Hong WC, Jones KT, Schmitt KC, Baumann MH, Partilla JS, Rothman RB, Katz JL (Feb 2015). "Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter". Drug and Alcohol Dependence. 147: 1–19. PMC . PMID 25548026. doi:10.1016/j.drugalcdep.2014.12.005.
- Quisenberry AJ, Baker LE (Dec 2015). "Dopaminergic mediation of the discriminative stimulus functions of modafinil in rats". Psychopharmacology. 232 (24): 4411–9. PMID 26374456. doi:10.1007/s00213-015-4065-0.
- Mereu, Maddalena; Bonci, Antonello; Newman, Amy Hauck; Tanda, Gianluigi (2013). "The neurobiology of modafinil as an enhancer of cognitive performance and a potential treatment for substance use disorders". Psychopharmacology. 229 (3): 415–434. ISSN 0033-3158. PMID 23934211. doi:10.1007/s00213-013-3232-4.
- Robert Stickgold; Matthew P. Walker (22 May 2010). The Neuroscience of Sleep. Academic Press. pp. 191–. ISBN 978-0-12-375722-7.
- Simon P, Hémet C, Ramassamy C, Costentin J (1995). "Non-amphetaminic mechanism of stimulant locomotor effect of modafinil in mice". Eur Neuropsychopharmacol. 5 (4): 509–14. PMID 8998404. doi:10.1016/0924-977x(95)00041-m.
- Dunn, Derek; Hostetler, Greg; Iqbal, Mohamed; Marcy, Val R.; Lin, Yin Guo; Jones, Bruce; Aimone, Lisa D.; Gruner, John; Ator, Mark A.; Bacon, Edward R.; Chatterjee, Sankar (2012). "Wake promoting agents: Search for next generation modafinil, lessons learned: Part III". Bioorganic & Medicinal Chemistry Letters. 22 (11): 3751–3753. ISSN 0960-894X. PMID 22546675. doi:10.1016/j.bmcl.2012.04.031.
- Chatterjie N, Stables JP, Wang H, Alexander GJ (2004). "Anti-narcoleptic agent modafinil and its sulfone: a novel facile synthesis and potential anti-epileptic activity". Neurochem. Res. 29 (8): 1481–6. PMID 15260124. doi:10.1023/b:nere.0000029559.20581.1a.
- Seeman P, Guan HC, Hirbec H (Aug 2009). "Dopamine D2High receptors stimulated by phencyclidines, lysergic acid diethylamide, salvinorin A, and modafinil". Synapse. 63 (8): 698–704. PMID 19391150. doi:10.1002/syn.20647.
- Korotkova, T.M.; Klyuch, B.P.; Ponomarenko, A.A.; Lin, J.S.; Haas, H.L.; Sergeeva, O.A. (2007). "Modafinil inhibits rat midbrain dopaminergic neurons through D2-like receptors". Neuropharmacology. 52 (2): 626–633. ISSN 0028-3908. PMID 17070873. doi:10.1016/j.neuropharm.2006.09.005.
- Bodenmann S, Xu S, Luhmann UF, Arand M, Berger W, Jung HH, Landolt HP (Mar 2009). "Pharmacogenetics of modafinil after sleep loss: catechol-O-methyltransferase genotype modulates waking functions but not recovery sleep". Clinical Pharmacology and Therapeutics. 85 (3): 296–304. PMID 19037200. doi:10.1038/clpt.2008.222.
- 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.
- Schwertner, Harvey A.; Kong, Suk Bin (2005). "Determination of modafinil in plasma and urine by reversed phase high-performance liquid-chromatography". Journal of Pharmaceutical and Biomedical Analysis. 37 (3): 475–479. ISSN 0731-7085. doi:10.1016/j.jpba.2004.11.014.
- Robertson, Philmore; Hellriegel, Edward T. (2003). "Clinical Pharmacokinetic Profile of Modafinil". Clinical Pharmacokinetics. 42 (2): 123–137. ISSN 0312-5963. PMID 12537513. doi:10.2165/00003088-200342020-00002.
- Wong, Y. Nancy; Wang, Lixia; Hartman, Linda; Simcoe, Donna; Chen, Yusong; Laughton, Watson; Eldon, Richard; Markland, Colin; Grebow, Peter (1998). "Comparison of the Single-Dose Pharmacokinetics and Tolerability of Modafinil and Dextroamphetamine Administered Alone or in Combination in Healthy Male Volunteers". The Journal of Clinical Pharmacology. 38 (10): 971–978. ISSN 0091-2700. doi:10.1002/j.1552-4604.1998.tb04395.x.
- Robertson, P (2002). "Effect of modafinil on the pharmacokinetics of ethinyl estradiol and triazolam in healthy volunteers". Clinical Pharmacology & Therapeutics. 71 (1): 46–56. ISSN 0009-9236. doi:10.1067/mcp.2002.121217.
- Wong YN, King SP, Laughton WB, McCormick GC, Grebow PE (Mar 1998). "Single-dose pharmacokinetics of modafinil and methylphenidate given alone or in combination in healthy male volunteers". Journal of Clinical Pharmacology. 38 (3): 276–82. PMID 9549666. doi:10.1002/j.1552-4604.1998.tb04425.x.
- 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.
- Spratley TK, Hayes PA, Geer LC, Cooper SD, McKibben TD (2005). "Analytical Profiles for Five "Designer" Tryptamines" (PDF). Microgram Journal. 3 (1–2): 54–68.
- "Modafinil reaction with the Froehde reagent and others". Reagent Tests UK. 13 December 2015. Retrieved 18 December 2015.
- Ballas CA, Kim D, Baldassano CF, Hoeh N (Jul 2002). "Modafinil: past, present and future". Expert Review of Neurotherapeutics. 2 (4): 449–57. PMID 19810941. doi:10.1586/1473722.214.171.1249.
- Healy M (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 S, ed. "The prevalence and cost of unapproved uses of top-selling orphan drugs". PloS One. 7 (2): e31894. PMC . PMID 22363762. doi:10.1371/journal.pone.0031894.
- Gerrard P, Malcolm R (Jun 2007). "Mechanisms of modafinil: A review of current research". Neuropsychiatric Disease and Treatment. 3 (3): 349–64. PMC . PMID 19300566.
- "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. October 31, 2010. Retrieved July 4, 2012.
- "Document 513 :: APOTEX, INC. v. CEPHALON, INC. et al". Pennsylvania Eastern District Court :: US Federal District Courts Cases :: Justia. October 31, 2010. Retrieved July 4, 2012.
- "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" (PDF). 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.
- "食品药品监管总局 公安部 国家卫生计生委关于公布麻醉药品和精神药品品种目录的通知". China Food and Drug Administration. Retrieved Nov 11, 2013.
- "Regulations Amending the Food and Drug Regulations (1184 — Modafinil)". Canada Gazette. 140 (20). March 26, 2005. Archived from the original (– Scholar search) on July 6, 2011.
- "Lääkealan turvallisuus- ja kehittämiskeskuksen päätöslääkeluettelosta". 2009.
- "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.
- SA Government (April 10, 2003). "GENERAL REGULATIONS MADE IN TERMS OF THE MEDICINES AND RELATED SUBSTANCES ACT 101 OF 1965, AS AMENDED Government Notice R510 in Government Gazette 24727 dated 10 April 2003. 22A/16/b; states that although import and export is restricted, possession is not illegal providing that a prescription is present." (PDF). Pretoria: SAFLII. Retrieved Nov 11, 2016.
- MHRA (April 3, 2013). "MHRA license for Modafinil in UK" (PDF). London: MHRA. Retrieved April 3, 2013.
- "Modafinil - International Brands". Drugs.com. Retrieved 8 January 2017.
- "Clinger given lifetime ban for second doping infraction". Cycling News. August 14, 2011. Retrieved October 8, 2014.
- "Taurasi tested positive for modafinil". The Washington Post. December 25, 2010. Retrieved December 31, 2013.
- sport, Guardian (November 23, 2015). "British rowers handed two-year bans for taking banned substances" – via The Guardian.
- 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 (Jun 2004). "Effects of acute modafinil ingestion on exercise time to exhaustion". Medicine and Science in Sports and Exercise. 36 (6): 1078–82. PMID 15179180. doi:10.1249/01.MSS.0000128146.12004.4F.
- "Super Soldiers? Military Drug New Rage". ABC News. 7 December 2008.
- "Like It or Not, "Smart Drugs" Are Coming to the Office". Harvard Business Review. May 2015.
- Cadwalladr, Carole (14 February 2015). "Students used to take drugs to get high. Now they take them to get higher grades". The Guardian.
- Talbot, Margaret. "Brain Gain". The New Yorker. Retrieved 9 April 2017.
- Plotz, David (21 August 2003). "Medikamente: 100 Milligramm Arbeitswut". Die Zeit. Retrieved 9 April 2017.
- "The 'Limitless Pill' Could Soon Turn Us All into Superhuman Workers". Vice. Retrieved 9 April 2017.
- "Why Can't We All Take Modafinil?". Vice. Retrieved 9 April 2017.
- "Seen At 11: A Real-Life Superhero Pill? Looking Into The 'Limitless' Drug". Retrieved 9 April 2017.
- "New pill could boost brain function, decision making". CBS 4. 11 November 2015. Retrieved 9 April 2017.
- Biederman J, Swanson JM, Wigal SB, Boellner SW, Earl CQ, Lopez FA (May 2006). "A comparison of once-daily and divided doses of modafinil in children with attention-deficit/hyperactivity disorder: a randomized, double-blind, and placebo-controlled study". The Journal of Clinical Psychiatry. 67 (5): 727–35. PMID 16841622. doi:10.4088/JCP.v67n0506.
- Greenhill LL, Biederman J, Boellner SW (May 2006). "A randomized, double-blind, placebo-controlled study of modafinil film-coated tablets in children and adolescents with attention-deficit/hyperactivity disorder". Journal of the American Academy of Child and Adolescent Psychiatry. 45 (5): 503–11. PMID 16601402. doi:10.1097/01.chi.0000205709.63571.c9.
- Cephalon, Inc. (21 December 2007). "Modavigil Product Information". healthlinks.net. healthlinks.net Pty. Ltd. Archived from the original (PDF) on July 21, 2008. Retrieved 2 July 2008.
- Kumar R (2008). "Approved and investigational uses of modafinil : an evidence-based review". Drugs. 68 (13): 1803–39. PMID 18729534. doi:10.2165/00003495-200868130-00003.
- 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.
- 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". Annals of Clinical Psychiatry. 19 (3): 153–9. PMID 17729016. doi:10.1080/10401230701464858.
- Frye MA, Grunze H, Suppes T, McElroy SL, Keck PE, Walden J, Leverich GS, Altshuler LL, Nakelsky S, Hwang S, Mintz J, Post RM (Aug 2007). "A placebo-controlled evaluation of adjunctive modafinil in the treatment of bipolar depression". The American Journal of Psychiatry. 164 (8): 1242–9. PMID 17671288. doi:10.1176/appi.ajp.2007.06060981.
- Calabrese JR, Ketter TA, Youakim JM, Tiller JM, Yang R, Frye MA (Oct 2010). "Adjunctive armodafinil for major depressive episodes associated with bipolar I disorder: a randomized, multicenter, double-blind, placebo-controlled, proof-of-concept study". The Journal of Clinical Psychiatry. 71 (10): 1363–70. PMID 20673554. doi:10.4088/JCP.09m05900gry.
- Tahsili-Fahadan P, Carr GV, Harris GC, Aston-Jones G (Oct 2010). "Modafinil blocks reinstatement of extinguished opiate-seeking in rats: mediation by a glutamate mechanism". Neuropsychopharmacology. 35 (11): 2203–10. PMC . PMID 20631691. doi:10.1038/npp.2010.94.
- Dackis CA, Kampman KM, Lynch KG, Pettinati HM, O'Brien CP (Jan 2005). "A double-blind, placebo-controlled trial of modafinil for cocaine dependence". Neuropsychopharmacology. 30 (1): 205–11. PMID 15525998. doi:10.1038/sj.npp.1300600.
- van Vliet SA, Vanwersch RA, Jongsma MJ, van der Gugten J, Olivier B, Philippens IH (Sep 2006). "Neuroprotective effects of modafinil in a marmoset Parkinson model: behavioral and neurochemical aspects". Behavioural Pharmacology. 17 (5–6): 453–62. PMID 16940766. doi:10.1097/00008877-200609000-00011.
- Turner DC, Clark L, Pomarol-Clotet E, McKenna P, Robbins TW, Sahakian BJ (Jul 2004). "Modafinil improves cognition and attentional set shifting in patients with chronic schizophrenia". Neuropsychopharmacology. 29 (7): 1363–73. PMID 15085092. doi:10.1038/sj.npp.1300457.
- Rammohan KW, Rosenberg JH, Lynn DJ, Blumenfeld AM, Pollak CP, Nagaraja HN (Feb 2002). "Efficacy and safety of modafinil (Provigil) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study". Journal of Neurology, Neurosurgery, and Psychiatry. 72 (2): 179–83. PMC . PMID 11796766. doi:10.1136/jnnp.72.2.179.
- Rabkin JG, McElhiney MC, Rabkin R, Ferrando SJ (Dec 2004). "Modafinil treatment for fatigue in HIV+ patients: a pilot study". The Journal of Clinical Psychiatry. 65 (12): 1688–95. PMID 15641875. doi:10.4088/JCP.v65n1215.
- Schwartz TL, Azhar N, Cole K, Hopkins G, Nihalani N, Simionescu M, Husain J, Jones N (Sep 2004). "An open-label study of adjunctive modafinil in patients with sedation related to serotonergic antidepressant therapy". The Journal of Clinical Psychiatry. 65 (9): 1223–7. PMID 15367049. doi:10.4088/JCP.v65n0910.
- Lundt L (Aug 2004). "Modafinil treatment in patients with seasonal affective disorder/winter depression: an open-label pilot study". Journal of Affective Disorders. 81 (2): 173–8. PMID 15306145. doi:10.1016/S0165-0327(03)00162-9.
- Umanoff DF (Dec 2005). "Trial of modafinil for cocaine dependence". Neuropsychopharmacology. 30 (12): 2298; author reply 2299–300. PMID 16294193. doi:10.1038/sj.npp.1300866.
- 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 (Sep 2009). "Modafinil for the treatment of cocaine dependence". Drug and Alcohol Dependence. 104 (1–2): 133–9. PMC . PMID 19560290. doi:10.1016/j.drugalcdep.2009.04.015.
- Hart CL, Haney M, Vosburg SK, Comer SD, Gunderson E, Foltin RW (Jul 2006). "Modafinil attenuates disruptions in cognitive performance during simulated night-shift work". Neuropsychopharmacology. 31 (7): 1526–36. PMID 16395298. doi:10.1038/sj.npp.1300991.
- Henderson DC, Louie PM, Koul P, Namey L, Daley TB, Nguyen DD (2005). "Modafinil-associated weight loss in a clozapine-treated schizoaffective disorder patient". Annals of Clinical Psychiatry. 17 (2): 95–7. PMID 16075662. doi:10.1080/10401230590932407.
- "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 (Aug 2006). "Modafinil for atypical depression: effects of open-label and double-blind discontinuation treatment". Journal of Clinical Psychopharmacology. 26 (4): 373–8. PMID 16855454. doi:10.1097/01.jcp.0000227700.263.75.39.
- Thase ME, Fava M, DeBattista C, Arora S, Hughes RJ (Feb 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 Spectrums. 11 (2): 93–102. PMID 16520686. doi:10.1017/s1092852900010622.
- Makris AP, Rush CR, Frederich RC, Kelly TH (Apr 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. PMID 15010183. doi:10.1016/j.appet.2003.11.003.
- Perez GA, Haney M, Foltin RW, Hart CL (Oct 2008). "Modafinil decreases food intake in humans subjected to simulated shift work". Pharmacology, Biochemistry, and Behavior. 90 (4): 717–22. PMID 18573275. doi:10.1016/j.pbb.2008.05.018.
- "Provigil" (PDF). Medication Guide. Cephalon, Inc. November 1, 2010. Retrieved December 31, 2013.
- Grady S, Aeschbach D, Wright KP, Czeisler CA (Aug 2010). "Effect of modafinil on impairments in neurobehavioral performance and learning associated with extended wakefulness and circadian misalignment". Neuropsychopharmacology. 35 (9): 1910–20. PMC . PMID 20505660. doi:10.1038/npp.2010.63.
- Turner DC, Robbins TW, Clark L, Aron AR, Dowson J, Sahakian BJ (Jan 2003). "Cognitive enhancing effects of modafinil in healthy volunteers". Psychopharmacology. 165 (3): 260–9. PMID 12417966. doi:10.1007/s00213-002-1250-8.
- Randall DC, Viswanath A, Bharania P, Elsabagh SM, Hartley DE, Shneerson JM, File SE (Apr 2005). "Does modafinil enhance cognitive performance in young volunteers who are not sleep-deprived?". Journal of Clinical Psychopharmacology. 25 (2): 175–9. PMID 15738750. doi:10.1097/01.jcp.0000155816.21467.25.
- Baranski JV, Pigeau R, Dinich P, Jacobs I (Jul 2004). "Effects of modafinil on cognitive and meta-cognitive performance". Human Psychopharmacology. 19 (5): 323–32. PMID 15252824. doi:10.1002/hup.596.
- Battleday RM, Brem AK (2015). "Modafinil for cognitive neuroenhancement in healthy non-sleep-deprived subjects: A systematic review". European Neuropsychopharmacology : the Journal of the European College of Neuropsychopharmacology. 25 (11): 1865–81. PMID 26381811. doi:10.1016/j.euroneuro.2015.07.028. Lay summary – Live Science.
- Müller U, Steffenhagen N, Regenthal R, Bublak P (Dec 2004). "Effects of modafinil on working memory processes in humans". Psychopharmacology. 177 (1–2): 161–9. PMID 15221200. doi:10.1007/s00213-004-1926-3.
- Randall DC, Shneerson JM, File SE (Sep 2005). "Cognitive effects of modafinil in student volunteers may depend on IQ". Pharmacology, Biochemistry, and Behavior. 82 (1): 133–9. PMID 16140369. doi:10.1016/j.pbb.2005.07.019.
- Ghahremani DG, Tabibnia G, Monterosso J, Hellemann G, Poldrack RA, London ED (Apr 2011). "Effect of modafinil on learning and task-related brain activity in methamphetamine-dependent and healthy individuals". Neuropsychopharmacology. 36 (5): 950–9. PMC . PMID 21289606. doi:10.1038/npp.2010.233.
- Turner D (2006). "A review of the use of modafinil for attention-deficit hyperactivity disorder". Expert Review of Neurotherapeutics. 6 (4): 455–68. PMID 16623645. doi:10.1586/14737126.96.36.1995.
- Minzenberg MJ, Carter CS (2008). "Modafinil: a review of neurochemical actions and effects on cognition". Neuropsychopharmacology. 33 (7): 1477–502. PMID 17712350. doi:10.1038/sj.npp.1301534.
- "Review of ‘smart drug’ shows modafinil does enhance cognition". University of Oxford. Retrieved 9 April 2017.
- Waugh, Rob (28 October 2015). "‘My brain is ninja level’: New ‘smart drug’ actually makes you cleverer". Metro. Retrieved 9 April 2017.
- "'Smart drug' taken by one in four students really does boost performance". The Telegraph. Retrieved 9 April 2017.
- Thomson, Helen (19 August 2015). "Narcolepsy medication modafinil is world's first safe 'smart drug'". The Guardian. Retrieved 9 April 2017.
- "Cognitive enhancing drugs can improve chess play, scientists show". Science Daily. Retrieved 9 April 2017.
- "A new study reveals that certain drugs may make us smarter than we thought". Business Insider. Retrieved 9 April 2017.
- Hamblin, James. "On Cognitive Doping in Chess (and Life)". The Atlantic. Retrieved 9 April 2017.
- "Special Report: New Study Finds Performance-Enhancing Drugs for Chess". World Chess. Retrieved 9 April 2017.
- Franke, Andreas G.; Gränsmark, Patrik; Agricola, Alexandra; Schühle, Kai; Rommel, Thilo; Sebastian, Alexandra; Balló, Harald E.; Gorbulev, Stanislav; Gerdes, Christer; Frank, Björn; Ruckes, Christian; Tüscher, Oliver; Lieb, Klaus (March 2017). "Methylphenidate, modafinil, and caffeine for cognitive enhancement in chess: A double-blind, randomised controlled trial". European Neuropsychopharmacology. 27 (3): 248–260. doi:10.1016/j.euroneuro.2017.01.006.
- Portela MA, Rubiales AS, Centeno C (Jun 2011). "The use of psychostimulants in cancer patients". Current Opinion in Supportive and Palliative Care. 5 (2): 164–8. PMID 21532350. doi:10.1097/SPC.0b013e3283462ff3.
- Mücke M, Mochamat CH, Peuckmann-Post V, Minton O, Stone P, Radbruch L (2015). "Pharmacological treatments for fatigue associated with palliative care". The Cochrane Database of Systematic Reviews. 30 (5): CD006788. PMID 26026155. doi:10.1002/14651858.CD006788.pub3.
- Hoyt, RE; Lawson, BD; McGee, HA; Strompolis, ML; McClellan, MA (August 2009). "Modafinil as a potential motion sickness countermeasure.". Aviation, space, and environmental medicine. 80 (8): 709–15. PMID 19653573. doi:10.3357/asem.2477.2009.
- Loland, Claus J.; Mereu, Maddalena; Okunola, Oluyomi M.; Cao, Jianjing; Prisinzano, Thomas E.; Mazier, Sonia; Kopajtic, Theresa; Shi, Lei; Katz, Jonathan L.; Tanda, Gianluigi; Newman, Amy Hauck (2012). "R-Modafinil (Armodafinil): A Unique Dopamine Uptake Inhibitor and Potential Medication for Psychostimulant Abuse". Biological Psychiatry. 72 (5): 405–413. ISSN 0006-3223. PMC . PMID 22537794. doi:10.1016/j.biopsych.2012.03.022.
- De Risi, Carmela; Ferraro, Luca; Pollini, Gian P.; Tanganelli, Sergio; Valente, Filippo; Veronese, Augusto C. (2008). "Efficient synthesis and biological evaluation of two modafinil analogues". Bioorganic & Medicinal Chemistry. 16 (23): 9904–9910. ISSN 0968-0896. PMID 18954992. doi:10.1016/j.bmc.2008.10.027.